Prevalence of intestinal metaplasia in the distal oesophagus, oesophagogastric junction and gastric cardia in symptomatic patients in north-east Italy: a prospective, descriptive survey. The Italian Ulcer Study Group "GISU".

BACKGROUND: Incidence of adenocarcinoma of distal oesophagus and gastric cardia, probably arising from areas of intestinal metaplasia, has been increasing rapidly. AIMS: To define prevalence of intestinal metaplasia of distal oesophagus, oesophagogastric junction and gastric cardia and to evaluate potential associated factors, by means of a prospective multicentre study including University and teaching hospitals, and primary and tertiary care centres. PATIENTS: Each of 24 institutions involved in study enrolled 10 consecutive patients undergoing first-time routine endoscopy for dyspeptic symptoms. METHODS: Patients answered symptom questionnaires and underwent gastroscopy Three biopsies were taken from distal oesophagus, oesophago-gastric junction and gastric cardia, and were stained with haematoxylin and eosin. Specimens were also evaluated for Helicobacter pylori infection. RESULTS: A total of 240 patients (124 male, 116 female; median age 56 years, range 20-90) were enrolled in study. Intestinal metaplasia affected distal oesophagus in 5, oesophago-gastric junction in 19 and gastric cardia in 10 patients. Low-grade dysplasia was found at distal oesophagus and/or oesophago-gastric junction of 3/24 patients with intestinal metaplasia vs 2/216 without intestinal metaplasia (p<0.05). A significant association was found between symptoms and presence of intestinal metaplasia, regardless of location, and between Helicobacter pylori infection and intestinal metaplasia at oesophago-gastric junction. CONCLUSIONS: Intestinal metaplasia of distal oesophagus, oesophagogastric-junction and gastric cardia is found in a significant proportion of symptomatic patients undergoing gastroscopy and is associated with dysplasia in many cases. Although prevalence of dysplasia seems to decrease when specialized columnar epithelium is found in short segment, or even focally in oesophago-gastric junction, these small foci of intestinal metaplastic cells may represent source of most adenocarcinomas of cardia.

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.

Ki-67 and c-jun expression in pancreatic cancer: a prognostic marker?

The proto-oncogene c-jun is involved in cell proliferation and Ki-67 antigen permits determination of the proportion of proliferating tumour cells. The expression of c-jun and Ki-67 in pancreatic cancer and their relation with tumour histological features and patients survival were evaluated. Specimens were obtained as follows: 14 pancreatic cancer from patients radically operated, 8 liver metastases from subjects submitted to palliation, 5 normal pancreas from organs donors and 5 chronic pancreatitis. Ki-67 and c-jun were studied by immunohistochemistry. The percentage of tumour cells stained for c-jun was increased in 11/14 cases. A high c-jun expression was more frequently found in liver metastases than in pancreatic cancer tissue (p=0.031). The frequency of high c-jun expression was more elevated in short-term as compared to long-term survivors (Fisher's exact test, p=0.031 and log-rank, p=0.03). The percentage of tumour positive cells for Ki-67 showed a mean value of 12.8% in primary pancreatic cancer and was lower than in the liver metastases (32.5%) (p=0.029). Significantly lower values were found in long-term (6.5%) as compared to the short-term survivors (18.1%) (p=0.032 and log-rank, p=0.006). A positive relation was demonstrated with stage (p<0.05), lymph node state (p=0.045) and perineural invasion (p=0.0001). In the multivariate analysis the Ki-67 staining was the most important determinant of long-term survival (p=0.005). c-jun and Ki-67 are overexpressed in pancreatic carcinoma, but only Ki-67 is a strong predictive factor.

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.

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.

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.

Natural history of gallstones in non-insulin-dependent diabetes mellitus. A prospective 5-year follow-up.

This prospective study was undertaken to assess the natural history of gallstones in patients with non-insulin-dependent diabetes. Four hundred forty outpatients with diabetes mellitus were studied; 81 of these had gallstones diagnosed by ultrasound. On the basis of the information they gave, they were divided into two groups: A, asymptomatic; and B, symptomatic (previous episode(s) of biliary pain) at recruitment. Five years after diagnosis, the patients were recalled and questioned about their symptoms. Three of 81 could not be traced and eight had died from diseases not related to gallstones. Seventy were finally evaluated, 47 belonging to group A, 23 to group B. The cumulative percentage of initially asymptomatic patients who presented with biliary pain or complications during the follow-up was 14.9% (4.2% for complications). Of group A patients, 17% underwent cholecystectomy (one prophylactic, six elective and two emergency). One patient (2.1%) died after operation of obstructive jaundice. Of group B patients, 47.8% had biliary symptoms or complications (8.7% cholecystitis); 21.7% were operated (17.4% elective, 4.3% emergency cholecystectomy). Since few patients with asymptomatic gallstones and non-insulin-dependent diabetes mellitus develop pain or complications over time, prophylactic cholecystectomy is probably not advisable.

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.

Clinical utility of TPS, TPA and CA 19-9 measurement in pancreatic cancer.

