神经胶质瘤的治疗策略

神经胶质瘤是来源于神经上皮的肿瘤,是颅内最常见的恶性肿瘤,约占中枢神经系统肿瘤的40%~50%。主要分为星型细胞瘤、胶质母细胞瘤、少突胶质细胞瘤、髓母细胞瘤、室管膜瘤等。如何提高胶质瘤的治疗效果,提高病人的生命质量,仍是神经外科医生面临的巨大难题。     

YKL-40在脑胶质母细胞瘤微环境中的作用

胶质母细胞瘤是大脑及其他中枢神经系统最常见的恶性肿瘤,其复杂的肿瘤微环境是胶质母细胞瘤临床治疗的主要挑战,也是胶质母细胞瘤患者复发率高、生存率低的主要原因。YKL-40,这一分泌性蛋白质与多种类型的癌症预后不良相关,且在高级别胶质瘤尤其是胶质母细胞瘤患者中血清水平与肿瘤组织表达水平显著升高,而在低级别胶质瘤中并未发现这一特征。这提示,YKL-40与胶质瘤分级及胶质母细胞瘤恶性发展过程密切相关。针对YKL-40的抗体治疗也被证明能够与电离辐射协同抑制胶质母细胞瘤血管生成及恶性发展。基于YKL-40的临床价值,本文将从肿瘤微环境的角度,归纳总结YKL-40在恶性肿瘤中的相关研究成果,并讨论其在胶质母细胞瘤发生发展中的相关作用及临床应用前景。     

多甲氧基黄酮对人胶质母细胞瘤细胞系生物学特性的影响

目的：多甲氧基黄酮（PMFs）因其抗氧化、抗癌、抗炎及抗动脉粥样硬化等多样的生物学活性受到国内外学者的广泛关注,但其在神经胶质瘤治疗中的潜在作用尚未见报道。本研究对多甲氧基黄酮处理人胶质母细胞瘤细胞系对其生物学特性的影响,初步探讨PMFs在神经胶质瘤治疗中的潜在应用。方法：不同浓度（0,20,40,60,80,100μg／mL）的PMFs处理人胶质母细胞瘤细胞系U251不同时间后．分别用Annexinv／PI双染法检测细胞凋亡的变化,MTT法检细胞活力的变化,Transwell小室实验检测细胞侵袭能力的变化。结果：随着多甲氧基黄酮的浓度及处理时间的增加,细胞的增殖明显受到抑制,同时诱导细胞大量凋亡,促使细胞生长停滞于G2／M期;此外,多甲氧基黄酮剂量依赖性的抑制胶质瘤细胞的侵袭。结论：PMFs能剂量和时间依赖性降低人胶质母细胞瘤细胞系U251的,同时显著诱导细胞瘤的凋亡和侵袭能力,提示PMFs可能对神经胶质瘤的高增殖性和侵袭性有一定的抑制作用,因此可能具有成为治疗神经胶质瘤药物的潜在应用价值。     

脑肿瘤及脑肿瘤图像分类的研究进展

脑肿瘤分类的方法很多,目前尚无统一的分类方法,并且各种肿瘤的组织发生与病理特征不同,其良性与恶性以及物学特性也不一样。通常按组织学可分类如下：（1）发源于神经胶质的肿瘤：星形细胞瘤、少支胶质细胞瘤、髓母细胞瘤等。（2）发源于脑膜的肿瘤：脑膜瘤、脑膜肉瘤、蛛网膜囊肿等。（3）发源于垂体的肿瘤：厌色细胞腺瘤,嗜酸、嗜碱性细胞腺瘤。（4）发源于颅神经的肿瘤：听神经瘤、三又神经瘤等各种神经鞘瘤。（5）发源于胚胎残余组织：颅咽管瘤、脊索瘤、皮样囊肿等。（6）发源于血管细胞：血管瘤及血管网织细胞瘤等。（7）由其它部位转移或侵入的肿瘤：各种转移瘤及鼻咽癌等。     

