Neocarzinostatin as previously reported, appeared to exhibit an intense cytotoxicity to the glioblastoma cells and some other malignant brain tumor cells, such as pineal germinoma or medulloblastoma, which are notoriously known to disseminate into the cerebrospinal fluid space. In vitro study, the minimum susceptibility of glioblastoma cells to neocarzinostatin was found to be below 0.005 microgram/ml, whereas normal glia cells were not affected at 0.3 microgram/ml. This study indicated that neocarzinostatin was extremely effective in the treatment of malignant brain tumor without affecting normal neural tissue. Pharmacokinetic study was performed in order to establish intermittent intrathecal perfusion therapy and to prevent subarachnoid dissemination of the brain tumor cells. Experimental results were applied to the treatment of 12 patients with brain tumor, who had shown positive cytology of the cerebrospinal fluid. Follow-up investigation showed quite a favorable result and it was considered that prophylactic irradiation to the entire spinal column could be replaced with intrathecal administration of neocarzinostatin. During clinical application no noticeable side effect was encountered and active stimulation of macrophages, which were mobilized into the CSF space, was another unexpected advantage of this treatment.

A Phase II study of a new fluorinated pyrimidine (TAC-278) was performed in 14 institutions from May 1980 to April 1981. 400-1200 mg of TAC-278 was orally administered in 2 to 4 divided doses every day for more than 4 weeks. Selection of patients and evaluation of clinical response were done according to the criteria for "Evaluation of Clinical Effects of Chemotherapy on Solid Tumors" by Koyama and Saito. A total of 188 patients were entered in the study and 96 of them were evaluable. Partial responses were observed in 9.4% (9/96) of the evaluated cases. Stomach cancer and colorectal cancer showed partial responses in 10.8% (4/37) and 20% (5/25), respectively. As for side effects, slight gastrointestinal symptoms (loss of appetite, nausea and vomiting etc.) were found in 24% and CNS-symptoms such as dizziness and disorientation were observed in approximately 8% of the patients.

The effect of NK-421(Bestatin) and Ge-132 (an organic germanium compound) on the ADCC and natural killing (NK) activities of the spleen cells of MH-134 tumor-bearing mice were studied. In the tumor-bearing mice, the ADCC activity was enhanced, and NK activity was reduced in accordance with the progress of the tumor. By oral administration of Bestatin at doses of 5, 10 and 50 mg/kg, ADCC activity was potentiated, and at a dose of 10 mg/kg, NK activity was significantly increased. Intraperitoneal administration of Ge-132 at 50 mg/kg potentiated the ADCC activity of tumor-bearing mice. A higher activity was observed in the plastic dish adherent fraction. Ge-132 also potentiated the reduced NK activity of tumor-bearing mice to higher level than normal mice. The elevated activities of ADCC and NK following Bestatin and Ge-132 administration were decreased with anti-Thy-1 antibody and complement; however, the percent reduction was lower compared to that of the control cancer animals. This result indicates that Bestatin and Ge-132 may act on non-T cells and augment ADCC and NK activities.

The sensitivity of leukemic progenitor cells (L-CFU) to cytosine arabinoside (Ara-C) and daunomycin (DM) in vitro was studied using PHA -LCM two step assay for L-CFU. Continuous exposure of leukemic and normal bone marrow cells to DM as well as Ara-C in vitro appeared to be more effective than pulse exposure because colony formation was suppressed by a dose dependent fashion. The relationship between in vitro sensitivity to DM and Ara-C and that of in vivo to chemotherapy was investigated in 17 untreated and 5 relapsed patients with acute nonlymphocytic leukemia. The sensitivity of L-CFU to the two chemotherapeutic agents varied from patient to patient. These studies indicated a clear-cut relationship between in vitro drug sensitivity and in vivo response to patients whose L-CFU were sensitive to both agents and entered complete remission, whereas patients whose L-CFU were insensitive to one or both drugs in vitro failed to enter remission. This assay system appears to be useful in predicting response of patients to chemotherapy and in selecting the most effective drugs for an individual patient use.

The vaginal smear specimens of the patients who received operative therapy, irradiation or chemotherapy for cervical carcinoma were examined. Long-term follow-up vaginal cytology following treatment of cervical carcinoma is effective for the detection of local reoccurrence in an early stage. Serial cytology is also useful in evaluation of the effects of irradiation and chemotherapy for cervical carcinoma. Radiosensitive and prognostic significance of vaginal smears before and after radiation therapy was discussed.

The combination effect of heat and anti-cancer drugs were studied by following the proliferation of cancer cells from a uterine cervix (OG cells). In animal experiment, tumor bearing mice were injected 5 microCi 14C-5FU, local hyperthermia was created in hot water baths of 37 degrees C, 43 degrees C and 45 degrees C for 30 minutes. At timed intervals, tissue was taken from the tumor and radioactivity was measured. The results were as follows: In vitro. The critical temperature for proliferation was between 40 degrees C and 41 degrees C with continuous heating. At 60 minutes of heating was between 45 degrees C and 46 degrees C. The simultaneous use of heat and anti-cancer drugs that inhibit cell proliferation was effective for Bleomycin, Cis-plantinum and Ifosfamide but not effective for Mitomycin and Adriamycin. In vivo. Immediately after the hyperthermia, the uptake of 14C-5FU within the tumor in the 37 degrees C group was (229 +/- 29) X 10dpm/g. The 43 degrees C group (1.47 times) and the 45 degrees C group (1.37 times) were significantly higher than this. Even 60 minutes after the hyperthermia, the heat-treated groups maintained levels 1.7-2. 0 times higher. The uptake within the tumor was better in the 43 degrees C group than 45 degrees C group.

UFT was given to two patients with carcinoid tumor of the stomach and the effect of the drug was evaluated. The first patient was a 67-year-old female. She was admitted because of upper abdominal tumor. Exploratory laparotomy revealed gastric tumor and additional huge tumor with liver metastasis and peritoneal dissemination. Histology of biopsy specimens from gastric tumor and metastatic lesions was a composite type, of carcinoid tumor. Postoperatively UFT (600 mg/day) was given to the patient. During three months of the treatment the size of the large tumor reduced from 10 X 10 cm to 4 X 4cm. The second patient was a 55-year-old male. He was admitted because of severe diarrhea. Biopsy from gastric lesion and metastatic skin lesions revealed carcinoid tumor. After administration of UFT and Mitomycin C, metastatic skin lesions became smaller and some of the lesions disappeared. Two cases suggest a possibility that UFT may be effective for carcinoid tumor of the stomach.

The cytology of the endoscopic biopsy materials from 85 cases of esophageal cancer were analyzed for effects of the combined radiotherapy with Bleomycin. Cancer cells were remarkably decreased in number after the combination therapy. Unaffected cancer cells declined to negligible levels in 64 of 79 esophageal cancer cases irradiated more than 6,000 rad. Out of 42 gastric cancer cases treated with only anticancer drugs, 37 cases exhibited hardly cytologic changes in the smears of biopsied materials. About the remnant 5 cases, cancer cells showed partially cytoplasmic swelling, nuclear enlargement and nuclear abnormal stain. The smears of the biopsy and resected specimens from 64 gastric cancer cases with radiation and chemotherapy were cytologically discussed. The combination therapy increased the amount of both necrotic materials and neutrophils in the smears. The cytoplasms of treated cancer cells were swollen, vacuolated and stained abnormally. The nuclei of cancer cells became enlarged, multiple, piknotic and/or stained pale. Nuclear swelling was more prominent in cancer cells of differentiated adenocarcinomas. Cancer cells were decreased in number almost in inverse proportion to irradiation dose. Unaffected cancer cells were disappeared in 13 of 24 cases irradiated more than 6,000 rad, in 7 of 35 cases irradiated in the range 3,000 to 6,000 rad, in none of 5 cases irradiated less than 3,000 rad.

