Nondysplastic Barrett's Esophagus Research Articles

Management of nondysplastic Barrett's esophagus: When to survey? When to ablate?

Barrett’s esophagus (BE), a precursor for esophageal adenocarcinoma (EAC), is defined as salmon-colored mucosa extending more than 1 cm proximal to the gastroesophageal junction with histological evidence of intestinal metaplasia. The actual risk of EAC in nondysplastic Barrett’s esophagus (NDBE) is low with an annual incidence of 0.3%. The mainstay in the management of NDBE is control of gastroesophageal reflux disease (GERD) along with enrollment in surveillance programs. The current recommendation for surveillance is four-quadrant biopsies every 2 cm (or 1 cm in known or suspected dysplasia) followed by biopsy of mucosal irregularity (nodules, ulcers, or other visible lesions) performed at 3- to 5-year intervals. Challenges to surveillance include missed cancers, suboptimal adherence to surveillance guidelines, and lack of strong evidence for efficacy. There is minimal role for endoscopic eradication therapy in NDBE. The role for enhanced imaging techniques, artificial intelligence, and risk prediction models using clinical data and molecular markers is evolving.

Retrospective, observational, cross-sectional study of detection of recurrent Barrett's esophagus and dysplasia in post-ablation patients with adjunctive use of wide-area transepithelial sample (WATS-3D).

BackgroundBarrett’s esophagus (BE) and dysplasia are often missed by Seattle protocol biopsies (SPB). Wide-area transepithelial sampling with 3-dimensional computer-assisted analysis (WATS-3D) with SPB improves detection in treatment-naïve patients. We aimed to determine to what extent WATS-3D adds to SPB in the detection of non-dysplastic BE (NDBE) and dysplasia in patients undergoing post-endoscopic eradication therapy (EET).MethodsThis retrospective, observational, cross-sectional study included patients who presented for post-EET surveillance with SPB and WATS-3D sampling from April 2019 to February 2020. BE patients with no previous EET were excluded. For the outcomes of NDBE and any dysplastic/neoplastic finding, we calculated both relative and absolute increases in yield by WATS-3D over SBP.ResultsIn 78 patients [mean age 68±10.4 years, 66 (84.6%) male], the prevalence of NDBE, any dysplastic/neoplastic finding, and any abnormality (NDBE or dysplasia/neoplasia) were 53.85%, 10.26%, and 55.13%. The absolute increase in yield of NDBE with WATS-3D over SPB was 26.9% (95% confidence interval [CI] 17.95-37.18%), with the number needed to treat (NNT) 3.71 (95%CI 2.69-5.57) and a relative increase in yield of 100% (95%CI 53.33-188.25%). For dysplasia/neoplasia, the absolute increase in yield was 6.4% (95%CI 1.28-12.82%), NNT 15.6 (95%CI 7.8-78.0), and relative increase of 167% (95%CI 33.33%-infinity). For any abnormal finding, the absolute increase in yield was 26.9% (95%CI 16.67-37.18%), NNT 3.71 (95%CI 2.69-6.00), and relative increase in yield 95% (95%CI 50-176.92%).ConclusionsWATS-3D with SPB improves the detection of residual/recurrent BE and dysplasia in post-ablation BE. However, randomized controlled trials are needed to validate these findings.

Diagnostic performance of volumetric laser endomicroscopy for Barrett's esophagus dysplasia amongst gastroenterology trainees.

Volumetric laser endomicroscopy (VLE) is an advanced imaging modality used in Barrett's esophagus (BE) surveillance. VLE image interpretation is challenged by subtle grayscale image variation across a large amount of data. Training in VLE interpretation is not standardized. This study aims to determine if VLE training can be incorporated into a gastroenterology (GI) fellowship curriculum with the use of a self-directed module. A standardized, self-directed training module (30 min) was created explaining the background and established VLE criteria for the diagnosis of BE dysplasia. A VLE image dataset was generated from a multicenter VLE database of targeted biopsies. GI trainees were asked to grade each image for the presence or absence of the following criteria (I) increased surface optical frequency domain imaging (OFDI) signal intensity and (II) atypical glands and provide a final diagnosis (dysplastic vs. non-dysplastic). Diagnostic performance was calculated and results compared to VLE expert interpretation using histology as the gold-standard. The dataset included 50 VLE images (10 high-grade dysplasia, 40 non-dysplastic BE). VLE images were reviewed in a randomized and blinded fashion by 5 GI trainees with no prior VLE experience and 5 experienced VLE users. Sensitivity, specificity and accuracy of GI trainees was 83.3% (95% CI: 71.5-91.7%), 59.0% (95% CI: 51.6-66.0%), and 64.8% (95% CI: 58.5-70.7%) compared to 80.0% (95% CI: 67.7-89.2%), 79.5% (95% CI: 73.0-85.0%), and 79.6% (95% CI: 74.1-84.4%) for VLE experts respectively. The difference in specificity and accuracy between the two groups were statistically significant with P<0.001. A brief training session on VLE is inadequate to reach competency in interpretation of VLE by GI trainees. Additional experience is required to accurately interpret VLE images.

Clonal Transitions and Phenotypic Evolution in Barrett’s Esophagus

Background & AimsBarrett’s esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression.MethodsUsing immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome.ResultsWe identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0–2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time.ConclusionsWe showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE.

P-OGC95 Understanding the molecular age of Barrett’s oesophagus in a population-representative sample of patients

Abstract Background The incidence of oesophageal adenocarcinoma (OAC) increases dramatically with patient age but only a small proportion of patients with diagnosed Barrett’s oesophagus (BO), the precursor to OAC, will develop dysplasia and/or cancer. Beyond chronological age, biomarkers of progression that capture biological aging offer largely untapped potential for objectively identifying BO patients at highest risk of progression, who could undergo personalised surveillance at shorter intervals. We have developed computational tools to determine tissue-specific aging using genome-wide methylation data as a “molecular clock” for estimating patient-specific BO dwell times at the time of incident diagnosis that cannot be clinically measured by other means. Methods Using the population-based Northern Ireland BO register in a retrospective study, we have identified 46 non-dysplastic BO patients who have 2-4 serial endoscopic biopsies each, and have not progressed to OAC (age range 29-77 years). FFPE biopsies for 10 age-matched patients who had prevalent HGD/OAC at index BO diagnosis were also retrieved. DNA has been extracted, quantified using fluorescence, quality checked through qPCR, and prepared for Illumina EPIC methylation arrays. We created a Python package called “MethylDrift” to determine genome-wide aging rates in patient data. Model outputs are used in the molecular clock for BO tissue age. Results We used MethylDrift to quantify aging rates in both cross-sectional data (population-level epigenetic drift) and longitudinal data within the same patients to obtain individual aging rates. Computational analyses using our previously developed Bayesian framework for the BO molecular clock will be applied to estimate the molecular age of BO in patients, i.e., how long the patient has been living with BO since onset of metaplasia. Results will be compared between age groups, birth cohorts, sex, and importantly between dysplastic and non-dysplastic BO to evaluate biomarker potential. Data analysis is ongoing, and the final results will be presented at the meeting. Conclusions Our results from this nested case-control study demonstrate feasibility and generate pilot data on molecular age as a proxy of BO duration at the time of incident diagnosis, in a large population-based registry of patients with BO. This will inform our computational tools for determining biological aging and can be applied in future work to investigate progression risk according to molecular age. Ultimately, this biomarker could inform surveillance frequency for BO patients, enable earlier detection of neoplastic progression, leading to improved patient outcomes and optimal distribution of limited endoscopy capacity for surveillance.

Targeted Hsp70 fluorescence molecular endoscopy detects dysplasia in Barrett’s esophagus

PurposeThe incidence of esophageal adenocarcinoma (EAC) has been increasing for decades without significant improvements in treatment. Barrett’s esophagus (BE) is best established risk factor for EAC, but current surveillance with random biopsies cannot predict progression to cancer in most BE patients due to the low sensitivity and specificity of high-definition white light endoscopy.MethodsHere, we evaluated the membrane-bound highly specific Hsp70-specific contrast agent Tumor-Penetrating Peptide (Hsp70-TPP) in guided fluorescence molecular endoscopy biopsy.ResultsHsp70 was significantly overexpressed as determined by IHC in dysplasia and EAC compared with non-dysplastic BE in patient samples (n = 12) and in high-grade dysplastic lesions in a transgenic (L2-IL1b) mouse model of BE. In time-lapse microscopy, Hsp70-TPP was rapidly taken up and internalized by human BE dysplastic patient–derived organoids. Flexible fluorescence endoscopy of the BE mouse model allowed a specific detection of Hsp70-TPP-Cy5.5 that corresponded closely with the degree of dysplasia but not BE. Ex vivo application of Hsp70-TPP-Cy5.5 to freshly resected whole human EAC specimens revealed a high (> 4) tumor-to-background ratio and a specific detection of previously undetected tumor infiltrations.ConclusionIn summary, these findings suggest that Hsp70-targeted imaging using fluorescently labeled TPP peptide may improve tumor surveillance in BE patients.

Molecular characterization of Barrett’s esophagus at single-cell resolution

Barrett's esophagus (BE) is categorized, based on morphological appearance, into different stages, which correlate with the risk of developing esophageal adenocarcinoma. More advanced stages are more likely to acquire chromosomal instabilities, but stage-specific markers remain elusive. Here, we performed single-cell DNA-sequencing experiments (scDNAseq) with fresh BE biopsies. Dysplastic BE cells frequently contained chromosomal instability (CIN) regions, and these CIN cells carried mutations corresponding to the COSMIC mutational signature SBS17, which were not present in biopsy-matched chromosomally stable (CS) cells or patient-matched nondiseased control cells. CS cells were predominantly found in nondysplastic BE biopsies. The single-base substitution (SBS) signatures of all CS BE cells analyzed were indistinguishable from those of nondiseased esophageal or gastric cells. Single-cell RNA-sequencing (scRNAseq) experiments with BE biopsies identified two sets of marker genes which facilitate the distinction between columnar BE epithelium and nondysplastic/dysplastic stages. Moreover, histological validation confirmed a correlation between increased CLDN2 expression and the presence of dysplastic BE stages. Our scDNAseq and scRNAseq datasets, which are a useful resource for the community, provide insight into the mutational landscape and gene expression pattern at different stages of BE development.

Abnormal TP53 Predicts Risk of Progression in Patients With Barrett’s Esophagus Regardless of a Diagnosis of Dysplasia

BACKGROUND AND AIMS:Barrett’s esophagus (BE) is the precursor to esophageal adenocarcinoma. A major challenge is identifying the small group with BE who will progress to advanced disease from the many who will not. Assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation have precluded its use. The aim of this study was to develop a robust criteria for grading abnormal immunohistochemical (IHC) expression of p53 and to test its utility as a biomarker for progression in BE.METHODS:Criteria for abnormal IHC of p53 were developed in BE biopsies and validated with sequencing to assess TP53 mutations. The utility of p53 IHC as a biomarker for progression of BE was tested retrospectively in 561 patients with BE with or without known progression. The findings were prospectively validated in a clinical practice setting in 1487 patients with BE.RESULTS:Abnormal p53 IHC highly correlated with TP53 mutation status (90.6% agreement) and was strongly associated with neoplastic progression in the retrospective cohorts, regardless of histologic diagnosis (P < .001). In the retrospective cohort, abnormal p53 was associated with a hazard ratio of 5.03 (95% confidence interval, 3.88–6.5) and a hazard ratio of 5.27 (95% confidence interval, 3.93–7.07) for patients with exclusively nondysplastic disease before progression. In the prospective validation cohort, p53 IHC predicted progression among nondysplastic BE, indefinite for dysplasia, and low-grade dysplasia (P < .001).CONCLUSIONS:p53 IHC identifies patients with BE at higher risk of progression, including in patients without evidence of dysplasia. p53 IHC is inexpensive, easily integrated into routine practice, and should be considered in biopsies from all BE patients without high-grade dysplasia or cancer.

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

First-in-human pilot study of snapshot multispectral endoscopy for early detection of Barrett's-related neoplasia.

