18f-faza and pimonidazole

(18)F-fluoroazomycinarabinoside ((18)F-FAZA) is a promising hypoxia radiopharmaceutical agent with outstanding biokinetic parameters. We aimed to determine the accuracy of (18)F-FAZA-PET/CT scan in detecting hypoxic regions within the tumor using immunohistochemical markers in a pilot study.. Eleven patients with primary or recurrent laryngeal squamous cell carcinoma were indicated for total laryngectomy (TLE). Patients underwent (18)F-FAZA-PET/CT scan before TLE. Hypoxic regions inside the laryngeal tumor were determined. After TLE, regions with high uptake on (18)F-FAZA-PET scan were selected for immunohistochemical examination for exogenous (pimonidazole) and endogenous (HIF1α, CA-IX and GLUT-1) hypoxia markers. To assess the accuracy of (18)F-FAZA-PET scanning, radiopharmacon accumulation was related with immunohistochemical expression of hypoxia markers.. Inter- and intratumoral heterogeneity of tumor hypoxia was observed on (18)F-FAZA-PET scan. Nine of the eleven tumors were hypoxic with (18)F-FAZA-PET. Hypoxia could also be detected with pimonidazole, HIF1α, CA-IX and GLUT-1 expression in some tumors. No clear association was observed between (18)F-FAZA uptake and hypoxia markers.. This pilot study could not prove the accuracy of (18)F-FAZA-PET in determining hypoxic subvolumes in laryngeal cancer. Further study is required to investigate the benefit of (18)F-FAZA-PET imaging in radiotherapy planning.

Topics: Aged; Aged, 80 and over; Biomarkers; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Hypoxia; Laryngeal Neoplasms; Laryngectomy; Male; Middle Aged; Multimodal Imaging; Neoplasm Recurrence, Local; Nitroimidazoles; Pilot Projects; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Squamous Cell Carcinoma of Head and Neck; Tomography, X-Ray Computed

PET allows non-invasive mapping of tumor hypoxia, but the combination of low resolution, slow tracer adduct-formation and slow clearance of unbound tracer remains problematic. Using a murine tumor with a hypoxic fraction within the clinical range and a tracer post-injection sampling time that results in clinically obtainable tumor-to-reference tissue activity ratios, we have analyzed to what extent inherent limitations actually compromise the validity of PET-generated hypoxia maps.. Mice bearing SCCVII tumors were injected with the PET hypoxia-marker fluoroazomycin arabinoside (FAZA), and the immunologically detectable hypoxia marker, pimonidazole. Tumors and reference tissue (muscle, blood) were harvested 0.5, 2 and 4h after FAZA administration. Tumors were analyzed for global (well counter) and regional (autoradiography) tracer distribution and compared to pimonidazole as visualized using immunofluorescence microscopy.. Hypoxic fraction as measured by pimonidazole staining ranged from 0.09 to 0.32. FAZA tumor to reference tissue ratios were close to unity 0.5h post-injection but reached values of 2 and 6 when tracer distribution time was prolonged to 2 and 4h, respectively. A fine-scale pixel-by-pixel comparison of autoradiograms and immunofluorescence images revealed a clear spatial link between FAZA and pimonidazole-adduct signal intensities at 2h and later. Furthermore, when using a pixel size that mimics the resolution in PET, an excellent correlation between pixel FAZA mean intensity and density of hypoxic cells was observed already at 2h post-injection.. Despite inherent weaknesses, PET-hypoxia imaging is able to generate quantitative tumor maps that accurately reflect the underlying microscopic reality (i.e., hypoxic cell density) in an animal model with a clinical realistic image contrast.

Topics: Animals; Carcinoma, Squamous Cell; Cell Count; Cell Hypoxia; Disease Models, Animal; Female; Hypoxia; Mice; Mice, Inbred C3H; Nitroimidazoles; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Random Allocation; Sensitivity and Specificity; Tissue Distribution

Tumor hypoxia adversely affects treatment outcome, especially in squamous cell carcinomas (SCCs). Image guided radiotherapy (IGRT) based on PET-generated tumor hypoxia maps allows dose boosting to hypoxic sub-volumes and has received considerable interest. However, the combination of slow oxygenation-dependent tracer retention, slow clearance of unbound tracer from non-hypoxic tissue and the necessity to average signal over large non-homogenous tissue areas due to the low PET resolution remains problematic.. To assess pitfalls inherent to low-resolution imaging we have analyzed the fine-scale distribution of a PET hypoxia tracer (autoradiograms) and tissue architecture (immunofluorescence microscopy) in sectioned experimental SCCs, and compared the results to those obtained when applying macroscopic averaging mimicking the resolution in clinical PET scanners.. We show that tumor areas that would be classified as non-hypoxic based on simple PET threshold identification, often contains foci of hypoxic cells, in particular in tumors where necrosis and severely hypoxic cells are intermixed. In contrast, in a non-necrotic tumor model we found that the risk of missing hypoxic cells was greatly reduced, however, its patchy hypoxic pattern made a clear delineation of a target to boost unfeasible. We discuss the implications of these and other complicating factors in PET hypoxia-imaging and outline future strategies to overcome or circumvent them.

Topics: Animals; Carcinoma, Squamous Cell; Cell Hypoxia; Mice; Mice, Nude; Microscopy, Fluorescence; Necrosis; Neoplasms, Experimental; Nitroimidazoles; Positron-Emission Tomography

Positron emission tomography (PET) allows noninvasive assessment of tumor hypoxia; however the combination of low resolution and slow tracer clearance from nonhypoxic tissue is problematic. The aim of this study was to examine the in vivo hypoxia selectivity of fluoroazomycin arabinoside ([18F]-FAZA), a promising tracer with improved washout kinetics from oxygenated tissue.. Three squamous cell carcinomas and one fibrosarcoma with widely differing spatial patterns of vascularization, hypoxia, and necrosis were grown in mice and evaluated with PET and complementary methods.. Eppendorf electrode measurements consistently demonstrated median PO2 values<1 mm Hg. In accordance with that, PET revealed that all tumors accumulated [18F]-FAZA in excess of reference tissue. Next the two-dimensional spatial distribution of [18F]-FAZA (from autoradiography) was compared with fluorescence images of the same tumor sections showing localization of the hypoxia marker pimonidazole and the perfusion marker Hoechst 33342. Pixel-by-pixel analysis of co-registered images showed a highly significant co-localization between the two hypoxia markers and an inverse correlation (except for the fibrosarcoma) between the distribution of [18F]-FAZA and Hoechst dye. Moreover intratumoral heterogeneity in tracer distribution was clearly visible on autoradiograms, with a [18F]-FAZA concentration approximately six times higher in poorly oxygenated areas than in vascular hot spots.. The distribution of [18F]-FAZA is consistent with hypoxia as the key driving force for tracer tissue retention in a selection of tumors with widely differing physiology.

Topics: Animals; Autoradiography; Carcinoma, Squamous Cell; Cell Hypoxia; Female; Fibrosarcoma; Fluorine Radioisotopes; Immunocompromised Host; Immunohistochemistry; Mice; Mice, Inbred C3H; Mice, Nude; Microscopy, Fluorescence; Nitroimidazoles; Oxygen; Polarography; Positron-Emission Tomography; Radiation-Sensitizing Agents; Transplantation, Heterologous