Diffuse Low-grade Gliomas Research Articles

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.

Oncological and functional outcomes support early resection of incidental IDH-mutated glioma.

The main objective was to assess the neuropsychological, epileptical, and oncological outcomes in a series of patients operated on for a IDH-mutated diffuse low-grade glioma (DLGG) of incidental discovery (iDLGG). We retrospectively reviewed a consecutive series of surgically treated adults with DLGG and selected cases incidentally discovered. Tumor volumes, growth rates, and extents of resection (EOR) were assessed by volumetric measures of fluid-attenuated inversion recovery magnetic resonance imaging. The data on oncological, functional, and epileptical results were retrieved from the patients' digital files. Among all patients with DLGG resected at our center between June 2011 and April 2022, we found eleven cases with an incidental discovery. Resection was supratotal, gross total, and subtotal in 45.5%, 26.4%, and 18.1% of cases, respectively. The rate of epileptic seizures after the surgery was 9.1%. There were 45.4% of patients that had tumor progressions and the overall mean time to tumor progression was 42months. After the surgery, 3 (27.3%) patients had mild neurocognitive deteriorations, which impeded the return to work in one patient (9.1%). There were no differences with previous series regarding clinical, radiological, and molecular characteristics. Similar results were also found for functional, surgical, epileptical, and oncological outcomes. Although the right approach for iDLGG is still a matter of debate, our data support the safety and effectiveness of early surgical resection. More studies are needed to firmly ground this early "preventive" surgery approach.

Classification and Diagnostics of Pediatric Brain Tumors

In childhood and young adulthood, a wide variety of brain tumors, such as medulloblastoma and ependymoma, frequently occur. Moreover, high- or low-grade diffuse gliomas, commonly found in adults, also emerge. Recent genomic research has revealed numerous molecular and genetic features of pediatric brain tumors. These molecular and genetic findings have been incorporated into the latest 2021 World Health Organization Classification of Tumors of the Central Nervous System(WHO CNS 5). WHO CNS 5 introduces separate classifications for adult- and pediatric-type diffuse gliomas, which were conventionally diagnosed using the same criteria. Classifying these adult- and pediatric-type gliomas using histopathological properties alone is challenging. Therefore, molecular diagnostics utilizing diverse molecular and genetic information, including variants, copy number alterations, structural abnormalities, and DNA methylation profiles, are imperative. Many molecular and genetic characteristics have been elucidated in the WHO CNS 5. Molecular diagnostics and classification are essential for accurately categorizing pediatric brain tumors, and the significance of molecular and genetic information will continue to grow.

The Role of Advanced MRI Sequences in the Diagnosis and Follow-Up of Adult Brainstem Gliomas: A Neuroradiological Review.

The 2021 WHO (World Health Organization) classification of brain tumors incorporated the rapid advances in the molecular, genetic, and pathogenesis understanding of brain tumor pathogenesis, behavior, and treatment response. It revolutionized brain tumor classification by placing great emphasis on molecular types and completely splitting adult-type and pediatric-type diffuse gliomas. Brainstem gliomas (BSGs) are the leading primary tumors of the brainstem, although they are quite uncommon in adults compared with the pediatric population, representing less than 2% of adult gliomas. Surgery is not always the treatment of choice since resection is rarely feasible and does not improve overall survival, and biopsies are not generally performed since the location is treacherous. Therefore, MRI (Magnetic Resonance Imaging) without and with gadolinium administration represents the optimal noninvasive radiological technique to suggest brainstem gliomas diagnosis, plan a multidisciplinary treatment and for follow-up evaluations. The MRI protocol encompasses morphological sequences as well as functional and advanced sequences, such as DWI/ADC (Diffusion-Weighted Imaging/Apparent Diffusion Coefficient), DTI (Diffusion Tensor Imaging), PWI (Perfusion-Weighted Imaging), and MRS (Magnetic Resonance Spectroscopy), which improve the accuracy of the diagnosis of BSGs by adding substantial information regarding the cellularity, the infiltrative behavior toward the v fiber tracts, the vascularity, and the molecular changes. Brainstem gliomas have been divided into four categories on the basis of their MRI radiological appearance, including diffuse intrinsic low-grade gliomas, enhancing malignant gliomas, localized tectal gliomas, and other forms. The aim of our review is to provide insight into the role of advanced MRI sequences in the diagnosis and follow-up of adult brainstem gliomas.

