Effect of glucocorticoid replacement on tumor growth after adrenalectomy in mice.

We studied the effects of glucocorticoid replacement on tumor growth after adrenalectomy of Meth A sarcoma in mice. Tumor growth was inhibited in the adrenalectomized mice when a minimum dose of corticosterone, 0.3 mg/day, was given for replacement, and higher doses led to an even greater inhibition. Corticosterone had no effect on tumor growth in the irradiated mice. Sinecomitant immunity in the case of growth of the retransplanted excised tumor was compromised in the adrenalectomized mice. In vivo neutralization and immunosuppressive activities were absent in the spleen cells of the adrenalectomized mice. It would thus appear that adrenalectomy suppresses tumor growth by mechanisms other than glucocorticoid ablation. For optimum tumor control, glucocorticoid replacement after adrenalectomy should be in excess of the minimum daily requirements.

Partial hepatectomy alters sensitivity of rat hepatocytes to 5-fluorouracil.

The sensitivity to 5-fluorouracil (5-FU) and the metabolism of 5-FU in the regenerating rat liver were investigated in vitro. Determination of cell viability using the succinate dehydrogenase inhibition test showed that the hepatocytes of the partially hepatectomized liver were more sensitive to 5-FU, compared to findings in the case of normal liver. The activities of 5-FU phosphorylation of the 3 pathways were higher in the regenerating than in the intact liver and the peak increase was seen 36 h after partial hepatectomy. The activity of 5-FU degradation decreased to about 30% at 36 h and then gradually increased reaching the normal range at 72 h after partial hepatectomy. These results suggest that the metabolic changes of 5-FU may be one of the causes for increased 5-FU susceptibility in the regenerating liver.

Deficient superoxide-generating activity and its activation of blood monocytes in cancer patients.

Superoxide (O2-)-generating activity of blood monocytes, the precursors of macrophages, from patients with advanced cancer and/or infection was studied. Monocytes from normal subjects generated 0.288 +/- 0.022 nmol O2-/min/10(5) cells (mean +/- S.E.M., n = 36) after sequential stimulation with cytochalasin E and wheat germ agglutinin. Monocytes from 69 non-infected adult patients with advanced malignancy of the stomach, esophagus and liver, and 7 pediatric patients with neoplastic disease released significantly less O2- than those from normal subjects (0.176 +/- 0.015, P less than 0.005). Infection increased the activity about 4-fold in patients with malignancy compared to non-infected cancer patients. These results suggest that monocytes of cancer patients are defective in secreting O2-, though the activity may be stimulated by infection.

Experimental gastric carcinoma induced by N-methyl-N'-nitro-N-nitrosoguanidine.

Serial studies by endoscopy and biopsy were made in a Beagle dog during and after oral administration of N-methyl-N'-nitro-N-nitroguanidine (MNNG). Between the 23rd and the 45th week of observation erosions and ulcers appeared at the angulus of the stomach and turned into ulcer scar. A depression with atypical glands was seen in the ulcer scar of the posterior wall of the angulus at the 94th week. It developed elevated margins at the 102nd week, when a well differentiated adenocarcinoma was found histopathologically. Ulceration and reepithelialization were observed in the early carcinoma. The carcinoma progressed into a larger one of Borrmann's type 2 at the 115th week and further into its type 3 at the 181st week. A second carcinoma with signet ring cell carcinoma developed in the anterior wall of the angulus. The two carcinomas fused and formed a single lesion. At autopsy in the 216th week the carcinoma invaded the serosa, and metastasis to regional lymph nodes was observed.

DNA cytophotometry on atypical glands in stomach carcinogenesis of dogs induced by N-methyl-N'-nitro-N-nitrosoguanidine.

Microspectrophotometric measurement of the DNA content of cell nuclei was performed on the lesions (including atypical glands) in gastric carcinogenesis of 15 male beagle dogs, which had been induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The distribution patterns of DNA content were classified into three types: normal, subnormal, and abnormal. The histograms of the distribution in normal and regenerative glands were a normal type and subnormal type, respectively, while adenocarcinoma showed an abnormal distribution type. In atypical glands, the distribution patterns in autopsy cases were subnormal and abnormal types. When sequential endoscopic observation of the angulus of the stomach in dog No. 3 was carried out, atypical glands were found in an ulcer in the early stage of MNNG administration and a precancerous lesion in the late stage after termination of MNNG. The atypical glands in the early stage were of the subnormal type, while the atypical glands in the late stage were of the abnormal type. According to the results, these two types-subnormal and abnormal - of distribution of DNA content on the atypical glands may be related to regeneration and subsequent development of cancer, respectively.

