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Martviset P, Chantree P, Tongsiri N, Plengsuriyakarn T, Na-Bangchang K. Targeting tumor-associated genes, immune response, and circulating tumor cells in intrahepatic cholangiocarcinoma: Therapeutic potential of Atractylodes lancea (Thunb.) DC. PLoS One 2025; 20:e0323732. [PMID: 40359186 PMCID: PMC12074528 DOI: 10.1371/journal.pone.0323732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/14/2025] [Indexed: 05/15/2025] Open
Abstract
Cholangiocarcinoma (CCA) is one of the most aggressive cancers with a poor prognosis. Current treatment strategies involve hepatobiliary surgery, chemotherapy, radiotherapy, and supportive care; however, the success of these treatments remains limited. Therefore, this study investigated the potential of Atractylodes lancea (Thunb) D.C. (AL) in limiting the progress of CCA by targeting the expression of cancer-related genes involved in immune responses and circulating tumor cells. The study was part of Phase 2A clinical trial in advanced-stage intrahepatic iCCA (iCCA) patients: Group 1 (n = 16) received low-dose AL (capsule formulation of the standardized extract of AL: CMC-AL) with standard supportive care, Group 2 (n = 16) received high-dose AL with standard supportive care, and Group 3 (n = 16) received standard supportive care alone. Venous whole blood samples (EDTA, 5 ml) were collected from each patient on Day 1 and Day 90 and the non-CCA subjects (n = 16) on Day 1. Fifty-nine samples (48 and 11 samples for Day 1 and Day 90, respectively) were processed for total RNA isolation. Gene expression was evaluated using reverse transcription followed by a PCR array. Regardless of dosage, gene expression patterns in the AL-treated groups closely resembled those of the healthy subjects. Specifically, cancer-associated genes, including VEGF-A, NR4A3, Ki-67, and EpCAM, were significantly down-regulated. Additionally, the expression levels of immune-related genes were modulated in AL-treated patients. The treatment groups exhibited lower levels of the pro-inflammatory cytokine IL-6, increased expression of the anti-inflammatory cytokine IL-10, and cell-mediated immune-related molecules such as CTLA4 and PFR1. These findings suggest the potential of AL for iCCA treatment. However, additional studies are required to confirm the correlation between gene and protein expression profiles, as well as CTCs profile.
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Affiliation(s)
- Pongsakorn Martviset
- Division of Parasitology, Department of Preclinical Science, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
- Graduate Program in Applied Biosciences, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Pathanin Chantree
- Graduate Program in Applied Biosciences, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
- Division of Anatomy, Department of Preclinical Science, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Nisit Tongsiri
- Department of Surgery, Sakon Nakhon Hospital, Sakon Nakhon, Thailand
| | - Tullayakorn Plengsuriyakarn
- Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
- Center of Excellence in Malaria and Cholangiocarcinoma, Thammasat University, Pathum Thani, Thailand
| | - Kesara Na-Bangchang
- Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
- Center of Excellence in Malaria and Cholangiocarcinoma, Thammasat University, Pathum Thani, Thailand
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de Scordilli M, Bortolot M, Torresan S, Noto C, Rota S, Di Nardo P, Fumagalli A, Guardascione M, Ongaro E, Foltran L, Puglisi F. Precision oncology in biliary tract cancer: the emerging role of liquid biopsy. ESMO Open 2025; 10:105079. [PMID: 40311184 DOI: 10.1016/j.esmoop.2025.105079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 03/01/2025] [Accepted: 04/04/2025] [Indexed: 05/03/2025] Open
Abstract
Liquid biopsy has already proven effective in aiding diagnosis, risk stratification and treatment personalization in several malignancies, and it could represent a practice-changing tool also in biliary tract cancer, even though clinical applications are currently still limited. It is promising for early diagnosis, especially in high-risk populations, and several studies on circulating free DNA (cfDNA), circulating tumour cells and differential microRNA (miRNA) profiles in this setting are ongoing. Circulating tumour DNA (ctDNA) also appears as a feasible noninvasive biomarker in the curative setting, in detecting minimal residual disease after resection and in monitoring disease recurrence. As of today, it can be particularly valuable in biliary tract cancer for genomic profiling, with a good concordance with tissue samples for most molecular alterations. CtDNA analysis may especially be considered in clinical practice when the tumour tissue is not sufficient for next-generation sequencing, or when urgent therapeutic decisions are needed. Moreover, it offers the possibility of providing a real-time picture to monitor treatment response and dynamically identify resistance mutations, potentially representing a way to optimize treatment strategies.
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Affiliation(s)
- M de Scordilli
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| | - M Bortolot
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| | - S Torresan
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| | - C Noto
- Department of Medicine, University of Udine, Udine, Italy; Medical Oncology, ASUGI, Ospedale Maggiore, Trieste, Italy
| | - S Rota
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| | - P Di Nardo
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - A Fumagalli
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - M Guardascione
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - E Ongaro
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - L Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
| | - F Puglisi
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
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Nishida N. Biomarkers and Management of Cholangiocarcinoma: Unveiling New Horizons for Precision Therapy. Cancers (Basel) 2025; 17:1243. [PMID: 40227772 PMCID: PMC11987923 DOI: 10.3390/cancers17071243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/31/2025] [Accepted: 04/03/2025] [Indexed: 04/15/2025] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive malignancy with limited methods for early detection, necessitating the development of reliable biomarkers for diagnosis and management. However, conventional tumor markers, such as CA19-9 and CEA, exhibit insufficient diagnostic accuracy. Recent advancements in molecular genetics have identified several actionable mutations in CCA, enabling molecularly targeted therapies that improve survival in patients harboring these genetic alterations. Cancer panels, which facilitate multiplex genetic profiling, are critical for identifying these mutations. Studies indicate that several actionable mutations are detected in CCA cases, with patients receiving mutation-guided therapies achieving markedly better outcomes. Liquid biopsies, including cell-free DNA and circulating tumor DNA, offer real-time, non-invasive approaches to monitoring tumor dynamics, heterogeneity, and treatment responses. Furthermore, numerous studies have identified non-coding RNAs in serum and bile as promising biomarkers for the diagnosis and management of CCA. On the other hand, immunotherapy, particularly immune checkpoint inhibitors, has shown efficacy in subsets of CCA patients. However, the success of these therapies is often affected by the status of the tumor immune microenvironment (TME), underscoring the need for comprehensive TME analysis to predict responses to immune checkpoint inhibitors. Despite these advances, no single biomarker currently demonstrates sufficient sensitivity or specificity for clinical application. The integration of multi-omics approaches with cutting-edge technologies holds promise for enhancing diagnostic accuracy, optimizing treatment stratification, and advancing precision medicine in CCA. These developments highlight the transformative potential of biomarkers to improve early detection, prognostic assessment, and personalized therapeutic interventions for CCA.
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Affiliation(s)
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University Osaka 589-8511, Japan
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Kotsifa E, Saffioti F, Mavroeidis VK. Cholangiocarcinoma: The era of liquid biopsy. World J Gastroenterol 2025; 31:104170. [PMID: 40124277 PMCID: PMC11924015 DOI: 10.3748/wjg.v31.i11.104170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/28/2025] [Accepted: 02/14/2025] [Indexed: 03/13/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive and heterogeneous malignancy arising from the epithelial cells of the biliary tract. The limitations of the current methods in the diagnosis of CCA highlight the urgent need for new, accurate tools for early cancer detection, better prognostication and patient monitoring. Liquid biopsy (LB) is a modern and non-invasive technique comprising a diverse group of methodologies aiming to detect tumour biomarkers from body fluids. These biomarkers include circulating tumour cells, cell-free DNA, circulating tumour DNA, RNA and extracellular vesicles. The aim of this review is to explore the current and potential future applications of LB in CCA management, with a focus on diagnosis, prognostication and monitoring. We examine both its significant potential and the inevitable limitations associated with this technology. We conclude that LB holds considerable promise, but further research is necessary to fully integrate it into precision oncology for CCA.
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Affiliation(s)
- Evgenia Kotsifa
- The Second Propaedeutic Department of Surgery, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens 11527, Greece
| | - Francesca Saffioti
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom
- University College London Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and University College London, London NW3 2QG, United Kingdom
- Division of Clinical and Molecular Hepatology, Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina 98124, Italy
| | - Vasileios K Mavroeidis
- Department of Transplant Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of Gastrointestinal Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of HPB Surgery, Bristol Royal Infirmary, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol BS2 8HW, United Kingdom
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Yu Q, Mahbubani A, Kwak D, Liao CY, Pillai A, Patel M, Navuluri R, Funaki B, Ahmed O. Survival Outcomes of Radiofrequency Ablation for Intrahepatic Cholangiocarcinoma from the Surveillance, Epidemiology, and End Results (SEER) Database: Comparison with Radiotherapy and Resection. J Vasc Interv Radiol 2025; 36:489-498.e3. [PMID: 39491643 DOI: 10.1016/j.jvir.2024.10.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 10/14/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024] Open
Abstract
PURPOSE To determine effectiveness of radiofrequency ablation for treatment of intrahepatic cholangiocarcinoma (iCCA) using a population-based database. MATERIALS AND METHODS Data were extracted from Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2020 to include 194 patients who underwent ablation for iCCA. Data on patient demographics, overall survival (OS), and cancer-specific survival were retrieved. Factors associated with survival were evaluated. Comparison between ablation and surgical resection (n = 2,653) or external beam radiotherapy (n = 1,068) was performed. RESULTS In the ablation group, patients diagnosed and treated after 2010 demonstrated improved OS than that in the 2000-2009 subgroup (median OS, 32 vs 21 months; hazard ratio, 0.50; 95% CI, 0.33-0.75; P = .001). Additional factors associated with OS included tumor size (≤3 cm vs >3 cm; P = .049) and tumor stage (P < .001). For patients diagnosed after 2010, the 1-, 3-, and 5-year OS were 82.8% (95% CI, 74.8%-88.4%), 43.5% (95% CI, 33.5%-53.1%), and 23.7% (95% CI, 15.3%-33.5%), respectively. Patients with local disease (1-year OS, 87.8%; 95% CI, 78.6%-93.3%) demonstrated improved OS compared with patients with regional (1-year OS, 81.3%; 95% CI, 52.5%-93.5%) and distant disease (50.2%; 95% CI, 34.0%-78.8%; P < .001). For tumors ≤3 cm, ablation and surgical resection offered comparable survival benefits (P = .561), although both were better than radiotherapy (P < .0001). CONCLUSIONS Survival of patients with iCCA who underwent thermal ablation has improved over the last 10 years. For tumors ≤3 cm, ablation could be as effective as resection with careful candidate selection, and may be considered front-line compared with radiotherapy in certain patient populations. Patient selection based on tumor size and disease stage could improve survival outcomes.
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Affiliation(s)
- Qian Yu
- Section of Vascular and Interventional Radiology, Department of Radiology, University of Chicago Medical Center, University of Chicago, Chicago, Illinois.
| | - Amar Mahbubani
- Nova Southeastern University College of Osteopathic Medicine, Davie, Florida
| | - Daniel Kwak
- Section of Vascular and Interventional Radiology, Department of Radiology, University of Chicago Medical Center, University of Chicago, Chicago, Illinois
| | - Chih-Yi Liao
- Section of Hematology and Oncology, Department of Medicine, University of Chicago Medical Center, University of Chicago, Chicago, Illinois
| | - Anjana Pillai
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Chicago Medical Center, University of Chicago, Chicago, Illinois
| | - Mikin Patel
- Section of Vascular and Interventional Radiology, Department of Radiology, University of Chicago Medical Center, University of Chicago, Chicago, Illinois
| | - Rakesh Navuluri
- Section of Vascular and Interventional Radiology, Department of Radiology, University of Chicago Medical Center, University of Chicago, Chicago, Illinois
| | - Brian Funaki
- Section of Vascular and Interventional Radiology, Department of Radiology, University of Chicago Medical Center, University of Chicago, Chicago, Illinois
| | - Osman Ahmed
- Section of Vascular and Interventional Radiology, Department of Radiology, University of Chicago Medical Center, University of Chicago, Chicago, Illinois. https://twitter.com/EndovasClarky
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Macias RIR, Kanzaki H, Berasain C, Avila MA, Marin JJG, Hoshida Y. The Search for Risk, Diagnostic, and Prognostic Biomarkers of Cholangiocarcinoma and Their Biological and Clinicopathologic Significance. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:422-436. [PMID: 39103092 PMCID: PMC11841489 DOI: 10.1016/j.ajpath.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/01/2024] [Accepted: 06/20/2024] [Indexed: 08/07/2024]
Abstract
Cholangiocarcinomas (CCAs) are a heterogeneous group of malignant tumors that originate from the biliary tract. They are usually diagnosed in advanced stages, leading to a poor prognosis for affected patients. As CCA often arises as a sporadic cancer in individuals lacking specific risk factors or with heterogeneous backgrounds, and there are no defined high-risk groups, the implementation of effective surveillance programs for CCA is problematic. The identification and validation of new biomarkers useful for risk stratification, diagnosis, prognosis, and prediction of treatment response remains an unmet need for patients with CCA, even though numerous studies have been conducted lately to try to discover and validate CCA biomarkers. In this review, we overview the available information about the different types of biomarkers that have been investigated in recent years using minimally invasive biospecimens (blood, serum/plasma, bile, and urine) and their potential usefulness in diagnosis, prognosis, and risk stratification. It is widely accepted that early detection of CCA will impact patients' outcomes, by improving survival rates, quality of life, and the possibility of less invasive and/or curative treatments; however, challenges to its translation and clinical application for patients with CCA need to be resolved.
