Ragunath, Krish

Abstract The proliferation of advanced endoscopic resection techniques has provided a minimally invasive alternative to esophagectomy and revolutionized outcomes for patients with early-stage esophageal adenocarcinoma (EAC). This paradigm shift and the resulting research data on clinical and histologic determinants of treatment outcome have highlighted the heterogeneity of outcomes within EAC staged as T1 by invasion depth. Multidisciplinary cancer care teams are now routinely facing difficult decisions regarding the management of high-risk T1 EAC to balance the risk of long-term lymph node (LNM) or distant metastasis against the risks of surgical resection. In this review, we summarize the current state of knowledge regarding the staging and risk stratification of T1 EAC, with particular attention to features that contribute to a higher risk of LNM and cancer mortality. We review recent clinical trial data on positioning the use of endoscopic resection (cap-assisted or submucosal dissection) versus surgical resection in high-risk T1 EAC patients and describe adjunctive techniques to further improve risk stratification and treatment. Finally, we explore emerging and future directions, such as artificial intelligence and advanced biomarker analysis to further aid decision-making and enhance patient outcomes.

INTRODUCTION: The performance of a high quality esophagogastroduodenoscopy (EGD) is dependent on the mucosal cleanliness. Recently, the Polprep: Effective Assessment of Cleanliness in EGD (PEACE) scale was created to assess the degree of mucosal cleanliness during EGD. The aim of this study was to validate this scoring system in a cohort of international endoscopists. METHODS: In total, 39 EGD videos, with different degrees of mucosal cleanliness were retrieved from a previously conducted prospective trial. All experts rated the cleanliness of the mucosa on each video using the PEACE scale. To evaluate agreement of all scores (0–3), intraclass correlation coefficient 2.1 was used. The agreement on adequate (scores 2 and 3) and inadequate (scores 0 and 1) cleanliness was assessed using kappa values. RESULTS: Videos evaluating esophagus, stomach, and duodenum cleanliness were reviewed by 16 endoscopists. The PEACE scores demonstrated good agreement (intraclass correlation coefficient 0.82, 95% CI 0.75–0.89), especially for esophagus (0.84; 95% CI 0.71–0.95) and stomach (0.81; 95% CI 0.69–0.91), while agreement was moderate for the duodenum (0.69; 95% CI 0.51–0.87). The agreement was similar between Eastern (0.86; 95% CI 0.79–0.92) and Western experts (0.80; 95% CI 0.72–0.88). Similarly, agreement regarding adequate cleanliness was comparable between Eastern (0.70; 95% CI 0.55–0.85) and Western (0.74; 95% CI 0.64–0.84) endoscopists being overall 0.75 (95% CI 0.65–0.85). DISCUSSION: The PEACE scoring system is a simple and reliable scale to assess the cleanliness during EGD. The score is now validated among international experts with high concordance, justifying its use in clinical practice.

Background Piecemeal endoscopic mucosal resection (EMR) is an acceptable technique for T1a esophageal adenocarcinoma, but en bloc R0 excision is advocated for T1b disease as it may offer a potential cure and mitigate recurrence. Thus, distinguishing between T1a and T1b disease is imperative under current treatment paradigms. We investigated whether expert Barrett’s endoscopists could make this distinction based on optical evaluation. Methods Endoscopic images of histologically confirmed high grade dysplasia (HGD), T1a, and T1b disease (20 sets for each) were compiled from consecutive patients at a single institution. Each set contained four images including an overview, a close-up in high definition white light, a near-focus magnification image, and a narrow-band image. Experts predicted the histology for each set. Results 19 experts from 8 countries (Australia, USA, Italy, Netherlands, Germany, Canada, Belgium, and Portugal) participated. The majority had been practicing for > 20 years, with a median (interquartile range) annual case volume of 50 (18–75) for Barrett’s EMR and 25 (10–45) for Barrett’s endoscopic submucosal dissection. Esophageal adenocarcinoma (T1a/b) could be distinguished from HGD with a pooled sensitivity of 89.1 % (95 %CI 84.7–93.4). T1b adenocarcinoma could be predicted with a pooled sensitivity of 43.8 % (95 %CI 29.9–57.7). Fleiss’ kappa was 0.421 (95 %CI 0.399–0.442; P < 0.001), indicating fair-to-moderate agreement. Conclusions Expert Barrett’s endoscopists could reliably differentiate T1a/T1b esophageal adenocarcinoma from HGD. Despite fair-to-moderate agreement for T staging, T1b disease could not be reliably distinguished from T1a disease. This may impact clinical decision making and selection of endoscopic techniques.

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.

Abstract Background and study aims Radiofrequency ablation (RFA) for dysplastic Barrett’s esophagus (BE) has resulted in a paradigm shift in the management of BE. Despite widespread adoption of RFA, the optimal surveillance interval of the ablated zone is unclear. Methods A patient-level discrete time cycle Markov model was developed to model clinical surveillance strategies post-RFA for BE. Three surveillance strategies were examined: the American College of Gastroenterology (ACG) strategy based on ACG guidelines for post-RFA surveillance, the Cotton strategy based on data from the USA and UK RFA registries, and the UK strategy in line with surveillance strategies in UK centers. Monte-Carlo deterministic and probabilistic analyses were performed over 10,000 iterations (i. e., representing 10,000 patient journeys) and sensitivity analyses were carried out on the variables used in the model. Results On base-case analysis, the ACG strategy was the most cost-effective strategy, at a mean cost of £ 11,733 ($ 16,396) (standard deviation (SD) 1520.15) and a mean effectiveness of 12.86 (SD 0.07) QALYs. Probabilistic sensitivity analysis demonstrated that the ACG model was the most cost-effective strategy with a net monetary benefit (NMB) of £ 5,136 ($ 7177) (SD 241) compared to the UK strategy and a NMB of £ 7017 ($ 9,806) (SD 379) compared to the Cotton strategy. At a willingness to pay (WTP) threshold of £ 20,000 ($ 27,949), the ACG model was superior to the other strategies as the most cost-effective strategy. Conclusions A post-RFA surveillance strategy based on the ACG guidelines seems to be the most cost-effective surveillance option.

INTRODUCTION: Minimally invasive tests for Barrett's esophagus (BE) detection have raised the prospect of broader nonreflux-based testing. Cost-effectiveness studies have largely studied men aged 50 years with chronic gastroesophageal reflux disease (GERD) symptoms. We evaluated the comparative cost effectiveness of BE screening tests in GERD-based and GERD-independent testing scenarios. METHODS: Markov modeling was performed in 3 scenarios in 50 years old individuals: (i) White men with chronic GERD (GERD-based); (ii) GERD-independent (all races, men and women), BE prevalence 1.6%; and (iii) GERD-independent, BE prevalence 5%. The simulation compared multiple screening strategies with no screening: sedated endoscopy (sEGD), transnasal endoscopy, swallowable esophageal cell collection devices with biomarkers, and exhaled volatile organic compounds. A hypothetical cohort of 500,000 individuals followed for 40 years using a willingness to pay threshold of $100,000 per quality-adjusted life year (QALY) was simulated. Incremental cost-effectiveness ratios (ICERs) comparing each strategy with no screening and comparing screening strategies with each other were calculated. RESULTS: In both GERD-independent scenarios, most non-sEGD BE screening tests were cost effective. Swallowable esophageal cell collection devices with biomarkers were cost effective (<$35,000/QALY) and were the optimal screening tests in all scenarios. Exhaled volatile organic compounds had the highest ICERs in all scenarios. ICERs were low (<$25,000/QALY) for all tests in the GERD-based scenario, and all non-sEGD tests dominated no screening. ICERs were sensitive to BE prevalence and test costs. DISCUSSION: Minimally invasive nonendoscopic tests may make GERD-independent BE screening cost effective. Participation rates for these strategies need to be studied.

Objective Surveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett’s oesophagus (BE) are currently empiric and not based on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines. Design Data on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies. Results 594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4–4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI −7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia). Conclusions BE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.

Introduction BO is the strongest precursor of oesophageal adenocarcinoma. Participation patterns and effectiveness of BO community screening using unsedated transnasal endoscopy (uTNE) is unknown. Feasibility of mobile van screening closer to home is also unknown. We aimed to assess the effectiveness of this technique compared to sedated endoscopy (SE). Methods A population cohort ≥50 years of age, with no history of endoscopic evaluation, was identified from a group of subjects who previously completed a validated symptom questionnaire. Patients were randomised (stratified by age, sex and reflux symptoms) and invited to undergo either uTNE in a mobile research van (muTNE), uTNE in outpatient endoscopy suite (huTNE) or SE. uTNE was performed using a portable oesophagoscope with a disposable sheath. Procedure performance characteristics and validated tolerability scales (0 = none and 10 = severe) were recorded. Results 459 subjects were contacted and 209 (46%) agreed to undergo study procedures (muTNE n = 76, huTNE n = 72, SE n = 61). Baseline characteristics were comparable among the three groups. Participation rates were numerically higher in the unsedated arms (muTNE 47.5%, huTNE 45.7%) than in the SE arm (40.7%) (p = 0.27). Patients with acid reflux symptoms ≥1/week were more likely to participate (odds ratio 2.94, 95% confidence interval 1.47, 5.88). Complete evaluation of the oesophagus was comparable using muTNE (99%), huTNE (96%) and SE (100%) techniques. Successful biopsy acquisition was lower in the muTNE (79%) and huTNE (83%) groups compared to SE (100%) (p = 0.001). Mean duration (minutes) of examination was shorter in the SE arm (4.7) than in muTNE (8.0) and huTNE (8.5) groups (p < 0.001). However, recovery time was much longer for SE (67.3) compared to muTNE (15.5) and huTNE (18.5) techniques (p < 0.001). While overall tolerability for SE was better than muTNE and huTNE (mean score 0.4 vs. 1.9 and 2.2 respectively, p < 0.001), the majority of patients who underwent muTNE and huTNE were willing to undergo the same procedure again in future (79% and 83%, respectively). No serious adverse events were reported. 16 subjects (7.6%) were diagnosed with BO. Conclusion In this first large randomised trial evaluating novel approaches for community screening for BO, unsedated mobile van and clinic screening with TNE was feasible and effective. The patients’ visit was significantly shorter with adequate tolerability, acceptability and safety profiles. Mobile and outpatient techniques may provide a cost-effective alternative to SE for BO screening. Disclosure of Interest S. Sami: None Declared, K. Dunagan: None Declared, M. Johnson: None Declared, C. Schlek: None Declared, A. Zinsmeister: None Declared, L. M. Wong Kee Song: None Declared, K. Wang: None Declared, D. Katzka: None Declared, K. Ragunath Grant/research support from: Olympus (keymed, UK) and Intromed Ltd. (Seoul, South Korea), P. Iyer: None Declared.