Biomedical subjects

Thomas L Chenevert

Publications and source records attributed to Thomas L Chenevert.

32 records · Page 2Linked to original sources

PubMed2004

Clinical applications of diffusion tensor imaging.

Directionally-ordered cellular structures that impede water motion, such as cell membranes and myelin, result in water mobility that is also directionally-dependent. Diffusion tensor imaging characterizes this directional nature of water motion and thereby provides structural information that cannot be obtained by standard anatomic imaging. Quantitative apparent diffusion coefficients and fractional anisotropy have emerged from being primarily research tools to methods enabling valuable clinical applications. This review describes the clinical utility of diffusion tensor imaging, including the basic principles of the technique, acquisition, data analysis, and the major clinical applications.

Anisotropy↗

PubMed2004

Spatio-temporal bandwidth-based acquisition for dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: To develop a k-space formalism that provides a rationale for the design of variable-rate acquisition schemes for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS AND MATERIALS: The formalism, termed spatio-temporal bandwidth-based (STBB) analysis, is demonstrated using a priori modeling of object and enhancement characteristics typically observed in DCE-MRI of breast tumors. A temporally enhancing lesion is considered as a two-dimensional (2D) space-time object that possesses a corresponding spatio-temporal (k(y)-k(t)) energy spectrum. The k(y)-k(t) space is segmented based on a threshold such that the total spectral energy in a finite number of k-space samples, constrained by the imaging experiment, is maximized. This thresholded map contains a set of spatial and corresponding temporal sampling prescriptions. These prescriptions are used in designing an acquisition scheme that is adequate for a range of contrast-enhancing breast lesions. The STBB scheme is compared to an equivalent "keyhole" acquisition, in terms of quantification of enhancement rate, K(trans), extracellular volume fraction, nu(e), and spatial fidelity. We chose object sizes Npix = 2, 5, 10, 15, 20, and 30 pixels and enhancement rates K(trans) = 1.5, 1, 0.6, 0.4, 0.3, and 0.2 minute(-1), and nu(e) was held at 0.3. RESULTS: The STBB scheme results in more accurate estimation of the rate and extracellular volume fraction parameters when the object size is small (two and five pixels) and the enhancement rates are rapid (1.5 and 1 minute(-1)), compared to the keyhole acquisition. The STBB scheme provides higher spatial fidelity for very small objects. For large object and slow enhancements, the keyhole and STBB scheme perform comparably. CONCLUSION: We have demonstrated an intuitive formalism applicable to DCE-MRI for a set of targeted/anticipated dynamic events as well as spatial features. This formalism can be extended to any dynamic imaging condition, and a corresponding variable-rate acquisition scheme can be designed.

Computer Simulation↗

PubMed2004

The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies.

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.

Animals↗

PubMed2004

Improving cerebral cortical magnetic resonance imaging using a readily available surface coil.

Subtle structural deformities of the cerebral cortex have been shown to be the cause of seizures in patients with refractory epilepsy. Brain imaging using high-resolution focused protocols with standard head coils may not provide sufficient image quality needed for evaluating subtle cortical abnormalities. The authors describe the use of a readily available shoulder coil placed over a specific area of the brain that has been clinically determined to enhance the signal to noise and resolution of the cortical surface. Delineating the cortical surface using a shoulder coil can help to detect subtle areas of cortical thickening, blurring of the gray-white matter junction, or focally abnormal gyral and sulcal patterns.

Cerebral Cortex↗

PubMed2003

Evaluation of (E)-2'-deoxy-2'-(fluoromethylene)cytidine on the 9L rat brain tumor model using MRI.

(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), was evaluated as a potential treatment for malignant gliomas using the rat 9L brain tumor model. FMdC was shown to be an effective inhibitor of cell proliferation in cultured 9L cells with an EC(50) of 40 ng/ml. In vitro studies also revealed that this compound significantly inhibited incorporation of [(3)H]thymidine in 9L cells. In vivo therapeutic efficacy of FMdC was evaluated in rats harboring intracerebral 9L tumors which were treated daily with 15 mg/kg, i.p. Treatment response was quantified from changes in tumor growth rates as assessed from sequential magnetic resonance imaging (MRI) tumor volume measurements. In vivo tumor cell kill in individual animals was calculated by fitting tumor volume data with an iterative computer routine. It was estimated that therapeutically responsive rats treated with FMdC daily produced a >/= 0.1 log kill per therapeutic dose which resulted in a significant reduction in tumor growth rate. In addition, localized (1)H-MRS of intracerebral 9L tumors revealed changes in metabolite levels which correlated with therapeutic response. These results provide evidence supporting the use of FMdC in clinical trials for the treatment of malignant gliomas and reveals that MR can play an important role in the pre-clinical evaluation of novel compounds using orthotopic tumor models.

Animals↗

PubMed2003

Hepatic arterial phase MR imaging with automated bolus-detection three-dimensional fast gradient-recalled-echo sequence: comparison with test-bolus method.

Sixty-two patients underwent magnetic resonance (MR) imaging of the liver with the automated contrast material bolus-detection technique. Arterial phase MR images were assessed quantitatively and qualitatively. In 23 patients, a test bolus of contrast material was injected intravenously before dynamic MR imaging. There was good correlation and agreement between delay times estimated with both timing methods. Eighty-three percent of arterial phase images obtained with automated contrast material bolus detection were optimal. There was good correlation and agreement between delay times estimated with both timing methods. Optimal hepatic arterial phase MR images can be obtained routinely with automated detection of a contrast material bolus.

Adult↗

PubMed2003

A novel polyacrylamide magnetic nanoparticle contrast agent for molecular imaging using MRI.

A novel polyacrylamide superparamagnetic iron oxide nanoparticle platform is described which has been synthetically prepared such that multiple crystals of iron oxide are encapsulated within a single polyacrylamide matrix (PolyAcrylamide Magnetic [PAM] nanoparticles). This formulation provides for an extremely large T2 and T2* relaxivity of between 620 and 1140 sec(-1) mM(-1). Administration of PAM nanoparticles into rats bearing orthotopic 9L gliomas allowed quantitative pharmacokinetic analysis of the uptake of nanoparticles in the vasculature, brain, and glioma. Addition of polyethylene glycol of varying sizes (0.6, 2, and 10 kDa) to the surface of the PAM nanoparticles resulted in an increase in plasma half-life and affected tumor uptake and retention of the nanoparticles as quantified by changes in tissue contrast using MRI. The flexible formulation of these nanoparticles suggests that future modifications could be accomplished allowing for their use as a targeted molecular imaging contrast agent and/or therapeutic platform for multiple indications.

Acrylic Resins↗

PubMed2003

Evaluation of cancer therapy using diffusion magnetic resonance imaging.

Assessment of the effectiveness of cancer therapy traditionally relies on comparison of tumor images acquired before and after therapeutic intervention by inspection of gross anatomical images to evaluate changes in tumor size. The potential for imaging to provide additional insights related to the therapeutic impact would be enhanced if a specific parameter or combination of parameters could be identified that reflect tissue changes at the cellular or physiological level. This information could also provide a more sensitive and earlier indicator of treatment response in an individual animal or patient. Diffusion magnetic resonance imaging can detect relatively small changes in tissue structure at the cellular level and thus provides an opportunity to quantitatively and serially follow therapeutic-induced changes in solid tumors. This article provides an overview of the use of diffusion magnetic resonance imaging as a surrogate marker for quantitating treatment responsiveness in both preclinical and clinical studies.

Animals↗

PubMed2002

Noninvasive real-time imaging of apoptosis.

Strict coordination of proliferation and programmed cell death (apoptosis) is essential for normal physiology. An imbalance in these two opposing processes results in various diseases including AIDS, neurodegenerative disorders, myelodysplastic syndromes, ischemiareperfusion injury, cancer, autoimmune disease, among others. Objective and quantitative noninvasive imaging of apoptosis would be a significant advance for rapid and dynamic screening as well as validation of experimental therapeutic agents. Here, we report the development of a recombinant luciferase reporter molecule that when expressed in mammalian cells has attenuated levels of reporter activity. In cells undergoing apoptosis, a caspase-3-specific cleavage of the recombinant product occurs, resulting in the restoration of luciferase activity that can be detected in living animals with bioluminescence imaging. The ability to image apoptosis noninvasively and dynamically over time provides an opportunity for high-throughput screening of proapoptotic and antiapoptotic compounds and for target validation in vivo in both cell lines and transgenic animals.

Animals↗

PubMed2002

Diffusion-weighted magnetic resonance imaging.

Diffusion-weighted magnetic resonance imaging is a specialized technique that measures the degree of diffusion of water molecules within extracellular space and between intracellular and extracellular space. Diffusion-weighted imaging signal is high (bright) when diffusion is restricted, as occurs in cytotoxic damage from ischemia, inflammation, trauma, or tumor. This technique, now available on most magnetic resonance imaging units, is especially helpful in detecting early ischemic stroke and multiple sclerosis and in differentiating arachnoid cyst from epidermoid tumor and brain abscess from neoplasm.

