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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Oncol.</journal-id>
<journal-title>Frontiers in Oncology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Oncol.</abbrev-journal-title>
<issn pub-type="epub">2234-943X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fonc.2024.1359093</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Oncology</subject>
<subj-group>
<subject>Case Report</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Case report: complete long-lasting response to multimodal third line treatment with neurosurgical resection, carmustine wafer implantation and dabrafenib plus trametinib in a <italic>BRAFV600E</italic> mutated high-grade glioma</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Castelli</surname>
<given-names>Barbara</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">*</xref>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Tellini</surname>
<given-names>Marco</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Guidi</surname>
<given-names>Melina</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Di Nicola</surname>
<given-names>Marco</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Giunti</surname>
<given-names>Laura</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/resources/"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Buccoliero</surname>
<given-names>Anna Maria</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/resources/"/>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Censullo</surname>
<given-names>Maria Luigia</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
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<contrib contrib-type="author">
<name>
<surname>Iacono</surname>
<given-names>Alessandro</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/resources/"/>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Desideri</surname>
<given-names>Isacco</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1192866"/>
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<contrib contrib-type="author">
<name>
<surname>Genitori</surname>
<given-names>Lorenzo</given-names>
</name>
<xref ref-type="aff" rid="aff5">
<sup>5</sup>
</xref>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Sardi</surname>
<given-names>Iacopo</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
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<contrib contrib-type="author">
<name>
<surname>Fonte</surname>
<given-names>Carla</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
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<aff id="aff1">
<sup>1</sup>
<institution>Neuro-oncology Department, Meyer Children&#x2019;s Hospital IRCCS</institution>, <addr-line>Florence</addr-line>, <country>Italy</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Pathology Department, Meyer Children&#x2019;s Hospital IRCCS</institution>, <addr-line>Florence</addr-line>, <country>Italy</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Radiology Department, Meyer Children&#x2019;s Hospital IRCCS</institution>, <addr-line>Florence</addr-line>, <country>Italy</country>
</aff>
<aff id="aff4">
<sup>4</sup>
<institution>Radiotherapy Department, Careggi Hospital</institution>, <addr-line>Florence</addr-line>, <country>Italy</country>
</aff>
<aff id="aff5">
<sup>5</sup>
<institution>Neurosurgery Department, Meyer Children&#x2019;s Hospital IRCCS</institution>, <addr-line>Florence</addr-line>, <country>Italy</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Gerardo Caruso, University Hospital of Policlinico G. Martino, Italy</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Byram Ozer, NCI Neuro-Oncology Branch, United States</p>
<p>Nicholas Gottardo, Perth Children&#x2019;s Hospital, Australia</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Barbara Castelli, <email xlink:href="mailto:Barbara.castelli@meyer.it">Barbara.castelli@meyer.it</email>
</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>07</day>
<month>05</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>14</volume>
<elocation-id>1359093</elocation-id>
<history>
<date date-type="received">
<day>20</day>
<month>12</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>21</day>
<month>03</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Castelli, Tellini, Guidi, Di Nicola, Giunti, Buccoliero, Censullo, Iacono, Desideri, Genitori, Sardi and Fonte</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Castelli, Tellini, Guidi, Di Nicola, Giunti, Buccoliero, Censullo, Iacono, Desideri, Genitori, Sardi and Fonte</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>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.</p>
</license>
</permissions>
<abstract>
<p>Dabrafenib plus trametinib is a promising new therapy for patients affected by <italic>BRAFV600E</italic>-mutant glioma, with high overall response and manageable toxicity. We described a complete and long-lasting response in a case of recurrent anaplastic pleomorphic xanthoastrocytoma CNS WHO-grade 3 <italic>BRAFV600E</italic> mutated. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients treated with the combined target therapy as third-line treatment. The emergence of optimized sequencing strategies and targeted agents, including multimodal and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG improving patient outcomes.</p>
</abstract>
<abstract abstract-type="graphical">
<title>Graphical Abstract</title>
<p>Timeline.</p>
<p>
<graphic xlink:href="fonc-14-1359093-g004.tif" position="anchor"/>
</p>
</abstract>
<kwd-group>
<kwd>high-grade glioma</kwd>
<kwd>MEK inhibitors</kwd>
<kwd>target therapy</kwd>
<kwd>dabrafenib</kwd>
<kwd>trametinib</kwd>
<kwd>pleomorphic xanthoastrocytoma</kwd>
<kwd>BRAFV600E</kwd>
<kwd>BRAF inhibitors</kwd>
</kwd-group>
<counts>
<fig-count count="3"/>
<table-count count="0"/>
<equation-count count="0"/>
<ref-count count="35"/>
<page-count count="6"/>
<word-count count="2393"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-in-acceptance</meta-name>
<meta-value>Neuro-Oncology and Neurosurgical Oncology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<label>1</label>
<title>Introduction</title>
<p>High-grade gliomas (HGGs), tumors of neuroepithelial origin (<xref ref-type="bibr" rid="B1">1</xref>), represent the most common primary intracranial tumor in adults (<xref ref-type="bibr" rid="B2">2</xref>, <xref ref-type="bibr" rid="B3">3</xref>). Differently, low- grade gliomas (LGGs) predominate in children (<xref ref-type="bibr" rid="B4">4</xref>, <xref ref-type="bibr" rid="B5">5</xref>).</p>
