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Background and ObjectivesD-2-hydroxyglutarate (2HG) characterizesIDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels.MethodsMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).ResultsMEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3;p= 0.02), voxel coverage (>75%;p= 0.002), and expansive presentation (defined by equal size of T1and FLAIR abnormalities,p= 0.04). 2HG levels were positively correlated withIDH-mutant allelic fraction (p= 0.03) and total choline levels (p< 0.001) and were higher inIDH2-mutant compared withIDH1R132H-mutant and non–R132HIDH1-mutant patients (p= 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities.DiscussionMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy ofIDHinhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

Purpose:The blood–brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations.Patients and Methods:A first-in-man, single-arm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy.Results:Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n = 11) had a median PFS of 4.11 months, and a median OS of 12.94 months.Conclusions:SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity.See related commentary by Sonabend and Stupp, p. 3750

Supplementary Table 1. The acoustic pressure levels are determined by a calibration of the implants in water prior to implantation in patients. The 95% confidence interval given in the table denotes the measurement uncertainty inherent to this process. Acoustic pressure levels reported previously (19) were re-evaluated using enhanced acoustic calibration methods with reduced uncertainty. The former values are given in the pold column to ease comparison with our previous publication. Supplementary Table 2. BBB disruption grade and acoustic pressure. Data are n (%). Supplementary Table 3. The secondary outcomes of the trial were calculated based on the grading assigned to post-contrast MR images evaluating the level of BBB disruption. Greater amounts of post-sonication BBB disruption resulted in a trend towards longer PFS and OS.

Background Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described. Methods We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression. Results In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions. Conclusion In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells are identified in patient and mouse GBMs. Partial removal of p16Ink4a-expressing malignant senescent cells, which make up less than 7 % of the tumor, modifies the tumor ecosystem and improves the survival of GBM-bearing female mice. By combining single cell and bulk RNA sequencing, immunohistochemistry and genetic knockdowns, we identify the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM.

The free choice paradigm constitutes one of the most explored paradigms of cognitive dissonance research. Typically, once asked to choose between two similarly rated items, subjects subsequently exhibit an increased preference for chosen items and a decreased preference for rejected ones. Recent studies have demonstrated that such choice-induced preference change (CIPC) occur exclusively for remembered choices, suggesting a mechanism that ensures subjective coherence across time. In the present work we predicted that in order for CIPC to occur, not only must past choices be remembered, but executive networks responsible for detecting and solving conflicts must also be functioning. We confirmed this prediction in a group of patients with frontal lobe lesions. While non-dysexecutive (NODYS) patients behaved as their matched controls did, dysexecutive (DYS) patients failed to change their subjective preferences even when they could remember their previous choices. We have therefore demonstrated the crucial role of executive functions mediated by the frontal lobe in cognitive dissonance resolution.

A high tumour mutational burden (hypermutation) is observed in some gliomas1–5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer. Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.

D-2-hydroxyglutarate (2HG) characterizesMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (27 cmMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of

BACKGROUND The distinction between grade 2 and 3 is instrumental to choose between observational follow-up and adjuvant treatment in resected astrocytoma IDH-mutant. However, criteria for discriminating grade 2 and 3 tumors have not been updated since the WHO 2007 classification. There is no consensus on the method of evaluation of the mitotic activity or a mitosis cut-off for grading. The objectives were to evaluate the maximal mitotic activity on a series of resected astrocytoma IDH-mutant and assess its prognostic impact on survival. METHODS Maximal mitotic activity on consecutive high-power fields corresponding to 3 mm2 was examined in 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity as well as other prognostic factors (including age, performance status, presurgical tumor volume, plurilobar involvement, postsurgical residual tumor volume, midline involvement) was assessed in tumors with (i) ATRX loss, and (ii) without CDKN2A homozygous deletion, lesional enhancement, histological necrosis nor microvascular proliferation. RESULTS Among the 75 (64%) tumors which had gone through observational follow-up after resection, maximal mitotic activity, post-surgical residual volume and plurilobar involvement were independent prognostic factors of TTT (p < 0.0001). A threshold of mitotic activity for grade 2 was fitted using TTT and OS parameters. Using this threshold, patients with “grade 2 tumors” had a median TTT of 55 months versus 19 months for “grade 3” (p= 0.0057) and a median OS of 102 months versus 73 months respectively (p= 0.001). Residual volume < 1 cm3 was associated with longer OS (113 months versus 88 months, p= 0.0021). CONCLUSIONS The combination of mitotic activity and postsurgical residual volume improves prognostication in resected astrocytoma IDH-mutant. This novel risk assessment method could identify the best candidates for observational follow-up.

Stereotactic frame-based brain biopsy is one of the most used procedures to obtain brain tissue. This procedure is usually considered as mini-invasive, quick, efficient, and safe even if results of the different studies are widely heterogenous. The objective of this review of the literature is to describe and analyze the complications of stereotactic frame-based brain biopsy. About 132 articles were found after a research in the Medline database. We only considered English references published between 1994 and June 2019. Additional studies were found by using the references from articles identified in the original search. This systematic review was conducted according to PRISMA guidelines. After applying exclusion criteria, we eventually considered 25 relevant studies. The mortality rate varies from 0.7 to 4%. Overall morbidity ranges from 3 to 13%. Most of the complications are revealed by the following symptoms: neurological impairment (transient or permanent), seizure, and unconsciousness. Symptomatic hemorrhage range varies from 0.9 to 8.6%, whereas considering asymptomatic bleeding, the range may be up to 59.8%. Complications were clinically evident within minutes to a few hours after the biopsy. Corrective surgeries are very rare (

BackgroundAstroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined.Materials and MethodsWe performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM.ResultsStrikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = .021). Mitogen-activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma.ConclusionWe suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway.Implications for PracticeAstroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.