Long-term follow up of patients with WHO grade 2 oligodendroglioma

PurposeSince the introduction of the molecular definition of oligodendrogliomas based on isocitrate dehydrogenase (IDH)-status and the 1p19q-codeletion, it has become increasingly evident how this glioma entity differs much from other diffuse lower grade gliomas and stands out with longer survival and often better responsiveness to adjuvant therapy. Therefore, apart from using a molecular oligodendroglioma definition, an extended follow-up time is necessary to understand the nature of this slow growing, yet malignant condition. The aim of this study was to describe the long-term course of the oligodendroglioma disease in a population-based setting and to determine which factors affect outcome in terms of survival.MethodsAll adults with WHO-grade 2 oligodendrogliomas with known 1p19q-codeletion from five Scandinavian neurosurgical centers and with a follow-up time exceeding 5 years, were analyzed regarding survival and factors potentially affecting survival.Results126 patients diagnosed between 1998 and 2016 were identified. The median follow-up was 12.0 years, and the median survival was 17.8 years (95% CI 16.0–19.6).Factors associated with shorter survival in multivariable analysis were age (HR 1.05 per year; CI 1.02–1.08, p < 0.001), tumor diameter (HR 1.05 per millimeter; CI 1.02–1.08, p < 0.001) and poor preoperative functional status (KPS < 80) (HR 4.47; CI 1.70–11.78, p = 0.002). In our material, surgical strategy was not associated with survival.ConclusionIndividuals with molecularly defined oligodendrogliomas demonstrate long survival, also in a population-based setting. This is important to consider for optimal timing of therapies that may cause long-term side effects. Advanced age, large tumors and poor function before surgery are predictors of shorter survival.Graphical

Multiparametric mapping of white matter reorganizations in patients with frontal glioma-related epilepsy.

Epilepsy is a common symptom in diffuse lower-grade glioma (DLGG). The specific role of white matter (WM) alteration in patients with glioma-related epilepsy (GRE) is largely unknown. This study aims to investigate the reorganization of WM tracts and changes in structural networks related to GRE. Diffusion-weighted images were collected from 70 patients with left frontal DLGG (GRE = 33, non-GRE = 37) and 41 healthy controls (HC). Tractometry with TractSeg was applied to segment tracts and quantify fractional anisotropy (FA) along each tract. Structural network was constructed using constrained spherical deconvolution and probabilistic tractography. FA and network properties were compared among three groups. Compared with HC, both GRE and non-GRE showed decreased FA in contralateral inferior fronto-occipital fasciculus, superior longitudinal fasciculus II and arcuate fasciculus, increased nodal efficiency in contralateral nodes of frontal-parietal and limbic networks, whereas decreased degree centrality and betweenness centrality in nodes of dorsal temporal lobe and rostral middle frontal gyrus (rMFG). Additionally, when compared GRE with non-GRE, increased FA in contralateral corticospinal tract (CST) and lower betweenness centrality in paracentral lobule (PCL) in GRE (all p < 0.05 after Bonferroni correction). This study indicates that patients with left frontal DLGG exhibit complex WM reorganization, and the altered regions mainly concentrated in the language, frontal-parietal and limbic networks. Moreover, the preserved integrity in contralateral CST and server decreased nodal betweenness in PCL may be potential neuroimaging markers underlying the occurrence of presurgical seizures of GRE.

Awake Craniotomy for Diffuse Low Grade Gliomas in a Resource Limited Setting: Lessons Learned with a Consecutive Series of 51 Surgeries

Despite benefits of awake craniotomy (AC) many centers do not have access to it. We demonstrated the oncological and functional results of our initial experience in implementing AC in a context of resource limited setting. This prospective, observational, descriptive study collected the first 51 AC for Diffuse Low Grade Glioma, classified according to the 2016 World Health Organization. Mean age was 35.09 ± 9.91 years-old. The most common clinical presentation was seizure (89.58%). The average segmented volume was 69.8 cc; with 51% of lesions with more than 6 cm in the largest diameter. Resection of more than 90% of the lesion was achieved in 49% of cases, and greater than 80% in 66.6% of cases. The mean follow-up was 835 days (2.29 years). Satisfactory Karnofsky performance status (KPS) (80 to 100) was observed in 90.1% pre-surgery, 50.9% at 5 days, 93.7% at 3 months, and 89.7% at 1-year post-op. At multivariate analysis, tumor volume, new postoperative deficit and extent of resection were related to KPS at 1 year of follow up. Functional decline was clearly observed in the immediate postoperative period, but excellent recovery of functional status was observed in the medium and long term. The data presented indicate the benefits of this mapping in both cerebral hemispheres, addressing several cognitive functions in addition to motricity and language.The proposed AC model is a reproducible technique, resource sparing, that can be performed safely and with good functional outcomes.

A comprehensive analysis of infantile central nervous system tumors to improve distinctive criteria for infant-type hemispheric glioma versus desmoplastic infantile ganglioglioma/astrocytoma.

Recent epigenomic analyses have revealed the existence of a new DNA methylation class (MC) of infant-type hemispheric glioma (IHG). Like desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA), these tumors mainly affect infants and are supratentorial. While DIG/DIA is characterized by BRAF or RAF1 alterations, IHG has been shown to have receptor tyrosine kinase (RTK) gene fusions (ALK, ROS1, NTRK1/2/3, and MET). However, in this rapidly evolving field, a more comprehensive analysis of infantile glial/glioneuronal tumors including clinical, radiological, histopathological, and molecular data is needed. Here, we retrospectively investigated data from 30 infantile glial/glioneuronal tumors, consecutively compiled from our center. They were analyzed by two experienced pediatric neuroradiologists in consensus, without former knowledge of the molecular data. We also performed a comprehensive clinical, and histopathological examination (including molecular evaluation by next-generation sequencing, RNA sequencing, and fluorescence in situ hybridization [FISH] analyses), as well as DNA methylation profiling for the samples having sufficient material available. The integrative histopathological, genetic, and epigenetic analyses, including t-distributed stochastic neighbor embedding (t-SNE) analyses segregated tumors into 10 DIG/DIA (33.3%), six IHG (20.0%), three gangliogliomas (10.0%), two pleomorphic xanthoastrocytomas (6.7%), two pilocytic astrocytomas (6.7%), two supratentorial ependymomas, ZFTA fusion-positive (6.7%), two supratentorial ependymomas, YAP1 fusion-positive (6.7%), two embryonal tumors with PLAGL2-family amplification (6.7%), and one diffuse low-grade glioma, MAPK-pathway altered. This study highlights the significant differential features, in terms of histopathology (leptomeningeal infiltration, intense desmoplasia and ganglion cells in DIG/DIA and necrosis, microvascular proliferation, and siderophages in IHG), and radiology between DIG/DIA and IHG. Moreover, these results are consistent with the literature data concerning the molecular dichotomy (BRAF/RAF1 alterations vs. RTK genes' fusions) between DIG/DIA and IHG. This study characterized histopathologically and radiologically two additional cases of the novel embryonal tumor characterized by PLAGL2 gene amplification.

Prediction of 1p/19q codeletion status in diffuse lower-grade glioma using multimodal MRI radiomics

To develop a noninvasive method for prediction of 1p/19q codeletion in diffuse lower-grade glioma (DLGG) based on multimodal magnetic resonance imaging (MRI) radiomics. We collected MRI data from 104 patients with pathologically confirmed DLGG between October, 2015 and September, 2022. A total of 535 radiomics features were extracted from T2WI, T1WI, FLAIR, CE-T1WI and DWI, including 70 morphological features, 90 first order features, and 375 texture features. We constructed logistic regression (LR), logistic regression least absolute shrinkage and selection operator (LRlasso), support vector machine (SVM) and Linear Discriminant Analysis (LDA) radiomics models and compared their predictive performance after 10-fold cross validation. The MRI images were reviewed by two radiologists independently for predicting the 1p/19q status. Receiver operating characteristic curves were used to evaluate classification performance of the radiomics models and the radiologists. The 4 radiomics models (LR, LRlasso, SVM and LDA) achieved similar area under the curve (AUC) in the validation dataset (0.833, 0.819, 0.824 and 0.819, respectively; P>0.1), and their predictive performance was all superior to that of resident physicians of radiology (AUC=0.645, P=0.011, 0.022, 0.016, 0.030, respectively) and similar to that of attending physicians of radiology (AUC=0.838, P>0.05). Multiparametric MRI radiomics models show good performance for noninvasive prediction of 1p/19q codeletion status in patients with in diffuse lower-grade glioma.

Characterization and clinical implications of different malignant transformation patterns in diffuse low-grade gliomas.

Malignant transformation (MT) of low-grade gliomas (LGGs) to a higher-grade variant seems inevitable, yet it remains unclear which LGG patients will progress to grade 3 or even directly to grade 4 after receiving a long course of treatment. To elucidate this, we conducted a retrospective cohort study based on 229 adults with recurrent LGG. Our study aimed to disclose the characteristics of different MT patterns and to build predictive models for patients with LGG. Patients were allocated into group 2-2 (n = 81, 35.4%), group 2-3 (n = 91, 39.7%), and group 2-4 (n = 57, 24.9%), based on their MT patterns. Patients who underwent MT showed lower Karnofsky performance scale (KPS) scores, larger tumor sizes, smaller extents of resection (EOR), higher Ki-67 indices, lower rates of 1p/19q codeletion, but higher rates of subventricular involvement, radiotherapy, chemotherapy, astrocytoma, and post-progression enhancement (PPE) compared with those in group 2-2 (p < 0.01). On multivariate logistic regression, 1p/19q codeletion, Ki-67 index, radiotherapy, EOR, and KPS score were independently associated with MT (p < 0.05). Survival analyses demonstrated that patients in group 2-2 had the longest survival, followed by group 2-3 and then group 2-4 (p < 0.0001). Based on these independent parameters, we constructed a nomogram model that exhibited superior potential (sensitivity: 0.864, specificity: 0.814, and accuracy: 0.843) compared with PPE in early prediction of MT. Combining the factors of 1p/19q codeletion, Ki-67 index, radiotherapy, EOR, and KPS score that were presented at initial diagnosis could precisely forecast the subsequent MT patterns of patients with LGG.

LGG-14. TREATMENT OF TWO PEDIATRIC FGFR-ALTERED LOW-GRADE GLIONEURONAL TUMORS WITH MEK INHIBITION

Abstract Somatic alterations in the fibroblast growth factor receptor (FGFR) gene family (FGFR1/2/3) have been implicated in tumorigenesis across pediatric low-grade glioneuronal neoplasms and represent a potential therapeutic target. FGFR rearrangements and internal tandem duplication (ITD) cause constitutive receptor tyrosine kinase activation, thereby promoting tumor cell growth, differentiation, and survival through complex downstream signaling, including via the mitogen activated protein kinase (MAPK) pathway. With increasing safety and efficacy data in pediatric neuro-oncology, MEK inhibitors may be considered to target MAPK pathway activation in FGFR-altered low-grade glioneuronal tumors, although clinical evidence within this specific molecular subgroup is lacking. Herein, we describe two cases of pediatric low-grade glioneuronal tumors harboring FGFR aberrations with encouraging clinical and radiographic response to MEK inhibition. The first patient has a multiply recurrent left parietal dysembryoplastic neuroepithelial tumor (DNET) with an FGFR1 ITD, diagnosed at eight years of age after presenting with seizures. Despite two surgical resections (with identical pathology), his disease slowly progressed. Oral MEK inhibitor therapy with trametinib was initiated, which he has remained on for the past 9+ months, with stable residual tumor without continued radiographic progression. The second patient was diagnosed at three years of age with focal epilepsy, prompting imaging demonstrating an infiltrative T2/FLAIR-hyperintense right temporal mass. Subtotal resection was performed, with pathology consistent with pediatric-type diffuse low-grade glioma. Molecular profiling identified an FGFR3-TACC3 fusion, with suspected enrichment for MAPK-pathway activation by preliminary RNA-sequencing analyses. Adjuvant therapy with trametinib was started, with small reduction in residual disease burden observed radiographically three months into treatment. Both patients continue on MEK inhibitor therapy with minimal toxicity and adequate control of underlying seizures. Though further research in larger, prospective cohorts with comprehensive biology data is necessary, oral MEK inhibitors represent a feasible and rational treatment consideration for pediatric FGFR-altered low-grade glioneuronal tumors.

Evaluation of a nnU-Net type automated clinical volumetric tumor segmentation tool for diffuse low-grade glioma follow-up

Background and purposeDiffuse low-grade gliomas (DLGG) are characterized by a slow and continuous growth and always evolve towards an aggressive grade. Accurate prediction of the malignant transformation is essential as it requires immediate therapeutic intervention. One of its most precise predictors is the velocity of diameter expansion (VDE). Currently, the VDE is estimated either by linear measurements or by manual delineation of the DLGG on T2 FLAIR acquisitions. However, because of the DLGG's infiltrative nature and its blurred contours, manual measures are challenging and variable, even for experts. Therefore we propose an automated segmentation algorithm using a 2D nnU-Net, to 1) gain time and 2) standardize VDE assessment. Materials and MethodsThe 2D nnU-Net was trained on 318 acquisitions (T2 FLAIR & 3DT1 longitudinal follow-up of 30 patients, including pre- & post-surgery acquisitions, different scanners, vendors, imaging parameters…). Automated vs. manual segmentation performance was evaluated on 167 acquisitions, and its clinical interest was validated by quantifying the amount of manual correction required after automated segmentation of 98 novel acquisitions. ResultsAutomated segmentation showed a good performance with a mean Dice Similarity Coefficient (DSC) of 0.82±0.13 with manual segmentation and a substantial concordance between VDE calculations. Major manual corrections (i.e., DSC<0.7) were necessary only in 3/98 cases and 81% of the cases had a DSC>0.9. ConclusionThe proposed automated segmentation algorithm can successfully segment DLGG on highly variable MRI data. Although manual corrections are sometimes necessary, it provides a reliable, standardized and time-winning support for VDE extraction to asses DLGG growth.

