Cerebral blood volume mapping with ferumoxytol in dynamic susceptibility contrast perfusion MRI: Comparison to standard of care.

BACKGROUND: Cerebral blood volume (CBV) mapping with a dynamic susceptibility contrast (DSC) perfusion technique has become a clinical tool in diagnosing and follow-up of brain tumors. Ferumoxytol, a long-circulating iron oxide nanoparticle, has been tested for CBV mapping, but the optimal dose has not been established. PURPOSE: To compare ferumoxytol DSC of two different doses to standard of care gadoteridol by analyzing time-intensity curves and CBV maps in normal-appearing brain regions. STUDY TYPE: Retrospective. SUBJECTS: Fifty-four patients with various brain disorders. FIELD STRENGTH/SEQUENCE: 3T MRI. DSC-MRI was performed with 0.1 mmol/kg gadoteridol and 1 day later with ferumoxytol in doses of 1 or 2 mg/kg. ASSESSMENT: Signal changes during first pass, relative CBV (rCBV) in normal-appearing thalamus, putamen, and globus pallidus, and contrast-to-noise ratio (CNR) of the CBV maps were compared between gadoteridol and various doses of ferumoxytol using an automated method. To subjectively assess the quality of the CBV maps, two blinded readers also assessed visual conspicuity of the putamen. STATISTICAL TESTS: Linear mixed effect model was used for statistical comparison. RESULTS: Compared to gadoteridol, 1 mg/kg ferumoxytol showed no difference in CNR (P = 0.6505), peak ΔR2*, and rCBV in the putamen (P = 0.2669, 0.0871) or in the thalamus (P = 0.517, 0.9787); 2 mg/kg ferumoxytol increased peak ΔR2* as well as the CNR (P < 0.0001), but also mildly increased rCBV in putamen and globus pallidus (P = 0.0005, 0.0012). Signal intensities during first pass remained highly above the noise level, with overlapping of 95% confidence intervals with noise only in 3 out of 162 tested regions. Compared to gadoteridol, the visual image quality showed mild improvement with 1 mg/kg (P = 0.02) and marked improvement with 2 mg/kg ferumoxytol (P < 0.0001). DATA CONCLUSION: 1 mg/kg ferumoxytol provides similar imaging results to standard gadoteridol for DSC-MRI, and 2 mg/kg has a benefit of increased CNR, but may also result in mildly increased rCBV values. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:441-448.

Current and potential imaging applications of ferumoxytol for magnetic resonance imaging.

Contrast-enhanced magnetic resonance imaging is a commonly used diagnostic tool. Compared with standard gadolinium-based contrast agents, ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA), used as an alternative contrast medium, is feasible in patients with impaired renal function. Other attractive imaging features of i.v. ferumoxytol include a prolonged blood pool phase and delayed intracellular uptake. With its unique pharmacologic, metabolic, and imaging properties, ferumoxytol may play a crucial role in future magnetic resonance imaging of the central nervous system, various organs outside the central nervous system, and the cardiovascular system. Preclinical and clinical studies have demonstrated the overall safety and effectiveness of this novel contrast agent, with rarely occurring anaphylactoid reactions. The purpose of this review is to describe the general and organ-specific properties of ferumoxytol, as well as the advantages and potential pitfalls associated with its use in magnetic resonance imaging. To more fully demonstrate the applications of ferumoxytol throughout the body, an imaging atlas was created and is available online as supplementary material.

Pseudo-extravasation rate constant of dynamic susceptibility contrast-MRI determined from pharmacokinetic first principles.

Dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) is widely used to obtain informative perfusion imaging biomarkers, such as the relative cerebral blood volume (rCBV). The related post-processing software packages for DSC-MRI are available from major MRI instrument manufacturers and third-party vendors. One unique aspect of DSC-MRI with low-molecular-weight gadolinium (Gd)-based contrast reagent (CR) is that CR molecules leak into the interstitium space and therefore confound the DSC signal detected. Several approaches to correct this leakage effect have been proposed throughout the years. Amongst the most popular is the Boxerman-Schmainda-Weisskoff (BSW) K2 leakage correction approach, in which the K2 pseudo-first-order rate constant quantifies the leakage. In this work, we propose a new method for the BSW leakage correction approach. Based on the pharmacokinetic interpretation of the data, the commonly adopted R2 * expression accounting for contributions from both intravascular and extravasating CR components is transformed using a method mathematically similar to Gjedde-Patlak linearization. Then, the leakage rate constant (KL ) can be determined as the slope of the linear portion of a plot of the transformed data. Using the DSC data of high-molecular-weight (~750 kDa), iron-based, intravascular Ferumoxytol (FeO), the pharmacokinetic interpretation of the new paradigm is empirically validated. The primary objective of this work is to empirically demonstrate that a linear portion often exists in the graph of the transformed data. This linear portion provides a clear definition of the Gd CR pseudo-leakage rate constant, which equals the slope derived from the linear segment. A secondary objective is to demonstrate that transformed points from the initial transient period during the CR wash-in often deviate from the linear trend of the linearized graph. The inclusion of these points will have a negative impact on the accuracy of the leakage rate constant, and even make it time dependent.

Ferumoxytol-enhanced MRI differentiation of meningioma from dural metastases: a pilot study with immunohistochemical observations.

Malignant dural neoplasms are not reliably distinguished from benign dural neoplasms with contrast-enhanced magnetic resonance imaging (MRI). MRI enhancement in central nervous system (CNS) diseases imaged with ferumoxytol has been attributed to intracellular uptake in macrophages rather than vascular leakage. We compared imaging to histopathology and immunohistochemistry in meningiomas and dural metastases having ferumoxytol-enhanced MRI (FeMRI) and gadolinium-enhanced MRI (GdMRI) in order to correlate enhancement patterns to macrophage presence and vascular state. All patients having extraaxial CNS tumors were retrospectively selected from one of two ongoing FeMRI studies. Enhancement was compared between GdMRI and FeMRI. Diagnoses were confirmed histologically and/or by characteristic imaging. Tumor and vascular histology was reviewed. Immunohistochemical staining for CD68 (a macrophage marker), Connexin-43 (Cx43) (a marker of normal gap junctions), and smooth muscle actin (SMA) as a marker of vascularity, was performed in seven study cases with available tissue. Immunohistochemistry was performed on archival material from 33 subjects outside of the current study as controls: 20 WHO grade I cases of meningioma and 13 metastatic tumors. Metastases displayed marked delayed enhancement on FeMRI, similar to GdMRI. Four patients with dural metastases and one patient with meningioma showed similar enhancement on FeMRI and GdMRI. Five meningiomas with typical enhancement on GdMRI lacked enhancement on FeMRI. Enhancement on FeMRI was better associated with decreased Cx43 expression than intralesional macrophages. These pilot data suggest that FeMRI may better differentiate metastatic disease from meningiomas than GdMRI, and that differences in tumor vasculature rather than macrophage presence could underlie differences in contrast enhancement.

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.

PURPOSE: To compare gadoteridol and ferumoxytol for measurement of relative cerebral blood volume (rCBV) in patients with glioblastoma multiforme (GBM) who showed progressive disease at conventional magnetic resonance (MR) imaging after chemo- and radiation therapy (hereafter, chemoradiotherapy) and to correlate rCBV with survival. MATERIALS AND METHODS: Informed consent was obtained from all participants before enrollment in one of four institutional review board-approved protocols. Contrast agent leakage maps and rCBV were derived from perfusion MR imaging with gadoteridol and ferumoxytol in 19 patients with apparently progressive GBM on conventional MR images after chemoradiotherapy. Patients were classified as having high rCBV (>1.75), indicating tumor, and low rCBV (≤ 1.75), indicating pseudoprogression, for each contrast agent separately, and with or without contrast agent leakage correction for imaging with gadoteridol. Statistical analysis was performed by using Kaplan-Meier survival plots with the log-rank test and Cox proportional hazards models. RESULTS: With ferumoxytol, rCBV was low in nine (47%) patients, with median overall survival (mOS) of 591 days, and high rCBV in 10 (53%) patients, with mOS of 163 days. A hazard ratio of 0.098 (P = .004) indicated significantly improved survival. With gadoteridol, rCBV was low in 14 (74%) patients, with mOS of 474 days, and high in five (26%), with mOS of 156 days and a nonsignificant hazard ratio of 0.339 (P = .093). Five patients with mismatched high rCBV with ferumoxytol and low rCBV with gadoteridol had an mOS of 171 days. When leakage correction was applied, rCBV with gadoteridol was significantly associated with survival (hazard ratio, 0.12; P = .003). CONCLUSION: Ferumoxytol as a blood pool agent facilitates differentiation between tumor progression and pseudoprogression, appears to be a good prognostic biomarker, and unlike gadoteridol, does not require contrast agent leakage correction.

