Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

Dubois, Lucette; Landuyt, Willy; Haustermans, Karin; Dupont, Patrick; Bormans, Guy; Vermaelen, Peter; Flamen, Patrick; Verbeken, Erik; Mortelmans, Luc

doi:10.1038/sj.bjc.6602219

Cited by 101 publications

(56 citation statements)

References 43 publications

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“…Simultaneously with tracer injection (20.430 ± 2.418 MBq), a dynamic emission scan in list mode (LM) was started for 60 min in one bed position encompassing the heart, tumor, and hind legs of the rat. Afterward, LM data were rebinned using Fourier rebinning, and PET images were reconstructed as previously described (5). Two hours post injection, the rats were repositioned using external markers and a dedicated laser-positioning system (LAP) for a CT scan, immediately followed by a second dynamic emission scan performed for 20 min (rebinned into four frames of 5 min each).…”

Section: Resultsmentioning

confidence: 99%

Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Dubois

Lieuwes

Janssen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

123

122

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Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [ 18 F] HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [ 18 F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 ± 0.926 and optimal imaging properties 4 h after injection. [ 18 F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [ 18 F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [ 18 F]HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P < 0.001) in [ 18 F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [ 18 F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.cancer | nuclear medicine | experimental research T he presence of hypoxic regions due to abnormalities in tumor vasculature, heterogeneously spread within solid tumors influences clinical outcome; as it is an independent predictor of poor prognosis-free survival in several types of cancer (1). In contrast, this unique tumor characteristic makes it an attractive target for novel drugs to increase the therapeutic effect of conventional cancer treatment modalities. Another approach is the use of intensity-modulated radiotherapy to give a higher dose to hypoxic areas while sparing the surrounding normal tissue (2, 3). Although treatments to counteract the negative effect of intratumoral hypoxia are under investigation, not all patients will benefit from such selective treatments. Therefore, to guide hypoxiadirected therapies in individual patients, it is important to evaluate tumor oxygenation using a reliable noninvasive method.To date, a variety of methods are available for assessment of tumor oxygenation in solid tumors, of which polarographic oxygen electrodes and immunohistological assays remain the gold standard (4). These standard invasive modalities have not yielded reliable 3D images of the whole tumor for clinical use, and therefore research has been focused on noninvasive imaging techniques, such as positron-emission tomography (PET) using nitroimidazoles. The 2-nitroimidazole derivative fluoromisonidazole (FMISO)...

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Section: Resultsmentioning

confidence: 99%

Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Dubois

Lieuwes

Janssen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

123

122

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“…[41][42][43][44][45][46][47][48] Early reports suggested that semiquantitative scoring of CAIX labeling was correlated with direct pO 2 measurements in solid tumors, but this has not been confirmed by other groups. [32][33][34][35][36][49][50][51][52][53] When we examined a series of single punch biopsies obtained from Figure 5 The 95% CI of the averaged per patient % carbonic anhydrase IX (CAIX) value, in full sections (a) and in tissue microarray (TMA) simulations (b and c).…”

Section: Discussionmentioning

confidence: 99%

Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX

Iakovlev

Pintilie

Morrison

et al. 2007

Laboratory Investigation

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“…Most solid tumors show evidence of hypoxia, presumably as a consequence of tumor cell proliferation outpacing neoangiogenesis (1)(2)(3). To date, three methods have been used to assess hypoxia in human tumors.…”

Section: Introductionmentioning

confidence: 99%

Reproducibility of Intratumor Distribution of 18F-Fluoromisonidazole in Head and Neck Cancer

Nehmeh

Lee

Schröder

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

192

130

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Purpose-Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. 18 F-fluoromisonidazole ( 18 F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of 18 F-FMISO intratumor distribution using two pretreatment PET scans.Methods and Materials-We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an 18 Ffluorodeoxyglucose study, followed by two 18 F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio ≥1.2. The 18 F-FMISO tracer distributions from the two 18 F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the 18 F-FMISO intensities of the corresponding spatial voxels was derived.Results-A voxel-by-voxel analysis of the 18 F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%.Conclusion-Variability in spatial uptake can occur between repeat 18 F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of 18 F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before singletime-point 18 F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy.

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Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

Cited by 101 publications

References 43 publications

Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX

Reproducibility of Intratumor Distribution of 18F-Fluoromisonidazole in Head and Neck Cancer

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Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

Cited by 101 publications

References 43 publications

Preclinical evaluation and validation of [ 18 F]HX4, a promising hypoxia marker for PET imaging

Preclinical evaluation and validation of [ 18 F]HX4, a promising hypoxia marker for PET imaging

Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX

Reproducibility of Intratumor Distribution of 18F-Fluoromisonidazole in Head and Neck Cancer

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Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging