It is necessary to establish an effective therapy to improve the survival of patients with advanced eholangiocarcinoma （CCM. Recently, with the development of pathology research in CCA, a lot of special bio-markers s...It is necessary to establish an effective therapy to improve the survival of patients with advanced eholangiocarcinoma （CCM. Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies.展开更多
Background and Objectives:Cholangiocarcinoma is a highly aggressive and heterogenous group of biliary malignancies arising from any site in the biliary tree,comprising 15%of all primary liver cancers.The nature of the...Background and Objectives:Cholangiocarcinoma is a highly aggressive and heterogenous group of biliary malignancies arising from any site in the biliary tree,comprising 15%of all primary liver cancers.The nature of the disease and nonspecific presentation leads to late diagnosis and ultimately poor outcomes for patients.Combination gemcitabine and cisplatin has been the standard of care for cholangiocarcinoma(CCA)since 2010,with a median overall survival of 11.7 months.The five-year survival for CCA remains 5-10%,revealing a clear need for improved treatment options.Methods:This targeted review highlights the role of next generation sequencing in CCA and the clinically relevant tumor biomarkers that have become the focus of therapeutic development.Key Content and Findings:These tumor biomarkers or actionable mutations hold the potential to enable earlier diagnosis,provide prognostic information,and guide treatment decisions for patients with CCA.Specifically,the FGFR2 fusion and IDH1 mutation have shown considerable promise in development of targeted therapies.Clinical trials with inhibitors targeting FGFR2 fusion and IDH1 mutation have created expectations that these drugs will soon enter clinical practice.Other biomarkers including KRAS and B-raf protooncogenes,Her2/neu genes,and BRCA1 and 2 tumor-suppressor genes have also been touted as potential targets for future therapies,with early data showing promise for new drug development.Conclusions:The discovery of these actionable mutations and identification of targeted therapies have challenged the notion of a“one-size fits all”for treatment of CCA,and generated optimism that these novel treatments will soon be available for patients with CCA.展开更多
Cholangiocarcinomas (CCA) are a group of rare cancers with an incidence of about 1.26 per 100,000 people. The disease reflects one of three different subtypes: intrahepatic, perihilar or hilar and distal cholangiocarc...Cholangiocarcinomas (CCA) are a group of rare cancers with an incidence of about 1.26 per 100,000 people. The disease reflects one of three different subtypes: intrahepatic, perihilar or hilar and distal cholangiocarcinoma. The preferred modality of definitive therapy is surgical resection with or without adjuvant therapy, however the majority of patients with this disease do not present at an early stage. Some efforts to improve survival rates have come in the form of offering neoadjuvant therapy prior to surgical resection or liver transplantation. Some new protocols are in the process of development for neoadjuvant therapy. Despite advancements in locally advanced or borderline resectable lesions, most patient present at an advanced stage. The mainstay of treatment for advanced stage disease is chemotherapy regardless of location. The mainstay of treatment in fit patients is the combination of gemcitabine and cisplatin. The addition of nab-paclitaxel to this backbone is currently being evaluated in phase III trial. In addition, the role of targeted therapy is currently being studied extensively through multiple different mutational pathways including isocitrate dehydrogenase-1 (IDH1), fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and ERBB2 (HER2/neu). CCA remains a significant challenge in medicine, however recent studies have shown that there is significant interest in advancing therapy in the form of neoadjuvant, adjuvant and palliative intent treatment.展开更多