Macrophage imaging within human cerebral aneurysms wall using ferumoxytol-enhanced MRI: a pilot study.

OBJECTIVE: Macrophages play a critical role in cerebral aneurysm formation and rupture. The purpose of this study is to demonstrate the feasibility and optimal parameters of imaging macrophages within human cerebral aneurysm wall using ferumoxytol-enhanced MRI. METHODS AND RESULTS: Nineteen unruptured aneurysms in 11 patients were imaged using T2*-GE-MRI sequence. Two protocols were used. Protocol A was an infusion of 2.5 mg/kg of ferumoxytol and imaging at day 0 and 1. Protocol B was an infusion of 5 mg/kg of ferumoxytol and imaging at day 0 and 3. All images were reviewed independently by 2 neuroradiologists to assess for ferumoxytol-associated loss of MRI signal intensity within aneurysm wall. Aneurysm tissue was harvested for histological analysis. Fifty percent (5/10) of aneurysms in protocol A showed ferumoxytol-associated signal changes in aneurysm walls compared to 78% (7/9) of aneurysms in protocol B. Aneurysm tissue harvested from patients infused with ferumoxytol stained positive for both CD68+, demonstrating macrophage infiltration, and Prussian blue, demonstrating uptake of iron particles. Tissue harvested from controls stained positive for CD68 but not Prussian blue. CONCLUSIONS: Imaging with T2*-GE-MRI at 72 hours postinfusion of 5 mg/kg of ferumoxytol establishes a valid and useful approximation of optimal dose and timing parameters for macrophages imaging within aneurysm wall. Further studies are needed to correlate these imaging findings with risk of intracranial aneurysm rupture.

Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model.

Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-α(V) integrin monoclonal antibody intetumumab binds cell surface proteins important for adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into four groups: (1) control; (2) intetumumab mixed with cells in vitro 5 min before infusion without further treatment; (3) intetumumab intravenously 4 h before and weekly after cell infusion; (4) intetumumab intravenously weekly starting 7 days after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal-Wallis test and Dunnett's test. Survival times were estimated using Kaplan-Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median = 14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median = 2, p = 0.0055), including 30 % of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ vs. 52 days, p = 0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.

Dual contrast perfusion MRI in a single imaging session for assessment of pediatric brain tumors.

Ferumoxytol, an iron nanoparticle used as an intravascular contrast agent for perfusion magnetic resonance imaging (MRI), has never been explored in the pediatric population. The purpose of this prospective study is to characterize the vascular and permeability properties of pediatric brain tumors using two contrast agents during a single imaging session: ferumoxytol for dynamic susceptibility weighted contrast (DSC) MRI and gadoteridol for dynamic contrast-enhanced (DCE) MRI. In a single imaging session, patients received intravenous ferumoxytol for DSC MRI followed by gadoteridol for DCE MRI. Relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), transfer coefficient (K(trans)), and extravascular extracellular space volume fraction (v(e)) of the brain lesions were calculated. Patients underwent serial imaging sessions over the course of 2 years. Of the 7 patients enrolled thus far, none has experienced an adverse event. Two patients with medulloblastoma were enrolled preoperatively. In the first, rCBV(max), rCBF, K(trans) max, and v(e) max values were 3.74, 3.12, 0.47 min (-1), and 0.08, respectively, while in the second patient, rCBV(max), rCBF, K(trans) max, and v(e) max values were 4.72, 3.47, 0.60 min(-1), and 0.05, respectively. Four patients were enrolled after new gadolinium enhancement was noted in the tumor resection cavity. In 80 % of these lesions, rCBV was <1 suggestive of pseudoprogression secondary to radiochemotherapy. These preliminary results demonstrate that use of ferumoxytol and gadoteridol contrast agents during a single imaging session is feasible, safe, and appears useful for assessing tumor perfusion and permeability characteristics in children.

Safety of intra-arterial chemotherapy with or without osmotic blood-brain barrier disruption for the treatment of patients with brain tumors.

Background: Intra-arterial administration of chemotherapy with or without osmotic blood-brain barrier disruption enhances delivery of therapeutic agents to brain tumors. The aim of this study is to evaluate the safety of these procedures. Methods: Retrospectively collected data from a prospective database of consecutive patients with primary and metastatic brain tumors who received intra-arterial chemotherapy without osmotic blood-brain barrier disruption (IA) or intra-arterial chemotherapy with osmotic blood-brain barrier disruption (IA/OBBBD) at Oregon Health and Science University (OHSU) between December 1997 and November 2018 is reported. Chemotherapy-related complications are detailed per Common Terminology Criteria for Adverse Events (CTCAE) guidelines. Procedure-related complications are grouped as major and minor. Results: 4939 procedures (1102 IA; 3837 IA/OBBBD) were performed on 436 patients with various pathologies (primary central nervous system lymphoma [26.4%], glioblastoma [18.1%], and oligodendroglioma [14.7%]). Major procedure-related complications (IA: 12, 1%; IA/OBBBD: 27, 0.7%; P = .292) occurred in 39 procedures including 3 arterial dissections requiring intervention, 21 symptomatic strokes, 3 myocardial infarctions, 6 cervical cord injuries, and 6 deaths within 3 days. Minor procedure-related complications occurred in 330 procedures (IA: 41, 3.7%; IA/OBBBD: 289, 7.5%; P = .001). Chemotherapy-related complications with a CTCAE attribution and grade higher than 3 was seen in 359 (82.3%) patients. Conclusions: We provide safety and tolerability data from the largest cohort of consecutive patients who received IA or IA/OBBBD. Our data demonstrate that IA or IA/OBBBD safely enhance drug delivery to brain tumors and brain around the tumor.

Improved perfusion MR imaging assessment of intracerebral tumor blood volume and antiangiogenic therapy efficacy in a rat model with ferumoxytol.

PURPOSE: To evaluate the consistency of tumor blood volume measurements and antiangiogenic therapy efficacy assessments with a low-molecular-weight gadolinium-based contrast agent (GBCA, gadodiamide) versus an iron oxide nanoparticle (ferumoxytol) in the presence or absence of a loading dose of contrast agent before perfusion magnetic resonance (MR) imaging (preload method). MATERIALS AND METHODS: The protocol was approved by the institutional animal care and use committee. U87MG tumor cells were implanted intracerebrally in 13 rats. All 13 rats underwent 11.75-T MR imaging with gadodiamide (60 µL) 13 days after tumor implantation. The next day, nine rats underwent MR imaging with ferumoxytol (60 µL). Immediately after ferumoxytol imaging, six rats received bevacizumab (45 mg/kg). MR imaging was repeated 48 hours after bevacizumab treatment with gadodiamide and 72 hours after treatment with ferumoxytol. Each study included three consecutive dynamic susceptibility-weighted contrast material-enhanced (DSC) MR acquisitions, which were performed without preload, with single-dose preload, and with double-dose preload. Tumor relative cerebral blood volume (rCBV) was estimated from each DSC MR acquisition. Two-way repeated measures analysis of variance was performed to test for differences between groups with both contrast agents. RESULTS: DSC MR imaging with gadodiamide and without preload showed low rCBV (≤ 1.75) in nine of the 13 tumors; estimated rCBV increased progressively with both single- and double-dose preloads (P < .001). Conversely, rCBVs obtained with ferumoxytol were high (>1.75) and remained constant with all three acquisitions. The magnitude of rCBV decrease after bevacizumab administration was dependent on the dose of gadodiamide preload, whereas the magnitude of rCBV decrease with ferumoxytol was constant regardless of whether contrast agent preload was used. CONCLUSION: With GBCA, tumor rCBV can be underestimated without preload and becomes dose dependent with preload correction. Conversely, ferumoxytol provides consistent assessment of tumor rCBV and antiangiogenic therapy efficacy.

