胶质母细胞瘤国际诊疗指南比较评价

胶质母细胞瘤是最常见的WHOⅣ级恶性胶质瘤,其特点是基因不稳定,临床特性难预测。尽管手术、放化疗等治疗手段不断进步,其预后仍然很差,中位生存期只有12~14个月。笔者从数据库和网络共检索到7个近年来不同国家发表的胶质母细胞瘤治疗指南或共识,结果显示,手术切除联合放疗和化疗仍然是胶质母细胞瘤的主要治疗手段,但是各国指南仍存在一些细节上的差异,如分子指标检测、化疗方案、复发后治疗方案等。本文通过对多国治疗指南比较,旨在为我国胶质母细胞瘤患者的治疗提供参考。     

多形性胶质母细胞瘤的治疗现状分析

多形性胶质母细胞瘤是颅内原发性恶性肿瘤之一。由于其生物学特征和中枢神经系统在解剖和生理机制方面的复杂性,传统治疗手段包括手术治疗、放射治疗和化学治疗,但是总体效果不佳。近些年来,随着对胶质母细胞瘤分子机制的理解以及在神经影像、手术、放疗技术和新药物方面取得的诸多进步,对于胶质母细胞瘤患者的预后有了一定的改善。本文对胶质母细胞瘤治疗的研究进展作一综述。     

多发脑胶质母细胞瘤的诊疗研究进展

多发脑胶质母细胞瘤是脑胶质母细胞瘤的一种少见亚型,其发病率相对较低,根据影像学特征进一步分为多灶性胶质母细胞瘤和多中心性胶质母细胞瘤;与单发胶质母细胞瘤相比,多发胶质母细胞瘤更具有异质性和侵袭性,预后更差.目前对于多发脑胶质母细胞瘤尚无标准治疗方案,多主张行手术治疗及辅助放疗和(或)化疗.本文通过对多发脑胶质母细胞瘤的...     

放疗联合免疫检查点抑制剂在胶质母细胞瘤治疗中的研究进展

胶质瘤是颅内最常见的原发性肿瘤,大部分患者表现为胶质母细胞瘤,发病率及致死率极高。尽管胶质母细胞瘤患者经过手术切除联合放、化疗的标准化治疗,但预后仍然很差。近年来,免疫治疗在多种实体肿瘤治疗中取得了突破性进展,但现有数据显示免疫治疗对提高胶质母细胞瘤患者生存期的效果不佳。然而研究表明,免疫治疗可以与放疗产生协同效应,放疗可以增加抗原呈递,并促进促炎性肿瘤微环境的形成,为免疫治疗提供更多相关靶点。本文旨在讨论放疗对肿瘤免疫微环境的影响,以及放疗联合免疫检查点抑制剂在胶质母细胞瘤治疗中的作用。     

肿瘤治疗电场在脑胶质母细胞瘤治疗中的现状与前景

肿瘤治疗电场是一种新的治疗方法,其通过低强度、中等频率的交变电场干扰肿瘤细胞有丝分裂,从而抑制肿瘤细胞增殖。在治疗复发胶质母细胞瘤患者的临床试验中,肿瘤治疗电场治疗组受试者与经验化疗组受试者相比生存期数据无显著性差异。而在治疗新发胶质母细胞瘤患者的临床试验中,肿瘤治疗电场联合替莫唑胺组受试者与替莫唑胺组受试者相比,生存期显著延长。鉴于肿瘤治疗电场在这两项Ⅲ期临床试验中的优异表现,其被美国国立综合癌症网络（NCCN）指南纳入复发和新发胶质母细胞瘤患者的一线治疗,其产品现已在美国、日本、以色列、中国香港获批准上市。本文对肿瘤治疗电场在脑胶质母细胞瘤治疗中的现状与前景进行综述。      

联合用药靶向胶质母细胞瘤样干细胞的治疗进展

胶质母细胞瘤作为常见的恶性胶质瘤,其等级系数高,致死性强.随着肿瘤干细胞理论的提出,为肿瘤靶向治疗提供了新的途径.通过联合用药抑制生长机制,阻止胶质母细胞瘤样干细胞的增殖,从而为靶向治疗恶性胶质瘤提供了可能.本文就联合用药靶向胶质母细胞瘤样干细胞进行简要综述.     