脑肿瘤及脑肿瘤图像分类的研究进展

脑肿瘤分类的方法很多,目前尚无统一的分类方法,并且各种肿瘤的组织发生与病理特征不同,其良性与恶性以及物学特性也不一样。通常按组织学可分类如下:(1)发源于神经胶质的肿瘤:星形细胞瘤、少支胶质细胞瘤、髓母细胞瘤等。(2)发源于脑膜的肿瘤:脑膜瘤、脑膜肉瘤、蛛网膜囊肿等。(3)发源于垂体的肿瘤:厌色细胞腺瘤,嗜酸、嗜碱性细胞腺瘤。(4)发源于颅神经的肿瘤:听神经瘤、三叉神经瘤等各种神经鞘瘤。(5)发源于胚胎残余组织:颅咽管瘤、脊索瘤、皮样囊肿等。(6)发源于血管细胞:血管瘤及血管网织细胞瘤等。(7)由其它部位转移或侵入的肿瘤:各种转移瘤及鼻咽癌等。     

寨卡病毒可作为溶瘤病毒特异杀伤胶质瘤干细胞

正胶质母细胞瘤(glioblastoma)是一种恶性程度最高的原发性脑肿瘤.由于肿瘤生长快、侵袭性强,常规手术、放疗、化疗等治疗后复发率极高,预后差,绝大多数患者生存期中位数低于两年[1].胶质母细胞瘤的成因复杂,最新研究显示胶质瘤干细胞(glioblastoma stem cells, GSCs)可能在其中发挥了关键作用.胶质瘤干细胞是一群具备无限增殖、自我更新和多向分化等类干细胞潜能的细胞,不仅参与促进肿瘤血管生成,而且能够抵抗放化疗的杀瘤作用[2].以胶质瘤干细胞为     

脑胶质瘤治疗相关时空演化机制及其在精准治疗中的应用

胶质母细胞瘤是成人中最恶性的颅内肿瘤,但其治疗方式在过去数十年未有突破. 随着近年精准医学和下一代测序技术的发展,使研究胶质母细胞瘤背后多维基因组学的复杂机制成为可能. 其中继发胶质母细胞瘤及与其配对的原发肿瘤是十分珍贵的数据,可用以分析低级别胶质瘤在时间和空间轴上的演化以及治疗对肿瘤的影响. 本综述阐述胶质母细胞瘤的复杂性,包括各种驱动突变、空间上的异形性和不同的演化方式;此外,会讨论如何将这些基因学上的发现应用在肿瘤预后的预测以及精准治疗上.     

脑胶质瘤治疗相关时空演化机制及其在精准治疗中的应用（英文）

胶质母细胞瘤是成人中最恶性的颅内肿瘤,但其治疗方式在过去数十年未有突破.随着近年精准医学和下一代测序技术的发展,使研究胶质母细胞瘤背后多维基因组学的复杂机制成为可能.其中继发胶质母细胞瘤及与其配对的原发肿瘤是十分珍贵的数据,可用以分析低级别胶质瘤在时间和空间轴上的演化以及治疗对肿瘤的影响.本综述阐述胶质母细胞瘤的复杂性,包括各种驱动突变、空间上的异形性和不同的演化方式;此外,会讨论如何将这些基因学上的发现应用在肿瘤预后的预测以及精准治疗上.     

研究报告: 星形胶质细胞瘤分泌一氧化氮促进炎性水肿带相关肿瘤微环境的研究

目的 检测在星形胶质细胞瘤中一氧化氮（nitric oxide，NO）的表达及促进炎性水肿带相关肿瘤微环境的作用。方法 收集27例星形胶质细胞瘤患者的临床资料和肿瘤标本（WHO II级10例、II-III级7例、IV级10例），磁共振成像确认水肿带及手术取材部位；格里斯试剂比色法检测亚硝酸盐含量；质谱分析不同级别星形胶质细胞瘤（不同级别各5例）水肿带炎性分子含量；通过ClusterProfiler包以及Proteomaps和Metascape网页工具进行富集分析预测肿瘤分泌的NO与微环境中互作的蛋白质。结果 星形胶质细胞瘤组织及水肿带中存在NO，胶质瘤组织中的NO高于水肿带中的NO。在WHO II-III级和WHO IV级胶质瘤的水肿带中，有大量超氧化物歧化酶、细胞色素C氧化酶、热休克蛋白、CD44抗原，白介素-8、白介素-24、凝溶胶蛋白、应激诱导磷酸蛋白1、丝裂原活化蛋白激酶、硫氧还蛋白过氧化物酶、S100蛋白等炎症相关蛋白质的表达。信号通路分析提示，与II-III级别星形胶质细胞瘤相比，Ⅳ级胶质母细胞瘤水肿带中的基因更多地参与无氧代谢，如糖酵解。更重要的是，这些目标基因显著参与多种氧化还原反应，如氧化还原酶活性和过氧化物酶活性。其中，诱导性一氧化氮合酶（inducible NOS，iNOS）、NO、过氧亚硝酸阴离子（ONOO^-）、铜/锌超氧化物歧化酶（Cu/Zn superoxide dismutase，SOD-1）在氧化还原反应中发挥重要作用。结论 星形胶质细胞瘤周围水肿带的形成是炎症反应的结果，胶质瘤细胞通过分泌NO调控SOD-1等炎性分子促进侵袭性炎性肿瘤微环境的形成。     

