NI-10 Reclassification of diffuse gliomas based on molecular diagnosis -evaluation of methionine uptake and treatment outcome-

Object: The revised 2016 WHO Classification of Tumours of the Central Nervous System incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. In this study, we reclassified diffuse gliomas with molecular diagnosis and examined for 11C-methionine uptake and prognosis. Methods. 182 diffuse glioma patients (Grade II in 42 patients, Grade III in 61 patients, Grade IV in 77 patients) treated at Tokyo Medical and Dental University Hospital from 2000 to 2018 were included in this study. The IDH1/2, ATRX and 1p19q status were analyzed using tumor samples. The tumor-to-normal ratio (T/N) of 11 C-methionine uptake was calculated by dividing the mean standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. Result. By molecular diagnosis, 11 diffuse astrocytomas and 17 anaplastic astrocytomas were diagnosed as “IDH-mutant”, while 14 diffuse astrocytomas and 29 anaplastic astrocytomas were diagnosed as “IDH-wild”. 5 out of 77 grade IV tumors had IDH mutation. 4 tumors were diagnosed as “Diffuse midline glioma, H3 K27M-mutant”. In the 32 oligodendroglial tumors, 12 oligodendrogliomas and 9 anaplastic oligodendrogliomas were diagnosed as “IDH-mutant and 1p/19q-codeleted”. The median T/N ratios in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” were significantly higher than those in astrocytic tumors with “IDH-mutant”. On the other hand, in tumors with the same genetic background, higher grade tumor has significant higher T/N ratio. Kaplan-Meier survival analysis revealed that oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” had significantly better outcomes regardless of WHO grade. Overall survival was 90.9% at 5 years and 77.9% at 10 years in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted”. IDH wild tumors had significantly worse outcomes.Conclusions. The results indicated that diffuse glioma categories reclassified with molecular classification correlate with the T/N ratio of methionine and the prognosis.

NI-8 Molecular diagnostic prediction combining T2-FLAIR mismatch sign, calcification, and methionine PET in grade II and III gliomas

Background: The 2016 WHO Classification classified grade II and III gliomas into three molecular subtypes depending on the presence of IDH mutation and 1p/19q codeletion. We combined T2-FLAIR mismatch sign, tumor calcification, and methionine PET uptake to examine whether molecular diagnosis could be predicted. Methods: 53 grade II and III glioma patients with preoperative MRI, CT, and MET-PET who underwent surgical resection or biopsy during 2000–2019 were included in this study. Out of the 53 cases, astrocytic tumors (A group: IDH-mutant, 1p19q non-codeleted) were 17, oligodendroglial tumors (O group: IDH-mutant, 1p19q codeleted) were 15, and IDH wild tumors (W group) were 21. MR and CT scans were evaluated by 3 independent reviewers to assess presence/absence of T2-FLAIR mismatch sign and calcification in the tumor, respectively. The tumor-to-normal (T/N) ratio of methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. Results: Out of the 53 cases, T2-FLAIR mismatch sign was present in 6 cases in group A and 9 cases in group W (p=0.008). Calcification in tumor was present in 2 cases in group A, 7 cases in group O, and 3 cases in group W (p=0.046). In the T2-FLAIR mismatch-positive cases, assuming MET-PET T/N>1.401 was group W and <1.401 was group A, sensitivity was 100% and specificity was 67%. In the T2-FLAIR mismatch-negative and calcification-positive cases, assuming those group O, the diagnostic predictive value was 70%. In the T2-FLAIR mismatch-negative and calcification-negative cases, assuming MET-PET T/N>2.349 was group W and <2.349 was group A or O, sensitivity was 60% and specificity was 94%. Conclusions: Combined diagnostic prediction of T2-FLAIR mismatch, calcification, and MET-PET T/N may be useful for preoperative molecular diagnosis of grade II and III gliomas.

