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1.
Medicine (Baltimore) ; 99(41): e22366, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031272

RESUMO

To investigate the prognoses associated with different locations of medulloblastoma (MB) in terms of survival through a case-control study and evaluate the prognostic factors for MB.The Surveillance, Epidemiology, and End Results database was used to identify MB patients diagnosed from 1975 to 2016. Each brainstem MB (bMB) patient was matched to a cerebellum MB (cMB) patient by propensity score matching based on age, sex, tumor size, extent of metastasis, extent of surgical resection, radiotherapy status and chemotherapy status. Univariate and multivariate analyses were performed to assess the effect of prognostic factors on overall survival. Ethical approval was not necessary as this study is based on a public database.A total of 172 bMB patients and 1417 cMB patients were included in the study. A total of 144 pairs of patients were matched to constitute the matched cohort. Within the matched cohort, the median survival times were 213 months and 96 months for cMB and bMB, respectively. Within the unmatched cohort, the median survival times were 111 months and 97 months for cMB and bMB, respectively. Brainstem location detrimentally affected the survival time of MB patients in both the matched cohort (hazard ratios =8.14, 95% confidence interval =5.98-11.08) and the unmatched cohort (hazard ratios =1.44, 95% confidence interval =1.20-1.74). Age <5 years and receipt of radiotherapy were favorable prognostic factors, whereas gross total resection, brainstem location and receipt of chemotherapy were unfavorable prognostic factors. Radiotherapy alone was associated with superior outcomes concerning adjuvant chemotherapy or radiotherapy.This study uncovers a survival advantage for cMB patients versus bMB patients. Additionally, prognostic factors include age, extent of surgical resection, and receipt of radiotherapy or chemotherapy. Radiotherapy after surgery and rational use of chemotherapy drugs are crucial for treatment of MB patients. Further studies of these prognostic factors are required to improve the survival time.


Assuntos
Neoplasias do Tronco Encefálico/mortalidade , Meduloblastoma/mortalidade , Neoplasias do Tronco Encefálico/terapia , Estudos de Casos e Controles , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/terapia , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Lactente , Masculino , Meduloblastoma/terapia , Prognóstico , Pontuação de Propensão , Sistema de Registros , Estudos Retrospectivos , Programa de SEER , Taxa de Sobrevida
2.
Nat Commun ; 11(1): 4323, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859895

RESUMO

Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we characterize differences in the tumor-initiating capacity of Wnt, Group 3, and Group 4 MB. With single cell RNA-seq technology, we demonstrate the presence of rare Wnt-active cells in non-Wnt MBs, which functionally retain the impaired tumorigenic potential of Wnt MB. In treating MB xenografts with a Wnt agonist, we provide a rational therapeutic option in which the protective effects of Wnt-driven MBs may be augmented in Group 3 and 4 MB and thereby support emerging data for a context-dependent tumor suppressive role for Wnt/ß-catenin signaling.


Assuntos
Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Proteínas Wnt/farmacologia , Proteínas Wnt/uso terapêutico , Animais , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Cerebelares/patologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Células-Tronco , Proteínas Wnt/genética , Via de Sinalização Wnt , beta Catenina/uso terapêutico
3.
Pediatr Blood Cancer ; 67(8): e28373, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32453481

RESUMO

BACKGROUND: As treatment modalities for medulloblastoma have developed and overall survival (OS) has improved, there are relatively limited data on the impact of long-term effects such as risk of second primary tumors (SPT). To address the knowledge gap, we analyzed factors associated with the risk of SPT and OS by treatment modality for medulloblastoma. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER)-18 database for patients diagnosed with medulloblastoma in 1973-2014. Patients were then grouped by age, gender, race, geographic region, histology, adjuvant treatment (no radiation [RT] and no chemotherapy [CT], RT and CT, RT alone, or CT alone), era of diagnosis (1973-1994 or 1995-2014), and survival time. Cumulative incidence, factors associated with SPT and OS were analyzed. RESULTS: Of 2271 patients, 146 developed SPT, of which 42 were benign. The incidence of SPT was 3.1% and 4.9% at 10 and 15 years, respectively. The incidence of SPT was 3.1% with RT + CT versus 3.7% with RT alone at 10 years. The most common site for an SPT was the central nervous system. Female gender (P = 0.01) and longer OS of ≥21 years (P < 0.01) were associated with higher risk of SPT. RT + CT led to better OS than RT only (66.1% and 61.4% vs 55.6% and 49.7% at 10 and 15 years) (P < 0.01). CONCLUSIONS: Medulloblastoma patients have a relatively low risk of SPT at 10 years with treatment. Use of RT + CT led to better OS with no statistical difference in SPT compared with the RT alone.


