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Two human gastric cancer xenograft lines (GC-YN and GC-SF) transplanted in nude mice were employed to evaluate and compare the anticancer effect of seven single anticancer agents and their various combinations. Mitomycin C, cisplatin (Briplatin) (CDDP) and 5-fluorouracil (5-FU) were screened out to be effective against GC-YN and only epirubicin (Farmorubicin) (EPIR) was effective against GC-SF. Combinations of two of these 'effective' agents revealed that FP (5-FU + CDDP) is the most effective two-agent combination regimen against both lines, and some of those 'ineffective' single agents showed synergistic effects against both lines when combined with 5-FU. Moreover, three-agent combinations composed of FP and one of the other five agents were also evaluated to select out the most effective regimen. All the combinations showed higher inhibition on the tumor growth of GC-YN than FP regimen, and FP + adriamycin (Adriacin) (ADR) and FP + EPIR were more effective against GC-SF than FP. However, taking toxic effects into consideration, the results suggest that CDDP + 5-FU + EPIR (FPEPIR) may be the regimen most worthy of clinical trial in the chemotherapy against human gastric cancer.

Radical operation with extensive dissection of lymph nodes (R1 48 patients; R2, 196 patients; R3, one patient) was performed in 245 out of 247 patients with early gastric cancer. The 5-year survival rate was only 73.2 per cent in the 34 patients with lymph node metastases (31·8 per cent). Analysis of factors influencing recurrence revealed that not only lymph node metastases but also the depth of cancer invasion could affect prognosis in early gastric cancer. This study suggests that radical operation with complete dissection of the first and second group of lymph nodes (R2 resection) is a safe and appropriate treatment even for early gastric cancer. We propose that the definition of early gastric cancer be modified to ‘carcinoma with invasion confined to the mucosa or submucosa and without evidence of lymph node metastases’.

The carcinoma SC42 was transplanted into the liver of its syngeneic mice DS, and the immunological integrity of the spleen and the effects of splenectomy on the growth and pulmonary metastasis of the liver tumor were assessed. On day 7 after liver tumor transplantation, the natural killer (NK) activity of the splenocytes was significantly elevated; it subsequently decreased at a later stage of the tumor. The response of the splenocytes to PHA and Con-A decreased significantly from the early stage of the tumor. However, the mixed lymphocyte-tumor cell reaction increased significantly from day 14 to day 28. The survival rate of the mice, which had undergone simultaneous splenectomy and liver tumor transplantation, was significantly lower than that of sham-operated control mice. The number of pulmonary metastases in splenectomized mice was significantly greater than in the control mice. There was, however, no difference between the two groups in the weight of the liver tumor. By contrast, splenectomies performed 14 days before or 14 days after tumor transplantation had no significant influence on the survival of the mice. Splenectomies performed on day 0 and on day 3 after tumor transplantation significantly increased the number of pulmonary metastases, Furthermore, the intravenous injection of anti-asialo GM1 antisera on day 0 and day 3 significantly increased the number of pulmonary metastases, but injection of anti-Thy 1,2 antisera had no effect. These results suggest that splenic NK cells may play an important role in the suppression of pulmonary metastasis at early stages of the liver tumor.

Radical pancreaticoduodenectomy was performed for cancer of the head of the pancreas in a 65-year-old male patient with congenital celiac occlusion. Preoperative angiography revealed that the arterial flow to the liver, spleen, and stomach was supplied via the pancreaticoduodenal arcade and that the dorsal pancreatic artery arose from the superior mesenteric artery. In order to perform radical pancreatectomy with sufficient clearance of lymph nodes and soft tissues around the pancreas, the celiac arterial circulation was reconstructed. The restoration of flow was effected via a saphenous vein graft between the common hepatic artery and the aorta. Postoperative angiography demonstrated patency of the graft. The patient's postoperative course was uneventful.

