Combined iron oxide nanoparticle ferumoxytol and gadolinium contrast enhanced MRI define glioblastoma pseudoprogression

Ramon Barajas, Bronwyn Hamilton, Daniel Schwartz, Heather L. Mcconnell, David Pettersson, Andrea Horvath, Laszlo Szidonya, Csanad G. Varallyay, Jenny Firkins, Jerry Jaboin, Charlotte D. Kubicky, Ahmed Raslan, Aclan Dogan, Justin Cetas, Jeremy Ciporen, Seunggu (Jude) Han, Prakash Ambady, Leslie Muldoon, Randall (Randy) Woltjer, William Rooney & 1 others Edward Neuwelt

Research output: Contribution to journalArticle

Abstract

Background. Noninvasively differentiating therapy-induced pseudoprogression from recurrent disease in patients with glioblastoma is prospectively difficult due to the current lack of a biologically specific imaging metric. Ferumoxytol iron oxide nanoparticle MRI contrast characterizes innate immunity mediated neuroinflammation; therefore, we hypothesized that combined ferumoxytol and gadolinium enhanced MRI could serve as a biomarker of glioblastoma pseudoprogression. Methods. In this institutional review board-approved, retrospective study, we analyzed ferumoxytol and gadolinium contrast enhanced T1-weighted 3T MRI in 45 patients with glioblastoma over multiple clinical timepoints. Isocitrate dehydrogenase 1 (IDH-1) mutational status was characterized by exome sequencing. Sum of products diameter measurements were calculated according to Response Assessment in Neuro-Oncology criteria from both gadolinium and ferumoxytol enhanced sequences. Enhancement mismatch was calculated as the natural log of the ferumoxytol to gadolinium sum of products diameter ratio. Analysis of variance and Student's t-test assessed differences in mismatch ratios. P-value <0.05 indicated statistical significance. Results. With the development of pseudoprogression we observed a significantly elevated mismatch ratio compared with disease recurrence (P < 0.01) within IDH-1 wild type patients. Patients with IDH-1 mutation demonstrated significantly reduced mismatch ratio with the development of pseudoprogression compared with disease recurrence (P < 0.01). Receiver operator curve analysis demonstrated 100% sensitivity and specificity for the use of mismatch ratios as a diagnostic biomarker of pseudoprogression. Conclusion. Our study suggests that ferumoxytol to gadolinium contrast mismatch ratios are an MRI biomarker for the diagnosis of pseudoprogression in patients with glioblastoma. This may be due to the unique characterization of therapy-induced neuroinflammation.

Original languageEnglish (US)
Pages (from-to)517-526
Number of pages10
JournalNeuro-Oncology
Volume21
Issue number4
DOIs
StatePublished - Mar 18 2019

Fingerprint

Ferrosoferric Oxide
Gadolinium
Glioblastoma
Nanoparticles
Isocitrate Dehydrogenase
Biomarkers
Exome
Recurrence
Research Ethics Committees
Innate Immunity
ferric oxide
Analysis of Variance
Retrospective Studies
Students
Sensitivity and Specificity
Mutation
Therapeutics

Keywords

  • ferumoxytol
  • glioblastoma
  • macrophage
  • pseudoprogression
  • RANO

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

@article{7978416888994c65bdd60920141f6ccf,
title = "Combined iron oxide nanoparticle ferumoxytol and gadolinium contrast enhanced MRI define glioblastoma pseudoprogression",
abstract = "Background. Noninvasively differentiating therapy-induced pseudoprogression from recurrent disease in patients with glioblastoma is prospectively difficult due to the current lack of a biologically specific imaging metric. Ferumoxytol iron oxide nanoparticle MRI contrast characterizes innate immunity mediated neuroinflammation; therefore, we hypothesized that combined ferumoxytol and gadolinium enhanced MRI could serve as a biomarker of glioblastoma pseudoprogression. Methods. In this institutional review board-approved, retrospective study, we analyzed ferumoxytol and gadolinium contrast enhanced T1-weighted 3T MRI in 45 patients with glioblastoma over multiple clinical timepoints. Isocitrate dehydrogenase 1 (IDH-1) mutational status was characterized by exome sequencing. Sum of products diameter measurements were calculated according to Response Assessment in Neuro-Oncology criteria from both gadolinium and ferumoxytol enhanced sequences. Enhancement mismatch was calculated as the natural log of the ferumoxytol to gadolinium sum of products diameter ratio. Analysis of variance and Student's t-test assessed differences in mismatch ratios. P-value <0.05 indicated statistical significance. Results. With the development of pseudoprogression we observed a significantly elevated mismatch ratio compared with disease recurrence (P < 0.01) within IDH-1 wild type patients. Patients with IDH-1 mutation demonstrated significantly reduced mismatch ratio with the development of pseudoprogression compared with disease recurrence (P < 0.01). Receiver operator curve analysis demonstrated 100{\%} sensitivity and specificity for the use of mismatch ratios as a diagnostic biomarker of pseudoprogression. Conclusion. Our study suggests that ferumoxytol to gadolinium contrast mismatch ratios are an MRI biomarker for the diagnosis of pseudoprogression in patients with glioblastoma. This may be due to the unique characterization of therapy-induced neuroinflammation.",
keywords = "ferumoxytol, glioblastoma, macrophage, pseudoprogression, RANO",
author = "Ramon Barajas and Bronwyn Hamilton and Daniel Schwartz and Mcconnell, {Heather L.} and David Pettersson and Andrea Horvath and Laszlo Szidonya and Varallyay, {Csanad G.} and Jenny Firkins and Jerry Jaboin and Kubicky, {Charlotte D.} and Ahmed Raslan and Aclan Dogan and Justin Cetas and Jeremy Ciporen and Han, {Seunggu (Jude)} and Prakash Ambady and Leslie Muldoon and Woltjer, {Randall (Randy)} and William Rooney and Edward Neuwelt",
year = "2019",
month = "3",
day = "18",
doi = "10.1093/neuonc/noy160",
language = "English (US)",
volume = "21",
pages = "517--526",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "4",

}

TY - JOUR

T1 - Combined iron oxide nanoparticle ferumoxytol and gadolinium contrast enhanced MRI define glioblastoma pseudoprogression

AU - Barajas, Ramon

AU - Hamilton, Bronwyn

AU - Schwartz, Daniel

AU - Mcconnell, Heather L.

AU - Pettersson, David

AU - Horvath, Andrea

AU - Szidonya, Laszlo

AU - Varallyay, Csanad G.

AU - Firkins, Jenny

AU - Jaboin, Jerry

AU - Kubicky, Charlotte D.

AU - Raslan, Ahmed

AU - Dogan, Aclan

AU - Cetas, Justin

AU - Ciporen, Jeremy

AU - Han, Seunggu (Jude)

AU - Ambady, Prakash

AU - Muldoon, Leslie

AU - Woltjer, Randall (Randy)

AU - Rooney, William

AU - Neuwelt, Edward

PY - 2019/3/18

Y1 - 2019/3/18

N2 - Background. Noninvasively differentiating therapy-induced pseudoprogression from recurrent disease in patients with glioblastoma is prospectively difficult due to the current lack of a biologically specific imaging metric. Ferumoxytol iron oxide nanoparticle MRI contrast characterizes innate immunity mediated neuroinflammation; therefore, we hypothesized that combined ferumoxytol and gadolinium enhanced MRI could serve as a biomarker of glioblastoma pseudoprogression. Methods. In this institutional review board-approved, retrospective study, we analyzed ferumoxytol and gadolinium contrast enhanced T1-weighted 3T MRI in 45 patients with glioblastoma over multiple clinical timepoints. Isocitrate dehydrogenase 1 (IDH-1) mutational status was characterized by exome sequencing. Sum of products diameter measurements were calculated according to Response Assessment in Neuro-Oncology criteria from both gadolinium and ferumoxytol enhanced sequences. Enhancement mismatch was calculated as the natural log of the ferumoxytol to gadolinium sum of products diameter ratio. Analysis of variance and Student's t-test assessed differences in mismatch ratios. P-value <0.05 indicated statistical significance. Results. With the development of pseudoprogression we observed a significantly elevated mismatch ratio compared with disease recurrence (P < 0.01) within IDH-1 wild type patients. Patients with IDH-1 mutation demonstrated significantly reduced mismatch ratio with the development of pseudoprogression compared with disease recurrence (P < 0.01). Receiver operator curve analysis demonstrated 100% sensitivity and specificity for the use of mismatch ratios as a diagnostic biomarker of pseudoprogression. Conclusion. Our study suggests that ferumoxytol to gadolinium contrast mismatch ratios are an MRI biomarker for the diagnosis of pseudoprogression in patients with glioblastoma. This may be due to the unique characterization of therapy-induced neuroinflammation.

AB - Background. Noninvasively differentiating therapy-induced pseudoprogression from recurrent disease in patients with glioblastoma is prospectively difficult due to the current lack of a biologically specific imaging metric. Ferumoxytol iron oxide nanoparticle MRI contrast characterizes innate immunity mediated neuroinflammation; therefore, we hypothesized that combined ferumoxytol and gadolinium enhanced MRI could serve as a biomarker of glioblastoma pseudoprogression. Methods. In this institutional review board-approved, retrospective study, we analyzed ferumoxytol and gadolinium contrast enhanced T1-weighted 3T MRI in 45 patients with glioblastoma over multiple clinical timepoints. Isocitrate dehydrogenase 1 (IDH-1) mutational status was characterized by exome sequencing. Sum of products diameter measurements were calculated according to Response Assessment in Neuro-Oncology criteria from both gadolinium and ferumoxytol enhanced sequences. Enhancement mismatch was calculated as the natural log of the ferumoxytol to gadolinium sum of products diameter ratio. Analysis of variance and Student's t-test assessed differences in mismatch ratios. P-value <0.05 indicated statistical significance. Results. With the development of pseudoprogression we observed a significantly elevated mismatch ratio compared with disease recurrence (P < 0.01) within IDH-1 wild type patients. Patients with IDH-1 mutation demonstrated significantly reduced mismatch ratio with the development of pseudoprogression compared with disease recurrence (P < 0.01). Receiver operator curve analysis demonstrated 100% sensitivity and specificity for the use of mismatch ratios as a diagnostic biomarker of pseudoprogression. Conclusion. Our study suggests that ferumoxytol to gadolinium contrast mismatch ratios are an MRI biomarker for the diagnosis of pseudoprogression in patients with glioblastoma. This may be due to the unique characterization of therapy-induced neuroinflammation.

KW - ferumoxytol

KW - glioblastoma

KW - macrophage

KW - pseudoprogression

KW - RANO

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U2 - 10.1093/neuonc/noy160

DO - 10.1093/neuonc/noy160

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JF - Neuro-Oncology

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