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The patient was a 61-year-old man with a diagnosis of carcinoma of the pancreatic head. Abdominal computed tomography( CT)showed no distant metastasis, and he underwent subtotal stomach-preserving pancreatoduodenectomy. Immediately after surgery, he received liver perfusion chemotherapy with 5-fluorouracil followed by systemic gemcitabine. Eighteen months after surgery, CT revealed liver metastasis in the S6 segment, and partial hepatectomy was performed. The pathological diagnosis was liver metastasis of pancreatic cancer. Postoperatively, the patient was treated with gemcitabine and S-1 therapy for 1 year and then switched to S-1 monotherapy for about 6 months. Four years after the initial surgery, CT showed 2 metastases in the right lung. After 2 months of S-1 monotherapy, wedge resection of the upper and lower lobes of the right lung was performed. Gemcitabine and nab-paclitaxel therapy were administered, after the metastasectomy, but pleural dissemination appeared on CT 5 years after the initial surgery. Modified FOLFIRINOX therapy was started and continued for 8 months, but CT revealed further disseminated lesions in the diaphragm. Palliative irradiation was provided, but the disease gradually progressed. After multidisciplinary treatment, the patient survived for 6 years and 3 months after the initial surgery.

A 66-year-old man was referred to our hospital with fever and abdominal pain. CT showed a mass in the intrapancreatic bile duct but no wall thickness in the perihilar bile ducts. Neither regional lymphadenopathy nor distant metastasis was observed. Biliary cytology showed adenocarcinoma. The diagnosis was distal cholangiocarcinoma, and pancreatoduodenectomy was performed. Intraoperative frozen section examination of the ductal resection margins at the right and left hepatic ducts was positive for carcinoma in situ, and the operation ultimately completed with R1 resection. Histological examination confirmed a diagnosis of cholangiocarcinoma with superficial spread and a single positive lymph node. Adjuvant chemotherapy with S-1 was administered for 1 year. Anastomotic recurrence at the hepaticojejunostomy was found 5 years after resection; biopsy specimens revealed adenocarcinoma. Thereafter, S-1 chemotherapy was resumed, and the patient remains alive and well 9 years and 1 month after resection.

Background: Gastric cancer (GC) patients with positive peritoneal lavage cytology (CY1) and/or localized peritoneum metastasis (P1a) are defined as stage IV in the 15th edition of the Japanese Classification of Gastric Cancer. In Japan, the most common treatment for patients with CY1 and/or P1a is gastrectomy followed by postoperative chemotherapy., Patients and Methods: Subjects in this multi-institutional retrospective study were GC patients with CY1 and/or P1a who received surgical resection that leaves no macroscopically visible disease. Patients were selected from 34 institutions in Japan between 2007 and 2012. Selection criteria included adenocarcinoma, no distant metastasis except CY1 and P1a, and no prior treatment for GC before surgery., Results: Among 824 patients registered, 506 were identified as eligible, with a background of P0CY1, P1aCY0, or P1aCY1 (72.5%, 16.0%, and 11.5% of subjects, respectively). Sixty-two patients had not received postoperative chemotherapy (no-Cx), whereas 444 patients had received postoperative chemotherapy: S-1 monotherapy (S-1; n = 267, 52.7%), cisplatin plus S-1 (CS; n = 114, 22.5%), and others (n = 63, 12.6%). Overall survival (OS) was 29.5, 24.7, 25.4 and 9.9 months in the S-1, CS, 'others', and no-Cx groups, respectively [CS vs. S-1: hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.89-1.50; p = 0.275]. In multivariate analysis, OS was similar between the S-1 and CS groups (CS vs. S-1: HR 1.19, 95% CI 0.92-1.55; p = 0.18)., Conclusions: Postoperative chemotherapy after gastrectomy that leaves no macroscopically visible disease may have some survival benefits for GC patients with CY1 and/or P1a. In contrast, S-1 plus cisplatin seems to have no additional benefit over S-1 treatment alone.

