PANCREAS ALERTS
Endoscopy 2003; 35(5):407-10. (AN 22586134, PMID 12701012)
Severity of acute gallstone pancreatitis in patients with pancreas divisum.
Boon N, Delhaye M, Le Moine O, De Maertelaer V, Deviere J.
Department of Gastroenterology, Erasmus University Hospital. Brussels, Belgium.
The presence of pancreas divisum may reduce the severity of acute gallstone pancreatitis, as stone impaction at the major papilla affects only the ventral pancreas. The severity of acute gallstone pancreatitis was compared retrospectively in patients with and without pancreas divisum.
Acute gallstone pancreatitis was defined by clinical, biological, radiological and endoscopic features. Thirteen patients with acute gallstone pancreatitis and pancreas divisum were studied. The pancreas divisum patients were compared to 39 controls having acute gallstone pancreatitis and a conjugate pancreas.
Patients with acute gallstone pancreatitis and pancreas divisum had a lower severity grade at CT scanning than the controls (P = 0.005), a shorter hospitalization period (P = 0.032), and lower mortality (P = 0.048).
The authors concluded that acute gallstone pancreatitis is less severe in patients with pancreas divisum than in those with a conjugate pancreas.
All patients underwent biliary sphincterotomy. Levels of serum amylases, lipases, C-reactive protein and white blood cells were compared in patients with acute gallstone pancreatitis and pancreas divisum, and in the controls before sphincterotomy.
The severity of the pancreatitis was assessed on the basis of C-reactive protein, Ranson's score, computed tomography, the need for intensive care and drainage of collections or necrosis, duration of hospitalization and mortality.
Serum amylase and lipase levels, white blood cells and Ranson's score tended to be lower in patients with acute gallstone pancreatitis and pancreas divisum but the difference was not significant when compared to the controls.
Biochem Pharmacol 2003; 65(8):1295-303. (AN 22580587, PMID 12694870)
Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin.
Jaster R, Brock P, Sparmann G, Emmrich J, Liebe S.
Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock. Rostock, Germany.
Pancreatic stellate cells play a key role in pancreatic fibrosis, a constant feature of chronic pancreatitis; pancreatic stellate cell activation occurs in response to profibrogenic mediators such as cytokines and involves proliferation, transition towards a myofibroblastic phenotype and enhanced production of extracellular matrix proteins. Pancreatic stellate cell activation correlates with the activity of the Ras-Raf-ERK (extracellular signal-regulated kinase) signalling cascade.
Using a rat culture model of pancreatic stellate cells, the authors evaluated the effects of lovastatin (a hydroxymethylglutaryl coenzyme A reductase inhibitor which interferes with protein isoprenylation) on pancreatic stellate cell viability and activation as well as on signalling through Ras proteins.
Apoptotic cells were detected applying the TUNEL assay. The proliferation of pancreatic stellate cells was quantified using the bromodeoxyuridine DNA incorporation assay. The expression of alpha-smooth muscle actin (an indicator of the myofibroblastic phenotype), ERK activation and membrane translocation of the Ras superfamily member RhoA were analysed by immunoblotting.
Lovastatin inhibited serum- and platelet-derived growth factor-stimulated pancreatic stellate cell proliferation in a dose-dependent manner. At drug concentrations above the level required for growth inhibition, a notable increase in apoptotic cells was observed. Furthermore, lovastatin inhibited induction of alpha-smooth muscle actin expression in the course of primary culture.
The authors suggested that the antifibrotic efficiency of statins should be tested in animal models having chronic pancreatitis.
Immunoblot experiments indicated that lovastatin suppressed both Ras-mediated ERK 1/2 activation and platelet-derived growth factor-induced membrane translocation of RhoA.
Together, these data suggest that lovastatin, through the interruption of Ras signalling, interferes with pancreatic stellate cell activation.
Gastroenterology 2003; 124(4):1010-9. (AN 22557594, PMID 12671898)
Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats.
Kuno A, Yamada T, Masuda K, Ogawa K, Sogawa M, Nakamura S, Nakazawa T, Ohara H, Nomura T, Joh T, Shirai T, Itoh M.
First Department of Internal Medicine, Nagoya City University Medical School. Nagoya, Aichi, Japan.
Pancreatic stellate cells have some similarities to hepatic stellate cells and an intrinsic renin-angiotensin system is present in the pancreas and is enhanced in acute pancreatitis and chronic pancreatic hypoxia.
The authors assessed the effects of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, on spontaneously occurring chronic pancreatitis.
Lisinopril in drinking water (20, 50, or 200 mg/L) was administered to 10-week-old male Wistar Bonn/Kobori (WBN/Kob) rats for 10 weeks and then the inflammatory parameters, fibrosis, serum and pancreatic ACE activity, and expression of transforming growth factor-beta1 (TGF-beta1) messenger RNA (mRNA) as well as positive immunostaining for alpha-smooth muscle actin (alpha-SMA) were assessed.
Lisinopril attenuated gross alterations in the pancreas. This protective effect was confirmed quantitatively by significant increases in pancreatic weight and decreases in pancreatic myeloperoxidase (MPO) activity (an index of granulocyte infiltration), pancreatic hydroxyproline content (an index of collagen deposition), the ratio of fibrous tissue and histologic scores. Lisinopril significantly reduced serum ACE activity but it did not affect pancreatic activity. High doses of lisinopril suppressed the overexpression of TGF-beta1 mRNA measured by a reverse-transcription polymerase chain reaction (RT-PCR) and decreased the number of alpha-SMA-positive cells (activated pancreatic stellate cells) in the pancreas.
The authors concluded that lisinopril alleviated chronic pancreatitis and fibrosis in male WBN/Kob rats. It suppressed the expression of TGF-beta1 mRNA, resulting in the prevention of pancreatic stellate cell activation, which may be involved in the observed protection.
Finally, the authors proposed that an ACE inhibitor may be useful for treating chronic pancreatitis.
Gastroenterology 2003; 124(4):949-60. (AN 22557588, PMID 12671892)
Up-regulation, nuclear import, and tumor growth stimulation of the adhesion protein p120 in pancreatic cancer.
Mayerle J, Friess H, Buchler MW, Schnekenburger J, Weiss FU, Zimmer KP, Domschke W, Lerch MM.
Department of Medicine B, Westfalische Wilhelms-Universitat. Munster, Germany.
Cell adhesion proteins have been said to act as tumor suppressors because they prevent malignant cells from dissociating their cell contacts.
The authors studied the role of p120ctn, a member of the cadherin/catenin family, in human pancreatic cancer.
In 32 resection specimens of pancreatic adenocarcinoma and 10 control samples, the expression of p120ctn was studied by Northern blot, immunocytochemistry and immunogold electron microscopy.
In pancreatic cancer, p120ctn messenger RNA (mRNA) was increased 3- to 4-fold. Although p120ctn was localized exclusively at cell contacts, in controls it was found in the cytosol and the nucleus of pancreatic cancer cells. This redistribution correlated to the degree of tumor dedifferentiation but was independent of tumor stage. The mean survival of patients with predominant membrane localization of p120ctn was 24 months vs. 9 months for patients with predominant cytoplasmic p120ctn expression (P < 0.05). Silencing of p120ctn with siRNA duplexes reduced pancreatic cancer cell growth by 40%.
The authors concluded that up-regulation, cytoplasmic redistribution, and nuclear import of p120ctn are associated with a more malignant phenotype of pancreatic cancer and that their study further represents conclusive evidence for a direct involvement of p120ctn in malignant tumor cell proliferation. Both p120ctn-defective tumor cell contacts and p120ctn-mediated growth signals appear to contribute to the aggressive spread of pancreatic cancer.
Patient survival data, tumor grading and staging were correlated to the experimental results.
In PaTu 8889 T pancreatic cancer cells, p120ctn expression was suppressed with 21-nucleotide small interfering RNA (siRNA) duplexes and proliferation was determined by bromodeoxyuridine (BrdU) incorporation.
Mol Cancer Ther 2003; 2(4):361-9. (AN 22586792, PMID 12700280)
Suppression of the malignant phenotype in human pancreatic cancer cells by the overexpression of manganese superoxide dismutase.
Weydert C, Roling B, Liu J, Hinkhouse MM, Ritchie JM, Oberley LW, Cullen JJ.
