Multicenter Safety and Practice for Off-Label Diagnostic Use of Ferumoxytol in MRI.

Background Ferumoxytol is approved for use in the treatment of iron deficiency anemia, but it can serve as an alternative to gadolinium-based contrast agents. On the basis of postmarketing surveillance data, the Food and Drug Administration issued a black box warning regarding the risks of rare but serious acute hypersensitivity reactions during fast high-dose injection (510 mg iron in 17 seconds) for therapeutic use. Whereas single-center safety data for diagnostic use have been positive, multicenter data are lacking. Purpose To report multicenter safety data for off-label diagnostic ferumoxytol use. Materials and Methods The multicenter ferumoxytol MRI registry was established as an open-label nonrandomized surveillance databank without industry involvement. Each center monitored all ferumoxytol administrations, classified adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1-5), and assessed the relationship of AEs to ferumoxytol administration. AEs related to or possibly related to ferumoxytol injection were considered adverse reactions. The core laboratory adjudicated the AEs and classified them with the American College of Radiology (ACR) classification. Analysis of variance was used to compare vital signs. Results Between January 2003 and October 2018, 3215 patients (median age, 58 years; range, 1 day to 96 years; 1897 male patients) received 4240 ferumoxytol injections for MRI. Ferumoxytol dose ranged from 1 to 11 mg per kilogram of body weight (≤510 mg iron; rate ≤45 mg iron/sec). There were no systematic changes in vital signs after ferumoxytol administration (P > .05). No severe, life-threatening, or fatal AEs occurred. Eighty-three (1.9%) of 4240 AEs were related or possibly related to ferumoxytol infusions (75 mild [1.8%], eight moderate [0.2%]). Thirty-one AEs were classified as allergiclike reactions using ACR criteria but were consistent with minor infusion reactions observed with parenteral iron. Conclusion Diagnostic ferumoxytol use was well tolerated, associated with no serious adverse events, and implicated in few adverse reactions. Registry results indicate a positive safety profile for ferumoxytol use in MRI. © RSNA, 2019 Online supplemental material is available for this article.

Pathogenic inflammation in the CNS of mice carrying human PLP1 mutations.

Progressive forms of multiple sclerosis lead to chronic disability, substantial decline in quality of life and reduced longevity. It is often suggested that they occur independently of inflammation. Here we investigated the disease progression in mouse models carrying PLP1 point mutations previously found in patients displaying clinical features of multiple sclerosis. These mouse models show loss-of-function of PLP1 associated with neuroinflammation; the latter leading to clinically relevant axonal degeneration, neuronal loss and brain atrophy as demonstrated by inactivation of the recombination activating gene 1. Moreover, these pathological hallmarks were substantially amplified when we attenuated immune regulation by inactivation of the programmed cell death-1 gene. Our observations support the view that primary oligodendroglial abnormalities can evoke pathogenically relevant neuroinflammation that drives neurodegeneration, as observed in some forms of multiple sclerosis but also in other, genetically-mediated neurodegenerative disorders of the human nervous system. As many potent immunomodulatory drugs have emerged during the last years, it is tempting to consider immunomodulation as a treatment option not only for multiple sclerosis, but also for so far non-treatable, genetically-mediated disorders of the nervous system accompanied by pathogenic neuroinflammation.

Quantitative comparison of delayed ferumoxytol T1 enhancement with immediate gadoteridol enhancement in high grade gliomas.

PURPOSE: Delayed ferumoxytol enhancement on T1 -weighted images appears visually similar to gadoteridol enhancement. The purpose of this study was to quantitatively compare ferumoxytol T1 enhancement to gadoteridol enhancement with an objective, semi-automated method. METHODS: 206 sets of post-gadoteridol and 24 h post-ferumoxytol T1 -weighted scans from 58 high grade glioma patients were analyzed (9 pre-chemoradiation, 111 < 90 days post-chemoradiation, 21 > 90 days post-chemoradiation, 65 post-bevacizumab scans). Enhancement volumes and signal intensities normalized to normal appearing tissue proximal to enhancement were calculated with a semi-automated method. Enhancement cube root volumes (D) and signal intensities (SI) were compared between the 2 contrast agents, and relative difference of D and SI were compared in different treatment groups with multivariate analysis. Within patient differences in D and SI before and after treatment with bevacizumab or steroid were assessed in 26 patients in each treatment group. RESULTS: When compared to gadoteridol, ferumoxytol D was 13.83% smaller and SI was 7.24% lower (P < 0.0001). The relative differences in D and SI between the 2 contrast agents were not significantly different between treatment groups (P > 0.05). Relative difference in D and SI did not change significantly in response to bevacizumab (P = 0.5234 and P = 0.2442, respectively) or to steroid (P = 0.3774, P = 0.0741) in the within patient comparison. CONCLUSION: The correlation between the 2 contrast agents' enhancement size and signal intensity and their similar behavior in response to therapy suggest that ferumoxytol can be used for revealing enhancement in high grade glioma patients. Magn Reson Med 80:224-230, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

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.

