Prashanth Vennalaganti

Development and Validation of a Classification System to Identify High-Grade Dysplasia and Esophageal Adenocarcinoma in Barrett's Esophagus Using Narrow-Band Imaging

BACKGROUND & AIMS Although several classification systems have been proposed for characterization of Barretts esophagus (BE) surface patterns based on narrow-band imaging (NBI), none have been widely accepted. The Barretts International NBI Group (BING) aimed to develop and validate an NBI classification system for identification of dysplasia and cancer in patients with BE. METHODS The BING working group, composed of NBI experts from the United States, Europe, and Japan, met to develop a validated, consensus-driven NBI classification system for identifying dysplasia and cancer in BE. The group reviewed 60 NBI images of nondysplastic BE, high-grade dysplasia, and esophageal adenocarcinoma to characterize mucosal and vascular patterns visible by NBI; these features were used to develop the BING criteria. We then recruited adult patients undergoing surveillance or endoscopic treatment for BE at 4 institutions in the United States and Europe, obtaining high-quality NBI images and performing histologic analysis of biopsies. Experts individually reviewed 50 NBI images to validate the BING criteria, and then evaluated 120 additional NBI images (not previously viewed) to determine whether the criteria accurately predicted the histology results. RESULTS The BING criteria identified patients with dysplasia with 85% overall accuracy, 80% sensitivity, 88% specificity, 81% positive predictive value, and 88% negative predictive value. When dysplasia was identified with a high level of confidence, these values were 92%, 91%, 93%, 89%, and 95%, respectively. The overall strength of inter-observer agreement was substantial (κ = 0.681). CONCLUSIONS The BING working group developed a simple, internally validated system to identify dysplasia and EAC in patients with BE based on NBI results. When images are assessed with a high degree of confidence, the system can classify BE with >90% accuracy and a high level of inter-observer agreement.

Quality Indicators for the Management of Barrett’s Esophagus, Dysplasia, and Esophageal Adenocarcinoma: International Consensus Recommendations from the American Gastroenterological Association Symposium

The development of and adherence to quality indicators in gastroenterology, as in all of medicine, is increasing in importance to ensure that patients receive consistent high-quality care. In addition, government-based and private insurers will be expecting documentation of the parameters by which we measure quality, which will likely affect reimbursements. Barretts esophagus remains a particularly important disease entity for which we should maintain up-to-date guidelines, given its commonality, potentially lethal outcomes, and controversies regarding screening and surveillance. To achieve this goal, a relatively large group of international experts was assembled and, using the modified Delphi method, evaluated the validity of multiple candidate quality indicators for the diagnosis and management of Barretts esophagus. Several candidate quality indicators achieved >80% agreement. These statements are intended to serve as a consensus on candidate quality indicators for those who treat patients with Barretts esophagus.

Inter-Observer Agreement among Pathologists Using Wide-Area Transepithelial Sampling With Computer-Assisted Analysis in Patients With Barrett's Esophagus.

OBJECTIVES:The histopathological diagnosis of Barrett’s esophagus (BE)-associated dysplasia has poor inter-observer agreement. The wide-area transepithelial sampling (WATS) procedure uses a minimally invasive brush biopsy technique for acquiring wide-area sampling of BE tissue followed by computer-assisted analysis. In this study, our aim was to assess inter-observer agreement among pathologists in the diagnosis of Barrett’s-associated dysplasia using the WATS computer-assisted analysis technique.METHODS:WATS slides with varying degrees of BE dysplasia were randomly selected and distributed to four pathologists. Each pathologist graded the slides as nondysplastic, low-grade dysplasia (LGD), or high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) and completed a standardized case report form (CRF) for each slide.RESULTS:In all, 149 BE slides were evaluated in a blinded manner by 4 pathologists. The slides included the following: no dysplasia (n=109), LGD, and HGD/EAC (n=40). The overall mean kappa value for all 3 diagnoses for the 4 observers was calculated at 0.86 (95% confidence interval (CI) 0.75–0.97). The kappa values (95% CI) for HGD/EAC, IND/LGD, and no dysplasia were 0.95 (0.88–0.99), 0.74 (0.61–0.85), and 0.88 (0.81–0.94), respectively.CONCLUSIONS:The diagnosis of BE and associated dysplasia using the WATS technique has very high inter-observer agreement. This appears to be significantly higher as compared with previously published data using standard histopathology.

