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Yeo D, Seyfi D, Bastian A, Strauss H, Leach A, Klemm V, Pirrello A, Spring K, Saxena P, Wahlroos S, Sutherland S, Grimison P, Park JS, Sandroussi C, Rasko JE. Portal venous circulating tumor cells as a biomarker for relapse prediction in resected pancreatic cancer. Cell Mol Life Sci 2025; 82:155. [PMID: 40208273 PMCID: PMC11985722 DOI: 10.1007/s00018-025-05669-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 03/16/2025] [Accepted: 03/19/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND Pancreatic cancer is an aggressive disease with poor prognosis. The only potentially curative treatment option is surgical resection, however recurrence is common. Biomarkers to detect minimal residual disease, assist with risk stratification, relapse and real time monitoring, are required. Circulating tumor cells (CTCs) are a promising liquid biopsy biomarker for solid tumors. However, their role in monitoring minimal residual disease in pancreatic cancer remains to be determined. Our study aimed to investigate whether detection and enumeration of CTCs could predict recurrence and provide monitoring of disease status. METHOD Participants planned for Whipple procedure or partial pancreatectomy were enrolled in this prospective pilot study. Intraoperatively, 7.5 mL of portal and peripheral venous blood were collected, and peripheral venous blood was also collected post-surgery. CTC identification and enumeration were performed using the AccuCyte-CyteFinder platform and CellSieve microfiltration. RESULTS Of 29 participants, 20 were confirmed to have epithelial cancer by histopathology, where 15 had pancreatic ductal adenocarcinoma. In those with epithelial cancer, CTCs were detected intraoperatively in 75% of portal venous blood samples, in contrast to 40% detected in peripheral venous blood (median: 6 and 0 per 7.5mL respectively). Only portal venous CTC detection was predictive of pancreatic ductal adenocarcinoma relapse. The positive (> 5) portal venous CTC group had a 6.67 times higher risk of recurring (odds ratio = 20.43, sensitivity = 1.00, specificity = 0.625). Detection of peripheral venous CTCs post-surgery was also correlated with relapse in a small subset of patients. CONCLUSIONS If validated, CTCs may provide a prognostic and monitoring biomarker in patients with pancreatic cancer undergoing surgery.
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Affiliation(s)
- Dannel Yeo
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia
- Precision Oncology Laboratory, Cancer Innovations, Centenary Institute, Camperdown, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
| | - Doruk Seyfi
- Department of Hepatobiliary and Upper Gastrointestinal Surgery, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
- Upper Gastrointestinal Surgery, Chris O'Brien Lifehouse, Camperdown, Australia
| | - Althea Bastian
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia
- Precision Oncology Laboratory, Cancer Innovations, Centenary Institute, Camperdown, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
| | - Heidi Strauss
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia
- Precision Oncology Laboratory, Cancer Innovations, Centenary Institute, Camperdown, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
| | - Anna Leach
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia
- Precision Oncology Laboratory, Cancer Innovations, Centenary Institute, Camperdown, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
| | - Vera Klemm
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia
- Precision Oncology Laboratory, Cancer Innovations, Centenary Institute, Camperdown, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
| | - Anthony Pirrello
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia
- Precision Oncology Laboratory, Cancer Innovations, Centenary Institute, Camperdown, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
| | - Kevin Spring
- Medical Oncology Group, Liverpool Clinical School, School of Medicine, Western Sydney University and Ingham Institute for Applied Medical Research, Liverpool, Australia
- Concord Institute of Academic Surgery, Sydney Local Health District, Concord, Australia
- South-West Sydney Clinical Campuses, UNSW Medicine & Health, Sydney, Australia
| | - Payal Saxena
- Division of Gastroenterology, Department of Medicine, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
- Gastroenterology, Chris O'Brien Lifehouse, Camperdown, Australia
| | - Sara Wahlroos
- Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia
| | - Sarah Sutherland
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia
| | - Peter Grimison
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia
| | - Jin-Soo Park
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Department of Hepatobiliary and Upper Gastrointestinal Surgery, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
- Upper Gastrointestinal Surgery, Chris O'Brien Lifehouse, Camperdown, Australia
| | - Charbel Sandroussi
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Department of Hepatobiliary and Upper Gastrointestinal Surgery, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
- Upper Gastrointestinal Surgery, Chris O'Brien Lifehouse, Camperdown, Australia
| | - John Ej Rasko
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia.
- Precision Oncology Laboratory, Cancer Innovations, Centenary Institute, Camperdown, Australia.
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia.
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Takematsu T, Hayashi H, Ogawa D, Nakao Y, Yamao T, Kitano Y, Nakagawa S, Mima K, Baba Y, Baba H. Molecular Alterations Influencing the Prognostic Outcome in Small Pancreatic Cancer (≤2 cm). Pancreas 2025; 54:e295-e302. [PMID: 40262101 DOI: 10.1097/mpa.0000000000002430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 11/01/2024] [Indexed: 04/24/2025]
Abstract
PURPOSE Pancreatic cancer (PC) is the most lethal cancer. The prognosis of small PC (tumor ≤ 20 mm) is better than that of larger PC, indicating the importance of detecting early-stage PC for patient outcome. The aim of this study was to elucidate the molecular features in small PC (≤20 mm). MATERIALS AND METHODS This study included 79 PC tumors (≤20 mm in pathological examination) resected between 2004 and 2022. c-Myc, Caveolin-1, Smad4, and Thrombospondin-1 were examined by immunostaining. These molecular alterations were compared in PC patients with tumor size ≤ 10 mm (n = 11) (14%) and 10 mm < tumor size ≤ 20 mm (n = 68) (86%). Mutation analyses of KRAS, PIK3CA, and BRAF were performed by pyrosequencing in 22 PCs. RESULTS PC with 10 mm < tumor size ≤ 20 mm showed significantly worse overall survival and disease-free survival than PC with tumor size < 10 mm (P = 0.024 and P = 0.028). Tumor c-Myc and stromal Caveolin-1 expressions were significantly increased in tumors larger than 10 mm (P = 0.02 and P = 0.04). c-Myc and Caveolin-1 expressions were associated with poor disease-free survival and overall survival. KRAS, PIK3CA, and BRAF mutation status did not differ between the 2 groups. CONCLUSIONS Tumor c-Myc and stromal Caveolin-1 overexpressions were detected in tumors larger than 10 mm. Their overexpressions were associated with worse prognosis even in small PC. These molecular alterations in small PC may be a clue for the detection of early-stage PC.
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Affiliation(s)
- Toru Takematsu
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Imamura Hospital, Saga, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Daisuke Ogawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yosuke Nakao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takanobu Yamao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuki Kitano
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kosuke Mima
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
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Yin H, Zhang M, Zhang Y, Zhang X, Zhang X, Zhang B. Liquid biopsies in cancer. MOLECULAR BIOMEDICINE 2025; 6:18. [PMID: 40108089 PMCID: PMC11923355 DOI: 10.1186/s43556-025-00257-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 02/14/2025] [Accepted: 02/23/2025] [Indexed: 03/22/2025] Open
Abstract
Cancer ranks among the most lethal diseases worldwide. Tissue biopsy is currently the primary method for the diagnosis and biological analysis of various solid tumors. However, this method has some disadvantages related to insufficient tissue specimen collection and intratumoral heterogeneity. Liquid biopsy is a noninvasive approach for identifying cancer-related biomarkers in peripheral blood, which allows for repetitive sampling across multiple time points. In the field of liquid biopsy, representative biomarkers include circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes. Many studies have evaluated the prognostic and predictive roles of CTCs and ctDNA in various solid tumors. Although these studies have limitations, the results of most studies appear to consistently demonstrate the correlations of high CTC counts and ctDNA mutations with lower survival rates in cancer patients. Similarly, a reduction in CTC counts throughout therapy may be a potential prognostic indicator related to treatment response in advanced cancer patients. Moreover, the biochemical characteristics of CTCs and ctDNA can provide information about tumor biology as well as resistance mechanisms against targeted therapy. This review discusses the current clinical applications of liquid biopsy in cancer patients, emphasizing its possible utility in outcome prediction and treatment decision-making.
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Affiliation(s)
- Hang Yin
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Manjie Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Yu Zhang
- Dalian Medical University, Dalian, 116000, China
| | - Xuebing Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Xia Zhang
- Dalian Fifth People's Hospital, Dalian, 116000, China.
| | - Bin Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China.
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Reduzzi C, Nicolo' E, Singhal S, Venetis K, Ortega-Franco A, de Miguel-Perez D, Dipasquale A, Gouda MA, Saldanha EF, Kasi PM, Jantus-Lewintre E, Fusco N, Malapelle U, Gandara DR, Rolfo C, Serrano MJ, Cristofanilli M. Unveiling the impact of circulating tumor cells: Two decades of discovery and clinical advancements in solid tumors. Crit Rev Oncol Hematol 2024; 203:104483. [PMID: 39159706 DOI: 10.1016/j.critrevonc.2024.104483] [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: 05/21/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 08/21/2024] Open
Abstract
Circulating tumor cells (CTCs) enumeration and molecular profiling hold promise in revolutionizing the management of solid tumors. Their understanding has evolved significantly over the past two decades, encompassing pivotal biological discoveries and clinical studies across various malignancies. While for some tumor types, such as breast, prostate, and colorectal cancer, CTCs are ready to enter clinical practice, for others, additional research is required. CTCs serve as versatile biomarkers, offering insights into tumor biology, metastatic progression, and treatment response. This review summarizes the latest advancements in CTC research and highlights future directions of investigation. Special attention is given to concurrent evaluations of CTCs and other circulating biomarkers, particularly circulating tumor DNA. Multi-analyte assessment holds the potential to unlock the full clinical capabilities of liquid biopsy. In conclusion, CTCs represent a transformative biomarker in precision oncology, offering extraordinary opportunities to translate scientific discoveries into tangible improvements in patient care.
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Affiliation(s)
- Carolina Reduzzi
- Department of Medicine, Weill Cornell Medicine, Englander Institute for Precision Medicine, New York Presbyterian Hospital, New York, NY 10021, USA.
| | - Eleonora Nicolo'
- Department of Medicine, Weill Cornell Medicine, Englander Institute for Precision Medicine, New York Presbyterian Hospital, New York, NY 10021, USA.
| | - Surbhi Singhal
- Division of Hematology and Oncology, Department of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA
| | - Konstantinos Venetis
- Division of Pathology, IEO European Institute of Oncology IRCCS, Milan 20141, Italy
| | - Ana Ortega-Franco
- Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom
| | - Diego de Miguel-Perez
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Angelo Dipasquale
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Mohamed A Gouda
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Erick F Saldanha
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, ON, Canada
| | - Pashtoon M Kasi
- Department of Medicine, Weill Cornell Medicine, Englander Institute for Precision Medicine, New York Presbyterian Hospital, New York, NY 10021, USA
| | - Eloisa Jantus-Lewintre
- Department of Biotechnology, Universitat Politècnica de València, Unidad Mixta TRIAL (Fundación para la Investigación del Hospital General Universitario de Valencia y Centro de Investigación Príncipe Felipe) and CIBERONC, Valencia, Spain
| | - Nicola Fusco
- Division of Pathology, IEO European Institute of Oncology IRCCS, Milan 20141, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan 20121, Italy
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Napoli 80131, Italy
| | - David R Gandara
- Division of Hematology and Oncology, Department of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA
| | - Christian Rolfo
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Maria Jose Serrano
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Liquid biopsy and Cancer Interception group, PTS Granada, Avenida de la Ilustración 114, Granada 18016, Spain; Pathological Anatomy Unit, Molecular Pathology Laboratory,Virgen de las Nieves. University Hospital, Av. Dr. Olóriz 16, Granada 18012, Spain
| | - Massimo Cristofanilli
- Department of Medicine, Weill Cornell Medicine, Englander Institute for Precision Medicine, New York Presbyterian Hospital, New York, NY 10021, USA
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5
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Tang J, Zheng Q, Wang Q, Zhao Y, Ananthanarayanan P, Reina C, Šabanović B, Jiang K, Yang MH, Meny CC, Wang H, Agerbaek MØ, Clausen TM, Gustavsson T, Wen C, Borghi F, Mellano A, Fenocchio E, Gregorc V, Sapino A, Theander TG, Fu D, Aicher A, Salanti A, Shen B, Heeschen C. CTC-derived pancreatic cancer models serve as research tools and are suitable for precision medicine approaches. Cell Rep Med 2024; 5:101692. [PMID: 39163864 PMCID: PMC11524981 DOI: 10.1016/j.xcrm.2024.101692] [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: 02/07/2024] [Revised: 05/12/2024] [Accepted: 07/25/2024] [Indexed: 08/22/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) poses significant clinical challenges, often presenting as unresectable with limited biopsy options. Here, we show that circulating tumor cells (CTCs) offer a promising alternative, serving as a "liquid biopsy" that enables the generation of in vitro 3D models and highly aggressive in vivo models for functional and molecular studies in advanced PDAC. Within the retrieved CTC pool (median 65 CTCs/5 mL), we identify a subset (median content 8.9%) of CXCR4+ CTCs displaying heightened stemness and metabolic traits, reminiscent of circulating cancer stem cells. Through comprehensive analysis, we elucidate the importance of CTC-derived models for identifying potential targets and guiding treatment strategies. Screening of stemness-targeting compounds identified stearoyl-coenzyme A desaturase (SCD1) as a promising target for advanced PDAC. These results underscore the pivotal role of CTC-derived models in uncovering therapeutic avenues and ultimately advancing personalized care in PDAC.
