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BACKGROUND: The term Gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features have not been established yet. METHODS: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. RESULTS: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-years survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n=49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wildtype (n=31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n=19), pedHGG_A/B (n=6), and pedHGG_MYCN (n=5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wildtype subgroup, recurrent alterations in EGFR (n=10) and BCOR (n=9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wildtype subgroup TP53 alterations had a significant negative effect on OS. CONCLUSION: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).
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BACKGROUND: High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies broadened our understanding of tumor biology, prospective data is lacking. METHODS: A cohort of children with histologically diagnosed HGG from the SJYC07 trial was augmented with nonprotocol patients with HGG treated at St. Jude Children's Research Hospital from November 2007 to December 2020. DNA methylome profiling and whole genome, whole exome, and RNA sequencing were performed. These data were integrated with histopathology to yield an integrated diagnosis. Clinical characteristics and preoperative imaging were analyzed. RESULTS: Fifty-six children (0.0-4.4 years) were identified. Integrated analysis split the cohort into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors. IHG was the most prevalent (nâ =â 22), occurred in the youngest patients (median ageâ =â 0.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95%CI: 35.52-79.47) and 90.91% (95%CI: 79.66-100.00) vs. 0.0% and 16.67% (95%CI: 2.78-99.74%) for HGG (pâ =â 0.0043, pâ =â 0.00013). EFS and OS were not different between IHG and LGG (pâ =â 0.95, pâ =â 0.43). Imaging review showed IHGs are associated with circumscribed margins (pâ =â 0.0047), hemispheric location (pâ =â 0.0010), and intratumoral hemorrhage (pâ =â 0.0149). CONCLUSIONS: HGG in young children is heterogeneous and best defined by integrating histopathological and molecular features. Patients with IHG have relatively good outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.
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Neoplasias Encefálicas , Glioma , Criança , Lactente , Humanos , Pré-Escolar , Estudos Retrospectivos , Estudos Prospectivos , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Glioma/tratamento farmacológico , Glioma/genética , Glioma/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genéticaRESUMO
How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin-DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB.
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Neoplasias Cerebelares , Meduloblastoma , Humanos , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Meduloblastoma/genética , Fosforilação , Epigenômica , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Moléculas de Adesão Celular Neuronais/farmacologia , Neoplasias Cerebelares/genética , Epigênese Genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
BACKGROUND: Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options. METHODS: We conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged <22 years with recurrent AT/RT. Patients received alisertib once daily (80 mg/m2 as enteric-coated tablets or 60 mg/m2 as liquid formulation) on Days 1-7 of a 21-day cycle until progressive disease (PD) occurred. Alisertib plasma concentrations were measured in cycle 1 on Days 1 (single dose) and 7 (steady state) and analyzed with noncompartmental pharmacokinetics. Trial efficacy end point was ≥10 participants with stable disease (SD) or better at 12 weeks. RESULTS: SD (n = 8) and partial response (PR) (n = 1) were observed among 30 evaluable patients. Progression-free survival (PFS) was 30.0% ± 7.9% at 6 months and 13.3% ± 5.6% at 1 year. One-year overall survival (OS) was 36.7% ± 8.4%. Two patients continued treatment for >12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h). CONCLUSIONS: Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.
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Antineoplásicos , Neoplasias do Sistema Nervoso Central , Tumor Rabdoide , Criança , Humanos , Antineoplásicos/uso terapêutico , Tumor Rabdoide/tratamento farmacológico , Azepinas/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Aurora Quinase A , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.
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Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioblastoma , Neoplasias Embrionárias de Células Germinativas , Tumores Neuroectodérmicos Primitivos , Neoplasias Encefálicas/terapia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Criança , Fatores de Transcrição Forkhead , Hospitais , Humanos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/terapiaRESUMO
Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.
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Neoplasias Encefálicas , Glioma , Metionina Adenosiltransferase/metabolismo , Animais , Neoplasias Encefálicas/genética , Epigenoma , Glioma/genética , Histonas/genética , Metionina/genética , CamundongosRESUMO
RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.
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Síndrome de Costello , Síndrome de Noonan , Síndrome de Costello/genética , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Síndrome de Noonan/genética , Transdução de Sinais , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.
