选择性化疗方案治疗恶性胶质瘤的疗效和生存情况分析

背景与目的：O^6-甲基鸟嘌呤-DNA甲基转移酶（O^6-methylguanine-DNA methyhransferase,MGMT）表达与胶质瘤患者的化疗耐药相关。本研究总结MGMT高表达和低表达恶性胶质瘤患者的化疗方案、近期疗效和生存情况．分析选择性化疗是否对MGMT高表达患者有益。方法：自2000年8月至2006年1月,中山大学肿瘤防治中心神经肿瘤科收治的经手术后病理确诊的成人恶性脑胶质瘤患者57例．所有病例化疗前均有可评价病灶。化疗前用免疫组化方法检测肿瘤组织MGMT表达情况．对MGMT高表达者．尽量避免使用亚硝脲类或替莫唑胺单药化疗,采用不含亚硝脲类或替莫唑胺方案,或由替莫唑胺（temozolomide,TMZ）和顺铂组成联合化疗方案;或亚硝脲类药物、替莫唑胺分别与其他细胞毒药物组成联合化疗方案（VM-26、DDP、CBP、IFO、VP16）;对MGMT低表达者,不限制亚硝脲类药物或替莫唑胺的应用。结果：35例患者MGMT高表达,22例MGMT低表达,MGMT低表达组的客观有效率（objective response,OR）和疾病控制率（response rate,RR）高于MGMT高表达组（40．9％：22．9％和72．7％：60.0%．但差异无统计学意义（P〉0．05）。57例中位随访时间11．7个月（0．7～53．4）。MGMT低表达组和高表达组中位无疾病进展时间（Drogressive-free survival,PFS）分别是8．5个月（95％CI 4．8—19．3）和6．7（95％CI 3．7—9．3）,中位生存时间（overail survival,OS）分别是20．3（95％CI 14．3～）和16．105％CI 11．1～26．2）,中位PFS和0S在MGMT低表达组和高表达组差异无统计学意义（P〉0．05）。结论：在化疗前检测恶性胶质瘤MGMT表达情况,对MGMT高表达患者选用有助于克服耐药的化疗方案进行选择性化疗。可使MGMT高表达患者的近期疗效（客观有效率和疾病控制率）和生存时间（无疾病进展生存和总生存）达到MGMT低表达患者水平。     

MGMT在人脑胶质瘤中的表达及其意义

目的：探讨MGMT的表达水平与脑胶质瘤的关系。方法：53例脑胶质瘤标本分为4组，经免疫组化染色后，观察MGMT的表达部位和程度。结果：MGMT在脑胶质瘤中的表达呈棕黄色或棕褐色粗大颗粒，定位于胞浆内，阳性细胞散在或局灶性，染色强度及分布不均、缺乏明显规律。不同病理分级脑胶质瘤的MGMT阳性表达率无显著性差异（P=0．335）；MGMT表达阳性与MGMT表达阴性的脑胶质瘤患者的平均年龄组间无显著性差异（P=0．457）；男性与女性脑胶质瘤患者的MGMT阳性表达率之问无显著性差异（P=0．519）。结论：MGMT的表达水平与脑胶质瘤的恶性度、患者的年龄及性别无明显相关性，仅根据肿瘤恶性度而使用烷化剂进行化疗是不科学的，测定MGMT在脑胶质瘤中的表达水平有助于评估人脑胶质瘤细胞对烷化剂的耐药程度。     

MGMT在人脑胶质瘤中的表达及其意义

目的:探讨MGMT的表达水平与脑胶质瘤的关系.方法: 53例脑胶质瘤标本分为4组,经免疫组化染色后,观察MGMT的表达部位和程度.结果: MGMT在脑胶质瘤中的表达呈棕黄色或棕褐色粗大颗粒,定位于胞浆内,阳性细胞散在或局灶性,染色强度及分布不均、缺乏明显规律.不同病理分级脑胶质瘤的MGMT阳性表达率无显著性差异(P=0.335);MGMT表达阳性与MGMT表达阴性的脑胶质瘤患者的平均年龄组间无显著性差异(P=0.457);男性与女性脑胶质瘤患者的MGMT阳性表达率之间无显著性差异(P=0.519).结论: MGMT的表达水平与脑胶质瘤的恶性度、患者的年龄及性别无明显相关性,仅根据肿瘤恶性度而使用烷化剂进行化疗是不科学的,测定MGMT在脑胶质瘤中的表达水平有助于评估人脑胶质瘤细胞对烷化剂的耐药程度.     

