Noninvasive mapping of spontaneous fluctuations in tumor oxygenation using 19 F MRI J. Magat and B. F. Jordan Biomedical Magnetic Resonance Unit, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels 1200, Belgium G. O. Cron Magnetic Resonance Imaging, Ottawa Health Research Institute, Ottawa, Ontario K1S 5B6, Canada B. Gallez a Biomedical Magnetic Resonance Unit, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels 1200, Belgium Received 21 April 2010; revised 10 August 2010; accepted for publication 10 August 2010; published 28 September 2010 Purpose: Acute hypoxia transient cycles of hypoxia-reoxygenation is known to occur in solid tumors and may be a poorly appreciated therapeutic problem as it can be associated with resistance to radiation therapy, impaired delivery of chemotherapeutic agents, or metastasis development. The objective of the present study was to use MR 19 F relaxometry maps to analyze the spontaneous fluctuations of partial pressure of oxygen pO 2  over time in experimental tumors. Methods: The pO 2 maps were generated after direct intratumoral administration of a fluorine compound hexafluorobenzene whose relaxation rate 1 / T 1  is proportional to the % O 2 . The authors used a SNAP inversion-recovery sequence at 4.7 T to acquire parametric images of the T 1 relaxation time with a high spatial and temporal resolution. Homemade routines were developed to perform regions of interest analysis, as well as pixel by pixel analysis of pO 2 over time. Results: The authors were able to quantify and probe the heterogeneity of spontaneous fluctuations in tumor pO 2 : i Spontaneous fluctuations in pO 2 occurred regardless of the basal oxygenation state i.e., both in oxygenated and in hypoxic regions and ii spontaneous fluctuations occurred at a rate of 1 cycle/12–47 min. For validation, the analysis was performed in dead mice for which acute changes did not occur. The authors thereby demonstrated that 19 F MRI technique is sensitive to acute change in pO 2 in tumors. Conclusions: This is the first approach that allows quantitative minimally invasive measurement of the spontaneous fluctuations of tumor oxygenation using a look-locker approach e.g., SNAP IR. This approach could be an important tool to characterize the phenomenon of tumor acute hypoxia, to understand its physiopathology, and to improve therapies. © 2010 American Association of Physicists in Medicine. DOI: 10.1118/1.3484056 Key words: 19 F MRI, acute hypoxia, tumor oxygenation, pO 2 fluctuations I. INTRODUCTION Two types of hypoxia have been identified in tumors: Chronic hypoxia caused by an increase in diffusion distances between tumor vessels with tumor expansion and acute hy- poxia caused by blood flow heterogeneities and temporally correlated with changes in red cell flux. 1,2 It is well known that acute hypoxia is associated with resistance to radiation therapy 3 and impaired delivery of chemotherapeutic agents. 4 Further studies have shown that intermittent hypoxia in- creases metastasis development 5 and promotes the survival of tumor cells. 6 Also, it has been recently shown that cycling through periods of acute hypoxia followed by reoxygenation will lead to an accumulation of unrepaired lesions and in- creased genomic instability. 7 Importantly, Rofstad et al. 8 demonstrated with immunochemistry that the fraction of acute hypoxic cells is larger than the fraction of chronic hy- poxic cells. All these results emphasize the fact that the study of acute hypoxia is of primary importance with regard to tumor development and cancer therapy and that there is a critical need for developing in vivo techniques to measure it with sufficient time and spatial resolutions. In the past, acute changes over time have been character- ized using multiple techniques: Intravital microscopy, 9–11 histologically based “mismatch” techniques, 12 and laser Doppler flowmetry. 13,14 Consecutively, both Eppendorf electrodes 15 and Oxylite fiberoptic probes 16,17 have been used to demonstrate transient changes in tumor oxygenation. In addition, the same group recently developed a first pass imaging microscopy technique in window chambers. 18 All these methods allowed to definitely establish the occurrence of acute hypoxia in solid experimental tumors but were ei- ther invasive, indirect, or limited by a lack of spatial infor- mation and/or real-time data acquisition. Magnetic resonance imaging MRI has therefore been considered to noninvasively study periodic changes in tumor pressure of oxygen pO 2 . First, it was demonstrated that T 2  5434 5434 Med. Phys. 37 „10…, October 2010 0094-2405/2010/37„10…/5434/8/$30.00 © 2010 Am. Assoc. Phys. Med.