cIMPACT-NOW update 11: Proposal on adaptation of diagnostic criteria for IDH- and H3-wildtype diffuse high-grade gliomas and for posterior fossa ependymal tumors.

The Consortium to Inform Molecular and Practical Approaches to Central Nervous System Tumor Taxonomy (cIMPACT-NOW) updates provide guidelines for the diagnosis of central nervous system (CNS) tumors and suggestions for future World Health Organization (WHO) classification. Following publication of the fifth edition WHO Classification of CNS Tumors (WHO CNS5) in 2021, the cIMPACT-NOW working group "Clarification" reviewed WHO CNS5 and prioritized two topics for further elucidation: (a) distinction of Glioblastoma, IDH-wildtype from Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype and (b) clarification of subgroups of posterior fossa (PF) ependymal tumors. Recommendations regarding the IDH- and H3-wildtype diffuse high-grade gliomas include: (1) use caution assigning CNS WHO grade 4 (diagnosis of Glioblastoma, IDH-wildtype) to a "TERT promoter only", histologically low-grade, IDH-wildtype tumor; (2) EGFR gene amplification and +7/-10 chromosome copy number alterations should not be used as solitary defining features for diagnosing high-grade gliomas as Glioblastoma, IDH-wildtype in patients <40 years of age; (3) Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype should be considered in the differential diagnosis in adults, especially those <40 years of age; (4) PDGFRA alteration, EGFR alteration, or MYCN amplification count as key molecular features of Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype only in patients <25 years.

Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling.

The evolutionary processes that drive malignant progression of IDH-mutant astrocytomas remain unclear. Here, we performed multiomics on matched initial and recurrent tumor samples from a cohort of 105 patients and overlaid the data with detailed clinical annotation. We identified overlapping features associated with malignant progression that are derived from three molecular mechanisms: cell cycling, tumor cell (de)differentiation and remodeling of the extracellular matrix.

Long-term survival and cure fraction estimates for paediatric central nervous system tumours in 31 European countries (EUROCARE-6): a population-based study.

Background: Clinically relevant survival outcomes, including cure fraction estimates, and long-term survival outcomes of paediatric CNS tumours from large-scale databases have not been reported for Europe. Moreover, various biases hinder direct geographical comparisons, thereby limiting the effective translation of population-based findings into cancer care, surveillance, and research. We aimed to estimate these survival outcomes across Europe through the EUROCARE database.

Multi-modal analysis of pediatric pilocytic astrocytomas reveals tumor location-associated cellular and transcriptional heterogeneity.

Background: Pilocytic astrocytomas (PAs) are the most common pediatric central nervous system (CNS) tumors, which present with limited genetic but significant clinical heterogeneity. Current treatment strategies are partly effective, but tumors often progress, and patients experience long-term side effects, highlighting the need for additional novel therapeutic approaches. A promising alternative approach could be targeting the tumor immune microenvironment (TIME), however, a comprehensive overview of the TIME of PAs across different anatomical tumor locations is currently lacking.

Dual targeting of / and / immune checkpoints potentiates NK cell-mediated cytotoxicity in medulloblastoma.

Background: Medulloblastoma (MB) is one of the most prevalent pediatric brain malignancies and makes up approximately 20% of all primary brain tumors in children. Current treatment options are not curative for approximately 30% of patients and leave survivors with an impaired quality of life. Immune checkpoint inhibition can offer a novel targeted therapy but largely remains understudied in MB.

Advancing CNS tumor diagnostics with expanded DNA methylation-based classification.

DNA methylation-based classification is integral to contemporary neuro-oncological diagnostics, as highlighted by the current World Health Organization (WHO) classification of central nervous system (CNS) tumors. We introduce the Heidelberg CNS Tumor Methylation Classifier version 12.8 (v12.

Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency.

Constitutional mismatch repair deficiency (CMMRD), caused by bi-allelic germline variants in mismatch repair (MMR) genes, is associated with high cancer incidence early in life. A better understanding of mutational processes driving sequential CMMRD tumors can advance optimal treatment. Here, we describe a genomic characterization on a representative collection of CMMRD-associated tumors consisting of 41 tumors from 17 individuals.

Molecular signatures define BAP1-altered meningioma as a distinct CNS tumor with deregulation of Polycomb repressive complex target genes.

Background: Meningiomas are the most common primary intracranial neoplasms, with highly variable patient outcomes. While most meningiomas are benign, a significant subset recurs postoperatively, presenting substantial treatment challenges. BAP1 gene inactivation has been suggested as a marker for aggressive meningiomas, although its precise molecular and clinical roles remain poorly understood.

Do we need B7-H3 immunohistochemistry for the inclusion of children with high-grade central nervous system tumors in clinical trials targeting B7-H3?

Background: Pediatric high-grade central nervous system (pHG-CNS) tumors are the leading cause of childhood cancer-related deaths, partly due to poor response to standard treatments. B7-H3 is reportedlyexpressed in pHG-CNS tumors, making antigen-targeting therapies, including anti-B7-H3 chimeric antigen receptor T-cell (CAR-T) therapy, promising. However, given substantial inter-tumoral protein expression diversity in CNS tumors, it's unclear which patients might benefit from these treatments.

Comparative Clinical and Imaging-Based Evaluation of Therapeutic Modalities in CNS Embryonal Tumours With PLAGL Amplification.

Aims: Embryonal tumours with PLAGL1 or PLAGL2 amplification (ET, PLAGL) show substantial heterogeneity regarding their clinical characteristics and have been treated inconsistently, resulting in diverse outcomes. In this study, we aimed to evaluate the clinical behaviour of ET, PLAGL and elucidate their response pattern across the different applied treatment regimens.

Methods: We conducted an in-depth retrospective analysis of clinical and serial imaging data of 18 patients with ET, PLAGL (nine each of PLAGL1 and PLAGL2 amplified).

Chromosome 1p Loss and 1q Gain for Grading of Meningioma.

Importance: The World Health Organization (WHO) classification of central nervous system tumors (CNS) grading for meningioma was updated in 2021 to include rare molecular features, namely homozygous deletions of CDKN2A or CDKN2B and TERT promotor alterations. Previous work, including the cIMPACT-NOW statement, has discussed the potential value of including chromosomal copy number alterations to help refine the current grading system.

Objective: To identify chromosomal copy number alterations that could be used to improve the current CNS WHO grading of meningioma.

cIMPACT-NOW update 9: Recommendations on utilization of genome-wide DNA methylation profiling for central nervous system tumor diagnostics.

Genome-wide DNA methylation signatures correlate with and distinguish central nervous system (CNS) tumor types. Since the publication of the initial CNS tumor DNA methylation classifier in 2018, this platform has been increasingly used as a diagnostic tool for CNS tumors, with multiple studies showing the value and utility of DNA methylation-based classification of CNS tumors. A Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) Working Group was therefore convened to describe the current state of the field and to provide advice based on lessons learned to date.

IDH-mutant astrocytomas with primitive neuronal component have a distinct methylation profile and a higher risk of leptomeningeal spread.

IDH-mutant astrocytomas are diffuse gliomas that are defined by characteristic mutations in IDH1 or IDH2 and do not have complete 1p/19q co-deletion. The established grading criteria include histological features of brisk mitotic activity (grade 3) and necrosis and/or microvascular proliferation (grade 4). In addition, homozygous deletion of the CDKN2A/B locus has recently been implemented as a molecular marker for grade 4 IDH-mutant astrocytomas.

Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma.

Isocitrate dehydrogenase 1/2 mutant (IDHmt) astrocytoma is considered a T cell-deprived tumor, yet little is known regarding the phenotypes underlying T cell exclusion. Using bulk, single nucleus and spatial RNA and protein profiling, we demonstrate that a distinct spatial organization underlies T cell confinement to the perivascular space (T cell cuff) in IDHmt astrocytoma. T cell cuffs are uniquely characterized by a high abundance of gemistocytic tumor cells (GTC) in the surrounding stroma.

Pathological diagnosis of central nervous system tumours in adults: what's new?

In the course of the last decade, the pathological diagnosis of many tumours of the central nervous system (CNS) has transitioned from a purely histological to a combined histological and molecular approach, resulting in a more precise 'histomolecular diagnosis'. Unfortunately, translation of this refinement in CNS tumour diagnostics into more effective treatment strategies is lagging behind. There is hope though that incorporating the assessment of predictive markers in the pathological evaluation of CNS tumours will help to improve this situation.

VGLL fusions define a new class of intraparenchymal central nervous system schwannoma.

Background: Intracerebral schwannomas are rare tumors resembling their peripheral nerve sheath counterparts but localized in the central nervous system (CNS). They are not classified as a separate tumor type in the 2021 World Health Organization classification. This study aimed to compile and characterize these rare neoplasms morphologically and molecularly.

M&M: an RNA-seq based pan-cancer classifier for paediatric tumours.

Background: With many rare tumour types, acquiring the correct diagnosis is a challenging but crucial process in paediatric oncology. Historically, this is done based on histology and morphology of the disease. However, advances in genome wide profiling techniques such as RNA sequencing now allow the development of molecular classification tools.

European Association of Neuro-Oncology guideline on molecular testing of meningiomas for targeted therapy selection.

Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy.

Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype.

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed.

Preoperative prediction of diffuse glioma type and grade in adults: a gadolinium-free MRI-based decision tree.

Objectives: To develop a gadolinium-free MRI-based diagnosis prediction decision tree (DPDT) for adult-type diffuse gliomas and to assess the added value of gadolinium-based contrast agent (GBCA) enhanced images.

Materials And Methods: This study included preoperative grade 2-4 adult-type diffuse gliomas (World Health Organization 2021) scanned between 2010 and 2021. The DPDT, incorporating eleven GBCA-free MRI features, was developed using 18% of the dataset based on consensus readings.

Updated EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection-Update 1.

The standard of care for adult patients with gliomas, glioneuronal, and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a major part of the standard treatment; however, the predictive significance of most of the targets for treatment in systemic cancer is less well-established in central nervous system tumors. In 2023 the European Association for NeuroOncology (EANO) Guideline Committee presented evidence-based recommendations for rational testing of molecular targets for targeted treatments.