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Aberrant methylation of CpG islands is a common mechanism for the dysregulation of tumor suppressor genes in a variety of human malignancies. Preproenkephalin ppENK) hypermethylation is recognized in 90% of pancreatic carcinoma (PCa) tissues, but not in normal pancreas. We analyzed ppENK hypermethylation in pure pancreatic juice (PPJ) in patients with PCa, intraductal papillary mucinous neoplasms (IPMN), and chronic pancreatitis (CP), and elucidated its usefulness as a marker in the diagnosis of PCa compared with p53 mutation. PPJ was collected endoscopically from 28 patients with PCa, 15 patients with IPMN, and 20 patients with CP. DNA was extracted from the supernatant and the sediment of PPJ. Methylation-specific polymerase chain reaction was performed for hypermethylation analysis of ppENK. In addition, single-strand conformation polymorphism and direct sequencing were performed simultaneously to identify p53 mutations. The incidence of ppENK hypermethylation in the supernatant and/or the sediment of PPJ was 50% (14 of 28) in patients with PCa. In contrast, the incidence of ppENK hypermethylation was 26.7% (4 of 15) in patients with IPMN, and 5% (1 of 20) in patients with CP (P < 0.002). The incidence of p53 mutations in the PPJ was 42.9% (12 of 28) in patients with PCa and 0% (0 of 20) in patients with CP. Furthermore, the incidence of ppENK hypermethylation and/or p53 mutations in the PPJ was enhanced to 67.9% (19 of 28) in patients with PCa in the combination assay. These results suggest that ppENK hypermethylation in PPJ is specific for cancer, and the combination assay with p53 enhances the genetic diagnosis of PCa.

Background. Abnormalities of the tumor suppressor gene p16 have been reported in a variety of human tumors but are rare in pancreatic carcinoma except for cancer cell lines and xenografts. Their clinicopathological significance remains unknown. The purpose of this study was to examine immunohistochemical and genetic alterations of p16 in primary pancreatic carcinoma tissues and to investigate the relation between abnormalities of p16 and clinicopathological parameters to elucidate their clinicopathological significance. Methods. We investigated p16 expression in 60 pancreatic carcinoma cases by immunohistochemistry using a monoclonal antibody clone G175-405. In addition, we analyzed genetic alterations of the p16 gene using DNA extracted from microdissected tissue of pancreatic carcinoma, by polymerase chain reaction, nonradioisotopic single-strand conformation polymorphism (non-RI-SSCP), DNA sequencing, and hypermethylation analyses using restriction enzymes. We compared the abnormalities of p16 alterations with clinicopathological parameters to elucidate their significance. Results. On immunohistochemical study, staining for p16 protein was strongly positive in 22 (37%) of 60 pancreatic carcinoma cases, weakly positive in 24 (40%), and negative in 14 (23%). In contrast, p16 mutations were recognized in 9 (15%) of the 60 pancreatic carcinoma cases. The incidence of p16 mutations was 2 (9%) in 22 cases of pancreatic carcinoma with strongly positive staining, 4 (17%) in 24 with weakly positive staining, and 3 (21%) in 14 with negative staining. Hypermethylation of p16 was detected in the two pancreatic carcinoma cases with weakly positive staining, although homozygous deletions were not found in any case. There was no significant correlation between the expression of p16 protein and any of the clinicopathological parameters. However, there was a tendency for the tumor to be larger in patients with decreased expression of p16 protein than in those with normal expression levels. In contrast, the tumor was significantly larger and the survival period significantly shorter for patients with pancreatic carcinoma with p16 mutation or hypermethylation than for those with pancreatic carcinoma with an intact p16 gene (P ≪ 0.05). Conclusions. These findings suggest that p16 alterations may participate in the aggressiveness of pancreatic carcinoma.