MGMT不同表达水平与替莫唑胺对胃肠胰神经内分泌肿瘤疗效的相关性

目的:通过检测肿瘤组织中O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的表达,探讨其与胃肠胰神经内分泌瘤以替莫唑胺为基础化疗患者预后的相关性。方法:收集2017年至2019年在我院接受替莫唑胺联合替吉奥化疗的15例晚期胃肠胰神经内分泌瘤患者的肿瘤组织,采用免疫组织化学法检测肿瘤组织中MGMT蛋白表达情况,根据表达情况分为MGMT阴性组和MGMT阳性组,并对患者长期随访,进行无进展生存时间和药物安全性的评定,对MGMT表达水平与替莫唑胺治疗效果行相关性分析。结果:15例患者肿瘤组织MGMT表达阴性者为8例（53.3%）,MGMT表达阳性者为7例（46.7%）;MGMT阴性组患者化疗6个疗程后,客观缓解率（ORR）为35.7%(3/8),明显高于MGMT阳性组的0(0/7);MGMT表达阳性组患者的中位无进展生存时间（mPFS）为6个月,而MGMT表达阴性组患者的mPFS目前无法得出,但明显长于MGMT阳性组,两组间差异具有统计学意义（P=0.000 2）。化疗不良反应均为2级以下的骨髓抑制和消化道反应。结论:基于替莫唑胺化疗方案的疗效与MGMT在肿瘤组织中的表达状态相关,MGMT表达与否可以用作胃肠胰神经内分泌瘤患者对替莫唑胺治疗反应的生物学指标。     

贝伐单抗联合化疗治疗复发性恶性胶质瘤:附12例经验

背景与目的 :美国综合癌症网(National Comprehensive Cancer Net,NCCN)治疗指南推荐贝伐单抗联合化疗治疗复发性恶性胶质瘤。但截至目前,中国脑胶质瘤患者这方面的报道较少。本文总结我们应用贝伐单抗联合化疗治疗12例复发性恶性胶质瘤的临床经验,探讨安全性与疗效。方法:12例复发性恶性胶质瘤均行贝伐单抗联合化疗。贝伐单抗5mg/kg,每两周一次。TMZ化疗方案的选择基于肿瘤组织DNA甲基转移酶(O6-methylguanine-DNA methyltransferase,MGMT)的免疫组化检测结果,行甲基化特异PCR(MSP-PCR)检测MGMT启动子甲基化程度。MGMT阴性表达(-)者,接受TMZ标准化疗[200 mg(/m2.d),d1-5,四周方案];MGMT阳性表达(+)者,或者MGMT阴性表达(-)者既往已接受标准剂量TMZ治疗但病情进展者,接受TMZ剂量密度方案[75mg(/m2.d),d1-21,四周方案]。结果:12例患者共接受63次贝伐单抗治疗,中位4次(3-10次)。12例患者均可评价客观疗效,完全缓解(complete remission,CR)2例(16.7%),部分缓解(partial remission,PR)2例(16.7%),微效(minimal remission,MR)8例(66.7%),疾病控制率(CR+PR+MR)为100%。中位无进展生存(progression freesurvival,PFS)为4.3个月(95%CI:2.4~7.3),6个月的PFS率为40.6%。最严重不良反应是Ⅲ度粒细胞减少症与白细胞减少症,各1例次(1.6%)。最常见的轻至中度不良反应包括Ⅱ度的腹泻8例次(12.7%)、Ⅱ度疲乏5例次(7.9%)、高血压2例次(3.2%)。结论:贝伐单抗联合化疗治疗国人复发恶性胶质瘤是安全的,疗效也令人满意。     

