Search

Objectives The aim of this multicenter retrospective study was to identify the optimal chemotherapeutic regimen for advanced pancreatic acinar cell carcinoma (PACC). Methods Fifty-eight patients with histopathologically confirmed advanced PACC who had received chemotherapy between 1996 and 2013 were enrolled. The clinical characteristics of the patients and the treatment efficacy data were collected from the medical records at 16 Japanese institutions, using standardized data collection instrument. Results The most commonly selected treatment regimens were gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens. The overall response rate in the patients who received first-line chemotherapy were 7% and 38%, respectively, and the median overall survival was 13.2 months. When the data for all the treatment lines were aggregated, the response rates to gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens were 7%, 18%, 40%, and 29%, respectively. The overall survival tended to be better in patients who had received a platinum-containing regimen (hazard ratio, 0.50; 95% confidence interval, 0.23-1.11; P = 0.08) or irinotecan-containing regimen (hazard ratio, 0.42; 95% confidence interval, 0.15-1.19; P = 0.09) at least once in the treatment course as compared with those who had not. Conclusions Our findings suggested that platinum- and irinotecan-containing regimens exhibited some potential efficacy in patients with advanced PACC.

BACKGROUND/PURPOSE Endoscopic transpapillary re-intervention (ETP-RI) after multiple self-expandable metallic stent (SEMS) placement for unresectable malignant hilar biliary obstruction (MHBO) is challenging, but endoscopic ultrasound-guided biliary drainage (EUS-BD) could be an alternative following failed ETP-RI. We investigated appropriate re-intervention (RI) methods in MHBO after multiple SEMS placement and evaluated RI with EUS-BD (EUS-RI) benefits following ETP-RI failure. METHODS Patients requiring RI after multiple SEMS placement for MHBO between October 2017 and April 2021 were enrolled. Patients' characteristics, metallic-stent type, stent-placement configuration, overall survival, stent patency, re-intervention results, and re-intervention technical and clinical success rates were reviewed. RESULTS Forty-nine patients underwent ETP-RI for MHBO. ETP-RI's technical success rate was 69.4%. Of 15 failed ETP-RI cases, all underwent EUS-RI, achieving technical and clinical success rates of 86.7% and 100%, respectively. Time to recurrent biliary obstruction (TRBO) after RI was significantly different between EUS-RI and ETP-RI (212 vs 84 days; P = .01). On multivariate analysis, EUS-RI was the only factor associated with TRBO (odds ratio: 4.48; 95% confidence interval: 1.01-19.91; P = .04). Acute pancreatitis and bile peritonitis were present in 6.1% of ETP-RI and 13.3% of EUS-RI cases, respectively; both improved conservatively. CONCLUSIONS EUS-RI was effective and safe in difficult ETP-RI cases after multiple SEMS placement for MHBO.

Streptozocin (STZ) is a key agent for treating advanced pancreatic neuroendocrine tumors (pNET). Most STZ regimens for pNET are daily and also include 5-fluorouracil (5FU), whereas STZ monotherapy and weekly regimens have also been applied in daily practice in Japan. The present study aimed to evaluate responses to weekly regimens and to STZ monotherapy, and to identify a predictive marker of a response to STZ. Clinical data regarding STZ-based chemotherapy for pNET were collected between 2015 and 2017 at 25 facilities. We analyzed the effects, safety, progression-free survival (PFS), and factors that correlate with responses to STZ. The overall objective response rate (ORR) of 110 patients who underwent STZ-based chemotherapy (monotherapy, 81.8%; weekly regimen 46.4%) was 21.8%, and PFS was 9.8 months. The ORR of weekly vs. daily regimens was 21.6 vs. 22.0% (P = 1.000), and that of monotherapy vs. combination therapy was 21.1 vs. 25.0% (P = 0.766). A Ki67 proliferation index (Ki67) of > 5% was a predictive marker of a response to STZ (P = 0.017), whereas regimen type, mono- or combination therapy, treatment line and liver tumor burden were not associated with responses. The frequencies of Grade ≥ 3 nausea and hematological adverse events were significantly lower for monotherapy than combination therapy (P = 0.032). The effects of weekly STZ monotherapy on pNET are comparable to those previously reported and the toxicity profile was acceptable. Ki67 > 5% was the sole predictive marker of an objective response.