替莫唑胺治疗胶质母细胞瘤的耐药性产生机制研究进展

胶质母细胞瘤作为胶质瘤中恶性程度最高的原发性脑部肿瘤,具有治愈率低、复发率高、呈浸润性生长等特点,在不使用化疗药物的情况下,患者中位生存期仅为12.1个月。胶质母细胞瘤患者的标准治疗方法以手术切除为主,放化疗为辅,其中替莫唑胺（temozolomide,TMZ）作为一种新型的口服烷化剂,是目前用于胶质瘤化学治疗的一线药物。但经过替莫唑胺治疗后,患者中位生存期仅提高了2个月,主要原因为胶质母细胞瘤可对TMZ产生耐药性。胶质母细胞瘤对TMZ产生的耐药机制主要为DNA修复机制,其包括了O⁶?甲基鸟嘌呤DNA甲基转移酶（O⁶?methyl guanine DNA methyltransferase,MGMT）对药物作用位点进行的直接修复、错配修复（mismatch repair,MMR）及碱基切除修复（base excision repair,BER）,这些修复机制可修复TMZ引起的DNA损伤,从而降低肿瘤细胞对TMZ敏感性。通过对近年来胶质母细胞瘤的TMZ耐药机制的研究进展进行介绍,旨在为发展新的治疗手段提供理论基础。     

综述——纳米材料与药物输递：基于肿瘤异常结构的纳米药物设计

肿瘤组织的血液供给在时间和空间上存在的非均质性、血管的高渗性、淋巴排出功能的低效性共同形成肿瘤微环境,阻碍治疗药物有效地运输到肿瘤,从而影响其疗效．与传统药物相比,纳米药物能优先递送到肿瘤,并具有多药载药与靶向运输等功能．但肿瘤中特有生理屏障的存在阻碍了纳米药物以有效浓度均匀地运输到肿瘤组织．一些美国食品药品管理局批准的纳米药物疗效并不显著,可能与这些生理屏障的阻碍有关．本文概述了肿瘤治疗时药物需跨过的生理屏障,并总结了克服这些生理屏障的方法,探讨了纳米药物研发时针对肿瘤异常结构优化药物递送需考虑的因素．     

The role of radiation-induced apoptosis as a determinant of tumor responses to radiation therapy

Ionizing radiation is an effective means of killing tumor cells. Approximately 50% of all American cancer patients are treated with radiotherapy at some time during the course of their disease, making radiation one of the most widely used cytotoxic therapies. Currently, much effort is focused on understanding the molecular pathways that regulate tumor cell survival following radiotherapy, with the long term goal of developing novel therapeutic strategies for specifically sensitizing tumors to radiation. At present, there is particular interest in the role of tumor cell apoptotic potential as a regulator of both intrinsic and extrinsic determinants of the response of tumors to radiation therapy. Here we review what is currently known about the role of apoptosis as a mechanism of tumor cell killing by ionizing radiation and the relative contribution of apoptosis to cellular radiosensitivity and the ability to control human cancers using radiotherapy. The following topics will be discussed: (1) radiation-induced apoptosis in normal and malignant cells, (2) clinical findings with respect to apoptosis in human cancers treated with radiotherapy, (3) the contribution of apoptosis to intrinsic radiosensitivity in vitro, (4) the relevance of apoptosis to treatment outcome in experimental tumor models in vivo and (5) the potential of exploiting apoptosis as a means to improve the therapeutic efficacy of radiotherapy.     