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Affiliation(s)
- Rocio I R Macias
- Experimental Hepatology and Drug Targeting Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases, Carlos III National Institute of Health, Madrid, Spain.
| | - Hiroaki Kanzaki
- Division of Digestive and Liver Diseases, Department of Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Carmen Berasain
- Center for the Study of Liver and Gastrointestinal Diseases, Carlos III National Institute of Health, Madrid, Spain; Hepatology Laboratory, Solid Tumors Program, Center for Applied Medical Research, Cancer Center University of Navarra, Pamplona, Spain
| | - Matias A Avila
- Center for the Study of Liver and Gastrointestinal Diseases, Carlos III National Institute of Health, Madrid, Spain; Hepatology Laboratory, Solid Tumors Program, Center for Applied Medical Research, Cancer Center University of Navarra, Pamplona, Spain
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases, Carlos III National Institute of Health, Madrid, Spain
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, Department of Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
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Fey RM, Billo A, Clister T, Doan KL, Berry EG, Tibbitts DC, Kulkarni RP. Personalization of Cancer Treatment: Exploring the Role of Chronotherapy in Immune Checkpoint Inhibitor Efficacy. Cancers (Basel) 2025; 17:732. [PMID: 40075580 PMCID: PMC11899640 DOI: 10.3390/cancers17050732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 02/01/2025] [Accepted: 02/15/2025] [Indexed: 03/14/2025] Open
Abstract
In the era of precision medicine, mounting evidence suggests that the time of therapy administration, or chronotherapy, has a great impact on treatment outcomes. Chronotherapy involves planning treatment timing by considering circadian rhythms, which are 24 h oscillations in behavior and physiology driven by synchronized molecular clocks throughout the body. The value of chronotherapy in cancer treatment is currently under investigation, notably in the effects of treatment timing on efficacy and side effects. Immune checkpoint inhibitor (ICI) therapy is a promising cancer treatment. However, many patients still experience disease progression or need to stop the therapy early due to side effects. There is accumulating evidence that the time of day at which ICI therapy is administered can have a substantial effect on ICI efficacy. Thus, it is important to investigate the intersections of circadian rhythms, chronotherapy, and ICI efficacy. In this review, we provide a brief overview of circadian rhythms in the context of immunity and cancer. Additionally, we outline current applications of chronotherapy for cancer treatment. We synthesize the 29 studies conducted to date that examine the impact of time-of-day administration on the efficacy of ICI therapy, its associated side effects, and sex differences in both efficacy and side effects. We also discuss potential mechanisms underlying these observed results. Finally, we highlight the challenges in this area and future directions for research, including the potential for a chronotherapeutic personalized medicine approach that tailors the time of ICI administration to individual patients' circadian rhythms.
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Affiliation(s)
- Rosalyn M. Fey
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA; (R.M.F.)
| | - Avery Billo
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA; (R.M.F.)
| | - Terri Clister
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA; (R.M.F.)
| | - Khanh L. Doan
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA; (R.M.F.)
| | - Elizabeth G. Berry
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA; (R.M.F.)
| | - Deanne C. Tibbitts
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Rajan P. Kulkarni
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA; (R.M.F.)
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Cancer Early Detection Advanced Research Center (CEDAR), Portland, OR 97239, USA
- Operative Care Division, U.S. Department of Veterans Affairs Portland Health Care System, Portland, OR 97239, USA
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Ma L, Guo H, Zhao Y, Liu Z, Wang C, Bu J, Sun T, Wei J. Liquid biopsy in cancer current: status, challenges and future prospects. Signal Transduct Target Ther 2024; 9:336. [PMID: 39617822 PMCID: PMC11609310 DOI: 10.1038/s41392-024-02021-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/10/2024] [Accepted: 10/14/2024] [Indexed: 12/06/2024] Open
Abstract
Cancer has a high mortality rate across the globe, and tissue biopsy remains the gold standard for tumor diagnosis due to its high level of laboratory standardization, good consistency of results, relatively stable samples, and high accuracy of results. However, there are still many limitations and drawbacks in the application of tissue biopsy in tumor. The emergence of liquid biopsy provides new ideas for early diagnosis and prognosis of tumor. Compared with tissue biopsy, liquid biopsy has many advantages in the diagnosis and treatment of various types of cancer, including non-invasive, quickly and so on. Currently, the application of liquid biopsy in tumor detection has received widely attention. It is now undergoing rapid progress, and it holds significant potential for future applications. Around now, liquid biopsies encompass several components such as circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. In addition, advances in the identification of liquid biopsy indicators have significantly enhanced the possibility of utilizing liquid biopsies in clinical settings. In this review, we will discuss the application, advantages and challenges of liquid biopsy in some common tumors from the perspective of diverse systems of tumors, and look forward to its future development prospects in the field of cancer diagnosis and treatment.
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Affiliation(s)
- Liwei Ma
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China.
| | - Huiling Guo
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China
| | - Yunxiang Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhibo Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China
| | - Chenran Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China
| | - Jiahao Bu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ting Sun
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China.
| | - Jianwei Wei
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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Capuozzo M, Santorsola M, Ferrara F, Cinque C, Farace S, Patrone R, Granata V, Zovi A, Nasti G, Ottaiano A. Intrahepatic cholangiocarcinoma biomarkers: Towards early detection and personalized pharmacological treatments. Mol Cell Probes 2024; 73:101951. [PMID: 38244704 DOI: 10.1016/j.mcp.2024.101951] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 01/22/2024]
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy originating from the biliary tree and is anatomically categorized as intrahepatic (iCCA), perihilar, and extrahepatic or distal. iCCA, the second most prevalent hepatobiliary cancer following hepatocellular carcinoma (HCC), constitutes 5-20 % of all liver malignancies, with an increasing incidence. The challenging nature of iCCA, combined with nonspecific symptoms, often leads to late diagnoses, resulting in unfavorable outcomes. The advanced phase of this neoplasm is difficult to treat with dismal results. Early diagnosis could significantly reduce mortality attributed to iCCA but remains an elusive goal. The identification of biomarkers specific to iCCA and their translation into clinical practice could facilitate diagnosis, monitor therapy response, and potentially reveal novel interventions and personalized medicine. In this review, we present the current landscape of biomarkers in each of these contexts. In addition to CA19.9, a widely recognized biomarker for iCCA, others such as A1BG, CYFRA 21-1, FAM19A5, MMP-7, RBAK, SSP411, TuM2-PK, WFA, etc., as well as circulating tumor DNA, RNA, cells, and exosomes, are under investigation. Advancing our knowledge and monitoring of biomarkers may enable us to improve diagnosis, prognostication, and apply treatments dynamically and in a more personalized manner.
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Affiliation(s)
| | - Mariachiara Santorsola
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy
| | | | - Claudia Cinque
- Pharmaceutical Department, ASL-Naples-3, 80056, Ercolano, Italy
| | - Stefania Farace
- Pharmaceutical Department, ASL-Naples-3, 80056, Ercolano, Italy
| | - Renato Patrone
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy
| | - Vincenza Granata
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy
| | - Andrea Zovi
- Hospital Pharmacist, Ministry of Health, 00144, Roma, Italy
| | - Guglielmo Nasti
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy
| | - Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy.
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10
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Liu F, Hao X, Liu B, Liu S, Yuan Y. Bile liquid biopsy in biliary tract cancer. Clin Chim Acta 2023; 551:117593. [PMID: 37839517 DOI: 10.1016/j.cca.2023.117593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/08/2023] [Accepted: 10/10/2023] [Indexed: 10/17/2023]
Abstract
Biliary tract cancers are heterogeneous in etiology, morphology and molecular characteristics thus impacting disease management. Diagnosis is complex and prognosis poor. The advent of liquid biopsy has provided a unique approach to more thoroughly understand tumor biology in general and biliary tract cancers specifically. Due to their minimally invasive nature, liquid biopsy can be used to serially monitor disease progression and allow real-time monitoring of tumor genetic profiles as well as therapeutic response. Due to the unique anatomic location of biliary tract cancer, bile provides a promising biologic fluid for this purpose. This review focuses on the composition of bile and the use of these various components, ie, cells, extracellular vesicles, nucleic acids, proteins and metabolites as potential biomarkers. Based on the disease characteristics and research status of biliary tract cancer, considerable effort should be made to increase understanding of this disease, promote research and development into early diagnosis, develop efficient diagnostic, therapeutic and prognostic markers.
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Affiliation(s)
- Fusheng Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, Hubei, PR China
| | - Xingyuan Hao
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, Hubei, PR China
| | - Bin Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, Hubei, PR China
| | - Songmei Liu
- Department of Clinical Laboratory, Center for Gene Diagnosis, and Program of Clinical Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China
| | - Yufeng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, Hubei, PR China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, PR China.
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11
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Conci S, Catalano G, Roman D, Zecchetto C, Lucin E, De Bellis M, Tripepi M, Guglielmi A, Milella M, Ruzzenente A. Current Role and Future Perspectives of Immunotherapy and Circulating Factors in Treatment of Biliary Tract Cancers. Int J Med Sci 2023; 20:858-869. [PMID: 37324191 PMCID: PMC10266048 DOI: 10.7150/ijms.82008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/07/2023] [Indexed: 06/17/2023] Open
Abstract
Biliary tract cancers (BTCs) are a heterogenous group of malignancies arising from the epithelial cells of the biliary tree and the gallbladder. They are often locally advanced or already metastatic at the time of the diagnosis and therefore prognosis remains dismal. Unfortunately, the management of BTCs has been limited by resistance and consequent low response rate to cytotoxic systemic therapy. New therapeutic approaches are needed to improve the survival outcomes for these patients. Immunotherapy, one of the newest therapeutic options, is changing the approach to the oncological treatment. Immune checkpoint inhibitors are by far the most promising group of immunotherapeutic agents: they work by blocking the tumor-induced inhibition of the immune cellular response. Immunotherapy in BTCs is currently approved as second-line treatment for patients whose tumors have a peculiar molecular profile, such as high levels of microsatellites instability, PD-L1 overexpression, or high levels of tumor mutational burden. However, emerging data from ongoing clinical trials seem to suggest that durable responses can be achieved in other subsets of patients. The BTCs are characterized by a highly desmoplastic microenvironment that fuels the growth of cancer tissue, but tissue biopsies are often difficult to obtain or not feasible in BTCs. Recent studies have hence proposed to use liquid biopsy approaches to search the blood circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to use as biomarkers in BTCs. So far studies are insufficient to promote their use in clinical management, however trials are still in progress with promising preliminary results. Analysis of blood samples for ctDNA to research possible tumor-specific genetic or epigenetic alterations that could be linked to treatment response or prognosis was already feasible. Although there are still few data available, ctDNA analysis in BTC is fast, non-invasive, and could also represent a way to diagnose BTC earlier and monitor tumor response to chemotherapy. The prognostic capabilities of soluble factors in BTC are not yet precisely determined and more studies are needed. In this review, we will discuss the different approaches to immunotherapy and tumor circulating factors, the progress that has been made so far, and the possible future developments.
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Affiliation(s)
- Simone Conci
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Giovanni Catalano
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Diletta Roman
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Camilla Zecchetto
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Eleonora Lucin
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Mario De Bellis
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Marzia Tripepi
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Alfredo Guglielmi
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Michele Milella
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Andrea Ruzzenente
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
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12
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Kefas J, Bridgewater J, Vogel A, Stein A, Primrose J. Adjuvant therapy of biliary tract cancers. Ther Adv Med Oncol 2023; 15:17588359231163785. [PMID: 37007632 PMCID: PMC10052632 DOI: 10.1177/17588359231163785] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 02/27/2023] [Indexed: 03/30/2023] Open
Abstract
Biliary tract cancers (BTCs) are rare and heterogeneous malignant tumours including cholangiocarcinoma and gallbladder cancer. They are very aggressive, often refractory to chemotherapy and associated with an overall poor prognosis. Surgical resection remains the only potentially curative treatment option but less than 35% present with resectable disease. Adjuvant treatments have been widely used but until recently, supportive data were limited to non-randomised, non-controlled retrospective studies. Recent evidence from the BILCAP trial has established adjuvant capecitabine as the standard of care. But there are still unanswered questions as to the role of adjuvant therapy. Further prospective data and translational research with reproducible evidence of clinical benefit are needed. In this review of adjuvant therapy in resectable BTCs, we will summarise the latest evidence setting current treatment standards and highlight future prospects.
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Affiliation(s)
- Joanna Kefas
- University College London Hospital NHS trust, 250 Euston Road, London NW1 2PG, UK
| | | | | | - Alexander Stein
- Hematology-Oncology Practice Eppendorf, University Cancer Center Hamburg, Hamburg, Germany
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13
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Choi WJ, Ivanics T, Gravely A, Gallinger S, Sapisochin G, O'Kane GM. Optimizing Circulating Tumour DNA Use in the Perioperative Setting for Intrahepatic Cholangiocarcinoma: Diagnosis, Screening, Minimal Residual Disease Detection and Treatment Response Monitoring. Ann Surg Oncol 2023; 30:3849-3863. [PMID: 36808320 DOI: 10.1245/s10434-023-13126-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/09/2023] [Indexed: 02/23/2023]
Abstract
In this review, we present the current evidence and future perspectives on the use of circulating tumour DNA (ctDNA) in the diagnosis, management and understanding the prognosis of patients with intrahepatic cholangiocarcinoma (iCCA) undergoing surgery. Liquid biopsies or ctDNA maybe utilized to: (1) determine the molecular profile of the tumour and therefore guide the selection of molecular targeted therapy in the neoadjuvant setting, (2) form a surveillance tool for the detection of minimal residual disease or cancer recurrence after surgery, and (3) diagnose and screen for early iCCA detection in high-risk populations. The potential for ctDNA can be tumour-informed or -uninformed depending on the goals of its use. Future studies will require ctDNA extraction technique validations, with standardizations of both the platforms and the timing of ctDNA collections.
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Affiliation(s)
- Woo Jin Choi
- HBP and Multi Organ Transplant Program, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.,Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.,HPB Surgical Oncology, University Health Network, Toronto, Ontario, Canada
| | - Tommy Ivanics
- Department of Surgery, Henry Ford Hospital, Detroit, MI, USA.,Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Annabel Gravely
- HPB Surgical Oncology, University Health Network, Toronto, Ontario, Canada
| | - Steven Gallinger
- HBP and Multi Organ Transplant Program, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.,HPB Surgical Oncology, University Health Network, Toronto, Ontario, Canada
| | - Gonzalo Sapisochin
- HBP and Multi Organ Transplant Program, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada. .,HPB Surgical Oncology, University Health Network, Toronto, Ontario, Canada.
| | - Grainne M O'Kane
- Department of Medical Oncology, Trinity St. James's Cancer Institute, Trinity College Dublin, Dublin, Ireland.
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14
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Ohaegbulam KC, Koethe Y, Fung A, Mayo SC, Grossberg AJ, Chen EY, Sharzehi K, Kardosh A, Farsad K, Rocha FG, Thomas CR, Nabavizadeh N. The multidisciplinary management of cholangiocarcinoma. Cancer 2023; 129:184-214. [PMID: 36382577 DOI: 10.1002/cncr.34541] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/11/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022]
Abstract
Cholangiocarcinoma is a lethal malignancy of the biliary epithelium that can arise anywhere along the biliary tract. Surgical resection confers the greatest likelihood of long-term survivability. However, its insidious onset, difficult diagnostics, and resultant advanced presentation render the majority of patients unresectable, highlighting the importance of early detection with novel biomarkers. Developing liver-directed therapies and emerging targeted therapeutics may offer improved survivability for patients with unresectable or advanced disease. In this article, the authors review the current multidisciplinary standards of care in resectable and unresectable cholangiocarcinoma, with an emphasis on novel biomarkers for early detection and nonsurgical locoregional therapy options.
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Affiliation(s)
- Kim C Ohaegbulam
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Yilun Koethe
- Department of Interventional Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Alice Fung
- Department of Diagnostic Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Skye C Mayo
- Department of Surgical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Aaron J Grossberg
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Emerson Y Chen
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Kaveh Sharzehi
- Division of Gastroenterology and Hepatology, Oregon Health & Science University, Portland, Oregon, USA
| | - Adel Kardosh
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Khashayar Farsad
- Department of Interventional Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Flavio G Rocha
- Department of Surgical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Charles R Thomas
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA.,Department of Radiation Oncology, Dartmouth School of Medicine, Hanover, New Hampshire, USA
| | - Nima Nabavizadeh
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
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15
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Fründt T, von Felden J, Krause J, Heumann A, Li J, Riethdorf S, Pantel K, Huber S, Lohse AW, Wege H, Schulze K. Circulating tumor cells as a preoperative risk marker for occult metastases in patients with resectable cholangiocarcinoma. Front Oncol 2022; 12:941660. [PMID: 36439492 PMCID: PMC9685781 DOI: 10.3389/fonc.2022.941660] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 10/21/2022] [Indexed: 11/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive tumor associated with a high rate of recurrence after resection. An important risk factor for recurrence is the presence of occult metasta-ses, which are not radiologically detectable at the time of diagnosis. There are currently no biomarkers for the preoperative assessment of micrometastases. A previous study demonstrated the prognostic relevance of circulating tumor cells (CTC) in patients with advanced CCA but the potential of CTCs as a preoperative marker for detecting occult metastases has not been investigated so far. In this two-phase study, we first recruited a cohort of 27 patients with histologically proven, metastatic CCA or gallbladder cancer (GBCA) to assess feasibility (feasibility cohort, FC). CTCs were measured in the peripheral blood using the CellSearch System (CSS) between October 2012 and January 2017. Subsequently, in 11 patients undergoing curative-intended resection for CCA (intrahepatic CCA: n =4; extrahepatic CCA n= 6; gallbladder cancer: n=1), peripheral and central venous blood specimens were obtained to improve detection rate by simultaneous measurement and to elucidate distribution of CTCs in different venous compartments. Presence of CTCs detection was correlated with postoperative TNM-status. In the FC, CTCs (range 1-3 cells, median: 1) were detected in 40% (11/27) patients and were signifi-cantly associated with worse overall survival (hazard ratio: 3.59; 95% CI: 1.79- 7.1; p = 0.04). By combined peripheral and central measurement, CTC detection was increased to 54% (6/11) in the resection cohort (RC) and was associated with metastases that were only identified during the surgical procedure (peritoneal carcinoma: n = 1; infiltration of the duodenum: n = 1) or immediately after surgery (evidence of pulmonary metastases by CT scan two days after resection, not evident on initial tumor staging prior resection). Taken together, in this single center pilot study, we demonstrated that CTCs are detectable in CCA patients and are associated with significantly impaired survival in patients at metastatic stage. Detection rate prior to surgery was improved to >50% by combined peripheral and central measurement. Moreover, preoperative CTC detection may indicate existing metastases and could help to stratify patients more accurately.
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16
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Brown ZJ, Patwardhan S, Bean J, Pawlik TM. Molecular diagnostics and biomarkers in cholangiocarcinoma. Surg Oncol 2022; 44:101851. [PMID: 36126350 DOI: 10.1016/j.suronc.2022.101851] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/26/2022] [Accepted: 09/09/2022] [Indexed: 10/14/2022]
Abstract
Regardless of anatomic origin, cholangiocarcinoma is generally an aggressive malignancy with a relatively high case fatality. Surgical resection with curative intent remains the best opportunity to achieve meaningful long-term survival. Most patients present, however, with advanced disease and less than 20% of patients are candidates for surgical resection. Unfortunately, even patients who undergo resection have a 5-year survival that ranges from 20 to 40%. Biomarkers are indicators of normal, pathologic, or biologic responses to an intervention and can range from a characteristic (i.e., blood pressure reading which can detect hypertension) to specific genetic mutations or proteins (i.e., carcinoembryonic antigen level). Novel biomarkers and improved molecular diagnostics represent an attractive opportunity to improve detection as well as to identify novel therapeutic targets for patients with cholangiocarcinoma. We herein review the latest advances in molecular diagnostics and biomarkers related to the early detection and treatment of patients with cholangiocarcinoma.
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Affiliation(s)
- Zachary J Brown
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
| | - Satyajit Patwardhan
- Dept of HPB Surgery and Liver Transplantation, Global Hospital, Mumbai, India
| | - Joal Bean
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
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17
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Current Perspectives on the Surgical Management of Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:cancers14092208. [PMID: 35565335 PMCID: PMC9104954 DOI: 10.3390/cancers14092208] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 04/21/2022] [Accepted: 04/21/2022] [Indexed: 02/08/2023] Open
Abstract
Cholangiocarcinoma (CCA) represents nearly 15% of all primary liver cancers and 2% of all cancer-related deaths worldwide. Perihilar cholangiocarcinoma (pCCA) accounts for 50-60% of all CCA. First described in 1965, pCCAs arise between the second-order bile ducts and the insertion of the cystic duct into the common bile duct. CCA typically has an insidious onset and commonly presents with advanced, unresectable disease. Complete surgical resection is technically challenging, as tumor proximity to the structures of the central liver often necessitates an extended hepatectomy to achieve negative margins. Intraoperative frozen section can aid in assuring negative margins and complete resection. Portal lymphadenectomy provides important prognostic and staging information. In specialized centers, vascular resection and reconstruction can be performed to achieve negative margins in appropriately selected patients. In addition, minimally invasive surgical techniques (e.g., robotic surgery) are safe, feasible, and provide equivalent short-term oncologic outcomes. Neoadjuvant chemoradiation therapy followed by liver transplantation provides a potentially curative option for patients with unresectable disease. New trials are needed to investigate novel chemotherapies, immunotherapies, and targeted therapies to better control systemic disease in the adjuvant setting and, potentially, downstage disease in the neoadjuvant setting.
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18
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Vij M, Puri Y, Rammohan A, G G, Rajalingam R, Kaliamoorthy I, Rela M. Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review. World J Gastrointest Oncol 2022; 14:607-627. [PMID: 35321284 PMCID: PMC8919011 DOI: 10.4251/wjgo.v14.i3.607] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/13/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Yogesh Puri
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Gowripriya G
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Rajesh Rajalingam
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
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19
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Brown ZJ, Hewitt DB, Pawlik TM. Biomarkers of intrahepatic cholangiocarcinoma: diagnosis and response to therapy. FRONT BIOSCI-LANDMRK 2022; 27:85. [PMID: 35345317 DOI: 10.31083/j.fbl2703085] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/31/2022] [Accepted: 02/10/2022] [Indexed: 01/03/2025]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer behind hepatocellular carcinoma (HCC) and carries a dismal prognosis. Improved genetic analysis has paved the way for a better understanding of the distinct somatic genomic landscapes of ICC. The use of next generation sequencing has paved the way for more personalized medicine through identifying unique mutations which may prove to be therapeutic targets. The ability to identify biomarkers specific to ICC will assist in establishing a diagnosis, monitoring response to therapy, as well as assist in identifying novel therapies and personalized medicine. Herein, we discuss potential biomarkers for ICC and how these markers can assist in diagnosis, monitor response to therapy, and potentially identify novel interventions for the treatment of ICC.
