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Kinetic Analysis of 3'-Deoxy-3'-¹⁸F-Fluorothymidine in Patients with Gliomas

¹ Department of Radiology, University of Washington, Seattle, Washington; ² Department of Neurology, University of Washington, Seattle, Washington; and ³ Department of Statistics, University College Cork, Cork, Ireland

Correspondence: For correspondence or reprints contact: Mark Muzi, MS, University of Washington–Radiology, Box 356004, 1959 N.E. Pacific St., Seattle, WA 98195-6004. E-mail: muzi{at}u.washington.edu

3'-Deoxy-3'-fluorothymidine (FLT), a thymidine analog, is under investigation for monitoring cellular proliferation in gliomas, a potential measure of disease progression and response to therapy. Uptake may result from retention in the biosynthetic pathway or leakage via the disrupted blood–tumor barrier. Visual analysis or static measures of ¹⁸F-FLT uptake are problematic as transport and retention cannot be distinguished. Methods: Twelve patients with primary brain tumors were imaged for 90 min of dynamic ¹⁸F-FLT PET with arterial blood sampling. Total blood activity was corrected for labeled metabolites to provide an FLT input function. A 2-tissue compartment, 4-rate-constant model was used to determine blood-to-tissue transport (K₁) and metabolic flux (K_FLT). Modeling results were compared with MR images of blood–brain barrier (BBB) breakdown revealed by gadolinium (Gd) contrast enhancement. Parametric image maps of K₁ and K_FLT were produced by a mixture analysis approach. Results: Similar to prior work with ¹¹C-thymidine, identifiability analysis showed that K₁ (transport) and K_FLT (flux) could be estimated independently for sufficiently high K₁ values. However, estimation of K_FLT was less robust at low K₁ values, particularly those close to normal brain. K₁ was higher for MRI contrast-enhancing (CE) tumors (0.053 ± 0.029 mL/g/min) than noncontrast-enhancing (NCE) tumors (0.005 ± 0.002 mL/g/min; P < 0.02), and K_FLT was higher for high-grade tumors (0.018 ± 0.008 mL/g/min, n = 9) than low-grade tumors (0.003 ± 0.003 mL/g/min, n = 3; P < 0.01). The flux in NCE tumors was indistinguishable from contralateral normal brain (0.002 ± 0.001 mL/g/min). For CE tumors, K₁ was higher than K_FLT. Parametric images matched region-of-interest estimates of transport and flux. However, no patient has ¹⁸F-FLT uptake outside of the volume of increased permeability defined by MRI T1+Gd enhancement. Conclusion: Modeling analysis of ¹⁸F-FLT PET data yielded robust estimates of K₁ and K_FLT for enhancing tumors with sufficiently high K₁ and provides a clearer understanding of the relationship between transport and retention of ¹⁸F-FLT in gliomas. In tumors that show breakdown of the BBB, transport dominates ¹⁸F-FLT uptake. Transport across the BBB and modest rates of ¹⁸F-FLT phosphorylation appear to limit the assessment of cellular proliferation using ¹⁸F-FLT to highly proliferative tumors with significant BBB breakdown.

Key Words: 3'-deoxy-3'-fluorothymidine • kinetic modeling • glioma • blood–brain barrier disruption • thymidine kinase 1

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