Purpose The behavior of 64Cu-ATSM in hypoxic tumors was examined through a combination of in vivo dynamic PET imaging, and ex vivo autoradiographic and histological evaluation using a xenograft model of H&N squamous cell carcinoma. Methods and Materials 64Cu-ATSM was administered during dynamic PET imaging, and temporal changes in 64Cu-ATSM distribution within tumors were evaluated for at least 1 h and up to 18 h. Animals were sacrificed at either 1 h (cohort A) or after 18 h (cohort B) post-injection of radiotracer and autoradiography performed. Ex vivo analysis of microenvironment sub-regions was conducted by immunohistochemical staining for markers of hypoxia (Pimonidazole Hydrochloride) and blood flow (Hoechst-33342). Results Kinetic analysis revealed rapid uptake of radiotracer by tumors. The net influx (Ki) constant was twelve-fold that of muscle, while the distribution volume (Vd) was five-fold. PET images showed large tumor-to-muscle ratios, which continually increased over the entire 18 h course of imaging. However, no spatial changes in 64Cu-ATSM distribution occurred in PET imaging after 20 minutes post-injection. Microscopic intratumoral distribution of 64Cu-ATSM and Pimonidazole were not correlated at 1 h or after 18 h post-injection, and neither was 64Cu-ATSM and Hoechst-33342. Conclusions The oxygen partial pressures at which 64CuATSM and Pimonidazole are reduced and bound in cells are theorized to be distinct and separable. However, this study demonstrated that microscopic distributions of these tracers within tumors are independent. Nonetheless, researchers have shown 64Cu-ATSM uptake to be specific to malignant expression, and this work has also demonstrated clear tumor targeting by the radiotracer.

The lymphatic system plays a critical role in the maintenance of healthy tissues. Its function is an important indicator of the presence and extent of disease. In oncology, metastatic spread to local lymph nodes (LNs) is a strong predictor of poor outcome. Clinical methods for the visualization of LNs involve regional injection and tracking of 99mTc-sulfur colloid (99mTc-SC) along with absorbent dyes. Intraoperatively, these techniques suffer from the requirement of administration of multiple contrast media (99mTc-SC and isosulfan blue), unwieldy γ-probes, and a short effective surgical window for dyes. Preclinically, imaging of transport through the lymphatics is further hindered by the resolution of lymphoscintigraphy and SPECT. We investigated multimodal imaging in animal models using intradermal administration of 18F-FDG for combined diagnostic and intraoperative use. PET visualizes LNs with high sensitivity and resolution and low background. Cerenkov radiation (CR) from 18F-FDG was evaluated to optically guide surgical resection of LNs. Methods Imaging of 18F-FDG uptake used PET and sensitive luminescent imaging equipment (for CR). Dynamic PET was performed in both sexes and multiple strains (NCr Nude, C57BL/6, and Nu/Nu) of mice. Biodistribution confirmed the uptake of 18F-FDG and was compared with that of 99mTc-SC. Verification of uptake and the ability to use 18F-FDG CR to guide nodal removal were confirmed histologically. Results Intradermal injection of 18F-FDG clearly revealed lymphatic vessels and LNs by PET. Dynamic imaging revealed rapid and sustained labeling of these structures. Biodistribution of the radiotracer confirmed the active transport of radioglucose in the lymphatics to the local LNs and over time into the general circulation. 18F-FDG also enabled visualization of LNs through CR, even before surgically revealing the site, and guided LN resection. Conclusion Intradermal 18F-FDG can enhance the preclinical investigation of the lymphatics through dynamic, high-resolution, and quantitative tomographic imaging. Clinically, combined PET/Cerenkov imaging has significant potential as a single-dose, dual-modality tracer for diagnostics (PET/CT) and guided resection of LNs (Cerenkov optical).

Background Previous evaluations of low-dose CT (LDCT) lung cancer screening programmes have taken very different approaches in the design of the informative trials and the methods applied to determine cost-effectiveness. Therefore, it has not been possible to determine if differences in costeffectiveness are due to different screening approaches or the evaluation methodology. This study reports the findings of an evaluation of the first round of a community-based, LDCT screening pilot Manchester, applying previously published methodology to ensure consistency.

18F-fluoromisonidazole PET, a noninvasive means of identifying hypoxia in tumors, has been widely applied but with mixed results, raising concerns about its accuracy. The objective of this study was to determine whether kinetic analysis of dynamic 18F-fluoromisonidazole data provides better discrimination of tumor hypoxia than methods based on a simple tissue-to-plasma ratio. Methods Eleven Dunning R3327-AT prostate tumor-bearing nude rats were immobilized in custom-fabricated whole-body molds, injected intravenously with 18F-fluoromisonidazole, and imaged dynamically for 105 min. They were then transferred to a robotic system for image-guided measurement of intratumoral partial pressure of oxygen (PO2). The dynamic 18F-fluoromisonidazole uptake data were fitted with 2 variants of a 2-compartment, 3-rate-constant model, one constrained to have K1 equal to k2 and the other unconstrained. Parametric images of the rate constants were generated. The PO2 measurements were compared with spatially registered maps of kinetic rate constants and tumor-to-plasma ratios. Results The constrained pharmacokinetic model variant was shown to provide fits similar to that of the unconstrained model and did not introduce significant bias in the results. The trapping rate constant, k3, of the constrained model provided a better discrimination of low PO2 than the tissue-to-plasma ratio or the k3 of the unconstrained model. Conclusion The use of kinetic modeling on a voxelwise basis can identify tumor hypoxia with improved accuracy over simple tumor-to-plasma ratios. An effective means of controlling noise in the trapping rate constant, k3, without introducing significant bias, is to constrain K1 equal to k2 during the fitting process.

Environmental factors have long been thought to have a role in the etiology of idiopathic Parkinson’s Disease (PD). Since the discovery of the selective neurotoxicity of MPTP to dopamine cells, suspicion has focused on paraquat, a common herbicide with chemical structure similar to 1-methyl-4-phenylpyridinium (MPP+), the MPTP metabolite responsible for its neurotoxicity. Although in vitro evidence for paraquat neurotoxicity to dopamine cells is well established, its in vivo effects have been ambiguous because paraquat is di-cationic in plasma, which raises questions about its ability to cross the blood brain barrier. This study assessed the brain uptake of [11C]-paraquat in adult male rhesus macaques using quantitative PET imaging. Results showed minimal uptake of [11C]-paraquat in the macaque brain. The highest concentrations of paraquat was seen in the pineal gland and the lateral ventricles. Global brain concentrations including those in known dopamine areas were consistent with the blood volume in those structures. This acute exposure study found that paraquat is excluded from the brain by the blood brain barrier and thus does not readily support the causative role of paraquat exposure in idiopathic Parkinson’s Disease.