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Biomedical subjects

Minoru Tada

Publications and source records attributed to Minoru Tada.

At least 19 recordsLinked to original sources
PubMed2006

Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract.

PURPOSE: It is important to identify the definitive molecular switches involved in the malignant transformation of premalignant tissues. Cellular senescence is a specific characteristic of precancerous tissues, but not of cancers, which might reflect tumorigenesis-protecting mechanisms in premalignant lesions. Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers. We hypothesized that Bmi1 expression would also be dysregulated in precancerous lesions in human digestive precancerous tissues. EXPERIMENTAL DESIGN: Bmi1 expression was investigated in cancerous and precancerous tissues of the digestive tract. The expression of p16, beta-catenin, and Gli1 and the in vivo methylation status of the p16 gene were also analyzed in serial sections of colonic precancerous lesions. RESULTS: Bmi1 was clearly overexpressed across a broad spectrum of gastrointestinal cancers, and the expression of Bmi1 increased in a manner that reflected the pathologic malignant features of precancerous colonic tissues (low-grade dysplasia, 12.9 +/- 2.0%; high-grade dysplasia, 82.9 +/- 1.6%; cancer, 87.5 +/- 2.4%). p16 was also strongly expressed in high-grade dysplasia, but not in cancers. p16 promoter methylation was detected only in some Bmi1-positive neoplastic cells. CONCLUSIONS: Bmi1 overexpression was correlated with the malignant grades of human digestive precancerous tissues, which suggests that advanced Bmi1 dysregulation might predict malignant progression. The abnormal Bmi1 expression might link to malignant transformation via the disturbance of orderly histone modification.

Cell Line, Tumor↗
PubMed2006

Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients.

BACKGROUND & AIMS: K-ras mutation is frequently detected in pancreatic juice of patients with pancreatic small cystic lesions, as well as those with pancreatic cancer. Those cystic lesions are often found by chance with modern radiologic imaging modalities. In this study, we prospectively examined the prognosis of patients with pancreatic cystic lesions, focusing on pancreatic cancer development. METHODS: A total of 197 patients with pancreatic cystic lesions, 80 with intraductal papillary mucinous neoplasm (IPMN) and 117 with non-IPMN cysts, were followed up for 3.8 years on average. Blood tests and imaging diagnosis were performed twice a year. The observed incidence of pancreatic cancer was compared with the expected incidence calculated on the basis of age- and gender-matched mortality of pancreatic cancer in the general Japanese population. RESULTS: Pancreatic cancer developed in 7 patients during the observation period (0.95% per year), infiltrating ductal carcinoma in 5 and intraductal papillary mucinous carcinoma in 2. Three of the ductal cancer cases had pancreatic non-IPMN cyst as preexisting lesion. At least 2 of the carcinomas arose in regions remote from preexisting lesions. The observed incidence of pancreatic cancer was 22.5 times higher (95% confidence interval, 11.0-45.3) than expected mortality from this cancer among general population. CONCLUSIONS: Patients with pancreatic cystic lesions are at a considerably high risk for pancreatic cancer, with a standardized incidence rate of 22.5. Cancer might develop in regions remote from the preexisting cystic lesion, suggesting diffuse pathologic changes predisposing to malignant transformation in the entire pancreas harboring cystic lesions.

Adult↗
PubMed2006

Endoscopic management of biliary complications after adult living donor liver transplantation.

OBJECTIVES: Biliary complications are one of the important issues to be addressed after liver transplantation. Endoscopic management of biliary complications after deceased donor liver transplantation (DDLT) is widely accepted, but it remains to be established in patients after living donor liver transplantation (LDLT). Endoscopic management in LDLT patients is difficult mainly because of the complexity of duct-to-duct reconstruction. METHODS: A total of 174 adult LDLTs with duct-to-duct reconstruction were performed in our institution. Biliary complications developed in 53 patients (30%). Among these, 18 patients were referred for endoscopic management and were the subjects of the present study. Success rate, early morbidity, and outcome were evaluated in these 18 patients. RESULTS: The type of graft was the right liver in six, left liver in eight, and right lateral sector in four patients. Ten out of 18 patients had one biliary anastomosis and the remaining eight had multiple anastomoses. Six patients had a previous history of surgical or percutaneous intervention for biliary complications after LDLT. Seventeen patients had one or more biliary strictures. Biliary casts were found in nine patients, three of whom had concomitant bile leaks. Strictures were successfully treated with endoscopic balloon dilation in 12 (71%) of the 17 patients (nasobiliary catheter placement in eight and stent placement in four patients). Bile leak was successfully managed in two of three patients. Biliary casts were removed by endoscopic papillary balloon dilation in eight of nine patients. Five patients with failed endoscopic therapy were converted to percutaneous or surgical intervention. Endoscopic-procedure-related cholangitis developed in one patient. During follow-up with median periods of 10 months (range 2-20 months), four of nine patients without stent placement developed biliary strictures, and these were relieved by additional endoscopic management. CONCLUSIONS: Endoscopic approach has the potential to be a first-line therapy for the management of biliary complications after LDLT.

Adult↗
PubMed2006

Cholecystitis after metallic stent placement in patients with malignant distal biliary obstruction.

BACKGROUND & AIMS: Cholecystitis after metallic stent (MS) placement is an issue requiring attention. From our experience, cholecystitis seemed to occur mainly in patients with tumor involvement to the cystic duct orifice. The aim of the present study was to identify risk factors for cholecystitis in patients treated with covered or uncovered MS. METHODS: We analyzed 246 patients who received MS placement (covered MS in 171 and uncovered in 75) between August 1997 and May 2005 for the treatment of unresectable distal malignant biliary obstruction. Causative diseases were as follows: pancreatic cancer in 162, papillary cancer in 10, bile duct cancer in 41, and metastatic nodes in 33 patients. Tumor involvement to orifice of the cystic duct (OCD) was diagnosed based on cholangiography and intraductal ultrasonography. RESULTS: Cholecystitis after MS placement was found in 13 patients (5.3%). There was no significant difference in the incidence of cholecystitis between covered (5.8%) and uncovered (4.0%) MS. By univariate analysis, tumor involvement of the OCD, MS placed above the papilla, and stricture located at midportion were associated significantly with cholecystitis. By multivariate analysis, only tumor involvement of the OCD was a risk factor, with an odds ratio of 47.206 (95% confidence interval, 5.84-381.60). CONCLUSIONS: Cholecystitis after MS placement is associated with tumor involvement to the orifice of the cystic duct, regardless of the type of stent.

Aged↗
PubMed2006

Serum IgG4 concentrations in pancreatic and biliary diseases.

BACKGROUND: Recently, it has been reported that the serum concentration of IgG4, a minor component of IgG subclasses, is increased in autoimmune pancreatitis. However, data regarding IgG4 concentrations in other pancreatic or biliary diseases have been insufficient. METHODS: Serum IgG4 was measured in 116 patients with pancreatic or biliary diseases (35 autoimmune pancreatitis, 24 chronic pancreatitis except autoimmune pancreatitis, 11 primary sclerosing cholangitis, 23 pancreatic cancer, 3 islet cell tumor, 2 papilla cancer, 15 bile duct cancer, and 3 gallbladder cancer patients). The cut-off concentration of IgG4 was 135 mg/dl. RESULTS: Increased serum IgG4 was observed in 33 of 35 patients with autoimmune pancreatitis, 0 of 24 with chronic pancreatitis, 4 of 11 with primary sclerosing cholangitis, 0 of 23 with pancreatic cancer, 0 of 3 with islet cell tumor, 0 of 2 with duodenal papilla cancer, 0 of 15 with bile duct cancer and 0 of 3 with gallbladder cancer patients. CONCLUSIONS: Serum IgG4 was increased in autoimmune pancreatitis and was within normal limits for other pancreatic or biliary diseases except primary sclerosing cholangitis.

Adolescent↗
PubMed2006

Efficacy of peppermint oil as an antispasmodic during endoscopic retrograde cholangiopancreatography.

BACKGROUND: During endoscopic retrograde cholangiopancreatography (ERCP), hyoscine-N-butylbromide (Buscopan) or glucagon is used to inhibit duodenal motility. However, they may cause adverse effects. Peppermint oil has an antispasmodic effect and is used as a less hazardous antispasmodic during colonoscopy and upper gastrointestinal endoscopy. The purpose of the present paper was therefore to investigate peppermint as an antispasmodic for ERCP. METHODS: Forty patients were enrolled prospectively. They were assigned to four groups according to the peppermint oil concentration and site of administration: group 1, 20 mL of 1.6% solution around duodenal papilla; group 2, 20 mL of 1.6% solution both to the antrum of the stomach and around the duodenal papilla; group 3, 20 mL of 3.2% solution around the duodenal papilla; and group 4, 3.2% solution both to the antrum and around the duodenal papilla. Glucagon or hyoscine-N-butylbromide was added when duodenal peristalsis was not adequately diminished. Sixteen patients undergoing ERCP with glucagon were employed as historical controls. RESULTS: The ERCP was attempted in all except one patient in group 2 who had bleeding from invaded tumor to the duodenum. Peppermint administration equally reduced duodenal motility in the groups. Duodenal movement was none or mild in 69.2% of patients. The ERCP was successfully performed with peppermint alone in 91.4% of patients (37/39). Glucagon or hyoscine-N-butylbromide was needed in one patient each in groups 1 and 4. Serious complications related to peppermint oil did not occur. Inhibitory effect of peppermint appears to be identical to that of glucagon. CONCLUSION: Duodenal relaxation was obtained with 20 mL of 1.6% peppermint oil solution in the duodenum, but additional administration may be required. Peppermint oil is useful as an antispasmodic agent for ERCP.

Adult↗
PubMed2005

p53-Independent negative regulation of p21/cyclin-dependent kinase-interacting protein 1 by the sonic hedgehog-glioma-associated oncogene 1 pathway in gastric carcinoma cells.

The activation of Hedgehog (Hh) signaling has been implicated in the growth of various tumor types, including gastric carcinoma. However, the precise mechanisms of Hh activation and suppression of tumor growth by the blockade of Hh signaling in gastric carcinoma cells remain unknown. The aim of this study was to elucidate the mechanism of abnormal Hh signaling and the key molecules contributing to dysregulated growth of gastric carcinoma. The Sonic hedgehog (Shh) ligand and its receptor Patched were expressed in all five gastric carcinoma cell lines examined (MKN1, MKN7, MKN45, MKN74, and AGS cells). The blockade of Hh signaling with anti-Shh antibody inhibited the growth of all five gastric carcinoma cell lines. Shh was overexpressed (mean, 12.8-fold) in 8 of 14 (57.0%) cancerous tissue samples from patients with gastric carcinoma as compared with expression in the surrounding noncancerous tissues. The disruption of glioma-associated oncogene 1 (Gli1) by small interfering RNA induced an increase in p21/cyclin-dependent kinase-interacting protein 1 (CIP1), interfered with the G1-S transition, and suppressed cell proliferation. The stimulation or inhibition of Hh signaling did not affect p53 activity and the induction of p21/CIP1 expression and the G1 arrest by inhibition of Hh signaling were not affected by the p53 status. These findings suggest that the overexpression of Shh contributes to constitutive Hh activation and that this signaling pathway negatively regulates p21/CIP1 through a Gli1-dependent and p53-independent mechanism in gastric carcinoma cells.

Adult↗
PubMed2005

Graft-versus-tumor effect against advanced pancreatic cancer after allogeneic reduced-intensity stem cell transplantation.

