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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.
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BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive primary brain malignancy. Novel therapeutic modalities like tumor electric field therapy (TEFT) have shown promise, but underlying mechanisms remain unclear. The extracellular matrix (ECM) is implicated in GBM progression, warranting investigation into TEFT-ECM interplay. METHODS: T98G cells were treated with TEFT (200 kHz, 2.2 V/m) for 72 h. Collagen type VI alpha 1 (COL6A1) was identified as hub gene via comprehensive bioinformatic analysis based on RNA sequencing (RNA-seq) and public glioma datasets. TEFT intervention models were established using T98G and Ln229 cell lines. Pre-TEFT and post-TEFT GBM tissues were collected for further validation. Focal adhesion pathway activity was assessed by western blot. Functional partners of COL6A1 were identified and validated by co-localization and survival analysis. RESULTS: TEFT altered ECM-related gene expression in T98G cells, including the hub gene COL6A1. COL6A1 was upregulated in GBM and associated with poor prognosis. Muti-database GBM single-cell analysis revealed high-COL6A1 expression predominantly in malignant cell subpopulations. Differential expression and functional enrichment analyses suggested COL6A1 might be involved in ECM organization and focal adhesion. Western blot (WB), immunofluorescence (IF), and co-immunoprecipitation (Co-IP) experiments revealed that TEFT significantly inhibited expression of COL6A1, hindering its interaction with ITGA5, consequently suppressing the FAK/Paxillin/AKT pathway activity. These results suggested that TEFT might exert its antitumor effects by downregulating COL6A1 and thereby inhibiting the activity of the focal adhesion pathway. CONCLUSION: TEFT could remodel the ECM of GBM cells by downregulating COL6A1 expression and inhibiting focal adhesion pathway. COL6A1 could interact with ITGA5 and activate the focal adhesion pathway, suggesting that it might be a potential therapeutic target mediating the antitumor effects of TEFT.
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Neoplasias Encefálicas , Colágeno Tipo VI , Terapia por Estimulación Eléctrica , Glioblastoma , Colágeno Tipo VI/genética , Colágeno Tipo VI/metabolismo , Humanos , Glioblastoma/genética , Glioblastoma/terapia , Glioblastoma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Terapia por Estimulación Eléctrica/métodos , Línea Celular Tumoral , Animales , Ratones Desnudos , RatonesRESUMEN
BACKGROUND: Intracranial germ cell tumors (IGCTs) are a rare group of malignancies that are clinically classified as germinomas and nongerminomatous germ cell tumors (NGGCTs). Previous studies have found that somatic mutations involving the mitogen-activated protein kinase/mTOR signaling pathway are common early events. However, a comprehensive genomic understanding of IGCTs is still lacking. METHODS: We established a cohort including over 100 IGCTs and conducted genomic and transcriptomic sequencing. RESULTS: We identified novel recurrent driver genomic aberrations, including USP28 truncation mutations and high-level copy number amplification of KRAS and CRKL caused by replication of extrachromosomal DNA. Three distinct subtypes associated with unique genomic and clinical profiles were identified with transcriptome analysis: Immune-hot, MYC/E2F, and SHH. Both immune-hot and MYC/E2F were predominantly identified in germinomas and shared similar mutations involving the RAS/MAPK signaling pathway. However, the immune-hot group showed an older disease onset age and a significant immune response. MYC/E2F was characterized by a younger disease onset age and increased genomic instability, with a higher proportion of tumors showing whole-genome doubling. Additionally, the SHH subtype was mostly identified in NGGCTs. CONCLUSIONS: Novel genomic aberrations and molecular subtypes were identified in IGCTs. These findings provide molecular basis for the potential introduction of new treatment strategies in this setting.
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Neoplasias Encefálicas , Neoplasias de Células Germinales y Embrionarias , Humanos , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/patología , Masculino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Adulto , Femenino , Adolescente , Adulto Joven , Niño , Mutación , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Pronóstico , Perfilación de la Expresión Génica , PreescolarRESUMEN
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.
