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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.

This study was performed to investigate the behavior of phospholipase A2 (PLA2) in serum and urine of patients with chronic pancreatic diseases and to ascertain whether any factors influenced the results. In 30 controls, 45 patients with pancreatic cancer, 54 with chronic pancreatitis, and 64 with extrapancreatic diseases, serum and urinary PLA2, pancreatic isoamylase and RNase, and urinary N-acetylglucosaminidase (NAG) were measured. Serum PLA2 levels were higher in patients with chronic pancreatitis than in all the other groups. In our patients, only occasionally was urinary PLA2 elevated, the increase occurring almost exclusively in the presence of an acute inflammatory disease, e.g., relapsed chronic pancreatitis or active inflammatory bowel disease. A correlation was found between serum PLA2 and serum RNase, an indicator of tissue damage, but not between serum PLA2 and pancreatic isoamylase. Urinary PLA2 output was correlated with its renal input and with RNase output. No correlation was found between PLA2 output and pancreatic isoamylase or NAG urinary excretion. In conclusion, (1) the determination of serum PLA2 activity may be an aspecific test of pancreatic disease; (2) PLA2 urinary excretion occasionally increases, especially in the presence of severe phlogosis, which occurs in chronic pancreatitis, in particular during relapse; and (3) irrespective of the tissue origin of urinary PLA2, its increased excretion may be accounted for in part by its increased circulating levels. It is, however, more likely the consequence of a renal tubular dysfunction, which is sometimes found in patients with pancreatic diseases.

In the last decades several markers of pancreatic neoplasia have been proposed to obtain a diagnosis as earlier as possible. Prerequisites of a good tumor marker are high sensitivity and specificity. Among the various substances, serum determination of pancreatic enzymes has been found of no utility in early diagnosis of pancreatic cancer, due to its lack in sensitivity and specificity. Similar results with ribonuclease and deoxyribonuclease. Oncofetal antigens (CEA and POA) have been initially considered promising indices; however, further studies showed their limits. In particular CEA is greatly influenced by the presence of hepatic metastases; therefore, serum levels are detectable only in advanced stages. TPA is characterized by a high sensitivity, but lacks in specificity and its use is now avoided. A real progress in the field of tumor markers has been made in the last years with the monoclonal antibody technique: among them CA 19-9 showed a good sensitivity and a satisfactory specificity as regards the diagnosis of pancreatic cancer. However, it cannot be considered as absolute aid, since it is influenced by several factors, as tumor spread, jaundice and liver dysfunction.

The usefulness of serum DU-PAN-2 in diagnosing pancreatic cancer and in distinguishing between this cancer and other benign and malignant diseases, and to assess the role of liver dysfunction in altering the serum levels of this marker were investigated. DU-PAN-2 was measured in the sera of 31 patients with pancreatic cancer, 32 with chronic pancreatitis, 20 with benign and 21 with malignant extra-pancreatic diseases. DU-PAN-2 was found to be above 300 U ml-1 in 21/31 patients with pancreatic cancer (sensitivity 68%). Only 3/32 patients with chronic pancreatitis had abnormal values. A substantial number of patients with both benign and malignant extra-pancreatic diseases had an elevated serum DU-PAN-2 (9/20 and 15/21, respectively). Correlations were found between DU-PAN-2 and (1) total bilirubin, (2) alanine-amino-transferase and (3) alkaline phosphatase. Of the patients with high DU-PAN-2 values, jaundice was found in: 2/3 with chronic pancreatitis, 9/10 with benign and 12/14 with malignant extra-pancreatic diseases. In conclusion, the serum DU-PAN-2 test for pancreatic malignancy is not completely satisfactory, because it is not sensitive enough. While the test for chronic pancreatitis has an acceptable specificity, the assay cannot distinguish between pancreatic cancer and other extra-pancreatic diseases, mainly of the liver and biliary tract. Liver dysfunction as well as jaundice seem to considerable affect the levels of this marker, as reported elsewhere for CA 19-9.

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 extra-hepatic cholestasis, possibly due to interference with the hepatic clearance of glycoproteins and destruction of ductal biliary epithelium.

Serum ferritin, prealbumin, pseudocholinesterase, alpha-1-antitrypsin and caeruloplasmin were determined in control subjects and patients with pancreatic cancer, chronic pancreatitis or extra-pancreatic disease mainly of gastrointestinal origin, in order to investigate the different hepatic changes which influence serum ferritin in chronic pancreatic and other digestive diseases. Increased circulating ferritin was found in pancreatic cancer and extra-pancreatic disease when compared to controls. Correlations were detected between ferritin and the other proteins investigated and between ferritin and total bilirubin, alkaline phosphatase and alanine aminotransferase. Multiple regression analysis demonstrated that cholestasis accounts for 45% of circulating ferritin, the acute-phase response accounted for 18% and decreased liver function accounted for 11%. We conclude that the increase in serum ferritin in chronic pancreatic and other gastrointestinal diseases largely depends on liver changes, with cholestasis probably playing a primary role.

A new tumour marker, CAR-3, was isolated using the monoclonal antibody technique and measured in the sera of 27 patients with pancreatic cancer, 25 chronic pancreatitis, 30 extra-pancreatic diseases and in that of 18 healthy controls in order (1) to evaluate the diagnostic role of CAR-3 in patients with pancreatic cancer and (2) to ascertain whether liver dysfunction influences CAR-3 serum levels. The increased levels were found in 12/27 patients with pancreatic cancer (sensitivity 44.4%). No increase was found in patients with chronic pancreatitis, whereas abnormal levels were found in patients with other gastrointestinal diseases, especially those of the liver and biliary tract. Correlations were found between serum CAR-3 and (1) total bilirubin and (2) alkaline phosphatase. In conclusion, CAR-3, an antigen structurally related to CA 19-9, does not appear to be accurate enough to be considered a tumour marker. Cholestasis seems to increase CAR-3 levels as well as those of other glycoproteic tumour markers, probably by interfering with the hepatic clearance of these substances.

Variations in urinary kallikrein in pancreatic diseases were ascertained, and possible influencing factors were investigated. Serum amylase and urinary excretion of glandular kallikrein, pancreatic ribonuclease (RNase), gamma-glutamyltransferase (GGT) and amylase were measured in 24 control subjects, 39 patients with pancreatic cancer, 49 with pancreatitis and 63 with extra-pancreatic diseases. Urinary kallikrein was found to be elevated in a substantial number of patients with pancreatitis. Higher levels were detected in patients with a relapse, which was diagnosed using clinical and biochemical examinations. RNase was also increased in a high number of patients with pancreatic diseases, but was not correlated with pancreatic damage. In patients with pancreatitis, a correlation was found between urinary kallikrein and RNase excretions. No correlations were found between kallikrein and serum or urinary amylase and GGT. We can conclude that urinary kallikrein excretion increases in pancreatitis, especially when a phlogistic involvement of the pancreas is present; this condition may lead to a release of this ultrafiltrable enzyme in the circulation. Renal tubular damage, which determines a reduced reabsorption of this enzyme, seems to play a concomitant but minor role in this process.

This study was performed in order to evaluate the role of various local and systemic alterations in influencing serum glycoproteic markers in patients with pancreatic cancer, and in healthy and diseased controls. Cancer antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), and ferritin were determined in the sera of 23 control subjects, 30 patients with pancreatic cancer, 27 with chronic pancreatitis, and 27 with extra-pancreatic diseases mainly of gastrointestinal origin. A number of acute-phase proteins and indices of liver function and cholestasis were also assayed. The three antigens increased only in patients with pancreatic cancer. Higher CA 19-9 and CEA, but not ferritin, levels were found only in patients with hepatic metastases. Acute-phase proteins and synthetic functional indices were found to be higher and lower, respectively, in patients with pancreatic malignancy when compared with controls. Multiple regression analysis documented the dependence of circulating ferritin, but not of CA 19-9 and CEA, on the systemic indices. Canonical correlation showed a similar trend for CA 19-9 and CEA, which differed from that of ferritin. Ferritin was found to depend on the presence of systemic and hepatic alterations, especially of cholestasis. We can conclude that the variations of serum glycoprotein markers in patients with pancreatic cancer depend on various regional and systemic factors. CA 19-9 and CEA are related mainly to the extent of the neoplasia. The influence of a decreased liver function capacity associated or not to cholestasis and the interrelation with the acute-phase response may also be suggested. Ferritin, on the other hand, is related to a higher degree than CA 19-9 and CEA to hepatic dysfunction and also behaves similar to an acute-phase protein.

The aim of this study was to compare the utility of two recently identified tumour markers of pancreatic cancer, CA 19-9 and CAR-3, and to ascertain the roles of some factors influencing both antigens. CA 19-9 and CAR-3 were measured in sera of 18 control subjects, 27 patients with pancreatic cancer, 25 with chronic pancreatitis, and 29 with extra-pancreatic diseases. CA 19-9 and CAR-3 were, respectively, found to be increased in 85 per cent and 44 per cent of patients with pancreatic cancer, 28 per cent and 0 per cent with chronic pancreatitis and 72 per cent and 28 per cent with extra-pancreatic diseases. The ROC curves showed that, for any serum value considered, CA 19-9 is more effective than CAR-3 in discriminating between pancreatic cancer and control subjects and chronic pancreatitis. With the combined use of both antigens the results were no better than those given by CA 19-9 alone. Correlations were found between liver function tests and CA 19-9 levels and between cholestasis indices only and CAR-3 values. Our findings show that CAR-3 is not a sufficiently reliable marker of pancreatic cancer, due to its low sensitivity. Nor does it offer any more information than CA 19-9. Both assays are influenced, at least in part, by the extent of the neoplasia. Cholestasis which can greatly influence a serum glycoproteic marker such as CA 19-9, was found also to affect, to a lesser extent, CAR-3, an epitope on the same mucin molecule.

