Nondysplastic Barrett's Esophagus Research Articles

The Amsterdam ReBus progressor cohort: identification of 165 Barrett's surveillance patients who progressed to early neoplasia and 723 nonprogressor patients.

Patient selection is suboptimal in most studies focused on identifying biological markers for neoplastic progression in Barrett's esophagus (BE). This study aims to describe a stringently selected community-based case-control cohort of non-dysplastic BE (NDBE) patients who progressed to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) and BE patients who never progressed to be used for future biomarker studies. We identified all patients referred for endoscopic work-up of BE neoplasia at three tertiary referral centers for treatment of BE neoplasia between 2000 and 2013. We performed a detailed registration of any endoscopic surveillance history before neoplastic progression. Controls were selected from a retrospective BE surveillance registration in 10 community hospitals. A total of 887 patients were referred for endoscopic work-up of BE neoplasia. Based on predefined selection criteria, we identified 165 progressor patients (82% men; mean age 55 years ± 10.4) with a baseline endoscopy demonstrating NDBE > 2 years before neoplastic progression. Using the same predefined selection criteria, 723 nonprogressor patients (67% men; mean age 57 years ± 11.3) with >2 years of endoscopic surveillance were identified. Median length of the BE segment was 5 cm (IQR 4-7) in progressors and 4 cm (IQR 2-6) in controls. Median duration of surveillance was 89 months (IQR 54-139) in progressors and 76 months (IQR 47-116) in nonprogressors. Paraffin embedded biopsies are available for biomarker research in all patients. Ethical approval was obtained and material transfer agreements were signed with all 58 contributing pathology labs. This is the largest community-based case-control cohort of BE patients with and without progression to early neoplasia. The stringent selection criteria and the availability of paraffin embedded biopsy specimens make this a unique cohort for biomarker studies.

A systematic review of epigenetic biomarkers in progression from non-dysplastic Barrett’s oesophagus to oesophageal adenocarcinoma

ObjectivesThe objective of this systematic review is to identify and summarise studies which examine epigenetic biomarkers in patients with Barrett’s oesophagus (BO) and their association with progression to oesophageal adenocarcinoma...

Su1118 APPEARANCE OR PROGRESSION OF DYSPLASIA AND CANCER IN BARRETT’S ESOPHAGUS UNDERGOING RADIOFREQUENCY ABLATION

Barrett’s esophagus (BE) is a known risk factor for esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) has been associated with a high rate of complete eradication for dysplasia and intestinal metaplasia. Data are limited on patients who have progression of dysplasia or development of EAC while undergoing RFA therapy. We aimed to better characterize these patients. This was a retrospective review of medical records at a tertiary academic medical center. We included patients with at least one RFA treatment for BE without EAC. Patients achieving complete eradication of dysplasia were excluded. Data collected included demographics, date of BE diagnosis, endoscopy findings, anatomic pathology, location of the newly developed dysplasia, length of BE, RFA adjuvant therapies, and date of death. A total of 475 patients underwent RFA, of which 39 (8.2%) progressed to low grade dysplasia (LGD), high grade dysplasia (HGD) or EAC while undergoing therapy. The distribution of these changes is depicted in Table 1. Only 1 patient was female. Patient demographic data is found in Table 2. For those with HGD receiving RFA, 12.6% progressed into cancer. The majority of cancer developed in the distal esophagus (13/23 = 56.5 %). Seven patients (30.4 %) had their original HGD distributed over the entire BE segment prior to initial RFA. The progression was observed after an average of 3.0 RFA sessions. Twenty patients had endoscopic mucosal resection (EMR) and 2 had esophagectomy. Four (17.4 %) patients died. Eight patients achieved complete remission of intestinal metaplasia. For those who underwent RFA for LGD, 6 patients progressed to cancer and 6 to HGD. The rate of progression into cancer was significantly lower (5.1%) than those undergoing treatment for HGD (12.6%) (p= 0.04). The average number of RFA sessions before progression was 2.6. All 6 developed cancer in the distal BE segment and 5 of these patients had original low grade dysplasia in the distal BE segment. All 6 patients received adjuvant EMR and 2 esophagectomy. Two of these patients died. The 2 patients with short segment BE (2cm and 2.75 cm) progressed to cancer. Of the 4 patients with non-dysplastic Barrett’s who progressed while receiving RFA, the dysplasia appeared in the distal BE segment in 2, in the proximal in 1 and in the mid distal in 1. One patient developed cancer, but ultimately achieved complete remission of intestinal metaplasia. Our study shows that 8.2% of patients receiving RFA for BE have progression of dysplasia or development of cancer. Those at highest risk for progression are patients initially treated for HGD with 12.6% progressing to cancer after an average of 3.0 RFA sessions. Further studies are needed to determine why this progression occurred and how it can be avoided.Tabled 1Table 1. Number of patients with progression of dysplasia or progression to cancer based on initial indication for RFA therapy.Progression to:RFA for NDBE/ID (175)RFA for LGD (117)RFA for HGD (183)Indefinite DysplasiaLow grade Dysplasia1High Grade Dysplasia26Cancer16*23*Total4 (2.3%)12 (10.3%)23 (12.6%)Abbreviations: non-dysplastic Barrett’s esophagus (NDBE), indefinite dysplasia (ID), low grade dysplasia (LGD), high grade dysplasia (HGD). *P = 0.04 for progression into cancer between LGD and HGD groups Open table in a new tab Tabled 1Table 2. Characteristics of patients who had progression of dysplasia or development of cancer after RFA.RFA for NDBE/IDRFA for LGDRFA for HGDMean Age First Dysplasia or Mean Age First BE for NDBE (Range)64.5 (60-74)68.5 (54-78)72.3 (52-84)Mean Age Diagnosis Highest Progression (Range)68.5 (61-76)71.6 (57-81)74.2 (52-82)Mean Length BE Segment cm (Range)3.8 (2-5)7.0 (2-17)7.0 (1-14)Mean Number RFA Sessions Before Progression (Range)2.0 (1-3)2.6 (1-5)3.0 (1-11)Original Site of Dysplasia in Barrett’s Segment Before RFANAProximal11Proximal Mid10Mid04Mid Distal11Distal67Entire27Unknown13Site of Progression In EsophagusProximal124Proximal Mid003Mid023Mid Distal110Distal2713Adjuvant TherapyEMR2720ESD001Chemo-radiation002Brachytherapy002Esophagectomy022Cryotherapy123Radiation001Rate of CRIM128Deaths114Abbreviations: non-dysplastic Barrett’s esophagus (NDBE), indefinite dysplasia (ID), low grade dysplasia (LGD), high grade dysplasia (HGD), not applicable (NA), complete remission of intestinal metaplasia (CRIM). Open table in a new tab

Tu1140 REGIONAL VARIATIONS AND TRENDS IN QUALITY INDICATOR (QI) PERFORMANCE IN BARRETT’S ESOPHAGUS (BE): RESULTS FROM A POPULATION-BASED STUDY USING A NATIONAL BENCHMARKING REGISTRY

QIs in BE have been defined with the goal of improving patient outcomes. While adherence to the Seattle biopsy protocol (4-quadrant q2 cm) and surveillance intervals in non-dysplastic BE patients (NDBE) of 3-5 yrs are proposed QIs, population-based data addressing regional variations are not available. Using a national benchmarking clinical registry, to evaluate regional variation in adherence to the Seattle biopsy protocol and adherence to recommended surveillance intervals in NDBE and low-grade dysplasia (LGD). We analyzed data from the GI Quality Improvement Consortium (GIQuIC) Registry, a national data repository of endoscopy quality measures. Upper endoscopy data include procedure indication, demographics, endoscopy findings, and pathology results. EGD records from 1/2012-9/2017 were assessed. Patients (pts) with an indication of BE screening or surveillance, or an endoscopic finding of BE, were included. Adherence to Seattle protocol was defined by dividing the BE length by number of pathology jars, with a ratio of ≤2.0 with rounding down (lenient definition) or rounding up (stringent definition) for odd BE lengths considered adherent. Adherence to surveillance for NDBE was calculated as the proportion recommended to undergo EGD between 3-5 yrs (non-adherent if EGD recommended at 3 months–2 yrs from the index EGD) for NDBE and the proportion recommended an EGD at ≤1 year for LGD. Cochran-Armitage test for trend was applied to detect improvement in adherence. 786,712 EGDs were assessed, and 58,709 (7.5%) EGDs in 53,541 pts met inclusion criteria [mean age 61.3 yrs (SD 12.6), 60.4% male, 90.2% Caucasian]. Majority of cases were performed by GIs (92.3%) with propofol (78.7%), and represented 263 practices nationwide and 1457 unique providers. Distribution of cases based on US census region was: Northeast (n=14735, 27.6%), South (n=16376, 30.7%), Midwest (n=10,068, 18.8%) and West (n=12,152, 22.8%). Mean BE length was 2.3 cm (SD 2.3). No significant regional variations were noted in demographics, proportion of pts undergoing biopsies and confirmed BE and BE pts diagnosed with dysplasia (Table 1). There are marked variations in adherence with Seattle protocol by region (Table 2), with the highest rates of adherence noted in the Northeast and the lowest in the Midwest. In time-trend analysis, there was an improvement in adherence rates in the Midwest and a decline in the South. Among NDBE pts, non-adherence rates with the 3-yr surveillance endoscopy threshold ranged from 24-33% with the highest rates in the Northeast (Table 2). Endoscopists in the Northeast are most likely to be compliant with adherence to the Seattle biopsy protocol, but least likely to be compliant with recommended surveillance intervals. Further research to understand the factors influencing non-adherence to guidelines is warranted.Tabled 1Table 1: Regional variations in patient demographics and endoscopy-based variablesVariableNortheastSouthMidwestWestOverallDemographics (patient-based)Mean age, yrs (SD)61.2 (12.6)61.5 (12.4)60.9 (13.0)61.4 (12.5)61.3 (12.6)Males (n,%)8772 (59.5%)9921 (60.6%)6188 (61.4%)7350 (60.4%)32,346 (60.4%)Caucasians (n,%)89.9%89.2%93.1%89.4%90.2%Endoscopy-based variablesGIs*13,198 (95.1%)15,406 (89.8%)9272 (91.7%)11,671 (93.6%)49,654 (92.3%)Propofol sedation6475 (83%)4775 (79.6%)3283 (65.1%)5686 (83%)20,264 (78.7%)Adverse event rate0.01%0.02%0.02%0.03%0.02%Mean BE length, cm, SD2.05 (1.97)2.4 (2.38)2.5 (2.46)2.3 (2.44)2.3 (2.3)Proportion of patients with biopsies (n, %)15,792 (97.3%)16,594 (92.7%)10,007 (90.3%)12,332 (92.9%)54,943 (93.6%)Confirmed BE (n, %)8413 (55%)8745 (54.9%)5709 (57.5%)7012 (56.8%)29,978 (55.8%)Pathology results (n, %)NDBE7311 (92.2%)7561 (91.7%)4782 (88.5%)6202 (92.7%)25,945 (91.5%)IND/LGD499 (6.3%)565 (6.8%)506 (9.3%)376 (5.6%)1951 (6.8%)HGD113 (1.4%)117 (1.4%)111 (2.1%)107 (1.6%)449 (1.6%) Open table in a new tab

Su1123 NEAR UNIVERSAL SUCCESS WITH MULTIMODAL ENDOTHERAPY FOR DYSPLASTIC LONG- AND ULTRALONG-SEGMENT BARRETT'S ESOPHAGUS

Radiofrequency ablation (RFA) and endoscopic mucosal resection (EMR) are established treatments for dysplastic Barrett's esophagus. Treatment of long segment and ultralong segment Barrett's esophagus (LSBE and ULSBE) with dysplasia or intramucosal carcinoma (IMC) may be associated with lower efficacy and higher complication rates. Although Barrett’s length is an independent predictor of neoplastic progression, there is limited literature regarding this high risk population. To determine the eradication rates, procedural burden and complication rates for patients with LSBE and ULSBE with low grade dysplasia (LGD), high grade dysplasia (HGD), or IMC treated at our center. We performed a retrospective analysis of patients who underwent endoscopic therapy for Barrett’s esophagus at the University of Washington between 2009 and 2014. Data on patient demographics, pathological diagnosis at entry, type of treatment, Barrett’s segment length, presence and size of hiatal hernia (HH), total number of treatment sessions, duration of follow up, and most recent pathology were collected. LSBE was defined as ≥3cm to <8cm and ULSBE as ≥8cm. Logistic regression analyses were used to identify clinical features that predicted treatment failure. A total of 378 patients were identified. After excluding patients with short segment BE (defined as <3cm), non-dysplastic BE, invasive adenocarcinoma and patients undergoing surveillance only, 31 cases of ULSBE and 69 cases of LSBE were included. Baseline demographics were similar in both groups (Table 1). Overall this was a high risk population but rates of dysplasia and IMC were similar between ULSBE vs LSBE: LGD (9.7% and 15.9%, p=0.4), HGD (54.8% and 62.3%, p=0.5) and IMC (35.5% and 21.7%, p=0.2). Complete remission of dysplasia (CRD), including IMC, was achieved in 92.9% of patients with ULSBE and 93.6% (p=0.9) of patients with LSBE. Complete remission of intestinal metaplasia (CRIM) was achieved in 71.4% vs 79.0% (p=0.4) for ULSBE and LSBE respectively. More treatments were required to achieve CRD in ULSBE compared to LSBE, and more treatments were required to achieve CRIM than CRD in both groups (Table 2). Complication rates were similar between groups, with strictures occurring at 22.6% and 21.7% (p=0.9) and bleeding at 32.3% and 31.9% (p=0.9) for ULSBE and LSBE, respectively. Recurrence of dysplasia and IM were similar between the two groups, over a mean follow up of 18 months. In this very high risk population we achieved near universal rates of CRD, and high rates of CRIM, with reasonable complication rates. Multimodal endotherapy is an effective strategy for treating dysplastic Barrett’s esophagus and IMC, even in ultra long segment, but requires repeated sessions for maximal efficacy. Even with successful treatment, ongoing surveillance is necessary.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Tu1126 - Risk of Progression of Non-Dysplastic Barrett's Esophagus (BE) by Length: A Systematic Review and Meta-Analysis

Tu1126 - Risk of Progression of Non-Dysplastic Barrett's Esophagus (BE) by Length: A Systematic Review and Meta-Analysis

95 - Over-Utilization of Repeat upper Endoscopy in Patients with Non-Dysplastic Barrett's Esophagus: A Population-Based Study Using a National Benchmarking Registry

95 - Over-Utilization of Repeat upper Endoscopy in Patients with Non-Dysplastic Barrett's Esophagus: A Population-Based Study Using a National Benchmarking Registry

Su1997 - Generation and Validation of New Confocal Laser Endomicroscopy Criteria for the Diagnosis of Low-Grade Dysplasia in Barrett's Esophagus

Introduction The diagnosis and interobserver agreement amongst pathologists for low-grade dysplasia in Barrett’s oesophagus (BO) is sub-optimal. Probe-based confocal laser endomicroscopy (pCLE) allows real-time histologic assessment of BO. pCLE criteria for high-grade dysplasia (HGD) are established, however criteria for low-grade dysplasia (LGD) are lacking. The aim of the study was to develop and validate novel diagnostic criteria for LGD in BO. Method In Phase I, one pathologist and one endoscopist expert in pCLE unblinded assessed 30 good quality pCLE videos (10 non-dysplastic BO, 10 LGD and 10 HGD) to identify criteria for LGD. These criteria were assessed blindly by these two investigators in an independent set of 25 videos (15 non-dysplastic BO and 10 LGD). Criteria with mean accuracy >80% and interobserver agreement κ >0.4 were taken forward. In Phase II, 6 endoscopists evaluated the criteria in an independent set of 37 videos (15 non-dysplastic BO and 22 LGD). The raters assessed each criterion separately and made an overall diagnosis. Sensitivity, specificity and interobserver agreement were calculated for each criterion and the overall diagnosis. A receiver operating characteristic (ROC) curve was constructed to evaluate the best cut-off to diagnose dysplasia. Results Of the initial set of 8 criteria, 6 achieved the agreement and accuracy thresholds in Phase I. These were: (1) dark non-round glands, (2) irregular gland shape, (3) lack of goblet cells, (4) variable degree of darkness with sharp cut-off, (5) variable cell size and (6) loss of nuclear polarity. In Phase II the interobserver agreement among the 6 endoscopists for the criteria ranged from fair (K=0.242; criterion 4) to substantial (K=0.637; criterion 2), with a substantial interobserver agreement for the overall diagnosis (κ=0.6). The best cut-off for LGD diagnosis was 3 positive criteria out of 6, which corresponded to a sensitivity and specificity of 81.6% and 67.6%, respectively and an area under the ROC curve of 0.860. The overall diagnosis had sensitivity and specificity of 77.2% and 72.2%, respectively an area under the ROC curve of 0.895. Conclusion We have developed and validated pCLE criteria for LGD in BO. The performance of these criteria compares favourably with the interobserver agreement among pathologists in a conventional histologic diagnosis. Disclosure of Interest None Declared

'Missed' oesophageal adenocarcinoma and high-grade dysplasia in Barrett's oesophagus patients: A large population-based study.

A systematic review suggests that 25% of oesophageal adenocarcinomas (OAC) are 'missed' at index endoscopy for Barrett's oesophagus (BO); however, this included few population-based studies and may be an overestimate. The objective of this article is to quantify the 'missed' rates of high-grade dysplasia (HGD) and OAC at index BO endoscopy. Patients from the Northern Ireland BO register diagnosed between 1993 and 2010 (n = 13,159) were linked to the Northern Ireland Cancer Registry to identify patients who developed OAC or HGD. Logistic regression analysis compared characteristics of 'missed' vs 'incident' HGD/OAC, defined as diagnoses within 3-12 months vs >1 year after incident BO, respectively. A total of 267 patients were diagnosed with HGD/OAC ≥3 months after BO diagnosis, of whom 34 (12.7%) were potentially 'missed'. The proportion of 'missed' HGD/OAC was 25% among BO patients with low-grade dysplasia (LGD) and 9% among non-dysplastic BO patients. Older age and BO-LGD carried a higher risk of 'missed' HGD/OAC. Non-dysplastic BO patients were more often diagnosed with a 'missed' OAC (rather than HGD; 89%), compared with BO-LGD patients (40%). Approximately one in 10 HGD/OAC cases are 'missed' at incident BO diagnosis, which is significant but lower than previous reports. However, 'missed' HGD/OAC cases represent only 0.26% of all BO patients.

