Distinct epigenetic and transcriptional profiles of Epstein-Barr virus (EBV) positive and negative primary CNS lymphomas.

Background: Epstein-Barr virus (EBV)+ and EBV- primary CNS lymphomas (PCNSL) carry distinct mutational landscapes, but their transcriptional and epigenetic profiles have not been integrated and compared. This precludes further insights into pathobiology and molecular differences, relevant for classification and targeted therapy.

Methods: 23 EBV- and 15 EBV+ PCNSL, histologically classified as diffuse large B-cell lymphomas, were subjected to RNA-Sequencing and EPIC methylation arrays.

Factors influencing timely diagnosis in neurolymphomatosis.

Background: Neurolymphomatosis refers to infiltration of the peripheral nervous system (PNS) by non-Hodgkin lymphoma (NHL). Diagnostic intervals in neurolymphomatosis and factors delaying diagnosis have not been evaluated. We therefore aimed to analyze diagnostic intervals in a large cohort.

Clinical Presentation, Management, and Outcome in Neurolymphomatosis: A Systematic Review.

Background And Objectives: 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.

Favorable Radiographic Response in a Patient With an Oligodendroglioma Treated With Azacitidine and Venetoclax for Acute Myeloid Leukemia.

The standard chemotherapy for treating oligodendrogliomas consists of a combination of procarbazine, lomustine, and vincristine (PCV). The combination of hypomethylating agents like azacitidine and BCL2 inhibitors like venetoclax has not been formally studied in the treatment of glial tumors. The combination of these two drugs is commonly used to treat acute myeloid leukemia (AML), with IDH-mutant disease being a particularly sensitive subtype.

Atypical presentation of dysembryoplastic neuroepithelial tumor in an adult without epilepsy: a case report.

Dysembryoplastic neuroepithelial tumor (DNET) is a rare glioneuronal tumor usually found in the temporal lobe of children and young adults. DNETs are commonly associated with drug-resistant partial seizures, with most cases diagnosed before age 20. Asymptomatic brain tumors are rare in the general healthy population, and the frequency of incidental DNETs in adults remains unknown.

Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas.

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.

Vascular steal and associated intratumoral aneurysms in highly vascular brain tumors: illustrative case.

Background: Intratumoral aneurysms in highly vascular brain tumors can complicate resection depending on their location and feasibility of proximal control. Seemingly unrelated neurological symptoms may be from vascular steal that can help alert the need for additional vascular imaging and augmenting surgical strategies.

Observations: A 29-year-old female presented with headaches and unilateral blurred vision, secondary to a large right frontal dural-based lesion with hypointense signal thought to represent calcifications.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors.

Myasthenia Gravis in the Setting of Immune Checkpoint Inhibitor Therapy: Practical Considerations and Opinion-Based Approach to Acute Management.

Use of immune checkpoint inhibitors (ICI) is increasing in patients with oncologic disease. Three classes of checkpoint inhibitors exist: anti-PD1 (nivolumab, pembrolizumab), anti-CTLA4 (ipilimumab), and anti-PDL1 (atezolizumab, avelumab, durvalumab). ICI therapy has been used in multiple malignancies including renal cell cancer, non-small-cell lung cancer, and melanoma.

Treatment Options for Recurrent Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses.

Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors.

Background: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors.

Methods: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks.

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter.

Background: Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase III randomized CheckMate 548 study was to evaluate RT + TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587).

Methods: Patients (N = 716) were randomized 1:1 to NIVO [(240 mg every 2 weeks × 8, then 480 mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 once daily during RT, then 150-200 mg/m2 once daily on days 1-5 of every 28-day cycle × 6)] or PBO + RT + TMZ following the same regimen.

Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial.

Background: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter.

Methods: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/day 5/28 days during maintenance).

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143.

Background: The phase 1 cohorts (1c+1d) of CheckMate 143 (NCT02017717) evaluated the safety/tolerability and efficacy of nivolumab plus radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma.

Methods: In total, 136 patients were enrolled. In part A (safety lead-in), 31 patients ( = 15, methylated/unknown promoter; = 16, unmethylated promoter) received nivolumab and RT+TMZ (NIVO+RT+TMZ) and 30 patients with unmethylated promoter received NIVO+RT.

Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas.

High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas.

Clinical Reasoning: A 73-Year-Old Woman With Episodic Dysarthria and Horizontal Binocular Diplopia.

A 73-year-old woman presented with transient episodes of dysarthria and horizontal diplopia. She had stereotactic radiosurgery 18 years prior for a retroclival meningioma. Neurologic examination was notable for right-sided tongue deviation, tongue fasciculations, and intermittent impaired abduction of the right eye.

Clinical Reasoning: A 64-Year-Old Man With History of Meningitis Presenting With Proximal Weakness of the Arms.

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 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.

Choreoathetosis in the Setting of Human Herpesvirus-6 Infection in a Transplant Recipient.

Background: Human herpesvirus-6 (HHV-6) has been associated with various neurologic disorders, but movement disorders are rare. This case describes a patient who developed a choreoathetotic movement disorder in the setting of HHV-6 infection.

Case Report: A 72-year-old woman with AML and recent HHV-6 encephalitis following stem cell transplant presented with involuntary movements.

Hemorrhage Into a Subependymal Giant Cell Astrocytoma in an Adult With Tuberous Sclerosis: Case Report.

Background: We present an uncommon cause of intracranial hemorrhage in a young adult. Tuberous sclerosis complex is a rare genetic disorder characterized by skin changes, benign systemic or central nervous system tumors [subependymal giant cell astrocytoma (SEGA)], mental retardation, or epilepsy. Hemorrhage into SEGA is exceedingly rare.

ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody.

The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting of brain tumors with an anti-DNA autoantibody. Deoxymab-1 (DX1) is a DNA-damaging autoantibody that localizes to tumors and is synthetically lethal to cancer cells with defects in the DNA damage response.

Exome sequencing identifies SLIT2 variants in primary CNS lymphoma.

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-naïve PCNSL patients, we identified novel SLIT2 variants (p.N63S, p.

Neurotoxicities associated with immune checkpoint inhibitor therapy.

Introduction: Immune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal complications of ICIs, and clinical experience is limited. The aim of this study is to further define the clinical spectrum and outcome of ICI-mediated neurotoxicities.

Extent and prognostic value of MGMT promotor methylation in glioma WHO grade II.

MGMT promotor methylation is associated with favourable outcome in high-grade glioma. In glioma WHO grade II, it is unclear whether the extent of MGMT promotor methylation and its prognostic role is independent from other molecular markers. We performed a retrospective analysis of 155 patients with glioma WHO grade II.

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice.