Usefulness of p16 and K-ras mutation in pancreatic adenocarcinoma and chronic pancreatitis differential diagnosis.
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BACKGROUND: The differentiation of chronic pancreatitis (CP) from pancreatic adenocarcinoma (PA) remains a great challenge. The purpose of the study was to compare the prevalence of p16 and K-ras mutation in PA and CP in order to evaluate their usefulness in differential diagnosis of those diseases. METHODS: The study included 44 patients who underwent Whipple resection or distal pancreatectomy for PA (23 subjects) or CP (21 subjects). DNA from pancreatic tissue was analysed for K-ras mutation (codon 12) and p16 mutations with PCR amplifications. RESULTS: The K-ras gene mutation has been shown in 17 (73,9%) cases with pancreatic adenocarcinoma which was significantly more often than in chronic pancreatitis - 9 (42,8%) (p<0,01). Prevalence of p16 mutations in patients with PA was 18 (78,3%) and with CP - 7 (33,3%) (p<0,01). K-ras and p16 mutations together have been observed in 16 (69,6%) cases in patients with PC and only in 3 (14,3%) - with CP (p<0,01). No statistically significant association between K-ras or p16 mutations and tumor size, sex or patient age has been observed. CONCLUSION: It is suggested that simultaneous measurement of K-ras and p16 mutations may provide an additional tool in differential diagnosis of chronic pancreatitis and pancreatic adenocarcinoma. (+info)
Duodenal acidity may increase the risk of pancreatic cancer in the course of chronic pancreatitis: an etiopathogenetic hypothesis.
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Chronic pancreatitis patients have an increased risk of developing pancreatic cancer. The cause of this increase has yet to be fully explained but smoking and inflammation may play an important role. To these, we must now add a new potential risk factor, namely duodenal acidity. Patients with chronic pancreatitis very often present pancreatic exocrine insufficiency combined with a persistently low duodenal pH in the postprandial period. The duodenal mucosa in chronic pancreas patients with pancreatic insufficiency has a normal concentration of s-cells and, therefore, the production of secretin is preserved. Pancreatic ductal cells are largely responsible for the amount of bicarbonate and water secretion in response to secretin stimulation. When gastric acid in the duodenum is not well-balanced by alkaline pancreatic secretions, it may induce a prolonged secretin stimulus which interacts with the pancreatic ductal cells resulting in an increased rate of ductular cell activity and turnover. N-Nitroso compounds from tobacco, identified in human pancreatic juice and known to be important carcinogens, may then act on these active cells, thereby increasing the risk of cancer. Duodenal acidity is probably of particular concern in patients who have undergone a duodenum-preserving pancreatic head resection, since, in this anatomic situation, pancreatic juice transits directly via the jejunal loop, bypassing the duodenum. Patients undergoing a Whipple procedure or side-to-side pancreaticojejunostomy are probably less critically affected because secretions transit, at least in part, via the papilla. If the duodenal acidity hypothesis proves correct, then, in addition to stopping smoking, reduction of duodenal acid load in patients with pancreatic insufficiency may help decrease the risk of pancreatic cancer. (+info)
Osteopontin influences the invasiveness of pancreatic cancer cells and is increased in neoplastic and inflammatory conditions.
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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with an overall 5-year survival rate of less than 5%. Invasive tumor growth and early metastasis are two important reasons for this dismal prognosis. Osteopontin (OPN) is a secretory protein with a variety of functions, for example in cell adhesion and migration, inflammatory reaction and apoptosis. In this study the functional role of OPN in human pancreatic cancer and its potential use as a disease marker were analyzed. By real time quantitative PCR, there was a 2.2-fold and 1.6-fold increase of OPN mRNA in pancreatic cancers (n = 23) and chronic pancreatitis samples (n = 22), respectively, compared to normal pancreatic tissues (n = 20). Immunohistochemical analysis demonstrated OPN staining in 60% of the primary pancreatic tumors and in 72% of the lymph node and liver metastases. ELISA analysis of serum samples obtained from pancreatic cancer patients (n = 70), chronic pancreatitis patients (n = 12), and healthy donors (n = 20) showed a 1.6-fold increase in OPN serum levels in patients with tumors and a 1.9-fold increase in patients with chronic pancreatitis. Recombinant human OPN significantly increased the invasiveness of pancreatic cancer cells, without having any impact on cell proliferation. In addition, down regulation of OPN by specific siRNA molecules decreased pancreatic cancer cell invasion. In conclusion, OPN serum levels in pancreatic cancer and chronic pancreatitis patients are not significantly different, thereby restricting its role as a prognostic or follow-up marker. Our results do suggest, however, that blockade of OPN might be useful as a therapeutic approach to inhibit invasion and metastasis of pancreatic cancer cells. (+info)
Diagnosis and management of chronic pancreatitis.
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Chronic pancreatitis represents a condition that is challenging for clinicians secondary to the difficulty in making an accurate diagnosis and the less than satisfactory means of managing chronic pain. This review emphasises the various manifestations that patients with chronic pancreatitis may have and describes recent advances in medical and surgical therapy. It is probable that many patients with chronic abdominal pain are suffering from chronic pancreatitis that is not appreciated. As the pathophysiology of this disorder is better understood it is probable that the treatment will be more successful. (+info)
Parenchymal regression in chronic pancreatitis spares islets reprogrammed for the expression of NFkappaB and IAPs.
