The effects of topical chemotherapy of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) on the lesions of mycosis fungoides were evaluated in 7 patients, ranging in age from 44 to 79 years old. Either 0.2% or 0.4% concentration of ACNU, in ointment and ethanol was used. 0.4% ACNU ethanol solution was effective in bringing the plaque lesions under satisfactory control with a complete clearance. ACNU was painted two to three times a week with a maximum dose of 50mg. Irritation and erosion of the applied areas were the major side effects, which were however, controlled by topical steroid ointment. No serious side effects of marrow and liver function were found even when ACNU was applied as long as 40 months (total ACNU dose: 16 gm). Histologically the cleared lesions revealed the thinning of epidermis, almost complete loss of lymphocytic infiltrates and fibrosis of dermis which was density infiltrated by lymphocytes prior to the ACNU therapy. Thus, topical chemotherapy of ACNU appears to be encouraged for modifying the plaque lesions of mycosis fungoides.

The primary site of metastasis of osteosarcoma is the lung. Even if a primary lesion was completely removed by radical surgery, more than 90% of the patients died of pulmonary metastasis in one to two years in the past. A control of osteosarcoma depends upon the prevention and treatment of its pulmonary metastasis. An introduction of chemotherapy consisting mainly of adriamycin and high-dose methotrexate dramatically improved the prognosis of osteosarcoma. We analyzed the clinical data, and gross as well as histopathologic post mortem findings, in 161 cases without chemotherapy and 42 cases with systemic adjuvant chemotherapy. Based on these analysis, we tried to clarify the nature of pulmonary metastasis of osteosarcoma and to evaluate its response to treatment from a standpoint of clinical pathology, hoping that this would yield a clue to future treatment of osteosarcoma.

From the recent progress in immunological study, many authors have reported immune suppression in patients with malignant brain tumors. On the other hand, many factors are considered to influence the patterns of cellular and humoral immune parameters in patients with brain tumors, pre- and post-operatively. We treated the patients with malignant brain tumors using ACNU and PSK pre- and post-operatively, and 4 year survival rate was 35.3% (N: 17) in glioblastomas. We planned this time to measure immune parameters (Ig,lymprocyte number,Lyn and T-cell, Tn) pre- and post-operatively in order to study the immune states of patients. The results were as follows: The most significant finding was the elevated serum level of IgG in longterm survival of the patients with glioblastoma and the reduced one in patients with postoperative death. No other humoral immunocompetence existed except slightly reduced IgM level in the patients with death. Contrary to many previous studies, our research has suggested that humoral immune parameters are considered to be valuable to understand postoperative immune states of patients, and administration of PSK be effective as an immunomodulator.

Recent advances in the chemotherapy of malignant diseases, particularly, in hematopoietic malignancies, has opened oncologists' eyes in wonder, whereas the chemotherapy of solid malignant diseases including the carcinoma of the lung is not satisfactory compared with the results of other modalities such as radiotherapy and surgery. The chemotherapy, however, gradually becomes a great importance because the majority of the cases of lung cancer is that of advanced one. Between June, 1974 and December 1980 we experienced 54 inoperable cases of lung cancers among which there were 11 cases diagnosed as an anaplastic carcinoma. The combination chemotherapy of vincristine (1 mg/body, iv, day 1), methotrexate (30 mg/body, iv, day 1 and 5), ACNU (100mg/body, iv, day 2) and adriamycin (40mg/m2, iv, day 2) was employed. Vincristine and methotrexate were given every 3 weeks and ACNU and adriamycin were repeated every 9 weeks. If the moderate degree of neuropathy due to vincristine occurred it was suspended and methotrexate was stopped if WBC was less than 2000/mm or if patients were suffered from stomatitis which disturbed their swallowing. According to the response criteria of Koyama-Saito 4, cases were responded and one of them survived 17 months after the initiation of above 4-drug combination chemotherapy, although she received another combination chemotherapy because of the relapse of disease. The combination chemotherapy of ACNU and adriamycin was tried to utilize the advantage of their time different effects on the bone marrow suppression and to cover heterogenous histopathological diagnosis of anaplastic carcinoma. The heterogeneity of anaplastic carcinoma included undifferentiated squamous cell carcinoma, adenocarcinoma, large cell carcinoma and even small cell carcinoma. In taking consideration of these points, the drug-combination was designed. Clinically, however, the long resting period made the tumor regrow in some cases due to severe delayed myelosuppression by the combination of ACNU and adriamycin. Thus, more cautiously-designed combination should be considered.

Comparative study of antiemetic effect on vomiting due to cancer chemotherapy was performed in 62 children with various malignant diseases. Twenty-one children were treated with metoclopramide, 23 children with domperidone and remaining 18 children received methylprednisolone. Each drug was administered intravenously after administration of anticancer agents, and repeated if necessary. The most effective antiemetics was methyl-prednisolone with effective rate of 89% in comparison with 51% of domperidone and 17% of metoclopromide treated group, respectively. Methyl-prednisolone may be useful for severe vomiting due to anticancer drugs. Safer and significantly better therapeutic efficacy was observed in the group treated with domperidone than that with metoclopromide.

In this paper, we reviewed the mechanisms, pathways and patterns of pulmonary metastasis from lung cancer. For seven years from 1975 to 1981, 1,158 patients with primary lung cancer were admitted to our hospital. On admission, pulmonary metastases were radiographically found in 44 of 529 patients with adenocarcinoma (8.3%), 8 of 427 patients with squamous cell carcinoma (1.9%) and 2 of 150 patients with small cell carcinoma (1.3%). In adenocarcinoma, the radiographical patterns of pulmonary metastasis were divided into 2 types, that is, "cannon ball" type and "snowstorm" type. Of 24 patients with "cannon ball" type, there were 17 bilateral, 4 contralateral and 3 ipsilateral pulmonary metastases. Of 20 patients with "snowstorm" type, 19 patients had bilateral and one patient contralateral metastasis. In squamous cell carcinoma, there were 3 bilateral, 4 contralateral and 1 ipsilateral metastasis. In small cell carcinoma, 1 bilateral and 1 contralateral metastasis. In extensive disease which had pulmonary metastases etc., response to chemotherapy did not directly lead to the prolongation of survival, the causes of which were discussed.

A preliminary use of Peplomycin (PEP) was investigated in 14 patients with advanced esophageal cancer. PEP was given intermittently with a dose of 10 mg intravenously twice a week. As side effects there were observed fever elevation in 8 cases, stomatitis in 4 cases, erosion of the skin of the scrotum in 1 case and pigmentation in 1 case, respectively. Dyspnea associated with decrease of PaO2 was observed in 4 cases, which recovered promptly after discontinuing of the administration. Out of 10 evaluable cases, partial response was observed in 1, minor response in 1, no change in 3 and progressive disease in 5 cases, respectively. While the effect was only limited in these experiences, the local injection of PEP into or around the tumor using the external fistula of the remaining esophagus which was made at the time of by-pass operation was discussed.

It has been suggested that flow cytometric analysis may offer an ability to select drugs for chemotherapy of malignant neoplasms. For this purpose perturbation of cell cycle travers which induced by several anti-cancer drugs were studied to determine the fundamental factors to evaluate the effectiveness of therapy for individual tumors. From these results, we have made a presumption that for the majority drugs studied, the perturbation of cell cycle travers will be proportional to tumor cell kill. Primary cultured cells from the human brain tumor were used to determine the effectiveness of drugs for its treatment using Factor B (the accumulated cells in SG2M phases after anti-cancer drug treatment as the percentage of cells that was previously in SG2M phases) in comparison with the results (dose-response curves) obtained by glioma cell line. The clinical application was tried using these results. A case with malignant astrocytoma had shown 20.8% for ACNU treatment, however, 85.7% for VCR treatment in maximum range of Factor B on the samples of the removed tumor at the operation (cultured cells). This patient was already treated with radiation, ACNU and other anti-cancer drugs but subsequently failed and revealed constant growth in tumor size. Thereafter patient was treated with VCR according to flow cytometric indication, there was a response, that was the first time after the desperate trials of various drugs. It was only one case, nevertheless, this result illustrates the type of studies for our plan to pursue in order to determine if flow cytometric analysis aids in the brain tumor chemotherapy by individualizing patient's treatment in near future.