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Affiliation(s)
- Zachary J Brown
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - D Brock Hewitt
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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20
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Wang Y, Yuan Z, Zhu S, Bao X, Fu Z, Zhen T, Xing K, Zhang Y, Li X, Sun J, Li Q, Wu L. The longitudinal change of circulating tumor cell during chemotherapy and its correlation with disease features, treatment response and survival profile of advanced gallbladder carcinoma. Am J Transl Res 2021; 13:13590-13598. [PMID: 35035699 PMCID: PMC8748159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 11/03/2021] [Indexed: 06/14/2023]
Abstract
The current study aimed to investigate the relation of circulating tumor cell (CTC) with clinicopathological features. In addition, its longitudinal change during chemotherapy and its correlation with prognosis in advanced gallbladder carcinoma (GBC) patients were explored. Totally 45 unresectable, locally advanced or metastatic GBC patients who underwent chemotherapy were enrolled in this prospective study. The CTC in 7.5 ml blood was detected at pre-treatment and 3 months post-treatment. CTC was almost detectable in all advanced GBC patients before treatment, whose count was positively correlated with metastatic disease (vs. local advanced disease) (P=0.002), number of organs with metastases (P=0.006), and CA199 level (P=0.002). After treatment, CTC count declined from 4.0 (range: 0.0-83.0) at pre-treatment to 2.0 (range: 0.0-36.0) at post-treatment (P=0.003). Interestingly, pre-treatment CTC count (P=0.270) was of no difference, while post-treatment CTC count was lower (P=0.038) in objective-response patients compared to that in non-objective-response patients; meanwhile, both pre-treatment CTC count (P=0.017) and post-treatment CTC count (P<0.001) were lower in disease-control patients compared with those in non-disease-control patients. Importantly, pre-treatment CTC count ≥2 (versus <2) was only correlated with worse progression-free survival (PFS) (P=0.014) but not overall survival (OS) (P=0.057); while pre-treatment CTC count ≥5 (versus <5), post-treatment CTC count ≥2 (versus <2), post-treatment CTC count ≥5 (versus <5), CTC count up (versus equal/down) were all correlated with poor PFS and OS (all P<0.050). In conclusion, higher CTC count during chemotherapy correlates with worse treatment response, PFS and OS in advanced GBC patients, which implies that CTC measurement may optimize the prognostication and individualized treatment in these patients.
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Affiliation(s)
- Yinping Wang
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 201112, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 200127, China
| | - Zhiqing Yuan
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 201112, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 200127, China
| | - Sibo Zhu
- Cinoasia InstituteShanghai 200438, China
| | - Xunxia Bao
- Cinoasia InstituteShanghai 200438, China
| | | | | | | | - Yijue Zhang
- Department of Anesthesiology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 200127, China
| | - Xinxing Li
- Department of General Surgery, Changzheng Hospital, The Second Military Medical UniversityShanghai 200003, China
- Department of Gastroenterological Surgery, Tongji Hospital, School of Medicine, Tongji UniversityShanghai 200065, China
| | - Jianhua Sun
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 201112, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 200127, China
| | - Qiwei Li
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 201112, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 200127, China
| | - Linshi Wu
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 201112, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai 200127, China
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21
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Yu J, Wang Z, Zhang H, Wang Y, Li DQ. Survivin-positive circulating tumor cells as a marker for metastasis of hepatocellular carcinoma. World J Gastroenterol 2021; 27:7546-7562. [PMID: 34887648 PMCID: PMC8613743 DOI: 10.3748/wjg.v27.i43.7546] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/19/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs) and survivin are indicators for tumor stage and metastasis, as well as epitheliomesenchymal transition, in various cancers, including hepatocellular cancer (HCC).
AIM To explore the potential of survivin-positive CTCs, specifically, as a marker for tumor progression in HCC patients.
METHODS We examined the survivin expression pattern in CTCs obtained from 179 HCC patients, and investigated the in vitro effects of survivin silencing and overexpression on the proliferation and invasion of HCC cells. CTC count and survivin expression in patient samples were examined using RNA in situ hybridization.
RESULTS All 179 patients were positive for CTC markers, and 94.41% of the CTCs were positive for survivin. The CTC and survivin-positive CTC counts were significantly higher in the HCC patients than in the normal controls, and were significantly associated with tumor stage and degree of differentiation. Further, survivin overexpression was found to induce HepG2 cell proliferation, reduce apoptosis, and improve invasive ability.
CONCLUSION Survivin shows upregulated expression (indicative of anti-apoptotic effects) in HCC. Thus, survivin-positive CTCs are promising as a predictor of HCC prognosis and metastasis, and their accurate measurement may be useful for the management of this cancer.
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Affiliation(s)
- Jing Yu
- Blood Transfusion Department, Wuhan Chinese and Western Medicine Hospital, Wuhan 430022, Hubei Province, China
| | - Zhan Wang
- Laboratory, Tianjin Hospital, Tianjin 300211, China
| | - Hua Zhang
- Laboratory, Guoyao Dongfeng Hospital, Shiyan 442008, Hubei Province, China
| | - Yi Wang
- Laboratory, Tianjin Hospital, Tianjin 300211, China
| | - Dong-Qing Li
- Department of Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430000, Hubei Province, China
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22
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Manne A, Woods E, Tsung A, Mittra A. Biliary Tract Cancers: Treatment Updates and Future Directions in the Era of Precision Medicine and Immuno-Oncology. Front Oncol 2021; 11:768009. [PMID: 34868996 PMCID: PMC8634105 DOI: 10.3389/fonc.2021.768009] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/13/2021] [Indexed: 12/12/2022] Open
Abstract
The effective management of biliary tract cancers (BTCs) has been hampered by limited options for systemic therapy. In recent years, the focus on precision medicine has made technologies such as next-generation sequencing (NGS) accessible to clinicians to identify targetable mutations in BTCs in tumor tissue (primarily) as well as blood, and to treat them with targeted therapies when possible. It has also expanded our understanding of functional pathways associated with genetic alterations and opened doors for identifying novel targets for treatment. Recent advances in the precision medicine approach allowed us to identify new molecular markers in BTCs, such as epigenetic changes (methylation and histone modification) and non-DNA markers such as messenger RNA, microRNA, and long non-coding RNA. It also made detecting these markers from non-traditional sources such as blood, urine, bile, and cytology (from fine-needle aspiration and biliary brushings) possible. As these tests become more accessible, we can see the integration of different molecular markers from all available sources to aid physicians in diagnosing, assessing prognosis, predicting tumor response, and screening BTCs. Currently, there are a handful of approved targeted therapies and only one class of immunotherapy agents (immune checkpoint inhibitors or ICIs) to treat BTCs. Early success with new targets, vascular endothelial growth factor receptor (VEGFR), HER2, protein kinase receptor, and Dickkopf-1 (DKK1); new drugs for known targets, fibroblast growth factor receptors (FGFRs) such as futabatinib, derazantinib, and erdafitinib; and ICIs such as durvalumab and tremelimumab is encouraging. Novel immunotherapy agents such as bispecific antibodies (bintrafusp alfa), arginase inhibitors, vaccines, and cellular therapy (chimeric antigen receptor-T cell or CAR-T, natural killer cells, tumor-infiltrating lymphocytes) have the potential to improve outcomes of BTCs in the coming years.
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Affiliation(s)
- Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Edward Woods
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Allan Tsung
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, OH, United States
| | - Arjun Mittra
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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23
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Ney A, Garcia-Sampedro A, Goodchild G, Acedo P, Fusai G, Pereira SP. Biliary Strictures and Cholangiocarcinoma - Untangling a Diagnostic Conundrum. Front Oncol 2021; 11:699401. [PMID: 34660269 PMCID: PMC8515053 DOI: 10.3389/fonc.2021.699401] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma is an uncommon and highly aggressive biliary tract malignancy with few manifestations until late disease stages. Diagnosis is currently achieved through a combination of clinical, biochemical, radiological and histological techniques. A number of reported cancer biomarkers have the potential to be incorporated into diagnostic pathways, but all lack sufficient sensitivity and specificity limiting their possible use in screening and early diagnosis. The limitations of standard serum markers such as CA19-9, CA125 and CEA have driven researchers to identify multiple novel biomarkers, yet their clinical translation has been slow with a general requirement for further validation in larger patient cohorts. We review recent advances in the diagnostic pathway for suspected CCA as well as emerging diagnostic biomarkers for early detection, with a particular focus on non-invasive approaches.
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Affiliation(s)
- Alexander Ney
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Andres Garcia-Sampedro
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - George Goodchild
- St. Bartholomew's hospital, Barts Health NHS Trust, London, United Kingdom
| | - Pilar Acedo
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Giuseppe Fusai
- Division of Surgery and Interventional Science - University College London, London, United Kingdom
| | - Stephen P Pereira
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
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24
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Han SY, Park SH, Ko HS, Jang A, Seo HI, Lee SJ, Kim GH, Kim DU. Vimentin-Positive Circulating Tumor Cells as Diagnostic and Prognostic Biomarkers in Patients with Biliary Tract Cancer. J Clin Med 2021; 10:4435. [PMID: 34640452 PMCID: PMC8509386 DOI: 10.3390/jcm10194435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 11/16/2022] Open
Abstract
Biliary tract cancer (BTC) has poor prognosis; thus, early diagnosis is important to decrease mortality. Although vimentin-positive circulating tumor cells (V-CTCs) are a good candidate for diagnostic and prognostic biomarkers, studies on the topic are limited. We aimed to evaluate the diagnostic efficacy of V-CTCs between BTC and benign biliary disease (BBD) and determine the prognostic value of V-CTCs in BTC patients. We recruited 69 participants who had BTCs and BBDs from a single tertiary referral center. We analyzed CTCs and V-CTCs in peripheral blood using the CD-PRIMETM system. Seven patients were excluded due to a technical failure of CTC detection. CTCs were detected in all 62 patients. CTC count > 40/mL blood (55.8% vs. 20%, p = 0.039), V-CTC count > 15/mL blood (57.7% vs. 10%, p = 0.005), and V-CTC/CTC ratio > 40% (48.1% vs. 10%, p = 0.025) were significantly different between BTCs and BBDs. Two or more of these three parameters (61.5% vs. 10%, p = 0.002) increased the accuracy. A combination of CTC markers with CA19-9 and biopsy increased the accuracy (90.4% vs. 10%, p = 0.000). V-CTC > 50/mL blood was a significant factor affecting survival (140 (66.6-213.3) vs. 253 (163.9-342.1) days, p = 0.008). V-CTC could be a potential biomarker for early diagnosis and predicting prognosis in patients with BTC.
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Affiliation(s)
- Sung Yong Han
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
| | - Sung Hee Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
| | - Hyun Suk Ko
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
| | - Aelee Jang
- Department of Nursing, University of Ulsan, Ulsan 44610, Korea;
| | - Hyung Il Seo
- Department of Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea;
| | - So Jeong Lee
- Department of Pathology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea;
| | - Gwang Ha Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
| | - Dong Uk Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
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25
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Zori AG, Yang D, Draganov PV, Cabrera R. Advances in the management of cholangiocarcinoma. World J Hepatol 2021; 13:1003-1018. [PMID: 34630871 PMCID: PMC8473501 DOI: 10.4254/wjh.v13.i9.1003] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/09/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a primary malignancy of the bile ducts with three anatomically and molecularly distinct entities: Intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. As a result of phenotypic and anatomic differences they differ significantly with respect to management. For each type of CCA there have been significant changes in management over the last several years which will be discussed in this review. Although resection remains the standard of care for all types of CCA, liver transplantation has been established as curative treatment for selected patients with pCCA and is being evaluated for iCCA with early success. With respect to systemic therapy capecitabine is now first line adjuvant therapy for all biliary tract malignancies after curative intent resection. Progress in exploiting the pathologic mutations and molecular abnormalities has also yielded regulatory approval of targeted therapy for CCA in patients with acquired alterations in the fibroblast growth factor receptor. There is also increased consensus in managing malignant biliary obstruction associated with CCA where pre-operative biliary stenting is not beneficial while self-expanding metal stents have been shown to be superior to plastic stents in patients who are not surgical candidates.
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Affiliation(s)
- Andreas G Zori
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL 32608, United States
| | - Dennis Yang
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL 32608, United States
| | - Peter V Draganov
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL 32608, United States
| | - Roniel Cabrera
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL 32608, United States
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26
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Shotton R, Lamarca A, Valle J, McNamara MG. Potential utility of liquid biopsies in the management of patients with biliary tract cancers: A review. World J Gastrointest Oncol 2021; 13:1073-1085. [PMID: 34616513 PMCID: PMC8465442 DOI: 10.4251/wjgo.v13.i9.1073] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 06/14/2021] [Accepted: 08/11/2021] [Indexed: 02/06/2023] Open
Abstract
Biliary tract cancer, comprising gallbladder cancer, cholangiocarcinoma and ampullary cancer, represents a more uncommon entity outside high-endemic areas, though global incidence is rising. The majority of patients present at a late stage, and 5-year survival remains poor. Advanced stage disease is incurable, and though palliative chemotherapy has been shown to improve survival, further diagnostic and therapeutic options are required in order to improve patient outcomes. Although certain subtypes of biliary tract cancer are relatively rich in targetable mutations, attaining tumour tissue for histological diagnosis and treatment monitoring is challenging due to locoregional anatomical constraints and patient fitness. Liquid biopsies offer a safe and convenient alternative to invasive procedures and have great potential as diagnostic, predictive and prognostic biomarkers. In this review, the current standard of care for patients with biliary tract cancer, future treatment horizons and the possible utility of liquid biopsies within a variety of contexts will be discussed. Circulating tumour DNA, circulating microRNA and circulating tumour cells are discussed with an overview of their potential applications in management of biliary tract cancer. A summary is also provided of currently recruiting clinical trials incorporating liquid biopsies within biliary tract cancer research.