MGMT基因启动子甲基化检测在脑胶质瘤化疗中的意义

背景与目的：如何预测和克服肿瘤细胞对化疗药物的耐药性,实施个体化治疗是肿瘤化疗急需解决的问题。与基因启动子甲基化密切相关的DNA损伤修复基因O^6-甲基鸟嘌呤-DNA甲基转移酶（O^6-methylguanine-DNA methyhransferase,MGMT）表观沉默与肿瘤对烷化剂药物化疗敏感性密切相关。本研究探讨检测MGMT基因启动子CpG岛甲基化在判断脑胶质瘤患者预后及预测肿瘤对烷化剂药物耐药性中的意义。方法：甲基化特异性PCR（MSP）法检测脑胶质瘤组织及肿瘤细胞株MGMT基因启动子甲基化状态,蛋白印迹和免疫组化法测定蛋白表达。MTF法检测肿瘤细胞株对烷化剂药物敏感性,将患者随访资料针对MGMT甲基化状态绘制Kaplan-Meier生存曲线,并进行log—rank检验分析。结果：39例脑胶质瘤患者组织MGMT基因启动子甲基化发生率为46．2％,蛋白表达阳性率为61．5％,且肿瘤组织中MGMT基因甲基化状态与蛋白表达显著相关（P〈0．05）：6例正常组织均未检测出基因甲基化。MGMT基因过甲基化的脑胶质瘤SHG44细胞株用5-Aza-CdR处理后完全脱甲基化．MGMT蛋白恢复了表达,同时细胞株对烷化剂药物敏感性也发生逆转．由敏感转变为耐受。在采用手术、放疗和烷化剂尼莫司汀化疗等综合治疗的39例脑胶质瘤患者中,MGMT基因甲基化的患者生存率显著高于MGMT基因未甲基化患者（P〈0．05）。结论：MGMT基因甲基化状态与蛋白表达及肿瘤细胞对烷化剂药物敏感性密切相关,有可能替代MGMT蛋白检测成为判断脑胶质瘤患者预后和预测肿瘤对烷化剂化疗耐药性的标志分子。     

胶质瘤MGMT启动子甲基化及其临床意义

目的 分析O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因启动子甲基化状态及其与胶质瘤临床病理特征、预后的关系。方法 收集2012年1月至2013年6月间行手术治疗的70例胶质瘤组织和14例非肿瘤患者正常脑组织，采用甲基化特异性 PCR法（MSP）检测MGMT甲基化水平，分析其与胶质瘤临床病理特征的关系。比较不同MGMT甲基化状态的高、低级别胶质瘤患者的总生存（OS），Cox比例风险回归模型分析影响低级别胶质瘤患者的OS的因素。结果 70例胶质瘤患者中48例（68.6％）MGMT基因启动子甲基化，而正常脑组织标本中仅2例（14.3％）MGMT甲基化，差异有统计学意义（P＜0.05）。MGMT甲基化与年龄、性别、肿瘤类型、KPS评分、p53和Ki-67表达无关（P＞0.05）；与病理分级有关（P＜0.05）。低级别脑胶质瘤患者中，MGMT甲基化患者中位OS为30个月，明显长于非甲基化者的11个月，差异具有统计学意义（P＜0.05）。单因素分析显示WHO病理分级、烷化剂化疗、MGMT甲基化与低级别脑胶质瘤患者OS有关（P＜0.05）。多因素分析WHOⅡ级、未接受烷化剂化疗、MGMT非甲基化是影响低级别胶质瘤患者OS的独立危险因素（P＜0.05）。结论 MGMT甲基化与胶质瘤的发生、发展有关，在判断胶质瘤恶性度、评估预后及指导临床治疗方面具有一定的价值。     

O~6-甲基鸟嘌呤-DNA甲基转移酶在恶性脑胶质瘤组织中的表达及意义

目的探讨O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)在恶性脑胶质瘤组织中的表达及其与预后的关系。方法选取2011年1月至2016年1月间中山市陈星海医院收治的经手术切除的64例恶性脑胶质瘤(Ⅲ、Ⅳ级)患者,采用免疫组化法检测肿瘤组织中MGMT蛋白的表达,评定治疗效果,追踪生存时间(OS),评价MGMT与生存时间之间的关系。结果 MGMT阳性表达率为62.5%,MGMT阴性表达率为37.5%。WHOⅢ级恶性胶质瘤组织中MGMT阳性表达率与Ⅳ级比较,差异无统计学意义(P>0.05);但Ⅳ级恶性胶质瘤MGMT(++)表达率为60.0%,明显高于Ⅲ级的48.3%,差异有统计学意义(P<0.05)。MGMT阴性患者总有效率(ORR)为62.5%,高于阳性患者的17.5%;与MGMT(-)比较,MGMT(+)和MGMT(++)平均OS均降低,差异均有统计学意义(均P<0.05)。MGMT阳性患者最长无进展生存时间(PFS)为32个月,MGMT(-)最长PFS为40个月。结论 MGMT表达与脑胶质瘤恶性程度有关,表达强度越高,恶性程度越高,检测MGMT可一定程度预知脑胶质瘤治疗的有效率及预后。     

