David Thomasson

Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound

Purpose: Objectives of this study were to: 1) develop iLTSL, a low temperature sensitive liposome co-loaded with an MRI contrast agent (ProHance® Gd-HP-DO3A) and doxorubicin, 2) characterise doxorubicin and Gd-HP-DO3A release from iLTSL and 3) investigate the ability of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) to induce and monitor iLTSL content release in phantoms and in vivo. Methods: iLTSL was passively loaded with Gd-HP-DO3A and actively loaded with doxorubicin. Doxorubicin and Gd-HP-DO3A release was quantified by fluorescence and spectroscopic techniques, respectively. Release with MR-HIFU was examined in tissue-mimicking phantoms containing iLTSL and in a VX2 rabbit tumour model. Results: iLTSL demonstrated consistent size and doxorubicin release kinetics after storage at 4°C for 7 days. Release of doxorubicin and Gd-HP-DO3A from iLTSL was minimal at 37°C but fast when heated to 41.3°C. The magnitude of release was not significantly different between doxorubicin and Gd-HP-DO3A over 10 min in HEPES buffer and plasma at 37°, 40° and 41.3°C (p > 0.05). Relaxivity of iLTSL increased significantly (p < 0.0001) from 1.95 ± 0.05 to 4.01 ± 0.1 mMs−1 when heated above the transition temperature. Signal increase corresponded spatially and temporally to MR-HIFU-heated locations in phantoms. Signal increase was also observed in vivo after iLTSL injection and after each 10-min heating (41°C), with greatest increase in the heated tumour region. Conclusion: An MR imageable liposome formulation co-loaded with doxorubicin and an MR contrast agent was developed. Stability, imageability, and MR-HIFU monitoring and control of content release suggest that MR-HIFU combined with iLTSL may enable real-time monitoring and spatial control of content release.

Reliability of Fiber Tracking Measurements in Diffusion Tensor Imaging for Longitudinal Study

UNLABELLED The statistical reliability of diffusion property measurements was evaluated in ten healthy subjects using deterministic fiber tracking to localize tracts affected in motor neuron disease: corticospinal tract (CST), uncinate fasciculus (UNC), and the corpus callosum in its entirety (CC), and its genu (GE), motor (CCM), and splenium (SP) fibers separately. Measurements of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda(1)), transverse diffusivity (lambda( perpendicular)), and volume of voxels containing fibers (VV) were obtained within each tract. To assess intra-rater and inter-rater reliability, two raters carried out fiber tracking five times on each scan. Scan-rescan and longitudinal reliability were assessed in a subset of four subjects who had six scans, with two sets of three scans separated by 1 year. The statistical reliability of repeated measurements was evaluated using intraclass correlation coefficients (ICC) and coefficients of variation (CV). Spatial agreement of tract shape was assessed using the kappa (kappa) statistic. RESULTS Repeated same-scan fiber tracking evaluations showed good geometric alignment (intra-rater kappa >0.90, inter-rater kappa >0.76) and reliable diffusion property measurements (intra-rater ICC >0.92, inter-rater ICC >0.77). FA, MD, and lambda( perpendicular) were highly reliable with repeated scans on different days, up to a year apart (ICC >0.8). VV also exhibited good reliability, but with higher CVs. We were unable to demonstrate reproducibility of lambda(1). Longitudinal reliability after one year was improved by averaging measurements from multiple scans at each time point. Fiber tracking provides a reliable tool for the longitudinal evaluation of white matter diffusion properties.

Measurement of glutathione in normal volunteers and stroke patients at 3T using J-difference spectroscopy with minimized subtraction errors

To develop and optimize a 1H magnetic resonance spectroscopy (MRS) method for measuring brain glutathione (GSH) levels.

Isotropic 3D Fast Spin-Echo with Proton-Density-Like Contrast: A Comprehensive Approach to Musculoskeletal MRI

OBJECTIVE Scanning time considerations have restricted routine use of 3D Fourier transform (3DFT)-encoded MRI to gradient-recalled echo sequences. We sought to combine isotropic 3DFT acquisition with fast spin-echo at a practical scan duration. This strategy offers versatile image contrast for musculoskeletal evaluation and facilitates image reformation tailored to the depiction of small anatomic features. CONCLUSION Isotropic 3DFT fast spin-echo is feasible on current MRI scanners and has the potential to improve musculoskeletal evaluation.

