Title : Focused ultrasound-mediated liquid biopsy (Sono biopsy) in high-grade gliomas: A systematic review
Abstract:
Background: The blood-brain barrier (BBB) severely restricts the release of brain-derived biomarkers into the peripheral circulation, limiting the utility of liquid biopsy in neuro-oncology. Focused ultrasound (FUS) combined with intravenously administered microbubbles can transiently and safely open the BBB. This systematic review evaluates the safety, feasibility, and quantitative yield of "sonobiopsy"—the use of FUS to enrich circulating biomarkers—in patients with high-grade gliomas (HGGs).
Methods: PubMed, Embase, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched according to PRISMA guidelines to identify studies evaluating FUS-mediated liquid biopsy in human patients with brain tumors. Data regarding study design, patient demographics, FUS modalities and parameters, targeted analytes, quantitative biomarker yield, and clinical safety were systematically extracted and synthesized.
Results: Four prospective clinical trials encompassing 54 enrolled patients with HGGs (predominantly glioblastoma) were included in this review. The interventions utilized either MR-guided FUS at 220 kHz or frameless neuronavigation-guided FUS at 500–650 kHz. Sonobiopsy successfully and consistently enriched multiple plasma biomarkers across all studies. Total cell-free DNA (cfDNA) and mononucleosome fragments exhibited acute post-FUS elevations ranging from 1.6-fold to 2.6-fold. Furthermore, sonobiopsy significantly enhanced the detection of tumor-specific circulating tumor DNA (ctDNA) and mutations, including TERT promoter mutations (up to a 5.6-fold increase), EGFR, and IDH1. It also enriched neuron-derived extracellular vesicles by 3.2-fold and brain-specific proteins (S100b) by 1.4-fold. Biomarker enrichment peaked between 10 and 30 minutes post-sonication and demonstrated positive correlations with sonication volume and cumulative acoustic emission
parameters. Crucially, longitudinal trajectory analyses of post-to-pre FUS cfDNA and fragment length ratios demonstrated high predictive concordance (up to 90%) with progression-free and overall survival. The procedure was proven highly safe across all trials, with no instances of FUS-induced intracranial hemorrhage, cytoarchitectural damage, or acute neuroinflammatory flares, while achieving reliable, transient BBB opening.
Conclusion: Sonobiopsy is a safe, feasible, and highly effective modality for enriching circulating brain-derived biomarkers in patients with high-grade gliomas. By overcoming the BBB, FUS-mediated liquid biopsy significantly enhances the detection of tumor-specific genetic signatures and offers robust prognostic value. These findings support the continued clinical translation of sonobiopsy as a non-invasive tool for the molecular diagnosis and longitudinal monitoring of brain tumors.