UNLABELLED: The aims of this study were to (1) evaluate the diagnostic utility of a new tumor marker, TPS, with respect to TPA and CA 19-9 in patients with pancreatic cancer; (2) ascertain the reliability of the markers in predicting survival, and (3) evaluate the effect of liver dysfunction on the results. CA 19-9, TPA and TPS were measured in the serum of 19 control subjects, 42 patients with pancreatic cancer, 29 with chronic pancreatitis, and 52 with extrapancreatic diseases. CA 19-9 was confirmed to be the best serological indicator of pancreatic cancer, while TPA and TPS lacked both sensitivity and specificity. Pancreatic cancer patients with liver metastases had higher mean CA 19-9 and TPA, but not TPS, values than pancreatic cancer patients without metastases. A shorter survival time was associated with the presence of liver metastases and with higher serum tumor marker levels. CA 19-9, TPA and TPS were found to be correlated with liver function test results (ALT, ALP and bilirubin). IN CONCLUSION: (1) TPS adds no significant information to that obtained using CA 19-9 in the diagnosis of pancreatic cancer; (2) CA 19-9 and TPA, but not TPS, are influenced by the presence of liver metastases; (3) the main factor to influence survival is advanced disease, which is in turn associated with higher tumor marker levels, and (4) liver dysfunction can influence not only CA 19-9 and TPA, as already described, but also TPS.

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.

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.

Biochemical and histopathological aspects in duodenogastric reflux gastritis patients with or without prior cholecystectomy.

The aim of this study was to evaluate some biochemical and histopathological aspects in a group of patients with a view to identifying any differences depending on whether the pathology was associated with previous cholecystectomy or idiopathic. The study involved 23 patients (8 post-cholecystectomy cases and 15 ulcer-free dyspeptic patients) with the diagnosis of duodenogastric reflux gastritis confirmed by endoscopic histopathological evaluation. The following parameters were considered: 1. pH and bile salt concentration in gastric juice; 2. histological classification of antral biopsies (Niemela's criteria); 3. dyspeptic symptoms (dyspepsia, pyrosis and epigastric pain, sense of repletion, foul-tasting mouth) graded on a scale from 0 to 4. All parameters were considered in relation to whether or not Helicobacter Pylori was found in the histological specimens. No significant differences were found between the two groups for pH and bile salt values or for Helicobacter Pylori positivity. No relationship was observed between the Helicobacter Pylori and either the severity of the histological picture, the features of the biochemical parameters or the severity of the clinical symptoms. Such findings confirm the common pathophysiological pattern of reflux gastritis regardless of any permanent biliary tract alterations and the low importance of Helicobacter Pylori infection in determining this syndrome.

Extra-hepatic cholestasis determines a reversible increase of glycoproteic tumour markers in benign and malignant diseases.

This study was performed in order to assess the relative role of cholestasis in increasing some serum glycoproteic markers of malignancy (CA 19-9, TPA, CEA). 30 Patients with benign and 16 with malignant extra-hepatic cholestasis were studied on admission (stage A) and after the operative or spontaneous resolution of the cholestatic picture (stage B). CA 19-9 and TPA were found to be lower in stage B than in stage A benign diseases. A similar behaviour was found in malignant diseases, although findings were significant only for CA 19-9. In neither of the patient groups was CEA found to present a significant trend. Extra-hepatic cholestasis appears able to increase per se serum glycoproteic markers in benign diseases, with variations proportional to the severity of the clinical picture. The same considerations can apply to malignancies, even if in these situations the production of tumour markers by the neoplastic growth should also be considered. We should therefore be cautious in assessing the diagnostic usefulness of new tumour markers when cholestasis is present.

Computed tomography in the identification of gallstones likely to respond to UDCA.

An unusual case of a patient with two biliary stones of different densities that responded differently to oral litholytic treatment with ursodeoxycholic acid (UDCA) is reported. The findings confirm, in an unusual experimental model, that CT is useful in the selection of those stones which have a high probability of dissolution under treatment with oral bile acids.

Acute reflux pancreatitis in rats: a comparison between two experimental models.

This study was undertaken in order to compare the reliability of two acute reflux pancreatitis models in rats, one performed by positioning a silicon tube in the duodenum and the other by creating a gastro-jejunal anastomosis. In two groups (A = 10 and B = 10 rats) a silicon tube was positioned in the duodenum; in the remaining two groups (C = 12 and D = 6 rats) a latero-lateral antecolic anisoperistaltic gastro-jejunal anastomosis was performed 30 days before surgery. A closed duodenal loop was created for 12 hours in groups A and C but not in B and D. Rats in both groups A and C developed acute pancreatic inflammation of a mild degree. Sham operated rats with silicon tube placement had higher histological damage scores than those with gastro-jejunal anastomosis. The difference found between the two groups of rats which underwent gastro-jejunal anastomosis was more marked than that between the two groups which had silicon tube placement. It was concluded that the creation of a gastro-jejunal anastomosis is probably the safer procedure to allow gastro-intestinal flow in acute reflux pancreatitis in rats.