脑胶质瘤免疫治疗研究进展

胶质瘤是最常见的脑肿瘤，约占颅内肿瘤总数的４０％。由于胶质瘤呈浸润性生长，手术后几乎无一例外地复发，预后很差，探索有效的辅助治疗措施很有必要。脑胶质瘤的免疫治疗是继手术，放疗，化疗之后的第４种治疗方法。本文综述了脑胶质瘤的过继性免疫治疗，免疫导向治疗，肿瘤疫苗疗法和免疫基因治疗的研究进展。     

脑胶质瘤的综合治疗

根据世界卫生组织1992年的统计,随地区和种族不同,原发性脑肿瘤（包括良性和恶性）的年发病率为2～19/10万人[1],其中原发良性脑肿瘤约占40％。在美国,原发恶性脑肿瘤的发病率为6.6/10万人[2],在所有的原发性脑肿瘤中约60％为胶质细胞瘤,其中大多数为高度恶性的星形细胞瘤。由于大多数胶质瘤呈浸润性生长,所以治疗十分困难。神经外科领域的二大革命(以CT问世为划时代标志的影像学诊断技术的进步和显微神经外科技术的应用)对神经外科的发展起了巨大的促进作用,然而,对恶性脑肿瘤的治疗似乎并没有突破性进展,恶性胶质瘤大多(77％)在确诊后一年内死亡。因此,如何提高恶性脑肿瘤特别是胶质瘤的治疗效果,是摆在我们面前的艰巨任务。     

Notch信号通路与脑胶质瘤干细胞的niche

研究表明极少数量肿瘤干细胞存在于脑胶质瘤中,但在其发生发展中起关键作用.脑胶质瘤干细胞与为其提供结构和功能支持的血管niche关系密切.在脑胶质瘤niche中,血管内皮细胞可以提供Notch配体给肿瘤干细胞,激活Notch信号通路,并与其他信号通路构成串话,维持肿瘤干细胞的自我更新,增加脑肿瘤干细胞对放疗的抵抗性.因此,Notch信号通路被认为是脑胶质瘤新的治疗靶点.     

CD44v6、MMP-9在脑转移瘤及恶性胶质瘤中的表达及意义

目的探讨CD44v6和基质金属蛋白酶MMP-9在脑转移瘤及恶性胶质瘤侵袭行为中的作用。方法应用免疫组织化学S-P法检测CD44v6和MMP-9在良性脑肿瘤、恶性胶质瘤和脑内转移瘤中的表达情况。结果CD44v6在脑内转移瘤中的表达明显高于正常脑组织、良性脑肿瘤组织和恶性胶质瘤组织(P<0.01),后三者CD44v6的表达无明显差异(P>0.05)。MMP-9在恶性脑肿瘤(恶性胶质瘤和脑内转移瘤)中的表达明显高于正常脑组织和良性肿瘤组织(P<0.01),但MMP-9在恶性胶质瘤和脑内转移瘤组织中的表达无明显差异(P>0.05)。结论CD44v6、MMP-9在脑内转移瘤的侵袭、转移中发挥着重要作用。其中CD44v6可作为脑内转移瘤的转移表型,MMP-9则体现脑内转移瘤和恶性胶质瘤的基质降解表型。     

蛋白质组技术在脑胶质瘤研究中的应用进展

脑胶质瘤是最常见的脑肿瘤，对脑胶质瘤的研究仍是当前的热点与难点。由于蛋白质组学技术具有大通量研究蛋白质组成和蛋白质差异的作用。已有研究将其用于胶质瘤特异性生物学标志物的鉴定、预后的评估、对治疗的反应及其生物学特性的研究中。本文就蛋白质组学技术的基本技术平台和在脑胶质瘤诊断、鉴别诊断、对治疗敏感性及反应和胶质瘤侵袭性研究中的进展作一综述。     

脑肿瘤p16基因缺失，突变及5’CpG岛甲基化研究

目的：探讨不同种类的脑肿瘤P16基因变异及其与脑肿瘤的发生,发展的关系。方法：利用PCR,PCR－SSCP及PCR－based甲基化技术检测了56例胶质瘤,15例脑膜瘤及2例原发性脑淋巴瘤P16基因缺失,突变及5’CpG岛甲基化状况,结果：18例高病理级别的脑胶质瘤及1例原发性脑淋巴瘤发生P16基因缺失;6例脑胶质瘤及1例原发性脑淋巴瘤发生P16基因5’CpG岛甲基化,无1例发生P16基因突变。结论：P16基因失活可能参与脑胶质瘤的发生,恶性进展及原发性脑淋巴瘤的发生,P16基因缺失是P16基因失活的主要机制。     

