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1.
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
2.
Nat Commun ; 11(1): 4660, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938908

RESUMO

Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.


Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Histona Desacetilase 1/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Feminino , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Humanos , Camundongos SCID , Fenilbutiratos/farmacologia , Transdução de Sinais , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
3.
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
4.
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
5.
Asia Pac J Clin Oncol ; 16(5): e223-e227, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32762134

RESUMO

AIM: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. In this study, we aimed to show the relationship between temporal muscle thickness (TMT) measurement and survival in newly diagnosed patients with GBM. METHODS: Forty-seven patients with newly diagnosed GBM were evaluated, retrospectively. TMT at diagnosis of GBM before any surgical procedure was measured on the contrast-enhanced axial longitudinal relaxation time (T1)-weighted magnetic resonance images. Overall survival (OS) was analyzed by the Kaplan-Meier method and log-rank test was used to determine the differences between the groups. The median TMT was used to determine the cutoff point. RESULTS: The median TMT was 4.7 mm (range, 2.8-6.6) in females and 5.4 mm (range, 2.9-8.1) in males. Median survival for TMT < 4.9 mm was 12.9 ± 3.5 (95% CI, 6.0-19.8) months, and 39.4 ± 11.9 (95% CI, 16.0-62.8) months for TMT ≥ 4.9 (P = .023). In the multivariate Cox regression model, the TMT group (Hazard ratio [HR] = 2.07, 95% CI, 0.92-4.61, P = .032) and age group (HR = 2.18, 95% CI, 1.01-4.67, P = .014) showed statistically significant difference. CONCLUSION: TMT is not an independent predictor of response but a predictor of sarcopenia and survival in newly diagnosed GBM. TMT measurement is an easy and practical method. Survival prediction will provide useful information in GBM patients having poor prognosis.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Glioblastoma/fisiopatologia , Músculo Temporal/patologia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Feminino , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
6.
Cancer Imaging ; 20(1): 55, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758279

RESUMO

BACKGROUND: This study aims to identify robust radiomic features for Magnetic Resonance Imaging (MRI), assess feature selection and machine learning methods for overall survival classification of Glioblastoma multiforme patients, and to robustify models trained on single-center data when applied to multi-center data. METHODS: Tumor regions were automatically segmented on MRI data, and 8327 radiomic features extracted from these regions. Single-center data was perturbed to assess radiomic feature robustness, with over 16 million tests of typical perturbations. Robust features were selected based on the Intraclass Correlation Coefficient to measure agreement across perturbations. Feature selectors and machine learning methods were compared to classify overall survival. Models trained on single-center data (63 patients) were tested on multi-center data (76 patients). Priors using feature robustness and clinical knowledge were evaluated. RESULTS: We observed a very large performance drop when applying models trained on single-center on unseen multi-center data, e.g. a decrease of the area under the receiver operating curve (AUC) of 0.56 for the overall survival classification boundary at 1 year. By using robust features alongside priors for two overall survival classes, the AUC drop could be reduced by 21.2%. In contrast, sensitivity was 12.19% lower when applying a prior. CONCLUSIONS: Our experiments show that it is possible to attain improved levels of robustness and accuracy when models need to be applied to unseen multi-center data. The performance on multi-center data of models trained on single-center data can be increased by using robust features and introducing prior knowledge. For successful model robustification, tailoring perturbations for robustness testing to the target dataset is key.


Assuntos
Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Aprendizado de Máquina , Imagem por Ressonância Magnética/métodos , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Análise de Sobrevida
7.
Int J Nanomedicine ; 15: 5491-5501, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848385

