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      Unlocking the power of precision medicine for pediatric low-grade gliomas: molecular characterization for targeted therapies with enhanced safety and efficacy

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          Abstract

          In the past decade significant advancements have been made in the discovery of targetable lesions in pediatric low-grade gliomas (pLGGs). These tumors account for 30-50% of all pediatric brain tumors with generally a favorable prognosis. The latest 2021 WHO classification of pLGGs places a strong emphasis on molecular characterization for significant implications on prognosis, diagnosis, management, and the potential target treatment. With the technological advances and new applications in molecular diagnostics, the molecular characterization of pLGGs has revealed that tumors that appear similar under a microscope can have different genetic and molecular characteristics. Therefore, the new classification system divides pLGGs into several distinct subtypes based on these characteristics, enabling a more accurate strategy for diagnosis and personalized therapy based on the specific genetic and molecular abnormalities present in each tumor. This approach holds great promise for improving outcomes for patients with pLGGs, highlighting the importance of the recent breakthroughs in the discovery of targetable lesions.

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          Most cited references184

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          The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

          The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.
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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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              Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children

              Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.
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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
                15 June 2023
                2023
                : 13
                : 1204829
                Affiliations
                [1] 1 Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, IRCCS , Rome, Italy
                [2] 2 Department of Experimental Medicine, Sapienza University of Rome , Rome, Italy
                [3] 3 Healthcare Genetics Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University , Clemson, SC, United States
                [4] 4 Department of Neurosciences, Neurosurgery Unit, Bambino Gesù Children’s Hospital, IRCCS , Rome, Italy
                Author notes

                Edited by: Jaroslav Sterba, Masaryk University, Czechia

                Reviewed by: Pasqualino De Antonellis, University of Toronto, Canada; Domenico Roberti, University of Campania Luigi Vanvitelli, Italy

                *Correspondence: Angela Mastronuzzi, angela.mastronuzzi@ 123456opbg.net
                Article
                10.3389/fonc.2023.1204829
                10311254
                37397394
                8240355b-a747-47cd-81d0-ff202cb95b80
                Copyright © 2023 Cipri, Del Baldo, Fabozzi, Boccuto, Carai and Mastronuzzi

                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 April 2023
                : 01 June 2023
                Page count
                Figures: 1, Tables: 3, Equations: 0, References: 213, Pages: 15, Words: 7312
                Funding
                This work was supported also by the Italian Ministry of Health with “Current Research funds”.
                Categories
                Oncology
                Review
                Custom metadata
                Pediatric Oncology

                Oncology & Radiotherapy
                pediatric low-grade glioma,brain tumors,neuro-oncology,molecular diagnostic,clinical trials,targeted therapies,risk stratification,glioma

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