In Vitro and In Vivo Assessment of Nonionic Iodinated Radiographic Molecules as Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Tumor Perfusion Agents.

OBJECTIVES: The aim of this study was to evaluate 4 nonionic x-ray iodinated contrast agents (CAs), commonly used in radiographic procedures, as novel chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) agents by assessing their in vitro exchange properties and preliminary in vivo use as tumor enhancing agents. MATERIALS AND METHODS: The CEST properties, as function of pH (range, 5.5-7.9) and of radio frequency conditions (irradiation field strength range of 1-9 µT and time of 1-9 seconds), have been determined at 7 T and 310 K for 4 x-ray CAs commonly used in clinical settings, namely, iomeprol, iohexol, ioversol, and iodixanol. Their in vivo properties have been investigated upon intravenous injection in a murine HER2+ breast tumor model (n = 4 mice for each CA) using both computed tomography (CT) and MRI modalities. RESULTS: The prototropic exchange rates measured for the 4 investigated iodinated molecules showed strong pH dependence with base catalyzed exchange rate that was faster for monomeric compounds (20-4000 Hz in the pH range of 5.5-7.9). Computed tomography quantification showed marked (up to 2 mg I/mL concentration) and prolonged accumulation (up to 30 minutes postinjection) inside tumor regions. Among the 4 agents we tested, iohexol and ioversol display good CEST contrast properties at 7 T, and in vivo results confirmed strong and prolonged contrast enhancement of the tumors, with elevated extravasation fractions (74%-91%). A strong and significant correlation was found between CT and CEST-MRI tumor-enhanced images (R = 0.70, P < 0.01). CONCLUSIONS: The obtained results demonstrate that iohexol and ioversol, 2 commonly used radiographic compounds, can be used as MRI perfusion agents, particularly useful when serial images acquisitions are needed to complement CT information.

Magnetic resonance imaging assessment of effective ablated volume following high intensity focused ultrasound.

Under magnetic resonance (MR) guidance, high intensity focused ultrasound (HIFU) is capable of precise and accurate delivery of thermal dose to tissues. Given the excellent soft tissue imaging capabilities of MRI, but the lack of data on the correlation of MRI findings to histology following HIFU, we sought to examine tumor response to HIFU ablation to determine whether there was a correlation between histological findings and common MR imaging protocols in the assessment of the extent of thermal damage. Female FVB mice (n = 34), bearing bilateral neu deletion tumors, were unilaterally insonated under MR guidance, with the contralateral tumor as a control. Between one and five spots (focal size 0.5 × 0.5 × 2.5 mm3) were insonated per tumor with each spot receiving approximately 74.2 J of acoustic energy over a period of 7 seconds. Animals were then imaged on a 7T MR scanner with several protocols. T1 weighted images (with and without gadolinium contrast) were collected in addition to a series of T2 weighted and diffusion weighted images (for later reconstruction into T2 and apparent diffusion coefficient maps), immediately following ablation and at 6, 24, and 48 hours post treatment. Animals were sacrificed at each time point and both insonated/treated and contralateral tumors removed and stained for NADH-diaphorase, caspase 3, or with hematoxylin and eosin (H&E). We found the area of non-enhancement on contrast enhanced T1 weighted imaging immediately post ablation correlated with the region of tissue receiving a thermal dose CEM43 ≥ 240 min. Moreover, while both tumor T2 and apparent diffusion coefficient values changed from pre-ablation values, contrast enhanced T1 weighted images appeared to be more senstive to changes in tissue viability following HIFU ablation.

Using optical spectroscopy to longitudinally monitor physiological changes within solid tumors.

The feasibility of using quantitative diffuse reflectance spectroscopy to longitudinally monitor physiological response to cancer therapy was evaluated in a preclinical model. This study included two groups of nude mice bearing 4T1 flank tumors (N = 50), half of which were treated with a maximum tolerated dose of doxorubicin (DOX). Diffuse reflectance spectra were collected from tumors during a period of 2 weeks using a fiber-optic probe coupled to a spectrometer. These spectra were quantified using an inverse scalable Monte Carlo model of light transport in tissue to extract the concentrations of oxygenated, deoxygenated hemoglobin (dHb), and a wavelength mean reduced scattering coefficient (). The tumor growth rates of the treated and control groups were nearly identical, as were changes in the scattering parameter during this time frame. However, tumors treated with DOX showed a transient but significant increase in blood oxygen saturation. A comparison between the optically derived and immunohistochemical end points in a subset of the 50 animals showed that the temporal kinetics of dHb concentration and were highly concordant with those of hypoxic and necrotic fractions, respectively. In conclusion, optical methods could function as a "screening" technology in longitudinal studies of small animal tumor models to accelerate development and testing of new anticancer drugs. This technique could isolate specific landmark time points at which more expensive and sophisticated imaging methods or immunohistochemistry could be performed.

