Growth inhibition and differentiation of pancreatic cancer cell lines by PPAR gamma ligand troglitazone.

INTRODUCTION: Ligand activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) results in growth inhibition and differentiation of various cancer cells. AIMS: We determined whether the PPAR gamma ligand, troglitazone, inhibits the growth of pancreatic cancer cells and clarified the underlying mechanisms with a special focus on restriction point control of the late G1 phase of the cell cycle. METHODOLOGY: Nine pancreatic cancer cell lines were used to study a variety of troglitazone effects on cell growth by MTT assay, on cell cycle by flow cytometry, on cell cycle regulating factors of late G1 phase by Western and Northern blotting and CDK2 kinase assay, and on morphology by collagen gel culture and electron-microscopy. RESULTS: Troglitazone showed a potent dose-response effect on the growth inhibition of six pancreatic cancer cell lines, which were suppressed to less than 50% of control at the concentration of 10 microM. The growth inhibition was linked to the G1 phase cell cycle arrest through the upregulation of p21 mRNA and protein expression simultaneously with the inhibition of CDK2 kinase activity and the hypophosphorylation of Rb protein. The upregulation of expression of p21 mRNA was mainly due to stabilization of mRNA. Troglitazone induced significant morphologic changes of duct structure with apoptotic cells in the lumen. CONCLUSION: Troglitazone had growth inhibitory and differentiation induction effects on the pancreatic cancer cell lines through the upregulation of p21 expression, suggesting that ligand activation of PPAR gamma is a new molecular target for effective therapy against pancreatic cancer.

Extracorporeal shock wave lithotripsy of pancreatic duct stones and patient factors related to stone disintegration.

BACKGROUND: Stones in the main pancreatic duct (MPD) are difficult to remove by endoscopic devices alone in some patients who have chronic pancreatitis. We treated these patients with extracorporeal shock wave lithotripsy (ESWL) and analyzed the patient factors related to disintegration. METHODS: Twenty-four patients were treated with ESWL alone or with combined endoscopic-ESWL to disintegrate or remove MPD stones. RESULTS: Ten patients were treated by ESWL alone and 14 by combined endoscopic-ESWL. A total of 19 patients (79%) were effectively treated by either method. The mean MPD diameter decreased significantly after ESWL. In most of the patients who had chronic abdominal symptoms, these symptoms were relieved at discharge. Severe side effects of complications did not occur during ESWL therapy. Acute abdominal symptoms and a significant increase in the white blood cell count, total bilirubin, and aspartate aminotransferase were observed only immediately after ESWL. Although there were no significant differences, we observed that the patients with a higher stone disintegration success rate showed the following factors: (1) female, (2) non-alcoholic pancreatitis, (3) younger age, (4) shorter duration of symptoms, (5) smaller stones, and (6) a lower Hounsfield unit value of stones. Although about half of the patients had recurring abdominal symptoms and stones during a follow-up period of 12 months, the stones which caused relapse in short-term intervals were disintegrated easily by ESWL. CONCLUSIONS: We may consider the application of ESWL therapies for patients who show the factors associated with easily disintegratable stone conditions. These therapies are highly effective and relatively safe procedures for pancreatic duct stones in such patients.

Usefulness of endoscopic observation of the main duodenal papilla in the diagnosis of sclerosing pancreatitis.

BACKGROUND: There are no descriptions of the appearance of the main duodenal papilla in sclerosing pancreatitis. The intent of the present study was to clarify the characteristics of the main duodenal papilla in patients with sclerosing pancreatitis. METHODS: Macroscopic findings at ERCP with reference to the main duodenal papilla of 17 patients with sclerosing pancreatitis were compared with those of 24 patients with normal ERCP findings, 11 with chronic pancreatitis, 13 with primary sclerosing cholangitis, 21 with pancreatic cancer, and 18 with bile duct cancer. Endoscopic photographs of the papilla were reviewed retrospectively by 3 observers blinded to the underlying pancreaticobiliary pathology. Degree of swelling was scored in all patients. Biopsy specimens from swollen papillae were assessed histopathologically in 3 patients with sclerosing pancreatitis. RESULTS: Severe swelling of the main duodenal papilla was observed in 7 (41%) of 17 patients with sclerosing pancreatitis. The total score for the degree of swelling in patients with sclerosing pancreatitis was significantly higher than that for patients with a normal ERCP, chronic pancreatitis, primary sclerosing cholangitis, pancreatic cancer, and bile duct cancer (p < 0.01). T-lymphocyte infiltration of the papilla was evident in the biopsies from 3 patients with sclerosing pancreatitis. CONCLUSIONS: A swollen main duodenal papilla was a characteristic finding in patients with sclerosing pancreatitis. T-lymphocyte infiltration is present in the swollen main duodenal papilla. These features may be useful in the diagnosis of sclerosing pancreatitis.

Autoimmune pancreatitis is closely associated with gastric ulcer presenting with abundant IgG4-bearing plasma cell infiltration.

BACKGROUND: Autoimmune pancreatitis is characterized by high serum IgG4 concentrations and lymphoplasmacytic infiltration. Because of the diversity of extrapancreatic involvement in this disease, the present study sought to identify other associated GI-tract lesions. METHODS: EGD findings were compared between a group of 23 patients with autoimmune pancreatitis undergoing ERCP for obstructive jaundice and 230 age- and gender-matched control patients. To clarify the histopathologic differences found between these two groups, the histopathologic findings (Updated Sydney System) and the immunohistochemistry of each IgG subclass were compared between 8 patients with autoimmune pancreatitis and gastric ulcer, and 23 control patients with gastric ulcer from which biopsy specimens had been obtained. RESULTS: Gastric ulcer was found significantly more frequently in patients with autoimmune pancreatitis compared with control patients (34.8% vs. 13.5%; p=0.007). There was no significant difference between the groups with respect to the frequency of other GI lesions. Four of 8 gastric ulcers in patients with autoimmune pancreatitis were linear, with the long axis perpendicular to the incisura on the lesser curvature of the stomach. The activity score for the gastric lesions was significantly lower in patients with autoimmune pancreatitis compared with control patients (mean score 0.38 vs. 1.08; p=0.012). There were no significant differences in histopathologic findings with respect to inflammation, atrophy, metaplasia, or Helicobacter pylori scores between the two groups. IgG4-bearing plasma cells were significantly more abundant in gastric lesions in patients with autoimmune pancreatitis compared with those in control patients (mean score 1.75 vs. 0.39; p=0.0008). CONCLUSIONS: Autoimmune pancreatitis is closely associated with gastric ulcer with abundant IgG4-bearing plasma cell infiltration.

Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis.

Sclerosing pancreatitis is associated with raised concentrations of IgG4. We treated 22 patients with sclerosing pancreatitis, and identified and followed-up three with concomitant hydronephrosis caused by ureteral mass, later diagnosed as retroperitoneal fibrosis. We histologically examined the ureteral and pancreatic lesions of these patients and noted abundant infiltration of IgG4-bearing plasma cells in both tissues. Treatment with corticosteroids lowered serum concentrations of IgG4. IgG4 might also have a pathological role in a systemic fibrosing process that includes pancreatic and retroperitoneal lesions.