학술논문
Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling.
Document Type
Academic Journal
Author
Hage S; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.; Kinkade S; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.; Girard R; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.; Flemming KD; Departments of Neurology (K.D.F.), Mayo Clinic, Rochester, MN.; Kim H; Department of Anesthesiology and Perioperative Care, Center for Cerebrovascular Research (H.K.), University of California, San Francisco.; Torbey MT; Department of Neurology (M.T.T.), University of New Mexico, Albuquerque.; Huang J; Department of Neurosurgery (J.H., J.F.).; Huston J 3rd; Radiology (J. Huston, Y.S.), Mayo Clinic, Rochester, MN.; Shu Y; Radiology (J. Huston, Y.S.), Mayo Clinic, Rochester, MN.; Selwyn RG; Department of Diagnostic Radiology (R.G.S., B.L.H.), University of New Mexico, Albuquerque.; Hart BL; Department of Diagnostic Radiology (R.G.S., B.L.H.), University of New Mexico, Albuquerque.; Mabray MC; Department of Radiology (M.C.M.), University of New Mexico, Albuquerque.; Feghali J; Department of Neurosurgery (J.H., J.F.).; Sair HI; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD (H.I.S.).; Narvid J; Department of Radiology and Biomedical Imaging (J.N., J.M.L.), University of California, San Francisco.; Lupo JM; Department of Radiology and Biomedical Imaging (J.N., J.M.L.), University of California, San Francisco.; Lee J; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.; Stadnik A; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.; Alcazar-Felix RJ; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.; Shenkar R; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.; Hobson N; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.; DeBiasse D; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.; Lane K; Brain Injury Outcomes Unit, Department of Neurology (K.L., N.A.M., K.T., N.O., Y.W., R.E.T., D.F.H.), Johns Hopkins University Medical Institutions, Baltimore, MD.; McBee NA; Brain Injury Outcomes Unit, Department of Neurology (K.L., N.A.M., K.T., N.O., Y.W., R.E.T., D.F.H.), Johns Hopkins University Medical Institutions, Baltimore, MD.; Treine K; Brain Injury Outcomes Unit, Department of Neurology (K.L., N.A.M., K.T., N.O., Y.W., R.E.T., D.F.H.), Johns Hopkins University Medical Institutions, Baltimore, MD.; Ostapkovich N; Brain Injury Outcomes Unit, Department of Neurology (K.L., N.A.M., K.T., N.O., Y.W., R.E.T., D.F.H.), Johns Hopkins University Medical Institutions, Baltimore, MD.; Wang Y; Brain Injury Outcomes Unit, Department of Neurology (K.L., N.A.M., K.T., N.O., Y.W., R.E.T., D.F.H.), Johns Hopkins University Medical Institutions, Baltimore, MD.; Thompson RE; Brain Injury Outcomes Unit, Department of Neurology (K.L., N.A.M., K.T., N.O., Y.W., R.E.T., D.F.H.), Johns Hopkins University Medical Institutions, Baltimore, MD.; Koenig JI; National Institute of Neurological Disorders and Stroke, Bethesda, MD (J.K.).; Carroll T; Department of Diagnostic Radiology (T.C.), University of Chicago Medicine and Biological Sciences, IL.; Hanley DF Jr; Brain Injury Outcomes Unit, Department of Neurology (K.L., N.A.M., K.T., N.O., Y.W., R.E.T., D.F.H.), Johns Hopkins University Medical Institutions, Baltimore, MD.; Awad IA; Neurovascular Surgery Program, Department of Neurological Surgery (S.H., S.K., R.G., J.L., A.S., R.J.A.-F., R.S., N.H., D.D., I.A.A.), University of Chicago Medicine and Biological Sciences, IL.
Source
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0235266 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4628 (Electronic) Linking ISSN: 00392499 NLM ISO Abbreviation: Stroke Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project.
Methods: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted.
Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH ( P =0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05.
Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations.
Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.
Competing Interests: Disclosures Dr Awad is a consultant and Dr Kim oversees data and safety monitoring board for Neurelis, Inc. Dr Awad reports compensation from Medicoegal consulting for expert witness services. S. Kinkade reports employment by UChicago. Drs Kim and Flemming are consultants for Recursion Pharmaceuticals. Dr Huang is the Director for the American Board of Neurological Surgery; reports compensation by Longevity Neuro Solutions; reports employment by School of Medicine, Johns Hopkins University; and reports other intellectual property for Fundamentals of Operative Neurosurgery. Dr Hutson is a stockholder in Navinetics and Resoundant; reports grants from Batterman Family Foundation; reports compensation from Eisai, Inc; and reports a provisional patent for Brain MR Elastography licensed to Mayo Clinic. Dr Lupo has a grant from GE Healthcare. Dr Mabray is employed by Mind Research Network and is a consultant for Smart Soft Healthcare. K. Lane and Dr Hanley report funding from the National Institute of Neurological Disorders and Stroke. N. Ostapkovich reports employment by Johns Hopkins University. Dr Koenig is employed by the National Institutes of Health (NIH). This report does not represent the official view of the NIH or any part of the US Federal Government, and no official support or endorsement of this article by the NIH is intended or should be inferred. The other authors report no conflicts.
Methods: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted.
Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH ( P =0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05.
Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations.
Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.
Competing Interests: Disclosures Dr Awad is a consultant and Dr Kim oversees data and safety monitoring board for Neurelis, Inc. Dr Awad reports compensation from Medicoegal consulting for expert witness services. S. Kinkade reports employment by UChicago. Drs Kim and Flemming are consultants for Recursion Pharmaceuticals. Dr Huang is the Director for the American Board of Neurological Surgery; reports compensation by Longevity Neuro Solutions; reports employment by School of Medicine, Johns Hopkins University; and reports other intellectual property for Fundamentals of Operative Neurosurgery. Dr Hutson is a stockholder in Navinetics and Resoundant; reports grants from Batterman Family Foundation; reports compensation from Eisai, Inc; and reports a provisional patent for Brain MR Elastography licensed to Mayo Clinic. Dr Lupo has a grant from GE Healthcare. Dr Mabray is employed by Mind Research Network and is a consultant for Smart Soft Healthcare. K. Lane and Dr Hanley report funding from the National Institute of Neurological Disorders and Stroke. N. Ostapkovich reports employment by Johns Hopkins University. Dr Koenig is employed by the National Institutes of Health (NIH). This report does not represent the official view of the NIH or any part of the US Federal Government, and no official support or endorsement of this article by the NIH is intended or should be inferred. The other authors report no conflicts.