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18F-fluorothymidine-pet imaging of glioblastoma multiforme: effects of radiation therapy on radiotracer uptake and molecular biomarker patterns.

Chandrasekaran S, Hollander A, Xu X, Benci JL, Davis JJ, Dorsey JF, Kao G - ScientificWorldJournal (2013)

Bottom Line: Conventional (18)F-FDG-PET imaging is of limited usefulness for imaging Glioblastoma Multiforme (GBM) due to high levels of glucose uptake by normal brain and the resultant signal-to-noise intensity. (18)F-Fluorothymidine (FLT) in contrast has shown promise for imaging GBM, as thymidine is taken up preferentially by proliferating cells.Results.Conclusions. (18)F-FLT-PET imaging is a promising tumor imaging modality for GBM, including assessing RT effects and biologically relevant biomarkers.

View Article: PubMed Central - PubMed

Affiliation: University of Washington School of Medicine, A-300 Health Sciences Center, Seattle, WA 98195, USA.

ABSTRACT
Introduction. PET imaging is a useful clinical tool for studying tumor progression and treatment effects. Conventional (18)F-FDG-PET imaging is of limited usefulness for imaging Glioblastoma Multiforme (GBM) due to high levels of glucose uptake by normal brain and the resultant signal-to-noise intensity. (18)F-Fluorothymidine (FLT) in contrast has shown promise for imaging GBM, as thymidine is taken up preferentially by proliferating cells. These studies were undertaken to investigate the effectiveness of (18)F-FLT-PET in a GBM mouse model, especially after radiation therapy (RT), and its correlation with useful biomarkers, including proliferation and DNA damage. Methods. Nude/athymic mice with human GBM orthografts were assessed by microPET imaging with (18)F-FDG and (18)F-FLT. Patterns of tumor PET imaging were then compared to immunohistochemistry and immunofluorescence for markers of proliferation (Ki-67), DNA damage and repair (γH2AX), hypoxia (HIF-1α), and angiogenesis (VEGF). Results. We confirmed that (18)F-FLT-PET uptake is limited in healthy mice but enhanced in the intracranial tumors. Our data further demonstrate that (18)F-FLT-PET imaging usefully reflects the inhibition of tumor by RT and correlates with changes in biomarker expression. Conclusions. (18)F-FLT-PET imaging is a promising tumor imaging modality for GBM, including assessing RT effects and biologically relevant biomarkers.

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Orthotopic brain tumors are readily imaged by FLT-PET. (a) Visual comparison of Bioluminescence Imaging (BLI) surface radiance (photons/sec/cm2/steradian) in orthotopic intracranial tumors with BLI Fluxmax⁡ (photons/second) values of 1 × 106 (1E + 6) and 1 × 109 (1E + 9). (b) Identification of an exponential growth pattern in intracranial tumors based on Fluxmax⁡ measurements (n = 5). (c) Comparison of %ID of intracranial 18F-FLT %ID at 1 and 7 weeks after injection. (d) Visual comparison of 18F-FLT uptake in intracranial tumors based on Fluxmax⁡ values of 1 × 106 and 1 × 109 (weeks 1 and 7, respectively). Tumor visualized at 7 weeks (yellow arrows).
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fig2: Orthotopic brain tumors are readily imaged by FLT-PET. (a) Visual comparison of Bioluminescence Imaging (BLI) surface radiance (photons/sec/cm2/steradian) in orthotopic intracranial tumors with BLI Fluxmax⁡ (photons/second) values of 1 × 106 (1E + 6) and 1 × 109 (1E + 9). (b) Identification of an exponential growth pattern in intracranial tumors based on Fluxmax⁡ measurements (n = 5). (c) Comparison of %ID of intracranial 18F-FLT %ID at 1 and 7 weeks after injection. (d) Visual comparison of 18F-FLT uptake in intracranial tumors based on Fluxmax⁡ values of 1 × 106 and 1 × 109 (weeks 1 and 7, respectively). Tumor visualized at 7 weeks (yellow arrows).

Mentions: We thus compared uptake patterns of 18F-FDG and 18F-FLT in intracranial tumors. Healthy nude/athymic mice (n = 5) were intracranially injected with U251-GFP-LUC glioma cells and underwent weekly BLI with subsequent 18F-FLT-PET imaging (Figure 2(a)). Intracranial tumor growth across all mice demonstrated an exponential growth pattern as measured by changes in mean BLI Fluxmax, with increased proliferation beyond 4 weeks (Figure 2(b)). 18F-FLT-PET imaging was performed in select mice (n = 2), and intracranial 18F-FLT uptake was quantified by %ID at weeks 1 and 7, which correlated with a BLI Fluxmax, of 1 × 106 and 1 × 109, respectively. Radiotracer uptake was ~4.7x greater at 7 weeks versus 1 week (%ID 1.58 versus 0.33, resp.) (Figure 2(c)). Visually, radiotracer uptake was most appreciated in the larger intracranial tumors (7 weeks after injection). Additionally, radiotracer uptake at 7 weeks was localized to the tumor site, with minimal uptake in the surrounding normal brain tissue (Figure 2(d)). These data demonstrate that 18F-FLT concentrates preferentially within tumor and suggest that radiotracer uptake correlates with tumor size.


