Temozolomide treatment of refractory epilepsy in a patient with an oligodendroglioma

A 40-year-old man with a left frontotemporal grade II oligodendroglioma developed seizures that were refractory to 14 antiepileptic medications, the ketogenic diet, and epilepsy surgery. With temozolomide therapy, his seizure frequency gradually changed from 30 partial seizures per day to a single simple partial seizure in 6 months. No additional therapeutic measures were introduced during this time. This reduction in seizure frequency appears attributable solely to temozolomide therapy.     

替莫唑胺在高级别脑胶质瘤术后同步放化疗中的临床研究

目的比较替莫唑胺不同的时效、应用剂量在成人脑恶性胶质瘤患者进行术后放疗同步替莫哇胺(TMZ)治疗中的疗效差异。方法 56例18周岁以上恶性胶质瘤患者,均经手术肉眼全切或部分切除肿瘤,Karnofsky评分60分以上,随机分为实验A组(TMZ小剂量组)和对照B组(TMZ标准剂量组)各28例。A组放疗剂量20Gy后口服替莫唑胺75mg/m2,连续服用5天,28天为1个周期,放疗结束后给予4周期化疗;B组放疗同步给予替莫唑胺75mg/m2直至放疗结束,结束后14天按150mg/m2连用5天,28天为1个周期,给予4周期化疗。观察A组和B组骨髓抑制、消化道、急性脑损伤发生率,以及两组患者近期疗效、中位生存时间和1、2年总生存率。结果 A组Ⅰ~Ⅱ度不良反应发生率较B组高(P<0.05),Ⅲ度血液毒性反应较B组低(P<0.05),A组Ⅰ~Ⅱ度不良胃肠道反应发生率较B组低(P<0.05)。A组中位生存期13.9个月,1、2年生存率分别为64.3%和0.0%,不差于B组的14.2个月及71.4%和3.6%(P>0.05)。结论应用小剂量替莫唑胺可降低同步放化疗过程中的血液毒性及胃肠道毒性反应,治疗有效率、患者生存期、疾病无进展时间与放疗联合替莫唑胺的标准剂量疗效相当。     

B-Raf inhibitor vemurafenib in combination with temozolomide and fotemustine in the killing response of malignant melanoma cells

In the treatment of metastatic melanoma, a highly therapy-refractory cancer, alkylating agents are used and, for the subgroup of BRAF^V600E cancers, the B-Raf inhibitor vemurafenib. Although vemurafenib is initially beneficial, development of drug resistance occurs leading to tumor relapse, which necessitates the requirement for combined or sequential therapy with other drugs, including genotoxic alkylating agents. This leads to the question whether vemurafenib and alkylating agents act synergistically and whether chronic vemurafenib treatment alters the melanoma cell response to alkylating agents. Here we show that a) BRAF^V600E melanoma cells are killed by vemurafenib, driving apoptosis, b) BRAF^V600E melanoma cells are neither more resistant nor sensitive to temozolomide/fotemustine than non-mutant cells, c) combined treatment with vemurafenib plus temozolomide or fotemustine has an additive effect on cell kill, d) acquired vemurafenib resistance of BRAF^V600E melanoma cells does not affect MGMT, MSH2, MSH6, PMS2 and MLH1, nor does it affect the resistance to temozolomide and fotemustine, e) metastatic melanoma biopsies obtained from patients prior to and after vemurafenib treatment did not show a change in the MGMT promoter methylation status and MGMT expression level. The data suggest that consecutive treatment with vemurafenib and alkylating drugs is a reasonable strategy for metastatic melanoma treatment.     

miR -21抑制替莫唑胺诱导U87细胞凋亡的体外实验研究

目的 探讨miR -21过表达在替莫唑胺诱导胶质瘤U87细胞凋亡中的作用及其机制.方法 miR - 21过表达载体转染U87细胞,Hoechst 33258染色和流式细胞分析凋亡,Westem blot验证Bax和Bcl -2表达及检测Caspase -3活性.结果 替莫唑胺可显著诱导U87细胞凋亡,上调Bax 表达、下调Bcl-2表达及增加Caspase -3活性.U87细胞预转染miR -21过表达载体后,替莫唑胺的这种效应可部分被抑制.结论 miR -21过表达可通过下调Bax/Bcl -2比率及Caspase -3活性部分抑制替莫唑胺诱导的U87细胞凋亡,提示胶质瘤中miR -21过表达可能是胶质瘤对替莫唑胺耐药的一大新的因素.     

Ⅲ、Ⅳ级脑胶质瘤术后调强放疗联合替莫唑胺化疗的临床研究

目的评价Ⅲ、Ⅳ级脑胶质瘤术后调强放疗同步替莫唑胺化疗的疗效和毒副反应。方法回顾性分析我科2006年1月至2009年1月22例Ⅲ、Ⅳ级脑胶质瘤术后患者资料,所有患者采用调强放疗同步整合加量技术,处方剂量为PGTV 60Gy/25次,2.4Gy/次;PCTV 50Gy/25次,2.0Gy/次。其中有9例患者在放疗开始时口服替莫唑胺,剂量为150mg·m-2·d-1,连服5天,每4周为1个周期,最多连续服用6个周期。结果全组1、2年总生存率是68.8%、56%。平均生存时间12.1个月。单因素分析结果显示病理分级（χ2=15.232,P=0.000）和化疗（χ2=7.128,P=0.008）是影响预后的因素。多因素分析结果显示病理分级（P=0.002）是影响预后的独立因素。结论调强放疗同步整合加量技术同步替莫唑胺化疗是安全有效的,生存结果同历史对照相似。更确切的疗效需扩大病例数进一步研究。     

