Introduction: Background and Purpose: 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 agents characterize innate immunity mediated neuroinflammation; therefore, we hypothesized that combined ferumoxytol and gadolinium enhanced MRI could serve as a biomarker of glioblastoma pseudoprogression.

Methods: Materials and Methods: In this institutional review board approved, retrospective study, we analyzed ferumoxytol and gadolinium contrast enhanced T1-weighted 3T MRI in patients with glioblastoma over multiple clinical time points. IDH-1 mutational status was characterized by exome sequencing. Sum of products diameter measurements were calculated according to RANO 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. Students T-test assessed differences in mismatch ratios. P-value < 0.05 indicated statistical significance.

Results: Results: With the development of pseudoprogression we observed a significantly elevated mismatch ratio when compared to disease progression (P< 0.01) within IDH-1 wild type patients. Patients with IDH-1 mutation demonstrated significantly reduced mismatch ratio with the development of pseudoprogression when compared to disease progression (P< 0.01). Receiver operator curve analysis demonstrated 100% sensitivity and specificity for the use of mismatch ratios as a diagnostic biomarker of pseudoprogression. Image guided tissue sampling sites from IDH-1 wild type glioblastoma disease recurrence were categorized by the presence of ferumoxytol or gadolinium enhancement. Ferumoxytol only enhancement demonstrated activated microglia or vascular hyalinization with scattered macrophages in the absence of viable tumor (Figure 2). Dual enhancing sites demonstrated highly cellular tumor with microvascular proliferation and epithelioid TAM.

Conclusions: Conclusion: We demonstrate that contrast mismatch ratios are a specific MRI biomarker for the diagnosis of pseudoprogression in patients with glioblastoma that may be due to the unique characterization of therapy-induced neuroinflammation.

Patient Care: We demonstrate that, unlike RANO recommended gadolinium SPD measurements alone, the ratio of iron to gadolinium enhancement SPD mismatch is diagnostic of pseudoprogression in IDH-1 mutated and wild type glioblastoma as well as in glioblastoma patients with non-methylated MGMT promoter. These results have the potential to improve patient care by establishing a non invasive means by which to guide clinical treatment of patients with glioblastoma.

Learning Objectives: To discuss the role of iron and gadolinium enhanced MRI in the diagnosis of glioblastoma pseudoprogression To discuss the role of iron as a specific biomarker to distinguish pseudoprogression from glioblastoma

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