Barrett's Adenocarcinoma Research Articles

Assisting Barrett's esophagus identification using endoscopic data augmentation based on Generative Adversarial Networks

Barrett's esophagus figured a swift rise in the number of cases in the past years. Although traditional diagnosis methods offered a vital role in early-stage treatment, they are generally time- and resource-consuming. In this context, computer-aided approaches for automatic diagnosis emerged in the literature since early detection is intrinsically related to remission probabilities. However, they still suffer from drawbacks because of the lack of available data for machine learning purposes, thus implying reduced recognition rates. This work introduces Generative Adversarial Networks to generate high-quality endoscopic images, thereby identifying Barrett's esophagus and adenocarcinoma more precisely. Further, Convolution Neural Networks are used for feature extraction and classification purposes. The proposed approach is validated over two datasets of endoscopic images, with the experiments conducted over the full and patch-split images. The application of Deep Convolutional Generative Adversarial Networks for the data augmentation step and LeNet-5 and AlexNet for the classification step allowed us to validate the proposed methodology over an extensive set of datasets (based on original and augmented sets), reaching results of 90% of accuracy for the patch-based approach and 85% for the image-based approach. Both results are based on augmented datasets and are statistically different from the ones obtained in the original datasets of the same kind. Moreover, the impact of data augmentation was evaluated in the context of image description and classification, and the results obtained using synthetic images outperformed the ones over the original datasets, as well as other recent approaches from the literature. Such results suggest promising insights related to the importance of proper data for the accurate classification concerning computer-assisted Barrett's esophagus and adenocarcinoma detection.

S0361 Endoscopic Submucosal Dissection vs Endoscopic Mucosal Resection for the Treatment of Dysplastic Barrett's Esophagus and Adenocarcinoma

INTRODUCTION: Barrett’s associated non-invasive adenocarcinoma and dysplastic lesions are commonly treated with endoscopic mucosal resection (EMR). However, EMR may be associated with incomplete resection resulting in local recurrence. Endoscopic submucosal dissection (ESD) has been recognized as an alternative treatment with durable results and lower risk of recurrence. The aim of this study is to evaluate the comparative effectiveness of EMR to ESD for Barrett’s associated non-invasive adenocarcinoma and dysplastic lesions. METHODS: This was a single-center retrospective study of adult patients that underwent EMR and ESD for the treatment of dysplastic Barrett’s esophagus and non-invasive adenocarcinoma from 2015 to 2019. Baseline data was collected for age, gender, size of lesion, prior EMR, procedure times, and pathology. Cases with invasive cancers were excluded. Primary outcomes were en-bloc resection and margin negative (R0) rates. Secondary outcomes were procedure related adverse events (AEs), stricture formation, and recurrence rates. Statistical analyses were performed using Student’s t-test or Fisher’s exact test. A multivariable logistic regression was performed controlling for age, EMR or ESD, lesion size, and prior EMR to determine predictors for stricture formation. RESULTS: A total of 16 patients underwent ESD, 33 patients underwent EMR. Baseline patient, lesion, procedure characteristics and outcomes are summarized in Table 1. Mean size of lesions was larger for patients that underwent ESD compared to EMR (42.50 ± 18.26 vs 10.42 ± 6.57 mm; P < 0.001) with no difference in prior EMR attempts (P = 0.141). En bloc resection was achieved in 100% of ESD and 87.9% of EMR cases (P = 0.152) with higher R0 rate for ESD (100.00% vs 57.58%; P = 0.002). Procedure time was significantly shorter for EMR (46.32 ± 13.74 vs 83.94 ± 27.46 min; P < 0.001). Procedure-related AEs were similar between ESD and EMR (12.50%% vs 3.03%, P = 0.203); esophageal stricture was more common after ESD (P = 0.039). Curative resection rate was higher for ESD (100.00% vs 66.67%, P = 0.008) while local recurrence was more common after EMR (45.45% vs 0.00%; P < 0.001). On multivariable logistic regression, ESD was not a significant predictor of stricture formation after controlling for confounders. CONCLUSION: ESD is associated with a higher rate of complete resection and a lower rate of local recurrence compared to EMR in patients with Barrett’s associated non-invasive adenocarcinoma and dysplastic lesions even when controlling for lesion size.Table 1.: Patient Characteristics and Procedure-Related Outcomes

