Esophageal Mucosa

PurposeEndoscopic submucosal dissection (ESD) is widely used to treat esophageal cancer, but some patients require additional treatment due to the possibility of lymph node metastasis. The aim of this study was to elucidate the clinical outcomes of these additional treatments.MethodsThe study included 59 patients who developed superficial esophageal squamous cell carcinoma after noncurative ESD treated between 2005 and 2016, of whom 28 underwent esophagectomy and 31 received chemoradiotherapy (CRT).ResultsThe median follow-up periods were 45 months in the esophagectomy group and 41 months in the CRT group. The overall survival did not differ significantly between the groups (P = 0.46). However, there were no recurrences in the esophagectomy group, and the disease-specific survival rate was significantly higher in this group (P = 0.042). Among the patients at high risk for recurrence due to massive tumor invasion (≥ SM2) with lymphovascular invasion (esophagectomy group, six patients; CRT group, ten patients), none in the esophagectomy group had recurrence, whereas four in the CRT group died of esophageal cancer (P = 0.031).ConclusionThe overall survival did not differ significantly between the groups. However, compared with CRT, esophagectomy provided more favorable disease control for patients with massive tumor invasion (≥ SM2) with lymphovascular invasion.

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Herein, we conduct whole-exome sequencing of a multigeneration EoE pedigree (discovery set) and 61 additional multiplex families with EoE (replication set). A series of rare, heterozygous, missense variants are identified in the genes encoding the desmosome-associated proteins DSP and PPL in 21% of the multiplex families. Esophageal biopsies from patients with these variants retain dilated intercellular spaces and decrease DSP and PPL expression even during disease remission. These variants affect barrier integrity, cell motility and RhoGTPase activity in esophageal epithelial cells and have increased susceptibility to calpain-14-mediated degradation. An acquired loss of esophageal DSP and PPL is present in non-familial EoE. Taken together, herein, we uncover a pathogenic role for desmosomal dysfunction in EoE, providing a deeper mechanistic understanding of tissue-specific allergic responses.

The Montreal definition of gastroesophageal reflux disease (GERD) provided a rationale for acid suppression medication without investigation, thus enhancing the management of the substantial symptom burden in these patients. Increased proton-pump inhibitor use has also highlighted their limitations, with one third of "typical" symptoms known to be refractory. Most refractory symptoms are ascribed to reflux hypersensitivity (RH) and functional heartburn (FH). RH may be caused by impaired esophageal mucosal barrier function and sensitization of peripheral esophageal receptors. Central sensitization may also contribute to the perception of non-pathologic reflux in RH, and the perception of physiological stimuli in FH. Importantly, mechanisms underlying GERD, RH, and FH are (in theory) not mutually exclusive, further complicating patient management. Methods used to distinguish GERD from RH and FH are impractical for use in epidemiological studies and pragmatic care and may have limited diagnostic accuracy. This is impeding accurate prevalence estimates and risk factor determination and the identification of new therapies. Direct assessment of mucosal barrier function by measuring impedance is a promising candidate for improved diagnosis. Ultimately though the concept of GERD as a composite, symptom-based entity needs re-evaluation, so that new understandings of upper GI symptoms can direct more precise management.

BackgroundEosinophilic esophagitis (EoE) is a chronic allergic disorder driven by type 2 inflammation, characterized by eosinophilic infiltration and esophageal epithelial abnormalities, including barrier dysfunction, basal cell hyperplasia, epithelial thickening, and loss of differentiation. Although proton pump inhibitor (PPI) therapy is frequently employed in the management of EoE and is known to reduce esophageal eosinophilia, improve barrier function, and exert anti-inflammatory effects, the precise mechanism by which PPIs modulate type 2 inflammation and epithelial integrity remains incompletely understood.MethodsAir-liquid interface culture of esophageal epithelial cells was used to investigate the impact of the PPI omeprazole on barrier integrity in IL-13-treated cultures. Epithelial chemokine secretion was assessed following stimulation with IL-13 and omeprazole, and eosinophil migration from healthy human donors was evaluated using 3 μm pore-sized transwells. A co-culture system of epithelial cells and eosinophils was used to examine chemokine secretion, eosinophil adhesion, and activation marker expression.ResultsOmeprazole treatment of IL-13-treated air-liquid interface (ALI) cultures restored barrier integrity compared with IL-13-treated ALI cultures and resulted in 186 differentially expressed genes. Omeprazole treatment reduced STAT6 phosphorylation, downregulated calpain 14 expression, and upregulated desmoglein-1 in IL-13-treated ALI samples. IL-13 treatment induced upregulation of Eotaxin-3, CXCL10, and periostin, which were downregulated by omeprazole. Eosinophils co-cultured with human esophageal epithelial cells in the presence of omeprazole had diminished CD11b, CD18, and CD69 expression compared to those cultured with IL-13 alone, and less eotaxin-3, CXCL10, CCL2, and CCL4 were recovered from the co-culture media.ConclusionOmeprazole diminished the effects of IL-13 in both the epithelial air-liquid interface model and eosinophil-epithelial co-cultures, alleviating barrier dysfunction, chemokine expression, and the upregulation of eosinophil adhesion markers.