中国抗癌协会

01
快速分子检测技术助力胶质瘤术中精准诊断
       胶质瘤不同分型意味着不同的治疗策略和预后，所以提供实时的分子突变信息，将允许外科医生根据每个患者的基因图谱调整手术策略。在大多数神经病理学实验室中，1p/19q共缺失是通过荧光原位杂交(FISH)检测，IDH突变(IDH1 R132H)则通过免疫组化（IHC）方法进行检测。其他更详细和精确的分子突变信息将会根据患者需求进一步进行基因测序分析。然而，基于下一代测序技术（NGS）的基因检测不仅价格较高，而且检测周期较长（5-14天），无法应用于术中检测。随着神经外科的发展，人工智能的融合，研究人员开发了基于MRI的影像组学技术，可用于术前无创预测IDH突变状态。然而大部分影像组学模型尚缺乏外部验证集，不能很好解释模型构建原理，影响了临床的应用和转化。与此同时，科学家们也在尝试对组织标本的术中检测技术。基因测序技术正在快速发展，分子检测已经从选择性使用标准PCR发展到常规使用实时定量PCR (Real Time-PCR)，再到最近的下一代测序或高通量测序。在整个演变过程中，桑格（Sanger）DNA测序一直是测定核酸序列的金标准，但每次反应只能检测少量的序列，且对检测标本要求较高（目标序列含量不少于20%）。NGS则可在大规模并行高通量测序时单次进行数百万到数十亿个的测序反应，明显缩短了检测时间和成本，增加了输出的序列，对科学研究和临床实践有重要意义。然而这些技术仍然耗时较长，操作复杂，只能用于对术后标本的检测。我们在临床实践中，主要是想通过术中检测获取少数已知关键分子的突变状态（如IDH、TERT等）。为此，科学家开发了一系列点突变检测的技术，使术中分子检测成为可能。

02

RANO工作组对胶质瘤切除分类标准、肿瘤组织取样及样本处理标准、治疗反应评价标准的更新

03
患者报告结局（PRO）利于准确评估信息并促进患者参与决策
       患者报告结局（PRO）是完全由患者本人报告的，不经医护人员及其他人员解释的原始信息，有助于医务人员准确评估患者的相关信息，并促进患者参与共同决策。目前已广泛应用于临床试验和公共卫生领域，其相关标准也在逐渐完善。但在我国胶质瘤领域，PRO在患者报告结局测量工具（PROM）的研发、PRO评估的伦理规范、PRO数据的处理等方面都明显不足。吴劲松教授团队联合17所医院的相关专家基于NCI的不良事件通用术语患者自我报告版本（PRO-CTCAE ®）条目库，针对中国成人型弥漫性胶质瘤患者在术后治疗相关的不良事件评价制定了“定制化PRO-CTCAE ®量表”。目前，应用该量表的一项前瞻性、非干预性、多中心的真实世界临床研究正在进行，以检验其效度、信度和反应度。
04
溶瘤病毒特异杀伤肿瘤细胞
       溶瘤病毒治疗，通常使用经过改造的病毒或野生型病毒，利用不同的给药方式进入体内。通过对病毒基因进行改造和利用肿瘤细胞本身的特征，可使病毒在肿瘤细胞内进行选择性复制。溶瘤病毒的抗肿瘤效应分为直接效应和间接效应。直接效应表现为肿瘤细胞内先天性免疫反应的激活，病毒在肿瘤细胞内大量复制，最终导致肿瘤细胞裂解死亡。肿瘤细胞裂解后，释放出肿瘤相关抗原、病原体相关分子模式（Pathogen-associated Molecular Patterns, PAMPs）和细胞危险相关分子模式信号（cellular danger-associated molecular pattern signals, DAMPs），诱导机体产生对肿瘤的适应性免疫反应，使得未感染病毒的肿瘤细胞也被识别，从而减轻肿瘤负荷、重建系统对肿瘤的免疫监视，把“冷”肿瘤变“热”肿瘤，而这也是溶瘤病毒治疗与其他免疫疗法结合的理论基础之一。
05
GTR与STR相比并不能使少突胶质细胞瘤患者获益
      江涛教授团队利用中国胶质瘤基因组图谱数据库（Chinese Glioma Genome Atlas database, CCGA）对449例胶质瘤患者的临床及病理信息分析发现，对于KPS＞80，年龄＞45岁的少突细胞胶质瘤患者，与次全切（Subtotal Resection, STR）相比，肿瘤的完全切除（Gross Total Resection, GTR）不能使患者受益。也就是说对于该分子分型的胶质瘤在手术切除时不必太过激进，少许残留不会影响患者预后。这可能是由于少突胶质细胞瘤呈惰性生长，且对常规术后辅助治疗（放疗及替莫唑胺化疗）较为敏感，即使不能完全切除肿瘤，患者仍可存活较长时间。该团队还提出对于这些肿瘤应该进行“有效的安全切除”，即在保留功能的前提下最大化切除肿瘤。Daniel等人也发现，少突胶质细胞瘤的肿瘤是否完全切除（GRT）对患者的总体生存影响不大。所以结合Berger教授对低级别胶质瘤的研究，对于分子分型为IDHmut+TERTmut的胶质瘤，可在保留功能前提下有效切除（EOR>80%）。
06
低级别星形细胞瘤提升切除范围可改善生存预后
       依据最新的胶质瘤分类指南WHO CNS5，IDHmut胶质瘤应诊断为：星形细胞瘤，IDH突变型，组织学等级分为2-4级，其中以低级别胶质瘤为主。低级别星形细胞瘤是一种生长相对缓慢的浸润性脑肿瘤，指南推荐低级别胶质瘤的影像学切除边界则为T2WI/FLAIR的高信号区域。Wijnenga等人研究分析发现，对于低级别IDHmut星形细胞瘤（WHO 2级），任何术后残留都会影响生存预后，甚至提出在确保患者安全的情况下进行二次手术，切除残余肿瘤，以达到肿瘤全切（GTR）的目的。江涛教授团队的研究也指出，对于低级别星形细胞瘤（IDHmut），提升切除范围（Extent Of Resection, EOR）可改善患者的生存预后。
07
多组学研究引领垂体神经内分泌新分类
      世界卫生组织(WHO)第5版与垂体相关的内分泌和神经内分泌肿瘤分类提供了基于肿瘤细胞谱系、细胞类型和相关特征的PitNET的详细组织学分型，脑垂体转录因子(PIT1, TPIT, SF1, GATA3和ERα)的免疫组织化学常规应用在这一分类中得到认可。
      体细胞突变常发生在少数已知基因，40%垂体GH腺瘤发生GNAS激活突变，35%ACTH腺瘤发生USP8激活突变。拷贝数变异、DNA甲基化改变、肿瘤抑制因子下调和cyclin D1、PTTG过表达等，通过表观遗传机制促进细胞增殖。多组学研究通过分析不同谱系PitNETs发生的遗传特征，发现不同肿瘤簇具有不同的免疫微环境和间质特征，为免疫检查点抑制剂治疗此类垂体神经内分泌肿瘤提供重要的理论依据。
   3D-SGE/3D-GRE增强序列、dMRI、CISS、FLAIR增强序列、各向同性3D快速自旋回波序列，超高场（7T）MRI、13N-Ammonia成像、影像组学模型可提高微腺瘤（＜3-4 mm）的检出效能。11C-MET PET联合容积MRI、18F?FET PET有利于检出异位垂体神经内分泌肿瘤。FLAIR增强序列、GRASP MRI肿瘤延迟廓清可鉴别无功能腺瘤与ACTH腺瘤。分子成像可作为判断术后残留/复发的补充。
08
多项研究助力脊髓肿瘤的分子基础研究、治疗及康复
        Carl Koschmann博士领导的密歇根大学安娜堡分校的团队通过两项多中心临床研究，评估了接受ONC201治疗的患者的临床结果、肿瘤序列以及组织/脑脊液样本。结果显示，ONC201通过干扰整合的代谢和表观遗传途径以及逆转H3K27me3的降低，显示出对H3K27M-DMG的疗效，为H3K27M突变DMG的治疗提供了新的方向。
       清华大学附属北京清华长庚医院神经中心主任王贵怀团队研究表明，通过基于术前磁共振的人工智能方法，可在无创的情况下，准确地预测脊髓胶质瘤的分级以及分子标记的突变状态。这一发现或改变脊髓胶质瘤的诊断和治疗方式，将深度学习技术的应用推向新的领域。在研究中，王贵怀团队运用了一种基于多模态特征的深度学习模型，以无创方式预测髓内胶质瘤的等级和分子标记的突变状态。研究团队提出的基于多模态融合特征的神经网络在预测髓内胶质瘤的分级、分子标记突变状态等方面的性能，优于其他主流模型。通过这项研究，研究者们首次基于多模态特征预测了ATRX和P53突变状态以及脊髓胶质瘤的等级，这或将无创地提供更多肿瘤特异性病理信息，以确定脊髓胶质瘤的治疗和预后。
      Konstantin Okonechnikov团队研究发现由结构变异引起的新的拓扑关联域，特定于分组的3D染色质环和CTCF绝缘体被DNA高甲基化所取代。验证了这些3D基因组构象所暗示的基因对于患者来源的室管膜瘤模型的生存至关重要，这种方法甚至适用于缺乏可靶向遗传改变的肿瘤，为缺乏可靶向遗传改变的肿瘤提供了揭示肿瘤依赖性基因的新方法。
       北京天坛医院贾文清团队利用H3 K27M突变脊髓弥漫性胶质瘤的基因组分析，深入探讨了H3 K27M突变脊髓弥漫性胶质瘤的临床病理学和分子特征，揭示了其与脑中线胶质瘤的差异性。组织学类型被证实是H3 K27M突变脊髓胶质瘤预后的独立因素，为临床治疗提供了重要信息。该研究为改善这种肿瘤的诊断和治疗策略提供了新的见解。
       瑞典的Karolinska Institutet的研究团队利用单细胞和空间多组学数据分析方法，创建了人类发育中脊髓的全面发育细胞图谱，揭示了神经祖细胞的细胞命运承诺是如何被特定基因集在时空上调控的，识别了人类和啮齿动物脊髓发育中的独特事件，包括神经干细胞的早期休眠、细胞分化的差异调控以及细胞命运选择的独特时空遗传调控。
09
脑转移瘤推崇综合治疗及个体化治疗
       当前脑转移瘤的治疗模式充分体现了综合治疗和个体化治疗的理念。针对不同原发灶病理和分子标志物的靶向药、免疫制剂在脑转移瘤方面均取得了较大的进展，尤其在EGFR、ALK等基因突变的NSCLC脑转移及Her-2阳性乳腺癌脑转移方面，新药层出不穷，近年来发表了多项成果。
       此外，在放射治疗方面，立体定向放疗（SRT）的适应征不断扩大，在小细胞肺癌及脑转移瘤术前放疗中均进行了回顾和前瞻性研究探索，整体治疗趋于精准化，强调正常脑组织的保护及神经认知功能保全。全脑放疗（WBRT）的地位继续受到挑战，且WBRT的方式亦有所改进。
10
替尼泊苷一线诱导化疗治疗新诊断的原发性中枢神经系统淋巴瘤
       高剂量甲氨蝶呤与替尼泊苷一线诱导化疗治疗新诊断的原发性中枢神经系统淋巴瘤患者：研究纳入了2007年至2016年在中国22个中心新诊断的PCNSL的免疫功能正常的成年患者。患者接受HD-MTX或TEN作为一线诱导治疗。分析每个患者队列的客观缓解率、无进展生存期和总生存期。结论：这是第一项使用TEN作为主要药物与HD-MTX比较新诊断的原发性中枢神经系统淋巴瘤的多中心研究。基于TEN的方案不劣于基于HD-MTX的方案，总体反应相似。
【主编】

朴浩哲   辽宁省肿瘤医院

陈忠平   中山大学肿瘤防治中心

杨学军   北京清华长庚医院

【副主编】（按姓氏拼音排序）

吴劲松   复旦大学附属华山医院

张俊平   首都医科大学三博脑科医院

马   军   北京天坛医院

高献书   北京大学第一医院

【编委】（按姓氏拼音排序）

刘丕楠   北京天坛医院

徐建国   四川大学华西医院

林志雄   福建三博福能脑科医院

王贵怀   北京清华长庚医院

肖建平   中国医学科学院肿瘤医院

张   烨   辽宁省肿瘤医院

陈   一   辽宁省肿瘤医院

马玉超   中国医学科学院肿瘤医院

刘志勇   四川大学华西医院

荆林凯   北京清华长庚医院

陈思源   北京天坛医院

吴赞艺   福建医科大学附属第一医院

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