Kinetic analysis of 3'-deoxy-3'-18F-fluorothymidine in patients with gliomas.
Kinetic analysis of 3'-deoxy-3'-18F-fluorothymidine in patients with gliomas.
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发表时间：
2006-10
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通讯作者：
M. Muzi;A. Spence;F. O’Sullivan;D. Mankoff;J. Wells;J. Grierson;J. Link;K. Krohn
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作者：
M. Muzi;A. Spence;F. O’Sullivan;D. Mankoff;J. Wells;J. Grierson;J. Link;K. Krohn
未标记的3 '-脱氧-3'-氟胸苷（FLT）是一种胸苷类似物，目前正在研究用于监测神经胶质瘤中的细胞增殖，这是一种潜在的疾病进展和治疗反应指标。摄取可能是由于生物合成途径中的滞留或通过破坏的血液-肿瘤屏障的泄漏。18F-FLT摄取的视觉分析或静态测量是有问题的，因为无法区分转运和保留。方法对12例原发性脑肿瘤患者进行90 min动态18F-FLT PET显像，并采集动脉血。校正标记代谢物的总血液活性，以提供FLT输入函数。采用2-组织室、4-速率常数模型测定血液-组织转运（K1）和代谢通量（K（FLT））。建模结果与钆（Gd）对比增强显示的血脑屏障（BBB）破裂的MR图像进行了比较。K1和K（FLT）的参数图像映射由混合物分析方法产生。结果与先前使用11 C-胸苷的工作相似，可鉴别性分析表明，对于足够高的K1值，可以独立估计K1（转运）和K（FLT）（通量）。然而，K（FLT）的估计在低K1值时不太稳健，特别是接近正常大脑的K1值。MRI对比增强（CE）肿瘤的K1较高（0.053 +/- 0.029 mL/g/min）比非对比增强（NCE）肿瘤（0.005 +/- 0.002 mL/g/min;高级别肿瘤的K（FLT）（0.018 +/- 0.008 mL/g/min，n = 9）高于低级别肿瘤（0.003 +/- 0.003 mL/g/min，n = 3; P < 0.01）。NCE肿瘤中的通量与对侧正常脑（0.002 +/-0.001 mL/g/min）不可区分。对于CE肿瘤，K1高于K（FLT）。参数图像匹配的区域感兴趣的运输和流量的估计。然而，没有患者的18F-FLT摄取超出MRI T1+Gd增强定义的渗透性增加的体积。结论对18F-FLT PET数据进行建模分析，获得了K1和K（FLT）的稳健估计，以增强具有足够高K1的肿瘤，并提供了更清晰的理解，18F-FLT在胶质瘤中的转运和保留之间的关系。在显示BBB破裂的肿瘤中，转运主导18F-FLT摄取。通过BBB的转运和18 F-FLT磷酸化的适度速率似乎限制了使用18 F-FLT对具有显著BBB破坏的高度增殖性肿瘤的细胞增殖的评估。
UNLABELLED 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.