-
Tal Teitz,
Jennifer J Stanke,
Sara Federico,
Cori L Bradley,
Rachel Brennan,
Jiakun Zhang,
Melissa D Johnson, Jan Sedlacik,
Madoka Inoue,
Ziwei M Zhang,
Sharon Frase,
Jerold E Rehg,
Claudia M Hillenbrand,
David Finkelstein,
Christopher Calabrese,
Michael A Dyer,
Jill M Lahti
[show abstract]
[hide abstract]
ABSTRACT: Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system.
Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents.
The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer.
PLoS ONE 01/2011; 6(4):e19133. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We compared the sensitivity and specificity of T2*-weighted gradient-echo imaging (T2*-GRE) and susceptibility-weighted imaging (SWI) in determining prevalence and cumulative incidence of intratumoral hemorrhages in children with diffuse intrinsic pontine glioma (DIPG) undergoing antiangiogenic and radiation therapy.
Patients were recruited from an institutional review board-approved prospective phase I trial of vandetanib administered in combination with radiation therapy. Patient consent was obtained before enrollment. Consecutive T2*-GRE and SWI exams of 17 patients (F/M: 9/8; age 3-17 years) were evaluated. Two reviewers (R1 and R2) determined the number and size of hemorrhages at baseline and multiple follow-ups (92 scans, mean 5.4/patient). Statistical analyses were performed using descriptive statistics, graphical tools, and mixed-effects Poisson regression models.
Prevalence of hemorrhages at diagnosis was 41% and 47%; the cumulative incidences of hemorrhages at 6 months by T2*-GRE and SWI were 82% and 88%, respectively. Hemorrhages were mostly petechial; 9.7% of lesions on T2*-GRE and 5.2% on SWI were hematomas (>5 mm). SWI identified significantly more hemorrhages than T2*-GRE did. Lesions were missed or misinterpreted in 36/39 (R1/R2) scans by T2*-GRE and 9/3 scans (R1/R2) by SWI. Hemorrhages had no clinically significant neurological correlates in patients.
SWI is more sensitive than T2*-GRE in detecting hemorrhages and differentiating them from calcification, necrosis, and artifacts. Also, petechial hemorrhages are more common in DIPG at diagnosis than previously believed and their number increases during the course of treatment; hematomas are rare.
Neuroradiology 09/2010; 52(12):1167-77. · 2.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The blood oxygenation level dependent signal of cerebral tissue can be theoretically derived using a network model formed by randomly oriented infinitely long cylinders. The validation of this model by phantom and in vivo experiments is still an object of research. A network phantom was constructed of solid polypropylene strings immersed in silicone oil, which essentially eliminated the effect of spin diffusion. The volume fraction and magnetic property of the string network was predetermined by independent methods. Ten healthy volunteers were measured for in vivo demonstration. The gradient echo sampled spin echo signal was evaluated with the cylinder network model. We found a strong interdependency between the two network characterizing parameters deoxygenated blood volume and oxygen extraction fraction. Here, different sets of deoxygenated blood volume/oxygen extraction fraction values were able to describe the measured signal equally well. However, by setting one parameter constant to a predetermined value, reasonable estimates of the other parameter were obtained. The same behavior was found for the in vivo demonstration. The signal theory of the cylinder network was validated by a well-characterized phantom. However, the found interdependency that was found between deoxygenated blood volume and oxygen extraction fraction requires an independent estimation of one variable to determine reliable values of the other parameter.
Magnetic Resonance in Medicine 04/2010; 63(4):910-21. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To perform systematic investigations on parameter selection of a dual-echo sequence (ToF-SWI) for combined 3D time-of-flight (ToF) angiography and susceptibility weighted imaging (SWI).
ToF-SWI was implemented on 1.5 T and 3 T MR scanners with complete 3D first-order flow compensation of the second echo. The efficiency of flow compensating the SWI echo was studied based on phantom and in vivo examinations. Arterial and venous contrasts were examined in volunteers as a function of flip angle and compared with additionally acquired single-echo ToF and single-echo SWI data.
Complete flow compensation is required to reduce arterial contamination in the SWI part caused by signal voids. A ramped flip angle of 20 degrees depicted arteries best while venous contrast was preserved. Comparing ToF-SWI with single-echo ToF demonstrated arteries with similar quality and delineated all major arteries equally well. Venous delineation was degraded due to lower SNR associated with the thinner slabs used with ToF-SWI compared to single-echo SWI acquisition.
A dual-echo sequence (ToF-SWI) with full flow compensation of the second echo in a single scan is feasible. This sequence allows simultaneous visualization of intrinsically coregistered arteries and veins without spatial mis-registration of vessels caused by oblique flow and with minimal signal loss in arteries.
