Oncological and functional neurosurgery: Perspectives for the decade regarding diffuse gliomas.

For decades, diffuse glioma (DG) studies mostly focused on oncological considerations, whereas functional outcomes received less attention. Currently, because overall survival has increased in DG, especially in low-grade glioma (overall survival > 15 years), quality of life including neurocognitive and behavioral aspects should be assessed and preserved more systematically, particularly regarding surgery. Indeed, early maximal tumor removal results in greater survival in both high-grade and low-grade gliomas, leading to propose "supra-marginal" resection, with excision of the peritumoral zone in diffuse neoplasms. To minimize functional risks while maximizing the extent of resection, traditional "tumor-mass resection" is replaced by "connectome-guided resection" conducted under awake mapping, taking into account inter-individual brain anatomo-functional variability. A better understanding of the dynamic interplay between DG progression and reactional neuroplastic mechanisms is critical to adapt a personalized multistage therapeutic strategy, with integration of functional neurooncological (re)operation(s) in a multimodal management scheme including repeated medical therapies. Because the therapeutic armamentarium remains limited, the aims of this paradigmatic shift are to predict one/several step(s) ahead glioma behavior, its modifications, and compensatory neural networks reconfiguration over time in order to optimize the onco-functional benefit of each treatment - either in isolation or in combination with others - in human beings bearing a chronic tumoral disease while enjoying an active familial and socio-professional life as close as possible to their expectations. Thus, new ecological endpoints such as return to work should be incorporated into future DG trials. "Preventive neurooncology" might also be envisioned, by proposing a screening policy to discover and treat incidental glioma earlier.

Multivariate Analysis of RNA Chemistry Marks Uncovers Epitranscriptomics-Based Biomarker Signature for Adult Diffuse Glioma Diagnostics.

One of the main challenges in cancer management relates to the discovery of reliable biomarkers, which could guide decision-making and predict treatment outcome. In particular, the rise and democratization of high-throughput molecular profiling technologies bolstered the discovery of "biomarker signatures" that could maximize the prediction performance. Such an approach was largely employed from diverse OMICs data (i.e., genomics, transcriptomics, proteomics, metabolomics) but not from epitranscriptomics, which encompasses more than 100 biochemical modifications driving the post-transcriptional fate of RNA: stability, splicing, storage, and translation. We and others have studied chemical marks in isolation and associated them with cancer evolution, adaptation, as well as the response to conventional therapy. In this study, we have designed a unique pipeline combining multiplex analysis of the epitranscriptomic landscape by high-performance liquid chromatography coupled to tandem mass spectrometry with statistical multivariate analysis and machine learning approaches in order to identify biomarker signatures that could guide precision medicine and improve disease diagnosis. We applied this approach to analyze a cohort of adult diffuse glioma patients and demonstrate the existence of an "epitranscriptomics-based signature" that permits glioma grades to be discriminated and predicted with unmet accuracy. This study demonstrates that epitranscriptomics (co)evolves along cancer progression and opens new prospects in the field of omics molecular profiling and personalized medicine.

The death of localizationism: The concepts of functional connectome and neuroplasticity deciphered by awake mapping, and their implications for best care of brain-damaged patients.

Although clinical neurology was mainly erected on the dogma of localizationism, numerous reports have described functional recovery after lesions involving presumed non-compensable areas in an inflexible view of brain processing. Here, the purpose is to review new insights into the functional connectome and the mechanisms underpinning neural plasticity, gained from intraoperative direct electrostimulation mapping and real-time behavioral monitoring in awake patients, combined with perioperative neuropsychological and neuroimaging data. Such longitudinal anatomo-functional correlations resulted in the reappraisal of classical models of cognition, especially by highlighting the dynamic interplay within and between neural circuits, leading to the concept of meta-network (network of networks), as well as by emphasizing that subcortical connectivity is the main limitation of neuroplastic potential. Beyond their contribution to basic neurosciences, these findings might also be helpful for an optimization of care for brain-damaged patients, such as in resective oncological or epilepsy neurosurgery in structures traditionally deemed inoperable (e.g., in Broca's area) as well as for elaborating new programs of functional rehabilitation, eventually combined with transcranial brain stimulation, aiming to change the connectivity patterns in order to enhance cognitive competences following cerebral injury.

