A cohort study of CNS tumors in Multiple Endocrine Neoplasia Type 1.

PURPOSE: Multiple Endocrine Neoplasia Type-1 (MEN1) is thought to increase the risk of meningioma and ependymoma. Hereby, we aimed to describe the frequency, the incidence and specific clinical and histological features of CNS tumors in the MEN1 population (except pituitary tumors). EXPERIMENTAL DESIGN: The study population included patients harboring CNS tumors diagnosed with MEN1 syndrome after 1990 and followed-up in the French MEN1 national cohort. Standardized incidence rate (SIR) was calculated based on the French Gironde CNS tumors registry. Genomic analyses were performed on somatic DNA from 7 CNS tumors including meningiomas and ependymomas from MEN1 patients, then in 50 sporadic meningiomas and ependymomas. RESULTS: Twenty-nine CNS tumors were found among the 1498 symptomatic patients (2%) (incidence=47.4/100'000 person-years; SIR=4.5), including 12 meningiomas (0.8%) (incidence=16.2/100'000; SIR=2.5), 8 ependymomas (0.5%) (incidence=10.8/100'000; SIR=17.6), 5 astrocytomas (0.3%) (incidence=6.7/100'000; SIR=5.8), and 4 schwannomas (0.3%) (incidence=5.4/100'000; SIR=12.7). Meningiomas in MEN1 patients were benign, mostly meningothelial, with 11 years earlier onset compared to the sporadic population and an F/M ratio of 1/1. Spinal and cranial ependymomas were mostly classified WHO grade 2. A biallelic MEN1 inactivation was observed in 4/5 ependymomas and 1/2 meningiomas from the MEN1 patients, whereas MEN1 deletion in one allele was present in respectively 3/41 and 0/9 sporadic meningiomas and ependymomas. CONCLUSIONS: Incidence of each CNS tumor was higher in the MEN1 population than in the French general population. Meningiomas and ependymomas should be considered part of the MEN1 syndrome, but somatic molecular data are missing to conclude for astrocytomas and schwannomas.

Evaluation of four tumour growth models to describe the natural history of meningiomas.

BACKGROUND: The incidence of newly diagnosed meningiomas, particularly those diagnosed incidentally, is continually increasing. The indication for treatment is empirical because, despite numerous studies, the natural history of these tumours remains difficult to describe and predict. METHODS: This retrospective single-centre study included 294 consecutive patients with 333 meningiomas who underwent three or more brain imaging scans. Linear, exponential, power, and Gompertz models were constructed to derive volume-time curves, by using a mixed-effect approach. The most accurate model was used to analyse tumour growth and predictors of rapid growth. FINDINGS: The Gompertz model provided the best results. Hierarchical clustering at the time of diagnosis and at the end of follow-up revealed at least three distinct groups, which can be described as pseudoexponential, linear, and slowing growth with respect to their parameters. Younger patients and smaller tumours were more frequent in the pseudo-exponential clusters. We found that the more "aggressive" the cluster, the higher the proportion of patients with grade II meningiomas and who have had a cranial radiotherapy. Over a mean observation period of 56.5 months, 21% of the tumours moved to a cluster with a lower growth rate, consistent with the Gompertz's law. INTERPRETATION: Meningiomas exhibit multiple growth phases, as described by the Gompertz model. The management of meningiomas should be discussed according to the growth phase, comorbidities, tumour location, size, and growth rate. Further research is needed to evaluate the associations between radiomics features and the growth phases of meningiomas. FUNDING: No funding.

Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/ß-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

Management after initial surgery of nonfunctioning pituitary adenoma: surveillance, radiotherapy or surgery?

INTRODUCTION: The first line of treatment for nonfunctioning pituitary adenoma (NFPA) is surgery. Adjuvant radiotherapy or surveillance and new treatment (second surgical operation or salvage radiotherapy) in case of recurrence are options discussed at the multidisciplinary tumor board. The purpose of this study was to evaluate the therapeutic outcome for each option. METHODS: The records of 256 patients followed with NFPA between 2007 and 2018 were retrospectively reviewed. Mean age at initial surgery was 55 years [18-86]. Post-operative MRI found a residual tumor in 87% of patients. Mean follow-up was 12.1 years [0.8-42.7]. RESULTS: After initial surgery, 40 patients had adjuvant radiotherapy. At 5, 10 and 15 years progression-free survival (PFS) was significantly different after surgery alone (77%, 58% and 40%) compared to surgery and adjuvant radiotherapy (84%, 78% and 78%) (HR = 0.24 [0-0.53] p < 0.0005). Overall, after first, second or third surgical operation, 69 patients had adjuvant radiotherapy and 41 salvage radiotherapy. Five-year PFS was similar for adjuvant (90%) and salvage radiotherapy (97%) (p = 0.62). After a second surgical operation, 62% and 71% of patients were irradiated after 2 and 5 years respectively. The risk of corticotropic and thyrotropic deficiency rates were 38% and 59% after second or third surgical operation and 40% and 73% after radiotherapy. Brain tumors occurred in 4 patients: 1 meningioma present at initial surgery, and after radiotherapy, 1 neurinoma which appeared at 5 years, 1 glioblastoma at 13 years and 1 meningioma at 20 years. CONCLUSION: Among patients treated by surgery for NFPA, a "wait-and-see" attitude should be an option since adjuvant radiotherapy is not superior to salvage radiotherapy. However, in case of recurrence or progression, the authors recommended delivery of salvage radiotherapy to avoid a second surgical operation.