胶质母细胞瘤经典亚型特征性基因变异的研究进展

目的 胶质母细胞瘤(Glioblastoma,GBM)是颅内最常见的原发恶性肿瘤,其恶性程度高、侵袭能力强、预后差。近年来随着生物学技术的发展,对GBM的理解也从病理学诊断逐步转向分子病理机制的研究。根据基因表达和DNA甲基化的模式将原发性GBM分为经典型、间质型、前神经元型和神经元型四种亚型。这些分子分型与胶质母细胞瘤的生物学特性密切相关。本文简要介绍了原发胶质母细胞瘤的分子分型,重点关注经典型GBM中EGFR、PTEN、PI3K和CDKN2A四种特征性基因的变异情况,并且对经典型胶质母细胞瘤的治疗策略进行了探讨。     

胶质母细胞瘤脂肪酸代谢与化疗耐药性关系的研究进展

细胞在癌变的过程中代谢模式会发生显著变化,涉及糖、脂质、氨基酸和核酸代谢等方面。 正是由于这些重要代谢 途径的异常激活和重新编程,赋予癌细胞无限增殖潜能和恶性生物学特征。 胶质母细胞瘤的代谢重编程也是肿瘤发生发展 过程中的显著特征之一,其中脂肪酸代谢在能量储存、细胞增殖、重要信号分子合成及化疗耐药方面发挥着重要作用。 目前 胶质母细胞瘤的治疗仍然面临巨大挑战,对标准治疗药物替莫唑胺产生耐药性是治疗难点之一。 与初发胶质母细胞瘤细胞 相比,化疗耐药的胶质母细胞瘤细胞表现出更加活跃的脂肪酸代谢能力。 伴随肿瘤相关代谢重编程的细胞内外代谢物的改 变,对基因表达、细胞分化和肿瘤微环境具有深远的影响。 化疗耐药的胶质母细胞瘤细胞的脂肪酸代谢关键酶及调节因子上 调,脂肪酸外源性摄取、从头合成及氧化能力增强,在治疗应激时为细胞提供主要的能量支持。 因此,靶向胶质母细胞瘤脂肪 酸代谢途径可能成为攻克胶质母细胞瘤化疗耐药的新策略。     

《中国肿瘤临床》文章推荐:肿瘤治疗电场在脑胶质母细胞瘤治疗中的现状与前景

肿瘤治疗电场是一种新的治疗方法,其通过低强度、中等频率的交变电场干扰肿瘤细胞有丝分裂,从而抑制肿瘤细胞增殖。在治疗复发胶质母细胞瘤患者的临床试验中,肿瘤治疗电场治疗组受试者与经验化疗组受试者相比生存期数据无显著性差异。而在治疗新发胶质母细胞瘤患者的临床试验中,肿瘤治疗电场联合替莫唑胺组受试者与替莫唑胺组受试者相比,生存期显著延长。鉴于肿瘤治疗电场在这两项Ⅲ期临床试验中的优异表现,其被美国国立综合癌症网络指南纳入复发和新发胶质母细胞瘤患者的一线治疗,其产品现已在美国、日本、以色列、中国香港获批准上市。为进一步了解肿瘤治疗电场在脑胶质母细胞瘤治疗中的现状与前景,2019年第24期《中国肿瘤临床》特邀首都医科大学附属北京天坛医院神经外科李文斌教授撰写《肿瘤治疗电场在脑胶质母细胞瘤治疗中的现状与前景》一文,为胶质母细胞瘤患者的一线治疗提供参考。     

基于Oncomine数据库及GEPIA数据库分析CHI3L2基因在胶质母细胞瘤中的表达及与预后的相关性

目的:基于Oncomine数据库及GEPIA数据库分析CHI3L2基因在胶质母细胞瘤中的表达及与预后的相关性。方法:检索Oncomine和GEPIA数据库中相关胶质母细胞瘤的数据集,分析胶质母细胞瘤组织与正常对照组织之间基因表达的差异,采用GEPIA数据库进行在线生存分析。结果:Oncomine数据库中共收集了449项关于CHI3L2基因在肿瘤与正常组织中表达比较的研究结果,表达差异有统计学意义的研究结果有23项,其中有9项研究结果呈高表达,14项研究结果呈低表达。与对照组相比,在胶质母细胞瘤组织中CHI3L2的表达显著高于正常组织（P＜0.05）。结论:CHI3L2在胶质母细胞瘤组织中呈高表达,且与胶质母细胞瘤患者预后相关,为临床胶质母细胞瘤的治疗及基因靶向药物的研制提供重要理论依据。     

Glioblastoma targeted therapy: updated approaches from recent biological insights

