The role of [18 F]FDOPA PET as an adjunct to conventional MRI in the diagnosis of aggressive glial lesions.

BACKGROUND: Amino acid PET is recommended for the initial diagnosis of brain lesions, but its value for identifying aggressive lesions remains to be established. The current study therefore evaluates the added-value of dynamic [18 F]FDOPA PET as an adjunct to conventional MRI for determining the aggressiveness of presumed glial lesions at diagnosis. METHODS: Consecutive patients, with a minimal 1 year-follow-up, underwent contrast-enhanced MRI (CE MRI) and dynamic [18 F]FDOPA PET to characterize their suspected glial lesion. Lesions were classified semi-automatically by their CE MRI (MRI-/+), and PET parameters (static tumor-to-background ratio, TBR; dynamic time-to-peak ratio, TTPratio). Diagnostic accuracies of MRI and PET parameters for the differentiation of tumor aggressiveness were evaluated by chi-square test or receiver operating characteristic analyses. Aggressive lesions were either defined as lesions with dismal molecular characteristics based on the WHO 2021 classification of brain tumors or with compatible clinico-radiological profiles. Time-to-treatment failure (TTF) and overall survival (OS) were evaluated. RESULTS: Of the 109 patients included, 46 had aggressive lesions (45 confirmed by histo-molecular analyses). CE MRI identified aggressive lesions with an accuracy of 73%. TBRmax (threshold of 3.2), and TTPratio (threshold of 5.4 min) respectively identified aggressive lesions with an accuracy of 83% and 76% and were independent of CE MRI and clinical factors in the multivariate analysis. Among the MRI-lesions, 11/56 (20%) were aggressive and respectively 55% and 50% of these aggressive lesions showed high TBRmax and short TTPratio in PET. High TBRmax and short TTPratio in PET were significantly associated to poorer survivals (p ≤ 0.009). CONCLUSION: Dynamic [18 F]FDOPA PET provides a similar diagnostic accuracy as contrast enhancement in MRI to identify the aggressiveness of suspected glial lesions at diagnosis. Both methods, however, are complementary and [18 F]FDOPA PET may be a useful additional tool in equivocal cases.

Differentiating high-grade glioma progression from treatment-related changes with dynamic [18F]FDOPA PET: a multicentric study.

OBJECTIVES: Diagnostic accuracy of amino-acid PET for distinguishing progression from treatment-related changes (TRC) is currently based on single-center non-homogeneous glioma populations. Our study assesses the diagnostic value of static and dynamic [18F]FDOPA PET acquisitions to differentiate between high-grade glioma (HGG) recurrence and TRC in a large cohort sourced from two independent nuclear medicine centers. METHODS: We retrospectively identified 106 patients with suspected glioma recurrences (WHO GIII, n = 38; GIV, n = 68; IDH-mutant, n = 35, IDH-wildtype, n = 71). Patients underwent dynamic [18F]FDOPA PET/CT (n = 83) or PET/MRI (n = 23), and static tumor-to-background ratios (TBRs), metabolic tumor volumes and dynamic parameters (time to peak and slope) were determined. The final diagnosis was either defined by histopathology or a clinical-radiological follow-up at 6 months. Optimal [18F]FDOPA PET parameter cut-offs were obtained by receiver operating characteristic analysis. Predictive factors and clinical parameters were assessed using univariate and multivariate Cox regression survival analyses. RESULTS: Surgery or the clinical-radiological 6-month follow-up identified 71 progressions and 35 treatment-related changes. TBRmean, with a threshold of 1.8, best-differentiated glioma recurrence/progression from post-treatment changes in the whole population (sensitivity 82%, specificity 71%, p < 0.0001) whereas curve slope was only significantly different in IDH-mutant HGGs (n = 25). In survival analyses, MTV was a clinical independent predictor of progression-free and overall survival on the multivariate analysis (p ≤ 0.01). A curve slope > -0.12/h was an independent predictor for longer PFS in IDH-mutant HGGs CONCLUSION: Our multicentric study confirms the high accuracy of [18F]FDOPA PET to differentiate recurrent malignant gliomas from TRC and emphasizes the diagnostic and prognostic value of dynamic acquisitions for IDH-mutant HGGs. KEY POINTS: • The diagnostic accuracy of dynamic amino-acid PET, for distinguishing progression from treatment-related changes, is currently based on single-center non-homogeneous glioma populations. • This multicentric study confirms the high accuracy of static [18F]FDOPA PET images for differentiating progression from treatment-related changes in a homogeneous population of high-grade gliomas and highlights the diagnostic and prognostic value of dynamic acquisitions for IDH-mutant high-grade gliomas. • Dynamic acquisitions should be performed in IDH-mutant glioma patients to provide valuable information for the differential diagnosis of recurrence and treatment-related changes.