576 P40, P63-NEGATIVE NON-SQUAMOUS CELL CARCINOMA OF ESOPHAGUS EXCEPT FOR ADENOCARCINOMA OF ESOPHAGOGASTRIC JUNCTION, REPORT OF TWO CASES

Abstract Esophageal cancer is the eighth most common human malignancy and the sixth most common cause of death from cancer worldwide. In Europe and the United States, the proportion of adenocarcinoma has increased due to the increase of Barrett's adenocarcinoma. On the other hands, in Japan most cases are squamous cell carcinoma and adenocarcinoma except esophagogstric junction including Barrett's adenocarcinoma is extremely rare. Methods We experienced two cases of tumors with morphologically no distinct squamous or glandular differentiation and confirmed not to be Barrett’s adenocarcinoma. No clear positive findings for p40 and p63 by immunohistochemistry. Case 1 is 69-year-old man. Esophagectomy was performed after neoadjuvant chemotherapy. Macroscopic findings of the resected specimen showed 59 × 43 mm of tumor (type 2) at upper to middle thoracic esophagus. Case 2 is 53-year-old man. Esophagectomy was performed without neoadjuvant chemotherapy. Macroscopic findings of the resected specimen showed 68 × 46 mm of tumor (type 1) at middle thoracic esophagus. Results Pathological examination revealed that the cancer cells showed mainly solid proliferation and no clear keratinization and gland formation was observed. The relationship with the duct of esophageal gland proper was not observed. Immunohistochemistry, tumor cells showed no neuroendocrine differentiation(ChromograninA-, synaptophysin-)and negative for p40, p63 and CK14, on the other hands tumor cells were positive for CK18. Conclusion By the WHO classification, in addition to adenocarcinoma of the esophagogastric junction, squamous cell carcinoma, neuroendocrine tumor, and salivary gland type tumor, there is an item of undifferentiated carcinoma. However, tumor cells of our cases had not such strong atypia, and immunohistochemical study showed glandular differentiation. Although we could not clarify the origin of tumor, it was suggested that there may be carcinoma other than adenocarcinoma of the esophagogastric junction, which may have glandular elements.

Recommendations of the Russian Gastroenterological Association in Diagnosis and Treatment of Gastroesophageal Reflux Disease

Aim . Current recommendations of the Russian Gastroenterological Association are developed to acquaint medical practitioners with modern diagnostics, treatment and trends in rational drug therapy for gastroesophageal reflux disease (GERD). General provisions . Incidence rate of GERD in the Russian Federation varies from 11.3 to 23.6%. GERD is diagnosed with medical history and laboratory examination evidence. Esophagogastroduodenoscopy (EGDS) allows detection of reflux esophagitis of various severity and cylindrical epithelial metaplasia of esophagus. The refractory form of disease (lack of conclusive clinical and endoscopic remission during 4-8 weeks of standard-dose PPI therapy), presence of strictures and Barrett's esophagus require EGDS with esophageal biopsy and bioptic histological examination. Patients should be conclusively performed esophageal 24-hour pH-metry or pH-impedance monitoring, high-resolution manometry to thoroughly examine functionality of esophagus, esophagogastric junction and assess disease prognosis and therapy outcomes. Treatment of GERD should be personalised accounting for clinical manifestations and severity, as well as aimed at symptom improvement, lesion healing in erosive esophagitis, averting complications, Barrett's esophagus progression, dysplasia and esophageal adenocarcinoma. Proton pump inhibitors (PPIs) are most effective agents in primary (4-8 weeks) and maintenance anti-GERD therapy. Antacids are recommended in monotherapy for occasional nonerosive heartburn and complex anti-GERD settings for fast symptom improvement. Prokinetics can be used in combination with PPIs for their properties to recover normal functionality of esophagus through affecting pathogenetic mechanisms of GERD. Complicated patients (repeated bleedings, peptic esophageal strictures) are recommended anti-reflux surgery with prior examination of esophageal functionality using pH-impedance and high-resolution manometry. Conclusion . Current recommendations provide an up-to-date evidential medicial review of GERD and guidelines to advance special medical care and timely preventive measures.

Evidence that dysplasia related microRNAs in Barrett's esophagus target PD-L1 expression and contribute to the development of esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is the cancer arising from the esophagus, which frequently develop from Barrett’s esophagus (BE). Extracellular vesicles (EVs), particularly exosomes, are nanosized vesicles of endosomal origin released from various types of cells that have been implicated in cancers. However, the significance of circulating exosomes during the progression of BE to EAC remains unknown. Sera exosmal microRNAs were profiled from 13 EAC and 12BE patients compared to 12 healthy controls. We found a substantial dysregulation of exosomal miRNA levels in BE compared to healthy control, and identified a unique signature of 24 up regulated and 14 down regulated miRNAs. Further validation showed exosomal miR-196a, -26b, -21, and -143 expression was significantly higher in BE and continued to have higher levels in EAC compared to healthy controls; while sera exosomal miR-378, -210, -205, and -200c-3p were significantly lower expressed in BE patients compared to compared to controls. Further, miR-378, -210, -205, and -200c-3p continue to have even lower levels in EAC patients compared to BE. Interestingly, sera expression levels of exosomal miR-15a, -16, and -193a-3p were significantly down regulated in BE PD-L1(+) patients; Sera exosomal miR-15a, -15b, -16, and -193a-3p expression levels in EAC PD-L1(+) patients were significantly lower (all p < 0.01) when compared to EAC PD-L1(-) patients. More importantly, the BE-EAC group had longitudinally decreased exosomal expression levels of miR-15a, -15b, -16, and -193a-3p from BE status to their EAC progression. In conclusion, distinct microRNA expression patterns were demonstrated in circulating exosomes from Barrett’s esophagus and esophageal adenocarcinoma; Furthermore exosomal microRNAs potentially targeting PD-L1 mRNA were down regulated in PD-L1 (+) BE and EAC patients.

Abstract 3604: Identification of genes involved in pathogenesis of esophageal adenocarcinoma using RNA sequencing from laser capture micro-dissected formalin-fixed paraffin-embedded tissue specimens

