Abstracts

Rationale: DNETs are low-grade, epileptogenic tumors with low glucose metabolism on PET. Our recent studies showed accumulation of ?[¹¹C]methyl-L-tryptophan (AMT), a PET tracer for the immuno-modulatory kynurenine pathway, in epileptogenic malformations and some DNETs. In this study we used 2-deoxy-2[¹⁸F]fluoro-D-glucose (FDG) and dynamic AMT PET scanning to evaluate the relation between glucose metabolism, AMT transport and metabolism as well as clinical seizure variables in children with epileptogenic DNETs. Resected DNET specimens were also studied for the presence of L-type amino acid transporter 1 (LAT1) and indoleamine 2,3-dioxygenase (IDO; a key enzyme of the kynurenine pathway). Methods: Twelve children (age: 2.5-17.5 years) who underwent resective surgery due to epilepsy associated with a DNET were included in the study. Tumors were outlined on MRIs and tumor volumes were calculated. The same tumor regions were superimposed on co-registered FDG and AMT PET images to obtain standardized uptake values (SUVs) and SUV ratios (tumor/contralateral cortex). Furthermore, kinetic parameters of AMT uptake characterizing the tracer transport (by the volume of distribution [VD]) and metabolic rate (by the unidirectional tracer uptake [K-complex]), as well as corresponding tumor/cortex ratios were also calculated in 10 patients and correlated with seizure variables. Resected tumor specimens were immuno-stained for IDO and LAT1. Results: Tumor volumes varied from 0.8 to 51.4 cm³ (median=4.2 cm³). All tumors showed glucose hypometabolism on FDG PET scans (SUV ratio: 0.29-0.64). However, tumor AMT SUV values were above cortical values in 8/12 cases (0.87-1.44) (Figure). Two patients showed increased AMT SUV in additional ipsilateral cortical areas. Kinetic analysis of AMT PET showed increased VD ratios in 8/10 children and high K-complex ratios in 3. Age at seizure onset showed a positive association with FDG SUV of the tumors (r=0.68; p=0.016, Spearman`s correlation). Longer epilepsy duration was associated with higher AMT K-complex values in DNETs (p=0.036). Tumor volumes did not correlate with any clinical and PET variables. Nine children had seizure-free outcome, while 3 had recurrent seizures, including the two cases with preoperative cortical AMT increases in areas which were not resected. All tumor specimens showed moderate to intense IDO and LAT1 staining. Conclusions: Despite low glucose metabolic rates and variable sizes, DNETs commonly show high AMT accumulation on PET, which is mostly driven by increased tryptophan transport but also due to tryptophan metabolism. Activation of kynurenine pathway may contribute to immune-resistance of these tumors but can also produce neurotoxic/epileptogenic metabolites. Association of higher tryptophan metabolic rates with longer epilepsy duration suggests a progressive activation of this pathway providing a potential therapeutic target for these lesions. In addition, AMT PET may detect potentially epileptogenic cortex outside DNETs in some cases; this may help optimize surgical resection to facilitate seizure-free outcome.