Earlier studies have reported that interstitial oedematous pancreatitis characterized by hyperamylasaemia can be seen during the early stage of stimulation of supramaximal dose of caerulein. The present study investigated the changes in both cellular and lysosomal fragility and the protective effects of a synthetic protease inhibitor gabexate mesilate (FOY) on this non-invasive model of experimental pancreatitis. The infusion of FOY (50 mg/kg/h) prevented the caerulein-induced increase in serum amylase and pancreatic oedema formation and reduced the elevated amylase content significantly. The administration of FOY with caerulein also reduced the increased lactic dehydrogenase (LDH) discharge significantly and inhibited the cathepsin B leakage from lysosomes in an in vitro incubation system. These results indicate that FOY plays its protective role at the subcellular level--that is, in lysosomes by inhibiting some proteases such as phospholipase A2. The importance of esterases in the pathogenesis of acute pancreatitis is demonstrated. This type of esterase inhibitor may be valuable clinically in the treatment of acute pancreatitis and these results also suggest the role of lysosomal fragility in the pathogenesis of progression of acute pancreatitis.

Fatal "postoperative erythroderma" (POE) developed in 2 patients treated with liver lobectomy and the transfusion of fresh blood. Their clinical features and skin-histological findings were indicative of acute graft-versus-host disease (GVHD). The HLA phenotypes of circulating lymphocytes of the 2 patients were heterozygous but became homozygous late in the clinical course and were identical with those of the blood donors. One of the patient's haplotypes was identical with the donor's homozygous haplotype. These findings suggest the mechanism of development of POE in apparently immunocompetent patients. The donor's T lymphocytes are histocompatible with the patient's tissues, are not rejected, and become engrafted. The patient's tissues are not histocompatible with the donor's, so that GVHD develops.

PSK, a protein-bound polysaccharide, has been widely used for cancer immunotherapy in Japan. However, the mechanism of its immunomodulatory effect has not been fully clarified. In the present study the in vitro effect of PSK on the lymphocytes of patients with gastric cancer was studied. Culturing lymphocytes with PSK at 5-100 micrograms/ml increased the level of DNA synthesis, and augmented the cytotoxicities against K562 and KATO-3. Flow-cytometric analysis also showed an increase in the proportion of interleukin-2 (IL-2)-receptor-positive cells after the lymphocytes were cultured with PSK. However the cytotoxicity of cells cultured with PSK was not augmented by the addition of recombinant interferon gamma (rIFN gamma) and rIL-2. Further experiments using fractionated PSK showed that its biological action is present mainly in fractions having molecular masses greater than 10(5) Da. However, these immunomodulations were not seen in all patients. These results suggest that the susceptibility of lymphocytes to PSK may be different in each patients, and that the immunomodulation by PSK may be mediated by mechanisms independent of IFN and IL-2.

Two hundred and ninety-eight patients with curatively resected colorectal cancer were classified into 12 categories according to the depth of tumour penetration (T1–T4), and lymph node status (N0 –N2). Using a computer, these categories were grouped into 2–12 stages in every possible combination, so a total of 146,975 logical classifications were generated. The optimal model was selected for each group of classifications with equal stage number, thus giving the greatest prognostic information on 5-year survival according to the Akaike criterion. The results showed that (1) 13% of the total classifications, including 85% of the 3-stage classifications, were better than the Dukes system in predicting our patients' outcomes; (2) the T-level was a stage-determinant even more important than the N-level; and (3) major changes in prognosis occurred at more advanced stages than the classical ‘turning points’. We conclude that in order to find an optimal staging of cancer, systematic computer-aided search through all the possible classifications is necessary, using the appropriate database.