Background and study aim Use of endoscopic ultrasound-guided biliary drainage (EUS-BD) has recently increased. In EUS-BD, after puncturing the bile duct, dilation is performed and the stent is deployed. Due to adverse events (AEs) such as unexpected displacement of the guidewire, simplified procedures are required. Currently, stents with small-diameter delivery systems are being rapidly developed, expanding the possibilities for of EUS-BD without dilation. In this retrospective study, we aimed to evaluate the success rates and AEs in patients who underwent EUS-guided hepaticogastrostomy (EUS-HGS) or EUS-guided hepaticojejunostomy (EUS-HJS) without dilation. Patients and methods Six consecutive patients with malignant biliary obstruction and failed transpapillary BD underwent EUS-HGS or EUS-HJS without dilation, deploying a 6-mm fully-covered self-expandable metallic stent with a 6-Fr delivery system. Results The technical and clinical success rates were 100 %. There was one case each of stent migration and stent occlusion, and no other AEs were noted. Conclusions EUS-HGS or EUS-HJS without dilation using a stent with a 6-Fr delivery system had high technical and clinical success rates; however, additional cases are required to validate the study findings.

Three or more stents may be needed in patients with extensive stricturing in Bismuth type IIIa/IV hilar malignant strictures. Partial stent-in-stent (PSIS) deployment has been the primary intervention for hilar malignant biliary stricture (MBS). However, simultaneous side-by-side (SBS) stent placement has become feasible with the development of the 6F diameter stent delivery system. Our aim was to assess the efficacy and safety of a new hybrid method combining PSIS and SBS stent placement for trisegment biliary drainage.This study included 17 consecutive patients with Bismuth IIIa or IV malignant strictures who underwent endoscopic drainage using the hybrid method. Diameters of the delivery stents were 5.4F (n = 10) and 5.7F (n = 7).The technical success rate was 82% (14/17), and the median length of procedures was 54 minutes. Two patients required predilatation for deployment of the third self-expandable metallic stent through the mesh of the first deployed stent. Two patients (12%) developed cholecystitis as early adverse events, and 1 patient (6%) developed liver abscess as a late adverse event. The time to recurrent biliary obstruction among those with successful initial trisegmental drainage was 189 days (95% confidence interval, 124-254).The hybrid method for unresectable hilar MBS is an effective endoscopic drainage method, and the ease of these procedures is partly attributed to the thinner stent delivery system.

Objectives This study investigated whether a risk assessment nomogram can predict the malignant potential of intraductal papillary mucinous neoplasms (IPMNs) and provide valuable information for the follow-up and counseling strategies of such patients. Methods We studied 126 of 589 patients with IPMN who were followed up for at least 36 months with annual endoscopic ultrasonography. We analyzed scores derived from our nomogram, incorporating the parameters of sex, lesion type, mural nodule height, and pancreatic juice cytology determined at the initial IPMN evaluation. Results The rate of malignant IPMNs was 5.5% (7/126). The initial average nomogram score was 19.8 (range, 0-55), and the final follow-up average was 23.8 (range, 0-109). When a cutoff score was set at 35 points, the sensitivity, specificity, and accuracy of the nomogram to assess malignancy risk were 87.5%, 96.6%, and 96%, respectively. The area under the receiver operating characteristic curve of malignant IPMN prediction during follow-up was 0.865. Conclusions The ability of the nomogram to predict malignancy in patients with IPMN was validated. Our findings can suggest that a follow-up for patients at high and low risk for cancer progression could be scheduled every 3 to 6 and 12 months, respectively.

We report three cases with unresectable locally advanced pancreatic cancer (PC) treated with a combination of chemoradiotherapy (CRT) and systemic chemotherapy, using gemcitabine (GEM) and/or S-1. All three cases were diagnosed as having locally advanced unresectable PC without distant metastatic lesions based on computed tomography, endoscopic retrograde pancreatography and/or blushing cytology. In Cases 1 and 2, we applied a so-called sandwich therapy, which consisted of induction chemotherapy before CRT and maintenance chemotherapy after CRT. The induction and maintenance chemotherapy in Cases 1 and 2 used a combination of GEM and S-1, whereas maintenance therapy with GEM or S-1 was applied in Case 3. S-1-based CRT was performed in Cases 1 and 2, and GEM-based CRT in Case 3. Survivals were 27 and 65 months, respectively, in two cases, and the disease remained stable in the other case 30 months after diagnosis. We show three cases with unresectable locally advanced PC who achieved long-term survival (27-65 months) after treatment with a combination of CRT and systemic chemotherapy, using GEM and/or S-1. Our findings indicate that sandwich therapy might be particularly effective for locally advanced PC.

