Tokimune Shibata

Chronic alcoholism and evolution of pain and prognosis in chronic pancreatitis.

To evaluate the influence of chronic alcoholism on clinical features of chronic pancreatitis in Japan, pain evolution, pancreatic insufficiency, and long-term prognosis were studied by comparing chronic alcoholic pancreatitis (N=88)with idiopathic pancreatitis (N=67).The 155 patients with known course of the disease over three years were followed-up further for five more years, and pain evolution was evaluated once at the start and once at the end of the follow-up period. At the time of diagnosis, severe pain (59 vs 33%, P < 0.001), pancreatic calcification (63 vs 31%, P<0.001), advanced exocrine pancreatic insufficiency (72 vs 60%, NS),and overt diabetes (48 vs 17%, P<0.007)were more common in alcoholic than in idiopathic pancreatitis, respectively. Pain evolution was similar in both pancreatitis, and the pain decreased with time. The rate of abstinence was higher in groups with pain relief than without in alcoholic pancreatitis. Cumulative mortality rate during the five years was higher in alcoholic than idiopathic pancreatitis (26 vs 10%, P<0.01).These results suggest more favorable evolution of the disease can be expected by abstinence from alcohol.

Usefulness of a new tumor marker, Span-1, for the diagnosis of pancreatic cancer.

Levels of serum Span‐1, a new tumor marker for pancreatic cancer, were assayed in 64 patients with pancreatic cancer, 90 with nonpancreatic cancer, and 254 with nonmalignancies, involving 55 healthy controls. Furthermore, Span‐1 was compared with other tumor markers (CA19‐9, carcinoembryonic antigen [CEA], and DU‐PAN‐2). Frequency of elevated Span‐1 levels was 81.3% in pancreatic cancer. False‐positive elevations of serum Span‐1 levels were rather common in liver cirrhosis (53.8%) and chronic hepatitis (26.3%). The sensitivity, specificity, and efficiency of this assay for pancreatic cancer, was 81.3%, 75.6%, and 76.5% against all subjects without pancreatic cancer, respectively. In comparison with other markers, sensitivity of Span‐1 tended to be highest with similar specificity to those of CA19‐9 and CEA. The Span‐1 assay has a high sensitivity and specificity for pancreatic cancer. It is almost equivalent to CA19‐9 assay. However, this assay is not specific for chronic liver diseases.

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.

Dissolution of pancreatic stones by oral trimethadione in a dog experimental model.

Experiments were conducted to develop a dissolution therapy for human pancreatic calculi in a dog experimental model of pancreatic calculi surgically prepared. On plain x-ray films of the abdomen, pancreatic calculi appeared in 19 of 39 dogs within 12 mo after operation. The antiepileptic agent trimethadione was given orally to 13 dogs at a dose of 1.0-1.5 g daily. Pancreatic calculi disappeared in 13 of 15 observations. The scanning electron microscopy, the elemental analysis, and the powder x-ray diffractometry of pancreatic calculi in this model revealed that the calculi closely resembled human pancreatic calculi, consisting mainly of a calcite of calcium carbonate. There was no histologic finding suggesting drug toxicity in the liver, the kidney, and the blood. Pancreatic calculi in 6 control dogs without the treatment neither disappeared nor diminished spontaneously. The oral treatment with trimethadione may have potential for dissolving human pancreatic calculi.

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.

Effectiveness of multivariate analysis of tumor markers in diagnosis of pancreatic carcinoma: a prospective study in multiinstitutions.

In 403 patients suspected of having pancreatic cancer, we prospectively studied a combination assay of various serum tumor markers: CA19-9, DUPAN2, tissue polypeptide antigen, elastase 1, γ-glutamyltranspepti-dase, lactate dehydrogenase, lipase, amylase, and alkaline phosphatase. The diagnostic value of each marker was compared with a multivariate analysis (computer-aided multivariate and pattern analysis system for pancreatic cancer examine-1: CAMPAS-PX1). Pancreatic cancer was subsequently identified in 47 patients. CAM-PAS-PX1 had higher negative in health and positive predictability than those of each marker used alone in the diagnosis of pancreatic cancer. CAMPAS-PX1 proved the most effective marker for diagnosing pancreatic cancer, but in terms of its codbenefit ration CAMPAS-PX1 was not superior to CA19-9 used alone. In this prospective trial, we experienced poor generalizability in the statistical models (CAMPAS-PX1). We believe that selection bias was present in samples used for model building. Based on this study a new model has been designed.

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.

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.

Feedback regulation of basal pancreatic secretion in humans.

The effect of intrajejunal infusion of pancreatic juice on basal pancreatic secretion was studied in patients who had received pancreatoduodenectomy for pancreatic, biliary, or duodenal malignancy. Pure pancreatic juice was obtained through a drainage tube inserted into the main pancreatic duct. There was little fibrosis in the pancreatic remnant and daily pancreatic juice output was more than 200 ml. After intraluminal infusion of pancreatic juice, water, protein, bicarbonate, and enzyme outputs were decreased significantly by about 30%. Intraluminal trypsin also reduced pancreatic secretion. Trypsin inhibitor (aprotinin) suppressed the significant decrease caused by autopancreatic juice or trypsin solution. We conclude that basal pancreatic secretion in humans is under negative feedback control by intestinal pancreatic juice or tryptic activity.

Peritoneal absorption of pancreatic enzymes in bile‐induced acute pancreatitis in dogs

To clarify the contribution of peritoneal absorption of enzyme‐rich exudate to the persistent elevation of serum amylase in bile‐induced pancreatitis in dogs, serum amylase, lipase and immunoreactive trypsin (IRT) levels were measured during 24 h after induction of pancreatitis with and without peritoneal lavage. The basal level of serum amylase activity (m±s.e. = 1291 ± 111 U/L) reached a plateau at 30 min (2688 ± 185) after induction of pancreatitis and continued to rise until 24 h (7201 ± 424). This persistent amylase elevation could be reduced significantly by peritoneal lavage. Serum IRT rose to a peak (378 ± 103 ng/mL) at 30 min from the basal (20 ± 5), then decreased until 3 h (211 ± 34) and maintained a consistent level thereafter. Serum lipase elevation took an intermediate course between the levels of serum amylase and IRT. Intraperitoneal injection of 5 mL pancreatic juice could reproduce similar elevations to those of the respective enzymes, except lipase, seen in pancreatitis. These results suggest that transperitoneal absorption of pancreatic enzymes contributes to the elevation in serum enzyme levels and that rates of peritoneal absorption and serum disappearance differ from enzyme to enzyme.