Treatment-Related Uptake of O-(2-¹⁸F-Fluoroethyl)-l-Tyrosine and l-[Methyl-³H]-Methionine After Tumor Resection in Rat Glioma Models

Abstract

Assessment of residual tumor after resection of cerebral gliomas can be difficult with MRI and may be improved by amino acid PET. The aim of this experimental study was to investigate uptake of 2-18 F-fluoroethyl-L-tyrosine (18 F-FET) and L-[methyl-3 H]-methionine (3 H-MET) in residual tumor after surgery and possible false-positive uptake in treatment-related changes. Methods: F98 or GS-9L rat gliomas were implanted into the brain of 64 rats. Tumors were resected after 1 wk of tumor growth, and sham surgery was performed in an additional 10 animals. At different time points after surgery (1, 2, 3, 7, and 14-16 d), rats underwent ex vivo dual-tracer autoradiography using 18 F-FET and 3 H-MET. Histologic slices were evaluated by immunostaining for cell density and astrogliosis. Tracer uptake was quantified by lesion-to-brain ratios (L/B) at the rim of the resection cavity (considered treatment-related uptake) and in residual or recurrent tumor tissue. Four animals showing no residual tumor underwent PET 3 d after surgery to examine timeactivity curves of 18 F-FET uptake in treatment-related changes. Results: Treatment-related uptake with a mean L/B of 2.0 ± 0.3 for 18 F-FET and a mean L/B of 1.7 ± 0.2 for 3 H-MET was noted at the rim of the resection cavity in the first week after surgery, decreasing significantly by 14-16 d (P , 0.01). Treatment-related tracer uptake was significantly higher for 18 F-FET than for 3 H-MET (P , 0.001). Tracer uptake in rat gliomas exceeded treatment-related tracer uptake at all time points (P , 0.001), but the latter was in the range of human gliomas. Reactive astrogliosis was noted near the resection cavity from the second day after surgery. Time-activity curves of 18 F-FET uptake in those areas revealed constantly increasing uptake. Conclusion: Surgery may induce significant treatment-related 18 F-FET and 3 H-MET uptake near the resection cavity in the first week after surgery, presumably caused by reactive astrogliosis. Treatment-related tracer uptake was less pronounced for 3 H-MET, indicating that 11 C-MET may be better suited for assessing the postoperative situation than 18 F-FET. Assessment of residual tumor after surgery by amino acid PET seems to be more reliable after an interval of 14 d.

Flare Phenomenon in O-(2-18F-Fluoroethyl)-l-Tyrosine PET After Resection of Gliomas

“…Firstly, the flare phenomenon might be caused by reactive astrocytosis. This explanation appears unlikely, because in previous animal studies 18 F-FET uptake in areas of reactive astrocytosis around the resection cavity was only moderately increased and not as pronounced as in the flare areas, which often occurred in remote regions (13). Another explanation may be a rapid tumor progression, which is not unusual in glioblastoma, but as the flare phenomenon occurred also in two cases of oligodendroglioma, this explanation also seems implausible.…”

“…In a recent experimental study with rat gliomas, we observed increased 18 F-FET uptake at the rim of the resection cavity within the first two weeks following glioma resection, especially in the first few days after surgery (13). Since this uptake decreased in the second week after surgery, it was recommended that 18 F-FET PET should be performed later than two weeks after resection.…”

“…Histopathological diagnosis was based on the World Health Organization (WHO) classification of 2007 since no molecular markers were available for the older cases (14). A further subdivision of the patients was made concerning the time interval of 18 F-FET PET investigation after surgery ( Fig.1), according to our previous study (13). Group A (n=23) had the second 18 F-FET PET within 5-14 days following tumor resection and group B was within 15-28 days (n=20).…”

Advantages and limitations of amino acid PET for tracking therapy response in glioma patients

“…In an experimental study with rat gliomas, we observed increased FET uptake at the rim of the resection cavity within the first two weeks following glioma resection, especially in the first few days after surgery [50]. Since this uptake decreased in the second week after surgery, it was recommended that FET PET should be performed later than two weeks after resection.…”

Ferroptosis in Glioma Immune Microenvironment: Opportunity and Challenge

“…demonstrated that methionine deprivation can reset numerous immune pathways such as macrophages, T cell activation pathways in glioma ( 48 ), as cystine and methionine are all in methionine cycle ( 49 ), and there should be cystine/methionine-ferroptosis-immunity related pathways. Simultaneously, glioma cells can selectively uptake methionine, cysteine, and serine ( 47 , 50 , 51 ), so other cells will uptake or store less of these amino acids than glioma cells, which limits the production of cysteine and GSH. It remains to be determined whether it would induce other cells to include immune cells more sensitive to ferroptosis than glioma cells and whether DNA/RNA methylation is vital for glioma escape ferroptosis, as methionine is the major methyl donor ( 52 , 53 ).…”