Scarpelli Matthew L, Healey Debbie R, Mehta Shwetal, Quarles C Chad
School of Health Sciences, Purdue University, West Lafayette, IN, United States.
Barrow Neuroimaging Innovation Center, Barrow Neurological Institute, Phoenix, AZ, United States.
Front Oncol. 2022 Jan 31;12:829050. doi: 10.3389/fonc.2022.829050. eCollection 2022.
Conventional methods of imaging brain tumors fail to assess metabolically active tumor regions, which limits their capabilities for tumor detection, localization, and response assessment. Positron emission tomography (PET) with F-fluciclovine (fluciclovine) provides regional assessment of amino acid uptake in tumors that could overcome some of the limitations of conventional imaging. However, the biological basis of enhanced fluciclovine uptake is insufficiently characterized in brain tumors, which confounds clinical interpretation and application. This study sought to address this gap by correlating multiple biologic quantities with fluciclovine PET uptake across a range of human glioblastoma xenograft models.
Thirty-one rats underwent orthotopic implantations with one of five different human glioblastoma cell lines. After tumors were established, fluciclovine PET and magnetic resonance imaging (MRI) scans were performed. The fluciclovine tumor-to-normal-brain (TN) uptake ratio was used to quantify fluciclovine uptake. MRI scans were used to assess tumor volume and gadolinium enhancement status. Histologic assessments quantified tumor cell proliferation, tumor cell density, and tumor cell amino acid transporters (LAT1 and ASCT2). Multivariate linear regression models related fluciclovine uptake with the other measured quantities.
Within the multivariate regression, the fluciclovine TN uptake ratio (measured 15 to 35 minutes after fluciclovine injection) was most strongly associated with tumor ASCT2 levels (β=0.64; P=0.001). The fluciclovine TN uptake ratio was also significantly associated with tumor volume (β=0.45; P=0.001) and tumor enhancement status (β=0.40; P=0.01). Tumor cell proliferation, tumor cell density, and LAT1 levels were not significantly associated with fluciclovine uptake in any of the multivariate models. In general, both enhancing and non-enhancing tumors could be visualized on fluciclovine PET images, with the median TN uptake ratio across the five tumor lines being 2.4 (range 1.1 to 8.9).
Increased fluciclovine PET uptake was associated with increased levels of the amino acid transporter ASCT2, suggesting fluciclovine PET may be useful for assessing brain tumor amino acid metabolism. Fluciclovine PET uptake was elevated in both enhancing and non-enhancing tumors but the degree of uptake was greater in larger tumors and tumors with enhancement, indicating these variables could confound fluciclovine metabolic measurements if not accounted for.
传统的脑肿瘤成像方法无法评估代谢活跃的肿瘤区域，这限制了它们在肿瘤检测、定位和反应评估方面的能力。使用F-氟代氯代脱氧葡萄糖（氟代氯代脱氧葡萄糖）的正电子发射断层扫描（PET）可对肿瘤中的氨基酸摄取进行区域评估，这可能克服传统成像的一些局限性。然而，在脑肿瘤中，氟代氯代脱氧葡萄糖摄取增加的生物学基础尚未得到充分表征，这使得临床解释和应用变得复杂。本研究试图通过在一系列人胶质母细胞瘤异种移植模型中，将多种生物学量与氟代氯代脱氧葡萄糖PET摄取相关联，来填补这一空白。
31只大鼠接受了五种不同人胶质母细胞瘤细胞系之一的原位植入。肿瘤形成后，进行氟代氯代脱氧葡萄糖PET和磁共振成像（MRI）扫描。氟代氯代脱氧葡萄糖肿瘤与正常脑（TN）摄取比用于量化氟代氯代脱氧葡萄糖摄取。MRI扫描用于评估肿瘤体积和钆增强状态。组织学评估量化肿瘤细胞增殖、肿瘤细胞密度和肿瘤细胞氨基酸转运体（LAT1和ASCT2）。多变量线性回归模型将氟代氯代脱氧葡萄糖摄取与其他测量量相关联。
在多变量回归中，氟代氯代脱氧葡萄糖TN摄取比（在注射氟代氯代脱氧葡萄糖后15至35分钟测量）与肿瘤ASCT2水平相关性最强（β=0.64；P=0.001）。氟代氯代脱氧葡萄糖TN摄取比也与肿瘤体积（β=0.45；P=0.001）和肿瘤增强状态（β=0.40；P=0.01）显著相关。在任何多变量模型中，肿瘤细胞增殖、肿瘤细胞密度和LAT1水平与氟代氯代脱氧葡萄糖摄取均无显著相关性。一般来说，增强和未增强的肿瘤在氟代氯代脱氧葡萄糖PET图像上均可显示，五种肿瘤细胞系的TN摄取比中位数为2.4（范围1.1至8.9）。
氟代氯代脱氧葡萄糖PET摄取增加与氨基酸转运体ASCT2水平升高相关，提示氟代氯代脱氧葡萄糖PET可能有助于评估脑肿瘤氨基酸代谢。增强和未增强的肿瘤中氟代氯代脱氧葡萄糖PET摄取均升高，但摄取程度在较大肿瘤和有增强的肿瘤中更高，表明如果不考虑这些变量，可能会混淆氟代氯代脱氧葡萄糖代谢测量结果。
