Modified duval procedure for small-duct chronic pancreatitis without head dominance.

PubMed

Oida, Takatsugu; Aramaki, Osamu; Kano, Hisao; Mimatsu, Kenji; Kawasaki, Atsushi; Kuboi, Youichi; Fukino, Nobutada; Kida, Kazutoshi; Amano, Sadao

2011-01-01

In the case of small-duct chronic pancreatitis, surgery for pain relief is broadly divided into resection and drainage procedures. These procedures should be selected according to the location of dominant lesion, diameter of the pancreatic duct and extent of the disease. The appropriate procedure for the treatment of small-duct chronic pancreatitis, especially small-duct chronic pancreatitis without head dominance, remains controversial. We developed the modified Duval procedure for the treatment of small-duct chronic pancreatitis without head dominance and determined the efficacy of this procedure. We retrospectively studied 14 patients who underwent surgical drainage with or without pancreatic resection for chronic pancreatitis with small pancreatic duct (<7mm) without head dominance. These patients were divided into 2 groups; the modified Puestow procedure group and the modified Duval procedure group. No complications occurred in the modified Duval group. In the modified Puestow procedure group, complete and partial pain relief were observed in 62.5%, and 37.5% of patients respectively. In contrast, complete pain relief was observed in all the patients in the modified Duval procedure group. Our modified Duval procedure is useful and should be considered the appropriate surgical technique for the treatment of small-duct chronic pancreatitis without head dominance.

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

PubMed Central

Stewart, Andrew K.; Shmukler, Boris E.; Vandorpe, David H.; Reimold, Fabian; Heneghan, John F.; Nakakuki, M.; Akhavein, Arash; Ko, Shigeru; Ishiguro, Hiroshi

2011-01-01

The secretin-stimulated human pancreatic duct secretes HCO3−-rich fluid essential for normal digestion. Optimal stimulation of pancreatic HCO3− secretion likely requires coupled activities of the cystic fibrosis transmembrane regulator (CFTR) anion channel and apical SLC26 Cl−/HCO3− exchangers. However, whereas stimulated human and guinea pig pancreatic ducts secrete ∼140 mM HCO3− or more, mouse and rat ducts secrete ∼40–70 mM HCO3−. Moreover, the axial distribution and physiological roles of SLC26 anion exchangers in pancreatic duct secretory processes remain controversial and may vary among mammalian species. Thus the property of high HCO3− secretion shared by human and guinea pig pancreatic ducts prompted us to clone from guinea pig pancreatic duct cDNAs encoding Slc26a3, Slc26a6, and Slc26a11 polypeptides. We then functionally characterized these anion transporters in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. In Xenopus oocytes, gpSlc26a3 mediated only Cl−/Cl− exchange and electroneutral Cl−/HCO3− exchange. gpSlc26a6 in Xenopus oocytes mediated Cl−/Cl− exchange and bidirectional exchange of Cl− for oxalate and sulfate, but Cl−/HCO3− exchange was detected only in HEK 293 cells. gpSlc26a11 in Xenopus oocytes exhibited pH-dependent Cl−, oxalate, and sulfate transport but no detectable Cl−/HCO3− exchange. The three gpSlc26 anion transporters exhibited distinct pharmacological profiles of 36Cl− influx, including partial sensitivity to CFTR inhibitors Inh-172 and GlyH101, but only Slc26a11 was inhibited by PPQ-102. This first molecular and functional assessment of recombinant SLC26 anion transporters from guinea pig pancreatic duct enhances our understanding of pancreatic HCO3− secretion in species that share a high HCO3− secretory output. PMID:21593449

Characterization of Insulin-Immunoreactive Cells and Endocrine Cells Within the Duct System of the Adult Human Pancreas.

PubMed

Li, Rong; Zhang, Xiaoxi; Yu, Lan; Zou, Xia; Zhao, Hailu

2016-01-01

The adult pancreatic duct system accommodates endocrine cells that have the potential to produce insulin. Here we report the characterization and distribution of insulin-immunoreactive cells and endocrine cells within the ductal units of adult human pancreas. Sequential pancreas sections from 12 nondiabetic adults were stained with biomarkers of ductal epithelial cells (cytokeratin 19), acinar cells (amylase), endocrine cells (chromogranin A; neuron-specific enolase), islet hormones (insulin, glucagon, somatostatin, pancreatic polypeptide), cell proliferation (Ki-67), and neogenesis (CD29). The number of islet hormone-immunoreactive cells increased from large ducts to the terminal branches. The insulin-producing cells outnumbered endocrine cells reactive for glucagon, somatostatin, or pancreatic polypeptide. The proportions of insulin-immunoreactive count compared with local islets (100% as a baseline) were 1.5% for the main ducts, 7.2% for interlobular ducts, 24.8% for intralobular ducts, 67.9% for intercalated ducts, and 348.9% for centroacinar cells. Both Ki-67- and CD29-labeled cells were predominantly localized in the terminal branches around the islets. The terminal branches also showed cells coexpressing islet hormones and cytokeratin 19. The adult human pancreatic ducts showed islet hormone-producing cells. The insulin-reactive cells predominantly localized in terminal branches where they may retain potential capability for β-cell neogenesis.

Tuft Cell Regulation of miRNAs in Pancreatic Cancer

DTIC Science & Technology

2013-10-01

are involved in chemosensensing of the microenvironment. With the successful deletion of Dclk1 throughout the pancreatic ducts , we can begin...characterization, which extends our understanding of the role tuft cells play within ducts and their broader effects on the overall pancreatic...characterization of Pdx-1-Cre;Dclk1flox/flox was completed which demonstrated the loss of Dclk1 expression within tuft cells in all pancreatic ducts

Biliary Stenosis and Gastric Outlet Obstruction: Late Complications After Acute Pancreatitis With Pancreatic Duct Disruption.

PubMed

Sugimoto, Motokazu; Sonntag, David P; Flint, Greggory S; Boyce, Cody J; Kirkham, John C; Harris, Tyler J; Carr, Sean M; Nelson, Brent D; Bell, Don A; Barton, Joshua G; Traverso, L William

2018-07-01

Pancreatic duct disruption (PDD) after acute pancreatitis can cause pancreatic collections in the early phase and biliary stenosis (BS) or gastric outlet obstruction (GOO) in the late phase. We aimed to document those late complications after moderate or severe acute pancreatitis. Between September 2010 and August 2014, 141 patients showed pancreatic collections on computed tomography. Percutaneous drainage was primarily performed for patients with signs or symptoms of uncontrolled pancreatic juice leakage. Pancreatic duct disruption was defined as persistent amylase-rich drain fluid or a pancreatic duct cut-off on imaging. Clinical course of the patients who developed BS or GOO was investigated. Among the 141 patients with collections, 33 patients showed PDD in the pancreatic head/neck area. Among them, 9 patients (27%) developed BS 65 days after onset and required stenting for 150 days, and 5 patients (15%) developed GOO 92 days after onset and required gastric decompression and jejunal tube feeding for 147 days (days shown in median). All 33 patients recovered successfully without requiring surgical intervention. Anatomic proximity of the bile duct or duodenum to the site of PDD and severe inflammation seemed to contribute to the late onset of BS or GOO. Conservative management successfully reversed these complications.

Application of "papillary-like main pancreatic duct invaginated" pancreaticojejunostomy for normal soft pancreas cases.

PubMed

Zhang, Bo; Xu, Jin; Liu, Chen; Long, Jiang; Liu, Liang; Xu, Yongfeng; Wu, Chuntao; Luo, Guopei; Ni, Quanxing; Li, Min; Yu, Xianjun

2013-01-01

Pancreaticojejunostomy is the key procedure of pancreaticoduodenectomy. Our study introduced a new pancreaticojejunal (PJ) anastomosis named "papillary-like main pancreatic duct invaginated" pancreaticojejunostomy. Nighty-two patients underwent pancreaticojejunostomy with either conventional duct-to-mucosa pancreaticojejunostomy or the new "papillary-like main pancreatic duct invaginated" techniques were analyzed retrospectively from January 2010 to September 2012. The incidence of pancreatic fistula was 15.7% (8/51) for the "papillary-like main pancreatic duct invaginated" group and 19.5% (8/41) for the duct-to-mucosa fashion respectively. It is noteworthy that the rate of grade B/C postoperative pancreatic fistula (POPF) in the "papillary-like main pancreatic duct invaginated" group was significantly lower than that of the duct-to-mucosa group (P = 0.039). There were no differences in the incidence of postoperative morbidity and mortality such as postoperative hemorrhage, delayed gastric emptying or remnant pancreatitis. The "papillary-like main pancreatic duct invaginated" pancreaticojejunostomy could provide a feasible option to pancreatic surgeons for patients with normal soft pancreas.

Extracorporeal shock wave lithotripsy for obstructing pancreatic duct calculi.

PubMed

Matthews, K; Correa, R J; Gibbons, R P; Weissman, R M; Kozarek, R A

1997-08-01

A review was done to determine the effectiveness of extracorporeal shock wave lithotripsy (ESWL) in the treatment of impacted pancreatic duct calculi. A total of 19 patients, who were potential candidates for radical pancreatic surgery after unsuccessful endoscopic retrograde cholangiopancreatography, sphincterotomy and attempted stone extraction from the pancreatic ducts, underwent ESWL of the calculi. Followup ranged from 6 months to 6 years. Of the 19 patients 14 avoided a major operation and 6 have remained pain-free for the long term. Two patients died of causes not related to ESWL or endoscopic retrograde cholangiopancreatography. Five patients eventually underwent a Whipple or Puestow procedure for relief of symptoms or persistent obstruction. Complications were minimal. ESWL is a valuable adjunct in patients with impacted pancreatic duct calculi unretrievable by primary endoscopic retrograde cholangiopancreatography.

Pancreatic duct stones in patients with chronic pancreatitis: surgical outcomes.

PubMed

Liu, Bo-Nan; Zhang, Tai-Ping; Zhao, Yu-Pei; Liao, Quan; Dai, Meng-Hua; Zhan, Han-Xiang

2010-08-01

Pancreatic duct stone (PDS) is a common complication of chronic pancreatitis. Surgery is a common therapeutic option for PDS. In this study we assessed the surgical procedures for PDS in patients with chronic pancreatitis at our hospital. Between January 2004 and September 2009, medical records from 35 patients diagnosed with PDS associated with chronic pancreatitis were retrospectively reviewed and the patients were followed up for up to 67 months. The 35 patients underwent ultrasonography, computed tomography, or both, with an overall accuracy rate of 85.7%. Of these patients, 31 underwent the modified Puestow procedure, 2 underwent the Whipple procedure, 1 underwent simple stone removal by duct incision, and 1 underwent pancreatic abscess drainage. Of the 35 patients, 28 were followed up for 4-67 months. There was no postoperative death before discharge or during follow-up. After the modified Puestow procedure, abdominal pain was reduced in patients with complete or incomplete stone clearance (P>0.05). Steatorrhea and diabetes mellitus developed in several patients during a long-term follow-up. Surgery, especially the modified Puestow procedure, is effective and safe for patients with PDS associated with chronic pancreatitis. Decompression of intraductal pressure rather than complete clearance of all stones predicts postoperative outcome.

Application of “Papillary-Like Main Pancreatic Duct Invaginated” Pancreaticojejunostomy for Normal Soft Pancreas Cases

PubMed Central

Zhang, Bo; Xu, Jin; Liu, Chen; Long, Jiang; Liu, Liang; Xu, Yongfeng; Wu, Chuntao; Luo, Guopei; Ni, Quanxing; Li, Min; Yu, Xianjun

2013-01-01

Pancreaticojejunostomy is the key procedure of pancreaticoduodenectomy. Our study introduced a new pancreaticojejunal (PJ) anastomosis named “papillary-like main pancreatic duct invaginated” pancreaticojejunostomy. Nighty-two patients underwent pancreaticojejunostomy with either conventional duct-to-mucosa pancreaticojejunostomy or the new “papillary-like main pancreatic duct invaginated” techniques were analyzed retrospectively from January 2010 to September 2012. The incidence of pancreatic fistula was 15.7% (8/51) for the “papillary-like main pancreatic duct invaginated” group and 19.5% (8/41) for the duct-to-mucosa fashion respectively. It is noteworthy that the rate of grade B/C postoperative pancreatic fistula (POPF) in the “papillary-like main pancreatic duct invaginated” group was significantly lower than that of the duct-to-mucosa group (P = 0.039). There were no differences in the incidence of postoperative morbidity and mortality such as postoperative hemorrhage, delayed gastric emptying or remnant pancreatitis. The “papillary-like main pancreatic duct invaginated” pancreaticojejunostomy could provide a feasible option to pancreatic surgeons for patients with normal soft pancreas. PMID:23797701

Indications and results of pancreatic stump duct occlusion after duodenopancreatectomy.

PubMed

Alfieri, Sergio; Quero, Giuseppe; Rosa, Fausto; Di Miceli, Dario; Tortorelli, Antonio Pio; Doglietto, Giovanni Battista

2016-09-01

Severe post-operative complications after pancreaticoduodenectomy (PD) are largely due to pancreatic fistula onset. The occlusion of the main pancreatic duct using synthetic glue may prevent these complications. Aim of this study is to describe this technique and to report short- and long-term results as well as the post-operative endocrine and exocrine insufficiency. Two hundred and four patients who underwent PD with occlusion of the main pancreatic duct in a period of 15 years were retrospectively analyzed. Post-operative complications and their management were the main aim of the study with particular focus on pancreatic fistula incidence and its treatment. At 1-year follow-up endocrine and exocrine functions were analyzed. We observed a 54 % pancreatic fistula incidence, most of which (77/204 patients) were a grade A fistula with little change in medical management. Twenty-eight patients developed a grade B fistula while only 2 % of patients (5/204) developed a grade C fistula. Nine patients required re-operation, 5 of whom had a post-operative grade C fistula. Post-operative mortality was 3.4 %. At 1-year follow-up, 31 % of patients developed a post-operative diabetes while exocrine insufficiency was encountered in 88 % of patients. The occlusion of the main pancreatic duct after PD can be considered a relatively safe and easy-to-perform procedure. It should be reserved to selected patients, especially in case of soft pancreatic texture and small pancreatic duct and in elderly patients with comorbidities, in whom pancreatic fistula-related complications could be life threatening.

Loss of Canonical Smad4 Signaling Promotes KRAS Driven Malignant Transformation of Human Pancreatic Duct Epithelial Cells and Metastasis

PubMed Central

Leung, Lisa; Radulovich, Nikolina; Zhu, Chang-Qi; Wang, Dennis; To, Christine; Ibrahimov, Emin; Tsao, Ming-Sound

2013-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in North America. Activating KRAS mutations and Smad4 loss occur in approximately 90% and 55% of PDAC, respectively. While their roles in the early stages of PDAC development have been confirmed in genetically modified mouse models, their roles in the multistep malignant transformation of human pancreatic duct cells have not been directly demonstrated. Here, we report that Smad4 represents a barrier in KRAS-mediated malignant transformation of the near normal immortalized human pancreatic duct epithelial (HPDE) cell line model. Marked Smad4 downregulation by shRNA in KRAS G12V expressing HPDE cells failed to cause tumorigenic transformation. However, KRAS-mediated malignant transformation occurred in a new HPDE-TGF-β resistant (TβR) cell line that completely lacks Smad4 protein expression and is resistant to the mito-inhibitory activity of TGF-β. This transformation resulted in tumor formation and development of metastatic phenotype when the cells were implanted orthotopically into the mouse pancreas. Smad4 restoration re-established TGF-β sensitivity, markedly increased tumor latency by promoting apoptosis, and decreased metastatic potential. These results directly establish the critical combination of the KRAS oncogene and complete Smad4 inactivation in the multi-stage malignant transformation and metastatic progression of normal human HPDE cells. PMID:24386371

Filling defects in the pancreatic duct on endoscopic retrograde pancreatography.

PubMed

Taylor, A J; Carmody, T J; Schmalz, M J; Wiedmeyer, D A; Stewart, E T

1992-12-01

Filling defects in the pancreatic duct are a frequent finding during endoscopic retrograde pancreatography (ERP) and have a variety of causes. Some filling defects may be artifactual or related to technical factors and, once their origin is recognized, can be disregarded. Others may be due to acute changes of pancreatitis and should prompt more careful injection of contrast material into the duct. Intraluminal masses may represent calculi or a neoplasm, either of which may require surgery or endoscopic intervention. The exact nature of these filling defects may not be apparent on radiographs, and other studies may be needed. This article reviews our approach to the evaluation of filling defects in the pancreatic duct.

[Spontaneous perforation of the hepatic duct during biliary lithiasis complicated by acute pancreatitis].

PubMed

Assadourian, R; Chometowski, S; Bourde, J; Poitout, D; Lamy, J

1975-10-01

The association of perforation of the common bile duct, cholecystitis and acute pancreatitis, should be emphasized. Physiopathology of perforation of the bile duct may be compared with that of pancreatitis. Repair of the bile duct may be delicate requiring hepatico-jejunostomy on an isolated loop.

[Retrograde pancreatic duct imaging and surgical tactics in hemorrhagic necrotizing pancreatitis. Preliminary report].

PubMed

Gebhardt, C; Gall, F P; Lux, G; Riemann, J; Link, W

1983-12-01

In patients with haemorrhagic necrotizing pancreatitis who are scheduled for surgery we have been carrying out a preoperative retrograde investigation of the pancreatic duct system for the past months. The results in, to date, ten patients revealed four different morphological findings of importance for the surgical tactic: 1. A normal pancreatic duct system with no signs of fistulae: only peripancreatic necrosectomy is required. - 2. Contrast medium leaks via a ductal fistula: left resection including the removal of the fistulous area must be done. - 3. Normal duct system with complete segmental parenchymal staining, representing total necrosis in this region: left resection of the pancreas. - 4. Duodenoscopically demonstrable perforation into the duodenum of a necrotic cavity in the head of the pancreas: conservative management only, no surgery, since this lesion resulting in drainage of the necrotic cavity into the bowel permits self-healing, while the site of the perforation within the necrotic wall cannot be dealt with by surgery. - The experience gained so far indicates that the surgical tactic can be determined with greater selectivity by the use of ERP.

Optimizing the Treatment of Acute Duct-Destructive Pancreatitis

ERIC Educational Resources Information Center

Zhakiev, Bazylbek S.; Karsakbayev, Uteugali G.; Kelimberdiev, Mersaid S.; ?uhamedgalieva, Bodagoz M.; K?nonenko, Aleksander F.

2016-01-01

The search for new methods for treating duct-destructive pancreatitis is a relevant problem. Endogenous intoxication and oxidative stress that accompany acute pancreatitis often progress even after surgery, which forces one to search for additional possibilities of preventing these severe consequences. This research studied the effect of small…

External Versus Internal Pancreatic Duct Drainage for the Early Efficacy After Pancreaticoduodenectomy: A Retrospectively Comparative Study.

PubMed

Wang, Gang; Li, Le; Ma, Yuan; Qu, Feng-Zhi; Zhu, Hong; Lv, Jia-Chen; Jia, Yue-Hui; Wu, Lin-Feng; Sun, Bei

2016-08-01

To compare the early efficacy of external versus internal pancreatic duct drainage after pancreaticoduodenectomy (PD), providing clinical evidence for selecting the optimal approach to pancreatic duct drainage. The clinical data of 395 consecutive patients undergoing PD from 2006 to 2013 were analyzed retrospectively. All the patients were divided into external and internal drainage group. Intraoperative blood loss, surgery duration, postoperative hospitalization duration, mortality rate, PF, and other complications were compared between the two groups. The perioperative relative risk factors that might induce PF were analyzed. External drainage significantly reduced the incidences of post-PD PF, delayed gastric emptying, abdominal infection, bowel obstruction, overall complications, and shortened the healing time of PF (p < .05). The univariate analysis showed that the pancreatic duct drainage method, body mass index (BMI), preoperative serum bilirubin level, perioperative blood transfusion, pancreaticojejunostomy approach, pancreatic texture, pancreatic duct diameter, and primary disease differed markedly between the two groups (p < .05). A multivariate analysis revealed that BMI ≥ 25 kg/m(2), internal pancreatic duct drainage, pancreatic duct diameter <3 mm, soft pancreatic texture, and ampullary disease were independent risk factors for PF. External pancreatic duct drainage can effectively reduce the morbidity of PF and overall complications after PD.

Biliary Tree Stem Cells, Precursors to Pancreatic Committed Progenitors: Evidence for Possible Life-long Pancreatic Organogenesis

PubMed Central

Wang, Yunfang; Lanzoni, Giacomo; Carpino, Guido; Cui, Cai-Bin; Dominguez-Bendala, Juan; Wauthier, Eliane; Cardinale, Vincenzo; Oikawa, Tsunekazu; Pileggi, Antonello; Gerber, David; Furth, Mark E.; Alvaro, Domenico; Gaudio, Eugenio; Inverardi, Luca; Reid, Lola M.

2013-01-01

Peribiliary glands (PBGs) in bile duct walls, and pancreatic duct glands (PDGs) associated with pancreatic ducts, in humans of all ages, contain a continuous, ramifying network of cells in overlapping maturational lineages. We show that proximal (PBGs)-to-distal (PDGs) maturational lineages start near the duodenum with cells expressing markers of pluripotency (NANOG,OCT4,SOX2), proliferation (Ki67), self-replication (SALL4), and early hepato-pancreatic commitment (SOX9,SOX17,PDX1,LGR5), transitioning to PDG cells with no expression of pluripotency or self-replication markers, maintenance of pancreatic genes (PDX1), and expression of markers of pancreatic endocrine maturation (NGN3,MUC6,insulin). Radial-axis lineages start in PBGs near the ducts’ fibromuscular layers with stem cells and end at the ducts’ lumens with cells devoid of stem cell traits and positive for pancreatic endocrine genes. Biliary tree-derived cells behaved as stem cells in culture under expansion conditions, culture plastic and serum-free Kubota’s Medium, proliferating for months as undifferentiated cells, whereas pancreas-derived cells underwent only ∼8-10 divisions, then partially differentiated towards an islet fate. Biliary tree-derived cells proved precursors of pancreas’ committed progenitors. Both could be driven by 3-dimensional conditions, islet-derived matrix components and a serum-free, hormonally defined medium for an islet fate (HDM-P), to form spheroids with ultrastructural, electrophysiological and functional characteristics of neoislets, including glucose regulatability. Implantation of these neoislets into epididymal fat pads of immuno-compromised mice, chemically rendered diabetic, resulted in secretion of human C-peptide, regulatable by glucose, and able to alleviate hyperglycemia in hosts. The biliary tree-derived stem cells and their connections to pancreatic committed progenitors constitute a biological framework for life-long pancreatic organogenesis. PMID

Induction of insulin-producing cells from human pancreatic progenitor cells.

PubMed

Noguchi, H; Naziruddin, B; Shimoda, M; Fujita, Y; Chujo, D; Takita, M; Peng, H; Sugimoto, K; Itoh, T; Tamura, Y; Olsen, G S; Kobayashi, N; Onaca, N; Hayashi, S; Levy, M F; Matsumoto, S

2010-01-01

We previously established a mouse pancreatic stem cell line without genetic manipulation. In this study, we sought to identify and isolate human pancreatic stem/progenitor cells. We also tested whether growth factors and protein transduction of pancreatic and duodenal homeobox factor-1 (PDX-1) and BETA2/NeuroD into human pancreatic stem/progenitor cells induced insulin or pancreas-related gene expressions. Human pancreata from brain-dead donors were used for islet isolation with the standard Ricordi technique modified by the Edmonton protocol. The cells from a duct-rich population were cultured in several media, based on those designed for mouse pancreatic or for human embryonic stem cells. To induce cell differentiation, cells were cultured for 2 weeks with exendin-4, nicotinamide, keratinocyte growth factor, PDX-1 protein, or BETA2/NeuroD protein. The cells in serum-free media showed morphologies similar to a mouse pancreatic stem cell line, while the cells in the medium for human embryonic stem cells formed fibroblast-like morphologies. The nucleus/cytoplasm ratios of the cells in each culture medium decreased during the culture. The cells stopped dividing after 30 days, suggesting that they had entered senescence. The cells treated with induction medium differentiated into insulin-producing cells, expressing pancreas-related genes. Duplications of cells from a duct-rich population were limited. Induction therapy with several growth factors and transduction proteins might provide a potential new strategy for induction of transplantable insulin-producing cells. Copyright 2010 Elsevier Inc. All rights reserved.

Factors associated with post-ERCP pancreatitis and the effect of pancreatic duct stenting in a pediatric population.

PubMed

Troendle, David M; Abraham, Omana; Huang, Rong; Barth, Bradley A

2015-01-01

Risk factors for the development of post-ERCP pancreatitis (PEP) have not been identified in the pediatric population. It remains unclear what constitutes appropriate prophylaxis in this patient population. To assess the prevalence and severity of PEP in the pediatric population and identify factors associated with developing PEP and to evaluate the effect of prophylactic pancreatic duct stenting in high-risk patients. Retrospective analysis of an ERCP database at a single large pediatric center. Academic center. A total of 432 ERCPs performed on 313 patients younger than 19 years of age from January 2004 to October 2013. ERCP for any indication. Rates and severity of PEP, preprocedural and procedural risk factors for the development of PEP, and the effect of pancreatic stents on preventing PEP in high-risk patients. PEP occurred after 47 procedures (prevalence, 10.9%). Thirty-four cases were mild, 9 were moderate, and 4 were severe. There was no mortality. On multiple logistic analysis, pancreatic duct injection (P<.0001; odds ratio 30.8; 95% confidence interval [CI], 9.1-103.9) and pancreatic sphincterotomy (P<.01; OR 3.8; 95% CI, 1.6-9.8) were positively associated with PEP. A history of chronic pancreatitis was negatively associated with PEP (P<.05; OR 0.37; 95% CI, 0.15-0.93). On subset analysis, placing a prophylactic pancreatic stent was associated with significantly increased rates of PEP in patients with pancreatic duct injection compared with those who had no attempt at stent placement (P<.01). Two patients with severe pancreatitis had prophylactic pancreatic stents in place. Retrospective investigation. In the pediatric population, pancreatic duct injection and pancreatic sphincterotomy are associated with significantly increased rates of PEP, whereas a history of chronic pancreatitis is negatively associated. Prophylactic pancreatic stenting is associated with higher rates of PEP in high-risk patients and does not eliminate severe PEP. Copyright © 2015

Volumetric laser endomicroscopy in the biliary and pancreatic ducts: a feasibility study with histological correlation.

PubMed

Corral, Juan E; Mousa, Omar Y; Krishna, Murli; Levink, Iris J M; Pursell, Khela R; Afsh, Mohammad; Kröner, Paul T; Harnois, Denise M; Wolfsen, Herbert C; Wallace, Michael B; Lukens, Frank J

2018-06-18

 Volumetric laser endomicroscopy (VLE) provides circumferential images 3 mm into the biliary and pancreatic ducts. We aimed to correlate VLE images with the normal and abnormal microstructure of these ducts. Samples from patients undergoing hepatic or pancreatic resection were evaluated. VLE images were collected using a low-profile VLE catheter inserted manually into the biliary and pancreatic ducts ex vivo. Histological correlation was assessed by two unblinded investigators.  25 patients (20 liver and 5 pancreatic samples) and 111 images were analyzed. VLE revealed three histological layers: epithelium, connective tissue, and parenchyma. It identified distinctive patterns for primary sclerosing cholangitis (PSC), pancreatic cysts, neuroendocrine tumor, and adenocarcinoma adjacent to the pancreatic duct or ampulla. VLE failed to identify dysplasia in a dominant stricture and inflammatory infiltrates in PSC. Reflectivity measurements of the liver parenchyma diagnosed liver cirrhosis with high sensitivity.  VLE can identify histological changes in the biliary and pancreatic ducts allowing real-time diagnosis. Further studies are needed to measure the accuracy of VLE in a larger sample and to validate our findings in vivo. © Georg Thieme Verlag KG Stuttgart · New York.

Genes and Proteins Differentially Expressed during In Vitro Malignant Transformation of Bovine Pancreatic Duct Cells1

PubMed Central

Jesnowski, R; Zubakov, Dmitri; Faissner, Ralf; Ringel, Jörg; Hoheisel, Jörg D; Lösel, Ralf; Schnölzer, Martina; Löhr, Matthias

2007-01-01

Abstract Pancreatic carcinoma has an extremely bad prognosis due to lack of early diagnostic markers and lack of effective therapeutic strategies. Recently, we have established an in vitro model recapitulating the first steps in the carcinogenesis of the pancreas. SV40 large T antigen-immortalized bovine pancreatic duct cells formed intrapancreatic adenocarcinoma tumors on k-rasmut transfection after orthotopic injection in the nude mouse pancreas. Here we identified genes and proteins differentially expressed in the course of malignant transformation using reciprocal suppression subtractive hybridization and 2D gel electrophoresis and mass spectrometry, respectively. We identified 34 differentially expressed genes, expressed sequence tags, and 15 unique proteins. Differential expression was verified for some of the genes or proteins in samples from pancreatic carcinoma. Among these genes and proteins, the majority had already been described either to be influenced by a mutated ras or to be differentially expressed in pancreatic adenocarcinoma, thus proving the feasibility of our model. Other genes and proteins (e.g., BBC1, GLTSCR2, and rhoGDIα), up to now, have not been implicated in pancreatic tumor development. Thus, we were able to establish an in vitro model of pancreatic carcinogenesis, which enabled us to identify genes and proteins differentially expressed during the early steps of malignant transformation. PMID:17356710

Imbedding pancreaticojejunostomy used in pure laparoscopic pancreaticoduodenectomy for nondilated pancreatic duct.

PubMed

Wang, Min; Xu, Simiao; Zhang, Hang; Peng, Shuyou; Zhu, Feng; Qin, Renyi

2017-04-01

LPD has been cautiously regarded as feasible and safe for resection and reconstruction. However, anastomosis of the remnant pancreas is still thought to be a critical obstacle to the dissemination of LPD in general practice. This study presents a new technique of pancreaticojejunostomy for nondilated pancreatic duct and evaluates its safety and reliability. From July 2014 to June 2015, a total of 52 patients underwent LPD with the new technique. A modified technique of duct-to-mucosa PJ was performed with transpancreatic interlocking mattress sutures, named the imbedding duct-to-mucosa PJ. Then the morbidity and mortality was calculated. This technique was applied in 52 patients after LPD all with nondilated pancreatic duct (1-3 mm). The mean operation time was 4.6 h (range, 3.5-8.3 h) and the median time for the anastomosis was 37 min (range, 24-53 min). Operative mortality was zero, and morbidity was 21.2 % (n = 11), including hemorrhage (n = 3, 5.8 %), biliary fistula (n = 1, 1.9 %), pulmonary infection (n = 1, 1.9 %), delayed gastric emptying (n = 2, 3.8 %), abdominal abscess caused by biliary fistula or PF formation (n = 2, 3.8 %), and POPF (n = 2, 3.8 %). Two patients developed a pancreatic fistula (one type A, one type B) classified according to the International Study Group on Pancreatic Fistula. The described technique is a simple and safe reconstruction procedure after LPD, especially for patients with nondilated pancreatic duct.

Pancreatic-duct-lavage cytology in candidates for surgical resection of branch-duct intraductal papillary mucinous neoplasm of the pancreas: should the International Consensus Guidelines be revised?

PubMed

Sai, Jin Kan; Suyama, Masafumi; Kubokawa, Yoshihiro; Watanabe, Sumio; Maehara, Tadayuki

2009-03-01

The International Consensus Guidelines are helpful for the management of branch-duct intraductal papillary mucinous neoplasms (IPMNs), because they allow us to exclude malignancy. However, it is not possible to predict malignancy with certainty, and further preoperative differentiation between benign and malignant IPMNs is required to avoid the false-positive results. To examine the usefulness of pancreatic-duct-lavage cytology by using an originally designed double-lumen catheter for discriminating benign and malignant IPMNs of the branch-duct type in candidates for surgical resection based on the International Consensus Guidelines. Pancreatic-duct-lavage cytology was investigated in 24 patients with branch-duct IPMNs who underwent surgical resection based on the International Consensus Guidelines, namely, they either had intramural nodules or the ectatic branch duct was >30 mm in diameter. Single-center retrospective study. Academic medical center. The sensitivity and specificity of pancreatic-duct-lavage cytology for discriminating benign from malignant IPMNs. More than 30 mL of pancreatic-duct-lavage fluid was obtained from each patient, and there were no patients with noninformative results. The sensitivity, specificity, positive predictive value, and negative predictive value of the cytologic diagnosis were 78%, 93%, 88%, and 88%, respectively. Single-center and small number of patients. Pancreatic-duct-lavage cytology can improve differentiation between benign and malignant IPMNs of the branch-duct type in candidates for surgical resection based on the International Consensus Guidelines.

Alcohol-induced chronic pancreatitis in rats after temporary occlusion of biliopancreatic ducts with Ethibloc.

PubMed

Pap, A; Boros, L

1989-01-01

Chronic obstructive pancreatitis-like histological and biochemical alterations were provoked in male Wistar rats with Ethibloc occlusion of the common bile duct and the main pancreatic ducts. After the disappearance of the glue from the ducts, a gradual and almost total recovery was demonstrated during a 2-month observation period. About 12 g/kg of alcohol (20% vol/vol) given daily by gastric intubation and ad libitum intake inhibited the recovery of pancreatic weight and enzyme contents in the occluded rats, and within a 2-month period chronic calcifying-type pancreatitis became evident with some signs of remaining obstructive pancreatitis-like lesions. Cessation of alcohol administration after 2 months resulted in a recovery of pancreatic weight and enzyme contents, although morphological regeneration was less pronounced and calcification remained visible in some rats. A 50% raw soy flour diet provoked some further changes in the proportion of enzymes without any supplementary increases of pancreatic weight and protein content. This animal model of chronic pancreatitis demonstrates that chronic obstructive and calcifying pancreatitis can appear together and earlier if the etiological factors act in combination. Suppression of pancreatic regeneration by alcohol seems to be necessary to maintain chronic pancreatitis-like lesions and to develop calcification.

The role of transpapillary drainage in management of patients with pancreatic fluid collections and pancreatic duct disruption as a consequences of severe acute pancreatitis.

PubMed

Jagielski, Mateusz; Smoczyński, Marian; Adrych, Krystian

In last thirty years we have been observing significant development of an endoscopic treatment of pancreatic fluid collections, including transmural drainage of walled-off pancreatic necrosis. Simultaneously, the use of endotherapy in treatment of main pancreatic ducts disruptions has increased. Despite many publications available in current literature, concerning the endoscopic treatment of consequences of acute necrotizing pancreatitis, the role of transpapillary drainage in management of patients with pancreatic fluid collections and pancreatic duct disruption as an after-effect of severe acute pancreatitis remains unclear and is still a current problem. This publication includes comment on the article entitled 'Early dual drainage combining transpapillary endotherapy and percutaneous catheter drainage in patients with pancreatic fistula associated with severe acute pancreatitis' published by Yokoi et al. in the July-August 2016 issue of Pancreatology together with questions to the authors. Furthermore, in the article we did pay particular attention to the role of transpapillary drainage in management of pancreatic fluid collections, especially of walled-of pancreatic necrosis. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Pressures in the sphincter of Oddi in patients with gallstones, common duct stones, and recurrent pancreatitis.

PubMed

Guelrud, M; Mendoza, S; Vicent, S; Gomez, M; Villalta, B

1983-02-01

To determine the significance of manometric pressure, measurements of the sphincter of Oddi in a control group and in patients with cholelithiasis with common duct stones with and without recurrent pancreatitis were studied. Sphincter of Oddi pressure was recorded continuously and by station pull-through by a triple lumen catheter. The basal sphincter of Oddi pressure, the mean pressure gradient between common duct and duodenum, and the sphincter of Oddi wave amplitude were measured. There was no significant difference between control subjects and patients with gallstones and common duct stones. In patients with common duct stones and recurrent pancreatitis the basal sphincter of Oddi pressure, the pressure gradient between common duct and duodenum, and the wave amplitude were significantly increased over control patients. These studies suggest that abnormalities in the sphincter of Oddi motor function are more common in patients with common duct stones with recurrent pancreatitis than in similar patients without pancreatitis.

In vitro expansion and differentiation of rat pancreatic duct-derived stem cells into insulin secreting cells using a dynamicthree-dimensional cell culture system.

PubMed

Chen, X C; Liu, H; Li, H; Cheng, Y; Yang, L; Liu, Y F

2016-06-27

In this study, a dynamic three-dimensional cell culture technology was used to expand and differentiate rat pancreatic duct-derived stem cells (PDSCs) into islet-like cell clusters that can secrete insulin. PDSCs were isolated from rat pancreatic tissues by in situ collagenase digestion and density gradient centrifugation. Using a dynamic three-dimensional culture technique, the cells were expanded and differentiated into functional islet-like cell clusters, which were characterized by morphological and phenotype analyses. After maintaining 1 x 108 isolated rat PDSCs in a dynamic three-dimensional cell culture for 7 days, 1.5 x 109 cells could be harvested. Passaged PDSCs expressed markers of pancreatic endocrine progenitors, including CD29 (86.17%), CD73 (90.73%), CD90 (84.13%), CD105 (78.28%), and Pdx-1. Following 14 additional days of culture in serum-free medium with nicotinamide, keratinocyte growth factor (KGF), and b fibroblast growth factor (FGF), the cells were differentiated into islet-like cell clusters (ICCs). The ICC morphology reflected that of fused cell clusters. During the late stage of differentiation, representative clusters were non-adherent and expressed insulin indicated by dithizone (DTZ)-positive staining. Insulin was detected in the extracellular fluid and cytoplasm of ICCs after 14 days of differentiation. Additionally, insulin levels were significantly higher at this time compared with the levels exhibited by PDSCs before differentiation (P < 0.01). By using a dynamic three-dimensional cell culture system, PDSCs can be expanded in vitro and can differentiate into functional islet-like cell clusters.

Oxidative stress and NO generation in the rat pancreatitis induced by pancreatic duct ligation.

PubMed

Buchwalow, Igor; Schnekenburger, Jürgen; Atiakshin, Dmitri; Samoilova, Vera; Wolf, Eduard; Boecker, Werner; Tiemann, Katharina

2017-04-01

The interaction between nitric oxide (NO) and superoxides is critical in the development of an acute pancreatitis. Previously, we reported that the expression of superoxides and of the NO-generating enzyme (NO synthase, NOS) was up-regulated in the human pancreatitis, especially within the exocrine compartment indicating an exceptional susceptibility of the exocrine parenchyma to oxidative stress. The aim of the present study was to compare the regulation of NO signalling pathways in the human pancreatitis and in an animal model of an acute pancreatitis induced by pancreatic duct ligation (PDL) in rats. In the PDL-induced rat pancreatitis, we revealed a similar pattern of oxidative stress and NOS up-regulation in acinar and in ductal compartments, like in the human pancreatitis. This demonstrates that the PDL-induced rat pancreatitis is a proper model for further studies of acute pancreatitis development in humans. Copyright © 2017 Elsevier GmbH. All rights reserved.

Modified fully covered self-expandable metal stents with antimigration features for benign pancreatic-duct strictures in advanced chronic pancreatitis, with a focus on the safety profile and reducing migration.

PubMed

Moon, Sung-Hoon; Kim, Myung-Hwan; Park, Do Hyun; Song, Tae Joon; Eum, Junbum; Lee, Sang Soo; Seo, Dong Wan; Lee, Sung Koo

2010-07-01

Fully covered self-expandable metal stent (FCSEMS) placement has recently been tried in the management of refractory pancreatic-duct strictures associated with advanced chronic pancreatitis. The major limitation of FCSEMSs was frequent migration. To assess the safety, migration rate, and removability of modified FCSEMSs with antimigration features used for the treatment of benign pancreatic-duct strictures. Prospective study. Tertiary academic center. Thirty-two patients with chronic painful pancreatitis and dominant ductal stricture. Transpapillary endoscopic placement of FCSEMSs in the pancreatic duct with removal after 3 months. Technical and functional success and adverse events associated with the placement of metal stents. FCSEMSs were successfully placed in all patients through the major (n = 27) or minor (n = 5) duodenal papilla. All patients achieved pain relief from stent placement. There was no occurrence of stent-induced pancreatitis or pancreatic sepsis. No stent migrated, and all stents were easily removed. Follow-up ERCP 3 months after stent placement showed resolution of duct strictures in all patients. Pancreatograms obtained at FCSEMS removal displayed de novo focal pancreatic duct strictures in 5 patients, but all were asymptomatic. No long-term follow-up. Temporary 3-month placement of FCSEMSs was effective in resolving pancreatic-duct strictures in chronic pancreatitis, with an acceptable morbidity profile. Modified FCSEMSs can prevent stent migration, but may be associated with de novo duct strictures. Further trials are needed to assess long-term safety and efficacy. Copyright 2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer.

PubMed

Alldinger, Ingo; Dittert, Dag; Peiper, Matthias; Fusco, Alberto; Chiappetta, Gennaro; Staub, Eike; Lohr, Matthias; Jesnowski, Ralf; Baretton, Gustavo; Ockert, Detlef; Saeger, Hans-Detlev; Grützmann, Robert; Pilarsky, Christian

2005-01-01

Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change >3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin beta-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer development. Copyright 2005 S. Karger AG, Basel.

Culturing primary mouse pancreatic ductal cells.

PubMed

Reichert, Maximilian; Rhim, Andrew D; Rustgi, Anil K

2015-06-01

The most common subtype of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). PDAC resembles ductal cells morphologically. To study pancreatic ductal cell (PDC) and pancreatic intraepithelial neoplasia (PanIN)/PDAC biology, it is essential to have reliable in vitro culture conditions. Here we describe a methodology to isolate, culture, and passage PDCs and duct-like cells from the mouse pancreas. It can be used to isolate cells from genetically engineered mouse models (GEMMs), providing a valuable tool to study disease models in vitro to complement in vivo findings. The culture conditions allow epithelial cells to outgrow fibroblast and other "contaminating" cell types within a few passages. However, the resulting cultures, although mostly epithelial, are not completely devoid of fibroblasts. Regardless, this protocol provides guidelines for a robust in vitro culture system to isolate, maintain, and expand primary pancreatic ductal epithelial cells. It can be applied to virtually all GEMMs of pancreatic disease and other diseases and cancers that arise from ductal structures. Because most carcinomas resemble ductal structures, this protocol has utility in the study of other cancers in addition to PDAC, such as breast and prostate cancers. © 2015 Cold Spring Harbor Laboratory Press.

Laparoscopic Longitudinal Pancreaticojejunostomy Using Barbed Sutures: an Efficient and Secure Solution for Pancreatic Duct Obstructions in Patients with Chronic Pancreatitis.

PubMed

Kim, Eun Young; Hong, Tae Ho

2016-04-01

We describe our laparoscopic longitudinal pancreaticojejunostomy (LPJ) technique using barbed sutures to manage a pancreatic duct obstruction. We performed laparoscopic longitudinal anterior pancreaticojejunostomy using barbed sutures (3-0 absorbable wound closure device, V-Loc, Covidien, Minneapolis, MN, USA) in 11 patients who presented with signs of a pancreas ductal obstruction and chronic pancreatitis. The surgical outcomes and follow-up records at the outpatient department were reviewed, and the effectiveness and feasibility of this method were analyzed. Mean patient age was 54.4 ± 9.5 years, and pancreatic duct stones were removed from all patients without conversion to laparotomy. Overall operative time was 200.7 ± 56.4 min, and estimated blood loss was 42.2 ± 11.2 ml. No pancreatic anastomosis leakage or postoperative bleeding was detected. Mean length of hospital stay was 6.5 ± 0.8 days, and mean time to start a soft diet was 4.8 ± 0.7 days. No patient complained of postoperative abdominal pain, and all patients recovered without significant complications or relapse of pancreatitis. The follow-up period was 4-21 months. Our new laparoscopic longitudinal anterior pancreaticojejunostomy technique (Puestow procedure) using barbed sutures is a potentially efficient and minimally invasive procedure for patients who suffer from pancreatic duct obstruction and chronic pancreatitis.

Adult human pancreas-derived cells expressing stage-specific embryonic antigen 4 differentiate into Sox9-expressing and Ngn3-expressing pancreatic ducts in vivo.

PubMed

Lee, Song; Lee, Chan Mi; Kim, Song Cheol

2016-11-11

Tissue-specific stem/progenitor cells are found in various adult tissues and may have the capacity for lineage-specific differentiation, facilitating applications in autologous transplantation. Stage-specific embryonic antigen 4 (SSEA-4), an early embryonic glycolipid antigen, is expressed in cells derived from adult human pancreas exocrine tissue. Here, we examined the characteristics and lineage-specific differentiation capacity of SSEA-4 + cells. Human adult partial pancreas tissues were obtained from different donors and cultured in vitro. SSEA-4 + and CA19-9 + cells were isolated from adult human pancreas exocrine cells using magnetic-activated cell sorting, and gene expression was validated by quantitative polymerase chain reaction. To confirm in-vivo differentiation, SSEA-4 + and CA19-9 + cells were transplanted into the dorsal subcutaneous region of mice. Finally, morphological features of differentiated areas were confirmed by immunostaining and morphometric analysis. SSEA-4-expressing cells were detected in isolated pancreas exocrine cells from adult humans. These SSEA-4 + cells exhibited coexpression of CA19-9, a marker of pancreatic duct cells, but not amylase expression, as shown by immunostaining and flow cytometry. SSEA-4 + cells exhibited higher relative expression of Oct4, Nanog, Klf4, Sox2, and c-Myc mRNAs than CA19-9 + cells. Pancreatic intralobular ducts (PIDs) were generated from SSEA-4 + or CA19-9 + cells in vivo at 5 weeks after transplantation. However, newly formed PIDs from CA19-9 + cells were less abundant and showed an incomplete PID morphology. In contrast, newly formed PIDs from SSEA-4 + cells were abundant in the transplanted area and showed a crowded morphology, typical of PIDs. Sox9 and Ngn3, key transcription factors associated with pancreatic development and regeneration, were expressed in PIDs from SSEA-4 + cells. SSEA-4-expressing cells in the adult human pancreas may have the potential for regeneration of the pancreas and may

Pain in chronic pancreatitis: managing beyond the pancreatic duct.

PubMed

Talukdar, Rupjyoti; Reddy, D Nageshwar

2013-10-14

Chronic pancreatitis (CP) continues to be a clinical challenge. Persistent or recurrent abdominal pain is the most compelling symptom that drives patients to seek medical care. Unfortunately, in spite of using several treatment approaches in the clinical setting, there is no single specific treatment modality that can be earmarked as a cure for this disease. Traditionally, ductal hypertension has been associated with causation of pain in CP; and patients are often subjected to endotherapy and surgery with a goal to decompress the pancreatic duct. Recent studies on humans (clinical and laboratory based) and experimental models have put forward several mechanisms, including neuroimmune alterations, which could be responsible for pain. This might explain the partial or no response to single modality treatment in a significant proportion of patients. The current review discusses the recent concepts of pain generation in CP and evidence based therapeutic approaches (other than ductal decompression) to handle persistent or recurrent pain. We focus primarily on parenchymal and neural components; and discuss the role of antioxidants and the existing controversies, drugs that interfere with neural transmission, pancreatic enzyme supplementation, celiac neurolysis, and pancreatic resection procedures. The review concludes with the treatment approach that we follow at our institute.

β-Cell dedifferentiation, reduced duct cell plasticity, and impaired β-cell mass regeneration in middle-aged rats.

PubMed

Téllez, Noèlia; Vilaseca, Marina; Martí, Yasmina; Pla, Arturo; Montanya, Eduard

2016-09-01

Limitations in β-cell regeneration potential in middle-aged animals could contribute to the increased risk to develop diabetes associated with aging. We investigated β-cell regeneration of middle-aged Wistar rats in response to two different regenerative stimuli: partial pancreatectomy (Px + V) and gastrin administration (Px + G). Pancreatic remnants were analyzed 3 and 14 days after surgery. β-Cell mass increased in young animals after Px and was further increased after gastrin treatment. In contrast, β-cell mass did not change after Px or after gastrin treatment in middle-aged rats. β-Cell replication and individual β-cell size were similarly increased after Px in young and middle-aged animals, and β-cell apoptosis was not modified. Nuclear immunolocalization of neurog3 or nkx6.1 in regenerative duct cells, markers of duct cell plasticity, was increased in young but not in middle-aged Px rats. The pancreatic progenitor-associated transcription factors neurog3 and sox9 were upregulated in islet β-cells of middle-aged rats and further increased after Px. The percentage of chromogranin A+/hormone islet cells was significantly increased in the pancreases of middle-aged Px rats. In summary, the potential for compensatory β-cell hyperplasia and hypertrophy was retained in middle-aged rats, but β-cell dedifferentiation and impaired duct cell plasticity limited β-cell regeneration. Copyright © 2016 the American Physiological Society.

Biliopancreatic duct injection of ethanol as an experimental model of acute and chronic pancreatitis in rats

PubMed Central

Unal, Ethem; Atalay, Suleyman; Tolan, Huseyin Kerem; Yuksekdag, Sema; Yucel, Metin; Acar, Aylin; Basak, Fatih; Gunes, Pembegul; Bas, Gurhan

2015-01-01

In the present study, we described an easily reproducable experimental pancreatits model induced by biliopancreatic duct injection of ethyl alcohol. Seventy Wistar albino rats were divided equally into seven groups randomly: the control group (group 1), acute pancreatitis groups; induced by 20% ethanol (group 2), 48% ethanol (group 3), 80% ethanol (group 4), chronic pancreatitis groups; induced by 20% ethanol (group 5), 48% ethanol (group 6) and by 80% ethanol (group 7). Acute pancreatitis groups were sacrified on postoperative day 3, while the control group and chronic pancreatitis groups were killed on postoperative day 7. Histopathologic evaluation was done, and P < 0.05 was accepted as statistically significant. All rats in group 3 developed acute pancreatitis (100%). Inflammatory infiltration of neutrophils and mononuclear cells, interstitial edema, and focal necrotic areas were seen in the pancreatic tissues. Similarly, all rats in group 6 developed chronic pancreatitis (100%). Interstitial fibrosis, lymphotic infiltration, ductal dilatation, acinar cell atrophy, periductal hyperplasia were seen in the pancreatic tissues. Mortality was seen only in group 7. The biliopancreatic ductal injection of 48% ethanol induced acute and chronic pancreatitis has 100% success rate. PMID:25785001

Cost-effectiveness of benign Wirsung duct strictures treatment in chronic pancreatitis.