Abstract Esophageal adenocarcinoma (EAC) is one of the most aggressive human cancers and the only major cancer in the United States with increasing incidence. The overall 5-year survival rate of EAC is below 20 percent and treatment remains largely ineffective due to the high resistance to chemotherapy, despite recent advances in systemic treatment options as well as surgical techniques. Gastroesophageal reflux disease (GERD) causes Barrett's esophagus (BE), a columnar metaplasia containing goblet cells of the esophagus strongly associated with the development of EAC. However, the mechanisms driving EAC development remains poorly understood. In this study, transcriptomic profiling was performed using RNA-sequencing (RNA-seq) on normal, premalignant Barrett's and malignant adenocarcinoma esophageal tissues for better understanding the pathogenesis of EAC. Pure population of cells were collected by laser capture microdissection (LCM) of histologically confirmed formalin-fixed paraffin-embedded (FFPE) esophageal tissues. Total RNA was extracted from micro-dissected sections using the Ambion RecoverAll kit followed by RNA quality assessment using Bioanalyzer to determine the RNA integrity number (RIN) and DV200 metric. 15 RNA samples with sufficient purity and appropriate concentrations were sent for library preparations and sequenced on an Illumina NextSeq500. Differential gene expression and network analysis methods were then applied to discover novel driver genes and pathways for EAC development. Clustering for RNA-seq data shows nice clustering of normal esophagus (NE), Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) samples in relation to gene expression patters. Comparing differentially expressed genes using FDR&amp;lt;0.001 we found many genes differentially expressed, especially between each of the BE and EAC when compared to the NE. Interestingly, there are much less differentially expressed genes when comparing each of the BE and EAD to each other. This shows that BE and EAC are closer to each other than to the normal esophagus, but there are still key differences between them. Using pathway analysis and functional annotation we have identified differentially expressed candidate genes and pathways in BE and EAC involving quite a few pathways including PI3 kinase, focal adhesion kinase and metabolic pathways. In summary, this transcriptomic profiling will improve our understanding of EAC pathogenesis and these candidate genes could be diagnostic and therapeutic targets for EAC. Citation Format: Matthew Guggenbiller, Md Sazzad Hassan, Min Yan, Jun Li, Victoria Makuru, Urs von Holzen. Identification of genes involved in pathogenesis of esophageal adenocarcinoma using RNA sequencing from laser capture micro-dissected formalin-fixed paraffin-embedded tissue specimens [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3604.

Abstract 2593: Inhibition of COX1/2-driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development

Abstract Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes. In this study, COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels in patient biopsy samples. Acetylsalicylic acid (ASA) suppressed BE and EAC growth by targeting the TXA2 pathway in a esophagoduodenostomy mouse model of reflux. Additionally, biopsies from patients showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation in a window opportunity clinical trial. Overall, this study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection. ASA targets the TXA2 pathway and suppresses BE and EAC. Citation Format: Tianshun Zhang, Qiushi Wang, Wei-Ya Ma, Keke Wang, Xiaoyu Chang, Michele L. Johnson, Ruihua Bai, Ann M. Bode, Nathan R. Foster, Gary W. Falk, Prasad G. Iyer, Zigang Dong. Inhibition of COX1/2-driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2593.

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.

Role of submucosal glands in the development and progression of carcinoma in Barrett's oesophagus

Oesophageal submucosal glands secrete mucins and other chemicals that are believed to serve as protectants of the mucosal surface from luminal noxious agents, either ingested or refluxed. Changes in the type, distribution or number of submucosal glands may contribute to, or be associated with, the development of Barrett's oesophagus and progression to cancer. The aim of this study was to investigate the anatomical, morphological and immunohistochemical characteristics of submucosal glands in Barrett's oesophagus-associated neoplasia in 64 oesophageal resections for Barrett's oesophagus-associated adenocarcinoma and 32 squamous cell carcinomas (as a control group). Gland density was not significantly different between the oesophageal adenocarcinoma (0.91/cm) and squamous cell carcinoma (0.81/cm) groups (p=0.7). In the oesophageal adenocarcinoma group, glands underlying Barrett's oesophagus-associated neoplastic epithelium showed a significant decrease in the percentage of mucinous acini and a significant increase in the percentage of atrophic acini compared to glands underlying epithelium without dysplasia or carcinoma (74% vs 83%, p=0.03; and 24% vs 14%, p=0.01). There was also an increase in the percentage of glands with moderate to severe inflammation underlying neoplastic epithelium compared to glands underlying epithelium without dysplasia or carcinoma (53% vs 33%, p=0.001). None of these differences was seen in the squamous cell carcinoma group. The immunohistochemical characteristics of the different histological subtypes were also distinct. Atrophic and oncocytic acini were diffusely and strongly positive for CK7, SOX2, SOX9 and CK5/6 (a progenitor cell phenotype) while mucinous acini showed weak or moderate staining for those markers. Our results suggest that submucosal glands play a role in the progression of neoplasia, possibly by offering less protection to the mucosal surface of the oesophageal epithelium from chemical injury.

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.

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.