Koichi Motojima

Detection of point mutations in the Kirsten-ras oncogene provides evidence for the multicentricity of pancreatic carcinoma.

It has been reported that multicentricity of pancreatic carcinomas extending beyond the pancreatic duct occur in 15% to 40% of patients. This has been difficult to confirm, however, with currently available histologic techniques. Mutations in the Kirsten (Ki)-ras oncogene, which can be detected frequently in pancreatic carcinomas using the polymerase chain reaction (PCR), may serve as a potential clonal marker of the cancer cells. Fifty-three patients with a histopathologic diagnosis of pancreatic carcinoma were selected for the determination of certain Ki-ras mutations through PCR. The authors identified mutations in the Ki-ras codon 12 in 46 of 53 tumors. Two of these 46 tumors had two different mutations to aspartic acid (GAT) and to valine (GTT) in Ki-ras codon 12. Another isolate had an additional mutation in Ki-ras codon 13. The detection of different mutations in the same tumor suggests that there may be multicentricity in pancreatic carcinomas and that its frequency may be as low as 6% of the carcinomas. These results imply that total pancreatectomy for eliminating tumor recurrence due to multicentricity may not be warranted.

Prevention of insulitis and diabetes in nonobese diabetic mice by administration of FK506

We investigated the preventive effect of the immunosuppressive agent FK506 on autoimmune insulitis in nonobese diabetic mice. The mice were given FK506 in a dose of 1.0 mg/kg, every other day, from age 2 to 12, 2 to 6, and 4 to 12 weeks, respectively; after which, the incidence of insulitis and overt diabetes was monitored. Effects of FK506 on immune reactions to beta cells were also investigated by using both syngeneic and allogeneic islet transplants. Treatment with FK506 in mice from age 2 weeks prevented completely the onset of overt diabetes, and the incidence of insulitis was reduced to less than 10% at age 30 weeks. Treatment of mice with FK506 from age 4 weeks was less effective in preventing insulitis and the onset of diabetes. In case of islet transplantation, FK506 treatment of NOD mice from age 2 to 6 weeks prevented autoimmune responses both in syngeneic islets and in allogeneic islets, which share the same H-2 antigen with the nonobese diabetic mouse. These results also indicate that the recognition of islet antigens and the generation of autoimmune-reactive T lymphocytes start between 2 and 4 weeks of age, and FK506 prevents an autoimmune reaction.

Solid and Cystic Tumor of the Pancreas in an Adult Male

A solid and cystic tumor (SCT) was located at the head of the pancreas in a 43‐year‐old Japanese male, and pancreatoduodenectomy was performed on the suspicion of papillary carcinoma or cystadenocarcinoma of the pancreas. The lesion, which measured 4.5 X 4.5 X 4.0 cm, was clearly demarcated by connective tissue. The cut surface showed solid grayish‐white areas with central cystic degenerative changes. The solid areas consisted of small round cells proliferating in a small solid or a pseudopapillary pattern. The tumor cells partially invaded the surrounding normal pancreatic parenchyma. Immunohistochemical studies revealed positive staining for alpha‐1‐antitrypsin and neuron‐specific enolase, but no staining for known pancreatic hormones. Moreover, ultrastructural studies showed the absence of zymogen granules and the presence of anullate lamellae and neurosecretory granules. On the basis of these findings, a diagnosis of SCT of the pancreas was established. In order to clarify the histogenesis and biological behavior of the tumor, it is necessary to accumulate and analyze similar cases, an endeavor which in turn will contribute to the successful management of this disease. Acta Pathol Jpn 41: 763‐770, 1991.

Solid and cystic tumor of the pancreas occurring without cyst formation in an adult male

SummaryA solid and cystic tumor (SCT) of the pancreas occurring in a 35-yr-old male is reported. Cut sections of the specimen revealed a solid, ill-defined mass measuring 2.5×2.3×2.0 cm, without cystic or necrotic changes. Histologically, the solid tumor consisted of small, round acidophilic cells invading the surrounding pancreatic parenchyma. The tumor cells were positive for α-1-antitrypsin and neuron-specific-enolase. Ultrastructural studies revealed clear nuclei with no zymogen, but immature secretory granules in the cytoplasm of the tumor cells, which had a junctional complex-like structure. These findings were consistent with the so-called solid and cystic tumor of the pancreas. There was neither a capsule surrounding the tumor nor a papillary structure, known to be characteristic findings of the SCT tumor. The small tumor reported in the present article might represent an early-stage SCT of the pancreas.

Expression of Kirsten-ras p21 in gastric cancer correlates with tumor progression and is prognostic.

The purpose of this study was to determine the correlation between expression of ras oncoproteins and the tumor stage or outcome of patients with gastric carcinoma. After the specificity of each anti-ra.v monoclonal antibody was confirmed by protein immunoblot analysis, immuno-histochemical assays for a common-ms antigen present in N-. Harvey- and Kirsten (K)-ras oncoproteins, as well as for K-ras specific antigen, were performed on paraffin-embedded carcinoma tissue from 110 patients who underwent curative resection. By Western blot analysis, there was more p21 in fresh cancer specimens than in normal specimens. K-ras expression distinguished advanced from early gastric carcinoma and correlated with depth of cancer invasion. Among the 110 patients, survival rates of those with carcinomas positive for the common-ra.? or K-ras antigens were significantly lower than of those with antigen-negative carcinomas (p < 0.05). In a multivariate analysis, nodal involvement (p = 0.002), serosal invasion (p = 0.012) and K-ras p21 expression (p = 0.044) were independently predictive of the recurrence. These results suggest that K-ras p21 is a useful marker of tumor progression and poor prognosis after curative resection.

Effective treatment of liver metastases from colon cancer with a combination of γ-interferon and cisplatin chemotherapy : report of a case

We report herein the case of a 63-year-old man with cancer of the sigmoid colon and metastatic nodules in the liver who was effectively treated with a combination of cisplatin regional chemotherapy, given through the hepatic artery, in conjunction with a 3-week course of intravenous γ-interferon (INF-γ), following palliative sigmoidectomy and dissection of the regional lymph nodes. This was followed-up by a 3-month course of oral 5-fluorouracil. Hepatic imaging performed 6 months postoperatively showed no masses in the right hepatic lobe and an apparent decrease in the size of the tumor in the left lobe. A second-look operation with resection performed at this time confirmed the efficacy of the chemotherapy. The patient survived in excess of 30 months following his initial surgery before succumbing to hepatic failure.

A comparison of endocrine and exocrine function after pancreatic fragment autotransplantation into splenic pulp, portal vein, and hepatic parenchyma

Three sites were evaluated for potential pancreatic fragment autotransplantation. Both endocrine and exocrine functions were evaluated following autotransplantation into splenic pulp, portal vein, or hepatic parenchyma in 44 pancreatectomized dogs. Cholecystic bile amylase concentrations in the hepatic parenchyma group surviving more than 2 months were elevated significantly, and choledochal bile amylase concentrations increased markedly following pancreozymin-secretin injection. In contrast, bile amylase concentrations in dogs with intrasplenic or intraportal implants were low and did not respond to PS injection. Histologically pancreatic autografts in hepatic parenchyma revealed marked proliferation of exocrine tissue with abundant zymogen granules and reconstruction of the acinar lobules with a few islets. These acinar cells in the hepatic parenchyma were ultrastructurally normal. Transplant endocrine function, estimated by K values, was significantly better after splenic pulp and portal vein than after a hepatic parenchyma implantation, but no group improved during 1-year follow-up. Glucose-stimulated initial insulin responses were abnormally low in all recipients. Islet B cells lacked mature insulin granules, such as seen in normal resting B cells. This ultrastructural finding implies a persistent demand on the B cells and may explain the spontaneous recurrence of hyperglycemia and the diminished initial insulin response to a glucose load. This study indicates that euglycemic recipients of pancreatic fragment autotransplantation remain unstable and prediabetic.

BILE SECRETION AND HISTOLOGY OF LIVER AUTOTRANSPLANTED INTO THE PANCREATIC PARENCHYMA

The pancreatic parenchyma was evaluated as a potential recipient site for hepatic fragment autotransplantation. Histologic and functional studies of hepatic autografts in the pancreas were performed in 15 mongrel dogs. Approximately 10 g of liver parenchyma was resected from each left lateral lobe. The remnant liver remained in situ. Bile secretion from the hepatic tissues implanted into the pancreas was estimated by measuring the indocyanine green (ICG)* concentration in pancreatic juice following intravenous ICG injection. One month following implantation, the hepatocytes in the pancreatic parenchyma were histologically colorless and did not have sinusoids. However, by the second month following implantation, hepatic nodules had grown extensively to become normal liver tissue, with sinusoids and a single liver cell-plate structure. At 4 months following intrapancreatic implantation the transplanted hepatic masses consisted of several hepatic lobules. Furthermore, ICG could be detected in the pancreatic juice of dogs surviving more than 2 months after implantation but no ICG could be detected in the pancreatic juice of normal controls. The present study provides direct evidence that hepatic grafts transplanted into the pancreas that has a ductal drainage system for bile secretion can reconstitute histologically normal liver tissue capable of secreting bile. This model can be used to understand the early steps of hepatic regeneration.

The surgical technique of retroperitoneal lavage for the treatment of extended necrotizing pancreatitis

For cases of extended necrotizing pancreatitis which involve the spread of infectious or hemorrhagic necrotic lesions to the retroperitoneal tissue, we recommend sequestrectomy and subsequent retroperitoneal lavage via the retroperitoneal access. For successful retroperitoneal lavage, as much liquefactive infectious necrotic tissue as possible should be removed from the retroperitoneal cavity during the operation. In addition, the necrotic cavity should be opened, adequately washed out, and catheters placed in the retroperitoneal cavity by retroperitoneal access. Although we have only applied this ideal technique in two patients so far, the details are presented herein. The significance of retroperitoneal lavage lies in the fact that it cleans the retroperitoneal foci of infection and necrosis, and that it eliminates the necrotic material, bacterial deposits, and biologically active substances produced after surgery. Ultimately, wound healing is markedly promoted, leading to improvement in the systemic condition.

Endocrine and exocrine function of pancreatic fragments autotransplanted into hepatic parenchyma.

We studied the use of hepatic parenchyma as a recipient site for pancreatic fragment transplantation. Endocrine and exocrine pancreatic functions were evaluated following pancreatic autotransplantation in 26 mongrel dogs that had undergone total pancreatectomy. The endocrine function of the pancreatic tissue transplanted to hepatic parenchyma was significantly inferior to that of normal controls. Cholecystic bile amylase concentrations were markedly elevated in six dogs that had been implanted with pancreatic fragments in their hepatic parenchyma and had survived more than 2 months. Also, choledochal bile amylase concentrations increased significantly following pancreozymin-secretion (PS) injection. In contrast, cholecystic bile amylase concentrations in normal dogs were low and choledochal bile amylase concentrations did not respond to a PS load. Histological examination of pancreatic autografts in hepatic parenchyma revealed marked proliferation of exocrine tissue with abundant zymogen granules and reconstruction of pancreatic lobules with a few islets.