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cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.

Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.

Diffuse gliomas are aggressive brain tumors that respond poorly to immunotherapy including immune checkpoint inhibition. This resistance may arise from an immunocompromised microenvironment and deficient immune recognition of tumor cells because of low mutational burden. The most prominent genetic alterations in diffuse glioma are mutations in the isocitrate dehydrogenase (IDH) genes that generate the immunosuppressive oncometabolite d‐2‐hydroxyglutarate. Our objective was to explore the association between IDH mutation and presence of cells expressing the immune checkpoint proteins galectin‐9 and/or T cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3). Astrocytic gliomas of World Health Organization (WHO) grades III or IV (36 IDH‐mutant and 36 IDH‐wild‐type) from 72 patients were included in this study. A novel multiplex chromogenic immunohistochemistry panel was applied using antibodies against galectin‐9, TIM‐3, and the oligodendrocyte transcription factor 2 (OLIG2). Validation studies were performed using data from The Cancer Genome Atlas (TCGA) project. IDH mutation was associated with decreased levels of TIM‐3+ cells (p < 0.05). No significant association was found between galectin‐9 and IDH status (p = 0.10). Most TIM‐3+ and galectin‐9+ cells resembled microglia/macrophages, and very few TIM‐3+ and/or galectin‐9+ cells co‐expressed OLIG2. The percentage of TIM‐3+ T cells was generally low, however, IDH‐mutant tumors contained significantly fewer TIM‐3+ T cells (p < 0.01) and had a lower interaction rate between TIM‐3+ T cells and galectin‐9+ microglia/macrophages (p < 0.05). TCGA data confirmed lower TIM‐3 mRNA expression in IDH‐mutant compared to IDH‐wild‐type astrocytic gliomas (p = 0.013). Our results show that IDH mutation is associated with diminished levels of TIM‐3+ cells and fewer interactions between TIM‐3+ T cells and galectin‐9+ microglia/macrophages, suggesting reduced activity of the galectin‐9/TIM‐3 immune checkpoint pathway in IDH‐mutant astrocytic gliomas. [ABSTRACT FROM AUTHOR]

Deletions of chromosome arm 10q are found in most glioblastomas and subsets of lower grade gliomas. Mutations in the PTEN gene at 10q23.3 are restricted to less than half of the 10q-deleted gliomas, suggesting additional glioma-associated tumor suppressors on 10q. We investigated 64 astrocytic gliomas of different malignancy grades for aberrant expression of 16 micro RNAs ( miRNAs) on 10q. Thereby, we identified four miRNAs ( miR-107, miR-146b-5p, miR-346, miR-1287-5p) whose expression was frequently down-regulated in anaplastic astrocytomas and/or glioblastomas. DNA methylation analyses revealed 5′- CpG site hypermethylation of miR-346 in more than two-thirds of primary glioblastomas, while aberrant 5′- CpG site methylation of miR-146b-5p was frequent in IDH1-mutant astrocytomas and secondary glioblastomas. Overexpression of either of the four miRNAs in glioma cell lines reduced cell proliferation and/or increased caspase-3/7 activity. Expression analyses of miRNA overexpressing glioma cells and 3′-untranslated region luciferase reporter gene assays revealed evidence that these miRNAs post-transcriptionally regulate expression of glioma-relevant genes, including CDK6 ( miR-107), EGFR ( miR-146b-5p, miR-1287-5p), TERT and SEMA6A ( miR-346), all of which are overexpressed in malignant gliomas in situ. In summary, we show that the 10q-located miRNAs miR-107, miR-146b-5p, miR-346 and miR-1287-5p are frequently down-regulated in malignant gliomas and thereby may support overexpression of important glioma growth-promoting genes. [ABSTRACT FROM AUTHOR]