Motofumi Yoshida

Splenectomy does not correlate with length of survival in patients undergoing curative total gastrectomy for gastric carcinoma. Univariate and multivariate analyses

The relationship between splenectomy and survival time after curative total gastrectomy for advanced gastric cancer was examined by reviewing retrospectively data on 252 patients treated in our clinics between 1965 and 1985. One hundred three patients (40.9%) did not undergo splenectomy and 149 (59.1%) did. In patients subjected to splenectomy, advanced stages of the malignancy were more frequent and metastasis was noticed in 8.1% of splenic hilar lymph nodes and in 10.1% of the lymph nodes associated with the splenic artery. A univariate analysis revealed that the survival time of patients with splenectomy was significantly less than those for whom splenectomy was not done (P < 0.05). In a subgroup of our patients stratified to adjust for the stage of disease, there was no significant difference between the survival rates. Subsequently, multivariate analysis using the Cox regression analysis adjusted for sex, age, and other covariates indicated that serosa invasion, lymph node metastasis, and tumor size were the most important prognostic factors, and there was no correlation whatever with splenectomy. Our findings rule out any relationship between splenectomy and length of survival time in patients undergoing curative total gastrectomy for advanced gastric cancer.

Predictive value of preoperative serum sialyl tn antigen levels in prognosis of patients with gastric cancer

Background. Expression of sialyl Tn antigen (STN) or serum STN levels were reported to be the independent prognostic factors of colon and ovarian cancers, respectively. The clinical significance of serum STN was evaluated as a tumor marker in gastric cancer.

Postoperative chemotherapy for patients with advanced gastric cancer

The relationship between postoperative chemotherapy and survival time after gastric resection in patients with advanced gastric cancer was examined by retrospectively reviewing data on 916 patients treated in our clinics between 1965 and 1985. Of these patients, 738 were treated postoperatively with antitumor drugs. Postoperative chemotherapy was more often prescribed for those in the advanced stages of malignancy. Univariate analysis revealed that the survival time of patients given postoperative chemotherapy was shorter than for those not receiving chemotherapy, but there was no statistical significance. Multivariate analysis using the Cox regression analysis adjusted for sex, age, and other covariants indicated that operative curability, liver metastasis, serosal invasion, lymph node metastasis, peritoneal dissemination, and tumor size were the important prognostic factors. There was no correlation with postoperative chemotherapy. Our findings rule out any relationship between postoperative chemotherapy and length of survival time for patients with advanced gastric cancer undergoing gastric resection.

Laser flow cytometric studies on the intracellular accumulation of anthracyclines when combined with heat

The effects of heat on intracellular accumulation of anthracyclines were investigated by laser flow cytometry analysis. Sarcoma-180 cells were exposed to Adriamycin (ADM), epirubicin (EPIR), daunomycin (DM), THP-Adriamycin (THP), ME-2303 (ME) and KRN-8602 (KRN) at 37°C and at higher temperatures. There was a dose-dependent increase in the fluorescence intensity of all drugs at 37°C, but heat varied the fluorescence intensity of each drug. At 43°C the cellular fluorescence of ADM and EPIR increased by approximately 200%, but for DM the increase was 110–130%. The cellular fluorescence of THP and ME was little affected by heat, and heat reduced that of KRN to 80–90%. Each drug showed was unique in the relationship between drug exposure time and the fluorescence intensity at 37°C and 43°C. Cytotoxicity determined by the MTT assay was enhanced with heat in the cases of ADM and EPIR, but not with DM, THP, ME, or KRN. Thus, ADM and EPIR are expected to show enhanced antitumor activities when given in combination with hyperthermia.

5-Fluorouracil's cytotoxicity is enhanced both in vitro and in vivo by concomitant treatment with hyperthermia and dipyridamole.

SummaryWe obtained evidence that the cytotoxic effect of 5-fluorouracil (5-FU) is augmented when the drug is given in combination with hyperthermia (HYP) and dipyridamole (DP). Nontoxic levels of DP enhanced the combined cytotoxicity of 5-FU and HYP against B16 melanoma and human tumor cells in vitro as measured by the succinate dehydrogenase inhibition (SDI) test. Growth of B16 melanoma that had been subcutaneously implanted into the feet of C57 BL mice was inhibited by treatment with the combinations of 5-FU and HYP, of 5-FU and DP, and of 5-FU, HYP and DP as compared with the administration of 5-FU alone. Treatment with HYP plus DP did not alter the body weight of mice that received 5-FU. The administration of DP plus HYP seemed to render the tumor cells more sensitive to 5-FU. The combination of 5-FU, HYP and DP shows promise for the treatment of patients suffering from malignant disease.

Relationship between tumor histopathology and in vitro sensitivity to antitumor drugs in gastric cancer.

The in vitro drug sensitivity of gastric cancer tissues obtained from 40 patients with advanced cancer was compared in terms of the pathological classifications which were assigned according to the General Rules for the Gastric Cancer Study in Surgery and Pathology in Japan. Cases of poorly differentiated adenocarcinoma which had penetrated the serosa were evaluated using the succinate dehydrogenase inhibition (SDI) test for determining the in vitro chemosensitivity. The sensitivity of the stage III group to cisplatin was higher than that of the stage IV group. Although there were no statistical differences in drug sensitivities according to macroscopic findings (Borrmanns classification), the expanding growth type was more susceptible that the infiltrating type to cisplatin, aclacinomycin A (ACR) and carboquone (CQ) microscopically. In cases of lymph node metastasis [n(+)] the sensitivity to cisplatin, ACR, CQ, adriamycin and mitomycin C was less than in those with or without primary lymph node metastasis [n(-)]; lymphatic invasion in the gastric wall (ly) was a significant factor linked to drug resistance. Our findings indicate that the evaluation of tumor pathology is important in predicting the chemosensitivity of poorly differentiated gastric cancers.