Comparative analysis of ferumoxytol and gadoteridol enhancement using T1- and T2-weighted MRI in neuroimaging.

OBJECTIVE: Ferumoxytol, an ultrasmall superparamagnetic iron oxide particle, has been suggested as a potential alternative MRI contrast agent in patients with renal failure. We compared ferumoxytol to gadoteridol enhancement on T1- and T2-weighted MRI in CNS disorders to explore its diagnostic utility. SUBJECTS AND METHODS: Data were collected from three protocols in 70 adults who underwent alternate-day gadoteridol- and ferumoxytol-enhanced MRI using identical parameters. Two neuroradiologists measured lesion-enhancing size and intensity on contrast-enhanced T1-weighted images in consensus. T2-weighted images were evaluated for the presence of contrast-enhanced hypointensity. Mixed model repeated measures analysis of variance determined differences between T1-weighted enhancement size and intensity for individual protocols and group. RESULTS: After exclusions, 49 MRI studies in 29 men and 20 women (mean age, 51 years) were assessed. T1-weighted estimated enhancing sizes were different between agents (p = 0.0456) as a group; however, no differences were observed with untreated gliomas (n = 17) in two protocols (p = 1.0 and p = 0.99, respectively). Differences in T1-weighted enhancement intensity between agents were significant for the group overall (p = 0.0006); however, three-way interactions were not significant (p = 0.1233). T2-weighted images were assessed for contrast-enhanced hypointensity, observed in 26 of 49 (53%) ferumoxytol and zero of 49 (0%) gadoteridol scans. CONCLUSION: Ferumoxytol may be a useful MRI contrast agent in patients who are unable to receive gadolinium-based contrast agents. Greater experience with a wider variety of disorders is necessary to understand differences in enhancement with ferumoxytol compared with gadolinium-based contrast agents, given their different mechanisms of action.

Mortality and Functional Outcome in Surgically Evacuated Acute Subdural Hematoma in Elderly Patients.

BACKGROUND: Significant morbidity and mortality is associated with surgical evacuation of acute subdural hematomas (ASDHs) in the elderly population. The literature remains mixed on risk factors associated with poor outcomes, specifically preoperative antithrombotic usage and postoperative seizures. METHODS: Between January 1, 2013, and December 31, 2017, we retrospectively identified 62 patients ≥65 years of age who underwent a craniotomy for evacuation of an ASDH, with the primary outcome being Glasgow Outcome Scale (GOS) score at discharge and 3- and 6-month follow-up. RESULTS: Of the patients, 52% were women, with a median age of 78 years (range, 65-93 years). The mechanism of injury was because of a fall in 40 patients. Twenty-eight patients (44%) had a poor outcome (GOS score 1-2) at discharge, increasing to 31 patients (50%) at 3-month follow-up. Eight patients (13%) had a good outcome (GOS score 4-5) at discharge, increasing to 17 patients (27%) at 3-month follow-up. Perioperative mortality rate was 39%, increasing to 44% at 3-month follow-up. The strongest associations with mortality in descending order were 24-hour postoperative Glasgow Come Scale (GCS) score, midline shift, preoperative GCS score, and pupillary abnormalities. Although age was not a statistically significant factor for mortality, patients with a favorable outcome (GOS score 4-5) had a median age of 71 years versus 78 years for GOS score 1-3. Preoperative antithrombotic usage and postoperative seizures were not significant predictors of outcome or mortality. CONCLUSIONS: A high percentage of morbidity and mortality remains in the management of ASDHs in the elderly population; however, a significant percentage (27%) can still go on to have a favorable outcome.

