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Concept: Barrett's esophagus

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Patients with Barrett’s esophagus (BE) are at an increased risk for developing esophageal adenocarcinoma (EAC); thus they may undergo regular endoscopic surveillance. If epithelial changes cannot be unequivocally classified as negative or positive for dysplasia, a diagnosis of indefinite for dysplasia (IND) is recommended. Several biomarkers have been proposed as markers or predictors of neoplasia in the general BE population; however, their significance is not clear in patients with BE-IND. We therefore performed a retrospective study to determine whether expression of these biomarkers was associated with the development of neoplasia in BE-IND patients.

Concepts: Cancer, Oncology, Retrospective, Gastroesophageal reflux disease, Esophagogastroduodenoscopy, Esophageal cancer, Barrett's esophagus, Metaplasia

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Gastroesophageal reflux disease (GERD) is associated with obesity and hiatal hernia, and often precedes the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). Epidemiological studies show that the global prevalence of GERD is increasing. GERD is a multifactorial disease with a complex genetic architecture. Genome-wide association studies (GWAS) have provided initial insights into the genetic background of GERD. The present review summarizes current knowledge of the genetics of GERD and a possible genetic overlap between GERD and BE and EA. The review discusses genes and cellular pathways that have been implicated through GWAS, and provides an outlook on how future molecular research will enhance understanding of GERD pathophysiology.

Concepts: Genetics, Epidemiology, Asthma, Obesity, Gastroenterology, Gastroesophageal reflux disease, Esophageal cancer, Barrett's esophagus

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Background There is convincing evidence that alcohol consumption increases the risk of cancer of the colorectum, breast, larynx, liver, esophagus, oral cavity and pharynx. Most of the data derive from studies that focused on the effect of moderate/high alcohol intakes, while little is known about light alcohol drinking (up to 1 drink/day). Patients and methods We evaluated the association between light drinking and cancer of the colorectum, breast, larynx, liver, esophagus, oral cavity and pharynx, through a meta-analytic approach. We searched epidemiological studies using PubMed, ISI Web of Science and EMBASE, published before December 2010. Results We included 222 articles comprising ∼92 000 light drinkers and 60 000 non-drinkers with cancer. Light drinking was associated with the risk of oropharyngeal cancer [relative risk, RR = 1.17; 95% confidence interval (CI) 1.06-1.29], esophageal squamous cell carcinoma (SCC) (RR = 1.30; 95% CI 1.09-1.56) and female breast cancer (RR = 1.05; 95% CI 1.02-1.08). We estimated that ∼5000 deaths from oropharyngeal cancer, 24 000 from esophageal SCC and 5000 from breast cancer were attributable to light drinking in 2004 worldwide. No association was found for colorectum, liver and larynx tumors. Conclusions Light drinking increases the risk of cancer of oral cavity and pharynx, esophagus and female breast.

Concepts: Epidemiology, Cancer, Breast cancer, Squamous cell carcinoma, Squamous epithelium, Esophagus, Esophageal cancer, Barrett's esophagus

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Endoscopic cryotherapy can eradicate neoplastic Barrett’s esophagus (BE). A new contact cryoballoon focal ablation system (CbFAS)) freezes esophageal mucosa with nitrous oxide. We studied the safety and efficacy of CbFAS for complete eradication of neoplastic Barrett’s esophagus.

Concepts: Esophageal cancer, Barrett's esophagus

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We report a biomarker-based non-endoscopic method for detecting Barrett’s esophagus (BE) based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma. Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve of 0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 min. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE.

Concepts: DNA, Restriction enzyme, Type I and type II errors, DNA methylation, Methylation, DNA methyltransferase, Esophageal cancer, Barrett's esophagus

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Also available: Consumer Reports Patient Resource on High-Value Care for GERD BACKGROUND: Upper endoscopy is commonly used in the diagnosis and management of gastroesophageal reflux disease (GERD). Evidence demonstrates that it is indicated only in certain situations, and inappropriate use generates unnecessary costs and exposes patients to harms without improving outcomes. METHODS: The Clinical Guidelines Committee of the American College of Physicians reviewed evidence regarding the indications for, and yield of, upper endoscopy in the setting of GERD, and to highlight how clinicians can increase the delivery of high-value health care. BEST PRACTICE ADVICE 1: Upper endoscopy is indicated in men and women with heartburn and alarm symptoms (dysphagia, bleeding, anemia, weight loss, and recurrent vomiting). BEST PRACTICE ADVICE 2: Upper endoscopy is indicated in men and women with:      Typical GERD symptoms that persist despite a therapeutic trial of 4 to 8 weeks of twice-daily proton-pump inhibitor therapy.      Severe erosive esophagitis after a 2-month course of proton-pump inhibitor therapy to assess healing and rule out Barrett esophagus. Recurrent endoscopy after this follow-up examination is not indicated in the absence of Barrett esophagus.      History of esophageal stricture who have recurrent symptoms of dysphagia. BEST PRACTICE ADVICE 3: Upper endoscopy may be indicated:      In men older than 50 years with chronic GERD symptoms (symptoms for more than 5 years) and additional risk factors (nocturnal reflux symptoms, hiatal hernia, elevated body mass index, tobacco use, and intra-abdominal distribution of fat) to detect esophageal adenocarcinoma and Barrett esophagus.      For surveillance evaluation in men and women with a history of Barrett esophagus. In men and women with Barrett esophagus and no dysplasia, surveillance examinations should occur at intervals no more frequently than 3 to 5 years. More frequent intervals are indicated in patients with Barrett esophagus and dysplasia.

