Nondysplastic Barrett's Esophagus Research Articles

Comparative diagnostic performance of volumetric laser endomicroscopy and confocal laser endomicroscopy in the detection of dysplasia associated with Barrett’s esophagus

Probe-based confocal laser endomicroscopy (pCLE) and volumetric laser endomicroscopy (VLE) (also known as frequency domain optical coherence tomography) are advanced endoscopic imaging modalities that may be useful in the diagnosis of dysplasia associated with Barrett's esophagus (BE). We performed pCLE examination in ex-vivo EMR specimens and compared the diagnostic performance of using the current VLE scoring index (previously established as OCT-SI) and a novel VLE diagnostic algorithm (VLE-DA) for the detection of dysplasia. A total of 27 patients with BE enrolled in a surveillance program at a tertiary-care center underwent 50 clinically indicated EMRs that were imaged with VLE and pCLE and classified into neoplastic (N = 34; high-grade dysplasia, intramucosal adenocarcinoma) and nonneoplastic (N = 16; low-grade dysplasia, nondysplastic BE), based on histology. Image datasets (VLE, N = 50; pCLE, N = 50) were rated by 3 gastroenterologists trained in the established diagnostic criteria for each imaging modality as well as a new diagnostic algorithm for VLE derived from a training set that demonstrated association of specific VLE features with neoplasia. Sensitivity, specificity, and diagnostic accuracy were assessed for each imaging modality and diagnostic criteria. The sensitivity, specificity, and diagnostic accuracy of pCLE for detection of BE dysplasia was 76% (95% confidence interval [CI], 59-88), 79% (95% CI, 53-92), and 77% (95% CI, 72-82), respectively. The optimal diagnostic performance of OCT-SI showed a sensitivity of 70% (95% CI, 52-84), specificity of 60% (95% CI, 36-79), and diagnostic accuracy of 67%; (95% CI, 58-78). The use of the novel VLE-DA showed a sensitivity of 86% (95% CI, 69-96), specificity of 88% (95% CI, 60-99), and diagnostic accuracy of 87% (95% CI, 86-88). The diagnostic accuracy of using the new VLE-DA criteria was significantly superior to the current OCT-SI (P < .01). The use of a new VLE-DA showed enhanced diagnostic performance for detecting BE dysplasia ex vivo compared with the current OCT-SI. Further validation of this algorithm in vivo is warranted.

SOX2 as a novel marker to predict neoplastic progression in Barrett's esophagus.

The value of Barrett's esophagus (BE) surveillance based on the histological diagnosis of low-grade dysplasia (LGD) remains debated given the lack of adequate risk stratification. The aim of this study was to evaluate the predictive value (PV) of SOX2 expression for neoplastic progression in BE patients. We conducted a case-control study within a prospective cohort of 720 BE patients. Patients with neoplastic progression, defined as the development of high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), were classified as cases and patients without neoplastic progression were classified as controls. SOX2 expression was determined by immunohistochemistry in more than 12,000 biopsies from 635 patients; these results were combined with our previous p53 immunohistochemical data. Nondysplastic BE showed homogeneous nuclear staining for SOX2, whereas SOX2 was progressively lost in dysplastic BE. Loss of SOX2 was seen in only 2% of biopsy series without dysplasia, in contrast to 28% in LGD and 67% in HGD/EAC. Loss of SOX2 expression was associated with an increased risk of neoplastic progression in BE patients after adjusting for gender, age, BE length, and esophagitis (adjusted relative risk 4.8; 95% CI 3.2-7.0). The positive PV for neoplastic progression increased from 16% with LGD alone to 56% with concurrent loss of SOX2 and aberrant p53 expression. SOX2 expression is lost during transition from nondysplastic BE to HGD/EAC, and it is associated with an increased risk of neoplastic progression. The highest PV is achieved by concurrent loss of SOX2 and aberrant p53 expression in BE patients with LGD. The use of these markers has the potential to significantly improve risk stratification of Barrett surveillance.

Incidence of Esophageal Adenocarcinoma and Causes of Mortality After Radiofrequency Ablation of Barrett’s Esophagus

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. 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. 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. 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.

Analysis of Dysplasia in Patients With Barrett’s Esophagus Based on Expression Pattern of 90 Genes

Diagnoses of dysplasia, based on histologic analyses, dictate management decisions for patients with Barrett's esophagus (BE). However, there is much intra- and inter-observer variation in identification of dysplasia-particularly low-grade dysplasia. We aimed to identify a biomarker that could be used to assign patients with low-grade dysplasia to a low- or high-risk group. We performed a stringent histologic assessment of 150 frozen esophageal tissues samples collected from 4 centers in the United Kingdom (from 2000 through 2006). The following samples with homogeneous diagnoses were selected for gene expression profiling: 28 from patients with nondysplastic BE, 10 with low-grade dysplasia, 13with high-grade dysplasia (HGD), and 8 from patients with esophageal adenocarcinoma. A leave-one-out cross-validation analysis was used identify a gene expression signature associated with HGD vs nondysplastic BE. Functional pathways associated with gene signature sets were identified using the MetaCore analysis. Gene expression signature sets were validated using gene expression data on BE and esophageal adenocarcinoma accessed through National Center for Biotechnology Information Gene Expression Omnibus, as well as a separate set of samples (n=169) collected from patients who underwent endoscopy in the United Kingdom or the Netherlands and analyzed histologically. We identified an expression pattern of 90 genes that could separate nondysplastic BE tissues from those with HGD (P < .0001). Genes in a pathway regulated by retinoic acid-regulated nuclear protein made the largest contribution to this gene set (P < .0001); the transcription factor MYC regulated at least 30% of genes within the signature (P < .0001). In the National Center for Biotechnology Information Gene Expression Omnibus validation set, the signature separated nondysplastic BE samples from esophageal adenocarcinoma samples (P=.0012). In the UK and Netherlands validation cohort, the signature identified dysplastic tissues with an area under the curve value of 0.87(95% confidence interval: 0.82-0.93). Of samples with low-grade dysplasia (LGD), 64%were considered high risk according to the 90-gene signature; these patients had a higher rate of disease progression than those with a signature categorized as low risk (P=.047). We identified an expression pattern of 90 genes in esophageal tissues of patients with BE that was associated with low- or high-risk for disease progression. This pattern might be used in combination with histologic analysis of biopsy samples to stratify patients for treatment. It would be most beneficial for analysis of patients without definitive evidence of HGD but for whom early endoscopic intervention is warranted.

Adherence to WCRF/AICR lifestyle recommendations for cancer prevention and the risk of Barrett's esophagus onset and evolution to esophageal adenocarcinoma: results from a pilot study in a high-risk population.

While adherence to the World Cancer Research Fund (WCRF) guidelines on lifestyle and cancer was recently proven to be associated with an increased risk of esophageal cancer, no investigation has yet been carried out on its role on Barrett's esophagus (BE) development and its progression to esophageal adenocarcinoma (EAC). The primary aim of this study was to evaluate the role of adherence to WCRF lifestyle recommendations in BE onset and progression. The secondary aim was to investigate the association between disease progression and specific aspects of diet and lifestyle. Established risk factors for BE and EAC development and adherence to WCRF guidelines were assessed in 107 consecutive patients undergoing an upper gastrointestinal endoscopy for symptoms suggesting gastroesophageal reflux (GERD) and a suspected diagnosis of BE/dysplasia on BE. Patients were divided according to histology: those with GERD without metaplasia, with non-dysplastic BE, with low-grade dysplasia, with high-grade dysplasia or with early EAC. The four groups were expressed as an ordered categorical variable of disease progression. An ordered logit model was estimated to identify the independent predictors of disease progression. Adherence to WCRF guidelines was identified as independent protective factor (OR 0.51, 95% CI 0.37-0.67) of disease progression. Disease progression was associated with reduced adherence to guidelines on physical activity (from 48.2 to 5.3%, p=0.001), sedentary habits (from 33.3 to 0%, p=0.03), fruit consumption (from 37.0 to 5.6%, p=0.02) and processed meat consumption (from 51.9 to 10.5%, p=0.002). Adherence to WCRF guidelines has a protective factor in BE onset and its evolution to EAC.

