10 results on '"BTC, biliary tract cancer"'
Search Results
2. Development and validation of circulating protein signatures as diagnostic biomarkers for biliary tract cancer.
- Author
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Christensen TD, Maag E, Larsen O, Feltoft CL, Nielsen KR, Jensen LH, Leerhøy B, Hansen CP, Chen IM, Nielsen DL, and Johansen JS
- Abstract
Background & Aims: Biliary tract cancer (BTC) is associated with a dismal prognosis, partly because it is typically diagnosed late, highlighting the need for diagnostic biomarkers. The purpose of this project was to identify and validate multiprotein signatures that could differentiate patients with BTC from non-cancer controls., Methods: In this study, we included treatment-naïve patients with BTC, healthy controls, and patients with benign conditions including benign biliary tract disease. Participants were divided into three non-overlapping cohorts: a case-control-based discovery cohort (BTC = 186, controls = 249); a case-control-based validation cohort (validation cohort 1: BTC = 113, controls = 241); and a cohort study-based validation cohort including participants (BTC = 8, controls = 132) referred for diagnostic work-up for suspected cancer (validation cohort 2). Immuno-Oncology (I-O)-related proteins were measured in serum and plasma using a proximity extension assay (Olink Proteomics). Lasso and Ridge regressions were used to generate protein signatures of I-O-related proteins and carbohydrate antigen 19-9 (CA19-9) in the discovery cohort., Results: Sixteen protein signatures, including 2 to 82 proteins, were generated. All signatures included CA19-9 and chemokine C-C motif ligand 20. Signatures discriminated between patients with BTC vs. controls, with AUCs ranging from 0.95 to 0.99 in the discovery cohort and 0.94 to 0.97 in validation cohort 1. In validation cohort 2, AUCs ranged from 0.84 to 0.94. Nine signatures achieved a specificity of 82% to 84% while keeping a sensitivity of 100% in validation cohort 2. All signatures performed better than CA19-9, and signatures including >15 proteins showed the best performance., Conclusion: The study demonstrated that it is possible to generate protein signatures that can successfully differentiate patients with BTC from non-cancer controls., Impact and Implications: We attempted to find blood sample-based protein profiles that could differentiate patients with biliary tract cancer from those without cancer. Several profiles were found and tested in different groups of patients. The profiles were successful at identifying most patients with biliary tract cancer, pointing towards the utility of multiprotein signatures in this context., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
3. Non-invasive detection of biliary tract cancer by low-coverage whole genome sequencing from plasma cell-free DNA: A prospective cohort study
- Author
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Xiang Wang, Teng Zhao, Zi-Liang Qian, Xiang Ruan, Yongjie Zhang, Bin Zhu, Xiao-Hui Fu, Lei Yin, Anqi Duan, and Wen-Long Yu
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system diseases ,CNV, copy number variation ,WGS, whole genome sequencing ,Aneuploidy ,CC, cholangiocarcinoma ,Plasma cell ,CIN, chromosomal instability ,Gastroenterology ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,Cell-free DNA ,0302 clinical medicine ,LCWG, low-coverage whole genome ,Internal medicine ,mental disorders ,Diagnosis ,Medicine ,Copy-number variation ,Prospective cohort study ,Low-coverage whole genome ,Whole genome sequencing ,business.industry ,Copy number variation ,Gallbladder ,Cancer ,cfDNA, cell-free DNA ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cell-free fetal DNA ,BTC, biliary tract cancer ,GBC, gallbladder cancer ,030220 oncology & carcinogenesis ,Biliary tract cancer ,CEA, carcinoembryonic antigen ,business - Abstract
Highlights • Non-invasive detection of copy number variations (CNVs) was firstly reported in patients with biliary tract cancer. • Biliary tract cancer harbors rich information of CNVs based on plasma cell-free DNA analyses. • The sensitivity and specificity of CNVs for diagnosing biliary tract cancer were 89.7% and 88.9%, respectively. The diagnostic performance of CNVs significantly outperformed CA 19-9 and CEA., Background The diagnosis of biliary tract cancer (BTC) is challenging in clinical practice. We performed a prospective study to evaluate the value of plasma copy number variation (CNV) assays in diagnosing BTC. Methods 47 treatment-naïve patients with suspicious biliary lesions were recruited. Plasma samples were collected at admission. Cell-free DNA was analyzed by low coverage whole genome sequencing, followed by CNV analyses via a customized bioinformatics workflow, namely the ultrasensitive chromosomal aneuploidy detector. Results 29 patients were pathologically diagnosed as BTC, including 