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Autoimmune pancreatitis (AIP) is a disease concept that originated in Japan. It is characterized by diffuse pancreatic enlargement and irregular narrowing of the main pancreatic duct. Although the usefulness of the histological diagnosis of AIP using endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) and EUS-guided fine-needle biopsy (FNB) has been reported, enhanced diagnostic performance is expected with improvements in tissue collection methods and fine-needle techniques. Guidance for establishing the tissue diagnosis of AIP has been developed and is useful for histological evaluation. Histopathological diagnosis by EUS-FNA/FNB is expected to play a central role in AIP diagnosis in the future.

Balloon enteroscopy-assisted endoscopic retrograde cholangiography (BEA-ERC) is useful and feasible in adults with pancreatobiliary diseases, but its efficacy and safety have not been established in pediatric patients. We compared the success rate and safety of BEA-ERC between adults and pediatric patients. This single-center retrospective study reviewed 348 patients (pediatric: 57, adult: 291) with surgically altered gastrointestinal anatomies who underwent BEA-ERC for biliary disorders from January 2007 to December 2019. The success rate of reaching the anastomosis or duodenal papilla was significantly lower in pediatric patients than in adult patients (66.7% vs. 88.0%, p &lt, 0.01). The clinical success rate was also significantly lower in pediatric patients (64.9% vs. 80.4%, p = 0.014). The rate of adverse events was significantly higher in pediatric patients than in adults (14.2% vs. 7.7%, p = 0.037). However, if the anastomotic sites were reached in pediatric patients, the treatment was highly successful (97.3%). The time of reaching target site was significantly longer in pediatric patients than in adult patients. This study shows that BEA-ERC in pediatric patients is more difficult than that in adult patients. However, in patients where the balloon enteroscope was advanced to the anastomosis, clinical outcomes comparable to those in adults can be achieved.

Autoimmune pancreatitis (AIP), which is characterized by pancreatic enlargement and irregular narrowing of the main pancreatic duct, is difficult to differentiate from malignancy. The irregular narrowing of the pancreatic duct, which can be detected via endoscopic retrograde cholangiopancreatography, is a characteristic feature of AIP; however, distinguishing between localized AIP and pancreatic cancer based on pancreatic duct imaging is difficult. This study overviews the efficacy of endoscopic ultrasound (EUS)-guided pancreatic sampling for the histopathological diagnosis of AIP. Recent enhancements in needle biopsy methodologies and technologies have contributed to improvement in the diagnostic efficacy of this technique. The guidance provided in this study for the histological diagnosis of AIP is anticipated to further advance in the histopathological diagnosis of AIP using EUS-guided pancreatic sampling.

The number of new cases of pancreatic ductal adenocarcinoma is increasing with a cumulative total of 495,773 cases worldwide, making it the fourteenth most common malignancy. However, it accounts for 466,003 deaths per year and is the seventh leading cause of cancer deaths. Regional differences in the number of patients with pancreatic ductal adenocarcinoma appear to reflect differences in medical care, as well as racial differences. Compared to the prevalence of other organ cancers in Japan, pancreatic ductal adenocarcinoma ranks seventh based on the number of patients, eighth based on morbidity, and fourth based on the number of deaths, with a continuing increase in the mortality rate. Risk factors for developing pancreatic ductal adenocarcinoma include family history, genetic disorders, diabetes, chronic pancreatitis, and intraductal papillary mucinous neoplasms. An issue that hinders improvement in the prognosis of patients with pancreatic ductal adenocarcinoma is the development of a strategy to identify patients with these risk factors to facilitate detection of the disease at a stage when intervention will improve survival.

Autoimmune pancreatitis (AIP) is characterized by enlargement of the pancreas and irregular narrowing of the main pancreatic duct. It is often associated with IgG4-related sclerosing cholangitis (IgG4-SC), in which the bile duct narrows. Although characteristic irregular narrowing of the pancreatic duct caused by endoscopic retrograde cholangiopancreatography is noted in AIP, it is difficult to differentiate between localized AIP and pancreatic carcinoma based on imaging of the pancreatic duct. While stenosis of the bile duct in IgG4-SC is characterized by longer-length stenosis than in cholangiocarcinoma, differentiation based on bile duct imaging alone is challenging. Endoscopic ultrasound (EUS) can characterize hypoechoic enlargement of the pancreas or bile duct wall thickening in AIP and IgG4-SC, and diagnosis using elastography and contrast-enhanced EUS are being evaluated. The utility of EUS-guided fine needle aspiration for the histological diagnosis of AIP has been reported and is expected to improve diagnostic performance for AIP. Findings in the bile duct wall from endoscopic retrograde cholangiopancreatography followed by intraductal ultrasonography are useful in differentiating IgG4-SC from cholangiocarcinoma. Diagnoses based on endoscopic ultrasonography play a central role in the diagnosis of AIP.

