Advanced gastric cancer, especially scirrhous gastric cancer with peritoneal dissemination, remains refractory to conventional therapies. G47D, a third-generation oncolytic herpes simplex virus type 1, is an attractive novel therapeutic agent for solid cancer. In this study, we investigated the therapeutic potential of G47D for human gastric cancer. In vitro, G47D showed good cytopathic effects and replication capabilities in nine human gastric cancer cell lines tested. In vivo, intratumoral inoculations with G47D (2 Â 10 5 or 1 Â 10 6 plaqueforming units [PFU]) significantly inhibited the growth of subcutaneous tumors (MKN45, MKN74, and 44As3). To evaluate the efficacy of G47D for advanced-stage models of gastric cancer, we generated an orthotopic tumor model and peritoneal dissemination models of human scirrhous gastric cancer (MKN45-luc and 44As3Luc), which have features mimicking intractable scirrhous cancer patients. G47D (1 Â 10 6 PFU) was constantly efficacious whether administered intratumorally or intraperitoneally in the clinically relevant models. Notably, G47D injected intraperitoneally readily distributed to, and selectively replicated in, disseminated tumors. Furthermore, flow cytometric analyses of tumor-infiltrating cells in subcutaneous tumors revealed that intratumoral G47D injections markedly decreased M2 macrophages while increasing M1 macrophages and natural killer (NK) cells. These findings indicate the usefulness of G47D for treating human gastric cancer, including scirrhous gastric cancer and the ones in advanced stages.
Summary
Adjuvant treatment after upfront esophagectomy for esophageal squamous cell carcinoma (ESCC) is indicated only for patients with lymph node metastasis in Japan. However, the recurrence rate after curative resection is high even for node-negative patients; thus, understanding the prognostic factors for patients with node-negative ESCC, which still remains unidentified, is important. Here, we aimed to reveal the prognostic factors for the long-term outcomes of patients with node-negative ESCC. Moreover, we compared the long-term outcomes among high-risk node-negative and node-positive patients. This single-institution retrospective study included 103 patients with pT1b-3N0 ESCC who underwent upfront surgery to identify the population at a high risk of recurrence. To compare overall survival (OS) and recurrence-free survival (RFS) between high-risk node-negative and node-positive patients, 51 node-positive ESCC patients with pStage IIIA or less who had undergone upfront surgery were also included. Univariable and multivariable analyses were performed using the Cox proportional hazard regression model. OS and RFS were compared using the log-rank test. Only lymphatic invasion (Ly+) was associated with worse 3-year OS (hazard ratio, 8.63; 95% confidence interval, 2.09–35.69; P = 0.0029) and RFS (hazard ratio, 4.87; 95% confidence interval, 1.69–14.02; P = 0.0034). The node-negative and Ly+ patients showed significantly worse OS (P = 0.0242) and RFS (P = 0.0114) than the node-positive patients who underwent chemotherapy. Ly+ is the only independent prognostic factor in patients with node-negative ESCC. Patients with node-negative and Ly+ ESCC may benefit from adjuvant treatment.
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