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LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1– and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer.Significance:EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer.This article is highlighted in the In This Issue feature, p. 517

Despite their rarity, PIK3CA mutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3ca mutations in post-natal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, wether alone or in association with Pik3ca and Nf2 mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3ca mutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca mutant background. Taken together, these results tend to suggest a prominent role of Pik3ca mutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter still to be discovered.

Phenotype alterations in the liver and brain of Lztr1-deleted mice

LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1– and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer.Significance:EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer.This article is highlighted in the In This Issue feature, p. 517

Table S1. List of ubiquitylated peptides from DiGly proteomics assay. Table S2. List of proteins differentially abundant in LZTR1-/- compared toLZTR1+/+ cells quantified by TMT.Table S3. List of top scoring LZTR1 interacting proteins from immunoprecipitation/mass spectrometry.

PFS6 and PFS12 depending of the in intention-to-treat or per protocole analyses as investigator or central review analyses.

Study of correlation between SSTR2A receptor expression and growth rate (GR) before and under treatment as with progression. No significant correlation was observed. Immunohistochemical detection of SSTR2A protein was performed on 5 µm thick formalin fixed paraffin embedded (FFPE) tissue sections with Ventana Benchmark XT. The monoclonal SSTR2A antibody (clone UMB1, Abcam) was used at 1/4000 dilution.

Purpose:Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas.Patients and Methods:Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety.Results:A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003).Conclusions:The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.

Capturing and utilising carbon dioxide (CO2) is a major challenge for developing a low- carbon economy. In addition, the reduction of CO2 allows the synthesis of platform molecules for the chemical and energy industry. Anaerobic mixed cultures contain homoacetogenic microorganisms (HAC) capable of reducing CO2 to acetate. However, one of the obstacles to their use is the understanding and control of their functional diversity. In particular, managing the competition between HAC and hydrogenotrophic methanogens (HM) that convert CO2 into methane is crucial to selectively produce acetate.This study contributes to bring new knowledge on the competition between HAC and HM. In this sense, mass transfer between the gas phase where the substrates are located, and the liquid phase which contains the microbial catalysts, as well as kinetic and thermodynamic aspects of biological reactions have been integrated in this work. The microbial competition between HM and HAC was studied in successive batches. The effect of temperature between 25 °C and 35 °C was investigated, as well as the time of each batch, leading to different states of mass transfer limitation in the system. A clear effect of temperature between 25 °C and 35 °C on the outcome of the competition between HM and HAC was highlighted, as well as the effect of mass transfer limitation. This study contributes to identify specific process parameters influencing the selection of HAC over HM and should help in the design of experiments depending on the target product from H2/CO2.In successive batches, lifting of mass transfer limitation, as well as lowering of the temperature to 25 °C made it possible to select HAC in mixed anaerobic cultures for acetate production by eliminating the methanogens, after four successive batches of 4 to 6 days each.

International audience; Background: Intracranial solitary fibrous tumour (iSFT) is an exceptional mesenchymal tumour with high recurrence rates. We aimed to analyse the clinical outcomes of newly diagnosed and recurrent iSFTs.Methods: We carried out a French retrospective multicentre (n = 16) study of histologically proven iSFT cases. Univariate and multivariate Cox models were used to estimate the prognosis value of the age, location, size, WHO grade, and surgical extent on overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS).Results: Eighty-eight patients were included with a median age of 54.5 years. New iSFT cases were treated with gross tumour resection (GTR) (n = 75) or subtotal resection (STR) (n = 9) and postoperative radiotherapy (PORT) (n = 32, 57%). The median follow-up time was 7 years. The median OS, PFS, and LRFS were 13 years, 7 years, and 7 years, respectively. Forty-two patients experienced recurrence. Extracranial metastasis occurred in 16 patients. Median OS and PFS after the first recurrence were 6 years and 15.4 months, respectively. A higher histological grade was a prognosis factor for PFS (p = 0.04) and LRFS (p = 0.03). GTR influenced LRFS (p = 0.03).Conclusion: GTR provided benefits as a first treatment for iSFTs. However, approximately 40% of patients experienced relapse, which remains a challenging state.

BackgroundMalignant meningiomas are fatal and lack effective therapy. As M2 macrophages are the most prevalent immune cell type in human meningiomas, we hypothesized that normalizing this immunosuppressive population would be an effective treatment strategy.MethodsWe used CIBERSORTx to examine the proportions of 22 immune subsets in human meningiomas. We targeted the colony-stimulating factor 1 (CSF1) or CSF1 receptor (CSF1R) axis, an important regulator of macrophage phenotype, using monoclonal antibodies (mAbs) in a novel immunocompetent murine model (MGS1) for malignant meningioma. RNA sequencing (RNA-seq) was performed to identify changes in gene expression in the tumor microenvironment (TME). Mass cytometry was used to delineate changes in immune subsets after treatment. We measured patients’ plasma CSF1 levels using ELISA and CSF1R expression using multiplex quantitative immunofluorescence in a human meningioma tissue microarray.ResultsHuman meningiomas are heavily enriched for immunosuppressive myeloid cells. MGS1 recapitulates the TME of human meningiomas, including an abundance of myeloid cells, a paucity of infiltrating T cells, and low programmed death ligand 1 (PD-L1) expression. Treatment of murine meningiomas with anti-CSF1/CSF1R, but not programmed cell death receptor 1 (PD-1), mAbs abrogate tumor growth. RNA-seq and mass cytometry analyses reveal a myeloid cell reprogramming with limited effect on T cells in the TME. CSF1 plasma levels are significantly elevated in human patients, and CSF1R is highly expressed on CD163+ macrophages within the human TME.ConclusionOur findings suggest that anti-CSF1/CSF1R antibody treatment may be an effective normalization cancer immunotherapy for malignant meningiomas.

Infections are a frequent cause of cerebral vasculitis, important to diagnose because a specific treatment may be required. Infection-associated vasculitis can be caused by angiotropic pathogens (varicella zoster virus, syphilis, aspergillus). They can be associated with subarachnoidal meningitis (tuberculosis, pyogenic meningitis, cysticercosis). They can appear contiguously to sinuses or orbital infection (aspergillosis, mucormycosis). Finally, they also may be due to an immune mechanism in the context of chronic infections (hepatitis B virus, hepatitis C virus, human immunodeficiency virus). Cerebral vasculitis are severe conditions and their prognosis is directly linked to early recognition and diagnosis. Infectious causes must therefore be systematically considered ahead of cerebral vasculitis, and the appropriate investigations must be determined according to the patient's clinical context. We propose here an update on the infectious causes of cerebral vasculitis, their diagnosis modalities, and therapeutic options.

International audience; PURPOSE: Meningiomas represent the most frequent tumor of the central nervous system in adults. While most meningiomas are efficiently treated by surgery and radiotherapy/radiosurgery, there is a small portion of radiation- and surgery-refractory tumors for which there is no clear recommendation for optimal management. The French National Tumor Board Meeting on Meningiomas (NTBM) offers a glimpse on the current management of such patients. METHODS: We retrospectively reviewed the charts of patients presented to the multidisciplinary Meeting between 2016 and 2019. We selected patients with a progressive disease after at least two treatments, including surgery and radiotherapy. RESULTS: In this multicentric cohort of 86 cases, patients harbored 17 (19.8%) WHO Grade I, 48 (55.8%) WHO Grade II and 21 (24.4%) WHO Grade III tumors. The median number of treatments received before inclusion was 3 (range: 2 - 11). Following the Board Meeting, 32 patients (37.2%) received chemotherapy, 11 (12.8%) surgery, 17 (19.8%) radiotherapy, 14 (16.3%) watchful observation and 12 (13.9%) palliative care. After a mean follow-up of 13 months post-inclusion, 32 patients (37.2%) had died from their disease. The mean progression free survival was 27 months after radiotherapy, 10 months after surgery, 8.5 months after chemotherapy (Bevacizumab: 9 months - Octreotide/Everolimus: 8 months). CONCLUSIONS: Surgery- and radiation-refractory meningiomas represent a heterogeneous group of tumors with a majority of WHO Grade II cases. If re-irradiation and redo-surgery are not possible, bevacizumab and octreotide-everolimus appear as a valuable option in heavily pre-treated patients considering the current EANO guidelines.

Hormone-associated meningiomas tend to stop growing or decrease in size after cessation of certain progestins, mainly cyproterone acetate. We report three observations on the natural history of hormone-associated intraosseous meningiomas, showing in a first patient that those tumors may grow rapidly under nomegestrol. We then demonstrate the sustained growth of intraosseous hormone-associated meningiomas after cessation of promesgestone and nomegestrol, independently of the intracranial portion, which concurrently decreased in size in the second case or was resected at the time of nomegestrol withdrawal in the third case, thus giving new insights into the tumorigenesis mechanisms of hormone-associated intraosseous meningiomas.

International audience; This study aimed at understanding how growth conditions influence the biofilm structural properties and the competition between microbial aggregates (biofilms, streamers, suspended biomass). The biological aggregates were developed during more than one month under contrasted conditions in terms of shear stress, hydraulic retention time (HRT), apparent surface organic loading rate (SOLR) and COD/N ratio (fourteen conditions). At high HRT (absence of streamers) an increase of shear stress led to a decrease of the average biofilm thickness whereas it increased with the apparent SOLR. In addition, biofilm density increased with shear stress and with the apparent SOLR at high shear stress. The presence of streamers was observed only at low HRT (< 3h). This presence has been attributed to the residual concentration in the bulk and to the hydrodynamic conditions of growth. Turbulent conditions and low substrate concentration considerably favor the development of streamers which benefit from a higher external mass transfer compared to biofilms due to their flapping movement. In some 2 conditions, the mass of streamers in the reactor were close to the biofilm one's, highlighting the necessity to consider such morphotypes in further studies since they can have a significant impact on the global microbial activity.

International audience; The biodeterioration of cement-based materials in sewer environments occurs because of the production of sulfuric acid from the biochemical oxidation of H2S by sulfur-oxidizing bacteria (SOB). In the perspective of determining the possible reaction pathways for the sulfur cycle in such conditions, hydrated ce-mentitious binders were exposed to an accelerated laboratory test (BAC test) to reproduce a biochemical attack similar to the one occurring in the sewer networks. Tetrathionate was used as a reduced sulfur source to naturally develop sulfur-oxidizing activities on the surfaces of materials.The transformation of tetrathionate was investigated on materials made from different binders: Portland cement, calcium aluminate cement, calcium sulfoaluminate cement and alkali-activated slag. The pH and the concentration of the different sulfur species were monitored in the leached solutions during 3 months of exposure. The results showed that the formation of different polythionates was independent of the nature of the material. The main parameter controlling the phenomena was the evolution of the pH of the leached solutions. Moreover, tetrathionate disproportionation was detected with the formation of more reduced forms of sulfur compounds (pentathionate, hexathionate and elemental sulfur) along with thiosulfate and sulfate. The experimental findings allowed numerical models to be developed to estimate the amount of sulfur compounds as a function of the pH evolution. In addition, biomass samples were collected from the exposed surface and from the deteriorated layers to identifythe microbial populations. No clear influence of the cementitious materials on the selected populations was detected, confirming the previous results concerning the impact of the materials on the selected reaction pathways for tetrathionate transformation.

Meningiomas are tumors arising from the meninges and represent the most frequent central nervous system tumors in adults. Recent large-scale genetic studies and preclinical meningioma mouse modelling led to a better comprehension of meningioma development and suggested evidences of close relationships between meningeal embryology and tumorigenesis. In this non-systematic review, we summarize the current knowledge on meningeal embryology and developmental biology, and illustrate how meningioma tumorigenesis is deeply related to meningeal embryology, concerning the potential cell of origin, the role of reactivation of embryonic stem cells, the influence of the embryonic tissue of origin, and the parallelism between topography-dependant molecular pathways involved in normal meninges and in meningioma development. Our study emphasizes why future studies on meningeal embryology are mandatory to affine our comprehension of mechanisms underlying meningioma initiation and development.

