Cytokines modulate MIA PaCa 2 and CAPAN-1 adhesion to extracellular matrix proteins.

Variations in cancer cell adhesion to extracellular matrix (ECM) proteins might underlie an enhanced metastatic potential. ECM binding is mediated by cell-adhesion molecules, the membrane expression of which might be influenced by soluble mediators, such as cytokines. The aims of our study were to ascertain whether epidermal growth factor (EGF), transforming growth factor beta1 (TGF-beta1), interleukin 1alpha (IL-1alpha), or interleukin 1beta (IL-1beta) can modify MIA PaCa 2 (pancreatic cancer cell line) and CAPAN-1 (metastatic pancreatic cancer cell line) adhesion to fibronectin, laminin, or type I collagen, and whether these cytokines can shift the membrane expression of the hyaluronic acid receptor (CD44). EGF significantly enhanced MIA PaCa 2, but not CAPAN-1, adhesion to fibronectin, laminin, and type I collagen. TGF-beta1 reduced MIA PaCa 2 adhesion to type I collagen, but enhanced CAPAN-1 adhesion to fibronectin and laminin. IL-1alpha was found to enhance MIA PaCa 2 adhesion to fibronectin, while reducing adhesion to type I collagen, whereas IL-1beta reduced the adhesion to laminin. IL-1alpha enhanced CAPAN-1 adhesion to laminin in a dose-dependent manner; IL-1beta slightly increased the adhesion of these cells to laminin at low dosage, and to type I collagen at high dosage. Both IL-1alpha and IL-1beta reduced CD44 membrane expression of MIA PaCa 2, while TGF-beta1 increased the percentage of CD44-positive CAPAN-1 cells. We suggest that the effects on cell adhesion induced by different cytokines depend on the status of the target pancreatic cancer cell. EGF and, in part, IL-1alpha can favor nonmetastatic pancreatic cancer cell adhesion to ECM, possibly favoring tumor spread. Metastatic cells seem to lose the responsiveness to EGF, while becoming hyperresponsive to IL-1alpha. TGF-beta1 might exert an antidiffusive effect on primary, and a prodiffusive effect on metastatic pancreatic cancer cells. Only IL-1alpha, IL-1beta, and TGF-beta1 seem to influence CD44 membrane expression. All the results presented in this study were obtained in vitro, and in vivo studies are needed to verify whether the studied cytokines can favor or counteract pancreatic cancer spread.

Cytokines and the progression of liver damage in experimental bile duct ligation.

1. Cytokines are soluble factors whose action has been documented in physiological and pathological conditions. Some may be involved in the pathogenesis of cholestasis, whether of acute or chronic origin. 2. The aim of the present study was to evaluate the influence of epidermal growth factor (EGF), transforming growth factor (TGF)-beta 1, interleukin (IL)-6 and tumour necrosis factor (TNF) on cholestasis. Findings from Sprague-Dawley rats submitted to bile duct ligation for 1-28 days were compared with those from controls, which underwent laparotomy but not bile duct ligation. 3. Biochemical and morphological findings confirmed that the experimental procedure was successful. At the end of each follow-up period, the hepatic levels of the cytokines were determined and compared with liver histology findings. 4. The four cytokines studied showed different patterns of activation: hepatic levels of EGF, higher in the experimental than the control group, were comparable with the proliferative picture. The TGF-beta 1 pattern was correlated with data of periportal, perivenular and perineoductular fibrosis, confirming that this cytokine has a role in mediating the synthesis of matrix proteins. A fluctuating, phasic pattern was found for TNF in the experimental group, with high values on day 0, a decrease on the first and second postoperative days and then two peaks on days 8 and 14. Finally, immediately after surgical manipulation, high levels of IL-6 were found in the experimental group, followed by a decrease in levels until zero values were obtained. 5. This suggests that the obstructive condition produces several cytokine responses, each of which contributes to determine the cholestatic condition.

Serum growth factors in patients with pancreatic cancer.

