Akihito Hiura

The detection of human pancreatic cancer‐associated antigen in the serum of cancer patients

A radioimmunoassay (RIA) test for human pancreatic cancer‐associated antigen (Span‐1) was developed to evaluate the diagnosis of various gastrointestinal disorders. Serum Span‐1 in normal subjects ranged from 5 to 275 U/ml, with a mean of 58.8 U/ml (±58.7, standard deviation). All control subjects had levels of less than 400 U/ml. Study subjects, 93% with pancreatic cancer, 59% with hepatobiliary cancers, 23% with gastric cancers, and 13% with colonic cancers had serum Span‐1 levels greater than 400 U/ml. Sensitivities of Span‐1, CA 19‐9, and Dupan‐2 for pancreatic cancer were 94%, 85%, and 38% respectively. Span‐1 in patients with Stage I pancreatic cancer showed a 50% positive rating but CA 19‐9 and Dupan‐2 showed only 0% and 25%. Although a positive rating of these three antibodies increased in advanced cases, Span‐1 showed the highest positive rating. Span‐1 reacted with colonic cancer tissues with Lewisa−b− phenotype. However, none of these tissues did not react against CA 19‐9. From these results, Span‐1 has a good predictive value for detecting pancreatic cancer compared with CA 19‐9 and Dupan‐2.

LEFT ACUTE SCROTUM ASSOCIATED WITH APPENDICITIS

A 10‐year‐old boy, who had a mild inguinal hernia in his left scrotum, was referred to our clinic because of redness of the scrotal skin and tenderness of the left scrotal contents. Scrotal echography showed a hypoechoic lesion around the normal testis and epididymis. Because torsion of either the testis or testicular appendage was suspected, the scrotum was opened and 1.5 mLof purulent fluid was observed in the tunica vaginalis with inflammatory tissue around the testis and epididymis. On the first postoperative day, a low grade fever and abdominal tenderness persisted, however, the abdomen was flat and soft. There was no marked tenderness over McBurneys point, butthere was moderate tenderness over Lanzs point on deep palpation. Abdominal sonography and magnetic resonance imaging revealed abscess formation between the bladder and the sacrum. With a diagnosis of perforation of the appendix, a laparotomy was performed. The inguinal hernia sac could not be observed on inspection, and it was not possible to palpate the left side because of severe adhesion due to infection. Also, the neck of the right inguinal sac could not be seen. The appendix specimen was gangrenous. On the second postsurgical day, all symptoms and signs disappeared. We present this rare condition and discuss the difficulty in establishing a diagnosis.

Renal function in experimentally induced acute pancreatitis in dogs: How it is affected by the nephrotoxic substance in pancreatic exudate from ascitic fluid

Renal failure occurring in dogs during experimental acute pancreatitis and the effect on renal function of intravenous injections of ascitic fluid which accumulated during the acute pancreatitis were studied. Five hours after the induction of acute pancreatitis, the accumulation of 200 to 400 ml of ascitic fluid, and an elevation in hematocrit as well as a decreased mean arterial pressure were observed, which suggested hypovolemia due to plasma loss. At the same time, the renal blood flow, glomerular filtration rate, and urinary output decreased significantly. Hypovolemia was observed to be the main cause of renal failure in accordance with previous reports. When the sterile ascitic fluid was injected into healthy dogs, temporary hypotension was observed without changes in the hematocrit. However, the renal blood flow, glomerular filtration rate and urinary output decreased, together with an elevation in renal vascular resistance, even after the hypotension had returned to normal. This study shows that renal failure associated with acute pancreatitis occurred mainly as a direct result of hypovolemia but also that the sterile ascitic fluid contained nephrotoxic substances which were suspected to be unrelated to vasoactive substances or protease. Their removal is therefore necessary for the treatment and prevention of renal failure complicating acute pancreatitis.