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In advanced chronic pancreatitis (CP), islets are preserved even in the midst of scarring. We recently showed in CP local production of interferon (IFN)gamma, transforming growth factor (TGF)beta and death receptor ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), along with functional death receptor neoexpression and apoptosis in exocrine but not in endocrine cells. However, islets are strongly induced for TRAIL-receptor (R)-4 lacking the functional death domain. TRAIL-R4 signaling in T cells induces NFkappaB, which activates antiapoptotic programs. Here, we demonstrate that in insulinoma cells CM, TGFbeta/IFNgamma/TRAIL in combination induced TRAIL-R4 surface expression. TRAIL/IFNgamma upregulated NFkappaB subunits and its target gene survivin while downmodulating IkappaB alpha mRNA. RelA transcriptional activity increased upon stimulation with IFNgamma and IFNgamma/TRAIL. In situ, normal pancreatic epithelia had low mRNA levels of NFkappaB subunits. These were higher in parenchymal areas of CP with severe fibrosis and highest in islets. NFkappaB-regulated proteins IkappaB alpha, survivin and another apoptosis inhibitor, cIAP1, were found in corresponding sites, again at highest levels in islets surrounded by fibrosis. In conclusion, islets in CP not only evade immune attack by nonexposure of functional death receptors in the presence of TRAIL-R4 but also additionally neoexpress NFkappaB and its target genes, survivin and cIAP1, to protect themselves from apoptosis. (+info)
Acute retinopathy following pancreatic head resection for chronic pancreatitis: a rare, severe complication.
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CONTEXT: Chronic pancreatitis is a pancreatic disorder affecting endocrine and exocrine pancreatic functions with a variety of mainly abdominal symptoms. CASE REPORT: We report the rare complication of acute retinopathy with visual loss following pancreatic head resection due to chronic pancreatitis. CONCLUSIONS: Acute retinal dysfunction is a rare severe complication of acute and chronic pancreatitis. Early recognition and therapy are of utmost importance in restoring normal visual acuity and avoiding irreversible damage. (+info)
Genetic polymorphism of alcohol dehydrogenase 3 in alcohol liver cirrhosis and in alcohol chronic pancreatitis.
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AIM: To find the ADH3 genotypes in the Polish population likely to be responsible for higher susceptibility to alcohol disease of the liver and chronic alcohol pancreatitis. METHOD: The ADH3 genotype and ADH3*1 and ADH3*2 alleles frequencies were examined in 198 patients. Genotyping of the ADH3 was performed using PCR-restriction fragment length polymorphism methods on a white cell DNA. RESULTS: The genotype ADH3*1/ADH3*1 was found to be significantly more frequent in alcohol abusers compared with non-drinkers. The examinations of the group of alcohol abusers showed that the genotype ADH3*2/ADH3*2 occurred statistically significantly less frequently in patients with chronic pancreatitis than in those without alimentary lesions (healthy drinkers). The alleles ADH3*1 and genotype ADH3*1/ADH3*1 were significantly more frequent in men than in women, whereas alleles ADH3*2 and genotype ADH3*2/ADH3*2 were more common in women. CONCLUSIONS: The genotype ADH3*2/ADH3*2 is likely to be a protective factor for chronic pancreatitis. Variations in ADH3 genotypes may account for some of the differences in prevalence of alcohol dependence between genders in the Polish population. (+info)
Application of proteomic technology in identifying pancreatic secretory trypsin inhibitor variants in urine of patients with pancreatitis.
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BACKGROUND: Although the analysis of genetic variability has traditionally been performed with molecular genetic techniques, the development of proteomic technology has raised the possibility of analyzing genetic variants at the protein level. This method provides additional information about posttranslational modifications and differences in expression. We used mass spectrometry to characterize 3 variants of the peptide encoded by the serine protease inhibitor Kazal type 1 (SPINK1) gene, pancreatic secretory trypsin inhibitor (PSTI). A genetic variant of PSTI, N34S, is associated with the development of pancreatitis. METHODS: We used a quadrupole/time-of-flight hybrid mass spectrometer equipped with an electrospray ionization source to analyze the molecular identity of PSTI purified from the urine of 12 patients with pancreatitis and from 3 controls. We also developed a rapid small-scale capture procedure to isolate and analyze PSTI from small volumes of urine. RESULTS: The mutations responsible for mass shifts of different PSTI variants could be verified. We observed differences in the expression of different variants as well as a novel proteolytic fragment of PSTI. Small-scale magnetic bead-mediated immunoaffinity chromatography PSTI enabled easy and rapid purification from small urine volumes, facilitating mass spectrometric analysis with adequate sensitivity. CONCLUSIONS: Pancreatitis-related PSTI variants occurring at nanomolar concentrations in urine can be detected and quantified by immunoaffinity purification and mass spectrometry. In addition, the N34S variant occurs at higher concentrations than the wild type. This finding casts new light on the possible role of PSTI as a cause of hereditary pancreatitis. (+info)