The aims of this study were (1) to assess possible variations in the serum levels of epidermal growth factor (EGF), insulin-like growth factor I (IGF I) and somatostatin in patients with pancreatic cancer as compared to other pancreatic or extrapancreatic diseases and (2) to ascertain the role of these substances in tumour growth and spread. 35 patients with pancreatic cancer were compared to 15 patients with chronic pancreatitis, 15 with benign hepatobiliary diseases, 23 with benign or malignant gastro-intestinal diseases and 22 control subjects. Increased EGF and IGF I serum levels were found in 10% of patients with pancreatic cancer. Somatostatin levels were increased in 8/16 (50%) patients with pancreatic cancer. No correlation was found between EGF, IGF I or somatostatin and tumour size or stage. In pancreatic cancer somatostatin serum levels were correlated with total bilirubin (p < 0.04), while EGF and IGF I were inversely correlated with fasting serum glucose levels (p < 0.05). In conclusion, (1) the serum levels of EGF, IGF I and somatostatin were not related to tumour size and clinical stage of pancreatic cancer, (2) the serum levels EGF and IGF I may be related to altered glucose metabolism, and (3) liver impairment can influence somatostatin serum levels.

An unidentified pancreatic cancer cell product alters some intracellular pathways of glucose metabolism in isolated rat hepatocytes.

In this study we assessed whether conditioned media from a human pancreatic cancer cell line (MIA PaCa 2) can interfere with some intracellular pathways involved in glucose metabolism in isolated rat hepatocytes. The hepatocytes, isolated from Male Wistar rats, were incubated with MIA PaCa 2-conditioned or nonconditioned media. Conditioned and nonconditioned hepatocytes were run for 120 min in the presence or absence of insulin (100 mM) and were sampled at fixed time intervals. Supernatant glucose levels decreased to a similar extent over time in both conditioned and nonconditioned hepatocytes, while lactate levels significantly increased in nonconditioned hepatocytes with respect to conditioned hepatocytes. A pyruvate kinase activity increase was observed only in nonconditioned hepatocytes and was biphasic in nature, since this increased activity was detected both after a few and after 30 min following insulin stimulation. The cyclic AMP level increase was significantly higher in conditioned than in nonconditioned hepatocytes. It appears that MIA PaCa 2 cells produce a factor(s) that may interfere with one of the insulin-mediated intracellular pathways of glucose metabolism, namely, glycolysis. This detrimental effect on glycolysis is supported by the blunted rise in lactate concentration in the medium after the glucose challenge. This substance(s) probably transfers its signal inside the target cells, activating the adenylate cyclase pathway. These results support the hypothesis that pancreatic cancer is the cause rather than the consequence of diabetes mellitus.

Cytokines may influence tumor growth and spread. An in vitro study in two human cancer cell lines.

Tumor spread may be favored by a reduced production and/or an enhanced degradation of extracellular matrix components (collagen, fibronectin, laminin). Most tumor cell behavior, from growth to spread, may be regulated by cytokines, the exact roles of which, however, are not yet fully understood. We here evaluate the effects of some cytokines (epidermal growth factor, transforming growth factor-beta 1, interleukin-1 alpha, and interleukin-1 beta) on both cell growth and the production of the aminoterminal peptide of type III procollagen, the urokinase plasminogen activator, and the plasminogen activator inhibitor-1 in neoplastic cell lines originating in the pancreas and colon. Cells were stimulated daily with the above cytokines and the aminoterminal peptide of type III procollagen, urokinase plasminogen activator, and plasminogen activator inhibitor-1 were measured in the conditioned media. Epidermal growth factor stimulated cell growth of both cell lines. Transforming growth factor-beta 1 counteracted cell proliferation and stimulated type III procollagen and plasminogen activator inhibitor-1 production only in the colon cancer cell line. Interleukin-1 alpha slightly stimulated cell growth, but inhibited plasminogen activator inhibitor-1 production in both cell lines; interleukin-1 beta did not affect cell growth, but stimulated plasminogen activator inhibitor-1 production by the colon cancer cell line. Our findings suggest that transforming growth factor-beta 1 and interleukin-1 beta may have an antidiffusive effect. These results confirm that cytokine-producing cells have a potential role in stimulating or counteracting tumor growth and spread and also confirm the pivotal role of host-tumor interactions in determining the outcome of a particular neoplasia.

Effects of pancreaticobiliary duct obstruction on the exocrine and endocrine rat pancreas.

Experimentally, biliary obstruction can produce morphological and functional changes in the pancreatic gland, whereas pancreatic obstruction may have short-term (hyperamylasemia, pancreatic edema, and lysosomal hydrolase redistribution) or long-term (acinar cell atrophy and interstitial fibrosis) effects. We created a pancreaticobiliary duct obstruction in rats to evaluate (a) exocrine and endocrine anatomobiochemical pancreatic modifications; (b) structural and functional liver alterations; and (c) the relationship, if any, between the alterations found in the two organs. Forty-five male Sprague-Dawley rats were subdivided on the basis of period of obstruction (from 1 to 28 days). In each rat serum we evaluated amylase, cholestatic and cytolytic indices, and glucose. In frozen pancreatic samples we measured insulin, glucagon, and DNA; in the liver the DNA content was determined. Histologically, ductal dilation and proliferation were evaluated for the liver, zymogen granules, and Langerhans' islets, and atrophy for the pancreas. Fibrosis was evaluated for both the liver and the pancreas. Short-term common pancreaticobiliary duct ligation caused an increase in serum amylase levels and mild pancreatic edema. Longer-term obstruction had either similar or different effects on the two organs. In the pancreas it caused fibrosis and exocrine and endocrine atrophy, but not acute pancreatitis. In the liver the main phenomena observed were fibrosis, ductal dilation, and proliferation.

The pancreatic cancer cell line MIA PaCa2 produces one or more factors able to induce hyperglycemia in SCID mice.

A reduced glucose tolerance or frank diabetes mellitus is a frequent finding in patients with pancreatic cancer. The aim of this study was to verify whether the pancreatic cancer cell line MIA PaCa2 was able to produce any factor which could induce hyperglycemia in SCID (severe complete immunodeficient) mice. MIA PaCa2 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) for 7 days. Twenty-five female SCID mice were used. They were daily i.p. injected with 300 ul of cell culture supernatants (Group T, n = 13) or with 300 ul of DMEM (Group C, n = 12) and followed up for 82 days. Blood glucose levels were significantly higher in Group T than in Group C on days 10 and 25. Intravenous glucose tolerance test, success-fully performed in 9 animals (4 controls and 5 treated), demonstrated a significantly reduced glucose tolerance in Group T compared to Group C mice. At sacrifice, plasma and pancreatic insulin and glucagon levels did not vary between groups. The ratio between pancreatic and plasma insulin was significantly lower in Group T than in Group C. We conclude that: 1. The pancreatic cancer cell line MIA PaCa2 produces one or more soluble factors able to cause hyperglycemia in vivo; 2. this effect is not immunologically mediated, and 3. this/these factor/s could both interfere with the pancreatic beta cells and/or with insulin peripheral action.

Tumor markers in the diagnosis, monitoring and therapy of pancreatic cancer: state of the art.

The present review focuses on the utility of serum tumor markers in screening, diagnosis, prognosis and monitoring of pancreatic cancer. Serum determination of all tumor markers studied offers no help in screening or early diagnosis of pancreatic cancer. For diagnosis, blood group-related antigens, in particular CA 19-9, are considered the best indicators of this neoplasm. However, as occurs with other glycoproteic tumor markers, the circulating levels of CA 19-9 are significantly influenced by jaundice, probably because its liver metabolism is reduced. Therefore, the finding of elevated CA 19-9 levels in jaundiced patients has to be evaluated with caution. Since pancreatic cancer recurrences are not susceptible to treatment, the clinical role of widespread use of tumor marker determination in follow-up programs is limited and calls for a critical evaluation.

Altered lipid peroxidation/glutathione ratio in experimental extrahepatic cholestasis.

1. Lipid peroxidation can occur in the presence of a cellular antioxidant-oxidant imbalance, but the role of lipid peroxides in cholestasis is not well understood. 2. This study was undertaken in order to: (i) evaluate the behaviour of a product of lipid peroxidation (thiobarbituric acid-reactive species), and of an important antioxidant tripeptide, reduced glutathione, in the course of experimental extrahepatic cholestasis; and (ii) ascertain whether there was a link between this aspect and the alterations in liver morphology. 3. Forty-five male Sprague-Dawley rats (250-300 g) were double bile duct ligated and followed from 1 to 28 days. At the end of each experimental period, blood and liver samples were collected for thiobarbituric acid-reactive species and glutathione determinations. 4. Bile duct ligated rats showed a marked increase in liver weight which was related to cholestasis duration and to some anatomical alterations such as bile duct proliferation and dilation and liver fibrosis (periportal, perivenular, perineoductular and parenchymal). 5. An increase in serum lipid peroxidation was also observed but this was not linked to hepatic thiobarbituric acid-reactive species. Erythrocyte and hepatic glutathione decreased in relation to cholestasis duration. Serum lipid peroxides and erythrocyte glutathione were correlated with liver cell necrosis. 6. In conclusion, experimental extrahepatic cholestasis determines bile duct proliferation and fibrosis, the degree of which is directly related to the duration of cholestasis itself and to liver cell necrotic phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of octreotide acetate on pancreatic exocrine and endocrine functions after pancreatoduodenal resection.