Renal Microcirculation in Experimental Acute Pancreatitis of Dogs

In order to understand the mechanism of acute renal failure frequently observed in severe acute pancreatitis, renal microcirculation and renal hemodynamics were investigated during experimental acute pancreatitis in dogs induced by autologous bile and trypsin mixture into the pancreatic duct. Renal tissue blood flow (hydrogen gas clearance method), renal arterial blood flow, and cardiac output (transonic blood flow meter) were each measured for 5 h after induction of pancreatitis. The effect on renal hemodynamics of a new synthesized protease inhibitor--E-3123; 4-(2-succinimidoethylthio)phenyl-4-quanidinobenzoate methane sulfonate--intravenously infused at the rate of 3 mg/kg/h was also investigated. The mean blood pressure and pulse pressure decreased after induction of pancreatitis. Renal microcirculation and renal artery blood flow decreased during the experiment. However, in dogs with treated by E-3123, renal microcirculation was preserved during the first hour of the experiment and decreased gradually afterward, but it was significantly higher than that of the dogs without E-3123 during 3-5 h. The mean blood pressure and pulse pressure were preserved nearly at preoperative levels during the experimental period. We concluded that renal microcirculation decreased concomitantly with a deterioration of acute pancreatitis, and that the new pancreatic protease inhibitor E-3123 may have some beneficial effect to improve renal hemodynamics in the early period of acute pancreatitis.

The measurement of serum immunoreactive pancreatic secretory trypsin inhibitor in gastrointestinal cancer and pancreatic disease

SummaryThe clinical usefulness of serum pancreatic secretory trypsin inhibitor (PSTI) in pancreatic disease and gastric and colorectal cancer has been examined.The results showed that serum PSTI in acute pancreatitis was significantly higher than in normal subjects and it was also raised in acute exacerbations of chronic pancreatitis. Although the sensitivities of serum PSTI, amylase and elastase I were similar, serum PSTI in necrotizing hemorrhagic pancreatitis was 2.7 times higher than in mild acute pancreatitis. Only a few patients with chronic pancreatitis showed increased concentrations and the mean value was near normal.The mean PSTI in patients with pancreatic and colorectal cancer was higher than normal, although that of gastric cancer was within normal limits. The sensitivity of serum PSTI measurements in patrents with these three malignant diseases was only about 30%.The results suggested that the measurement of serum PSTI could be useful in the diagnosis of acute pancreatitis, but of limited value in the diagnosis of other disease which we examined.

Effect of a synthetic protease inhibitor (Fut-175) on coagulation abnormalities during experimental acute pancreatitis in dogs

SummaryThe coagulation disturbance observed during severe acute pancreatitis before and after the infusion of a new synthetic low molecular weight protease inhibitor (Fut-175) was compared. The coagulofibrinolytic changes after acute pancreatitis was induced by the intraductal injection of an autologous bile and trypsin mixture showed decreased platelet counts, decreased plasma fibrinogen levels, prolonged partial prothrombin time and increased fibrinogen degradation products. In addition, markers of hypercoagulation showed increased fibrin-opeptide A and decreased antithrombin III. The two markers of fibrinolysis showed increased Bβ15–42 immunoreactive peptide and decreased α2 antiplasmin. After the infusisn of Fut-175, the coagulo-fibrinolytic abnormalities, which were bserved during severe acute pancreatitis without infusion of Fut-175, were improved. Furthermore, Fut-175 could suppress the rise in fibrino-peptide A and Bβ15–42 immunoreactive peptide and decrease in antithrombin III and α2 antiplasmin. Thus, Fut-175 seems to be an effective inhitor of protease-mediated hypercoagulation and fibrinolysis in severe acute pancreatitis.

Management of pancreatic pseudocyst

The natural course, complications, and management of 37 patients with pancreatic pseudocyst treated at our institution were reviewed. The lesions were classified into three groups, cysts secondary to acute pancreatitis, to chronic pancreatitis, and to trauma. Spontaneous resolution or cyst diminution was observed in 75% of the patients with acute pancreatitis and trauma, but in only 33% of those with chronic pancreatitis. The interval until resolution or diminution in chronic pancreatitis was shorter than that in pseudocyst of other etiologies, but the incidence of complications in patients with chronic pancreatitis was not significantly higher than that among patients with other etiologies. Multiple complications were found only among the patients with chronic pancreatitis. Surgical management was performed in 25% of the patients with acute pancreatitis and trauma and 66% of the patients with chronic pancreatitis. The postoperative mortality rate was 10%. Reoperation was necessary in 6 of 7 patients who had undergone external drainage, including 3 patients treated with ultrasonography-guided percutaneous catheter drainage (US-PCD). These results suggest that it is necessary to closely monitor patients with chronic pancreatitis and/or external drainage, and in these patients it may become necessary to reoperate. US-PCD was useful as an emergency procedure in pseudocyst patients whose general condition was poor, despite the disadvantages of the piercing of adjacent organs by the catheter, infection, and pseudocyst recurrence.