Cellular and molecular characterization of IDH1-mutated diffuse low grade gliomas reveals tumor heterogeneity and absence of EGFR/PDGFRα activation.

Diffuse low grade gliomas (DLGG, grade II gliomas) are slowly-growing brain tumors that often progress into high grade gliomas. Most tumors have a missense mutation for IDH1 combined with 1p19q codeletion in oligodendrogliomas or ATRX/TP53 mutations in astrocytomas. The phenotype of tumoral cells, their environment and the pathways activated in these tumors are still ill-defined and are mainly based on genomics and transcriptomics analysis. Here we used freshly-resected tumors to accurately characterize the tumoral cell population and their environment. In oligodendrogliomas, cells express the transcription factors MYT1, Nkx2.2, Olig1, Olig2, Sox8, four receptors (EGFR, PDGFRα, LIFR, PTPRZ1) but not the co-receptor NG2 known to be expressed by oligodendrocyte progenitor cells. A variable fraction of cells also express the more mature oligodendrocytic markers NOGO-A and MAG. DLGG cells are also stained for the young-neuron marker doublecortin (Dcx) which is also observed in oligodendrocytic cells in nontumoral human brain. In astrocytomas, MYT1, PDGFRα, PTPRZ1 were less expressed whereas Sox9 was prominent over Sox8. The phenotype of DLGG cells is overall maintained in culture. Phospho-array screening showed the absence of EGFR and PDGFRα phosphorylation in DLGG but revealed the strong activation of p44/42 MAPK/ERK which was present in a fraction of tumoral cells but also in nontumoral cells. These results provide evidence for the existence of close relationships between the cellular phenotype and the mutations found in DLGG. The slow proliferation of these tumors may be associated with the absence of activation of PDGFRα/EGFR receptors.

A new concept of diffuse (low-grade) glioma surgery.

Preservation and even improvement of the quality of life is currently a priority in surgery for gliomas, in addition to the optimization of the extent of resection with significant increase of the overall survival. In this setting, the goal of the present review is to revisit technical aspects of glioma surgery in the lights of new concepts both in the fields of neurooncology and cognitive neurosciences, which recently emerged from translational researches - with special emphasis on diffuse low grade gliomas.Firstly, the vascularisation (arteries and veins) has to be more systematically spared, by performing subpial dissection and by limiting the use of coagulation within the brain. Secondly, individual cortical as well as subcortical mapping must be more regularly considered, with the aim of better understanding and preserving the white matter pathways underlying the functional connectivity - even in presumed "non-eloquent areas", to perform "supra-complete" resection.Therefore, brain surgeons should change their state of mind, in order to operate the nervous system involved by a chronic tumoral disease (and no more by operating a tumor mass within the brain). In other words, the neurosurgeon should see first the brain, and not the glioma, to adapt his surgical procedure to the three-dimensional anatomo-functional organization of each patient. It implies that brain surgeon must change his technique within the central nervous system, which has to be different from the surgical technique outside the brain. This perspective seems to represent the best way to build a modern and personalized "functional surgical neurooncology".

Guidelines on management of low-grade gliomas: report of an EFNS-EANO Task Force.

BACKGROUND: Diffuse infiltrative low-grade gliomas of the cerebral hemispheres in the adult are a group of tumors with distinct clinical, histological and molecular characteristics, and there are still controversies in management. METHODS: The scientific evidence of papers collected from the literature was evaluated and graded according to EFNS guidelines, and recommendations were given accordingly. RESULTS AND CONCLUSIONS: WHO classification recognizes grade II astrocytomas, oligodendrogliomas and oligoastrocytomas. Conventional MRI is used for differential diagnosis, guiding surgery, planning radiotherapy and monitoring treatment response. Advanced imaging techniques can increase the diagnostic accuracy. Younger age, normal neurological examination, oligodendroglial histology and 1p loss are favorable prognostic factors. Prophylactic antiepileptic drugs are not useful, whilst there is no evidence that one drug is better than the others. Total/near total resection can improve seizure control, progression-free and overall survival, whilst reducing the risk of malignant transformation. Early post-operative radiotherapy improves progression-free but not overall survival. Low doses of radiation are as effective as high doses and better tolerated. Modern radiotherapy techniques reduce the risk of late cognitive deficits. Chemotherapy can be useful both at recurrence after radiotherapy and as initial treatment after surgery to delay the risk of late neurotoxicity from large-field radiotherapy. Neurocognitive deficits are frequent and can be caused by the tumor itself, tumor-related epilepsy, treatments and psychological distress.

Measuring the electrophysiological effects of direct electrical stimulation after awake brain surgery.

OBJECTIVE: Direct electrical stimulation (DES) at 60 Hz is used to perform real-time functional mapping of the brain, and guide tumour resection during awake neurosurgery. Nonetheless, the electrophysiological effects of DES remain largely unknown, both locally and remotely. APPROACH: In this study, we lowered the DES frequency to 1-10 Hz and we used a differential recording mode of electro-corticographic (ECoG) signals to improve the focality with a simple algorithm to remove the artefacts due to the response of the acquisition chain. MAIN RESULTS: Doing so, we were able to observe different components in the evoked potentials triggered by simulating the cortex or the subcortical white matter pathways near the recording electrodes and by stimulating the cortex remotely from the recording site. More particularly, P0 and N1 components were repeatedly observed on raw ECoG signals without the need to average the data. SIGNIFICANCE: This new methodology is important to probe the electrophysiological states and the connectivity of the brain in vivo and in real time, namely to perform electrophysiological brain mapping on human patients operated in the neurosurgical room and to better understand the electrophysiological spreading of DES.

Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL, a Negative Regulator of Glioma Growth.

IDH1-mutated gliomas are slow-growing brain tumours which progress into high-grade gliomas. The early molecular events causing this progression are ill-defined. Previous studies revealed that 20% of these tumours already have transformation foci. These foci offer opportunities to better understand malignant progression. We used immunohistochemistry and high throughput RNA profiling to characterize foci cells. These have higher pSTAT3 staining revealing activation of JAK/STAT signaling. They downregulate RNAs involved in Wnt signaling (DAAM2, SFRP2), EGFR signaling (MLC1), cytoskeleton and cell-cell communication (EZR, GJA1). In addition, foci cells show reduced levels of RNA coding for Ethanolamine-Phosphate Phospho-Lyase (ETNPPL/AGXT2L1), a lipid metabolism enzyme. ETNPPL is involved in the catabolism of phosphoethanolamine implicated in membrane synthesis. We detected ETNPPL protein in glioma cells as well as in astrocytes in the human brain. Its nuclear localization suggests additional roles for this enzyme. ETNPPL expression is inversely correlated to glioma grade and we found no ETNPPL protein in glioblastomas. Overexpression of ETNPPL reduces the growth of glioma stem cells indicating that this enzyme opposes gliomagenesis. Collectively, these results suggest that a combined alteration in membrane lipid metabolism and STAT3 pathway promotes IDH1-mutated glioma malignant progression.

Resting state network plasticity related to picture naming in low-grade glioma patients before and after resection.

The dynamic connectome perspective states that brain functions arise from the functional integration of distributed and/or partly overlapping networks. Diffuse low-grade gliomas (DLGG) have a slow infiltrating character. Here we addressed whether and how anatomical disconnection following DLGG growth and resection might interfere with functional resting-state connectivity, specifically in relation to picture naming. Thirty-nine native French persons with a left DLGG were included. All underwent awake surgical resection of the tumor using direct brain electrostimulation to preserve critical eloquent regions. The anatomical disconnectivity risk following the DLGG volume and the resection, and the functional connectivity of resting-state fMRI images in relation to picture naming were evaluated prior to and three months after surgery. Resting-state connectivity patterns were compared with nineteen healthy controls. It was demonstrated that picture naming was strongly dependent on the semantic network that emerged from the integration and interaction of regions within multiple resting-state brain networks, in which their specific role could be explained in the light of the broader resting-state network they take part in. It emphasized the importance of a whole brain approach with specific clinical data input, during resting-state analysis in case of lesion. Adaptive plasticity was found in secondary regions, functionally connected to regions close to the tumor and/or cavity, marked by an increased connectivity of the right and left inferior parietal lobule with the left inferior temporal gyrus. In addition, an important role was identified for the superior parietal lobe, connected with the frontal operculum, suggesting functional compensation by means of attentional resources in order to name a picture via recruitment of the frontoparietal attention network.

Adult human spinal cord harbors neural precursor cells that generate neurons and glial cells in vitro.

Adult human and rodent brains contain neural stem and progenitor cells, and the presence of neural stem cells in the adult rodent spinal cord has also been described. Here, using electron microscopy, expression of neural precursor cell markers, and cell culture, we investigated whether neural precursor cells are also present in adult human spinal cord. In well-preserved nonpathological post-mortem human adult spinal cord, nestin, Sox2, GFAP, CD15, Nkx6.1, and PSA-NCAM were found to be expressed heterogeneously by cells located around the central canal. Ultrastructural analysis revealed the existence of immature cells close to the ependymal cells, which display characteristics of type B and C cells found in the adult rodent brain subventricular region, which are considered to be stem and progenitor cells, respectively. Completely dissociated spinal cord cells reproducibly formed Sox2(+) nestin(+) neurospheres containing proliferative precursor cells. On differentiation, these generate glial cells and gamma-aminobutyric acid (GABA)-ergic neurons. These results provide the first evidence for the existence in the adult human spinal cord of neural precursors with the potential to differentiate into neurons and glia. They represent a major interest for endogenous regeneration of spinal cord after trauma and in degenerative diseases.

White matter functional connectivity as an additional landmark for dominant temporal lobectomy.

Dominant temporal lobectomy is classically performed based on two criteria: a perfect knowledge of the temporo-mesial microsurgical anatomy and cortical landmarks laterally. However, the functional anatomy of the subcortical white matter tracts is taken into account less, despite the risk of inducing a permanent deficit (especially aphasia) if damaged. Even if Klinger's technique allows dissection of fibres on cadaveric specimens, the exact three dimensional geometry of these fasciculi remains poorly described. Tractography, based on diffusion tensor imaging (DTI), is a powerful tool to build three dimensional images of several fasciculi, helping neurosurgeons to create a mental representation of their relationships. Moreover, intraoperative subcortical electrostimulation enables mapping of the function of these pathways. Here we review the recent findings on the white matter anatomo-functional connectivity of the dominant temporal lobe, based on combined anatomical data provided by DTI and functional information provided by intraoperative stimulation. We then discuss their implications for temporal lobectomy, by using white matter functional connectivity as an additional landmark.

Brain plasticity and tumors.

Brain plasticity is the potential of the nervous system to reshape itself during ontogeny, learning or following injuries. The first part of this article reviews the pathophysiological mechanisms underlying plasticity at different functional levels. Such plastic potential means that the anatomo-functional organization of the brain in humans, both physiological and pathological, has flexibility. Patterns of reorganization may differ according to the time-course of cerebral damage, with better functional compensation in more slowly growing lesions. The second part of this review analyzes the interactions between tumor growth and brain reshaping, using non-invasive (neuroimaging) and invasive (electrophysiological) methods of functional mapping. Finally, the therapeutic implications provided by a greater understanding of these mechanisms of cerebral redistribution are explored from a surgical point of view. Enhanced preoperative prediction of an individual's potential for reorganization might be integrated into surgical planning and preserving quality of life through tailored rehabilitation programmes to optimize functional recovery following resection of a brain tumor.

Reversible deficit affecting the perception of tone of a human voice after tumour resection from the right auditory cortex.

We report on a young woman operated for a ganglioglioma involving the right auditory cortex (AC), presenting with auditory seizures. Despite a normal pre-operative examination, a specific post-operative disorder affecting the perception of a human voice occurred. The patient was unable to recognise the tone of familiar voices while she recognised the expressed content. A temporal lobectomy for recurrence was performed two years later. The patient recovered from the voice perception deficit. This report shows that (1) a discrete site within the AC is specifically involved in the perception of tone of the human voice (2) functional compensation is possible.

[Plea for a systematic initiation to research during neurosurgical educational program]. / Plaidoyer pour une initiation systématique à la recherche au sein de l'enseignement de neurochirurgie.

To acquire, improve, and pass on expertise in the operating room and at the bedside is the essential mission of the neurosurgeon. However, this is not sufficient. Learning scientific reasoning with an eye turned to applied research is the key to continually evolving neurosurgery, which should occur in close interaction with the dynamics of the fundamental neurosciences. The current reorganization of the education program should make this official and budget a systematic initiation to research during training, essential for the future of French neurosurgery.