放射性同位素^32P治疗脑肿瘤的初步观察

目的：探讨放射性同位素^32P治疗脑肿瘤的疗效。方法：采用立体定向仪和开颅手术方法,通过肿瘤囊内注入和术中肿瘤残腔内放入放射性同位素^32P胶体。结果：14例患者中,3例颅咽管瘤瘤体缩小。3例脑转移瘤和8例脑胶质瘤疗效满意,毒副反应轻微。结论：放射性同位素^32P胶体治疗脑肿瘤有良好的效果。     

脑胶质瘤诊疗进展

尽管目前脑胶质瘤的诊断随着WHO诊断指南的更新在不断改变,但是目前的治疗方法依然以手术治疗为主、辅以放疗和化疗。高级别脑胶质瘤的治疗效果仍不如人意,如何改善患者预后是目前医学探索脑胶质瘤领域的重点问题。目前脑胶质瘤的诊疗研究涌现出许多新思路、新方法,其中以电场治疗为代表的一部分临床试验取得了较好的效果,此外,免疫治疗领域和靶向治疗领域也有了一定的进展。本文旨在分享、探讨这些新方法,总结脑胶质瘤诊疗进展。     

聚酸酐控释片瘤内化疗治疗脑胶质瘤的进展

 恶性脑胶质瘤是脑肿瘤中最富挑战性的肿瘤之一,约占脑肿瘤发病率的百分之四十左右,由于肿瘤呈浸润性生长,使各种治疗手段均难以达到根治程度。尽管近年来在影像诊断技术、神经外科手术技术、放疗、化疗及肿瘤学研究等方面已经取得了很大进展,但恶性脑胶质瘤病人总的预后仍然很差,绝大多数患者经过手术、放疗和传统化疗之后复发,并在一年以内死亡[1,2]。因此,国内外学者力图寻找多种给药方法来改善恶性脑胶质瘤的预后效果。鉴于恶性脑胶质瘤基本在原位2厘米范围内复发且极少发生转移[3],近年来高分子药物释放技术瘤内化疗治疗恶性脑胶质瘤引起人们的高度重视,并取得了较好的预后效果[4,5]。自八十年代末,Brem[6,7]等采用生物可降解聚合物药物控制释放技术,开展了卡氮芥(BCNU)一聚酸酐控释片(商品名:Gliadel)瘤内辅助化疗治疗恶性脑胶质瘤新方法的研究,并取得了较好的临床治疗效果。在对大量临床试验结果反复论证后,美国FDA于1996年批准Gliadel控释片用于治疗复发多形性胶质母细胞瘤(GBM)[8],这是近20年来美国推出的第一个治疗脑胶质瘤的新剂型。最近,Gliadel已获欧美等十几个国家的批准应用于临床。     

荧光示踪指导下高侵袭性胶质瘤的手术治疗

1 原理 胶质瘤是颅内最常见的原发性脑肿瘤,占恶性脑肿瘤的80％[1].目前脑胶质瘤的治疗仍以手术为主,术后加以放疗与化疗,但是预后不佳,胶质母细胞瘤患者的平均生存时间仅为12-15月[2].胶质瘤患者的预后与年龄、肿瘤部位、术前基础状态等许多因素有关.最新研究报道,肿瘤的切除程度影响患者预后,增加肿瘤的切除程度可以改善预后,延长生存时间[3].因此应对胶质瘤治疗增加肿瘤的切除程度,尤其是肿瘤边界的切除程度,只有这样才能改善患者的预后.     

Radiothérapie en conditions stéréotaxiques des gliomes de haut grade : une revue de la littérature

The purpose of this literature systematic review was the use of stereotactic radiotherapy in glioma. Research was performed in Medline/PubMed and associated references found in published articles without publication date limit. The quality of series is variable and many biases can be evidenced. Only two randomized trials have been published using stereotactic radiotherapy for up-front treatment. There is a lack of evidence of survival advantages to use this treatment at the time of diagnosis or relapse. There is also insufficient evidence regarding the benefice/harms in the use of stereotactic fractionated radiation therapy for patients with glioma. No recommendations can be enounced. Stereotactic irradiation as boost in primary diagnosed glioma or relapsed tumour is not associated with survival improvement. For relapsed patients, treatment needs to be discussed according to the other treatment options.     