Objectives To elucidate the role of transforming growth factor (TGF) beta1 and extracellular matrix (ECM) after acute necrotizing pancreatitis, we studied the regulation of TGF-beta1 and ECM after induction of pancreatitis. Methods We examined the serial changes of levels of plasma TGF-beta1 by enzyme-linked immunoassay and expression of TGF-beta1 and ECM by Northern and Western blot analyses, respectively, in the pancreas after induction of sodium taurocholate-induced acute pancreatitis. Results Plasma total (active and inactive) TGF-beta1 levels at 3 hours after induction of pancreatitis were significantly increased compared with baseline values. The levels of TGF-beta1 messenger RNA (mRNA) were unaltered by day 2. Levels of fibronectin mRNA at 3 hours after induction of pancreatitis were already higher than the baseline values. Latency-associated peptide-TGF-beta1 showed a peak on day 7. Thus, the expression of ECM mRNA increased earlier than that of TGF-beta1 mRNA. Conclusions These results suggest that the increase in plasma TGF-beta1 concentration probably results from the elevated secretion of TGF-beta1 from several cells and/or the redistribution of TGF-beta1 protein and that the increase in expression of ECM probably is associated with the activation of TGF-beta1. It is conceivable that both increased plasma concentration and focal activation of TGF-beta1 play an important role in ECM production during the early stage of acute pancreatitis.

Background and aims The imbalance between synthesis and degradation of extracellular matrix (ECM) proteins is a characteristic feature in chronic pancreatitis. We evaluated the relationship between type IV collagen structure in the basement membrane (BM) and the development of acinar atrophy or the regeneration from acinar injury. Methods Three different models of pancreatitis were induced in rats by repetitive intraperitoneal injections of 500 mg/100 g body weight of arginine (Arg) or 20 microg/kg body weight of caerulein (Cn) or a single retrograde intraductal infusion of 40 microL/100 g body weight of 3% sodium taurocholate (NaTc). We examined the changes in type IV collagen structure by immunostaining, and the serial changes in the gelatinolytic activity of pro- and active matrix metalloproteinase-2 by zymography in these models of pancreatitis. Results The pancreas appeared to be histologically normal on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc, whereas 85% to 90% of acinar tissue was replaced by fatty tissue and dilated pancreatic ducts on day 54 after the first intraperitoneal Arg injection. Immunoreactivity for type IV collagen appeared as a discontinuous line along the BM of ducts, vessels, tubular complexes, and acinar cells on day 40 in Arg-induced pancreatitis, whereas it was detected as a continuous line along the BM on day 35 in Cn-induced pancreatitis and on day 42 in NaTc-induced pancreatitits. Gelatinolytic activity of active MMP-2 increased significantly from day 13 to day 40 after the first intraperitoneal Arg injection, whereas it decreased to the baseline level on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc. Conclusions Our findings indicate that a long-term increase in gelatinolytic activity of active MMP-2 in Arg-induced pancreatitis causes continuous disorganization of type IV collagen in the BM and progressive acinar atrophy, whereas a transient increase in gelatinolytic activity of active MMP-2 is involved in the regeneration of type IV collagen structure in the BM and recovery from acinar injury.