Background: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is standard care for stage II gastric cancer. Whether the duration of S-1 could be shortened to 6 months (corresponding to four courses) without worsening survival is unclear. The aim of this study was to investigate the non-inferiority of four courses of S-1 compared with eight courses of S-1 for patients with stage II gastric cancer., Methods: We did a phase 3, open-label, randomised controlled, non-inferiority trial at 59 hospitals in Japan. Patients aged 20-80 years with stage II adenocarcinoma of the stomach were randomly assigned (1:1) to eight courses or four courses of S-1. Randomisation was done by the Japan Clinical Oncology Group Data Center website, using a minimisation method with a random component using institution, stage (IIA vs IIB), age (<70 years vs ≥70 years), and mode of operation (open gastrectomy with bursectomy vs open gastrectomy without bursectomy vs laparoscopic gastrectomy) as adjustment factors. One course was 80 mg/day per m 2 of S-1 administered for 4 weeks followed by a rest for 2 weeks. The primary endpoint was relapse-free survival, analysed by intention to treat, with a non-inferiority margin for the hazard ratio (HR) set at 1·37. This study is registered at UMIN-Clinical Trial Registry, number UMIN000007306., Findings: Between Feb 16, 2012, and March 19, 2017, 590 patients were enrolled (295 per group). 528 (89%) patients were analysed at the first planned interim analysis in March, 2017, at which time the point estimate of HR for the four-course group compared with the eight-course group was 2·52 (95% CI 1·11-5·77), which exceeded 1·37 and met the prespecified criteria for early termination. Predictive probability for showing non-inferiority at the final analysis was calculated to be 2·9%. The study was stopped for futility. Updated 3-year relapse-free survival analysed in May, 2017, was 93·1% (95% CI 87·8-96·1) for the eight-course group and 89·8% (84·2-93·5) for the four-course group (HR 1·84, 95% CI 0·93-3·63). The most common grade 3-4 adverse event was neutropenia, observed in 46 (16%) patients in the eight-course group and 51 (17%) patients in the four-course group., Interpretation: S-1 for 1 year should remain as standard adjuvant chemotherapy for stage II gastric cancer., Funding: Japan Agency for Medical Research and Development; the Ministry of Health, Labour and Welfare of Japan; the National Cancer Center Research and Development Fund, Japan., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Neoadjuvant chemotherapy (NAC) followed by radical surgery is a promising strategy to improve survival of patients with stage III gastric cancer, but is associated with the risk of preoperative overdiagnosis by which patients with early disease may receive unnecessary intensive chemotherapy., Methods: We assessed the validity of a preoperative diagnostic criterion in a prospective multicenter study. Patients with gastric cancer with a clinical diagnosis of T2/T3/T4, M0, except for diffuse large tumors and extensive bulky nodal disease, were eligible. Prospectively recorded clinical diagnoses (cT category, cN category) were compared with postoperative pathological diagnoses (pT category, pN category, and pathological stage). The primary endpoint was the proportion of pathological stage I tumors among those diagnosed as cT3/T4, which we expected to be 5% or less., Results: Data from 1260 patients enrolled from 53 institutions were analyzed. The proportion of pathological stage I tumors in those with a diagnosis of cT3/T4 (primary endpoint) was 12.3%, which was much higher than the prespecified value. The positive predictive value and the sensitivity for pathological stage III tumors were 43.6% and 87.8% respectively. The sensitivity and specificity of contrast-enhanced CT for lymph node metastasis were 62.5% and 65.7% respectively. After exploring several diagnostic criteria, we propose, for future NAC trials in Japan, a diagnosis of "cT3/T4 with cN1/N2/N3," by which inclusion of pathological stage I tumors was reduced to 6.5%, although its sensitivity for pathological stage III tumors decreased to 64.5%., Conclusion: Clinical diagnosis of T3/T4 tumors was not an optimal criterion to select patients for intensive NAC trials because more than 10% of patients with pathological stage I disease were included. We propose the criterion "cT3/T4 and cN1/N2/N3" instead.

The standard treatment for T4 locally advanced gastric cancer is gastrectomy with D2 lymph node dissection followed by adjuvant chemotherapy with S-1 for 12 months; however, prognostic outcome in Stage IIIb has been insufficient. It is expected that survival is improved by preoperative treatment with a triplet regimen of docetaxel, cisplatin and S-1 (divided DCS therapy). A multicenter Phase II study has been conducted to evaluate the safety and efficacy of two courses of preoperative chemotherapy followed by gastrectomy. Fifty-five patients are required for this study. The primary endpoint of the study is pathological response rate of primary lesions. Secondary endpoints are overall survival, disease-free survival, R0 resection rate and adverse events.

We have experienced successful treatment of a multiple hepatic metastasis of rectal cancer with combination chemotherapy. The patient is a 57-year-old male with bowel obstruction accompanied by rectal cancer (SE, N3, P1, H3, M (-) stage IV) who underwent a Hartmann operation with D3 lymph node dissection on July 6, 2000. The histopathological findings revealed a well-differentiated adenocarcinoma (se, INFbeta, n3, ly2, v2, p1). From the 11th postoperative day, combination chemotherapy using 5-FU 750 mg/day and LV 300 mg/day was performed once a week. When he underwent 5 combination chemotherapy treatments, adverse effects of grade 3 occurred, and the serum CEA level rose rapidly. We changed his regimen at that time. He underwent 2 courses of combination chemotherapy with 5-FU 500 mg/day and CDDP 10 mg/day for 5 days. Additional courses of combination chemotherapy with 5-FU 500 mg/day, LV 25 mg/day and CDDP 10 mg/day were performed weekly in the outpatient department. The treatment was effective, and a complete response (CR) was noted 4 months after the chemotherapy. The same combination chemotherapy was performed biweekly for one year after CR. The patient has been receiving a subsequent single administration of UFT and has remained in remission for 3 years and 7 months after surgery.

