RESUMO
BACKGROUND: The clinical features of cerebellar high-grade gliomas (cHGGs) in adults have not been thoroughly explored. This large-scale, population-based study aimed to comprehensively outline these traits and construct a predictive model. METHODS: Patient records diagnosed with gliomas were collected from various cohorts and analyzed to compare the features of cHGGs and supratentorial HGGs (sHGGs). Cox regression analyses were employed to identify prognostic factors for overall survival and to develop a nomogram for predicting survival probabilities in patients with cHGGs. Multiple machine learning methods were applied to evaluate the efficacy of the predictive model. RESULTS: There were significant differences in prognosis, with SEER-cHGGs showing a median survival of 7.5 months and sHGGs 14.9 months (p < 0.001). Multivariate Cox regression analyses revealed that race, WHO grade, surgical procedures, radiotherapy, and chemotherapy were independent prognostic factors for cHGGs. Based on these factors, a nomogram was developed to predict 1-, 3-, and 5-year survival probabilities, with AUC of 0.860, 0.837, and 0.810, respectively. The model's accuracy was validated by machine learning approaches, demonstrating consistent predictive effectiveness. CONCLUSIONS: Adult cHGGs are distinguished by distinctive clinical features different from those of sHGGs and are associated with an inferior prognosis. Based on these risk factors affecting cHGGs prognosis, the nomogram prediction model serves as a crucial tool for clinical decision-making in patient care.
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Neoplasias Cerebelares , Glioma , Nomogramas , Humanos , Feminino , Masculino , Glioma/mortalidade , Glioma/patologia , Glioma/terapia , Pessoa de Meia-Idade , Adulto , Prognóstico , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/terapia , Gradação de Tumores , Idoso , Aprendizado de Máquina , Programa de SEER , Adulto JovemRESUMO
Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. A better understanding of these malignancies has led to their classification into four major molecular subgroups. This classification not only facilitates the stratification of clinical trials, but also the development of more effective therapies. Despite recent progress, approximately 30% of children diagnosed with MB experience tumor relapse. Recurrent disease in MB is often metastatic and responds poorly to current therapies. As a result, only a small subset of patients with recurrent MB survive beyond one year. Due to its dismal prognosis, novel therapeutic strategies aimed at preventing or managing recurrent disease are urgently needed. In this review, we summarize recent advances in our understanding of the molecular mechanisms behind treatment failure in MB, as well as those characterizing recurrent cases. We also propose avenues for how these findings can be used to better inform personalized medicine approaches for the treatment of newly diagnosed and recurrent MB. Lastly, we discuss the treatments currently being evaluated for MB patients, with special emphasis on those targeting MB by subgroup at diagnosis and relapse.
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Neoplasias Cerebelares , Meduloblastoma , Recidiva Local de Neoplasia , Humanos , Meduloblastoma/patologia , Meduloblastoma/genética , Meduloblastoma/terapia , Meduloblastoma/tratamento farmacológico , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Animais , Criança , Antineoplásicos/uso terapêutico , Medicina de PrecisãoRESUMO
Medulloblastoma (MB) is a primary brain malignancy. However, updated epidemiological data and long-term outcomes are lacking.The clinical and epidemiological datasets of patients with MB in the current study were obtained from the Surveillance, Epidemiology, and End Results (SEER) databases. Joinpoint regression models were used to assess the rate of changes in the incidence, prevalence, and treatment trends in patients with MB. Cox hazard and competition risk model analyses were used to assess overall survival (OS) and cancer-specific survival (CSS).The age-adjusted incidence of MB remained relatively stable at 0.15 per 100,000 individuals in 2019. The annual percentage change (APC) of females remained stable, whereas that of males increased over time. The 20-year limited-duration prevalence of patients with MB increased significantly from 0.00016 % in 1999 to 0.00203 % in 2018. Patients aged 5-19 years accounted for 46.7 % of all age groups, and the trend for the three treatments was increased. Average annual percentage change (AAPC) for the chemotherapy group was increased in patients aged 20 + years MB [AAPC = 2.66 (95 % CI 0.93-6.31)]. Multivariate analysis revealed that OS and CSS varied significantly according to age, year of diagnosis, histology, stage, surgery, and radiotherapy. Subgroup analysis showed that chemotherapy was associated with a favorable prognosis in high-risk groups.The incidence of MB remained relatively stable, and its prevalence increased significantly. This current population-based study further identified the prognostic factors in patients with MB. Moreover, the use of chemotherapy was associated with better survival in high-risk groups.