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Affiliation(s)
- Rohan Shotton
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, United Kingdom
| | - Juan Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, United Kingdom
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, United Kingdom
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27
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[Influence of molecular pathology on oncological surgery of liver and bile duct tumors]. Chirurg 2021; 92:1003-1010. [PMID: 34519849 DOI: 10.1007/s00104-021-01495-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Molecular pathology is increasingly being used to guide treatment in oncology. Approximately 25% of all hepatocellular carcinomas (HCC) and 50% of cholangiocarcinomas (CCA) present with known cancer-relevant mutations; however, the impact of the mutations on the treatment of these tumors is not yet sufficiently understood. PURPOSE To evaluate the current literature on molecular pathological advances in HCC/CCA and the potential impact on oncological surgery. MATERIAL AND METHODS A comprehensive search of the available literature on currently known molecular biomarkers in HCC/CCA was performed in PubMed and clinitrials.gov. Following review, the potential impact of these biomarkers on oncological surgery was analyzed and is discussed. CONCLUSION Molecular pathological investigations can be used to support the classification of tumors and to determine the dignity of HCC/CCA. Predictive molecular biomarkers are not yet established in routine diagnostics but can be used to individualize advanced oncological treatment.
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28
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Next-Generation Biomarkers for Cholangiocarcinoma. Cancers (Basel) 2021; 13:cancers13133222. [PMID: 34203269 PMCID: PMC8269024 DOI: 10.3390/cancers13133222] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/16/2021] [Accepted: 06/22/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Early and non-invasive diagnosis of cholangiocarcinoma (CCA) is still challenging, thus largely contributing to the increased mortality rates observed worldwide. Consequently, several efforts have been made in order to report novel biomarkers for CCA, that would aid on diagnosis and also to predict prognosis and therapy response. We herein aim to provide an in-depth and critical revision on the next-generation biomarkers for CCA that have been recently proposed. Abstract The increasing mortality rates of cholangiocarcinoma (CCA) registered during the last decades are, at least in part, a result of the lack of accurate non-invasive biomarkers for early disease diagnosis, making the identification of patients who might benefit from potentially curative approaches (i.e., surgery) extremely challenging. The obscure CCA pathogenesis and associated etiological factors, as well as the lack of symptoms in patients with early tumor stages, highly compromises CCA identification and to predict tumor development in at-risk populations. Currently, CCA diagnosis is accomplished by the combination of clinical/biochemical features, radiological imaging and non-specific serum tumor biomarkers, although a tumor biopsy is still needed to confirm disease diagnosis. Furthermore, prognostic and predictive biomarkers are still lacking and urgently needed. During the recent years, high-throughput omics-based approaches have identified novel circulating biomarkers (diagnostic and prognostic) that might be included in large, international validation studies in the near future. In this review, we summarize and discuss the most recent advances in the field of biomarker discovery in CCA, providing new insights and future research directions.
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29
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Zhang H, Lin X, Huang Y, Wang M, Cen C, Tang S, Dique MR, Cai L, Luis MA, Smollar J, Wan Y, Cai F. Detection Methods and Clinical Applications of Circulating Tumor Cells in Breast Cancer. Front Oncol 2021; 11:652253. [PMID: 34150621 PMCID: PMC8208079 DOI: 10.3389/fonc.2021.652253] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/29/2021] [Indexed: 12/18/2022] Open
Abstract
Circulating Tumor Cells (CTCs) are cancer cells that split away from the primary tumor and appear in the circulatory system as singular units or clusters, which was first reported by Dr. Thomas Ashworth in 1869. CTCs migrate and implantation occurs at a new site, in a process commonly known as tumor metastasis. In the case of breast cancer, the tumor cells often migrate into locations such as the lungs, brain, and bones, even during the early stages, and this is a notable characteristic of breast cancer. Survival rates have increased significantly over the past few decades because of progress made in radiology and tissue biopsy, making early detection and diagnosis of breast cancer possible. However, liquid biopsy, particularly that involving the collection of CTCs, is a non-invasive method to detect tumor cells in the circulatory system, which can be easily isolated from human plasma, serum, and other body fluids. Compared to traditional tissue biopsies, fluid sample collection has the advantages of being readily available and more acceptable to the patient. It can also detect tumor cells in blood earlier and in smaller numbers, possibly allowing for diagnosis prior to any tumor detection using imaging methods. Because of the scarcity of CTCs circulating in blood vessels (only a few CTCs among billions of erythrocytes and leukocytes), thorough but accurate detection methods are particularly important for further clinical applications.
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Affiliation(s)
- Hongyi Zhang
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoyan Lin
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuan Huang
- Cellomics International Limited, Hong Kong, China
| | - Minghong Wang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Chunmei Cen
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shasha Tang
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Marcia R Dique
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lu Cai
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Manuel A Luis
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jillian Smollar
- Department of Biomedical Engineering, The City College of New York, New York, NY, United States
| | - Yuan Wan
- Department of Biomedical Engineering, The City College of New York, New York, NY, United States
| | - Fengfeng Cai
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
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30
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Boilève A, Hilmi M, Delaye M, Tijeras-Raballand A, Neuzillet C. Biomarkers in Hepatobiliary Cancers: What is Useful in Clinical Practice? Cancers (Basel) 2021; 13:2708. [PMID: 34070929 PMCID: PMC8198554 DOI: 10.3390/cancers13112708] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) exhibit a poor prognosis with 5-year overall survival rates around 15%, all stages combined. Most of these primary liver malignancies are metastatic at diagnostic, with only limited therapeutic options, relying mainly on systemic therapies. Treatment modalities are different yet partially overlapping between HCC and BTC. The complex molecular profile of BTC yields to several actionable therapeutic targets, contrary to HCC that remains the field of antiangiogenic drugs in non-molecularly selected patients. Immunotherapy is now validated in the first line in HCC in combination with bevacizumab, while clinical activity of single agent immunotherapy appears limited to a subset of patients in BTC, still poorly characterized, and combinations are currently under investigation. In this review, we provide a critical evaluation and grading of clinical relevance on (i) the main prognostic biomarkers in HCC and BTC, (ii) the main theragnostic biomarkers in both tumors, and lastly (iii) what is recommended in clinical practice.
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Affiliation(s)
- Alice Boilève
- Gustave Roussy, Département de Médecine Oncologique, 94805 Villejuif, France;
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
| | - Marc Hilmi
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- Département de Médecine Oncologique, Curie Institute, 92210 Saint-Cloud, France
| | - Matthieu Delaye
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- Département de Médecine Oncologique, Curie Institute, 92210 Saint-Cloud, France
| | - Annemilaï Tijeras-Raballand
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- OncoMEGA, 75010 Paris, France
| | - Cindy Neuzillet
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- Département de Médecine Oncologique, Curie Institute, 92210 Saint-Cloud, France
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31
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Rompianesi G, Di Martino M, Gordon-Weeks A, Montalti R, Troisi R. Liquid biopsy in cholangiocarcinoma: Current status and future perspectives. World J Gastrointest Oncol 2021; 13:332-350. [PMID: 34040697 PMCID: PMC8131901 DOI: 10.4251/wjgo.v13.i5.332] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/02/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) are a heterogeneous group of tumors in terms of aetiology, natural history, morphological subtypes, molecular alterations and management, but all sharing complex diagnosis, management, and poor prognosis. Several mutated genes and epigenetic changes have been detected in CCA, with the potential to identify diagnostic and prognostic biomarkers and therapeutic targets. Accessing tumoral components and genetic material is therefore crucial for the diagnosis, management and selection of targeted therapies; but sampling tumor tissue, when possible, is often risky and difficult to be repeated at different time points. Liquid biopsy (LB) represents a way to overcome these issues and comprises a diverse group of methodologies centering around detection of tumor biomarkers from fluid samples. Compared to the traditional tissue sampling methods LB is less invasive and can be serially repeated, allowing a real-time monitoring of the tumor genetic profile or the response to therapy. In this review, we analysis the current evidence on the possible roles of LB (circulating DNA, circulating RNA, exosomes, cytokines) in the diagnosis and management of patients affected by CCA.
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Affiliation(s)
- Gianluca Rompianesi
- Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Napoli 80131, Italy
| | - Marcello Di Martino
- Hepato-Bilio-Pancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital Universitario La Princesa, Madrid 28006, Spain
| | - Alex Gordon-Weeks
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Roberto Montalti
- Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Napoli 80131, Italy
| | - Roberto Troisi
- Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Napoli 80131, Italy
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32
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Lang SA, Bednarsch J, Joechle K, Amygdalos I, Czigany Z, Heij L, Ulmer TF, Neumann UP. Prognostic biomarkers for cholangiocarcinoma (CCA): state of the art. Expert Rev Gastroenterol Hepatol 2021; 15:497-510. [PMID: 33970740 DOI: 10.1080/17474124.2021.1912591] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction:Although advances in understanding the molecular basis of cholangiocarcinoma (CCA) have been made, surgery is the only curative therapy option and the overall prognosis of patients suffering from the disease remains poor. Therefore, estimation of prognosis based on known and novel biomarkers is essential for therapy guidance of CCA in both, curative and palliative settings.Areas covered:An extensive literature search on biomarkers for CCA with special emphasis on prognosis was performed. Based on this, prognostic biomarkers from serum, tumor tissue and other compartments that are currently in use or under evaluation for CCA were summarized in this review. Furthermore, an overview of new biomarkers was provided including those determined from extracellular vesicles (EVs), metabolites and nucleic acids. Finally, prognostic markers associated with potential new therapy options for the treatment of CCA were summed up.Expert opinion:So far, an optimal prognostic biomarker for CCA has not been described. However, based on the increasing knowledge about the molecular basis of CCA but also due to novel, innovative technologies, a plethora of novel prognostic biomarkers is currently under evaluation and will be available for CCA in future.
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Affiliation(s)
- Sven A Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Katharina Joechle
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Lara Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Tom F Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulf P Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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33
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Hu CL, Zhang YJ, Zhang XF, Fei X, Zhang H, Li CG, Sun B. 3D Culture of Circulating Tumor Cells for Evaluating Early Recurrence and Metastasis in Patients with Hepatocellular Carcinoma. Onco Targets Ther 2021; 14:2673-2688. [PMID: 33888992 PMCID: PMC8057830 DOI: 10.2147/ott.s298427] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
Purpose Circulating tumor cells (CTCs) are considered to be a key factor involved in tumor metastasis. However, the isolation and culture of CTCs in vitro remains challenging, and their clinical application for predicting prognosis and survival is still limited. The development of accurate evaluating system for CTCs will benefit for clinical assessment of HCC. Methods Density gradient centrifugation and magnetic separation based on CD45 antibody were used to isolate CTCs. 3D culture was used to maintain and amplify CTCs and HCC cells. Cellular immunofluorescence was used to identify CTCs and spheroids. The cutoff value of CTC spheroid was calculated using X-tile software. The relationship between clinicopathological variables and CTC spheroids in HCC patients is analyzed. In vivo models were used to evaluate tumor growth and metastasis of CTC spheroids. Results Patient-derived CTCs/HCC cells were isolated and expanded to form spheroids using 3D culture. CTC spheroids could be used to predict short-term recurrence of CTCs compared with conventional CTC enumeration. Different cell lines exhibited different formation rates and grew to different sizes. Identification of CTC spheroids revealed that EpCAM and β-catenin were expressed in spheroids derived from HCC cells and in the HCC/CTCs. EpCAM-positive HCC cells exhibited improved spheroid formation in 3D culture and were more tumorigenic and likely to metastasize to the lung in vivo. Abnormal activation of the Wnt/β-catenin signaling pathway was observed in EpCAM positive cells. Conclusion CTC spheroids could predict prognosis of HCC more precisely compared with conventional CTC enumeration. EpCAM may participate in the formation and survival of CTC spheroids which dependent on Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Cong-Li Hu
- Translational Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, People's Republic of China.,Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center for Liver Cancer, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Yan-Jun Zhang
- School of Health and Social Care, Shanghai Urban Construction Vocational College, Shanghai, 201415, People's Republic of China
| | - Xiao-Feng Zhang
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center for Liver Cancer, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Xiang Fei
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Hai Zhang
- Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, People's Republic of China
| | - Chun-Guang Li
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Bin Sun
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center for Liver Cancer, Second Military Medical University, Shanghai, 200438, People's Republic of China
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Cadamuro M, Lasagni A, Lamarca A, Fouassier L, Guido M, Sarcognato S, Gringeri E, Cillo U, Strazzabosco M, Marin JJ, Banales JM, Fabris L. Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic. Expert Opin Investig Drugs 2021; 30:377-388. [PMID: 33622120 DOI: 10.1080/13543784.2021.1880564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Until recently, cholangiocarcinoma (CCA) was a largely overlooked disease, and among CCAs, extrahepatic CCA (eCCA) was even more neglected. Despite the growing impact of molecularly targeted therapies and immunotherapy, prognosis of eCCA is dismal. Therefore, unraveling the complex molecular landscape of eCCA has become an urgent need. Deep phenotyping studies have revealed that eCCA is a heterogeneous tumor, harboring specific alterations categorizable into four classes, 'Mesenchymal', 'Proliferation', 'Immune', 'Metabolic'. Molecular alterations convey the activation of several pro-oncogenic pathways, where either actionable drivers or outcome predictors can be identified.Areas covered: We offer insights on perturbed pathways, molecular profiling, and actionable targets in eCCA and present a perspective on the potential stepping-stones to future progress. A systematic literature search in PubMed/ClinicalTrials.gov websites was performed by authors from different disciplines according to their specific topic knowledge to identify the newest and most relevant advances in precision medicine of eCCA.Expert opinion: eCCA is a distinct entity with unique features in terms of molecular classes, oncogenic drivers, and tumor microenvironment. Since more prevalent mutations are currently undruggable, and immunotherapy can be offered only to a minority of patients, international collaborations are instrumental to improve the understanding of the molecular underpins of this disease.
