A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function.

Drug-induced liver injury (DILI) is a leading cause of acute liver failure and transplantation. DILI can be the result of impaired hepatobiliary transporters, with altered bile formation, flow, and subsequent cholestasis. We used gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), combined with pharmacokinetic modelling, to measure hepatobiliary transporter function in vivo in rats. The sensitivity and robustness of the method was tested by evaluating the effect of a clinical dose of the antibiotic rifampicin in four different preclinical imaging centers. The mean gadoxetate uptake rate constant for the vehicle groups at all centers was 39.3 +/- 3.4 s-1 (n = 23) and 11.7 +/- 1.3 s-1 (n = 20) for the rifampicin groups. The mean gadoxetate efflux rate constant for the vehicle groups was 1.53 +/- 0.08 s-1 (n = 23) and for the rifampicin treated groups was 0.94 +/- 0.08 s-1 (n = 20). Both the uptake and excretion transporters of gadoxetate were statistically significantly inhibited by the clinical dose of rifampicin at all centers and the size of this treatment group effect was consistent across the centers. Gadoxetate is a clinically approved MRI contrast agent, so this method is readily transferable to the clinic. CONCLUSION: Rate constants of gadoxetate uptake and excretion are sensitive and robust biomarkers to detect early changes in hepatobiliary transporter function in vivo in rats prior to established biomarkers of liver toxicity.

Response-Derived Input Function Estimation for Dynamic Contrast-Enhanced MRI Demonstrated by Anti-DLL4 Treatment in a Murine U87 Xenograft Model.

PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) is an accepted method to evaluate tumor perfusion and permeability and anti-vascular cancer therapies. However, there is no consensus on the vascular input function estimation method, which is critical to kinetic modeling and K trans estimation. This work proposes a response-derived input function (RDIF) estimated from the response of the tumor, modeled as a linear, time-invariant (LTI) system. PROCEDURES: In an LTI system, an unknown input can be estimated from the system response. If applied to DCE MRI, this method would eliminate need of distal image-derived inputs, model inputs, or reference regions. The RDIF method first determines each tumor pixel's best-fit input function, and then combines the individual fits into a single input function for the entire tumor. The method was tested with simulations and a xenograft study with anti-vascular drug treatment. RESULTS: Simulations showed successful estimation of input function expected values and good performance in the presence of noise. In vivo, significant reductions in K trans and AUC occurred 2 days following anti-delta-like ligand 4 treatment. The in vivo study results yielded K trans consistent with published data in xenograft models. CONCLUSION: The RDIF method for DCE analysis offers an alternative, easy-to-implement method for estimating the input function in tumors. The method assumes that during the DCE experiment, the changes observed by MRI result solely from vascular perfusion and permeability kinetics, and that information can be used to model the input function. Importantly, the method is demonstrated in a murine xenograft study to yield K trans results consistent with literature values and suitable for compound studies.

Multimodal microvascular imaging reveals that selective inhibition of class I PI3K is sufficient to induce an antivascular response.

The phosphatidylinositol 3-kinase (PI3K) pathway is a central mediator of vascular endothelial growth factor (VEGF)-driven angiogenesis. The discovery of small molecule inhibitors that selectively target PI3K or PI3K and mammalian target of rapamycin (mTOR) provides an opportunity to pharmacologically determine the contribution of these key signaling nodes in VEGF-A-driven tumor angiogenesis in vivo. This study used an array of micro-vascular imaging techniques to monitor the antivascular effects of selective class I PI3K, mTOR, or dual PI3K/mTOR inhibitors in colorectal and prostate cancer xenograft models. Micro-computed tomography (micro-CT) angiography, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), vessel size index (VSI) MRI, and DCE ultrasound (DCE-U/S) were employed to quantitatively evaluate the vascular (structural and physiological) response to these inhibitors. GDC-0980, a dual PI3K/mTOR inhibitor, was found to reduce micro-CT angiography vascular density, while VSI MRI demonstrated a significant reduction in vessel density and an increase in mean vessel size, consistent with a loss of small functional vessels and a substantial antivascular response. DCE-MRI showed that GDC-0980 produces a strong functional response by decreasing the vascular permeability/perfusion-related parameter, K (trans). Interestingly, comparable antivascular effects were observed for both GDC-980 and GNE-490 (a selective class I PI3K inhibitor). In addition, mTOR-selective inhibitors did not affect vascular density, suggesting that PI3K inhibition is sufficient to generate structural changes, characteristic of a robust antivascular response. This study supports the use of noninvasive microvascular imaging techniques (DCE-MRI, VSI MRI, DCE-U/S) as pharmacodynamic assays to quantitatively measure the activity of PI3K and dual PI3K/mTOR inhibitors in vivo.

Erratum to: Ungersma SE, Pacheco G, Ho C, Yee SF, Ross J, van Bruggen N, Peale FV Jr, Ross S, Carano RA. Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis. Magn Reson Med 2010;63:1637­1647.

Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density (Q). Here, this technique is validated with direct comparisons to ex vivo micro-computed tomography angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and Q by two antiangiogenic therapeutics [anti-vascular endothelial growth factor (anti-VEGF) and anti-neuropilin-1] on an HM7 colorectal tumor model. Anti-vascular endothelial growth factor reduced blood volume by 36±3% (p<0.0001) and Q by 52±3% (p<0.0001) at 48 h post-treatment; the effects of anti-neuropilin-1 were roughly half as strong with a reduction in blood volume of 18±6% (p<0.05) and a reduction in Q of 33±5% (p<0.05) at 48 h post-treatment.

