The nitrosourea compounds are often used in the treatment of patients with malignant brain tumors in combination with anticonvulsants, such as phenobarbital (PB). Since PB can induce hepatic microsomal enzyme--P 450 and degrade nitrosoureas in vivo, the effect of PB on tumoricidal activity in relation to toxicity of 3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) was studied using a rat brain tumor model. To determine toxicity, CD-Fisher rats were treated for 4 days with 19 and 38 mg/kg/day of PB (i.m), 0.4 and 0.7 g/kg/day of sodium valproate--SV (p.o), or 3 days with 50 mg/kg of phenytoin (i.v) prior to an administration of 47 mg/kg of ACNU (i.p). The mortality rate by the toxicity within 14 days after administration of ACNU was calculated in each group. The toxicity of ACNU was markedly reduced in PB pretreated rats compared with those without pretreatment or treated with SV or phenytoin. The tumoricidal activity of ACNU was evaluated in CD-Fisher rats with RG 12 brain tumors. Rats received 20 mg/kg ACNU after pretreatment with 19 mg/kg/day of PB (i.m) or 0.2 g/kg/day of SV (p.o) for 4 days. The mean survival days and the percentage increase in life span (%ILS) were compared in each group. Pretreatment with PB significantly reduced the tumoricidal activity of ACNU as compared with control without pretreatment (p less than 0.001) or pretreatment with SV (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The combined effects of ACNU and X-irradiation on cultured HeLaS3 cells were investigated. Pretreatment with either ACNU or X-ray induced a substantial reduction in shoulder width the D0 value of the dose-response curve for the other agent, given later was unchanged. ACNU did not inhibit the recovery of sublethal damage (SLD) induced by X-ray when this treatment preceded the split-dose experiment. Our results indicate that some cell damage induced by each agent is transmissible to the progeny of the surviving cells and that the interaction of ACNU and X-irradiation was lethal to the cells.

Twenty-two patients with adult acute non-lymphocytic leukemia treated with intensive combination chemotherapy between November 1975 and April 1982 were retrospectively analyzed to see if we could find useful clinical parameters which could predict those patients who, after failing their initial treatment cycle, would respond to subsequent cycles of the same regimen. Three groups of patients were identified. Eight patients achieved complete remission with one cycle of chemotherapy; seven patients achieved complete remission with a second cycle of the same regimen and seven patients did not respond. Marrow studies performed approximately 3 weeks following the first cycle of therapy were analyzed. Patients who subsequently responded to the regimen differed from non-responders in the residual blasts percentage in the marrow obtained 20-24 days after the initiation of the first cycle. Patients who responded to a second cycle had 11-36% blasts (mean 24%), while non-responders had 35-96% blasts (mean 66%) (p less than 0.01). No patients with more than 40% blasts in their bone marrow achieved complete remission. We concluded that patients with more than 40% blasts in their bone marrow 20-24 days after the initiation of the first cycle of the chemotherapy regimens used should receive an alternate regimen for a second cycle of induction therapy.

Three patients with malignant gliomas were treated with the high-dose chemotherapy with autologous bone marrow transplantation. In the first two cases, the autologous bone marrow cells were stored and transplanted 48 hours after single high-dose of ACNU therapy. (800 mg/m2, 600 mg/m2) One died of intratumorous bleeding on the 18th day and the other of pulmonary fibrosis on the 35th day. Their autopsy specimens revealed that most of the tumor had degenerated with only a small portion of viable cells. The third patient was treated with high-doses of ADM (100 mg/m2), VCR (1.5 mg/m2), DDP (80 mg/m2), and EX (800 mg/m2) within eight days, prior to the cryopreserved bone marrow transplantation. Granulocytes and platelets began to increase from ten days after the transplantation and became normalized within three weeks thereafter. CT scan performed six months after the chemotherapy revealed 89% reduction of the tumor. The number of our cases is still small, but the results showed that the autologous bone marrow transplantation made high-dose chemotherapy possible. The necessity for cryopreservation of bone marrow was discussed.

Twelve patients with recurrent breast cancer were treated with Peplomycin monotherapy. Peplomycin was given intermittently with a dose of 10 mg intramuscularly twice a week. As side effects of Peplomycin, fever elevation in 75% (9/12), malaise in 67%, nausea and vomiting in 42%, anorexia in 42%, pulmonary toxicity in 8%, and loss of hair in 8%, were observed. Out of 8 evaluable cases, CR was obtained in 1, PR in 1, NC in 3, and PD in 3 cases, respectively.

