Yuzo Sakai

Sensitive serum markers for detecting pancreatic cancer.

Serum amylase, immunoreactive elastase (IRE), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA 19‐9) were measured in 40 patients with pancreatic cancer. IRE and CA 19‐9 were further assayed in nonpancreatic malignancies (n = 98) and chronic nonmalignant disease (n = 194). In pancreatic cancer, elevated values were observed for amylase in 30% of the patients, for IRE in 70%, for CEA in 28%, and for CA 19‐9 in 68%. Elevation of IRE and/or CA 19‐9 was found in 95% of the 40 patients. Elevated serum IRE was observed more frequently in head cancer and resectable cancer, whereas elevation in CA 19‐9 occurred more often in body‐tail cancer and unresectable cancer. Elevation of serum IRE tends to occur at earlier stages of pancreatic cancer. No one test is adequate for the accurate diagnosis of pancreatic cancer. However, the two assays complement each other, and their combined use would provide a sensitive clue for tentative diagnosis of pancreatic cancer.

Serum insulin-like growth factor II in chronic liver disease

Insulin-like growth factor II is secreted primarily by the liver and is reported to be transcribed in many primary hepatocellular carcinoma (PHC) cell lines. We have studied diagnostic significance of serum IGF- II in chronic liver diseases using specific enzyme immunoassay. Serum IGF-II levels (mean±se) were decreased in chronic hepatitis (538 ±51 ng/ml; N=29), liver cirrhosis (427±45; 50) and PHC (260±41; 17) compared to controls (830±49; 57). Serum IGF- II was not different from controls in any of nonhepatic diseases such as diabetes (1032±97; 19). pancreatic cancer (1413±282; 8), chronic pancreatitis (999±126; 17), peptic ulcer (1186±43; 11), irritable bowel syndrome (1002 ±109; 12), gastrointestinal tract cancer (1250±216; 21) and chronic renal failure (733±135; 14). In liver diseases serum IGF-II showed a significant correlation with liver function test (negative with retention of indocyanine green and total bile acids; positive with albumin, thrombo-test, and cholinesterase). These results suggest that serum IGF-II reflects a reduced production of IGF-II in the liver and that it can be an index for the residual capacity of liver function.

Prevention of Experimental Acute Pancreatitis by Intraduodenal Trypsin Inhibitor in Rat

To confirm that trypsin activity is a most important initiating factor in closed duodenal loop pancreatitis in rats, we observed the course of acute pancreatitis when trypsinogen activation was inhibited by intraduodenal infusion of a potent synthetic trypsin inhibitor (TI, nafamostat mesilate) but the other conditions were left unchanged. Intraduodenal and intrapancreatic trypsinogen activation was inhibited for 16 hr after the intraduodenal infusion of the inhibitor, although elevation of serum amylase and immunoreactive trypsin and pancreatic trypsinogen remained similar both in the TI and control groups. The mortality decreased from 44% (control) to 4% (TI) at 48 hr after establishing the model. Active trypsin in duodenal reflux is an initiating factor for further development of acute pancreatitis in the closed loop model, and inhibition of the initial activation of trypsinogen has a favorable effect on acute pancreatitis even if other deleterious factors remain unchanged.

Familial adenomatous polyposis associated with multiple endocrine neoplasia type 1-related tumors and thyroid carcinoma: a case report with clinicopathologic and molecular analyses.

We describe a sporadic case with familial adenomatous polyposis, multiple endocrine neoplasia type 1 (MEN1)-related tumors (an endocrine cell tumor of the pancreas and bilateral parathyroid tumors), and a papillary thyroid carcinoma. To clarify how mutations of the adenomatous polyposis coli (APC) gene and the MEN1 gene, responsible for familial adenomatous polyposis and MEN1, respectively, might have contributed to tumorigenesis in this case, we studied germline mutations in both genes and loss of heterozygosity at their genetic loci in multiple lesions. In addition, we performed immunohistochemistry for &bgr;-catenin, associated with the function of the APC gene. A germline mutation was found in the APC gene but not in the MEN1 gene. Normal allelic loss at the APC gene locus was observed in bilateral parathyroid tumors. Immunohistochemical staining of &bgr;-catenin demonstrated accumulation in the cytoplasm in addition to membrane staining in all analyzed tumors and a strong nuclear reaction in the endocrine cell tumor of the pancreas. The presence of normal allelic deletions of the APC gene in bilateral parathyroid tumors and nuclear staining of &bgr;-catenin in the pancreatic tumor in addition to the germline mutations suggests that functional loss of the APC gene played an important role not only in familial adenomatous polyposis but also in the MEN1-related tumors in this case.