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。     

手术联合替莫唑胺治疗维族与汉族成人恶性胶质瘤的疗效观察

0引言目前国内外针对恶性胶质瘤的治疗原则是以手术为基础的综合治疗,由于肿瘤复发较快,治疗效果不理想.替莫唑胺( Temozolomide,TMZ)是新一代烷化剂类化疗药物,易透过血脑屏障、服用方法简便、有效率高、不良反应小的特点,为治疗恶性胶质瘤带来了突破[1,2].作者应用TMZ对维吾尔和汉族两个民族共29例恶性成人胶质瘤患者进行治疗,对比其疗效.     

O<Superscript>6</Superscript>-methylguanine DNA methyltransferase status determined by promoter methylation and immunohistochemistry in gliosarcoma and their clinical implications

O⁶-methylguanine-DNA methyltransferase (MGMT) is known as a DNA repair protein, and loss of function in MGMT is related to an increase in survival in patients with malignant gliomas treated with alkylating agents. In the present study, we determined the status of MGMT using methylation-specific polymerase chain reaction (PCR) and immunohistochemistry on paraffin-embedded specimens in 12 human gliosarcomas, and these results were then related to overall survival (OS) and response to alkylating agents. The MGMT promoter was methylated in six patients. Immunostaining of MGMT was positive in 58.3% of patients. MGMT methylation status was correlated with immunostaining results in five patients (41.7%). The median OS and progression-free survival (PFS) of the whole population were 13.4 months [95% confidence interval (CI), 12.3–14.5 months] and 8.3 months (95% CI, 7.4–9.2 months), respectively. In patients with methylated MGMT promoter, median OS was 15.0 months, compared with 11.3 months in the unmethylated group. Median PFS of gliosarcoma patients was 10.3 months for the methylated group, whereas it was 7.3 months for the unmethylated group. On multivariate analysis, patients with methylated MGMT promoter had better prognosis than patients with unmethylated MGMT promoter with respect to OS and PFS (P = 0.045 and 0.034, respectively). However, there was no statistical significance between MGMT protein expression and survival. The results show that a significant fraction of gliosarcomas have MGMT promoter methylation and protein expression, and suggest that patient survival is associated with MGMT methylation status.     

尼妥珠单抗联合化疗治疗恶性胶质瘤

目的 评价尼妥珠单抗联合化疗治疗恶性胶质瘤的疗效及不良反应.方法 尼妥珠单抗200 mg/次,每周1次,连续8周后改为每2周1次;根据患者O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)蛋白表达状况和既往化疗效果,采用个体化的化疗方案.结果 14例恶性胶质瘤患者共接受尼妥珠单抗治疗122次,中位治疗7.5次(2～20次).联合的化疗方案中,替莫唑胺21 d方案10例,替莫唑胺5 d力案2例,替尼泊甙联合顺铂方案1例,替尼泊甙联合尼莫司汀方案1例.PR 3例(21.4%),SD 6例(42.9%),客观有效率为21.4%,疾病控制率(PR+SD)为64.3%.中位无进展生存期(PFS)为4个月(95%CI0.7～7.3),6个月的疾病无进展生存率为30.6%.主要的不良反应为Ⅰ～Ⅱ度的中性粒细胞下降(2例)、血小板下降(2例)、淋巴细胞下降(1例)、恶心呕吐(3例)和无症状的转氨,升高(1例).1例替尼泊甙联合顺铂方案化疗的患者发生Ⅳ度中性粒细胞下降和血小板下降.1例患者出现尼妥珠单抗治疗相关痤疮样皮疹.结论 尼妥珠单抗联合化疗治疗恶性胶质瘤有一定疗效,患者耐受性好,值得进一步扩大病例数开展临床研究.

