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Yungming Jeng - One of the best experts on this subject based on the ideXlab platform.
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s100p immunostaining identifies a subset of peripheral type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas
Histopathology, 2012Co-Authors: Jiahuei Tsai, Wenchih Huang, Kuanting Kuo, Rayhwang Yuan, Yuling Chen, Yungming JengAbstract:Tsai J-H, Huang W-C, Kuo K-T, Yuan R-H, Chen Y-L & Jeng Y-M (2012) Histopathology S100P immunostaining identifies a subset of peripheral-type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas Aims: S100P is a calcium-binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar Cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic Cholangiocarcinoma (ICC). Methods and results: Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19-9 than those with S100P-negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P-positive peripheral ICCs were highly associated with ‘bile duct’ morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic Cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic Cholangiocarcinomas, S100P-positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N-cadherin-negative, than S100P-negative cases. Notably, K-RAS mutations were only detected in S100P-positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have poor prognoses than those with S100P-negative tumours. Conclusions: S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic Cholangiocarcinomas.
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S100P immunostaining identifies a subset of peripheral‐type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas
Histopathology, 2012Co-Authors: Jiahuei Tsai, Wenchih Huang, Kuanting Kuo, Rayhwang Yuan, Yuling Chen, Yungming JengAbstract:Tsai J-H, Huang W-C, Kuo K-T, Yuan R-H, Chen Y-L & Jeng Y-M (2012) Histopathology S100P immunostaining identifies a subset of peripheral-type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas Aims: S100P is a calcium-binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar Cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic Cholangiocarcinoma (ICC). Methods and results: Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19-9 than those with S100P-negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P-positive peripheral ICCs were highly associated with ‘bile duct’ morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic Cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic Cholangiocarcinomas, S100P-positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N-cadherin-negative, than S100P-negative cases. Notably, K-RAS mutations were only detected in S100P-positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have poor prognoses than those with S100P-negative tumours. Conclusions: S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic Cholangiocarcinomas.
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Viral hepatitis is associated with intrahepatic Cholangiocarcinoma with cholangiolar differentiation and N-cadherin expression
Modern Pathology, 2011Co-Authors: Rayhwang Yuan, Yuling Chen, Wan-ching Yang, Hey-chi Hsu, Yungming JengAbstract:Viral hepatitis-associated intrahepatic Cholangiocarcinoma is thought to have common disease processes with hepatocellular carcinoma, but until now the histomorphological and genetic features of viral hepatitis-associated intrahepatic Cholangiocarcinoma is still unknown. From 2000 to 2010, 170 patients with intrahepatic Cholangiocarcinoma who received detailed pathological assessment and regular follow-up at the National Taiwan University Hospital were selected for this study. Of 170 patients, 69 (41%) were positive for hepatitis B and/or C virus. These patients were younger, were more frequently male, and had elevated serum α -fetoprotein levels as compared with seronegative intrahepatic Cholangiocarcinoma patients. Grossly these tumors were mostly of the mass-forming type, and histologically, cholangiolar differentiation was more frequently seen. We identified N-cadherin as an immunohistochemical marker strongly associated with hepatitis virus infection. The prevalence of viral hepatitis in patients with N-cadherin-positive intrahepatic Cholangiocarcinoma was 75%, and that in N-cadherin-negative patients was only 37%. N-cadherin-positive patients were younger, had elevated α -fetoprotein, and had no hepatolithiasis. All N-cadherin-positive intrahepatic Cholangiocarcinomas were of the mass-forming type. N-cadherin positivity was strongly associated with cholangiolar morphology and lack of carcinoembryonic antigen and MUC2 expression, whereas K-RAS mutations were less frequent. Our results indicate that a subgroup of intrahepatic Cholangiocarcinoma characterized by cholangiolar differentiation and N-cadherin expression is strongly associated with viral hepatitis.
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CD24 expression is a prognostic factor in intrahepatic Cholangiocarcinoma
Cancer letters, 2005Co-Authors: Chiun Hsu, Hsin-lien Kao, Yungming JengAbstract:CD24, a cell surface protein originally identified in hematological malignancy, were found to be expressed in a large variety of solid tumors. It can function as a ligand for P-selectin, an adhesion receptor on activated endothelial cells and platelets. Overexpression of CD24 enhances the metastatic potential of cancer cells. We examined the expression of CD24 in 70 intrahepatic Cholangiocarcinomas by immunohistochemistry and correlated the expression with clinicopathological parameters. CD24 was expressed in 36 of 70 (51%) intrahepatic Cholangiocarcinomas. The expression did not significantly correlate the tumor size, stage, lymph node and distant metastasis. Patients with CD24 positive tumors had significant shorter survival time. In a multivariant analysis, CD24 expression and tumor stage were independent prognostic factors. Our data suggest that CD24 expression in intrahepatic Cholangiocarcinoma is a novel prognostic marker for intrahepatic Cholangiocarcinoma.
Gyeong Hoon Kang - One of the best experts on this subject based on the ideXlab platform.
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DLEC1 methylation is associated with a better clinical outcome in patients with intrahepatic Cholangiocarcinoma of the small duct subtype
Virchows Archiv, 2019Co-Authors: Younghoon Kim, Nam-yun Cho, Kyoungbun Lee, Seorin Jeong, Xianyu Wen, Gyeong Hoon KangAbstract:Intrahepatic Cholangiocarcinoma is a complex disease with three different histologic subtypes, the large duct, small duct, and bile ductular types. In the present study, we elucidated whether the three histological subtypes have differences in their methylation profiles and developed a DNA methylation marker that might help identify a subset of ICC with a different prognosis. We screened 113 promoter CpG island loci against 10 cases of intrahepatic Cholangiocarcinoma and normal cystic ducts using the MethyLight assay and selected 30 CpG island loci with cancer-associated hypermethylation. Then, we analyzed 172 intrahepatic Cholangiocarcinomas for the methylation state at these 30 loci. Six loci, including DLEC1 , were more frequently methylated in the bile ductular type and small duct type, whereas six loci were more frequently methylated in the large duct type. Of these 30 loci, DLEC1 methylation was found mainly in the bile ductular type and small duct type but rarely in the large duct type. DLEC1 methylation was significantly associated with a better clinical outcome in intrahepatic Cholangiocarcinomas of the small duct type but not of the bile ductular type. DLEC1 methylation was an independent prognostic variable in both cancer-specific survival and recurrence-free survival. For patients with intrahepatic Cholangiocarcinoma of the small duct type ( n = 68), DLEC1 methylation was found in 26 (38.2%) and was associated with a better clinical outcome for both cancer-specific survival and recurrence-free survival. Our findings suggest that DLEC1 methylation can be utilized to identify a subset with a better prognosis in intrahepatic Cholangiocarcinomas of the small duct type.
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Methylation Profiles of Multiple CpG Island Loci in Extrahepatic Cholangiocarcinoma Versus Those of Intrahepatic Cholangiocarcinomas
Archives of Pathology & Laboratory Medicine, 2007Co-Authors: Baek-hee Kim, Nam-yun Cho, Minhee Choi, Sun Lee, Ja June Jang, Gyeong Hoon KangAbstract:Abstract Context.—CpG island hypermethylation is attracting attention because of its importance as a tumor marker and its potential mechanism for the development of human cancers. Extrahepatic Cholangiocarcinoma has been poorly investigated with respect to CpG island hypermethylation, and the number of genes known to be methylated in extrahepatic Cholangiocarcinomas is fewer than 20. Objective.—To generate methylation profiles of 24 CpG island loci in extrahepatic Cholangiocarcinomas, to correlate methylation findings with clinicopathologic findings, and to compare these findings with those of intrahepatic Cholangiocarcinomas. Design.—Sixty-three extrahepatic Cholangiocarcinomas and 48 intrahepatic Cholangiocarcinomas were investigated for hypermethylation in 24 CpG island loci by using methylation-specific polymerase chain reaction. Results.—A total of 61 (96.8%) of 63 extrahepatic Cholangiocarcinomas showed hypermethylation in at least one of the examined loci, and a high methylation frequency was seen in HOXA1 (95.2%), HPP1 (69.8%), and NEUROG1 (61.9%). The number of methylated CpG island loci was greater in extrahepatic Cholangiocarcinomas with nodal metastasis than in those without nodal metastasis (P = .047), and hypermethylation of TIG1 was closely associated with nodal metastasis of extrahepatic Cholangiocarcinomas (P = .007). CDH1 and NEUROG1 were more frequently methylated in extrahepatic Cholangiocarcinoma than in intrahepatic Cholangiocarcinoma, whereas CHFR, GSTP1, IGF2, MGMT, MINT31, p14, and RBP1 were more frequently methylated in intrahepatic Cholangiocarcinoma: the differences was statistically significant (P < .05). Conclusions.—A close relationship exists between CpG island hypermethylation and nodal metastasis of extrahepatic Cholangiocarcinomas. Methylation profiles of extrahepatic Cholangiocarcinomas are somewhat similar to but distinct from those of intrahepatic Cholangiocarcinomas.
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Methylation profiles of multiple CpG island loci in extrahepatic Cholangiocarcinoma versus those of intrahepatic Cholangiocarcinomas
Archives of pathology & laboratory medicine, 2007Co-Authors: Baek-hee Kim, Nam-yun Cho, Minhee Choi, Sun Lee, Ja June Jang, Gyeong Hoon KangAbstract:Abstract Context.—CpG island hypermethylation is attracting attention because of its importance as a tumor marker and its potential mechanism for the development of human cancers. Extrahepatic Cholangiocarcinoma has been poorly investigated with respect to CpG island hypermethylation, and the number of genes known to be methylated in extrahepatic Cholangiocarcinomas is fewer than 20. Objective.—To generate methylation profiles of 24 CpG island loci in extrahepatic Cholangiocarcinomas, to correlate methylation findings with clinicopathologic findings, and to compare these findings with those of intrahepatic Cholangiocarcinomas. Design.—Sixty-three extrahepatic Cholangiocarcinomas and 48 intrahepatic Cholangiocarcinomas were investigated for hypermethylation in 24 CpG island loci by using methylation-specific polymerase chain reaction. Results.—A total of 61 (96.8%) of 63 extrahepatic Cholangiocarcinomas showed hypermethylation in at least one of the examined loci, and a high methylation frequency was seen ...
Rayhwang Yuan - One of the best experts on this subject based on the ideXlab platform.
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s100p immunostaining identifies a subset of peripheral type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas
Histopathology, 2012Co-Authors: Jiahuei Tsai, Wenchih Huang, Kuanting Kuo, Rayhwang Yuan, Yuling Chen, Yungming JengAbstract:Tsai J-H, Huang W-C, Kuo K-T, Yuan R-H, Chen Y-L & Jeng Y-M (2012) Histopathology S100P immunostaining identifies a subset of peripheral-type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas Aims: S100P is a calcium-binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar Cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic Cholangiocarcinoma (ICC). Methods and results: Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19-9 than those with S100P-negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P-positive peripheral ICCs were highly associated with ‘bile duct’ morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic Cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic Cholangiocarcinomas, S100P-positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N-cadherin-negative, than S100P-negative cases. Notably, K-RAS mutations were only detected in S100P-positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have poor prognoses than those with S100P-negative tumours. Conclusions: S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic Cholangiocarcinomas.
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S100P immunostaining identifies a subset of peripheral‐type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas
Histopathology, 2012Co-Authors: Jiahuei Tsai, Wenchih Huang, Kuanting Kuo, Rayhwang Yuan, Yuling Chen, Yungming JengAbstract:Tsai J-H, Huang W-C, Kuo K-T, Yuan R-H, Chen Y-L & Jeng Y-M (2012) Histopathology S100P immunostaining identifies a subset of peripheral-type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas Aims: S100P is a calcium-binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar Cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic Cholangiocarcinoma (ICC). Methods and results: Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19-9 than those with S100P-negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P-positive peripheral ICCs were highly associated with ‘bile duct’ morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic Cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic Cholangiocarcinomas, S100P-positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N-cadherin-negative, than S100P-negative cases. Notably, K-RAS mutations were only detected in S100P-positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have poor prognoses than those with S100P-negative tumours. Conclusions: S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic Cholangiocarcinomas.