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Neoplasias Cerebelares , Meduloblastoma , Programa de SEER , Humanos , Meduloblastoma/mortalidade , Meduloblastoma/epidemiologia , Meduloblastoma/terapia , Feminino , Masculino , Adolescente , Criança , Pré-Escolar , Adulto Jovem , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/epidemiologia , Neoplasias Cerebelares/terapia , Incidência , Lactente , Prevalência , IdosoRESUMO
INTRODUCTION: Advances in molecular biology have led to consensus classification of medulloblastoma into four broad molecular subgroups - wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4, respectively. Traditionally, children >3 years of age, with no/minimal residual tumor (<1.5 cm2) and lack of metastasis were classified as average-risk disease with >80% long-term survival. Younger age (<3 years), large residual disease (≥1.5 cm2), and leptomeningeal metastases either alone or in combination were considered high-risk features yielding much worse 5-year survival (30-60%). This clinico-radiological risk-stratification has been refined by incorporating molecular/genetic information. Contemporary multi-modality management for non-infantile medulloblastoma entails maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. Aggressive multi-modality management achieves good survival but is associated with substantial dose-dependent treatment-related toxicity prompting conduct of subgroup-specific prospective clinical trials. AREAS COVERED: We conducted literature search on PubMed from 1969 till 2023 to identify putative prognostic factors and risk-stratification for medulloblastoma, including molecular subgrouping. Based on previously published data, including our own institutional experience, we discuss molecular risk-stratification focusing on WNT-pathway medulloblastoma to identify candidates suitable for treatment de-intensification to strike the optimal balance between survival and quality of survivorship. EXPERT OPINION: Prospective clinical trials and emerging biological information should further refine risk-stratification in WNT-pathway medulloblastoma.
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Neoplasias Cerebelares , Meduloblastoma , Via de Sinalização Wnt , Humanos , Meduloblastoma/terapia , Meduloblastoma/patologia , Neoplasias Cerebelares/terapia , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/genética , Criança , Pré-Escolar , Taxa de Sobrevida , Terapia Combinada , Prognóstico , Medição de Risco , Fatores Etários , Neoplasia ResidualRESUMO
PURPOSE: This study aims to provide an exhaustive analysis of pediatric low-grade gliomas (pLGGs) in the cerebellar hemispheres, focusing on incidence, clinical characteristics, surgical outcomes, and prognosis. It seeks to enhance understanding and management of pLGGs in the pediatric population. METHODS: We conducted an observational, descriptive, retrospective, and cross-sectional study at a pediatric hospital, reviewing medical records of 30 patients with cerebellar hemispheric pLGGs treated from December 2014 to January 2023. Data collection included demographics, clinical presentation, imaging findings, surgical approach, postoperative complications, histopathological diagnosis, hydrocephalus management, and follow-up. Molecular markers and adjuvant therapies were also analyzed. RESULTS: The cohort predominantly presented with cerebellar symptoms, with 60% showing hydrocephalus at diagnosis. MRI with gadolinium was crucial for diagnosis. Surgical focus was on achieving gross total resection (GTR), accomplished in 70% of cases. Postsurgical hydrocephalus was less common, and cerebellar mutism was not reported. While a complete molecular analysis was not performed in all cases, available data suggest significant influence of molecular markers on prognosis and therapeutic options of pLGGs. CONCLUSIONS: This study highlights the unique clinical and molecular characteristics of cerebellar hemispheric pLGGs in children. The lower incidence of postoperative hydrocephalus and absence of cerebellar mutism are notable findings. Emphasizing a multidisciplinary approach, our findings contribute to a deeper understanding of pediatric pLGGs, underscoring the need for personalized treatment strategies and vigilant follow-up.
