Identification of intrinsic subtype-specific prognostic microRNAs in primary glioblastoma

Background

Glioblastoma multiforme (GBM) is the most malignant type of glioma. Integrated classification based on mRNA expression microarrays and whole–genome methylation subdivides GBM into five subtypes: Classical, Mesenchymal, Neural, Proneural-CpG island methylator phenotype (G-CIMP) and Proneural-non G-CIMP. Biomarkers that can be used to predict prognosis in each subtype have not been systematically investigated.

Methods

In the present study, we used Cox regression and risk-score analysis to construct respective prognostic microRNA (miRNA) signatures in the five intrinsic subtypes of primary glioblastoma in The Cancer Genome Atlas (TCGA) dataset.

Results

Patients who had high-risk scores had poor overall survival compared with patients who had low-risk scores. The prognostic miRNA signature for the Mesenchymal subtype (four risky miRNAs: miR-373, miR-296, miR-191, miR-602; one protective miRNA: miR-223) was further validated in an independent cohort containing 41 samples.

Conclusion

We report novel diagnostic tools for deeper prognostic sub-stratification in GBM intrinsic subtypes based upon miRNA expression profiles and believe that such signature could lead to more individualized therapies to improve survival rates and provide a potential platform for future studies on gene treatment for GBM.     

Role of microRNAs in glioblastoma

Glioblastoma is the most common and aggressive primary human brain cancer. MicroRNAs (miRNAs) are a set of small endogenous non-coding RNA molecules which play critical roles in different biological processes including cancer. The realization of miRNA regulatory functions in GBM has demonstrated that these molecules play a critical role in its initiation, progression and response to therapy. In this review we discuss the studies related to miRNA discovery and function in glioblastoma. We first summarize the typical miRNAs and their roles in GBM. Then we debate the potential for miRNA-based therapy for glioblastoma, including various delivery strategies. We surmise that future directions identified by these studies will point towards the necessity for therapeutic development and optimization to improve the outcomes for patients with glioblastoma.     

Targeting apoptosis pathways in glioblastoma

The treatment of glioblastoma remains a major challenge for clinicians since these highly aggressive brain tumors are relatively resistant towards radio- and chemotherapy. The pathways that control apoptosis are altered in glioblastoma cells leading to resistance towards apoptotic stimuli in general. In this review we describe the alterations affecting the p53 pathway, the BCL-2 protein family, the inhibitor of apoptosis proteins and several growth factor pathways involved in the regulation of programmed cell death and define possible targets for new therapies within these apoptotic pathways in glioblastomas. Moreover, we review strategies to target death receptor pathways, most notably to render the glioblastoma cells more susceptible towards this approach without enhancing toxicity in general. Most of the strategies targeting apoptosis in glioblastomas presented here are in a pre-clinical stage of development, however, they all share the ultimative goal to improve the outcome for glioblastoma patients.     

Possible explanation of radioresistance of glioblastoma in situ

The response of human glioblastoma to radiation was studied in the logarithmic phase and in the plateau phase of growth, and was compared with those of HeLa S3 irradiated under identical conditions. There was no major difference in the in vitro survival curve parameters between glioblastoma and HeLa in the logarithmic growth phase. However, the surviving fractions for glioblastoma with radiation doses in the range used clinically were higher not only when irradiated in the logarithmic growth phase, but also when subcultured 6 hours after irradiation in the plateau phase, than those for HeLa treated under identical conditions. This suggests that the relatively low cure rate of glioblastoma can be partially explained by the intrinsic radiosensitivity in the logarithmic growth phase and by a high surviving fraction for cells irradiated in the plateau phase.     

人脑胶质母细胞瘤微循环模式观察

背景与目的:胶质母细胞瘤是一种以微血管增生为特征的高度血管化的异生组织,但现有的抗血管生成药物对胶质瘤的治疗效果却不尽如人意。本文通过分析胶质母细胞瘤的微循环模式,为更好地理解胶质母细胞瘤的微循环构筑和靶向肿瘤养分供给系统的治疗提供新的视角。方法:采用CD34-PAS双重染色技术分析胶质母细胞瘤的微循环构筑。结果:胶质母细胞瘤的微血管密度大于正常脑组织,两者差异有统计学意义(P<0.001)。胶质母细胞瘤中存在血管内皮依赖性血管、肿瘤细胞依赖性血管、细胞外基质依赖性血管和马赛克血管4种微循环模式。结论:胶质母细胞瘤的微循环模式具有异质性。     

Nonsurgical treatment of recurrent glioblastoma

Standard treatment for glioblastoma multiforme is surgery followed by radiotherapy and chemotherapy, generally with temozolomide. However, disease recurs in almost all patients. Diagnosis of progression is complex given the possibility of pseudoprogression.The Response Assessment in Neuro-Oncology criteria increase the sensitivity for detecting progression. Most patients will not be candidates for new surgery or re-irradiation, and anticancer drugs are the most common approach for second-line treatment, if the patient’s condition allows. Antiangiogenics, inhibitors of the epidermal growth factor receptor, nitrosoureas, and re-treatment with temozolomide have been studied in the second line, but a standard therapy has not yet been established. This review considers currently available medical treatment options for patients with glioblastoma recurrence.     

微小RNA与肿瘤相关性

微小RNA(miRNA)在动植物体内形成RNA沉默复合体,介导目的基因mRNA的切割与翻译抑制,产生转录后基因沉默效应,调控基因的表达,从而调节生物发育、细胞分化与凋亡,参与肿瘤、复杂遗传病的发生及其他生命过程。近年来,在有关miRNA和肿瘤发生研究领域取得了一系列进展。     

胶质母细胞瘤术后热疗同步放化疗初步生存分析

目的:初步探讨已行肿瘤切除术的胶质母细胞瘤(GBM)患者热疗同步放化疗是否延长患者生存期。方法:回顾分析2016—2019年间郑州大学第一附属医院61例GBM术后患者,根据治疗方式不同分为对照组34例,观察组27例。对照组采用三维放疗60 Gy联合替莫唑胺化疗,观察组在对照组基础上同步40~41℃,15~20次热疗。 ...     

微小RNA与肿瘤相关性

微小RNA（miRNA）在动植物体内形成RNA沉默复合体,介导目的基因mRNA的切割与翻译抑制,产生转录后基因沉默效应,调控基因的表达,从而调节生物发育、细胞分化与凋亡,参与肿瘤、复杂遗传病的发生及其他生命过程。近年来,在有关miRNA和肿瘤发生研究领域取得了一系列进展。     

多形性胶质母细胞瘤的适形放疗新进展

多形性胶质母细胞瘤(glioblastoma multiforme, GBM)是最常见的脑胶质瘤之一,为高分级脑胶质瘤,放疗是其重要的治疗手段。Chang等研究表明,接受肿瘤局部放疗患者的中位生存时间(7个     

MiR-152 functions as a tumor suppressor in glioblastoma stem cells by targeting Krüppel-like factor 4

Glioblastoma (GBM) is the most common central nervous system tumor and the molecular mechanism driving its development is still largely unknown, limiting the treatment of this disease. In the present study, we explored the potential role of miR-152 in glioblastoma stem cells (GSCs) as well as the possible molecular mechanisms. Our results proved that miR-152 was down-regulated in human GSCs. Restoring the expression of miR-152 dramatically reduced the cell proliferation, cell migration and invasion as well as inducing apoptosis. Mechanistic investigations defined Krüppel-like factor 4 (KLF4) as a direct and functional downstream target of miR-152, which was involved in the miR-152-mediated tumor-suppressive effects in GSCs. Meanwhile, this process was coincided with the down-regulated LGALS3 that could be bound and promoted by KLF4, leading to attenuate the activation of MEK1/2 and PI3K signal pathways. Moreover, the in vivo study showed that miR-152 over-expression and KLF4 knockdown produced the smallest tumor volume and the longest survival in nude mice. Taken together, these results elucidated the function of miR-152 in GSCs progression and suggested a promising application of it in glioma treatment.     

Super fractionation in glioblastoma multiforme-results of a phase II study

A suquential series of 30 patients who were referred to a cancer treatment hospital with glioblastoma multiforme were treated with superfractionated cobalt 60 y radiation, three treatments per day, 100 rad per fraction. Their survival was compared to that of a historical group of 90 patients who had been referred for the same disease. Survival of the study patients was significantly longer than the historical patients, both for those who underwent resection (48.6 weeks median survival vs. 35.1 weeks), and for those who did not (35.1 weeks vs. 11.7 weeks). A retrospective survey of the historical group led to the following conclusions about this group: 1. Survival for patients who were well enough to be referred was unchanged after steroids came into general use; 2. Younger patients (under 50 years) did not have a longer survival than older patients; 3. The size of the dose of irradiation did not affect survival over the range of doses employed; 4. The size of the treatment volume employed did not affect survival over the range of treatment volumes employed.     

Utilization of hypofractionated radiation therapy in older glioblastoma patients

Background

Though the optimal treatment regimen in older patients with glioblastoma multiforme (GBM) remains to be established, multiple randomized studies have supported the use of hypofractionated (1–3?weeks) versus traditional regimens (6?weeks). Here we examine hypofractionated regimen practice patterns among older patients with GBM.

Epithelioid glioblastoma: a case report

A 43-year-old woman who had undergone breast cancer surgery 1 year previously complained of headache and nausea. Her brain computed tomography (CT) scan and magnetic resonance imaging (MRI) showed a well-circumscribed, heterogeneously enhanced tumor in the right thalamus. She underwent gross total resection of the tumor followed by radiochemotherapy, and her clinical course was uneventful after surgery. Histological examination revealed a moderate number of tumor cells with fine bipolar processes in a mucoid matrix, which suggested pilocytic astrocytoma. The tumor was associated with microvascular proliferation but did not show significant mitosis or necrosis. In some areas, it had an epithelioid appearance, with ribbon-like, cribriform, and pseudoglandular patterns involving cuboid-shaped cells showing nuclear atypia and mitotic figures. Immunohistochemically, the tumor cells were positive for glial fibrillary acidic protein (GFAP) and vimentin in the area resembling pilocytic astrocytoma, but in the epithelioid area they were negative for GFAP and vimentin as well as for breast cancer markers, including AE1/AE3. The proliferating potential, represented by the MIB-1 labeling index, was high (82.5%) in the area of epithelioid appearance, compared to only 3% in the area of pilocytic astrocytoma-like appearance. As a rare histoarchitectural variant of glioblastoma, the epithelioid pattern may represent a very primitive tumor cell phenotype. Typically, this pattern is characterized by well-circumscribed masses, although its clinical significance is unknown.     

Dapsone induced methemoglobinemia in a patient with glioblastoma

Primary brain tumor patients have multiple risk factors for Pneumocystis jiroveci and may require prophylaxis with TMP-SMZ or dapsone. Although dapsone is generally safe and efficacious, we present a case of a patient diagnosed with a brain stem glioblastoma who developed methemoglobinemia and haemolytic anemia after presenting with worsening confusion and cardiopulmonary system dysfunction. This case highlights one of the potentially severe complications associated with dapsone therapy. Although this illustrates an unusual toxicity of dapsone, a high index of suspicion should be given to high-risk patients due to ethnic heritage, anemia, or advanced age. Furthermore, given the toxicities of TMP-SMZ and dapsone, further work is needed to determine the threshold CD4⁺ count at which empiric prophylaxis should be initiated.     

Molecular targeted therapy of glioblastoma

Glioblastomas are intrinsic brain tumors thought to originate from neuroglial stem or progenitor cells. More than 90% of glioblastomas are isocitrate dehydrogenase (IDH)-wildtype tumors. Incidence increases with age, males are more often affected. Beyond rare instances of genetic predisposition and irradiation exposure, there are no known glioblastoma risk factors. Surgery as safely feasible followed by involved-field radiotherapy plus concomitant and maintenance temozolomide chemotherapy define the standard of care since 2005. Except for prolonged progression-free, but not overall survival afforded by the vascular endothelial growth factor antibody, bevacizumab, no pharmacological intervention has been demonstrated to alter the course of disease. Specifically, targeting cellular pathways frequently altered in glioblastoma, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), the p53 and the retinoblastoma (RB) pathways, or epidermal growth factor receptor (EGFR) gene amplification or mutation, have failed to improve outcome, likely because of redundant compensatory mechanisms, insufficient target coverage related in part to the blood brain barrier, or poor tolerability and safety. Yet, uncommon glioblastoma subsets may exhibit specific vulnerabilities amenable to targeted interventions, including, but not limited to: high tumor mutational burden, BRAF mutation, neurotrophic tryrosine receptor kinase (NTRK) or fibroblast growth factor receptor (FGFR) gene fusions, and MET gene amplification or fusions. There is increasing interest in targeting not only the tumor cells, but also the microenvironment, including blood vessels, the monocyte/macrophage/microglia compartment, or T cells. Improved clinical trial designs using pharmacodynamic endpoints in enriched patient populations will be required to develop better treatments for glioblastoma.     

Feasibility and clinical usefulness of modelling glioblastoma migration in adjuvant radiotherapy

Glioblastoma (GBM) is one of the most common primary brain tumours in adults, with a dismal prognosis despite aggressive multimodality treatment by a combination of surgery and adjuvant radiochemotherapy. A detailed knowledge of the spreading of glioma cells in the brain might allow for more targeted escalated radiotherapy, aiming to reduce locoregional relapse. Recent years have seen the development of a large variety of mathematical modelling approaches to predict glioma migration.The aim of this study is hence to evaluate the clinical applicability of a detailed micro- and meso-scale mathematical model in radiotherapy. First and foremost, a clinical workflow is established, in which the tumour is automatically segmented as input data and then followed in time mathematically based on the diffusion tensor imaging data. The influence of several free model parameters is individually evaluated, then the full model is retrospectively validated for a collective of 3 GBM patients treated at our institution by varying the most important model parameters to achieve optimum agreement with the tumour development during follow-up. Agreement of the model predictions with the real tumour growth as defined by manual contouring based on the follow-up MRI images is analyzed using the dice coefficient.The tumour evolution over 103-212 days follow-up could be predicted by the model with a dice coefficient better than 60% for all three patients. In all cases, the final tumour volume was overestimated by the model by a factor between 1.05 and 1.47.To evaluate the quality of the agreement between the model predictions and the ground truth, we must keep in mind that our gold standard relies on a single observer's (CB) manually-delineated tumour contours. We therefore decided to add a short validation of the stability and reliability of these contours by an inter-observer analysis including three other experienced radiation oncologists from our department. In total, a dice coefficient between 63% and 89% is achieved between the four different observers. Compared with this value, the model predictions (62-66%) perform reasonably well, given the fact that these tumour volumes were created based on the pre-operative segmentation and DTI.