Journal of Magnetic Resonance Imaging 07/2009; 29(6):1478-84. · 2.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of our work was to investigate the process of myelination in healthy patients using the diffusion parameters apparent diffusion coefficient (ADC), relative anisotropy (RA), fractional anisotropy (FA), and eigenvalues. Age-dependent changes were assessed using the slope m of the fit functions that best described the data.
Seventy-two patients (3 weeks-19 years) without pathological magnetic resonance imaging findings were selected from all pediatric patients scanned with diffusion tensor imaging over a 5-year period at our institution. ADC, RA, FA, and eigenvalue maps were calculated and regions of interest were selected in anterior/posterior pons, genu/splenium of corpus callosum (CC), anterior/posterior limb of internal capsule (IC), and white matter (WM) regions (frontal, temporal, parietal, occipital WM). Statistical analysis was performed using Spearman correlation coefficient and regression analysis.
Mean values ranged 71.6 x 10(-5) to 90.3 x 10(-5) mm(2)/s (pons/parietal WM) for ADC, 0.32-0.94 (frontal WM/CC) for RA, and 0.36-0.81 (frontal WM/splenium) for FA. Logarithmic fit functions best described the data. Strong age influences were observed for CC, pons, and parietal/frontal WM and changes were significant for all three eigenvalues, most pronounced for perpendicular eigenvalues. Changes in RA and FA differed depending on the structure anisotropy.
Changes observed for ADC, RA, FA, and eigenvalues with age were consistent with previous findings. Changes detected for RA and FA varied due to the different scaling of both parameters. We found that the use of the largely linear scaled RA adds more valuable information for the assessment of age-dependent structural changes as compared to FA. Additionally, we report normative values for the diffusion parameters studied.
Neuroradiology 02/2009; 51(4):253-63. · 2.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The transverse magnetization of a single vein and its surrounding tissue is subject to spin dephasing caused by the local magnetic field inhomogeneity which is induced by the very same vessel. This phenomenon can be approximated and simulated by applying the model of an infinitely long and homogeneously magnetized cylinder embedded in a homogeneous tissue background. It is then possible to estimate the oxygenation level of the venous blood by fitting the simulated magnetization-time-course to the measured signal decay. In this work we demonstrate the ability of this approach to quantify the blood oxygenation level (Y) of small cerebral veins in vivo, not only under normal physiologic conditions (Y(native) = 0.5-.55) but also during induced changes of physiologic conditions which affect the cerebral venous blood oxygenation level. Changes of blood's oxygenation level induced by carbogen (5% CO2, 95%0 02) and caffeine were observed and quantified, resulting in values of Y(carbogen) = 0.7 and Y(caffeine) = 0.42, respectively. The proposed technique may ultimately help to better understand local changes in cerebral physiology during neuronal activation by quantifying blood oxygenation in veins draining active brain areas. It may also be beneficial in clinical applications where it may improve diagnosis of cerebral pathologies as well as monitoring of responses to therapy.
Zeitschrift für Medizinische Physik 02/2009; 19(1):48-57. · 1.21 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We present numerical simulations and experimental results for susceptibility weighted imaging (SWI) at 7 T. Magnitude, phase, and SWI contrast were simulated for different voxel geometries and imaging parameters, resulting in an echo time of 14 msec for optimum contrast between veins and surrounding tissue. Slice thickness of twice the in-plane voxel size or more resulted in optimum vessel visibility. Phantom and in vivo data are in very good agreement with the simulations and the delineation of vessels at 7 T was superior compared to lower field strengths. The phase of the complex data reveals anatomical details that are complementary to the corresponding magnitude images. Susceptibility weighted imaging at very high field strengths is a promising technique because of its high sensitivity to tissue susceptibility, its low specific absorption rate, and the phase's negligible sensitivity to B(1) inhomogeneities.
Magnetic Resonance in Medicine 12/2008; 60(5):1155-68. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Breathing carbogen (5% CO2 / 95% O2) dramatically increases cerebral blood flow (CBF), which induces a blood oxygenation level dependent (BOLD) related vascular signal change due to the concomitantly increased oxyhemoglobin concentration in the veins. However, carbogen often causes discomfort due to its forced strong and deep breathing which also may lead to severe motion artifacts in magnetic resonance imaging. In this study, susceptibility-weighted imaging (SWI) was performed with CO2 levels of 0, 1.67%, 3.33% and 5% to measure the induced BOLD signal changes in venous vessels and brain tissue. Susceptibility-weighted imaging data from 15 healthy subjects and one patient with a brain tumor were acquired. The signal magnitude of cortical veins increased relative to pure oxygen by 3.5+/-3.8%, 10.3+/-4.5%, and 22.7+/-8.8% for CO2 concentrations of 1.67%, 3.33%, and 5%, respectively. Significant signal changes were detected in segmented white matter for 5% CO2, and gray matter for both 3.3% and 5% CO2. The influence of motion artifacts was clearly traceable by the broadening of the signal distribution in segmented tissue. Heterogeneous signal changes were observed in the patient for the same tumor regions at both 3.33% and 5% CO2. Signal phase values of white and gray matter changed only very slightly with increasing CO2. Based on our findings we recommend the reduction of CO2 concentration to about 3% when using a mixture of O2 and CO2. All subjects also reported highly improved breathing comfort at 3.3% CO2 as compared to 5%. The marginal phase change of white and gray matter supports the assumption that deoxygenated blood alone does not explain the commonly observed phase difference between the two tissues.
NeuroImage 08/2008; 43(1):36-43. · 5.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Caffeine lowers the blood oxygenation level-dependent (BOLD) signal by acting as an adenosine antagonist, thus decreasing the cerebral blood flow (CBF). The aims of this study were to demonstrate the sensitivity of susceptibility-weighted imaging (SWI) to caffeine-induced changes in CBF and to investigate the time course and magnitude of signal change in caffeine-habituated and -abstinent volunteers. High-resolution susceptibility-weighted images were acquired with both groups at 1.5 T using a fully velocity compensated 3D gradient echo sequence. Following a native scan, subjects were given a tablet containing 200 mg of caffeine. Scans were repeated for about 1 h and the acquired 3D data sets were co-registered to each other. BOLD signal changes of several venous vessels were analyzed in dedicated ROIs. Maps of relative signal change clearly visualized the caffeine-induced signal response of veins. Only very weak signal changes of about -2+/-1% were found in both, grey and white matter and -1+/-2% in the ventricles. Maximum signal decrease of veins occurred 40-50 min after caffeine ingestion. The signal decrease was -16.5+/-6.5% and -22.7+/-8.3% for the caffeine users group and abstainers, respectively. The signal difference of both groups was statistically significant (Student's t-test, t=2.16, p=0.021). Data acquired at 1.5, 3 and 7 T with echo times scaled to the respective field strength display very similar temporal signal behavior.
NeuroImage 04/2008; 40(1):11-8. · 5.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The MR signal decay in gradient echo sequences includes signal loss due to spin dephasing caused by static magnetic field inhomogeneities. This decay can be calculated for different geometries of the susceptibility distribution, such as spheres, cylinders, or cylinder networks. In particular, the model of an infinitely long cylinder is a good approximation for single straight blood vessels. Blood oxygenation and blood volume fraction are important parameters, which influence the signal in a characteristic way. In this work the signal decays for a single cylindrical vessel were investigated and evaluated in simulations, phantom measurements as well as in vivo measurements of small single veins in the human brain by using a 3D multiecho gradient echo sequence. Good agreement between simulations and phantom experiments was obtained for different experimental settings. Based on the simulations, physiologically consistent values of venous blood oxygenation level, Y, were extracted from the in vivo measurements of different veins and volunteers (Y = 0.55 +/- 0.02). The methods ability to measure changes in venous blood oxygenation induced by carbogen breathing was demonstrated in one volunteer, where an increase from Y approximately 0.5 to Y approximately 0.7 was observed.
Magnetic Resonance in Medicine 12/2007; 58(5):1035-44. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Susceptibility-weighted imaging (SWI) is a novel method, that combines magnitude and phase information from a high-resolution, fully velocity compensated 3D T2-weighted gradient echo sequence. Phase images are unwrapped and high pass filtered to highlight phase changes associated with venous vessels and converted into a mask that is multiplied with the corresponding phase image. This technique has been applied thus far to the imaging of tumors, vascular malformations, trauma, stroke, micro-hemorrhages, and as a functional imaging method. The purpose of this paper is to present an overview of the current status of the technique and to illustrate its potential.
Zeitschrift für Medizinische Physik 02/2006; 16(4):240-50. · 1.21 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Susceptibility weighted imaging (SWI) is a BOLD-sensitive method for visualizing anatomical features such as small cerebral veins in high detail. The purpose of this study was to evaluate high-resolution SWI in combination with a modulation of blood oxygenation by breathing of air, carbogen, and oxygen and to directly visualize the effects of changing blood oxygenation on the magnetic field inside and around venous blood vessels. Signal changes associated with the response to carbogen and oxygen breathing were evaluated in different anatomic regions in healthy volunteers and in two patients with brain tumors. In the magnitude images inhalation of carbogen led to significant signal intensity changes ranging from +4.4 +/- 1.9% to +9.5 +/- 1.4% in gray matter and no significant changes in thalamus, putamen, and white matter. During oxygen breathing mean signal changes were smaller than during carbogen breathing. The method is capable of producing high-resolution functional maps of BOLD response to carbogen and oxygen breathing as well as high-resolution images of venous vasculature. Its sensitivity to changes in blood oxygenation was demonstrated by in vivo visualization of the BOLD effect via phase imaging.
