Benefits of interferon-β and temozolomide combination therapy for newly diagnosed primary glioblastoma with the unmethylated MGMT promoter: A multicenter study

BACKGROUND:

The aim of the current study was to catalog genomic and epigenomic abnormalities in newly diagnosed glioblastoma patients and determine the correlation among clinical, genetic, and epigenetic profiles and clinical outcome.

METHODS:

This study retrospectively included 68 consecutive patients who underwent surgical treatment and received standard radiotherapy with temozolomide (TMZ)‐based chemotherapy. Of a total of 68 patients, 39 patients (57.4%) received interferon (IFN)‐β in combination of TMZ.

RESULTS:

The genetic and epigenetic alterations frequently observed were EGFR amplification (51.5%), TP53 mutation (33.8%), CDKN2A loss (32.4%), TP53 loss (16.2%), methylation of the MGMT promoter (33.8%) and IDH1 mutation (5.9%). Multivariate analysis revealed that methylated MGMT promoter and the combination of TMZ and IFN‐β were independent prognostic factors associated with survival. The median survival time (MST) of the patients who received the combination of IFN‐β and TMZ was significantly greater with 19.9 months as compared to the TMZ alone group (12.7 months). Notably, in even patients whose tumors had unmethylated MGMT promoter, the MST prolonged to 17.2 months when receiving TMZ with IFN‐β, compared to 12.5 months in those receiving TMZ without IFN‐β.

CONCLUSIONS:

Taken together, addition of IFN‐β for newly diagnosed primary GBM achieved a favorable outcome, particularly in patients with unmethylated MGMT promoter. Cancer 2011. © 2010 American Cancer Society.     

Glycinamide ribonucleotide formyl transferase is frequently overexpressed in glioma and critically regulates the proliferation of glioma cells

Aims

Current treatments for the most common form of brain tumor, glioma, are disappointing in their effectiveness. Low expression levels of GART, an enzyme in the core nucleotide metabolism, significantly correlate with chemosensitivity, conferring a survival advantage to tumor cells. Our study aimed to explore the expression and function of GART in glioma.

Methods

Immunohistochemical and Western blot analysis were performed in 70 cases of human gliomas and normal brain tissues. We mainly used cell growth assay and multicellular tumor spheroid formation assay to evaluate the proliferation and chemosensitivity of glioma cells.

Results

High GART expression (most cancer cells cytoplasm stained) was observed in 70 specimens and was related to the grade of malignancy. We also reviewed each grade of tumors separately and investigated whether GART expression predicted patient survival within each subgroup. In brief, GART overexpression was significantly associated with overall survival (P = 0.03). Interestingly, transfecting cells with GART-siRNA suppressed proliferation and enhanced temozolomide (TMZ)-induced apoptosis in glioma cells.

Conclusion

The current results showed that GART expression was associated with glioma grade and that high GART protein expression might be related to poor outcome.     

First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response

Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1–5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.     

N-methylpurine DNA glycosylase and DNA polymerase beta modulate BER inhibitor potentiation of glioma cells to temozolomide

Temozolomide (TMZ) is the preferred chemotherapeutic agent in the treatment of glioma following surgical resection and/or radiation. Resistance to TMZ is attributed to efficient repair and/or tolerance of TMZ-induced DNA lesions. The majority of the TMZ-induced DNA base adducts are repaired by the base excision repair (BER) pathway and therefore modulation of this pathway can enhance drug sensitivity. N-methylpurine DNA glycosylase (MPG) initiates BER by removing TMZ-induced N3-methyladenine and N7-methylguanine base lesions, leaving abasic sites (AP sites) in DNA for further processing by BER. Using the human glioma cell lines LN428 and T98G, we report here that potentiation of TMZ via BER inhibition [methoxyamine (MX), the PARP inhibitors PJ34 and ABT-888 or depletion (knockdown) of PARG] is greatly enhanced by over-expression of the BER initiating enzyme MPG. We also show that methoxyamine-induced potentiation of TMZ in MPG expressing glioma cells is abrogated by elevated-expression of the rate-limiting BER enzyme DNA polymerase β (Polβ), suggesting that cells proficient for BER readily repair AP sites in the presence of MX. Further, depletion of Polβ increases PARP inhibitor-induced potentiation in the MPG over-expressing glioma cells, suggesting that expression of Polβ modulates the cytotoxic effect of combining increased repair initiation and BER inhibition. This study demonstrates that MPG overexpression, together with inhibition of BER, sensitizes glioma cells to the alkylating agent TMZ in a Polβ-dependent manner, suggesting that the expression level of both MPG and Polβ might be used to predict the effectiveness of MX and PARP-mediated potentiation of TMZ in cancer treatment.     

Early post-treatment pseudo-progression amongst glioblastoma multiforme patients treated with radiotherapy and temozolomide: a retrospective analysis

Introduction: To evaluate the incidence and impact of early post‐chemoradiation (cRT) ‘pseudoprogression’ (PsPD) amongst glioblastoma multiforme (GBM) patients treated with the current standard of care – 60 Gy conformal radiotherapy with concurrent low‐dose temozolomide, followed by six cycles of high‐dose temozolomide (the ‘Stupp protocol’). Methods: Clinical notes and radiology reports for GBM patients treated as per the Stupp protocol were reviewed. PsPD was defined as apparent radiological progression on the first post‐cRT scan, with further imaging within 3 months being stable or improving, while true early progression (ePD) was confirmed by continued progression in the subsequent 3 months following the first post‐cRT scan. Results: Of the 68 patients evaluated, 14 (21%) and 27 (40%) experienced PsPD and ePD, respectively; 3/14 (21%) patients experiencing PsPD and 14/27(52%), ePD were symptomatic for progression on first post‐cRT follow‐up (P = 0.096 for difference). Median survival for patients with ePD, PsPD and neither were 10.4, 27.4 and 13.0 months, respectively (P = 0.003 for ePD vs. PsPD, P = 0.19 for neither vs. PsPD groups). Conclusion: These data confirm a significant incidence of PsPD in post‐cRT GBM patients, associated with improved median survival compared with those with neither ePD nor PsPD (not statistically significant). It appears likely that PsPD actually represents tumour response, conflicting with the traditional notion that increase in lesion size on contrast‐enhanced imaging represents disease progression. Early post‐cRT imaging should thus be interpreted with caution. Accompanying clinical symptoms are more commonly associated with ePD, but do not reliably distinguish PsPD from ePD.     

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。     

Enhanced antitumour immunity by combined use of temozolomide and TAT-survivin pulsed dendritic cells in a murine glioma

Although chemotherapy remains among the best treatment options for most cancers, adjuvant therapies such as dendritic cell (DC)-based immunotherapy have been added to treatment protocols to destroy residual tumour cells. Combination treatment with low-dose temozolomide (TMZ) chemotherapy followed by vaccination with TAT-survivin-pulsed DCs enhanced T-cell responses specific for survivin and improved survival rate, as compared with DC alone or TMZ alone. Moreover, antigen-specific immunity appears to be mediated by CD8(+) T cells, as determined by in vitro T-cell subset depletion. These studies demonstrated that a combination of low-dose TMZ chemotherapy and TAT-based DC immunotherapy may be a novel strategy for safe and effective treatment of malignant gliomas.     

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.     

Temozolomide as salvage treatment for recurrent intracranial ependymomas of the adult: a retrospective study

Background

Few data are available on temozolomide (TMZ) in ependymomas.We investigated the response, survival, and correlation with MGMT promoter methylation in a cohort of patients with adult intracranial ependymoma receiving TMZ as salvage therapy after failure of surgery and radiotherapy.

Patients and Methods

We retrieved clinical information from the institutional database and follow-up visits, and response to TMZ on MRI was evaluated according to the MacDonald criteria.

Results

Eighteen patients (median age, 42 y), with either WHO grade III (10) or grade II (8) ependymoma were evaluable. Tumor location at diagnosis was supratentorial in 11 patients and infratentorial in 7. Progression before TMZ was local in 11 patients, local and spinal in 6 patients, and spinal only in one patient. A median of 8 cycles of TMZ (1–24) was administered. Response to TMZ consisted of complete response (CR) in one (5%) patient, partial response (PR) in 3 (17%) patients, stable disease (SD) in 7 (39%) patients, and progressive disease (PD) in 7 (39%) patients. Maximum response occurred after 3, 10, 14, and 15 cycles, respectively, with neurological improvement in 2 patients. All 4 responding patients were chemotherapy naïve. Both anaplastic (2) and grade II (2) tumors responded. Median progression-free survival and overall survival were 9.69 months (95% CI, 3.22–30.98) and 30.55 months (95% CI, 12.85–52.17), respectively. MGMT methylation was available in 11 patients and was not correlated with response or outcome.

Conclusion

TMZ has a role in recurrent chemo-naïve adult patients with intracranial ependymoma, regardless of tumor grade and MGMT methylation. We suggest that, after failure of surgery and radiotherapy, TMZ should be considered as a possible first-line treatment for recurrent ependymoma.