Summary We have examined the effect of synthetic human cholecystokinin (CCK-33 and CCK-8) on pancreatic blood flow and protein output in anesthetized dogs. Human CCK-33 and CCK-8 increased pancreatic blood flow and protein output in a dose-related manner. There were no significant differences in increasing pancreatic blood flow between human CCK-33 and CCK-8, and increases in blood flow were closely related to the increase of the pancreatic enzyme secretion. L-364,718 (20 nmollkg) caused a potent inhibition of CCKstimulated pancreatic blood flow as well as protein output. The degree of inhibition by L-364,718 was dependent on the amount of CCK infused. This study demonstrates that increasing effect on pancreatic blood flow may be one of the biological actions of CCK mediated via CCK receptor. The CCK-33, one of longer molecular forms of CCK, is an important biological stimulator of pancreatic blood flow as well as of exocrine pancreatic secretion.

The factors influencing prognosis and the indications for curative resection by radical pancreatectomy were evaluated in 74 patients treated with pancreatectomy for ductal cell carcinoma of the head of the pancreas. The 5-yr survival rates for patients without lymph node metastasis, capsular invasion, portal system involvement, or retroperitoneal invasion were 21.2, 20.2, 25.5, and 19.6%, respectively; the 5-yr survival rate for patients with lymph node metastasis or capsular invasion was 5.3% and 6.4%, respectively, and the 2-yr survival rate for patients with portal system involvement or retroperitoneal invasion was 0%. The 5-yr survival rate for 32 patients treated with radical pancreatectomy was 33.4%, and the 3-yr survival rate for 42 patients treated with nonradical pancreatectomy was 0%. Our results suggest that, in patients with ductal adenocarcinoma of the pancreas without factors limiting prognosis, curative resection by radical pancreatectomy is feasible; however, in patients with positive factors, particularly portal system involvement or retroperitoneal invasion, a comprehensive therapeutic program combining extensive surgery, radiation, chemotherapy and/or immunotherapy is necessary to obtain better results.

The wound healing process is initiated as soon as tissue is injured. Herein, we demonstrate that c-fos and c-myc mRNA transcripts are promptly increased in the wounded tissue in vivo and in vitro. A buffer solution from scraped serum-starved quiescent fibroblasts, when added to resting fibroblasts, caused the increase of c-fos and c-myc mRNA among the indicator cells. Soluble factors contained in the wounding supernatant are responsible for these phenomena and we call them wounding factors. Addition of proteinase inhibitors to the culture medium drastically reduced the c-fos mRNA induction by the wounding factors. Exogenously added trypsin or thrombin mimicked the activity of wounding factors. These results suggest that wounding causes soluble factors including various proteinases to be released from the damaged cells, which trigger the adjacent cells to respond to the injury.

Biliary obstruction induces a increase in the permeability between blood and bile, and a decrease in the rate of immunoglobulin A (IgA) transport into bile. We investigated the effects of percutaneous transhepatic biliary drainage (PTBD) on these derangements. PTBD reduced the extent of elevation of the bile-to-serum ratio of Immunoglobulin G (IgG; IgG-BS ratio) in patients with obstructive jaundice. Because IgG is known to be passively transported from serum to bile, the results indicate that PTBD restores the blood-bile barrier function. The IgA-BS ratio/IgG-BS ratio index (IgA/IgG index) and the IgM/IgG index, which indicated the function of selective transport of IgA and IgM into bile, initially decreased and then returned to the normal range 17 days after PTBD in patients who experienced a rapid resolution of hyperbilirubinemia. However these indices remained low in patients who did not experience this resolution. The serum secretory IgA levels in patients who did not experienced rapid resolution of hyperbilirubinemia markedly increased before PTBD. The serum secretory IgA levels in the patients who did and those who did not experience rapid resolution of hyperbilirubinemia, after initially increasing, decreased after PTBD. However the level returned to the control range only in patients who experienced a rapid resolution. These results indicate that the secretory IgA level is a sensitive indicator of hepatobiliary function, and measurement of the level of secretory IgA could predict the effect of PTBD.

The chemosensitivities of primary tumors (PT) and simultaneous metastatic lymph nodes (MN) to mitomycin C (MMC), 5-fluorouracil (5-FU), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), carboquone (CQ), or cisplatin (CDDP) were assessed in a group of 29 patients (11 gastric, 8 colorectal, 4 breast, and 6 other cancers) by a DNA synthesis (3H-thymidine incorporation) inhibition assay. PT and MN from the same patient showed heterogeneity in chemosensitivity. MN were more sensitive to the agents than PT. PT were sensitive to 5-FU, whereas MN were sensitive to CDDP. An analysis of the sensitivity correlations showed that the sensitivities of PT to MMC, 5-FU, CQ, and CDDP correlated with each other, but ADR sensitivity correlated with only CQ sensitivity. The sensitivities of MN correlated with each other, except for those to ADR and CDDP. In contrast, MMC, ADR, or CQ sensitivity showed a correlation between PT and MN. These results suggest that patients should be treated according to the sensitivity of the target lesion. However, if the sensitivity assay is not available, the sensitivity correlation may be useful when choosing the agent. It also may be important that ADR sensitivity does not correlate with the sensitivities of other agents.

The receptor binding of CCK analogues was determined in terms of the inhibition of [125I]CCK binding in isolated rat pancreatic acini. The inhibition curve produced by CCK-8 showed the same feature as that produced by synthetic human CCK-33. The relative potency values of CCK analogues to half-maximally inhibit specific CCK binding were calculated; CCK-8 was equal to human CCK-33, 3-fold stronger than natural porcine CCK-33 and 39, and 700-fold stronger than the unsulphated form of synthetic human CCK-33. Our data suggest that CCK-33, one of the longer molecular forms of CCK, is as important as CCK-8 in the mechanism of physiological actions of CCK.

The immunohistochemical distribution of CA19-9 in normal and tumor tissue of the kidney was investigated. CA19-9 was detected in the cytoplasm and apical surface of renal proximal tubules, distal tubules and uroepithelium of the renal pelvis. Eight of 28 renal cell carcinomas (29%) expressed CA19-9. CA19-9 was also detected in 2 cases of transitional cell carcinoma and 1 of 4 cases of Wilm's tumor, but not in angiomyolipoma. As the measurement of CA19-9 is widely used to detect gastrointestinal carcinoma, the expression of CA19-9 in normal and neoplastic kidney tissue might have some clinical significance.

We studied the therapeutic effect of OK-432 combined with adoptive immunotherapy in 19 cases of liver metastases from breast cancer. Of the 14 patients who received intraarterial OK-432 injection and transfer of cultured lymphocytes, 9 responded to this therapy, whereas no patients responded to intravenous administration. The minimum cell number for a therapeutic response was 8 x 10(8) cells. Metastatic lesions other than those in the liver regressed after therapy in 4 patients. The serum carcinoembryonic antigen level paralleled the therapeutic effect. There were no severe side-effects accompanying this therapy. These results indicate that intraarterial adoptive immunotherapy combined with OK-432 is effective as a new therapeutic approach against liver metastases from breast cancer.

Oxygen-derived free radicals have been implicated as mediators of cellular injury in several model systems. In order to clarify the role of oxygen radicals in endotoxemia, we measured the serial lipid peroxide changes resulting from systemic radical reactions using a newly developed colormetric method. To determine the effect of a free radical scavenger on mortality in endotoxemia, a new synthetic scavenger, 2-Octadecylascorbic acid (CV-3611), which overcome the detrimental properties (circulation half-life and cell penetration) of native SOD, was used in the model of mouse endotoxemia induced by the i.p. administration of E-coli endotoxin (10 mg/kg). Serial LPO (Lipid Peroxide) changes revealed significant elevations from the basal level of 4.52 +/- 0.79 nmol/ml to 10.5 +/- 2.04 nmol/ml at 2h (P less than 0.05), 12.0 +/- 2.44 nmol/ml at 8h (P less than 0.05), 32.8 +/- 12.5 nmol/ml at 12h (P less than 0.05) and 13.6 +/- 2.40 nmol/ml at 24h (P less than 0.05) following i.p. administration of E-coli. The circulation half life of CV-3611 was checked by a reversed-phase HPLC after 10 mg/kg s.c. administration. The level of CV-3611 reached peak levels of 0.54 +/- 0.10 micrograms/ml at 1h and 0.52 +/- 0.20 micrograms/ml at 2h then gradually decreased to the level of 0.04 +/- 0.004 micrograms/ml at 6h and to a non-detectable level at 24h after s.c. administration. Increased survival was seen at 2 days (P less than 0.001) after E-coli endotoxin administration in the CV-3611 treated group compared to the control group. These results suggest that oxygen derived free radicals contribute to mortality in mouse endotoxemia and that antioxidants such as CV-3611 may provide a new therapeutic avenue by improving survival of patients with gram-negative bacterial sepsis.