A case of biliary cystadenoma with obstructive jaundice.

Biliary cystadenoma is a rare cause of obstructive jaundice. We report a case of a 78-year-old Japanese man with biliary cystadenoma presenting repetitive abdominal pain and jaundice. Ultrasound sonography revealed a hyperechoic mass in the left lateral lobe of the liver. Histological examination revealed a biliary cystadenoma. Intracystic hemorrhage was assumed to be the cause of obstruction of the bile ducts.

Decreased superoxide (O2-)-generating activity of blood monocytes from patients with hepatic cirrhosis.

The superoxide-generating activity of blood monocytes from patients with hepatic cirrhosis was studied by the rapid and sensitive method using cytochalasin E and wheat germ agglutinin as triggering agents. The initial rates of superoxide generation by the patients' monocytes were 0.110 +/- 0.072 n mol/min/10(5) cells (mean +/- SD, n = 22) after sequential treatment with cytochalasin E and wheat germ agglutinin, while those of controls were 0.305 +/- 0.123 n mol/min/10(5) cells (mean +/- SD, n = 33) (P less than 0.001). The activity correlated inversely with indocyanine green retention rates; the regression line was Y = 0.220-0.0028 X (Y; superoxide-generating activity, n mol/min/10(5) cells, X; indocyanine green retention rate, per cent), whose test of significance of the regression coefficient was 0.010 less than P less than 0.025. The presence of ascites, a decreased in the number of white blood cells, and increased serum total bilirubin, also inversely correlated with the superoxide-generating activity. These show that in cirrhotic patient, the superoxide-generating activity of blood monocyte, which may reflect NAD(P)H oxidase activity, is impaired in proportion as the grade of hepatic cirrhosis increases.

[Clinical studies on effect of cefbuperazone on surgical infections].

We conducted clinical studies on the efficacy and safety of cefbuperazone (CBPZ) on surgical infections with the following results. 1) In evaluable 32 patients, CBPZ was evaluated to be clinically effective in 23 (71.9%) and the efficacy rate was better in those who were administered 4 g/day of CBPZ (87.5%, 14/16) than in those who were given 2 g/day (57.1%, 8/14). 2) Antibacterial activity of CBPZ was evaluated in 41 isolated bacterial strains. Pathogen eradication rate by bacterial species was 75.6% (31/41). CBPZ exerted excellent antibacterial effects on Escherichia coli (100%, 8/8) and anaerobic bacteria such as Bacteroides (88.9%, 8/9). Resistant bacteria to CBPZ were Enterococcus faecalis and Pseudomonas aeruginosa. 3) No serious side effects were noted in any of the 34 patients who entered in this study. Abnormal laboratory test results were noted in 2 patients (5.9%) and they were transient elevation of transaminases and alkaline phosphatase. From the results shown above, CBPZ appears to be a highly useful antibiotic for the treatment of surgical infection.

[Surgery and adjuvant therapy of gastric cancer].

A remarkable improvement of prognosis has been obtained in surgery for patients with gastric cancer in Japan. This is attributed to the standardization of prophylactic lymphadenectomy and the prescription of adjuvant anticancer chemotherapy. Postoperative long-term cancer chemotherapy (PLCC), available from 1970, using MMC, Tegafur and PSK in addition to curative surgery has prolonged the survival time of patients with serosal and/or secondary lymphatic metastasis. To confirm the efficacy of adjuvant chemotherapy on a wide basis, the Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer was organized in 1975. The first and the second study revealed that postoperative bolus injection of MMC and long-term administration of Tegafur improved the survival rate of patients with stage III and lymphatic with serosal metastasis. The third pilot study showed that immunotherapy using PSK and/or OK-432 with anticancer drugs might be effective for gastric cancer. To promote extensive investigations of a large number of patients, the Japanese Foundation for Multidisciplinary Treatment of Cancer was founded in 1980, and the first study suggested that immunochemotherapy using MMC, Tegafur, PSK and OK-432 is effective for gastric cancer. Efficacy of MMC and Tegafur treatment was obtained in some types, such as female cases, those with undifferentiated adenocarcinoma of Borrmann types II and IV and those given curative resection. It is therefore necessary to seek a proper regimen for each type of patient for the concept of Type-oriented Therapy (TOT).