The eligibilities for chemotherapy, prognostic factors and effects of chemotherapy were evaluated in pulmonary metastasis from uterine cervical carcinoma. There was no difference in median survival between patients treated with surgery and those with chemotherapy. The mediastinal lymph node involvement and vascular invasion were demonstrated to be important prognostic factors in patients treated with surgery, and it was suggested that systemic chemotherapy should be given to the patients with mediastinal lymph node involvement. The median survivals of patients treated with chemotherapy were 12.3 months in patients with pulmonary metastasis alone and 5 months in those with both pulmonary and other visceral metastasis, respectively. Responders to chemotherapy survived longer than non-responders. Overall response rate was 42.7% (44/103), and the response rate of MDU (Mitomycin C+Dextran sulfate+Urokinase) (62.3%) was higher than other chemotherapeutic regimens, which suggested that appropriate chemotherapy would prolong the survival of patients with pulmonary metastasis from uterine carcinoma.

In this study, we treated severe infections (21 cases) accompanied with induction chemotherapy in 20 patients with acute leukemia by the combination of a large dose (600 approximately 1,200 mg/day) of amikacin with other antibiotics. Infections during induction chemotherapy of acute leukemia consisted of sepsis (8 cases), pneumonia (7) and others (6), and most of causative organisms were Gram-negative bacteria, such as Ps. aeruginosa (7 strains), Flavobacterium (5), Serratia (3), Ps. cepacia (2), E. coli (2) and others. The combination chemotherapy of a large dose of amikacin with other antibiotics was found to be effective (71.4%) for such infections. Side effects were negligible except for drug eruption. Therefore, a large dose of amikacin should be given for the treatment of severe infections accompanied with induction chemotherapy of acute leukemia.

Perfluorochemicals (Fluosol-43) is characterized with its small size and high propensity for carrying oxygen and carbon dioxide, and also have the function to improve the cerebral microcirculation. These characteristic features of Fluosol-43 may have a beneficial effect on brain-tumor chemotherapy in terms of the oxygenation of hypoxic cells, and/or the improvement of the pharmacokinetics of anticancer drugs. This study was undertaken to identify the combined effect of perfluorochemicals (Fluosol-43, 20 ml/kg) and chemotherapeutic agent (BCNU, LD10 dose; 13.3 mg/kg) in a rat brain-tumor model. Brain-tumor model was made by the intracerebral implantation of C6 rat glioma cells (1 X 10(5) cells/10 microliters). At 10 days after implantation, control animals had a macrotumor weighing about 100 mg with large part of central necrosis. The tumor-bearing rats for 10 days after implantation were randomly divided into 4 groups; a control group, a Fluosol-43 treatment group, a BCNU treatment group, and a Fluosol-43 plus BCNU treatment group. Control animals had mean survival time of 19.94 +/- 2.41 (S.D.) days, and mean survival time of Fluosol-43 treatment group was 19.47 +/- 1.36 days. BCNU treatment alone prolonged the mean survival time to 28.36 +/- 7.94 days (p less than 0.001). Fluosol-43 plus BCNU treatment group showed 36.00 +/- 10.15 days, which was significantly greater than that of BCNU treatment alone group (p less than 0.005). The long survivals lived over 50 days after implantation were 7 out of 27 rats in Fluosol-43 plus BCNU treatment group, in contrast to one out of 25 rats in BCNU treatment alone group. Perfluorochemicals (Fluosol-43) may have the synergistic effect on BCNU chemotherapy for brain tumors. It was speculated for the above results that following the oxygenation of hypoxic cells by Fluosol-43, hypoxic cells might be sensitized to BCNU, which might be much delivered into hypoxic area. And further studies should be done for the evaluation of the mechanism of perfluorochemicals on brain tumor experimentally before clinical application.

