Society: AGA

Introduction:
Barrett’s esophagus (BE), a pre-malignant precursor of esophageal adenocarcinoma (EAC), when recognized early through screening, could potentially allow for endoscopic surveillance or endoscopic eradication therapy. As such, major GI societies recommend targeted screening for BE based on age, race, obesity, smoking, chronic gastroesophageal reflux disease (GERD) and family history of BE/EAC. However, at-risk population is defined variably across societal recommendations, which has led to ambiguity in defining the potential population eligible for BE screening.

Aim:
To estimate the national burden of BE screen-eligible population in accordance with GI societal recommendations.

Methods:
We used the nationally representative 2012 National Health Interview Survey (NHIS) to estimate the U.S. national burden of BE screening based on guidance documents from four major societies (ACG Guidelines 2022, AGA Clinical Practice Update 2022, ASGE Guidelines 2019, BSG Guidelines 2014). We also estimated the number of screen-eligible patients based on different combinations of risk factors in the entire U.S. adult population. Analyses accounted for complex sampling of NHIS.

Results:
The non-institutionalized population in the U.S. in 2012 was 234,920,670. Of these, 43.6% were age ≥50y, 48.1% were males, 76.1% were non-Hispanic white, 39.9% were ever-smokers (17.9% were current smokers), and 27.3% were obese. Overall, 22.7% reported GERD symptoms in the prior year. Based on GI societies’ BE screening recommendations, the screen-eligible population ranged from 19.7 million (8.4%) based on BSG 2014 recommendations to 120.1 million (51.1%) based on AGA Clinical Practice Update 2022 (Table 1). There was wide variation in the number of risk factors in the screen-eligible population, ranging from 78.1% with ≥2 risk factors to 24.7% with ≥4 risk factors. GERD patients had fewer other risk factors: 19.6% with ≥2 risk factors, and 5.4% with ≥4 risk factors (Figure 1).

Conclusions:
The estimated burden of BE screen-eligible population based on current societal recommendations is high and variable, potentially imposing a considerable resource burden, especially if endoscopic screening is pursued. Better understanding of risks and benefits of screening, precise risk stratification and high-performing, scalable, non-invasive screening modalities are needed to improve appropriate targeting and reduce the burden on patients and resources associated with population-based BE screening.

<b>Table 1.</b> Societal recommendations for screening for Barrett’s esophagus, and estimated burden of screen-eligible adult population in the United States based on the National Health Interview Survey 2012

Table 1. Societal recommendations for screening for Barrett’s esophagus, and estimated burden of screen-eligible adult population in the United States based on the National Health Interview Survey 2012

<b>Figure 1</b>: Estimated burden of screening for Barrett’s esophagus in the United States based on the National Health Interview Survey 2012 based on number of risk factors

Figure 1: Estimated burden of screening for Barrett’s esophagus in the United States based on the National Health Interview Survey 2012 based on number of risk factors

Background-Patients with short segment Barrett’s oesophagus (BO) and no intestinal metaplasia (IM) may inadvertently end up on surveillance programmes and contribute to an unnecessary burden on healthcare resources, interventional risk, patient anxiety and environmental footprint. In the UK BO is defined by the presence of IM on histology and the presence of visible columnar epithelium above the gastroesophageal junction (GOJ) at gastroscopy. National guidelines recommend surveillance is offered to those with maximal BO length (M)>= 3cm. A Cytosponge service to triage patients on Barrett’s surveillance to gastroscopy and avoid diagnostic delay was established in 2020 to address COVID19 delays. The surrogate biomarker for IM on Cytosponge cytology is trefoil factor (TFF3).
Methods-All patients on BO surveillance programme due between 30/11/2020 and 30/11/2022 were offered Cytosponge. Exclusions were previous dysplasia of any grade, previous fundoplication, strictures, pregnancy and patient preference. 2 research nurses and 3 clinical nurse specialists were trained in delivering Cytosponge. Results were relayed to patients within 4 weeks of the procedure. Patients with dysplasia/atypia/p53 or TFF3+ve are described elsewhere. Those with negative or equivocal TFF3 were identified and their previous gastroscopy and histology reports were reviewed for the presence of visible BO (Prague criteria) and IM respectively. Patients with M <3cm and no previous IM were discharged from surveillance following consultation with the specialist nurse, advice and safety netting. Figure 1 shows the decision tree used for managing patients with a negative TFF3.
Results- Over the 2y period 313 patients had a successful Cytosponge with adequate cytology sampling. 232 (74.2%) patients had a positive TFF3. 81 (25.8%) had negative or equivocal TTF3. Of these, at last gastroscopy 24 (7.7%) had Barrett’s length reported to be 3cm or greater and continue on surveillance programme with next gastroscopy in 12-18 months. 57 had Barrett’s length of <3cm or unspecified length reported at last gastroscopy. 22 of these had M<3cm without IM at previous gastroscopy and were discharged without further investigation. The remaining 35 had or await repeat gastroscopy and to date 36/313 (11.5% of the programme) were discharged.
Conclusion- An additional unexpected benefit from the Barrett’s surveillance Cytosponge service was to identify at least 11.5% patients not requiring ongoing surveillance. This has a positive impact to patients, healthcare systems and helps reduce the healthcare carbon footprint.

