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We studied the effect of α2-macroglobulin (α2MG) on the proliferative response of lymphocytes to several different lectins. This response to concanavalin A (Con A) and phytohaemagglutinin (PHA) was markedly reduced by addition of α2MG to the reaction mixture, while that to lipopolysaccharidc (LPS) was reduced to a lesser extent. Preincubation of lymphocytes with α2MG had little effect on the response of the lymphocytes to lectin, when the protein was washed out before addition of the lectin. The response of the lymphocytes to lectin was reduced when α2MG was added within 12 hr after the addition of the lectin, while the reduction was not apparent when the protein was added 24 hr after thc lectin. 125I-α2MG prepared by the chloramine T method which maintained a 30% trypsin-protein esterase (TPE) activity did not bind to the cells, while the labelled protein prepared using the lactoperoxidase method which had full TPE activity, did bind to the cells. The binding of α2MG with Con A was also demonstrated. Thus, the inhibitory effect of the protein on the proliferative response of lymphocytes to lectin may be due to binding of the protein to lymphocytes and consequently blocks the binding of the lectin to the cells or due to interaction of the protein with the lectin so as to diminish the number of the lectin molecules acting on the cells. [ABSTRACT FROM AUTHOR]

Background: Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC., Methods: We investigated the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) for CPT-11 given i.v. (90-min infusion) and bolus 5-FU plus biologically active l-LV administered weekly for 3 weeks every 28 days (modified Saltz regimen) in Japanese patients with metastatic CRC. Eighteen patients with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and adequate organ functions were enrolled., Results: At dose level 2 (CPT-11, 100 mg/m(2); 5-FU, 400 mg/m(2); and l-LV, 25 mg/body), 1 of 6 patients had DLT (febrile neutropenia). At dose level 3 (CPT-11, 100 mg/m(2); 5-FU, 500 mg/m(2); and l-LV, 25 mg/body), 2 of 6 patients had DLT (febrile neutropenia and grade 4 neutropenia lasting more than 4 days). To determine whether level 3 was the MTD level, an additional 3 patients were treated at this level, but no DLT was observed. Consequently, 2 of 9 patients had DLT at level 3, this level thus being considered as the RD. At this level, grade 3-4 neutropenia was common but manageable. Nonhematological toxicities were mild. Seven partial responses were observed in the 18 enrolled patients (response rate [RR], 39%), and 8 patients (44%) experienced stable disease., Conclusion: This CPT-11/5-FU/ l-LV regimen administered weekly for 3 weeks every 28 days has substantial antitumor activity, with manageable toxicities. A multicenter phase II study is currently underway. Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC.

We treated a patient in whom a hepatocellular carcinoma and a hyperplastic nodule of the liver concomitantly grew in association with long term phosphate diethylstilbestrol therapy for a carcinoma of the prostate. A 72-year-old Japanese man was admitted for investigation of hepatic masses. A diagnosis of prostate carcinoma had been made seven years ago and phosphate diethylstilbestrol 200 mg daily had been prescribed. A small mass was first detected in the liver four years later and another mass appeared three years after the appearance of the first mass. Histology of the excised tissue showed the former mass to be a hyperplastic nodule and the latter one hepatocellular carcinoma. Findings of cirrhosis, hepatitis or fibrosis were nil but fatty metamorphosis of the hepatocytes was apparent. These histological changes were considered to be associated with long-term phosphate diethylstilbestrol therapy therefore careful follow-up using amazing diagnosis is recommended for patients on phosphate diethylstilbestrol therapy.

Discussed is the case of a 71-year-old man with multiple large hepatocellular carcinomas. His serum AFP level had markedly increased to 115 X 10(4) ng/ml. His AFP level also elevated and multiple lung metastatic tumors appeared after the second TAE therapy of 30 mg ADM, 10 mg MMC. To arrest these rises 100 mg of CDDP was given intravenously, followed by 3.0 g/day of PSK given orally. Five months later, shadows of the metastatic tumor disappeared and AFP to 540 ng/dl. As the mechanism responsible this improvement, it is felt that the CDDP attacked the metastatic tumors directly, and that this was aided by the follow-up immunotherapy with PSK. The abscopal effect of TAE also may have played a role.

We studied whether familial case histories of a liver cancers might be associated with the high mortality rate from liver cancers in Saga prefecture. Examined were 285 familial case histories of a hepatocellular carcinoma (HCC) incurred by parents, siblings, and children during the past 10 years. Familial case histories of patients with a gastric cancer and/or apoplexy also were studied as controls. The incidence of various types of cancers, including liver cancers and gastric cancers, in the family members of the HCC group was found to be the same as seen in family members of the gastric cancer group, but higher than in the families of the apoplexy group. Further, the HCC incidence rate in family members in the HCC group was not high as compared to the average for the whole of Japan. The HBsAg was not found to be associated with the rate of liver cancer in family members in the HCC group. Also, there was no high incidence of liver cancer was observed in children of parents with a liver cancer. From these results, we have concluded that high incidence of liver cancer seen in Saga prefecture was not associated with any familial clustering of HCC cases.

The presence of insulin and various carbohydrates in long term cultures of hepatocytes was studied to examine the mechanism by which insulin and glycolytic metabolites regulate L-pyruvate kinase activity. When hepatocytes were isolated from a control rat and cultured in the presence of insulin, a constant level of enzyme activity (16 EU/mg DNA) was maintained for 12 days. The L-pyruvate kinase activity in hepatocytes from refed rats initially was elevated (45 EU/mg DNA) and decreased to control values by the 5th day in culture. Cells isolated from a fasted rat initially contained a low level of L-pyruvate kinase activity (5 EU/mg DNA) which increased to control values by the 8th day in culture. The enzyme activity was 5 EU/mg DNA when control cells were cultured for 4 days in medium containing either glucose, glycerol or fructose without insulin; 10 EU/mg DNA in medium containing galactose and insulin but without glucose, glycerol or fructose; and 20 EU/mg DNA in medium containing both insulin and either glucose, glycerol or fructose. It is suggested that insulin is essential for the induction and maintainance of L-pyruvate kinase activity, that carbohydrates in the absence of insulin are unable to maintain the enzyme activity in cultures of hepatocytes, and that insulin and glycolytic metabolites may act synergistically to increase the activity of L-pyruvate kinase by increasing the synthesis of the enzyme.

Two hundred and ninety-three cases of hepatocellular carcinoma (HCC) of recent ten years during 1979 and 1988 were analysed on its diagnosis, therapy and prognosis. Angiography was the most useful diagnostic method for the first 5 years. During recent 5 years and for the tumor with size less than 2 cm, however, ultrasonography was the best method. 24.7% cases showed negative AFP and only 42.5% cases showed the level over 400 ng/ml. According to the tumor occupying-rate at the diagnosis, the number of cases of E1 had increased annually, the other cases being unchanged. 88.6% cases had liver cirrhosis microscopically as being reported previously. As a therapy TAE was most frequently performed, followed by operation, arterial infusion of antitumor drugs et al. The prognosis of the patients depended on the tumor occupying-rate. For the case of E1, the prognosis was the best by the therapy of ethanol injection therapy, operation and TAE. For the cases with tumor of larger than E1, frequent TAE was the best. From these results we concluded that we must make efforts to find small tumors to get the good prognosis.

We treated a Japanese man with Rendu-Osler-Weber disease and a recurrent encephalopathy with hyperammonemia concomitant with recurrent epistaxis, G-I bleeding, congestive heart failure with aortic and mitral regurgitation, and chronic renal failure. At peritoneoscopy, several telangiectasia were noted on the surface of the liver. Angiographical studies revealed widened and tortuous hepatic arteries with early filling of hepatic veins and small pools of contrast medium scattered throughout the parenchyma. The recurrent encephalopathy was attributed to the porto-systemic shunt formed in the liver.

Rat alpha 2-macroglobulin was isolated and purified from the pooled sera of turpentine-injected rats by sequential use of dextran sulphate, DEAE-cellulose and gel filtration chromatography. The final protein product obtained by this procedure proved to be alpha 2-macroglobulin of a high degree of purity based on electrophoretic, immunologic and centrifugal analysis. The alpha 2-macroglobulin preparation also binds stoichiometrically to trypsin preventing subsequent inhibition by protein trypsin inhibitors. SDS-polyacrylamide gel electrophoresis of rat alpha 2-macroglobulin after incubation with trypsin suggested that there are at least two susceptible peptide bonds in the 170,000-dalton alpha 2-macroglobulin subunit. The concentration of alpha 2-macroglobulin in the sera of rats was measured by electroimmuno assay a monospecific antiserum against alpha 2-macroglobulin. Purified alpha 2-macroglobulin was used as a standard. Sera from normal male rats contained 32 +/- 4 micrograms of alpha 2-macroglobulin per ml. To determine the time course of response of alpha 2-macroglobulin to inflammation, rats were subjected to either laparotomy or subcutaneous injection of turpentine. After either type of injury, the concentration of alpha 2-macroglobulin increased rapidly, reaching a maximum value of 110-140 times that of the control value by 24 h. Little difference was noted in responsiveness between the two sexes.