Cholangiocarcinoma(CCA)encompasses a range of neoplasms,namely intrahepatic CCA,perihilar CCA,and distal CCA,which are distinguished by their anatomical origin.In cases where radical resection of CCA is feasible and t...Cholangiocarcinoma(CCA)encompasses a range of neoplasms,namely intrahepatic CCA,perihilar CCA,and distal CCA,which are distinguished by their anatomical origin.In cases where radical resection of CCA is feasible and the patient’s physical condition permits surgical intervention,it is advisable to proceed with surgical treatment(1).However,the insidious onset of the disease restricts surgical candidacy to only 20-30%of patients(2,3).For those with unresectable CCAs,the recommended initial treatment is gemcitabine plus cisplatin(GemCis)chemotherapy(4).展开更多
The genetic landscape of cholangiocarcinoma(CCA)remains largely unexplored.It is one of the deadliest cancers(1),with the gold standard treatment for all anatomical forms(intrahepatic-iCCA,perihilar-pCCA and distal-dC...The genetic landscape of cholangiocarcinoma(CCA)remains largely unexplored.It is one of the deadliest cancers(1),with the gold standard treatment for all anatomical forms(intrahepatic-iCCA,perihilar-pCCA and distal-dCCA)being surgical resection(with adjuvant capecitabine also recommended in the newest guidelines)(2,3).The importance of genetic markers in terms of postoperative and oncological outcomes is being increasingly recognized,but few actionable mutations have been identified so far(2,4).This is particularly pertinent for patients with advanced/irresectable disease,who rely on systemic therapy.Survival outcomes are poor in these patients[5-year survival up to 10%-(5)]and they would profit the most from novel,targeted therapies.展开更多
胆管癌是一种起病隐匿、侵袭性强、致死率高的原发性恶性肿瘤。多聚嘧啶区结合蛋白1(polypyrimidine tract-binding protein 1,PTBP1)已被报道,在多种类型肿瘤组织中异常高表达并参与癌症进展,但其在胆管癌中的作用仍未见报道。该研究...胆管癌是一种起病隐匿、侵袭性强、致死率高的原发性恶性肿瘤。多聚嘧啶区结合蛋白1(polypyrimidine tract-binding protein 1,PTBP1)已被报道,在多种类型肿瘤组织中异常高表达并参与癌症进展,但其在胆管癌中的作用仍未见报道。该研究旨在探讨PTBP1在胆管癌中的生物学功能,并初步解析其分子机制。本文利用公开的癌症基因组图谱(the cancer genome atlas,TCGA)数据,分析了胆管癌及癌旁组织中的PTBP1 mRNA表达水平。结果显示,PTBP1在胆管癌组织中的表达水平显著高于癌旁组织(P<0.05)。随后,在胆管癌细胞系RBE和HuH28中,通过CCK-8和细胞平板克隆实验,评价了PTBP1对胆管癌细胞生长能力的影响。结果显示,过表达PTBP1可显著促进胆管癌细胞的生长(P<0.01),而敲低PTBP1显著抑制胆管癌细胞的生长(P<0.001)。Transwell和Invasion实验结果显示,过表达PTBP1可显著促进胆管癌细胞的迁移和侵袭(P<0.001),而敲低PTBP1显著抑制胆管癌细胞的迁移和侵袭(P<0.001)。转录物组测序和通路富集分析结果显示,在胆管癌细胞中,敲低PTBP1后上调表达的基因显著富集于p53信号通路;而下调表达的基因显著富集于胆固醇代谢、Rho GTPase和TGF-β等信号通路。基于上述转录物组测序数据,本文还分析发现,敲低PTBP1可导致一系列基因发生异常的mRNA可变剪接事件,例如参与TGF-β调控的TGIF1及与p53活性相关的GNAS基因等。综上所述,PTBP1可能通过调控一系列基因的可变剪接而影响多个癌症相关的信号通路,从而促进胆管癌的进展。展开更多
Primary sclerosing cholangitis(PSC)is a chronic,idiopathic,cholestatic liver disease characterized by inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts.It can affect individuals of all age g...Primary sclerosing cholangitis(PSC)is a chronic,idiopathic,cholestatic liver disease characterized by inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts.It can affect individuals of all age groups and gender,has no established pharmacotherapy,and is associated with a variety of neoplastic(e.g.cholangiocarcinoma)and non-neoplastic(e.g.dominant strictures)hepatobiliary complications.Given these considerations,endoscopy plays a major role in the care of patients with PSC.In this review,we discuss and provide updates regarding endoscopic considerations in the management of hepatobiliary manifestations and complications of PSC.Where evidence is limited,we suggest pragmatic approaches based on currently available data and expert opinion.展开更多
Primary liver cancer is the fifth most common cancer and the third leading cause of cancer death worldwide.MicroRNAs(miRNAs)are small non-coding RNA molecules that downregulate gene expression by binding to the 30-unt...Primary liver cancer is the fifth most common cancer and the third leading cause of cancer death worldwide.MicroRNAs(miRNAs)are small non-coding RNA molecules that downregulate gene expression by binding to the 30-untranslated region of target miRNAs.MiRNAs function as tumor suppressors or oncogenes by regulating oncogene or tumor suppressor gene expression and their related signaling pathways involved in liver cancers including hepatocellular carcinoma,cholangiocarcinoma,and hepatoblastoma.In this review,we provide a systematic evaluation of the relationship between miRNAs and liver cancers,and describe the potential applications of miRNAs in liver cancer diagnosis and treatment.展开更多
Objectives:The difficulties in the early detection consequent to the lack of sensitive biomarkers render patients with cholangiocarcinoma(CCA)to have poor outcomes.Recently,sensitive and specific volatile organic comp...Objectives:The difficulties in the early detection consequent to the lack of sensitive biomarkers render patients with cholangiocarcinoma(CCA)to have poor outcomes.Recently,sensitive and specific volatile organic compounds(VOCs)were identified in several cancers.However,the VOC profiles in CCA are not well-studied.Thus,we investigated the VOC profiles in exhaled breath of CCA patients and controls.Methods:We prospectively collected exhaled breath samples from 30 consecutive patients newly diagnosed with CCA and 30 controls who did not have CCA(seven had benign biliary strictures and 23 had other medical conditions).Exhaled VOCs were identified using gas chromatography mass spectrometry Triple Quadrupoles system.Analysis of the significant differences in VOCs between cases and controls was conducted using supervised multivariate regression analysis.Further validation was performed for these VOCs in another cohort of 18 CCA patients and 22 controls.Results:Levels of six compounds were significantly different between CCA patients and controls,namely,acetone,isopropyl alcohol,dimethyl sulfide,1,4-pentadiene,allyl methyl sulfide,and N,N-dimethylacetamide.Acetone and dimethyl sulfide were independently associated with CCA as demonstrated in the multivariate analysis.Using the cut-off value of 8.59107 arbitrary unit(AU),acetone had a sensitivity and specificity of 82.1%and 75.8%,respectively,with an area under the receiving operator curve(AUROC)of 0.85 for the CCA diagnosis.Acetone level was also significantly different between cases and controls in the validation cohort.Using the same cut-off value,the sensitivity,specificity,and AUROC was 59.1%,66.7%,and 0.85,respectively.Conclusion:Breath analysis may potentially be useful for CCA diagnosis.A cohort of patients with earlystage CCA in further studies is needed to confirm the ability of exhaled VOCs for the early detection of CCA.展开更多
文摘It is necessary to establish an effective therapy to improve the survival of patients with advanced eholangiocarcinoma （CCM. Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies.
文摘Background and Objectives:Cholangiocarcinoma is a highly aggressive and heterogenous group of biliary malignancies arising from any site in the biliary tree,comprising 15%of all primary liver cancers.The nature of the disease and nonspecific presentation leads to late diagnosis and ultimately poor outcomes for patients.Combination gemcitabine and cisplatin has been the standard of care for cholangiocarcinoma(CCA)since 2010,with a median overall survival of 11.7 months.The five-year survival for CCA remains 5-10%,revealing a clear need for improved treatment options.Methods:This targeted review highlights the role of next generation sequencing in CCA and the clinically relevant tumor biomarkers that have become the focus of therapeutic development.Key Content and Findings:These tumor biomarkers or actionable mutations hold the potential to enable earlier diagnosis,provide prognostic information,and guide treatment decisions for patients with CCA.Specifically,the FGFR2 fusion and IDH1 mutation have shown considerable promise in development of targeted therapies.Clinical trials with inhibitors targeting FGFR2 fusion and IDH1 mutation have created expectations that these drugs will soon enter clinical practice.Other biomarkers including KRAS and B-raf protooncogenes,Her2/neu genes,and BRCA1 and 2 tumor-suppressor genes have also been touted as potential targets for future therapies,with early data showing promise for new drug development.Conclusions:The discovery of these actionable mutations and identification of targeted therapies have challenged the notion of a“one-size fits all”for treatment of CCA,and generated optimism that these novel treatments will soon be available for patients with CCA.