Assuntos
Neoplasias Cerebelares , Bases de Dados Factuais , Meduloblastoma , Segunda Neoplasia Primária , Adolescente , Adulto , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/terapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Meduloblastoma/diagnóstico , Meduloblastoma/mortalidade , Meduloblastoma/terapia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
4.
Nat Med ; 26(5): 720-731, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341580

RESUMO

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.


Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Líquido Cefalorraquidiano/efeitos dos fármacos , Ependimoma/terapia , Imunoterapia Adotiva/métodos , Meduloblastoma/terapia , Animais , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/líquido cefalorraquidiano , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/terapia , Líquido Cefalorraquidiano/imunologia , Criança , Pré-Escolar , Sistemas de Liberação de Medicamentos/métodos , Ependimoma/líquido cefalorraquidiano , Ependimoma/imunologia , Ependimoma/patologia , Feminino , Células HEK293 , Humanos , Lactente , Injeções Intraventriculares , Masculino , Meduloblastoma/líquido cefalorraquidiano , Meduloblastoma/imunologia , Meduloblastoma/patologia , Camundongos , Metástase Neoplásica , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Clin Neurosci ; 75: 112-116, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32184042

RESUMO

The utilization of proton beam therapy (PBT) as the primary treatment of adults with primary brain tumors (APBT) was evaluated through query of the National Cancer Database (NCDB) between the years 2004 and 2015. International Classification of Diseases for Oncology code for each patient was stratified into six histology categories; high-grade gliomas, medulloblastomas, ependymomas, other gliomas, other malignant tumors, or other benign intracranial tumors. Demographics of the treatment population were also analyzed. A total of 1,296 patients received PBT during the 11-year interval for treatment of their primary brain tumor. High-grade glioma, medulloblastoma, ependymoma, other glioma, other malignant, and other benign intracranial histologies made up 39%, 20%, 13%, 12%, 13%, and 2% of the cohort, respectively. The number of patients treated per year increased from 34 to 300 in years 2004 to 2015. Histologies treated with PBT varied over the 11-year interval with high-grade gliomas comprising 75% and 45% at years 2004 and 2015, respectively. The majority of the patient population was 18-29 years of age (59%), Caucasian race (73%), had median reported income of over $63,000 (46%), were privately insured (68%), and were treated at an academic institution (70%). This study characterizes trends of malignant and benign APBT histologies treated with PBT. Our data from 2004 through 2015 illustrates a marked increase in the utilization of PBT in the treatment of APBT and shows variability in the tumor histology treated over this time.


Assuntos
Neoplasias Encefálicas/terapia , Terapia com Prótons/estatística & dados numéricos , Adolescente , Adulto , Neoplasias Encefálicas/classificação , Ependimoma/terapia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Glioma/terapia , Humanos , Seguro Médico Ampliado/estatística & dados numéricos , Masculino , Meduloblastoma/terapia , Classe Social , Estados Unidos , Adulto Jovem
6.
PLoS One ; 15(1): e0227693, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31971950

RESUMO

Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping "Speed", and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation [CSI] or local radiotherapy [LRT]). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes.


