MGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel.

We examined the relationship between the O(6)-methylguanine-methyltransferase (MGMT) methylation status and clinical outcomes in newly diagnosed glioblastoma multiforme (GBM) patients who were treated with Gliadel wafers (Eisai, Tokyo, Japan). MGMT promoter methylation has been associated with increased survival among patients with GBM who are treated with various alkylating agents. MGMT promoter methylation, in DNA from 122 of 160 newly diagnosed GBM patients treated with Gliadel, was determined by a quantitative methylation-specific polymerase chain reaction, and was correlated with overall survival (OS) and recurrence-free survival (RFS). The MGMT promoter was methylated in 40 (32.7%) of 122 patients. The median OS was 13.5 months (95% confidence interval [CI] 11.0-14.5) and RFS was 9.4 months (95% CI 7.8-10.2). After adjusting for age, Karnofsky performance score, extent of resection, temozolomide (TMZ) and radiation therapy (RT), the newly diagnosed GBM patients with MGMT methylation had a 15% reduced mortality risk, compared to patients with unmethylated MGMT (hazard ratio 0.85; 95% CI 0.56-1.31; p=0.46). The patients aged over 70 years with MGMT methylation had a significantly longer median OS of 13.5 months, compared to 7.6 months in patients with unmethylated MGMT (p=0.027). A significant difference was also found in older patients, with a median RFS of 13.1 versus 7.6 months for methylated and unmethylated MGMT groups, respectively (p=0.01). Methylation of the MGMT promoter in newly diagnosed GBM patients treated with Gliadel, RT and TMZ, was associated with significantly improved OS compared to the unmethylated population. In elderly patients, methylation of the MGMT promoter was associated with significantly better OS and RFS.

Grossman R ，Burger P ，Soudry E ，Tyler B ，Chaichana KL ，Weingart J ，Olivi A ，Gallia GL ，Sidransky D ，Quiñones-Hinojosa A ，Ye X ，Brem H ... -  《-》

Correlation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide.

Minniti G ，Salvati M ，Arcella A ，Buttarelli F ，D'Elia A ，Lanzetta G ，Esposito V ，Scarpino S ，Maurizi Enrici R ，Giangaspero F ... -  《-》

MGMT gene promoter methylation as a potent prognostic factor in glioblastoma treated with temozolomide-based chemoradiotherapy: a single-institution study.

Recently, cells deficient in O(6)-methylguanine-DNA methyltransferase (MGMT) were found to show increased sensitivity to temozolomide (TMZ). We evaluated whether hypermethylation of MGMT was associated with survival in patients with glioblastoma multiforme (GBM). We retrospectively analyzed 93 patients with histologically confirmed GBM who received involved-field radiotherapy with TMZ from 2001 to 2008. The median age was 58 years (range, 24-78 years). Surgical resection was total in 39 patients (42%), subtotal in 30 patients (32%), and partial in 17 patients (18%); only a biopsy was performed in 7 patients (8%). Postoperative radiotherapy began within 3 weeks of surgery in 87% of the patients. Radiotherapy doses ranged from 50 to 74 Gy (median, 70 Gy). MGMT gene methylation was determined in 78 patients; MGMT was unmethylated in 43 patients (55%) and methylated in 35 patients (45%). The median follow-up period was 22 months (range, 3-88 months) for all patients. The median overall survival (OS) was 22 months, and progression-free survival (PFS) was 11 months. MGMT gene methylation was an independently significant prognostic factor for both OS (p = 0.002) and PFS (p = 0.008) in multivariate analysis. The median OS was 29 months for the methylated group and 20 months for the unmethylated group. In 35 patients with methylated MGMT genes, the 2-year and 5-year OS rates were 54% and 31%, respectively. Six patients with combined prognostic factors of methylated MGMT genes, age ≤50 years, and total/subtotal resections are all alive 38 to 77 months after operation, whereas the median OS in 8 patients with unmethylated MGMT genes, age >50 years, and less than subtotal resection was 13.2 months. We confirmed that MGMT gene methylation is a potent prognostic factor in patients with GBM. Our results suggest that early postoperative radiotherapy and a high total/subtotal resection rate might further improve the outcome.

Kim YS ，Kim SH ，Cho J ，Kim JW ，Chang JH ，Kim DS ，Lee KS ，Suh CO ... -  《-》

Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles.

Barbagallo GM ，Paratore S ，Caltabiano R ，Palmucci S ，Parra HS ，Privitera G ，Motta F ，Lanzafame S ，Scaglione G ，Longo A ，Albanese V ，Certo F ... -  《Neurosurgical Focus》

IDH mutation and MGMT promoter methylation are associated with the pseudoprogression and improved prognosis of glioblastoma multiforme patients who have undergone concurrent and adjuvant temozolomide-based chemoradiotherapy.

This study aimed to investigate the potential association between IDH mutation and O6-methyl-guanine methyl transferase (MGMT) gene promoter methylation and pseudoprogression disease (psPD) in glioblastoma multiforme (GBM) patients after concurrent temozolomide (TMZ)-based chemoradiotherapy. A total of 157 GBM patients who received concurrent TMZ-based chemoradiotherapy were included in this retrospective study. The association between psPD and a number of demographic and genetic factors, including IDH mutation and MGMT promoter methylation, were analyzed based on logistic regression, Cox regression, and multivariate analysis. Of the 157 GBM patients, 145 (92.36%) patients, including 38 patients with psPD, 38 patients with early progression (ePD), and 69 patients with non-progression (non-PD), were followed up for six to 56 months. We identified a higher rate of MGMT promoter methylation and IDH1 mutation in psPD patients compared with ePD patients (P=0.002). In addition, MGMT promoter methylation and IDH1 mutation predicted a high probability of psPD development in GBM patients (P=0.001 and P<0.001, respectively). MGMT promoter methylation, IDH1 mutation, Karnofsky performance score (KPS) ≥70, and psPD were associated with a significantly longer overall survival of GBM patients (P=0.001, 0.001, 0.002, and P<0.001, respectively). Both of MGMT promoter methylation and IDH mutation had a cumulative effect on the OS of GBM patients. GBM patients with psPD (39.2±2.1months, P<0.001) had a longer median survival (MS) than GBM patients with ePD (11.9±1.1months) or with non-PD (24.4±2.4months). MGMT promoter methylation and IDH1 mutation were associated with PsPD and predicted a longer median survival in GBM patients after TMZ-based chemoradiotherapy. Genetic analyses of the MGMT promoter and IDH1 may allow us to effectively treat GBM patients.

Li H ，Li J ，Cheng G ，Zhang J ，Li X ... -  《-》