Introduction Dibutyltin dichloride (DBTC) is widely used as a stabilizer for polyvinylchloride plastics and is of particular toxicologic interest. Aim To examine the effects of DBTC on pancreatic exocrine function in isolated rat pancreatic acini. Methodology Isolated rat pancreatic acini were incubated with various secretagogues in the presence or absence of DBTC. We investigated the effects of DBTC on amylase release, receptor binding, and protein kinase C (PKC) enzyme activity. Results DBTC reduced cholecystokinin octapeptide (CCK-8)–stimulated and carbamylcholine-stimulated amylase release and the binding of [125I]CCK-8 to isolated rat pancreatic acini. Conversely, DBTC potentiated secretin-stimulated amylase release, although it slightly inhibited [125I]secretin binding to its receptors. In addition, DBTC potentiated amylase release stimulated by vasoactive intestinal peptide, 8-bromoadenosine 3´, 5´-monophosphate (8Br-cAMP) or calcium ionophore A23187, whereas it had no influence on amylase release stimulated by 12-O-tetradecanoylphorbol 13-acetate. The protein kinase C (PKC) inhibitor calphostin C abolished the DBTC-induced potentiation of amylase release stimulated by 8Br-cAMP or A23187. Moreover, DBTC caused a significant translocation of PKC enzyme activity from cytosol to membrane fraction. Conclusions These results indicate that DBTC reduces CCK-8- and carbamylcholine-stimulated amylase release by inhibiting their receptor bindings to pancreatic acini, whereas it potentiates cAMP-mediated amylase release by activating PKC in isolated rat pancreatic acini.

Considered to be an etiologic factor of acute pancreatitis, hypersecretion of pancreatic juice and digestive enzymes is often associated with hyperbilirubinemia. We explored the intracellular mechanisms through which bilirubin affects pancreatic exocrine secretory function by examining the effect of bilirubin on isolated rat pancreatic acini. Bilirubin stimulated amylase release in a concentration- and time-dependent manner, significantly increasing amylase release at concentrations >5 mg/100 ml and after 15 min of incubation. Coincubation of bilirubin with vasoactive intestinal polypeptide, 8-bromo-cAMP, or A-23187 had a synergistic effect on amylase release, whereas coincubation with CCK-8, carbamylcholine, or 12- O-tetradecanoylphorbol 13-acetate had an additive effect. Bilirubin did not affect acinar cAMP content or Ca2+efflux. Intracellular Ca2+pool depletion had no influence on bilirubin-evoked amylase release. The protein kinase C (PKC) inhibitors staurosporine and calphostin C partially but significantly inhibited bilirubin-stimulated amylase release, whereas the PKA inhibitor H-89 did not. The tyrosine kinase (TK) inhibitor genistein, phospholipase A2(PLA2) inhibitor indoxam, and PLC inhibitor U-73122 also inhibited amylase release. Bilirubin significantly translocated PKC activity from the cytosol to the membrane fraction and activated TK in cytosol and membrane fractions. These results indicate that bilirubin stimulates amylase release by activating PKC and TK in rat pancreatic acini and that PLC and PLA2partly mediate this process.

Background/objectives Despite advances in imaging techniques, diagnosis and management of pancreatic cystic lesions still remains challenging. The objective of this study was to determine the utility of cyst fluid analysis (CEA, CA 19-9, CA 125, amylase, and cytology) in categorizing pancreatic cystic lesions, and in differentiating malignant from benign cystic lesions. Methods A retrospective analysis of 68 patients with histologically and clinically confirmed cystic lesions was performed. Cyst fluid was obtained by surgical resection ( n = 45) or endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) ( n = 23). Cyst fluid tumor markers and amylase were measured and compared between the cyst types. Results Receiver operating characteristic (ROC) curve analysis of the tumor markers demonstrated that cyst fluid CEA provided the greatest area under ROC curve (AUC) (0.884) for differentiating mucinous versus non-mucinous cystic lesions. When a CEA cutoff value was set at 67.3 ng/ml, the sensitivity, specificity and accuracy for diagnosing mucinous cysts were 89.2%, 77.8%, and 84.4%, respectively. The combination of cyst fluid CEA content >67.3 ng/ml and cyst fluid CA 125 content >10.0 U/ml segregated 77.8% (14/18) of mucinous cystic neoplasms (MCNs) from other cyst subtypes. On the other hand, no fluid marker was useful for differentiating malignant versus benign cystic lesions. Although cytology (accuracy 83.3%) more accurately diagnosed malignant cysts than CEA (accuracy 65.6%), it lacked sensitivity (35.3%). Conclusions Our results demonstrate that cyst fluid CEA can be a helpful marker in differentiating mucinous from non-mucinous, but not malignant from benign cystic lesions. A combined CEA and CA 125 approach may help segregate MCNs from IPMNs.

