People can Safely Undergo Ultrasound-Based Brain Biopsy

The blood-brain barrier, the body’s technique of protecting sensitive brain tissue from viruses, poisons, and other hazardous substances in the blood, can be a challenge for doctors caring for patients with suspected brain disorders like cancer. Molecular and genetic data would be essential for confirming a diagnosis and guiding treatment recommendations, but such molecules are generally restricted to the brain by the barrier. Neurosurgeons commonly perform surgical brain biopsy to get this information on brain tumor, but such operations are risky and not appropriate for many cancers or many other types of brain illnesses.

Researchers at Washington University in St. Louis have developed sonobiopsy, an anatomically precise technique that uses ultrasound and microbubbles to temporarily disrupt the barrier, allowing RNA, DNA, and proteins from the brain to spill out into the blood, where they can be detected and analyzed. The approach was created and previously tested in animals by the researchers. They demonstrated that the procedure is viable and safe for application in humans in a new study published online in the journal NPJ Precision Oncology, and that it could pave the way for noninvasive biopsies for suspected brain tumors and other brain illnesses.

“Magnetic resonance imaging (MRI) revolutionized the field of brain disease diagnosis in the 1980s and ‘90s by allowing for structural and functional imaging of the brain,” said Eric C. Leuthardt, MD, the co-senior author on the paper and co-inventor of the technology. Leuthardt is the Shi Hui Huang Professor of Neurosurgery and a professor of biomedical engineering, of mechanical engineering and of neuroscience. “Sonobiopsy is the third revolution, the molecular revolution. With this technique, we can obtain a blood sample that reflects the gene expression and the molecular features at the site of a lesion in the brain. It’s like doing a brain biopsy without the dangers of brain surgery.”

Leuthardt and Hong Chen, PhD, an associate professor of biomedical engineering and neurosurgery, pioneered the procedure. Leuthardt is the director of the Division of Neurotechnology in the Department of Neurosurgery, and Chen is a member of the Division of Neurotechnology, which focuses on intensely multidisciplinary research to create breakthrough engineered solutions that can be applied to patients with neurologic illnesses. The sonobiopsy technology is patented by Washington University.

The method works by using focused ultrasound to precisely target a lesion in the brain, followed by the infusion of microbubbles into the bloodstream. The microbubbles travel to the desired location before popping, breaking microscopic breaches in the blood-brain barrier that seal within a few hours, causing little long-term damage. That window of time allows biomolecules from the lesion to escape into the bloodstream, where they can be retrieved using a standard blood draw.

“We’ve essentially initiated a new field of study for brain conditions,” said Chen, the other co-senior author on the paper and co-inventor of the technology. “With this capability to noninvasively, nondestructively access every part of the brain, we can get genetic information on tumors before going in surgically, which would help a neurosurgeon determine how best to approach the surgery. If they see something suspicious on imaging, they could confirm whether a tumor is recurring or not. We can now start to interrogate diseases for which surgical biopsies aren’t done, such as neurodevelopmental, neurodegenerative and psychiatric disorders.”

The researchers had previously used a commercially available ultrasonic device that was coupled with an MRI scanner. The equipment is costly and limited to areas with MRI scanning capabilities. To make the process easier, Chen’s team developed a portable, handheld ultrasound probe that was coupled to a stereotactic pointer, which is commonly used by neurosurgeons to target brain lesions. The technology was integrated into the clinical workflow without the need for further neurosurgeon training.

“It’s very easy to use,” Leuthardt said. “We used it in the OR for this study, but it could be used in a clinic or at a patient’s hospital bedside. It’s a step toward democratizing access to advanced diagnostics. We can interrogate patients’ brains, and we don’t need a high-tech, multimillion-dollar scanner to do it.”

The researchers used this gadget to perform sonobiopsies on five persons with brain malignancies. The tumors were then surgically removed in accordance with usual practice. Co-first authors Jinyun Yuan, PhD, a research scientist, and Lu Xu and Chih-Yen Chien, both graduate students in the Department of Biomedical Engineering at Washington University’s McKelvey School of Engineering, joined Chen and Leuthardt on the research team.

The approach raised circulating tumor DNA 1.6-fold to 5.6-fold, depending on the kind of DNA tested, in blood samples obtained before and after sonication. The genetic variations in a patient’s tumor that indicate how aggressively the tumor should be treated are contained in circulating tumor DNA. Furthermore, there were no symptoms of brain tissue injury, indicating that the surgery is safe.

In 2018, Chen and Leuthardt released their first publication describing sonobiopsy, and the technique’s promise was soon recognized.

“Already there are multiple sites evaluating sonobiopsy in clinical trials around the world,” Chen said. “In one conference I attended recently, there was a whole session dedicated to sonobiopsy. This project exemplifies team science. Since introducing the concept of sonobiopsy in 2018, up to the publication of this clinical study, it has been a joint endeavor involving several investigators.”

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