Barrett Esophageal Adenocarcinoma Research Articles

Mucosa-Associated Microbiota in Barrett's Esophagus, Dysplasia, and Esophageal Adenocarcinoma Differ Similarly Compared With Healthy Controls

INTRODUCTION:Alterations in the composition of the human gut microbiome and its metabolites have been linked to gut epithelial neoplasia. We hypothesized that differences in mucosa-adherent Barrett's microbiota could link to risk factors, providing risk of progression to neoplasia.Methods:Paired biopsies from both diseased and nonaffected esophagus (as well as gastric cardia and gastric juice for comparison) from patients with intestinal metaplasia (n = 10), low grade dysplasia (n = 10), high grade dysplasia (n = 10), esophageal adenocarcinoma (n = 12), and controls (n = 10) were processed for mucosa-associated bacteria and analyzed by 16S ribosomal ribonucleic acid V4 gene DNA sequencing. Taxa composition was tested using a generalized linear model based on the negative binomial distribution and the log link functions of the R Bioconductor package edgeR.Results:The microbe composition of paired samples (disease vs nondisease) comparing normal esophagus with intestinal metaplasia, low grade dysplasia, high grade dysplasia, and adenocarcinoma showed significant decreases in the phylum Planctomycetes and the archaean phylum Crenarchaeota (P < 0.05, false discovery rate corrected) in diseased tissue compared with healthy controls and intrasample controls (gastric juice and unaffected mucosa). Genera Siphonobacter, Balneola, Nitrosopumilus, and Planctomyces were significantly decreased (P < 0.05, false discovery rate corrected), representing <10% of the entire genus community. These changes were unaffected by age, tobacco use, or sex for Crenarcha.DISCUSSSION:There are similar significant changes in bacterial genera in Barrett's esophageal mucosa, dysplasia, and adenocarcinoma compared with controls and intrapatient unaffected esophagus. Further work will establish the biologic plausibility of these specific microbes' contributions to protection from or induction of esophageal epithelial dysplasia.

Integrated PPI- and WGCNA-Retrieval of Hub Gene Signatures Shared Between Barrett's Esophagus and Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a deadly cancer with high mortality rate, especially in economically advanced countries, while Barrett's esophagus (BE) is reported to be a precursor that strongly increases the risk of EAC. Due to the complexity of these diseases, their molecular mechanisms have not been revealed clearly. This study aims to explore the gene signatures shared between BE and EAC based on integrated network analysis. We obtained EAC- and BE-associated microarray datasets GSE26886, GSE1420, GSE37200, and GSE37203 from the Gene Expression Omnibus and ArrayExpress using systematic meta-analysis. These data were accompanied by clinical data and RNAseq data from The Cancer Genome Atlas (TCGA). Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis were conducted to explore the relationship between gene sets and clinical traits as well as to discover the key relationships behind the co-expression modules. A differentially expressed gene-based protein–protein interaction (PPI) complex was used to extract hub genes through Cytoscape plugins. As a result, 403 DEGs were excavated, comprising 236 upregulated and 167 downregulated genes, which are involved in the cell cycle and replication pathways. Forty key genes were identified using modules of MCODE, CytoHubba, and CytoNCA with different algorithms. A dark-gray module with 207 genes was identified which having a high correlation with phenotype (gender) in the WGCNA. Furthermore, five shared hub gene signatures (SHGS), namely, pre-mRNA processing factor 4 (PRPF4), serine and arginine-rich splicing factor 1 (SRSF1), heterogeneous nuclear ribonucleoprotein M (HNRNPM), DExH-Box Helicase 9 (DHX9), and origin recognition complex subunit 2 (ORC2), were identified between BE and EAC. SHGS enrichment denotes that RNA metabolism and splicosomes play a key role in esophageal cancer development and progress. We conclude that the PPI complex and WGCNA co-expression network highlight the importance of phenotypic identifying hub gene signatures for BE and EAC.

