Methodological and Ethical Challenges in the Use of Focused Ultrasound for Blood-brain Barrier Disruption in Neuro-oncology

Overview

Journal Acta Neurochir (Wien)

Specialty Neurosurgery

Date 2023 Sep 6

PMID 37672093

Authors

Santhosh G Thavarajasingam

John L Kilgallon

Daniele S C Ramsay

Leila Motedayen Aval

Ishaan Ashwini Tewarie

Andreas Kramer

Dannis van Vuurden

Marike L D Broekman

Affiliations

Soon will be listed here.

Abstract

Background: Focused ultrasound (FUS) shows promise for enhancing drug delivery to the brain by temporarily opening the blood-brain barrier (BBB), and it is increasingly used in the clinical setting to treat brain tumours. It remains however unclear whether FUS is being introduced in an ethically and methodologically sound manner. The IDEAL-D framework for the introduction of surgical innovations and the SYRCLE and ROBINS-I tools for assessing the risk of bias in animal studies and non-randomized trials, respectively, provide a comprehensive evaluation for this.

Objectives And Methods: A comprehensive literature review on FUS in neuro-oncology was conducted. Subsequently, the included studies were evaluated using the IDEAL-D framework, SYRCLE, and ROBINS-I tools.

Results: In total, 19 published studies and 12 registered trials were identified. FUS demonstrated successful BBB disruption, increased drug delivery, and improved survival rates. However, the SYRCLE analysis revealed a high risk of bias in animal studies, while the ROBINS-I analysis found that most human studies had a high risk of bias due to a lack of blinding and heterogeneous samples. Of the 15 pre-clinical stage 0 studies, only six had formal ethical approval, and only five followed animal care policies. Both stage 1 studies and stage 1/2a studies failed to provide information on patient data confidentiality. Overall, no animal or human study reached the IDEAL-D stage endpoint.

Conclusion: FUS holds promise for enhancing drug delivery to the brain, but its development and implementation must adhere to rigorous safety standards using the established ethical and methodological frameworks. The complementary use of IDEAL-D, SYRCLE, and ROBINS-I tools indicates a high risk of bias and ethical limitations in both animal and human studies, highlighting the need for further improvements in study design for a safe implementation of FUS in neuro-oncology.

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References

Alonso A, Reinz E, Leuchs B, Kleinschmidt J, Fatar M, Geers B . Focal Delivery of AAV2/1-transgenes Into the Rat Brain by Localized Ultrasound-induced BBB Opening. Mol Ther Nucleic Acids. 2013; 2:e73. PMC: 3586801. DOI: 10.1038/mtna.2012.64. View

Elias W, Lipsman N, Ondo W, Ghanouni P, Kim Y, Lee W . A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med. 2016; 375(8):730-9. DOI: 10.1056/NEJMoa1600159. View

Fan C, Ting C, Chang Y, Wei K, Liu H, Yeh C . Drug-loaded bubbles with matched focused ultrasound excitation for concurrent blood-brain barrier opening and brain-tumor drug delivery. Acta Biomater. 2015; 15:89-101. DOI: 10.1016/j.actbio.2014.12.026. View

Harary M, Segar D, Huang K, Tafel I, Valdes P, Cosgrove G . Focused ultrasound in neurosurgery: a historical perspective. Neurosurg Focus. 2018; 44(2):E2. DOI: 10.3171/2017.11.FOCUS17586. View

Hirst A, Philippou Y, Blazeby J, Campbell B, Campbell M, Feinberg J . No Surgical Innovation Without Evaluation: Evolution and Further Development of the IDEAL Framework and Recommendations. Ann Surg. 2018; 269(2):211-220. DOI: 10.1097/SLA.0000000000002794. View

Hooijmans C, Rovers M, De Vries R, Leenaars M, Ritskes-Hoitinga M, Langendam M . SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol. 2014; 14:43. PMC: 4230647. DOI: 10.1186/1471-2288-14-43. View

Hsu P, Wei K, Huang C, Wen C, Yen T, Liu C . Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound. PLoS One. 2013; 8(2):e57682. PMC: 3584045. DOI: 10.1371/journal.pone.0057682. View

Hynynen K, Clement G, McDannold N, Vykhodtseva N, King R, White P . 500-element ultrasound phased array system for noninvasive focal surgery of the brain: a preliminary rabbit study with ex vivo human skulls. Magn Reson Med. 2004; 52(1):100-7. DOI: 10.1002/mrm.20118. View

Idbaih A, Canney M, Belin L, Desseaux C, Vignot A, Bouchoux G . Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. Clin Cancer Res. 2019; 25(13):3793-3801. DOI: 10.1158/1078-0432.CCR-18-3643. View

10.

Kinoshita M, McDannold N, Jolesz F, Hynynen K . Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci U S A. 2006; 103(31):11719-23. PMC: 1544236. DOI: 10.1073/pnas.0604318103. View

11.

Lipsman N, Meng Y, Bethune A, Huang Y, Lam B, Masellis M . Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound. Nat Commun. 2018; 9(1):2336. PMC: 6060168. DOI: 10.1038/s41467-018-04529-6. View

12.

Liu H, Hua M, Yang H, Huang C, Chu P, Wu J . Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain. Proc Natl Acad Sci U S A. 2010; 107(34):15205-10. PMC: 2930577. DOI: 10.1073/pnas.1003388107. View

13.

Liu H, Hua M, Chen P, Chu P, Pan C, Yang H . Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology. 2010; 255(2):415-25. DOI: 10.1148/radiol.10090699. View

14.

McCulloch P, Altman D, Glasziou P, Marshall J, Aronson J, Barkun J . No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 2009; 374(9695):1105-12. DOI: 10.1016/S0140-6736(09)61116-8. View

15.

McDannold N, Vykhodtseva N, Hynynen K . Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity. Phys Med Biol. 2006; 51(4):793-807. DOI: 10.1088/0031-9155/51/4/003. View

16.

McDannold N, Clement G, Black P, Jolesz F, Hynynen K . Transcranial magnetic resonance imaging- guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. Neurosurgery. 2010; 66(2):323-32. PMC: 2939497. DOI: 10.1227/01.NEU.0000360379.95800.2F. View

17.

McDannold N, Arvanitis C, Vykhodtseva N, Livingstone M . Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques. Cancer Res. 2012; 72(14):3652-63. PMC: 3533365. DOI: 10.1158/0008-5472.CAN-12-0128. View

18.

McDannold N, Zhang Y, Supko J, Power C, Sun T, Peng C . Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model. Theranostics. 2019; 9(21):6284-6299. PMC: 6735504. DOI: 10.7150/thno.35892. View

19.

Mehier-Humbert S, Bettinger T, Yan F, Guy R . Plasma membrane poration induced by ultrasound exposure: implication for drug delivery. J Control Release. 2005; 104(1):213-22. DOI: 10.1016/j.jconrel.2005.01.007. View

20.

Mei J, Cheng Y, Song Y, Yang Y, Wang F, Liu Y . Experimental study on targeted methotrexate delivery to the rabbit brain via magnetic resonance imaging-guided focused ultrasound. J Ultrasound Med. 2009; 28(7):871-80. DOI: 10.7863/jum.2009.28.7.871. View