Monitoring Combretastatin A4-induced tumor hypoxia and hemodynamic changes using endogenous MR contrast and DCE-MRI.

PURPOSE: To benchmark MOBILE (Mapping of Oxygen By Imaging Lipid relaxation Enhancement), a recent noninvasive MR method of mapping changes in tumor hypoxia, electron paramagnetic resonance (EPR) oximetry, and dynamic contrast-enhanced MRI (DCE-MRI) as biomarkers of changes in tumor hemodynamics induced by the antivascular agent combretastatin A4 (CA4). METHODS: NT2 and MDA-MB-231 mammary tumors were implanted subcutaneously in FVB/N and nude NMRI mice. Mice received 100 mg/kg of CA4 intraperitoneally 3 hr before imaging. The MOBILE sequence (assessing R1 of lipids) and the DCE sequence (assessing K(trans) hemodynamic parameter), were assessed on different cohorts. pO2 changes were confirmed on matching tumors using EPR oximetry consecutive to the MOBILE sequence. Changes in tumor vasculature were assessed using immunohistology consecutive to DCE-MRI studies. RESULTS: Administration of CA4 induced a significant decrease in lipids R1 (P = 0.0273) on pooled tumor models and a reduction in tumor pO2 measured by EPR oximetry. DCE-MRI also exhibited a significant drop of K(trans) (P < 0.01) that was confirmed by immunohistology. CONCLUSION: MOBILE was identified as a marker to follow a decrease in oxygenation induced by CA4. However, DCE-MRI showed a higher dynamic range to follow changes in tumor hemodynamics induced by CA4.

Mapping of oxygen by imaging lipids relaxation enhancement: a potential sensitive endogenous MRI contrast to map variations in tissue oxygenation.

PURPOSE: Because of its paramagnetic properties, oxygen may act as an endogenous magnetic resonance imaging contrast agent by changing proton relaxation rates. Changes in tissue oxygen concentrations have been shown to produce changes in relaxation rate R1 of water. The aim of the study was to improve the sensitivity of oxygen enhanced R1 imaging by exploiting the higher solubility of oxygen in lipids (as compared with water) to sensitively monitor changes in tissue oxygen levels by selectively measuring the R1 of lipids. METHODS: The method, with the acronym "MOBILE" (mapping of oxygen by imaging lipids relaxation enhancement), was applied in different mouse models of hypoxic processes on a 11.7 T magnetic resonance imaging system. MOBILE was compared with R*2, R1 of water, and with pO2 measurements (using electron paramagnetic resonance oximetry). MOBILE was also applied in the brain of healthy human volunteers exposed to an oxygen breathing challenge on a 3 T magnetic resonance imaging system. RESULTS: MOBILE was shown to be able to monitor changes in oxygenation in tumor, peripheral, liver, and brain tissues. The clinical translation was demonstrated in human volunteers. CONCLUSION: MOBILE arises as a promising noninvasive and sensitive tool for diagnosis and therapeutic guidance in disorders involving hypoxia.

Application of MOBILE (mapping of oxygen by imaging lipids relaxation enhancement) to study variations in tumor oxygenation.

The aim of the study was to sensitively monitor changes in tumor oxygen using the MOBILE (mapping of oxygen by imaging lipids relaxation enhancement) technique. This method was applied in mammary tumor mouse models on an 11.7T Bruker MRI system. MOBILE was compared with functional imaging R2*, R1 of water and with pO2 measurements (using EPR oximetry and O2-dependent fluorescence quenching measurements). MOBILE was shown to be capable to monitor changes in oxygenation in tumor tissues.

Assessing Tumor Oxygenation for Predicting Outcome in Radiation Oncology: A Review of Studies Correlating Tumor Hypoxic Status and Outcome in the Preclinical and Clinical Settings.

Tumor hypoxia is recognized as a limiting factor for the efficacy of radiotherapy, because it enhances tumor radioresistance. It is strongly suggested that assessing tumor oxygenation could help to predict the outcome of cancer patients undergoing radiation therapy. Strategies have also been developed to alleviate tumor hypoxia in order to radiosensitize tumors. In addition, oxygen mapping is critically needed for intensity modulated radiation therapy (IMRT), in which the most hypoxic regions require higher radiation doses and the most oxygenated regions require lower radiation doses. However, the assessment of tumor oxygenation is not yet included in day-to-day clinical practice. This is due to the lack of a method for the quantitative and non-invasive mapping of tumor oxygenation. To fully integrate tumor hypoxia parameters into effective improvements of the individually tailored radiation therapy protocols in cancer patients, methods allowing non-invasively repeated, safe, and robust mapping of changes in tissue oxygenation are required. In this review, non-invasive methods dedicated to assessing tumor oxygenation with the ultimate goal of predicting outcome in radiation oncology are presented, including positron emission tomography used with nitroimidazole tracers, magnetic resonance methods using endogenous contrasts (R1 and [Formula: see text]-based methods), and electron paramagnetic resonance oximetry; the goal is to highlight results of studies establishing correlations between tumor hypoxic status and patients' outcome in the preclinical and clinical settings.

Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study.