Wnt/β-Catenin Signaling Activation beyond Robust Nuclear β-Catenin Accumulation in Nondysplastic Barrett’s Esophagus: Regulation via Dickkopf-1

INTRODUCTION: Wnt/β-catenin signaling activation has been reported only during the late steps of Barrett’s esophagus (BE) neoplastic progression, but not in BE metaplasia, based on the absence of nuclear β-catenin. However, β-catenin transcriptional activity has been recorded in absence of robust nuclear accumulation. Thus, we aimed to investigate the Wnt/β-catenin signaling in nondysplastic BE. METHODS: Esophageal tissues from healthy and BE patients without dysplasia were analyzed for Wnt target gene expression by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. Esophageal squamous (EPC1-& EPC2-hTERT), BE metaplastic (CP-A), and adenocarcinoma (OE33) cell lines were characterized for Wnt activation by qRT-PCR, Western blot, and luciferase assay. Wnt activity regulation was examined by using recombinant Wnt3a and Dickkopf-1 (Dkk1) as well as Dkk1 short interfering RNA. RESULTS: Wnt target genes (AXIN2, c-MYC, Cyclin D1, Dkk1) and Wnt3a were significantly upregulated in nondysplastic BE compared with squamous mucosa. Elevated levels of dephosphorylated β-catenin were detected in nondysplastic BE. Nuclear active β-catenin and TOPflash activity were increased in CP-A and OE33 cells compared with squamous cells. Wnt3a-mediated β-catenin signaling activation was abolished by Dkk1 in CP-A cells. TOPFlash activity was elevated following Dkk1 silencing in CP-A but not in OE33 cells. Dysplastic and esophageal adenocarcinoma tissues demonstrated further Dkk1 and AXIN2 overexpression. CONCLUSIONS: Despite the absence of robust nuclear accumulation, β-catenin is transcriptionally active in nondysplastic BE. Dkk1 overexpression regulates β-catenin signaling in BE metaplastic but not in adenocarcinoma cells, suggesting that early perturbation of Dkk1-mediated signaling suppression may contribute to BE malignant transformation.

Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study.

The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.

PTH-188 Is it more cost-effective to treat patients with non-dysplastic barrett’s oesophagus with aspirin and statins rather than to undertake endoscopic surveillance?: Abstract PTH-188 Table 1

Introduction Endoscopic surveillance and therapy with endoscopic mucosal resection and radio-frequency ablation have an established role in dysplasia in Barrett’s oesophagus (BO). However, the most cost-effective strategy in non-dysplastic BO remains uncertain. Aspirin and Statins are associated with a reduced risk of oesophageal adenocarcinoma. We have examined the cost-effectiveness of Aspirin and Statins without endoscopic surveillance in non-dysplastic BO in comparison with other potential strategies. Method A Markov model was created using a base population of 1,000 50-year old Caucasian males with non-dysplastic BO followed to 75 years of age. All subjects were assumed fit for oesophagectomy. Subjects on Aspirin and Statin therapy did not undergo surveillance and this cohort was compared with subjects undergoing endoscopic surveillance at 1, 2, 3, 4 and 5-yearly intervals with endoscopic therapy used to treat dysplasia. These cohorts were referenced to a base population who did not undergo surveillance and in whom the natural history was modelled. Cost-effectiveness was expressed as net amount per quality adjusted life year (QALY) and base-costs for treatment were obtained from the Department of Health HRG tariffs for 2014. Monte Carlo simulation and probabilistic sensitivity analysis were carried out. Results The most cost-effective strategy was 2-yearly surveillance of non-dysplastic BO with an average cost per subject of £5184, yielding 14.69 QALY and an ICER of 21763. Aspirin and Statin therapy without surveillance resulted in a cost of £1735 per subject and 14.23 QALY and was more cost-effective than no surveillance, due to an overall reduction in the incidence of dysplasia with Aspirin and Statins. However, a strategy of using Aspirin and Statins was not as cost-effective as 2-yearly, 3-yearly or 5-yearly surveillance with endoscopic therapy for dysplasia, due to the cost of palliation of incident advanced cancers in the Aspirin and Statin population (not undergoing surveillance). Conclusion Aspirin and Statin therapy in non-dysplastic BO is more cost-effective than no surveillance but is less cost-effective than endoscopic surveillance and therapy for incident dysplasia. The most cost-effective strategy for all patients for BO remains 2-yearly surveillance. Disclosure of interest None Declared.