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Affiliation(s)
- Massimiliano Cadamuro
- Department of Molecular Medicine (DMM), University of Padua, Padua. Italy.,International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy
| | - Alberto Lasagni
- Division of General Medicine, Padua University-Hospital, Padua, Italy
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, United Kingdom.,Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Laura Fouassier
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy.,Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Samantha Sarcognato
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy.,Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation, Padua University-Hospital, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation, Padua University-Hospital, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Mario Strazzabosco
- International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy.,Digestive Disease Section, Liver Center, Yale University, New Haven, CT, US
| | - Jose Jg Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital -, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, Padua. Italy.,International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy.,Division of General Medicine, Padua University-Hospital, Padua, Italy.,Digestive Disease Section, Liver Center, Yale University, New Haven, CT, US
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Nara S, Esaki M, Ban D, Takamoto T, Shimada K, Ioka T, Okusaka T, Ishii H, Furuse J. Adjuvant and neoadjuvant therapy for biliary tract cancer: a review of clinical trials. Jpn J Clin Oncol 2021; 50:1353-1363. [PMID: 33037430 DOI: 10.1093/jjco/hyaa170] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 08/21/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer originating in the biliary tract can be classified as bile duct cancer (cholangiocarcinoma), gallbladder cancer, or ampullary cancer. Bile duct cancer is further divided to intrahepatic, perihilar and distal bile duct subtypes according to the anatomical location of the tumor. The biological characteristics of each tumor are heterogeneous. However, because of the rarity of each disease, the efficacy of new drugs has been tested in groups of patients with different biliary tract cancers. In patients with metastatic or recurrent biliary tract cancer, recent randomized clinical trials revealed the non-inferiority of gemcitabine + S-1 and the superiority of gemcitabine + cisplatin + S-1 compared with gemcitabine + cisplatin in terms of overall survival, thereby establishing a new standard treatment. In the field of adjuvant therapy for biliary tract cancer, the British BILCAP (capecitabine compared with observation in resected biliary tract cancer) study revealed longer median overall survival in the capecitabine group than in the observation group in the per-protocol analysis (but not in the intention-to-treat analysis), bringing a shift toward postoperative management. Several other studies of adjuvant therapy are ongoing, and they may lead to reforms in treatment strategy for resectable biliary tract cancer in the future. The use of neoadjuvant therapy for biliary tract cancer is in its infancy, but it is expected to overcome the limitations of adjuvant therapy for this malignancy. In this review, we summarized the evidence available from clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and described ongoing clinical trials.
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Affiliation(s)
- Satoshi Nara
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Minoru Esaki
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takeshi Takamoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tatsuya Ioka
- Oncology Center, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi Ube-shi, Yamaguchi, 755-8505, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hiroshi Ishii
- Division of Gastroenterology, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan
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Konno N, Suzuki R, Takagi T, Sugimoto M, Asama H, Sato Y, Irie H, Hikichi T, Ohira H. Clinical utility of a newly developed microfluidic device for detecting circulating tumor cells in the blood of patients with pancreatico-biliary malignancies. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:115-124. [PMID: 33090657 DOI: 10.1002/jhbp.850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The development of an optimal screening method is required to improve the prognosis of pancreatico-biliary (PB) cancers. A recently developed microfluidic device achieved a high diagnostic yield by detecting circulating tumor cells (CTCs) in the blood of cancer patients. We conducted this study to investigate the clinical utility of measuring CTCs in peripheral venous blood to diagnose PB cancer. METHODS Sixty-three subjects were enrolled in this study (29 with pancreatic cancer [PC], 19 with biliary cancer [BC] and 16 non-tumor controls). Using a microfluidic chip device and image analyzer, circulating blood cells were selected based on their size and immunocytochemistry staining pattern. The primary endpoint was the diagnostic accuracy of CTCs with regard to distinguishing between PB cancer patients and controls. We divided all cases into the training set (n = 32) and validation set (n = 31). The diagnostic accuracy of CTCs, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9) were analyzed. RESULTS In both the training set and validation set, CTCs showed the highest diagnostic accuracy (training set: CTCs 90.6%, CA19-9 90.6%, CEA 65.6%, validation set: CTCs 87.5%, CA19-9 78.1%, CEA 81.2). Regarding non-metastatic PC (cStage I-III, n = 11), CTCs also had the highest diagnostic accuracy among the three markers tested (CTCs: 84.6%, CA19-9:80.7%, CEA 73.0%). CONCLUSIONS A newly developed microfluidic device could diagnose PB cancers by detecting CTCs. This trial was registered with the UMIN Clinical Trials Registry, no. UMIN000029808.
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Affiliation(s)
- Naoki Konno
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Rei Suzuki
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tadayuki Takagi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Mitsuru Sugimoto
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroyuki Asama
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yuki Sato
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroki Irie
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Takuto Hikichi
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
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Zhou J, Zhang Z, Zhou H, Leng C, Hou B, Zhou C, Hu X, Wang J, Chen X. Preoperative circulating tumor cells to predict microvascular invasion and dynamical detection indicate the prognosis of hepatocellular carcinoma. BMC Cancer 2020; 20:1047. [PMID: 33129301 PMCID: PMC7603758 DOI: 10.1186/s12885-020-07488-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 10/02/2020] [Indexed: 02/06/2023] Open
Abstract
Background This study explored the diagnostic power of preoperative circulating tumor cells (CTCs) for the presence of microvascular invasion (MVI) and the relationship between dynamic changes in postoperative CTCs and prognosis. Methods A total of 137 patients were recruited for the study. Preoperative blood samples were collected from all patients to detect CTCs. The time points for blood collection were before the operation, during the operation, and at 1 week, 1 month, 2 months, 3 months, 6 months, and 1 year after surgery. The predictive power of CTC count for the presence of MVI was analyzed by receiver operating characteristic (ROC) curve analysis. According to recurrence status, 137 patients were divided into three groups: no recurrence, early recurrence, and non-early recurrence groups. Results A threshold CTC count of 5 showed the most significant power for predicting the existence of MVI. In multivariate analysis, the parameters of preoperative CTC count, alpha-fetoprotein (AFP) and tumor diameter were independent predictors of MVI (P < 0.05). A CTC count greater than or equal to 5 had better predictive value than AFP > 400 μg/L and tumor diameter > 5 cm. The number of intraoperative CTCs in the three groups did not increase compared to that before surgery (P > 0.05). The number of CTCs in the nonrecurrence group and the non-early recurrence group decreased significantly 1 week after surgery compared with the intraoperative values (P < 0.001), although there was no significant difference in the early recurrence group (P = 0.95). Patients with mean CTC count ≥5 had significantly worse long-term outcomes than those with mean CTC count < 5 (P < 0.001). Conclusion The preoperative CTC counts in the peripheral blood of patients with HCC are closely correlated with MVI. The intraoperative manipulation of the lesion by the surgeon does not increase the number of CTCs in peripheral blood. Surgical removal of the tumor decreases the number of CTCs. The persistence of CTCs at a high level (≥ 5) after surgery suggests a risk of early recurrence. Clinical trial registration Registration number is ChiCTR-OOC-16010183, date of registration is 2016-12-18.
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Affiliation(s)
- Jiangmin Zhou
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Zhiwei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
| | - Honghao Zhou
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Chao Leng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Bingwu Hou
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Chenyang Zhou
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Xinsheng Hu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jinlin Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Xiaoping Chen
- Translational Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
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Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Ilyas SI, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17:557-588. [PMID: 32606456 PMCID: PMC7447603 DOI: 10.1038/s41575-020-0310-z] [Citation(s) in RCA: 1457] [Impact Index Per Article: 291.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2020] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
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Affiliation(s)
- Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
| | - Jose J G Marin
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Shahid A Khan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Luke Boulter
- MRC-Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Rocio I R Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Eugenio Gaudio
- Division of Human Anatomy, Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | | | - Mario Strazzabosco
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Universita Politecnica delle Marche, Ancona, Italy
| | | | - Laura Fouassier
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center of Autoimmune Liver Diseases, Department of Medicine and Surgery, San Gerardo Hospital, University of Milano, Bicocca, Italy
| | - Joachim C Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Sumera I. Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | | | | | - Jordi Bruix
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Alejandro Forner
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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Marin JJG, Prete MG, Lamarca A, Tavolari S, Landa-Magdalena A, Brandi G, Segatto O, Vogel A, Macias RIR, Rodrigues PM, Casta AL, Mertens J, Rodrigues CMP, Fernandez-Barrena MG, Da Silva Ruivo A, Marzioni M, Mentrasti G, Acedo P, Munoz-Garrido P, Cardinale V, Banales JM, Valle JW, Bridgewater J, Braconi C. Current and novel therapeutic opportunities for systemic therapy in biliary cancer. Br J Cancer 2020; 123:1047-1059. [PMID: 32694694 PMCID: PMC7525457 DOI: 10.1038/s41416-020-0987-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/22/2020] [Accepted: 06/25/2020] [Indexed: 12/22/2022] Open
Abstract
Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.
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Affiliation(s)
- José J G Marin
- IBSAL, University of Salamanca, Salamanca, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, ES, Spain
| | - Maria Giuseppina Prete
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center - IRCCS -, Rozzano (MI), Italy
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Simona Tavolari
- Medical Oncology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Ana Landa-Magdalena
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Oreste Segatto
- Unit of Oncogenomics and Epigenetics, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Rocío I R Macias
- IBSAL, University of Salamanca, Salamanca, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, ES, Spain
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Adelaida La Casta
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Joachim Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Cecilia M P Rodrigues
- Research Insitute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | | | - Marco Marzioni
- Università Politecnica delle Marche/Ospedali Riuniti di Ancona, Ancona, Italy
| | - Giulia Mentrasti
- Università Politecnica delle Marche/Ospedali Riuniti di Ancona, Ancona, Italy
| | - Pilar Acedo
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Patricia Munoz-Garrido
- Biotech Research & Innovation Centre (BRIC), University of Copenhaghen, Copenhagen, Denmark
| | | | - Jesus M Banales
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, ES, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | | | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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Cheng H, He W, Yang J, Ye Q, Cheng L, Pan Y, Mao L, Chu X, Lu C, Li G, Qiu Y, He J. Ligand-targeted polymerase chain reaction for the detection of folate receptor-positive circulating tumour cells as a potential diagnostic biomarker for pancreatic cancer. Cell Prolif 2020; 53:e12880. [PMID: 32707596 PMCID: PMC7507398 DOI: 10.1111/cpr.12880] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 06/23/2020] [Accepted: 06/28/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES To detect folate receptor (FR)-positive circulating tumour cells (FR+ CTCs) by using ligand-targeted polymerase chain reaction (LT-PCR) in periampullary cancer patients and to investigate the diagnostic value of FR+ CTCs in distinguishing pancreatic cancer (PC) from benign pancreatic disease. MATERIALS AND METHODS CTCs were enriched from 3 mL of peripheral blood and portal vein blood by immunomagnetic depletion of leucocytes and were then detected by LT-PCR. The diagnostic performance of FR+ CTCs in PC was investigated by receiver-operating characteristic curve analysis. RESULTS In total, 57 consecutive patients, including 46 patients with PC, five patients with non-pancreatic periampullary cancer (non-PC) and six patients with benign pancreatic diseases, were enrolled. FR+ CTC levels were significantly higher in patients with malignant diseases (PC and non-PC) than in patients with benign pancreatic diseases (P < .01). There was no notable difference in CTC levels between patients with PC and those with non-PC (P > .05). The combination of FR+ CTCs with carbohydrate antigen 19-9 (CA19-9) had better diagnostic efficiency than each of these two markers alone, with high sensitivity (97.8%) and specificity (83.3%). CONCLUSIONS LT-PCR is feasible and reliable for detecting FR+ CTCs in patients with periampullary cancer. FR+ CTCs, especially when used in combination with CA19-9, have potential as a biomarker for the diagnosis of PC.
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Affiliation(s)
- Hao Cheng
- Nanjing Drum Tower Hospital Clinical College of Nanjing Medical UniversityNanjingChina
- Department of Hepatobiliary and Pancreatic SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Wei He
- Department of MedicineGeno Biotech Co LtdShanghaiChina
| | - Jun Yang
- Department of PathologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Qing Ye
- Department of PathologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Lu Cheng
- Department of Research and DevelopmentGeno Biotech Co LtdShanghaiChina
| | - Yiming Pan
- Department of Hepatobiliary and Pancreatic SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Liang Mao
- Department of Hepatobiliary and Pancreatic SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Xuehui Chu
- Department of Hepatobiliary and Pancreatic SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Chenglin Lu
- Department of Hepatobiliary and Pancreatic SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Gang Li
- Department of Hepatobiliary and Pancreatic SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Yudong Qiu
- Nanjing Drum Tower Hospital Clinical College of Nanjing Medical UniversityNanjingChina
- Department of Hepatobiliary and Pancreatic SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Jian He
- Department of RadiologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
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Ahrens TD, Bang-Christensen SR, Jørgensen AM, Løppke C, Spliid CB, Sand NT, Clausen TM, Salanti A, Agerbæk MØ. The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis. Front Cell Dev Biol 2020; 8:749. [PMID: 32984308 PMCID: PMC7479181 DOI: 10.3389/fcell.2020.00749] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/17/2020] [Indexed: 12/14/2022] Open
Abstract
Circulating tumor cells (CTCs) are accessible by liquid biopsies via an easy blood draw. They represent not only the primary tumor site, but also potential metastatic lesions, and could thus be an attractive supplement for cancer diagnostics. However, the analysis of rare CTCs in billions of normal blood cells is still technically challenging and novel specific CTC markers are needed. The formation of metastasis is a complex process supported by numerous molecular alterations, and thus novel CTC markers might be found by focusing on this process. One example of this is specific changes in the cancer cell glycocalyx, which is a network on the cell surface composed of carbohydrate structures. Proteoglycans are important glycocalyx components and consist of a protein core and covalently attached long glycosaminoglycan chains. A few CTC assays have already utilized proteoglycans for both enrichment and analysis of CTCs. Nonetheless, the biological function of proteoglycans on clinical CTCs has not been studied in detail so far. Therefore, the present review describes proteoglycan functions during the metastatic cascade to highlight their importance to CTCs. We also outline current approaches for CTC assays based on targeting proteoglycans by their protein cores or their glycosaminoglycan chains. Lastly, we briefly discuss important technical aspects, which should be considered for studying proteoglycans.
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Affiliation(s)
- Theresa D. Ahrens
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sara R. Bang-Christensen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- VarCT Diagnostics, Copenhagen, Denmark
| | | | - Caroline Løppke
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Charlotte B. Spliid
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Nicolai T. Sand
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Thomas M. Clausen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Ali Salanti
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mette Ø. Agerbæk
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- VarCT Diagnostics, Copenhagen, Denmark
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Ma WJ, Jin YW, Wu ZR, Yang Q, Wang JK, Liu F, Shi YJ, Li QS, Cheng NS. Meta-analysis of randomized clinical trials of adjuvant chemotherapy for resected biliary tract cancers. HPB (Oxford) 2020; 22:939-949. [PMID: 32349925 DOI: 10.1016/j.hpb.2020.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 12/29/2019] [Accepted: 02/09/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND This meta-analysis was performed by analyzing randomized controlled trials (RCTs) to assess the potential prognostic value of adjuvant chemotherapy (ACT) for patients with resected biliary tract cancers (BTCs). METHODS PubMed, EMBASE, and the Cochrane Library were searched for relevant articles published. Only RCTs affected by tumors of gallbladder, intrahepatic, perihilar, and distal bile ducts were considered. Data were pooled using a random-effects model. The primary endpoint of the study was overall survival (OS). RESULTS The study identified 1192 patients who met the inclusion and exclusion criteria. ACT had nearly reached a significant better OS (HR, 0.88; 95% CI, 0.77-1.01; P = 0.07) and achieved a significant better RFS (HR, 0.83; 95% CI, 0.69-0.99; P = 0.04). The effectiveness of ACT for OS was significantly modified by fluorouracil-based ACT (HR, 0.83; 95% CI, 0.70-0.99; P = 0.04), but not by gemcitabine-based ACT (HR, 0.91; 95% CI, 0.74-1.12; P = 0.36). The survival benefit was also not modified by primary disease site, resection margin status, and lymph node status. CONCLUSIONS ACT is correlated with favorable relapse-free survival compared with non-ACT for resected BTCs patients. Fluorouracil-based ACT could be viewed as a standard practice for resected BTCs patients regardless of the primary cancer site, lymph node or margin status.
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Affiliation(s)
- Wen-Jie Ma
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yan-Wen Jin
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhen-Ru Wu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qin Yang
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jun-Ke Wang
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fei Liu
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yu-Jun Shi
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Quan-Sheng Li
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Nan-Sheng Cheng
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Chelakkot C, Ryu J, Kim MY, Kim JS, Kim D, Hwang J, Park SH, Ko SB, Park JW, Jung MY, Kim RN, Song K, Kim YJ, Choi YL, Lee HS, Shin YK. An Immune-Magnetophoretic Device for the Selective and Precise Enrichment of Circulating Tumor Cells from Whole Blood. MICROMACHINES 2020; 11:mi11060560. [PMID: 32486306 PMCID: PMC7345362 DOI: 10.3390/mi11060560] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/22/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023]
Abstract
Here, we validated the clinical utility of our previously developed microfluidic device, GenoCTC, which is based on bottom magnetophoresis, for the isolation of circulating tumor cells (CTCs) from patient whole blood. GenoCTC allowed 90% purity, 77% separation rate, and 80% recovery of circulating tumor cells at a 90 μL/min flow rate when tested on blood spiked with epithelial cell adhesion molecule (EpCAM)-positive Michigan Cancer Foundation-7 (MCF7) cells. Clinical studies were performed using blood samples from non-small cell lung cancer (NSCLC) patients. Varying numbers (2 to 114) of CTCs were found in each NSCLC patient, and serial assessment of CTCs showed that the CTC count correlated with the clinical progression of the disease. The applicability of GenoCTC to different cell surface biomarkers was also validated in a cholangiocarcinoma patient using anti-EPCAM, anti-vimentin, or anti-tyrosine protein kinase MET (c-MET) antibodies. After EPCAM-, vimentin-, or c-MET-positive cells were isolated, CTCs were identified and enumerated by immunocytochemistry using anti-cytokeratin 18 (CK18) and anti-CD45 antibodies. Furthermore, we checked the protein expression of PDL1 and c-MET in CTCs. A study in a cholangiocarcinoma patient showed that the number of CTCs varied depending on the biomarker used, indicating the importance of using multiple biomarkers for CTC isolation and enumeration.
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Affiliation(s)
- Chaithanya Chelakkot
- Technical Research Center, Genobio Corp., Seoul 08394, Korea; (C.C.); (J.R.); (D.K.); (J.H.); (S.H.P.); (S.B.K.)
| | - Jiyeon Ryu
- Technical Research Center, Genobio Corp., Seoul 08394, Korea; (C.C.); (J.R.); (D.K.); (J.H.); (S.H.P.); (S.B.K.)
| | - Mi Young Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Korea; (M.Y.K.); (J.-S.K.)
| | - Jin-Soo Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Korea; (M.Y.K.); (J.-S.K.)
| | - Dohyeong Kim
- Technical Research Center, Genobio Corp., Seoul 08394, Korea; (C.C.); (J.R.); (D.K.); (J.H.); (S.H.P.); (S.B.K.)
| | - Juhyun Hwang
- Technical Research Center, Genobio Corp., Seoul 08394, Korea; (C.C.); (J.R.); (D.K.); (J.H.); (S.H.P.); (S.B.K.)
| | - Sung Hoon Park
- Technical Research Center, Genobio Corp., Seoul 08394, Korea; (C.C.); (J.R.); (D.K.); (J.H.); (S.H.P.); (S.B.K.)
| | - Seok Bum Ko
- Technical Research Center, Genobio Corp., Seoul 08394, Korea; (C.C.); (J.R.); (D.K.); (J.H.); (S.H.P.); (S.B.K.)
| | - Jeong Won Park
- IT Convergence Technology Research Laboratory, Electronic and Telecommunications Research Institute, Daejon 34129, Korea; (J.W.P.); (M.Y.J.)
| | - Moon Youn Jung
- IT Convergence Technology Research Laboratory, Electronic and Telecommunications Research Institute, Daejon 34129, Korea; (J.W.P.); (M.Y.J.)
| | - Ryong Nam Kim
- Bio-MAX/N-Bio, Seoul National University, Seoul 08826, Korea;
| | - Kyoung Song
- The Center for Companion Diagnostics, LOGONE Bio Convergence Research Foundation, Seoul 08394, Korea; (K.S.); (Y.J.K.)
| | - Yu Jin Kim
- The Center for Companion Diagnostics, LOGONE Bio Convergence Research Foundation, Seoul 08394, Korea; (K.S.); (Y.J.K.)
| | - Yoon-La Choi
- Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 08394, Korea;
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Hun Seok Lee
- Technical Research Center, Genobio Corp., Seoul 08394, Korea; (C.C.); (J.R.); (D.K.); (J.H.); (S.H.P.); (S.B.K.)
- Correspondence: (H.S.L.); (Y.K.S.)
| | - Young Kee Shin
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul 08826, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea
- The Center for Anti-Cancer Companion Diagnostics, Bio-MAX/N-Bio, Seoul National University, Seoul 08826, Korea
- Correspondence: (H.S.L.); (Y.K.S.)
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Coyne GO'S, Wang L, Zlott J, Juwara L, Covey JM, Beumer JH, Cristea MC, Newman EM, Koehler S, Nieva JJ, Garcia AA, Gandara DR, Miller B, Khin S, Miller SB, Steinberg SM, Rubinstein L, Parchment RE, Kinders RJ, Piekarz RL, Kummar S, Chen AP, Doroshow JH. Intravenous 5-fluoro-2'-deoxycytidine administered with tetrahydrouridine increases the proportion of p16-expressing circulating tumor cells in patients with advanced solid tumors. Cancer Chemother Pharmacol 2020; 85:979-993. [PMID: 32314030 PMCID: PMC7188725 DOI: 10.1007/s00280-020-04073-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 04/06/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Following promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs). METHODS Patients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m2) and THU (350 mg/m2) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis. RESULTS Ninety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal-though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response. CONCLUSION Further study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement.
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Affiliation(s)
- Geraldine O 'Sullivan Coyne
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA
| | - Lihua Wang
- Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Jennifer Zlott
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA
| | - Lamin Juwara
- Clinical Monitoring Research Program, Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Joseph M Covey
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA
| | - Jan H Beumer
- Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA
| | - Mihaela C Cristea
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
| | - Edward M Newman
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
| | | | - Jorge J Nieva
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Agustin A Garcia
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
- Louisiana State University, New Orleans, LA, 70112, USA
| | - David R Gandara
- University of California Davis Cancer Center, Sacramento, CA, USA
| | - Brandon Miller
- Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Sonny Khin
- Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Sarah B Miller
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA
| | - Seth M Steinberg
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Larry Rubinstein
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA
| | - Ralph E Parchment
- Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Robert J Kinders
- Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Richard L Piekarz
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA
| | - Shivaani Kummar
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA
| | - Alice P Chen
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA
| | - James H Doroshow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA.