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Astrocitoma , Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Adolescente , Adulto , Neoplasias do Tronco Encefálico/genética , Criança , Glioma/genética , Humanos , Sistema de Registros , Adulto JovemRESUMO
Differentiating tumor recurrence or progression from pseudoprogression during surveillance of pediatric high-grade gliomas (PHGGs) using MRI, the primary imaging modality for evaluation of brain tumors, can be challenging. The aim of this study was to evaluate whether 11C-methionine PET, a molecular imaging technique that detects functionally active tumors, is useful for further evaluating MRI changes concerning for tumor recurrence during routine surveillance. Methods: Using 11C-methionine PET during follow-up visits, we evaluated 27 lesions in 26 patients with new or worsening MRI abnormalities for whom tumor recurrence was of concern. We performed quantitative and qualitative assessments of both 11C-methionine PET and MRI data to predict the presence of tumor recurrence. Further, to assess for an association with overall survival (OS), we plotted the time from development of the imaging changes against survival. Results: Qualitative evaluation of 11C-methionine PET achieved 100% sensitivity, 60% specificity, and 93% accuracy to correctly predict the presence of tumors in 27 new or worsening MRI abnormalities. Qualitative MRI evaluation achieved sensitivity ranging from 86% to 95%, specificity ranging from 40% to 60%, and accuracy ranging from 85% to 89%. The interobserver agreement for 11C-methionine PET assessment was 100%, whereas the interobserver agreement was only 50% for MRI (P < 0.01). Quantitative MRI and 11C-methionine PET evaluation using receiver-operating characteristics demonstrated higher specificity (80%) than did qualitative evaluations (40%-60%). Postcontrast enhancement volume, metabolic tumor volume, tumor-to-brain ratio, and presence of tumor as determined by consensus MRI assessment were inversely associated with OS. Conclusion:11C-methionine PET has slightly higher sensitivity and accuracy for correctly predicting tumor recurrence, with excellent interobserver agreement, than does MRI. Quantitative 11C-methionine PET can also predict OS. These findings suggest that 11C-methionine PET can be useful for further evaluation of MRI changes during surveillance of previously treated PHGGs.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/patologia , Criança , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Metionina , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Tomografia por Emissão de Pósitrons/métodosRESUMO
Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. Here we report establishment of 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulate histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and include rare subgroups not well-represented by existing models. We deploy 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predict variable in vivo response to PI3K/mTOR and MEK pathway inhibitors. These unique new models and an online interactive data portal for exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.
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Heterogeneidade Genética/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/genética , Animais , Neoplasias Encefálicas , Linhagem Celular Tumoral , Proliferação de Células , Criança , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioblastoma (GBM) remains an aggressive brain tumor with a high rate of mortality. Immune checkpoint (IC) molecules are expressed on tumor infiltrating lymphocytes (TILs) and promote T cell exhaustion upon binding to IC ligands expressed by the tumor cells. Interfering with IC pathways with immunotherapy has promoted reactivation of anti-tumor immunity and led to success in several malignancies. However, IC inhibitors have achieved limited success in GBM patients, suggesting that other checkpoint molecules may be involved with suppressing TIL responses. Numerous IC pathways have been described, with current testing of inhibitors underway in multiple clinical trials. Identification of the most promising checkpoint pathways may be useful to guide the future trials for GBM. Here, we analyzed the The Cancer Genome Atlas (TCGA) transcriptomic database and identified PD1 and TIGIT as top putative targets for GBM immunotherapy. Additionally, dual blockade of PD1 and TIGIT improved survival and augmented CD8+ TIL accumulation and functions in a murine GBM model compared with either single agent alone. Furthermore, we demonstrated that this combination immunotherapy affected granulocytic/polymorphonuclear (PMN) myeloid derived suppressor cells (MDSCs) but not monocytic (Mo) MDSCs in in our murine gliomas. Importantly, we showed that suppressive myeloid cells express PD1, PD-L1, and TIGIT-ligands in human GBM tissue, and demonstrated that antigen specific T cell proliferation that is inhibited by immunosuppressive myeloid cells can be restored by TIGIT/PD1 blockade. Our data provide new insights into mechanisms of GBM αPD1/αTIGIT immunotherapy.
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Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores Imunológicos/antagonistas & inibidores , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
PURPOSE: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. MATERIALS AND METHODS: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3-21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. RESULTS: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS. CONCLUSIONS: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.
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Biomarcadores Tumorais , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/etiologia , Teratoma/diagnóstico , Teratoma/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Metilação de DNA , Diagnóstico Diferencial , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Mutação em Linhagem Germinativa , Humanos , Lactente , Masculino , Mutação , Prognóstico , Tumor Rabdoide/mortalidade , Tumor Rabdoide/terapia , Proteína SMARCB1/genética , Teratoma/mortalidade , Teratoma/terapia , Resultado do TratamentoRESUMO
PURPOSE: SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort (P = .74) or when patients were stratified by clinical risk (P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION: These results establish a new risk stratification for future medulloblastoma trials.
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Biomarcadores Tumorais/genética , Neoplasias Cerebelares/terapia , Metilação de DNA , Meduloblastoma/terapia , Mutação , Adolescente , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Epigenoma , Epigenômica , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imageamento por Ressonância Magnética , Masculino , Meduloblastoma/genética , Meduloblastoma/mortalidade , Meduloblastoma/secundário , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Platelet-derived growth factor receptor (PDGFR) signaling has been directly implicated in pediatric high-grade gliomagenesis. This study evaluated the safety and tolerability of crenolanib, a potent, selective inhibitor of PDGFR-mediated phosphorylation, in pediatric patients with high-grade glioma (HGG). METHODS: We used a rolling-6 design to study the maximum tolerated dose (MTD) of once-daily crenolanib administered during and after focal radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (stratum A) or with recurrent/progressive HGG (stratum B). Pharmacokinetics were studied during the first cycle at the first dose and at steady state (day 28). Alterations in PDGFRA were assessed by Sanger or exome sequencing and interphase fluorescence in situ hybridization or single nucleotide polymorphism arrays. RESULTS: Fifty evaluable patients were enrolled in the 2 strata, and an MTD of 170 mg/m2 was established for both. Dose-limiting toxicities were primarily liver enzyme elevations and hematologic count suppression in both strata. Crenolanib AUC0-48h and C MAX did not differ significantly for crushed versus whole-tablet administration. Overall, PDGFRA alterations were observed in 25% and 30% of patients in stratum A and B, respectively. Neither crenolanib therapy duration nor survival outcomes differed significantly by PDGFRA status, and overall survival of stratum A was similar to that of historical controls. CONCLUSIONS: Children tolerate crenolanib well at doses slightly higher than the established MTD in adults, with a toxicity spectrum generally similar to that in adults. Studies evaluating intratumoral PDGFR pathway inhibition in biomarker-enriched patients are needed to evaluate further the clinical utility of crenolanib in this population.
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The group of CNS mesenchymal (non-meningothelial) and primary glial/neuronal tumors in association with EWSR1-non-ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1-rearranged tumors confirmed by at least one molecular technique. Extra-axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1-ETS family fusions) were excluded. Additional studies, including anchored multiplex-PCR with next-generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1-WT1; n = 1) and tumors of uncertain histogenesis (EWSR1-CREM, n = 1; EWSR1-CREB1, n = 1; EWSR1-PLAGL1, n = 1; and EWSR1-PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1-CREM, EWSR1-PLAGL1 and EWSR1-PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow-up of 30 months. In conclusion, we describe five primary EWSR1-non-ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteína EWS de Ligação a RNA/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genética , Adulto JovemRESUMO
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is an almost universally fatal pediatric brain cancer. There has been no improvement in event-free survival (EFS) or overall survival (OS) despite immense effort through a multitude of clinical trials to find a cure. Recently, there has been a surge in the knowledge of DIPG biology, including the discovery of a recurrent H3F3A mutation in over 80% of these tumors. AREAS COVERED: The authors review the most recent approaches to diagnosis and treatment of DIPG including chemotherapy, biologics, surgical approaches, and immunotherapy. EXPERT OPINION: The authors propose four main opportunities to improve long-term survival. First, patients should be enrolled in scientifically sound clinical trials that include molecularly profiling either via stereotactic biopsy or liquid biopsy. Second, clinical trials should include more innovative endpoints other than traditional EFS and OS such as MRI/PET imaging findings combined with surrogates of activity (e.g. serial liquid biopsies) to better ascertain biologically active treatments. Third, innovative clinical trial approaches are needed to help allow for the rapid development of combination therapies to be tested. Finally, effort should be concentrated on reversing the effects of the histone mutation, as this malfunctioning development program seems to be key to DIPG relentlessness.