Role of 1p/19q Codeletion in Diffuse Low-grade Glioma Tumour Prognosis.

In the latest 2021 WHO classification of central nervous system tumours (CNS), gliomas that present isocitrate dehydrogenase (IDH) mutations are defined as diffuse low-grade gliomas (DLGGs). IDH mutations are commonly observed in this tumour type. The Extent of Resection (EOR) positively influence survival; however, it is still debated whether the predictive value of EOR is independent of the 1p/19q co-deletion. We carried out a retrospective analysis on patients operated on for DLGG at the Sant'Andrea University Hospital Sapienza University of Rome, correlating the outcome with the presence of 1p/19q co-deletion and EOR. The study examined 66 patients with DLGG who had undergone surgery for tumour resection between 2008 and 2018. Patients with DLGG were divided into two groups; diffuse astrocytoma (DA) in which 1p/19q codeletion is absent and oligodendroglioma (OG) in which 1p/19q codeletion is present. According to EOR, both groups were divided into two subgroups: subtotal resection (STR) and gross total resection (GTR). Three end-point variables were considered: overall survival (OS), progression-free survival (PFS) and time to malignant transformation (TMT). In the DA group, the GTR subgroup had an average OS of 81.6 months, an average PFS of 45.9 months and an average TMT of 63.6 months. After surgery, these patients had an average Karnofsky Performance Score (KPS) of 83.4. The STR subgroup had an average OS of 60.4 months, PFS was 38.7 months, and TMT was 46.4 months, post-operative KPS was 83.4. In contrast, in the OG group, the GTR averagely had 101.7 months of OS, 64.9 months of PFS, 80.3 months of TMT and an average post-operative KPS of 84.2, and the STR subgroup had an average of OS of 73.3 months, PFS of 48.2 months, TMT of 57.3 and an average postoperative KPS of 96.2. In patients affected by DLGGs, 1p/19q codeletion is significantly associated with prolonged survival and longer time-to-malignant transformation (TMT) compared to the absence of 1p/19q codeletion. Also, the extent of surgical resection (EOR) in DLGG patients has been confirmed as one of the main prognostic factors. However, its predictive value is substantially influenced by the presence of the 1p/19q codeletion.

The clinical value of proneural, classical and mesenchymal protein signatures in WHO 2021 adult-type diffuse lower-grade gliomas.

Accumulating evidence shows that mesenchymal transition of glioblastomas is associated with a more aggressive course of disease and therapy resistance. In WHO2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition of the tumor phenotype over time, has not been studied. Most efforts to correlate proneural, classical or mesenchymal phenotype with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype predicted survival and tumor recurrence in a clinical cohort of dLGGs, re-classified according to the 2021 WHO criteria. Using a TMA-based approach with five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2), we investigated 183 primary and 49 recurrent tumors derived from patients with previously diagnosed dLGG. Of the 49 relapses, nine tumors recurred a second time, and one a third time. In total, 71.0% of all tumors could be subtyped. Proneural was most dominant in IDH-mut tumors (78.5%), mesenchymal more common among IDH-wt tumors (63.6%). There was a significant difference in survival between classical, proneural and mesenchymal phenotypes in the total cohort (p<0.001), but not after molecular stratification (IDH-mut: p = 0.220, IDH-wt: p = 0.623). Upon recurrence, proneural was retained in 66.7% of the proneural IDH-mut dLGGs (n = 21), whereas IDH-wt tumors (n = 10) mainly retained or gained mesenchymal phenotype. No significant difference in survival was found between IDH-mut gliomas remaining proneural and those shifting to mesenchymal phenotype (p = 0.347). Subtyping into classical, proneural and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but protein signatures did not correlate with patient survival in our WHO2021-stratified cohort. At recurrence, IDH-mut tumors mainly retained proneural, while IDH-wt tumors mostly retained or gained mesenchymal signatures. This phenotypic shift, associated with increased aggressiveness in glioblastoma, did not affect survival. Group sizes were, however, too small to draw any firm conclusions.