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      Review: Neurological Complications From Therapies for Pediatric Brain Tumors

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          Abstract

          Surgery, chemotherapy and radiation have been the mainstay of pediatric brain tumor treatment over the past decades. Recently, new treatment modalities have emerged for the management of pediatric brain tumors. These therapies range from novel radiotherapy techniques and targeted immunotherapies to checkpoint inhibitors and T cell transfer therapies. These treatments are currently investigated with the goal of improving survival and decreasing morbidity. However, compared to traditional therapies, these novel modalities are not as well elucidated and similarly has the potential to cause significant short and long-term sequelae, impacting quality of life. Treatment complications are commonly mediated through direct drug toxicity or vascular, infectious, or autoimmune mechanisms, ranging from immune effector cell associated neurotoxicity syndrome with CART-cells to neuropathy with checkpoint inhibitors. Addressing treatment-induced complications is the focus of new trials, specifically improving neurocognitive outcomes. The aim of this review is to explore the pathophysiology underlying treatment related neurologic side effects, highlight associated complications, and describe the future direction of brain tumor protocols. Increasing awareness of these neurologic complications from novel therapies underscores the need for quality-of-life metrics and considerations in clinical trials to decrease associated treatment-induced morbidity.

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          Most cited references173

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          Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

          In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
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            Molecular and cellular insights into T cell exhaustion.

            In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called 'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.
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              Mutations of the BRAF gene in human cancer.

              Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                11 April 2022
                2022
                : 12
                : 853034
                Affiliations
                [1] 1 Department of Pediatrics, University of San Francisco , San Francisco, CA, United States
                [2] 2 Department of Neurology, Neurosurgery and Pediatrics, University of San Francisco , San Francisco, CA, United States
                [3] 3 Division of Neurology, Department of Pediatrics, Baylor College of Medicine , Houston, TX, United States
                Author notes

                Edited by: Rupert Handgtretinger, University of Tübingen, Germany

                Reviewed by: Martin Ebinger, University Children’s Hospital Tübingen, Germany; Ute Katharina Bartels, University of Toronto, Canada

                *Correspondence: Thien Nguyen, thien.nguyen3@ 123456ucsf.edu

                This article was submitted to Pediatric Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2022.853034
                9035987
                35480100
                df614eb0-6ce2-4135-9e90-421f16ae1782
                Copyright © 2022 Nguyen, Mueller and Malbari

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 12 January 2022
                : 15 March 2022
                Page count
                Figures: 0, Tables: 1, Equations: 0, References: 173, Pages: 14, Words: 6670
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                neurological complications,brain,cancer,therapeutics,pediatrics
                Oncology & Radiotherapy
                neurological complications, brain, cancer, therapeutics, pediatrics

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