TULIPs decorate the three-dimensional genome of PFA ependymoma.

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.

Precocious puberty and other endocrine disorders during mitotane treatment for paediatric adrenocortical carcinoma - case series and literature review.

INTRODUCTION: Adrenocortical carcinoma (ACC) is rare and an aggressive tumour. Mitotane is the mainstay adjuvant drug in treating ACC. The study aimed to describe patients diagnosed with precocious puberty (PP) and other endocrinological complications during mitotane therapy. MATERIAL AND METHODS: This retrospective study enrolled 4 patients with ACC treated with mitotane therapy complicated by PP. We analysed clinical manifestations, radiological, histopathological findings, and hormonal results. RESULTS: The median age at the diagnosis of ACC was 1.5 years. All patients were treated with surgery and mitotane, accompanied by chemotherapy regimens in 2 cases. The median time from surgery to the initiation of mitotane therapy was 26 days. During mitotane treatment, PP was confirmed based on symptoms, and hormonal and imaging tests. In one patient, incomplete peripheral PP was followed by central PP. The median time from the therapy initiation to the first manifestations of PP was 4 months. Additionally, due to mitotane-induced adrenal insufficiency, patients required a supraphysiological dose of hydrocortisone (HC), and in one patient, mineralocorticoid (MC) replacement with fludrocortisone was necessary. In 2 patients, hypothyroidism was diagnosed. All patients presented neurological symptoms of varying expression, which were more severe in younger children. CONCLUSIONS: The side effects of using mitotane should be recognized quickly and adequately treated. In prepubertal children, PP could be a complication of therapy. The need to use supraphysiological doses of HC, sometimes with MC, should be highlighted. Some patients require levothyroxine replacement therapy. The neurotoxicity of mitotane is a significant clinical problem.

Adrenal cortical carcinoma: Paediatric aspects - literature review.

INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare malignancy in children. Because of this, each patient with suspected ACC requires individualised management, which should be determined at a meeting of a team of multidisciplinary experts in the field. AIM OF THE STUDY: To summarise data on symptoms, genetic predisposition, and diagnostic procedures for ACC in children. MATERIAL AND METHODS: Papers were searched in the PubMed database to identify published randomised clinical trials, reviews, systematic reviews, meta-analyses, and case reports. RESULTS: Most cases of ACC in children occur under the age of 5 years. The most common presenting symptom in 60-80% of paediatric patients is rapidly progressive virilisation. Diagnostics are based on laboratory and imaging evaluation. The mainstay of treatment is surgery, with laparotomy being the preferred method of surgery. Diagnosis is based on histological examination of surgically removed tissue. The Wieneke index is most commonly used in paediatric practice. However, some cases are still classified as "indeterminate histology". Predisposing genetic factors are found in most children with ACC, most commonly a mutation of the TP53 gene. CONCLUSIONS: Patients should be diagnosed in large clinical centres with experience in this field. The treatment strategy should be individualised. Genetic testing for TP53 gene mutations is indicated in patients with ACC.

Transformation of IDH-wildtype glioblastoma to gliosarcoma with features of osteosarcoma.

Gliosarcoma (GS) is a rare variant of IDH-wildtype glioblastoma. It is classified as grade 4 in the latest WHO CNS classification of both glial and mesenchymal components. Gliosarcoma may arise de novo or secondary from glioblastoma. It occurs in up to 2% of patients diagnosed with glioblastoma. We present a case report of a 51-year-old patient who was initially diagnosed with glioblastoma multiforme, which transformed into secondary gliosarcoma with an osteosarcoma component 16 months after the initial diagnosis. We believe that increasing reporting of secondary gliosarcoma (sGS) will be helpful in understanding, diagnosing and providing more effective treatment for this cancer.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue of the dura mimicking meningioma: a case report and literature review.

MALT lymphoma of the dura is a very rare type of low-grade B-cell lymphoma. Little more than 100 cases have been reported in the literature to date. We report a 43-year-old woman who was referred to hospital because of a series of three tonic-clonic seizures on the day of admission. Neurological examination revealed confusion and aphasia. Magnetic resonance imaging (MRI) showed a contrast-enhanced, broad-based lesion along the dura in the left parieto-occipital area. The suspicion of an en plaque meningioma was raised. The tumour invaded the brain parenchyma with visible extension into the brain sulci. There was a marked brain oedema surrounding the lesion and causing the midline shift 8 mm to the right. After stabilization of neurological condition (intravenous diuretics and steroids), the operation was performed. The diagnosis of dural MALT lymphoma was established. During the pathological examination, it was especially problematic to distinguish MALT lymphoma from follicular lymphoma, but the final diagnosis was MALT lymphoma. Surgical partial removal with additional R-CVP immunochemotherapy (rituximab, cyclophosphamide, vincristine and prednisone) resulted in complete remission. The follow-up period is 1 year. Our presented case of a MALT lymphoma highlights the fact that surgical partial removal with additional immunochemotherapy is an available option in these rare intracranial tumours.

Quantitative digital pathology enables automated and quantitative assessment of inflammatory activity in patients with autoimmune hepatitis.

Background: Chronic liver disease diagnoses depend on liver biopsy histopathological assessment. However, due to the limitations associated with biopsy, there is growing interest in the use of quantitative digital pathology to support pathologists. We evaluated the performance of computational algorithms in the assessment of hepatic inflammation in an autoimmune hepatitis in which inflammation is a major component. Methods: Whole-slide digital image analysis was used to quantitatively characterize the area of tissue covered by inflammation [Inflammation Density (ID)] and number of inflammatory foci per unit area [Focal Density (FD)] on tissue obtained from 50 patients with autoimmune hepatitis undergoing routine liver biopsy. Correlations between digital pathology outputs and traditional categorical histology scores, biochemical, and imaging markers were assessed. The ability of ID and FD to stratify between low-moderate (both portal and lobular inflammation ≤1) and moderate-severe disease activity was estimated using the area under the receiver operating characteristic curve (AUC). Results: ID and FD scores increased significantly and linearly with both portal and lobular inflammation grading. Both ID and FD correlated moderately-to-strongly and significantly with histology (portal and lobular inflammation; 0.36≤R≤0.69) and biochemical markers (ALT, AST, GGT, IgG, and gamma globulins; 0.43≤R≤0.57). ID (AUC: 0.85) and FD (AUC: 0.79) had good performance for stratifying between low-moderate and moderate-severe inflammation. Conclusion: Quantitative assessment of liver biopsy using quantitative digital pathology metrics correlates well with traditional pathology scores and key biochemical markers. Whole-slide quantification of disease can support stratification and identification of patients with more advanced inflammatory disease activity.

DMRTA2 supports glioma stem-cell mediated neovascularization in glioblastoma.

Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Due to its fast proliferation, diffusive growth and therapy resistance survival times are less than two years for patients with IDH-wildtype GBM. GBM is noted for the considerable cellular heterogeneity, high stemness indices and abundance of the glioma stem-like cells known to support tumor progression, therapeutic resistance and recurrence. Doublesex- and mab-3-related transcription factor a2 (DMRTA2) is involved in maintaining neural progenitor cells (NPC) in the cell cycle and its overexpression suppresses NPC differentiation. Despite the reports showing that primary GBM originates from transformed neural stem/progenitors cells, the role of DMRTA2 in gliomagenesis has not been elucidated so far. Here we show the upregulation of DMRTA2 expression in malignant gliomas. Immunohistochemical staining showed the protein concentrated in small cells with high proliferative potential and cells localized around blood vessels, where it colocalizes with pericyte-specific markers. Knock-down of DMRTA2 in human glioma cells impairs proliferation but not viability of the cells, and affects the formation of the tumor spheres, as evidenced by strong decrease in the number and size of spheres in in vitro cultures. Moreover, the knockdown of DMRTA2 in glioma spheres affects the stabilization of the glioma stem-like cell-dependent tube formation in an in vitro angiogenesis assay. We conclude that DMRTA2 is a new player in gliomagenesis and tumor neovascularization and due to its high expression in malignant gliomas could be a biomarker and potential target for new therapeutic strategies in glioblastoma.

H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells.

Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine-to-methionine substitution (H3K27M). Patients with DIPG have a dismal prognosis with no effective therapy. We show that histone deacetylase (HDAC) inhibitors lead to a significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines. We discover that the SB939-mediated H3.3K27M loss is partially blocked by a lysosomal inhibitor, chloroquine. The H3.3K27M loss is facilitated by co-occurrence of H2A.Z, as evidenced by the knockdown of H2A.Z isoforms. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. We discover a mechanism showing that HDAC inhibition in DIPG leads to pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings show the possibility of directly targeting the H3.3K27M oncohistone.

Oxidative stress in metabolic dysfunction-associated steatotic liver disease (MASLD): How does the animal model resemble human disease?

Despite decades of research, the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) is still not completely understood. Based on the evidence from preclinical models, one of the factors proposed as a main driver of disease development is oxidative stress. This study aimed to search for the resemblance between the profiles of oxidative stress and antioxidant defense in the animal model of MASLD and the group of MASLD patients. C57BL/6J mice were fed with the Western diet for up to 24 weeks and served as the animal model of MASLD. The antioxidant profile of mice hepatic tissue was determined by liquid chromatography-MS3 spectrometry (LC-MS/MS). The human cohort consisted of 20 patients, who underwent bariatric surgery, and 6 controls. Based on histological analysis, 4 bariatric patients did not have liver steatosis and as such were also classified as controls. Total antioxidant activity was measured in sera and liver biopsy samples. The hepatic levels of antioxidant enzymes and oxidative damage were determined by Western Blot. The levels of antioxidant enzymes were significantly altered in the hepatic tissue of mice with MASLD. In contrast, there were no significant changes in the antioxidant profile of hepatic tissue of MASLD patients, except for the decreased level of carbonylated proteins. Decreased protein carbonylation together with significant correlations between the thioredoxin system and parameters describing metabolic health suggest alterations in the thiol-redox signaling. Altogether, these data show that even though the phenotype of mice closely resembles human MASLD, the animal-to-human translation of cellular and molecular processes such as oxidative stress may be more challenging.

An Asymptomatic, Ectopic Mass as a Presentation of Adrenocortical Carcinoma Due to a Novel Germline TP53 p.Phe338Leu Tetramerisation Domain Variant.

Adrenocortical carcinoma (ACC) is a rare cancer in childhood. ACC is frequently associated with germline TP53 variants, with founder effects especially due to the p.Arg337His mutation. ACC leads to the secretion of adrenocortical hormones, resulting in endocrine syndromes, which is the usual trigger for establishing the diagnosis. We present a surprising ACC pathology in a non-secreting, ectopic retroperitoneal tumour in a 4-year-old boy, successfully controlled with chemotherapy and mitotane after microscopically incomplete tumour resection with spillage. Genomic analysis (gene panel sequencing and copy-number microarray) demonstrated a novel p.Phe338Leu tetramerisation domain (TD) TP53 variant in the proband and his cancer-free mother and a monoallelic deletion encompassing the TP53 locus in cancer tissue, consistent with cancer-predisposition syndrome. While the recurrent p.Arg337His variant translates into high ACC risk, residue 338 and, in general, TD domain variants drive heterogeneous clinical scenarios, despite generally being considered less disruptive than TP53 DNA-binding domain mutations.

Adrenocortical carcinoma - 12-year observation period in a single centre. Case report with literature review.

BACKGROUND: Adrenocortical carcinoma (ACC) accounts for 0.2% of childhood malignancies. The most common symptom in children is rapidly progressive androgenization. Herein, we report a case of a patient with symptoms of hypercortisolaemia and androgenization, who was diagnosed with ACC. CASE PRESENTATION: In a 10-year-old patient with ACC the course of the disease was complicated by 3 recurrences. She was treated with surgery, chemo-, and radiotherapy. Currently, 8 years after the end of treatment, there have been no signs of recurrence. CONCLUSIONS: A patient after ACC treatment requires regular check-ups and long-term observation. Constant supervision enables early diagnosis of disease recurrence, and the use of treatment improves the prognosis.

Morphological alterations of the neuronal Golgi apparatus upon seizures.

AIMS: Epilepsy is one of the most common chronic neurological disorders, affecting around 50 million people worldwide, but its underlying cellular and molecular events are not fully understood. The Golgi is a highly dynamic cellular organelle and can be fragmented into ministacks under both physiological and pathological conditions. This phenomenon has also been observed in several neurodegenerative disorders; however, the structure of the Golgi apparatus (GA) in human patients suffering from epilepsy has not been described so far. The aim of this study was to assess the changes in GA architecture in epilepsy. METHODS: Golgi visualisation with immunohistochemical staining in the neocortex of adult patients who underwent epilepsy surgery; 3D reconstruction and quantitative morphometric analysis of GA structure in the rat hippocampi upon kainic acid (KA) induced seizures, as well as in vitro studies with the use of Ca2+ chelator BAPTA-AM in primary hippocampal neurons upon activation were performed. RESULTS: We observed GA dispersion in neurons of the human neocortex of patients with epilepsy and hippocampal neurons in rats upon KA-induced seizures. The structural changes of GA were reversible, as GA morphology returned to normal within 24 h of KA treatment. KA-induced Golgi fragmentation observed in primary hippocampal neurons cultured in vitro was largely abolished by the addition of BAPTA-AM. CONCLUSIONS: In our study, we have shown for the first time that the neuronal GA is fragmented in the human brain of patients with epilepsy and rat brain upon seizures. We have shown that seizure-induced GA dispersion can be reversible, suggesting that enhanced neuronal activity induces Golgi reorganisation that is involved in aberrant neuronal plasticity processes that underlie epilepsy. Moreover, our results revealed that elevated cytosolic Ca2+ is indispensable for these KA-induced morphological alterations of GA in vitro.

BCOR expression in paediatric pineoblastoma.

BCOR is expressed in a new brain tumour entity, i.e. 'CNS tumour with BCOR internal tandem duplication' (HGNET BCOR) but not in several other high grade paediatric brain tumours investigated. Immunohistochemical detection of BCOR expression may therefore serve as a potential diagnostic marker. Nevertheless, in rare paediatric glioma cases recurrent EP300-BCOR fusions were detected, which resulted in strong BCOR immunopositivity. We have therefore examined other, not analysed so far, types of central nervous system (CNS) tumours, pineoblastoma and germinoma, to assess a potential involvement of BCOR in these tumours. Levels of BCOR RNA expression were investigated by NanoString nCounter system analysis in a series of altogether 66 high grade paediatric tumours, including four pineoblastoma cases. Immunohistological detection of BCOR was performed in eight pineoblastoma, five germinoma and four atypical teratoid rhabdoid tumours (ATRTs), all located in the pineal region. We detected BCOR expression in all pineoblastomas, at the RNA and protein levels, but not in germinomas and ATRTs. Further analysis of pineoblastoma samples did not reveal the presence of either BCOR internal tandem duplication or BCOR fusion involvement. Positive immunohistological BCOR nuclear reaction in pineoblastoma may therefore differentiate this type of tumour from other high grade tumours located in the pineal region.

Risk-Adapted Treatment Strategies with Pre-Irradiation Chemotherapy in Pediatric Medulloblastoma: Outcomes from the Polish Pediatric Neuro-Oncology Group.

Craniospinal irradiation (CSI) has been a major component of the standard of care treatment backbone for childhood medulloblastoma. However, chemotherapy regimens have varied based on protocol, patient age, and molecular subtyping. In one of the largest studies to date, we analyzed treatment outcomes in children with newly-diagnosed medulloblastoma treated with pre-irradiation chemotherapy followed by risk-adapted radiotherapy and maintenance chemotherapy. A total of 153 patients from the Polish Pediatric Neuro-Oncology Group were included in the analysis. The median age at diagnosis was 8.0 years, and median follow-up time was 6.4 years. Sixty-seven patients were classified as standard-risk and eighty-six as high-risk. Overall survival (OS) and event-free survival (EFS) for standard-risk patients at 5 years (±standard error) were 87 ± 4.3% and 84 ± 4.6%, respectively, while 5-year OS and EFS for high-risk patients were 81 ± 4.3% and 79 ± 4.5%, respectively. Only one patient had disease progression prior to radiotherapy. This study demonstrates promising survival outcomes in patients treated with pre-irradiation chemotherapy followed by risk-adapted CSI and adjuvant chemotherapy. Such an approach may be useful in cases where the initiation of radiotherapy may need to be delayed, a common occurrence in many institutions globally.

Recommendations of the Polish Association of Neuropathologists on performing post-mortem examination of the brain and spinal cord.

Neuropathological central nervous system (CNS) post-mortem examination is a highly specialistic element of the autopsy procedure with methodological specificity. Herein we propose updated recommendations for CNS autopsy for pathologists and neuropathologists. The protocol includes the compendium of neuroanatomy with current nomenclature, consecutive steps of gross examination, as well as appropriate sampling algorithms in different clinical and pathological settings. The significance of pathoclinical cooperation in differential diagnosis is exposed. We believe it is essential to create and promote the guidelines to improve the quality of CNS post-mortem examination at the national level.

Targeted sequencing of cancer-related genes reveals a recurrent TOP2A variant which affects DNA binding and coincides with global transcriptional changes in glioblastoma.

High-grade gliomas are aggressive, deadly primary brain tumors. Median survival of patients with glioblastoma (GBM, WHO grade 4) is 14 months and <10% of patients survive 2 years. Despite improved surgical strategies and forceful radiotherapy and chemotherapy, the prognosis of GBM patients is poor and did not improve over decades. We performed targeted next-generation sequencing with a custom panel of 664 cancer- and epigenetics-related genes, and searched for somatic and germline variants in 180 gliomas of different WHO grades. Herein, we focus on 135 GBM IDH-wild type samples. In parallel, mRNA sequencing was accomplished to detect transcriptomic abnormalities. We present the genomic alterations in high-grade gliomas and the associated transcriptomic patterns. Computational analyses and biochemical assays showed the influence of TOP2A variants on enzyme activities. In 4/135 IDH-wild type GBMs we found a novel, recurrent mutation in the TOP2A gene encoding topoisomerase 2A (allele frequency [AF] = 0.03, 4/135 samples). Biochemical assays with recombinant, wild type (WT) and variant proteins demonstrated stronger DNA binding and relaxation activity of the variant protein. GBM patients carrying the altered TOP2A had shorter overall survival (median OS 150 vs 500 days, P = .0018). In the GBMs with the TOP2A variant we found transcriptomic alterations consistent with splicing dysregulation. luA novel, recurrent TOP2A mutation, which was found exclusively in four GBMs, results in the TOP2A E948Q variant with altered DNA binding and relaxation activities. The deleterious TOP2A mutation resulting in transcription deregulation in GBMs may contribute to disease pathology.

Infrared Spectroscopy as a Potential Diagnostic Tool for Medulloblastoma.

INTRODUCTION: Medulloblastoma (MB) is the most common malignant tumor of the central nervous system in childhood. FTIR spectroscopy provides a holistic view of the chemical composition of biological samples, including the detection of molecules such as nucleic acids, proteins, and lipids. This study evaluated the applicability of FTIR spectroscopy as a potential diagnostic tool for MB. MATERIALS AND METHODS: FTIR spectra of MB samples from 40 children (boys/girls: 31/9; age: median 7.8 years, range 1.5-21.5 years) treated in the Oncology Department of the Children's Memorial Health Institute in Warsaw between 2010 and 2019 were analyzed. The control group consisted of normal brain tissue taken from four children diagnosed with causes other than cancer. Formalin-fixed and paraffin-embedded tissues were sectioned and used for FTIR spectroscopic analysis. The sections were examined in the mid-infrared range (800-3500 cm-1) by ATR-FTIR. Spectra were analysed using a combination of principal component analysis, hierarchical cluster analysis, and absorbance dynamics. RESULTS: FTIR spectra in MB were significantly different from those of normal brain tissue. The most significant differences related to the range of nucleic acids and proteins in the region 800-1800 cm-1. Some major differences were also revealed in the quantification of protein conformations (α-helices, ß-sheets, and others) in the amide I band, as well as in the absorbance dynamics in the 1714-1716 cm-1 range (nucleic acids). It was not, however, possible to clearly distinguish between the various histological subtypes of MB using FTIR spectroscopy. CONCLUSIONS: MB and normal brain tissue can be distinguished from one another to some extent using FTIR spectroscopy. As a result, it may be used as a further tool to hasten and enhance histological diagnosis.

Exploring Novel Therapeutic Opportunities for Glioblastoma Using Patient-Derived Cell Cultures.

Glioblastomas (GBM) are the most common, primary brain tumors in adults. Despite advances in neurosurgery and radio- and chemotherapy, the median survival of GBM patients is 15 months. Recent large-scale genomic, transcriptomic and epigenetic analyses have shown the cellular and molecular heterogeneity of GBMs, which hampers the outcomes of standard therapies. We have established 13 GBM-derived cell cultures from fresh tumor specimens and characterized them molecularly using RNA-seq, immunoblotting and immunocytochemistry. Evaluation of proneural (OLIG2, IDH1R132H, TP53 and PDGFRα), classical (EGFR) and mesenchymal markers (CHI3L1/YKL40, CD44 and phospho-STAT3), and the expression of pluripotency (SOX2, OLIG2, NESTIN) and differentiation (GFAP, MAP2, ß-Tubulin III) markers revealed the striking intertumor heterogeneity of primary GBM cell cultures. Upregulated expression of VIMENTIN, N-CADHERIN and CD44 at the mRNA/protein levels suggested increased epithelial-to-mesenchymal transition (EMT) in most studied cell cultures. The effects of temozolomide (TMZ) or doxorubicin (DOX) were tested in three GBM-derived cell cultures with different methylation status of the MGMT promoter. Amongst TMZ- or DOX-treated cultures, the strongest accumulation of the apoptotic markers caspase 7 and PARP were found in WG4 cells with methylated MGMT, suggesting that its methylation status predicts vulnerability to both drugs. As many GBM-derived cells showed high EGFR levels, we tested the effects of AG1478, an EGFR inhibitor, on downstream signaling pathways. AG1478 caused decreased levels of phospho-STAT3, and thus inhibition of active STAT3 augmented antitumor effects of DOX and TMZ in cells with methylated and intermediate status of MGMT. Altogether, our findings show that GBM-derived cell cultures mimic the considerable tumor heterogeneity, and that identifying patient-specific signaling vulnerabilities can assist in overcoming therapy resistance, by providing personalized combinatorial treatment recommendations.

Specialized functions and sexual dimorphism explain the functional diversity of the myeloid populations during glioma progression.

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.