Assuntos
Neoplasias do Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/terapia , Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/mortalidade , Criança , Glioma Pontino Intrínseco Difuso/diagnóstico , Glioma Pontino Intrínseco Difuso/mortalidade , HumanosRESUMO
BACKGROUND: Craniopharyngiomas account for approximately 1.2-4% of all CNS tumors. They are typically treated with a combination of surgical resection and focal radiotherapy. Unfortunately, treatment can lead to permanent deleterious effects on behavior, learning, and endocrine function. METHODS: The Pediatric Brain Tumor Consortium performed a multicenter phase 2 study in children and young adults with unresectable or recurrent craniopharyngioma (PBTC-039). Between December 2013 and November 2017, nineteen patients (median age at enrollment, 13.1 y; range, 2-25 y) were enrolled in one of 2 strata: patients previously treated with surgery alone (stratum 1) or who received radiation (stratum 2). RESULTS: Eighteen eligible patients (8 male, 10 female) were treated with weekly subcutaneous pegylated interferon alpha-2b for up to 18 courses (108 wk). Therapy was well tolerated with no grade 4 or 5 toxicities. 2 of the 7 eligible patients (28.6%) in stratum 1 had a partial response, but only one response was sustained for more than 3 months. None of the 11 stratum 2 patients had an objective radiographic response, although median progression-free survival was 19.5 months. CONCLUSIONS: Pegylated interferon alpha-2b treatment, in lieu of or following radiotherapy, was well tolerated in children and young adults with recurrent craniopharyngiomas. Although objective responses were limited, progression-free survival results are encouraging, warranting further studies.
Assuntos
Neoplasias Encefálicas , Craniofaringioma , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adolescente , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Criança , Pré-Escolar , Craniofaringioma/tratamento farmacológico , Craniofaringioma/radioterapia , Feminino , Humanos , Lactente , Masculino , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/radioterapia , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
Diffuse intrinsic pontine glioma (DIPG) is most commonly diagnosed based on imaging criteria, with biopsy often reserved for pontine tumors with imaging features not typical for DIPG (atypical DIPG, 'aDIPG'). The histopathologic and molecular spectra of the clinical entity aDIPG remain to be studied systematically. In this study, thirty-three patients with newly diagnosed pontine-centered tumors with imaging inconsistent with DIPG for whom a pathologic diagnosis was subsequently obtained were included. Neoplasms were characterized by routine histology, immunohistochemistry, interphase fluorescence in situ hybridization, Sanger and next-generation DNA/RNA sequencing, and genome-wide DNA methylome profiling. Clinicopathologic features and survival outcomes were analyzed and compared to those of a contemporary cohort with imaging features consistent with DIPG (typical DIPG, 'tDIPG'). Blinded retrospective neuroimaging review assessed the consistency of the initial imaging-based diagnosis and correlation with histopathology. WHO grade II-IV infiltrating gliomas were observed in 54.6% of the cases; the remaining were low-grade gliomas/glioneuronal tumors or CNS embryonal tumors. Histone H3 K27M mutation, identified in 36% of the cases, was the major prognostic determinant. H3 K27M-mutant aDIPG and H3 K27M-mutant tDIPG had similar methylome profiles but clustered separately from diffuse midline gliomas of the diencephalon and spinal cord. In the aDIPG cohort, clinicoradiographic features did not differ by H3 status, yet significant differences in clinical and imaging features were observed between aDIPG without H3 K27M mutation and tDIPG. Neuroimaging review revealed discordance between the classification of aDIPG and tDIPG and did not correlate with the histology of glial/glioneuronal tumors or tumor grade. One patient (3.1%) developed persistent neurologic deficits after surgery; there were no surgery-related deaths. Our study demonstrates that surgical sampling of aDIPG is well-tolerated and provides significant diagnostic, therapeutic, and prognostic implications, and that neuroimaging alone is insufficient to distinguish aDIPG from tDIPG. H3 K27M-mutant aDIPG is epigenetically and clinically similar to H3 K27M-mutant tDIPG.
Assuntos
Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/patologia , Glioma Pontino Intrínseco Difuso/diagnóstico , Glioma Pontino Intrínseco Difuso/patologia , Adolescente , Neoplasias do Tronco Encefálico/genética , Criança , Pré-Escolar , Glioma Pontino Intrínseco Difuso/genética , Feminino , Histonas/genética , Humanos , Masculino , Mutação , Prognóstico , Estudos RetrospectivosRESUMO
Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.