Study design Single-center retrospective study OBJECTIVE.: We discuss the widespread misdiagnosis of primary extraosseous spinal Ewing's Sarcomas (PESES) to begnin tumors leading to poor treatment SUMMARY OF BACKGROUND DATA.: Primary extraosseous spinal Ewing's Sarcomas (PESES) is a particular entity of Spinal Ewing's sarcoma (SES) appearing in a similar shape and features to benign tumors such as schwannomas. This imaging mimicry and subsequent possible misdiagnosis lead to primary surgery, without neoadjuvant chemotherapy, which remain deleterious for survival and progression. Methods We identified a total of 13 patients: 7 women (53.8%) and 6 men operated between 2001-2018 for PESES and initially misdiagnosed as schwannomas or ependymomas RESULTS.: The mean age of our series was 35.8 years (range, 18.1-47.2y). The first clinical symptom was neuralgia (61.5%) followed or associated with nerves deficits (38.5%). Median progression free survival (PFS) was 31.7 months (SD 5.8). Tumor recurrence rates at 1 and 3 years were respectively 21.2% (SD 3.1) and 60.1% (SD 15.8). Median overall survival (OS) was 61.5 months (SD 16.27). The 1-year, 2-year, and 5-year survival estimates were 100.0%, 88.9% (SD 10.5), and 44.4% (SD 16.6). 6 patients (46.13%) died following their SES. In univariate analyses, patients with metastastic PESES had a significantly lower OS than others (41.2 months, p = 0.03). Conclusion PESES must be ruled out at diagnosis of a spinal tumor when facing a fast-growing lesion with neurological deficits in a young adult. Thoraco-abdomino-pelvic extension should be carried out. Pre-surgical biopsy must be performed. In case of PESES, neoadjuvant chemotherapy must be established before considering surgical intervention. Level of evidence 4.

Purpose of review To discuss recent advances in the meningioma biology and their clinical implications. Recent findings Meningioma is the most common primary intracranial tumor. Mostly benign, 20% of cases display an aggressive behavior despite best standard of care. The genetic landscape of meningiomas is divided according to NF2 mutational status. Although about 60% of meningiomas display NF2 mutations, the other share is more heterogenous. Mutations in TRAF7, SMO, v-akt murine thymoma viral oncogene homolog 1 (AKT1), PI3KCA and KLF4 are seen mostly in WHO grade 1 meningiomas. In higher grade meningiomas, mutations of the TERT promoter and deletions of CDKN2A/B emerge and have prognostic value. Moreover, mutations in DMD, BAP1 and PBRM1 have recently been discovered and are being further explored. DNA methylation subgroups offer valuable insight into meningioma prognosis and its implementation in clinical setting is under evaluation. Moreover, the study of distinct meningioma populations such as radiation-induced meningioma and progestin-associated meningioma may provide further insight into meningioma oncogenesis and potential therapeutic targets. Summary The mutational landscape of meningioma has expanded following the use of the new genetic sequencing approaches. Novel mutations have been characterized and reveal their prognostic and therapeutic applications. This improved understanding of meningioma biology has promising implications for novel treatment strategies.

Little information about the natural history of peripheral nerve schwannomas exists in the literature. The aim of this study was to determine the natural history of those tumors both in sporadic and schwannomatosis cases to determine their growth rates and patterns. In 44 patients from 3 surgical centers, hospital charts, follow-up records, and imaging studies were reviewed. Of these patients, 7 had sporadic schwannomatosis. Histological diagnosis was obtained in 37 patients (84%). Tumor growth rates were determined by calculating the absolute and relative growth rates. On the 47 tumors analyzed, the median tumor size at diagnosis was 1.8 cm3, and the majority of tumors were located in the lower limb (62%). The absolute growth rate ranged from − 1.13 to 23.17 cm3/year (mean, 1.69 cm3/year). Relative annual growth rates ranged from − 9 to 166%/year (mean, 33.9%/year). There was no clear correlation between initial tumor size, age at diagnosis, and tumor growth rate. Six patients (13%) harbored “fast-growing” tumors (absolute growth rate > 2 cm3/year and relative growth rate > 35%/year) while 19% of tumors demonstrate no growth or negative growth. In schwannomatosis patients, each tumor displayed a distinct growth pattern. This study confirms the slow-growing nature of most, but not all, peripheral nerve schwannomas. Additional studies are mandatory to explore the environmental factors influencing growth in sporadic cases and the precise growth patterns in schwannomatosis cases to detect the rare cases of malignant transformation and pave the way to the evaluation of future clinical trials.

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 (

BackgroundTERT gene alterations (TERT-alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought.MethodsWe applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to TERT-alt (n=59) or TERT promoter wild-type (TERTp-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs.ResultsTERT-alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all TERT-alt patients versus 101 months for all TERTp-wt patients. The HR for TERT-alt was 3.74 in reference to TERTp-wt. For all TERT-alt patients versus all TERTp-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for TERT-alt was 2.77 compared with TERTp-wt. TERT-alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II TERT-alt patients compared with WHO-III TERTp-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II TERT-alt patients compared with WHO-III TERTp-wt patients.ConclusionsTERT-alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. TERT-alt should be managed and surveilled aggressively. We propose that TERT-alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification.Trial registration numberPROSPERO: CRD42018110566.

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 (

Primary central nervous system lymphoma (PCNSL) is a distinct extranodal lymphoma presenting with limited stage disease but variable response rates to treatment despite homogenous pathological presentation. The likely underlying molecular heterogeneity and its clinical impact is poorly understood.We performed a comprehensive genome-wide analysis of 147 PCNSL from fresh-frozen tumor tissue from immunocompetent, treatment naïve PCNSL patients, employing whole-exome sequencing, assessment of somatic copy number alterations and DNA methylation, and RNA expression. These data were integrated and correlated with the clinico-radiological characteristics and outcomes of the patients. We validated our results in an independent series of 93 PCNSL formalin-fixed, paraffin-embedded (FFPE) samples.Consensus clustering of multi-omics data identified four robust, non-overlapping, prognostically significant clusters (CS) within PCNSL. The CS1 group, characterized by high proliferation and Polycomb Repressive Complex 2 (PRC2) complex activity had an intermediate outcome between CS2/CS3 and CS4. Patients who had PCNSL with an “immune-hot” (CS4) profile had the most favorable clinical outcome. In contrast, patients with the immune-cold hypermethylated CS2 and the heterogenous-immune CS3 groups had a poor prognosis. Nearly all PCNSL patients with meningeal infiltration harbored HIST1H1E mutations, enriched in the CS3 group. The integrated analysis suggests that the CS4 group may be more susceptible to immunotherapy. The integration of genome-wide data from multi-omics data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that significantly improved the current clinical stratification. This molecular classification using FFPE samples facilitates routine use in clinical practice and provides potential precision-medicine strategies in PCNSL.

International audience; Anaerobic digestion allows renewable energy to be produced through the degradation of bio-waste. The process, which is of economic and ecological interest, is implemented industrially in concrete digesters. Bio-waste is a complex medium with a composition that can vary in time and space. It contains several chemical compounds, including volatile fatty acids, ammonium, and CO2, which are aggressive towards concrete and compromise its durability. The individual effects of the different compounds on concrete are significantly different. To move toward a better design of concrete intended for the building of biogas digesters, this paper aims to understand the mechanisms and intensity of alteration associated with the different components of biowaste and their contribution to the total deterioration. Ordinary Portland cement pastes were immersed for 16 weeks in six synthetic solutions made of the three metabolites, taken alone or in mixes. The mass variations of the specimens, the pH, and the concentration of the chemical elements in solution were monitored over time. The microstructural, chemical and mineralogical changes of the samples were analysed by scanning electron microscopy, electron probe micro-analysis and X-Ray diffraction analyses and showed phenomena of dissolution, leaching and carbonation. The results show that the acetic acid solution was the most aggressive, in accordance with its pH value, and had a predominant effect in mixed solutions, whereas sodium bicarbonate solution induced carbonation and showed a protective effect. Interestingly, despite its reputed high aggressiveness, ammonium nitrate did not have a major impact in mixed solutions.

In drinking water production from groundwaters, biological rapid sand filters (RSFs) can be used for ammonium and manganese removal in aerobic conditions. However, in some boreholes, a start-up duration of several months is required to reach the required removal capacity, leading to significant water losses. Moreover, in specific industrial cases, no exogenous biomass under the form of backwash water or activated sludge can be added to accelerate the process, and different approaches are seldom considered in the literature. With the aim of saving water, start-up strategies coupling water temperature increase and substrate dosing were studied to accelerate the installation of biological activities in a pilot plant fed with borehole water. These set-ups enabled a substantial acceleration of nitrification but no improvement of manganese oxidation in the experimental conditions, although the experiments showed no clear negative influence of nitrification, through nitrite accumulation, on biological manganese oxidation. To further save energy and reduce water loss, outlet water recirculation at a rate of 75% during the start-up phase was validated. The proposed start-up strategy enabled the complete installation of active biofilms with a mean start-up time reduction of 36% and water use reduction of 84% compared to the reference natural conditions.

LZTR1, the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase is among the most frequently mutated ubiquitin ligase coding gene in syndromic and sporadic human cancers including glioblastoma multiforme, in which approximately 27% of cases harbor inactivating mutations and copy number loss. However, both the identity of the protein substrates targeted by LZTR1-mediated ubiquitylation and the biological contexts regulated by specific LZTR1-substrate(s) interactions remain uncertain. Here, we combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations and in a new conditional Lztr1 knockout mouse. Multiple screens converged on the receptor tyrosine kinases EGFR and AXL as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome by LZTR1-CUL3 complexes. Pathogenic mutations affecting LZTR1 failed to promote degradation of EGFR and AXL in human tumors. Mice harboring conditional deletion of the LZTR1 gene combined with loss of CDKN2A in the neural progenitor compartment generated peripheral nervous system tumors including schwannoma like and malignant peripheral nervous system tumors (MPNST). Tumors from the LZTR1-mutant mouse model accumulated very high levels of EGFR and AXL and exhibited potent and specific vulnerability to the combinatorial inhibition of EGFR and AXL kinases. These findings explain the mechanism of tumorigenesis associated with LZTR1 inactivation and offer a therapeutic strategy to patients affected by tumors carrying mutations of LZTR1.

TERT promoter mutations have been associated with increased risk of recurrence in meningioma cohorts, thus a potential biomarker for aggressive phenotypes. A main purpose of refining tumour classification is better predictions on the patient level. We compiled data from previous published cohorts to investigate patient-level predictions of recurrence based on TERTp-mut status. Implementation of TERTp-mut into the WHO grading led to better patient prognostication by improved prediction of recurrence. Our results support implementation of TERTp-mut into diagnostics and classification of meningiomas.

Background Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood. Methods We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis. Results We found that in mice expressing one of two common genetic drivers of meningioma - Pik3ca H1047R or AKT1 E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating PIK3CA and AKT1 mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the CCM genes. We analyzed lesions induced by the activating mutations Pik3ca H1074R and AKT1 E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin. Conclusions In tissue samples from sporadic CCMs, mutations in PIK3CA were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).

In numerous contexts, concrete can be exposed to chemically aggressive conditions that can damage their microstructure and reduce their lifespan. The concrete facilities from the agricultural and agro-food industries dedicated to the storage or the treatment of effluents are more particularly exposed to organic acids coming from the microbial activity naturally occurring in such media. This biodeterioration leads mainly to mineralogical transformations, such as hydrated and anhydrous phase dissolution, and to ion exchanges between acidic effluents and cement-based materials. The poorly crystalline mineralogy of hydrated cement pastes and their reactivity makes the geochemical behavior of such materials difficult to investigate and thus to predict over large periods of time and wide variety of chemical conditions. The degradation of cementitious materials in these aggressive conditions mainly leads to the leaching of calcium and the precipitation of amorphous secondary phases. The purpose of this work is (i) to assess the stability of the cement phases involved in such chemical conditions as well as to identify the alterations products, and (ii) to understand the evolution of concentration and the behavior of elements in solution such as aluminum or silicon. A thermodynamic model of cement pastes subjected to acid attacks has been developed, in order to reproduce, experimental data also presented here. Our model reproduces a major part of the behaviors shown by the experiments, i.e. a progressive decalcification of solid matrix (successive dissolution of portlandite, aluminates hydrates and C-S-H) during acid degradation and the identification of alteration zones in agreement with the experimental observations.

Consider immune reconstitution syndrome in case of neurologic worsening during nivolumab treatment given for progressive multifocal leukoencephalopathy.

Prophylaxis or treatment of tumor-associated seizures is adaily concern in neurosurgical practice but is often guided by the surgeon's habits rather than evidence from clinical trials, which is lacking. The present study reviews the literature on the incidence, clinical aspects and treatment of epilepsy and epileptic seizures in patients undergoing surgery for meningioma. Based on the published data, we then performed a French nationwide survey of neurosurgeons’ practices regarding perioperative management of meningioma-related epilepsy and epileptic seizures.

Primary CNS lymphomas (PCNSL) are rare and poor prognosis diffuse large B-cell lymphomas. Because of the brain tumor environment and the restricted distribution of drugs in the CNS, specific PCNSL patient-derived orthotopic xenograft (PDOX) models are needed for preclinical research to improve the prognosis of PCNSL patients. PCNSL patient specimens (n = 6) were grafted in the caudate nucleus of immunodeficient nude mice with a 83% rate of success, while subcutaneous implantation in nude mice of human PCNSL sample did not generate lymphoma, supporting the role of the brain microenvironment in the PCNSL physiopathology. PDOXs showed diffuse infiltration of B-cell lymphoma cells in the brain parenchyma. Each model had a unique mutational signature for genes in the BCR and NF-κB pathways and retained the mutational profile of the primary tumor. The models can be stored as cryopreserved biobank. Human IL-10 levels measured in the plasma of PCNSL-PDOX mice showed to be a reliable tool to monitor the tumor burden. Treatment response could be measured after a short treatment with the targeted therapy ibrutinib. In summary, we established a panel of human PCNSL-PDOX models that capture the histological and molecular characteristics of the disease and that proved suitable for preclinical experiments. Our methods of generation and characterization will enable the generation of additional PDOX-PCNSL models, essential tools for cognitive and preclinical drug discovery.

Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family, may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome or targeted sequencing. AID synergizes initial hotspot mutations by a second composite mutation. Analysis of 2.5 million cells, normal and oncogenic, revealed AICDA expression activation after oncogenic transformation and cell cycle regulation loss. AID mutational load was found to be independently associated with favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2,000 samples. Finally, we found that AID related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity and T-cell exhaustion, which may increase ICI sensitivity.In BriefA combined bulk and single cell multi-omic analysis of over 50,000 patients and 2.5 million cells across 80 tumor types reveals oncogenic acquired AICDA expression inducing composite mutations and clonal immunogenic neoepitopes that are associated with favorable outcome in patients treated by immune-checkpoint inhibitors.Highlights•Pan-cancer analysis of AID mutations using > 50,000 samples, 2,000 ICI treated cases and 2.5 million cells with genome, exome and transcriptome data•Oncogenic transient AICDA expression induces mutations mainly during transcription of its off-target genes in virtually all cancers•AID is implicated in composite mutations on weakly functional alleles and immunogenic clonal neoepitopes at hotspots with greater positive selection•AID mutational load predicts response and is associated with favorable outcome in ICI treated patients

International audience; AimsMutations activating the Hedgehog (Hh) signalling pathway have been described in anterior skull base meningiomas, raising hope for the use of targeted therapies. However, identification of Hh-activated tumours is hampered by the lack of a reliable immunohistochemical marker. We report the evaluation of GAB1, an immunohistochemical marker used to detect Hh pathway activation in medulloblastoma, as a potential marker of Hh-activated meningiomas.MethodsGAB1 staining was compared to SMO mutation detection with Sanger and NGS techniques as well as Hh pathway activation study through mRNA expression level analyses in a discovery set of 110 anterior skull base meningiomas and in a prospective validation set of 21 meningiomas.ResultsUsing an expression score ranging from 0 to 400, we show that a cut-off score of 250 lead to excellent detection of Hh pathway mutations (sensitivity 100%, specificity 86%). The prospective validation set confirmed the excellent negative predictive value of GAB1 to exclude Hedgehog independent meningiomas. We describe a large series of 32 SMO-mutant meningiomas and define multiple ways of Hh activation, either through somatic mutations or associated with mutually co-exclusive SHH (Sonic Hedgehog) or IHH (Indian Hedgehog) overexpression independent of the mutations.ConclusionThe assessment of GAB1 expression by an immunohistochemical score is a fast and cost-efficient tool to screen anterior skull base meningiomas for activation of the Hedgehog pathway. It could facilitate the identification of selected cases amenable to sequencing for hedgehog pathway genes as predictive markers for targeted therapy.