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1.
Medicine (Baltimore) ; 100(11): e20722, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33725920

RESUMO

ABSTRACT: Bladder cancer-associated transcript 1 (BLACAT1) is one of the most common cancer-associated long non-coding RNAs (lncRNAs), which has been reported as a tumor promotor in several malignancies. Previously, BLACAT1 was found to be overexpressed in glioma tissues and cell lines. Functional assays determined that BLACAT1 promoted glioma cell proliferation, migration, invasion and epithelial-mesenchymal transition, suggesting that BLACAT1 might serve as an oncogene in glioma. In the present study, we aimed to investigate its clinical significance and prognostic value in glioma patients.A total of 137 paired glioma tissue samples and adjacent normal brain tissue samples were collected from 137 glioma patients who underwent surgery from May 2014 to February 2019. The Student t test was applied to determine the statistical significance of the observed differences between 2 groups. Survival curves were constructed and differences among groups were calculated using the Kaplan-Meier method.The relative expression of BLACAT1 in glioma samples was significantly higher than that of matched normal tissues (P < .001). The expression level of tissue BLACAT1 was statistically correlated with tumor size (P = .04), Karnofsky Performance Status (KPS) (P = .006), and WHO grade (P = .017). Kaplan-Meier analysis with the log-rank test revealed that BLACAT1 up-regulation was correlated with shorter overall survival time of patients with glioma (Log Rank test, P = .012). In multivariate Cox analysis, BLACAT1 expression was found to be an independent prognostic factor for overall survival in patients with glioma (HR = 2.739; 95% CI: 1.785-8.229; P = .035). Our study demonstrates that up-regulation of BLACAT1 is able to predict aggressive clinicopathologic characteristics and poor prognosis of glioma patients. These findings may have significant implications for potential treatment options and prognosis for patients with glioma.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Glioma/genética , RNA Longo não Codificante/metabolismo , Regulação para Cima/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Prognóstico , Modelos de Riscos Proporcionais
2.
Medicine (Baltimore) ; 100(6): e23980, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578515

RESUMO

ABSTRACT: Hepatic leukemia factor (HLF) is an oncogenic transcript factor, but its role in gliomas is unclear.With the open-access data from the Cancer Genome Atlatls (TCGA), HLF expression was compared between normal and glioma tissues and its correlation to patient survival, age, gender, race, and tumor grade was analyzed. Multivariate Cox regression was adopted to explore the independent risk factors for patient survival. Survivals between high and low HLF expression, and high and low model predicted risk subgroups were compared. 1, 2, 3, and 5-year patient survival were predicted with the Cox regression model. Gene set enrichment analysis (GSEA) was performed to predict the potential function of HLF.Expression and clinical data of 5 normal brain samples and 655 glioma samples were obtained from TCGA. HLF expression was downregulated in gliomas than normal brain tissue (P = .007), and negatively related to patient age and advancing tumor grade (P < .001). HLF was a protective factor for patient survival (OR = 0.81, 95%CI 0.67-0.99, P = .035). Patients' survivals were poorer in low HLF expression subgroups and the Cox regression model predicted high-risk subgroups (P < .001). The accuracy of the model in predicting 1, 2, 3, and 5-year patient survival was 0.864, 0.895, 0.907, and 0.893, respectively. GSEA revealed HLF mainly took part in regulating tumor cell metabolism and cell cycle.HLF was downregulated in gliomas than normal tissue, negatively related to patient age and tumor grade, and was an independent protective factor for glioma patients.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/mortalidade , Fatores de Transcrição de Zíper de Leucina Básica/farmacologia , Estudos de Casos e Controles , Ciclo Celular , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Gradação de Tumores/métodos , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Proteção , Fatores de Risco , Análise de Sobrevida
3.
Medicine (Baltimore) ; 100(4): e20426, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33530151

