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The objective of this study was to evaluate the therapeutic usefulness of chemoradiotherapy (CRT) followed by surgery in patients with clinically T4 (cT4) esophageal cancer involving adjacent organs such as the trachea, main bronchi, and large vessels. Thirty-seven patients with cT4 squamous cell carcinoma of the thoracic esophagus were enrolled in this study. The CRT regimen comprised cisplatin (70 mg/m2) on day 1, 5-fluorouracil (700 mg/m2) on days 1-4 and external irradiation (200 cGy/day, total 30 Gy) on either days 8-26 (sequential schedule, n=15) or days 1-19 (concurrent schedule, n022). Two courses of CRT were given. The results of CRT were complete response in nine patients, partial response in 19, no change in three (minor response in two), and progressive disease in six patients. The median response duration in all responders was 172 days (range: 56-2469, n=19). After CRT, 13 patients received surgery. In 12 of these patients, tumors were completely resected. Histopathologic examination of the resected specimen revealed a discrepancy between clinical response and histopathologic effect. The median duration of survival and the 1-, 2- and 5-year survival rates were 304 days (84-3155), 45%, 35% and 23% in all patients, respectively, 866 days (190-3155), 83%, 83% and 57% in the 13 patients whose tumors were resected, and 187 days (84--2630), 25%, 5% and 5% in the 24 patients whose tumors were not resected. Grade 3 toxicity, especially hematological reactions, was noted in 13.5% (5/37) of the patients. There was one toxicity-related death (sepsis). A good outcome may be obtained with CRT, followed by surgery when feasible. However, CRT can cause toxic reactions, and close monitoring of patients is required.

Aims: Amino acids, especially branched chain amino acids (BCAAs), have important regulatory roles in protein synthesis. Recently studies revealed that BCAAs protect against ischemia/reperfusion (I/R) injury. We studied the signaling pathway and mitochondrial function affecting a cardiac preconditioning of BCAAs.Main methods: An in vivo model of I/R injury was tested in control, mTOR +/+ , and mTOR +/-. Mice were randomly assigned to receive BCAAs, rapamycin, or BCAAs + rapamycin. Furthermore, isolated cardiomyocytes were subjected to simulated ischemia and cell death was quantified.Biochemical and mitochondrial swelling assays were also performed. Key findings: Mice treated with BCAAs had a significant reduction in infarct size as a percentage of the area at risk compared to controls (34.1 ± 3.9% vs. 44.7 ± 2.6%, P = 0.001), whereas mice treated with the mTOR inhibitor rapamycin were not protected by BCAA administration (42.2 ± 6.5%, vs. control, P = 0.015). This protection was not detected in our hetero knockout mice of mTOR. Western blot analysis revealed no change in AKT signaling whereas activation of mTOR was identified. Furthermore, BCAAs prevented swelling which was reversed by the addition of rapamycin. In myocytes undergoing simulated I/R, BCAA treatment significantly preserved cell viability (71.7 ± 2.7% vs. 34.5 ± 1.6%, respectively, p < 0.0001), whereas rapamycin prevented this 4 BCAA-induced cardioprotective effect (43.5 ± 3.4% vs. BCAA, p < 0.0001).Significance: BCAA treatment exhibits a protective effect in myocardial I/R injury and that mTOR plays an important role in this preconditioning effect.