bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023‒01‒15
fourteen papers selected by
Oltea Sampetrean
Keio University
  1. Phenotype Switching in Glioblastoma Promotes Therapy Escape.
  2. Specialized functions and sexual dimorphism explain the functional diversity of the myeloid populations during glioma progression.
  3. Olig1/2-expressing intermediate lineage progenitors are predisposed to PTEN/p53-loss-induced gliomagenesis and harbor specific therapeutic vulnerabilities.
  4. Phagocytosis of glioma cells enhances the immunosuppressive phenotype of bone marrow-derived macrophages.
  5. Objective response rate (ORR) targets for recurrent glioblastoma clinical trials based on the historic association between ORR and median overall survival.
  6. Reconciling the Contemporary Molecular Diagnosis of Glioblastoma With Past Clinical Trial Data.
  7. Targeting the IL4 Receptor with MDNA55 in Patients with Recurrent Glioblastoma: Results of a Phase 2b Trial.
  8. Antibodies to varicella-zoster virus and three other herpesviruses and survival in adults with glioma.
  9. Histological and Molecular Classifications of Pediatric Glioma with Time-dependent Diffusion MRI based Microstructural Mapping.
  10. Interaction of glioma-associated microglia/macrophages and anti-PD1 immunotherapy.
  11. EANO guideline on rational molecular testing of gliomas, glioneuronal and neuronal tumors in adults for targeted therapy selection.
  12. MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors.
  13. NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.
  14. Pediatric high-grade glioma MYCN is frequently associated with Li-Fraumeni syndrome.
  1. Cancer Discov. 2023 Jan 13. OF1
    Phenotype Switching in Glioblastoma Promotes Therapy Escape.
      A shift to a mesenchymal phenotype characterizes recurrence in glioblastoma and is mediated by AP1.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-005
  2. Cell Rep. 2023 Jan 10. pii: S2211-1247(22)01875-7. [Epub ahead of print]42(1): 111971
    Specialized functions and sexual dimorphism explain the functional diversity of the myeloid populations during glioma progression.
    Natalia Ochocka, Pawel Segit, Kamil Wojnicki, Salwador Cyranowski, Julian Swatler, Karol Jacek, Wiesława Grajkowska, Bozena Kaminska.
      Malignant gliomas are aggressive, hard-to-treat brain tumors. Their tumor microenvironment is massively infiltrated by myeloid cells, mostly brain-resident microglia, bone marrow (BM)-derived monocytes/macrophages, and dendritic cells that support tumor progression. Single-cell omics studies significantly dissected immune cell heterogeneity, but dynamics and specific functions of individual subpopulations were poorly recognized. We use Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) to precisely dissect myeloid cell identities and functionalities in murine GL261 gliomas. We demonstrate that the diversity of myeloid cells infiltrating gliomas is dictated by cell type and cell state. Glioma-activated microglia are the major source of cytokines attracting other immune cells, whereas BM-derived cells show the monocyte-to-macrophage transition in the glioma microenvironment. This transition is coupled with a phenotypic switch from the IFN-related to antigen-presentation and tumor-supportive gene expression. Moreover, we found sex-dependent differences in transcriptional programs and composition of myeloid cells in murine and human glioblastomas.
    Keywords:  CITE-seq; CP: Cancer; CP: Immunology; glioblastoma; glioma; immune microenvironment; immunosuppression; macrophages; microglia; monocytes; single-cell
    DOI:  https://doi.org/10.1016/j.celrep.2022.111971
  3. Cancer Res. 2023 Jan 12. pii: CAN-22-1577. [Epub ahead of print]
    Olig1/2-expressing intermediate lineage progenitors are predisposed to PTEN/p53-loss-induced gliomagenesis and harbor specific therapeutic vulnerabilities.
    Ravinder Verma, Xiameng Chen, Dazhuan Xin, Zaili Luo, Sean Ogurek, Mei Xin, Rohit Rao, Kalen Berry, Q Richard Lu.
      Malignant gliomas such as glioblastoma are highly heterogeneous with distinct cells of origin and varied genetic alterations. It remains elusive whether the specific states of neural cell lineages are differentially susceptible to distinct genetic alterations during malignant transformation. Here, an analysis of TCGA databases revealed that co-mutations of PTEN and TP53 are most significantly enriched in human high-grade gliomas. Therefore, we selectively ablated Pten and Trp53 in different progenitors to determine which cell lineage states are susceptible to malignant transformation. Mice with PTEN/p53 ablation mediated by multilineage-expressing human GFAP (hGFAP)-promoter-driven Cre developed glioma but with incomplete penetrance and long latency. Unexpectedly, ablation of Pten and Trp53 in Nestin+ neural stem cells (NSCs) or Pdgfra+/NG2+ committed oligodendrocyte precursor cells (OPCs), two major cells of origin in glioma, did not induce glioma formation in mice. Strikingly, mice lacking Pten and Trp53 in Olig1+/Olig2+ intermediate precursors (pri-OPCs) prior to the committed OPCs developed high-grade gliomas with 100% penetrance and short latency. The resulting tumors exhibited distinct tumor phenotypes and drug sensitivities from NSC- or OPC-derived glioma subtypes. Integrated transcriptomic and epigenomic analyses revealed that PTEN/p53-loss induced activation of oncogenic pathways, including HIPPO-YAP and PI3K signaling, to promote malignant transformation. Targeting the core regulatory circuitries YAP and PI3K signaling effectively inhibited tumor cell growth. Thus, our multi-cell state in vivo mutagenesis analyses suggests that transit-amplifying states of Olig1/2 intermediate-lineage precursors are predisposed to PTEN/p53-loss-induced transformation and gliomagenesis, pointing to subtype-specific treatment strategies for gliomas with distinct genetic alterations.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1577
  4. Cancer Res. 2023 Jan 09. pii: CAN-22-1570. [Epub ahead of print]
    Phagocytosis of glioma cells enhances the immunosuppressive phenotype of bone marrow-derived macrophages.
    Min Wu, Lingxiang Wu, Wei Wu, Mengyan Zhu, Jianyu Li, Ziyu Wang, Jie Li, Rong Ding, Yuan Liang, Liangyu Li, Tingting Zhang, Bin Huang, Yun Cai, Kening Li, Lu Li, Rui Zhang, Baoli Hu, Fan Lin, Xiuxing Wang, Siyuan Zheng, Jian Chen, Yongping You, Tao Jiang, Junxia Zhang, Hongshan Chen, Qianghu Wang.
      Tumor-associated macrophages (TAMs) play a crucial role in immunosuppression. However, how TAMs are transformed into immunosuppressive phenotypes and influence the tumor microenvironment (TME) is not fully understood. Here, we utilized single-cell RNA sequencing and whole-exome sequencing data of glioblastoma (GBM) tissues and identified a subset of TAMs dually expressing macrophage and tumor signatures, which were termed double-positive TAMs. Double-positive TAMs tended to be bone marrow-derived macrophages (BMDMs) and were characterized by immunosuppressive phenotypes. Phagocytosis of glioma cells by BMDMs in vitro generated double-positive TAMs with similar immunosuppressive phenotypes to double-positive TAMs in the GBM TME of patients. The double-positive TAMs were transformed into M2-like macrophages and drove immunosuppression by expressing immune checkpoint proteins CD276, PD-L1, and PD-L2 and suppressing the proliferation of activated T cells. Together, glioma cell phagocytosis by BMDMs in the TME leads to the formation of double-positive TAMs with enhanced immunosuppressive phenotypes, shedding light on the processes driving TAM-mediated immunosuppression in GBM.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1570
  5. Neuro Oncol. 2023 Jan 07. pii: noad002. [Epub ahead of print]
    Objective response rate (ORR) targets for recurrent glioblastoma clinical trials based on the historic association between ORR and median overall survival.
    Benjamin M Ellingson, Patrick Y Wen, Susan M Chang, Martin van den Bent, Michael A Vogelbaum, Gang Li, Shanpeng Li, Jiyoon Kim, Gilbert Youssef, Wolfgang Wick, Andrew B Lassman, Mark R Gilbert, John F de Groot, Michael Weller, Evanthia Galanis, Timothy F Cloughesy.
      Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4,793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1%[95% CI 4.23; 8.76%] for cytotoxic chemotherapies (ORR=7.59% for CCNU, 7.57% for TMZ, 0.64% for CPT-11, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2=0.4078,P<0.0001), biologics (R2=0.4003,P=0.0003), and immunotherapy trials (R2=0.8994,P<0.0001), but not anti-angiogenic agents (R2=0, P=0.8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2=0.3900, P<0.0001; mOS[weeks]=1.4xORR+24.8). Assuming an ineffective cytotoxic (control) therapy has ORR=7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P<0.01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.
    DOI:  https://doi.org/10.1093/neuonc/noad002
  6. JCO Oncol Pract. 2023 Jan 13. OP2200784
    Reconciling the Contemporary Molecular Diagnosis of Glioblastoma With Past Clinical Trial Data.
    Nicole A Shonka, Craig M Horbinski.
      
    DOI:  https://doi.org/10.1200/OP.22.00784
  7. Neuro Oncol. 2023 Jan 14. pii: noac285. [Epub ahead of print]
    Targeting the IL4 Receptor with MDNA55 in Patients with Recurrent Glioblastoma: Results of a Phase 2b Trial.
    John H Sampson, Achal Singh Achrol, Manish K Aghi, Krystof Bankiewiecz, Martin Bexon, Steven Brem, Andrew Brenner, Chandtip Chandhasin, Sajeel Chowdhary, Melissa Coello, Benjamin M Ellingson, John R Floyd, Seunggu Han, Santosh Kesari, Yael Mardor, Fahar Merchant, Nina Merchant, Dina Randazzo, Michael Vogelbaum, Frank Vrionis, Eva Wembacher-Schroeder, Miroslaw Zabek, Nicholas Butowski.
      BACKGROUND: MDNA55 is an IL4R-targeting toxin in development for recurrent GBM, a universally fatal disease. IL4R is overexpressed in GBM as well as cells of the tumor microenvironment. High expression of IL4R is associated with poor clinical outcome.METHOD: MDNA55-05 is an open-label, single-arm Phase 2b study of MDNA55 in recurrent GBM (rGBM) patients with an aggressive form of GBM (de novo GBM, IDH wild-type, and non-resectable at recurrence) on their 1 st or 2 nd recurrence. MDNA55 was administered intratumorally as a single dose treatment (dose range of 18 to 240 ug) using convection enhanced delivery (CED) with up to 4 stereo-tactically placed catheters. It was co-infused with a contrast agent (Gd-DTPA, Magnevist®) to assess distribution in and around the tumor margins. The flow rate of each catheter did not exceed 10μL/min to ensure that the infusion duration did not exceed 48 hours. Primary endpoint was mOS, with secondary endpoints determining the effects of IL4R status on mOS and PFS.
    RESULTS: MDNA55 showed an acceptable safety profile at doses up to 240 μg. In all evaluable patients (n=44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A sub-group (n=32) consisting of IL4R High and IL4R Low patients treated with high dose MDNA55 (>180 ug) showed best benefit with mOS of 15 months, OS-12 of 55%. Based on mRANO criteria, tumor control was observed in 81% (26/32), including those patients who exhibited pseudo-progression (15/26).
    CONCLUSIONS: MDNA55 demonstrated tumor control and promising survival and may benefit rGBM patients when treated at high dose irrespective of IL4R expression level.
    Keywords:  Convection Enhanced Delivery (CED); IL4R; MDNA55; immunotherapy; recurrent glioblastoma; treatment outcome
    DOI:  https://doi.org/10.1093/neuonc/noac285
  8. Neuro Oncol. 2023 Jan 04. pii: noac283. [Epub ahead of print]
    Antibodies to varicella-zoster virus and three other herpesviruses and survival in adults with glioma.
    Geno Guerra, Lucie McCoy, Helen M Hansen, Terri Rice, Annette M Molinaro, Joseph L Wiemels, John K Wiencke, Margaret Wrensch, Stephen S Francis.
      BACKGROUND: Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed survival of adults with glioma in relation to their antibody measurements to 4 common herpes viral infections, including VZV, measured post-diagnosis.MATERIALS AND METHODS: We analyzed IgG antibody measurements to VZV, cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and Epstein-Barr virus (EBV) collected from 1378 adults with glioma diagnosed between 1991 and 2010. Blood was obtained a median of 3 months after surgery. Associations of patient IgG levels with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw, and tumor grade. Models were stratified by recruitment series and meta-analyzed to account for time-dependent treatment effects.
    RESULTS: VZV antibody seropositivity was associated with improved survival outcomes in adults with glioma (Hazard ratio, HR=0.70, 95% Confidence Interval 0.54-0.90, p=0.006). Amongst cases who were seropositive for VZV antibodies, survival was significantly improved for those above the 25th percentile of continuous reactivity measurements versus those below (HR=0.76, 0.66-0.88, p=0.0003). Antibody seropositivity to EBV was separately associated with improved survival (HR=0.71, 0.53-0.96, p=0.028). Antibody positivity to two other common viruses (CMV, HSV) was not associated with altered survival.
    CONCLUSIONS: Low levels of VZV or EBV antibodies are associated with poorer survival outcomes for adults with glioma. Differential immune response rather than viral exposure may explain these findings.
    Keywords:  Adult Glioma; Cytomegalovirus (CMV); Epstein-Barr virus (EBV); Herpes simplex virus (HSV); antibodies to varicella-zoster virus (VZV); glioblastoma; survival
    DOI:  https://doi.org/10.1093/neuonc/noac283
  9. Neuro Oncol. 2023 Jan 07. pii: noad003. [Epub ahead of print]
    Histological and Molecular Classifications of Pediatric Glioma with Time-dependent Diffusion MRI based Microstructural Mapping.
    Hongxi Zhang, Kuiyuan Liu, Ruicheng Ba, Zelin Zhang, Yi Zhang, Ye Chen, Weizhong Gu, Zhipeng Shen, Qiang Shu, Junfen Fu, Dan Wu.
      BACKGROUND: Gliomas are the most common type of central nervous system tumors in children, and the combination of histological and molecular classification is essential for prognosis and treatment. Here, we proposed a newly developed microstructural mapping technique based on diffusion-time-dependent diffusion MRI (td-dMRI) theory to quantify tumor cell properties, and tested these microstructural markers in identifying histological grade and molecular alteration of H3K27.METHODS: This prospective study included 69 pediatric glioma patients aged 6.14±3.25 years old, who underwent td-dMRI with pulsed and oscillating gradient diffusion sequences on a 3T scanner. dMRI data acquired at varying tds were fitted into a two-compartment microstructural model to obtain intracellular fraction (fin), cell diameter, cellularity, etc. Apparent diffusivity coefficient (ADC) and T1 and T2 relaxation times were also obtained. H&E stained histology was used to validate the estimated microstructural properties.
    RESULTS: For histological classification of low- and high-grade pediatric gliomas, the cellularity index achieved the highest area under the receiver-operating-curve (AUC) of 0.911 among all markers, while ADC, T1, and T2 showed AUCs of 0.906, 0.885, and 0.886. For molecular classification of H3K27-altered glioma in 39 midline glioma patients, cell diameter showed the highest discriminant power with an AUC of 0.918, and the combination of cell diameter and extracellular diffusivity further improved AUC to 0.929. The td-dMRI estimated fin correlated well with the histological groundtruth with r=0.7.
    CONCLUSIONS: The td-dMRI-based microstructural properties outperformed routine MRI measurements in diagnosing pediatric gliomas, and the different microstructural features showed complimentary strength in histological and molecular classifications.
    Keywords:  H3K27-altered; diffusion MRI; histological grading; microstructure; pediatric glioma
    DOI:  https://doi.org/10.1093/neuonc/noad003
  10. Cancer Immunol Immunother. 2023 Jan 09.
    Interaction of glioma-associated microglia/macrophages and anti-PD1 immunotherapy.
    Chunhua Wang, Quan Chen, Meiqing Chen, Sizhen Guo, Ping Hou, Yulian Zou, Jun Wang, Bailin He, Qiuyu Zhang, Lieping Chen, Liqun Luo.
      Anti-PD-1-based therapy has resulted in a minimal clinical response in malignant gliomas. Gliomas contain numerous glioma-associated microglia/macrophages (GAMs), reported to contribute to an immunosuppressive microenvironment and promote glioma progression. However, whether and how GAMs affect anti-PD-1 immunotherapy in glioma remains unclear. Here, we demonstrated that M1-like GAMs contribute to the anti-PD-1 therapeutic response, while the accumulation of M2-like GAMs is associated with therapeutic resistance. Furthermore, we found that PD-L1 ablation reverses GAMs M2-like phenotype and is beneficial to anti-PD-1 therapy. We also demonstrated that tumor-induced impairment of the antigen-presenting function of GAMs could limit the antitumor immunity of CD4+ T cells in anti-PD-1 therapy. Our study highlights the impact of GAMs activation on anti-PD-1 treatment and provides new insights into the role of GAMs in regulating anti-PD-1 therapy in gliomas.
    Keywords:  CD4+ T cells; Glioma; Glioma-associated microglia/macrophages; Immunotherapy; PD-1 (programmed death-1); PD-L1 (programmed death-ligand 1)
    DOI:  https://doi.org/10.1007/s00262-022-03358-3
  11. Neuro Oncol. 2023 Jan 12. pii: noad008. [Epub ahead of print]
    EANO guideline on rational molecular testing of gliomas, glioneuronal and neuronal tumors in adults for targeted therapy selection.
    David Capper, Guido Reifenberger, Pim J French, Leonille Schweizer, Michael Weller, Mehdi Touat, Simone P Niclou, Philipp Euskirchen, Christine Haberler, Monika E Hegi, Sebastian Brandner, Emilie Le Rhun, Roberta Rudà, Marc Sanson, Ghazaleh Tabatabai, Felix Sahm, Patrick Y Wen, Pieter Wesseling, Matthias Preusser, Martin J van den Bent.
      The mainstay of treatment 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 part of standard of care, however the predictive significance of most of these targets in CNS tumors remains less well studied. Despite that, there is an increasing use of advanced molecular diagnostics that identify potential targets, and tumor agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, FGFR, NTRK, PDGFRA, ROS1), in cell cycle signaling (CDK4/6, MDM2/4, TSC1/2) and altered genomic stability (mismatch repair, POLE, high TMB, HRD) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials.
    Keywords:  Adults; EANO; Glioma; Guideline; Targeted treatments
    DOI:  https://doi.org/10.1093/neuonc/noad008
  12. Cancer Cell. 2022 Dec 30. pii: S1535-6108(22)00593-1. [Epub ahead of print]
    MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors.
    Michael Kilian, Ron Sheinin, Chin Leng Tan, Mirco Friedrich, Christopher Krämer, Ayelet Kaminitz, Khwab Sanghvi, Katharina Lindner, Yu-Chan Chih, Frederik Cichon, Benjamin Richter, Stefanie Jung, Kristine Jähne, Miriam Ratliff, Robert M Prins, Nima Etminan, Andreas von Deimling, Wolfgang Wick, Asaf Madi, Lukas Bunse, Michael Platten.
      Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of NFAT2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.
    Keywords:  CD8 T cell dysfunction; MHC class II; NFAT; TOX; glioblastoma; glioma; macrophages; microenvironment; myeloid cells; osteopontin
    DOI:  https://doi.org/10.1016/j.ccell.2022.12.007
  13. J Natl Compr Canc Netw. 2023 01;21(1): 12-20
    NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.
    Craig Horbinski, Louis Burt Nabors, Jana Portnow, Joachim Baehring, Ankush Bhatia, Orin Bloch, Steven Brem, Nicholas Butowski, Donald M Cannon, Samuel Chao, Milan G Chheda, Andrew J Fabiano, Peter Forsyth, Pierre Gigilio, Jona Hattangadi-Gluth, Matthias Holdhoff, Larry Junck, Thomas Kaley, Ryan Merrell, Maciej M Mrugala, Seema Nagpal, Lucien A Nedzi, Kathryn Nevel, Phioanh L Nghiemphu, Ian Parney, Toral R Patel, Katherine Peters, Vinay K Puduvalli, Jason Rockhill, Chad Rusthoven, Nicole Shonka, Lode J Swinnen, Stephanie Weiss, Patrick Yung Wen, Nicole E Willmarth, Mary Anne Bergman, Susan Darlow.
      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. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.
    DOI:  https://doi.org/10.6004/jnccn.2023.0002
  14. Acta Neuropathol Commun. 2023 Jan 06. 11(1): 3
    Pediatric high-grade glioma MYCN is frequently associated with Li-Fraumeni syndrome.
    Léa Guerrini-Rousseau, Arnault Tauziède-Espariat, David Castel, Etienne Rouleau, Philipp Sievers, Raphaël Saffroy, Kévin Beccaria, Thomas Blauwblomme, Lauren Hasty, Franck Bourdeaut, Jacques Grill, Pascale Varlet, Marie-Anne Debily.
      
    DOI:  https://doi.org/10.1186/s40478-022-01490-w
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