PWE-183 Survivin expression increases in the progression to oesophageal adenocarcinoma

Introduction It has been postulated that the process of apoptosis leads to the development of neoplastic clones with prolonged survival. Survivin, an inhibitor of apoptosis, is an integral to this process. The primary aim of this study is to examine the expression of Survivin in the progression from Barrett’s Oesophagus (BO) to oesophageal adenocarcinoma (OAC). Method Endoscopic biopsies containing the relevant pathologies from 72 patients were immunostained for Survivin expression - normal squamous (Sq) 14, non-dysplastic BE (NDBE) 14, low-grade dysplasia (LGD) 17, high-grade dysplasia (HGD) 17 and oesophageal adenocarcinoma (OAC) 7. Survivin expression was scored by 2 expert GI pathologists using the Allred system (a score comprising both intensity and extent of staining) and analysed using one-way ANOVA with Bonferroni post-hoc analysis to examine the trend between the various groups in the upper GI sequence. Results Multivariate analysis using one-way ANOVA and Bonferroni post-hoc analysis showed a strongly significant increase in both intensity and extent of Survivin expression in the progression from squamous, through non dysplastic Barrett’s oesophagus, low-grade dysplasia, high-grade dysplasia and invasive adenocarcinoma (OAC) p Conclusion This study shows that Survivin expression follows a linear incremental up-regulation in the progression to OAC. This early up-regulation suggests increasingly prominent roles for apoptosis inhibition in this pathway. In addition, the results suggest that inhibitors of Survivin might play a role in the prevention of progression as well as the treatment of OAC. Disclosure of interest None Declared.

OC-040 First in-vivo study on the use of lectin-based molecular imaging in barrett’s oesophagus

Introduction The current standard for Barrett’s oesophagus (BO) endoscopic surveillance is based on random quadrantic biopsies every 2 cm. This is limited by sampling error due to inconspicuous dysplasia. We have previously found that an edible lectin (wheat germ agglutinin or WGA) has lower affinity for dysplastic compared to non-dysplastic BO and in an ex vivomodel of molecular imaging we showed that WGA-fluorescein in combination with autofluorescence imaging (AFI) can target dysplasia in BO (Bird-Lieberman, Nat Med, 2012). In this study we used a pre-operative setting to investigate in vivoWGA-based molecular imaging Method Inclusion criteria were: i. MDT referral to oesophagectomy for oesophageal adenocarcinoma (OAC) and ii.evidence of endoscopically visible BO associated to OAC on index endoscopy or staging endoscopic ultrasound. In the operating theatre prior to oesophagectomy, the oesophagus was first inspected by white light imaging to locate the tumour and measure the size of the associated BO. Imaging was then switched to AFI to locate AFI positive areas (red-purple colour). Up to two AFI negative areas (green colour) were also selected for control biopsy sampling. 20–30 mL of 5 µg/mL WGA-fluorescein were then sprayed onto the mucosal surface. After 5 min, the mucosa was gently washed with water and the oesophagus was inspected again in AFI mode. On WGA-enhanced AFI, areas of high WGA binding were located (WGA positive, green colour), as well as areas of low binding (WGA negative, red-purple and hence high risk). Targeted biopsies were taken for histopathological correlation. Histological outcome was binarised based on the presence or absence of dysplasia. Chi-squared test was used to compare diagnostic accuracy for dysplasia of AFI alone and WGA-enhanced AFI Results 16 patients were recruited at a single centre, of which 12 completed the protocol. 4 patients were excluded due to absence of visible BO associated with the OAC at the time of resection. Across the 12 patients a total of 41 endoscopic locations were selected for biopsy of which 29 were WGA negative and 12 were WGA positive. The overall sensitivity for dysplasia of AFI alone was 78% and the specificity was 50%. When compared to AFI alone, WGA improved sensitivity from 78% to 88%, with a slight increase in the specificity to 56%. AFI and WGA-enhanced AFI had an equal false positive rate (24%). No toxicity events where recorded. Conclusion WGA-based molecular imaging is safe and feasible in vivo. The use of WGA may improve the sensitivity of AFI for dysplasia, but larger studies in a surveillance population are required Disclosure of interest None Declared.