RESUMO

ABSTRACT: The present study aimed to investigate the association of A-kinase interacting protein 1 (AKIP1) with clinical characteristics, and further explore the prognostic value of AKIP1 in glioma patients.Totally 168 glioma patients who underwent tumor resection were analyzed, and their tumor tissue specimens were acquired for the detection of AKIP1 expression by immunohistochemistry (IHC), which was scored by a semi-quantitative method considering staining intensity and staining density.According to AKIP1 expression in tumor tissues of glioma patients, there were 65 (38.7%) patients with AKIP1 low expression (IHC score 0-3), 48 (28.6%) patients with AKIP1 high + expression (IHC score 4-6), 42 (25.0%) patients with AKIP1 high++ expression (IHC score 7-9) and 13 (7.7%) patients with AKIP1 high+++ expression (IHC score 10-12), respectively. AKIP1 expression was positively associated with World Health Organization grade. Overall survival (OS) was the lowest in the patients with AKIP1 high+++ expression, followed by those with AKIP1 high++ expression and those with AKIP1 high+ expression, and highest in those with AKIP1 low expression. Further subgroup analysis exhibited that AKIP1 expression was negatively associated with OS especially in high-grade glioma patients. In addition, AKIP1 expression was negatively associated with OS in all subgroups of patients with/without adjuvant radiotherapy, with/without adjuvant chemotherapy. Further multivariate Cox's regression exhibited that AKIP1 high expression was an independent predictive factor for worse OS.AKIP1 presents with the potential to be a novel biomarker for tumor management and prognosis surveillance in glioma patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Glioma/genética , Glioma/mortalidade , Proteínas Nucleares/metabolismo , Adulto , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Gradação de Tumores/normas , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Organização Mundial da Saúde
4.
Medicine (Baltimore) ; 100(3): e23985, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33545987

RESUMO

PURPOSE: To assess expression levels of Ephrin type-A receptor 2 (EphA2), vascular endothelial growth factor (VEGF), and von Willebrand factor (vWF), and assess their potentials as prognostic biomarkers to predict the risk of poor survival in patients with primary lower grade glioma. METHOD: The study included75 patients with histopathologically confirmed primary glioma (World Health Organization Grade IV). All patients underwent combined surgery and postoperative radiotherapy for the management of primary glioma. Immuno-histochemical analysis was performed to evaluate expression levels ofEphA2 and VEGF. Evaluation of tumor microvessel density was also performed at angiogenesis hot spots due to tumor growth. Main outcomes of the study were the prognostic efficiencies of EphA2, VEGF, and vWF in primary low-grade glioma, as well as whether their expression levels were associated with cancer progression. RESULTS: Of the patients with glioma, 67% had very strong expression of EphA2. Overall survival was inversely correlated with the expression of EphA2. Regarding VEGF expression, 38 patients (51%) had strong expression, 29 patients (39%) had weak expression, and 8 patients (11%) had no expression. Strong VEGF expression was associated with poor prognosis and poor survival. CONCLUSION: EphA2, VEGF, and vWF could be considered prognostic markers for assessment of primary glioma.


Assuntos
Neoplasias do Sistema Nervoso Central/mortalidade , Efrina-A2/metabolismo , Glioma/mortalidade , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator de von Willebrand/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/genética , Feminino , Glioma/genética , Humanos , Imuno-Histoquímica , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Neovascularização Patológica , Prognóstico
5.
Cell Prolif ; 54(3): e12988, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33442944

RESUMO

OBJECTIVES: Circadian rhythm controls complicated physiological activities in organisms. Circadian clock genes have been related to tumour progression, but its role in glioma is unknown. Therefore, we explored the relationship between dysregulated circadian clock genes and glioma progression. MATERIALS AND METHODS: Samples were divided into different groups based on circadian clock gene expression in training dataset (n = 672) and we verified the results in other four validating datasets (n = 1570). The GO and GSEA enrichment analysis were conducted to explore potential mechanism of how circadian clock genes affected glioma progression. The single-cell RNA-Seq analysis was conducted to verified previous results. The immune landscape was evaluated by the ssGSEA and CIBERSORT algorithm. Cell proliferation and viability were confirmed by the CCK8 assay, colony-forming assay and flow cytometry. RESULTS: The cluster and risk model based on circadian clock gene expression can predict survival outcome. Samples were scoring by the least absolute shrinkage and selection operator regression analysis, and high scoring tumour was associated with worse survival outcome. Samples in high-risk group manifested higher activation of immune pathway and cell cycle. Tumour immune landscape suggested high-risk tumour infiltrated more immunocytes and more sensitivity to immunotherapy. Interfering TIMELESS expression affected circadian clock gene expression, inhibited tumour cell proliferation and arrested cell cycle at the G0/G1 phase. CONCLUSIONS: Dysregulated circadian clock gene expression can affect glioma progression by affecting tumour immune landscape and cell cycle. The risk model can predict glioma survival outcome, and this model can also be applied to pan-cancer.


