Benjamin R. Alsop

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.

Incidence of pancreatic fistula after distal pancreatectomy and efficacy of endoscopic therapy for its management: results from a tertiary care center.

Pancreatic fistula is a known complication of distal pancreatectomy. Endotherapy with pancreatic duct stent placement and pancreatic sphincterotomy has been shown to be effective in its management; however, experience of endotherapy in the management of this complication has not been extensively reported from the United States. Preoperative endoscopic retrograde cholangiopancreatography (ERCP) with pancreatic stent placement has also been proposed to prevent this complication after distal pancreatectomy. In our cohort of 59 patients who underwent distal pancreatectomy, 13 (22%) developed a pancreatic fistula in the immediate postoperative period, of whom 8 (14%) patients (5 female, mean age 52 years) were referred for an ERCP because of ongoing symptoms related to the pancreatic fistula. The pancreatic fistula resolved in all patients after a median duration of 62 days from the index ERCP. The median number of ERCPs required to document resolution of the pancreatic fistula was 2. Although a sizeable percentage of patients develop a pancreatic fistula after distal pancreatectomy, only a small percentage of patients require ERCP for management of this complication. Given the high success rate of endotherapy in resolving pancreatic fistula and the fact that the majority of patients who undergo distal pancreatectomy never require an ERCP, performing ERCP for prophylactic pancreatic duct stent prior to distal pancreatectomy might not be necessary.

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.

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.

Limitations of endoscopic ablation in Barrett’s esophagus

In the last 5–10 years, endoscopic ablative therapies have been gaining ground as treatment for Barrett’s esophagus associated with high-grade dysplasia and early cancer, and they are becoming the most preferred technique over surgery as the standard of care. These therapies are associated with a lower rate of complications and mortality than surgery; studies have found them to be safe, effective and tolerable. Endoscopic ablative therapies are not, however, without their drawbacks. There is a paucity of data on long-term efficacy, and direct comparisons of the different modalities are lacking. Unlike surgery, current data suggest that endoscopic ablation treatments may not be curative in all patients, so patients require ongoing surveillance and acid suppression. Questions remain regarding durability as well as factors promoting recurrence after endoscopic therapy. The authors conducted a systematic review of the literature on ablative therapies in Barrett’s esophagus to describe the modalities currently available and to provide an understanding of their limitations.

Su2006 Performance of Novel Criteria for Distinguishing Dysplastic From Non-Dysplastic Barrett's Esophagus (NDBE) Using Volumetric Laser Endomicroscopy (VLE) Among Experts and GI Trainees

G A A b st ra ct s histology. Methods: BE patients with and without early neoplasia underwent endoscopic resection (ER) of areas marked in-vivo with electrocoagulation markers (ECM). Subsequently ER specimens underwent additional ex-vivo marking with several different markers (ink, pin, ECM) followed by ex-vivo VLE scanning. Tissue blocks were carefully sectioned guided by the placed markers. After further histological processing a histopathology slide was sectioned from each block. When necessary, extensive sectioning of tissue blocks was performed in order to visualize all markers that were included in the tissue block on histology. All histopathology and VLE slides were evaluated by 2 researchers and considered a match if a) ≥ 2 markers were visible on both modalities and b) mucosal patterns aside from these markers matched on both histology and VLE. All slides were evaluated by an expert BE pathologist. Results: From 16 ER specimens (overall diagnosis: 7 non-dysplastic BE, 9 dysplastic BE (1 LGD, 4 HGD, 4 EAC)) 120 tissue blocks were sectioned of which 57 contained multiple markers and thus could potentially be matched with VLE. Based on several combinations of these markers in total 14 histology-VLE matches could ultimately be constructed. Markers that achieved the best yield of matches respectively were: invivo placed ECMs (8 matches with 12 markers), pins (7 with 11), and ink (4 with 5). Histopathological evaluation was not hindered by marker use. In this pilot study the last 6 ER specimens yielded 9/14 matches demonstrating a clear learning curve due to methodological improvements in marker placement and tissue block sectioning. Conclusion: One-to-one correlation of VLE and histology is complex but feasible. The groundwork laid in this study will provide high-quality histology-VLE correlations that will allow further research on VLE structures and VLE features of early neoplasia in BE.

Tu1067 In-Class Didactic vs. Self-Directed Teaching Probe-Based Confocal Laser Endomicroscopy (pCLE) Criteria for Barrett's Esophagus (BE); A Randomized Controlled Trial

Background: With the advent of advanced imaging techniques like pCLE, education and teaching of criteria for disease recognition is critical; however, optimal training methods are unclear. Aim: To compare in-class didactic vs. self-directed teaching in diagnosing dysplastic and non-dysplastic BE using pCLE. Methods: pCLE videos from a previously conducted multicenter trial evaluating the utility of pCLE in BE patients were used for this study. Study participants (gastroenterology fellows and medical students) with no previous pCLE experience were randomized to in-class didactic teaching and self-directed teaching groups

Perception of High Esophageal Cancer (EC) Risk is Associated With Decreased Quality of Life (QOL) in Patients With Barrett's Esophagus (BE)

visible lesions, 3) patients with HGD/EAC, and 4) number of HGD/EAC areas Methods: Data from a prospective, multi-center, randomized controlled trial evaluating the role of novel imaging techniques [High Definition White Light Endoscopy (HD-WLE), narrow band imaging (NBI), and probe based confocal endomicroscopy (pCLE)] were reviewed. As part of the protocol, coordinators at each study site recorded the time spent inspecting the BE mucosa using HD-WLE (Olympus 180 HD, with clear cap, no magnification) using a stop watch prior to biopsies being obtained. All visible lesions were described using the Paris classification system. To determine each patients final histologic diagnosis, every patient was examined with HD-WLE, NBI, and pCLE. All suspicious areas as well as four quadrant random locations were biopsied then reviewed by a central pathologist. Fishers exact test and an unpaired t-test were used to compare categorical and continuous variables, respectively. Results: 112 patients (mean age 65.5; 83.9% men, 100% Caucasian) with a mean BE length of 3.7cm were enrolled. The mean BIT with HD-WLE was 3.8min (SD 2.5min). 57 patients had a visible lesion seen on HD-WLE examination and 38 patients had a final diagnosis of HGD/EAC. Patients with a BIT with HD-WLE < 5 min were less likely to have a visible lesion (32.4% vs. 82.9%, p<0.001) and less likely to have a final diagnosis of HGD/ EAC (22.5% vs. 53.7%, p=0.002) compared to patients with a BIT ≥ 5 min. In addition, patients with a BIT of < 5 min had fewer visible lesions (0.51 vs. 1.95, p<0.0001) and fewer areas with HGD/Ca (0.51 vs. 2.29, p=0.004). This was despite no significant difference in mean BE length between patients with BIT < 5 and ≥ 5 min (3.3cm vs. 4.4cm, p=0.11). When patients with Paris I and III lesions were excluded, patients with a BIT < 5 minutes were still less likely to have a visible lesion (29.4% vs. 79.4%, p<0.001) less likely to have a final diagnosis of HGD/EAC (19.1% vs. 50.0%, p=0.002), had fewer visible lesions (0.43 vs. 1.82, p<0.0001), and had fewer areas with HGD/EAC (0.45 vs. 1.91, p=0.003). Conclusion: A longer inspection time of the BE mucosa is associated with a higher rate of detection of endoscopically visible lesions, patients with HGD/EAC, and areas with HGD/EAC. Endoscopists practicing BE surveillance should spend on average approximately 1 min per cm of BE using HD-WLE prior to obtaining biopsies.