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Affiliation(s)
- Jiajia Tang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Quan Zheng
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qi Wang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yaru Zhao
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Preeta Ananthanarayanan
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy
| | - Chiara Reina
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy
| | - Berina Šabanović
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy
| | - Ke Jiang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ming-Hsin Yang
- Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Clara Csilla Meny
- 2(nd) Institute for Pathology and Experimental Oncology Research, Semmelweis University, 1085 Budapest, Hungary
| | - Huimin Wang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Mette Ø Agerbaek
- Centre for Translational Medicine and Parasitology (CMP) at Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen N, Denmark; VarCT Diagnostics, Ole Maaloes vej 3, 2200 Copenhagen, Denmark
| | - Thomas Mandel Clausen
- Centre for Translational Medicine and Parasitology (CMP) at Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Tobias Gustavsson
- Centre for Translational Medicine and Parasitology (CMP) at Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen N, Denmark; VAR2Pharmaceuticals, Ole Maaloes vej 3, 2200 Copenhagen, Denmark
| | - Chenlei Wen
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Felice Borghi
- Department of Surgical Oncology, Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy
| | - Alfredo Mellano
- Department of Surgical Oncology, Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy
| | - Elisabetta Fenocchio
- Department of Medical Oncology, Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy
| | - Vanesa Gregorc
- Department of Medical Oncology, Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy
| | - Anna Sapino
- Department of Pathology, Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy
| | - Thor G Theander
- Centre for Translational Medicine and Parasitology (CMP) at Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Da Fu
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Alexandra Aicher
- Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404328, Taiwan; Immunology Research and Development Center, China Medical University, Taichung 404328, Taiwan
| | - Ali Salanti
- Centre for Translational Medicine and Parasitology (CMP) at Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Baiyong Shen
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Christopher Heeschen
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy.
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6
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Galletti G, Halima A, Gjyrezi A, Zhang J, Zimmerman B, Worroll D, Kallergi G, Barreja R, Ocean A, Saxena A, McGraw TE, Nanus DM, Elemento O, Altorki NK, Tagawa ST, Giannakakou P. Transferrin receptor-based circulating tumor cell enrichment provides a snapshot of the molecular landscape of solid tumors and correlates with clinical outcomes. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.06.16.24309003. [PMID: 38947080 PMCID: PMC11213041 DOI: 10.1101/2024.06.16.24309003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Circulating tumor cells (CTCs) captured from the bloodstream of patients with solid tumors have the potential to accelerate precision oncology by providing insight into tumor biology, disease progression and response to treatment. However, their potential is hampered by the lack of standardized CTC enrichment platforms across tumor types. EpCAM-based CTC enrichment, the most commonly used platform, is limited by EpCAM downregulation during metastasis and the low EpCAM expression in certain tumor types, including the highly prevalent and lethal NSCLC. In this study we demonstrate that Transferrin Receptor (TfR) is a selective, efficient biomarker for CTC identification and capture in patients with prostate, pancreatic and NSCLC. TfR identifies significantly higher CTC counts than EpCAM, and TfR + -CTC enumeration correlates with disease progression in metastatic prostate and pancreatic cancers, and overall survival and osimetrinib-resistance in non-small cell lung cancer (NSCLC). Profiling of TfR + -CTCs provides a snapshot of the molecular landscape of each respective tumor type and identifies potential mechanisms underlying treatment response to EGFR TKi and immune checkpoint inhibitors in NSCLC. One sentence summary Transferrin Receptor identifies circulating tumor cells in solid tumors.
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7
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Shishido SN, Lin E, Nissen N, Courcoubetis G, Suresh D, Mason J, Osipov A, Hendifar AE, Lewis M, Gaddam S, Pandol S, Kuhn P, Lo SK. Cancer-related cells and oncosomes in the liquid biopsy of pancreatic cancer patients undergoing surgery. NPJ Precis Oncol 2024; 8:36. [PMID: 38360856 PMCID: PMC10869814 DOI: 10.1038/s41698-024-00521-0] [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: 07/27/2023] [Accepted: 01/15/2024] [Indexed: 02/17/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of less than 10% due to its late diagnosis, rapid metastasis, and chemotherapeutic resistance. For a small proportion (10-20%) of early-stage patients however, surgical resection of the pancreatic tumor offers the best chance for survival but the effect of surgery on disease dissemination is unknown. The primary objective of this study was to characterize cellular and acellular blood-based analytes in portal and peripheral blood before pancreatic manipulation, during tumor dissection and immediately after surgical resection to determine the effects of the surgery. This study used the non-enriching third generation High-Definition Single Cell Assay (HDSCA3.0) workflow to investigate heterogeneous circulating rare cell population in the blood. Blood from both sites taken before surgical manipulation of the pancreas had significantly greater incidence of total rare cellular and acellular analytes than normal donor samples. Post-surgery portal and peripheral blood had significantly greater incidence of specific cellular and acellular subtypes compared to the matched pre- and during-surgery samples. Our results reveal that in patients with PDAC liquid biopsy analytes are increased in both the portal and peripheral blood; portal blood contains a higher frequency of analytes than in the peripheral blood; total analytes in the portal and peripheral blood samples were significantly associated with the tumor volume and pathological T stage; and the surgical procedure increased the blood levels of circulating cellular and acellular analytes, but not Epi.CTCs or Mes.CTCs. This study demonstrates liquid biopsy's utility in monitoring patients with PDAC with surgically resectable disease.
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Affiliation(s)
- Stephanie N Shishido
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Emmeline Lin
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Nicholas Nissen
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - George Courcoubetis
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Divya Suresh
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Jeremy Mason
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
- Institute of Urology, Catherine & Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Arsen Osipov
- IM Hematology Oncology, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Andrew E Hendifar
- IM Hematology Oncology, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Michael Lewis
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
- Greater Los Angeles Veterans Affairs System, Los Angeles, CA, 90073, USA
- Clark Atlanta University, Center for Cancer Research and Therapeutic Development, Atlanta, GA, 30314, USA
| | - Srinivas Gaddam
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Stephen Pandol
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Peter Kuhn
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA.
- Institute of Urology, Catherine & Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA.
- Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA.
- Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
| | - Simon K Lo
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA.
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Stosic K, Senar OA, Tarfouss J, Bouchart C, Navez J, Van Laethem JL, Arsenijevic T. A Comprehensive Review of the Potential Role of Liquid Biopsy as a Diagnostic, Prognostic, and Predictive Biomarker in Pancreatic Ductal Adenocarcinoma. Cells 2023; 13:3. [PMID: 38201207 PMCID: PMC10778087 DOI: 10.3390/cells13010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most lethal malignant diseases, with a mortality rate being close to incidence. Due to its heterogeneity and plasticity, as well as the lack of distinct symptoms in the early phases, it is very often diagnosed at an advanced stage, resulting in poor prognosis. Traditional tissue biopsies remain the gold standard for making a diagnosis, but have an obvious disadvantage in their inapplicability for frequent sampling. Blood-based biopsies represent a non-invasive method which potentially offers easy and repeated sampling, leading to the early detection and real-time monitoring of the disease and hopefully an accurate prognosis. Given the urgent need for a reliable biomarker that can estimate a patient's condition and response to an assigned treatment, blood-based biopsies are emerging as a potential new tool for improving patients' survival and surveillance. In this article, we discuss the current advances and challenges in using liquid biopsies for pancreatic cancer, focusing on circulating tumour DNA (ctDNA), extracellular vesicles (EVs), and circulating tumour cells (CTCs), and compare the performance and reliability of different biomarkers and combinations of biomarkers.
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Affiliation(s)
- Kosta Stosic
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Oier Azurmendi Senar
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Jawad Tarfouss
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Christelle Bouchart
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Radiation Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Julie Navez
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Hepato-Biliary-Pancreatic Surgery, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Jean-Luc Van Laethem
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
| | - Tatjana Arsenijevic
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
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Zhang ZH, Bao YW, Zhao YJ, Wang JQ, Guo JT, Sun SY. Circulating tumor cells as potential prognostic biomarkers for early-stage pancreatic cancer: A systematic review and meta-analysis. World J Clin Oncol 2023; 14:504-517. [PMID: 38059182 PMCID: PMC10696218 DOI: 10.5306/wjco.v14.i11.504] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/14/2023] [Accepted: 10/26/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Pancreatic cancer is difficult to be diagnosed early clinically, while often leads to poor prognosis. If optimal personalized treatment plan can be provided to pancreatic cancer patient at an earlier stage, this can greatly improve overall survival (OS). Circulating tumor cells (CTCs) are a collective term for various types of tumor cells present in the peripheral blood (PB), which are formed by detachment during the development of solid tumor lesions. Most CTCs undergo apoptosis or are phagocytosed after entering the PB, whereas a few can escape and anchor at distal sites to develop metastasis, increasing the risk of death for patients with malignant tumors. AIM To investigate the significance of CTCs in predicting the prognosis of early pancreatic cancer patients. METHODS The PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine, and ChinaInfo databases were searched for articles published through December 2022. Studies were considered qualified if they included patients with early pancreatic cancer, analyzed the prognostic value of CTCs, and were full papers reported in English or Chinese. Researches were selected and assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and the Newcastle-Ottawa Scale criteria. We used a funnel plot to assess publication bias. RESULTS From 1595 publications, we identified eight eligible studies that collectively enrolled 355 patients with pancreatic cancer. Among these original studies, two were carried out in China; three in the United States; and one each in Italy, Spain, and Norway. All eight studies analyzed the relevance between CTCs and the prognosis of patients with early-stage pancreatic cancer after surgery. A meta-analysis showed that the patients that were positive pre-treatment or post-treatment for CTCs were associated with decreased OS [hazard ratio (HR) = 1.93, 95% confidence interval (CI): 1.197-3.126, P = 0.007] and decreased relapse-free/disease-free/progression-free survival (HR = 1.27, 95%CI: 1.137-1.419, P < 0.001) in early-stage pancreatic cancer. Additionally, the results suggest no statistically noticeable publication bias for overall, disease-free, progression-free, and recurrence-free survival. CONCLUSION This pooled meta-analysis shows that CTCs, as biomarkers, can afford reliable prognostic information for patients with early-stage pancreatic cancer and help develop individualized treatment plans.
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Affiliation(s)
- Zi-Han Zhang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Yi-Wen Bao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Ya-Jun Zhao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Jian-Quan Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Jin-Tao Guo
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Si-Yu Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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Lee HS, Jung EH, Shin H, Park CS, Park SB, Jung DE, Leem G, Kim SJ, Jo JH, Chung MJ, Park JY, Bang S, Park SW, Song SY. Phenotypic characteristics of circulating tumor cells and predictive impact for efficacy of chemotherapy in patients with pancreatic cancer: a prospective study. Front Oncol 2023; 13:1206565. [PMID: 37736542 PMCID: PMC10509470 DOI: 10.3389/fonc.2023.1206565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 08/14/2023] [Indexed: 09/23/2023] Open
Abstract
Objective Early chemoresistance and tumor mass progression are associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor cells (CTCs) have been studied as potential predictors of treatment response and prognosis in PDAC; however, this approach has yet to be applied in clinical practice. The aim of our study was to investigate the phenotypic characteristics of CTCs and determine their predictive value for PDAC progression. Methods We prospectively enrolled 40 patients who were pathologically diagnosed with PDAC and collected blood samples at diagnosis, 2 months after diagnosis, and during disease progression or recurrence. We used a microfabricated filter-based enrichment system to retrieve and analyze CTCs, which were classified using immunofluorescence staining (CD45, EpCAM, and vimentin). Results Our study included 20 women and 20 men (median age, 66 years). Overall, 45% of the patients (18/40) had disseminated disease, and 77.5% (31/40) received chemotherapy. Multivariate analysis revealed that the total CTC count and carbohydrate antigen 19-9 level at 2 months after diagnosis were associated with disease progression (P<0.05). Linear mixed model analysis revealed that the total CTC count and vimentin-positive CTCs were significantly correlated with treatment response during chemotherapy (P=0.024 and 0.017, respectively). Kaplan-Meier analysis showed that total CTC positivity at 2 months was significantly associated with poor progression-free survival (P=0.038). Conclusion Our study's findings suggest that CTCs can serve as predictive biomarkers of clinical outcomes in patients with PDAC receiving palliative chemotherapy. In particular, the total CTC count and vimentin-positive CTCs showed changes associated with the chemotherapy response.
