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Trends in Cancer Oct 2023Diffuse midline glioma (DMG) is a fatal pediatric cancer of the central nervous system (CNS). The location and infiltrative nature of DMG prevents surgical resection and... (Review)
Review
Diffuse midline glioma (DMG) is a fatal pediatric cancer of the central nervous system (CNS). The location and infiltrative nature of DMG prevents surgical resection and the benefits of palliative radiotherapy are temporary; median overall survival (OS) is 9-11 months. The tumor immune microenvironment (TIME) is 'cold', and has a dominant immunosuppressive myeloid compartment with low levels of infiltrating lymphocytes and proinflammatory molecules. Because survival statistics have been stagnant for many decades, and therapies targeting the unique biology of DMG are urgently needed, this has prompted the clinical assessment of chimeric antigen receptor (CAR) T cell therapies in this setting. We highlight the current landscape of CAR T cell therapy for DMG, the role the TIME may play in the response, and strategies to overcome treatment obstacles.
Topics: Child; Humans; Immunotherapy, Adoptive; Central Nervous System; Tumor Microenvironment; Glioma
PubMed: 37541803
DOI: 10.1016/j.trecan.2023.07.007 -
British Journal of Cancer Jan 2021The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide...
BACKGROUND
The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search for glioma risk factors.
METHODS
We performed an MR-PheWAS analysing 316 phenotypes, proxied by 8387 genetic variants, and summary genetic data from a GWAS of 12,488 glioma cases and 18,169 controls. Causal effects were estimated under a random-effects inverse-variance-weighted (IVW-RE) model, with robust adjusted profile score (MR-RAPS), weighted median and mode-based estimates computed to assess the robustness of findings. Odds ratios per one standard deviation increase in each phenotype were calculated for all glioma, glioblastoma (GBM) and non-GBM tumours.
RESULTS
No significant associations (P < 1.58 × 10) were observed between phenotypes and glioma under the IVW-RE model. Suggestive associations (1.58 × 10 < P < 0.05) were observed between leukocyte telomere length (LTL) with all glioma (OR = 3.91, P = 9.24 × 10) and GBM (OR = 4.86, P = 3.23 × 10), but the association was primarily driven by the TERT variant rs2736100. Serum low-density lipoprotein cholesterol and plasma HbA1C showed suggestive associations with glioma (OR = 1.11, P = 1.39 × 10 and OR = 1.28, P = 1.73 × 10, respectively), both associations being reliant on single genetic variants.
CONCLUSIONS
Our study provides further insight into the aetiological basis of glioma for which published data have been mixed.
Topics: Brain Neoplasms; Genetic Variation; Genome-Wide Association Study; Glioma; Humans; Mendelian Randomization Analysis; Risk Factors
PubMed: 33020596
DOI: 10.1038/s41416-020-01083-1 -
Current Treatment Options in Oncology Jul 2020Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a... (Review)
Review
Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compared with standard chemotherapy in patients with recurrent GBM (rGBM). TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. Having several MoAs makes TTFields an attractive modality to combine with standard, salvage, and novel treatment regimens (e.g., radiotherapy, chemotherapy, and immunotherapy). Treatment within the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in GBM, discuss MOA and treatment delivery, and consider the potential for its wider adoption in other gliomas.
Topics: Algorithms; Brain Neoplasms; Clinical Decision-Making; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Factor Analysis, Statistical; Glioblastoma; Glioma; Humans; Radiofrequency Ablation; Treatment Outcome
PubMed: 32734509
DOI: 10.1007/s11864-020-00773-5 -
Advances in Experimental Medicine and... 2023Benign glioma broadly refers to a heterogeneous group of slow-growing glial tumors with low proliferative rates and a more indolent clinical course. These tumors may...
Benign glioma broadly refers to a heterogeneous group of slow-growing glial tumors with low proliferative rates and a more indolent clinical course. These tumors may also be described as "low-grade" glioma (LGG) and are classified as WHO grade I or II lesions according to the Classification of Tumors of the Central Nervous System (CNS) (Louis et al. in Acta Neuropathol 114:97-109, 2007). Advances in molecular genetics have improved understanding of glioma tumorigenesis, leading to the identification of common mutation profiles with significant treatment and prognostic implications. The most recent WHO 2016 classification system has introduced several notable changes in the way that gliomas are diagnosed, with a new emphasis on molecular features as key factors in differentiation (Wesseling and Capper in Neuropathol Appl Neurobiol 44:139-150, 2018). Benign gliomas have a predilection for younger patients and are among the most frequently diagnosed tumors in children and young adults (Ostrom et al. in Neuro Oncol 22:iv1-iv96, 2020). These tumors can be separated into two clinically distinct subgroups. The first group is of focal, well-circumscribed lesions that notably are not associated with an increased risk of malignant transformation. Primarily diagnosed in pediatric patients, these WHO grade I tumors may be cured with surgical resection alone (Sturm et al. in J Clin Oncol 35:2370-2377, 2017). Recurrence rates are low, and the prognosis for these patients is excellent (Ostrom et al. in Neuro Oncol 22:iv1-iv96, 2020). Diffuse gliomas are WHO grade II lesions with a more infiltrative pattern of growth and high propensity for recurrence. These tumors are primarily diagnosed in young adult patients, and classically present with seizures (Pallud et al. Brain 137:449-462, 2014). The term "benign" is a misnomer in many cases, as the natural history of these tumors is with malignant transformation and recurrence as grade III or grade IV tumors (Jooma et al. in J Neurosurg 14:356-363, 2019). For all LGG, surgery with maximal safe resection is the treatment of choice for both primary and recurrent tumors. The goal of surgery should be for gross total resection (GTR), as complete tumor removal is associated with higher rates of tumor control and seizure freedom. Chemotherapy and radiation therapy (RT), while not typically a component of first-line treatment in most cases, may be employed as adjunctive therapy in high-risk or recurrent tumors and in some select cases. The prognosis of benign gliomas varies widely; non-infiltrative tumor subtypes generally have an excellent prognosis, while diffusely infiltrative tumors, although slow-growing, are eventually fatal (Sturm et al. in J Clin Oncol 35:2370-2377, 2017). This chapter reviews the shared and unique individual features of the benign glioma including diffuse glioma, pilocytic astrocytoma and pilomyxoid astrocytoma (PMA), subependymal giant cell astrocytoma (SEGA), pleomorphic xanthoastrocytoma (PXA), subependymoma (SE), angiocentric glioma (AG), and chordoid glioma (CG). Also discussed is ganglioglioma (GG), a mixed neuronal-glial tumor that represents a notable diagnosis in the differential for other LGG (Wesseling and Capper 2018). Ependymomas of the brain and spinal cord, including major histologic subtypes, are discussed in other chapters.
Topics: Young Adult; Humans; Child; Neoplasm Recurrence, Local; Brain Neoplasms; Glioma; Astrocytoma; Brain
PubMed: 37452934
DOI: 10.1007/978-3-031-23705-8_2 -
Nature Aug 2019Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of... (Comparative Study)
Comparative Study
Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.
Topics: Animals; Cerebellar Neoplasms; Cerebellum; Child; Evolution, Molecular; Female; Fetus; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Glioma; Humans; Medulloblastoma; Mice; Sequence Analysis, RNA; Single-Cell Analysis; Time Factors; Transcription, Genetic; Transcriptome
PubMed: 31043743
DOI: 10.1038/s41586-019-1158-7 -
Seminars in Cancer Biology Jun 2023Glioma represents a dominant primary intracranial malignancy in the central nervous system. Artificial intelligence that mainly includes machine learning, and deep... (Review)
Review
Glioma represents a dominant primary intracranial malignancy in the central nervous system. Artificial intelligence that mainly includes machine learning, and deep learning computational approaches, presents a unique opportunity to enhance clinical management of glioma through improving tumor segmentation, diagnosis, differentiation, grading, treatment, prediction of clinical outcomes (prognosis, and recurrence), molecular features, clinical classification, characterization of the tumor microenvironment, and drug discovery. A growing body of recent studies apply artificial intelligence-based models to disparate data sources of glioma, covering imaging modalities, digital pathology, high-throughput multi-omics data (especially emerging single-cell RNA sequencing and spatial transcriptome), etc. While these early findings are promising, future studies are required to normalize artificial intelligence-based models to improve the generalizability and interpretability of the results. Despite prominent issues, targeted clinical application of artificial intelligence approaches in glioma will facilitate the development of precision medicine of this field. If these challenges can be overcome, artificial intelligence has the potential to profoundly change the way patients with or at risk of glioma are provided with more rational care.
Topics: Humans; Artificial Intelligence; Glioma; Machine Learning; Brain Neoplasms; Precision Medicine; Tumor Microenvironment
PubMed: 36907387
DOI: 10.1016/j.semcancer.2023.03.006 -
Science Translational Medicine Jul 2020Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM...
Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor-1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has translational relevance for enhancing the efficacy of standard-of-care treatment in gliomas.
Topics: Animals; Glioblastoma; Glioma; Humans; Macrophages; Mice; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed: 32669424
DOI: 10.1126/scitranslmed.aaw7843 -
Continuum (Minneapolis, Minn.) Dec 2020This article highlights important aspects of the evaluation, diagnosis, and treatment of adult gliomas, including lower-grade astrocytomas and oligodendrogliomas,... (Review)
Review
PURPOSE OF REVIEW
This article highlights important aspects of the evaluation, diagnosis, and treatment of adult gliomas, including lower-grade astrocytomas and oligodendrogliomas, glioblastomas, and ependymomas.
RECENT FINDINGS
The appropriate initial evaluation and accurate diagnosis of gliomas require an understanding of the spectrum of clinical and radiographic presentations. Recent advances in the understanding of distinct molecular prognostic subtypes have led to major revisions in the diagnostic classification of gliomas. Integration of these new diagnostic and molecular classifications is an important part of the modern management of gliomas and facilitates better understanding and interpretation of the efficacy of different therapies in specific glioma subtypes.
SUMMARY
The management of adult gliomas is a multidisciplinary endeavor. However, despite recent molecular and treatment advances, the majority of diffuse gliomas remain incurable, and efforts aimed at the development and testing of new therapies in clinical trials are ongoing.
Topics: Adult; Astrocytoma; Brain Neoplasms; Glioblastoma; Glioma; Humans; Oligodendroglioma
PubMed: 33273168
DOI: 10.1212/CON.0000000000000935 -
Theranostics 2022Accumulating evidence demonstrated that long noncoding RNAs (lncRNAs) involved in the regulation of the immune system and displayed a cell-type-specific pattern in...
Machine learning-based identification of tumor-infiltrating immune cell-associated lncRNAs for improving outcomes and immunotherapy responses in patients with low-grade glioma.
Accumulating evidence demonstrated that long noncoding RNAs (lncRNAs) involved in the regulation of the immune system and displayed a cell-type-specific pattern in immune cell subsets. Given the vital role of tumor-infiltrating lymphocytes in effective immunotherapy, we explored the tumor-infiltrating immune cell-associated lncRNA (TIIClncRNA) in low-grade glioma (LGG), which has never been uncovered yet. This study utilized a novel computational framework and 10 machine learning algorithms (101 combinations) to screen out TIIClncRNAs by integratively analyzing the sequencing data of purified immune cells, LGG cell lines, and bulk LGG tissues. The established TIIClnc signature based on the 16 most potent TIIClncRNAs could predict outcomes in public datasets and the Xiangya in-house dataset with decent efficiency and showed better performance when compared with 95 published signatures. The TIIClnc signature was strongly correlated to immune characteristics, including microsatellite instability, tumor mutation burden, and interferon γ, and exhibited a more active immunologic process. Furthermore, the TIIClnc signature predicted superior immunotherapy response in multiple datasets across cancer types. Notably, the positive correlation between the TIIClnc signature and CD8, PD-1, and PD-L1 was verified in the Xiangya in-house dataset. The TIIClnc signature enabled a more precise selection of the LGG population who were potential beneficiaries of immunotherapy.
Topics: Glioma; Humans; Immunologic Factors; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Machine Learning; RNA, Long Noncoding
PubMed: 35966587
DOI: 10.7150/thno.74281 -
Pediatric and Developmental Pathology :... 2022Pediatric glial tumors are unique from their adult counterparts. This important distinction is recognized and incorporated into the World Health Organization...
Pediatric glial tumors are unique from their adult counterparts. This important distinction is recognized and incorporated into the World Health Organization classification of central nervous system tumors and applies to both high- and low-grade gliomas, incorporating their specific molecular profiles. Molecular alterations in pediatric high-grade gliomas provide important prognostic information, for example in H3 K27M-mutant tumors. The integration of molecular information is also important for pediatric low-grade gliomas due to their overlapping morphologies and the prognostic and therapeutic implications of these molecular alterations. In this paper, we cover a variety of glial tumors, encompassing neoplasms with predominantly glial histology, astrocytic tumors, oligodendroglial tumors, and mixed glioneuronal tumors. Considering the complexity of this evolving field, the purpose of this article is to offer a practical approach to the diagnosis of pediatric gliomas, including the selection of the most appropriate molecular surrogate immunohistochemical stains, basic molecular studies, and more sophisticated techniques if needed. The goal is to reach a rapid, sound diagnosis, helping guide clinical decision-making regarding prognosis and potential therapies.
Topics: Adult; Brain Neoplasms; Child; Glioma; Humans; Mutation; Neuroglia; Prognosis
PubMed: 33872106
DOI: 10.1177/10935266211009101