We encountered 7 non-Hodgkin's lymphomas involving the central nervous system (CNS) among 78 cases of lymphomas seen at the 3rd Dept. of Internal Med. between 1965 and 1980; 5 cases were diffuse histiocytic lymphomas (DH) and 2 were diffuse poorly differentiated lymphomas (DPDL). The age ranged from 27 to 66 years, there were 6 males and 1 female. In 4 cases, CNS involvement was the presenting symptom at the time of diagnosis of lymphoma. The diagnostic procedures in CNS lymphoma included complete neurological physical examination by a neurologist, spinal fluid cytology, surface marker study on lymphocytes of spinal fluid, if possible, computed tomography scan, and myelogram if spinal cord compression was suspected. The prognosis of patients with CNS involvement by lymphoma was poor even if early diagnosis was made. The conventional therapy for CNS lymphoma included cranial irradiation, systemic chemotherapy, and intrathecal instillation of methotrexate and/or cytosine arabinoside, or a combined modality; however, these treatments were only effective temporarily.

The purpose of this study was to detect possible factors related to the occurrence of DIC in carcinoma patients. I) We studied 20 carcinoma cases accompanied with DIC. Results; The carcinomas most frequently accompanied with DIC were cancers of the biliary system, gastric, hepatic and pancreatic cancer, especially those with distant metastases. Pneumonia, UTI and biliary tract infections seemed to be the most important triggers of DIC. No significant relationship was found between anti-cancer chemotherapy and the DIC incidence. Endotoxemia was more frequently detected in patients having received anti-cancer drugs than in those who not. II) The effects of anti-cancer chemotherapy on the incidence of endotoxemia was examined in rats. A higher incidence of endotoxemia was noted in the groups treated with high doses of 5-FU or Cyclophosphamide. The incidence of endotoxemia seemed to run parallel with the incidence of diarrhea and of weight loss in each animal group.

The clinical usefulness of estrogen receptor (ER) assays in the management of breast cancer has been established. However, several problems remained. In this paper, the problematic aspects of ER such as the molecular forms, inter-site variations, relationships to histological pattern, with regard to the effectiveness of chemotherapy and to prognosis, and ER in male breast cancer, are reviewed and discussed.

A new chemotherapeutic method for the treatment of tracheal and bronchial tree cancers, and of lung cancer with invasion to the bronchial tree has been developed. It is named Nebulization Chemotherapy or NC therapy. This method is based on vaporizing the anti-cancer drug (5-Fluorouracil, 5-FU) solution with a supersonic nebulizer, and inhaling the vaporized anticancer drug trans-orally through the bronchial tree. Patients were divided into two groups. The first group, where NC therapy was the main method of treatment used, included 6 patients. Of these, 4 (2CR and 2PR) showed a good anti-cancer response to the treatment. The other was a group receiving combination treatment with our CMAF protocol (cis-platinum, mitomycin C, adriamycin and 5-FU) and NC therapy. This group included 6 patients, 5 of whom (2CR, 2PR and 1MR) showed a remarkable anti-tumor response. Side-effects to the bronchial tree, pulmonary parenchyma or other systemic toxicity have not been noted so far after NC therapy. However, a few patients showed glottitis. Only trace amounts of circulating 5-FU were detected in serial serum samples.

A 9-year-old boy with non-resectable hepatocellular carcinoma was treated with irradiation and intra-hepatic arterial infusion of antitumor agents. His blood was positive for hepatitis B surface antigen (HBs Ag), but negative for hepatitis B e antigen (HBe Ag). Maternal transmission was suspected, because his mother's blood was positive for HBs Ag and his grand mother died from hepatic cirrhosis. The patient received a total dose of 4000 rad in 30 fractions. A chemotherapy cycle consisted of 5-FU (6 mg/M2/day, given continuously), EX (300 mg/M2, given on 1st, 3rd, 5th, 7th, and 9th week), VCR (1.5 mg/M2, on 2nd, 4th, 6th, 8th, and 10th week), and ADM (30 mg/M2, on 13th and 16th week). Since 6 months after the initiation of the chemotherapy, alpha-fetoprotein has become negative (less than or equal to 100n g/ml), and now, 2 years and 11 months after the diagnosis was settled, the patient remains a disease free state. His blood continues to be positive for HBs Ag.

A combination chemotherapy "VEMA" consisting of vincristine (VCR), cyclophosphamide (Endoxan, EX), methotrexate (MTX) and nimustine (ACNU) has been carried out for the treatment of small cell bronchogenic carcinoma since September, 1978. "VEMA" regimen consists of VCR 1.3 mg/m2 iv push on day 1, EX 500 mg/m2 iv infusion on day 1 and 2, MTX 28 mg/m2 iv push on day 1, 2 and 3, and ACNU 67 mg/m2 iv push on day 3. This dose schedule was repeated every 3 to 4 weeks. The regimen was given to 14 patients and 12 patients were evaluable. In the 12 evaluable cases, 2 case of complete response (CR), 7 cases of partial response (PR) and 2 cases of effusion effective were obtained. Response rate of CR + PR was 90%. Response rate including CR, PR and effusion effective was 91.7%. The major clinical toxicity of "VEMA" therapy was bone marrow suppression. Other side effects were anorexia, nausea, vomiting, alopecia and stomatitis: etc; however, these side effects were not life threatening to terminate "VEMA" therapy. In conclusion, "VEMA" regimen is a new potent combination chemotherapy in the treatment of small cell bronchogenic carcinoma.

