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BACKGROUND: Progression of Barrett esophagus (BE) to esophageal adenocarcinoma occurs among a minority of BE patients. To date, BE behavior cannot be predicted on the basis of histologic features. AIMS: We compared BE samples that did not develop dysplasia or carcinoma upon follow-up of ≥ 7 years (BE nonprogressed [BEN]) with BE samples that developed carcinoma upon follow-up of 3 to 4 years (BE progressed [BEP]). METHODS: The NanoString nCounter miRNA assay was used to profile 24 biopsy samples of BE, including 13 BENs and 11 BEPs. Fifteen samples were randomly selected for miRNA prediction model training; nine were randomly selected for miRNA validation. RESULTS: Unpaired t tests with Welch’s correction were performed on 800 measured miRNAs to identify the most differentially expressed miRNAs for cases of BEN and BEP. The top 12 miRNAs (P < .003) were selected for principal component analyses: miR-1278, miR-1301, miR-1304–5p, miR-517b-3p, miR-584–5p, miR-599, miR-103a-3p, miR-1197, miR-1256, miR-509–3–5p, miR-544b, miR-802. The 12-miRNA signature was first self-validated on the training dataset, resulting in 7 out of the 7 BEP samples being classified as BEP (100% sensitivity) and 7 out of the 8 BEN samples being classified as BEN (87.5% specificity). Upon validation, 4 out of the 4 BEP samples were classified as BEP (100% sensitivity) and 4 out of the 5 BEN samples were classified as BEN (80% specificity). Twenty-four samples were evaluated, and 22 cases were correctly classified. Overall accuracy was 91.67%. CONCLUSION: Using miRNA profiling, we have identified a 12-miRNA signature able to reliably differentiate cases of BEN from BEP.

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).

Summary Sampling error during screening and surveillance endoscopy is a well-recognized problem. Wide-area transepithelial sampling with three-dimensional computer-assisted analysis (WATS3D), used adjunctively to forceps biopsy (FB), has been shown to increase the detection of Barrett’s esophagus (BE) and BE-associated neoplasia. We evaluated the clinical utility of WATS3D and its impact on the management of patients with BE and dysplasia. Between 2013 and 2018, 432 consecutive patients who had a WATS3D positive and an accompanying FB negative result were identified. Physicians were contacted to determine if the WATS3D result impacted their decision to enroll patients in surveillance or increase the frequency of surveillance, recommend ablation, and/or initiate or increase the dose of proton pump inhibitors (PPIs). WATS3D directly impacted the management of 97.8% of 317 BE patients; 96.2% were enrolled in surveillance and 60.2% were started on PPIs or their dose was increased. WATS3D impacted the management of 94.9% and 94.1% of the 98 low-grade dysplasia and 17 high-grade dysplasia patients, respectively. As a result of WATS3D, 33.7% of low-grade dysplasia and 70.6% of high-grade dysplasia patients underwent endoscopic therapy. More than 37% of all dysplasia patients were enrolled in a surveillance program, and nearly 30% were scheduled to be surveilled more frequently. PPIs were either initiated, or the dose was increased in more than 54% of all dysplasia patients. We demonstrate that WATS3D has high clinical utility. By prompting physicians to change their clinical management in patients with negative FB results, WATS3D, used adjunctively to FB, directly impacts patient management, and improves patient outcomes.

BACKGROUND: CDX-2 is a nuclear homeobox transcription factor not normally expressed in esophageal and gastric epithelia, reported to highlight intestinal metaplasia (IM) in the esophagus. Pathological absence of goblet cells at initial screening via hematoxylin and eosin (HE) and alcian blue (AB) staining results in patient exclusion from surveillance programs. AIMS: This study aimed to determine whether non-goblet cell IM, as defined by CDX-2 positivity, can be considered to be a precursor to Barrett’s esophagus (BE). METHODS: This study received IRB approval (17,284). Patients with gastroesophageal reflux disease (n = 181) who underwent upper-gastrointestinal endoscopy with biopsies of the distal esophagus to rule out BE using HE/AB staining and CDX-2 immunostaining were followed for 3 years. Initial and follow-up staining results were evaluated for age/sex. RESULTS: Differences between development of goblet cell IM in CDX-2-negative and CDX-2-positive groups were evaluated. A Kaplan–Meier curve showed that, out of the 134 patients initially positive for CDX-2, 25 (18.7%) had developed goblet cell IM after 2 years and 106 (79.1%) after 3 years. Conversely, of the 47 patients initially negative for CDX-2, 8 (17.9%) developed goblet cell IM after 24 months and only 11 (23.8%) after 40 to 45 months (P = .049; age-adjusted Cox proportional hazard regression model). CONCLUSION: In cases that are initially AB negative and CDX-2 positive, CDX-2 was demonstrated to have a potential prognostic utility for early detection of progression to BE. CDX-2 expression is significantly predictive for risk of goblet cell IM development 40 to 45 months after initial biopsy.