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Affiliation(s)
- Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Hye Jung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyejung Shin
- Biostatistics Collaboration Unit, Medical Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chan Su Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Been Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dawoon E. Jung
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Galam Leem
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - So Jung Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung Hyun Jo
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Moon Jae Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Youp Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Si Young Song
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
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Yang L, Zeng X, Yang G, Li Y, Pan Y. Predictive value of circulating tumor cell counts during the treatment of cancer: interactions with the blood microenvironment. Int J Clin Oncol 2023; 28:1011-1022. [PMID: 37243775 DOI: 10.1007/s10147-023-02355-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 05/05/2023] [Indexed: 05/29/2023]
Abstract
OBJECTIVE This study aimed to evaluate the prognostic value of circulating tumor cell (CTC) in tumor patients during treatment. METHODS This study retrospectively analyzed clinical data obtained from 174 cancer patients during treatment. The relationship between the CTC counts and clinicopathological variables was analyzed. A ROC curve was applied to determine the optimal cut-off values and assess the predictive ability of the prognostic indicators. The overall survival (OS) for different prognostic factors was calculated using the Kaplan-Meier method, and the difference between the survival curves was then compared using the log-rank test. Cox regression model was used to investigate the effect of independent factors on patients' survival. RESULTS The CTC-positive rate was positively correlated with the clinicopathological variables of TNM stage, tumor differentiation, serum CEA level, and ki-67%. In the differential analysis of hematological microenvironment parameters in CTC-positive and CTC-negative samples, the complete blood count, blood biological chemistry, tumor markers (CEA, CA19-9, CA72-4), and lymphocyte subpopulation were statistically significant. The results of the ROC curve analysis indicated that the serum CEA level was the best diagnostic indicator to discriminate the CTC count in tumor patients. Additionally, the results of the univariate and multivariate analyses of OS in relation to clinical variables revealed that the CTC counts were an independent prognostic factor for unfavorable OS. CONCLUSION The CTC counts in patients with tumors undergoing treatment were significantly correlated with hematological microenvironment parameters. The detection of CTCs may therefore be used as an indicator of tumor prognosis.
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Affiliation(s)
- Liu Yang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Xiaojiao Zeng
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Gui Yang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Yirong Li
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.
| | - Yunbao Pan
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.
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Tan Q, Chen C, Wang Z, Zhang H, Liu X, Ke N. Prognostic role of radiological splenic vessel involvement in patients with resectable pancreatic ductal adenocarcinoma of the body and tail: A retrospective analysis based on a large population. Eur J Radiol 2023; 165:110952. [PMID: 37421772 DOI: 10.1016/j.ejrad.2023.110952] [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: 03/25/2023] [Revised: 06/24/2023] [Accepted: 06/27/2023] [Indexed: 07/10/2023]
Abstract
BACKGROUND Tumors located in the pancreatic body or tail are more likely to invade splenic vessels; however, splenic artery (SpA) or vein (SpV) involvement is not included in the criteria for resectability. We aimed to analyze the prognostic role of radiological splenic vessel involvement in patients with resectable pancreatic ductal adenocarcinoma (PDAC) of the body and tail. METHODS Patients with resetable PDAC were retrospectively reviewed and analyzed. SpA and SpV involvement were graded as clear, abutment and encasement. Multivariate Cox and logistic regression analyses were used to identify prognostic factors for overall survival (OS) and risk factors for early recurrence, respectively. RESULTS Of the 234 patients, 94 patients had radiologic SpA invasion, including abutment in 47 patients and encasement in 47 patients, while 123 patients had radiological SpV invasion, including abutment in 69 patients and encasement in 54 patients. Patients with SpA or SpV encasement showed a significantly worse OS and recurrence-free survival than those with SpA or SpV clear (P < 0.001, respectively). In multivariate analysis, both SpA and SpV encasement were independently associated with poor OS (SpA: hazard ratio [HR] 1.89, P = 0.010; SpV: HR 2.01, P = 0.001) and early recurrence (SpA: odds ratio [OR] 4.98, P < 0.001; SpV: OR 3.71, P = 0.002). CONCLUSION Radiological SpA or SpV encasement independently decreases OS, and is associated with early recurrence of resectable PDAC of the body/tail.
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Affiliation(s)
- Qingquan Tan
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Chen Chen
- Department of Radiology, The First People's Hospital of Chengdu, Chengdu, Sichuan Province, China; Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ziyao Wang
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Haoqi Zhang
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xubao Liu
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Nengwen Ke
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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13
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Peller MT, Das KK. Blood-Based Biomarkers in the Diagnosis and Risk Stratification of Pancreatic Cysts. Gastrointest Endosc Clin N Am 2023; 33:559-581. [PMID: 37245936 DOI: 10.1016/j.giec.2023.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
The use of blood-based biomarkers for the assessment of pancreatic cystic lesions is a rapidly growing field with incredible potential. CA 19-9 remains the only blood-based marker in common use, while many novel biomarkers are in early stages of development and validation. We highlight current work in the fields of proteomics, metabolomics, cell-free DNA/circulating tumor DNA, extracellular vesicles, and microRNA among others, as well as barriers to development and future directions in the work of blood-based biomarkers for pancreatic cystic lesions.
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Affiliation(s)
- Matthew T Peller
- Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue Campus Box 8124, Saint Louis, MO 63110, USA
| | - Koushik K Das
- Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue Campus Box 8124, Saint Louis, MO 63110, USA.
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14
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Javed AA, Floortje van Oosten A, Habib JR, Hasanain A, Kinny-Köster B, Gemenetzis G, Groot VP, Ding D, Cameron JL, Lafaro KJ, Burns WR, Burkhart RA, Yu J, He J, Wolfgang CL. A Delay in Adjuvant Therapy Is Associated With Worse Prognosis Only in Patients With Transitional Circulating Tumor Cells After Resection of Pancreatic Ductal Adenocarcinoma. Ann Surg 2023; 277:866-872. [PMID: 36111839 DOI: 10.1097/sla.0000000000005710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The aim of the study was to assess the association of circulating tumor cells (CTCs) with survival as a biomarker in pancreatic ductal adenocarcinoma (PDAC) within the context of a delay in the initiation of adjuvant therapy. BACKGROUND Outcomes in patients with PDAC remain poor and are driven by aggressive systemic disease. Although systemic therapies improve survival in resected patients, factors such as a delay in the initiation of adjuvant therapy are associated with worse outcomes. CTCs have previously been shown to be predictive of survival. METHODS A retrospective study was performed on PDAC patients enrolled in the prospective CircuLating tUmor cellS in pancreaTic cancER trial (NCT02974764) on CTC-dynamics at the Johns Hopkins Hospital. CTCs were isolated based on size (isolation by size of epithelial tumor cells; Rarecells) and counted and characterized by subtype using immunofluorescence. The preoperative and postoperative blood samples were used to identify 2 CTC types: epithelial CTCs (eCTCs), expressing pancytokeratin, and transitional CTCs (trCTCs), expressing both pancytokeratin and vimentin. Patients who received adjuvant therapy were compared with those who did not. A delay in the receipt of adjuvant therapy was defined as the initiation of therapy ≥8 weeks after surgical resection. Clinicopathologic features, CTCs characteristics, and outcomes were analyzed. RESULTS Of 101 patients included in the study, 43 (42.5%) experienced a delay in initiation and 20 (19.8%) did not receive adjuvant therapy. On multivariable analysis, the presence of trCTCs ( P =0.002) and the absence of adjuvant therapy ( P =0.032) were associated with worse recurrence-free survival (RFS). Postoperative trCTC were associated with poorer RFS, both in patients with a delay in initiation (12.4 vs 17.9 mo, P =0.004) or no administration of adjuvant chemotherapy (3.4 vs NR, P =0.016). However, it was not associated with RFS in patients with timely initiation of adjuvant chemotherapy ( P =0.293). CONCLUSIONS Postoperative trCTCs positivity is associated with poorer RFS only in patients who either experience a delay in initiation or no receipt of adjuvant therapy. This study suggests that a delay in the initiation of adjuvant therapy could potentially provide residual systemic disease (trCTCs) a window of opportunity to recover from the surgical insult. Future studies are required to validate these findings and explore the underlying mechanisms involved.
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Affiliation(s)
- Ammar A Javed
- Department of Surgery, New York University Langone Hospital, New York City, NY
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Anne Floortje van Oosten
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht University, The Netherlands
| | - Joseph R Habib
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Alina Hasanain
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Benedict Kinny-Köster
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Georgios Gemenetzis
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Vincent P Groot
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ding Ding
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Manhasset, NY
| | - John L Cameron
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Kelly J Lafaro
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - William R Burns
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Richard A Burkhart
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jun Yu
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jin He
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
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15
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Zheng S, Girgis MD, Tomlinson JS. Circulating Tumor Cells: Metastases Caught in the Act. Ann Surg 2023; 277:873-876. [PMID: 36994706 DOI: 10.1097/sla.0000000000005846] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 02/11/2023] [Indexed: 03/31/2023]
Affiliation(s)
- Serena Zheng
- Department of Surgery, University of California, Los Angeles
| | - Mark D Girgis
- Department of Surgery, University of California, Los Angeles
- Department of Surgery, Greater Los Angeles VA Medical Center, Los Angeles
| | - James S Tomlinson
- Department of Surgery, University of California, Los Angeles
- Department of Surgery, Greater Los Angeles VA Medical Center, Los Angeles
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16
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Poellmann MJ, Bu J, Liu S, Wang AZ, Seyedin SN, Chandrasekharan C, Hong H, Kim Y, Caster JM, Hong S. Nanotechnology and machine learning enable circulating tumor cells as a reliable biomarker for radiotherapy responses of gastrointestinal cancer patients. Biosens Bioelectron 2023; 226:115117. [PMID: 36753988 PMCID: PMC10034717 DOI: 10.1016/j.bios.2023.115117] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/13/2023] [Accepted: 01/31/2023] [Indexed: 02/04/2023]
Abstract
A highly sensitive, circulating tumor cell (CTC)-based liquid biopsy was used to monitor gastrointestinal cancer patients during treatment to determine if CTC abundance was predictive of disease recurrence. The approach used a combination of biomimetic cell rolling on recombinant E-selectin and dendrimer-mediated multivalent immunocapture at the nanoscale to purify CTCs from peripheral blood mononuclear cells. Due to the exceptionally high numbers of CTCs captured, a machine learning algorithm approach was developed to efficiently and reliably quantify abundance of immunocytochemically-labeled cells. A convolutional neural network and logistic regression model achieved 82.9% true-positive identification of CTCs with a false positive rate below 0.1% on a validation set. The approach was then used to quantify CTC abundance in peripheral blood samples from 27 subjects before, during, and following treatments. Samples drawn from the patients either prior to receiving radiotherapy or early in chemotherapy had a median 50 CTC ml-1 whole blood (range 0.6-541.6). We found that the CTC counts drawn 3 months post treatment were predictive of disease progression (p = .045). This approach to quantifying CTC abundance may be a clinically impactful in the timely determination of gastrointestinal cancer progression or response to treatment.
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Affiliation(s)
- Michael J Poellmann
- Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, 53705, USA; Capio Biosciences, Inc., Madison, WI, 53719, USA and Capio Biosciences Korea, Incheon, 21983 South Korea
| | - Jiyoon Bu
- Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, 53705, USA; Capio Biosciences, Inc., Madison, WI, 53719, USA and Capio Biosciences Korea, Incheon, 21983 South Korea; Department of Biological Engineering, Inha University, Incheon, 22212, South Korea
| | - Stanley Liu
- Capio Biosciences, Inc., Madison, WI, 53719, USA and Capio Biosciences Korea, Incheon, 21983 South Korea
| | - Andrew Z Wang
- Capio Biosciences, Inc., Madison, WI, 53719, USA and Capio Biosciences Korea, Incheon, 21983 South Korea; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Steven N Seyedin
- Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697, USA
| | | | - Heejoo Hong
- Department of Clinical Pharmacology & Therapeutics, Asan Medical Center, University of Ulsan, Seoul, 05505, South Korea
| | - YoungSoo Kim
- Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon, 21983, South Korea
| | - Joseph M Caster
- Department of Radiation Oncology, University of Iowa, Iowa City, IA, 52242, USA
| | - Seungpyo Hong
- Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, 53705, USA; Capio Biosciences, Inc., Madison, WI, 53719, USA and Capio Biosciences Korea, Incheon, 21983 South Korea; Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon, 21983, South Korea; Lachman Institute for Pharmaceutical Development, University of Wisconsin-Madison, Madison, WI, 53705, USA; Wisconsin Center for NanoBioSystems, University of Wisconsin-Madison, Madison, WI, 53705, USA.