The immunohistochemical localization of DU-PAN-2 antigen and CA19-9 antigen in carcinomas of the digestive tract was studied using an immunoperoxidase technique. Staining for DU-PAN-2 antigen and CA19-9 antigen was observed in 104 (79%) and 96 (73%) of 131 carcinomas of the digestive tract, respectively. Diffuse staining (more than 20% of carcinoma cell stained) for DU-PAN-2 was detected in 14 of 21 (67%) pancreatic carcinomas and 11 of 19 (58%) carcinomas of the biliary tract (including cholangiocarcinoma). Diffuse staining for CA19-9 was detected in 15 (71%) of pancreatic carcinomas and nine (47%) of the carcinomas of the biliary tract. In colon carcinomas, no diffuse staining for DU-PAN-2 was observed, whereas diffuse staining for CA19-9 was found in 41%. There was a positive correlation between the differentiation degree (or grade) of the adenocarcinomas of the colon and the expression of CA19-9, but not that of DU-PAN-2. These immunohistochemical studies showed that DU-PAN-2 antigen is expressed diffusely in most cases of adenocarcinoma of the pancreas and biliary tract and is more specific for adenocarcinomas of the pancreas and biliary tract than CA19-9.

Peripheral blood lymphocytes, regional lymph node lymphocytes or malignant effusion lymphocytes from cancer patients were incubated with crude IL-2 (cIL-2) for 13 days. These effectors, which frequently expressed IL-2 receptor (IL-2R), proliferated well and possessed augmented killing activity against fresh autologous tumor cells and K562. However, when recombinant IL-2 (rIL-2) was added for the last 4 days of culture instead of cIL-2, IL-2R expression and killing activity against fresh autologous tumor cells decreased significantly (P less than 0.05). Phenotypic analysis indicated that cIL-2 significantly promoted the expansion of the cytotoxic population (CD8+.11b-)(P less than 0.05). The decreases in killing activity and IL-2R expression were restored by 0.004% PHA plus rIL-2, but not in the presence of rIFN-gamma, rIL-1 alpha, rIL-1 beta, rIL-4 or rIL-6. PHA-free cIL-2 maintained killing activity, but not IL-2R expression. We conclude that some factors in cIL-2 and a low dose of PHA-P are necessary for the maintenance of killing activity and IL-2R expression of cultured lymphocytes in the late phase of culture.

The effect of intravenous administration of human epidermal growth factor on the splanchnic blood flows was examined in anesthetized dogs, using an ultrasonic transit-time volume flow meter. Human epidermal growth factor (0.1, 0.5 and 1 microgram/kg) significantly increased blood flows in the portal vein (36.9 +/- 7.4% at 1 microgram/kg) and the superior mesenteric artery (49.0 +/- 16.8% at 1 microgram/kg). Systemic blood pressure monitored simultaneously was significantly decreased (8.4 +/- 1.2% at 1 microgram/kg). This study is the first to demonstrate that intravenous administration of epidermal growth factor increases the portal venous blood flow.

