***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: O(6)-methylguanine DNA-methyltransferase ( MGMT ) promoter methylation status is a prognostic factor in newly diagnosed glioblastoma patients . However , it is not yet clear whether , and if so how , MGMT methylation status may change . Moreover , it is unknown whether the prognostic role of this epigenetic feature is retained during the disease course . A retrospective analysis was made using a data base of 614 glioblastoma patients treated prospect ively from January 2000 to August 2008 . We evaluated only patients who met the following inclusion criteria : age > or = 18 years ; performance status 0 - 2 ; histological diagnosis of glioblastoma at both first and second surgery for recurrence ; postoperative treatment consisting of : ( i )  radiotherapy ( RT ) followed by adjuvant temozolomide ( TMZ ) until 2005 and ( ii ) TMZ concurrent with and adjuvant to RT after 2005 ; a time interval > or = 3 months between first and second surgery . MGMT status was evaluated at first and second surgery in all 44 patients ( M : F 32:12 , median age : 49 years , range : 27 - 67 years ) . In 38 patients ( 86.4 % ) , MGMT promoter status was assessable at both first and second surgery . MGMT methylation status , changed in 14 patients ( 37 % ) of second surgery sample s and more frequently in methylated than in unmethylated patients ( 61.5 % vs 24 % , P = .03 ) . The median survival was significantly influenced only by MGMT methylation status determined at first surgery ( P = .04 ) . Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases . MGMT methylation status determined at first surgery appears to be of prognostic value ; however , it is not predictive of outcome following second surgery Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O6-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide . Hence , the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma . Since various different techniques are available for MGMT promoter methylation analysis , a generally accepted consensus as to the most suitable diagnostic method remains an unmet need . Here , we assessed methylation-specific polymerase chain reaction ( MSP ) as a qualitative and semi-quantitative method , pyrosequencing ( PSQ ) as a quantitative method , and methylation-specific multiplex ligation-dependent probe amplification ( MS-MLPA ) as a semi-quantitative method in a series of 35 formalin-fixed , paraffin-embedded glioblastoma tissues derived from patients treated in a prospect i ve clinical phase II trial that tested up-front chemoradiotherapy with dose-intensified temozolomide ( UKT-05 ) . Our goal was to determine which of these three diagnostic methods provides the most accurate prediction of progression-free survival ( PFS ) . The MGMT promoter methylation status was assessable by each method in almost all cases ( n = 33/35 for MSP ; n = 35/35 for PSQ ; n = 34/35 for MS-MLPA ) . We were able to calculate significant cut-points for the continuous methylation signals at each CpG site analysed by PSQ ( range , 11.5 to 44.9 % ) and at one CpG site assessed by MS-MLPA ( 3.6 % ) indicating that a dichotomisation of continuous methylation data as a prerequisite for comparative survival analyses is feasible . Our results show that , unlike MS-MLPA , MSP and PSQ provide a significant improvement of predicting PFS compared with established clinical prognostic factors alone ( likelihood ratio tests : p<0.001 ) . Conclusively , taking into consideration prognostic value , cost effectiveness and ease of use , we recommend pyrosequencing for analyses of MGMT promoter methylation in high-throughput setting s and MSP for clinical routine diagnostics with low sample numbers BACKGROUND A r and omised trial published by the European Organisation for Research and Treatment of Cancer ( EORTC ) and the National Cancer Institute of Canada ( NCIC ) Clinical Trials Group ( trial 26981 - 22981/CE.3 ) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival . We aim ed to undertake an exploratory sub analysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma , derive nomograms that predict an individual patient 's prognosis , and suggest stratification factors for future trials . METHODS Data from 573 patients with newly diagnosed glioblastoma who were r and omly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this sub analysis . Survival modelling was done in three patient population s : intention-to-treat population of all r and omised patients ( population 1 ) ; patients assigned temozolomide and radiotherapy ( population 2 , n=287 ) ; and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection ( population 3 , n=103 ) . Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation status . Nomograms were developed to predict an individual patient 's median and 2-year survival probabilities . No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new st and ard of care . FINDINGS Independent of the MGMT promoter methylation status , analysis in all r and omised patients ( population 1 ) identified combined treatment with temozolomide , more extensive tumour resection , younger age , Mini-Mental State Examination ( MMSE ) score of 27 or higher , and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome . In patients assigned temozolomide and radiotherapy ( population 2 ) , younger age , better performance status , more extensive tumour resection , and MMSE score of 27 or higher were associated with better survival . In patients who had tumours resected , who were assigned temozolomide and radiotherapy , and who had available MGMT promoter methylation status ( population 3 ) , methylated MGMT , better performance status , and MMSE score of 27 or higher were associated with improved survival . Nomograms were developed and are available at http://www.eortc.be/tools/g bmc alculator . INTERPRETATION MGMT promoter