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      Technologies for circulating tumor cell separation from whole blood

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          Abstract

          The importance of early cancer diagnosis and improved cancer therapy has been clear for years and has initiated worldwide research towards new possibilities in the care strategy of patients with cancer using technological innovations. One of the key research fields involves the separation and detection of circulating tumor cells (CTC) because of their suggested important role in early cancer diagnosis and prognosis, namely, providing easy access by a liquid biopsy from blood to identify metastatic cells before clinically detectable metastasis occurs and to study the molecular and genetic profile of these metastatic cells. Provided the opportunity to further progress the development of technology for treating cancer, several CTC technologies have been proposed in recent years by various research groups and companies. Despite their potential role in cancer healthcare, CTC methods are currently mainly used for research purposes, and only a few methods have been accepted for clinical application because of the difficulties caused by CTC heterogeneity, CTC separation from the blood, and a lack of thorough clinical validation. Therefore, the standardization and clinical application of various developed CTC technologies remain important subsequent necessary steps. Because of their suggested future clinical benefits, we focus on describing technologies using whole blood samples without any pretreatment and discuss their advantages, use, and significance. Technologies using whole blood samples utilize size-based, immunoaffinity-based, and density-based methods or combinations of these methods as well as positive and negative enrichment during separation. Although current CTC technologies have not been truly implemented yet, they possess high potential as future clinical diagnostic techniques for the individualized therapy of patients with cancer. Thus, a detailed discussion of the clinical suitability of these new advanced technologies could help prepare clinicians for the future and can be a foundation for technologies that would be used to eliminate CTCs in vivo.

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          Most cited references98

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          Tumor metastasis: molecular insights and evolving paradigms.

          Metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and/or epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. Recent advances provide provocative insights into these cell-biological and molecular changes, which have implications regarding the steps of the invasion-metastasis cascade that appear amenable to therapeutic targeting. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases.

            The purpose of this study was to determine the accuracy, precision, and linearity of the CellSearch system and evaluate the number of circulating tumor cells (CTCs) per 7.5 mL of blood in healthy subjects, patients with nonmalignant diseases, and patients with a variety of metastatic carcinomas. The CellSearch system was used to enumerate CTCs in 7.5 mL of blood. Blood samples spiked with cells from tumor cell lines were used to establish analytical accuracy, reproducibility, and linearity. Prevalence of CTCs was determined in blood from 199 patients with nonmalignant diseases, 964 patients with metastatic carcinomas, and 145 healthy donors. Enumeration of spiked tumor cells was linear over the range of 5 to 1,142 cells, with an average recovery of >/=85% at each spike level. Only 1 of the 344 (0.3%) healthy and nonmalignant disease subjects had >/=2 CTCs per 7.5 mL of blood. In 2,183 blood samples from 964 metastatic carcinoma patients, CTCs ranged from 0 to 23,618 CTCs per 7.5 mL (mean, 60 +/- 693 CTCs per 7.5 mL), and 36% (781 of 2,183) of the specimens had >/=2 CTCs. Detection of >/=2 CTCs occurred at the following rates: 57% (107 of 188) of prostate cancers, 37% (489 of 1,316) of breast cancers, 37% (20 of 53) of ovarian cancers, 30% (99 of 333) of colorectal cancers, 20% (34 of 168) of lung cancers, and 26% (32 of 125) of other cancers. The CellSearch system can be standardized across multiple laboratories and may be used to determine the clinical utility of CTCs. CTCs are extremely rare in healthy subjects and patients with nonmalignant diseases but present in various metastatic carcinomas with a wide range of frequencies.
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              Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.

              A method for enumerating circulating tumor cells (CTC) has received regulatory clearance. The primary objective of this prospective study was to establish the relationship between posttreatment CTC count and overall survival (OS) in castration-resistant prostate cancer (CRPC). Secondary objectives included determining the prognostic utility of CTC measurement before initiating therapy, and the relationship of CTC to prostate-specific antigen (PSA) changes and OS at these and other time points. Blood was drawn from CRPC patients with progressive disease starting a new line of chemotherapy before treatment and monthly thereafter. Patients were stratified into predetermined Favorable or Unfavorable groups ( or =5 CTC/7.5mL). Two hundred thirty-one of 276 enrolled patients (84%) were evaluable. Patients with Unfavorable pretreatment CTC (57%) had shorter OS (median OS, 11.5 versus 21.7 months; Cox hazard ratio, 3.3; P 26 to 9.3 months). CTC are the most accurate and independent predictor of OS in CRPC. These data led to Food and Drug Administration clearance of this assay for the evaluation of CRPC.
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                Author and article information

                Contributors
                petrabanko94@gmail.com
                sylee78@jbnu.ac.kr
                nagygyorgy@gmail.com
                mikloszrinyi@gmail.com
                changhoon.chae@med.semmelweis-univ.hu
                obgyn2001@jbnu.ac.kr
                prof.andras.telekes@gmail.com
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                14 May 2019
                14 May 2019
                2019
                : 12
                : 48
                Affiliations
                [1 ]ISNI 0000 0001 2180 0451, GRID grid.6759.d, Department of Biochemical Engineering, , Budapest University of Technology and Economics, ; Budapest, Hungary
                [2 ]ISNI 0000 0004 0647 1516, GRID grid.411551.5, Department of Radiation Oncology, , Chonbuk National University Hospital, ; Jeonju, Republic of Korea
                [3 ]ISNI 0000 0004 0647 1516, GRID grid.411551.5, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical, , Research Institute of Chonbuk National University Hospital, ; Jeonju, Republic of Korea
                [4 ]Celldi Kft, Budapest, Hungary
                [5 ]ISNI 0000 0001 0942 9821, GRID grid.11804.3c, Laboratory of Nanochemistry, Department of Biophysics and Radiation Biology, , Semmelweis University, ; Budapest, Hungary
                [6 ]ISNI 0000 0004 0647 1516, GRID grid.411551.5, Department of Obstetrics and Gynecology, , Chonbuk National University Hospital, ; Jeonju, Republic of Korea
                [7 ]Department of Oncology, St. Lazarus Hospital, Salgótarján, Hungary
                Article
                735
                10.1186/s13045-019-0735-4
                6518774
                31088479
                b65e61c0-6b24-4144-b1c0-41ca5bf193ac
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 January 2019
                : 18 April 2019
                Funding
                Funded by: NNational Research Foundation of Korea
                Award ID: 2017R1A2B4012353
                Award Recipient :
                Funded by: Research Base Construction Fund Support Program” Funded by Chonbuk National University in 2018.
                Award ID: 00000000
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                cancer,ctc,circulating,tumor cell,whole blood,separation
                Oncology & Radiotherapy
                cancer, ctc, circulating, tumor cell, whole blood, separation

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