In 41 cases of primary breast cancer preoperative treatment was performed using 2 methods consisting CPA + FT-207 (5-FUDS) (for Group I) and CPA + FT-207 (5-FUDS) + MMC (for Group II) to determine clinical and histological efficacies. A daily dose of each anticancer drug was: CPA 50-200 mg, FT-207 200-600 mg, and 5-FUDS 200 mg orally, and MMC 4-20 mg intravenously. The mean total doses were 1.8 g, 6.3 g, 3.4 g and 26.3 mg, respectively. Reduction in tumor size was obtained in 11 cases (37.9%) in Group I and 6 cases (50.0%) in Group II. According to Ohboshi's criteria, histological efficacy as defined over Grade II a was seen in 5 cases (17.2%) in Group I and 6 cases (50.0%) in Group II, while the efficacy classified as Grade III was not seen in any of the cases. Although the clinical effect was not always consistent with the histological effect, there was a tendency of agreement between them in Group II. As to the dosages of anticancer drugs, more effective cases were seen when dosages of more than 25 mg/kg of CPA, 80 mg/kg of FT-207 (5-FUDS) or 0.5 mg/kg of MMC were used. Reduction in tumor size began to appear at 2 to 3 weeks after the initiation of treatment.

Five cases of recurrent cervical carcinoma with restricted recurrent site in the pelvis were treated with intra-arterial infusion of oncostatics via the internal iliac artery. The tip of the catheter was put in the internal iliac artery, just proximal to the superior glutea artery, through the a. glutea inferior or superior with ligation of both the a. glutea superior and inferior so as to get a high concentration of drugs at the lesion. Several chemotherapeutic agents, such as Cisplatin, adriamycin, pepleomycin, mitomycin C and 5-FU, were infused through the other end of the catheter, which was fixed at the subclavian fossa of the anterior chest. The clinical efficacies according to Karnofsky's criteria were 0-C in one case, 1-A in 1 case and 1-B in 3 cases. The overall response rate above 1-B was 60%. Two cases were dead, one due to inflammation in the pelvic dead space and D.I.C. and other due to myocarditis and heart failure. The other three were alive and treated with weekly intra-arterial infusion at our outpatient clinic. No troubles, such as spontaneous removal of the catheter, inflammation around the catheter or bleeding, have been encountered. The toxicities in the case of intra-arterial infusion were less prominent than in the case of intravenous administration of the same dosage of the oncostatics.

Sequential assays of estrogen receptors (ER) were done in 940 breast cancer in various stages of progression, and changes of ER were evaluated in relation to treatments and progression of cancer. The percentage of ER(+) cancers in primary breast cancer was shown to be 53.8% (333/619). In the preterminal stages, only 20% (6/30) of cancers were ER(+). During the disease-free interval, 37% (10/27) of ER(+) tumors changed to ER(-), and all ER(-) tumors remained negative. There was a most drastic change of ER(+) to ER(-) among patients with advanced breast cancer receiving adreno-oophorectomy or chemo-endocrine therapy. Appearent changes of ER during chemotherapy seem to be minimum.

I treated 116 patients with pulmonary metastasis from renal cell carcinoma (312 cases). My experience with anticancer chemotherapy indicates that complete response was elicited in 1/15, 0/14, 0/10, 1/6, 0/5 and 0/20 of cases receiving Ft-207, CCNU, vinblastine, adriamycin, ifosfamide and MFC, respectively. Progesterone therapy produced complete response in one of 60 and partial response in 2 of 60. Interferon therapy was effective in 2 of 10 cases. Surgical removal of pulmonary metastatic lesion was done in only 6% (7/116) of cases, which was worth trying especially in low grade cases. The 3 and 5 year survival Jap. rates for the entire 116 cases were 20% and 6%, respectively.

One hundred-thirty-nine patients with advanced breast cancer were treated during five years since 1977 in our Department. Treatments consisted of chemotherapy (ACF and ACFM), hormone therapy (tamoxifen) and their combination (ACFT). Seventy patients had lung metastases at the initiation of these therapies. An overall response rate was 41%, whereas a response rate for metastatic lung lesions was 26% (18/69). Breast cancer is known as a systemic disease, thus other therapies such as pulmonary resection or irradiation had a limited indication to control the lung metastasis. Our result indicates that favorable responses to advanced breast cancer with systemic therapies will improve the prognosis of breast cancer patients with lung metastasis.