Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine in patients with gliomas

Mark Muzi, Alexander M. Spence, Finbarr O'Sullivan, David A. Mankoff, Joanne M. Wells, John R. Grierson, Jeanne Link, Kenneth Krohn

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

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 (KFLT). 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 KFLT were produced by a mixture analysis approach. Results: Similar to prior work with 11C-thymidine, identifiability analysis showed that K1 (transport) and KFLT (flux) could be estimated independently for sufficiently high K1 values. However, estimation of KFLT 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 KFLT 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 KFLT. 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 KFLT 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.

Original languageEnglish (US)
Pages (from-to)1612-1621
Number of pages10
JournalJournal of Nuclear Medicine
Volume47
Issue number10
StatePublished - Oct 1 2006
Externally publishedYes

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Glioma
Neoplasms
Blood-Brain Barrier
Gadolinium
Thymidine
Cell Proliferation
alovudine
Biosynthetic Pathways
Brain
Brain Neoplasms
Disease Progression
Permeability
Phosphorylation

Keywords

  • 3′-deoxy-3′-fluorothymidine
  • Blood-brain barrier disruption
  • Glioma
  • Kinetic modeling
  • Thymidine kinase 1

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Muzi, M., Spence, A. M., O'Sullivan, F., Mankoff, D. A., Wells, J. M., Grierson, J. R., ... Krohn, K. (2006). Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine in patients with gliomas. Journal of Nuclear Medicine, 47(10), 1612-1621.

Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine in patients with gliomas. / Muzi, Mark; Spence, Alexander M.; O'Sullivan, Finbarr; Mankoff, David A.; Wells, Joanne M.; Grierson, John R.; Link, Jeanne; Krohn, Kenneth.

In: Journal of Nuclear Medicine, Vol. 47, No. 10, 01.10.2006, p. 1612-1621.

Research output: Contribution to journalArticle

Muzi, M, Spence, AM, O'Sullivan, F, Mankoff, DA, Wells, JM, Grierson, JR, Link, J & Krohn, K 2006, 'Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine in patients with gliomas', Journal of Nuclear Medicine, vol. 47, no. 10, pp. 1612-1621.
Muzi M, Spence AM, O'Sullivan F, Mankoff DA, Wells JM, Grierson JR et al. Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine in patients with gliomas. Journal of Nuclear Medicine. 2006 Oct 1;47(10):1612-1621.
Muzi, Mark ; Spence, Alexander M. ; O'Sullivan, Finbarr ; Mankoff, David A. ; Wells, Joanne M. ; Grierson, John R. ; Link, Jeanne ; Krohn, Kenneth. / Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine in patients with gliomas. In: Journal of Nuclear Medicine. 2006 ; Vol. 47, No. 10. pp. 1612-1621.
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abstract = "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 (KFLT). 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 KFLT were produced by a mixture analysis approach. Results: Similar to prior work with 11C-thymidine, identifiability analysis showed that K1 (transport) and KFLT (flux) could be estimated independently for sufficiently high K1 values. However, estimation of KFLT 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 KFLT 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 KFLT. 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 KFLT 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.",
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AU - Muzi, Mark

AU - Spence, Alexander M.

AU - O'Sullivan, Finbarr

AU - Mankoff, David A.

AU - Wells, Joanne M.

AU - Grierson, John R.

AU - Link, Jeanne

AU - Krohn, Kenneth

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N2 - 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 (KFLT). 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 KFLT were produced by a mixture analysis approach. Results: Similar to prior work with 11C-thymidine, identifiability analysis showed that K1 (transport) and KFLT (flux) could be estimated independently for sufficiently high K1 values. However, estimation of KFLT 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 KFLT 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 KFLT. 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 KFLT 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.

AB - 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 (KFLT). 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 KFLT were produced by a mixture analysis approach. Results: Similar to prior work with 11C-thymidine, identifiability analysis showed that K1 (transport) and KFLT (flux) could be estimated independently for sufficiently high K1 values. However, estimation of KFLT 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 KFLT 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 KFLT. 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 KFLT 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.

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