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Raufi AG, May MS, Hadfield MJ, Seyhan AA, El-Deiry WS. Advances in Liquid Biopsy Technology and Implications for Pancreatic Cancer. Int J Mol Sci 2023; 24:4238. [PMID: 36835649 PMCID: PMC9958987 DOI: 10.3390/ijms24044238] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 12/23/2022] [Accepted: 12/29/2022] [Indexed: 02/23/2023] Open
Abstract
Pancreatic cancer is a highly aggressive malignancy with a climbing incidence. The majority of cases are detected late, with incurable locally advanced or metastatic disease. Even in individuals who undergo resection, recurrence is unfortunately very common. There is no universally accepted screening modality for the general population and diagnosis, evaluation of treatment response, and detection of recurrence relies primarily on the use of imaging. Identification of minimally invasive techniques to help diagnose, prognosticate, predict response or resistance to therapy, and detect recurrence are desperately needed. Liquid biopsies represent an emerging group of technologies which allow for non-invasive serial sampling of tumor material. Although not yet approved for routine use in pancreatic cancer, the increasing sensitivity and specificity of contemporary liquid biopsy platforms will likely change clinical practice in the near future. In this review, we discuss the recent technological advances in liquid biopsy, focusing on circulating tumor DNA, exosomes, microRNAs, and circulating tumor cells.
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Affiliation(s)
- Alexander G. Raufi
- Division of Hematology/Oncology, Department of Medicine, Lifespan Health System, Providence, RI 02903, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
- Joint Program in Cancer Biology, Brown University, Providence, RI 02903, USA
| | - Michael S. May
- Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Matthew J. Hadfield
- Division of Hematology/Oncology, Department of Medicine, Lifespan Health System, Providence, RI 02903, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
| | - Attila A. Seyhan
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
- Joint Program in Cancer Biology, Brown University, Providence, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Wafik S. El-Deiry
- Division of Hematology/Oncology, Department of Medicine, Lifespan Health System, Providence, RI 02903, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
- Joint Program in Cancer Biology, Brown University, Providence, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
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18
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Watanabe F, Suzuki K, Noda H, Rikiyama T. Liquid biopsy leads to a paradigm shift in the treatment of pancreatic cancer. World J Gastroenterol 2022; 28:6478-6496. [PMID: 36569270 PMCID: PMC9782840 DOI: 10.3748/wjg.v28.i46.6478] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/25/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most cancers. Its 5-year survival rate is very low. The recent induction of neoadjuvant chemotherapy and improvements in chemotherapy for patients with pancreatic cancer have resulted in improved survival outcomes. However, the prognosis of pancreatic cancer is still poor. To dramatically improve the prognosis, we need to develop more tools for early diagnosis, treatment selection, disease monitoring, and response rate evaluation. Recently, liquid biopsy (circulating free DNA, circulating tumor DNA, circulating tumor cells, exosomes, and microRNAs) has caught the attention of many researchers as a new biomarker that is minimally invasive, confers low-risk, and displays an overall state of the tumor. Thus, liquid biopsy does not employ the traditional difficulties of obtaining tumor samples from patients with advanced PDAC to investigate their molecular biological status. In addition, it allows for long-term monitoring of the molecular profile of tumor progression. These could help in identifying tumor-specific alterations that use the target structure for tailor-made therapy. Through this review, we highlighted the latest discoveries and advances in liquid biopsy technology in pancreatic cancer research and showed how it can be applied in clinical practice.
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Affiliation(s)
- Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hiroshi Noda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
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19
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ALCAM: A Novel Surface Marker on EpCAMlow Circulating Tumor Cells. Biomedicines 2022; 10:biomedicines10081983. [PMID: 36009530 PMCID: PMC9405826 DOI: 10.3390/biomedicines10081983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Current strategies in circulating tumor cell (CTC) isolation in pancreatic cancer heavily rely on the EpCAM and cytokeratin cell status. EpCAM is generally not considered a good marker given its transitory change during Epithelial to Mesenchymal Transition (EMT) or reverse EMT. There is a need to identify other surface markers to capture the complete repertoire of PDAC CTCs. The primary objective of the study is to characterize alternate surface biomarkers to EpCAM on CTCs that express low or negligible levels of surface EpCAM in pancreatic cancer patients. Methods: Flow cytometry and surface mass spectrometry were used to identify proteins expressed on the surface of PDAC CTCs in culture. CTCs were grown under conditions of attachment and in co-culture with naïve neutrophils. Putative biomarkers were then validated in GEMMs and patient samples. Results: Surface proteomic profiling of CTCs identified several novel protein biomarkers. ALCAM was identified as a novel robust marker in GEMM models and in patient samples. Conclusions: We identified several novel surface biomarkers on CTCs expressed under differing conditions of culture. ALCAM was validated and identified as a novel alternate surface marker on EpCAMlow CTCs.
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20
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Hartlapp I, Valta-Seufzer D, Siveke JT, Algül H, Goekkurt E, Siegler G, Martens UM, Waldschmidt D, Pelzer U, Fuchs M, Kullmann F, Boeck S, Ettrich TJ, Held S, Keller R, Anger F, Germer CT, Stang A, Kimmel B, Heinemann V, Kunzmann V. Prognostic and predictive value of CA 19-9 in locally advanced pancreatic cancer treated with multiagent induction chemotherapy: results from a prospective, multicenter phase II trial (NEOLAP-AIO-PAK-0113). ESMO Open 2022; 7:100552. [PMID: 35970013 PMCID: PMC9434418 DOI: 10.1016/j.esmoop.2022.100552] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/30/2022] [Accepted: 07/03/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND The prognostic and predictive value of carbohydrate antigen 19-9 (CA 19-9) in locally advanced pancreatic cancer (LAPC) has not yet been defined from prospective randomized controlled trials (RCTs). PATIENTS AND METHODS A total of 165 LAPC patients were treated within the NEOLAP RCT for 16 weeks with multiagent induction chemotherapy [ICT; either nab-paclitaxel/gemcitabine alone or nab-paclitaxel/gemcitabine followed by FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin)] followed by surgical exploration of all patients without evidence of disease progression. CA 19-9 was determined at baseline and after ICT and correlated with overall survival (OS) and secondary R0 resection rate. RESULTS From the NEOLAP study population (N = 165) 133 patients (81%) were evaluable for CA 19-9 at baseline and 81/88 patients (92%) for post-ICT CA 19-9 response. Median OS (mOS) in the CA 19-9 cohort (n = 133) was 16.2 months [95% confidence interval (CI) 13.0-19.4] and R0 resection (n = 31; 23%) was associated with a significant survival benefit [40.8 months (95% CI 21.7-59.8)], while R1 resected patients (n = 14; 11%) had no survival benefit [14.0 (95% CI 11.7-16.3) months, hazard ratio (HR) 0.27; P = 0.001]. After ICT most patients showed a CA 19-9 response (median change from baseline: -82%; relative decrease ≥55%: 83%; absolute decrease to ≤50 U/ml: 43%). Robust CA 19-9 response (decrease to ≤50U/ml) was significantly associated with mOS [27.8 (95% CI 18.4-37.2) versus 16.5 (95% CI 11.7-21.2) months, HR 0.49; P = 0.013], whereas CA 19-9 baseline levels were not prognostic for OS. Multivariate analysis demonstrated that a robust CA 19-9 response was an independent predictive factor for R0 resection. Using a CA 19-9 decrease to ≤61 U/ml as optimal cut-off (by receiver operating characteristic analysis) yielded 72% sensitivity and 62% specificity for successful R0 resection, whereas CA 19-9 nonresponders (<20% decrease or increase) had no chance for successful R0 resection. CONCLUSIONS CA 19-9 response after multiagent ICT provides relevant prognostic and predictive information and is useful in selecting LAPC patients for explorative surgery. CLINICAL TRIAL NUMBER ClinicalTrials.govNCT02125136; https://clinicaltrials.gov/ct2/show/NCT02125136; EudraCT 2013-004796-12; https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004796-12/results.
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Affiliation(s)
- I Hartlapp
- Department of Internal Medicine II, Medical Oncology and Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany
| | - D Valta-Seufzer
- Department of Internal Medicine II, Medical Oncology and Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany
| | - J T Siveke
- Department of Medical Oncology, Bridge Institute of Experimental Tumor Therapy, University Medicine Essen, Essen, Germany; Division of Solid Tumor Translational Oncology (DKTK Partner Site Essen, DKFZ Heidelberg), West German Cancer Center, University Medicine Essen, Essen, Germany
| | - H Algül
- Comprehensive Cancer Center Munich (CCCM(TUM)) at the Klinikum rechts der Isar, Department of Internal Medicine II, Technical University Munich, Munich, Germany
| | - E Goekkurt
- Hämatologisch-Onkologische Praxis Eppendorf (HOPE), Hamburg and University Cancer Center Hamburg (UCCH), Hamburg, Germany
| | - G Siegler
- Department of Internal Medicine 5, Hematology and Medical Oncology, Paracelsus Medical University, Nürnberg, Germany
| | - U M Martens
- Department of Internal Medicine III, SLK-Clinics Heilbronn GmbH, Heilbronn, Germany
| | - D Waldschmidt
- Department of Gastroenterology and Hepatology, University Hospital Cologne, Cologne, Germany
| | - U Pelzer
- Division of Oncology and Hematology, Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - M Fuchs
- Clinic for Gastroenterology, Hepatology and GI-Oncology, München Klinik Bogenhausen, Munich, Germany
| | - F Kullmann
- Department of Internal Medicine I, Kliniken Nordoberpfalz AG, Klinikum Weiden, Weiden, Germany
| | - S Boeck
- Department of Medical Oncology and Comprehensive Cancer Center, Ludwig Maximilians University-Grosshadern, Munich, Germany
| | - T J Ettrich
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - S Held
- Department of Biometrics, ClinAssess GmbH, Leverkusen, Germany
| | - R Keller
- Clinical Research, AIO Studien gGmbH, Berlin, Germany
| | - F Anger
- Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery and Comprehensive Cancer Center Mainfranken Würzburg, University Hospital Würzburg, Würzburg, Germany
| | - C T Germer
- Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery and Comprehensive Cancer Center Mainfranken Würzburg, University Hospital Würzburg, Würzburg, Germany
| | - A Stang
- Department of Haematology, Oncology and Palliative Care Medicine, Asklepios Hospital Barmbek, Hamburg, Germany
| | - B Kimmel
- Department of Internal Medicine II, Medical Oncology and Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany
| | - V Heinemann
- Department of Medical Oncology and Comprehensive Cancer Center, Ludwig Maximilians University-Grosshadern, Munich, Germany
| | - V Kunzmann
- Department of Internal Medicine II, Medical Oncology and Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany.
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21
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Chen J, Wang H, Zhou L, Liu Z, Tan X. A combination of circulating tumor cells and CA199 improves the diagnosis of pancreatic cancer. J Clin Lab Anal 2022; 36:e24341. [PMID: 35334495 PMCID: PMC9102772 DOI: 10.1002/jcla.24341] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/29/2022] [Accepted: 02/27/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to the lack of effective screening tests. CA199, the standard biomarker for PDAC management, is not sufficiently reliable for early diagnosis. This prospective study aimed to evaluate whether circulating tumor cells (CTCs) could complement or perform better than CA199 in determining PDAC. METHODS A total of 168 blood samples were collected from 80 patients with PDAC, 32 patients with acute pancreatitis, 22 patients with benign pancreatic masses, and 34 healthy donors. CTCs were detected by a novel system combining negative enrichment with immunostaining and fluorescence in situ hybridization (NE-imFISH). Next, ROC curves and AUC analyses were conducted to assess diagnostic abilities of CA199, CTCs, and the combination of the two biomarkers in PDAC. RESULTS CTCs were stained as CD45-/DAPI+/CEP8 ≥3. With 2 CTCs/3.2 ml as the cut-off value, the sensitivity/specificity of the CTC number was 0.76/0.94, which was comparable to that of CA199 (0.78/0.83; Delong test p = 0.3360). Improved performance was achieved through a logistic regression model integrating CA199 and CTC number (AUCCTC+CA199 = 0.95, AUCCA199 = 0.80, AUCCTC number = 0.85; Delong test p vs . CA199 < 0.0001 and p vs . CTC number = 0.0002). CTC subtype was inferior to CTC number as a diagnostic marker (AUCCTC subtype = 0.73; Delong test p vs . CTC number < 0.0001). CONCLUSION The dual-marker panel consisting of CA199 and CTC number can significantly improve upon the diagnostic performance of CA199 alone, highlighting the promising clinical utilization as an effective strategy for PDAC surveillance.