Phase I study of a new antitumor antibiotic, neothramycin which belongs to anthramycins was performed by a cooperative study group involving 15 major institutions. A total of 63 cases including 42 various solid tumors and 21 hematologic tumors refractory to standard treatments underwent the study during June 1979 to June 1981. Doses of single injection were escalated from an initial dose of 2 mg/m2 estimated by one twentieth of LD10 in mice up to 60 mg/m2. The most frequent and severest toxicity was nausea and vomiting seen in about the half of patients being administered dosages ranged from 24 mg/m2 to 40 mg/m2, and 3 out of 4 patients received dosages exceeding 50 mg/m2 required clinical managements; moreover, 1 out of 2 patients administered 60 mg/m2 was ranked as grade 4 of the criterion of toxicities in WHO handbook. Other clinical toxicities such as skin rash, hepatotoxicity or nephrotoxicity observed in the minority of the patients were reversible. Furthermore, hematologic toxicity was extremely mild and appeared not to be dose dependent. One patient with chronic myelogeneous leukemia had a hematological improvement and the other with esophageal cancer had a partial response. The result indicates that a dose limiting factor of neothramycin is nausea and vomiting, and a maximum tolerated dose of a single injection is 60 mg/m2. A dose schedule of 30-40 mg/m2 appears to be an optimal dose for Phase II study.

A phase II study of a new fluoropyrimidine antitumor agent, carmofur (HCFU) fine granules, was performed in 24 institutions. The eligibility of patients and the criteria of response evaluation were based on the "Japanese Criteria for Evaluation of Clinical Effects of Cancer Chemotherapy on Solid Tumors." Out of 119 patients entered in the study, 65 patients were evaluable: 63 patients among them had measurable or evaluable lesions. Positive responses better than PR (Partial Response) were obtained in five (17.9%) out of 28 patients with gastric cancer, four (36.4%) out of 11 patients with colorectal cancer and five (45.5%) out of 11 patients with breast cancer. The total positive response rate was 22.2%. Optimal doses for the clinical use were ranged from 9 to 18mg/kg, and the median duration of PR was 19.6 weeks. In addition to the similar gastrointestinal toxicities observed in other fluoropyrimidines, hot sensation, pollakiuria and frequent defecation were seen in 12.4%, 10.1% and 3.4% of patients, respectively.

Human motor endplate acetylcholinesterase was inhibited in vitro by alkylating antineoplastic agents, most strongly by mechlorethamine, followed by DTIC, ACNU, cyclophosphamide and ifosfamide. Eleven other antineoplastic agents did not inhibit the enzyme substantially nor interfered with cholinesterase measurement. Cyclophosphamide and mechlorethamine inhibited human plasma pseudocholinesterase most strongly, followed by thiotepa, ACNU, DTIC, ifosfamide and BCNU. Mechlorethamine, ACNU and ifosfamide inhibited the motor endplate and plasma cholinesterase practically equally, DTIC inhibited motor endplate cholinesterase more strongly, while cyclophosphamide was a more selective inhibitor of plasma cholinesterase. Inhibition of human red blood cell acetylcholinesterase was identical to that of motor endplate acetylcholinesterase; therefore, red cells would be a preferable indicator in monitoring cholinesterase inhibition by antineoplastic agents.

The effects of various anticancer agents on human choriocarcinoma transplanted to nude mice, specifically, inhibition effects on tumor growth and survival rate were studied to establish an appropriate chemotherapy for refractory choriocarcinoma. The agents studied were methotrexate (MTX), actinomycin D (ACD), cyclophosphamide (CPM), vincristine (VCR), L-PAM (MPI), bleomycin (BLM), carboquone (CQ), cisplatin (CDDP), ACNU, MCNU, vinblastine (VLB), VP16-213, OK-432, Maruyama vaccine (SSM) and metronidazole (ME), and the following results were obtained: 1) The inhibition effects on tumor growth were obtained in the groups of VCR, VP16-213, CDDP, MPL, CPM and CQ; 2) The survival rate was 100% in the groups of MPL, BLM, and CQ. In the groups of ACD VLB, VP16-213 and VCR, all mice died. 3) MPL was found to be the most effective agent in terms of inhibitory effect and survival rate. In the future, combination chemotherapy including MPL and maintenance chemotherapy with MPL to refractory choriocarcinoma should be studied.