Evaluation of <i>MGMT</i> Gene Methylation in Neuroendocrine Neoplasms

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O6 -methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high-resolution, next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in welldifferentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs.     

Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer

Temozolomide is an oral alkylating agent used for treating several cancers including glioblastoma and melanoma. Promising, albeit limited, activity and efficacy of temozolomide have been reported in pretreated patients with metastatic colorectal cancer bearing MGMT promoter methylation. MGMT silencing and proficiency of the mismatch repair system were considered the major predictive biomarkers of sensitivity to temozolomide. Refinement of established biomarkers and integration with those related to alteration in specific DNA-damage response pathways such as base excision repair are promising strategies for selecting metastatic colorectal patients to this old drug with several potential novel applications. Then, mounting preclinical and clinical observations have linked acquired resistance to temozolomide to emergence of alterations in the mismatch repair system. Whilst accounting for tumor cells capability of escaping apoptosis when exposed to temozolomide, inactivation of key mismatch-repair proteins will ultimately lead to increasing tumor mutational burden. This drug-induced mismatch deficient-like phenotype is being exploited in proof-of-concept trials combining temozolomide and immune checkpoint inhibitors in metastatic colorectal cancer.     

替莫唑胺联合放疗治疗胶质瘤患者的生存情况分析

目的 探讨分析替莫唑胺联合放疗治疗对胶质瘤患者生存情况的影响.方法 选取64例胶质瘤患者为研究对象,采用数字表法将其平均分成两组,对照组患者在术后行放疗,观察组患者在放疗基础上联合应替莫唑胺化疗,比较两组患者治疗后的生存情况及不良反应情况.结果 观察组临床疾病控制率(50.00％)明显高于对照组(25.00％),有统计学意义(P＜0.05);观察组患者无进展生存时间为(11.24±3.09)个月和生存时间为(15.64±3.87)个月,较对照组患者的无进展生存时间[(6.09±1.97)个月]和生存时间[(8.71±2.56)个月]明显要长,有统计学意义(P＜0.05);观察组患者白细胞下降、头皮溃疡、恶心呕吐、腹泻、血小板计数下降等不良反应发生率均低于对照组,均可自行缓解或对症用药后可控制.结论 胶质瘤患者术后采用替莫唑胺联合放疗治疗,与单纯的放疗相比较,能够有效控制肿瘤生长情况,延长患者无进展生存时间和总生存时间,治疗期间不良反应少,安全有效.     

大分割放疗联合替莫唑胺治疗大体积脑转移瘤的效果观察

目的 观察大分割放疗联合替莫唑胺治疗大体积脑转移瘤的临床疗效.方法 选取90例大体积脑转移瘤患者为研究对象,随机将患者分为对照组和实验组,每组45例.对照组患者给予大分割放疗治疗,实验组患者在大分割放疗的基础上每日加服1次替莫唑胺150 mg/m2,连续口服28天即1个放疗周期结束后,每个放疗周期的前5天给予每天1次口服替莫唑胺200 mg/m2辅助治疗.治疗6个疗程后观察2组的临床疗效及不良反应,并分析患者1年随访记录.结果 实验组患者的临床治疗有效率为75.56%,明显高于对照组的48.89%(P<0.05).实验组患者半年及1年生存率高于对照组,复发率低于对照组(P<0.05).2组患者均有放射性脑水肿、放射性脑坏死、脑神经损伤、恶心呕吐及发热等不良反应,实验组患者临床还表现出骨髓抑制及贫血等不良反应,但均可耐受.结论 大分割放疗联合替莫唑胺对临床治疗大体积脑转移瘤安全有效,患者临床症状可得到明显改善,临床不良反应较轻,值得推广应用.     

老年胶质母细胞瘤患者MGMT甲基化状态对放化疗及预后影响

目的:探讨O-6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)基因启动子甲基化状态对老年胶质母细胞瘤(GBM)治疗及预后的影响。方法:回顾性分析天津市环湖医院2012—2018年收治的65例新诊断的老年GBM患者的临床资料。所有患者均在术后接受了调强放疗,49例患者接受了替莫唑胺单药化疗。依据MGMT启动子甲基化状态分为M...     

Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma

Purpose: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide. Methods: The treatment schedule was 150–200 mg/m² per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging. Results: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity. Conclusions: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas. Received: 24 October 1996 / Accepted 5 February 1997     

替莫唑胺联合放疗治疗高级别脑胶质瘤的临床分析

目的 观察替莫唑胺(temozolomide, TMZ)联合放疗治疗高级别脑胶质瘤（high-grade glioma, HGG）患者的疗效和安全性,探讨影响HGG患者预后的因素。方法 回顾性分析50例采用TMZ联合放疗治疗初诊HGG患者临床资料。采用三维适形或调强放疗治疗,患者放疗期间均同步口服TMZ,剂量为75 mg/（m²·d） ;放化疗结束后,再行TMZ辅助化疗,方案为（150~200）mg/（m²·d）,连续服用5天,28天为1周期。观察患者的疗效及安全性,并对患者性别、年龄、KPS评分、手术切除程度、病理分级、手术至放疗开始间隔时间、放疗技术及TMZ辅助化疗周期数等因素对患者预后的影响进行多因素分析。结果 全组患者中位随访时间为21.4月（6.6~57.5月）,28例患者出现肿瘤进展或复发,22例患者死亡;全组1、2和3年总生存率（OS）和无进展生存率（PFS）分别为85.8%和71.8%、54.9%和44.2%及51.2%和44.2%。服用TMZ期间常见不良反应为恶心、呕吐,并伴有中性粒细胞及血小板的减少,但大多数患者均能耐受。多因素分析显示KPS评分、病理分级及辅助化疗周期数是影响OS的独立预后因素;手术切除程度、病理分级及辅助化疗周期数是影响PFS的独立预后因素。结论 TMZ联合放疗治疗初诊HGG疗效肯定,安全性较好。KPS评分、手术方式、病理分级及辅助化疗周期数是影响患者预后的重要预后因素。     

Anti-proliferative effect of the gastrin-release peptide receptor antagonist RC-3095 plus temozolomide in experimental glioblastoma models

Malignant gliomas have a dismal prognosis despite multi-modality treatments like neurosurgical resection, radiation therapy and chemotherapy. Evidence has indicated that gastrin-releasing peptide (GRP) and its receptor (GRPR) play a role in the development of a variety of cancers including gliomas. In the present study, we investigated the effects of RC-3095, a selective GRPR antagonist, alone or in combination with temozolomide (TMZ), a DNA alkylating agent, in in vitro and in vivo experimental rat C6 glioma models. Cellular proliferation was significantly reduced by all treatments with the combined administration of TMZ and RC-3095 being the most effective treatment. In in vivo experiments, the control group displayed the largest tumors (52 ± 15.5 mm³), whereas RC-3095 reduced the tumor size, with the most significant effect at the dose of 0.3 mg/kg (21 ± 9.7 mm³). The combined therapy produced further reduction in tumor size (10 ± 7.5 mm³). Our results show that the combination of RC-3095 with TMZ produced an important reduction in in vitro and in vivo glioma growth therefore making RC-3095 a candidate drug to potentiate the effects of the DNA alkylating agent TMZ in the treatment of glioma. An erratum to this article can be found at     

Radiotherapy Plus Procarbazine,Lomustine, and Vincristine Versus Radiotherapy Plus Temozolomide for IDH-Mutant Anaplastic Astrocytoma: A Retrospective Multicenter Analysis of the French POLA Cohort

Background IDH‐mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ) after radiotherapy (RT) remains unclear.MethodsIn a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression‐free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity.ResultsThe 4‐year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.38–0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41–0.97; p = .0348) in multivariable analysis. The 4‐year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30–1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001).ConclusionRT + PCV significantly improved PFS compared with RT + TMZ for IDH‐mutant AA. However, RT + TMZ was better tolerated.Implications for PracticeIn the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH‐mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH‐mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression‐free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH‐mutant AA.