[In vitro chemosensitivity of various human tumors evaluated by the succinate dehydrogenase inhibition (SDI) test (2)].

In vitro chemosensitivity was evaluated by succinate dehydrogenase inhibition (SDI) test in 94 human tumors including 59 gastric cancers, 27 colo-rectal cancers and 8 malignant lymphomas. Tumor fragments were exposed to 12 kinds of antitumor drugs at ten times peak plasma concentration. Evaluable rates were 86/94 (91%) for all cases, 56/59 (95%) for gastric cancers, 22/27 (81%) for colo-rectal cancers and 8/8 (100%) for malignant lymphomas. The mean of SD activity was decreased to 48% of that of control cells with aclacinomycin, 49% with carboquone, 53% with actinomycin D, 54% with mitomycin C and 54% with daunomycin for gastric cancers, 59% with adriamycin for colo-rectal cancers and 33% with cyclophosphamide (40487 S), and 33% with actinomycin D, 37% with vinblastine and 39% with adriamycin for malignant lymphomas. When the SD activity was reduced to below 50% by antitumor drugs, the chemosensitivity was defined as positive. The antitumor drugs which had a higher chemosensitive-positive rate were aclacinomycin, carboquone and mitomycin C for gastric cancers, adriamycin for colo-rectal cancers and 40487 S, daunomycin and vinblastine for malignant lymphomas. Our results suggest that the origin of a tumor is a critical factor in its chemosensitivity.

[In vitro chemosensitivity testing evaluated by intracellular ATP level: ATP assay].

In vitro chemosensitivity was evaluated by bioluminescence ATP assay in 12 human tumors including 7 gastric cancers and 5 colo-rectal cancers. Tumor fragments minced with scissors were exposed to 6 kinds of antitumor drugs: carboquone, adriamycin, aclacinomycin A, mitomycin C, cisplatin and 5-FU at peak plasma concentration or ten times peak plasma concentration. After 3 days at 37 degrees C, each tumor fragment suspension was washed with phosphate-buffered saline, boiled for 3 min and assayed for its intracellular ATP level using the luciferin-luciferase method. The ATP level of the drug-untreated group was 6.01 +/- 4.55 X 10(-10) moles/mg tissue protein in gastric cancers and 9.77 +/- 8.46 X 10(-10) moles/mg tissue protein in colo-rectal cancers. The percentages of cases in which the ATP level was reduced to less than 50% by the antitumor drugs were 70% for carboquone, 11% for adriamycin, 30% for aclacinomycin A, 45% for mitomycin C, 13% for cisplatin and 18% for 5-FU at peak plasma concentration, and 90% for carboquone, 78% for adriamycin, 80% for aclacinomycin A, 82% for mitomycin C, 63% for cisplatin and 82% for 5-FU at ten times peak plasma concentration. The test for chemosensitivity prediction is thus available at peak plasma concentration of antitumor drugs in ATP assay.

[In vitro chemosensitivity of various human tumors evaluated by the SDI (succinate dehydrogenase inhibition) test].

In vitro chemosensitivity was evaluated by SDI test in various human tumors including 1 lymph node metastasis of esophageal cancer, 10 gastric cancers, 4 colo-rectal cancers, 1 hepatoma, 2 lung cancers, 2 breast cancers and 1 gallbladder cancer. Tumor fragments cut with scissors were exposed to twelve kinds of antitumor drugs at five to ten times peak plasma concentration. After 3 days at 37 degrees C, each tumor fragment suspension was washed with phosphate-buffered saline and assayed for succinate dehydrogenase (SD) activity using 3-(4,5- dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) as a hydrogen acceptor. When the SD activity of the drug-treated cells was reduced to below 50% that of control cells, the chemosensitivity to the antitumor drug was considered positive. The chemosensitivity of each tumor varied individually. Mitomycin C or 5-fluorouracil are regularly used to treat gastric cancer patients, but, some specimens of gastric cancer in this study showed a resistance to these drugs and an unexpected sensitivity to other drugs. Our results show that the SDI test is a convenient method for clinical use and gives significant information about drug sensitivity.

[Influence of PSK on the metabolism of FT-207].

The influence of PSK on the metabolism of FT-207 was studied in patients with gastric cancer. The 5-FU concentration in the blood was determined 15 min, 30 min, 1 hour and 3 hours after intravenous injection of FT-207, 400mg. The blood level of 5-FU remained constant in 86% of patients after administration of PSK for 7 days, but decreased in 14% of patients. After administration of PSK for 8 to 14 months, no change in the blood level of 5-FU was detected. These results suggest that PSK has no distinct influence on the activation of FT-207.

[Changes in nonspecific suppressor factors in the serum of gastric cancer patients after surgery and immunochemotherapy].

After curative surgery for gastric cancers judged macroscopically to be at stage 2 or 3, patients were divided into 4 groups by randomization. As the basic treatment, patients were given one-shot Mitomycin and Tegafur as maintenance therapy for 8 months (group A). PSK (group B), OK-432 (group C) or both PSK and OK-432 (group D) were added to the treatment of group A for 8 months. Sera were obtained from these groups of patients at 4 weeks and 3, 6, 9 and 12 months after surgery. In all of these groups, values of IAP increased slightly at 4 weeks but decreased at 3 months and were maintained at such a level by 12 months. On the other hand, suppressive effects of such sera on the blastogenesis of murine spleen cells in response to PHA varied among these group. In groups A and C, the suppressive effect of sera increased after surgery and was detected continuously by 12 months. In groups B and D, in contrast, the suppressive effect disappeared from 3 to 12 months. The rise and fall of such a suppressive effect of sera may reflect the mode of action of PSK.

[Phase II study of (2''R)-4'-0-tetrahydropyranyladriamycin (THP) in gastrointestinal cancer].

A phase II study of a new anthracycline, (2''R)-4'-0-tetrahydropyranyladriamycin (THP) was performed on 37 patients with gastrointestinal cancer in 6 co-operative study institutions. Twenty-five patients out of 37 were evaluable for response according to the Koyama-Saito's criteria. THP was administered weekly at doses of 10 to 30 mg/body or every 3 to 4 weeks at doses of 40 to 60 mg/body intravenously. Of the 14 patients with gastric cancer, we obtained one complete response and 3 partial responses (response rate 28.6%), and of the 6 patients with rectal cancer, we obtained one partial response (16.7%). Leukopenia of less than 3 X 10(3)/mm3 and erythrocytopenia of less than 300 X 10(4)/mm3 were seen in 48% and 26% of cases. Neither cardiotoxicity nor hair loss were seen. These results suggest that THP is useful in the treatment of patients with gastrointestinal cancer.

[Effect of postoperative long-term cancer chemotherapy (PLCC) on non-curative gastric cancer of stage IV].

We studied the effect of postoperative long-term cancer chemotherapy (PLCC) on the survival of the patients with stage IV gastric cancer, subjected to non-curative resection. The study was carried out with 90 patients receiving the PLCC from 1970 to 1978, and 95 patients received intraoperative one shot I.V. injection of Mitomycin-C from 1964 to 1978, and 106 patients without chemotherapy from 1964 to 1970. The PLCC consisted of the following combination: MMC intermittent intravenous injection (20 mg of MMC during operation followed by 10 mg on the next day, 4th week and every 3 months respectively): postoperative oral administration of FT-207 (600 mg/day) and; PSK (3 g/day) for more than 4 months after operation. The background factors were not significantly different among 3 groups. Two year survival rate was 18.9% in PLCC group, significantly higher than that of 7.4% in MMC group and 2.0% in no chemotherapy group which was respectively (P less than 0.05). The PLCC also demonstrated its be effective mess in prolonging the survival of the patients with hepatic metastasis or peritoneal dissemination.

[A multi-institutional study on postoperative adjuvant immunochemotherapy of gastric cancer (II)].

A multi-institutional cooperative study of postoperative immunochemotherapy for gastric cancer was studied using PSK and/or OK-432 combined with Tegafur (FT) and/or MMC. A total of 3,630 gastrectomized patients from 412 institutions were entered into the study using 6 randomly assigned protocols. Unbiased background cases were analyzed by 4-year or 5-year survival rates (SVR) for each protocol. The efficacy of combined PSK with FT was noticed in all cases of curative operation macroscopically and in n(-) X ps(+) cases (4-y SVR). The combination of MMC, FT and PSK produced better survival than MMC with FT or PSK administration in all cases of macroscopic curative operation (5-y SVR) and in non-curative operation (4-y SVR). The combination of MMC, FT, PSK and OK-432 was effective for poorly differentiated cancer (4-y SVR). Immunochemotherapy with MMC, FT, PSK and OK-432 was more effective in patients with preoperative positive PPD skin test than in those with negative PPD skin test. These results suggested that adjuvant immunochemotherapy using PSK and/or OK-432 combined with MMC and FT is effective for the improved survival of gastrectomized patients with gastric cancer.

[Prospective controlled study on the usefulness of Carmofur as a postoperative adjuvant chemotherapy for colorectal cancer].

A prospective controlled study, the 7th cooperative study of the Japanese Foundation for Multidisciplinary Treatment, was conducted to evaluate the usefulness of concomitant therapy with MMC + HCFU as a postoperative adjuvant therapy in patients with colorectal cancer who had undergone curative resection for a period of 2 years and 11 months from February, 1986. The Dukes B and C patients with colorectal cancer classified by macroscopic examination who had an intravenous MMC 6 mg/m2 on the day of operation and followed by oral HCFU for 12 months from 2 weeks after operation (Group X) were compared with patients who had operation only (Group Y). Some 978 patients with colon cancer and 713 patients with rectal cancer were enrolled in the study, 85 (5.0%) of whom were not eligible. The 5-year survival rate of Group X in colon cancer was 79.3% and that of Group Y was 76.4%: thus the survival rate of Group X was slightly better than that of Group Y, but no significant difference was found between the two groups. Subset analysis revealed that the survival rate of Group X in advanced cancer of stage III b + IV, according to the General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus in Japan, was 62.4% and that of Group Y was 46.2%. Thus, the survival rate of Group X was significantly better than that of Group Y (logrank test: p = 0.035, generalized Wilcoxon test: p = 0.025). The disease-free survival rate was not significantly different between the groups with colon cancer and rectal cancer. The above results suggest that HCFU is useful for patients with a high risk of recurrence who had advanced colon cancer (stage III b + IV). However, additional prospective studies are required to verify them.

[Effect of levamisole in postoperative adjuvant immunochemotherapy of stomach cancer--randomized controlled study of MMC-tegafur combination therapy with or without levamisole. 1].

The effects of levamisole used in combination with Mitomycin C and Tegafur in patients with resectable stomach cancer were investigated in 10 cooperative institutes. The patients were randomly allocated to the treatment with either control or levamisole by envelope method. Levamisole group was treated with Mitomycin C (day 0, 20 mg, day 1, 10 mg, one shot i.v.), Tegafur (600 mg/day, p.o.) and levamisole (150 mg/day, p.o.). Levamisole was administered 3 consecutive days prior to surgery, and 3 consecutive days every fortnight after surgery. The control group was administered Mitomycin C and Tegafur. The both drugs were administered by the same method as above. Two hundred and twenty-two patients were entered in this trial. However, with the exclusion of 67 patients, the eligible patients were 155, consisting of 77 in the control group and 78 in the levamisole group. In stage III patients, the disease-free interval and survival time were significantly prolonged in the levamisole group compared to the control group (generalized Wilcoxon test p less than 0.05). The side effects were observed a little more frequently in the levamisole group. However, there was no significant difference. From this result, it can be considered that levamisole is effective in delaying recurrence and in prolonging survival time of the patients when used in combination with adjuvant chemotherapy after resection of stomach cancer.

[Effect of levamisole in postoperative adjuvant immunochemotherapy of stomach cancer--randomized controlled study of MMC-5-FU combination therapy with or without levamisole. 1].

A randomized controlled study by envelope method was carried out with the purpose of evaluating effects and side effects of levamisole in patients with resectable stomach cancer. The patients were randomly allocated to the treatment either with control or levamisole according to the indication of the envelope opened at least 3 days prior to surgery. The control group was treated with Mitomycin C (day 0, 20 mg day 1, 10 mg, one shot i.v.) and 5-FU(150 mg/day, p.o.). The levamisole group was treated with Mitomycin C, 5-FU and levamisole. Levamisole was administered at a daily dose of 150 mg for 3 consecutive days before surgery, and the 3 consecutive days administration schedule was repeated every fortnight for one year after surgery. Four hundred and forty-six patients were entered in this trial. However, with the exclusion of 104 patients as exceptions and dropouts, the total eligible patients were 342, consisting of 167 in the control group and 175 in the levamisole group. The effects were evaluated by comparing the disease-free interval or the survival time of both groups. There was no significant difference in the disease-free interval and survival. In this study, we have not yet reached the conclusion that levamisole is effective in prolonging disease-free interval and survival time, because high survival rates are still maintained in both groups for 2 years after surgery. The final conclusion would be drawn with the follow-up results in the future.