NI-14 estimation of property of MRI non-contrast enhanced lesion of Glioblastoma using T1/T2 ratio

Background: Tumor mass of glioblastoma is considered to exist beyond gadolinium-enhancing lesion into T2/FLAIR-high intensity lesions (T2/FL-HIL) on MRI. However, it is challenging to differentiate non-enhancing tumor region (NET) from pure brain edema for T2/FL-HIL. The T1/T2 ratio (rT1/T2) is an MRI metric considered to semi-quantify the tissue relaxation time on MRI. This research tested the hypothesis that rT1/T2 is useful for identifying NET within T2/FL-HIL by comparing it with 11C-methionine positron emission tomography (MET-PET). Method: Forty-six glioblastoma (GBM) patients at Osaka International Cancer Institute and Osaka University Hospital where T1-, T2- and contrast-enhanced T1-weighted MRI and MET-PET were available were included in this study. rT1/T2 maps were obtained after signal corrections were performed, as reported previously. Region-of-interests (ROIs) were defined within T2/FL-HILs beyond the gadolinium-enhanced lesion. MET-PET and rT1/T2 maps were co-registered to the same coordinate system, and the relationship between methionine uptake and rT1/T2 values was examined in a voxel-wise manner.ResultApproximately three million voxels were included for analysis. Lesions with methionine uptake higher than 5.0 on T/N showed 0.7 &lt rT1/T2 &lt 0.98. For those with methionine uptake higher than 3.0, rT1/T2 was between 0.70 and 1.04.DiscussionThis report suggested that rT1/T2 represents histological characteristics of the glioblastoma within T2/FL-HIL. It also indicated that rT1/T2 could be a useful biomarker for detecting NET within T2/FL-HIL for glioblastoma.

Ventricle contact may be associated with higher 11C methionine PET uptake in glioblastoma

Purpose Ventricle contact is associated with a worse prognosis and more aggressive tumor characteristics in glioblastoma (GBM). This is hypothesized to be a result of neural stem cells located around the lateral ventricles, in the subventricular zone. 11C Methionine positron emission tomography (metPET) is an indicator for increased proliferation, as it shows uptake of methionine, an amino acid needed for protein synthesis. This study is the first to study metPET characteristics of GBM in relation to ventricle contact. Methods A total of 12 patients with IDH wild-type GBM were included. Using MRI, the following regions were determined: primary tumor (defined as contrast enhancing lesion on T1) and peritumoral edema (defined as edema visible on FLAIR excluding the enhancement). PET parameters in these areas were extracted using PET fused with MRI imaging. Parameters extracted from the PET included maximum and mean tumor-to-normal ratio (TNRmax and TNRmean) and metabolic tumor volume (MTV). Results TNRmean of the primary tumor showed significantly higher values for the ventricle-contacting group compared to that for the non-contacting group (4.44 vs 2.67, p = 0.030). Other metPET parameters suggested higher values for the ventricle-contacting group, but these differences did not reach statistical significance. Conclusion GBM with ventricle contact demonstrated a higher methionine uptake and might thus have increased proliferation compared with GBM without ventricle contact. This might explain survival differences and should be considered in treatment decisions.

Role of 11C Methionine Positron Emission Tomography (11CMETPET) for Surgery and Radiation Therapy Planning in Newly Diagnosed Glioblastoma Patients Enrolled into a Phase II Clinical Study

(1) Background: We investigated the role of [11C]-methionine PET in a cohort of newly diagnosed glioblastoma multiforme (GBM) patients to evaluate whether it could modify the extent of surgical resection and improve radiation therapy volume delineation. (2) Methods: Newly diagnosed GBM patients, ages 18–70, with a Karnofsky performance scale (KPS) ≥ 70 with available MRI and [11C]-methionine PET were included. Patients were treated with different amounts of surgical resection followed by radio-chemotherapy. The role of [11C]-methionine PET in surgical and RT planning was analyzed. A threshold of SUVmax was searched. (3) Results: From August 2013 to April 2016, 93 patients were treated and included in this analysis. Residual tumor volume was detected in 63 cases on MRI and in 78 on [11C]-methionine PET, including 15 receiving gross total resection. The location of uptake was mainly observed in FLAIR abnormalities. [11C]-methionine uptake changed RT volume in 11% of patients. The presence of [11C]-methionine uptake in patients receiving GTR proved to influence survival (p = 0.029). The threshold of the SUVmax conditioning outcome was five. (4) Conclusions: [11C]-methionine PET allowed to detect areas at higher risk of recurrence located in FLAIR abnormalities in patients affected by GBM. A challenging issue is represented by integrating morphological and functional imaging to better define the extent of surgical resection to perform.

