Background: Survivin and octamer-binding transcription factor 4 (OCT4) are reportedly up-regulated in esophageal cancer (EC) and have been correlated with high tumor proliferative activity and poor prognosis.Oncolytic viruses encoding specific transgenes have been considered as therapeutic methods to increase therapeutic efficacy in a variety of solid tumors. Methods:In this study, an oncolytic adenovirus carrying short hairpin RNA (shRNA) of survivin (shSRVN) and OCT4 (shOCT4) was constructed to achieve dual knockdown of survivin and OCT4 and to explore the potential effect of the oncolytic adenovirus in EC. Results:The oncolytic adenovirus replicated abundantly in human EC cells, with the replication multiplying by up to 192,085 and 620,055 times in esophageal carcinoma (Eca)-109 cells transfected with purified and completed recombinant adenoviruses called AdSProE1a-dual shRNA (shSRVN + shOCT4) and TE1 cells transfected with AdSProE1a-survivin shRNA (shSRVN) 96 hours after infection, respectively.The shRNAs targeting survivin and OCT4 significantly downregulated the expression levels of survivin and OCT4 in cells, thereby inhibiting the proliferative activity of cancer cells. Furthermore, E-cadherin and vimentin, which are both considered epithelial mesenchymal transition (EMT) markers, were found to be upregulated and downregulated, respectively, in cancer cells after exposure to the viral infection. The interference of survivin and OCT4 also contributed to cell cycle arrest and apoptosis, the half maximal inhibitory concentrations (IC50s) of oncolytic adenovirus loaded with AdSProE1a-shSRVN + shOCT4 in the Eca109 cells and the TE1 cells were 0.7271 and 0.1032 pfu/mL, respectively. Xenograft experiments in vivo showed that oncolytic adenovirus-mediated dual knockdown of survivin and OCT4 effectively inhibited the growth of xenografts and induced cancer cell apoptosis. We concluded that therapies targeting survivin and OCT4 have great potential for improving the therapeutic efficacy in EC. Conclusions:The dual target design strategy ensured the efficacy and safety of the treatment system and provided a novel and effective adjuvant target therapy for EC.

Background: Esophageal neuroendocrine neoplasms (E-NENs) are a rare and poorly reported subtype of esophageal carcinoma. We analyzed the differences in clinicopathological features, prognosis, and tumor-infiltrating lymphocytes (TILs) between E-NENs and esophageal squamous cell carcinoma (ESCC). Methods: A total of 3620 patients who underwent esophagectomy were enrolled retrospectively. The study cohort was divided into two groups (E-NENs and ESCC) through propensity-score matching, and the prognosis and TILs were compared between the two groups. The TILs were assessed using tumor specimens (including six cases of ESCC, six cases of neuroendocrine carcinomas [NECs], and six cases of mixed neuroendocrine–non-neuroendocrine neoplasms [MiNENs]). Results: E-NENs accounted for 3.0% (107/3620) of cases, among which there were just 3 neuroendocrine tumor cases, 51 NEC cases, and 53 MiNENs cases. After matching, esophageal neuroendocrine carcinomas (E-NECs) showed both poorer 5-year overall survival (OS; 35.4% vs. 54.8%, p = 0.0019) and recurrence-free survival (RFS; 29.3% vs. 48.9%, p < 0.001) compared with ESCC. However, the differences were not prominent in the subgroup with stage I. No significant survival benefit was observed for E-NECs with multimodal therapy. Multivariate analysis demonstrated that E-NECs are an independent risk factor for OS and RFS. In the exploratory analysis, E-NECs were associated with less infiltration of immune cells compared with ESCC. Conclusion: E-NECs are significantly associated with a poorer prognosis than ESCC except for early-stage disease. The fewer TILs within the tumor microenvironment of E-NECs compared with ESCC results in weaker anti-tumor immunity and may lead to a poorer prognosis.

Salvage esophagectomy is indicated for esophageal cancer patients for recurrent/persistent disease after definitive CRT (dCRT). Salvage esophagectomy reportedly has higher postoperative complications and poor survival. This study aimed to compare the perioperative outcomes and survival of patients with dCRT followed by salvage esophagectomy (DCRE) and neoadjuvant chemoradiotherapy (nCRT) followed by planned esophagectomy (NCRE) in esophageal squamous cell carcinoma (ESCC). Patients were identified from a prospectively maintained database at single institution from 2018 to 2021. All locally advanced ESCC patients receiving neoadjuvant/definitive chemoradiotherapy and following esophagectomy were reviewed. A total of 41 DCRE (24 persistent-disease, 17 recurrence) and 261 NCRE patients were included. Propensity score matching (PSM) was used to compensate for differences in some baseline characteristics. No significant between-group differences were identified in in-hospital mortality, postoperative complications (Figure A), overall-survival and progression-free survival (all p &gt; 0.05) (Figure B-C). The median CRT-to-surgery interval was 47d in NCRE group, 43d and 440d in DCRE group of persistent-disease and recurrence, respectively. DCRE group was observed with more advanced ypT stage (63% vs 38%, p = 0.001), poorer differentiation (32% vs 15%, p = 0.005) and more lymphovascular invasion (29% vs 11%, p = 0.001) compared with NCRE. Similar results were obtained after PSM. Analyses comparing DCRE (due to persistent-disease), DCRE (due to recurrence) and NCRE groups showed no differences in postoperative complications, in-hospital mortality and survival. Postoperative complications and prognosis were equivalent between DCRE and NCRE. DCRE has acceptable outcomes and is appropriate for selected patients.