Distinguishing Extravascular from Intravascular Ferumoxytol Pools within the Brain: Proof of Concept in Patients with Treated Glioblastoma.

BACKGROUND AND PURPOSE: Glioblastoma-associated macrophages are a major constituent of the immune response to therapy and are known to engulf the iron-based MR imaging contrast agent, ferumoxytol. Current ferumoxytol MR imaging techniques for localizing macrophages are confounded by contaminating intravascular signal. The aim of this study was to assess the utility of a newly developed MR imaging technique, segregation and extravascular localization of ferumoxytol imaging, for differentiating extravascular-from-intravascular ferumoxytol contrast signal at a delayed 24-hour imaging time point. MATERIALS AND METHODS: Twenty-three patients with suspected post-chemoradiotherapy glioblastoma progression underwent ferumoxytol-enhanced SWI. Segregation and extravascular localization of ferumoxytol imaging maps were generated as the voxelwise difference of the delayed (24 hours) from the early (immediately after administration) time point SWI maps. Continuous segregation and extravascular localization of ferumoxytol imaging map values were separated into positive and negative components. Image-guided biologic correlation was performed. RESULTS: Negative segregation and extravascular localization of ferumoxytol imaging values correlated with early and delayed time point SWI values, demonstrating that intravascular signal detected in the early time point persists into the delayed time point. Positive segregation and extravascular localization of ferumoxytol imaging values correlated only with delayed time point SWI values, suggesting successful detection of the newly developed extravascular signal. CONCLUSIONS: Segregation and extravascular localization of ferumoxytol MR imaging improves on current techniques by eliminating intrinsic tissue and intravascular ferumoxytol signal and may inform glioblastoma outcomes by serving as a more specific metric of macrophage content compared with uncorrected T1 and SWI techniques.

Diagnostic impact of preoperative corticosteroids in primary central nervous system lymphoma.

PURPOSE: High dose corticosteroids are an effective tool for rapidly alleviating neurologic symptoms caused by intracranial mass lesions. However, there is concern that preoperative corticosteroids limit the ability to obtain a definitive pathologic diagnosis, particularly if imaging features suggest primary central nervous system lymphoma (PCNSL). METHODS: To explore the impact of preoperative corticosteroids in newly diagnosed PCNSL patients, from 2009 to 2018 treated at our institution. RESULTS: We identified 54 patients; 18 had received corticosteroids prior to biopsy or resection. Only in one case did the patient have a prior non-diagnostic biopsy, requiring a second procedure. The cumulative doses of preoperative dexamethasone ranged from 4 mg to 120 mg (mean 32 mg, median 24 mg), given over 1-14 days (mean 2 days, median 1 day), and the majority had received corticosteroids for only 1-2 days. There was a trend for a larger diameter of lesional T1 contrast enhancement for patients who received steroids (39 mm vs. 34 mm, p = 0.11). In this series of cases with pathologically and clinically proven PCNSL, preoperative corticosteroids had been given in a third of cases, suggesting that they may be given for symptomatic relief without compromising pathologic diagnosis. CONCLUSIONS: Despite the commonly held tenet that preoperative corticosteroids can obscure the pathologic diagnosis in PCNSL, this is likely not the case in the majority of patients who receive a short course preoperatively. Obtaining a second stereotactic scan to confirm continued presence of the lesion prior to tissue sampling may also mitigate these concerns.

Radiation-Induced Myelitis: Initial and Follow-Up MRI and Clinical Features in Patients at a Single Tertiary Care Institution during 20 Years.

Myelitis is a rare complication of radiation exposure to the spinal cord and is often a diagnosis of exclusion. A retrospective review of clinical records and serial imaging was performed to identify subjects with documented myelitis and a history of prior radiation. Eleven patients fulfilled the inclusion criteria. All patients had longitudinally extensive cord involvement with homogeneous precontrast T1 hyperintense signal in the adjacent vertebrae, corresponding to the radiation field. T2 signal abnormalities involving the central two-thirds of the cord were seen in 6/11 patients (55%). The degree of cord expansion and contrast enhancement was variable but was seen in 6 (54%) and 5 (45%) patients, respectively. On follow-up, 2 patients developed cord atrophy, while complete resolution was noted in 1. Clinical improvement was noted in 5 patients, with symptom progression in 2 patients. Our results suggest that radiation myelitis is neither universally progressive nor permanent, and some radiographic and clinical improvement may occur.

Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors.

The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is epigenetically silenced in some tumors by MGMT gene promoter methylation. MGMT-hypermethylated solid tumors have enhanced susceptibility to the cytotoxic effects of alkylating chemotherapy such as temozolomide, compared with non-methylated tumors. In glioblastoma, subjects with MGMT hypermethylation have significantly longer survival rates after chemoradiotherapy. We report the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified anti-MGMT morpholino oligonucleotide (AMON) sequences. We demonstrate >40% reduction in the in vitro proliferation index and cell viability in radiation-primed MGMT-expressing human solid tumor cells treated with a single dose of AMONs and temozolomide. We further demonstrate the feasibility of using a non-ablative dose of radiation in vivo to guide and enhance the delivery of intravenously administered AMONs to achieve 50% MGMT knockdown only at radiation-primed tumor sites in a subcutaneous tumor model. Local upregulation of physiological endocytosis after radiation may have a role in radiation-guided uptake of AMONs. This approach holds direct translational significance in glioblastoma and brain metastases where radiation is part of the standard of care; our approach to silence MGMT could overcome the significant problem of MGMT-mediated chemoresistance.

What Does the Boxed Warning Tell Us? Safe Practice of Using Ferumoxytol as an MRI Contrast Agent.

BACKGROUND AND PURPOSE: Despite the label change and the FDA's boxed warning added to the Feraheme (ferumoxytol) label in March 2015, radiologists have shown increasing interest in using ferumoxytol as an MR imaging contrast agent as a supplement or alternative to gadolinium. The goals of this study were to provide information regarding ferumoxytol safety as an imaging agent in a single center and to assess how the Feraheme label change may affect this potential, currently off-label indication. MATERIALS AND METHODS: This retrospective study evaluated the overall frequency of ferumoxytol-related adverse events when used for CNS MR imaging. Patients with various CNS pathologies were enrolled in institutional review board-approved imaging studies. Ferumoxytol was administered as multiple rapid bolus injections. The risk of adverse events was correlated with demographic data/medical history. RESULTS: The safety of 671 ferumoxytol-enhanced MR studies in 331 patients was analyzed. No anaphylactic, life-threatening, or fatal (grade 4 or 5) adverse events were recorded. The overall proportion of ferumoxytol-related grade 1-3 adverse events was 10.6% (8.6% occurring within 48 hours), including hypertension (2.38%), nausea (1.64%), diarrhea (1.04%), and headache (1.04%). History of 1 or 2 allergies was associated with an increased risk of adverse events (14.61% versus 7.51% [no history]; P = .007). CONCLUSIONS: The frequency of mild ferumoxytol-related adverse events was comparable with literature results, and no serious adverse event was recorded. Although the recommendations in the boxed warning should be followed, serious adverse events appear to be rare, and with proper precautions, ferumoxytol may be a valuable MR imaging agent.