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NI-11 PATHOLOGICAL ASSESSMENT IN THE IMPACT OF ONE-SHOT BEVACIZUMAB ON UPTAKE OF 11C-METHIONINE

Abstract BACKGROUND This study aimed to clarify how one-time administration of bevacizumab (BEV) changes histological features in glioblastoma, and how histological changes affect the uptake of 11C-methyl-L-methionine (11C-met) as an amino-acid tracer. MATERIALS AND METHODS Subjects were 18 patients with newly diagnosed glioblastoma who were assigned to 2 groups: BEV group, single intravenous administration of BEV before surgical tumor removal; and control group, surgical tumor removal alone. After surgery, we compared the densities of tumor cells and microvessels, and microvascular structures including vascular pericytes and L-type amino acid transporter-1 (LAT1), between the BEV and control groups. Correlations between 11C-met uptake on positron emission tomography before surgery, microvascular density, and LAT1 expression were assessed in each group. RESULTS BEV induced significant reductions in microvascular density, while tumor cell density and proliferation were retained in the BEV group. Percentages of vessels with pericytes and vascular endothelium with LAT1 expression were lower in the BEV group than in controls. Uptake of 11C-met correlated significantly with microvascular density in the BEV group, but not with LAT1expression. CONCLUSIONS The present study showed that even one course of BEV administration induced reductions in microvessels, vascular pericytes, and LAT1 expression in glioblastomas. One course of BEV therapy also reduced 11C-met uptake, which might have been largely attributed to reductions in microvessels rather than reductions in LAT1 expression, in addition to reduction of vascular permeability.

INTRODUCTION: Magnetic resonance perfusion imaging is considered to be available as grading of brain tumor and follow-up of brain treatment. One of the methods, arterial spin labeling (ASL), is a test that is useful for patients with renal impairment and contrast agent allergy and has low invasiveness because it does not use a contrast agent. However, there have been no reports of ASL in intraoperative MRI (iMRI). PURPOSE: In this hospital iMRI (1.5T), it was examined whether ASL could be used to evaluate residual tumor in patients under general anesthesia. CASE STUDY: A 75-year-old woman with right temporal lobe Glioblastoma. 43-year-old man, left temporal lobe Diffuse astrocytoma. All performed ASL at the time of MRI imaging for navigation before induction of anesthesia just before surgery and iMRI. In all cases, the blood pressure at iMRI was maintained, and Post Label Delay (PLD) calculated the optimal PLD from the carotid artery velocity measured by iMRI, and defined it as 1800-2200 ms, and performed ASL. RESULTS: Actually, imaging by iMRI was almost difficult to visualize, and reflux was not recognized not only in the tumor but also in the gray matter. DISCUSSION: The blood flow velocity measurement in the internal carotid artery is performed by the phase contrast method by intraoperative MRI, and the CBF decreases because propofol used during the operation decreases the CBF and also the brain metabolism. However, it has been suggested that it is one of the factors that make evaluation with ASL difficult. Although the iMRI of our hospital is 1.5 T, which is also a subject of investigation, it is thought that there is a limit to ASL imaging in the case of general anesthesia with propofol even from the calculated PLD. CONCLUSION: ASL in iMRI at our hospital was not useful.

CLINICAL SIGNIFICANCE OF T2-FLAIR MISMATCH SIGN IN LOWER GRADE GLIOMAS
Shoichi Deguchi 1 , Koichi Mitsuya 1 , Yuko Kakuda, Takuma Oishi, Nakamasa Hayashi 1 ; 1 Division of Neurosurgery, Shizuoka Cancer Center, Nagaizumi-cho, Shizuoka, Japan Lower grade glioma is classified based on genetic information of mutation of IDH1/2 gene and co-deletion of chromosome 1p19q. Knowledge of these genetic information preoperatively is useful for making surgical planning, treatment strategy and prognostication. Recently, T2-FLAIR mismatch sign has been reported to be specific for astrocytoma with IDH mutation (mut) / non-1p19q co-deletion (co-del). This study aims to verify it in our patients. We retrospectively analyzed 152 patients aged over 15 years who were pathologically diagnosed with WHO grade 2 or 3 gliomas from April 2003 to December 2018. We excluded 88 patients without genetic information or without T2-weighted and FLAIR images. T2-FLAIR mismatch sign was defined as in the original description, namely, with homogeneously hyperintense signal on T2-weighted image and a peripheral hyperintense signal with central hypointensity signal on FLAIR image. Among 22 patients with IDH mut / non-1p19q codel, 10 were positive for T2-FLAIR mismatch sign. On the other hand, only one patient was positive for T2-FLAIR mismatch sign respectively in 19 with IDH mut / 1p19q codel and 23 patients with IDH wild-type. Sensitivity, specificity, positive predictive value, and negative predictive value of T2-FLAIR mismatch for the patients with IDH mut / non-1p19q codel are 0.46 (95% confidence interval: 0.24-0.68), 0.95 (0.84-0.99), 0.83 (0.52-0.98). and 0.77 (0.63-0.88), respectively. In 22 patients with IDH mut / non-1p19q codel, we compared 10 patients with and 12 without T2-FLAIR mismatch sign. Median age was 35 and 39 years old. WHO grade 3 was 3 patients each. Tumor location was frontal lobe in 9 (90%) and 10 patients (83%). A statistically significant difference was not found in these factors. PFS and OS were not reached in both groups. The specificity of the T2-FLAIR mismatch sign for astrocytoma with IDH mut / non-1p19q codel was very high, which may be helpful as preoperative imaging marker.

AVAILABILITY OF AMIDE PROTON TRANSFER-WEIGHTED MRI METRICS IN GLIOMA
Shinji Yamashita 1 , Minako Azuma, Kiyotaka Saito 1 , Takashi Watanabe 1 , Kiyotaka Yokogami 1 , Hideo Takeshima 1 ; 1 Division of Neurosurgery, Department of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki OBJECTIVE: Chemical exchange saturation transfer (CEST) is a novel MR imaging contrast technique that relies on the molecular characteristics of the sample. Amide proton transfer (APT) imaging is an emerging CESTbased MR imaging technique that is sensitive to mobile proteins and peptides in the tissue. APT imaging has become increasingly recognized as a promising imaging modality for glioma. Several reports suggest that APT signals are a promising imaging biomarker for glioma grading and prediction of molecular marker status. In this study, we assessed the utility of APT imaging in glioma by evaluating the relationship between APT signals and clinical parameters in glioma. METHODS: We enrolled 23 glioma patients (25 lesions) who underwent preoperative MRI with APT imaging and surgery at our institution between May 2018 and July 2019. The median age of patients was 64 years old (range, 14-84). 2 patients had Grade 2, 1 patient had Grade 3, and 22 patients had Grade 4. APT signals were measured inside the ROI that was manually placed in the solid portion of tumor that best represented the entire tumor signal on raw APT images. RESULTS: We could see that the high APT signals seemed to be related to IDH wild status and high glioma grading (IDH status; p=0.171, Grade; p=0.113). Moreover, the high APT signals were significantly strong related to high Mib-1 LI (p=0.0068, cutoff: 3.295%, sensitivity: 83%, specificity: 71%). CONCLU-SIONS: APT imaging might be associated with IDH mutation status and glioma grading. Especially, high APT signal was a great predictor of high MIB-1 LI in glioma.

NI-11 PATHOLOGICAL ASSESSMENT IN THE IMPACT OF ONE-SHOT BEVACIZUMAB ON UPTAKE OF 11 C-METHIONINE
Takaaki Beppu 1 , Yuichi Sato 1 , Kuniaki Ogasawara 1 ; 1 Department of Neurosurgery, Iwate Medical University, Morioka, Japan BACKGROUND: This study aimed to clarify how one-time administration of bevacizumab (BEV) changes histological features in glioblastoma, and how histological changes affect the uptake of 11C-methyl-Lmethionine (11C-met) as an amino-acid tracer. MATERIALS AND METHODS: Subjects were 18 patients with newly diagnosed glioblastoma who were assigned to 2 groups: BEV group, single intravenous administration of BEV before surgical tumor removal; and control group, surgical tumor removal alone. After surgery, we compared the densities of tumor cells and microvessels, and microvascular structures including vascular pericytes and L-type amino acid transporter-1 (LAT1), between the BEV and control groups. Correlations between 11C-met uptake on positron emission tomography before surgery, microvascular density, and LAT1 expression were assessed in each group. RESULTS: BEV induced significant reductions in microvascular density, while tumor cell density and prolifer-ation were retained in the BEV group. Percentages of vessels with pericytes and vascular endothelium with LAT1 expression were lower in the BEV group than in controls. Uptake of 11C-met correlated significantly with microvascular density in the BEV group, but not with LAT1expression. CONCLUSIONS: The present study showed that even one course of BEV administration induced reductions in microvessels, vascular pericytes, and LAT1 expression in glioblastomas. One course of BEV therapy also reduced 11C-met uptake, which might have been largely attributed to reductions in microvessels rather than reductions in LAT1 expression, in addition to reduction of vascular permeability. is a critical modality for the determination of glioblastoma (GBM) treatment strategy, as it is thought to reflect the biology of the tumor to some extent. The authors attempted to predict prognosis of newly diagnosed GBM (nGBM) using machine learning-based texture analysis of preoperative MRI in this study. METHOD: A total of 160 nGBMs with determined overall survival were collected from Kansai Molecular Diagnosis Network for CNS tumors. Preoperative MRI scans (T1WI, T2WI, and Gd-T1WI) from all cases were semi-quantitatively analyzed leading to acquisition of 489 texture features as explanatory variables using Matlab-based in-house software. Dichotomous overall survival (OS) with a cutoff of 15 months was regarded as the response variable (short or long OS). Lasso regression was employed for feature selection to ensure robustness of the prediction model. One hundred patients were randomly assigned as training dataset (TR), followed by predictive model construction via 5-fold cross-validation. Subsequently, the constructed model was transferred to the remaining 60 patients, which was assigned as test dataset (TD). The survival distribution between populations with predicted short and long OS was compared using log-rank test. RE-SULTS: Distributions of the analyzed data were as follows; 53 short OS cases in the TR (53.0%) and 27 cases in the TD (45.0%). As for the result of transfer analysis in TD, 38 cases out of 60 (63.3%) were predicted to be short OS (76.3 % of recall, 54.3% of precision, and 63.5% of F-measure). The population of predicted short OS significantly showed poorer prognosis (median OS 14.0 vs 19.1 months) (p=0.02, log-rank test). CON-CLUSION: Short OS was successfully identified from preoperative MRI with high recall rates with our algorithm. The presented result ensures the potential of machine learning-based texture analysis for prognostic stratification of nGBM.

EVALUATION OF PREOPERATIVE APPARENT DIFFUSION COEFFICIENT (ADC) OF PERITUMORAL LESION FOR PREDICTING SITE PRONE TO RECURRENCE IN PATIENTS WITH GLIOBLASTOMA
Kenichiro Matsuda 1 , Kaori Sakurada 1 , Takamasa Kayama 1 , Yukihiko Sonoda 1 ; 1 Department of Neurosurgery, Faculty of Medicine, Yamagata University, Yamagata, Japan PURPOSE: In the surgery of glioblastoma (GBM), the maximum safe resection is desired in order to prevent recurrence. The purpose of this study is to make it possible to evaluate the site in which the recurrence after resection of the tumor occur, according to the findings in preoperative MRI, and to avoid the recurrence. METHOD: The 26 initial cases with GBM treated in our department was investigated. Preoperative MRI, postoperative MRI, and follow-up MRI during the course were analyzed in a retrospective view. In the FLAIR high-signal area around the contrast-enhanced tumor body in preoperative MRI, we investigated the relationship between the site and the ADC value, from the standpoint of whether a recurrence occurred or not. RESULTS: For preoperative MRI of 26 patients, the FLAIR high-signal region was set to a total of 54 ROI, and several values, such as the ADC values, were measured. In the preoperative images, ADC were higher in the site where the no recurrence occurred during the postoperative course and lower in the site where the recurrence occurred. CONCLUSION: In the FLAIR high-signal area around the tumor in preoperative images, ADC value is useful in evaluating whether it has tendency to develop the recurrence in the future course or not. It was suggested that significant recurrence occurs at part with low-ADC value. It is considered useful for the planning of the extent of resection in the surgery and the irradiation range in radiation treatment.

NI-15 THE USEFULNESS OF PET IMAGING IN MOLECULAR DIAGNOSIS OF GLIOMA
Tomoya Ogawa 1 , Keisuke Miyake 1 , Takeshi Fujimori 1 , Daisuke Ogawa 1 , Masaki Okada 1 , Tetsuhiro Hatakeyama 1 , Masanobu Okauchi 1 , Atsushi Shindo 1 , Masahiko Kawanishi 1 , Takashi Tamiya 1 ; 1 Department of Neurological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan OBJECTIVE: After WHO 2016 Classification of Tumors of the Central Nervous System have published, molecular diagnosis became part of the diagnostic criteria. In this study, we investigated the correlation between PET images and molecular diagnosis of glioma. METHODS: We performed retrospective review of newly diagnosed supratentorial glioma patients who preoperatively underwent all four PET examinations ( 18 F-FDG, 11 C-MET, 18 F-FLT and 18 F-FMISO) from April 2009 to March 2019. The standardized uptake value (SUV) from the accumulation of each PET tracers, TNR (tumor to contralateral normal tissue ratio) of 18 F-FDG, 11 C-MET and 18 F-FLT, TBR (tumor to blood values ratio) of 18 F-FMISO were measured. We investigated the correlation between these PET images and molecular diagnosis of glioma. RESULTS: Data from total of 79 patients which were 42 cases of IDH wild type glioblastoma, 2 cases of IDH mutated glioblastoma, 9 cases of IDH wild type astrocytoma, 13 cases of IDH mutated astrocytoma and 13 cases of IDH mutated and 1p/19q co-deleted oligodendroglioma were included in this study. Both TNR of 11 C-MET(p<0.01) and 18 F-FLT(p<0.01), and also TBR of 18 F-FMISO(p<0.01) in IDH wild type gliomas showed significantly higher than IDH mutated gliomas. In WHO Gr2-3 gliomas, only TNR of 18 F-FLT showed a significant difference between IDH wild type gliomas and IDH mutated gliomas(p<0.01). TNR of 18 F-FLT(p<0.01) and TBR of 18 F-FMISO(p<0.01) in 1p/19q co-deleted gliomas were significantly lower than gliomas without 1p/19q co-deletion, but there were no significant differences in WHO Gr2-3 gliomas. Among IDH mutated gliomas, TNR of 11 C-MET in 1p/19q co-deleted gliomas showed significantly higher uptake than gliomas without 1p/19q co-deletion(p<0.05). CONCLUSION: Preoperative PET evaluation of each PET tracers may be useful for the molecular diagnosis of glioma.

T2-FLAIR MISMATCH SIGN IN DIFFUSE GLIOMA AND DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR
Shumpei Onishi 1 , Fumiyuki Yamasaki 1 , Motoki Takano 1 , Ushio Yonezawa 1 , Kazuhiko Sugiyama, Kaoru Kurisu 1 ; 1 Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University BACKGROUND: T2-FLAIR mismatch sign was reported as a specific imaging marker for diffuse astrocytoma with IDH-mutant and 1p/19q noncodeletion. However, most of the previous studies for T2-FLAIR mismatch were confirmed only among low grade glioma. The purpose of this study is to assess the T2-FLAIR mismatch sign in supratentorial diffuse glioma, diffuse midline glioma and dysembryoplastic neuroepithelial tumor (DNT) to unveil the exception rules of the sign. METHODS: In total, 51 patients were included in this study; 33 supratentorial diffuse glioma (18 diffuse astrocytoma with IDH mutant (IDHmut-Noncodel), 12 oligodendroglioma with IDH-mutant and 1p19q codeletion (IDHmut-Codel), 3 diffuse astrocytoma with IDH wildtype (IDHwt)), 18 diffuse midline glioma and 11 DNT. The tumors were evaluated by 2 independent reviewers to assess presence or absence of T2-FLAIR mismatch sign. RESULT: Ten out of 18 cases of IDHmut-Noncodel presented T2-FLAIR mismatch sign. None of the other supratentorial diffuse glioma (IDHmut-Codel and IDHwt) presented T2-FLAIR mismatch. The T2-FLAIR mismatch sign for IDHmut-Noncodel presented 100% positive predictive values among supratentorial diffuse glioma. However, 8 out of 18 cases of diffuse midline glioma and 8 out of 11 cases of DNT also presented the T2-FLAIR mismatch. CONCLU-SION: The T2-FLAIR mismatch sign was specific marker for IDHmut-NonCodel among supratentorial diffuse glioma. Physicians need to be aware that diffuse midline glioma and DNT could present the T2-FLAIR mismatch sign.