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Background/Aims: We previously reported early-stage pancreatic histological features in an experimental chronic pancreatitis model, prepared by injecting oleic acid into the pancreatic duct. In this model, on day 2 after injection, reactive fibroblasts in association with inflammation appeared in the stroma, however, myofibroblasts, which were activated fibroblasts, were not detected. On day 4, myofibroblasts appeared in the stroma, and the lobular architecture was destroyed. On day 28, pancreatic acinar cells were completely necrotized and exfoliated, and the stroma was replaced by collagen fibers. On the other hand, it is known that the long-term oral administration of a protease inhibitor (PI) to rats causes pancreatic enlargement as a trophic effect. In this study, we investigated the trophic effect of an oral PI on the rat pancreas. And we examined the trophic effect on pancreatic regeneration in a pancreatic fibrosis model. Subjects: Male Wistar rats weighing about 200 g were used. ONO-3403 (Ono Pharmaceutical Co., Ltd., Osaka, Japan) was used as a potent oral PI. The PI action of ONO-3403 is five-fold stronger than that of camostat mesilate, the only oral PI now used clinically in Japan. Methods: (1) Normal rats were fed with standard feed or 0.1% ONO-3403-containing feed. The pancreases were removed on day 7, 14, 25. Pancreatic amylase, protein, and DNA contents, as well as pancreatic wet weights, were measured. (2) The abdominal cavity of rats was opened, 100 μl of oleic acid, a cytotoxic agent, was injected into the pancreatic duct, and the cavity was closed. Administration of 0.1% ONO-3403-containing feed was started from day 2 (A gourp) or from day 4 (B group) after injection. On day 28, the pancreases were removed and examined. Results: (1) On day 25 after ONO-3403 administration, the pancreatic wet weights increased over time by about 2.2 times. The amylase, protein, and DNA contents increased by about 3.7, 2.9, and 1.8 times, respectively. The increased protein content suggestive of “hypertrophy” was more marked than the increased DNA content suggestive of “hyperplasia”. (2) In the A group on day 28, pancreatic histological features showed the inhibition of pancreatic fibrosis and regeneration of pancreatic acinar cells. In addition, the pancreatic wet weights and contents similarly increased. However, in the B group on day 28, no improvement of pancreatic fibrosis was found. Conclusions: (1) The long-term oral administration of a potent PI showed marked trophic effects on the rat pancreas, however, the trophic effects contributed to hypertrophy rather than hyperplasia. (2) In a pancreatic fibrosis model, the long-term oral administration of a potent PI, from an early stage when no myofibroblasts appeared in the pancreatic stoma, also showed pancreatic trophic effects and led to the regeneration of pancreatic acinar cells.

Background: “Bull's eye calculi” and a preserved pancreatic parenchyma have been founded in patients suffering from chronic pancreatitis associated with gene mutation (CPgm+). Aim: To evaluate radiological pancreatic findings in patients suffering from chronic calcifying pancreatitis. Patients and methods: From May 2006 to June 2007, 27 patients suffering from chronic calcifying pancreatitis were prospectively enrolled. Exclusion criteria were: patients with previous pancreatic surgery. All patients were underwent genetic tests (35 main CFTR gene mutations, R121H and N29I gene mutations on PRSS1 gene, and N34S gene mutation on SPINK1 gene) and MDCT. Images analysis was evaluated by two independent radiologists. Qualitative criteria were: structure of the endoductal calculi (homogeneous/ heterogeneous with presence of a non-calcified central core “bull's eye”), pancreatic parenchyma contrast-enhancement in pancreatic phase compared to renal cortex (hypo-/iso-/ hyper-vascular). Quantitative criteria were: number and diameter of endoductal calculi, size of pancreatic parenchyma (head, body, tail), size of main pancreatic duct (MPD). Results: 27 patients (17 males and 10 females mean age 45 ± 12 yrs) were enrolled in the study. We found 8 gene mutations in seven pts (26%) (4 CFTR, 3 SPINK1 and 1 PRSS1). Heterogeneous calculi with non-calcified central core (“bull's eye”) were observed in 7 out of 27 pts (25%), 5 out of 7 in CPgm+ group (71%) and 2 out of 20 (10%) in CPgmgroup (p= 0.005). The 2 CPgmpatients with presence of “bull's eyes” calculi at MDCT had clinical characteristic suggestive for the presence of gene mutations (age at onset 20 and 25 yrs). The other radiological qualitative and quantitative analysis is reported in Table. Conclusions: The presence of “bull's eye” calculi at MDCT are suggestive for chronic pancreatitis associated with gene mutations.