Lipsman, Nir

Since its US Food and Drug Administration approval in 2016, magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy has grown into one of the procedures of choice among patients with essential tremor (ET). Approved applications for the procedure have expanded over time from unilateral thalamotomy to treat ET and Parkinson disease tremor to bilateral staged thalamotomy for ET. As the procedure expands to healthcare environments beyond large academic centers, guidance is required to ensure that the responsible clinicians are appropriately trained to undertake this operative procedure. Although multidisciplinary movement disorder teams are important for the optimal management of patients, MRgFUS lesions are inherently surgical interventions. Neurosurgeons are trained to evaluate these patients, consider surgical alternatives and conduct these operations, particularly after completing a fellowship in the subspecialty of stereotactic and functional neurosurgery. At present, all high-level evidence regarding the safety and efficacy of MRgFUS lesions to treat movement disorders derives from procedures performed by neurosurgeons, so those results may not be generalizable to other physicians. Based on these considerations and potential liability issues, the American Society for Stereotactic and Functional Neurosurgery, which acts as the joint section representing the field of stereotactic and functional neurosurgery on behalf of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, puts forth this position statement that only neurosurgeons appropriately trained to conduct functional neurosurgery procedures should conduct MRgFUS surgical lesions.

Background Psychiatric disorders are increasingly contributing to global disability. Despite advances in conservative management, the prevalence of treatment-resistant cases remains high. Meanwhile, neurosurgery for psychiatric disorders (NPD) remains underused, largely due to strict regulations and historical concerns, particularly those related to neuropsychological side effects (NPSE). Objective To address this issue, we conducted a systematic review with meta-analysis to compare NPSE associated with radiofrequency ablative NPD to those observed in neuro-oncological, neurovascular and epilepsy surgeries. Methods PubMed, Embase and LILACS databases were searched in April 2024 for articles published in English/Spanish from 1990 to 2022, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results A total of 48 articles with 2678 participants were included. The frequency of transient and permanent NPSE in the NPD group ranged from 0.94% to 11.50% and 0.94% to 2.03%, respectively, comparable to the other surgical groups (epilepsy: 0.31–11.70%; vascular: 0.52–22.90%; oncology: 0.94–17.60% for transient NPSE; epilepsy: 0.31–12%; vascular: 0.40–1.96% and oncology: 0.84–1.48% for permanent NPSE). Regarding permanent NPSE, arguably the most critical consideration, the NPD group showed better outcomes in memory, language and social cognition than the epilepsy group, but worse outcomes in executive and perceptual-motor functions. Compared with the vascular group, the NPD group had better executive function but worse complex attention. Finally, the NPD group had fewer permanent deficits than the oncology group in executive function, complex attention and perceptual-motor domains, although language performance was lower. Conclusions Contemporary NPD apparently carries a similar risk of NPSE as other conventional neurosurgical procedures, challenging misconceptions and this unjustified barrier to its broader use.

OBJECTIVE Magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy has become a popular tool in the neurosurgical armamentarium for managing tremor in patients with essential tremor (ET) and Parkinson’s disease (PD). METHODS Given the recent exponential growth in the use of this technology, the American Society for Stereotactic and Functional Neurosurgery, which acts as the joint section representing the field of stereotactic and functional neurosurgery on behalf of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, provides an update on treatment indications and the efficacy and safety of MRgFUS for the treatment of tremor. RESULTS In ET, the efficacy of MRgFUS thalamotomy is supported by several open-label and 1 prospective, double-blind, sham-controlled randomized clinical trial (RCT) that showed a 47% improvement in hand tremor in the short term. Follow-up studies demonstrated that the benefits of MRgFUS for ET are sustained in the long term. Studies investigating the effects of bilateral staged MRgFUS thalamotomy in patients with ET have shown that tremor improvement on the second side was as significant as that observed after the first procedure. The efficacy of MRgFUS thalamotomy for PD tremor is supported by a systematic meta-analysis that consisted predominantly of smaller, nonrandomized studies; 1 RCT; and 1 prospective cohort study. Despite a significant short-term improvement in PD tremor, the long-term effects of this therapy remain unknown. Common early adverse effects of MRgFUS thalamotomy include gait disturbance and paresthesias. These, however, tend to subside over time. Other reported side effects are dysarthria, ataxia, taste disturbance, motor deficits, and speech difficulty. CONCLUSIONS MRgFUS thalamotomy is a safe, effective, and durable intervention for refractory ET in appropriately selected patients. The procedure appears to be safe and effective for PD tremor, although the long-term durability of the technique remains a concern. Early experience with bilateral staged lesions for ET suggests the procedure to be safe and effective.

