Tadao Manabe

Over-expression of facilitative glucose transporter genes in human cancer

The expression of five facilitative glucose transporter genes, GLUT1 (erythrocyte type), GLUT2 (liver type), GLUT3 (brain type), GLUT4 (muscle/fat type), and GLUT5 (small intestine type), was examined in human cancer tissues of the digestive system by RNA blotting analysis. The amounts of the GLUT1, GLUT2, and GLUT3 transcripts were elevated in most cancer tissues studied, although the expression of the GLUT2 gene is primarily restricted to the liver. On the other hand, mRNA levels of GLUT4 and GLUT5 were below sensitivity in all cancer tissues examined. These results suggest that over-expression of GLUT1 and GLUT3 might be closely related with tissue development and that the acceleration of glucose uptake by transformed cells may result, at least in part, from the increase in the expression of these two glucose transporters.

High dose, external beam and intraoperative radiotherapy in the treatment of resectable and unresectable pancreatic cancer

Ninety patients with pancreatic cancer were treated by external beam radiotherapy (EBRT) and/or intraoperative radiotherapy (IORT) with or without surgical resection of the tumor, and the results were compared with those of a historical control comprising 112 patients treated by surgery alone. At an early stage of this study, postoperative EBRT (50-60 Gy) or IORT (25-33 Gy) was given alone, but recently the two modalities have been combined. The combination of high doses of EBRT and IORT was well tolerated provided that the gastrointestinal tract was not irradiated during IORT. Although EBRT plus IORT appeared to yield better results than either EBRT or IORT alone, the difference was not significant on multivariate analysis, and patients receiving EBRT, IORT, or EBRT + IORT were grouped together. Patients receiving radiotherapy in addition to macroscopically curative surgery had a slightly longer median survival time (14 months) than those receiving curative surgery alone (10 months), but the 3-year survival rate was similar (21% vs. 19%). In patients who underwent noncurative resection, the median survival time was significantly longer for the irradiated group (12 months) than for the control group (6.5 months). Also, in patients with unresectable lesions but no distant metastases, irradiation prolonged the median survival time significantly (8 vs. 3.5 months). In this group, there was one 5-year survivor, who received EBRT of 55 Gy plus IORT of 30 Gy to his unresectable pancreatic body lesion. Patients with metastases were also treated for palliation of symptoms, but it was found that irradiation prolonged the median survival time even in such cases (4.5 vs. 2.5 months). Based on these results, we plan to use EBRT plus IORT in all pancreatic cancer patients with no metastases.

Role of ischemia in acute pancreatitis. Hemorrhagic shock converts edematous pancreatitis to hemorrhagic pancreatitis in rats.

Ischemia has been considered to play a role in the development of acute pancreatitis. The aim of this study was to investigate the effect of ischemia, caused by hemorrhagic shock, on cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by the intravenous infusion of a supramaximally stimulating dose of cerulein (10 μg/kg/hr) for 6 hr. Hemorrhagic shock was induced by the removal of blood until the mean arterial blood pressure reached 35 mm Hg. This level was maintained for 30 min, after which time all the blood was reinfused. Hemorrhagic shock alone induced no morphological change in the pancreas. However, after the induction of hemorrhagic shock in animals treated with cerulein, hemorrhage and parenchymal necrosis were frequently observed in the pancreas. Seven of 20 rats (35%) receiving cerulein plus hemorrhagic shock had died by 48 hr after the start of cerulein infusion, whereas none of the rats in the cerulein or shock group died during this experiment. Cathepsin B activity in the pancreas of the cerulein plus shock group was significantly higher than in the other groups at 48 hr. These results suggest that ischemia may be a contributing factor in the pathogenesis of acute pancreatitis.

Small carcinoma of the pancreas. Clinical and pathologic evaluation of 17 patients.

The clinical and pathologic characteristics of 17 small carcinomas (less than 2 cm in diameter) of the pancreas are reviewed in this article. All the tumors were located in the head of the pancreas, and the clue to the diagnosis was jaundice in ten patients and abdominal pain in seven. Carcinoembryonic antigen (CEA) and CA 19‐9 were not reliable markers for detecting small carcinomas of the pancreas. Ultrasonography (US), computerized tomography (CT), percutaneous transhepatic cholangiography (PTC), and endoscopic retrograde cholangiopancreatography (ERCP) were useful diagnostic tools. Lymph node metastases were found in 41% of affected patients, capsular invasion in 24%, retroperitoneal invasion in 24%, and portal system involvement in 29%. In five patients the carcinoma was Stage I; in eight patients, Stage II; in two patients, Stage III, and in two patients, Stage IV. Fifteen patients with Stages I to III and one patient with Stage IV underwent curative pancreaticoduodenectomy or total pancreatectomy, and one patient with liver metastasis and Stage IV underwent noncurative pancreaticoduodenectomy. The cumulative 4‐year survival rate was 37%. Although four patients with Stage I disease lived for more than 48 months, the survival period of the 12 patients with Stages II to IV disease was less than 25 months. Thus, small carcinoma of the pancreas is not always curable; however, a small, localized lesion without any extratumoral extension can be resected with a chance of cure.

Changes of Xanthine Oxidase, Lipid Peroxide and Superoxide Dismutase in Mouse Acute Pancreatitis

The role of free radicals in the development of pancreatitis was evaluated by measuring the level of activities of xanthine oxidase (XOD), lipid peroxide (LPO) and superoxide dismutase (SOD). Acute pancreatitis was induced in female mice fed a choline-deficient meal containing 0.5% DL-ethionine (CDE meal). Acute pancreatitis was confirmed by the changes in serum amylase level and other typical features observed microscopically 24 h after the meal was taken. Activity of XOD was elevated significantly (p less than 0.05) from the baseline of 1.13 +/- 0.19 U/g tissue to 2.34 +/- 0.46, 2.59 +/- 0.33 and 3.46 +/- 0.70 U/g tissue, 8, 12 and 24 h, respectively, after the CDE meal. The LPO level was also increased from an undetectable amount to 1.10 +/- 0.47 nmol/ml (p less than 0.05), 1.03 +/- 0.18 (p less than 0.01) at 6 and 8 h, respectively, and then returned to an undetectable amount at 12 h. The peak level of LPO was shown at 24 h, 1.76 +/- 0.40 nmol/ml (p less than 0.01) and gradually decreased until 48 h, 1.17 +/- 0.37 nmol/ml (p less than 0.01) after the CDE meal. Changes of LPO took a biphasic pattern. SOD was decreased significantly from 47.1 +/- 3.4 mU/g tissue to 30.7 +/- 2.5, 24.8 +/- 1.7 and 20.6 +/- 1.1 mU/g tissue at 8 (p less than 0.01), 12 (p less than 0.01), and 24 (p less than 0.01) h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between Secretory IgA, IgA-Containing (C3-Fixing) Circulating Immune Complexes, and Complement Components (C3, C4) in Patients with Obstructive Jaundice

Serum secretory IgA, IgA-containing circulating immune complexes (IgA-CIC), complement components, and major immunoglobulins were measured in patients with biliary tract stones and/or tumors of the biliary tract or pancreas. The levels of secretory IgA and total IgA were increased in patients with and without obstructive jaundice. The levels of both C3 and C4 were significantly higher in patients with or without obstructive jaundice than in healthy controls. In patients with obstructive jaundice the increased levels of secretory IgA, total IgA, and IgA-CIC were correlated with the increase of C3 but not with that of C4.

Serum cathepsin B levels and urinary excretion of cathepsin B in the cancer patients with remote metastasis

Serum cathepsin B levels and urinary excretion of cathepsin B in the cancer patients without remote metastasis were significantly higher than those in the control non-cancer patients. Moreover, these parameters in the cancer patients with remote (liver or lung) metastasis were significantly higher than those in the cancer patients without remote metastasis. After radical curative operations, these parameters were restored to the control values. These results suggest a possible role of lysosomal enzyme, cathepsin B in the pathogenesis of tumor metastasis, and also suggest that these parameters might be possible indicators for tumor malignancy such as remote metastasis.

Galanin-Induced Hyperglycemia: Effect on Insulin and Glucagon

Synthetic galanin, infused at a rate of 4 micrograms/kg body weight/h for 30 min, elicited a mild but significant hyperglycemia in conscious dogs and a fall in plasma insulin. Pancreatic glucagon, epinephrine, norepinephrine, cortisol and growth hormone levels were not affected significantly. The mild hyperglycemic action of galanin seems to be due to an inhibition of insulin production. Thus galanin appears to be involved in glucose homeostasis.

Bradykinin involvement in the aggravation of acute pancreatitis in rabbits

This study was designed to investigate the role of bradykinin in the aggravation of acute pancreatitis. After injection of bradykinin 2 micrograms/kg to anesthetized rabbits with cerulein-induced acute pancreatitis, the pancreatic blood flow through gastroduodenal and superior mesenteric arteries (GDAF and SMAF) was determined with electromagnetic blood flow meters, the serum amylase level was measured, and pancreatic tissue was observed histologically. In rabbits treated with a supramaximal dose of cerulein alone (20 micrograms/kg/h), pancreatic blood flow was decreased and the serum amylase level was increased significantly by the early phase, and histological examination showed acute edematous pancreatitis. In rabbits treated with cerulein and bradykinin, GDAF and SMAF were significantly diminished at 300 min (51 +/- 5% and 50 +/- 4%, respectively, p < 0.05), and the serum amylase level rose significantly at 180 and 300 min (730 +/- 130% and 1,190 +/- 200%, respectively, p < 0.01) compared with rabbits treated with cerulein alone, and histological examination revealed pancreatic necrosis and greater inflammatory cell infiltration. These findings suggest that bradykinin has an additive role in the aggravation of acute pancreatitis.

K-ras and p53 Alterations in Genomic DNA and Transcripts of Human Pancreatic Adenocarcinoma Cell Lines

We analyzed 15 human pancreatic adenocarcinoma cell lines for alterations of the K‐ras and the p53 genes and their transcripts. In 11 cell lines (73.3%), point mutations of the K‐ras gene were found at codon 12 in exon 1. In 9 cell lines one allele was mutated and the other was wild type, and both the alleles were expressed into mRNA. In one cell line both alleles of codon 12 were mutated to TGT and GTT, respectively, hut only TGT was transcribed into mRNA. Alterations in mRNA of the p53 gene were detected in 10 cell lines (66.7%). Analysis of the genomlc sequence of the p53 gene revealed that the alterations consisted of 6 cases of base pair substitutions and 1 case of 1‐bp deletion in evolutionarily conserved exons 5 to 8, 2 cases of splicing mutations in exon 4, and 1 case of novel deletion from exons 2 to 9. In 14 cell lines (93.3%), alterations were identified in the K‐ras or p53 gene. Of these, 4 cell lines harbored K‐ras mutations without p53 alteration, whereas 3 cell lines exhibited p53 alterations without K‐ras mutation. Thus, it is suggested that activation of the K‐ras gene and inactivation of the p53 gene are strongly and cooperatively associated with pancreatic carcinogenesis.