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Viral hepatitis is associated with intrahepatic Cholangiocarcinoma with cholangiolar differentiation and N-cadherin expression
Modern Pathology, 2011Co-Authors: Rayhwang Yuan, Yuling Chen, Wan-ching Yang, Hey-chi Hsu, Yungming JengAbstract:Viral hepatitis-associated intrahepatic Cholangiocarcinoma is thought to have common disease processes with hepatocellular carcinoma, but until now the histomorphological and genetic features of viral hepatitis-associated intrahepatic Cholangiocarcinoma is still unknown. From 2000 to 2010, 170 patients with intrahepatic Cholangiocarcinoma who received detailed pathological assessment and regular follow-up at the National Taiwan University Hospital were selected for this study. Of 170 patients, 69 (41%) were positive for hepatitis B and/or C virus. These patients were younger, were more frequently male, and had elevated serum α -fetoprotein levels as compared with seronegative intrahepatic Cholangiocarcinoma patients. Grossly these tumors were mostly of the mass-forming type, and histologically, cholangiolar differentiation was more frequently seen. We identified N-cadherin as an immunohistochemical marker strongly associated with hepatitis virus infection. The prevalence of viral hepatitis in patients with N-cadherin-positive intrahepatic Cholangiocarcinoma was 75%, and that in N-cadherin-negative patients was only 37%. N-cadherin-positive patients were younger, had elevated α -fetoprotein, and had no hepatolithiasis. All N-cadherin-positive intrahepatic Cholangiocarcinomas were of the mass-forming type. N-cadherin positivity was strongly associated with cholangiolar morphology and lack of carcinoembryonic antigen and MUC2 expression, whereas K-RAS mutations were less frequent. Our results indicate that a subgroup of intrahepatic Cholangiocarcinoma characterized by cholangiolar differentiation and N-cadherin expression is strongly associated with viral hepatitis.
Jiahuei Tsai - One of the best experts on this subject based on the ideXlab platform.
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s100p immunostaining identifies a subset of peripheral type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas
Histopathology, 2012Co-Authors: Jiahuei Tsai, Wenchih Huang, Kuanting Kuo, Rayhwang Yuan, Yuling Chen, Yungming JengAbstract:Tsai J-H, Huang W-C, Kuo K-T, Yuan R-H, Chen Y-L & Jeng Y-M (2012) Histopathology S100P immunostaining identifies a subset of peripheral-type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas Aims: S100P is a calcium-binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar Cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic Cholangiocarcinoma (ICC). Methods and results: Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19-9 than those with S100P-negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P-positive peripheral ICCs were highly associated with ‘bile duct’ morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic Cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic Cholangiocarcinomas, S100P-positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N-cadherin-negative, than S100P-negative cases. Notably, K-RAS mutations were only detected in S100P-positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have poor prognoses than those with S100P-negative tumours. Conclusions: S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic Cholangiocarcinomas.
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S100P immunostaining identifies a subset of peripheral‐type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas
Histopathology, 2012Co-Authors: Jiahuei Tsai, Wenchih Huang, Kuanting Kuo, Rayhwang Yuan, Yuling Chen, Yungming JengAbstract:Tsai J-H, Huang W-C, Kuo K-T, Yuan R-H, Chen Y-L & Jeng Y-M (2012) Histopathology S100P immunostaining identifies a subset of peripheral-type intrahepatic Cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic Cholangiocarcinomas Aims: S100P is a calcium-binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar Cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic Cholangiocarcinoma (ICC). Methods and results: Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19-9 than those with S100P-negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P-positive peripheral ICCs were highly associated with ‘bile duct’ morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic Cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic Cholangiocarcinomas, S100P-positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N-cadherin-negative, than S100P-negative cases. Notably, K-RAS mutations were only detected in S100P-positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic Cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have poor prognoses than those with S100P-negative tumours. Conclusions: S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic Cholangiocarcinomas.