Concepts: Obesity, Gastroenterology, Gastroesophageal reflux disease, Esophagogastroduodenoscopy, Achalasia, Esophageal cancer, Barrett's esophagus, Esophageal stricture

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Bacteria may play a role in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although evidence is limited to cross-sectional studies. In this study, we examined the relationship of oral microbiota with EAC and ESCC risk in a prospective study nested in two cohorts. Oral bacteria were assessed using 16S rRNA gene sequencing in prediagnostic mouthwash samples from n = 81/160 EAC and n = 25/50 ESCC cases/matched controls. Findings were largely consistent across both cohorts. Metagenome content was predicted using PiCRUST. We examined associations between centered log-ratio transformed taxon or functional pathway abundances and risk using conditional logistic regression adjusting for BMI, smoking, and alcohol. We found the periodontal pathogen Tannerella forsythia to be associated with higher risk of EAC. Furthermore, we found that depletion of the commensal genus Neisseria and the species Streptococcus pneumoniae was associated with lower EAC risk. Bacterial biosynthesis of carotenoids was also associated with protection against EAC. Finally, the abundance of the periodontal pathogen Porphyromonas gingivalis trended with higher risk of ESCC. Overall, our findings have potential implications for the early detection and prevention of EAC and ESCC. Cancer Res; 77(23); 6777-87. ©2017 AACR.

Concepts: Archaea, Bacteria, Pneumonia, Ribosomal RNA, 16S ribosomal RNA, Squamous cell carcinoma, Esophageal cancer, Barrett's esophagus

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In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett’s oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett’s oesophagus in terms of the presence of intestinal goblet cells. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63(+)KRT5(+)KRT7(+)) at the squamous-columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous-columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett’s metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett’s oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63(+)KRT5(+)KRT7(+) basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett’s oesophagus.

Concepts: Digestive system, Epithelium, Gastroenterology, Stomach, Squamous epithelium, Epithelial cells, Goblet cell, Barrett's esophagus

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Patients with gastroesophageal reflux disease (GERD) often seek alternative therapy for inadequate symptom control, with over 40 % not responding to medical treatment. We evaluated the long-term safety, efficacy, and durability of response to radiofrequency treatment of the lower esophageal sphincter (Stretta).

Concepts: Medicine, Obesity, Gastroesophageal reflux disease, Esophagus, Cardia, Esophageal cancer, Barrett's esophagus, Stretta procedure

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Esophageal cancer (EsC) is one of the least studied and deadliest cancers worldwide because of its extremely aggressive nature and poor survival rate. It ranks sixth among all cancers in mortality. In retrospective studies of EsC, smoking, hot tea drinking, red meat consumption, poor oral health, low intake of fresh fruit and vegetables, and low socioeconomic status have been associated with a higher risk of esophageal squamous cell carcinoma. Barrett’s esophagus is clearly recognized as a risk factor for EsC, and dysplasia remains the only factor useful for identifying patients at increased risk, for the development of esophageal adenocarcinoma in clinical practice. Here, we investigated the epidemiologic patterns and causes of EsC. Using population based cancer data from the Surveillance, Epidemiology and End Results Program of the United States; we generated the most up-to-date stage distribution and 5-year relative survival by stage at diagnosis for 1998-2009. Special note should be given to the fact that esophageal cancer, mainly adenocarcinoma, is one of the very few cancers that is contributing to increasing death rates (20%) among males in the United States. To further explore the mechanism of development of EsC will hopefully decrease the incidence of EsC and improve outcomes.

Concepts: Epidemiology, Cancer, Lung cancer, Obesity, Carcinoma, Squamous cell carcinoma, Esophageal cancer, Barrett's esophagus