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.

We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in Rag1(-/-) mice lacking lymphocytes. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with the ischemic brain endothelium via the LFA-1/ICAM-1 pathway and platelets and these findings were confirmed in vitro. Ablation of Tregs reduced microvascular thrombus formation and improved cerebral reperfusion on stroke, as revealed by ultra-high-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Tregs had no functional relevance. We define herein a novel and unexpected role of Tregs in a primary nonimmunologic disease state.

Functional near-infrared spectroscopy to probe state- and trait-like conditions in chronic tinnitus: a proof-of-principle study.

OBJECTIVE: Several neuroscience tools showed the involvement of auditory cortex in chronic tinnitus. In this proof-of-principle study we probed the capability of functional near-infrared spectroscopy (fNIRS) for the measurement of brain oxygenation in auditory cortex in dependence from chronic tinnitus and from intervention with transcranial magnetic stimulation. METHODS: Twenty-three patients received continuous theta burst stimulation over the left primary auditory cortex in a randomized sham-controlled neuronavigated trial (verum = 12; placebo = 11). Before and after treatment, sound-evoked brain oxygenation in temporal areas was measured with fNIRS. Brain oxygenation was measured once in healthy controls (n = 12). RESULTS: Sound-evoked activity in right temporal areas was increased in the patients in contrast to healthy controls. Left-sided temporal activity under the stimulated area changed over the course of the trial; high baseline oxygenation was reduced and vice versa. CONCLUSIONS: By demonstrating that rTMS interacts with auditory evoked brain activity, our results confirm earlier electrophysiological findings and indicate the sensitivity of fNIRS for detecting rTMS induced changes in brain activity. Moreover, our findings of trait- and state-related oxygenation changes indicate the potential of fNIRS for the investigation of tinnitus pathophysiology and treatment response.

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.

C1-inhibitor protects from brain ischemia-reperfusion injury by combined antiinflammatory and antithrombotic mechanisms.

BACKGROUND AND PURPOSE: Inflammation and thrombosis are pathophysiological hallmarks of ischemic stroke still unamenable to therapeutic interventions. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is involved in stroke development. C1-inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-inhibitor in models of ischemic stroke. METHODS: Male and female C57Bl/6 mice and rats of different ages were subjected to middle cerebral artery occlusion and treated with C1-inhibitor after 1 hour or 6 hours. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood-brain barrier damage, thrombus formation, and the local inflammatory response were determined poststroke. RESULTS: Treatment with 15.0 U C1-inhibitor, but not 7.5 U, 1 hour after stroke reduced infarct volumes by ≈60% and improved clinical scores in mice of either sex on day 1. This protective effect was preserved at later stages of infarction as well as in elderly mice and in another species, ie, rats. Delayed C1-inhibitor treatment still improved clinical outcome. Blood-brain barrier damage, edema formation, and inflammation were significantly lower compared with controls. Moreover, C1-inhibitor showed strong antithrombotic effects. CONCLUSIONS: C1-inhibitor is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings.

Diagnostic performance of DSC perfusion MRI to distinguish tumor progression and treatment-related changes: a systematic review and meta-analysis.

Background: In patients with high-grade glioma (HGG), true disease progression and treatment-related changes often appear similar on magnetic resonance imaging (MRI), making it challenging to evaluate therapeutic response. Dynamic susceptibility contrast (DSC) MRI has been extensively studied to differentiate between disease progression and treatment-related changes. This systematic review evaluated and synthesized the evidence for using DSC MRI to distinguish true progression from treatment-related changes. Methods: We searched Ovid MEDLINE and the Ovid MEDLINE in-process file (January 2005-October 2019) and the reference lists. Studies on test performance of DSC MRI using relative cerebral blood volume in HGG patients were included. One investigator abstracted data, and a second investigator confirmed them; two investigators independently assessed study quality. Meta-analyses were conducted to quantitatively synthesize area under the receiver operating curve (AUROC), sensitivity, and specificity. Results: We screened 1177 citations and included 28 studies with 638 patients with true tumor progression, and 430 patients with treatment-related changes. Nineteen studies reported AUROC and the combined AUROC is 0.85 (95% CI, 0.81-0.90). All studies contributed data for sensitivity and specificity, and the pooled sensitivity and specificity are 0.84 (95% CI, 0.80-0.88), and 0.78 (95% CI, 0.72-0.83). Extensive subgroup analyses based on study, treatment, and imaging characteristics generally showed similar results. Conclusions: There is moderate strength of evidence that relative cerebral blood volume obtained from DSC imaging demonstrated "excellent" ability to discriminate true tumor progression from treatment-related changes, with robust sensitivity and specificity.

Material Suitability Testing for Nonmedical Grade Community Face Masks to Decrease Viral Transmission During a Pandemic.

OBJECTIVES: Cloth face covering has been recommended by the Centers for Disease Control and Prevention to decrease community viral transmission. This study aims to determine the filtration efficiency and airflow resistance of common household materials available for homemade mask production by comparing numbers of fabrics, various layers, and manipulation. METHODS: Common household woven, knitted, and nonwoven fabrics were tested for filtration efficiency using a fit testing setup and airflow resistance with pressure gauge setup. Three different levels of layering (1, 2, and 4) were tested. Some fabric material was further tested after washing and drying. Filtration performance, the area under the fitted curve comparing airflow resistance and filtration efficiency, was calculated for each fabric material and compared. RESULTS: Layering increased filtration efficiency and airflow resistance (P < 0.0001 and P < 0.01, respectively). Polyester felt demonstrated the highest filtration performance index (P < 0.0001), higher than all tested 100% cotton materials (all P < 0.05) as well as surgical masks (P < 0.05). Washing plus drying did not alter filtration performance significantly (P > 0.05). CONCLUSIONS: A filtration performance of common household fabrics were compared. Homemade mask designers and producers will have improved data to better balance effectiveness, availability, and comfort with the goal of decreasing community viral transmission.

Long-Term Outcomes of Intra-Arterial Chemotherapy for Progressive or Unresectable Pilocytic Astrocytomas: Case Studies.

BACKGROUND: Progressive and/or unresectable pilocytic astrocytomas (PAs) carry a poor prognosis compared to typical PA. Early radiotherapy (RT) may have severe long-term neurocognitive side effects in this patient population. Intra-arterial (IA) chemotherapy is a viable alternative or addition to intravenous (IV) chemotherapy, which may be beneficial in avoidance of early RT. OBJECTIVE: To evaluate the safety and efficacy of IA chemotherapy in this subset of patients. METHODS: This is a retrospective review of medical records of PA patients who are treated with IA chemotherapy at Oregon Health & Science University from 1997 until 2019. Response to treatment was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Progression free survival (PFS) and overall survival (OS) are also reported. RESULTS: Twelve patients were identified. All patients experienced progression prior to initiation of IA chemotherapy. The most common grade 3 or 4 toxicities related to chemotherapy were thrombocytopenia (66%), neutropenia (66%), leukopenia (50%), anemia (33%), and lymphopenia (16%). Responses achieved were CR in 1, PR in 3, SD in 7, and PD in 1. Median PFS and median OS were 16.5 and 83.5 mo, respectively. A total of 112 procedures (IA injections) were performed and 250 arteries were catheterized. There were 3 minor and no major complications attributable to procedures. CONCLUSION: This study demonstrates that IA chemotherapy can be safely used in patients with unresectable or progressive PA.

Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)?

Gadolinium (Gd) based contrast agents (GBCAs) in magnetic resonance imaging (MRI) are used in daily clinical practice and appear safe in most patients; however, nephrogenic systemic fibrosis (NSF) is a recently recognized severe complication associated with GBCAs. It affects primarily patients with renal disease, such as stage 4 or 5 chronic kidney disease (CKD; glomerular filtration rate <30 ml/min per 1.73 m(2)), acute kidney injury, or kidney and liver transplant recipients with kidney dysfunction. Contrast-enhanced MRI and computed tomography (CT) scans provide important clinical information and influence patient management. An alternative contrast agent is needed to obtain adequate imaging results while avoiding the risk of NSF in this vulnerable patient group. One potential alternative is ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, which provide enhancement characteristics similar to GBCAs. We review our experience in approximately 150 patients on the potential benefits of the USPIOs ferumoxtran-10 and ferumoxytol. We focus on central nervous system (CNS) MRI but also review imaging of other vascular beds. Safety studies, including USPIO administration (ferumoxytol) as iron supplement therapy in CKD patients on and not on dialysis, suggest that decreased kidney function does not alter the safety profile. We conclude that for both CNS MR imaging and MR angiography, USPIO agents like ferumoxytol are a viable option for patients at risk for NSF.