Neoplasia Detection Rate in Barrett’s Esophagus and Its Impact on Missed Dysplasia: Results from a Large Population-Based Database

It is a challenge to detect dysplasia in Barrett's esophagus (BE) and esophageal adenocarcinomas (EACs) are missed in 25%-33% of cases. The neoplasia detection rate (NDR), defined as the rate of high-grade dysplasia (HGD) or EAC detection during initial surveillance endoscopy, has been proposed as a quality metric for endoscopic evaluation of patients with BE. However, current estimates are from referral center cohorts, which might overestimate NDR. Effects on rates of missed dysplasia are also unknown. We analyzed data from a large cohort of patients with BE to estimate the NDR and factors associated with it, and assess the effects of the NDR on the rate of missed dysplasia. We analyzed data from 1066 patients in the Rochester Epidemiology Project-linked medical record system, a population-based cohort of patients with BE (confirmed by review of the endoscopic and histologic reports) from 11 southeastern Minnesota counties from 1991 through 2019. Biopsies reported to contain dysplasia were confirmed by expert gastrointestinal pathologists. The NDR was calculated as the rate of HGD or EAC detected by histologic analyses of biopsies collected during the first surveillance endoscopy. Patients without HGD or EAC at their initial endoscopy (n=391) underwent repeat endoscopy within 12 months; HGD or EAC detected at the repeat endoscopy were considered to be missed on index endoscopy. Factors associated with NDR and missed dysplasia were identified using univariate and multivariate logistic regression models. The NDR was 4.9% (95% CI, 3.8-6.4); 3.1% of patients had HGD, 1.8% had EAC, and 10.6% had low-grade dysplasia. Factors associated with higher rates of detection of neoplasia included older age, male sex, smoking, increasing length of BE, and surveillance endoscopies by gastroenterologists. This NDR was associated with a substantially lower rate of missed dysplasia (13%). In an analysis of 1066 patients with BE in a population-based cohort, we found a lower NDR and lower rate of missed dysplasia than previously reported. NDR may have value as a quality metric in BE surveillance if validated in other cohorts.

Circulating exosomal miRNAs as potential biomarkers for Barrett's esophagus and esophageal adenocarcinoma.

Exosomes, a class of extracellular vesicles, are small membrane-bound vesicles derived from almost all cell types that can play important roles in intercellular communication. Exosomes contain proteins, lipids, and nucleic acids that are obtained from the parental cells and participate in various pathophysiological processes, including cell growth, migration, inflammation, immune regulation, and tumor pathogenesis. Moreover, exosomes might be applied in clinical settings, such as diagnosis, treatment, and outcome prediction of diseases, including various cancers. The incidence rates of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) have increased in recent decades, and studies have proposed specific factors that may contribute to the development and progression of these diseases. However, how exosomes play a role in this pathological process needs to be clarified. Studies have identified candidate microRNAs (miRNAs) that might be related to BE/EAC. Further studies are needed to ascertain whether circulating exosomal miRNAs are altered before or after disease onset, which could also help understand the pathophysiology of and find potential targets for prevention, diagnosis, and therapy in BE/EAC. This review summarizes recent findings on the features of circulating exosomal miRNAs in BE/EAC, which could be valuable for the early diagnosis, therapeutic approaches, and outcome prediction of BE/EAC.

DCLK1 inhibition attenuates tumorigenesis and improves chemosensitivity in esophageal squamous cell carcinoma by inhibiting β-catenin/c-Myc signaling.