Gregory J Gores - One of the best experts on this subject based on the ideXlab platform.
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Cholangiocarcinoma evolving concepts and therapeutic strategies
Nature Reviews Clinical Oncology, 2018Co-Authors: Sumera Rizvi, Shahid A Khan, Christopher L Hallemeier, Robin Kate Kelley, Gregory J GoresAbstract:Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: Cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of Cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of Cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each Cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical Cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of Cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of Cholangiocarcinoma.
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molecular profiling of Cholangiocarcinoma shows potential for targeted therapy treatment decisions
Human Pathology, 2013Co-Authors: Jesse S Voss, Leonard M Holtegaard, Sarah E Kerr, Emily Barr G Fritcher, Lewis R Roberts, Gregory J Gores, Jun Zhang, Edward W Highsmith, Kevin C Halling, Benjamin R KippAbstract:Summary Cholangiocarcinoma is a highly lethal cancer of the biliary tract. The intrahepatic subtype of Cholangiocarcinoma is increasing in incidence globally. Despite technologic advancements over the past decade, little is known about the somatic changes that occur in these tumors. The goal of this study was to determine the frequency of common oncogenes in resected Cholangiocarcinoma specimens that could provide potential therapeutic targets for patients diagnosed with Cholangiocarcinoma. Formalin-fixed, paraffin-embedded tissue blocks from 94 resected Cholangiocarcinomas were used to extract DNA from areas comprising more than 20% tumor. Specimens were evaluated using the Sequenom MassARRAY OncoCarta Mutation Profiler Panel (San Diego, CA). This matrix-assisted laser desorption/ionization–time of flight mass spectrometry single genotyping panel evaluates 19 oncogenes for 238 somatic mutations. Twenty-five mutations were identified in 23 of the 94 Cholangiocarcinomas within the following oncogenes: KRAS (n = 12), PIK3CA (n = 5), MET (n = 4), EGFR (n = 1), BRAF (n = 2), and NRAS (n = 1). Mutations were identified in 7 (26%) of 27 extrahepatic Cholangiocarcinomas and 16 (24%) of 67 intrahepatic Cholangiocarcinomas. When combined with IDH1/2 testing, 40 (43%) of the 94 Cholangiocarcinomas had a detectable mutation. MassARRAY technology can be used to detect mutations in a wide variety of oncogenes using paraffin-embedded tissue. Clinical testing for somatic mutations may drive personalized therapy selection for Cholangiocarcinomas in the future. The variety of mutations detected suggests that a multiplexed mutation detection approach may be necessary for managing patients with biliary tract malignancy.
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bh3 only protein mimetic obatoclax sensitizes Cholangiocarcinoma cells to apo2l trail induced apoptosis
Molecular Cancer Therapeutics, 2008Co-Authors: Justin L Mott, Scott H Kaufmann, Steve F Bronk, Ruben A Mesa, Gregory J GoresAbstract:Human Cholangiocarcinomas evade apoptosis by overexpression of Mcl-1. The drug obatoclax (GX15-070) inhibits antiapoptotic members of the Bcl-2 family including Mcl-1. The purpose of this study is to determine if obatoclax sensitizes human Cholangiocarcinoma cells to apoptosis. The human Cholangiocarcinoma cell lines, KMCH, KMBC, and TFK, were employed for these studies. Protein expression was assessed by immunoblot and protein-protein interactions detected by coprecipitation of the polypeptide of interest with S-tagged Mcl-1. Activation of Bak and Bax was observed by immunocytochemistry with conformation-specific antisera. Obatoclax induced minimal apoptosis alone; however, it increased apoptosis 3- to 13-fold in all three cancer cell lines when combined with Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Obatoclax did not alter cellular expression of Bid, Bim, Puma, Noxa, Bak, Bax, Mcl-1, or cFLIP. Mcl-1 binding to Bak was readily identified in untreated cells, and this association was disrupted by treating the cells with obatoclax. Additionally, Bim binding to Mcl-1 was markedly decreased by obatoclax treatment. We also identified alterations in Bak and Bax conformation following treatment with obatoclax plus Apo2L/TRAIL but not with either Apo2L/TRAIL or obatoclax alone. In conclusion, obatoclax releases Bak and Bim from Mcl-1 and sensitizes human Cholangiocarcinoma cells to Apo2L/TRAIL-induced apoptosis. Obatoclax is a potentially promising adjunctive agent for the treatment of this cancer.