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Affiliation(s)
- Junliang Chen
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Huaitao Wang
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Lei Zhou
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Zhihao Liu
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Xiaodong Tan
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
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22
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Yang X, Lv J, Zhou Z, Feng D, Zhou R, Yuan B, Wu Q, Yu H, Han J, Cao Q, Gu M, Li P, Yang H, Lu Q. Clinical Application of Circulating Tumor Cells and Circulating Endothelial Cells in Predicting Bladder Cancer Prognosis and Neoadjuvant Chemosensitivity. Front Oncol 2022; 11:802188. [PMID: 35186716 PMCID: PMC8851236 DOI: 10.3389/fonc.2021.802188] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/28/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose To investigate the role of circulating rare cells (CRCs), namely, circulating tumor cells (CTCs) and circulating endothelial cells (CECs), in aiding early intervention, treatment decision, and prognostication in bladder cancer. Methods A total of 196 patients with pathologically confirmed bladder cancer, namely, 141 non-muscle invasive bladder cancer (NMIBC) and 55 muscle invasive bladder cancer (MIBC) patients. There were 32 patients who received cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). Subtraction enrichment combined with immunostaining-fluorescence in situ hybridization (SE-iFISH) strategy was used for CTC/CEC detection. Kaplan–Meier analysis and Cox regression were used to evaluate the overall survival (OS) and recurrence-free survival (RFS). Receiver operator characteristic analysis was used to discriminate NAC sensitivity. Results CTCs and CECs were related to clinicopathological characteristics. Triploid CTCs, tetraploid CTCs, and total CECs were found to be higher in incipient patients than in relapse patients (P = 0.036, P = 0.019, and P = 0.025, respectively). The number of total CECs and large cell CECs was also associated with advanced tumor stage (P = 0.028 and P = 0.033) and grade (P = 0.028 and P = 0.041). Remarkably, tumor-biomarker-positive CTCs were associated with worse OS and RFS (P = 0.026 and P = 0.038) in NMIBC patients underwent TURBT. CECs cluster was an independent predictor of recurrence in non-high-risk NMIBC patients underwent TURBT (HR = 9.21, P = 0.040). For NAC analysis, pre-NAC tetraploid CTCs and small cell CTCs demonstrated the capability in discriminating NAC-sensitive from insensitive patients. Additionally, tetraploid CTCs and single CTCs elevated post-NAC would indicate chemoresistance. Conclusion CTCs and CECs may putatively guide in diagnosis, prognosis prediction, and therapeutic decision-making for bladder cancer.
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Affiliation(s)
- Xiao Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jiancheng Lv
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zijian Zhou
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dexiang Feng
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rui Zhou
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Baorui Yuan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qikai Wu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Yu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiang Cao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Gu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pengchao Li
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haiwei Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiang Lu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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23
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Exploring the Clinical Utility of Pancreatic Cancer Circulating Tumor Cells. Int J Mol Sci 2022; 23:ijms23031671. [PMID: 35163592 PMCID: PMC8836025 DOI: 10.3390/ijms23031671] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 01/27/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type, characterized by a dismal prognosis due to late diagnosis, frequent metastases, and limited therapeutic response to standard chemotherapy. Circulating tumor cells (CTCs) are a rare subset of tumor cells found in the blood of cancer patients. CTCs has the potential utility for screening, early and definitive diagnosis, prognostic and predictive assessment, and offers the potential for personalized management. However, a gold-standard CTC detection and enrichment method remains elusive, hindering comprehensive comparisons between studies. In this review, we summarize data regarding the utility of CTCs at different stages of PDAC from early to metastatic disease and discuss the molecular profiling and culture of CTCs. The characterization of CTCs brings us closer to defining the specific CTC subpopulation responsible for metastasis with the potential to uncover new therapies and more effective management options for PDAC.
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24
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Santos V, Freitas C, Fernandes MGO, Sousa C, Reboredo C, Cruz-Martins N, Mosquera J, Hespanhol V, Campelo R. Liquid biopsy: the value of different bodily fluids. Biomark Med 2022; 16:127-145. [DOI: 10.2217/bmm-2021-0370] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Liquid biopsies have gained an increasing interest in the last years among medical and scientific communities. Indeed, the value of liquid effusions, while less invasive and more accurate techniques, has been markedly highlighted. Peripheral blood comprises the most often analyzed sample, but recent evidences have pointed out the huge importance of other bodily fluids, including pleural and peritoneal fluids, urine, saliva and cerebrospinal fluid in the detection and monitoring of different tumor types. In face to these advances, this review aims to provide an overview of the value of tumor-associated mutations, detectable in different effusions, and how they can be used in clinical practice, namely in prognosis assessment and early disease and minimal disease recurrence detection, and in predicting the treatment response or acquired-resistance development.
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Affiliation(s)
- Vanessa Santos
- Department of Pulmonology, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, Porto, 4200319, Portugal
| | - Cláudia Freitas
- Department of Pulmonology, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, Porto, 4200319, Portugal
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, 4200319, Portugal
| | - Maria GO Fernandes
- Department of Pulmonology, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, Porto, 4200319, Portugal
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, 4200319, Portugal
- Institute for Research & Innovation in Health (I3S), University of Porto, Rua Alfredo Allen, Porto, 4200135, Portugal
- Institute of Molecular Pathology & Immunology of the University of Porto (IPATIMUP), Porto, 4200135, Portugal
| | - Catarina Sousa
- Department of Pulmonology, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, Porto, 4200319, Portugal
| | - Cristina Reboredo
- Department of Lung Cancer & Thoracic Tumours, Complejo Hospitalario Universitario de A Coruña, As Xubias, 84, 15006, A Coruña, La Coruña, Spain
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, 4200319, Portugal
- Institute for Research & Innovation in Health (I3S), University of Porto, Rua Alfredo Allen, Porto, 4200135, Portugal
| | - Joaquín Mosquera
- Department of Lung Cancer & Thoracic Tumours, Complejo Hospitalario Universitario de A Coruña, As Xubias, 84, 15006, A Coruña, La Coruña, Spain
| | - Venceslau Hespanhol
- Department of Pulmonology, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, Porto, 4200319, Portugal
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, 4200319, Portugal
- Institute for Research & Innovation in Health (I3S), University of Porto, Rua Alfredo Allen, Porto, 4200135, Portugal
- Institute of Molecular Pathology & Immunology of the University of Porto (IPATIMUP), Porto, 4200135, Portugal
| | - Rosário Campelo
- Department of Lung Cancer & Thoracic Tumours, Complejo Hospitalario Universitario de A Coruña, As Xubias, 84, 15006, A Coruña, La Coruña, Spain
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25
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Carneiro A, Piairo P, Teixeira A, Ferreira D, Cotton S, Rodrigues C, Chícharo A, Abalde-Cela S, Santos LL, Lima L, Diéguez L. Discriminating Epithelial to Mesenchymal Transition Phenotypes in Circulating Tumor Cells Isolated from Advanced Gastrointestinal Cancer Patients. Cells 2022; 11:cells11030376. [PMID: 35159186 PMCID: PMC8834092 DOI: 10.3390/cells11030376] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 01/27/2023] Open
Abstract
Gastrointestinal (GI) cancers constitute a group of highest morbidity worldwide, with colorectal cancer (CRC) and gastric cancer being among the most frequently diagnosed. The majority of gastrointestinal cancer patients already present metastasis by the time of diagnosis, which is widely associated with cancer-related death. Accumulating evidence suggests that epithelial-to-mesenchymal transition (EMT) in cancer promotes circulating tumor cell (CTCs) formation, which ultimately drives metastasis development. These cells have emerged as a fundamental tool for cancer diagnosis and monitoring, as they reflect tumor heterogeneity and the clonal evolution of cancer in real-time. In particular, EMT phenotypes are commonly associated with therapy resistance. Thus, capturing these CTCs is expected to reveal important clinical information. However, currently available CTC isolation approaches are suboptimal and are often targeted to capture epithelial CTCs, leading to the loss of EMT or mesenchymal CTCs. Here, we describe size-based CTCs isolation using the RUBYchip™, a label-free microfluidic device, aiming to detect EMT biomarkers in CTCs from whole blood samples of GI cancer patients. We found that, for most cases, the mesenchymal phenotype was predominant, and in fact a considerable fraction of isolated CTCs did not express epithelial markers. The RUBYchip™ can overcome the limitations of label-dependent technologies and improve the identification of CTC subpopulations that may be related to different clinical outcomes.
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Affiliation(s)
- Adriana Carneiro
- International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga s/n, 4715-330 Braga, Portugal; (A.C.); (A.T.); (C.R.); (A.C.); (S.A.-C.)
- IPO Experimental Pathology and Therapeutics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (D.F.); (S.C.); (L.L.S.); (L.L.)
| | - Paulina Piairo
- International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga s/n, 4715-330 Braga, Portugal; (A.C.); (A.T.); (C.R.); (A.C.); (S.A.-C.)
- Correspondence: (P.P.); (L.D.)
| | - Alexandra Teixeira
- International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga s/n, 4715-330 Braga, Portugal; (A.C.); (A.T.); (C.R.); (A.C.); (S.A.-C.)
| | - Dylan Ferreira
- IPO Experimental Pathology and Therapeutics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (D.F.); (S.C.); (L.L.S.); (L.L.)
| | - Sofia Cotton
- IPO Experimental Pathology and Therapeutics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (D.F.); (S.C.); (L.L.S.); (L.L.)
| | - Carolina Rodrigues
- International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga s/n, 4715-330 Braga, Portugal; (A.C.); (A.T.); (C.R.); (A.C.); (S.A.-C.)
| | - Alexandre Chícharo
- International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga s/n, 4715-330 Braga, Portugal; (A.C.); (A.T.); (C.R.); (A.C.); (S.A.-C.)
| | - Sara Abalde-Cela
- International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga s/n, 4715-330 Braga, Portugal; (A.C.); (A.T.); (C.R.); (A.C.); (S.A.-C.)
| | - Lúcio Lara Santos
- IPO Experimental Pathology and Therapeutics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (D.F.); (S.C.); (L.L.S.); (L.L.)
- Department of Surgical Oncology, Portuguese Institute of Oncology (IPO Porto), 4200-072 Porto, Portugal
| | - Luís Lima
- IPO Experimental Pathology and Therapeutics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (D.F.); (S.C.); (L.L.S.); (L.L.)
| | - Lorena Diéguez
- International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga s/n, 4715-330 Braga, Portugal; (A.C.); (A.T.); (C.R.); (A.C.); (S.A.-C.)
- Correspondence: (P.P.); (L.D.)
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Schreyer D, Neoptolemos JP, Barry ST, Bailey P. Deconstructing Pancreatic Cancer Using Next Generation-Omic Technologies-From Discovery to Knowledge-Guided Platforms for Better Patient Management. Front Cell Dev Biol 2022; 9:795735. [PMID: 35096825 PMCID: PMC8793685 DOI: 10.3389/fcell.2021.795735] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Comprehensive molecular landscaping studies reveal a potentially brighter future for pancreatic ductal adenocarcinoma (PDAC) patients. Blood-borne biomarkers obtained from minimally invasive "liquid biopsies" are now being trialled for early disease detection and to track responses to therapy. Integrated genomic and transcriptomic studies using resectable tumour material have defined intrinsic patient subtypes and actionable genomic segments that promise a shift towards genome-guided patient management. Multimodal mapping of PDAC using spatially resolved single cell transcriptomics and imaging techniques has identified new potentially therapeutically actionable cellular targets and is providing new insights into PDAC tumour heterogeneity. Despite these rapid advances, defining biomarkers for patient selection remain limited. This review examines the current PDAC cancer biomarker ecosystem (identified in tumour and blood) and explores how advances in single cell sequencing and spatially resolved imaging modalities are being used to uncover new targets for therapeutic intervention and are transforming our understanding of this difficult to treat disease.
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Affiliation(s)
- Daniel Schreyer
- Institute of Cancer Sciences, University of Glasgow, Scotland, United Kingdom
| | - John P. Neoptolemos
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Simon T. Barry
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Peter Bailey
- Institute of Cancer Sciences, University of Glasgow, Scotland, United Kingdom
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Section Surgical Research, University Clinic Heidelberg, Heidelberg, Germany
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Lin D, Shen L, Luo M, Zhang K, Li J, Yang Q, Zhu F, Zhou D, Zheng S, Chen Y, Zhou J. Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther 2021; 6:404. [PMID: 34803167 PMCID: PMC8606574 DOI: 10.1038/s41392-021-00817-8] [Citation(s) in RCA: 466] [Impact Index Per Article: 116.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/06/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.
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Affiliation(s)
- Danfeng Lin
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Breast Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lesang Shen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Meng Luo
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kun Zhang
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinfan Li
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Yang
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fangfang Zhu
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dan Zhou
- Department of Surgery, Traditional Chinese Medical Hospital of Zhuji, Shaoxing, China
| | - Shu Zheng
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiding Chen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jiaojiao Zhou
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Zhang Y, Su H, Wang H, Xu C, Zhou S, Zhao J, Shen S, Xu G, Wang L, Zou X, Zhang S, Lv Y. Endoscopic Ultrasound-Guided Acquisition of Portal Venous Circulating Tumor Cells as a Potential Diagnostic and Prognostic Tool for Pancreatic Cancer. Cancer Manag Res 2021; 13:7649-7661. [PMID: 34675662 PMCID: PMC8502022 DOI: 10.2147/cmar.s330473] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/16/2021] [Indexed: 12/11/2022] Open
Abstract
Background Circulating tumor cells (CTCs) were a promising liquid biopsy for pancreatic cancer (PC) but circulate in low counts in peripheral blood. We evaluated the diagnostic and prognostic values of portal vein (PoV) CTCs in PC patients. Methods PoV was aspirated under EUS guidance from 40 patients with suspected pancreaticobiliary cancers. Epithelial–mesenchymal-transition-related subtypes of CTCs were identified via immunofluorescence using EpCAM and Twist antibodies. The diagnostic and prognostic performance of PoV CTCs was investigated by receiver-operating characteristic (AUC) curve and Kaplan–Meier survival analysis. Results In total, 40 patients including 31 with PC, 4 with non-pancreatic periampullary cancer and 5 with benign pancreatic diseases (BPD) were enrolled. CTCs were detected more in PoV compared with peripheral blood. PoV CTC numbers in BPD patients were lower than in PC patients. The number of PoV CTCs, especially mesenchymal-CTCs (M-CTCs), was positively correlated with the tumor burden, instead of epithelial-CTCs (E-CTCs). The combination of PoV CTC numbers and CA19-9 demonstrated better diagnostic efficiency (AUC value 0.987) than either alone in differentiating PC with BPD. Moreover, the diagnostic efficacy of PoV CTCs and M-CTCs were obviously better than that of E-CTCs and CA19-9 in distinguishing early and late stage PC. Lastly, high PoV CTC and M-CTC numbers were both associated with shorter overall survival. Conclusion Acquisition of the PoV samples in PC patients via EUS-guided procedures has been proved safe and feasible. PoV CTCs, especially M-CTCs, have great potentials in diagnosing and predicting the prognosis of PC, especially in combination with CA19-9.
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Affiliation(s)
- Yixuan Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Haochen Su
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People's Republic of China
| | - Haibo Wang
- Cyttelbio Corporation, Beijing, People's Republic of China
| | - Chenghu Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Siqi Zhou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated of Jiangsu University, Nanjing, People's Republic of China
| | - Jing Zhao
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Shanshan Shen
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Guifang Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Lei Wang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Shu Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Ying Lv
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
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Zhu P, Liu HY, Liu FC, Gu FM, Yuan SX, Huang J, Pan ZY, Wang WJ. Circulating Tumor Cells Expressing Krüppel-Like Factor 8 and Vimentin as Predictors of Poor Prognosis in Pancreatic Cancer Patients. Cancer Control 2021; 28:10732748211027163. [PMID: 34378430 PMCID: PMC8361509 DOI: 10.1177/10732748211027163] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs) with an epithelial-mesenchymal transition phenotype in peripheral blood may be a useful marker of carcinomas with poor prognosis. The aim of this study was to determine the prognostic significance of CTCs expressing Krüppel-like factor 8 (KLF8) and vimentin in pancreatic cancer (PC). METHODS CTCs were isolated by immunomagnetic separation from the peripheral blood of 40 PC patients before undergoing surgical resection. Immunocytochemistry was performed to identify KLF8+ and vimentin+ CTCs. The associations between CTCs and time to recurrence (TTR), clinicopathologic factors, and survival were assessed. Univariate and multivariate analyzes were performed to identify risk factors. RESULTS Patients with CTCs (n = 30) had a higher relapse rate compared to those without (n = 10) (70.0% vs 20.0%; P < 0.01). The proportion of KLF8+/vimentin+ CTCs to total CTCs was inversely related to TTR (r = -0.646; P < 0.01); TTR was reduced in patients with > 50% of CTCs identified as KLF8+/vimentin+ (P < 0.01). Independent risk factors for recurrence were perineural invasion and > 50% KLF8+/vimentin+ CTCs (both P < 0.05). CONCLUSION Poor prognosis can be predicted in PC patients when > 50% of CTCs are positive for KLF8 and vimentin.
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Affiliation(s)
- Peng Zhu
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Hui-Ying Liu
- Department of Biotherapy, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Fu-Chen Liu
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Fang-Ming Gu
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Sheng-Xian Yuan
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jian Huang
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Ze-Ya Pan
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Wei-Jun Wang
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
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Early detection of pancreatic cancer using DNA-based molecular approaches. Nat Rev Gastroenterol Hepatol 2021; 18:457-468. [PMID: 34099908 DOI: 10.1038/s41575-021-00470-0] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2021] [Indexed: 02/08/2023]
Abstract
Due to its poor prognosis and the late stage at which it is typically diagnosed, early detection of pancreatic cancer is a pressing clinical problem. Advances in genomic analysis of human pancreatic tissue and other biospecimens such as pancreatic cyst fluid, pancreatic juice and blood have opened the possibility of DNA-based molecular approaches for early detection of pancreatic cancer. In this Review, we discuss and focus on the pathological and molecular features of precancerous lesions of the pancreas, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, which are target lesions of early detection approaches. We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. We highlight the latest discoveries related to genetic heterogeneity and multifocal neoplasia in precancerous lesions. In addition, we review specific approaches, challenges and clinically available assays for early detection of pancreatic cancer using DNA-based molecular techniques. Although detection and risk stratification of precancerous pancreatic neoplasms are difficult problems, progress in this field highlights the promise of molecular approaches for improving survival of patients with this disease.
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Vasseur A, Kiavue N, Bidard F, Pierga J, Cabel L. Clinical utility of circulating tumor cells: an update. Mol Oncol 2021; 15:1647-1666. [PMID: 33289351 PMCID: PMC8169442 DOI: 10.1002/1878-0261.12869] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/21/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022] Open
Abstract
The prognostic role of circulating tumor cells (CTCs) has been clearly demonstrated in many types of cancer. However, their roles in diagnostic and treatment strategies remain to be defined. In this review, we present an overview of the current clinical validity of CTCs in nonmetastatic and metastatic cancer, and the main studies or concepts investigating the clinical utility of CTCs. In particular, we focus on breast, lung, colorectal, and prostate cancer. Two major topics concerning the clinical utility of CTC are discussed: treatment based on CTC count or CTC variations, and treatment based on the molecular characteristics of CTCs. Although some of these studies are inconclusive, many are still ongoing, and their results could help to define the role of CTCs in the management of cancers. A summary of published or ongoing phase II-III trials is also presented.
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Affiliation(s)
- Antoine Vasseur
- Department of Medical OncologyParis and Saint‐Cloud Institut CurieFrance
| | - Nicolas Kiavue
- Department of Medical OncologyParis and Saint‐Cloud Institut CurieFrance
| | - François‐Clément Bidard
- Department of Medical OncologyParis and Saint‐Cloud Institut CurieFrance
- UVSQParis‐Saclay UniversityFrance
- Circulating Tumor Biomarkers laboratoryInserm CIC‐BT 1428Institut CurieParisFrance
| | - Jean‐Yves Pierga
- Department of Medical OncologyParis and Saint‐Cloud Institut CurieFrance
- Circulating Tumor Biomarkers laboratoryInserm CIC‐BT 1428Institut CurieParisFrance
- Paris UniversityFrance
| | - Luc Cabel
- Department of Medical OncologyParis and Saint‐Cloud Institut CurieFrance
- Circulating Tumor Biomarkers laboratoryInserm CIC‐BT 1428Institut CurieParisFrance
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Circulating Tumor Cells from Enumeration to Analysis: Current Challenges and Future Opportunities. Cancers (Basel) 2021; 13:cancers13112723. [PMID: 34072844 PMCID: PMC8198976 DOI: 10.3390/cancers13112723] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 05/25/2021] [Indexed: 01/19/2023] Open
Abstract
Simple Summary With estimated numbers of 1–10 per mL of blood, circulating tumor cells (CTCs) are extremely rare compared to white (a few million) or red (billions) blood cells. Given their critical role in metastasis, CTCs have enormous potential as a biomarker for cancer diagnosis, prognosis, and monitoring of treatment response. There are now efforts to characterize CTCs more precisely through molecular and functional analysis, expanding the CTC effort from one of diagnosis and prognosis to now include the use of CTCs to specifically target cancers and discover therapeutic solutions, establishing CTCs as critical in precision medicine. This article summarizes current knowledge about CTC isolation technologies and discusses the translational benefits of different types of downstream analysis approaches, including single-CTC analysis, ex vivo expansion of CTCs, and characterization of CTC-associated cells. Abstract Circulating tumor cells (CTCs) have been recognized as a major contributor to distant metastasis. Their unique role as metastatic seeds renders them a potential marker in the circulation for early cancer diagnosis and prognosis as well as monitoring of therapeutic response. In the past decade, researchers mainly focused on the development of isolation techniques for improving the recovery rate and purity of CTCs. These developed techniques have significantly increased the detection sensitivity and enumeration accuracy of CTCs. Currently, significant efforts have been made toward comprehensive molecular characterization, ex vivo expansion of CTCs, and understanding the interactions between CTCs and their associated cells (e.g., immune cells and stromal cells) in the circulation. In this review, we briefly summarize existing CTC isolation technologies and specifically focus on advances in downstream analysis of CTCs and their potential applications in precision medicine. We also discuss the current challenges and future opportunities in their clinical utilization.
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Heredia-Soto V, Rodríguez-Salas N, Feliu J. Liquid Biopsy in Pancreatic Cancer: Are We Ready to Apply It in the Clinical Practice? Cancers (Basel) 2021; 13:1986. [PMID: 33924143 PMCID: PMC8074327 DOI: 10.3390/cancers13081986] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/14/2021] [Accepted: 04/16/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC.
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Affiliation(s)
- Victoria Heredia-Soto
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
| | - Nuria Rodríguez-Salas
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain
| | - Jaime Feliu
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain
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Xu W, Yang W, Wu C, Ma X, Li H, Zheng J. Enolase 1 Correlated With Cancer Progression and Immune-Infiltrating in Multiple Cancer Types: A Pan-Cancer Analysis. Front Oncol 2021; 10:593706. [PMID: 33643901 PMCID: PMC7902799 DOI: 10.3389/fonc.2020.593706] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 12/22/2020] [Indexed: 12/13/2022] Open
Abstract
Enolase 1 (ENO1) is an oxidative stress protein expressed in endothelial cells. This study aimed to investigate the correlation of ENO1 with prognosis, tumor stage, and levels of tumor-infiltrating immune cells in multiple cancers. ENO1 expression and its influence on tumor stage and clinical prognosis were analyzed by UCSC Xena browser, Gene Expression Profiling Interactive Analysis (GEPIA), The Cancer Genome Atlas (TCGA), and GTEx Portal. The ENO1 mutation analysis was performed by cBio Portal, and demonstrated ENO1 mutation (1.8%) did not impact on tumor prognosis. The relationship between ENO1 expression and tumor immunity was analyzed by Tumor Immune Estimation Resource (TIMER) and GEPIA. The potential functions of ENO1 in pathways were investigated by Gene Set Enrichment Analysis. ENO1 expression was significantly different in tumor and corresponding normal tissues. ENO1 expression in multiple tumor tissues correlated with prognosis and stage. ENO1 showed correlation with immune infiltrates including B cells, CD8+ and CD4+ T cells, macrophages, neutrophils, and dendritic cells, and tumor purity. ENO1 was proved to be involved in DNA replication, cell cycle, apoptosis, glycolysis process, and other processes. These findings indicate that ENO1 is a potential prognostic biomarker that correlates with cancer progression immune infiltration.
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Affiliation(s)
- Wenhua Xu
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Wenna Yang
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Chunfeng Wu
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Xiaocong Ma
- Graduate School, Guangxi University of Chinese Medicine, Nanning City, China
| | - Haoyu Li
- Department of Ophthalmology, Jingliang Eye Hospital Affiliated to Guangxi Medical University, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Jinghui Zheng
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
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Preoperative CTC-Detection by CellSearch ® Is Associated with Early Distant Metastasis and Impaired Survival in Resected Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13030485. [PMID: 33513877 PMCID: PMC7865868 DOI: 10.3390/cancers13030485] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/23/2022] Open
Abstract
In patients with presumed pancreatic ductal adenocarcinoma (PDAC), biomarkers that may open for personalised, risk-adapted treatment are lacking. The study analysed the impact of CTCs-presence on the patterns of recurrence and survival in 98 patients resected for PDAC with 5-10 years of follow-up. Preoperative samples were analysed by the CellSearch® system for EpCAM+/DAPI+/CK+/CD45-CTCs. CTCs were detected in 7 of the 98 patients. CTCs predicted a significantly shorter median disease-free survival (DFS) of 3.3 vs. 9.2 months and a median cancer specific survival (CSS)of 6.3 vs. 18.5 months. Relapse status was confirmed by imaging for 87 patients. Of these, 58 patients developed distant metastases (DM) and 29 developed isolated local recurrence (ILR) as the first sign of cancer relapse. All patients with CTCs experienced DM. pN-status and histological grade >2 were other independent risk factors for DM, but only CTCs predicted significantly shorter cancer-specific, disease-free and post-recurrence survival. Preoperative parameters did not affect clinical outcome. We conclude that CTC presence in resected PDAC patients predicted early distant metastasis and impaired survival. Preoperative CTCs alone or in combination with histopathological factors may guide initial treatment decisions in patients with resectable PDAC in the future.
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Park Y, Jun HR, Choi HW, Hwang DW, Lee JH, Song KB, Lee W, Kwon J, Ha SH, Jun E, Kim SC. Circulating tumour cells as an indicator of early and systemic recurrence after surgical resection in pancreatic ductal adenocarcinoma. Sci Rep 2021; 11:1644. [PMID: 33462311 PMCID: PMC7814057 DOI: 10.1038/s41598-020-80383-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
Early recurrence in pancreatic ductal adenocarcinoma (PDAC) is a decisive factor in determining a patient's prognosis. We determined in our current study whether circulating tumour cells (CTCs) exist in the blood of PDAC patients and can be used as a predictor of recurrence patterns (i.e. time and site) after surgical resection. Between December 2017 and November 2018, the mononuclear cell layer was obtained from the peripheral blood of 36 patients diagnosed with PDAC. CTCs were then isolated using the CD-PRIME™ platform and detected via immunostaining. The patient records were analyzed to correlate these data with survival and recurrence patterns. Twelve patients were CTC-positive (33.3%) and showed a significantly frequent rate of systemic recurrence (distant metastases and peritoneal dissemination) (p = 0.025). On multi-variable logistic regression analysis, CTC positivity was an independent risk factor for early recurrence (p = 0.027) and for systemic recurrence (p = 0.033). In summary, the presence or absence of CTC in the blood of the patients with PDAC could help predict the recurrence pattern after surgery. PDAC patients with CTC positivity at tumour diagnosis should therefore undergo a comprehensive strategy for systemic therapy and active monitoring to detect possible early recurrence.
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MESH Headings
- Aged
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Carcinoma, Pancreatic Ductal/blood
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/surgery
- Humans
- Male
- Middle Aged
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/surgery
- Neoplastic Cells, Circulating/pathology
- Prognosis
- Survival Rate
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Affiliation(s)
- Yejong Park
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye Ryeong Jun
- Biomedical Engineering Research Center, Asan Medical Center, Seoul, Republic of Korea
| | - Hwi Wan Choi
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
| | - Dae Wook Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Hoon Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ki Byung Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Woohyung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jaewoo Kwon
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Su Hyeon Ha
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eunsung Jun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea.
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea.
| | - Song Cheol Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Pang TCY, Po JW, Becker TM, Goldstein D, Pirola RC, Wilson JS, Apte MV. Circulating tumour cells in pancreatic cancer: A systematic review and meta-analysis of clinicopathological implications. Pancreatology 2021; 21:103-114. [PMID: 33309014 DOI: 10.1016/j.pan.2020.11.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The detection and quantification of circulating tumour cells (CTCs) in pancreatic cancer (PC) has the potential to provide prognostic information. The aim of this review was to provide an overview of the literature surrounding CTCs in PC. METHODS A systematic literature review on CTCs in PC between 2005-2020 was performed. Data based on peripheral vein samples were used to determine the positivity rate of CTCs, their prognostic significance and their relative numbers compared to portal vein (PV) samples. RESULTS The overall CTC detection rate in forty-four articles was 65% (95%CI: 55-75%). Detection rate for CellSearch was 26% (95%CI: 14-38%), which was lower than for both filtration and microfluidic techniques. In nine studies with >50 patients, overall survival was worse with CTC positivity (HR 1.82; 95%CI: 1.61-2.05). Five of seven studies which described PV CTC collection provided patient-level data. PV CTC yield was 7.7-fold (95%CI 1.35-43.9) that of peripheral blood. CONCLUSIONS CTCs were detected in the peripheral circulation of most patients with PC and may be related to prognosis and disease stage. PV blood contains more CTCs than peripheral blood sampling. This review points to the maturation of techniques of CTC enrichment, and its evidence base for eventual clinical deployment.
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Affiliation(s)
- Tony C Y Pang
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia; Surgical Innovations Unit, Westmead Hospital, Westmead, Australia; Westmead Clinical School, University of Sydney, Westmead, Australia
| | - Joseph W Po
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, South Western Clinical School, University of New South Wales, School of Medicine, Western Sydney University, Australia; Surgical Innovations Unit, Westmead Hospital, Westmead, Australia; Westmead Clinical School, University of Sydney, Westmead, Australia
| | - Therese M Becker
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, South Western Clinical School, University of New South Wales, School of Medicine, Western Sydney University, Australia
| | - David Goldstein
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Romano C Pirola
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Minoti V Apte
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia.
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Pan Y, Li D, Yang J, Wang N, Xiao E, Tao L, Ding X, Sun P, Li D. Portal Venous Circulating Tumor Cells Undergoing Epithelial-Mesenchymal Transition Exhibit Distinct Clinical Significance in Pancreatic Ductal Adenocarcinoma. Front Oncol 2021; 11:757307. [PMID: 34778073 PMCID: PMC8582019 DOI: 10.3389/fonc.2021.757307] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/05/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Much importance is attached to the clinical application value of circulating tumor cells (CTCs), meanwhile tumor-proximal CTCs detection has interested researchers for its unique advantage. This research mainly discusses the correlation of portal venous (PoV) CTCs counts in different epithelial-mesenchymal transition status with clinicopathologic parameters and postoperative prognosis in resectable pancreatic ductal adenocarcinoma patients (PDAC). METHODS PDAC patients (n=60) who received radical resection were enrolled in this research. PoV samples from all patients and peripheral venous (PV) samples from 32 patients among them were collected to verify spatial heterogeneity of CTCs distribution, and explore their correlation with clinicopathologic parameters and clinical prognosis. RESULTS CTCs detectable rate and each phenotype count of PoV were higher than those of PV. Patients with recurrence had higher PV and PoV epithelial CTCs (E-CTCs) counts than recurrence-free patients (P<0.05). Some unfavourable clinicopathologic parameters were closely related to higher PoV CTCs counts. Multivariate regression analysis demonstrated that PoV mesenchymal CTC (M-CTC)s≥1/5 ml was an independent risk factor for metastasis free survival (MFS) (P=0.003) and overall survival (OS) (P=0.043). CONCLUSIONS Our research demonstrated that portal venous was a preferable vessel for CTC test, and patients with PoV M-CTC≥1/5 ml had shorter MFS and OS time in resectable PDAC patients. PoV CTC phenotype detection has the potential to be a reliable and accurate tool to identify resectable PDAC patients with high tendency of postoperative metastasis for better stratified management.
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Affiliation(s)
- Yujin Pan
- Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Minimally Invasive Treatment for Liver Cancer, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Hepatobiliary and Pancreatic Diseases, Henan Provincial People's Hospital, Zhengzhou, China
| | - Deyu Li
- Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Minimally Invasive Treatment for Liver Cancer, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Hepatobiliary and Pancreatic Diseases, Henan Provincial People's Hospital, Zhengzhou, China
| | - Jiuhui Yang
- Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Minimally Invasive Treatment for Liver Cancer, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Hepatobiliary and Pancreatic Diseases, Henan Provincial People's Hospital, Zhengzhou, China
| | - Ning Wang
- Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Minimally Invasive Treatment for Liver Cancer, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Hepatobiliary and Pancreatic Diseases, Henan Provincial People's Hospital, Zhengzhou, China
| | - Erwei Xiao
- Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Minimally Invasive Treatment for Liver Cancer, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Hepatobiliary and Pancreatic Diseases, Henan Provincial People's Hospital, Zhengzhou, China
| | - Lianyuan Tao
- Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Minimally Invasive Treatment for Liver Cancer, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Hepatobiliary and Pancreatic Diseases, Henan Provincial People's Hospital, Zhengzhou, China
| | - Xiangming Ding
- Zhengzhou Key Laboratory of Minimally Invasive Treatment for Liver Cancer, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Hepatobiliary and Pancreatic Diseases, Henan Provincial People's Hospital, Zhengzhou, China
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Peichun Sun
- Zhengzhou Key Laboratory of Minimally Invasive Treatment for Liver Cancer, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Hepatobiliary and Pancreatic Diseases, Henan Provincial People's Hospital, Zhengzhou, China
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital Zhengzhou, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Dongxiao Li
- Zhengzhou Key Laboratory of Minimally Invasive Treatment for Liver Cancer, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Hepatobiliary and Pancreatic Diseases, Henan Provincial People's Hospital, Zhengzhou, China
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
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GAS2L1 Is a Potential Biomarker of Circulating Tumor Cells in Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12123774. [PMID: 33333841 PMCID: PMC7765300 DOI: 10.3390/cancers12123774] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/10/2020] [Accepted: 12/13/2020] [Indexed: 12/25/2022] Open
Abstract
Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions. CLIC4 and GAS2L1 were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of GAS2L1 in pancreatic CTCs. A combinatorial approach using both GAS2L1 and EPCAM expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples. GAS2L1 is thus proposed as a novel biomarker of pancreatic cancer CTCs.
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40
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Chapman CG, Ayoub F, Swei E, Llano EM, Li B, Siddiqui UD, Waxman I. Endoscopic ultrasound acquired portal venous circulating tumor cells predict progression free survival and overall survival in patients with pancreaticobiliary cancers. Pancreatology 2020; 20:1747-1754. [PMID: 33082106 DOI: 10.1016/j.pan.2020.10.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/26/2020] [Accepted: 10/08/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Despite recent advances, patients with pancreaticobiliary cancers have a poor prognosis. We previously demonstrated the efficacy of endoscopic ultrasound (EUS) guided acquisition of portal vein (PV) blood for enumeration of circulating tumor cells (CTCs). The aim of this study was to assess PV-CTCs as potential biomarkers for the assessment of progression-free (PFS) and overall survival (OS) in patients with pancreaticobiliary cancers. METHODS 17 patients with biopsy-proven pancreaticobiliary malignancy were enrolled. CTCs were enumerated from both peripheral and PV blood. All patients were followed until death. PFS and OS were evaluated with the log-rank test and summarized with the use of Kaplan-Meier methods. Unadjusted and adjusted Cox-proportional hazards models were fitted to study the relationship between PV-CTCs and PFS and OS. RESULTS After 3.5 years of follow-up, all patients had expired. PV-CTCs were detected in all patients (median PV-CTCs 62.0/7.5 mL (interquartile range [IQR] 17-132). The mean PFS in patients with PV-CTCs <185/7.5 mL was significantly longer than patients with PV-CTCs ≥185/7.5 mL (43.3 weeks vs. 12.8 weeks, log-rank p = 0.002). The mean OS in patients with PV-CTCs <185/7.5 mL was significantly longer than patients with PV-CTCs ≥185/7.5 mL (75.8 weeks vs. 29.5 weeks, log-rank p = 0.021). In an adjusted Cox-proportional hazards model, PV-CTCs were significant predictors of both PFS and OS (HR 1.004, p = 0.037; HR 1.004, p = 0.044 respectively). CONCLUSION In this pilot and feasibility study, EUS-acquired PV-CTCs predicted PFS and OS. Our findings suggest that PV-CTCs can help provide important prognostic data for both providers and patients.
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Affiliation(s)
- Christopher G Chapman
- Center for Endoscopic Research and Therapeutics (CERT), The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Fares Ayoub
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Eric Swei
- Section of General Internal Medicine, Department of Medicine, The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Ernesto M Llano
- Section of General Internal Medicine, Department of Medicine, The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Betty Li
- Section of General Internal Medicine, Department of Medicine, The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Uzma D Siddiqui
- Center for Endoscopic Research and Therapeutics (CERT), The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Irving Waxman
- Center for Endoscopic Research and Therapeutics (CERT), The University of Chicago Medicine, Chicago, IL, 60637, USA.
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Okabe T, Togo S, Fujimoto Y, Watanabe J, Sumiyoshi I, Orimo A, Takahashi K. Mesenchymal Characteristics and Predictive Biomarkers on Circulating Tumor Cells for Therapeutic Strategy. Cancers (Basel) 2020; 12:E3588. [PMID: 33266262 PMCID: PMC7761066 DOI: 10.3390/cancers12123588] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/22/2022] Open
Abstract
Metastasis-related events are the primary cause of cancer-related deaths, and circulating tumor cells (CTCs) have a pivotal role in metastatic relapse. CTCs include a variety of subtypes with different functional characteristics. Interestingly, the epithelial-mesenchymal transition (EMT) markers expressed in CTCs are strongly associated with poor clinical outcome and related to the acquisition of circulating tumor stem cell (CTSC) features. Recent studies have revealed the existence of CTC clusters, also called circulating tumor microemboli (CTM), which have a high metastatic potential. In this review, we present current opinions regarding the clinical significance of CTCs and CTM with a mesenchymal phenotype as clinical surrogate markers, and we summarize the therapeutic strategy according to phenotype characterization of CTCs in various types of cancers for future precision medicine.