Doublecortin-like kinase 1 (DCLK1) is involved in tumorigenesis, tumor growth and metastasis, and epithelial-to-mesenchymal transition in many digestive tract tumors. It is reportedly highly expressed in Barrett's esophagus and esophageal adenocarcinoma, but its effects on the occurrence and progression of esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, real-time PCR and western blot analysis confirmed significant upregulation of DCLK1 expression in human ESCC tissues and cell lines. CCK-8 assay showed that transfection with siRNA against DCLK1 (si-DCLK1) markedly inhibited cell proliferation and colony formation in the ESCC cell lines Eca109 and TE1. Transwell assay revealed that si-DCLK1 transfection inhibited the migratory and invasive capacities of Eca109 and TE1 cells. Moreover, si-DCLK1 increased the chemosensitivity of these cells to cisplatin, as indicated by inhibited cell viability and colony formation, and increased ROS and apoptosis in cisplatin-treated cells. Western blot assay revealed that expression of nuclear β-catenin and c-Myc was significantly increased in ESCC tissues and that si-DCLK1 markedly downregulated nuclear β-catenin and c-Myc in Eca109 cells. Treatment with lithium chloride, an activator of β-catenin signaling, partially abolished the si-DCLK1-induced inhibition of proliferation, migration, invasion, and chemoresistance of ESCC cells. These findings suggest that knockdown of DCLK1 may inhibit the progression of ESCC by regulating proliferation, migration, invasion, and chemosensitivity via suppressing the β-catenin/c-Myc pathway, supporting a promising therapeutic target against ESCC.

Patterns of esophageal acidification and impairment of esophageal motility in gastroesophageal reflux disease and Barrett's esophagus

Background: Gastroesophageal reflux disease (GERD) has a high prevalence worldwide and plays a major role in the development of Barrett's esophagus (BЕ) and esophageal adenocarcinoma.&#x0D; Aims: To evaluate the patterns of esophageal acidification and esophageal motility in patients with BЕ in comparison with various GERD phenotypes and control subjects.&#x0D; Materials and methods: 100 patients were examined: 31 patients with nonerosive reflux disease (NERD), 20 patients with erosive reflux disease (ERD), 17 patients with BE, 32 healthy individuals who made up the control group. All patients underwent 24-hours pH-impedance and high-resolution esophageal manometry.&#x0D; Results: According to the 24-hour pH-impedanсe, the total time with pH 4 in the esophagus was 1,9% in control patients, 11.6% in the NERD group, 19.35 in the ERD group and 28% in patients with BE. The average number of acid refluxes was 18.0 in the control group, 58.0 in the group with NERD, 78. in the group with ERD and 89.0 in patients with BE. The number of acidic refluxes was significantly correlated with the time on the acidification of the esophagus (r = 0.5439; p0.05). The analysis of the mean nocturnal baseline impedance (MNBI) revealed a tendency to decrease the values in patients with GERD relative to the control subjects, and there was a decrease in the values of MNBI as the severity of GERD from NERD to ERD and BE (p0.05). Manometric signs of hiatal hernia and/or hypotension of the lower esophageal sphincter were more often registered in the groups of patients with ERD (70%) and BE (65%) than in patients with NERD (32%) and in control group (12%).&#x0D; Conclusions: Increase in level of total time with pH 4, number of acid refluxes, reduced values of MNBI, as well as disorders of the structure and function of the esophagogastric junction and motility of the esophagus are associated with the severity of esophagus diseases.

Low Risk of Progression of Barrett's Esophagus to Neoplasia in Women.

Men are at a higher risk for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), but little is known about BE progression to dysplasia and EAC in women. We performed a retrospective, multicenter cohort study to assess risk of BE progression to dysplasia and EAC in women compared with men. We also investigated comorbidities, medication use, and endoscopic features that contribute to sex differences in risk of BE progression. We collected data from large cohort of patients with BE seen at 6 centers in the United States and Europe, followed for a median 5.7 years. We obtained demographic information (age, sex, ethnicity), clinical history (tobacco use, body mass index, comorbidities), endoscopy results (procedure date, BE segment length), and histopathology findings. Neoplasia was graded as low-grade dysplasia, high-grade dysplasia (HGD), or EAC. Rates of disease progression between women and men were compared using χ2 analysis and the Student t test. Multivariable logistic regression was used to assess the association between sex and disease progression after adjusting for possible confounding variables. Of the total 4263 patients in the cohort, 2145 met the inclusion criteria, including 324 (15%) women. There was a total of 34 (1.6%) incident EACs, with an overall annual incidence of 0.3% (95% confidence interval: 0.2%-0.4%). We found significant differences between women and men in annual incidence rates of EAC (0.05% for women vs. 0.3% in men; P=0.04) and in the combined endpoint of HGD or EAC (0.1% for women vs. 1.1% for men; P<0.001). Female gender was an independent predictor for reduced progression to HGD or EAC when rates of progression were adjusted for body mass index, smoking history, race, use of aspirin, nonsteroidal anti-inflammatory drugs, proton-pump inhibitors, or statins, hypertriglyceridemia, BE length, and histology findings at baseline (hazard ratio: 0.11; 95% confidence interval: 0.03-0.45; P=0.002). In a multicenter study of men versus women with BE, we found a significantly lower risk of disease progression to cancer and HGD in women. The extremely low risk of EAC in women with BE (0.05%/y) indicates that surveillance endoscopy may not be necessary for this subgroup of patients with BE.

Epidemiologic Risk Factors in a Comparison of a Barrett Esophagus Registry (BarrettNET) and a Case-Control Population in Germany.

Endoscopic screening for Barrett's esophagus as the major precursor lesion for esophageal adenocarcinoma is mostly offered to patients with symptoms of gastroesophageal reflux disease (GERD). However, other epidemiologic risk factors might affect the development of Barrett's esophagus and esophageal adenocarcinoma. Therefore, efforts to improve the efficiency of screening to find the Barrett's esophagus population "at risk" compared with the normal population are needed. In a cross-sectional analysis, we compared 587 patients with Barrett's esophagus from the multicenter German BarrettNET registry to 1976 healthy subjects from the population-based German KORA cohort, with and without GERD symptoms. Data on demographic and lifestyle factors, including age, gender, smoking, alcohol consumption, body mass index, physical activity, and symptoms were collected in a standardized epidemiologic survey. Increased age, male gender, smoking, heavy alcohol consumption, low physical activity, low health status, and GERD symptoms were significantly associated with Barrett's esophagus. Surprisingly, among patients stratified for GERD symptoms, these associations did not change. Demographic, lifestyle, and clinical factors as well as GERD symptoms were associated with Barrett's esophagus development in Germany, suggesting that a combination of risk factors could be useful in developing individualized screening efforts for patients with Barrett's esophagus and GERD in Germany.

Helicobacter pylori eradication treatment and the risk of Barrett's esophagus and esophageal adenocarcinoma.

Helicobacter pylori (H.pylori) is associated with lower risks of Barrett's esophagus and esophageal adenocarcinoma, but whether H.pylori eradication increases the risk of these conditions is unknown. This study aimed to test the hypothesis that H.pylori eradication leads to gradually increased risks of Barrett's esophagus and esophageal adenocarcinoma over time, while esophageal squamous cell carcinoma was assessed for comparison reasons. This Swedish nationwide, population-based cohort study in 2005-2012 used data from the Swedish Prescribed Drug Registry to assess eradication treatment for H.pylori. Barrett's esophagus was identified from the Swedish Patient Registry, and esophageal adenocarcinoma and squamous cell carcinoma from the Swedish Cancer Registry. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by dividing the observed risk in the H.pylori eradication treatment cohort by the expected risk derived from the Swedish population of the same age, sex, and calendar period. The cohort included 81919 patients having had eradication treatment. For Barrett's esophagus (n=178), the overall SIR was increased (SIR 3.67, 95% CI 3.15-4.25), but the SIRs slightly decreased over time after eradication treatment. For esophageal adenocarcinoma (n=11), the overall SIR was 1.26 (95% CI 0.62-2.26), and the SIRs did not increase over time. The SIRs of esophageal squamous cell carcinoma (n=10) were not influenced by eradication treatment. This study did not provide any evidence of an increasing risk of Barrett's esophagus or esophageal adenocarcinoma (or esophageal squamous cell carcinoma) over time after eradication treatment for H.pylori.

Validation and Comparison of Tools for Selecting Individuals to Screen for Barrett’s Esophagus and Early Neoplasia

Guidelines suggest endoscopic screening of individuals who are at increased risk for Barrett's esophagus (BE) and esophageal adenocarcinoma. Tools based on clinical factors are available for identifying patients at risk, but only some have been validated. We aimed to compare and validate available tools. We performed a prospective study of 1241 patients, ages 40 to 79 years, presenting either for their first esophagogastroduodenoscopy (EGD) or their first endoscopic therapy of early neoplastic BE, from April 2015 through June 2018. We calculated risk scores for 6 previously published tools (the Gerson, Locke, Thrift, Michigan BE pREdiction Tool [M-BERET], Nord-Trøndelag Health Study [HUNT], and Kunzmann tools). We also investigated the accuracy of frequency and duration of gastroesophageal reflux disease (GERD), using data from a randomly selected 50% of patients undergoing their first EGD. We compared the ability of all these tools to discriminate patients with BE and early neoplasia from patients without BE, using findings from endoscopy as the reference standard. BE was detected in 81 of 1152 patients during their first EGD (7.0%). GERD symptoms alone identified patients with BE with an area under the receiver operating characteristic curve (AuROC) of 0.579. All of the tools were more accurate in identifying patients with BE than the frequency and duration of GERD (AuROC for GERD, 0.579 vs range for other tools, 0.660-0.695), and predicted risk correlated well with observed risk (calibration). The AUROCs of the HUNT tool (0.796), the M-BERET (0.773), and the Kunzmann tool (0.763) were comparable in discriminating between patients with early neoplasia (n= 94) vs no BE. Each tool was more accurate in discriminating BE with early neoplasia than GERD frequency and duration alone (AuROC, 0.667; P < .01). The HUNT, M-BERET, and Kunzmann tools identify patients with BE with AuROC values ranging from 0.665 to 0.695, and discriminate patients with early neoplasia from patients without BE with AuROC values ranging from 0.763 to 0.796. These tools are more accurate than frequency and duration of GERD in identifying individuals at risk for neoplastic BE.

Clinical, endoscopic and pathological features of early Barrett esophageal adenocarcinoma and its treatment efficacy by endoscopic submucosal dissection

Objective To investigate the clinical, endoscopic and pathological characteristics of early Barrett esophageal adenocarcinoma (BEA) and to evaluate the treatment efficacy of endoscopic submucosal dissection (ESD). Methods Data of 13 patients who were diagnosed as early BEA and treated by ESD in Beijing Friendship Hospital from November 2015 to June 2018 were retrospectively analyzed, including clinical data, endoscopic manifestations and pathological information. Results Out of 13 patients, 10 were male. One had underlying long-segment Barrett esophagus (LSBE), 6 had short-segment Barrett esophagus (SSBE), and 6 had super short-segment Barrett esophagus (less than 1 cm). Two arose from circumferential Barrett esophageal (BE) and 11 from tongue-like BE. Ten lesions were located on the right anterior side wall (12-2 o′clock) of the esophagogastric junction (EGJ), and 12 lesions were superficial type (0-Ⅱ). ESD was successfully conducted in all the patients without any complication. The en bloc and curative resection rate was 100% (13/13) and 92% (12/13), respectively. Pathology examination found 9 well-differentiated adenocarcinoma and 10 intramucosal cancer. No recurrence was detected in 11 patients during follow-up of 3.3-29.3 months. Conclusion Early BEA tends to occur in elderly male, and mostly originated from non-LSBE and tongue-like BE. Most lesions are superficial type and located on the right anterior side wall of EGJ. In pathology, most lesions are well-differentiated adenocarcinoma and limited to the mucosa. ESD is a safe and efficient treatment for BEA. Key words: Barrett esophagus; Adenocarcinoma; Clinical feature; Endoscopic feature; Pathologic feature; Endoscopic submucosal dissection

Reduced Esophageal Contractility Is Associated with Dysplasia Progression in Barrett's Esophagus: A Multicenter Cohort Study.