Neurovascular Unit: Basic and Clinical Imaging with Emphasis on Advantages of Ferumoxytol.

Physiological and pathological processes that increase or decrease the central nervous system's need for nutrients and oxygen via changes in local blood supply act primarily at the level of the neurovascular unit (NVU). The NVU consists of endothelial cells, associated blood-brain barrier tight junctions, basal lamina, pericytes, and parenchymal cells, including astrocytes, neurons, and interneurons. Knowledge of the NVU is essential for interpretation of central nervous system physiology and pathology as revealed by conventional and advanced imaging techniques. This article reviews current strategies for interrogating the NVU, focusing on vascular permeability, blood volume, and functional imaging, as assessed by ferumoxytol an iron oxide nanoparticle.

Evaluation of pseudoprogression in patients with glioblastoma multiforme using dynamic magnetic resonance imaging with ferumoxytol calls RANO criteria into question.

BACKGROUND: Diagnosis of pseudoprogression in patients with glioblastoma multiforme (GBM) is limited by Response Assessment in Neuro-Oncology (RANO) criteria to 3 months after chemoradiotherapy (CRT). Frequency of pseudoprogression occurring beyond this time limit was determined. Survival comparison was made between pseudoprogression and true progression patients as determined by using perfusion magnetic resonance imaging with ferumoxytol (p-MRI-Fe). METHODS: Fifty-six patients with GBM who demonstrated conventional findings concerning for progression of disease post CRT were enrolled in institutional review board-approved MRI protocols. Dynamic susceptibility-weighted contrast-enhanced p-MRI-Fe was used to distinguish true progression from pseudoprogression using relative cerebral blood volume (rCBV) values. rCBV of 1.75 was assigned as the cutoff value. Participants were followed up using RANO criteria, and survival data were analyzed. RESULTS: Twenty-seven participants (48.2%) experienced pseudoprogression. Pseudoprogression occurred later than 3 months post CRT in 8 (29.6%) of these 27 participants (ie, 8 [14.3%] of the 56 patients meeting the inclusion criteria). Overall survival was significantly longer in participants with pseudoprogression (35.2 months) compared with those who never experienced pseudoprogression (14.3 months; P < .001). CONCLUSIONS: Pseudoprogression presented after 3 months post CRT in a considerable portion of patients with GBM, which raises doubts about the value of the 3-month time limit of the RANO criteria. Accurate rCBV measurement (eg, p-MRI-Fe) is suggested when there are radiographical concerns about progression of disease in GBM patients, regardless of any time limit. Pseudoprogression correlates with significantly better survival outcomes.

Incidence of Pneumocystis jirovecii pneumonia after temozolomide for CNS malignancies without prophylaxis.

AIMS: Prophylaxis against Pneumocystis jiroveci pneumonia (PJP) is currently recommended for patients receiving chemoradiation with temozolomide for newly diagnosed glioblastoma multiforme. At our institution, PJP prophylaxis during temozolomide treatment has not been routinely given because of the paucity of supporting data. We investigated the rate of PJP infections in our patients. PATIENTS & METHODS: We conducted a retrospective chart review of 240 brain tumor patients treated between 1999 and 2012 with temozolomide and no PJP prophylaxis, 127 of which received concurrent chemoradiation. RESULTS: One in 240 patients (0.4%; 95% CI: 0.01-2.00; median total dose: 7375 mg/m(2); interquartile range: 1300) were diagnosed with PJP. CONCLUSION: There was a <1% rate of PJP for brain tumor patients treated with temozolomide until progression without PJP prophylaxis.

Diagnosis of pseudoprogression using MRI perfusion in patients with glioblastoma multiforme may predict improved survival.

