基于IDH1基因检测联合体外药敏试验的恶性脑胶质瘤个体化综合治疗的疗效评价
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摘要
目的:研究恶性脑胶质瘤患者异柠檬酸脱氢酶-1(isocitrate dehydrogenase-1,IDH1)突变状态与体外药敏试验结果相关性,以及基于二者的恶性脑胶质瘤患者个体化综合治疗的疗效评价。方法:选择术后病理确诊为恶性脑胶质瘤的患者67例,用Sanger测序法检测IDH1基因突变状态,并取其新鲜标本采用胶滴肿瘤药敏检测技术(CD-DST法)进行体外药敏试验,分析二者之间关联性。根据是否按照体外药敏实验结果进行规范疗程的化疗,将患者分为个体化治疗组和非个体化治疗组,比较两组患者临床疗效。结果:67例患者中,IDH1基因突变者14例,未突变者53例,IDH1基因突变患者卡莫司汀(BCUN)、依托泊苷(VP-16)、替莫唑胺(TMZ)体外药敏试验敏感性高于IDH1野生型患者,差异具有统计学意义(P<0.05)。IDH1基因突变患者中位生存期为30个月,IDH1野生型患者为14个月,差异具有统计学意义(P<0.05)。个体化治疗组患者中位生存时间为22个月,非个体化治疗组患者中位生存时间为14个月,差异具有统计学意义(P<0.05)。IDH1基因突变并行个体化治疗亚组中位生存时间为32个月,明显长于其他亚组,差异具有统计学意义(P<0.05)。结论:IDH1基因检测联合体外药敏试验指导恶性脑胶质瘤患者的个体化综合治疗能获得较好的临床疗效。
Objective:To study the correlation between the mutational status of isocitrate dehydrogenase-1(isocitrate dehydrogenase-1,IDH1) and the results of in vitro drug sensitivity test in patients with malignant gliomas and to evaluate the efficacy of the two methods in individual chemotherapy of malignant gliomas.Methods:Sanger sequencing was used to detect the mutation status of IDH1 in 67 patients with malignant glioma diagnosed by pathology after operation,and the drug sensitivity test in vitro was performed by colloidal drop tumor susceptibility assay(CD-DST) in fresh samples. Then analyze the relationship between them. Patients were divided into individualized treatment group and non-individualized treatment group according to whether conduct chemotherapy individually and standardly by the result of the drug sensitivity test or not. Results: Among the 67 patients,14 had mutation of IDH1 gene and53 had not. The drug sensitivity of BCUN,VP-16 and TMZ in mutant-type was higher than that of wild-type IDH1 patients by in vitro. The difference was statistically significant( P < 0. 05). The median survival time of IDH1 mutation patients was 30 months and that of IDH1 wild type patients was 14 months. The difference was statistically significant( P < 0. 05). The median survival time of individualized treatment patients was 22 months and that of non-individualized treatment group was 14 months. The difference was statistically significant( P < 0. 05). The median survival time of IDH1 mutation combined with individualized treatment subgroup was 32 months,which was significantly longer than that of other subgroups. The difference was statistically significant( P < 0. 05). Conclusion: The combination of IDH1 gene detection and external drug sensitivity test to guide individual comprehensive treatment in patients with malignant brain glioma can obtain better clinical effect.
Objective:To study the correlation between the mutational status of isocitrate dehydrogenase-1(isocitrate dehydrogenase-1,IDH1) and the results of in vitro drug sensitivity test in patients with malignant gliomas and to evaluate the efficacy of the two methods in individual chemotherapy of malignant gliomas.Methods:Sanger sequencing was used to detect the mutation status of IDH1 in 67 patients with malignant glioma diagnosed by pathology after operation,and the drug sensitivity test in vitro was performed by colloidal drop tumor susceptibility assay(CD-DST) in fresh samples. Then analyze the relationship between them. Patients were divided into individualized treatment group and non-individualized treatment group according to whether conduct chemotherapy individually and standardly by the result of the drug sensitivity test or not. Results: Among the 67 patients,14 had mutation of IDH1 gene and53 had not. The drug sensitivity of BCUN,VP-16 and TMZ in mutant-type was higher than that of wild-type IDH1 patients by in vitro. The difference was statistically significant( P < 0. 05). The median survival time of IDH1 mutation patients was 30 months and that of IDH1 wild type patients was 14 months. The difference was statistically significant( P < 0. 05). The median survival time of individualized treatment patients was 22 months and that of non-individualized treatment group was 14 months. The difference was statistically significant( P < 0. 05). The median survival time of IDH1 mutation combined with individualized treatment subgroup was 32 months,which was significantly longer than that of other subgroups. The difference was statistically significant( P < 0. 05). Conclusion: The combination of IDH1 gene detection and external drug sensitivity test to guide individual comprehensive treatment in patients with malignant brain glioma can obtain better clinical effect.
引文
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[15] Yanxin Lu,Jakub Kwintkiewicz,Yang Liu,et al.Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair[J].Cancer Res,2007,77(7):1709-1718.
[16] Selzer MJ,Bennett BD,Joshi AD,et al.Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1[J].Cancer Res,2010,70:8981-8987.
[17] Zhang C,Moore LM,Li X,et al.IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma[J].Neuro-Oncology,2013,15(9):1114-1126.