TPS2094 Background: Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating tumor (ct) and cell-free (cf) DNA levels in blood due to the blood-brain barrier (BBB). This limits the identification of blood-based tumor biomarkers along with the development and use of biomarker-driven systemic therapies. Low intensity focused ultrasound combined with intravenously administered microbubble oscillators (MB-FUS), leads to non-invasive BBB opening. This trial aims to evaluate the utility of LIFU for bolstering blood ctDNA and cfDNA for enhance liquid biopsy in patients with GBM. Methods: LIBERATE is an ongoing, prospective, multi-center, self-controlled, pivotal trial evaluating safety and technical efficacy of transcranial MR-guided MB-FUS for increasing blood ctDNA and cfDNA levels in adults, aged 18-80 years with GBM. Patients with suspected GBM planned for tumor biopsy or resection at 17 centers in US and Canada are being enrolled. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV microbubbles for enhanced sonication, after which MR-guided BBB opening using a 220 kHz device, with 1024-element phased array transducer, is performed with real-time acoustic feedback control for effective cavitation. Pre- and post-procedure, phlebotomy and MRI brain are done. Patients are offered optional 2 nd procedure during adjuvant chemotherapy phase if willing. Primary efficacy endpoint is correlation between biomarker patterns in tumor tissue collected during surgery/biopsy and blood collected following MB-FUS procedure. Confirmatory secondary efficacy endpoint is ratio between greatest yield of cfDNA in blood post-MB-FUS compared to cfDNA level in blood pre-MB-FUS. The primary study hypothesis is that agreement rate on biomarker pattern between resected/biopsied tumor tissue and blood is > 70%. The secondary hypothesis is that MB-FUS BBBO leads to a ≥2-fold rise in blood cfDNA. Assuming the true agreement rate expected is 89%, a sample of N = 50 patients will provide 90% power to meet the primary endpoint (Exact test, Binomial Proportion, one-sided Alpha = 0.025). Exploratory endpoints include (1) sensitivity of detection of known specific somatic mutations in ctDNA from blood samples collected before and after MB-FUS, (2) estimation of ctDNA levels in samples collected at 30-minutes, 1-hour, 2-hour, and 3-hour post-MB-FUS to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBB opening and ctDNA-based biomarkers from post-MB-FUS blood samples, (4) biomarker correlation between plasma cfDNA sampled during adjuvant chemotherapy phase and tumor tissue harvested at surgery. Patient enrollment commenced in 2022 and is ongoing (NCT05383872). Clinical trial information: NCT05383872 .

Abstract BACKGROUND Liquid biopsy in glioblastoma (GBM) is hindered by insufficient requisite circulating-tumor (ct) and cell-free (cf) DNA in blood due to blood-brain barrier (BBB). This limits the identification of blood-based tumor biomarkers along with biomarker-driven systemic therapies. Real-time image-guided low-intensity focused ultrasound (LIFU) plus IV microbubble oscillators, leads to non-invasive BBB disruption. METHODS LIBERATE is an ongoing, prospective, multi-center, self-controlled, pivotal trial investigating safety and technical efficacy of LIFU-based BBB disruption for increasing blood ctDNA and cfDNA levels in adult GBM patients (aged 18-80 years). Patients with suspected GBM planned for biopsy/resection at ten US centers are being enrolled. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV microbubbles for enhanced sonication effects, after which MR-guided BBB disruption using 220kHz LIFU device is performed with real-time acoustic-feedback-control for effective microbubble activation. Pre- and post-LIFU, phlebotomy and MRI brain are performed. Primary study endpoint is defined, per subject, as ratio between their blood cfDNA level 1-hour post-LIFU procedure compared to blood cfDNA pre-procedure. Primary study hypothesis is that BBB disruption leads to ≥2-fold rise in blood cfDNA. Secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in blood cfDNA sample obtained 1-hour post-LIFU and biomarker pattern in tumor tissue obtained later. Trial is powered to evaluate both primary and secondary hypotheses. Based on assumed true agreement rate of 91% and one-sided alpha=0.025, an exact test for binomial proportions provides N=50 with 84% power for secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of specific somatic mutations in ctDNA from blood collected pre- and post-LIFU, (2) ctDNA estimation in samples collected at 30-minutes, 1-hour, 2-hour, and 3-hour post-LIFU to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBB disruption and ctDNA-based biomarkers from post-LIFU blood samples. Patient enrollment commenced in 2022 and remains ongoing (NCT05383872).