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
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Gopinathan P, Chiang N, Bandaru A, Sinha A, Huang W, Hung S, Shan Y, Lee G. Exploring Circulating Tumor Cells in Cholangiocarcinoma Using a Novel Glycosaminoglycan Probe on a Microfluidic Platform. Adv Healthc Mater 2020; 9:e1901875. [PMID: 32329247 DOI: 10.1002/adhm.201901875] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/26/2020] [Accepted: 03/12/2020] [Indexed: 12/14/2022]
Abstract
The search of alternative approaches to epithelial cell adhesion molecule (EpCAM), for the isolation of circulating tumor cells (CTC), is on the rise. This work attempts at evaluating the feasibility of using a new glycosaminoglycan, SCH45, as a probe to isolate CTCs from the peripheral blood of 65 advanced/metastatic cholangiocarcinoma (CCA) patients. The positive enrichment of CTCs from 1 mL of blood using SCH45-bound magnetic beads and subsequent staining on an integrated microfluidic platform is demonstrated. Results detailing CTC concentrations averaging ≥1 CTCs mL-1 of blood are shown, and a conventional protein biomarker, EpCAM, has been used to corroborate the finding that 100% of the patients possess CTCs in their blood. Studies detailing the use of CTCs in the prognostic monitoring and treatment effectiveness of advanced/metastatic CCA are scarce, and the isolation of CTCs from all CCA patients tested has not been reported yet. A strong correlation between CTC counts and disease progression at the time of and/or in advance of radiographic imaging in patients receiving chemotherapy is also reported. This study is one of its kind with the new probe and reduced sample volume and has potential for use in CCA diagnosis and prognosis in the near future.
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Affiliation(s)
- Priya Gopinathan
- Institute of Nanoengineering and MicrosystemsNational Tsing Hua University Hsinchu 30013 Taiwan
| | - Nai‐Jung Chiang
- Institute of Clinical MedicineCollege of MedicineNational Cheng Kung University Tainan 70457 Taiwan
- National Institute of Cancer ResearchNational Health Research Institutes Miaoli 35053 Taiwan
- Department of Internal MedicineNational Cheng Kung University HospitalCollege of MedicineNational Cheng Kung University Tainan 70403 Taiwan
| | - Anandaraju Bandaru
- Genomics Research CentreAcademia Sinica Taipei Taiwan 11529 Republic of China
| | - Anirban Sinha
- Institute of Nanoengineering and MicrosystemsNational Tsing Hua University Hsinchu 30013 Taiwan
| | - Wen‐Yen Huang
- Department of Power Mechanical EngineeringNational Tsing Hua University Hsinchu City 30013 Taiwan
| | - Shang‐Cheng Hung
- Genomics Research CentreAcademia Sinica Taipei Taiwan 11529 Republic of China
- Department of Applied ScienceNational Taitung University Taitung 95053 Taiwan
| | - Yan‐Shen Shan
- Institute of Clinical MedicineCollege of MedicineNational Cheng Kung University Tainan 70457 Taiwan
- Department of SurgeryNational Cheng Kung University HospitalCollege of MedicineNational Cheng Kung University Tainan 70403 Taiwan
| | - Gwo‐Bin Lee
- Institute of Nanoengineering and MicrosystemsNational Tsing Hua University Hsinchu 30013 Taiwan
- Department of Power Mechanical EngineeringNational Tsing Hua University Hsinchu City 30013 Taiwan
- Institute of Biomedical EngineeringNational Tsing Hua University Hsinchu 30013 Taiwan
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Chen Q, Zheng Y, Zhao H, Cai J, Wang L, Zhao J, Bi X, Li Z, Huang Z, Zhang Y, Zhou J, Wu J. The combination of preoperative D-dimer and CA19-9 predicts lymph node metastasis and survival in intrahepatic cholangiocarcinoma patients after curative resection. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:192. [PMID: 32309339 PMCID: PMC7154446 DOI: 10.21037/atm.2020.01.72] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background To investigate the predictive role of D-dimer and its combination of preoperative CA19-9 for lymph node metastasis (LNM) and prognosis in intrahepatic cholangiocarcinoma (ICC) patients who underwent curative-intent resection. Methods One hundred and seventy-three patients admitted to our hospital between April 2012 and December 2018 were included. The combination of preoperative D-dimer and CA19-9 (CPDC) was scored as 0 (decreased D-dimer levels with decreased CA19-9 levels), 2 (elevated D-dimer levels with elevated CA19-9 levels), or 1 (all other combinations). Multivariate logistic regression analysis was performed to identify independent factors. Cox proportional hazard regression was adopted for the multivariate survival analysis. Results The CPDC score was an independent predictor of LNM and overall survival (OS) in the multivariate analyses. For the prediction of LNM, the area under the curve (AUC) for the CPDC score was 0.722 (95% CI: 0.613–0.831, P<0.001), and for the prediction of survival, the AUC for the CPDC score was 0.756 (95% CI: 0.658–0.854, P<0.001). The predictive capacity of the CPDC score was higher than that of D-dimer or CA19-9. Kaplan-Meier curve analysis revealed that a CPDC =2 was significantly associated with a worse OS (P<0.001, median OS: 8.00 versus 19.00 months versus not reached) and shorter progression-free survival (PFS) (P<0.001, median PFS: 4.00 versus 11.00 versus 15.00 months) than a CPDC =1 or CPDC =0 in ICC patients. There were significant differences in the OS comparisons between any two groups. Decreased preoperative CPDC was associated with worse OS and PFS in all subgroups except in the HBsAg (+) group. In the cirrhosis, HBsAg (−) and tumour size ≥5 cm subgroups, there were significant differences in the OS and PFS comparisons between any two groups. Conclusions The preoperative CPDC score is a convenient and powerful prognostic biomarker to predict LNM and OS for ICC patients after curative resection. Especially for radiologically-negative metastatic lymph node in ICC patients, CPDC could be helpful to assess the extent of lymph node dissection and make follow-up plans.
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Affiliation(s)
- Qichen Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yiling Zheng
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhiyu Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yefan Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jianguo Zhou
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jianxiong Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Panayotova GG, Paterno F, Guarrera JV, Lunsford KE. Liver Transplantation for Cholangiocarcinoma: Insights into the Prognosis and the Evolving Indications. Curr Oncol Rep 2020; 22:49. [PMID: 32297105 DOI: 10.1007/s11912-020-00910-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Cholangiocarcinoma (CCA) is a rare malignancy of the biliary ducts that can be classified as intrahepatic, perihilar, or distal based on anatomic location. Although surgical resection can be curative, complete excision with negative margins is often difficult to achieve. In patients with unresectable disease, long-term survival is rarely seen with medical therapy alone. A multimodal treatment approach, including liver transplantation (LT) for select patients with unresectable CCA, should be considered. RECENT FINDINGS While currently only an approved indication for early, liver-limited, perihilar cholangiocarcinoma, promising results have been achieved for LT in localized intrahepatic disease. The absolute indication for transplant for intrahepatic tumors is currently the subject of multiple investigations. Continued advances in neoadjuvant/adjuvant therapy and better understanding of tumor biology may further augment the number of candidates for surgical therapies, with liver transplant acting as a promising tool to improve patient outcomes. Thorough consideration for any expansion in the indication for liver transplant in malignancy is necessary in order to balance patient outcomes with utilization of the scarce donor organ resources.
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Affiliation(s)
- Guergana G Panayotova
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, 185 South Orange Ave, MSB G586, Newark, NJ, 07103, USA
| | - Flavio Paterno
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, 185 South Orange Ave, MSB G586, Newark, NJ, 07103, USA
| | - James V Guarrera
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, 185 South Orange Ave, MSB G586, Newark, NJ, 07103, USA
| | - Keri E Lunsford
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, 185 South Orange Ave, MSB G586, Newark, NJ, 07103, USA.
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Cholangiocarcinoma Disease Modelling Through Patients Derived Organoids. Cells 2020; 9:cells9040832. [PMID: 32235647 PMCID: PMC7226733 DOI: 10.3390/cells9040832] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 12/17/2022] Open
Abstract
Cancer organoids are 3D phenotypic cultures that can be established from resected or biopsy tumour samples and can be grown as mini tumours in the dish. Flourishing evidence supports the feasibility of patient derived organoids (PDO) from a number of solid tumours. Evidence for cholangiocarcinoma (CCA) PDO is still sparse but growing. CCA PDO lines have been established from resected early stage disease, advanced cancers and highly chemorefractory tumours. Cancer PDO was shown to recapitulate the 3D morphology, genomic landscape and transcriptomic profile of the source counterpart. They proved to be a valued model for drug discovery and sensitivity testing, and they showed to mimic the drug response observed in vivo in the patients. However, PDO lack representation of the intratumour heterogeneity and the tumour-stroma interaction. The efficiency rate of CCA PDO within the three different subtypes, intrahepatic, perihilar and distal, is still to be explored. In this manuscript we will review evidence for CCA PDO highlighting advantages and limitations of this novel disease model.
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Reduzzi C, Vismara M, Silvestri M, Celio L, Niger M, Peverelli G, De Braud F, Daidone MG, Cappelletti V. A novel circulating tumor cell subpopulation for treatment monitoring and molecular characterization in biliary tract cancer. Int J Cancer 2019; 146:3495-3503. [PMID: 31814120 PMCID: PMC7217035 DOI: 10.1002/ijc.32822] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 10/28/2019] [Accepted: 12/02/2019] [Indexed: 12/19/2022]
Abstract
In biliary tract cancer (BTC), tissue biopsies to guide treatment are rarely feasible, thus implementing liquid biopsy approaches to improve patient management represents a priority. So far, studies on circulating tumor cells (CTCs) in BTC are insufficient to promote their use in patient clinical management and are limited to EpCAM‐enriched CTCs evaluated with the CellSearch. We applied a single‐cell protocol allowing identification not only of epithelial CTCs (eCTCs), but also of nonconventional CTCs (ncCTCs) lacking epithelial and leukocyte markers, but presenting aberrant genomes as confirmed by copy number alterations and therefore representing a distinct subpopulation of bona fide CTCs. In 41 blood samples longitudinally collected from 21 patients with advanced‐stage BTC, addition of ncCTC to classic eCTC led to a CTC‐positivity increase from 19% to 83%. Patients presenting with at least 1 eCTC/10 ml of blood at baseline prior to treatment start had a significantly shorter median disease‐specific survival (DSS) compared to those lacking eCTCs (9 months vs. 19 months, p = 0.03 by log‐rank test). No differences in DSS were observed according to ncCTC‐positivity, conversely, variations in ncCTC counts during, and at the end of treatment, were associated with the RECIST response supporting their role in treatment monitoring. Moreover, in 88 ncCTCs collected at different times during treatment, unsupervised clustering evidenced segregation of cells by patient's best response, allowing identification of genomic regions possibly involved in resistance mechanisms. The presence of ncCTCs beside eCTCs opens the way to exploiting liquid biopsy for optimizing clinical management in BTC. What's new? Late diagnosis of advanced biliary tract cancer (BTC) limits tissue biopsy for molecular analyses, resulting in missed opportunities for personalized therapy. Meanwhile, circulating tumor cells (CTCs) are promising tissue surrogates, but current CTC‐based methods detect only a fraction of BTC patients. Here, using unbiased CTC‐enrichment, coupled with identification and recovery of single cells, the authors identify a novel CTC subpopulation detectable in all BTC patient samples prior to treatment. The presence of even a single epithelial CTC was associated with reduced disease‐specific survival. This novel approach to CTC detection could be useful for treatment‐response monitoring and molecular characterization in BTC.
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Affiliation(s)
- Carolina Reduzzi
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Marta Vismara
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Marco Silvestri
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Luigi Celio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Monica Niger
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Giorgia Peverelli
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Filippo De Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.,University of Milan, Milan, Italy
| | - Maria G Daidone
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Vera Cappelletti
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
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Ejaz A, Cloyd JM, Pawlik TM. Advances in the Diagnosis and Treatment of Patients with Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2019; 27:552-560. [PMID: 31555936 DOI: 10.1245/s10434-019-07873-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Indexed: 12/27/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive biliary tract cancer (BTC) that arises from the biliary tract epithelium distal to the secondary biliary radicals. Over the past decade, significant advances have been made in the diagnosis, staging, and treatment of ICC. Emerging data have highlighted the importance of lymphadenectomy for elucidating patient prognosis as well as the at-risk nodal basins based on tumor location (de Jong et al. in J Clin Oncol 29(23):3140-3145, 2011). Several large randomized controlled trials have recently been published clarifying the role of adjuvant therapy for BTCs (Cloyd and Pawlik in J Oncol Pract 14(12):723-724, 2018). In addition, the molecular understanding of ICC pathogenesis has increased over time, leading to new potential molecular biomarkers and opening opportunities for novel targeted and immunologic therapies (Rizvi et al. in Nat Rev Clin Oncol 15(2):95-111, 2018). These recent advances serve to only improve our understanding of the optimal multidisciplinary treatment of this difficult disease.
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Affiliation(s)
- Aslam Ejaz
- James Cancer Center, The Ohio State University, Columbus, OH, USA. .,Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
| | - Jordan M Cloyd
- James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Timothy M Pawlik
- James Cancer Center, The Ohio State University, Columbus, OH, USA
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