BACKGROUND: The prognosis of advanced pancreatic cancer is extremely poor and therefore a novel treatment strategy is desired. The authors thus started a prospective study of allogeneic reduced-intensity hematopoietic stem cell transplantation (RIST) for patients with advanced pancreatic cancer to evaluate the feasibility and efficacy of this approach for such patients. METHODS: Only patients with pathologically proven pancreatic cancer that was locally advanced or metastatic and not amenable to curative resection were included. The conditioning regimen consisted of gemcitabine, fludarabine, and busulfan. RESULTS: In the first stage of this study, the authors treated seven patients. Treatment-related mortality before day 100 was observed in one patient. The median survival after RIST was 229 days. An objective response on computed tomographic scan was observed in two patients and another had a tumor marker response. Marked tumor shrinkage was observed in one of the remaining patients after donor lymphocyte infusion. These antitumor effects appeared after the effect of the conditioning regimen had disappeared. In addition, some of these responses were associated with an increase in the serum anticarcinoembryonic antigen antibody level. CONCLUSIONS: Pancreatic cancer appeared to be sensitive to a graft-versus-tumor effect; therefore, a larger clinical study with a refined strategy is warranted.

Adult↗
PubMed2005

Detection of common bile duct stones: comparison between endoscopic ultrasonography, magnetic resonance cholangiography, and helical-computed-tomographic cholangiography.

OBJECTIVES: New modalities, namely, endoscopic ultrasonography (EUS), magnetic resonance cholangiopancreatography (MRCP), and helical computed-tomographic cholangiography (HCT-C), have been introduced recently for the detection of common bile duct (CBD) stones and shown improved detectability compared to conventional ultrasound or computed tomography. We conducted this study to compare the diagnostic ability of EUS, MRCP, and HCT-C in patients with suspected choledocholithiasis. METHODS: Twenty-eight patients clinically suspected of having CBD stones were enrolled, excluding those with cholangitis or a definite history of choledocholithiasis. Each patient underwent EUS, MRCP, and HCT-C prior to endoscopic retrograde cholangio-pancreatography (ERCP), the result of which served as the diagnostic gold standard. RESULTS: CBD stones were detected in 24 (86%) of 28 patients by ERCP/IDUS. The sensitivity of EUS, MRCP, and HCT-C was 100%, 88%, and 88%, respectively. False negative cases for MRCP and HCT-C had a CBD stone smaller than 5mm in diameter. No serious complications occurred while one patient complained of itching in the eyelids after the infusion of contrast agent on HCT-C. CONCLUSIONS: When examination can be scheduled, MRCP or HCT-C will be the first choice because they were less invasive than EUS. MRCP and HCT-C had similar detectability but the former may be preferable considering the possibility of allergic reaction in the latter. When MRCP is negative, EUS is recommended to check for small CBD stones.

Adult↗
PubMed2005

Efficacy and safety of the covered Wallstent in patients with distal malignant biliary obstruction.

BACKGROUND: The aim of this study was to evaluate the efficacy and the safety of the covered Wallstent, a commercially available silicone-covered, self-expandable metallic stent (covered Wallstent), for the treatment of distal malignant biliary obstruction. METHODS: Sixty-nine consecutive patients with unresectable distal malignant biliary obstruction who underwent covered Wallstent placement between October 2001 and October 2003 were studied at 4 affiliated hospitals. RESULTS: Mean stent patency and mean survival were 139.1 days and 200.9 days, respectively. Stent occlusion occurred in 7 cases (10.1%), but tumor ingrowth was not observed. Seventeen complications, including 5 cholangitis (7.2%), 4 stent migration (5.8%), 4 cholecystitis (5.8%), and 4 pancreatitis (5.8%) were observed in 16 patients (23.2%). Stent misplacement was observed in 7 patients (10.1%). CONCLUSIONS: Covered Wallstent is effective in preventing tumor ingrowth for the treatment of distal malignant biliary obstruction. However, the overall complication rate may be higher than uncovered self-expanding metal stents and covered self-expanding metal stents of different design.

Adult↗
PubMed2005

Ulinastatin for pancreatitis after endoscopic retrograde cholangiopancreatography: a randomized, controlled trial.

