Ferumoxytol-Enhanced MRI in Children and Young Adults: State of the Art

Abstract

Ferumoxytol is an ultrasmall iron oxide nanoparticle that was originally approved by the FDA in 2009 for IV treatment of iron deficiency in adults with chronic kidney disease. Subsequently, its off-label use as an MRI contrast agent increased in clinical practice, particularly in pediatric patients in North America. Unlike conventional MRI contrast agents that are based on the rare earth metal gadolinium (gadolinium-based contrast agents), ferumoxytol is biodegradable and carries no potential risk of nephrogenic systemic fibrosis. At FDA-approved doses, ferumoxytol shows no long-term tissue retention in patients with intact iron metabolism. Ferumoxytol provides unique MRI properties, including long-lasting vascular retention (facilitating high-quality vascular imaging) and retention in reticuloendothelial system tissues, thereby supporting a variety of applications beyond those possible with gadolinium-based contrast agents (GBCAs). This Clinical Perspective describes clinical and early translational applications of ferumoxytol-enhanced MRI in children and young adults through off-label use in a variety of settings, including vascular, cardiac, and cancer imaging, drawing on the institutional experience of the authors. In addition, we describe current advances in pre-clinical and clinical research using ferumoxytol in cellular and molecular imaging as well as the use of ferumoxytol as a novel potential cancer therapeutic agent.

Keywords: cancer imaging; ferumoxytol; molecular imaging; pediatric MRI.

Figure 1.

Schematic overview of off-label clinical applications of ferumoxytol-enhanced MRI in children and young adults. Primary applications include vascular imaging (including pre-transplant vessel assessment), cardiac imaging, and cancer imaging. Cancers most commonly evaluated by ferumoxytol-enhanced MRI are depicted. Credit: Created with BioRender.com.

Figure 2.

20-year-old female patient with arteriovenous malformation (AVM) of left supraclavicular region adjacent to left brachial plexus, evaluated by 3-T MRI after slow administration of ferumoxytol. a, Coronal maximum intensity projection (MIP) image from 4D ferumoxytol-enhanced MRA acquisition shows that dominant arterial feeder of AVM arises from anterior aspect of proximal left subclavian artery (single arrow), distal to left internal mammary artery takeoff (two arrows). b, Coronal fat-saturated T1-weighted ferumoxytol-enhanced LAVA image shows feeder artery (arrow). c, Axial fat-saturated T1-weighted ferumoxytol-enhanced LAVA image shows AVM. d, Coronal image from ferumoxytol-enhanced 4D flow MRI illustrates direction of blood flow in arterial inflow and venous outflow for treatment purposes; arrow indicates dominant feeder artery. In present patient, technique allowed quantification and measurement of flow within both feeder arteries and draining veins. e, Image from ferumoxytol-enhanced 4D flow MRI demonstrates example measurement of flow within dominant feeder artery (arrow), measuring 0.63 L/m. Case illustrates use of ferumoxytol-enhanced 4D flow MRI to enable high-resolution imaging of vascular anomalies.

Figure 3.

15-year-old male patient with subtotal resection of left cerebral hemorrhagic glioblastoma, evaluated by 3-T MRI before and 24 hours after administration of ferumoxytol. a, Axial T2-weighted MR image shows resection cavity with hemorrhagic component and large nonenhancing soft tissue component in left cerebral white matter (arrow). b and c, Axial T1-weighted MPRAGE images before (b) and after (c) ferumoxytol administration. Ferumoxytol-enhanced MRI shows area of hyperintense enhancement indicative of residual tumor area (region indicated by arrow in b and c). Case illustrates use of ferumoxytol-enhanced MRI to clearly delineate cerebral vessels.

Figure 4.

17-year-old male patient with left femur osteosarcoma, evaluated by 3-T FDG PET/MRI immediately after bolus administration of gadolinium-based contrast agent (GBCA) and 24 hours after slow administration of ferumoxytol. Imaging demonstrated ill-defined intra- and extraosseous enhancing lesion in distal left femur with peripheral FDG uptake (SUVmax 6.34) and pathologic fracture of distal left lateral femur metaphysis. a, Coronal maximum intensity projection image from FDG PET shows FDG-avid disease in left femur. b, Unenhanced axial fat-saturated T2-weighted image shows tumor mass in distal femur and extensive perilesional edema. C, Delayed axial fat-saturated T2-weighted image following ferumoxytol administration shows hypointense (dark) enhancement of periphery of tumor tissue (two white arrows) and sparing of central tumor areas that might represent necrosis. d, Axial fat-saturated T1-weighted ferumoxytol-enhanced MR image overlaid with FDG PET image shows peripheral FDG uptake. e, Unenhanced axial fat-saturated T1-weighted image shows intermediate signal of lesion. f, Axial postcontrast fat-saturated T1-weighted image following GBCA injection shows peripheral hyperintense enhancement of tumor tissue during arterial phase (arrow), with sparing of central area of necrosis. g, Axial fat-suppressed T1-weighted image obtained 24 hours following ferumoxytol administration demonstrates hyperintense peripheral tumor enhancement (two white arrows). MIM Software Inc., Cleveland, OH was used for MRI/PET fusion.

