NI-6 Preoperative differential diagnosis of grade II and grade III in cases with astrocytoma, IDH mutant

Purpose: We attempted to differentiate between IDH-mutant astrocytoma Grade II and grade III by using methionine (MET) positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). Subjects and Methods: We retrospectively analyzed 41 adult supratentorial glioma cases with confirmed histological diagnosis and IDH status from June 2015 to June 2020. These included 21 males, with an average age of 38.5 years (19–59 years), including seven astrocytoma grade II (A-II) and 34 grade III (A-III) cases. We determined the accumulation value rate of the maximum tumor to normal cortex accumulation value (T/N ratio) in MET-PET. We obtained the peak ratios of N-acetyl aspartate (NAA)/ creatine (Cr), choline (Cho)/Cr, and Cho/NAA. We investigated the correlation between the T/N ratios and MRS parameters and examined the contrast effects on MRI. Results: There were no significant differences in the T/N ratio and MRS parameters between A-IIs and A-IIIs. Only Cho/NAA ratios were significantly correlated with the T/N ratios (r = 0.443, P = 0.0037). We divided the distribution map into four areas with the highest T/N ratio of AII (1.59) and the highest Cho/NAA ratio (3.66). That is, 1) T/N ratio ≤ 1.59 & Cho/NAA ≤ 3.66, 2) >1.59 & ≤ 3.66, 3) ≤1.59 & > 3.66, 4) &gt 1.59 & &gt 3.66. The diagnostic rates for A-III were 1) 61.1% (11/18), 2) 100% (7/7), 3) 100% (9/9), and 4) 100% (7/7). We found the contrast effects in only 7 cases (20.6%) of A-III, which were distributed in areas 2) to 4). Conclusion: A-IIs and A-IIIs distributed in area 1) were difficult to distinguish, and they need careful observation as a step before the transition to areas 2)-4). Meanwhile, A-IIIs reaching widespread distribution to areas 2)-4) because of their wide range of malignancies require clinically aggressive treatment. The method might be beneficial in grade analysis of IDH-mutant astrocytomas.

DDRE-28. MECHANISTIC AND THERAPEUTIC LINKS BETWEEN PURINE BIOSYNTHESIS AND DNA DAMAGE IN GLIOBLASTOMA

Glioblastoma (GBM) is the most common and aggressive adult brain cancer. Radiation therapy (RT) is a critical treatment modality, and development of RT resistance is the predominant cause of recurrence and mortality in GBM patients. Using cell line models as well as patient-derived xenografts and neurospheres in orthotopic brain tumor models, we have identified increased rates and dependence upon de novo purine biosynthesis as a hallmark of GBM RT resistance. More recently, we have discovered that radiation treatment acutely stimulates flux through de novo purine synthesis in cell line and neurosphere models of GBM. This RT-induced increase in de novo purine synthesis is dependent on signaling through the DNA damage response and thus appears to be an adaptive mechanism to supply purines to repair radiation-induced DNA damage. To determine whether this regulatory mechanism also exists in vivo, we have used advanced metabolomic and metabolic tracing techniques with 13C-labeled glucose and 15N-labeled glutamine in mice bearing RT-resistant GBM patient-derived orthotopic brain tumors. We found that that orthotopic GBM PDXs had elevated activity of de novo purine synthesis that increased further after RT, while normal cortex had little activity even after RT. These observations have therapeutic relevance, as targeting this metabolic pathway with the FDA-approved purine biosynthesis inhibitor mycophenolate mofetil (MMF) overcomes GBM radiation resistance in mouse models in vivo. The lack of de novo purine synthesis in normal cortex suggests that targeting this pathway may be tumor specific. Collectively our data suggest that de novo synthesis of purines mediates RT resistance in GBM and that treatment of brain tumors with MMF in combination with RT may be a promising therapeutic strategy in patients.

Glucose Loading Enhances the Value of 18F-FDG PET/CT for the Characterization and Delineation of Cerebral Gliomas

This study aimed to assess how to enhance the value of 18F-Fluorodeoxyglucose (FDG) PET/CTs for glioma grading and better delineation of the tumor boundary by glucose loading. In mouse models of brain tumor using U87MG cells, 18F-FDG-PET images were obtained after fasting and after glucose loading. There was a significant difference in the tumor-to-normal cortex-uptake ratio (TNR) between the fasting and glucose-loading scans. 14C-2-Deoxy-D-glucose (14C-DG) uptake was measured in vitro using U87MG, U373MG and primary neurons cultured with different concentrations of glucose. The tumor-to-neuron ratio of 14C-DG uptake increased with up to 10 mM of glucose. Finally, 10 low-grade and 17 high-grade glioma patients underwent fasting and glucose loading 18F-FDG PET/CT and the TNR was compared between scans. The effect of glucose loading was significant in high-grade but not in low-grade gliomas. The receiver operating characteristic curve analyses with a cut-off TNR of 0.81 showed a higher area under the curve after glucose loading than fasting for differentiating low-grade versus high-grade gliomas. In addition, the glucose loading PET/CT was more useful than the fasting PET/CT for the discrimination of oligodendrogliomas from IDH-wildtype glioblastomas. Glucose loading resulted in a greater reduction in 18F-FDG uptake in the normal cortex than in tumors, which increases the usefulness of 18F-FDG PET/CT for grading.

Defining the phenotypical spectrum associated with variants in TUBB2A

BackgroundVariants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis.MethodsIn order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed.ResultsWe report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy.ConclusionThe imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype–phenotype correlations could be established, suggesting the role of additional modifiers.

Arterial spin labeling magnetic resonance imaging: toward noninvasive diagnosis and follow-up of pediatric brain arteriovenous malformations

OBJECT Arterial spin labeling (ASL)-MRI is becoming a routinely used sequence for ischemic strokes, as it quantifies cerebral blood flow (CBF) without the need for contrast injection. As brain arteriovenous malformations (AVMs) are highflow vascular abnormalities, increased CBF can be identified inside the nidus or draining veins. The authors aimed to analyze the relevance of ASL-MRI in the diagnosis and follow-up of children with brain AVM. METHODS The authors performed a retrospective analysis of 21 patients who had undergone digital subtraction angiography (DSA) and pseudo-continuous ASL-MRI for the diagnosis or follow-up of brain AVM after radiosurgery or embolization. They compared the AVM nidus location between ASL-MRI and 3D contrast-enhanced T1 MRI, as well as the CBF values obtained in the nidus (CBFnidus) and the normal cortex (CBFcortex) before and after treatment. RESULTS The ASL-MRI correctly demonstrated the nidus location in all cases. Nidal perfusion (mean CBFnidus 137.7 ml/100 mg/min) was significantly higher than perfusion in the contralateral normal cortex (mean CBFcortex 58.6 ml/100 mg/min; p < 0.0001, Mann-Whitney test). Among 3 patients followed up after embolization, a reduction in both AVM size and CBF values was noted. Among 5 patients followed up after radiosurgery, a reduction in the nidus size was observed, whereas CBFnidus remained higher than CBFcortex. CONCLUSIONS In this study, ASL-MRI revealed nidus location and patency after treatment thanks to its ability to demonstrate focal increased CBF values. Absolute quantification of CBF values could be relevant in the follow-up of pediatric brain AVM after partial treatment, although this must be confirmed in larger prospective trials.

The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation

We show that the splicing regulator PTBP2 controls a genetic program essential for neuronal maturation. Depletion of PTBP2 in developing mouse cortex leads to degeneration of these tissues over the first three postnatal weeks, a time when the normal cortex expands and develops mature circuits. Cultured Ptbp2−/− neurons exhibit the same initial viability as wild type, with proper neurite outgrowth and marker expression. However, these mutant cells subsequently fail to mature and die after a week in culture. Transcriptome-wide analyses identify many exons that share a pattern of mis-regulation in the mutant brains, where isoforms normally found in adults are precociously expressed in the developing embryo. These transcripts encode proteins affecting neurite growth, pre- and post-synaptic assembly, and synaptic transmission. Our results define a new genetic regulatory program, where PTBP2 acts to temporarily repress expression of adult protein isoforms until the final maturation of the neuron.