Assuntos
Neoplasias Encefálicas/terapia , Ependimoma/terapia , Meduloblastoma/terapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Terapia Combinada , Radiação Cranioespinal/efeitos adversos , Estudos Transversais , Ependimoma/patologia , Ependimoma/fisiopatologia , Feminino , Seguimentos , Alemanha , Humanos , Lactente , Inteligência , Masculino , Meduloblastoma/fisiopatologia , Meduloblastoma/psicologia , Destreza Motora , Análise Multivariada , Testes Neuropsicológicos , Resultado do Tratamento
7.
Nat Rev Cancer ; 20(1): 42-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819232

RESUMO

Medulloblastoma, a malignant brain tumour primarily diagnosed during childhood, has recently been the focus of intensive molecular profiling efforts, profoundly advancing our understanding of biologically and clinically heterogeneous disease subgroups. Genomic, epigenomic, transcriptomic and proteomic landscapes have now been mapped for an unprecedented number of bulk samples from patients with medulloblastoma and, more recently, for single medulloblastoma cells. These efforts have provided pivotal new insights into the diverse molecular mechanisms presumed to drive tumour initiation, maintenance and recurrence across individual subgroups and subtypes. Translational opportunities stemming from this knowledge are continuing to evolve, providing a framework for improved diagnostic and therapeutic interventions. In this Review, we summarize recent advances derived from this continued molecular characterization of medulloblastoma and contextualize this progress towards the deployment of more effective, molecularly informed treatments for affected patients.


Assuntos
Suscetibilidade a Doenças , Meduloblastoma/diagnóstico , Meduloblastoma/etiologia , Animais , Biomarcadores Tumorais , Terapia Combinada , Gerenciamento Clínico , Epigenômica/métodos , Estudos de Associação Genética , Genômica/métodos , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/terapia , Técnicas de Diagnóstico Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Proteômica/métodos , Recidiva , Resultado do Tratamento , Microambiente Tumoral
8.
Int J Pediatr Otorhinolaryngol ; 126: 109640, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442874

RESUMO

Medulloblastoma is the most common pediatric malignant brain tumor and carries a relatively grim prognosis despite recent advances in multimodality therapy. Delays in diagnosis and treatment initiation may contribute to worst outcomes. Signs of increased intracranial pressure and ataxia are known presentations of posterior fossa tumors, but sensorineural hearing loss (SNHL) is a seldom reported symptom. We report the case of a 2-year-old girl who had progressive unilateral SNHL since birth, which was later found to have a posterior fossa medulloblastoma when a head magnetic resonance imaging was ordered following subsequent progression to bilateral hearing impair. We further report our review of 17 additional cases of medulloblastoma presenting with SNHL and their associated head and neck findings. The present study provides insight into the current state of the literature on this rare symptom of a commonly encountered diagnosis, while highlighting the need to consider dedicated brain imaging in pediatric unilateral SNHL when a syndromic etiology or inner ear anomaly is not readily identified on initial investigations.


Assuntos
Perda Auditiva Neurossensorial/etiologia , Neoplasias Infratentoriais/diagnóstico por imagem , Meduloblastoma/diagnóstico por imagem , Pré-Escolar , Feminino , Perda Auditiva Bilateral/etiologia , Humanos , Neoplasias Infratentoriais/terapia , Imagem por Ressonância Magnética , Meduloblastoma/terapia
9.
Cytotherapy ; 21(9): 973-986, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31351799

RESUMO

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in childhood and adolescence. Although some patients present with distinct genetic alterations, such as mutated TP53 or MYC amplification, pediatric medulloblastoma is a tumor entity with minimal mutational load and low immunogenicity. METHODS: We identified tumor-specific mutations using next-generation sequencing of medulloblastoma DNA and RNA derived from primary tumor samples from pediatric patients. Tumor-specific mutations were confirmed using deep sequencing and in silico analyses predicted high binding affinity of the neoantigen-derived peptides to the patients' human leukocyte antigen molecules. Tumor-specific peptides were synthesized and used to induce a de novo T-cell response characterized by interferon gamma and tumor necrosis factor alpha release of CD8+ cytotoxic T cells in vitro. RESULTS: Despite low mutational tumor burden, at least two immunogenic tumor-specific peptides were identified in each patient. T cells showed a balanced CD4/CD8 ratio and mostly effector memory phenotype. Induction of a CD8-specific T-cell response was achieved for the neoepitopes derived from Histidine Ammonia-Lyase (HAL), Neuraminidase 2 (NEU2), Proprotein Convertase Subtilisin (PCSK9), Programmed Cell Death 10 (PDCD10), Supervillin (SVIL) and tRNA Splicing Endonuclease Subunit 54 (TSEN54) variants. CONCLUSION: Detection of patient-specific, tumor-derived neoantigens confirms that even in tumors with low mutational load a molecular design of targets for specific T-cell immunotherapy is possible. The identified neoantigens may guide future approaches of adoptive T-cell transfer, transgenic T-cell receptor transfer or tumor vaccination.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia , Meduloblastoma/genética , Meduloblastoma/terapia , Mutação/genética , Linfócitos T/imunologia , Adolescente , Sequência de Aminoácidos , Criança , Epitopos/imunologia , Feminino , Humanos , Lactente , Masculino , Meduloblastoma/imunologia , Peptídeos/química
10.
Pediatr Blood Cancer ; 66(10): e27910, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31264356

