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Simultaneous characterization of tumor cellularity and the Warburg effect with PET, MRI and hyperpolarized 13C-MRSI
Theranostics ( IF 12.4 ) Pub Date : 2018-09-09 , DOI: 10.7150/thno.25162
Christian Hundshammer , Miriam Braeuer , Christoph A. Müller , Adam E. Hansen , Mathias Schillmaier , Stephan Düwel , Benedikt Feuerecker , Steffen J. Glaser , Axel Haase , Wilko Weichert , Katja Steiger , Jorge Cabello , Franz Schilling , Jan-Bernd Hövener , Andreas Kjær , Stephan G. Nekolla , Markus Schwaiger

Modern oncology aims at patient-specific therapy approaches, which triggered the development of biomedical imaging techniques to synergistically address tumor biology at the cellular and molecular level. PET/MR is a new hybrid modality that allows acquisition of high-resolution anatomic images and quantification of functional and metabolic information at the same time. Key steps of the Warburg effect-one of the hallmarks of tumors-can be measured non-invasively with this emerging technique. The aim of this study was to quantify and compare simultaneously imaged augmented glucose uptake and LDH activity in a subcutaneous breast cancer model in rats (MAT-B-III) and to study the effect of varying tumor cellularity on image-derived metabolic information.

Methods: For this purpose, we established and validated a multimodal imaging workflow for a clinical PET/MR system including proton magnetic resonance (MR) imaging to acquire accurate morphologic information and diffusion-weighted imaging (DWI) to address tumor cellularity. Metabolic data were measured with dynamic [18F]FDG-PET and hyperpolarized (HP) 13C-pyruvate MR spectroscopic imaging (MRSI). We applied our workflow in a longitudinal study and analyzed the effect of growth dependent variations of cellular density on glycolytic parameters.

Results: Tumors of similar cellularity with similar apparent diffusion coefficients (ADC) showed a significant positive correlation of FDG uptake and pyruvate-to-lactate exchange. Longitudinal DWI data indicated a decreasing tumor cellularity with tumor growth, while ADCs exhibited a significant inverse correlation with PET standard uptake values (SUV). Similar but not significant trends were observed with HP-13C-MRSI, but we found that partial volume effects and point spread function artifacts are major confounders for the quantification of 13C-data when the spatial resolution is limited and major blood vessels are close to the tumor. Nevertheless, analysis of longitudinal data with varying tumor cellularity further detected a positive correlation between quantitative PET and 13C-data.

Conclusions: Our workflow allows the quantification of simultaneously acquired PET, MRSI and DWI data in rodents on a clinical PET/MR scanner. The correlations and findings suggest that a major portion of consumed glucose is metabolized by aerobic glycolysis in the investigated tumor model. Furthermore, we conclude that variations in cell density affect PET and 13C-data in a similar manner and correlations of longitudinal metabolic data appear to reflect both biochemical processes and tumor cellularity.

Keywords: PET/MR, [18F]FDG-PET, hyperpolarized 13C-MRSI, DNP, diffusion-weighted imaging, multimodal imaging, NMR, spectroscopy



中文翻译:

PET,MRI和超极化13 C-MRSI同时表征肿瘤细胞和Warburg效应

现代肿瘤学针对特定患者的治疗方法,这触发了生物医学成像技术的发展,以在细胞和分子水平上协同解决肿瘤生物学问题。PET / MR是一种新的混合模式,可以同时获取高分辨率的解剖图像并量化功能和代谢信息。沃伯格效应的关键步骤-肿瘤的标志之一-可以通过这种新兴技术无创地进行测量。这项研究的目的是量化和比较在大鼠皮下乳腺癌模型(MAT-B-III)中同时成像的增加的葡萄糖摄取和LDH活性,并研究变化的肿瘤细胞对图像衍生的代谢信息的影响。

方法:为此,我们建立并验证了用于临床PET / MR系统的多模式成像工作流程,包括质子磁共振(MR)成像以获取准确的形态学信息和弥散加权成像(DWI)以解决肿瘤细胞性。用动态[ 18 F] FDG-PET和超极化(HP)13 C-丙酮酸MR光谱成像(MRSI)测量代谢数据。我们在纵向研究中应用了我们的工作流程,并分析了细胞密度对糖酵解参数的生长依赖性变化的影响。

结果:具有相似表观扩散系数(ADC)的细胞相似的肿瘤显示FDG摄取与丙酮酸-乳酸交换显着正相关。纵向DWI数据表明,随着肿瘤的生长,肿瘤细胞数量减少,而ADC与PET标准摄取值(SUV)呈显着负相关。使用HP- 13 C-MRSI观察到相似但不明显的趋势,但是我们发现部分体积效应和点扩散函数伪像是定量分析13种的主要混杂因素当空间分辨率受限且主要血管靠近肿瘤时的C数据。尽管如此,对具有可变肿瘤细胞性的纵向数据的分析进一步检测到定量PET与13 C数据之间存在正相关。

结论:我们的工作流程允许在临床PET / MR扫描仪上对啮齿动物中同时采集的PET,MRSI和DWI数据进行定量。相关性和发现表明,在所研究的肿瘤模型中,消耗的葡萄糖的大部分通过有氧糖酵解代谢。此外,我们得出结论,细胞密度的变化以相似的方式影响PET和13 C数据,并且纵向代谢数据的相关性似乎反映了生化过程和肿瘤细胞的形成。

关键词:PET / MR,[ 18 F] FDG-PET,超极化13 C-MRSI,DNP,扩散加权成像,多峰成像,NMR,光谱

更新日期:2018-09-25
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