Bevacizumab and carboplatin increase survival and asymptomatic tumor volume in a glioma model.

To evaluate efficacy and MRI findings after intravenous bevacizumab and/or carboplatin in a human glioma animal model, we randomized male nude rats with intracerebral UW28 human glioma xenografts to four groups: (1) controls (n = 9), (2) bevacizumab 10 mg/kg (n = 6), (3) carboplatin 200 mg/m(2) (n = 6), and (4) bevacizumab + carboplatin (n = 6). MRI was performed on the day of treatment (day 7-10) and 1 week later, and rats were followed for survival. Dynamic MRI was done in three controls and three rats treated with bevacizumab with or without carboplatin before and 24 h after treatment. Median overall survival (OS) was as follows: group 1, 16 days; group 2, 23 days; group 3, 22 days; group 4, 36 days. OS was significantly longer in group 4 than in group 1 (p = 0.0011), group 2 (p = 0.0014), and group 3 (p = 0.0015), and rats had significantly larger tumors. No objective tumor responses were observed on MR images at 1 week after treatment; however, after bevacizumab, dynamic MRI showed reduced gadolinium enhancement intensity and increased time to peak, consistent with decreased vascular permeability. Carboplatin + bevacizumab is effective and superior over bevacizumab or carboplatin monotherapy in this animal model. Increased survival concomitant with increased asymptomatic tumor volume is suggestive that vascular targeting with reduced peritumoral edema and mass effect contributes to the efficacy of bevacizumab. The promising survival data warrant future clinical trials using bevacizumab + carboplatin.

Efficacy and MRI of rituximab and methotrexate treatment in a nude rat model of CNS lymphoma.

To determine the efficacy of methotrexate and/or rituximab in a CNS lymphoma model and to evaluate MRI modalities for monitoring efficacy, we inoculated female athymic nude rats (rnu/rnu) intracerebrally with human MC116 B-lymphoma cells. Between days 16 and 26, rats were randomized to receive intravenous (IV) treatment with (1) saline (controls, n = 15), (2) methotrexate 1,000 mg/m(2) (n = 6), (3) rituximab 375 mg/m(2) (n = 6), or (4) rituximab plus methotrexate (n = 6). T2/fluid-attenuated inversion recovery (FLAIR) and gadolinium contrast-enhanced T1 MRI sequences were performed prior to and 1 week after treatment. IV rituximab gave an objective tumor response in four of six animals (>50% reduction in tumor volume comparing pre- and posttreatment T2/FLAIR MRI) and resulted in stable disease (50%-125% of baseline) in another animal. The percent change in tumor volume on T2/FLAIR images was significantly different in the control versus rituximab group (p = 0.0051). IV methotrexate slowed tumor growth, compared to controls, but only one of six animals had an objective response. In untreated controls, tumor histological volumes correlated well with T2/FLAIR or contrast-enhanced T1 images (r = 0.877). In the treatment groups, T2/FLAIR correlation was good, but the gadolinium-enhanced T1 MRI was not significantly correlated with histology (r = 0.19). The MC116 CNS lymphoma model seems valuable for preclinical testing of efficacy and toxicity of treatment regimens. IV rituximab was highly effective, but methotrexate was only minimally effective. T2/FLAIR was superior to contrast-enhanced T1 for monitoring efficacy.

Combined iron oxide nanoparticle ferumoxytol and gadolinium contrast enhanced MRI define glioblastoma pseudoprogression.

