Endoscopic Submucosal Dissection for Early Esophageal Adenocarcinoma: Low Rates of Metastases in Mucosal Cancers with Poor Differentiation.

BACKGROUND AND AIMS: Endoscopic resection (ER) is accepted as standard treatment for intramucosal esophageal adenocarcinoma (EAC) with well or moderate differentiation. Poor differentiation (PD) is judged as a risk factor for lymph node metastasis (LNM) and surgery is recommended. However, the evidence for this recommendation is weak. Study aim was to analyze the clinical course of patients after ER of EAC with PD. PATIENTS AND METHODS: Patients undergoing endoscopic submucosal dissection for EAC were included from 16 German centers. Inclusion criteria were PD in the resection specimen, R0 resection and endoscopic follow-up. Primary outcome was the metastasis rate during follow-up. Analysis was performed retrospectively in a prospectively collected database. RESULTS: 25 patients with PD as single risk factor (group A) and 15 patients with PD and additional risk factors (submucosal invasion and/or lymphovascular invasion) were included. The metastasis rate was was 1/25 (4.0%; 95%CI 0.4-17.2) in group A and 3/15 (20.0%; 95%CI 6.0-44.4%) in group B, respectively (p=0.293). The rate of EAC-associated deaths was 1/25 (4%; 95%CI 0.4-17.2%) versus 3/15 (20%; 95%CI 6.0-44.4%) in group B (p=0.293) while the overall death rate was 7/25 (28.0%; 95%CI 13.5-47.3%) versus 3/15 (20%; 95%CI 6.0-44.4%) (p=0.715). Median follow-up was 30 months (IQR 15-53). CONCLUSIONS: During long-term follow-up the risk of metastasis is low after ER of mucosal EAC with PD as single risk factor. A conservative approach seems justified in this small patient group. However, the treatment strategy has to be determined on an individualized basis until further prospective data are available.

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level.

OBJECTIVE: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. DESIGN: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. RESULTS: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. CONCLUSION: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Peroral endoscopic myotomy (POEM) is effective in treatment of noncardiac chest pain caused by hypercontractile esophageal motility disorders: results of the POEM-HYPE-Study.

BACKGROUND: Noncardiac chest pain (NCCP) is recurrent angina pectoris-like pain without evidence of coronary heart disease in conventional diagnostic evaluation. In gastroenterology, managing of patients with NCCP is ambiguous to detect gastroesophageal reflux and hypercontractile esophageal motility disorders. Recently, peroral endoscopic myotomy (POEM) was established as treatment option in achalasia. However, limited data exist on the effectivity of POEM in NCCP with hypercontractile esophageal motility disorders. MATERIAL AND METHODS: In this prospective study (POEM-HYPE), we evaluated 14 patients with NCCP and hypercontractile esophageal motility disorders (type III achalasia, n = 7; hypercontractile esophagus, n = 6; distal esophageal spasm, n = 1). All patients underwent standardized diagnostic work-up including esophagogastroduodenoscopy with esophageal biopsies, high-resolution esophageal manometry, and combined intraluminal impedance and pH testing before and 3 weeks after POEM. A standardized symptom questionnaire was disposed before POEM, 3 weeks after, and every 6 months after the POEM. RESULTS: After POEM, 12 patients showed significant symptom relief (pre-Eckardt score: 7.78 ±â€Š1.47, 3 weeks post: 1.64 ± 1.44, 6 months: 2.0 ±â€Š1.84 and 1.86 ±â€Š1.89 after 15.0 ±â€Š10.0 months post-intervention). High-resolution manometry showed significant reduction in integrated relaxation pressure (pre-POEM: 24.74 ±â€Š18.9 mm Hg, post-POEM: 13.8 ±â€Š16.5 mm Hg) and distal contractile integral (pre-POEM: 2880 ±â€Š3700 mmHg*s*cm, post-POEM: 1109 ±â€Š1042 mmHg*s*cm). One lesion of the submucosal tunnel occurred as a moderate adverse event and was handled endoscopically. The long-term clinical success rate was 85.7 %. No severe gastroesophageal reflux occurred after interventions. Two patients required secondary therapy with injection of botulinum toxin in the tubular esophagus and balloon dilation. CONCLUSION: The results suggest that POEM is an effective and safe therapeutic option for patients with NCCP and hypercontractile esophageal motility disorders.

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.