PubMed

Łaski, Dariusz; Hać, Stanisław; Marek, Iwona; Kobiela, Jarosław; Kostro, Justyna; Adrych, Krystian; Śledziński, Zbigniew

2018-03-01

Chronic pancreatitis (CP) is an important problem for modern medicine, the healthcare system (Poland - NFZ) and the national insurance system (Poland - ZUS). The chronic nature of the disease, the lack of targeted treatment and the low mortality rate lead to an accumulation of patients who demand expensive treatment, both conservative and invasive. Rising costs in health care are forcing the need for a more cost-effective method of treatment. The primary aim of this study was to perform a retrospective calculation of costs in both surgical and endoscopic treatment, hospital stay, healthcare, and public insurance of patients suffering from chronic pancreatitis. Parallel quality of life analysis was performed. It was possible to develop a cost-effective therapeutic algorithm for patients with an uncomplicated stricture of Wirsung's duct within the Polish health care system. In Poland, the hospital costs of endoscopic treatment of patients with chronic pancreatitis were higher than those of the surgical treatment group despite both resulting in a similar life quality. From a cost-effectiveness perspective, it was shown that surgical intervention is a more cost-effective therapy than endotherapy. Furthermore, patients with benign stricture of the main pancreatic duct in chronic pancreatitis should not be treated with endotherapy for longer than 12 months.

Cost-effectiveness of benign Wirsung duct strictures treatment in chronic pancreatitis

PubMed Central

Hać, Stanisław; Marek, Iwona; Kobiela, Jarosław; Kostro, Justyna; Adrych, Krystian; Śledziński, Zbigniew

2018-01-01

Introduction Chronic pancreatitis (CP) is an important problem for modern medicine, the healthcare system (Poland – NFZ) and the national insurance system (Poland – ZUS). The chronic nature of the disease, the lack of targeted treatment and the low mortality rate lead to an accumulation of patients who demand expensive treatment, both conservative and invasive. Rising costs in health care are forcing the need for a more cost-effective method of treatment. Aim The primary aim of this study was to perform a retrospective calculation of costs in both surgical and endoscopic treatment, hospital stay, healthcare, and public insurance of patients suffering from chronic pancreatitis. Parallel quality of life analysis was performed. It was possible to develop a cost-effective therapeutic algorithm for patients with an uncomplicated stricture of Wirsung’s duct within the Polish health care system. Results In Poland, the hospital costs of endoscopic treatment of patients with chronic pancreatitis were higher than those of the surgical treatment group despite both resulting in a similar life quality. Conclusions From a cost-effectiveness perspective, it was shown that surgical intervention is a more cost-effective therapy than endotherapy. Furthermore, patients with benign stricture of the main pancreatic duct in chronic pancreatitis should not be treated with endotherapy for longer than 12 months. PMID:29643954

Downregulation of tight junction-associated MARVEL protein marvelD3 during epithelial-mesenchymal transition in human pancreatic cancer cells.

PubMed

Kojima, Takashi; Takasawa, Akira; Kyuno, Daisuke; Ito, Tatsuya; Yamaguchi, Hiroshi; Hirata, Koichi; Tsujiwaki, Mitsuhiro; Murata, Masaki; Tanaka, Satoshi; Sawada, Norimasa

2011-10-01

The novel tight junction protein marvelD3 contains a conserved MARVEL (MAL and related proteins for vesicle trafficking and membrane link) domain like occludin and tricellulin. However, little is yet known about the detailed role and regulation of marvelD3 in normal epithelial cells and cancer cells, including pancreatic cancer. In the present study, we investigated marvelD3 expression in well and poorly differentiated human pancreatic cancer cell lines and normal pancreatic duct epithelial cells in which the hTERT gene was introduced into human pancreatic duct epithelial cells in primary culture, and the changes of marvelD3 during Snail-induced epithelial-mesenchymal transition (EMT) under hypoxia, TGF-β treatment and knockdown of FOXA2 in well differentiated pancreatic cancer HPAC cells. MarvelD3 was transcriptionally downregulated in poorly differentiated pancreatic cancer cells and during Snail-induced EMT of pancreatic cancer cells in which Snail was highly expressed and the fence function downregulated, whereas it was maintained in well differentiated human pancreatic cancer cells and normal pancreatic duct epithelial cells. Depletion of marvelD3 by siRNAs in HPAC cells resulted in downregulation of barrier functions indicated as a decrease in transepithelial electric resistance and an increase of permeability to fluorescent dextran tracers, whereas it did not affect fence function of tight junctions. In conclusion, marvelD3 is transcriptionally downregulated in Snail-induced EMT during the progression for the pancreatic cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

Isolation Efficiency of Mouse Pancreatic Stem Cells Is Age Dependent.

PubMed

Kuise, Takashi; Noguchi, Hirofumi; Saitoh, Issei; Kataoka, Hitomi Usui; Watanabe, Masami; Noguchi, Yasufumi; Fujiwara, Toshiyoshi

2013-11-10

Mouse pancreatic stem cells have been isolated from mouse pancreata. This study evaluated the efficacy of isolating mouse pancreatic stem cells using mice of different ages. The pancreata of newborn mice, 8-week-old mice, and 24-week-old mice were harvested and digested by using collagenase. The "duct-like" cells in the digested pancreatic tissue were then inoculated into 96-well plates, cloned by limiting dilution, and cultured in DMEM with 20% FBS. Pancreatic stem cells were isolated from the pancreata of all newborn mice, while cells could only be isolated from 10% of the pancreata of 8-week-old mice and could not be isolated from the pancreata of any 24-week-old mice. These data suggest that young mice may have some pancreatic stem cells and that older mice may only have a few pancreatic stem cells. These data also indicate that it is extremely difficult to isolate pancreatic stem cells from older mice, suggesting that future research focus its efforts on finding methods of isolating pancreatic stem cells from adult mice.

Clinical response to dorsal duct drainage via the minor papilla in refractory obstructing chronic calcific pancreatitis

PubMed Central

Kwon, Chang-Il; Gromski, Mark A.; Sherman, Stuart; El Hajj, Ihab I.; Easler, Jeffrey J.; Watkins, James; McHenry, Lee; Lehman, Glen A.; Fogel, Evan L.

2017-01-01

Background and study aims Complete stone removal from the main pancreatic duct might not be achieved in all patients with obstructive chronic calcific pancreatitis. We report our results for endoscopic dorsal pancreatic duct (DPD) bypass of obstructing stones in the ventral pancreatic duct (VPD). Patients and methods 16 patients with obstructive chronic calcific pancreatitis were treated with a DPD bypass. Clinical success was defined as significant pain relief and no hospital admissions for pain management during the ongoing treatment period. Results Among 16 patients meeting entry criteria, 10 (62.5%) had a history of unsuccessful endoscopic therapy, and 8 had failed extracorporeal shockwave lithotripsy (ESWL). Clinical success was achieved in 12 patients (75 %). Among these responders, 10 patients (83.3 %) had markedly improved or complete pain relief after the first stent placement, which persisted throughout the follow-up period; 11 patients (91.7 %) were able to discontinue their daily analgesics. Conclusions In selected patients with obstructive chronic calcific pancreatitis, the DPD bypass may be considered as a rescue endoscopic therapy, potentially obviating the need for surgery when standard endoscopic methods and ESWL fail. PMID:28201840

Pancreatoduodenectomy for circumportal pancreas accompanying the retroportal pancreatic duct: a case report and review of the literature.

PubMed

Shonaka, Tatsuya; Inagaki, Mitsuhiro; Akabane, Hiromitsu; Yanagida, Naoyuki; Shomura, Hiroki; Kudo, Takeaki; Orimo, Tatsuya; Oikawa, Futoshi; Aiyama, Takeshi; Yanagawa, Nobuyuki; Oikawa, Kensuke; Nakano, Shiro

2012-10-01

Circumportal pancreas (CP) is an extremely rare pancreatic fusion anomaly which is usually asymptomatic. This report presents the case of a patient with a tumor in the head of a CP and the retroportal accessory pancreatic duct in the pancreatic tissue behind the portal vein. A 53-year-old male was diagnosed with a nonfunctioning neuroendocrine tumor of the pancreas and resection of the tumor was scheduled. The patient was revealed to have CP on preoperative computed tomography and endoscopic retrograde cholangiopancreatography, which showed the pancreatic tissue encircling the portal vein and the retroportal accessory pancreatic duct. The patient safely underwent pylorus-preserving pancreatoduodenectomy reconstructed with pancreaticogastrostomy.

Characterization of human pancreatic progenitor cells.

PubMed

Noguchi, Hirofumi; Naziruddin, Bashoo; Jackson, Andrew; Shimoda, Masayuki; Ikemoto, Tetsuya; Fujita, Yasutaka; Chujo, Daisuke; Takita, Morihito; Kobayashi, Naoya; Onaca, Nicholas; Hayashi, Shuji; Levy, Marlon F; Matsumoto, Shinichi

2010-01-01

β-Cell replacement therapy via islet transplantation is an effective treatment for diabetes mellitus, but its widespread use is severely limited by the shortage of donor organs. Because pancreatic stem/progenitor cells are abundantly available in the pancreas of these patients and in donor organs, the cells could become a useful target for β-cell replacement therapy. We previously established a mouse pancreatic stem cell line without genetic manipulation. In this study, we used the techniques to identify and isolate human pancreatic stem/progenitor cells. The cells from a duct-rich population were cultured in 23 kinds of culture media, based on media for mouse pancreatic stem cells or for human embryonic stem cells. The cells in serum-free media formed "cobblestone" morphologies, similar to a mouse pancreatic stem cell line. On the other hand, the cells in serum-containing medium and the medium for human embryonic stem cells formed "fibroblast-like" morphologies. The cells divided actively until day 30, and the population doubling level (PDL) was 6-10. However, the cells stopped dividing after 30 days in any culture conditions. During the cultures, the nucleus/cytoplasm (N/C) ratio decreased, suggesting that the cells entered senescence. Exendin-4 treatment and transduction of PDX-1 and NeuroD proteins by protein transduction technology into the cells induced insulin and pancreas-related gene expression. Although the duplications of these cells were limited, this approach could provide a potential new source of insulin-producing cells for transplantation.

Pancreatic duct stenosis: Differential diagnosis between malignant and benign conditions at secretin-enhanced MRCP.

PubMed

Boninsegna, Enrico; Manfredi, Riccardo; Negrelli, Riccardo; Avesani, Giacomo; Mehrabi, Sara; Pozzi Mucelli, Roberto

To define imaging criteria of benign and malignant nature in patients with main pancreatic duct (MPD) stenosis. S-MRCPs of 35 patients with pancreatitis and 14 with adenocarcinoma were evaluated. Adenocarcinoma caused higher prevalence of complete stenosis (14/14-100% vs 17/35-49%), dilated side-branches (14/14-100% vs 18/35-51%) and lower prevalence of duct-penetrating sign (0/14-0% vs 31/35-89%). The number of stenoses was higher in benign conditions (mean 1.4 Vs 1). Upstream MPD diameter was higher in cancer-induced stenoses (4.5 vs 2.9mm). Single complete stenosis with dilated side branches, increased MPD caliber and absent duct-penetrating sign are suggestive of malignancy. Copyright © 2016 Elsevier Inc. All rights reserved.

A role for gamma-glutamyl transpeptidase and the amino acid transport system xc- in cystine transport by a human pancreatic duct cell line.

PubMed Central

Sweiry, J H; Sastre, J; Viña, J; Elsässer, H P; Mann, G E

1995-01-01

1. The roles of the gamma-glutamyl cycle and the anionic amino acid transport system xc- in mediating L-cystine uptake were investigated in cultured human pancreatic duct PaTu 8902 cells. This cell line exhibits morphological features of normal pancreatic duct cells and expresses gamma-glutamyl transpeptidase (gamma-GT, EC 2.3.2.2), an enzyme involved in the metabolism and regulation of intracellular glutathione (GSH). 2. Uptake of L-cystine (10 microM) was linear for up to 10 min, temperature dependent, Na+ independent, saturable (Michaelis-Menten constant (Km), 86 +/- 25 microM; maximal velocity (Vmax), 109 +/- 33 nmol (mg protein)-1 h-1) and reduced by 80-90% by a 50-fold excess concentration of L-glutamate and L-homocysteic acid, but not L-aspartate. These transport properties resemble those described for system xc-, which exchanges cystine for intracellular glutamate. 3. Acivicin, a known inhibitor of gamma-GT, decreased gamma-GT activity from 2.58 +/- 0.96 to 0.97 +/- 0.11 mU (mg protein)-1 and decreased the initial rates of L-cystine and L-glutamine uptake by 41-55%. Anthglutin (1-gamma-L-glutamyl-2-(2-carboxyphenylhyl)hydrazine), a structurally different inhibitor of gamma-GT, also caused a concentration-dependent (0.01-1 mM) decrease in gamma-GT activity and L-cystine uptake. 4. Neither acivicin nor anthglutin inhibited the uptake of L-glutamate, a poor substrate for gamma-GT. 5. In the presence of a 500-fold excess concentration of glutamate, which should abolish entry of cystine via system xc-, the remaining fraction of cystine transport was inhibited by 50% by acivicin, suggesting that transport is, in part, dependent on the activity of gamma-GT. 6. Cystine transport was also 60-80% inhibited by a series of gamma-glutamyl amino acids (5 mM) including gamma-glutamyl-glutamate, gamma-glutamyl-glutamine and gamma-glutamyl-glycine. alpha-Dipeptides inhibited cystine transport by only 6-22%. 7. These findings demonstrate that in human pancreatic duct Pa

Cytosolic Double-Stranded DNA as a Damage-Associated Molecular Pattern Induces the Inflammatory Response in Rat Pancreatic Stellate Cells: A Plausible Mechanism for Tissue Injury-Associated Pancreatitis

PubMed Central

Nakamura, Taichi; Ito, Tetsuhide; Igarashi, Hisato; Uchida, Masahiko; Hijioka, Masayuki; Oono, Takamasa; Fujimori, Nao; Niina, Yusuke; Suzuki, Koichi; Jensen, Robert T.; Takayanagi, Ryoichi

2012-01-01

Pancreatitis is an inflammatory disease of unknown causes. There are many triggers causing pancreatitis, such as alcohol, common bile duct stone, virus and congenital or acquired stenosis of main pancreatic duct, which often involve tissue injuries. Pancreatitis often occurs in sterile condition, where the dead/dying pancreatic parenchymal cells and the necrotic tissues derived from self-digested-pancreas were observed. However, the causal relationship between tissue injury and pancreatitis and how tissue injury could induce the inflammation of the pancreas were not elucidated fully until now. This study demonstrates that cytosolic double-stranded DNA increases the expression of several inflammatory genes (cytokines, chemokines, type I interferon, and major histocompatibility complex) in rat pancreatic stellate cells. Furthermore, these increase accompanied the multiple signal molecules genes, such as interferon regulatory factors, nuclear factor-kappa B, low-molecular-weight protein 2, and transporter associated with antigen processing 1. We suggest that this phenomenon is a plausible mechanism that might explain how cell damage of the pancreas or tissue injury triggers acute, chronic, and autoimmune pancreatitis; it is potentially relevant to host immune responses induced during alcohol consumption or other causes. PMID:22550608

Long-term outcomes of endoscopic vs surgical drainage of the pancreatic duct in patients with chronic pancreatitis.

PubMed

Cahen, Djuna L; Gouma, Dirk J; Laramée, Philippe; Nio, Yung; Rauws, Erik A J; Boermeester, Marja A; Busch, Olivier R; Fockens, Paul; Kuipers, Ernst J; Pereira, Stephen P; Wonderling, David; Dijkgraaf, Marcel G W; Bruno, Marco J

2011-11-01

A randomized trial that compared endoscopic and surgical drainage of the pancreatic duct in patients with advanced chronic pancreatitis reported a significant benefit of surgery after a 2-year follow-up period. We evaluated the long-term outcome of these patients after 5 years. Between 2000 and 2004, 39 symptomatic patients were randomly assigned to groups that underwent endoscopic drainage or operative pancreaticojejunostomy. In 2009, information was collected regarding pain, quality of life, morbidity, mortality, length of hospital stay, number of procedures undergone, changes in pancreatic function, and costs. Analysis was performed according to an intention-to-treat principle. During the 79-month follow-up period, one patient was lost and 7 died from unrelated causes. Of the patients treated by endoscopy, 68% required additional drainage compared with 5% in the surgery group (P = .001). Hospital stay and costs were comparable, but overall, patients assigned to endoscopy underwent more procedures (median, 12 vs 4; P = .001). Moreover, 47% of the patients in the endoscopy group eventually underwent surgery. Although the mean difference in Izbicki pain scores was no longer significant (39 vs 22; P = .12), surgery was still superior in terms of pain relief (80% vs 38%; P = .042). Levels of quality of life and pancreatic function were comparable. In the long term, symptomatic patients with advanced chronic pancreatitis who underwent surgery as the initial treatment for pancreatic duct obstruction had more relief from pain, with fewer procedures, than patients who were treated endoscopically. Importantly, almost half of the patients who were treated with endoscopy eventually underwent surgery. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

The Main Anatomical Variations of the Pancreatic Duct System: Review of the Literature and Its Importance in Surgical Practice.

PubMed

Dimitriou, Ioannis; Katsourakis, Anastasios; Nikolaidou, Eirini; Noussios, George

2018-05-01

Anatomical variations or anomalies of the pancreatic ducts are important in the planning and performance of endoscopic retrograde cholangiopancreatography (ERCP) and surgical procedures of the pancreas. Normal pancreatic duct anatomy occurs in approximately 94.3% of cases, and multiple variations have been described for the remaining 5.7%. The purpose of this study was to review the literature on the pancreatic duct anatomy and to underline its importance in daily invasive endoscopic and surgical practice. Two main databases were searched for suitable articles published from 2000 to 2017, and results concerning more than 8,200 patients were included in the review. The most common anatomical variation was that of pancreas divisum, which appeared in approximately 4.5% of cases.

miR-146a Suppresses Invasion of Pancreatic Cancer Cells

PubMed Central

Li, Yiwei; VandenBoom, Timothy G.; Wang, Zhiwei; Kong, Dejuan; Ali, Shadan; Philip, Philip A.; Sarkar, Fazlul H.

2010-01-01

The aggressive course of pancreatic cancer is believed to reflect its unusually invasive and metastatic nature, which is associated with epidermal growth factor receptor (EGFR) overexpression and NF-κB activation. MicroRNAs (miRNA) have been implicated in the regulation of various pathobiological processes in cancer, including metastasis in pancreatic cancer and in other human malignancies. In this study, we report lower expression of miR-146a in pancreatic cancer cells compared with normal human pancreatic duct epithelial cells. Reexpression of miR-146a inhibited the invasive capacity of pancreatic cancer cells with concomitant downregulation of EGFR and the NF-κB regulatory kinase interleukin 1 receptor–associated kinase 1 (IRAK-1). Cellular mechanism studies revealed crosstalk between EGFR, IRAK-1, IκBα, NF-κB, and MTA-2, a transcription factor that regulates metastasis. Treatment of pancreatic cancer cells with the natural products 3,3′-diinodolylmethane (DIM) or isoflavone, which increased miR-146a expression, caused a downregulation of EGFR, MTA-2, IRAK-1, and NF-κB, resulting in an inhibition of pancreatic cancer cell invasion. Our findings reveal DIM and isoflavone as nontoxic activators of a miRNA that can block pancreatic cancer cell invasion and metastasis, offering starting points to design novel anticancer agents. PMID:20124483

IL2RG, identified as overexpressed by RNA-seq profiling of pancreatic intraepithelial neoplasia, mediates pancreatic cancer growth

PubMed Central

Ayars, Michael; O’Sullivan, Eileen; Macgregor-Das, Anne; Shindo, Koji; Kim, Haeryoung; Borges, Michael; Yu, Jun; Hruban, Ralph H.; Goggins, Michael

2017-01-01

Pancreatic ductal adenocarcinoma evolves from precursor lesions, the most common of which is pancreatic intraepithelial neoplasia (PanIN). We performed RNA-sequencing analysis of laser capture microdissected PanINs and normal pancreatic duct cells to identify differentially expressed genes between PanINs and normal pancreatic duct, and between low-grade and high-grade PanINs. One of the most highly overexpressed transcripts identified in PanIN is interleukin-2 receptor subunit gamma (IL2RG) encoding the common gamma chain, IL2Rγ. CRISPR-mediated knockout of IL2RG in orthotopically implanted pancreatic cancer cells resulted in attenuated tumor growth in mice and reduced JAK3 expression in orthotopic tumors. These results indicate that IL2Rγ/JAK3 signaling contributes to pancreatic cancer cell growth in vivo. PMID:29137350

Extracorporeal shock wave lithotripsy for pancreatic and large common bile duct stones

PubMed Central

Tandan, Manu; Reddy, D Nageshwar

2011-01-01

Extraction of large pancreatic and common bile duct (CBD) calculi has always challenged the therapeutic endoscopist. Extracorporeal shockwave lithotripsy (ESWL) is an excellent tool for patients with large pancreatic and CBD calculi that are not amenable to routine endotherapy. Pancreatic calculi in the head and body are targeted by ESWL, with an aim to fragment them to < 3 mm diameter so that they can be extracted by subsequent endoscopic retrograde cholangiopancreatography (ERCP). In our experience, complete clearance of the pancreatic duct was achieved in 76% and partial clearance in 17% of 1006 patients. Short-term pain relief with reduction in the number of analgesics ingested was seen in 84% of these patients. For large CBD calculi, a nasobiliary tube is placed to help target the calculi, as well as bathe the calculi in saline - a simple maneuver which helps to facilitate fragmentation. The aim is to fragment calculi to < 5 mm size and clear the same during ERCP. Complete clearance of the CBD was achieved in 84.4% of and partial clearance in 12.3% of 283 patients. More than 90% of the patients with pancreatic and biliary calculi needed three or fewer sessions of ESWL with 5000 shocks being delivered at each session. The use of epidural anesthesia helped in reducing patient movement. This, together with the better focus achieved with newer third-generation lithotripters, prevents collateral tissue damage and minimizes the complications. Complications in our experience with nearly 1300 patients were minimal, and no extension of hospital stay was required. Similar rates of clearance of pancreatic and biliary calculi with minimal adverse effects have been reported from the centers where ESWL is performed regularly. In view of its high efficiency, non-invasive nature and low complication rates, ESWL can be offered as the first-line therapy for selected patients with large pancreatic and CBD calculi. PMID:22110261

Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells.

PubMed

Lee, Jonghyeob; Sugiyama, Takuya; Liu, Yinghua; Wang, Jing; Gu, Xueying; Lei, Ji; Markmann, James F; Miyazaki, Satsuki; Miyazaki, Jun-Ichi; Szot, Gregory L; Bottino, Rita; Kim, Seung K

2013-11-19

Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001.

Autoimmune pancreatitis can develop into chronic pancreatitis

PubMed Central

2014-01-01

Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into ordinary chronic pancreatitis resembling alcoholic pancreatitis over a long-term course based on several clinical findings, most notably frequent pancreatic stone formation. In this review article, we describe a series of study results to confirm our hypothesis and clarify that: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of AIP patients experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsung’s and Santorini’s ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised Japanese Clinical Diagnostic Criteria, with independent risk factors being pancreatic head swelling and non-narrowing of the pancreatic body duct. PMID:24884922

Autoimmune pancreatitis can develop into chronic pancreatitis.

PubMed

Maruyama, Masahiro; Watanabe, Takayuki; Kanai, Keita; Oguchi, Takaya; Asano, Jumpei; Ito, Tetsuya; Ozaki, Yayoi; Muraki, Takashi; Hamano, Hideaki; Arakura, Norikazu; Kawa, Shigeyuki

2014-05-21

Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into ordinary chronic pancreatitis resembling alcoholic pancreatitis over a long-term course based on several clinical findings, most notably frequent pancreatic stone formation. In this review article, we describe a series of study results to confirm our hypothesis and clarify that: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of AIP patients experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsung's and Santorini's ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised Japanese Clinical Diagnostic Criteria, with independent risk factors being pancreatic head swelling and non-narrowing of the pancreatic body duct.

Pancreatic β-cell regeneration: Facultative or dedicated progenitors?

PubMed

Afelik, Solomon; Rovira, Meritxell

2017-04-15

The adult pancreas is only capable of limited regeneration. Unlike highly regenerative tissues such as the skin, intestinal crypts and hematopoietic system, no dedicated adult stem cells or stem cell niche have so far been identified within the adult pancreas. New β cells have been shown to form in the adult pancreas, in response to high physiological demand or experimental β-cell ablation, mostly by replication of existing β cells. The possibility that new β cells are formed from other sources is currently a point of major controversy. Under particular injury conditions, fully differentiated pancreatic duct and acinar cells have been shown to dedifferentiate into a progenitor-like state, however the extent, to which ductal, acinar or other endocrine cells contribute to restoring pancreatic β-cell mass remains to be resolved. In this review we focus on regenerative events in the pancreas with emphasis on the restoration of β-cell mass. We present an overview of regenerative responses noted within the different pancreatic lineages, following injury. We also highlight the intrinsic plasticity of the adult pancreas that allows for inter-conversion of fully differentiated pancreatic lineages through manipulation of few genes or growth factors. Taken together, evidence from a number of studies suggest that differentiated pancreatic lineages could act as facultative progenitor cells, but the extent to which these contribute to β-cell regeneration in vivo is still a matter of contention. Copyright © 2016. Published by Elsevier B.V.

Improving patient and user safety during endoscopic investigation of the pancreatic and biliary ducts

NASA Astrophysics Data System (ADS)

Chandler, John E.; Melville, C. David; Lee, Cameron M.; Saunders, Michael D.; Burkhardt, Matthew R.; Seibel, Eric J.

2011-03-01

Endoscopic investigation of the main pancreatic duct and biliary ducts is called endoscopic retrograde cholangiopancreatography (ERCP), and carries a risk of pancreatitis for the patient. During ERCP, a metal guidewire is inserted into the pancreatobiliary duct from a side-viewing large endoscope within the duodenum. To verify correct placement of the ERCP guidewire, an injection of radiopaque dye is required for fluoroscopic imaging, which exposes the patient and clinical team to x-ray radiation. A safer and more effective means to access the pancreatobiliary system can use direct optical imaging, although the endoscope diameter and stiffness will be significantly larger than a guidewire's. To quantify this invasiveness before human testing, a synthetic force-sensing pancreas was fabricated and attached to an ERCP training model. The invasiveness of a new, 1.7-mm diameter, steerable scanning fiber endoscope (SFE) was compared to the standard ERCP guidewire of 0.89-mm (0.035") diameter that is not steerable. Although twice as large and significantly stiffer than the ERCP guidewire, the SFE generated lower or significantly less average force during insertion at all 4 sensor locations (P<0.05) within the main pancreatic duct. Therefore, the addition of steering and forward visualization at the tip of the endoscope reduced the invasiveness of the in vitro ERCP procedure. Since fluoroscopy is not required, risks associated with dye injection and x-ray exposure can be eliminated when using direct optical visualization. Finally, the SFE provides wide-field high resolution imaging for image-guided interventions, laser-based fluorescence biomarker imaging, and spot spectral analysis for future optical biopsy.

Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression.

PubMed

Ferreira, Rute M M; Sancho, Rocio; Messal, Hendrik A; Nye, Emma; Spencer-Dene, Bradley; Stone, Richard K; Stamp, Gordon; Rosewell, Ian; Quaglia, Alberto; Behrens, Axel

2017-10-24

The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs), duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development. Copyright © 2017 Francis Crick Institute. Published by Elsevier Inc. All rights reserved.

Secretin stimulates HCO3(-) and acetate efflux but not Na+/HCO3(-) uptake in rat pancreatic ducts.

PubMed

Novak, I; Christoffersen, B C

2001-03-01

Pancreatic ducts secrete HCO3(-), but transport mechanisms are unresolved and possibly vary between species. Our aim was to study the intracellular pH (pHi) regulation and thus H+/HCO3- transport in rat pancreatic ducts. Of particular interest was the Na+/HCO3(-) cotransporter, thought to be important in HCO3(-) -transporting epithelia. pHi was measured with BCECF in freshly isolated intralobular ducts. A reduction in extracellular Na+ concentration or application of HOE 694 (1 microM) decreased pHi by 0.1 to 0.6 pH units, demonstrating Na+/H+ exchanger activity. A reduction in extracellular Cl- concentration or addition of H2DIDS (10 microM) increased pHi by 0.1 to 0.5 pH units, demonstrating Cl-/ HCO(3)- (OH ) exchanger activity. In experimental acidosis, extracellular HCO3(-)/CO2 buffer did not increase the rate of pHi recovery, indicating that provision of HCO3(-) by the Na+/HCO3(-) cotransporter was not apparent. Most importantly, Na+/HCO3(-) cotransport was not stimulated by secretin (1 nM). In contrast, in experimental alkalosis the pHi recovery was increased in HCO3(-)/CO2 buffer, possibly due to Na+/HCO3(-) cotransport in the efflux mode. Secretin (1 nM) and carbachol (1 microM) stimulated HCO3(-) efflux, which can account for the observed HCO3(-) concentrations in rat pancreatic juice. Acetate and HCO3(-) buffers were handled similarly, indicating similar transport mechanisms in pancreatic ducts.

[Separate entrance of the main pancreatic duct and of the common bile duct: is it synonymous with easy retrograde cholangiography using endoscopic approach?

PubMed

Benatta, Mohammed Amine

2018-01-01

This study focused on endoscopic examination of a prominent papilla which showed two separate orifices revealing separate entrance of the main pancreatic duct and of the common bile duct (A). This was the most rare anatomoendoscopic variation, accounting for only 10% of retrograde cholangiopancreatographies using endoscopic approach (ERCP). However, it facilitated selective biliary catheterization (SBC) in our patient, as one might have expected. Papilla had a pseudo polypoid appearance and a biliary orifice (BO) at the right angle toward the duodenal wall; hence this was a more difficult approach than that via the pancreatic orifice (PO) which, on the other hand, required undesired pancreatic catheterization (B). As SBC was the approach we decided to adopt, the special techniques to consider in this particular case were: transpancreatic sphincterotomy (TPS) alone or TPS after implantation of a pancreatic stent (PS). We opted for the second technique (STP + PS) and we noticed that the implantation of a PS resulted in better BO visualization (C). We could perform SBC without recourse to TPS. In this specific case, as in other cases of difficult SBC in our practice, PS has proven effectiveness.

Clinical effect of pancreaticojejunostomy with a long-internal stent during pancreaticoduodenectomy in patients with a main pancreatic duct of small diameter.

PubMed

Yamamoto, Tomohisa; Satoi, Sohei; Yanagimoto, Hiroaki; Hirooka, Satoshi; Yamaki, So; Ryota, Hironori; Kotsuka, Masaya; Matsui, Yoichi; Kon, Masanori

2017-06-01

Post-operative pancreatic fistula (POPF) is one of the most common causes of death following pancreaticoduodenectomy (PD). The aim of this study was to evaluate the clinical effect of a long-internal stent on the development of POPF in patients with a main pancreatic duct diameter of 3 mm or less. Patients (N = 108) with a main pancreatic duct (≤3 mm) who underwent PD were included in this single-institution historical control study. Between January 2012 and December 2013, 54 patients had undergone PJ with a long-internal stent across the duct-to-mucosa anastomosis (long-stent group), and between February 2009 and December 2011, 54 patients had undergone PJ without a stent (control). There was no significant difference between groups (long-stent vs control) in the incidence of POPF (70% vs. 56%, p = 0.110) and grade B/C POPF (26% vs. 26%, p = 1.000). Univariate analysis identified body mass index, extent of blood loss and soft pancreatic parenchyma as risk factors related to POPF. Multivariate analysis identified extent of blood loss and soft pancreatic parenchyma as significant risk factors. Placement of a long-internal stent during PJ did not reduce POPF after PD in patients with a main pancreatic duct of small diameter. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Chronic pancreatitis.

PubMed

Kleeff, Jorg; Whitcomb, David C; Shimosegawa, Tooru; Esposito, Irene; Lerch, Markus M; Gress, Thomas; Mayerle, Julia; Drewes, Asbjørn Mohr; Rebours, Vinciane; Akisik, Fatih; Muñoz, J Enrique Domínguez; Neoptolemos, John P

2017-09-07

Chronic pancreatitis is defined as a pathological fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathological responses to parenchymal injury or stress. Potential causes can include toxic factors (such as alcohol or smoking), metabolic abnormalities, idiopathic mechanisms, genetics, autoimmune responses and obstructive mechanisms. The pathophysiology of chronic pancreatitis is fairly complex and includes acinar cell injury, acinar stress responses, duct dysfunction, persistent or altered inflammation, and/or neuro-immune crosstalk, but these mechanisms are not completely understood. Chronic pancreatitis is characterized by ongoing inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Functional consequences include recurrent or constant abdominal pain, diabetes mellitus (endocrine insufficiency) and maldigestion (exocrine insufficiency). Diagnosing early-stage chronic pancreatitis is challenging as changes are subtle, ill-defined and overlap those of other disorders. Later stages are characterized by variable fibrosis and calcification of the pancreatic parenchyma; dilatation, distortion and stricturing of the pancreatic ducts; pseudocysts; intrapancreatic bile duct stricturing; narrowing of the duodenum; and superior mesenteric, portal and/or splenic vein thrombosis. Treatment options comprise medical, radiological, endoscopic and surgical interventions, but evidence-based approaches are limited. This Primer highlights the major progress that has been made in understanding the pathophysiology, presentation, prevalence and management of chronic pancreatitis and its complications.

Acinar cell-specific knockout of the PTHrP gene decreases the proinflammatory and profibrotic responses in pancreatitis.

PubMed

Bhatia, Vandanajay; Rastellini, Cristiana; Han, Song; Aronson, Judith F; Greeley, George H; Falzon, Miriam

2014-09-01

Pancreatitis is a necroinflammatory disease with acute and chronic manifestations. Accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic pancreatitis (CP). Pancreatic parathyroid hormone-related protein (PTHrP) levels are elevated in a mouse model of cerulein-induced AP. Here, we show elevated PTHrP levels in mouse models of pancreatitis induced by chronic cerulein administration and pancreatic duct ligation. Because acinar cells play a major role in the pathophysiology of pancreatitis, mice with acinar cell-specific targeted disruption of the Pthrp gene (PTHrP(Δacinar)) were generated to assess the role of acinar cell-secreted PTHrP in pancreatitis. These mice were generated using Cre-LoxP technology and the acinar cell-specific elastase promoter. PTHrP(Δacinar) exerted protective effects in cerulein and pancreatic duct ligation models, evident as decreased edema, histological damage, amylase secretion, pancreatic stellate cell (PSC) activation, and extracellular matrix deposition. Treating acinar cells in vitro with cerulein increased IL-6 expression and NF-κB activity; these effects were attenuated in PTHrP(Δacinar) cells, as were the cerulein- and carbachol-induced elevations in amylase secretion. The cerulein-induced upregulation of procollagen I expression was lost in PSCs from PTHrP(Δacinar) mice. PTHrP immunostaining was elevated in human CP sections. The cerulein-induced upregulation of IL-6 and ICAM-1 (human acinar cells) and procollagen I (human PSCs) was suppressed by pretreatment with the PTH1R antagonist, PTHrP (7-34). These findings establish PTHrP as a novel mediator of inflammation and fibrosis associated with CP. Acinar cell-secreted PTHrP modulates acinar cell function via its effects on proinflammatory cytokine release and functions via a paracrine pathway to activate PSCs. Copyright © 2014 the American Physiological Society.

Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells

PubMed Central

Lee, Jonghyeob; Sugiyama, Takuya; Liu, Yinghua; Wang, Jing; Gu, Xueying; Lei, Ji; Markmann, James F; Miyazaki, Satsuki; Miyazaki, Jun-ichi; Szot, Gregory L; Bottino, Rita; Kim, Seung K

2013-01-01

Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001 PMID:24252877

Duct Diameter and Size of Stones Predict Successful Extracorporeal Shock Wave Lithotripsy and Endoscopic Clearance in Patients With Chronic Pancreatitis and Pancreaticolithiasis.

PubMed

Lapp, Robert T; Wolf, J Stuart; Faerber, Gary J; Roberts, William W; McCarthy, Sean T; Anderson, Michelle A; Wamsteker, Erik-Jan; Elta, Grace H; Scheiman, James M; Kwon, Richard S

2016-09-01

The need for endoscopic therapy before extracorporeal shock wave lithotripsy (SWL) to facilitate pancreatic duct stone removal is unclear. Predictive factors associated with successful fragmentation and subsequent complete duct clearance are variable. We hypothesize pancreatic duct strictures and large stones, but not pre-SWL endotherapy, correlate with successful fragmentation and complete duct clearance. A retrospective cohort study of patients with pancreaticolithiasis who underwent SWL and endoscopic retrograde cholangiopancreatography between January 2009 and June 2014 was evaluated. Thirty-seven patients were treated. Technical success (TS) of fragmentation was achieved in 22 patients (60%). Technical success was associated with fewer stones and SWL sessions and smaller stone and duct size. By multivariate logistic regression, only duct dilation was associated with TS. Endoscopic success of complete duct clearance was achieved in 29 patients (80%). Endoscopic success was more frequent with stones 12 mm or less and with successful TS. By multivariate logistic regression, stones greater than 12 mm were associated with endoscopic failure. Pre-SWL endotherapy does not affect stone fragmentation. Patients with a dilated duct (>8 mm) and pancreatic stones 12 mm or greater were associated with unsuccessful TS and endoscopic success, respectively, and may benefit from early referral for surgical decompression.

Pancreatic fibrosis correlates with exocrine pancreatic insufficiency after pancreatoduodenectomy.

PubMed

Tran, T C K; van 't Hof, G; Kazemier, G; Hop, W C; Pek, C; van Toorenenbergen, A W; van Dekken, H; van Eijck, C H J

2008-01-01

Obstruction of the pancreatic duct can lead to pancreatic fibrosis. We investigated the correlation between the extent of pancreatic fibrosis and the postoperative exocrine and endocrine pancreatic function. Fifty-five patients who were treated for pancreatic and periampullary carcinoma and 19 patients with chronic pancreatitis were evaluated. Exocrine pancreatic function was evaluated by fecal elastase-1 test, while endocrine pancreatic function was assessed by plasma glucose level. The extent of fibrosis, duct dilation and endocrine tissue loss was examined histopathologically. A strong correlation was found between pancreatic fibrosis and elastase-1 level less than 100 microg/g (p < 0.0001), reflecting severe exocrine pancreatic insufficiency. A strong correlation was found between pancreatic fibrosis and endocrine tissue loss (p < 0.0001). Neither pancreatic fibrosis nor endocrine tissue loss were correlated with the development of postoperative diabetes mellitus. Duct dilation alone was neither correlated with exocrine nor with endocrine function loss. The majority of patients develop severe exocrine pancreatic insufficiency after pancreatoduodenectomy. The extent of exocrine pancreatic insufficiency is strongly correlated with preoperative fibrosis. The loss of endocrine tissue does not correlate with postoperative diabetes mellitus. Preoperative dilation of the pancreatic duct per se does not predict exocrine or endocrine pancreatic insufficiency postoperatively. Copyright 2008 S. Karger AG, Basel.

Cross-Species Analysis of Nicotine-Induced Proteomic Alterations in Pancreatic Cells

PubMed Central

Paulo, Joao A.; Urrutia, Raul; Kadiyala, Vivek; Banks, Peter

2014-01-01

Background Toxic compounds in tobacco, such as nicotine, may have adversely affect pancreatic function. We aim to determine nicotine-induced protein alterations in pancreatic cells, which may reveal a link between nicotine exposure and pancreatic disease. Methods We compared the proteomic alterations induced by nicotine treatment in cultured pancreatic cells (mouse, rat and human stellate cells and human duct cells) using mass spectrometry-based techniques, specifically GeLC-MS/MS and spectral counting. Results We identified thousands of proteins in pancreatic cells, hundreds of which were identified exclusively or in higher abundance in either nicotine-treated or untreated cells. Inter-species comparisons of stellate cell proteins revealed several differentially-abundant proteins (in nicotine treated versus untreated cells) common among the 3 species. Proteins appearing in all nicotine-treated stellate cells include amyloid beta (A4), procollagen type VI alpha 1, integral membrane protein 2B,and Toll interacting protein. Conclusions Proteins which were differentially expressed upon nicotine treatment across cell lines, were enriched in certain pathways, including nAChR, cytokine, and integrin signaling. At this analytical depth, we conclude that similar pathways are affected by nicotine, but alterations at the protein level among stellate cells of different species vary. Further interrogation of such pathways will lead to insights into the potential effect of nicotine on pancreatic cells at the biomolecular level and the extension of this concept to the effect of nicotine on pancreatic disease. PMID:23456891

Narcotic Independence After Pancreatic Duct Stenting Predicts Narcotic Independence After Lateral Pancreaticojejunostomy for Chronic Pancreatitis.

PubMed

Kwon, Richard S; Young, Benjamin E; Marsteller, William F; Lawrence, Christopher; Wu, Bechien U; Lee, Linda S; Mullady, Daniel; Klibansky, David A; Gardner, Timothy B; Simeone, Diane M

2016-09-01

This study aimed to determine if the improved pain response to endoscopic retrograde cholangiopancreatogrphy (ERCP) and pancreatic stent placement (EPS) predicts pain response in patients with chronic pancreatitis after modified lateral pancreaticojejunostomy (LPJ). A multi-institutional, retrospective review of patients who underwent successful EPS before LPJ between 2001 and 2010 was performed. The primary outcome was narcotic independence (NI) within 2 months after ERCP or LPJ. A total of 31 narcotic-dependent patients with chronic pancreatitis underwent successful EPS before LPJ. Ten (32%) achieved post-LPJ NI (median follow-up, 8.5 months; interquartile range [IQR], 2-38 months). Eight (80%) of 10 patients with NI post-ERCP achieved NI post-LPJ. Two (10%) without NI post-ERCP achieved NI post-LPJ. Narcotic independence post-EPS was associated strongly with NI post-LPJ with an odds ratio of 38 (P = 0.0025) and predicted post-LPJ NI with a sensitivity, specificity, positive predictive value, and negative predictive value of 80%, 90.5%, 80%, and 90.5%, respectively. Narcotic independence after EPS is associated with NI after LPJ. Failure to achieve NI post-ERCP predicts failure to achieve NI post-LPJ. These results support the need for larger studies to confirm the predictive value of pancreatic duct stenting for better selection of chronic pancreatitis patients who will benefit from LPJ.

Chimeric analysis of EGFP and DsRed2 transgenic mice demonstrates polyclonal maintenance of pancreatic acini.

PubMed

Ryu, Je-Young; Siswanto, Antoni; Harimoto, Kenichi; Tagawa, Yoh-ichi

2013-06-01

The pancreatic islet is an assembly of specific endocrine cells. There are many conflicting reports regarding whether the acinus develops from single or multiple progenitor cells. This study investigated the development and maintenance clonality of the pancreatic acinus and duct using a chimeric analysis with EGFP and DsRed2 transgenic mice. Chimeric mice (G-R mice) were obtained by the aggregation method, using 8-cell stage embryos from EGFP and DsRed2 transgenic mice. The islets from the G-R mice were chimeric and mosaic, consisting of either EGFP- or DsRed2-positive populations, as in previous reports. On the other hand, most acini developed from either EGFP or DsRed2 origin, but some were chimeric. Interestingly, these chimeric acini were clearly separated into two-color regions and were not mosaic. Some large intralobular pancreatic ducts consisting of more than 10 cells were found to be chimeric, but no small ducts made up of less than 9 cells were chimeric. Our histological observations suggest that the pancreatic acinus polyclonally and directionally is maintained by multiple progenitor cells. Pancreatic large ducts also seem to develop polyclonally and might result from the assembly of small ducts that develop from a single origin. These findings provide useful information for further understanding pancreatic maintenance.

Isolation of major pancreatic cell types and long-term culture-initiating cells using novel human surface markers.

PubMed

Dorrell, Craig; Abraham, Stephanie L; Lanxon-Cookson, Kelsea M; Canaday, Pamela S; Streeter, Philip R; Grompe, Markus

2008-09-01

We have developed a novel panel of cell-surface markers for the isolation and study of all major cell types of the human pancreas. Hybridomas were selected after subtractive immunization of Balb/C mice with intact or dissociated human islets and assessed for cell-type specificity and cell-surface reactivity by immunohistochemistry and flow cytometry. Antibodies were identified by specific binding of surface antigens on islet (panendocrine or alpha-specific) and nonislet pancreatic cell subsets (exocrine and duct). These antibodies were used individually or in combination to isolate populations of alpha, beta, exocrine, or duct cells from primary human pancreas by FACS and to characterize the detailed cell composition of human islet preparations. They were also employed to show that human islet expansion cultures originated from nonendocrine cells and that insulin expression levels could be increased to up to 1% of normal islet cells by subpopulation sorting and overexpression of the transcription factors Pdx-1 and ngn3, an improvement over previous results with this culture system. These methods permit the analysis and isolation of functionally distinct pancreatic cell populations with potential for cell therapy.

[External pancreatic fistulas management].

PubMed

Stepan, E V; Ermolov, A S; Rogal', M L; Teterin, Yu S

The main principles of treatment of external postoperative pancreatic fistulas are viewed in the article. Pancreatic trauma was the reason of pancreatic fistula in 38.7% of the cases, operations because of acute pancreatitis - in 25.8%, and pancreatic pseudocyst drainage - in 35.5%. 93 patients recovered after the treatment. Complex conservative treatment of EPF allowed to close fistulas in 74.2% of the patients with normal patency of the main pancreatic duct (MPD). The usage of octreotide 600-900 mcg daily for at least 5 days to decrease pancreatic secretion was an important part of the conservative treatment. Endoscopic papillotomy was performed in patients with major duodenal papilla obstruction and interruption of transporting of pancreatic secretion to duodenum. Stent of the main pancreatic duct was indicated in patients with extended pancreatic duct stenosis to normalize transport of pancreatic secretion to duodenum. Surgical formation of anastomosis between distal part of the main pancreatic duct and gastro-intestinal tract was carried out when it was impossible to fulfill endoscopic stenting of pancreatic duct either because of its interruption and diastasis between its ends, or in the cases of unsuccessful conservative treatment of external pancreatic fistula caused by drainage of pseudocyst.

Smad2/3 Linker Phosphorylation Is a Possible Marker of Pancreatic Stem/Progenitor Cells in the Regenerative Phase of Acute Pancreatitis.

PubMed

Sakao, Masayuki; Sakaguchi, Yutaku; Suzuki, Ryo; Takahashi, Yu; Kishimoto, Masanobu; Fukui, Toshiro; Uchida, Kazushige; Nishio, Akiyoshi; Matsuzaki, Koichi; Okazaki, Kazuichi

The aims of this study are to characterize cell proliferation and differentiation during regeneration after pancreatitis and pancreatic buds during development to evaluate the role of Smad2/3, phosphorylated at the specific linker threonine residues (pSmad2/3L-Thr) in positive cells. Male C57BL/6 mice received hourly intraperitoneal injections of cerulein and were analyzed after induced pancreatitis. Pancreatitis-affected tissue sections and pancreatic buds were immunostained for pSmad2/3L-Thr, with other markers thought to be stem/progenitor markers of the pancreas. pSmad2/3L-Thr immunostaining-positive cells increased as the pancreatitis progressed. The expression of pSmad2/3L-Thr was seen in acinar cells and ductlike tubular complexes. These results suggest that pSmad2/3L-Thr is expressed during acinar-ductal metaplasia. Immunohistochemical colocalization of pSmad2/3L-Thr with Ki67 was never observed. pSmad2/3L-Thr-positive cells may remain in an undifferentiated state. During the pancreatic development process, pSmad2/3L-Thr was expressed as other markers. pSmad2/3L-Thr develops in duct structure of the undifferentiated cell population in the last part of viviparity that acinar structure is formed clearly. pSmad2/3L-Thr expression occurs during acinar-ductal metaplasia after pancreatitis and may represent the contribution of stem cells and/or progenitor cells to the differentiation of the pancreas.

Clinicopathological Features of Intraductal Pancreatic Neuroendocrine Tumors.

PubMed

Chang, Xiao-Yan; Jia, Cong-Wei; Meng, Yun-Xiao; Chen, Jie

2016-10-10

Objective To evaluate the clinical and pathologic characteristics of intraductal pancreatic neuroendocrine tumors (PanNETs). Methods Four cases of intraductal PanNETs were studied by light microscopy and immunohistochemistry with the analysis of morphologic features and review of relevant literatures. Results Two female patients and two male patients aged 41- 58 years were enrolled in this study. The chief complaint was abdominal pain in two patients,vomiting in one patient,and jaundice in the last patient. Imaging examination showed intraductal neoplasm with diagnosis as intraductal papillary mucinous neoplasm (IPMN) in case 1; space-occupying lesions were found in the head of pancreas in the other three cases with pancreatic ductal ectasia and distal pancreatic atrophy. Grossly the masses were located in pancreatic main duct and invaded into surrounding pancreatic parachyma. Microscopically the tumors arranged with solid pattern,with some trabecular structures in the last two cases. Small duct and ductules were seen in intraductal PanNETs. The immunohistochemical expression showed that SYN and CgA were positive in neoplastic cells and negative in small duct and ductules.Conclusions Intraductal PanNETs are rare conditions. The clinical symptoms and imaging findings are similar to IPMN or pancreatic carcinoma. The tumors are located within pancreatic duct partly and can invade the pancreatic parenchyma. Microscopically the neuroendocrine tumors mix with small duct and forms ductulo-insular structure,which should be differentiated with mixed ductal endocrine carcinoma. The grade and prognosis are similar to those of classical neuroendocrine tumors.

Histopathology and pathogenesis of caerulein-, duct ligation-, and arginine-induced acute pancreatitis in Sprague-Dawley rats and C57BL6 mice.

PubMed

Zhang, Jun; Rouse, Rodney L

2014-09-01

Three classical rodent models of acute pancreatitis were created in an effort to identify potential pre-clinical models of drug-induced pancreatitis (DIP) and candidate non-invasive biomarkers for improved detection of DIP. Study objectives included designing a lexicon to minimize bias by capturing normal variation and spontaneous and injury-induced changes while maintaining the ability to statistically differentiate degrees of change, defining morphologic anchors for novel pancreatic injury biomarkers, and improved understanding of mechanisms responsible for pancreatitis. Models were created in male Sprague-Dawley rats and C57BL6 mice through: 1) administration of the cholecystokinin analog, caerulein; 2) administration of arginine; 3) surgical ligation of the pancreatic duct. Nine morphologically detectable processes were used in the lexicon; acinar cell hypertrophy; acinar cell autophagy; acinar cell apoptosis; acinar cell necrosis; vascular injury; interstitial edema, inflammation and hemorrhage; fat necrosis; ductal changes; acinar cell atrophy. Criteria were defined for scoring levels (0 = absent, 1 = mild, 2 = moderate, 3 = severe) for each lexicon component. Consistent with previous studies, histopathology scores were significant greater in rats compared to mice at baseline and after treatment. The histopathology scores in caerulein and ligation-treated rats and mice were significantly greater than those of arginine-treated rats and mice. The present study supports a multifaceted pathogenesis for acute pancreatitis in which intra-acinar trypsinogen activation, damage to acinar cells, fat cells, and vascular cells as well as activation/degranulation of mast cells and activated macrophages all contribute to the initiation and/or progression of acute inflammation of the exocrine pancreas.

