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      Sonobiopsy for minimally invasive, spatiotemporally-controlled, and sensitive detection of glioblastoma-derived circulating tumor DNA

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          Abstract

          Though surgical biopsies provide direct access to tissue for genomic characterization of brain cancer, they are invasive and pose significant clinical risks. Brain cancer management via blood-based liquid biopsies is a minimally invasive alternative; however, the blood-brain barrier (BBB) restricts the release of brain tumor-derived molecular biomarkers necessary for sensitive diagnosis.

          Methods: A mouse glioblastoma multiforme (GBM) model was used to demonstrate the capability of focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) to improve the diagnostic sensitivity of brain tumor-specific genetic mutations compared with conventional blood-based liquid biopsy. Furthermore, a pig GBM model was developed to characterize the translational implications of sonobiopsy in humans. Magnetic resonance imaging (MRI)-guided FUS sonication was performed in mice and pigs to locally enhance the BBB permeability of the GBM tumor. Contrast-enhanced T 1-weighted MR images were acquired to evaluate the BBB permeability change. Blood was collected immediately after FUS sonication. Droplet digital PCR was used to quantify the levels of brain tumor-specific genetic mutations in the circulating tumor DNA (ctDNA). Histological staining was performed to evaluate the potential for off-target tissue damage by sonobiopsy.

          Results: Sonobiopsy improved the detection sensitivity of EGFRvIII from 7.14% to 64.71% and TERT C228T from 14.29% to 45.83% in the mouse GBM model. It also improved the diagnostic sensitivity of EGFRvIII from 28.57% to 100% and TERT C228T from 42.86% to 71.43% in the porcine GBM model.

          Conclusion: Sonobiopsy disrupts the BBB at the spatially-targeted brain location, releases tumor-derived DNA into the blood circulation, and enables timely collection of ctDNA. Converging evidence from both mouse and pig GBM models strongly supports the clinical translation of sonobiopsy for the minimally invasive, spatiotemporally-controlled, and sensitive molecular characterization of brain cancer.

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          The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.

          David N Louis, Arie Perry, Guido Reifenberger … (2016)
          The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.
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            Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

            Roger Stupp, Warren P Mason, Martin van den Bent … (2005)
            Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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              QuPath: Open source software for digital pathology image analysis

              Peter Bankhead, Maurice B Loughrey, Jose A Gegundez Fernandez … (2017)
              QuPath is new bioimage analysis software designed to meet the growing need for a user-friendly, extensible, open-source solution for digital pathology and whole slide image analysis. In addition to offering a comprehensive panel of tumor identification and high-throughput biomarker evaluation tools, QuPath provides researchers with powerful batch-processing and scripting functionality, and an extensible platform with which to develop and share new algorithms to analyze complex tissue images. Furthermore, QuPath’s flexible design makes it suitable for a wide range of additional image analysis applications across biomedical research.
              Article 0 comments Cited 1927 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Theranostics
                Journal ID (iso-abbrev): Theranostics
                Journal ID (publisher-id): thno
                Title: Theranostics
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1838-7640
                Publication date Collection: 2022
                Publication date (Electronic): 1 January 2022
                Volume: 12
                Issue: 1
                Pages: 362-378
                Affiliations
                [1 ]Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA.
                [2 ]Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
                [3 ]Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, 63110, USA.
                [4 ]Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, 63110, USA.
                [5 ]Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, USA.
                [6 ]Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
                [7 ]University of Illinois Cancer Center, Chicago, IL, 60612, USA.
                [8 ]Division of Comparative Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
                [9 ]Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
                [10 ]Department of Computer Science and Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA.
                [11 ]Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.
                [12 ]Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
                [13 ]Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
                Author notes
                ✉ Corresponding author: Hong Chen, Ph.D. Department of Biomedical Engineering and Radiation Oncology, Washington University in St. Louis. 4511 Forest Park Ave. St. Louis, MO, 63108, USA. Email: hongchen@ 123456wustl.edu

                # These two authors contributed equally to this study.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                Publisher ID: thnov12p0362
                DOI: 10.7150/thno.65597
                PMC ID: 8690937
                PubMed ID: 34987650
                SO-VID: 95957abc-57ce-4703-aca3-292ce8b5f6c5
                Copyright © © The author(s)
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                Date received : 1 August 2021
                Date accepted : 6 October 2021
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Molecular medicine
                Keywords: image-guided focused ultrasound,blood-brain barrier,blood-based liquid biopsy,glioblastoma mutation,droplet digital pcr
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: image-guided focused ultrasound, blood-brain barrier, blood-based liquid biopsy, glioblastoma mutation, droplet digital pcr

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