To ascertain modifications in the activation products derived from oxygen free radicals in patients with chronic pancreatic and extra-pancreatic diseases, lipid peroxide activity was measured in the sera of 40 control subjects, 28 patients with pancreatic cancer, 49 with chronic pancreatitis, and 53 with extra-pancreatic diseases. In 142 of the subjects, elastase 1, amylase, and pancreatic isoamylase activities were also determined. Increased lipid peroxide activities were found in some patients with both chronic pancreatic and extra-pancreatic diseases. Patients with chronic pancreatitis studied during relapse had higher activities of lipid peroxides than those without active disease. No difference was found between the values in patients with pancreatic cancer with liver metastases and those without. Correlations were found between lipid peroxides and both amylase and pancreatic isoamylase activities; no correlation was detected between lipid peroxides and elastase 1. In benign biliary tract disease a correlation was detected between lipid peroxides and alanine aminotransferase and alkaline phosphatase activities. In all patients, however, a correlation was found between alkaline phosphatase and lipid peroxide activities. It is concluded that activation of oxygen derived free radicals occurs in chronic pancreatic as well as in extra-pancreatic disease; it seems to reflect the degree of inflammation.

Serum CA 19-9 was determined in 83 control subjects, 99 patients with pancreatic cancer, 104 with chronic pancreatitis and 137 with extra-pancreatic diseases mainly of gastrointestinal origin in order to evaluate whether hepatic factors can influence circulating CA 19-9 in pancreatic cancer. Sensitivity, specificity and accuracy of this test in determining pancreatic malignancy were: 74%, 83% and 57%. We divided patients into two groups: group A (159 cases) and group B (181 cases) with and without anatomical liver damage (presence of primary or metastatic cancer, cirrhosis, hepatitis, steatofibrosis, cholangitis). Group A presented higher CA 19-9 values as compared to group B. Significant correlations were found in group B but not in group A between CA 19-9 and ALT, ALP and total bilirubin. Multiple regression analysis (CA 19-9 dependent and ALT, ALP and total bilirubin predictor variables) was significant only in group B. The standardized partial regression coefficients found to be significant were those of ALP and total bilirubin. We can conclude that CA 19-9 is an index of pancreatic cancer with satisfactory sensitivity and specificity. The presence of anatomical liver damage seems to increase the value of this index, probably releasing CA 19-9 into the bloodstream. Extra-hepatic cholestasis may also be an important factor in elevating CA 19-9 probably by reducing the hepatic catabolism of this glycoprotein.

In order to evaluate the renal metabolism of amylase and immunoreactive trypsin (IRT) in chronic pancreatic disease, we assayed amylase, IRT and creatinine in serum and urine and gamma-glutamyl transferase (GGT) in dialyzed urine as well as alpha-glucosidase (AGL) and ribonuclease (RNase) in 24 control subjects, 34 patients with pancreatic cancer, 52 with chronic pancreatitis and 32 with extra-pancreatic diseases. Urinary amylase and IRT outputs were found to be more elevated in chronic pancreatitis than in control subjects. The levels of serum amylase, its renal inputs and outputs were correlated with the corresponding IRT values. Multiple regression analyses (dependent on amylase or IRT urinary outputs, circulating levels of the two enzymes, creatinine clearance and the excretion of GGT, AGL and RNase predictor variables) showed significant correlations. The standardized partial regression coefficients found to be significant were: GGT, RNase and serum amylase for amylase, and GGT and RNase for IRT. No difference was found between amylase and IRT outputs in patients with chronic pancreatitis, taking the presence or the absence of alcohol abuse, exocrine insufficiency and pancreatic pseudocysts into consideration. Urinary GGT excretion correlated with serum amylase and IRT levels.(ABSTRACT TRUNCATED AT 250 WORDS)

In patients with pancreatic cancer deoxyribonuclease I (DNase I) serum levels were compared with those of other known pancreatic enzymes. Serum deoxyribonuclease I, elastase 1, immunoreactive trypsin, amylase and phospholipase A2 were determined in 40 healthy controls, 28 patients with pancreatic cancer, 49 with chronic pancreatitis and 40 with extra-pancreatic diseases. The analysis of variance showed a significant difference among groups for serum DNase I values. However, none of the 3 groups of patients had a mean deoxyribonuclease I value higher than that of the healthy controls. In pancreatic cancer and chronic pancreatitis patients, increases in the 4 pancreatic enzymes values were found in percentages that were higher than those for DNase I. A significant correlation was found between DNase I and phospholipase A2, but not between DNase I and elastase 1, immunoreactive trypsin and amylase serum activities. The findings indicate that deoxyribonuclease I serum determination is an even less satisfactory index of pancreatic malignancy than the other pancreatic enzymes. Rather than expressing pancreatic damage, any variations in this enzyme appear more likely to reflect an aspecific phenomenon.