Effects of a newly synthesized pancreatic protease inhibitor (PATM) on pancreatic microcirculation in experimental acute pancreatitis

SummaryPancreatic inschemia, especially due to pancreatic microcirculation disturbance, has been considered to trigger and aggravate acute pancreatitis. In this work experimental acute pancreatitis was produced by autologous bile and trypsin in mongrel dogs to study the time-course changes in systemic and local hemodynamics in association with disease progress. In addition, the effects of a new synthetic pancreatic protease inhibitor (PATM, 3 mg/kg/hr, i.v.) on systemic and local circulation were examined. In animals with untreated pancreatitis the mean baseline pancreatic microflow was 55.6 ± 17.0 ml/min/ 100g before the onset of pancreatitis and this decreased by 22% and 52% at 1 hr and 5 hr, respectively. The femoral arterial pressure and cardiac index also decreased during the 5 hr experiment at period in comparison with the respective preoperative levels. The portal venous flow showed a sharp reduction immediately after the onset of pancreatitis, staying at a low level thereafter. The pancreatic microflow was significantly improved by PATM treatment for the first 60 min and the portal venous flow for the first 120 min. PATM treatment prevented the decrease in femoral arterial pressure, although it failed to exert any appreciable effect upon the cardiac index. These findings suggest that intravenous administration of PATM might be of value for improving the pancreatic microflow and portal venous flow, at least in the early stage of experimental acute pancreatitis in dogs.

ROLE OF ENDOGENOUS AND EXOGENOUS CHOLECYSTOKININ IN EXPERIMENTAL ACUTE PANCREATITIS INDUCED IN RATS BY THE DUODENAL LOOP TECHNIQUE

The role of endogenous cholecstokinin (CCK) release and exogenous CCK-8 administration in the development and progression of acute pancreatitis and in the early recovery phase of acute pancreatitis were investigated in rats with closed duodenal loop (CDL)-induced pancreatitis. The subcutaneous injection of CCK-8 (2 μg/kg) stimulated a physiological level of pancreatic enzyme secretion in normal control rats, but did not lead to any biochemical or histological evidence of acute pancreatitis. A higher dose of CCK-8 (8 μg/kg), however, did produce both biochemical and histological evidence of acute pancreatitis in the normal control rats. When 2 μg/kg of CCK-8 was injected subcutaneously in rats 6 and 12h after the creation of the CDL, either the biochemical nor the histological findings of acute pancreatitis showed any progression compared with the changes in controls given to CCK-8. Serum CCK levels, measured by radio-immunoassay, increased significantly from mean levels of 5.39 pg/ml (±0.95 SD) before creation of the CDL to 42.06 pg/ml (±2.27 SD) 6h after, and 41.95 pg/ml (±1.88 SD) 12h after its creation (P<0.01). The difference between serum CCK levels at 6 and 12h was not statistically significant. Following the release of the loop, serum CCK levels decreased gradually, especially in rats in which the loop was released 6h after being created. Although no marked biochemical and histological changes of acute pancreatitis were observed following the admistration of 2 μg/kg of CCK-8 to rats upon release of the loop 6h and 12h after its creation, a higher dose of CCK-8 (8 μg/kg) in these rats adversely affected both the biochemical and histological findings of acute pancreatitis. Based on these findings, it was concluded that neither endogenous CCK release, as a result of the CDL, nor physiological stimulation of the pancreas by exogenous CCK-8 administration, caused progression from edematous to hemorrhagic acute pancreatitis, and neither CCK treatment had any adverse effect on the early recovery phase of CDL-induced acute pancreatitis. A pharmacological dose of CCK, however, exacerbated the acute pancreatitis, even in the early recovery stage.

Three-portal technique for laparoscopic cholecystectomy

We devised special maneuvers and techniques, which we refer to as “the three-portal technique,” for the performance of laparoscopic cholecystectomy. With this technique, the primary surgeon operates from the right side of the patient, beginning dissection at the posterior surface of the gallbladder and advancing until the neck of the gallbladder is sufficiently separated from the hepatic bed. The particular advantages of our technique are that the quadrate lobe of the liver does not obstruct the operative field, because of the direction of the dissecting forceps controlled by the operator’s right hand, and there is less contact between the various instruments. Sixteen patients with gallstones were successfully treated with this new technique, and no morbidity was attributable to the procedure.