BACKGROUND: Noninvasively differentiating therapy-induced pseudoprogression from recurrent disease in patients with glioblastoma is prospectively difficult due to the current lack of a biologically specific imaging metric. Ferumoxytol iron oxide nanoparticle MRI contrast characterizes innate immunity mediated neuroinflammation; therefore, we hypothesized that combined ferumoxytol and gadolinium enhanced MRI could serve as a biomarker of glioblastoma pseudoprogression. METHODS: In this institutional review board-approved, retrospective study, we analyzed ferumoxytol and gadolinium contrast enhanced T1-weighted 3T MRI in 45 patients with glioblastoma over multiple clinical timepoints. Isocitrate dehydrogenase 1 (IDH-1) mutational status was characterized by exome sequencing. Sum of products diameter measurements were calculated according to Response Assessment in Neuro-Oncology criteria from both gadolinium and ferumoxytol enhanced sequences. Enhancement mismatch was calculated as the natural log of the ferumoxytol to gadolinium sum of products diameter ratio. Analysis of variance and Student's t-test assessed differences in mismatch ratios. P-value <0.05 indicated statistical significance. RESULTS: With the development of pseudoprogression we observed a significantly elevated mismatch ratio compared with disease recurrence (P < 0.01) within IDH-1 wild type patients. Patients with IDH-1 mutation demonstrated significantly reduced mismatch ratio with the development of pseudoprogression compared with disease recurrence (P < 0.01). Receiver operator curve analysis demonstrated 100% sensitivity and specificity for the use of mismatch ratios as a diagnostic biomarker of pseudoprogression. CONCLUSION: Our study suggests that ferumoxytol to gadolinium contrast mismatch ratios are an MRI biomarker for the diagnosis of pseudoprogression in patients with glioblastoma. This may be due to the unique characterization of therapy-induced neuroinflammation.

Characterization and magnetic resonance imaging of a rat model of human B-cell central nervous system lymphoma.

PURPOSE: The incidence of primary central nervous system lymphoma (PCNSL) is increasing. Therapeutic approaches remain controversial. An animal model that mimics the clinical situation would be useful for evaluating PCNSL biology and treatment. EXPERIMENTAL DESIGN: Nude rats received intracerebral (caudate nucleus, n = 49) or intraventricular (n = 4) inoculation of human B-lymphoma cell line MC116. Two to five weeks after tumor inoculation, magnetic resonance imaging (MRI) was done (n = 24), and rat brains were assessed for pathology. Five rats each received whole-brain radiotherapy (WBRT, 20 Gy) or high-dose i.v. methotrexate (3 g/m2). RESULTS: Intracerebral tumors developed in 84% of evaluable animals with no pretreatment, 79% of rats pretreated with 4 Gy total body irradiation, and 92% of rats pretreated with cyclophosphamide (300 mg/m2). MRI showed abnormal T2 signal and gadolinium enhancement on T1-weighted images, consistent with tumor growth 19 to 24 days after inoculation. Tumor cells staining positively for B-lymphoma markers infiltrated within the inoculated hemisphere, along fiber tracks to the contralateral hemisphere, and along the subarachnoid space and ventricles. Tumors showed reactive gliosis. Intraventricular tumor cell injection resulted in periventricular parenchymal infiltration in both hemispheres. Radiation and methotrexate were effective in vitro, but only WBRT was clearly effective after 1 week in the intracerebral model. CONCLUSION: This model closely mimics human PCNSL in terms of imaging, histology, and treatment sensitivity and will be useful for the development of future therapeutic strategies for PCNSL.

Dominant intraprostatic cancer confirmed by direct MRI-guided biopsy: Concordance with histopathological findings.

PURPOSE: To investigate the concordance between dominant intraprostatic cancer seen on endorectal multiparametric MRI and confirmed by MRI-targeted biopsy with histopathological findings at radical prostatectomy, since existing literature has emphasized the miss rather than the concordance rate of MRI. MATERIALS AND METHODS: We retrospectively identified 20 patients who underwent radical prostatectomy after a dominant intraprostatic cancer focus was identified at endorectal multiparametric MRI and confirmed by MRI-targeted biopsy. Concordance was determined by comparing the location and Gleason grade group of dominant tumor at MRI with the location and Gleason grade group determined at histopathological review. RESULTS: Mean patient age was 65 years (range, 48 to 76) and median serum prostatic specific antigen level was 9.4 ng/mL (range, 4.6 to 58.0). In all 20 patients, the location of dominant tumor based on MRI and targeted biopsy corresponded with the dominant tumor location at histopathology. In 9 patients, Gleason grade group was the same at targeted biopsy and final histopathology. In 9 patients, final Gleason grade group was higher and in two patients it was lower. CONCLUSION: Our preliminary results suggest dominant tumor as determined by endorectal multiparametric MRI and confirmed by a positive MRI-targeted biopsy has high concordance with histopathological findings at radical prostatectomy for location, and reasonable concordance for Gleason grade group.

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.