It is of great importance to define the manner in which cells are damaged and how intracellular derangement becomes irreversible during shock. When supply of both oxygen and substrates to cells is limited during shock, cellular energy metabolism of vital organs is severely depressed. In this experiment, the relationship was clarified between the reversibility of shock and the cellular energy status, from the viewpoint of hepatic energy change, mitochondrial redox state, ATP synthesis of isolated mitochondria, and fragility of mitochondrial membrane in rat livers. The derangement of energy metabolism passed through a series of four stages during hemorrhagic shock. At Stage I (initial stage), the cellular energy level decreased greatly due to marked energy consumption, without any organic damages in the mitochondria. Stage II (cell distress stage) showed that cellular energy imbalance occurred due to the depressed mitochondrial activity in vivo, although it was reversible when the blood supply was restored. Stage III (transitional stage) was the phase at which mitochondrial fragility increased severely. At Stage IV (terminal stage), mitochondria were markedly damaged organically and cellular energy metabolism was not remedied by any intensive therapies, which inevitably meant the death of vital organs.

Changes in arterial and hepatic venous blood ketone bodies were investigated following transcatheter hepatic artery embolization (THAE) in patients with hepatocellular carcinoma. Acetoacetate/ beta-hydroxybutyrate ratio (ketone body ratio) in arterial blood was positively correlated with those of hepatic venous blood (r = 0.960, p less than 0.001), which reflects the mitochondrial redox potential in the embolized lobe. Nine cirrhotic patients were classified into three groups according to the changes in arterial blood ketone body ratio following THAE: Type A without decrease to below 0.7; Type B with a transient decrease to below 0.7, followed by its restoration within 5 hours; and Type C with decrease to below 0.7 without recovery within 5 hours. There were no serious complications in Type A and B patients. By contrast, severe sepsis and hepatic failure developed in Type C patients, possibly due to the extended embolization of both lobes. It is suggested that THAE can be successfully performed even in severely cirrhotic patients, as long as the embolized area is restricted to one lobe. In addition, changes in arterial blood ketone body ratios can give early information about the likely consequences of the THAE procedure just performed.

The clinicopathological features showing the malignancy of hepatocellular carcinoma were investigated by retrospectively analyzing the postoperative prognosis after hepatic resection. The long-term prognosis was strongly affected by the existence of portal tumor invasion or intrahepatic metastasis as indicated by the following results. The 3-year cumulative survival rates were 61% and 38% for patients in portal vein tumor invasion groups (Vp0 and Vp1 (P less than 0.05). No patients with Vp2 or Vp3 could survive beyond 3 years after hepatic resection. Similarly, patients with intrahepatic metastasis IM0 showed a better prognosis, compared to those with IM2 or IM3 (P less than 0.05). In addition, the grade of tumor cell anaplasia to some extent affected the prognosis, but not the tumor growth pattern at the tumor/non-tumor boundary. The tumor growth rate, estimated by the alpha-fetoprotein doubling time, was not connected with venous invasion or intrahepatic metastasis, but it became shorter at the time of a recurrence. It is concluded that, from the standpoint of a long-term prognosis, the pathological features showing malignancy appear in venous invasion and intrahepatic metastasis.

教室で維持している慢性膵胃痩犬による意識下実験の成果について述べるとともに, 新しく開発した慢性胆膵胃瘻犬の作製維持の方法とその意義について述べた. 慢性膵胃痩犬は, (1) 空腹時, (2) 十二指腸内刺激前後, (3) 外因性刺激前後, (4) 食餌負荷前後の膵外分泌動態の観察検討に有用であった. 慢性膵胃瘻犬作製維持の技術, 経験から慢性胆膵胃瘻犬を開発した. 慢性胆膵胃瘻犬の作製後2ヵ月生存率は71.4%であり, また6ヵ月以上の長期生存を得た. 十二指腸内オレイン酸刺激実験により慢性胆膵胃痩犬が生理的な反応系を有することが確認され, 本モデルが今後肝胆膵胃臓器相関の研究に有用であると考えられた.

Summary Immunoglobulin A-containing circulating immune complexes, immunoglobulin G-containg circulating immune complexes, and endotoxin were measured in the sera of patients with obstructive jaundice. The bile of patients with percutaneous transhepatic biliary drainage was also cultured for bacteriologic studies. There was a significantly positive correlation between the endotoxin levels and both immunoglobulin A-containing circulating immune complex and immunoglobulin G-containing circulating immune complex. The endotoxin levels of the patients with gram-negative infections were significantly increased compared with those of the patients with sterile cultures. The immunoglobulin G-containing circulating immune complex levels of the patients with bacteria in bile were significantly increased compared with those of the patients with sterile cultures. The immunoglobulin A-containing circulating immune complex levels of the patients with bacteria in bile were slightly increased, but the difference did not reach statistical significance. These results indicate that one of the causes of increased circulating immune complex levels may be endotoxemia in combination with biliary infection in patients with biliary obstruction.

In an effort to increase the cure rate of carcinoma of the head of the pancreas involving the portal system and/or associated arteries, en bloc radical pancreatectomy with associated vascular structur

In a conventional manner, the tritriacontapeptide amide corresponding to the entire amino acid sequence of the desulfated form of porcine cholecystokinin-pancreozymin (CCKPZ) was synthesized by applying protecting groups removable by hydrogen fluoride. Synthetic peptide, though it is not too biological active, was smoothly and efficiently converted to the labeled compound with 126I (specific activity 200-250 μci/μg).

The distribution of immunoglobulin (Ig)- containing cells in the gastric antral mucosa of patients with various abnormalities of the stomach was studied by fluorescent antibody techniques. IgA-containing cells comprised about 80% of all Ig-containing cells and were diffusely distributed in the interstitial spaces of gastric glands. IgA was observed in the apical portion of the cytoplasm of cells in some pyloric glands, and IgM was seen extracellularly between the epithelial cells and in the lumen. At the base of gastric cancers, adjacent to the invading cancer mass, IgG-containing immunocytes were found in intermuscular spaces, and some cells that appeared to be cancer cells reacted with anti-IgG or anti-IgM.

Effects of intravenously administered synthetic kassinin on splanchnic circulation and exocrine pancreatic secretion were examined in six anesthetized dogs. Kassinin caused dose-related increases in the blood flow in superior mesenteric artery and portal vein, and produced an initial increase followed by a decrease in pancreatic blood flow, but did not affect the exocrine pancreatic secretion. This study demonstrates that kassinin affects splanchnic blood flow in dogs, and suggests that kassinin or a kassinin-like substance functions as a neuropeptide controlling the splanchnic circulation in mammalian species.

The heptacosapeptide amide corresponding to the entire amino acid sequence of porcine gastrin releasing peptide (GRP), which had been isolated from porcine non-antral and intestinal tissue by McDonald et al. (5) and its amino acid sequence tentatively determined, was synthesized by Yajima et al. (11). Albino rabbits were immunized with this synthesized GRP and specific antiserum was obtained. Using an immunofluorescence antibody technique, cellular localization of GRP in the human stomach was examined.GRP containing cells were clearly demonstrated in the mucosa of antrum of the stomach of a patient with a duodenal ulcer.

The present study emphasizes the principle of using liver support to restore the blood ketone body ratio (acetoacetate/beta-hydroxybutyrate), which reflects the redox potential of liver mitochondria and correlates with hepatic energy charge (ATP + 0.5ADP/ATP + ADP + AMP). Eleven surgical patients with grade IV hepatic coma were treated by an ex vivo pig or baboon liver cross-hemodialysis with an interposed Cuprophan membrane when their blood ketone body ratios had decreased to below 0.4 compared with the normal of above 0.7. Three patients were treated by cross-hemodialysis using a standard Cuprophan membrane dialyzer without increase of blood ketone body ratio and without marked beneficial effect. However, five of eight patients who had blood ketone body ratios of above 0.25 became fully alert after treatment by cross-hemodialysis using the larger pore size and greater surface area Cuprophan membrane, concurrent with a rise in the decreased blood ketone body ratio, and three of them were later discharged. By contrast, in the three patients with blood ketone body ratios below 0.25, there was no restoration of consciousness and no improvement in their blood ketone body ratios by this liver support. It is suggested that, as long as the blood ketone body ratio remained over 0.25, this metabolic liver support is effective in restoring grade IV hepatic coma.

A 66-yr-old woman had several attacks resembling relapsing acute pancreatitis with elevation of serum amylase for about three months. Obstruction of the main pancreatic duct was detected with endoscopic retrograde pancreatoductography, though no abnormality was revealed on celiac and mesenteric arteriograms. At that time she had no jaundice. Laparotomy revealed a walnut-sized tumor in the head of the pancreas compressing the main pancreatic duct. Pancreaticoduodenectomy was performed. The pathological diagnosis of the tumor was well-differentiated papillary cysto-adenocarcinoma of the pancreas. She had no attack of hyperamylasemia since the operation, and is well 2 years after the surgery. Close attention to persistent elevation of pancreatic amylase levels in serum and urine would enhance the chance of detection of small pancreatic cancers before the development of jaundice.

Eight peptide fragments were prepared by known amide-forming reactions as building blocks for the solution synthesis of the dotetracontapeptide corresponding to the entire amino acid sequence of human intestinal GIP (gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide). Besides Lys(Z), Trp(Mts) and Gln-OBzl, two new amino acid derivatives, Asp(OChp) and Glu(OChp) [Mts=mesitylenesulfonyl, Chp=cycloheptyl], were employed to suppress various side reactions. These fragments were successively assembled by the azide procedure to minimize racemization and all protecting groups employed were removed from the protected GIP by using 1M trifluoromethanesulfonic acid-thioanisole in trifluoroacetic acid.Synthetic GIP exhibited a significant glucose-dependent insulinotropic activity in dogs, but failed to produce any notable anti-gastric activity in rats.

BALB/c mice inoculated IP with a syngeneic plasmacytoma MOPC104E were treated with a combination of a streptococcal preparation, OK-432 (1 KE, 0.1 mg/mouse), low-dose of cyclophosphamide (CPA, 1 mg/kg) and adoptive transfer of tumor-bearer-spleen cells (2 x 10(7) cells) cultured with IL2 and sonicated tumor extract (adoptive immunotherapy; AIT). The consecutive protocol of OK-432 (day 8, 9 post inoculation) - CPA (day 10) - AIT (day 11) was the most effective. Rate of complete remission was highest when recombinant (r-) IL2 was injected to the mice after AIT. Moreover, another bacterial preparation, Nocardia rubra cell wall skeleton and another low-dose chemotherapy, Mitomycin C could be used successfully instead of OK-432 or CPA. Transfer test of intraperitoneal cells (tumor cells plus host cells) of mice on day 11 post inoculation (on the day of AIT) revealed that OK-432 augmented the susceptibility of peritoneal cells to cultured lymphocytes in inhibition of transplantability, and that CPA after OK-432 augmented the anti-tumor effect of tumor-bearer-spleen cells which act synergistically with cultured lymphocytes. This therapy schedule seems to be the best model to augment the effect of AIT with minimal side effect.

We developed an easy enzyme-linked immunosorbent assay (ELISA) for anti-mitochondrial antibodies, and detected high levels of anti-mitochondrial antibodies in MRL/Mp-lpr/lpr (MRL 1/1) mice. The influence of the presence of anti-DNA antibodies in the tested sera on this assay was also evaluated. The monoclonal anti-DNA antibodies, which were made from non-immunized MRL 1/1 mice, did not react with the mitochondrial antigens adhering to polystyrene plates. Absorption with DNA had little effect on the levels of mitochondrial antibodies in MRL 1/1 sera. Our assay for mitochondria-binding antibody was very easy and sensitive, although it could not differentiate among heterogeneous anti-mitochondrial antibodies.