Serum C reactive protein was determined in 30 control subjects, 32 patients with pancreatic cancer, 28 with chronic pancreatitis and 23 with extra-pancreatic diseases of the upper gastrointestinal tract. The aim was to ascertain possible alterations of this index in chronic pancreatic disease and to speculate on some influencing factors. Higher C reactive protein levels were found in pancreatic cancer as compared to controls. Pancreatic cancer patients with systemic metastases had higher levels of this index compared to those with non-metastatic disease. Raised concentrations of C reactive protein were detected in 7/28 subjects with chronic pancreatitis. In this group these higher levels were found in patients in a relapsing phase of the disease; no association was observed with pancreatic pseudocysts. Among all subjects a correlation was found, between C reactive protein and age; patients with abnormal fasting blood glucose levels or increased white blood cell count had higher levels of this protein as compared to the remaining patients. We may conclude that C reactive protein increases in pancreatic cancer, specially in relation to tumour extent; in chronic pancreatitis it reflects the inflammatory status of the gland. While acting in the context of the acute phase response, this test may provide an adjunct in evaluating patients with a chronic pancreatic disease.

Serum RBP, prealbumin, and zinc were evaluated in normal subjects and patients with pancreatic cancer and chronic pancreatitis. A significant decrease of RPB was found in pancreatic cancer patients compared with controls. A concomitant reduction of prealbumin and zinc was also observed. Multiple regression analysis suggested that the modification of RBP serum levels might be accounted for mainly by diminished prealbumin levels, while the direct role of zinc is negligible.

Serum ferritin, described as increased in patients with pancreatic cancer, was studied in 109 subjects by an immunoradiometric technique in order to assess its reliability in detecting pancreatic malignancy. A significant increase of serum ferritin was found in pancreatic cancer as compared to controls (p less than 0.01), to calcifying (p less than 0.05), non-calcifying (p less than 0.05), and recurrent (p less than 0.01) chronic pancreatitis. Nevertheless, high levels of serum ferritin were found in 10 out of the 36 chronic pancreatitis patients and in 10 out of the 26 patients with non-pancreatic diseases, whilst values within the normal range were detected in 6 out of the 22 pancreatic cancer patients. These data suggest that serum ferritin, although frequently increased in pancreatic cancer, cannot be considered a marker of pancreatic malignancy.

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.

In order to investigate the role of circulating free trypsinogen and renal tubular dysfunction in affecting trypsin plasma-urine transfer, serum immunoreactive trypsin (IRT), its urinary output, IRT molecular size distribution, filtrable immunoreactive trypsin, gamma-glutamyltransferase and alpha-glucosidase outputs were studied in 6 control subjects, 9 patients with pancreatic cancer and 15 with chronic pancreatitis. The majority of immunoreactivity was always eluted at a molecular weight of about 24,000 and might therefore be considered as free trypsinogen. Variable amounts of IRT at higher molecular weights, possibly represented by trypsin-inhibitor complexes, were also detected. Increasing IRT levels were generally accounted for by free trypsinogen, regardless of the nature of the disease. Unlike serum free trypsinogen levels, renal tubular damage, evaluated by means of the excretion of two high-molecular weight urinary enzymes, seems to play a prominent role in explaining trypsin plasma-urine transfer.

The study of cytology in duodenal and/or pure pancreatic juice has been proposed in the differential diagnosis of pancreatic cancer. In our experience the sensitivity of cytology in duodenal juice, collected during Secretin-Cholecystokinin test, in diagnosing pancreatic cancer was 66.6%. False positive results were obtained only rarely (1.4%) in patients with chronic pancreatitis and benign diseases of the gastrointestinal tract. The cytological evaluation of pure pancreatic juice, obtained by ERCP, increases sensitivity up to 80-90%, especially when the combination of the results of ERCP and cytology is performed. Cytological examination of duodenal and/or pure pancreatic juice is a useful tool in detecting pancreatic malignancy and in differential diagnosis with chronic pancreatitis.