Background: Esophageal adenocarcinoma (EAC) is an aggressive malignancy with an increasing incidence in the US. Progression of Barrett's Esophagus (BE) to EAC occurs via a stepwise process, and consequently periodic esophageal biopsies are utilized in order to monitor patients with BE. While a small percent of BE patients will progress to dysplasia and cancer, the majority of them will continue to have long-standing BE without progression. In the absence of dysplasia, the behavior of BE cannot be predicted based on evaluation of histologic features alone. Studies have demonstrated the utility of microRNAs in differentiating between the specific evolutionary events in the progression of BE to dysplasia and cancer. To date, there has yet to be a comparison between cases of BE that have not progressed to dysplasia or carcinoma, or cases of BE-Non-progression (BEN), and cases of BE that have progressed to dysplasia and/or carcinoma, or cases of BE- Progression (BEP). Through miRNA profiling, we have determined an assay of candidate miRNAs that reliably differentiate cases of BEN from BEP. Methods: Fifty cases of BE were profiled with two different miRNA profiling techniques: the HTG EdgeSeq miRNA WT Assay and the nanoString Assay. There were 15 cases of BEN (follow up >7 years) as well as of 11 cases of BEP (progression to dysplasia and/or EAC within 3 years). These cases were used for miRNA discovery and miRNA prediction model training. Another independent patient data set of 24 BE cases (13 cases of BEN and 11 cases of BEP; namely Normalized Nano), was profiled with nanoString miRNA Assay. This set was used as an independent validating cohort. Results: Six significant miRNAs were identified and confirmed using two different statistical methods (Limma test and Wilcoxen rank sum test). Family-wise error rate for type I error (FWER) was set to less than 0.05 in order to minimize the probability of discovering false positives. The final miRNA model demonstrated a high prediction performance at the optimal cutoff with a specificity of 80% and 50%; as well as sensitivity 100% and 75% for the two sets in order to capture a high proportion of the BEPs. We then independently validated this miRNA signature with the Normalized Nano set, which demonstrated a sensitivity of 70% and a specificity of 67.5% in this independent validation. While the prediction performance was weaker, we consistently validated its prediction power and clinical utility on an independent patient cohort with a completely different miRNA profiling technique. Conclusion: The reliability of these candidate miRNAs support further investigation in a larger population of patients, and may have potentially prognostic utility in the evaluation of BE patients with the goal of early detection of BE progression. Citation Format: James Saller, Kun Jiang, Kevin Neill, Zachary Mayer, Jae Lee, Luis Pena, F. Scott Corbett, Jose Pimiento, Mokenge Malafa, Anthony Magliocco, Domenico Coppola. An miRNA signature selects patients at risk for Barrett's Esophagus progression to dysplasia and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5410.

Chronic radiation proctopathy (CRP) is a common sequela occurring even many years after pelvic radiation. Current ablative therapies for bleeding ectatic vessels have the potential for deep tissue injury leading to ulcerations, perforation, and fistulas. Radiofrequency ablation (RFA) therapy avoids deep tissue injury and is a promising treatment for CRP.To assess the long-term safety and efficacy of RFA for the treatment of CRP.Multicenter, retrospective analysis of a prospectively collected database.Veterans Affairs Boston Healthcare System, Massachusetts; Sarasota Memorial Hospital and Suncoast Endoscopy of Sarasota, Florida.A total of 39 consecutive patients with CRP.Endoscopic RFA of CRP.The primary endpoint of the study was complete resolution of rectal bleeding. Secondary endpoints included visually scored improvement of CRP on endoscopic follow-up by using a rectal telangiectasia density (RTD) grading score, improvement in hemoglobin level, and adverse events related to the procedure.A total of 39 male patients (mean [± standard deviation {SD}] age 72.9 ± 6.6 years) were included in the study. The mean number of RFA sessions was 1.49 (median 1, interquartile range [IQR] 1-2, range 1-4), with a mean interval of 18 weeks between sessions. Rectal bleeding stopped completely in all patients during the mean follow-up of 28 months (range 7-53 months). A significant improvement occurred in the mean (± SD) hemoglobin level from 11.8 ± 2 to 13.5 ± 1.6 g % (P .0001). Endoscopic severity also improved significantly with an improvement in the median RTD score from 3 (IQR 2-3) to 0 (IQR 0-1) (P .0001). Treatment with RFA led to discontinuation of blood transfusion and iron therapy in 92% and 82% patients, respectively.Retrospective analysis, lack of control group.RFA therapy led to complete resolution of rectal bleeding in all treated CRP patients, with improvement in clinical and endoscopic indices without any major adverse events. Further controlled studies are needed to establish RFA as the endoscopic therapy of choice for treatment of CRP.

Ongoing gastroesophageal reflux may impair healing and re-epithelialization after radiofrequency ablation (RFA) of Barrett’s esophagus (BE). Because prior fundoplication may improve reflux control, our aim was to assess the relationship between prior fundoplication and the safety/efficacy of RFA. We assessed the U.S. RFA Registry, a nationwide registry of BE patients receiving RFA at 148 institutions, to compare the safety and efficacy of ablation between those with prior fundoplication and those with medical management (proton pump inhibition). Among 5,537 patients receiving RFA, 301 (5.4 %) had prior fundoplication. Of fundoplication subjects, 1.0 % developed stricture and 1.0 % were hospitalized after RFA. Rates of stricture, bleeding, and hospitalization were not statistically different (p = ns) between patients with and without prior fundoplication. Complete eradication of intestinal metaplasia and complete eradication of dysplasia were achieved in 71 % and 87 % of fundoplication patients, and 73 % and 87 % of patients without fundoplication, respectively (p = ns for both). Patients with prior fundoplication needed similar numbers of RFA sessions for eradication compared with those without fundoplication. Radiofrequency ablation, with or without prior fundoplication, is safe and effective in eradicating BE. Prior fundoplication was associated with similar adverse event and efficacy rates when compared with medical management.

Background & Aims Radiofrequency ablation (RFA) is commonly used to treat Barrett's esophagus (BE). We assessed the incidence of esophageal adenocarcinoma (EAC) after RFA, factors associated with the development of EAC, and EAC-specific and all-cause mortality. Methods We collected data for outcomes of patients who underwent RFA for BE from July 2007 through July 2011 from US multicenter RFA Patient Registry. Patients were followed until July 2014. Kaplan-Meier curves of EAC incidence were stratified by baseline histology. Crude EAC incidence and mortality (all-cause and EAC-specific) were calculated, and adjusted all-cause mortality was assessed. Logistic regression models were constructed to assess predictors of EAC and all-cause mortality. Results Among 4982 patients, 100 (2%) developed EAC (7.8/1000 person-years [PY]) and 9 patients (0.2%) died of EAC (0.7/1000 PY) in a mean 2.7 ± 1.6 years. The incidence of EAC in nondysplastic BE was 0.5/1000 PY. Overall, 157 patients (3%) died during follow-up (all-cause mortality, 11.2/1000 PY). On multivariate logistic regression, baseline BE length (odds ratio, 1.1/ cm) and baseline histology (odds ratios, 5.8 and 50.3 for low-grade dysplasia and high-grade dysplasia [HGD] respectively) predicted EAC incidence. Among 9 EAC deaths, 6 (67%) had baseline HGD, and 3 (33%) had baseline intramucosal EAC. The most common causes of death were cardiovascular (15%) and extraesophageal cancers (15%). No deaths were associated with RFA. Conclusions Based on analysis of a multicenter registry of patients who underwent RFA of BE, less than 1% died from EAC. The incidence of EAC was markedly lower in this study than in other studies of disease progression, with the greatest absolute benefit observed in patients with HGD.

What Is the Histology of Subsquamous Intestinal Metaplasia (SSIM) in Patients With Prior Radiofrequency Ablation (RFA) for Treatment of Barrett's Esophagus (BE)? Results From the U.S. RFA Registry Kelly E. Hathorn, William J. Bulsiewicz, Ronald E. Pruitt, Gary W. Chmielewski, Ryan D. Madanick, F Scott Corbett, Richard I. Rothstein, Charles J. Lightdale, George Triadafilopoulos, Nicholas J. Shaheen

Background: Inflammatory bowel disease (IBD) is a chronic disorder that affects approximately 1.4 million Americans, with an annual cost of $10-18 billion. A uniform approach to patient care, such as utilization of practice guidelines, may be beneficial in reducing morbidity and improving patient outcome. Objective: The aim of this study is to determine if proposed American Gastroenterological Association (AGA) quality of care guidelines can be met at a teaching program gastroenterology clinic and to determine if adherence to guidelines results in improved patient outcome. Methods: We performed a retrospective single center study of patients with IBD. Consecutive patients were identified using pharmacy, pathology, and clinic records. 234 patients were identified as having IBD. Of the 234 patients, 126 were followed in the gastroenterology clinic and included in the analysis; the remaining patients used the VA hospital for medication only. The electronic medical record was reviewed for: adherence to the ten quality improvement measures proposed by the AGA, hospitalizations and surgeries within 3 years. Results: 126 patients with IBD were included, patient characteristics are in Table 1. The AGA guidelines were met as follows: Inflammatory Bowel Disease type (99.2%), disease location (92.8%), and disease activity (96%), screening/ cessation counseling in tobacco abusers (98.8%), use of corticosteroid sparing therapy (97.6%), administration of inpatient veno-thromboembolism prophylaxis (89.5%), Yearly Influenza Vaccination (83%), inpatient testing for Clostridium difficile (74%), hepatitis B status prior to initiation of biologic therapy (73%), assessment of bone loss related to corticosteroid therapy (69%), pneumococcus vaccine administration (65%), testing for latent TB prior to initiation of biologic therapy (65%). Overall; 91 patients (72%) met 80% of the quality care guidelines. During the study period of 3 years, 17 patients were admitted for IBD related illness, 10 for non-IBD related illness and 6 patients underwent surgery. We did not find any correlation between adherence to quality of care indications and reduction in hospitalization or surgery (Table 2). Conclusions: Proposed quality of care guidelines can be met in a majority of patients in clinical practice. Adherence to guidelines did not correlate with improved patient outcomes as measured by hospitalization or surgery. Further work is required in identifying quality care measures that correlate with improvement in patient outcomes. Table 1. Patient Characteristics

bivariate analysis (p 0.2). The model was reduced using the likelihood ratio test to determine any independent predictors of SSIM (p 0.05). Results: At least one biopsy session was performed in 4691 of 5530 (85%) patients treated with RFA for BE, among whom 410 (8.7%) were found to have SSIM on at least one occasion on follow-up endoscopic biopsies. Compared to those without subsquamous metaplasia, patients with SSIM were older (64.0 vs. 61.6 years, p 0.0001); more commonly male (79 vs. 73%, p 0.02); had longer BE segments (5.3 vs. 3.9 cm, p 0.0001); more frequently had advanced neoplasia (high-grade dysplasia, intramucosal carcinoma, invasive cancer) before treatment (35% vs 23%, p 0.001); required more RFA treatment sessions (2.7 vs. 2.3, p 0.0001); and had more biopsy sessions performed (1.7 vs. 1.3, p 0.0001). In our multivariable logistic regression model, SSIM was independently associated with: 1) increased age (OR 1.02 per year, 95% CI 1.01 1.03); 2) length of Barrett’s (1.08 per cm, 1.05 1.11); 3) number of RFA treatment sessions (1.11 per session, 1.05 1.17); 4) PPI compliance during treatment (1.47, 1.10 1.96); and 5) number of biopsy sessions (1.19 per session; 1.13 1.26). Conclusions: Of subjects treated with RFA for BE in a national registry, 8.7% were found to have SSIM at some point on follow-up biopsies. SSIM was independently associated with age, BE length, number of RFA treatment sessions, PPI compliance, and number of biopsy sessions performed. Surveillance biopsies of endoscopically normal mucosa are warranted after RFA, particularly among patients with these risk factors. Novel approaches to identify sub-squamous disease may have utility in surveillance of the post-ablation patients, particularly those at high risk for SSIM.

Length of Barrett’s Esophagus Predicts Likelihood of Complete Eradication of Intestinal Metaplasia and Number of Treatment Sessions of Radiofrequency Ablation (RFA): Results From the U.S. RFA Registry Anthony Infantolino*, William J. Bulsiewicz, Atilla Ertan, Srinadh Komanduri, Richard I. Rothstein, Herbert C. Wolfsen, Gary W. Chmielewski, F. Scott Corbett, Daniel S. Camara, Nicholas J. Shaheen University of North Carolina School of Medicine, Chapel Hill, NC; Thomas Jefferson University, Philadelphia, PA; University of Texas Health, Houston, TX; Northwestern University, Chicago, IL; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Mayo Clinic Florida, Jacksonville, FL; Rush University Medical Center, Chicago, IL; Sarasota Memorial Hospital, Sarasota, FL; Sisters of Charity Hospital, Buffalo, NY Background: Radiofrequency ablation (RFA) is an effective treatment for Barrett’s esophagus (BE). The predictors of complete eradication of intestinal metaplasia (CEIM) and the number of treatment sessions required to eradicate IM are poorly understood. We used data from a nationwide, multicenter registry of patients treated with RFA to assess the relationship between length of BE and outcomes of RFA. Methods: The U.S. RFA Registry is a prospective study of patients with BE treated with RFA at 148 institutions (113 community-based, 35 academicaffiliated). Information collected includes demographic data, histology prior to treatment, endoscopic findings, date and number of treatment sessions, ablation outcomes, and complications. Complete eradication of intestinal metaplasia was achieved if biopsies 12 months after enrollment showed no evidence of intestinal metaplasia. Patients in the highest quartile for number of treatment sessions to achieve CEIM were considered relatively “difficult to ablate.” The relationship of BE length and difficulty to ablate was assessed using Student’s t-test. Pertinent variables (p 0.20 on bivariate analysis) were included in both a logistic regression and multiple linear regression model to assess the association between length of BE and increased number of treatment sessions, as well as length of BE and CEIM, controlling for potentially confounding variables. Results: Among 2,166 patients who received RFA for BE and had data available from biopsies obtained 12 months after enrollment, CEIM was achieved in 1,570 patients (72%). The mean number of treatment sessions to CEIM was 2.6 1.4; patients in the highest quartile required 4.0 or more sessions to achieve CEIM (“difficult to ablate” BE). Mean BE length was 5.7 3.4cm in those with difficult to ablate BE, vs. 3.2 2.6cm in the remainder. BE length was independently associated with being difficult to ablate in logistic regression (OR 1.28 per additional cm of BE, p 0.001), controlling for age, race, sex, and degree of baseline dysplasia. Length of BE was also an independent predictor of number of RFA treatment sessions in linear regression ( 0.19, p 0.001), controlling for age, race, sex, and degree of baseline dysplasia. BE length was additionally a predictor of CEIM. On average, patients with 2-, 5-, and 8cm of BE can be expected to require 2.4, 2.9, and 3.5 treatment sessions, respectively (see figure). Conclusions: In the largest reported cohort of patients treated with RFA for BE, longer segment length of BE was associated with the need of 4 or more sessions for CEIM; a lower likelihood of CEIM within the time frame of the current follow-up, and an increasing number of treatment sessions needed for CEIM.

Methods: Subjects had BE with biopsy confirming non-dysplastic intestinal metaplasia (IM), low-grade (LGD) or high-grade dysplasia (HGD). RFA was performed every 2-4 months with follow-up biopsy at each endoscopy after RFA and/or upon achieving complete endoscopic eradiation of BE. The primary endpoint is histology-based: complete response for dysplasia (CR-D) and IM (CR-IM), defined as no biopsy showing each respective finding. Three cohorts were considered: Safety (all subjects); Efficacy-A (subjects with any post-RFA biopsy despite some not having completed therapy); 3) Efficacy B (subjects with post-RFA biopsy >1 year post-RFA).