18F-DOPA PET-MRI was performed on a 38-year-old man referred for complementary imaging after a brain tumor was discovered, according to EANM/RANO recommendations. We performed a simultaneous PET with 3-T brain MRI, which revealed 2 high 18F-DOPA uptakes, with no multimodal MRI sign of aggressiveness. An awake surgery was performed and found a grade III anaplastic astrocytoma IDH1-R132L mutant, according to the 2016 WHO classification. This was probably the aggressive transition of a grade II diffuse astrocytoma. This case illustrates the added value of 18F-DOPA PET to multimodal MRI to distinguish low- and high-grade gliomas.

Background Isocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined. Methods We searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989–2020). Results Out of 517 grade II gliomas, 47 were “diffuse astrocytomas, IDHwt.” Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%). Conclusions Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.

International audience; Background: For nonneoplastic neurological diseases, no recommendation exists regarding the place or appropriate timing of brain biopsy. The aim of this study was to evaluate the diagnostic yield and safety of brain biopsies from patients with neurological diseases of unknown etiology.Methods: We performed a retrospective cohort study from January 1, 2008 to December 31, 2018. We analyzed 1847 brain-biopsied patients, including 178 biopsies indicated for neurological diseases of unknown etiology. Specific histological and final diagnosis rates, positive diagnosis-associated factors, complication rate and complication-associated factors were assessed.Results: Specific histological diagnosis and final diagnosis rates were 71.3% and 83.1%, respectively, leading to therapeutic management change(s) for 75.3% of patients. Brain- biopsy-related mortality and permanent neurological morbidity occurred in 1.1% and 0.6% of the patients, respectively. The multivariable logistic-regression model retained (odds ratio [95% CI] only immunodepression (2.2 [1.1-4.7]; P=.04) as being independently associated with specific histological diagnosis, while supratentorial biopsy-targeted lesions (4.1 [1.1-15.2]; P=.04) were independently associated with a final diagnosis. Biopsies obtained from comatose patients were less contributive to the diagnosis (0.2 [0.05-0.7]; P=.01). Prebiopsy platelet count

Background We quantified the spontaneous imaging growth rate of oligodendrogliomas. We assessed whether (i) it discriminates between World Health Organization (WHO) grade II and grade III oligodendrogliomas, and (ii) grade III oligodendrogliomas with neo-angiogenesis are associated with more fast growth rates (≥8 mm/y). Methods This work employed a retrospective bicentric cohort study (2010–2016) of adult patients harboring a newly diagnosed supratentorial oligodendroglioma, isocitrate dehydrogenase (IDH) mutant and 1p/19q codeleted (WHO 2016 classification), with a minimum of 2 available MRIs before any treatment (minimum 6-week interval) to measure the spontaneous tumor growth rate. Results We included 108 patients (age 44.7 ± 14.1 y, 60 males). The tumor growth rate was higher in grade III oligodendrogliomas with neo-angiogenesis (n = 37, median 10.4 mm/y, mean 10.0 ± 6.9) than in grade III oligodendrogliomas with increased mitosis count only (cutoff ≥6 mitoses, n = 18, median 3.9 mm/y, mean 4.5 ± 3.2; P = 0.004), and higher than in grade II oligodendrogliomas (n = 53, median 2.3 mm/y, mean 2.8 ± 2.2; P < 0.001). There was increased prevalence of fast tumor growth rates in grade III oligodendrogliomas with neo-angiogenesis (54.1%) compared with grade III oligodendrogliomas with increased mitosis count only (11.1%; P < 0.001), and in grade II oligodendrogliomas (0.0%; P < 0.001). The tumor growth rate trends did not differ between centers (P = 0.121). Neo-angiogenesis (P < 0.001) and mitosis count at ≥9 (P = 0.013) were independently associated with tumor growth rates ≥8 mm/year. A tumor growth rate ≥8 mm/year was the only predictor independently associated with shorter progression-free survival (P = 0.041). Conclusions The spontaneous tumor growth rate recapitulates oligodendroglioma aggressiveness, permits identification of grade III oligodendrogliomas preoperatively when ≥8 mm/year, and questions the grading by mitosis count.

Background Actionable fibroblast growth factor receptor 3 (FGFR3)–transforming acidic coiled-coil protein 3 fusions (F3T3) are found in approximately 3% of gliomas, but their characteristics and prognostic significance are still poorly defined. Our goal was to characterize the clinical, radiological, and molecular profile of F3T3 positive diffuse gliomas. Methods We screened F3T3 fusion by real-time (RT)-PCR and FGFR3 immunohistochemistry in a large series of gliomas, characterized for main genetic alterations, histology, and clinical evolution. We performed a radiological and radiomic case control study, using an exploratory and a validation cohort. Results We screened 1162 diffuse gliomas (951 unselected cases and 211 preselected for FGFR3 protein immunopositivity), identifying 80 F3T3 positive gliomas. F3T3 was mutually exclusive with IDH mutation (P < 0.001) and EGFR amplification (P = 0.01), defining a distinct molecular cluster associated with CDK4 (P = 0.04) and MDM2 amplification (P = 0.03). F3T3 fusion was associated with longer survival for the whole series and for glioblastomas (median overall survival was 31.1 vs 19.9 mo, P = 0.02) and was an independent predictor of better outcome on multivariate analysis. F3T3 positive gliomas had specific MRI features, affecting preferentially insula and temporal lobe, and with poorly defined tumor margins. F3T3 fusion was correctly predicted by radiomics analysis on both the exploratory (area under the curve [AUC] = 0.87) and the validation MRI (AUC = 0.75) cohort. Using Cox proportional hazards models, radiomics predicted survival with a high C-index (0.75, SD 0.04), while the model combining clinical, genetic, and radiomic data showed the highest C-index (0.81, SD 0.04). Conclusion F3T3 positive gliomas have distinct molecular and radiological features, and better outcome.

Our aim was to evaluate the contribution of pseudo-continuous arterial spin labelling (pCASL) in the detection of a postoperative residual lesion in adult brain tumours. Seventy-five patients were prospectively included. Following the results of preoperative DSC-PWI assessment, intra-axial lesions, including high-grade gliomas (n = 43) and certain metastases (n = 14), were classified as hyper-vascular (HV+ group, n = 57); other lesions, including low-grade gliomas and certain metastases, were classified as non-hyper-vascular (HV− group, n = 18). To confirm the absence/presence of a residual lesion or disease progression, postoperative MRI including pCASL sequence and follow-up-MRI were performed within 72 h and 1–6 months after the resection, respectively. Two raters evaluated the images. Mean and maximal ASL cerebral blood flow (CBF) values were measured in the perioperative region and normalised to the contralateral tissue. The pCASL-CBF maps and post-contrast T1WI were visually assessed for residual lesion. Quantitative data were analysed with unpaired Student t and Mann-Whitney U tests and the visual diagnostic performance with the McNemar test. In the HV+ group, the mean normalised CBF was 1.97 ± 0.59 and 0.97 ± 0.29 (p < 0.0001, AUC = 0.964, cut-off = 1.27) for patients with or without residual tumours, respectively. The mean normalised CBF was not discriminative for assessing residual tumours in the HV− group (p = 0.454). Visual CBF evaluation allowed 92.98% patients belonging to the HV+ group to be correctly classified (sensitivity 93.02%, specificity 92.86%, p < 0.001). Visual evaluation was correlated with contrast enhancement evaluation and with the mean normalised CBF values (r = 0.505, p < 0.0001 and 0.838, p < 0.0001, respectively). Qualitative and quantitative ASL evaluation shows high diagnostic performance in postoperative assessment of hyper-perfused tumours. In this case, postoperative pCASL may be useful, especially if contrast injection cannot be performed or when contrast enhancement is doubtful. • Evaluation of postoperative residual lesion in the case of brain tumours is an imaging challenge. • This prospective monocentric study showed that increased normalised cerebral blood flow assessed by pseudo-continuous arterial spin labelling (pCASL) correlates well with the presence of a residual tumour in the case of hyper-vascular tumour diagnosed on preoperative MRI. • Qualitative and quantitative pCASL is an informative sequence for hyper-vascular residual tumour, especially if acquired more than 48 h after brain tumour surgery, when contrast enhancement can give ambiguous results due to blood-brain barrier disruption.

Purpose The practical management of cavernous angioma located within eloquent brain area before, during and after surgical resection is poorly documented. We assessed the practical pre-operative, intra-operative, and post-operative management of cavernous angioma located within eloquent brain area. Method An online survey composed of 61 items was sent to 26 centers to establish a multicenter international retrospective cohort of adult patients who underwent a surgical resection as the first-line treatment of a supratentorial cavernous angioma located within or close to eloquent brain area. Results 272 patients from 19 centers (mean 13.6 ± 16.7 per center) from eight countries were included. The pre-operative management varied significantly between centers and countries regarding the pre-operative functional assessment, the pre-operative epileptological assessment, the first given antiepileptic drug, and the time to surgery. The intra-operative environment varied significantly between centers and countries regarding the use of imaging systems, the use of functional mapping with direct electrostimulations, the extent of resection of the hemosiderin rim, the realization of a post-operative functional assessment, and the time to post-operative functional assessment. The present survey found a post-operative improvement, as compared to pre-operative evaluations, of the functional status, the ability to work, and the seizure control. Conclusions We observed a variety of practice between centers and countries regarding the management of cavernous angioma located within eloquent regions. Multicentric prospective studies are required to solve relevant questions regarding the management of cavernous angioma-related seizures, the timing of surgery, and the optimal extent of hemosiderin rim resection.

ObjectiveTo determine the prevalence of developmental venous anomaly in adult patients with diffuse glioma.MethodsWe performed a retrospective cohort study (2010–2016) of consecutive adult patients harboring a supratentorial diffuse glioma in 2 centers: Sainte-Anne Hospital (experimental and control sets) and Pitié-Salpêtrière Hospital (external validation set). We included 219 patients with diffuse glioma (experimental set), 252 patients with brain metastasis (control set), and 200 patients with diffuse glioma (validation set). The inclusion criteria were age ≥18 years at diagnosis, histopathologic diagnosis of diffuse glioma according to the 2016 World Health Organization classification of tumors of the CNS, surgery as first-line treatment without previous oncologic treatment, available presurgical MRI performed with similar acquisition protocol, and absence of a nodular-like or a ring-like pattern of contrast enhancement on MRI that may preclude the identification of a possible developmental venous anomaly within the glioma.ResultsWe found more developmental venous anomaly in the experimental set (21.5%) than in the control set (5.2%, p < 0.001). Similarly, we found more developmental venous anomaly in the validation set (23.5%) than in the control set (5.2%, p < 0.001). There was no difference in the developmental venous anomaly prevalence between the experimental and validation sets. The developmental venous anomaly distribution was not significantly associated with histopathologic, molecular, or imaging findings of the diffuse gliomas.ConclusionsWe report and replicate in an external cohort a high prevalence of developmental venous anomaly in adult patients with diffuse glioma, which suggests a potential underlying common predisposition or a causal relationship that requires deeper investigations.

Introduction Surgical resection of supratentorial cavernous angiomas located in eloquent areas poses a significant risk to the patient of postoperative neurological impairment and justifies intraoperative functional monitoring. Methods Multicentre retrospective series of adult patients with cavernous angiomas located within eloquent areas and treated with functional-based surgical resection according to functional boundaries under intraoperative functional cortico-subcortical monitoring under awake conditions. Results Fifty patients (18 males, mean 36.3 ± 10.8 year-old) underwent surgical resection with intraoperative cortico-subcortical functional mapping using direct electrostimulation under awake conditions for a cavernous angioma located in eloquent areas with a mean postoperative follow-up of 21.0 ± 21.2 months. At presentation, the cavernous angioma had previously resulted in severe impairment (neurological deficit in 34%, seizures in 70%, uncontrolled seizures in 34%, reduced Karnofsky Performance Status score of 70 or less in 24%, inability to work in 52%). Functional-based surgical resection allowed complete removal of the cavernous angioma in 98% and of the haemosiderin rim in 82%. Postoperative seizures and other complications were rare, and similarly so across all centres included in this series. Postoperatively, we found functional improvement in 84% of patients (reduced Karnofsky Performance Status score of 70 or less in 6%, uncontrolled seizures in 16%, and inability to work in 11%). Conclusion Functional-based surgical resection aids the safe and complete resection of cavernous angiomas located in eloquent areas while minimizing the surgical risks. Functional mapping has to be considered in such challenging cases.

Introduction La mutation IDH offre une information diagnostique et pronostique cruciale dans les gliomes. Le 2-hydroxyglutarate (2HG) est un metabolite specifique des gliomes IDH-mutes qui est decelable par une sequence de spectroscopie editee (MEGA-PRESS). Nous avons examine (1) les parametres radiologiques et genetiques affectant l’accumulation de 2HG, (2) la variation de 2HG sous traitements et (3) la valeur pronostique de 2HG. Methode Soixante-dix gliomes (24 non-traites, 46 IDH-mutes traites) ont ete etudies sur un systeme 3 T (Verio, Siemens) avec des sequences 3DT1 EG, 3DT1 FLAIR, DTI (12 directions) et MEGA-PRESS (TR : 2s, TE : 68 ms, taille du voxel : 9,8 ml ± 2,8, dure : 8 min). Neuf gliomes IDH mutes ont ete aussi suivi pour un ans pendant radio-chimiotherapie. Nous avons analyse des parametres radiologiques (volume tumoral, volumes des portions kystiques, pourcentage de tumeur dans le voxel, profil spectroscopique, valeurs de MD, FA) ainsi que genetiques (mutation IDH1R132H, IDH2 et IDH1 mineurs). Le 2HG a ete aussi mesure dans des echantillons tumoraux, dans le plasma et dans les urines en utilisant la chromatographie en phase gazeuse couplee a la spectrometrie de masse (GCMS). Resultats MEGA-PRESS a detecte le 2HG avec une sensibilite de 95 % chez les patients non traites, de 69 % chez les patients traites et avec une specificite de 100 % dans les deux groupes. Les valeurs de 2HG ont montre une correlation positive avec la choline (r = 0,58 p = 0,0001) et negative avec le myo-inositol (r = −0,29 p = 0,03) ( Fig. 1 C–D). Le 2HG a ete plus facilement mesure en absence de lesions kystiques (p = 0,04), lorsque le volume tumoral etait > 26,9 cm3 (p = 0,02) ou le pourcentage de tumeur dans le voxel etait > 72 % (p = 0,04). Les mesures estimees par MEGA-PRESS ont correle avec les valeurs obtenues par CGSM sur des echantillons tumoraux (r = 0,68, p = 0,0009) et dans les urines (r = 0,80 p = 0,003). La concentration de 2HG est reduite chez les patients traites par rapport a ceux qui n’ont pas recu des traitements (1,1 versus 2,3 mm, p = 0,02), elle est plus elevee chez les gliomes IDH2 mutes par rapport a les plus frequentes gliomes IDH1 R132H mutes (4,7 vs 2,4 mm, p = 0,02) et plus faible chez les patients presentant des mutations IDH1 autres que R132H (1,12 vs 2,4 mm, p = 0,004). Enfin, les gliomes IDH mutes qui ont montre une concentration de 2HG plus elevees ont eu une plus longue survie ( Fig. 1 F). Conclusion La densite des cellules IDH-mutees, le volume tumoral, les traitements et les caracteristiques genetiques de la tumeur determinent la detection de 2HG. Cet oncometabolite peut etre surveille de facon fiable sous radio-chimiotherapie et a un valeur pronostique positive per se, independant de la mutation IDH.

Microglia exhibit multiple, phenotype-dependent motility patterns often triggered by purinergic stimuli. However, little data exist on motility of human microglia in pathological situations. Here we examine motility of microglia stained with a fluorescent lectin in tissue slices from female and male epileptic patients diagnosed with mesial temporal lobe epilepsy or cortical glioma (peritumoral cortex). Microglial shape varied from ramified to amoeboid cells predominantly in regions of high neuronal loss or closer to a tumor. Live imaging revealed unstimulated or purine-induced microglial motilities, including surveillance movements, membrane ruffling, and process extension or retraction. At different concentrations, ADP triggered opposing motilities. Low doses triggered process extension. It was suppressed by P2Y12 receptor antagonists, which also reduced process length and surveillance movements. Higher purine doses caused process retraction and membrane ruffling, which were blocked by joint application of P2Y1 and P2Y13 receptor antagonists. Purinergic effects on motility were similar for all microglia tested. Both amoeboid and ramified cells from mesial temporal lobe epilepsy or peritumoral cortex tissue expressed P2Y12 receptors. A minority of microglia expressed the adenosine A2A receptor, which has been linked with process withdrawal of rodent cells. Laser-mediated tissue damage let us test the functional significance of these effects. Moderate damage induced microglial process extension, which was blocked by P2Y12 receptor antagonists. Overall, the purine-induced motility of human microglia in epileptic tissue is similar to that of rodent microglia in that the P2Y12 receptor initiates process extension. It differs in that retraction is triggered by joint activation of P2Y1/P2Y13 receptors.SIGNIFICANCE STATEMENTMicroglial cells are brain-resident immune cells with multiple functions in healthy or diseased brains. These diverse functions are associated with distinct phenotypes, including different microglial shapes. In the rodent, purinergic signaling is associated with changes in cell shape, such as process extension toward tissue damage. However, there are little data on living human microglia, especially in diseased states. We developed a reliable technique to stain microglia from epileptic and glioma patients to examine responses to purines. Low-intensity purinergic stimuli induced process extension, as in rodents. In contrast, high-intensity stimuli triggered a process withdrawal mediated by both P2Y1 and P2Y13 receptors. P2Y1/P2Y13 receptor activation has not previously been linked to microglial morphological changes.

BACKGROUND: The postoperative outcomes and the predictors of seizure control are poorly studied for supratentorial cavernous angiomas (CA) within or close to the eloquent brain area. OBJECTIVE: To assess the predictors of preoperative seizure control, postoperative seizure control, and postoperative ability to work, and the safety of the surgery. METHODS: Multicenter international retrospective cohort analysis of adult patients benefitting from a functional-based surgical resection with intraoperative functional brain mapping for a supratentorial CA within or close to eloquent brain areas. RESULTS: A total of 109 patients (66.1% women; mean age 38.4 ± 12.5 yr), were studied. Age >38 yr (odds ratio [OR], 7.33; 95% confidence interval [CI], 1.53-35.19; P =. 013) and time to surgery > 12 mo (OR, 18.21; 95% CI, 1.11-296.55; P =. 042) are independent predictors of uncontrolled seizures at the time of surgery. Focal deficit (OR, 10.25; 95% CI, 3.16-33.28; P

BACKGROUND Even if medulloblastoma is considered as a curable disease, recurrent medulloblastoma has a poor prognosis, independently of therapy used. Medulloblastoma is very rare in adults, unlike children, and therapeutic strategies at recurrence are lacking. Nevertheless, adult teams sometimes use as “compassionate” chemotherapy some regimens published in children, such as the MEMMAT metronomic combination. However, this treatment, targeting both endothelial and proliferating tumor cells, has to date not been studied in the adult population. MATERIAL AND METHODS We present the case of a 40-year-old man, suffering from a right cerebellar SHH mutated medulloblastoma initially diagnosed and treated in 2014 by craniospinal radiotherapy associated with 4 cycles of carboplatine-VP16 following complete resection. Since April 2016, date of first relapse, numerous successive recurrences occurred, initially focal, treated by several surgeries (April and November 2016, January 2017), chemotherapy (rechallenge by carboplatine-VP16) then stereotactic radiotherapy. He then developed in October 2017 a new relapse in the posterior fossa, also associated with a meningeal dissemination on lumbar MRI. IK was 90%. He was then treated by TOTEM regimen (Temozolomide-Topotecan) followed by “Packer” regimen (Cisplatin-Belustine-Vincristin), without tumor control. However, because patient was non symptomatic with a KPS of 80%, we decided, according to the AJA French group, to propose what we presumed to be a “compassionate” chemotherapy, by metronomic pediatric regimen “MEMMAT”. For “supportive care” reasons, we decided not to realize the “Intrathecal part” of this regimen and administered to the patient intravenous bevacizumab (10 mg/kg d1-d14-d21), thalidomide (100 mg/d), celecoxib (300 mg bid), fenofibrate (160 mg/d) and etoposide (100 mg/d d1-21), alternating with cyclophosphamide (100 mg/d d22-42). RESULTS Clinical tolerance was very good, except grade 1 heel pain and fatigue; hematological toxicity was mild (transient grade 3 neutropenia, grade 4 lymphopenia); renal impairment, already present at the beginning, was increasing, and justified dose adjustment after 5 cycles and nephrologic explorations, ongoing. Radiological evaluation showed a complete radiological response with complete disappearance of enhancing lesions on first MRIs realized after 3 months (2 cycles); this response was confirmed after 6 months (4 cycles) and 9 months (6 cycles) on both cerebral and spinal MRI. Patient is now receiving the 7th cycle. CONCLUSION We report here the first case of a complete and sustaining response of an adult multi-recurrent metastatic medulloblastoma treated by a pediatric antiangiogenic metronomic regimen “MEMMAT”. This promising result incites to develop a dedicated prospective trial in adults in view to confirm the interest of this strategy.

Stereotactic frame-based brain biopsy is one of the most used procedures to obtain brain tissue. This procedure is usually considered as mini-invasive, quick, efficient, and safe even if results of the different studies are widely heterogenous. The objective of this review of the literature is to describe and analyze the complications of stereotactic frame-based brain biopsy. About 132 articles were found after a research in the Medline database. We only considered English references published between 1994 and June 2019. Additional studies were found by using the references from articles identified in the original search. This systematic review was conducted according to PRISMA guidelines. After applying exclusion criteria, we eventually considered 25 relevant studies. The mortality rate varies from 0.7 to 4%. Overall morbidity ranges from 3 to 13%. Most of the complications are revealed by the following symptoms: neurological impairment (transient or permanent), seizure, and unconsciousness. Symptomatic hemorrhage range varies from 0.9 to 8.6%, whereas considering asymptomatic bleeding, the range may be up to 59.8%. Complications were clinically evident within minutes to a few hours after the biopsy. Corrective surgeries are very rare ( 1%). Complications occurring after a frame-based stereotactic brain biopsy are rare but with serious side effects. It rarely leads to death or to permanent neurological impairment. Description and classification of complications are often heterogeneous in the literature. The use of a grading scale could help comparisons between series from around the world. Future studies should establish a score that allows neurosurgeon to predict post-biopsy complications.

International audience; Objective: IDH wild-type glioblastoma is the most common and aggressive primary brain cancer in adults. At tumor recurrence, treatment decision-making is not standardized; several options include second surgery, reirradiation, and a second line of chemotherapy. In this retrospective monocentric study conducted at the era of WHO 2016 classification, we investigated IDH wild-type glioblastoma patients below the age of 70 to see (i) the clinical benefit of second surgery at recurrence and (ii) the prognostic factors in resected recurrent glioblastoma patients.Methods: 229 newly diagnosed IDH wild-type glioblastoma patients below the age of 70 treated with the standard of care (SOC) were enrolled in the current study and stratified into two subgroups according to treatment at recurrence: re-resection and no re-resection.Results: All experienced tumor recurrence with a median progression-free survival of 11 months. 25 % of patients were reoperated. Patients reoperated at recurrence had longer post-progression median overall survival compared to their non-reoperated counterparts (14 versus 9 months, p < .05). Initial surgical resection and a long time from the initial diagnosis to the first recurrence were independent prognostic factors for good outcomes in resected recurrent IDH-wild-type glioblastoma patients; however, tumor size before and after surgery did not impact post-surgical survival.Conclusion: Our study supports surgical resection at recurrence as therapeutic in IDH wild-type glioblastoma patients aged below 70 and in good clinical condition regardless of preoperative tumor size, particularly in patients who experienced a longer time before first recurrence and surgery at initial diagnosis. Further prospective and larger studies are warranted to validate our findings.

Introduction Les determinants des survies longues et courtes des glioblastomes sont mal connus, en dehors des mutations d’IDH (Isocitrate DeHydrogenase), associees a la survie longue. Objectifs L’objectif de cette etude est de clarifier les caracteristiques cliniques et moleculaires associees a ces survies inhabituelles (survie > 5 ans ou Patients et methodes Des caracteristiques cliniques (âge au diagnostic, index de Karnofsky (IK), type de chirurgie, biopsie vs resection, symptomes revelateurs) et moleculaires (mutations IDH, TP53, du promoteur de TERT, amplifications EGFR, deletion de P16, gain ou perte de bras chromosomiques, methylation du promoteur de MGMT (O6-methylguanine-DNA methyltransferase)) ont ete comparees entre les 74 long-survivants (LS, survie > 5 ans) et 376 court-survivants (CS, survie Resultats L’âge (p Discussion L’âge jeune, l’IK, et la resection chirurgicale sont des caracteristiques associees aux LS. La methylation du promoteur de MGMT, la perte du 10 et le gain du 19 pourraient etre des facteurs pronostiques benefiques notamment pour les patients sans mutation IDH. Conclusion Cette etude rapporte, a notre connaissance, la plus grande cohorte de patients atteints de glioblastomes avec survie superieure a 5 ans, et met en evidence de nouveaux facteurs pronostiques potentiels.

High tumor mutational burden (hypermutation) is observed in some gliomas; however, its mechanisms of development and whether it predicts immunotherapy response are poorly understood. Here, we comprehensively analyze the molecular determinants of mutational burden and signatures in 10,294 gliomas including AACR Project GENIE and institutional datasets. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after temozolomide treatment. Experimentally, the mutational signature of post-treatment hypermutated gliomas was only recapitulated by temozolomide-induced damage in cells harboring MMR deficiency. MMR-deficient gliomas exhibited unique features including the lack of prominent T-cell infiltrates, extensive intratumoral heterogeneity, poor survival and low response rate to PD-1 blockade. Moreover, while microsatellite instability in MMR-deficient gliomas was not detected by bulk analyses, single-cell whole-genome sequencing of post-treatment hypermutated glioma cells demonstrated microsatellite mutations. This study shows that chemotherapy can drive acquisition of hypermutated populations without promoting response to PD-1 blockade and supports diagnostic use of mutational burden and signatures in cancer. Citation Format: Mehdi Touat, Yvonne Y. Li, Adam N. Boynton, Liam F. Spurr, Bryan Iorgulescu, Craig L. Bohrson, Isidro Cortes-Ciriano, Jack E. Geduldig, Kristine Pelton, Mary J. Lim-Fat, Sangita Pal, Shakti H. Ramkissoon, Frank Dubois, Charlotte Bellamy, Naomi Currimjee, Kenin Qian, Seth Malinowski, Aniket Shetty, Kin-Hoe Chow, Maïté Verreault, Erell Guillerm, Samy Ammari, Frédéric Beuvon, Karima Mokhtari, Agusti Alentorn, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Dimitri Psimaras, Alexandre Carpentier, Philippe Cornu, Laurent Capelle, Bertrand Mathon, Jill S. Barnholtz-Sloan, Arnab Chakravarti, Wenya L. Bi, Garrett M. Frampton, Marc Sanson, Brian M. Alexander, Andrew Cherniack, Patrick Y. Wen, David A. Reardon, Aurelien Marabelle, Peter J. Park, Ahmed Idbaih, Rameen Beroukhim, Pratiti Bandopadhayay, Franck Bielle, Keith L. Ligon. Mechanisms and therapeutic implications of hypermutation in gliomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5705.

Purpose: The blood–brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations. Patients and Methods: A first-in-man, single-arm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy. Results: Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n = 11) had a median PFS of 4.11 months, and a median OS of 12.94 months. Conclusions: SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity. See related commentary by Sonabend and Stupp, p. 3750

BACKGROUND: Epileptic seizures impair quality of life in diffuse low-grade glioma (DLGG) patients. Tumor resection significantly impacts postoperative seizure control, but the precise extent of resection (EOR) required for optimal seizure control is not clear yet. OBJECTIVE: To identify the EOR and residual tumor volume that correlated to postoperative seizure control, defined as a total seizure freedom (Class 1A in reference to Engel classification system) with and without antiepileptic drugs in patients undergoing surgical resection of supratentorial DLGG. METHODS: A retrospective review was conducted of all patients who underwent first-line surgical resection of supratentorial DLGG who presented with preoperative seizures without adjuvant oncological treatment. EOR and residual tumor volume were quantified from pre- and post-operative magnetic resonance imagings. Receiver operating characteristic curves were plotted to determine the EOR and residual tumor volume that corresponded to optimal postoperative seizure control. RESULTS: Of the 346 included patients, 65.5% had controlled seizures postoperatively, with higher age at resection (adjusted OR per unit, 1.03 [95% confidence interval:1.01-1.06], P = .043) and higher percentage of resection (adjusted OR per unit, 1.02 [95% confidence interval:1.00-1.03], P < .001) found as independent predictors of postoperative seizure control. Optimal EOR was ≥91% and optimal residual tumor volume was ≤19 cc to improve postoperative seizure control. CONCLUSION: Postoperative seizure control is more likely when EOR is ≥91% and/or when residual tumor volume is ≤19 cc in supratentorial DLGG gliomas who present with seizures. Resected peritumoral cortex should, however, be taken into account in future studies.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors. An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.

Life expectancy of patients treated for brain tumors has lengthened due to the therapeutic improvements. Cognitive impairment has been described following brain radiotherapy, but the mechanisms leading to this adverse event remain mostly unknown. Technical evolutions aim at enhancing the therapeutic ratio. Sparing of the healthy tissues has been improved using various approaches; however, few dose constraints have been established regarding brain structures associated with cognitive functions. The aims of this literature review are to report the main brain areas involved in cognitive adverse effects induced by radiotherapy as described in literature, to better understand brain radiosensitivity and to describe potential future improvements.

Introduction L’evaluation de l’exerese chirurgicale des tumeurs cerebrales sur l’IRM post-operatoire est un defi. Notre objectif etait d’evaluer la contribution de l’arterial-spin-labelling pseudocontinu (pCASL) dans la recherche d’une lesion residuelle post-operatoire. Materiel et methode L’etude prospective a inclus 64 adultes avec tumeur cerebrale primitive ou secondaire. L’imagerie de perfusion dynamique injectee pre-operatoire a permis d’etablir deux groupes : groupe hyperperfusion (HP+, n = 49), comprenant gliomes de haut-grade (31), certaines metastases (11), meningiomes (4), autres (3) ; et groupe sans hyperperfusion (HP-, n = 15) comprenant gliomes de bas-grade (10), certaines metastases (2), autres (3). Pour confirmer l’absence/presence d’un residu ou progression lesionnelle, IRM post-operatoire comprenant pCASL et IRM de suivi ont ete realisees respectivement dans les 48 heures et 1-6mois apres la resection. Les IRM ont ete analysees par deux lecteurs, qualitativement et quantitativement. Le debit sanguin cerebral (DSC), obtenu en placant le ROI dans la region peri-operatoire, a distance des artefacts, a ete normalise par le parenchyme cerebral controlateral sain. Les cartographies de DSC en pCASL et le rehaussement ont ete analyses visuellement. Resultats Dans le groupe HP+, le DSC moyen normalise etait 2,21 ± 1,03 ou 0,99 ± 0,31 (p Fig. 1 , Fig. 2 ) pour les patients avec ou sans tumeur residuelle, respectivement. Le DSC moyen normalise n’etait pas discriminant pour evaluer la tumeur residuelle dans le groupe HP- (p = 0,639). L’evaluation visuelle du DSC a permis de classer correctement 94,1 % des patients du groupe HP+ (sensibilite 94,12 %, specificite 86,67 %, p Conclusion L’evaluation qualitative et quantitative de l’ASL a une haute performance diagnostique dans l’analyse post-operatoire des tumeurs hyperperfusees. Dans cette situation, le pCASL post-operatoire pourrait etre une sequence utile, en particulier en cas de contre-indication a l’injection de gadolinium ou lorsque le rehaussement est douteux dans la zone peri-operatoire [1] , [2] , [3] , [4] , [5] .

Purpose: Objective Shear wave elastography (SWE) enabled living tissue assessment of stiffness. This is routinely used for breast, thyroid and liver diseases, but there is currently no data for the brain. We aim to characterize elasticity of normal brain parenchyma and brain tumors using SWE. Materials and Methods: Patients with scheduled brain tumor removal were included in this study. In addition to standard ultrasonography, intraoperative SWE using an ultrafast ultrasonic device was used to measure the elasticity of each tumor and its surrounding normal brain. Data were collected by an investigator blinded to the diagnosis. Descriptive statistics, box plot analysis as well as intraoperator and interoperator reproducibility analysis were also performed. Results: 63 patients were included and classified into four main types of tumor: meningiomas, low-grade gliomas, high-grade gliomas and metastasis. Young’s Modulus measured by SWE has given new insight to differentiate brain tumors: 33.1 ± 5.9 kPa, 23.7 ± 4.9 kPa, 11.4 ± 3.6 kPa and 16.7 ± 2.5 kPa, respectively, for the four subgroups. Normal brain tissue has been characterized by a reproducible mean stiffness of 7.3 ± 2.1 kPa. Moreover, low-grade glioma stiffness is different from high-grade glioma stiffness (p = 0.01) and normal brain stiffness is very different from low-grade gliomas stiffness (p Conclusion: This study demonstrates that there are significant differences in elasticity among the most common types of brain tumors. With intraoperative SWE, neurosurgeons may have innovative information to predict diagnosis and guide their resection.

OBJECTIVEThe goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk.METHODSIn this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma.RESULTSFor gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal.CONCLUSIONSWhen a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management.■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.

Epilepsies are characterized by recurrent seizures, which disrupt normal brain function. Alterations in neuronal excitability and excitation-inhibition balance have been shown to promote seizure generation, yet molecular determinants of such alterations remain to be identified. Pannexin channels are nonselective, large-pore channels mediating extracellular exchange of neuroactive molecules. Recent data suggest that these channels are activated under pathological conditions and regulate neuronal excitability. However, whether pannexin channels sustain or counteract chronic epilepsy in human patients remains unknown. We studied the impact of pannexin-1 channel activation in postoperative human tissue samples from patients with epilepsy displaying epileptic activity ex vivo. These samples were obtained from surgical resection of epileptogenic zones in patients suffering from lesional or drug-resistant epilepsy. We found that pannexin-1 channel activation promoted seizure generation and maintenance through adenosine triphosphate signaling via purinergic 2 receptors. Pharmacological inhibition of pannexin-1 channels with probenecid or mefloquine-two medications currently used for treating gout and malaria, respectively-blocked ictal discharges in human cortical brain tissue slices. Genetic deletion of pannexin-1 channels in mice had anticonvulsant effects when the mice were exposed to kainic acid, a model of temporal lobe epilepsy. Our data suggest a proepileptic role of pannexin-1 channels in chronic epilepsy in human patients and that pannexin-1 channel inhibition might represent an alternative therapeutic strategy for treating lesional and drug-resistant epilepsies.

Background Mutations in the isocitrate dehydrogenase (IDH) enzyme affect 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG) and to compare performance of these methods with DNA sequencing and tissue 2HG analysis. Methods Twenty-four subjects with suspected diagnosis of low-grade glioma were included prospectively in the study. For all subjects, MRS data were acquired at 3T using 2 MRS methods, edited MRS using Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and a PRESS sequence optimized for 2HG detection, using a volume of interest larger than 6 mL. IDH mutational status was determined by a combination of automated immunohistochemical analysis and Sanger sequencing. Levels of 2HG in tissue samples measured by gas chromatography-mass spectrometry were compared with those estimated by MRS. Results Edited MRS provided 100% specificity and 100% sensitivity in the detection of 2HG. The 2HG levels estimated by this technique were in line with those derived from tissue samples. Optimized PRESS provided lower performance, in agreement with previous findings. Conclusions Our results suggest that edited MRS is one of the most reliable tools to predict IDH mutation noninvasively, showing high sensitivity and specificity for 2HG detection. Integrating edited MRS in clinical practice may be highly beneficial for noninvasive diagnosis of glioma, prognostic assessment, and treatment planning.

Diffuse WHO grade II and III gliomas (DGII/IIIG) are rare tumors, with few specific epidemiological studies. We aimed at describing the geographical distribution of a homogeneous series of histologically confirmed DGII/IIIG, over a four-year period (2006-2009), at a national level. The methodology is based on a multidisciplinary national network already established by the French Brain Tumor DataBase and data collected directly from every neuropathology department. Personal home addresses were collected for confirmed cases. For each region, the incidence of DGII/IIIG was analyzed and standardized on the age and sex distribution of the French population. The number of patients with newly diagnosed, histologically confirmed DGII/IIIG was 4,790. The overall crude rate was 19.4/10(6). To enable international comparisons, standardized rates were calculated as follows: 19.8/10(6), 18.8/10(6) and 16.0/10(6) (reference population, Europe, US and world, respectively). The geographical distribution by region showed significant differences, with higher incidence rates in Northeast and central parts of France. This work is the first studying the geographical distribution of a pure series of DGII/IIIG at a national level. It demonstrates significant heterogeneity in the distribution, and raises the question of the role of environmental and/or genetic risk(s) factor(s) for DGII/IIIG.