Use of the Succinate Dehydrogenase Inhibition Test in Assessing the Heat Sensitivity of Tumor Cells

The in vitro succinate dehydrogenase (SD) inhibition (SDI) test was used to determine the heat sensitivity of tumor cell lines and human tumor cells. The tumor cells were exposed to heat in vitro and the decrease in SD activity was assayed using a colorimetric assay, the SDI test. With respect to survival curves of HeLa cells, the SDI test correlated well with the clonogenic assay and the dye exclusion assay. Decrease in the SD activity of HeLa cells after the heat treatment (41-44 degrees C, 10 min to 5 h) depended on both the temperature and the duration of heat exposure. S- and G2/M-phase-rich HeLa cells were more sensitive to heat than were the G1-phase-rich cells. The SDI test exhibited a wide variation in the heat sensitivity among four cell lines (HeLa, B-16, V-79, and a human GT-1 squamous cell carcinoma). Variation in heat sensitivity was also detected among individual tumor tissues obtained from clinical specimens of gastric, esophageal, and colorectal cancers. Gastric cancer tissues were more sensitive to heat than were esophageal and colorectal tissues. We recommended that if the SDI test is used to assess the heat sensitivity of clinical tumor tissues in vitro, appropriate therapy for individual patients can be designed.

Hyperthermia enhances the inhibition of tumor growth by 1-(2-tetrahydrofuryl)-5-fluorouracil/uracil (1:4) in tumors in mice and humans.

The cytotoxicity of several antitumor drugs is enhanced by hyperthermia (HT). Using mouse Sarcoma‐180 (S‐180) tumors, the authors examined the effects of 5‐fluoroura‐cil (5‐FU) and a combined oral preparation of l‐(Gtetra‐hydrofuryl)‐5‐fluorouracil (FT) and uracil in a molar ratio of 1:4 (UFT), in combination with HT. The antitumor effect of 5‐FU was not enhanced significantly by HT. Growth inhibition by UFT plus HT was significantly greater than that by UFT alone, whereas inhibition by UFT alone was significantly greater than that by 5‐FU. The intracellular metabolism of 5‐FU and FT in whole homogenates of S‐180 cells, human tumor cell lines (SC‐2 and Lu‐99), and five fresh human tumor tissues also was investigated. Conversion of FT to 5‐FU, phosphorylation, and degradation of 5‐FU were assayed with [3H]FT or [3H]5‐FU, and the products were separated by thin‐layer chromatography. The conversion of FT to 5‐FU and the phosphorylation of 5‐FU were more rapid at 43°C than at 37°C, whereas the degradation of 5‐FU to 2‐fluoro‐β‐alanine remained unchanged. This acceleration of the active metabolism of FT and 5‐FU may be one explanation for the enhanced effect of UFT by HT. Cancer 1992; 70:1177–1182.

Metabolism of 1-(2-tetrahydrofuryl)-5-fluorouracil to 5-fluorouracil in partially hepatectomized rats.

Changes in the metabolism of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) to 5-fluorouracil (5-FU) were examined in the plasma, lung, liver, stomach, small intestine, spleen and kidney in two-thirds partially hepatectomized rats. Concentrations of tegafur and 5-FU in plasma and tissues were determined 30 min after injecting 100 mg/kg of tegafur via the tail vein. The 5-FU concentration in the plasma remained unchanged for the first 7 days after hepatectomy. The tissue level of 5-FU was higher in the liver and kidney than in other organs examined, but there were no changes in levels of 5-FU in each organ examined. Our observations support the peroposal that the conversion of tegafur to 5-FU is maintained in partially hepatectomized rats.

Competencies necessary for becoming a leader in the field of community medicine: a Japanese qualitative interview study

Objectives To clarify competencies for inclusion in our curriculum that focuses on developing leaders in community medicine. Design Qualitative interview study. Setting All six regions of Japan, including urban and rural areas. Participants Nineteen doctors (male: 18, female: 1) who play an important leadership role in their communities participated in semistructured interviews (mean age 48.3 years, range 34–59; mean years of clinical experience 23.1 years, range 9–31). Method Semistructured interviews were held and transcripts were independently analysed and coded by the first two authors. The third and fourth authors discussed and agreed or disagreed with the results to give a consensus agreement. Doctors were recruited by maximum variation sampling until thematic saturation was achieved. Results Six themes emerged: (1)‘Medical ability’: includes psychological issues and difficult cases in addition to basic medical problems. High medical ability gives confidence to other medical professionals. (2)‘Long term perspective’: the ability to develop a long-term, comprehensive vision and to continuously work to achieve the vision. Cultivation of future generations of doctors is included. (3) ‘Team building’:the ability to drive forward programmes that include residents and local government workers, to elucidate a vision, to communicate and to accept other medical professionals. (4)‘Ability to negotiate’: the ability to negotiate with others to ensure that programmes and visions progress smoothly (5) ‘Management ability’: the ability to run a clinic, medical unit or medical association. (6) ‘Enjoying oneself’: doctors need to feel an attraction to community medicine, that it be fun and challenging for them. Conclusions We found six competencies that are needed by leaders in the field of community medicine. The results of this study will contribute to designing a curriculum that develops such leaders.