Abstract：

Objective Nimotuzumab is a humanized monoclonal antibody targeted against epidermal growth factor receptor (EGFR). Recent clinical studies show that patients with malignant gliomas could benefit from nimotuzumab treatment. The aim of the present study was to evaluate the efficacy and side effects of nimotuzumab in combination with chemotherapy for patients with malignant gliomas. Methods The patients received 200 mg of nimotuzumab infusion intravenously over 60 minutes once weekly for the first eight weeks and then once every two weeks until unacceptable toxicity or tumor progression occurred.Individualized chemotherapy was administered based on O6-methylguanine-DNA methyltransferase (MGMT)expression and previous chemotherapy responses in combined with nimotuzumab. Results Fourteen patients received a total of 122 times of nimotuzumab ranging from 2 to 20 ( median 7.5 times ). Combined chemotherapy regimens included:continuous 21-day temozolomide ( 10 cases), standard 5-day temozolomide (2 cases), teniposide plus cisplatin ( 1 case), and teniposide plus nimustine ( 1 case). Partial response (PR) and stable disease (SD) were found in 3 patients (21.4%)and 6 patients (42.9%), respectively.Disease control rate ( PR + SD) was 64.3%. The median progression-free survival (PFS) was 4 months (95%CI:0.7-7.3) and PFS at 6 months was 30. 6%. The most common toxicities include grade Ⅰ -Ⅱ neutropenia (2 cases), thrombocytopenia ( 2 cases), lymphopenia ( 1 case), nausea and vomitting ( 3case) and asymptomatic transaminase increase ( 1 case). One patient developed grade Ⅳ neutropenia and thrombocytopenia. One patient developed nimotuzumab-related acneiform rash. Conclusions Nimotuzumab in combination with chemotherapy has moderate activity in patients with malignant gliomas and the toxicities are well tolerable, therefore, worth further investigation.     

Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas

Hypermethylation of the DNA repair gene O(6)-methyl-guanine DNA methyltransferase (MGMT) has been linked to prolonged survival in glioblastoma patients treated with alkylating agents. It was aimed to analyze prospectively whether the MGMT status of malignant gliomas could be determined from small-sized stereotactic biopsies (maximum volume: 1 mm(3)). Special attention was directed towards the intratumoral distribution of the MGMT promoter methylation, the MGMT protein expression and potential correlations between both. Twenty-five adult patients were included (20 patients with primary World Health Organisation (WHO) Grade III or IV malignant gliomas, 5 patients with secondary malignant gliomas). About 2-4 biopsy specimens per tumor were collected from different sites within the tumor. Promoter methylation of the MGMT gene was assessed by methylation-specific PCR (MSP) and sodium bisulfite sequencing in each of the collected specimens (overall number of specimens: 69). Both methods were validated for application in small-sized tissue samples (1 mm(3)). The MGMT protein expression was analyzed by immunohistochemistry. The overall MGMT promoter methylation rate was 30% in the de novo group and 80% in the tumor progression group. The success rates of MSP and sequencing were 100% and 80%, respectively. Sequence analysis and MSP exhibited 100% concordant findings. No differences in MGMT promoter methylation were detected between the different samples of each individual tumor in 24 of 25 patients. One false negative result was obtained due to the contamination of the biopsy specimen by necrotic tissue. Tissue samples taken from different sites of each individual tumor (13 tumors investigated) exhibited equal or highly similar MGMT protein expression. No correlation between MGMT protein expression and MGMT promoter methylation was observed. The MGMT promoter methylation status of malignant gliomas can be reliably determined from small-sized stereotactic biopsies. The methylation profile, as defined by MSP and sodium bisulfite sequencing, constitutes a homogeneous marker throughout malignant gliomas. The lack of correlation between MGMT status and MGMT protein expression needs further evaluation.     

Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas

BACKGROUND: The objective of this prospective cohort study was to determine the efficacy of stereotactic radiosurgery (SRS) as a salvage treatment in patients with recurrent malignant gliomas. METHODS: Between January 2000 and December 2006, 114 consecutive patients were treated with SRS as a salvage treatment for recurrent malignant gliomas at a single institution. Clinical outcome and its prognostic factors were analyzed and compared with the historical control group who were treated at the same institution between 1995 and 1999. RESULTS: The median overall survival from the time of diagnosis was 37.5 months (95% confidence interval [95% CI], 11.7-63.2 months) for patients with grade 3 gliomas (according to World Health Organization criteria) and was 23 months (95% CI, 16.2-29.3 months) for patients with glioblastomas. The median progression-free survival after SRS was 8.6 months (95% CI, 1.1-16.2 months) for patients with grade 3 gliomas and 4.6 months for patients with glioblastomas (95% CI, 4.0-5.2 months). With regard to treatment-related complications, radiation-induced necrosis was observed in 22 of 114 patients (24.4%). Compared with this historic control group, SRS significantly prolonged survival as a salvage treatment in patients with recurrent glioblastomas (23 months vs 12 months; P < .0001), but it was not found to provide a significant surgical benefit in patients with recurrent grade 3 gliomas (37.5 months vs 26 months; P = .789). On univariate analysis of prognostic factors, tumor volume (<10 mL) and low histologic grade were found to significantly influence better survival (P = .009 and P = .041, respectively). CONCLUSIONS: SRS is a safe and effective modality in selected patients with recurrent small-sized glioblastomas. However, the efficacy of SRS for recurrent grade 3 gliomas needs to be further evaluated in well-designed clinical studies.     

Predictive impact of MGMT promoter methylation in glioblastoma of the elderly

O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation identifies a subpopulation of glioblastoma patients with more favorable prognosis and predicts a benefit from alkylating agent chemotherapy (CT). Little is known about its prevalence and clinical significance in older glioblastoma patients. We studied 233 glioblastoma patients aged 70 years or more (144 males, 89 females, median age: 74 years, range: 70.0-86.6 years), who were prospectively enrolled in the German Glioma Network, for MGMT promoter methylation by methylation-specific PCR (MSP) in all patients and DNA pyrosequencing in 166 patients. MGMT data were correlated with patient outcome. Median progression-free survival (PFS) was 4.8 months (95% CI: 4.3-5.3) and median overall survival (OS) was 7.7 months (95% CI: 6.3-9.0). MGMT promoter methylation was detected by MSP in 134 patients (57.5%). For the whole cohort, PFS was 5.2 versus 4.7 months (p = 0.207) and OS was 8.4 versus 6.4 months (p = 0.031) in patients with versus without MGMT promoter methylation. Patients with MGMT methylated tumors had longer PFS when treated with radiotherapy (RT) plus CT or CT alone compared to patients treated with RT alone. Patients with MGMT unmethylated tumors appeared to derive no survival benefit from CT, regardless of whether given at diagnosis together with RT or as a salvage treatment. Patients treated with RT plus CT or CT alone demonstrated longer OS when pyrosequencing revealed >25% MGMT methylated alleles. Taken together, MGMT promoter methylation may be a useful biomarker to stratify elderly glioblastoma patients for treatment with versus without alkylating agent CT.     

替尼泊苷与尼莫司汀联合治疗MGMT阴性表达的恶性胶质瘤：附18例经验

背景与目的：化疗是胶质瘤重要的辅助治疗方法。本研究联合替尼泊苷（VM-26）与尼莫司汀（ACNU）治疗O^6-甲基鸟嘌呤-DNA甲基转移酶（O^6-metllylguanine—DNA methyltransferase,MGMT）阴性表达的恶性胶质瘤患者,观察其疗效．评价其不良反应。方法：2006年12月至2008年12月,18例患者经手术或立体定向活检确诊为恶性胶质瘤（WHO分级为Ⅲ或Ⅳ级）,患者既往均接受过放疗,其中大多数（13例）接受过化疗后复发者。肿瘤组织免疫组织化学检测提示MGMT蛋白呈阴性表达,接受VM-26与ACNU联合方案化疗。化疗方案为VM-26,80～100mg／（m^2·d）,d1-3;ACNU,2～3mg／kg,d1,6-8周重复一次。按WHO实体瘤疗效评价标准评价疗效。按美国国立癌症研究所（National Cancer Institute,NCI）评价标准评价不良反应。结果：18例患者共行70周期化疗,平均3．9个周期（2—6个周期）。化疗的主要剂量限制性毒性为骨髓抑制,Ⅲ、Ⅳ级中性粒细胞减少症发生率分别为51．4％（36,70）、25．7％（18/70）,Ⅲ、Ⅳ级血小板减少症发生率分别为24．3％（17／70）、12．9％（9,70）。按既往是否接受化疗．患者可分为既往接受化疗组、未接受化疗组,两组间Ⅲ、Ⅳ级中性粒细胞减少症及Ⅲ、Ⅳ级血小板减少症发生率无显著性差异（均P〉0．05）。18例患者中,无完全缓解（complete response,CR）病例,1例（5．6％）部分缓解（partial response,PR）,13例（72．2％）微效（minor response,MR）,3例（16．7％）稳定（stable disease,SD）,1例（5．6％）进展（progressive disease,PD）。客观有效率（CR＋PR）为5．6％,总反应率（CR＋PR＋MR）为88．9％。疾病控制率（CR＋PR＋MR＋SD）为94．4％。从使用本方案化疗开始计算,患者中位无进展生存期（PFS）为2．6个月（95％CI：2．49—2．90）,6个月PFS％为36％;中位总生存（OS）为6．7个月（95％CI：3135—11．1）。结论：VM-2-与ACNU联合方案主要不良反应为Ⅲ、Ⅳ级骨髓抑制．但可控制。VM-26与ACNU联合方案治疗恶性脑胶质瘤．可取得较高的总反应率和疾病控制率。     

