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Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in â¼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.
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Neoplasias Encefálicas , Éxons , Glioblastoma , Mutação , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Ratos Sprague-Dawley , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: In previous studies, patients with intracranial germ cell tumour (iGCT) with pure choriocarcinoma or mixed germ cell tumours with choriocarcinoma element showed similar dismal prognoses, with median overall survival (OS) of 22 months and 1-year survival rate of approximately 60%. However, these conclusions need to be updated because radiotherapy, which is the mainstay for this disease, was not applied in a number of patients. Additionally, prognostic factors need to be explored in this population. METHODS: Clinical data of patients with iGCTs with histologically confirmed choriocarcinoma element or beta-human chorionic gonadotropin (ß-HCG) > 500 IU/L were collected from the archives of our institution and retrospectively studied. RESULTS: A total of 76 patients were eligible for this study. Except for two early deaths, all patients received radiotherapy (craniospinal irradiation [CSI], n = 23; non-CSI, n = 51). The median follow-up duration for the entire series was 63 months (range, 6-188 months). The 5-year event-free survival (EFS) and OS rates were 81.5% and 84.1%, respectively. Among patients who did not have early death or progressive disease after induction chemotherapy, multivariate analysis revealed that chemotherapy cycles (> 4 vs. ≤ 4) (hazard ratio [HR] for EFS 0.144, p = 0.020; HR for OS 0.111, p = 0.028) and ß-HCG levels (> 3000 IU/L vs. ≤ 3000 IU/L) (HR for EFS 4.342, p = 0.059; HR for OS 6.614, p = 0.033) were independent factors for survival. CONCLUSIONS: Patients with iGCTs with choriocarcinoma element or ß-HCG > 500 IU/L showed improved survival with radiotherapy-based treatments. Additional chemotherapy cycles could result in additional survival benefits. Patients with ß-HCG level > 3000 IU/L had poorer prognosis.
Assuntos
Neoplasias Encefálicas , Coriocarcinoma , Neoplasias Embrionárias de Células Germinativas , Feminino , Humanos , Estudos Retrospectivos , Neoplasias Encefálicas/patologia , Resultado do Tratamento , Neoplasias Embrionárias de Células Germinativas/terapia , Coriocarcinoma/terapia , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Fatores de Risco , Gonadotropina Coriônica/metabolismoRESUMO
OBJECTIVES: The histologic subtype of intracranial germ cell tumours (IGCTs) is an important factor in deciding the treatment strategy, especially for teratomas. In this study, we aimed to non-invasively diagnose teratomas based on fractal and radiomic features. MATERIALS AND METHODS: This retrospective study included 330 IGCT patients, including a discovery set (n = 296) and an independent validation set (n = 34). Fractal and radiomic features were extracted from T1-weighted, T2-weighted, and post-contrast T1-weighted images. Five classifiers, including logistic regression, random forests, support vector machines, K-nearest neighbours, and XGBoost, were compared for our task. Based on the optimal classifier, we compared the performance of clinical, fractal, and radiomic models and the model combining these features in predicting teratomas. RESULTS: Among the diagnostic models, the fractal and radiomic models performed better than the clinical model. The final model that combined all the features showed the best performance, with an area under the curve, precision, sensitivity, and specificity of 0.946 [95% confidence interval (CI): 0.882-0.994], 95.65% (95% CI: 88.64-100%), 88.00% (95% CI: 77.78-96.36%), and 91.67% (95% CI: 78.26-100%), respectively, in the test set of the discovery set, and 0.944 (95% CI: 0.855-1.000), 85.71% (95% CI: 68.18-100%), 94.74% (95% CI: 83.33-100%), and 80.00% (95% CI: 58.33-100%), respectively, in the independent validation set. SHapley Additive exPlanations indicated that two fractal features, two radiomic features, and age were the top five features highly associated with the presence of teratomas. CONCLUSION: The predictive model including image and clinical features could help guide treatment strategies for IGCTs. CLINICAL RELEVANCE STATEMENT: Our machine learning model including image and clinical features can non-invasively predict teratoma components, which could help guide treatment strategies for intracranial germ cell tumours (IGCT). KEY POINTS: ⢠Fractals and radiomics can quantitatively evaluate imaging characteristics of intracranial germ cell tumours. ⢠Model combing imaging and clinical features had the best predictive performance. ⢠The diagnostic model could guide treatment strategies for intracranial germ cell tumours.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Teratoma , Humanos , Estudos Retrospectivos , Fractais , Diagnóstico Diferencial , Radiômica , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Teratoma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Cell division cycle 6 (CDC6) has been proven to be associated with the initiation and progression of human multiple tumors. However, it's role in glioma, which is ranked as one of the common primary malignant tumor in the central nervous system and is associated with high morbidity and mortality, is unclear. METHODS: In this study, we explored CDC6 gene expression level in pan-cancer. Furthermore, we focused on the relationships between CDC6 expression, its prognostic value, potential biological functions, and immune infiltrates in glioma patients. We also performed vitro experiments to assess the effect of CDC6 expression on proliferative, apoptotic, migrant and invasive abilities of glioma cells. RESULTS: As a result, CDC6 expression was upregulated in multiple types of cancer, including glioma. Moreover, high expression of CDC6 was significantly associated with age, IDH status, 1p/19q codeletion status, WHO grade and histological type in glioma (all p < 0.05). Meanwhile, high CDC6 expression was associated with poor overall survival (OS) in glioma patients, especially in different clinical subgroups. Furthermore, a univariate Cox analysis showed that high CDC6 expression was correlated with poor OS in glioma patients. Functional enrichment analysis indicated that CDC6 was mainly involved in pathways related to DNA transcription and cytokine activity, and Gene Set Enrichment Analysis (GSEA) revealed that MAPK pathway, P53 pathway and NF-κB pathway in cancer were differentially enriched in glioma patients with high CDC6 expression. Single-sample gene set enrichment analysis (ssGSEA) showed CDC6 expression in glioma was positively correlated with Th2 cells, Macrophages and Eosinophils, and negative correlations with plasmacytoid dendritic cells, CD8 T cells and NK CD56bright cells, suggesting its role in regulating tumor immunity. Finally, CCK8 assay, flow cytometry and transwell assays showed that silencing CDC6 could significantly inhibit proliferation, migration, invasion, and promoted apoptosis of U87 cells and U251 cells (p < 0.05). CONCLUSION: In conclusion, high CDC6 expression may serve as a promising biomarker for prognosis and correlated with immune infiltrates, presenting to be a potential immune therapy target in glioma.
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Neoplasias Encefálicas , Glioma , Biomarcadores , Neoplasias Encefálicas/metabolismo , Proteínas de Ciclo Celular/genética , Glioma/patologia , Humanos , NF-kappa B , Proteínas Nucleares/genética , PrognósticoRESUMO
BACKGROUND: The radiation dose for patients with low-grade gliomas (LGGs) is controversial. The objective of this study was to investigate the impact of the radiation dose on survival for patients with LGGs and especially for molecularly defined subgroups. METHODS: Three hundred fifty-one patients with newly diagnosed LGGs from the multicenter Chinese Glioma Cooperative Group received postoperative radiotherapy (RT) in 2005-2018. The RT dose, as a continuous variable, was entered into a Cox regression model using penalized spline regression to allow for a nonlinear relationship between the RT dose and overall survival (OS) or progression-free survival (PFS). Inverse probability of treatment weighting (IPTW)-adjusted propensity scores were used to correct for potential confounders. Dose effects on survival within IDH mutation and 1p/19q codeletion defined subgroups were analyzed. RESULTS: The risk of mortality and disease progression decreased sharply until 54 Gy. High-dose RT (≥54 Gy) was associated with significantly better 5-year OS (81.7% vs 64.0%; hazard ratio [HR], 0.33; P < .001) and PFS (77.4% vs 54.5%; HR, 0.46; P < .001) than low-dose RT (<54 Gy). IPTW correction confirmed the associations (HR for OS, 0.44; P = .001; HR for PFS, 0.48; P = .003). High-dose RT was associated with longer PFS (HR, 0.25; P = .002; HR, 0.21; P = .039) and OS (HR, 0.27; P = .006; HR, 0.07; P = .017) in IDH-mutant/1p/19q noncodeleted and IDH wild-type subgroups, respectively. No significant difference in survival was observed with high-dose RT in the IDH-mutant/1p/19q codeleted subgroup. CONCLUSIONS: High-dose RT (≥54 Gy) was effective in LGGs. Patients with an IDH mutation/1p/19q noncodeletion or IDH wild-type may need to be considered for high-dose RT. LAY SUMMARY: The radiotherapy dose-response was observed in patients with low-grade gliomas, and high-dose radiotherapy (≥54 Gy) was associated with improved survival. Patients with an IDH mutation/1p/19q noncodeletion or wild-type IDH may have improved survival with the administration of high-dose radiotherapy.
Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Cromossomos Humanos Par 1 , Glioma/genética , Glioma/radioterapia , Humanos , Isocitrato Desidrogenase/genética , Mutação , Gradação de Tumores , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Intracranial germ cell tumors (iGCTs) are classified into two pathological subtypes (germinomas [GEs] and nongerminomatous germ cell tumors [NGGCTs]), with distinct treatment strategy and prognosis. Accurate preoperative determination of iGCT subtypes is essential to guide clinical decision-making and prognosis assessment. PURPOSE: To investigate the diagnostic value of diffusion-weighted imaging (DWI), susceptibility weighted imaging (SWI), and dynamic susceptibility-contrast perfusion-weighted imaging (DSC-PWI) combined with conventional magnetic resonance imaging (cMRI) in finding subtypes of iGCTs. STUDY TYPE: Retrospective. POPULATION: A total of 40 patients (45% male and 55% female) with iGCTs. FIELD STRENGTH/SEQUENCE: A 3 T; <T1WI, T2WI, T1WI + C, DWI, SWI, DSC-PWI>. ASSESSMENT: The parameters of DWI and DSC-PWI were calculated based on extracted parameters of multiparametric MRIs. The characteristics of SWI and cMRI were also compared in GEs and NGGCTs. STATISTICAL TESTS: The diagnostic efficacy of the minimum apparent diffusion coefficient (ADCmin), time-to-peak (TTP), relative mean transit time (rMTT), relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV) maps, and cMRI features in iGCT classification was evaluated by receiver operating characteristic curve (ROC) analyses. We calculated the sensitivity, specificity, AUC, and Youden index of the hybrid MR evaluation methods. A prospective cohort (five GEs and five NGGCTs) was designed as a simulation set to test the model. The significance threshold was set at P < 0.01. RESULTS: The ADCmin (1039.100 ± 453.830 vs. 1400.050 ± 394.650), rCBF values (20.650 ± 6.260 vs. 51.170 ± 6.570), and TTP values (24.450 ± 3.160 vs. 28.950 ± 5.120) were significantly lower in GEs than in NGGCTs. The combination of ADCmin, DSC-PWI, and cMRI showed the heights AUC (AUC = 0.962). The iGCT multiparametric framework showed the AUC was 0.958 in the simulation set. DATA CONCLUSION: The iCGT multiparametric framework might be an effective diagnostic approach of iGCT subtype. The application of cMRI (T1WI, T2WI, and Gd-T1WI) with advanced imaging modalities (DWI, SWI, and PWI) had the best performance for classifying iGCT subtypes. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.
Assuntos
Neoplasias Encefálicas , Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias Embrionárias de Células Germinativas , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Perfusão , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias TesticularesRESUMO
BACKGROUND: Little is known about depression and anxiety among paediatric intracranial germ cell tumour (iGCT) survivors. We aimed to evaluate the risk factors associated with depression, anxiety and health-related quality of life (HRQoL) in paediatric iGCT survivors. METHODS: We recruited 200 iGCT patients (and their parents) from Beijing Tiantan Hospital and assessed their HRQoL using the Paediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales. The Children's Depression Inventory, Screen for Child Anxiety Related Emotional Disorders, and Symptom Checklist 90 were used to evaluate depression and anxiety. The results were analysed based on disease recurrence, tumour location and treatment strategies. RESULTS: Survivors with recurrent tumours had worse HRQoL scores than those with non-recurrent tumours. Patients with tumours involving both the suprasellar and basal ganglia regions had the worst HRQoL scores. A large proportion of survivors had depression or anxiety. Both depression and anxiety scores were highly correlated with the HRQoL emotional functioning scores. The parent proxy-reports (PPR) and child self-reports were highly correlated in all domains. CONCLUSIONS: This study demonstrated the clinical factors affecting paediatric iGCT survivors' depression, anxiety, and HRQoL. Therefore, psychological interventions should be implemented. It also suggests that the PedsQL PPR would be helpful for routine screening.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Qualidade de Vida , Ansiedade , Criança , Depressão , Humanos , Recidiva Local de Neoplasia , Neoplasias Embrionárias de Células Germinativas/terapia , Inquéritos e Questionários , SobreviventesRESUMO
Engineering a stable solid electrolyte interphase (SEI) is one of the critical maneuvers in improving the performance of a lithium anode for high-energy-density rechargeable lithium batteries. Herein, we build a fluorinated lithium/sodium hybrid interphase via a facile electroless electrolyte-soaking approach to stabilize the repeated plating/stripping of lithium metal. Jointed experimental and computational characterizations reveal that the fluorinated hybrid SEI mainly consisting of NaF, LiF, LixPOyFz, and organic components features a mosaic polycrystalline structure with enriched grain boundaries and superior interfacial properties toward Li. This LiF/NaF hybrid SEI exhibits improved ionic conductivity and mechanical strength in comparison to the SEI without NaF. Remarkably, the fluorinated hybrid SEI enables an extended dendrite-free cycling of metallic Li over 1300 h at a high areal capacity of 10 mAh cm-2 in symmetrical cells. Furthermore, full cells based on the LiFePO4 cathode and hybrid SEI-protected Li anode sustain long-term stability and good capacity retention (96.70% after 200 cycles) at 0.5 C. This work could provide a new avenue for designing robust multifunctional SEI to upgrade the metallic lithium anode.
RESUMO
BACKGROUND: Primary right brachium pontis germinoma with hypertrophic olivary degeneration (HOD) is extremely rare. A preoperative diagnosis is challenging due to the absence of characterized clinical and neuroimaging features, and biopsy should be considered. CASE PRESENTATION: A 20-year-old male patient presented with a case of primary intracranial germinoma originating from right brachium pontis with HOD manifesting as ocular myoclonus, nystagmus in both eyes, ataxic gait and incoordination of the limbs. Magnetic resonance imaging (MRI) revealed an irregular patchy lesion with hyperintensity on T2-weighted images (T2WI) and T2 fluid-attenuated inversion recovery (FLAIR) without enhancement by gadolinium (Gd). Furthermore, a focal hyperintense nodule on T2WI in the left inferior olive nucleus (ION) of the medulla oblongata was considered hypertrophic olivary degeneration (HOD) based on the patient's symptoms and neuroimaging findings. Due to suspected demyelinating disease and low-grade glioma (LGG), a biopsy was planned. The pathological diagnosis was germinoma. Subsequently, he received chemoradiation therapy, resulting in the improvement of neurological deficits and the disappearance of the lesion on MRI. CONCLUSION: A case of "Primary right brachium pontis germinoma with HOD" is reported for the first time. A preoperative diagnosis is challenging due to the fact of absence of clinical signs and symptoms and neuroimaging characteristics. However, patients can have favourable prognoses with appropriate evaluation and treatment.
Assuntos
Neoplasias Encefálicas/patologia , Germinoma/patologia , Pedúnculo Cerebelar Médio/patologia , Núcleo Olivar/patologia , Humanos , Hipertrofia/etiologia , Hipertrofia/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Bulbo/patologia , Mioclonia/etiologia , Adulto JovemRESUMO
PURPOSE: To explore the characteristics of growth disturbance in patients with intracranial germinoma with different origins. METHODS: Clinical data of 151 patients with single-origin germinomas were studied retrospectively. Z-score of height (ZSOH) at both diagnosis and the last follow-up was calculated using the WHO AnthroPlus software. Linear regression was used to analyse the correlation between the absolute change in ZSOH (|ZSOH last follow-up - ZSOH diagnosis|) and clinical factors. RESULTS: The mean ZSOH decreased significantly in every origin subgroup at the last follow-up. In patients with sellar germinoma (n = 62), the mean ZSOH values at both diagnosis and the last follow-up were significantly lower than those in patients with pineal (n = 30) (p < 0.001) or basal ganglia germinomas (n = 59) (p < 0.001), respectively. In patients with basal ganglia germinoma, the mean absolute change in ZSOH decreased significantly compared to that in the patients with sellar (p = 0.006) or pineal germinomas (p = 0.04). Linear analysis revealed that sex (male vs female; p = 0.003) and age at diagnosis (≤10 years vs >10 years; p = 0.026) had negative correlations, while radiation dose at the hypothalamic-pituitary axis (HPA) (≤40 Gy vs >40 Gy; p = 0.085) had a marginally positive correlation, with absolute change in ZSOH. CONCLUSIONS: Patients with germinoma experienced growth retardation after treatments. The growth disturbance was consistent and more severe in patients with germinoma of sellar origin, while the greatest aggravation was observed in patients with germinoma of basal ganglia origin. Decreasing radiation dose to the HPA may minimize the negative impact of radiotherapy on growth.
Assuntos
Neoplasias Encefálicas , Germinoma , Glândula Pineal , Feminino , Germinoma/complicações , Humanos , Masculino , Glândula Pineal/diagnóstico por imagem , Estudos RetrospectivosRESUMO
Tumor-associated macrophages (TAMs) are regarded as the most abundantly infiltrating immune cells around the tumor microenvironment in gliomas, which plays an important role in tumorgenesis and immunosuppression. A total of 216 patients diagnosed with primary glioma were obtained from the Chinese Glioma Genome Atlas of which the RNA sequencing data was used as training set. RNA sequencing from the Cancer Genome Atlas was applicated for validation. We found that mesenchymal subtype showed strong positive correlation with macrophage-related genes (MRGs) expression. Survival analysis showed that high expression level of MRG predicted poor prognosis. A TAM-based nine-gene signature was constructed, which divided the samples into high- and low-risk of unfavorable outcome. The result of Cox regression analysis showed that the risk score was an independent prognostic factor in gliomas. Hence, the expression of TAMs was correlated with patient survival. The nine-TAM-related gene signature can predict patient survival efficiently.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Macrófagos Associados a Tumor/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sequência de RNA/métodos , Análise de Sobrevida , Microambiente Tumoral/genéticaRESUMO
OBJCTIVE: To study the clinical effect of surgery combined with chemotherapy and radiotherapy in children with central primitive neuroectodermal tumor (cPNET), as well as the risks factors for poor prognosis. METHODS: A retrospective analysis was performed for the clinical data of 42 children who were diagnosed with cPNET from June 2012 to September 2018. RESULTS: The 42 children had a median overall survival (OS) time of 2.0 years and a median event-free survival (EFS) time of 1.3 years; the 1-, 3-, and 5-year OS rates were 76.2%±6.6%, 41.4%±8.7%, 37.3%±8.8% respectively, and the 1-, 3-, and 5-year EFS rates were 64.3%±7.4%, 32.7%±8.0%, 28.0%±8.1% respectively. The univariate analysis showed that there were significant differences in the OS and EFS rates among the children with different patterns of surgical resection, chemotherapy cycles, and risk grades (P<0.05), and there was also a significant difference in the OS rate between the children receiving radiotherapy and those not receiving radiotherapy (P<0.05). The multivariate Cox regression analysis showed that chemotherapy cycles and risk grade were independent influencing factors for EFS and OS rates (P<0.05). The EFS and OS rates increased with the increase in chemotherapy cycles and the reduction in risk grade. CONCLUSIONS: Multimodality therapy with surgery, chemotherapy, and radiotherapy is an effective method for the treatment of cPNET in children. Early diagnosis and treatment and adherence to chemotherapy for as long as possible may improve EFS and OS rates.
Assuntos
Tumores Neuroectodérmicos Primitivos , Protocolos de Quimioterapia Combinada Antineoplásica , Criança , Terapia Combinada , Intervalo Livre de Doença , Humanos , Prognóstico , Estudos RetrospectivosRESUMO
OBJECTIVES: The aim of this study was to differentiate primary central nervous system lymphoma (PCNSL) from glioblastomas (GBM) using the fractal analysis of conventional MRI data. MATERIALS AND METHODS: Sixty patients with PCNSL and 107 patients with GBM with MRI data available were enrolled. Fractal dimension (FD) and lacunarity values of the tumour region were calculated using fractal analysis. A predictive model combining fractal parameters and anatomical characteristics was built using logistic regression. The role of FD, lacunarity and the predictive model in differential diagnosis was evaluated using receiver-operating characteristic (ROC) curve analysis. The association between fractal parameters and anatomical characteristics of tumours was also investigated. RESULTS: PCNSL had lower FD values (p < 0.001) and higher lacunarity values (p < 0.001) than GBM. ROC curve analysis revealed that FD, lacunarity, and the predictive model could distinguish PCNSL from GBM (area under the curve: 0.895, 0.776, and 0.969, respectively). The following associations were observed between fractal parameters and anatomical characteristics: multiple lesions were significantly associated with higher lacunarity (p = 0.024), necrosis with higher FD (p = 0.027), corpus callosum involvement with higher lacunarity (p < 0.001) in PCNSL and subventricular zone involvement with higher FD (p < 0.001) in GBM. CONCLUSIONS: The findings of the study indicate that fractal analysis on conventional MRI performs well in distinguishing PCNSL from GBM. KEY POINTS: ⢠Fractal dimension and lacunarity were capable of differentiating PCNSL from GBM. ⢠PCNSL and GBM exhibited different anatomical characteristics. ⢠Fractal parameters were associated with some of these anatomical characteristics.
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Corpo Caloso/patologia , Fractais , Glioblastoma/diagnóstico , Linfoma/diagnóstico , Imageamento por Ressonância Magnética/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Adulto JovemRESUMO
BACKGROUND: How germline single nucleotide polymorphisms are involved in the etiology of medulloblastoma remans poorly understood. We hypothesized that CCDKN2A/B rs1063192 and rs4977756 and also the long noncoding RNA (lncRNA) CDKN2BAS rs2157719 glioma susceptibility polymorphisms identified by genome-wide association studies may contribute to medulloblastoma predisposition. METHODS: To test this hypothesis, we genotyped these genetic variants among 160 medulloblastoma patients and 443 health controls in a Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS: We found that only the lncRNA CDKN2BAS rs2157719 T>C genetic polymorphism was significantly associated with an increased medulloblastoma risk (C allele: OR = 1.85, 95% CI = 1.32-2.58; p = 2.7 × 10-4 ). The stratified analyses showed an elevated risk of pediatric medulloblastoma associated with CDKN2BAS rs2157719 CC or TC genotype (both p < 0.05). Moreover, the association between the CDKN2BAS rs2157719 polymorphism and medulloblastoma risk is more pronounced in males (OR = 2.22, 95% CI = 1.36-3.62; p = 0.001). CONCLUSIONS: The findings of the present study provide important insights into the genetic complexities and predisposition of medulloblastoma in Chinese, especially at the lncRNA germline variation level.
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Biomarcadores Tumorais/genética , Neoplasias Cerebelares/genética , Meduloblastoma/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Adolescente , Estudos de Casos e Controles , Neoplasias Cerebelares/epidemiologia , Neoplasias Cerebelares/patologia , China/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Meduloblastoma/epidemiologia , Meduloblastoma/patologia , PrognósticoRESUMO
Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.
Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Glioma/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes , Western Blotting , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Quimiorradioterapia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/secundário , Glioma/patologia , Glioma/terapia , Células HEK293 , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA , Temozolomida , Translocação Genética , Adulto JovemRESUMO
OBJECTIVE: To evaluate the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for predicting tumor response to radiotherapy in patients with suspected primary central nervous system (CNS) germ cell tumors (GCTs). METHODS: DCE-MRI parameters of 35 patients with suspected primary CNS GCTs were obtained prior to diagnostic radiation, using the Tofts and Kermode model. Radiosensitivity was determined in tumors diagnosed 2 weeks after radiation by observing changes in tumor size and markers as a response to MRI. Taking radiosensitivity as the gold standard, the cut-off value of DCE-MRI parameters was measured by receiver operating characteristic (ROC) curve. Diagnostic accuracy of DCE-MRI parameters for predicting radiosensitivity was evaluated by ROC curve. RESULTS: A significant elevation in transfer constant (K(trans)) and extravascular extracellular space (Ve) (P=0.000), as well as a significant reduction in rate constant (Kep) (P=0.000) was observed in tumors. K(trans), relative K(trans), and relative Kep of the responsive group were significantly higher than non-responsive groups. No significant difference was found in Kep, Ve, and relative Ve between the two groups. Relative K(trans) showed the best diagnostic value in predicting radiosensitivity with a sensitivity of 100%, specificity of 91.7%, positive predictive value (PPV) of 95.8%, and negative predictive value (NPV) of 100%. CONCLUSIONS: Relative K(trans) appeared promising in predicting tumor response to radiation therapy (RT). It is implied that DCE-MRI pre-treatment is a requisite step in diagnostic procedures and a novel and reliable approach to guide clinical choice of RT.
RESUMO
Recent genome-wide association studies have identified several leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Our previous data demonstrated that two SNPs (rs398652 on 14q21 and rs621559 on 1p34.2) were associated with LTL and risk of esophageal squamous cell carcinoma in Chinese. However, the role of these genetic variants on glioma risk is still unknown. Therefore, we examined if these genetic variants have impact on the genetic susceptibility of glioma in Chinese. On the basis of analyzing 404 glioma patients and frequency-matched 820 controls, we found that subjects having the 1p34.2 rs621559 AG or GG genotype had an OR of 1.82 (95 % CI = 1.07-3.09, P = 0.026) or 2.12 (95 % CI = 1.26-3.56, P = 0.005) for developing glioma, respectively, compared with subjects having the rs621559 AA genotype. Similarly, the 14q21 rs398652 AG or GG genotype was associated with increased glioma risk (OR = 1.39, 95 % CI = 1.07-1.80, P = 0.012; OR = 1.52, 95 % CI = 1.04-2.20, P = 0.029) compared to AA genotype. In all, our results highlight the possible role of telomere in carcinogenesis.
Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 1 , Predisposição Genética para Doença , Glioma/genética , Homeostase do Telômero/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Glioma/metabolismo , Glioma/patologia , Haplótipos , Humanos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Telômero , Adulto JovemRESUMO
As a crucial homologous recombination repair gene, RAD52 participates in maintenance of genomic stability and prevention of tumorigenesis. Although several cancer susceptibility RAD52 single nucleotide polymorphisms (SNPs) have been identified previously, little was known on how the RAD52 SNPs are involved in glioma development in Han Chinese. Therefore, we examined the association between five RAD52 SNPs (rs1051669, rs10774474, rs11571378, rs7963551 and rs6489769) and glioma risk using a case-control design. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. We found that only the RAD52 rs7963551 SNP was significantly associated with glioma risk, with the odds of having the rs7963551 AC or CC genotype in patients was 0.49 (95 % CI 0.37-0.65, P = 9.2 × 10(-6)) or 0.39 (95 % CI 0.18-0.81, P = 0.012) compared with the AA genotype. These data are consistent with functional relevance of allelic regulation of RAD52 expression by the rs7963551 SNP and miRNA let-7 in cancer cells. Stratified analyses elucidated that statistically significant association between glioma and rs7963551 SNP only existed in either astrocytic tumors (P = 6.3 × 10(-6)) or oligoastrocytic tumors (P = 0.002). In conclusion, our results support the hypothesis that genetic variants influencing miRNA-mediated regulation of tumor suppressor genes or oncogenes may contribute glioma susceptibility.
Assuntos
Povo Asiático/genética , Neoplasias Encefálicas/etiologia , Glioma/etiologia , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Glioma/patologia , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: High-grade gliomas (HGGs) have a rapid relapse and short survival. Studies have identified many clinical characteristics and biomarkers associated with progression-free survival (PFS) and over-survival (OS). However, there has not yet a comprehensive study on survival after the first progression (SAP). METHODS: From CGGA and TCGA, 319 and 308 HGGs were confirmed as the first progression. The data on clinical characteristics and biomarkers were analyzed in accordance with OS, PFS, and SAP. RESULTS: Analysis of 319 patients from CGGA, significant predictors of improved OS/PFS/SAP were WHO grade, MGMT promoter methylation, and Ki-67 expression in univariate analysis. Further multivariate analysis showed MGMT promoter methylation and Ki-67 expression were independent predictors. However, an analysis of 308 patients from TCGA found MGMT promoter methylation is the only prognostic marker. A longer SAP was observed in patients with methylated MGMT promoter after standard chemoradiotherapy. In our data, HGGs could be divided into low, intermediate, and high-risk groups for SAP by MGMT methylation and Ki-67 expression. CONCLUSIONS: Patients with MGMT promoter methylation have a prolonger SAP after standard chemoradiotherapy. HGGs could be divided into low, intermediate, and high-risk groups for SAP according to MGMT status and Ki-67 expression.
RESUMO
OBJECTIVE: IDH-mutant grade 4 astrocytomas (AIDHmut/G4) are divided into primary de novo (pAIDHmut/G4) and secondary with a history of prior lower-grade gliomas (LGGs; sAIDHmut/G4). The mutational spectrum and DNA methylation patterns are homogeneous within de novo pAIDHmut/G4 and evolved sAIDHmut/G4, but the two groups have different diagnoses, management, and outcomes. This study sought to systematically compare the clinical, pathological, and survival characteristics between them. METHODS: Of the 871 grade 4 astrocytomas with data for IDH mutation, 698 (80.1%) were primary and 173 (19.9%) were secondary. Of the 698 primary tumors, 103 (14.8%) were pAIDHmut/G4, and of the 173 secondary tumors, 108 (62.4%) were sAIDHmut/G4. Clinical, pathological, and survival features were compared between pAIDHmut/G4 and sAIDHmut/G4. Multivariate analyses were performed to identify prognostic factors. RESULTS: Patients with sAIDHmut/G4 had significantly shorter median overall survival (OS; 11.8 vs 34.2 months, hazard ratio [HR] 2.69, 95% confidence interval [CI] 1.367-5.306, p = 0.004) and progression-free survival (PFS; 8.5 vs 24.3 months, HR 2.83, 95% CI 1.532-5.235, p = 0.001) than patients with pAIDHmut/G4. In patients with sAIDHmut/G4, resection status and chemotherapy were independent prognostic factors for OS and PFS; in patients with pAIDHmut/G4, LGG component, resection status, and O6-methylguanine DNA methyltransferase promoter methylation were independent prognostic factors. The therapeutic strategies of LGGs did not influence survival of patients with sAIDHmut/G4, but patients who had not received radiotherapy or chemotherapy when they were diagnosed with LGGs were found to benefit from radiotherapy or chemotherapy when they progressed to sAIDHmut/G4. CONCLUSIONS: The different clinical characteristics, survival, and risk factors between sAIDHmut/G4 and pAIDHmut/G4 provide a reference to guide treatment decisions in AIDHmut/G4.