Bile duct cancer (BDC) has a lower propensity for distant metastasis during the early part of its natural history, and local extension into adjacent vessels and longitudinal intraductal extension are of critical prognostic importance. Superficial intraductal spread (SIDS) is a characteristic feature of this tumor and is associated with a more-differentiated phenotype and a less-aggressive clinical course. However, the presence of SIDS correlates with positive resection margins after surgery. Hence, preoperative identification of the exact proximal and distal margins is important for deciding whether the surgical approach should comprise extrahepatic bile duct resection with or without pancreatoduodenectomy (PD) and whether rightor left-sided hepatectomy is needed. Direct cholangioscopic intraductal visualization, with or without narrow-band imaging, is important for evaluating SIDS. Despite these enhanced imaging techniques, stent-induced or cholangitis-induced mucosal changes are often difficult to differentiate from neoplastic involvement in a segment of bile duct, without tissue sampling. The use of intraductal biopsy specimens for diagnosing SIDS of BDC can be performed by percutaneous transhepatic cholangioscopy, but this technique is time consuming, invasive, and might result in cancer seeding. Hence, using an endoscopic route for obtaining transpapillary biopsy specimens may be preferable. Although the use of forceps biopsy in the diagnosis of stenotic bile duct lesions with fluoroscopic targeting or

A prospective clinical study was conducted to evaluate the safety, feasibility, and efficacy of endoscopic ultrasound (EUS)-guided choledochoduodenostomy (CDS) with direct metallic stent placement using a prototype forward-viewing echoendoscope. The indication for EUS – CDS in this study was lower biliary obstruction only, and not failed endoscopic biliary drainage, because the aim was to evaluate EUS – CDS for first-line biliary drainage therapy. The technical and functional success rates were 94 % (17 /18) and 94 % (16 /17), respectively. Early complications (focal peritonitis) were encountered in two patients (11 %). No patients developed late complications. EUS – CDS with direct metallic stent placement using a forward-viewing echoendoscope was generally feasible and effective for malignant distal biliary tract obstruction. The forward-viewing echoendoscope was useful, especially for deploying the metallic stent.

Objectives We examined the effect of the overexpression of Smad6 on pancreatic fibrosis after chronic pancreatic injury. Methods Chronic pancreatic injury was induced in transgenic mice overexpressing Smad6 (Tg mice) in acini and wild-type (Wt) mice by 3 episodes of acute pancreatitis per week for 1 to 4 consecutive weeks. Acute pancreatitis was elicited by 6 intraperitoneal injections of caerulein (Cn) at 50 microg/kg of body weight at hourly intervals. Pancreatic fibrosis was evaluated by histological examination and hydroxyproline content before and 1, 2, 3, and 4 weeks of repetitive episodes of Cn-induced acute pancreatitis. We further determined transforming growth factor beta1 (TGF-beta1) messenger RNA expression and trypsin activity in the pancreas. Results After repetitive episodes of acute pancreatitis, pancreatic fibrosis in Tg mice was significantly severer than that in Wt mice at all time points (weeks 1-4). The expression of TGF-beta1 messenger RNA and the activity of trypsin in the pancreas in the Tg mice were significantly high compared with those in the Wt mice at all corresponding time points after repetitive episodes of acute pancreatitis. Conclusions These results demonstrated that overexpression of Smad6 in acini enhanced the development of pancreatic fibrosis after chronic pancreatic injury.

Transforming growth factor-beta (TGF-beta) is an important cytokine in the fibrogenesis in many organs, including the pancreas. Using an adenoviral vector expressing the entire extracellular domain of type II human TGF-beta receptor (AdTbeta-ExR), we investigated whether inhibition of TGF-beta action is effective against persistent pancreatic fibrosis, and whether it exerts a beneficial effect on the pancreas in the process of chronic injury. To induce chronic pancreatic injury and pancreatic fibrosis, mice were subjected to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 microg/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTbeta-ExR, or with a control adenoviral vector expressing bacterial beta-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for alpha-smooth muscle actin. Apoptosis and proliferation of acinar cells were assessed by immunostaining of ssDNA and Ki-67, respectively. Three-week cerulein injection induced pancreatic fibrosis and pancreatic atrophy with proliferation of activated PSCs. In AdTbeta-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTbeta-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTbeta-ExR did not change the proportion of proliferating acinar cells, whereas it reduced the number of apoptotic acinar cells. Our results demonstrate that inhibition of TGF-beta action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.