替莫唑胺化疗方案联合全脑放疗治疗非免疫功能缺陷PCNSL的临床观察

目的研究替莫唑胺化疗方案联合全脑放疗治疗非免疫功能缺陷PCNSL的临床效果。方法回顾性分析应用替莫唑胺化疗方案联合全脑放疗治疗的168例非免疫功能缺陷PCNSL患者的基本资料、临床表现、化疗周期、化疗疗效、不良反应、生存分析、随访时间等数据信息,研究了替莫唑胺化疗方案联合全脑放疗治疗非免疫功能缺陷PCNSL患者的临床疗效。结果 168例患者治疗后随访时间为0~24个月;平均生存期为(11.8±2.3)个月。CR 51例(30.35%)、PR 63例(37.50%)、SD 23例(13.69%)、PD 31例(18.45%)、有效率67.86%以及临床控制率81.55%。不良反应主要有:贫血、骨髓抑制、疲劳、恶心呕吐等。结论替莫唑胺化疗方案联合全脑放疗治疗能够比较有效地提高患者生存率,值得临床推广应用。     

评价替莫唑胺对脑胶质瘤治疗敏感性的新方法

背景与目的：替莫唑胺（temozolomide,TMZ）是治疗胶质母细胞瘤的唯一化疗药。O⁶-甲基鸟嘌呤DNA甲基转移酶（O⁶-methylguanine-DNA methyltransferase,MGMT）基因启动子甲基化是评价TMZ敏感性的唯一指标。但通过检测MGMT的甲基化程度来评估TMZ的敏感性是不够的,因为目前MGMT检测只是定性检测,而且这种检测只能反映DNA损伤修复的一条通路,而另两条通路的修复情况却没有反映出来。方法：该研究一方面是应用高分辨率熔解曲线（high resolution melting,HRM）,对MGMT的甲基化进行定量检测,同时应用实时荧光定量聚合酶链反应（real-time fluorescent quantitative polymerase chain reaction,RTFQPCR）来探讨另外两条修复通路蛋白N-甲基化嘌呤DNA糖基化酶（N-methylpurine DNA glycosylase,MPG）和人类烷烃羟化酶基因同系物2（alkane hydroxylase gene homolog 2,ALKBH2）的mRNA表达。将MPG和ALKBH2的表达分为高表达和低表达。结果：结合MGMT的甲基化（阳性）和非甲基化（阴性）程度,再把MPG和ALKBH2结合起来评估患者对TMZ的敏感性。三阳性（MGMT非甲基化,MPG阳性和ALKBH2阳性）为化疗抵抗,两阳性为不感,两阴性为次敏感,三阴性（MGMT甲基化,MPG阴性和ALKBH2阴性）为最敏感。结合8例胶质母细胞瘤患者的检测和生存期,结果与我们的判断结果相吻合,三阴性的患者生存时间最长,三阳性的患者的生存时间最短。结论：通过定量检测MGMT同时结合MPG和ALKBH2可以更精准地判断TMZ的敏感性。     

替莫唑胺治疗复发性原发中枢神经系统淋巴瘤的临床效果

目的：回顾性分析替莫唑胺辅助治疗原发性中枢神经系统淋巴瘤的临床效果。方法：确诊复发的原发性中枢神经系统淋巴瘤46例,根据治疗方式分为非替莫唑胺组（26例）和替莫唑胺组（20例）,非替莫唑胺组予以大剂量甲氨蝶呤联合利妥昔单抗化疗,替莫唑胺组予以增加同步替莫唑胺化疗,统计不良反应、缓解效果,随访生存期。结果：替莫唑胺组治疗有效率85%,显著高于非替莫唑胺组的有效率50%（P＜0.05）,替莫唑胺组患者复发后生存期中位数高于非替莫唑胺组（P＜0.05）,且替莫唑胺组Kaplan?Meier生存期曲线较非替莫唑胺组也显著延长。结论：替莫唑胺对治疗复发性原发中枢神经系统淋巴瘤有一定疗效,可改善预后。     

Targeting Aurora kinase B attenuates chemoresistance in glioblastoma via a synergistic manner with temozolomide

BackgroundRecent studies have demonstrated that aberrant expression or activation of kinases results in oncogenesis of a wide range of cancers including GBM. Inhibition of kinases expression induces a reduction of therapy resistance. In this study, we investigate the underlying mechanism by which glioblastoma (GBM) cells acquire resistance to Temozolomide (TMZ) through Aurora kinase B (AURKB) thus to identify novel therapeutic targets and prognostic biomarkers for GBM.MethodsAURKB was identified as a key candidate kinase-encoding gene in chemoresistance regulation by using kinome-wide bioinformatic analysis. Afterwards, the potential biological functions of AURKB in oncogenesis and chemoresistance were investigated by lentivirus-dependent silencing of AURKB combined with qRT-PCR, western blot and in vivo intra-cranial xenograft mice models. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of AURKB in glioma patients. Lastly, Chou-Talalay method was used to confirm the synergistic effect of TMZ combined with AURKB inhibitor.ResultsAURKB was among the most significantly up-regulated kinase-coding genes in TMZ resistant GBM cells according to database GSE68029, moreover, an increased expression of AURKB was closely associated with poor prognosis in glioma and GBM patients. AURKB knock-down resensitized U87 resistant cells to TMZ both in vitro and in vivo. Additionally, the combination of TMZ and Hesperadin, a specific AURKB inhibitor, significantly suppressed the proliferation of TMZ resistant GBM cells thus dramatically prolonged the survival of xenograft mice viaa synergistic effect with TMZ.ConclusionElevated AURKB expression was strongly correlated to TMZ resistant acquisition and poor prognosis, furthermore, targeting AURKB would be a potential therapeutic target for GBM patients.