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).
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.
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).
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.
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).
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.
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.
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.
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 (range1.3–4.1), 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.
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.
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.
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.
A new method, similar to Gjedde–Patlak linearization, is proposed to correct the leakage effect of gadolinium (Gd)‐based contrast agent in dynamic susceptibility contrast‐magnetic resonance imaging (DSC‐MRI). Using the DSC data of high‐molecular‐weight, iron‐based, intravascular Ferumoxytol (FeO), the pharmacokinetic interpretation of the new paradigm is empirically validated. Compared with the relative cerebral blood volume (rCBV) color map obtained with FeO (E), Gd rCBV without leakage correction often results in underestimation (B) and Gd rCBV with current correction results in slight overestimation (C); the new method shows an improved result (D).
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.
OBJECTIVERefractory anaplastic oligodendroglioma and oligoastrocytoma tumors are challenging to treat. This trial primarily evaluated toxicity and estimated the maximum tolerated dose of ...intra-arterial (IA) melphalan, IA carboplatin, and intravenous (IV) etoposide phosphate in conjunction with blood-brain barrier disruption in these tumors. The secondary measure was efficacy.METHODSThirteen patients with temozolomide-refractory anaplastic oligodendroglioma (11 patients) or oligoastrocytoma (2 patients) underwent blood-brain barrier disruption with carboplatin (IA, 200 mg/m2/d), etoposide phosphate (IV, 200 mg/m2/d), and melphalan (IA, dose escalation) every 4 weeks, for up to 1 year. Patients underwent melphalan dose escalation (4, 8, 12, 16, and 20 mg/m2/d) until the maximum tolerated dose (1 level below that producing grade 4 toxicity) was determined. Toxicity and efficacy were assessed.RESULTSTwo of 4 patients receiving IA melphalan at 8 mg/m2/d developed grade 4 thrombocytopenia; thus, the melphalan maximum tolerated dose was 4 mg/m2/d. Adverse events included asymptomatic subintimal tear (1 patient) and grade 4 thrombocytopenia (3 patients). Two patients demonstrated complete response, 3 had partial responses, 5 demonstrated stable disease, and 3 progressed. Median overall progression-free survival was 11 months. Patients with complete or partial response demonstrated deletion of chromosomes 1p and 19q. In the 5 patients with stable disease, 2 demonstrated 1p and 19q deletion, and 3 demonstrated 19q deletion only.CONCLUSIONIn patients with anaplastic oligodendroglioma or oligoastrocytoma tumors in whom temozolomide treatment has failed, osmotic blood-brain barrier disruption with IA carboplatin, IV etoposide phosphate, and IA melphalan (4 mg/m2/d for 2 days) shows acceptable toxicity and encouraging efficacy, especially in patients demonstrating 1p and/or 19q deletion.
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.
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