The Presence of Genetic Mutations at Key Loci Predicts Progression to Esophageal Adenocarcinoma in Barrett's Esophagus.

OBJECTIVES:Risk stratification in Barrett's esophagus (BE) is challenging. We evaluated the ability of a panel of genetic markers to predict progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC).METHODS:In this case–control study, we assessed a measure of genetic instability, the mutational load (ML), in predicting progression to HGD or EAC. Cases had nondysplastic BE or low-grade dysplasia (LGD) at baseline and developed HGD/EAC ≥1 year later. Controls were matched 2:1, had nondysplastic BE or LGD, and no progression at follow-up. Formalin-fixed, paraffin-embedded tissue was microdissected for the epithelium. Loss of heterozygosity (LOH) and microsatellite instability (MSI) were assessed. ML was calculated from derangements in 10 genomic loci. High-clonality LOH mutations were assigned a value of 1, low-clonality mutations were assigned a value of 0.5, and MSI 0.75 at the first loci, and 0.5 for additional loci. These values were summed to the ML. Receiver operator characteristic (ROC) curves were created.RESULTS:There were 69 patients (46 controls and 23 cases). Groups were similar in age, follow-up time, baseline histology, and the number of microdissected targets. Mean ML in pre-progression biopsies was higher in cases (2.21) than in controls (0.42; P<0.0001). Sensitivity was 100% at ML ≥0.5 and specificity was 96% at ML ≥1.5. Accuracy was highest at 89.9% for ML ≥1. ROC curves for ML ≥1 demonstrated an area under the curve (AUC) of 0.95.CONCLUSIONS:ML in pre-progression BE tissue predicts progression to HGD or EAC. Although further validation is necessary, ML may have utility as a biomarker in endoscopic surveillance of BE.

Yield of Repeat Endoscopy in Barrett's Esophagus with No Dysplasia and Low-Grade Dysplasia: A Population-Based Study.

The yield of early repeat endoscopy in patients with Barrett's esophagus (BE) is not well established. To determine how often early repeat endoscopy detected missed dysplasia or esophageal adenocarcinoma (EAC) in a population-based cohort of patients with BE. Secondary aims were to identify risk factors for missed dysplasia/EAC and compare detection of prevalent versus incident HGD/EAC. A population-based cohort of BE subjects in Olmsted County, MN, was studied. Patients with initial non-dysplastic BE or low-grade dysplasia (LGD) who underwent repeat endoscopy within 24 months were included. Those with a worse histologic diagnosis on repeat endoscopy were considered to have missed dysplasia/EAC. Baseline characteristics among patients with and without missed dysplasia/EAC were compared. The absolute numbers of asymptomatic prevalent or missed, and incident HGD/EAC in the entire cohort were ascertained. Of 488 BE cases, 210 were included for the primary aim of this study. Repeat endoscopy revealed four HGD/EAC (1.9 %) and 16 LGD (8.8 %) for a combined miss rate of 9.5 %. Long-segment BE (LSBE) and lack of PPI use were predictors of missed dysplasia/EAC (P = 0.008), but adherence to biopsy protocol was not. Increased prevalent HGD/EAC (n = 30) rather than incident HGD/EAC (n = 22) was identified during a median 4.8 years of follow-up in this cohort. Dysplasia/EAC is commonly missed at initial BE diagnosis, particularly in patients with LSBE and no PPI use. Efforts should be made to enhance the sensitivity of detecting dysplasia/neoplasia around the time of initial BE diagnosis.

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.

Tu1538 Relationship Between Baseline Histology and Recurrence Histology After Successful Endoscopic Ablation for Barrett's Esophagus