8 gallbladder cancers (GBCs) and 21 cholangiocarcinomas (CCs). Cancer patients had more CNV signals as compared with benign patients (26/29 vs. 2/18, P < 0.001). The most frequent copy number gains were chr3q (7/29) and chr8q (6/29). The most frequent copy number losses were chr7p (6/29), chr17p (6/29), and chr19p (6/29). The sensitivity and specificity of plasma CNV assays in diagnosing BTC were 89.7% and 88.9%, respectively. For CA 19-9 (cutoff: 37 U/ml), the sensitivity was 58.6% and the specificity was 72.2%. The diagnostic accuracy of CNV assays significantly outperformed CA 19-9 (AUC 0.91 vs. 0.62, P = 0.004). Compared with CA 19-9 alone, the adding of CNV profiles to CA 19-9 increased the sensitivity in diagnosing GBC (75.0% vs. 25.0%) and CC (100% vs. 52.4%). Higher CNV burden was also associated with decreased overall survival (Hazard ratio = 4.32, 95% CI 2.06–9.08, P = 0.033). Discussion Our results suggest that BTC harbors rich plasma CNV signals, and their assays might be useful for diagnosing BTC.
- Published
- 2021
4. Circulating levels of soluble urokinase plasminogen activator receptor predict outcome after resection of biliary tract cancer
- Author
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Tom Luedde, Christian Trautwein, Alexander Koch, Sven H. Loosen, Ulf P. Neumann, Thomas Longerich, Anjali A. Roeth, Frank Tacke, Jonathan F. Brozat, Mihael Vucur, Georg Lurje, Thomas Ritz, Patrick H. Alizai, Christoph Roderburg, Annemarie Breuer, Joao Gorgulho, Jan Bednarsch, Sophia M. Schmitz, Tom Florian Ulmer, Pia Paffenholz, and Jakob Nikolas Kather
- Subjects
BMI, body mass index ,AST, aspartate aminotransferase ,Gastroenterology ,CEA ,0302 clinical medicine ,Carcinoembryonic antigen ,Immunology and Allergy ,Medicine ,biology ,BTC ,CA19-9 ,3. Good health ,acute kidney injury ,BTC, biliary tract cancer ,030220 oncology & carcinogenesis ,CRP, C-reactive protein ,uPAR, urokinase plasminogen activator receptor ,biomarker ,Biomarker (medicine) ,030211 gastroenterology & hepatology ,cholangiocarcinoma ,Research Article ,medicine.medical_specialty ,AKI, acute kidney injury ,IRS, immunoreactive score ,suPAR ,Primary sclerosing cholangitis ,OS, overall survival ,03 medical and health sciences ,CA19-9, carbohydrate antigen 19-9 ,ALT, alanine aminotransferase ,Internal medicine ,Internal Medicine ,lcsh:RC799-869 ,CCA ,ALP, alkaline phosphatase ,Hepatology ,business.industry ,C-reactive protein ,Cancer ,ECOG PS, Eastern Cooperative Oncology Group performance status ,medicine.disease ,HR, hazard ratio ,OR, odds ratio ,Urokinase receptor ,PSC, primary sclerosing cholangitis ,SuPAR ,biology.protein ,lcsh:Diseases of the digestive system. Gastroenterology ,CEA, carcinoembryonic antigen ,suPAR, soluble uPAR ,business - Abstract
Background & Aims Surgical resection is the only potentially curative therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has been associated with distinct types of cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing BTC resection. Methods Tumor expression of uPAR was analyzed by immunohistochemistry in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 patients with BTC and 76 healthy controls. Results High tumoral uPAR expression was associated with an adverse outcome after BTC resection. Accordingly, circulating levels of suPAR were significantly elevated in patients with BTC compared to healthy controls, as well as in patients with primary sclerosing cholangitis. Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72 ng/ml for patients with BTC. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including various clinicopathological parameters such as tumor stage, markers of inflammation and organ dysfunction, as well as tumor markers, revealed circulating suPAR levels as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative of acute kidney injury after tumor resection. Conclusion Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might help to preoperatively identify the ideal candidates for liver surgery. Lay summary Surgical resection represents the only curative treatment option for patients with biliary tract cancer, but not all patients benefit to the same extent in terms of overall survival. Here, we provide evidence that serum levels of an inflammatory mediator (suPAR) are indicative of a patient's postoperative outcome and might thus help to identify the ideal surgical candidates., Graphical abstract, Highlights • Biliary tract cancer is associated with poor outcomes and increasing incidence. • Surgical resection is the only potentially curative treatment option for patients with biliary tract cancer. • The identification of ideal surgical candidates has remained challenging. • Circulating suPAR represents a novel diagnostic and prognostic biomarker in resectable patients. • SuPAR might be useful to identify patients with biliary tract cancer who will benefit most from tumor resection.
