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      Phylogenetic ctDNA analysis depicts early stage lung cancer evolution

      1 , 1 , 2 , 1 , 2 , 1 , 3 , 3 , 4 , 4 , 1 , 1 , 1 , 5 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , 6 , 4 , 4 , 7 , 2 , 2 , 1 , 7 , 8 , 9 , 8 , 9 , 3 , 1 , 1 , 1 , 1 , 2 , 2 , 6 , 6 , 10 , 2 , 11 , 1 , 2 , 12 , 1 , 1 , 12 , 12 , 5 , 5 , 13 , 13 , 13 , 13 , 1 , 14 , 15 , 14 , 16 , 17 , 18 , 18 , 3 , 3 , 3 , 3 , 19 , 20 , 20 , 21 , 22 , 23 , 24 , 24 , 25 , 26 , 27 , 28 , 29 , 4 , 30 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 1 , 1 , 44 , 44 , 45 , 46 , 46 , 46 , 2 , 6 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 53 , 54 , 55 , 56 , 3 , 3 , 8 , 9 , 57 , 46 , 4 , 3 , 1 , 2

      Nature

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          The early detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a tumour-specific phylogenetic approach to ctDNA profiling in the first 100 TRACERx ( TRAcking non-small cell lung Cancer Evolution through therapy ( Rx)) study participants, including one patient co-recruited to the PEACE ( Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies

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          Most cited references 17

          • Record: found
          • Abstract: found
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          Lung cancer proliferation correlates with [F-18]fluorodeoxyglucose uptake by positron emission tomography.

          Tumor proliferation has prognostic value in resected early-stage non-small cell lung cancer (NSCLC). We evaluated whether [F-18]fluorodeoxyglucose (FDG) uptake of NSCLC correlates with tumor proliferation and, thus, could noninvasively grade NSCLCs (refining patient prognosis and therapy). Thirty-nine patients with potentially resectable NSCLC underwent whole-body FDG positron emission tomography (PET) 45 min after i.v. injection of 10 mCi of FDG. Tumor FDG uptake was quantitated with the maximum pixel standardized uptake value (maxSUV). The lesion diameter from computed tomography was used to correct the maxSUV for partial volume effects using recovery coefficients determined for the General Electric Advance PET scanner. Thirty-eight patients underwent complete surgical staging (bronchoscopy and mediastinoscopy, with or without thoracotomy). One stage IV patient by PET underwent bronchoscopic biopsy only. Immunohistochemistry for Ki-67 (proliferation index marker) was performed on all of the 39 NSCLC specimens (35 resections, 1 percutaneous, and 3 surgical biopsies). The specimens were reviewed for cellular differentiation (poor, moderate, well) and tumor type. Lesions ranged from 0.7 to 6.1 cm. The correlation found between uncorrected maxSUV and lesion size (Rho, 0.56; P = 0.0006) disappeared when applying the recovery coefficients (Rho, -0.035; P = 0.83). Ki-67 expression (percentage of positive cells) correlated strongly with FDG uptake (corrected maxSUV: Rho, 0.73; P < 0.0001). The correlation was stronger for stage I lesions (11 stage IA, 15 stage IB): Rho, 0.79; P < 0.0001) and strongest in stage IB (Rho, 0.83; P = 0.0019). A significant association (P < 0.0001) between tumor differentiation and corrected SUV was noted. FDG PET may be used to noninvasively assess NSCLC proliferation in vivo, identifying rapidly growing NSCLCs with poor prognosis that could benefit from preoperative chemotherapy.
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            Does the cell number 10(9) still really fit one gram of tumor tissue?

             U. DEL CARRO (2009)
            A tumor reaching the size of 1 cm(3) (approximately 1 g wet weight) is commonly assumed to contain 1 x 10(9) cells. This paper comments on the probable origin of this "magic" number and on some possible reasons why it has remained in use until now. However, mostly in epithelial tumors (85% of all human tumors) a cell number one order of magnitude smaller would be more realistic.
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              FDG PET measurement of the proliferative potential of non-small cell lung cancer.

               Y Arisaka,  Y. Ueda,  M Oguchi (1999)
              The goals of this study were to correlate FDG uptake with cell proliferation and cellular density in non-small cell lung cancer. Thirty-one patients with 32 non-small cell lung cancers were examined with FDG PET. For semiquantitative analysis, standardized uptake values (SUVs) were calculated. All patients underwent thoracotomy within 4 wk after the FDG PET study. Cell proliferation was immunohistochemically assessed as the relative number of cells expressing the proliferating cell nuclear antigen ([PCNA] labeling index). Cellular density was also evaluated using light microscopy. SUVs correlated significantly with PCNA labeling index (r = 0.740; P < 0.0001) but only weakly with cellular density (r = 0.392; P = 0.0266). High FDG uptake correlated with high PCNA expression. The PCNA labeling index and SUVs were significantly lower in bronchioloalveolar carcinomas (n = 8) (12.3 +/- 9.45% and 1.45 +/- 0.76, respectively) than in nonbronchioloalveolar carcinomas (n = 19) (33.5 +/- 21.8%, P = 0.015, and 3.75 +/- 1.93, P = 0.003, respectively). However, no significant differences in cellular density were seen between bronchioloalveolar carcinomas and nonbronchioloalveolar carcinomas. FDG uptake is related to cell proliferation rather than to the cellular density of non-small cell lung cancer.
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                Author and article information

