《中国恶性肿瘤学科发展报告（2021）》——神经肿瘤研究进展篇

概述

中枢神经系统（Central Nervous System , CNS）的恶性肿瘤包括原发于颅内和椎管内的肿瘤，以及从远隔部位转移或由邻近结构侵犯至 CNS 的肿瘤。中国癌症年报显示，在我国癌症发病率及死亡率统计中，恶性脑肿瘤的发病率及死亡率均居第九位，儿童恶性脑肿瘤发病率和死亡率均仅次于白血病，居第二位。2021 年，神经肿瘤领域发布了多项诊疗指南，另外新研究、新方法层出不穷。为了梳理 2021 年度神经肿瘤学科的研究进展，推动学科建设，更好地服务临床，在中国抗癌协会的领导和组织下，神经肿瘤专业委员会对本领域中胶质瘤、脑膜瘤、垂体瘤、脊髓肿瘤、儿童脑肿瘤、原发性中枢神经系统淋巴瘤、脑转移瘤等过去一年中的研究进展和未来展望进行总结和阐述。  

1.临床试验助力胶质瘤国内外指南更新

国际指南：美国国家综合癌症网络发布的《中枢神经系统肿瘤指南》[1] 2021年更新两版。美国神经肿瘤学会、美国临床肿瘤学会等推出了《ASCO-SNO成人弥漫星形细胞瘤及少突细胞瘤指南》[2]、“神经外科医生大会关于放射治疗在成人进展性和复发性胶质母细胞瘤管理中的作用的系统综述和循证指南更新”[3]。 国际癌症研究机构发布WHO第5版中枢神经系统肿瘤分类[4，5]，确立了中枢神经系统肿瘤命名和分级的新方法，并对成人和儿童进行区分；分子检测更新定义了多种肿瘤类型和相关亚型，并强调了整合诊断和分层报告的重要性。 国内指南：国家卫健委推出首部《儿童脑胶质瘤诊疗规范》[6]，中国抗癌协会脑胶质瘤专委会发表《胶质母细胞瘤的肿瘤电场治疗专家共识》[7]，中国抗癌协会神经肿瘤专业委员会与上海市抗癌协会神经肿瘤专业委员会同NCCN合作翻译《NCCN脑胶质瘤患者指南中文版》[8]。 国内进展：Chen[9]提出如术中免疫荧光导航也为更大范围切除肿瘤提供可能。Zhang[10]，Yang[11]提出使用纳米材料包裹的材料运送药物，破除血脑屏障限制，使得胶质瘤的复发率有所下降。Zhang[12]等提出了一种可注射水凝胶系统，用于GBM 术后刺激抗肿瘤免疫而减少GBM复发可能。 国内临床试验：2021年已在Clinical Trails注册的临床试验有31个，包括靶向治疗、免疫治疗、新型物理治疗、手术策略等方向。

2.脑膜瘤的分子病理和治疗进展

脑膜瘤在分子病理进行大量研究，为探索脑膜瘤分子病理分型，深入认识脑膜瘤提供了方向。Farshad Nassiri等学者在Nature发表通过DNA体细胞拷贝数畸变、DNA体细胞点突变、DNA甲基化和信使RNA丰度检测对脑膜瘤进行分型，结果显示与现有的脑膜瘤分类方案相比，这些分子分型能更准确地预测了临床预后[13]。每个分子类型（免疫学基因，良性NF2野生型，高代谢和增殖）都表现出独特的原型生物有助于治疗策略制定。 同时脑膜瘤治疗方面亦进行大量研究，越来越多研究结果支持对于偶然发现无症状脑膜瘤进行动态随访观察的治疗策略，同时对于颅底脑膜瘤主张多学科综合治疗，在尽量减小术后神经功能障碍和认知功能障碍的情况最大程度切除肿瘤，对于残留肿瘤术后行立体定向放射神经外科补充治疗，更重视治疗术后患者生活质量的改善[14]。此外有研究证实生长抑素受体的表达可作为配体（如DOTATOC或DOTATATE）进行脑膜瘤放射性核素治疗的靶点[15]。 在中国抗癌协会的大力支持下，神经肿瘤专业委员会脑膜瘤学组已完成《脑膜瘤诊疗指南》的初稿编写。