Tu1538 Relationship Between Baseline Histology and Recurrence Histology After Successful Endoscopic Ablation for Barrett’s Esophagus Karthik Ragunathan*, Rajesh Krishnamoorthi, Sairaman Nagarajan, Prasad G. Iyer Dept of Internal Medicine, University of Illinois College of medicine, Peoria, IL, Peoria, IL; Mayo Clinic, Rochester, MN; Harvard university, Boston, MA Background: Several studies have reported risk of recurrence of Barrett’s esophagus (BE) after achieving complete remission of intestinal metaplasia (CRIM) through endotherapy. Recurrence risk after CRIM in non-dysplastic BE (NDBE) subjects undergoing ablation versus those with LGD, HGD or IMC (dysplastic BE, D-BE) is unclear. Additionally, the relationship between baseline histology and recurrence histology has not been studied. We aimed to study these relationships through a systematic review and meta-analysis. Methods: We conducted a comprehensive search of multiple electronic databases and conference proceedings (from inception through July, 2014) to identify cohort studies reporting the recurrence of IM, dysplasia and/or esophageal adenocarcinoma (EAC) after CRIM following endotherapy for Barrett’s related neoplasia. We excluded studies which 1) with cohorts consisting of a combination of D-BE and NDBE patients, 2) did not report baseline and recurrence histology, and 3) did not report follow up duration after CRIM. Studies were categorised into Dysplastic group (low grade, high grade and/ or EAC) and Nondysplastic group based on baseline histology. Dysplastic recurrence (DR) was defined as recurrence of BE with dysplasia (LGD or HGD) or EAC after CRIM. Non Dysplastic recurrence (NDR)was defined as recurrence of BE without dysplasia after CRIM. Risk of dysplastic recurrence (RDR) was defined as difference between DR and NDR. Primary outcome was RDR in dysplastic and non-dysplastic groups. Results: A total of 12 studies were included with 7 studies in dysplastic group(118 recurrences in 676 patients with 1282.35 patient years of follow up) and 5 studies in nondysplastic group(39 recurrences in 360 patients with 2159.83 years of follow up).The pooled IR in the dysplastic and non-dysplastic group was 7.4 % per patient year (95% CI of 0.59-0.89) and was 0.7% per patient year(95% CI of 0.3-1.0) respectively. RDR in the dysplastic group and non dysplastic group was 0.04(95% CI -0.05 to 0.13) and -0.11(95%CI -0.14 to -0.07) respectively (Figure 1 and 2). Conclusion: Recurrence rates after endoscopic therapy in BE subjects with baseline dysplasia undergoing endoscopic therapy is about 10 times the rate in the NDBE patients. Given the higher rates of recurrence and possibility of dysplastic recurrence, D-BE patients should stay in long term surveillance after CRIM. Conversely, given the lower rates of recurrence and high likelihood of recurrence histology to be NDBE, surveillance intervals in NDBE patients could potentially be lengthened.

340 Proportion of Missed Cancer and High-grade Dysplasia During Barrett's Esophagus Diagnosis: a Systematic Review and Meta-Analysis

