Naohito Yoshizaki

A phase I/II study of S-1 plus cisplatin in patients with advanced gastric cancer: 2-week S-1 administration regimen.

BackgroundThe combination of a new oral dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine (S-1) and cisplatin (CDDP) is one of the most active chemotherapy regimens for gastric cancer. However, the optimum schedule for this combination has not yet been determined. This study was conducted to establish the maximum tolerated dose (MTD) and the recommended dose of CDDP when combined with 2-week S-1 administration, and to observe the safety and efficacy of the regimen as treatment for patients with advanced gastric cancer.MethodsS-1 was administered orally at a dose of 80 mg/m2 per day for 2 weeks, followed by a 2-week rest. CDDP was administered intravenously on day 8 of each course; the initial dose of CDDP was 60 mg/m2 and it was increased in 10-mg/m2 increments. Treatment was repeated every 4 weeks unless disease progression was observed.ResultsEleven patients were enrolled. The main toxicities were leucopenia, neutropenia, nausea, and anorexia. These toxicities were not severe, and were reversible and manageable. The MTD for CDDP was established as 80 mg/m2, as 2 of 5 (40%) patients developed dose-limiting toxicity (DLT) at this level. Therefore, the recommended dose of CDDP was determined to be 70 mg/m2. All 11 patients were evaluable for a response: 8 achieved a partial response and 1 had stable disease. The overall response rate was 73%.ConclusionThis regimen is considered to be generally well-tolerated and has substantial antitumor activity.

Platelet aggregation induced by adenosine diphosphate released from cloned murine fibrosarcoma cells is positively correlated with the experimental metastatic potential of the cells.

We established five clones (ML‐01, ML‐02, MH‐01, MH‐02, MH‐03) from murine 3‐methylcholan‐threne‐induced fibrosarcoma A (Meth A), and investigated their experimental metastatic potentials in relation to their platelet‐aggregating activities. A clone with a high metastatic potential (MH‐02) showed a characteristic biphasic pattern of platelet aggregation, of which the first peak was not present in the aggregation patterns of the clone with low metastatic potential (ML‐01). The first peak was eliminated by treatment of the cells with apyrase, indicating that adenosine diphosphate (ADD was the causative substance of this particular peak. The metastatic potential of clones correlated well with the ADP concentration of the culture media. These results suggest that the increased ADP production and consequential enhancement of platelet‐aggregating activity are closely related to the increment of pulmonary metastatic potential of MH‐02 clone.

Augmented Expression of a Type IV Collagen-binding Protein in a Highly Metastatic Murine Fibrosarcoma Clone

The adhesive properties of highly and weakly metastatic murine sarcoma (Meth A) clones were investigated. A highly metastatic clone, MH‐02, preferentially adhered to type IV collagen‐coated plastic dishes and to bovine pulmonary arterial endothelial cell‐coated plastic dishes as compared to a weakly metastatic clone, ML‐01. Pretreatment of MH‐02 and ML‐01 cells with antisera against MH‐02 cells resulted in almost equivalent adhesiveness to type IV collagen. Preincubation of 125I‐radiolabeled tumor cells with the antisera against MH‐02 significantly reduced the arrest of MH‐02 cells in the lung, but ML‐01 cells were not affected. The number of pulmonary metastatic nodules of MH‐02 cells was reduced to the same level as that of ML‐01 cells by preincubation of the tumor cells with the antisera in an experimental metastasis experiment. These results indicated that the high metastatic ability of MH‐02 can be attributed to its preferential adhesiveness to type IV collagen. The type IV collagen‐binding proteins of MH‐02 and ML‐01 were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE) and autoradiography. Among several proteins which bound to type IV collagen, expression of a protein with a molecular weight of 29 kD was significantly greater in MH‐02 than in ML‐01. These results suggest that the greater adhesion of highly metastatic MH‐02 cells to type IV collagen is due to enhanced expression of the type IV collagen‐binding 29 kD protein.