Kinetic assessment of breast tumors using high spatial resolution signal enhancement ratio (SER) imaging.

The goal of this study was to investigate the relationship between an empirical contrast kinetic parameter, the signal enhancement ratio (SER), for three-timepoint, high spatial resolution contrast-enhanced (CE) MRI, and a commonly analyzed pharmacokinetic parameter, kep, using dynamic high temporal resolution CE-MRI. Computer simulation was performed to investigate: 1) the relationship between the SER and the contrast agent concentration ratio (CACR) of two postcontrast timepoints (tp1 and tp2); 2) the relationship between the CACR and the redistribution rate constant (kep) based on a two-compartment pharmacokinetic model; and 3) the sensitivity of the relationship between the SER and kep to native tissue T1 relaxation time, T10, and to errors in an assumed vascular input function. The relationship between SER and kep was verified experimentally using a mouse model of breast cancer. The results showed that a monotonic mathematical relationship between SER and kep could be established if the acquisition parameters and the two postinjection timepoints of SER, tp1, tp2, were appropriately chosen. The in vivo study demonstrated a close correlation between SER and kep on a pixel-by-pixel basis (Spearman rank correlation coefficient=0.87+/-0.03). The SER is easy to calculate and may have a unique role in breast tissue characterization.

Technical aspects: development, manufacture and installation of a cryo-cooled HTS coil system for high-resolution in-vivo imaging of the mouse at 1.5 T.

Signal-to-noise ratio improvement is of major importance to achieve microscopic spatial resolution in magnetic resonance experiments. Magnetic resonance imaging of small animals is particularly concerned since it typically requires voxels of less than (100 microm)(3) to observe the small anatomical structures having size reduction by a factor of more than 10 as compared to human being. The signal-to-noise ratio can be increased by working at high static magnetic field strengths, but the biomedical interest of such high-field systems may be limited due to field-dependent contrast mechanisms and severe technological difficulties. An alternative approach that allows working in clinical imaging system is to improve the sensitivity of the radio-frequency receiver coil. This can be done using small cryogenically operated coils made either of copper or high-temperature superconducting material. We report the technological development of cryo-cooled superconducting coils for high-resolution imaging in a whole-body magnetic resonance scanner operating at 1.5 T. The technological background supporting this development is first addressed, including HTS coil design, simulation tools, cryogenic mean description and electrical characterization procedure. To illustrate the performances of superconducting coils for magnetic resonance imaging at intermediate field strength, in-vivo mouse images of various anatomic sites acquired with a 12 mm diameter cryo-cooled superconducting coil are presented.

[Direct-current treatment of chemically induced mammary carcinoma in an animal model: MR volumetric assessment of the effect of the therapy]. / Gleichstrombehandlung des chemisch induzierten Mammakarzinoms im Tiermodell: MR-volumetrische Erfassung des Therapieeinflusses.

PURPOSE: To investigate the effect of direct current treatment (DCT) on the growth of mammary carcinomas in rats by MR-volumetry. METHODS: Chemically induced mammary adenocarcinomas in a control group (n = 17) were compared with treated tumours (18 C/cm3 in group A: n = 7 or 36 C/cm3 in group B: n = 12). 31 untreated tumours were situated near a treated tumour (group C). Experiments were carried out using one positive electrode in the tumour centre and three negative electrodes in the periphery. The tumour volume was measured by MRI before, and 1, 3, 6, 9 and 12 weeks after treatment. RESULTS: 12 weeks after DCT, the mean tumour volume in group A (164% +/- 158%, p < 0.05) and group B (13% +/- 24%, p < 0.001) was significantly reduced compared to the control group (434% +/- 230, Mann-Whitney U-Test). Complete tumour regression occurred in 42% of tumours in group B and was not achieved in group A, C and control group. Tumour growth in group C was decreased compared to the control group. CONCLUSIONS: The effectiveness of DCT was found to depend on the applied dosage -36 C/cm3 was more effective than 18 C/cm3. The effect of DCT is not limited to the area between the electrodes.