RESUMO

Purpose: Currently, the treatment of brain metastases from non-small cell lung cancer (NSCLC) is rather difficult in the clinic. A combination of small molecule-targeted drug and chemo-drug is a promising therapeutic strategy for the treatment of NSCLC brain metastases. But the efficacy of this combination therapy is not satisfactory due to the blood-brain barrier (BBB). Therefore, it is urgent to develop a drug delivery system to enhance the synergistic therapeutic effects of small molecule-targeted drug and chemo-drug for the treatment of NSCLC brain metastases. Methods: T7 peptide installed and osimertinib (AZD9291) loaded intracellular glutathione (GSH) responsive doxorubicin prodrug self-assembly nanocarriers (T7-DSNPs/9291) have been developed as a targeted co-delivery system to enhance the combined therapeutic effect on brain metastases from NSCLC. In vitro cell experiments, including intracellular uptake assay, in vitro BBB transportation, and MTT assay were used to demonstrate the efficacy of T7-DSNPs/9291 in NSCLC brain metastasis in vitro. Real-time fluorescence imaging analysis, magnetic resonance imaging analysis, and Kaplan-Meier survival curves were used to study the effect of T7-DSNPs/9291 on an animal model in vivo. Results: T7-DSNPs/9291 could significantly enhance BBB penetration of AZD9291 and doxorubicin via transferrin receptor-mediated transcytosis. Moreover, T7-DSNPs/9291 showed significant anti-NSCLC brain metastasis effect and prolonged median survival of an intracranial NSCLC brain metastasis animal model. Conclusion: T7-DSNPs/9291 is a potential drug delivery system for the combined therapy of brain metastasis from NSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Portadores de Fármacos/administração & dosagem , Neoplasias Pulmonares/patologia , Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Colágeno Tipo IV/química , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Fragmentos de Peptídeos/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Receptores da Transferrina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
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
9.
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
10.
Anticancer Res ; 40(7): 4081-4086, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620656

RESUMO

BACKGROUND/AIM: Treatment for elderly patients with few brain metastases is controversial. A score was generated to predict distant brain metastases (DBMs) after stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). PATIENTS AND METHODS: Ten characteristics were retrospectively analyzed for freedom from new DBMs in 104 elderly patients receiving SRS or FSRT alone for 1-3 brain metastases. Characteristics that were significant or showed a trend on multivariate analysis were used for the score. RESULTS: On multivariate analysis, favorable histology (p=0.026) and single brain metastasis (p=0.006) showed significant associations with freedom from DBMs. A trend was found for supra-tentorial location only (p=0.065). Three groups were designed, 10-14, 16-20 and 21-25 points, with 6-month rates of freedom from DBMs of 10%, 54% and 95%, respectively (p<0.0001). Positive predictive values to predict DBMs and freedom from DBMs at 6 months were 91% and 94%. CONCLUSION: This new score provided high accuracy in predicting DBMs and freedom from DBMs.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Radiocirurgia , Idoso , Neoplasias Encefálicas/mortalidade , Feminino , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Risco
11.
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
12.
Anticancer Res ; 40(6): 3387-3393, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487635

RESUMO

AIM: To retrospectively assess toxicity and survival in 15 selected Glioblastoma patients treated with a sequential fractionated stereotactic radiotherapy (FSRT) boost after chemo-radiotherapy (CHT-RT) and compare their survival outcomes with a control group. PATIENTS AND METHODS: Toxicity was assessed with the CTCAE 3.0 scale. The Kaplan-Meier method was used to design survival curves, log-rank test for bivariate analysis and Cox proportional hazard regression model for multivariate analysis. RESULTS: The median follow-up was 16 months (range=5-60). One case of headache and one of radionecrosis (RN) occurred. Median overall survival (OS) was 25 months in the boost group vs. 14 in the no-boost group (p=0.004). Median progression-free survival (PFS) was 15 months in the boost group versus 8 in the no-boost group (p=0.046). At multivariate analysis FSRT boost resulted significantly associated with OS and PFS. CONCLUSION: In our series a sequential FSRT boost resulted in safe outcomes and significantly associated with survival.


Assuntos
Neoplasias Encefálicas/radioterapia , Fracionamento da Dose de Radiação , Glioblastoma/radioterapia , Radiocirurgia , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Estudos de Coortes , Feminino , Glioblastoma/diagnóstico , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Radiocirurgia/métodos , Planejamento da Radioterapia Assistida por Computador , Radioterapia Guiada por Imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
13.
Anticancer Res ; 40(6): 3499-3504, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487650

RESUMO

BACKGROUND/AIM: Seizures represent a major problem for patients with brain metastases. This study evaluated the role of seizures in patients receiving single-fraction radiosurgery (SRS) or multi-fraction stereotactic radiotherapy (FSRT). PATIENTS AND METHODS: This retrospective study included 195 patients receiving SRS (n=164) or FSRT (n=31) alone for one to three brain metastases. The prevalence of pre-SRS/FSRT seizures and correlations with pre-treatment factors were investigated. These factors plus pre-SRS/FSRT seizures were assessed in regard to survival. RESULTS: Thirty-three patients had pre-SRS/FSRT seizures (prevalence=16.9%). Seizures were significantly correlated with age ≤61 years. Trends were observed for seizures being more frequent in those with NSCLC and those without extra-cranial metastatic spread. On multivariate analysis, significant associations with improved survival were found for Karnofsky performance score ≥80%, breast cancer, and an interval from diagnosis of malignant disease to SRS/FSRT ≥21 months. CONCLUSION: Younger age, NSCLC and absence of extra-cranial spread appeared to be risk factors for seizures prior to SRS/FSRT. Having seizures prior to SRS/FSRT showed no association with survival.


Assuntos
Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/secundário , Radiocirurgia/efeitos adversos , Convulsões/etiologia , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Fracionamento da Dose de Radiação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Radiocirurgia/métodos , Dosagem Radioterapêutica , Estudos Retrospectivos
14.
BMC Public Health ; 20(1): 1002, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32586298

RESUMO

BACKGROUND: Relative survival is the most common method used for measuring survival from population-based registries. However, the relative survival concept of 'survival as far as the cancer is concerned' can be biased due to differing non-cancer risk of death in the population with cancer (competing risks). Furthermore, while relative survival can be stratified or standardised, for example by sex or age, adjustment for a broad range of sociodemographic variables potentially influencing survival is not possible. In this paper we propose Fine and Gray competing risks multivariable regression as a method that can assess the probability of death from cancer, incorporating competing risks and adjusting for sociodemographic confounders. METHODS: We used whole of population, person-level routinely linked Western Australian cancer registry and mortality data for individuals diagnosed from 1983 to 2011 for major cancer types combined, female breast, colorectal, prostate, lung and pancreatic cancers, and grade IV glioma. The probability of death from the index cancer (cancer death) was evaluated using Fine and Gray competing risks regression, adjusting for age, sex, Indigenous status, socio-economic status, accessibility to services, time sub-period and (for all cancers combined) cancer type. RESULTS: When comparing diagnoses in 2008-2011 to 1983-1987, we observed substantial decreases in the rate of cancer death for major cancer types combined (N = 192,641, - 31%), female breast (- 37%), prostate (- 76%) and colorectal cancers (- 37%). In contrast, improvements in pancreatic (- 15%) and lung cancers (- 9%), and grade IV glioma (- 24%) were less and the cumulative probability of cancer death for these cancer types remained high. CONCLUSION: Considering the justifiable expectation for confounder adjustment in observational epidemiological studies, standard methods for tracking population-level changes in cancer survival are simplistic. This study demonstrates how competing risks and sociodemographic covariates can be incorporated using readily available software. While cancer has been focused on here, this technique has potential utility in survival analysis for other disease states.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias/mortalidade , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Idoso , Austrália , Neoplasias Encefálicas/mortalidade , Causas de Morte , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Probabilidade , Prognóstico , Medição de Risco , Análise de Sobrevida , Taxa de Sobrevida
16.
PLoS One ; 15(5): e0233188, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413077

RESUMO

Glioblastoma (GBM) has the highest fatality rate among primary malignant brain tumors and typically tends to recur locally just adjacent to the original tumor site following surgical resection and adjuvant radiotherapy. We conducted a study to evaluate the survival outcomes between a standard dose (≤ 60 Gy) and moderate radiation dose escalation (>60 Gy), and to identify prognostic factors for GBM. We retrospectively reviewed the medical records of primary GBM patients diagnosed between 2005 and 2016 in two referral hospitals in Taiwan. They were identified from the cancer registry database and followed up from the date of diagnosis to October 2018. The progression-free survival (PFS) and overall survival (OS) were compared between the two dose groups, and independent factors for survival were analyzed through Cox proportional hazard model. We also affirmed the results using Cox regression with least absolute shrinkage and selection operator (LASSO) approach. From our cancer registry database, 142 GBM patients were identified, and 84 of them fit the inclusion criteria. Of the 84 patients, 52 (62%) were males. The radiation dose ranged from 50.0 Gy to 66.6 Gy, but their treatment volumes were similar to the others. Fifteen (18%) patients received an escalated dose boost >60.0 Gy. The escalated group had a longer median PFS (15.4 vs. 7.9 months, p = 0.01 for log-rank test), and a longer median OS was also longer in the escalation group (33.8 vs. 12.5 months, p <0.001) than the reference group. Following a multivariate analysis, the escalated dose was identified as a significant predictor for good prognosis (PFS: hazard ratio [HR] = 0.48, 95% confidence interval [95%CI]: 0.23-0.98; OS: HR = 0.40, 95%CI: 0.21-0.78). Using the LASSO approach, we found age > 70 (HR = 1.55), diagnosis after 2010 (HR = 1.42), and a larger radiation volume (≥ 250ml; HR = 0.81) were predictors of PFS. The escalated dose (HR = 0.47) and a larger radiation volume (HR = 0.76) were identified as predictors for better OS. Following detailed statistical analysis, a moderate radiation dose escalation (> 60 Gy) was found as an independent factor affecting OS in GBM patients. In conclusion, a moderate radiation dose escalation (> 60 Gy) was an independent predictor for longer OS in GBM patients. However, prospective studies including more patients with more information, such as molecular markers and completeness of resection, are needed to confirm our findings.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Doses de Radiação , Estudos Retrospectivos , Taxa de Sobrevida , Taiwan , Adulto Jovem
17.
Brain Tumor Pathol ; 37(2): 50-59, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32361941

RESUMO

Aging is a known negative prognostic factor in glioblastomas (GBM). Whether particular genetic backgrounds are a factor in poor outcomes of elderly patients with GBM warrants investigation. We aim to elucidate any differences between older and younger adult patients with IDH-wildtype GBM regarding both molecular characteristics and clinical outcomes. We collected adult cases diagnosed with IDH-wildtype GBM from the Kansai Network. Clinical and pathological characteristics were analyzed retrospectively and compared between older (≥ 70 years) and younger (≤ 50 years) cases. Included were 92 older vs. 33 younger cases. The older group included more patients with preoperative Karnofsky performance status score < 70 and had a shorter survival time than the younger group. MGMT promoter was methylated more frequently in the older group. TERT promoter mutation was more common in the older group. There were significant differences in DNA copy-number alteration profiles between age groups in PTEN deletion and CDK4 amplification/gain. In the older group, no molecular markers were identified, but surgical resection was an independent prognostic factor. Age-specific survival difference was significant in the MGMT methylated and TERT wildtype subgroup. Elderly patients have several potential factors in poor prognosis of glioblastomas. Varying molecular profiles may explain differing rates of survival between generations.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Estudos de Coortes , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Feminino , Glioblastoma/mortalidade , Humanos , Japão , Masculino , Metilação , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
18.
Clin Exp Metastasis ; 37(3): 391-399, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32356218

RESUMO

Brain metastases (BMs) are frequently occurred in lung adenocarcinoma with driver mutation. There is a need to explore multi-discipline treatments and prognostic factors in those patients with most frequent driver mutations: EGFR mutation and ALK fusion. In the retrospective study, different therapies and prognostic factors were compared between EGFR and ALK-driven lung adenocarcinoma with BMs. 516 patients with EGFR mutation and 76 with ALK fusion were screened for this study, 303 (58.7%) and 34 (44.7%) had BM respectively. In multivariate analyses, the pretreatment factors including delayed BMs and asymptomatic BMs, treatment strategies including the first-generation tyrosine kinase inhibitor (TKI) and cranial radiotherapy (RT) treatment, were associated with much better OS in EGFR mutation patients. Moreover, we found EGFR-mutation patients receiving erlotinib would achieve better survival than those receiving gefitinib (P = 0.032). However, BM patients with ALK fusion treated by only the first generation TKI (HR = 0.23, P = 0.036) or cranial RT (HR = 0.12, P = 0.003), had better OS. After balancing of baseline characteristics of the two groups, there was no significant difference in the survival between BM patients with EGFR mutation and ALK fusion. And only cranial RT was associated with better survival in those patients (HR = 0.52, P < 0.001). In the BM patients of lung adenocarcinoma with driver mutation, TKI underlie the therapy strategies, but cranial RT still plays an important role while receiving the first generation TKI.


Assuntos
Adenocarcinoma de Pulmão/terapia , Neoplasias Encefálicas/terapia , Irradiação Craniana , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Quimiorradioterapia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Estudos Retrospectivos , Adulto Jovem
19.
Clin Exp Metastasis ; 37(3): 435-444, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32377943

RESUMO

Brain metastasis (BM) affects up to one-third of adults with cancer and carries a historically bleak prognosis. Despite advances in stereotactic radiosurgery (SRS), rates of in-field recurrence (IFR) after SRS range from 10 to 25%. High rates of neurologic death have been reported after SRS failure, particularly for recurrences deep in the brain and surgically inaccessible. Laser interstitial thermal therapy (LITT) is an emerging option in this setting, but its ability to prevent a neurologic death is unknown. In this study, we investigate the causes of death among patients with BM who undergo LITT for IFR after SRS. We conducted a single institution retrospective case series of patients with BM who underwent LITT for IFR after SRS. Clinical and demographic data were collected via chart review. The primary endpoint was cause of death. Between 2010 and 2018, 70 patients with BM underwent LITT for IFR after SRS. Median follow-up after LITT was 12.0 months. At analysis, 49 patients died; a cause was determined in 44. Death was neurologic in 20 patients and non-neurologic in 24. The 24-month cumulative incidence of neurologic and non-neurologic death was 35.1% and 38.6%, respectively. Etiologies of neurologic death included local recurrence (n = 7), recovery failure (n = 7), distant progression (n = 5), and other (n = 1). Among our patient population, LITT provided the ability to stabilize neurologic disease in up to 2/3 of patients. For IFR after SRS, LITT may represent a reasonable treatment strategy for select patients. Additional work is necessary to determine the extent to which LITT can prevent neurologic death after recurrence of BM.


Assuntos
Morte Encefálica/diagnóstico , Neoplasias Encefálicas/terapia , Hipertermia Induzida , Recidiva Local de Neoplasia/terapia , Radiocirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/efeitos da radiação , Morte Encefálica/patologia , Morte Encefálica/fisiopatologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/secundário , Causas de Morte , Progressão da Doença , Feminino , Seguimentos , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/fisiopatologia , Seleção de Pacientes , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
20.
Nat Commun ; 11(1): 2177, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358581

RESUMO

Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8+ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.


Assuntos
Astrocitoma/imunologia , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/imunologia , Microglia/imunologia , Midkina/metabolismo , Neurofibromatose 1/metabolismo , Neurônios/metabolismo , Glioma do Nervo Óptico/imunologia , Animais , Apoptose/imunologia , Astrocitoma/mortalidade , Astrocitoma/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Quimiocina CCL4/metabolismo , Quimiocina CCL5/metabolismo , Criança , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Neurofibromatose 1/genética , Glioma do Nervo Óptico/mortalidade , Glioma do Nervo Óptico/patologia , Microambiente Tumoral/imunologia
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