Assuntos
Proliferação de Células/fisiologia , Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Glioma/patologia , Ciclo Celular/fisiologia , Progressão da Doença , Glioma/mortalidade , Humanos
6.
J Clin Neurosci ; 84: 8-14, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33485604

RESUMO

PURPOSE: Primary spinal cord tumors are rare, particularly in the adult population, and national guidelines remain ambiguous with regard to management approaches. To address this knowledge gap, we evaluated management, outcomes, and prognostic factors of these neoplasms. METHODS: The National Cancer Database was queried (2004-2016) for newly-diagnosed, histologically-confirmed WHO grades I-III astrocytomas and glioblastoma. Statistics included Kaplan-Meier overall survival (OS) analysis, along with Cox proportional hazards modeling. RESULTS: Of 1,033 subjects, 196 (19%) were pilocytic astrocytomas (PAs), 539 (52%) were grade II/III astrocytomas, and 298 (29%) were glioblastomas (GBMs). Respectively, 11%, 30%, and 27% did not undergo resection (biopsy only). RT was delivered to 27%, 54%, and 73%; chemotherapy was given to 5%, 21%, and 37%, respectively. The median OS was not reached for PAs, but was 101.2 months for grade II/III astrocytomas, and 23.9 months for GBMs (p < 0.001). Neither chemotherapy nor RT (or dose thereof) was associated with increased OS for grade II/III astrocytomas (p > 0.05 for all), though there was a trend toward improved OS with the use of chemotherapy for patients with GBM. Surgical resection was associated with improved OS for grade II/III astrocytomas and GBM (p < 0.05). Independent prognostic factors for survival in this cohort included histologic classification and resection (compared to biopsy only) (p < 0.05 for both). CONCLUSIONS: This study sheds light onto the management of these rare tumors; surgery was associated with OS benefit for patients with GBM and Grade II/III astrocytomas. Neither RT nor chemotherapy were associated with OS benefit. Although not implying causation, these data can be used to guide patient counseling and therapeutic approaches.


Assuntos
Glioma/terapia , Neoplasias da Medula Espinal/mortalidade , Neoplasias da Medula Espinal/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico
7.
Int J Mol Sci ; 22(1)2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33375517

RESUMO

Despite advances in the diagnosis and treatment of the central nervous system malignancy glioma, overall survival remains poor. Cytoskeleton-associated protein 2-like (CKAP2L), which plays key roles in neural progenitor cell division, has also been linked to poor prognosis in lung cancer. In the present study, we investigated the role of CKAP2L in glioma. From bioinformatics analyses of datasets from The Cancer Gene Atlas and the Chinese Glioma Genome Atlas, we found that CKAP2L expression correlates with tumor grade and overall survival. Gene set enrichment analysis (GSEA) showed that MITOTIC_SPINDLE, G2M_CHECKPOINT, and E2F_TARGETS are crucially enriched phenotypes associated with high CKAP2L expression. Using U87MG, U118MG, and LNZ308 human glioma cells, we confirmed that CKAP2L knockdown with siCKAP2L inhibits glioma cell proliferation, migration, invasion, and epithelial-mesenchymal transition. Interestingly, CKAP2L knockdown also induced cell cycle arrest at G2/M phase, which is consistent with the GSEA finding. Finally, we observed that CKAP2L knockdown led to significant increases in miR-4496. Treating cells with exogenous miR-4496 mimicked the effect of CKAP2L knockdown, and the effects of CKAP2L knockdown could be suppressed by miR-4496 inhibition. These findings suggest that CKAP2L is a vital regulator of miR-4496 activity and that CKAP2L is a potentially useful prognostic marker in glioma.