Figure 5.

6-month-old female patient with hepatoblastoma who underwent 3-T MRI immediately after slow infusion of ferumoxytol to evaluate hepatic vasculature prior to planned resection. a, Axial fat-saturated T2-weighted image shows large circumscribed heterogeneous mass in right hepatic lobe (three arrows); image has high liver-to-lesion contrast with low signal intensity of surrounding liver tissue. b, Axial fat-saturated ferumoxytol-enhanced T1 image shows large mass and a marked enhancement and improved of abdominal vessels, which are well delineated. Tumor tissue shows less enhancement than liver parenchyma and causes mass effect on intrahepatic inferior vena cava (IVC), with at least 50% abutment (arrow). c, Maximum intensity projection image constructed to depict hepatic vasculature as guide for surgical planning for possible resection. Image shows middle hepatic vein (MHV) and left hepatic vein (LHV) (arrows). Middle hepatic vein (MHV) contacts mass as it drains to IVC, but shows no clear tumor invasion. Right hepatic vein is not seen and infiltrated or occluded by mass.

Figure 6.

14-year-old male patient with large focal nodular hyperplasia occupying most of right hepatic lobe and caudate segment, evaluated by 3-T MRI performed immediately after bolus administration of gadolinium-based contrast agent (GBCA) and 24 hours after slow administration of ferumoxytol. a, Coronal unenhanced single-shot T2-weighted MR image shows large liver mass (two white arrows) that is not well delineated from surrounding normal liver tissue. b and c, Axial fat-saturated GBCA-enhanced T1-weighted image (b) and axial fat-saturated ferumoxytol-enhanced T1-weighted image (c) provide similar delineation of mass (three arrows, b and c). Limitation of ferumoxytol when following FDA’s recommendations of slow administration is that first-pass arterial phase images cannot be obtained. However, arterial branches can be clearly delineated and followed at later time points due to high vessel contrast. d, Axial ferumoxytol-enhanced maximum intensity projection (MIP) image of hepatic vasculature shows enlarged right hepatic vein (RHV, nearly 7 mm), left hepatic vein (LHV), and portal vein (PV) (dots and arrows). e, 3D MIP image of liver clearly depicts RHV and LHV (dots and arrows). f, Additional 3D MIP image shows right hepatic artery (RHA), which was selected at angiography; common hepatic artery (CHA) originates from superior mesenteric artery. RHA and CHA are indicated by dots and arrows. Case illustrates use of ferumoxytol-enhanced MRI for high-quality vascular mapping.

Figure 7.

25-year-old male patient with desmoplastic small round cell tumor evaluated by 3-T FDG PET/MRI performed immediately after bolus administration of gadolinium-based contrast agent (GBCA) and 24 hours after slow administration of ferumoxytol. a, Axial fat-saturated T2-weighted MR image shows multiple T2-hyperintense focal tumor lesions along liver and peritoneal lining (exemplary lesions marked with arrows). b, Axial fat-saturated GBCA-enhanced T1-weighted LAVA image shows moderate enhancement of both liver and focal tumor lesions (arrows), leading to limited tumor-to-liver contrast. c, Axial fat-saturated T2-weighted image after infusion of ferumoxytol shows hypointense enhancement of liver, and hyperintense enhancement of tumor nodules (arrows), leading to high tumor-to-liver contrast. d, Axial fat-saturated T1-weighted ferumoxytol-enhanced LAVA image shows less enhancement of tumor nodules (arrows) compared to liver, leading to high tumor-to-liver contrast. e, Axial fat-saturated ferumoxytol-enhanced T1-weighted LAVA image overlaid with axial image from simultaneously acquired FDG PET shows hypermetabolic tumor nodules (arrows). Hyperintense vascular enhancement by ferumoxytol allows clear localization of tumor in relation to vessels. MIM Software Inc., Cleveland, OH was used for MRI/PET fusion.