Diffuse Low-grade Gliomas Research Articles

Awake Craniotomy for Gliomas in the Non-Dominant Right Hemisphere: A Comprehensive Review.

Awake surgery has become a standard practice for managing diffuse low-grade gliomas (LGGs), particularly in eloquent brain areas, and is established as a gold standard technique for left-dominant-hemisphere tumors. However, the intraoperative monitoring of functions in the right non-dominant hemisphere (RndH) is often neglected, highlighting the need for a better understanding of neurocognitive testing for complex functions in the right hemisphere. This article aims to comprehensively review the current literature on the benefits of awake craniotomy in gliomas of the non-dominant right hemisphere. A systematic review was conducted using the PubMed and ScienceDirect databases with keywords such as "right hemisphere", "awake surgery", "direct electrical brain stimulation and mapping", and "glioma". The search focused on anatomical and surgical aspects, including indications, tools, and techniques of awake surgery in right cerebral hemisphere gliomas. The literature search identified 74 sources, including original articles, books, monographs, and review articles. Two papers reported large series of language assessment cases in 246 patients undergoing awake surgery with detailed neurological semiology and mapping techniques, while the remaining studies were predominantly neuroradiological and neuroimaging in nature. Awake craniotomy for non-dominant-hemisphere gliomas is an essential tool. The term "non-dominant" should be revised, as this hemisphere contributes significantly to essential cognitive functions in the human brain.

Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma.

Pediatric-type diffuse low-grade gliomas (pLGG) harboring recurrent genetic alterations involving MYB or MYBL1 are closely related tumors. Detailed treatment and outcome data of large cohorts are still limited. This study aimed to comprehensively evaluate pLGG with these alterations to define optimal therapeutic strategies. We retrospectively reviewed details of pLGG with MYB or MYBL1 alterations from patients treated or referred for pathologic review at St. Jude Children's Research Hospital. Tumor specimens were centrally reviewed, and clinical data were collated. Thirty-three patients (18 male; median age, 5 years) were identified. Two tumors had MYBL1 alterations; 31 had MYB alterations, MYB::QKI fusion being the most common (n = 10, 30%). Most tumors were in the cerebral hemispheres (n = 22, 67%). Two patients (6%) had metastasis at diagnosis. The median follow-up was 6.1 years. The 5-year event-free survival (EFS) rate was 81.3% ± 8.3%; the 5-year overall survival (OS) rate was 96.4% ± 4.1%. Patients receiving a near-total or gross-total resection had a 5-year EFS of 100%; those receiving a biopsy or subtotal resection had a 5-year EFS rate of 56.6% ± 15.2% (P < .01). No difference in EFS was observed based on location, histology, or molecular alterations. However, the tumors that progressed or metastasized may have distinct methylation profiles with evidence of activation of the MAPK and PI3K/AKT/mTOR pathways. pLGG with MYB/MYBL1 alterations have good outcomes. Our findings suggest that surgical resectability is a crucial determinant of EFS. Further characterization is required to identify optimal treatment strategies for progressive tumors.

Verbal fluency predicts work resumption after awake surgery in low-grade glioma patients.

Resuming professional activity after awake surgery for diffuse low-grade glioma (DLGG) is an important goal, which is not reached in every patient. Cognitive deficits can occur and persist after surgery. In this study, we analyzed the impact of mild cognitive impairments on the work resumption. Fifty-four surgeries (including five redo surgeries) performed between 2012 and 2020 for grade 2 (45) and 3 (nine) DLGG in 49 professionally active patients (mean age 40 [range 23-58.) were included. We retrospectively extracted the results of semantic and phonemic verbal fluency tests from preoperative and 4-month postoperative cognitive assessments. Patients were interviewed about their working life after surgery, between April and June 2021. Patients (85%) returned to work, most within 3 to 6months. Patients (76%) reported subjective complaints (primarily fatigue). Self-reported symptoms and individual and clinical variables had no impact on the work resumption. Late-postoperative average Z-scores in verbal fluency tasks were significantly lower than preoperative for the entire cohort (Wilcoxon test, p < 0.001 for semantic and p = 0.008 for phonemic fluency). The decrease in Z-scores was significantly greater (Mann Whitney U-test, semantic, p = 0.018; phonemic, p = 0.004) in the group of patients who did not return to work than in the group of patients who did. The proportion of patients returning to work was comparable to similar studies. A decrease in verbal fluency tasks could predict the inability to return to work.