The incidence of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) continues to rise, and risk stratification of patients with BE is needed. Impaired esophageal motility is associated with gastroesophageal reflux disease; however, whether esophageal dysmotility is a risk factor for dysplasia progression in BE is incompletely understood. This study aimed to characterize esophageal motility patterns in patients with BE and identify physiologic factors associated with dysplasia progression in BE. This multicenter retrospective study assessed data from adult patients with histologically confirmed BE who underwent high-resolution esophageal manometry from 1/2014 to 1/2018 at four tertiary care centers. Longitudinal data were collected when available among patients with non-dysplastic BE (NDBE) and separated as: no dysplastic progression or positive dysplastic progression. Multivariable logistic regression assessed for independent predictors of dysplasia progression. Among 193 patients, histology at index endoscopy identified 152 (79%) NDBE, 23 (12%) low-grade dysplasia, 14 (7%) high-grade dysplasia, and 4 (2%) EAC. Ninety-eight (51%) had abnormal esophageal motor function on manometry. Longitudinal data were available for 84 of 152 patients with initial NDBE. Twelve (14%) exhibited dysplastic progression to low-grade (6) or high-grade (6) dysplasia. Mean esophageal distal contractile integral was lower for patients that progressed [455mmHgscm (SD 515)] compared with patients who did not progress [987mmHgscm (SD 953); aOR 1.21 (95% CI 1.01, 1.44)]. In this retrospective study of 193 BE patients, the majority exhibited abnormal esophageal motor function. Reduced esophageal contractility was independently associated with dysplastic progression in BE. Characterizing esophageal physiology in BE may help to risk stratify patients.

Indications, contraindications and limitations of endoscopic therapy for Barrett's esophagus and early esophageal adenocarcinoma.

Endoscopic eradication therapy (EET) has revolutionized management of Barrett’s esophagus (BE)-associated neoplasia, traditionally treated by esophagectomy, which carries very high mortality and morbidity. EET, usually performed in the outpatient setting, has a safe risk profile. It is indicated in patients with BE with high-grade dysplasia and intramucosal cancer, confirmed, and persistent low-grade dysplasia, and in highly selected cases of non-dysplastic BE and submucosal cancers. Multiple EET modalities are available and can be categorized into two groups: ablation therapies and resection techniques with resection techniques usually reserved for nodular/raised lesions or lesions with suspected neoplasia. Patients usually require multiple ablation sessions with a goal of achieving complete eradication of metaplasia. Despite very good results, EET has its limitations and is not 100% effective: it targets a small subset of patients along the spectrum of BE and esophageal adenocarcinoma, as most patients with esophageal adenocarcinoma remain asymptomatic until the disease has progressed to advanced stages. Post-ablation surveillance is mandatory, as recurrences are common. An area of concern is buried metaplasia reported to occur following ablation therapy and thought to be from de novo growth of metaplastic tissue underneath the neosquamous epithelium, following ablation. The focus of this review article is to present the indications, contraindications and limitations of EET.

Identification of loci of functional relevance to Barrett's esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data.

Esophageal adenocarcinoma (EA) and its precancerous condition Barrett’s esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10−8) and novel candidate loci (5×10−8 ≤ P ≤ 5×10−5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10−7 and rs1540, Pcombined = 4.16×10−6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.

An Approach to Obesity Management for Gastroenterologists and Hepatologists.

Obesity is associated with multiple gastrointestinal and liver diseases such as gastroesophageal reflux disease, Barrett's esophagus, esophageal adenocarcinoma, cholelithiasis, colon polyps, and fatty liver disease. To effectively manage obesity, it is imperative to understand current and emerging therapies and procedures. Obesity is becoming increasingly prevalent and is associated with a growing monetary health care burden. Cardiac disease, cerebrovascular disease, and diabetes are among the leading causes of preventable and premature death of Americans related to obesity. In addition to behavioral modification (diet and exercise) and bariatric surgery, multiple pharmacotherapies and endoscopic procedures are newly approved and available for the management of obesity. This paper reviews the current literature on the treatments available for the management of obesity including behavior modification, pharmacotherapy, endoscopic weight loss procedures (endobariatrics), and bariatric surgery.