In this paper the clinical usefulness of CEA and ferritin in the diagnosis of pancreatic cancer was pointed out. CEA was found to be increased in 51% of patients with pancreatic cancer; it was also abnormal in 22% of chronic pancreatitis and 31% of extra-pancreatic diseases. In patients with metastatic pancreatic cancer CEA was found to be more elevated than in those with localized tumor. CEA correlated with the age of the subjects in all material; in liver cirrhosis with IgG and in extra-pancreatic gastro-intestinal malignancies with alkaline-phosphatase. Ferritin was found to be increased in 73% of pancreatic cancer patients; it was also abnormal in 40% of chronic pancreatitis and in 38% of extra-pancreatic diseases. Patients with chronic pancreatitis studied during a relapsing phase all had elevated serum ferritin. We can conclude that neither CEA nor ferritin are useful indices of pancreatic malignancy, due to the lack of sensitivity or specificity. Both are influenced by several factors: CEA mainly by age and liver dysfunction, ferritin by the presence of an acute inflammation with cell necrosis.

Elastase 1 and immunoreactive trypsin were assessed by a RIA technique in the sera of 29 control subjects, 24 pancreatic cancer patients, 22 patients with chronic pancreatitis and 31 with extra-pancreatic diseases to ascertain and compare their usefulness in chronic pancreatic disease diagnosis. Increased levels of elastase 1 were detected in 60.9% of pancreatic cancer and in 61.1% of chronic pancreatitis patients; low values were found in only two subjects with pancreatic disease. A close correlation between the two enzymes was found in patients suffering from pancreatic cancer and chronic pancreatitis. These data suggest that serum elastase 1, as well as immunoreactive trypsin, is of limited value in chronic pancreatic disease diagnosis; increased levels of the two enzymes always occur simultaneously; low immunoreactive trypsin values together with normal elastase 1 serum levels are detectable in a number of patients with chronic pancreatitis and severe exocrine insufficiency.

Serum copper and zinc levels and their ratio were evaluated in 48 control subjects, 29 patients with pancreatic cancer, 46 with chronic pancreatitis and 32 with extra-pancreatic diseases, with the purpose of ascertaining modifications in chronic pancreatic disease. Hepatic involvement and age were also investigated as possible factors influencing results. Cu/Zn ratio was found to be significantly increased in pancreatic cancer (2.66 +/- 0.16, mean +/- SE) as compared to controls (1.39 +/- 0.06, p less than 0.001), chronic pancreatitis (1.82 +/- 0.09. p less than 0.001) and extra-pancreatic diseases (1.81 +/- 0.18, p less than 0.001), but without practical clinical value. Serum zinc levels appear to decrease with age, while copper and Cu/Zn ratio increase. However, covariance analysis demonstrated that age does not play an important role in influencing copper and Cu/Zn ratio. A decreased liver synthetic function, at least in part age-related, seems to be an additional factor in decreasing serum zinc values.

In order to assess the value of serum markers and simple clinical data in the differential diagnosis of pancreatic cancer, we studied 32 control subjects and 28 patients with pancreatic cancer, 26 with chronic pancreatitis, and 37 with extra-pancreatic diseases. CA 19-9 was found to be the best marker in detecting pancreatic cancer. Among the clinical data, presence and onset of pain attacks, age, and weight loss were selected as the most informative in assessing chronic pancreatic disease. Clinical data correctly classified 88.5% of chronic pancreatitis and 75.0% of pancreatic cancer; serum markers identified pancreatic tumor in 67.9% of the patients. The adjunct of serum markers to clinical data did not improve accuracy in diagnosing chronic pancreatic disease. Since clinical data and serum markers generally become positive at an advanced stage of the disease, early diagnosis of pancreatic cancer is a goal still to be attained.

In order to assess the relative value of CA 19-9, Tissue Polypeptide Antigen (TPA) and Carcinoembryonic Antigen (CEA), evaluated alone and in combination, in diagnosing pancreatic malignancy, serum CA 19-9, TPA and CEA were determined in 25 control subjects (CS), 26 pancreatic cancer (PC), 23 chronic pancreatitis (CP) and 21 benign extra-pancreatic diseases (EPD). The three markers were able to allocate the subjects correctly in 56.8% of the cases (CS 100%, PC 73.1%, CP 17.4%, EPD 28.6%). Sensitivity, specificity and diagnostic accuracy in detecting pancreatic cancer were respectively: 77%, 91% and 68% for CA 19-9; 92%, 75% and 67% for TPA; 50%, 84% and 34% for CEA; 73%, 91% and 64% for the three parameters evaluated simultaneously. CA 19-9 and TPA appear to be useful indices of pancreatic cancer with a satisfactory specificity when related to chronic pancreatitis; their diagnostic value seems to be comparable and better than that of CEA; the combination of these markers does not improve the results obtained by CA 19-9 or TPA alone.