Brain↗

PubMed2002

Diffusion MRI: a new strategy for assessment of cancer therapeutic efficacy.

The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular or physiologic level. This would provide an early indicator or treatment response/outcome in an individual patient before completion of therapy. Moreover, response of a tumor to therapeutic intervention may be heterogeneous. The use of imaging could assist in delineating therapeutic-induced spatial heterogeneity within a tumor mass by providing information related to specific regions that are resistant or responsive to treatment. Largely untapped potential resides in exploratory methods such as diffusion MRI, which is a nonvolumetric intravoxel measure of tumor response based upon water molecular mobility. Alterations in water mobility reflect changes in tissue structure at the cellular level. While the clinical utility of diffusion MRI for oncologic practice is still under active investigation, this overview on the use of diffusion MRI for the evaluation of brain tumors will serve to introduce how this approach may be applied in the future for the management of patients with solid tumors.

Brain Neoplasms↗

PubMed2002

Morphologic and functional magnetic resonance imaging of renal artery stenosis: a multireader tricenter study.

The effect of combined morphologic and functional magnetic resonance (MR) imaging on the interobserver and intermodality variability for the grading of renal artery stenosis is assessed. In a randomized, blinded tricenter analysis, seven readers evaluated 43 renal arteries on x-ray digital subtraction angiography (DSA), 3D-Gadolinium MR angiography (3D-Gd-MRA), cine phase-contrast flow measurement (PC-flow), and a combined analysis of the last two. Interobserver variability was assessed for the grading of renal artery stenosis as well as regional vessel visibility. Intermodality variability for stenosis grading was analyzed in cases in which the readers agreed on the degree of stenosis in DSA. DSA had a substantial interobserver variability for the grading of stenosis (mean kappa kappa 0.64). 3D-Gd-MRA revealed a slightly improved interobserver variability but incorrectly graded 6 of 34 stenoses on a two-point scale (<50%, > or =50%). The combined approach of 3D-Gd-MRA and PC-flow revealed the best (P = 0.0003) interobserver variability (median kappa = 0.75) and almost perfect intermodality agreement with DSA (97% of cases). These findings were confirmed in a prospective analysis of 97 renal arteries. The vessel visibility of the renal artery ostium was significantly better in 3D-Gd-MRA than in DSA, whereas the visibility of the hilar and intrarenal vessels was significantly worse (P = 0.0001). A combined morphologic and functional MR examination significantly reduces interobserver variability and offers reliable and reproducible grading of renal artery stenosis based on stenosis morphology and hemodynamic changes. It can be considered a safe and noninvasive alternative for diagnostic DSA in cases that do not require assessment of intrarenal vessels.

Aged↗

PubMedDate not supplied

Molecular imaging of gene expression and efficacy following adenoviral-mediated brain tumor gene therapy.

Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD) along with an optical reporter gene (luciferase). Following intratumoral injection of the vector into orthotopic 9 L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC) gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging for assessment of gene expression and therapeutic efficacy.

Adenoviridae↗

PubMedDate not supplied

A methodology for registration of a histological slide and in vivo MRI volume based on optimizing mutual information.

We present a method for registering histology and in vivo imaging that requires minimal microtoming and is automatic following the user's initialization. In this demonstration, we register a single hematoxylin-and-eosin-stained histological slide of a coronal section of a rat brain harboring a 9L gliosarcoma with an in vivo 7T MR image volume of the same brain. Because the spatial resolution of the in vivo MRI is limited, we add the step of obtaining a high spatial resolution, ex vivo MRI in situ for intermediate registration. The approach taken was to maximize mutual information in order to optimize the registration between all pairings of image data whether the sources are MRI, tissue block photograph, or stained sample photograph. The warping interpolant used was thin plate splines with the appropriate basis function for either 2-D or 3-D applications. All registrations were implemented by user initialization of the approximate pose between the two data sets, followed by automatic optimization based on maximizing mutual information. Only the higher quality anatomical images were used in the registration process; however, the spatial transformation was directly applied to a quantitative diffusion image. Quantitative diffusion maps from the registered location appeared highly correlated with the H&E slide. Overall, this approach provides a robust method for coregistration of in vivo images with histological sections and will have broad applications in the field of functional and molecular imaging.

Animals↗