Diffuse Low-grade Gliomas Research Articles

P01.006 Gamma knife radiosurgery for diffuse low-grade gliomas: An Egyptian experience.

P01.006 Gamma knife radiosurgery for diffuse low-grade gliomas: An Egyptian experience.

Neurosurgical patterns of care for diffuse low-grade gliomas in Sweden between 2005 and 2015.

BackgroundIn the last decade, increasing evidence has evolved for early and maximal safe resection of diffuse low-grade gliomas (LGGs) regarding survival. However, changes in clinical practice are known to occur slowly and we do not know if the scientific evidence has yet resulted in changes in neurosurgical patterns of care.MethodsThe Swedish Brain Tumor Registry was used to identify all patients with a first-time histopathological diagnosis of LGG between 2005 and 2015. For analysis of surgical treatment patterns, we subdivided assessed time periods into 2005-2008, 2009-2012, and 2013-2015. Population-based data on patient and disease characteristics, surgical management, and outcomes were extracted.ResultsA total of 548 patients with diffuse World Health Organization grade II gliomas were identified: 142 diagnosed during 2005-2008, 244 during 2009-2012, and 162 during 2013-2015. Resection as opposed to biopsy was performed in 64.3% during 2005-2008, 74.2% during 2009-2012, and 74.1% during 2013-2015 (P = .08). There was no difference among the 3 periods regarding overall survival (P = .11). However, post hoc analysis of data from the 4 (out of 6) centers that covered all 3 time periods demonstrated a resection rate of 64.3% during 2005-2008, 77.4% during 2009-2012, and 75.4% during 2013-2015 (P = .02) and longer survival of patients diagnosed 2009 and onward (P = .04).ConclusionIn this nationwide, population-based study we observed a shift over time in favor of LGG resection. Further, a positive correlation between the more active surgical strategy and longer survival is shown, although no causality can be claimed because of possible confounding factors.

The Risk Assessment in Low-Grade Gliomas: An Analysis of the European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) criteria.

Diffuse low-grade gliomas (LGG) are rare tumors that affect young adult patients. The European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) have both developed their own clinical prognostic scores to assist clinicians in treatment decision-making. These criteria have been used to include patients in phase III studies. To date, it is unknown which is the best score to define the prognosis of LGG. Additionally, a pure clinical classification is probably not a sufficiently informative basis for choosing the proper treatment in different situations. A combined score with both clinical and molecular features will likely be indispensable.

Imaging practice in low-grade gliomas among European specialized centers and proposal for a minimum core of imaging

ObjectiveImaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers.MethodsAn online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery.ResultsA total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI.ConclusionA minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of ≤ 3 mm. No common standard could be obtained regarding advanced MRI protocols and PET.Importance of the studyWe believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed “minimal core of imaging” in clinical routine will facilitate future cooperative studies.

IDH wild-type WHO grade II diffuse low-grade gliomas. A heterogeneous family with different outcomes. Systematic review and meta-analysis

WHO grade II diffuse low-grade gliomas (DLGGs) were recently divided into sub-groups on the basis of their molecular profiles. IDH wild-type (IDH-wt) tumors seem to be associated with unfavorable prognoses due to biological similarities to glioblastomas. The authors performed a systematic review and meta-analysis of literature examining epidemiology, clinical characteristics, management, and the outcome of IDH-wt grade II DLGGs. According to PRISMA guidelines, a comprehensive review of studies published from January 2009 to October 2017 was carried out. The authors identified series that examined the prevalence rate, clinical and radiological characteristics, treatment, and outcome of IDH-wt DLGGs. Variables influencing outcomes were analyzed using a random-effects meta-analysis model. Finally, a meta-regression analysis was performed to examine the impact of therapeutic strategies on the effect-size. Twenty-two studies were included in this systematic review. The IDH-wt prevalence rate was 22.9% (95% CI 18.4-27.4%). The hazard ratio for this molecular subgroup in the DLGGs population was 3.46 (95% CI 2.24-5.36; p < 0.001), and the heterogeneity was significant (I2= 85%, τ2 = 0.88) (HR range 1.28-376). Nonetheless, publication bias did not affect the analysis (p = 0.176). The meta-regression revealed that the extent of resection and post-operative chemotherapy affected the outcome in the IDH-wt subgroup (p < 0.001 and 0.015, respectively), with no significant association of the HR with the rate of RT or RT + CHT. The prevalence of IDH-wt tumors is approximately 23% of DLGGs. The absence of IDH mutation is associated with a heterogeneous outcome, and its therapeutic relevance for postoperative management remains unclear. Maximal surgical resection improves the overall survival in the DLGGs population, beyond molecular status. Further molecular stratification is needed to better understand IDH-wt behavior and therapeutic response.