<p>HGGs display a dismal prognosis despite surgical and chemo radiotherapeutic advances (<xref ref-type="bibr" rid="B1">1</xref>) and standard of care is commonly not curative. Throughout the understanding of molecular basis of tumors and recent insights, survival outcomes modestly increased, however, remaining limited and challenging. Therefore, worldwide researches are moving towards new frontiers and ongoing trials are investigating novel targeted agents (<xref ref-type="bibr" rid="B1">1</xref>). In the last years, important advances in the field of molecular biology and pathology have been accomplished (<xref ref-type="bibr" rid="B6">6</xref>).</p>
<p>MAPK (mitogen-activated protein kinase) pathway, implicated in carcinogenesis, has been found altered in most glial tumors (<xref ref-type="bibr" rid="B7">7</xref>, <xref ref-type="bibr" rid="B8">8</xref>), promoting cellular overgrowth and overcoming metabolic stress (<xref ref-type="bibr" rid="B9">9</xref>). The pathway includes a small G protein (RAS) and three protein kinases in a downstream signaling pathway (respectively RAF &#x2013; composed of A-RAF, B-RAF and RAF-1 or C-RAF kinases, MEK &#x2013; composed of MEK1 and MEK2, ERK &#x2013; composed of ERK1 and ERK2) (<xref ref-type="bibr" rid="B10">10</xref>, <xref ref-type="bibr" rid="B11">11</xref>). ERK (extracellular signal-regulated kinase) is a MAPK that functions as the major effector of the RAS oncoprotein, translocating to the nucleus to activate transcription factors (<xref ref-type="bibr" rid="B10">10</xref>). Driving oncogenic mutations should develop upstream of the MAPK pathway (<xref ref-type="bibr" rid="B11">11</xref>).</p>
<p>Most <italic>BRAF</italic> variants are missense mutations at amino acid position 600, resulting in an exchange of valine for glutamate (referred to as <italic>BRAFV600E</italic>) (<xref ref-type="bibr" rid="B12">12</xref>). Activating <italic>BRAFV600E</italic> kinase mutations occur in ~7% of human malignancies (<xref ref-type="bibr" rid="B13">13</xref>). Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors (<xref ref-type="bibr" rid="B14">14</xref>). High mutation frequencies have been detected in pleomorphic xanthoastrocytomas (PXA), gangliogliomas and extra-cerebellar pilocytic astrocytomas (<xref ref-type="bibr" rid="B14">14</xref>), but the mutation has also been found in others HGGs (<xref ref-type="bibr" rid="B12">12</xref>), in particular in epithelioid glioblastoma (<xref ref-type="bibr" rid="B15">15</xref>).</p>
<p>The BRAF inhibitors vemurafenib, dabrafenib and encorafenib selectively target BRAF kinase, interfering with MAPK signaling pathway (<xref ref-type="bibr" rid="B16">16</xref>). Selumetinib and trametinib are MEK inhibitors (MEKi) (<xref ref-type="bibr" rid="B7">7</xref>). The combination of BRAF and MEK inhibitor have been approved in various cancers by the US Food and Drugs Administration (FDA) (<xref ref-type="bibr" rid="B17">17</xref>) and the European Medicines Agency (EMA). It is known that the blockage of two downstream pathway components with dual BRAF/MEK inhibition may improve tumor control and patient survival (<xref ref-type="bibr" rid="B18">18</xref>).</p>
<p>Recently, MEK inhibitors and BRAF inhibitors have been successfully used in pediatric LGG patients (<xref ref-type="bibr" rid="B19">19</xref>), with a relatively well-tolerated side effect profile (<xref ref-type="bibr" rid="B1">1</xref>). Few data are available on their efficacy in relapsing refractory HGGs.</p>
<p>Herein we report a case of complete long-lasting response to combined dabrafenib/trametinib as third-line therapy in a patient with frontal HGG.</p>
</sec>
<sec id="s2">
<label>2</label>
<title>Case report</title>
<p>In February 2016, a 21-year-old white female presented her first seizure episode. In August 2016 she was admitted to Anna Meyer Children&#x2019;s Hospital IRCCS in Florence for recurrent episodes. Imaging revealed a left frontal lesion (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>). A partial resection was performed. The histological examination diagnosed anaplastic PXA <italic>BRAFV600E</italic> mutated CNS WHO-grade 3. The lesion was composed of pleomorphic, xanthomatous and oligodendrocyte-like cells. Perivascular lymphocytic cuffing and numerous granular bodies were present. Mitoses (more than 5 X 10 HPF) and necrosis were seen (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2</bold>
</xref>). At immunohistochemistry GFAP, CD34 and <italic>BRAF</italic> p.V600E resulted positive; rare cells expressed synaptophysin. Molecular study confirmed <italic>BRAF</italic> p.V600E mutation (c. 1799T&gt;A) whereas FISH analysis documented homozygous deletion of <italic>CDKN2A</italic>.</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>Brain CT scan at diagnosis, August 2016 [<bold>(A)</bold>: axial, <bold>(B)</bold>: coronal, <bold>(C)</bold>: sagittal].</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1359093-g001.tif"/>
</fig>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>Pleomorphic xanthoastrocytoma, CNS WHO grade 3, lesion composed of pleomorphic cells <bold>(A)</bold> and oligodendrocyte-like cells <bold>(C)</bold>. Perivascular lymphocyte cuffing and granular bodies are present <bold>(A)</bold> as well as necrosis [<bold>(B)</bold>, arrow] and mitoses [<bold>(C, D)</bold>, arrows]. Hematoxylin and eosin stain <bold>(A-D)</bold>; Original magnification: a-b 10 X, c 40 X, d 20 X.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1359093-g002.tif"/>
</fig>
<p>From October 2016 to December 2016&#xa0;a volumetric modulated radiotherapy course was delivered for a total dose of 59,4 Gy in 33 fractions with concomitant and adjuvant temozolomide therapy (Stupp regimen). However, O6-methylguanine-DNA methyltransferase (MGMT) promoter was not methylated. Brain MRI at the end of radiotherapy revealed residual disease (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3A</bold>
</xref>).</p>
<fig id="f3" position="float">
<label>Figure&#xa0;3</label>
<caption>
<p>Axial T1 contrast-enhanced brain MRI [<bold>(A)</bold>: after first line therapy, January 2017; <bold>(B)</bold>: at first progression, October 2017; <bold>(C)</bold>: at second progression, presurgical, December 2018; <bold>(D)</bold>: complete response during target therapy, December 2021; <bold>(E)</bold>: persistence complete response one month after target therapy interruption, January 2024].</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1359093-g003.tif"/>
</fig>
<p>In October 2017 (14 months after first surgical resection), a brain MRI showed progressive disease next to the resected area (first progression, <xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3B</bold>
</xref>), therefore six courses of chemotherapy with procarbazine, lomustine and vincristine (PCV) were administered (the last in June 2018) with disease control.</p>
