Masuo Tokoo

Elevated serum levels of Dupan-2 in pancreatic cancer patients negative for Lewis blood group phenotype.

CA19-9, a serum marker for pancreatic cancer, gives false-negative results in patients who are negative for the Lewis blood group phenotype. To determine whether other markers may compensate for this drawback, serum levels of CA50, Span-1, sialyl SSEA-1 and Dupan-2 were assayed and compared with those of CA19-9 in 207 normal subjects and in 200 patients with pancreatic carcinoma whose Lewis blood group phenotypes were confirmed. In normal subjects with the Lewis negative phenotype, the serum levels of CA50 and Span-1, as well as CA19-9, were significantly low, whereas those of sialyl SSEA-1 were independent of the Lewis blood group phenotype. Serum levels of Dupan-2 were significantly higher in normal subjects with the Le (a-b-) phenotype as compared with those with Le(a-b+). The sensitivity for pancreatic carcinoma was 81% for CA19-9, 84% for CA50, 82% for Span-1, 51% for sialyl SSEA-1 and 63% for Dupan-2. Among the 39 CA19-9 negative patients, 13 were determined as being Lewis negative by the serum dot-ELISA technique. Although the positive rates were essentially comparable when each marker was combined with CA19-9, a highly elevated serum level of Dupan-2, which strongly suggested the presence of malignancy, was most frequently encountered in 39 patients who were not diagnosed by CA19-9 assay, especially those with Lewis negative blood groups. With regard to the three other markers, we found few patients with a highly elevated serum level in either the Lewis-negative or -positive groups. We conclude that Dupan-2 tended to be elevated in patients with pancreatic cancer who were negative for the Lewis blood group phenotype.

Comparative study of CA242 and CA19-9 for the diagnosis of pancreatic cancer.

A comparative study of a new tumour marker, CA242, and CA19-9 was conducted with special reference to their diagnostic usefulness in pancreatic cancer. CA242 showed sensitivity similar to that of CA19-9 for overall cases and early cases (stage I tumour) of pancreatic cancer. For other malignancies, the positive rates of CA242 were lower than those of CA19-9 except for colorectal cancer. An important characteristics of CA242 was that it was only slightly and infrequently elevated in the sera of patients with benign diseases such as chronic pancreatitis, chronic hepatitis and liver cirrhosis. This characteristic was more apparent in the patients with benign obstructive jaundice, indicating that the serum level of this marker was scarcely affected by cholestasis. Using cut-off levels corresponding to a 90% specificity, the clinical results obtained with CA242 in the diagnosis of pancreatic cancer were similar to those obtained with CA19-9, except that CA19-9 was falsely negative in some patients with early-stage pancreatic cancer. These findings suggest the usefulness of this marker for screening pancreatic cancer in patients on their first hospital visit. However, CA242 was found to be influenced by the Lewis blood group system. This unfavourable result is attributed to the C241 catcher antibody of this assay system, which has almost the same epitope specificity as the C50 and the NS19-9 monoclonal antibodies. In conclusion, CA242 is superior to CA19-9 in diagnosing pancreatic cancer by virtue of its higher specificity.

Epitope analysis of SPan-1 and DUPAN-2 using synthesized glycoconjugates sialyllact-N-fucopentaose II and sialyllact-N-tetraose

Epitope analysis of Span-1 and DUPAN-2 was compared with that of CA19-9 using the synthesized glycoconjugate sialyllacto-N-fucopentaose II (SLF11, sialyl-Lewisc) and its precursor, sialyllact-N-tetraose (LSTa, sialyl-Lewis”), conjugated to human serum albumin. The CA19-9 and DUPAN-2 assay systems specifically recognized SLF II and LSTa, respectively. The Span-1 assay system recognized both SLF IIIand LSTa, although the reactivity with the former was far stronger than that with the latter. These results were, in general, compatible with those obtained from assaying these markers in the sera of two pancreatic cancer patients with definite Lewis-negative phenotype and in the sera of 39 CA19-9-negative pancreatic cancer patients. In conclusion, DUPAN-2 is the precursor of CA19-9 and is accumulated in the sera of pancreatic cancer patients with Lewis-negative phenotype and Span-1 has an advantage over CA19-9 in the diagnosis of patients with Lewis-negative phenotype, although both markers have almost the same sensitivity for this malignancy.