/Objectives: Identifying reliable pretreatment imaging biomarkers for pancreatic neuroendocrine neoplasm (PanNEN) is a key imperative. Extracellular volume (ECV) fraction quantified with equilibrium contrast-enhanced CT can be easily integrated into routine examinations. This study aimed to determine whether ECV fraction with equilibrium contrast-enhanced computed tomography (CECT) could predict long-term outcomes in patients with PanNEN.This study was a retrospective observational study of 80 patients pathologically diagnosed with PanNEN at a single institution. ECV fraction of the primary lesion was calculated using region-of-interest measurement within PanNEN and the aorta on unenhanced and equilibrium CECT. The impact of clinical factors and tumor ECV fraction on progression-free survival (PFS) and overall survival (OS) was assessed with univariate and multivariate analyses using Cox proportional hazards models. The correlation between WHO classification and tumor ECV fraction was evaluated using Kendall rank correlation coefficients.PFS and OS rates were estimated as 93.4% and 94.6%, 78.7% and 86.2%, 78.7% and 77.0%, and 78.7% and 66.6% at 1, 3, 5, and 10 years, respectively. Multivariate analysis revealed that Union for International Cancer Control (UICC) stage (hazard ratio [HR] = 3.95, P = 0.003), WHO classification (HR = 12.27, P = 0.003), and tumor ECV fraction (HR = 11.93, P = 0.039) were independent predictors of PFS. Patient age (HR = 1.11, P 0.001), UICC stage (HR = 3.14, P = 0.001), and tumor ECV fraction (HR = 5.27, P = 0.024) were independent significant variables for predicting OS. Tumor ECV fraction had a weak inverse relationship with WHO classification (P = 0.045, τ = -0.178).ECV fraction determined by equilibrium CECT and UICC stage may predict survival in patients with PanNEN.

Background and aim Septal thickness (ST) can predict a malignant branch-duct (BD) and mixed-type intraductal papillary mucinous neoplasm (IPMN) of the pancreas, but its cut-off value has not been established. The aim of the present study was to determine the optimal ST cut-off value to predict malignancy using endoscopic ultrasound (EUS). Methods We retrospectively identified 200 patients with IPMN, including 132 with BD- and mixed-IPMN, who underwent surgical resection between 1989 and 2017. ST was defined as the septum or lesion wall with the maximum diameter in BD- and mixed-IPMN. The possibility of ST as a malignant predictor was examined, as well as the diagnostic ability of ST combined with mural nodule (MN) height for malignant IPMN. Results Among the 132 IPMN patients, pathological diagnosis was benign in 81 (61.4%) and malignant in 51 (38.6%). Area under the curve for the diagnosis of malignancy using ST was 0.74 for pathological specimens, 0.70 for EUS and 0.56 for computed tomography. Multivariate analysis showed that the odds ratios for ST ≥2.5 mm and MN height ≥5 mm were 3.51 [95% confidence interval (CI), 1.55-7.97, P = 0.003] and 3.36 (95% CI, 1.52-7.45, P = 0.003), respectively. Conclusions Septal thickness was an independent predictive factor similar to MN height for malignant IPMN in a multivariate analysis. The ST on EUS appeared to be the thickness of a fibrotic septum associated with the malignant transformation of IPMN. An ST cut-off value of 2.5 mm might provide an accurate prediction of malignant IPMN.

Although endoscopic retrograde cholangiopancreatography (ERCP) is technically difficult in patients with altered gastrointestinal tract, double-balloon endoscopy (DBE) allows endoscopic access to pancreato-biliary system in such patients. Balloon dilation of biliary stricture and extraction of bile duct stones, placement of biliary stent in patients with Roux-en-Y or Billroth-II reconstruction, using DBE have been reported. However, two major technical parts are required for double-balloon ERCP (DB-ERCP). One is insertion of DBE and the other is an ERCP-related procedure. The important point of DBE insertion is a sure approach to the afferent limb with Roux-en-Y reconstruction or Braun anastomosis. Short type DBE with working length 152 cm is beneficial for DB-ERCP because it is short enough for most biliary accessory devices. In this paper, we introduce our tips and tricks for successful DB-ERCP.

An 84-year-old male status post Roux-en-Y anastomosis and cirrhosis presented with fever and jaundice. Double-balloon endoscopy showed bleeding from the papilla of Vater and endoscopic retrograde cholangiopancreatography was performed. Cholangiography revealed an intraductal filling defect due to blood clots probably caused by bleeding from the hepatocellular carcinoma. Placement of an endoscopic nasobiliary drainage tube relieved the jaundice and cholangitis. Subsequent transarterial chemoembolization for hepatocellular carcinoma was performed to control the bleeding. After removal of the tube, he was discharged. The patient developed obstructive jaundice caused by a hepatocellular carcinoma. A short double-balloon endoscope with a 2.8 mm working channel enabled metal stent placement. Double-balloon ERCP enabled biliary drainage in a patient with surgically altered anatomy and cirrhosis, and provided effective relief of symptoms.