Efficacy and Feasibility of Combination Chemotherapy with S-1 and Cisplatin (2 Weeks Regimen) for Advanced Gastric Cancer

OBJECTIVE Although combination chemotherapy with 3 weeks of S-1 and cisplatin is effective for advanced gastric cancer, the toxicities of S-1 which mostly occur during the third week of administration are a major problem. To achieve fewer adverse effects with S-1 and higher dose intensity of cisplatin, we performed combination chemotherapy with 2 weeks of S-1 and cisplatin as first line. The aim of this retrospective study was to analyse the efficacy and feasibility of this regimen. METHODS S-1 (40-60 mg depending on patients body surface area) was given orally twice daily for 2 consecutive weeks, and 70 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period. RESULTS Forty-eight patients received a total of 184 courses of chemotherapy. Overall response rate was 40.6% and median survival time was 411 days. Dose intensities were 257.6 mg/m(2)/week for S-1 and 16.4 mg/m(2)/week for cisplatin. The incidences of grade 3/4 haematological toxicities were leucopenia (19%), neutropenia (29%) and anaemia (17%), and those of grade 3 non-haematological toxicities were anorexia (31%) and nausea (21%). The rate of treatment discontinuation owing to toxicity was 10%. CONCLUSIONS This regimen may be effective as an alternative therapy to 3 weeks of S-1 and cisplatin to reduce the toxicity of chemotherapy for advanced gastric cancer.

Enhanced expression of type IV collagen-binding protein (p29) in Fyn-transfected murine fibrosarcoma cells.

We investigated the mechanism of the enhancement of metastatic potential induced by transfection of the fyn gene, a member of the src family. We employed two murine fyn cDNA‐transfected clones, ML‐SN1 and ML‐SN2, which were previously established from an ML‐01 low‐metastatic clone of Meth A sarcoma of BALB/c mice and were proven to have higher metastatic ability than ML‐01 and the mock‐transfected clone ML‐MT‐neo (Takayama et al., 1993). Our present investigation revealed that the two transfectants showed higher metastatic ability and higher rates of adherence to type IV collagen than ML‐MT‐neo. However, no difference was found in in vitro or in vivo growth rates, attachment to laminin or endothelial cells or cell motility through a reconstituted basement membrane. Analysis of surface membrane proteins labeled with 125I on SDS‐PAGE showed that a 29 kD band specifically bound to type IV collagen‐coupled beads was more intense in ML‐SN2 than in ML‐MT‐neo. Genistein, a protein tyrosine kinase inhibitor, dramatically reduced protein tyrosine kinase (PTK) activity of ML‐SN2 in a dose‐dependent fashion, corresponding to the reduction of adhesiveness to type IV collagen. The expression of the type IV collagen‐binding protein (p29) of ML‐SN2 was also reduced significantly by genistein treatment. These results suggested that the fyn product in Meth A cells augments the expression of a type IV collagen‐binding protein through elevation of the PTK activity of the membrane fraction and thus facilitates the metastasis of Meth A.

Risk factors and management for gastric stenosis after endoscopic submucosal dissection for gastric epithelial neoplasm

BackgroundOnly a few studies have reported treatment options for stenosis after endoscopic submucosal dissection (ESD) for gastric neoplasms. This study aimed to identify the risk factors for and evaluate the management of stenosis after ESD for gastric epithelial neoplasms in the cardia and antrum.MethodsWe retrospectively reviewed 1218 patients (1447 gastric epithelial neoplasms) who underwent ESD at Tonan Hospital from June 2004 to November 2015. Post-ESD stenosis was defined when a standard endoscope could not be passed through the site.ResultsPost-ESD stenosis occurred in 10 (21.3%) of the 47 cardia cases and 14 (3.2%) of the 432 antrum cases. A wide resection of more than three fourths of the circumferential extent was the sole significant risk factor related to post-ESD stenosis in both cardia and antrum. Prophylactic endoscopic balloon dilation (EBD) was performed in 3 of 10 patients with cardiac stenosis and 4 of 14 with antral stenosis. Post-EBD bleeding occurred in one cardia (10%) and one antrum (7.1%) case each and was endoscopically treated. Perforation during EBD occurred in two (14.3%) antrum cases, both of which required emergency open surgery. All complications were observed in patients with conventional EBD, and no complications were associated with prophylactic EBD.ConclusionsA wide resection of more than three fourths of the circumferential extent was the significant risk factor for post-ESD stenosis in both cardia and antrum, and prophylactic EBD could be a promising procedure for the management of post-ESD stenosis.