胶质瘤患者中3'-脱氧-3'-18F-氟胸苷的动力学分析。
Kinetic analysis of 3'-deoxy-3'-18F-fluorothymidine in patients with gliomas.
作者信息
Muzi Mark, Spence Alexander M, O'Sullivan Finbarr, Mankoff David A, Wells Joanne M, Grierson John R, Link Jeanne M, Krohn Kenneth A
机构信息
Department of Radiology, University of Washington, Seattle, Washington 98195-6004, USA.
出版信息
J Nucl Med. 2006 Oct;47(10):1612-21.
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.
未标记
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，这是疾病进展和治疗反应的一种潜在指标。摄取可能是由于在生物合成途径中的滞留或通过受损的血脑屏障泄漏所致。18F-FLT摄取的视觉分析或静态测量存在问题，因为无法区分转运和滞留。
方法
对12例原发性脑肿瘤患者进行了90分钟的动态18F-FLT PET成像，并采集动脉血样。对总血活度进行标记代谢物校正，以提供FLT输入函数。使用双组织室、四速率常数模型来确定血-组织转运（K1）和代谢通量（K(FLT)）。将建模结果与钆（Gd）对比增强显示的血脑屏障（BBB）破坏的磁共振图像进行比较。通过混合分析方法生成K1和K(FLT)的参数图像。
结果
与先前使用11C-胸苷的研究相似，可识别性分析表明，对于足够高的K1值，可以独立估计K1（转运）和K(FLT)（通量）。然而，在低K1值时，尤其是接近正常脑的K1值时，K(FLT)的估计不太可靠。MRI对比增强（CE）肿瘤的K1（0.053±0.029 mL/g/min）高于非对比增强（NCE）肿瘤（0.005±0.002 mL/g/min；P<0.02），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）无法区分。对于CE肿瘤，K1高于K(FLT)。参数图像与感兴趣区域的转运和通量估计值相符。然而，没有患者的18F-FLT摄取超出MRI T1+Gd增强定义的通透性增加区域。
结论
对18F-FLT PET数据进行建模分析，对于K1足够高的增强肿瘤，能够可靠地估计K1和K(FLT)，并更清楚地了解18F-FLT在神经胶质瘤中的转运和滞留之间的关系。在显示BBB破坏的肿瘤中，转运主导18F-FLT摄取。穿过BBB的转运和适度的18F-FLT磷酸化速率似乎限制了使用18F-FLT对细胞增殖的评估，仅限于具有显著BBB破坏的高增殖性肿瘤。
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