.Significance: The early detection of dysplasia in patients with Barrett’s esophagus could improve outcomes by enabling curative intervention; however, dysplasia is often inconspicuous using conventional white-light endoscopy.Aim: We sought to determine whether multispectral imaging (MSI) could be applied in endoscopy to improve detection of dysplasia in the upper gastrointestinal (GI) tract.Approach: We used a commercial fiberscope to relay imaging data from within the upper GI tract to a snapshot MSI camera capable of collecting data from nine spectral bands. The system was deployed in a pilot clinical study of 20 patients (ClinicalTrials.gov NCT03388047) to capture 727 in vivo image cubes matched with gold-standard diagnosis from histopathology. We compared the performance of seven learning-based methods for data classification, including linear discriminant analysis, -nearest neighbor classification, and a neural network.Results: Validation of our approach using a Macbeth color chart achieved an image-based classification accuracy of 96.5%. Although our patient cohort showed significant intra- and interpatient variance, we were able to resolve disease-specific contributions to the recorded MSI data. In classification, a combined principal component analysis and -nearest-neighbor approach performed best, achieving accuracies of 95.8%, 90.7%, and 76.1%, respectively, for squamous, non-dysplastic Barrett’s esophagus and neoplasia based on majority decisions per-image.Conclusions: MSI shows promise for disease classification in Barrett’s esophagus and merits further investigation as a tool in high-definition “chip-on-tip” endoscopes.

S3276 Review of American and International Guidelines for Endoscopic Management of Barrett's Esophagus

Introduction: Gastroesophageal reflux disease (GERD) is seen in approximately 10 to 20 % of the Western population. Complications of GERD include Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). EAC has been increasing in the past few decades and now encompasses over 60% of all esophageal cancers in the US. Dysplasia in BE further increases the risk of progression from low grade dysplasia (LGD) to high grade dysplasia (HGD) and eventually EAC.The objective of this study was to perform a review of the current guidelines from American and international gastroenterology societies for the endoscopic management of BE. Methods: Guidelines and recommendations from major American and other prominent international GI societies were reviewed from January 25th to 29th, 2021 on the management of BE. We included ACG, AGA, ASGE, ESGE, BSG, SFED, Japanese GI and Internal Medicine societies, CAG, and AMG. Results: While there is a common consensus among the international GI community in diagnosis and management of BE, there are also major notable differences. Screening for BE in the general population is usually not recommended but many suggest individualized assessment. The American societies generally manage nondysplastic Barrett’s esophagus (NDBE) with surveillance endoscopy every 3 to 5 years. However, the ASGE considers endoscopic ablation (RFA) in high-risk groups. After diagnosis of BE is made, the majority provide guidelines for surveillance intervals based on the presence and grading of dysplasia. The ESGE, BSG, and SFED provide varying intervals for NDBE based on BE segment length. Endoscopic eradication therapy (EET) is recommended by some societies for LGD, while all societies recommend it for HGD. Post-EET surveillance is often performed in practice, but officially recommended by 5 out of 9 societies. EAC only accounts for 5% of all esophageal cancers in Japan. Additionally, Japanese societies do not require intestinal metaplasia for diagnosis of BE and also have different endoscopic landmarks for the gastroesophageal junction, biopsy protocols, and histologic definition of BE. Conclusion: Most societies agree on endoscopic surveillance for NDBE and EET for HGD. Endoscopic therapy with RFA for NDBE is controversial and not widely accepted. However, EET for LGD is becoming more common in the US and some parts of Europe. BE in Japan is diagnosed and managed differently than in the West; further studies are warranted to provide a fair comparison.

Persistent or recurrent Barrett's neoplasia after an endoscopic therapy session is associated with DNA content abnormality and can be detected by DNA flow cytometric analysis of paraffin-embedded tissue

