Abstract. Chemoradiotherapy is a useful treatment strategy in patients with locally advanced cancers. In particular, combination of 5-fluorouracil (5-FU) with X-ray irradiation is effective for the treatment of some types of gastrointestinal cancers. We investigated the antitumor effects of combination treatment with X-ray and S-1, a unique formulation of 5-FU, on human cancer xenografts in nude mice and compared the efficacy of this treatment to that of radiotherapy combined with cisplatin, UFT, another oral 5-FU prodrug, and intravenous 5-FU. Tumors implanted into the left hind legs of mice were treated with a dose of 2 or 5 Gy X-ray irradiation on days 1 and 8, and S-1, UFT and 5-FU were administered for 14 days. The efficacy of combined treatment with 8.3 mg/kg S-1 and 2 Gy X-ray irradiation in treating non-small cell lung cancer xenografts (Lu-99 and LC-11) was significantly higher than that of treatment with S-1 alone or 2 Gy X-ray irradiation alone, and the antitumor activity of combined treatment was similar to that of 5 Gy X-ray irradiation alone. Although 8.3 mg/kg S-1 and 17.5 mg/kg UFT had equivalent antitumor activity; the antitumor efficacy of combination treatment with S-1 and 2 Gy X-ray irradiation on LC-11 tumors was significantly higher than that of combination treatment with UFT and 2 Gy X-ray irradiation. Combination treatment with S-1 and X-ray irradiation was also more effective against pancreatic tumors than combination treatment with intravenous 5-FU and X-ray irradiation. To elucidate the reason for the increased antitumor efficacy of combination treatment with S-1 and X-ray irradiation, the antitumor effect of gimeracil, one of the components of S-1, was tested in combination with 2 Gy X-ray irradiation. These experiments demonstrated that gimeracil enhanced the efficacy of X-ray irradiation against lung as well as head and neck cancer xenografts in a dosedependent manner. Furthermore, we observed decreased expression of Á-H2AX protein, a marker of DNA repair, in LC-11 tumors treated with X-ray irradiation and gimeracil compared to that observed in tumors treated with X-ray irradiation alone, suggesting that gimeracil may inhibit rapid repair of X-ray-induced DNA damage in tumors. The present study suggests that chemoradiotherapy using S-1 acts through a novel mechanism and may prove useful in treating patients with locally advanced cancers whose disease progression is difficult to control using chemotherapy alone.

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To elucidate the mechanism of bacterial exoprotease in promotion of the intravascular dissemination of Pseudomonas aeruginosa, we examined the possible involvement of bradykinin (whose generation is induced by pseudomonal proteases in septic foci) in the invasion by bacteria, and in access of bacterial toxins to systemic blood circulation. P. aeruginosa 621 (PA 621), which produces very little protease, was injected intraperitoneally into mice together with pseudomonal exoproteases (elastase/alkaline protease). Dissemination of bacteria from the peritoneal septic foci to the blood was assessed by counting viable bacteria in the blood and spleen by use of the colony-forming assay. The results showed that pseudomonal proteases markedly enhanced (10-to 100-fold) intravascular dissemination of bacteria in mice. This enhancement was induced not only by pseudomonal proteases but also by bradykinin. More importantly, the increased spread of PA 621 induced by pseudomonal protease and bradykinin was significantly augmented by the addition of kininase inhibitors, indicating the direct involvement of bradykinin in bacterial dissemination. Similarly, bradykinin caused effective dissemination of pseudomonal toxins such as endotoxin (lipopolysaccharide) and exotoxin A when the toxins were injected into the peritoneal cavity with bradykinin. Furthermore, the lethality of the infection with PA 621 was strongly enhanced by pseudomonal proteases given i.p. simultaneously with PA 621. On the basis of these results, it is strongly suggested that pseudomonal proteases as well as bradykinin generated in infectious foci are involved in facilitation of bacterial dissemination in vivo.

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Objectives The increasingly elderly worldwide population has affected the incidence of colorectal cancer. Establishment of reliable assessment of frailty and proposals for multi‐disciplinary interventions are urgently required in oncology practices. Kihon Checklist (KCL) was published by the Japanese Ministry of Health, Labor and Welfare originally to identify individuals ≥ 65 years old at probable risk for requiring care or social support. We investigate the validity of KCL for frailty assessment to predict postoperative complication in older patients with colorectal cancer. Methods Consecutive colorectal cancer patients aged ≥ 65 (n = 500) were prospectively examined between May 2017 and December 2018. Preoperative frailty assessment was conducted by the G8 questionnaire and KCL. The main outcome measures were correlation between frailty, other clinical variables, and postoperative complications within 30 days after elective surgery. Results Of the 500 patients, 278 (55.6%) and 164 (32.8%) patients were classified as ‘frail’ by G8 and KCL, respectively. Overall complications counted among 97 patients (19.4%), and they were significantly associated with KCL ≥ 8‐frail (46/164, p = 0.001), as opposed to G8 ≤ 14‐frail (56/278, p = 0.531). Multivariate analysis showed that KCL ≥ 8 (hazard ratio 1.88, 95% confidence interval 1.16–3.04, p = 0.011) was an independent risk factor for these complications. Conclusions KCL assessment can identify frail older patients likely to suffer from postoperative complications after colorectal cancer surgery. Preoperative screening of frailty, particularly by KCL, would help older patients prevent their worse outcomes in colorectal cancer. Trial registration UMIN000026689.