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Potential of Ferumoxytol as an Intraoperative Contrast Agent and for Imaging Adult and Pediatric Brain Tumors - AJNR News Digest
August 2013
Brain

Potential of Ferumoxytol as an Intraoperative Contrast Agent and for Imaging Adult and Pediatric Brain Tumors

Hunt MA, Bagó AG, Neuwelt E. Single-Dose Contrast Agent for Intraoperative MR Imaging of Intrinsic Brain Tumors by Using Ferumoxtran-10. AJNR Am J Neuroradiol 2005;26:1084–88

Matthew A. Hunt

Matthew A. Hunt

Daniel Guillaume

Daniel Guillaume

Intraoperative MRI during surgical resection of brain tumors has been developed to improve the extent of resection of glioblastoma and other malignant brain tumors in adults and children. The technique provides nearly immediate feedback as to whether the intended surgical goals have been attained (Figure 1).  Early on, the risks of repeat administration of gadolinium-based contrast agents (GBCA) were recognized as a potential pitfall of intraoperative MRI.  This problem resulted mainly from surgically induced disruption of the BBB or alterations in the regional perfusion around the surgical cavity.  Ultrasmall paramagnetic iron oxide (USPIO) nanoparticle imaging emerged as a potential solution to this problem, given its unique properties. Rather than rapidly crossing the leaky BBB and rapidly exiting, USPIO nanoparticles, and particularly ferumoxtran-10, which was used in this report, have a long plasma half-life, cross the BBB slowly, and then are trapped after being taken up by tumor-associated inflammatory cells.

This paper showed that the early-generation USPIO ferumoxtran-10 provides a way to decrease non-tumor-related enhancement during intraoperative MRI from surgically induced BBB injury or vascular changes when compared to GBCA. Subsequently, ferumoxytol has become the preferred USPIO imaging agent due to advantages in administration as well as an FDA-approved indication for iron replacement. This agent has similar imaging properties to ferumoxtran-10 and the ability to be administered as a bolus, which has also allowed for dynamic and vascular blood pool imaging studies.

Figure 1. Intraoperative post-resection T1-weighted MR image in a patient with glioblastoma multiforme receiving ferumoxtran-10 for intraoperative imaging, demonstrating residual enhancing lesion posteriorly (arrow). This lesion was then localized by using integrated frameless stereotaxy and resected. Reproduced from Hunt et al, AJNR 2005.

Figure 1. Intraoperative postresection T1WI in a patient with glioblastoma multiforme receiving ferumoxtran-10 for intraoperative imaging, demonstrating residual enhancing lesion posteriorly (arrow). This lesion was then localized by using integrated frameless stereotaxy and resected. Reproduced from Hunt et al, AJNR 2005.

Clinical studies also used the early intravascular characteristic of the USPIOs to measure blood volume in intracerebral lesions using perfusion MRI.1,2 Building on our preclinical and clinical findings, a clinical study

showed that ferumoxytol-based relative cerebral blood volume (rCBV) measurements were consistent regardless of preload dose or correction algorithms, and improved the differentiation of actively growing tumor from pseudoprogression in high-grade glioma.3  An analogous study was done in the pediatric population by Thomson  et al.4 The study concluded that ferumoxytol-based DSC MRI was a useful tool, preoperatively, in devising a tumor resection plan; intraoperatively, in localizing the tumor and the most vascular regions of the tumor using ultrasound; and postoperatively, in the evaluation of true tumor progression versus pseudoprogression (Figure 2). A new technique providing higher resolution CBV maps can be obtained using USPIO-enhanced steady-state susceptibility-weighted images.5

Figure 2. Axial dynamic MRI parametric maps of a pediatric patient with anaplastic oligoastrocytoma receiving ferumoxytol and gadolinium in a single imaging session. Circles indicate regions of interest. The top row images were obtained after a new small area of enhancement was noted in the resection cavity (A, arrow) on post-gadolinium T1-weighted MRI. Post-ferumoxytol DSC MRI parametric maps (B-C) demonstrate low vascularity: rCBVmax = 0.85 and rCBF = 0.57, while DCE MRI parametric maps (D-E) demonstrate elevated permeability: Ktrans max ≈ 0.23 and ve max ≈ 0.18. The bottom row images (F-J), obtained 3 months after the first DSC MRI, demonstrate minimally increased post-gadolinium enhancement (F) and post-ferumoxytol dynamic MRI parametric maps (G-J): rCBVmax = 0.99, rCBF = 0.90, Ktrans max ≈ 0.47, ve max ≈ 0.19. Findings on both studies and the lack of substantial temporal progression support pseudoprogression. Reproduced from J Neurooncol, 2012, with kind permission from Springer Science+Business Media B.V.4

Figure 2. Axial dynamic MRI parametric maps of a pediatric patient with anaplastic oligoastrocytoma receiving ferumoxytol and gadolinium in a single imaging session. Circles indicate regions of interest. The top row images were obtained after a new small area of enhancement was noted in the resection cavity (A, arrow) on postgadolinium T1WI. Postferumoxytol DSC MRI parametric maps (B-C) demonstrate low vascularity: rCBVmax = 0.85 and rCBF = 0.57, while DCE MRI parametric maps (D-E) demonstrate elevated permeability: Ktrans max ≈ 0.23 and Ve max ≈ 0.18. The bottom row images (F-J), obtained 3 months after the first DSC MRI, demonstrate minimally increased postgadolinium enhancement (F) and postferumoxytol dynamic MRI parametric maps (G-J): rCBVmax = 0.99, rCBF = 0.90, Ktrans max ≈ 0.47, Ve max ≈ 0.19. Findings on both studies and the lack of substantial temporal progression support pseudoprogression. Reproduced from J Neurooncol 2012, with kind permission from Springer Science+Business Media B.V.4

At the University of Minnesota, our ultimate goal is the ability to use ferumoxytol to guide decision making from the intraoperative period through the course of care for patients with malignant brain tumors through multimodality imaging and anatomic and physiologic parameters.

References

  1. Neuwelt EA, Várallyay CG, Manninger S, et al. The potential of ferumoxytol nanoparticle magnetic resonance imaging, perfusion, and angiography in central nervous system malignancy: a pilot study. Neurosurgery 2007;60:601–11. doi: 10.1227/01.NEU.0000255350.71700.37
  2. Weinstein J, Várallyay C, Dósa E, et al. Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab 2010;30:15–35. doi: 10.1038/jcbfm.2009.192
  3. Gahramanov S, Muldoon LL, Kraemer DF, et al. Pseudoprogression of glioblastoma after chemo- and radiation therapy: diagnosis by using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging with ferumoxytol versus gadoteridol and correlation with survival. Radiology 2013;266:842–52. doi: 10.1148/radiol.12111472
  4. Thompson EM, Guillaume DJ, Dósa E, et al. Dual contrast perfusion MRI in a single imaging session for assessment of pediatric brain tumors. J Neurooncol 2012;109:105–14. doi: 10.1007/s11060-012-0872-x
  5. Várallyay CG, Nesbit E, Fu R, et al. High-resolution steady-state cerebral blood volume maps in patients with central nervous system neoplasms using ferumoxytol, a superparamagnetic iron oxide nanoparticle. J Cereb Blood Flow Metab 2013;33:780–86. doi: 10.1038/jcbfm.2013.36