AIMS: This retrospective study determined the survival of glioblastoma patients with or without pseudoprogression. METHODS: A total of 68 patients were included. Overall survival was compared between patients showing pseudoprogression (in most cases diagnosed using perfusion MRI with ferumoxytol) and in patients without pseudoprogession. MGMT methylation status was also analyzed in the pseudoprogression cases. RESULTS: Median survival in 24 (35.3%) patients with pseudoprogression was 34.7 months (95% CI: 20.3-54.1), and 13.4 months (95% CI: 11.1-19.5) in 44 (64.7%) patients without pseudoprogression (p < 0.0001). The longest survival was a median of 54.1 months in patients with combination of pseudoprogression and (MGMT) promoter methylation. CONCLUSION: Pseudoprogression is associated with better outcome, especially if concurring with MGMT promoter methylation. Patients never diagnosed with pseudoprogression had poor survival. This study emphasizes the importance of differentiating tumor progression and pseudoprogression using perfusion MRI.

High-resolution steady-state cerebral blood volume maps in patients with central nervous system neoplasms using ferumoxytol, a superparamagnetic iron oxide nanoparticle.

Cerebral blood volume (CBV) measurement complements conventional magnetic resonance imaging (MRI) to indicate pathologies in the central nervous system (CNS). Dynamic susceptibility contrast (DSC) perfusion imaging is limited by low resolution and distortion. Steady-state (SS) imaging may provide higher resolution CBV maps but was not previously possible in patients. We tested the feasibility of clinical SS-CBV measurement using ferumoxytol, a nanoparticle blood pool contrast agent. SS-CBV measurement was analyzed at various ferumoxytol doses and compared with DSC-CBV using gadoteridol. Ninety nine two-day MRI studies were acquired in 65 patients with CNS pathologies. The SS-CBV maps showed improved contrast to noise ratios, decreased motion artifacts at increasing ferumoxytol doses. Relative CBV (rCBV) values obtained in the thalamus and tumor regions indicated good consistency between the DSC and SS techniques when the higher dose (510 mg) ferumoxytol was used. The SS-CBV maps are feasible using ferumoxytol in a clinical dose of 510 mg, providing higher resolution images with comparable rCBV values to the DSC technique. Physiologic imaging using nanoparticles will be beneficial in visualizing CNS pathologies with high vascularity that may or may not correspond with blood-brain barrier abnormalities.

Using iron oxide nanoparticles to diagnose CNS inflammatory diseases and PCNSL.

OBJECTIVE: The study goal was to assess the benefits and potential limitations in the use of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles in the MRI diagnosis of CNS inflammatory diseases and primary CNS lymphoma. METHODS: Twenty patients with presumptive or known CNS lesions underwent MRI study. Eighteen patients received both gadolinium-based contrast agents (GBCAs) and 1 of 2 USPIO contrast agents (ferumoxytol and ferumoxtran-10) 24 hours apart, which allowed direct comparative analysis. The remaining 2 patients had only USPIO-enhanced MRI because of a renal contraindication to GBCA. Conventional T1- and T2-weighted MRI were acquired before and after contrast administration in all patients, and perfusion MRI for relative cerebral blood volume (rCBV) assessment was obtained in all 9 patients receiving ferumoxytol. RESULTS: USPIO-enhanced MRI showed an equal number of enhancing brain lesions in 9 of 18 patients (50%), more enhancing lesions in 2 of 18 patients (11%), and fewer enhancing lesions in 3 of 18 patients (17%) compared with GBCA-enhanced MRI. Four of 18 patients (22%) showed no MRI enhancement. Dynamic susceptibility-weighted contrast-enhanced perfusion MRI using ferumoxytol showed low rCBV (ratio <1.0) in 3 cases of demyelination or inflammation, modestly elevated rCBV in 5 cases of CNS lymphoma or lymphoproliferative disorder (range: 1.3-4.1), and no measurable disease in one case. CONCLUSIONS: This study showed that USPIO-enhanced brain MRI can be useful in the diagnosis of CNS inflammatory disorders and lymphoma, and is also useful for patients with renal compromise at risk of nephrogenic systemic fibrosis who are unable to receive GBCA.

Dynamic magnetic resonance imaging assessment of vascular targeting agent effects in rat intracerebral tumor models.

We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting α(V)-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4-6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting α(V)-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy.