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Esophageal adenocarcinoma (EAC) is an aggressive cancer necessitating the development of improved risk stratification tools for personalized care. Previously, microRNAs have been shown to correlate with the progression and prognosis of various cancer types; however, the value in EAC remains largely unexplored. We performed global microRNA profiling on 32 formalin-fixed, paraffin-embedded EAC specimens to identify microRNAs associated with progression. Literature search and pathway analysis further refined output to five significantly deregulated candidate biomarkers. Four of the five microRNAs (miR-652-5p, miR-7-2-3p, miR-3925-3p, and miR-219-3p) were validated by qRT-PCR. Survival outcomes were evaluated in testing set of 26 stage II/III EAC patients to determine the prognostic relevance of the selected microRNAs. In the testing set, miR-652-5p and miR-7-2-3p expressions were significantly associated with progression-free survival (p-value = .00771 and p-value = .00293). The highest area under receiver operating characteristic (ROC) curve was 0.8212 for the combination of miR-652-5p and miR-7-2-3p. Collectively, our findings demonstrated that the miR-652-5p/miR-7-2-3p signature may serve as a promising prognostic marker in patients with locally advanced EAC.

Background: Treatment of esophageal adenocarcinoma often involves surgical resection. Newer technologies in interventional endoscopy have led to a substantial paradigm shift in the management of early-stage neoplasia in Barrett's esophagus comprising high-grade dysplasia (HGD), intramucosal carcinoma, and, in some cases, submucosal carcinoma. However, there has been no consensus regarding the indications for esophageal preservation in these cases. In this work, consensus guidelines were established for the management of early-stage esophageal neoplasia considering clinically relevant aspects (age, comorbidities, and social environment) in each scenario., Methods: Seventeen experts were invited to participate based on their background and clinical expertise at high-volume centers. A questionnaire was created that included four clinical scenarios covering a wide range of situations within HGD and/or early esophageal neoplasia, particularly where controversies are likely to exist. Each of the clinical scenarios was open to discussion subdivided by patient age (20, 50, and 80 s). For each clinical scenario an expert was chosen to defend that position. Each defense triggered a subsequent discussion during a consensus meeting. Conclusions of that discussion together with an accompanying literature analysis allowed experts to confirm or change their original choices and served as the basis for the recommendations stated in this article., Results: There was 100 % consensus supporting esophageal preservation in patients with HGD, independent of patient age or Barrett's length. In patients with T1a adenocarcinoma, consensus for preservation was not reached (65 %) for young and middle-aged individuals but was supported for elderly patients (100 %). For T1b adenocarcinoma, consensus was reached for surgical resection (90 %), leaving organ preservation for patients with very low risk of nodal invasion or poor surgical candidates., Conclusion: Advances in endoscopic imaging and therapy allow for organ preservation in most settings of early-stage neoplasia of the esophagus, provided that the patient understands the implications of this decision.

Background: Survivin is an inhibitor of apoptosis and its over expression is associated with poor prognosis in several malignancies. While several studies have analyzed survivin expression in esophageal squamous cell carcinoma, few have focused on esophageal adenocarcinoma (EAC) and/or cancer-adjacent squamous epithelium (CASE). The purpose of this study was 1) to determine the degree of survivin up regulation in samples of EAC and CASE, 2) to evaluate if survivin expression in EAC and CASE correlates with recurrence and/or death, and 3) to examine the effect of survivin inhibition on apoptosis in EAC cells., Methods: Fresh frozen samples of EAC and CASE from the same patient were used for qRT-PCR and Western blot analysis, and formalin-fixed, paraffin-embedded tissue was used for immunohistochemistry. EAC cell lines, OE19 and OE33, were transfected with small interfering RNAs (siRNAs) to knockdown survivin expression. This was confirmed by qRT-PCR for survivin expression and Western blot analysis of cleaved PARP, cleaved caspase 3 and survivin. Survivin expression data was correlated with clinical outcome., Results: Survivin expression was significantly higher in EAC tumor samples compared to the CASE from the same patient. Patients with high expression of survivin in EAC tumor had an increased risk of death. Survivin expression was also noted in CASE and correlated with increased risk of distant recurrence. Cell line evaluation demonstrated that inhibition of survivin resulted in an increase in apoptosis., Conclusion: Higher expression of survivin in tumor tissue was associated with increased risk of death; while survivin expression in CASE was a superior predictor of recurrence. Inhibition of survivin in EAC cell lines further showed increased apoptosis, supporting the potential benefits of therapeutic strategies targeted to this marker.

The Hedgehog (Hh) pathway is known to be active in Barrett's carcinogenesis. Therefore, we evaluated the efficacy and underlying mechanisms of inhibition of cancer cell growth by the smoothened (Smo) antagonist BMS-833923 in esophageal adenocarcinoma (EAC) cell lines. Cell proliferation and apoptosis were evaluated by flow cytometry, Western blotting, immunofluorescence, and quantitative reverse transcription polymerase chain reactions. Results showed that the Smo antagonist led to reduced Hh pathway activity, resulting in decreased cell proliferation and induction of apoptosis via the intrinsic pathway in the esophageal cancer cells. In conclusion, the Smo antagonist may have application as an EAC chemotherapeutic agent.

Background: Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis., Methods: GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed., Results: Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene)., Conclusions: Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.

Surgical resection remains the mainstay of potentially curative therapy for gastroesophageal junction (GEJ) tumors. However, because of the location of the tumor at the boundary between the esophagus and stomach, GEJ tumors have been a source of controversy in regard to their definition, classification, staging and surgical management. The definition of GEJ tumors was addressed with the development of the three-tiered Siewert's classification scheme. There remain many controversies regarding the appropriate surgical approach and the extent of the lymphadenectomies for these tumors. For locally advanced, resectable GEJ tumors, an aggressive surgical resection should be considered and the approach predicated by tumor location as defined by the Siewert's classification. Limited resections for earlier stage tumors have also been evaluated., (Copyright © 2013. Published by Elsevier Inc.)

Background: The optimal treatment strategy of esophageal high-grade dysplasia (HGD) and superficial adenocarcinoma remains controversial., Methods: Here, we describe endoscopic, circumferential mucosal-submucosal en-bloc resection of the entire abnormal esophageal epithelium with extracellular matrix (ECM) placement to regenerate neoepithelium and minimize stricture. That procedure was then followed by a laparoscopic fundoplication as a novel esophageal-preserving approach to treat HGD and superficial adenocarcinoma in the face of chronic gastroesophageal reflux disease (GERD)., Conclusions: This approach could be an ideal option as an alternative to esophagectomy in selected patients.

The management of esophageal high-grade dysplasia (HGD) and intramucosal adenocarcinoma remains controversial. Because lymph node involvement is unlikely in this setting, interest in the treatment strategies for esophageal preservation has grown. Esophageal preservation indicates any endoluminal procedure that is used in an attempt to completely eradicate disease while preserving the anatomic structure of the esophagus. The goal of esophagus-preserving approaches is to provide definitive therapy while avoiding the morbidity of esophagectomy. This article describes the patient selection and the status of currently available esophagus-preserving options, and discusses the strategy for treating HGD and intramusocal adenocarcinoma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: Endoscopic local procedures are increasingly applied in patients with superficial esophageal cancer as an alternative to radical oncologic resection. The objective of this article is to determine the risk of nodal metastases in submucosal (sm) esophageal cancer, comparing the two predominating histologic tumor types, squamous cell cancer (SCC) and adenocarcinoma (ADC)., Methods: A query of PubMed, MEDLINE, Embase and Cochrane Library (1980-2009) using predetermined search terms revealed 675 abstracts, of which 485 full-text articles were reviewed. A total of 105 articles met the selection criteria. A review of article references and consultation with experts revealed additional articles for inclusion. Studies that enrolled patients with submucosal esophageal cancer and provided adequate extractable data were included., Results: The pooled outcomes of 7645 patients with esophageal cancer involving the sm level of infiltration were included in the analysis. Overall, the percentage of lymph node metastasis in submucosal cancer was 37%. Lymph node (N), lymphatic (L) and vascular (V) invasion in sm1 esophageal cancers was 27, 46 and 22%, respectively. Within sm2 lesions, N, L and V invasion were involved in 38, 63 and 38% of patients, respectively. Finally, N, L and V involvement in patients with sm3 lesions was 54, 69 and 47%, respectively. The rates of lymph node metastasis for sm1 and sm2 were higher in SCC compared with ADC, whereas the lymph node metastasis for sm3 was comparable, with >50% involvement in both histologic subtypes. SCC revealed an overall more aggressive behavior compared with ADC (N+: 45 vs 26%; L+: 57 vs 37%; V+: 40 vs 18%)., Discussion: While endoscopic therapy may be adequate in selected patients with 'low-risk' sm1 ADC, submucosal SCC necessitates esophageal resection and systematic lymphadenectomy because of its aggressive nature and tendency for early metastasis.