KSA Antigen Ep-CAM Mediates Cell–Cell Adhesion of Pancreatic Epithelial Cells: Morphoregulatory Roles in Pancreatic Islet Development

PubMed Central

Cirulli, V.; Crisa, L.; Beattie, G.M.; Mally, M.I.; Lopez, A.D.; Fannon, A.; Ptasznik, A.; Inverardi, L.; Ricordi, C.; Deerinck, T.; Ellisman, M.; Reisfeld, R.A.; Hayek, A.

1998-01-01

Cell adhesion molecules (CAMs) are important mediators of cell–cell interactions and regulate cell fate determination by influencing growth, differentiation, and organization within tissues. The human pancarcinoma antigen KSA is a glycoprotein of 40 kD originally identified as a marker of rapidly proliferating tumors of epithelial origin. Interestingly, most normal epithelia also express this antigen, although at lower levels, suggesting that a dynamic regulation of KSA may occur during cell growth and differentiation. Recently, evidence has been provided that this glycoprotein may function as an epithelial cell adhesion molecule (Ep-CAM). Here, we report that Ep-CAM exhibits the features of a morphoregulatory molecule involved in the development of human pancreatic islets. We demonstrate that Ep-CAM expression is targeted to the lateral domain of epithelial cells of the human fetal pancreas, and that it mediates calcium-independent cell–cell adhesion. Quantitative confocal immunofluorescence in fetal pancreata identified the highest levels of Ep-CAM expression in developing islet-like cell clusters budding from the ductal epithelium, a cell compartment thought to comprise endocrine progenitors. A surprisingly reversed pattern was observed in the human adult pancreas, displaying low levels of Ep-CAM in islet cells and high levels in ducts. We further demonstrate that culture conditions promoting epithelial cell growth induce upregulation of Ep-CAM, whereas endocrine differentiation of fetal pancreatic epithelial cells, transplanted in nude mice, is associated with a downregulation of Ep-CAM expression. In addition, a blockade of Ep-CAM function by KS1/4 mAb induced insulin and glucagon gene transcription and translation in fetal pancreatic cell clusters. These results indicate that developmentally regulated expression and function of Ep-CAM play a morphoregulatory role in pancreatic islet ontogeny. PMID:9508783

Resolving external pancreatic fistulas in patients with disconnected pancreatic duct syndrome: using rendezvous techniques to avoid surgery (with video).

PubMed

Irani, Shayan; Gluck, Michael; Ross, Andrew; Gan, S Ian; Crane, Robert; Brandabur, John J; Hauptmann, Ellen; Fotoohi, Mehran; Kozarek, Richard A

2012-09-01

An external pancreatic fistula (EPF) generally results from an iatrogenic manipulation of a pancreatic fluid collection (PFC), such as walled-off pancreatic necrosis (WOPN). Severe necrotizing pancreatitis can lead to complete duct disruption, causing disconnected pancreatic duct syndrome (DPDS) with viable upstream pancreas draining out of a low-pressure fistula created surgically or by a percutaneous catheter. The EPF can persist for months to years, and distal pancreatectomy, often the only permanent solution, carries a high morbidity and defined mortality. To describe 3 endoscopic and percutaneous rendezvous techniques to completely resolve EPFs in the setting of DPDS. A retrospective review of a prospective database of 15 patients who underwent rendezvous internalization of EPFs. Tertiary-care pancreatic referral center. Fifteen patients between October 2002 and October 2011 with EPFs in the setting of DPDS and resolved WOPN. Three rendezvous techniques that combined endoscopic and percutaneous procedures to internalize EPFs by transgastric, transduodenal, or transpapillary methods. EPF resolution and morbidity. Fifteen patients (12 men) with a median age of 51 years (range 24-65 years) with EPFs and DPDS (cutoff/blowout of pancreatic duct, with inability to demonstrate upstream body/tail of pancreas on pancreatogram) resulting from severe necrotizing pancreatitis underwent 1 of 3 rendezvous procedures to eliminate the EPFs. All patients were either poor surgical candidates or refused surgery. At the time of the rendezvous procedure, WOPN had fully resolved, DPDS was confirmed on pancreatography, and the EPF had persisted for a median of 5 months (range 1-48 months), producing a median output of 200 mL/day (range 50-700 mL/day). The rendezvous technique in 10 patients used the existing percutaneous drainage fistula to puncture into the stomach/duodenum to deliver wires that were captured endoscopically. The transenteric fistula was dilated and two

Isolated Main Pancreatic Duct Dilatation: CT Differentiation Between Benign and Malignant Causes.

PubMed

Kim, Se Woo; Kim, Se Hyung; Lee, Dong Ho; Lee, Sang Min; Kim, Yeon Soo; Jang, Jin Young; Han, Joon Koo

2017-11-01

The purpose of this study is to retrospectively evaluate the differential CT features of isolated benign and malignant main pancreatic duct (MPD) dilatation and to investigate whether the diagnostic performance of radiologists can be improved with knowledge of these differential CT features. Forty-one patients who had isolated MPD dilatation without any visible mass on CT from January 2000 to October 2016 were retrospectively enrolled in the study. Two radiologists reviewed CT images in consensus for the location, shape (smooth vs abrupt), length of transition, dilated pancreatic duct (PD) diameter, presence of duct penetrating sign, parenchymal atrophy, attenuation difference, associated pancreatitis, calcification, PD or common bile duct (CBD) enhancement, and perilesional cyst. The chi-square test, Fisher exact test, and t test were used to find the differential CT features of benign and malignant MPD dilatation. Two successive review sessions for differentiation between the two disease entities were then independently performed by three other reviewers with differing expertise, with the use of a 5-point confidence scale. The first session provided no information for differentiation; however, reviewers were aware of the results of univariate analyses in the second session. The diagnostic performance of the radiologists was evaluated using a pairwise comparison of ROC curves. A total of 19 benign and 22 malignant MPD dilatations were identified. In patients with benign MPD dilatation, transition areas were frequently located in the head (57.9% [11/19] vs 13.6% [3/22], p = 0.003) and showed significantly shorter (< 6.1 mm) (78.9% [15/19] vs 9.1% [2/22], p < 0.0001) and smooth transition (89.5% [17/19] vs 9.1% [2/22], p < 0.0001). Duct penetrating sign was exclusively observed in patients with benign MPD dilatation (73.7% [14/19] vs 0% [0/22], p < 0.0001). In contrast, malignant MPD dilatation frequently was accompanied by attenuation difference (63.6% [14/22] vs

Surgical Injury to the Mouse Pancreas through Ligation of the Pancreatic Duct as a Model for Endocrine and Exocrine Reprogramming and Proliferation

PubMed Central

De Groef, Sofie; Leuckx, Gunter; Van Gassen, Naomi; Staels, Willem; Cai, Ying; Yuchi, Yixing; Coppens, Violette; De Leu, Nico; Heremans, Yves; Baeyens, Luc; Van de Casteele, Mark; Heimberg, Harry

2015-01-01

Expansion of pancreatic beta cells in vivo or ex vivo, or generation of beta cells by differentiation from an embryonic or adult stem cell, can provide new expandable sources of beta cells to alleviate the donor scarcity in human islet transplantation as therapy for diabetes. Although recent advances have been made towards this aim, mechanisms that regulate beta cell expansion and differentiation from a stem/progenitor cell remain to be characterized. Here, we describe a protocol for an injury model in the adult mouse pancreas that can function as a tool to study mechanisms of tissue remodeling and beta cell proliferation and differentiation. Partial duct ligation (PDL) is an experimentally induced injury of the rodent pancreas involving surgical ligation of the main pancreatic duct resulting in an obstruction of drainage of exocrine products out of the tail region of the pancreas. The inflicted damage induces acinar atrophy, immune cell infiltration and severe tissue remodeling. We have previously reported the activation of Neurogenin (Ngn) 3 expressing endogenous progenitor-like cells and an increase in beta cell proliferation after PDL. Therefore, PDL provides a basis to study signals involved in beta cell dynamics and the properties of an endocrine progenitor in adult pancreas. Since, it still remains largely unclear, which factors and pathways contribute to beta cell neogenesis and proliferation in PDL, a standardized protocol for PDL will allow for comparison across laboratories. PMID:26273954

Pancreatic trauma.

PubMed

Lahiri, R; Bhattacharya, S

2013-05-01

Pancreatic trauma occurs in approximately 4% of all patients sustaining abdominal injuries. The pancreas has an intimate relationship with the major upper abdominal vessels, and there is significant morbidity and mortality associated with severe pancreatic injury. Immediate resuscitation and investigations are essential to delineate the nature of the injury, and to plan further management. If main pancreatic duct injuries are identified, specialised input from a tertiary hepatopancreaticobiliary (HPB) team is advised. A comprehensive online literature search was performed using PubMed. Relevant articles from international journals were selected. The search terms used were: 'pancreatic trauma', 'pancreatic duct injury', 'radiology AND pancreas injury', 'diagnosis of pancreatic trauma', and 'management AND surgery'. Articles that were not published in English were excluded. All articles used were selected on relevance to this review and read by both authors. Pancreatic trauma is rare and associated with injury to other upper abdominal viscera. Patients present with non-specific abdominal findings and serum amylase is of little use in diagnosis. Computed tomography is effective in diagnosing pancreatic injury but not duct disruption, which is most easily seen on endoscopic retrograde cholangiopancreaticography or operative pancreatography. If pancreatic injury is suspected, inspection of the entire pancreas and duodenum is required to ensure full evaluation at laparotomy. The operative management of pancreatic injury depends on the grade of injury found at laparotomy. The most important prognostic factor is main duct disruption and, if found, reconstructive options should be determined by an experienced HPB surgeon. The diagnosis of pancreatic trauma requires a high index of suspicion and detailed imaging studies. Grading pancreatic injury is important to guide operative management. The most important prognostic factor is pancreatic duct disruption and in these cases

[Mediastinal Pancreatic Pseudocyst with Pancreatic Pleural Effusion].

PubMed

Sasajima, Motoko; Kawai, Hideki; Suzuki, Yohei; Saito, Yoshitaro; Eto, Takeshi

2017-06-01

A 72-year-old man with chronic alcohol related pancreatitis was admitted for dyspnea and pain at the upper body. Chest X-ray showed right massive pleural effusion. Chest and abdominal contrast enhanced thin slice computed tomography revealed the route from the pancreatic head reaching the right thoracic cavity via the esophagus hiatus and the communication between the cystic lesion and main pancreatic duct. We drained the pleural effusion that showed abnormally high amylase activity. We diagnosed his illness as mediastinal pancreatic pseudocyst with pancreatic pleural effusion. Endoscopic Nasopancreatic Drainage catheter was placed in the main pancreatic duct, and the pleural effusion disappeared.

Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting.

PubMed

Suzuki, Atsushi; Nakauchi, Hiromitsu; Taniguchi, Hideki

2004-08-01

During pancreatic development, neogenesis, and regeneration, stem cells might act as a central player to generate endocrine, acinar, and duct cells. Although these cells are well known as pancreatic stem cells (PSCs), indisputable proof of their existence has not been reported. Identification of phenotypic markers for PSCs leads to their prospective isolation and precise characterization to clear whether stem cells exist in the pancreas. By combining flow cytometry and clonal analysis, we show here that a possible pancreatic stem or progenitor cell candidate that resides in the developing and adult mouse pancreas expresses the receptor for the hepatocyte growth factor (HGF) c-Met, but does not express hematopoietic and vascular endothelial antigens such as CD45, TER119, c-Kit, and Flk-1. These cells formed clonal colonies in vitro and differentiated into multiple pancreatic lineage cells from single cells. Some of them could largely expand with self-renewing cell divisions in culture, and, following cell transplantation, they differentiated into pancreatic endocrine and acinar cells in vivo. Furthermore, they produced cells expressing multiple markers of nonpancreatic organs including liver, stomach, and intestine in vitro. Our data strongly suggest that c-Met/HGF signaling plays an important role in stem/progenitor cell function in both developing and adult pancreas. By using this antigen, PSCs could be isolated prospectively, enabling a detailed investigation of stem cell markers and application toward regenerative therapies for diabetes.

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

PubMed Central

Antonucci, Laura; Fagman, Johan B.; Kim, Ju Youn; Todoric, Jelena; Gukovsky, Ilya; Mackey, Mason; Ellisman, Mark H.; Karin, Michael

2015-01-01

Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures. PMID:26512112

Pseudocyst in the pancreatic tail associated with chronic pancreatitis successfully treated by transpapillary cyst drainage.

PubMed

Naitoh, Itaru; Ohara, Hirotaka; Okayama, Yasutaka; Nakazawa, Takahiro; Ando, Tomoaki; Hayashi, Kazuki; Okumura, Fumihiro; Kitajima, Yasuhiro; Ban, Tessin; Miyabe, Katsuyuki; Ueno, Koichiro; Joh, Takashi; Sano, Hitoshi

2008-09-01

We report a 50-year-old male with pseudocysts in the pancreatic tail associated with chronic pancreatitis successfully treated by transpapillary cyst drainage. He had previously undergone ultrasonography-guided percutaneous cyst drainage for a pancreatic pseudocyst in our hospital. He was readmitted due to abdominal pain and fever. Computed tomography showed recurrence of a pseudocyst in the pancreatic tail measuring 5 cm in diameter. Since conservative treatment failed, endoscopic retrograde pancreatography was performed. There was communication between the pseudocyst and the main pancreatic duct, and pancreatic duct stenosis proximal to the pseudocyst. First, transpapillary pancreatic duct drainage was performed using a plastic stent, but the pseudocyst did not decrease in size and became infected. After removal of the stent, a pigtail type nasocystic catheter was placed in the pseudocyst via the pancreatic duct. The pseudocyst infection immediately disappeared, and the pseudocyst gradually decreased and disappeared. After removal of the nasocystic catheter, no recurrence was observed. As transpapillary drainage of pancreatic pseudocyst, cyst drainage and pancreatic duct drainage have been reported. In our patient with pseudocyst in the pancreatic tail, duct drainage was ineffective and the pseudocyst was infected, whereas cyst drainage was very effective. We considered that cyst drainage by a nasocystic catheter was the first-line therapy as the transpapillary drainage of the pancreatic pseudocyst.

Pseudocyst in the Pancreatic Tail Associated with Chronic Pancreatitis Successfully Treated by Transpapillary Cyst Drainage

PubMed Central

Naitoh, Itaru; Ohara, Hirotaka; Okayama, Yasutaka; Nakazawa, Takahiro; Ando, Tomoaki; Hayashi, Kazuki; Okumura, Fumihiro; Kitajima, Yasuhiro; Ban, Tessin; Miyabe, Katsuyuki; Ueno, Koichiro; Joh, Takashi; Sano, Hitoshi

2008-01-01

We report a 50-year-old male with pseudocysts in the pancreatic tail associated with chronic pancreatitis successfully treated by transpapillary cyst drainage. He had previously undergone ultrasonography-guided percutaneous cyst drainage for a pancreatic pseudocyst in our hospital. He was readmitted due to abdominal pain and fever. Computed tomography showed recurrence of a pseudocyst in the pancreatic tail measuring 5 cm in diameter. Since conservative treatment failed, endoscopic retrograde pancreatography was performed. There was communication between the pseudocyst and the main pancreatic duct, and pancreatic duct stenosis proximal to the pseudocyst. First, transpapillary pancreatic duct drainage was performed using a plastic stent, but the pseudocyst did not decrease in size and became infected. After removal of the stent, a pigtail type nasocystic catheter was placed in the pseudocyst via the pancreatic duct. The pseudocyst infection immediately disappeared, and the pseudocyst gradually decreased and disappeared. After removal of the nasocystic catheter, no recurrence was observed. As transpapillary drainage of pancreatic pseudocyst, cyst drainage and pancreatic duct drainage have been reported. In our patient with pseudocyst in the pancreatic tail, duct drainage was ineffective and the pseudocyst was infected, whereas cyst drainage was very effective. We considered that cyst drainage by a nasocystic catheter was the first-line therapy as the transpapillary drainage of the pancreatic pseudocyst. PMID:21897788

Dasatinib and Gemcitabine Hydrochloride or Gemcitabine Hydrochloride Alone in Treating Patients With Pancreatic Cancer Previously Treated With Surgery

ClinicalTrials.gov

2018-01-05

Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Recurrent Pancreatic Cancer; Stage IA Pancreatic Cancer; Stage IB Pancreatic Cancer; Stage IIA Pancreatic Cancer; Stage IIB Pancreatic Cancer; Stage III Pancreatic Cancer

Albumin expression distinguishes bile duct adenomas from metastatic adenocarcinoma.

PubMed

Moy, Andrea P; Arora, Kshitij; Deshpande, Vikram

2016-09-01

Bile duct adenomas may be difficult to distinguish from metastatic carcinomas, particularly well-differentiated pancreatic ductal adenocarcinoma. Prior studies have evaluated the utility of various immunohistochemical markers, although these markers are notable for low sensitivity and/or specificity. The aim of this study was to investigate the utility of albumin and BRAFV600E expression in distinguishing between metastatic pancreatic adenocarcinoma and bile duct adenoma. We studied 26 bile duct adenomas, three bile duct hamartomas, and 158 pancreatic ductal adenocarcinomas. Branched-chain in-situ hybridization (bISH) for albumin was performed; bISH is based on the branched DNA technology, wherein signal amplification is achieved via a series of sequential steps. Additionally, BRAFV600E immunohistochemistry (IHC) was performed on a subset of cases. Twenty-three of 25 (92%) bile duct adenomas were positive for albumin; 18 (72%) showed diffuse staining, and five showed focal staining (20%), including two challenging examples. Two bile duct hamartomas also stained positively. All pancreatic adenocarcinomas were negative for albumin. Seven of 16 (44%) bile duct adenomas and five of 106 (5%) pancreatic ductal adenocarcinomas were positive for BRAFV600E by IHC. The sensitivity and specificity of expression of albumin, as detected by bISH, for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 92% and 100%, respectively; the sensitivity and specificity of BRAFV600E IHC for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 43.8% and 95.3%, respectively. Diagnostically challenging examples of bile duct adenoma may be distinguished from metastatic pancreatic adenocarcinoma by the use of albumin bISH. © 2016 John Wiley & Sons Ltd.

Pancreatic trauma

PubMed Central

Bhattacharya, S

2013-01-01

Introduction Pancreatic trauma occurs in approximately 4% of all patients sustaining abdominal injuries. The pancreas has an intimate relationship with the major upper abdominal vessels, and there is significant morbidity and mortality associated with severe pancreatic injury. Immediate resuscitation and investigations are essential to delineate the nature of the injury, and to plan further management. If main pancreatic duct injuries are identified, specialised input from a tertiary hepatopancreaticobiliary (HPB) team is advised. Methods A comprehensive online literature search was performed using PubMed. Relevant articles from international journals were selected. The search terms used were: ‘pancreatic trauma’, ‘pancreatic duct injury’, ‘radiology AND pancreas injury’, ‘diagnosis of pancreatic trauma’, and ‘management AND surgery’. Articles that were not published in English were excluded. All articles used were selected on relevance to this review and read by both authors. Results Pancreatic trauma is rare and associated with injury to other upper abdominal viscera. Patients present with non-specific abdominal findings and serum amylase is of little use in diagnosis. Computed tomography is effective in diagnosing pancreatic injury but not duct disruption, which is most easily seen on endoscopic retrograde cholangiopancreaticography or operative pancreatography. If pancreatic injury is suspected, inspection of the entire pancreas and duodenum is required to ensure full evaluation at laparotomy. The operative management of pancreatic injury depends on the grade of injury found at laparotomy. The most important prognostic factor is main duct disruption and, if found, reconstructive options should be determined by an experienced HPB surgeon. Conclusions The diagnosis of pancreatic trauma requires a high index of suspicion and detailed imaging studies. Grading pancreatic injury is important to guide operative management. The most important

Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kikuta, Kazuhiro; Masamune, Atsushi, E-mail: amasamune@med.tohoku.ac.jp; Watanabe, Takashi

2010-12-17

Research highlights: {yields} Recent studies have shown that pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. {yields} Pancreatic cancer cells co-cultured with PSCs showed loose cell contacts and scattered, fibroblast-like appearance. {yields} PSCs decreased the expression of epithelial markers but increased that of mesenchymal markers, along with increased migration. {yields} This study suggests epithelial-mesenchymal transition as a novel mechanism by which PSCs contribute to the aggressive behavior of pancreatic cancer cells. -- Abstract: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There ismore » accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Because epithelial-mesenchymal transition (EMT) plays a critical role in the progression of pancreatic cancer, we hypothesized that PSCs promote EMT in pancreatic cancer cells. Panc-1 and SUIT-2 pancreatic cancer cells were indirectly co-cultured with human PSCs isolated from patients undergoing operation for pancreatic cancer. The expression of epithelial and mesenchymal markers was examined by real-time PCR and immunofluorescent staining. The migration of pancreatic cancer cells was examined by scratch and two-chamber assays. Pancreatic cancer cells co-cultured with PSCs showed loose cell contacts and a scattered, fibroblast-like appearance. The expression of E-cadherin, cytokeratin 19, and membrane-associated {beta}-catenin was decreased, whereas vimentin and Snail (Snai-1) expression was increased more in cancer cells co-cultured with PSCs than in mono-cultured cells. The migration of pancreatic cancer cells was increased by co-culture with PSCs. The PSC-induced decrease of E-cadherin expression was not

Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamada, Shin; Masamune, Atsushi, E-mail: amasamune@med.tohoku.ac.jp; Takikawa, Tetsuya

2012-05-04

Highlights: Black-Right-Pointing-Pointer Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. Black-Right-Pointing-Pointer Pancreatic cancer cells co-cultured with PSCs showed enhanced spheroid formation. Black-Right-Pointing-Pointer Expression of stem cell-related genes ABCG2, Nestin and LIN28 was increased. Black-Right-Pointing-Pointer Co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. Black-Right-Pointing-Pointer This study suggested a novel role of PSCs as a part of the cancer stem cell niche. -- Abstract: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression ofmore » pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called 'cancer stem cells', within the entire cancer tissue harbor highly tumorigenic and chemo-resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the 'stemness' of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell-like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche.« less

Progressive loss of pancreatic function in chronic pancreatitis is delayed by main pancreatic duct decompression. A longitudinal prospective analysis of the modified puestow procedure.

PubMed

Nealon, W H; Thompson, J C

1993-05-01

This study evaluated the effect of operative drainage of the main pancreatic duct (MPD) on functional derangements associated with chronic pancreatitis (CP). The author previously reported delayed functional impairment in an evaluation of the impact of operative drainage in patients with CP. The author now reports on a prospective study of 143 patients with this diagnosis. Each patient underwent 1) ERCP, 2) the Bentiromide PABA, 3) 72-hour fecal fat test, 4) oral glucose tolerance test (OGTT) and 5) fat meal (LIPOMUL)--stimulated pancreatic polypeptide release (PP). All patients were stratified as mild/moderate (M/M) or severe CP on the basis of a 5-point system that was developed by the author. Patients were studied at 16-month intervals. All 143 patients underwent initial and follow-up evaluations in a mean follow-up of 47.3 months; 83 of 143 patients had M/M grade at initial evaluation. Eighty-seven patients underwent (MPD) decompression to relieve abdominal pain. In a separate prospective 17 patients with a diagnosis of CP, a grade of M/M and non-disabling abdominal pain were randomized to operative or non-operative treatment; 9 of these randomized patients were operated upon and 8 were not. No patient improved their grade during follow-up; 47 of 83 M/M patients had operative drainage and 36 did not. This grade was preserved in 41 of 47 (87%) operated patients but in only 8 of the 36 non-operated patients (22%). In the randomized trial, seven of nine operated patients retained their functional status in follow-up, whereas only two of eight patients (25%) randomized to non-operation preserved their functional grade. These data in this large study as well as among a previous randomized sample, support a policy of early operative drainage before the development of irreversible functional impairment in patients with chronic pancreatitis and associated dilation of the main pancreatic duct.

Progressive loss of pancreatic function in chronic pancreatitis is delayed by main pancreatic duct decompression. A longitudinal prospective analysis of the modified puestow procedure.

PubMed Central

Nealon, W H; Thompson, J C

1993-01-01

OBJECTIVE: This study evaluated the effect of operative drainage of the main pancreatic duct (MPD) on functional derangements associated with chronic pancreatitis (CP). SUMMARY BACKGROUND DATA: The author previously reported delayed functional impairment in an evaluation of the impact of operative drainage in patients with CP. The author now reports on a prospective study of 143 patients with this diagnosis. METHODS: Each patient underwent 1) ERCP, 2) the Bentiromide PABA, 3) 72-hour fecal fat test, 4) oral glucose tolerance test (OGTT) and 5) fat meal (LIPOMUL)--stimulated pancreatic polypeptide release (PP). All patients were stratified as mild/moderate (M/M) or severe CP on the basis of a 5-point system that was developed by the author. Patients were studied at 16-month intervals. RESULTS: All 143 patients underwent initial and follow-up evaluations in a mean follow-up of 47.3 months; 83 of 143 patients had M/M grade at initial evaluation. Eighty-seven patients underwent (MPD) decompression to relieve abdominal pain. In a separate prospective 17 patients with a diagnosis of CP, a grade of M/M and non-disabling abdominal pain were randomized to operative or non-operative treatment; 9 of these randomized patients were operated upon and 8 were not. No patient improved their grade during follow-up; 47 of 83 M/M patients had operative drainage and 36 did not. This grade was preserved in 41 of 47 (87%) operated patients but in only 8 of the 36 non-operated patients (22%). In the randomized trial, seven of nine operated patients retained their functional status in follow-up, whereas only two of eight patients (25%) randomized to non-operation preserved their functional grade. CONCLUSIONS: These data in this large study as well as among a previous randomized sample, support a policy of early operative drainage before the development of irreversible functional impairment in patients with chronic pancreatitis and associated dilation of the main pancreatic duct. PMID

Expression patterns of epiplakin1 in pancreas, pancreatic cancer and regenerating pancreas.

PubMed

Yoshida, Tetsu; Shiraki, Nobuaki; Baba, Hideo; Goto, Mizuki; Fujiwara, Sakuhei; Kume, Kazuhiko; Kume, Shoen

2008-07-01

Epiplakin1 (Eppk1) is a plakin family gene with its function remains largely unknown, although the plakin genes are known to function in interconnecting cytoskeletal filaments and anchoring them at plasma membrane-associated adhesive junction. Here we analyzed the expression patterns of Eppk1 in the developing and adult pancreas in the mice. In the embryonic pancreas, Eppk1+/Pdx1+ and Eppk1+/Sox9+ pancreatic progenitor cells were observed in early pancreatic epithelium. Since Pdx1 expression overlapped with that of Sox9 at this stage, these multipotent progenitor cells are Eppk1+/Pdx1+/Sox9+ cells. Then Eppk1 expression becomes confined to Ngn3+ or Sox9+ endocrine progenitor cells, and p48+ exocrine progenitor cells, and then restricted to the duct cells and a cells at birth. In the adult pancreas, Eppk1 is expressed in centroacinar cells (CACs) and in duct cells. Eppk1 is observed in pancreatic intraepithelial neoplasia (PanIN), previously identified as pancreatic ductal adenocarcinoma (PDAC) precursor lesions. In addition, the expansion of Eppk1-positive cells occurs in a caerulein-induced acute pancreatitis, an acinar cell regeneration model. Furthermore, in the partial pancreatectomy (Px) regeneration model using mice, Eppk1 is expressed in "ducts in foci", a tubular structure transiently induced. These results suggest that Eppk1 serves as a useful marker for detecting pancreatic progenitor cells in developing and regenerating pancreas.

Caffeine Inhibits Fluid Secretion by Interlobular Ducts From Guinea Pig Pancreas.

PubMed

Mochimaru, Yuka; Yamamoto, Akiko; Nakakuki, Miyuki; Yamaguchi, Makoto; Taniguchi, Ituka; Ishiguro, Hiroshi

2017-04-01

Caffeine is contained in coffee, tea, and numerous beverages and foods. We examined the direct effects of caffeine on the physiological function of pancreatic duct cells by using interlobular duct segments isolated from guinea pig pancreas. The rate of fluid secretion was continuously measured by monitoring the luminal volume of isolated duct segments. Changes in intracellular Ca concentration ([Ca]i) were estimated by microfluorometry in ducts loaded with Fura-2. Both secretin-stimulated and acetylcholine (ACh)-stimulated fluid secretions were substantially and reversibly inhibited by relatively low concentrations of caffeine as low as 0.03 mM relevant to blood levels after ingestion of caffeine-containing beverages. Caffeine inhibited ACh-induced elevation of [Ca]i and secretin-induced fluctuation of [Ca]i. Caffeine abolished thapsigargin-induced intracellular Ca release but did not affect the entry of extracellular Ca. Caffeine (0.05 mM) abolished ethanol (1 mM)-induced fluid hypersecretion in secretin-stimulated pancreatic duct. Low concentrations of caffeine directly inhibit pancreatic ductal fluid secretion stimulated by secretin or ACh and also ethanol-induced fluid hypersecretion. The inhibition by caffeine seems to be mediated by the blockade of intracellular Ca mobilization. Daily intake of caffeine may reduce the volume of pancreatic juice secretion.

Veliparib, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Advanced Biliary, Pancreatic, Urothelial, or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2013-07-01

Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage III Pancreatic Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Bladder Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Transitional Cell Carcinoma of the Bladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

Clinical profiles and outcomes in idiopathic duct-centric chronic pancreatitis (type 2 autoimmune pancreatitis): the Mayo Clinic experience.

PubMed

Hart, Phil A; Levy, Michael J; Smyrk, Thomas C; Takahashi, Naoki; Abu Dayyeh, Barham K; Clain, Jonathan E; Gleeson, Ferga C; Pearson, Randall K; Petersen, Bret T; Topazian, Mark D; Vege, Santhi S; Zhang, Lizhi; Chari, Suresh T

2016-10-01

Idiopathic duct-centric chronic pancreatitis (IDCP), also known as type 2 autoimmune pancreatitis (AIP), is an uncommon subtype of AIP. International Consensus Diagnostic Criteria for IDCP propose that the diagnosis requires pancreatic histology and/or concurrent IBD. We examined our experience with IDCP (type 2 AIP) to assess the appropriateness of these criteria, and identify unique characteristics in patients presenting with acute pancreatitis. We reviewed the Mayo Clinic AIP database through May 2014 to identify subjects with either definitive (n=31) or probable (n=12) IDCP. We compared demographic and clinical factors based on strength of diagnostic confidence (definitive versus probable), presence of IBD, and acute pancreatitis as the presenting manifestation. Relapse-free survival was determined using the Kaplan-Meier method. The clinical profiles were similar irrespective of the diagnostic criteria fulfilled. Common clinical presentations included acute pancreatitis (n=25, 58.1%, 12 of whom (27.9%) had recurrent pancreatitis) and pancreatic mass/obstructive jaundice (n=15, 34.9%). The cumulative relapse rate was 10.6% at 3 years (median follow-up 2.9 years). Relapse-free survival was similar for the different diagnostic categories, but was decreased in those initially presenting with acute pancreatitis (p=0.047) or treated with steroids (vs surgery, p=0.049). The current diagnostic classification of probable IDCP and the inclusion of IBD as a supportive criterion appear valid, because patients have similar clinical profiles and disease-related outcomes to those with definitive IDCP. Concurrent IBD, especially in young patients, may suggest when IDCP is the underlying cause of recurrent acute pancreatitis, but additional studies are needed for validation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The role of pancreatic leakage on rising of postoperative complications following pancreatic surgery.

PubMed

Benzoni, Enrico; Saccomano, Enrico; Zompicchiatti, Aron; Lorenzin, Dario; Baccarani, Umberto; Adani, Gian Luigi; Uzzau, Alessandro; Noce, Luigi; Cedolini, Carla; Bresadola, Fabrizio; De Anna, Dino; Intini, Sergio

2008-10-01

The variations in methods of pancreatic stump management and the volume of literature available on both main pancreatic duct and pancreaticoenetric anastomosis leak indicates the concern associated with the leak and the continuing efforts to prevent it. Herein we analyzed the role of pancreatic leakage followed by pancreatic surgery on the incidence of postoperative morbidity. From 1989 to 2005, we performed 76 pancreaticoduodenectomy (PD) and 26 distal pancreatectomy (DP), assumed as control case). During DP the parenchymal transection was performed with a linear stapler. The surgical reconstruction after PD was as follows: 11 manual nonabsorbable stitch closure of the main duct, 24 closure of the main duct with linear stapler, 17 temporary occlusion of the main duct with neoprene glue, and 24 duct-to-mucosa anastomosis. In the PD group, morbidity rate was 60%, caused by pancreatic leakage, with an incidence of 48%, hemorrhagic complication, occurred in 10% of patients following surgical procedure and infectious complication, with an incidence of 15%. After distal pancreatectomy we recorded 80, 7% no complications, 3, 9% leakage, 15, 4% hemoperitoneum. By multivariate analysis bleeding complications, biliary anastomosis leakage, and infectious complications were consequences of pancreatic leakage (P = 0.025, P = 0.025, and P = 0.025, respectively). A significant statistical difference was recorded analyzing re-operation rates between closure of the main duct with linear stapler versus temporary occlusion of the main duct with neoprene glue (t = 0.049) and closure of the main duct with linear stapler versus duct-to-mucosa anastomosis (t = 0.003). On the ground of our results of bleeding complication, biliary anastomosis leakage and infectious complication were consequences of pancreatic leakage: failure of a surgical anastomosis has serious consequences, particularly in case of anastomosis of the pancreas to the small bowel, because of the digestive capacities of

Successful endoscopic removal of a rare, large impacted pancreatic duct stone using grasping forceps: A case report with video.

PubMed

Liu, Qin; Wang, Yiping; Zeng, Hongze; Hu, Bing

2018-04-01

As a main complication of chronic pancreatitis (CP), pancreatic duct stones (PDSs) are often associated with ductal obstruction resulting in increasing intraductal and parenchymal pressure and long-lasting pain. There are many methods for removing PDSs. However, for large stones, it is technically difficult to remove them entirely by endoscopic retrograde cholangiopancreatography (ERCP). A 57-year-old man presented with a chief complaint of severe epigastric pain radiating to his back 3 or 4 times annually for 2 years. The abdominal computed tomography scan revealed dilation of the proximal pancreatic duct with an irregular high-density calcification shadow located at the head of the pancreas. A pancreatic stent was placed initially by ERCP to relieve epigastric pain and alleviate symptom. Repeated ERCP was subsequently performed 2 months later to extract the impacted large pancreatic stone. By using grasping forceps, the huge coralloid stone (272 × 0 mm) was successfully extracted in an en bloc manner. Then, a 7-French × 5 cm plastic pancreatic stent was placed for 2 weeks. The patient was free of any pancreatic pain during the 2-year follow-up. Generally, for large or impacted pancreatic stones, endoscopic removal is technically difficult to achieve. Pancreatic stenting can be an effective method of alleviating abdominal pain and facilitating subsequent endoscopic lithoextraction. Extraction of large stones with grasping forceps can be an alternative approach instead of extracorporeal shock wave lithotripsy or surgery when stones are impacted at the papilla's orifice and partially protruding into the duodenal lumen.

Anomalous pancreatico-biliary ductal union with cystic dilatation of the bile duct.

PubMed

Richer, J P; Faure, J P; Morichau-Beauchant, M; Dugue, T; Maillot, N; Kamina, P; Carretier, M

1998-01-01

We report, in an adult, an asymptomatic association between cystic dilation of the bile duct (type IV A in Todani's classification) and anomalous pancreatico-biliary ductal union (APBD) with stones in a long common channel. In APBD, the connection between the common bile duct and the main pancreatic duct is located outside the duodenal wall andis therefore not under the influence of the sphincter of Boyden. An abnormally long common channel is in excess of 15 mm. Two types of convergence anomalies are defined according to whether the bile duct opens into the main pancreatic duct (BP) or the main pancreatic duct into the bile duct (PB). In APBD, there is probably a reverse pressure gradient between the bile and pancreatic ducts, with regurgitation of pancreatic juice into the bile duct, repeated attacks of cholangitis, stenosis and cystic dilatation. A long common channel is associated with a higher incidence of carcinoma of the gall bladder of the bile duct.

Guadecitabine and Durvalumab in Treating Patients With Advanced Liver, Pancreatic, Bile Duct, or Gallbladder Cancer

ClinicalTrials.gov

2018-04-27

Extrahepatic Bile Duct Adenocarcinoma, Biliary Type; Gallbladder Adenocarcinoma, Biliary Type; Metastatic Pancreatic Adenocarcinoma; Recurrent Cholangiocarcinoma; Recurrent Gallbladder Carcinoma; Recurrent Hepatocellular Carcinoma; Recurrent Intrahepatic Cholangiocarcinoma; Recurrent Pancreatic Carcinoma; Stage III Gallbladder Cancer AJCC V7; Stage III Hepatocellular Carcinoma AJCC v7; Stage III Intrahepatic Cholangiocarcinoma AJCC v7; Stage III Pancreatic Cancer AJCC v6 and v7; Stage IIIA Gallbladder Cancer AJCC v7; Stage IIIA Hepatocellular Carcinoma AJCC v7; Stage IIIB Gallbladder Cancer AJCC v7; Stage IIIB Hepatocellular Carcinoma AJCC v7; Stage IIIC Hepatocellular Carcinoma AJCC v7; Stage IV Gallbladder Cancer AJCC v7; Stage IV Hepatocellular Carcinoma AJCC v7; Stage IV Pancreatic Cancer AJCC v6 and v7; Stage IVA Gallbladder Cancer AJCC v7; Stage IVA Hepatocellular Carcinoma AJCC v7; Stage IVA Intrahepatic Cholangiocarcinoma AJCC v7; Stage IVB Gallbladder Cancer AJCC v7; Stage IVB Hepatocellular Carcinoma AJCC v7; Stage IVB Intrahepatic Cholangiocarcinoma AJCC v7; Unresectable Gallbladder Carcinoma; Unresectable Pancreatic Carcinoma

A case of annular pancreas with Wirsung's duct encircling the duodenum: embryological hypothesis based on cholangiopancreatographic and immunohistochemical findings.

PubMed

Fukai, Manami; Kamisawa, Terumi; Horiguchi, Shin-Ichirou; Hishima, Tsunekazu; Kuruma, Sawako; Chiba, Kazuro; Koizumi, Satomi; Tabata, Taku; Nagao, Sayaka; Kikuyama, Masataka; Honda, Goro; Kurata, Masanao

2017-06-01

We present a resected case of annular pancreas in which Wirsung's duct encircled the duodenum and continued directly to the main pancreatic duct in the body and tail. Furthermore, Wirsung's duct coursed along the right side of the lower bile duct near the major duodenal papilla. Histologically, the islets of Langerhans in the annular pancreas were irregular in shape and were characterized by a striking abundance of pancreatic polypeptide (PP)-positive cells. The PP-rich area that encircled the duodenum was fused with the PP-poor area in the head of the pancreas. The following embryological hypothesis is proposed. The tip of the ventral pancreatic anlage adhered to the duodenal wall and stretched to form a ring during clockwise rotation. The rotation was incomplete, and the pancreatic duct did not cross over the lower bile duct. Since there was adequate ventral anlage in the lower part of the head of the pancreas, fusion between the ducts of the ventral and dorsal anlagen did not occur. The tip of the ventral anlage overgrew and adhered to the dorsal anlage, and the annular duct fused with the main duct of the dorsal anlage.

Identification of a novel putative pancreatic stem/progenitor cell marker DCAMKL-1 in normal mouse pancreas.

PubMed

May, Randal; Sureban, Sripathi M; Lightfoot, Stan A; Hoskins, Aimee B; Brackett, Daniel J; Postier, Russell G; Ramanujam, Rama; Rao, Chinthalapally V; Wyche, James H; Anant, Shrikant; Houchen, Courtney W

2010-08-01

Stem cells are critical in maintaining adult homeostasis and have been proposed to be the origin of many solid tumors, including pancreatic cancer. Here we demonstrate the expression patterns of the putative intestinal stem cell marker DCAMKL-1 in the pancreas of uninjured C57BL/6 mice compared with other pancreatic stem/progenitor cell markers. We then determined the viability of isolated pancreatic stem/progenitor cells in isotransplantation assays following DCAMKL-1 antibody-based cell sorting. Sorted cells were grown in suspension culture and injected into the flanks of athymic nude mice. Here we report that DCAMKL-1 is expressed in the main pancreatic duct epithelia and islets, but not within acinar cells. Coexpression was observed with somatostatin, NGN3, and nestin, but not glucagon or insulin. Isolated DCAMKL-1+ cells formed spheroids in suspension culture and induced nodule formation in isotransplantation assays. Analysis of nodules demonstrated markers of early pancreatic development (PDX-1), glandular epithelium (cytokeratin-14 and Ep-CAM), and isletlike structures (somatostatin and secretin). These data taken together suggest that DCAMKL-1 is a novel putative stem/progenitor marker, can be used to isolate normal pancreatic stem/progenitors, and potentially regenerates pancreatic tissues. This may represent a novel tool for regenerative medicine and a target for anti-stem cell-based therapeutics in pancreatic cancer.

Identification of a novel putative pancreatic stem/progenitor cell marker DCAMKL-1 in normal mouse pancreas

PubMed Central

May, Randal; Sureban, Sripathi M.; Lightfoot, Stan A.; Hoskins, Aimee B.; Brackett, Daniel J.; Postier, Russell G.; Ramanujam, Rama; Rao, Chinthalapally V.; Wyche, James H.; Anant, Shrikant

2010-01-01

Stem cells are critical in maintaining adult homeostasis and have been proposed to be the origin of many solid tumors, including pancreatic cancer. Here we demonstrate the expression patterns of the putative intestinal stem cell marker DCAMKL-1 in the pancreas of uninjured C57BL/6 mice compared with other pancreatic stem/progenitor cell markers. We then determined the viability of isolated pancreatic stem/progenitor cells in isotransplantation assays following DCAMKL-1 antibody-based cell sorting. Sorted cells were grown in suspension culture and injected into the flanks of athymic nude mice. Here we report that DCAMKL-1 is expressed in the main pancreatic duct epithelia and islets, but not within acinar cells. Coexpression was observed with somatostatin, NGN3, and nestin, but not glucagon or insulin. Isolated DCAMKL-1+ cells formed spheroids in suspension culture and induced nodule formation in isotransplantation assays. Analysis of nodules demonstrated markers of early pancreatic development (PDX-1), glandular epithelium (cytokeratin-14 and Ep-CAM), and isletlike structures (somatostatin and secretin). These data taken together suggest that DCAMKL-1 is a novel putative stem/progenitor marker, can be used to isolate normal pancreatic stem/progenitors, and potentially regenerates pancreatic tissues. This may represent a novel tool for regenerative medicine and a target for anti-stem cell-based therapeutics in pancreatic cancer. PMID:20522640

Effect of L-cysteine on remote organ injury in rats with severe acute pancreatitis induced by bile-pancreatic duct obstruction.

PubMed

Yang, Li-Juan; Wan, Rong; Shen, Jia-Qing; Shen, Jie; Wang, Xing-Peng

2013-08-01

Remote organ failure occurs in cases of acute pancreatitis (AP); however, the reports on AP induced by pancreatic duct obstruction are rare. In this study we determined the effect of L-cysteine on pancreaticobiliary inflammation and remote organ damage in rats after pancreaticobiliary duct ligation (PBDL). AP was induced by PBDL in rats with 5/0 silk. Sixty rats were randomly divided into 4 groups. Groups A and B were sham-operated groups that received injections of saline or L-cysteine (10 mg/kg) intraperitoneally (15 rats in each group). Groups C and D were PBDL groups that received injections of saline or L-cysteine (10 mg/kg) intraperitoneally (15 rats in each group). The tissue samples of the pancreas and remote organs such as the lung, liver, intestine and kidney were subsequently examined for pathological changes under a light microscope. The samples were also stored for the determination of malondialdehyde and glutathione levels. Blood urea nitrogen (BUN), plasma amylase, ALT and AST levels were determined spectrophotometrically using an automated analyzer. Also, we evaluated the effect of L-cysteine on remote organ injury in rats with AP induced by retrograde infusion of 3.5% sodium taurocholate (NaTc) into the bile-pancreatic duct. Varying degrees of injury in the pancreas, lung, liver, intestine and kidney were observed in the rats 24 hours after PBDL. The severity of injury to the lung, liver and intestine was attenuated, while injury status was not changed significantly in the pancreas and kidney after L-cysteine treatment. Oxidative stress was also affected by L-cysteine in PBDL-treated rats. The concentration of tissue malondialdehyde decreased in the pancreas and remote organs of PBDL and L-cysteine administrated rats, and the concentration of glutathione increased more significantly than that of the model control group. However, L-cysteine administration reduced the severity of injury in remote organs but not in the pancreas in rats with Na

Hilar cholangiocarcinoma is pathologically similar to pancreatic duct adenocarcinoma: suggestions of similar background and development.

PubMed

Nakanuma, Yasuni; Sato, Yasunori

2014-07-01

Routine experiences suggest that cholangiocarcinomas (CCAs) show different clinicopathological behaviors along the biliary tree, and hilar CCA apparently resembles pancreatic duct adenocarcinoma (PDAC). Herein, the backgrounds for these similarities were reviewed. While all cases of PDAC, hilar CCA, intrahepatic CCA (ICCA) and CCA components of combined hepatocellular-cholangiocarcinoma (cHC-CCA) were adenocarcinomas, micropapillary patterns and columnar carcinoma cells were common in PDAC and hilar CCA, and trabecular components and cuboidal carcinoma cells were common in ICCA and CCA components of cHC-CCA. Anterior gradient protein-2 and S100P were frequently expressed in perihilar CCA and PDAC, while neural cell adhesion molecule and luminal epithelial membrane antigen were common in CCA components of c-HC-CCA. Pdx1 and Hes1 were frequently and markedly expressed aberrantly in PDAC and perihilar CCA, although their expression was rare and mild in CCA components in cHC-CCA and ICCA. Hilar CCA showed a similar postoperative prognosis to PDAC but differed from ICCA and cHC-CCA. Taken together, hilar CCA may differ from ICCA and CCA components of cHC-CCA but have a similar development to PDAC. These similarities may be explained by the unique anatomical, embryological and reactive nature of the pancreatobiliary tract. Further studies of these intractable malignancies are warranted. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Distribution of type IV collagen in pancreatic adenocarcinoma and chronic pancreatitis.

PubMed Central

Lee, C. S.; Montebello, J.; Georgiou, T.; Rode, J.

1994-01-01

Changes in the basement membrane are present in various neoplastic conditions such as neurofibrosarcoma, cervical carcinoma, colorectal cancers and hepatoblastoma. This study examines the expression of type IV collagen in the basement membrane, using an immunohistochemical method, in the normal pancreas (n = 10), chronic pancreatitis (n = 15) and pancreatic adenocarcinoma (n = 30). The formalin fixed, paraffin embedded tissue was sectioned and pretreated with protease prior to immunostaining for type IV collagen. There was a statistically significant difference in type IV collagen expression between pancreatic carcinoma and chronic pancreatitis (P = 0.0001; chi 2 test with continuity correction). In pancreatic adenocarcinoma, type IV collagen distribution in the basement membrane was discontinuous and irregular or absent around individual or groups of neoplastic cells (n = 30). Most cases of chronic pancreatitis showed continuous pattern of basement membrane type IV collagen around residual ducts (n = 10). In the normal pancreas, only one of the ten cases showed discontinuous basement membrane around pancreatic ducts, while in the rest of the cases, the pattern was continuous. This study suggests that there is abnormal distribution of type IV collagen in the basement membrane in pancreatic carcinoma, which may be related to either abnormal deposition or degradation of the collagen. Immunostaining for type IV collagen may be of some diagnostic use for distinguishing pancreatic adenocarcinoma from problematic cases of chronic pancreatitis. Images Figure 1 Figure 2 Figure 3 PMID:8199008

Factors and outcomes associated with pancreatic duct disruption in patients with acute necrotizing pancreatitis.

PubMed

Jang, Ji Woong; Kim, Myung-Hwan; Oh, Dongwook; Cho, Dong Hui; Song, Tae Jun; Park, Do Hyun; Lee, Sang Soo; Seo, Dong-Wan; Lee, Sung Koo; Moon, Sung-Hoon

Acute necrotizing pancreatitis (ANP) can affect main pancreatic duct (MPD) as well as parenchyma. However, the incidence and outcomes of MPD disruption has not been well studied in the setting of ANP. This retrospective study investigated 84 of 465 patients with ANP who underwent magnetic resonance cholangiopancreatography and/or endoscopic retrograde cholangiopancreatography. The MPD disruption group was subclassified into complete and partial disruption. MPD disruption was documented in 38% (32/84) of the ANP patients. Extensive necrosis, enlarging/refractory pancreatic fluid collections (PFCs), persistence of amylase-rich output from percutaneous drainage, and amylase-rich ascites/pleural effusion were more frequently associated with MPD disruption. Hospital stay was prolonged (mean 55 vs. 29 days) and recurrence of PFCs (41% vs. 14%) was more frequent in the MPD disruption group, although mortality did not differ between ANP patients with and without MPD disruption. Subgroup analysis between complete disruption (n = 14) and partial disruption (n = 18) revealed a more frequent association of extensive necrosis and full-thickness glandular necrosis with complete disruption. The success rate of endoscopic transpapillary pancreatic stenting across the stricture site was lower in complete disruption (20% vs. 92%). Patients with complete MPD disruption also showed a high rate of PFC recurrence (71% vs. 17%) and required surgery more often (43% vs. 6%). MPD disruption is not uncommon in patients with ANP with clinical suspicion on ductal disruption. Associated MPD disruption may influence morbidity, but not mortality of patients with ANP. Complete MPD disruption is often treated by surgery, whereas partial MPD disruption can be managed successfully with endoscopic transpapillary stenting and/or transmural drainage. Further prospective studies are needed to study these items. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Enterovirus strain and type-specific differences in growth kinetics and virus-induced cell destruction in human pancreatic duct epithelial HPDE cells.

PubMed

Smura, Teemu; Natri, Olli; Ylipaasto, Petri; Hellman, Marika; Al-Hello, Haider; Piemonti, Lorenzo; Roivainen, Merja

2015-12-02

Enterovirus infections have been suspected to be involved in the development of type 1 diabetes. However, the pathogenetic mechanism of enterovirus-induced type 1 diabetes is not known. Pancreatic ductal cells are closely associated with pancreatic islets. Therefore, enterovirus infections in ductal cells may also affect beta-cells and be involved in the induction of type 1 diabetes. The aim of this study was to assess the ability of different enterovirus strains to infect, replicate and produce cytopathic effect in human pancreatic ductal cells. Furthermore, the viral factors that affect these capabilities were studied. The pancreatic ductal cells were highly susceptible to enterovirus infections. Both viral growth and cytolysis were detected for several enterovirus serotypes. However, the viral growth and capability to induce cytopathic effect (cpe) did not correlate completely. Some of the virus strains replicated in ductal cells without apparent cpe. Furthermore, there were strain-specific differences in the growth kinetics and the ability to cause cpe within some serotypes. Viral adaptation experiments were carried out to study the potential genetic determinants behind these phenotypic differences. The blind-passage of non-lytic CV-B6-Schmitt strain in HPDE-cells resulted in lytic phenotype and increased progeny production. This was associated with the substitution of a single amino acid (K257E) in the virus capsid protein VP1 and the viral ability to use decay accelerating factor (DAF) as a receptor. This study demonstrates considerable plasticity in the cell tropism, receptor usage and cytolytic properties of enteroviruses and underlines the strong effect of single or few amino acid substitutions in cell tropism and lytic capabilities of a given enterovirus. Since ductal cells are anatomically close to pancreatic islets, the capability of enteroviruses to infect and destroy pancreatic ductal cells may also implicate in respect to enterovirus induced type 1

CXCL12 Chemokine Expression Suppresses Human Pancreatic Cancer Growth and Metastasis

PubMed Central

Roy, Ishan; Zimmerman, Noah P.; Mackinnon, A. Craig; Tsai, Susan; Evans, Douglas B.; Dwinell, Michael B.

