In Vivo Characterization of RIF-1 Tumors via Diffusion and Fluorine-19 NMR Methods

Meiler, Michael Rudolf

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In Vivo Characterization of RIF-1 Tumors via Diffusion and Fluorine-19 NMR Methods

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Diffusion-weighted nuclear magnetic resonance has gained widespread use in the characterization of various diseases. Developments in the area of porous media theory have been successfully transferred and adapted for the use in biological tissue. Measurement of the displacement of diffusing water molecules can reveal structural information about the environment in which the molecules translate. The return-to-the-origin (RTO) probability and the apparent diffusion coefficient (ADC) are based on the diffusion behavior of water molecules in a restricted environment. Water molecules in restricted space have smaller displacements, for a given diffusion time, than water molecules diffusing in bulk solution. The cell membranes and organelles in healthy biological tissue impart more restrictions on diffusing water molecules as compared to necrotic tumor tissue. In necrotic tissue the degradation of cellular structures by auto- and/or heterolysis allows water molecules to diffuse over larger distances without encountering restrictions. The spectroscopic measurement of the RTO probability and the RTO enhancement in RIF-1 tumors showed that the RTO probability is sensitive to these changes in structure. The study showed that smaller tumors, which are less necrotic, have a larger RTO probability and enhancement than larger RIF-1 tumors with a higher fraction of necrotic tumor tissue. Extension of the methodology to NMR imaging was used to answer the question if the RTO probability can provide spatial information about the necrotic area within RIF-1 tumors. The necrotic area measured by the ADC and histology were compared. While neither ADC or RTO could show its superiority over the other, both methods showed a good correlation between their mean values and the necrotic area fraction as measured by histology. The mean ADC and the mean RTO enhancement had a correlation with the necrotic tumor fraction, as determined by histology, of r = 0.86 and r = -0.82, respectively. Conventional T2-weighted images of the same tumor slice showed a poorer correlation (r = 0.62) with the necrotic fraction and no visual agreement with the histology. The general features of the ADC and RTO enhancement were in agreement with histology, however, more exact comparisons where not possible due to the large differences in slice thickness between the two techniques. Structural changes similar to those caused by tumor tissue necrosis can be induced by chemo- and radiation therapy and ADC and RTO enhancement were used to monitor these changes non-invasively. RIF-1 tumors were grown on the hind leg of C3H mice and monitored daily by diffusion-weighted MRI. ADC and RTO-enhancement maps were created using data acquired from control animals and animals treated with 100 mg/kg 5-Fluorouracil. Both ADC and RTO proved to be useful in the early detection of the efficacy of treatment as well as for monitoring the progress of therapy. Diffusion measurements by pulsed-field-gradient (PFG) MRI have become an important tool for detecting of pathophysiological changes caused by cancer and stroke. The increasing popularity of diffusion measurements has initiated their use on clinical MRI systems that have limited magnetic-field-gradient strength. These limitations make it necessary to lengthen the diffusion-gradient duration to ensure sufficient signal attenuation for calculating the ADC. Unfortunately, increasing of the diffusion-gradient duration to a large extent violates the theoretical model used in the ADC calculation. The diffusion measurements are not performed in the finite pulse width regime, but rather in the constant gradient regime, requiring a different interpretation of the results. Examination of the differences in the measured diffusion coefficient showed that increasing both the diffusion-gradient duration and the echo time have a significant impact on the results of a diffusion measurement. A different way to assess changes in RIF-1 tumors as a function of treatment is the measurement of the tissue oxygen status. Cell hypoxia has long been linked with treatment resistivity and reoccurrence in cancers, where the oxygen status is a determining factor of treatment outcome. Perfluorocarbons (PFC's) have been used successfully to assess the tumor oxygen status in the past, but required a large MRI slice thickness due to compensate for the low PFC concentration. The tissue oxygen status of the tumor is assessed by intravenous injection of a PFC that is subsequently sequestered in the tumor. The measurement of the T1-relaxation time of the PFC allows the calculation of the oxygen content, which is linearly related to the relaxivity and the temperature. Fluorine-19, multiple-slice, inversion-recovery echo-planar imaging (EPI) allowed high spatial resolution assessment of the tissue oxygen status over the entire tumor. The results demonstrated that there is a large variation in tissue oxygenation between adjacent slices. Comparison of the oxygen distribution between various tumors also showed that there is no common pattern in the spatial distribution of oxygen within the tumor. Monitoring of the oxygen status during chemotherapy showed an increase in hypoxic tissue and a reduction in tumor size in response to the toxicity of the chemotherapeutic agent. As the effects of the treatment subsided, rapid cell proliferation caused the tumor to regrow and a subsequent decrease in tissue oxygen tension was observed. The study clearly demonstrated the changes in oxygen tension in response to chemotherapy and the need for multi-slice MRI acquisition at high spatial resolution to detect these changes.

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