In view of forecasting the effect of octreotide acetate (Sandostatin) in preventing fistula formation after pancreatic surgery, 9 patients, who had pancreatoduodenectomy 8-12 days before, underwent a 2-day study. The first day, by means of a catheter located in the jejunal loop separately anastomosed to the pancreatic remnant, basal and after secretin stimulation pancreatic secretion was evaluated. During the 2nd day the possible inhibitory effect of octreotide on basal and stimulated secretion was investigated. Under the experimental conditions of the study Sandostatin showed little effect on the water and bicarbonate increase as stimulated by secretin. A greater hormone inhibitory effect on amylase production and pancreatic endocrine function was seen. On the basis of these results the use of Sandostatin can hardly be seen as useful in preventing fistula formation after pancreatic resection.

Is CA242 really a new tumour marker for pancreatic adenocarcinoma?

CA 242, a sialylated carbohydrate epitope situated on the same macromolecule as CA 50 has been proposed as a new tumour marker for pancreatic cancer (PC). The aims of the present study were: (1) to evaluate serum CA 242 versus CA 19-9 in PC patients, and (2) to assess whether these markers can predict tumour spread or patient survival. We studied 59 healthy controls, 27 PC patients, 12 chronic pancreatitis cases, 107 with extra-pancreatic gastrointestinal tumours, 30 with benign jaundice and 24 with benign extra-pancreatic gastrointestinal diseases. Mean CA 242 values were significantly higher in PC than in any other group; CA 19-9 showed a similar pattern. The best diagnostic efficacy (ROC curves analysis) in diagnosing PC was 86% for CA 242 and 84% for CA 19-9, using cut-off values of 60 and 80 U/ml, respectively. In PC, serum levels of both markers were unrelated to tumour spread or size; in PC patients with high levels of CA 242 or CA 19-9 survival was significantly shorter. CA 242 and CA 19-9 were correlated both when considering all the patients together (r = 0.962, p < 0.001) and PC alone (r = 0.880, p < 0.001). Given the very close relationship between CA 242 and CA 19-9, we tested for cross-reactivity between CA 242 antigen and CA 19-9 antibody: CA 242 antigen with CA 19-9 antibody produced a similar curve to CA 242 antigen and its corresponding antibody. In conclusion, CA 242 showed similar diagnostic values to CA 19-9 in assessing PC patients; both seem unrelated to tumour size or spread, but seem to predict survival. Their remarkably similar behaviour is due to cross-reactivity between CA 242 antigen and CA 19-9 antibody, so CA 242 cannot, in our opinion, be considered a new tumour marker for PC.

Insulin-like growth factor-I, interleukin-1 alpha and beta in pancreatic cancer: role in tumor invasiveness and associated diabetes.

We evaluated levels of insulin-like growth factor-I and interleukin-1 alpha and beta in patients with pancreatic cancer; the role of these substances in tumor spread and in hyperglycemia was also investigated. Thirty pancreatic cancer patients (21 with hyperglycemia) were compared with others with diseases causing hyperglycemia [liver cirrhosis (14 cases, 12 with hyperglycemia), chronic pancreatitis (20 cases, 12 with hyperglycemia), type I diabetes mellitus (13 cases, all hyperglycemic)]. Insulin-like growth factor-I was significantly reduced in patients with liver cirrhosis, probably due to a reduced hepatic capacity for synthesis. It was increased in 6 of 30 pancreatic cancer patients; in these subjects it was correlated with alanine aminotransferase and C-peptide, but not with tumor diameter or the presence of metastases. Interleukin-1 alpha and beta were both elevated in pancreatic cancer patients. The former was high, while the latter was low when liver metastases were present. Neither was related to glucose or C-peptide levels. In summary, insulin-like growth factor-I levels are increased in some pancreatic cancer patients but this does not seem to favor tumor spread; however IGF-I could be involved influencing glucose homeostasis. Interleukin-1 alpha increased, while interleukin-1 beta decreased in pancreatic cancer patients with metastases, suggesting a different involvement of these two substances in pancreatic cancer spread.

