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While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7- expressing neural crest. Somatic and inherited mutations disrupt TRAF7–IFT57 interactions leading to cilia degradation. TRAF7 -mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7 -driven meningiomas and developmental heart defects.

Background and purpose Population‐based studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccines may trigger immune‐mediated thrombotic thrombocytopenia (VITT) raising concerns for other autoimmune responses. The aim was to characterize neurological autoimmunity after SARS‐CoV‐2 vaccinations. Methods In this single‐centre prospective case study patients with neurological autoimmunity in temporal association (≤6 weeks) with SARS‐CoV‐2 vaccinations and without other triggers are reported. Clinical, laboratory and imaging data were collected with a median follow‐up of 49 days. Results In the study period 232,603 inhabitants from the main catchment area of our hospital (Rhein‐Neckar‐Kreis, county) received SARS‐CoV‐2 vaccinations. Twenty‐one cases (new onset n = 17, flares n = 4) diagnosed a median of 11 days (range 3–23) following SARS‐CoV‐2 vaccinations (BNT162b2 n = 12, ChAdOx1 n = 8, mRNA‐1273 n = 1) were identified. Cases included VITT with cerebral venous sinus thrombosis (n = 3), central nervous system demyelinating diseases (n = 8), inflammatory peripheral neuropathies (n = 4), myositis (n = 3), myasthenia (n = 1), limbic encephalitis (n = 1) and giant cell arteritis (n = 1). Patients were predominantly female (ratio 3.2:1) and the median age at diagnosis was 50 years (range 22–86). Therapy included administration of steroids (n = 15), intravenous immunoglobulins in patients with Guillain–Barré syndrome or VITT (n = 4), plasma exchange in cases unresponsive to steroids (n = 3) and anticoagulation in VITT. Outcomes were favourable with partial and complete remissions achieved in 71% and 24%, respectively. Two patients received their second vaccination without further aggravation of autoimmune symptoms under low‐dose immunosuppressants. Conclusions In this study various neurological autoimmune disorders encountered following SARS‐CoV‐2 vaccinations are characterized. Given the assumed low incidence and mostly favourable outcome of autoimmune responses, the benefits of vaccinations outweigh the comparatively small risks., In this prospective case study, 21 consecutive cases of neurological autoimmunity, which occurred 3–23 days following SARS‐CoV‐2 vaccinations (BNT162b2 n = 12, ChAdOx1 n = 8, mRNA‐1273 n = 1), are reported. Cases included vaccine‐induced immune thrombotic thrombocytopenia (n = 3), central nervous system demyelinating diseases (n = 8), inflammatory peripheral neuropathies (n = 4), myositis (n = 3), myasthenia (n = 1), limbic encephalitis (n = 1) and giant cell arteritis (n = 1). As outcomes were favourable in most patients and the risk of autoimmune complications appears low (

Population-based studies suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may trigger neurological autoimmunity including immune-mediated thrombotic thrombocytopenia. Long-term characterization of cases is warranted to facilitate patient care and inform vaccine-hesitant individuals.In this single-center prospective case study with a median follow-up of 387 days long-term clinical, laboratory and imaging characteristics of patients with neurological autoimmunity diagnosed in temporal association (≤6 weeks) with SARS-CoV-2 vaccinations are reported.Follow-up data were available for 20 cases (central nervous system demyelinating diseases n = 8, inflammatory peripheral neuropathies n = 4, vaccine-induced immune thrombotic thrombocytopenia n = 3, myositis n = 2, myasthenia n = 1, limbic encephalitis n = 1, giant cell arteritis n = 1). Following therapy, the overall disability level improved (median modified Rankin Scale at diagnosis 3 vs. 1 at follow-up). The condition of two patients worsened despite immunosuppressants possibly related to their autoimmune diagnoses (limbic encephalitis n = 1, giant cell arteritis n = 1). At 12 months' follow-up, 12 patients achieved complete clinical remissions with partial responses in five and stable disease in one case. Correspondingly, autoimmune antibodies were non-detectable or titers had significantly lowered in all, and repeat imaging revealed radiological responses in most cases. Under vigilant monitoring 15 patients from our cohort underwent additional SARS-CoV-2 vaccinations (BNT162b2 n = 12, mRNA-1273 n = 3). Most patients (n = 11) received different vaccines than prior to diagnosis of neurological autoimmunity. Except for one short-lasting relapse, which responded well to steroids, re-vaccinations were well tolerated.In this study long-term characteristics of neurological autoimmunity encountered after SARS-CoV-2 vaccinations are defined. Outcome was favorable in most cases. Re-vaccinations were well tolerated and should be considered on an individual risk/benefit analysis.

Background: Brain-tumor-initiating cells (BTICs) of proneural and mesenchymal origin contribute to the highly malignant phenotype of glioblastoma (GB) and resistance to current therapies. Methods: BTICs of different subtypes representing tumor heterogeneity were challenged with OXPHOS (oxidative phosphorylation) inhibition to assess the differential effects of metabolic intervention on key resistance features. Results: Whereas mesenchymal BTICs were more invasive, more glycolytic and less responsive to OXPHOS-inhibition, proneural BTICs were less invasive, catabolized glucose more via the pentose phosphate pathways, and responded better to OXPHOS inhibition. Conclusion: Targeting glycolysis may be a promising approach to inhibit highly invasive tumor cells of mesenchymal origin, whereas proneural cells are more responsive to OXPHOS inhibition. Future clinical trials exploring metabolic interventions should account for metabolic heterogeneity of brain tumors to overcome resistance to current treatments.

Background and purpose Primary melanotic tumors of the nervous system (PMTNS) are thought to be an exceedingly rare group of tumors not captured by tumor registries. We aimed to determine relative incidence, clinical presentation, diagnostic findings, patient management, and outcome. Methods We retrospectively searched the database of the Section of Neuro-Oncology at the Yale Cancer Center for patients with primary or metastatic melanotic lesions of the nervous system. For patients with PMTNS, we recorded demographic data, clinical presentation, histopathological and imaging findings, therapy, and outcome. Results A total of 116 patients with melanotic lesions were identified, including four patients with PMTNS. The relative incidence of PMTNS was therefore calculated as 3.4%. Histology of PMTNS patients revealed melanocytoma in three patients and psammomatous melanotic schwannoma in one patient. Symptoms were non-specific and attributed to tumor mass effect. Magnetic resonance imaging showed hyperintensity on pre-contrast T1-weighted imaging, hypointensity on T2-weighted imaging, and homogenous contrast enhancement in all PMTNS patients. Definitive diagnosis was based on tissue analysis, with detection of melanin-containing cells on conventional histology and S100-positivity on immunohistochemistry. Molecular analysis for GNAQQ209L mutation assisted in establishing diagnosis when only small amounts of tissue were available. Aggressive surgical treatment showed favorable outcomes in all cases; radiation therapy was used for residual or relapsed disease. The median follow-up was 7.5 ± 5 years, and all patients were alive on the day of database closure. Conclusion Primary melanotic tumors of the nervous system are rare nervous system tumors. Outcome appears excellent, and complete surgical resection may form the basis for favorable outcome. Radiation therapy may represent a therapeutic approach for residual or relapsed disease.

Recent studies suggest a relatively high prevalence of autoimmune disorders (AD) among primary CNS lymphoma (PCNSL) patients, however, the literature is limited to case reports. To gain a better understanding of AD-PCNSL we reviewed and analyzed all cases described in the literature. We searched the MEDLINE database using the search terms ‘central nervous system lymphoma’ or ‘CNS lymphoma’ along with AD-related terms. We selected 39 records for qualitative synthesis of data and identified 50 AD-PCNSL. Clinical, imaging and outcome data were collected. Overall survival (OS) was analyzed with the Kaplan–Meier method. Univariate and multivariate analyses were performed using log rank test and Cox proportional hazard model. Most common AD were systemic lupus erythematosus (24%), multiple sclerosis (16%), and myasthenia gravis (14%). All patients had received immunosuppressants for their AD. Median interval from AD until PCNSL diagnosis was 108 months (range: 11–420). Male-to-female ratio was 0.42 and AD-PCNSL was diagnosed at a median age of 57 years (range: 2–88). On imaging lesions typically localized to the hemispheres (65%) and displayed peripheral enhancement (74%). Pathological evaluation revealed diffuse large-B-cell lymphoma (DLBCL) subtype (80%) and Epstein-Barr virus positivity (75%) in most AD-PCNSL. Median OS was 31 months. Age > 60 years (p = 0.014) was identified as a significant prognostic factor. AD requiring immunosuppression appear over-represented in the population of PCNSL patients. Aggressive polychemotherapy can accomplish long term OS in AD-PCNSL comparable to immunocompetent patients. Age > 60 may serve as a prognostic factor.

A 64-year-old man presented for evaluation of proximally pronounced weakness of the arms with preserved facial and lower extremity strength. Symptoms slowly developed over the last 2 years, and the patient's history was notable for severe Listeria monocytogenes meningitis 4 years before presentation, which was adequately treated with antibiotics. On examination, symptoms clinically reassembled man-in-the-barrel syndrome and localized to the cervicothoracic central cord. Blood analysis was unremarkable, and CSF analysis showed no recurrent or persistent infection. Spinal MRI revealed pockets of sequestered CSF from C3 to C4 and areas of CSF space effacement from C3 to T12. MRI findings were interpreted as cord tethering suggestive of adhesive arachnoiditis. CT myelogram showed insufficient contrast agent migration above T10 and contour irregularities of the conus medullaris, confirming the postulated pathomechanism of cord tethering. Final diagnosis was therefore cervicothoracic central cord damage due to cord tethering in the setting of postinfectious adhesive arachnoiditis following bacterial meningitis. The patient failed a course of pulsed methylprednisolone therapy, and symptoms progressed. Best supportive care was provided. The clinical presentation of adhesive arachnoiditis is variable, and advanced imaging techniques and invasive studies such as CT myelogram may be required to establish the diagnosis. Timely diagnosis is warranted as early surgical or medical therapy can improve symptoms.

Background Leptomeningeal dissemination (LD) in adults is an exceedingly rare complication of low-grade neuroepithelial CNS tumors (LGNs). We aimed to determine relative incidence, clinical presentation, and predictors of outcome. Methods We searched the quality control database of the Section of Neuro-Oncology, Yale Cancer Center, for patients with LGN (WHO grade I/II) seen between 2002 and 2017. For cases complicated by LD, we recorded demographics, clinical signs, histopathological diagnosis, and imaging findings. A comprehensive literature review was performed. Results Eleven consecutive patients with LD were identified, representing 2.3% of individuals with LGN seen at our institution between 2002 and 2017 (n = 475). Ependymoma was the predominant histological entity. Mean time interval from diagnosis of LGN to LD was 38.6 ± 10 months. Symptoms were mostly attributed to communicating hydrocephalus. Tumor deposits of LD were either nodular or linear with variable enhancement (nonenhancing lesions in 4 of 11 patients). Localized (surgery, radiosurgery, involved-field, or craniospinal radiation therapy) or systemic treatments (chemotherapy) were provided. All patients progressed radiographically. Median overall survival after LD was 102 months. Survival was prolonged when a combination of localized and systemic therapies was administered (188.5 vs 25.5 months; P = .03). Demographics and tumor spectrum reported in the literature were similar to our cohort. Conclusions LD is a rare complication of LGNs. A high level of suspicion is required for timely diagnosis as early symptoms are nonspecific and commonly do not occur until years after initial tumor diagnosis. Repeated aggressive treatment appears to be beneficial in improving survival.

SLIT2 constitutes a known tumour suppressor gene, which has not yet been implicated in the pathogenesis of primary central nervous system lymphoma (PCNSL). Performing exome sequencing on paired blood and tumour DNA samples from six treatment-naive PCNSL patients, we identified novel SLIT2 variants (p.N63S, p.T590M, p.T732S) that were associated with shorter progression-free survival in our cohort and shorter overall survival in a large validation cohort of lymphoid malignancies from the cBio Cancer Genomics Portal. WNT- and NF-κB-reporter luciferase assays suggest detected alterations are loss-of-function variants. Given the possible prognostic implications, the role of SLIT2 in PCNSL pathogenesis and progression warrants further investigation.

Primary CNS lymphoma (PCNSL) represents an extranodal variant of non-Hodgkin’s lymphoma (NHL) confined to the central nervous system (CNS) at diagnosis.1 Few cases of PCNSL following an initial diagnosis of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), an inflammatory CNS condition with suspected autoimmune aetiology, have previously been described in the literature.2–4 In a recent study, 13 of 42 presumptive CLIPPERS cases were eventually diagnosed with various CLIPPERS mimics.3 NHL represented the largest subset of CLIPPERS mimics including two cases of PCNSL. Whether PCNSL represents a CLIPPERS mimic or complication remains subject of ongoing discussion. Some authors hypothesised CLIPPERS could be an early phase of CNS lymphomatoid granulomatosis (LYG) with subsequent Epstein-Barr virus (EBV)-associated neoplastic transformation into CNS lymphoma.5 Characteristics of PCNSL following CLIPPERS remain poorly defined. Here, we analysed 10 cases and explored implications for CLIPPERS management and PCNSL outcome. A comprehensive review on PCNSL following CLIPPERS was independently conducted by two authors using the Medline database in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in August 2020. ‘CLIPPERS’ was used as the primary search term. Boolean operator ‘and’ was applied together with the secondary search term ‘lymphoma’ to narrow results. A total of 433 articles underwent screening for eligibility. Only cases with a diagnosis of ‘probable’ or ‘definite’ CLIPPERS according to updated diagnostic criteria and a tissue-based diagnosis of PCNSL or high-grade LYG were included.4 Eight articles matched inclusion criteria and were selected for data synthesis. One additional …

Background Clinical experience is limited for primary central nervous system (CNS) lymphoma that arises from the dura mater, which is denoted with the term primary dural lymphoma (PDL). This study was aimed at determining the relative incidence, presentation, and outcomes of PDL. Methods The institutional databases of the Divisions of Neuro-Oncology at the Massachusetts General Hospital and the Yale School of Medicine were retrospectively searched for patients with primary CNS lymphoma. Patients with pathologically confirmed dural lymphoma and no evidence of primary cerebral or systemic involvement were identified. Clinical data, diagnostic findings, treatments, and outcomes were recorded. Results A total of 20 patients with PDL were identified, and they represented 6.3% of the individuals with primary CNS lymphomas (20 of 316). Histopathological examination of PDL revealed the following underlying subtypes: diffuse large B-cell lymphoma (10 of 20 patients), marginal zone lymphoma (6 of 20), follicular lymphoma (2 of 20), undefined B-cell non-Hodgkin lymphoma (1 of 20), and T-cell non-Hodgkin lymphoma (1 of 20). On imaging, all tumors appeared as extra-axial masses with avid contrast enhancement and mostly mimicked meningioma. The median apparent diffusion coefficient value was 667 ± 26 mm2 /s. Cerebrospinal fluid analyses and symptoms were nonspecific, and the diagnosis rested on tissue analysis. Therapeutic approaches included surgery, radiotherapy, and chemotherapy. The median overall survival was not reached after 5 years. Three patients were deceased at database closure because of tumor progression. The extent of tumor resection correlated positively with overall survival (P = .044). Conclusions PDL is a rare variant of primary CNS lymphoma that can be radiographically mistaken for meningioma. The outcome is excellent with multimodality treatment, and aggressive surgery may convey a survival advantage in select cases.

BACKGROUND Recent studies suggest a relatively high prevalence of autoimmune diseases (AD) among primary CNS lymphoma (PCNSL) patients, however the literature is limited to case reports. To gain a better understanding of AD-associated PCNSL we reviewed all previous cases described in the literature. MATERIAL AND METHODS We mined the MEDLINE database using the search terms ‘central nervous system lymphoma’ or ‘CNS lymphoma’ along with AD-related terms, such as ‘immunosuppression’, ‘autoimmune’, the name of various AD, or commonly prescribed immunosuppressants. We selected 35 records for qualitative synthesis of data. We identified 43 AD-associated PCNSL in the literature and added five unpublished cases from our institution. Clinical, imaging and outcome data were collected. RESULTS Most prevalent ADs were systemic lupus erythematosus (22.9%), multiple sclerosis (18.8%) and myasthenia gravis (14.6%). Male-to-female ratio was 1:2 and median age at diagnosis was 57 years (range: 2.5–88). Most common immunosuppressants included prednisone (58.7%), mycophenolate (43.5%), and azathioprine (41.3%). Median interval from diagnosis of AD until diagnosis of PCNSL was 96 months (range: 11–360). Lesions typically localized to the hemispheres (64.1%) and displayed peripheral contrast enhancement (75.8%). Histology revealed diffuse large-B-cell lymphomas (76.7%) and Epstein-Barr virus (EBV) positivity (78.4%). Treatment included reduction of immunosuppression (100%) and chemotherapy (85.4%) in most cases. Median overall survival was 31 months. CONCLUSION AD-associated PCNSL are characterized by peripheral contrast enhancement on imaging and EBV positivity. AD that require severe immunosuppression appear over-represented. Median interval of immunosuppression and overall survival seem longer than in other immunodeficiency-associated PCNSL.

Immunodeficiency is a major risk factor for primary central nervous system lymphoma (PCNSL), but data on the disease in immunocompromised hosts are scarce. We aimed to define clinical and imaging features and determine prognostic factors for immunodeficiency-associated PCNSL.All PCNSL cases seen at Yale-New Haven Hospital between 2002 and 2017 were retrospectively screened for immunodeficiency. For patients with immunosuppression, biopsies were evaluated and clinical data were collected. Predictors of survival were identified using Kaplan-Meier survival analysis and log-rank test. p values 0.05 were considered significant.23 patients with immunodeficiencies were identified: eleven on immunosuppressants after solid organ transplantation, seven with human immunodeficiency virus infection, and five on immunosuppressive treatment due to various autoimmune disorders. PCNSL cases were largely Epstein-Barr-Virus positive (78%), histologically classified as diffuse large B cell lymphomas (87%), and showed peripheral contrast enhancement (81%) and corresponding heterogeneous diffusion-weighted imaging patterns (DWI) on magnetic resonance imaging (MRI) (71%). Median overall survival was 31 months. Age 60 years at diagnosis (p 0.01), peripheral enhancement of the mass on MRI (p = 0.04), heterogeneous DWI patterns (p = 0.04), and clonal immunoglobulin heavy chain gene rearrangement (IgHR) (p = 0.03) were found to be negative prognostic markers.Immunodeficiency-associated PCNSL presents with similar clinical, pathological and imaging features. Age 60 years, clonal IgHR, heterogeneous DWI pattern and peripheral enhancement on MRI may serve as predictors of less favorable outcome.

Nature Communications 8: Article number: 14433 (2017) Published online 14 February 2017; Updated 20 April 2018 In this Article, a subset of the H3K27ac ChIP-seq data (15 benign meningiomas and 2 dura samples (Sample IDs: MN-297, MN-288, MN-292, MN-163, MN-1037, MN-105, MN-201, MN-249, MN-191, MN-1066, MN-169, MN-291, MN-24, MN-79, MN-1044, CONTROL1, CONTROL2) was reported previously in a publication by the corresponding author1.

Neurolymphomatosis (NL) is defined as lymphomatous invasion of cranial or peripheral nerves by non-Hodgkin lymphoma (NHL). While most cases of NL are due to secondary dissemination from systemic or CNS sites, in rare cases it can be the primary manifestation of the malignancy.1–3 Early recognition of the disease and its precise neuroanatomic localization is critical for successful treatment.

Gliomas represent approximately 30\% of all central nervous system tumors and 80\% of malignant brain tumors(1). To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.