嵌合抗原受体T细胞治疗多形性胶质母细胞瘤的最新进展

多形性胶质母细胞瘤（glioblastoma multiforme,GBM）是恶性程度最高的脑胶质瘤,传统手术结合放、化疗疗效有限。嵌合抗原受体是由单一分子组成的抗原重组受体,重新定向T细胞的特异性和功能,由CD28或4-1BB构成的第二代CAR-T能识别抗原,完全活化T细胞并增强T细胞功能和持久性,是新兴GBM疗法的关注焦点。本文从CAR-T研究现状出发,主要介绍其发展历程和GBM相关的有效靶点,综述其理论基础,着重以白介素13受体α2、表皮生长因子受体变异Ⅶ、人表皮生长因子受体2和酪氨酸蛋白激酶受体A2这四种胶质瘤相关抗原为例,探讨靶点的结构、功能特性、前期研究和临床研究前景。选择性表达在GBM的白介素13受体α2在临床Ⅰ期治疗复发性GBM是安全有效的;表皮生长因子受体变异Ⅷ只存在于癌细胞和胶质母细胞瘤干细胞,与预后不良密切相关,正在进行Ⅰ、Ⅱ期临床试验;表皮生长因子受体2和酪氨酸蛋白激酶受体A也取得重大进展。这些特异性CAR-T可能成为治疗相应靶向阳性的GBM的重要免疫疗法。本文集中总结了目前CAR-T治疗GBM的应用价值及挑战。      

胶质瘤放疗中国专家共识(2017)中华医学会放射肿瘤治疗学分会

胶质瘤是指起源于神经胶质细胞的肿瘤,是最常见的原发性颅内肿瘤,WHO中枢神经系统肿瘤分类将胶质瘤分为WHO Ⅰ—Ⅳ级,WHOⅠ、Ⅱ级为低级别胶质瘤,Ⅲ、Ⅳ级为高级别胶质瘤。随着现代放疗技术的发展和放射生物学的深入研究,放射治疗已成为胶质瘤的重要治疗手段之一,不同级别胶质瘤的特点不同,放射治疗原则也不尽相同。2016年,我国发布了《中国中枢神经系统胶质瘤诊断与治疗指南》,阐述了胶质瘤的诊断和综合治疗策略,但目前国内尚无针对胶质瘤放疗的相关共识。因此,中华医学会放射肿瘤学分会胶质瘤共识撰写小组对胶质瘤放射治疗中的相关问题达成共识。该共识主要包括WHO Ⅲ、Ⅳ级胶质瘤、WHOⅡ级胶质瘤、弥漫性中线胶质瘤、室管膜瘤、恶性胶质瘤假性进展、胶质瘤脑脊液播散、老年和儿童胶质瘤患者等放疗相关问题。它将围绕临床工作中的焦点问题作出深入分析和归纳总结,力求进一步规范放射治疗技术在胶质瘤治疗中的应用,为大家的临床工作提供循证医学证据和实践指导。     

Angiogenesis and invasion in glioma

Despite advances in surgical and medical therapy, glioblastoma consistently remains a fatal disease. Over the last 20 years, no significant increase in survival has been achieved for patients with this disease. The formation of abnormal tumor vasculature and glioma cell invasion along white matter tracts are believed to be the major factors responsible for the resistance of these tumors to treatment. Therefore, investigation of angiogenesis and invasion in glioblastoma is essential for the development of a curative therapy. In our report, we first reviewed certain histopathological studies that focus on angiogenesis and invasion of human malignant gliomas. Second, we considered several animal models of glioma available for studying angiogenesis and invasion, including our novel animal models. Third, we focused on the molecular aspects of glioma angiogenesis and invasion, and the key mediators of these processes. Finally, we discussed the recent and ongoing clinical trials targeting tumor angiogenesis and invasion in glioma patients. A better understanding of the mechanism of glioma angiogenesis and invasion will lead to the development of new treatment methods.     