光免疫治疗的抗肿瘤研究进展

光免疫治疗是一种新兴的肿瘤靶向光疗手段,它将单克隆抗体的肿瘤特异性与光吸收剂的光毒性相结合,可以快速且极具免疫原选择性地诱导靶肿瘤细胞的死亡。由于靶向性强,光免疫治疗的副作用小。而且因为该疗法诱导的免疫原性死亡会引起垂死肿瘤细胞周围未成熟树突状细胞的快速成熟,继而将肿瘤抗原提呈给CD8+T细胞,导致治疗后CD8+T细胞的激活和增殖,增强宿主抗肿瘤免疫反应。不仅如此,光免疫治疗还能通过增强纳米药物的肿瘤组织穿透性而提高疗效。鉴于光免疫治疗的优良应用前景,文中从其免疫激活机制、超级高渗透长滞留效应、新进展与联合治疗等方面进行综述,旨在为其深入研究和临床转化提供参考。     

肿瘤生物治疗的新方法——减毒鼠伤寒沙门菌的应用

减毒鼠伤寒沙门菌由于具有肿瘤靶向性,能在肿瘤组织中复制并产生抗肿瘤效果的能力,使肿瘤治疗获得了新契机。减毒鼠伤寒沙门菌作为细菌载体使目的基因在肿瘤组织内特异表达,表现出良好治疗效果。近期研究发现,单独使用突变后的菌株A1-R在裸鼠模型上治疗乳腺癌和前列腺癌分别可达到40％和50％的治愈率;在小鼠肿瘤转移模型中也展现出良好的治疗效果。鼠伤寒沙门菌作为肿瘤治疗制剂有诱人的前景。本文就这些研究的最新进展做一综述。     

Anticancer innovative therapy congress: Highlights from the 10th anniversary edition

During the Tenth Edition of the Annual Congress on “Anticancer Innovative Therapy” [Milan, 23/24 January 2020], experts in the fields of immuno-oncology, epigenetics, tumor cell signaling, and cancer metabolism shared their latest knowledge on the roles of i] epigenetics, and in particular, chromatin modifiers, ii] cancer metabolism, iii] cancer stem cells [CSCs], iv] tumor cell signaling, and iv] the immune system. The novel therapeutic approaches presented included epigenetic drugs, cell cycle inhibitors combined with ICB, antibiotics and other off-label drugs, small-molecules active against CSCs, liposome-delivered miRNAs, tumor-specific CAR-T cells, and T-cell–based immunotherapy. Moreover, important evidence on possible mechanisms of resistance to these innovative therapies were also discussed, in particular with respect to resistance to ICB. Overall, this conference provided scientists and clinicians with a broad overview of future challenges and hopes to improve cancer treatment reasonably in the medium-short term.     

Multi-omic analyses of hepatocellular carcinoma to determine immunological characteristics and key nodes in gene-expression network

Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide, but effective immunotherapy is still limited for those affected. Therefore, there is an urgent need to explore the specific mechanisms governing tumor immunity to improve the survival rate for those diagnosed with HCC. In the present study, we performed a new immune stratification of HCC samples into two subclasses (A and B) from The Cancer Genome Atlas and the International Cancer Genome Consortium databases, and comprehensive multi-omic analyses of major histocompatibility complex genes, gene copy-number variations, somatic mutations, DNA methylation, and non-coding RNAs. Subclass A was found to have a higher survival rate compared with subclass B, and there were significant immunological differences between the two clusters. Based on these differences, we identified DRD1 and MYCN as key hub genes in the immune-phenotype gene expression regulatory network. These results provide novel ideas and evidence for HCC regulatory mechanisms that may improve immunotherapy for this cancer.     

Approaches to improve tumor accumulation and interactions between monoclonal antibodies and immune cells

Monoclonal antibodies (mAb) have become a mainstay in tumor therapy. Clinical responses to mAb therapy, however, are far from optimal, with many patients presenting native or acquired resistance or suboptimal responses to a mAb therapy. MAbs exert antitumor activity through different mechanisms of action and we propose here a classification of these mechanisms. In many cases mAbs need to interact with immune cells to exert antitumor activity. We summarize evidence showing that interactions between mAbs and immune cells may be inadequate for optimal antitumor activity. This may be due to insufficient tumor accumulation of mAbs or immune cells, or to low-affinity interactions between these components. The possibilities to improve tumor accumulation of mAbs and immune cells, and to improve the affinity of the interactions between these components are reviewed. We also discuss future directions of research that might further improve the therapeutic efficacy of antitumor mAbs.     

Targeting gene-virotherapy of cancer

Our purpose is to completely elimination of xenograft tumor in animal tumor model in order to work out a protocal for the cure of patient. Gene therapy and viral therapy for cancer have got some therapeutic effects, but both have no great breakthrough. Therefore, we worked out a new strategy called Targeting Gene-Virotherapy of Cancer which is a combination of the advantage of gene therapy and virotherapy. This new strategy has stronger antitumor effect than either of them alone. A tumor specific replicative adenovirus vector ZD55 (E1B 55KD deleted Adv.) which is similar to ONYX-015 in targeting fuction but significant different in construction was produced and various single therapeutic gene was inserted into ZD55. Now such a conception as Targeting Gene-Virotherapy of Cancer was raised and systemically studied before, although there are some works on ONYX-015-tk, -cd or cd/-tk etc. separately. The antitumor effect of ZD55-Gene (for example IL-24 gene) is much better than ZD55 (virotherapy) alone and hundred fold high than that of Ad-IL-24 (gene therapy) alone. ZD55-IL-24 was in preclinal studying in the ZD55-IL-24 therapy, completely elimination of tumor mass was occurred in some mice but not in all mice, that means one gene was not effictive enough to eliminate all the tumor mass in all mice. Therefore two genes with compensative or synergetic effect were inserted into ZD55 separately and used in combination. This strategy was called Targeting Dual Gene-Virotherapy of Cancer (with PCT patent). Then much better results were obtained and all the xenograft tumor masses were completely eliminated in all mice, if two suitable genes were chosen. On the basis of the initiation of two gene results, it was thought about that using two tumors promoter to control the virus vector will be better for the targeting effect and the safty of the drugs. Then double tumor controlled virus vector harboring two genes for cancer therapy was worked out. Better results have been obtained and another patent has been applied. This antitumor strategy could be used to kill all the tumor cells completely in all mice with minimum damage to normal cells.     

Anti-tumor immune responses following neoadjuvant immunotherapy with a recombinant adenovirus expressing HSP72 to rodent tumors

Gene modification of tumor cells is commonly utilized in various strategies of immunotherapy preventive both as treatment and a means to modify tumor growth. Gene transfer prior to surgery as neoadjuvant therapy has not been studied systematically. We addressed, whether direct intra-tumoral injection of a recombinant adenovirus expressing the immunomodulatory molecule, heat shock protein 72 (ADHSP72), administered prior to surgery could result in sustainable anti-tumor immune responses capable of affecting tumor progression and survival in a number of different murine and rat tumor models. Using intra-dermal murine models of melanoma (B16), colorectal carcinoma (CT26), prostate cancer (TrampC2) and a rat model of glioblastoma (9L), tumors were treated with vehicle or GFP expressing adenovirus (ADGFP) or ADHSP72. Tumors were surgically excised after 72 h. Approximately 25–50% of animals in the ADHSP72 treatment group but not in control groups showed sustained resistance to subsequent tumor challenge. Tumor resistance was associated with development of anti-tumor cellular immune responses. Efficacy of ADHSP72 as neoadjuvant therapy was dependent on the size of the initial tumor with greater likelihood of immune response generation and tumor resistance associated with smaller tumor size at initial treatment. ADHSP72 neoadjuvant therapy resulted in prolonged survival of animals upon re-challenge with autologous tumor cells compared to ADGFP or vehicle control groups. To study the effects on tumor progression of distant metastases, a single tumor focus of animals with multifocal intra-dermal tumors was treated. ADHSP72 diminished progression of the secondary tumor focus and prolonged survival, but only when the secondary tumor focus was <50 mm³ . Our results indicate that gene modification of tumors prior to surgical intervention may be beneficial to prevent recurrence in specific circumstances.     

Data mining analysis of the PP2A cell cycle axis in mesothelioma patients

Mesothelioma is an aggressive tumor that affects thousands of people every year. The therapeutic options for patients are limited; hence, a better understanding of mesothelioma biology is crucial to improve patient survival. To find new molecular targets and therapeutic strategies related to the protein phosphatase 2A (PP2A) network, we analyzed the gene expression of known PP2A inhibitors in mesothelioma patient samples. Our analysis disclosed a general overexpression of all PP2A-negative regulators in mesothelioma patients. Moreover, the expression of ANP32E and CIP2A genes, increased in 16% and 11% of cases, positively correlates with the ones of all the other PP2A regulators and the ones of the main cyclins and CDKs, suggesting the existence of a feed-forward loop that might contribute to the mesothelioma progression via PP2A inactivation. Overall, our study indicates the existence of a strategic and targetable axis between PP2A inhibitors (ANP32E and CIP2A) and cell cycle regulators (cyclin B2/CDK1) and provides a valuable rationale for using a personalized combinational therapy approach to improve mesothelioma patient survival.