A phase II study of Vindesine (VDS) was carried out in 20 patients with carcinoma of the lung (14 adenocarcinomas, 3 squamous cell carcinomas, 2 large cell carcinomas and 1 small cell carcinoma), and in 18 patients with metastatic pulmonary tumor (primary organ: 4 colons, 2 uteri, 2 lungs, one each tongue, pharynx, maxillary sinus, esophagus, mediastinum, bile duct, pancreas, kidney, rectum and sarcoma). VDS was given weekly by i. v. push at a dose of 3 mg/m2. Patients should be given at least three times of VDS for eligibility. Of 18 evaluable patients with carcinoma of the lung, 3 patients with adenocarcinoma showed a partial response. Response rates were 17% for patients with carcinoma of the lung, and 25% for 12 patients with adenocarcinoma. Two responders (uterine cervical carcinoma and mediastinal embryonal carcinoma) were observed in 14 evaluable patients with metastatic pulmonary tumor. In addition, one patient with metastatic maxillary sinus tumor showed a minor response. Major hematologic toxicities of VDS were leukopenia (less than 4000 cells/mm3--92%, less than 2000 cells/mm3--28%), anemia (less than 10.0 g/dl, 38%) and thrombocytopenia (less than 10 X 10(4) cells/mm3, 11%). Major non-hematologic toxicities were numbness (24%), constipation (11%), anorexia (21%), fever (16%) and liver dysfunction (21%). The dose limiting factor of VDS was leukopenia.

We have previously reported the clinical effect of NF therapy (NCS 5,000 units and 5-FU 500 mg intravenously; twice a week) on patients with advanced carcinoma of the digestive system. In the present study, NFO therapy (NCS 2,000 units and 5-FU 500 mg intravenously, Picibanil 1-2K. E. intramuscularly; twice a week) was applied for those patients to take advantage over NF modality. Treated were 62 patients with NFO and 48 were evaluated for its clinical effects. In comparison of NFO and NF, the antitumor effects were noted in 9 of 48 patients (18.8%) for NFO, and 2 of 27 (7.4%) for NF therapy judged by Koyama & Saito's criterion. If the Karnofsky's criterion was applied, I-A category or more were obtained in 10 of 48 patients (20.8%) for NFO and in 2 of 27 (7.4%) for NF therapy. In particular, NFO therapy resulted in the advantageous clinical effects on patients with hepatic and pancreatic carcinomas irrespective of primary or metastatic. The adverse effects of NFO were not more frequent than those of NF therapy. From these results, a new combination regimen, NFO, is thought to bring about a considerable benefit in the treatment of advanced carcinoma of the digestive organs.

Recent progress of the chemotherapy for malignant brain tumors has made some prolongation of survival time of the patient. However, it is still far away from our satisfactions and still we are even irritable about the results of brain tumor therapies in neurosurgical practice. One of the major side effects of these chemotherapeutic agents is myelosupression which is dose-dependent. When applying the chemotherapy to the brain tumor patients aggressively, we experience that occasionally we are having a chance to see the so-called "chemotherapy death" caused by agranulocytosis and severe infections. In this report we introduced the granulocyte transfusion by the method of filtration leukapheresis in the neurosurgical field, especially its technical aspects, its advantages, and its indications. And we presented a case of pontine glioma who had been successfully treated with the granulocyte transfusion for the agranulocytosis with serious infection. The indication of granulocyte transfusion are as follows: (1) The count of granulocyte is under 500/mm3. (2) The patient has the infection that has no response to the intensive antibiotic therapy for about two days. The advantages of this method of granulocyte transfusion are as follows: (1) Low cost and simple process. (2) The contamination of lymphocyte is little. (3) A large number of granulocyte (1.93 X 10(10)) are obtained from one donor for about two hours. (4) Side effects to donor and patient are very few. We concluded hereafter that this method of granulocyte transfusion should be prepared broadly on the neurosurgical wards in cases of agranulocytosis during the chemotherapy for malignant brain tumors.

Paraaminobenzoic acid-N-xyloside (K-247) is a new antitumor drug, which has no direct effect on immunologic status. Clinical trial of K-247 was performed in 8 patients with for advanced or recurred gastrointestinal cancer, who had short life expectancy. Oral administration of K-247, 600 to 900 mg/day, was carried out in combination with antitumor treatments using MMC, FT-207, 5-FU, PSK or irradiation. No toxic symptoms were observed in all patients. Of the 8 patients studied, one showed an encouraging response, while the remaining 7 patients were too far advanced to respond to these treatments.

A comparative trial of a combination of daunorubicin and cytosine arabinoside (Regimen A) and a combination of aclarubicin and cytosine arabinoside (Regimen B) was performed. Sixteen patients with acute non-lymphocytic leukemia, previously untreated, were entered into this study. Five of 8 patients (62.5%) obtained a complete remission (CR) in Regimen A and B, respectively. The days required for achieving a CR varied from 37 to 46 days in Regimen A and from 22 to 56 days in Regimen B. The total doses of daunorubicin and cytosine arabinoside were from 100 to 240 mg and from 640 to 1,120 mg in Regimen A, respectively. Those of aclarubicin were from 180 to 300 mg and from 660 to 1,000 mg in cytosine arabinoside in Regimen B. In a comparative study on hematological changes, toxic effects on peripheral white blood cell, platelet and nucleated cell counts in bone marrow tended to appear later in Regimen B compared to those in Regimen A. Side effects on digestive system such as nausea and vomiting and vascular pain were more frequently recognized in patients treated with Regimen B, although they were managed by symptomatic treatment. The results indicated the usefullness of aclarubicin in combination chemotherapy for the treatment of acute non-lymphocytic leukemia.

In this study the duration of complete remission by daunomycin, cytosine arabinoside (Ara-C), 6MP and prednisolone (DCMP) therapy using a large dose of Ara-C (200 mg) (protocol 2M-80) was compared with that of DCMP therapy with a low dose of Ara-C (80-160 mg) in acute non-lymphocytic leukemia (ANLL). In protocol 2M-80, the chemotherapy was continued until leukemic blasts in marrow were attained below 3%. Complete remission was induced in about 80% of ANLL patients in both chemotherapies. However, the duration of remission in protocol 2M-80 appeared to be much longer than that of DCMP therapy with a low, dose of Ara-C. This difference was dependent not on the consolidation and maintenance therapy, but on the total dose of Ara-C used and leukemic blasts left in marrow at the end of chemotherapy. This suggests that it is important to reduce leukemic blasts in marrow as low as possible by induction chemotherapy to obtain a long-term remission in ANLL.

The levels of anticancer drugs in tissue were measured by bioassay method in 28 patients with gastrointestinal cancer, who were treated with intravenous administration of 500 mg of 5-FU combined with ANG-II during surgery. The levels of 5-FU in the cancerous tissue of the stomach and the regional lymph nodes were higher in the cases who received 5-FU and ANG-II than in the cases received 5-FU alone. Based on this result, we carried out cancer chemotherapy combined with ANG-II for 15 patients with advanced cancer. The good clinical response was observed in 4 out of 15 cases (26.7%) including 2 complete (CR) and 2 partial responses (PR), respectively. According to Karnofsky's criteria of response, more than I-A response was observed in 5 out of 15 cases (33.3%). The major side effects of ANG-II therapy were nausea, vomiting and breast pain. The incidence of the side effects was 8.7% in total.

Immunization with MMC-treated EL-4 tumor cells could raise cytotoxic activity of non-adherent PE cells and resistance against rechallenge with small or medium doses of viable tumor cells. Administration of PSK augmented the generation of cytotoxic lymphocytes and the induction of resistance against rechallenge in mice immunized with such MMC-treated tumor cells. Augmented generation of cytotoxic lymphocytes may be ascribed to systemic effects of PSK but not to local effects in the peritoneal cavity, since augmenting effects of PSK were observed not only after intraperitoneal administration but also after oral administration. Either after intraperitoneal administration or after oral administration cytotoxic activity was detected in PE cells but not in spleen cells. Cytotoxic activity was detected in PE cells but not in spleen cells after intraperitoneal injections of MMC-treated tumor cells. Cytotoxic lymphocytes appear to differentiate to their mature form capable of being detected by 51Cr-release test principally at the site of direct graft rejection. Intraperitoneal administration of PSK was more effective in the augmentation of cytotoxicity of PE cells than oral administration. PSK may be able to have contact with precursors of cytotoxic lymphocytes more efficiently after intraperitoneal administration. Immunity against syngeneic tumor cells appears to be effective in elimination of small doses of tumor cells but to be overcome by medium or large doses of tumor cells at the rechallenge. Administration of PSK increased the threshold number to be eliminated by immune hosts. This finding seems to be important in relation to augmentation of resistance against metastasis or local implantation with a limited number of tumor cells.