2014-01-01

Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites. PMID:24594697

Age-related change of the secretory flow of pancreatic juice in the main pancreatic duct: evaluation with cine-dynamic MRCP using spatially selective inversion recovery pulse.

PubMed

Torigoe, Teruyuki; Ito, Katsuyoshi; Yamamoto, Akira; Kanki, Akihiko; Yasokawa, Kazuya; Tamada, Tsutomu; Yoshida, Koji

2014-05-01

The purpose of this study is to evaluate age-related changes in the secretory flow of pancreatic juice in the main pancreatic duct noninvasively by means of nonpharmacologic cine-dynamic MRCP using spatially selective inversion recovery (IR) pulse. Fifty-three subjects without a history of pancreatic disease were included. Four-second breath-hold MRCP using spatially selective IR pulse was performed every 15 seconds during 5 minutes (acquiring a total of 20 images) in cine-dynamic fashion. The secretion grade was classified into five grades by the distance of pancreatic juice inflow within the tagged area. The mean secretion grade and the frequency of secretion in cine-dynamic MRCP were compared among three age-range groups (group 1, < 40 years; group 2, 40-70 years; and group 3, > 70 years). Statistical analysis was performed using Spearman rank correlation coefficient and Kruskal-Wallis and Mann-Whitney U tests. The secretion grade and the frequency of secretion were significantly reduced with aging (r = -0.77, p < 0.001; and r = -0.74, p < 0.001, respectively). The mean secretion grade and the frequency of secretion were significantly lower in group 3 than in group 2 (mean grade, 0.36 vs 1.48, p = 0.001; and 4.8 vs 11.9 times, p = 0.001) and were lower in group 2 than in group 1 (mean grade, 1.48 vs 2.48, p < 0.001; and 11.9 vs 16.2 times, p = 0.011). Cine-dynamic MRCP using spatially selective IR pulse was able to show the age-related decrease of the secretory flow of pancreatic juice in the main pancreatic duct visually and noninvasively.

Alcohol and the pancreas. II. Pancreatic morphology of advanced alcoholic pancreatitis.

PubMed

Noronha, M; Bordalo, O; Dreiling, D A

1981-08-01

The histopathology of advanced chronic alcoholic pancreatitis is dominated by cellular degeneration, atrophy and fibrosis. Sequential changes in the histopathology of alcoholic pancreatic disease has been defined and traced from initial injury to end-stage disease. These sequential histopathologies have been correlated with clinical syndrome and secretory patterns. The data are more consistent with a toxic-metabolic pathogenesis of alcoholic pancreatitis than the previous Big Duct and Small Duct hypotheses.

A unifying concept: pancreatic ductal anatomy both predicts and determines the major complications resulting from pancreatitis.

PubMed

Nealon, William H; Bhutani, Manoop; Riall, Taylor S; Raju, Gottumukkala; Ozkan, Orhan; Neilan, Ryan

2009-05-01

Precepts about acute pancreatitis, necrotizing pancreatitis, and pancreatic fluid collections or pseudocyst rarely include the impact of pancreatic ductal injuries on their natural course and outcomes. We previously examined and established a system to categorize ductal changes. We sought a unifying concept that may predict course and direct therapies in these complex patients. We use our system categorizing ductal changes in pseudocyst of the pancreas and severe necrotizing pancreatitis (type I, normal duct; type II, duct stricture; type III, duct occlusion or "disconnected duct"; and type IV, chronic pancreatitis). From 1985 to 2006, a policy was implemented of routine imaging (cross-sectional, endoscopic retrograde cholangiopancreatography, or magnetic resonance cholangiopancreatography). Clinical outcomes were measured. Among 563 patients with pseudocyst, 142 resolved spontaneously (87% of type I, 5% of type II, and no type III, and 3% of type IV). Percutaneous drainage was successful in 83% of type I, 49% of type II, and no type III or type IV. Among 174 patients with severe acute pancreatitis percutaneous drainage was successful in 64% of type I, 38% of type II, and no type III. Operative debridement was required in 39% of type I and 83% and 85% of types II and III, respectively. Persistent fistula after debridement occurred in 27%, 54%, and 85% of types I, II, and III ducts, respectively. Late complications correlated with duct injury. Pancreatic ductal changes predict spontaneous resolution, success of nonoperative measures, and direct therapies in pseudocyst. Ductal changes also predict patients with necrotizing pancreatitis who are most likely to have immediate and delayed complications.

Nonoperative measurement of pancreatic and common bile duct pressures with a microtransducer catheter and effects of duodenoscopic sphincterotomy.

PubMed

Tanaka, M; Ikeda, S; Nakayama, F

1981-06-01

Duodenoscopic manometry of the pancreatic duct (PD) and common bile duct (CBD) using a microtransducer catheter was distinct advantages over infusion manometry, giving absolute values of in situ intraluminal pressure. Microtransducer manometry was performed without medication in 49 patients with gallbladder stones (10), common bile duct stones (24), hepatic duct stones (6) and common bile duct dilatation (9), and was successful in 42 (86%) for PD and 36 (73%) for CBD. Ductal pressures showed respiration-synchronized biphasic variations superimposed by the arterial pulsation effect. Considerable postural change of the pressure values suggested that the recording posture should be predetermined. The PD-to-duodenum pressure gradient was higher than the CBD-to-duodenum gradient in most cases. Both were lower than those obtained previously by infusion methods. No significant differences were found in pressure profiles of the four disease groups. Endoscopic sphincterotomy significantly reduced not only CBD pressure but also PD pressure.

Bicarbonate-rich fluid secretion predicted by a computational model of guinea-pig pancreatic duct epithelium.

PubMed

Yamaguchi, Makoto; Steward, Martin C; Smallbone, Kieran; Sohma, Yoshiro; Yamamoto, Akiko; Ko, Shigeru B H; Kondo, Takaharu; Ishiguro, Hiroshi

2017-03-15

The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO 3 - concentrations as high as 140 mm during hormonal stimulation. A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea-pig pancreatic ducts. The model was readily able to secrete 140 mm HCO 3 - . Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers. We conclude that the main requirement for secreting high HCO 3 - concentrations is to minimize the secretion of Cl - ions. These findings help to clarify the mechanism responsible for pancreatic HCO 3 - secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease. A computational model of guinea-pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO 3 - ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least-squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP-stimulated secretion were well replicated by increasing the activities of the basolateral Na + -HCO 3 - cotransporter (NBC1) and apical Cl - /HCO 3 - exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K + permeability and apical Cl - and HCO 3 - permeabilities (CFTR), and reducing the activity of the basolateral Cl - /HCO 3 - exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ∼140 mm HCO 3 - at a rate of ∼3 nl min -1  mm -2 , which is consistent with experimental

Endoscopic Therapies for Chronic Pancreatitis.

PubMed

Adler, Jeffrey M; Gardner, Timothy B

2017-07-01

Chronic pancreatitis is a fibroinflammatory disease of the pancreas leading to varying degrees of endocrine and exocrine dysfunction. Treatment options are generally designed to control the pain of chronic pancreatitis, and endoscopic therapy is one of the main treatment modalities. Herein, we describe the endoscopic management of pancreatic duct calculi and strictures, entrapment of the intrapancreatic bile duct, celiac plexus interventions, and drainage of pancreatic pseudocysts.

Stem cell marker prominin-1/AC133 is expressed in duct cells of the adult human pancreas.

PubMed

Lardon, Jessy; Corbeil, Denis; Huttner, Wieland B; Ling, Zhidong; Bouwens, Luc

2008-01-01

Many efforts are spent in identifying stem cells in adult pancreas because these could provide a source of beta cells for cell-based therapy of type 1 diabetes. Prominin-1, particularly its specific glycosylation-dependent AC133 epitope, is expressed on stem/progenitor cells of various human tissues and can be used to isolate them. We, therefore, examined its expression in adult human pancreas. To detect prominin-1 protein, monoclonal antibody CD133/1 (AC133 clone), which recognizes the AC133 epitope, and the alphahE2 antiserum, which is directed against the human prominin-1 polypeptide, were used. Prominin-1 RNA expression was analyzed by real-time polymerase chain reaction. We report that all duct-lining cells of the pancreas express prominin-1. Most notably, the cells that react with the alphahE2 antiserum also react with the AC133 antibody. After isolation and culture of human exocrine cells, we found a relative increase in prominin-1 expression both at protein and RNA expression level, which can be explained by an enrichment of cells with ductal phenotype in these cultures. Our data show that pancreatic duct cells express prominin-1 and surprisingly reveal that its particular AC133 epitope is not an exclusive stem and progenitor cell marker.

Chronic pancreatitis with multiple pseudocysts and pancreatic panniculitis: A case report.

PubMed

Gu, Yuqing; Qian, Zhuyin

2018-06-01

Pancreatic pseudocyst can present single or multiple, inside or outside the pancreas. Pancreatic panniculitis is a rare skin lesion in pancreatic disease patients. The purpose of this study is to report a case of chronic pancreatitis coexisting with multiple pseudocysts and pancreatic panniculitis. A 46-year-old man with chronic pancreatitis presented multiple small cystic lesions inside the head of the pancreas and two large cystic lesions adjacent to the tail of the pancreas. The patient also developed subcutaneous nodules involving upper and lower limbs, hands, and lower abdomen bilaterally. The patient was diagnosed with pancreatic pseudocyst and pancreatic panniculitis resulted from chronic pancreatitis. Bile duct stent and pancreatic duct stent placement was performed endoscopicly. Panniculitis faded three weeks later and the pancreatic pseudocysts disappeared six weeks later. Clinicians should be aware of the manifestation of multiple pancreatic pseudocyst and pancreatic panniculitis, and endoscopic transpapillary drainage may be a effective way in this scenario.

Ductal cancers of the pancreas frequently express markers of gastrointestinal epithelial cells.

PubMed

Sessa, F; Bonato, M; Frigerio, B; Capella, C; Solcia, E; Prat, M; Bara, J; Samloff, I M

1990-06-01

It has been found by immunohistochemical staining that antigens normally found in gastric and/or intestinal epithelial cells are expressed in most differentiated duct cell carcinomas of the pancreas. Among 88 such tumors, 93% and 92%, respectively, expressed M1 and cathepsin E, markers of gastric surface-foveolar epithelial cells, 51% expressed pepsinogen II, a marker of gastroduodenal mucopeptic cells, 48% expressed CAR-5, a marker of colorectal epithelial cells, and 35% expressed M3SI, a marker of small intestinal goblet cells. Most of the tumors also expressed normal pancreatic duct antigens; 97% expressed DU-PAN-2, and 59% expressed N-terminus gastrin-releasing peptide. In agreement with these findings, electron microscopy revealed malignant cells with fine structural features of gastric foveolar cells, gastric mucopeptic cells, intestinal goblet cells, intestinal columnar cells, pancreatic duct epithelial cells, and cells with features of more than one cell type. Normal pancreatic duct epithelium did not express any marker of gastrointestinal epithelial cells, whereas such benign lesions as mucinous cell hypertrophy and papillary hyperplasia commonly expressed gut-type antigens but rarely expressed pancreatic duct cell markers. By contrast, lesions characterized by atypical papillary hyperplasia commonly expressed both gastric and pancreatic duct cell markers. Metaplastic pyloric-type glands expressed pepsinogen II and, except for their expression of cathepsin E, were indistinguishable from normal pyloric glands. In marked contrast, the immunohistochemical and ultrastructural features of 14 ductuloacinar cell tumors were those of cells lining terminal ductules, centroacinar cells, and/or acinar cells; none expressed any gut-type antigen. The results indicate that gastrointestinal differentiation is common in both benign and malignant lesions of pancreatic duct epithelium and suggest that duct cell carcinomas are histogenetically related to gastric- and

Redox-mediated enrichment of self-renewing adult human pancreatic cells that possess endocrine differentiation potential.

PubMed

Linning, Katrina D; Tai, Mei-Hui; Madhukar, Burra V; Chang, C C; Reed, Donald N; Ferber, Sarah; Trosko, James E; Olson, L Karl

2004-10-01

The limited availability of transplantable human islets has stimulated the development of methods needed to isolate adult pancreatic stem/progenitor cells capable of self-renewal and endocrine differentiation. The objective of this study was to determine whether modulation of intracellular redox state with N-acetyl-L-cysteine (NAC) would allow for the propagation of pancreatic stem/progenitor cells from adult human pancreatic tissue. Cells were propagated from human pancreatic tissue using a serum-free, low-calcium medium supplemented with NAC and tested for their ability to differentiate when cultured under different growth conditions. Human pancreatic cell (HPC) cultures coexpressed alpha-amylase, albumin, vimentin, and nestin. The HPC cultures, however, did not express other genes associated with differentiated pancreatic exocrine, duct, or endocrine cells. A number of transcription factors involved in endocrine cell development including Beta 2, Islet-1, Nkx6.1, Pax4, and Pax6 were expressed at variable levels in HPC cultures. In contrast, pancreatic duodenal homeobox factor 1 (Pdx-1) expression was extremely low and at times undetectable. Overexpression of Pdx-1 in HPC cultures stimulated somatostatin, glucagon, and carbonic anhydrase expression but had no effect on insulin gene expression. HPC cultures could form 3-dimensional islet-like cell aggregates, and this was associated with expression of somatostatin and glucagon but not insulin. Cultivation of HPCs in a differentiation medium supplemented with nicotinamide, exendin-4, and/or LY294002, an inhibitor of phosphatidylinositol-3 kinase, stimulated expression of insulin mRNA and protein. These data support the use of intracellular redox modulation for the enrichment of pancreatic stem/progenitor cells capable of self-renewal and endocrine differentiation.

Unraveling Pancreatic Segmentation.

PubMed

Renard, Yohann; de Mestier, Louis; Perez, Manuela; Avisse, Claude; Lévy, Philippe; Kianmanesh, Reza

2018-04-01

Limited pancreatic resections are increasingly performed, but the rate of postoperative fistula is higher than after classical resections. Pancreatic segmentation, anatomically and radiologically identifiable, may theoretically help the surgeon removing selected anatomical portions with their own segmental pancreatic duct and thus might decrease the postoperative fistula rate. We aimed at systematically and comprehensively reviewing the previously proposed pancreatic segmentations and discuss their relevance and limitations. PubMed database was searched for articles investigating pancreatic segmentation, including human or animal anatomy, and cadaveric or surgical studies. Overall, 47/99 articles were selected and grouped into 4 main hypotheses of pancreatic segmentation methodology: anatomic, vascular, embryologic and lymphatic. The head, body and tail segments are gross description without distinct borders. The arterial territories defined vascular segments and isolate an isthmic paucivascular area. The embryological theory relied on the fusion plans of the embryological buds. The lymphatic drainage pathways defined the lymphatic segmentation. These theories had differences, but converged toward separating the head and body/tail parts, and the anterior from posterior and inferior parts of the pancreatic head. The rate of postoperative fistula was not decreased when surgical resection was performed following any of these segmentation theories; hence, none of them appeared relevant enough to guide pancreatic transections. Current pancreatic segmentation theories do not enable defining anatomical-surgical pancreatic segments. Other approaches should be explored, in particular focusing on pancreatic ducts, through pancreatic ducts reconstructions and embryologic 3D modelization.

L-Cysteine Administration Attenuates Pancreatic Fibrosis Induced by TNBS in Rats by Inhibiting the Activation of Pancreatic Stellate Cell

PubMed Central

Hu, GuoYong; Shen, Jie; Wang, Feng; Xu, Ling; Dai, WeiQi; Xiong, Jie; Ni, JianBo; Guo, ChuanYong; Wan, Rong; Wang, XingPeng

2012-01-01

Background and Aims Recent studies have shown that activated pancreatic stellate cells (PSCs) play a major role in pancreatic fibrogenesis. We aimed to study the effect of L-cysteine administration on fibrosis in chronic pancreatitis (CP) induced by trinitrobenzene sulfonic acid (TNBS) in rats and on the function of cultured PSCs. Methods CP was induced by TNBS infusion into rat pancreatic ducts. L-cysteine was administrated for the duration of the experiment. Histological analysis and the contents of hydroxyproline were used to evaluate pancreatic damage and fibrosis. Immunohistochemical analysis of α-SMA in the pancreas was performed to detect the activation of PSCs in vivo. The collagen deposition related proteins and cytokines were determined by western blot analysis. DNA synthesis of cultured PSCs was evaluated by BrdU incorporation. We also evaluated the effect of L-cysteine on the cell cycle and cell activation by flow cytometry and immunocytochemistry. The expression of PDGFRβ, TGFβRII, collagen 1α1 and α-SMA of PSCs treated with different concentrations of L-cysteine was determined by western blot. Parameters of oxidant stress were evaluated in vitro and in vivo. Nrf2, NQO1, HO-1, IL-1β expression were evaluated in pancreas tissues by qRT-PCR. Results The inhibition of pancreatic fibrosis by L-cysteine was confirmed by histological observation and hydroxyproline assay. α-SMA, TIMP1, IL-1β and TGF-β1 production decreased compared with the untreated group along with an increase in MMP2 production. L-cysteine suppressed the proliferation and extracellular matrix production of PSCs through down-regulating of PDGFRβ and TGFβRII. Concentrations of MDA+4-HNE were decreased by L-cysteine administration along with an increase in GSH levels both in tissues and cells. In addition, L-cysteine increased the mRNA expression of Nrf2, NQO1 and HO-1 and reduced the expression of IL-1β in L-cysteine treated group when compared with control group. Conclusion L

Ngn3+ endocrine progenitor cells control the fate and morphogenesis of pancreatic ductal epithelium

PubMed Central

Magenheim, Judith; Klein, Allon M.; Stanger, Ben Z.; Ashery-Padan, Ruth; Sosa-Pineda, Beatriz; Gu, Guoqiang; Dor, Yuval

2013-01-01

Summary During pancreas development, endocrine and exocrine cells arise from a common multipotent progenitor pool. How these cell fate decisions are coordinated with tissue morphogenesis is poorly understood. Here we have examined ductal morphology, endocrine progenitor cell fate and Notch signaling in Ngn3−/− mice, which do not produce islet cells. Ngn3 deficiency results in reduced branching and enlarged pancreatic duct-like structures, concomitant with Ngn3 promoter activation throughout the ductal epithelium and reduced Notch signaling. Conversely, forced generation of surplus endocrine progenitor cells causes reduced duct caliber and an excessive number of tip cells. Thus, endocrine progenitor cells normally provide a feedback signal to adjacent multipotent ductal progenitor cells that activates Notch signaling, inhibits further endocrine differentiation and promotes proper morphogenesis. These results uncover a novel layer of regulation coordinating pancreas morphogenesis and endocrine/exocrine differentiation, and suggest ways to enhance the yield of beta-cells from stem cells. PMID:21888903

Bicarbonate‐rich fluid secretion predicted by a computational model of guinea‐pig pancreatic duct epithelium

PubMed Central

Yamaguchi, Makoto; Steward, Martin C.; Smallbone, Kieran; Sohma, Yoshiro; Yamamoto, Akiko; Ko, Shigeru B. H.; Kondo, Takaharu

2017-01-01

Key points The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO3 − concentrations as high as 140 mm during hormonal stimulation.A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea‐pig pancreatic ducts.The model was readily able to secrete 140 mm HCO3 −. Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers.We conclude that the main requirement for secreting high HCO3 − concentrations is to minimize the secretion of Cl− ions.These findings help to clarify the mechanism responsible for pancreatic HCO3 − secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease. Abstract A computational model of guinea‐pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO3 − ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least‐squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP‐stimulated secretion were well replicated by increasing the activities of the basolateral Na+‐HCO3 − cotransporter (NBC1) and apical Cl−/HCO3 − exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K+ permeability and apical Cl− and HCO3 − permeabilities (CFTR), and reducing the activity of the basolateral Cl−/HCO3 − exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ∼140 mm HCO3 − at a rate of ∼3 nl min−1 mm−2, which is

Dynamic Contrast Enhanced MRI in Patients With Advanced Breast or Pancreatic Cancer With Metastases to the Liver or Lung

ClinicalTrials.gov

2014-05-28

Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Liver Metastases; Lung Metastases; Recurrent Breast Cancer; Recurrent Pancreatic Cancer; Stage IV Breast Cancer; Stage IV Pancreatic Cancer

[Pancreatic anastomosis in operative treatment of chronic pancreatitis].

PubMed

Bellon, E; Izbicki, J R; Bockhorn, M

2017-01-01

Chronic pancreatitis (CP) is an irreversible, inflammatory process, which is characterized by progressive fibrosis of the pancreas and leads to abdominal pain, endocrine and exocrine insufficiency. Surgical therapy is indicated by the absence of pain relief and local complications. The target of the surgical approach is to relieve the pancreatic and bile ducts and resection of the fibrotic and calcified parenchyma. Drainage procedures, such as the Partington-Rochelle method, are used in patients with isolated congestion of the pancreatic duct without further organ complications, such as inflammatory processes of the pancreatic head; however, patients with CP often have an inflammatory swelling of the pancreatic head. In this case classical pancreatoduodenectomy (PD) or organ-sparing duodenum-preserving pancreatic head resection (DPPHR) with its various techniques (e.g. Beger, Frey, Bern and V‑shape) can be applied. Due to similar long-term results PD should be carried out in cases of suspicion or detection of malignancies and DPPHR for treatment of CP.

Alleviation of hyperglycemia in diabetic rats by intraportal injection of insulin-producing cells generated from surgically resected human pancreatic tissue.

PubMed

Shyu, Jia-Fwu; Wang, Hwai-Shi; Shyr, Yi-Ming; Wang, Shin-E; Chen, Chia-Hsiang; Tan, Joo-Shin; Lin, Meng-Feng; Hsieh, Po-Shiuan; Sytwu, Huey-Kang; Chen, Tien-Hua

2011-03-01

Although islet transplantation holds promise for the treatment of diabetes, the scarcity of donor tissue remains a major drawback. The aim of this study is to generate insulin-producing cells from adult human pancreatic cells isolated from surgically resected pancreatic tissue. To isolate pancreatic endocrine precursor cells from 57 surgically resected pancreases, the cells were cultured and propagated in conditioned medium after which they were differentiated in Matrigel. The resultant cells were characterized using morphology, immunofluorescent studies, expression of differentiated pancreatic islet-specific genes using quantitative reverse transcription-PCR, and glucose-induced insulin secretion through analysis of C-peptide secretion. The relationships between propagation of insulin-producing cells and clinical variables of the donor were also analyzed. Finally, insulin-producing cell function was examined in streptozotocin-induced diabetic rats. Pancreatic endocrine precursor cells were successfully cultured; insulin-producing cells cultured from soft pancreas parenchyma had a significantly higher success rate. Morphological examination revealed islet-like cluster formation upon transfer to Matrigel. The presence of the neural stem cell marker nestin, duct cell marker cytokeratin 19, and endocrine cell markers C-peptide and pancreatic and duodenal homeobox 1, was also observed. In addition, glucose-stimulated C-peptide release was significantly increased in the insulin-producing cells. Furthermore, in diabetic rats, transplantation of insulin-producing cells reduced hyperglycemia. Isolated pancreatic endocrine precursor cells from surgically resected pancreatic tissue differentiated into insulin-producing cells and showed characteristics of functional endocrine cells. Thus, surgically resected pancreatic tissue may represent an alternative source of functional insulin-producing cells.

Pancreatic bicarbonate secretion involves two proton pumps.

PubMed

Novak, Ivana; Wang, Jing; Henriksen, Katrine L; Haanes, Kristian A; Krabbe, Simon; Nitschke, Roland; Hede, Susanne E

2011-01-07

Pancreas secretes fluid rich in digestive enzymes and bicarbonate. The alkaline secretion is important in buffering of acid chyme entering duodenum and for activation of enzymes. This secretion is formed in pancreatic ducts, and studies to date show that plasma membranes of duct epithelium express H(+)/HCO(3)(-) transporters, which depend on gradients created by the Na(+)/K(+)-ATPase. However, the model cannot fully account for high-bicarbonate concentrations, and other active transporters, i.e. pumps, have not been explored. Here we show that pancreatic ducts express functional gastric and non-gastric H(+)-K(+)-ATPases. We measured intracellular pH and secretion in small ducts isolated from rat pancreas and showed their sensitivity to H(+)-K(+) pump inhibitors and ion substitutions. Gastric and non-gastric H(+)-K(+) pumps were demonstrated on RNA and protein levels, and pumps were localized to the plasma membranes of pancreatic ducts. Quantitative analysis of H(+)/HCO(3)(-) and fluid transport shows that the H(+)-K(+) pumps can contribute to pancreatic secretion in several species. Our results call for revision of the bicarbonate transport physiology in pancreas, and most likely other epithelia. Furthermore, because pancreatic ducts play a central role in several pancreatic diseases, it is of high relevance to understand the role of H(+)-K(+) pumps in pathophysiology.

[Hepaticojejunostomy after pancreatic head resection - technical aspects for reconstruction of small and fragile bile ducts with T-tube drainage].

PubMed

Herzog, T; Belyaev, O; Uhl, W; Seelig, M H; Chromik, A

2012-12-01

After pancreatic head resection the reconstruction of small and fragile bile ducts is technically demanding, resulting in more postoperative bile leaks. One option for the reconstruction is the placement of a T-tube drainage at the site of the anastomosis. Standard reconstruction after pancreatic head resection was an end-to-side hepaticojejunostomy with PDS 5.0, 15-25 cm distally from the pancreaticojejunostomy. For patients with a small bile duct diameter (≤ 5 mm) or a fragile bile duct wall the reconstruction was performed with PDS 6.0 and a T-tube drainage at the side of the anastomosis. The reconstruction with a T-tube drainage at the site of the anastomosis is technically easy to perform and offers the opportunity for immediate visualisation of the anastomosis in the postoperative period by application of water soluble contrast medium. If a bile leak occurs, biliary deviation through the T-tube drainage can enable a conservative management without revisional laparotomy in selected patients. Whether or not a conservative management of postoperative bile leaks will lead to more bile duct strictures is a subject for further investigations. A T-tube drainage at the site of the anastomosis can probably not prevent postoperative bile leaks from a difficult hepaticojejunostomy, but in selected patients it offers the opportunity for a conservative management resulting in less re-operations. Therefore we recommend the augmentation of a difficult hepaticojejunostomy with a T-tube drainage. Georg Thieme Verlag KG Stuttgart · New York.

Stimulation of cAMP signalling allows isolation of clonal pancreatic precursor cells from adult mouse pancreas.

PubMed

Yamamoto, T; Yamato, E; Taniguchi, H; Shimoda, M; Tashiro, F; Hosoi, M; Sato, T; Fujii, S; Miyazaki, J-I

2006-10-01

Duct cells of the pancreas are thought to include latent progenitors of islet endocrine cells that can be induced to differentiate by appropriate morphogens. Here we developed a method for isolating pancreatic ductal epithelial cells from adult mice that overcomes the shortcomings of previous methods. Pancreatic ductal cells were grown in serum-free DMEM/F12 medium in the presence of cholera toxin or 8-bromo-cyclic adenosine monophosphate, which is known to be an intracellular cAMP generator. Single cell cloning was performed by limiting dilution in serum-free medium. The isolated clonal cells expressed high levels of cytokeratin and Ipf1 (formerly known as Pdx-1). Adenovirus-mediated expression of ngn3 (also known as Neurog3) and Ptf1a in these cells induced expression of insulin and somatostatin, and of carboxypeptidase A, respectively. Furthermore, albumin production was induced by dexamethasone or by long-term culture in serum-containing medium. Stimulation of the cAMP-dependent signalling allowed us to isolate clonal pancreatic ductal cells from adult mice. These cells are able to partially differentiate into endocrine cells, exocrine cells and hepatocyte-like cells and are therefore considered to have the characteristics of endodermal progenitor cells.

A Review of Double Common Bile Duct and Its Sequelae.

PubMed

Kolli, Sindhura; Etienne, Denzil; Reddy, Madhavi; Shahzad, Ghulamullah

2018-02-01

A double or accessory common bile duct (ACBD) is a rare congenital anomaly. We report the case of a 60-year-old American Asian male, who was found to have a double or duplicated common bile duct after being admitted for evaluation of a pancreatic mass. A duplicated bile duct has the same mucosa histologically as a single bile duct. However, the opening of a duplicated bile duct lacks a sphincter allowing retrograde flow of gut contents which results in a higher probability of intraductal calculus formation. On rare occasions, it can predispose to liver abscesses, pancreatitis, pancreatic cancer, gallbladder cancer, gastric cancer, and ampullary cancer depending on the location of the opening of the ACBD. We present an integrative review of the limited cases of ACBD with correlation to the current case and discussion regarding the aspects of diagnosis and management.

Exosomes Derived From Pancreatic Stellate Cells: MicroRNA Signature and Effects on Pancreatic Cancer Cells.

PubMed

Takikawa, Tetsuya; Masamune, Atsushi; Yoshida, Naoki; Hamada, Shin; Kogure, Takayuki; Shimosegawa, Tooru

2017-01-01

Pancreatic stellate cells (PSCs) interact with pancreatic cancer cells in the tumor microenvironment. Cell constituents including microRNAs may be exported from cells within membranous nanovesicles termed exosomes. Exosomes might play a pivotal role in intercellular communication. This study aimed to clarify the microRNA signature of PSC-derived exosomes and their effects on pancreatic cancer cells. Exosomes were prepared from the conditioned medium of immortalized human PSCs. MicroRNAs were prepared from the exosomes and their source PSCs, and the microRNA expression profiles were compared by microarray. The effects of PSC-derived exosomes on proliferation, migration, and the mRNA expression profiles were examined in pancreatic cancer cells. Pancreatic stellate cell-derived exosomes contained a variety of microRNAs including miR-21-5p. Several microRNAs such as miR-451a were enriched in exosomes compared to their source PSCs. Pancreatic stellate cell-derived exosomes stimulated the proliferation, migration and expression of mRNAs for chemokine (C - X - C motif) ligands 1 and 2 in pancreatic cancer cells. The stimulation of proliferation, migration, and chemokine gene expression by the conditioned medium of PSCs was suppressed by GW4869, an exosome inhibitor. We clarified the microRNA expression profile in PSC-derived exosomes. Pancreatic stellate cell-derived exosomes might play a role in the interactions between PSCs and pancreatic cancer cells.

Pancreatic cysts suspected to be branch duct intraductal papillary mucinous neoplasm without concerning features have low risk for development of pancreatic cancer.

PubMed

Lawson, Robert D; Hunt, Gordon C; Giap, Andrew Q; Krinsky, Mary L; Slezak, Jeff; Tang, Raymond S; Gonzalez, Ingrid; Kwong, Wilson T; Fehmi, Syed A; Savides, Thomas J

2015-01-01

The risk of developing pancreatic cancer is uncertain in patients with clinically suspected branch duct intraductal papillary mucinous neoplasm (BD-IPMN) based on the "high-risk stigmata" or "worrisome features" criteria proposed in the 2012 international consensus guidelines ("Fukuoka criteria"). Retrospective case series involving patients referred for endoscopic ultrasound (EUS) of indeterminate pancreatic cysts with clinical and EUS features consistent with BD-IPMN. Rates of pancreatic cancer occurring at any location in the pancreas were compared between groups of patients with one or more Fukuoka criteria ("Highest-Risk Group", HRG) and those without these criteria ("Lowest-Risk Group", LRG). After exclusions, 661 patients comprised the final cohort (250 HRG and 411 LRG patients), 62% female with an average age of 67 years and 4 years of follow up. Pancreatic cancer, primarily adenocarcinoma, occurred in 60 patients (59 HRG, 1 LRG). Prevalent cancers diagnosed during EUS, immediate surgery, or first year of follow up were found in 48/661 (7.3%) of cohort and exclusively in HRG (33/77, 42.3%). Using Kaplan-Meier method, the cumulative incidence of cancer at 7 years was 28% in HRG and 1.2% in LRG patients (P<0.001). This study supports using Fukuoka criteria to stratify the immediate and long-term risks of pancreatic cancer in presumptive BD-IPMN. The risk of pancreatic cancer was highest during the first year and occurred exclusively in those with "high-risk stigmata" or "worrisome features" criteria. After the first year all BD-IPMN continued to have a low but persistent cancer risk.

Role of bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective

PubMed Central

Feng, Hui-Yi; Chen, Yang-Chao

2016-01-01

The role of bile acids in colorectal cancer has been well documented, but their role in pancreatic cancer remains unclear. In this review, we examined the risk factors of pancreatic cancer. We found that bile acids are associated with most of these factors. Alcohol intake, smoking, and a high-fat diet all lead to high secretion of bile acids, and bile acid metabolic dysfunction is a causal factor of gallstones. An increase in secretion of bile acids, in addition to a long common channel, may result in bile acid reflux into the pancreatic duct and to the epithelial cells or acinar cells, from which pancreatic adenocarcinoma is derived. The final pathophysiological process is pancreatitis, which promotes dedifferentiation of acinar cells into progenitor duct-like cells. Interestingly, bile acids act as regulatory molecules in metabolism, affecting adipose tissue distribution, insulin sensitivity and triglyceride metabolism. As a result, bile acids are associated with three risk factors of pancreatic cancer: obesity, diabetes and hypertriglyceridemia. In the second part of this review, we summarize several studies showing that bile acids act as cancer promoters in gastrointestinal cancer. However, more question are raised than have been solved, and further oncological and physiological experiments are needed to confirm the role of bile acids in pancreatic cancer carcinogenesis. PMID:27672269

Trypsin Reduces Pancreatic Ductal Bicarbonate Secretion by Inhibiting CFTR Cl- channel and Luminal Anion Exchangers

PubMed Central

Pallagi, Petra; Venglovecz, Viktória; Rakonczay, Zoltán; Borka, Katalin; Korompay, Anna; Ózsvári, Béla; Judák, Linda; Sahin-Tóth, Miklós; Geisz, Andrea; Schnúr, Andrea; Maléth, József; Takács, Tamás; Gray, Mike A.; Argent, Barry E.; Mayerle, Julia; Lerch, Markus M.; Wittmann, Tibor; Hegyi, Péter

2012-01-01

Background & Aims The effects of trypsin on pancreatic ductal epithelial cells (PDEC) vary among species and depend on localization of proteinase-activated receptor-2 (PAR-2). Bicarbonate secretion is similar in human and guinea pig PDEC; we compared its localization in these cell types and isolated guinea pig ducts to study the effects of trypsin and a PAR-2 agonist on this process. Methods PAR-2 localization was analyzed by immunohistochemistry in guinea pig and human pancreatic tissue samples (from 15 patients with chronic pancreatitis and 15 without pancreatic disease). Functions of guinea pig PDEC were studied by microperfusion of isolated ducts, measurements of intracellular pH (pHi) and Ca2+ concentration [Ca2+]i, and patch clamp analysis. The effect of pH on trypsinogen autoactivation was assessed using recombinant human cationic trypsinogen. Results PAR-2 localized to the apical membrane of human and guinea pig PDEC. Trypsin increased [Ca2+]i and pHi, and inhibited secretion of bicarbonate by the luminal anion exchanger and the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Autoactivation of human cationic trypsinogen accelerated when the pH was reduced from 8.5 to 6.0. PAR-2 expression was strongly down-regulated, at transcriptional and protein levels, in the ducts of patients with chronic pancreatitis, consistent with increased activity of intraductal trypsin. Importantly, in PAR-2 knockout mice, the effects of trypsin were PAR-2 dependent. Conclusions Trypsin reduces pancreatic ductal bicarbonate secretion via PAR-2–dependent inhibition of the apical anion exchanger and the CFTR Cl- channel. This could contribute to the development of chronic pancreatitis, decreasing luminal pH and promoting premature activation of trypsinogen in the pancreatic ducts. PMID:21893120

Isolated Roux-en-Y anastomosis of the pancreatic stump in a duct-to-mucosa fashion in patients with distal pancreatectomy with en-bloc celiac axis resection.

PubMed

Okada, Ken-Ichi; Kawai, Manabu; Tani, Masaji; Hirono, Seiko; Miyazawa, Motoki; Shimizu, Atsushi; Kitahata, Yuji; Yamaue, Hiroki

2014-03-01

A pancreatic fistula is one of the most serious complications in distal pancreatectomy with en bloc celiac axis resection (DP-CAR), because the pancreatic transection is performed on the right side of the portal vein, which results in a large cross-section surface, and because post-pancreatectomy hemorrhage is hard to treat by interventional radiology. Therefore, a procedure to decrease the incidence of postoperative pancreatic fistula is urgently needed. Twenty-six consecutive patients who underwent DP-CAR between April 2008 and August 2012 were reviewed retrospectively. The first 13 consecutive patients underwent DP-CAR with no anastomosis, and the subsequent 13 consecutive patients were treated with Roux-en-Y pancreaticojejunostomy (PJ) in a duct-to-mucosa fashion. Extremely high amylase levels (>4000 IU/l) of all drainage fluid specimens on postoperative day (POD) 1, 3 and 4 were detected more frequently in cases with no anastomosis (n = 7) compared to those with PJ (n = 1) (P = 0.056). The incidence of grade B/C pancreatic fistulas was 15.4% in cases with isolated Roux-en-Y anastomosis of the pancreatic stump performed in a duct-to-mucosa fashion, and we are currently examining whether this anastomosis method reduces the pancreatic fistula rate in a multicenter, randomized controlled trial for distal pancreatectomy patients (ClinicalTrials.gov NCT01384617). © 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice.

PubMed

Fazio, Elena N; Young, Claire C; Toma, Jelena; Levy, Michael; Berger, Kurt R; Johnson, Charis L; Mehmood, Rashid; Swan, Patrick; Chu, Alphonse; Cregan, Sean P; Dilworth, F Jeffrey; Howlett, Christopher J; Pin, Christopher L

2017-09-01

Pancreatitis is a debilitating disease of the exocrine pancreas that, under chronic conditions, is a major susceptibility factor for pancreatic ductal adenocarcinoma (PDAC). Although down-regulation of genes that promote the mature acinar cell fate is required to reduce injury associated with pancreatitis, the factors that promote this repression are unknown. Activating transcription factor 3 (ATF3) is a key mediator of the unfolded protein response, a pathway rapidly activated during pancreatic insult. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that ATF3 is bound to the transcriptional regulatory regions of >30% of differentially expressed genes during the initiation of pancreatitis. Of importance, ATF3-dependent regulation of these genes was observed only upon induction of pancreatitis, with pathways involved in inflammation, acinar cell differentiation, and cell junctions being specifically targeted. Characterizing expression of transcription factors that affect acinar cell differentiation suggested that acinar cells lacking ATF3 maintain a mature cell phenotype during pancreatitis, a finding supported by maintenance of junctional proteins and polarity markers. As a result, Atf3 -/- pancreatic tissue displayed increased tissue damage and inflammatory cell infiltration at early time points during injury but, at later time points, showed reduced acinar-to-duct cell metaplasia. Thus our results reveal a critical role for ATF3 as a key regulator of the acinar cell transcriptional response during injury and may provide a link between chronic pancreatitis and PDAC. © 2017 Fazio et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

New developments in endoscopic treatment of chronic pancreatitis.

PubMed

Didden, P; Bruno, M; Poley, J W

2012-12-01

The aim of endoscopic therapy of chronic pancreatitis (CP) is to treat pain by draining the pancreatic duct or managing loco-regional complications. Recent decennia were characterized by continuous improvement of endoscopic techniques and devices, resulting in a better clinical outcome. Novel developments now also provide the opportunity to endoscopically treat refractory CP-related complications. Especially suboptimal surgical candidates could potentially benefit from these new developments, consequently avoiding invasive surgery. The use of fully covered self-expandable metal stents (SEMS) has been explored in pancreatic and CP-related biliary duct strictures, resistant to conventional treatment with plastic endoprotheses. Furthermore, endosonography-guided transmural drainage of the main pancreatic duct via duct-gastrostomy is an alternative treatment option in selected cases. Pancreatic pseudocysts represent an excellent indication for endoscopic therapy with some recent case series demonstrating effective drainage with the use of a fully covered SEMS. Although results of these new endoscopic developments are promising, high quality randomized trials are required to determine their definite role in the management of chronic pancreatitis.

Pancreatic cysts suspected to be branch duct intraductal papillary mucinous neoplasm without concerning features have low risk for development of pancreatic cancer

PubMed Central

Lawson, Robert D.; Hunt, Gordon C.; Giap, Andrew Q.; Krinsky, Mary L.; Slezak, Jeff; Tang, Raymond S.; Gonzalez, Ingrid; Kwong, Wilson T.; Fehmi, Syed A.; Savides, Thomas J.

2015-01-01

Background The risk of developing pancreatic cancer is uncertain in patients with clinically suspected branch duct intraductal papillary mucinous neoplasm (BD-IPMN) based on the “high-risk stigmata” or “worrisome features” criteria proposed in the 2012 international consensus guidelines (“Fukuoka criteria”). Methods Retrospective case series involving patients referred for endoscopic ultrasound (EUS) of indeterminate pancreatic cysts with clinical and EUS features consistent with BD-IPMN. Rates of pancreatic cancer occurring at any location in the pancreas were compared between groups of patients with one or more Fukuoka criteria (“Highest-Risk Group”, HRG) and those without these criteria (“Lowest-Risk Group”, LRG). Results After exclusions, 661 patients comprised the final cohort (250 HRG and 411 LRG patients), 62% female with an average age of 67 years and 4 years of follow up. Pancreatic cancer, primarily adenocarcinoma, occurred in 60 patients (59 HRG, 1 LRG). Prevalent cancers diagnosed during EUS, immediate surgery, or first year of follow up were found in 48/661 (7.3%) of cohort and exclusively in HRG (33/77, 42.3%). Using Kaplan-Meier method, the cumulative incidence of cancer at 7 years was 28% in HRG and 1.2% in LRG patients (P<0.001). Conclusions This study supports using Fukuoka criteria to stratify the immediate and long-term risks of pancreatic cancer in presumptive BD-IPMN. The risk of pancreatic cancer was highest during the first year and occurred exclusively in those with “high-risk stigmata” or “worrisome features” criteria. After the first year all BD-IPMN continued to have a low but persistent cancer risk. PMID:26423829

Long-term patency, pancreatic function, and pain relief after lateral pancreaticojejunostomy for chronic pancreatitis.

PubMed

Warshaw, A L; Popp, J W; Schapiro, R H

1980-08-01

Ten patients, all with intractable pain due to chronic pancreatitis, were selected for treatment by lateral pancreaticojejunostomy (modified Puestow procedure) after preoperative endoscopic pancreatography in each had revealed dilatation of the main pancreatic duct. Follow-up endoscopic pancreatograms performed 1 yr after surgery show a patent anastomosis in all 10 patients. Eight of these 10 are largely or completely pain-free, but 2 continiue to have pain without improvement after the operation. Surgical success in relieving pain was accompanied neither by improvement in pancreatic function, nor by protection against its further deterioration: Whereas 2 patients had malabsorption and 3 were diabetic preoperatively, 6 had malabsorption and 5 had diabetes postoperatively. This progression of exocrine or endorine pancreatic insufficiency indicates that decompression of the dilated pancreatic duct, although an effective means for relief of pain in chronic pancreatitis, does not prevent continuing destruction of pancreatic glandular tissue.

Bacteriological profile of pancreatic juice in patients with chronic pancreatitis.

PubMed

Parida, Salil Kumar; Pottakkat, Biju; Raja, Kalayarasan; Vijayahari, Ranjit; Lakshmi, Chandrasekharan Padma

2014-09-28

Information regarding the association of bacteria in the pancreatic fluid in patients with chronic pancreatitis is limited. This study was designed to analyze the prevalence of bacteria in pancreatic juice in patients with chronic pancreatitis and the association of positive pancreatic fluid culture with pre-operative and post-operative parameters. All patients with chronic pancreatitis who underwent operation from November 2011 to October 2013 were prospectively included in the study. Intra-operatively pancreatic duct fluid was collected and sent for culture sensitivity in all patients. The bacteriology of the fluid was analyzed and was correlated with preoperative, intraoperative and postoperative parameters. A total of 26 patients were analyzed. Two patients underwent endoscopic retrograde cholangio-pancreatography (ERCP) preoperatively. Bacteria was present in pancreatic duct fluid in 11 (42%) patients. Both patients who underwent ERCP had positive cultures. Most common organism observed was Escherichia coli (6/11, 55%) followed by Klebsiella pneumonia (3/11, 27%). Five patients with positive culture developed wound infection. Bacteria isolated from the wound were similar to pancreatic fluid. Bacteria is commonly present in the pancreatic juice in patients with chronic pancreatitis and its presence may have an effect on the post-operative infections following operations. Based on the pancreatic fluid culture results appropriate antibiotic can be given to the patients who will develop septic complications following surgery. Role of bacteria in the pathogenesis of the chronic calcific pancreatitis needs to be investigated in future studies.

[Pancreatic trauma].

PubMed

Arvieux, C; Guillon, F; Létoublon, Ch; Oughriss, M

2003-10-01

Early diagnosis of pancreatic trauma has always been challenging because of the lack of correlation between the initial clinical symptomatology, radiologic and laboratory findings, and the severity of the injury. Thanks to the improved performance of spiral CT scanning and magnetic resonance pancreatography, it is now often possible to make an early diagnosis of pancreatic contusion, to localize the site of the injury, and (most importantly) to identify injury to the main pancreatic duct which has major implications for the management of the case. When the trauma victim is unstable, radiologic work-up may be impossible and urgent laparotomy is required. Control of hemorrhage is the primary concern here and a damage control approach with packing may be appropriate; if the pancreatic head has been destroyed, a pancreaticoduodenectomy with delayed reconstruction may be required. If the trauma victim is stable, the treatment strategy will be governed by a variety of parameters--age, clinical condition, associated local anatomic findings (pancreatitis, injury to the duodenum or biliary tract), involvement of the pancreatic duct, and localization of the injury within the gland (to right or left of the mesenteric vessels).

Surgical therapy in chronic pancreatitis.

PubMed

Neal, C P; Dennison, A R; Garcea, G

2012-12-01

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas which causes chronic pain, as well as exocrine and endocrine failure in the majority of patients, together producing social and domestic upheaval and a very poor quality of life. At least half of patients will require surgical intervention at some stage in their disease, primarily for the treatment of persistent pain. Available data have now confirmed that surgical intervention may produce superior results to conservative and endoscopic treatment. Comprehensive individual patient assessment is crucial to optimal surgical management, however, in order to determine which morphological disease variant (large duct disease, distal stricture with focal disease, expanded head or small duct/minimal change disease) is present in the individual patient, as a wide and differing range of surgical approaches are possible depending upon the specific abnormality within the gland. This review comprehensively assesses the evidence for these differing approaches to surgical intervention in chronic pancreatitis. Surgical drainage procedures should be limited to a small number of patients with a dilated duct and no pancreatic head mass. Similarly, a small population presenting with a focal stricture and tail only disease may be successfully treated by distal pancreatectomy. Long-term results of both of these procedure types are poor, however. More impressive results have been yielded for the surgical treatment of the expanded head, for which a range of surgical options now exist. Evidence from level I studies and a recent meta-analysis suggests that duodenum-preserving resections offer benefits compared to pancreaticoduodenectomy, though the results of the ongoing, multicentre ChroPac trial are awaited to confirm this. Further data are also needed to determine which of the duodenum-preserving procedures provides optimal results. In relation to small duct/minimal change disease total pancreatectomy represents the only

Pancreatic hardness: Correlation of surgeon's palpation, durometer measurement and preoperative magnetic resonance imaging features.

PubMed

Hong, Tae Ho; Choi, Joon-Il; Park, Michael Yong; Rha, Sung Eun; Lee, Young Joon; You, Young Kyoung; Choi, Moon Hyung

2017-03-21

To evaluate the correlation between subjective assessments of pancreatic hardness based on the palpation, objective measurements using a durometer, and magnetic resonance imaging (MRI) findings for assessing pancreatic hardness. Eighty-three patients undergoing pancreatectomies were enrolled. An experienced surgeon subjectively evaluated the pancreatic hardness in the surgical field by palpation. The pancreatic hardness was also objectively evaluated using a durometer. Preoperative MRI findings were evaluated by a radiologist in terms of the apparent diffusion coefficient (ADC) values, the relative signal intensity decrease (RSID) of the pancreatic parenchyma, and the diameter of the pancreatic parenchyma and duct. Durometer measurement results, ADC values, RSID, pancreatic duct and parenchyma diameters, and the ratio of the diameters of the duct and parenchyma were compared between pancreases judged to be soft or hard pancreas on the palpation. A correlation analysis was also performed between the durometer and MRI measurements. The palpation assessment classified 44 patients as having a soft pancreas and 39 patients as having a hard pancreas. ADC values were significantly lower in the hard pancreas group. The ductal diameter and duct-to-pancreas ratio were significantly higher in the hard pancreas group. For durometer measurements, a correlation analysis showed a positive correlation with the ductal diameter and the duct-to-pancreas ratio and a negative correlation with ADC values. Hard pancreases showed lower ADC values, a wider pancreatic duct diameter and a higher duct-to-pancreas ratio than soft pancreases. Additionally, the ADC values, diameter of the pancreatic duct and duct-to-pancreas ratio were closely correlated with the durometer results.

Prospective assessment of the influence of pancreatic cancer resection on exocrine pancreatic function.

PubMed

Sikkens, E C M; Cahen, D L; de Wit, J; Looman, C W N; van Eijck, C; Bruno, M J

2014-01-01

Exocrine insufficiency frequently develops in patients with pancreatic cancer owing to tumour ingrowth and pancreatic duct obstruction. Surgery might restore this function by removing the primary disease and restoring duct patency, but it may also have the opposite effect, as a result of resection of functional parenchyma and anatomical changes. This study evaluated the course of pancreatic function, before and after pancreatic resection. This prospective cohort study included patients with tumours in the pancreatic region requiring pancreatic resection in a tertiary referral centre between March 2010 and August 2012. Starting before surgery, exocrine function was determined monthly by measuring faecal elastase 1 levels (normal value over 0.200 µg per g faeces). Endocrine function, steatorrhoea-related symptoms and bodyweight were also evaluated before and after surgery. Subjects were followed from diagnosis until 6 months after surgery, or until death. Twenty-nine patients were included, 12 with pancreatic cancer, 14 with ampullary carcinoma and three with bile duct carcinoma (median tumour size 2.6 cm). Twenty-six patients underwent pancreaticoduodenectomy and three distal pancreatectomy. Thirteen patients had exocrine insufficiency at preoperative diagnosis. After a median follow-up of 6 months, this had increased to 24 patients. Diabetes was present in seven patients at diagnosis, and developed in one additional patient within 1 month after surgery. Most patients with tumours in the pancreatic region requiring pancreatic resection either had exocrine insufficiency at diagnosis or became exocrine-insufficient soon after surgical resection. © 2013 BJS Society Ltd. Published by John Wiley & Sons Ltd.

Clinical impact of duodenal pancreatic heterotopia - Is there a need for surgical treatment?

PubMed

Betzler, Alexander; Mees, Soeren T; Pump, Josefine; Schölch, Sebastian; Zimmermann, Carolin; Aust, Daniela E; Weitz, Jürgen; Welsch, Thilo; Distler, Marius

2017-05-08

Pancreatic heterotopia (PH) is defined as ectopic pancreatic tissue outside the normal pancreas and its vasculature and duct system. Most frequently, PH is detected incidentally by histopathological examination. The aim of the present study was to analyze a large single-center series of duodenal PH with respect to the clinical presentation. A prospective pancreatic database was retrospectively analyzed for cases of PH of the duodenum. All pancreatic and duodenal resections performed between January 2000 and October 2015 were included and screened for histopathologically proven duodenal PH. PH was classified according to Heinrich's classification (Type I acini, ducts, and islet cells; Type II acini and ducts; Type III only ducts). A total of 1274 pancreatic and duodenal resections were performed within the study period, and 67 cases of PH (5.3%) were identified. The respective patients were predominantly male (72%) and either underwent pancreatoduodenectomy (n = 60); a limited pancreas resection with partial duodenal resection (n = 4); distal pancreatectomy with partial duodenal resection (n = 1); total pancreatectomy (n = 1); or enucleation (n = 1). Whereas 65 patients (83.5%) were asymptomatic, 11 patients (18.4%) presented with symptoms related to PH (most frequently with abdominal pain [72%] and duodenal obstruction [55%]). Of those, seven patients (63.6%) had chronic pancreatitis in the heterotopic pancreas. The risk of malignant transformation into adenocarcinoma was 2.9%. PH is found in approximately 5% of pancreatic or duodenal resections and is generally asymptomatic. Chronic pancreatitis is not uncommon in heterotopic pancreatic tissue, and even there is a risk of malignant transformation. PH should be considered for the differential diagnosis of duodenal lesions and surgery should be considered, especially in symptomatic cases.

Proton Pump Inhibitors Inhibit Pancreatic Secretion: Role of Gastric and Non-Gastric H+/K+-ATPases

PubMed Central

Tozzi, Marco; Giannuzzo, Andrea; Sørensen, Christiane E.; Novak, Ivana

2015-01-01

The mechanism by which pancreas secretes high HCO3 - has not been fully resolved. This alkaline secretion, formed in pancreatic ducts, can be achieved by transporting HCO3 - from serosa to mucosa or by moving H+ in the opposite direction. The aim of the present study was to determine whether H+/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar localizations in duct cell monolayers (Capan-1) and human pancreas, and notably the gastric pumps are localized on the luminal membranes. In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis. Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3 -, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3 - secretion. We propose that proton transport is driving secretion, and that in addition it may provide a protective pH buffer zone and K+ recirculation. Furthermore, it seems relevant to re-evaluate whether PPIs should be used in treatment therapies where pancreatic functions are already compromised. PMID:25993003

BPC 157 therapy to detriment sphincters failure-esophagitis-pancreatitis in rat and acute pancreatitis patients low sphincters pressure.

PubMed

Petrovic, I; Dobric, I; Drmic, D; Sever, M; Klicek, R; Radic, B; Brcic, L; Kolenc, D; Zlatar, M; Kunjko, K; Jurcic, D; Martinac, M; Rasic, Z; Boban Blagaic, A; Romic, Z; Seiwerth, S; Sikiric, P

2011-10-01

Possibly, acute esophagitis and pancreatitis cause each other, and we focused on sphincteric failure as the common causative key able to induce either esophagitis and acute pancreatitis or both of them, and thereby investigate the presence of a common therapy nominator. This may be an anti-ulcer pentadecapeptide BPC 157 (tested for inflammatory bowel disease, wound treatment) affecting esophagitis, lower esophageal and pyloric sphincters failure and acute pancreatitis (10 μg/kg, 10 ng/kg intraperitoneally or in drinking water). The esophagitis-sphincter failure procedure (i.e., insertion of the tubes into the sphincters, lower esophageal and pyloric) and acute pancreatitis procedure (i.e., bile duct ligation) were combined in rats. Esophageal manometry was done in acute pancreatitis patients. In rats acute pancreatitis procedure produced also esophagitis and both sphincter failure, decreased pressure 24 h post-surgery. Furthermore, bile duct ligation alone immediately declines the pressure in both sphincters. Vice versa, the esophagitis-sphincter failure procedure alone produced acute pancreatitis. What's more, these lesions (esophagitis, sphincter failure, acute pancreatitis when combined) aggravate each other (tubes into sphincters and ligated bile duct). Counteraction occurred by BPC 157 therapies. In acute pancreatitis patients lower pressure at rest was in both esophageal sphincters in acute pancreatitis patients. We conclude that BPC 157 could cure esophagitis/sphincter/acute pancreatitis healing failure.

CT and MRI assessment of symptomatic organized pancreatic fluid collections and pancreatic duct disruption: an interreader variability study using the revised Atlanta classification 2012.

PubMed

Kamal, Ayesha; Singh, Vikesh K; Akshintala, Venkata S; Kawamoto, Satomi; Tsai, Salina; Haider, Maera; Fishman, Elliot K; Kamel, Ihab R; Zaheer, Atif

2015-08-01

Compare CT and MRI for fluid/debris component estimate and pancreatic duct (PD) communication with organized pancreatic fluid collections in acute pancreatitis. Evaluate fat density globules on CT as marker for debris. 29 Patients with 46 collections with CECT and MRI performed ≥4 weeks of symptom onset assessed for necrotizing pancreatitis, estimated percentage of fluid volume and PD involvement by two radiologists on separate occasions. T2WI used as standard for estimated percentage of fluid volume. Presence of fat globules and fluid attenuation on CT was recorded. Spearman rank correlation and kappa statistics were used to assess the correlation between imaging techniques and interreader agreement, respectively. Necrotizing pancreatitis seen on CT in 27 (93%, κ 0.119) vs. 20 (69%, κ 0.748) patients on MRI. CT identified 42 WON and 4 pseudocysts vs. 34 WON, and 12 pseudocysts on MRI. Higher interreader agreement for percentage fluid volume on MRI (κ = 0.55) vs. CT (κ = 0.196). Accuracy of CT in evaluation of percentage fluid volume was 65% using T2WI MRI used as standard. Fat globules identified on CT in 13(65%) out of 20 collections containing <75% fluid vs. 4(15%) out of 26 collections containing >75% fluid (p = 0.0001). PD involvement confidently excluded on CT in 68% collections vs. 93% on MRI. MRI demonstrates higher reproducibility for fluid to debris component estimation. Fat globules on CT were frequently seen in organized pancreatic fluid collections with large amount of debris. PD disruption more confidently excluded on MRI. This information may be helpful for pre-procedure planning.

Risk factors for pancreatic stone formation in autoimmune pancreatitis over a long-term course.

PubMed

Maruyama, Masahiro; Arakura, Norikazu; Ozaki, Yayoi; Watanabe, Takayuki; Ito, Tetsuya; Yoneda, Suguru; Maruyama, Masafumi; Muraki, Takashi; Hamano, Hideaki; Matsumoto, Akihiro; Kawa, Shigeyuki

2012-05-01

Autoimmune pancreatitis (AIP) has the potential to progress to a chronic state that forms pancreatic stones. The aim of this study was to clarify the risk factors underlying pancreatic stone formation in AIP. Sixty-nine patients with AIP who had been followed for at least 3 years were enrolled for evaluation of clinical and laboratory factors as well as computed tomography and endoscopic retrograde cholangiopancreatography findings. During the course of this study, increased or de novo stone formation was seen in 28 patients, who were defined as the stone-forming group. No stones were observed in 32 patients, who were defined as the non-stone-forming group. Nine patients who had stones at diagnosis but showed no change during the course of this study were excluded from our cohort. Univariate analysis revealed no significant differences in clinical or laboratory factors associated with AIP-specific inflammation between the two groups. However, pancreatic head swelling (P = 0.006) and narrowing of both Wirsung's and Santorini's ducts in the pancreatic head region (P = 0.010) were significantly more frequent in the stone-forming group. Furthermore, multivariate analysis identified Wirsung and Santorini duct narrowing at diagnosis as a significant independent risk factor for pancreatic stone formation (OR 4.4, P = 0.019). A primary risk factor for pancreatic stone formation in AIP was narrowing of both Wirsung's and Santorini's ducts, which most presumably led to pancreatic juice stasis and stone development.

New developments in diagnosis and non-surgical treatment of chronic pancreatitis.

PubMed

Inui, Kazuo; Yoshino, Junji; Miyoshi, Hironao; Yamamoto, Satoshi; Kobayashi, Takashi

2013-12-01

Chronic pancreatitis is progressive and irreversible, leading to digestive and absorptive disorders by destruction of the exocrine pancreas and to diabetes mellitus by destruction of the endocrine pancreas. When complications such as pancreatolithiasis and pseudocyst occur, elevated pancreatic ductal pressure exacerbates pain and induces other complications, worsening the patient's general condition. Combined treatment with extracorporeal shock-wave lithotripsy and endoscopic lithotripsy is a useful, minimally invasive, first-line treatment approach that can preserve pancreatic exocrine function. Pancreatic duct stenosis elevates intraductal pressure and favor both pancreatolithiasis and pseudocyst formation, making effective treatment vitally important. Endoscopic treatment of benign pancreatic duct stenosis stenting frequently decreases pain in chronic pancreatitis. Importantly, stenosis of the main pancreatic duct increases risk of stone recurrence after treatment of pancreatolithiasis. Recently, good results were reported in treating pancreatic duct stricture with a fully covered self-expandable metallic stent, which shows promise for preventing stone recurrence after lithotripsy in patients with pancreatic stricture. Chronic pancreatitis has many complications including pancreatic carcinoma, pancreatic atrophy, and loss of exocrine and endocrine function, as well as frequent recurrence of stones after treatment of pancreatolithiasis. As early treatment of chronic pancreatitis is essential, the new concept of early chronic pancreatitis, including characteristics findings in endoscopic ultrasonograms, is presented. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

[Surgical options for chronic pancreatitis].

PubMed

Tan, C L; Nuer, Emms; Abulaiti, Aizezi; Zhang, H; Chen, Y H; Liu, X B

2016-11-01

Objective: Discuss the surgical options for the chronic pancreatitis on the basis of anatomical morphological changes. Methods: A retrospective review of chronic pancreatitis patients in Department of Pancreatic Surgery, West China Hospital, Sichuan University between January 2010 and December 2014 was performed. The data of medical records, image feature, surgical types and records of follow-up were collected. Total 295 patients including 275 male and 20 female aged from 14 to 74 years with median age of 51 years. The clinical symptoms included abdominal pain in 280 cases, jaundice in 3 cases, single hemorrhage in digestive tract, diarrhea or mellitus in 12 cases. The anatomical morphological changes included pancreatic fibrosis and atrophy of the main pancreatic duct lesions in 44 cases (14.9%), inflammatory mass in the pancreatic head in 69 cases (22.4%), sporadic stones with calcification in the pancreatic head in 165 cases(55.9%), hyperplasia mass of pancreatic head and body in 14 cases (4.8%), sporadic stones with calcification in whole branch ducts accompanied with different degree of hyperplasia in whole pancreas in 3 cases (1.0%). The surgical options included longitudinal pancreaticojejunostomy, duodenum-preserving pancreatic head resection, Frey/Frey+ distal pancreatectomy, total and subtotal pancreatectomy. All patients were followed-up for 3 to 6 months in the outpatient. A cross-sectional study was carried out by telephone, letters, questionnaire and outpatient from April to June 2016. Results: Among 295 patients, 267 cases were followed-up for an average time of 40 months(18 to 78 months), 28 cases were lost to followed-up(9.5%). Pain remission rate of pancreatic fibrosis and atrophy of the main pancreatic duct lesions patients was 97.0%, of inflammatory mass in the pancreatic head patients was 96.8%, of sporadic stones with calcification in the pancreatic head patients was 96.6%, of hyperplasia mass of pancreatic head and body patients was 12/13, of

Critical role for NHE1 in intracellular pH regulation in pancreatic acinar cells.

PubMed

Brown, David A; Melvin, James E; Yule, David I

2003-11-01

The primary function of pancreatic acinar cells is to secrete digestive enzymes together with a NaCl-rich primary fluid which is later greatly supplemented and modified by the pancreatic duct. A Na+/H+ exchanger(s) [NHE(s)] is proposed to be integral in the process of fluid secretion both in terms of the transcellular flux of Na+ and intracellular pH (pHi) regulation. Multiple NHE isoforms have been identified in pancreatic tissue, but little is known about their individual functions in acinar cells. The Na+/H+ exchange inhibitor 5-(N-ethyl-N-isopropyl) amiloride completely blocked pHi recovery after an NH4Cl-induced acid challenge, confirming a general role for NHE in pHi regulation. The targeted disruption of the Nhe1 gene also completely abolished pHi recovery from an acid load in pancreatic acini in both HCO3--containing and HCO3--free solutions. In contrast, the disruption of either Nhe2 or Nhe3 had no effect on pHi recovery. In addition, NHE1 activity was upregulated in response to muscarinic stimulation in wild-type mice but not in NHE1-deficient mice. Fluctuations in pHi could potentially have major effects on Ca2+ signaling following secretagogue stimulation; however, the targeted disruption of Nhe1 was found to have no significant effect on intracellular Ca2+ homeostasis. These data demonstrate that NHE1 is the major regulator of pHi in both resting and muscarinic agonist-stimulated pancreatic acinar cells.

Dendritic Cells Promote Pancreatic Viability in Mice with Acute Pancreatitis

PubMed Central

Bedrosian, Andrea S.; Nguyen, Andrew H.; Hackman, Michael; Connolly, Michael K.; Malhotra, Ashim; Ibrahim, Junaid; Cieza-Rubio, Napoleon E.; Henning, Justin R.; Barilla, Rocky; Rehman, Adeel; Pachter, H. Leon; Medina-Zea, Marco V.; Cohen, Steven M.; Frey, Alan B.; Acehan, Devrim; Miller, George

2011-01-01

Background & Aims Acute pancreatitis increases morbidity and mortality from organ necrosis by mechanisms that are incompletely understood. Dendritic cells (DCs) can promote or suppress inflammation, depending on their subtype and context. We investigated the roles of DC in development of acute pancreatitis. Methods Acute pancreatitis was induced in CD11c.DTR mice using caerulein or L-arginine; DCs were depleted by administration of diphtheria toxin. Survival was analyzed using Kaplan-Meier analysis. Results Numbers of MHC II+CD11c+DC increased 100-fold in pancreas of mice with acute pancreatitis, to account for nearly 15% of intra-pancreatic leukocytes. Intra-pancreatic DC acquired an immune phenotype in mice with acute pancreatitis; they expressed higher levels of MHC II and CD86 and increased production of interleukin-6, membrane cofactor protein (MCP)-1, and tumor necrosis factor (TNF)-α. However, rather than inducing an organ-destructive inflammatory process, DC were required for pancreatic viability; the exocrine pancreas died in mice that were depleted of DC and challenged with caerulein or L-arginine. All mice with pancreatitis that were depleted of DC died from acinar cell death within 4 days. Depletion of DC from mice with pancreatitis resulted in neutrophil infiltration and increased levels of systemic markers of inflammation. However, the organ necrosis associated with depletion of DC did not require infiltrating neutrophils, activation of NF-κB, or signaling by mitogen-activated protein kinase or TNF-α. Conclusions DC are required for pancreatic viability in mice with acute pancreatitis and might protect organs against cell stress. PMID:21801698

Complement Component 5 Mediates Development of Fibrosis, via Activation of Stellate Cells, in 2 Mouse Models of Chronic Pancreatitis

PubMed Central

Sendler, Matthias; Beyer, Georg; Mahajan, Ujjwal M.; Kauschke, Vivien; Maertin, Sandrina; Schurmann, Claudia; Homuth, Georg; Völker, Uwe; Völzke, Henry; Halangk, Walter; Wartmann, Thomas; Weiss, Frank-Ulrich; Hegyi, Peter; Lerch, Markus M.; Mayerle, Julia

2015-01-01

Background & Aims Little is known about the pathogenic mechanisms of chronic pancreatitis. We investigated the roles of complement component 5 (C5) in pancreatic fibrogenesis in mice and patients. Methods Chronic pancreatitis was induced by ligation of the midpancreatic duct, followed by a single supramaximal intraperitoneal injection of cerulein, in C57Bl6 (control) and C5-deficient mice. Some mice were given injections of 2 different antagonists of the receptor for C5a over 21 days. In a separate model, mice were given injections of cerulein for 10 weeks to induce chronic pancreatitis. Direct effects of C5 were studied in cultured primary cells. We performed genotype analysis for the single-nucleotide polymorphisms rs 17611 and rs 2300929 in C5 in patients with pancreatitis and healthy individuals (controls). Blood cells from 976 subjects were analyzed by transcriptional profiling. Results During the initial phase of pancreatitis, levels of pancreatic damage were similar between C5-deficient and control mice. During later stages of pancreatitis, C5-deficient mice and mice given injections of C5a-receptor antagonists developed significantly less pancreatic fibrosis than control mice. Primary pancreatic stellate cells were activated in vitro by C5a. There were no differences in the rs 2300929 SNP between subjects with or without pancreatitis, but the minor allele rs17611 was associated with a significant increase in levels of C5 in whole blood. Conclusions In mice, loss of C5 or injection of a C5a-receptor antagonist significantly reduced the level of fibrosis of chronic pancreatitis, but this was not a consequence of milder disease in early stages of pancreatitis. C5 might be a therapeutic target for chronic pancreatitis. PMID:26001927

Pathogenic mechanisms of pancreatitis

PubMed Central

Manohar, Murli; Verma, Alok Kumar; Venkateshaiah, Sathisha Upparahalli; Sanders, Nathan L; Mishra, Anil

2017-01-01

Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for

Pancreatic hardness: Correlation of surgeon’s palpation, durometer measurement and preoperative magnetic resonance imaging features

PubMed Central

Hong, Tae Ho; Choi, Joon-Il; Park, Michael Yong; Rha, Sung Eun; Lee, Young Joon; You, Young Kyoung; Choi, Moon Hyung

2017-01-01

AIM To evaluate the correlation between subjective assessments of pancreatic hardness based on the palpation, objective measurements using a durometer, and magnetic resonance imaging (MRI) findings for assessing pancreatic hardness. METHODS Eighty-three patients undergoing pancreatectomies were enrolled. An experienced surgeon subjectively evaluated the pancreatic hardness in the surgical field by palpation. The pancreatic hardness was also objectively evaluated using a durometer. Preoperative MRI findings were evaluated by a radiologist in terms of the apparent diffusion coefficient (ADC) values, the relative signal intensity decrease (RSID) of the pancreatic parenchyma, and the diameter of the pancreatic parenchyma and duct. Durometer measurement results, ADC values, RSID, pancreatic duct and parenchyma diameters, and the ratio of the diameters of the duct and parenchyma were compared between pancreases judged to be soft or hard pancreas on the palpation. A correlation analysis was also performed between the durometer and MRI measurements. RESULTS The palpation assessment classified 44 patients as having a soft pancreas and 39 patients as having a hard pancreas. ADC values were significantly lower in the hard pancreas group. The ductal diameter and duct-to-pancreas ratio were significantly higher in the hard pancreas group. For durometer measurements, a correlation analysis showed a positive correlation with the ductal diameter and the duct-to-pancreas ratio and a negative correlation with ADC values. CONCLUSION Hard pancreases showed lower ADC values, a wider pancreatic duct diameter and a higher duct-to-pancreas ratio than soft pancreases. Additionally, the ADC values, diameter of the pancreatic duct and duct-to-pancreas ratio were closely correlated with the durometer results. PMID:28373771

Primary Pancreatic Head Tuberculosis: Great Masquerader of Pancreatic Adenocarcinoma

PubMed Central

Gupta, Dhaval; Patel, Jatin; Rathi, Chetan; Ingle, Meghraj; Sawant, Prabha

2015-01-01

Isolated pancreatic tuberculosis (TB) is considered an extremely rare condition, even in the developing countries. Most reported cases of pancreatic TB are diagnosed after exploratory laparotomy or autopsy. Pancreatic TB is a potential mimic of invasive pancreatic malignancy and the presence of vascular invasion does not distinguish one condition from the other. Every effort should be made for the earliest diagnosis of this condition as TB is a treatable condition and it avoids unnecessary management of pancreatic carcinoma. Here we report a rare case of primary pancreatic head TB in a 58-year-old male who presented with hypodense lesion in head of pancreas with double duct sign and portal vein invasion mimicking non-resectable pancreatic carcinoma. PMID:27785295

Pancreatogenic choledocholithiasis in common bile duct stump after Roux-en-Y hepaticojejunostomy

PubMed Central

Jiang, Yuan-Hui; Zhang, An-Hong; Zhou, Shao-Jun

2017-01-01

Abstract Rationale: Choledocholithiasis in common bile duct (CBD) stump after Roux-en-Y hepaticojejunostomy (RYHJ) is incredibly rare and its pathophysiology is poorly understood. Patient concerns: A 79-year-old woman was admitted to our hospital with upper abdominal pain radiating through to the back in November 2016. Diagnoses: Abdominal computed tomography (CT) scan and magnetic resonance cholangiopancreatography (MRCP) revealed filling defects in CBD stump, chronic pancreatitis, and dilatation of CBD stump and main pancreatic duct (MPD). Interventions: During the endoscopic retrograde cholangiopancreatography (ERCP), cannulation proceeded easily from MPD to CBD through a variant pancreatic duct, and then white crushed stones extracted from the CBD stump. Elemental analysis and infrared spectrophotometry demonstrated that the main constituent of the calculi was calcium carbonate. Outcomes: After a therapeutic ERCP, the patient's symptoms disappeared, and a 9-month follow-up indicated no remaining stones or lithiasis relapse. Lessons: This type of choledocholithiasis in CBD stump after RYHJ has never been reported before. We nominated it as “pancreatogenic choledocholithiasis,” and pancreatobiliary reflux caused by a variant pancreatic duct may be the main cause. PMID:29145338

Management of pancreatic trauma.

PubMed

Girard, E; Abba, J; Arvieux, C; Trilling, B; Sage, P Y; Mougin, N; Perou, S; Lavagne, P; Létoublon, C

2016-08-01

Pancreatic trauma (PT) is associated with high morbidity and mortality; the therapeutic options remain debated. Retrospective study of PT treated in the University Hospital of Grenoble over a 22-year span. The decision for initial laparotomy depended on hemodynamic status as well as on associated lesions. Main pancreatic duct lesions were always searched for. PT lesions were graded according to the AAST classification. Of a total of 46 PT, 34 were grades II or I. Hemodynamic instability led to immediate laparotomy in 18 patients, for whom treatment was always drainage of the pancreatic bed; morbidity was 30%. Eight patients had grade III injuries, six of whom underwent immediate operation: three underwent splenopancreatectomy without any major complications while the other three who had simple drainage required re-operation for peritonitis, with one death related to pancreatic complications. Four patients had grades IV or V PT: two pancreatoduodenectomies were performed, with no major complication, while one patient underwent duodenal reconstruction with pancreatic drainage, complicated by pancreatic and duodenal fistula requiring a hospital stay of two months. The post-trauma course was complicated for all patients with main pancreatic duct involvement. Our outcomes were similar to those found in the literature. In patients with distal PT and main pancreatic duct involvement, simple drainage is associated with high morbidity and mortality. For proximal PT, the therapeutic options of drainage versus pancreatoduodenectomy must be weighed; pancreatoduodenectomy may be unavoidable when the duodenum is injured as well. Two-stage (resection first, reconstruction later) could be an effective alternative in the emergency setting when there are other associated traumatic lesions. Copyright © 2016. Published by Elsevier Masson SAS.

The management of complex pancreatic injuries.

PubMed

Krige, J E J; Beningfield, S J; Nicol, A J; Navsaria, P

2005-08-01

Major injuries of the pancreas are uncommon, but may result in considerable morbidity and mortality because of the magnitude of associated vascular and duodenal injuries or underestimation of the extent of the pancreatic injury. Prognosis is influenced by the cause and complexity of the pancreatic injury, the amount of blood lost, duration of shock, speed of resuscitation and quality and nature of surgical intervention. Early mortality usually results from uncontrolled or massive bleeding due to associated vascular and adjacent organ injuries. Late mortality is a consequence of infection or multiple organ failure. Neglect of major pancreatic duct injury may lead to life-threatening complications including pseudocysts, fistulas, pancreatitis, sepsis and secondary haemorrhage. Careful operative assessment to determine the extent of gland damage and the likelihood of duct injury is usually sufficient to allow planning of further management. This strategy provides a simple approach to the management of pancreatic injuries regardless of the cause. Four situations are defined by the extent and site of injury: (i) minor lacerations, stabs or gunshot wounds of the superior or inferior border of the body or tail of the pancreas (i.e. remote from the main pancreatic duct), without visible duct involvement, are best managed by external drainage; (ii) major lacerations or gunshot or stab wounds in the body or tail with visible duct involvement or transection of more than half the width of the pancreas are treated by distal pancreatectomy; (iii) stab wounds, gunshot wounds and contusions of the head of the pancreas without devitalisation of pancreatic tissue are managed by external drainage, provided that any associated duodenal injury is amenable to simple repair; and (iv) non-reconstructable injuries with disruption of the ampullary-biliary-pancreatic union or major devitalising injuries of the pancreatic head and duodenum in stable patients are best treated by

Surgical treatment of pancreas divisum causing chronic pancreatitis: the outcome benefits of duodenum-preserving pancreatic head resection.

PubMed

Schlosser, W; Rau, B M; Poch, B; Beger, H G

2005-01-01

Pancreas divisum (PD) represents a duct anomaly in the pancreatic head ducts, leading frequently leading to recurrent acute pancreatitis (rAP) or chronic pancreatitis (CP). Based on endoscopic retrograde cholangiopancreatography, pancreas divisum can be found in 1% to 6% of patients with pancreatitis. The correlation of this abnormality with pancreatic disease is an issue of continuing controversy. Because of the underlying duct anomalies and major pathomorphological changes in the pancreatic head, duodenum-preserving pancreatic head resection (DPPHR) offers an option for causal treatment. Thirty-six patients with pancreatitis caused by PD were treated surgically. Thirty patients suffered from CP, 6 from rAP. The mean duration of the disease was 47.5 and 49.8 months, respectively. The age at the time of surgery was 39.2 years in the CP group, and 27.6 years in the rAP group. Median hospitalization since diagnosis was 18.8 weeks for CP patients and 24.6 weeks for rAP patients. Previous procedures performed in these patients included endoscopic papillotomy (30%), duct stenting (14%), and surgical treatment (17%). The median preoperative pain score was 8 on a visual analog scale. According to the classification of pancreas divisum, 10 patients demonstrated a complete PD, 25 had a functionally incomplete PD, and 1 had a dorsal duct type. The pain status as well as the endocrine (oral glucose tolerance test) and exocrine (pancreolauryl test) function were evaluated preoperatively and early and late postoperatively with a median follow-up time of 39.3 months. There was no operative-related mortality. The follow-up was 100%; 4 patients died (1 from suicide, 1 from cardiac arrest, and 2 from cancer of the esophagus). Fifty percent of the patients were completely pain-free, 31% had a significant reduction of pain with a median pain score of 2 (P < 0.001). Six patients (5 CP, 1 rAP) had further attacks of acute pancreatitis with a need for hospitalization. DPPHR reduced pain

Pancreatic Lipomatous Hamartoma: A Hitherto Unrecognized Variant.

PubMed

Tanaka, Mariko; Ushiku, Tetsuo; Ikemura, Masako; Takazawa, Yutaka; Igari, Toru; Shimizu, Michio; Yamaguchi, Hiroshi; Fukushima, Noriyoshi; Sakuma, Kei; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Watadani, Takeyuki; Nakai, Yousuke; Koike, Kazuhiko; Fukayama, Masashi

2018-05-04

Pancreatic masses consisting of lipomatous components clinically include lipoma, liposarcoma, lipomatous pseudohypertrophy of the pancreas, fat-containing neoplasms such as perivascular epithelioid cell tumor, and malignant neoplasm with lipoid degeneration. We present pancreatic lipomatous hamartoma, which has not been reported hitherto. A solid pancreatic mass was detected from a computed tomographic scan check-up in each of 3 cases of Japanese men. Macroscopically, well-demarcated solid lipomatous masses were detected at the uncus, body, and tail of the pancreas, respectively. Microscopically, the masses predominantly consisted of mature adipocytes with no atypia, but contained characteristics components of pancreatic hamartoma, such as small ducts, a well-preserved acinar structure, and/or fibrous stroma. On the basis of the unique features, lack of islets and absence of periductal elastic fibers, these tumors are a distinct variant of pancreatic hamartoma. Furthermore, high-mobility group AT-hook 2 expression in the fibro-adipocytes of this tumor indicated that these cells are an integral component of the pancreatic lipomatous hamartoma. Consequently, the unique tumors described herein are pancreatic lipomatous hamartoma, which must be discriminated from other lipomatous lesions of the pancreas.

Safety and efficacy of pancreatic sphincterotomy in chronic pancreatitis.

PubMed

Ell, C; Rabenstein, T; Schneider, H T; Ruppert, T; Nicklas, M; Bulling, D

1998-09-01

Endoscopic pancreatic sphincterotomy (EPS) is being performed with increasing frequency as a prerequisite to interventional measures in the pancreatic duct. The aim of this study was to evaluate EPS with regard to technique, success, complications, and mortality in patients with chronic pancreatitis. Between January 1989 and September 1996, the results of all consecutive EPSs in patients with chronic pancreatitis were documented in a standardized form. Patients were followed by clinical investigation and blood sample analysis at 4, 24, and 48 hours after EPS. Complications were classified according to commonly accepted criteria. EPS was performed in 118 patients with chronic pancreatitis (men 75%, women 25%, 48+/-10 years). Ninety-four patients (80%) underwent guidewire-assisted EPS, and 24 patients (20%) underwent needle-knife EPS. Seventy-seven EPS procedures (65%) were primarily successful (guidewire EPS: 60 of 94, 64%; needle-knife EPS: 17 of 24, 71%). Additional endoscopic cutting techniques (needle-knife papillotomy, biliary endoscopic sphincterotomy) were required in 41 patients (35%). In total, EPS was successful in 116 patients (98%). The complication rate was 4.2% (4 cases of moderate pancreatitis, 1 severe bleeding, no deaths). All complications were managed nonoperatively. In patients with chronic pancreatitis, EPS with a standard sphincterotome or with a needle-knife offers an effective and reliable approach to the pancreatic duct system. Additional cutting techniques may be necessary in approximately one third of cases before an EPS can be successfully performed. The complication rate of EPS in patients with chronic pancreatitis appears to be lower than the complication rate of biliary sphincterotomy for other indications.

Cystic pancreatic neoplasms evaluation by CT and magnetic resonance cholangiopancreatography.

PubMed

Sahani, Dushyant; Prasad, Srinivasa; Saini, Sanjay; Mueller, Peter

2002-10-01

CT provides limited assistance in the differentiation between serous and mucinous neoplasms. Because of the variability in the radiographic appearance of serous cystadenomas and overlap in CT characteristics with mucinous neoplasms, most serous neoplasms still require ancillary testing such as biopsy to reach a definitive diagnosis. MRCP is useful in differentiating benign and malignant mucinous tumors including IPMT of the pancreas. The presence of mural nodules is suggestive of malignancy; however, the absence of mural nodules does not indicate that the tumor is benign. A maximum main pancreatic duct diameter of greater than 15 mm and diffuse dilatation of the main pancreatic duct are suggestive of malignancy in main duct-type tumors. Among branch duct-type tumors, malignant tumors tend to be larger than benign tumors; however, this finding is variable. The presence of main pancreatic duct dilatation may be helpful in determining malignancy of branch duct-type tumors.

[Pancreas divisum--a rare cause of chronic pancreatitis].

PubMed

Vasile, D; Grigoriu, M; Turcu, Fl; Ilco, Al; Tenovici, G; Vasile, Raluca

2007-01-01

Pancreas divisum (P.D.) is a congenital anatomic variant, characterized by the nonunion of dorsal and ventral pancreatic ducts. A 20 years old man followed for 8 years with reccurent abdominal pain and relapsing acute pancreatitis develope chronic calcific pancreatitis. He was diagnosed with P.D. on endoscopic retrograde pancreatography and operative pancreatography. The patient was treated with longitudinal pancreatico-jejunostomy (PUESTOW-GILLESBY procedure). His pain resolved following surgical drainage of the pancreatic duct. Evaluation of the clinical course of this patient and critical review of other such cases in the literature support the role of compromised ductal drainage of the pancreas in the pathogenesis of chronic pancreatitis in P.D.

MRI assessed pancreatic morphology and exocrine function are associated with disease burden in chronic pancreatitis.

PubMed

Madzak, Adnan; Olesen, Søren Schou; Lykke Poulsen, Jakob; Bolvig Mark, Esben; Mohr Drewes, Asbjørn; Frøkjær, Jens Brøndum

2017-11-01

The aim of this study was to explore the association between morphological and functional secretin-stimulated MRI parameters with hospitalization, quality of life (QOL), and pain in patients with chronic pancreatitis (CP). This prospective cohort study included 82 patients with CP. Data were obtained from clinical information, QOL, and pain as assessed by questionnaires (The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and modified Brief Pain Inventory short form). Secretin-stimulated MRI morphological parameters included pancreatic gland volume, main pancreatic duct diameter, the modified Cambridge Classification of Duct Abnormality, apparent diffusion coefficient, fat signal fraction, and the pancreatic secretion volume as a functional parameter. The primary outcomes were time to first hospitalization related to the CP, as well as annual hospitalization frequency and duration. The secondary outcomes were pain severity, QOL, and pain interference scores. A main pancreatic duct diameter below 5 mm was associated with reduced time to first hospitalization (hazard ratio=2.06; 95% confidence interval: 1.02-4.17; P=0.043). Pancreatic secretion volume was correlated with QOL (r=0.31; P=0.0072) and pain interference score (r=-0.27; P=0.032), and fecal elastase was also correlated with QOL (r=0.28; P=0.017). However, functional and morphological findings were not related to pain intensity. Advanced pancreatic imaging techniques may be a highly sensitive tool for prognostication and monitoring of disease activity and its consequences.

Pancreatic stellate cell: Pandora's box for pancreatic disease biology.

PubMed

Bynigeri, Ratnakar R; Jakkampudi, Aparna; Jangala, Ramaiah; Subramanyam, Chivukula; Sasikala, Mitnala; Rao, G Venkat; Reddy, D Nageshwar; Talukdar, Rupjyoti

2017-01-21

Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways ( e.g ., JAK-STAT, Smad, Wnt signaling, Hedgehog etc .), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.

Pancreatic stellate cell: Pandora's box for pancreatic disease biology

PubMed Central

Bynigeri, Ratnakar R; Jakkampudi, Aparna; Jangala, Ramaiah; Subramanyam, Chivukula; Sasikala, Mitnala; Rao, G Venkat; Reddy, D Nageshwar; Talukdar, Rupjyoti

2017-01-01

Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma. PMID:28210075

Understanding the Mechanical forces of Self-Expandable Metal Stents in the Biliary Ducts.

PubMed

Isayama, Hiroyuki; Nakai, Yousuke; Hamada, Tsuyoshi; Matsubara, Saburo; Kogure, Hirofumi; Koike, Kazuhiko

2016-12-01

Self-expandable metallic stent (SEMS) was an effective biliary endoprosthesis. Mechanical properties of SEMS, radial and axial force (RF, AF), may play important roles in the bile duct after placement. RF was well known dilation force and influenced on the occurrence of migration. AF, newly proposed by this author, was defined as the recovery force when the SEMS vended. AF was related with the cause of bile duct kinking, pancreatitis, and cholecystitis due to the compression of the bile duct, orifice of the cystic duct, and pancreatic orifice. Ideal SEMS may show high RF and low AF.

Selective drainage for pancreatic, biliary, and duodenal obstruction secondary to chronic fibrosing pancreatitis.

PubMed Central

Sugerman, H J; Barnhart, G R; Newsome, H H

1986-01-01

Twenty-eight patients underwent surgery for intractable pain, duodenal or extrahepatic biliary obstruction secondary to chronic pancreatitis. Eleven had pancreatic duct obstruction alone, six biliary obstruction alone, seven combined pancreatic and biliary, two combined biliary and duodenal, one combined pancreatic and duodenal, and one simultaneous pancreatic, biliary, and duodenal obstruction. Pancreatitis was secondary to alcohol in all but one case. The following operations were performed: longitudinal pancreatojejunostomy (20), choledochoduodenostomy (8), choledochojejunostomy (7), cholecystojejunostomy (1), and gastrojejunostomy (4). Of the 20 patients with pancreatic duct drainage, pain relief was complete in 11 and partial in six. Initial incomplete relief of pain, or recurrence, stimulated further diagnostic procedures, leading to improvement or correction of the problem in five patients. A significant (p less than 0.01) fall in alkaline phosphatase (935 +/- 228 to 219 +/- 61 U/L) occurred following surgery. One patient was subsequently found to have pancreatic carcinoma. Two patients were lost to follow-up and four patients died (one perioperative and three late). In conclusion, the possibility of pancreatic, biliary, and duodenal obstruction must be considered in symptomatic patients with chronic pancreatitis. Surgery must be individualized. Drainage procedures, either alone or in combination, are associated with a low morbidity and improved clinical condition and may be preferable to resection in the surgical management of these patients. Images FIG. 1. FIG. 2. FIG. 4. PMID:3707234

Cholecystokinin induces caspase activation and mitochondrial dysfunction in pancreatic acinar cells. Roles in cell injury processes of pancreatitis.

PubMed

Gukovskaya, Anna S; Gukovsky, Ilya; Jung, Yoon; Mouria, Michelle; Pandol, Stephen J

2002-06-21

Apoptosis and necrosis are critical parameters of pancreatitis, the mechanisms of which remain unknown. Many characteristics of pancreatitis can be studied in vitro in pancreatic acini treated with high doses of cholecystokinin (CCK). We show here that CCK stimulates apoptosis and death signaling pathways in rat pancreatic acinar cells, including caspase activation, cytochrome c release, and mitochondrial depolarization. The mitochondrial dysfunction is mediated by upstream caspases (possibly caspase-8) and, in turn, leads to activation of caspase-3. CCK causes mitochondrial alterations through both permeability transition pore-dependent (cytochrome c release) and permeability transition pore-independent (mitochondrial depolarization) mechanisms. Caspase activation and mitochondrial alterations also occur in untreated pancreatic acinar cells; however, the underlying mechanisms are different. In particular, caspases protect untreated acinar cells from mitochondrial damage. We found that caspases not only mediate apoptosis but also regulate other parameters of CCK-induced acinar cell injury that are characteristic of pancreatitis; in particular, caspases negatively regulate necrosis and trypsin activation in acinar cells. The results suggest that the observed signaling pathways regulate parenchymal cell injury and death in CCK-induced pancreatitis. Protection against necrosis and trypsin activation by caspases can explain why the severity of pancreatitis in experimental models correlates inversely with the extent of apoptosis.

Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis.

PubMed

Apte, M V; Haber, P S; Darby, S J; Rodgers, S C; McCaughan, G W; Korsten, M A; Pirola, R C; Wilson, J S

1999-04-01

The pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells play a major role in fibrogenesis by synthesising increased amounts of collagen and other extracellular matrix (ECM) proteins when activated by profibrogenic mediators such as cytokines and oxidant stress. To determine whether cultured rat pancreatic stellate cells produce collagen and other ECM proteins, and exhibit signs of activation when exposed to the cytokines platelet derived growth factor (PDGF) or transforming growth factor beta (TGF-beta). Cultured pancreatic stellate cells were immunostained for the ECM proteins procollagen III, collagen I, laminin, and fibronectin using specific polyclonal antibodies. For cytokine studies, triplicate wells of cells were incubated with increasing concentrations of PDGF or TGF-beta. Cultured pancreatic stellate cells stained strongly positive for all ECM proteins tested. Incubation of cells with 1, 5, and 10 ng/ml PDGF led to a significant dose related increase in cell counts as well as in the incorporation of 3H-thymidine into DNA. Stellate cells exposed to 0.25, 0.5, and 1 ng/ml TGF-beta showed a dose dependent increase in alpha smooth muscle actin expression and increased collagen synthesis. In addition, TGF-beta increased the expression of PDGF receptors on stellate cells. Pancreatic stellate cells produce collagen and other extracellular matrix proteins, and respond to the cytokines PDGF and TGF-beta by increased proliferation and increased collagen synthesis. These results suggest an important role for stellate cells in pancreatic fibrogenesis.

Hereditary chronic pancreatitis

PubMed Central

Rosendahl, Jonas; Bödeker, Hans; Mössner, Joachim; Teich, Niels

2007-01-01

Hereditary chronic pancreatitis (HCP) is a very rare form of early onset chronic pancreatitis. With the exception of the young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. As well, diagnostic criteria and treatment of HCP resemble that of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, most patients have a mild disease. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2), the serine protease inhibitor, Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) have been found to be associated with chronic pancreatitis (idiopathic and hereditary) as well. Genetic testing should only be performed in carefully selected patients by direct DNA sequencing and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. Pancreatic cancer risk is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer. PMID:17204147

Simultaneous characterization of pancreatic stellate cells and other pancreatic components within three-dimensional tissue environment during chronic pancreatitis

NASA Astrophysics Data System (ADS)

Hu, Wenyan; Fu, Ling

2013-05-01

Pancreatic stellate cells (PSCs) and other pancreatic components that play a critical role in exocrine pancreatic diseases are generally identified separately by conventional studies, which provide indirect links between these components. Here, nonlinear optical microscopy was evaluated for simultaneous characterization of these components within a three-dimensional (3-D) tissue environment, primarily based on multichannel detection of intrinsic optical emissions and cell morphology. Fresh rat pancreatic tissues harvested at 1 day, 7 days, and 28 days after induction of chronic pancreatitis were imaged, respectively. PSCs, inflammatory cells, blood vessels, and collagen fibers were identified simultaneously. The PSCs at day 1 of chronic pancreatitis showed significant enlargement compared with those in normal pancreas (p<0.001, analysis of variance linear contrast; n=8 for each group). Pathological events relating to these components were observed, including presence of inflammatory cells, deposited collagen, and phenotype conversion of PSCs. We demonstrate that label-free nonlinear optical microscopy is an efficient tool for dissecting PSCs and other pancreatic components coincidently within 3-D pancreatic tissues. It is a prospect for intravital observation of dynamic events under natural physiological conditions, and might help uncover the key mechanisms of exocrine pancreatic diseases, leading to more effective treatments.

Surgical management of failed endoscopic treatment of pancreatic disease.

PubMed

Evans, Kimberly A; Clark, Colby W; Vogel, Stephen B; Behrns, Kevin E

2008-11-01

Endoscopic therapy of acute and chronic pancreatitis has decreased the need for operative intervention. However, a significant proportion of patients treated endoscopically require definitive surgical management for persistent symptoms. Our aim was to determine which patients are likely to fail with endoscopic therapy, and to assess the clinical outcome of surgical management. Patients were identified using ICD-9 codes for pancreatic disease as well as CPT codes for endoscopic therapy followed by surgery. Patients with documented acute or chronic pancreatitis treated endoscopically prior to surgical therapy were included (N = 88). The majority of patients (65%) exhibited chronic pancreatitis due to alcohol abuse. Common indicators for surgery were: persistent symptoms, anatomy not amenable to endoscopic treatment and unresolved common bile duct or pancreatic duct strictures. Surgical salvage procedures included internal drainage of a pseudocyst or an obstructed pancreatic duct (46%), debridement of peripancreatic fluid collections (25%), and pancreatic resection (31%). Death occurred in 3% of patients. The most common complications were hemorrhage (16%), wound infection (13%), and pulmonary complications (11%). Chronic pancreatitis with persistent symptoms is the most common reason for pancreatic surgery following endoscopic therapy. Surgical salvage therapy can largely be accomplished by drainage procedures, but pancreatic resection is common. These complex procedures can be performed with acceptable mortality but also with significant risk for morbidity.

Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction.

PubMed

Javeed, Naureen; Sagar, Gunisha; Dutta, Shamit K; Smyrk, Thomas C; Lau, Julie S; Bhattacharya, Santanu; Truty, Mark; Petersen, Gloria M; Kaufman, Randal J; Chari, Suresh T; Mukhopadhyay, Debabrata

2015-04-01

Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion. We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown. Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into

The management of pancreatic trauma.

PubMed

Khan, M A; Cameron, I

2010-12-01

Pancreatic trauma is an uncommon occurrence and so a consensus about optimal management is not readily available. Isolated pancreatic injury occurs only occasionally, as in the majority of cases there is concurrent visceral or vascular injury. Morbidity and mortality are related to delay in diagnosis, concurrent organ injury or the presence and extent of pancreatic duct injury.

Intraductal Papillary Mucinous Neoplasm (IPMN) with Extra-Pancreatic Mucin: A Case Series and Review of the Literature

PubMed Central

Stein, Louis H.; Witkiewicz, Agnieszka K.; Kennedy, Eugene P.; Yeo, Charles J.

2012-01-01

Background Intraductal papillary mucinous neoplasm (IPMN) is an increasingly recognized pancreatic neoplasm characterized by excessive mucin secretion by ductal epithelial cells resulting in a cystic dilation of the pancreatic duct. Aim The objective of this study was to review Thomas Jefferson University’s experience and the literature to determine the significance of extra-pancreatic mucin when associated with an IPMN. Results A retrospective analysis at our institution revealed only two cases of IPMN associated with extra-pancreatic mucin, which were classic IPMNs with rupture of the pancreatic duct and peritoneal mucin spillage. This specific finding is not previously described, although is assumed as five cases were reported in the literature with IPMN and mucin extension demonstrated by pseudomyxoma peritonei (PMP). We propose IPMN of the pancreas may be grossly compared to a mucocele of the appendix, as both are characterized by excessive secretion of mucin by ductal epithelial cells. A morbid complication of a mucocele is PMP. The presence of extra-pancreatic mucin with an IPMN could present a rare but important marker of the eventual seeding of tumor outside the primary IPMN. This has been documented with cases of iatrogenic spilling of pancreatic mucin, as well as multiple cases of IPMN associated with pseudomyxoma peritonei. Conclusions At this time, there is scant reporting and consensus for the treatment of IPMN with extra-pancreatic mucin. PMID:22258877

Alkaline pH induces IRR-mediated phosphorylation of IRS-1 and actin cytoskeleton remodeling in a pancreatic beta cell line.

PubMed

Deyev, Igor E; Popova, Nadezhda V; Serova, Oxana V; Zhenilo, Svetlana V; Regoli, Marì; Bertelli, Eugenio; Petrenko, Alexander G

2017-07-01

Secretion of mildly alkaline (pH 8.0-8.5) juice to intestines is one of the key functions of the pancreas. Recent reports indicate that the pancreatic duct system containing the alkaline juice may adjoin the endocrine cells of pancreatic islets. We have previously identified the insulin receptor-related receptor (IRR) that is expressed in islets as a sensor of mildly alkaline extracellular media. In this study, we show that those islet cells that are in contact with the excretory ducts are also IRR-expressing cells. We further analyzed the effects of alkaline media on pancreatic beta cell line MIN6. Activation of endogenous IRR but not of the insulin receptor was detected that could be inhibited with linsitinib. The IRR autophosphorylation correlated with pH-dependent linsitinib-sensitive activation of insulin receptor substrate 1 (IRS-1), the primary adaptor in the insulin signaling pathway. However, in contrast with insulin stimulation, no protein kinase B (Akt/PKB) phosphorylation was detected as a result of alkali treatment. We observed overexpression of several early response genes (EGR2, IER2, FOSB, EGR1 and NPAS4) upon alkali treatment of MIN6 cells but those were IRR-independent. The alkaline medium but not insulin also triggered actin cytoskeleton remodeling that was blocked by pre-incubation with linsitinib. We propose that the activation of IRR by alkali might be part of a local loop of signaling between the exocrine and endocrine parts of the pancreas where alkalinization of the juice facilitate insulin release that increases the volume of secreted juice to control its pH and bicabonate content. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Biliary and pancreatic ductal dilation in patients on methadone maintenance therapy.

PubMed

Bates, David D B; Tamayo-Murillo, Dorathy; Kussman, Steven; Luce, Adam; LeBedis, Christina A; Soto, Jorge A; Anderson, Stephan W

2017-03-01

To determine whether the diameter of intrahepatic and extrahepatic bile ducts and pancreatic ducts in patients on methadone maintenance therapy is increased when compared with control subjects. Between January 1, 2000 and March 15, 2013, a total of 97 patients (mean age 49.9, range 22-79, 65 male, 32 female) were identified who were receiving chronic methadone maintenance therapy (MMT) when they underwent imaging with abdominal MRI or a contrast-enhanced abdominopelvic CT. A group of 97 consecutive non-MMT control patients (mean age 51.4, range 21-86, 45 male, 52 female) who underwent imaging with abdominal MRI or contrast-enhanced abdominopelvic CT were identified. Patients with known pancreaticobiliary pathology that may confound biliary ductal measurements were excluded. Blinded interpretation was performed, documenting the diameters of the intrahepatic and extrahepatic bile ducts and pancreatic ducts. Descriptive statistics were performed. Patients on MMT demonstrated increased bile duct diameter, with an average increase in duct diameter of 2.39 mm for the common bile duct (p < 0.001; 95% CI 1.88-2.90 mm), 1.43 mm for the intrahepatic bile ducts (p < 0.001; 95% CI 1.12-1.74 mm), and 0.90 mm for the pancreatic duct (p < 0.001; 95% CI 0.64-1.16 mm). No statistically significant correlation was found between ductal diameters and the daily dose of methadone. Patients on methadone maintenance therapy demonstrate significantly increased intra- and extrahepatic bile duct and pancreatic duct diameter when compared with controls. There was no correlation between the dose of methadone and ductal diameter.

HDAC gene expression in pancreatic tumor cell lines following treatment with the HDAC inhibitors panobinostat (LBH589) and trichostatine (TSA).

PubMed

Mehdi, Ouaïssi; Françoise, Silvy; Sofia, Costa Lima; Urs, Giger; Kevin, Zemmour; Bernard, Sastre; Igor, Sielezneff; Anabela, Cordeiro-da-Silva; Dominique, Lombardo; Eric, Mas; Ali, Ouaïssi

2012-01-01

In this study, the effect of LBH589 and trichostatin (TSA), a standard histone deacetylase inhibitor (HDACi) toward the growth of pancreatic cancer cell lines was studied. Thus, we examined for the first time, the HDAC family gene expression levels before and after drug treatment. Several human pancreatic cancer cell lines (Panc-1, BxPC-3, SOJ-6) and a normal human pancreatic duct immortalized epithelial cell line (HPDE/E6E7) were used as target cells. The cell growth was measured by MTT assay, cell cycle alteration, membrane phosphatidylserine exposure, DNA fragmentation, mitochondrial membrane potential loss, RT-PCR and Western blots were done using standard methods. The effect of drugs on tumor growth in vivo was studied using subcutaneous xenograft model. Except in the case of certain HDAC gene/tumor cell line couples: (SIRT1/HPDE-SOJ6/TSA- or LBH589-treated cells; LBH589-treated Panc-1 Cells; HDAC2/BxPC-3/LBH589-treated cells or TSA-treated SOJ-6-1 cells), there were no major significant changes of HDACs genes transcription in cells upon drug treatment. However, significant variation in HDACs and SIRTs protein expression levels could be seen among individual cell samples. The in vivo results showed that LBH589 formulation exhibited similar tumor reduction efficacy as the commercial drug gemcitabine. Our data demonstrate that LBH589 induced the death of pancreatic tumor cell by apoptosis. In line with its in vitro activity, LBH589 achieved a significant reduction in tumor growth in BxPC-3 pancreatic tumor cell line subcutaneous xenograft mouse model. Furthermore, exploring the impact of LBH589 on HDACs encoding genes expression revealed for the first time that some of them, depending on the cell line considered, seem to be regulated during translation. Copyright © 2012 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Endocrine pancreatic insufficiency secondary to chronic herpesvirus pancreatitis in a cockatiel (Nymphicus hollandicus).

PubMed

Phalen, David N; Falcon, Michelle; Tomaszewski, Elizabeth K

2007-06-01

A cockatiel (Nymphicus hollandicus) examined because of weight loss, polydipsia, and polyuria was diagnosed with diabetes mellitus based on the presence of glucosuria and marked hyperglycemia. Medical attempts to manage the diabetes mellitus were unsuccessful, and the bird was euthanatized. Histopathologic examination of the pancreas revealed a chronic active pancreatitis with herpesviral inclusions in many of the pancreatic acinar and duct cells. Psittacid herpesvirus-1 (PsHV-1) DNA was amplified from the lesion by polymerase chain reaction. Sequencing of the amplicon showed it to be the genotype 1 variant, which is most commonly associated with Pacheco's disease, an acute rapidly fatal systemic infection. The findings in this case suggest that the PsHV-1 genotype may also cause a localized disease of the pancreas. Infection with this virus should be considered as a differential diagnosis in birds with pancreatitis with or without diabetes mellitus.

Curcumin Modulates Pancreatic Adenocarcinoma Cell-Derived Exosomal Function

PubMed Central

Osterman, Carlos J. Diaz; Lynch, James C.; Leaf, Patrick; Gonda, Amber; Ferguson Bennit, Heather R.; Griffiths, Duncan; Wall, Nathan R.

2015-01-01

Pancreatic cancer has the highest mortality rates of all cancer types. One potential explanation for the aggressiveness of this disease is that cancer cells have been found to communicate with one another using membrane-bound vesicles known as exosomes. These exosomes carry pro-survival molecules and increase the proliferation, survival, and metastatic potential of recipient cells, suggesting that tumor-derived exosomes are powerful drivers of tumor progression. Thus, to successfully address and eradicate pancreatic cancer, it is imperative to develop therapeutic strategies that neutralize cancer cells and exosomes simultaneously. Curcumin, a turmeric root derivative, has been shown to have potent anti-cancer and anti-inflammatory effects in vitro and in vivo. Recent studies have suggested that exosomal curcumin exerts anti-inflammatory properties on recipient cells. However, curcumin’s effects on exosomal pro-tumor function have yet to be determined. We hypothesize that curcumin will alter the pro-survival role of exosomes from pancreatic cancer cells toward a pro-death role, resulting in reduced cell viability of recipient pancreatic cancer cells. The main objective of this study was to determine the functional alterations of exosomes released by pancreatic cancer cells exposed to curcumin compared to exosomes from untreated pancreatic cancer cells. We demonstrate, using an in vitro cell culture model involving pancreatic adenocarcinoma cell lines PANC-1 and MIA PaCa-2, that curcumin is incorporated into exosomes isolated from curcumin-treated pancreatic cancer cells as observed by spectral studies and fluorescence microscopy. Furthermore, curcumin is delivered to recipient pancreatic cancer cells via exosomes, promoting cytotoxicity as demonstrated by Hoffman modulation contrast microscopy as well as AlamarBlue and Trypan blue exclusion assays. Collectively, these data suggest that the efficacy of curcumin may be enhanced in pancreatic cancer cells through

Animal models for investigating chronic pancreatitis

PubMed Central

2011-01-01

Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed. PMID:22133269

Establishment of a pancreatic cancer stem cell model using the SW1990 human pancreatic cancer cell line in nude mice.

PubMed

Pan, Yan; Gao, Song; Hua, Yong-Qiang; Liu, Lu-Ming

2015-01-01

To establish a pancreatic cancer stem cell model using human pancreatic cancer cells in nude mice to provide a platform for pancreatic cancer stem cell research. To establish pancreatic cancer xenografts using human pancreatic cancer cell line SW1990, nude mice were randomly divided into control and gemcitabine groups. When the tumor grew to a volume of 125 mm3, they treated with gemcitabine at a dose of 50 mg/kg by intraperitoneal injection of 0.2 ml in the gemcitabine group, while the mice in control group were treated with the same volume of normal saline. Gemcitabine was given 2 times a week for 3 times. When the model was established, the proliferation of pancreatic cancer stem cells was observed by clone formation assay, and the protein and/or mRNA expression of pancreatic stem cell surface markers including CD24, CD44, CD133, ALDH, transcription factors containing Oct-4, Sox-2, Nanog and Gli, the key nuclear transcription factor in Sonic Hedgehog signaling pathway was detected by Western blot and/or RT-PCR to verify the reliability of this model. This model is feasible and safe. During the establishment, no mice died and the weight of nude mice maintained above 16.5 g. The clone forming ability in gemcitabine group was stronger than that of the control group (p<0.01). In gemcitabine group, the protein expression of pancreatic cancer stem cell surface markers including CD44, and ALDH was up-regulated, the protein and mRNA expression of nuclear transcription factor including Oct-4, Sox-2 and Nanog was also significantly increased (P<0.01). In addition, the protein expression of key nuclear transcription factor in Sonic Hedgehog signaling pathway, Gli-1, was significantly enhanced (p<0.01). The pancreatic cancer stem cell model was successfully established using human pancreatic cancer cell line SW1990 in nude mice. Gemcitabine could enrich pancreatic cancer stem cells, simultaneously accompanied by the activation of Sonic Hedgehog signaling pathway.

A holistic approach to dissecting SPARC family protein complexity reveals FSTL-1 as an inhibitor of pancreatic cancer cell growth.

PubMed

Viloria, Katrina; Munasinghe, Amanda; Asher, Sharan; Bogyere, Roberto; Jones, Lucy; Hill, Natasha J

2016-11-25

SPARC is a matricellular protein that is involved in both pancreatic cancer and diabetes. It belongs to a wider family of proteins that share structural and functional similarities. Relatively little is known about this extended family, but evidence of regulatory interactions suggests the importance of a holistic approach to their study. We show that Hevin, SPOCKs, and SMOCs are strongly expressed within islets, ducts, and blood vessels, suggesting important roles for these proteins in the normal pancreas, while FSTL-1 expression is localised to the stromal compartment reminiscent of SPARC. In direct contrast to SPARC, however, FSTL-1 expression is reduced in pancreatic cancer. Consistent with this, FSTL-1 inhibited pancreatic cancer cell proliferation. The complexity of SPARC family proteins is further revealed by the detection of multiple cell-type specific isoforms that arise due to a combination of post-translational modification and alternative splicing. Identification of splice variants lacking a signal peptide suggests the existence of novel intracellular isoforms. This study underlines the importance of addressing the complexity of the SPARC family and provides a new framework to explain their controversial and contradictory effects. We also demonstrate for the first time that FSTL-1 suppresses pancreatic cancer cell growth.

Autoimmune Pancreatitis.

PubMed

Majumder, Shounak; Takahashi, Naoki; Chari, Suresh T

2017-07-01

Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disease of the pancreas that belongs to the spectrum of immunoglobulin G-subclass4-related diseases (IgG4-RD) and typically presents with obstructive jaundice. Idiopathic duct-centric pancreatitis (IDCP) is a closely related but distinct disease that mimics AIP radiologically but manifests clinically most commonly as recurrent acute pancreatitis in young individuals with concurrent inflammatory bowel disease. IgG4 levels are often elevated in AIP and normal in IDCP. Histologically, lymphoplasmacytic acinar inflammation and storiform fibrosis are seen in both. In addition, the histologic hallmark of IDCP is the granulocyte epithelial lesion: intraluminal and intraepithelial neutrophils in medium-sized and small ducts with or without granulocytic acinar inflammation often associated with destruction of ductal architecture. Initial treatment of both AIP and IDCP is with oral corticosteroids for duration of 4 weeks followed by a gradual taper. Relapses are common in AIP and relatively uncommon in IDCP, a relatively rare disease for which the natural history is not well understood. For patients with relapsing AIP, treatment with immunomodulators and more recently rituximab has been recommended. Although rare instances of pancreaticobiliary malignancy has been reported in patients with AIP, overall the lifetime risk of developing pancreatic cancer does not appear to be elevated.

A Duodenal Ulcer Caused by Pancreatic Ductal Hypertension with Chronic Pancreatitis.

PubMed

Imoto, Akira; Masuda, Daisuke; Okuda, Atsushi; Takagi, Wataru; Onda, Saori; Sano, Tatsushi; Mikami, Takashi; Mohamed, Malak; Ogura, Takeshi; Higuchi, Kazuhide

2015-01-01

We herein describe the case of a 67-year-old woman with a duodenal ulcer thought to be caused by elevated pancreatic ductal pressure. The patient complained of continuous upper abdominal pain. Her medical history included idiopathic chronic pancreatitis. Endoscopy revealed a huge duodenal ulcer located on the inferior duodenal angle, which had not been seen on endoscopic retrograde pancreatography two months previously. A combination study using endoscopy and contrast imaging confirmed the relationship between the duodenal ulcer and the pancreatic branch duct. To our knowledge, this is the first case of duodenal ulcer thought to be caused by elevated pancreatic ductal pressure.

Intravital characterization of tumor cell migration in pancreatic cancer

PubMed Central

Beerling, Evelyne; Oosterom, Ilse; Voest, Emile; Lolkema, Martijn; van Rheenen, Jacco

2016-01-01

ABSTRACT Curing pancreatic cancer is difficult as metastases often determine the poor clinical outcome. To gain more insight into the metastatic behavior of pancreatic cancer cells, we characterized migratory cells in primary pancreatic tumors using intravital microscopy. We visualized the migratory behavior of primary tumor cells of a genetically engineered pancreatic cancer mouse model and found that pancreatic tumor cells migrate with a mesenchymal morphology as single individual cells or collectively as a stream of non-cohesive single motile cells. These findings may improve our ability to conceive treatments that block metastatic behavior. PMID:28243522

Lysosome associated membrane proteins maintain pancreatic acinar cell homeostasis: LAMP-2 deficient mice develop pancreatitis.

PubMed

Mareninova, Olga A; Sendler, Matthias; Malla, Sudarshan Ravi; Yakubov, Iskandar; French, Samuel W; Tokhtaeva, Elmira; Vagin, Olga; Oorschot, Viola; Lüllmann-Rauch, Renate; Blanz, Judith; Dawson, David; Klumperman, Judith; Lerch, Markus M; Mayerle, Julia; Gukovsky, Ilya; Gukovskaya, Anna S

2015-11-01

The pathogenic mechanism of pancreatitis is poorly understood. Recent evidence implicates defective autophagy in pancreatitis responses; however, the pathways mediating impaired autophagy in pancreas remain largely unknown. Here, we investigate the role of lysosome associated membrane proteins (LAMPs) in pancreatitis. We analyzed changes in LAMPs in experimental models and human pancreatitis, and the underlying mechanisms: LAMP de-glycosylation and degradation. LAMP cleavage by cathepsin B (CatB) was analyzed by mass spectrometry. We used mice deficient in LAMP-2 to assess its role in pancreatitis. Pancreatic levels of LAMP-1 and LAMP-2 greatly decrease across various pancreatitis models and in human disease. Pancreatitis does not trigger LAMPs' bulk de-glycosylation, but induces their degradation via CatB-mediated cleavage of LAMP molecule close to the boundary between luminal and transmembrane domains. LAMP-2 null mice spontaneously develop pancreatitis that begins with acinar cell vacuolization due to impaired autophagic flux, and progresses to severe pancreas damage characterized by trypsinogen activation, macrophage-driven inflammation, and acinar cell death. LAMP-2 deficiency causes a decrease in pancreatic digestive enzymes content, stimulates the basal and inhibits CCK-induced amylase secretion by acinar cells. The effects of LAMP-2 knockout and acute cerulein pancreatitis overlap, which corroborates the pathogenic role of LAMP decrease in experimental pancreatitis models. The results indicate a critical role for LAMPs, particularly LAMP-2, in maintaining pancreatic acinar cell homeostasis, and provide evidence that defective lysosomal function, resulting in impaired autophagy, leads to pancreatitis. Mice with LAMP-2 deficiency present a novel genetic model of human pancreatitis caused by lysosomal/autophagic dysfunction.

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors.

PubMed

Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe; Zhang, Chang Xian

2015-10-01

The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a(+) and neurogenin 3-expressing (Ngn3(+)) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

PubMed Central

Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F.; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe

2015-01-01

The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a+ and neurogenin 3-expressing (Ngn3+) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. PMID:26169832

"Puestow modified procedure in the era of advanced endoscopic interventions for the management of chronic lithiasic pancreatitis. A two cases report".

PubMed

Fragulidis, Georgios P; Vezakis, Αntonios; Dellaportas, Dionissios; Sotirova, Ira; Koutoulidis, Vassilis; Kontis, Elliseos; Polydorou, Andreas

2015-01-01

Pancreatic duct calculi in chronic pancreatitis (CP) patients are the main cause of intractable pain which is their main symptom. Decompression options of for the main pancreatic duct are both surgical and advanced endoscopic procedures. A 64-year-old male with known CP due to alcohol consumption and a 36-year-old female with known idiopathic CP and pancreatic duct calculi were managed recently in our hospital where endoscopic procedures were unsuccessful. A surgical therapy was considered and a longitudinal pancreaticojejunostomy (modified Puestow procedure) in both patients was performed with excellent results. Over the last 30 years, endoscopic procedures are developed to manage pancreatic duct strictures and calculi of the main pancreatic duct in CP patients. In both of our cases endoscopic therapy was first attempted but failed to extract the pancreatic duct stones, due to their size and speculations. Modified Puestow procedure was performed for both and it was successful for long term pain relief. Despite advancement in endoscopic interventions and less invasive therapies for the management of chronic lithiasic pancreatitis we consider that classic surgical management can be appropriate in certain cases. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical strategies for pancreatic β cell differentiation, reprogramming, and regeneration.

PubMed

Ma, Xiaojie; Zhu, Saiyong

2017-04-01

Generation of unlimited functional pancreatic β cells is critical for the study of pancreatic biology and treatment of diabetes mellitus. Recent advances have suggested several promising directions, including directed differentiation of pancreatic β cells from pluripotent stem cells, reprogramming of pancreatic β cells from other types of somatic cells, and stimulated proliferation and enhanced functions of existing pancreatic β cells. Small molecules are useful in generating unlimited numbers of functional pancreatic cells in vitro and could be further developed as drugs to stimulate endogenous pancreatic regeneration. Here, we provide an updated summary of recent major achievements in pancreatic β cell differentiation, reprogramming, proliferation, and function. These studies will eventually lead to significant advances in the field of pancreatic biology and regeneration. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Molecular Mechanism of Pancreatic and Salivary Glands Fluid and HCO3− Secretion

PubMed Central

Lee, Min Goo; Ohana, Ehud; Park, Hyun Woo; Yang, Dongki; Muallem, Shmuel

2013-01-01

Fluid and HCO3− secretion is a vital function of all epithelia and is required for the survival of the tissue. Aberrant fluid and HCO3− secretion is associated with many epithelial diseases, such as cystic fibrosis, pancreatitis, Sjögren’s syndrome and other epithelial inflammatory and autoimmune diseases. Significant progress has been made over the last 20 years in our understanding of epithelial fluid and HCO3− secretion, in particular by secretory glands. Fluid and HCO3− secretion by secretory glands is a two step process. Acinar cells secrete isotonic fluid in which the major salt is NaCl. Subsequently, the duct modifies the volume and electrolyte composition of the fluid to absorb the Cl− and secrete HCO3−. The relative volume secreted by acinar and duct cells and modification of electrolyte composition of the secreted fluids varies among secretory glands to meet their physiological functions. In the pancreas, acinar cells secrete small amount of NaCl-rich fluid, while the duct absorbs the Cl− and secretes HCO3− and the bulk of the fluid in the pancreatic juice. Fluid secretion appears to be driven by active HCO3− secretion. In the salivary glands, acinar cells secrete the bulk of the fluid in the saliva that contains high concentrations of Na+ and Cl− and fluid secretion is mediated by active Cl− secretion. The salivary glands duct absorbs both the Na+ and Cl− and secretes K+ and HCO3−. In this review, we focus on the molecular mechanism of fluid and HCO3− secretion by the pancreas and salivary glands, to highlight the similarities of the fundamental mechanisms of acinar and duct cell functions, and point the differences to meet glands specific secretions. PMID:22298651

Pancreatic Duct in Autoimmune Pancreatitis: Intraindividual Comparison of Magnetic Resonance Pancreatography at 1.5 T and 3.0 T.

PubMed

Kim, Jin Hee; Byun, Jae Ho; Kim, Myung-Hwan; Lee, Sung Koo; Kim, Song Cheol; Kim, Hyoung Jung; Lee, Seung Soo; Kim, So Yeon; Lee, Moon-Gyu

2017-08-01

The aim of this study was to intraindividually compare magnetic resonance pancreatography (MRP) image quality at 1.5 T and 3.0 T when demonstrating main pancreatic duct (MPD) abnormalities in patients with autoimmune pancreatitis (AIP). Thirty prospectively enrolled patients with AIP underwent MRP at both 1.5 T and 3.0 T followed by endoscopic retrograde pancreatography before treatment. Two readers independently analyzed the MRP images and graded the visualization of MPD strictures and full-length MPD, using endoscopic retrograde pancreatography as the reference standard, as well as overall image artifacts on a 4-point scale. The contrast between the MPD and periductal area was calculated using a region-of-interest measurement. Visualization scores of MPD strictures and full-length MPD, and summed scores of each qualitative analysis, were significantly greater at 3.0-T MRP than at 1.5-T MRP for both readers (P ≤ 0.02). There were less image artifacts at 3.0 T compared with 1.5 T (P ≤ 0.052). The contrast between the MPD and periductal area was significantly greater at 3.0-T MRP than at 1.5-T MRP (P < 0.001). The MRP at 3.0 T was superior to 1.5-T MRP for demonstrating MPD abnormalities in AIP, with better image contrast and fewer image artifacts. Consequently, 3.0-T MRP may be useful for the diagnosis and management of patients with AIP.

Immune cell functions in pancreatic cancer.

PubMed

Plate, J M; Harris, J E

2000-01-01

Pancreatic cancer kills nearly 29,000 people in the United States annually-as many people as are diagnosed with the disease. Chemotherapeutic treatment is ineffective in halting progression of the disease. Yet, specific immunity to pancreatic tumor cells in subjects with pancreatic cancer has been demonstrated repeatedly during the last 24 years. Attempts to expand and enhance tumor-specific immunity with biotherapy, however, have not met with success. The question remains, "Why can't specific immunity regulate pancreatic cancer growth?" The idea that tumor cells have evolved protective mechanisms against immunity was raised years ago and has recently been revisited by a number of research laboratories. In pancreatic cancer, soluble factors produced by and for the protection of the tumor environment have been detected and are often distributed to the victim's circulatory system where they may effect a more generalized immunosuppression. Yet the nature of these soluble factors remains controversial, since some also serve as tumor antigens that are recognized by the same T cells that may become inactivated by them. Unless the problem of tumor-derived immunosuppressive products is addressed directly through basic and translational research studies, successful biotherapeutic treatment for pancreatic cancer may not be forthcoming.

Engineered T cells for pancreatic cancer treatment

PubMed Central

Katari, Usha L; Keirnan, Jacqueline M; Worth, Anna C; Hodges, Sally E; Leen, Ann M; Fisher, William E; Vera, Juan F

2011-01-01

Objective Conventional chemotherapy and radiotherapy produce marginal survival benefits in pancreatic cancer, underscoring the need for novel therapies. The aim of this study is to develop an adoptive T cell transfer approach to target tumours expressing prostate stem cell antigen (PSCA), a tumour-associated antigen that is frequently expressed by pancreatic cancer cells. Methods Expression of PSCA on cell lines and primary tumour samples was confirmed by immunohistochemistry. Healthy donor- and patient-derived T cells were isolated, activated in vitro using CD3/CD28, and transduced with a retroviral vector encoding a chimeric antigen receptor (CAR) targeting PSCA. The ability of these cells to kill tumour cells was analysed by chromium-51 (Cr51) release. Results Prostate stem cell antigen was expressed on >70% of the primary tumour samples screened. Activated, CAR-modified T cells could be readily generated in clinically relevant numbers and were specifically able to kill PSCA-expressing pancreatic cancer cell lines with no non-specific killing of PSCA-negative target cells, thus indicating the potential efficacy and safety of this approach. Conclusions Prostate stem cell antigen is frequently expressed on pancreatic cancer cells and can be targeted for immune-mediated destruction using CAR-modified, adoptively transferred T cells. The safety and efficacy of this approach indicate that it deserves further study and may represent a promising novel treatment for patients with pancreatic cancer. PMID:21843265

Postoperative complications linked to pancreaticoduodenectomy. An analysis of pancreatic stump management.

PubMed

Benzoni, Enrico; Zompicchiatti, Aron; Saccomano, Enrico; Lorenzin, Dario; Baccarani, Umberto; Adani, Gianluigi; Noce, Luigi; Uzzau, Alessandro; Cedolini, Carla; Bresadola, Fabrizio; Intini, Sergio

2008-03-01

To analyze the role of different procedures in the management of pancreatic stump according to the incidence of postoperative morbidity derived from the data of a single center surgical population. From 1989 to 2005 we performed 76 pancreaticoduodenectomies (PD) and 26 distal pancreatectomies (DP). The surgical reconstruction after PD was as follows: 11 manual non-absorbable stitches closure of the main duct, 24 closures of the main duct with linear stapler, 17 occlusions of the main duct with neoprene glue and 24 duct-to-mucosa anastomosis. In the PD group, the morbidity rate was 60%, caused by: pancreatic leakage in 48% of patients, hemorrhagic complications in 10% following surgical procedure and infectious complications in 15%. After DP we recorded: leakage in 3.9%, haemoperitoneum in 15.4% and no complications in 80.7%. The multivariate analysis showed that the in-hospital mortality was linked to the surgical procedure (PD, p=0.003) and to the following complications: pancreatic leakage (p=0.004), haemoperitoneum (p=0.00045) and infectious complications (p=0.0077). Bleeding complications, biliary anastomosis leakage and infectious complications were consequences of pancreatic leakage (p=0.025, p=0.025 and p=0.025 respectively). Manual non-absorbable stitch closure of the main duct and occlusion of the main duct with neoprene glue should be avoided in the reconstructive phase.

“Puestow modified procedure in the era of advanced endoscopic interventions for the management of chronic lithiasic pancreatitis. A two cases report”

PubMed Central

Fragulidis, Georgios P.; Vezakis, Αntonios; Dellaportas, Dionissios; Sotirova, Ira; Koutoulidis, Vassilis; Kontis, Elliseos; Polydorou, Andreas

2015-01-01

Introduction Pancreatic duct calculi in chronic pancreatitis (CP) patients are the main cause of intractable pain which is their main symptom. Decompression options of for the main pancreatic duct are both surgical and advanced endoscopic procedures. Presentation of cases A 64-year-old male with known CP due to alcohol consumption and a 36-year-old female with known idiopathic CP and pancreatic duct calculi were managed recently in our hospital where endoscopic procedures were unsuccessful. A surgical therapy was considered and a longitudinal pancreaticojejunostomy (modified Puestow procedure) in both patients was performed with excellent results. Discussion Over the last 30 years, endoscopic procedures are developed to manage pancreatic duct strictures and calculi of the main pancreatic duct in CP patients. In both of our cases endoscopic therapy was first attempted but failed to extract the pancreatic duct stones, due to their size and speculations. Modified Puestow procedure was performed for both and it was successful for long term pain relief. Conclusion Despite advancement in endoscopic interventions and less invasive therapies for the management of chronic lithiasic pancreatitis we consider that classic surgical management can be appropriate in certain cases. PMID:26318135

In Patients with a Soft Pancreas, a Thick Parenchyma, a Small Duct, and Fatty Infiltration Are Significant Risks for Pancreatic Fistula After Pancreaticoduodenectomy.

PubMed

Sugimoto, Motokazu; Takahashi, Shinichiro; Kojima, Motohiro; Kobayashi, Tatsushi; Gotohda, Naoto; Konishi, Masaru

2017-05-01

This study sought to characterize soft and hard pancreatic textures radiologically and histologically, and to identify specific risks in a soft pancreas associated with postoperative pancreatic fistula (POPF) formation after pancreaticoduodenectomy (PD). Consecutive 145 patients who underwent PD at a single institution between January 2010 and May 2013 were studied. Pancreatic consistency was intraoperatively judged as soft or hard. Pancreatic configuration was assessed using preoperative CT. Histologic components of the pancreatic stump were evaluated using a morphometric analysis. Clinicopathologic parameters were then analyzed for the risk of clinically relevant POPF. Compared with patients with a hard pancreas (n = 66), those with a soft pancreas (n = 79) had a smaller main pancreatic duct (MPD) diameter and a larger parenchymal thickness on CT, had a smaller fibrosis ratio and a larger lobular ratio histologically, and developed clinically relevant POPF more frequently (P < 0.001 for all). In patients with a soft pancreas, an MPD diameter <2 mm, a parenchymal thickness ≥10 mm, a lobular ratio <75%, and a fat ratio ≥20% were independently associated with clinically relevant POPF (P < 0.010 for all). In patients with a soft pancreas, a thick parenchyma, a small MPD, and fatty infiltration were strongly associated with clinically relevant POPF after PD.

Endoscopic transpapillary drainage for external fistulas developing after surgical or radiological pancreatic interventions.

PubMed

Rana, Surinder Singh; Bhasin, Deepak Kumar; Nanda, Mohit; Siyad, Ismail; Gupta, Rajesh; Kang, Mandeep; Nagi, Birinder; Singh, Kartar

2010-06-01

External pancreatic fistulas (EPFs) are a therapeutic challenge. The present study was conducted to evaluate the efficacy of endoscopic transpapillary nasopancreatic drainage (NPD) in patients with EPF. Over 12 years, 23 patients (19 males) with EPF underwent attempted endoscopic transpapillary NPD. The end points were fistula closure with healing of pancreatic duct disruption on nasopancreatogram, or need for surgery. All 23 patients had persistent drain output (>50 mL/day) for >6 weeks. The mean output volume of the fistula was 223 mL (range: 60 mL to 750 mL). Sixteen patients had partial and seven patients had complete pancreatic duct disruption. The NPD could be successfully placed in 21/23 (91.3%) patients. Disruption was bridged in 15 of 16 patients with partial duct disruption. EPF healed in 2-8 weeks of placement of NPD in all of the patients with partial duct disruption that was bridged and there was no recurrence at a mean follow-up of 38 months. The EPF resolved in only 2/6 (33%) patients with complete duct disruption. External pancreatic fistulas developing following percutaneous drainage of pancreatic fluid collections or surgical necrosectomy can be effectively treated by transpapillary nasopancreatic drain placement especially when there is partial ductal disruption and the disruption can be bridged.

Identification of risk factors for post-endoscopic retrograde cholangiopancreatography pancreatitis in a high volume center.

PubMed

Phillip, Veit; Schwab, Miriam; Haf, David; Algül, Hana

2017-01-01

Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Several patients´ or procedure related risk factors for post-ERCP pancreatitis (PEP) have been suggested. The aim of this study was to validate the risk factors for PEP in a high-volume center. All patients undergoing first time ERCP at a tertiary referral center between December 2010 and October 2013 were retrospectively included. PEP was defined according to the Atlanta Classification. 344 patients were included in the final analysis. The risk to develop PEP was increased in patients with chronic pancreatitis (odds ratio 3.7) and after inadvertent cannulation of the pancreatic duct (odds ratio 2.2), which occurred in 26.5% of the patients. Inadvertent cannulation occurred significantly more frequently in patients with difficult cannulation of the papilla duodeni major (odds ratio 12.7; p<0.001). ERCP on call was associated with an increased risk for difficult cannulation (odds ratio 3.0). Inadvertent cannulation of the pancreatic duct is a procedure related risk factor for PEP. Measurements on preventing inadvertent cannulation of the pancreatic duct should be established and studies on prophylactic measurements should focus particularly on patients with inadvertent cannulation of the pancreatic duct.

What is the role of endoscopic retrograde cholangiopancreatography in assessing traumatic rupture of the pancreatic in children?

PubMed

Keil, Radan; Drabek, Jiri; Lochmannova, Jindra; Stovicek, Jan; Rygl, Michal; Snajdauf, Jiri; Hlava, Stepan

2016-01-01

Trauma is one of the most common causes of morbidity and mortality in the pediatric population. The diagnosis of pancreatic injury is based on clinical presentation, laboratory and imaging findings, and endoscopic methods. CT scanning is considered the gold standard for diagnosing pancreatic trauma in children. This retrospective study evaluates data from 25 pediatric patients admitted to the University Hospital Motol, Prague, with blunt pancreatic trauma between January 1999 and June 2013. The exact grade of injury was determined by CT scans in 11 patients (47.8%). All 25 children underwent endoscopic retrograde cholangiopancreatography (ERCP). Distal pancreatic duct injury (grade III) was found in 13 patients (52%). Proximal pancreatic duct injury (grade IV) was found in four patients (16 %). Major contusion without duct injury (grade IIB) was found in six patients (24%). One patient experienced duodeno-gastric abruption not diagnosed on the CT scan. The diagnosis was made endoscopically during ERCP. Grade IIB pancreatic injury was found in this patient. One patient (4%) with pancreatic pseudocyst had a major contusion of pancreas without duct injury (grade IIA). Four patients (16%) with grade IIB, III and IV pancreatic injury were treated exclusively and nonoperatively with a pancreatic stent insertion and somatostatine. Two patients (8%) with a grade IIB injury were treated conservatively only with somatostatine without drainage. Eighteen (72 %) children underwent surgical intervention within 24 h after ERCP. ERCP is helpful when there is suspicion of pancreatic duct injury in order to exclude ductal leakage and the possibility of therapeutic intervention. ERCP can speed up diagnosis of higher grade of pancreatic injuries.

Excess intraoperative fluid volume administration is associated with pancreatic fistula after pancreaticoduodenectomy

PubMed Central

Han, In Woong; Kim, Hongbeom; Heo, JinSeok; Oh, Min Gu; Choi, Yoo Shin; Lee, Seung Eun; Lim, Chang-Sup

2017-01-01

Abstract Recent studies on perioperative fluid administration in patients undergoing pancreaticoduodenectomy (PD) have suggested that increased fluid loads are associated with worse perioperative outcomes. The purpose of this study was to investigate the relationship between intraoperative fluid (IOF) administration and postoperative pancreatic fistula (POPF), and to determine additional risk factors affecting pancreatic fistula in patients undergoing PD. From 2005 to 2014, a total of 182 patients with various periampullary diseases after PD were reviewed retrospectively at Dongguk University Ilsan Hospital, Chung-Ang University Hospital, and Dongnam Institute of Radiological and Medical Sciences. Patients were assigned to high or low IOF groups based on more or less fluid administration for supplementation of estimated blood loss and maintenance volume (12.5 mL/kg/h) than planned, respectively. The associations between IOF administration, pancreatic fistula development, and perioperative outcomes were evaluated. A total of 98 patients were assigned to the high-IOF group, and 84 to the low-IOF group. Risk factors for pancreatic fistula after univariate analysis were assignment to the high-IOF group, higher preoperative serum hemoglobin level, ampullary or bile duct cancer, pylorus preserving PD, small pancreatic duct, duct-to-mucosa pancreatojejunostomy, use of a stent, and mesh application to pancreatojejunal anastomosis. Among these, assignment to the high-IOF group (hazard ratio [HR] = 5.501, 95% CI 1.624–18.632, P = .006) and a small (<4 mm) pancreatic duct (HR = 4.129, 95% CI 1.569–14.658, P = .035) were identified as independent risk factors for the development of pancreatic fistula after multivariate analysis. However, long-term survival rate did not differ according to IOF group or duct size. Excessive IOF volume administration is associated with an increased incidence of pancreatic fistula after pancreaticoduodenectomy. PMID

Duodenal duplication cyst (DDC) communicating with the pancreatobiliary duct--a rare cause of recurrent acute pancreatitis in adults.

PubMed

Bong, Jan Jin; Spalding, Duncan

2010-01-01

Duodenal duplication cysts (DDC) are rare congenital anomalies that usually present in infancy and childhood. Acute presentation in adults is even rarer. We report a case of a 34-year-old man who presented with recurrent acute pancreatitis and was found to have a cystic lesion in the second part of his duodenum. Further investigations revealed communication between the cystic lesion and the distal common bile duct. We describe the details of the operative approach taken to resect the DDC. We describe the differential diagnoses and the criteria for diagnosing DDC. Management options for DDC are discussed along with our recommendations.

Transdifferentiation of human periodontal ligament stem cells into pancreatic cell lineage.

PubMed

Lee, Jeong Seok; An, Seong Yeong; Kwon, Il Keun; Heo, Jung Sun

2014-10-01

Human periodontal ligament-derived stem cells (PDLSCs) demonstrate self-renewal capacity and multilineage differentiation potential. In this study, we investigated the transdifferentiation potential of human PDLSCs into pancreatic islet cells. To form three-dimensional (3D) clusters, PDLSCs were cultured in Matrigel with media containing differentiation-inducing agents. We found that after 6 days in culture, PDLSCs underwent morphological changes resembling pancreatic islet-like cell clusters (ICCs). The morphological characteristics of PDLSC-derived ICCs were further assessed using scanning electron microscopy analysis. Using reverse transcription-polymerase chain reaction analysis, we found that pluripotency genes were downregulated, whereas early endoderm and pancreatic differentiation genes were upregulated, in PDLSC-derived ICCs compared with undifferentiated PDLSCs. Furthermore, we found that PDLSC-derived ICCs were capable of secreting insulin in response to high concentrations of glucose, validating their functional differentiation into islet cells. Finally, we also performed dithizone staining, as well as immunofluorescence assays and fluorescence-activated cell sorting analysis for pancreatic differentiation markers, to confirm the differentiation status of PDLSC-derived ICCs. These results demonstrate that PDLSCs can transdifferentiate into functional pancreatic islet-like cells and provide a novel, alternative cell population for pancreatic repair. Copyright © 2014 John Wiley & Sons, Ltd.

English language version of the S3-consensus guidelines on chronic pancreatitis: Definition, aetiology, diagnostic examinations, medical, endoscopic and surgical management of chronic pancreatitis.

PubMed

Hoffmeister, A; Mayerle, J; Beglinger, C; Büchler, M W; Bufler, P; Dathe, K; Fölsch, U R; Friess, H; Izbicki, J; Kahl, S; Klar, E; Keller, J; Knoefel, W T; Layer, P; Loehr, M; Meier, R; Riemann, J F; Rünzi, M; Schmid, R M; Schreyer, A; Tribl, B; Werner, J; Witt, H; Mössner, J; Lerch, M M

2015-12-01

Chronic pancreatitis is a disease of the pancreas in which recurrent inflammatory episodes result in replacement of pancreatic parenchyma by fibrous connective tissue. This fibrotic reorganization of the pancreas leads to a progressive exocrine and endocrine pancreatic insufficiency. In addition, characteristic complications arise, such as pseudocysts, pancreatic duct obstructions, duodenal obstruction, vascular complications, obstruction of the bile ducts, malnutrition and pain syndrome. Pain presents as the main symptom of patients with chronic pancreatitis. Chronic pancreatitis is a risk factor for pancreatic carcinoma. Chronic pancreatitis significantly reduces the quality of life and the life expectancy of affected patients. These guidelines were researched and compiled by 74 representatives from 11 learned societies and their intention is to serve evidence-based professional training as well as continuing education. On this basis they shall improve the medical care of affected patients in both the inpatient and outpatient sector. Chronic pancreatitis requires an adequate diagnostic workup and systematic management, given its severity, frequency, chronicity, and negative impact on the quality of life and life expectancy. © Georg Thieme Verlag KG Stuttgart · New York.

Nestin-expressing cells in the pancreatic islets of Langerhans.

PubMed

Hunziker, E; Stein, M

2000-04-29

The pancreatic islets of Langerhans produce several peptide hormones, predominantly the metabolically active hormones insulin and glucagon, which are critical for maintaining normal fuel homeostasis. Some evidence exists that pancreatic endocrine cells turn over at a slow rate and can regenerate in certain conditions. This could be due to the presence of pluripotent cells residing in the pancreas. Recently the intermediate filament protein nestin has been identified to be a marker for a multipotent stem cell in the central nervous system. Given the similarity between the pancreatic islets and neuronal cells, we hypothesized that stem cells expressing nestin might be present in the pancreas. Here we present evidence that a subset of cells in the pancreatic islets express the stem cell marker nestin. These cells might serve as precursors of differentiated pancreatic endocrine cells. Copyright 2000 Academic Press.

Frey procedure combined with biliary diversion in chronic pancreatitis.

PubMed

Merdrignac, Aude; Bergeat, Damien; Rayar, Michel; Harnoy, Yann; Turner, Kathleen; Courtin-Tanguy, Laetitia; Boudjema, Karim; Meunier, Bernard; Sulpice, Laurent

2016-11-01

The Frey procedure has become the standard operative treatment in chronic painful pancreatitis. Biliary diversion could be combined when associated with common bile duct obstruction. The aim of the present study was to evaluate the impact of the type of biliary diversion combined with the Frey procedure on late morbidity. The data from consecutive patients undergoing the Frey procedure and having a minimum follow-up of 2 years were extracted from a maintained prospective database. The mean endpoint was the rate of secondary biliary stricture after the Frey procedure combined with biliary diversion (bilioenteric anastomosis or common bile duct reinsertion in the resection cavity). Between 2006 and 2013, 55 consecutive patients underwent the Frey procedure. Twenty-nine patients had common bile duct obstruction (52.7%). The technique of biliary diversion resulted in bilioenteric anastomosis in 19 patients (65.5%) and common bile duct reinsertion in 10 patients (34.5%). Preoperative characteristics and early surgical outcomes were comparable. Pain control was similar. There was significantly more secondary biliary stricture after common bile duct reinsertion than after bilioenteric anastomosis (60% vs 11%, P = .008). Combined bilioenteric anastomosis during the Frey procedure is an efficient technique for treating common bile duct obstruction that complicates chronic painful pancreatitis. Bilioenteric anastomosis was associated with less secondary biliary stricture than common bile duct reinsertion in the pancreatic resection cavity. Copyright © 2016 Elsevier Inc. All rights reserved.

IL-8 Expression in Granulocytic Epithelial Lesions of Idiopathic Duct-centric Pancreatitis (Type 2 Autoimmune Pancreatitis).

PubMed

Ku, Yuna; Hong, Seung-Mo; Fujikura, Kohei; Kim, Sung Joo; Akita, Masayuki; Abe-Suzuki, Shiho; Shiomi, Hideyuki; Masuda, Atsuhiro; Itoh, Tomoo; Azuma, Takeshi; Kim, Myung-Hwan; Zen, Yoh

2017-08-01

Type 2 autoimmune pancreatitis (type 2 AIP) develops in isolation or sometimes in association with ulcerative colitis. Its diagnosis requires the histologic confirmation of granulocytic epithelial lesions (GELs) with no diagnostic biomarker currently available. This study aimed to elucidate the tissue expression of cytokines and their diagnostic value in this condition. In quantitative polymerase chain reaction for multiple cytokines using tissue-derived mRNA, the expression level of interleukin (IL)-8 was markedly higher in type 2 AIP than in type 1 AIP (P<0.001). In immunostaining, IL-8 expression was detected in the ductal/ductular epithelium (11/13; 85%) and infiltrating neutrophils or lymphocytes (12/12; 100%) in type 2 AIP, but was almost entirely negative in type 1 AIP (n=13; both, P<0.001). Although obstructive pancreatitis adjacent to pancreatic cancers (peritumoral pancreatitis) exhibited IL-8 expression in the epithelium (3/12; 25%) and inflammatory cells (10/12; 83%), expression levels were significantly lower than those in type 2 AIP (P<0.001 and 0.020, respectively). The presence of either GELs or IL-8-positive epithelium discriminated type 2 AIP from type 1 AIP or obstructive pancreatitis with 92% sensitivity and 92% to 100% specificity. Furthermore, CD3/IL-8-coexpressing lymphocytes were almost restricted to type 2 AIP. Interestingly, a similar pattern of IL-8 expression was also observed in colonic biopsies of ulcerative colitis. In conclusion, the overexpression of IL-8 may underlie the development of GELs in type 2 AIP, and IL-8 immunostaining or IL-8/CD3 double staining may become an ancillary method for its diagnosis. The similar expression pattern of IL-8 in ulcerative colitis also suggests a pathogenetic link between the 2 conditions.

Automated quantification of pancreatic β-cell mass

PubMed Central

Golson, Maria L.; Bush, William S.

2014-01-01

β-Cell mass is a parameter commonly measured in studies of islet biology and diabetes. However, the rigorous quantification of pancreatic β-cell mass using conventional histological methods is a time-consuming process. Rapidly evolving virtual slide technology with high-resolution slide scanners and newly developed image analysis tools has the potential to transform β-cell mass measurement. To test the effectiveness and accuracy of this new approach, we assessed pancreata from normal C57Bl/6J mice and from mouse models of β-cell ablation (streptozotocin-treated mice) and β-cell hyperplasia (leptin-deficient mice), using a standardized systematic sampling of pancreatic specimens. Our data indicate that automated analysis of virtual pancreatic slides is highly reliable and yields results consistent with those obtained by conventional morphometric analysis. This new methodology will allow investigators to dramatically reduce the time required for β-cell mass measurement by automating high-resolution image capture and analysis of entire pancreatic sections. PMID:24760991

Redox Homeostasis in Pancreatic β Cells

PubMed Central

Ježek, Petr; Dlasková, Andrea; Plecitá-Hlavatá, Lydie

2012-01-01

We reviewed mechanisms that determine reactive oxygen species (redox) homeostasis, redox information signaling and metabolic/regulatory function of autocrine insulin signaling in pancreatic β cells, and consequences of oxidative stress and dysregulation of redox/information signaling for their dysfunction. We emphasize the role of mitochondrion in β cell molecular physiology and pathology, including the antioxidant role of mitochondrial uncoupling protein UCP2. Since in pancreatic β cells pyruvate cannot be easily diverted towards lactate dehydrogenase for lactate formation, the respiration and oxidative phosphorylation intensity are governed by the availability of glucose, leading to a certain ATP/ADP ratio, whereas in other cell types, cell demand dictates respiration/metabolism rates. Moreover, we examine the possibility that type 2 diabetes mellitus might be considered as an inevitable result of progressive self-accelerating oxidative stress and concomitantly dysregulated information signaling in peripheral tissues as well as in pancreatic β cells. It is because the redox signaling is inherent to the insulin receptor signaling mechanism and its impairment leads to the oxidative and nitrosative stress. Also emerging concepts, admiting participation of redox signaling even in glucose sensing and insulin release in pancreatic β cells, fit in this view. For example, NADPH has been firmly established to be a modulator of glucose-stimulated insulin release. PMID:23304259

A Minireview on Vasopressin-regulated Aquaporin-2 in Kidney Collecting Duct Cells.

PubMed

Park, Eui-Jung; Kwon, Tae-Hwan

2015-06-01

The kidney collecting duct is an important renal tubular segment for the regulation of body water and salt homeostasis. Water reabsorption in the collecting duct cells is regulated by arginine vasopressin (AVP) via the vasopressin V2-receptor (V2R). AVP increases the osmotic water permeability of the collecting duct cells through aquaporin-2 (AQP2) and aquaporin-3 (AQP3). AVP induces the apical targeting of AQP2 and transcription of AQP2 gene in the kidney collecting duct principal cells. The signaling transduction pathways resulting in the AQP2 trafficking to the apical plasma membrane of the collecting duct principal cells, include AQP2 phosphorylation, RhoA phosphorylation, actin depolymerization and calcium mobilization, and the changes of AQP2 protein abundance in water balance disorders have been extensively studied. These studies elucidate the underlying cellular and molecular mechanisms of body water homeostasis and provide the basis for the treatment of body water balance disorders.

Susceptibility of ATM-deficient pancreatic cancer cells to radiation.

PubMed

Ayars, Michael; Eshleman, James; Goggins, Michael

2017-05-19

Ataxia telangiectasia mutated (ATM) is inactivated in a significant minority of pancreatic ductal adenocarcinomas and may be predictor of treatment response. We determined if ATM deficiency renders pancreatic cancer cells more sensitive to fractionated radiation or commonly used chemotherapeutics. ATM expression was knocked down in three pancreatic cancer cell lines using ATM-targeting shRNA. Isogenic cell lines were tested for sensitivity to several chemotherapeutic agents and radiation. DNA repair kinetics were analyzed in irradiated cells using the comet assay. We find that while rendering pancreatic cancer cells ATM-deficient did not significantly change their sensitivity to several chemotherapeutics, it did render them exquisitely sensitized to radiation. Pancreatic cancer ATM status may help predict response to radiotherapy.

Specifying pancreatic endocrine cell fates.

PubMed

Collombat, Patrick; Hecksher-Sørensen, Jacob; Serup, Palle; Mansouri, Ahmed

2006-07-01

Cell replacement therapy could represent an attractive alternative to insulin injections for the treatment of diabetes. However, this approach requires a thorough understanding of the molecular switches controlling the specification of the different pancreatic cell-types in vivo. These are derived from an apparently identical pool of cells originating from the early gut endoderm, which are successively specified towards the pancreatic, endocrine, and hormone-expressing cell lineages. Numerous studies have outlined the crucial roles exerted by transcription factors in promoting the cell destiny, defining the cell identity and maintaining a particular cell fate. This review focuses on the mechanisms regulating the morphogenesis of the pancreas with particular emphasis on recent findings concerning the transcription factor hierarchy orchestrating endocrine cell fate allocation.

Endotherapy is effective for pancreatic ductal disruption: A dual center experience.

PubMed

Das, Rohit; Papachristou, Georgios I; Slivka, Adam; Easler, Jeffrey J; Chennat, Jennifer; Malin, Jessica; Herman, Justin B; Laique, Sobia N; Hayat, Umar; Ooi, Yinn Shaung; Rabinovitz, Mordechai; Yadav, Dhiraj; Siddiqui, Ali A

2016-01-01

Pancreatic duct (PD) disruptions occur as a result of different etiologies and can be managed medically, endoscopically, or surgically. The aim of this study was to provide an evaluation on the efficacy of endotherapy for treatment of PD disruption in a large cohort of patients and identify factors that predict successful treatment outcome. We retrospectively evaluated consecutive patients who underwent endoscopic retrograde pancreatography (ERP) for transpapillary pancreatic stent placement for PD disruption from 2008 to 2013 at two tertiary referral institutions. PD disruption was defined as extravasation of contrast from the pancreatic duct as seen on ERP. Therapeutic success was defined by resolution of PD leak on ERP, clinical, and/or imaging evaluation. We evaluated 107 patients (58% male, mean age 53 years) with PD disruption. Etiologies of PD disruption were acute pancreatitis (36%), post-operative (31%), chronic pancreatitis (29%), and trauma (4%). PD disruption was successfully bridged by a stent in 45 (44%) patients. Two patients developed post-sphincterotomy bleeding, two had stent migration, and two patients died as a result of post-ERP related complications. Placement of a PD stent was successful in 103/107 (96%) patients. Therapeutic success was achieved in 80/107 (75%) patients. Non-acute pancreatitis etiologies and absence of complete duct disruption were independent predictors of therapeutic success. Endoscopic therapy using a transpapillary stent for PD disruption is safe and effective. Absence of complete duct disruption and non-AP etiologies determine a favorable endoscopic outcome. Published by Elsevier India Pvt Ltd.

Robotic enucleation of benign pancreatic tumors

PubMed Central

Ore, Ana Sofia; Barrows, Courtney E.; Solis-Velasco, Monica; Shaker, Jessica

2017-01-01

Robot-assisted enucleation provides the dual benefits of a minimally-invasive technique and pancreatic parenchymal conservation to selected patients with functional pancreatic neuroendocrine tumors (F-pNETs) and serous cystadenomas. Insulinomas, the most common F-pNETs, are ideal candidates for enucleation when <2 cm given the 80% probability of being benign. Current evidence suggests enucleation for the following: benign, isolated lesions with a distance between tumor and main pancreatic duct ≥3 mm (no focal stricture or dilation), insulinomas, gastrinomas <2 cm, and nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) <1–2 cm and low Ki67 mitotic index. Minimally-invasive enucleation is an imaging-dependent procedure that requires recognizable anatomic landmarks for successful completion, including tumor proximity to the pancreatic duct as well as localization relative to major structures such as the gastroduodenal artery, bile duct, and portal vein. Tumor localization often mandates intraoperative ultrasound aided by duplex studies of intratumoral blood flow and frozen section confirmation. Five patients have undergone robot-assisted enucleation at Beth Israel Deaconess Medical Center between January 2014 and January 2017 with median tumor diameter of 1.3 cm (0.9–1.7 cm) located in the pancreatic head [2] and tail [3]. Surgical indications included insulinoma [2] and NF-pNETs [3]. Median operative time was 204 min (range, 137–347 min) and estimated blood loss of 50 mL. There were no conversions to open or transfusions. Robotic enucleation is a safe and feasible technique that allows parenchymal conservation in a minimally-invasive setting, reducing operative time and length of stay with equivalent pathological outcomes compared to open surgery. PMID:29302427

Pancreatic injury.

PubMed

Ahmed, Nasim; Vernick, Jerome J

2009-12-01

Injury to the pancreas, because of its retroperitoneal location, is a rare occurrence, most commonly seen with penetrating injuries (gun shot or stab wounds). Blunt trauma to the pancreas accounts for only 25% of the cases. Pancreatic injuries are associated with high morbidity and mortality due to accompanying vascular and duodenal injuries. Pancreatic injuries are not always easy to diagnose resulting in life threatening complications. Physical examination as well as serum amylase is not diagnostic following blunt trauma. Computed tomography (CT) scan can delineate the injury or transaction of the pancreas. Endoscopic retrograde pancreaticography (ERCP) is the main diagnostic modality for evaluation of the main pancreatic duct. Unrecognized ductal injury leads to pancreatic pseudocyst, fistula, abscess, and other complications. Management depends upon the severity of the pancreatic injury as well as associated injuries. Damage control surgery in hemodynamic unstable patients reduces morbidity and mortality.

Orpk mouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization.

PubMed

Cano, David A; Murcia, Noel S; Pazour, Gregory J; Hebrok, Matthias

2004-07-01

Polycystic kidney disease (PKD) includes a group of disorders that are characterized by the presence of cysts in the kidney and other organs, including the pancreas. Here we show that in orpk mice, a model system for PKD that harbors a mutation in the gene that encodes the polaris protein, pancreatic defects start to occur at the end of gestation, with an initial expansion of the developing pancreatic ducts. Ductal dilation continues rapidly after birth and results in the formation of large, interconnected cysts. Expansion of pancreatic ducts is accompanied by apoptosis of neighboring acinar cells, whereas endocrine cell differentiation and islet formation appears to be unaffected. Polaris has been shown to co-localize with primary cilia, and these structures have been implicated in the formation of renal cysts. In the orpk pancreas, cilia numbers are reduced and cilia length is decreased. Expression of polycystin-2, a protein involved in PKD, is mislocalized in orpk mice. Furthermore, the cellular localization of beta-catenin, a protein involved in cell adhesion and Wnt signaling, is altered. Thus, polaris and primary cilia function are required for the maturation and maintenance of proper tissue organization in the pancreas.

Divergent Effects of Dendritic Cells on Pancreatitis

DTIC Science & Technology

2015-09-01

role of dendritic cells in pancreatitis. Dendritic cells are professional antigen presenting cells which initiate innate and adaptive immune... Lymphoid -tissue-specific homing of bone- marrow-derived dendritic cells . Blood. 113:6638–6647. http://dx.doi .org/10.1182/blood-2009-02-204321 Dapito...Award Number: W81XWH-12-1-0313 TITLE: Divergent Effects of Dendritic Cells on Pancreatitis PRINCIPAL INVESTIGATOR: Dr. George Miller

Isolation of pancreatic progenitor cells with the surface marker of hematopoietic stem cells.

PubMed

Ma, Fengxia; Chen, Fang; Chi, Ying; Yang, Shaoguang; Lu, Shihong; Han, Zhongchao

2012-01-01

To isolate pancreatic progenitor cells with the surface markers of hematopoietic stem cells, the expression of stem cell antigen (Sca-1) and c-Kit and the coexpression of them with pancreatic duodenal homeobox-1 (PDX-1), neurogenin 3 (Ngn3), and insulin were examined in murine embryonic pancreas. Then different pancreatic cell subpopulations were isolated by magnet-activated cell sorting. Isolated cells were cultured overnight in hanging drops. When cells formed spheres, they were laid on floating filters at the air/medium interface. With this new culture system, pancreatic progenitor cells were induced to differentiate to endocrine and exocrine cells. It was shown that c-Kit and Sca-1 were expressed differently in embryonic pancreas at 12.5, 15.5, and 17.5 days of gestation. The expression of c-Kit and Sca-1 was the highest at 15.5 days of gestation. c-Kit rather than Sca-1 coexpressed with PDX-1, Ngn3, and insulin. Cells differentiated from c-Kit-positive cells contained more insulin-producing cells and secreted more insulin in response to glucose stimulation than that from c-Kit-negative cells. These results suggested that c-Kit could be used to isolate pancreatic progenitor cells and our new culture system permitted pancreatic progenitor cells to differentiate to mature endocrine cells.

Dynamic Proteomic Analysis of Pancreatic Mesenchyme Reveals Novel Factors That Enhance Human Embryonic Stem Cell to Pancreatic Cell Differentiation.

PubMed

Russ, Holger A; Landsman, Limor; Moss, Christopher L; Higdon, Roger; Greer, Renee L; Kaihara, Kelly; Salamon, Randy; Kolker, Eugene; Hebrok, Matthias

2016-01-01

Current approaches in human embryonic stem cell (hESC) to pancreatic beta cell differentiation have largely been based on knowledge gained from developmental studies of the epithelial pancreas, while the potential roles of other supporting tissue compartments have not been fully explored. One such tissue is the pancreatic mesenchyme that supports epithelial organogenesis throughout embryogenesis. We hypothesized that detailed characterization of the pancreatic mesenchyme might result in the identification of novel factors not used in current differentiation protocols. Supplementing existing hESC differentiation conditions with such factors might create a more comprehensive simulation of normal development in cell culture. To validate our hypothesis, we took advantage of a novel transgenic mouse model to isolate the pancreatic mesenchyme at distinct embryonic and postnatal stages for subsequent proteomic analysis. Refined sample preparation and analysis conditions across four embryonic and prenatal time points resulted in the identification of 21,498 peptides with high-confidence mapping to 1,502 proteins. Expression analysis of pancreata confirmed the presence of three potentially important factors in cell differentiation: Galectin-1 (LGALS1), Neuroplastin (NPTN), and the Laminin α-2 subunit (LAMA2). Two of the three factors (LGALS1 and LAMA2) increased expression of pancreatic progenitor transcript levels in a published hESC to beta cell differentiation protocol. In addition, LAMA2 partially blocks cell culture induced beta cell dedifferentiation. Summarily, we provide evidence that proteomic analysis of supporting tissues such as the pancreatic mesenchyme allows for the identification of potentially important factors guiding hESC to pancreas differentiation.

Dynamic Proteomic Analysis of Pancreatic Mesenchyme Reveals Novel Factors That Enhance Human Embryonic Stem Cell to Pancreatic Cell Differentiation

PubMed Central

Russ, Holger A.; Landsman, Limor; Moss, Christopher L.; Higdon, Roger; Greer, Renee L.; Kaihara, Kelly; Salamon, Randy; Kolker, Eugene; Hebrok, Matthias

2016-01-01

Current approaches in human embryonic stem cell (hESC) to pancreatic beta cell differentiation have largely been based on knowledge gained from developmental studies of the epithelial pancreas, while the potential roles of other supporting tissue compartments have not been fully explored. One such tissue is the pancreatic mesenchyme that supports epithelial organogenesis throughout embryogenesis. We hypothesized that detailed characterization of the pancreatic mesenchyme might result in the identification of novel factors not used in current differentiation protocols. Supplementing existing hESC differentiation conditions with such factors might create a more comprehensive simulation of normal development in cell culture. To validate our hypothesis, we took advantage of a novel transgenic mouse model to isolate the pancreatic mesenchyme at distinct embryonic and postnatal stages for subsequent proteomic analysis. Refined sample preparation and analysis conditions across four embryonic and prenatal time points resulted in the identification of 21,498 peptides with high-confidence mapping to 1,502 proteins. Expression analysis of pancreata confirmed the presence of three potentially important factors in cell differentiation: Galectin-1 (LGALS1), Neuroplastin (NPTN), and the Laminin α-2 subunit (LAMA2). Two of the three factors (LGALS1 and LAMA2) increased expression of pancreatic progenitor transcript levels in a published hESC to beta cell differentiation protocol. In addition, LAMA2 partially blocks cell culture induced beta cell dedifferentiation. Summarily, we provide evidence that proteomic analysis of supporting tissues such as the pancreatic mesenchyme allows for the identification of potentially important factors guiding hESC to pancreas differentiation. PMID:26681951

Pancreatic surgery.

PubMed

Donahue, Timothy R; Reber, Howard A

2013-09-01

To summarize published research on pancreatic surgery over the past year. A number of studies aiming to reduce the costs associated with pancreatic surgery were reported. Retrospective analyses confirmed previous findings that neither the routine use of pancreatic duct stents decreases the rate of fistula formation nor does placement of a drain at the time of surgery change the morbidity in patients who develop one. Minimally invasive approaches, both laparoscopic and robot-assisted, are being performed more frequently to remove pancreatic cancers. A randomized trial confirmed that reinforcement of stapled closure during distal pancreatectomy reduces the rate of fistula formation. Controversy remains over whether small pancreatic neuroendocrine tumors need to be surgically resected or can be treated nonoperatively. Patients with chronic pancreatitis should be screened thoroughly before being offered surgical treatment; two studies reported preoperative factors that can be used to identify those most likely to experience pain relief. Studies published on pancreatic surgery last year focused on a wide-range of topics. The morbidity and mortality of patients undergoing pancreatic surgery continues to improve, and we anticipate that incorporation of these new findings will lead to even better outcomes.

[Massive pleural effusion complicating chronic pancreatitis. Treatment by endoscopic closure of a pancreatic-mediastinal fistula].

PubMed

Trudzinski, F C; Rädle, J; Treiber, G; Kramm, T; Sybrecht, G W

2008-11-01

A 53-year-old man was admitted because of anuria, dyspnea and a septic temperature. The patients' history included chronic alcoholism, chronic pancreatitis, COPD and a right nephrectomy because of nephrolithiasis. Urosepsis was initially suspected. The patients' clinical condition and nutritional state were severely reduced. Laboratory findings revealed severe systemic inflammation (leucocyte count: 22.4/nl, CRP: 324 mg/l). Computed tomography showed a large left-sided pleural effusion, encapsulated abdominal fluid below the diaphragm and alongside the pancreatic tail. After aspiration of the pleural effusion the diagnosis of an exsudate with elevated concentration of lipase (56,000 U/l) was confirmed. Endoscopic ultrasound showed a 3-4 cm pseudocystic mass originating in the region of the pancreatic tail. The ERP depicted chronic pancreatitis with strictures and destruction of the pancreatic duct. Two fistulae were identified, one proximal to a ductal stricture in the pancreatic head and a second one in the pancreatic tail which corresponded to the reported pseudocyst. The patient was admitted to the ICU with symptoms of impending sepsis. The pleural effusion was treated with CT-guided chest drainage. The initial endoscopic attempt at stent closure of the fistula failed because it was possible to pass through the ductal stricture only with a thin hydrophilic wire and small-lumen catheter. However, injection of fibrin glue into the proximal pancreatic duct over a length of 2 cm obliterated the fistula and the pleural effusion was resolved. Pancreatic-pleural or pancreatic-mediastinal fistula is a rare complication of pancreatitis associated with unilateral pleural effusion. Combined internal endoscopic drainage and external chest drainage is the treatment of choice. After failure of routine endoscopic therapy, endoscopic closure of fistulas using fibrin glue might offer an alternative treatment strategy.

Surgical approaches to chronic pancreatitis: indications and imaging findings.

PubMed

Hafezi-Nejad, Nima; Singh, Vikesh K; Johnson, Stephen I; Makary, Martin A; Hirose, Kenzo; Fishman, Elliot K; Zaheer, Atif

2016-10-01

Chronic pancreatitis (CP) is an irreversible, inflammatory process characterized by progressive fibrosis of the pancreas that can result in abdominal pain, exocrine insufficiency, and diabetes. Inadequate pain relief using medical and/or endoscopic therapies is an indication for surgery. The surgical management of CP is centered around three main operations including pancreaticoduodenectomy (PD), duodenum-preserving pancreatic head resection (DPPHR) and drainage procedures, and total pancreatectomy with islet autotransplantation (TPIAT). PD is the method of choice when there is a high suspicion for malignancy. Combined drainage and resection procedures are associated with pain relief, higher quality of life, and superior short-term and long-term survival in comparison with the PD. TPIAT is a reemerging treatment that may be promising in subjects with intractable pain and impaired quality of life. Imaging examinations have an extensive role in pre-operative and post-operative evaluation of CP patients. Pre-operative advanced imaging examinations including CT and MRI can detect hallmarks of CP such as calcifications, pancreatic duct dilatation, chronic pseudocysts, focal pancreatic enlargement, and biliary ductal dilatation. Post-operative findings may include periportal hepatic edema, pneumobilia, perivascular cuffing and mild pancreatic duct dilation. Imaging can also be useful in the detection of post-operative complications including obstructions, anastomotic leaks, and vascular lesions. Imaging helps identify unique post-operative findings associated with TPIAT and may aid in predicting viability and function of the transplanted islet cells. In this review, we explore surgical indications as well as pre-operative and post-operative imaging findings associated with surgical options that are typically performed for CP patients.

Diagnosis of mild chronic pancreatitis (Cambridge classification): comparative study using secretin injection-magnetic resonance cholangiopancreatography and endoscopic retrograde pancreatography.

PubMed

Sai, Jin-Kan; Suyama, Masafumi; Kubokawa, Yoshihiro; Watanabe, Sumio

2008-02-28

To investigate the usefulness of secretin injection-MRCP for the diagnosis of mild chronic pancreatitis. Sixteen patients having mild chronic pancreatitis according to the Cambridge classification and 12 control subjects with no abnormal findings on the pancreatogram were examined for the diagnostic accuracy of secretin injection-MRCP regarding abnormal branch pancreatic ducts associated with mild chronic pancreatitis (Cambridge Classification), using endoscopic retrograde cholangiopancreatography (ERCP) for comparison. The sensitivity and specificity for abnormal branch pancreatic ducts determined by two reviewers were respectively 55%-63% and 75%-83% in the head, 57%-64% and 82%-83% in the body, and 44%-44% and 72%-76% in the tail of the pancreas. The sensitivity and specificity for mild chronic pancreatitis were 56%-63% and 92%-92%, respectively. Interobserver agreement (kappa statistics) concerning the diagnosis of an abnormal branch pancreatic duct and of mild chronic pancreatitis was good to excellent. Secretin injection-MRCP might be useful for the diagnosis of mild chronic pancreatitis.

Analysis of survival after pancreatic resection for oncological pathologies.

PubMed

Benzoni, Enrico; Rossit, Luca; Cojutti, Alessandro; Favero, Alessandro; Saccomano, Enrico; Zompicchiatti, Aron; Noce, Luigi; Bresadola, Fabrizio; Intini, Sergio

2007-01-01

Surgical treatment of pancreatic cancer is to date the only modality that offers a chance of long-term survival. Potentially curative surgery is an option for only about 15% of patients with pancreatic adenocarcinoma. The aim of this study was to determine the survival and to assess the association of clinical, pathological, and treatment features with survival of patients who underwent resection of pancreatic cancer at the Department of Surgery of Udine University Hospital. From November 1989 to December 2005, 137 consecutive patients, who underwent surgical procedures for pancreatic cancer, were followed in our department. We performed 76 pancreatico-duodenectomy, 26 distal pancreatectomies and 35 total pancreatectomies. The surgical reconstruction after pancreatico-duodenectomy was as follows: 11 closures of the main duct with manual nonabsorbable stitches, 24 closures of the main duct with a linear stapler, 17 occlusions of the main duct with neoprene glue and 24 duct-to-mucosa anastomoses. Mean survival time was 27.7 +/- 26.93 months (mean +/- SD) and mean disease-free survival time was 25.4 +/- 23.06 months (mean +/- SD). 1, 3, 5, 7 and 9-year survival rates were 63.9, 33.7, 21.17, 12.7 and 10.2%, respectively. Significant differences in survival were recorded by the Log-rank test for age > 70 (p = 0.001), surgical procedures (p = 0.00046) and presence of metastases (p = 0.0055) The treatment of pancreatic cancer is undertaken with two different aims. The first is radical surgery for patients with early-stage disease, mainly stage I and partly stage II. In all other cases, the aim of treatment is the palliation of the several distressing symptoms related to this cancer. The standard treatment option for resectable tumours is radical pancreatic resection according to the Whipple procedure or total pancreatectomy.

Dexamethasone treatment induces the reprogramming of pancreatic acinar cells to hepatocytes and ductal cells.

PubMed

Al-Adsani, Amani; Burke, Zoë D; Eberhard, Daniel; Lawrence, Katherine L; Shen, Chia-Ning; Rustgi, Anil K; Sakaue, Hiroshi; Farrant, J Mark; Tosh, David

2010-10-27

The pancreatic exocrine cell line AR42J-B13 can be reprogrammed to hepatocytes following treatment with dexamethasone. The question arises whether dexamethasone also has the capacity to induce ductal cells as well as hepatocytes. AR42J-B13 cells were treated with and without dexamethasone and analyzed for the expression of pancreatic exocrine, hepatocyte and ductal markers. Addition of dexamethasone inhibited pancreatic amylase expression, induced expression of the hepatocyte marker transferrin as well as markers typical of ductal cells: cytokeratin 7 and 19 and the lectin peanut agglutinin. However, the number of ductal cells was low compared to hepatocytes. The proportion of ductal cells was enhanced by culture with dexamethasone and epidermal growth factor (EGF). We established several features of the mechanism underlying the transdifferentiation of pancreatic exocrine cells to ductal cells. Using a CK19 promoter reporter, we show that a proportion of the ductal cells arise from differentiated pancreatic exocrine-like cells. We also examined whether C/EBPβ (a transcription factor important in the conversion of pancreatic cells to hepatocytes) could alter the conversion from acinar cells to a ductal phenotype. Overexpression of an activated form of C/EBPβ in dexamethasone/EGF-treated cells provoked the expression of hepatocyte markers and inhibited the expression of ductal markers. Conversely, ectopic expression of a dominant-negative form of C/EBPβ, liver inhibitory protein, inhibited hepatocyte formation in dexamethasone-treated cultures and enhanced the ductal phenotype. These results indicate that hepatocytes and ductal cells may be induced from pancreatic exocrine AR42J-B13 cells following treatment with dexamethasone. The conversion from pancreatic to hepatocyte or ductal cells is dependent upon the expression of C/EBPβ.

Endocrine pancreatic development: impact of obesity and diet

PubMed Central

O'Dowd, Jacqueline F.; Stocker, Claire J.

2013-01-01

During embryonic development, multipotent endodermal cells differentiate to form the pancreas. Islet cell clusters arising from the pancreatic bud form the acini tissue and exocrine ducts whilst pancreatic islets form around the edges of the clusters. The successive steps of islet differentiation are controlled by a complex network of transcription factors and signals that influence cell differentiation, growth and lineage. A Westernized lifestyle has led to an increased consumption of a high saturated fat diet, and an increase in maternal obesity. The developing fetus is highly sensitive to the intrauterine environment, therefore any alteration in maternal nutrition during gestation and lactation which affects the in-utero environment during the key developmental phases of the pancreas may change the factors controlling β-cell development and β-cell mass. Whilst the molecular mechanisms behind the adaptive programming of β-cells are still poorly understood it is established that changes arising from maternal obesity and/or over-nutrition may affect the ability to maintain fetal β-cell mass resulting in an increased risk of type 2 diabetes in adulthood. PMID:23882220

FGF7 and cell density are required for final differentiation of pancreatic amylase-positive cells from human ES cells.

PubMed

Takizawa-Shirasawa, Sakiko; Yoshie, Susumu; Yue, Fengming; Mogi, Akimi; Yokoyama, Tadayuki; Tomotsune, Daihachiro; Sasaki, Katsunori

2013-12-01

The major molecular signals of pancreatic exocrine development are largely unknown. We examine the role of fibroblast growth factor 7 (FGF7) in the final induction of pancreatic amylase-containing exocrine cells from induced-pancreatic progenitor cells derived from human embryonic stem (hES) cells. Our protocol consisted in three steps: Step I, differentiation of definitive endoderm (DE) by activin A treatment of hES cell colonies; Step II, differentiation of pancreatic progenitor cells by re-plating of the cells of Step I onto 24-well plates at high density and stimulation with all-trans retinoic acid; Step III, differentiation of pancreatic exocrine cells with a combination of FGF7, glucagon-like peptide 1 and nicotinamide. The expression levels of pancreatic endodermal markers such as Foxa2, Sox17 and gut tube endoderm marker HNF1β were up-regulated in both Step I and II. Moreover, in Step III, the induced cells expressed pancreatic markers such as amylase, carboxypeptidase A and chymotrypsinogen B, which were similar to those in normal human pancreas. From day 8 in Step III, cells immunohistochemically positive for amylase and for carboxypeptidase A, a pancreatic exocrine cell product, were induced by FGF7. Pancreatic progenitor Pdx1-positive cells were localized in proximity to the amylase-positive cells. In the absence of FGF7, few amylase-positive cells were identified. Thus, our three-step culture protocol for human ES cells effectively induces the differentiation of amylase- and carboxypeptidase-A-containing pancreatic exocrine cells.

Interrogation of Multidrug Resistance (MDR1) P-glycoprotein (Pgp, ABCB1) Expression in Human Pancreatic Carcinoma Cells: Correlation of 99mTc-Sestamibi Uptake with Western Blot Analysis

PubMed Central

Harpstrite, Scott E.; Gu, Hannah; Natarajan, Radhika; Sharma, Vijay

2014-01-01

Objective Histopathological studies indicate approximately 63% of pancreatic tumors express MDR1 Pgp and its polymorphic variants. However, Pgp expression detected at the messenger RNA or protein level does not always correlate with functional transport activity. Because Pgp transport activity is affected by specific mutations as well as the phosphorylation state of the protein, altered or less active forms of Pgp may also be detected by PCR or immunohistochemistry, which do not accurately reflect the status of tumor cell resistance. To interrogate status of functional expression of MDR1 Pgp in MiaPaCa-2 and PANC-1 cells, cellular transport studies using 99mTc-Sestamibi were performed and correlated with western blot analysis. Methods Biochemical transport assays in human pancreatic carcinoma MiaPaCa-2 and PANC-1 cells, human epidermal carcinoma drug sensitive KB-3-1 cells and human breast carcinoma MCF-7 cells (negative controls), and human epidermal carcinoma drug resistant KB-8-5 cells, human breast carcinoma stably transfected with Pgp MCF-7/MDR1Pgp cells, and liver carcinoma HepG2 cells (positive controls) were performed. Protein levels were determined using a monoclonal antibody C219. Results 99mTc-Sestamibi demonstrates accumulation in human pancreatic carcinoma MiaPaCa-2 and PANC-1 cells. Uptake profiles are not affected by treatment with LY335979, a Pgp-inhibitor, and correlate to Western blot analysis. Conclusions These cellular transport studies indicate an absence of Pgp at a functional level in MiaPaCa-2 and PANC-1 cells. Because major pancreatic tumors originate from pancreatic duct and 99mTc-Sestamibi undergoes a dominant hepatobiliary mode of excretion, it would not be a sensitive probe for imaging pancreatic adenocarcinomas. Following interrogation of the functional status of Pgp in other pancreatic carcinoma cells, chemotherapeutic drugs that are also MDR1 substrates could offer alternative therapeutics for treating pancreatic adenocarcinomas

Acute recurrent pancreatitis: Etiopathogenesis, diagnosis and treatment

PubMed Central

Testoni, Pier Alberto

2014-01-01

Acute recurrent pancreatitis (ARP) refers to a clinical entity characterized by episodes of acute pancreatitis which occurs on more than one occasion. Recurrence of pancreatitis generally occurs in a setting of normal morpho-functional gland, however, an established chronic disease may be found either on the occasion of the first episode of pancreatitis or during the follow-up. The aetiology of ARP can be identified in the majority of patients. Most common causes include common bile duct stones or sludge and bile crystals; sphincter of oddi dysfunction; anatomical ductal variants interfering with pancreatic juice outflow; obstruction of the main pancreatic duct or pancreatico-biliary junction; genetic mutations; alcohol consumption. However, despite diagnostic technologies, the aetiology of ARP still remains unknown in up to 30% of cases: in these cases the term “idiopathic” is used. Because occult bile stone disease and sphincter of oddi dysfunction account for the majority of cases, cholecystectomy, and eventually the endoscopic biliary and/or pancreatic sphincterotomy are curative in most of cases. Endoscopic biliary sphincterotomy appeared to be a curative procedure per se in about 80% of patients. Ursodeoxycholic acid oral treatment alone has also been reported effective for treatment of biliary sludge. In uncertain cases toxin botulin injection may help in identifying some sphincter of oddi dysfunction, but this treatment is not widely used. In the last twenty years, pancreatic endotherapy has been proven effective in cases of recurrent pancreatitis depending on pancreatic ductal obstruction, independently from the cause of obstruction, and has been widely used instead of more aggressive approaches. PMID:25493002

Neurotensin protects pancreatic beta cells from apoptosis.

PubMed

Coppola, Thierry; Béraud-Dufour, Sophie; Antoine, Aurélie; Vincent, Jean-Pierre; Mazella, Jean

2008-01-01

The survival of pancreatic beta cells depends on the balance between external cytotoxic and protective molecular systems. The neuropeptide neurotensin (NT) has been shown to regulate certain functions of the endocrine pancreas including insulin and glucagon release. However, the mechanism of action of NT as well as the identification of receptors involved in the pancreatic functions of the peptide remained to be studied. We demonstrate here that NT is an efficient protective agent of pancreatic beta cells against cytotoxic agents. Both beta-TC3 and INS-1E cell lines and the mouse pancreatic islet cells express the three known NT receptors. The incubation of beta cells with NT protects cells from apoptosis induced either by staurosporine or by IL-1beta. In beta-TC3 cells, NT activates both MAP and PI-3 kinases pathways and strongly reduces the staurosporine or the Il-1beta-induced caspase-3 activity by a mechanism involving Akt activation. The NTSR2 agonist levocabastine displays the same protective effect than NT whereas the NTSR1 antagonist is unable to block the effect of NT suggesting the predominant involvement of the NTSR2 in the action of NT on beta cells. These results clearly indicate for the first time that NT is able to protect endocrine beta cells from external cytotoxic agents, a role well correlated with its release in the circulation after a meal.

Combined Endoscopic-Radiological Rendezvous for Distal Tail Postoperative Pancreatic Fistula (POPF)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lucatelli, Pierleone, E-mail: pierleone.lucatelli@gmail.com; Sacconi, Beatrice, E-mail: beatrice.sacconi@fastwebnet.it; Cereatti, Fabrizio, E-mail: fcereatti@yahoo.com

Postoperative pancreatic fistula (POPF) with leakage of pancreatic juice is a rare, severe complication following pancreatic resection or, less commonly, splenectomy. Definitive treatment can require multidisciplinary approaches. We report a case of stenosis of the main pancreatic duct with distal tail GRADE C POPF, occurred after splenectomy for Hodgkin lymphoma, successfully treated with combined radiological-endoscopic approach.

Role of CCK-A receptor for pancreatic function in mice: a study in CCK-A receptor knockout mice.

PubMed

Takiguchi, Soichi; Suzuki, Shinji; Sato, Yuko; Kanai, Setsuko; Miyasaka, Kyoko; Jimi, Atsuo; Shinozaki, Hirotsugu; Takata, Yutaka; Funakoshi, Akihiro; Kono, Akira; Minowa, Osamu; Kobayashi, Tomoko; Noda, Tetsuo

2002-04-01

The cholecystokinin (CCK) family of peptides and receptors is present throughout the brain and gastrointestinal tract. The CCK receptors can be pharmacologically subdivided into two subtypes: CCK-A and CCK-B. CCK-A receptor is enriched in the pancreas of mice. To determine pancreatic functions in a CCK-A receptor deficient mouse mutant generated by gene targeting in embryonic stem cells. The targeting vector contained lacZ and neo insertions in exon 2. To examine exocrine functions, amylase release from the dispersed acini in vitro was examined. In the in vivo study, the mixture of bile-pancreatic juice was collected, and amylase, bicarbonate, and bile acid outputs were determined after the administration of various stimulants. The cystic duct of the gallbladder and the pylorus were ligated to exclude the involvement of gallbladder contraction and gastric acid. Pancreatic enzyme content was measured, and histologic examinations by HE and lacZ staining were conducted. To examine endocrine functions, oral glucose tolerance test (2 g/kg) was determined. The body weight, pancreatic wet weight, and enzyme content in the pancreas were similar among the three genotypes. Amylase release in vivo and in vitro and bicarbonate secretion in vivo were not stimulated by CCK-8 in CCK-AR (-/-) mice, whereas the responses to other stimulants were substantial in (-/-) mice. Administration of secretin did not increase bicarbonate secretion regardless of genotype. A normal glucose tolerance was observed in (-/-) mice. Acinar cells, islets, and duct cells were stained by lacZ, and HE staining revealed no pathologic findings. The CCK-A receptor is important for pancreatic exocrine secretion, but not essential for maintaining glucose concentration and pancreatic growth in mice.

Duodenal Loop Obstruction as an Unusual Cause of Acute Pancreatitis: A Case Series.

PubMed

Lee, Hyeonmin; Choi, Yonghyeok; Jeong, Hyewon; Lim, Jae Kyu; Jung, Taeyoung; Han, Joung Ho; Park, Seon Mee

2016-12-25

Duodenal loop obstruction is an unusual cause of acute pancreatitis. Increased intraluminal pressure hinders pancreatic flow, causing dilatation of the pancreatic duct and inducing acute pancreatitis. We experienced three cases of acute pancreatitis that resulted from duodenal loop obstruction after (1) an esophagectomy with gastric pull-up procedure for esophageal cancer, (2) a gastrectomy with Billroth I reconstruction for gastric cancer, and (3) a gastrojejunostomy for abdominal trauma. An abdominal CT scan revealed a distended duodenal loop, dilated pancreatic duct, and inflamed pancreas with fluid collection. Acute pancreatitis with duodenal loop obstruction was diagnosed by abdominal pain, elevated serum amylase/lipase, and abdominal CT findings. Immediate decompression with a nasogastric tube was performed, and all patients showed improvement within one week after admission. Each patient was followed up for more than two years without recurrence. Our findings suggest the usefulness of nasogastric tube decompression as the first line of treatment for acute pancreatitis related to duodenal loop obstruction.

Unique Aspects of Cryptochrome in Chronobiology and Metabolism, Pancreatic β-Cell Dysfunction, and Regeneration: Research into Cysteine414-Alanine Mutant CRY1.

PubMed

Okano, Satoshi

2016-01-01

Cryptochrome proteins (CRYs), which can bind noncovalently to cofactor (chromophore) flavin adenine dinucleotide (FAD), occur widely among organisms. CRYs play indispensable roles in the generation of circadian rhythm in mammals. Transgenic mice (Tg mice), ubiquitously expressing mouse CRY1 having a mutation in which cysteine414 (the zinc-binding site of CRY1) being replaced with alanine, display unique phenotypes in their circadian rhythms. Moreover, male Tg mice exhibit symptoms of diabetes characterized by beta-cell dysfunction, resembling human maturity onset diabetes of the young (MODY). The lowered proliferation of β -cells is a primary cause of age-dependent β -cell loss. Furthermore, unusually enlarged duct-like structures developed prominently in the Tg mice pancreases. The duct-like structures contained insulin-positive cells, suggesting neogenesis of β -cells in the Tg mice. This review, based mainly on the author's investigation of the unique features of Tg mice, presents reported results and recent findings related to molecular processes associated with mammalian cryptochromes, especially their involvement in the regulation of metabolism. New information is described with emphasis on the aspects of islet architecture, pancreatic β -cell dysfunction, and regeneration.

Conservative treatment of chronic pancreatitis.

PubMed

Löhr, J-Matthias; Haas, Stephen L; Lindgren, Fredrik; Enochsson, Lars; Hedström, Aleksandra; Swahn, Fredrik; Segersvärd, Ralf; Arnelo, Urban

2013-01-01

Chronic pancreatitis is a progressive inflammatory disease giving rise to several complications that need to be treated accordingly. Because pancreatic surgery has significant morbidity and mortality, less invasive therapy seems to be an attractive option. This paper reviews current state-of-the-art strategies to treat chronic pancreatitis without surgery and the current guidelines for the medical therapy of chronic pancreatitis. Endoscopic therapy of complications of chronic pancreatitis such as pain, main pancreatic duct strictures and stones as well as pseudocysts is technically feasible and safe. The long-term outcome, however, is inferior to definitive surgical procedures such as resection or drainage. On the other hand, the medical therapy of pancreatic endocrine and exocrine insufficiency is well established and evidence based. Endoscopic therapy may be an option to bridge for surgery and in children/young adolescents and those unfit for surgery. Pain in chronic pancreatitis as well as treatment of pancreatic exocrine insufficiency follows established guidelines. Copyright © 2013 S. Karger AG, Basel.

Pain in Patients with Pancreatic Cancer: Prevalence, Mechanisms, Management and Future Developments.

PubMed

Koulouris, Andreas I; Banim, Paul; Hart, Andrew R

2017-04-01

Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patients' quality of life and survival.

Pancreatic stellate cells: a starring role in normal and diseased pancreas

PubMed Central

Apte, Minoti V.; Pirola, Romano C.; Wilson, Jeremy S.

2012-01-01

While the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC), had remained undiscovered until as recently as 20 years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas—chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies have also implied other functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans. During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumor growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer. PMID:22973234

Pancreatic stellate cells: a starring role in normal and diseased pancreas.

PubMed

Apte, Minoti V; Pirola, Romano C; Wilson, Jeremy S

2012-01-01

While the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC), had remained undiscovered until as recently as 20 years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas-chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies have also implied other functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans. During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumor growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer.

EF5 and Motexafin Lutetium in Detecting Tumor Cells in Patients With Abdominal or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2013-01-15

Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Fallopian Tube Cancer; Gastrointestinal Stromal Tumor; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Gastrointestinal Carcinoid Tumor; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Primary Peritoneal Cavity Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Adult Soft Tissue Sarcoma; Recurrent Colon Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Small Intestine Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage 0 Non-small Cell Lung Cancer; Stage I Adult Soft Tissue Sarcoma; Stage I Colon Cancer; Stage I Gastric Cancer; Stage I Non-small Cell Lung Cancer; Stage I Ovarian Epithelial Cancer; Stage I Ovarian Germ Cell Tumor; Stage I Pancreatic Cancer; Stage I Rectal Cancer; Stage I Uterine Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage II Colon Cancer; Stage II Gastric Cancer; Stage II Non-small Cell Lung Cancer; Stage II Ovarian Epithelial Cancer; Stage II Ovarian Germ Cell Tumor; Stage II Pancreatic Cancer; Stage II Rectal Cancer; Stage II Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Colon Cancer; Stage III Gastric Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Uterine Sarcoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage IV Colon Cancer; Stage

Pancreatic acinar cells-derived cyclophilin A promotes pancreatic damage by activating NF-κB pathway in experimental pancreatitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Ge; Wan, Rong; Hu, Yanling

2014-01-31

Highlights: • CypA is upregulated in experimental pancreatitis. • CCK induces expression and release of CypA in acinar cell in vitro. • rCypA aggravates CCK-induced acinar cell death and inflammatory cytokine production. • rCypA activates the NF-κB pathway in acinar cells in vitro. - Abstract: Inflammation triggered by necrotic acinar cells contributes to the pathophysiology of acute pancreatitis (AP), but its precise mechanism remains unclear. Recent studies have shown that Cyclophilin A (CypA) released from necrotic cells is involved in the pathogenesis of several inflammatory diseases. We therefore investigated the role of CypA in experimental AP induced by administration ofmore » sodium taurocholate (STC). CypA was markedly upregulated and widely expressed in disrupted acinar cells, infiltrated inflammatory cells, and tubular complexes. In vitro, it was released from damaged acinar cells by cholecystokinin (CCK) induction. rCypA (recombinant CypA) aggravated CCK-induced acinar cell necrosis, promoted nuclear factor (NF)-κB p65 activation, and increased cytokine production. In conclusion, CypA promotes pancreatic damage by upregulating expression of inflammatory cytokines of acinar cells via the NF-κB pathway.« less

Nuclear receptors in pancreatic tumor cells.

PubMed

Damaskos, Christos; Garmpis, Nikolaos; Karatzas, Theodore; Kostakis, Ioannis D; Nikolidakis, Lampros; Kostakis, Alkiviadis; Kouraklis, Gregory

2014-12-01

This review focuses on nuclear receptors expressed in pancreatic cancer. An extensive search of articles published up to March 2013 was conducted using the MEDLINE database. The key words used were "pancreatic cancer", "molecular receptors" and "growth factors". A total of 112 articles referred to pancreatic cancer, molecular receptors and/or growth factors were included. Receptors of growth factors, such as the epithelial growth factor receptor, insulin-like growth factor-1 receptor, vascular endothelial growth factor receptor and others, such as integrin α5β1, somatostatin receptors, the death receptor 5, claudin, notch receptors, mesothelin receptors, follicle-stimulating hormone receptors, the MUC1 receptor, the adrenomedullin receptor, the farnesoid X receptor, the transferrin receptor, sigma-2 receptors, the chemokine receptor CXCR4, the urokinase plasminogen activator receptor, the ephrine A2 receptor, the GRIA3 receptor, the RON receptor and the angiotensin II receptor AT-1 are expressed in pancreatic tumor cells. These molecules are implicated in tumor growth, apoptosis, angiogenesis, metastasis etc. After identifying the molecular receptors associated with the pancreatic cancer, many more target molecules playing important roles in tumor pathophysiology and senescence-associated signal transduction in cancer cells will be identified. This may have a significant influence on diagnosis, therapy and prognosis of pancreatic cancer. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The potent activation of Ca(2+)-activated K(+) current by NVP-AUY922 in the human pancreatic duct cell line (PANC-1) possibly independent of heat shock protein 90 inhibition.

PubMed

Chiang, Nai-Jung; Wu, Sheng-Nan; Chen, Li-Tzong

2015-04-01

NVP-AUY922 (AUY) is a potent inhibitor of heat shock protein 90 (HSP90). Whether this compound can exert additional effects on membrane ion channels remains elusive. We investigated the effect of AUY on ion currents in human pancreatic duct epithelial cells (PDECs), including PANC-1 and MIA PaCa-2. AUY increased the amplitude of the K(+) current (IK) in PANC-1 cells shown by whole-cell configuration. Single-channel recordings revealed a large-conductance Ca(2+)-activated K(+) (BKCa) channel in PANC-1, but not in MIA PaCa-2. In cell-attached mode, AUY increased the probability of BKCa channel opening and also potentiated the activity of stretch-induced channels. However, other HSP inhibitors, 17-AAG or BIIB021 only slightly increased the activity of BKCa channels. In inside-out recordings, sodium hydrosulphide or caffeic acid phenethyl ester increased the activity of BKCa channels, but AUY did not. We further evaluated whether conductance of Ca(2+)-activated K(+) channels (IK(Ca)) influenced secretion of HCO3(-) and fluid in PDECs by using a modified Whitcomb-Ermentrout model. Simulation studies showed that an increase in IK(Ca) resulted in additional secretion of HCO3(-) and fluid by mimicking the effect of AUY in PDECs. Collectively, AUY can interact with the BKCa channel to largely increase IK(Ca) in PDECs. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

The Inactivation of Arx in Pancreatic α-Cells Triggers Their Neogenesis and Conversion into Functional β-Like Cells

PubMed Central

Courtney, Monica; Gjernes, Elisabet; Druelle, Noémie; Ravaud, Christophe; Vieira, Andhira; Ben-Othman, Nouha; Pfeifer, Anja; Avolio, Fabio; Leuckx, Gunter; Lacas-Gervais, Sandra; Burel-Vandenbos, Fanny; Ambrosetti, Damien; Hecksher-Sorensen, Jacob; Ravassard, Philippe; Heimberg, Harry; Mansouri, Ahmed; Collombat, Patrick

2013-01-01

Recently, it was demonstrated that pancreatic new-born glucagon-producing cells can regenerate and convert into insulin-producing β-like cells through the ectopic expression of a single gene, Pax4. Here, combining conditional loss-of-function and lineage tracing approaches, we show that the selective inhibition of the Arx gene in α-cells is sufficient to promote the conversion of adult α-cells into β-like cells at any age. Interestingly, this conversion induces the continuous mobilization of duct-lining precursor cells to adopt an endocrine cell fate, the glucagon+ cells thereby generated being subsequently converted into β-like cells upon Arx inhibition. Of interest, through the generation and analysis of Arx and Pax4 conditional double-mutants, we provide evidence that Pax4 is dispensable for these regeneration processes, indicating that Arx represents the main trigger of α-cell-mediated β-like cell neogenesis. Importantly, the loss of Arx in α-cells is sufficient to regenerate a functional β-cell mass and thereby reverse diabetes following toxin-induced β-cell depletion. Our data therefore suggest that strategies aiming at inhibiting the expression of Arx, or its molecular targets/co-factors, may pave new avenues for the treatment of diabetes. PMID:24204325

Proximal migration of transanastomotic pancreatic stent following pancreaticoduodenectomy and pancreaticojejunostomy.

PubMed

Ammori, B J; White, C M

1999-06-01

The use of catheters to stent the pancreaticojejunal anastomosis following pancreaticoduodenectomy is practiced by some surgeons. Their long-term effects in this setting, however, remain unknown. A 60-yr-old woman underwent a potentially curative pylorus preserving pancreaticoduodenectomy for Stage I ampullary carcinoma. Roux-en-Y pancreaticojejunostomy was constructed over a short stent. She presented 4 yr later with abdominal pain, steatorrhea, and weight loss. Computed tomography revealed a stent within the proximal pancreatic duct, with gross upstream ductal dilatation and parenchymal features of chronic pancreatitis. Laparotomy revealed no disease recurrence. The stent, removed through a jejunotomy, was occluded. On-table pancreatogram demonstrated a 3-cm proximal duct stricture. Drainage was achieved with a lateral pancreaticojejunostomy (modified Puestow procedure). Recovery was uneventful, with clinical recovery of pancreatic exocrine function at 6 mo follow-up. Proximal migration of transanastomotic pancreatic stent with subsequent development of chronic pancreatitis is a potential complication following pancreaticoduodenectomy. It can be managed effectively with stent removal and a lateral pancreaticojejunostomy.

Afatinib Dimaleate and Capecitabine in Treating Patients With Advanced Refractory Solid Tumors, Pancreatic Cancer or Biliary Cancer

ClinicalTrials.gov

2017-10-26

Advanced Malignant Solid Neoplasm; Bile Duct Carcinoma; Recurrent Malignant Solid Neoplasm; Recurrent Pancreatic Carcinoma; Stage III Pancreatic Cancer AJCC v6 and v7; Stage IVA Pancreatic Cancer; Stage IVB Pancreatic Cancer

Pancreatic stellate cell: physiologic role, role in fibrosis and cancer.

PubMed

Apte, Minote; Pirola, Romano C; Wilson, Jeremy S

2015-09-01

Ever since the first descriptions of methods to isolate pancreatic stellate cells (PSCs) from rodent and human pancreas 17 years ago, rapid advances have been made in our understanding of the biology of these cells and their functions in health and disease. This review updates recent literature in the field, which indicates an increasingly complex role for the cells in normal pancreas, pancreatitis and pancreatic cancer. Work reported over the past 12 months includes improved methods of PSC immortalization, a role for PSCs in islet fibrosis, novel factors causing PSC activation as well as those inducing quiescence, and translational research aimed at inhibiting the facilitatory effects of PSCs on disease progression in chronic pancreatitis as well as pancreatic cancer. Improved understanding of the role of PSCs in pancreatic pathophysiology has prompted a focus on translational studies aimed at developing novel approaches to modulate PSC function in a bid to improve clinical outcomes of two major fibrotic diseases of the pancreas: chronic pancreatitis and pancreatic cancer.

Gastro-pancreaticojejunostomy for treatment of pancreatic ductal obstruction in a post-Whipple procedure patient.

PubMed

Rodrigues-Pinto, Eduardo; Grimm, Ian S; Baron, Todd H

2015-01-01

We report a case of a woman with a medical history of classic Whipple surgery who underwent endoscopic ultrasound (EUS)-guided pancreatic drainage due to smouldering acute pancreatitis secondary to an obstructing pancreatic ductal stone. A gastro-pancreaticojejunostomy anastomosis was created anterogradely, with dilation of both the anastomoses in the same procedure, with subsequent decompression of the pancreatic duct. Endoscopic retrograde pancreatography (ERP) is often impossible to perform in patients with post-Whipple procedure anatomy due to inaccessibility to the pancreaticojejunostomy anastomosis. EUS-guided pancreatic drainage may be offered in these patients in whom the pancreatic duct cannot be accessed at ERP. It has been used as a platform for access to and drainage of the pancreatic duct either by rendezvous or transmural drainage. However, only one of four patients achieve successful completion of the rendezvous procedure. There are limited data regarding safety and long-term outcome of this procedure, as well as scant guidelines on the optimal time for leaving stents in place. We believe definitive endoscopic therapy should be attempted, whenever possible, after relief of obstruction. In our case, we expect that stent occlusion is inevitable and that long-term drainage is possible due to drainage occurring between the stent and the stone.

Collecting Duct Intercalated Cell Function and Regulation

PubMed Central

Roy, Ankita; Al-bataineh, Mohammad M.

2015-01-01

Intercalated cells are kidney tubule epithelial cells with important roles in the regulation of acid-base homeostasis. However, in recent years the understanding of the function of the intercalated cell has become greatly enhanced and has shaped a new model for how the distal segments of the kidney tubule integrate salt and water reabsorption, potassium homeostasis, and acid-base status. These cells appear in the late distal convoluted tubule or in the connecting segment, depending on the species. They are most abundant in the collecting duct, where they can be detected all the way from the cortex to the initial part of the inner medulla. Intercalated cells are interspersed among the more numerous segment-specific principal cells. There are three types of intercalated cells, each having distinct structures and expressing different ensembles of transport proteins that translate into very different functions in the processing of the urine. This review includes recent findings on how intercalated cells regulate their intracellular milieu and contribute to acid-base regulation and sodium, chloride, and potassium homeostasis, thus highlighting their potential role as targets for the treatment of hypertension. Their novel regulation by paracrine signals in the collecting duct is also discussed. Finally, this article addresses their role as part of the innate immune system of the kidney tubule. PMID:25632105

The pancreatic stellate cell: a star on the rise in pancreatic diseases

PubMed Central

Omary, M. Bishr; Lugea, Aurelia; Lowe, Anson W.; Pandol, Stephen J.

2007-01-01

Pancreatic stellate cells (PaSCs) are myofibroblast-like cells found in the areas of the pancreas that have exocrine function. PaSCs are regulated by autocrine and paracrine stimuli and share many features with their hepatic counterparts, studies of which have helped further our understanding of PaSC biology. Activation of PaSCs induces them to proliferate, to migrate to sites of tissue damage, to contract and possibly phagocytose, and to synthesize ECM components to promote tissue repair. Sustained activation of PaSCs has an increasingly appreciated role in the fibrosis that is associated with chronic pancreatitis and with pancreatic cancer. Therefore, understanding the biology of PaSCs offers potential therapeutic targets for the treatment and prevention of these diseases. PMID:17200706

Pancreatic trauma: A concise review

PubMed Central

Debi, Uma; Kaur, Ravinder; Prasad, Kaushal Kishor; Sinha, Saroj Kant; Sinha, Anindita; Singh, Kartar

2013-01-01

Traumatic injury to the pancreas is rare and difficult to diagnose. In contrast, traumatic injuries to the liver, spleen and kidney are common and are usually identified with ease by imaging modalities. Pancreatic injuries are usually subtle to identify by different diagnostic imaging modalities, and these injuries are often overlooked in cases with extensive multiorgan trauma. The most evident findings of pancreatic injury are post-traumatic pancreatitis with blood, edema, and soft tissue infiltration of the anterior pararenal space. The alterations of post-traumatic pancreatitis may not be visualized within several hours following trauma as they are time dependent. Delayed diagnoses of traumatic pancreatic injuries are associated with high morbidity and mortality. Imaging plays an important role in diagnosis of pancreatic injuries because early recognition of the disruption of the main pancreatic duct is important. We reviewed our experience with the use of various imaging modalities for diagnosis of blunt pancreatic trauma. PMID:24379625

Endoscopic versus surgical drainage treatment of calcific chronic pancreatitis.

PubMed

Jiang, Li; Ning, Deng; Cheng, Qi; Chen, Xiao-Ping

2018-04-21

Endoscopic therapy and surgery are both conventional treatments to remove pancreatic duct stones that developed during the natural course of chronic pancreatitis. However, few studies comparing the effect and safety between surgery drainage and endoscopic drainage (plus Extracorporeal Shock Wave Lithotripsy, ESWL).The aim of this study was to compare the benefits between endoscopic and surgical drainage of the pancreatic duct for patients with calcified chronic pancreatitis. A total of 86 patients were classified into endoscopic/ESWL (n = 40) or surgical (n = 46) treatment groups. The medical records of these patients were retrospectively analyzed. Pain recurrence and hospital stays were similar between the endoscopic/ESWL treatment and surgery group. However, endoscopic/ESWL treatment yielded significantly lower medical expense and less complications compared with the surgical treatment. In selective patients, endoscopic/ESWL treatment could achieve comparable efficacy to the surgical treatment. With lower medical expense and less complications, endoscopic/ESWL treatment would be much preferred to be the initial treatment of choice for patients with calcified chronic pancreatitis. Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Contribution of partial pancreatectomy, systemic hormone delivery, and duct obliteration to glucose regulation in canine pancreas. Importance in pancreas transplantation.

PubMed

van der Burg, M P; Gooszen, H G; Guicherit, O R; Jansen, J B; Frölich, M; van Haastert, F A; Lamers, C B

1989-09-01

Our aim was to isolate and determine the contribution of partial pancreatectomy, systemic delivery of pancreatic hormones, and duct obliteration to glucose regulation after segmental pancreas transplantation in dogs. Fasting, postprandial, and intravenous glucose-stimulated glucose, insulin, glucagon, pancreatic polypeptide (PP), and cholecystokinin (CCK) and intravenous bombesin-stimulated PP levels were studied in beagles at three successive intervals in a crossover design. The first was 6 wk after partial (approximately 70%) pancreatectomy with intact regular enteric exocrine drainage from the duodenal pancreatic remnant, the next was 2 wk after venous transposition with systemic delivery of pancreatic hormones, and the third was 6 wk after in situ duct obliteration of the remnant. With partial pancreatectomy, K values were modestly diminished (30%), and a concomitant reduction of second-phase intravenous glucose-stimulated insulin release was observed. Other parameters were not significantly affected. Venous transposition doubled peripheral plasma levels of insulin under all conditions. Fasting glucose, PP, and CCK levels decreased slightly. Other parameters were not affected. Duct obliteration of the systemic draining pancreatic remnants seriously impaired glucose sensitivity, resulting in a 50% reduction of K values and fasting and sustained postprandial hyperglycemia (approximately 8 mM) and a 70-50% reduction (acute and overall responses, respectively) of intravenous glucose-stimulated insulin. Fasting hormone and postprandial insulin, glucagon, and CCK levels were not affected. The postprandial PP response was severely reduced, and bombesin-stimulated PP release was abolished by duct obliteration. We conclude that histological changes associated with duct obliteration are the major determinants of glucose regulation in segmental pancreas transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cigarette Smoke Induces Stem Cell Features of Pancreatic Cancer Cells via PAF1.

PubMed

Nimmakayala, Rama Krishna; Seshacharyulu, Parthasarathy; Lakshmanan, Imayavaramban; Rachagani, Satyanarayana; Chugh, Seema; Karmakar, Saswati; Rauth, Sanchita; Vengoji, Raghupathy; Atri, Pranita; Talmon, Geoffrey A; Lele, Subodh M; Smith, Lynette M; Thapa, Ishwor; Bastola, Dhundy; Ouellette, Michel M; Batra, Surinder K; Ponnusamy, Moorthy P

2018-06-01

Cigarette smoking is a major risk factor for pancreatic cancer. Aggressive pancreatic tumors contain cancer cells with stem cell features. We investigated whether cigarette smoke induces stem cell features in pancreatic cancer cells. Kras G12D ; Pdx1-Cre (KC) mice were exposed to cigarette smoke or clean air (controls) for up to 20 weeks; pancreata were collected and analyzed by histology, quantitative reverse transcription PCR, and confocal immunofluorescence microscopy. HPNE and Capan1 cells were exposed to cigarette smoke extract (CSE), nicotine and nicotine-derived carcinogens (NNN or NNK), or clean air (controls) for 80 days and evaluated for stem cell markers and features using flow cytometry-based autofluorescence, sphere formation, and immunoblot assays. Proteins were knocked down in cells with small interfering RNAs. We performed RNA sequencing analyses of CSE-exposed cells. We used chromatin immunoprecipitation assays to confirm the binding of FOS like 1, AP-1 transcription factor subunit (FOSL1) to RNA polymerase II-associated factor (PAF1) promoter. We obtained pancreatic ductal adenocarcinoma (PDAC) and matched non-tumor tissues (n=15) and performed immunohistochemical analyses. Chronic exposure of HPNE and Capan1 cells to CSE caused them to increase markers of stem cells, including autofluorescence and sphere formation, compared to control cells. These cells increased expression of ABCG2, SOX9 and PAF1, via cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) signaling to mitogen-activated protein kinase 1 and FOSL1. Pancreatic cell lines with knockdown of PAF1 did not develop features of stem cells upon exposure to CSE. Exposure of cells to NNN and NNK led to increased expression of CHRNA7, FOSL1, and PAF1 along with stem cell features. Pancreata from KC mice exposed to cigarette smoke had increased levels of PAF1 mRNA and protein, compared with control mice, as well as increased expression of SOX9. Levels of PAF1 and FOSL1 were increased in PDAC

Is endoscopic therapy the treatment of choice in all patients with chronic pancreatitis?

PubMed

Jabłońska, Beata

2013-01-07

Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas characterized by destruction of the pancreatic parenchyma with subsequent fibrosis that leads to pancreatic exocrine and endocrine insufficiency. Abdominal pain and local complications (bile duct or duodenal stenosis and pancreatic tumor) secondary to CP are indications for therapy. At the beginning, medical therapy is used. More invasive treatment is recommended for patients with pancreatic duct stones (PDS) and pancreatic obstruction in whom standard medical therapy is not sufficient. Recently, Clarke et al assessed the long-term effectiveness of endoscopic therapy (ET) in CP patients. The authors compared ET with medical treatment. They reported that ET was clinically successful in 50% of patients with symptomatic CP. In this commentary, current CP treatment, including indications for ET and surgery in CP patients, is discussed. Recommendations for endoscopic treatment of CP according to the European Society of Gastrointestinal Endoscopy Clinical Guidelines are reviewed. Different surgical methods used in the treatment of CP patients are also discussed. ET is the most useful in patients with large PDS, pancreatic duct obstruction and dilation. It should be the first-line option because it is less invasive than surgery. Surgery should be the first-line option in patients in whom ET has failed or in those with a pancreatic mass with suspicion of malignancy. ET is a very effective and less invasive procedure, but it cannot be recommended as the treatment of choice in all CP patients.

Islet inflammation and ductal proliferation may be linked to increased pancreatitis risk in type 2 diabetes

PubMed Central

Schludi, Belinda; Moin, Abu Saleh Md; Montemurro, Chiara; Gurlo, Tatyana; Matveyenko, Aleksey V.; Kirakossian, David; Dawson, David W.; Dry, Sarah M.; Butler, Peter C.; Butler, Alexandra E.

2017-01-01

Pancreatitis is more frequent in type 2 diabetes mellitus (T2DM), although the underlying cause is unknown. We tested the hypothesis that ongoing β cell stress and apoptosis in T2DM induces ductal tree proliferation, particularly the pancreatic duct gland (PDG) compartment, and thus potentially obstructs exocrine outflow, a well-established cause of pancreatitis. PDG replication was increased 2-fold in human pancreas from individuals with T2DM, and was associated with increased pancreatic intraepithelial neoplasia (PanIN), lesions associated with pancreatic inflammation and with the potential to obstruct pancreatic outflow. Increased PDG replication in the prediabetic human-IAPP-transgenic (HIP) rat model of T2DM was concordant with increased β cell stress but preceded metabolic derangement. Moreover, the most abundantly expressed chemokines released by the islets in response to β cell stress in T2DM, CXCL1, -4, and -10, induced proliferation in human pancreatic ductal epithelium. Also, the diabetes medications reported as potential modifiers for the risk of pancreatitis in T2DM modulated PDG proliferation accordingly. We conclude that chronic stimulation and proliferation of the PDG compartment in response to islet inflammation in T2DM is a potentially novel mechanism that serves as a link to the increased risk for pancreatitis in T2DM and may potentially be modified by currently available diabetes therapy. PMID:28679961

Gene and cell therapy for pancreatic cancer.

PubMed

Singh, Hans Martin; Ungerechts, Guy; Tsimberidou, Apostolia M

2015-04-01

The clinical outcomes of patients with pancreatic cancer are poor, and the limited success of classical chemotherapy underscores the need for new, targeted approaches for this disease. The delivery of genetic material to cells allows for a variety of therapeutic concepts. Engineered agents based on synthetic biology are under clinical investigation in various cancers, including pancreatic cancer. This review focuses on Phase I - III clinical trials of gene and cell therapy for pancreatic cancer and on future implications of recent translational research. Trials available in the US National Library of Medicine (www.clinicaltrials.gov) until February 2014 were reviewed and relevant published results of preclinical and clinical studies were retrieved from www.pubmed.gov . In pancreatic cancer, gene and cell therapies are feasible and may have synergistic antitumor activity with standard treatment and/or immunotherapy. Challenges are related to application safety, manufacturing costs, and a new spectrum of adverse events. Further studies are needed to evaluate available agents in carefully designed protocols and combination regimens. Enabling personalized cancer therapy, insights from molecular diagnostic technologies will guide the development and selection of new gene-based drugs. The evolving preclinical and clinical data on gene-based therapies can lay the foundation for future avenues improving patient care in pancreatic cancer.

Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells.

PubMed

Masamune, Atsushi; Yoshida, Naoki; Hamada, Shin; Takikawa, Tetsuya; Nabeshima, Tatsuhide; Shimosegawa, Tooru

2018-01-01

Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of α-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor β1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC-derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment. Copyright © 2017 Elsevier Inc. All rights reserved.

Recurrence of inflammatory pseudotumor in the distal bile duct: Lessons learned from a single case and reported cases

PubMed Central

Fernández, EM López-Tomassetti; Luis, H Díaz; Malagón, A Martín; González, I Arteaga; Pallarés, A Carrillo

2006-01-01

Inflammatory myofibroblastic tumors (IMTs) or inflammatory pseudotumors (IPs) have been extensively discussed in the literature. They are usually found in the lung and upper respiratory tract. However, reporting of cases involving the biliopancreatic region has increased over recent years. Immunohistochemical study of these lesions limited to the pancreatic head or distal bile duct seems to be compatible with those observed in a new entity called autoimmune pancreatitis, but usually intense fibrotic reaction (zonation) predominates producing a mass. When this condition is limited to the pancreatic head, the common bile duct might be involved by the inflammatory process and jaundice may occur often resembling adenocarcinoma of the pancreas. We have previously reported a case of IMT arising from the bile duct associated with autoimmune pancreatitis which is an extremely rare entity. Four years after Kaush-Whipple resection, radiological examination on routine follow-up revealed a tumor mass, suggesting local recurrence. Ultrasound-guided FNA confirmed our suspicious diagnosis. This present case, as others, suggests that persistent follow-up is necessary in order to prevent irreversible liver damage at this specific location. PMID:16804988

P-HPB-21: Isolated pancreatic tuberculosis mimicking inoperable pancreatic cancer

PubMed Central

Sahu, Manoj Kumar; Singh, Ayashkanta; Behera, Debasmita; Behera, Manas; Narayan, Jimmy

2017-01-01

Background: Pancreatic tuberculosis is an uncommon disease, presenting as hypoechoic mass on imaging mimicking malignancy. Consequently, it represents a diagnostic challenge necessitating a tissue diagnosis. Case Report: A 75-year-old female presented with progressive jaundice and weight loss; imaging with computed tomography (CT) showed a large (5.8 cm × 4.6 cm) pancreatic head mass with encasement of portal and superior mesenteric veins, peripancreatic nodes, atrophic pancreatic parenchyma, and dilated main pancreatic duct. Cancer antigen 19-9 was moderately elevated. With a diagnosis of inoperable pancreatic malignancy, she was planned for tissue diagnosis and palliative chemotherapy. Endoscopic ultrasonography (EUS) showed a heterogeneous mass with vascular invasion as in the CT. Fine needle aspiration (FNA) and biliary decompression with a plastic stent performed in the same sitting. Cytology demonstrated granuloma with caseous necrosis and presence of acid-fast bacilli. Antituberculosis treatment was started, and repeat CT after 6 months showed resolution of the mass. Discussion and Conclusion: A diagnosis of isolated pancreatic tuberculosis is rare and is difficult by clinical presentation alone; in India, it should be considered as a differential diagnosis of a pancreatic tumor. Benign lesions can also present with vascular invasions mimicking inoperable malignancy. EUS FNA is a very useful tool in accurate diagnosis of pancreatic head mass avoiding unnecessary surgeries.

Risk Factors for Migration, Fracture, and Dislocation of Pancreatic Stents

PubMed Central

Kawaguchi, Yoshiaki; Lin, Jung-Chun; Kawashima, Yohei; Maruno, Atsuko; Ito, Hiroyuki; Ogawa, Masami; Mine, Tetsuya

2015-01-01

Aim. To analyze the risk factors for pancreatic stent migration, dislocation, and fracture in chronic pancreatitis patients with pancreatic strictures. Materials and Methods. Endoscopic stent placements (total 386 times) were performed in 99 chronic pancreatitis patients with pancreatic duct stenosis at our institution between April 2006 and June 2014. We retrospectively examined the frequency of stent migration, dislocation, and fracture and analyzed the patient factors and stent factors. We also investigated the retrieval methods for migrated and fractured stents and their success rates. Results. The frequencies of stent migration, dislocation, and fracture were 1.5% (5/396), 0.8% (3/396), and 1.2% (4/396), respectively. No significant differences in the rates of migration, dislocation, or fracture were noted on the patient factors (etiology, cases undergoing endoscopic pancreatic sphincterotomy, location of pancreatic duct stenosis, existence of pancreatic stone, and approach from the main or minor papilla) and stent factors (duration of stent placement, numbers of stent placements, stent shape, diameter, and length). Stent retrieval was successful in all cases of migration. In cases of fractured stents, retrieval was successful in 2 of 4 cases. Conclusion. Stent migration, fracture, and dislocation are relatively rare, but possible complications. A good understanding of retrieval techniques is necessary. PMID:25945085

Long-term follow-up of nutritional status, pancreatic function, and morphological changes of the pancreatic remnant after pancreatic tumor resection in children.

PubMed

Sugito, Kiminobu; Furuya, Takeshi; Kaneda, Hide; Masuko, Takayuki; Ohashi, Kensuke; Inoue, Mikiya; Ikeda, Taro; Koshinaga, Tsugumichi; Tomita, Ryouichi; Maebayashi, Toshiya

2012-05-01

The objectives of the present study were to determine nutritional status, pancreatic function, and morphological changes of the pancreatic remnant after pancreatic tumor resection in children. The nutritional status was evaluated by the patterns of growth. Pancreatic function was evaluated by using a questionnaire, the Bristol stool form chart, the serum levels of fasting blood glucose, and hemoglobin A1c (HbA1c). Morphological changes of the pancreatic remnant were evaluated by computed tomography, magnetic resonance image, or magnetic resonance cholangiopancreatography. The present study consisted of 6 patients with pancreatic tumor (5 solid pseudopapillary tumors of the pancreas and 1 pancreatoblastoma) who underwent the following operations: tumor enucleation (3), distal pancreatectomy with splenectomy (1), and pylorus-preserving pancreatoduodenectomy (PPPD [2]). The serum levels of HbA1c have been gradually elevated in 2 patients with PPPD. A significant decrease in pancreatic parenchymal thickness and dilatation of the main pancreatic duct were observed in 2 patients with PPPD. Endocrine pancreatic insufficiency after PPPD may be explainable by obstructive pancreatitis after operation. Taking together the results of pancreatic endocrine function and morphological changes of pancreatic remnant after PPPD, tumor enucleation should be considered as surgical approach in children with pancreas head tumor whenever possible.

Clinical trial investigates experimental drug for advanced pancreatic cancer | Center for Cancer Research

Cancer.gov

The pancreas, a large gland that sits behind the stomach, produces enzymes that aid digestion and hormones that regulate blood sugar. Pancreatic cancer develops when cells that make up the ducts in the pancreas start to grow out of control. Udo Rudloff, M.D., is leading a clinical trial of a combination immunotherapy regimen to optimally help the immune system attack the tumor.

Stem cells and regenerative medicine for diabetes mellitus.

PubMed

Sumi, Shoichiro; Gu, Yuanjun; Hiura, Akihito; Inoue, Kazutomo

2004-10-01

A profound knowledge of the development and differentiation of pancreatic tissues, especially islets of Langerhans, is necessary for developing regenerative therapy for severe diabetes mellitus. A recent developmental study showed that PTF-1a is expressed in almost all parts of pancreatic tissues, in addition to PDX-1, a well-known transcription factor that is essential for pancreas development. Another study suggested that alpha cells and beta cells individually, but not sequentially, differentiated from neurogenin-3--expressing precursor cells. Under strong induction of pancreas regeneration, it is likely that pancreatic duct cells dedifferentiate to grow, express PDX-1, and re-differentiate toward other cell types including islet cells. Duct epithelium-like cells can be cultivated from crude pancreatic exocrine cells and can be induced to differentiate toward islet-like cell clusters under some culture conditions. These cell clusters made from murine pancreas have been shown to control hyperglycemia when transplanted into diabetic mice. Liver-derived oval cells and their putative precursor H-CFU-C have been shown to differentiate toward pancreatic cells. Furthermore, extrapancreatic cells contained in bone marrow and amniotic membrane are reported to become insulin-producing cells. However, their exact characterization and relationship between these cell types remain to be elucidated. Our recent study has shown that islet-like cell clusters can be differentiated from mouse embryonic stem cells. Transplantation of these clusters could ameliorate hyperglycemia of STZ-induced diabetic mice without forming teratomas. Interestingly, these cells expressed several genes specific to exocrine pancreatic tissue in addition to islet-related genes, suggesting that stable and efficient differentiation toward certain tissues can only be achieved through a process mimicking normal development of the tissue. Perhaps recent developments in these fields may rapidly lead to an

Reflux-Associated Cholecystopathy: Analysis of 76 Gallbladders From Patients With Supra-Oddi Union of the Pancreatic Duct and Common Bile Duct (Pancreatobiliary Maljunction) Elucidates a Specific Diagnostic Pattern of Mucosal Hyperplasia as a Prelude to Carcinoma.

PubMed

Muraki, Takashi; Memis, Bahar; Reid, Michelle D; Uehara, Takeshi; Ito, Tetsuya; Hasebe, Osamu; Okaniwa, Shinji; Horigome, Naoto; Hisa, Takeshi; Mittal, Pardeep; Freedman, Alexa; Maithel, Shishir; Sarmiento, Juan M; Krasinskas, Alyssa; Koshiol, Jill; Adsay, Volkan

2017-09-01

Pancreaticobiliary maljunction (PBM) is the anomalous union of the main pancreatic duct and common bile duct outside the Oddi-sphincter, allowing the reflux of pancreatic juice to the gallbladder. There is only limited awareness and understanding of the pathologic correlates of this condition, mostly from Japan; this entity is largely unrecognized in the West. In this study, 76 gallbladders from patients with PBM (64 from Japan; 12 from the United States) were analyzed and contrasted with 66 from non-PBM patients. These were predominantly females (54 vs. 22), mean age, 53 (range: 14 to 81). Cholelithiasis was uncommon (16% vs. 80% in non-PBM, P<0.01) whereas cholesterolosis was more common (49% vs. 29%, P=0.02) suggesting an altered chemical milieu. There was a distinctive diffuse mucosal hyperplasia (82% vs. 42%, P<0.01) with markedly elongated folds (mean: 1.1 vs. 0.7 mm, P<0.01) composed of compact villoglandular proliferation, often showing broad-based pushing into muscle, accompanied by prominent and more complex Rokitansky-Aschoff sinus formation (2.0 vs. 1.0/cm, P<0.01) at the base. At the tips, this villiform hyperplasia displayed frequent horizontal bridging of the folds (68% vs. 47%, P=0.01), bulbous dilatation (52% vs. 21%, P<0.01) as well as deposition of a peculiar amyloid-like hyaline material (56% vs. 15%, P<0.01). Despite paucity of inflammation and gallstones, findings attributed to mucosal injury were common including: pyloric gland metaplasia (70% vs. 48%, P=0.01) and intestinal metaplasia (24% vs. 6%, P<0.01). Invasive gallbladder carcinoma was present in 22 (29%) of the cases with 6 of these (27%) arising in association with intracholecystic papillary tubular neoplasm. Five cases had bile duct carcinoma at the time of cholecystectomy and 1 developed it 4 years after. In conclusion, gallbladders with patients with PBM display a distinctive pattern of mucosal hyperplasia with distinguishing features, which in constellation render it a

A CCR2+ myeloid cell niche required for pancreatic β cell growth

PubMed Central

Mussar, Kristin; Pardike, Stephanie; Hohl, Tobias M.; Hardiman, Gary; Cirulli, Vincenzo

2017-01-01

Organ-specific patterns of myeloid cells may contribute tissue-specific growth and/or regenerative potentials. The perinatal stage of pancreas development marks a time characterized by maximal proliferation of pancreatic islets, ensuring the maintenance of glucose homeostasis throughout life. Ontogenically distinct CX3CR1+ and CCR2+ macrophage populations have been reported in the adult pancreas, but their functional contribution to islet cell growth at birth remains unknown. Here, we uncovered a temporally restricted requirement for CCR2+ myeloid cells in the perinatal proliferation of the endocrine pancreatic epithelium. CCR2+ macrophages are transiently enriched over CX3CR1+ subsets in the neonatal pancreas through both local expansion and recruitment of immature precursors. Using CCR2-specific depletion models, we show that loss of this myeloid population leads to a striking reduction in β cell proliferation, dysfunctional islet phenotypes, and glucose intolerance in newborns. Replenishment of pancreatic CCR2+ myeloid compartments by adoptive transfer rescues these defects. Gene profiling identifies pancreatic CCR2+ myeloid cells as a prominent source of IGF2, which contributes to IGF1R-mediated islet proliferation. These findings uncover proproliferative functions of CCR2+ myeloid subsets and identify myeloid-dependent regulation of IGF signaling as a local cue supporting pancreatic proliferation. PMID:28768911

Wnt signaling regulates pancreatic β cell proliferation

PubMed Central

Rulifson, Ingrid C.; Karnik, Satyajit K.; Heiser, Patrick W.; ten Berge, Derk; Chen, Hainan; Gu, Xueying; Taketo, Makoto M.; Nusse, Roel; Hebrok, Matthias; Kim, Seung K.

2007-01-01

There is widespread interest in defining factors and mechanisms that stimulate proliferation of pancreatic islet cells. Wnt signaling is an important regulator of organ growth and cell fates, and genes encoding Wnt-signaling factors are expressed in the pancreas. However, it is unclear whether Wnt signaling regulates pancreatic islet proliferation and differentiation. Here we provide evidence that Wnt signaling stimulates islet β cell proliferation. The addition of purified Wnt3a protein to cultured β cells or islets promoted expression of Pitx2, a direct target of Wnt signaling, and Cyclin D2, an essential regulator of β cell cycle progression, and led to increased β cell proliferation in vitro. Conditional pancreatic β cell expression of activated β-catenin, a crucial Wnt signal transduction protein, produced similar phenotypes in vivo, leading to β cell expansion, increased insulin production and serum levels, and enhanced glucose handling. Conditional β cell expression of Axin, a potent negative regulator of Wnt signaling, led to reduced Pitx2 and Cyclin D2 expression by β cells, resulting in reduced neonatal β cell expansion and mass and impaired glucose tolerance. Thus, Wnt signaling is both necessary and sufficient for islet β cell proliferation, and our study provides previously unrecognized evidence of a mechanism governing endocrine pancreas growth and function. PMID:17404238

Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models

PubMed Central

Wen, Li; Voronina, Svetlana; Javed, Muhammad A.; Awais, Muhammad; Szatmary, Peter; Latawiec, Diane; Chvanov, Michael; Collier, David; Huang, Wei; Barrett, John; Begg, Malcolm; Stauderman, Ken; Roos, Jack; Grigoryev, Sergey; Ramos, Stephanie; Rogers, Evan; Whitten, Jeff; Velicelebi, Gonul; Dunn, Michael; Tepikin, Alexei V.; Criddle, David N.; Sutton, Robert

2015-01-01

Background & Aims Sustained activation of the cytosolic calcium concentration induces injury to pancreatic acinar cells and necrosis. The calcium release–activated calcium modulator ORAI1 is the most abundant Ca2+ entry channel in pancreatic acinar cells; it sustains calcium overload in mice exposed to toxins that induce pancreatitis. We investigated the roles of ORAI1 in pancreatic acinar cell injury and the development of acute pancreatitis in mice. Methods Mouse and human acinar cells, as well as HEK 293 cells transfected to express human ORAI1 with human stromal interaction molecule 1, were hyperstimulated or incubated with human bile acid, thapsigargin, or cyclopiazonic acid to induce calcium entry. GSK-7975A or CM_128 were added to some cells, which were analyzed by confocal and video microscopy and patch clamp recordings. Acute pancreatitis was induced in C57BL/6J mice by ductal injection of taurolithocholic acid 3-sulfate or intravenous' administration of cerulein or ethanol and palmitoleic acid. Some mice then were given GSK-7975A or CM_128, which inhibit ORAI1, at different time points to assess local and systemic effects. Results GSK-7975A and CM_128 each separately inhibited toxin-induced activation of ORAI1 and/or activation of Ca2+ currents after Ca2+ release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells (inhibition >90% of the levels observed in control cells). The ORAI1 inhibitors also prevented activation of the necrotic cell death pathway in mouse and human pancreatic acinar cells. GSK-7975A and CM_128 each inhibited all local and systemic features of acute pancreatitis in all 3 models, in dose- and time-dependent manners. The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis. Conclusions Cytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis. ORAI1 inhibitors might be developed

Adipose Stem Cell Therapy Mitigates Chronic Pancreatitis via Differentiation into Acinar-like Cells in Mice.

PubMed

Sun, Zhen; Gou, Wenyu; Kim, Do-Sung; Dong, Xiao; Strange, Charlie; Tan, Yu; Adams, David B; Wang, Hongjun

2017-11-01

The objective of this study was to assess the capacity of adipose-derived mesenchymal stem cells (ASCs) to mitigate disease progression in an experimental chronic pancreatitis mouse model. Chronic pancreatitis (CP) was induced in C57BL/6 mice by repeated ethanol and cerulein injection, and mice were then infused with 4 × 10 5 or 1 × 10 6 GFP + ASCs. Pancreas morphology, fibrosis, inflammation, and presence of GFP + ASCs in pancreases were assessed 2 weeks after treatment. We found that ASC infusion attenuated pancreatic damage, preserved pancreas morphology, and reduced pancreatic fibrosis and cell death. GFP + ASCs migrated to pancreas and differentiated into amylase + cells. In further confirmation of the plasticity of ASCs, ASCs co-cultured with acinar cells in a Transwell system differentiated into amylase + cells with increased expression of acinar cell-specific genes including amylase and chymoB1. Furthermore, culture of acinar or pancreatic stellate cell lines in ASC-conditioned medium attenuated ethanol and cerulein-induced pro-inflammatory cytokine production in vitro. Our data show that a single intravenous injection of ASCs ameliorated CP progression, likely by directly differentiating into acinar-like cells and by suppressing inflammation, fibrosis, and pancreatic tissue damage. These results suggest that ASC cell therapy has the potential to be a valuable treatment for patients with pancreatitis. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Dact2 is expressed in the developing ureteric bud/collecting duct system of the kidney and controls morphogenetic behavior of collecting duct cells.

PubMed

Lee, Wen-Chin; Hough, Melinda T; Liu, Weijia; Ekiert, Robert; Lindström, Nils O; Hohenstein, Peter; Davies, Jamie A

2010-10-01

The overall pattern of the developing kidney is set in large part by the developing ureteric bud/collecting duct system, and dysgenesis of this system accounts for a variety of clinically significant renal diseases. Understanding how the behavior of cells in the developing ureteric bud/collecting duct is controlled is therefore important to understanding the normal and abnormal kidney. Dact proteins have recently been identified as cytoplasmic regulators of intracellular signaling. Dact1 inhibits Wnt signaling, and Dact2 inhibits transforming growth factor (TGF)-β signaling. Here, we report that Dact2 is expressed in developing and adult mouse kidneys, specifically in the ureteric bud/collecting duct epithelium, a structure whose morphogenesis is controlled partially by TGF-β. When small interfering RNA is used to knock down Dact2 expression in collecting duct cells, they show some constitutive phospho-Smad2, undetectable in controls, and elevated phospho-Smad2 in response to TGF-β. They also show defective migration and, in a monolayer wound-healing assay, they fail to assemble a leading edge "cable" of actomyosin and advance instead as a disorganized mass of lamellipodium-bearing cells. This effect is seriously exacerbated by exogenous TGF-β, although control cells tolerate it well. In three-dimensional culture, Dact2 knockdown cells form cysts and branching tubules, but the outlines of the cysts made by knockdown cells are ragged rather than smooth and the branching tubules are decorated with many fine spikes not seen in controls. These data suggest Dact2 plays a role in regulating morphogenesis by renal collecting duct cells, probably by protecting cells from overly strong TGF-β pathway activation.

Oxalate nephropathy associated with chronic pancreatitis.

PubMed

Cartery, Claire; Faguer, Stanislas; Karras, Alexandre; Cointault, Olivier; Buscail, Louis; Modesto, Anne; Ribes, David; Rostaing, Lionel; Chauveau, Dominique; Giraud, Patrick

2011-08-01

Enteric overabsorption of oxalate may lead to hyperoxaluria and subsequent acute oxalate nephritis (AON). AON related to chronic pancreatitis is a rare and poorly described condition precluding early recognition and treatment. We collected the clinical characteristics, treatment, and renal outcome of 12 patients with chronic pancreatitis-associated AON followed in four French renal units. Before AON, mild to moderate chronic kidney disease was present in all patients, diabetes mellitus in eight (insulin [n = 6]; oral antidiabetic drugs [n = 2]), and known chronic pancreatitis in only eight. At presentation, pancreas imaging showed gland atrophy/heterogeneity, Wirsung duct dilation, calcification, or pseudocyst. Renal findings consisted of rapidly progressive renal failure with tubulointerstitial profile. Acute modification of glomerular filtration preceded the AON (i.e., diarrhea and diuretics). Increase in urinary oxalate excretion was found in all tested patients and hypocalcemia in nine (<1.5 mmol/L in four patients). Renal biopsy showed diffuse crystal deposits, highly suggestive of oxalate crystals, with tubular necrosis and interstitial inflammatory cell infiltrates. Treatment consisted of pancreatic enzyme supplementation, oral calcium intake, and an oxalate-free diet in all patients and renal replacement therapy in five patients. After a median follow-up of 7 months, three of 12 patients reached end-stage renal disease. AON is an under-recognized severe crystal-induced renal disease with features of tubulointerstitial nephritis that may occur in patients with a long history of chronic pancreatitis or reveal the pancreatic disease. Extrinsic triggering factors should be prevented.

Effects of bone sialoprotein on pancreatic cancer cell growth, invasion and metastasis.

PubMed

Kayed, Hany; Kleeff, Jörg; Keleg, Shereen; Felix, Klaus; Giese, Thomas; Berger, Martin R; Büchler, Markus W; Friess, Helmut

2007-01-08

Bone sialoprotein (BSP) is an acidic glycoprotein that plays an important role in cancer cell growth, migration and invasion. The expression, localization and possible function of BSP in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) were analyzed by QRT-PCR, laser capture microdissection, DNA microarray analysis, immunoblotting, radioimmunoassays and immunohistochemistry as well as cell growth, invasion, scattering, and adhesion assays. BSP mRNA was detected in 40.7% of normal, in 80% of CP and in 86.4% of PDAC samples. The median BSP mRNA levels were 6.1 and 0.9copies/microl cDNA in PDAC and CP tissues, respectively, and zero copies/microl cDNA in normal pancreatic tissues. BSP was weakly present in the cytoplasm of islet cells and ductal cells in 20% of normal pancreatic tissues. BSP was localized in the tubular complexes of both CP and PDAC, as well as in pancreatic cancer cells. Five out of 8 pancreatic cancer cell lines expressed BSP mRNA. Recombinant BSP (rBSP) inhibited Capan-1 and SU8686 pancreatic cancer cell growth, with a maximal effect of -46.4+/-12.0% in Capan-1 cells and -45.7+/-14.5% in SU8686 cells. rBSP decreased the invasion of SU8686 cells by -59.1+/-11.2% and of Capan-1 cells by -13.3+/-3.8% (P<0.05), whereas it did not affect scattering or adhesion of both cell lines. In conclusion, endogenous BSP expression levels in pancreatic cancer cells and low to absent BSP expression in the surrounding stromal tissue elements may indirectly act to enhance the proliferation and invasion of pancreatic cancer cells.

TLR9 ligation in pancreatic stellate cells promotes tumorigenesis

PubMed Central

Zambirinis, Constantinos P.; Levie, Elliot; Nguy, Susanna; Avanzi, Antonina; Barilla, Rocky; Xu, Yijie; Seifert, Lena; Daley, Donnele; Greco, Stephanie H.; Deutsch, Michael; Jonnadula, Saikiran; Torres-Hernandez, Alejandro; Tippens, Daniel; Pushalkar, Smruti; Eisenthal, Andrew; Saxena, Deepak; Ahn, Jiyoung; Hajdu, Cristina; Engle, Dannielle D.; Tuveson, David

2015-01-01

Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis. PMID:26481685

Differentiation of benign and malignant hilar bile duct stenosis.

PubMed

Liu, Xiaolei; Yang, Zhiying; Tan, Haidong; Shao, Chen; Liu, Liguo; Si, Shuang; Xu, Li; Sun, Yongliang

2016-06-15

Failure to differentiate benign and malignant hilar bile duct stenosis may lead to inappropriate treatment. We retrospectively analyzed the methods for differentiation. A total of 53 patients with hilar bile duct stenosis were included, comprising 41 malignant cases (hilar cholangiocarcinoma) and 12 benign cases (six primary sclerosing cholangitis and six IgG4-associated sclerosing cholangitis). Data of clinical histories, laboratory tests, imaging studies, and liver pathologies were collected, and comparison was made between benign and malignant groups. Compared with malignant group, patients in the benign group were more likely to have multiorgan involvement of clinical histories (P < 0.001). There was no difference on bilirubin, liver enzyme, and serum tumor marker between the two groups, whereas serum IgG4 levels were higher in the benign group (P = 0.003). Patients in the benign group were more likely to have pancreatic changes (P < 0.001) and multiple-segmental bile duct stenosis (P < 0.001) on imaging. Compared with the malignant group, patients in the benign group were more likely to show severe periportal inflammation in noninvolved liver (P < 0.001), fibrosis around intrahepatic bile duct (P < 0.001), and more IgG4-positive plasma cells (P < 0.001) on liver pathology. Benign lesion should be considered for patients with history of multiorgan involvement, pancreas changes, or multiple-segmental bile duct stenosis on imaging. Liver biopsy could be helpful for differential diagnosis before surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

Lateral Pancreaticojejunostomy for Chronic Pancreatitis and Pancreatic Ductal Dilation in Children.

PubMed

Shah, Adil A; Petrosyan, Mikael; Kane, Timothy D

2018-06-06

Pancreatic ductal obstruction leading to ductal dilation and recurrent pancreatitis is uncommon in children. Treatment is dependent upon etiology but consists of decompression of the pancreatic duct (PD) proximally, if possible, by endoscopic retrograde cholangiopancreatography (ERCP) intervention or surgical decompression with pancreaticojejunal anastomosis. After institutional review board approval, we retrospectively reviewed the records for 2 children who underwent lateral pancreaticojejunostomy for pancreatic ductal dilation. Data, including demographics, diagnostic studies, operative details, complications, outcomes, and follow-up, were analyzed. Case 1 was a 4-year-old female with pancreatic ductal obstruction with multiple episodes of recurrent pancreatitis and failure of ERCP to clear her PD of stones. She underwent a laparoscopic cholecystectomy with a lateral pancreaticojejunostomy (Puestow procedure). She recovered well with no further episodes of pancreatitis and normal pancreatic function 4 years later. Case 2 was a 2-year-old female who developed recurrent pancreatitis and was found to have papillary stenosis and long common bile-PD channel. Despite multiple sphincterotomies, laparoscopic cholecystectomy, and laparoscopic hepaticoduodenostomy, she continued to experience episodes of pancreatitis. She underwent a laparoscopy converted to open lateral pancreaticojejunostomy. Her recovery was also smooth having had no episodes of pancreatitis or hospital admissions for over 2 years following the Puestow. Indication for lateral pancreaticojejunostomy or Puestow procedure is rare in children and even less often performed using laparoscopy. In our small experience, both patients with pancreatic ductal obstruction managed with Puestow's procedure enjoy durable symptom and pain relief in the long term.

The effect of no naked pancreatic surface in the cavity of jejunum on pancreaticojejunostomy in 132 consecutive cases.

PubMed

Zhang, Fumin; Jin, Jichun; Jiang, Hao; Wang, Shiyang; Gu, Hanbao; Jin, Xinglin

2015-01-01

To prevent the pancreatic fistulas, we designed a technique termed "no naked pancreatic surface in the cavity of jejunum" on pancreaticojejunostomy. We adopted pancreatic exocrine secretions following the pancreatic duct by drainage; there was no naked pancreatic surface in the cavity of jejunum, and entail 2-3 cm sheath of the jejunum to the pancreatic stump. Only 3 (2.27%) cases developed pancreatic fistulas, 1 patient had a grade A leak, and 2 patients had grade B leakage. The overall morbidity was 25.76%. There was no dilatation of pancreatic duct or pancreatic enzyme deficiency shown during followed-up. The duration for accomplishing the anastomosis was 20 minutes averagely. The technique of no naked pancreatic surface in the cavity of jejunum can be routinely used in any case with pancreaticojejunostomy. It is a safe, simple, and effective technique that avoids the primary complication of anastomotic leakage.

Characteristics of Notch2(+) pancreatic cancer stem-like cells and the relationship with centroacinar cells.

PubMed

Zhou, Zhu-Chao; Dong, Qiang-Gang; Fu, De-Liang; Gong, Yi-Yi; Ni, Quan-Xing

2013-08-01

Notch2, a surface marker in cell lines, is used to isolate, identify and localise pancreatic cancer stem-like cells and is a target for therapy of these cells. Sphere formation was induced in Panc-1 and Bxpc-3 pancreatic cancer cell lines, and Notch2(+) cells were separated from Bxpc-3 and Panc-1 cell lines by magnetic activated cell sorting (MACS). Expression of stem cell-related markers, OCT4, Nanog and PDX1, were measured by immunofluorescent (IF) staining. Expression of Notch2 was also determined immunohistochemically in pancreatic tissues. Notch2(+) cells were transplanted in subcutaneous of mice. AQP1 and AQP5 were also measured by IF in Bxpc-3 cells. The Notch signal pathway inhibitor, Compound E (CE), was used to treat Notch2(+) Bxpc-3 cells, and their vitalities were subsequently measured by the CCK-8 method. Positive expression of OCT4, Nanog and PDX1 was observed in Notch2(+) cells. Notch2(+) cells at centroacinar cell (CAC) and terminal ductal locations expressed AQP1 and AQP5. They were strongly tumourigenic in mice, and CE inhibited proliferation of Notch2(+) Bxpc-3 cells to some degree. OCT4 and Nanog can be used as markers of self-renewal in pancreatic cancer stem cells. Notch2(+) cells in human pancreatic cancer Bxpc-3 and Panc-1 cell lines had the properties of cancer stem cells. The results suggest that Notch2(+) pancreatic cancer stem-like cells had a close relationship with CAC. © 2013 International Federation for Cell Biology.

Small Arteriovenous Malformation of the Common Bile Duct Causing Hemobilia in a Patient with Hereditary Hemorrhagic Telangiectasia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayashi, Sadao, E-mail: hayashi@m.kufm.kagoshima-u.ac.jp; Baba, Yasutaka; Ueno, Kazuto

We report a 54-year-old male patient with arteriovenous malformation located at the common bile duct and hereditary hemorrhagic telangiectasia. The patient was treated as gallstone pancreatitis at first. Three days after endoscopic nasobiliary drainage (ENBD) for biliary drainage to subside gallstone pancreatitis, hemobilia was drained from the ENBD tube and the serum hemoglobin level gradually decreased. Cholangioscopy and angiography revealed that hemobilia was due to a small arteriovenous malformation located at the common bile duct. Subsequently, the patient was successfully treated by endovascular intervention.

Assessing the secretory capacity of pancreatic acinar cells.

PubMed

Geron, Erez; Schejter, Eyal D; Shilo, Ben-Zion

2014-08-28

Pancreatic acinar cells produce and secrete digestive enzymes. These cells are organized as a cluster which forms and shares a joint lumen. This work demonstrates how the secretory capacity of these cells can be assessed by culture of isolated acini. The setup is advantageous since isolated acini, which retain many characteristics of the intact exocrine pancreas can be manipulated and monitored more readily than in the whole animal. Proper isolation of pancreatic acini is a key requirement so that the ex vivo culture will represent the in vivo nature of the acini. The protocol demonstrates how to isolate intact acini from the mouse pancreas. Subsequently, two complementary methods for evaluating pancreatic secretion are presented. The amylase secretion assay serves as a global measure, while direct imaging of pancreatic secretion allows the characterization of secretion at a sub-cellular resolution. Collectively, the techniques presented here enable a broad spectrum of experiments to study exocrine secretion.

Pathophysiology of chronic pancreatitis.

PubMed

Brock, Christina; Nielsen, Lecia Møller; Lelic, Dina; Drewes, Asbjørn Mohr

2013-11-14

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by progressive fibrotic destruction of the pancreatic secretory parenchyma. Despite the heterogeneity in pathogenesis and involved risk factors, processes such as necrosis/apoptosis, inflammation or duct obstruction are involved. This fibrosing process ultimately leads to progressive loss of the lobular morphology and structure of the pancreas, deformation of the large ducts and severe changes in the arrangement and composition of the islets. These conditions lead to irreversible morphological and structural changes resulting in impairment of both exocrine and endocrine functions. The prevalence of the disease is largely dependent on culture and geography. The etiological risk-factors associated with CP are multiple and involve both genetic and environmental factors. Throughout this review the M-ANNHEIM classification system will be used, comprising a detailed description of risk factors such as: alcohol-consumption, nicotine-consumption, nutritional factors, hereditary factors, efferent duct factors, immunological factors and miscellaneous and rare metabolic factors. Increased knowledge of the different etiological factors may encourage the use of further advanced diagnostic tools, which potentially will help clinicians to diagnose CP at an earlier stage. However, in view of the multi factorial disease and the complex clinical picture, it is not surprising that treatment of patients with CP is challenging and often unsuccessful.

Acute and chronic pancreatitis: surgical management.

PubMed

Dzakovic, Alexander; Superina, Riccardo

2012-08-01

Pancreatitis is becoming increasingly prevalent in children, posing new challenges to pediatric health care providers. Although some general adult treatment paradigms are applicable in the pediatric population, diagnostic workup and surgical management of acute and chronic pancreatitis have to be tailored to anatomic and pathophysiological entities peculiar to children. Nonbiliary causes of acute pancreatitis in children are generally managed nonoperatively with hydration, close biochemical and clinical observation, and early initiation of enteral feeds. Surgical intervention including cholecystectomy or endoscopic retrograde cholangiopancreatography is often required in acute biliary pancreatitis, whereas infected pancreatic necrosis remains a rare absolute indication for pancreatic debridement and drainage via open, laparoscopic, or interventional radiologic procedure. Chronic pancreatitis is characterized by painful irreversible changes of the parenchyma and ducts, which may result in or be caused by inadequate ductal drainage. A variety of surgical procedures providing drainage, denervation, resection, or a combination thereof are well established to relieve pain and preserve pancreatic function. Copyright © 2012. Published by Elsevier Inc.

Expression of human cationic trypsinogen (PRSS1) in murine acinar cells promotes pancreatitis and apoptotic cell death

PubMed Central

Athwal, T; Huang, W; Mukherjee, R; Latawiec, D; Chvanov, M; Clarke, R; Smith, K; Campbell, F; Merriman, C; Criddle, D; Sutton, R; Neoptolemos, J; Vlatković, N

2014-01-01

Hereditary pancreatitis (HP) is an autosomal dominant disease that displays the features of both acute and chronic pancreatitis. Mutations in human cationic trypsinogen (PRSS1) are associated with HP and have provided some insight into the pathogenesis of pancreatitis, but mechanisms responsible for the initiation of pancreatitis have not been elucidated and the role of apoptosis and necrosis has been much debated. However, it has been generally accepted that trypsinogen, prematurely activated within the pancreatic acinar cell, has a major role in the initiation process. Functional studies of HP have been limited by the absence of an experimental system that authentically mimics disease development. We therefore developed a novel transgenic murine model system using wild-type (WT) human PRSS1 or two HP-associated mutants (R122H and N29I) to determine whether expression of human cationic trypsinogen in murine acinar cells promotes pancreatitis. The rat elastase promoter was used to target transgene expression to pancreatic acinar cells in three transgenic strains that were generated: Tg(Ela-PRSS1)NV, Tg(Ela-PRSS1*R122H)NV and Tg(Ela-PRSS1*N29I)NV. Mice were analysed histologically, immunohistochemically and biochemically. We found that transgene expression is restricted to pancreatic acinar cells and transgenic PRSS1 proteins are targeted to the pancreatic secretory pathway. Animals from all transgenic strains developed pancreatitis characterised by acinar cell vacuolisation, inflammatory infiltrates and fibrosis. Transgenic animals also developed more severe pancreatitis upon treatment with low-dose cerulein than controls, displaying significantly higher scores for oedema, inflammation and overall histopathology. Expression of PRSS1, WT or mutant, in acinar cells increased apoptosis in pancreatic tissues and isolated acinar cells. Moreover, studies of isolated acinar cells demonstrated that transgene expression promotes apoptosis rather than necrosis. We therefore

Inhibition of Cell Survival by Curcumin Is Associated with Downregulation of Cell Division Cycle 20 (Cdc20) in Pancreatic Cancer Cells

PubMed Central

Zhang, Yu; Xue, Ying-bo; Li, Hang; Qiu, Dong; Wang, Zhi-wei; Tan, Shi-sheng

2017-01-01

Pancreatic cancer is one of the most aggressive human tumors in the United States. Curcumin, a polyphenol derived from the Curcuma longa plant, has been reported to exert its antitumor activity in pancreatic cancer. However, the molecular mechanisms of curcumin-mediated tumor suppressive function have not been fully elucidated. In the current study, we explore whether curcumin exhibits its anti-cancer function through inhibition of oncoprotein cell division cycle 20 (Cdc20) in pancreatic cancer cells. We found that curcumin inhibited cell growth, enhanced apoptosis, induced cell cycle arrest and retarded cell invasion in pancreatic cancer cells. Moreover, we observed that curcumin significantly inhibited the expression of Cdc20 in pancreatic cancer cells. Furthermore, our results demonstrated that overexpression of Cdc20 enhanced cell proliferation and invasion, and abrogated the cytotoxic effects induced by curcumin in pancreatic cancer cells. Consistently, downregulation of Cdc20 promoted curcumin-mediated anti-tumor activity. Therefore, our findings indicated that inhibition of Cdc20 by curcumin could be useful for the treatment of pancreatic cancer patients. PMID:28165402

Inhibition of Cell Survival by Curcumin Is Associated with Downregulation of Cell Division Cycle 20 (Cdc20) in Pancreatic Cancer Cells.

PubMed

Zhang, Yu; Xue, Ying-Bo; Li, Hang; Qiu, Dong; Wang, Zhi-Wei; Tan, Shi-Sheng

2017-02-04

Pancreatic cancer is one of the most aggressive human tumors in the United States. Curcumin, a polyphenol derived from the Curcuma longa plant, has been reported to exert its antitumor activity in pancreatic cancer. However, the molecular mechanisms of curcumin-mediated tumor suppressive function have not been fully elucidated. In the current study, we explore whether curcumin exhibits its anti-cancer function through inhibition of oncoprotein cell division cycle 20 (Cdc20) in pancreatic cancer cells. We found that curcumin inhibited cell growth, enhanced apoptosis, induced cell cycle arrest and retarded cell invasion in pancreatic cancer cells. Moreover, we observed that curcumin significantly inhibited the expression of Cdc20 in pancreatic cancer cells. Furthermore, our results demonstrated that overexpression of Cdc20 enhanced cell proliferation and invasion, and abrogated the cytotoxic effects induced by curcumin in pancreatic cancer cells. Consistently, downregulation of Cdc20 promoted curcumin-mediated anti-tumor activity. Therefore, our findings indicated that inhibition of Cdc20 by curcumin could be useful for the treatment of pancreatic cancer patients.

Antisense oligodeoxynucleotide to the cystic fibrosis gene inhibits anion transport in normal cultured sweat duct cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sorscher, E.J.; Kirk, K.L.; Weaver, M.L.

The authors have tested the hypothesis that the cystic fibrosis (CF) gene product, called the CF transmembrane conductance regulator (CFTR), mediates anion transport in normal human sweat duct cells. Sweat duct cells in primary culture were treated with oligodeoxynucleotides that were antisense to the CFTR gene transcript in order to block the expression of the wild-type CFTR. Anion transport in CFTR transcript antisense-treated cells was then assessed with a halide-specific dye, 6-methoxy-N-(3-sulfopropryl)quinolinium, and fluorescent digital imaging microscopy to monitor halide influx and efflux from single sweat duct cells. Antisense oligodeoxynucleotide treatment for 24 hr virtually abolished Cl{sup {minus}} transport inmore » sweat duct cells compared with untreated cells or control cells treated with sense oligodeoxynucleotides. Br{sup {minus}} uptake into sweat duct cells was also blocked after a 24-hr CFTR transcript antisense treatments, but not after treatments for only 4 hr. Lower concentrations of antisense oligodeoxynucleotides were less effective at inhibiting Cl{sup {minus}} transport. These results indicate that oligodeoxynucleotides that are antisense to CFTR transcript inhibit sweat duct Cl{sup {minus}} permeability in both a time-dependent and dose-dependent manner. This approach provides evidence that inhibition of the expression of the wild-type CFTR gene in a normal, untransfected epithelial cell results in an inhibition of Cl{sup {minus}} permeability.« less

Surgical Approaches to Chronic Pancreatitis: Indications and Techniques.

PubMed

Dua, Monica M; Visser, Brendan C

2017-07-01

There are a number of surgical strategies for the treatment of chronic pancreatitis. The optimal intervention should provide effective pain relief, improve/maintain quality of life, preserve exocrine and endocrine function, and manage local complications. Pancreaticoduodenectomy was once the standard operation for patients with chronic pancreatitis; however, other procedures such as the duodenum-preserving pancreatic head resections and its variants have been introduced with good long-term results. Pancreatic duct drainage via a lateral pancreaticojejunostomy continues to be effective in ameliorating symptoms and expediting return to normal lifestyle in many patients. This review summarizes operative indications and gives an overview of the different surgical strategies in treating chronic pancreatitis.

In vivo SPECT imaging with 111In-DOTA-c(RGDfK) to detect early pancreatic cancer in a hamster pancreatic carcinogenesis model.

PubMed

Yoshimoto, Mitsuyoshi; Hayakawa, Takuya; Mutoh, Michihiro; Imai, Toshio; Tsuda, Keisuke; Kimura, Sadaaki; Umeda, Izumi O; Fujii, Hirofumi; Wakabayashi, Keiji

2012-05-01

Early detection of pancreatic cancer is key to overcoming its poor prognosis. α(v)β(3)-integrin is often overexpressed in pancreatic tumor cells, whereas it is scarcely expressed in normal pancreatic cells. In this study, we investigated the usefulness of SPECT imaging with (111)In-1,4,7,10-tetraazacylododecane-N,N',N″,N'''-tetraacetic acid-cyclo-(Arg-Gly-Asp-d-Phe-Lys) [(111)In-DOTA-c(RGDfK)], an imaging probe of α(v)β(3)-integrin, for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. Hamsters were subcutaneously injected with the pancreatic duct carcinogen N-nitrosobis(2-oxopropyl)amine to induce pancreatic cancer. N-nitrosobis(2-oxopropyl)amine-treated hamsters underwent in vivo SPECT with (111)In-DOTA-c(RGDfK). After imaging, the tumor-to-normal pancreatic tissue radioactivity ratios in excised pancreatic samples were measured with autoradiography (ARG) and compared with the immunopathologic findings for α(v)β(3)-integrin. In a mouse model in which inflammation was induced with turpentine, the uptake of (111)In-DOTA-c(RGDfK) in inflammatory regions was evaluated with ARG and compared with that of (18)F-FDG. (111)In-DOTA-c(RGDfK) was clearly visualized in pancreatic cancer lesions as small as 3 mm in diameter. ARG analysis revealed high tumor-to-normal pancreatic tissue radioactivity ratios (4.6 ± 1.0 [mean ± SD] in adenocarcinoma and 3.3 ± 1.4 in atypical hyperplasia). The uptake of (111)In-DOTA-c(RGDfK) strongly correlated with α(v)β(3)-integrin expression. In the inflammatory model, inflammation-to-muscle ratios for (18)F-FDG and (111)In-DOTA-c(RGDfK) were 8.37 ± 4.37 and 1.98 ± 0.60, respectively. These results imply that (111)In-DOTA-c(RGDfK) has a lower rate of false-positive tumor detection than (18)F-FDG. Our findings suggest that SPECT with (111)In-DOTA-c(RGDfK) has great potential for the early and accurate detection of pancreatic cancer.

[Delayed complications after pancreatic surgery: Pancreatic insufficiency, malabsorption syndrome, pancreoprivic diabetes mellitus and pseudocysts].