The ability of MRI to differentiate between normal and radioresistant cancer was investigated in prostate tumour xenografts in mice. Specifically, the process of magnetization exchange between water and other molecules was studied. It was found that magnetization transfer from semisolid macromolecules (MT) and chemical exchange saturation transfer (CEST) combined were significantly different between groups (p < 0.01). Further, the T2 relaxation of the semisolid macromolecular pool (T2,B), a parameter specific to MT, was found to be significantly different (p < 0.01). Also significantly different were the rNOE contributions associated with methine groups at −0.9 ppm with a saturation B1 of 0.5 µT (p < 0.01) and with other aliphatic groups at −3.3 ppm with 0.5 and 2 µT (both p < 0.05). Independently, using a live-cell metabolic assay, normal cells were found to have a greater metabolic rate than radioresistant ones. Thus, MRI provides a novel, in vivo method to quantify the metabolic rate of tumours and predict their radiosensitivity.
Saturation transfer MRI can be useful in the characterization of different tumour types. It is sensitive to tumour metabolism, microstructure, and microenvironment. This study aimed to use saturation transfer to differentiate between intratumoural regions, demarcate tumour boundaries, and reduce data acquisition times by identifying the imaging scheme with the most impact on segmentation accuracy. Saturation transfer-weighted images were acquired over a wide range of saturation amplitudes and frequency offsets along with T 1 and t 2 maps for 34 tumour xenografts in mice. Independent component analysis and Gaussian mixture modelling were used to segment the images and identify intratumoural regions. Comparison between the segmented regions and histopathology indicated five distinct clusters: three corresponding to intratumoural regions (active tumour, necrosis/ apoptosis, and blood/edema) and two extratumoural (muscle and a mix of muscle and connective tissue). The fraction of tumour voxels segmented as necrosis/apoptosis quantitatively matched those calculated from TUNEL histopathological assays. An optimal protocol was identified providing reasonable qualitative agreement between MRI and histopathology and consisting of T 1 and t 2 maps and 22 magnetization transfer (MT)-weighted images. A three-image subset was identified that resulted in a greater than 90% match in positive and negative predictive value of tumour voxels compared to those found using the entire 24-image dataset. The proposed algorithm can potentially be used to develop a robust intratumoural segmentation method. Tumours are highly heterogeneous. Not only do they vary considerably between different individuals, but a single tumour often demonstrates regional variations in cell density, cell death, vasculature, and metabolic activity, among other factors 1. These subregions can be due to genetic or local microenvironmental differences 1,2. Differentiation between active tumour and necrosis is of particular clinical interest 3,4 since heterogeneity is often predictive of survival, therapeutic response, or metastatic potential 2,5,6. There is a diagnostic advantage to the segmentation of heterogeneous tumours prior to further analysis. Considering the tumour as a single entity and calculating whole-tumour metrics, such as perfusion parameters, can result in a loss of correlation between biomarkers 5. Magnetic resonance imaging (MRI) is ideal for identifying intratumoural regions as it is non-invasive and does not utilize ionizing radiation. While tumour heterogeneity can be observed on conventional T 2-weighted and post-contrast agent injection T 1-weighted 7,8 MRI, quantitative techniques are generally required in order to accurately segment intratumoural regions 5,9. Manual segmentation is certainly possible 2,10. However, it is time consuming, subjective, and typically based on a single image contrast.
Histopathology is currently the most reliable tool in assessing the aggressiveness and prognosis of solid tumours. However, developing non-invasive modalities for tumour evaluation remains crucial due to the side effects and complications caused by biopsy procedures. In this study, saturation transfer MRI was used to investigate the microstructural and metabolic properties of tumour xenografts in mice derived from the prostate cancer cell lines 22Rv1 and DU145, which express different aggressiveness. The magnetization transfer (MT) and chemical exchange saturation transfer (CEST) effects, which are associated with the microstructural and metabolic properties in biological tissue, respectively, were analyzed quantitatively and compared amongst different tumour types and regions. Histopathological staining was performed as a reference. Higher cellular density and metabolism expressed in more aggressive tumours (22Rv1) were associated with larger MT and CEST effects. High collagen content in the necrotic regions might explain their higher MT effects compared to tumour regions.
Stereotactic radiosurgery for the treatment of brain metastases delivers a high dose of radiation with excellent local control, but increases the likelihood of radiation necrosis. As shown in our previous work, saturation transfer MRI, consisting of quantitative magnetization transfer (qMT) and chemical exchange saturation transfer (CEST), is a promising technique for distinguishing radiation necrosis (RN) from tumour progression (TP) in brain metastases. A 3D qMT/CEST acquisition was recently implemented and over 100 patients have been scanned to date. The purpose of this work is to assess the ability of advanced MRI parameters, including qMT and CEST metrics, which are sensitive to macromolecules and metabolism. The specific metrics that were explored included the amide and NOE contributions of the magnetization transfer ratio (MTR), the MTR asymmetry, the apparent exchange-dependent relaxation (AREX), the qMT semi-solid pool fraction and the T1 and T2 relaxation times. For a subset of the patients, dynamic susceptibility contrast (DSC) perfusion images were acquired. Examples of confirmed tumour progression and radiation necrosis cases will be presented, comparing the structural images (pre- and post-contrast T1-weighted and FLAIR images) with parameter maps from qMT and CEST and also the relative cerebral blood flow (rCBF) from DSC perfusion imaging. Interim cohort results will be presented. Approaches for standardizing the parameters across multiple MRI vendors are also explored.
Stereotactic radiosurgery for the treatment of brain metastases delivers a high dose of radiation with excellent local control, but increases the likelihood of radiation necrosis. CEST is a promising technique for distinguishing radiation necrosis from tumour progression in brain metastases, but its application has been limited to a single MRI system and CEST sequence. This study explores the use of scaling of the magnetization transfer ratio (MTR) by the white matter (WM) of each patient for comparison across vendors/sequences. It was found that the WM-scaled MTR showed improved correspondence across the MR systems, across two CEST sequences.
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