文摘Cholangiocarcinomas (CCA) are a group of rare cancers with an incidence of about 1.26 per 100,000 people. The disease reflects one of three different subtypes: intrahepatic, perihilar or hilar and distal cholangiocarcinoma. The preferred modality of definitive therapy is surgical resection with or without adjuvant therapy, however the majority of patients with this disease do not present at an early stage. Some efforts to improve survival rates have come in the form of offering neoadjuvant therapy prior to surgical resection or liver transplantation. Some new protocols are in the process of development for neoadjuvant therapy. Despite advancements in locally advanced or borderline resectable lesions, most patient present at an advanced stage. The mainstay of treatment for advanced stage disease is chemotherapy regardless of location. The mainstay of treatment in fit patients is the combination of gemcitabine and cisplatin. The addition of nab-paclitaxel to this backbone is currently being evaluated in phase III trial. In addition, the role of targeted therapy is currently being studied extensively through multiple different mutational pathways including isocitrate dehydrogenase-1 (IDH1), fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and ERBB2 (HER2/neu). CCA remains a significant challenge in medicine, however recent studies have shown that there is significant interest in advancing therapy in the form of neoadjuvant, adjuvant and palliative intent treatment.
基金supported by the Project of the Natural Science Foundation of China(No.81802767,No.81860117)in acquisition of the patients’data and contact with patient.
文摘Cholangiocarcinoma(CCA)encompasses a range of neoplasms,namely intrahepatic CCA,perihilar CCA,and distal CCA,which are distinguished by their anatomical origin.In cases where radical resection of CCA is feasible and the patient’s physical condition permits surgical intervention,it is advisable to proceed with surgical treatment(1).However,the insidious onset of the disease restricts surgical candidacy to only 20-30%of patients(2,3).For those with unresectable CCAs,the recommended initial treatment is gemcitabine plus cisplatin(GemCis)chemotherapy(4).
文摘The genetic landscape of cholangiocarcinoma(CCA)remains largely unexplored.It is one of the deadliest cancers(1),with the gold standard treatment for all anatomical forms(intrahepatic-iCCA,perihilar-pCCA and distal-dCCA)being surgical resection(with adjuvant capecitabine also recommended in the newest guidelines)(2,3).The importance of genetic markers in terms of postoperative and oncological outcomes is being increasingly recognized,but few actionable mutations have been identified so far(2,4).This is particularly pertinent for patients with advanced/irresectable disease,who rely on systemic therapy.Survival outcomes are poor in these patients[5-year survival up to 10%-(5)]and they would profit the most from novel,targeted therapies.
文摘胆管癌是一种起病隐匿、侵袭性强、致死率高的原发性恶性肿瘤。多聚嘧啶区结合蛋白1(polypyrimidine tract-binding protein 1,PTBP1)已被报道,在多种类型肿瘤组织中异常高表达并参与癌症进展,但其在胆管癌中的作用仍未见报道。该研究旨在探讨PTBP1在胆管癌中的生物学功能,并初步解析其分子机制。本文利用公开的癌症基因组图谱(the cancer genome atlas,TCGA)数据,分析了胆管癌及癌旁组织中的PTBP1 mRNA表达水平。结果显示,PTBP1在胆管癌组织中的表达水平显著高于癌旁组织(P<0.05)。随后,在胆管癌细胞系RBE和HuH28中,通过CCK-8和细胞平板克隆实验,评价了PTBP1对胆管癌细胞生长能力的影响。结果显示,过表达PTBP1可显著促进胆管癌细胞的生长(P<0.01),而敲低PTBP1显著抑制胆管癌细胞的生长(P<0.001)。Transwell和Invasion实验结果显示,过表达PTBP1可显著促进胆管癌细胞的迁移和侵袭(P<0.001),而敲低PTBP1显著抑制胆管癌细胞的迁移和侵袭(P<0.001)。转录物组测序和通路富集分析结果显示,在胆管癌细胞中,敲低PTBP1后上调表达的基因显著富集于p53信号通路;而下调表达的基因显著富集于胆固醇代谢、Rho GTPase和TGF-β等信号通路。基于上述转录物组测序数据,本文还分析发现,敲低PTBP1可导致一系列基因发生异常的mRNA可变剪接事件,例如参与TGF-β调控的TGIF1及与p53活性相关的GNAS基因等。综上所述,PTBP1可能通过调控一系列基因的可变剪接而影响多个癌症相关的信号通路,从而促进胆管癌的进展。
基金This work was completed in part through T32 fellowship funding support for Dr.J.H.Tabibian from the United States National Institutes of Health(grant DK007198).
文摘Primary sclerosing cholangitis(PSC)is a chronic,idiopathic,cholestatic liver disease characterized by inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts.It can affect individuals of all age groups and gender,has no established pharmacotherapy,and is associated with a variety of neoplastic(e.g.cholangiocarcinoma)and non-neoplastic(e.g.dominant strictures)hepatobiliary complications.Given these considerations,endoscopy plays a major role in the care of patients with PSC.In this review,we discuss and provide updates regarding endoscopic considerations in the management of hepatobiliary manifestations and complications of PSC.Where evidence is limited,we suggest pragmatic approaches based on currently available data and expert opinion.
文摘Primary liver cancer is the fifth most common cancer and the third leading cause of cancer death worldwide.MicroRNAs(miRNAs)are small non-coding RNA molecules that downregulate gene expression by binding to the 30-untranslated region of target miRNAs.MiRNAs function as tumor suppressors or oncogenes by regulating oncogene or tumor suppressor gene expression and their related signaling pathways involved in liver cancers including hepatocellular carcinoma,cholangiocarcinoma,and hepatoblastoma.In this review,we provide a systematic evaluation of the relationship between miRNAs and liver cancers,and describe the potential applications of miRNAs in liver cancer diagnosis and treatment.
基金This work was funded by the Thailand Research Fund(TRF)and The Office of the Higher Education Commission(OHEC)(MRG6180227 to R.Chaiteerakij)Research Grant:GAT2018 to R.Chaiteerakij,The Gastroenterological Association of Thailandand Research Grant for New Scholar Ratchadaphiseksomphot Endowment Fund Chulalongkorn University(RGN_2559_055_10_30 to R.Chaiteerakij).
文摘Objectives:The difficulties in the early detection consequent to the lack of sensitive biomarkers render patients with cholangiocarcinoma(CCA)to have poor outcomes.Recently,sensitive and specific volatile organic compounds(VOCs)were identified in several cancers.However,the VOC profiles in CCA are not well-studied.Thus,we investigated the VOC profiles in exhaled breath of CCA patients and controls.Methods:We prospectively collected exhaled breath samples from 30 consecutive patients newly diagnosed with CCA and 30 controls who did not have CCA(seven had benign biliary strictures and 23 had other medical conditions).Exhaled VOCs were identified using gas chromatography mass spectrometry Triple Quadrupoles system.Analysis of the significant differences in VOCs between cases and controls was conducted using supervised multivariate regression analysis.Further validation was performed for these VOCs in another cohort of 18 CCA patients and 22 controls.Results:Levels of six compounds were significantly different between CCA patients and controls,namely,acetone,isopropyl alcohol,dimethyl sulfide,1,4-pentadiene,allyl methyl sulfide,and N,N-dimethylacetamide.Acetone and dimethyl sulfide were independently associated with CCA as demonstrated in the multivariate analysis.Using the cut-off value of 8.59107 arbitrary unit(AU),acetone had a sensitivity and specificity of 82.1%and 75.8%,respectively,with an area under the receiving operator curve(AUROC)of 0.85 for the CCA diagnosis.Acetone level was also significantly different between cases and controls in the validation cohort.Using the same cut-off value,the sensitivity,specificity,and AUROC was 59.1%,66.7%,and 0.85,respectively.Conclusion:Breath analysis may potentially be useful for CCA diagnosis.A cohort of patients with earlystage CCA in further studies is needed to confirm the ability of exhaled VOCs for the early detection of CCA.
