Journal articles on the topic 'Glioma tumors'
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1
Rao, Rohit, Feng Zhang, Ravinder Verma, Jincheng Wang, Dazhuan Xin, and Richard Lu. "TMIC-55. CHARACTERIZATION OF TUMOR-MICROENVIRONMENT INTERACTIONS IN GLIOBLASTOMAS AT THE SINGLE-CELL LEVEL." Neuro-Oncology 21, Supplement_6 (November 2019): vi259—vi260. http://dx.doi.org/10.1093/neuonc/noz175.1089.
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Abstract Glioblastomas are malignant brain tumors that carry a poor prognosis. The tumor microenvironment has been identified as an important regulator of tumor growth and may represent a novel target for therapy. Transcriptional subtypes of glioma are a major source of heterogeneity of expression in gliomas. Gliomas are highly heterogeneous diseases and can be classified into different subtypes including proneural, classical and mesenchymal tumors. We hypothesized that different subtypes of glioma will have different microenvironmental composition and exhibit distinct responses to therapies. To understand whether gliomas induced by different oncogenic drivers affect microenvironment composition, we induced mouse gliomas using a PDGFB and dnp53 driver to model proneural glioma and HRasV12 and dnp53 to model mesenchymal glioma, respectively. We performed single cell transcriptomic profiling to characterize the tumor microenvironment in these glioma models. We found that in the PDGFB/dnp53 glioma model had a large microglia contribution with about 30% tumor-associated microglia. In contrast, the HRasV12/dnp53 glioma model had only sparse microenvironmental cells. In addition, microglia in each model displayed subtype-specific gene expression programs, with microglia in the HRasV12/dnp53 tumor model expressing increased antigen presenting genes while increased levels of osteopontin in the PDGFB/dnp53 tumor model. To determine the tumor-microenvironment interactions, we performed receptor-ligand analysis using CellPhoneDb to identify secretory ligands that support tumor cell growth in microenvironmental cells. We found that tumor-associated pericytes are an important source of growth factor ligands in both PDGFB/dnp53 and HRasV12/dnp53 glioma models. We are investigating the contribution of microglia and pericytes to tumor growth and survival through cell depletion and pharmacological inhibition and determining whether the differences in tumor microglia between the models affects sensitivity to therapies including immunotherapy. Understanding how tumor-intrinsic signaling modulates microenvironment niches and tumor-microenvironment communications aids rational design of combinations targeting the malignant brain tumors.
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Morrone, Fernanda Bueno, Pedro Vargas, Liliana Rockenbach, and Thamiris Becker Scheffel. "P2Y12 Purinergic Receptor and Brain Tumors: Implications on Glioma Microenvironment." Molecules 26, no. 20 (October 12, 2021): 6146. http://dx.doi.org/10.3390/molecules26206146.
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Gliomas are the most common malignant brain tumors in adults, characterized by a high proliferation and invasion. The tumor microenvironment is rich in growth-promoting signals and immunomodulatory pathways, which increase the tumor’s aggressiveness. In response to hypoxia and glioma therapy, the amounts of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) strongly increase in the extracellular space, and the purinergic signaling is triggered by nucleotides’ interaction in P2 receptors. Several cell types are present in the tumor microenvironment and can facilitate tumor growth. In fact, tumor cells can activate platelets by the ADP-P2Y12 engagement, which plays an essential role in the cancer context, protecting tumors from the immune attack and providing molecules that contribute to the growth and maintenance of a rich environment to sustain the protumor cycle. Besides platelets, the P2Y12 receptor is expressed by some tumors, such as renal carcinoma, colon carcinoma, and gliomas, being related to tumor progression. In this context, this review aims to depict the glioma microenvironment, focusing on the relationship between platelets and tumor malignancy.
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Amin, Samirkumar, Kevin Anderson, Beth Bourdreau, Emmanuel Martínez, Emre Kocakavuk, Kevin C. Johnson, Floris Barthel, et al. "GENE-57. COMPARATIVE MOLECULAR LIFE HISTORY OF SPONTANEOUS CANINE AND HUMAN GLIOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi110. http://dx.doi.org/10.1093/neuonc/noz175.459.
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Abstract Diffuse gliomas are the commonest of malignant brain tumors with high-grade tumors carrying dismal prognosis. Preclinical models have proven themselves as poor predictors of clinical efficacy, attributed to the lack of a comparable tumor microenvironment. Comparative genomics of canine and human gliomas provide an attractive alternative modality to identify conserved drivers and underlying mutational processes of glioma as well as evaluate life history tradeoffs related to tissue context and aging that can shape type and relative timing of drivers in gliomagenesis. We performed a comparative genomics analysis between whole genome-, exome-, transcriptome- and methylation-sequencing of 77 canine gliomas, and human pediatric (n=217) and adult gliomas (n=822). We found alterations in common with those in human pediatric and adult gliomas in the Tp53 and cell cycle pathways, receptor tyrosine kinase and Idh1 R132 mutations. Canine gliomas showed similarity to human pediatric gliomas in terms of lower mutational rates (0.2–0.29 per megabase), hotspot mutations and amplifications of Pdgfrα, and robust aneuploidy constrained within the syntenic regions of Pdgfrα and Myc, but also in the known pediatric drivers, Hist1 and Acvr1 genes. A mutational signature reflecting homologous repair defect was detected in canine and pediatric but not adult gliomas, potentially resulting in the observed higher rates of genomic instability. Canine gliomas in majority classified as pediatric tumors using a commonly used human brain methylation classifier (Capper et al. 2018) and cell-of-origin analysis by deconvoluting canine transcriptome using lineage-specific gene signatures. By providing a large canine glioma genomic-sequencing dataset and comparing it with human glioma, our study provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations. Further, our results effectively position preclinical models of spontaneous canine glioma for use in understanding glioma drivers, and evaluate novel therapies targeting aneuploidy, especially for pediatric brain tumors.
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Irvin, David, Hannah Roberts, Vladislav Sharin, Ahsan Farooqi, Sharvari Dharmaiah, Christian Alvarez, and Jason Huse. "CSIG-09. ATRX DEFICIENCY IN GLIOMA IMPACTS TRANSCRIPTIONAL PROFILES AND THE IMMUNE MICROENVIRONMENT IN VIVO." Neuro-Oncology 22, Supplement_2 (November 2020): ii29. http://dx.doi.org/10.1093/neuonc/noaa215.121.
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Abstract Current treatment for diffuse astrocytoma fails to address its underlying molecular mechanisms leading to inevitable disease progression and eventual patient death. Genomic studies have implicated ATRX alterations as critical to low grade glioma biology. Our lab has previously shown in vitro that ATRX influences glioma motility, cellular differentiation state, and epigenetic programming, however, the influence of ATRX alterations in vivo remains unclear. Here, we leveraged an RCAS/tva mouse tumor model to probe the role of ATRX deficiency in glioma. Atrx deficient murine tumors exhibited lower histopathological grade and were associated with longer survival than Atrx-intact counterparts, and syngeneic allografts of cell lines derived from primary tumors mirrored the differential degrees of aggressiveness seen in primary tumors. Tumor-derived Atrx-deficient cell lines showed increased susceptibility to G-quadruplex stabilizing compounds, pointing to increased replication stress and recapitulating a key phenotype of ATRX-mutant gliomas in humans. Transcriptional profiling revealed enrichments in MYC target genes, E2F targets as well as G2/M checkpoint pathways in Atrx-intact tumors and cells, and enrichment in RAS signaling in Atrx-deficient tumors and cells. Finally, Atrx deficient murine gliomas displayed increased levels of NK cells, a phenotype recapitulated in ATRX-mutant human gliomas, and primary Atrx-deficient glioma lines exhibited increased levels of NK cell-attracting cytokines. These latter findings suggest that ATRX deficiency could influence interactions between glioma cells and their immune microenvironment by way of phenotypically relevant molecular mechanisms.
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Wirth, Thomas, Farizan Ahmad, Agnieszka Pacholska, Haritha Samaranayake, and Seppo Ylä-Herttuala. "The Syngeneic BT4C Rat Malignant Glioma is a Valuable Model to study Myelomonocytic cells in Tumors." Cancer Growth and Metastasis 5 (January 2012): CGM.S9314. http://dx.doi.org/10.4137/cgm.s9314.
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Background The impact of infiltrating macrophages on tumor progression in malignant gliomas has been studied extensively. However, there is a lack of animal models for studying the role of infiltrating macrophages in malignant gliomas. Material and methods: The BT4C rat malignant glioma model was characterized by immunohistochemical analysis of inflammatory cell types associated with the tumors. Results BT4C malignant gliomas are highly vascularized tumors with an infiltrative behavior. BT4C gliomas demonstrated a high infiltration rate of macrophages. Particularly, a CD68/VEGFR-1 positive subtype of macrophages was detected at the edges of malignant gliomas. Also, CD133 positive cells were located mainly at the infiltrative edges of gliomas, whereas VEGFR-2 was highly expressed throughout the malignant glioma. Conclusion The immunocompetent BT4C rat malignant glioma model shows features similar to its human counterpart, which makes it a valuable model to study the impact of tumor associated macrophages in the pathology of malignant gliomas.
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Nguyen, Hoang Dong, Phedias Diamandis, Michelle S. Scott, and Maxime Richer. "Deciphering of Adult Glioma Vulnerabilities through Expression Pattern Analysis of GABA, Glutamate and Calcium Neurotransmitter Genes." Journal of Personalized Medicine 12, no. 4 (April 14, 2022): 633. http://dx.doi.org/10.3390/jpm12040633.
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Adult infiltrating gliomas are highly aggressive tumors of the central nervous system with a dismal prognosis despite intensive multimodal therapy (chemotherapy and/or radiotherapy). In this study, we studied the expression, methylation and interacting miRNA profiles of GABA-, glutamate- and calcium-related genes in 661 adult infiltrating gliomas available through the TCGA database. Neurotransmitter-based unsupervised clustering identified three established glioma molecular subgroups that parallel major World Health Organization glioma subclasses (IDH-wildtype astrocytomas, IDH-mutant astrocytomas, IDH-mutant oligodendroglioma). In addition, this analysis also defined a novel, neurotransmitter-related glioma subgroup (NT-1), mostly comprised of IDH-mutated gliomas and characterized by the overexpression of neurotransmitter-related genes. Lower expression of neurotransmission-related genes was correlated with increased aggressivity in hypomethylated IDH-wildtype tumors. There were also significant differences in the composition of the tumor inflammatory microenvironment between neurotransmission-based tumor categories, with lower estimated pools of M2-phenotype macrophages in NT-1 gliomas. This multi-omics analysis of the neurotransmission expression landscape of TCGA gliomas—which highlights the existence of neurotransmission-based glioma categories with different expression, epigenetic and inflammatory profiles—supports the existence of operational neurotransmitter signaling pathways in adult gliomas. These findings could shed new light on potential vulnerabilities to exploit in future glioma-targeting drug therapies.
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Berg, Tracy, Carolina Marques, Vasiliki Pantazopoulou, Elinn Johansson, Kristoffer von Stedingk, David Lindgren, Elin Pietras, et al. "TAMI-05. THE IRRADIATED BRAIN MICROENVIRONMENT SUPPORTS GLIOMA STEMNESS AND SURVIVAL VIA ASTROCYTE-DERIVED TRANSGLUTAMINASE 2." Neuro-Oncology 22, Supplement_2 (November 2020): ii213—ii214. http://dx.doi.org/10.1093/neuonc/noaa215.894.
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Abstract The highest-grade gliomas invariably recur as incurable tumors following standard of care comprising surgery, radiotherapy, and chemotherapy. The majority of the recurrent tumors form within the area of the brain receiving high-dose irradiation during treatment of the primary tumor, indicating that the recurrent tumor forms in an irradiated microenvironment. The tumor microenvironment has been demonstrated to influence the therapeutic response and stemness characteristics of tumor cells, but the influence of radiation on the microenvironment and its subsequent consequences for tumor cells are incompletely understood. Here, we used genetically engineered glioma mouse models and human glioma samples to characterize the impact of standard of care radiotherapy on the brain tumor microenvironment. We found that tumor-associated astrocytes subjected to radiation in vitro could enhance tumor cell stemness and survival of co-cultured glioma cells. More aggressive gliomas formed in vivo when mouse brains were irradiated prior to tumor cell implantation, suggesting that the irradiated brain microenvironment supports tumor growth. We isolated the effect of irradiated astrocytes to extracellular matrix secreted by these cells, and specifically found that astrocyte-derived transglutaminase 2 (TGM2) is a stromal promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in glioma mouse models. Recombinant TGM2 enhanced, and TGM2 inhibitors blocked, glioma cell stemness. In human GBM tissue, TGM2 levels were increased in recurrent vs. primary tumors. In summary, in addition to supporting TGM2 as a potential therapeutic target in glioma, our data indicate that radiotherapy results in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.
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Mellinghoff, Ingo K., Benjamin M. Ellingson, Mehdi Touat, Elizabeth Maher, Macarena I. De La Fuente, Matthias Holdhoff, Gregory M. Cote, et al. "Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma." Journal of Clinical Oncology 38, no. 29 (October 10, 2020): 3398–406. http://dx.doi.org/10.1200/jco.19.03327.
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PURPOSE Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m IDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION In patients with m IDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
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Wroblewski, Tadeusz, Philip Tatman, Anthony Fringuello, Sam Scherer, William Foreman, Denise Damek, Samy Youssef, Kevin Lillehei, David Ormond, and Michael Graner. "DDRE-20. HIGH-THROUGHPUT SCREENING OF FDA-APPROVED COMPOUNDS IN GLIOMA AND GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTICS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi78. http://dx.doi.org/10.1093/neuonc/noab196.304.
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Abstract BACKGROUND Glioma and glioblastoma comprise 28% of all primary central nervous system tumors and cause the majority of primary brain tumor deaths. Despite substantial research into the molecular pathogenesis and genetic landscape of glioma, no currently approved therapies are curative for any glioma or glioblastoma. Patients with glioblastoma have an average survival time of 12-15 months, while patients with grade III gliomas have an average survival time of 3-5 years, and patients with grade II gliomas have an average survival time of 8-15 years. The lack of a curative treatment for these tumors necessitates additional research into novel therapies. METHODS In this study, we developed a high-throughput drug screen and culture system to identify existing FDA-approved therapies with the potential to inhibit glioma viability. RESULTS In total, we screened 39 tumors: 21 glioblastoma, 10 oligodendroglioma, and 8 astrocytoma. Carfilzomib was the most effective compound across the cohort, decreasing the average tumor viability to 39.0% +/- 16.5%SD. Regardless of tumor grade, MGMT methylation, EGFR amplification, tumor recurrence and etiology, tumor histology, prior treatment, and patient gender, carfilzomib significantly reduced cell viability in every tumor; though was not necessarily the most effective compound in each of these groups. We found HDAC inhibition to be the most effective treatment in grade 1 astrocytomas. However, HDAC inhibition was surpassed by carfilzomib and RNA transcription inhibitors in all higher grades. Interestingly, EGFR inhibition, while significantly effective in 36 tumors, was consistently less effective than carfilzomib across the cohort, though did surpass the effectiveness of HDAC inhibition in grade III gliomas. CONCLUSIONS FDA approved compounds can effectively inhibit glioma tumor viability. Specifically, carfilizomib holds great promise. Further in vivo studies are needed to confirm these findings.
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Pedersen, L. K. "P05.02.A 18F-FACBC PET/MRI in diagnostic assessment of gliomas." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii36. http://dx.doi.org/10.1093/neuonc/noac174.121.
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Abstract Background and Theory MRI and histopathological tissue sampling are routinely done as part of the diagnostic work-up of patients with glioma. MRI provides anatomical images with high resolution and excellent soft-tissue contrast. But this modality has limitations in identifying tumor grade, true tumor extension and differentiate viable tumor tissue from treatment induced changes. PET can provide quantitative information of cellular activity and metabolism, and may therefore have additional value compared to MRI alone. Objective The aim of this study was to find the sensitivity of [18F]FACBC PET in gliomas, and evaluate if PET imaging with this tracer can improve differentiation between low-and high-grade gliomas. Methods Patients with suspicion of primary (n=19) or recurrent gliomas (n=8) were recruited to this study from St. Olavs hospital, Trondheim University Hospital, Trondheim, and from the University Hospital of North Norway, Tromsø. PET acquisitions (30-45 min post injection) using the amino acid radiotracer [18F]FACBC (3 MBq/kg) were performed simultaneously to MRI acquisitions (T1 with and without contrast, FLAIR, and UTE for attenuation correction. The sensitivity of [18F]FACBC PET in glioma detection was assessed using histopathology as reference. Tumor-to-background ratios (TBRs) were compared to tumor subtype and grade to assess the diagnostic value of this tracer for glioma diagnostics. Results Histopathology revealed 2 WHO grade 1 gliomas (pilocytic astrocytoma n=1, pilocytic astrocytoma/ganglioglioma n=1), 7 WHO grade 2 gliomas(astrocytoma n=4, oligodendroglioma n=3), 7 WHO grade 3 gliomas(astrocytoma n=5, oligodendroglioma n=2) and 12 WHO grade 4 tumors(astrocytoma n=1, glioblastoma n=11). [18F]FACBC PET provided a sensitivity of 74.1% in the detection of gliomas. PET uptake was observed in all grade 4 tumors, 5/7 grade 3 tumors, 2/7 grade 2 tumors, and all grade 1 tumors. TBRpeak was high with a median value of 9.4 (range: 2.1-34.9) in PET positive tumors. Only tumors with a TBRpeak > 2.0 were detected with [18F]FACBC PET. TBRpeak was highest for grade 1 gliomas with a median value of 20.6, and increased significantly from grade 2 to grade 4 tumors with median values of 1.7 (grade 2), 6.2 (grade 3) and 12.4 (grade 4) (Kruskal-Wallis, p=0.001). Conclusion [18F]FACBC PET demonstrated high uptake in the majority of gliomas, and there was a clear tendency to higher uptake in the higher grade tumors. [18F]FACBC PET may be useful in the differentiation between glioms grades and subtypes. A future study using the same patient data will be performed to evaluate the assessment of [18F]FACBC PET in neurosurgical treatment planning. Image-localized biopsies from different regions of each tumor will be correlated to fused PET/MRI images to evaluate if [18F]FACBC PET can be used to guide surgical resection and to improve accuracy in histopathological tissue sampling.
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Kawashima, Masatou, Katsumi Doh-ura, Eisuke Mekada, Masashi Fukui, and Toru Iwaki. "CD9 Expression in Solid Non-neuroepithelial Tumors and Infiltrative Astrocytic Tumors." Journal of Histochemistry & Cytochemistry 50, no. 9 (September 2002): 1195–203. http://dx.doi.org/10.1177/002215540205000906.
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The tetraspan membrane protein CD9 is normally expressed in the mature myelin sheath and is believed to suppress the metastatic potential of certain human tumors. In this study we identified CD9 in a variety of brain tumors by immunohistochemical (IHC) and immunoblotting analyses. We examined 96 tumor samples and three glioma cell lines in addition to a murine brain tumor model of transplanted glioma cells in CD9-deficient mice and control mice. CD9 was expressed not only in solid non-neuroepithelial tumors but also in infiltrative malignant neuroepithelial tumors. Among the neuroepithelial tumors, high-grade astrocytic tumors, including glioblastomas and anaplastic astrocytomas, showed higher immunoreactivity than low-grade cerebral astrocytomas. Thus, CD9 expression in astrocytic tumors correlated with their malignancy. In the murine brain tumor model, transplanted glioma cells were shown to grow and spread through myelinated areas irrespective of the presence or absence of CD9 expression in the recipient's brain. These results indicate that the CD9 expression of astrocytic tumors plays a significant role in the malignancy independent of CD9 expression in the surrounding tissue. This might be explained by the observation that the CD9 molecule is associated with a mitogenic factor, membrane-anchored heparin-binding epidermal growth factor, which is known to be upregulated in malignant gliomas.
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Sriwidyani, Ni Putu, Ida Ayu Ika Wahyuniari, Herman Saputra, and I. Gusti Kamasan Nyoman Arijana. "IDH1 mutation in Balinese glioma patients and its relationship with clinicopatological parameters." Bali Medical Journal 9, no. 3 (December 1, 2020): 819–22. http://dx.doi.org/10.15562/bmj.v9i2.2077.
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Purpose: Isocitrate dehydrogenase 1 (IDH1) mutation plays an important role in the carcinogenesis of gliomas. The most recent WHO classification of central nervous system tumors has added molecular genetic in addition to the histological features of the tumor, including status of IDH mutation in glial tumors. The purpose of this study was to determine the prevalence of IDH1 mutations in Balinese glioma patients and its association with clinicopathological features.Patients and methods: This study was conducted from 30 glioma patients at Sanglah General Hospital during January 2018 until June 2019. DNA extractions were carried out from the FFPE of tumor tissue, followed by amplification of codon 132 in exon 4 of the IDH1 gene by allele specific PCR. Relationship between IDH1 mutation status and clinicopathological features was tested with X2 with 0.05 significance.Results: The age range of patients is 14-81 years with an average age of 43.4 years (SD±17.9 years). Most patients with astrocytic tumors (25/30; 83.3%), others were oligodendroglial tumor (2/30; 6.7%) and oligoastrocytic tumor (3/30; 10%). Most patients were found with grade IV glioblastoma (18/30; 60%). Genotyping analysis showed IDH1 mutations in the majority of glioma patients (90%). Most cases (92.6%) of mutant IDH1 showed heterozygous mutations (GA genotype) while the rest showed homozygous mutations (AA genotype). There were no significant relationship between IDH1 status and age (p=0.09), sex (p=0.63) and histologic type (0.14), but there was significant relationship between IDH1 mutation status and tumor grade (p=0.01). All of IDH1 mutation were found in diffuse glioma (grade II and III gliomas and grade IV glioblastoma).Conclusion: Most of diffuse glioma (grade II-IV glioma) patients in Bali had IDH1 mutation and IDH1 mutation status has significant relationship with tumor grade. Further research about genetic abnormalities in order to improve therapeutic efficacy against IDH-mutated gliomas is needed.
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Krane, Gregory A., Carly A. O’Dea, David E. Malarkey, Andrew D. Miller, C. Ryan Miller, Debra A. Tokarz, Heather L. Jensen, et al. "Immunohistochemical evaluation of immune cell infiltration in canine gliomas." Veterinary Pathology 58, no. 5 (July 1, 2021): 952–63. http://dx.doi.org/10.1177/03009858211023946.
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Evasion of the immune response is an integral part of the pathogenesis of glioma. In humans, important mechanisms of immune evasion include recruitment of regulatory T cells (Tregs) and polarization of macrophages toward an M2 phenotype. Canine glioma has a robust immune cell infiltrate that has not been extensively characterized. The purpose of this study was to determine the distribution of immune cells infiltrating spontaneous intracranial canine gliomas. Seventy-three formalin-fixed, paraffin-embedded tumor samples were evaluated using immunohistochemistry for CD3, forkhead box 3 (FOXP3), CD20, Iba1, calprotectin (Mac387), CD163, and indoleamine 2,3-dioxygenase (IDO). Immune cell infiltration was present in all tumors. Low-grade and high-grade gliomas significantly differed in the numbers of FoxP3+ cells, Mac387+ cells, and CD163+ cells ( P = .006, .01, and .01, respectively). Considering all tumors, there was a significant increase in tumor area fraction of CD163 compared to Mac387 ( P < .0001), and this ratio was greater in high-grade tumors than in low-grade tumors ( P = .005). These data warrant further exploration into the roles of macrophage repolarization or Treg interference therapy in canine glioma.
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Parajuli, Prahlad, Sandeep MIttal, Sreenivasa Chinni, Lawrence Lum, Archana Thakur, and Murali Guthikonda. "Interaction between tumor and myeloid cells induce/expand Th17 cells in malignant gliomas (48.28)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 48.28. http://dx.doi.org/10.4049/jimmunol.186.supp.48.28.
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Abstract Th17 cells, a recently discovered inflammatory T cell subtype, have been reported in several tumors, where they are implicated with either pro- or anti-tumor activity, depending on the tumor type. Th17 cells have not been studied with respect to brain tumors. We have been studying the mechanism of induction and role of Th17 cells in malignant gliomas using primary tumor as well as glioma cell lines. We report here that: 1) There is considerable prevalence of Th17 cells and myeloid (CD11b) cells among glioma-infiltrating immune cells; 2) Glioma cells express the cytokines TGF-β1 and IL-6, while the infiltrating myeloid cells express IL-1β and IL-23; 3) Naïve T cells cultured with anti-CD2/CD3/CD28-loaded microbeads in the presence of glioma culture supernatants differentiate into Th17 cells, which is inhibited by antibodies to TGF-β1 and IL-6; 4) Supernatant from glioma-monocyte co-culture generates significantly higher frequency of Th17 cells compared to glioma supernatant, which is abrogated by antibodies to IL-1β and IL-23. Moreover, 5) Th17 cells generated in the presence of supernatant from glioma-monocyte co-culture have low IFN-γ and high IL-10 expression, suggesting that glioma-associated Th17 cells may be immune suppressive. Further studies on the mechanism of tumor-infiltration, developmental pathways and pro-/anti-tumor functions of Th17 cells will provide rationale for developing novel adjuvant immunotherapeutic strategies for malignant gliomas.
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Comba, Andrea, Patrick J Dunn, Anna E Argento, Padma Kadiyala, Sebastien Motsch, Alon Kahana, Phillip E Kish, Maria Castro, and Pedro Lowenstein. "TMIC-58. THE CELLULAR AND MOLECULAR BASIS FOR MESENCHYMAL TRANSFORMATION IN GLIOMAS." Neuro-Oncology 21, Supplement_6 (November 2019): vi260. http://dx.doi.org/10.1093/neuonc/noz175.1092.
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Abstract Mesenchymal gliomas are the most aggressive tumors that carry the worst prognosis. The origins of mesenchymal cells within brain tumors, remains poorly understood. They could originate either from invading mesenchymal cells, from perivascular smooth muscle actin+ cells, or from a mesenchymal transformation of tumor cells. Identifying the origin and function of mesenchymal cells within gliomas is essential as these cells contribute to increased glioma aggressiveness and tumor progression. In this study we used human biopsies and implantable and genetically engineered mouse models (GEMM) of GBM to study tumor mesenchymal transformation. GBM implantable models were used to analyze the molecular landscape by laser microdissection followed by RNA-Seq and bioinformatics analysis. Time lapse confocal imagining was implemented to analyze GBM cells dynamics. Our results indicate the existence of a complex intratumoral and peritumoral dynamic organization of glioma cells (i.e., Oncostreams). Multicellular structures of elongated cells compatible with mesenchymal differentiation. These structures play important roles in intratumoral movements, peritumoral invasion of normal brain, and overall glioma progression. We also show that oncostreams are molecularly distinct and display increased expression of mesenchymal genes such as Col1a1. Knocking down of Col1a1 in a GEMM of aggressive gliomas reduced tumor progression and significantly increased animal survival. Histological examination confirmed absence of Col1a1, and absence of morphologically identifiable oncostreams. Our results show that tumor cells, especially within oncostreams, display a fibroblastic-like morphology and express proteins typical of mesenchymal cells. The knockout of Col1a1 from tumoral cells eliminated oncostreams from tumors and delayed tumor progression. These data suggest that tumor cells expressing mesenchymal genes regulate the organization of mesenchymal multicellular structures, and determine glioma progression. We propose that inhibiting mesenchymal transformation of glioma cells will assist in the treatment of glioblastoma.
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Lanza, Marika, Giovanna Casili, Michela Campolo, Irene Paterniti, Cristina Colarossi, Marzia Mare, Raffella Giuffrida, Maria Caffo, Emanuela Esposito, and Salvatore Cuzzocrea. "Immunomodulatory Effect of Microglia-Released Cytokines in Gliomas." Brain Sciences 11, no. 4 (April 7, 2021): 466. http://dx.doi.org/10.3390/brainsci11040466.
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Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). Microglia substantially contribute to the growth and invasion of tumor mass in brain tumors including glioblastoma (GB). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors. Large numbers of glioma associated microglia and macrophages (GAMs) can accumulate within the tumor where they appear to have an important role in prognosis. GAMs constitute the largest portion of tumor infiltrating cells, contributing up to 30% of the entire glioma mass and upon interaction with neoplastic cells. GAMs acquire a unique phenotype of activation, including both M1 and M2 specific markers. It has been demonstrated that microglia possess a dual role: on one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors. Concluding, as microglia significantly may contribute to glioma biology, favoring tumor growth and invasiveness, these cells represent a valuable alternative/additional target for the development of more effective treatments for gliomas.
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Jaraíz-Rodríguez, Myriam, Rocío Talaverón, Laura García-Vicente, Sara G. Pelaz, Marta Domínguez-Prieto, Andrea Álvarez-Vázquez, Raquel Flores-Hernández, et al. "Connexin43 peptide, TAT-Cx43266–283, selectively targets glioma cells, impairs malignant growth, and enhances survival in mouse models in vivo." Neuro-Oncology 22, no. 4 (December 28, 2019): 493–504. http://dx.doi.org/10.1093/neuonc/noz243.
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Abstract Background Malignant gliomas are the most frequent primary brain tumors and remain among the most incurable cancers. Although the role of the gap junction protein, connexin43 (Cx43), has been deeply investigated in malignant gliomas, no compounds have been reported with the ability to recapitulate the tumor suppressor properties of this protein in in vivo glioma models. Methods TAT-Cx43266–283 a cell-penetrating peptide which mimics the effect of Cx43 on c-Src inhibition, was studied in orthotopic immunocompetent and immunosuppressed models of glioma. The effects of this peptide in brain cells were also analyzed. Results While glioma stem cell malignant features were strongly affected by TAT-Cx43266–283, these properties were not significantly modified in neurons and astrocytes. Intraperitoneally administered TAT-Cx43266–283 decreased the invasion of intracranial tumors generated by GL261 mouse glioma cells in immunocompetent mice. When human glioma stem cells were intracranially injected with TAT-Cx43266–283 into immunodeficient mice, there was reduced expression of the stemness markers nestin and Sox2 in human glioma cells at 7 days post-implantation. Consistent with the role of Sox2 as a transcription factor required for tumorigenicity, TAT-Cx43266–283 reduced the number and stemness of human glioma cells at 30 days post-implantation. Furthermore, TAT-Cx43266–283 enhanced the survival of immunocompetent mice bearing gliomas derived from murine glioma stem cells. Conclusion TAT-Cx43266–283 reduces the growth, invasion, and progression of malignant gliomas and enhances the survival of glioma-bearing mice without exerting toxicity in endogenous brain cells, which suggests that this peptide could be considered as a new clinical therapy for high-grade gliomas.
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Yu, Di, Qiuhui Xuan, Chaoqi Zhang, Chunxiu Hu, Yanli Li, Xinjie Zhao, Shasha Liu, et al. "Metabolic Alterations Related to Glioma Grading Based on Metabolomics and Lipidomics Analyses." Metabolites 10, no. 12 (November 24, 2020): 478. http://dx.doi.org/10.3390/metabo10120478.
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Gliomas are the most aggressive phenotypes of brain tumors and are classified into four grades according to the malignancy degree by the World Health Organization. Metabolic profiling can provide an overview of metabolic reprogramming at a specific stage of tumor initiation and development. Studies about metabolic alterations related to different grades of gliomas are helpful to understand the molecular mechanism for progression of glioma. In the current study, metabolomics and lipidomics analyses based on chromatography-mass spectrometry were performed on different grades of glioma tissues. Differential metabolites between glioma and para-tumor tissues were studied and used as the basis to explore metabolic alterations related to glioma grading. It was found that short-chain acylcarnitines were elevated, whereas lysophosphatidylethanolamines (LPEs) were decreased in high-grade gliomas. Furthermore, the gene expression of short/branched-chain acyl-coenzyme dehydrogenase (ACADSB), which is involved in fatty acid oxidation, was found down-regulated with glioma progression by analyzing related genes and pathways. In addition, LPE metabolism showed a significant difference among different grades of gliomas. These important metabolic pathways related to glioma progression may provide potential clues for further study on the mechanisms and treatment of glioma.
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Chaudhary, Reeta, Nishi Tandon, Andleeb Zehra, Jyoti Jaiswal, Nirupma Lal, and Bandhul Tiwari. "HIGH GRADE GLIOMA IN A 2 1/2 YEAR OLD: A CASE REPORT." Era's Journal of Medical Research 9, no. 1 (June 2022): 114–16. http://dx.doi.org/10.24041/ejmr2022.18.
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Gliomas are the tumor of glial cells found in Central nervous System. High Grade Gliomas are rare in pediatric age group. Definitive diagnosis is made by histopathological examination. A 2 ½ year old male admitted with the complaint of abnormal tonic-clonic body movements along with headache, nausea, vomiting and fever. CT scan showed a poorly circumscribed hypodense lesion involving frontoparietal region. Surgery was performed and specimen sent for histopathological examination. Histopathological examination showed mfeatures of high grade glioma like microvascular proliferation, necrosis and haemorrhage. Cerebral tumors are the most common childhood neoplastic tumors. Gliomas are generally classified into low grade glioma and high grade glioma. High Grade glioma is rare in pediatric age group. Most commonly they present in supra tentorial compartment. The most common cerebral cortex involved are frontal lobe followed by parietal and temporal. Clinical signs and symptoms of High grade gliomas are seizure, headache, nausea, vomiting and visual disturbances. CT scan showed a poorly circumscribed hypodense lesion involving left frontoparietal region mainly. Definitive diagnosis of high grade glioma is by histopathological examination. Histopathological examination showed hypercellular heterogeneous tumor lying on a fibrillary background. Areas of microvascular proliferation along with necrosis and haemorrhage are also seen. Surgical resection followed by chemotherapy and local radiotherapy are the present recommendation. High grade gliomas are rare pediatric tumor associated with poor outcome. Surgery was performed due to neurological worsening, which was unsuccessful and patient died. Diagnosis was confirmed on histopathological examination. Poor prognosis and high morbidity even after evolution of treatment, demands further research to improve the prognosis and reduce morbidities.
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Lulla, Rishi R., Amanda Muhs Saratsis, and Rintaro Hashizume. "Mutations in chromatin machinery and pediatric high-grade glioma." Science Advances 2, no. 3 (March 2016): e1501354. http://dx.doi.org/10.1126/sciadv.1501354.
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Pediatric central nervous system tumors are the most common solid tumor of childhood. Of these, approximately one-third are gliomas that exhibit diverse biological behaviors in the unique context of the developing nervous system. Although low-grade gliomas predominate and have favorable outcomes, up to 20% of pediatric gliomas are high-grade. These tumors are a major contributor to cancer-related morbidity and mortality in infants, children, and adolescents, with long-term survival rates of only 10 to 15%. The recent discovery of somatic oncogenic mutations affecting chromatin regulation in pediatric high-grade glioma has markedly improved our understanding of disease pathogenesis, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. We review the current perspective on pediatric high-grade glioma genetics and epigenetics, and discuss the emerging and experimental therapeutics targeting the unique molecular abnormalities present in these deadly childhood brain tumors.
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Nechipay, E. A., M. B. Dolgushin, A. I. Pronin, E. A. Kobyakova, and L. M. Fadeeva. "Dynamic Contrast Enhanced MRI in Glioma Diagnosis." Medical Visualization, no. 4 (August 28, 2017): 88–96. http://dx.doi.org/10.24835/1607-0763-2017-4-88-96.
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The aim: to examine the possibility of using dynamic contrast enhanced magnetic resonance imaging (DCE MRI) in clarifying the diagnosis of glial brain tumors and the differentiation between them on the basis of the malignancy degree. In this regard, the authors evaluated the effectiveness of perfusion parameters (Ktrans, Kep, Ve and iAUC).Materials and methods.The study included examination of 54 patients with an established presence of brain glial tumors. Glioma Grade I–II diagnosed in 13 (24.1%) and glioma Grade III–IV in 41 (75.9%) cases. Morphological verification of the diagnosis obtained as a result of either surgical removal of the tumor or stereotactic biopsy was achieved in 31 (57.4%) patients: glial tumors Grade I–II identified in 6 (19.4%), and glioma Grade III–IV – 25 (80.6%) cases. Results. According to DCE increasing of the malignancy degree of glial tumors is followed by increasing of all perfusion parameters: thus, the lowest values of Ktrans, Kep, Ve and iAUC were identified in low grade gliomas (0.026 min−1, 0.845 min−1, 0.024 and 1.757, respectively), the highest in gliomas Grade III–IV (0.052 min−1 1.083 min−1, 0.06 and 2.694, respectively). The most informative parameters with sensi tivity 90% and specificity 100% in the differential diagnosis of gliomas Grade I-II and Grade III-IV are Ktrans (cut-off = 0.16 min−1) and Ve (cut-off = 0.13).Conclusion.DCE MRI can be used in differential diagnosis of glial brain tumors of different malignancy grade.
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Van Houdt, Winan J., Yosef S. Haviv, Baogen Lu, Minghui Wang, Angel A. Rivera, Ilya V. Ulasov, Martine L. M. Lamfers, et al. "The human survivin promoter: a novel transcriptional targeting strategy for treatment of glioma." Journal of Neurosurgery 104, no. 4 (April 2006): 583–92. http://dx.doi.org/10.3171/jns.2006.104.4.583.
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Object Malignant brain tumors have been proved to be resistant to standard treatments and therefore require new therapeutic strategies. Survivin, a recently described member of the inhibitor of apoptosis protein family, is overexpressed in several human brain tumors, primarily gliomas, but is downregulated in normal tissues. The authors hypothesized that the expression of tumor-specific survivin could be exploited for treatment of gliomas by targeting the tumors with gene therapy vectors. Methods Following confirmation of survivin expression in glioma cell lines, an adenoviral vector containing the survivin promoter and the reporter gene luciferase was tested in established and primary glioma cells, normal astrocytic cells, and normal human brain tissues. High levels of reporter gene expression were observed in established tumor and primary tumor cell lines and low levels of expression in astrocytes and normal human brain tissue. To test oncolytic potency, the authors constructed survivin promoter–based conditionally replicative adenoviruses (CRAds), composed of survivin promoter–regulated E1 gene expression and an RGD-4C capsid modification. These CRAds could efficiently replicate within and kill a variety of established glioma tumor cells, but were inactive in a normal human liver organ culture. Finally, survivin promoter–based CRAds significantly inhibited the growth of glioma xenografts in vivo. Conclusions Together these data indicate that the survivin promoter is a promising tumor-specific promoter for transcriptional targeting of adenovirus-based vectors and CRAds for malignant gliomas. The strategy of using survivin–CRAds may thus translate into an experimental therapeutic approach that can be used in human clinical trials.
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Costa, Amanda De Andrade, and David H. Gutmann. "Brain tumors in neurofibromatosis type 1." Neuro-Oncology Advances 2, Supplement_1 (October 26, 2019): i85—i97. http://dx.doi.org/10.1093/noajnl/vdz040.
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Abstract AbstractAs a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One of the most common locations for these cancers is the central nervous system, where low-grade gliomas predominate in children. During early childhood, gliomas affecting the optic pathway are most frequently encountered, whereas gliomas of the brainstem and other locations are observed in slightly older children. In contrast, the majority of gliomas arising in adults with NF1 are malignant cancers, typically glioblastoma, involving the cerebral hemispheres. Our understanding of the pathogenesis of NF1-associated gliomas has been significantly advanced through the use of genetically engineered mice, yielding new targets for therapeutic drug design and evaluation. In addition, Nf1 murine glioma models have served as instructive platforms for defining the cell of origin of these tumors, elucidating the critical role of the tumor microenvironment in determining tumor growth and vision loss, and determining how cancer risk factors (sex, germline NF1 mutation) impact on glioma formation and progression. Moreover, these preclinical models have permitted early phase analysis of promising drugs that reduce tumor growth and attenuate vision loss, as an initial step prior to translation to human clinical trials.
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Tamura, Kaoru, Masaru Aoyagi, Noboru Ando, Takahiro Ogishima, Hiroaki Wakimoto, Masaaki Yamamoto, and Kikuo Ohno. "Expansion of CD133-positive glioma cells in recurrent de novo glioblastomas after radiotherapy and chemotherapy." Journal of Neurosurgery 119, no. 5 (November 2013): 1145–55. http://dx.doi.org/10.3171/2013.7.jns122417.
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Object Recent evidence suggests that a glioma stem cell subpopulation may determine the biological behavior of tumors, including resistance to therapy. To investigate this hypothesis, the authors examined varying grades of gliomas for stem cell marker expressions and histopathological changes between primary and recurrent tumors. Methods Tumor samples were collected during surgery from 70 patients with varying grades of gliomas (Grade II in 12 patients, Grade III in 16, and Grade IV in 42) prior to any adjuvant treatment. The samples were subjected to immunohistochemistry for MIB-1, factor VIII, GFAP, and stem cell markers (CD133 and nestin). Histopathological changes were compared between primary and recurrent tumors in 31 patients after radiation treatment and chemotherapy, including high-dose irradiation with additional stereotactic radiosurgery. Results CD133 expression on glioma cells was confined to de novo glioblastomas but was not observed in lower-grade gliomas. In de novo glioblastomas, the mean percentage of CD133-positive glioma cells in sections obtained at recurrence was 12.2% ± 10.3%, which was significantly higher than that obtained at the primary surgery (1.08% ± 1.78%). CD133 and Ki 67 dual-positive glioma cells were significantly increased in recurrent de novo glioblastomas as compared with those in primary tumors (14.5% ± 6.67% vs 2.16% ± 2.60%, respectively). In contrast, secondary glioblastomas rarely expressed CD133 antigen even after malignant progression following radiotherapy and chemotherapy. Conclusions The authors' results indicate that CD133-positive glioma stem cells could survive, change to a proliferative cancer stem cell phenotype, and cause recurrence in cases with de novo glioblastomas after radiotherapy and chemotherapy.
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Hicks, William H., Cylaina E. Bird, Jeffrey I. Traylor, Diana D. Shi, Tarek Y. El Ahmadieh, Timothy E. Richardson, Samuel K. McBrayer, and Kalil G. Abdullah. "Contemporary Mouse Models in Glioma Research." Cells 10, no. 3 (March 23, 2021): 712. http://dx.doi.org/10.3390/cells10030712.
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Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models.
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Comba, Andrea, Patrick J. Dunn, Anna E. Argento, Padma Kadiyala, Maria Ventosa, Priti Patel, Daniel B. Zamler, et al. "Fyn tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates antiglioma immune responses." Neuro-Oncology 22, no. 6 (January 17, 2020): 806–18. http://dx.doi.org/10.1093/neuonc/noaa006.
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Abstract Background High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. Fyn tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinase pathway and is overexpressed in human gliomas. Fyn’s role in vivo in glioma growth remains unknown. We investigated whether Fyn regulates glioma initiation, growth and invasion. Methods We evaluated the role of Fyn using genetically engineered mouse glioma models (GEMMs). We also generated Fyn knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (nonobese diabetic severe combined immunodeficient gamma mice [NSG], CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA sequencing and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the Fyn knockdown glioma TME. Results We demonstrate that Fyn knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontology (GO) analysis of differentially expressed genes in wild-type versus Fyn knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG and CD8−/− and CD4−/− immune-deficient mice, Fyn knockdown gliomas failed to show differences in survival. These data suggest that the expression of Fyn in glioma cells reduces antiglioma immune activation. Examination of glioma immune infiltrates by flow cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells in the Fyn glioma TME. Conclusions Gliomas employ Fyn mediated mechanisms to enhance immune suppression and promote tumor progression. We propose that Fyn inhibition within glioma cells could improve the efficacy of antiglioma immunotherapies.
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Andersen, Johannes K., Hrvoje Miletic, and Jubayer A. Hossain. "Tumor-Associated Macrophages in Gliomas—Basic Insights and Treatment Opportunities." Cancers 14, no. 5 (March 4, 2022): 1319. http://dx.doi.org/10.3390/cancers14051319.
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Glioma refers to a group of primary brain tumors which includes glioblastoma (GBM), astrocytoma and oligodendroglioma as major entities. Among these, GBM is the most frequent and most malignant one. The highly infiltrative nature of gliomas, and their intrinsic intra- and intertumoral heterogeneity, pose challenges towards developing effective treatments. The glioma microenvironment, in addition, is also thought to play a critical role during tumor development and treatment course. Unlike most other solid tumors, the glioma microenvironment is dominated by macrophages and microglia—collectively known as tumor-associated macrophages (TAMs). TAMs, like their homeostatic counterparts, are plastic in nature and can polarize to either pro-inflammatory or immunosuppressive states. Many lines of evidence suggest that immunosuppressive TAMs dominate the glioma microenvironment, which fosters tumor development, contributes to tumor aggressiveness and recurrence and, very importantly, impedes the therapeutic effect of various treatment regimens. However, through the development of new therapeutic strategies, TAMs can potentially be shifted towards a proinflammatory state which is of great therapeutic interest. In this review, we will discuss various aspects of TAMs in the context of glioma. The focus will be on the basic biology of TAMs in the central nervous system (CNS), potential biomarkers, critical evaluation of model systems for studying TAMs and finally, special attention will be given to the potential targeted therapeutic options that involve the TAM compartment in gliomas.
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Varela, Maria Luisa, Andrea Comba, Mohammad Faisal Syed, Bhuvna R. Murthy, Marcus N. Barissi, Maria Castro, and Pedro Lowenstein. "CNSC-14. ROLE OF A COLLAGEN RECEPTOR, LAIR-1, IN GLIOMA CELLS: A POTENTIAL THERAPEUTIC TARGET." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii24—vii25. http://dx.doi.org/10.1093/neuonc/noac209.095.
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Abstract Most primary brain tumors are gliomas, among which Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. GBM has a median survival of 15-18 months, and despite extensive research remains incurable. Previous work in our lab has shown the importance of Collagen I, expressed by glioma cells, in glioma growth. Employing genetically engineered mouse models (GEMM) of glioma, NPA (NRas, shP53, shATRX), we identified that Collagen 1α1 (Col1A1) plays a key role in tumor malignancy. Molecular ablation of Col1A1 extends median survival, with a reduction in migration and proliferation. However, the mechanisms underlining these changes in survival, and the receptors mediating these effects remain unknown. Several collagen receptors are present in glioma cells. LAIR-1 is a collagen receptor that was originally described as an inhibitory receptor in hematopoietic cells. Since then, it has been demonstrated that LAIR-1 plays critical roles in the immune imbalance of autoimmune diseases and cancers. There have been several studies postulating the expression of LAIR-1 in tumor cells, including non-hematopoietic tumors. These studies suggest that LAIR-1 may constitute a novel receptor that tumor cells exploit to promote tumor growth and achieve immune evasion, yet its role in glioma remains unclear. Here we describe that glioma cells express LAIR-1, and that its molecular ablation in vitro showed reduced cell proliferation. In addition, GEMM lacking LAIR-1 (NRas, shP53, shATRX, shLAIR-1) exhibit improved median survival. Our preliminary data suggest that LAIR-1 expressed in glioma cells has a role in glioma aggressiveness. Currently we are further characterizing the role of LAIR-1 in high grade gliomas, as well as its potential as a therapeutic target. We hypothesize that blocking the interaction between LAIR-1 and collagen in the tumor microenvironment may improve median survival by reducing tumor proliferation.
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Nassiri, Farshad, Ankur Chakravarthy, Shengrui Feng, Roxana Shen, Romina Nejad, Jeffrey Zuccato, Mathew Voisin, et al. "BIOM-62 SENSITIVE DETECTION AND DISCRIMINATION OF INTRACRANIAL TUMORS BY BLOOD." Neuro-Oncology 22, Supplement_2 (November 2020): ii15. http://dx.doi.org/10.1093/neuonc/noaa215.059.
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Abstract BACKGROUND The diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Non-invasive diagnostic approaches, particularly for patients with brain tumours, provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. We reasoned that DNA methylation profiles of circulating tumor DNA in blood can be used as a clinically useful biomarker for patients with brain tumors, given the specificity of DNA methylation profiles for cell-of-origin. METHODS We generated methylation profiles on the plasma of 608 patients with cancer (219 intracranial, 388 extracranial) and 60 healthy controls using a cell-free methylated DNA immunoprecipitation combined with deep sequencing (cfMeDIP-seq) approach. Using machine-learning approaches we generated and evaluated models to distinguish brain tumors from extracranial cancers that may metastasize to the brain, as well as additional models to discriminate common brain tumors included in the differential diagnosis of solitary extra-axial and intra-axial tumors. RESULTS We observed high sensitivity and discriminative capacity for our models to distinguish gliomas from other cancerous and healthy patients (AUC=0.99, 95%CI 0.96–1), with similar performance in IDH mutant and wildtype gliomas as well as in lower- and high-grade gliomas. Excluding non-malignant contributors to plasma methylation did not change model performance (AUC=0.982, 95%CI 0.93–1). Models generated to discriminate intracranial tumors from each other also demonstrated high accuracy for common extra-axial tumors (AUCmeningioma=0.89, 95%CI 0.80–0.97; AUChemangiopericytoma=0.95, 95%CI 0.73–1) as well as intra-axial tumors ranging from low-grade indolent glial-neuronal tumors (AUC 0.93, 95%CI 0.80 – 1) to diffuse intra-axial gliomas with distinct molecular composition (AUCIDH-mutant glioma = 0.82, 95%CI 0.66 -0.98; AUCIDH-wildtype-glioma = 0.71, 95%CI 0.53 – 0.9). Plasma cfMeDIP-seq signals originated from corresponding tumor tissue DNA methylation signals (r=0.37, p< 2.2e-16). CONCLUSIONS These results demonstrate the potential for cfMeDIP-seq profiles to not only detect circulating tumor DNA, but to accurately discriminate common intracranial tumors that share cell-of-origin lineages.
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Merickel, Joshua L., G. Elizabeth Pluhar, Aaron Rendahl, and M. Gerard O’Sullivan. "Prognostic histopathologic features of canine glial tumors." Veterinary Pathology 58, no. 5 (July 5, 2021): 945–51. http://dx.doi.org/10.1177/03009858211025795.
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Gliomas are relatively common tumors in aged dogs (especially brachycephalic breeds), and the dog is proving to be useful as a translational model for humans with brain tumors. Hitherto, there is relatively little prognostic data for canine gliomas and none on outcome related to specific histological features. Histologic sections of tumor biopsies from 33 dogs with glioma treated with surgical resection and immunotherapy and 21 whole brains obtained postmortem were reviewed. Tumors were diagnosed as astrocytic, oligodendroglial, or undefined glioma using Comparative Brain Tumor Consortium criteria. Putative features of malignancy were evaluated, namely, mitotic counts, glomeruloid vascularization, and necrosis. For biopsies, dogs with astrocytic tumors lived longer than those with oligodendroglial or undefined tumor types (median survival 743, 205, and 144 days, respectively). Dogs with low-grade gliomas lived longer than those with high-grade gliomas (median survival 734 and 194 days, respectively). Based on analysis of tumor biopsies, low mitotic counts, absence of glomeruloid vascularization, and absence of necrosis correlated with increased survival (median 293, 223, and 220 days, respectively), whereas high mitotic counts, glomeruloid vascularization, and necrosis correlated with poor survival (median 190, 170, and 154 days, respectively). Mitotic count was the only histological feature in biopsy samples that significantly correlated with survival ( P < .05). Whole-brain analyses for those same histologic features had similar and more robust correlations, and were statistically significant for all features ( P < .05). The small size of biopsy samples may explain differences between biopsy and whole-brain tumor data. These findings will allow more accurate prognosis for gliomas.
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Casili, Giovanna, Marika Lanza, Alessia Filippone, Maria Caffo, Irene Paterniti, Michela Campolo, Lorenzo Colarossi, et al. "Overview on Common Genes Involved in the Onset of Glioma and on the Role of Migraine as Risk Factor: Predictive Biomarkers or Therapeutic Targets?" Journal of Personalized Medicine 12, no. 12 (November 28, 2022): 1969. http://dx.doi.org/10.3390/jpm12121969.
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Gliomas are relatively rare but fatal cancers, and there has been insufficient research to specifically evaluate the role of headache as a risk factor. Nowadays, gliomas are difficult to cure due to the infiltrative nature and the absence of specific adjuvant therapies. Until now, mutations in hundreds of genes have been identified in gliomas and most relevant discoveries showed specific genes alterations related to migraine as potential risk factors for brain tumor onset. Prognostic biomarkers are required at the time of diagnosis to better adapt therapies for cancer patients. In this review, we aimed to highlight the significant modulation of CLOCK, BMLA1 and NOTCH genes in glioma onset and development, praising these genes to be good as potentially attractive therapeutic markers for brain tumors. A improved knowledge regarding the role of these genes in triggering or modulating glioma maybe the key to early diagnosing brain tumor onset in patients affected by a simple headache. In addition, investigating on these genes we can suggest potential therapeutic targets for treating brain tumors. These considerations open up the possibility of personalized treatments that can target each brain tumor’s specific genetic abnormality.
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Rao, Rohit, Rong Han, Sean Ogurek, Lai Man Wu, Liguo Zhang, Jian Hu, Matthew Garrett, Tim Phoenix, Stephen N. Waggoner, and Qing Richard Lu. "TAMI-31. GLIOBLASTOMA GENETIC DRIVERS DICTATE THE FUNCTION OF TUMOR-ASSOCIATED MACROPHAGES/MICROGLIA AND RESPONSES TO CSF1R INHIBITION." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi204. http://dx.doi.org/10.1093/neuonc/noab196.815.
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Abstract Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting. We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth and progression. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment compositions and functions between the proneural-like and mesenchymal-like glioma models. We found that the growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal human GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas mesenchymal RAS-driven gliomas elicited TAMs enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and tumor mass in RAS-driven gliomas. Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of microenvironment landscape characterization to optimally stratify glioma patients for TAM-targeted therapy.
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Tatman, Philip, Tadeusz Wroblewski, Anthony Fringuello, Sam Scherer, William Foreman, Denise Damek, Samy Youssef, Kevin Lillehei, David Ormond, and Michael Graner. "DDRE-10. SCREENING OF EPIGENETIC COMPOUNDS IN GLIOMA AND GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTICS FOR THEIR POTENTIAL TREATMENT." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi76. http://dx.doi.org/10.1093/neuonc/noab196.294.
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Abstract BACKGROUND 28% of primary central nervous system tumors are glioma and glioblastoma. These tumors are responsible for 80% of malignant brain neoplasms and most brain tumor related deaths. Despite modern therapies, patients with grade II gliomas have an average survival of 8-15 years, while patients with grade III tumors have an average survival of 3-5 years, and patients with glioblastoma have an average survival of 12-15 months. The lack of a curative treatment for this group of tumors supports additional research and novel approaches to identify more effective therapies. METHODS In this study, we developed a high-throughput drug screen and culture system to identify epigenetic inhibitor compounds with the potential to reduce glioma and glioblastoma viability. RESULTS We screened 33 tumors: 18 glioblastoma, 8 oligodendroglioma, and 7 astrocytoma. The top three most effective compounds across the full glioma cohort were all HDAC inhibitors; in order from most effective: panobinostat (average tumor viability = 52.5% +/-14.1SD; p=2.16x10-61), LAQ824 (average tumor viability = 58.1% +/-18SD; p=1.48x10-45), and HC Toxin (average tumor viability = 64% +/-21.1SD; p= 1.16x10-33). Additionally, HDAC inhibition was also the most effective across each histopathological glioma type: astrocytoma, oligodendroglioma, and glioblastoma. UNC0631(G9a inhibitor) and JIB-04(KDM inhibitor) were the most effective compounds in the six recurrent tumors, though HDAC inhibition was still significantly effective in this group. We also evaluated drug sensitivity with respect to tumor grade, prior treatment, de novo vs progressive etiology, EGFR amplification, IDH mutation, MGMT methylation, and patient gender. CONCLUSIONS After screening a large glioma cohort against a panel of epigenetic inhibitors, we found HDAC inhibition most effectively reduced tumor viability across all histopathological types and grades. These findings require further in vivo validation.
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Yu, Kai, Yuqiong Hu, Fan Wu, Qiufang Guo, Zenghui Qian, Waner Hu, Jing Chen, et al. "Surveying brain tumor heterogeneity by single-cell RNA-sequencing of multi-sector biopsies." National Science Review 7, no. 8 (May 30, 2020): 1306–18. http://dx.doi.org/10.1093/nsr/nwaa099.
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Abstract Brain tumors are among the most challenging human tumors for which the mechanisms driving progression and heterogeneity remain poorly understood. We combined single-cell RNA-seq with multi-sector biopsies to sample and analyze single-cell expression profiles of gliomas from 13 Chinese patients. After classifying individual cells, we generated a spatial and temporal landscape of glioma that revealed the patterns of invasion between the different sub-regions of gliomas. We also used single-cell inferred copy number variations and pseudotime trajectories to inform on the crucial branches that dominate tumor progression. The dynamic cell components of the multi-region biopsy analysis allowed us to spatially deconvolute with unprecedented accuracy the transcriptomic features of the core and those of the periphery of glioma at single-cell level. Through this rich and geographically detailed dataset, we were also able to characterize and construct the chemokine and chemokine receptor interactions that exist among different tumor and non-tumor cells. This study provides the first spatial-level analysis of the cellular states that characterize human gliomas. It also presents an initial molecular map of the cross-talks between glioma cells and the surrounding microenvironment with single-cell resolution.
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Liu, Handong, and Keqi Hu. "The Long Intergenic Noncoding RNA 00707 Sponges MicroRNA-613 (miR-613) to Promote Proliferation and Invasion of Gliomas." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382096209. http://dx.doi.org/10.1177/1533033820962092.
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Background: Glioma is one of the most deadly malignant tumors in humans. Long non-coding RNA (lncRNA) plays a key role in the occurrence, development and invasion of tumors by regulating oncogenic and tumor suppressor pathways. However, the role and action mechanism of long intergenic non-coding RNA 00707 (LINC00707) in gliomas have not been elucidated. This study aimed to investigate the interaction between LINC00707 and miR-613 as well as its role in gliomas. Materials and Methods: The expression levels of LINC00707 and miR-613 were detected by qRT-PCR. The chi-square test was used to analyze the correlation between LINC00707 expression and clinicopathological parameters. CCK-8 and colony formation assays were used to detect glioma cell proliferation; and wound healing and transwell assays were used to detect glioma cell migration and invasion. The relationship between LINC00707 and miR-613 was predicted by Starbase, and verified by qRT-PCR and dual luciferase reporter gene assay. Results: LINC00707 was up-regulated in gliomas. Up-regulated LINC00707 increased the proliferation, migration and invasion of glioma cells, and silenced LINC00707 reduced these abilities. The increase of the expression level of LINC00707 down-regulated miR-613 in glioma cells, while the inhibition of the expression level of LINC00707 up-regulated miR-613 in glioma cells. The high expression of LINC00707 was related to the Karnofsky performance status (KPS) score and WHO staging. LINC00707 could offset the ability of miR-613 to inhibit glioma proliferation and invasion. Conclusion: LINC00707 promotes proliferation and invasion of glioma cells by sponging miR-613. The regulatory axis of LINC00707/miR-613 provides new insights into the mechanism and treatment of gliomas.
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Comba, Andrea, Syed M. Faisal, Maria Luisa Varela, Anna Argento, Patrick Dunn, Clifford Abel, Todd Hollon, et al. "TMIC-62. INHIBITION OF TUMOR-ASSOCIATED COL1A1 MATRIX ARRESTS GLIOMA MESENCHYMAL TRANSFORMATION AND REPROGRAMS THE TUMOR MICROENVIRONMENT." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii285. http://dx.doi.org/10.1093/neuonc/noac209.1106.
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Abstract Tumor mesenchymal transformation (MT) is a hallmark of high-grade gliomas. The mesenchymal state is associated with specific changes related to cell adhesion, migration, and the extracellular matrix. Collagen 1a1 (COL1A1) is a main component of the extracellular matrix in gliomas, and its expression correlates inversely with patient survival. However, the cellular and molecular mechanisms of the tumor-associated COL1A1 matrix in gliomas remains elusive. Our study integrates histopathological features, spatially resolved transcriptomics, cellular dynamics and microenvironment alterations associated with MT in high-grade gliomas. Using deep learning analysis of mouse and human glioma histological samples we identified that the density of areas of MT, named oncostreams, correlates with tumor aggressiveness. Spatial transcriptomics analysis, using laser capture microdissection, identified a signature enriched in extracellular matrix related proteins, in which COL1A1 appeared as a key determinant of mesenchymal organization. Correspondingly, human and mouse high-grade gliomas showed prominent alignment of collagen fibers along these mesenchymal fascicles and higher COL1A1 expression compared to low-grade gliomas. Moreover, RNA fluorescent multiplex assays identified at single cell level that different cells within glioma tumors contribute to COL1A1 expression, including neoplastic cells and perivascular non-neoplastic cells such as ACTA2+, CYR61+ and FAP+. Inhibition of COL1A1 using genetically engineered mouse models decreased areas of mesenchymal transformation and increased survival. COL1A1 downregulation impaired tumor cell proliferation and remodeled the tumor microenvironment by reducing CD68+ macrophages/microglia cells, CD31+ endothelial cells, ACTA2+, CYR61+ and FAP+ perivascular cells, and increased GFAP+ astrocytes infiltration withing the tumor mass. Further studies, using ex-vivo glioma explants demonstrated that CO1A1 downregulation decreased collective invasion of the normal brain, supporting its importance in tumor progression. We propose that COL1A1 expression is a valuable marker for diagnosis, and COL1A1 depletion within glioma tumors is a promising direct or complementary therapeutic approach to reprogram mesenchymal transformation, and halt tumor growth.
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Nayak, Sonali, Ashorne Mahenthiran, Yongyong Yang, Mark McClendon, Barbara Mania-Farnell, Charles David James, John A. Kessler, et al. "Bone Morphogenetic Protein 4 Targeting Glioma Stem-Like Cells for Malignant Glioma Treatment: Latest Advances and Implications for Clinical Application." Cancers 12, no. 2 (February 24, 2020): 516. http://dx.doi.org/10.3390/cancers12020516.
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Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicates its potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, with an emphasis on pediatric malignant gliomas. We also summarize BMP4 delivery strategies, highlighting biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.
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Badu, S. K. "The role of angiogenic factors eNOS / VEGF in the treatment of anaplastic glioma." Vestnik nevrologii, psihiatrii i nejrohirurgii (Bulletin of Neurology, Psychiatry and Neurosurgery), no. 11 (October 20, 2022): 883–92. http://dx.doi.org/10.33920/med-01-2211-07.
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Introduction: Anaplastic gliomas (AG) account for 6–15 % of all primary brain tumors. These include: anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligoastrocytoma (AOA), and rarer forms — anaplastic pleomorphic xanthoastrocytoma and anaplastic ganglioma. According to the data on these factors, endothelial nitric oxide synthase (eNOS) is promising in terms of the prognostic value of the course of the tumor process. It was reported that a number of vascular VEGF factors interact with eNOS, contributing to the formation of an intra-tumor vascular network, which can create conditions for uneven prolonged hypoxia, leading to the emergence of more stable tumor cells. Its role in the development of a higher anaplasia level has not been studied in isolation, which determines the relevance of this study. The prognostic role of changes in endothelial nitric oxide synthase (eNOS) in the continued growth and malignant transformation of anaplastic gliomas was studied. Results: Histological samples of brain tumors of 22 patients at the University Clinic in Nizhny Novgorod from 2017 to 2019 were examined and verified for the presence of high-grade III glioma, according to the data of the World Health Organization. The average age of the patients was 50.7 years. The material was obtained as a result of surgical removal of recurrent tumors after chemo and radiotherapy. Discussion: The microenvironment of anaplastic glioma plays an essential role in its pathogenesis. More importantly, angiogenesis, which causes the supply of glioma cells with oxygen, growth factors, nutrients, and hormones, is a significant process of tumor dissemination and growth. The degree of microvascular proliferation and angiogenesis was associated with poor survival rate, transition from a lower grade to a high grade, and relapse. In high-grade glioma, such as anaplastic glioma, neoangiogenesis is an important physiological process that provides adequate blood supply for the proliferation, survival, and invasion of glioma cells. Conclusion: The high mortality rate in gliomas underscores the urgent need for effective treatment. The glioma pathogenesis is complex and can be caused by various mechanisms, as evidenced by abnormal activation of tumor angiogenesis and mutation of isocitrate dehydrogenase. VEGF acts as a regulator of angiogenesis and is widely recognized as a critical factor in glioma development and progression. Our results suggest that VEGF and eNOS inhibition may be an effective way to control and/or block endothelial barrier damage and prevent tumor progression.
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Tom, Martin C., Daniel P. Cahill, Jan C. Buckner, Jörg Dietrich, Michael W. Parsons, and Jennifer S. Yu. "Management for Different Glioma Subtypes: Are All Low-Grade Gliomas Created Equal?" American Society of Clinical Oncology Educational Book, no. 39 (May 2019): 133–45. http://dx.doi.org/10.1200/edbk_238353.
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Following the identification of key molecular alterations that provided superior prognostication and led to the updated 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification, the understanding of glioma behavior has rapidly evolved. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are present in the majority of adult grade 2 and 3 gliomas, and when used in conjunction with 1p/19q codeletion for classification, the prognostic distinction between grade 2 versus grade 3 is diminished. As such, the previously often used term of “low-grade glioma,” which referred to grade 2 gliomas, has now been replaced by the phrase “lower-grade glioma” to encompass both grade 2 and 3 tumors. Additional molecular characterization is ongoing to even further classify this heterogeneous group of tumors. With such a colossal shift in the understanding of lower-grade gliomas, management of disease is being redefined in the setting of emerging molecular-genetic biomarkers. In this article, we review recent progress and future directions regarding the surgical, radiotherapeutic, chemotherapeutic, and long-term management of adult lower-grade gliomas.
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Campos Paiva, Aline, João Luiz Vitorino Araujo, Guilherme Brasileiro de Aguiar, Gabriel Rezende Batistella, Marcos Maldaum, and José Esteves veiga. "SURG-11. NEOADJUVANT CHEMOTHERAPY FOR DIFFUSE GLIOMAS: A FEASIBLE OPTION?" Neuro-Oncology 22, Supplement_2 (November 2020): ii205. http://dx.doi.org/10.1093/neuonc/noaa215.858.
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Abstract BACKGROUND Diffuse gliomas are slow-growing tumors with predilection for deep and eloquent structures such as supplementary motor area and insula. They can reach huge dimensions which is a surgical challenging. OBJECTIVE Describe indications and limitations of neoadjuvant chemotherapy for diffuse gliomas. METHODS Systematic review was performed in November/2019 using Pubmed, Bireme and Cochrane databases. The following combinations were used: “Chemotherapy” AND “neoadjuvant” AND “diffuse glioma”, “Chemotherapy” AND “neoadjuvant” AND “low grade glioma”, “Chemotherapy” AND “preoperative” AND “diffuse glioma”, “Neoadjuvant” AND “Chemotherapy” AND “temozolomide” AND “diffuse glioma”. RESULTS After carefully analysis, 7 papers were selected. They had mixed surgical interventions and used different drugs. In general, it was observed that neoadjuvant Temozolomide for Oligodendrogliomas 1p19q codeleted with MGMT methylation had better response than other molecular groups. Tumor reduction was significant. CONCLUSIONS Quality of life is a main goal in neurooncology. Tumor reduction using chemotherapy is a promising therapeutic. Surgery, especially in eloquent areas, could remove more tumors with less morbidity. Recent publications are using this approach with good outcomes, however further studies with more patients and uniformization are required to stablish this approach.
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XI, Guifa, Ashorne Mahenthiran, Benjamin Best, Sonali Nayak, Cara Smith, Mark McClendon, Barbara Mania-Farnell, et al. "EXTH-18. PEPTIDE NANO-STRUCTURES ENHANCE PEDIATRIC BRAIN TUMOR CHEMOTHERAPEUTIC EFFICACY." Neuro-Oncology 21, Supplement_6 (November 2019): vi86. http://dx.doi.org/10.1093/neuonc/noz175.352.
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Abstract Pediatric gliomas, particularly high-grade gliomas, which include diffuse intrinsic pontine gliomas (DIPGs), are among the most formidable and devastating cancers in children. These tumors remain incurable, despite many treatment approaches. We recently identified a small population of glioma cells with stem-like features in pediatric gliomas (glioma stem cells: GSCs), that may be responsible, for therapeutic resistance. Bone morphogenetic protein 4 (BMP4), essential for CNS development, increases GSC therapeutic sensitivity and is a promising adjuvant for glioma treatment. Mechanisms through which BMP4 increases therapeutic sensitivity need to be elucidated, as this can lead to identification of additional treatment targets and delivery systems for BMP4 administration in a clinical setting. Additionally, extension of BMP4 short half-life would enhance its’ clinical application. Here we show that BMP4 increases chemosensitivity by decreasing H3K4me3 at the promoter of multidrug resistant gene 1 (MDR1), resulting in decreased MDR1 expression. BMP4 appears to bring about this effect by decreasing hSETD1A, an H3K4me3 methyltransferase. Our work also demonstrates the first use of a novel sulfated glycopeptide (glyco-PA) nanostructure as a vector for BMP4 delivery. Glyco-PA markedly extended and enhanced BMP4 function, and increased chemotherapeutic anti-tumor activity against pediatric malignant glioma cells in culture. Overall, this work illuminates BMP4 effects on pediatric glioma therapeutic sensitivity through epigenetic mechanisms, and demonstrates the potential of bioactive glyco-PA nanostructures as a delivery mechanism for treating pediatric malignant gliomas and other tumors.
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Chaturvedi, Sneha, Arohi Saxena, Ahmad Hassan, and Nicole Brossier. "NFB-23. Extent of tumor but not location may be predictive of longitudinal disease severity in children with NF1-associated gliomas requiring treatment." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i132—i133. http://dx.doi.org/10.1093/neuonc/noac079.483.
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Abstract BACKGROUND: Children with Neurofibromatosis Type 1 (NF1) are at risk for developing gliomas in multiple locations, particularly the optic pathway and brainstem. The goal of this study is to determine if glioma location in NF1 impacts tumor progression and accumulation of neurological deficits over time. METHODS: Retrospective chart review of 98 pediatric patients with NF1-associated gliomas between 1999-2021 at St. Louis Children’s Hospital. Patients who had never received treatment were excluded from analysis. Each glioma was categorized into one of four locations: posterior fossa (PF, n=12, 21%), supratentorial midline (SM, n=33, 57%) supratentorial cortical (SC, n=4, 7%), brainstem (BS, n=9, 15%). Patients with gliomas in different locations had each tumor counted separately (58 total gliomas analyzed). RESULTS: No SC tumors progressed. Time to first progression was comparable across the other 3 locations, and there was no meaningful different in neurologic deficits over time by tumor location. The majority of patients who demonstrated three or more clinical or radiographic progressions had tumors in the SM region. Within the SM tumor group, each tumor was further characterized as a deep extensive glioma (DEG; 36%) or an optic pathway glioma without deep extension (nonDEG; 64%). DEG had a slightly higher number of neurological deficits at baseline (DEG 2.08, nonDEG 1.19), fewer patients with no neurologic deficits (8.3% DEG vs 28.6% nonDEG) and a higher proportion of patients with a first progression event (41% DEG vs 24% nonDEG). However, DEG and nonDEG had similar risk of subsequent progressions after the initial event. CONCLUSION: Among children with NF1 who required glioma treatment, location was not a significant predictor of multiple progression or neurologic morbidity over time. Within the SM location, DEGs represent a newly characterized group that exhibit potentially higher rates of progression and neurological deficits. Multi-institutional analysis is needed to confirm these findings.
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Du, Peng, Hongyi Chen, Kun Lv, and Daoying Geng. "A Survey of Radiomics in Precision Diagnosis and Treatment of Adult Gliomas." Journal of Clinical Medicine 11, no. 13 (June 30, 2022): 3802. http://dx.doi.org/10.3390/jcm11133802.
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Glioma is the most common primary malignant tumor of the adult central nervous system (CNS), which mostly shows invasive growth. In most cases, surgery is often difficult to completely remove, and the recurrence rate and mortality of patients are high. With the continuous development of molecular genetics and the great progress of molecular biology technology, more and more molecular biomarkers have been proved to have important guiding significance in the individualized diagnosis, treatment, and prognosis evaluation of glioma. With the updates of the World Health Organization (WHO) classification of tumors of the CNS in 2021, the diagnosis and treatment of glioma has entered the era of precision medicine in the true sense. Due to its ability to non-invasively achieve accurate identification of glioma from other intracranial tumors, and to predict the grade, genotyping, treatment response, and prognosis of glioma, which provides a scientific basis for the clinical application of individualized diagnosis and treatment model of glioma, radiomics has become a research hotspot in the field of precision medicine. This paper reviewed the research related to radiomics of adult gliomas published in recent years and summarized the research proceedings of radiomics in differential diagnosis, preoperative grading and genotyping, treatment and efficacy evaluation, and survival prediction of adult gliomas.
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Pisapia, David J. "The Updated World Health Organization Glioma Classification: Cellular and Molecular Origins of Adult Infiltrating Gliomas." Archives of Pathology & Laboratory Medicine 141, no. 12 (December 1, 2017): 1633–45. http://dx.doi.org/10.5858/arpa.2016-0493-ra.
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Context.— In the recently updated World Health Organization (WHO) classification of central nervous system tumors, our concept of infiltrating gliomas as a molecular dichotomy between oligodendroglial and astrocytic tumors has been codified. Advances in animal models of glioma and a wealth of sophisticated molecular analyses of human glioma tissue have led to a greater understanding of some of the biologic underpinnings of gliomagenesis. Objective.— To review our understanding of gliomagenesis in the setting of the recently updated WHO classification of central nervous system tumors. Topics addressed include a summary of an updated diagnostic schema for infiltrating gliomas, the crucial importance of isocitrate dehydrogenase mutations, candidate cells of origin for gliomas, environmental and other posited contributing factors to gliomagenesis, and the possible role of chromatin topology in setting the stage for gliomagenesis. Data Sources.— We conducted a primary literature search using PubMed. Conclusions.— With multidimensional molecular data sets spanning increasingly larger numbers of patients with infiltrating gliomas, our understanding of the disease at the point of surgical resection has improved dramatically and this understanding is reflected in the updated WHO classification. Animal models have demonstrated a diversity of candidates for glioma cells of origin, but crucial questions remain, including the role of neural stem cells, more differentiated progenitor cells, and glioma stem cells. At this stage the increase in data generated from human samples will hopefully inform the creation of newer animal models that will recapitulate more accurately the diversity of gliomas and provide novel insights into the biologic mechanisms underlying tumor initiation and progression.
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Robinson, M. Hope, Juan Vasquez, Akhilesh Kaushal, Tobey J. MacDonald, José E. Velázquez Vega, Matthew Schniederjan, and Kavita Dhodapkar. "Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma." Journal for ImmunoTherapy of Cancer 8, no. 2 (August 2020): e001066. http://dx.doi.org/10.1136/jitc-2020-001066.
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Brain tumors are the leading cause of cancer-related mortality in children and have distinct genomic and molecular features compared with adult glioma. However, the properties of immune cells in these tumors has been vastly understudied compared with their adult counterparts. We combined multiplex immunofluorescence immunohistochemistry coupled with machine learning and single-cell mass cytometry to evaluate T-cells infiltrating pediatric glial tumors. We show that low-grade tumors are characterized by greater T-cell density compared with high-grade glioma (HGG). However, even among low-grade tumors, T-cell infiltration can be highly variable and subtype-dependent, with greater T-cell density in pleomorphic xanthoastrocytoma and ganglioglioma. CD3+ T-cell infiltration correlates inversely with the expression of SOX2, an embryonal stem cell marker commonly expressed by glial tumors. T-cells within both HGG and low-grade glioma (LGG) exhibit phenotypic heterogeneity and tissue-resident memory T-cells consist of distinct subsets of CD103+ and TCF1+ cells that exhibit distinct spatial localization patterns. TCF1+ T-cells are located closer to the vessels while CD103+ resident T-cells reside within the tumor further away from the vasculature. Recurrent tumors are characterized by a decline in CD103+ tumor-infiltrating T-cells. BRAFV600E mutation is immunogenic in children with LGG and may serve as a target for immune therapy. These data provide several novel insights into the subtype-dependent and grade-dependent changes in immune architecture in pediatric gliomas and suggest that harnessing tumor-resident T-cells may be essential to improve immune control in glioma.
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Zhang, Junfeng, Heng Liu, Haipeng Tong, Sumei Wang, Yizeng Yang, Gang Liu, and Weiguo Zhang. "Clinical Applications of Contrast-Enhanced Perfusion MRI Techniques in Gliomas: Recent Advances and Current Challenges." Contrast Media & Molecular Imaging 2017 (2017): 1–27. http://dx.doi.org/10.1155/2017/7064120.
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Gliomas possess complex and heterogeneous vasculatures with abnormal hemodynamics. Despite considerable advances in diagnostic and therapeutic techniques for improving tumor management and patient care in recent years, the prognosis of malignant gliomas remains dismal. Perfusion-weighted magnetic resonance imaging techniques that could noninvasively provide superior information on vascular functionality have attracted much attention for evaluating brain tumors. However, nonconsensus imaging protocols and postprocessing analysis among different institutions impede their integration into standard-of-care imaging in clinic. And there have been very few studies providing a comprehensive evidence-based and systematic summary. This review first outlines the status of glioma theranostics and tumor-associated vascular pathology and then presents an overview of the principles of dynamic contrast-enhanced MRI (DCE-MRI) and dynamic susceptibility contrast-MRI (DSC-MRI), with emphasis on their recent clinical applications in gliomas including tumor grading, identification of molecular characteristics, differentiation of glioma from other brain tumors, treatment response assessment, and predicting prognosis. Current challenges and future perspectives are also highlighted.
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Groblewska, Magdalena, and Barbara Mroczko. "Pro- and Antiangiogenic Factors in Gliomas: Implications for Novel Therapeutic Possibilities." International Journal of Molecular Sciences 22, no. 11 (June 7, 2021): 6126. http://dx.doi.org/10.3390/ijms22116126.
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Angiogenesis, a complex, multistep process of forming new blood vessels, plays crucial role in normal development, embryogenesis, and wound healing. Malignant tumors characterized by increased proliferation also require new vasculature to provide an adequate supply of oxygen and nutrients for developing tumor. Gliomas are among the most frequent primary tumors of the central nervous system (CNS), characterized by increased new vessel formation. The processes of neoangiogenesis, necessary for glioma development, are mediated by numerous growth factors, cytokines, chemokines and other proteins. In contrast to other solid tumors, some biological conditions, such as the blood–brain barrier and the unique interplay between immune microenvironment and tumor, represent significant challenges in glioma therapy. Therefore, the objective of the study was to present the role of various proangiogenic factors in glioma angiogenesis as well as the differences between normal and tumoral angiogenesis. Another goal was to present novel therapeutic options in oncology approaches. We performed a thorough search via the PubMed database. In this paper we describe various proangiogenic factors in glioma vasculature development. The presented paper also reviews various antiangiogenic factors necessary in maintaining equilibrium between pro- and antiangiogenic processes. Furthermore, we present some novel possibilities of antiangiogenic therapy in this type of tumors.
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Kitano, Yotaro, Kosuke Aoki, Takao Yasui, Kazuya Motomura, Fumiharu Ohka, Kuniaki Tanahashi, Masaki Hirano, et al. "PATH-36. MACHINE LEARNING TO DETECT GLIOMAS IN URINE-BASED LIQUID BIOPSY." Neuro-Oncology 21, Supplement_6 (November 2019): vi151. http://dx.doi.org/10.1093/neuonc/noz175.632.
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Abstract BACKGROUND Diffuse gliomas are the most common primary malignant brain tumors, whose overall prognosis is quite dismal. Tumor-cell-secreted extracellular vesicles (EVs) participate in physiological and pathological processes and have potential applications to diagnostics of malignant tumors including diffuse gliomas. Because urine is less invasive to collect, development of early diagnosis based on urine EVs is eagerly awaited. In this study, we captured urine EVs of patients with gliomas efficiently with the nanowire device and compared expression profile of microRNAs (miRNAs) within urine EVs with that of healthy donors to identify diagnostic accuracy by a machine learning algorithm. METHODS 62 patients with diffuse gliomas, including 27 glioblastoma and 35 lower grade gliomas, and 100 healthy donors were analyzed, along with orthotopic transplant mouse model. Urinary EVs were obtained with the nanowire device which could collect EVs more efficiently than the conventional ultracentrifugation method (Yasui et.al., Science Adv.2017). Machine learning methods were performed to select the miRNAs which could distinguish patients with gliomas from healthy control. RESULTS More than 2400 miRNAs were obtained from all urine samples. We identified miRNA panels that provided high diagnostic accuracy of diffuse gliomas (92.5%). There were 440 miRNAs whose expression increased by more than 1.5 fold (p< 0.05) as compared to healthy donor samples (glioma-upregulated miRNAs), whereas the expression of 87 miRNAs decreased to less than 2/3-fold (p< 0.05) (glioma-downregulated miRNAs). Mouse miRNAs which were homologous to glioma-upregulated and -downregulated miRNAs showed significantly high and low level expressions, respectively, in glioma mouse models as compared to normal control mice, confirming the reliability of urine miRNA-based diagnosis. Furthermore, some of these glioma-upregulated miRNAs has been reported to be involved in tumor progression. CONCLUSIONS miRNAs obtained from urine could be biomarkers for detection of gliomas by machine learning and some of these could be associated with tumor progression.
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den Hartog, Sanne J., Anja van der Kolk, Annette Bruggink, Tatjana Seute, Pieter Wesseling, and Joyce Wilbers. "Pathology-proven extradural (“distant”) metastases of gliomas in adults in the Netherlands between 1971 and 2018: a systematic case series." Neuro-Oncology Practice 8, no. 3 (January 22, 2021): 317–24. http://dx.doi.org/10.1093/nop/npab006.
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Abstract Background Diffuse gliomas are the most frequent primary tumors originating in the central nervous system parenchyma. Although the majority of these tumors are highly malignant, extradural metastases (EDM) are extremely rare. We aimed to perform a systematic review of patients with pathology-proven EDM of diffuse gliomas in the Netherlands. Methods From the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands information on all cases with EDM between 1971 and October 2018 was retrieved. Patients aged < 18 years or with a diagnosis of ependymoma or continuous tumor growth from intradural to extradural were excluded. Demographics, initial tumor diagnosis, treatment characteristics, location of the EDM, and survival data were collected. IDH1 R132H immunohistochemistry was performed on cases in which a paraffin block of the metastatic tumor could be retrieved. Results Twenty-five patients with diffuse glioma and pathology-proven EDM were identified. Median age at diagnosis of glioma was 46 years (IQR: 35-59); 21 patients (84%) were male. Histopathologic diagnosis was glioblastoma in 17 patients (68%) and lower-grade tumor in eight patients. In 3 out of 12 patients of which a paraffin block could be retrieved immunohistochemistry revealed an IDH1-mutant glioma. Most frequent EDM locations were bone/bone marrow (14/25 patients; 56%), and lymph nodes (6/25 patients; 24%). Conclusion EDM of diffuse glioma are rare. They occur most frequently in patients with glioblastoma, however, they can also originate from lower-grade, IDH-mutant gliomas. In daily practice, EDM of diffuse glioma should be considered in patients with tumefactive lesions of the bone or lymph nodes.
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Hurmach, Y., M. Rudyk, V. Svyatetska, and L. Skivka. "Functional characteristics of circulating phagocytes in rats with C6 glioma." Bulletin of Taras Shevchenko National University of Kyiv. Series: Biology 76, no. 2 (2018): 12–16. http://dx.doi.org/10.17721/1728_2748.2018.76.12-16.
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Gliomas, tumors of the central nervous system, are a heterogeneous group of neoplasms of neuroectodermal origin. Gliomas are the most common primary brain tumors and cmprise about 80% of all malignant neoplasms of this location. The growth of malignant glioma is accompanied by the development of local and systemic immunosuppression that is a distinctive characteristics of the disease. At the early stages of tumor growth, glioma cells secrete numerous chemokines, cytokines and other biologically active mediators that contribute to the infiltration of tumor tissue by immune cells: resident microglial cells, as well as monocytes, granulocytes, T-cells, B-cells etc. Tumor-associated phagocytes comprise most significant part of the immunocytes in the microenvironment of malignant gliomas. These cells play a leading role in the development of local immunosuppression. The triggers of systemic immunosuppression, as well as the relationship between local and systemic immunosuppression is virtually unexplored and requires an in-depth study of the functional characteristics of circulating cells of the immune system. The aim of this work was to determine the phenotypic and functional characteristics of circulating phagocytes in rats with C6 glioma. Metabolic and phenotypic indices of circulating phagocytes were examined at different time point of tumor growth. It has been established that the late stages of C6 glioma growth in rats are associated with changes in the functional characteristics of peripheral blood mono- and polymorphonuclear phagocytes: a decrease in oxidative metabolism, an increase in phagocytic activity along with an increase CD206 expression. Taken together these alteration are characteristic for alternatively activated phagocytes that can participate in the development of glioma-associated systemic immunosupression. Keywords.