Adult brainstem glioma differential diagnoses: an MRI-based approach in a series of 68 patients.

BACKGROUND: Brainstem gliomas are rare in adults. The diagnosis is often difficult, as some teams still consider brainstem biopsies dangerous and often avoid this procedure. The aim of this study was to describe differential diagnoses that can mimic brainstem glioma, to help clinicians avoid diagnostic and therapeutic mistakes, and to propose a diagnostic algorithm according to radiological presentations. METHODS: The French network of adult brainstem gliomas (GLITRAD) retrospectively collected all reported cases of differential diagnoses between 2006 and 2017. The inclusion criteria were as follows: age over 18 years, lesion epicenter in the brainstem, radiological pattern suggestive of a glioma and diagnostic confirmation (histopathological or not, depending on the disease). RESULTS: We identified a total of 68 cases. Most cases (58/68, 85%) presented as contrast-enhancing lesions. The most frequent final diagnosis in this group was metastases in 24/58 (41%), followed by central nervous system lymphoma in 8/58 (14%). Conversely, MRI findings revealed 10/68 nonenhancing lesions. The most frequent diagnosis in this group was demyelinating disease (3/10, 30%). CONCLUSION: The risk of diagnostic mistakes illustrates the need to consider the more systematic use of a brainstem biopsy when reasonably possible. However, we propose an MRI-based approach to the differential diagnosis of gliomas to limit the risk of misdiagnosis in cases where a biopsy is not a reasonable option.

Descriptive Epidemiology of Ependymal Tumors in Gironde, France: Results from the Gironde Registry for the 2000-2018 Period.

BACKGROUND: The Gironde Central Nervous System (CNS) Tumor Registry, in collaboration with the French National Cancer Institute, is the largest population-based registry focused exclusively on primary CNS tumors in France and represents a population of 1.62 million. This report focuses on ependymal tumors to refine current knowledge and provide up-to-date data on the epidemiology of these rare tumors. MATERIAL AND METHODS: All of the ependymal tumors were extracted from the Gironde CNS Tumor Registry for the years 2000-2018. Demographic and clinical characteristics, incidence rates, and time trends as well as survival outcomes were analyzed. RESULTS: One hundred forty-four ependymal tumors were retrieved, which represented 2.3% of all the CNS tumors recorded in the same period. Histological subtype was significantly dependent on age and topography in the CNS. The median age at diagnosis was 46 years. The annual incidence rates varied between 0.15/100,000 (2004) and 0.96/100,000 (2016), with a significant increase over the study period by 4.67% per year. Five-year and 10-year OS rates were 87% and 80%, respectively. CONCLUSION: An increase in the incidence of ependymal tumors was observed over the past two decades. Further studies are needed to confirm this result and provide etiological clues.

A case series of percutaneous transforamen ovale biopsies in cavernous sinus lesions.

BACKGROUND: The majority of cavernous sinus lesions are meningiomas, for which treatment (fractioned radiotherapy or radiosurgery), if indicated, is usually initiated upon image-based diagnosis. However, this region can be affected by a wide variety of pathological processes and the risk of misdiagnosis exists. As pathological diagnosis can be obtained by biopsy through the foramen ovale in selected cases, we asked the question as to whether systematically performing this procedure before treatment would provide additional, relevant diagnostic information. METHODS: All the cases referred to our department between January 2008 and December 2019 for cavernous sinus lesions that were considered for treatment and anatomically suitable for transforamen ovale biopsy were included. Outcomes and subsequent treatment or follow-up data were collected. RESULTS: Thirty-five patients were included. Twenty-six were highly suspected to have meningioma or schwannoma at imaging, among whom biopsy allowed diagnosis confirmation in 17 cases (65%). For the nine patients for whom biopsy was indicated upon suspected malignancy or inflammatory disease on imaging, biopsy revealed three meningiomas and one lymphoma and was not contributory in five cases (56%), three of which underwent open surgery. Three patients (8.5%) had persistent neuralgia at the last follow-up. CONCLUSIONS: When cavernous sinus meningioma or schwannoma is highly suspected upon predefined imaging criteria by an experienced neuroradiologist, invasive exploration before treatment does not seem to be indicated. Otherwise, transforamen ovale biopsy might be consider in selected cases as a minimally invasive option to obtain pathological analysis.

Prevalence, Severity, and Clinical Management of Brain Incidental Findings in Healthy Young Adults: MRi-Share Cross-Sectional Study.

Background and Objectives: Young adults represent an increasingly large proportion of healthy volunteers in brain imaging research, but descriptions of incidental findings (IFs) in this age group are scarce. We aimed to assess the prevalence and severity of IFs on brain MRIs of healthy young research participants aged 18-35 years, and to describe the protocol implemented to handle them. Methods: The study population comprised 1,867 participants aged 22.1 ± 2.3 years (72% women) from MRi-Share, the cross-sectional brain MRI substudy of the i-Share student cohort. IFs were flagged during the MRI quality control. We estimated the proportion of participants with IFs [any, requiring medical referral, potentially serious (PSIFs) as defined in the UK biobank]: overall, by type and severity of the final diagnosis, as well as the number of IFs. Results: 78/1,867 participants had at least one IF [4.2%, 95% Confidence Interval (CI) 3.4-5.2%]. IFs requiring medical referral (n = 38) were observed in 36/1,867 participants (1.9%, 1.4-2.7%), and represented 47.5% of the 80 IFs initially flagged. Referred IFs were retrospectively classified as PSIFs in 25/1,867 participants (1.3%, 0.9-2.0%), accounting for 68.4% of anomalies referred (26/38). The most common final diagnosis was cysts or ventricular abnormalities in all participants (9/1,867; 0.5%, 0.2-0.9%) and in those with referred IFs (9/36; 25.0%, 13.6-41.3%), while it was multiple sclerosis or radiologically isolated syndrome in participants with PSIFs (5/19; 26.3%, 11.5-49.1%) who represented 0.1% (0.0-0.4%) and 0.2% (0.03-0.5%) of all participants, respectively. Final diagnoses were considered serious in 11/1,867 participants (0.6%, 0.3-1.1%). Among participants with referred IFs, 13.9% (5/36) required active intervention, while 50.0% (18/36) were put on clinical surveillance. Conclusions: In a large brain imaging study of young healthy adults participating in research we observed a non-negligible frequency of IFs. The etiological pattern differed from what has been described in older adults.

Occupational exposure to pesticides and central nervous system tumors: results from the CERENAT case-control study.

BACKGROUND: The etiology of the central nervous system (CNS) tumors remains largely unknown. The role of pesticide exposure has been suggested by several epidemiological studies, but with no definitive conclusion. OBJECTIVE: To analyze associations between occupational pesticide exposure and primary CNS tumors in adults in the CERENAT study. METHODS: CERENAT is a multicenter case-control study conducted in France in 2004-2006. Data about occupational pesticide uses-in and outside agriculture-were collected during detailed face-to-face interviews and reviewed by experts for consistency and exposure assignment. Odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated with conditional logistic regression. RESULTS: A total of 596 cases (273 gliomas, 218 meningiomas, 105 others) and 1 192 age- and sex-matched controls selected in the general population were analyzed. Direct and indirect exposures to pesticides in agriculture were respectively assigned to 125 (7.0%) and 629 (35.2%) individuals and exposure outside agriculture to 146 (8.2%) individuals. For overall agricultural exposure, we observed no increase in risk for all brain tumors (OR 1.04, 0.69-1.57) and a slight increase for gliomas (OR 1.37, 0.79-2.39). Risks for gliomas were higher when considering agricultural exposure for more than 10 years (OR 2.22, 0.94-5.24) and significantly trebled in open field agriculture (OR 3.58, 1.20-10.70). Increases in risk were also observed in non-agricultural exposures, especially in green space workers who were directly exposed (OR 1.89, 0.82-4.39), and these were statistically significant for those exposed for over 10 years (OR 2.84, 1.15-6.99). DISCUSSION: These data support some previous findings regarding the potential role of occupational exposures to pesticides in CNS tumors, both inside and outside agriculture.

Multimodal management of surgery- and radiation-refractory meningiomas: an analysis of the French national tumor board meeting on meningiomas cohort.

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.

Spatial mechanistic modeling for prediction of the growth of asymptomatic meningiomas.

BACKGROUND AND OBJECTIVE: Mathematical modeling of tumor growth draws interest from the medical community as they have the potential to improve patients' care and the use of public health resources. The main objectives of this work are to model the growth of meningiomas - slow-growing benign tumors requiring extended imaging follow-up - and to predict tumor volume and shape at a later desired time using only two times examinations. METHODS: We develop two variants of a 3D partial differential system of equations (PDE) which yield after a spatial integration systems of ordinary differential equations (ODE) that relate tumor volume with time. Estimation of models parameters is a crucial step to obtain a personalized model for a patient that can be used for descriptive or predictive purposes. As PDE and ODE systems share the same parameters, they are both estimated by fitting the ODE systems to the tumor volumes obtained from MRI examinations acquired at different times. A population approach allows to compensate for sparse sampling times and measurement uncertainties by constraining the variability of the parameters in the population. RESULTS: Description capabilities of the models are investigated in 39 patients with benign asymptomatic meningiomas who had had at least three surveillance MRI examinations. The two models can fit to the data accurately and more realistically than a naive linear regression. Prediction performances are validated for 33 patients using a population approach. Mean relative errors in volume predictions are less than 10% with ODE systems versus 12.5% with the naive linear model using only two times examinations. Concerning the shape, the mean Sørensen-Dice coefficients are 85% with the PDE systems in a subset of 10 representative patients. CONCLUSIONS: Our strategy - based on personalization of mathematical model - provides a good insight on meningioma growth and may help decide whether to extend the follow-up or to treat the tumor.

Prognostic Value of Histopathological Features and Loss of H3K27me3 Immunolabeling in Anaplastic Meningioma: A Multicenter Retrospective Study.

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

Increased Incidence of Intracranial Meningiomas in Patients With Acromegaly.

BACKGROUND: An increased incidence of various neoplasms has been described in patients with acromegaly, and there is evidence to suggest that growth factors are risk factors for the development of meningiomas. OBJECTIVE: To study if patients with acromegaly are more at risk for developing intracranial meningiomas. METHODS: We conducted an observational study on 221 consecutive acromegalic patients recruited between January 1, 2000 and December 31, 2015, and 357 consecutive patients with a nonsomatotropic pituitary adenoma recruited between March 1, 2015 and December 31, 2016, in our institution. Patients underwent a gadolinium-enhanced 3D T1 brain magnetic resonance imaging to look for meningiomas. The proportion of meningiomas was compared between the 2 groups, and the standardized incidence ratio (SIR) was computed from the incidence rates of meningiomas observed in the population of acromegalic patients and compared to that of the general population given by the local registry of central nervous system tumors. RESULTS: Patients with acromegaly had a significant risk for developing intracranial meningiomas as compared to patients without acromegaly (7.7% vs 2.2%, P = .005, OR = 3.45 [1.46; 8.15]). There was a significant increased incidence of intracranial meningiomas in patients with acromegaly (SIR = 126 [25; 367]) as compared to the general population. CONCLUSION: Our study suggests strongly that patients with acromegaly are more at risk for developing intracranial meningiomas.

Combining 3'-Deoxy-3'-[18F] fluorothymidine and MRI increases the sensitivity of glioma volume detection.

OBJECTIVE: 3'-Deoxy-3'-[18F] fluorothymidine (18F-FLT) is a marker of cell proliferation and displays a high tumor-to-background ratio in brain tumor lesions. We determined whether combining 18F-FLT PET and MRI study improves the detection of tumoral tissue compared to MRI alone and whether 18F-FLT uptake has a prognostic value by studying its association with histopathological features. METHODS: Thirteen patients with a supratentorial malignant glioma were recruited and scheduled for surgery. The tumor volume was defined in all patients on both 18F-FLT PET and MRI images. The images were coregistered and uploaded onto a neuronavigation system. During surgery, an average of 11 biopsies per patient were taken in regions of the brain that were positive to one or both imaging modalities, as well as from control peritumoral regions. The standardized uptake values (SUVs) of each biopsy region were correlated to histopathological data (i.e., proliferation index and number of mitoses) and the SUV values of high and low-grade samples were compared. RESULTS: Out of a total of 149 biopsies, 109 contained tumoral tissue at histopathological analysis. The positive predictive value was 93.1% for MRI alone and 78.3% for MRI and PET combined. In addition, 40% of the biopsy samples taken from areas of the brain that were negative at both PET and MRI had evidence of malignancy at pathology. The SUV values were not significantly correlated to either the proliferation index or the number of mitoses, and could not differentiate between high- and low-grade samples. CONCLUSION: In patients with newly diagnosed glioma, a combination of MRI and 18F-FLT-PET detects additional tumoral tissue and this may lead to a more complete surgical resection. Also, the addition of a negative PET to a negative MRI increases the negative predictive value. However, 18F-FLT still underestimated the margins of the lesion and did not correlate with histopathological features.

Coexistence of schwannomatosis and glioblastoma in two families.

Schwannomatosis is a rare affection predisposing to multiple peripheral neurologic tumors development. Approximatively, one third of patients with schwannomatosis are carriers of a germline mutation in LZTR1 (Leucin Zipper Transcription Regulator 1). Tumorigenesis in schwannomatosis responds to a somatic 5-hit/3-step mechanism resulting in a loss of function (LOF) of LZTR1 and the contiguous genes of locus 22q11.2q12.2. Effectively, LZTR1 is mapped on 22q11.2 and centromeric to SMARCB1 also implicated in the determinism of schwannomatosis and NF2, responsible for neurofibromatosis type 2. On a somatic point of view, LZTR1 mutations are known to drive with a significant frequency glioblastoma (GB) development. We report here two families in which segregate both multiple schwannomas and GB. In the first family, the proband received a diagnosis with of schwannomatosis after a surgery for a lumbar schwannoma at age 43, molecularly confirmed by identification of a germline heterozygous mutation in LZTR1. Her father, having unremarkable medical history deceased from an apparently isolated GB at age 59. In the second family, LZTR1-related schwannomatosis was diagnosed in the index case at age 70 after multiple schwannomas surgeries. Her elder sister had no neurological medical history before occurrence of a lethal GB at age 78. Molecular analysis of GB sample from both affected relatives showed the presence of the familial mutation. These observations hypothesize a potential link between schwannomatosis and the GB development.

The molecular landscape of glioma in patients with Neurofibromatosis 1.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.

Increasing incidence of central nervous system (CNS) tumors (2000-2012): findings from a population based registry in Gironde (France).

BACKGROUND: Although some countries have observed a stabilization in the incidence of CNS, an increasing incidence has been reported from multiple studies. Recent observations point out to the heterogeneity of incidence trends according to histological subtypes, gender and age-groups. Using a high-quality regional CNS tumor registry, this article describes the trends of CNS tumor incidence for main histological subtypes, including benign and malignant tumors, in the French department of Gironde from 2000 to 2012. METHODS: Crude and age-standardized incidence rates were calculated globally, by histological subtypes, malignant status, gender and age groups. For trends, annual percent changes (APC) were obtained from a piecewise log-linear model. RESULTS: A total of 3515 CNS tumors was registered during the period. The incidence of overall CNS tumors was 19/100000 person-years (8.3/100000 for neuroepithelial tumors and 7.3/100000 for meningeal tumors). An increased incidence of overall CNS tumors was observed from 2000 to 2012 (APC = + 2.7%; 95%-confidence interval (CI): 1.8-3.7). This trend was mainly explained by an increase in the incidence of meningiomas over the period (APC = + 5.4%, 95%-CI: 3.8-7.0). The increased incidence rate of CNS tumors was more pronounced in female and in older patients even though the incidence rate increased in all age groups. CONCLUSIONS: Part of the temporal variation may be attributed to improvement in registration, diagnosis and clinical practices but also to changes in potential risk factors. Thus, etiological studies on CNS tumors are needed to clarify this rising trend.

Contralateral Transcranial Approach to Tuberculum Sellae Meningiomas: Long-Term Visual Outcomes and Recurrence Rates.

BACKGROUND: One of the most challenging aspects of the surgical treatment of tuberculum sellae meningioma is to control the involvement of the inferomedial side of the optic nerve, which is not directly visualized by an ipsilateral approach and thus requires optic nerve mobilization. METHODS: Between 2003 and 2017, 21 consecutive patients were operated on using this approach. The surgical technique is described and the visual outcomes, resection and recurrence rates, and complications are analyzed. RESULTS: Twenty patients were included, with a median follow-up of 5.6 years. Regarding visual outcomes, among the 19 patients who had a visual impairment before surgery, 14 (74%) improved, 2 were stabilized (10%), and 2 (10%) showed a worsening of the most-compromised optic nerve and 1 (5%) of the less-compromised optic nerve. Gross total resection was achieved in 18 patients (90%) and 1 patient experienced recurrence 10 years after the initial surgery. CONCLUSIONS: This approach allowed lower mobilization of the compromised optic nerve, better preservation of the vascularization of the visual pathways, and direct access to the inferomedial side of the optic nerve.