3.垂体腺瘤研究新进展和治疗新突破

目前用于垂体腺瘤诊断的影像学方法包括MRI及分子功能成像。研究发现，磁共振指纹成像（MRF）可很好地鉴别促性腺激素腺瘤及非促性腺激素腺瘤，对治疗方案的制定具有指导意义[16-19]。 影像学进展方面，分子功能成像包括多种受体显像技术。促肾上腺皮质激素释放激素受体（CRHR）显像中，68Ga-CRH-PET-CT以CRHR为靶点，不仅可以勾画出促肾上腺皮质激素细胞腺瘤的范围，为术中肿瘤切除导航提供有价值的信息，还有助于鉴别垂体和垂体外来源促肾上腺皮质激素依赖的库兴氏综合征。11C-蛋氨酸（11C-Met）PET 与18F-FDG比较，可提高垂体腺瘤检出的敏感性，与MRI图像配准，可更准确的定位11C-Met摄取范围、更可靠地区分肿瘤与正常垂体组织。18F-氟代乙酯-L-酪氨酸（18F-FET）PET可用于生长激素细胞腺瘤的显像及进展、复发评估[18，20-22]。遗传学方面，近几年大量的遗传学研究发现了与垂体肿瘤相关的体细胞突（GNAS，USP8，GPR101）和种系突变（MEN1，细胞周期蛋白依赖性激酶抑制基因，AIP，DICER1，PRKAR1A，PRKACA，SDHx和GPR101）。垂体腺瘤中种系突变约占5% - 7%。除了种系突变，在GPR101中也描述了嵌合现象。嵌合GPR101复制迄今仅在男性患者中被报道[23-42]。 治疗学上，最近几年，癌症免疫治疗是一种很有前途的治疗方法，最近受到越来越多的关注。Mei等报道PD-L1表达在人类功能性腺瘤中，与无功能腺瘤相比，显著较高，提示存在垂体肿瘤的免疫反应。因此，这些研究提高了对于难治性垂体腺瘤考虑免疫治疗的可能性[43-49]。

4.脊髓高级别胶质瘤的精准诊断和治疗

脊髓胶质瘤（Spinal cord glioma）是一种罕见的起源于脊髓神经胶质细胞的原发性肿瘤，年发病率约为0.22/10万人，不超过脊髓肿瘤的30%，脊髓髓内肿瘤的80%[50]。在2021年世界卫生组织（WHO）发布的第五版中枢神经系统肿瘤分类中，新版肿瘤分类的诊断术语采用通用名附加分子特征的方法，进一步细化及整合了胶质瘤在组织学及分子特征信息，对未来指导临床诊断与治疗以及判断预后等方面提供帮助，为脊髓高级别胶质瘤的精准诊断和个体化治疗提供支持[51，52]。然而，脊髓高级别胶质瘤的治疗对于神经外科医师仍然是一项艰巨的挑战，所有治疗方案仅使其存活率略有提高，标准的治疗方案主要以手术为主，根据病理结果辅以放疗和化疗[53-56]。

5.基础与临床研究助力儿童神经肿瘤学科发展

2021年度，儿童中枢神经系统恶性肿瘤的诊疗有了很多进展。Leary等[57]报告在放疗期间增加了carboplatin，可以将Group 3亚型高危型髓母细胞瘤的无事件生存率从54%提高到73%。Liu等[58]报告在高危进展的髓母细胞瘤中，脑脊液cfDNA有着明显的相关性。国内Sun等[59]也证明脑脊液cfDNA在检测髓母细胞瘤疾病进展和临床预后的作用。另外，李昊[60]通过体内及体外实验表明外泌体来源的miRNA分子在儿童髓母细胞瘤发生发展过程中发挥重要作用。儿童髓母细胞瘤、脉络丛乳头状肿瘤等中遗传性胚系突变的研究也取得进展[61- 66]。 儿童室管膜瘤的基础研究近年来进展迅速，国内多家单位在儿童室管膜瘤研究中做出了很好的成绩。例如陈忠平团队[68]发现了ADGRL3突变在室管膜瘤演化过程中的驱动作用。李昊[67]团队证实PARP抑制剂联合放疗是治疗儿童颅内PFA型室管膜瘤的有效手段。 复发或者进展型视路胶质瘤靶向治疗也取得进展[68]，靶向GD2的CAR-T治疗DIPG进行了临床试验[69]，并取得一定的效果。