Department of Radiation Oncology, University of Iowa College of Medicine. Iowa City, Iowa, USA.
Cells contain a large number of antioxidants to prevent or repair the damage caused by reactive oxygen species. One component of the antioxidant system, manganese superoxide dismutase, is localized in the mitochondria, and the levels of this protein have been previously shown to inversely correlate with pancreatic cancer cell growth.
The authors studied the possible role of manganese superoxide dismutase overexpression in suppressing the in vitro and in vivo malignant phenotype of a human pancreatic cancer cell line.
Tumor cell behavior was determined in the pancreatic cancer cell line MIA PaCa-2 by examining cell growth, plating efficiency and anchorage-independent growth in soft agar.
Manganese superoxide dismutase was overexpressed in the pancreatic cancer cell line MIA PaCa-2 by infection with an adenovirus-manganese superoxide dismutase construct. Cells were also injected subcutaneously in nude mice and tumor volume was calculated. Single and multiple direct injections of the adenoviral manganese superoxide dismutase construct were delivered to the tumor.
Increases in manganese superoxide dismutase immunoreactivity and activity were seen after transduction with the adenovirus-manganese superoxide dismutase construct. Increasing manganese superoxide dismutase levels correlated with increased doubling time. Cell growth, plating efficiency, and growth in soft agar decreased with increasing amounts of the adenovirus manganese superoxide dismutase construct.
The authors concluded that manganese superoxide dismutase may be a tumor suppressor gene in human pancreatic cancer. Delivery of the manganese superoxide dismutase gene may prove beneficial for suppression of pancreatic cancer growth.
Tumors grew slower and survival was increased in nude mice injected with the adenoviral manganese superoxide dismutase construct as compared to the parental cell line, whereas multiple injections of the adenoviral manganese superoxide dismutase construct further inhibited tumor cell growth and extended survival.
Am J Surg Pathol 2003; 27(4):461-8. (AN , PMID )
Ductulo-insular pancreatic endocrine neoplasms: clinicopathologic analysis of a unique subtype of pancreatic endocrine neoplasms.
Deshpande V, Selig MK, Nielsen GP, Fernandez-Del Castillo C, Lauwers GY.
Departments of Pathology and Surgery, Massachusetts General Hospital. Boston, Massachusetts, USA.
Pancreatic neoplasms with mixed ductal and endocrine components are a heterogeneous group of tumors. The least recognized of these are pancreatic endocrine tumors displaying benign-appearing tumor-associated ductules.
To characterize these ductulo-insular pancreatic endocrine tumors, the authors reviewed a series of 92 resected pancreatic endocrine tumors.
A total of 15 pancreatic endocrine tumors fulfilled our criteria (16.3%). The average age of the ductulo-insular pancreatic endocrine tumor patients was similar to patients having typical pancreatic endocrine tumors (54 years and 56 years, respectively). These tumors were smaller and more often insulin-positive than typical pancreatic endocrine tumors (P < 0.05). Diffuse stromal fibrosis was more frequent in ductulo-insular pancreatic endocrine tumors as compared to pancreatic endocrine tumors (P < 0.05). The tumor-associated ductules were composed of cuboidal cells with dense eosinophilic cytoplasm and round nuclei without atypia or mitoses. They were positive for cytokeratin 7 and cytokeratin 19 and lacked any neuroendocrine markers. On the contrary, the endocrine component was negative for cytokeratin 7 and cytokeratin 19 and positive for neuroendocrine markers. Ultrastructural examination of the ductulo-insular units confirmed a dual ductal and endocrine differentiation with amphicrine differentiation in one case. Follow-up was available in 12 cases with an average follow-up of 70.1 months. Ten patients were still alive, and two patients had died 81 and 158 months after surgery.
The authors concluded that ductulo-insular pancreatic endocrine tumors are not uncommon and that they are biologically similar to other pancreatic endocrine tumors; the authors also hypothesized that the ductal cells develop by transdifferentiation of the endocrine cells.
To be considered as a ductulo-insular pancreatic endocrine tumor, the authors required the presence and tight intermingling of the ductules with the dominant endocrine component (including the presence of ductulo-insular units).