Biomarkers of Barrett's Esophagus: From the Laboratory to Clinical Practice.

The currently recommended approach to managing cancer risk for patients with Barrett's esophagus is endoscopic surveillance including a biopsy protocol to sample the esophageal tissue randomly to detect dysplasia. However, there are numerous limitations in this practice that rely on the histopathological grading of dysplasia alone to make clinical decisions. The availability of in silico models demonstrating the potential cost-effectiveness of biomarker-based stratification has increased interest in finding a clinically relevant "Barrett's biomarker." The success of endoscopic eradication therapy in preventing neoplastic progression of dysplastic Barrett's esophagus has promoted the desire to stratify non-dysplastic Barrett's esophagus to those with "high risk" that may benefit from endotherapy. Furthermore, on the other end of the spectrum, there is interest in searching for a "low risk" marker that may identify those that would not likely benefit from endoscopy screening or surveillance. This review highlights recent data from the genomics (r)evolution revealing new genetic biomarkers of susceptibility to the development of Barrett's esophagus and novel pathways for its neoplastic progression, addresses the development of new modes of tissue sampling and imaging to detect early neoplasia in Barrett's esophagus, and discusses current progress in moving biomarkers from the laboratory into clinical practice in the era of precision medicine.

Development of Evidence-Based Surveillance Intervals After Radiofrequency Ablation of Barrett’s Esophagus

Barrett's esophagus (BE) recurs in 25% or more of patients treated successfully with radiofrequency ablation (RFA), so surveillance endoscopy is recommended after complete eradication of intestinal metaplasia (CEIM). The frequency of surveillance is informed only by expert opinion. We aimed to model the incidence of neoplastic recurrence, validate the model in an independent cohort, and propose evidence-based surveillance intervals. We collected data from the United States Radiofrequency Ablation Registry (US RFA, 2004-2013) and the United Kingdom National Halo Registry (UK NHR, 2007-2015) to build and validate models to predict the incidence of neoplasia recurrence after initially successful RFA. We developed 3 categories of risk and modeled intervals to yield 0.1% risk of recurrence with invasive adenocarcinoma. We fit Cox proportional hazards models assessing discrimination by Cstatistic and 95% confidence limits. The incidence of neoplastic recurrence was associated with most severe histologic grade before CEIM, age, endoscopic mucosal resection, sex, and baseline BE segment length. In multivariate analysis, a model based solely on most severe pre-CEIM histology predicted neoplastic recurrence with a C statistic of 0.892 (95% confidence limit, 0.863-0.921) in the US RFA registry. This model also performed well when we used data from the UK NHR. Our model divided patients into 3 risk groups based on baseline histologic grade: non-dysplastic BE; indefinite for dysplasia, low-grade dysplasia, and high-grade dysplasia; or intramucosal adenocarcinoma. For patients with low-grade dysplasia, we propose surveillance endoscopy at 1 and 3 years after CEIM; for patients with high-grade dysplasia or intramucosal adenocarcinoma, we propose surveillance endoscopy at 0.25, 0.5, and 1 year after CEIM, then annually. In analyses of data from the US RFA and UK NHR for BE, a much-attenuated schedule of surveillance endoscopy would provide protection from invasive adenocarcinoma. Adherence to the recommended surveillance intervals could decrease the number of endoscopies performed yet identify unresectable cancers at rates less than 1/1000 endoscopies.

Validation of a biomarker panel in Barrett's esophagus to predict progression to esophageal adenocarcinoma.

In a prior study, baseline mutational load (ML) predicted progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in Barrett's esophagus (BE) with an area under the curve (AUC) of 0.95. We aimed to validate the test characteristics of this predictive biomarker panel using crude DNA lysates in a larger well-characterized cohort. We performed a nested case-control study of BE patients from three tertiary referral centers in the Netherlands. Cases had baseline nondysplastic BE (NDBE) and developed HGD/EAC≥2 years later. Controls were matched 2:1, had baseline NDBE, and no progression. Polymerase chain reaction (PCR)-based mutational analysis was performed on crude lysates from formalin-fixed, paraffin-embedded tissue. ML was calculated from loss of heterozygosity (LOH) and microsatellite instability (MSI) at 10 genomic loci. Receiver operator characteristic (ROC) curves were created to assess the diagnostic utility of various cutoffs of ML for progression. Of 159 subjects, 58 were progressors and 101 were nonprogressors, there was no difference in mean ML in preprogression tissue in progressors and nonprogressors (ML=0.73±0.69 vs. ML=0.74±0.61, P=0.93). ROC curves showed poor discrimination of ML in predicting progression with AUC of 0.50 at ML≥1. AUC did not vary with different ML cut-points. The utility of the ML to stratify BE patients for risk of progression was not confirmed in this study. The etiology for discrepancies between this and prior studies showing high predictiveness is likely due to the use of crude lysates in this study, but requires further investigation.

Predicting Progression in Barrett's Esophagus: Development and Validation of the Barrett's Esophagus Assessment of Risk Score (BEAR Score).

To develop and validate a scoring tool capable of accurately predicting which patients with Barrett's esophagus (BE) will progress to dysplasia and/or esophageal adenocarcinoma. Endoscopic therapies have emerged capable of eradicating BE with high efficacy and low complication rates, but which patients should receive treatment is still debated. Current knowledge of risk factors is insufficient to allow for the accurate prediction of which patients will progress to dysplasia or adenocarcinoma. We retrospectively collected data from a cohort of BE patients over a 13-year period. A multivariable logistic regression model was constructed to predict progression. A simplified risk of progression (ROP) score was developed from weighted beta coefficients. Internal validation was performed using bootstrap analysis, and model discrimination was assessed using k-fold cross-validation. The cohort included 2591 BE patients of which 133 progressed to dysplasia/adenocarcinoma. Multivariable analysis with bootstrap internal validation resulted in 5 variables associated with an increased ROP (age ≥70 years, male sex, lack of proton-pump inhibitor use, segment greater than 3 cm, and history of esophageal candidiasis). Using this model, we developed a simple ROP score between 0 and 8. Receiver operating characteristic analysis showed a cutoff of 3 or higher to have a sensitivity and specificity of 70% and 79%, respectively. Patients with a score of 3 or higher had an odds ratio of 9.04 (95% confidence interval 6.06-13.46). The c-statistic obtained from 10-fold cross-validation was 0.76 (95% confidence interval 0.72-0.79), indicating good overall discrimination. Our data show the development and internal validation of the Barrett's Esophagus Assessment of Risk Score as capable of quantifying the likelihood of progression to dysplasia/adenocarcinoma. The Barrett's Esophagus Assessment of Risk Score can be used clinically to guide treatment decisions in nondysplastic BE patients.

Low Incidence of Esophageal Adenocarcinoma After Eradication of Helicobacter pylori in Japan

Low Incidence of Esophageal Adenocarcinoma After Eradication of Helicobacter pylori in Japan

Adherence to Surveillance Guidelines in Nondysplastic Barrett's Esophagus.

Surveillance patterns in Barrett's esophagus (BE) are not well characterized. Guidelines published between 2002 and 2008 recommended surveillance esophagogastroduodenoscopy (sEGD) at 3-year intervals for nondysplastic BE (NDBE). We assessed guideline adherence in incident NDBE in a Veterans Affairs (VA)-based study. At a single VA center, we identified incident cases of biopsy-confirmed NDBE between January, 2006 and December, 2008. We excluded patients aged 76 years and above and those who developed BE-associated dysplasia or cancer during follow-up. All sEGDs through October, 2014 were documented. Our primary criteria classified cases as guideline adherent if a sEGD was performed within 6 months of each expected 3-year surveillance interval; in cases with ≥2 sEGDs, 1 sEGD >6 months, and ≤1 year outside an interval was allowed if the average interval was between 2.5 and 3.5 years. Comorbidity, primary care encounters, presence of long-segment BE (LSBE), endoscopist recommendations, and Charlson comorbidity index (CCI) were assessed. We identified 110 patients (96.4% male, 93.6% white) with mean age 58.9±8.5 years at index EGD. Median follow-up was 6.7 years (range, 3.7 to 8.6). Thirty-three (30.0%) cases were guideline adherent; 77 (70.0%) cases were nonadherent, including 52 (47.3%) with irregular surveillance and 25 (22.7%) with no surveillance. Forty cases (14 adherent) had 1 sEGD, 36 (18 adherent) had 2, 8 (1 adherent) had 3, and 1 nonadherent case had 4. Adherent cases were significantly older (61.5 vs. 57.9 y, P=0.04), and tended to have more LSBE (33.3% vs. 20.8%, P=0.16). There were no differences between adherent and nonadherent cases in annual primary care encounters (72.7% vs. 66.2%, P=0.66), CCI≥4 (15.2% vs. 15.6%, P=0.95), biopsy-positive sEGDs (75.8% vs. 76.6%, P=0.92), and any recommendation for subsequent surveillance (81.8% vs. 77.9%, P=0.65). A logistic regression model using age, CCI, and LSBE showed an independent association between adherence and older age (P=0.03). In a single-center VA cohort, sEGD of NDBE was mostly nonadherent to guidelines. Adherent cases were older at baseline with a trend toward more LSBE. A larger study is needed to identify medical and social factors associated with adherence or nonadherence to surveillance.

Substantial Interobserver Agreement in the Diagnosis of Dysplasia in Barrett Esophagus Upon Review of a Patient's Entire Set of Biopsies.

The pathologic diagnosis of dysplasia in Barrett esophagus (BE) suffers from interobserver disagreement. Many of the studies demonstrating disagreement in the diagnosis of dysplasia have pathologists review individual biopsy slides in isolation. To more closely mimic daily practice, 3 pathologists reviewed hematoxylin and eosin slides made from 549 individual biopsy jars obtained from 129 unique patients with a diagnosis of BE. Each pathologist reviewed the entirety of a given patient's biopsy material. The grade of dysplasia present in each biopsy jar was given as well as an overall highest grade of dysplasia from the patient's entire set of biopsies. The interobserver agreement in the diagnosis of dysplasia per biopsy jar and per patient's set of biopsies was measured by Fleiss κ statistic for multiple raters. The κ values for each diagnosis was higher in the per patient analysis compared with the per biopsy jar analysis indicating that pathologists are more likely to agree on the overall grade of dysplasia compared with the grade in an individual biopsy jar. In the per patient analysis, the interobserver agreement in the diagnosis of nondysplastic BE and high-grade dysplasia were substantial (κ=0.66; 95% confidence interval [CI], 0.56-0.76 and κ=0.76; 95% CI, 0.66-0.86, respectively). The interobserver agreement in the diagnosis of low-grade dysplasia (LGD) was fair (κ=0.31; 95% CI, 0.21-0.42). When LGD and high-grade dysplasia were collapsed into 1 category of positive for dysplasia, the interobserver agreement in the per patient analysis remained substantial (κ=0.70; 95% CI, 0.60-0.80), suggesting that much of the disagreement in LGD is not due to lack of recognition of dysplastic Barrett's mucosa, but rather the degree of dysplasia. These results indicate that pathologists can reliably distinguish between nondysplastic BE and dysplastic BE when a patient's entire set of biopsies is reviewed as a group. When second opinions are obtained, all available slides from that endoscopic procedure should be sent for review.

Adherence to quality indicators and surveillance guidelines in the management of Barrett's esophagus: a retrospective analysis.

Background Adherence to quality indicators and surveillance guidelines in the management of Barrett’s esophagus (BE) promotes high-quality, cost-effective care. The aims of this study were (1) to evaluate adherence to standardized classification (Prague Criteria) and systematic (four-quadrant) biopsy protocol, (2) to identify predictors of practice patterns, and (3) to assess adherence to surveillance guidelines for non-dysplastic BE (NDBE). Methods This was a single-center retrospective study of esophagogastroduodenoscopy (EGD) performed for BE (June 2008 to December 2015). Patient demographics, procedure characteristics, and histology results were obtained from the procedure report-generating database and chart review. Adherence to Prague Criteria and systematic biopsies was based on operative report documentation. Multiple logistic regression analysis was performed to identify predictors of practice patterns. Guideline adherent surveillance EGD was defined as those performed within 6 months of the recommended 3- to 5-year interval. Results In total, 397 patients (66.5 % male; mean age 60.1 ± 12.5 years) had an index EGD during the study period. Adherence to Prague Criteria and systematic biopsies was 27.4 % and 24.1 %, respectively. Endoscopists who performed therapeutic interventions for BE were more likely to use the Prague Criteria (OR: 3.16; 95 %CI: 1.47 – 6.82; P < 0.01) than those who did not. Longer time in practice was positively associated with adherence to Prague Criteria (OR 1.07; 95 %CI: 1.02 – 1.12; P < 0.01) but with a lower likelihood of performing systematic biopsies (OR 0.91; 95 %CI: 0.85 – 0.97; P < 0.01). More than half (55.6 %) of patients with NDBE underwent surveillance EGD sooner (range 1 – 29 months) than the recommended interval. Conclusion Adherence to quality indicators and surveillance guidelines in BE is low. Operator characteristics, including experience with endoscopic therapy for BE and time in practice predicted practice pattern. Future efforts are needed to reduce variability in practice and promote high-value care.

Improved diagnostic stratification of digitised Barrett's oesophagus biopsies by p53 immunohistochemical staining.

Interobserver agreement for dysplasia in Barrett's oesophagus (BO) is low, and guidelines advise expert review of dysplastic cases. The aim of this study was to assess the added value of p53 immunohistochemistry (IHC) for the homogeneity within a group of dedicated gastrointestinal (GI) pathologists. Sixty-single haematoxylin and eosin (HE) slide referral BO cases [20 low-grade dysplasia (LGD); 20 high-grade dysplasia (HGD); and 20 non-dysplastic BO reference cases] were digitalised and independently assessed twice in random order by 10 dedicated GI pathologists. After a 'wash-out' period, cases were reassessed with the addition of a corresponding p53 IHC slide. Outcomes were: (i) proportion of 'indefinite for dysplasia' (IND) diagnoses; (ii) interobserver agreement; and (iii) diagnostic accuracy as compared with a consensus 'gold standard' diagnosis defined at an earlier stage by five core expert BO pathologists after their assessment of this case set. Addition of p53 IHC decreased the mean proportion of IND diagnoses from 10 of 60 to eight of 60 (P = 0.071). Mean interobserver agreement increased significantly from 0.45 to 0.57 (P = 0.0021). The mean diagnostic accuracy increased significantly from 72% to 82% (P = 0.0072) after p53 IHC addition. Addition of p53 IHC significantly improves the histological assessment of BO biopsies, even within a group of dedicated GI pathologists. It decreases the proportion of IND diagnoses, and increases interobserver agreement and diagnostic accuracy. This justifies the use of accessory p53 IHC within our upcoming national digital review panel for BO biopsy cases.

Use of Appropriate Surveillance for Patients With Nondysplastic Barrett’s Esophagus

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Guidelines recommend that patients with nondysplastic BE (NDBE) undergo surveillance endoscopy every 3-5 years. We aimed to identify factors associated with surveillance endoscopy of patients with NDBE and identify trends in appropriate surveillance endoscopy of NDBE at a large tertiary care center. We performed a retrospective analysis of data from a Barrett's Esophagus Registry, identifying patients with NDBE who underwent endoscopy in 2002 or later. We identified patients with NDBE and collected data on length of BE segment, esophageal lesions, demographic features, medications, histology findings, comorbidities, development of EAC, and dates of follow-up endoscopies. We defined appropriate surveillance as 3-5 years between 2nd and 3rd endoscopies, over-utilizers as patients who had less than 3 years between their 2nd and 3rd endoscopies, under-utilizers as patients who had more than 5 years between their 2nd and 3rdendoscopies; and never-surveilled as patients who never received a 2nd endoscopy. The primary outcomes were effects of patient factors, year, and referring providers on appropriateness of surveillance intervals. We identified 477 patients with NDBE. Only 15.9% had appropriate surveillance; 37.9% were over-utilizers 15.7% were under-utilizers and 30.4% were never surveilled. Patients were less likely to be over-surveilled if their primary care physician referred them for their 3rd endoscopy instead of a gastroenterologist (adjusted odds ratio, 0.51; 95% CI, 0.27-0.95). Male patients or those with an increased number of comorbidities were more likely to be under-surveilled or never-surveilled, whereas patients with long BE segment were more likely to be over-surveilled. In a retrospective analysis of data from a registry of patients with BE, we found that less than 16% receive appropriate surveillance for NDBE. A primary care provider in the same health system as the endoscopy clinic reduced risk of over-surveillance. This could reflect better coordination of care between specialists and primary care providers.

Immunohistochemical assessment of Survivin and Bcl3 expression as potential biomarkers for NF-κB activation in the Barrett metaplasia-dysplasia-adenocarcinoma sequence.

Non-dysplastic Barrett's oesophagus (NDBE) occurs as a consequence of an inflammatory response triggered through prolonged gastro-oesophageal reflux and it may precede the development of oesophageal adenocarcinoma. NF-κB activation as a result of the inflammatory response has been shown in NDBE, but the possible mechanism involved in the process is unknown. The aim of this study was to assess, using immunohistochemistry, Survivin and Bcl3 expression as potential biomarkers for NF-κB activation along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Survivin is an NF-κB-inducible anti-apoptotic protein, and Bcl3 is a negative regulator of NF-κB. There was progressive upregulation of Survivin expression along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Bcl3 expression was upregulated in non-dysplastic Barrett's oesophagus, low-grade, high-grade dysplasia and oesophageal adenocarcinoma when compared to squamous group. The study shows the differential expression of Bcl3 between the squamous and Barrett's stage, suggesting that Bcl3 could be a surrogate marker for early event involving constitutive NF-κB activation. In addition, the study suggests that NF-κB activation may infer resistance to apoptosis through the expression of anti-apoptotic genes such as Survivin, which showed progressive increase in expression throughout the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. This ability to avoid apoptosis may underlie the persistence and malignant predisposition of Barrett's metaplasia.