A 21-year-old female underwent a Kasai hepatoportoenterostomy with Roux-en-Y reconstruction for typeIII biliary atresia at age 63 days. At the age of 19 years, she developed cholangitis and CT scan revealed hepatolithiasis. She presented for treatment of the intrahepatic stone and the hepatportoenterostomy was directly visualized with double-balloon endoscopy (DBE). Endoscopic findings showed multiple intrahepatic bile ducts open to the jejunum through multiple orifices. Cholangiography showed narrowing of intrahepatic bile duct branches with a "fire-like" appearance. These findings have not been previously reported, since endoscopic approaches to patients with a hepaticojejunostomy were limited. DBE was useful to directly visualize the anastomosis in a patient status-post the Kasai operation for biliary atresia with a Rouxen-Y reconstruction.

Obtaining histological evidence of gallbladder carcinoma (GBC) is difficult due to its extraductal nature, and pathological confirmation remains challenging. We compared the diagnostic value and safety of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) with endoscopic retrograde cholangiography (ERC) in patients with suspected GBC.Eighty-three patients with GBC were evaluated. Prior to definitive management, pathological evidence of GBC was obtained through either ERC cytopathologic sampling (n = 33), EUS-FNA (n = 24) or both (n = 26).Among the 83 patients, 59 (71.0%) with biliary obstruction were sampled using ERC with 47.4% (28/59) sensitivity. In 19 of the remaining 31 cases, EUS-FNA sampling had 100% diagnostic sensitivity. Likewise, 50 (60.2%) of the 83 patients with suspected GBC underwent EUS-FNA of regional lymph nodes or the gallbladder (GB) mass itself with 94.8% sensitivity. The overall diagnostic sensitivity rates of ERC and EUS-FNA were 47.4 and 96%, respectively (P 0.001). Post-procedural complications were seen in 6.7% of the ERC group (4/59, all were mild pancreatitis), and in none of the EUS-FNA group (P = 0.10).Gallbladder carcinoma sampling using ERC and EUS-FNA should be incorporated into the diagnostic workup of GB lesions as complementary tools, and EUS-FNA should be applied in the setting of failed or not indicated ERC.

We report a case of main pancreatic duct (MPD)-type intraductal papillary mucinous neoplasms of the pancreas (IPMNs), in whom diagnostic imaging modalities showed abnormal findings after 4 episodes of acute pancreatitis. The patient was 51 years old at his first admission for acute pancreatitis. He experienced two more episodes of acute pancreatitis, though repeated computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP) showed no abnormality to explain the cause of the pancreatitis. After 3½ years from his first episode of pancreatitis, CT and endoscopic ultrasonography revealed pancreatic duct dilation of the pancreas head. Seven years after the first admission, a second ERCP and intraductal ultrasonography revealed a partially dilated MPD with papillary tumors. He underwent pancreaticoduodenectomy, and the pathological diagnosis was intraductal papillary mucinous adenoma with moderate atypia. This case suggests that acute pancreatitis can precede visualized IPMNs. Therefore, acute recurrent pancreatitis with unknown etiology should be followed up for the possibility of IPMNs, in order to detect neoplastic changes in the early stage to provide a better prognosis for the patient.

Metastasis to the pancreas (MP) is a rare entity that is difficult to identify by imaging alone. Few reports have described endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) findings. Herein, we try to describe the EUS and EUS-FNA characteristics of MP.This retrospective study compared 28 patients with MP (13 males; mean age: 60.1 ± 12.6 years) and 60 control patients (30 males; 62.7 ± 11.5 years) with pancreatic ductal adenocarcinoma (PDAC). All lesions were characterized by EUS, and MP was diagnosed by EUS-FNA (n = 16), surgery (n = 6) or both (n = 6).Multivariate logistic regression revealed that the presence of regular borders (p = 0.004; OR: 8.81, 95% CI: 1.97-39.4), the absence of retention cysts (p = 0.045; OR: 12.5, 95% CI: 1.06-147.0), and the absence of main pancreatic duct (MPD) dilation (p = 0.003; OR: 8.18, 95% CI: 2.04-32.8) were predictors of MP rather than PDAC. The EUS-FNA sampling adequacy was 95.4% (21/22), and the correct diagnosis was obtained in 95.2% (20/21) of cases when K-ras mutation analysis and/or immunostaining were added.The presence of regular borders, the absence of retention cysts and the presence of nondilated MPD on EUS indicate MP rather than PDAC. This diagnosis can be accurately confirmed by EUS-FNA with immunostaining and/or K-ras analysis.

Background: No study has compared covered metallic stents with Tannenbaum stents. We evaluated the efficacy of the DoubleLayer stent (DLS) and Covered Wallstent (CWS) in patients with pancreatic head cancer (PHC). Patients & Methods: This was a multicenter, prospective randomized study. Between October 2005 and December 2007, we enrolled 113 patients (58 DLS, 55 CWS) with unresectable PHC with distal biliary obstructions and observed them for at least 6 months. Results: No significant difference in patient survival was found between groups, with a median survival of 231 and 248 days in the DLS and CWS groups, respectively. The cumulative stent patency was significantly higher (P = 0.0072) in the CWS group. The respective mean and median stent patency was 202 and 133 days in the DLS group and 285 and 419 days in the CWS group. The incidence of DLS occlusion (53.5%) was significantly higher than that of CWS (23.6%; P = 0.0019). The respective causes of occlusion were tumor overgrowth (0, 1), ingrowth (0, 2), sludge (24, 2), food impaction (3, 5), kinking bile duct (2, 0), and other (2, 3). Other complications were cholecystitis (0, 4), pancreatitis (0, 1), migration (1, 5), liver abscess (2, 0), and other (1, 2). No significant difference in the incidence of complications between groups was observed. Conclusion: CWS had significantly longer patency than DLS for the management of PHC with obstructive jaundice. The incidence of complications other than stent occlusion was higher in CWS, but this difference did not reach significance.

Purpose. To evaluate gallbladder motility on ultrasonography after the ingestion of different forms and quantities of fat.Methods. After a fast, 111 volunteers underwent ultrasonography to measure gallbladder volumes before, 30 min, and 60 min after ingesting Calorie Mate Liquid®, Calorie Mate Jelly®, Terumeal 2.0®, or Terumeal 2.0α®, which are used as nutritional supplements. The Calorie Mate products contain 4.4 g of fat, while the Terumeal products contain 15 g of fat. Most of the fat in these products is composed of long-chain fatty acids except for Terumeal 2.0α®, in which 15% of the fat is composed of medium-chain fatty acids. Gallbladder volume and the ejection fraction were measured using the ellipsoid method.Results. There were significant differences in gallbladder volume before, 30 min, and 60 min after taking Calorie Mate Liquid® and Terumeal 2.0α®, and in gallbladder volume before and 30 min after taking Calorie Mate Jelly® and Terumeal 2.0®. There were significant differences in the 30-min ejection fraction between Calorie Mate Jelly® and Calorie Mate Liquid® and Terumeal 2.0α®, and in the 60-min ejection fraction between Calorie Mate Jelly® and Terumeal 2.0® and Terumeal 2.0α®. There were no other significant differences.Conclusions. Calorie Mate Liquid®, which contains 4.4 g of fat, can be used as an appropriate gallbladder stimulant. Gallbladder contractions were weaker with jellies than with others; thus, jelly meals are not appropriate for evaluating gallbladder contraction. There was no difference in gallbladder contraction between the meal containing a medium-chain fatty acid component of 15% and the other meals.

We reported previously that intestinal metaplasia in the gallbladder is strongly associated with expression of caudal-related homeobox transcription factor Cdx2. It has been documented that occult pancreatobiliary reflux, even in the absence of pancreaticobiliary maljunction, is associated with elevated risk of biliary malignancy. We ascertained the correlation between intestinal metaplasia in the gallbladder and occult pancreatobiliary reflux. In 196 patients with a normal pancreaticobiliary ductal arrangement who had undergone laparoscopic cholecystectomy, we performed intraoperative cholangiography and measured amylase levels in bile sampled from the gallbladder. The cutoff value for high cystic amylase was defined as a biliary amylase level higher than the normal upper limit of serum amylase (215 IU/L). We also retrospectively reviewed the cholecystectomized tissue specimens to investigate the presence of intestinal metaplasia and expression of Cdx2. Then, we explored the relationship between intestinal metaplasia in the gallbladder and occult choledocho-pancreatic reflux. Intestinal metaplasia was found in 16.8% (33/196) of the gallbladders. The prevalence of choledocho-pancreatic reflux revealed by intraoperative cholangiography was not significantly different between cases with intestinal metaplasia (5/33, 15.2%) and those without (25/163, 15.3%; P = .81). However, in cases with intestinal metaplasia, the rate of high cystic amylase (13/33, 39.4%) was significantly higher compared with cases without intestinal metaplasia (26/163, 16.0%, P = .005). In conclusion, intestinal metaplasia in the gallbladder is significantly correlated with high amylase levels in bile in patients with a morphologically normal pancreaticobiliary ductal arrangement.

Indian hedgehog (Ihh) is a member of hedgehog peptides family that exerts diverse effects on multiple cellular functions. Since Ihh expression is elevated in the pancreas of chronic pancreatitis patients, Ihh has been assumed to participate in the chronic pancreatic injury, especially in pancreatic fibrosis. However, its function in pancreatic fibrosis is still unknown. We thus examined Ihh effects on rat activated pancreatic stellate cells (PSCs) that play a central role in pancreatic fibrosis. Activated PSCs express both patched-1 and smoothened that are essential components of hedgehog receptor system. Ihh did not alter the PSC expression of collagen-1 or α-smooth muscle actin, a parameter of PSC transformation, or did not change PSC proliferation. However, Ihh enhanced PSC migration in both chemotactic and chemokinetic manners. Furthermore, Ihh increased the amount of membrane-type 1 matrix metalloproteinase (MT1-MMP) and altered its localization on the plasma membrane, which plays a stimulatory role in cellular migration. In addition, tissue inhibitor of metalloproteinase-2 (TIMP-2) attenuated Ihh-stimulated PSC migration. Since most hedgehog intracellular signals are mediated by Gli-1 transcription factor, we investigated its contribution to Ihh-enhancement of PSC migration. Ihh induced Gli-1 nuclear accumulation in PSCs, indicating that Ihh stimulates Gli-1-dependent signaling pathway in PSCs. Unexpectedly, however, adenovirus-mediated Gli-1 overexpression blocked the Ihh enhancement of both MT1-MMP localization on the plasma membrane and PSC migration. Furthermore, reduction of Gli-1 expression with RNA interference augmented Ihh-stimulated PSC migration. These data indicate that Ihh promotes PSC migration by enhancing MT1-MMP localization on the plasma membrane but is negatively regulated by Gli-1. J. Cell. Physiol. 216: 38–46, 2008. © 2008 Wiley-Liss, Inc.

When performing endoscopic retrograde cholangiopancreatography (ERCP), the smooth introduction of the duodenoscope into the papilla of Vater, an appropriate view of the papilla of Vater, and deep cannulation of the bile duct are essential. The operator must know the difference between the side-viewing endoscope and the forward-viewing endoscope. The rotation of the body and the left arm of the operator, switching with the left wrist, and dialing of the endoscope are essential for appropriately viewing the papilla of Vater. When training operators to do ERCP, a model is useful for helping them understand basic handling. The approach to deep cannulation of the bile duct should be selected based on the type of papilla (slit type, onion type, tongue protrusion type, flat type, and tumor type). Cannulation is more difficult in patients with the tongue protrusion-type of papilla than with a slit type, onion type, or tumor type. According to previous reports, therapeutic ERCP requires the ability to cannulate the common bile duct deeply 80% of the time; 180 to 200 supervised ERCP are necessary to achieve this success rate.

To determine the optimal method of endoscopic preoperative biliary drainage for malignant distal biliary obstruction.Multicenter retrospective study was conducted in patients who underwent plastic stent (PS) or nasobiliary catheter (NBC) placement for resectable malignant distal biliary obstruction followed by surgery between January 2010 and March 2012. Procedure-related adverse events, stent/catheter dysfunction (occlusion or migration of PS/NBC, development of cholangitis, or other conditions that required repeat endoscopic biliary intervention), and jaundice resolution (bilirubin level3.0 mg/dL) were evaluated. Cumulative incidence of jaundice resolution and dysfunction of PS/NBC were estimated using competing risk analysis. Patient characteristics and preoperative biliary drainage were also evaluated for association with the time to jaundice resolution and PS/NBC dysfunction using competing risk regression analysis.In total, 419 patients were included in the study (PS, 253 and NBC, 166). Primary cancers included pancreatic cancer in 194 patients (46%), bile duct cancer in 172 (41%), gallbladder cancer in three (1%), and ampullary cancer in 50 (12%). The median serum total bilirubin was 7.8 mg/dL and 324 patients (77%) had ≥ 3.0 mg/dL. During the median time to surgery of 29 d [interquartile range (IQR), 30-39 d]. PS/NBC dysfunction rate was 35% for PS and 18% for NBC [Subdistribution hazard ratio (SHR) = 4.76; 95%CI: 2.44-10.0, P0.001]; the pig-tailed tip was a risk factor for PS dysfunction. Jaundice resolution was achieved in 85% of patients and did not depend on the drainage method (PS or NBC).PS has insufficient patency for preoperative biliary drainage. Given the drawbacks of external drainage via NBC, an alternative method of internal drainage should be explored.

Pancreatic ductal carcinoma (PDC) remains one of the most intractable human malignancies, mainly because of the lack of sensitive detection methods. Although gene expression profiling by DNA microarray analysis is a promising tool for the development of such detection systems, a simple comparison of pancreatic tissues may yield misleading data that reflect only differences in cellular composition. To directly compare PDC cells with normal pancreatic ductal cells, we purified MUC1-positive epithelial cells from the pancreatic juices of 25 individuals with a normal pancreas and 24 patients with PDC. The gene expression profiles of these 49 specimens were determined with DNA microarrays containing >44 000 probe sets. Application of both Welch's analysis of variance and effect size-based selection to the expression data resulted in the identification of 21 probe sets corresponding to 20 genes whose expression was highly associated with clinical diagnosis. Furthermore, correspondence analysis and 3-D projection with these probe sets resulted in separation of the transcriptomes of pancreatic ductal cells into distinct but overlapping spaces corresponding to the two clinical classes. To establish an accurate transcriptome-based diagnosis system for PDC, we applied supervised class prediction algorithms to our large data set. With the expression profiles of only five predictor genes, the weighted vote method diagnosed the class of samples with an accuracy of 81.6%. Microarray analysis with purified pancreatic ductal cells has thus provided a basis for the development of a sensitive method for the detection of PDC.

During the last decade significant advances in gene therapy have made it possible to treat various pancreatic disorders in both animal models and in humans. For example, insulin gene delivery to non-beta-cell tissues has been shown to reverse hyperglycemia in diabetic mice, and islet transplantation, based on in vitro differentiation of beta cells and concomitant gene targeting to prevent host autoimmune responses, has become more feasible. Additionally, introduction of the glucokinase regulatory protein and protein kinase C-zeta have been shown to improve glucose tolerance in non-insulin-dependent diabetes mellitus animal models. Pancreatic cancer studies utilize several DNA-based strategies for tumor treatment including introduction of tumor suppressor genes, suppression of oncogenes, suicide gene/prodrug therapy, and restricted replication-competent virus therapy. Tumor-specific targeting is an important part of suicide gene therapy, and tumor-specific promoters are used for cell-specific targeting. Tumor-specific suicide gene therapy directed by the rat insulin promoter has been used to eliminate insulinoma tumors in a mouse model. This review compiles a compendium of information related to the treatment of pancreatic disorders using gene therapy.

Many transcription factors are involved in the molecular control of intestinal epithelial cell differentiation. We report in this study that the transcription factor Cdx2 functions to define absorptive enterocytes during intestinal epithelial differentiation. Cdx2 is expressed in the villi of the normal small intestine. Intestinal metaplasia, which expresses Cdx2, occurs as a pathological condition in gastric mucosa. We have previously established Cdx2 transgenic mice expressing Cdx2 exclusively in the gastric epithelium. In this study using Cdx2 transgenic mice, we show that Cdx2 plays a key role in the differentiation of intestinal absorptive enterocytes. The gastric mucosa of Cdx2 transgenic mice was morphologically completely changed into intestinal metaplastic mucosa. Absorptive enterocytes had microvilli which were observed by electron microscope. The intestinal metaplastic mucosa of Cdx2 transgenic mice expressed sucrase and peptide transporter PepT1. Disaccharidase and leucine aminopeptidase activities were observed in the intestinal metaplastic mucosa. Glucose and amino acids were absorbed from Cdx2 transgenic mouse stomach with intestinal metaplasia. Finally we generated mice whose intestine was extensively excised. Cdx2 transgenic mice with intestinal metaplasia survived even after extensive intestinal excision. We successfully demonstrated that Cdx2 induced not only morphological but also functional absorptive enterocytes in the intestinal metaplastic mucosa in vivo. Our results suggest that Cdx2 is necessary and sufficient by itself to specify the development of intestinal absorptive enterocytes, whereas other factors which are expressed in the small intestine are not always necessary for the differentiation of functional absorptive enterocytes.

Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor-beta(1) (TGF-beta(1)) regulates PSC activation and proliferation in an autocrine manner. The intracellular signaling pathways of the regulation were examined in this study. Immunoprecipitation and immunocytochemistry revealed that Smad2, Smad3, and Smad4 were functionally expressed in PSCs. Adenovirus-mediated expression of Smad2, Smad3, or dominant-negative Smad2/3 did not alter TGF-beta(1) mRNA expression level or the amount of autocrine TGF-beta(1) peptide. However, expression of dominant-negative Smad2/3 inhibited PSC activation and enhanced their proliferation. Co-expression of Smad2 with dominant-negative Smad2/3 restored PSC activation inhibited by dominant-negative Smad2/3 expression without changing their proliferation. By contrast, co-expression of Smad3 with dominant-negative Smad2/3 attenuated PSC proliferation enhanced by dominant-negative Smad2/3 expression without altering their activation. Exogenous TGF-beta(1) increased TGFbeta(1) mRNA expression in PSCs. However, PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MEK1), inhibited ERK activation by TGF-beta(1), and consequently attenuated TGF-beta(1) enhancement of its own mRNA expression in PSCs. We propose that TGF-beta(1) differentially regulates PSC activation, proliferation, and TGF-beta(1) mRNA expression through Smad2-, Smad3-, and ERK-dependent pathways, respectively.

Background and aim: The present study was conducted to examine the effect of activin A on activation of rat pancreatic stellate cells (PSCs). Methods: PSCs were prepared from rat pancreas using collagenase digestion and centrifugation with Nycodenz gradient. Activation of PSCs was examined by determining smooth muscle actin expression with western blotting. The presence of activin A receptors in PSCs was investigated by reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunocytochemistry. Expression of activin A and transforming growth factor β (TGF-β) mRNA was examined by RT-PCR. Activin A and TGF-β peptide concentrations were examined with ELISA. Existence of activin A peptide in PSCs was investigated by immunocytochemistry. Collagen secretion was determined by Sirius red dye binding. Results: Activin A receptors I and IIa were present in PSCs. PSCs expressed activin A mRNA and secreted activin A. Activin A enhanced PSC activation and collagen secretion in a dose dependent manner. TGF-β and activin A increased each other’s secretion and mRNA expression of PSCs. Follistatin decreased TGF-β mRNA expression and TGF-β secretion of PSCs, and inhibited both PSC activation and collagen secretion. Conclusion: Activin A is an autocrine activator of PSCs. Follistatin can inhibit PSC activation and collagen secretion by blocking autocrined activin A and decreasing TGF-β expression and secretion of PSCs.

