Current Role at Stanford
Director of Pre-clinical MRI, Radiology
Director of Pre-clinical MRI, Radiology
A restricted field of view (rFOV) approach for imaging a dynamic time series of volumes of limited spatial extent within a larger subject is described. The shorter readout with rFOV-MRI can be exploited to either limit image artifacts or increase spatial resolution. To accomplish rFOV imaging of a multislice volume for a dynamic series, an outer volume suppression (OVS) preparation that saturates signal external to a cylinder through the subject is followed by slice-selective excitation and a spiral readout. The pass- and stopband efficiencies of the OVS in an agar gel phantom were 97% (+/-1.5%) and 3% (+/-1%), respectively. Profiles of the temporal signal-to-noise ratio (SNR) were measured in a phantom and an adult brain. The rFOV sequence reduced distortions from off-resonance signal and T2*-induced blurring compared to a conventional sequence. Sequence utility is demonstrated for high-resolution rFOV functional MRI (fMRI) in the visual cortex. The rFOV sequence may prove to be useful for other multislice dynamic and high-resolution imaging applications.
View details for DOI 10.1002/mrm.21115
View details for Web of Science ID 000243946300009
View details for PubMedID 17260360
To describe approaches for determining optimal spatial and temporal resolutions for the proton resonance frequency shift method of quantitative magnetic resonance temperature imaging (MRTI) guidance of transurethral ultrasonic prostate ablation.Temperature distributions of two transurethral ultrasound applicators (90 degrees sectored tubular and planar arrays) for canine prostate ablation were measured via MRTI during in vivo sonication, and agree well with two-dimensional finite difference model simulations at various spatial resolutions. Measured temperature distributions establish the relevant signal-to-noise ratio (SNR) range for thermometry in an interventional MR scanner, and are reconstructed at different resolutions to compare resultant temperature measurements. Various temporal resolutions are calculated by averaging MRTI frames.When noise is added to simulated temperature distributions for tubular and planar applicators, the minimum root mean squared (RMS) error is achieved by reconstructing to pixel sizes of 1.9 and 1.7 mm, respectively. In in vivo measurements, low spatial resolution MRTI data are shown to reduce the noise without significantly affecting thermal dose calculations. Temporal resolution of 0.66 frames/minute leads to measurement errors of more than 12 degrees C during rapid heating.Optimizing MRTI pixel size entails balancing large pixel SNR gain with accuracy in representing underlying temperature distributions.
View details for DOI 10.1002/jmri.20339
View details for Web of Science ID 000230128900015
View details for PubMedID 15971190
We hypothesize that the difference in image quality between the traditional kilovoltage (kV) prescription radiographs and megavoltage (MV) treatment radiographs is a major factor hindering our ability to accurately measure, thus correct, setup error in radiation therapy. The objective of this work is to study the accuracy of on-line correction of setup errors achievable using either kV- or MV-localization (i.e., open-field) radiographs.Using a gantry mounted kV and MV dual-beam imaging system, the accuracy of on-line measurement and correction of setup error using electronic kV- and MV-localization images was examined based on anthropomorphic phantom and patient imaging studies. For the phantom study, the user's ability to accurately detect known translational shifts was analyzed. The clinical study included 14 patients with disease in the head and neck, thoracic, and pelvic regions. For each patient, 4 orthogonal kV radiographs acquired during treatment simulation from the right lateral, anterior-to-posterior, left lateral, and posterior-to-anterior directions were employed as reference prescription images. Two-dimensional (2D) anatomic templates were defined on each of the 4 reference images. On each treatment day, after positioning the patient for treatment, 4 orthogonal electronic localization images were acquired with both kV and 6-MV photon beams. On alternate weeks, setup errors were determined from either the kV- or MV-localization images but not both. Setup error was determined by aligning each 2D template with the anatomic information on the corresponding localization image, ignoring rotational and nonrigid variations. For each set