Meggiato T

Beta-cell function in pancreatic adenocarcinoma.

To evaluate beta-cell function in patients with pancreatic cancer, the glucagon stimulation test was performed in seven patients with pancreatic adenocarcinoma, seven patients with type I diabetes mellitus, seven patients with type II diabetes mellitus, and in seven healthy controls. C-peptide serum levels were determined before and after a 1-mg i.v. glucagon injection. Basal C-peptide values were normal or slightly increased in pancreatic cancer and type II diabetic patients and low in type I diabetic patients. Following glucagon stimulation, no significant increase was observed in C-peptide values of type I diabetics and pancreatic cancer patients, whereas significant increases occurred in controls and type II diabetics. It is concluded that the altered beta-cell function found in pancreatic cancer patients may lead to hyperglycemia, which is frequently associated with this tumor type.

Spontaneous apoptosis and proliferation in human pancreatic cancer.

Several studies have documented the role of programmed cell death in the development and/or progression of cancer. The aims of this study were to analyze (a) the spontaneous apoptosis in human pancreatic duct carcinoma by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labeling (TUNEL); (b) its correlation with the proliferation rate of the tumor (determined by immunohistochemistry by using monoclonal antibody MIB-1); and (c) the association of apoptotic and mitotic index with the histologic features of the tumor and the outcome of patients. In pancreatic cancer, the apoptotic index (AI) was 4.9 ± 4.8, and the mitotic index (MI) was 1.3 ± 1.0 (mean ± SD). AI was higher in small (< 4 cm) than in large (>4 cm) size primary tumors (p = 0.02) and in undifferentiated as compared with differentiated cancers (p = 0.05). Significantly higher values of MI were detected in advanced as compared with early-stage carcinomas (p = 0.03) and when perineural invasion was present (p = 0.03). No correlation was found between AI and MI. Patients with AI > 2.3 survived significantly less than those with lower AI values (p = 0.03). Mitotic index >0.5 was associated with a worse survival (p = 0.006). These results suggest that in pancreatic cancer, spontaneous apoptosis is present and is more evident in small and undifferentiated tumors. Proliferation is increased in the advanced stage of cancer and seems to be independent of apoptosis. Higher levels of apoptosis and proliferation are negative prognostic indexes.

SERUM NEUROTENSIN IN HUMAN PANCREATIC CANCER

The role of neurotensin as a physiologic regulator of exocrine pancreatic secretion is known, but the hormone has only recently been recognized as important mitogen in vitro for human cancer cells. The aim of this study was to evaluate the variations of serum levels of neurotensin in pancreatic cancer. We studied 58 patients: 13 control subjects, 20 pancreatic cancer patients, 11 chronic pancreatitis patients, and 14 cases of extrapancreatic disease. No differences were found between serum values of neurotensin in pancreatic cancer and control subjects or extrapancreatic disease. Significantly higher values were detected in chronic pancreatitis than in pancreatic cancer patients (P <0.04). In chronic pancreatitis patients, the serum levels of neurotensin were correlated with serum amylase (r = 0.95, P <0.01). Lower levels of neurotensin were found in stage IV pancreatic cancer than in stages I-II (t = 1.82, P <0.04) and in grade II than in grade I (t = 2.21, P <0.02). Significant correlations were found between serum levels of neurotensin and two indices of nutrition: albumin (r = 0.60, P <0.05) and the percentage reduction in body weight (Z = 2.20, P <0.02). No correlations were found between serum levels of the hormone and size of the neoplasm or the survival of patients. We can conclude that the serum variations of neurotensin do not seem to be related to the progression of human pancreatic cancer. The variation of serum levels of the hormone may be linked to a poor nutritional status of the patient.

Comparison of two newly identified tumor markers (CAR-3 and DU-PAN-2) with CA 19-9 in patients with pancreatic cancer

We compared the diagnostic utility of DU-PAN-2 and CAR-3 with that of CA 19-9 in differentiating pancreatic cancer (23 patients) from chronic pancreatitis (16 patients) and various extra-pancreatic diseases (28 patients) mainly of the upper gastrointestinal and biliary tract. The influence of some pathophysiologic variables on the three markers was also assessed. The sensitivities of the three markers in detecting pancreatic cancer were: CA 19-9, 83%; DU-PAN-2, 56%; and CAR-3, 39%. In patients with chronic pancreatitis and extra-pancreatic diseases, CA 19-9 gave the highest number of false positives. Receiver-operating characteristic curves showed that the ability of CAR-3 to discriminate between pancreatic cancer and other diseases was similar to that of CA 19-9, whereas DU-PAN-2 was a less reliable discriminator. Correlations were found between the behavior of all three markers and that of the cholestasis indices (ALP and GGT). Our findings indicate that DU-PAN-2 and CAR-3 serum determinations do not provide any more information than does CA 19-9 alone. The latter remains the marker of choice in the differential diagnosis of pancreatic cancer, even though it cannot be considered a definitive aid. Serum levels of all three markers increase in the presence of extrahepatic cholestasis, possibly due to interference with the hepatic clearance of glycoproteins and destruction of ductal biliary epithelium.

Tumor-associated trypsin inhibitor in patients with chronic pancreatic diseases.

SummarySerum TATI (tumor-associated trypsin inhibitor) was measured in 41 control subjects, 30 patients with pancreatic cancer, 53 with chronic pancreatitis, and 47 with extrapancreatic diseases, mainly of gastrointestinal origin. TATI was found to be elevated in some subjects in all groups of patients; patients with chronic pancreatitis studied during an acute exacerbation of the disease had the highest percentage (68%) of pathological values. TATI was found to be correlated with elastase 1, tissue polypeptide antigen, and total and pancreatic isoamylase. A significant relationship was also found between TATI and serum creatinine levels.

Urinary elastase 1 in chronic pancreatic disease

Serum and urine elastase 1, its renal output and clearance and urinary gamma-glutamyltransferase and ribonuclease excretions were measured in 16 patients with pancreatic cancer, 23 with chronic pancreatitis and in 22 healthy controls in order to evaluate elastase 1 plasma-urine transfer in chronic pancreatic disease and to investigate any factors that might influence the clearance of this enzyme. In an additional group of 17 patients with different pancreatic diseases the serum molecular size distribution of elastase 1 after chromatography was ascertained. An increased urinary elastase 1 output was found in 4/16 patients with pancreatic cancer and in 6/23 with chronic pancreatitis. No correlation was found between circulating elastase 1 and its urinary output; a negative correlation was detected between the serum levels of this enzyme and its clearance. The excretion of ribonuclease and gamma-glutamyltransferase was correlated with elastase 1 output and clearance. While the majority of elastase 1 in serum was accounted for by high molecular forms, probably the expression of complexes with serum inhibitors, free circulating enzyme was present in all patients with high serum elastase 1. Our findings suggest that elastase 1 urinary excretion increases in some patients with chronic pancreatic disease regardless of the neoplastic or inflammatory nature of the illness. Although the availability of different amounts of ultrafiltrable enzyme may play a role in influencing elastase 1 plasma-urine transfer, renal tubular damage appears to be the most important factor influencing the increase in the urinary output of elastase 1.

Does acetylsalicylic acid interfere with stimulated pancreatic secretion? An experimental study in the rat.

To evaluate the effect of the prostaglandin inhibitor acetylsalicylic acid (ASA) on rat exocrine pancreas secretion, three groups of rats were administered ASA by infusion: Groups 1–3, 50, 100, and 200 mg/kg body wt, respectively; Group 4 received saline. Twenty minutes later these ASA-pretreated groups were given intraarterial secretin (18 CU/kg) and cholecystokinin (CCK) (18 μg.kg). In an additional three groups of seven rats each, saline solution rather than secretin-CCK was given after ASA pretreatment. Pancreatic juice was collected every 10 min by means of a chronic pancreatic fistula. Bicarbonate and protein concentrations were measured and variations in outputs observed. No significant variations were found in the bicarbonate concentrations and outputs of rats with different types of pharmacological treatment, while protein concentrations and outputs were found to vary with time and type of experiment. There was, however, no interaction between these two variables. At lower ASA dosages, the bicarbonate and protein concentrations and outputs of secretin-CCK stimulated rats were higher than the basal values and the levels of rats without hormonal stimulation. At higher dosages, no difference was found between the two groups. In conclusion, ASA seems to interfere with stimulated pancreatic exocrine secretion of proteins, even when its effect on bicarbonate concentration is factored in, and its effect seems to be present at the highest dosages considered in the study. Among the various hypotheses that may explain this phenomenon, an antagonizing effect of ASA on secretin-CCK action should be the first to be considered.