First-in-human prospective trial of sonobiopsy in high-grade glioma patients using neuronavigation-guided focused ultrasound.

Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in high-grade glioma patients to evaluate its feasibility and safety in enriching plasma circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed that sonobiopsy enriched plasma circulating tumor DNA (ctDNA), including a maximum increase of 1.6-fold for the mononucleosome cell-free DNA (cfDNA) fragments (120-280 bp), 1.9-fold for the patient-specific tumor variant ctDNA level, and 5.6-fold for the TERT mutation ctDNA level. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and nonsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes. Only 2 out of 17,982 total detected genes related to the immune pathways were upregulated. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.

Introduction

Purpose sonobiopsy

Study Objective to evaluate the use of sonobiopsy, a technology the combined FUS, on

Animal model / Human subject Four men and one woman; average 60 years, range 34-74 years

Disease model glioma

MRI or image guidance method specific brain coordinates was directed by MRI and CT combined with the neuronavigation system.

Targeted brain region(s) Brain Tumor Region, Targeted By Imaging Devices

Target coordinates spatial registration, location, is found by loading MRI and CT images into the neuronavigation system (stealth S8, Medtronic)

Cargo name and characteristics did not have one

Route of administration intravenous

Outcomes and Safety

Summary of Outcomes The nimble design of the FUS device allowed for direct attachment of the FUS device to a neuronavigation probe used by any clinical neuronavigation system, enabling precise positioning of the FUS transducer with high accuracy. sonobiopsy could be integrated with advanced blood-based biomarker analysis techniques for the noninvasive and spatially targeted molecular diagnosis of brain tumors without causing tissue damage. Sonobiopsy enriched the plasma level of mononucleosome cfDNA fragment (120–280 bp), patient-specific tumor variant ctDNA, and TERT mutation ctDNA. A significant increase in cfDNA level was detected in 4 out of 5 patients ddPCR was used in our study to detect ctDNA with prior knowledge of the mutations expressed by the GBM tumors. The GBM tumors are known to have TERT mutation but no IDH1 mutation. The ddPCR results demonstrate that sonobiopsy dramatically enriched the level of TERT mutation in 2 (G02 and G03) out of 4 patients who had the TERT mutantion without affecting the amount of IDH1 mutation, implying that sonobiopsy can improve the sensitivity in mutation detection without affecting its specificity.

Duration of biological effect The FUS lasts no less than 30mins. Researchers collected the Blood samples immediately before (5 min pre- FUS) and at different time points post-sonication (5, 10, and 30min post-FUS).

Safety-related matter This study incoporated a pilot study to verify the safety of sonobiopsy surgery. And patients are monitored during the surgery.

Brain Region

Ultrasound Parameters

Ultrasound instrument A FUS transducer consisting of 15 concentric individual ring transducers with a center frequency of 650 kHz (Imasonics, Voray- sur-l’Ognon, France) The FUS transducer was driven by a commercial FUS system (Image Guided Therapy, Pessac, France). The transducer was coupled to the passive blunt probe (Stealth S8, Medtronic)

FUS Frequency 650kHz

FUS Intensity ISPPA: not mentioned ISPTA: not mentioned

FUS Pressure not mentioned

FUS Mode pulsed

Pulse duration 10ms

Duration of a single FUS session 3min

Focal Characteristics FWHM of the transducer: 20mm and 3.0mm Aperture of the transducer: 65mm Focal distance: 65mm, F=1

Treatment frequency single session

We are open to feedback. If you see a mistake or have a suggestion, please contact us.