Jaundice in hyperemesis gravidarum may cause physicians to suspect several underlying diseases. Jaundice appeared in a woman with hyperemesis gravidarum and an ultrasound revealed biliary sludge. Hydration concomitantly ameliorated the symptoms, jaundice and the biliary sludge. Another woman with hyperemesis gravidarum showed elevated aminotransferases, with biliary sludge also being present. Hydration ameliorated the symptoms and liver dysfunction, and reduced the total bilirubin level. Biliary sludge appeared, but was ameliorated according to the symptoms of hyperemesis gravidarum.

Background: The introduction of a guidewire through bile duct strictures may facilitate transpapillary bile duct biopsy and subsequent biliary drainage. Methods: Endoscopic bile duct biopsy was attempted in 61 patients with bile duct strictures. After the introduction of a guidewire into the bile duct, biopsy forceps were inserted via the papilla. Both devices were inserted through the working channel (3.2 mm in diameter) of a conventional duodenoscope. After the procedure, an endoscopic naso-biliary drainage catheter was advanced along the guidewire. The success rate of inserting the biopsy forceps, the sensitivity of the biopsy, and the success rate of endoscopic biliary drainage after the biopsy were analyzed prospectively. Results: The final diagnosis was malignant strictures in 50 patients and benign strictures in 11. The success rate of inserting biopsy forceps without performing endoscopic papillary balloon dilation was 85%. The sensitivity of the biopsy for primary bile duct cancer (83%) was significantly higher (P < 0.05) than that of pancreatic cancer (47%). All patients had successful endoscopic biliary drainage after the procedure. Conclusion: A previously placed guidewire facilitates insertion of biopsy forceps and endoscopic biliary drainage. The histological diagnosis of cancer is more likely with bile duct cancer than with pancreatic cancer. © 2002 Blackwell Science Asia Pty Ltd

Although endoscopic retrograde cholangiopancreatography (ERCP) is technically difficult in patients with altered gastrointestinal tract, double-balloon endoscopy (DBE) allows endoscopic access to pancreato-biliary system in such patients. Balloon dilation of biliary stricture and extraction of bile duct stones, placement of biliary stent in patients with Roux-en-Y or Billroth-II reconstruction, using DBE have been reported. However, two major technical parts are required for double-balloon ERCP (DB-ERCP). One is insertion of DBE and the other is an ERCP-related procedure. The important point of DBE insertion is a sure approach to the afferent limb with Roux-en-Y reconstruction or Braun anastomosis. Short type DBE with working length 152 cm is beneficial for DB-ERCP because it is short enough for most biliary accessory devices. In this paper, we introduce our tips and tricks for successful DB-ERCP.

Background:We wanted to distinguish wall thickening caused by cancer extension from that caused by inflammation after placing a biliary catheter on intraductal ultrasonography (IDUS). Methods: We studied 51 patients with biliary tract malignancies who had undergone placement of biliary drainage catheters before IDUS. IDUS was performed from a transhepatic (n = 34) or transpapillary (n = 17) route with a thin-caliber ultrasonic probe (2.0 mm in diameter, 20-MHz frequency). At the hepatic side of the tumor, the thickness, asymmetry, outer margin, inner margin, and internal echoes of the bile duct wall were reviewed prospectively and correlated with the histologic findings of the surgically resected specimens in all cases. Results: When IDUS showed wall thickening in a semicircular fashion, notched outer margin, rigid inner margin, papillary inner margin, and heterogeneous internal echoes, each finding had a positive predictive value for diagnosing cancer extension (100%, 100%, 83%, 100%, and 90%, respectively). When these factors were used as the diagnostic criteria of cancer extension, IDUS accurately demonstrated suitable surgical margins in 76% of all patients and 71% of patients with bile duct carcinoma. Conclusion: Wall thickening in a semicircular fashion, notched outer margin, rigid or papillary inner margin, and heterogeneous internal echoes are specific for cancer extension. However, surgical margins can be inaccurately assessed in some patients.

Background and Aim: Tumor thrombi in the bile duct caused by hepatocellular carcinoma (HCC), and cholangiocarcinoma show polypoid lesions on cholangiographic findings. This study prospectively compared the images of intraductal ultrasonography between HCC and polypoid cholangiocarcinoma. Methods: In five patients with tumor thrombi in the bile duct caused by HCC, a 2.0 mm diameter ultrasonic probe with a frequency of 20 MHz was inserted into the bile duct via the transpapillary route (n = 4) or the transhepatic route (n = 1). The images were compared to that of 65 patients with cholangiocarcinoma. Results: In all patients with HCC, intraductal ultrasonography showed a ‘polypoid tumor with a narrow base’. In 16 of 65 patients with cholangiocarcinoma, it showed a ‘polypoid tumor with a narrow base’. When intraductal ultrasonography showed a ‘polypoid tumor with a narrow base’, the findings of a positive ‘nodule within a nodule’ (40 vs 0%; P < 0.05), and the absence of a ‘papillary-surface pattern’ (80 vs 13%; P < 0.05) were more highly associated with tumor thrombi caused by HCC than to polypoid-type cholangiocarcinoma. Conclusions: Intraductal ultrasonography was useful to distinguish between tumor thrombi caused by HCC and polypoid-type cholangiocarcinoma.

The utility of intraductal US via the transpapillary route prior to biliary drainage in the assessment of longitudinal extension of extrahepatic bile duct carcinoma was investigated.In 19 patients with extrahepatic bile duct carcinoma who underwent surgical resection, an ultrasonic probe (diameter, 2.0 mm; frequency, 20 MHz) was inserted into the bile duct via the transpapillary route prior to biliary drainage. Longitudinal cancer extension along the bile duct was prospectively determined and compared with the histologic findings in the resected specimens.Results on the hepatic side were as follows: Intraductal US demonstrated more extensive longitudinal cancer spread than cholangiography in 9 of 19 patients with one instance of overdiagnosis. The accuracy of intraductal US in assessing the extent of spread (84%) was superior to that of cholangiography (47%) (p0.05). Results on the duodenal side were as follows: In patients with suprapancreatic bile duct cancer (n = 14), intraductal US demonstrated more extensive longitudinal cancer spread than cholangiography in 8 of 14 patients. The accuracy of intraductal US in assessing the extent of the spread (86%) was superior to that of cholangiography (43%) (p0.05).Transpapillary intraductal US prior to biliary drainage is useful in demonstrating longitudinal extension of bile duct cancer. However, the surgical margins were inaccurate in some patients.

Background: This is the first study to correlate intraductal ultrasonography (IDUS) with cholangioscopy in evaluating the patency of biliary metallic stents. Methods: The findings of IDUS (probe 2.0 mm in diameter and 20-MHz frequency) through a percutaneous transhepatic (n = 24) or transpapillary (n = 2) approach were retrospectively reviewed without other information. Criteria for IDUS are as follows: type 1, the inside of the stent is free; type 2, the inner edge is smooth; type 3, the inner edge is irregular; type 4, the inside of the stent is totally occupied; type 5, the solid echo is connected to the outside mass; type 2+D, a hypoechoic line is seen between the bile duct wall and the inside solid component and the inner edge of the bile duct wall is smooth; type 3+D, an irregular hypoechoic line is seen between the bile duct wall and the inside solid component. Results: In the control group (n = 11), IDUS showed type 1 (n = 9) or type 2 (n = 2). In the occluded group (n = 15), when IDUS showed type 3 or 5, the patients (n= 5) required additional stents (n = 3), microwave coagulation of the tumor (n= 1), or transient external drainage (n= 1). When IDUS showed type 4 (n = 5), after washing, the findings changed to type 2+D (n = 4). When IDUS after washing showed a smooth inner edge (type 2+D), the patients were treated without additional stents more frequently than the other groups (eight of nine vs. two of six), a significant distinction (p < 0.05). Conclusion: IDUS is useful in assessing the patency of metallic stents. When the inside of the stent is totally occupied, however, examination after washing is necessary.

Background: Transpapillary procurement of bile duct biopsy specimens is an effective diagnostic technique in cases of biliary structure. The utility of new ropeway-type bile duct biopsy forceps with a side slit for a guidewire was investigated in this study. Methods: The 12 patients in this study had bile duct cancer (n = 3), cancer of the head of the pancreas (n = 4), gallbladder cancer (n = 1), and benign bile duct stenosis (n = 4). After endoscopic retrograde cholangiography, a guidewire was placed in the bile duct across the stenosis. The new forceps (1.8-mm diameter clamshell-type biopsy forceps without needle) was then introduced through the intact papilla along the guidewire. Results: In all patients, sufficient tissue for histopathologic evaluation was obtained without complication. In one patient, biopsy specimens were selectively obtained of the left hepatic duct, which was impossible with conventional forceps. In another patient, histologic examination of specimens obtained by using this new forceps showed adenocarcinoma, whereas specimens obtained with a conventional forceps did not contain adenocarcinoma. However, in another patient, biopsy specimens obtained with a conventional forceps contained adenocarcinoma that was not evident in specimens obtained with the new forceps. Dislodgement of the guidewire during procurement of biopsy specimens occurred in 1 patient. In the other 11 patients, an endoscopic biliary drain was inserted over the guidewire. Conclusion: The new ropeway-type biopsy forceps is useful for selectively obtaining biopsy specimens of the bile duct. With this system, access for subsequent endoscopic biliary drainage is maintained.