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Cholangiocarcinoma modern advances in understanding a deadly old disease
Journal of Hepatology, 2006Co-Authors: Harmeet Malhi, Gregory J GoresAbstract:Cholangiocarcinomas are tumors that arise anywhere in the biliary tract, presumably of cholangiocyte origin. The global incidence of this rare disease is on the rise. Several known risk factors exist, and link chronic biliary inflammation to the pathogenesis of Cholangiocarcinoma. Among these, amplification of the epidermal growth factor receptor, the interleukin-6 signaling pathway, inducible nitric oxide, erb-2, and cyclooxygenase-2 are well defined. Most patients present late, with a median survival of months. Although, imaging studies and clinical context often indicate Cholangiocarcinoma, pathologic and cytologic diagnosis is difficult to obtain. Advanced cytologic tests with fluorescence in situ hybridization or digital image analysis can increase diagnostic sensitivity. Surgical resection is the current therapy of choice for both intrahepatic and ductal Cholangiocarcinomas. However, the 5-year survival is poor, with 60 to greater than 90% recurrence rates. In a single center experience, liver transplantation with neoadjuvant chemoirradiation, for highly selected patients, has a 5-year disease free survival of greater than 80%. Future targeted therapies will depend on a better understanding of the cellular and molecular biology of Cholangiocarcinomas.
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mcl 1 mediates tumor necrosis factor related apoptosis inducing ligand resistance in human Cholangiocarcinoma cells
Cancer Research, 2004Co-Authors: Makiko Taniai, Annette Grambihler, Hajime Higuchi, Nate Werneburg, Steve F Bronk, Daniel J Farrugia, Scott H Kaufmann, Gregory J GoresAbstract:Cholangiocarcinomas are usually fatal neoplasms originating from bile duct epithelia. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for cancer therapy, including Cholangiocarcinoma. However, many Cholangiocarcinoma cells are resistant to TRAIL-mediated apoptosis. Thus, our aim was to examine the intracellular mechanisms responsible for TRAIL resistance in human Cholangiocarcinoma cell lines. Three TRAIL-resistant human Cholangiocarcinoma cell lines were identified. All of the cell lines expressed TRAIL receptor 1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5. Expression of TRAIL decoy receptors and the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) was inconsistent across the cell lines. Of the antiapoptotic Bcl-2 family of proteins profiled (Bcl-2, Bcl-x L , and Mcl-1), Mcl-1 was uniquely overexpressed by the cell lines. When small-interfering-RNA (siRNA) technology was used to knock down expression of Bcl-2, Bcl-x L , and Mcl-1, only the Mcl-1-siRNA sensitized the cells to TRAIL-mediated apoptosis. In a cell line stably transfected with Mcl-1-small-hairpin-RNA (Mcl-1-shRNA), Mcl-1 depletion sensitized cells to TRAIL-mediated apoptosis despite Bcl-2 expression. TRAIL-mediated apoptosis in the stably transfected cells was associated with mitochondrial depolarization, Bax activation, cytochrome c release from mitochondria, and caspase activation. Finally, flavopiridol, an anticancer drug that rapidly down-regulates Mcl-1, also sensitized cells to TRAIL cytotoxicity. In conclusion, these studies not only demonstrate that Mcl-1 mediates TRAIL resistance in Cholangiocarcinoma cells by blocking the mitochondrial pathway of cell death but also identify two strategies for circumventing this resistance.