[18] Wick W,Hartmann C,Engel C,et al.NOA-04 randomized phase Ⅲ trial of sequential radiochemotherapy of anaplastic glioma with procarbazine,lomustine,and vincristine or temozolomide[J].J Clin Oncol,2009,27(35):5874-5880.
[19] Li Ting,Jia Yuming,Lei Kaijian.An introduction to the methods of drug sensitivity test of tumor cells in vitro[J].Modern Oncology,2016,24(5):828-830.[李婷,贾钰铭,雷开键.体外肿瘤细胞药敏试验方法概论[J].现代肿瘤医学,2016,24(5):828-830.]
[20] Chen ZP,Zhang JP,Chen JW,et al.Predictive chemotherapy for malignant glioma guided by in vitro drug susceptibility test[J].Guangdong Medical Journal,2005,26(9):1183-1185.[陈忠平,张俊平,陈建文,等.体外药敏试验指导的恶性脑胶质瘤预见性化疗[J].广东医学,2005,26(9):1183-1185.]
[2] Ostrom QT,Gittleman H,Fulop J,et al.CBTRUS statistical report:Primary brain and central nervous system tumors diagnosed in the United States in 2008-2012[J].Neuro Oncol,2015,17(Suppl 4):iv1-iv62.
[3] Louis DN,Perry A,Reifenberger G,et al.The 2016 world health organization classification of tumours of the central nervous system:A summary[J].Acta Neuropathol,2016,131(6):803-820.
[4] National Comprehension Cancer Network.NCCN clinical practice guidelines in oncology:Central nervous system cancer(2018,V1)[EB/OL].(2018-3-20).http://www.nccn.org/professional/physician_gla/pdf/cns.pdf.
[5] Jiang T,Wang RZ,Zhou LF,et al.Consensus of Chinese experts on multidisciplinary diagnosis and treatment of glioma in(MDT)[J].Chinese Journal of Neurosurgery,2018,34(2):113-118.[江涛,王任直,周良辅,等.胶质瘤多学科诊治(MDT)中国专家共识[J].中华神经外科杂志,2018,34(2):113-118.]
[6] Jiang T,Mao Y,Chen ZP,et al.Guidelines for molecular diagnosis and treatment of brain gliomas in China[J].Chinese Journal of Neurosurgery,2014,30(5):435-444.[江涛,毛颖,陈忠平,等.中国脑胶质瘤分子诊疗指南[J].中华神经外科杂志,2014,30(5):435-444.]
[7] Parsons DW,Jones S,Zhang X,et al.An integrates genomic analysis of human glioblastoma multiforme[J].Science,2008,321(5897):1807-1812.
[8] Montalban-Bravo G,DiNardo CD.The role of IDH mutant in acute myeloid leukemia[J].Future Oncol,2018,14(10):979-993.
[9] Waitkus MS,Diplas BH,Yan H.Biological role and therapeutic potential of IDH mutation in cancer[J].Cancer Cell,2018,34(2):186-195.
[10] Bleeker FE,Lamba S,Leenstra S,et al.IDH1 mutations at residue PR132[IDH1(R132)] occur frequently in high-grade gliomas but not in other solid tumors[J].Hum Mutat,2009,30(1):7-11.
[11] Kang MR,Kim MS,Oh JE,et al.Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers[J].Int J Cancer,2009,125(2):353-355.
[12] Huixia Zhu,Ye Zhang,Jianfeng Chen,et al.IDH1 R132H mutation enhances cell migration by activating AKT-mTOR signaling pathway,but sensitize cells to 5-FU treatment as NADPH and GSH are reduced[J].PLoS One,2017,12(1):e0169038.
[13] Wang JB,Dong DF,Wang MD,et al.IDH1 overexpression induced chemotherapy resistance and IDH1 mutation enhanced chemotherapy sensitivity in glioma cells in vitro and in vivo[J].Asian Pac J Cancer Prev,2014,15(1):427-432.
[14] Tateishi K,Wakimoto H,Iafrate AJ,et al.Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion[J].Cancer Cell,2015,28(6):773-784.
[15] Yanxin Lu,Jakub Kwintkiewicz,Yang Liu,et al.Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair[J].Cancer Res,2007,77(7):1709-1718.
[16] Selzer MJ,Bennett BD,Joshi AD,et al.Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1[J].Cancer Res,2010,70:8981-8987.
[17] Zhang C,Moore LM,Li X,et al.IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma[J].Neuro-Oncology,2013,15(9):1114-1126.
[18] Wick W,Hartmann C,Engel C,et al.NOA-04 randomized phase Ⅲ trial of sequential radiochemotherapy of anaplastic glioma with procarbazine,lomustine,and vincristine or temozolomide[J].J Clin Oncol,2009,27(35):5874-5880.
[19] Li Ting,Jia Yuming,Lei Kaijian.An introduction to the methods of drug sensitivity test of tumor cells in vitro[J].Modern Oncology,2016,24(5):828-830.[李婷,贾钰铭,雷开键.体外肿瘤细胞药敏试验方法概论[J].现代肿瘤医学,2016,24(5):828-830.]
[20] Chen ZP,Zhang JP,Chen JW,et al.Predictive chemotherapy for malignant glioma guided by in vitro drug susceptibility test[J].Guangdong Medical Journal,2005,26(9):1183-1185.[陈忠平,张俊平,陈建文,等.体外药敏试验指导的恶性脑胶质瘤预见性化疗[J].广东医学,2005,26(9):1183-1185.]