Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial

Background

The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days.

Methods

Forty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m²/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment.

Results

Median age was 10 years (range, 2–21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%).

Conclusions

TMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile.     

MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review

BackgroundThe DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use.MethodsWe performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients.ResultsMethylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP.ConclusionsWe cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.     

替莫唑胺衍生物治疗人脑胶质瘤的实验研究

目的 观察替莫唑胺(TMZ)类水溶性衍生物2T-P400、2T-P600对人脑胶质瘤的抑制效应.方法 体外抑瘤实验:以MTT法测定2T-P400、2T-P600、PEG400、PEG600、TMZ相对于空白对照组对胶质瘤细胞SHG-44的抑制率.体内抑瘤实验:制备荷SHG44人脑胶质瘤裸小鼠模型,将荷瘤鼠随机分为TMZ组、2T-P400组、2T-P600组、聚乙二醇(PEG)组及生理盐水组,TMZ口服给药,其他药物均为鼠尾静脉注射给药,每4天测量肿瘤体积.结果 体外抑瘤效应:2T-P400和2T-P600对SHG44细胞的杀伤效果与TMZ相近,均明显优于PEG400和PEG600 (P ＜0.01).体内抑瘤效应:TMZ组、2T-P400组和2T-P600组抑瘤率亦明显高于PEG组及生理盐水组(P＜0.05),未见明显药物不良反应.结论 2T-P400、2T-P600保留TMZ的抑瘤活性,为胶质瘤病人在术后TMZ类药物化疗提供新的药物及用药途径选择.     

恶性脑胶质瘤14例术后替莫唑胺联合放疗效果观察

目的：探讨三维适形放疗（3D-CRT）联合替莫唑胺治疗（TMZ）术后高分级脑胶质瘤的疗效及安全性。方法：经术后病理证实为高分级胶质瘤28例,随机分成三维适形放射治疗并同期替莫唑胺化疗组（A组）和三维适形放射治疗组（B组）各14例。A组在三维适形放射治疗合并TMZ化疗,B组仅行放射治疗。两组患者放射治疗方法及剂量相同。结果：所有患者都经全脑CT或MRI显示肿瘤治疗有效率及疾病控制率：A组为54.54%和81.81%,B组为20.00%和30.00%。A组中位无进展生存时间（PFS）和总生存时间（OS）分别为14.00个月和21.00个月,B组中位PFS和OS分别为8.85个月和16.64个月。两组总的疾病控制率（DCR）、中位PFS和中位OS差异有统计学意义（P〈0.05）。两组不良反应差异无统计学意义。结论：三维适形放射治疗联合替莫唑胺治疗术后高分级的脑胶质瘤的疗效优于单纯放射治疗且不良反应轻。     

替莫唑胺治疗老年广泛期小细胞肺癌疗效观察

目的:观察对于60~85岁老年广泛期小细胞肺癌（small cell lung cancer,SCLC）患者给予一线化疗药物治疗后6月内复发后二线化疗药物临床疗效及耐受性。方法:选取2013年1月至2017年1月间在研究中心就诊的经过EP方案一线治疗后6月内复发的老年广泛期小细胞肺癌患者44例,分为替莫唑胺组（n=22）和对照组（n=22）。替莫唑胺组给予替莫唑胺每天150 mg/m2,连续服用5天,28天为一周期。对照组给予伊立替康65 mg/m2,d1、8+顺铂75 mg/m2分3天,d2~4,静脉输注。2周期复查评价治疗效果。对比两组有效率、疾病控制率、无进展生存期及不良反应发生率。结果:替莫唑胺组与对照组的有效率、疾病控制率分别为18％ vs 18％、23％ vs 27％,差异无统计学意义（P＞0.05）;替莫唑胺组与对照组的无进展生存时间分别为5.3个月和5.5个月,差异无统计学意义（P＞0．05）;替莫唑胺组的胃肠道反应、腹泻及骨髓抑制明显低于对照组,差异有统计学意义（P＜0．05）。结论:替莫唑胺口服28天一周期方案化疗有效率高,老年患者耐受性好,是经一线治疗后6月内复发的老年广泛期小细胞肺癌患者值得选择的化疗方案。     

Biomarkers and therapeutic advances in glioblastoma multiforme

Glioblastoma multiforme (GBM) is a malignant tumor within the brain. Generally classified as primary and secondary with several different subtypes, ample molecular biomarkers have risen throughout the years which have garnered the attention of researchers. The advancements in genomics and proteomics have allowed researchers to gather prominent molecular biomarkers. All these biomarkers are gathered by means of biopsy or bodily fluid sample collection and are quantitatively analyzed by polymerase chain reaction coupled with other computational technologies. This review highlights the significance, regulation and prevalence of molecular biomarkers such as O⁶‐methylguanine‐DNA methyltransferase, epidermal growth factor receptor vIII, isocitrate dehydrogenase mutation and several others which expressed differently in different types and molecular subtypes of GBM. The discoveries and roles of GBM‐specific microRNAs including miR‐21 and miR‐10b as biomarkers with promising prognostic values were also delineated. The role and mechanism of biomarkers in GBM tumorigenesis are essential in the development of therapy for patients suffering from the disease itself. Thus, this review also discusses the mechanisms, effects and limitations of therapy such as temozolomide, viral gene transfer, biomarker‐based vaccines or even engineered T cells for more specific responses. Biomarkers have displayed a high value and could eventually be utilized as drug targets. It is hoped that by combining different aspects of the disease which present with different biomarkers could lead to the development of a robust, effective and innovative take on GBM therapy.     

不同浓度七氟醚对人脑胶质瘤细胞U251替莫唑胺抵抗的影响及机制初探

目的 探究不同浓度七氟醚对人脑胶质瘤细胞U251替莫唑胺(TMZ)抵抗的影响,并探讨其可能的作用机制.方法 培养对数生长期的人脑胶质瘤细胞U251,传代后将细胞分为3组:对照组、低七氟醚组及高七氟醚组.对照组在5%CO2气体条件下培养,低七氟醚组在5%CO2+1%七氟醚气体条件下培养,高七氟醚组在5%CO2+2.5%七氟醚气体条件下培养,总气流量为2 L/min.MTT法检测3组细胞TMZ半抑制浓度(IC50)的变化,荧光定量链式聚合酶反应(qPCR)检测细胞缺氧诱导因子-1α(HIF-1α)mRNA表达水平的变化,蛋白免疫印迹(Western blotting)检测HIF-1α蛋白表达水平的变化.结果 MTT结果显示对照组细胞TMZ IC50值显著高于高七氟醚组IC50值(P<0.05),而与低七氟醚组IC50值差异无统计学意义(P>0.05).qPCR结果显示对照组HIF-1αmRNA相对表达水平显著高于低七氟醚组及高七氟醚组(P<0.05),且低七氟醚组HIF-1αmRNA相对表达水平显著高于高七氟醚组(P<0.05),Western blotting结果显示对照组HIF-1α蛋白表达水平明显高于低七氟醚组及高七氟醚组,且低七氟醚组HIF-1α蛋白表达水平明显高于高七氟醚组.结论 七氟醚促进人脑胶质瘤细胞U251对TMZ的敏感性,可能与下调HIF-1α有关.