                Contributors
                On behalf of : on behalf of the TRACERx and PEACE consortia
                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                20 July 2017
                26 April 2017
                14 February 2018
                : 545
                : 7655
                : 446-451
                Affiliations
                [1 ]Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT
                [2 ]Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT
                [3 ]Natera Inc., 201 Industrial Rd., San Carlos, United States, CA 94070
                [4 ]Cancer Studies, University of Leicester, Leicester, United Kingdom, LE2 7LX
                [5 ]Department of Pathology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [6 ]Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT
                [7 ]Department of Nuclear Medicine, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [8 ]Brigham and Women’s Hospital, Boston, MA 02115, USA
                [9 ]Harvard Medical School, Boston, MA 02115, USA
                [10 ]Tumour Profiling Unit Genomics Facility, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB
                [11 ]Renal and Skin Units, The Royal Marsden Hospital, London, SW3 6JJ
                [12 ]Department of Oncology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [13 ]Department of Cardiothoracic Surgery, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [14 ]Department of Respiratory Medicine, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [15 ]Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, Rayne Building. University College London, 5 University Street. London. WC1E 6JF
                [16 ]Department of Radiology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [17 ]Institute of Cancer Studies, University of Manchester, Oxford Road, Manchester, M13 9PL
                [18 ]The Christie Hospital, Manchester, United Kingdom, M20 4BX
                [19 ]Department of Cardiothoracic Surgery, University Hospital South Manchester, Manchester, M23 9LT
                [20 ]Department of Pathology, University Hospital South Manchester, Manchester, M23 9LT
                [21 ]North West Lung Centre, University Hospital South Manchester, Manchester, United Kingdom, M23 9LT
                [22 ]Department of Thoracic Surgery, Birmingham Heartlands Hospital, Birmingham, United Kingdom, B9 5SS
                [23 ]Department of Medical Oncology, Birmingham Heartlands Hospital, Birmingham, United Kingdom, B9 5SS
                [24 ]Department of Cellular Pathology, Birmingham Heartlands Hospital, Birmingham, United Kingdom, B9 5SS
                [25 ]Department of Medical Oncology, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom, AB25 2ZN
                [26 ]Department of Cardiothoracic Surgery, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, United Kingdom, AB25 2ZD
                [27 ]Department of Pathology, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom, AB25 2ZD
                [28 ]Department of Respiratory Medicine, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, United Kingdom, AB25 2ZN
                [29 ]Department of Radiology, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom, AB25 2ZN
                [30 ]Department of Thoracic Surgery, Glenfield Hospital, Leicester, LE3 9QP
                [31 ]Department of Radiotherapy, North Middlesex University Hospital, London N18 1QX
                [32 ]Department of Respiratory Medicine, Royal Free Hospital, Pond Street, London, NW3 2QG
                [33 ]Department of Respiratory Medicine, Barnet and Chase Farm Hospitals, Wellhouse Lane, Barnet, United Kingdom, EN5 3DJ
                [34 ]Department of Respiratory Medicine, The Princess Alexandra Hospital, Hamstel Rd, Harlow CM20 1QX
                [35 ]Department of Clinical Oncology, St.Luke's Cancer Centre, Royal Surrey County Hospital, Guildford, GU2 7XX
                [36 ]Department of Pathology, Ashford and St. Peters' Hospital, Guildford Road, Chertsey, Surrey, KT16 0PZ
                [37 ]Department of Respiratory Medicine, Ashford and St. Peters' Hospital, Guildford Road, Chertsey, Surrey, KT16 0PZ
                [38 ]Department of Radiology, Ashford and St. Peters' Hospital, Guildford Road, Chertsey, Surrey, KT16 0PZ
                [39 ]Department of Clinical Oncology, Velindre Hospital, Cardiff, Wales, United Kingdom, CF14 2TL
                [40 ]Department of Cardiothoracic Surgery, University Hospital Llandough, Cardiff, Wales, United Kingdom, CF64 2XX
                [41 ]Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Heath Park Cardiff, Wales U.K
                [42 ]Department of Radiology, University Hospital Llandough, Cardiff, Wales, United Kingdom, CF64 2XX
                [43 ]Department of Respiratory Medicine, University Hospital Llandough, Cardiff, Wales, United Kingdom, CF64 2XX
                [44 ]UCL ECMC GCLP Facility, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT
                [45 ]Department of Respiratory Medicine, The Whittington Hospital NHS Trust, United Kingdom, N19 5NF
                [46 ]University College London, Cancer Research UK & UCL Cancer Trials Centre, London, United Kingdom, W1T 4TJ
                [47 ]Centre for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark
                [48 ]Computational Health Informatics Program (CHIP), Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
                [49 ]MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary
                [50 ]Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
                [51 ]Bill Lyons Informatics Centre, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT
                [52 ]Department of Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT
                [53 ]Cancer Immunology Unit, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT
                [54 ]Cancer Genomics Laboratory, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT
                [55 ]Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium
                [56 ]Cancer Research UK Manchester Institute, Manchester, United Kingdom, M20 4BX
                [57 ]Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, United States, MA 02215-5450
                Author notes
                Correspondence should be addressed to C.S. Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 3rd Floor South West, 1 Midland Road, London, NW1 1A, Charles.Swanton@ 123456crick.ac.uk , Office +44 203 796 2047
                [*]

                These authors contributed equally to this work

                [+]

                These authors contributed equally to this work

                Article
                EMS72313
                10.1038/nature22364
                5812436
                28445469

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