The renin-angiotensin system (RAS) plays important roles in various pathophysiological processes. However, the role of the RAS in pancreatic fibrosis has not been established. We investigated the role of angiotensin II (ANG II)-ANG II type 1 (AT1) receptor pathway in the development of pancreatic fibrosis with AT1areceptor-deficient [AT1a(−/−)] mice. To induce pancreatic fibrosis, AT1a(−/−) and wild-type (WT) mice were submitted to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 μg/kg body wt cerulein at hourly intervals, per week, for four consecutive weeks. Pancreatic fibrosis was assessed by histology and hydroxyproline content. Pancreatic stellate cell (PSC) activation and the localization of AT1receptors were assessed by Western blot analysis for α-smooth muscle actin and immunostaining. Transforming growth factor-β1(TGF-β1) mRNA expression in the pancreas was assessed by RT-PCR. Six intraperitoneal injections of cerulein induced acute pancreatitis in both AT1a(−/−) and WT mice. There were no significant differences between two groups with regard to serum amylase and histological changes. Pancreatic fibrosis induced by repeated episodes of acute pancreatitis was significantly attenuated in AT1a(−/−) mice compared with that in WT mice. This finding was accompanied by a reduction of activated PSCs. Dual-immunofluorescence staining in WT mice revealed that activated PSCs express AT1receptors. The level of TGF-β1mRNA was lower in AT1a(−/−) mice than in WT mice. Our results demonstrate that the ANG II-AT1receptor pathway is not essential for the local pancreatic injury in acute pancreatitis but plays an important role in the development of pancreatic fibrosis through PSC activation and proliferation.

incomplete exam included intubated patients (2/14), inadequate sedation (9/14), and inability to see the entire hypopharynx (3/14). The mean time of the WLE was 20.2 seconds while the NBI evaluation took 15.6 seconds for a mean 35.8 seconds for the entire exam of the hypopharynx and larynx. All patients then had successful examination of the esophagus/stomach/duodenum. There were 6 patients who had hypopharyngeal abnormalities seen on both WLE and NBI (5.4%) and were subsequently referred to otolaryngology. Of the 6 referrals, one patient had a vocal cord biopsy showing leukoplakia while the others were deemed normal anatomic variants. Minor procedural complications occurred in 3/111 (2.7%) of the patients and included hypotension, tachycardia, and hypoxia. Conclusion: Evaluation of the hypopharynx can be accomplished by gastrointestinal endoscopists at the time of EGD in the majority of patients in a safe manner while adding only about 35 seconds to the overall exam time.

Pancreatic stellate cells (PSCs) play a central role in development of pancreatic fibrosis. In chronic pancreatitis, pancreatic tissue pressure is higher than that of the normal pancreas. We here evaluate the effects of pressure on the activation of rat PSCs. PSCs were isolated from the pancreas of Wistar rat using collagenase digestion and centrifugation with Nycodenz gradient. Pressure was applied to cultured rat PSCs by adding compressed helium gas into the pressure-loading apparatus to raise the internal pressure. Cell proliferation rate was assessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation. MAPK protein levels and alpha-smooth muscle actin (alpha-SMA) expression were evaluated by Western blot analysis. Concentration of activated transforming growth factor-beta1 (TGF-beta1) secreted from PSCs into culture medium was determined by ELISA. Collagen type I mRNA expression and collagen secretion were assessed by quantitative PCR and Sirius red dye binding assay, respectively. Application of pressure significantly increased BrdU incorporation and alpha-SMA expression. In addition, pressure rapidly increased the phosphorylation of p44/42 and p38 MAPK. Treatment of PSCs with an MEK inhibitor and p38 MAPK inhibitor suppressed pressure-induced cell proliferation and alpha-SMA expression, respectively. Moreover, pressure significantly promoted activated TGF-beta1 secretion, collagen type I mRNA expression, and collagen secretion. Our results demonstrate that pressure itself activates rat PSCs and suggest that increased pancreatic tissue pressure may accelerate the development of pancreatic fibrosis in chronic pancreatitis.