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Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

The assessment of gliomas by (18)F-FDOPA PET imaging as an adjunct to MRI showed high performance by combining static and dynamic features to noninvasively predict the isocitrate dehydrogenase (IDH) mutations and the 1p/19q codeletion, which the World Health Organization classified as significant parameters in 2016. The current study evaluated whether other (18)F-FDOPA PET radiomics features further improve performance and the contributions of each of these features to performance. Methods: Our study included 72 retrospectively selected, newly diagnosed glioma patients with (18)F-FDOPA PET dynamic acquisitions. A set of 114 features, including conventional static features and dynamic features, as well as other radiomics features, were extracted and machine-learning models trained to predict IDH mutations and the 1p/19q codeletion. Models were based on a machine-learning algorithm built from stable, relevant, and uncorrelated features selected by hierarchic clustering followed by a bootstrapped feature selection process. Models were assessed by comparing area under the curve using a nested cross-validation approach. Feature importance was assessed using Shapley additive explanations values. Results: The best models were able to predict IDH mutations (logistic regression with L2 regularization) and the 1p/19q codeletion (support vector machine with radial basis function kernel) with an area under the curve of 0.831 (95% CI, 0.790–0.873) and 0.724 (95% CI, 0.669–0.782), respectively. For the prediction of IDH mutations, dynamic features were the most important features in the model (time to peak, 35.5%). In contrast, other radiomics features were the most useful for predicting the 1p/19q codeletion (up to 14.5% of importance for the small-zone low-gray-level emphasis). Conclusion: (18)F-FDOPA PET is an effective tool for the noninvasive prediction of glioma molecular parameters using a full set of amino-acid PET radiomics features. The contribution of each feature set shows the importance of systematically integrating dynamic acquisition for prediction of the IDH mutations as well as developing the use of radiomics features in routine practice for prediction of the 1p/19q codeletion.

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 (

Cough is a major lower airway defense mechanism that can be triggered by exercise in asthma patients. Studies on cough reflex in experimental animal models revealed a decrease of cough reflex sensitivity during exercise in healthy animals, but a lack of desensitization in ovalbumin-sensitized rabbits. The aim of our study is to evaluate the impact of inhaled corticosteroids on cough reflex during artificial limb exercise in an animal model of eosinophilic airway inflammation.Sixteen adult ovalbumin-sensitized rabbits were randomly divided into two groups. The "OVA-Corticoid" group (All rabbits were significantly sensitized but there was no difference in eosinophilic inflammation on bronchoalveolar lavage or tissue sections between the two groups. Artificial limb exercise resulted in a significant (Inhaled corticosteroids are able to restore desensitization of the cough reflex during artificial limb exercise in an animal model of airway eosinophilic inflammation. Airway inflammation thus appears to be involved in the physiopathology of exercise-induced cough in this ovalbumin sensitized rabbit model. Inhaled anti-inflammatory treatments could have potential benefit for the management of exercise-induced cough in asthma patients.

International audience; Introduction : L’application PELICAN (« Partager efficacement en laboratoire les informations des comptes rendus anatomopathologiques ») est un outil permettant de générer des comptes rendus standardisés et de renseigner automatiquement une base de données, utilisée au CHRU de Nancy depuis 2014 en neuropathologie tumorale. L’objectif de cet article était d’illustrer l’utilisation de cette application pour les méningiomes, avec une première exploitation statistique.Matériels et méthodes : L’étude inclut les cas de méningiomes enregistrés dans l’application PELICAN jusqu’en juillet 2018. L’application PELICAN est un fichier Microsoft Excel comportant un logiciel écrit en Visual Basic pour Applications, utilisé par le pathologiste pour élaborer le compte rendu. Les principales données cliniques ont été recueillies à partir de la fiche de recensement du Registre de l’Hérault. Le suivi était renseigné de façon systématique pour les méningiomes atypiques.Résultats : Deux cent quatre-vingt-quinze méningiomes ont été analysés dont 250 méningiomes de grade I, 42 méningiomes de grade II et 3 méningiomes de grade III. Dans les méningiomes de grade II, on constatait une proportion significativement plus élevée d’hommes (p = 0,002) et d’infiltration de la dure-mère (p < 0,001), une augmentation significative de l’indice Ki-67 (p < 0,0001) et une diminution significative de l’expression des récepteurs à la progestérone (p < 0,001). Dans les méningiomes atypiques, un indice Ki-67 de plus de 20 % était corrélé significativement à une survie sans progression plus courte (p = 0,032).Conclusion : L’application PELICAN est un outil d’utilisation simple, permettant de générer des comptes rendus standardisés tout en alimentant une base de données, ouvrant de très intéressantes perspectives d’un point de vue épidémiologique et scientifique.

International audience; Meningiomas are the most common primary tumors of the central nervous system. Based on the 2021 WHO classification, they are classified into three grades reflecting recurrence risk and aggressiveness. However, the WHO’s histopathological criteria defining these grades are somewhat subjective. Together with reliable immunohistochemical proliferation indices, other molecular markers such as those studied with genome-wide epigenetics promise to revamp the current prognostic classification. In this study, 48 meningiomas of various grades were randomly included and explored for DNA methylation with the Infinium MethylationEPIC microarray over 850k CpG sites. We conducted differential and correlative analyses on grade and several proliferation indices and markers, such as mitotic index and Ki-67 or MCM6 immunohistochemistry. We also set up Cox proportional hazard models for extensive associations between CpG methylation and survival. We identified loci highly correlated with cell growth and a targeted methylation signature of regulatory regions persistently associated with proliferation, grade, and survival. Candidate genes under the control of these regions include SMC4, ESRRG, PAX6, DOK7, VAV2, OTX1, and PCDHA-PCDHB-PCDHG, i.e., the protocadherin gene clusters. This study highlights the crucial role played by epigenetic mechanisms in shaping dysregulated cellular proliferation and provides potential biomarkers bearing prognostic and therapeutic value for the clinical management of meningioma.

Background Nasal intestinal-type adenocarcinomas (ITAC) are strongly related to chronic wood dust exposure: The intestinal phenotype relies on CDX2 overexpression but underlying molecular mechanisms remain unknown. Our objectives were to investigate transcriptomic and methylation differences between healthy non-exposed and tumor olfactory cleft mucosae and to compare transcriptomic profiles between non-exposed, wood dust-exposed and ITAC mucosa cells. Methods We conducted a prospective monocentric study (NCT0281823) including 16 woodworkers with ITAC, 16 healthy exposed woodworkers and 13 healthy, non-exposed, controls. We compared tumor samples with healthy non-exposed samples, both in transcriptome and in methylome analyses. We also investigated wood dust-induced transcriptome modifications of exposed (without tumor) male woodworkers’ samples and of contralateral sides of woodworkers with tumors. We conducted in parallel transcriptome and methylome analysis, and then, the transcriptome analysis was focused on the genes highlighted in methylome analysis. We replicated our results on dataset GSE17433. Results Several clusters of genes enabled the distinction between healthy and ITAC samples. Transcriptomic and IHC analysis confirmed a constant overexpression of CDX2 in ITAC samples, without any specific DNA methylation profile regarding the CDX2 locus. ITAC woodworkers also exhibited a specific transcriptomic profile in their contralateral (non-tumor) olfactory cleft, different from that of other exposed woodworkers, suggesting that they had a different exposure or a different susceptibility. Two top-loci (CACNA1C/CACNA1C-AS1 and SLC26A10) were identified with a hemimethylated profile, but only CACNA1C appeared to be overexpressed both in transcriptomic analysis and in immunohistochemistry. Conclusions Several clusters of genes enable the distinction between healthy mucosa and ITAC samples even in contralateral nasal fossa thus paving the way for a simple diagnostic tool for ITAC in male woodworkers. CACNA1C might be considered as a master gene of ITAC and should be further investigated. Trial registration: NIH ClinicalTrials, NCT0281823, registered May 23d 2016, https://www.clinicaltrials.gov/NCT0281823.

Background Atypical meningioma is a variant of meningioma with a high risk of recurrence. Gross total resection is the standard of treatment, while no consensus on optimal adjuvant management has been found. Methods Between 2008 and 2018, a retrospective search identified 216 grade II meningiomas treated in six centers. Clinical, histological, and therapeutic data were analyzed to determine the prognostic factors of recurrence and survival. Results In total, 216 patients underwent surgical resection. Among these, 122 patients (56%) underwent gross total resection, and 21% of the patients received adjuvant radiotherapy. Univariate analysis reported subtotal resection, high Ki-67, negative progesterone receptor (PR) and histological grade evolution as unfavorable prognosis factors. According to multivariate analysis, the Ki-67 proliferative index (cut-off value of 17.5%) was the only prognostic factor of recurrence (HR 1.1; 95% CI, 1.0-1.2, P=0.048). Gross total resection improved progression-free survival (PFS) (P=0.03) but without impact on overall survival (OS) (P=0.2). Median PFS and OS times were longer for patients receiving adjuvant radiotherapy than those who did not receive adjuvant radiotherapy. PFS (P=0.3) and OS (P=0.7) were associated with adjuvant RT by trend only. After a median follow-up time of 6.7 years, 99 (46%) patients relapsed. Median progression-free and OS rates were 4.5 (95% CI, 3.5-5.5) and 14.7 years (11.4-NA), respectively. Conclusions In this study, Ki-67 proliferative index was significantly associated with recurrence. Gross total resection significantly improved PFS without impacting OS. Adjuvant radiotherapy delayed recurrence and improved OS, but a longer follow-up time is needed to distinguish a statistically significant difference. Large prospective studies are needed to determine postoperative treatment guidelines.

Current histoprognostic parameters and prognostic scores used in paragangliomas and pheochromocytomas do not adequately predict the risk of metastastic progression and survival. Here, using a series of 147 cases of paraganglioma and pheochromocytoma, we designed and evaluated the potential of a new score, the COPPS (COmposite Pheochromocytoma/paraganglioma Prognostic Score), by taking into consideration three clinico-pathological features (including tumor size, necrosis, and vascular invasion), and the losses of PS100 and SDHB immunostain to predict the risk of metastasis. We compared also the performance of the COPPS with several presently used histoprognostic parameters in risk assessment of these tumors. A PASS score (Pheochromocytoma of the Adrenal gland Scaled Score) ≥ 6 was significantly associated with the occurrence of metastases (P

International audience; The physiological mechanism induced by the isocitrate dehydrogenase 1 (IDH1) mutation, associated with better treatment response in gliomas, remains unknown. The aim of this preclinical study was to characterize the IDH1 mutation through in vivo multiparametric MRI and MRS. Multiparametric MRI, including the measurement of blood flow, vascularity, oxygenation, permeability, and in vivo MRS, was performed on a 4.7 T animal MRI system in rat brains grafted with human‐derived glioblastoma U87 cell lines expressing or not the IDH1 mutation by the CRISPR/Cas9 method, and secondarily characterized with additional ex vivo HR‐MAS and histological analyses. In univariate analyses, compared with IDH1−, IDH1+ tumors exhibited higher vascular density (p

International audience; Anaplastic oligodendroglioma (AO), IDH‐mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high‐grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki‐67, in a large series of IDHmut+/1p19qcodel AO included in the POLA (“Prise en charge des Oligodendrogliomes Anaplasiques”) French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labelling indices (LI) of MCM6 and Ki‐67 were obtained via computer‐assisted color image analyses on immunostained AO tissues of the cohort (n=220). Furthermore, a subgroup of AO (n=68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki‐67 (≥ 15%) correlated with shorter overall survival, both in univariate (P=0.013 and P=0.004, respectively) and multivariate analyses (P=0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki‐67). MCM6 and Ki‐67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro‐neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta‐amyloid binding, and postsynaptic specialization.In conclusion, the overexpression of MCM6 and/or Ki‐67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy‐to‐use and cost‐effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down‐regulated immune response and lower microglial cells activation, and bears pro‐neural phenotype.

Microvascular proliferation (MVP) is a hallmark of glioblastoma. Endothelial cell hypertrophy (ECH), also known as endothelial hyperplasia, is correlated with a shorter survival of patients with gliomas. However, the prognostic value of these 2 morphological features has not been studied in meningiomas. The aim of this study was to evaluate the prognostic value of angiogenesis in meningiomas, most notably ECH, MVP, and microvascular density, which were evaluated using immunohistochemistry with antibodies against CD34 and CD105 (a marker of neovascularization) in a series of 139 meningiomas. ECH, MVP, and CD105 immunoreactivity were significantly correlated with higher histological grades (p

PELICAN ("Partager Efficacement en Laboratoire les Informations des Comptes rendus ANatomopathologiques") is a software, which generates standardized reports, and allows to automatically create a database. It has been used in central nervous system tumor pathology at the University Hospital of Nancy since 2014. The purpose of this article was to illustrate the use of this application for meningiomas, with a first statistical evaluation.The export of data included all cases of meningiomas recorded in the PELICAN application until July 2018. The PELICAN application is a Microsoft Excel file containing a software, written in Visual Basic for Applications, and used by the pathologist to create the report. The main clinical data were collected from the Hérault Register census form. Follow-up was systematically reported for atypical meningiomas.Two hundred and ninety-five meningiomas were analyzed, including 250 grade I meningiomas, 42 grade II meningiomas, and 3 grade III meningiomas. Grade II meningiomas were characterized by a significantly higher proportion of men (P=0.002) and dural infiltration (P0.001), a significant increase in the Ki-67 index (P0.0001), and a significant decrease in progesterone receptor expression (P0.001). In atypical meningiomas, a Ki-67 index of more than 20 % was significantly correlated with a shorter progression-free survival (P=0.032).The PELICAN software is an easy-to-use tool that allows to generate standardized reports and feed a database, opening very interesting perspectives from an epidemiological and scientific point of view.