Ying Meng1,2, Christopher B Pople1, Suganth Suppiah2, Maheleth Llinas1, Yuexi Huang1, Arjun Sahgal1,3,4, James Perry1,3,5, Julia Keith1,6, Benjamin Davidson1,2, Clement Hamani1,2, Yutaka Amemiya1, Arun Seth1,6, Hon Leong1,7, Chinthaka C Heyn1,8, Isabelle Aubert1,6, Kullervo Hynynen1,7, Nir Lipsman1,2. 1. Sunnybrook Research Institute, Toronto, Ontario, Canada. 2. Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada. 3. Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. 4. Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. 5. Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 6. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 7. Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. 8. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND: Liquid biopsy is promising for early detection, monitoring of response and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy. METHODS: Nine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma (NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening alone (NCT03739905). RESULTS: Brain regions averaging 7.8±6.0 cm 3 (range 0.8-23.1 cm 3) were successful treated within 111±39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6±1.2 fold, p<0.01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2±1.9 fold, p<0.01), and brain specific protein S100b (1.4±0.2 fold, p<0.01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease and post-BBB opening specific, in keeping with our hypothesis. We also found cfDNA mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbour the tumor mutation. CONCLUSIONS: This first-in-human proof-of concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.
BACKGROUND: Liquid biopsy is promising for early detection, monitoring of response and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy. METHODS: Nine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma (NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumorpatients undergoing BBB opening alone (NCT03739905). RESULTS: Brain regions averaging 7.8±6.0 cm 3 (range 0.8-23.1 cm 3) were successful treated within 111±39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6±1.2 fold, p<0.01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2±1.9 fold, p<0.01), and brain specific protein S100b (1.4±0.2 fold, p<0.01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease and post-BBB opening specific, in keeping with our hypothesis. We also found cfDNA mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbour the tumor mutation. CONCLUSIONS: This first-in-human proof-of concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.
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