30 Perceived versus quantified growth trajectory of serially-imaged low-grade gliomas

Background. Diffuse low-grade gliomas (LGGs) are infiltrative, slow-growing primary brain tumours that remain relatively asymptomatic for long periods of time before transforming into aggressive high-grade gliomas. Surveillance of tumour stability is performed primarily by serial imaging. Methods. We retrospectively identified LGG patients that were managed by observation with numerous (≥8) serial magnetic resonance imaging (MRI) studies. Tumour volumes were measured by manual segmentation on imaging. Demographic information, tumour histopathological data, and radiological interpretations were collected from electronic medical records. MRI radiology reports of tumour volume stability were classified into "growth" and "no growth" interpretations. Results. Of 74 LGG patients, 10 (13.5%) patients were included in the study. A median of 11 MRIs (range, 8-18) over a median of 79.7 months (range, 39.8-113.8 months) were analyzed per patient. Tumour diameter linearly increased at a median rate of 2.17 mm/year. Cox regression analysis showed that initial tumour volume predicted time to clinical intervention, and Mann-Whitney U test found that tumours of patients diagnosed before age 50 grew more slowly. Radiology interpretations that reported "no growth" (n=66) corresponded to a median measured growth of 3.90 mL and 11.0% compared to the comparison scan. Reports of "growth" (n=36) corresponded to median measured volume increases of 9.36 mL and 20.5%. Conclusion. We retrospectively analyzed the natural history of LGGs in serially-imaged patients at a single institution. Comparisons to the literature suggest that this is a subset of particularly slow-growing and low-risk tumours. We also highlight the clinical value of performing accurate LGG volumetric analyses.

P.043 Volumetric analysis of low-grade glioma growth in serially-imaged patients

Background: Diffuse low-grade gliomas (LGGs) are infiltrative, slow-growing primary brain tumors that remain relatively asymptomatic for long periods of time before progressing to aggressive high-grade gliomas. Methods: We retrospectively identified LGG patients that were stably managed by observation with numerous (≥ 8) serial magnetic resonance imaging (MRI) studies. Tumour volumes were measured by manual segmentation on imaging to study the growth of the lesion. Patient demographic information, tumour characteristics, and histological data were collected from electronic medical records. Results: Of 74 LGG patients, 10 (13.5%) patients were included in the study. The number of MRIs acquired ranged from 8 to 18 (median, 11) over a median of 79.7 months (range, 39.8-113.8 months). Tumor diameter increased at a median rate of 2.17 mm/year in a linear trajectory. Cox regression analysis revealed that initial tumour volume predicted time to clinical intervention, and Mann-Whitney U test found that patients diagnosed prior to age 50 had significantly slower-growing tumors. Clinical intervention was more likely for tumours larger than 73.8 mL. Conclusions: We retrospectively analyzed the natural history of LGGs in patients with numerous serial MRIs managed at a single institution. Comparisons to the literature suggest that this is a subset of particularly slow-growing and low-risk tumours.

29 Unraveling molecular drivers of brain cancers at the clinical setting

Brain tumor behavior is driven by aberrations in the genome and epigenome. Many of these changes, such as IDH mutations in diffuse low-grade glioma (DLGG), are common amongst the same class of tumour and can be incorporated into the diagnostic criteria. However, any given tumor may have other, less common genomic aberrations that are essential for its biological behavior and may inform on underlying aberrant cellular pathways, and potential therapeutic agents. Precision oncology is a genomics-based approach which profiles these alterations to better manage cancer patients and has established itself within the practice of oncology and is slowly making its way into neuro-oncology. The BC Cancer’s Personalized OncoGenomics (POG) program has profiled 16 adult tumours originating from the central nervous system using whole genome and transcriptome analysis (WGTA), for the first time, within a meaningful clinical timeframe/setting. As expected, primary genomic drivers were consistent with their respective diagnoses, though secondary drivers were found to be unique to each tumour. Although these analyses did not result in altered clinical management for these patients, primarily due to availability of drug or clinical trials, they highlight the heterogeneity of secondary drivers in cancers and provide clinicians with meaningful biological information. Lastly, the data generated by POG has highlighted the frequency and complexity of novel driver fusions which are predicted to behave similarly to canonical driver events in their respective tumours. The information available to clinicians through POG has provided paramount knowledge into the biology of each unique tumour.

Tumor growth dynamics in serially-imaged low-grade glioma patients.

Diffuse low-grade gliomas (LGGs) are infiltrative, slow-growing primary brain tumors that remain relatively asymptomatic for long periods of time before progressing into aggressive and fatal high-grade gliomas. We retrospectively identified LGG patients with numerous (≥ 8) serial magnetic resonance imaging (MRI) studies. Tumor volumes were measured by manual segmentation on serial imaging to study the natural history and growth of the lesion. Patient demographic information, tumor characteristics, and histological data were collected from electronic medical records and paper charts. Out of 74 LGG patients, 10 patients (13.5%) were identified to meet the study criteria with number of MRIs acquired ranging from 8 to 18 (median, 11.5) over a median of 79.7months (range 39.8-113.8months). Tumor diameter increased at a median of 2.17mm/year in a linear trajectory. Cox regression analysis revealed that initial tumor volume was an independent predictor of time to clinical intervention, and Mann-Whitney U test found that patients younger than 50years old had significantly slower-growing tumors. Clinical intervention was more likely for tumors above a volume threshold of 73.6mL. We retrospectively analyzed the natural history of LGGs of patients managed at a single institution with numerous serial MRI scans. Comparisons of our cohort to the literature suggest that this is a subset of particularly slow-growing and low-risk tumors.

Whole-Genome Expression Microarray Combined with Machine Learning to Identify Prognostic Biomarkers for High-Grade Glioma.

The aim of our study is to build a framework for a better understanding of high-grade glioma (HGG) prognostic-related biomarkers. Whole-genome gene expression microarray was performed to identify differently expressed genes between HGGs and low-grade diffuse gliomas. Several machine learning algorithms were used to filter prognostic-related genes. One hundred ninety-three HGG patients after surgical resection were selected for survival analysis. Immunohistochemistry were performed on these tumor samples to analyze IDH1 mutation status and protein expression of WEE1. qRT-PCR, western blotting, transwell assays, and scratch wound healing assays were performed to evaluate the effect of WEE1 knockdown or overexpression in HGG cells. Three prognostic-related genes (WEE1, IGF2PB3, and EMP3) were demonstrated to separate HGG patients into two different survival subgroups. The area under receiver operating characteristic curve of WEE1 was higher than that of IGF2BP3, EMP3, age, IDH status, 1p/19q status, and MGMT promoter status. WEE1 was an independent covariate compared with IDH status, age, and WHO grade. Knockdown or overexpression of WEE1 can inhibit or promote migration and invasion in U251 and U87 cell lines. WEE1, EMP3, and IGF2BP3 are reliable prognostic-related genes at the mRNA level. WEE1 is an independent prognostic biomarker in survival analysis and has potential diagnostic value for HGG patients. WEE1 can induce HGG cell migration and invasion in vitro.

Damage to the left uncinate fasciculus is associated with heightened schizotypal traits: A multimodal lesion-mapping study

A growing body of evidence suggests that individuals with pronounced schizotypal traits also display particular neurophysiological and morphological features – notably with regard to left frontotemporal connectivity. However, the studies published to date have focused on subclinical subjects and psychiatric patients, rather than brain-damaged patients. Here, we used the French version of the Schizotypal Personality Questionnaire to assess schizotypal traits in a sample of 97 patients having undergone surgical resection of a diffuse low-grade glioma. Patients having received other neurooncological treatments (including chemotherapy and radiotherapy) were not included. A combination of ROI-based based voxel-wise and tract-wise lesion-symptom mapping and a disconnectome analysis were performed, in order to identify the putative neural network associated with schizotypy. The ROI-based lesion-symptom mapping revealed a significant relationship between the cognitive-perceptual (positive) dimension of schizotypy and the left inferior gyrus (including the pars opercularis and the pars orbitalis). Importantly, we found that disconnection of the left uncinate fasciculus (UF) was a powerful predictor of the positive dimension of schizotypy. Lastly, the disconnection analysis indicated that the positive dimension of schizotypy was significantly associated with the white matter fibres deep in the left orbital and inferior frontal gyri and the left superior temporal pole, which mainly correspond to the spatial topography of the left UF. Taken as a whole, our results suggest that dysconnectivity of the neural network supplied by the left UF is associated with heightened positive schizotypal traits. Our new findings may be of value in interpreting current research in the field of biological psychiatry.

Electrical stimulation of the dorsolateral prefrontal cortex impairs semantic cognition

To identify the prefrontal cortical structures causally involved in verbal and nonverbal semantic cognition in both cerebral hemispheres. We retrospectively screened the intraoperative brain mapping data of 584 patients who underwent neurosurgery for neoplastic tumor under local anesthesia with direct cortical electrostimulation. Patients were included if they were right-handed, recently diagnosed with a diffuse low-grade glioma, and had a positive language mapping for verbal (naming task) and nonverbal (visual semantic association task) semantic cognition in the prefrontal cortex (n = 49). Among these, 30 were tested intraoperatively with both the naming and the semantic association tasks, while 19 were tested with the naming task only. Subsequently, each semantic site (n = 85) was plotted individually onto a common stereotaxic space for detailed analyses. The cortical sites associated with verbal semantic disturbances (n = 45) were distributed in the pars opercularis (n = 14) and pars triangularis (n = 19) of the left inferior frontal gyrus, and left dorsolateral prefrontal cortex (dlPFC, n = 12); only 2 sites were observed in the right dlPFC. In contrast, all but one cortical site associated with nonverbal semantic disturbances were observed in the left dorsolateral cortex (n = 8). In the right hemisphere, the same disturbances were found in the dlPFC (n = 14) and pars opercularis (n = 2). The present study demonstrated the critical role of the dlPFC in the semantic network, and indicated its specific and bilateral involvement in nonverbal semantic cognition in right-handers.

Functional-Based Resection Does Not Worsen Quality of Life in Patients with a Diffuse Low-Grade Glioma Involving Eloquent Brain Regions: A Prospective Cohort Study.

We assessed the impact of surgery on postoperative cognitive function and ability to work in adult patients with a diffuse low-grade glioma involving eloquent brain regions and having a functional-based maximal surgical resection using intraoperative corticosubcortical mapping under awake conditions. We prospectively included 39 consecutive patients with diffuse isocitrate dehydrogenase-mutant low-grade glioma without preoperative and adjuvant oncologic treatment and assessed preoperative (mean, 24.1 ± 21.2 days before surgery) and postoperative (mean, 14.6 ± 13.2 months after surgery) cognitive evaluations and ability to work together with clinical, imaging, therapeutic, and follow-up characteristics before tumor progression. None of the 3 patients without preoperative cognitive deficit had postoperative worsening. We observed a significant inverse interaction between worsened postoperative cognitive function and extent of resection: 80.0%, 18.8%, and 16.7% of worsening after partial, subtotal, and total resection, respectively (P= 0.020). We observed an independent interaction between improved postoperative cognitive function and extent of resection: 20.0%, 43.7%, and 44.4% of improvement after partial, subtotal, and total resection, respectively (P= 0.022). Of the employed patients, 61.8% were unable to work preoperatively and 82.4% resumed their employment postoperatively (mean, 6.9± 5.5 months). We observed an independent interaction between postoperative ability to work, similar or superior to preoperative work capacity and extent of resection (P<0.001): 20.0%, 87.5%, and 100% ability to work after partial, subtotal resection, and total resection. The extent of the functional-based surgical resection and the residual tumor for diffuse low-grade gliomas involving eloquent brain regions correlate with postoperative cognitive outcomes and return to work rates.

PD-1 (PDCD1) Promoter Methylation Is a Prognostic Factor in Patients With Diffuse Lower-Grade Gliomas Harboring Isocitrate Dehydrogenase (IDH) Mutations

Immune checkpoints are important targets for immunotherapies. However, knowledge on the epigenetic modification of immune checkpoint genes is sparse. In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas.PD-L1, PD-L2, and CTLA-4 mRNA expression levels showed a significant inverse correlation with promoter methylation (PD-L1: p=0.005; PD-L2: p<0.001; CTLA-4: p<0.001). Furthermore, immune checkpoint methylation was significantly associated with age (PD-L2: p=0.003; PD-1: p=0.015), molecular alterations, i.e. MGMT methylation (PD-L1: p<0.001; PD-L2: p<0.001), ATRX mutations (PD-L2: p<0.001, PD-1: p=0.001), and TERT mutations (PD-L1: p=0.035, PD-L2: p<0.001, PD-1: p<0.001, CTLA4: p<0.001) as well as methylation subgroups and immune cell infiltrates. In multivariate Cox proportional hazard analysis, PD-1 methylation qualified as strong prognostic factor (HR=0.51 [0.34–0.76], p=0.001).Our findings suggest an epigenetic regulation of immune checkpoint genes via DNA methylation in LGG. PD-1 methylation may assist the identification of patients that might benefit from an alternative treatment, particularly in the context of emerging immunotherapies.

Neuropsychological evidence for the crucial role of the right arcuate fasciculus in the face-based mentalizing network: A disconnection analysis

Recent evidence from axonal stimulation mapping studies suggests that at least two white matter connectivities in the right hemisphere may be involved in face-based mentalizing, i.e. the ability to infer complex cognitive and affective states from human faces: the inferior fronto-occipital (IFOF) and the superior longitudinal/arcuate (SLF/AF) fasciculi. However, to date, only a handful of neuropsychological studies have focused on the white matter tracts subserving mentalizing in general, and face-based mentalizing in particular. Therefore, the main goal of this study was to confirm the abovementioned results by applying voxelwise and tractwise lesion-symptom analyses to a set of behavioral data obtained from a large and homogeneous group of neurological participants. More precisely, 122 patients operated on for diffuse low-grade glioma were assessed postoperatively with the well-validated “Reading the Mind in the Eyes” (RME) test. For each patient, the resection cavity and the residual tumor infiltration were mapped separately on the respective postoperative structural MRI. Behavioral data, previously controlled for sociodemographic factors, were then submitted to a standard voxel-based and to a less conservative, region-of-interest (ROI)-based, lesion-deficit analyses. Results were invariably the same: no anatomo-functional relationships were pinpointed by these investigations, making thus impossible the cortical topological localization of mentalizing deficits. In a second time, two kinds of tractwise lesion-symptom analyses based on the damaged volume and the disconnection probabilities of the white matter tracts, were performed. All results were corrected with the Bonferroni correction. Converging and strong evidence was found that resection-related disconnection of the right AF is especially deleterious for face-based mentalizing. More anecdotally, we identified the involvement of certain ventral tracts, especially the IFOF and the uncinate fasciculus (UF). Taken as a whole, the reported findings confirm the critical role of the right AF in mentalizing abilities. From a more clinical standpoint, they highlight the necessity to perform an intraoperative map of this connectivity during awake surgery in order to avoid long-lasting social cognition disorders.

Relevance of two manual tumour volume estimation methods for diffuse low-grade gliomas.

Management of diffuse low-grade glioma (DLGG) relies extensively on tumour volume estimation from MRI datasets. Two methods are currently clinically used to define this volume: the commonly used three-diameters solution and the more rarely used software-based volume reconstruction from the manual segmentations approach. The authors conducted an initial study of inter-practitioners’ variability of software-based manual segmentations on DLGGs MRI datasets. A panel of 13 experts from various specialties and years of experience delineated 12 DLGGs’ MRI scans. A statistical analysis on the segmented tumour volumes and pixels indicated that the individual practitioner, the years of experience and the specialty seem to have no significant impact on the segmentation of DLGGs. This is an interesting result as it had not yet been demonstrated and as it encourages cross-disciplinary collaboration. Their second study was with the three-diameters method, investigating its impact and that of the software-based volume reconstruction from manual segmentations method on tumour volume. They relied on the same dataset and on a participant from the first study. They compared the average of tumour volumes acquired by software reconstruction from manual segmentations method with tumour volumes obtained with the three-diameters method. The authors found that there is no statistically significant difference between the volumes estimated with the two approaches. These results correspond to non-operated and easily delineable DLGGs and are particularly interesting for time-consuming CUBE MRIs. Nonetheless, the three-diameters method has limitations in estimating tumour volumes for resected DLGGs, for which case the software-based manual segmentation method becomes more appropriate.

Intraoperative Identification and Preservation of Verbal Memory in Diffuse Gliomas: A Matched-Pair Cohort Study.

Recent glioma surgery series with intraoperative electrical stimulation (IES) language mapping have demonstrated high rates of postoperative memory impairment, raising a question regarding the efficacy of this approach to preserve memory. To evaluate if intraoperative identification and preservation of verbal memory sites with IES mapping in diffuse gliomas in eloquent areas consistently protect patients from long-term postoperative decline in short-term memory. A cohort of 16 subjects with diffuse low-grade or anaplastic gliomas that were operated with IES and intraoperative evaluation of language and verbal memory (cohort A) was matched by tumor side, pathology, and radiotherapy with a cohort of 16 subjects that were operated with IES and evaluation of language (cohort B). Detailed neuropsychological assessment was performed before and 6 mo after surgery. Intraoperative memory mapping was a strong predictor of verbal memory prognosis. In cohort A, 4 patients (26.7%) had a decline of at least one of the 4 short-term memory tests evaluated. In cohort B, 11 patients (73.3%) had a decline of at least one of the 4 tests. This difference was statistically significant in multivariate analysis (P=.022; odds ratio=9.88; 95% confidence interval=1.39-70.42). Verbal memory areas identified intraoperatively with the current paradigm are critically involved in verbal memory, as memory impairment can be significantly reduced by adapting the resection to avoid those memory areas. Incorporation of verbal memory evaluation in stimulation mapping protocols might assist in reducing postoperative sequelae and preserving the patient's quality of life.

