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液体活检技术能否实现脑肿瘤的早诊早治?——聆听美国麻省总医院临床神经外科首席专家卡特博士的临床经验

2017-11-13 佚名 ioncology

2017年11月4日,卡特博士来中国北京进行学者访问工作。我们特邀卡特博士进行了一场关于神经肿瘤手术的未来发展方向、液体活检技术在脑肿瘤中的应用以及神经胶质肿瘤前沿治疗方法的访谈。

美国麻省总医院(Massachusetts General Hospital)建立于1811年,是美国历史最悠久的三所医院之一,也是新英格兰地区建立最早、规模最大的医院和哈佛医学院建立最早、规模最大的教学医院。作为全球公认的权威医院,在癌症、心血管、儿科、神经、脑血管、眼、耳鼻喉、风湿免疫、血液、内分泌等疾病治疗方面世界领先,它具有全球最先应用癌症全基因检测技术,在癌症的基因定位治疗、Proton治疗、放疗手术等方面全球闻名。

美国麻省总院(MGH)为现代医学的发展做出过突出贡献。在外科学领域,1846年,MGH率先将乙醚麻醉应用于外科手术。MGH神经外科主席,哈佛医科大学客座教授---卡特博士(Dr. Bob Carter)为美国临床神经外科首席医学专家之一,MGH医院脑部肿瘤项目主要负责人。作为美国临床神经外科医生领导者之一,卡特博士带领百余位研究人员,长期致力于脑部临床治疗、研究和教学等方面的工作。而作为资深的研究人员,卡特博士的研究工作,主要包括对EGFRvIII (突变体III)发展对外做出首次报道以及关于CAR T细胞治疗的导向和外来液体在胶质母细胞瘤的主要特征等等进行广泛的研究。卡特博士领导的临床医生组成的团队,在肿瘤和血管神经外科手术中发挥了“大数据”的作用。

2017年11月4日,卡特博士来中国北京进行学者访问工作。我们特邀卡特博士进行了一场关于神经肿瘤手术的未来发展方向、液体活检技术在脑肿瘤中的应用以及神经胶质肿瘤前沿治疗方法的访谈

卡特博士在访谈中表示,脑肿瘤是一种非常恶性的肿瘤,大脑主导人体认知、言语、运动等功能,是人类最基本、最重要的部位。大脑恶性肿瘤侵略性强,患者存活率为1年左右。目前针对这类恶性疾病已经有了包括外科手术在内的很多治疗策略,通过收集患者的基因信息可以更好地了解疾病,为患者提供合理的个体化治疗方案。

“安全、无创、多次”——液体活检技术的三大法宝

近年来,液体活检由于其安全、无创、便利等优势在肿瘤领域备受瞩目。收集患者的血液或体液进行检测可以使我们更好地了解肿瘤的信息,因为肿瘤细胞会在血液中释放一些特异性的物质,例如脑肿瘤细胞能够释放一种外泌体exosome,它是一种包含RNA和DNA的小分子,我们可以对其进行基因排序获得脑肿瘤突变的信息,从而指导患者的临床治疗,例如存在IDH1 突变的患者手术治疗疗效比没有IDH1突变的患者更好。

目前中国的一些医疗机构也有很好的液体活检技术,例如北京天坛和上海华山两家医院等。安全的液体活检技术可以帮助我们了解肿瘤突变的信息,例如针对IDH1突变脑肿瘤患者可以在术前进行液体活检以确定最优的外科手术方案,从而给患者带来最佳获益,而没有IDH1突变的脑肿瘤患者液体活检的意义不大,因为这类患者很难从外科手术中获益。

某些脑肿瘤的部位很深,很难触及,例如脑干,用针进行穿刺取材活检非常危险,而此时液体活检的安全性优势就非常突出了。液体活检的另外一个优势就是可以进行多次活检,从而可以帮助患者监测某种治疗过程的疗效。

此外,液体活检还可以发现患者的循环肿瘤细胞(CTC),它包含了很多游离状态的RNA,可以提供给我们更多关于肿瘤的信息。目前检测外泌体的手段比以往有了很大进步,我们能够从外泌体分泌物中获得大量的信息后进行分析排序,可以得到更好的治疗方案。

早期脑肿瘤患者无明显不适症状,当肿瘤体积逐渐变大并开始压迫大脑组织,就会出现头痛、四肢无力、言语障碍等症状。液体活检技术可以帮忙我们在很早期的阶段就发现脑肿瘤中的IDH1突变,最近进行的一项纳入10例病例的研究显示,70%的早期脑肿瘤患者可以检测到IDH1的突变,准确性还是很可观的。

通过MRI发现脑肿瘤后临床医生会利用手术治疗将肿瘤切除,或采取放化疗等其他治疗手段。然而在治疗过程中,很难确定患者是否会复发,那么通过液体活检观察肿瘤突变的变化情况可以帮助监测患者是否复发。

也有人担心液体活检在脑肿瘤中应用的准确性和特异性问题,对此,卡特博士称:“AFP是一种蛋白质标志物,机体不同部位都存在这类标志物的表达,针对性不强,不能明确诊断癌症的发生。而液体活检检测的是基因标志物,敏感性和特异性都很强。而且由于有保护膜包裹DNA,即使对12年前的样本进行分析,检测结果也不会受太大影响,功能非常强大。”

目前,针对IDH1,EGFRvIII突变了解地比较多,获得相应的信息可以指导患者的外科手术治疗,未来可能会找到更多的突变基因或者可以采用免疫治疗等其它手段治疗。

在神经胶质瘤等脑肿瘤领域,我们希望通过正确的诊断为患者选择合适的治疗方案,即个体化精准治疗。卡特博士总结道:“美国麻省总医院是美国最大的脑肿瘤的治疗中心,可选择的治疗方案众多,包括手术治疗、放疗、免疫治疗以及化疗等,液体活检技术可以帮助临床医生为患者选择合适的治疗方案,进一步提高疗效。”

蛋白质分析有助于脑肿瘤的早期诊断

蛋白质组学本质上指的是在大规模水平上研究蛋白质的特征,包括蛋白质的表达水平,翻译后的修饰,蛋白与蛋白相互作用等,由此获得蛋白质水平上的关于疾病发生、细胞代谢等过程的整体而全面的认识。卡特博士在访谈中表示,目前蛋白质组学在脑肿瘤领域也有很好的应用前景。脑肿瘤细胞分泌的蛋白质和外泌体中的蛋白质是不一样的,我们可以将它们进行配对、分析和比较。例如他们所作的一项研究比较24例脑肿瘤患者和8例正常人蛋白表达情况的研究发现,脑肿瘤患者能够特异性地分泌某种蛋白质,而正常人则不然,这说明蛋白质的发现在临床上有很好的特异性和准确性,也可以用于指导脑肿瘤的早期诊断和治疗。

CAR-T细胞疗法在脑肿瘤中的尝试

在访谈的最后,卡特博士还给我们分享了神经胶质肿瘤前沿治疗方面的进展。神经胶质瘤是一种严重的、侵袭性非常强的疾病,治疗方案包括标准治疗和一些还在进行试验的治疗方案。标准治疗包括手术切除、放疗、化疗等,平均存活率为15个月左右,有些机构可以达到18个月。目前已经出现了一些令人振奋的新治疗方法,例如一种可以靶向肿瘤突变基因并特异性杀死肿瘤细胞的“毒丸”,这其实是一种嵌合抗原受体T细胞免疫治疗(CAR-T),即通过对人体的T细胞进行基因修饰,导入能够编码CAR的基因,使其能够表达识别肿瘤细胞的受体,在杀死肿瘤细胞的同时还能加强自体免疫功能,保护未被感染的细胞。目前这种治疗方案还处于临床试验阶段,还需要更多的数据进行支持验证,期待这种新疗法能带给大家更多的惊喜。

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    2017-11-15 smlt2008
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WCLC 2017:再添新桂|王洁教授团队BENEFIT研究证实液体活检指导一线TKI疗效的可行性

王洁教授,医学科学院肿瘤医院肿瘤内科,主任医师,教授,博士生导师,国家杰出青年基金获得者,中国抗癌协会肺癌专业委员会常委,北京医学会肿瘤分会副主任委员,中华结核与呼吸杂志、中国肺癌杂志Lung Cancer、Clin. Lung Cancer编委,国家百千万人才工程入选者、获中国突出贡献中青年专家称号,国务院政府特殊津贴获得者。

盘点:欧洲泌尿外科学《European Urology》期刊九月文章一览。

此研究结果表明:相比无病生存的患者,转移性复发患者的ctDNA水平显著升高(P<0.001)。 从开始进行血浆ctDNA检测到术后转移复发的中位时间为101天(0–932 天)。因此,液体活检作为一种新的、敏感度较高的技术可早期检测转移复发和监测治疗反应,同时能够支持临床工作开展和指导医生的治疗决策

Nature Materials:癌症液体活检获重大突破

来自中山大学肿瘤防治中心,加州大学圣地亚哥分校等处的研究人员证实可以通过检测少量血液中循环肿瘤DNA(ctDNA)特定位点甲基化水平,早期诊断和预后预测肝细胞癌(HCC)。

我国医生攻克难题 液体活检或成肝癌筛查新宠

肝癌素有“癌王”之称。早期获得诊断的患者经过有效治疗,5年生存率可达到50%以上,而到了晚期,5年生存率只有10%~15%,因此如果能对肝癌进行早期诊断,将使患者大大获益。近日,中美研究团队攻克了肝癌早期诊断的世界性难题,新型诊断手段有望应用于临床中。

CLIN CHEM:液体活检靶向重测序如何多重消除野生型DNA?

从液体活组织检查中收集的临床样品和循环的无细胞DNA(cfDNA)在癌症中的诊断和预后的应用正在迅速发展,人们希望一种能够有减少过量野生型(WT)样品部分影响的改良方法。近日,国际杂志 《CLIN CHEM》在线发表一项关于使用WT 的DNA酶降解来对包含突变序列进行突变富集,突变富集与在多重闭管反应中进行的高分辨率熔解(HRM)结合,作为靶向重测序之前的快速有效的筛选工具。

Nature Commun:转移性癌症患者有望从液体活检中受益

通过检测血液中的游离DNA(cfDNA),究竟能否提供癌症的线索,这个问题困扰了人们很久。近日,Broad研究所的研究人员在《Nature Communications》上发表文章称,90%的肿瘤遗传特征可通过血液样本的全外显子组测序检测到,这种方法可应用在近半的晚期癌症患者身上。

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