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.

Purpose: Primary central nervous system (CNS) gliomas can be classified by characteristic genetic alterations. In addition to solid tissue obtained via surgery or biopsy, cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) is an alternative source of material for genomic analyses. Experimental Design: We performed targeted next-generation sequencing of CSF cfDNA in a representative cohort of 85 patients presenting at two neurooncological centers with suspicion of primary or recurrent glioma. Copy-number variation (CNV) profiles, single-nucleotide variants (SNV), and small insertions/deletions (indel) were combined into a molecular-guided tumor classification. Comparison with the solid tumor was performed for 38 cases with matching solid tissue available. Results: Cases were stratified into four groups: glioblastoma (n = 32), other glioma (n = 19), nonmalignant (n = 17), and nondiagnostic (n = 17). We introduced a molecular-guided tumor classification, which enabled identification of tumor entities and/or cancer-specific alterations in 75.0% (n = 24) of glioblastoma and 52.6% (n = 10) of other glioma cases. The overlap between CSF and matching solid tissue was highest for CNVs (26%–48%) and SNVs at predefined gene loci (44%), followed by SNVs/indels identified via uninformed variant calling (8%–14%). A molecular-guided tumor classification was possible for 23.5% (n = 4) of nondiagnostic cases. Conclusions: We developed a targeted sequencing workflow for CSF cfDNA as well as a strategy for interpretation and reporting of sequencing results based on a molecular-guided tumor classification in glioma.

Neurolymphomatosis (NL) refers to lymphomatous infiltration of the peripheral nervous system (PNS). NL diagnosis and treatment are challenging given the broad differential diagnosis of peripheral neuropathy, the lack of larger cohorts, and the subsequent unavailability of prognostic factors or consensus therapy. This study aimed to define characteristics and prognostic factors of NL. A systematic review of the literature (2004-2023) was performed using PubMed and Scopus databases and reported following PRISMA guidelines. Studies reporting individual patient data on cases with definitive NL diagnosis were included. Clinical, radiologic, pathologic, and outcome information were extracted. Univariable and multivariable survival analyses were performed using log-rank tests and Cox proportional hazard models. A total of 459 NL cases from 264 studies were accumulated. NL was the first manifestation of malignancy (primary NL) in 197 patients. PNS relapse of known non-Hodgkin lymphoma (secondary NL) occurred in 262 cases after a median 12 months. NL predominantly presented with rapidly deteriorating, asymmetric painful polyneuropathy. Infiltrated structures included peripheral nerves (56%), nerve roots (52%), plexus (33%), and cranial nerves (32%). Diagnosis was established at a median of 3 months after symptom onset with substantial delays in primary NL. It mainly relied on PNS biopsy or FDG-PET, which carried high diagnostic yields (>90%). Postmortem diagnoses were rare (3%). Most cases were classified as B-cell (90%) lymphomas. Tumor-directed therapy was administered in 96% of patients and typically consisted of methotrexate or rituximab-based polychemotherapy. The median overall survival was 18 months. Primary NL without concurrent systemic disease outside the nervous system (hazard ratio [HR]: 0.44; 95% CI 0.25-0.78; p = 0.005), performance status (ECOG <2, HR: 0.30; 95% CI 0.18-0.52; p < 0.0001), and rituximab-based treatment (HR: 0.46; 95% CI 0.28-0.73; p = 0.001) were identified as favorable prognostic markers on multivariable analysis when adjusting for clinical and sociodemographic parameters. Advances in neuroimaging modalities, particularly FDG-PET, facilitate NL diagnosis and offer a high diagnostic yield. Yet, diagnostic delays in primary NL remain common. Rituximab-based therapy improves NL outcome. Findings may assist clinicians in early recognition, prognostic stratification, and treatment of NL.

Purpose: The EORTC-26101 study was a randomized phase II and III clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allow for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma. Experimental Design: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable with the overall study cohort in regard to baseline characteristics, study treatment, and survival. Results: Of patients' samples, 295/380 (78%) were classified into one of the main glioblastoma groups, receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared with mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment. Conclusions: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.

Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV⁺) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. In this study, a comprehensive genetic analysis of 22 EBV⁺ PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV⁺ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24–217) and 2 insertions/deletions (range 0–22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79–53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV⁻ PCNSL. Instead, EBV⁺ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV⁺ PCNSL. In addition to novel insights into the pathobiology of EBV⁺ PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.