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1.
Radiology ; 293(3): 554-564, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31638489

RESUMO

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.


Assuntos
Meios de Contraste/efeitos adversos , Óxido Ferroso-Férrico/efeitos adversos , Imageamento por Ressonância Magnética , Uso Off-Label , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Sistema de Registros
2.
Magn Reson Med ; 80(1): 224-230, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29205477

RESUMO

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.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Meios de Contraste/química , Óxido Ferroso-Férrico/química , Glioma/diagnóstico por imagem , Compostos Heterocíclicos/química , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética , Compostos Organometálicos/química , Adulto , Bevacizumab , Quimiorradioterapia , Feminino , Gadolínio/química , Humanos , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade , Reconhecimento Automatizado de Padrão
3.
J Magn Reson Imaging ; 48(2): 441-448, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29314418

RESUMO

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.


Assuntos
Circulação Cerebrovascular , Compostos Férricos/química , Óxido Ferroso-Férrico/química , Compostos Heterocíclicos/química , Imageamento por Ressonância Magnética , Compostos Organometálicos/química , Adulto , Idoso , Mapeamento Encefálico , Meios de Contraste , Feminino , Gadolínio/química , Humanos , Masculino , Nanopartículas Metálicas , Pessoa de Meia-Idade , Perfusão , Estudos Retrospectivos
4.
Kidney Int ; 92(1): 47-66, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28434822

RESUMO

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.


Assuntos
Meios de Contraste/administração & dosagem , Óxido Ferroso-Férrico/administração & dosagem , Imageamento por Ressonância Magnética/métodos , Adolescente , Adulto , Animais , Atlas como Assunto , Pré-Escolar , Meios de Contraste/efeitos adversos , Meios de Contraste/farmacocinética , Feminino , Óxido Ferroso-Férrico/efeitos adversos , Óxido Ferroso-Férrico/farmacocinética , Hematínicos/administração & dosagem , Humanos , Rim/fisiopatologia , Imageamento por Ressonância Magnética/efeitos adversos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Eliminação Renal , Insuficiência Renal Crônica/fisiopatologia , Reprodutibilidade dos Testes
5.
NMR Biomed ; 30(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28885746

RESUMO

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.


Assuntos
Meios de Contraste , Extravasamento de Materiais Terapêuticos e Diagnósticos , Imageamento por Ressonância Magnética/métodos , Volume Sanguíneo , Humanos
6.
Radiology ; 266(3): 842-52, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23204544

RESUMO

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.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Óxido Ferroso-Férrico , Compostos Heterocíclicos , Angiografia por Ressonância Magnética/métodos , Compostos Organometálicos , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Quimiorradioterapia , Meios de Contraste , Feminino , Gadolínio , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade , Estatística como Assunto , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento
7.
Kidney Int ; 75(5): 465-74, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18843256

RESUMO

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.


Assuntos
Meios de Contraste/efeitos adversos , Óxido Ferroso-Férrico , Ferro , Nefropatias/complicações , Imageamento por Ressonância Magnética/métodos , Dermopatia Fibrosante Nefrogênica/prevenção & controle , Óxidos , Sistema Nervoso Central/patologia , Doença Crônica , Dextranos , Óxido Ferroso-Férrico/toxicidade , Gadolínio/toxicidade , Taxa de Filtração Glomerular , Humanos , Ferro/toxicidade , Nefropatias/diagnóstico , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética/efeitos adversos , Nanopartículas de Magnetita , Masculino , Pessoa de Meia-Idade , Nanopartículas/toxicidade , Dermopatia Fibrosante Nefrogênica/induzido quimicamente , Óxidos/toxicidade , Fatores de Risco
8.
Neuro Oncol ; 11(2): 142-50, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18772353

RESUMO

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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Modelos Animais de Doenças , Glioma/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Bevacizumab , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Carboplatina/administração & dosagem , Glioma/mortalidade , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Nus , Taxa de Sobrevida , Carga Tumoral
9.
Neuro Oncol ; 11(5): 503-13, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19158414

RESUMO

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.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Metotrexato/administração & dosagem , Animais , Anticorpos Monoclonais Murinos , Linhagem Celular Tumoral , Feminino , Humanos , Aumento da Imagem , Ratos , Ratos Nus , Rituximab , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Neuro Oncol ; 21(4): 517-526, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30277536

RESUMO

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.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Óxido Ferroso-Férrico , Gadolínio , Glioblastoma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adulto , Neoplasias Encefálicas/patologia , Meios de Contraste , Feminino , Glioblastoma/patologia , Humanos , Nanopartículas de Magnetita , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos
11.
J Cereb Blood Flow Metab ; 33(5): 780-6, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23486297

RESUMO

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.


Assuntos
Determinação do Volume Sanguíneo/métodos , Encéfalo/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Meios de Contraste , Nanopartículas de Magnetita , Volume Sanguíneo , Encéfalo/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Neoplasias do Sistema Nervoso Central/patologia , Circulação Cerebrovascular , Gadolínio , Compostos Heterocíclicos , Humanos , Compostos Organometálicos
12.
Int J Radiat Oncol Biol Phys ; 79(2): 514-23, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20395065

RESUMO

PURPOSE: We evaluated dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging (DSC-MRI) using gadoteridol in comparison to the iron oxide nanoparticle blood pool agent, ferumoxytol, in patients with glioblastoma multiforme (GBM) who received standard radiochemotherapy (RCT). METHODS AND MATERIALS: Fourteen patients with GBM received standard RCT and underwent 19 MRI sessions that included DSC-MRI acquisitions with gadoteridol on Day 1 and ferumoxytol on Day 2. Relative cerebral blood volume (rCBV) values were calculated from DSC data obtained from each contrast agent. T1-weighted acquisition post-gadoteridol administration was used to identify enhancing regions. RESULTS: In seven MRI sessions of clinically presumptive active tumor, gadoteridol-DSC showed low rCBV in three and high rCBV in four, whereas ferumoxytol-DSC showed high rCBV in all seven sessions (p = 0.002). After RCT, seven MRI sessions showed increased gadoteridol contrast enhancement on T1-weighted scans coupled with low rCBV without significant differences between contrast agents (p = 0.9). Based on post-gadoteridol T1-weighted scans, DSC-MRI, and clinical presentation, four patterns of response to RCT were observed: regression, pseudoprogression, true progression, and mixed response. CONCLUSION: We conclude that DSC-MRI with a blood pool agent such as ferumoxytol may provide a better monitor of tumor rCBV than DSC-MRI with gadoteridol. Lesions demonstrating increased enhancement on T1-weighted MRI coupled with low ferumoxytol rCBV are likely exhibiting pseudoprogression, whereas high rCBV with ferumoxytol is a better marker than gadoteridol for determining active tumor. These interesting pilot observations suggest that ferumoxytol may differentiate tumor progression from pseudoprogression and warrant further investigation.


Assuntos
Neoplasias Encefálicas/patologia , Meios de Contraste , Progressão da Doença , Glioblastoma/patologia , Compostos Heterocíclicos , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita , Compostos Organometálicos , Adulto , Idoso , Volume Sanguíneo , Barreira Hematoencefálica , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Feminino , Óxido Ferroso-Férrico , Gadolínio , Glioblastoma/irrigação sanguínea , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Adulto Jovem
13.
J Cereb Blood Flow Metab ; 30(1): 15-35, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19756021

RESUMO

Superparamagnetic iron oxide nanoparticles have diverse diagnostic and potential therapeutic applications in the central nervous system (CNS). They are useful as magnetic resonance imaging (MRI) contrast agents to evaluate: areas of blood-brain barrier (BBB) dysfunction related to tumors and other neuroinflammatory pathologies, the cerebrovasculature using perfusion-weighted MRI sequences, and in vivo cellular tracking in CNS disease or injury. Novel, targeted, nanoparticle synthesis strategies will allow for a rapidly expanding range of applications in patients with brain tumors, cerebral ischemia or stroke, carotid atherosclerosis, multiple sclerosis, traumatic brain injury, and epilepsy. These strategies may ultimately improve disease detection, therapeutic monitoring, and treatment efficacy especially in the context of antiangiogenic chemotherapy and antiinflammatory medications. The purpose of this review is to outline the current status of superparamagnetic iron oxide nanoparticles in the context of biomedical nanotechnology as they apply to diagnostic MRI and potential therapeutic applications in neurooncology and other CNS inflammatory conditions.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/patologia , Compostos Férricos , Inflamação/diagnóstico , Inflamação/patologia , Imageamento por Ressonância Magnética/métodos , Animais , Barreira Hematoencefálica , Meios de Contraste , Espectroscopia de Ressonância de Spin Eletrônica , Compostos Férricos/farmacologia , Compostos Férricos/uso terapêutico , Humanos , Nanopartículas , Tamanho da Partícula
14.
J Magn Reson ; 206(2): 190-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20674422

RESUMO

The accurate mapping of the tumor blood volume (TBV) fraction (vb) is a highly desired imaging biometric goal. It is commonly thought that achieving this is difficult, if not impossible, when small molecule contrast reagents (CRs) are used for the T1-weighted (Dynamic-Contrast-Enhanced) DCE-MRI technique. This is because angiogenic malignant tumor vessels allow facile CR extravasation. Here, a three-site equilibrium water exchange model is applied to DCE-MRI data from the cerebrally-implanted rat brain U87 glioma, a tumor exhibiting rapid CR extravasation. Analyses of segments of the (and the entire) DCE data time-course with this "shutter-speed" pharmacokinetic model, which admits finite water exchange kinetics, allow TBV estimation from the first-pass segment. Pairwise parameter determinances were tested with grid searches of 2D parametric error surfaces. Tumor blood volume (vb), as well as ve (the extracellular, extravascular space volume fraction), and Ktrans (a CR extravasation rate measure) parametric maps are presented. The role of the Patlak Plot in DCE-MRI is also considered.


Assuntos
Determinação do Volume Sanguíneo/métodos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Gadolínio DTPA/farmacocinética , Glioma/metabolismo , Glioma/patologia , Animais , Volume Sanguíneo , Linhagem Celular Tumoral , Simulação por Computador , Meios de Contraste/farmacocinética , Glioma/irrigação sanguínea , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética , Masculino , Taxa de Depuração Metabólica , Modelos Neurológicos , Ratos , Ratos Nus
15.
Neoplasia ; 11(2): 187-95, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19177203

RESUMO

The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.


Assuntos
Neoplasias Encefálicas/patologia , Ciclofosfamida/farmacologia , Modelos Animais de Doenças , Glioma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Proliferação de Células/efeitos dos fármacos , Glioma/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética , Ratos , Ratos Nus
16.
J Cereb Blood Flow Metab ; 29(4): 853-60, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19142191

RESUMO

The vascular effects of antiangiogenic treatment may pose problems for evaluating brain tumor response based on contrast-enhanced magnetic resonance imaging (MRI). We used serial dynamic contrast-enhanced MRI at 12 T to assess vascular responses to antiangiogenic versus steroid therapy. Athymic rats with intracerebral U87MG human glioma (n=17) underwent susceptibility-weighted perfusion MRI with ferumoxytol, a solely intravascular ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle, followed by T1-weighted dynamic gadodiamide-enhanced MRI to measure vascular permeability. Rats were imaged before and after 24, 48, and 72 h of treatment with the antiangiogenic agent bevacizumab or the corticosteroid dexamethasone. Contrast agent extravasation was seen rapidly after gadodiamide, but not with ferumoxytol administration. Bevacizumab significantly decreased the blood volume and decreased permeability in tumors as determined by increased time-to-peak enhancement. A single dose of 45 mg/kg bevacizumab resulted in changes analogous to dexamethasone given in an extremely high dose (12 mg/kg per day), and was significantly more effective than dexamethasone at 2 mg/kg per day. We conclude that dynamic perfusion MRI measurements with ferumoxytol USPIO to assess cerebral blood volume, along with dynamic gadodiamide-enhanced MR to assess vascular permeability, hold promise in more accurately detecting therapeutic responses to antiangiogenic therapy.


Assuntos
Corticosteroides/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Compostos Férricos , Glioma/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Nanopartículas , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Bevacizumab , Permeabilidade Capilar , Circulação Cerebrovascular/efeitos dos fármacos , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Monitoramento de Medicamentos/métodos , Gadolínio DTPA , Glioma/diagnóstico , Humanos , Cinética , Ratos
17.
Neurosurgery ; 60(4): 601-11; discussion 611-2, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17415196

RESUMO

OBJECTIVE: Ferumoxytol, an iron oxide nanoparticle that targets phagocytic cells, can be used in magnetic resonance imaging of malignant brain tumors and can be administered as a bolus, allowing dynamic imaging. Our objectives were to determine the optimum time of delayed contrast enhancement of ferumoxytol, and to compare ferumoxytol and gadolinium contrast agents for magnetic resonance angiography and perfusion. METHODS: Twelve patients with malignant brain tumors underwent serial magnetic resonance imaging multiple times up to 72 hours after ferumoxytol injection at both 1.5 and 3-T. The enhancement time course was determined for ferumoxytol and compared with a baseline gadolinium scan. Perfusion, time-of-flight and dynamic magnetic resonance angiography and T1-weighted scans were compared for the two agents. RESULTS: The lesions were detectable at all field strengths, even with an intraoperative 0.15-T magnet. Maximal ferumoxytol enhancement intensity was at 24 to 28 hours after administration, and the enhancing volume subsequently expanded with time into a non-gadolinium-enhancing, high T2-weighted signal region of tumor-infiltrated brain. Dynamic studies were assessed with both agents, indicating early vascular leak with gadolinium but not with ferumoxytol. CONCLUSION: Our most important finding was that gadolinium leaks out of blood vessels early after injection, whereas ferumoxytol stays intravascular in the "early" phase, thereby increasing the accuracy of tumor perfusion assessment. As a magnetic resonance imaging contrast agent, ferumoxytol visualizes brain tumors at all field strengths evaluated, with delayed enhancement peaking at 24 to 28 hours after administration.


Assuntos
Neoplasias Encefálicas/diagnóstico , Óxido Ferroso-Férrico/administração & dosagem , Gadolínio DTPA/administração & dosagem , Aumento da Imagem/métodos , Angiografia por Ressonância Magnética/métodos , Adulto , Idoso , Meios de Contraste/administração & dosagem , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nanopartículas , Perfusão/métodos , Projetos Piloto
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