18F-fluorothymidine-pet imaging of glioblastoma multiforme: effects of radiation therapy on radiotracer uptake and molecular biomarker patterns.

Chandrasekaran S, Hollander A, Xu X, Benci JL, Davis JJ, Dorsey JF, Kao G - ScientificWorldJournal (2013)

Orthotopic brain tumors are readily imaged by FLT-PET. (a) Visual comparison of Bioluminescence Imaging (BLI) surface radiance (photons/sec/cm2/steradian) in orthotopic intracranial tumors with BLI Fluxmax⁡ (photons/second) values of 1 × 106 (1E + 6) and 1 × 109 (1E + 9). (b) Identification of an exponential growth pattern in intracranial tumors based on Fluxmax⁡ measurements (n = 5). (c) Comparison of %ID of intracranial 18F-FLT %ID at 1 and 7 weeks after injection. (d) Visual comparison of 18F-FLT uptake in intracranial tumors based on Fluxmax⁡ values of 1 × 106 and 1 × 109 (weeks 1 and 7, respectively). Tumor visualized at 7 weeks (yellow arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3649687&req=5

fig2: Orthotopic brain tumors are readily imaged by FLT-PET. (a) Visual comparison of Bioluminescence Imaging (BLI) surface radiance (photons/sec/cm2/steradian) in orthotopic intracranial tumors with BLI Fluxmax⁡ (photons/second) values of 1 × 106 (1E + 6) and 1 × 109 (1E + 9). (b) Identification of an exponential growth pattern in intracranial tumors based on Fluxmax⁡ measurements (n = 5). (c) Comparison of %ID of intracranial 18F-FLT %ID at 1 and 7 weeks after injection. (d) Visual comparison of 18F-FLT uptake in intracranial tumors based on Fluxmax⁡ values of 1 × 106 and 1 × 109 (weeks 1 and 7, respectively). Tumor visualized at 7 weeks (yellow arrows).
Mentions: We thus compared uptake patterns of 18F-FDG and 18F-FLT in intracranial tumors. Healthy nude/athymic mice (n = 5) were intracranially injected with U251-GFP-LUC glioma cells and underwent weekly BLI with subsequent 18F-FLT-PET imaging (Figure 2(a)). Intracranial tumor growth across all mice demonstrated an exponential growth pattern as measured by changes in mean BLI Fluxmax, with increased proliferation beyond 4 weeks (Figure 2(b)). 18F-FLT-PET imaging was performed in select mice (n = 2), and intracranial 18F-FLT uptake was quantified by %ID at weeks 1 and 7, which correlated with a BLI Fluxmax, of 1 × 106 and 1 × 109, respectively. Radiotracer uptake was ~4.7x greater at 7 weeks versus 1 week (%ID 1.58 versus 0.33, resp.) (Figure 2(c)). Visually, radiotracer uptake was most appreciated in the larger intracranial tumors (7 weeks after injection). Additionally, radiotracer uptake at 7 weeks was localized to the tumor site, with minimal uptake in the surrounding normal brain tissue (Figure 2(d)). These data demonstrate that 18F-FLT concentrates preferentially within tumor and suggest that radiotracer uptake correlates with tumor size.

Bottom Line: Conventional (18)F-FDG-PET imaging is of limited usefulness for imaging Glioblastoma Multiforme (GBM) due to high levels of glucose uptake by normal brain and the resultant signal-to-noise intensity. (18)F-Fluorothymidine (FLT) in contrast has shown promise for imaging GBM, as thymidine is taken up preferentially by proliferating cells.Results.Conclusions. (18)F-FLT-PET imaging is a promising tumor imaging modality for GBM, including assessing RT effects and biologically relevant biomarkers.

View Article: PubMed Central - PubMed

Affiliation: University of Washington School of Medicine, A-300 Health Sciences Center, Seattle, WA 98195, USA.

ABSTRACT
Introduction. PET imaging is a useful clinical tool for studying tumor progression and treatment effects. Conventional (18)F-FDG-PET imaging is of limited usefulness for imaging Glioblastoma Multiforme (GBM) due to high levels of glucose uptake by normal brain and the resultant signal-to-noise intensity. (18)F-Fluorothymidine (FLT) in contrast has shown promise for imaging GBM, as thymidine is taken up preferentially by proliferating cells. These studies were undertaken to investigate the effectiveness of (18)F-FLT-PET in a GBM mouse model, especially after radiation therapy (RT), and its correlation with useful biomarkers, including proliferation and DNA damage. Methods. Nude/athymic mice with human GBM orthografts were assessed by microPET imaging with (18)F-FDG and (18)F-FLT. Patterns of tumor PET imaging were then compared to immunohistochemistry and immunofluorescence for markers of proliferation (Ki-67), DNA damage and repair (γH2AX), hypoxia (HIF-1α), and angiogenesis (VEGF). Results. We confirmed that (18)F-FLT-PET uptake is limited in healthy mice but enhanced in the intracranial tumors. Our data further demonstrate that (18)F-FLT-PET imaging usefully reflects the inhibition of tumor by RT and correlates with changes in biomarker expression. Conclusions. (18)F-FLT-PET imaging is a promising tumor imaging modality for GBM, including assessing RT effects and biologically relevant biomarkers.

Show MeSH
Related in: MedlinePlus