BACKGROUND & AIMS: Pancreatitis remains the major complication of endoscopic retrograde cholangiopancreatography (ERCP), and hyperenzymemia after ERCP is common. Because ulinastatin, a protease inhibitor, has proved effective in the treatment of acute pancreatitis, the aim of this study was to assess the efficacy of ulinastatin for the prevention of post-ERCP pancreatitis and hyperenzymemia. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial, patients undergoing a first ERCP were randomized to receive ulinastatin (150,000 U) or placebo by intravenous infusion for 10 minutes starting immediately before ERCP. All patients were hospitalized at least 24 hours after ERCP for evaluation of clinical symptoms. Serum pancreatic enzyme levels were measured before and at 4 and 18 hours after ERCP. The primary end point was the incidence of post-ERCP pancreatitis and the secondary objective was the occurrence of hyperenzymemia. RESULTS: A total of 406 patients were enrolled (204 in the ulinastatin group and 202 in the placebo group). There were no differences between the 2 groups regarding baseline characteristics, details of fluoroscopic findings, or endoscopic procedure. The incidence of hyperenzymemia was significantly lower in the ulinastatin group than in the placebo group (amylase, P = .011; lipase, P = .008). Six patients in the ulinastatin group and 15 patients in the placebo group developed pancreatitis (2.9% vs. 7.4%, P = .041). There was no case of severe pancreatitis in either group. Patients who received ulinastatin did not present any side effects related to the medication. CONCLUSIONS: Prophylactic short-term administration of ulinastatin decreases the incidence of pancreatitis and hyperenzymemia after ERCP.

Acute Disease↗
PubMed2005

Risk factors for pancreatitis in patients with common bile duct stones managed by endoscopic papillary balloon dilation.

OBJECTIVES: Endoscopic papillary balloon dilation has been accepted as a possible alternative to endoscopic sphincterotomy, especially in patients with impaired hemostasis. However, pancreatitis associated with endoscopic papillary balloon dilation has remained a controversial, serious issue. The aim of the study was to investigate the risk factors for postendoscopic papillary balloon dilation pancreatitis in a single-center study. METHODS: A total of 304 patients who underwent endoscopic papillary balloon dilation for the management of common bile duct stones were enrolled. The risk of postendoscopic papillary balloon dilation pancreatitis was evaluated and the risk factors were analyzed by univariate and multivariate analysis. Definition and grade of the severity of postendoscopic papillary balloon dilation pancreatitis were based on the 1991 consensus guidelines. RESULTS: Common bile duct was cleared in 292 of 304 patients (96%). Procedure-related pancreatitis occurred in 15 patients (5.0%). The grade was mild in 8 and moderate in 7. Two risk factors, stone diameter and contrast medium injection to the pancreas, were identified by univariate analysis. Finally, only the contrast medium injection to the pancreas was statistically significant by multivariate analysis. Prior history of pancreatitis was identified as a risk factor for postendoscopic papillary balloon dilation pancreatitis in previous studies, but this factor was not identified as a risk factor in our series. CONCLUSIONS: Although the pathogenesis of pancreatitis after endoscopic papillary balloon dilation remains unresolved, the unnecessary injection of contrast medium to the pancreas can certainly be considered to be associated with the increased risk of pancreatitis.

Aged↗
PubMed2005

Identifying genes with differential expression in gemcitabine-resistant pancreatic cancer cells using comprehensive transcriptome analysis.

Pancreatic cancer is often unresectable at diagnosis, and chemotherapy using gemcitabine is now the standard treatment for advanced pancreatic cancer. However, acquired resistance to gemcitabine resulting in therapeutic failure is often encountered. Therefore, we sought to identify genes that determine gemcitabine resistance by evaluating the relationship between gene expression profiles and gemcitabine sensitivity to provide molecular targets for overcoming gemcitabine resistance. First, the gemcitabine concentration needed for 50% growth inhibition was examined in six pancreatic cancer cell lines. By exposing MIA PaCa-2 cells to long-term gemcitabine, we established gemcitabine-resistant cells. The gene expression profiles of the six pancreatic cancer cell lines and gemcitabine-resistant cells were determined using cDNA microarray analysis. By comparing the results, 30 genes were identified as differentially expressed genes correlated with gemcitabine sensitivity. Differentially expressed genes in the parental cell lines were also examined, and six overlapping genes were identified as genes correlated with gemcitabine sensitivity in both assays. Of these genes, the down-regulated expression of TNFSF6 protein, also known as Fas ligand, was confirmed in the gemcitabine-resistant cell line. These results should provide therapeutic molecular targets for overcoming gemcitabine resistance.