of 4 orthogonal images, the results from template alignments were averaged. Based on the results from the phantom study and a parallel study of the inter- and intraobserver template alignment variability, a threshold for minimum correction was set at 2 mm in any direction. Setup correction was applied by translating the treatment couch in the lateral, superior-to-inferior and vertical directions only. During treatment, kV open-field images were acquired for off-line treatment verification and analysis. Each patient study spanned 2-6 weeks. The 14 patient studies were completed with 8248 electronic images acquired and analyzed.Results from the phantom studies showed that the users were able to detect the applied translational shift to better than 2 mm, and mostly to within 1 mm. The intraobserver variability of template alignment was on the order of 1 mm using a sample of either MV or kV patient images. The difference between using MV or kV images was significant for only a few cases. However in most cases, interobserver alignment variability was larger when using MV images than kV. For on-line setup correction, the study procedure added 10 min. to conventional treatment time. Setup variation measured with either kV- or MV-localization images was similar. The initial magnitude of setup error was appreciable, with a mean displacement of about 6.6 +/- 2.4 mm for the 14 patients. On-line correction using either kV- or MV-localization images improved setup accuracy. Over all study patients, setup errors occurred with standard deviations greater than 2 mm in any direction with a frequency of 48% before correction, and were reduced to 16% after correction. On average, kV image-based correction reduced radial setup variation to 2.6 +/- 1.6 mm compared to the 3.3 +/- 1.8 mm attained using MV images. The difference detected between the kV and MV data was not statistically significant when averaged over all patients. However, for on-line corrections in the neck and thoracic regions, using kV-localization images reduced setup error significantly more than using MV images.In our anatomic template alignment study, interobserver variability was smaller using kV images than MV images. Intraobserver variability was smaller for alignments on kV images
View details for Web of Science ID 000087393900039
View details for PubMedID 10837971
To evaluate whether ultrasmall superparamagnetic iron oxide nanoparticle (USPIO)-enhanced magnetic resonance imaging (MRI) can detect allograft rejection in pediatric kidney transplant patients.The USPIO ferumoxytol has a long blood half-life and is phagocytosed by macrophages. In an IRB-approved single-center prospective clinical trial, 26 pediatric patients and adolescents (age 10-26 years) with acute allograft rejection (n = 5), non-rejecting allografts (n = 13), and normal native kidneys (n = 8) underwent multi-echo T2* fast spoiled gradient-echo (FSPGR) MRI after intravenous injection (p.i.) of 5 mg Fe/kg ferumoxytol. T2* relaxation times at 4 h p.i. (perfusion phase) and more than 20 h p.i. (macrophage phase) were compared with biopsy results. The presence of rejection was assessed using the Banff criteria, and the prevalence of macrophages on CD163 immunostains was determined based on a semi-quantitative scoring system. MRI and histology data were compared among patient groups using t tests, analysis of variance, and regression analyses with a significance threshold of p < 0.05.At 4 h p.i., mean T2* values were 6.6 ± 1.5 ms for native kidneys and 3.9 ms for one allograft undergoing acute immune rejection. Surprisingly, at 20-24 h p.i., one rejecting allograft showed significantly prolonged T2* relaxation times (37.0 ms) compared to native kidneys (6.3 ± 1.7 ms) and non-rejecting allografts (7.6 ± 0.1 ms). Likewise, three additional rejecting allografts showed significantly prolonged T2* relaxation times compared to non-rejecting allografts at later post-contrast time points, 25-97 h p.i. (p = 0.008). Histological analysis revealed edema and compressed microvessels in biopsies of rejecting allografts. Allografts with and without rejection showed insignificant differences in macrophage content on histopathology (p = 0.44).After ferumoxytol administration, renal allografts undergoing acute rejection show prolonged T2* values compared to non-rejecting allografts. Since histology revealed no significant differences in macrophage content, the increasing T2* value is likely due to the combined effect of reduced perfusion and increased edema in rejecting allografts.
View details for DOI 10.1007/s11307-017-1084-8
View details for PubMedID 28411307
Purpose To determine whether endogenous labeling of macrophages with clinically applicable nanoparticles enables noninvasive detection of innate immune responses to stem cell transplants with magnetic resonance (MR) imaging. Materials and Methods Work with human stem cells was approved by the institutional review board and the stem cell research oversight committee, and animal experiments were approved by the administrative panel on laboratory animal care. Nine immunocompetent Sprague-Dawley rats received intravenous injection of ferumoxytol, and 18 Jax C57BL/6-Tg (Csf1r-EGFP-NGFR/FKBP1A/TNFRSF6) 2Bck/J mice received rhodamine-conjugated ferumoxytol. Then, 48 hours later, immune-matched or mismatched stem cells were implanted into osteochondral defects of the knee joints of experimental rats and calvarial defects of Jax mice. All animals underwent serial MR imaging and intravital microscopy (IVM) up to 4 weeks after surgery. Macrophages of Jax C57BL/6-Tg (Csf1r-EGFP-NGFR/FKBP1A/TNFRSF6) 2Bck/J mice express enhanced green fluorescent protein (GFP), which enables in vivo correlation of ferumoxytol enhancement at MR imaging with macrophage quantities at IVM. All quantitative data were compared between experimental groups by using a mixed linear model and t tests. Results Immune-mismatched stem cell implants demonstrated stronger ferumoxytol enhancement than did matched stem cell implants. At 4 weeks, T2 values of mismatched implants were significantly lower than those of matched implants in osteochondral defects of female rats (mean, 10.72 msec for human stem cells and 11.55 msec for male rat stem cells vs 15.45 msec for sex-matched rat stem cells; P = .02 and P = .04, respectively) and calvarial defects of recipient mice (mean, 21.7 msec vs 27.1 msec, respectively; P = .0444). This corresponded to increased recruitment of enhanced GFP- and rhodamine-ferumoxytol-positive macrophages into stem cell transplants, as visualized with IVM and histopathologic examination. Conclusion Endogenous labeling of macrophages with ferumoxytol enables noninvasive detection of innate immune responses to stem cell transplants with MR imaging. (©) RSNA, 2017 Online supplemental material is available for this article.
View details for DOI 10.1148/radiol.2017161139
View details for PubMedID 28128708
Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-? receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected. Imaging data correlated with significantly decreased tumor interstitial fluid pressure, while tumor vascular density remained unchanged. This immediately clinically translatable concept involving Alk5 inhibitor pretreatment prior to an imaging study could be leveraged for improved tumor delivery of macromolecular and nanoparticle-based imaging probes and, thereby, facilitate development of more sensitive imaging tests for cancer diagnosis, enhanced tumor characterization, and personalized, image-guided therapies.
View details for PubMedID 27182558
View details for PubMedCentralID PMC4864003
Combining (18)F-FDG PET with whole-body MR for paediatric cancer staging is practically feasible if imaging protocols can be streamlined. We compared (18)F-FDG PET/STIR with accelerated (18)F-FDG PET/FSPGR for whole-body tumour imaging in children and young adults.Thirty-three children and young adults (17.5?±?5.5 years, range 10-30) with malignant lymphoma or sarcoma underwent a (18)F-FDG PET staging examination, followed by ferumoxytol-enhanced STIR and FSPGR whole-body MR. (18)F-FDG PET scans were fused with MR data and the number and location of tumours on each integrated examination were determined. Histopathology and follow-up imaging served as standard of reference. The agreement of each MR sequence with the reference and whole-body imaging times were compared using Cohen's kappa coefficient and Student's t-test, respectively.Comparing (18)F-FDG PET/FSPGR to (18)F-FDG PET/STIR, sensitivities were 99.3 % for both, specificities were statistically equivalent, 99.8 versus 99.9 %, and the agreement with the reference based on Cohen's kappa coefficient was also statistically equivalent, 0.989 versus 0.992. However, the total scan-time for accelerated FSPGR of 19.8?±?5.3 minutes was significantly shorter compared to 29.0?±?7.6 minutes for STIR (p?=?0.001).F-FDG PET/FSPGR demonstrated equivalent sensitivities and specificities for cancer staging compared to (18)F-FDG PET/STIR, but could be acquired with shorter acquisition time.? Breath-hold FSPGR sequences shorten the data acquisition time for whole-body MR and PET/MR. ? Ferumoxytol provides long-lasting vascular contrast for whole-body MR and PET/MR. ? (18) F-FDG PET/FSPGR data provided equal sensitivity and specificity for cancer staging compared to (18) F-FDG PET/STIR.
View details for PubMedID 27048532
-Ascending aortic dissection and rupture remain a life-threatening complication in patients with Marfan syndrome (MFS). The extracellular matrix provides strength and elastic recoil to the aortic wall, thereby preventing radial expansion. We have previously shown that ascending aortic aneurysm formation in Marfan mice (Fbn1(C1039G/+)) is associated with decreased aortic wall elastogenesis and increased elastin breakdown. In this study, we test the feasibility of quantifying aortic wall elastin content using magnetic resonance imaging (MRI) with a gadolinium-based elastin-specific contrast agent (ESMA) in Fbn1(C1039G/+) mice.-Ascending aorta elastin content was measured in 32-week-old Fbn1(C1039G/+) mice and wild-type (WT) (n=9 and n=10, respectively) using 7T MRI with a T1-mapping sequence. Significantly lower enhancement (i.e., lower R1 values, where R1=1/T1) was detected post-ESMA in Fbn1(C1039G/+) compared to WT ascending aortas (1.15±0.07 vs. 1.36±0.05, p<0.05). Post-ESMA R1 values correlated with ascending aortic wall gadolinium content directly measured by inductively coupled mass spectroscopy (p=0.006).-Herein, we demonstrate that MRI with ESMA accurately measures elastin bound gadolinium within the aortic wall and detects a decrease in aortic wall elastin in Marfan mice compared to WT controls. This approach has translational potential for non-invasively assessing aneurysm tissue changes and risk, as well as monitoring elastin content in response to therapeutic interventions.
View details for DOI 10.1161/CIRCIMAGING.114.001658
View details for PubMedID 24814820
The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [(18)F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([(18)F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model.Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography.[(18)F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [(18)F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET.[(18)F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/neuroinflammation in other disease models.
View details for DOI 10.1007/s11307-013-0664-5
View details for Web of Science ID 000329793200014
View details for PubMedID 23836504
Aim: To develop a clinically applicable MRI technique for tracking stem cells in matrix-associated stem-cell implants, using the US FDA-approved iron supplement ferumoxytol. Materials & methods: Ferumoxytol-labeling of adipose-derived stem cells (ADSCs) was optimized in vitro. A total of 11 rats with osteochondral defects of both femurs were implanted with ferumoxytol- or ferumoxides-labeled or unlabeled ADSCs, and underwent MRI up to 4 weeks post matrix-associated stem-cell implant. The signal-to-noise ratio of different matrix-associated stem-cell implant was compared with t-tests and correlated with histopathology. Results: An incubation concentration of 500 µg iron/ml ferumoxytol and 10 µg/ml protamine sulfate led to significant cellular iron uptake, T2 signal effects and unimpaired ADSC viability. In vivo, ferumoxytol- and ferumoxides-labeled ADSCs demonstrated significantly lower signal-to-noise ratio values compared with unlabeled controls (p < 0.01). Histopathology confirmed engraftment of labeled ADSCs, with slow dilution of the iron label over time. Conclusion: Ferumoxytol can be used for in vivo tracking of stem cells with MRI. Original submitted 28 February 2012; Revised submitted 8 November 2012.
View details for DOI 10.2217/nnm.12.198
View details for PubMedID 23534832
Tumor-associated macrophages (TAM) maintain a chronic inflammation in cancers, which is associated with tumor aggressiveness and poor prognosis. The purpose of this study was to: (1) evaluate the pharmacokinetics and tolerability of the novel ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) compound GEH121333; (2) assess whether GEH121333 can serve as a MR imaging biomarker for TAM; and (3) compare tumor MR enhancement profiles between GEH121333 and ferumoxytol. Blood half-lives of GEH121333 and ferumoxytol were measured by relaxometry (n?=?4 each). Tolerance was assessed in healthy rats injected with high dose GEH121333, vehicle or saline (n?=?4 each). Animals were monitored for 7?days regarding body weight, complete blood counts and serum chemistry, followed by histological evaluation of visceral organs. MR imaging was performed on mice harboring MMTV-PyMT-derived breast adenocarcinomas using a 7?T scanner before and up to 72?h post-injection (p.i.) of GEH121333 (n?=?10) or ferumoxytol (n?=?9). Tumor R1 , R2 * relaxation rates were compared between different experimental groups and time points, using a linear mixed effects model with a random effect for each animal. MR data were correlated with histopathology. GEH121333 showed a longer circulation half-life than ferumoxytol. Intravenous GEH121333 did not produce significant adverse effects in rats. All tumors demonstrated significant enhancement on T1 , T2 and T2 *-weighted images at 1, 24, 48 and 72?h p.i. GEH121333 generated stronger tumor T2 * enhancement than ferumoxytol. Histological analysis verified intracellular compartmentalization of GEH121333 by TAM at 24, 48 and 72?h p.i. MR imaging with GEH121333 nanoparticles represents a novel biomarker for TAM assessment. This new USPIO MR contrast agent provides a longer blood half-life and better TAM enhancement compared with the iron supplement ferumoxytol. Copyright © 2013 John Wiley & Sons, Ltd.
View details for DOI 10.1002/cmmi.1526
View details for PubMedID 23606432
To develop a clinically applicable imaging technique for monitoring differential migration of macrophages into viable and apoptotic matrix-associated stem cell implants (MASIs) in arthritic knee joints.With institutional animal care and use committee approval, six athymic rats were injected with intravenous ferumoxytol (0.5 mmol iron per kilogram of body weight) to preload macrophages of the reticuloendothelial system with iron oxide nanoparticles. Forty-eight hours later, all animals received MASIs of viable adipose-derived stem cells (ADSCs) in an osteochondral defect of the right femur and mitomycin-pretreated apoptotic ADSCs in an osteochondral defect of the left femur. One additional control animal each received intravenous ferumoxytol and bilateral scaffold-only implants (without cells) or bilateral MASIs without prior ferumoxytol injection. All knees were imaged with a 7.0-T magnetic resonance (MR) imaging unit with T2-weighted fast spin-echo sequences immediately after, as well as 2 and 4 weeks after, matrix-associated stem cell implantation. Signal-to-noise ratios (SNRs) of viable and apoptotic MASIs were compared by using a linear mixed-effects model. MR imaging data were correlated with histopathologic findings.All ADSC implants showed a slowly decreasing T2 signal over 4 weeks after matrix-associated stem cell implantation. SNRs decreased significantly over time for the apoptotic implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 16.9, 10.9, and 6.7, respectively; P = .0004) but not for the viable implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 17.7, 16.2, and 15.7, respectively; P = .2218). At 4 weeks after matrix-associated stem cell implantation, SNRs of apoptotic ADSCs were significantly lower than those of viable ADSCs (mean, 6.7 vs 15.7; P = .0013). This corresponded to differential migration of iron-loaded macrophages into MASIs.Iron oxide loading of macrophages in the reticuloendothelial system by means of intravenous ferumoxytol injection can be utilized to monitor differential migration of bone marrow macrophages into viable and apoptotic MASIs in a rat model.