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Neoplasias Encefálicas , Coriocarcinoma , Neoplasias de Células Germinales y Embrionarias , Femenino , Humanos , Estudios Retrospectivos , Neoplasias Encefálicas/patología , Resultado del Tratamiento , Neoplasias de Células Germinales y Embrionarias/terapia , Coriocarcinoma/terapia , Coriocarcinoma/metabolismo , Coriocarcinoma/patología , Factores de Riesgo , Gonadotropina Coriónica/metabolismoRESUMEN
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.
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Neoplasias de Células Germinales y Embrionarias , Teratoma , Humanos , Estudios Retrospectivos , Fractales , Diagnóstico Diferencial , Radiómica , Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Teratoma/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
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.
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Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Glioma/patología , Supervivencia sin Progresión , Metilación de ADN/genética , Glioblastoma/genética , Isocitrato Deshidrogenasa/genética , Astrocitoma/genética , Astrocitoma/terapia , Mutación/genéticaRESUMEN
Intracranial germ cell tumors are rare tumors that mainly affect children and adolescents. Radiotherapy is the cornerstone of interdisciplinary treatment methods. Radiation of the whole ventricle system and the local tumor can reduce the complications in the late stage of radiotherapy while ensuring the curative effect. However, manually delineating the ventricular system is labor-intensive and time-consuming for physicians. The diverse ventricle shape and the hydrocephalus-induced ventricle dilation increase the difficulty of automatic segmentation algorithms. Therefore, this study proposed a fully automatic segmentation framework. Firstly, we designed a novel unsupervised learning-based label mapper, which is used to handle the ventricle shape variations and obtain the preliminary segmentation result. Then, to boost the segmentation performance of the framework, we improved the region growth algorithm and combined the fully connected conditional random field to optimize the preliminary results from both regional and voxel scales. In the case of only one set of annotated data is required, the average time cost is 153.01 s, and the average target segmentation accuracy can reach 84.69%. Furthermore, we verified the algorithm in practical clinical applications. The results demonstrate that our proposed method is beneficial for physicians to delineate radiotherapy targets, which is feasible and clinically practical, and may fill the gap of automatic delineation methods for the ventricular target of intracranial germ celltumors.
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Neoplasias de Células Germinales y Embrionarias , Neoplasias , Niño , Humanos , Adolescente , Aprendizaje Automático no Supervisado , Algoritmos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
BACKGROUND: PTPRZ1-MET fusion was reported to associate with glioma progression from low-grade to high-grade glioma, which was a target by a MET inhibitor vebreltinib. However, little is known about the further efficacy of vebreltinib among more glioma patients. This trial aims to evaluate the safety and efficacy of vebreltinib enteric-coated capsules in the treatment of sGBM/IDH mutant glioblastoma patients with the ZM fusion gene. METHODS: This multicentric, randomized, open-label, controlled trial plans to include 19 neurosurgical centers and recruit 84 sGBM or IDH mutant glioblastoma patients with the ZM fusion gene. This trial enrolls sGBM or IDH mutant glioblastoma patients with the inclusion criteria and without the exclusion criteria. It was registered with chinadrugtrials.org.cn (CTR20181664). The primary efficacy endpoint is overall survival (OS). The secondary endpoints are progression-free survival (PFS) and objective response rate (ORR). DISCUSSION: If proven effective, this targeted multifaceted intervention protocol will be extended for more glioma patients as a protocol to evaluate the safety and efficacy of MET inhibitors. TRIAL REGISTRATION: It was registered with chinadrugtrials.org.cn (CTR20181664).
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Radiotherapy is one of the cornerstone of the glioblastoma treatment paradigm. However, the resistance of tumor cells to radiation results in poor survival. The mechanism of radioresistance has not been fully elucidated. This study aimed to screen the differential expressed genes related with radiosensitivity. The differentially expressed genes were screened based on RNA sequencing in 15 pairs of primary and recurrent glioblastoma that have undergone radiotherapy. Candidate genes were validated in 226 primary and 134 recurrent glioblastoma (GBM) obtained from the Chinese Glioma Genome Atlas (CGGA) database. RNA and protein expression were verified by Quantitative Real-time PCR (qPCR) and western blot in irradiated GBM cell lines. The candidate gene was investigated to explore the relationship between mRNA levels and clinical characteristics in the CGGA and The Cancer Genome Atlas dataset. Kaplan-Meier survival analysis and Cox regression analysis were used for survival analysis. Gene ontology and KEGG pathway analysis were used for bioinformatics analysis. Four genes (TMEM59L, Gelsolin, ZBTB7A and ATX) were screened. TMEM59L expression was significantly elevated in recurrent glioblastoma and lower in normal brain tissue. We selected TMEM59L as the target gene for further study. The increasing of TMEM59L expression induced by radiation was confirmed by mRNA and western blot in irradiated GBM cell. Further investigation revealed that high expression of TMEM59L was enriched in IDH mutant and MGMT methylated gliomas and associated with a better prognosis. Gene ontology and KEGG pathway analysis revealed that TMEM59L was closely related to the DNA damage repair and oxidative stress respond process. We speculated that the high expression of TMEM59L might enhance radiotherapy sensitivity by increasing ROS-induced DNA damage and inhibiting DNA damage repair process.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Glioblastoma/radioterapia , Glioblastoma/tratamiento farmacológico , Línea Celular Tumoral , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Factores de Transcripción , Recurrencia Local de Neoplasia , Proteínas de Unión al ADN , ARN Mensajero/genética , Tolerancia a Radiación/genéticaRESUMEN
Background: Skull base chordoma and chondrosarcoma are exceptionally rare bone tumors with high propensity for local recurrence. Different postoperative radiation modalities are often used to improve the clinical efficacy. Proton therapy (PT) might be among the most promising ones because of the unique ballistic characteristics of high-energy particles. However, previous meta-analysis often included studies with combined radiation techniques. No systematic review to date has directly analyzed the survival and toxicity of pure PT for these two types of malignancies. Methods: By following the PRISMA guidelines, a systematic search of three databases was conducted. Articles were screened and data were extracted according to a prespecified scheme. R 4.2.0 software was used to conduct the meta-analysis. Normal distribution test was used for the incidence rate of each subgroup. Results: A total of seven studies involving 478 patients were included in this analysis. The quality of included articles ranged from moderate to high quality. All patients were histopathologically diagnosed with chordoma or chondrosarcoma, and the follow-up time of the cohort ranged from 21 to 61.7 months. For PT planning, the median target volume ranged from 15 cc to 40 cc, and the administered median dose varied from 63 to 78.4 GyRBE at 1.8-2.0 GyRBE per fraction. The 1-, 2-, 3-, 5-, and 7-year local control and overall survival rates were 100%, 93%, 87%, 78%, and 68%, and 100%, 99%, 89%, 85%, and 68%, respectively. The late grade 3 or higher toxicities were reported in only two involved articles. Conclusions: Until now, medical centers worldwide have exerted PT to improve outcomes of skull base chordomas and chondrosarcomas. PT not combined with other radiation modalities showed favorable local control and survival with a low incidence of severe radiation-induced toxicities, which manifests promising clinical benefits. However, high-quality evidence is still limited, requiring future clinical trials and prospective studies in selected patients.
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OBJECTIVE: IDH-mutant lower-grade gliomas (LGGs, grade 2 or 3) eventually transform into secondary grade 4 astrocytomas (sAIDHmut/G4). Here, we sought to describe the transformation time, risk factors, and outcomes in malignant transformation of IDH-mutant LGGs. METHODS: We screened data for 108 patients with sAIDHmut/G4 in the Chinese Glioma Genome Atlas who had initial IDH-mutant LGGs and underwent reoperation during 2005-2021. We evaluated the transformation time from IDH-mutant LGGs to sAIDHmut/G4, and associated risk factors and outcomes. Malignant transformation was defined as pathological confirmation of grade 4 astrocytoma. RESULTS: The median age of the 108 patients with IDH-mutant LGGs was 35 years (range, 19-54); the median age at transformation was 40 years (range, 25-62); and the median follow-up time for all patients was 146 months (range, 121-171). The average transformation time was 58.8 months for all patients with LGGs (range, 5.9-208.1); 63.5 and 51.9 months for grade 2 and 3 gliomas, respectively; and 58.4 and 78.1 months for IDH-mutant/1p/19q-non-codeleted astrocytomas and IDH-mutant/1p/19q-codeleted oligodendrogliomas, respectively. Univariate and multivariate analysis indicated that radiotherapy [hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.137-0.595; P = 0.001] and non-A blood type (HR, 0.37; 95% CI, 0.203-0.680; P = 0.001) were protective factors against delayed malignant transformation. Radiotherapy was associated with improved survival after transformation (HR, 0.44; 95% CI, 0.241-0.803; P = 0.008), overall survival (HR, 0.50; 95% CI, 0.265-0.972; P = 0.041), and progression-free survival (HR, 0.25; 95% CI, 0.133-0.479; P < 0.0001) in patients with IDH-mutant gliomas. CONCLUSIONS: Radiotherapy is associated with delayed malignant transformation and improved survival in patients with IDH-mutant gliomas.
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Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Oligodendroglioma , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Isocitrato Deshidrogenasa/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patología , Glioma/genética , Glioma/radioterapia , Glioma/patología , Astrocitoma/genética , Astrocitoma/radioterapia , Astrocitoma/cirugía , Transformación Celular Neoplásica/genéticaRESUMEN
Primary central nervous system lymphoma (PCNSL) is a type of central nervous system restricted non-Hodgkin lymphoma, whose histopathological diagnosis is majorly large B cell lymphoma. To provide specific, evidence-based recommendations for medical professionals and to promote more standardized, effective and safe treatment for patients with PCNSL, a panel of experts from the Chinese Neurosurgical Society of the Chinese Medical Association and the Society of Hematological Malignancies of the Chinese Anti-Cancer Association jointly developed an evidence-based consensus. After comprehensively searching literature and conducting systematic reviews, two rounds of Delphi were conducted to reach consensus on the recommendations as follows: The histopathological specimens of PCNSL patients should be obtained as safely and comprehensively as possible by multimodal tomography-guided biopsy or minimally invasive surgery. Corticosteroids should be withdrawn from, or not be administered to, patients with suspected PCNSL before biopsy if the patient's status permits. MRI (enhanced and DWI) should be performed for diagnosing and evaluating PCNSL patients where whole-body PET-CT be used at necessary time points. Mini-mental status examination can be used to assess cognitive function in the clinical management. Newly diagnosed PCNSL patients should be treated with combined high-dose methotrexate-based regimen and can be treated with a rituximab-inclusive regimen at induction therapy. Autologous stem cell transplantation can be used as a consolidation therapy. Refractory or relapsed PCNSL patients can be treated with ibrutinib with or without high-dose chemotherapy as re-induction therapy. Stereotactic radiosurgery can be used for PCNSL patients with a limited recurrent lesion who were refractory to chemotherapy and have previously received whole-brain radiotherapy. Patients with suspected primary vitreoretinal lymphoma (PVRL) should be diagnosed by vitreous biopsy. PVRL or PCNSL patients with concurrent VRL can be treated with combined systemic and local therapy.
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Neoplasias del Sistema Nervioso Central , Trasplante de Células Madre Hematopoyéticas , Linfoma no Hodgkin , Neoplasias de la Retina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/terapia , Consenso , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Metotrexato/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Retina/inducido químicamente , Neoplasias de la Retina/tratamiento farmacológico , Rituximab/efectos adversos , Trasplante Autólogo , Cuerpo Vítreo/patologíaRESUMEN
Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A-FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow-derived macrophages through activation of the FOSL2-ANXA1-FPR1/3 axis. These polarized macrophages can efficiently suppress T-cell activity and accelerate NES transition in tumor cells. Moreover, the polarized macrophages could upregulate CCL2 to induce tumor cell migration. SIGNIFICANCE: GBM progression could be induced by hypoxia via the HIF1A-FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow-derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration. This article is highlighted in the In This Issue feature, p. 2711.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Isocitrato Deshidrogenasa/genética , Pronóstico , Hipoxia/genéticaRESUMEN
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/patología , Humanos , FN-kappa B , Proteínas Nucleares/genética , PronósticoRESUMEN
To summarize randomized controlled trials (RCTs) evidence for the effectiveness of available treatment strategies for elderly patients with glioblastoma (GBM) (defined as 60 years old and above) and to identify research gaps, we conducted this evidence map. Finally, 22 RCTs (with 3052 participants) were included. For newly diagnosed elderly patients with GBM (16 RCTs), 75% was identified about the effectiveness of chemotherapy, radiotherapy and chemo-radiotherapy, while there was relatively less evidence evaluating targeted therapy (12.5%), immunotherapy (18.75%) and tumor treating fields (TTFs) therapy (6.25%). Less evidence was identified in elderly patients with recurrent GBM (6 RCTs), including 2 RCTs for immunotherapy and 4 RCTs for targeted therapy. Current RCTs revealed some beneficial treatment strategies. However, more are needed to optimize regimens of RT and chemo-radiotherapy, explore potential new therapies such as targeted therapy, immunotherapy and combination therapies, and identify biomarkers to guide appropriate patient and treatment selection.
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Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Anciano , Neoplasias Encefálicas/tratamiento farmacológico , Quimioradioterapia , Terapia Combinada , Glioblastoma/tratamiento farmacológico , Humanos , Inmunoterapia , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
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Neoplasias Encefálicas , Imágenes de Resonancia Magnética Multiparamétrica , Neoplasias de Células Germinales y Embrionarias , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Perfusión , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias TesticularesRESUMEN
BACKGROUND: Adjuvant temozolomide (TMZ) chemotherapy with standard regimen remarkably improves survival in patients with high-grade glioma (HGG). However, the influence of long-term TMZ chemotherapy on serum ions concentration is unclear. METHODS: One hundred and thirty-eight patients with HGG were included. Their blood samples were collected for blood biochemistry and routine test. The alteration in serum ions concentration, total protein, albumin, globin, and blood cells counts were used to identify the impact of long-term TMZ chemotherapy. RESULTS: Through the comparation of quantitative value of diverse parameters among different chemotherapy cycles, we identified that serum potassium concentration had a downward trend after TMZ administration (1st vs. 6th, p < 0.001; 1st vs. 12th, p < 0.001). Additionally, the correlation analysis showed that platelets was negatively correlated with chemotherapy cycles (r = - 0.649, p = 0.023). The hematological adverse events mainly centered on grade 1 to 2. CONCLUSION: Long-term administration of TMZ may lead to serum ions disturbance. Besides the myelosuppression, we should pay attention to the alteration in serum ions concentration, and give patients proper symptomatic treatment when necessary.
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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.
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Neoplasias de Células Germinales y Embrionarias , Calidad de Vida , Ansiedad , Niño , Depresión , Humanos , Recurrencia Local de Neoplasia , Neoplasias de Células Germinales y Embrionarias/terapia , Encuestas y Cuestionarios , SobrevivientesRESUMEN
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.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Cromosomas Humanos Par 1 , Glioma/genética , Glioma/radioterapia , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Clasificación del Tumor , Modelos de Riesgos ProporcionalesRESUMEN
PURPOSE: Patients with grade II/III diffuse glioma (lower grade glioma, LGG) with isocitrate dehydrogenase wild-type (IDH-wt) and telomerase reverse-transcriptase promoter mutation (TERTp-mut) experience shorter overall survival (OS) time than IDH mutant patients. The optimal treatment strategy for these patients is unclear. We compared the effects of radiotherapy (RT) alone vs. RT concurrent with temozolomide (TMZ) followed by adjuvant TMZ in these LGG patients. PATIENTS AND METHODS: Thirty-seven LGG patients with IDH-wt and TERTp-mut were randomly allocated to either RT alone treatment (RT group, n = 18; 60 Gy in 30 daily fractions) or RT concurrent with TMZ (75 mg/m2/d, 7 d/week) followed by adjuvant TMZ (CRT group, n = 19). The median follow-up duration was 17 months. Log-rank test was used for OS and PFS comparisons. RESULTS: The 1-year OS rate was 94.1% [95% confidence interval (CI) 82.9-100] in the CRT group and 74.6% (95% CI, 52.9-96.4) in the RT group. The median OS values in the CRT and RT groups were statistically different [25 vs. 17 months, respectively; hazard ratio (HR) 0.271; 95% CI, 0.092-0.793; P = 0.017], while PFS values were not (16 vs. 7 months, respectively; HR, 0.917; 95% CI, 0.397-2.120; P = 0.840). Multivariate analysis indicated that CRT treatment and female sex were associated with significantly longer OS (P = 0.001, P = 0.016, respectively). CONCLUSION: CRT treatment for IDH-wt/TERTp-mut grade II/III gliomas resulted in significantly longer OS than RT alone. Female sex was a significant favorable prognostic factor.