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis.

Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density. Here, this technique is validated with direct comparisons to ex vivo micro-CT angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and vessel density by two antiangiogenic therapeutics (anti-VEGF and anti-neuropilin-1) on an HM7 colorectal tumor model. Anti-VEGF reduced blood volume by 36 +/- 3% (P < 0.0001) and vessel density by 52 +/- 3% (P < 0.0001) at 48 h posttreatment; the effects of anti-neuropilin-1 were roughly half as strong with a reduction in blood volume of 18 +/- 6% (P < 0.05) and a reduction in vessel density of 33 +/- 5% (P < 0.05) at 48 h posttreatment.

Three-dimensional prepolarized magnetic resonance imaging using rapid acquisition with relaxation enhancement.

Prepolarized MRI (PMRI) with pulsed electromagnets has the potential to produce diagnostic quality 0.5- to 1.0-T images with significantly reduced cost, susceptibility artifacts, specific absorption rate, and gradient noise. In PMRI, the main magnetic field cycles between a high field (B(p)) to polarize the sample and a homogeneous, low field (B(0)) for data acquisition. This architecture combines the higher SNR of the polarizing field with the imaging benefits of the lower field. However, PMRI can only achieve high SNR efficiency for volumetric imaging with 3D rapid imaging techniques, such as rapid acquisition with relaxation enhancement (RARE) (FSE, TSE), because slice-interleaved acquisition and longitudinal magnetization storage are both inefficient in PMRI. This paper demonstrates the use of three techniques necessary to achieve efficient, artifact-free RARE in PMRI: quadratic nulling of concomitant gradient fields, electromotive force cancelation during field ramping, and phase compensation of CPMG echo trains. This paper also demonstrates the use of 3D RARE in PMRI to achieve standard T(1) and fat-suppressed T(2) contrast in phantoms and in vivo wrists. These images show strong potential for future clinical application of PMRI to extremity musculoskeletal imaging and peripheral angiography.

Prepolarized magnetic resonance imaging around metal orthopedic implants.

A prepolarized MRI (PMRI) scanner was used to image near metal implants in agar gel phantoms and in in vivo human wrists. Comparison images were made on 1.5- and 0.5-T conventional whole-body systems. The PMRI experiments were performed in a smaller bore system tailored to extremity imaging with a prepolarization magnetic field of 0.4 T and a readout magnetic field of 27-54 mT (1.1-2.2 MHz). Scan parameters were chosen with equal readout gradient strength over a given field of view and matrix size to allow unbiased evaluation of the benefits of lower readout frequency. Results exhibit substantial reduction in metal susceptibility artifacts under PMRI versus conventional scanners. A new artifact quantification technique is also presented, and phantom results confirm that susceptibility artifacts improve as expected with decreasing readout magnetic field using PMRI. This proof-of-concept study demonstrates that prepolarized techniques have the potential to provide diagnostic cross-sectional images for postoperative evaluation of patients with metal implants.

Magnetic resonance imaging with T1 dispersion contrast.

Prepolarized MRI uses pulsed magnetic fields to produce MR images by polarizing the sample at one field strength (approximately 0.5 T) before imaging at a much lower field (approximately 50 mT). Contrast reflecting the T(1) of the sample at an intermediate field strength is achieved by polarizing the sample and then allowing the magnetization to decay at a chosen "evolution" field before imaging. For tissues whose T(1) varies with field strength (T(1) dispersion), the difference between two images collected with different evolution fields yields an image with contrast reflecting the slope of the T(1) dispersion curve between those fields. Tissues with high protein content, such as muscle, exhibit rapid changes in their T(1) dispersion curves at 49 and 65 mT due to cross-relaxation with nitrogen nuclei in protein backbones. Tissues without protein, such as fat, have fairly constant T(1) over this range; subtracting images with two different evolution fields eliminates signal from flat T(1) dispersion species. T(1) dispersion protein-content images of the human wrist and foot are presented, showing clear differentiation between muscle and fat. This technique may prove useful for delineating regions of muscle tissue in the extremities of patients with diseases affecting muscle viability, such as diabetic neuropathy, and for visualizing the protein content of tissues in vivo.

Shim design using a linear programming algorithm.

The advent of open magnetic resonance imaging (MRI) scanners and dedicated MRI scanners tailored to specific body parts has led to an increasing number of noncylindrical MRI scanner geometries, for which noncylindrical gradients and shims are needed. These new scanner geometries are driving the need for fast, flexible shim design methods that can design shim coils for any geometry. A linear programming (LP) algorithm was developed to design minimum-power resistive shim coils on an arbitrary surface. These coils can be designed to produce any order shim field over an arbitrarily shaped target region, which can be placed anywhere within the coil. The resulting designs are relatively sparse and can be readily constructed. This algorithm was used to design and construct a seven-coil cylindrical shim set for a knee imaging magnet with a cylindrical homogeneous region. The algorithm was then used to design shim coils for a biradial head imager with an asymmetrically located spherical target region for brain imaging.