methylation status , age , performance status , extent of resection , and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma . Stratifying by MGMT promoter methylation status should be m and atory in all glioblastoma trials that use alkylating chemotherapy . Nomograms can be used to predict an individual patient 's prognosis , and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management PURPOSE O6-methylguanine-methyltransferase ( MGMT ) promoter methylation has been shown to predict survival of patients with glioblastomas if temozolomide is added to radiotherapy ( RT ) . It is unknown if MGMT promoter methylation is also predictive to outcome to RT followed by adjuvant procarbazine , lomustine , and vincristine ( PCV ) chemotherapy in patients with anaplastic oligodendroglial tumors ( AOT ) . PATIENTS AND METHODS In the European Organisation for the Research and Treatment of Cancer study 26951 , 368 patients with AOT were r and omly assigned to either RT alone or to RT followed by adjuvant PCV . From 165 patients of this study , formalin-fixed , paraffin-embedded tumor tissue was available for MGMT promoter methylation analysis . This was investigated with methylation specific multiplex ligation-dependent probe amplification . RESULTS In 152 cases , an MGMT result was obtained , in 121 ( 80 % ) cases MGMT promoter methylation was observed . Methylation strongly correlated with combined loss of chromosome 1p and 19q loss ( P = .00043 ) . In multivariate analysis , MGMT promoter methylation , 1p/19q codeletion , tumor necrosis , and extent of resection were independent prognostic factors . The prognostic significance of MGMT promoter methylation was equally strong in the RT arm and the RT/PCV arm for both progression-free survival and overall survival . In tumors diagnosed at central pathology review as glioblastoma , no prognostic effect of MGMT promoter methylation was observed . CONCLUSION In this study , on patients with AOT MGMT promoter methylation was of prognostic significance and did not have predictive significance for outcome to adjuvant PCV chemotherapy . The biologic effect of MGMT promoter methylation or pathogenetic features associated with MGMT promoter methylation may be different for AOT compared with glioblastoma In 2011 , we reported a predominant prognostic/predictive role of MGMT promoter methylation status on progression-free survival ( PFS ) in unresectable glioblastoma patients undergoing upfront radiotherapy plus concomitant and maintenance temozolomide ( RTX/TMZ → TMZ ) .  We , here , present the final results of this prospect i ve study focussing on the prognostic/predictive value of MGMT promoter methylation status for death risk stratification . Overall , 56 adult patients with unresectable , biopsy proven glioblastoma were prospect ively assigned to upfront RTX/TMZ → TMZ treatment between March 2006 and August 2008 . Last follow-up was performed in June 2016 . MGMT promoter methylation was determined using methylation-specific PCR ( MSP ) and sodium bisulfite sequencing . Analyses were done by intention to treat . Prognostic factors were obtained from proportional hazard models . At the time of the final analysis 55 patients showed progressive disease and 53 patients had died . MGMT promoter was methylated ( unmethylated ) in 30 ( 26 ) patients . Methylation of the MGMT promoter was the strongest favorable predictor for overall survival ( OS , median : 20.3 vs. 7.3 months , p < 0.001 , HR 0.30 , 95 % CI 0.16–0.55 ) , and PFS ( median : 15.0 vs. 6.1 months , p < 0.001 , HR 0.31 , 95 % CI 0.17–0.57 ) and was also associated with higher frequencies of treatment response and prolonged post-recurrence survival ( PRS , median : 4.5 vs. 1.4 months , p < 0.002 , HR 0.39 , 95 % CI 0.21–0.71 ) . Knowledge of MGMT promoter methylation status is essential for patients ’ counseling , prognostic evaluation , and for the design of future trials dealing with unresectable glioblastomas PURPOSE Glioblastomas are notorious for resistance to therapy , which has been attributed to DNA-repair proficiency , a multitude of deregulated molecular pathways , and , more recently , to the particular biologic behavior of tumor stem-like cells . Here , we aim ed to identify molecular profiles specific for treatment resistance to the current st and ard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide . PATIENTS AND METHODS Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy . Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy . RESULTS An expression signature dominated by HOX genes , which comprises Prominin-1 ( CD133 ) , emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy  ( n = 42 ; hazard ratio = 2.69 ; 95 % CI , 1.38 to 5.26 ; P = .004 ) . This association could be vali date d in an independent data set . Provocatively , the HOX cluster was reminiscent of a " self-renewal " signature ( P = .008 ; Gene Set Enrichment Analysis ) recently characterized in a mouse leukemia model . The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis , adjusted for the O-6-methylguanine-DNA methyltransferase ( MGMT ) methylation status , a known predictive factor for benefit from temozolomide , and age . Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion , and innate immune response . CONCLUSION This study provides first clinical evidence for the implication of a " glioma stem cell " or " self-renewal " phenotype in treatment resistance of glioblastoma . Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and 
    Output:
    
In each subgroup divided by areas , the prognostic significance still remained highly significant .
The proportion of methylation in each group was in inverse proportion to the corresponding HR in the univariate and multivariate analyses of PFS .
However , from the perspective of OS , compared with data from Europe and the US , higher methylation rates in Asia did not bring better returns