Recurrent Malignant Gliomas

In almost all patients, malignant glioma recurs following initial treatment with maximal safe resection, conformal radiotherapy, and temozolomide. This review describes the many options for treatment of recurrent malignant gliomas, including reoperation, alternating electric field therapy, chemotherapy, stereotactic radiotherapy or radiosurgery, or some combination of these modalities, presenting the evidence for each approach. No standard of care has been established, though the antiangiogenic agent, bevacizumab; stereotactic radiotherapy or radiosurgery; and, perhaps, combined treatment with these 2 modalities appear to offer modest benefits over other approaches. Clearly, randomized trials of these options would be advantageous, and novel, more efficacious approaches are urgently needed.     

Dendritic cell-based glioma immunotherapy (review)

Despite advances in radiation and chemotherapy along with surgical resectioning, the prognosis of patients with malignant glioma is poor. Among the new treatments currently being investigated for malignant glioma, immunotherapy is theoretically very attractive, since it offers the potential for high tumor-specific cytotoxicity. There are increasing reports demonstrating that systemic immunotherapy using dendritic cells is capable of inducing an antiglioma response. Therefore, dendritic cell-based immunotherapy could be a new treatment modality for patients with glioma. In this review, we will discuss the implications of these findings for glioma therapy. A literature review of dendritic cell-based glioma immunotherapy was used to overview the dendritic cell in immunobiology, in the central nervous system and in tumor immunology, glioma-associated antigens, dendritic cell therapy in animal glioma model, dendritic cell therapy in clinical trials and future directions in dendritic cell therapy. Dendritic cell-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and increase survival in patients with glioma. Dendritic cell therapy of glioma seems to be safe and without major side effects. Its efficacy should be further determined in randomized, controlled clinical trials. The development of methods for manipulating dendritic cells for the purpose of vaccination will enhance the clinical usefulness of these cells for biotherapy for malignant glioma.     

Correlative studies in neuro-oncology trials: Should they influence treatment?

Recent molecular correlative studies accompanying clinical trials in glioma have provided strong evidence for prognostic markers and predictive factors for treatment response. However, to what extent can these markers influence the limited choice of therapeutic options? Do we further validate the markers in the next trials or move on, incorporate the markers for patient selection or stratification, aim at improving the modestly effective treatments by adding new drugs, and develop alternative therapy strategies for patients selected for their bad predictor?     

Therapeutic strategies for local recurrent malignant glioma

Opinion statement Patients with local recurrent malignant gliomas present diagnostic and therapeutic challenges for the neuro-oncology practitioner. Management must be individualized depending on the patient’s age, performance status, histology, response to initial therapy, type of recurrence (local vs diffuse), and time since original diagnosis. Treatment options may be classified into surgery, additional radiation therapy, or chemotherapy. Results of treatment are often difficult to determine because of limitations of conventional imaging. Symptom palliation is an important goal that often requires additional adjuvant medical therapy. Quality of life issues are also of paramount importance in patients with recurrent malignant glioma and frequently will guide management strategy. Finally, patients with recurrent malignant gliomas should be encouraged to consider participation in a clinical trial in the hopes that better treatment alternatives will be available for this group of patients within the next few years.     

环状RNA在胶质母细胞瘤中的研究进展

胶质母细胞瘤(glioblastoma,GBM)是一种致命的脑癌,约占美国恶性脑瘤的80%。目前有许多治疗方法可用于GBM,但是其预后水平低,中位生存时间不到15个月。因此,为了创造更有效的靶向治疗的新可能性,人们正在进行大量的研究,以了解GBM发展和进展的分子和遗传基础。CircRNA是普遍存在于各种生物体内,但最近才被发掘和证明,并逐步引起注重和深刻研讨的一种非编码RNA。环状RNA与癌症的发生息息相关。但对于胶质母细胞瘤来说,环状RNA的作用仍未知。本文以环状RNA在恶性胶质瘤(GBM)病理生物学中的作用,以及它们在恶性胶质瘤治疗中的潜在应用作一综述。     

Colon perforation during antiangiogenic therapy for malignant glioma

Antiangiogenic drugs have emerged as effective treatment options for patients with recurrent malignant gliomas (MGs). Though this class of drugs is generally well tolerated, rare life-threatening complications, including thromboembolism, hemorrhage, and gastrointestinal (GI) perforation, are reported. We describe six cases of GI perforation among 244 glioma patients (2.5%) during treatment with antiangiogenic agents in combination with chemotherapy and corticosteroids. Two patients succumbed to this complication, and the others recovered. Because GI perforation is a life-threatening yet treatable complication, neurooncologists must have a low threshold to consider it in patients on antiangiogenic drug therapy who present with abdominal pain and other GI complaints.