Kiichi Tamada

Characterization of biliary strictures using intraductal ultrasonography: comparison with percutaneous cholangioscopic biopsy.

BACKGROUND We determined the accuracy of intraductal ultrasonography (IDUS) in distinguishing between bile duct cancer and benign bile duct disease. METHODS Patients (n=42) who required bile duct biopsy using percutaneous transhepatic cholangioscopy (PTCS) to evaluate bile duct strictures or filling defects were studied. A thin-caliber ultrasonic probe (2.0 mm diameter and 20 MHz frequency) was inserted into the bile duct, and its images were prospectively reviewed before PTCS. RESULTS Disruption of the bile duct wall structure, seen on IDUS, was associated with malignancy in 25 of 26 patients. When IDUS demonstrated a lesion with normal bile duct structure, six of nine patients were found to have no malignancy. IDUS demonstrated no intraductal lesion in seven patients, and bile duct biopsy also did not indicate cancer in any of these patients. The accuracy, sensitivity, and specificity of IDUS for diagnosing bile duct cancer were 76%, 89%, and 50%, respectively. When used in tandem with IDUS, the sensitivity of bile cytology (64%) and PTCS (93%) improved to 96% and 100%, respectively. CONCLUSIONS The accuracy of IDUS for diagnosing bile duct cancer was less than that of PTCS (95%). However, the sensitivity for bile cytology, or bile duct biopsy improved when performed in combination with IDUS.

Development of Gastric Carcinoma from Intestinal Metaplasia in Cdx2-transgenic Mice

In the progression of chronic gastritis, gastric mucosal cells deviate from the normal pathway of gastric differentiation to an intestinal phenotype. Many epidemiologic studies have found an association between the formation of intestinal metaplasia and the development of gastric carcinoma. However, there is no direct evidence that shows intestinal metaplasia is a precursor lesion of gastric carcinoma, to date. We periodically examined the intestinal metaplastic mucosa of Cdx2-transgenic mice we have previously generated. Gastric polyps developed from intestinal metaplastic mucosa in all stomachs of Cdx2-transgenic mice examined. These gastric polyps consisted of intestinal-type adenocarcinoma that invaded the submucosa and muscularis propria and occasionally spread into the subserosa. p53 and APC gene mutations were recognized in the adenocarcinomas. The participation of APC and p53 gene mutations in gastric carcinogenesis from the intestinal metaplasia was verified by the Cdx2-transgenic mice, carrying ApcMin mutation or p53 deficiency, that developed gastric polyps much earlier than Cdx2 alone. We successfully showed that long-term intestinal metaplasia induces invasive gastric carcinoma. These results indicate that intestinal metaplasia itself plays a significant role in the genesis and progression of gastric carcinoma.

Endoscopic transpapillary bile duct biopsy with the combination of intraductal ultrasonography in the diagnosis of biliary strictures

Background: When endoscopic retrograde cholangiopancreatography (ERCP) guided bile duct biopsy fails to demonstrate malignancy, it remains unclear how to manage patients with presumably malignant strictures. Aims: To evaluate the value of intraductal ultrasonography (IDUS) when bile duct biopsy is negative. Methods: Sixty two patients with strictures of the bile duct were studied prospectively. During ERCP, IDUS was performed using an ultrasonic probe (diameter 2.0 mm; frequency 20 MHz). Following IDUS, a bile duct biopsy was performed using forceps (diameter 1.8 mm). The IDUS images of the tumour were classified as polypoid lesions, localised wall thickening, intraductal sessile tumours, sessile tumour outside of the bile duct, or absence of apparent lesion. The bile duct wall structures at the site of the tumour as well as the maximum diameter of the tumour were also analysed. The IDUS findings were compared with the histological findings or clinical course. Results: When the IDUS images showed a polypoid lesion (n=19), localised wall thickening (n=8), intraductal sessile tumour (n=13), and sessile tumour outside of the bile duct (n = 20), the sensitivities of the biopsy were 80%, 50%, 92%, and 53%, respectively. Multiple regression analysis showed that the presence of sessile tumour (intraductal or outside of the bile duct: p<0.05), tumour size greater than 10.0 mm (p<0.001), and interrupted wall structure (p<0.05) were independent variables that predicted malignancy. Conclusion: When biopsy fails to demonstrate evidence of malignancy, the presence of sessile tumour (intraductal or outside of the bile duct), tumour size greater than 10.0 mm, and interrupted wall structure on IDUS images are factors that can predict malignancy.

Transpapillary intraductal US prior to biliary drainage in the assessment of longitudinal spread of extrahepatic bile duct carcinoma

BACKGROUND 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. METHODS 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 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%) (p < 0.05). 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%) (p < 0.05). CONCLUSIONS 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.

Activin A is an autocrine activator of rat pancreatic stellate cells: potential therapeutic role of follistatin for pancreatic fibrosis

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.

Influence of biliary drainage catheter on bile duct wall thickness as measured by intraductal ultrasonography

OBJECTIVE To determine the influence of biliary drainage catheter placement on bile duct wall thickness, we performed intraductal ultrasonography (IDUS) in patients before and after biliary drainage. METHODS Patients underwent IDUS before and after either short-term (n = 9, 6 to 8 days) or long-term (n = 9, 14 to 35 days) biliary drainage using a thin (2.0 mm diameter), 20 MHz probe inserted by means of a transpapillary route or a percutaneous tract. The bile duct wall thickness (mean +/- standard deviation) was retrospectively measured at the upper portion of the common hepatic duct. RESULTS The bile duct wall thickness increased from 0.8+/-0.4 mm (predrainage) to 2.0+/-1.6 mm (post-drainage) in the long-term group (p < 0.001) but was not significantly increased in the short-term group. CONCLUSIONS The bile duct wall thickness as measured on IDUS appears to be increased after placement of biliary drainage catheters.