In this study we evaluated some pathophysiological aspects of pancreatic and liver ribonucleases and alkaline deoxyribonuclease and their clinical usefulness in diagnosing pancreatic cancer. Pancreatic RNase was found to be a sensitive index of pancreatic malignancy; however it was not specific in distinguishing pancreatic malignancy from chronic pancreatitis or other pathologies. Liver RNase and alkaline DNase did not provide better results than pancreatic RNase. These three enzymes were found to be age-dependent and related to each other. Therefore serum nucleases are not useful for clinical purposes since they are influenced, at least in part, by different non-specific factors.

Tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA) were determined in the sera of 36 control subjects, 30 patients with pancreatic cancer, 35 with chronic pancreatitis and 25 with non-pancreatic digestive disease to evaluate their role in detecting pancreatic malignancy. Abnormal values of TPA and CEA were found in 28 and 19 of 30 patients with pancreatic cancer, and in four and seven of 35 patients with chronic pancreatitis, respectively. Raised titres of TPA were observed more often than equivalent serum CEA in simulated pancreatic diseases. The receiver-operating (ROC) characteristic curves showed that TPA was more discriminating than CEA in detecting pancreatic cancer. Specificity was enhanced when both titres were abnormally high and sensitivity when one titre was raised, but the diagnostic accuracy of TPA alone has not improved, which satisfactorily discriminates pancreatic cancer from chronic pancreatitis.

The so-called "plasma" ribonuclease (RNase), described as increased in most patients with pancreatic cancer, was studied in the blood of 92 subjects utilizing the method of Reddi and Holland, to evaluate its reliability in detecting pancreatic tumors. A significant increase of "plasma" RNase was found in pancreatic cancer (p less than 0.01) as compared with controls, non-calcifying chronic pancreatitis (p less than 0.01), calcifying chronic pancreatitis (p less than 0.01), and chronic recurrent pancreatitis (p less than 0.01). Nevertheless increased "plasma" RNase activity was also found in 18/43 patients with chronic pancreatitis, as well as in the majority of the non-pancreatic malignant tumors studied. Furthermore, in 2 out of 22 subjects with pancreatic cancer the enzyme activity was found to be normal. These data suggest that increased "plasma" RNase, although very frequent in pancreatic cancer, is not a marker of pancreatic malignancy.

CA 19-9 serum concentration was determined by a immunoradiometric technique in 130 subjects to evaluate its role in differentiating pancreatic cancer from chronic pancreatitis. Two threshold values were chosen, 17 and 37 U/ml. With the former, sensitivity, specificity and diagnostic accuracy were 86.7, 62.3 and 49.0 respectively, with the latter 73.3, 87.0 and 60.3%. The receiver-operating characteristic curves demonstrated a satisfactory discriminating capacity of CA 19-9 as regards pancreatic cancer and chronic pancreatitis; in contrast, the discrimination was poor for other gastrointestinal diseases, mainly of a malignant nature.

In 116 subjects, serum ribonuclease (RNase) and ferritin were determined in order to evaluate whether their combined evaluation might improve the diagnostic accuracy of each test. Significantly higher levels were found in pancreatic cancer patients both for RNase and ferritin than in control subjects and chronic pancreatitis. Sensitivity and specificity in diagnosing pancreatic cancer were 86% and 46%, respectively for RNase; 76% and 65% for ferritin. One of the two tests was pathological in 100% of pancreatic cancer, with a specificity of 29.9%; both were pathological in 62.1%, with a specificity of 82.1%. The results emphasize the limits of the combined assessment of pancreatic cancer markers.

In order to verify the role of CEA in the differential diagnosis of pancreatic cancer and to evaluate some influencing factors like age, tumor spread and liver dysfunction, this antigen was measured in the sera of 60 control subjects, 45 patients with pancreatic cancer, 37 with chronic pancreatitis, 67 with benign, and 28 with malignant extra-pancreatic diseases. CEA was found to be elevated in 23/45 pancreatic cancers, in 8/37 chronic pancreatitis, in 17/67 benign and in 9/28 malignant extra-pancreatic diseases. Significant correlations were documented between CEA and age in all the subjects; between CEA and immunoglobulins G in liver cirrhosis and between CEA and alkaline phosphatase in gastrointestinal extra-pancreatic malignancies. In pancreatic cancer higher CEA levels were detected in patients with metastases. We can conclude that CEA is of limited value in the differential diagnosis of pancreatic cancer; it does not seem to be able to detect early pancreatic tumors. Age and liver dysfunction may contribute towards elevating this marker in serum.

Urinary ribonuclease output and indices of renal tubular integrity were evaluated in control subjects and patients with pancreatic cancer, chronic pancreatitis and extrapancreatic diseases. The aim of the study was to ascertain the contribution to such diagnoses of ribonuclease determination in urine, and the possible influence of tubular damage on the extent of ribonuclease excretion. Information from the ribonuclease assay in urine offered no advantage over that obtained by the same determination in serum; tubular damage may contribution in some cases to an elevated ribonuclease excretion.