RESUMO

BACKGROUND: A previous study based on Norwegian Cancer Registry data suggested regional differences in overall survival (OS) after treatment for medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. The purpose of the present study was to confirm in an extended cohort whether there were regional differences in outcome or not, and if so try to identify possible explanations. MATERIAL AND METHODS: Data from patients aged 0-20 years diagnosed with and treated for MB/CNS-PNET at all four university hospitals in Norway from 1974 to 2013 were collected and compared. RESULTS: Of 266 identified patients, 251 fulfilled inclusion criteria. MB was diagnosed in 200 and CNS-PNET in 51 patients. Five-year OS and event-free survival (EFS) were 59% and 52%, respectively. There was a significant difference in five-year OS and EFS between MB and CNS-PNET patients; 62% versus 47% (P =  0.007) and 57% versus 35% (P < 0.001). In multivariable analysis, two factors were found to significantly contribute to improved five-year OS and EFS, whereas one factor contributed to improved five-year OS only. Gross total resection (GTR) versus non-GTR (hazard ratio [HR] 0.53, P =  0.003; HR 0.46, P < 0.001) and cerebrospinal irradiation (CSI) versus non-CSI (HR 0.24, P < 0.001; HR 0.28, P < 0.001) for both, and treatment outside Oslo University Hospital for OS only (HR 0.64, P =  0.048). CONCLUSION: Survival was comparable with data from other population-based studies, and the importance of GTR and CSI was confirmed. The cause for regional survival differences could not be identified.


Assuntos
Neoplasias Cerebelares/mortalidade , Meduloblastoma/mortalidade , Tumores Neuroectodérmicos Primitivos/mortalidade , Neoplasias Supratentoriais/mortalidade , Adolescente , Neoplasias Cerebelares/terapia , Criança , Pré-Escolar , Terapia Combinada/métodos , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Meduloblastoma/terapia , Tumores Neuroectodérmicos Primitivos/terapia , Noruega/epidemiologia , Estudos Retrospectivos , Neoplasias Supratentoriais/terapia , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
11.
Ann Clin Transl Neurol ; 6(5): 990-1005, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31139698

RESUMO

SHH-activated medulloblastomas (SHH-MB) account for 25-30% of all medulloblastomas (MB) and occur with a bimodal age distribution, encompassing many infant and adult, but fewer childhood cases. Different age groups are characterized by distinct survival outcomes and age-specific alterations of regulatory pathways. Here, we review SHH-specific genetic aberrations and signaling pathways. Over 95% of SHH-MBs contain at least one driver event - the activating mutations frequently affect sonic hedgehog signaling (PTCH1, SMO, SUFU), genome maintenance (TP53), and chromatin modulation (KMT2D, KMT2C, HAT complexes), while genes responsible for transcriptional regulation (MYCN) are recurrently amplified. SHH-MBs have the highest prevalence of damaging germline mutations among all MBs. TP53-mutant MBs are enriched among older children and have the worst prognosis among all SHH-MBs. Numerous genetic aberrations, including mutations of TERT, DDX3X, and the PI3K/AKT/mTOR pathway are almost exclusive to adult patients. We elaborate on the newest development within the evolution of molecular subclassification, and compare proposed risk categories across emerging classification systems. We discuss discoveries based on preclinical models and elaborate on the applicability of potential new therapies, including BET bromodomain inhibitors, statins, inhibitors of SMO, AURK, PLK, cMET, targeting stem-like cells, and emerging immunotherapeutic strategies. An enormous amount of data on the genetic background of SHH-MB have accumulated, nevertheless, subgroup affiliation does not provide reliable prediction about response to therapy. Emerging subtypes within SHH-MB offer more layered risk stratifications. Rational clinical trial designs with the incorporation of available molecular knowledge are inevitable. Improved collaboration across the scientific community will be imperative for therapeutic breakthroughs.