Magnetic Resonance in Medicine 08/2005; 54(1):87-95. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: There is interest in applying novel methods to dynamic MR mammography (MRM). One such possibility is to administer an exogenous hyperoxic contrast agent, such as carbogen (95-98% O2 and 2-5% CO2) or pure oxygen (100% O2). We report our first experiences with these agents in a patient with an invasive lobular carcinoma. Fourteen dynamic series were acquired with an rf-spoiled 2D multislice gradient echo sequence, including three measurements while breathing air, four measurements with 100% oxygen, three measurements with air and four measurements with carbogen. Afterwards, 0.1 mmol/kg bw of Gd-DTPA was administered to obtain dynamic T1-weighted double-echo 3D axial gradient echo images (TR/TE1/TE2/alpha=7.8 ms/2 ms/4.76 ms/15 degrees) every 90 s up to 4.5 min after injection. The lesion was well delineated on the contrast-enhanced images, contrary to magnitude images reconstructed from the raw data sets acquired during air/oxygen/carbogen breathing. A ROI-based median-filtered signal-time course revealed a tumor signal increase of roughly 15% between scans acquired during air and oxygen breathing. Though preliminary, these first results are encouraging concerning the exploration of these alternative contrast agents in MRM in greater detail.
European Radiology 05/2005; 15(4):829-32. · 3.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: MR gradient echo imaging is sensitive to the magnetic susceptibility of different tissue types. The purpose of this study was to investigate the diagnostic potential of MR phase imaging of the human brain.
High-spatial-resolution, T2*-weighted, single-echo images were acquired in five volunteers and one patient with a brain tumor on a 1.5T system by applying a 3D, first-order, velocity-compensated gradient echo sequence by using a quadrature transmit-receive head coil. Phase images were reconstructed from the raw data and unwrapped by using a region-growing phase-unwrapping algorithm. Low-spatial-frequency components originating from static background susceptibility effects were removed by high-pass filtering.
Phase images showed excellent image contrast and revealed anatomic structures that were not visible on the corresponding magnitude images.
Improved processing of susceptibility-weighted MR phase images offers a new means of contrast for neuroimaging applications.
American Journal of Neuroradiology 05/2005; 26(4):736-42. · 2.93 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Susceptibility-weighted (SW) magnetic resonance (MR) imaging provides high-resolution, distortion-free blood oxygen level-dependent (BOLD) data for assessment of cerebral veins, blood products, and brain lesions. Currently, reconstruction of SW imaging data is not implemented on all MR imaging systems or is restricted in terms of parameter adjustments. New developments in SW imaging have been implemented into a graphical user interface (GUI), which is named GUIBOLD. The GUI was designed for imaging system-independent off-line data reconstruction with interactive setting of parameters on the basis of k-space data and Digital Imaging and Communications in Medicine images. GUIBOLD is capable of presenting magnitude, unwrapped phase, and SW images in different orientations and parallel projections with various rendering methods and region-of-interest-based data analysis tools. Moreover, GUIBOLD affords easy and comprehensive data reconstruction possibilities for venographic and arterial imaging and anatomic phase imaging. As a direct application, differentiation between cavernous and calcified lesions on the basis of their magnetic susceptibility on phase images was performed. GUIBOLD widens the range of potential applications of SW imaging and makes it more accessible for use in the clinical routine as well as in medical research.
Radiographics 28(3):639-51. · 2.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study examines the identifiability of the intratemporal motor facial nerve using 3-T and 1.5-T magnetic resonance imaging (MRI).
Twenty subjects underwent T1- and T2-weighted MRI of the temporal bone. Acquisition was performed using a head coil at 3 and 1.5 T as well as a surface coil at 3 T. Layer thicknesses were 0.6 mm for 3-T and 0.8 mm for 1.5-T MRI. Eight topodiagnostically relevant facial nerve and branch structures were statistically evaluated.
The main trunk could be identified in all examinations. Sequences acquired with a head coil at 3 T yielded statistically significant superiority (P < 0.001) over 3-T surface coil and 1.5-T head coil measurements. The precise identifiability of the smallest structures (eg, stapedial nerve) succeeded best by means of T1-weighted 3-T MRI.
Due to the precise identifiability of the smallest branches, 3-T MRI improves diagnostics particularly with regard to preoperative planning.
Journal of computer assisted tomography 33(5):782-8. · 1.38 Impact Factor