The sensitivity of bile cytology for the diagnosis of biliary tract carcinoma (BTCa) is still low. In addition, the incidence of detection of genetic mutations in the bile of BTCa is not satisfactory yet. To improve the molecular diagnosis of BTCa, we analyzed p53 and K-ras mutations in DNA extracted from not only the sediment but the supernatant of bile samples. Methods: Polymerase chain reaction-single-strand conformation polymorphism and direct sequencing were used for analyses of p53 mutations in exons 5 through 8. K-ras mutations at codon 12 were examined by mutant allele-specific amplification. Results: In bile supernatant from patients with BTCa, p53 and K-ras mutations were detected in 50.0% (15/30) and 56.7% (17/30) of cases, respectively. The incidence of p53 and K-ras mutations in the sediment was 33.3% and 43.3%, respectively. When a combination assay with both genes was used, molecular abnormalities were detected in 80.0% of cases, including 3 in which p53 alone was positive. In addition, either p53 or K-ras mutations were detected in 12 of 15 (80.0%) cases of BTCa in which the cytologic diagnoses were negative. p53 mutations were detected in neither supernatant nor sediment in 20 patients with cholelithiasis, although the incidence of K-ras mutations in the sediment was 20%. Conclusions: The incidence of p53 and K-ras mutations is higher in the supernatant than in the sediment, and simultaneous analyses of p53 and K-ras in the two bile fractions could enhance the genetic diagnosis of BTCa. Notably, the specificity of p53 mutations for cancer was very high in bile samples, and the sensitivity was also relatively high.

A 22-year-old woman with Gardner's syndrome in whom long-term sulindac therapy, without surgical treatment, was effective in inducing complete regression of colonic adenomas is reported. One hundred milligrams of sulindac was administered twice daily after endoscopic polypectomy. Follow-up colonoscopy 6 months later revealed an encouraging regression of colonic adenomas. The tumors had disappeared after 40 months of sulindac treatment. A sustained effect was identified even after 51 months. Ten milligrams of famotidine was coadministered to prevent side effects of sulindac. Although the effect of sulindac on colorectal adenomas may be transient, this therapy may be useful for postponing prophylactic colectomy, especially for the sparse type of familial adenomatous polyposis.

An aberrant hepatic duct directly connected to the main pancreatic duct with anomalous arrangement of the pancreato-biliary ductal system is reported here, the first report of such a case, to our knowledge. A 53-year-old woman was admitted to our hospital because of cholecystolithiasis with abdominal pain in the right upper quadrant. Endoscopic retrograde cholangiopancreatography (ERCP) showed that an aberrant hepatic duct, which independently drained the right posterior segment of the liver, connected to the main pancreatic duct at a high insertion site distal to the sphincter area of the major papilla. The common bile duct (containing stones), on the other hand, united with the main pancreatic duct in a normal fashion. Cholecystectomy and bile duct lithotomy were performed. The aberrant hepatic duct was separated from the main pancreatic duct just above the junction, and was anastomosed side-by-side to the common hepatic duct. The embryologic development of this lesion is not clear, but is discussed in this report.

An 82-year-old woman complaining of abdominal pain and vomiting was admitted to our emergency department. Abdominal X-ray, ultrasonography, and computed tomography showed hepatic portal venous gas, as well as pneumatosis intestinalis. We first suspected superior mesenteric arterial thrombosis. However, her physical findings, including computed tomography scanning and laboratory data, did not support the presence of bowel necrosis. The gas disappeared after 1 day. After the 12th day, she had recovered with conservative therapy, and she was discharged on the 41st day. Many reports indicate that hepatic portal venous gas is often associated with bowel necrosis, and urgent operation is recommended in such instances. In this patient, total colonoscopy on the 7th day revealed longitudinal redness, suggesting mesenteric ischemia. Thus, we speculate that this is a rare case of mesenteric ischemia without bowel necrosis associated with both pneumatosis intestinalis and hepatic portal venous gas.

We report a patient with primary biliary cirrhosis (PBC) associated with type A gastritis, chronic thyroiditis, and iron deficiency anemia. The patient was a 45-year-old Japanese woman who was admitted to our hospital with severe microcytic and hypochromic anemia, abnormal results for liver function tests, and a diffuse goiter. The diagnosis of PBC (Scheuer's stage II) was confirmed by the presence of specific anti-mitochondrial antibody in high titers and histological examination showing chronic non-suppurative destructive cholangitis with bridging fibrosis. Additionally, marked atrophic mucosa throughout the body and fundus of the stomach was observed endoscopically, and there was positivity for intrinsic factor antibody, an extremely low ratio of serum pepsinogen A to C, and hypergastrinemia, indicating coexisting type A gastritis. The severe anemia was thought to be caused by failure of dietary iron absorption related to achlorhydria with this gastritis. However, the serum level of vitamin B12 was normal. She also had autoimmune thyroiditis. PBC is frequently associated with extrahepatic autoimmune diseases, including ductular lesions. However, the association of PBC with type A gastritis is quite rare, although the stomach is also an exocrine glandular structure. This particular case, in addition to previous reports, leads to a discussion of whether type A gastritis should be regarded as a possible, although uncommon, component disorder of so-called dry gland syndrome.