Serum ribonuclease (RNase) and deoxyribonuclease (DNase) were investigated in 18 control subjects, and in 22 patients with pancreatic cancer, 13 with chronic pancreatitis and 29 with extrapancreatic diseases in order to assess their clinical usefulness in pancreatic cancer diagnosis and to evaluate whether modifications were consensual and/or age-related. Increased DNase and RNase values were found not only in a notable proportion of pancreatic cancer, but also in chronic pancreatitis and extra-pancreatic diseases. Thus the clinical value of both enzymes in pancreatic cancer diagnosis is negligible. DNase does not seem to be strictly age-dependent, whereas serum RNase does. Elevated levels of the two enzymes, when present, were consensual, suggesting that factors involved in such an increase were partially common to both.

The clinical usefulness of tissue polypeptide antigen, galactosyltransferase II and pancreatic oncofetal antigen was evaluated in detecting pancreatic cancer and in differentiating this malignancy from chronic pancreatitis and other diseases (mainly of the liver and biliary tract) which may enter in differential diagnosis. TPA seems to be the most sensitive among these indices in detecting pancreatic cancer and appears to discriminate this malignancy quite satisfactorily from chronic pancreatitis. It is also frequently pathological in a number of other diseases and is influenced by the presence of liver dysfunction. GT II and POA do not grossly differ from TPA in specificity, but they appear to be less sensitive. Both are frequently pathological in hepato-biliary diseases. All these markers seem, therefore, to be of limited value in the diagnosis of pancreatic cancer.

This study was performed to ascertain the role of serum markers and simple clinical data in detecting pancreatic cancer and in distinguishing this malignancy from chronic pancreatitis and other gastrointestinal diseases. Serum CA 19-9, tissue polypeptide antigen and carcinoembryonic antigen were measured in 38 control subjects, 37 patients with pancreatic cancer, 39 with chronic pancreatitis and 44 with extra-pancreatic diseases mainly of gastrointestinal origin. Clinical data recorded included age, sex, presence of pancreatic calcifications, weight loss, pain, jaundice, alcohol abuse, diabetes mellitus. Serum markers gave a correct allocation of the subjects in 48.1% of the cases with pancreatic cancer patients correctly predicted in 62.2%. Clinical data correctly diagnosed 74.2% of subjects. Chronic pancreatitis was identified in 84.6% of the cases and pancreatic cancer in 64.9%. The first clinical variables selected were pain and age. The addition of serum markers to clinical data did not enhance accuracy of the results. We conclude that the diagnosis of chronic pancreatic diseases should first be suspected on the basis of accurately recorded simple clinical data; serum markers seem to be only occasionally useful. Since indicative clinical data and serum markers become positive in the advanced phases of pancreatic cancer, early diagnosis of this malignancy still remains an objective to reach.

The behavior of trypsin/creatinine clearance ratio (Ctr/Ccr) and serum immunoreactive trypsin (IRT) was evaluated in a total of 168 subjects with pancreatic cancer, chronic pancreatitis and non-pancreatic digestive diseases. Amylase/creatinine clearance ratio (Cam/Ccr) and serum amylase levels were also evaluated in order to establish their possible relationship with Ctr/Ccr and IRT values. Elevated Ctr/Ccr and IRT values were observed in several patients with pancreatic cancer and chronic pancreatitis. Abnormal IRT and Ctr/Ccr values were found in 28.2 and 4% of non-pancreatic digestive diseases, respectively. IRT and amylase serum levels showed consensual modifications, while Ctr/Ccr showed a behavior different from that of Cam/Ccr. Liver damage seems to play a role in increasing serum IRT levels of patients without pancreatic involvement, while the increased Ctr/Ccr seems to depend on other factors, for instance renal tubular dysfunction.

CA 19-9 (Centocor, Malvern, PA) and carcinoembryonic antigen (CEA), two recently developed immunoradiometric assays utilizing monoclonal antibodies, were evaluated in the sera of 139 subjects in order to assay their individual and combined value in pancreatic cancer diagnosis and to assess the influence of jaundice. Sensitivity, specificity, and accuracy in detecting pancreatic cancer were 69%, 85%, and 54% for CA 19-9; and 28%, 78%, and 6% for CEA, respectively. Combined evaluation gave the highest specificity (95%) when both, and the highest sensitivity (79%) when at least one, gave pathologic results. The receiver-operating characteristic curves demonstrated that CA 19-9 is more discriminating than CEA, for any serum value. A correlation between serum bilirubin and CA 19-9 was demonstrated in pancreatic and extrapancreatic disease. CEA determination, performed using monoclonal antibodies, seems to be unsatisfactory as compared to CA 19-9 in pancreatic cancer diagnosis, and combined assessment does not improve the results of CA 19-9 alone. Jaundice may influence serum CA 19-9 in pancreatic and extrapancreatic diseases.

