RESUMO
Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.
Assuntos
Inteligência Artificial , Humanos , Criança , Oncologia/métodos , Família , Neoplasias Encefálicas/terapiaRESUMO
Molecular classification of medulloblastoma is critical for the treatment of this brain tumor. Array-based DNA methylation profiling has emerged as a powerful approach for brain tumor classification. However, this technology is currently not widely available. We present a machine-learning decision support system (DSS) that enables the classification of the principal molecular groups-WNT, SHH, and non-WNT/non-SHH-directly from quantitative PCR (qPCR) data. We propose a framework where the developed DSS appears as a user-friendly web-application-EpiGe-App-that enables automated interpretation of qPCR methylation data and subsequent molecular group prediction. The basis of our classification strategy is a previously validated six-cytosine signature with subgroup-specific methylation profiles. This reduced set of markers enabled us to develop a methyl-genotyping assay capable of determining the methylation status of cytosines using qPCR instruments. This study provides a comprehensive approach for rapid classification of clinically relevant medulloblastoma groups, using readily accessible equipment and an easy-to-use web-application.t.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Glioma , Neoplasias Pulmonares , Humanos , Lactente , Quinase do Linfoma Anaplásico/genética , Evolução Molecular , Glioma/tratamento farmacológico , Glioma/genética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaAssuntos
Transplante de Células-Tronco Hematopoéticas , Neoplasias Embrionárias de Células Germinativas , Neoplasias , Humanos , Adolescente , Neoplasias Embrionárias de Células Germinativas/terapia , Mobilização de Células-Tronco Hematopoéticas , Transplante Autólogo , Fator Estimulador de Colônias de GranulócitosRESUMO
Medulloblastoma (MB) is a malignant embryonal tumor that develops especially in childhood, with overall survival (OS) at 5 years of up to 70%. The objective of this study is to analyze treatment delivery variables in a retrospective cohort and evaluate the impact of these treatment quality parameters on survival. From 2000 to 2018, 40 pediatric patients with medulloblastoma, treated according to current international protocols, were retrospectively analyzed. Treatment delivery quality indicators were analyzed including the extent of surgery, radiotherapy (RT) parameters, and chemotherapy variables, related with time and dose-intensity deviations. With a median follow-up of 74 months (range, 6-195), OS at 5 years was 74 ± 7%, 81 ± 8% for standard-risk, and 55 ± 16% for high-risk patients (p = 0.090). Disease-free survival at 5 years was not significantly affected by extent of surgery (p = 0.428) and RT-related variables such as surgery-RT interval (p = 0.776) neither RT duration (p = 0.172) or maintenance chemotherapy compliance (p = 0.634). Multivariate analysis identified risk groups predictive of worse DFS (p = 0.032) and leptomeningeal dissemination associated with inferior OS (p = 0.029).Conclusion: Treatment delivery optimization has improved survival rates of patients with MB. Despite this, in our study, we have not established a clear influence of the considered radiotherapy and chemotherapy treatment quality parameters on outcomes. What is Known: ⢠Improvement in treatment modalities during the last decades has reached a 5-year OS of up to 70% in these patients. ⢠Extent of resection and radiotherapy parameters such as interval between surgery-radiotherapy and radiotherapy duration has been described as probable survival prognostic factors. What is New: ⢠Differences in medulloblastoma survival rates between prospective studies and retrospective series. ⢠The impact on survival of the three main treatment variables, surgery, radiotherapy and chemotherapy, susceptible to improvement.
Assuntos
Neoplasias Cerebelares , Meduloblastoma , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Cerebelares/tratamento farmacológico , Criança , Humanos , Meduloblastoma/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoAssuntos
Neoplasias do Tronco Encefálico/radioterapia , Radiação Cranioespinal/métodos , Glioma Pontino Intrínseco Difuso/radioterapia , Terapia de Salvação/métodos , Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/patologia , Criança , Glioma Pontino Intrínseco Difuso/patologia , Humanos , Imageamento por Ressonância Magnética , MasculinoAssuntos
Antineoplásicos , Asparaginase/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
Childhood cancer patients are at risk of developing important adverse effects, mortality and disease relapse after treatments, which has a substantial economic impact on healthcare systems. The objective of this study was to determine the effects of supervised inhospital exercise on clinical endpoints during childhood cancer treatment. 169 children with a new diagnosis of cancer were divided into an exercise intervention (n = 68, 11 ± 4 years) or a control group (n = 101, 11 ± 3 years). The cohort was followed up from the start of treatment for up to five years. Supervised inhospital exercise intervention was performed during the neoadjuvant (for solid tumors) or intensive chemotherapy treatment period (for leukemias). The median duration of the intervention was 22 (interquartile range, 14-28) weeks. We assessed survival, risk of disease relapse or metastasis, and days of hospitalization (primary outcomes), and cardiovascular function, anthropometry and blood variables (secondary outcomes). No exercise-related adverse events were noted. The exercise group had significantly less days of hospitalization than the control group (P = .031), resulting in a lower (~-17%) mean total economic cost of hospitalization in the former. Moreover, echocardiography-determined left ventricular function (ejection fraction and fractional shortening) was significantly impaired in the control group after treatment compared with baseline, whereas it was maintained in the exercise group (P = .024 and .021 for the between-group differences, respectively). In conclusion, supervised inhospital exercise intervention is safe and plays a cardioprotective role, at least in the short term, in children with cancer, also reducing hospitalization time, and therefore alleviating the economic burden.
Assuntos
Terapia por Exercício , Hospitalização , Neoplasias/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia , Estudos Prospectivos , Recidiva , Função Ventricular EsquerdaRESUMO
Intracranial germ cell tumors (GCT) account for less than 5% of all central nervous system tumors in children in Western countries. Approximately 40% are nongerminomatous GCT (NGGCT). Despite correct treatment, 16% to 47% of the patients will relapse. There are no standard approaches in case of recurrence, and treatment in this situation remains a challenge. We report three patients diagnosed with relapsed intracranial NGGCT treated with gemcitabine, paclitaxel, and oxaliplatin, in whom the tumor showed a remarkable response with normalization of tumor markers.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Terapia de Salvação , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Neoplasias Encefálicas/patologia , Criança , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Oxaliplatina/administração & dosagem , Paclitaxel/administração & dosagem , Prognóstico , Neoplasias Testiculares/patologia , GencitabinaRESUMO
Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA , Epigenômica/métodos , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/metabolismo , Feminino , Glioma/classificação , Glioma/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Análise de Sobrevida , Sequenciamento do Exoma/métodosRESUMO
Medulloblastoma is the most common malignant brain tumor in children. Approximately 30% of children with medulloblastoma will progress or relapse despite being treated. New therapies have been proposed in recent years, including high-dose chemotherapy, immunotherapy, and targeted therapy. However, the best treatment for these patients remains unclear, and in this situation prognosis is poor. Oral etoposide has been used as a single agent or in combination for treating relapsed brain tumors since the 1990s. We report an 8-year-old patient with recurrent metastatic medulloblastoma who had an excellent response after treatment with oral etoposide, maintaining a great quality of life. As clinicians, we must always try to include our patients in clinical trials; however, when this is not possible, we should not forget that "old drugs" such as oral etoposide may work in some patients, with a good response of the tumor, and what is most important, providing the patient with a good quality of life.