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Affiliation(s)
- Takahiro Okabe
- Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Shinsaku Togo
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Yuichi Fujimoto
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Junko Watanabe
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Issei Sumiyoshi
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Akira Orimo
- Departments of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Kazuhisa Takahashi
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
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Frappart PO, Hofmann TG. Pancreatic Ductal Adenocarcinoma (PDAC) Organoids: The Shining Light at the End of the Tunnel for Drug Response Prediction and Personalized Medicine. Cancers (Basel) 2020; 12:E2750. [PMID: 32987786 PMCID: PMC7598647 DOI: 10.3390/cancers12102750] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents 90% of pancreatic malignancies. In contrast to many other tumor entities, the prognosis of PDAC has not significantly improved during the past thirty years. Patients are often diagnosed too late, leading to an overall five-year survival rate below 10%. More dramatically, PDAC cases are on the rise and it is expected to become the second leading cause of death by cancer in western countries by 2030. Currently, the use of gemcitabine/nab-paclitaxel or FOLFIRINOX remains the standard chemotherapy treatment but still with limited efficiency. There is an urgent need for the development of early diagnostic and therapeutic tools. To this point, in the past 5 years, organoid technology has emerged as a revolution in the field of PDAC personalized medicine. Here, we are reviewing and discussing the current technical and scientific knowledge on PDAC organoids, their future perspectives, and how they can represent a game change in the fight against PDAC by improving both diagnosis and treatment options.
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Affiliation(s)
- Pierre-Olivier Frappart
- Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
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Exploration of Circulating Tumour Cell (CTC) Biology: A Paradigm Shift in Liquid Biopsy. Indian J Clin Biochem 2020; 36:131-142. [PMID: 33867703 PMCID: PMC7994460 DOI: 10.1007/s12291-020-00923-4] [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: 06/15/2020] [Accepted: 09/01/2020] [Indexed: 01/07/2023]
Abstract
Circulating tumour cells (CTCs), are disseminated tumour cells found in the blood in solid tumour malignancies. Identification of CTCs act as emerging tools in the field of the Liquid Biopsy. Majority of the studies focused on detection and enumeration of CTCs due to technological challenges those results from the rarity of CTCs in the blood. Enumeration of CTCs has already proven their value as prognostic as well as predictive biomarkers for disease prognosis. However, recent advances in technology permitted to study the molecular and functional features of CTCs and these features have the potential to change the diagnostic, prognostic and predictive landscape in oncology. In this review, we summarize the paradigm shift in the field of liquid biopsy-based cancer diagnostics using CTC isolation and detection. We have discussed recent advances in the technologies for molecular characterization of CTCs which have aided a shift from CTC enumeration to an in-depth analysis of the CTC genome, transcriptomes, proteins, epigenomes along with various functional features. Finally, as a prognosticating strategy, the potentials of CTCs as a tool of liquid biopsy to predict micrometastasis, monitor prognosis and how to use them as an additional tool for cancer staging has been discussed.
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Lozar T, Jesenko T, Kloboves Prevodnik V, Cemazar M, Hosta V, Jericevic A, Nolde N, Grasic Kuhar C. Preclinical and Clinical Evaluation of Magnetic-Activated Cell Separation Technology for CTC Isolation in Breast Cancer. Front Oncol 2020; 10:554554. [PMID: 33042837 PMCID: PMC7522616 DOI: 10.3389/fonc.2020.554554] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 08/25/2020] [Indexed: 01/06/2023] Open
Abstract
Circulating tumor cell (CTC) count is an independent prognostic factor in early breast cancer. CTCs can be found in the blood of 20% of patients prior to neoadjuvant therapy. We aimed to assess the suitability of magnetic-activated cell separation (MACS) technology for isolation and cytological characterization of CTCs. In the preclinical part of the study, cell lines were spiked into buffy coat samples derived from healthy donors, and isolated using MACS. Breast cancer cells with preserved cell morphology were successfully isolated. In the clinical part, blood for CTC isolation was drawn from 44 patients with early and locally advanced breast cancer prior to neoadjuvant chemotherapy. Standard Giemsa, Papanicolaou and pancytokeratin staining was applied. 2.3% of samples contained cells that meet both the morphological and immunocytochemical criteria for CTC. In 32.6% of samples, partially degenerated pancytokeratin negative cells with morphological features of tumor cells were observed. In 65.1% of samples, CTCs were not found. In conclusion, our results demonstrate that morphologically intact tumor cells can be isolated using MACS technology. However, morphologically intact tumor cells were not detected in the clinical part of the study. At present, MACS technology does not appear suitable for use in a clinical cytopathology laboratory.
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Affiliation(s)
- Taja Lozar
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tanja Jesenko
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.,Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Veronika Kloboves Prevodnik
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.,Department of Cytopathology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Maja Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.,Faculty of Health Sciences, University of Primorska, Izola, Slovenia
| | - Violeta Hosta
- Department of Dermatovenereology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Anja Jericevic
- Department of Cytopathology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Natasa Nolde
- Department of Cytopathology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Cvetka Grasic Kuhar
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.,Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
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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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Hasanain A, Blanco BA, Yu J, Wolfgang CL. The importance of circulating and disseminated tumor cells in pancreatic cancer. Surg Open Sci 2020; 1:49-55. [PMID: 32754693 PMCID: PMC7391911 DOI: 10.1016/j.sopen.2019.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/24/2019] [Accepted: 08/30/2019] [Indexed: 12/26/2022] Open
Abstract
Pancreatic cancer is a lethal disease in a large part due to the systemic nature at the time of diagnosis. In those patients who undergo a potentially curative resection of pancreatic cancer, the overwhelming majority will have systemic relapse. Circulating tumor cells are an important mediator of the development of metastases. Circulating tumor cells have been identified in patients with clinically localized resectable pancreatic cancer and exist as several phenotypes. Mesenchymal and stem cell-like phenotypes of circulating tumor cells predict early recurrence and worse survival. This review focuses on the current understanding of circulating tumor cells in pancreatic cancer and how this information can be used in developing more effective therapy in the future.
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Affiliation(s)
- Alina Hasanain
- Department of Surgery, Division of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21287.,The Johns Hopkins Pancreatic Cancer Precision Medicine Program
| | | | - Jun Yu
- Department of Surgery, Division of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21287.,The Johns Hopkins Pancreatic Cancer Precision Medicine Program
| | - Christopher L Wolfgang
- Department of Surgery, Division of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21287.,The Johns Hopkins Pancreatic Cancer Precision Medicine Program
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Ge L, Song Y, Yang F, Zhao G, Lu M, Zhang S, Ma L. Clinical significance of circulating tumor cells detection in renal cell carcinoma with thrombus: A STROBE-compliant study. Medicine (Baltimore) 2020; 99:e20615. [PMID: 32481476 DOI: 10.1097/md.0000000000020615] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The aim of the study was to evaluate the potential role of circulating tumor cell (CTC) detection in the surgical assessment of renal cell carcinoma (RCC) patients with thrombi.Nine patients diagnosed with renal mass and thrombi were enrolled from June 2018 to January 2019. Blood samples were collected for CTC detection using SE-iFISH assay. CD45, DAPI, programmed death ligand 1, and fluorescence in situ hybridization with the centromere of chromosome 8 (CEP8) were immune-stained for analysis. Patient demographics, clinical features, pathological characteristics, and CTC detection results were extracted for analysis.Seven of 9 patients (77.8%) had 12 detectable CTCs, 5 of which were with CEP8-positive signal ≥5 and the others were CEP8-positive signal = 3. All 3 patients (100%) with IVC invasion had detectable CTCs, whereas CTCs were detected in 4 of 6 patients (66.7%) without IVC invasion. CEP8 analysis revealed that CTCs in IVC invasion patients were all of CEP8-positive signal ≥5 status, whereas only half of the CTCs in patients without IVC invasion were of CEP8-positive signal ≥5 pattern.In conclusion, both CTC subtype and total CTC number may serve as a marker for predicting inferior vena cava invasion in RCC patients.
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Affiliation(s)
| | | | | | | | - Min Lu
- Department of Pathology, Peking University Third Hospital, Beijing, PR China
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Hugenschmidt H, Labori KJ, Brunborg C, Verbeke CS, Seeberg LT, Schirmer CB, Renolen A, Borgen EF, Naume B, Wiedswang G. Circulating Tumor Cells are an Independent Predictor of Shorter Survival in Patients Undergoing Resection for Pancreatic and Periampullary Adenocarcinoma. Ann Surg 2020; 271:549-558. [PMID: 30216219 DOI: 10.1097/sla.0000000000003035] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE We evaluated the prognostic impact of circulating tumor cells (CTCs) for patients with presumed resectable pancreatic and periampullary cancers. SUMMARY OF BACKGROUND DATA Initial treatment decisions for this group are currently taken without a reliable prognostic marker. The CellSearch system allows standardized CTC-testing and has shown excellent specificity and prognostic value in other applications. METHODS Preoperative blood samples from 242 patients between September 2009 and December 2014 were analyzed. One hundred seventy-nine patients underwent tumor resection, of whom 30 with stage-I tumors and duodenal cancer were assigned to the low-risk group, and the others to the high-risk group. Further 33 had advanced disease, 30 benign histology. Observation ended in December 2016. Cancer-specific survival (CSS) and disease-free survival (DFS) were calculated by log-rank and Cox regression. RESULTS CTCs (CTC-positive; ≥1 CTC/7.5 mL) were detected in 6.8% (10/147) of the high-risk patients and 6.2% (2/33) with advanced disease. No CTCs (CTC-negative) were detected in the low-risk patients or benign disease. In high-risk patients, median CSS for CTC-positive versus CTC-negative was 8.1 versus 20.0 months (P < 0.0001), and DFS 4.0 versus 10.5 months (P < 0.001). Median CSS in advanced disease was 7.7 months. Univariate hazard ratio (HR) of CTC-positivity was 3.4 (P < 0.001). In multivariable analysis, CTC-status remained independent (HR: 2.4, P = 0.009) when corrected for histological type (HR: 2.7, P = 0.030), nodal status (HR: 1.7, P = 0.016), and vascular infiltration (HR: 1.7, P = 0.001). CONCLUSION Patients testing CTC-positive preoperatively showed a detrimental outcome despite successful tumor resections. Although the low CTC-rate seems a limiting factor, results indicate high specificity. Thus, preoperative analysis of CTCs by this test may guide treatment decisions and warrants further testing in clinical trials.
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Affiliation(s)
- Harald Hugenschmidt
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Transplantation Surgery, Division of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Department of GI-Surgery, Division of Surgery and Oncology, Oslo University Hospital, Oslo, Norway
| | - Knut Jørgen Labori
- Department of GI-Surgery, Division of Surgery and Oncology, Oslo University Hospital, Oslo, Norway
| | - Cathrine Brunborg
- Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway
| | - Caroline Sophie Verbeke
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Lars Thomas Seeberg
- Department of GI-Surgery, Division of Surgery and Oncology, Oslo University Hospital, Oslo, Norway.,Department of Gastrointestinal Surgery, Vestfold Hospital Trust, Tønsberg, Norway
| | | | - Anne Renolen
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | | | - Bjørn Naume
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Gro Wiedswang
- Department of GI-Surgery, Division of Surgery and Oncology, Oslo University Hospital, Oslo, Norway
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Wang Y, Yu X, Hartmann D, Zhou J. Circulating tumor cells in peripheral blood of pancreatic cancer patients and their prognostic role: a systematic review and meta-analysis. HPB (Oxford) 2020; 22:660-669. [PMID: 31786054 DOI: 10.1016/j.hpb.2019.11.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/28/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND It has been shown that circulating tumor cells in peripheral blood can be used to predict survival in patients with breast, prostate and other epithelial tumors. In the present study, we performed a meta-analysis to evaluate the prognostic role of circulating tumor cells (CTCs) in patients with pancreatic cancer. METHODS A systematic literature search of the databases was conducted from the inception to Jul 20, 2019. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated under a fixed or random effect model. RESULTS A total of 19 studies with 1320 confirmed individuals were included. Our meta-analysis showed that patients in the CTC-positive group had a significantly shorter overall survival (OS) (RR = 0.47, 95%CI = 0.33-0.61, P < 0.001) and progression-free survival (PFS) (P = 0.003) than CTC-negative patients. Moreover, subgroup analysis by ethnicity indicated that CTC-positive patients had a significantly shorter OS in both Asian and Western populations. Further subgroup analysis by detection methods, treatments, and Tumor Node Metastasis (TNM) stages also indicated that CTC-positive patients were associated with significant decreases in both OS and PFS in most subgroups. CONCLUSION Our meta-analysis indicates that CTC-positive patients have a worse OS and PFS than CTC-negative patients, which suggests that CTCs may act as predictive biomarkers for pancreatic cancer patients before treatment.
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Affiliation(s)
- Yang Wang
- Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Nanjing, 210009, China; Department of Hepatobiliary Surgery Research Institute, Southeast University, Nanjing, 210009, China
| | - Xiaojin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Daniel Hartmann
- Department of Surgery, Klinikum rechts der Isar der Technischen Universitat Munchen, Munchen, 81675, Germany
| | - Jiahua Zhou
- Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Nanjing, 210009, China; Department of Hepatobiliary Surgery Research Institute, Southeast University, Nanjing, 210009, China.
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