Comparative Study of CA-50 (Time-Resolved Fluoroimmunoassay), Span-1, and CA19-9 in the Diagnosis of Pancreatic Cancer

The clinical diagnostic utility of CA-50 (time-resolved fluoroimmunoassay) and Span-1 was compared with that of CA19-9 by measuring their levels in sera from patients with pancreatic cancer and other diseases. In pancreatic cancer CA-50, Span-1, and CA19-9 showed similar positive rates (84%, 82%, and 81%, respectively). With regard to the ability to distinguish pancreatic cancer from chronic pancreatitis, however, the specificity of CA-50 and Span-1 was higher than that of CA19-9 (85%, 85%, and 79%, respectively). Despite the similar positive rates of CA-50 and Span-1 in pancreatic cancer, the correlation between these two markers was low. Thus, used in combination, they compensated for each other in the diagnosis of pancreatic cancer. In chronic liver diseases, serum levels of both CA-50 and Span-1 were correlated with that of biliary tract enzymes, alkaline phosphatase, and r-glutamyl transpeptidase. And these two markers were more affected by the biliary system than CA19-9, resulting in the significantly higher positive rates. In these diseases immunohistochemical study showed that all three markers were localized in the epithelial cells of the bile duct, with CA-50 and Span-1 showing a similar tissue distribution.

Comparative study of CA242 and CA19-9 in chronic pancreatitis

CA242 has been proved to be useful in the diagnosis of pancreatic cancer. The aim of the present study was to clarify the mechanisms contributing to the high specificity of CA242 as compared with CA19-9 resulting from scarce serum elevation of this antigen in patients with chronic pancreatitis by correlating serum levels and endoscopic retrograde choledocho-pancreatography (ERCP) findings and by immunohistochemical analysis. Serum CA19-9 levels were significantly elevated in patients with calcification and with main pancreatic duct (MPD) stenosis or obstruction. On the other hand, serum CA242 levels showed no significant elevation in patients with such factors. Even though such pathological conditions were considered to lead to the stagnation of pancreatic juice, serum CA242 levels seemed to be less affected than serum CA19-9 levels. Immunohistochemical studies of chronic pancreatitis tissues revealed that CA242 was expressed less frequently and less intensely than CA19-9, and the difference in expression was more prominent in the centroacinar cells and terminal ductules. From the results of the present study, it is conceivable that CA242 is less influenced by the stagnation of the pancreatic juice than CA19-9 because of the low levels of expression in ductal systems, which results in the release of this antigen into the circulation in lower amounts than that of CA19-9.

Clinical evaluation of pancreatic cancer-associated mucin expressing CA19-9, CA50, Span-1, sialyl SSEA-1, and Dupan-2.

We have previously described the purification and partial characterization of a new pancreatic cancer-associated antigen, a pancreatic cancer-associated mucin expressing CA19-9, CA50, Span-1, sialyl SSEA-1, and Dupan-2. This study describes the clinical evaluation of various assay systems for this antigen which depend on measuring respective serum levels. Elevated levels of antigen were detected in the sera from both patients with malignant and non-malignant diseases. However, elevated serum levels of CA19-9 and Lewisa and Lewisb epitopes on moieties were restricted to pancreatic and biliary tract cancers, although adequate sensitivity was not attained. Coordinate evaluation of these three markers improved the sensitivity to some extent without loss of specificity for the diagnosis of pancreatic and biliary tract cancers, because of the heterogeneity of the coexpression of these epitopes. We developed additional assay systems with a combination of this antigen and two lectins (Bauhinia purpurea (BPA) and Vicia villosa (VVA)). Elevated levels of BPA- and VVA-reactive antigens were detected in 41% and 31%, respectively, of pancreatic cancer sera samples. Few patients with chronic pancreatitis had an elevated serum level of either antigen, and higher elevated levels of these markers were restricted to the sera of patients with malignancies. Our results suggest that this antigen is found in the sera of patients with various conditions and in the sera of normal subjects but that antigens bearing CA19-9 or Lewisa or Lewisb epitopes and an altered carbohydrate structure recognized by BPA and VVA lectins are preferentially present in the sera of patients with pancreatic and other malignancies.

Growth hormone-releasing hormone (GRH)-producing pancreatic tumor with no evidence of multiple endocrine neoplasia type 1.

The characteristic features of a 48-year-old male presenting with isolated acromegaly caused by a GRH-producing pancreatic endocrine tumor bearing no relation to MEN1 was reported. The clinical features, laboratory findings, and sellar enlargement were improved after removal of the pancreatic tumor. The resected pancreatic tumor showed positive GRH immunoreactivity and contained abundant GRH mRNA. This tumor is extremely rare and to date only 10 cases have been reported. In the management of acromegaly, the measurement of GRH is recommended and the search for an ectopic source will prevent unnecessary and potentially ineffective pituitary surgery.