Assuntos
Neoplasias Cerebelares/genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , Meduloblastoma/terapia , Adulto , Carcinogênese , Criança , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Lactente , Mutação , Proteômica , Transdução de Sinais
12.
Cancer Radiother ; 23(3): 179-187, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31109839

RESUMO

PURPOSE: Medulloblastoma is the most common primary malignant central nervous system tumour in children. These last decades, treatment modalities have largely evolved resulting in better survival rates. Nevertheless, long-term toxicity is a major concern in this setting. The purpose of this study was to analyse the clinical results and medical outcomes of a cohort of paediatric patients treated for medulloblastoma in Xhinhua Hospital in Shanghai. These results are compared with those from other centres reported in literature. PATIENTS AND METHODS: This was a retrospective study conducted at Xhinhua Hospital in Shanghai, China. It included 121 patients treated for medulloblastoma from 1993 to December 2013. RESULTS: Mean age at diagnosis was 6.7 years (range: 1-14.3 years). Total surgical resection was achieved in 60% of the cases. Classic medulloblastoma was found in 59% of the cases. Adjuvant radiotherapy was delivered in all cases and chemotherapy concerned 70.2% of the studied cohort. The median follow-up time of the study was 84 months (range: 24-120 months). Five- and 10 years progression-free survival rates were 83.2%, and 69.5% and 5 years and 10 years. Overall survival rates were 82.5%, and 72.5%. Patient's age significantly influenced survival: patients under 3 years old had the worse outcomes (P=0.01). T and M stages also significantly impacted survival rates: advanced stages were associated with lower rates (P=0.08 and 0.05 respectively). Finally, patients receiving temezolomide had bad outcomes when compared to the new standard protocol used in the department (P=0.03). The most commonly reported late toxicity was growth suppression in 35 patients (52.2%). Hypothyroidism requiring hormone replacement was recorded in 29% of the cases. Hearing loss, and problems including poor concentration, poor memory and learning difficulties were reported in 19% and 25% of the cases respectively. Second cancers were noted in three cases. CONCLUSION: Overall, our results are comparable to those reported in literature. Nevertheless, efforts should be made to ensure longer follow-ups and correctly assess treatment-related toxicity.


Assuntos
Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
13.
Clin Transl Oncol ; 21(12): 1687-1698, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30937816

RESUMO

PURPOSE: Elevated mortality and morbidity rates persist in pediatric patients with medulloblastoma. We present a clinical audit of a real-world cohort of patients in search for pragmatic measures to improve their management and outcome. METHODS/PATIENTS: All pediatric patients with medulloblastoma treated between 2003 and 2016 at a Spanish reference center were reviewed. In the absence of internationally accepted quality indicators (QIs) for pediatric CNS tumors, diagnostic, therapeutic, survival, and time QIs were defined and assessed. RESULTS: Fifty-eight patients were included, 24% were younger children (< 3 years), 36% high risk (anaplastic, metastasis, or surgical residue > 1.5 cm2), and 40% standard risk. Five-year OS was 59.2% (95% CI 47-75); 5-year PFS 36.4% (95% CI 25-53). Five main areas of quality assurance were identified: diagnosis, global strategy, frontline treatment modalities, outcomes, and long-term and end-of-life care. A set of 34 QIs was developed and applied. Lack of central pathology review, delay in the incorporation of novel molecular markers, and absence of a neurocognitive and quality-of-life evaluation program were some of the audit findings. CONCLUSIONS: This real-world research study resulted in the development of a pragmatic set of QIs, aimed to improve clinical audits and quality of care given to children and adolescents with medulloblastoma. We hope that our findings will serve as a reference to further develop a quality assurance system with specific QIs for pediatric CNS tumors in the future and that this will ultimately improve the survival and quality of life of these patients.


