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Background—The pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells (vitamin A storing cells) play a significant role in the development of fibrosis. Aims—To determine whether cells resembling hepatic stellate cells are present in rat pancreas, and if so, to compare their number with the number of stellate cells in the liver, and isolate and culture these cells from rat pancreas. Methods—Liver and pancreatic sections from chow fed rats were immunostained for desmin, glial fibrillary acidic protein (GFAP), and α smooth muscle actin (α-SMA). Pancreatic stellate shaped cells were isolated using a Nycodenz gradient, cultured on plastic, and examined by phase contrast and fluorescence microscopy, and by immunostaining for desmin, GFAP, and α-SMA. Results—In both liver and pancreatic sections, stellate shaped cells were observed; these were positive for desmin and GFAP and negative for α-SMA. Pancreatic stellate shaped cells had a periacinar distribution. They comprised 3.99% of all pancreatic cells; hepatic stellate cells comprised 7.94% of all hepatic cells. The stellate shaped cells from rat pancreas grew readily in culture. Cells cultured for 24 hours had an angular appearance, contained lipid droplets manifesting positive vitamin A autofluorescence, and stained positively for desmin but negatively for α-SMA. At 48 hours, cells were positive for α-SMA. Conclusions—Cells resembling hepatic stellate cells are present in rat pancreas in a number comparable with that of stellate cells in the liver. These stellate shaped pancreatic cells can be isolated and cultured in vitro.

Background: Biliary tract cancer (BTC) and benign biliary strictures can be difficult to differentiate using standard tumour markers such as serum carbohydrate antigen 19-9 (CA19-9) as they lack diagnostic accuracy. Methods: Two-dimensional difference gel electrophoresis and tandem mass spectrometry were used to profile immunodepleted serum samples collected from cases of BTC, primary sclerosing cholangitis (PSC), immunoglobulin G4-associated cholangitis and healthy volunteers. The serum levels of one candidate protein, leucine-rich α -2-glycoprotein (LRG1), were verified in individual samples using enzyme-linked immunosorbent assay and compared with serum levels of CA19-9, bilirubin, interleukin-6 (IL-6) and other inflammatory markers. Results: We report increased LRG1, CA19-9 and IL-6 levels in serum from patients with BTC compared with benign disease and healthy controls. Immunohistochemical analysis also demonstrated increased staining of LRG1 in BTC compared with cholangiocytes in benign biliary disease. The combination of receiver operating characteristic (ROC) curves for LRG1, CA19-9 and IL-6 demonstrated an area under the ROC curve of 0.98. In addition, raised LRG1 and CA19-9 were found to be independent predictors of BTC in the presence of elevated bilirubin, C-reactive protein and alkaline phosphatase. Conclusion: These results suggest LRG1, CA19-9 and IL-6 as useful markers for the diagnosis of BTC, particularly in high-risk patients with PSC.

Background—The mechanisms responsible for the initiation of alcoholic pancreatitis remain elusive. However, there is an increasing body of evidence that reactive oxygen species play a role in both acute and chronic pancreatitis. In the liver, cytochrome P4502E1 (CYP2E1, the inducible ethanol metabolising enzyme) is one of the proposed pathways by which ethanol induces oxidative stress. Aims—To determine whether CYP2E1 is present in the pancreas and, if so, whether it is inducible by chronic ethanol feeding. Methods—Eighteen male Sprague-Dawley rats were pair fed liquid diets with or without ethanol as 36% of energy for four weeks. CYP2E1 levels were determined by western blotting of microsomal protein from both pancreas and liver. Messenger RNA (mRNA) levels for CYP2E1 were quantified using dot blots of total pancreatic RNA. Results—CYP2E1 was found in the pancreas. Furthermore, the amount of CYP2E1 was greater in the pancreas of rats fed ethanol compared with controls (mean increase over controls 5.1-fold, 95% confidence intervals 2.4 to 7.7, p<0.02). In the liver, induction by ethanol of CYP2E1 was similar (mean increase over controls 7.9-fold, 95% confidence intervals 5.2 to 10.6, p<0.005). Pancreatic mRNA levels for CYP2E1 were similar in ethanol fed and control rats. Conclusions—CYP2E1 is present in the rat pancreas and is inducible by chronic ethanol administration. Induction of pancreatic CYP2E1 is not regulated at the mRNA level. The metabolism of ethanol via CYP2E1 may contribute to oxidative stress in the pancreas during chronic ethanol consumption.

Periampullary adenomas are an increasingly recognized condition, both in those with familial adenomatous polyposis syndromes (FAP) as well as sporadic cases. Endoscopic management has been advocated for these lesions without differentiating between these two patient groups regarding aim of therapy. The aims of this study were to determine the safety and effectiveness of endoscopic surveillance and ablative therapy of periampullary adenomas in patients with both sporadic and FAP-associated lesions. Retrospective analysis of 59 patients with FAP and 32 with sporadic lesions who were all enrolled in a program of endoscopic surveillance and ablative therapy. Median follow-up was 24 months (range, 1–134 months). Ampullary ablative therapy has resulted in return to normal histology in 44 and 34% of sporadic and FAP-associated lesions, respectively. Complications of endoscopic therapy were mild in 12 patients and severe in 3 patientsthe latter category involved one occurrence of asymptomatic duodenal stenosis and one occurrence of postcoagulation syndrome—both after Nd-YAG laser therapy—and necrotizing pancreatitis after ampullary biopsy in one patient. Thirteen patients have been referred for surgical intervention. There has been no mortality and no cases of advanced malignancy missed by endoscopy. Endoscopic surveillance and ablative therapy of periampullary lesions is safe and can be effective, although eradication of ampullary tissue requires multiple ablative sessions.

To determine the effect of endoscopic ultrasonography (EUS) on endoscopic drainage of pancreatic pseudocysts and to determine patency with fistula dilation and placement of multiple stents. Between September 1995 and January 1999, 19 patients underwent endoscopic drainage of pancreatic pseudocysts, 17 of whom were assessed by EUS before drainage. Radial EUS scanning was used to detect an optimal site of apposition of pseudocyst and gut wall, free of intervening vessels. A fistula was created with a fistulatome, followed by balloon dilation of the fistula tract. Patency was maintained with multiple double pigtail stents. The primary goal of this retrospective study was to determine whether EUS affected the practice of endoscopic drainage of pancreatic pseudocysts. In 3 patients, drainage was not attempted based on EUS findings. In the other 13 patients (14 pseudocysts), creation of a fistula was successful on 13 occasions, and no immediate complications occurred. However, 1 patient subsequently developed sepsis that required surgery. All other patients were treated with balloon dilation, multiple stents, and antibiotics, with no septic complications. Of 14 pseudocysts (in 13 patients), 13 (93%) resolved. Results of EUS may alter management of patients considered for endoscopic drainage of pancreatic pseudocysts. Endoscopic ultrasonography was useful for selecting an optimal and safe drainage site. The combination of balloon dilation, multiple stents, and antibiotics appears to resolve pancreatic pseudocysts without septic complications.

The aim of the study was to examine whether endoscopic intralesional corticosteroid injection into recalcitrant peptic esophageal strictures reduces the need for repeat stricture dilation. Patients with a peptic esophageal stricture and recurrent dysphagia having had at least one dilation in the preceding 18 months were enrolled in a prospective randomized, double-blind study comparing steroid and sham injection. After endoscopic confirmation of recurrent stricture, patients were randomized to receive either 0.5 cc/quadrant triamcinolone (40 mg/cc) or sham injection into the stricture followed by balloon dilation of the stricture. Patients were stratified by the number of dilations required in the preceding 18 months, severity of dysphagia, the presence of esophagitis, stricture severity, and prior therapy with a proton-pump inhibitor. Patients and their physicians were blinded to the type of intervention received. Baseline dysphagia questionnaires were completed. Post-procedurally all patients were placed on a standardized proton-pump inhibitor regimen and standardized telephone follow-up questionnaires were completed at 1 wk and at 1, 3, 6, 9, and 12 months. The original sample-size calculation of 60 patients could not be met in a timely fashion because of a low incidence of recalcitrant peptic stricture patients. A total of 30 patients were enrolled, 15 in the steroid group (10 men, mean age 66 yr) and 15 in the sham group (11 M, mean age 67 yr). Patients were followed for 1 yr, unless they underwent an antireflux operation or died. Two patients, one per group, died of non-esophageal causes at 1 and 12 months. Four patients had fundoplication, two in each group, unrelated to stricture or dysphagia. Two patients in the steroid group (13%) and nine in the sham group (60%) required repeat dilation (p= 0.011). In patients with recalcitrant peptic esophageal stricture, steroid injection into the stricture combined with acid suppression significantly diminishes both the need for repeat dilation and the average time to repeat dilation compared to sham injection and acid suppression alone.

Many technical advances have offered enhanced capabilities in noninvasive imaging of the pancreas. Although these technical advances are impressive, current studies do not always define clearly the benefits that these advances will confer in patient management. A critical overview of these imaging modalities is offered here, with respect to diagnosis and patient management. Outcomes from various studies are summarized for modalities including transabdominal ultrasound, computed tomography, magnetic resonance imaging with and without pancreatography, and positron emission tomography.

Biliary tract cancer (BTC) and benign biliary strictures can be difficult to differentiate using standard tumour markers such as serum carbohydrate antigen 19-9 (CA19-9) as they lack diagnostic accuracy. Two-dimensional difference gel electrophoresis and tandem mass spectrometry were used to profile immunodepleted serum samples collected from cases of BTC, primary sclerosing cholangitis (PSC), immunoglobulin G4-associated cholangitis and healthy volunteers. The serum levels of one candidate protein, leucine-rich α-2-glycoprotein (LRG1), were verified in individual samples using enzyme-linked immunosorbent assay and compared with serum levels of CA19-9, bilirubin, interleukin-6 (IL-6) and other inflammatory markers. We report increased LRG1, CA19-9 and IL-6 levels in serum from patients with BTC compared with benign disease and healthy controls. Immunohistochemical analysis also demonstrated increased staining of LRG1 in BTC compared with cholangiocytes in benign biliary disease. The combination of receiver operating characteristic (ROC) curves for LRG1, CA19-9 and IL-6 demonstrated an area under the ROC curve of 0.98. In addition, raised LRG1 and CA19-9 were found to be independent predictors of BTC in the presence of elevated bilirubin, C-reactive protein and alkaline phosphatase. These results suggest LRG1, CA19-9 and IL-6 as useful markers for the diagnosis of BTC, particularly in high-risk patients with PSC.

IntroductionDistinguishing biliary tract cancer (BTC: cholangiocarcinoma and gallbladder carcinoma) from benign biliary disease such as pre-malignant primary sclerosing cholangitis (PSC) or immunoglobulin G4-associated cholangitis (IAC) can be difficult. Serum markers such as CA19.9 and immunoglobulin G4 lack sensitivity and specificity. There is a need for better biomarkers to differentiate these clinically similar diseases. We aimed to perform serum immunoaffinity depletion, 2-dimensional difference gel electrophoresis (2-DIGE) and liquid chromatography tandem mass spectrometry to identify differential biomarkers in benign and malignant biliary disease and healthy volunteers.MethodsBlood was prospectively collected from 37 patients with BTC, 11 with PSC, 7 with IAC and 30 healthy volunteers. Serum was pooled into the four clinical groups and immunoaffinity depleted via fast protein liquid chromatography to remove highly abundant proteins. Following 2-DIGE using minimal labelling Cy-dyes, gels were scanned then analysed with DeCyder software. Protein spots with a >2-fold differential expression (p<0.01, Student t test) were picked, trypsin digested and subjected to nanoflow reversed-phase liquid chromatography coupled to electrospray ionisation tandem mass spectrometry for protein identification.ResultsThe median age of BTC, PSC, IAC and healthy groups were similar at 68 (range 27–93), 47 (range 22–76), 63 (range 43–71) and 64 (range 40–79) years, respectively. The median serum bilirubin in the BTC, PSC and IAC groups was 40 (range 8–616), 20 (range 7–457) and 12 (range 5–40) μmol/l, respectively. 30/37 BTC, 4/11 PSC and 1/4 IAC patients, had elevated (>37 IU/ml) CA 19.9 levels. 61 protein spots were picked, of which 34 were upregulated and 13 downregulated in BTC vs healthy, 32 upregulated and 9 downregulated in BTC vs PSC, and 7 upregulated and 12 downregulated in PSC vs IAC. Leucine-rich glycoprotein, apolipoprotein A-IV and E, MASP2, CLEC3B, RAD1 and vimentin were upregulated and Hsp90, C4BPA and SERPIND1 downregulated in BTC vs PSC. Carbonic anhydrase 1, lumican and twinfilin-2 were upregulated and IgG4 chain C region and MASP2 were downregulated in PSC vs IAC, respectively. Serum validation of putative markers is underway.ConclusionDifferentially expressed serum proteins in benign and malignant biliary disease were identified using this proteomic approach. These putative markers may be useful in monitoring patients with PSC who are at increased risk of BTC.

To determine the effect of endoscopic ultrasonography (EUS) on endoscopic drainage of pancreatic pseudocysts and to determine patency with fistula dilation and placement of multiple stents. Between September 1995 and January 1999, 19 patients underwent endoscopic drainage of pancreatic pseudocysts, 17 of whom were assessed by EUS before drainage. Radial EUS scanning was used to detect an optimal site of apposition of pseudocyst and gut wall, free of intervening vessels. A fistula was created with a fistulatome, followed by balloon dilation of the fistula tract. Patency was maintained with multiple double pigtail stents. The primary goal of this retrospective study was to determine whether EUS affected the practice of endoscopic drainage of pancreatic pseudocysts. In 3 patients, drainage was not attempted based on EUS findings. In the other 13 patients (14 pseudo-cysts), creation of a fistula was successful on 13 occasions, and no immediate complications occurred. However, 1 patient subsequently developed sepsis that required surgery. All other patients were treated with balloon dilation, multiple stents, and antibiotics, with no septic complications. Of 14 pseudocysts (in 13 patients), 13 (93%) resolved. Results of EUS may alter management of patients considered for endoscopic drainage of pancreatic pseudocysts. Endoscopic ultrasonography was useful for selecting an optimal and safe drainage site. The combination of balloon dilation, multiple stents, and antibiotics appears to resolve pancreatic pseudocysts without septic complications.