Barrett's oesophagus length is established at the time of initial endoscopy and does not change over time: results from a large multicentre cohort

Objective It is unclear whether Barretts oesophagus (BO) length changes over time or whether the full length of the segment is established at the onset of disease recognition. The objectives of this study were to evaluate the association of age and BO length and to evaluate the changes in BO length over time. Design This is a prospective, multicentre cohort study involving patients with BO from five centres. Patients were divided into groups based on the decade of initial diagnosis of BO. The mean BO length and the mean change in BO length were calculated for each age decade. The mean change in BO length was also calculated between the index endoscopy and the last surveillance endoscopy. Results 3635 patients with BO were included in the study: 87.8% men, 92.8% Caucasians, mean age 60.9 years and mean BO length 3.5 cm. The mean change in BO length was 0.9 cm. The mean BO length did not significantly change for each age category: <30 years (4.6 cm), 30–39.9 years (3.2 cm), 40–49.9 years (3.1 cm), 50–59.9 years (3.1 cm), 60–69.9 years (3.6 cm), 70–79.7 (4.0 cm) and >80 years (4.5 cm), p=0.47. On subgroup analysis of patients with non-dysplastic BO who had at least 1 year of endoscopic follow up, there was a significant decrease in mean change in BO length across age categories ranging from +1.7 to −0.8 cm, p=0.03. Conclusions There was no significant difference in BO length by age category in decades. In addition, the change in BO length from index to follow-up endoscopy was similar among patients >30 years. These findings suggest that a patients BO segment length attains its full extent by the time of the initial endoscopic examination.

In-class didactic versus self-directed teaching of the probe-based confocal laser endomicroscopy (pCLE) criteria for Barrett's esophagus.

BACKGROUND AND AIMS Optimal teaching methods for disease recognition using probe-based confocal laser endomicroscopy (pCLE) have not been developed. Our aim was to compare in-class didactic teaching vs. self-directed teaching of Barretts neoplasia diagnosis using pCLE. METHODS This randomized controlled trial was conducted at a tertiary academic center. Study participants with no prior pCLE experience were randomized to in-class didactic (group 1) or self-directed teaching groups (group 2). For group 1, an expert conducted a classroom teaching session using standardized educational material. Participants in group 2 were provided with the same material on an audio PowerPoint. After initial training, all participants graded an initial set of 20 pCLE videos and reviewed correct responses with the expert (group 1) or on audio PowerPoint (group 2). Finally, all participants completed interpretations of a further 40 videos. RESULTS Eighteen trainees (8 medical students, 10 gastroenterology trainees) participated in the study. Overall diagnostic accuracy for neoplasia prediction by pCLE was 77 % (95 % confidence interval [CI] 74.0 % - 79.2 %); of predictions made with high confidence (53 %), the accuracy was 85 % (95 %CI 81.8 % - 87.8 %). The overall accuracy and interobserver agreement was significantly higher in group 1 than in group 2 for all predictions (80.4 % vs. 73 %; P = 0.005) and for high confidence predictions (90 % vs. 80 %; P < 0.001). Following feedback (after the initial 20 videos), the overall accuracy improved from 73 % to 79 % (P = 0.04), mainly driven by a significant improvement in group 1 (74 % to 84 %; P < 0.01). Accuracy of prediction significantly improved with time in endoscopy training (72 % students, 77 % FY1, 82 % FY2, and 85 % FY3; P = 0.003). CONCLUSION For novice trainees, in-class didactic teaching enables significantly better recognition of the pCLE features of Barretts esophagus than self-directed teaching. The in-class didactic group had a shorter learning curve and were able to achieve 90 % accuracy for their high confidence predictions.