Assuntos
Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Qualidade da Assistência à Saúde , Adolescente , Criança , Pré-Escolar , Feminino , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia , Prognóstico , Intervalo Livre de Progressão , Garantia da Qualidade dos Cuidados de Saúde , Espanha , Resultado do Tratamento
14.
J Pediatr Hematol Oncol ; 41(8): e499-e505, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30973484

RESUMO

PURPOSE: The purpose of this work was to study the diversity of sonic hedgehog (SHH) medulloblastoma across different age groups with an emphasis on patterns of relapse. METHODS: All data for the study were obtained through review of medical records, imaging, radiation charts, treatment planning, and chemotherapy details. RESULTS: Sixty-three patients with SHH medulloblastoma were identified from a prospectively maintained database and classified into 3 groups-infantile: ≤3 years (i-SHH, n=11); pediatric: >3 to <18 years (p-SHH, n=21); and adult: ≥18 years (a-SHH; n=31). Lateralized tumors were common with increasing age (81% a-SHH, 67% p-SHH, 27% i-SHH; P=0.01). Large cell anaplastic histology was relatively common for p-SHH (33%), while the nodular/desmoplastic variant was more frequent in i-SHH (64%) and adults (51%). Median follow-up was 38 months (range, 5 to 91 mo). Five-year event-free survival was 80%, 31%, and 52% for i-SHH, p-SHH, and a-SHH, respectively (P=0.001). Median time to failure for p-SHH and a-SHH were 12 and 36 months, respectively. For p-SHH, 83% were metastatic relapses compared with localized failure in 75% for a-SHH. Five-year overall survival for i-SHH, p-SHH, and a-SHH were 91%, 31%, and 70%, respectively (P=0.001). On univariate analysis, event-free survival was significantly worse for superiorly located tumors (P=0.01), nondesmoplastic histology (P=0.02), and histology alone for overall survival (P=0.04) (none on multivariate analysis). CONCLUSIONS: SHH medulloblastoma demonstrates varied outcomes depending on age, with p-SHH associated with early and metastatic relapses, while for a-SHH it tends to be delayed and localized.


Assuntos
Bases de Dados Factuais , Proteínas Hedgehog/metabolismo , Meduloblastoma , Proteínas de Neoplasias/metabolismo , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Meduloblastoma/metabolismo , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Meduloblastoma/terapia , Metástase Neoplásica , Taxa de Sobrevida
15.
J Clin Neurosci ; 64: 33-35, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30905661

RESUMO

BACKGROUND: To describe an exceptional case of late recurrence of medulloblastoma after 17 years of complete remission. CASE DESCRIPTION: A 42-year-old male consulted in ER for 10-day occipital headache. He had a previous history of cerebellar medulloblastoma 17 years ago treated with gross total resection, chemotherapy and radiotherapy. During his yearly follow-up he had maintained complete remission. MRi showed a cerebellar mass suggestive of medulloblastoma recurrence vs radio-induced tumor. Craniotomy and complete resection of the tumor was performed. The anatomopathological analysis confirmed the recurrence of medulloblastoma. The patient received high dose of adjuvant chemotherapy and he maintains complete remission after 18 months. CONCLUSION: Recurrence of medulloblastoma may occur despite more than 15 years of complete remission. Because of this fact it is mandatory to continue the follow-up of these patients. Aggressive management of recurrence is recommended in absence of disease dissemination.


Assuntos
Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto , Neoplasias Cerebelares/terapia , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Terapia Combinada/métodos , Humanos , Masculino , Meduloblastoma/terapia , Indução de Remissão
16.
J Hematol Oncol ; 12(1): 29, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876441

RESUMO

Childhood medulloblastomas (MB) are heterogeneous and are divided into four molecular subgroups. The provisional non-wingless-activated (WNT)/non-sonic hedgehog-activated (SHH) category combining group 3 and group 4 represents over two thirds of all MBs, coupled with the highest rates of metastases and least understood pathology. The molecular era expanded our knowledge about molecular aberrations involved in MB tumorigenesis, and here, we review processes leading to non-WNT/non-SHH MB formations.The heterogeneous group 3 and group 4 MBs frequently harbor rare individual genetic alterations, yet the emerging profiles suggest that infrequent events converge on common, potentially targetable signaling pathways. A mutual theme is the altered epigenetic regulation, and in vitro approaches targeting epigenetic machinery are promising. Growing evidence indicates the presence of an intermediate, mixed signature group along group 3 and group 4, and future clarifications are imperative for concordant classification, as misidentifying patient samples has serious implications for therapy and clinical trials.To subdue the high MB mortality, we need to discern mechanisms of disease spread and recurrence. Current preclinical models do not represent the full scale of group 3 and group 4 heterogeneity: all of existing group 3 cell lines are MYC-amplified and most mouse models resemble MYC-activated MBs. Clinical samples provide a wealth of information about the genetic divergence between primary tumors and metastatic clones, but recurrent MBs are rarely resected. Molecularly stratified treatment options are limited, and targeted therapies are still in preclinical development. Attacking these aggressive tumors at multiple frontiers will be needed to improve stagnant survival rates.


Assuntos
Biomarcadores Tumorais/metabolismo , Meduloblastoma/diagnóstico , Meduloblastoma/terapia , Criança , Humanos , Meduloblastoma/patologia
17.
World Neurosurg ; 127: e58-e64, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30797919

RESUMO

OBJECTIVE: To study the prevalence of OTX1 and OTX2 gene expression in 60 medulloblastoma specimen samples and to establish correlations between gene expression and clinical and histopathological aspects. METHODS: We performed a retrospective analysis of 60 patients with a diagnosis of medulloblastoma at the Clinicas Hospital of the School of Medicine, University of São Paulo, and the Cancer Hospital of Barretos. We created a database of the 60 patients containing information on the gene expression of OTX1 and OTX2 (obtained using real-time polymerase chain reaction) and clinical and epidemiological data. Statistical tests were performed to verify potential correlations of clinicopathological data and follow-up aspects with gene expression. RESULTS: The OTX1 gene was expressed in 52% of the study population. Expression varied with age (higher in adults), location (predominantly by hemisphere), and histological type (desmoplastic). The OTX2 gene was expressed in 62% of the study population. Expression varied with age (higher in younger age groups), location (predominantly vermis), and histological type (classic and anaplastic). A statistical correlation between OTX2 gene expression and the development of leptomeningeal metastases was observed. CONCLUSIONS: The relative expression of OTX1 and OTX2 was dependent on patient age, tumor location, and histological variant. In addition, OTX2 expression might be a predictive factor for leptomeningeal metastases of medulloblastoma. The OTX pathway should be consider as an important venue for medulloblastomas development.


Assuntos
Neoplasias Cerebelares/genética , Meduloblastoma/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição Otx/genética , Adolescente , Adulto , Fatores Etários , Brasil , Neoplasias Cerebelares/epidemiologia , Neoplasias Cerebelares/terapia , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Meduloblastoma/epidemiologia , Meduloblastoma/secundário , Meduloblastoma/terapia , Neoplasias Meníngeas/secundário , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Adulto Jovem
18.
J Clin Oncol ; 37(9): 731-740, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30730781

RESUMO

PURPOSE: Treatment of medulloblastoma has evolved from surgery and radiotherapy to contemporary multimodal regimens. However, the impact on long-term health outcomes remains unknown. METHODS: Cumulative incidence of late mortality (5 or more years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of medulloblastoma diagnosed between 1970 and 1999. Outcomes were evaluated by treatment exposure, including historical therapy (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), high risk (CSI ≥ 30 Gy + chemotherapy), standard risk (CSI < 30 Gy + chemotherapy), and by treatment decade (1970s, 1980s, 1990s). Rate ratios (RRs) and 95% CIs estimated long-term outcomes using multivariable piecewise exponential models. RESULTS: Among 1,311 eligible survivors (median age, 29 years [range, 6 to 60 years]; median time from diagnosis, 21 years [range, 5 to 44 years]), the 15-year cumulative incidence rate of all-cause late mortality was 23.2% (diagnosed 1970s) versus 12.8% (1990s; P = .002), with a recurrence-related mortality rate of 17.7% versus 9.6% ( P = .008). Lower late mortality rates as a result of other health-related causes were not observed. Among 997 survivors who completed a baseline survey, the 15-year cumulative incidence of SNs was higher among survivors with multimodal therapy (standard risk, 9.5%; historical, 2.8%; P = .03). Survivors treated in the 1990s had a higher cumulative incidence of severe, disabling, life-threatening, and fatal chronic health conditions (56.5% in 1990s v 39.9% in 1970s; P < .001) and were more likely to develop multiple conditions (RR, 2.89; 95% CI, 1.31 to 6.38). However, survivors of standard-risk therapy were less likely to use special education services than high-risk therapy survivors (RR, 0.84; 95% CI, 0.75 to 0.93). CONCLUSION: Historical changes in medulloblastoma therapy that improved 5-year survival have increased the risk for SNs and debilitating health conditions for survivors yet reduced the need for special education services.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Inquéritos e Questionários , Adolescente , Adulto , Neoplasias Cerebelares/mortalidade , Quimiorradioterapia/métodos , Criança , Tratamento Farmacológico/métodos , Feminino , Humanos , Masculino , Meduloblastoma/mortalidade , Pessoa de Meia-Idade , Morbidade , Recidiva Local de Neoplasia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
19.
Cells ; 8(2)2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30754726

RESUMO

Hedgehog (Hh) signaling is a critical developmental regulator and its aberrant activation,due to somatic or germline mutations of genes encoding pathway components, causes Basal CellCarcinoma (BCC) and medulloblastoma (MB). A growing effort has been devoted at theidentification of druggable vulnerabilities of the Hedgehog signaling, leading to the identificationof various compounds with variable efficacy and/or safety. Emerging evidence shows that anaberrant polyamine metabolism is a hallmark of Hh-dependent tumors and that itspharmacological inhibition elicits relevant therapeutic effects in clinical or preclinical models ofBCC and MB. We discuss here the current knowledge of polyamine metabolism, its role in cancerand the available targeting strategies. We review the literature about the connection betweenpolyamines and the Hedgehog signaling, and the potential therapeutic benefit of targetingpolyamine metabolism in two malignancies where Hh pathways play a well-established role: BCCand MB.


Assuntos
Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/terapia , Proteínas Hedgehog/metabolismo , Meduloblastoma/metabolismo , Meduloblastoma/terapia , Terapia de Alvo Molecular , Poliaminas/metabolismo , Animais , Carcinogênese/metabolismo , Humanos
20.
Nat Rev Dis Primers ; 5(1): 11, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765705

RESUMO

Medulloblastoma (MB) comprises a biologically heterogeneous group of embryonal tumours of the cerebellum. Four subgroups of MB have been described (WNT, sonic hedgehog (SHH), Group 3 and Group 4), each of which is associated with different genetic alterations, age at onset and prognosis. These subgroups have broadly been incorporated into the WHO classification of central nervous system tumours but still need to be accounted for to appropriately tailor disease risk to therapy intensity and to target therapy to disease biology. In this Primer, the epidemiology (including MB predisposition), molecular pathogenesis and integrative diagnosis taking histomorphology, molecular genetics and imaging into account are reviewed. In addition, management strategies, which encompass surgical resection of the tumour, cranio-spinal irradiation and chemotherapy, are discussed, together with the possibility of focusing more on disease biology and robust molecularly driven patient stratification in future clinical trials.


Assuntos
Meduloblastoma/diagnóstico , Meduloblastoma/terapia , Quimioterapia Adjuvante/métodos , Humanos , Imagem por Ressonância Magnética/métodos , Programas de Rastreamento/métodos , Meduloblastoma/epidemiologia , Prognóstico , Qualidade de Vida/psicologia , Fatores de Risco
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