Future of image enhanced endoscopy of esophageal adenocarcinoma.

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

Issue Highlights

Is Complete Endoscopic Resection Still a Viable Option for Barrett’s-Related Dysplasia and Neoplasia?

SummaryBackgroundOesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma.MethodsWe did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms.FindingsOur sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC00208 and BLK (rs10108511; p=2·1 × 10−9), KHDRBS2 (rs62423175; p=3·0 × 10−9), TPPP and CEP72 (rs9918259; p=3·2 × 10−9), TMOD1 (rs7852462; p=1·5 × 10−8), SATB2 (rs139606545; p=2·0 × 10−8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10−8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10−8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10−6) belonged to muscle cell differentiation and to mesenchyme development and differentiation.InterpretationOur meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies.FundingUS National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.

Objective. To investigate the relationship between use of asthma medication and nitrates and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Material and methods. Data were collected on use of asthma medication and nitrates at least 1 year before interview from patients with reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Associations between use of asthma medications and nitrates and the risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma were estimated using multiple logistic regression. Results. Nine hundred and forty-one subjects were recruited: 230 reflux oesophagitis, 224 Barrett's oesophagus, 227 oesophageal adenocarcinoma patients and 260 population controls. Barrett's oesophagus patients were more likely than controls to have had a diagnosis of asthma (odds ratio 2.15, 95% confidence interval 1.15–4.03) and to have used asthma medications (odds ratio 2.13, 95% confidence interval 1.09–4.16). No significant associations were observed between use of asthma medication or nitrates and reflux oesophagitis or oesophageal adenocarcinoma. Conclusions. Gastro-oesophageal reflux symptoms appear to confound the association between asthma medication use and Barrett's oesophagus. However, it is possible that asthma medications may increase the risk of Barrett's oesophagus by other mechanisms.

Cost-Effectiveness of Endoscopic Screening Followed by Surveillance for Barrett's Esophagus: A Review

Purpose: Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma.Experimental Design: Here we utilized an IL1β transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis.Results: IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer.Conclusion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. Clin Cancer Res; 24(5); 1048-61. ©2017 AACR.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Here we utilized an &lt;i&gt;IL1β&lt;/i&gt; transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4&lt;sup&gt;+&lt;/sup&gt;) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4&lt;sup&gt;+&lt;/sup&gt; columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in &lt;i&gt;ex vivo&lt;/i&gt; fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusion:&lt;/b&gt; In conclusion, the recruitment of CXCR4&lt;sup&gt;+&lt;/sup&gt; immune cells and expansion of CXCR4&lt;sup&gt;+&lt;/sup&gt; epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. &lt;i&gt;Clin Cancer Res; 24(5); 1048–61. ©2017 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Here we utilized an &lt;i&gt;IL1β&lt;/i&gt; transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4&lt;sup&gt;+&lt;/sup&gt;) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4&lt;sup&gt;+&lt;/sup&gt; columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in &lt;i&gt;ex vivo&lt;/i&gt; fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusion:&lt;/b&gt; In conclusion, the recruitment of CXCR4&lt;sup&gt;+&lt;/sup&gt; immune cells and expansion of CXCR4&lt;sup&gt;+&lt;/sup&gt; epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. &lt;i&gt;Clin Cancer Res; 24(5); 1048–61. ©2017 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Alcohol Drinking and the Risk of Barrett's Esophagus and Esophageal Adenocarcinoma

The incidence of esophageal adenocarcinoma has increased dramatically over recent years and Barrett's esophagus is considered the most established risk factor for its development. Endoscopic surveillance of Barrett's esophagus is therefore recommended but hinges on histological interpretation of randomly taken biopsies which is poorly reproducible. The use of biomarkers presents an opportunity to improve our ability to risk-stratify these patients.We examined three biomarkers namely p504s, CD133, and Twist in the setting of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma to evaluate differential expression between benign, dysplastic, and malignant Barrett's tissue in an exploratory cross-sectional study. Twenty-five cases each of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma were included along-with 25 cases of esophagectomy resections for Barrett's adenocarcinoma. The biomarkers were immunostained on automated Ventana(®) immunostainer. The biopsies were assessed for biomarker expression by two independent observers. Granular cytoplasmic staining of p504s was observed in dysplastic Barrett's biopsies and esophageal adenocarcinoma but not in Barrett's esophagus. Apical and membranous CD133 expression was also observed in dysplastic Barrett's and esophageal adenocarcinoma. Nuclear Twist expression was seen predominantly in stromal cells. There was increased p504s expression in dysplastic Barrett's esophagus and esophageal adenocarcinoma compared with controls. CD133 expression was detected for the first time in esophageal adenocarcinoma and dysplastic Barrett's esophagus. Twist expression was not convincing enough to be labeled as Barrett's biomarker. p504s and CD133 have the potential to differentiate benign from malignant Barrett's tissue in this exploratory study. Their validity should be established in prospective longitudinal studies.

Tips for improving the identification of neoplastic visible lesions in Barrett’s esophagus

&lt;div&gt;Abstract&lt;p&gt;Esophageal adenocarcinoma is an increasingly common disease with a dismal 5-year survival rate of 10% to 15%. In the first systematic evaluation of the PD-1 pathway in esophageal adenocarcinoma, we identify expression of PD-L2 in cancer cells in 51.7% of esophageal adenocarcinomas. Epithelial PD-L1 was expressed on only 2% of cases, although PD-L1&lt;sup&gt;+&lt;/sup&gt; immune cells were observed in 18% of esophageal adenocarcinomas. We also evaluated expression in the precursor lesion of esophageal adenocarcinoma, Barrett's esophagus, which emerges following gastric reflux–induced esophageal inflammation, and found PD-L2 expression in Barrett's esophagus but not in non–Barrett's esophagus esophagitis. Because the progression from squamous esophagitis to Barrett's esophagus is accompanied by a transition from a T&lt;sub&gt;H&lt;/sub&gt;1 to T&lt;sub&gt;H&lt;/sub&gt;2 immune response, we hypothesized that the T&lt;sub&gt;H&lt;/sub&gt;2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in esophageal adenocarcinoma cell lines. These results suggest that the inflammatory environment in Barrett's esophagus and esophageal adenocarcinoma may contribute to the expression of PD-L2. Furthermore, the potential for PD-1 receptor blockade to be effective in esophageal adenocarcinomas with epithelial PD-L2 or immune cell PD-L1 expression should be evaluated in clinical trials. &lt;i&gt;Cancer Immunol Res; 3(10); 1123–9. ©2015 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

There has been a dramatic rise in incidences of Barrett's oesophagus and oesophageal adenocarcinoma. It has been suggested that the introduction and use of acid suppression therapy may be a factor in the rising incidences of Barrett's oesophagus and oesophageal adenocarcinoma. This was a record linkage study, using a prescribing database and an endoscopy database. Patients who had undergone their first endoscopy during the period 1992-1995 and received the diagnosis of Barrett's oesophagus or oesophagitis were identified. The prescribing of acid suppressants was compared for the 3 years prior to endoscopy, between those with Barrett's oesophagus and those with oesophagitis. There was no significant difference between the Barrett's patients and the oesophagitis patients in the proportion that had been exposed to acid suppression therapy (53.4% vs. 51.7%, P=0.704). The mean number of days of prescribing among those who had been exposed to acid suppression therapy was higher in the Barrett's group (340.5 vs. 237.0 days, P=0.001). Patients with Barrett's oesophagus have received more acid suppressant therapy prior to diagnosis. The reasons for this are not clear. However, 46.6% of Barrett's patients have not been exposed to acid suppressant therapy.

Hypomethylation of Noncoding DNA Regions and Overexpression of the Long Noncoding RNA, AFAP1-AS1, in Barrett's Esophagus and Esophageal Adenocarcinoma