Expression of Glycoconjugates in Pancreatic, Gastric, and Colonic Tissue by Bauhinia purpurea, Vicia villosa, and Peanut Lectins

We have earlier prepared a pancreatic cancer-associated mucin, whose altered carbohydrate structure was recognized by Vicia villosa (VVA), Bauhinia purpurea (BPA), and peanut (PNA) lectins and which was found preferentially in the sera of patients with pancreatic or gastric cancer. Cancer-associated structures of the sugar chain on serum antigen may reflect those occurring in malignant tissues. Accordingly, we investigated the tissue distribution of carbohydrate structures reactive to these lectins by using lectin histochemistry in pancreatic cancer, gastric cancer, and colonic cancer tissue specimens and in their normal counterparts. VVA showed a higher affinity for pancreatic cancer (77.5%), gastric cancer (89%), and colonic cancer (87%) cells than for the cells of their normal counterparts, whose affinity was 0%, 41.7%, and 36.4%, respectively. PNA showed a higher affinity for pancreatic (70%) and colonic cancer cells (86.5%). BPA failed to show significant binding differences between neoplastic and normal cells in any of the pancreatic, gastric, or colonic tissue specimens. It did, however, bind to intraductal contents in most of the pancreatic cancer tissues but bound to intraductal contents in only a few chronic pancreatitis and normal pancreatic tissues. VVA and PNA did not bind to intraductal contents in any of the normal, chronic pancreatitis, or pancreatic cancer tissues. These results imply that, among the lectins used so far, VVA has the highest affinity for neoplastic cells, and it may provide a supplement for use in the pathologic diagnosis of malignant diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Single Dose Pharmacokinetics of Temocapril, an ACE Inhibitor with Preferential Biliary Excretion, in Dialysis Patients

SummaryThe single dose pharmacokinetics of temocapril, a novel prodrug type angiotensin converting enzyme (ACE) inhibitor with preferential biliary excretion, were evaluated in 6 patients maintained on haemodialysis and in 1 patient on continuous ambulatory peritoneal dialysis (CAPD). In a crossover design, each haemodialysis patient received a single oral dose of temocapril 1mg after breakfast on two occasions, on dialysis and nondialysis days, at an interval of 1 week. The CAPD patient received a single oral dose of temocapril 1mg. Plasma concentrations of temocapril and its active metabolite (diacid) and ACE activity were determined after drug administration. Area under the plasma concentration-time curves (AUC) in haemodialysis patients on the non-dialysis day were significantly greater than those in patients with normal renal function who were used as a reference (p < 0.01). Other pharmacokinetic parameters such as maximum plasma drug concentration (Cmax), biological half-life (t½) and time to reach Cmax (tmax) were not significantly different between the 2 groups. 24 hours after administration, the ACE inhibitions in haemodialysis patients were significantly higher than those in patients with normal renal function. There were no other significant differences between the 2 groups. The peak level of diacid (Cmax) in haemodialysis patients on the nondialysis day was significantly greater than that on the dialysis day (p < 0.05). Other pharmacokinetic parameters such as AUC, t½ and tmax were not significantly different between these 2 days. These parameters in the CAPD patient were similar to those in the haemodialysis patients on dialysis day. The results suggest that the elimination route of temocapril is mainly via the biliary route, but is partially a route permeated through a dialyser membrane or peritoneal membrane. It is suggested that temocapril is preferable to ACE inhibitors with renal elimination in the treatment of patients with hypertension undergoing dialysis.

Antihypertensive Effects and Pharmacokinetics of Temocapril, an Angiotensin Converting Enzyme Inhibitor with Preferential Biliary Excretion, in Patients with Impaired Renal Function

Since the discovery of captopril, the first angiotensin converting enzyme (ACE) inhibitor, by Ondetti et al. in 1977, many ACE inhibitors have been developed (Hui et al. 1991; Ondetti et al. 1977). However, almost all ACE inhibitors currently available, with the exception of fosinopril (Gavras & Gavras 1988), are excreted mainly in the urine through the kidneys. Therefore, in order to prevent an unnecessary increase in plasma concentrations in patients with impaired renal function, careful attention should be paid to the dose, the dose interval and the choice of drug (Oizumi et al. 1988; Suzuki et al. 1992). Temocapril is a novel ACE inhibitor that has been shown in experimental animals and man to be primarily excreted in faeces through the bile (Nakashima et al. 1992; Oguchi et al. 1993). A pharmacokinetic study of a single dose of temocapril has been performed in patients with impaired renal function (Nakashima et al. 1992; Oguchi et al. 1993), and showed that the pharmacokinetics of the drug were similar to those in patients with normal renal function. Another pharmacokinetic study has shown that temocapril is eliminated preferentially through the biliary route and that its bioactivity is hardly affected in patients with liver dysfunction (Furuta et al. 1993). The present study was conducted to evaluate the pharmacokinetics and antihypertensive effects of temocapril in hypertensive patients with severely impaired renal function during administration of temocapril for 7 consecutive days.