Patterns of T2-FLAIR discordance across a cohort of adult-type diffuse gliomas and deviations from the classic T2-FLAIR mismatch sign.

T2-FLAIR mismatch serves as a highly specific but insensitive marker for IDH-mutant (IDHm) astrocytoma with potential limitations in real-world application. We aimed to assess the utility of a broader definition of T2-FLAIR discordance across a cohort of adult-type diffuse lower-grade gliomas (LrGG) to see if specific patterns emerge and additionally examine factors determining deviation from the classic T2-FLAIR mismatch sign. Preoperative MRIs of non-enhancing adult-type diffuse LrGGs were reviewed. Relevant demographic, molecular, and MRI data were compared across tumor subgroups. Eighty cases satisfied the inclusion criteria. Highest discordance prevalence and > 50% T2-FLAIR discordance volume were noted with IDHm astrocytomas (P < 0.001), while < 25% discordance volume was associated with oligodendrogliomas (P = 0.03) and IDH-wildtype (IDHw) LrGG (P = 0.004). "T2-FLAIRmatched pattern" was associated with IDHw LrGG (P < 0.001) and small or minimal areas of discordance with oligodendrogliomas (P = 0.03). Sensitivity and specificity of classic mismatch sign for IDHm astrocytoma were 25.7% and 100%, respectively (P = 0.06). Retained ATRX expression and/or non-canonical IDH mutation (n = 10) emerged as a significant factor associated with absence of classic T2-FLAIR mismatch sign in IDHm astrocytomas (100%, P = 0.02) and instead had minimal discordance or matched pattern (40%, P = 0.04). T2-FLAIR discordance patterns in adult-type diffuse LrGGs exist on a diverging but distinct spectrum of classic mismatch to T2-FLAIRmatched patterns. Specific molecular markers may play a role in deviations from classic mismatch sign.

T2-FLAIR mismatch sign and machine learning-based multiparametric MRI radiomics in predicting IDH mutant 1p/19q non-co-deleted diffuse lower-grade gliomas

To investigate the application of the T2-weighted (T2)-fluid-attenuated inversion recovery (FLAIR) mismatch sign and machine learning-based multiparametric magnetic resonance imaging (MRI) radiomics in predicting 1p/19q non-co-deletion of lower-grade gliomas (LGGs). One hundred and forty-six patients, who had pathologically confirmed isocitrate dehydrogenase (IDH) mutant LGGs were assigned randomly to the training cohort (n=102) and the testing cohort (n=44) at a ratio of 7:3. The T2-FLAIR mismatch sign and conventional MRI features were evaluated. Radiomics features extracted from T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), FLAIR, apparent diffusion coefficient (ADC), and contrast-enhanced T1WI images (CE-T1WI). The models that displayed the best performance of each sequence were selected, and their predicted values as well as the T2-FLAIR mismatch sign data were collected to establish a final stacking model. Receiver operating characteristic curve (ROC) analyses and area under the curve (AUC) values were applied to evaluate and compare the performance of the models. The T2-FLAIR mismatch sign was more common in the IDH mutant 1p/19q non-co-deleted group (p<0.05) and the area under the curve (AUC) value was 0.692 with sensitivity 0.397, specificity 0.987, and accuracy 0.712, respectively. The stacking model showed a favourable performance with an AUC of 0.925 and accuracy of 0.882 in the training cohort and an AUC of 0.886 and accuracy of 0.864 in the testing cohort. The stacking model based on multiparametric MRI can serve as a supplementary tool for pathological diagnosis, offering valuable guidance for clinical practice.

EZH2 Inhibition Sensitizes IDH1R132H-Mutant Gliomas to Histone Deacetylase Inhibitor.

Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

Clinicopathological analysis of BRAF and non-BRAF MAPK pathway-altered gliomas in paediatric and adult patients: a single-institution study of 40 patients

AimsMitogen-activated protein kinase (MAPK) pathway alteration is a major oncogenic driver in paediatric low-grade gliomas (LGG) and some adult gliomas, encompassing BRAF (most common) and non-BRAF alterations. The aim was...