Effectiveness of focal vs. balloon radiofrequency ablation devices in the treatment of Barrett’s esophagus

Background and aims The safety and efficacy of radiofrequency ablation (RFA) in treatment of Barrett’s esophagus (BE)-associated dysplasia has been well established. The effectiveness of focal and balloon RFA devices has not been compared. Therefore, the aim of our study was to assess the effectiveness of focal and balloon RFA devices in the treatment of BE by calculating absolute and percentage change in BE length with RFA therapy by comparing pre- and post-treatment BE length. Patients and methods This is a retrospective cross-sectional study of patients who underwent at least one treatment with either focal and/or balloon RFA devices who were identified from two tertiary centers. Patients’ demographics, hiatal hernia, pre- and post-treatment BE length, prior use of endoscopic therapies and number of sessions were recorded. Results Sixty-one patients who had undergone 161 RFA treatment sessions met inclusion criteria. There was no significant difference in percentage change in BE length with greater number of RFA sessions. RFA with a focal device resulted in greater percentage reduction in BE length compared to the balloon system (73% vs. 39%, p < 0.01). After adjusting for initial BE length, pre-treatment BE length, hernia status, prior endoscopic mucosal resection (EMR), prior RFA, and prior EMR/RFA sessions, RFA with a focal device at each session remained an independent predictor for a significant reduction in BE extent as compared to the balloon system. Conclusion The focal RFA device alone was more effective in treatment of BE compared to the balloon system, with a greater reduction in extent of BE. The focal RFA device for endoscopic eradication therapy of BE should be considered the preferred technique.

Long-term results of the mucosal ablation of Barrett's esophagus: efficacy and recurrence.

Background and study aims: It has been postulated that the endoscopic ablation of Barrett’s esophagus can lead to complete eradication of the disease. This study was undertaken to evaluate the efficacy of endoscopic eradication therapy for Barrett’s esophagus and the rates of recurrence of intestinal metaplasia. Patients and methods: As part of an initial randomized controlled trial, patients with nondysplastic or low grade dysplastic Barrett’s esophagus underwent mucosal ablation. Following ablation, the patients had annual surveillance endoscopies. Recurrence was defined as the presence of intestinal metaplasia after initial complete eradication had been achieved. Results: A total of 28 patients with Barrett’s esophagus were followed for a mean of 6.4 years after ablation therapy. At baseline, the majority of the patients had nondysplastic Barrett’s esophagus (79 %). Initial complete eradication of intestinal metaplasia was achieved at a mean of 4.1 months. During long-term follow-up, initial recurrence of intestinal metaplasia was seen in 14 of the 28 of patients (50 %) at a mean of 40 months, and further maintenance ablation therapy was applied. At the final follow-up, 36 % of the patients had complete eradication of intestinal metaplasia, 18 % of the patients had intestinal metaplasia, and 21 % had died of unrelated causes; invasive esophageal adenocarcinoma had developed in 1 patient. Conclusions: The long-term results of this study demonstrate a recurrence rate of 50 % after complete eradication of Barrett’s esophagus with endoscopic eradication therapy. In addition, re-recurrence (in 36 %), even after further maintenance endoscopic eradication therapy, and deaths unrelated to the disease (21 %) occurred. Complete remission of Barrett’s esophagus appears to be a difficult goal to achieve. These results call into question the role of ablation in patients with low risk Barrett’s esophagus.

Lower Annual rate of Progression of Short-segment vs Long-segment Barrett’s Esophagus to Esophageal Adenocarcinoma

BACKGROUND & AIMS: European guidelines recommend different surveillance intervals of non‐dysplastic Barretts esophagus (NDBE) based on segment length, as opposed to guidelines in the United States, which do recommend surveillance intervals based on BE length. We studied rates of progression of NDBE to high‐grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in patients with short‐segment BE using the definition of BE in the latest guidelines (length ≥1 cm). METHODS: We collected demographic, clinical, endoscopy, and histopathology data from 1883 patients with endoscopic evidence of NDBE (mean age, 57.3 years; 83.5% male; 88.1% Caucasians) seen at 7 tertiary referral centers. Patients were followed for a median 6.4 years. Cases of dysplasia or EAC detected within 1 year of index endoscopy were considered prevalent and were excluded. Unadjusted rates of progression to HGD or EAC were compared between patients with short (≥1 and <3) and long (≥3) BE lengths using log‐rank tests. A subgroup analysis was performed on patients with a documented Prague C&M classification. We used a multivariable proportional hazards model to evaluate the association between BE length and progression. Adjusted hazards ratios were calculated after adjusting for variables associated with progression. RESULTS: We found 822 patients to have a short‐segment BE (SSBE) and 1061 to have long segment BE (LSBE). We found patients with SSBE to have a significantly lower annual rate of progression to EAC (0.07%) than of patients with LSBE (0.25%) (P = .001). For the combined endpoint of HGD or EAC, annual progression rates were significantly lower among patients with SSBE (0.29%) compared to compared to LSBE (0.91%) (P < .001). This effect persisted in multivariable analysis (hazard ratio, 0.32; 95% CI, 0.18–0.57; P < .001). CONCLUSION: We analyzed progression of BE (length ≥1 cm) to HGD or EAC in a large cohort of patients seen at multiple centers and followed for a median 6.4 years. We found a lower annual rate of progression of SSBE to EAC (0.07%/year) than of LSBE (0.25%/year). We propose lengthening current surveillance intervals for patients with SSBE.