Background: WATS^3D (CDx Diagnostics, Suffern NY) is a diagnostic platform that utilizes mucosal brush sampling combined with neural network technology to enhance detection of dysplasia in Barrett’s Esophagus (BE) when used as an adjunct to forceps biopsies (FB). Diagnostic reproducibility among pathologists evaluating FB has been suboptimal. The purpose of this study was to evaluate interobserver variability in diagnosing BE-associated dysplasia in WATS^3D brush specimens among academic GI pathologists previously inexperienced with this technology.

Methods: After a 4 hour combined in person/virtual training session of WATS^3D diagnostic criteria, 5 academic GI pathologists with no prior experience with this technology assessed WATS^3D brush samples from 60 BE patients. Each of the 60 brush samples was processed into one formalin-fixed paraffin-embedded (FFPE) H and E-stained slide and one PAP-stained smear slide (120 slides in total), all of which were scanned digitally for pathology evaluation. Study pathologists were asked to assess the images for either non-dysplastic BE (NDBE), Indefinite for dysplasia (Indef), low (LGD) or high grade dysplasia/carcinoma (HGD/CA) from each of the two digitalized slides separately, and also when combined into a final worst diagnosis per patient. All WATS^3D cases selected for this study had their diagnosis (20 with NDBE, 20 with LGD, 20 with HGD/CA) confirmed in the FB that was obtained at the same endoscopic procedure by 1 pathologist who did not participate in the interobserver analysis. Kappa statistics were performed for diagnostic variability.

Results: Overall, all 5 pathologists agreed on the final patient diagnosis in 88.3% of cases (≥4/5 agreed in 98.3%). The Kappa value for overall worst diagnosis was 0.93 (CI=0.87-0.98), which is considered excellent (Kappa=0.93 for FFPE slides, 0.97 for smear slides). The Kappa values based on specific diagnoses were as follows: NDBE=0.94, LGD=0.90, HGD/CA=0.95. Only one pathologist diagnosed Indef, and this was applied in only two cases. When the analysis was based only on the presence or absence of dysplasia (either LGD or HGD/CA), all 5 pathologists agreed on the patient’s final diagnosis in 95.0% of cases (Kappa=0.95), and this value reached 100% in the smear slide specifically. Finally, there was 100% agreement between the WATS^3D dysplasia diagnoses rendered by the majority of study pathologists and the FB diagnoses.

Conclusions: Interobserver agreement of WATS^3D specimens for BE-associated dysplasia is extremely high among non-industry GI pathologists without any prior cytology or WATS^3D training. The results are considerably higher than prior studies based on FB alone. Most notably, determination of dysplasia vs no dysplasia was nearly perfect. After focused training, WATS^3D can be utilized in non-industry settings with excellent diagnostic accuracy.

Figure 1a. WATS<sup>3D</sup> case showing high grade dysplasia in a formalin-fixed paraffin-embedded (FFPE) H and E-stained sample.

Figure 1a. WATS^3D case showing high grade dysplasia in a formalin-fixed paraffin-embedded (FFPE) H and E-stained sample.

Figure 1b. WATS<sup>3D</sup> case showing high grade dysplasia in a PAP-stained smear sample.

Figure 1b. WATS^3D case showing high grade dysplasia in a PAP-stained smear sample.

Background:
Similar to the concept of post-colonoscopy colorectal cancer, post-endoscopy esophageal adenocarcinoma (PEEC) and post-endoscopy esophageal neoplasia (PEEN), occurring after an ostensibly normal screening and surveillance for Barrett’s esophagus (BE) undermines the effectiveness of these practices. Population-based estimates of PEEC and PEEN have not been described.

Aims:
Using a population-based cohort study, we aimed to assess the magnitude of: (i) PEEC and PEEN and (ii) neoplasia detection rates (NDR) among newly diagnosed BE patients.

Methods:
This population-based cohort study was conducted in Denmark, Finland and Sweden from 2006-2020. Data were retrieved from the national and complete patient, cancer, cause of death and prescribed drug registries. Patients with newly diagnosed BE were included. We excluded patients with prior esophageal or gastric cardia cancer, prior endoscopic eradication therapy or diagnosis of BE without an accompanying endoscopy code. Data on the following variables were collected: age, sex, country, year of diagnosis, smoking, Charlson comorbidity index score, medications and hospital volume. PEEC and PEEN were defined as esophageal adenocarcinoma (EAC) or HGD/EAC, respectively, diagnosed 30-365 days from BE diagnosis (index endoscopy). NDR was defined as HGD/EAC diagnosed from 0-29 days and incident HGD/EAC was diagnosed >365 days from BE diagnosis. Patients were followed until HGD/EAC, death or end of study period. Incidence rates (IR) per 100,000 person-years and incidence rate ratios (IRR) with 95% CI were calculated using Poisson regression.

Results:
This cohort included 20,588 newly diagnosed BE patients (mean age 64.6 years, 67% men). Among 279 patients diagnosed with EAC: NDR (n=41, 14.6%), PEEC (n=65, 23.2%) and incident EAC (173, 62%) (Table 1). The IRs/100,000 person-years for NDR, PEEC and incident EAC were 2521 (95% CI 1857-3425), 369 (95% CI 289-470) and 199 (95% CI 172-231), respectively. Diagnoses of HGD were only available in the Swedish database, where 279 patients were diagnosed with HGD/EAC: NDR (n=41, 14.6%), PEEN (n=48, 17.2%) and incident HGD/EAC (n=190, 68,1%). The IRs/100,000 person-years for NDR, PEEN and incident HGD/EAC were 3906 (95% CI 2876-5305), 421 (95% CI 317-558) and 285 (95% CI 247-328), respectively (Table 2). Sensitivity analysis that defined PEEC/PEEN as EAC or HGD/EAC diagnosed between 30 days-3 years showed that 45.8% of EACs (IR 262/100,000; 95% CI 220-311) and 39% of HGD/EACs (IR 337/100,000; 95% CI 279-406) were classified as PEEC or PEEN, respectively.

Conclusions:
Results from this large population-based cohort suggest that nearly 25% of all EACs are diagnosed within one year after index endoscopy. Ascertaining a baseline rate of PEEC/PEEN will allow its use as a quality metric in BE, and as a yardstick for future intervention trials to reduce PEEC/PEEN in practice.

<b>Table 1: Characteristics of newly diagnosed patients with Barrett’s esophagus (overall, patients diagnosed with esophageal adenocarcinoma (EAC) within 0-29 days of Barrett’s esophagus diagnosis – neoplasia detection rates (NDR), within 30-365 days – post-endoscopy esophageal adenocarcinoma (PEEC) and >365 days – incident EAC) and incidence rates and incidence rate ratios of EAC in a population-based cohort </b>

Table 1: Characteristics of newly diagnosed patients with Barrett’s esophagus (overall, patients diagnosed with esophageal adenocarcinoma (EAC) within 0-29 days of Barrett’s esophagus diagnosis – neoplasia detection rates (NDR), within 30-365 days – post-endoscopy esophageal adenocarcinoma (PEEC) and >365 days – incident EAC) and incidence rates and incidence rate ratios of EAC in a population-based cohort

<b>Table 2: Characteristics of newly diagnosed patients with Barrett’s esophagus (overall, patients diagnosed with high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) within 0-29 days of Barrett’s esophagus diagnosis – neoplasia detection rates (NDR), within 30-365 days – post-endoscopy esophageal neoplasia (PEEN) and >365 days – incident EAC) and incidence rates and incidence rate ratios of EAC in a population-based cohort (Sweden only)</b>

Table 2: Characteristics of newly diagnosed patients with Barrett’s esophagus (overall, patients diagnosed with high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) within 0-29 days of Barrett’s esophagus diagnosis – neoplasia detection rates (NDR), within 30-365 days – post-endoscopy esophageal neoplasia (PEEN) and >365 days – incident EAC) and incidence rates and incidence rate ratios of EAC in a population-based cohort (Sweden only)

Introduction:
Bariatric surgery is an effective treatment for obesity, and sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are the most commonly performed bariatric procedures. Gastroesophageal reflux disease has been noted to be a common occurrence after sleeve gastrectomy, and case series and retrospective studies have raised concern for the high prevalence of Barrett’s esophagus (BE) in patients with a history of SG. However, comparative data is lacking and reported numbers are small. We compared the rates of diagnosis of Barrett’s esophagus between patients who underwent SG and RYGB in this large multi-institutional research network analysis.