Assuntos
Neoplasias Encefálicas/metabolismo , Proliferação de Células/genética , Proteínas do Citoesqueleto/metabolismo , Transição Epitelial-Mesenquimal/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/metabolismo , MicroRNAs/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/patologia , Proteínas do Citoesqueleto/genética , Bases de Dados Genéticas , Fatores de Transcrição E2F/genética , Fatores de Transcrição E2F/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Glioblastoma/genética , Glioma/genética , Glioma/metabolismo , Glioma/mortalidade , Glioma/patologia , Humanos , Imuno-Histoquímica , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica/genética , Prognóstico , Análise Serial de Tecidos
8.
Nat Commun ; 11(1): 4997, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020472

RESUMO

Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Interleucina-33/metabolismo , Animais , Neoplasias Encefálicas/mortalidade , Carcinogênese , Núcleo Celular/metabolismo , Citocinas/metabolismo , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/mortalidade , Humanos , Inflamação , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos SCID , Microglia , Análise de Sobrevida , Linfócitos T/metabolismo , Linfócitos T/patologia , Microambiente Tumoral/imunologia
9.
BMC Bioinformatics ; 21(Suppl 13): 383, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32938364

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors and its average survival time is less than 1 year after diagnosis. RESULTS: Firstly, this study aims to develop the novel survival analysis algorithms to explore the key genes and proteins related to GBM. Then, we explore the significant correlation between AEBP1 upregulation and increased EGFR expression in primary glioma, and employ a glioma cell line LN229 to identify relevant proteins and molecular pathways through protein network analysis. Finally, we identify that AEBP1 exerts its tumor-promoting effects by mainly activating mTOR pathway in Glioma. CONCLUSIONS: We summarize the whole process of the experiment and discuss how to expand our experiment in the future.


Assuntos
Algoritmos , Neoplasias Encefálicas/genética , Biologia Computacional/métodos , Glioblastoma/genética , Glioma/genética , Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Glioma/mortalidade , Humanos , Análise de Sobrevida
10.
Brain Tumor Pathol ; 37(4): 136-144, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32761533

RESUMO

Oncogenic gene fusions have been reported in diffuse gliomas and may serve as potential therapeutic targets. Here, using next-generation sequencing analysis (Illumina TruSight Tumor 170 panel), we analyzed a total of 356 diffuse gliomas collected from 2017 to 2019 to evaluate clinical, pathological, and genetic features of gene fusion. We found 53 cases of glioblastomas harboring the following oncogenic gene fusions: MET (n = 18), EGFR (n = 14), FGFR (n = 12), NTRK (n = 5), RET (n = 2), AKT3 (n = 1), and PDGFRA fusions (n = 1). Gene fusions were consistently observed in both IDH-wildtype and IDH-mutant glioblastomas (8.8% and 9.4%, p = 1.000). PTPRZ1-MET fusion was the only fusion that genetically resembled secondary glioblastomas (i.e., high frequency of IDH mutation, ATRX loss, TP53 mutation, and absence of EGFR amplification), whereas other gene fusion types were similar to primary glioblastomas (i.e., high frequency of IDH-wildtype, TERT mutation, EGFR amplification, and PTEN mutation). In IDH-wildtype glioblastoma patients, multivariable analysis revealed that the PTPRZ1-MET fusion was associated with poor progression-free survival (HR [95% CI]: 5.42 (1.72-17.05), p = 0.004). Additionally, we described two novel cases of CCDC6-RET fusion in glioma. Collectively, our findings indicate that targetable gene fusions are associated with aggressive biological behavior and can aid the clinical treatment strategy for glioma patients.


Assuntos
Neoplasias Encefálicas/genética , Fusão Gênica/genética , Estudos de Associação Genética , Glioblastoma/genética , Glioma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Proteínas do Citoesqueleto/genética , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/mortalidade , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-ret/genética , Taxa de Sobrevida
11.
Cancer Invest ; 38(7): 394-405, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32643440

RESUMO

The study investigated the human cytomegalovirus (HCMV) and human papillomavirus (HPV) in gliomas. A retrospective study was conducted on 112 samples. HCMV was investigated by PCR, in situ hybridization (ISH) and immunohistochemistry. HPV was tested by PCR and DNA ISH. HCMV was identified in 60 gliomas, including 55 GBM. However, RNA ISH and immunohistochemistry failed to detect HCMV positivity. HPV was identified in 44 GBM. No significant relationship was identified between HCMV and HPV and tumour characteristics (p > 0.05). Our findings support the HCMV and HPV presence in gliomas. Further assays are required to more explore the potential efficient antiviral management.


Assuntos
Neoplasias Encefálicas/virologia , Citomegalovirus/isolamento & purificação , Glioma/virologia , Papillomaviridae/isolamento & purificação , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Tunísia , Adulto Jovem
12.
Medicine (Baltimore) ; 99(28): e21147, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664146

RESUMO

High-grade gliomas (HGGs) are a rapidly progressive and highly recurrent group of primary brain tumors. Despite aggressive surgical resection with chemoradiotherapy, prognoses remained poor. Valproic acid (VPA), a histone deacetylase inhibitor has shown the potential to inhibit glioma cell growth in vitro through several diverse mechanisms. However clinical studies regarding the effect of VPA on HGGs are limited. This study aimed to investigate whether using VPA in patients with HGGs under temozolomide (TMZ) would lead to a better overall survival (OS).We used the Taiwan National Health Insurance Research database to conduct this population-based cohort study. A total of 2379 patients with HGGs under TMZ treatment were included and were further classified into VPA (n = 1212, VPA ≥ 84 defined daily dose [DDD]) and non-VPA (n = 1167, VPA < 84 DDD) groups. Each patient was followed from 1998 to 2013 or until death. A Cox proportional hazard regression was performed to evaluate the effect of VPA and OS.The VPA group had a longer mean OS time compared with the non-VPA group (OS: 50.3 ±â€Š41.0 vs 42.0 ±â€Š37.2 months, P < .001). In patients between 18 and 40 years old, the difference is most significant (OS: 70.5 ±â€Š48.7 vs 55.1 ±â€Š46.0, P = .001). The adjusted hazard ratio is 0.81 (95% confidence interval, 0.72-0.91) for the VPA group relative to the non-VPA group.VPA at over 84 DDD improved OS in HGGs TMZ treatment.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Estadiamento de Neoplasias , Vigilância da População/métodos , Temozolomida/uso terapêutico , Ácido Valproico/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Inibidores Enzimáticos/uso terapêutico , Feminino , Seguimentos , Glioma/diagnóstico , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Taiwan/epidemiologia , Adulto Jovem
13.
BMC Neurol ; 20(1): 259, 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600353

RESUMO

BACKGROUND: To investigate associations between lower-grade glioma (LGG) mRNA-based subtypes (R1-R4) and MR features. METHODS: mRNA-based subtyping was obtained from the LGG dataset in The Cancer Genome Atlas (TCGA). We identified matching patients (n = 145) in The Cancer Imaging Archive (TCIA) who underwent MR imaging. The associations between mRNA-based subtypes and MR features were assessed. RESULTS: In the TCGA-LGG dataset, patients with the R2 subtype had the shortest median OS months (P < 0.05). The time-dependent ROC for the R2 subtype was 0.78 for survival at 12 months, 0.76 for survival at 24 months, and 0.76 for survival at 36 months. In the TCIA-LGG dataset, 41 (23.7%) R1 subtype, 40 (23.1%) R2 subtype, 19 (11.0%) R3 subtype and 45 (26.0%) R4 subtype cases were identified. Multivariate analysis revealed that enhancing margin (ill-defined, OR: 9.985; P = 0.003) and T1 + C/T2 mismatch (yes, OR: 0.091; P = 0.023) were associated with the R1 subtype (AUC: 0.708). The average accuracy of the ten-fold cross validation was 71%. Proportion of contrast-enhanced (CE) tumour (> 5%, OR: 14.733; P < 0.001) and necrosis/cystic changes (yes, OR: 0.252; P = 0.009) were associated with the R2 subtype (AUC: 0.832). The average accuracy of the ten-fold cross validation was 82%. Haemorrhage (yes, OR: 8.55; P < 0.001) was positively associated with the R3 subtype (AUC: 0.689). The average accuracy of the ten-fold cross validation was 87%. Proportion of CE tumour (> 5%, OR: 0.14; P < 0.001) was negatively associated with the R4 subtype (AUC: 0.672). The average accuracy of the ten-fold cross validation was 71%. For the prediction of the R2 subtype, the nomogram showed good discrimination and calibration. Decision curve analysis demonstrated that prediction with the R2 model was clinically useful. CONCLUSIONS: Patients with the R2 subtype had the worst prognosis. We demonstrated that MRI features can identify distinct LGG mRNA-based molecular subtypes.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Glioma/diagnóstico por imagem , Glioma/genética , RNA Mensageiro/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Genômica/métodos , Glioma/mortalidade , Glioma/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Anticancer Res ; 40(7): 3961-3965, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620638

RESUMO

BACKGROUND/AIM: Seizures represent a common manifestation of gliomas. This study evaluated the prevalence of pre-radiotherapy seizures, potential risk factors and associations with survival. PATIENTS AND METHODS: Eight factors were analyzed in 222 patients for associations with seizures including number, size and location of glioma, World Health Organization (WHO) grade, performance score, gender, age and upfront resection. These factors plus pre-radiotherapy symptoms and seizures were assessed for survival. RESULTS: Prevalence of pre-radiotherapy seizures was 29.3%. A significant correlation was found for grade II (p=0.002), trends for age ≤59 years (p=0.123) and lack of upfront resection (p=0.113). Unifocal gliomas (p<0.001), grade II (p=0.045) and upfront resection (p<0.001) showed significant associations with survival (univariate analyses). A trend was found for seizures (p=0.075) and age ≤59 years (p=0.091). In the multivariate analysis, grade II (p=0.002) and upfront resection (p=0.004) maintained significance; unifocal gliomas showed a trend (p=0.062). CONCLUSION: Pre-radiotherapy seizures appeared to be correlated with WHO grade, age and lack of upfront resection, and with better survival.


Assuntos
Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/radioterapia , Glioma/mortalidade , Glioma/radioterapia , Convulsões/mortalidade , Feminino , Glioma/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Convulsões/epidemiologia
15.
Nat Commun ; 11(1): 3077, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555164

RESUMO

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease.


Assuntos
Neoplasias do Tronco Encefálico/genética , Epigenoma , Glioma/genética , Adolescente , Adulto , Neoplasias do Tronco Encefálico/mortalidade , Criança , Pré-Escolar , Análise por Conglomerados , Metilação de DNA , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genômica , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Anticancer Res ; 40(5): 2777-2785, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366424

RESUMO

BACKGROUND/AIM: Understanding of the molecular events associated with progression and survival differences in patients with lower-grade gliomas (LGGs) is still unclear. The comparison of findings across studies using different datasets and methods is essential for a new molecular-based classification system. The aim of the study was to identify biomarkers for prognostic classification of patients with LGGs, and furthermore to lay a foundation for future development of targeted therapies for LGGs. PATIENTS AND METHODS: Using information-theoretic and statistical approaches, we analyzed mRNA expression data for 18,413 genes from LGG samples in order to identify candidate biomarkers for survival. The candidate genes were then evaluated for their potential as prognostic biomarkers using multivariable Cox regression analyses that adjusted for the effects of age and grade. RESULTS: WEE1, EMP3, E2F7, CD58 and NSUN7 genes were identified as candidate biomarkers of LGGs and their high expression was associated with significantly shorter survival. The hazard ratios for mortality were 5.02 (95% CI=3.40-7.40) for WEE1, 5.45 (95% CI=3.63-8.18) for EMP3, 4.49 (95% CI=3.03-6.66) for E2F7, 4.77 (95% CI=3.22-7.06) for CD58 and 4.38 (95% CI=2.97-6.47) for NSUN7. In addition, the expression pattern of these genes, associated with shorter survival in LGGs, was also observed in glioblastoma multiforme. CONCLUSION: Identification of genes associated with poor outcomes will provide insights into novel biological mechanisms that may lead to improvement in progression and survival for patients with LGGs.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Neoplasias Encefálicas/mortalidade , Progressão da Doença , Feminino , Glioma/mortalidade , Humanos , Masculino , Gradação de Tumores , Análise de Sobrevida
17.
Cell Prolif ; 53(6): e12832, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32452127

RESUMO

OBJECTIVES: Tumour cell proliferation requires high metabolism to meet the bioenergetics and biosynthetic needs. Dauer in Caenorhabditis elegans is characterized by lower metabolism, and we established an approach with C elegans to find potential tumour therapy targets. MATERIALS AND METHODS: RNAi screening was used to find dauer-related genes, and these genes were further analysed in glp-1(-) mutants for tumour-suppressing testing. The identified tumour-related genes were verified in clinical tumour tissues. RESULTS: The lifespan of glp-1(-) mutants was found to be extended by classical dauer formation signalling. Then, 61 of 287 kinase-coding genes in Caenorhabditis elegans were identified as dauer-related genes, of which 27 were found to be homologous to human oncogenes. Furthermore, 12 dauer-related genes were randomly selected for tumour-suppressing test, and six genes significantly extended the lifespan of glp-1(-) mutants. Of these six genes, F47D12.9, W02B12.12 and gcy-21 were newly linked to dauer formation. These three new dauer-related genes significantly suppressed tumour cell proliferation and thus extended the lifespan of glp-1(-) mutants in a longevity- or dauer-independent manner. The mRNA expression profiles indicated that these dauer-related genes trigged similar low metabolism pattern in glp-1(-) mutants. Notably, the expression of homolog gene DCAF4L2/F47D12.9, TSSK6/W02B12.12 and NPR1/gcy-21 was found to be higher in glioma compared with adjacent normal tissue. In addition, the high expression of TSSK6/W02B12.12 and NPR1/gcy-21 correlated with a worse survival in glioma patients. CONCLUSIONS: Dauer gene screening in combination with tumour-suppressing test in glp-1(-) mutants provided a useful approach to find potential targets for tumour therapy via suppressing tumour cell proliferation and rewiring tumour cell metabolism.


Assuntos
Caenorhabditis elegans/genética , Glioma/metabolismo , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proliferação de Células , Células Germinativas/citologia , Glioma/mortalidade , Glioma/patologia , Humanos , Estimativa de Kaplan-Meier , Longevidade/genética , Mutação , Neoplasias/genética , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Receptores do Fator Natriurético Atrial/metabolismo
19.
Cochrane Database Syst Rev ; 5: CD011475, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32437039

RESUMO

BACKGROUND: This is an updated version of the original Cochrane Review published in Issue 8, 2016. High grade glioma (HGG) is a rapidly growing brain tumour in the supporting cells of the nervous system, with several subtypes such as glioblastoma (grade IV astrocytoma), anaplastic (grade III) astrocytoma and anaplastic (grade III) oligodendroglioma. Studies have investigated the best strategy to give radiation to people with HGG. Conventional fractionated radiotherapy involves giving a daily radiation dose (called a fraction) of 180 cGy to 200 cGy. Hypofractionated radiotherapy uses higher daily doses, which reduces the overall number of fractions and treatment time. Hyperfractionated radiotherapy which uses a lower daily dose with a greater number of fractions and multiple fractions per day to deliver a total dose at least equivalent to external beam daily conventionally fractionated radiotherapy in the same time frame. The aim is to reduce the potential for late toxicity. Accelerated radiotherapy (dose escalation) refers to the delivery of multiple fractions per day using daily doses of radiation consistent with external beam daily conventionally fractionated radiotherapy doses. The aim is to reduce the overall treatment time; typically, two or three fractions per day may be delivered with a six to eight hour gap between fractions. OBJECTIVES: To assess the effects of postoperative external beam radiation dose escalation in adults with HGG. SEARCH METHODS: We searched CENTRAL, MEDLINE Ovid and Embase Ovid to August 2019 for relevant randomised phase III trials. SELECTION CRITERIA: We included adults with a pathological diagnosis of HGG randomised to the following external beam radiation regimens: daily conventionally fractionated radiotherapy versus no radiotherapy; hypofractionated radiotherapy versus daily conventionally fractionated radiotherapy; hyperfractionated radiotherapy versus daily conventionally fractionated radiotherapy or accelerated radiotherapy versus daily conventionally fractionated radiotherapy. DATA COLLECTION AND ANALYSIS: The primary outcomes were overall survival and adverse effects. The secondary outcomes were progression free survival and quality of life. We used the standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Since the last version of this review, we identified no new relevant trials for inclusion. We included 11 randomised controlled trials (RCTs) with 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for people with HGG receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 favouring postoperative radiotherapy (95% confidence interval (CI) 1.58 to 2.55; P < 0.00001; moderate-certainty evidence). Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17; P = 0.63; very low-certainty evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one participant in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in the subset of two trials (293 participants) which included participants aged 60 years and older with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46; P = 0.21; high-certainty evidence). There were two trials which compared hyperfractionated radiotherapy versus conventional radiation and one trial which compared accelerated radiotherapy versus conventional radiation. However, the results could not be pooled. The conventionally fractionated radiotherapy regimens were 4500 cGy to 6000 cGy given in 180 cGy to 200 cGy daily fractions, over five to six weeks. All trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher. The risk of selection bias was generally low among these RCTs. The number of participants lost to follow-up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life. AUTHORS' CONCLUSIONS: Postoperative conventional daily radiotherapy probably improves survival for adults with good performance status and HGG compared to no postoperative radiotherapy. Hypofractionated radiotherapy has similar efficacy for survival compared to conventional radiotherapy, particularly for individuals aged 60 years and older with glioblastoma. There are insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy). There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These HGG individuals with poor prognosis have generally been excluded from randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these people with poor prognosis. Since the last version of this review, we found no new relevant studies. The search identified three new trials, but all were excluded as none had a conventionally fractionated radiotherapy arm.


Assuntos
Neoplasias Encefálicas/radioterapia , Irradiação Craniana/métodos , Fracionamento da Dose de Radiação , Glioma/radioterapia , Adulto , Fatores Etários , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Irradiação Craniana/mortalidade , Intervalo Livre de Doença , Glioma/mortalidade , Glioma/patologia , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida
20.
J Pathol ; 251(3): 249-261, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32391583

RESUMO

Central nervous system (CNS) tumors are the most common solid tumor in pediatrics, accounting for approximately 25% of all childhood cancers, and the second most common pediatric malignancy after leukemia. CNS tumors can be associated with significant morbidity, even those classified as low grade. Mortality from CNS tumors is disproportionately high compared to other childhood malignancies, although surgery, radiation, and chemotherapy have improved outcomes in these patients over the last few decades. Current therapeutic strategies lead to a high risk of side effects, especially in young children. Pediatric brain tumor survivors have unique sequelae compared to age-matched patients who survived other malignancies. They are at greater risk of significant impairment in cognitive, neurological, endocrine, social, and emotional domains, depending on the location and type of the CNS tumor. Next-generation genomics have shed light on the broad molecular heterogeneity of pediatric brain tumors and have identified important genes and signaling pathways that serve to drive tumor proliferation. This insight has impacted the research field by providing potential therapeutic targets for these diseases. In this review, we highlight recent progress in understanding the molecular basis of common pediatric brain tumors, specifically low-grade glioma, high-grade glioma, ependymoma, embryonal tumors, and atypical teratoid/rhabdoid tumor (ATRT). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Cerebelares/genética , Ependimoma/genética , Glioma/genética , Meduloblastoma/genética , Tumor Rabdoide/genética , Teratoma/genética , Idade de Início , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Ependimoma/classificação , Ependimoma/mortalidade , Ependimoma/patologia , Predisposição Genética para Doença , Glioma/classificação , Glioma/mortalidade , Glioma/patologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Gradação de Tumores , Fenótipo , Tumor Rabdoide/classificação , Tumor Rabdoide/mortalidade , Tumor Rabdoide/patologia , Teratoma/classificação , Teratoma/mortalidade , Teratoma/patologia
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