Accuracy of Radiomics in Predicting IDH Mutation Status in Diffuse Gliomas: A Bivariate Meta-Analysis.

Purpose To perform a systematic review and meta-analysis assessing the predictive accuracy of radiomics in the noninvasive determination of isocitrate dehydrogenase (IDH) status in grade 4 and lower-grade diffuse gliomas. Materials and Methods A systematic search was performed in the PubMed, Scopus, Embase, Web of Science, and Cochrane Library databases for relevant articles published between January 1, 2010, and July 7, 2021. Pooled sensitivity and specificity across studies were estimated. Risk of bias was evaluated using Quality Assessment of Diagnostic Accuracy Studies-2, and methods were evaluated using the radiomics quality score (RQS). Additional subgroup analyses were performed according to tumor grade, RQS, and number of sequences used (PROSPERO ID: CRD42021268958). Results Twenty-six studies that included 3280 patients were included for analysis. The pooled sensitivity and specificity of radiomics for the detection of IDH mutation were 79% (95% CI: 76, 83) and 80% (95% CI: 76, 83), respectively. Low RQS scores were found overall for the included works. Subgroup analyses showed lower false-positive rates in very low RQS studies (RQS < 6) (meta-regression, z = -1.9; P = .02) compared with adequate RQS studies. No substantial differences were found in pooled sensitivity and specificity for the pure grade 4 gliomas group compared with the all-grade gliomas group (81% and 86% vs 79% and 79%, respectively) and for studies using single versus multiple sequences (80% and 77% vs 79% and 82%, respectively). Conclusion The pooled data showed that radiomics achieved good accuracy performance in distinguishing IDH mutation status in patients with grade 4 and lower-grade diffuse gliomas. The overall methodologic quality (RQS) was low and introduced potential bias. Keywords: Neuro-Oncology, Radiomics, Integration, Application Domain, Glioblastoma, IDH Mutation, Radiomics Quality Scoring Supplemental material is available for this article. Published under a CC BY 4.0 license.

Diffuse low-grade glioma: What is the optimal linear measure to assess tumor growth?

Radiological follow-up of diffuse low-grade gliomas (LGGs) growth is challenging. Approximative visual assessment still predominates over objective quantification due to the complexity of the pathology. The infiltrating character, diffuse borders and presence of surgical cavities demand LGG-based linear measurement rules to efficiently and precisely assess LGG evolution over time. We compared optimized 1D, 2D, and 3D linear measurements with manual volume segmentation as a reference to assess LGG tumor growth in 36 patients with LGG (340 magnetic resonance imaging scans), using the clinically important mean tumor diameter (MTD) and the velocity diameter expansion (VDE). LGG-specific progression thresholds were established using the high-grade gliomas-based RECIST, Macdonald, and RANO criteria, comparing the sensitivity to identify progression/non-progression for each linear method compared to the ground truth established by the manual segmentation. 3D linear volume approximation correlated strongly with manually segmented volume. It also showed the highest sensitivity for progression detection. The MTD showed a comparable result, whereas the VDE highlighted that caution is warranted in the case of small tumors with multiple residues. Novel LGG-specific progression thresholds, or the critical change in estimated tumor volume, were increased for the 3D (from 40% to 52%) and 2D methods (from 25% to 33%) and decreased for the 1D method (from 20% to 16%). Using the 3D method allowed a ~5-minute time gain. While manual volumetric assessment remains the gold standard for calculating growth rate, the 3D linear method is the best time-efficient standardized alternative for radiological evaluation of LGGs in routine use.

Longitudinal assessment of quality of life, neurocognition, and psychopathology in patients with low-grade glioma on first-line temozolomide: A feasibility study.

