Katsusuke Satake

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.

CA19-9 as a screening and diagnostic tool in symptomatic patients: the Japanese experience.

Although the prognosis for pancreatic cancer is generally poor, the Japanese Pancreatic Cancer Register reported in 1992 that the survival rate for resected pancreatic cancer was much higher than that for more conservative treatment. T1 and T2 pancreatic tumors are much more frequently resectable than are T3 and T4 tumors, and the 5-year survival rate for unresected T2, T3, and T4 cases is 0%. These findings emphasize the importance of early diagnosis of resectable pancreatic cancer. CA19-9 has shown satisfactory sensitivity in detecting advanced pancreatic cancer; we sought to determine the effectiveness of CA19-9 as part of a screening program for early cancer. Using elastase 1, CA19-9, and ultrasonography, we developed and tested a program of mass screening on persons presenting with and without abdominal complaints.

Clinical evaluation of oral administration of a cholecystokinin-A receptor antagonist (loxiglumide) to patients with acute, painful attacks of chronic pancreatitis: a multicenter dose-response study in Japan.

Introduction Cholecystokinin (CCK)–receptor antagonists have been found to markedly reduce the severity of pancreatitis and improve survival in experimental animal models of acute pancreatitis. CCK appears to play an important role in the development and progression of acute pancreatitis, and the recent development of CCK antagonists has provided a new approach to the treatment of acute pancreatitis in humans. Aims The therapeutic efficacy of a CCK-A receptor antagonist, loxiglumide, in patients with painful acute attacks of chronic pancreatitis was evaluated. Methodology A multicenter dose–response controlled trial was conducted at 110 institutions in Japan from June 1993 to December 1994. Chronic pancreatitis was diagnosed for all patients on the basis of the Japanese criteria for chronic pancreatitis. Two-hundred seven patients were randomized to oral treatment with loxiglumide (300, 600, and 1,200 mg/d) or placebo for 4 weeks. The efficacy of treatment was evaluated on the basis of clinical symptoms, physical signs, and serum pancreatic enzyme levels. The groups were comparable with respect to age, sex, etiology, complications, and previous treatment. Results The improvement rate of the abdominal and/or back pain was 46% in the loxiglumide 300-mg group, 59% in the 600-mg group, and 52% in the 1,200-mg group, and it was 36% in the placebo group (600 mg versus placebo:p < 0.05). The physical signs evaluated—abdominal tenderness and resistance—improved in all three loxiglumide groups, and the serum pancreatic amylase and trypsin levels decreased significantly in the 600-mg group (p < 0.05). The overall clinical improvement rate was 46% in the 300-mg loxiglumide group, 58% in the 600-mg group, and 52% in the 1,200-mg group, and it was 34% in the placebo group. Conclusion These results indicate that oral administration of loxiglumide may be useful in the treatment of patients with acute, painful attacks of chronic pancreatitis, and 600 mg/d is recommended as a beneficial dosage.

Comparison of Ca19-9 with Other Tumor Markers in the Diagnosis of Cancer of the Pancreas

The carbohydrate antigen 19–9 (CA19-9) and radioimmunoassay have been shown to offer new hope for improving the diagnosis of pancreatic cancer, and various tumor markers (including SPan-1, DUPAN-2, and CASO) have been established. While clinical studies of these markers have found satisfactory sensitivities, only a few studies have compared these tumor markers on the same blood samples. We therefore evaluated the clinical efficacy of SPan-1, CA19-9, DUPAN-2, CA50, carcino-embryonic antigen, and Elastase 1 in detecting pancreatic cancer in identical blood samples.

Serum elastase I levels in pancreatic disease.

The radioimmunoassay for human elastase I used in this study is accurate, sensitive, and specific, which we have confirmed. The assay can be done within 4 hours, which is important for clinical purposes. A total o 103 subjects were examined, and levels of 99 to 370 ng/dl (mean 200) in normal human sera were determined. The serum elastase levels in acute, acute relapsing, and chronic relapsing pancreatitis were significantly higher than normal. Although serial determinations returned to normal within 5 days after the onset of the attack, they decreased gradually and remained high on the 7th, 10th, and 11th days in patients who still had residual signs of pancreatitis. The values in patients with chronic pancreatitis and various other diseases were normal. The values in patients with acute pancreatitis were significantly higher than in those with hyperamylasemia of nonpancreatic origin. Twelve of 19 patients with pancreatic cancer had abnormal serum elastase levels; this was especially true in patients with cancer of the pancreatic head. We believe that the measurement of serum elastase levels by radioimmunoassay will become a useful diagnostic method for pancreatic disease in the future.

Inhibitory effect of green tea extract on the process of pancreatic carcinogenesis induced by N-nitrosobis-(2-oxypropyl)amine (BOP) and on tumor promotion after transplantation of N-nitrosobis-(2-hydroxypropyl)amine (BHP)-induced pancreatic cancer in Syrian hamsters

Epidemiologic studies have shown a lower risk of gastrointestinal cancer in green tea drinkers. In the present study, the inhibitory effect of green tea extract (GTE) on the process of pancreatic carcinogenesis induced by N-nitrosobis-(2-oxypropyl)amine (BOP) and on tumor promotion after transplantation of N-nitrosobis-(2-hydroxypropyl)amine (BHP)-induced pancreatic cancer were investigated in hamsters. In the first experiment, shortly after the initiation of pancreatic carcinogenesis by BOP, the animals in the GTE group were given GTE (0.5 mg/L) in their drinking water and the control group was given tap water. All animals were sacrificed 24 weeks later. There were no significant differences in body weight, water intake, or food consumption between the two groups during the experiments. GTE consumption was ∼1.25 mg/day/100 g body weight during this experiment. Seven of the 13 hamsters (54%) in the control group were found to have pancreatic tumors, versus six of the 18 hamsters (33%) in the GTE group. The average number of tumors in the control group was 1.0/hamster, compared with 0.5/hamster in the GTE group. The overall incidence of macroscopic pancreatic tumors in the GTE group was about half that in the control group. The incidence of pancreatic cancer was 54% (12/13) in the control group and 44% (8/18) in the GTE group. The number of pancreatic cancers, including invasive carcinoma and carcinoma in situ, in the GTE group was 0.88/hamster, significantly lower than in the control group (1.68/hamster) (p < 0.05). The incidence of atypical ductal hyperplasia, which is thought to be an early pancreatic cancer, was also significantly lower in the GTE group than in the control group (1.50/hamster vs. 4.65/hamster) (p < 0.05). In the second experiment, 1-mm3 pieces of BHP-induced pancreatic cancer were transplanted into the back of hamsters. The control group (N = 16) was maintained on the basal diet and tap water throughout the experiment, and the GTE group (N = 16) was also maintained on the basal diet and tap water for the first 3 weeks after transplantation, when successful transplantation was confirmed and, thereafter, given tap water containing GTE (0.5 mg/L) for an additional 12 weeks. Tumor growth was similar in both groups until 11 weeks after transplantation, but inhibition of tumor growth became apparent after 11 weeks in the GTE group. At 13 weeks, the average tumor volume in the GTE group was 1.01 ± 0.11 × 104 mm3, significantly smaller than that in the control group (1.98 ± 0.37 × 104 mm3) (p < 0.05). The results demonstrated that GTE has an inhibitory effect on the process of pancreatic carcinogenesis and on tumor promotion of transplanted pancreatic cancer. These results suggest that GTE may come to serve as a chemopreventive and chemotherapeutic agent for pancreatic cancer.

Effects of cerulein on the normal pancreas and on experimental pancreatic carcinoma in the Syrian golden hamster

The effects of cerulein on normal pancreas and on N-nitrobis (2-hydroxypropyl) amine (BHP)-induced experimental pancreatic carcinoma in Syrian golden hamsters were studied. Twenty hamsters received a subcutaneous injection of cerulein (20 μg/kg) twice daily for 10 days. The 10 control hamsters received normal saline (1 ml/kg). The results showed that when cerulein was injected subcutaneously for 10 days, pancreatic weight and amylase increased. DNA and the pancreatic weight/DNA ratio were also increased significantly in treated hamsters compared with controls (p <0.02 versus p <0.01). These results indicated that chronic cerulein injection had hypertrophic and hyperplastic effects. DNA synthesis, as measured by histoautoradiography of tritiated thymidine-labeled tissue, increased in pancreatic acinar cells (p <0.01) and increased slightly in islet cells and in ductal cells. Tritiated thymidine uptake in the pancreas of the treated group indicated a rather selective exocrine gland incorporation by acinar rather than ductal cells. Sixty hamsters received a subcutaneous injection of BHP (500 mg/kg) once a week, while 63 hamsters received BHP (500 mg/kg) plus cerulein (20 pg/kg). Twenty-seven hamsters received cerulein (20 μg/kg) alone. All animals were killed from 8 to 27 weeks later, and no cancer-bearing hamsters were observed during the eighth and ninth week following administration. From the 10th to 14th weeks after administration of BHP and cerulein, 87.9% (13 of 15) had tumors compared with 18.7% (3 of 16) after BHP alone (p <0.01). One of three and two of 13 tumors were adenoma. The earliest appearance of cancer, including carcinoma in situ and intraductal carcinoma, was at the 14th week after the administration of BHP alone and the 10th week after BHP and cerulein. During the 10th to the 14th weeks after administration of BHP and cerulein, cancer was found in 73.3%, which was statistically higher than after the administration of BHP alone (12.5%; p <0.01). All tumors were of exocrine origin in both groups. There were no special differences in histology, and no tumors were observed in cerulein-treated hamsters. This study has shown that cerutein stimulates pancreatic growth, especially acinar cell hyperplasia, and augments the carcinogenicity of N-nitrobis (2-hydroxypropyl) amine in the hamster pancreas.

Estrogen receptors in pancreatic tumors.

Objectives: Although a potential role for estrogen receptors (ER) in pancreatic tumors has been debated for many years, the importance of the receptors in these neoplasms remains unknown. Even the expression of the 2 ER isoforms, ER-&agr; and ER-&bgr;, in histological subtypes of pancreatic neoplasms is controversial. The aim of the present study was to systematically review the available literature about ER expression in pancreatic tumors and to discuss the potential importance of estrogen signaling in them. Methods: We performed a comprehensive literature search and analyzed the results regarding ER expression in pancreatic tumors, with special emphasis on the specificity of the antibodies used for immunohistochemistry. Results: Many articles have been published investigating the expression of ERs in pancreatic tumors, but the results are inconsistent. Moreover, most studies used antibodies that detected only ER-&agr;, not ER-&bgr;. Thus, the expression pattern of ER-&bgr; in pancreatic neoplasm remains especially unclear. Conclusions: The lack of detailed studies evaluating the expression of both ER-&agr; and ER-&bgr; receptors using isoform-specific antibodies likely contributes to the inconsistency of published results concerning ER expression in pancreatic tumors. Available published evidence suggests that a thorough reexamination of the potential role of ERs in pancreatic neoplasms is warranted.

The possibility of diagnosing small pancreatic cancer (less than 4.0 cm) by measuring various serum tumor markers. A retrospective study

Comparative studies measuring various tumor markers such as SPan‐1, CA 19‐9, carcinoembryonic antigen (CEA), DUPAN‐2, and elastase I were done in 74 patients with small pancreatic cancer including 23 cases of T1 pancreatic cancer (tumor size less than 2.0 cm) and 51 cases of T2 pancreatic cancer (tumor size between 2.1 to 4.0 cm), retrospectively. Although the mean value of these tumor markers in T1 and T2 pancreatic cancer were higher than those of the control cutoff levels, their sensitivities were different. In T1 pancreatic cancer, 13 of 23 cases (56.5%) of SPan‐1 and 14 of 23 cases of (60.7%) of CA 19‐9 had levels above normal. Although the numbers of patients were small, sensitivities of CEA, DUPAN‐2, and elastase I were 30.8%, 22.2%, and 28.6%, respectively. In T2 pancreatic cancer, 41 of 51 cases (80.4%) of SPan‐1 and 40 of 51 cases (78.4%) of CA 19‐9 showed higher levels than normal, but only 46.9% of CEA, 40.0% of DUPAN‐2, and 52.6% of elastase I were positive. The overall sensitivities in small pancreatic cancer (less than 4.0 cm) were 73% for SPan‐1 and CA 19‐9 but were less for CEA, DUPAN‐2, and elastase I. These results indicate that even small pancreatic cancers release detectable pancreatic cancer‐associated antigens in serum in more than 70% of cases, especially SPan‐1 and CA 19‐9. The measurement of these two tumor markers makes it possible to detect small pancreatic cancers after using imaging diagnostic procedures.

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.