Serum pancreatic stone protein in pancreatic diseases.

SummarySerum pancreatic stone protein (PSP) was determined in sera of pancreatic and nonpancreatic diseases using enzyme immunoassay specific to human PSP to study the diagnostic and pathophysiological significance of PSP. Serum PSP in acute pancreatitis (mean±SD=1075.4±2849.1 ng/mL,n=33) was significantly higher than that in controls (78.6±31.8 ng/mL,n=37,p<0.01), chronic pancreatitis (156.8±82.8 ng/mL,n=32,p<0.05), and pancreatic cancer (148.468.8 ng/mL,n=26,p<0.05). No significant difference was found between noncalcified and calcified chronic pancreatitis. Serum PSP levels were significantly higher in chronic renal failure under hemodialysis (1796.0±1492.9 ng/mL) than in other diseases such as peptic ulcer, liver cirrhosis, gallstone, and diabetes mellitus. Low but significant correlation was obtained between serum PSP and serum immunoreactive trypsin (r=0.22,p<0.05). Increased serum PSP levels in acute pancreatitis and chronic renal failure suggest that serum PSP levels reflect reflux from pancreatic secretion, release from damaged pancreatic acinar cells, or retention in circulation, and can be useful for diagnosis of acute pancreatitis, but not chronic calcified pancreatitis.

Effect of a new synthetic trypsin inhibitor on taurocholate-induced acute pancreatitis in rats

The effect of a novel synthetic trypsin inhibitor, 4-sulfamoylphenyl 4-guanidinobenzoate methanesulfonate (ONO-3307), on severe acute pancreatitis was studied by changing its timing, frequency, and dose in trypsintaurocholate- induced acute experimental pancreatitis in rats. Rats were divided into four groups according to difference of ONO-3307 administration: group A, 2 md0.5 ml of ONO-3307 S.C. I h before and after induction of pancreatitis; group B, 2 md0.5 ml S.C. 1 and 3 h after; group C, 4 mg/l ml S.C. 1 h before; group D, 4 mg/1 ml s.c. 1 h after. The survival rate at 24 h was significantly improved in group A (75% in A vs. 17% in control; p <0.01) and in group B (57 vs. 29%; p <0.051, but not in group C or D. Amylase and immunoreactive trypsin in serum and ascites of the treated were significantly lower than those of controls in both groups A and B. The survival rates were improved dose dependently when ONO-3307 was administered 1 h before and after induction of pancreatitis. ONO-3307 showed favorable effects on the initial stage of severe acute pancreatitis when given in divided doses to maintain the effective serum levels.

Enzyme immunoassay for serum pancreatic lipase in the diagnosis of pancreatic diseases

SummaryTo evaluate the diagnositc utility of serum immunoreactive lipase (IRL), serum lipase was determined using an enzyme immunoassay and a turbidimetric method along with total serum amylase in 41 healthy controls, 76 patients with pancreatic disease and 60 with nonpancreatic disease. Serum IRL was elevated in 12 of 13 patients with acute pancreatitis, 12 of 44 with chronic pancreatitis and in 12 of 19 with pancreatic cancer. The IRL was low in 9 of the 44 patients with chronic pancreatitis, which coincided with advanced exocrine pancreatic insufficiency. Overall sensitivities in pancreatic diseases were 59% for serum IRL, 38% for turbidimetric lipase and 51% for amylase, specificities in healthy controls and nonpancreatic diseases were 80% for serum IRL, 86% for turbidimetric lipase and 88% for serum amylase. Serum IRL determination is useful for diagnosis in pancreatic diseases when compared with the conventional determination of serum lipase.