Endoscopic therapy is currently the standard of care for the treatment of high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) in patients with Barrett's esophagus (BE). Visible lesions are treated with endoscopic mucosal resection (EMR), which is often coupled with radiofrequency ablation (RFA). However, endoscopic therapy may require multiple sessions (one session every 2-3 months) and does not always assure complete eradication of neoplasia. Furthermore, despite complete eradication, recurrences are not uncommon. This study assesses which potential risk factors can predict a poor response after endoscopic sessions. Forty-five BE patients who underwent at least one endoscopic session (EMR alone or ablation with or without preceding EMR) for the treatment of HGD/IMC, low-grade dysplasia (LGD), or indefinite for dysplasia (IND) were analyzed. DNA flow cytometry was performed on 82 formalin-fixed paraffin-embedded samples from the 45 patients, including 78 HGD/IMC, 2 LGD, and 2 IND. Eight non-dysplastic BE samples were used as controls. Three to four 60-micron thick sections were cut from each tissue block, and the area of HGD/IMC, LGD, or IND was manually dissected. Potential associations between clinicopathologic risk factors and persistent/recurrent HGD/IMC following each endoscopic session were examined using univariate and multivariate Cox models with frailty terms. Sixty (73%) of the 82 specimens showed abnormal DNA content (aneuploidy or elevated 4N fraction). These were all specimens with HGD/IMC (representing 77% of that group). Of these 60 HGD/IMC samples with abnormal DNA content, 42 (70%) were associated with subsequent development of persistent/recurrent HGD/IMC (n = 41) or esophageal adenocarcinoma (EAC; n = 1) within a mean follow-up time of 16 months (range: 1 month to 9.4 years). In contrast, only 6 (27%, all HGD/IMC) of the 22 remaining samples (all with normal DNA content) were associated with persistent/recurrent HGD/IMC. For outcome analysis per patient, 11 (24%) of the 45 patients developed persistent/recurrent HGD/IMC or EAC, despite multiple endoscopic sessions (mean: 3.6, range: 1–11). In a univariate Cox model, the presence of abnormal DNA content (hazard ratio [HR] = 3.8, p = 0.007), long BE segment ≥ 3 cm (HR = 3.4, p = 0.002), endoscopic nodularity (HR = 2.5, p = 0.042), and treatment with EMR alone (HR = 2.9, p = 0.006) were significantly associated with an increased risk for persistent/recurrent HGD/IMC or EAC. However, only abnormal DNA content (HR = 6.0, p = 0.003) and treatment with EMR alone (HR = 2.7, p = 0.047) remained as significant risk factors in a multivariate analysis. Age ≥ 60 years, gender, ethnicity, body mass index (BMI) ≥ 30 kg/m2, presence of hiatal hernia, and positive EMR lateral margin for neoplasia were not significant risk factors for persistent/recurrent HGD/IMC or EAC (p > 0.05). Three-month, 6-month, 1-year, 3-year, and 6-year adjusted probabilities of persistent/recurrent HGD/IMC or EAC in the setting of abnormal DNA content were 31%, 56%, 67%, 79%, and 83%, respectively. The corresponding probabilities in the setting of normal DNA content were 10%, 21%, 28%, 38%, and 43%, respectively. In conclusion, in BE patients with baseline HGD/IMC, both DNA content abnormality and treatment with EMR alone were significantly associated with persistent/recurrent HGD/IMC or EAC following each endoscopic session. DNA content abnormality as detected by DNA flow cytometry identifies HGD/IMC patients at highest risk for persistent/recurrent HGD/IMC or EAC, and it also serves as a diagnostic marker of HGD/IMC with an estimated sensitivity of 77%. The diagnosis of HGD/IMC in the setting of abnormal DNA content may warrant alternative treatment strategies as well as long-term follow-up with shorter surveillance intervals.

Videoconference microscopy is a reliable alternative to conventional microscopy in the evaluation of Barrett’s esophagus: Zooming into a new era

Telepathology, practicing pathology from a distance, allows experts to review cases without the need to transfer glass slides. Due to significant intra- and inter-observer variabilities in the histological evaluation of Barrett's esophagus (BE), current guidelines recommend expert consultation in cases of dysplasia. We aimed to determine whether telepathology using microscope videoconferencing can be reliably used for evaluation of BE. Biopsies from 62 patients with endoscopic findings of salmon colored mucosa extending ≥1cm proximal to the gastroesophageal junction were randomly selected to represent benign esophagus, non-dysplastic BE, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. Three gastrointestinal-trained pathologists reviewed the cases via videoconference microscopy followed by conventional microscopy. Intra-observer and pairwise inter-observer agreements between the conventional microscopy and videoconference methodologies were calculated for each of the three pathologists using Fleiss-Cohen weighted kappa (K) analysis. The intra-observer agreement for each pathologist's assessment of videoconference microscopy and glass slide readings showed very good reliability (K = 0.94, 95% confidence interval = 0.89-0.99; 0.88, 95% confidence interval = 0.79-0.98; 0.93, 95% confidence interval = 0.90-0.97). Mean pairwise inter-observer agreement was 0.90 for videoconference and 0.91 for conventional microscopy. Diagnosis and grading of BE using videoconference microscopy show similar reliability as conventional microscopy. Based on our findings, we propose that videoconferencing pathology is a valid instrument for evaluating BE.

