Epileptic seizures in diffuse low-grade gliomas in adults

Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes

Brain mapping through a direct cortical and subcortical electrical stimulation during an awake craniotomy has gained an increasing popularity as a powerful tool to prevent neurological deficit while increasing extent of resection of hemispheric diffuse low-grade gliomas in adults. However, few case reports or very limited series of awake surgery in children are currently available in the literature. In this paper, we review the oncological and functional differences between pediatric and adult populations, and the methodological specificities that may limit the use of awake mapping in pediatric low-grade glioma surgery. This could be explained by the fact that pediatric low-grade gliomas have a different epidemiology and biologic behavior in comparison to adults, with pilocytic astrocytomas (WHO grade I glioma) as the most frequent histotype, and with WHO grade II gliomas less prone to anaplastic transformation than their adult counterparts. In addition, aside from the issue of poor collaboration of younger children under 10years of age, some anatomical and functional peculiarities of children developing brain (cortical and subcortical myelination, maturation of neural networks and of specialized cortical areas) can influence direct electrical stimulation methodology and sensitivity, limiting its use in children. Therefore, even though awake procedure with cortical and axonal stimulation mapping can be adapted in a specific subgroup of children with a diffuse glioma from the age of 10years, only few pediatric patients are nonetheless candidates for awake brain surgery.

Recently, I was discussing the treatment of a pediatric patient who had gliomatosis cerebri. A pediatric neuro-oncologist, one of my respectable friends, insisted on chemotherapy with temozolomide. Because the histologic type was anaplastic astrocytoma (as determined by open biopsy), many would consider radiotherapy the primary option; thus, there was an exciting discussion. On another occasion, the same colleague and I were discussing a pediatric patient with a symptomatic diffuse astrocytoma of the posterior thalamus; this time as well, he insisted on a trial of chemotherapy with carboplatin and vincristine. My colleague's philosophy is that because pediatric gliomas are different from adult gliomas, chemotherapy to defer or avoid radiotherapy is reasonable in cases of low-grade and sometimes even high-grade glioma. Maybe my colleague is right regarding the difference between pediatric and adult gliomas. There have been numerous reports showing substantial differences in the molecular features underlying pediatric and adult high-grade gliomas. Pediatric and adult glioblastomas were shown to be clearly distinguished by frequent gain of chromosome 1q and lower frequency of chromosome 7 gain and 10q loss in the pediatric form. Platelet-derived growth factor receptor-α (PDGFR-α) was found to be the predominant gene subject to focal amplification in childhood high-grade gliomas.1,2 Among the pediatric low-grade gliomas, pilocytic astrocytoma is the predominant histologic type and diffuse astrocytomas are quite rare. In this issue of Neuro-Oncology, Stokland et al. from the Children's Brain Tumour Research Centre, University of Nottingham, UK, report on 639 pediatric patients with low-grade gliomas, 63.7% of which were pilocytic astrocytomas and only 5.9% of which were diffuse fibrillary astrocytomas.3 The predominance of the former type is consistent with other evidence. For instance, in the Brain Tumor Registry of Japan, the incidence of pilocytic astrocytomas peaks in patients between 5 and 9 years old, while that of diffuse astrocytomas peaks in patients between 40 and 44 years old. In the Central Brain Tumor Registry of the United States (CBTRUS), 1,834 pediatric patients (those between 0 and 19 years old) with pilocytic astrocytomas are registered, while only 101 cases of diffuse astrocytoma are found in the pediatric population. Therefore, pediatric low-grade gliomas are mostly pilocytic astrocytomas, and adult low-grade gliomas are mostly diffuse astrocytomas. Pilocytic astrocytomas and diffuse astrocytomas are classified as WHO grades I and II, respectively. However, pilocytic astrocytoma is not a precursor of diffuse astrocytoma, as there is a distinct difference between the molecular features of the two. There appears to be no role for either TP53 mutations or aberrant PDGF signaling in the development of pilocytic astrocytomas, in contrast to the role of TP53 mutations and increased expression of PDGF-A and PDGFR-α as common, early events in the formation of diffuse astrocytomas.4 Pilocytic astrocytomas also differ from diffuse astrocytomas in their altered and increased expression of immune response genes. Hierarchical clustering analysis using a set of 1,176 genes distinguished pilocytic astrocytomas from diffuse astrocytomas and oligodendrogliomas.5 Pilocytic astrocytomas are also different from the diffuse astrocytomas clinically, as evidenced by the fact that histology is one prognostic factor in pediatric low-grade gliomas.3 Fear of radiation-induced adverse effects has been used to justify the use of chemotherapy for unresectable pilocytic astrocytomas. A number of chemotherapy regimens have been used to delay the need for radiotherapy, including carboplatin and vincristine. A recent randomized trial, Children's Oncology Group A9952, compared the combination of carboplatin and vincristine with the combination of procarbazine, thioguanine, lomustine, and vincristine and reported 5-year event-free survival rates of 40%-50%. More than 400 low-grade gliomas were registered, and 83% of them were pilocytic astrocytomas.6 However, although a small study is under way, the role of chemotherapy in the management of pediatric diffuse astrocytomas remains unclear. In adult diffuse astrocytomas, a randomized study comparing radiotherapy and temozolomide is now ongoing in Europe and North America. Yes, pediatric and adult gliomas are different. Pediatric and adult high-grade gliomas are biologically different. On the other hand, differences between pediatric and adult low-grade gliomas are mainly due to the difference in their histologies. Whether pediatric diffuse astrocytomas are chemosensitive remains unproven. The UK study reported in this issue also suggests that, because of the small number of diffuse astrocytomas in the pediatric population, international cooperation will be needed to address the issue of the optimal management of this entity.

Introduction: The disease course of patients with diffuse low-grade gliomas (LGGs) is notoriously unpredictable. Detailed analysis of the genetic make-up is therefore key to understand this wide variety in overall survival of patients diagnosed with LGGs. Reports on the prognostic value of CNAs other than 1p/19q co-deletion are conflicting, which may be explained by spatial copy number heterogeneity. Aim: Prognostic implications of spatial and temporal copy number aberrations in LGGs by whole genome sequencing. Methods: Approximately 25% of LGG patients have a life expectation of more than 20 years following diagnosis, which necessitates collection of samples with long clinical follow up information. Therefore archival material was selected for this project and WGS was developed to access these samples without the requirement for a normal reference. We collected 156 formalin-fixed and paraffin-embedded (FFPE) samples in a discovery cohort of 98 LGG patients with extensive clinical follow-up data, which included recurrent tumours and spatially distinct regions. An independent cohort of 126 samples was obtained from a recently published study (Alentorn et al, Neuro-oncology 2014). Technical challenges for genome-wide inference of copy number aberrations include repetitive and common DNA sequences in the genome and sequence variation across the general population, as well as the compromised and variable quality of DNA obtained from archived tissues. We developed a robust and cost effective method that infers copy number aberrations from WGS data of approximately 0.1x coverage, without the need for a reference signal. This method implements (1) a combined LOESS correction for mappability and GC content, and improves on previous methods by (2) comprehensive filtering based on public genome project data, 1000-Genomes project and ENCODE blacklists. Results: Both prognostic value, temporal evolution and spatial heterogeneity of CNA were assessed by WGS. We confirmed prognostic favourable value of 1p/19q co-deletion, and demonstrated loss of 10q to be an unfavourable marker. In paired recurrences 10q loss was invariably maintained and surfaced in 4 additional recurrences of the discovery cohort. In spatial regions of LGGs we recognized extensive copy number heterogeneity; 15 of 17 LGGs show spatial variability of CNAs. 1p/19q co-deletion is homogeneous, while loss of 10q is heterogeneously present. Conclusions: we present clinically relevant CNAs, but also demonstrate extensive spatial copy number heterogeneity in diffuse LGGs that might complicate unequivocal biomarker discovery. Citation Format: Ilari Scheinin, Hinke F. van Thuijl, Daoud Sie, Hendrik F. van Essen, Paul P. Eijk, Francois Rustenburg, Ahmed Idbaih, Agusti Alentorn, Gerrit A. Meijer, Mark A. van der Wiel, Henrik Bengtsson, Adam Olshen, Eleonora Aronica, Jan J. Heimans, Jaap C. Reijneveld, Pieter Wesseling, Donna G. Albertson, Dan Pinkel, Bauke Ylstra. A novel approach to copy number assessment by whole genome sequencing reveals extensive spatial heterogeneity in diffuse low-grade glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3426. doi:10.1158/1538-7445.AM2014-3426

Because diffuse low-grade glioma (DLGG) is constantly migrating in the brain until malignant transformation, the historic wait-and-watch attitude was replaced by an early therapeutic management. Moreover, advances in cognitive neurosciences allowed an improved understanding of neuroplasticity reactional to DLGG growth. Here, the aim is to reevaluate the role of surgery regarding both oncological and functional outcomes. Recent data evidenced the significant benefit of maximal well tolerated resection on survival and quality of life (QoL). By removing a diffuse neoplastic disease up to eloquent neural networks identified by intraoperative awake mapping and cognitive monitoring, overall survival is about the double compared with biopsy, whereas the rate of severe persistent deficits was significantly reduced. Postoperative QoL may even be improved owing to functional rehabilitation and epilepsy control. Early and functional mapping-guided surgery is currently the first treatment in DLGG. Surgical resection(s) should be integrated in a global personalized management that must be tailored to the brain connectome of each patient. To optimize the oncofunctional balance, the next step is a screening, to detect and to treat DLGG patients earlier, and to increase the rate of 'supramarginal excision' in the setting of a 'prophylactic connectomal neurooncological surgery'.

Multicentric diffuse low-grade gliomas (DLGGs) are defined as widely separated lesions in different lobes or hemispheres where there is no anatomical continuity between lesions. This condition is rare and its clinicopathological characteristics have been scarcely described in the literature. Here, the authors report the first consecutive surgical series of multicentric DLGGs with functional and oncological outcomes. A retrospective review of patients surgically treated for histopathologically confirmed multicentric DLGGs between 2000 and 2012 was performed. Information regarding clinical features, surgical procedures, histopathological results, and clinical outcomes was collected and analyzed. Five consecutive patients were included in this study. There were 3 men and 2 women, whose mean age was 27.4 years (range 23-35 years). The mean follow-up period after surgery was 46 months (range 11-138 months). Gross-total or subtotal resection was achieved in all cases, using a single surgery in 3 patients and a 2-stage surgery in 2 patients. There was no mortality or permanent morbidity associated with surgery. The Karnofsky Performance Scale score ranged between 90 and 100 in all cases. Adjuvant chemotherapy was administered in 2 patients because of tumor regrowth with no malignant transformation. Multicentric DLGGs can be removed safely without inducing severe permanent neurological deficits. Interestingly, a single-stage resection of multiple lesions within different lobes may be performed if tumors are located in the same hemisphere. Therefore, the authors suggest considering surgery as the first therapeutic option for multicentric DLGGs, as in solitary DLGGs.

Pediatric-Type Diffuse Low Grade Glioma.

BACKGROUND Insular gliomas pose great challenges to maximal safe resection. Perioperative morbidity is comparably high due to adjacent functional structures and vascular anatomy. Synaptic density in limbic/ paralimbic structures, including the insula, is known to be high. According to current concepts of cancer neuroscience, functional connectivity may drive tumor proliferation. Conversely, glioma increase neuronal excitability. This study investigates [18F]FET PET hypermetabolic foci distribution in insular gliomas to explore a potential link between cancer neuroscience and metabolic heterogeneity. MATERIAL AND METHODS A monocentric retrospective analysis identifies therapy-naïve patients with preoperative [18F]FET PET, that were later diagnosed with diffuse lower-grade glioma (DLGG). Fisher’s exact test is performed to compare insular glioma with other DLGG regarding location of hypermetabolic foci (background SUVmean x 1.6). Insular gliomas are categorized according to Yasargil’s classification for limbic/ paralimbic tumors. RESULTS Thirty-five (100%) patients with insular glioma, comprising 5 patients (14%) with tumors restricted to the insula exclusively, 20 patients (57%) with tumors extending to adjacent paralimbic structures (Yasargil type 5A), and 7 patients (20%) with tumors extending to limbic structures (Yasargil Type 5B), were included. There was no significant difference in the prevalence of [18F]FET hypermetabolic foci between insular gliomas and other lobar DLGG (p = 0.63), with foci identified in 75% of insular gliomas versus 78% in other DLGG. Of all insular gliomas, 19% exhibited [18F]FET hypermetabolic foci within the insula. In type 5A and 5B tumors, hotspots were predominantly located in paralimbic (52%) and limbic (28%) regions. There was no significant correlation of tumor heterogeneity and locoregional distribution within the group of insular gliomas. CONCLUSION This data demonstrates high intratumoral heterogeneity in the group of insular gliomas. However, theoretical high synaptic density in this particular anatomical region does not translate into of [18F]FET hypermetabolic foci distribution. An ongoing study evaluates locoregional distribiton of hypermetabolic foci in lobar DLGG.

Impact of repeated operations for progressive low-grade gliomas

Predictors and mechanisms of epilepsy occurrence in cerebral gliomas: What to look for in clinicopathology

Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Molecular characterization of these tumors led to the development of new classification system comprising specific glioma subtypes. While this provides novel molecular insight into gliomas it does not fully explain the variability in patient outcome. To identify and characterize a predictive signature of outcome in diffuse gliomas, we utilized an integrative molecular analysis (methylation, mRNA, copy number variation (CNV) and mutation data) using multiple molecular platforms, including a total of 310 IDH mutant glioma samples from University Health Network (UHN) and German Cancer Research Center (DKFZ) together with 419 samples from The Cancer Genome Atlas (TCGA). Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival (p-value < 0.0001). The CpG-based signatures were reliably validated using two independent datasets from TCGA and DKFZ cohorts (both p-values < 0.0001). The results show that the methylation signatures that predict poor outcome also correlated with G-CIMP low status, elevated CNV instability and hypermethylation of a set of HOX gene probes. Further study in diffuse lower-grade glioma (LGG) using integrated mRNA and methylation (iRM) analyses showed that parallel HOX gene overexpression and hypermethylation in the same direction were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value < 0.0001). Furthermore, this iRM high group was characterized by a 7-HOX gene signature showed significant survival differences not only in IDH mutant LGG but also in IDH wildtype LGG. These results demonstrate the importance of HOX genes in predicting the outcome of diffuse gliomas to identify relevant molecular subtyping independent of histology.

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.

Difuzni nizkostupňove gliomy se typicky vyskytuji u lidi v produktivnim věku. Představuji znacne riziko objemove progrese spojene s neurologickým deficitem a zaroveň riziko malignizace. Diagnostika a klasifikace těchto nadorů doznala v posledni dekadě znacných změn, zejmena v souvislosti s rozvojem multimodalnich technik magneticke rezonance a cytogenetiky. Gentický profil nadoru umožňuje odhadnout jeho prognozu a citlivost na onkologickou lecbu. Indikace maximalně bezpecne neurochirurgicke resekce v prvni linii lecby je obecně přijimana. Naopak postaveni radioterapie a chemoterapie v lecebnem algoritmu nizkostupňových gliomů je předmětem diskuzi a probihajicich studii.

Clinical Neurophysiology: EEG–Video Monitoring

For many decades, interactions between diffuse lower-grade glioma (LGG) and brain connectome were neglected. However, the neoplasm progression is intimately linked to its environment, especially the white matter (WM) tracts and their myelin status. First, while the etiopathogenesis of LGG is unclear, this tumor seems to appear during the adolescence, and it is mostly located within anterior and associative cerebral areas. Because these structures correspond to those which were myelinated later in the brain maturation process, WM myelination could play a role in the development of LGG. Second, WM fibers and the myelin characteristics also participate in LGG diffusion, since glioma cells migrate along the subcortical pathways, especially when exhibiting a demyelinated phenotype, which may result in a large invasion of the parenchyma. Third, such a migratory pattern can induce functional (neurological, cognitive and behavioral) disturbances, because myelinated WM tracts represent the main limitation of neuroplastic potential. These parameters are critical for tailoring an individualized therapeutic strategy, both (i) regarding the timing of active treatment(s) which must be proposed earlier, before a too wide glioma infiltration along the WM bundles, (ii) and regarding the anatomic extent of surgical resection and irradiation, which should take account of the subcortical connectivity. Therefore, the new science of connectomics must be integrated in LGG management, based upon an improved understanding of the interplay across glioma dissemination within WM and reactional neural networks reconfiguration, in order to optimize long-term oncological and functional outcomes. To this end, mechanisms of activity-dependent myelin plasticity should be better investigated.