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      Circulating biomarkers in patients with glioblastoma

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          Abstract

          Gliomas are the most common tumours of the central nervous system and the most aggressive form is glioblastoma (GBM). Despite advances in treatment, patient survival remains low. GBM diagnosis typically relies on imaging techniques and postoperative pathological diagnosis; however, both procedures have their inherent limitations. Imaging modalities cannot differentiate tumour progression from treatment-related changes that mimic progression, known as pseudoprogression, which might lead to misinterpretation of therapy response and delay clinical interventions. In addition to imaging limitations, tissue biopsies are invasive and most of the time cannot be performed over the course of treatment to evaluate ‘real-time’ tumour dynamics. In an attempt to address these limitations, liquid biopsies have been proposed in the field. Blood sampling is a minimally invasive procedure for a patient to endure and could provide tumoural information to guide therapy. Tumours shed tumoural content, such as circulating tumour cells, cell-free nucleic acids, proteins and extracellular vesicles, into the circulation, and these biomarkers are reported to cross the blood–brain barrier. The use of liquid biopsies is emerging in the field of GBM. In this review, we aim to summarise the current literature on circulating biomarkers, namely circulating tumour cells, circulating tumour DNA and extracellular vesicles as potential non-invasively sampled biomarkers to manage the treatment of patients with GBM.

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          Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.

          Previously undescribed prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit markers either of proliferation or of angiogenesis and mesenchyme. Upon recurrence, tumors frequently shift toward the mesenchymal subclass. Chromosomal locations of genes distinguishing tumor subclass parallel DNA copy number differences between subclasses. Functional relevance of tumor subtype molecular signatures is suggested by the ability of cell line signatures to predict neurosphere growth. A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.
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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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              Current state of immunotherapy for glioblastoma

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                Author and article information

                Contributors
                +61 7 3138 0830 , chamindie.punyadeera@qut.edu.au
                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group UK (London )
                0007-0920
                1532-1827
                31 October 2019
                31 October 2019
                4 February 2020
                : 122
                : 3
                : 295-305
                Affiliations
                [1 ]ISNI 0000000089150953, GRID grid.1024.7, Saliva and Liquid Biopsy Translational Research Team, The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, , Queensland University of Technology, ; Kelvin Grove, QLD 4059 Australia
                [2 ]ISNI 0000000406180938, GRID grid.489335.0, Translational Research Institute, ; Woolloongabba, QLD 4102 Australia
                [3 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Faculty of Medicine, , University of Queensland, ; 288 Herston Road, Herston, QLD 4006 Australia
                [4 ]ISNI 0000 0001 0688 4634, GRID grid.416100.2, Cancer Care Services, , Royal Brisbane and Women’s Hospital, ; Herston, QLD 4029 Australia
                [5 ]ISNI 0000000089150953, GRID grid.1024.7, School of Biomedical Sciences, Faculty of Health, , Queensland University of Technology, ; Gardens Point, QLD 4000 Australia
                [6 ]ISNI 0000 0001 2294 1395, GRID grid.1049.c, Cell and Molecular Biology Department, Sid Faithfull Brain Cancer Laboratory, , QIMR Berghofer MRI, ; Brisbane, QLD 4006 Australia
                Article
                603
                10.1038/s41416-019-0603-6
                7000822
                31666668
                7ad82967-b40c-4bc6-a846-c5d889ece062
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 22 May 2019
                : 23 August 2019
                : 23 September 2019
                Funding
                Funded by: ATM LATAM QUT Post Graduate Research Scholarship
                Funded by: FundRef https://doi.org/10.13039/501100000925, Department of Health | National Health and Medical Research Council (NHMRC);
                Award ID: APP1157741
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001111, Cancer Australia;
                Award ID: APP1145657
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © Cancer Research UK 2020

                Oncology & Radiotherapy
                cns cancer,tumour biomarkers
                Oncology & Radiotherapy
                cns cancer, tumour biomarkers

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