Molecular Characterization of the Dual Effect of the GPER Agonist G-1 in Glioblastoma.

Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite conventional treatment, consisting of a chirurgical resection followed by concomitant radio-chemotherapy, the 5-year survival rate is less than 5%. Few risk factors are clearly identified, but women are 1.4-fold less affected than men, suggesting that hormone and particularly estrogen signaling could have protective properties. Indeed, a high GPER1 (G-protein-coupled estrogen receptor) expression is associated with better survival, especially in women who produce a greater amount of estrogen. Therefore, we addressed the anti-tumor effect of the GPER agonist G-1 in vivo and characterized its molecular mechanism of action in vitro. First, the antiproliferative effect of G-1 was confirmed in a model of xenografted nude mice. A transcriptome analysis of GBM cells exposed to G-1 was performed, followed by functional analysis of the differentially expressed genes. Lipid and steroid synthesis pathways as well as cell division processes were both affected by G-1, depending on the dose and duration of the treatment. ANGPTL4, the first marker of G-1 exposure in GBM, was identified and validated in primary GBM cells and patient samples. These data strongly support the potential of G-1 as a promising chemotherapeutic compound for the treatment of GBM.

Integration of dynamic parameters in the analysis of 18F-FDopa PET imaging improves the prediction of molecular features of gliomas.

PURPOSE: 18F-FDopa PET imaging of gliomas is routinely interpreted with standardized uptake value (SUV)-derived indices. This study aimed to determine the added value of dynamic 18F-FDopa PET parameters for predicting the molecular features of newly diagnosed gliomas. METHODS: We retrospectively included 58 patients having undergone an 18F-FDopa PET for establishing the initial diagnosis of gliomas, whose molecular features were additionally characterized according to the WHO 2016 classification. Dynamic parameters, involving time-to-peak (TTP) values and curve slopes, were tested for the prediction of glioma types in addition to current static parameters, i.e., tumor-to-normal brain or tumor-to-striatum SUV ratios and metabolic tumor volume (MTV). RESULTS: There were 21 IDH mutant without 1p/19q co-deletion (IDH+/1p19q-) gliomas, 16 IDH mutants with 1p/19q co-deletion (IDH+/1p19q+) gliomas, and 21 IDH wildtype (IDH-) gliomas. Dynamic parameters enabled differentiating the gliomas according to these molecular features, whereas static parameters did not. In particular, a longer TTP was the single best independent predictor for identifying (1) IDH mutation status (area under the curve (AUC) of 0.789, global accuracy of 74% for the criterion of a TTP ≥ 5.4 min) and (2) 1p/19q co-deletion status (AUC of 0.679, global accuracy of 69% for the criterion of a TTP ≥ 6.9 min). Moreover, the TTP from IDH- gliomas was significantly shorter than those from both IDH+/1p19q- and IDH+/1p19q+ (p ≤ 0.007). CONCLUSION: Prediction of the molecular features of newly diagnosed gliomas with 18F-FDopa PET and especially of the presence or not of an IDH mutation, may be obtained with dynamic but not with current static uptake parameters.

A probabilistic map of negative motor areas of the upper limb and face: a brain stimulation study.

Negative motor responses (NMRs) are defined as movement arrests induced by direct electrical stimulation of the brain. The NMRs manifest themselves after the disruption of a corticosubcortical network involved in motor control, referred to as the 'negative motor network'. At present, the spatial topography of the negative motor areas (NMAs) is poorly known. Hence, the objectives of the present study were to establish the first probabilistic map of the NMAs of the upper limbs and face, identify potential subareas, and investigate the NMAs' relationships with the primary motor cortex. A total of 117 patients with low grade glioma underwent awake surgery with direct electrostimulation. The Montreal Neurological Institute coordinates of sites eliciting NMRs (face and upper limbs) were registered. A probabilistic map was created, and subareas were identified in a cluster analysis. Each cluster was then plotted on the Glasser atlas and the 1200 Subjects Group Average Data from the Human Connectome Project, in order to study connectivity and compare the results with recent parcellation data. We elicited 386 NMRs (mean ± standard deviation current intensity: 2.26 ± 0.5 mA) distributed throughout the precentral gyrus in both hemispheres. In each hemisphere, we found two clusters for facial NMRs. For upper limb NMRs, we found two clusters in the right hemisphere; and three in the left. Each cluster overlapped with parcellations from the Glasser atlas. For the face, the NMAs were associated with areas 55b and 6v. For the upper limbs, the NMAs were linked to areas 6v, 6d, and 55b. Each NMA cluster showed a specific pattern of functionally connected areas, such as the inferior frontal gyrus, supplementary motor area, parietal areas, and posterior superior temporal gyrus. The white matter pathways projecting to these subareas involved the frontal aslant tract and the frontostriatal tract-both of which are well known to be associated with NMRs. This study constitutes the largest series to date of NMRs mapped to the lateral surface of both hemispheres. Rather than being randomly distributed, the NMAs appeared to be well structured and corresponded to parcellations identified by functional neuroimaging. Moreover, the white matter pathways known to drive NMRs are also connected to regions encompassing NMAs. Taken as a whole, our results suggest that NMAs belong to a large-scale modulatory motor network. Our new probabilistic map might constitute a valuable tool for use in further clinical and fundamental studies of motor control.

New insights into the neural foundations mediating movement/language interactions gained from intrasurgical direct electrostimulations.

Interactions between language and motricity have been a topic of interest in brain development as well as in pathological models. The role of the motor system in language has been investigated through neuroimaging and non-invasive brain stimulation methods. However, little is known about the neural basis that might be involved in such interactions. Meanwhile, brain direct electrostimulations (DES) have provided essential knowledges about the connectomic organization of both motor and language systems. We propose here to review the literature about DES from the outlook of interactions between language and motricity and to investigate common cortico-subcortical structures shared by both networks. Then we will report an experimental study about the spatial distribution of DES eliciting simultaneous speech and contralateral upper limb negative motor response in a series of 100 patients operated on under awake condition for a low-grade glioma. From the probabilistic map obtained, a structural connectivity analysis was performed to reveal the cortico-subcortical networks involved in language and motricity interactions. The embodiment suggested by these results takes place in parallel and distributed bilateral fronto-temporo-parietal networks rather than in a single and somatopically well defined organization as previously suggested.

Astrocytoma: A Hormone-Sensitive Tumor?

Astrocytomas and, in particular, their most severe form, glioblastoma, are the most aggressive primary brain tumors and those with the poorest vital prognosis. Standard treatment only slightly improves patient survival. Therefore, new therapies are needed. Very few risk factors have been clearly identified but many epidemiological studies have reported a higher incidence in men than women with a sex ratio of 1:4. Based on these observations, it has been proposed that the neurosteroids and especially the estrogens found in higher concentrations in women's brains could, in part, explain this difference. Estrogens can bind to nuclear or membrane receptors and potentially stimulate many different interconnected signaling pathways. The study of these receptors is even more complex since many isoforms are produced from each estrogen receptor encoding gene through alternative promoter usage or splicing, with each of them potentially having a specific role in the cell. The purpose of this review is to discuss recent data supporting the involvement of steroids during gliomagenesis and to focus on the potential neuroprotective role as well as the mechanisms of action of estrogens in gliomas.

[Use of the PELICAN software for the creation and export of standardized pathology reports in central nervous system tumors: Example of meningiomas]. / Utilisation du logiciel PELICAN pour la saisie et l'export de comptes rendus standardisés dans les tumeurs du système nerveux central : application aux méningiomes.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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 (P<0.001), a significant increase in the Ki-67 index (P<0.0001), and a significant decrease in progesterone receptor expression (P<0.001). In atypical meningiomas, a Ki-67 index of more than 20 % was significantly correlated with a shorter progression-free survival (P=0.032). CONCLUSION: 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.

Cytoplasmic overexpression of RNA-binding protein HuR is a marker of poor prognosis in meningioma, and HuR knockdown decreases meningioma cell growth and resistance to hypoxia.

HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro-oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti-proliferative effects of HuR knockdown in two meningioma cell lines (IOMM-Lee and Ben-Men-1) and conducted transcriptome-wide analyses (IOMM-Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade (p = 1.2 × 10-8 ) and negatively with progression-free and overall survival (p = 0.01) time in human meningioma tissues. In vitro, siHuR-induced HuR knockdown was shown to reduce the growth of both Ben-Men-1 (p = 2 × 10-8 ) and IOMM-Lee (p = 4 × 10-9 ) cells. Transcriptome analyses revealed HuR knockdown in IOMM-Lee cells to deregulate the HIF1A signalling pathway (p = 1.5 × 10-6 ) and to up-regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide-excision repair, poly(A)-specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [p(FDR) < 0.001]. Interestingly, HuR knockdown under hypoxic culture conditions further potentiated the effects of HuR knockdown on cell growth, apoptosis, and HIF1A expression. We thus conclude that cytoplasmic HuR expression is a marker of poor prognosis in meningioma and that HuR is a promising potential therapeutic target for use in tumours refractory to standard therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Survey on current cognitive practices within the European Low-Grade Glioma Network: towards a European assessment protocol.

BACKGROUND: The European Low-Grade Glioma network indicated a need to better understand common practices regarding the managing of diffuse low-grade gliomas. This area has experienced great advances in recent years. METHOD: A general survey on the managing of diffuse low-grade gliomas was answered by 21 centres in 11 European countries. Here we focused on specific questions regarding perioperative and intraoperative cognitive assessments. RESULTS: More centres referred to the same speech and language therapist and/or neuropsychologist across all assessments; a core of assessment tools was routinely used across centres; fluency tasks were commonly used in the perioperative stages, and object naming during surgery; tasks that tapped on attention, executive functions, visuospatial awareness, calculation and emotions were sparsely administered; preoperative assessments were performed 1 month or 1 week before surgery; timing for postoperative assessments varied; finally, more centres recommended early rehabilitation, whenever needed. CONCLUSIONS: There is an emerging trend towards following similar practices for the management of low-grade gliomas in Europe. Our results are descriptive and formalise current discussions in our group. Also, they contribute towards the development of a European assessment protocol.

Disruption of bimanual movement by unilateral subcortical electrostimulation.

OBJECTIVES: Cortical areas involved in bimanual coordination have been regularly studied by functional neuroimaging and electroencephalography. However, the subcortical connectivity underlying this complex function has received less attention. Here, we used the technique of direct electrostimulation in awake patients who underwent surgery for brain glioma, with the goal to investigate the white matter pathways subserving bimanual coordination. EXPERIMENTAL DESIGN: Eight patients were operated under local anesthesia for a frontal low-grade glioma. Intraoperative subcortical electrostimulation mapping was used to search interference with bimanual coordination. The corresponding stimulation sites were reported on brain MRI. PRINCIPAL OBSERVATIONS: All patients presented a complete arrest of the movement of both hands during unilateral subcortical stimulation of the white matter underneath the dorsal premotor cortex and the posterior part of the supplementary motor area, rostrally to the corticospinal tract, until the caudate nucleus and the anterior arm of the internal capsule. No movement deficits, especially no disturbances of bimanual coordination, were observed 3 months after surgery. CONCLUSIONS: This is the first evidence of bilateral negative motor responses elicited by unilateral subcortical stimulation. Such findings support the existence of a bilateral cortico-subcortical network connecting the premotor cortices, basal ganglia, and spinal cord, involved in the control of bimanual coordination. A better understanding of this modulatory motor circuit may have important implications in fundamental neurosciences as well as in brain surgery.

Beyond Avoiding Hemiplegia after Glioma Surgery: The Need to Map Complex Movement in Awake Patient to Preserve Conation.

Improving the onco-functional balance has always been a challenge in glioma surgery, especially regarding motor function. Given the importance of conation (i.e., the willingness which leads to action) in patient's quality of life, we propose here to review the evolution of its intraoperative assessment through a reminder of the increasing knowledge of its neural foundations-based upon a meta-networking organization at three levels. Historical preservation of the primary motor cortex and pyramidal pathway (first level), which was mostly dedicated to avoid hemiplegia, has nonetheless shown its limits to prevent the occurrence of long-term deficits regarding complex movement. Then, preservation of the movement control network (second level) has permitted to prevent such more subtle (but possibly disabling) deficits thanks to intraoperative mapping with direct electrostimulations in awake conditions. Finally, integrating movement control in a multitasking evaluation during awake surgery (third level) enabled to preserve movement volition in its highest and finest level according to patients' specific demands (e.g., to play instrument or to perform sports). Understanding these three levels of conation and its underlying cortico-subcortical neural basis is therefore critical to propose an individualized surgical strategy centered on patient's choice: this implies an increasingly use of awake mapping and cognitive monitoring regardless of the involved hemisphere. Moreover, this also pleads for a finer and systematic assessment of conation before, during and after glioma surgery as well as for a stronger integration of fundamental neurosciences into clinical practice.

Estrogen signaling in healthy and tumor brain.

Sex-specific differences in brain organization and function are widely explored in multidisciplinary studies, ranging from sociology and biology to digital modelling. In addition, there is growing evidence that natural or disturbed hormonal environments play a crucial role in the onset of brain disorders and pathogenesis. For example, steroid hormones, but also enzymes involved in steroidogenesis and receptors triggering hormone signaling are key players of gliomagenesis. In the present review we summarize the current knowledge about steroid hormone, particularly estrogens synthesis and signaling, in normal brain compared to the tumor brain. We will focus on two key molecular players, aromatase and the G Protein-Coupled Estrogen Receptor, GPER.

Radiological evolution of progestogen-induced meningioma: A monocentric retrospective study.

Cyproterone acetate (CPA) is known to induce meningioma, and recently, nomegestrol acetate (NMA) and chlormadinone acetate (CMA) were also involved. Progestagen-induced meningioma management starts with progestogen discontinuation and is either interventional (surgery and/or radiotherapy) or conservative (clinical and MRI radiological follow-up). We performed a retrospective volumetric radiological outcomSe study of progestogen-induced meningiomas diagnosed in our hospital. We analysed progestogen-related meningiomas diagnosed until 30 June 2021, with at least one diagnostic and one follow-up MRI results. Meningioma volumes were centrally retrospectively measured using a T1-weighted 3D millimeter sequence with gadolinium injection on a postprocessing console. We analysed 98 meningiomas of 38 females and one transgender (male-to-female), of which 25 (64.1%) had taken CPA, seven (17.9%) NMA, three (7.7%) CMA, and four (10.2%) several progestogens. Eleven patients (24 meningiomas) underwent interventional management, seven patients had meningiomas followed by conservative or interventional management, and 21 patients (51 meningiomas) had only conservative management. Of these 21 patients, 17 had discontinued their progestogen less than 6 months before, of which 14 (82.3%) had decreased or stable meningioma(s) during a 24-month median follow-up (3 to 75) period. Overall, four of the 39 patients experienced meningioma progression (three during conservative treatment and one after surgery), including two patients who had continued NMA or CMA treatment several years after diagnosis. Our study confirms a generally favourable outcome of progestogen-related meningioma after conservative treatment, especially for CPA. It also underlines the need for progestogen discontinuation at meningioma diagnosis.

A High MCM6 Proliferative Index in Atypical Meningioma Is Associated with Shorter Progression Free and Overall Survivals.

The aim of this study was to evaluate the prognostic value of MCM6, in comparison with Ki-67, in two series of grade 1 and 2 meningiomas, and to evaluate its correlation with methylation classes. The first cohort included 100 benign (grade 1, World Health Organization 2021) meningiomas, and the second 69 atypical meningiomas (grade 2). Immunohistochemical Ki-67 and MCM6 labeling indices (LI) were evaluated independently by two observers. Among the atypical meningiomas, 33 cases were also studied by genome-wide DNA methylation. In grade 2 meningiomas, but not grade 1, both Ki-67 and MCM6 LIs were correlated with PFS (p = 0.004 and p = 0.005, respectively; Cox univariate analyses). Additionally, MCM6 was correlated with overall survival only in univariate analysis. In a multivariate model, including mitotic index, Ki-67, MCM6, age, sex, and the quality of surgical resection, only MCM6 was correlated with PFS (p = 0.046). Additionally, we found a significant correlation between PTEN loss and high MCM6 or Ki-67 LIs. Although no correlation was found with the methylation classes and subtypes returned by the meningioma algorithm MNGv2.4., MCM6 LI was significantly correlated with the methylation of 2 MCM6 gene body loci. In conclusion, MCM6 is a relevant prognostic marker in atypical meningiomas. This reproducible and easy-to-use marker allows the identification of a highly aggressive subtype of proliferative meningiomas, characterized notably by frequent PTEN losses, which was previously reported to be sensitive to histone deacetylase inhibitors.

MicroRNAs miR-16 and miR-519 control meningioma cell proliferation via overlapping transcriptomic programs shared with the RNA-binding protein HuR.

Introduction: Meningiomas are the most common type of primary central nervous system tumors. In about 80% cases, these tumors are benign and grow very slowly, but the remainder 20% can unlock higher proliferation rates and become malignant. In this study we examined two miRs, miR-16 and miR-519, and evaluated their role in tumorigenesis and cell growth in human meningioma. Methods: A cohort of 60 intracranial grade 1 and grade 2 human meningioma plus 20 healthy meningeal tissues was used to quantify miR-16 and miR-519 expressions. Cell growth and dose-response assays were performed in two human meningioma cell lines, Ben-Men-1 (benign) and IOMM-Lee (aggressive). Transcriptomes of IOMM-lee cells were measured after both miR-mimics transfection, followed by integrative bioinformatics to expand on available data. Results: In tumoral tissues, we detected decreased levels of miR-16 and miR-519 when compared with arachnoid cells of healthy patients (miR-16: P=8.7e-04; miR-519: P=3.5e-07). When individually overexpressing these miRs in Ben-Men-1 and IOMM-Lee, we observed that each showed reduced growth (P<0.001). In IOMM-Lee cell transcriptomes, downregulated genes, among which ELAVL1/HuR (miR-16: P=6.1e-06; miR-519:P=9.38e-03), were linked to biological processes such as mitotic cell cycle regulation, pre-replicative complex, and brain development (FDR<1e-05). Additionally, we uncovered a specific transcriptomic signature of miR-16/miR-519-dysregulated genes which was highly enriched in HuR targets (>6-fold; 79.6% of target genes). Discussion: These results were confirmed on several public transcriptomic and microRNA datasets of human meningiomas, hinting that the putative tumor suppressor effect of these miRs is mediated, at least in part, via HuR direct or indirect inhibition.

Identification of Gender- and Subtype-Specific Gene Expression Associated with Patient Survival in Low-Grade and Anaplastic Glioma in Connection with Steroid Signaling.

Low-grade gliomas are rare primary brain tumors, which fatally evolve to anaplastic gliomas. The current treatment combines surgery, chemotherapy, and radiotherapy. If gender differences in the natural history of the disease were widely described, their underlying mechanisms remain to be determined for the identification of reliable markers of disease progression. We mined the transcriptomic and clinical data from the TCGA-LGG and CGGA databases to identify male-over-female differentially expressed genes and selected those associated with patient survival using univariate analysis, depending on molecular characteristics (IDH wild-type/mutated; 1p/19q codeleted/not) and grade. Then, the link between the expression levels (low or high) of the steroid biosynthesis enzyme or receptors of interest and survival was studied using the log-rank test. Finally, a functional analysis of gender-specific correlated genes was performed. HOX-related genes appeared to be differentially expressed between males and females in both grades, suggesting that a glioma could originate in perturbation of developmental signals. Moreover, aromatase, androgen, and estrogen receptor expressions were associated with patient survival and were mainly related to angiogenesis or immune response. Therefore, consideration of the tight control of steroid hormone production and signaling seems crucial for the understanding of glioma pathogenesis and emergence of future targeted therapies.

Correlation between DNA Methylation and Cell Proliferation Identifies New Candidate Predictive Markers in Meningioma.

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.

18F-FDOPA PET for the Noninvasive Prediction of Glioma Molecular Parameters: A Radiomics Study.

The assessment of gliomas by 18F-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 18F-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 18F-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:18F-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.