454 Usefulness of Linked Color Imaging in Reflux Esophagitis

INTRODUCTION: Barrett's esophagus and esophageal adenocarcinoma are increasing because of rising prevalence of gastro esophageal reflux disease. Accurate diagnosis of reflux esophagitis is important in daily clinical practice. Linked Color Imaging (LCI) was newly developed for image-enhanced endoscopy that makes easy to recognize differences in mucosal color. Therefore, we investigated the visibility of LCI in reflux esophagitis compared with white light imaging (WLI). METHODS: Consecutive patients who underwent esophagogastroduodenoscopy using WLI, LCI between April 2017 and March 2018 in our hospital were selected retrospectively. 5 endoscopists compared WLI images with LCI of 109 images obtained from 109 patients. Physicians assessed visibility as follows: 5 (improved), 4 (somewhat improved), 3 (equivalent), 2 (somewhat decreased), 1 (decreased). Scores were totaled and defined more than 20 points as improved visibility, 10-20 points as equivalent to white light, less than 10 points as decreased visibility. Inter-rater reliability (Intra-class Correlation Coefficient: ICC) was also evaluated. Images were objectively evaluated based on L* a* b* color values and color differences (ΔE*) between normal esophageal mucosa and reflux esophagitis in a CIELAB color space system. RESULTS: Improved visibility compared with WLI achieved for All: 29.4% (32/109), LA-M: 21.3% (13/61), LA-A: 41.2% (14/34), LA-B: 50.0% (5/10), LA-C: 0%, LA-D: 0%. Decreased visibility was not detected in LCI. ICC of LCI compared with WLI was 0.470 and inter-rater reliability is moderate. The color difference (ΔE*) revealed WLI: 22.8 ± 7.0, LCI: 33.5 ± 8.4 and statistically significant difference between WLI and LCI was observed (P &lt; 0.001). CONCLUSION: LCI improves visibility of reflux esophagitis compared with WLI especially for LA-M, A, B when evaluated both subjectively and objectively. LCI enables the clear visualization of reflux esophagitis and provides better contrasting images between normal esophageal mucosa and reflux esophagitis.

Elucidation of the AGR2 Interactome in Esophageal Adenocarcinoma Cells Identifies a Redox-Sensitive Chaperone Hub for the Quality Control of MUC-5AC.

Aims: AGR2 is a tissue-restricted member of the protein disulfide isomerase family that has attracted interest because it is highly expressed in a number of cancers, including gastroesophageal adenocarcinoma. The behavior of AGR2 was analyzed under oxidizing conditions, and an alkylation trapping and immunoprecipitation approach were developed to identify novel AGR2 interacting proteins. Results: The data show that AGR2 is induced in esophageal adenocarcinoma, where it participates in redox-responsive, disulfide-dependent complexes. AGR2 preferentially engages with MUC-5 as a primary client and is coexpressed with the acidic mucin in Barrett's esophagus and esophageal adenocarcinoma tissue. Innovation: New partner chaperones for AGR2 have been identified, including peroxiredoxin IV, ERp44, P5, ERp29, and Ero1α. AGR2 interacts with unexpected metabolic enzymes, including aldehyde dehydrogenase (ALDH)3A1, and engages in an alkylation-sensitive association with the autophagy receptor SQSTM1, suggesting a potential mechanism for the postendoplasmic reticulum targeting of AGR2 to mucin granules. Disulfide-driven AGR2 complex formation provides a framework for a limited number of client proteins to interact, rather than for the recruitment of multiple novel clients. Conclusion: The extended AGR2 interactome will facilitate the development of therapeutics to target AGR2/mucin pathways in esophageal cancer and other conditions, including chronic obstructive pulmonary disease.

Z-line alterations and gastroesophageal reflux: an endoscopic population-based prospective cohort study

Background and study aims: Barrett's esophagus is a premalignant condition in the distal esophagus associated with esophageal adenocarcinoma. Since gastroesophageal reflux is known to be of etiological importance in both Barrett's esophagus and esophageal adenocarcinoma, we aimed to study which endoscopic alterations at the Z-line can be attributed to a previous history of reflux symptoms.Patients and methods: From 1988, a population cohort in Sweden has been prospectively studied regarding gastrointestinal symptoms, using a validated questionnaire. In 2012, the population was invited to undergo a gastroscopy and participate in the present study. In order to determine which endoscopic alterations that can be attributed to a previous history of gastroesophageal reflux, three different endoscopic definitions of columnar-lined esophagus (CLE) were used: (1) ZAP I, An irregular Z-line with a suspicion of tongue-like protrusions; (2) ZAP II/III, Distinct, obvious tongues of metaplastic columnar epithelium; (3) CLE ≥1 cm, The Prague C/M-classification with a minimum length of 1 cm.Results: A total of 165 community subjects were included in the study. Of these, 40 had CLE ≥ 1 cm, 99 had ZAP I, and 26 had ZAP II/III. ZAP II/III was associated with an over threefold risk of previous GER symptoms (OR: 3.60, CI: 1.49–8.70). No association was found between gastroesophageal reflux and ZAP I (OR: 2.06, CI: 0.85–5.00), or CLE ≥1 cm (OR: 1.64, CI: 0.77–3.49).Conclusions: In a general community, the only endoscopic alteration to the Z-line definitely linked to longstanding GER symptoms was the presence of obvious tongues of metaplastic columnar epithelium (ZAP II/III).

Krüppel-like Factor 5 Promotes Sonic Hedgehog Signaling and Neoplasia in Barrett's Esophagus and Esophageal Adenocarcinoma

Krüppel-like Factor 5 (KLF5) is a zinc-finger transcription factor associated with cell cycle progression and cell survival. KLF5 plays a key role in mammalian intestinal epithelium development and maintenance, expressed at high levels in basal proliferating cells and low levels in terminally differentiated cells. Considering Barrett's esophagus (BE) and esophageal adenocarcinoma's (EAC) histopathological similarities to intestinal epithelium, we sought to determine KLF5’s role in BE and EAC, as well as KLF5’s possible connection to the sonic hedgehog (SHH) pathway which is highly active in BE and EAC development. Low levels of KLF5 mRNA were found in BE cell lines and tissue– similar to what has been reported in differentiated intestinal epithelium. In contrast, higher KLF5 levels were observed in EAC cells and tissues. KLF5 knockdown in EAC cells caused significant decreases in cell migration, proliferation, and EAC-associated gene expression. Moreover, KLF5 knockdown led to decreased SHH signaling. These results suggest that KLF5 is connected to the SHH pathway in BE and EAC and may represent a potential drug target in EAC; further studies are now indicated to verify these findings and elucidate underlying mechanisms involved.

Per-oral endoscopic myotomy and gastroesophageal reflux: Where do we stand after a decade of "POETRY"?

Per-oral endoscopic myotomy (POEM) was introduced nearly a decade ago. Since then, the literature on its safety and efficacy has been ever increasing. Initial studies focused solely on the feasibility and efficacy of this procedure in patients with idiopathic achalasia. Subsequent studies analyzed the incidence of gastroesophageal reflux disease (GERD) in addition to the efficacy of POEM. These studies depict a high incidence of GERD after POEM. However, vast majority of these studies lacked a comprehensive evaluation of GERD after POEM. Consequently, it is difficult to provide a true estimate of the incidence of GERD in these patients. Majority of the patients with post-POEM GERD are asymptomatic and those with symptoms usually respond well to proton pump inhibitors. However, the long-term consequences of asymptomatic GERD with increased esophageal acid exposure are not well known. These patients should probably undergo regular surveillance due to theoretical risks of complications like Barrett's esophagus and esophageal adenocarcinoma. It should be acknowledged that there is no well-controlled study to support the strategy of surveillance in this group of patients. Given the high incidence of GERD after POEM, it is time to devise minimally invasive novel strategies to prevent and manage post-POEM GERD. The current literature suggests that the technique of POEM and other factors like type of achalasia do not influence the occurrence of GERD after POEM. Therefore, the endoscopists will need to think out of the box to prevent post-POEM GERD.