Urinary excretion of alpha-glucosidase (AGL), gamma-glutamyltransferase (GGT) and ribonuclease (RNase), and serum amylase and immunoreactive trypsin (IRT) were determined in 38 control subjects, 48 patients with pancreatic cancer, 77 with chronic pancreatitis and 47 with extrapancreatic diseases in order to ascertain the presence of a renal tubular damage and to investigate its etiology. A significantly increased frequency of pathological results for all urinary enzymes was documented in the various groups of patients as compared to controls. Significant correlations were detected among AGL, GGT and RNase. Considering the subjects as a whole, GGT and RNase excretions correlated with serum IRT and amylase; the two urinary enzymes were found to be higher when jaundice was present. In chronic pancreatic disease enzymuria was related to increased serum pancreatic enzymes; in extrapancreatic diseases it was associated to hyperbilirubinemia. The vast majority of patients with pancreatic cancer and elevated urinary enzymes presented hepatic metastases and/or jaundice. We can conclude that an anatomical and functional tubular impairment is detectable in some patients with chronic pancreatic and extrapancreatic diseases. Tubular damage seems to least in part to be related to pancreatic inflammation and necrosis in chronic pancreatic disease, while jaundice may be found to play an important role in diseases of the hepatobiliary tract. In pancreatic cancer, liver dysfunction (presence of liver metastases and/or extrahepatic cholestasis) also appears to be involved in altering tubular cells.

Serum 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.

This study was undertaken in order to ascertain the role of CA 19-9 in pancreatic cancer diagnosis. Therefore CA 19-9 was determined in the sera of 83 control subjects, 108 patients with pancreatic cancer, 112 with chronic pancreatitis and 126 with extrapancreatic diseases. Sensitivity, specificity and accuracy in detecting pancreatic cancer were: 75%, 86% and 61% respectively. The receiver-operating characteristic curves showed that CA 19-9 is able to well discriminate pancreatic cancer from controls; satisfactorily it differentiated pancreatic malignancy from chronic pancreatitis and other benign extrapancreatic diseases. Extrapancreatic neoplasms were not accurately separated. No difference was detected in CA 19-9 levels between pancreatic cancer patients with or without hepatic metastases. We can conclude that CA 19-9 is a test for pancreatic malignancy with a satisfactory sensitivity and specificity in respect of other pancreatic and extrapancreatic benign pathologies; the presence of hepatic metastases is only one of the factors which may increase its serum levels.

In order to ascertain the clinical usefulness of CA 19-9 in detecting pancreatic cancer in comparison with CEA, and to verify the influence of age and liver dysfunction on serum levels of these two antigens, serum CA 19-9 and CEA were assessed in 32 control subjects, 32 patients with pancreatic cancer, 26 with chronic pancreatitis and 43 with gastrointestinal extra-pancreatic diseases. Sensitivity, specificity and diagnostic accuracy of CA 19-9 and CEA in detecting pancreatic cancer were: 69% and 44%, 91% and 75%, 60% and 19% respectively. Linear correlations were observed between the age of the subjects on the one hand and CA 19-9 or CEA on the other. Significant relationships were also noticed between alanine-amino-transferase or bilirubin serum levels and CA 19-9 values. Serum CA 19-9 seems to be a better diagnostic tool than CEA in the assessment of pancreatic cancer; nevertheless the influence of liver dysfunction and age to some extent limits the diagnostic value of CA 19-9.

CA 19-9 and tissue polypeptide antigen (TPA) were determined in the sera of 28 control subjects, 29 patients with pancreatic cancer, 26 with chronic pancreatitis and 62 with benign and malignant extra pancreatic diseases in order to compare their usefulness in diagnosing pancreatic cancer, to verify whether the combined assessment of the two indices could improve the results given by a single parameter and to speculate on the role of liver dysfunction in increasing their serum levels. The sensitivity, specificity and accuracy of CA 19-9 and TPA in diagnosing pancreatic malignancy were: 76, 85 and 61% for CA 19-9 and 79, 52 and 32% for TPA. The receiver-operating characteristic curves showed that CA 19-9 and TPA similarly discriminate pancreatic cancer from controls and chronic pancreatitis, while CA 19-9 is more useful than TPA in differentiating pancreatic malignancy from benign and malignant extra pancreatic abdominal diseases. TPA did not seem to add further information as compared to CA 19-9 alone when both markers were combined. Liver dysfunction may contribute to increasing serum levels of both markers.