Results of a Japanese multicenter, randomized trial of endoscopic stenting for non-resectable pancreatic head cancer (JM-test): Covered Wallstent versus DoubleLayer stent.

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).

Bile duct wall thickness measured by intraductal US in patients who have not undergone previous biliary drainage

BACKGROUND We investigated the bile duct wall thickness measured on intraductal US in patients who had not undergone biliary drainage, with special attention to the influence of cancer at the distal bile duct, bile duct stones, obstructive jaundice, longitudinal cancer extension, and primary sclerosing cholangitis on wall thickness. METHODS The study included 183 patients. Patients who had undergone previous biliary drainage were excluded. Intraductal US was performed by the transpapillary route with use of a thin-caliber ultrasonic probe (2.0 mm diameter, 20 MHz frequency). The bile duct wall thickness (width of the inside hypoechoic layer) was retrospectively measured on US images. RESULTS Bile duct wall thicknesses of the common hepatic duct for the control group (n = 95), cancer at the distal bile duct group (n = 9), bile duct stone group (n = 56), and obstructive jaundice group (n = 17) were 0.6 +/- 0.3 mm (mean +/- SD), 0.8 +/- 0.5 mm, 0.8 +/- 0.6 mm, and 0.8 +/- 0. 5 mm, respectively. No significant differences (p > 0.05) were found between them. However, wall thickness for the cancer extension to the common hepatic duct group (n = 4, 2.0 +/- 0.4 mm) and sclerosing cholangitis group (n = 2, 2.5 +/- 0.4 mm) were significantly greater than in the other groups (p < 0.005). CONCLUSIONS In patients who have not undergone previous biliary drainage, the bile duct wall thickness was not thicker in patients with obstructive jaundice. However, the duct wall was significantly thicker in patients with either longitudinal cancer extension or primary sclerosing cholangitis compared with that of other groups.

Assessment of residual bile duct stones with use of intraductal US during endoscopic balloon sphincteroplasty: comparison with balloon cholangiography

BACKGROUND We sought to determine the utility of intraductal ultrasonography (IDUS) in detecting residual bile duct stones during endoscopic balloon sphincteroplasty. METHODS Eighty-one consecutive patients with bile duct stones who underwent IDUS during endoscopic balloon sphincteroplasty were studied. IDUS was performed with a thin-caliber ultrasonic probe (diameter 2.0 mm, frequency 20 MHz) by a transpapillary route after stone extraction. When IDUS or balloon-retrograde cholangiography suggested residual stones, the bile duct was cleared again with a Dormia basket. Extraction of the stones was confirmed by direct duodenoscopic visualization. Videotapes of IDUS and cholangiograms were reviewed retrospectively without knowledge of the results of other diagnostic modalities. RESULTS In 27 of 81 patients (33%), IDUS detected small residual stones not seen on cholangiography. When stones were fragmented with mechanical lithotripsy, the accuracy of IDUS in detecting small residual stones was significantly greater than that of balloon-endoscopic retrograde cholangiography (95% vs 50%, p < 0. 001). When the bile duct was greater than 10 mm in diameter, the accuracy of IDUS in detecting small residual stones was significantly greater than that of cholangiography (92% vs. 56%, p < 0.001). CONCLUSIONS IDUS is useful for detecting small residual bile duct stones during endoscopic balloon sphincteroplasty when stones are fragmented by mechanical lithotripsy or when there is evidence of a dilated bile duct (>10 mm).

Existence of autocrine loop between interleukin‐6 and tranforming growth factor‐β1 in activated rat pancreatic stellate cells

Interleukin (IL)‐6 is a proinflammatory cytokine assumed to participate in pancreatic fibrosis by activating pancreatic stellate cells (PSCs). Autocrine TGF‐β1 is to central in PSC functional regulation. In this study, we examined IL‐6 secretion from culture‐activated rat PSCs and its regulatory mechanism. Activated PSCs express and secrete IL‐6. When anti‐TGF‐β1 neutralizing antibody was added in the culture medium, IL‐6 secretion from activated PSCs was inhibited, whereas exogenous TGF‐β1 added in the culture medium enhanced IL‐6 expression and secretion by PSCs in a dose dependent manner. Infection of PSCs with an adenovirus expressing dominant‐negative Smad2/3 attenuated basal and TGF‐β1‐stimulated IL‐6 expression and secretion of PSCs. We also demonstrated the reciprocal effect of PSCs‐secreted IL‐6 on autocrine TGF‐β1. Anti‐IL‐6 neutralizing antibody inhibited TGF‐β1 secretion from PSCs. Preincubation of cells with 10 nM PD98059, an extracellular signal‐regulated kinase (ERK)‐dependent pathway inhibitor, attenuated IL‐6‐enhanced TGF‐β1 expression and secretion of PSCs. In addition, IL‐6 activated ERK in PSCs. These data indicate the existence of autocrine loop between IL‐6 and TGF‐β1 through ERK‐ and Smad2/3‐dependent pathways in activated PSCs. J. Cell. Biochem.