Antimetabolites, Antineoplastic↗
PubMed2004

Novel small GTPase subfamily capable of associating with tubulin is required for chromosome segregation.

The small GTPase superfamily, which includes the Ras, Rho/Rac, Rab, Arf and Ran subfamilies, serves as a signal transducer to regulate cell proliferation and differentiation, actin cytoskeleton, membrane trafficking, and nuclear transport. Here, we identify novel GTPases (human Gie1 and Gie2) that form a distinct subfamily of the small GTPases in terms of their sequences and intracellular function. Gie stands for 'novel GTPase indispensable for equal segregation of chromosomes', and this subfamily is conserved in multicellular organisms. Expression of dominant-negative Gie mutants in mammalian cells or knockdown of Gie transcripts using RNA interference in Drosophila S2 cells induced abnormal morphology in the chromosome segregation. Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis. Furthermore, overexpression of Gie mutants that lack putative effector domains but have tubulin-binding ability induced micronucleus formation. Thus, this is the first report showing that a small GTPase subfamily capable of associating with microtubules might be involved in chromosome segregation.

ADP-Ribosylation Factors↗
PubMed2004

Pancreatic mass lesions associated with raised concentration of IgG4.

Autoimmune pancreatitis (AIP) is a recognized benign disease characterized by irregular narrowing of the pancreatic duct, swelling of parenchyma, lymphoplasmacytic infiltration and fibrosis, and a favorable response to corticosteroid treatment. In this condition, the whole pancreas is diffusely affected. Recently, however, a few cases with locally affected lesions were reported, with some of them showing features similar to cancer. We reviewed 138 patients with pancreatic mass lesion, of which 17 were not initially diagnosed despite examinations. Serum IgG4 levels were elevated in seven of them. Their biopsy specimens had a similar appearance to those of AIP. We considered that they should be diagnosed as AIP or conditions related to AIP. Among the 10 patients without elevated IgG4, 4 patients were diagnosed as pancreatic cancer after follow-up, 1 presented with an islet cell tumor, 1 presented AIP with sclerosing cholangitis, and the other 4 had chronic pancreatitis.

Adult↗
PubMed2003

Involvement of the biliary system in autoimmune pancreatitis: a follow-up study.

BACKGROUND & AIMS: The aim of this study was to define the bile duct changes associated with autoimmune pancreatitis. METHODS: Eight patients with autoimmune pancreatitis were followed for a mean of 4 years. The clinical features of these patients, including extrapancreatic bile duct changes, were examined by using biochemical parameters and several imaging modalities. Pathologic features of the pancreas and liver were examined by using the biopsy specimens of 7 patients. RESULTS: Diffuse or focal narrowing of the main pancreatic duct was observed in all patients. Histologic examination of the pancreas showed lymphoplasmacyte infiltration with severe fibrosis and acinar cell depletion. In 6 patients extrapancreatic bile duct changes such as stricture of the bile duct at hilus or intrahepatic area were observed. In 2 patients abnormalities in the bile duct and pancreas were detected simultaneously at diagnosis, and changes in the bile duct were observed later in 4 patients. Lymphoplasmacyte infiltration and fibrosis were observed in the portal area of all 7 liver biopsy samples. Five of the patients with bile duct changes received steroid therapy, and the pathological changes improved. CONCLUSIONS: Extrapancreatic bile duct changes are frequently associated with autoimmune pancreatitis. Similar pathogenic mechanism might produce the biliary tract and pancreatic abnormalities in autoimmune pancreatitis resulting in a similar histopathology in the liver and pancreas and response to steroid therapy.

Aged↗