Assuntos
Neoplasias Cerebelares , Glioma , Humanos , Feminino , Masculino , Criança , Glioma/cirurgia , Glioma/terapia , Glioma/diagnóstico , Neoplasias Cerebelares/cirurgia , Neoplasias Cerebelares/terapia , Pré-Escolar , Estudos Retrospectivos , Adolescente , Estudos Transversais , Lactente , Hospitais Pediátricos , Centros de Atenção Terciária , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Procedimentos Neurocirúrgicos/métodosRESUMO
RATIONALE: Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant form of non-Hodgkin lymphoma categorized under the diffuse large B-cell type. It accounts for merely 1% of all non-Hodgkin lymphoma cases and comprises approximately 3% of all brain tumors. The involvement of the cerebellum is observed in only 9% of these cases. Recently, we came across an unusual instance: a young man presenting with multiple lesions located specifically within the cerebellum. PATIENT CONCERNS: A 26-year-old male was admitted to the hospital due to severe headaches. He has a medical history of sporadic headaches, accompanied by dizziness, nausea, and vomiting persisting for a month. Over the last 10 days, his headaches have intensified, coupled with decreased vision and protrusion of the eyeballs. Magnetic resonance imaging (MRI) revealed abnormal signals in both cerebellar hemispheres. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Diagnostic procedures included cerebellar biopsy, posterior fossa decompression, and lateral ventricle drainage. Histopathological examination identified diffuse large B-cell lymphoma (DLBCL) with high proliferative activity. To minimize neurotoxicity, chemotherapy involved intrathecal methotrexate (MTX) injections combined with the CHOP program. The patient has shown good tolerance to the treatment so far. LESSONS: While the definitive optimal treatment approach remains elusive, current chemotherapy centered on high-dose MTX stands as the standard induction therapy. Integrating surgery with radiotherapy and chemotherapy significantly extends patient survival.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Cerebelares , Linfoma Difuso de Grandes Células B , Humanos , Masculino , Adulto , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Cerebelares/terapia , Neoplasias Cerebelares/patologia , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Vincristina/uso terapêutico , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Metotrexato/uso terapêutico , Metotrexato/administração & dosagem , Prednisona/uso terapêutico , Prednisona/administração & dosagem , Terapia Combinada , Imageamento por Ressonância Magnética , Cerebelo/patologia , Cerebelo/diagnóstico por imagemRESUMO
Patients with brain cancers including medulloblastoma lack treatments that are effective long-term and without side effects. In this study, a multifunctional fluoropolymer-engineered iron oxide nanoparticle gene-therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood-brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) - as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity - meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment-focused MRI-siRNA theranostics for the better treatment and diagnosis of medulloblastoma.
Assuntos
Barreira Hematoencefálica , Inativação Gênica , Meduloblastoma , RNA Interferente Pequeno , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/terapia , Barreira Hematoencefálica/metabolismo , Animais , Camundongos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/administração & dosagem , Humanos , Modelos Animais de Doenças , Nanopartículas de Magnetita/química , Imageamento por Ressonância Magnética/métodos , Linhagem Celular Tumoral , Polímeros/química , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/terapiaRESUMO
PURPOSE: Medulloblastoma (MB), the most common childhood malignant brain tumor, has a poor prognosis in about 30% of patients. The current standard of care, which includes surgery, radiation, and chemotherapy, is often responsible for cognitive, neurologic, and endocrine side effects. We investigated whether chimeric antigen receptor (CAR) T cells directed toward the disialoganglioside GD2 can represent a potentially more effective treatment with reduced long-term side effects. EXPERIMENTAL DESIGN: GD2 expression was evaluated on primary tumor biopsies of MB children by flow cytometry. GD2 expression in MB cells was also evaluated in response to an EZH2 inhibitor (tazemetostat). In in vitro and in vivo models, GD2+ MB cells were targeted by a CAR-GD2.CD28.4-1BBζ (CAR.GD2)-T construct, including the suicide gene inducible caspase-9. RESULTS: GD2 was expressed in 82.68% of MB tumors. The SHH and G3-G4 subtypes expressed the highest levels of GD2, whereas the WNT subtype expressed the lowest. In in vitro coculture assays, CAR.GD2 T cells were able to kill GD2+ MB cells. Pretreatment with tazemetostat upregulated GD2 expression, sensitizing GD2dimMB cells to CAR.GD2 T cells cytotoxic activity. In orthotopic mouse models of MB, intravenously injected CAR.GD2 T cells significantly controlled tumor growth, prolonging the overall survival of treated mice. Moreover, the dimerizing drug AP1903 was able to cross the murine blood-brain barrier and to eliminate both blood-circulating and tumor-infiltrating CAR.GD2 T cells. CONCLUSIONS: Our experimental data indicate the potential efficacy of CAR.GD2 T-cell therapy. A phase I/II clinical trial is ongoing in our center (NCT05298995) to evaluate the safety and therapeutic efficacy of CAR.GD2 therapy in high-risk MB patients.
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Gangliosídeos , Imunoterapia Adotiva , Meduloblastoma , Receptores de Antígenos Quiméricos , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Meduloblastoma/terapia , Meduloblastoma/imunologia , Meduloblastoma/patologia , Meduloblastoma/genética , Meduloblastoma/metabolismo , Animais , Camundongos , Gangliosídeos/metabolismo , Gangliosídeos/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Linhagem Celular Tumoral , Criança , Feminino , Linfócitos T/imunologia , Linfócitos T/metabolismo , Neoplasias Cerebelares/terapia , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/metabolismo , Morfolinas/farmacologia , Masculino , Pré-Escolar , Benzamidas , Compostos de Bifenilo , PiridonasRESUMO
Aim: Adult medulloblastomas (MB) are rare, and optimal post-craniospinal irradiation (CSI) chemotherapy is not yet defined. We investigated hematological toxicity in patients treated with platinum-etoposide (EP) post-CSI. Methods: Retrospective, single-institution study to determine hematological toxicity in adult MB patients treated with EP (1995-2022). Results: Thirteen patients with a median follow-up of 50 months (range, 10-233) were analyzed. Four discontinued treatment due to toxicity, one after 1, 3 after 3 cycles. Hematological toxicities included grade 3 (5 patients) and grade 4 (6 patients). Two patients experienced post-treatment progression and died 16 and 37 months from diagnosis. Conclusion: Post-CSI EP demonstrates acceptable hematological toxicity in adult MB. However, the small cohort precludes definitive survival outcome conclusions. Prospective studies for comprehensive comparisons with other regimens are needed in this context.
Our study aimed to understand the effect of a chemotherapy combination (platinum and etoposide) on blood counts in adult patients with medulloblastoma after craniospinal radiation. Medulloblastoma is a rare brain cancer in adults. We analyzed data from 13 adult patients with medulloblastoma. The results show that the treatment leads to significant blood count-related side effects. Four of the patients discontinued their treatment early. Blood counts improved again after completion of treatment. Two patients had the tumor grow back after treatment and died later. Overall, the effect from this chemotherapy combination on blood counts was felt to be acceptable. The number of patients in this study was small, and more research is needed to determine the overall effectiveness of this treatment.