Methods:
A retrospective cohort propensity-matched (PSM) analysis was performed using the multi-institutional research network TriNetX. Patients who underwent SG or RYGB for obesity were identified and included if they had no prior history of BE diagnosis. PSM was performed for known risk factors of BE, including age, gender, ethnicity, history of smoking or alcohol abuse, prior diagnosis of GERD, and obesity. Cox Proportional Hazard analysis with time-dependent covariates was performed to compare the two cohorts at follow-up; outcomes were assessed after a lag phase of one year.

Results:
A total of 64,904 and 45,277 patients were identified and included in the SG and RYGB cohorts, respectively, and after 1:1 propensity score matching, 40,053 patients were included in each matched cohort. The cohorts were well-matched in all assessed covariates (Standardized Mean Difference <0.1). In the propensity-matched analysis, a higher risk of BE diagnosis at follow-up was noted in the SG cohort (HR:1.30;95%CI:1.023-1.65, Log-Rank p:<0.01). A higher risk of GERD diagnosis was also noted in the SG cohort (HR:1.54;95%CI:1.45-1.65 Log-Rank p:<0.01). There was no difference in PPI usage rates between the two cohorts (HR: 1.01,95%CI:0.98-1.04, Log-Rank p:0.58). Increasing exposure lag to 3 years [HR:2.30(1.68,3.14)] and 5 years [HR:2.95(1.89,4.62)] led to a further increase in hazard ratios for BE diagnosis, strengthening the association and its time dependence. For the secondary analysis, only those patients who underwent endoscopic evaluation after bariatric surgery were then identified from the cohorts and 3244 patients in both cohorts were included after 1:1 PSM. A higher risk of BE in the SG cohort was noted (Table 1). Rates of BE diagnosis for patients undergoing EGDs after 1-year, 3-year and 5-year of SG were 3.51%, 4.70%, and 6.40%, respectively.

Conclusion:
In this analysis of a large cohort, a higher risk of BE diagnosis after SG was noted compared to RYGB. High rates of BE diagnosis at follow-up EGDs after SG were noted. Acid suppression therapy, as well as EGD surveillance after SG, may be warranted in high-risk patients, and provider vigilance is advised.

Background: Management of Barrett’s esophagus (BE), a precursor of esophageal adenocarcinoma (EAC), relies on diagnoses of dysplasia i.e., Non-dysplastic (ND), Low-grade Dysplasia (LGD), Indefinite for Dysplasia (IND), or High-grade Dysplasia (HGD). However, even after years of evidence-based, rigorous surveillance programs, prediction of progression of BE patients is difficult due to high interobserver variability, inaccuracy, and rarity of dysplasia (absent in 90% of BE cases). We therefore validated a biomarker model developed at Johns Hopkins University School of Medicine as a simple, precise clinical assay to stratify BE patients for risk of progression to HGD or EAC. Methods: We led a blinded, retrospective study of 275 BE patients across 7 clinical sites. All index patient samples had pathology reports with histologic diagnoses (ND, IND, or LGD) and follow-up data with time between index biopsy and outcome biopsy (ND, IND, LGD, HGD, or EAC). First, we tested 13 genes with consistent and ample evidence as epigenetic biomarkers of BE progression. DNAs from de-identified formalin-fixed paraffin-embedded endoscopic biopsies were extracted, bisulfite-treated, and analyzed using quantitative real-time methylation-specific PCR (qMSP) to measure methylation levels. Time-to-event was defined by dates of index and outcome (final) biopsies for each patient. Outcome diagnoses of HGD or EAC were labeled as progressors, whereas diagnoses of ND, IND, or LGD as non-progressors. Randomized data was permanently split into training (185) and test (90) sets. In the training set, we performed uni- and multivariate analyses, variable selection (Lasso regression), and Cox proportional hazards method. Data was further sorted into three risk groups (Low, Medium, or High) via conditional tree method. Predictive performance for this new algorithm was validated in the test set. Results: Progressors (99) had a median of outcome biopsy (HGD/EAC) of 3.3 years; non-progressors (176) had median outcome biopsy of 7.6 years. In the training set, the multivariate model produced a panel of 4 biomarkers, age, and gender adjustments to yield a C-index of 0.67. The predictive performance in the risk categories yielded a time-dependent area under the curve (AUC) of 0.72 at 5 years. Validation of the test set gave a Hazard Ratio of 4.91 (95% CI 1.63-14.75, p = 0.005) for High vs. Low risk categories. Conclusion: This epigenetic biomarker model has value as a laboratory-developed test to predict future risk of neoplastic progression in BE patients. In our test set, 90% of progressors fell into medium or high risk categories, with 54% in high risk. The ability to risk-stratify BE patients can improve care management by finding high-risk patients who may benefit from increased surveillance or intervention, but also finding low-risk patients who may not need as frequent surveillance.

Andrew Kalra

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