***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: This study assessed the prognostic value of several markers involved in gliomagenesis , and compared it with that of other clinical and imaging markers already used . Four-hundred and sixteen adult patients with newly diagnosed glioma were included over a 3-year period and tumour suppressor genes , oncogenes , MGMT and hTERT expressions , losses of heterozygosity , as well as relevant clinical and imaging information were recorded . This prospect i ve study was based on all adult gliomas . Analyses were performed on patient groups selected according to World Health Organization histoprognostic criteria and on the entire cohort . The endpoint was overall survival , estimated by the Kaplan – Meier method . Univariate analysis was followed by multivariate analysis according to a Cox model . p14ARF , p16INK4A and PTEN expressions , and 10p 10q23 , 10q26 and 13q LOH for the entire cohort , hTERT expression for high- grade tumours , EGFR for glioblastomas , 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only . This study confirms the prognostic value of several markers . However , the scattering of the values explained by tumour heterogeneity prevents their use in individual decision-making 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 Glioblastoma is the commonest neuroectodermal tumor and the most malignant in the range of cerebral astrocytic gliomas . The prognostic utility of various biological markers for glioblastomas has been broadly tested but the results obtained are regarded as controversial . In the present study , 302 glioblastoma specimens were studied to evaluate a possible association between clinical outcome and expression of some immunohistochemical variables . Furthermore , tumors examined were subdivided on the three cytological subsets – small-cell ( SGB ) , pleomorphic-cell ( PGB ) and gemistocytic ( GGB ) . Immunohistochemical variables differed between various subsets : the number of p53-positive tumors was found to be prevailed among the PGB , whereas the number of tumors with EGFR and mdm2 positivity was significantly greater in SGB . GGB contained significantly lowest mean proliferating cell nuclear antigen ( PCNA ) labeling index ( LI ) , greater number of p21ras positive cases , and higher mean apoptotic index ( AI ) . Survival time in patients with SGB , EGFR and mdm2-positivity and PCNA LI > 40 % was found to be significantly shorter , whereas presence of p21ras and AI > 0.5 % were associated with prolonged survival . Multivariate analysis revealed that survival time is associated with SGB , EGFR-positivity , and AI ( p = 0.0023 , p = 0.0035 and p = 0.0029 respectively ) . We conclude that although some immunohistochemical variables were found to be significant for glioblastoma outcome , they appear to be closely related to biology of single cytological subsets . Furthermore , these variables exhibited no prognostic value when they were analyzed within each cytological subset separately . Therefore , the glioblastoma subdivision on three cytological subsets proposed by us is carrying some element of rationality but , undoubtedly , requires further prospect i ve studies PURPOSE Analysis of tumor-derived genetic lesions has provided insights into molecular pathogenesis of human gliomas . Because these changes represent only one of several mechanisms that alter gene expression during tumorigenesis , it is likely that further information will be obtained from a careful analysis of important regulatory proteins present in these tumors . EXPERIMENTAL DESIGN We have quantified the levels of key cell cycle/signaling proteins in 94 prospect ively collected , meticulously preserved , " snap frozen " glioma specimens  and have compared these levels with histopathological data and patient outcome . RESULTS The results of these experiments confirm that the levels of wild-type tumor suppressor proteins , such as p53 , pRB , PTEN , p14(ARF ) , and p16(INK4 ) , are lost or severely reduced in most gliomas , and that epidermal growth factor receptor , 2human telomerase reverse transcriptase , and cyclin-dependent kinase 4 are overexpressed frequently and with a few exceptions , almost exclusively , in glioblastomas . In addition , we report frequent underexpression of E2F-1 ( in 55 % of gliomas ) and cyclin E overexpression ( in 26 % of gliomas ) , which have not yet been reported on the genomic level . Several of these markers significantly correlated with histopathological grade , and the levels of five proteins showed significant association with patient outcome . In particular , overexpression of epidermal growth factor receptor , human telomerase reverse transcriptase , cyclin-dependent kinase 4 , and cyclin E was largely restricted to glioblastomas and was significantly associated with reduced patient survivals . CONCLUSIONS We conclude that the quantitation of cell cycle/signaling proteins from meticulously preserved glioma specimens provides further insights into the molecular pathogenesis of human gliomas and yields valuable prognostic information Background Nestin is an intermediate filament protein that has been implicated in early stages of neuronal lineage commitment . Based on the heterogeneous expression of nestin in GBM and its potential to serve as a marker for a dedifferentiated , and perhaps more aggressive phenotype , the Radiation Therapy Oncology Group ( RTOG ) sought to determine the prognostic value of nestin expression in newly diagnosed GBM patients treated on prior prospect i ve RTOG clinical trials . Methods Tissue microarrays were prepared from 156 patients enrolled in these trials . These specimens were stained using a mouse monoclonal antibody specific for nestin and expression was measured by computerized quantitative image analysis using the Ariol SL-50 system . The parameters measured included both staining intensity and the relative area of expression within a specimen . This result ed into 3 categories : low , intermediate , and high nestin expression , which was then correlated with clinical outcome . Results A total of 153 of the 156 sample s were evaluable for this study . There were no statistically significant differences between pretreatment patient characteristics and nestin expression . There was no statistically significant difference in either overall survival or progression-free survival ( PFS ) demonstrated , although a trend in decreased PFS was observed with high nestin expression ( p = 0.06 ) . Conclusion Although the correlation of nestin expression and histologic grade in glioma is of considerable interest , the presented data does not support its prognostic value in newly diagnosed GBM . Further studies evaluating nestin expression may be more informative when studied in lower grade glioma , in the context of markers more specific to tumor stem cells , and using more recent specimens from patients treated with temozolomide in conjunction with radiation 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 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 respective marker development for individual 
    Output:
    
This study demonstrates a novel literature and meta-analytical based approach to maximise the value that can be derived from the plethora of literature reports of molecular and genetic factors in GBM .