JOP. J Pancreas (Online) 2006; 7(6):676-678.
PANCREAS ALERTS
Am J Clin Pathol 2006; 126:572-9. (PMID: 17019794)
Biomarkers in diagnosis of pancreatic carcinoma in fine-needle aspirates.
Jhala N, Jhala D, Vickers SM, Eltoum I, Batra SK, Manne U, et al.
Department of Pathology, University of Alabama at Birmingham. Birmingham, AL, USA.
This study was undertaken to determine whether recently identified proteins could be translated to clinical practice as markers to distinguish pancreatic adenocarcinoma from chronic pancreatitis on fine-needle aspirate (FNA) samples. Resected pancreatic tissue sections (n=40) and FNA samples (n=65) were stained for clusterin-beta, MUC4, survivin, and mesothelin. For each biomarker, the staining patterns in adenocarcinoma and in reactive ductal epithelium were evaluated and compared. Clusterin-beta stained reactive ductal epithelium significantly more frequently than pancreatic adenocarcinoma. In comparison, MUC4 and mesothelin were expressed more frequently in pancreatic adenocarcinoma on tissue sections. Positive staining for MUC4 (91% vs. 0%; P<0.001) and mesothelin (62% vs. 0%; P=0.01) and absence of staining for clusterin-beta (90% vs. 7%; P<0.001) were noted significantly more frequently in adenocarcinoma cells than in reactive cells in FNA samples. Clusterin-beta and MUC4 can help distinguish reactive ductal epithelial cells from the cells of pancreatic adenocarcinoma in FNA samples.
FASEB J 2006; 20:1982-91. (PMID: 17012250)
Probing the human kinome for kinases involved in pancreatic cancer cell survival and gemcitabine resistance.
Giroux V, Iovanna J, Dagorn JC.
INSERM, Unite 624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy. Marseille, France.
Except for gemcitabine, chemotherapeutic agents are ineffective with pancreatic adenocarcinoma because this cancer is resistant to apoptosis induction. Involvement of specific kinases in such resistance is likely. We developed a systematic strategy to screen the human kinome and select kinases whose inhibition in pancreatic cancer cells can increase 1) spontaneous apoptosis or 2) gemcitabine-induced apoptosis. The pancreatic adenocarcinoma cell line MiaPaCa-2 was transfected with 645 pairs of siRNAs directed to all human kinases. The same experiment was conducted in cells treated with 150 microM gemcitabine. Apoptosis was measured after 2 days and the results were normalized for cell viability. A panel of 56 kinases whose inhibition increased spontaneous apoptosis by at least 50% was established. Ten of them gave similar results on Panc1 and BxPC3 pancreatic adenocarcinoma cell lines. A panel of 83 kinases whose inhibition increased gemcitabine-induced apoptosis by 50% or more was also established. Twelve kinases appeared in both panels. A cumulative increase in apoptosis was observed when inhibiting simultaneously several kinases. Such a systematic approach allowed characterization of all kinases involved in pancreatic cancer cell survival and resistance to gemcitabine. Inhibitors of these kinases, used alone or in combination, might improve the treatment of pancreatic adenocarcinoma.
Nat Clin Pract Gastroenterol Hepatol 2006; 3:552-62. (PMID: 17008925)
Drug insight: statins and gastrointestinal cancer.
Bhuket TP, Higgins PD.
University of Michigan. Ann Arbor, MI, USA.
Statins are popular lipid-lowering drugs that have had a great impact on the primary and secondary prevention of cardiovascular diseases. Basic and clinical research have also revealed that statins have biologic activities that go beyond lipid lowering, and suggest that they might have other therapeutic benefits. Perhaps the most exciting of these additional biologic effects is the finding that statins can exert an anticancer effect on cultured cancer cells, and in animal models. Clinical studies of statins for the treatment and prevention of cancer have, however, produced conflicting results. This review critically evaluates the current body of literature on the role of statins in the treatment and prevention of gastrointestinal cancers, with particular focus on clinical and observational studies.
Pediatrics 2006; 118:1660-3. (PMID: 17015559)
The spectrum of valproic acid-associated pancreatitis.
Werlin SL, Fish DL.
Department of Pediatrics, Medical College of Wisconsin. Milwaukee, WI, USA.
