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Abstract The diagnosis of anaplastic meningioma (AM) (WHO grade III) is based on the presence of a high mitotic index (MI) and/or overt anaplasia. Only few data exist about the reproducibility and prognostic value of overt anaplasia. Additionally, the prognostic value of H3K27me3 loss in AM has not yet been demonstrated. Our objectives were to evaluate the reproducibility and prognostic value of WHO criteria and H3K27me3 loss in a multicenter series of 66 AM. Interobserver reproducibility was good for the determination of WHO grade (Kappa = 0.671) and MI (intraclass correlation coefficient [ICC] = 0.649), and fair for assessment of overt anaplasia (Kappa = 0.366). Patients with meningiomas showing high MI had significantly shorter overall survival (OS) than patients with meningiomas showing overt anaplasia without high MI (p = 0.009). OS was significantly lower in case of overt anaplasia with low MI (<20/1.6 mm2) than in atypical meningiomas (p = 0.008). H3K27me3 loss was present in 10/47 (21%) of AM and independently associated with shorter OS (p = 0.036; Cox multivariate analysis), with a good reproducibility (Kappa = 0.643). In conclusion, the presence of overt anaplasia could give additional prognostic information in tumors lacking high MI. Finally, loss of H3K27me3 is an easy-to-use and reproducible marker of poorer prognosis.

Meningioma is the most common primary intracranial extra-axial tumor. Total surgical removal is the standard therapeutic method to treat this type of brain tumors. However, the risk of recurrence depends on the tumor grade and the extent of the resection including the infiltrated dura mater and, if necessary, the infiltrated bone. Therefore, proper resection of all invasive tumor borders without touching eloquent areas is of primordial in order to decrease the risk of recurrence. Nowadays, none of the intraoperative used tools is able to provide a precise real-time histopathological information on the tumor surrounding areas to help the surgeon to achieve a gross total removal. To respond to this problem, our team is developing a multimodal two-photon fluorescence endomicroscope, compatible with the surgeon tool, to better delimitate tumor boundaries, relying on the endogenous fluorescence of brain tissues. In this context, we are building a tissue database in order to specify each brain tissue, whether healthy or tumoral, with its specific optical signature. In this study, we present a multimodal and multiscale optical measurements on non-tumoral control brain tissue obtained in epilepsy surgery patients and several meningioma grades. We investigated tissue auto-fluorescence to track the molecular changes associated with the tumor grade from deep ultra-violet (DUV) to near infrared (NIR) excitation. Micro-spectroscopy, fluorescence lifetime imaging, two-photon fluorescence imaging and Second Harmonic Generation (SHG) imaging were performed. Several optically derived parameters such as collagen crosslinks fluorescence in DUV, SHG emission in NIR and long lifetime intensity fraction of Nicotinamide Adenine Dinucleotide and Flavins were correlated to discriminate cancerous tissue from control one. While collagen response managed to discriminate meningioma grades from control samples with a 100% sensitivity and 90% specificity through a 3D discriminative algorithm.

BackgroundDiagnosing probable cerebral amyloid angiopathy (CAA) after lobar intra-cerebral hemorrhage (l-ICH) currently relies on the MR-based modified Boston criteria (mBC). However, MRI has limited availability and the mBC have moderate sensitivity, with isolated l-ICH being classified as “possible CAA”. A recent autopsy-based study reported potential value of finger-like projections (FLP) and subarachnoid hemorrhage (SAH) on acute CT. Here we assessed these markers’ performance in a cohort most of whom survived the index episode.MethodsWe included all patients from a prospective pathology database with non-traumatic l-ICH, admission CT and available tissue sample showing no alternative cause. CT was assessed by two blinded independent neuroradiologists. Interobserver reproducibility was almost perfect for SAH and substantial for FLP.ResultsSixteen patients were eligible [age 65.8 ± 7.2 yrs; hematoma volume: 39(26, 71)mls; hematoma evacuation sample 15 patients; autopsy one patient]. MRI was available in 11 patients. ICH-related death affected six patients. Aβ40–42 immunohistochemistry revealed CAA in seven patients (44%). SAH and FLP were present in 12/16 (75%) and 10/16 (62%) patients, respectively. SAH had 100% sensitivity for CAA but low specificity; FLP had lower performance. Using either pathology or MRI as reference standard yielded essentially similar results. All patients with possible CAA on MRI but CAA on pathology had SAH.ConclusionsIn patients with moderate-size l-ICH who mostly survived the index event, SAH had perfect sensitivity and better performance than FLP. In addition, SAH appeared to add onto MRI in possible CAA, the clinically most relevant scenario. Studies in larger samples are however warranted.

Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.

Among all the tumors of the central nervous system (CNS), glioma are the most deadly and the most malignant. Surgical resection is the standard therapeutic method to treat this type of brain cancer. But the diffusive character of these tumors create many problems for surgeons during the operation. In fact, these tumors migrate outside the tumor solid zone and invade the surrounding healthy tissues. These infiltrative tissues have the same visual appearance as healthy tissues, making it very difficult for surgeons to distinguish the healthy ones from the diffused ones. The surgeon, therefore, cannot properly remove the tumor margins increasing the recurrence risk of the tumor. To resolve this problem, our team has developed a multimodal two-photon fibered endomicroscope, compatible with the surgeon trocar, to better delimitate tumor boundaries by relying on the endogenous fluorescence of brain tissues. In this context, and in order to characterize the optical signature of glioma tumors, this study offers multimodal and multi-scaled optical measurements from healthy tissues to high grade glioma. We can interrogate tissue from deep ultra-violet to near infrared excitation by working with spectroscopy, fluorescence lifetime imaging, two-photon fluorescene imaging and Second Harmonic Generation (SHG) imaging. Optically derived ratios such as the Tryptophan/Collagen ratio, the optical redox ratio and the long lifetime intensity fraction, discriminated diseased tissue from its normal counterparts when fitted by Gaussian ellipsoids and choosing a threshold for each. Additionally two-photon fluorescence and SHG images were shown to display similar histological features as Hematoxylin-Eosin stained images.

Recent epigenomic analyses have revealed the existence of a new DNA methylation class (MC) of infant‐type hemispheric glioma (IHG). Like desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA), these tumors mainly affect infants and are supratentorial. While DIG/DIA is characterized by BRAF or RAF1 alterations, IHG has been shown to have receptor tyrosine kinase (RTK) gene fusions (ALK, ROS1, NTRK1/2/3, and MET). However, in this rapidly evolving field, a more comprehensive analysis of infantile glial/glioneuronal tumors including clinical, radiological, histopathological, and molecular data is needed. Here, we retrospectively investigated data from 30 infantile glial/glioneuronal tumors, consecutively compiled from our center. They were analyzed by two experienced pediatric neuroradiologists in consensus, without former knowledge of the molecular data. We also performed a comprehensive clinical, and histopathological examination (including molecular evaluation by next‐generation sequencing, RNA sequencing, and fluorescence in situ hybridization [FISH] analyses), as well as DNA methylation profiling for the samples having sufficient material available. The integrative histopathological, genetic, and epigenetic analyses, including t‐distributed stochastic neighbor embedding (t‐SNE) analyses segregated tumors into 10 DIG/DIA (33.3%), six IHG (20.0%), three gangliogliomas (10.0%), two pleomorphic xanthoastrocytomas (6.7%), two pilocytic astrocytomas (6.7%), two supratentorial ependymomas, ZFTA fusion‐positive (6.7%), two supratentorial ependymomas, YAP1 fusion‐positive (6.7%), two embryonal tumors with PLAGL2‐family amplification (6.7%), and one diffuse low‐grade glioma, MAPK‐pathway altered. This study highlights the significant differential features, in terms of histopathology (leptomeningeal infiltration, intense desmoplasia and ganglion cells in DIG/DIA and necrosis, microvascular proliferation, and siderophages in IHG), and radiology between DIG/DIA and IHG. Moreover, these results are consistent with the literature data concerning the molecular dichotomy (BRAF/RAF1 alterations vs. RTK genes' fusions) between DIG/DIA and IHG. This study characterized histopathologically and radiologically two additional cases of the novel embryonal tumor characterized by PLAGL2 gene amplification. Differences between desmoplastic infantile gangliogliomas/astrocytomas and infant‐type hemispheric gliomas.

The major limitation to reaching a curative radiation dose in radioresistant tumors such as malignant gliomas is the high sensitivity to radiation and subsequent damage of the surrounding normal tissues. Novel dose delivery methods such as minibeam radiation therapy (MBRT) may help to overcome this limitation. MBRT utilizes a combination of spatial fractionation of the dose and submillimetric (600 μm) field sizes with an array (“comb”) of parallel thin beams (“teeth”). The dose profiles in MBRT consist of peaks and valleys. In contrast, the seamless irradiations of the several squared centimeter field sizes employed in standard radiotherapy result in homogeneous dose distributions (and consequently, flat dose profiles). The innovative dose delivery methods employed in MBRT, unlike standard radiation therapy, have demonstrated remarkable normal tissue sparing. In this pilot work, we investigated the tolerance of the rat brain after whole-brain MBRT irradiation. A dose escalation was used to study the tissue response as a function of dose, so that a threshold could be established: doses as high as 100 Gy in one fraction were still well tolerated by the rat brain. This finding suggests that MBRT may be used to deliver higher and potentially curative radiation doses in clinical practice.

Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies.

Objectives The diffuse intrinsic pontine gliomas (DIPGs) are now defined by the type of histone H3 mutated at lysine 27. We aimed to correlate the multimodal MRI features of DIPGs, H3K27M mutant, with their histological and molecular characteristics. Methods Twenty-seven treatment-naïve children with histopathologically confirmed DIPG H3K27M mutant were prospectively included. MRI performed prior to biopsy included multi-b-value diffusion-weighted imaging, ASL, and dynamic susceptibility contrast (DSC) perfusion imaging. The ADC and cerebral blood flow (CBF) and blood volume (CBV) were measured at the biopsy site. We assessed quantitative histological data, including microvascular density, nuclear density, and H3K27M-positive nuclear density. Gene expression profiling was also assessed in the samples. We compared imaging and histopathological data according to histone subgroup. We correlated MRI quantitative data with histological data and gene expression. Results H3.1K27M mutated tumors showed higher ADC values (median 3151 μm 2 /s vs 1741 μm 2 /s, p = 0.003), and lower perfusion values (DSC-rCBF median 0.71 vs 1.43, p = 0.002, and DSC-rCBV median 1.00 vs 1.71, p = 0.02) than H3.3K27M ones. They had similar microvascular and nuclear density, but lower H3K27M-positive nuclear density ( p = 0.007). The DSC-rCBV was positively correlated to the H3K27M-positive nuclear density (rho = 0.74, p = 0.02). ADC values were not correlated with nuclear density nor perfusion values with microvascular density. The expression of gated channel activity–related genes tended to be inversely correlated with ADC values and positively correlated with DSC perfusion. Conclusions H3.1K27M mutated tumors have higher ADC and lower perfusion values than H3.3K27M ones, without direct correlation with microvascular or nuclear density. This may be due to tissular edema possibly related to gated channel activity–related gene expression. Key Points • H3.1K27M mutant DIPG had higher apparent diffusion coefficient (p = 0.003), lower α (p = 0.048), and lower relative cerebral blood volume (p = 0.02) than H3.3K27M mutant DIPG at their biopsy sites. • Biopsy samples obtained within the tumor’s enhancing portion showed higher microvascular density (p = 0.03) than samples obtained outside the tumor’s enhancing portion, but similar H3K27M-positive nuclear density (p = 0.84). • Relative cerebral blood volume measured at the biopsy site was significantly correlated with H3K27M-positive nuclear density (rho = 0.74, p = 0.02).