Hydrogen-1 MR Spectroscopy for Measurement and Diagnosis of Hepatic Steatosis

OBJECTIVE Hydrogen-1 MR spectroscopy ((1)H-MRS) is gaining acceptance as a noninvasive technique for assessment of hepatic steatosis, and the findings have been found to correlate closely with histopathologic grade. The aims of this study were to validate (1)H-MRS performed with a 3-T MRI system for quantifying hepatic steatosis and to determine threshold values of (1)H-MRS proton density fat fraction corresponding to standard histopathologic grade in patients undergoing diagnostic liver biopsy. SUBJECTS AND METHODS We conducted a prospective cross-sectional liver MRS study with 52 subjects undergoing diagnostic liver biopsy. The diagnostic accuracy of (1)H-MRS was evaluated with receiver operating characteristic curves. RESULTS The diagnostic accuracy of (1)H-MRS for hepatic steatosis was high with an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.88-1.0). Results were similar for three (1)H-MRS measurements obtained at different locations in the liver, for two independent pathologists, and whether fibrosis was present or absent. One third of participants had elevated transaminase concentrations of unknown cause, and (1)H-MRS estimates of steatosis had perfect agreement with histopathologic grade in this group. Calculated (1)H-MRS proton density fat fraction thresholds for histologic grades were less than 17% for grade 0 or trace steatosis, 17-38.6% for grade 1, and greater than 38.6% for grade 2 or higher. CONCLUSION Hydrogen-1 MR spectroscopy is an effective, noninvasive technique that can be used to diagnose and quantify hepatic steatosis. Hydrogen-1 MR spectroscopy thresholds corresponded with histopathologic grades and may be useful in the workup of patients with elevated transaminase concentrations.

Increased uptake of [123I]meta-iodobenzylguanidine, [18F]fluorodopamine, and [3H]norepinephrine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors

[¹³¹I]meta-iodobenzylguanidine ([¹³¹I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [¹²³I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [(18)F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1 ± 3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9 ± 0.6%; P<0.001). Biodistribution analysis after inhibitors treatment confirmed the PET results. The uptake of [(123)I]MIBG was significantly increased in liver metastases 9.5 ± 1.1% compared to 3.19 ± 0.4% in untreated control liver metastases (P<0.05). We found that HDAC inhibitors caused an increase in the amount of norepinephrine transporter expressed in tumors. HDAC inhibitors may enhance the therapeutic efficacy of [(131)I]MIBG treatment in patients with advanced malignant pheochromocytoma and paraganglioma.

A comparison of pharmacokinetic models of dynamic contrast enhanced MRI

Dynamic contrast enhanced MRI (DCE-MRI) is often employed as an indicator of drug activity in clinical trials of angiogenic inhibitors. The data obtained with DCE-MRI is reported semi quantitatively using parameters derived from pharmacokinetic models. Most MRI kinetic models were developed from nuclear medicine quantitative studies but the limitations of MRI dictated specific modifications. A number of these MRI models are in current use. In this work, we review several pharmacokinetic models used in DCE-MRI in order to determine the most appropriate model to assess tumor angiogenesis. These models are compared with respect to their physiological appropriateness; compartmental analysis; initial and boundary conditions; and clinically relevant output parameters.

Automatic Determination of Arterial Input Function for Dynamic Contrast Enhanced MRI in Tumor Assessment

Dynamic Contrast Enhanced MRI (DCE-MRI) is today one of the most popular methods for tumor assessment. Several pharmacokinetic models have been proposed to analyze DCE-MRI. Most of them depend on an accurate arterial input function (AIF). We propose an automatic and versatile method to determine the AIF. The method has two stages, detection and segmentation, incorporating knowledge about artery structure, fluid kinetics, and the dynamic temporal property of DCE-MRI. We have applied our method in DCE-MRIs of four different body parts: breast, brain, liver and prostate. The results show that we achieve average 89.5% success rate for 40 cases. The pharmacokinetic parameters computed from the automatic AIF are highly agreeable with those from a manually derived AIF (R2 = 0.89, P (T <=t) = 0.19) and a semiautomatic AIF (R2 = 0.98, P(T <=t) = 0.01).

Combination of multichannel single-voxel MRS signals using generalized least squares

To propose using the generalized least square (GLS) algorithm for combining multichannel single‐voxel magnetic resonance spectroscopy (MRS) signals.

Dynamic contrast-enhanced magnetic resonance imaging in the assessment of early response to tumor necrosis factor alpha in a colon carcinoma model.

Objective:We describe the effects of tumor necrosis factor alpha (TNFα) on tumor microvasculature in a murine colon carcinoma model using serial dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Material and Methods:Mice with subcutaneous murine colon carcinomas (MC-38) were imaged at 4.7 T after administration of 0.2 mmol/kg gadolinium-DTPA. Both treated and control mice (each group, n = 4), were scanned at baseline and 2, 4, 6, and 96 hours. A 2-compartment pharmacokinetic model generated parameters such as Ktrans, kep, and initial area under the gadolinium concentration curve (IAUC). Results:The treatment group revealed significant differences in Ktrans at all time points after TNFα. kep and IAUC were significantly reduced at 2, 6, and 96 hours. The coefficient of variation in control animals ranged from 0.13 for IAUC to 0.30 for Ktrans. Mild histologic changes were observed at 2 to 6 hours, but considerable central necrosis with a vascular tumor rim was seen at 96 hours. Conclusion:DCE MRI can be used to detect early effects of TNFα. Serial DCE MRI is a promising tool in assessing the early effects of antivascular therapies.