421 Development and Validation of a NBI Classification System for the Prediction of Dysplasia in Barrett's Esophagus (BE): Consensus Results From an International Working Group

Background/Purpose: Visceral hypersensitivity for acid, extension and temperature stimuli in stomach and duodenum are involved in functional dyspepsia (FD). While the involvement of TRPV1 and TRPA1 have been reported in a number of animal experiments, data remains conflicting. On the other hand, ATP-gated ion channels, especially P2X3 receptor have recently been worthy of attention for its role in visceral hypersensitivity. We have reported that TRPV4 is expressed in esophageal, gastric and intestinal epithelia (J Physiol 2011, DDW2013, Am J Physiol 2013) and that ATP exocytosis is induced by TRPV4 activation in esophageal keratinocytes. We hypothesized that various physiological stimuli induced ATP release from gastric and duodenal (intestinal) epithelia through each different receptor and that excessive ATP release was involved in the pathophysiology of visceral hypersensitivity. METHODS: TRPV4 expression was examined in normal rat gastric epithelial cell line (RGE), human gastric cancer cell line (AGS) and rat intestinal cell line (IEC-6) by RT-PCR, immunostaining or Western blotting. ATP releases responding to various physiological stimuli (chemicals, low osmotic pressure, acid, extension, temperature) from each cell line were examined using luciferin-luciferase reaction. Acidic (pH 4.0), warm (40 °C) and standard (25 °C, pH7.4) solutions were used as acidic, warm stimuli or a control, respectively. Stretch stimuli was applied to cells cultured on a silicon chamber using a stretching apparatus (STREX Inc, Osaka, Japan). RESULTS: TRPV4 was expressed in RGE, IEC-6 but not in AGS. Specific TRPV4 agonist (GSK1016790A) or endogenous TRPV4 activator (5,6-EET) significantly enhanced ATP release from RGE cells but not AGS. Low osmotic, acidic, stretch or temperature stimuli significantly enhanced ATP release in RGE or IEC-6 cells. Stretchinduced ATP release from RGE cells was inhibited by pretreatment with a specific TRPV4 inhibitor, HC067047. Cell viability after each stimulus was confirmed by Trypan blue staining. Conclusion: Gastric and duodenal (intestinal) epithelial cells release ATP responding various physiological stimuli partially via TRPV4 activation . Excessive ATP release from epithelial cells might be involved in the pathophysiology of visceral hypersensitivity.

Epidemiology of Gastroesophageal Reflux in Asia

Gastroesophageal reflux disease (GERD) is the most common gastrointestinal complaint seen across the world. It has often been perceived as Western disease due to its high prevalence of around 10–20%. In Asia, limited data showed that the prevalence was 2.5–6.7% and that most patients had mild disease. However, within the last decade, research in GERD showed that the prevalence of weekly heartburn ranges from 8 to 20%, which is higher than previous estimates; however, erosive esophagitis was seen in less than 20% of patients. This increase in prevalence could be due to the changing dynamics mainly due to interaction of environmental, genetic, and recent socioeconomical development in Asia. The diversity in ethnic populations in Asia leads to problem in evaluation of the prevalence of gastroesophageal disease mainly due to the cultural, social, and language differences. The aim of this chapter is to review the epidemiological studies of gastroesophageal disease, including those of erosive esophagitis and Barrett’s esophagus in Asia, and provide an understanding of the regional variation and the changes seen over the last decade.