View details for DOI 10.1148/radiol.12112393
View details for Web of Science ID 000308645500022
View details for PubMedID 22820731
View details for PubMedCentralID PMC3426856
Listeriosis is one of the most lethal bacterial diseases for fetuses and infants. However, pregnant women who get infected with Listeria may experience only mild symptoms, making the diagnosis difficult, even when the fetus is fatally infected.To reveal features of this infection, we conducted a multimodality imaging study of Listeria-induced miscarriage, using a pregnant mouse model. In this model, fetal morbidity and mortality can be observed in utero, noninvasively, and the timing and extent of infection can be carefully controlled. By employing in vivo bioluminescence imaging (BLI), perinatal infections were localized over time such that a correlation of infection to outcome could be determined without the need to kill the animal subject. The morbidity and viability of fetuses were assessed with ultrasound, and fetal morphology was imaged using magnetic resonance imaging (MRI).The ultrasound revealed sustained fetal bradycardia, the slowing of the fetal heartbeat, in infected fetuses, with an association between slowed fetal heart rate and strong bioluminescent signal.Uninfected fetuses showing no bioluminescent signal in the same uterine horn exhibited normal heartbeats. Thus, fetal bradycardia during infection was localized to the infected fetus and was not systemic or disseminated.
View details for DOI 10.1038/pr.2012.2
View details for Web of Science ID 000303373300003
View details for PubMedID 22314663
Macrophage infiltration is a prominent feature of abdominal aortic aneurysm (AAA) progression. We used a combined imaging approach with bioluminescence (BLI) and magnetic resonance imaging (MRI) to study macrophage homing and accumulation in experimental AAA disease. Murine AAAs were created via intra-aortic infusion of porcine pancreatic elastase. Mice were imaged over 14 days after injection of prepared peritoneal macrophages. For BLI, macrophages were from transgenic mice expressing luciferase. For MRI, macrophages were labeled with iron oxide particles. Macrophage accumulation during aneurysm progression was observed by in situ BLI and by in vivo 7T MRI. Mice were sacrificed after imaging for histologic analysis. In situ BLI (n ?=? 32) demonstrated high signal in the AAA by days 7 and 14, which correlated significantly with macrophage number and aortic diameter. In vivo 7T MRI (n ?=? 13) at day 14 demonstrated T?* signal loss in the AAA and not in sham mice. Immunohistochemistry and Prussian blue staining confirmed the presence of injected macrophages in the AAA. BLI and MRI provide complementary approaches to track macrophage homing and accumulation in experimental AAAs. Similar dual imaging strategies may aid the study of AAA biology and the evaluation of novel therapies.
View details for DOI 10.2310/7290.2011.00033
View details for Web of Science ID 000307645900004
View details for PubMedID 22469240
Multiecho echo-planar imaging (EPI) was implemented for blood-oxygenation-level-dependent functional MRI at 1.5 T and compared to single-echo EPI with and without parallel imaging acceleration. A time-normalized breath-hold task using a block design functional MRI protocol was carried out in combination with up to four echo trains per excitation and parallel imaging acceleration factors R = 1-3. Experiments were conducted in five human subjects, each scanned in three sessions. Across all reduction factors, both signal-to-fluctuation-noise ratio and the total number of activated voxels were significantly lower using a single-echo EPI pulse sequence compared with the multiecho approach. Signal-to-fluctuation-noise ratio and total number of activated voxels were also considerably reduced for nonaccelerated conventional single-echo EPI when compared to three-echo measurements with R = 2. Parallel imaging accelerated multiecho EPI reduced geometric distortions and signal dropout, while it increased blood-oxygenation-level-dependent signal sensitivity all over the brain, particularly in regions with short underlying T*(2). Thus, the presented method showed multiple advantages over conventional single-echo EPI for standard blood-oxygenation-level-dependent functional MRI experiments.
View details for DOI 10.1002/mrm.22222
View details for Web of Science ID 000276064300013
View details for PubMedID 20373397
View details for Web of Science ID 000238329700015