Progression of Barrett’s esophagus, crypt dysplasia, and low-grade dysplasia diagnosed by wide-area transepithelial sampling with 3-dimensional computer-assisted analysis: a retrospective analysis

Wide-area transepithelial sampling with 3-dimensional computer-assisted analysis (WATS3D) is used as an adjunct to forceps biopsy sampling in Barrett's esophagus (BE). BE-associated crypt dysplasia (CD), which can be detected by WATS3D, involves crypts but not surface epithelium. The risk of neoplastic progression of CD has never been evaluated. The prognosis of WATS3D-diagnosed nondysplastic BE (NDBE) and low-grade dysplasia (LGD) is also unknown. We assessed the risk of progression of WATS3D-reported NDBE, CD, and LGD with high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC). We analyzed patients who underwent WATS3D in routine care. Eligible patients had 2 WATS3D≥12 months apart. Patients were categorized by the initial WATS3D finding as NDBE, CD, or LGD. Patient-years of observation were calculated by multiplying the mean follow-up by the number of patients. Progression, defined as a subsequent finding of HGD/EAC on forceps biopsy sampling, was assessed. The crude progression rate was calculated, and Kaplan-Meier analysis compared progression rates stratified by baseline histology. Bivariate analysis identified progression risk factors. Of 151,224 WATS3D cases, 43,145 (29%) had BE. Of these, 4545 patients had 2 WATS3D separated by≥12 months. The mean follow-up was 1.97 years (range, 1.0-6.42). In patients with baseline NDBE, progression was .08% per patient-year (95% confidence interval [CI], .02%-.14%). Progression of baseline CD was significantly higher, at 1.42% per patient-year (95% CI, 0%-3.01%). For baseline LGD, progression was 5.79% per patient-year (95% CI, 1.02%-10.55%). Other risk factors for progression were increasing age and BE segment length. NDBE found on WATS3D has a very low risk of progression. CD reported on WATS3D appears to be a neoplastic precursor lesion, with a risk of progression in this study significantly higher than NDBE but lower than LGD. The clinical utility of CD requires further investigation.

Genetic profiles of Barrett\u2019s esophagus and esophageal adenocarcinoma in Japanese patients

The genetic characteristics of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) in the Japanese population is unclear. This study aims to investigate the genetic characteristics from nondysplastic BE (NDBE) to early EAC in Japan. Clinical information was collected. Moreover, the genetic profile of NDBE without concurrent dysplasia, early EAC, and surrounding BE were also investigated using endoscopic biopsy samples and formalin-fixed, paraffin-embedded specimens from Japanese patients by targeted next-generation sequencing. Immunohistochemical staining for p53 was also performed for EAC lesions. Targeted NGS was performed for 33 cases with 77 specimens. No significant difference exists in the NDBE group between the number of putative drivers per lesion in the short-segment Barrett’s esophagus (SSBE) and long-segment Barrett’s esophagus (LSBE) [0 (range, 0–1) vs. 0 (range, 0–1). p = 1.00]. TP53 putative drivers were found in two patients (16.7%) with nondysplastic SSBE. TP53 was the majority of putative drivers in both BE adjacent to EAC and EAC, accounting for 66.7% and 66.7%, respectively. More putative drivers per lesion were found in the EAC than in the NDBE group [1 (range, 0–3) vs. 0 (range, 0–1). p < 0.01]. The genetic variants of TP53 in the Japanese early EAC were similar to those in western countries. However, TP53 putative drivers were detected even in Japanese patients with nondysplastic SSBE. This is significant because such nondysplastic SSBE might have higher risk of progressing to high-grade dysplasia or EAC. The risks of progression may not be underestimated and appropriate follow-ups may be necessary even in patients with SSBE.Trial registration: This study was registered at the University Hospital Medical Information Network (UMIN000034247).

Improving cost-effectiveness of endoscopic surveillance for Barrett's esophagus by reducing low-value care: a review of economic evaluations.

Individuals with Barrett's esophagus are believed to be at 30-120× risk of developing esophageal adenocarcinoma (EAC). Early detection and endoscopic treatment of dysplasia/early cancer confers a significant advantage to patients under surveillance; however, most do not progress past the non-dysplastic state of Barrett's esophagus (NDBE), which is potentially an inefficient distribution of health care resources. This article aimed to review the outcomes of cost-effectiveness studies reducing low-value care in the context of endoscopic surveillance for non-dysplastic Barrett's esophagus (NDBE). A systematic search was conducted by two reviewers in accordance with PRISMA guidelines. cost-utility analyses of endoscopic surveillance of NDBE patients with at least one treatment strategy focused on reduction of surveillance. A narrative synthesis of economic evaluations was undertaken, along with an in-depth analysis of input parameters contributing to stated Incremental cost-effectiveness ratios (ICER). Study appraisal was performed using the consolidated health economic evaluation reporting standards (CHEERS) tool. 10 Studies met inclusion criteria. There was significant variation in cost-model structures, input parameters, ICER values, and willingness-to-pay thresholds between studies. All studies except one concluded guideline-specified endoscopic surveillance for NDBE patients was not cost-effective. Studies that explored a modified surveillance by deselection of low-risk NDBE patients found it to be a cost-effective strategy. Guideline specified endoscopic surveillance for NDBE was not found to be cost-effective in the studies examined. A modified endoscopic surveillance strategy removing individuals with the lowest risk for progression from NDBE to adenocarcinoma is likely to be cost-effective but is dependent on risk profile of patients excluded from surveillance.

Systematic review with meta-analysis: neoplasia detection rate and post-endoscopy Barrett's neoplasia in Barrett's oesophagus.

Neoplasia detection rate, the proportion of Barrett's oesophagus patients with high-grade dysplasia or oesophageal adenocarcinoma detected at index surveillance endoscopy has been proposed as a quality metric. However, the correlation between neoplasia detection rate and a clinically relevant outcome like post-endoscopy Barrett's neoplasia remains unknown. Post-endoscopy Barrett's neoplasia refers to the rate of high-grade dysplasia or oesophageal adenocarcinoma on repeat endoscopy within one year of an index screening examination revealing non-dysplastic Barrett's oesophagus or low-grade dysplasia. To assess correlation between neoplasia detection rate and post-endoscopy Barrett's neoplasia. We performed a systematic search of multiple databases from date of inception to June 2021 to identify cohort studies reporting both neoplasia detection rate and post-endoscopy Barrett's neoplasia. Data from each study were pooled using a random effects model, and their correlation assessed using meta-regression. Heterogeneity was assessed and a priori planned subgroup analyses were conducted. Ten studies with 27894 patients with Barrett's oesophagus were included. The pooled neoplasia detection rate and post-endoscopy Barrett's neoplasia were 5.0% (95% CI: 3.4%-7.1%, I2 =97%) and 19.6% (95% CI: 10.1%-34.7%, I2 =96%), respectively. Meta-regression revealed a statistically significant inverse relationship between the two variables (coefficient -3.50, 95% CI: -4.63 to -2.37, P<0.01). With every 1% increase of neoplasia detection rate, post-endoscopy Barrett's neoplasia decreased by 3.50%. Heterogeneity was high despite adjusting for study quality and performing several subgroup analyses. We observed a statistically significant inverse correlation between neoplasia detection rate and post-endoscopy Barrett's neoplasia. Additional studies are needed to further validate this correlation.

Alteration of protein expression and spliceosome pathway activity during Barrett\u2019s carcinogenesis

BackgroundBarrett’s esophagus (BE) is a known precursor lesion and the strongest risk factor for esophageal adenocarcinoma (EAC), a common and lethal type of cancer. Prediction of risk, the basis for efficient intervention, is commonly solely based on histologic examination. This approach is challenged by problems such as inter-observer variability in the face of the high heterogeneity of dysplastic tissue. Molecular markers might offer an additional way to understand the carcinogenesis and improve the diagnosis—and eventually treatment. In this study, we probed significant proteomic changes during dysplastic progression from BE into EAC.MethodsDuring endoscopic mucosa resection, epithelial and stromal tissue samples were collected by laser capture microdissection from 10 patients with normal BE and 13 patients with high-grade dysplastic/EAC. Samples were analyzed by mass spectrometry-based proteomic analysis. Expressed proteins were determined by label-free quantitation, and gene set enrichment was used to find differentially expressed pathways. The results were validated by immunohistochemistry for two selected key proteins (MSH6 and XPO5).ResultsComparing dysplastic/EAC to non-dysplastic BE, we found in equal volumes of epithelial tissue an overall up-regulation in terms of protein abundance and diversity, and determined a set of 226 differentially expressed proteins. Significantly higher expressions of MSH6 and XPO5 were validated orthogonally and confirmed by immunohistochemistry.ConclusionsOur results demonstrate that disease-related proteomic alterations can be determined by analyzing minute amounts of cell-type-specific collected tissue. Further analysis indicated that alterations of certain pathways associated with carcinogenesis, such as micro-RNA trafficking, DNA damage repair, and spliceosome activity, exist in dysplastic/EAC.

Diagnosis and Management of Barrett Esophagus

Barrett esophagus (BE) is defined by the presence of intestinal metaplasia in the esophageal mucosa. This condition is associated with an increased risk of esophageal adenocarcinoma. BE develops from chronic insult to the esophageal mucosa due to gastroesophageal reflux disease (GERD). Its diagnosis requires endoscopy with multiple biopsies. Numerous image-enhanced modalities have been developed to improve the endoscopic diagnosis of BE and dysplasia. Surveillance has a central role to monitor for progression of metaplastic to dysplastic mucosa and early diagnosis of invasive carcinoma. Whereas nondysplastic BE can benefit from medical or surgical treatment of GERD, today multiple therapies are available to treat dysplastic BE with a low rate of complications. Key words: Barrett esophagus, biopsy, dysplasia endoscopy, endoscopic mucosal resection, esophageal adenocarcinoma, gastroesophageal reflux metaplasia, proton pump inhibitor, surveillance

Diagnostic utility of a novel magnifying endoscopic classification system for superficial Barrett\u2019s esophagus-related neoplasms: a nationwide multicenter study

BackgroundCurrently, no classification system using magnification endoscopy for the diagnosis of superficial Barrett’s esophagus (BE)-related neoplasia has been widely accepted. This nationwide multicenter study aimed to validate the diagnostic accuracy and reproducibility of the magnification endoscopy classification system, including the diagnostic flowchart developed by the Japan Esophageal Society—Barrett’s esophagus working group (JES-BE) for superficial Barrett’s esophagus-related neoplasms.MethodsThe JES-BE acquired high-definition magnification narrow-band imaging (HM-NBI) images of non-dysplastic and dysplastic BE from 10 domestic institutions. A total of 186 high-quality HM-NBI images were selected. Thirty images were used for the training phase and 156 for the validation (test) phase. We invited five non-experts and five expert reviewers. In the training phase, the reviewers discussed how to correctly predict the histology based on the JES-BE criteria. In the validation phase, they evaluated whether the criteria accurately predicted the histology results according to the diagnostic flowchart. The validation phase was performed immediately after the training phase and at 6 weeks thereafter.ResultsThe sensitivity and specificity for all reviewers were 87% and 97%, respectively. Overall accuracy, positive predictive value, and negative predictive value were 91%, 98%, and 83%, respectively. The overall strength of inter-observer and intra-observer agreements for dysplastic histology prediction was κ = 0.77 and κ = 0.83, respectively. No significant difference in diagnostic accuracy and reproducibility between experts and non-experts was found.ConclusionThe JES-BE classification system, including the diagnostic flowchart for predicting dysplastic BE, is acceptable and reliable, regardless of the clinician’s experience level.