Cold Tumor Research
报告归档病情分析行动清单

分级行动清单

按证据强度与可行性排序的检测与治疗候选，以及可以带进诊室逐条勾选的问题清单。
分级依据
第 0 级全部可用现有石蜡蜡块完成，不需要重新取材，不增加孩子任何负担； 第 1 级需要额外送检或安排；第 2 级是有生物学依据但证据等级中等的候选，主要用于复发时或维持期结束后讨论。 每一项的推导见分析正文。
第 0 级现在就做全部用现有蜡块 · 费用低 · 约一周出结果
# 项目 解决什么问题 备注
1DNA 甲基化芯片定分子亚型，可能直接改变治疗与预后判断[28][29]已申请 ✓ 优先级最高
2MGMT 启动子甲基化 + MGMT 蛋白 IHCTMZ 是否值得继续；能否加用 CCNU[11][12]报告全程未检测此项
3RB1 蛋白 IHCCDK4/6 抑制剂是否有生物学依据 —— 伴随诊断逻辑chr13q 缺失一条，需确认蛋白状态
4B7-H3（CD276）IHC为将来 CAR-T 入组铺路
5EZHIP IHC解释三家医院不一致的 H3K27me3 判读；可能打开 ONC201 的门[30][31]
第 1 级值得投入
6RNA 融合测序DNA panel 对融合有方法学盲区，这是唯一还可能检出可成药融合的检查
7家系 TP53 检测 + 遗传咨询为父母和兄弟姐妹做；也能确认是否为新发突变
8正式讨论电场治疗（TTFields / Optune）见第 2 级第 14 项
9建立 LFS 长期随访方案Toronto 方案；今后尽量用 MRI 代替 CT
第 2 级有生物学依据，证据等级中等复发时的候选，或维持期后的叠加
# 方案 依据 前提条件
10阿贝西利（首选）或瑞波西利，± TMZ，± 依维莫司CDK4 扩增 35.2 拷贝；儿童 I 期已确定剂量；CDK4 扩增用药先例见去分化脂肪肉瘤与 NCI-MATCH Z1C[1][7][9][10][8]必须先确认 RB1 蛋白保留
11卡铂 ± PARP 抑制剂BRCA2 / RAD51 / REV3L 单拷贝丢失（假说级）先做 HRD 评分
12WEE1 / ATR 抑制剂p53 双等位失活 → G2/M 合成致死[25][26][27]需入组临床试验
13B7-H3 CAR-TB2M / HLA 丢失 → 绕开 MHC 的免疫治疗更合理[21][22][23]先做 B7-H3 IHC
14电场治疗（TTFields）成人 GBM 一线获批，依据为 EF-14 III 期；中国 2020 年批准。标签 ≥22 岁，儿童属超说明书[36][37]幕上、右额顶颞、已完成放疗 —— 位置合适；毒性几乎只有头皮反应
15洛莫司汀（CCNU）儿童 HGG 复发的标准骨干药之一；若 MGMT 甲基化，TMZ+CCNU 有成人 III 期数据（CeTeG/NOA-09）[13]看第 2 项结果
16再次手术复发若局限可切，最大安全切除仍是最有效的单一干预
17贝伐珠单抗控制水肿、改善症状、减激素 —— 不延长生存，定位要清楚
不建议依据不足或机制上不成立的方向
PD-1 / PD-L1 抑制剂单药B2M 缺失 + HLA-B/DRB1/DQB1 缺失 + TMB 0.64（极低）+ MSS —— 四条独立证据都指向无效
哌柏西利入脑差（P-gp/BCRP 强底物）。同为 CDK4/6i，应选阿贝西利或瑞波西利
MDM2 抑制剂需要野生型 p53 才有用；本例 p53 已双等位失活
伏瑞西替尼等 IDH 抑制剂IDH1/2 野生型
达拉非尼 + 曲美替尼等 BRAF/MEK 抑制剂BRAF V600E 阴性，且全 panel 无 MAPK 通路改变
ONC201 / 多达韦普隆（现阶段）2025 年 FDA 加速批准的适应症限于 H3 K27M 突变型弥漫中线胶质瘤（ORR 22%），本例 H3K27M 阴性且位于半球。除非 EZHIP IHC 阳性，否则依据不足[38][39]

可以带进诊室的问题清单

可以逐条勾选。打印时勾选框会一并印出。

  • 甲基化芯片什么时候出结果？出来后是否会重新召集 MDT？

  • 能否正式判定切除程度为 GTR（全切）？

    2026-06-02 的增强 MRI 报告「原占位现未明确见显示」，环形强化判读为术后反应；但该检查在术后第 5 天，已过 72 小时窗口。请主刀结合术中所见给出分级。

  • 能不能用现有蜡块加做 MGMT 启动子甲基化？如果未甲基化，维持期方案是否会调整？

  • 能不能加做 RB1 蛋白免疫组化？

    用途：判断 CDK4/6 抑制剂是否有生物学依据

  • 能不能加做 B7-H3（CD276）和 EZHIP 免疫组化？

  • 能不能补做一次 RNA 层面的融合检测？

    DNA panel 对融合的检出有盲区，且本例插入片段偏短（140 bp）

  • 鉴于胚系 TP53（李-佛美尼），今后的随访能否以 MRI 为主、减少 CT？是否可以启动 Toronto 方案的全身监测？

  • 父母和其他家庭成员的 TP53 检测如何安排？

  • 本院或合作单位是否有可入组的儿童高级别胶质瘤临床试验？

    CDK4/6 抑制剂、B7-H3 CAR-T、WEE1/ATR 抑制剂方向

  • 电场治疗（TTFields）在本例是否可行？13 岁属超说明书，医院是否有使用经验？

  • 放疗后第一次复查 MRI 如果看起来变差，如何鉴别假性进展与真进展？能否加做灌注成像（PWI/DSC）或 MRS？

  • 如果复发，预设的挽救方案是什么？（洛莫司汀？卡铂？再手术？）

    提前问，比复发后再问要从容得多。

参考文献

正文中的上标编号对应下表。点击编号可跳到条目，点击条目标题可打开原文。

  1. [1]
    Phase 1 study of abemaciclib in children with recurrent and refractory solid tumors including malignant brain tumors

    Mol Cancer Ther 2019 (AACR abstract C002)

  2. [2]
    P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib

    Invest New Drugs 2015

  3. [3]
    Clinical pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib

    Clin Pharmacokinet 2020

  4. [4]
    Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma

    J Neurooncol 2019

  5. [5]
    A phase 0 trial of ribociclib in recurrent glioblastoma incorporating a tumor PD- and PK-guided expansion cohort

    Clin Cancer Res 2019

  6. [6]
    Single nucleus transcriptomics, PK and PD of combined CDK4/6 and mTOR inhibition in recurrent high-grade glioma

    medRxiv 2024

  7. [7]
    Ribociclib and everolimus in children with recurrent or refractory malignant brain tumors (NCT03387020)

    ClinicalTrials.gov

  8. [8]
    Adolescent glioma subtype responds to CDK4/6 inhibitor

    Dana-Farber Cancer Institute, 2024

  9. [9]
    Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with the CDK4 inhibitor palbociclib: a phase 2 trial

    JAMA Oncol 2016

  10. [10]
    NCI-MATCH subprotocol Z1C: palbociclib in cancers with CDK4 or CDK6 amplification

    ClinicalTrials.gov

  11. [11]
    Crosstalk between repair pathways elicits double-strand breaks in alkylated DNA and implications for the action of temozolomide

    eLife 2021

  12. [12]
    MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma

    Pediatr Blood Cancer 2007

  13. [13]
    Lomustine-temozolomide combination therapy versus standard temozolomide therapy in newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial

    Lancet 2019

  14. [14]
    Radiotherapy results in decreased time to second cancer in children with Li-Fraumeni syndrome

    JNCI 2025

  15. [15]
    Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53-related cancer syndromes

    Lancet Oncol 2021

  16. [16]
    A systematic review of high-grade glioma associated with Li-Fraumeni syndrome

    Neurosurg Rev 2025

  17. [17]
    Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11-year follow-up of a prospective observational study

    Lancet Oncol 2016

  18. [18]
    Resistance to checkpoint blockade therapy through inactivation of antigen presentation

    Nat Commun 2017

  19. [19]
    Antitumor immune responses in B2M-deficient cancers

    Cancer Immunol Res 2023

  20. [20]
    B2M loss of heterozygosity in melanoma is associated with increased numbers of activated NK cells

    Cancer Res 2023 (AACR abstract 5965)

  21. [21]
    CAR T cells redirected to B7-H3 for pediatric solid tumors: current status and future perspectives

    Front Immunol 2024

  22. [22]
    BrainChild-03: B7-H3-specific CAR T cell locoregional immunotherapy for DIPG/DMG and recurrent pediatric CNS tumors (NCT04185038)

    ClinicalTrials.gov

  23. [23]
    Loc3CAR: locoregional delivery of B7-H3-CAR T cells for pediatric patients with primary CNS tumors (NCT05835687)

    ClinicalTrials.gov

  24. [24]
    CAR-T cell therapy for pediatric high-grade gliomas: opportunities, challenges and future directions

    Neoplasia / EJC Paediatr Oncol 2026

  25. [25]
    Wee1 kinase inhibitor adavosertib with radiation in newly diagnosed DIPG: a Children's Oncology Group phase I consortium study

    Neurooncol Adv 2022

  26. [26]
    Phase I/II study of the WEE1 inhibitor adavosertib in combination with carboplatin in children (AcSé-ESMART Arm C)

    Clin Cancer Res 2024

  27. [27]
    ATR inhibitor elimusertib suppresses drug persister clones in TP53-mutated disease

    Blood 2024

  28. [28]
    cIMPACT-NOW update 9: recommendations on utilization of genome-wide DNA methylation profiling for CNS tumor diagnostics

    Neurooncol Adv 2025

  29. [29]
    Enhancing the accuracy of molecular classification of pediatric CNS tumors: a dual-classifier approach using DNA methylation profiling

    Acta Neuropathol Commun 2025

  30. [30]
    EZHIP is a specific diagnostic biomarker for posterior fossa ependymoma group PFA and diffuse midline glioma H3-WT with EZHIP overexpression

    Acta Neuropathol Commun 2020

  31. [31]
    PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism

    Nat Commun 2019

  32. [32]
    Pediatric-type diffuse high-grade gliomas: prognosis by methylation subgroup

    MedLink Neurology

  33. [33]
    Molecular landscape of pediatric-type IDH-wildtype, H3-wildtype hemispheric glioblastomas

    Lab Invest 2022

  34. [34]
    Extent of tumor resection and survival in pediatric patients with high-grade gliomas: a systematic review and meta-analysis

    J Neurosurg Pediatr 2022

  35. [35]
    Treatment of high-grade glioma in children and adolescents (HIT-GBM-C outcomes)

    Neurosurg Focus 2010

  36. [36]
    Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma (EF-14): a randomized clinical trial

    JAMA 2017

  37. [37]
    Impact of tumor treating fields on overall and progression-free survival in newly diagnosed glioblastoma: a systematic review and meta-analysis

    Neurosurg Rev 2026

  38. [38]
    FDA grants accelerated approval to dordaviprone (Modeyso) for H3 K27M-mutated diffuse midline glioma in patients aged 1 year and older

    National Brain Tumor Society, 2025

  39. [39]
    Dordaviprone for diffuse midline glioma: a landmark approval or a premature step?

    PubMed 2025

  40. [40]
    Recent application of advanced MR imaging to predict pseudoprogression in high-grade glioma patients

    Magn Reson Med Sci 2017