IMMU-17. SYSTEMIC IMMUNOSUPPRESSION OF CD4+ T HELPER CELLS IN GLIOMA

Cancer is a systemic disease. Due to the exceedingly rare occurrence of metastasis of cerebral glioma, systemic alterations have, however, not been considered to play a major role in disease progression of glioma. CD4+ T helper (TH) cells orchestrate the adaptive immune response in an antigen-specific, cytokine mediated manner. The aim of our study was to investigate how far cerebral glioma impacts the systemic CD4+ immune repertoire. We therefore analyzed the peripheral blood CD4+ TH cell phenotype and cytokine production in 100 patients with IDHwt, 30 IDHmut and 16 IDHmut 1p19q co-deleted gliomas in comparison with age-matched healthy donors (HD). We found a significant skewing of the peripheral phenotype in IDHwt glioma patients, showing a TH1 expansion and reduced numbers of T follicular helper cells (TFH), TH1* and mucosa associated invariant T (MAIT) cells, while TH2 and TH17 percentages remained stable compared to IDHmut and HD. Interestingly, although TH1 cells were dominant in IDHwt patients, intracellular cytokine staining showed a distinct reduction of IFNg and TNFa production after in vitro stimulation, while IL-4 was significantly increased compared to HD. No alterations between all groups were observed in IL-2, IL-10 or IL-17 production. Profiling of metabolic surface markers further revealed three distinct groups of CD4+ T cells which are altered in IDHwt patients, indicating a metabolic shift in the CD4+ repertoire compared to HD. Taken together, our results show a CD4+ TH cell type specific skewing of the peripheral immune repertoire in patients with IDHwt gliomas. Our data highlights the importance of considering malignant glioma as a systemic disease that fundamentally alters the immune repertoire in affected patients.

Correlation of dual energy computed tomography electron density measurements with cerebral glioma grade

Objective To correlate dual energy computed tomography electron density measurements with histopathological cerebral glioma grading to determine whether it can be used as a non-invasive predictor of cerebral glioma grade. Materials and methods Fifty patients with suspected cerebral gliomas on imaging scheduled to undergo resection were included. We tested our hypothesis that with increasing glioma grade, increased tumor cellularity should translate into increased electron density and if a statistically significant difference between electron density of low-grade gliomas and high-grade gliomas is seen, we may have a clinical use of dual energy computed tomography as a non-invasive tool to predict cerebral glioma grade. A pre-operative dual energy computed tomography scan of the brain was performed, and electron density measurements calculated from the solid part of the tumor. Obtaining a ratio with electron density of contralateral normal brain parenchyma normalized these values. The minimum, maximum and mean electron density and their normalized values recorded between high-grade gliomas and low-grade gliomas were compared for presence of statistical significance. Results A statistically significant difference was found between all six parameters recorded (minimum electron density and normalized values, mean electron density and normalized values, maximum electron density and normalized values) between low-grade gliomas and high-grade gliomas. The predictivity ranged from 75% (for minimum electron density and maximum normalized values) to 81.25% (for mean normalized values). All six parameters were found to have statistically significant positive correlation with Ki-67 index. Conclusion Dual energy computed tomography electron density measurements in cerebral gliomas are predictive of pre-operative differentiation of low-grade gliomas from high-grade gliomas and show a linear, statistically significant positive correlation with Ki-67 index.

P16.03 Cerebral gliom alters the peripheral CD4+ T helper cell phenotype

BACKGROUND Cancer is a systemic disease. Due to the exceedingly rare occurrence of metastasis of cerebral glioma, systemic alterations have, however, not been considered to play a major role in disease progression of glioma. CD4+ T helper (TH) cells orchestrate the adaptive immune response in an antigen-specific, cytokine mediated manner. The aim of our study was to investigate how far cerebral glioma impacts the systemic CD4+ immune repertoire. MATERIAL AND METHODS We performed flow-cytometry analysis of the peripheral blood CD4+ TH cell phenotype and cytokine production in 100 patients with IDHwt, 30 IDHmut and 16 IDHmut 1p19q co-deleted gliomas in comparison with age-matched healthy donors (HD). Data was analyzed using a Fortessa LSR and Diva software. Multiparameter analyses were performed using UMAP and SpadeVizR trees. The study was approved by the ethics committee (PV4904). RESULTS We found a significant skewing of the peripheral immunophenotype in IDHwt glioma patients, showing a TH1 expansion and reduced numbers of T follicular helper cells (TFH), TH1* and mucosa associated invariant T (MAIT) cells (p<0.001), while TH2 and TH17 percentages remained stable compared to IDHmut and HD. Although TH1 cells were dominant in IDHwt patients (p<0.01), intracellular cytokine staining showed a reduction of IFNγ and TNFα production after in vitro stimulation, while IL-4 was significantly increased compared to HD (p<0.05). No alterations between all groups were observed in IL-2, IL-10 or IL-17 production. Profiling of metabolic surface markers further revealed increased expression of GLUT1 on CD4+ T cells in IDHwt patients, indicating an activated CD4+ repertoire compared to HD. CONCLUSION Taken together, our results show a CD4+ TH cell type specific skewing of the peripheral immune repertoire in patients with IDHwt gliomas. Our data highlights the importance of considering malignant glioma as a disease with profound systemic effects fundamentally altering the immune repertoire in affected patients.

Two Different Subcortical Networks of Language System: Morphogram and Phonogram, Through the Analysis of Unique Japanese Characters

Language systems worldwide are based on morphograms or phonograms, and Japanese is a unique language that uses a complicated combination of kanji (morphogram) and kana (phonogram) characters. The white matter networks associated with reading have been investigated previously but remain unclear. In this study, we performed intraoperative language mapping under local anesthesia and postoperative language assessments of 65 consecutive patients who underwent surgical resection for cerebral glioma within the dominant temporal or parietal lobe. The cases showing intraoperative dyslexia elicited by direct electrical stimulation (DES) or postoperative kanji and/or kana dyslexia were extracted. Five patients showed transient kanji or kana dyslexia intraoperatively, and 8 patients showed kanji or kana dyslexia postoperatively. During intraoperative mapping, kanji or kana dyslexia were indeed reproduced by DES. We investigated the maximal overlapping lesions of the resection cavity that were associated with kanji or kana dyslexia, and then determined the subcortical elicited points that evoked kanji or kana dyslexia. These areas were localized near three white matter bundles: the arcuate fascicle, posterior superior longitudinal fascicle, and inferior longitudinal fascicle (ILF). The intraoperative DES distributions for kanji dyslexia were especially associated with the anterior-inferior side of the ILF. On the other hand, the DES point associated with kana dyslexia was localized on the posterior-superior side of the complex of these three tracts. These results suggested the presence of specific non-interfering networks that subserved the reading process for morphograms and phonograms.

Hemisphere-Specific Functional Remodeling and Its Relevance to Tumor Malignancy of Cerebral Glioma Based on Resting-State Functional Network Analysis

Background: Functional remodeling may vary with tumor aggressiveness of glioma. Investigation of the functional remodeling is expected to provide scientific relevance of tumor characterization and disease management of glioma. In this study, we aimed to investigate the functional remodeling of the contralesional hemisphere and its utility in predicting the malignant grade of glioma at the individual level with multivariate logistic regression (MLR) analysis. Subjects and Methods: One hundred and twenty-six right-handed subjects with histologically confirmed cerebral glioma were included with 80 tumors located in the left hemisphere (LH) and 46 tumors located in the right hemisphere (RH). Resting-state functional networks of the contralesional hemisphere were constructed using the human brainnetome atlas based on resting-state fMRI data. Functional connectivity and topological features of functional networks were quantified. The performance of functional features in predicting the glioma grade was evaluated using area under (AUC) the receiver operating characteristic curve (ROC). The dataset was divided into training and validation datasets. Features with high AUC values in malignancy classification in the training dataset were determined as predictive features. An MLR model was constructed based on predictive features and its classification performance was evaluated on the training and validation datasets with 10-fold cross validation. Results: Predictive functional features showed apparent hemispheric specifications. MLR classification models constructed with age and predictive functional connectivity features (AUC of 0.853 ± 0.079 and 1.000 ± 0.000 for LH and RH group, respectively) and topological features (AUC of 0.788 ± 0.150 and 0.897 ± 0.165 for LH and RH group, respectively) achieved efficient performance in predicting the malignant grade of gliomas. Conclusion: Functional remodeling of the contralesional hemisphere was hemisphere-specific and highly predictive of the malignant grade of glioma. Network approach provides a novel pathway that may innovate glioma characterization and management at the individual level.

The diagnostic value of quantitative analysis of ASL, DSC-MRI and DKI in the Grading of Cerebral Gliomas: A Meta-Analysis

Objective To perform quantitative analysis on the efficacy of using relative cerebral blood flow (rCBF) in arterial spin labeling (ASL), relative cerebral blood volume (rCBV) in dynamic magnetic sensitivity contrast-enhanced magnetic resonance imaging(DSC-MRI), and mean kurtosis (MK) in diffusion kurtosis imaging (DKI) to grade cerebral gliomas. Methods Literature regarding ASL, DSC-MRI, or DKI in cerebral glioma grading in both English and Chinese were searched from PubMed, Embase, Web of Science, CBM, China National Knowledge Infrastructure (CNKI), and Wanfang Database as of April 2019. A Meta-Analysis was performed to evaluate the efficacy of ASL, DSC-MRI, and DKI in the grading of cerebral glioma. Result A total of 54 articles (11 in Chinese and 43 in English) were included. Three quantitative parameters in the grading of cerebral glioma, rCBF in ASL, rCBV in DSC-MRI,and MK in DKI had an overall sensitivity of 0.88[95%CI(0.83,0.92)], 92[95%CI(0.83,0.96)],0.88[95%CI(0.82,0.92)], and an overall specificity of 0.91[95%CI(0.84,0.94)],0.81[95%CI(0.73,0.88)], 0.86[95%CI(0.78,0.91)] respectively. The overall area under the ROC curve were 0.95[95%CI(0.93,0.97)], 0.91[95%CI(0.89,0.94)], 0.93[95%CI(0.91,0.95)] respectively. Conclusion Quantitative parameters rCBF, rCBV and MK have high diagnostic efficacy for preoperative grading of cerebral gliomas.