The treatment timing and choice after neurosurgical resection in patients with newly diagnosed diffuse low-grade glioma (DLGG) remain controversial. Indeed, the effect of such treatments must be balanced with the possible side effects. This study evaluated the feasibility of longitudinal exhaustive quality of life (QoL) and neuropsychological assessments in patients with DLGG receiving first-line temozolomide. QoL, neurocognition, and psychological disorders were assessed prospectively until disease progression, using testing, clinician-reported, and self-reported questionnaires. The primary endpoint was the participation and adherence to this complete assessment at Baseline (before temozolomide initiation), months 6 and 12 of treatment, and month 6 post-treatment. The QoL and neuropsychological changes over time also were described. Twenty-six of the twenty-nine eligible patients were enrolled (participation rate: 89.7%, 95% CI: 72.6-97.8). The adherence rate was 95.7% (95% CI: 78.1-99.9; n = 23 because 3 patients progressed in the first 12 months of treatment). Up to month 6 post-treatment, QoL and fatigue remained stable (EORTC QLQC30 and BN20, MFI-20); some specific symptoms were transitory. Both subjective (FACT-Cog) and objective (Z-scores of neurocognitive tests) neurocognitive outcomes remained stable or tended to improve. The percentage of patients with severe depression (BDI-II), anxiety (STAI-Y), or anger (STAXI-II) was stable over time. This prospective study demonstrated the feasibility of an exhaustive and longitudinal evaluation of QoL, neurocognition, and psychological disorders, with high acceptability by patients with DLGG undergoing chemotherapy. First-line temozolomide seems to have limited short-term effects on QoL and neurocognition. These findings must be confirmed in the long term and in a larger cohort.

10006-PEDT-1 PEDIATRIC LOWER GRADE GLIOMA SURGERY IN THE ERA OF GENOMIC MEDICINE

Abstract INTRODUCTION In the new WHO Brain Tumor Classification of 2021, pediatric-type gliomas are classified separately from adult-type tumors. Additionally, with the advancement of cancer genomics, treatment options have expanded. Here we consider surgery for pediatric low-grade gliomas. METHODS We retrospectively analyzed 41 cases of low-grade gliomas or glioneuronal tumors in patients under 18 years of age who underwent surgery at our institute from 2002 to March 2023. We discussed surgical strategies based on molecular classification. RESULTS Among the cases, there were 34 gliomas and 7 glioneuronal tumors. According to the new WHO classification, they corresponded to 1) Adult-type diffuse gliomas, 2) Pediatric-type diffuse low-grade gliomas, 3) Circumscribed astrocytic tumors, or 4) Glioneuronal and neuronal tumors. Cases without molecular diagnosis were also considered in light of the new WHO classification. DISCUSSION Among molecularly diagnosed astrocytomas involving the cerebral hemisphere, brain stem, spinal cord, there were no cases of 1), and 2) 3) were the main cases. It is important in surgical selection to note that these cases generally have a more favorable prognosis compared to the adult type and have usefulness in diagnosing MAPK pathway abnormalities leading to the selection of molecularly targeted drugs. 3) includes pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma. Among these, in the treatment of pilocytic astrocytomas located in the optic pathway and hypothalamus, biopsy becomes necessary for molecular diagnosis and the selection of appropriate therapeutic agents. Conversely, for unilateral optic nerve gliomas, options other than resection may be considered. 4) is primarily associated with epilepsy-related tumors. Surgical resection holds the promise of controlling epilepsy in these cases. However, various genetic abnormalities have been identified, which could prove useful in diagnosis and treatment. CONCLUSION Based on the new WHO classification, a reevaluation of treatment strategies for pediatric brain tumors is necessary.

NCOG-15. COMPARATIVE ANALYSIS OF GLIOMA INDUCED IMPAIRMENT MODELS

Abstract Speech is produced by the coordination of neural networks involved in language processing and motor control of vocal outputs, both of which can be disrupted by diffuse gliomas. Natural language is the instinctual written or spoken language profile that an individual has developed throughout his or her lifetime. Recent psycholinguistic analyses suggest that patterns of natural language may be an accurate measure for assessing clinical and behavioral conditions. One important feature of natural language is speech onset. Speech delays are common complaints among patients with glioma. Here, we assess the relationship between speech onset and histologic-molecular features of glioma. Speech onset was defined as acoustic measure of the interval of time between the release of the oral constriction in a stop consonant and the onset of subsequent voicing. Audio samples and video analysis of oral kinetics were analyzed from patients with newly diagnosed low- and high-grade glioma. Features were extracted by manual segmentation and aligned for each trial with high-density electrode arrays to record task specific responses from gliomas projecting to the cortical surface. A total of 1,120 stimuli (672 = picture naming (PN) and 448 auditory naming (AN) trials were presented. As expected, patients with glioblastoma had higher picture and auditory naming error rates (p &amp;lt; 0.001, Mann-Whitney U test) compared with diffuse low-grade gliomas. Assuming speech errors produce slower response times, we next measured only correct behavioral responses which demonstrated 7% slower speech initiation responses (p &amp;lt; 0.0001, Mann-Whitney U test) when comparing patients with glioblastoma and diffuse low-grade gliomas. Slowed speech responses did not require glioma infiltration into canonical cortical speech areas of the lateral prefrontal cortex and superior temporal gyrus. Finally, we identified electrophysiological biomarkers of speech errors. These results deepen our understanding of speech processing impairments, which are not based purely on coding errors.

EXTH-20. A MOUSE MODEL REVEALS VULNERABILITY OF IDH1-MUTATED GLIOMA TO FERROPTOSIS

Abstract The molecular classification of gliomas is currently based on the presence of IDH1 mutation, which is associated with better prognosis and longer survival. The hallmark of the IDH1 mutation is the production of D-2-Hydroxyglutarate with subsequent effects that are not fully understood. Ferroptosis, an iron-dependent mechanism of non-apoptotic cell death, is mostly triggered through blocking system Xc- or suppressing the antioxidant enzyme glutathione peroxidase 4 (GPX-4). In this study, we generated a mouse model of glioma harboring the IDH1(R132H) mutation in heterozygous condition, in combination with p53-deletion induced by the expression of PDGFA. We show that IDH1(R132H)-expressing mice survive longer compared to their wild-type counterparts, while histological analysis reveals characteristics of low-grade diffuse gliomas. We generated cell lines from primary tumors and analyzed their metabolic profile and response to mitochondrial stress and Ferroptosis. We treated them in vitro with RSL3, a GPX-4 inhibitor, alone or in combination with Cysteine and Methionine restriction. We show that IDH1(R132H)-expressing cells are far more sensitive to Ferroptosis in vitro. Finally, we show that convection-enhanced delivery of RSL3 in combination with dietary Cysteine and Methionine restriction in vivo, significantly prolongs survival of the IDH1(R132H)-expressing mice. Our findings suggest that Ferroptosis provides promising therapeutic potential worth exploring further and our mouse model could be used to test the efficacy of different treatments for IDH1(R132H) gliomas.

RICH2 decreases the mitochondrial number and affects mitochondrial localization in diffuse low-grade glioma-related epilepsy

Epilepsy, a common complication of diffuse low-grade gliomas (DLGGs; diffuse oligodendroglioma and astrocytoma collectively), severely compromises the quality of life of patients. DLGG epileptogenicity may primarily be generated by interactions between the tumor and the neocortex. Neuronal uptake of dysfunctional mitochondria from the extracellular environment can lead to abnormal neuronal discharge. Mitochondrial dysfunction is frequently observed in gliomas that can transmigrate across the plasma membranes. Here, we examined the role of the Rho GTPase-activating protein 44 (RICH2) in mitochondrial dynamics and DLGG-related epilepsy. We investigated the association between mitochondrial and RICH2 expression in human DLGG tissues using immunohistochemistry. We examined the association between RICH2 and epilepsy in nude mouse glioma models by electrophysiology. The effect of RICH2 on mitochondrial morphology and calcium motility were assessed by single cell fluorescence microscopy. Quantitative RT-PCR (qRT-PCR) and Western blot analysis were performed to characterize RICH2 induced expression changes in the genes related to mitochondrial dynamics, mitogenesis and mitochondrial function. We found that RICH2 expression was higher in oligodendroglioma than in astrocytoma and was correlated with better prognosis and higher epilepsy rate in patients. The expression of mitochondria may be associated with clinical DLGG-related epilepsy and reduced by RICH2 overexpression. And RICH2 could promote DLGG-related epilepsy in tumorigenic nude mice. RICH2 overexpression decreased calcium flow and the mitochondria released from glioma cells (SW1088 and U251) into the extracellular environment, potentially via downregulation of MFN-1/MFN-2 levels which suggests reduced mitochondrial fusion. In addition, we observed decreased mitochondrial trafficking into neurons (released from glioma cells and trafficked into neurons), which could explain the higher incidence of DLGG-related epilepsy due to reduced neuroprotection. Furthermore, RICH2 downregulated MAPK/ERK/HIF-1 pathway. In conclusion, these results suggest that RICH2 could promote epilepsy by (i) inhibiting mitochondrial fusion via MFN downregulation and Drp-1 upregulation; (ii) altering the MAPK/ERK/Hif-1 signaling axis. RICH2 may be a potential target in the treatment of DLGG-related epilepsy.

Review on neuroimaging in pediatric-type diffuse low-grade gliomas.

The fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5) has identified a new classification system for tumors of the brain and spinal cord, highlighting the pivotal role of molecular diagnosis in accurately categorizing neoplasms. In addition to previous classifications, one of the key distinctions lies in categorizing pediatric-type diffuse low-grade gliomas (pDLGGs) and pediatric-type diffuse high-grade gliomas (pDHGGs) as distinct tumor types. Although similar in histology and morphology, pediatric diffuse gliomas are completely different from the adult type with respect to the molecular genetic characteristics, prognosis, and treatment strategies. pDLGG includes four tumor types, namely, diffuse astrocytoma, MYB- or MYBL1-altered; angiocentric glioma; polymorphous low-grade neuroepithelial tumor of the young (PLNTY); and diffuse low-grade glioma, MAPK pathway-altered, three types of which are newly recognized tumor types. Herein, we review the clinical characteristics, histopathological and molecular genetic characteristics, neuroimaging features, and prognosis of pDLGG and summarize the neuroimaging key points in diagnosing different tumor types. This review aims to evaluate and update the relevant pDLGG features and advances in neuroimaging that may assist in differential diagnosis, surgery planning, and prognostic determination of these tumor types and provide accurate diagnostic information for clinical colleagues.

Surgical, functional, and oncological considerations regarding awake resection for giant diffuse lower-grade glioma of more than 100 cm3.

Surgery for giant diffuse lower-grade gliomas (LGGs) is challenging, and very few data have been reported on this topic in the literature. In this article, the authors investigated surgical, functional, and oncological aspects in patients who underwent awake resection for large LGGs with a volume > 100 cm3. The authors retrospectively reviewed a consecutive cohort of patients who underwent surgery in an awake condition for an LGG (WHO grade 2 with possible foci of grade 3 transformation) with a volume > 100 cm3. A total of 108 patients were included, with a mean age of 36.1 ± 8.5 years. The mean presurgical LGG volume was 136.7 ± 34.5 cm3. In all but 2 patients a disconnection resective surgery up to functional boundaries was possible thanks to active patient collaboration during the awake period. At 3 months of follow-up, all but 1 patient had a normal neurological examination, with a mean Karnofsky Performance Status (KPS) score of 89.8 ± 10.36. In all patients with preoperative epilepsy, there was postoperative control or significant reduction of seizure events. Moreover, 85.1% of patients returned to work. The mean extent of resection (EOR) was 88.9% ± 7.0%, with a mean residual tumor volume (RTV) of 16.3 ± 12.0 cm3 (median RTV 15 cm3). Pathological examination revealed 73 grade 2 gliomas (67.6%; 26 oligodendrogliomas and 47 astrocytomas) and 35 gliomas with foci of grade 3 (32.4%; 19 oligodendrogliomas and 16 astrocytomas). During the postoperative period, 93.6% of patients underwent adjuvant chemotherapy with a median interval between surgery and first chemotherapy of 14 months (IQR 2-26 months), and 55% of patients had radiotherapy with a median interval of 38.5 months (IQR 18-59.8 months). At the last follow-up, 69.7% of patients were still alive with a median follow-up of 62 months (IQR 36-99 months). Overall survival (OS) rates at 1, 5, and 10 years were 100% (95% CI 0.99-1), 80% (95% CI 0.72-0.9), and 58% (95% CI 0.45-0.73), respectively. The median OS was 138 months. In multivariable Cox regression analysis, RTV was established as the only independent prognostic factor for survival. With the application of rigorous surgical methodology based on functional-guided resection, resection of giant LGGs (volume > 100 cm3) can be reproducibly achieved during surgery with patients under awake mapping with both favorable functional results (< 1% permanent neurological worsening) and favorable long-term oncological outcomes (median OS > 11 years, with a more significant benefit when the RTV is < 15 cm3).

Adjuvant Chemoradiotherapy within One Year of Resection for Molecularly Defined Astrocytoma

Treatments for diffuse low-grade gliomas (LGG) are controversial. Level I evidence supports the use of adjuvant radiotherapy (RT) and PCV chemotherapy for histologic LGG, but integration of molecular biomarkers in recent WHO classification and the emergence of temozolomide chemotherapy for gliomas necessitates additional investigation of the optimal treatment and timing of postoperative interventions. We hypothesized molecularly-defined LGG (IDH-mutant astrocytoma (astro) and IDH-mutant, 1p/19q-codeleted oligodendroglioma (oligo)) may have different clinical outcomes following adjuvant RT (aRT) with chemotherapy (aRT+chemo) vs observation or chemo alone. A retrospective analysis of consecutive adult patients diagnosed with WHO Grade 2 astrocytoma or oligodendroglioma who underwent initial resection at a single institution from January 1998 to November 2017 was performed. Wilcoxon rank sum and Chi-squared tests were used to compare continuous and categorical variables, respectively. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards models. Patients without clinical progression or death were censored at the date of last follow-up. Pre-operative and post-operative T2 FLAIR hyperintense tumor volumes were quantified using 3D Slicer to calculate extent of resection (EOR). A total of 342 patients with molecularly-defined LGG (178 astro, 164 oligo) were identified with a median follow up of 9.1 yr. 171 (50%) patients received RT during their treatment course, of which 31 (18%) were treated with aRT within 1 year of diagnosis. The median aRT dose was 54 Gy (range: 40-60 Gy). aRT was more likely for astro (58%) vs oligo (41%, p = 0.001) and for patients who had resections with lower median EOR (88% vs 95%, p = 0.014). 53 patients (15%) were treated with chemo alone, and 136 patients (40%) were treated with aRT+chemo. Temozolomide was used for 161 patients (85%). For astro, aRT+chemo was associated with longer PFS (median 14.9 yr) compared to observation (4.8 yr, p = 0.05), aRT without chemo (5.2 yr, p = 0.01), or chemo alone (4.7 yr, p = 0.02). For oligo, aRT+chemo was associated with longer PFS (median not reached) compared to aRT without chemo (1.6 yr, p = 0.03), but not when compared to observation (median not reached, p = 0.47), or chemo alone (7.9 yr, p = 0.45). Multivariate analysis showed preoperative tumor volume, EOR, and aRT+chemo (but not aRT or chemo alone) were independently associated with astro PFS compared to observation. Propensity matching based on pre-operative tumor volume, EOR, and age demonstrated longer astro PFS after aRT+chemo (14.9 yr) compared to observation or chemo alone (4.5 yr, p = 0.015), without significant difference in OS (18.2 vs. 11.5 yr, p = 0.40). Retrospective data from a single institution support the use of adjuvant radiotherapy with chemotherapy for patients with molecular astrocytomas, while the role of this approach for oligodendrogliomas is unclear in this cohort.

Machine learning models based on multi-parameter MRI radiomics for prediction of molecular glioblastoma: a new study based on the 2021 World Health Organization classification.

The 2021 World Health Organization (WHO) classification considers a histological low grade glioma with specific molecular characteristics as molecular glioblastoma (mGBM). Accurate identification of mGBM will aid in risk stratification of glioma patients. To explore the value of machine learning models based on magnetic resonance imaging (MRI) radiomics features in predicting mGBM. In total, 166 patients histologically diagnosed as low-grade diffuse glioma (WHO II and III) were included in the study. Fifty-three cases were reclassified as mGBM based on molecular status. Four dimensionality reduction methods including distance correlation (DC), gradient boosted decision tree (GBDT), least absolute shrinkage and selection operator (LASSO) and minimal redundancy maximal relevance (MRMR) were used to select the optimal signatures. Six machine learning algorithms including support vector machine (SVM), linear discriminant analysis (LDA), neural network (NN), logistic regression (LR), K-nearest neighbour (KNN) and decision tree (DT) were used to develop the classifiers. The relative SD was used to evaluate the stability of the models, and the area under the curve values in the independent test group were used to evaluate their performances. NN_DC was determined as the optimal classifier due to the highest area under the curve of 0.891 in the test group. The classification accuracy, sensitivity, specificity, positive predictive value and negative predictive value of NN_DC were 0.915, 0.842, 0.950, 0.889 and 0.927, respectively. Machine learning models can predict mGBM non-invasively, which may help to develop personalized treatment strategies for neurosurgeons and provide an effective tool for accurate stratification in clinical trials.

The 2021 WHO Classification for Gliomas and Implications on Imaging Diagnosis: Part 3-Summary of Imaging Findings on Glioneuronal and Neuronal Tumors.

The fifth edition of the World Health Organization classification of central nervous system tumors published in 2021 reflects the current transitional state between traditional classification system based on histopathology and the state-of-the-art molecular diagnostics. This Part 3 Review focuses on the molecular diagnostics and imaging findings of glioneuronal and neuronal tumors. Histological and molecular features in glioneuronal and neuronal tumors often overlap with pediatric-type diffuse low-grade gliomas and circumscribed astrocytic gliomas (discussed in the Part 2 Review). Due to this overlap, in several tumor types of glioneuronal and neuronal tumors the diagnosis may be inconclusive with histopathology and genetic alterations, and imaging features may be helpful to distinguish difficult cases. Thus, it is crucial for radiologists to understand the underlying molecular diagnostics as well as imaging findings for application on clinical practice. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

P02.21.A A BIOBANK OF IDH1-MUTANT CELL LINES FOR STUDYING TUMOR HETEROGENEITY, PROGRESSION AND TARGET IDENTIFICATION

Abstract BACKGROUND Diffuse low grade gliomas are grade II brain tumors mainly affecting young patients. Most of these tumors have a mutation in the IDH1 gene (isocitrate dehydrogenase 1) gene causing differentiation defects and cell accumulation in the brain. These tumors are classified as astrocytomas or oligodendrogliomas and often progress into high grade gliomas (i.e IDH1-mutant grade IV astrocytomas and grade III oligodendrogliomas). We and others have shown that IDH1-mutant diffuse low grade gliomas contain 3 types of tumoral cells, resembling astrocytes, oligodendrocytes and neural progenitors, the formation of which is regulated by Notch signaling (Augustus et al, 2021, Cells, Suvà et al, 2020, Cancer Cell). There is a significant lack of cellular tools to study these tumors in vitro, hindering the development of new therapies. We aimed to address this by creating a fully annotated biobank of IDH1-mutant cell lines derived from different grades of tumors and carrying various rare mutations. MATERIAL AND METHODS We derived and collected 8 IDH1-mutant cell lines (4 astrocytomas grade II/III/IV and 4 grade III oligodendrogliomas). These cell lines were characterized using bulk RNA sequencing under different culture conditions, single-cell RNA sequencing to determine their cellular heterogeneity, and immunofluorescence and western blotting. RESULTS Our findings show that these IDH1-mutant cell lines exhibit different growth rates and morphologies and are phenotypically related to brain radial glial cells, oligodendrocyte progenitor cells, or more mature oligodendrocytes. Some of these cell lines are multipotent and contain astrocyte-like and oligodendrocyte-like cells. Our current work aims to purify different cell subpopulations to study their properties and plasticity. Additionally, we are analyzing pathways and differentially expressed genes involved in IDH1-mutant cell quiescence and malignant progression. CONCLUSION In summary, we present a novel and deeply-annotated biobank of 8 IDH1-mutant cell lines derived from different grades of gliomas, providing an invaluable resource to study the cellular and molecular heterogeneity of IDH1-mutant gliomas, their progression to high-grade gliomas, and the identification of new therapeutic targets. We anticipate that our biobank may facilitate the development of personalized medicine for patients with IDH1-mutant gliomas and accelerate the discovery of new therapeutic strategies.