Study on intracranial meningioma using PET ligand investigation during follow-up over years (SIMPLIFY)

Purpose Radiologic follow-up of patients with a meningioma at the skull base or near the venous sinuses with magnetic resonance imaging (MRI) after stereotactic radiotherapy (SRT) and neurosurgical resection(s) can be difficult to interpret. This study evaluates the addition of 11C-methionine positron emission tomography (MET-PET) to the regular MRI follow-up. Methods This prospective pilot study included patients with predominantly WHO grade I meningiomas at the skull base or near large vascular structures. Previous SRT was part of their oncological treatment. A MET-PET in adjunct to their regular MRI follow-up was performed. The standardized uptake value (SUV) was determined for the tumor and the healthy brain, on the pre-SRT target delineation MET-PET and the follow-up MET-PET. Tumor-to-normal ratios were calculated, and 11C-methionine uptake over time was analyzed. Agreement between the combined MRI/MET-PET report and the MRI-only report was determined using Cohen’s κ. Results Twenty patients with stable disease underwent an additional MET-PET, with a median follow-up of 84 months after SRT. Post-SRT SUV T/N ratios ranged between 2.16 and 3.17. When comparing the pre-SRT and the post-SRT MET-PET, five categories of SUV T/N ratios did not change significantly. Only the SUVpeak T/Ncortex decreased significantly from 2.57 (SD 1.02) to 2.20 (SD 0.87) [p = 0.004]. A κ of 0.77 was found, when comparing the MRI/MET-PET report to the MRI-only report, indicating no major change in interpretation of follow-up data. Conclusion In this pilot study, 11C-methionine uptake remained remarkably high in meningiomas with long-term follow-up after SRT. Adding MET-PET to the regular MRI follow-up had no impact on the interpretation of follow-up imaging.

Ventricle Contact Is Associated With Higher 11C Methionine PET Uptake in Glioblastoma

Introduction: Ventricle contact is associated with a worse prognosis and more aggressive tumor characteristics in glioblastoma (GBM). This is hypothesized to be a result of neural stem cells located around the lateral ventricles, in the subventricular zone. 11C methionine Positron Emission Tomography (metPET) is an indicator for increased proliferation, as it shows uptake of methionine, an amino acid needed for protein synthesis. This study is the first to study metPET characteristics of GBM in relation to ventricle contact. Methods: 12 patients with IDH wild type GBM a were included. Using MRI, the following regions were determined: primary tumor (defined as contrast enhancing lesion on T1) and peritumoral edema (defined as edema visible on FLAIR excluding the enhancement). PET parameters in these areas were extracted using PET fused with MRI imaging. Parameters extracted from the PET included: maximum and mean tumor-to-normal ratio (TNRmax and TNRmean) and metabolic tumor volume (MTV). Results: TNRmean of the primary tumor showed significantly higher values for the ventricle contacting group compared to the non-contacting group (4.44 vs 2.67, p=0.015). Other metPET parameters suggested higher values for the ventricle contacting group, but these differences did not reach statistical significance. Conclusion: GBM with ventricle contact show a higher methionine uptake and thus increased proliferation compared with GBM without ventricle contact. This might explain survival differences and should be considered in treatment decisions.

CS-03 BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young

We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography imaging demonstrated a region with heterogeneous high 11 C-methionine uptake and a region with homogenous low 18 F- fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor as BRAF V600E-mutated PLNTY (polymorphous low-grade neuroepithelial tumor of the young). Within the high-methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1) and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also found that LAT1 expression was linked to BRAF V600E mutation and subsequent activation of MAPK signaling. Pharmacological inhibition of the MAPK pathway suppressed LAT1 expression and cell viability in PLNTY cells. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease.