脑胶质瘤术后联合放化疗效果观察

目的：探讨脑胶质瘤术后放射治疗联合替莫唑胺化疗的治疗效果。方法：选取2008年1月-2010年12月本院收治的WHOⅢ～Ⅳ级脑胶质瘤患者54例,随机分为A组和B组各27例,两组均在手术切除肿瘤后给予放射治疗,B组进行放射治疗,A组在放射治疗的基础上使用替莫唑胺化疗。对比两组的近期疗效、生存率和不良反应。结果：A组有效率为77.8%;高于B组的48.1%,比较差异有统计学意义（P〈0.05）;两组的1年生存率比较差异无统计学意义（P〉0.05）,A组的2年生存率为48.1%,高于B组的22.2%,比较差异有统计学意义（P〈0.05）。A组的不良反应与B组比较,差异无统计学意义（P〉0.05）。结论：脑胶质瘤术后联合放化疗能有效提高治疗效果,延长患者的生存期,值得推广应用。     

替莫唑胺抑制胶质瘤细胞系U251体外侵袭能力的研究

背景与目的：胶质瘤是原发性脑肿瘤中发病率最高且预后较差的肿瘤,本文旨在研究替莫唑胺是否可以通过改变TGF-β2表达水平来抑制U251细胞侵袭。方法：MTT法检测替莫唑胺对U251增殖力的影响,Transwell法检测U251细胞侵袭能力．Real-time RT—PCR检测替莫唑胺作用后U251细胞中TGF-βmRNA表达．ELISA法检测TGF-β2蛋白表达。结果：替莫唑胺抑制U251细胞侵袭力,MTY试验证实替莫唑胺（50μmol／L）在24小时内对U251细胞存活力无影响。Realtime RT—PCR和ELISA法证实替莫唑胺降低了U251细胞中TGF-β2表达。通过引入TGF-β2抗体,发现替莫唑胺通过抑制TGF-β2表达降低了U251细胞的侵袭作用。结论：替莫唑胺可以通过抑制TGF-β2表达来降低U251细胞的侵袭作用,因此替莫唑胺不仅可以应用在化疗领域,而且还可以运用到生物治疗领域．从而为胶质瘤的治疗提供新靶点。     

替莫唑胺联合放射治疗治疗恶性脑胶质瘤的疗效观察

目的探讨替莫唑胺(TMZ)联合放射治疗治疗恶性脑胶质瘤的临床疗效和安全性评价。方法收集56例病理学诊断为恶性脑胶质瘤的患者,其中III级患者为32例,IV级患者为24例。根据不同的治疗方法将患者分为TMZ联合放疗(TMZ-RT)组(30例)和单纯放疗(RT)组(26例)。TMZ-RT组患者采用放疗联合TMZ化疗(75 mg·m-2·d-1)治疗6周,放疗后继续给予TMZ序贯/辅助(150²00 mg·m-2·d-1)化疗2200 mg·m-2·d-1)化疗2⁴周。RT组患者接受立体定向适形放射治疗1.84周。RT组患者接受立体定向适形放射治疗1.8³Gy/d,部分患者接受超分割放射治疗,总剂量为603Gy/d,部分患者接受超分割放射治疗,总剂量为60⁷5 Gy。治疗结束后评估两组患者的生存率和近期疗效。结果影像学结果显示,TMZ-RT组完全缓解8例,部分缓解9例,稳定10例,进展3例;RT组完全缓解6例,部分缓解8例,稳定8例,进展4例,两组差异无统计学意义(P>0.05)。TMZ-RT组患者的1、2、3年生存率分别为86.7%、80.0%和56.7%。RT组患者的1、2、3年生存率分别为73.1%、30.8%和11.5%,两组患者的2年和3年生存率比较,差异有统计学意义(P<0.05)。TMZRT组和RT组患者的中位复发时间分别为(23.1±8.7)个月和(15.8±8.9)个月,两组差异有统计学意义(P<0.05)。TMZ-RT组和RT组患者化疗后KPS评分别为(89.8±9.7)分和(65.4±10.3)分,两组间差异有统计学意义(P<0.05)。TMZ-RT组患者的不良反应发生率较低且,患者的生活质量水平显著高于RT组患者(P<0.05)。结论 TMZ联合放疗与单纯放疗治疗恶性脑胶质瘤的近期疗效相当,但TMZ联合放疗能够显著提高2年和3年的生存率并延缓复发时间。TMZ联合放疗治疗不良反应轻,安全性高,能够改善患者的生活质量,值得临床进一步推广。     

Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines

Background and purpose

Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or “xenolines”).

Materials and methods

Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling.

Results

Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance.

Conclusion

GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.     

Temozolomide during and after Radiotherapy for Newly Diagnosed Glioblastomas : A Prospective Multicenter Study of Korean Patients

Objective

This study was performed to determine the safety and outcome of concurrent chemoradiotherapy (CCRT) and adjuvant chemotherapy with temozolomide for Korean patients with a newly diagnosed glioblastoma.

Methods

Patients were recruited from four institutions between 2004 and 2007. The patients received fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks and daily temozolomide, followed by 6 cycles of adjuvant temozolomide. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS), response, and safety.

Results

A total of 103 patients were enrolled in this study. Ninety-six patients (93%) completed the CCRT and 54 patients (52%) received 6 cycles of adjuvant temozolomide. The response rate was 73% (53/73) and the tumor control rate was 92% (67/73). Of the 96 patients who completed the CCRT, the median OS was 18.0 months and the 1- and 2-year OS rates were 74 and 38%, respectively. The median PFS was 10.0 months and the 1- and 2-year PFS rates were 33 and 16%, respectively. The only significant prognostic factor of survival was the extent of surgical resection (p<0.05). CCRT resulted in grade 3 or 4 hematologic toxic effects in 8% of patients. No opportunistic infections were noted.

Conclusion

This study is the first prospective multi-institutional report of CCRT and adjuvant chemotherapy with temozolomide for patients with a newly diagnosed glioblastoma in Korea. The current protocol may prolong the survival of Korean patients with a glioblastoma and may be tolerable in terms of toxicity.     

ACNU-based chemotherapy for recurrent glioma in the temozolomide era

No standard of care for patients with recurrent glioblastoma has been defined since temozolomide has become the treatment of choice for patients with newly diagnosed glioblastoma. This has renewed interest in the use of nitrosourea-based regimens for patients with progressive or recurrent disease. The most commonly used regimens are carmustine (BCNU) monotherapy or lomustine (CCNU) combined with procarbazine and vincristine (PCV). Here we report our institutional experience with nimustine (ACNU) alone (n = 14) or in combination with other agents (n = 18) in 32 patients with glioblastoma treated previously with temozolomide. There were no complete and two partial responses. The progression-free survival (PFS) rate at 6 months was 20% and the survival rate at 12 months 26%. Grade III or IV hematological toxicity was observed in 50% of all patients and led to interruption of treatment in 13% of patients. Non-hematological toxicity was moderate to severe and led to interruption of treatment in 9% of patients. Thus, in this cohort of patients pretreated with temozolomide, ACNU failed to induce a substantial stabilization of disease in recurrent glioblastoma, but caused a notable hematotoxicity. This study does not commend ACNU as a therapy of first choice for patients with recurrent glioblastomas pretreated with temozolomide.     

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     

替莫唑胺与洛莫司汀治疗脑胶质瘤的临床观察

目的 比较替莫唑胺（TMZ）与洛莫司汀（CCNU）治疗脑胶质瘤的疗效、生存期及不良反应。方法 64例首次术后脑胶质瘤患者随机分为TMZ组和CCNU组各32例,两组患者先给予常规放疗,2Gy/d,5d/W,共持续4～6W,射线总剂量50～60Gy。放疗结束后1周开始化疗。TMZ组口服TMZ（0.015～0.02）mg/(cm2·d),5d/W,每5天为1个疗程,每疗程间隔23天,28天为1个治疗周期,根据患者耐受情况给药3～5个周期。CCNU组口服CCNU(0.005～0.006)mg/(cm2·d),5d/W,疗程和治疗周期同TMZ组。结果 TMZ组疗效明显优于CCNU组（U=1.9675,P=0.0245）;TMZ组平均生存期（14.5±2.5）月,明显高于CCNU组（10.5±1.5）月（t=7.7611,P=0.000）;TMZ组恶心、呕吐、乏力的发生率明显低于CCNU组（χ2=4.0635,P=0.0437）;TMZ组骨髓抑制程度明显低于CCNU组（U=3.2314,P=0.0006）。结论 TMZ比CCNU更明显地缩小肿瘤体积,延长患者的生存期,副作用少,提高患者的生活质量,值得临床推广应用。