Transient immediate postoperative homotopic functional disconnectivity in low-grade glioma patients.

Background and purposeThe aim of this longitudinal study is to evaluate large-scale perioperative resting state networks reorganization in patients with diffuse low-grade gliomas following awake surgery.Materials and methodsEighty-two patients with diffuse low-grade gliomas were prospectively enrolled and underwent awake surgical resection. Resting-state functional images were acquired at three time points: preoperative (MRI-1), immediate postoperative (MRI-2) and three months after surgery (MRI-3). We simultaneously performed perfusion-weighted imaging.ResultsComparing functional connectivity between MRI-1 and MRI-2, we observed a statistically significant functional homotopy decrease in cortical and subcortical supratentorial structures (P < 0.05). A functional homotopy increase was observed between MRI-2 and MRI-3 in parietal lobes, cingulum and putamen (P < 0.05). No significant functional connectivity modification was noticed between MRI-1 and MRI-3. Regional cerebral blood flow appeared transiently reduced on MRI-2 (P < 0.05). No correlation between neurological deficit and interhemispheric connectivity results was found.Conclusion/interpretationWe found a supratentorial widely distributed functional homotopy disruption between preoperative and immediate postoperative time points with a complete restitution three months after surgery with simultaneous variation of regional cerebral blood flow.

An attempt to conceptualize the individual onco-functional balance: Why a standardized treatment is an illusion for diffuse low-grade glioma patients.

In the era of evidence-based medicine, clinicians aim to establish standards of care from randomized studies. Following, personalized medicine has emerged, as new individualized biomarkers could help to predict sensitivity to specific treatment. In this paper, we show that, for diffuse low-grade glioma, some specificities - dual goal of both survival and functional gain, long duration of the disease with multistep treatments, multiparametric evaluation of the onco-functional balance of each treatment modality - call for a change of paradigm. After summarizing how to weight the benefits and risks of surgery, chemotherapy and radiotherapy, we show that the overall efficacy of a treatment modality cannot be assessed per se, as it depends on its integration in the whole sequence. Then, we revisit the notion of personalized medicine: instead of decision-making based solely on molecular profile, we plead for a recursive algorithm, allowing a dynamic evaluation of the onco-functional balance, integrating many individual characteristics of the patient's tumor and brain function.

An NF-κB signature predicts low-grade glioma prognosis: a precision medicine approach based on patient-derived stem cells.

While recent genome-wide association studies have suggested novel low-grade glioma (LGG) stratification models based on a molecular classification, we explored the potential clinical utility of patient-derived cells. Specifically, we assayed glioma-associated stem cells (GASC) that are patient-derived and representative of the glioma microenvironment. By next-generation sequencing, we analyzed the transcriptional profile of GASC derived from patients who underwent anaplastic transformation either within 48 months (GASC-BAD) or ≥7 years (GASC-GOOD) after surgery. Gene set enrichment and pathway enrichment analyses were applied. The prognostic role of a nuclear factor-kappaB (NF-κB) signature derived from GASC-BAD was tested in 530 newly diagnosed diffuse LGG patients comprised within The Cancer Genome Atlas (TCGA) database. The prognostic value of the GASC upstream regulator p65 NF-κB was assessed, by univariate and multivariate Cox analyses, in a single center case study, including 146 grade II LGGs. The key elements differentiating the transcriptome of GASC isolated from LGG with different prognoses were mostly related to hallmarks of cancer (eg, inflammatory/immune process, NF-κB activation). Consistently, the NF-κB signature extrapolated from the GASC study was prognostic in the dataset of TCGA. Finally, the nuclear expression of the NF-kB-p65 protein, assessed using an inexpensive immunohistochemical method, was an independent predictor of both overall survival and malignant progression-free survival in 146 grade II LGGs. This study demonstrates for the first time the independent prognostic role of NF-kB activation in LGG and outlines the role of patient-based stem cell models as a tool for precision medicine approaches.