Renal functional alterations in extrahepatic cholestasis: can oxidative stress be involved?

Renal function may be compromised by extrahepatic cholestasis. In this context, the nephrotoxic role of bile salts is well known. Recently, however, it has been claimed that other factors, such as lipid peroxides, are involved. We therefore created bile duct ligation in 40 Sprague-Dawley rats. During the follow-up (from 1 to 28 days), significant variations were found in liver histological parameters, but not in renal morphology. Fourteen days after ligation, significant increases were found in serum and urinary thiobarbituric-acid-reactive species and phospholipase A2 (indirect indices of lipid peroxidation), whereas 8-10 days after ligation, a significant decrease was observed in erythrocytic and hepatic GSH levels. The variations in urinary thiobarbituric-acid-reactive species and in phospholipase A2 were not correlated with concomitant variations in the sera. Urinary lipid peroxides were directly correlated with the degree of liver morphological alterations and inversely with circulating GSH. Urinary outputs of lipid peroxides, phospholipase A2 and N-acetyl-glucosaminidase were correlated with each other. These results suggest that there is an imbalance in the oxidative-antioxidant hepatic system in experimental extrahepatic cholestasis. The reduced bioavailability of blood GSH may alter the oxidative equilibrium in other organs, such as the kidney, triggering and favoring the lipoperoxidative cascade.

Diabetes mellitus in pancreatic cancer follow-up.

The aim of this study was to assess the behavior of fasting serum glucose, C-peptide levels and OGTT in pancreatic cancer follow-up. We studied 49 patients with pancreatic cancer (stage I = 8 pts; II = 16 pts; III = 12 pts; IV = 13 pts). At diagnosis 13/49 patients had fasting serum glucose levels of above 140 mg/dL. Of the remaining 36 pts, 22 underwent OGTT, which indicated diabetes mellitus in 9/22 (41%) and impaired glucose tolerance in 7/22 (32%) cases. C-peptide basal values were within the normal range (0.8-2.0 micrograms/L) in 14/49 (28%), above 2.0 micrograms/L in 6/49 (13%) and below 0.8 micrograms/L in 29/49 (59%) of the cases. No significant correlation was found between tumor stage or size and the presence of diabetes or of a reduced glucose tolerance. Twenty-four patients underwent curative resection (group 1) and 16 palliative resection, while the remaining nine did not undergo surgery (group 2). Group 1 and 2 patients had a follow-up of 2 to 40 months (mean = 14 months) and from 1 to 7.5 months (mean = 3.5 months) respectively. In group 1 patients no significant difference was found between pre- and post-operative fasting serum glucose levels. However, in 11/15 (73%) patients who underwent OGTT before and after surgery, an improvement in glucose tolerance was observed after tumor resection. In group 2 patients, a significant increase in fasting serum glucose levels was found during follow-up. In neither of the groups studied were significant variations found in C-peptide levels during the follow-up, although a slight increase was observed in patients who did not undergo surgery. In conclusion, the reduced glucose tolerance or frank diabetes mellitus, which frequently occurs during the onset of pancreatic cancer, does not seem to be related to tumor stage or size. Curative resection ameliorates glucose intolerance, while tumor persistence can enhance serum glucose levels.

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.

Lipid peroxidation and renal tubular damage in chronic pancreatic diseases: is there any relationship?