The diagnostic value of serum pancreatic phospholipase A2 (PLA2) in pancreatic diseases

SummaryThe diagnostic significance of serum immunoreactive pancreatic phospholipase A2 (PLA2) was studied in 119 patients with pancreatic disease, 200 with various non-pancreatic disease, and 203 healthy controls using radioimmunoassay (RIA) specific to human pancreatic PLA2. This newly developed RIA using monoclonal antibody was satisfactorily sensitive and reliable. Serum PLA2 was elevated in all six patients with acute pancreatitis. Frequency of abnormal serum PLA2 levels was 60% in chronic pancreatitis (n=52) and 67% in pancreatic cancer (n=61). Serum PLA2 levels were low in chronic pancreatitis with severe exocrine insufficiency and advanced pancreatic cancer. In chronic pancreatitis, patients with low serum PLA2 level showed lower enzyme output in secretin test than patients with normal or high serum PLA2 level. Frequency of abnormal PLA2 levels was 27% in non-pancreatic disease and, in particular, patients with renal failure showed high PLA2 levels. Sensitivity (62%) and efficiency (69%) of serum PLA2 assay in pancreatic disease were superior to those of amylase. In conclusion, serum PLA2 determination using RIA was useful for the diagnosis of acute pancreatitis by high serum PLA2 levels and the diagnosis of severe exocrine pancreatic insufficiency by low serum PLA2 levels.

Elevation of serum phospholipase A2 in patients at an intensive care unit

SummaryTo evaluate the organ specificity of pancreatic phospholipase A2 (PLA2) and the diagnostic value of the elevation of serum PLA2 levels in patients with serious diseases not involving the pancreas, we studied the organ distribution of PLA2 in autopsy specimens and serum level of PLA2 in patients who required admission to an intensive care unit (ICU). PLA2 was measured by a specific radioimmunoassay (RIA), using monoclonal antibody against human pancreatic PLA2. Organ distribution of PLA2 revealed that the pancreas showed a much higher content of pancreatic PLA2 immunoreactivity than any other organ. An abnormally high value of serum PLA2 was observed in 18 of 30 patients (60%) at ICU. Both serum PLA2 and pancreatic isoamylase were elevated in 11 patients (37%). Of 11 patients with hyperphospholipasemia and hyperamylasemia, serum creatinine was elevated in five patients and blood urea nitrogen in nine patients. Serum PLA2 levels did not always rise comparably to serum creatinine and blood urea nitrogen levels. Serum PLA2 values showed the best correlation with serum lactate dehydrogenase levels among routine blood-chemistry tests. The elevation of serum PLA2 was ascribable to renal dysfunction or ischemic pancreatic damage secondary to circulatory collapse with multiple organ failure.

Urinary and serum zinc levels in chronic pancreatitis

Urinary and serum zinc levels were determined in 51 patients with chronic pancreatitis. Urinary zinc excretion in patients with chronic calcified pancreatitis (832 ± 111 μg/day) (mean ± SE) but not in noncalcified pancreatitis (684 ± 65 μg/day) was significantly higher than in normal controls (418 ± 46 μg/day). The urinary zinc excretion increased with deterioration of exocrine pancreatic function. Serum zinc levels in advanced pancreatitis (105.9 ± 4.5 μg/100ml) were significantly higher when compared to the pancreatitis with normal exocrine pancreatic function (91.6 ± 3.0 μg/l00 ml), but the difference was less pronounced than for urinary zinc excretion. This may be due to complicating diabetes, which usually lowers serum zinc. Serum zinc and urinary zinc excretion were low in a patient with chronic calcified pancreatitis complicated with a pulmonary abscess and hypoalbuminemia. In conclusion, urinary and serum zinc levels in chronic pancreatitis were increased as a result of exocrine pancreatic dysfunction. Association of diabetes may lower serum zinc, and associated malnutrition depresses both urinary and serum zinc levels.