<p>In January 2019 (7 months after the end of second line treatment) a cranial MRI showed progression of disease (second progression, <xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3C</bold>
</xref>) and another neurosurgical partial resection with carmustine wafers implantation was performed. The histological analysis confirmed the previous diagnosis. Considering the residual disease, in April 2019 the 24-year-old female patient with <italic>BRAF</italic> mutated anaplastic PXA started third-line therapy with dabrafenib. In August 2019 she suffered from Herpes Zoster reactivation, leading to temporary target drug suspension. The well-known tumor residue was less evident on the subsequent MRIs performed every three/four months. Given the literature data of the most effectiveness with better tolerability and the reduced possibility of resistance (<xref ref-type="bibr" rid="B13">13</xref>, <xref ref-type="bibr" rid="B20">20</xref>&#x2013;<xref ref-type="bibr" rid="B22">22</xref>), in August 2020 the patient started combination treatment with dabrafenib plus trametinib. Temporary interruption was required for pyrexia and in September 2020 for the occurrence of erythema nodosum grade 3 Common Terminology Criteria for Adverse Events (CTCAE) v.4. Dabrafenib and trametinib were then continued at a reduced dose (25%-50% reduction). The combined therapy was overall well tolerated. Since December 2021 the residual tumor has not been longer visible (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3D</bold>
</xref>). MRI evaluation, performed on July&#xa0;27<sup>th,</sup>2023, showed no recurrence of the disease, three years after BRAF/MEK inhibitor combination treatment beginning. In December 2023, considering the optimal response and the reported toxicity, the dual target treatment was interrupted. Last MRI, performed on January 29<sup>th</sup>, 2024 (one month after drug cessation, 5 years after second progression) revealed persistent complete response (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3E</bold>
</xref>).</p>
</sec>
<sec id="s3" sec-type="discussion|conclusion">
<label>3</label>
<title>Discussion and conclusion</title>
<p>PXA is a tumor with a wide range of morphology (<xref ref-type="bibr" rid="B19">19</xref>). Two WHO grades (CNS WHO 2 or 3) are assigned, based on a mitotic count of more than 5 mitoses per 10 microscopic high power fields (<xref ref-type="bibr" rid="B19">19</xref>). Grade 3 includes the anaplastic variant (<xref ref-type="bibr" rid="B23">23</xref>). Anaplastic PXA is associated with poorer clinical outcomes compared with PXA CNS WHO 2 (<xref ref-type="bibr" rid="B24">24</xref>). Anaplastic variant of PXA shows histological characteristics as well as clinical course comparable with Grade 3 astrocytoma (<xref ref-type="bibr" rid="B25">25</xref>). Gross total resection should be the goal of initial treatment and it remains unclear whether adjuvant radiation and chemotherapy are able to prevent progression or dissemination (<xref ref-type="bibr" rid="B24">24</xref>). Early disease recurrence in anaplastic PXA is associated with fatal outcomes (<xref ref-type="bibr" rid="B25">25</xref>). <italic>BRAFV600E</italic> mutation can be detected in up to 70% of these tumors, combined with <italic>CDKN2A</italic> homozygous deletion in greater than 90% (<xref ref-type="bibr" rid="B19">19</xref>). Considering the emerging molecular landscape and the frequent failure of conventional therapies, novel therapeutic strategies are under investigation in the treatment of HGGs.</p>
<p>Targeted therapies, including mutant BRAF inhibitors (dabrafenib) and MEK inhibitors (trametinib), have yet shown promising results in other cancers refractory to conventional chemotherapy (<xref ref-type="bibr" rid="B26">26</xref>). The safety and effectiveness of MEKi treatment have also been established in improving symptomatology and quality of life in patients affected by plexiform neurofibromas in Neurofibromatosis Type I (<xref ref-type="bibr" rid="B7">7</xref>). Considering brain tumors, MAPK inhibitors have shown encouraging results in LGG showing alterations of this pathway. Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with <italic>BRAFV600</italic>-mutant LGG (<xref ref-type="bibr" rid="B27">27</xref>). Trametinib was an active and feasible treatment for progressive pediatric MAPK-aberrant LGGs, leading to disease control (<xref ref-type="bibr" rid="B28">28</xref>). Recently, the Food and Drug Administration (FDA) approved dabrafenib in combination with trametinib for the treatment of pediatric <italic>BRAFV600E</italic> LGG (<xref ref-type="bibr" rid="B29">29</xref>). Instead, data are still limited on their efficacy in <italic>BRAFV600E</italic> mutated HGGs. In 2014 Robinson et&#xa0;al. described the first known case of complete response in a <italic>BRAFV600E</italic>-mutated HGG to vemurafenib (BRAF inhibitor) therapy (<xref ref-type="bibr" rid="B20">20</xref>). In 2022 Arbour et&#xa0;al. reported an 18-year-old female with a grade 3 PXA treated upfront with dabrafenib and trametinib and conducted a systematic literature review of patients with HGG and <italic>BRAFV600E</italic> mutations treated with BRAF inhibitors (<xref ref-type="bibr" rid="B30">30</xref>).</p>
<p>In a phase 2 Rare Oncology Agnostic Research (ROAR) basket trial (NCT02034110) Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory HGG: 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses (<xref ref-type="bibr" rid="B31">31</xref>). Further ongoing studies are evaluating MEK inhibition also in HGG patients. An Open Label, multi-center Roll-over Study is assessing Long-term effect of BRAFV600E and MEK inhibition with dabrafenib and trametinib in a subset of HGG (NCT03975829) (<xref ref-type="bibr" rid="B1">1</xref>). A phase I/II Trial is designed to study the combination of Dabrafenib, Trametinib and Hydroxychloroquine for Patients with Recurrent LGG or HGG with a BRAF aberration (NCT04201457). Another phase II trial studies how well the combination of dabrafenib and trametinib after radiation therapy in children and young adults with <italic>BRAF V600</italic> mutated HGG (NCT03919071).</p>
<p>Our case report suggests that BRAF/MEK inhibition is a potential promising strategy also in the treatment of recurrent and refractory HGG, non-stable responsive to surgery, radiotherapy, first and second line chemotherapy. The patient on the third-line combined target therapy achieved even a complete extraordinary response, with disappearance of residual disease.</p>
<p>The patient started a therapy with BRAF and MEK inhibitors on the basis that previous studies on melanoma suggested the possibility of resistance (<xref ref-type="bibr" rid="B13">13</xref>, <xref ref-type="bibr" rid="B20">20</xref>), Moreover, Hargrave et&#xa0;al. in a phase II trial in pediatric relapsed/refractory <italic>BRAFV600</italic>&#x2013;mutant HGG assessed tolerable safety and durable responses of the combined therapy, compared to traditional chemotherapy (<xref ref-type="bibr" rid="B32">32</xref>). Hypotheses for mechanisms of acquired resistance to BRAF inhibition include secondary mutations in <italic>BRAF</italic>, MAPK reactivation, and activation of alternative survival pathways (<xref ref-type="bibr" rid="B13">13</xref>). Reports in colorectal cancer suggest <italic>BRAF</italic>-mutant tumors may escape inhibition by amplifying receptor tyrosine kinases (<xref ref-type="bibr" rid="B20">20</xref>, <xref ref-type="bibr" rid="B33">33</xref>), Additionally, combination of MEK and BRAF inhibitors reduces squamous cell carcinoma risk observed with BRAF inhibitors monotherapy (<xref ref-type="bibr" rid="B1">1</xref>). Combined treatment is reported to be well tolerated with mostly moderate and reversible side effects (<xref ref-type="bibr" rid="B21">21</xref>). In an open-label study involving patients with metastatic melanoma with <italic>BRAFV600</italic> mutations, dabrafenib and trametinib were safety combined at full monotherapy doses, with significatively improvement of progression-free survival (<xref ref-type="bibr" rid="B22">22</xref>). In our case in combined therapy temporary interruption was required in two events: pyrexia and for the occurrence of erythema nodosum, recurred some months later. Dabrafenib was then continued at a reduced dose (25% reduction) and the combined therapy was overall well tolerated.</p>
<p>Data on long-term response are still poor. Our case report describes an extremely great 3-year persistent response on combined target therapy. We must take into account that the combined target therapy was a component of a multimodal approach including neurosurgery and carmustine wafers implantation (CW). Approved to treat newly or recurrent HGG, CW efficacy was reported doubtful: CW may provide a therapeutic coverage during the usual radiotherapy delay of 2 to 6 weeks (<xref ref-type="bibr" rid="B34">34</xref>). In our case, the optimal neuro radiological response was observed at almost two years since CW implantation, therefore it was most likely related to the dual target treatment. However, CW was a part of the third line therapy, thus composed of a multimodal approach.</p>
<p>Despite promising preclinical and clinical trials, several issues persist (<xref ref-type="bibr" rid="B1">1</xref>). Disease control after MEKi withdrawal was not sustained in a fraction of patients (<xref ref-type="bibr" rid="B28">28</xref>). Even on temporary effect, therapeutic goals could include extending survival and improving quality of life in patients with relapsed disease (<xref ref-type="bibr" rid="B20">20</xref>). CNS tumors with alternative <italic>BRAF</italic> alterations, such as alternate <italic>V600</italic> mutations or <italic>BRAF</italic> fusions, may differently respond to target therapy (<xref ref-type="bibr" rid="B20">20</xref>): for example it is important to note that BRAF inhibitor therapy in patients with <italic>BRAF</italic> gene fusion or duplications activates the MAPK signaling pathway in cells with wild-type <italic>BRAF</italic> at <italic>V600</italic> (<xref ref-type="bibr" rid="B27">27</xref>), therefore in this setting MEK inhibitors represent the strategy of choice (<xref ref-type="bibr" rid="B35">35</xref>).</p>
<p>Moreover, several studies are investigating the use of targeted therapy as a first-line treatment (<xref ref-type="bibr" rid="B26">26</xref>), which could open extraordinary perspectives.</p>
<p>Long term follow up would supply data on disease evolution after treatment discontinuation and further studies are expected to provide standardized treatment duration indications.</p>
<p>In conclusion, our case report suggests that BRAF/MEK inhibition may represent a potential therapeutic strategy also in patients with refractory relapsing HGGs <italic>BRAF</italic> mutated, not responsive to conventional therapies. The achieved complete response in a recurrent disease is an exceptional reached goal. The long-lasting response is also of great importance, giving long-term insights in combined target therapy. However, this is a limited study, reporting our favorable experience only in a single patient. Further studies are ongoing and more data on larger cohorts are needed to clarify present issues. Despite this exciting result, ongoing prospective studies will determine whether dabrafenib and trametinib combination can improve relapsed HGGs <italic>BRAF</italic> mutated outcomes.</p>
</sec>
<sec id="s4" sec-type="data-availability">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.</p>
</sec>
<sec id="s5" sec-type="ethics-statement">
<title>Ethics statement</title>
<p>The studies involving humans were approved by Comitato Etico Regione Toscana, Azienda Ospedaliera Universitaria Meyer IRCCS. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants&#x2019; legal guardians/next of kin in accordance with the national legislation and institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.</p>
</sec>
<sec id="s6" sec-type="author-contributions">
<title>Author contributions</title>
<p>BC: Conceptualization, Data curation, Formal analysis, Methodology, Resources, Validation, Writing &#x2013; original draft. MT: Writing &#x2013; original draft. MG: Validation, Visualization, Writing &#x2013; review &amp; editing. MD: Validation, Visualization, Writing &#x2013; review &amp; editing. LaG: Resources, Validation, Writing &#x2013; review &amp; editing. AB: Resources, Validation, Writing &#x2013; review &amp; editing. MC: Visualization, Writing &#x2013; review &amp; editing. AI: Resources, Validation, Writing &#x2013; review &amp; editing. ID: Resources, Validation, Writing &#x2013; review &amp; editing. LG: Supervision, Validation, Visualization, Writing &#x2013; review &amp; editing. IS: Conceptualization, Data curation, Supervision, Validation, Visualization, Writing &#x2013; review &amp; editing. CF: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing &#x2013; review &amp; editing.</p>
</sec>
</body>
<back>
<sec id="s7" sec-type="funding-information">
<title>Funding</title>
<p>The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Combined target therapy granted by &#x201c;Agenzia italiana del farmaco&#x201d; (AIFA) 5% fund. This work was supported by a grant from Fondazione Anna Meyer, Florence, Italy.</p>
</sec>
<sec id="s8" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>CF took part in the Advisory Board financed by Novartis on September 5th 2022 and she took part as principal investigator in CDRB436G2201 NCT02684058 study.</p>
<p>The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
<p>The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.</p>
</sec>
<sec id="s9" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors&#xa0;and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<ref-list>
<title>References</title>
<ref id="B1">
<label>1</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rallis</surname> <given-names>KS</given-names>
</name>
<name>
<surname>George</surname> <given-names>AM</given-names>
</name>
<name>
<surname>Wozniak</surname> <given-names>AM</given-names>
</name>
<name>
<surname>Bigogno</surname> <given-names>CM</given-names>
</name>
<name>
<surname>Chow</surname> <given-names>B</given-names>
</name>
<name>
<surname>Hanrahan</surname> <given-names>JG</given-names>
</name>
<etal/>
</person-group>. <article-title>Molecular genetics and targeted therapies for pediatric high-grade glioma</article-title>. <source>Cancer Genomics Proteomics</source>. (<year>2022</year>) <volume>19</volume>:<fpage>390</fpage>&#x2013;<lpage>414</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.21873/cgp.20328</pub-id>
</citation>
</ref>
<ref id="B2">
<label>2</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ostrom</surname> <given-names>QT</given-names>
</name>
<name>
<surname>Bauchet</surname> <given-names>L</given-names>
</name>
<name>
<surname>Davis</surname> <given-names>FG</given-names>
</name>
<name>
<surname>Deltour</surname> <given-names>I</given-names>
</name>
<name>
<surname>Fisher</surname> <given-names>JL</given-names>
</name>
<name>
<surname>Langer</surname> <given-names>CE</given-names>
</name>
<etal/>
</person-group>. <article-title>The epidemiology of glioma in adults: a &#x201c;state of the science&#x201d; review</article-title>. <source>Neuro-Oncology</source>. (<year>2014</year>) <volume>16</volume>:<fpage>896</fpage>&#x2013;<lpage>913</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1093/neuonc/nou087</pub-id>
</citation>
</ref>
<ref id="B3">
<label>3</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Aggarwal</surname> <given-names>P</given-names>
</name>
<name>
<surname>Luo</surname> <given-names>W</given-names>
</name>
<name>
<surname>Pehlivan</surname> <given-names>KC</given-names>
</name>
<name>
<surname>Hoang</surname> <given-names>H</given-names>
</name>
<name>
<surname>Rajappa</surname> <given-names>P</given-names>
</name>
<name>
<surname>Cripe</surname> <given-names>TP</given-names>
</name>
<etal/>
</person-group>. <article-title>Pediatric versus adult high grade glioma: Immunotherapeutic and genomic considerations</article-title>. <source>Front Immunol</source>. (<year>2022</year>) <volume>13</volume>:<elocation-id>1038096</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.3389/fimmu.2022.1038096</pub-id>
</citation>
</ref>
<ref id="B4">
<label>4</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Buccoliero</surname> <given-names>AM</given-names>
</name>
<name>
<surname>Giunti</surname> <given-names>L</given-names>
</name>
<name>
<surname>Moscardi</surname> <given-names>S</given-names>
</name>
<name>
<surname>Castiglione</surname> <given-names>F</given-names>
</name>
<name>
<surname>Provenzano</surname> <given-names>A</given-names>
</name>
<name>
<surname>Sardi</surname> <given-names>I</given-names>
</name>
<etal/>
</person-group>. <article-title>Pediatric high grade glioma classification criteria and molecular features of a case series</article-title>. <source>Genes</source>. (<year>2022</year>) <volume>13</volume>:<fpage>624</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.3390/genes13040624</pub-id>
</citation>
</ref>
<ref id="B5">
<label>5</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sturm</surname> <given-names>D</given-names>
</name>
<name>
<surname>Pfister</surname> <given-names>SM</given-names>
</name>
<name>
<surname>Jones</surname> <given-names>DTW</given-names>
</name>
</person-group>. <article-title>Pediatric gliomas: current concepts on diagnosis, biology, and clinical management</article-title>. <source>JCO</source>. (<year>2017</year>) <volume>35</volume>:<page-range>2370&#x2013;7</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1200/JCO.2017.73.0242</pub-id>
</citation>
</ref>
<ref id="B6">
<label>6</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zhang</surname> <given-names>ZH</given-names>
</name>
<name>
<surname>Lin</surname> <given-names>MT</given-names>
</name>
<name>
<surname>Chen</surname> <given-names>L</given-names>
</name>
</person-group>. <article-title>Editorial: molecular advances in diagnosis and treatment of CNS tumors</article-title>. <source>Front Oncol</source>. (<year>2020</year>) <volume>10</volume>:<elocation-id>590293</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.3389/fonc.2020.590293</pub-id>
</citation>
</ref>
<ref id="B7">
<label>7</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cacchione</surname> <given-names>A</given-names>
</name>
<name>
<surname>Fabozzi</surname> <given-names>F</given-names>
</name>
<name>
<surname>Carai</surname> <given-names>A</given-names>
</name>
<name>
<surname>Colafati</surname> <given-names>GS</given-names>
</name>
<name>
<surname>del Baldo</surname> <given-names>G</given-names>
</name>
<name>
<surname>Rossi</surname> <given-names>S</given-names>
</name>
<etal/>
</person-group>. <article-title>Safety and efficacy of mek inhibitors in the treatment of plexiform neurofibromas: A retrospective study</article-title>. <source>Cancer Control</source>. (<year>2023</year>) <volume>30</volume>:<fpage>107327482211449</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1177/10732748221144930</pub-id>
</citation>
</ref>
<ref id="B8">
<label>8</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Grave</surname> <given-names>N</given-names>
</name>
<name>
<surname>Scheffel</surname> <given-names>TB</given-names>
</name>
<name>
<surname>Cruz</surname> <given-names>FF</given-names>
</name>
<name>
<surname>Rockenbach</surname> <given-names>L</given-names>
</name>
<name>
<surname>Goettert</surname> <given-names>MI</given-names>
</name>
<name>
<surname>Laufer</surname> <given-names>S</given-names>
</name>
<etal/>
</person-group>. <article-title>The functional role of p38 MAPK pathway in Malignant brain tumors</article-title>. <source>Front Pharmacol</source>. (<year>2022</year>) <volume>13</volume>:<elocation-id>975197</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.3389/fphar.2022.975197</pub-id>
</citation>
</ref>
<ref id="B9">
<label>9</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yuan</surname> <given-names>J</given-names>
</name>
<name>
<surname>Dong</surname> <given-names>X</given-names>
</name>
<name>
<surname>Yap</surname> <given-names>J</given-names>
</name>
<name>
<surname>Hu</surname> <given-names>J</given-names>
</name>
</person-group>. <article-title>The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy</article-title>. <source>J Hematol Oncol</source>. (<year>2020</year>) <volume>13</volume>:<fpage>113</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1186/s13045-020-00949-4</pub-id>
</citation>
</ref>
<ref id="B10">
<label>10</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>McCain</surname> <given-names>J</given-names>
</name>
<name>
<surname>The</surname> <given-names>MAPK</given-names>
</name>
</person-group>. <article-title>(ERK) pathway: investigational combinations for the treatment of BRAF-mutated metastatic melanoma</article-title>. <source>P T</source>. (<year>2013</year>) <volume>38</volume>:<fpage>96</fpage>&#x2013;<lpage>108</lpage>.</citation>
</ref>
<ref id="B11">
<label>11</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Burotto</surname> <given-names>M</given-names>
</name>
<name>
<surname>Chiou</surname> <given-names>VL</given-names>
</name>
<name>
<surname>Lee</surname> <given-names>J</given-names>
</name>
<name>
<surname>Kohn</surname> <given-names>EC</given-names>
</name>
</person-group>. <article-title>The <sc>MAPK</sc> pathway across different Malignancies: A new perspective</article-title>. <source>Cancer</source>. (<year>2014</year>) <volume>120</volume>:<page-range>3446&#x2013;56</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1002/cncr.28864</pub-id>
</citation>
</ref>
<ref id="B12">
<label>12</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kyung Myung</surname> <given-names>J</given-names>
</name>
<name>
<surname>Cho</surname> <given-names>H</given-names>
</name>
<name>
<surname>Park</surname> <given-names>CK</given-names>
</name>
<name>
<surname>Kim</surname> <given-names>SK</given-names>
</name>
<name>
<surname>Lee</surname> <given-names>SH</given-names>
</name>
<name>
<surname>Park</surname> <given-names>SH</given-names>
</name>
</person-group>. <article-title>Analysis of the BRAFV600E mutation in central nervous system tumors</article-title>. <source>Trans Oncol</source>. (<year>2012</year>) <volume>5</volume>:<page-range>430&#x2013;6</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1593/tlo.12328</pub-id>
</citation>
</ref>
<ref id="B13">
<label>13</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Nazarian</surname> <given-names>R</given-names>
</name>
<name>
<surname>Shi</surname> <given-names>H</given-names>
</name>
<name>
<surname>Wang</surname> <given-names>Q</given-names>
</name>
<name>
<surname>Kong</surname> <given-names>X</given-names>
</name>
<name>
<surname>Koya</surname> <given-names>RC</given-names>
</name>
<name>
<surname>Lee</surname> <given-names>H</given-names>
</name>
<etal/>
</person-group>. <article-title>Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation</article-title>. <source>Nature</source>. (<year>2010</year>) <volume>468</volume>:<page-range>973&#x2013;7</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1038/nature09626</pub-id>
</citation>
</ref>
<ref id="B14">
<label>14</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Schindler</surname> <given-names>G</given-names>
</name>
<name>
<surname>Capper</surname> <given-names>D</given-names>
</name>
<name>
<surname>Meyer</surname> <given-names>J</given-names>
</name>
<name>
<surname>Janzarik</surname> <given-names>W</given-names>
</name>
<name>
<surname>Omran</surname> <given-names>H</given-names>
</name>
<name>
<surname>Herold-Mende</surname> <given-names>C</given-names>
</name>
<etal/>
</person-group>. <article-title>Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma</article-title>. <source>Acta Neuropathol</source>. (<year>2011</year>) <volume>121</volume>:<fpage>397</fpage>&#x2013;<lpage>405</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s00401-011-0802-6</pub-id>
</citation>
</ref>
<ref id="B15">
<label>15</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kleinschmidt-DeMasters</surname> <given-names>BK</given-names>
</name>
<name>
<surname>Aisner</surname> <given-names>DL</given-names>
</name>
<name>
<surname>Birks</surname> <given-names>DK</given-names>
</name>
<name>
<surname>Foreman</surname> <given-names>NK</given-names>
</name>
</person-group>. <article-title>Epithelioid GBMs show a high percentage of BRAF V600E mutation</article-title>. <source>Am J Surg Pathol</source>. (<year>2013</year>) <volume>37</volume>:<page-range>685&#x2013;98</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/PAS.0b013e31827f9c5e</pub-id>
</citation>
</ref>
<ref id="B16">
<label>16</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Proietti</surname> <given-names>I</given-names>
</name>
<name>
<surname>Skroza</surname> <given-names>N</given-names>
</name>
<name>
<surname>Michelini</surname> <given-names>S</given-names>
</name>
<name>
<surname>Mambrin</surname> <given-names>A</given-names>
</name>
<name>
<surname>Balduzzi</surname> <given-names>V</given-names>
</name>
<name>
<surname>Bernardini</surname> <given-names>N</given-names>
</name>
<etal/>
</person-group>. <article-title>BRAF inhibitors: molecular targeting and immunomodulatory actions</article-title>. <source>Cancers</source>. (<year>2020</year>) <volume>12</volume>:<fpage>1823</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.3390/cancers12071823</pub-id>
</citation>
</ref>
<ref id="B17">
<label>17</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Subbiah</surname> <given-names>V</given-names>
</name>
<name>
<surname>Baik</surname> <given-names>C</given-names>
</name>
<name>
<surname>Kirkwood</surname> <given-names>JM</given-names>
</name>
</person-group>. <article-title>Clinical development of BRAF plus MEK inhibitor combinations</article-title>. <source>Trends Cancer</source>. (<year>2020</year>) <volume>6</volume>:<fpage>797</fpage>&#x2013;<lpage>810</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.trecan.2020.05.009</pub-id>
</citation>
</ref>
<ref id="B18">
<label>18</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kata</surname> <given-names>K</given-names>
</name>
<name>
<surname>Rodriguez-Quintero</surname> <given-names>JC</given-names>
</name>
<name>
<surname>Arevalo</surname> <given-names>OD</given-names>
</name>
<name>
<surname>Zhang</surname> <given-names>JJ</given-names>
</name>
<name>
<surname>Bhattacharjee</surname> <given-names>MB</given-names>
</name>
<name>
<surname>Ware</surname> <given-names>C</given-names>
</name>
<etal/>
</person-group>. <article-title>BRAF/MEK dual inhibitors therapy in progressive and anaplastic pleomorphic xanthoastrocytoma: case series and literature review</article-title>. <source>J Natl Compr Cancer Network</source>. (<year>2022</year>) <volume>20</volume>:<page-range>1193&#x2013;202</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.6004/jnccn.2022.7046</pub-id>
</citation>
</ref>
<ref id="B19">
<label>19</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rud&#xe0;</surname> <given-names>R</given-names>
</name>
<name>
<surname>Capper</surname> <given-names>D</given-names>
</name>
<name>
<surname>Waldman</surname> <given-names>AD</given-names>
</name>
<name>
<surname>Pallud</surname> <given-names>J</given-names>
</name>
<name>
<surname>Minniti</surname> <given-names>G</given-names>
</name>
<name>
<surname>Kaley</surname> <given-names>TJ</given-names>
</name>
<etal/>
</person-group>. <article-title>EANO - EURACAN - SNO Guidelines on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors</article-title>. <source>Neuro-Oncology</source>. (<year>2022</year>) <volume>24</volume>:<page-range>2015&#x2013;34</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1093/neuonc/noac188</pub-id>
</citation>
</ref>
<ref id="B20">
<label>20</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Robinson</surname> <given-names>GW</given-names>
</name>
<name>
<surname>Orr</surname> <given-names>BA</given-names>
</name>
<name>
<surname>Gajjar</surname> <given-names>A</given-names>
</name>
</person-group>. <article-title>Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy</article-title>. <source>BMC Cancer</source>. (<year>2014</year>) <volume>14</volume>:<fpage>258</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1186/1471-2407-14-258</pub-id>
</citation>
</ref>
<ref id="B21">
<label>21</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Heinzerling</surname> <given-names>L</given-names>
</name>
<name>
<surname>Eigentler</surname> <given-names>TK</given-names>
</name>
<name>
<surname>Fluck</surname> <given-names>M</given-names>
</name>
<name>
<surname>Hassel</surname> <given-names>JC</given-names>
</name>
<name>
<surname>Heller-Schenck</surname> <given-names>D</given-names>
</name>
<name>
<surname>Leipe</surname> <given-names>J</given-names>
</name>
<etal/>
</person-group>. <article-title>Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management</article-title>. <source>ESMO Open</source>. (<year>2019</year>) <volume>4</volume>:<elocation-id>e000491</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.1136/esmoopen-2019-000491</pub-id>
</citation>
</ref>
<ref id="B22">
<label>22</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Flaherty</surname> <given-names>KT</given-names>
</name>
<name>
<surname>Infante</surname> <given-names>JR</given-names>
</name>
<name>
<surname>Daud</surname> <given-names>A</given-names>
</name>
<name>
<surname>Gonzalez</surname> <given-names>R</given-names>
</name>
<name>
<surname>Kefford</surname> <given-names>RF</given-names>
</name>
<name>
<surname>Sosman</surname> <given-names>J</given-names>
</name>
<etal/>
</person-group>. <article-title>Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations</article-title>. <source>N Engl J Med</source>. (<year>2012</year>) <volume>367</volume>:<page-range>1694&#x2013;703</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1056/NEJMoa1210093</pub-id>
</citation>
</ref>
<ref id="B23">
<label>23</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Shaikh</surname> <given-names>N</given-names>
</name>
<name>
<surname>Brahmbhatt</surname> <given-names>N</given-names>
</name>
<name>
<surname>Kruser</surname> <given-names>TJ</given-names>
</name>
<name>
<surname>Kam</surname> <given-names>KL</given-names>
</name>
<name>
<surname>Appin</surname> <given-names>CL</given-names>
</name>
<name>
<surname>Wadhwani</surname> <given-names>N</given-names>
</name>
<etal/>
</person-group>. <article-title>Pleomorphic xanthoastrocytoma: a brief review</article-title>. <source>CNS Oncol</source>. (<year>2019</year>) <volume>8</volume>:<fpage>CNS39</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.2217/cns-2019-0009</pub-id>
</citation>
</ref>
<ref id="B24">
<label>24</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rutkowski</surname> <given-names>MJ</given-names>
</name>
<name>
<surname>Oh</surname> <given-names>T</given-names>
</name>
<name>
<surname>Niflioglu</surname> <given-names>GG</given-names>
</name>
<name>
<surname>Safaee</surname> <given-names>M</given-names>
</name>
<name>
<surname>Tihan</surname> <given-names>T</given-names>
</name>
<name>
<surname>Parsa</surname> <given-names>AT</given-names>
</name>
</person-group>. <article-title>Pleomorphic xanthoastrocytoma with anaplastic features: retrospective case series</article-title>. <source>World Neurosurg</source>. (<year>2016</year>) <volume>95</volume>:<page-range>368&#x2013;74</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.wneu.2016.07.068</pub-id>
</citation>
</ref>
<ref id="B25">
<label>25</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Choudry</surname> <given-names>UK</given-names>
</name>
<name>
<surname>Khan</surname> <given-names>SA</given-names>
</name>
<name>
<surname>Qureshi</surname> <given-names>A</given-names>
</name>
<name>
<surname>Bari</surname> <given-names>E</given-names>
</name>
</person-group>. <article-title>Primary anaplastic pleomorphic xanthoastrocytoma in adults. Case report and review of literature</article-title>. <source>Int J Surg Case Rep</source>. (<year>2016</year>) <volume>27</volume>:<page-range>183&#x2013;8</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.ijscr.2016.08.022</pub-id>
</citation>
</ref>
<ref id="B26">
<label>26</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Leclair</surname> <given-names>NK</given-names>
</name>
<name>
<surname>Lambert</surname> <given-names>W</given-names>
</name>
<name>
<surname>Roche</surname> <given-names>K</given-names>
</name>
<name>
<surname>Gillan</surname> <given-names>E</given-names>
</name>
<name>
<surname>Gell</surname> <given-names>JJ</given-names>
</name>
<name>
<surname>Lau</surname> <given-names>CC</given-names>
</name>
<etal/>
</person-group>. <article-title>Early experience with targeted therapy as a first-line adjuvant treatment for pediatric low-grade glioma</article-title>. <source>Neurosurg Focus</source>. (<year>2022</year>) <volume>53</volume>:<fpage>E15</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.3171/2022.9.FOCUS22410</pub-id>
</citation>
</ref>
<ref id="B27">
<label>27</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hargrave</surname> <given-names>DR</given-names>
</name>
<name>
<surname>Bouffet</surname> <given-names>E</given-names>
</name>
<name>
<surname>Tabori</surname> <given-names>U</given-names>
</name>
<name>
<surname>Broniscer</surname> <given-names>A</given-names>
</name>
<name>
<surname>Cohen</surname> <given-names>KJ</given-names>
</name>
<name>
<surname>Hansford</surname> <given-names>JR</given-names>
</name>
<etal/>
</person-group>. <article-title>Efficacy and safety of dabrafenib in pediatric patients with <italic>BRAF</italic> V600 mutation&#x2013;positive relapsed or refractory low-grade glioma: results from a phase I/IIa study</article-title>. <source>Clin Cancer Res</source>. (<year>2019</year>) <volume>25</volume>:<page-range>7303&#x2013;11</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1158/1078-0432.CCR-19-2177</pub-id>
</citation>
</ref>
<ref id="B28">
<label>28</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Selt</surname> <given-names>F</given-names>
</name>
<name>
<surname>van Tilburg</surname> <given-names>CM</given-names>
</name>
<name>
<surname>Bison</surname> <given-names>B</given-names>
</name>
<name>
<surname>Sievers</surname> <given-names>P</given-names>
</name>
<name>
<surname>Harting</surname> <given-names>I</given-names>
</name>
<name>
<surname>Ecker</surname> <given-names>J</given-names>
</name>
<etal/>
</person-group>. <article-title>Response to trametinib treatment in progressive pediatric low-grade glioma patients</article-title>. <source>J Neurooncol</source>. (<year>2020</year>) <volume>149</volume>:<fpage>499</fpage>&#x2013;<lpage>510</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s11060-020-03640-3</pub-id>
</citation>
</ref>
<ref id="B29">
<label>29</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Barbato</surname> <given-names>MI</given-names>
</name>
<name>
<surname>Nashed</surname> <given-names>J</given-names>
</name>
<name>
<surname>Bradford</surname> <given-names>D</given-names>
</name>
<name>
<surname>Ren</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Khasar</surname> <given-names>S</given-names>
</name>
<name>
<surname>Miller</surname> <given-names>CP</given-names>
</name>
<etal/>
</person-group>. <article-title>FDA approval summary: dabrafenib in combination with trametinib for <italic>BRAF</italic> V600E mutation&#x2013;positive low-grade glioma</article-title>. <source>Clin Cancer Res</source>. (<year>2024</year>) <volume>30</volume>:<page-range>263&#x2013;8</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1158/1078-0432.CCR-23-1503</pub-id>
</citation>
</ref>
<ref id="B30">
<label>30</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Arbour</surname> <given-names>G</given-names>
</name>
<name>
<surname>Ellezam</surname> <given-names>B</given-names>
</name>
<name>
<surname>Weil</surname> <given-names>AG</given-names>
</name>
<name>
<surname>Cayrol</surname> <given-names>R</given-names>
</name>
<name>
<surname>Vanan</surname> <given-names>MI</given-names>
</name>
<name>
<surname>Coltin</surname> <given-names>H</given-names>
</name>
<etal/>
</person-group>. <article-title>Upfront BRAF/MEK inhibitors for treatment of high-grade glioma: A case report and review of the literature</article-title>. <source>Neuro-Oncol Adv</source>. (<year>2022</year>) <volume>4</volume>:<fpage>vdac174</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1093/noajnl/vdac174</pub-id>
</citation>
</ref>
<ref id="B31">
<label>31</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wen</surname> <given-names>PY</given-names>
</name>
<name>
<surname>Stein</surname> <given-names>A</given-names>
</name>
<name>
<surname>van den Bent</surname> <given-names>M</given-names>
</name>
<name>
<surname>De Greve</surname> <given-names>J</given-names>
</name>
<name>
<surname>Wick</surname> <given-names>A</given-names>
</name>
<name>
<surname>de Vos</surname> <given-names>FYFL</given-names>
</name>
<etal/>
</person-group>. <article-title>Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicenter, open-label, single-arm, phase 2, basket trial</article-title>. <source>Lancet Oncol</source>. (<year>2022</year>) <volume>23</volume>:<fpage>53</fpage>&#x2013;<lpage>64</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/S1470-2045(21)00578-7</pub-id>
</citation>
</ref>
<ref id="B32">
<label>32</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hargrave</surname> <given-names>DR</given-names>
</name>
<name>
<surname>Terashima</surname> <given-names>K</given-names>
</name>
<name>
<surname>Hara</surname> <given-names>J</given-names>
</name>
<name>
<surname>Kordes</surname> <given-names>UR</given-names>
</name>
<name>
<surname>Upadhyaya</surname> <given-names>SA</given-names>
</name>
<name>
<surname>Sahm</surname> <given-names>F</given-names>
</name>
<etal/>
</person-group>. <article-title>Phase II trial of dabrafenib plus trametinib in relapsed/refractory <italic>BRAF</italic> V600&#x2013;mutant pediatric high-grade glioma</article-title>. <source>JCO</source>. (<year>2023</year>) <volume>41</volume>:<page-range>5174&#x2013;83</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1200/JCO.23.00558</pub-id>
</citation>
</ref>
<ref id="B33">
<label>33</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Prahallad</surname> <given-names>A</given-names>
</name>
<name>
<surname>Sun</surname> <given-names>C</given-names>
</name>
<name>
<surname>Huang</surname> <given-names>S</given-names>
</name>
<name>
<surname>Di Nicolantonio</surname> <given-names>F</given-names>
</name>
<name>
<surname>Salazar</surname> <given-names>R</given-names>
</name>
<name>
<surname>Zecchin</surname> <given-names>D</given-names>
</name>
<etal/>
</person-group>. <article-title>Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR</article-title>. <source>Nature</source>. (<year>2012</year>) <volume>483</volume>:<page-range>100&#x2013;3</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1038/nature10868</pub-id>
</citation>
</ref>
<ref id="B34">
<label>34</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Champeaux</surname> <given-names>C</given-names>
</name>
<name>
<surname>Weller</surname> <given-names>J</given-names>
</name>
</person-group>. <article-title>Implantation of carmustine wafers (Gliadel&#xae;) for high-grade glioma treatment. A 9-year nationwide retrospective study</article-title>. <source>J Neurooncol</source>. (<year>2020</year>) <volume>147</volume>:<page-range>159&#x2013;69</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s11060-020-03410-1</pub-id>
</citation>
</ref>
<ref id="B35">
<label>35</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Trinder</surname> <given-names>SM</given-names>
</name>
<name>
<surname>McKay</surname> <given-names>C</given-names>
</name>
<name>
<surname>Power</surname> <given-names>P</given-names>
</name>
<name>
<surname>Topp</surname> <given-names>M</given-names>
</name>
<name>
<surname>Chan</surname> <given-names>B</given-names>
</name>
<name>
<surname>Valvi</surname> <given-names>S</given-names>
</name>
<etal/>
</person-group>. <article-title>BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience</article-title>. <source>Front Oncol</source>. (<year>2023</year>) <volume>13</volume>:<elocation-id>1154246</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.3389/fonc.2023.1154246</pub-id>
</citation>
</ref>
</ref-list>
</back>
</article>