Abstract BACKGROUND Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating tumor (ct) and cell-free (cf) DNA levels in blood due to the blood-brain barrier (BBB). This limits the identification of blood-based tumor biomarkers along with the development and use of biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with intravenously administered microbubble oscillators, leads to non-invasive disruption of the BBB. This trial aims to evaluate the utility of LIFU for boosting blood ctDNA and cfDNA for enhanced liquid biopsy in GBM patients. MATERIAL AND METHODS LIBERATE is an ongoing, prospective, multi-center, self-controlled, pivotal trial evaluating safety and technical efficacy of LIFU-based BBB disruption for increasing blood ctDNA and cfDNA levels in adults, aged 18-80 years with GBM. Patients with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being enrolled. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV microbubbles for enhanced sonication effects, after which MR-guided BBB disruption using a 220 kHz LIFU device is performed with real-time acoustic feedback control for effective microbubble activation. Before and after procedure, phlebotomy and MRI brain are performed to evaluate outcomes. Primary study endpoint is defined, per subject, as ratio between their cfDNA level in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. Primary study hypothesis is that BBB disruption with LIFU leads to a ≥2-fold rise in blood cfDNA. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in blood cfDNA sample obtained 1-hour post-LIFU and the biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N = 50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known specific somatic mutations in ctDNA from blood samples collected before and after LIFU, (2) estimation of ctDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hour, and 3 hour to determine the time of greatest yield, (3) correlation of MRI parameters related to grading of BBB disruption and ctDNA-based biomarkers from post-LIFU blood samples. RESULTS Patient enrollment commenced in 2022, and 22 patients have been recruited by 05/2024. CONCLUSION Findings from this trial will be critical to liquid biopsy in GBM (Clinical trial information: NCT05383872).

TPS2098 Background: Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating tumor (ct) and cell-free (cf) DNA levels in blood due to the blood-brain barrier (BBB). This limits the identification of blood-based tumor biomarkers along with the development and use of biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with intravenously administered microbubble oscillators, leads to non-invasive disruption of the BBB. This trial aims to evaluate the utility of LIFU for boosting blood ctDNA and cfDNA for enhanced liquid biopsy in GBM patients. Methods: LIBERATE is an ongoing, prospective, multi-center, self-controlled, pivotal trial evaluating safety and technical efficacy of LIFU-based BBB disruption for increasing blood ctDNA and cfDNA levels in adults (aged 18-80 years) with GBM. Patients with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being enrolled. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV microbubbles for enhanced sonication effects, after which MR-guided BBB disruption using a 220 kHz LIFU device is performed with real-time acoustic feedback control for effective microbubble activation. Before and after procedure, phlebotomy and MRI brain are performed to evaluate outcomes. Primary study endpoint is defined, per subject, as ratio between their cfDNA level in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. Primary study hypothesis is that BBB disruption with LIFU leads to a ≥2-fold rise in blood cfDNA. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in blood cfDNA sample obtained 1-hour post-LIFU and the biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N = 50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known specific somatic mutations in ctDNA from blood samples collected before and after LIFU, (2) estimation of ctDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hour, and 3 hour to determine the time of greatest yield, (3) correlation of MRI parameters related to grading of BBB disruption and ctDNA-based biomarkers from post-LIFU blood samples. Patient enrollment commenced in 2022 and 22 patients have been recruited by January 2024. Clinical trial information: NCT05383872 .

Abstract BACKGROUND Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) blood levels in due to the blood-brain barrier (BBB). Real-time image-guided low-intensity focused ultrasound (LIFU) with intravenously administered microbubble oscillators non-invasively causes BBB disruption (BBBD). This clinical trial aimed to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. METHODS LIBERATE is an ongoing, prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating the safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged 18-80 years with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being included. Patients are administered intravenous oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using 220 kHz LIFU device is performed, with real-time acoustic feedback for effective sonication. Pre- and post-procedure, phlebotomies, and MRI brain are performed. The primary study endpoint is defined, per subject, as the ratio between cfDNA levels in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% concordance between biomarker patterns in the cfDNA sample from 1-hour post-LIFU sample and tumor tissue obtained later. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels in samples collected at 30 minutes, 1 hour, 2 hours, and 3 hours post-LIFU to determine the time of greatest yield, (3) correlation of MRI parameters related to BBBD grading and biomarkers in cfDNA from post-LIFU samples. Patient enrollment commenced in 2022, and 13 patients have been recruited by 06/09/2023. Clinical trial information: NCT05383872.

Abstract BACKGROUND Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with intravenously administered microbubble oscillators non-invasively causes BBB disruption (BBBD). This clinical trial aimed to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. METHODS LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating the safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged 18-80 years with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered intravenous oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after the procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to a ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hours, and 3 hours to determine the time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples. RESULTS Patient enrollment commenced in 2022, and 8 patients have been recruited by 04/11/2023. CONCLUSION Findings from this trial will be critical to liquid biopsy in GBM (Clinical trial information: NCT05383872).

TPS2084 Background: Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with IV microbubble oscillators (DEFINITY), non-invasively causes BBB disruption (BBBD). This clinical trial aims to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. Methods: LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged >18-80 years with suspected GBM planned for tumor biopsy or resection at eleven centers in North America are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hour, and 3 hour to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples. Patient enrollment commenced in 2022 and 7 patients have been recruited by 02/13/2023. Clinical trial information: NCT05383872 .