Assuntos
Neoplasias Cerebelares , Etoposídeo , Meduloblastoma , Humanos , Masculino , Estudos Retrospectivos , Adulto , Feminino , Meduloblastoma/radioterapia , Meduloblastoma/tratamento farmacológico , Etoposídeo/efeitos adversos , Etoposídeo/administração & dosagem , Adulto Jovem , Pessoa de Meia-Idade , Neoplasias Cerebelares/radioterapia , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/terapia , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Seguimentos , Adolescente , Radiação Cranioespinal/efeitos adversos , Platina/uso terapêuticoRESUMO
Medulloblastoma is one of the most common malignant pediatric brain tumors derived from posterior fossa. The current treatment includes maximal safe surgical resection, radiotherapy, whole cranio-spinal radiation and adjuvant with chemotherapy. However, it can only limitedly prolong the survival time with severe side effects and relapse. Defining the intratumoral heterogeneity, cellular origin and identifying the interaction network within tumor microenvironment are helpful for understanding the mechanisms of medulloblastoma tumorigenesis and relapse. Due to technological limitations, the mechanisms of cellular heterogeneity and tumor origin have not been fully understood. Recently, the emergence of single-cell technology has provided a powerful tool for achieving the goal of understanding the mechanisms of tumorigenesis. Several studies have demonstrated the intratumoral heterogeneity and tumor origin for each subtype of medulloblastoma utilizing the single-cell RNA-seq, which has not been uncovered before using conventional technologies. In this review, we present an overview of the current progress in understanding of cellular heterogeneity and tumor origin of medulloblastoma and discuss novel findings in the age of single-cell technologies.
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Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Criança , Humanos , Meduloblastoma/genética , Meduloblastoma/terapia , Meduloblastoma/patologia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Neoplasias Cerebelares/patologia , Recidiva Local de Neoplasia , Neoplasias Encefálicas/patologia , Recidiva , Carcinogênese , Microambiente Tumoral/genéticaRESUMO
OBJECTIVE: Medulloblastoma is the most common malignant intracranial tumor affecting the pediatric population. Despite advancements in multimodal treatment over the past 2 decades yielding a 5-year survival rate > 75%, children who survive often have substantial neurological and cognitive sequelae. The authors aimed to identify risk factors and develop a clinically friendly online calculator for prognostic estimation in pediatric patients with medulloblastoma. METHODS: Pediatric patients with a histopathologically confirmed medulloblastoma were extracted from the Surveillance, Epidemiology, and End Results database (2000-2018) and split into training and validation cohorts in an 80:20 ratio. The Cox proportional hazards model was used to identify the univariate and multivariate survival predictors. Subsequently, a calculator with those factors was developed to predict 2-, 5-, and 10-year overall survival as well as median survival months for pediatric patients with medulloblastoma. The performance of the calculator was determined by discrimination and calibration. RESULTS: One thousand seven hundred fifty-nine pediatric patients with medulloblastoma met the prespecified inclusion criteria. Age, sex, race, ethnicity, median household income, county attribute, laterality, anatomical location, tumor grade, tumor size, surgery status, radiotherapy, and chemotherapy were variables included in the calculator (https://spine.shinyapps.io/Peds_medullo/). The concordance index was 0.769 in the training cohort and 0.755 in the validation cohort, denoting clinically useful predictive accuracy. Good agreement between the predicted and observed outcomes was demonstrated by the calibration plots. CONCLUSIONS: An easy-to-use prognostic calculator for a large cohort of pediatric patients with medulloblastoma was established. Future efforts should focus on improving granularity of population-based registries and externally validating the proposed calculator.
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Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Humanos , Criança , Meduloblastoma/terapia , Prognóstico , Neoplasias Cerebelares/terapia , Aprendizado de MáquinaRESUMO
PURPOSE OF REVIEW: Review recent advances in the understanding of pediatric medulloblastoma including etiology, biology, radiology, and management of pediatric medulloblastoma. RECENT FINDINGS: The classic four subgroups have been reclassified and further subdivided based on new molecular findings. Research is revealing the cell origins of the different subtypes of medulloblastoma. There has been continued personalization of management based on molecular parameters. While many advances have been made in the knowledge base of this most common malignant pediatric brain tumor, there has not yet been translation into more effective therapies to prolong survival in all subgroups with the possible exception of children with group 3 disease. Quality of life remains a major challenge for long-term survivors.
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Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Criança , Humanos , Meduloblastoma/genética , Meduloblastoma/terapia , Meduloblastoma/patologia , Qualidade de Vida , Neoplasias Encefálicas/terapia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapiaRESUMO
ABSTRACT: BACKGROUND: With the improvement of technology and the advancement of medical treatment in recent decades, more and more pediatric medulloblastoma survivors reintegrate to the community. This study aimed to examine the experiences of pediatric medulloblastoma survivors. METHODS: A qualitative research was conducted. Twenty Chinese pediatric medulloblastoma survivors were interviewed. Interviews were recorded and transcribed. Colaizzi's analysis method was used to analyze data. RESULTS: There were 4 themes in this study: physical health issues, community reintegration challenges, overcoming psychological pressure, and multiple unmet needs. CONCLUSION: Pediatric medulloblastoma survivors face challenges in the physical, psychological, and social aspects of their health, along with multiple unmet healthcare needs. Nurses should comprehensively assess the survivor's needs from admission, plan for discharge, and provide regular follow-up care after discharge. Furthermore, nurses should collaborate with caregivers, clinicians, and schoolteachers to develop programs aimed at enhancing the quality of life for survivors. It is also important to explore the survival experiences of individuals in different regions.
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Neoplasias Cerebelares , Meduloblastoma , Criança , Humanos , Acontecimentos que Mudam a Vida , População do Leste Asiático , Meduloblastoma/terapia , Qualidade de Vida , Pesquisa Qualitativa , Sobreviventes , Neoplasias Cerebelares/terapiaRESUMO
Central nervous system (CNS) embryonal tumors, commonly found in pediatric patients, represent a heterogeneous mix of lesions with an overall poor (though improving) prognosis. Medulloblastomas are by far the most frequently encountered and most widely studied subtype, though others include atypical teratoid/rhabdoid tumors (AT/RTs), embryonal tumor with multilayered rosettes (ETMRs), and CNS neuroblastomas, FOX-R2 activated. The classification, diagnosis, and treatment of these lesions have evolved drastically over the years as their molecular underpinnings have been elucidated. We describe the most recent 2021 WHO Classification system, discuss current understanding of the genetic basis, and demonstrate current thinking in treatment for these highly complex tumors. Since surgical resection continues to remain a mainstay of treatment, preventing and managing surgical complications, especially cerebellar mutism syndrome (CMS), is paramount. We describe the current theories for the etiology of CMS and two centers' experience in mitigating its risks. As our surgical toolbox continues to evolve along with our understanding of these tumors, we hope future patients can benefit from both improved overall survival and quality of life.
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Neoplasias do Sistema Nervoso Central , Doenças Cerebelares , Neoplasias Cerebelares , Meduloblastoma , Mutismo , Neoplasias Embrionárias de Células Germinativas , Criança , Humanos , Meduloblastoma/genética , Mutismo/etiologia , Mutismo/terapia , Qualidade de Vida , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias Cerebelares/terapia , Neoplasias Cerebelares/genéticaRESUMO
Background: Non-WNT/non-SHH medulloblastoma (MB) is one of the subtypes with the highest genetic heterogeneity in MB, and its current treatment strategies have unsatisfactory results and significant side effects. As a member of the centromere protein (CENP) family, centromeric protein E (CENPE) is a microtubule plus-end-directed kinetochore protein. Heterozygous mutations in CENPE can leads to primary microcephaly syndrome. It has been reported that CENPE is upregulated in MB, but its role in MB development is still unknown. Methods: We downloaded the relevant RNA seq data and matched clinical information from the GEO database. Bioinformatics analysis includes differential gene expression analysis, Kaplan-Meier survival analysis, nomogram analysis, ROC curve analysis, immune cell infiltration analysis, and gene function enrichment analysis. Moreover, the effects of CENPE expression on cell proliferation, cell cycle, and p53 signaling pathway of non-WNT/non-SHH MB were validated using CENPE specific siRNA in vitro experiments. Results: Compared with normal tissues, CENPE was highly expressed in MB tissues and served as an independent prognostic factor for survival in non-WNT/non-SHH MB patients. The nomogram analysis and ROC curve further confirmed these findings. At the same time, immune cell infiltration analysis showed that CENPE may participate in the immune response and tumor microenvironment (TME) of non-WNT/non-SHH MB. In addition, gene enrichment analysis showed that CENPE was closely related to the cell cycle and p53 pathway in non-WNT/non-SHH MB. In vitro experimental validation showed that knockdown of CENPE inhibited cell proliferation by activating the p53 signaling pathway and blocking the cell cycle. Conclusion: The expression of CENPE in non-WNT/non-SHH MB was positively correlated with poor prognosis. CENPE may affect tumor progression by regulating cell cycle, p53 pathway, and immune infiltration. Hence, CENPE is highly likely a novel biomarker and potential therapeutic target for non-WNT/non-SHH MB.
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Neoplasias Cerebelares , Meduloblastoma , Microcefalia , Humanos , Meduloblastoma/genética , Meduloblastoma/terapia , Proteína Supressora de Tumor p53 , Biomarcadores , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Microambiente Tumoral/genéticaRESUMO
Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is disproportionately damaging to very young children. As a result, trials have attempted to delay, omit, and replace this therapy. Although success has been limited, the approach has not been a complete failure. In fact, this approach has cured a significant number of children with medulloblastoma. However, many children have endured intensive regimens of chemotherapy only to experience relapse and undergo salvage treatment with CSI, often at higher doses and with worse morbidity than they would have initially experienced. Recent advancements in molecular diagnostics have proven that response to therapy is biologically driven. Medulloblastoma in infants and young children is divided into 2 molecular groups: Sonic Hedgehog (SHH) and group 3 (G3). Both are chemotherapy-sensitive, but only the SHH medulloblastomas are reliably cured with chemotherapy alone. Moreover, SHH can be molecularly parsed into 2 groups: SHH-1 and SHH-2, with SHH-2 showing higher cure rates with less intensive chemotherapy and SHH-1 requiring more intensive regimens. G3 medulloblastoma, on the other hand, has a near universal relapse rate after chemotherapy-only regimens. This predictability represents a significant breakthrough and affords oncologists the ability to properly risk-stratify therapy in such a way that the most curative and least toxic therapy is selected. This review examines the treatment of medulloblastoma in infants and young children, discusses the molecular advancements, and proposes how to use this information to structure the future management of this disease.
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Neoplasias Cerebelares , Meduloblastoma , Criança , Lactente , Humanos , Adolescente , Pré-Escolar , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Meduloblastoma/terapia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Proteínas Hedgehog/genética , Proteínas Hedgehog/uso terapêutico , Recidiva Local de Neoplasia , RecidivaRESUMO
Medulloblastoma (MB) is the most common type of malignant pediatric brain cancer. The current standard of care (SOC) involves maximal safe resection and chemoradiotherapy in individuals older than 3 years, often leading to devastating neurocognitive and developmental deficits. Out of the four distinct molecular subgroups, Group 3 and 4 have the poorest patient outcomes due to the aggressive nature of the tumor and propensity to metastasize and recur post therapy. The toxicity of the SOC and lack of response in specific subtypes to the SOC underscores the urgent need for developing and translating novel treatment options including immunotherapies. To identify differentially enriched surface proteins that could be evaluated for potential future immunotherapeutic interventions, we leveraged N-glycocapture surfaceome profiling on Group 3 MB cells from primary tumor, through therapy, to recurrence using our established therapy-adapted patient derived xenograft model. Integrin ð¼5 (ITGA5) was one of the most differentially enriched targets found at recurrence when compared to engraftment and untreated timepoints. In addition to being enriched at recurrence, shRNA-mediated knockdown and small molecule inhibition of ITGA5 have resulted in marked decrease in proliferation and self-renewal in vitro and demonstrated a survival advantage in vivo. Together, our data highlights the value of dynamic profiling of cells as they evolve through therapy and the identification of ITGA5 as a promising therapeutic target for recurrent Group 3 MB.
Assuntos
Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Humanos , Criança , Meduloblastoma/terapia , Encéfalo , Agressão , Neoplasias Cerebelares/terapiaRESUMO
BACKGROUND AND OBJECTIVES: Medulloblastomas are embryonal tumors predominantly affecting children. Recognition of molecularly defined subgroups has advanced management. Factors influencing the management and prognosis of adult patients with medulloblastoma remains poorly understood. METHODS: We examined the management, prognostic factors, and, when possible, molecular subgroup differences (subset) in adult patients (aged 18 years or older) with medulloblastoma from our center (specialty Neuro-Oncology clinic within a large academic practice) diagnosed between 1992 and 2020. Molecular subtyping corresponding to the 2021 WHO Classification was performed. Kaplan-Meier estimates (with log-rank test) were performed for univariate survival analysis with Cox regression used for multivariate analyses. RESULTS: We included 76 adult patients with medulloblastoma (62% male), with a median age of 32 years at diagnosis (range: 18-66) and median follow-up of 7.7 years (range: 0.6-27). A subset of 58 patients had molecular subgroup characterization-37 SHH-activated, 12 non-WNT/non-SHH, and 9 WNT-activated. Approximately 67% underwent gross total resection, 75% received chemotherapy at diagnosis, and 97% received craniospinal irradiation with boost. The median overall survival (OS) for the whole cohort was 14.8 years. The 2-, 5-, and 10-year OS rates were 93% (95% CI 88-99), 86% (78-94), and 64% (53-78), respectively. Survival was longer for younger patients (aged 30 years or older: 9.9 years; younger than 30 years: estimated >15.4 years; log-rank p < 0.001). There was no survival difference by molecular subgroup or extent of resection. Only age at diagnosis remained significant in multivariate survival analyses. DISCUSSION: We report one of the largest retrospective cohorts in adult patients with medulloblastoma with molecular subtyping. Survival and molecular subgroup frequencies were similar to prior reports. Survival was better for adult patients younger than 30 years at diagnosis and was not significantly different by molecular subgroup or management characteristics (extent of resection, RT characteristics, or chemotherapy timing or regimen).
Assuntos
Neoplasias Cerebelares , Meduloblastoma , Criança , Humanos , Adulto , Masculino , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Feminino , Meduloblastoma/terapia , Meduloblastoma/diagnóstico , Estudos Retrospectivos , Neoplasias Cerebelares/terapia , Neoplasias Cerebelares/diagnóstico , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.
Assuntos
Neoplasias Cerebelares , Síndrome de Li-Fraumeni , Meduloblastoma , Criança , Humanos , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/terapia , Meduloblastoma/terapia , Meduloblastoma/tratamento farmacológico , Estudos Retrospectivos , Estudos Prospectivos , Neoplasias Cerebelares/terapia , Neoplasias Cerebelares/tratamento farmacológico , Mutação em Linhagem Germinativa , Proteína Supressora de Tumor p53/genéticaRESUMO
Medulloblastoma (MB) is one of the most common malignant childhood brain tumors (WHO grade IV). Its high degree of malignancy leads to an unsatisfactory prognosis, requiring more precise and personalized treatment in the near future. Multi-omics and artificial intelligence have been playing a significant role in precise medical research, but their implementation needs a large amount of clinical information and biomaterials. For these reasons, it is urgent for current MB researchers to establish a large sample-size database of MB that contains complete clinical data and sufficient biomaterials such as blood, cerebrospinal fluid (CSF), cancer tissue, and urine. Unfortunately, there are few biobanks of pediatric central nervous system (CNS) tumors throughout the world for limited specimens, scarce funds, different standards collecting methods and et cl. Even though, China falls behind western countries in this area. The present research set up a standard workflow to construct the Beijing Children's Hospital Medulloblastoma (BCH-MB) biobank. Clinical data from children with MB and for collecting and storing biomaterials, along with regular follow-up has been collected and recorded in this database. In the future, the BCH-MB biobank could make it possible to validate the promising biomarkers already identified, discover unrevealed MB biomarkers, develop novel therapies, and establish personalized prognostic models for children with MB upon the support of its sufficient data and biomaterials, laying the foundation for individualized therapies of children with MB.