Glioblastoma (WHO grade IV astrocytoma) is the most frequent primary brain tumor in adults, representing a highly heterogeneous group of neoplasms that are among the most aggressive and challenging cancers to treat. An improved understanding of the molecular pathways that drive malignancy in glioblastoma has led to the development of various biomarkers and the evaluation of several agents specifically targeting tumor cells and the tumor microenvironment. A number of rational approaches are being investigated, including therapies targeting tumor growth factor receptors and downstream pathways, cell cycle and epigenetic regulation, angiogenesis and antitumor immune response. Moreover, recent identification and validation of prognostic and predictive biomarkers have allowed implementation of modern trial designs based on matching molecular features of tumors to targeted therapeutics. However, while occasional targeted therapy responses have been documented in patients, to date no targeted therapy has been formally validated as effective in clinical trials. The lack of knowledge about relevant molecular drivers in vivo combined with a lack of highly bioactive and brain penetrant-targeted therapies remain significant challenges. In this article, we review the most promising biological insights that have opened the way for the development of targeted therapies in glioblastoma, and examine recent data from clinical trials evaluating targeted therapies and immunotherapies. We discuss challenges and opportunities for the development of these agents in glioblastoma.     

Mechanisms of disease: temozolomide and glioblastoma--look to the future

Glioblastoma is both the most common and most aggressive primary brain tumor. Until recently, the standard of care involved maximal safe surgical resection followed by radiation therapy with or without nitrosourea-based chemotherapy. In 2005, the results of a large clinical trial examining the role of adjuvant chemotherapy in management of newly diagnosed glioblastoma were published. This study created a new standard of adjuvant treatment, using concurrent and sequential temozolomide in the initial therapy of glioblastoma. A companion tumor biology study identified the prognostic role of O(6)-methylguanine-DNA methyltransferase (MGMT) status in patients with newly diagnosed glioblastoma. Several preliminary studies have been initiated to address the issue of resistance and suppression of MGMT activity, and have used alternative temozolomide dosing schedules and O(6)-guanine mimetic agents as substrates for MGMT. In addition, recent studies have attempted to define mechanisms responsible for the apparent synergy between temozolomide and radiotherapy. Lastly, an increased understanding of the molecular biology of glioblastoma has provided new leads for the adjuvant treatment of this disease. This Review summarizes new developments in treatment of glioblastoma and speculates on possible future treatment strategies for managing this aggressive cancer.     

Towards personalized therapy for patients with glioblastoma

Combined therapy with temozolomide and radiotherapy is a standard treatment and improves the survival for patients with newly diagnosed glioblastoma. However, the prognosis remains poor, with a median survival time of 12–15 months. Currently, several clinical trials of dose-dense temozolomide regimen or molecular-targeting therapies have been performed to overcome the resistance of glioblastoma. In these therapies, rational prognostic biomarkers have also been investigated to predict their outcome and response to treatment. This advanced understanding of the biological markers can help to develop personalized therapies for glioblastoma patients. Generally, due to a reduced tolerance, elderly patients do not seem to benefit from intensive treatment. This population needs individual treatments depended on their age or performance status. In this article, we review the recent studies that can provide personalized therapy for glioblastoma, based on molecular tumor profiling or patients’ physical status.     

Towards personalized therapy for patients with glioblastoma

Combined therapy with temozolomide and radiotherapy is a standard treatment and improves the survival for patients with newly diagnosed glioblastoma. However, the prognosis remains poor, with a median survival time of 12-15 months. Currently, several clinical trials of dose-dense temozolomide regimen or molecular-targeting therapies have been performed to overcome the resistance of glioblastoma. In these therapies, rational prognostic biomarkers have also been investigated to predict their outcome and response to treatment. This advanced understanding of the biological markers can help to develop personalized therapies for glioblastoma patients. Generally, due to a reduced tolerance, elderly patients do not seem to benefit from intensive treatment. This population needs individual treatments depended on their age or performance status. In this article, we review the recent studies that can provide personalized therapy for glioblastoma, based on molecular tumor profiling or patients' physical status.     

Bevacizumab and glioblastoma: Scientific review,newly reported updates,and ongoing controversies

Anti‐angiogenic therapy for glioblastoma has been in the spotlight for several years, as researchers and clinicians strive to find agents with meaningful efficacy against glioblastoma. Bevacizumab in particular, in the second half of the last decade, became the most significant breakthrough in anti‐glioblastoma therapy since temozolomide. Optimism for bevacizumab has been somewhat challenged given recent clinical trials that have raised questions regarding its clinical effectiveness, the optimal timing of its use and the validity of endpoints, among other issues. In addition, uncertainty has recently arisen regarding the effects of bevacizumab on quality of life and neurocognitive function, two key clinical endpoints of unquestionable significance among glioblastoma patients. In this review, we highlight these controversies and other recent work related to bevacizumab for glioblastoma. Cancer 2015;121:997–1007. © 2014 American Cancer Society.     

Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells

The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma, making it a compelling molecular target for therapy. We have recently shown that coexpression of EGFRvIII and PTEN protein by glioblastoma cells is strongly associated with clinical response to EGFR kinase inhibitor therapy. PTEN loss, by dissociating inhibition of the EGFR from downstream phosphatidylinositol 3-kinase (PI3K) pathway inhibition, seems to act as a resistance factor. Because 40% to 50% of glioblastomas are PTEN deficient, a critical challenge is to identify strategies that promote responsiveness to EGFR kinase inhibitors in patients whose tumors lack PTEN. Here, we show that the mammalian target of rapamycin (mTOR) inhibitor rapamycin enhances the sensitivity of PTEN-deficient tumor cells to the EGFR kinase inhibitor erlotinib. In two isogenic model systems (U87MG glioblastoma cells expressing EGFR, EGFRvIII, and PTEN in relevant combinations, and SF295 glioblastoma cells in which PTEN protein expression has been stably restored), we show that combined EGFR/mTOR kinase inhibition inhibits tumor cell growth and has an additive effect on inhibiting downstream PI3K pathway signaling. We also show that combination therapy provides added benefit in promoting cell death in PTEN-deficient tumor cells. These studies provide strong rationale for combined mTOR/EGFR kinase inhibitor therapy in glioblastoma patients, particularly those with PTEN-deficient tumors.     

A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma

Glioblastoma, the most common primary malignant brain tumor among adults, is a highly angiogenic and deadly tumor. Angiogenesis in glioblastoma, driven by hypoxia-dependent and independent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encouraging rates of radiographic response and progression-free survival, and adequate safety, led the FDA to grant accelerated approval of bevacizumab, a humanized monoclonal antibody against VEGF, for the treatment of recurrent glioblastoma in May 2009. These results have triggered significant interest in additional antiangiogenic agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antipermeability effect of VEGF inhibitors, the Radiologic Assessment in Neuro-Oncology (RANO) criteria were recently implemented to better assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mechanisms to VEGF inhibitors and identification of effective therapy after bevacizumab progression are currently a critical need for patients with glioblastoma.     

胶质母细胞瘤恶性亚型形成与临床相关性探讨

胶质母细胞瘤（glioblastoma,GBM）是一种最常见恶性的原发性脑肿瘤,即使行标准化治疗后,患者中位总生存期仅12～16个月。GBM的治疗瓶颈主要来自于肿瘤的异质性。近年来,单细胞组学和细胞生物学研究的进展揭示了GBM中转录组亚型的混合和交互转化与其治疗效果密切相关。本文从GBM亚型分布特点,重点对恶性亚型（间充质亚型）形成及转化过程中的分子机制及环境因素进行综述,并讨论表型重塑相关机制,研究其在逆转胶质母细胞临床治疗抗性中的应用前景。      

Treatment modalities for malignant gliomas with reference to their pathophysiology

The histological classification, pathophysiology, and treatment modalities of malignant gliomas (glioblastoma, malignant astrocytoma) were reviewed with reference to the WHO classification of primary brain tumors and the recent progress made in glioma biology. Patients with glioblastoma and malignant astrocytoma showed, respectively, 10.6% and 22.2 of the five-year survival rate according to the All Japan Brain Tumor Registry. In order to improve the prognosis of malignant glioma patients, many clinical trials have been conducted throughout the world. Malignant gliomas that grow in and invade the brain parenchyma cannot be cured by surgical resection. One should treat the residual tumor with irradiation, chemotherapy and immunotherapy. Radiation therapy alone and radiation therapy plus chemotherapy using nitrosoureas or procarbazine have been proved statistically to be more effective for malignant gliomas than supportive care and radiation therapy alone, respectively. Prospective clinical trials support the view that malignant gliomas should be treated vigorously using a multimodal approach that includes surgical resection, high-dose radiation therapy, and prolonged maintenance chemotherapy.