Trial Readiness in Cavernous Angiomas With Symptomatic Hemorrhage (CASH)

Polster, Sean P.; Cao, Ying; Carroll, Timothy J.; Flemming, Kelly D.; Girard, Romuald; Hanley, Daniel F.; Hobson, Nicholas; Kim, Helen; Koenig, James I.; Koskimäki, Janne; Lane, Karen; Majersik, Jennifer J.; McBee, Nichol; Morrison, Leslie; Shenkar, Robert; Stadnik, Agnieszka; Thompson, Richard E.; Zabramski, Joseph M.; Zeineddine, Hussein A.; Awad, Issam A.

doi:10.1093/neuros/nyy108

Cited by 40 publications

(63 citation statements)

References 62 publications

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“…These are specific aims in the ongoing multisite trial readiness project, funded by the National Institutes of Health. 13 Preliminary assessment of baseline lesional QSM and DCEQP in CA patients with symptomatic hemorrhage is indeed in the same range as that recorded in pilot studies at the development site (Fig. 6).…”

Section: Discussionsupporting

confidence: 61%

“…Future work in this project involves clinical validation of baseline QSM and DCEQP measures in CA patients across sites, stability in stable patients, and replication of changes in association with clinical activity and potential response to therapy. These are specific aims in the ongoing multisite trial readiness project, funded by the National Institutes of Health . Preliminary assessment of baseline lesional QSM and DCEQP in CA patients with symptomatic hemorrhage is indeed in the same range as that recorded in pilot studies at the development site (Fig.…”

Section: Discussionmentioning

confidence: 76%

“…We report on a prototypical multicontrast, multifunction "traveling phantom" and validation protocol developed for the evaluation of clinical trials of hemosiderin deposition and altered vascular permeability in cavernous angioma (CA, also known as cerebral cavernous malformation, CCM). [1][2][3][4][5][6][7][8][9][10][11][12][13] This addresses the applicability of quantitative susceptibility (QSM) and dynamic contrast-enhanced permeability (DCEQP) in this disease and potentially other pathological entities.…”

mentioning

confidence: 99%

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Phantom validation of quantitative susceptibility and dynamic contrast‐enhanced permeability MR sequences across instruments and sites

Hobson

Polster

Cao

et al. 2019

Magnetic Resonance Imaging

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Background Quantitative susceptibility mapping (QSM) and dynamic contrast‐enhanced quantitative permeability (DCEQP) on magnetic resonance (MR) have been shown to correlate with neurovascular disease progression as markers of vascular leakage and hemosiderin deposition. Applying these techniques as monitoring biomarkers in clinical trials will be necessary; however, their validation across multiple MR platforms and institutions has not been rigorously verified. Purpose To validate quantitative measurement of MR biomarkers on multiple instruments at different institutions. Study Type Phantom validation between platforms and institutions. Phantom Model T1/susceptibility phantom, two‐compartment dynamic flow phantom. Field Strength/Sequence 3T/QSM, T1 mapping, dynamic 2D SPGR. Assessment Philips Ingenia, Siemens Prisma, and Siemens Skyra at three different institutions were assessed. A QSM phantom with concentrations of gadolinium, corresponding to magnetic susceptibilities of 0, 0.1, 0.2, 0.4, and 0.8 ppm was assayed. DCEQP was assessed by measuring a MultiHance bolus as the consistency of the width ratio of the curves at the input and outputs over a range of flow ratios between outputs. Statistical Tests Each biomarker was assessed by measures of accuracy (Pearson correlation), precision (paired t‐test between repeated measurements), and reproducibility (analysis of covariance [ANCOVA] between instruments). Results QSM accuracy of r2 > 0.997 on all three platforms was measured. Precision (P = 0.66 Achieva, P = 0.76 Prisma, P = 0.69 Skyra) and reproducibility (P = 0.89) were good. T1 mapping of accuracy was r2 > 0.98. No significant difference between width ratio regression slopes at site 2 (P = 0.669) or site 3 (P = 0.305), and no significant difference between width ratio regression slopes between sites was detected by ANCOVA (P = 0.48). Data Conclusion The phantom performed as expected and determined that MR measures of QSM and DCEQP are accurate and consistent across repeated measurements and between platforms. Level of Evidence: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1192–1199.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

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Phantom validation of quantitative susceptibility and dynamic contrast‐enhanced permeability MR sequences across instruments and sites

Hobson

Polster

Cao

et al. 2019

Magnetic Resonance Imaging

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“…therapy that stabilizes the CASH and prevent future hemorrhagic sequelae (1,3). CASH lesions have been singularly targeted for therapeutic development and trial readiness (NIH 1-U01-NS104157-01) (3).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Biomarkers of cavernous angioma with symptomatic hemorrhage

Lyne¹,

Girard²,

Koskimäki³

et al. 2019

JCI Insight

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BACKGROUND. Cerebral cavernous angiomas (CAs) with a symptomatic hemorrhage (CASH) have a high risk of recurrent hemorrhage and serious morbidity. METHODS. Eighteen plasma molecules with mechanistic roles in CA pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as that minimizing the Akaike information criterion and validated using machine learning, and was compared with the prognostic CASH biomarker predicting bleeding in the subsequent year. Biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the lesional neurovascular unit (NVU) transcriptome and in plasma miRNAs from CASH and non-CASH patients. RESULTS. The diagnostic CASH biomarker included a weighted combination of soluble CD14 (sCD14), VEGF, C-reactive protein (CRP), and IL-10 distinguishing CASH patients with 76% sensitivity and 80% specificity (P = 0.0003). The prognostic CASH biomarker (sCD14, VEGF, IL-1β, and sROBO-4) was confirmed to predict a bleed in the subsequent year with 83% sensitivity and 93% specificity (P = 0.001). Genes associated with diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen plasma miRNAs were differentially expressed between CASH and non-CASH patients. CONCLUSION. Shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA are mechanistically linked to lesional transcriptome and miRNA. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.

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“…Therefore, QSM and DCEQP were proposed as monitoring biomarkers of lesional bleeding and responses to therapy. 109 Projects are underway to validate these biomarkers at multiple sites as part of the CASH Trial Readiness initiative, 72 and to test their change as affected by ROCK inhibition using atorvastatin in the first Phase I-IIa proof-of-concept (AT CASH EPOC) trial. 74 Greater CA disease severity has been identified in association with genetic modifiers causing proinflammatory states.…”

Section: Implications For Biomarker Developmentmentioning

confidence: 99%

Cavernous angiomas: deconstructing a neurosurgical disease

Awad

Polster

2019

Journal of Neurosurgery

103

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Cavernous angioma (CA) is also known as cavernoma, cavernous hemangioma, and cerebral cavernous malformation (CCM) (National Library of Medicine Medical Subject heading unique ID D006392). In its sporadic form, CA occurs as a solitary hemorrhagic vascular lesion or as clustered lesions associated with a developmental venous anomaly. In its autosomal dominant familial form (Online Mendelian Inheritance in Man #116860), CA is caused by a heterozygous germline loss-of-function mutation in one of three genes—CCM1/KRIT1, CCM2/Malcavernin, and CCM3/PDCD10—causing multifocal lesions throughout the brain and spinal cord.In this paper, the authors review the cardinal features of CA’s disease pathology and clinical radiological features. They summarize key aspects of CA’s natural history and broad elements of evidence-based management guidelines, including surgery. The authors also discuss evidence of similar genetic defects in sporadic and familial lesions, consequences of CCM gene loss in different tissues at various stages of development, and implications regarding the pathobiology of CAs.The concept of CA with symptomatic hemorrhage (CASH) is presented as well as its relevance to clinical care and research in the field. Pathobiological mechanisms related to CA include inflammation and immune-mediated processes, angiogenesis and vascular permeability, microbiome driven factors, and lesional anticoagulant domains. These mechanisms have motivated the development of imaging and plasma biomarkers of relevant disease behavior and promising therapeutic targets.The spectrum of discoveries about CA and their implications endorse CA as a paradigm for deconstructing a neurosurgical disease.

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Trial Readiness in Cavernous Angiomas With Symptomatic Hemorrhage (CASH)

Abstract: The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.

Cited by 40 publications

References 62 publications

Phantom validation of quantitative susceptibility and dynamic contrast‐enhanced permeability MR sequences across instruments and sites

Phantom validation of quantitative susceptibility and dynamic contrast‐enhanced permeability MR sequences across instruments and sites

Biomarkers of cavernous angioma with symptomatic hemorrhage

Cavernous angiomas: deconstructing a neurosurgical disease

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