The Use of Longitudinal 18F-FET MicroPET Imaging to Evaluate Response to Irinotecan in Orthotopic Human Glioblastoma Multiforme Xenografts

Abstract

ObjectivesBrain tumor imaging is challenging. Although 18F-FET PET is widely used in the clinic, the value of 18F-FET MicroPET to evaluate brain tumors in xenograft has not been assessed to date. The aim of this study therefore was to evaluate the performance of in vivo 18F-FET MicroPET in detecting a treatment response in xenografts. In addition, the correlations between the 18F-FET tumor accumulation and the gene expression of Ki67 and the amino acid transporters LAT1 and LAT2 were investigated. Furthermore, Ki67, LAT1 and LAT2 gene expression in xenograft and archival patient tumors was compared.MethodsHuman GBM cells were injected orthotopically in nude mice and 18F-FET uptake was followed by weekly MicroPET/CT. When tumor take was observed, mice were treated with CPT-11 or saline weekly. After two weeks of treatment the brain tumors were isolated and quantitative polymerase chain reaction were performed on the xenograft tumors and in parallel on archival patient tumor specimens.ResultsThe relative tumor-to-brain (T/B) ratio of SUVmax was significantly lower after one week (123±6%, n = 7 vs. 147±6%, n = 7; p = 0.018) and after two weeks (142±8%, n = 5 vs. 204±27%, n = 4; p = 0.047) in the CPT-11 group compared with the control group. Strong negative correlations between SUVmax T/B ratio and LAT1 (r = −0.62, p = 0.04) and LAT2 (r = −0.67, p = 0.02) were observed. In addition, a strong positive correlation between LAT1 and Ki67 was detected in xenografts. Furthermore, a 1.6 fold higher expression of LAT1 and a 23 fold higher expression of LAT2 were observed in patient specimens compared to xenografts.Conclusions 18F-FET MicroPET can be used to detect a treatment response to CPT-11 in GBM xenografts. The strong negative correlation between SUVmax T/B ratio and LAT1/LAT2 indicates an export transport function. We suggest that 18F-FET PET may be used for detection of early treatment response in patients.

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

“…LAT1 mRNA and protein expression varies in GBM [47] and the expression of LAT1 was reported to be higher in infiltrating glioma cells than in cells located in the tumor center [46]. A strong positive correlation between LAT1 and Ki67 [48] and a correlation between high LAT1 protein expression with poor survival were demonstrated [49]. This contrasts with our analysis of the TCGA dataset, which showed a favorable outcome for high LAT1 mRNA expression.…”

Combined PET Imaging of the Inflammatory Tumor Microenvironment Identifies Margins of Unique Radiotracer Uptake

“…PET images were acquired on a high-resolution small animal PET scanner (32 module quadHIDAC, Oxford Positron Systems Ltd.) with uniform spatial resolution (<1 mm FWHM). PET data were reconstructed using one-pass list mode expectation maximization algorithm with resolution recovery (26) (7,8,10,27). After each PET acquisition, the animal bed was transferred into the computed tomography (CT) scanner (Inveon, Siemens Medical Solutions) for anatomic coregistration with the PET images using the image analysis software VINCI (Version: 4.19.0; http://www.nf.mpg.de/vinci3/; refs.…”

The impact of bevacizumab treatment on survival and quality of life in newly diagnosed glioblastoma patients

“…This would be expected to positively impact QOL due to lower corticosteroid dose and, therefore, less corticosteroid-related toxicity. 9 , 18 , 63 , 81 – 85 Moreover, the steroid-sparing effect of BVZ is associated with clinical response and improved neurological symptoms in high-grade glioma, or GBM. 84 , 86 – 88 …”