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      Detection of Circulating Tumor Cells in the Diagnostic Leukapheresis Product of Non-Small-Cell Lung Cancer Patients Comparing CellSearch ® and ISET

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          Abstract

          Circulating tumor cells (CTCs) detected by CellSearch are prognostic in non-small-cell lung cancer (NSCLC), but rarely found. CTCs can be extracted from the blood together with mononuclear cell populations by diagnostic leukapheresis (DLA), therefore concentrating them. However, CellSearch can only process limited DLA volumes (≈2 mL). Therefore, we established a protocol to enumerate CTCs in DLA products with Isolation by SizE of Tumor cells (ISET), and compared CTC counts between CellSearch ® and ISET. DLA was performed in NSCLC patients who started a new therapy. With an adapted protocol, ISET could process 10 mL of DLA. CellSearch detected CTCs in a volume equaling 2 × 10 8 leukocytes (mean 2 mL). CTC counts per mL were compared. Furthermore, the live cell protocol of ISET was tested in eight patients. ISET successfully processed all DLA products—16 with the fixed cell protocol and 8 with the live cell protocol. In total, 10–20 mL of DLA was processed. ISET detected CTCs in 88% (14/16), compared to 69% (11/16, p < 0.05) with CellSearch. ISET also detected higher number of CTCs (ISET median CTC/mL = 4, interquartile range [IQR] = 2–6, CellSearch median CTC/mL = 0.9, IQR = 0–1.8, p < 0.01). Cells positive for the epithelial cell adhesion molecule (EpCAM+) per mL were detected in similar counts by both methods. Eight patients were processed with the live cell protocol. All had EpCAM+, CD45−, CD235- cells isolated by fluorescence-activated cell sorting (FACS). Overall, ISET processed larger volumes and detected higher CTC counts compared to CellSearch. EpCAM+ CTCs were detected in comparable rates.

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          Detection of mutations in EGFR in circulating lung-cancer cells.

          The use of tyrosine kinase inhibitors to target the epidermal growth factor receptor gene (EGFR) in patients with non-small-cell lung cancer is effective but limited by the emergence of drug-resistance mutations. Molecular characterization of circulating tumor cells may provide a strategy for noninvasive serial monitoring of tumor genotypes during treatment. We captured highly purified circulating tumor cells from the blood of patients with non-small-cell lung cancer using a microfluidic device containing microposts coated with antibodies against epithelial cells. We performed EGFR mutational analysis on DNA recovered from circulating tumor cells using allele-specific polymerase-chain-reaction amplification and compared the results with those from concurrently isolated free plasma DNA and from the original tumor-biopsy specimens. We isolated circulating tumor cells from 27 patients with metastatic non-small-cell lung cancer (median number, 74 cells per milliliter). We identified the expected EGFR activating mutation in circulating tumor cells from 11 of 12 patients (92%) and in matched free plasma DNA from 4 of 12 patients (33%) (P=0.009). We detected the T790M mutation, which confers drug resistance, in circulating tumor cells collected from patients with EGFR mutations who had received tyrosine kinase inhibitors. When T790M was detectable in pretreatment tumor-biopsy specimens, the presence of the mutation correlated with reduced progression-free survival (7.7 months vs. 16.5 months, P<0.001). Serial analysis of circulating tumor cells showed that a reduction in the number of captured cells was associated with a radiographic tumor response; an increase in the number of cells was associated with tumor progression, with the emergence of additional EGFR mutations in some cases. Molecular analysis of circulating tumor cells from the blood of patients with lung cancer offers the possibility of monitoring changes in epithelial tumor genotypes during the course of treatment. 2008 Massachusetts Medical Society
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            Prediction of blood volume in normal human adults.

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              Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer.

              Lung cancer is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) lacks validated biomarkers to predict treatment response. This study investigated whether circulating tumor cells (CTCs) are detectable in patients with NSCLC and what their ability might be to provide prognostic information and/or early indication of patient response to conventional therapy. In this single-center prospective study, blood samples for CTC analysis were obtained from 101 patients with previously untreated, stage III or IV NSCLC both before and after administration of one cycle of standard chemotherapy. CTCs were measured using a semiautomated, epithelial cell adhesion molecule-based immunomagnetic technique. The number of CTCs in 7.5 mL of blood was higher in patients with stage IV NSCLC (n = 60; range, 0 to 146) compared with patients with stage IIIB (n = 27; range, 0 to 3) or IIIA disease (n = 14; no CTCs detected). In univariate analysis, progression-free survival was 6.8 v 2.4 months with P < .001, and overall survival (OS) was 8.1 v 4.3 months with P < .001 for patients with fewer than five CTCs compared with five or more CTCs before chemotherapy, respectively. In multivariate analysis, CTC number was the strongest predictor of OS (hazard ratio [HR], 7.92; 95% CI, 2.85 to 22.01; P < .001), and the point estimate of the HR was increased with incorporation of a second CTC sample that was taken after one cycle of chemotherapy (HR, 15.65; 95% CI, 3.63 to 67.53; P < .001). CTCs are detectable in patients with stage IV NSCLC and are a novel prognostic factor for this disease. Further validation is warranted before routine clinical application.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                07 April 2020
                April 2020
                : 12
                : 4
                : 896
                Affiliations
                [1 ]Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; m.tamminga@ 123456umcg.nl (M.T.); t.j.n.hiltermann@ 123456umcg.nl (T.J.N.H.)
                [2 ]Department of Medical Cell BioPhysics, Faculty of Sciences and Technology, University of Twente, 7522 NB Enschede, The Netherlands; k.c.andree@ 123456utwente.nl (K.C.A.); l.w.m.m.terstappen@ 123456utwente.nl (L.W.M.M.T.)
                [3 ]Rarecells Diagnostics, 75 280 Paris CEDEX, France; maximilien.jayat@ 123456rarecells.com
                [4 ]Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; E.schuuring@ 123456umcg.nl (E.S.); w.timens@ 123456umcg.nl (W.T.)
                [5 ]European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands; h.van.den.bos@ 123456umcg.nl (H.v.d.B.); d.c.j.spierings@ 123456umcg.nl (D.C.J.S.); p.m.lansdorp@ 123456umcg.nl (P.M.L.)
                [6 ]Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
                [7 ]Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
                Author notes
                [* ]Correspondence: h.j.m.groen@ 123456umcg.nl ; Tel.: +31-503-616-161; Fax: +31-503-619-230
                Author information
                https://orcid.org/0000-0001-6508-2623
                https://orcid.org/0000-0002-7807-6289
                https://orcid.org/0000-0001-9787-8597
                https://orcid.org/0000-0002-4146-6363
                https://orcid.org/0000-0001-5944-3787
                Article
                cancers-12-00896
                10.3390/cancers12040896
                7226321
                32272669
                cbbf7052-e6af-4812-bc28-a0b0371e9ca5
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 March 2020
                : 03 April 2020
                Categories
                Article

                dla,ctc,nsclc,liquid biopsy,biomarker,iset,cellsearch
                dla, ctc, nsclc, liquid biopsy, biomarker, iset, cellsearch

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