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Objective: Delayed esophagectomy (DE) following chemoradiation therapy (CXRT) for esophageal carcinoma is undertaken in selected patients. This study aimed to assess both short-term outcomes and long-term survival for patients with adenocarcinoma undergoing DE., Methods: The National Cancer Database was queried for patients with American Joint Committee on Cancer clinical stage II-III esophageal adenocarcinoma undergoing esophagectomy after CXRT. Patients were categorized as (1) DE, ≥90 days between completion of CXRT and surgery or (2) nondelayed esophagectomy (NDE), <90 days. Cox regression was performed to identify factors associated with mortality., Results: A total of 8157 patients met criteria. Age >69, nonwhite race, Medicare/Medicaid insured patients preferentially underwent DE. Five-year overall survival (OS) favored NDE (36% vs. 31%, p = 0.008). Cox regression identified DE, clinical stage >T2, or >N0 as factors associated with mortality. Within the DE group, OS favored early cT-status. DE fared worse than NDE in 30- and 90-day mortality (4.5%/11.1% vs. 2.9%/6.5%, p < 0.01/p < 0.001) and margin positive resection (7.1% vs. 4.2%, p < 0.001)., Conclusions: For esophageal adenocarcinoma, DE is associated with decreased OS compared to NDE. For DE, cT-status is prognostic for OS, while cN-status was not. Increased 30-/90-day mortality and margin positive resection rates for DE question whether patients with locally advanced (cT3/T4) primary esophageal adenocarcinoma should undergo intentional DE., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Esophageal cancer remains a significant cause of cancer-related mortality among men and women in the United States. The utility of surgery, as either an immediate or delayed resection in the form of esophagectomy following neoadjuvant therapy in local-regionally advanced esophageal cancer, remains controversial. While neoadjuvant therapy followed by immediate surgery is a guideline-concordant treatment, emerging data suggests that active surveillance with delayed resection at the time of local-regional recurrence may be considered., (© 2023 Wiley Periodicals LLC.)

Background: Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas., Methods: Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and β-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability., Results: Sequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01). Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-β-catenin complex, markedly depleted β-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells. A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs) following Zeocin™ exposure, as well as Li Fraumeni fibroblasts in the absence of pharmacologically-induced DNA damage., Conclusions: A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal cancer cells. These findings warrant further analysis of A279T expression in esophageal cancers and premalignant esophageal lesions.

Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell-related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies., (©2012 AACR.)