Thymidylate synthetase (TS) and thymidine kinase (TK) are key enzymes in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively. A high incidence of colorectal adenocarcinomas with varied grades of cell differentiation can be induced by 1,2-dimethylhydrazine (DMH) in rats. The marked increases of TS and TK activities were found in the poorly and well-differentiated adenocarcinomas of the colon, respectively. Oral administration of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil (UFT) markedly reduced the number and accumulated area of colonic carcinomas, and TS activity in the poorly differentiated adenocarcinomas. A potential balance between the de novo and the salvage pathways for pyrimidine nucleotide synthesis was suggested to be related with the histopathological grades of cell differentiation. Suppression of colonic TS activity by UFT administration reduced the colonic carcinogenesis and the potency of the poorly differentiated adenocarcinomas of the colon.

Thymidine kinase (TK) and thymidylate synthetase (TS) are known to catalyse the phosphorylation of thymidine for the salvage synthesis of dTMP and the methylation of dUMP for the de novo synthesis of dTMP, respectively. High TK and TS activities and the existence of TK isozymes have been observed in rapidly proliferating tissues. In this work I measured TK, TK-isozyme and TS activities, and DNA and RNA in human gastric cancer tissue. Tissue containing gastric cancer, (well differentiated adenocarcinoma (well: n = 29), poorly differentiated adenocarcinoma (por: n = 28)), and noninvolved paired normal gastric mucosa were obtained from fresh surgical specimens. Total TK and peak A TK activity of gastric cancer increased to 184% and 299% of activity of normal gastric mucosa. TK activity of "well" was higher than that of "por". On the other hand TS activity of gastric cancer increased to 122% of activity of normal gastric mucosa. TS activity of "por" was higher than that of "well". DNA and RNA content of gastric cancer increased to 294% and 228% than that of normal gastric mucosa. But difference wasn't observed between "well" and "por". These characteristics of gastric cancer suggest its susceptibility to control by inhibition of TK and TS.

5-Fluorouracil, a potent anticancer drug, is clinically known to be more effective on a poorly differentiated gastric carcinoma than on a well-differentiated type. We investigated activities of thymidylate synthetase (TS) and thymidine kinase (TK) involved in de novo and salvage pathways, respectively, for pyrimidine nucleotide synthesis and histological features in 57 human gastric carcinomas. The average activities of TS in 28 poorly differentiated carcinomas and TK in 29 well-differentiated type were significantly increased to 128 and 166%, respectively, of those in normal gastric mucosa. The TK/TS ratio in the well-differentiated type was 1.7-fold higher than that in the poorly-differentiated type. Therefore, the de novo pathway for pyrimidine nucleotide synthesis is so predominant in a poorly differentiated carcinoma, but not in a well-differentiated type, that the potent TS inhibitor 5-FU or its derivatives are suggested to suppress the growth of the poorly-differentiated gastric carcinoma.

It has been known that a high incidence of adenocarcinoma in distal colon can be induced by s.c. injection of 1, 2-dimethylhydrazine (DMH) into rats at weekly intervals. We investigated effects of radiofrequency hyperthermia (RF-HT) in combination with anti-cancer drug UFT (a combination of tegafur and uracil) on activities of DNA-synthesizing enzymes, using colon carcinomas induced by DMH treatment in rats. 1) Thymidylate synthetase (TS), DNA-synthesizing enzyme in de novo pathway of pyrimidine metabolism, increased to approximately 7-fold that of normal control colon in DMH-induced colon carcinomas in activity, but was markedly reduced to 48% of that in the carcinomas by administration of UFT. 2) Thymidine kinase (TK) in salvage pathway increased to approximately 8-fold that of the control in the carcinomas in activity, but was markedly reduced to 25% of that in the carcinomas by RF-HT treatment. 3) The TK-isozyme, that was thought to be a fetal type in the intracellularly cytoplasmic fraction and closely involved in rapid DNA replication, increased to approximately 24-fold that of the control in the carcinomas in activity, but was reduced to the nearly same level as that of the control by RF-HT treatment. This isozyme was labile in thermostability and easy to be inactivated in low pH. 4) The activities of TS and TK in the carcinomas were extremely suppressed by UFT administration in combination with RF-HT treatment. These results indicate that hyperthermochemotherapy with UFT may serve as an available treatment for colon carcinomas.