Phase II study of combination chemotherapy of 5-fluorouracil, low-dose leucovorin, and oxaliplatin (FLOX regimen) in pretreated advanced gastric cancer.

BACKGROUND: This phase II study describes the efficacy and safety of combination chemotherapy of 5-fluorouracil (5-FU), low-dose leucovorin, and oxaliplatin (FLOX regimen) for pretreated advanced gastric cancer. PATIENTS AND METHODS: Patients who had been previously treated with greater than or equal to one regimen were enrolled. Patients received an oxaliplatin 75 mg/m(2) on day 1, 5-FU 1000 mg/m(2) on days 1-3, and leucovorin 20 mg/m(2) on days 1-3, every 3 weeks. The primary end point was overall survival (OS). RESULTS: Among the 52 patients enrolled, 26 patients were treated as second line, and the remaining 26 patients were enrolled as third- or fourth line. A total of 203 cycles of chemotherapy were administered with the median being three cycles (range 1-15) per patient. The median OS was 6.6 months [95% confidence interval (CI) 4.5-8.8] and the median progression-free survival was 2.5 months (95% CI 1.9-3.0). The response rate was 4% (95% CI 0-9%), and the disease control rate was 48% (95% CI 34-62%). The most common toxic effects of grade 3/4 were neutropenia (16%) and vomiting (6%). CONCLUSIONS: The FLOX regimen showed modest activity as a salvage treatment in pretreated advanced gastric cancer with a favorable compliance.     

A phase II trial of S-1 and cisplatin in patients with metastatic or relapsed biliary tract cancer.

BACKGROUND: Optimal chemotherapy for advanced biliary tract cancer (BTC) is yet to be defined. We carried out this study to evaluate the efficacy and toxicity of combination chemotherapy with S-1 and cisplatin in metastatic or relapsed BTC. PATIENTS AND METHODS: Patients with pathologically proven BTC were eligible. The chemotherapy regimen consisted of S-1 (40 mg/m(2) p.o. b.i.d. from D1-14) and cisplatin (60 mg/m(2) on D1), repeated every 3 weeks. RESULTS: Fifty-one BTC patients (metastatic:relapsed = 37:14, Gall-bladder:intrahepatic bile ducts:extrahepatic bile ducts = 16:25:10) were enrolled from January 2005 to December 2006. Median age was 57 years (range, 31-71) and most patients had a good performance status. The overall response rate was 30% [95% confidence interval (CI), 17.3-42.7] and complete response was observed in two patients (4%), partial response in 13 (26%), stable disease in 21 (42%), and progressive disease in 9 (18%). With a median follow-up of 12.4 months, the median time to progression was 4.8 months (95% CI, 3.3-6.3) and median overall survival was 8.7 months (95% CI, 6.0-11.4). Major toxic effects were grade 3/4 neutropenia (8.9% of all cycles) and febrile neutropenia was observed in six cycles (2.7% of all cycles). CONCLUSION: Combination chemotherapy with S-1 and cisplatin was a moderately effective outpatient-based regimen in BTC patients. Toxic effects were moderate but manageable.