调强适形放疗联合替莫唑胺治疗恶性脑胶质瘤的临床观察

[目的]观察调强适形放疗(IMRT)联合替莫唑胺(TMZ)治疗恶性脑胶质瘤的临床疗效。[方法]28例术后病理诊断为高级别胶质瘤(WHOⅢ～Ⅳ)的患者,术后放射治疗为全脑左、右对穿野常规照射(WBRT)并后程调强加量照射。常规放射治疗剂量为40Gy/20f/4w,调强放射治疗剂量为20Gy/4f/2w;放疗同步口服替莫唑胺(TMZ)治疗6个周期,之后再接受至少2个周期的常规TMZ治疗。[结果]中位生存时间及无进展生存时间分别为11.5个月和7.2个月;1年总生存率为53.57%,2年总生存率为25.00%。常见的不良反应为恶心、呕吐,血液学毒性是白细胞和血小板下降,但仅限于Ⅰ～Ⅱ度。[结论]IMRT同步TMZ治疗恶性脑胶质瘤,安全有效,不良反应轻微。     

Pyrimethamine sensitizes pituitary adenomas cells to temozolomide through cathepsin B‐dependent and caspase‐dependent apoptotic pathways

Invasive pituitary adenomas (PAs) are generally refractory to conventional therapy and salvage treatment with temozolomide (TMZ). In addition to antiprotozoan effects, pyrimethamine (PYR) has recently shown its strong antitumor activity as an antineoplastic agent or in combination with TMZ in metastatic melanoma cells. In this study, the effects of TMZ, PYR or TMZ/PYR combination on rat/mouse PA cell lines αT3‐1, GH3, MMQ and ATt‐20 as well as GH3 xenograft tumor model were evaluated. TMZ/PYR combination synergistically inhibited proliferation, invasion and induced apoptosis of these PA cell lines in vitro. Strikingly, combination treatment with TMZ and PYR produced synergistic antitumor activity and enhanced the survival rate of GH3 xenograft tumor models without increasing systemic side effects. In addition, TMZ/PYR induced cell cycle arrest, increased DNA damage, upregulated the expression of cathepsin B, BAX, cleaved PARP and phosphorylated histone H2AX as well as elevated caspase3/7, 8 and 9 activities. The decreased expression of Bcl‐2, MMP‐2 and MMP‐9 alone with cytochrome c release from mitochondria into the cytosol was also observed in the TMZ/PYR combination group. The increase in cell apoptosis due to combination with PYR was rescued by leucovorin. These data suggest that PYR may enhance the efficacy of TMZ via triggering both cathepsin B‐dependent and caspase‐dependent apoptotic pathways. Therefore, combination of PYR and TMZ may provide a novel regimen for invasive PAs refractory to standard therapy and TMZ.     

Temozolomide plus rituximab in the treatment of recurrent central nervous system lymphoma： Case report and literature review

Objective： The aim of our study was to investigate the treatment of recurrent central nervous system lymphoma. Methods： A case of recurrent central nervous system lymphoma in a 46-year-old male was treated with temozolomide 150 mg/m2 per day for 5 days; rituximab 750 mg/m2 on dl and d8, injected from Ommaya capsule to lateral ventricle, cycles were repeated every 28 days. Results： The patient achieved complete remission and the side effects was light after the treatment. Conclusion： Using this therapy method had certain curative effect on recurrent central nervous system lymphoma. Further studies should be needed on its indication.     

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.     

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.     

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.     

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.