A 72-year-old woman was admitted because of jaundice and hepatocellular dysfunction. She was diagnosed with autoimmune hepatitis from laboratory test results showing high titers of antinuclear antibodies and negativity for hepatitis viral markers. Steroid i.v. pulse therapy and oral administration of prednisolone were effective in improving the liver function test results, except for hyperbilirubinemia. Elevated serum bilirubin levels, of approximately 20 mg/dl persisted for more than 6 months, despite the administration of ursodeoxycholic acid. Insulin-glucagon therapy was given for normalization of transaminases and then withdrawn 3 weeks after admission, but it was resumed at 3 months, resulting in a dramatic decrease in serum bilirubin levels, which then normalized in 2.5 months. Liver biopsy 6 months after onset showed chronic active hepatitis with bile plugs. Insulin-glucagon therapy, because of its choleretic effect, may be worth continuing even after recovery of acute hepatic failure.

We report a case of Cruveihier-Baumgarten syndrome associated with portal vein thrombosis that developed, slowly during a 2-year period after, endoscopic variceal sclerotherapy. The thrombosis led to the disappearance of the venous hum and the dilated abdominal wall veins characteristic of this syndrome. A 73-year-old woman was hospitalized for treatment of esophageal varices in April 1988. Her spleen was markedly enlarged, and the histologic findings of her liver were not consistent with hepatic cirrhosis, but with idiopathic portal hypertension. A venous hum was audible in the upper abdomen. Superior mesenteric angiography revealed a porto-systemic shunt vessel under the abdominal wall, originating from the umbilical vein. She was injected four times with a sclerosant, and this brought about disappearance of the esophageal varices. Two years after the first admission, the venous hum was no longer audible, but there was a recurrence of the esophageal varices. More than 2 years later (4 years after the first admission), ultrasonographic study, computed tomography, and angiography showed a large thrombus, which completely obstructed the portal vein at the origin of the umbilical vein, and the development of collateral vessels, seen as a “cavernous transformation”.

An enzyme-linked immunosorbent assay, based on two monoclonal antibodies (Hreg1-1 and Hreg101-1) specific for pancreatic stone protein (PSP)/reg-protein, was developed to determine the concentration of this protein in serum from individuals with various diseases. The serum concentration of PSP/reg-protein was significantly higher in patients with various pancreatic diseases than in normal controls, and was also significantly higher in patients with acute pancreatitis or chronic relapsing pancreatitis than in patients with chronic pancreatitis. Furthermore, the serum PSP/reg-protein concentration was also significantly increased in liver cirrhosis, choledocholithiasis, and various cancers of the digestive system, and was extremely high in all patients tested with chronic renal failure. A significant correlation was apparent between the serum concentration of PSP/reg-protein and elastase-I in 68 patients with chronic pancreatitis or pancreatic cancer. Whereas only 7 of these patients showed a normal serum PSP/reg-protein concentration and a significantly increased elastase-I concentration, 15 of these patients showed a significantly increased serum PSP/reg-protein coecentration and a normal serum elastase-1 concentration. These results indicate that the serum PSP/reg-protein concentration may reflect pancreatic damage, especially in acute pancreatitis, and may be as sensitive a marker for such damage as elastase-I, although false positivity was apparent in renal failure and in some patients with hepatic dysfunction or digestive system malignancies.

The clinical significance of the measurement of c-erbB-2 oncogene product was evaluated. The subjects consisted of 404 patients, including 248 with cancer of the digestive organs and 128 with benign digestive diseases. Serum c-rebB-2 protein levels were measured by sandwich immunoenzyme assay. The positive rates of c-erbB-2 protein, at a cut-off value of 17.0 U/ml, were, for cancers: hepatocellular carcinoma 61.6%, biliary tract cancer 54.8%, pancreatic cancer 25.0%, esophageal cancer 33.3%, gastric cancer 16.9%, and colorectal cancer 5.0%. For benign digestive diseases, the rates were: liver cirrhosis 63.3%, chronic hepatitis 43.2%, acute hepatitis 42.9%, other liver diseases 42.8%, cholelithiasis 30.0%, and chronic pancreatitis 0%. Serum c-erbB-2 protein levels were significantly correlated with the markers of hepatic functional reserve, the indocyanine green retention rate and the hepaplastin test. These findings suggest that serum c-erbB-2 protein levels are greatly influenced by liver dysfunction and that their clinical usefulness as a serum tumor marker is questionable.