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Purpose: Definitive chemoradiotherapy (dCRT) is one of the standard treatments for esophageal squamous cell carcinoma. Patients with a response to dCRT have a better prognosis than those resistant to dCRT while survival benefits for patients with residual tumors are limited. Nevertheless, few molecular markers to predict the response to dCRT are currently available. Here, we aimed to establish a DNA methylation marker to predict the response to dCRT., Methods: A total of 104 patients were divided into screening (n = 43) and validation (n = 61) sets. A genome-wide DNA methylation analysis was performed using an Infinium HumanMethylation450 BeadChip array. Methylation levels were measured by quantitative methylation-specific PCR and normalized by the fraction of cancer cells in a sample., Results: The genome-wide methylation analysis of seven responders and eight non-responders identified 18 genomic regions specifically (un)methylated in the responders. Among these, methylation of the promoter CpG island of ZNF695 was significantly associated with the response to dCRT in the screening set (P = 0.004), and a cutoff value was determined. In the validation set, the association was successfully validated (P = 0.021), and a high specificity (90 %) for the prediction of responders was obtained using the prefixed cutoff value. In addition, a multivariate analysis showed that ZNF695 methylation was an independent predictive factor for the response to dCRT (OR 7.55, 95 % CI 2.12-26.9, P = 0.002)., Conclusion: ZNF695 methylation was significantly associated with the response to dCRT and is a promising predictive marker for the response to dCRT.

Objectives: The objective of this study was to review the prognostic factors for increased survival after salvage esophagectomy after definitive chemoradiotherapy for esophageal squamous carcinoma and determine the importance of lymphadenectomy from a prognostic view., Methods: Clinical data for all patients from January 1999 to December 2012 who underwent salvage esophagectomy for residual tumor or tumor recurrence after definitive chemoradiotherapy were retrospectively collected. Survival was determined and prognostic factors were analyzed with univariate and multivariate analyses., Results: Survival after 1, 3, and 5 years postoperatively was 74.4%, 39.8%, and 29.5%, respectively. The independent predictive factors for increased postoperative survival were tumor recurrence rather than residual tumor as the indication for salvage surgery (P < .001; odds ratio [OR], 0.292); complete tumor resection (P < .001; OR, 4.520); N category (P = .089; OR, 1.304); M category (P = .081; OR, 2.215), and total mediastinal dissection with 15 or more dissected mediastinal lymph nodes (P = .034; OR, 0.546)., Conclusions: Salvage indications of recurrence, earlier disease, and complete tumor resection are related to longer survival. The total area of mediastinal dissection with a sufficient number of dissected mediastinal lymph nodes improves survival. Additional neck dissection does not add benefit. The optimal procedure for lymph node dissection in salvage esophagectomy should be established in future studies., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Definitive chemoradiotherapy (dCRT) is the major treatment for esophageal squamous cell carcinoma (ESCC), and prediction of the response to dCRT is important so as not to miss an opportunity to cure an ESCC. Nevertheless, few validated markers are available. Here, we aimed to identify a highly reproducible marker using multi-layer omics analysis. 117 ESCC samples from 67 responders and 50 non-responders were divided into screening, validation, and re-validation sets. In the screening cohort (n = 41), somatic mutations in 114 genes showed no association with dCRT response. Genome-wide DNA methylation analysis using Infinium HumanMethylation450 BeadChip array identified four genic regions significantly associated with dCRT response. Among them, FGF5 methylation was validated to be associated with dCRT response (n = 34; P = 0.001), and further re-validated (n = 42; P = 0.020) by bisulfite-pyrosequencing. The sensitivity and specificity in the combined validation and re-validation sets (n = 76) were 45% and 90%, respectively, by using the cut-off value established in the screening set, and FGF5 methylation had predictive power independent from clinicopathological parameters. In ESCC cell lines, FGF5 promoter methylation repressed its expression. FGF5 expression was induced by cisplatin (CDDP) treatment in three unmethylated cell lines, but not in two methylated cell lines. Exogenous FGF5 overexpression in a cell line with its methylation conferred resistance to CDDP. In non-cancerous esophageal tissues, FGF5 was not expressed, and its methylation was present in a small fraction of cells. These results showed that FGF5 methylation is a validated marker for ESCC sensitivity to dCRT. [ABSTRACT FROM AUTHOR]