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Purpose: This study aimed to assess the benefit-risk ratio by determining diagnostic yield and safety of brainstem biopsies in adult patients. The secondary objectives were (i) to compare brainstem biopsy safety and postbiopsy patients' outcomes and survival with those of patients biopsied for a brain or cerebellar lesion, and (ii) to assess the impact of brainstem biopsy on final diagnosis and further therapeutic management., Methods: Among 1784 stereotactic biopsies performed in adult patients at a tertiary center between April 2009 and October 2020, we retrospectively examined 50 consecutive brainstem biopsies. We compared variables regarding diagnostic yield, safety and post-biopsy outcomes between brainstem biopsy patients and brain/cerebellum biopsy patients., Results: Brainstem biopsy led to a diagnosis in 86% of patients (94.6% in patients with suspected tumor). Lesion contrast enhancement on imaging was the sole predictor of obtaining a diagnosis. Rates of symptomatic complications and mortality were significantly higher in brainstem biopsy patients compared to brain/cerebellum biopsy patients (20% vs 0%; p < 0.001 and 6% vs 0%; p = 0.01, respectively). Transfrontal trajectory and prebiopsy swallowing disorders were predictors of brainstem biopsy-related symptomatic complications. Brainstem biopsy findings led to diagnostic change in 22% of patients., Conclusions: Stereotactic biopsy in adult patients with brainstem lesion has a high diagnostic yield. Although stereotactic brainstem biopsy is associated with more functional and fatal complications than biopsies targeting the brain/cerebellum, its safety profile appears acceptable. Thus, the benefit-risk ratio of stereotactic biopsy in patients with brainstem lesion is favorable but should nevertheless be carefully weighted on a case-by-case basis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuropathological examination of the temporal lobe provides a better understanding and management of a wide spectrum of diseases. We focused on inflammatory diseases, epilepsy, and neurodegenerative diseases, and highlighted how the temporal lobe is particularly involved in those conditions. Although all these diseases are not specific or restricted to the temporal lobe, the temporal lobe is a key structure to understand their pathophysiology. The main histological lesions, immunohistochemical markers, and molecular alterations relevant for the neuropathological diagnostic reasoning are presented in relation to epidemiology, clinical presentation, and radiological findings. The inflammatory diseases section addressed infectious encephalitides and auto-immune encephalitides. The epilepsy section addressed (i) susceptibility of the temporal lobe to epileptogenesis, (ii) epilepsy-associated hippocampal sclerosis, (iii) malformations of cortical development, (iv) changes secondary to epilepsy, (v) long-term epilepsy-associated tumors, (vi) vascular malformations, and (vii) the absence of histological lesion in some epilepsy surgery samples. The neurodegenerative diseases section addressed (i) Alzheimer's disease, (ii) the spectrum of frontotemporal lobar degeneration, (iii) limbic-predominant age-related TDP-43 encephalopathy, and (iv) α-synucleinopathies. Finally, inflammatory diseases, epilepsy, and neurodegenerative diseases are considered as interdependent as some pathophysiological processes cross the boundaries of this classification., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The literature shows discrepancies in stereotactic brain biopsy complication rates, severities, and outcomes. Little is known about the timeline of postbiopsy complications. This study aimed to analyze 1) complications following brain biopsies, using a graded severity scale, and 2) a timeline of complication occurrence. The secondary objectives were to determine factors associated with an increased risk of complications and to assess complication-related management and extra costs., Methods: The authors retrospectively examined 1500 consecutive stereotactic brain biopsies performed in adult patients at their tertiary medical center between April 2009 and April 2019., Results: Three hundred eighty-one biopsies (25.4%) were followed by a complication, including 88.2% of asymptomatic hemorrhages. Symptomatic complications involved 3.0% of the biopsies, and 0.8% of the biopsies were fatal. The severity grading scale had a 97.6% interobserver reproducibility. Twenty-three (51.1%) of the 45 symptomatic complications occurred within the 1st hour following the biopsy, while 75.6% occurred within the first 6 hours. Age ≥ 65 years, second biopsy procedures, gadolinium-enhanced lesions, glioblastomas, and lymphomas were predictors of biopsy-related complications. Brainstem biopsy-targeted lesions and cerebral toxoplasmosis were predictive of mortality. Asymptomatic hemorrhage was associated with delayed (> 6 hours) symptomatic complications. Symptomatic complications led to extended hospitalization in 86.7% of patients. The average extra cost for management of a patient with postbiopsy symptomatic complication was $35,702., Conclusions: Symptomatic complications from brain biopsies are infrequent but associated with substantial adverse effects and cost implications for the healthcare system. The use of a severity grading scale, as the authors propose in this article, helps to classify complications according to the therapeutic consequences and the patient's outcome. Because this study indicates that most complications occur within the first few hours following the biopsy, postbiopsy monitoring can be tailored accordingly. The authors therefore recommend systematic monitoring for 2 hours in the recovery unit and a CT scan 2 hours after the end of the biopsy procedure. In addition, they propose a modern algorithm for optimal postoperative management of patients undergoing stereotactic biopsy.

Cell-free DNA (cfDNA) analysis is a minimally invasive method that can be used to detect genomic abnormalities by directly testing a blood sample. This method is particularly useful for immunosuppressed patients, who are at high risk of complications from tissue biopsy. The cfDNA tumor fraction (TF) varies greatly across cancer type and between patients. Thus, the detection of molecular alterations is highly dependent on the circulating TF. In our study, we aimed to calculate the TF and characterize the copy number aberration (CNA) profile of cfDNA from patients with rare malignancies occurring in immunosuppressed environments or immune-privileged sites. To accomplish this, we recruited 36 patients: 19 patients with non-Hodgkin lymphoma (NHL) who were either human immunodeficiency virus (HIV)-positive or organ transplant recipients, 5 HIV-positive lung cancer patients, and 12 patients with glioma. cfDNA was extracted from the patients' plasma and sequenced using low-coverage whole genome sequencing (LC-WGS). The cfDNA TF was then calculated using the ichorCNA bioinformatic algorithm, based on the CNA profile. In parallel, we performed whole exome sequencing of patient tumor tissue and cfDNA samples with detectable TFs. We detected a cfDNA TF in 29% of immune-suppressed patients (one patient with lung cancer and six with systemic NHL), with a TF range from 8 to 70%. In these patients, the events detected in the CNA profile of cfDNA are well-known events associated with NHL and lung cancer. Moreover, cfDNA CNA profile correlated with the CNA profile of matched tumor tissue. No tumor-derived cfDNA was detected in the glioma patients. Our study shows that tumor genetic content is detectable in cfDNA from immunosuppressed patients with advanced NHL or lung cancer. LC-WGS is a time- and cost-effective method that can help select an appropriate strategy for performing extensive molecular analysis of cfDNA. This technique also enables characterization of CNAs in cfDNA when sufficient tumor content is available. Hence, this approach can be used to collect useful molecular information that is relevant to patient care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bouzidi, Labreche, Baron, Veyri, Denis, Touat, Sanson, Davi, Guillerm, Jouannet, Charlotte, Bielle, Choquet, Boëlle, Cadranel, Leblond, Autran, Lacorte, Spano, Coulet and the IDEATION study group.)

Activation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation or overexpression of CDKs can support tumourigenesis including glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. The incurability of GBM highlights the need to discover novel and more effective treatment options. Since CDKs 2, 7 and 9 were found to be overexpressed in GBM, we tested the therapeutic efficacy of two CDK inhibitors (CKIs) (CYC065 and THZ1) in a heterogeneous panel of GBM patient-derived cell lines (PDCLs) cultured as gliomaspheres, as preclinically relevant models. CYC065 and THZ1 treatments suppressed invasion and induced viability loss in the majority of gliomaspheres, irrespective of the mutational background of the GBM cases, but spared primary cortical neurons. Viability loss arose from G2/M cell cycle arrest following treatment and subsequent induction of apoptotic cell death. Treatment efficacies and treatment durations required to induce cell death were associated with proliferation velocities, and apoptosis induction correlated with complete abolishment of Mcl-1 expression, a cell cycle-regulated antiapoptotic Bcl-2 family member. GBM models generally appeared highly dependent on Mcl-1 expression for cell survival, as demonstrated by pharmacological Mcl-1 inhibition or depletion of Mcl-1 expression. Further analyses identified CKI-induced Mcl-1 loss as a prerequisite to establish conditions at which the BH3-only protein Bim can efficiently induce apoptosis, with cellular Bim amounts strongly correlating with treatment efficacy. CKIs reduced proliferation and promoted apoptosis also in chick embryo xenograft models of primary and recurrent GBM. Collectively, these studies highlight the potential of these novel CKIs to suppress growth and induce cell death of patient-derived GBM cultures in vitro and in vivo, warranting further clinical investigation., (© 2021. The Author(s).)

Purpose: Myxopapillary ependymoma (MPE) is the most frequent tumor affecting the medullary conus. The surgical therapeutic management is still debated and only few studies have focused on the postoperative clinical outcome of patients. This study aimed to demonstrate long-term postoperative outcome and to assess the predictive factors of recurrence as well as the clinical evolution of these patients., Methods: From 1984 to 2019, in four French centers, 101 adult patients diagnosed with MPE were retrospectively included., Results: Median age at surgery was 39 years. Median tumor size was 50 mm and lesions were multifocal in 13% of patients. All patients benefited from surgery and one patient received postoperative radiotherapy. Gross total resection was obtained in 75% of cases. Sixteen percent of patients presented recurrence after a median follow-up of 70 months. Progression free survival at 5 and 10 years were respectively estimated at 83% and 79%. After multivariable analysis, sacral localization, and subtotal resection were shown to be independently associated with tumor recurrence. 85% of the patients had a favorable evolution concerning pain. 12% of the patients presented a postoperative deterioration of sphincter function and 4% of motor function., Conclusion: Surgery alone is an acceptable option for MPE patients. Patients with sacral location or incomplete resection are at high risk of recurrence and should be carefully monitored.

Background: Diffuse hemispheric gliomas, H3 G34-mutant (DHG H3G34-mutant) constitute a distinct type of aggressive brain tumors. Although initially described in children, they can also affect adults. The aims of this study were to describe the characteristics of DHG H3G34-mutant in adults and to compare them to those of established types of adult WHO grade IV gliomas., Methods: The characteristics of 17 adult DHG H3G34-mutant, 32 H3.3 K27M-mutant diffuse midline gliomas (DMG), 100 IDH-wildtype, and 36 IDH-mutant glioblastomas were retrospectively analyzed., Results: Median age at diagnosis in adult DHG H3G34-mutant was 25 years (range: 19-33). All tumors were hemispheric. For 9 patients (56%), absent or faint contrast enhancement initially suggested another diagnosis than a high-grade glioma, and diffusion-weighted imaging seemed retrospectively more helpful to suspect an aggressive tumor than MR-spectroscopy and perfusion MRI. All cases were IDH-wildtype. Most cases were immunonegative for ATRX (93%) and Olig2 (100%) and exhibited MGMT promoter methylation (82%). The clinical and radiological presentations of adult DHG H3G34-mutant were different from those of established types of adult grade IV gliomas. Median overall survival of adult DHG H3G34-mutant was 12.4 months compared to 19.6 months ( P = .56), 11.7 months ( P = .45), and 50.5 months ( P = .006) in H3.3 K27M-mutant DMG, IDH-wildtype, and IDH-mutant glioblastomas, respectively., Conclusions: Adult DHG H3G34-mutant are associated with distinct characteristics compared to those of established types of adult WHO grade IV gliomas. This study supports considering these tumors as a new type of WHO grade IV glioma in future classifications., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

The transcriptomic classification of glioblastoma (GBM) has failed to predict survival and therapeutic vulnerabilities. A computational approach for unbiased identification of core biological traits of single cells and bulk tumors uncovered four tumor cell states and GBM subtypes distributed along neurodevelopmental and metabolic axes, classified as proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic. Each subtype was enriched with biologically coherent multiomic features. Mitochondrial GBM was associated with the most favorable clinical outcome. It relied exclusively on oxidative phosphorylation for energy production, whereas the glycolytic/plurimetabolic subtype was sustained by aerobic glycolysis and amino acid and lipid metabolism. Deletion of the glucose-proton symporter SLC45A1 was the truncal alteration most significantly associated with mitochondrial GBM, and the reintroduction of SLC45A1 in mitochondrial glioma cells induced acidification and loss of fitness. Mitochondrial, but not glycolytic/plurimetabolic, GBM exhibited marked vulnerability to inhibitors of oxidative phosphorylation. The pathway-based classification of GBM informs survival and enables precision targeting of cancer metabolism., Competing Interests: Competing interests A.L. and A.I. are inventors of a biomarker technology that has been licensed to QIAGEN. A.I. received sponsored research funding from AstraZeneca and Taiho Pharmaceutical and has served as a paid consultant/advisor to AIMEDBIO Inc. A.L. received sponsored research funding from Celgene. All other authors declare no competing interests.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The neuropathology of epilepsy aims at diagnosing the cerebral lesions underlying epilepsy that are obtained from epilepsy surgery, or rarely from biopsy or autopsy. The main histopathological and immunohistochemical characteristics of several entities are described: epilepsy-associated hippocampal sclerosis, long-term epilepsy-associated tumours, cortical malformations, vascular malformations, glial scars, encephalitides, and focal neuronal lipofuscinosis. The diagnostic approach, the differential diagnosis and the histochemical and immunohistochemical tools are detailed in order to provide the pathologist with a summarized toolkit to handle the broad range of epileptogenic lesions., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

For most adolescent and young adult (AYA) cancers, age-specific molecular features are poorly understood. EORTC-SPECTA, an academic translational research infrastructure for biomaterial collection, will explicitly recruit AYA patients and will therefore collect empirical data to bridge the molecular gap between pediatric and adult oncology. The initial pilot study, activated in February 2019 across Europe, will recruit 100 AYA patients (aged 12-29 years) with newly diagnosed or relapsed high-grade gliomas and high-grade bone and soft tissue sarcomas. The primary objective of the pilot is to determine feasibility and recruitment rates. Formalin-fixed tumor tissue and whole blood from study participants will be prospectively collected with clinical data and stored centrally at the Integrated BioBank of Luxembourg. Whole exome sequencing of matched tumor and blood, and tumor RNA sequencing and DNA methylation profiling will be performed at the German Cancer Research Center, Heidelberg, Germany. Virtual central pathology review of scanned diagnostic slides will be undertaken by an international expert panel, and diagnostic material returned to the participating centers. A multidisciplinary molecular tumor board will release a clinically validated report to referring clinicians within 4-6 weeks after biopsy. SPECTA-AYA constitutes a major opportunity to gain knowledge about the tumor biology of this unique age group. It incorporates notable innovative aspects: AYA specificity, pan-European academic collaboration, centralized biobanking, comprehensive molecular profiling and virtual central pathology review, among others. SPECTA-AYA will help untangle the tumor particularities of AYAs with cancer and aims to improve their access to novel drugs and personalized medicine., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

A high tumour mutational burden (hypermutation) is observed in some gliomas 1-5 ; 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.

Objective: The negative biopsy rate approaches 5% in the literature. In our institution, this rate was 2.6% (42/1638) over a ten-year period (2007-2016). We aimed to assess the diagnostic yield of intraoperative smear during stereotactic biopsies to reduce this negative biopsy rate., Patients and Methods: We retrospectively analyzed all consecutive MRI-guided frame-based stereotactic biopsies for which an intraoperative histological smear was carried out, performed over 29 months from January 2017 to May 2019 at the Pitié-Salpêtrière University Hospital (Paris, France)., Results: 145 stereotactic biopsies for which an intraoperative histological smear was carried out were performed in 145 adult patients. Mean age at biopsy was 52.4 ± 12.2 years. Histological diagnoses encountered in this series were: primary or secondary cerebral neoplasm (90.3%), inflammatory diseases (4.8%) and infectious diseases (4.8%). All biopsies were contributory to diagnosis. The negative biopsy rate was therefore significantly lower in the patient group for which an intraoperative histological smear was carried out than in our historical control group (0% versus 2.6%, p = 0.04)., Conclusion: Considering the diagnostic yield benefit contributed by the intraoperative histological smear, we advocate for its routine use during brain stereotactic biopsies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The blood-spinal cord barrier (BSCB) considerably limits the delivery and efficacy of treatments for spinal cord diseases. The blood-brain barrier can be safely opened with low-intensity pulsed ultrasound when microbubbles are simultaneously administered intravenously. This technique was tested on the BSCB in a rabbit model in this work. Twenty-three segments of spinal cord were sonicated with a 1-MHz unfocused pulsed ultrasound device and compared with non-sonicated segments. BSCB disruption was assessed using Evan's blue dye (EBD) extravasation. Tolerance was assessed by histologic analysis. An increased EBD concentration indicating BSCB disruption was clearly observed in sonicated segments compared with controls (p = 0.004). On one animal, which received 10 sonications, repetitive BSCB disruptions revealed no evidence of cumulative toxicity. BSCB can be disrupted using an unfocused pulsed ultrasound device in combination with microbubbles without neurotoxicity even in case of repeated sonications., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Meningiomas account for 30-35% of intracranial tumors. Grade I meningiomas are most common and carry the best prognosis. Grade II and III meningiomas are more aggressive and the outcomes after surgical resection alone remain unsatisfactory. The main objective of this retrospective, single-center study was to assess our results of treatment of grade II-III intracranial meningioma with helical tomotherapy (HT). We retrospectively reviewed patients with histologically proven (WHO 2007) grade II-III meningioma irradiated with HT. Patients were treated one session a day, 5 days a week, to a total dose of 59.4 Gy and 68.4 Gy delivered in 33 and 38 fractions of 1.8 Gy each to the LR PTV and HR PTV, with or without simultaneous integrated boost. From May 2011 to January 2015, 19 patients (15 with grade II and 4 with grade III meningiomas) were treated. Median follow-up for patients with Grade II or Grade III meningiomas, was 29.2 months (range, 10.7-52.4) and 21.3 months (range, 2.4-51.3), respectively. Disease free survival at 1, 2 and 3 years was 89.2%, 83.6% and 56.3% respectively. Overall survival at 1, 2 and 3 years was 94.7%, 94.7% and 78.9%, respectively. No patient had neurological toxicity greater than grade 2 in the acute period. During follow-up, only one patient had neurological toxicity greater than or equal to grade 3. The management of grade II to III meningiomas using HT with doses exceeding 60 Gy is associated with good local control and acceptable survival results., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: BRAF V600 mutations are frequently found in several glioma subtypes, including pleomorphic xanthoastrocytoma (PXA) and ganglioglioma and much less commonly in glioblastoma. We sought to determine the activity of vemurafenib, a selective inhibitor of BRAF V600 , in patients with gliomas that harbor this mutation., Patients and Methods: The VE-BASKET study was an open-label, nonrandomized, multicohort study for BRAF V600 -mutant nonmelanoma cancers. Patients with BRAF V600 -mutant glioma received vemurafenib 960 mg twice per day continuously until disease progression, withdrawal, or intolerable adverse effects. Key end points included confirmed objective response rate by RECIST version 1.1, progression-free survival, overall survival, and safety., Results: Twenty-four patients (median age, 32 years; 18 female and six male patients) with glioma, including malignant diffuse glioma (n = 11; six glioblastoma and five anaplastic astrocytoma), PXA (n = 7), anaplastic ganglioglioma (n = 3), pilocytic astrocytoma (n = 2), and high-grade glioma, not otherwise specified (n = 1), were treated. Confirmed objective response rate was 25% (95% CI, 10% to 47%) and median progression-free survival was 5.5 months (95% CI, 3.7 to 9.6 months). In malignant diffuse glioma, best response included one partial response and five patients with stable disease, two of whom had disease stabilization that lasted more than 1 year. In PXA, best response included one complete response, two partial responses, and three patients with stable disease. Additional partial responses were observed in patients with pilocytic astrocytoma and anaplastic ganglioglioma (one each). The safety profile of vemurafenib was generally consistent with that of previously published studies., Conclusion: Vemurafenib demonstrated evidence of durable antitumor activity in some patients with BRAF V600 -mutant gliomas, although efficacy seemed to vary qualitatively by histologic subtype. Additional study is needed to determine the optimal use of vemurafenib in patients with primary brain tumors and to identify the mechanisms driving differential responses across histologic subsets.

Somatic activating mutations of smoothened (SMO), a component of the embryonic sonic hedgehog (SHH) signaling pathway, are found in 3-5% of grade I meningiomas, most of them corresponding to meningothelial meningiomas located at the anterior skull base. By generating different developmental stage-specific conditional activations in mice, we define a restricted developmental window during which conditional activation of Smo in Prostaglandin D2-synthase-positive mesoderm-derived meningeal layer of the skull base results in meningothelial meningioma formation. We show a selective vulnerability of the arachnoid from the skull base to Smo activation to initiate tumor development. This prenatal period and specific topography are correlated to the timing and location of SHH signaling involvement in the formation of craniofacial and meninges patterning, strongly corroborating the hypothesis of a developmental origin for Smo-activated meningiomas. Finally, we provide preclinical in vitro evidence of the efficacy of the SMO-inhibitor Sonidegib, supporting further preclinical and clinical evaluation of targeted treatment for refractory SMO-mutant meningiomas.

Objective: To characterize the prevalence and prognostic significance of major driver molecular alterations in adult midline diffuse gliomas (MLG)., Methods: Adults with histologically proven MLG diagnosed between 1996 and 2017 were identified from our tumor bank, systematically reviewed, and reclassified according to WHO 2016. Targeted sequencing was performed, including determination of H3F3A , HIST1H3B , TERTp , IDH1/2 , FGFR1 , p16/CDKN2A , and EGFR status., Results: A total of 116 adult patients (M/F 71/45, median age 46.5 years) with MLG (17 cerebellar, 8 spinal, 30 brainstem, 57 thalamic, and 4 diencephalic nonthalamic) were identified. Most patients had high-grade disease at presentation (grade II: 11%, grade III: 15%, grade IV: 75%). Median overall survival was 17.3 months (14.5-23.8 months). Main molecular alterations observed were TERT promoter, H3F3A , and hotspot FGFR1 (N546 and K656) mutations, in 37%, 34%, and 18% of patients, respectively. IDH1 mutations only affected brainstem gliomas (6/24 vs 0/78; p = 7.5 × 10 -5 ), were mostly non-R132H (contrasting with hemispheric gliomas, p = 0.0001), and were associated with longer survival (54 vs 12 months). TERT promoter mutation (9.1 vs 24.2 months), CDKN2A deletion (9.9 vs 23.8 months), and EGFR amplification (4.3 vs 23.8 months) were associated with shorter survival. Of interest, in contrast with pediatric MLG, H3K27M mutations were not associated with worse prognosis (23 vs 15 months)., Conclusions: Patients with adult MLG present with unique clinical and molecular characteristics, differing from their pediatric counterparts. The identification of potentially actionable FGFR1 mutations in a subset of adult MLG highlights the importance of comprehensive genomic analysis in this rare affection., (© 2018 American Academy of Neurology.)

Background: Hippocampal sclerosis is the most common cause of drug-resistant epilepsy amenable for surgical treatment and seizure control. This study aimed to analyze morbidities related to surgery of mesial temporal lobe epilepsy associated with hippocampal sclerosis and to identify possible risk factors for complications., Methods: A retrospective analysis of postoperative complications was made for 389 operations performed between 1990 and 2015 on patients aged 15-67 years (mean 36.8). Three surgical approaches were used: anterior temporal lobectomy (ATL) (n = 209), transcortical selective amygdalohippocampectomy (SAH) (n = 144), and transsylvian SAH (n = 36). Complications were classified as minor or major if there was a neurologic impairment or if further surgical or medical treatment was necessary., Results: Complications followed 15.4% of operations. They were classed as major for 4.1% of patients, but there were no mortalities. Persistent neurologic deficits occurred in 0.5% of patients. In 3 cases (0.8%) additional surgery was necessary to treat an intracranial hematoma, a delayed hydrocephalus, and a subdural empyema. Symptomatic visual field defects (VFDs) were frequent and included contralateral superior quadrantanopia (8.2%) or hemianopia (1.3%). Overall complications (P = 0.04) and symptomatic VFDs (P = 0.04) were most frequent in operations on men. Major complications occurred most often with the ATL surgical approach than with transcortical SAH (P = 0.03)., Conclusions: Major complications occur rarely after mesial temporal surgery on epileptic patients. They occur more often following the ATL rather than transcortical SAH approach. Complications tend to be temporary with symptoms of limited duration for surgery performed by experienced teams on carefully selected and evaluated patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Peripheral neuroblastic tumors are the most commonly occurring extracranial tumors in children. Although a reliable diagnosis is achievable in the majority of cases, diagnosis of a minority of peripheral neuroblastic tumor cases (especially undifferentiated neuroblastoma) poses a challenge compared with that of other pediatric small round blue-cell tumors. A panel of immunohistochemical markers and fusion transcripts is available for the diagnosis of such tumors, but the markers for neuroblastoma lack specificity and sensitivity. As the transcription factor PHOX2B is highly specific for the peripheral autonomic nervous system from which peripheral neuroblastic tumors are derived, we have assessed PHOX2B immunolabeling as a diagnostic tool in pediatric small round blue-cell tumors. We observed PHOX2B expression in all peripheral neuroblastic tumors, paragangliomas, and pheochromocytomas tested but in no other pediatric tumors among the 388 cases studied by expression microarray and the 109 cases studied by immunohistochemical analysis. We then assessed the results of PHOX2B immunohistochemistry in 12 cases of undifferentiated pediatric neoplasms: PHOX2B was expressed in 6/6 undifferentiated neuroblastomas and in no other small round blue-cell tumors. Finally, we showed that PHOX2B immunohistochemical analysis improves the diagnosis of undifferentiated neuroblastoma with high specificity and sensitivity.