6.原发性中枢神经系统淋巴瘤诊疗指南即将发布

原发性中枢神经系统淋巴瘤（primary central nervous system lymphoma , PCNSL）是原发于脑实质、颅神经、软脑膜、眼或脊髓，无其他部位受累。是一种罕见的原发结外非霍奇金淋巴瘤亚型，约占所有非霍奇金淋巴瘤1％，所有脑肿瘤的4％[70]。国际上多个区域性或国家的学术组织，针对原发性中枢神经系统淋巴瘤，制定了诊治指南或共识。其中包括美国国家综合癌症网络（National Comprehensive Cancer Network , NCCN）发布的《CNS肿瘤指南》原发性中枢神经系统淋巴瘤部分及英国血液学会（British Society for Haematology, BSH）发布的《原发性中枢神经系统弥漫性大B细胞淋巴瘤诊断与治疗指南》。 在中国抗癌协会的大力支持下，神经肿瘤专业委员会原发性中枢神经系统淋巴瘤学组已完成《中国肿瘤整合诊治指南-原发性中枢神经系统淋巴瘤整合诊治指南》， 拟于2022年进行发布。

7.脑转移瘤领域新药不断研制及强调功能保护

越来越多的新型药物可透过血脑屏障，显示出对颅内病灶良好的疗效。韩国III期ALTA-1L研究[71]的最终结果报道：对于ALK阳性局部晚期或转移性非小细胞肺癌，布加替尼比一代克唑替尼明显提高了3年PFS（43% vs. 19%），对于初诊即发现脑转移的患者可提高总生存。Lancet oncology杂志发表的CheckMate 204研究[72]最终结果表明：纳武利尤单抗联合伊匹木单抗治疗黑色素瘤脑转移，无神经症状和有症状患者3年IPFS 和OS率分别为54.1% vs. 18.9%和71.9% vs. 36.6%。最常见的严重治疗相关不良反应为结肠炎、腹泻、垂体功能下降、肝脏转氨酶升高，发生率约5%，无症状组有1例患者因心肌炎死亡。 放疗联合靶向治疗的研究也有继续报道。一项国内多中心III期随机对照研究[73]结果表明：在全脑放疗的基础上联合同步厄洛替尼并不能进一步提高IPFS和OS，即使是EGFR基因突变患者两组结果亦未达统计学差异。放疗同步药物治疗的时机、目标人群、用药选择等仍需进一步研究。 全脑放疗（WBRT）对认知功能的损伤一直是其应用受限的主要原因，对于认知功能的保护来说，海马回避是一种有效的手段[74]。2021年JCO上发表了一项小细胞肺癌脑预防照射，行海马保护对比常规全脑照射的III期随机对照研究[75]，结果表明在疗后3月神经认知功能评分下降在两组的比例分别为5.8%和23.5%。在疗后6月及疗后2年海马保护组的认知功能均明显优于常规治疗组，而两组的脑部失败率及总生存无差异。台湾一项研究[76]在脑转移患者中进行了类似研究，结果发现海马保护组患者疗后半年的记忆功能明显优于对照组。2021年ASCO-SNO-ASTRO脑转移指南中推荐对于全脑放疗的患者进行海马保护[77]。

【主编】

朴浩哲   辽宁省肿瘤医院

杨学军   清华大学附属北京清华长庚医院

陈忠平   中山大学肿瘤防治中心

【副主编】

马   军   首都医科大学附属北京天坛医院

张俊平   首都医科大学三博脑科医院

吴劲松   复旦大学附属华山医院

高献书   北京大学第一医院

【编委】（按姓氏拼音排序）

毕   楠

毕智勇

陈虹旭

陈家贤

陈思源

陈   一

丛玉玮

窦长武

段   炼

姜   涛

姜   新

李   昊

李志铭

刘志勇

马   辉

马玉超

任青青

邵凌东

沈慧聪

司马秀田

孙时斌

王   洁

王镛斐

王玉林

王跃龙

杨智君

张红梅

张瑞剑

张   烨

【审稿专家】

王贵怀   清华大学附属北京清华长庚医院

刘丕楠   首都医科大学附属北京天坛医院

肖建平   中国医学科学院肿瘤医院

林志雄   福建三博福能脑科医院

徐建国   四川大学华西医院

参考文献

[1]NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. 2021 Version 1. And 2021 Version 2.

[2]Mohile NA, Messersmith H, Gatson NT,et al. Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline. J Clin Oncol. 2022 Feb 1;40(4):403-426.

[3]Ziu M, Goyal S, Olson JJ. Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of radiation therapy in the management of progressive and recurrent glioblastoma in adults. J Neurooncol. 2021 Nov 8.

[4]Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 Aug 2;23(8):1231-1251.

[5]Wen PY, Packer RJ. The 2021 WHO Classification of Tumors of the Central Nervous System: clinical implications. Neuro Oncol. 2021 Aug 2;23(8):1215-1217.

[6]中华人民共和国国家卫生健康委员会. 儿童脑胶质瘤诊疗规范(2021 年版)[J]. 肿瘤

综合治疗电子杂志, 2021, 7(3):10.

[7]中国抗癌协会脑胶质瘤专业委员会, 胶质母细胞瘤的肿瘤电场治疗专家共识撰写组. 胶质母细胞瘤的肿瘤电场治疗专家共识[J]. 中华神经外科杂志, 2021, 37(11):9.

[8]NCCN 脑胶质瘤患者指南

https://www.nccn.org/patients/guidelines/content/PDF/Brain-Gliomas-Chinese-app.pdf

[9]Chen K-T, Chai W-Y, Lin Y-J, et al. Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors. Sci Adv. 2021;7(6):eabd0772.

[10]Zhang J, Chen C, Li A, et al. Immunostimulant hydrogel for the inhibition of malignant glioma relapse post-resection. Nat Nanotechnol. 2021;16(5):538-548.

[11]Yang Z, Du Y, Sun Q, et al. Albumin-Based Nanotheranostic Probe with Hypoxia Alleviating Potentiates Synchronous Multimodal Imaging and Phototherapy for Glioma. ACS Nano. 2020;14(5):6191-6212.

[12]Zhang J, Chen C, Li A, et al. Immunostimulant hydrogel for the inhibition of malignant glioma relapse post-resection. Nat Nanotechnol. 2021 May;16(5):538-548.

[13]Nassiri F, Liu J, Patil V, et al. A clinically applicable integrative molecular classification of meningiomas. Nature. 2021 Sep;597(7874):119-125.

[14]Goldbrunner R, Stavrinou P, Jenkinson MD, et al. EANO guideline on the diagnosis and management of meningiomas. Neuro Oncol. 2021 Jun 28:noab150. 15. Hartrampf PE, [15]Hänscheid H, Kertels O, et al. Long -term results of multimodal peptide receptor radionuclide therapy and fractionated external beam radiotherapy for treatment of advanced symptomatic meningioma. Clin Transl Radiat Oncol. 2020;22:29–32.

[16]Ugga L, Cuocolo R, Solari D, et al. Prediction of high proliferative index in pituitary macroadenomas using MRI-based radiomics and machine learning. Neuroradiology 2019;61(12):1365–73.

[17]Zeynalova A, Kocak B, Durmaz ES, et al. Preoperative evaluation of tumour consistency in pituitary macroadenomas: a machine learning-based histogram analysis on conventional T2-weighted MRI. Neuroradiology 2019;61(7):767–74.

[18]Tjornstrand A, Casar-Borota O, Heurling K, et al. Lower 68 Ga-DOTATOC uptake in nonfunctioning pituitary neuroendocrine tumours compared to normal pituitary gland-a proof-of-concept study. Clin Endocrinol (Oxf) 2019.

[19]Patel V, Liu CSJ, Shiroishi MS, et al. Ultra-high field magnetic resonance imaging for localization of corticotropin-secreting pituitary adenomas. Neuroradiology 2020.

[20]Sanei Taheri M, Kimia F, Mehrnahad M, et al. Accuracy of diffusion-weighted

imaging-magnetic resonance in differentiating functional from non-functional pituitary

macro-adenoma and classification of tumor consistency. Neuroradiol J 2019;32(2):74–85.

[21]Hu J, Yan J, Zheng X, et al. Magnetic resonance spectroscopy may serve as a presurgical predictor of somatostatin analog therapy response in patients with growth hormone-secreting pituitary macroadenomas. J Endocrinol Invest 2019; 42(4):443–51.

[22]Neou M, Villa C, Armignacco R, et al. Pangenomic classification of pituitary neuroendocrine tumors. Cancer Cell 2020;37:123–34.e5.

[23]Asa SL, Ezzat S. An Update on Pituitary Neuroendocrine Tumors Leading to Acromegaly and Gigantism. J Clin Med. 2021 May 22;10(11):2254.

[24]Barry S, Korbonits M. Update on the Genetics of Pituitary Tumors. Endocrinol Metab Clin North Am. 2020 Sep;49(3):433-452.

[25]Lim CT, Korbonits M. UPDATE ON THE CLINICOPATHOLOGY OF PITUITARY ADENOMAS. Endocr Pract. 2018 May;24(5):473-488.

[26]WHO Classification of Tumours Editorial Board.World Health Organization Classification of Tumours of Endocrine Organs .4th edition. Lyon :International Agency for Research on Cancer 2017.

[27]Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770–1786.

[28]Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. NEURO-ONCOLOGY. Advance Access date 29 June 2021.

[29]Saeger W, von Schöning J, Flitsch J, et al. Co -occurrence of Pituitary Neuroendocrine Tumors (PitNETs) and Tumors of the Neurohypophysis. Endocr Pathol .2021 Jun 15.

30.Melmed S. Pituitary-tumor endocrinopathies. N Engl J Med 2020;382(10):937–50. Longo DL, ed

[31]Cohen M, Persky R, Stegemann R, et al. Germline USP8 mutation associated with pediatric Cushing disease and other clinical features: a new syndrome. J Clin Endocrinol Metab 2019;104:4676–82.

[32]Wise-Oringer BK, Zanazzi GJ, Gordon RJ, et al. Familial X-linked acrogigantism:

postnatal outcomes and tumor pathology in a prenatally diagnosed infant and his mother. J Clin Endocrinol Metab 2019;104:4667–75.

[33]Beijers H, Stikkelbroeck NML, Mensenkamp AR, et al. Germline and somatic mosaicism in a family with multiple endocrine neoplasia type 1 (MEN1) syndrome. Eur J Endocrinol 2019;180:K15–9.

[34]Mauchlen R, Carty D, Talla M, et al. Multiple endocrine neoplasia type 1 (MEN1) mosaicism caused by a c.124G>A variant in the MEN1 gene. Endocrine Abstracts 2019;65:CC4.

[35]Stiles CE, Korbonits M. Familial isolated pituitary adenoma. ENDOTEXT, Neuroendocrinology 2020. Chapter 11a11.

[36]Flak MB, Koenis DS, Sobrino A, et al. GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections. J Clin Invest 2020;130:359–73.

[37]Doros L, Schultz KA, Stewart DR, et al. DICER1-Related disorders. In:Pagon RA, Bird TA, Dolan CR, et al, editors. GeneReviews. Seattle (WA): University of Washington; 2020.

[38]Guerrero-Perez F, Fajardo C, Torres Vela E, et al. 3P association (3PAs): pituitary adenoma and pheochromocytoma/paraganglioma. A heterogeneous clinical syndrome associated with different gene mutations. Eur J Intern Med 2019;69:14–9.

[39]Drummond J, Roncaroli F, Grossman AB, et al. Clinical and Pathological Aspects of Silent Pituitary Adenomas. J Clin Endocrinol Metab. 2019;104:2473–2489.

[40]Pepe S, Korbonits M, Iacovazzo D. Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects. J Endocrinol. 2019;240:R21–R45.

[41]Turchini J, Sioson L, Clarkson A, et al. Utility of GATA-3 Expression in the Analysis of Pituitary Neuroendocrine Tumour (PitNET) Transcription Factors. Endocr Pathol.2020;31:150–155.

[42]Trouillas J, Jaffrain-Rea M-L, Vasiljevic A, et al. How to Classify the Pituitary Neuroendocrine Tumors (PitNET)s in 2020. Cancers (Basel). 2020;12.

[43]MacFarlane J, Bashari WA, Senanayake R, et al. Advances in the Imaging of Pituitary Tumors. Endocrinol Metab Clin North Am. 2020 Sep;49(3):357-373.

[44]Dai C, Liu X, Ma W, et al. The Treatment of Refractory Pituitary Adenomas. Front

Endocrinol (Lausanne). 2019 May 29;10:334.

[45]AlMalki MH, Ahmad MM, Brema I, et al. Contemporary Management of Clinically Non-functioning Pituitary Adenomas: A Clinical Review. Clin Med Insights Endocrinol Diabetes. 2020 Jun 24;13:1179551420932921.

[46]Sheehan JM, Vance ML, Sheehan JP, et al. Radiosurgery for Cushing’s disease after failed transsphenoidal surgery. J Neurosurg.(2000)93:738-42.doi:10.3171/jns.2000.93.5.0738.

[47]Tatsi C, Stratakis CA. Aggressive pituitary tumors in the young and elderly. Rev Endocr Metab Disord. 2020;21:213–223.

[48]Dekkers OM, Karavitaki N, Pereira AM. The epidemiology of aggressive pituitary tumors (and its challenges). Rev Endocr Metab Disord. 2020;21:209–212.

[49]Colao A, Grasso L, Giustina A, et al. Acromegaly. Nat Rev Dis Primers. (2019) 5:20.

[50]MILANO M T, JOHNSON M D, SUL J, et al. Primary spinal cord glioma: a Surveillance, Epidemiology, and End Results database study.[J]. Journal of Neuro-Oncology, 2010,98(1): 83-92.

[51]杨学军, 陈宏, 李佳博, 等. 2021年世界卫生组织中枢神经系统肿瘤分类(第五版)整合及分层诊断解读[J]. 中国现代神经疾病杂志 2021年21卷9期764-768页ISTIC PKU, 2021.

[52]LOUIS D N, ARIE P, PIETER W, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary[J]. Neuro-Oncology, 2021.

[53]KOTECHA R, MEHTA M P, CHANG E L, et al. Updates in the management of intradural spinal cord tumors: a radiation oncology focus[J]. Neuro-Oncology, 2019,21(6): 707-718.

[54]YANG K, MAN W, JING L, et al. Clinical Features and Outcomes of Primary Spinal Cord Glioblastoma: A Single-Center Experience and Literature Review[J]. World Neurosurgery, 2020,143.

[55]SUN Z, JING L, FAN Y, et al. Fluorescein-guided surgery for spinal gliomas: Analysis of

220 consecutive cases[J]. International Review of Neurobiology, 2020,151.

[56]ZHU M, CHANG W, JING L, et al. Dual-modality optical diagnosis for precise in vivo identification of tumors in neurosurgery[J]. Theranostics, 2019,9(10): 2827-2842.

[57]Leary SE, Packer RJ, Li Y, et al. Efficacy of carboplatin and isotretinoin in children with high-risk medulloblastoma: a randomized clinical trial from the Children’s Oncology Group. JAMA oncology 2021;7:1313-1321.

[58]Liu AP, Smith KS, Kumar R, et al. Serial assessment of measurable residual disease in medulloblastoma liquid biopsies. Cancer cell 2021;39:1519-1530. e1514.

[59]Sun Y, Li M, Ren S, et al. Exploring genetic alterations in circulating tumor DNA from cerebrospinal fluid of pediatric medulloblastoma. Scientific reports 2021;11:1-8.

[60]Xue P,Huang SH,Han X,et al.Exosomal miR-101-3p and miR-423-5p inhibit medulloblastoma tumorigenesis through targeting FOXP4 and EZH2. Cell Death Differ, 2021；29(1), 82-95.

[61]Massimino M, Signoroni S, Boschetti L, et al. Medulloblastoma and familial adenomatous polyposis: Good prognosis and good quality of life in the long‐term? Pediatric Blood & Cancer 2021;68:e28912.

[62]Verkouteren BJ, Cosgun B, Vermeulen RJ, et al. Prevalence of medulloblastoma in basal cell nevus syndrome patients with a PTCH1 mutation. Neuro-oncology 2021;23:1035-1036.

[63]Li Y, Liu H, Li T, et al. Choroid Plexus Carcinomas With TP53 Germline Mutations: Management and Outcome. Frontiers in oncology 2021:3706.

[64]Liu AP, Wu G, Orr BA, et al. Outcome and molecular analysis of young children with choroid plexus carcinoma treated with non-myeloablative therapy: results from the SJYC07 trial. Neuro-oncology advances 2021;3:vdaa168.

[65]Thomas C, Soschinski P, Zwaig M, et al. The genetic landscape of choroid plexus tumors in children and adults. Neuro-oncology 2021;23:650-660.

[66]Wang J, Xi S-Y, Zhao Q, et al. Driver mutations in ADGRL3 are involved in the evolution of ependymoma. Laboratory Investigation 2022:1-9.

[67]Han J, Yu M, Bai Y, et al. Elevated CXorf67 expression in PFA ependymomas suppresses DNA repair and sensitizes to PARP inhibitors. Cancer Cell 2020;38:844-856. e847.

[68]Fangusaro J, Onar-Thomas A, Poussaint TY, et al. A phase II trial of selumetinib in

children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a

Pediatric Brain Tumor Consortium study. Neuro-oncology 2021;23:1777-1788.

[69]Majzner RG, Ramakrishna S, Yeom KW, et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 2022:1-10.

[70]田东亮,刘海英,张学新.原发性中枢神经系统淋巴瘤诊疗进展[J].国际神经病学神经

外科学志,2021,48(06):567-570.

[71]Camidge DR,Kim HR, Ahn MJ, et al. Brigatinib Versus Crizotinib in ALK Inhibitor–NaiveAdvanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial. Journal of Thoracic Oncology. 2021;16(12):2091–2108.

[72]Tawbi HA, Forsyth PA, Hodi FS, et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncology. 2021;22(12):1692-1704.

[73]Yang TJ, Wijetunga NA, Yamada J, et al. Whole-brain radiotherapy with and without concurrent erlotinib in NSCLC with brain metastases: a multicenter, open-label, randomized, controlled phase III trial.Neuro-Oncology. 2021;23(6):967-978.

[74]Brown PD, Gondi V, Pugh S, et al. Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: Phase III trial NRG Oncology CC001. Journal of Clinical Oncology. 2020; 38:1019-1029.

[75]Dios NR, Counago F, Murcia Mejia M, et al. Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR Study. Journal of Clinical Oncology. 2021;30(28):3118-3127.

[76]Yang W, Chen Y, Yang C, et al. Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial. Neuro-Oncology. 2021;23(3):478-486.

[77]Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. Journal of Clinical Oncology. 2021;40(5):492-516.