340 Proportion of Missed Cancer and High-grade Dysplasia During Barrett’s Esophagus Diagnosis: a Systematic Review and MetaAnalysis Kavel Visrodia*, Siddharth Singh, Rajesh Krishnamoorthi, Prasad G. Iyer, David A. Katzka Mayo Clinic Rochester, Rochester, MN Background: Esophageal adenocarcinoma (EAC) and/or high-grade dysplasia (HGD) detected within one year of Barrett’s esophagus (BE) diagnosis is considered prevalent disease and therefore likely to have been “missed” during the initial endoscopy. Recent large BE surveillance studies suggest a sizeable portion of all EAC/HGD is found within this timeframe. This stands in contrast to the emphasis on BE surveillance occurring years after diagnosis. Aim: We conducted a systematic review and meta-analysis comparing the proportion of missed vs incident EAC/HGD detected after a negative index exam (IE). Methods: We performed a systematic literature search of the PubMed, EMBASE, and Web of Science databases (August 2014) for studies reporting the timing of EAC/HGD development in patients with BE during a follow-up of R 2 years. Missed EAC/HGD was defined as those developing within 12 years of BE diagnosis, after a negative IE. Incident EAC/HGD was defined as those occurring after the timeframe used in each study to define missed EAC/HGD. Prevalent EAC/HGD was defined as those diagnosed at the time of IE, regardless of presence or absence of symptoms. Pooled estimates for proportions of missed vs incident EAC/HGD, and prevalent+missed vs incident EAC/HGD were calculated for all studies; sensitivity analysis was performed for studies with BE cohorts comprised of only patients with baseline non-dysplastic BE (NDBE) or low-grade dysplasia (LGD). Results: 53 studies met the inclusion criteria; 51 had a missed EAC/HGD cutoff% 12 months. Meta-analysis of 38 studies and 1,321 patients with EAC showed that after a negative IE, 1/3 were classified as having missed EAC (pooled prevalence, 33.5%; 95% CI, 27.5-40.5) and the remainder as having incident EAC. Results from analysis of 20 studies including 1,481 patients with EAC/HGD were identical (33.5%; 95% CI, 23.9-44.7). On restricting analysis to a subset of patients with NDBE or LGD, the proportions of missed EAC (26.4%; 95% CI, 16.1-40.0) or EAC/HGD (34.8%; 95% CI, 24.7-46.5) were slightly lower or similar, respectively. As expected, with increasing duration of follow-up, the proportion of all EAC classified as incident cases increased: 2-5 years (nZ20 studies): 39.0% vs 61.0%; 5-8 years (nZ12 studies): 26.7% vs 73.3%; O 8 years (nZ4 studies): 12.8% vs 87.2%. In studies reporting data on prevalent, missed, and incident EAC (nZ20 studies and 615 patients with EAC), the majority of EAC were classified as prevalent or missed (83.5%; 95% CI, 77.4-88.2) vs incident (16.5%, 95% CI, 11.8-22.6). Conclusions: One-fourth EAC and 1/3 EAC/ HGD detected during surveillance are potentially present and missed at the time of initial BE diagnosis. Therefore, efforts to improve detection of EAC/HGD at or soon after BE diagnosis should be increased and perhaps even shifted from long-term surveillance. Table 1A. Proportion of missed and incident EAC and EAC/HGD in all BE cohorts, independent of baseline grade of dysplasia www.giejournal Missed (% Missed+Incident EAC)

Tu1549 Perception of Risk and Management Among Patients With Barrett's Esophagus

Nondysplastic Barrett's esophagus (NDBE) carries a risk of progression to esophageal adenocarcinoma (EAC) as low as 0.3% per person per yr, and low grade dysplasia (LGD) as low as 0.5%. Decision-making regarding management options for those with Barrett's Esophagus (BE) varies. Little is known about patient perceptions of risk and decisions about management. The aim of this study is to identify factors that influence patient perceptions about risk and management regarding BE.

Su1715 Ultrahigh Speed Endoscopic Optical Coherence Tomography Angiography for Visualization of Subsurface Vasculature in Barrett's Esophagus and Dysplasia

Angiogenesis is associated with the neoplastic progression of Barrett's esophagus (BE). A statistically significant increase in microvasculature density has been observed in non-dysplastic BE (NDBE), BE with low grade dysplasia (LGD) and high grade dysplasia (HGD). Narrow banding imaging (NBI) and magnification NBI have been used to detect dysplasia. However, mag NBI has limited field of view and only visualizes the surface vascular pattern. Ultrahigh speed endoscopic optical coherence tomography (OCT) technology with precision micromotor scanning probes can acquire dense volumetric data enabling depth resolved en face OCT to visualize surface mucosal patterns.

Tu1537 Rapid Progression From LGD to HGD Barrett's - Myth or Reality

Low dysplasia (LGD) in Barrett's oesophagus (BO) has been considered to have only a modestly increased risk of progression compared to non-dysplastic BO. However, recent studies have suggested a much higher rate of progression in the community setting and that RFA may be indicated for all cases of Low grade dysplasia(LGD) Barrett's. Aim 1) To investigate natural history of LGD by comparing the referral scope with assessment scope done by a Barrett's specialist and review of external histology by an expert pathologist to determine rate of pathology upstage and downstage for diagnoses of LGD2) Determine rate of prevalent HGD/Cancer diagnosed by endoscopic assessment in expert center, for individuals with diagnosis of LGD in community3) Determine the true rate of progression in individuals with true LGD - following expert pathology review and endoscopic assessment.

423 Can In-Vivo Volumetric Laser Endomicroscopy Detect Barrett's Esophagus Dysplasia Missed on Surveillance Biopsies?

G A A b st ra ct s using VLE for surveillance of dysplasia associated with BE require the interpretation of large volumes of VLE image data by an expert to identify pathologies of interest. The main objective of the current study is to explore the feasibility of developing a diagnostic computer algorithm to assist in the interpretation of VLE image data. METHODS: Retrospective data analysis study. De-identified VLE images from the esophagus obtained with the NvisionVLE radial OCT system (NinePoint Medical, Cambridge, MA), along with their corresponding validated pathology classifications were used in the study. We used the discrete wavelet transform to analyze and characterize the local spatial distribution of gray levels in the VLE images. Three classification problems relevant to the current clinical use of VLE in BE were considered: distinguishing gastric cardia (GC) from BE (analogous to determining the location of the esophagogastric junction), normal squamous (NS) from BE (finding the top of the BE segment), and non-dysplastic BE (NDBE) from BE with dysplasia (BED). Features extracted from the wavelet components that were found to be statistically significant based on a 2sample t-test were used as inputs to a Naive Bayes classifier. Leave-one-out cross-validation was used to obtain performance estimates for each of the classification problems. RESULTS: A total of 60 images (18 from NS, 15 from NDBE, 14 from BED, and 13 from GC) from 38 patients were analyzed. Distinguishing GC from BE (NDBE as well as BED) resulted in per-class accuracies of 77% and 93% respectively. Distinguishing NS from BE resulted in per-class accuracies of 83% for both classes. A sensitivity of 86% and specificity of 93% were obtained when distinguishing NDBE from BED. CONCLUSION: Real-time identification of potential areas of dysplasia by VLE imaging can help to better target biopsies when compared to the standard protocol of random biopsies. Computer-assisted interpretation of VLE images may provide a novel approach to making objective, real-time assessments of pathologies relevant to dysplasia surveillance in BE. Our results offer promise for the feasibility of such an approach, where VLE images could be instantaneously analyzed and interpreted on-the-fly to guide endoscopic diagnosis and treatment.

Sa1070 Has High Grade Dysplasia in Barrett's Esophagus Changed Over the Last Decade?

Background: The overall risk of progression to esophageal adenocarcinoma (EAC) in BE subjects without dysplasia is lower than previously estimated. There is hence lack of consensus on the effectiveness of current surveillance programs. Stratification of risk of progression is appealing, as it may help identify BE patients at higher risk who can be monitored more intensively or offered endoscopic therapy. Though several studies have identified factors predicting progression, evidence on several clinically relevant risk factors influencing progression is not consistent. We aimed to identify the predictors of progression in BE subjects without high grade dysplasia by performing a systematic review and meta-analysis of relevant studies. Methods: A comprehensive search of several databases including PubMed, EMBASE, and Web of Science databases (earliest inception to July 28th, 2014) was performed and studies reporting outcomes of BE cohorts under surveillance were identified. We included studies that reported predictors of progression to HGD/ EAC as an outcome in patients with non-dysplastic BE (NDBE) and BE-low grade dysplasia (LGD). A pooled estimate (odds ratio) of the potential of age, sex, smoking, alcohol use, BMI, baseline LGD (vs NDBE), BE length, and medication use in predicting progression to HGD/EAC in NDBE/ LGD patients was calculated. Results: 23 studies reporting predictors of progression as an outcome were identified from the systematic review. 1231 events in 74943 patients in 204926.2 patient years of follow-up were analyzed. Table 1 shows the pooled odds ratio (OR) of predictors analyzed. Increasing age, male sex, ever smoking (current or past), and increasing BE segment length were predictive of increased risk of progression to HGD/EAC with low heterogeneity (9-13 studies). Patients with LGD had an almost four fold increased risk of progression compared to those with no dysplasia. NSAID and statin use were protective against progression to HGD/EAC without heterogeneity. Alcohol use and obesity as measured by BMI did not influence progression rates. Conclusion: Age, male sex, ever smoking (current or past), and BE length are predictive of increased risk of progression to HGD/ EAC. Subjects with baseline LGD are at 4 times increased risk of progression compared to those without dysplasia. These factors may be used to risk stratify BE subjects as part of a prediction score, to identify those who could potentially benefit from intensive surveillance or endoscopic therapy. Smoking is a modifiable risk factor for cancer prevention in BE subjects. Table 1: Pooled odds ratio (OR) of predictors of progression to HGD / EAC.