The goal of this study was to characterize valproic acid-associated pancreatitis in children. The charts of all patients with pancreatitis (diagnosed by using strict criteria) associated with valproic acid during a 10-year period were reviewed. Clinical and laboratory results were abstracted. Twenty-two patients with valproic acid-associated pancreatitis were seen during the study period. Symptoms were similar to those of patients with pancreatitis from other etiologies and included abdominal pain/tenderness (83%), vomiting/retching (74%), abdominal distention (30%), and fever/chills (26%). Valproic acid levels were in the therapeutic range in all but 1 patient. The mean duration of therapy before the onset of pancreatitis was 32 months. The serum lipase level was >3 times the reference value in all patients, but the serum amylase level was not significantly elevated in 31% of the patients tested. Imaging studies altered clinical management in only 1 patient. The length of stay was generally brief (mean: 8 days). Two patients died. Of the 5 patients who were rechallenged, 4 had relapses. In conclusions, valproic acid-associated pancreatitis does not depend on valproic acid serum level and may occur any time after the onset of therapy. The serum lipase level is more sensitive than the serum amylase level and should be obtained when pancreatitis is suspected. Early imaging studies did not change clinical management. Rechallenge with valproic acid is dangerous and should be avoided.
Am J Physiol Gastrointest Liver Physiol 2006; 291:G700-8. (PMID: 16959955)
A new model of chronic pancreatitis in rats.
Yamamoto M, Otani M, Otsuki M.
Department of Gastroenterology and Metabolism, School of Medicine, University of Occupational and Environmental Health. Kitakyushu, Japan.
This study was designed to examine whether continuous pancreatic ductal hypertension (PDH) plays an important role in the onset and development of chronic pancreatitis (CP). Pancreatic, biliary, and duodenal cannulas were implanted in male Wistar rats. PDH was induced by vertically raising the free end of the pancreatic duct cannula to exert a hydrostatic pressure and maintained for 2 wk. PDH was gradually increased, but when the pancreatic juice (PJ) flow was interrupted, PDH was decreased to restore PJ flow. The induction of PDH resulted in a marked reduction of amylase activity in PJ and an increase in serum amylase activity. At 2 wk after persistent PDH, pancreatic exocrine function was markedly decreased in response to a bolus injection of secretin (100 pmol/kg) compared with the control group. Histological examination revealed interlobular as well as intralobular fibrosis in the form of nodular pancreatitis at 2 wk after the induction of PDH. Immunohistochemistry revealed the expression of fibronectin and collagen types I and III. Quantitative real-time RT-PCR showed an increase in transforming growth factor-beta1) mRNA expression in the pancreas during PDH. The present results suggest that PDH plays an important role in the onset and development of CP. Furthermore, this animal model seems useful for investigating the mechanisms of CP in rats.
J Pediatr Gastroenterol Nutr 2006; 43:299-306. (PMID: 16954950)
Analysis of CFTR, SPINK1, PRSS1 and AAT mutations in children with acute or chronic pancreatitis.
Sobczynska-Tomaszewska A, Bak D, Oralewska B, Oracz G, Norek A, Czerska K, et al.
Department of Medical Genetics, Institute of Mother and Child. Warsaw, Poland.
Defects of PRSS1, SPINK1, CFTR and AAT are considered causative or predisposing to pancreatitis. The aim of this study was to evaluate the impact of these defects into molecular pathology of chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP). Ninety-two children with CP or ARP, 55 family members and 50 controls were investigated. The subjects were screened for PRSS1 mutations: R122H, R122C, A16V, N29I; SPINK1 N34S variant; panel of 14 CFTR defects: INNOLiPA CFTR12, CFTRdele2,3 and IVS8-T variant or panel of 3 CFTR defects-F508del, CFTRdele2,3 and IVS8-T; AAT mutations: E264V, E342K. The authors identified 1 mutated allele in at least 1 of 4 genes in 31 of 92 patients and 12 of 50 controls (P=0.157). Mutations in SPINK1 and PRSS1 were most frequent. PRSS1 mutations were identified mainly in CP patients (9.6% of CP vs. 2.5% of ARP alleles, P=0.094), whereas N34S SPINK1 mutation was present with comparable frequency in CP and ARP patients (7.7% vs. 10.0%, P=0.768). The frequency of mutations in CFTR alleles was similar to controls (4.9% vs. 5%, P=0.587). Overall frequency of AAT mutations was lower than in the controls. Family studies showed that defects in the examined genes did not always segregate with disease. In conclusion, PRSS1 defects seem to be causative for pancreatitis, whereas defects in SPINK1 are suggested to be associated with the disease. No association between CFTR mutations and pancreatitis was observed. The importance of AAT variants remains speculative.