In examining 293 patients with a hepatocellular carcinoma (HCC), 27 patients (9.2%) were found to have another primary malignancy located elsewhere. Of this number, fifteen were male and twelve were female, with ages that ranged from 53 to 81 years (mean 67.3 + 8.9 years). Twenty-four of these patients were found to have two other malignancies, where in 13 had both malignancies with a one year interval and other 11 after more than one year. The remains, three patients, had triple malignancies. These associated cancers included eight gastric cancers, four uterine, four colon cancers and other such cancers. The proportion of females with double cancers was higher than in those with only an HCC, although there were no difference in the HBsAg, age, past history of blood transfusion, the positive rate of familial malignancy, and the HCC between those with solely an HCC and those with other cancers as well. This suggests that the occurrence of an HCC concomitant with or followed by the development of another primary malignancy is not rare.

1. Pyruvate kinase isozyme shift in a regenerating rat liver was studied. Rats were subjected to a 70% hepatectomy and the liver homogenate or hepatocyte preparations were obtained from the regenerating liver. 2. Using thin layer polyacrylamide gel electrophoresis, liver homogenates from an intact normal rat appeared to contain the L-type isozyme in the greatest number and M2-type to a lesser extent. 3. The ratio of the M2- to L-type increased in the preparations obtained from the regenerating liver. 4. In the hepatocyte preparations prepared from a regenerating rat liver by the conventional method, a small amount of M2-type isozyme was detected. 5. However, the M2-type isozyme was hardly detected in the highly purified hepatocyte preparations prepared using Percoll. 6. Similar results were obtained by separation of the enzyme by DEAE cellulose column chromatography. 7. These results suggest that there is no pyruvate kinase isozyme shift from L- to M2-type in hepatocytes in the course of regeneration. 8. The increased M2-type isozyme in the regenerating rat liver is considered to originate from nonparenchymal cells.

We studied on the prognosis-related factors on 17 cases of Japanese encephalitis experienced during the last ten years and compared the clinical features with those in previous reports, especially when the disease was prevalent. The patients, ranging from 33 to 91 years old, consisted of 7 men and 10 women. All of them showed an encephalitis type. 47.1% of the patients were completely cured, 35.3% cured with sequelae and 17.6% died. The mortality rate was decreased compared to that of previous reports. All of the death cases were women. There was no relationship between the mortality rate and the patients' age. As previously reported, the more severe the disturbance of consciousness, the higher the mortality was. However the rate of death was lower than that of previous reports. We conclude from this study that clinical features of the disease have changed when compared with that of the older days.

Two hundred and ninety-three cases of hepatocellular carcinoma (HCC) admitted to the key hospital of the rural area of western Japan, Saga Prefectural Hospital, during 10 years since 1979 to 1988 were analysed retrospectively. The male to female ratio was 3.7 to 1 and the ratio of HBs-Ag positive to negative was 3.5 to 1. The peak of the age distribution was seventh decade. The incidence increased annually, especially in HBs-Ag negative males. Their past history of blood transfusion was considered as an etiology of HCC in 19 (9.9%). The HCC was diagnosed approximately 10 years earlier in habitual drinkers than non-habitual drinkers of both positive and negative HBs-Ag. The incidence of small tumors is associated with the past history of chronic liver disease, negativity of HBs-Ag, lack of symptoms and old age.

Glucagon caused a marked decrease in the total L-pyruvate kinase activity of control hepatocytes maintained in monolayer culture (t1/2 = 54 h), while the addition of insulin to hepatocytes isolated from a fasted rat caused a four- to fivefold increase in the total enzyme activity. Maintenance of L-pyruvate kinase in control cultures of hepatocytes was shown to require insulin. However, when 1 microM glucagon was present in the medium, the total L-pyruvate kinase activity was not maintained even in the presence of 1 microM insulin, but rather the total L-pyruvate kinase activity of the cells steadily declined from 12.1 to 5.7 units/mg DNA by the 6th day in culture. The increase in the total L-pyruvate kinase activity of fasted hepatocytes cultured in the presence of insulin was shown to result from an increase in protein synthesis, since actinomycin D and cycloheximide blocked the insulin-induced increase in the enzyme activity. The addition of 1 microM glucagon to cultures of fasted hepatocytes also blocked the insulin-induced increase in total L-pyruvate kinase activity. Since glucagon decreased the total L-pyruvate kinase activity in control hepatocytes and blocked the increase in L-pyruvate kinase activity in fasted hepatocytes, it is suggested that, in addition to the phosphorylation of L-pyruvate kinase by a cAMP-dependent protein kinase, glucagon also acts to decrease the synthesis of L-pyruvate kinase in vitro.