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)...

The SUV(max)-based RI calculated after the first 2 weeks of RCT provided the best predictor of pathological treatment response, reaching AUCs of 0.87 and 0.84 for the TRG and the ypT stage, respectively. However, a few patients presented with peritumoral inflammatory reactions, which led to mispredictions. Exclusion of these patients further enhanced the predictive accuracy of PET imaging to AUCs of 0.97 and 0.89 for TRG and ypT, respectively.

Background and purpose Noninvasive PET imaging of tumour hypoxia could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers. In this phase I trial, we aimed to determine the toxicity of [ 18 F]HX4, a member of the 2-nitroimidazole family, at different dose levels. The secondary aim was to analyse image quality related to the HX4 dose and the timing of imaging. Methods Patients with a histologically proven solid cancer without curative treatment options were eligible for this study. A study design with two dose steps was used in which a single dose of a maximum of 222 MBq (step 1) or 444 MBq (step 2) [ 18 F]HX4 was injected. Toxicity was scored on day 0 and on days 3 and 7 after injection, according to the CTCAE 3.0 scoring system. PET/CT images of the largest tumour site were acquired 30, 60 and 120 min after injection. Results Six patients with stage IV carcinoma were included, four with non-small-cell lung carcinoma, one with thymus carcinoma, and one with colon carcinoma. No toxicity was observed in any of the patients at either dose level. The median tumour to muscle ratio 120 min after injection was 1.40 (range 0.63-1.98). Conclusion The findings of this study showed that [ 18 F] HX4 PET imaging for the detection of hypoxia is not associated with any toxicity. Imaging was successful; however, future trials are needed to determine the optimal image parameters.