基于分子分型的个体化治疗在儿童髓母细胞瘤治疗中的应用

doi:10.3969/j.issn.1672-6731.2020.04.008

摘要/Abstract

摘要：

目的探讨基于肿瘤分子分型的个体化治疗在儿童髓母细胞瘤治疗中的临床价值。方法 2017年12月至2019年12月共23例髓母细胞瘤患儿均予手术切除并经术后病理检查证实诊断，并行肿瘤基因检测，根据肿瘤分子分型进行术后5年生存率风险分层并予以个体化放化疗，记录肿瘤切除率、术后并发症、对放化疗的反应以及肿瘤复发情况。结果 23例髓母细胞瘤患儿分子分型为WNT型3例、SHH型7例、Group3型5例和Group4型8例，基于上述分子分型，风险分层为低危组（5例）、标危组（8例）、高危组（5例）和极高危组（5例）。肿瘤全切除20例，次全切除3例。术后3例脑积水加重，2例出现小脑缄默，3例出现呛咳、面瘫等神经系统症状，经对症治疗后缓解。根据风险分层术后辅以相应放化疗方案。术后平均随访（15.15±3.45）个月，低危组和标危组放化疗耐受程度较强，未见肿瘤复发；高危组和极高危组放化疗后出现明显骨髓抑制和消化道症状，经对症治疗后缓解，高危组有2例、极高危组有3例肿瘤复发。结论根据髓母细胞瘤的分子分型进行风险分层更加精准，基于该分子分型的个体化治疗方案可以避免临床过度治疗或治疗不足，值得临床推广。

关键词: 髓母细胞瘤, 儿童, 基因分型技术, 精准医学

Abstract:

Objective To explore the clinical efficacy of individualized therapy based on molecular classification in the treatment of medulloblastoma in children. Methods The clinical data of 23 children with medulloblastoma confirmed by pathology after surgery from December 2017 to December 2019 were analyzed retrospectively. The 5-year survival rate risk was stratified according to tumor molecular classification, and individualized chemoradiotherapy were given. Chemoradiotherapy response, postoperative complications and tumor recurrence were recorded. Results There were 23 cases of medulloblastoma. The tumor molecular genes were classified as WNT type 3 cases, SHH type 7 cases, Group3 type 5 cases and Group4 type 8 cases. The patients were divided into 4 groups according to the results of molecular classification as risk factors:low risk group (n=5), standard risk group (n=8), high risk group (n=5) and very high risk group (n=5). Total tumor resection was performed in 20 cases, subtotal resection in 3 cases. Three cases with hydrocephalus aggravated after surgery, 2 cases with cerebellar silence, 3 cases with cough paralysis and other neurological symptoms, which were relieved after symptomatic treatment. Individualized treatment (radiotherapy + chemotherapy) was carried out according to the risk stratification. The mean postoperative follow-up period was (15.15±3.45) months. The tolerance of radiotherapy and chemotherapy in the low risk group and the standard risk group was strong, and no tumor recurrence was observed. After radiotherapy and chemotherapy, the high risk group and the very high risk group showed obvious bone marrow suppression and gastrointestinal symptoms, which were relieved after symptomatic treatment, and there were 2 cases in the high risk group and 3 cases in the very high risk group occuring tumor recurrence. Conclusions The risk stratification based on molecular classification is more accurate, and the individualized therapy could avoid excessive or insufficient clinical treatment, which is worthy of clinical promotion.

Key words: Medulloblastoma, Child, Genotyping techniques, Precision medicine

施伟, 薛萍, 余建忠, 赵瑞, 张毅, 李昊. 基于分子分型的个体化治疗在儿童髓母细胞瘤治疗中的应用[J]. 中国现代神经疾病杂志, 2020, 20(4): 294-300.

SHI Wei, XUE Ping, YU Jian-zhong, ZHAO Rui, ZHANG Yi, LI Hao. Application of individualized therapy based on molecular classification in the treatment of medulloblastoma in children[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2020, 20(4): 294-300.

http://journal11.magtechjournal.com/cjcnn/CN/Y2020/V20/I4/294

参考文献

[1] Gajjar AJ, Robinson GW. Medulloblastoma-translating discoveries from the bench to the bedside[J]. Nat Rev Clin Oncol, 2014, 11:714-722.
[2] Smoll NR, Drummond KJ. The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children[J]. J Clin Neurosci, 2012, 19:1541-1544.
[3] Ramaswamy V, Remke M, Bouffet E, Bailey S, Clifford SC, Doz F, Kool M, Dufour C, Vassal G, Milde T, Witt O, von Hoff K, Pietsch T, Northcott PA, Gajjar A, Robinson GW, Padovani L, André N, Massimino M, Pizer B, Packer R, Rutkowski S, Pfister SM, Taylor MD, Pomeroy SL. Risk stratification of childhood medulloblastoma in the molecular era:the current consensus[J]. Acta Neuropathol, 2016, 131:821-831.
[4] Holgado BL, Guerreiro Stucklin A, Garzia L, Daniels C, Taylor MD. Tailoring medulloblastoma treatment through genomics:making a change, one subgroup at a time[J]. Annu Rev Genomics Hum Genet, 2017, 18:143-166.
[5] Lafay-Cousin L, Smith A, Chi SN, Wells E, Madden J, Margol A, Ramaswamy V, Finlay J, Taylor MD, Dhall G, Strother D, Kieran MW, Foreman NK, Packer RJ, Bouffet E. Clinical, pathological, and molecular characterization of infant medulloblastomas treated with sequential high-dose chemotherapy[J]. Pediatr Blood Cancer, 2016, 63:1527-1534.
[6] Cohen BH, Geyer JR, Miller DC, Curran JG, Zhou T, Holmes E, Ingles SA, Dunkel IJ, Hilden J, Packer RJ, Pollack IF, Gajjar A, Finlay JL; Children's Oncology Group. Pilot study of intensive chemotherapy with peripheral hematopoietic cell support for children less than 3 years of age with malignant brain tumors, the CCG-99703 phase Ⅰ/Ⅱ study:a report from the children's oncology group[J]. Pediatr Neurol, 2015, 53:31-46.
[7] Tchelebi L, Ashamalla H, Graves PR. Mutant p53 and the response to chemotherapy and radiation[J]. Subcell Biochem, 2014, 85:133-159.
[8] Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, Kranenburg TA, Hogg T, Poppleton H, Martin J, Finkelstein D, Pounds S, Weiss A, Patay Z, Scoggins M, Ogg R, Pei Y, Yang ZJ, Brun S, Lee Y, Zindy F, Lindsey JC, Taketo MM, Boop FA, Sanford RA, Gajjar A, Clifford SC, Roussel MF, McKinnon PJ, Gutmann DH, Ellison DW, Wechsler-Reya R, Gilbertson RJ. Subtypes of medulloblastoma have distinct developmental origins[J]. Nature, 2010, 468:1095-1099.
[9] Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO, Rutkowski S, McCabe M, Collins VP, B äcklund ML, Haberler C, Bourdeaut F, Delattre O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM. Molecular subgroups of medulloblastoma:an international Meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas[J]. Acta Neuropathol, 2012, 123:473-484.
[10] Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJ, Martin DC, Castelo-Branco P, Baskin B, Ray PN, Bouffet E, von Bueren AO, Jones DT, Northcott PA, Kool M, Sturm D, Pugh TJ, Pomeroy SL, Cho YJ, Pietsch T, Gessi M, Rutkowski S, Bognar L, Klekner A, Cho BK, Kim SK, Wang KC, Eberhart CG, Fevre-Montange M, Fouladi M, French PJ, Kros M, Grajkowska WA, Gupta N, Weiss WA, Hauser P, Jabado N, Jouvet A, Jung S, Kumabe T, Lach B, Leonard JR, Rubin JB, Liau LM, Massimi L, Pollack IF, Shin Ra Y, Van Meir EG, Zitterbart K, Schüller U, Hill RM, Lindsey JC, Schwalbe EC, Bailey S, Ellison DW, Hawkins C, Malkin D, Clifford SC, Korshunov A, Pfister S, Taylor MD, Tabori U. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma[J]. J Clin Oncol, 2013, 31:2927-2935.
[11] Shih DJ, Northcott PA, Remke M, Korshunov A, Ramaswamy V, Kool M, Luu B, Yao Y, Wang X, Dubuc AM, Garzia L, Peacock J, Mack SC, Wu X, Rolider A, Morrissy AS, Cavalli FM, Jones DT, Zitterbart K, Faria CC, Schüller U, Kren L, Kumabe T, Tominaga T, Shin Ra Y, Garami M, Hauser P, Chan JA, Robinson S, Bognár L, Klekner A, Saad AG, Liau LM, Albrecht S, Fontebasso A, Cinalli G, De Antonellis P, Zollo M, Cooper MK, Thompson RC, Bailey S, Lindsey JC, Di Rocco C, Massimi L, Michiels EM, Scherer SW, Phillips JJ, Gupta N, Fan X, Muraszko KM, Vibhakar R, Eberhart CG, Fouladi M, Lach B, Jung S, Wechsler-Reya RJ, Fèvre-Montange M, Jouvet A, Jabado N, Pollack IF, Weiss WA, Lee JY, Cho BK, Kim SK, Wang KC, Leonard JR, Rubin JB, de Torres C, Lavarino C, Mora J, Cho YJ, Tabori U, Olson JM, Gajjar A, Packer RJ, Rutkowski S, Pomeroy SL, French PJ, Kloosterhof NK, Kros JM, Van Meir EG, Clifford SC, Bourdeaut F, Delattre O, Doz FF, Hawkins CE, Malkin D, Grajkowska WA, Perek-Polnik M, Bouffet E, Rutka JT, Pfister SM, Taylor MD. Cytogenetic prognostication within medulloblastoma subgroups[J]. J Clin Oncol, 2014, 32:886-896.
[12] Skowron P, Ramaswamy V, Taylor MD. Genetic and molecular alterations across medulloblastoma subgroups[J]. J Mol Med (Berl), 2015, 93:1075-1084.
[13] Jiang T, Jia G, Zhang YQ. Risk classification, diagnosis and treatment of medulloblastoma[J]. Zhonghua Shen Jing Wai Ke Za Zhi, 2014, 30:743-746.[姜涛, 甲戈, 张玉琪. 髓母细胞瘤的危险度分级和诊疗现状[J]. 中华神经外科杂志, 2014, 30:743-746.]
[14] Jiang T, Wang JM, Du J. The clinical prognosis of medulloblastoma in children and the analysis of risk factors[J]. Zhonghua Shen Jing Wai Ke Za Zhi, 2016, 32:338-343.[姜涛,王军梅, 杜江. 儿童髓母细胞瘤的临床预后及危险因素分析[J]. 中华神经外科杂志, 2016, 32:338-343.]
[15] Ramaswamy V, Remke M, Adamski J, Bartels U, Tabori U, Wang X, Huang A, Hawkins C, Mabbott D, Laperriere N, Taylor MD, Bouffet E. Medulloblastoma subgroup-specific outcomes in irradiated children:who are the true high-risk patients[J]? Neuro Oncol, 2016, 18:291-297.
[16] Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, Gururangan S, McLendon RE, Bigner DD, Lipp ES, Perreault S, Cho YJ, Grant G, Kim SK, Lee JY, Rao AA, Giannini C, Li KK, Ng HK, Yao Y, Kumabe T, Tominaga T, Grajkowska WA, Perek-Polnik M, Low DCY, Seow WT, Chang KTE, Mora J, Pollack IF, Hamilton RL, Leary S, Moore AS, Ingram WJ, Hallahan AR, Jouvet A, Fèvre-Montange M, Vasiljevic A, Faure-Conter C, Shofuda T, Kagawa N, Hashimoto N, Jabado N, Weil AG, Gayden T, Wataya T, Shalaby T, Grotzer M, Zitterbart K, Sterba J, Kren L, Hortobágyi T, Klekner A, László B, Pócza T, Hauser P, Schüller U, Jung S, Jang WY, French PJ, Kros JM, van Veelen MC, Massimi L, Leonard JR, Rubin JB, Vibhakar R, Chambless LB, Cooper MK, Thompson RC, Faria CC, Carvalho A, Nunes S, Pimentel J, Fan X, Muraszko KM, López-Aguilar E, Lyden D, Garzia L, Shih DJ, Kijima N, Schneider C, Adamski J, Northcott PA, Kool M, Jones DT, Chan JA, Nikolic A, Garre ML, Van Meir EG, Osuka S, Olson JJ, Jahangiri A, Castro BA, Gupta N, Weiss WA, Moxon-Emre I, Mabbott DJ, Lassaletta A, Hawkins CE, Tabori U, Drake J, Kulkarni A, Dirks P, Rutka JT, Korshunov A, Pfister SM, Packer RJ, Ramaswamy V, Taylor MD. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup:a retrospective integrated clinical and molecular analysis[J]. Lancet Oncol, 2016, 17:484-495.
[17] Thompson EM, Bramall A, Herndon JE 2nd, Taylor MD, Ramaswamy V. The clinical importance of medulloblastoma extent of resection:a systematic review[J]. J Neurooncol, 2018, 139:523-539.
[18] Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, Gröbner S, Segura-Wang M, Zichner T, Rudneva VA, Warnatz HJ, Sidiropoulos N, Phillips AH, Schumacher S, Kleinheinz K, Waszak SM, Erkek S, Jones DTW, Worst BC, Kool M, Zapatka M, Jä ger N, Chavez L, Hutter B, Bieg M, Paramasivam N, Heinold M, Gu Z, Ishaque N, Jä ger-Schmidt C, Imbusch CD, Jugold A, Hübschmann D, Risch T, Amstislavskiy V, Gonzalez FG, Weber UD, Wolf S, Robinson GW, Zhou X, Wu G, Finkelstein D, Liu Y, Cavalli FM, Luu B, Ramaswamy V, Wu X, Koster J, Ryzhova M, Cho YJ, Pomeroy SL, Herold-Mende C, Schuhmann M, Ebinger M, Liau LM, Mora J, McLendon RE, Jabado N, Kumabe T, Chuah E, Ma Y, Moore RA, Mungall AJ, Mungall KL, Thiessen N, Tse K, Wong T, Jones SJM, Witt O, Milde T, Von Deimling A, Capper D, Korshunov A, Yaspo ML, Kriwacki R, Gajjar A, Zhang J, Beroukhim R, Fraenkel E, Korbel JO, Brors B, Schlesner M, Eils R, Marra MA, Pfister SM, Taylor MD, Lichter P. The whole-genome landscape of medulloblastoma subtypes[J]. Nature, 2017, 547:311-317.
[19] Kann BH, Park HS, Lester-Coll NH, Yeboa DN, Benitez V, Khan AJ, Bindra RS, Marks AM, Roberts KB. Postoperative radiotherapy patterns of care and survival implications for medulloblastoma in young children[J]. JAMA Oncol, 2016, 2:1574-1581.
[20] Grill J, Sainte-Rose C, Jouvet A, Gentet JC, Lejars O, Frappaz D, Doz F, Rialland X, Pichon F, Bertozzi AI, Chastagner P, Couanet D, Habrand JL, Raquin MA, Le Deley MC, Kalifa C; French Society of Paediatric Oncology. Treatment of medulloblastoma with postoperative chemotherapy alone:an SFOP prospective trial in young children[J]. Lancet Oncol, 2005, 6:573-580.
[21] Hoff KV, Hinkes B, Gerber NU, Deinlein F, Mittler U, Urban C, Benesch M, Warmuth-Metz M, Soerensen N, Zwiener I, Goette H, Schlegel PG, Pietsch T, Kortmann RD, Kuehl J, Rutkowski S. Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT'91[J]. Eur J Cancer, 2009, 45:1209-1217.
[22] Kortmann RD, Kühl J, Timmermann B, Mittler U, Urban C, Budach V, Richter E, Willich N, Flentje M, Berthold F, Slavc I, Wolff J, Meisner C, Wiestler O, Sörensen N, Warmuth-Metz M, Bamberg M. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood:results of the German prospective randomized trial HIT'91[J]. Int J Radiat Oncol Biol Phys, 2000, 46:269-279.
[23] Yang YX, He XS. Diagnosis and treatment progress of medulloblastoma in children[J]. Zhonghua Shen Jing Yi Xue Za Zhi, 2019, 18:847-850.[杨勇祥, 贺晓生. 儿童髓母细胞瘤的诊断和治疗进展[J]. 中华神经医学杂志, 2019, 18:847-850.]
[24] Guerreiro Stucklin AS, Ramaswamy V, Daniels C, Taylor MD. Review of molecular classification and treatment implications of pediatric brain tumors[J]. Curr Opin Pediatr, 2018, 30:3-9.

选择文件类型/文献管理软件名称

选择包含的内容

2 基于分子分型的个体化治疗在儿童髓母细胞瘤治疗中的应用

Application of individualized therapy based on molecular classification in the treatment of medulloblastoma in children

RichHTML

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	宫剑. 积极促进我国小儿神经外科的发展[J]. 中国现代神经疾病杂志, 2023, 23(5): 383-387.
[2]	曾高, 刘雨桐, 孙澎, 杜建新. 儿童脑动静脉畸形治疗策略[J]. 中国现代神经疾病杂志, 2023, 23(5): 388-392.
[3]	韩国庆, 蒲珂, 李庆国. 儿童脑海绵状血管瘤临床特点及发病机制研究进展[J]. 中国现代神经疾病杂志, 2023, 23(5): 393-397.
[4]	徐琛, 张毅, 王敏, 赵瑞, 施伟, 李昊. 不同年龄段儿童终丝脂肪浸润/脂肪瘤型脊髓拴系综合征临床特征与手术疗效分析[J]. 中国现代神经疾病杂志, 2023, 23(5): 398-404.
[5]	魏民, 蒋文彬, 詹琪佳, 李森, 刘晨, 肖波. 选择性脊神经后根切断术治疗痉挛型脑瘫患儿疗效与影响因素分析[J]. 中国现代神经疾病杂志, 2023, 23(5): 405-411.
[6]	郭中印, 彭鹏, 陈籽荣, 张晓琳, 董民海, 曾括, 万丽君, 向网, 万锋. 幕上肿瘤患儿手术后行脑室-腹腔分流术危险因素分析[J]. 中国现代神经疾病杂志, 2023, 23(5): 412-417.
[7]	彭小娇, 葛明, 吴迪, 蔡英杰, 陈佳树, 梁琛. 单中心儿童颅咽管瘤手术后下丘脑性肥胖危险因素分析[J]. 中国现代神经疾病杂志, 2023, 23(5): 418-424.
[8]	韩国庆, 蒲珂, 黄志发, 尚彦国, 李庆国. 儿童脑动静脉畸形治疗方式及预后分析[J]. 中国现代神经疾病杂志, 2023, 23(5): 425-432.
[9]	刘智强, 陈金桃, 唐文龙, 翁超群, 张金锋, 林志雄. Dandy-Walker综合征患儿腹腔分流术前后临床与影像学特征分析[J]. 中国现代神经疾病杂志, 2023, 23(5): 433-438.
[10]	汤亚南. 儿童和青少年功能性神经系统疾病诊断与治疗进展[J]. 中国现代神经疾病杂志, 2023, 23(2): 143-147.
[11]	王孟泽, 杨雷, 赵迁浩. 儿童黏液样胶质神经元肿瘤一例[J]. 中国现代神经疾病杂志, 2022, 22(5): 439-443.
[12]	邱银凤, 郭艺. 儿童线粒体病神经影像学特征[J]. 中国现代神经疾病杂志, 2022, 22(12): 1094-1098.
[13]	孙崇然, 许晶虹, 张布衣, 许素素, 董飞, 卫博星, 蒋飚, 张建民. 2021年世界卫生组织中枢神经系统肿瘤分类（第五版）儿童型弥漫性胶质瘤分类解读[J]. 中国现代神经疾病杂志, 2021, 21(9): 791-803.
[14]	袁兴, 田茂强, 余小华, 杨昌键, 窦庆阳, 束晓梅. 神经刺激术治疗儿童难治性癫研究进展[J]. 中国现代神经疾病杂志, 2021, 21(8): 696-700.
[15]	王俊华, 张玉琪, 张庆琳, 刘伟, 李杰飞, 陈拓宇. 术前化疗在儿童颅内恶性肿瘤中的应用[J]. 中国现代神经疾病杂志, 2021, 21(5): 416-422.

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

2 基于分子分型的个体化治疗在儿童髓母细胞瘤治疗中的应用

Application of individualized therapy based on molecular classification in the treatment of medulloblastoma in children

RichHTML

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价