Changes in the number of gut mucosal T-lymphocytes and macrophages in patients treated by external biliary drainage.

OBJECTIVE: To examine the changes in the number of T cells and macrophages in the mucosal lamina propria in the presence or absence of bile in the gastrointestinal tract. DESIGN: Clinical study. SETTING: University hospital, Japan. SUBJECTS: 6 patients with obstructive jaundice who had external biliary drainage (drainage group) and 6 patients with no signs of obstructive jaundice (control group). INTERVENTIONS: Gastrointestinal specimens were taken at the time of operation. MAIN OUTCOME MEASURES: The number of CD4+ T cells, CD8+ T cells and CD68+ macrophages in the lamina propria mucosae in each group measured immunohistochemically. RESULTS: The numbers of CD8 T cells and CD68+ macrophages in the lamina propria of the patients treated by external drainage were significantly less than in the control group (p < 0.01). However, there was no difference in the number of CD4+ T cells between the groups (p = 0.45). CONCLUSIONS: In the absence of bile, mucosal immune function fails as a result of reduced numbers of CD8+ T cells and macrophages.

[A noteworthy case of postoperative liver metastasis from gastric cancer which responded well to UFT therapy].

A 66-year-old male underwent partial gastrectomy (resection of the pyloric side of the stomach) at another hospital on the basis of a diagnosis of gastric cancer (Fig. 1). Five months later, his CEA level began to rise. At that time, multiple liver metastases were detected by ultrasonography and CT scans. The patient received oral UFT therapy (400 mg/day) at our hospital. A reduction in CEA was observed 63 days after the start of this therapy. A judgment of CR (complete response) was made after 4 months of the therapy. At present, 2 years and 4 months after UFT was first administered, the patient shows no signs of tumor recurrence. This case is noteworthy since there has been no previous report of a case where UFT showed a high efficacy in treating liver metastasis after surgical resection of gastric cancer.

The role of S100A4 gene encoding an S100-related calcium-binding protein in human bile duct adenocarcinoma cell lines: correlation of S100A4 expression and invasive growth in Matrigel Matrix.

S100A4, one of the tandemly arranged S100 genes at chromosome 1q21, has been suggested to play a functional role in cell motility and invasiveness of tumor cell growth. We investigated the expression of S100A4 and the in vitro invasiveness of 4 human bile duct adenocarcinoma cell lines by the Matrigel assay. S100A4 was abundantly expressed in 2 adenocarcinoma cell lines whose growth pattern was highly invasive. Induction of antisense S100A4 into one of the cell lines decreased S100A4 mRNA levels and reduced invasiveness. In contrast, induction of sense S100A4 expression into non-invasive KMBC adenocarcinoma cells, which originally lacked S100A4 expression, resulted in apparent invasive potential in the transfected cells compared with the cells with the vector alone. These results suggest that S100A4 expression is well correlated with the invasiveness of human bile duct adenocarcinomas.

[Correlation between pyrimidine nucleoside phosphorylase (PyNPase) and clinicopathological factors in patients with gastric cancer].

Pyrimidine nucleoside phosphorylase (PyNPase) is a general term for enzymes which phosphorolyse pyrimidine class nucleosides; convert 5'-deoxy-5-fluorouridine (5'-DFUR), a fluoropyrimidine class anticancer drug, to an active type of 5-fluorouracil (5-FU); and demonstrate higher concentrations in tumor tissue. These findings have attracted attention from the standpoint of drug delivery systems. With regard to immunohistochemical staining studies, PyNPase expression correlated with cancer proliferation and metastasis. However, few have shown a relation between PyNPase assay and prognosis. We measured PyNPase value in tumor tissue of operative specimens from 60 gastric cancer patients. The results showed that the PyNPase value in tumor tissue was significantly higher (1.9 times) than in normal mucosa. There was no correlation between the PyNPase level in tumor tissue and clinicopathologic factors. However, many patients with relatively early gastric cancer had high enzyme levels, indicating that PyNPase may influence cancer proliferation and metastasis as well as prognosis. By detecting such a factor as PyNPase, and clinically applying the results, 5'-DFUR is promising for the treatment of patients with respect to prognosis.

Complete agenesis of the dorsal pancreas.

Pancreatic anomalies are occasionally reported, but complete agenesis of the dorsal pancreas is extremely rare. We report a 47-year-old woman with complete agenesis of the dorsal pancreas. This patient initially presented with jaundice. Computed tomography did not reveal the pancreatic corpus or tail. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography did not visualize the dorsal pancreatic duct. Choledochojejunostomy was performed because she had obstructive jaundice. At laparotomy, there was an enlarged pancreatic head, but no distal pancreas was seen. Histological examination of the pancreatic biopsy specimen showed scattered islets of Langerhans in diffuse fibrosis, with destruction of the glandular parenchyma. This case was diagnosed as complete agenesis of the dorsal pancreas.

Surgical results of operations for carcinoma of the gallbladder.

We evaluated the surgical results for carcinoma of the gallbladder. Between 1971 and 1995 we treated 258 patients, 74 of whom were treated with simple cholecystectomy, 71 with extended cholecystectomy, and 24 with more extended operations. The tumors were classified according to the stage proposed by the Japanese Society of Biliary Surgery. For m and pm carcinoma simple cholecystectomy may have an excellent result. However, it is difficult to know cancer depth exactly before or during operation, especially when combined with inflammation due to gallstones. In Stage I disease, extended cholecystectomy had an excellent result. So extended cholecystectomy is needed even in the early stage of the disease. Second operation is needed in inapparent carcinoma of the gallbladder if the tumor is more than pm or the margin is positive. More extended operations may be needed in advanced stages for curative resection. Extended hepatic lobectomy combined with pancreaticoduodenectomy should be indicated only if the patients are in good condition because of its high postoperative mortality and morbidity without a significant improvement in survival.

Diagnostic imaging of early gallbladder cancer: retrospective study of 53 cases.

To diagnose early gallbladder carcinoma is difficult but essential to improve the survival of the patients with this cancer. Fifty-three early gallbladder cancers were macroscopically divided into protruding and flat types. The diagnostic devises [ultrasonography (US), computed tomography (CT), and drip infusion cholangiography (DIC)] were compared for their ability of early detection. The specimens were examined cytologically for diagnosis during operation and the p53 protein was investigated. Thirty-three cases were of the protruding type, eighteen of the flat type, and two unclassified. Carcinoma tended to be missed when gallstones were present. Preoperative diagnosis of the flat type was difficult. Tumor location did not always correlate with the preoperative diagnosis. Of the misdiagnosed cases of the protruding type, half were missed with US and CT and were not visualized clearly by DIC. Among the flat type cancers, only three had no abnormal findings by diagnostic imaging. Cytologic examination was effective, and p53 was expressed only in early carcinoma, not in adenoma or dysplasia. Even in the presence of gallstones or cholecystitis, any abnormal findings should make one suspicious of gallbladder cancer. Cytology and p53 expression may be useful for the intraoperative diagnosis, and a combination of diagnostic methods is important.

Spontaneous rupture of an intrahepatic bile duct with biloma treated by percutaneous drainage and endoscopic sphincterotomy.

A case of spontaneous rupture of an intrahepatic bile duct with biloma formation treated by percutaneous drainage and endoscopic sphincterotomy is reported. A 73-yr-old woman was admitted with fever and abdominal pain. There was no past history of abdominal surgery, instrumentation, or trauma. Ultrasound and computed tomography revealed a massive fluid collection in the abdominal cavity. Endoscopic retrograde cholangiography demonstrated extravasation of contrast medium from a distal biliary radicle in the left lobe of the liver. After successful treatment by percutaneous drainage and endoscopic sphincterotomy, the patient did well. Ultrasound and computed tomography showed resolution of the biloma. Nontraumatic bilomas are very rare: in fact, only 24 cases of spontaneous biloma have been reported. Endoscopic treatment for patients with spontaneous bilomas can be safe and effective, and should be considered.

Impaired response of gastric vessels to prostaglandin E2 in rats with persistent obstructive jaundice.

We investigated the response of gastric vessels to prostaglandin (PG) E2 after intra-duodenal release of bile in rats with obstructive jaundice. The animals were divided in four groups according to duration of bile duct obstruction (BDO): control and 1 week (W), 2W, and 3W groups. Prolonged BDO decreased gastric mucosal blood flow (BF) significantly. The BF recovered after the release of BDO in the 1W and 2W groups, but not in the 3W group. BDO decreased PGE2 content in gastric mucosa in the 1W, 2W, and 3W groups. PGE2 decreased vascular perfusion pressure of the isolated stomach in the control and 2W groups, but not in the 3W group. The response of gastric vessels to PGE2 was poor in the 3W group compared with the control and 2W groups. Decreased PGE2 in the gastric mucosa and decreased response of gastric vessels to PGE2 may affect gastric blood flow in obstructive jaundice.

Increased activity of group II phospholipase A2 in plasma in rat sodium deoxycholate induced acute pancreatitis.

BACKGROUND: Two different types of secretory phospholipase A2 (PLA2), pancreatic group I (PLA2-I) and non-pancreatic group II (PLA2-II), have been identified and postulated to be associated with the pathogenesis of various diseases, such as acute pancreatitis, septic shock, and multiple organ failure. AIMS: To investigate the type of secretory PLA2 responsible for its catalytic activity found in plasma and ascites of experimental acute pancreatitis. METHODS: Acute pancreatitis of differing severity was induced by the injection of different concentrations (1% or 10%) of sodium deoxycholate (DCA) into the common biliopancreatic duct in rats, and catalytic PLA2 activity in plasma and ascites were differentiated by anti-PLA2-I antibody and specific inhibitor of PLA2-II. Survival rate and plasma amylase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were also measured. RESULTS: In 1% and 10% DCA induced acute pancreatitis, plasma amylase values as well as PLA2 activity in ascites were greatly increased. PLA2 activity in plasma was also notably increased in 10% DCA induced acute pancreatitis, but not in 1% DCA induced acute pancreatitis. PLA2-I specific polyclonal antibody significantly inhibited PLA2 activity in ascites but not that in plasma. In contrast, plasma PLA2 activity was completely suppressed by PLA2-II specific inhibitor. In addition, a high mortality (93% at five hours) and a significant increase in plasma AST and ALT were noted in 10% DCA induced pancreatitis. CONCLUSION: Ascites PLA2 activity is mainly derived from PLA2-I, whereas plasma PLA2 activity is mostly derived from PLA2-II in severe acute pancreatitis, suggesting that increased plasma PLA2-II activity might be implicated in hepatic failure arising after severe acute pancreatitis.

p53 protein expression and prognosis in gallbladder carcinoma and premalignant lesions.

BACKGROUND/AIMS: p53 protein expression in gallbladder carcinoma has recently been detected by immunohistochemical techniques, but the relationship between p53 expression and prognosis or clinico-pathological factors is still obscure. MATERIALS AND METHODS: We investigated 48 gallbladder carcinoma, 7 adenoma and 11 dysplasia cases for p53 expression by immunohistochemical techniques. RESULTS: p53 expression was positive in 39.6% of gallbladder cancer cases, but in no adenoma or dysplasia cases. No significant correlation was found between p53 overexpression and prognosis or recurrence in 20 patients with carcinoma involvement up to the subserosal layer. p53 overexpression was correlated with DNA aneuploidy pattern and the absence of stones, but was not correlated with clinical staging or lymph node metastasis. CONCLUSION: These results suggest that p53 gene mutation is related to the transition from premalignancy to malignancy in gallbladder carcinogenesis, as well as DNA ploidy alterations and carcinogenesis unassociated with gallstones, but has no bearing on the prognosis.

K-ras gene mutation in gall bladder carcinomas and dysplasia.

Epithelial dysplasia of gall bladder is an important precancerous lesion of gall bladder carcinogenesis. To investigate the frequency of K-ras gene mutation in gall bladder carcinoma and dysplasia, K-ras codon 12 mutations were investigated by the polymerase chain reaction/restriction enzyme based method following direct sequencing. Mutation was detected in 59% (30 of 51) of gall bladder carcinomas, in 73% (8 of 11) of gall bladder dysplasia in gall stone cases, and in 0% of the normal gall bladder epithelium. There was, however, no correlation between K-ras mutation and clinicopathological factors of gall bladder carcinoma. K-ras gene mutation occurs even in gall bladder dysplasia at an incidence similar to that in carcinomas, suggesting that testing for K-ras gene mutation may prove useful as an adjunct to bile cytological or biopsy analysis.

Detection of point mutations in K-ras gene at codon 12 in bile from percutaneous transhepatic choledochal drainage tubes for diagnosis of biliary strictures.

Detection of K-ras mutations at codon 12 constitutes one modality for diagnosis of pancreatic tumors. We attempted to detect K-ras mutations in DNA from bile collected through percutaneous transhepatic choledochal drainage (PTCD) tubes as a diagnostic approach to biliary strictures. Since bile salts induce cell damage, we first investigated the degeneration of cells according to bile exposure time using cell lines. High-mol-wt DNA could be extracted from cells exposed to bile for 6 h, but not from those exposed for 12 h. However, DNA exposed to bile for up 12 h could be amplified by the polymerase chain reaction (PCR) method. Therefore, K-ras mutations in fresh bile specimens collected from 15 patients through PTCD tubes were examined using PCR with restriction enzyme digestion. K-ras mutations were found in five out of five (100%) pancreatic cancers, all of which were negative according to cytodiagnosis of the same bile. On the other hand, K-ras mutations were not detected in bile from biliary tract cancers or metastatic neoplasms, except for one bile duct carcinoma and one metastatic case. Thus, although K-ras mutation alone is not an absolute marker for cancer, detection of K-ras mutations in fresh bile from PTCD tubes is a useful adjunct for diagnosis of pancreatic carcinomas in cases of biliary tract strictures.

Extended cholecystectomy for carcinoma of the gallbladder.

We evaluated extended cholecystectomy, wedge resection of the gallbladder bed, and regional lymphadenectomy for carcinoma of the gallbladder. Between 1971 and 1993 we treated 227 patients, 59 of whom were treated with simple cholecystectomy and 66 with extended cholecystectomy. The tumors were classified according to the stages proposed by the Japanese Society of Biliary Surgery. For Stage I and II disease extended cholecystectomy had a better result than simple cholecystectomy. For the extended cholecystectomy cases the cumulative 5-year survival rate was 78.9% for Stage I, 63.6% for Stage II, 44.4% for Stage III, and 8.3% for Stage IV. The survival of Stage I patients was excellent. For cases more advanced than Stage II (S3, N2, Hinf1, and Binf1), the prognosis was significantly worse. In these cases more aggressive surgery may be needed.

[Primary and experimental study of a new treatment for hepatolithiasis by injection of resin in the intrahepatic bile duct].

In the treatment of hepatolithiasis, it is sometimes difficult to remove the stones completely and residual stones are closely related to the prognosis. In cases with residual stones, cholangitis frequently recurs and sometimes it causes fatal hepatic failure. We postulated that filling the hepatic bile duct with resin may be useful for the prevention of the progress of this disease. This experiment is the preliminary study on this new treatment for hepatolithiasis. After the injection of Neoprene resin into the left intrahepatic bile duct of a mongrel dog, histological changes of the liver and biochemical changes in peripheral blood were serially analyzed. After six months, the Neoprene plug remained in place. In the lobe treated with Neoprene, volume and weight decreased, and fibrosis around the bile duct and interlobular connective tissue increased, while, the number of hepatocytes was not changed. There was neither abscess nor biloma in the liver. Blood analysis revealed only a transitional increase of GOT, GPT and ALP. No complication was caused by this treatment. From this result, we conclude that this new method may be useful for the treatment of hepatolithiasis.

[Diagnosis of gallbladder cancer by imaging techniques: problems, limitations and their explanations, especially with ss invasive cancer].

The preoperative diagnosis of less than ss depth gallbladder cancer is difficult. Its preoperative diagnosis rate was low (27.5%), and even lower with the presence of concomitant gallstone. In the latter case, the diagnosis rate was particularly low when the stones diameter was greater than 1 cm. Gallstones are frequently associated with macromorphologically invasive type of gallbladder cancer and this may be the reason for the lower diagnostic rate. We compared preoperative diagnosis rate of ultrasonography (US), computed tomography (CT) and drip infusion cholecystography (DIC) for each invasion depth. In US, the preoperative diagnosis rate for m depth invasion was 6/16 (37.5%), pm depth was 1/13 (7.7%), and ss depth was 14/41 (34.1%). In CT, its rate for m depth was 3/11 (27.3%), pm depth was 1/10 (10.0%), and ss depth was 11/37 (29.7%). In DIC, its rate for m depth was 3/11 (27.3%), pm depth was 1/10 (10.0%), and ss was depth 1/23 (4.3%). None of the currently used imaging techniques were very accurate in diagnosing gallbladder cancer. Thus, during preoperative work up, if one discovers a gallbladder full of stones, stones of greater than 1 cm in diameter, thickened gallbladder wall, or a non visualized gallbladder with DIC, gallbladder cancer must be highly suspected.

Diagnosis of post-transfusion graft-versus-host disease after formalin-fixation.

A 72-year-old woman with multiple recurrence of gallbladder cancer was treated by intrahepatic-arterial infusion of doxorubicin using an extracorporeal system of direct hemoperfusion with venovenous bypass. During this treatment, the patient received 600 ml of fresh whole blood and 30 units of platelet concentrate from five unrelated donors. Thereafter, high fever, skin rash over the whole body, and watery diarrhea developed, followed by leukopenia progressing to a fatal sepsis. Post-transfusion graft-versus-host disease (PT-GVHD) was suspected by the clinical manifestations and postmortem pathologic findings. To establish the diagnosis of PT-GVHD, polymerase chain reaction (PCR) amplification of DNA polymorphism associated with length variation in dinucleotide or trinucleotide microsatellite repeats at the loci of D6S89, int-2 protooncogene, and human growth factor with each of the different primer sets was performed using DNA from blood drawn from the patient with clinically established PT-GVHD of a donor origin and formalin-fixed pancreas of recipient origin. Genetic analysis revealed the changes in the patient's lymphocytes from that of the patient to that of donor origin. The present finding that formalin-fixed tissues can be used as a material of patient origin may contribute to accurate diagnosis of PT-GVHD after autopsy.

[Treatment and present status of pancreatic cancer].

The Pancreatic Cancer Registry of the Japan Pancreas Society registered 11,317 patients of pancreatic cancer during these ten years. Among these patients, resectional procedures were performed on only 3,743 cases (33.1%). The actual 5-year survival rate of the patients who underwent resection was 16.6%. As for small cancer which was less than 2cm, the 5-year survival rate was 41.0%. In pancreatic cancer local recurrence was more frequent than other cancers of pancreatic head lesions. Extended operation which means lymphangiectomy more than R2 has not improved survival rate generally But some patients who underwent extended operation have survived long period. Multi-disciplinary treatment of pancreatic cancer has been tried.

Left ventricular dysfunction during dynamic exercise in noninsulin-dependent diabetic patients with retinopathy.

Systolic time intervals were obtained from 19 middle-aged noninsulin-dependent diabetic patients without clinically evident cardiovascular disease (8 patients had and 11 did not have retinopathy) and 14 normal subjects using ear densitography. All subjects had neither ischemic electrocardiographic response nor chest pain during maximal treadmill exercise. Although left ventricular ejection time (LVET) and preejection period (PEP) did not differ significantly at rest between the three groups, a prolongation of LVET with a nearly identical PEP response was observed during exercise in diabetic patients with retinopathy. These data indicate that the diabetic patients with retinopathy relied on the enhanced ventricular filling in maintaining stroke volume during exercise. Thus, retinopathy is associated with impaired left ventricular systolic function in noninsulin-dependent diabetic patients.

Hemodynamic response to ibopamine in acute myocardial infarction.

To determine the effects of ibopamine on hemodynamic parameters, 9 patients with cardiac dilation after acute myocardial infarction were studied. Although there were no significant changes in mean blood pressure, heart rate and rate pressure product after administration of ibopamine, cardiac index and urine volume increased significantly. These data indicate that ibopamine exerts a positive inotropic effect on the myocardium and vasodilating effect on renal vasculature without increasing myocardial oxygen consumption. However, pulmonary capillary wedge pressure increased significantly at 30 min after ibopamine and decreased to the control value at 120 min. A significant increase in heart rate was observed in 3 patients which was followed by chest pain. In addition to increase in cardiac contractile force and decrease in subendocardial perfusion from elevated left ventricular end diastolic pressure, increase in heart rate would decrease diastole time, while increase in oxygen consumption results in aggravation of ischemia especially in patients with multivessel coronary disease. From these findings it is considered that ibopamine should be administered with care to patients with multivessel coronary disease.