Contribution of cortical and subcortical electrostimulation in brain glioma surgery: methodological and functional considerations.

The aim of brain glioma surgery is to maximize the quality of resection, while minimizing the risk of sequelae. Due to the frequent location of gliomas in "eloquent areas" and because of major interindividual anatomofunctional variability, the cortical functional organization, effective connectivity and potential for plasticity must be studied for each patient individually. Consequently, in addition to preoperative functional neuroimaging, intraoperative electrostimulation (IES) can be used, under general anesthesia for motor mapping or on awake patient for language and cognitive mapping. This is an easy, accurate, reliable, and safe technique of detection of both cortical and subcortical functionally essential structures. Thus, IES enables: (i) to study the individual cortical functional organization before any resection; (ii) to understand the pathophysiology of areas involved by gliomas; (iii) to map the subcortical structures along the resection, allowing a study of the anatomofunctional connectivity; (iv) to analyze the mechanisms of on-line short-term plasticity, using repeated IES; (v) to tailor the resection according to individual cortico-subcortical functional boundaries, enabling to optimize the benefit:risk ratio of surgery. Moreover, IES can be combined with perioperative functional neuroimaging, before and after surgery, to validate these noninvasive techniques and to better understand the short-term and long-term plasticity mechanisms based on functional cortical reshaping and connectivity changes. Such individual knowledge allows planning multiple-stages surgery. In conclusion, IES enables to increase the impact of surgery on the natural history of gliomas, to preserve the quality of life, and to better understand the dynamic functional anatomy of the brain.

[Functional magnetic resonance imaging: physiopathology, techniques and applications]. / IRM fonctionnelle cérébrale: bases physiologiques, techniques et applications cliniques.

Brain functional MRI (fMRI) provides an indirect mapping of cerebral activity, based on the detection of local changes in blood flow and oxygenation levels that are associated with neuronal activity (BOLD contrast). fMRI allows noninvasive studies of normal and pathological aspects of the brain's functional organization. It is based on the comparison of two or more cognitive states. Echoplanar imaging is the technique of choice, providing the quickest study of the entire brain. Activation maps are calculated from a statistical analysis of the local signal changes. fMRI has become one of the most widely used functional imaging techniques in neuroscience. In clinical practice, fMRI can identify eloquent areas involved in motor and language functions in surgical patients and can evaluate the risk of postoperative neurological deficit.

Hodotopy, neuroplasticity and diffuse gliomas.

BACKGROUND AND PURPOSE: The historical approach in neurooncology is used to mainly investigate the tumor, with very few considerations regarding the brain itself. Nonetheless, to select the best personalized therapeutic management for each patient with a diffuse glioma, i.e. to optimize the "onco-functional balance", the brain reaction induced by glioma growth and migration should be studied. Indeed, due to strong interactions between the glioma and the brain, cerebral adaptive phenomena often occur in order to maintain neurological and cognitive functions, as well as to compensate glioma spreading. Here, the goal is to detail mechanisms underlying neuroplasticity and its implications for surgical neurooncology. METHODS: Data issues from cerebral mapping and functional outcomes in patients who underwent awake surgery for gliomas were discussed. RESULTS: Massive resections of the brain, including so-called "eloquent areas", are possible without generating permanent neurological deficits in adult patients harbouring a diffuse glioma. CONCLUSION: From a fundamental point of view, these findings open the door to a hodotopical anatomo-functional organization of the brain, i.e. organized in dynamic and interactive parallel large-scale distributed networks, able to compensate for each other. Furthermore, cognitive neurosciences represent valuable help to neuro-oncology, by leading to the elaboration of new treatment strategies, such as multistage surgical approach, made possible thanks to cerebral remapping over years. In other words, understanding neuroplasticity in a connectomal account of brain processing permitted a dramatic improvement of both quality of life as well as overall survival in glioma patients, and resulted in the proposal of an "individualized functional neurooncology".

Supratotal resection of diffuse gliomas - an overview of its multifaceted implications.

Successful management of diffuse low-grade and high-grade gliomas in adults is a challenge for neuro-oncologists. Indeed, due to their highly infiltrative feature, these diseases remain incurable despite therapeutic advances. Nevertheless, the elaboration of individualized therapeutic strategies has led to an improvement of both overall survival and quality of life. In particular, the impact of surgical resection on diffuse glioma survival has been extensively demonstrated. However, this impact is significant only when the resection is total (i.e., complete removal of the T2-hyperintensity in diffuse low-grade gliomas, or complete removal of the enhancement in high-grade gliomas), or at least subtotal. Interestingly, biopsy samples within and beyond the abnormalities, defined by magnetic resonance imaging, have shown that the actual spatial extent of gliomas was underestimated by this conventional imaging modality, since glioma cells were present outside the signal abnormalities. Thus, it was suggested that the removal of a margin around the tumor visible on magnetic resonance imaging, i.e. "supratotal resection", might improve the outcomes in diffuse gliomas. To achieve this type of supramaximal resection, while preserving the quality of life, a new concept is to switch from an image-guided surgery to a functional-guided surgery, i.e. to pursue the resection up to the eloquent neural networks using intraoperative direct electrical stimulation mapping in awake patients. The aim of this article was to review the recent data about supratotal resection, including both oncological and functional results. Favorable outcomes have recently opened the door to the principle of "preventive surgery" in incidentally discovered gliomas, and to the proposal of a medical screening.

Intraoperative identification of the negative motor network during awake surgery to prevent deficit following brain resection in premotor regions.

INTRODUCTION: Surgical resection in premotor areas can lead to supplementary motor area syndrome as well as a permanent deficit. However, recent findings suggest a putative role of the negative motor network in those dysfunctions. Our objective was to compare the functional results in two groups of adult patients who underwent the resection of a frontal glioma with and without resection of the negative motor networks. MATERIAL AND METHODS: Twelve patients (total of 13 surgeries) were selected for awake surgery for a frontal glioma. Negative motor responses were monitored during surgery at the cortical and subcortical levels. Sites eliciting negative motor responses were first identified then spared (n=8) or removed (n=5) upon oncological requirements. RESULTS: In the group with removal of the negative motor network (n=5), all patients presented a complete supplementary motor area syndrome with akinesia and mutism. At 3months, they all presented bimanual coordination dysfunction and fine movement disorders. In the group with preservation of the negative motor network (n=8), all patients presented transient and slight disorders of speech or upper limb, they all recovered completely at 3months. DISCUSSION: The negative motor network is a part of a modulatory motor network involved in the occurrence of the supplementary motor area syndrome and the permanent deficit after resection in premotor areas. Then, intraoperative functional cortico-subcortical mapping using direct electrostimulation under awake surgery seems mandatory to avoid deficit in bimanual coordination and fine movements during surgery in premotor areas.

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

OBJECTIVE: Incidentally discovered diffuse low-grade gliomas progress in a fashion similar to their symptomatic counterparts. Their early detection allows more effective pre-emptive and individualized oncological treatment. We assessed the safety and efficacy of maximal safe resection according to functional boundaries for incidental diffuse low-grade gliomas in eloquent areas. MATERIAL AND METHODS: Two-centre retrospective series of adult patients with incidental diffuse low-grade gliomas located within/close to eloquent areas in the dominant hemisphere, treated with maximal surgical resection according to functional boundaries under intraoperative functional cortico-subcortical monitoring under awake conditions, and with a minimal follow-up of 24months. RESULTS: The series included 19 patients (8 men, 11 women) with no preoperative neurological deficit but with a radiologically enlarged glioma. No intraoperative seizure, postoperative infection, haematoma or wound-healing problem was observed. In the immediate postsurgical period, a transient neurological worsening occurred in 10 patients. The resection (mean rate 96.4%; range, 82.4-100) was supratotal in 5 cases, total in 5 cases, subtotal in 7 cases, and partial in 2 cases. Six months after surgery, all patients recovered after functional rehabilitation, with no permanent neurological deficit, Karnofsky Performance Status was 100 (except for one patient who received early postoperative radiotherapy) and no seizures were observed. The survival without progression requiring oncological treatment was significantly longer in patients with a total/supratotal resection than in patients with a partial/subtotal resection. CONCLUSIONS: These results suggest the reproducibility, safety, and effectiveness of an early maximal functionally based resection within cortico-subcortical functional boundaries for incidental diffuse low-grade gliomas in adults in centres hyperspecialized in surgical neuro-oncology.