Lipid peroxidation is one of the most important expression of oxidative stress induced by oxygen-derived free radicals. Here we evaluate the behavior of malondialdehyde (MDA) in the serum and urine from patients with chronic pancreatic diseases, with respect to patients with extra-pancreatic digestive diseases and glomerulonephritis. Serum and urinary phospholipase A2 (PLA2) activity was also determined, since this enzyme contributes to damage of plasma membranes. MDA and PLA2 levels increased in the sera from most of the patients with pancreatic and extra-pancreatic digestive diseases. In glomerulonephritis, pathological MDA levels (36%), but not PLA2 levels, were found. Serum MDA correlated with gamma-glutamyl transpeptidase (GGT), while PLA2 correlated with alanine-phosphodiesterase (ALP), GGT, alanine-aminotransferase (ALT) and creatinine. In urine, MDA and PLA2 behaved differently from the corresponding serum values. MDA increased in some patients with pancreatic cancer, extra-pancreatic diseases and glomerulonephritis. PLA2 levels did not significantly vary between groups. Urinary MDA correlated with some indicators of renal tubular damage [urinary ribonuclease, beta-2-microglobulin (B-2-M) and N-acetyl-glucosaminidase (NGA)] and with serum bilirubin. Urinary PLA2 correlated only with ribonuclease (RNase). We conclude that serum MDA increases aspecifically in pancreatic and extra-pancreatic diseases, probably reflecting an aspecific phlogistic phenomenon; PLA2, although sharing a similar pattern with MDA, seems mainly related to hepato-biliary damage. Urinary MDA reflects the presence of renal tubular damage, which may be the cause or a consequence of lipid peroxidation; little variations in PLA2 are recorded in urine, and mainly reflect the presence of impaired tubular function.

C-peptide pattern in patients with pancreatic cancer.

The pathogenetic mechanism underlying glucose intolerance in pancreatic cancer is still unclear. We studied the pattern of three glucose regulating hormones (C-peptide, glucagon and GH) in pancreatic cancer patients with (N = 34) and without (N = 8) hyperglycemia, and compared the findings made with those from subjects with other hyperglycemic conditions of well-known origin [type I diabetes mellitus (8 cases) and diabetes mellitus secondary to chronic pancreatitis (13 cases) or liver cirrhosis (4 cases)]. In hyperglycemic pancreatic cancer patients, C-peptide was absent in 26% of the cases, reduced in 24%, elevated in 29% and within the normal range in the remaining 21%. In normoglycemic pancreatic cancer this hormone was reduced in two cases (25%) and within the normal range in all the others. GH was within the normal range in all cases: glucagon was below the normal range in some hyperglycemic pancreatic cancer patients (41%) or within the normal range in all the remaining patients. No correlations were found between the three hormones when findings from subjects were considered all together. However, in pancreatic cancer C-peptide and glucagon presented consensual variations. C-peptide, glucagon and GH levels were not related to tumor volume; glucagon was found to be associated with liver metastases. C-peptide was correlated with serum ALT and ALP. We may conclude that hyperglycemia associated with pancreatic cancer may be caused by different mechanisms. In some cases a reduced secretion of both insulin and glucagon was observed, as occurs in chronic pancreatitis. In the majority of patients, beta cell function appears normal, and the hyperglycemic state may depend on an altered peripheral sensitivity to insulin due to the pancreatic pathology itself or to consensual liver involvement.

Increased serum phospholipase A2 activity in advanced chronic liver disease as an expression of the acute phase response.

Phospholipase A2 (PLA2) modifications were investigated in patients with acute and chronic liver diseases, PLA2 variations were related to indices of liver function as well as to parameters of the acute phase response. Serum PLA2 activity modifications were fluorimetrically measured in 105 patients affected by acute and chronic liver diseases or extra-hepatic diseases. One-way ANOVA demonstrated a significant difference among groups (F = 4.53, P < 0.001); Bonferroni's test for pairwise comparisons showed that patients with hepatocellular carcinoma had higher mean values than subjects with benign extra-hepatic diseases (P < 0.01) and mild chronic liver disease (P < 0.05). Multiple regression analysis, performed choosing PLA2 as the dependent variable and blood urea nitrogen, C-reactive protein, alkaline phosphatase and alpha 1-fetoprotein as predictor variables was significant (multiple R = 0.7056, multiple R2 = 0.4978, F = 15.36, P = < 0.0001). The standardized regression coefficients found to be significant were those of C-reactive protein, blood urea nitrogen and alpha 1-fetoprotein. In conclusion, in patients with chronic liver disease, serum PLA2 activity increases parallel to disease severity and accompanies the expression of proteins of the acute phase response that, like PLA2 activity, increase in serum while liver synthesis declines.

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 micrograms/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.