PURPOSE: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R1, water R1, lipids R1, and R2*. R1 is sensitive to dissolved molecular oxygen, whereas R2* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R1, water R1, lipids R1, and R2* with pO2 assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). METHODS AND MATERIALS: R1, R2*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O2, 5% CO2). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. RESULTS: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO2. Global and lipids R1 were found to be correlated to pO2 in the rhabdomyosarcoma model, whereas R2* was found to be inversely correlated to pO2 in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R2* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. (18)F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. CONCLUSION: This work illustrates the sensitivity of oxygen-sensitive R1 and R2* parameters to changes in tumor oxygenation. However, R1 parameters showed limitations in terms of predicting the outcome of RT in the tumor models studied, whereas R2* was found to be correlated with the outcome in the responsive model.

Mapping of global R1 and R2* values versus lipids R1 values as potential markers of hypoxia in human glial tumors: A feasibility study.

Availability of an innocuous and repeatable technique for monitoring tumor oxygenation throughout therapeutic course should be a key factor for adaptative therapeutic strategies. We previously qualified lipids R1 as a marker of oxygen level on experimental tumor models. The objectives of the present study were to assess the applicability of measuring lipids R1 in primary central nervous system malignancies in a clinical setting as well as to compare lipids R1 with global (water+lipids) R1 and R2* which are also sensitive to the oxygen environment. 25 patients with brain neuroepithelial tumors were examined on a clinical 3T MR system. Values obtained within regions of interest contouring contrast-enhanced tumor (C+), unenhanced tumor (C-), peritumoral edema, and normal appearing white matter (NAWM) were compared to those obtained for the normal brain parenchyma of 17 healthy volunteers. Global R1 and lipids R1 values were significantly lower in tumors than in NAWM of patients or healthy brain of normal volunteers. In contrast, R2* values were not significantly different in tumors compared to NAWM or healthy brains. None of them showed significant difference between C+ and C- tumors. Global R1 values within NAWM were significantly different from that of both tumor and peritumoral edema, but lacked sensitivity to differentiate between tumor and peritumoral edema. In turn, lipids R1 measurements enabled discrimination between tumor areas and peritumoral edema. In conclusion, global R1 and lipids R1 deserve further attention as potential markers of tumor hypoxia in primary brain tumors.

Oxygen Mapping within Healthy and Acutely Infarcted Brain Tissue in Humans Using the NMR Relaxation of Lipids: A Proof-Of-Concept Translational Study.

The clinical applicability of brain oxygenation mapping using the MOBILE (Mapping of Oxygen By Imaging Lipids relaxation Enhancement) magnetic resonance (MR) technique was assessed in the clinical setting of normal brain and of acute cerebral ischemia as a founding proof-of-concept translational study. Changes in the oxygenation level within healthy brain tissue can be detected by analyzing the spin-lattice proton relaxation ('Global T1' combining water and lipid protons) because of the paramagnetic properties of molecular oxygen. It was hypothesized that selective measurement of the relaxation of the lipid protons ('Lipids T1') would result in enhanced sensitivity of pO2 mapping because of higher solubility of oxygen in lipids than in water, and this was demonstrated in pre-clinical models using the MOBILE technique. In the present study, 12 healthy volunteers and eight patients with acute (48-72 hours) brain infarction were examined with the same clinical 3T MR system. Both Lipids R1 (R1 = 1/T1) and Global R1 were significantly different in the infarcted area and the contralateral unaffected brain tissue, with a higher statistical significance for Lipids R1 (median difference: 0.408 s-1; p<0.0001) than for Global R1 (median difference: 0.154 s-1; p = 0.027). Both Lipids R1 and Global R1 values in the unaffected contralateral brain tissue of stroke patients were not significantly different from the R1 values calculated in the brain tissue of healthy volunteers. The main limitations of the present prototypic version of the MOBILE sequence are the long acquisition time (4 min), hampering robustness of data in uncooperative patients, and a 2 mm slice thickness precluding accurate measurements in small infarcts because of partial volume averaging effects.

Qualification of a noninvasive magnetic resonance imaging biomarker to assess tumor oxygenation.

PURPOSE: Although hypoxia has been long recognized as a crucial factor impairing tumor response in many therapeutic schemes, atraumatic and reliable methods of individually quantifying tumor oxygenation are still lacking in day-to-day clinical practice. The aim of this work was to investigate the potentially quantitative properties of our recently described noninvasive magnetic resonance (MR) technique "MOBILE" (mapping of oxygen by imaging lipids relaxation enhancement) and to qualify this endogenous contrast as a tumor hypoxia marker. EXPERIMENTAL DESIGN: The "MOBILE" technique, which assesses the longitudinal MR relaxation rate, R1, of lipid protons, was benchmarked with the parent technique which assesses the global (or water) R1, in response to a hyperoxic challenge (carbogen breathing) and to a hypoxic challenge (combretastatin A4) in MDA-MB-231 xenografts and in NT2 mammary tumors. Electron paramagnetic resonance (EPR) oximetry was used to quantitatively assess the tumor pO2 in matching tumors longitudinally. RESULTS AND CONCLUSION: Our study evidenced that (i) positive and negative changes in tumor oxygenation can be detected using MOBILE; (ii) a change in the R1 of lipids is positively correlated with a change in the tumor pO2 (P = 0.0217, r = 0.5097); (iii) measured lipid R1 values are positively correlated with absolute pO2 values in both tumor models (P = 0.0275, r = 0.3726); and (iv) changes in the R1 of lipids are more sensitive than changes in the global R1. As this technique presents unique translational properties, it seems promising for the individual longitudinal monitoring of tumor oxygenation in a clinical setting.