- Published
- 2020
5. A bispecific antibody targeting HER2 and PD-L1 inhibits tumor growth with superior efficacy
- Author
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Xinyuan Liu, Yue Cui, Mei-Qing Feng, Lei Tang, Yi-Li Chen, Liu Guojian, Xingchen Dong, Chunhe Wang, and Yifeng Hung
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Receptor, ErbB-2 ,Programmed Cell Death 1 Receptor ,Biochemistry ,Antibodies, Monoclonal, Murine-Derived ,Mice ,ADCC, antibody-dependent cell-mediated cytotoxicity ,DC, dendritic cell ,Antineoplastic Agents, Immunological ,human epidermal growth factor receptor 2 (HER2) ,Antibodies, Bispecific ,BLI, biolayer interferometry ,HER2, human epidermal growth factor receptor 2 ,skin and connective tissue diseases ,Cytotoxicity ,SDS-PAGE, sodium dodecyl sulfate–polyacrylamide gel electrophoresis ,Antibody-dependent cell-mediated cytotoxicity ,GEJC, gastroesophageal junction cancer ,biology ,Chemistry ,PD-1/PD-L1, programmed cell death protein 1 and programmed cell death ligand 1 ,BTC, biliary tract cancer ,CRC, colorectal cancer ,GC, gastric cancer ,VH, variable heavy ,Signal transduction ,mAbs, monoclonal antibodies ,Research Article ,PBMC, peripheral blood mononuclear cell ,BC, breast cancer ,medicine.drug_class ,antibody-dependent cell-mediated cytotoxicity ,NSCLC, non-small-cell lung cancer ,DSF, differential scanning fluorimetry ,Monoclonal antibody ,Peripheral blood mononuclear cell ,MLR, mixed lymphocyte reaction ,breast cancer ,In vivo ,Cell Line, Tumor ,PD-L1 ,medicine ,Animals ,Humans ,CDC, complement-dependent cytotoxicity ,Molecular Biology ,Antibody-Dependent Cell Cytotoxicity ,VL, variable light ,Neoplasms, Experimental ,Cell Biology ,Xenograft Model Antitumor Assays ,MOA, mechanisms of action ,In vitro ,BsAbs, bispecific antibodies ,programmed death ligand 1 ,Cancer research ,biology.protein ,SEC, size exclusion chromatography - Abstract
Activation of the programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) signaling axis plays important roles in intrinsic or acquired resistance to human epidermal growth factor receptor 2 (HER2)-directed therapies in the clinic. Therefore, therapies simultaneously targeting both HER2 and PD-1/PD-L1 signaling pathways are of great significance. Here, aiming to direct the anti-PD-L1 responses towards HER2-expressing tumor cells, we constructed a humanized bispecific IgG1 subclass antibody targeting both HER2 and PD-L1 (HER2/PD-L1; BsAb), which displayed satisfactory purity, thermostability, and serum stability. We found that BsAb showed enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. In the late phase of peripheral blood mononuclear cell (PBMC)-humanized HER2+ tumor xenograft models, BsAb showed superior therapeutic efficacies as compared to monoclonal antibodies (mAbs) or combination treatment strategies. In cynomolgus monkeys, BsAb showed favorable pharmacokinetics and toxicity profiles when administered at a 10 mg/kg dosage. Thus, HER2/PD-L1 BsAb was demonstrated as a potentially effective option for managing HER2+ and trastuzumab-resistant tumors in the clinic. We propose that the enhanced anti-tumor activities of BsAb in vivo may be due to direct inhibition of HER2 signaling or activation of T cells.
- Published
- 2021
6. Cell of origin in biliary tract cancers and clinical implications
- Author
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Philipp K. Haber, Agrin Moeini, and Daniela Sia
- Subjects
ER, estrogen receptor ,ARID1A ,Cell of origin ,ERBB2/3, Erb-B2 Receptor Tyrosine Kinase 2/3 ,TP53, Tumor Protein P53 ,PRKACA/B, Protein Kinase CAMP-Activated Catalytic Subunit Alpha/Beta ,Review ,Personalized therapy ,NA, not applicable ,RNF43, Ring Finger Protein 43 ,Lineage tracing ,PIK3CA, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha ,Bioinformatics ,medicine.disease_cause ,Cholangiocarcinoma ,ORR, objective response rate ,Immunology and Allergy ,iCCA, intrahepatic cholangiocarcinoma ,BAP1 ,CDKN2A/B, cyclin-dependent kinase inhibitor 2A/B ,Gastroenterology ,TBG, thyroid binding globulin ,Genomics ,PBG, peribiliary gland ,pCCA, perihilar cholangiocarcinoma ,BTC, biliary tract cancer ,GBC, gallbladder cancer ,Biliary tract ,CLC, cholangiolocarcinoma ,eCCA, extrahepatic cholangiocarcinoma ,KRAS ,FGFR2, Fibroblast Growth Factor Receptor 2 ,CK, cytokeratin ,DCR, disease control rate ,NAFLD, non-alcoholic fatty liver disease ,CCA, cholangiocarcinoma ,FGFR, fibroblast growth factor receptor ,MST1, Macrophage Stimulating 1 ,NASH, non-alcoholic steatohepatitis ,PLC, primary liver cancer ,Biliary tract cancers ,IDH, isocitrate dehydrogenase ,NTRK, Neurotrophic Receptor Tyrosine Kinase 1 ,Biology ,GEMM, genetically engineered mouse models ,WHO, World Health Organization ,OS, overall survival ,PFS, progression- free survival ,Prominin-1 ,HPCs, hepatic progenitor cells ,Internal Medicine ,medicine ,Gallbladder cancer ,CoH, Canal of Hering ,ARID1A, AT-rich interactive domain-containing protein 1A ,Hepatology ,BAP1, BRCA1-associated protein 1 ,PROM1, Prominin 1 ,mo, months ,medicine.disease ,KRAS, Kirsten Rat Sarcoma Viral Oncogene Homolog ,NR, not reported ,NGS, next-generation sequencing ,MET, Hepatocyte Growth Factor Receptor ,PSC, primary sclerosing cholangitis ,SMAD4, SMAD Family Member 4 ,HCC, hepatocellular carcinoma ,BRAF, v-Raf murine sarcoma viral oncogene homolog B ,dCCA, distal cholangiocarcinoma - Abstract
Summary Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, their incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need to improve current diagnostic and therapeutic strategies. BTCs show high inter- and intra-tumour heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to effective interventions. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cells of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumours.
- Published
- 2021
7. Characterisation of the immune-related transcriptome in resected biliary tract cancers
- Author
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Pietro Carotenuto, Umberto Cillo, Ian Said-Huntingford, Lorenza Rimassa, Claudia Mescoli, Andrea Lampis, Armando Santoro, Alessandro Zerbi, Matteo Fassan, Chiara Braconi, Massimo Rugge, Michele Ghidini, Maria C. Previdi, Nicola Valeri, Massimo Roncalli, Maya Raj, Francesco Trevisani, Jens C. Hahne, Guido Torzilli, Luciano Cascione, Ghidini, M., Cascione, L., Carotenuto, P., Lampis, A., Trevisani, F., Previdi, M. C., Hahne, J. C., Said-Huntingford, I., Raj, M., Zerbi, A., Mescoli, C., Cillo, U., Rugge, M., Roncalli, M., Torzilli, G., Rimassa, L., Santoro, A., Valeri, N., Fassan, M., and Braconi, C.
- Subjects
Male ,Oncology ,CD80, cluster of differentiation 80 ,Cancer Research ,Time Factors ,CTLA4, cytotoxic T-lymphocyte antigen-4 ,T-Lymphocytes ,Kaplan-Meier Estimate ,Bioinformatics ,POLR2A, RNA polymerase II subunit A ,T-Lymphocytes, Regulatory ,R1, positive resection margins ,Cholangiocarcinoma ,Transcriptome ,0302 clinical medicine ,CD80 ,Retrospective Studie ,TGFB1, transforming growth factor beta ,ECC, extrahepatic CCA ,Tumor Microenvironment ,CTLA-4 Antigen ,Lymphocytes ,Multivariate Analysi ,Adjuvant ,CTLA4 ,Biliary tract neoplasm ,Tumor ,Treg ,Adult ,Aged ,B7-1 Antigen ,Biliary Tract Neoplasms ,Biliary Tract Surgical Procedures ,Biomarkers, Tumor ,Disease-Free Survival ,Female ,Forkhead Transcription Factors ,Gene Expression Profiling ,Gene Expression Regulation, Neoplastic ,Humans ,Italy ,Lymphocytes, Tumor-Infiltrating ,Middle Aged ,Multivariate Analysis ,Proportional Hazards Models ,Retrospective Studies ,Treatment Outcome ,Tumor Escape ,FOXP3 ,TT, tumour tissue ,Regulatory ,IL-6, interleukin 6 ,Treg, T regulatory cell ,BTC, biliary tract cancer ,GBC, gallbladder cancer ,Biliary Tract Neoplasm ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,PBK, PDZ binding kinase ,Human ,medicine.medical_specialty ,CCA, cholangiocarcinoma ,Time Factor ,AT, adjacent tissue ,chemical and pharmacologic phenomena ,Biology ,Article ,03 medical and health sciences ,Immune system ,Internal medicine ,RFS, relapse-free survival ,medicine ,ICC, intrahepatic CCA ,Tumor-Infiltrating ,FFPE, formalin fixed paraffin embedded ,Neoplastic ,Tumor microenvironment ,Cluster of differentiation ,IP, immune profile ,Forkhead Transcription Factor ,IPA, ingenuity pathway analysis ,Gene expression profiling ,Biliary Tract Surgical Procedure ,R0, clear resection margins ,APC, antigen-presenting cell ,Gene Expression Regulation ,Proportional Hazards Model ,Biomarkers - Abstract
Although biliary tract cancers (BTCs) are known to have an inflammatory component, a detailed characterisation of immune-related transcripts has never been performed. In these studies, nCounter PanCancer Immune Profiling Panel was used to assess the expression of 770 immune-related transcripts in the tumour tissues (TTs) and matched adjacent tissues (ATs) of resected BTCs. Cox regression analysis and Kaplan–Meier methods were used to correlate findings with relapse-free survival (RFS). The first analysis in the TT and AT of an exploratory set (n = 22) showed deregulation of 39 transcripts associated with T-cell activation. Risk of recurrence was associated with a greater number of genes deregulated in AT in comparison to TT. Analysis in the whole set (n = 53) showed a correlation between AT cytotoxic T-lymphocyte antigen-4 (CTLA4) expression and RFS, which maintained statistical significance at multivariate analysis. CTLA4 expression correlated with forkhead box P3 (FOXP3) expression, suggesting enrichment in T regulatory cells. CTLA4 is known to act by binding to the cluster of differentiation 80 (CD80). No association was seen between AT CD80 expression and RFS. However, CD80 expression differentiated prognosis in patients who received adjuvant chemotherapy. We showed that the immunomodulatory transcriptome is deregulated in resected BTCs. Our study includes a small number of patients and does not enable to draw definitive conclusions; however, it provides useful insights into potential transcripts that may deserve further investigation in larger cohorts of patients. Transcript Profiling Nanostring data have been submitted to GEO repository: GSE90698 and GSE90699., Highlights • BTCs harbour a derangement of immune-related transcripts with an important role for the cytotoxic T-lymphocyte antigen-4 (CTLA4) axis. • CTLA4 expression in the peritumoural areas correlates with outcome and represents a potential promising prognostic factor. • Our data suggest that immunotherapy may have an impact in BTCs as a mean to re-address the host immune response to the tumour.
- Published
- 2017
8. Cell of origin in biliary tract cancers and clinical implications.
- Author
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Moeini A, Haber PK, and Sia D
- Abstract
Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, their incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need to improve current diagnostic and therapeutic strategies. BTCs show high inter- and intra-tumour heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to effective interventions. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cells of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumours., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
9. Non-invasive detection of biliary tract cancer by low-coverage whole genome sequencing from plasma cell-free DNA: A prospective cohort study.
- Author
-
Wang X, Fu XH, Qian ZL, Zhao T, Duan AQ, Ruan X, Zhu B, Yin L, Zhang YJ, and Yu WL
- Abstract
Background: The diagnosis of biliary tract cancer (BTC) is challenging in clinical practice. We performed a prospective study to evaluate the value of plasma copy number variation (CNV) assays in diagnosing BTC., Methods: 47 treatment-naïve patients with suspicious biliary lesions were recruited. Plasma samples were collected at admission. Cell-free DNA was analyzed by low coverage whole genome sequencing, followed by CNV analyses via a customized bioinformatics workflow, namely the ultrasensitive chromosomal aneuploidy detector., Results: 29 patients were pathologically diagnosed as BTC, including 8 gallbladder cancers (GBCs) and 21 cholangiocarcinomas (CCs). Cancer patients had more CNV signals as compared with benign patients (26/29 vs. 2/18, P < 0.001). The most frequent copy number gains were chr3q (7/29) and chr8q (6/29). The most frequent copy number losses were chr7p (6/29), chr17p (6/29), and chr19p (6/29). The sensitivity and specificity of plasma CNV assays in diagnosing BTC were 89.7% and 88.9%, respectively. For CA 19-9 (cutoff: 37 U/ml), the sensitivity was 58.6% and the specificity was 72.2%. The diagnostic accuracy of CNV assays significantly outperformed CA 19-9 (AUC 0.91 vs. 0.62, P = 0.004). Compared with CA 19-9 alone, the adding of CNV profiles to CA 19-9 increased the sensitivity in diagnosing GBC (75.0% vs. 25.0%) and CC (100% vs. 52.4%). Higher CNV burden was also associated with decreased overall survival (Hazard ratio = 4.32, 95% CI 2.06-9.08, P = 0.033)., Discussion: Our results suggest that BTC harbors rich plasma CNV signals, and their assays might be useful for diagnosing BTC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)
- Published
- 2020
- Full Text
- View/download PDF
10. Circulating levels of soluble urokinase plasminogen activator receptor predict outcome after resection of biliary tract cancer.
- Author
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Loosen SH, Breuer A, Tacke F, Kather JN, Gorgulho J, Alizai PH, Bednarsch J, Roeth AA, Lurje G, Schmitz SM, Brozat JF, Paffenholz P, Vucur M, Ritz T, Koch A, Trautwein C, Ulmer TF, Roderburg C, Longerich T, Neumann UP, and Luedde T
- Abstract
Background & Aims: Surgical resection is the only potentially curative therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has been associated with distinct types of cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing BTC resection., Methods: Tumor expression of uPAR was analyzed by immunohistochemistry in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 patients with BTC and 76 healthy controls., Results: High tumoral uPAR expression was associated with an adverse outcome after BTC resection. Accordingly, circulating levels of suPAR were significantly elevated in patients with BTC compared to healthy controls, as well as in patients with primary sclerosing cholangitis. Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72 ng/ml for patients with BTC. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including various clinicopathological parameters such as tumor stage, markers of inflammation and organ dysfunction, as well as tumor markers, revealed circulating suPAR levels as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative of acute kidney injury after tumor resection., Conclusion: Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might help to preoperatively identify the ideal candidates for liver surgery., Lay Summary: Surgical resection represents the only curative treatment option for patients with biliary tract cancer, but not all patients benefit to the same extent in terms of overall survival. Here, we provide evidence that serum levels of an inflammatory mediator (suPAR) are indicative of a patient's postoperative outcome and might thus help to identify the ideal surgical candidates., Competing Interests: The authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)
- Published
- 2020
- Full Text
- View/download PDF
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