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Open Access 06-09-2023 | Ultrasound | Original Article

Methodological and ethical challenges in the use of focused ultrasound for blood–brain barrier disruption in neuro-oncology

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

Published in: Acta Neurochirurgica | Issue 12/2023

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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Alonso A, Reinz E, Leuchs B et al (2013) Focal delivery of AAV2/1-transgenes into the rat brain by localized ultrasound-induced BBB opening. Mol Ther Nucleic Acids 2:e73. https://doi.org/10.1038/MTNA.2012.64CrossRefPubMedPubMedCentral

Bottigliengo D, Baldi I, Lanera C et al (2021) Oversampling and replacement strategies in propensity score matching: a critical review focused on small sample size in clinical settings. BMC Med Res Methodol 21(1). https://doi.org/10.1186/s12874-021-01454-z

Carpentier A, Canney M, Vignot A et al (2016) Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med 8(343). https://doi.org/10.1126/SCITRANSLMED.AAF6086/SUPPL_FILE/8-343RE2_SM.PDF

Chen PY, Hsieh HY, Huang CY, Lin CY, Wei KC, Liu HL (2015) Focused ultrasound-induced blood-brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: a preclinical feasibility study. J Transl Med 13(1):1–12. https://doi.org/10.1186/S12967-015-0451-Y/TABLES/1CrossRef

Conti A, Kamimura HAS, Novell A, Duggento A, Toschi N (2020) Magnetic resonance methods for focused ultrasound-induced blood-brain barrier opening. Front Phys 8. https://doi.org/10.3389/fphy.2020.547674

Elias WJ, Lipsman N, Ondo WG et al (2016) A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med 375(8):730–739. https://doi.org/10.1056/NEJMOA1600159CrossRefPubMed

Fan CH, Ting CY, Chang YC, Wei KC, Liu HL, Yeh CK (2015) Drug-loaded bubbles with matched focused ultrasound excitation for concurrent blood–brain barrier opening and brain-tumor drug delivery. Acta Biomater 15:89–101. https://doi.org/10.1016/J.ACTBIO.2014.12.026CrossRefPubMed

Harary M, Segar DJ, Huang KT, Tafel IJ, Valdes PA, Cosgrove GR (2018) Focused ultrasound in neurosurgery: a historical perspective. Neurosurg Focus 44(2):E2. https://doi.org/10.3171/2017.11.FOCUS17586CrossRefPubMed

Higgins JPT, Thomas J, Chandler J, et al (2019) Cochrane Handbook for Systematic Reviews of Interventions. https://doi.org/10.1002/9781119536604

10.

Hirst A, Philippou Y, Blazeby J et al (2019) No surgical innovation without evaluation: evolution and further development of the IDEAL framework and recommendations. Ann Surg 269(2):211–220. https://doi.org/10.1097/SLA.0000000000002794CrossRefPubMed

11.

Hooijmans CR, Rovers MM, De Vries RBM, Leenaars M, Ritskes-Hoitinga M, Langendam MW (2014) SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 14(1):43. https://doi.org/10.1186/1471-2288-14-43CrossRefPubMedPubMedCentral

12.

Hsu PH, Wei KC, Huang CY et al (2013) Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound. PLoS One 8(2):e57682. https://doi.org/10.1371/JOURNAL.PONE.0057682CrossRefPubMedPubMedCentral

13.

Hynynen K, Clement GT, McDannold N et al (2004) 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 52(1):100–107. https://doi.org/10.1002/MRM.20118CrossRefPubMed

14.

Idbaih A, Canney M, Belin L et al (2019) Safety and feasibility of repeated and transient blood-brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma. Clin Cancer Res 25(13):3793–3801. https://doi.org/10.1158/1078-0432.CCR-18-3643/74166/AM/SAFETY-AND-FEASIBILITY-OF-REPEATED-AND-TRANSIENTCrossRefPubMed

15.

Ioannidis JPA (2018) Why most published research findings are false. In: Getting to Good: Research Integrity in the Biomedical Sciences. https://doi.org/10.1371/journal.pmed.0020124

16.

Karmur BS, Philteos J, Abbasian A et al (2020) Blood-brain barrier disruption in neuro-oncology: strategies, failures, and challenges to overcome. Front Oncol 10:1811. https://doi.org/10.3389/FONC.2020.563840/BIBTEXCrossRef

17.

Kinoshita M, McDannold N, Jolesz FA, Hynynen K (2006) 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 103(31):11719–11723. https://doi.org/10.1073/PNAS.0604318103/SUPPL_FILE/04318FIG4.PDFCrossRefPubMedPubMedCentral

18.

Kovacsa ZI, Kima S, Jikariaa N et al (2017) Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci U S A 114(1):E75–E84. https://doi.org/10.1073/PNAS.1614777114/SUPPL_FILE/PNAS.201614777SI.PDFCrossRef

19.

Lipsman N, Meng Y, Bethune AJ et al (2018) Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun 9(1):2336. https://doi.org/10.1038/s41467-018-04529-6CrossRefPubMedPubMedCentral

20.

Liu HL, Hua MY, Yang HW et al (2010) Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain. Proc Natl Acad Sci U S A 107(34):15205–15210. https://doi.org/10.1073/PNAS.1003388107/SUPPL_FILE/PNAS.201003388SI.PDFCrossRefPubMedPubMedCentral

21.

Liu HL, Hua MY, Chen PY et al (2010) Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology 255(2):415–425. https://doi.org/10.1148/RADIOL.10090699/ASSET/IMAGES/LARGE/10090699FIG08F.JPEGCrossRefPubMed

22.

Lynn JG, Putnam TJ (1944) Histology of cerebral lesions produced by focused ultrasound. Am J Pathol. 20(3):637. Accessed May 21, 2023. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2033152/

23.

Mainprize T, Lipsman N, Huang Y et al (2019) Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci Rep 9(1):1–7. https://doi.org/10.1038/s41598-018-36340-0CrossRef

24.

McCulloch P, Altman DG, Campbell WB et al (2009) No surgical innovation without evaluation: the IDEAL recommendations. Lancet 374(9695):1105–1112. https://doi.org/10.1016/S0140-6736(09)61116-8CrossRefPubMed

25.

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

26.

McDannold N, Clement GT, Black P, Jolesz F, Hynynen K (2010) Transcranial magnetic resonance imaging- guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. Neurosurgery 66(2):323–332. https://doi.org/10.1227/01.NEU.0000360379.95800.2FCrossRefPubMed

27.

McDannold N, Arvanitis CD, Vykhodtseva N, Livingstone MS (2012) Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques. Cancer Res 72(14):3652–3663. https://doi.org/10.1158/0008-5472.CAN-12-0128/650292/AM/TEMPORARY-DISRUPTION-OF-THE-BLOOD-BRAIN-BARRIER-BYCrossRefPubMedPubMedCentral

28.

McDannold N, Zhang Y, Supko JG et al (2019) 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 9(21):6284. https://doi.org/10.7150/THNO.35892CrossRefPubMedPubMedCentral

29.

Mehier-Humbert S, Bettinger T, Yan F, Guy RH (2005) Plasma membrane poration induced by ultrasound exposure: implication for drug delivery. J Control Release 104(1):213–222. https://doi.org/10.1016/J.JCONREL.2005.01.007CrossRefPubMed

30.

Mei J, Cheng Y, Song Y et al (2009) Experimental study on targeted methotrexate delivery to the rabbit brain via magnetic resonance imaging–guided focused ultrasound. J Ultrasound Med 28(7):871–880. https://doi.org/10.7863/JUM.2009.28.7.871CrossRefPubMed

31.

Meng Y, Pople CB, Budiansky D, Li D, Suppiah S, Lim-Fat MJ, Perry J, Sahgal A, Lipsman N (2022) Current state of therapeutic focused ultrasound applications in neuro-oncology. J Neurooncol 156(1):49–59. https://doi.org/10.1007/s11060-021-03861-0CrossRefPubMed

32.

Muhlhausler BS, Bloomfield FH, Gillman MW (2013) Whole animal experiments should be more like human randomized controlled trials. PLoS Biol 11(2). https://doi.org/10.1371/JOURNAL.PBIO.1001481

33.

Ota HCU, Smith BG, Alamri A et al (2020) The IDEAL framework in neurosurgery: a bibliometric analysis. Acta Neurochir (Wien) 162(12):2939–2947. https://doi.org/10.1007/S00701-020-04477-5/TABLES/2CrossRefPubMed

34.

Park SH, Kim MJ, Jung HH et al (2020) Safety and feasibility of multiple blood-brain barrier disruptions for the treatment of glioblastoma in patients undergoing standard adjuvant chemotherapy. J Neurosurg 134(2):475–483. https://doi.org/10.3171/2019.10.JNS192206CrossRefPubMed

35.

R Core Team (n.d.) R: a language and environment for statistical. R Foundation for statistical Computing, Vienna, Austria

36.

Recommendations - Ideal. Accessed May 21, 2023. https://www.ideal-collaboration.net/the-ideal-framework/recommendations/

37.

Search of: focused ultrasound | Brain Cancer - List Results - ClinicalTrials.gov. Accessed May 23, 2023. https://clinicaltrials.gov/ct2/results?cond=Brain+Cancer&term=focused+ultrasound&cntry=&state=&city=&dist=

38.

Sterne JA, Hernán MA, Reeves BC et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ (Online) 355. https://doi.org/10.1136/bmj.i4919

39.

Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. https://doi.org/10.1056/NEJMOA043330/SUPPL_FILE/987SA1.PDFCrossRefPubMed

40.

Treat LH, McDannold N, Vykhodtseva N, Zhang Y, Tam K, Hynynen K (2007) Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int J Cancer 121(4):901–907. https://doi.org/10.1002/IJC.22732CrossRefPubMed

41.

von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP (2014) The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Int J Surg 12(12):1495–1499. https://doi.org/10.1016/j.ijsu.2014.07.013CrossRef

42.

Wei KC, Chu PC, Wang HYJ et al (2013) Focused ultrasound-induced blood–brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study. PLoS One 8(3):e58995. https://doi.org/10.1371/JOURNAL.PONE.0058995CrossRefPubMedPubMedCentral

43.

Ziadloo A, Burks SR, Gold EM et al (2012) Enhanced homing permeability and retention of bone marrow stromal cells by noninvasive pulsed focused ultrasound. Stem Cells 30(6):1216–1227. https://doi.org/10.1002/STEM.1099CrossRefPubMed

Title: Methodological and ethical challenges in the use of focused ultrasound for blood–brain barrier disruption in neuro-oncology
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
Publication date: 06-09-2023
Publisher: Springer Vienna
Keywords: Ultrasound
Ultrasound
Glioblastoma
Glioblastoma
Glioblastoma
Glioma
Glioma
Glioma
Brain Tumor
Published in: Acta Neurochirurgica / Issue 12/2023
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
DOI: https://doi.org/10.1007/s00701-023-05782-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Methodological and ethical challenges in the use of focused ultrasound for blood–brain barrier disruption in neuro-oncology

Abstract

Background

Objectives and methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objectives and methods

Results

Conclusion

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