***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: PURPOSE Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma ( GBM ) by increasing the therapeutic index , overcoming common mechanisms of temozolomide resistance , or both . The goal of this r and omized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM . PATIENTS AND METHODS Adult patients with newly diagnosed GBM were r and omly assigned to receive st and ard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense ( 150 mg/m(2 ) days 1 to 7 and 15 to 21 ) or metronomic ( 50 mg/m(2 ) continuous daily ) temozolomide . Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression . The primary end point was overall survival ( OS ) at 1 year . Tumor tissue was assayed to determine O(6)-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation status . RESULTS Eighty-five eligible patients were enrolled ; 42 were r and omly assigned to dose-dense and 43 to metronomic temozolomide . The 1-year survival rate was 80 % for the dose-dense arm and 69 % for the metronomic arm ; median OS was 17.1 months ( 95 % CI , 14.0 to 28.1 months ) and 15.1 months ( 95 % CI , 12.3 to 18.9 months ) , respectively . The most common toxicities were myelosuppression ( leukopenia , neutropenia , and thrombocytopenia ) and elevated liver enzymes . Pseudoprogression was observed in 37 % of assessable patients and may have had an impact on estimates of progression-free survival ( 6.6 months in the dose-dense arm and 5.0 months in the metronomic arm ) . CONCLUSION Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity . The dose-dense regimen appears promising , with 1-year survival of 80 % PURPOSE Approximately 50 % of glioblastomas ( GBMs ) are characterized by overexpression of the epidermal growth factor receptor ( EGFR ) and EGFR gene amplification . In approximately 25 % of instances , constitutively activated EGFR mutants are present . These observations make EGFR-inhibiting drugs a logical approach for trials in recurrent GBM . PATIENTS AND METHODS In a r and omized , controlled , phase II trial , 110 patients with progressive GBM after prior radiotherapy were r and omly assigned to either erlotinib or a control arm that received treatment with either temozolomide or carmustine ( BCNU ) . The primary end point was 6-month progression-free survival ( PFS ) . Tumor specimens obtained at first surgery were investigated for EGFR expression ; EGFRvIII mutants ; EGFR amplification ; EGFR mutations in exons 18 , 19 , and 21 ; and pAkt . These results were correlated with outcome . Pharmacokinetic analysis was part of the study . RESULTS ; Treatment was well tolerated in general ; skin toxicity was the most frequent adverse effect of erlotinib . The 6-month PFS rate in the erlotinib arm was 11.4 % ( 95 % CI , 4.6 % to 21.5 % ) , and it was 24 % in the control arm . Of all explored biomarkers , only low pAkt expression appeared to be of borderline significance to an improved outcome . None of the eight patients who had tumors with EGFRvIII mutant presence and PTEN expression had 6-month PFS . The use of enzyme-inducing anticonvulsants significantly increased erlotinib clearance , but pharmacokinetic findings were not related to outcome . CONCLUSION Erlotinib has insufficient single-agent activity in unselected GBM . No clear biomarker associated with improved outcome to erlotinib was identified BACKGROUND In this r and omized phase III study , the effectiveness as well as the side-effects of intraarterial [ i.a . ] ( 17 patients ) versus intravenous [ i.v . ] ( 16 patients ) ACNU [ Nimustine ] administration in newly diagnosed glioblastoma , were compared . PATIENTS AND METHODS All patients undenwent extensive surgical resection , and both groups were homogeneous for the other known risk factors . Thirty-three patients with glioblastoma were treated with ACNU at the dose of 80 - 100 mg/m2 . Treatment was repeated every 5 - 8 weeks for a minimum of 2 and maximum of 14 cycles . Total survival time ( TST ) and to time to progression were chosen as outcome variables . RESULTS AND CONCLUSION No significant differences in systemic and hematological toxicity between the i.a . and iv . ACNU administration routes were detected . In both groups , tolerance of the procedure was excellent . Analysis of the main outcome measured showed no significant differences between i.a . and i.v . ACNU administration : time to progression was 6 months for i.a . ACNU and 4 months for i.v . ACNU and total survival time was 17 months for i.a . ACNU and 20 months for i.v . ACNU . In spite of ACNU dose incrementation , obtained through i.a . route administration , and subsequent higher concentration in the tumor bed , no improvement could be achieved in effectiveness Using MRI techniques , we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset , is prolonged but reversible , and has the significant clinical benefit of alleviating edema . Reversal of normalization began by 28 days , though some features persisted for as long as four months . Basic FGF , SDF1alpha , and viable circulating endothelial cells ( CECs ) increased when tumors escaped treatment , and circulating progenitor cells ( CPCs ) increased when tumors progressed after drug interruption . Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor Summary Purpose Because raised matrix metalloprotease ( MMP ) levels are associated with glioma invasion and angiogenesis , we tested the efficacy of marimastat ( MT ) an orally active drug that can reduce MMP levels , in patients with gliomas . Patients and Methods A total of 162 patients with intracranial glioblastoma multiforme or gliosarcomas who had undergone surgery and radiotherapy participated in this multicenter , double-blind , placebo-controlled , parallel group study conducted at 20 institutions . Seventy-nine patients ( 57 male , 22 female , median age 58 years ) were r and omized to receive placebo ( PB ) , and 83 patients ( 51 male , 32 female , median age 57 years ) were r and omized to receive MT , 10 mg orally twice daily , until tumor progression . Results This intention-to-treat efficacy analysis showed no statistically significant difference between MT and PB groups with respect to survival ( P=0.38 , log rank test ) . The median survival time from protocol initiation was 37.9 weeks for the PB group and 42.9 weeks for the MT group , with a hazard ratio of 1.16 ( 95 % CI 0.83 to 1.60 ) . There were no statistically significant differences in quality of life between the PB and MT groups , as assessed by the FACT-BR question naire . Musculoskeletal toxicities led to dose modification or withdrawal in 20 % of MT-treated and 1.2 % of PB-treated patients . Conclusion MT does not improve survival in patients with glioblastoma or gliosarcoma following surgery and radiotherapy . Therefore , single-agent MT appears unwarranted ; however , MT in combination with cytotoxic chemotherapy may be warranted , as suggested by observations in our study and other studies PURPOSE This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma ( WHO grade 4 ) . PATIENTS AND METHODS Patients were r and omly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d ( 1,125-mg loading dose , day 1 ) or lomustine ( 100 to 130 mg/m(2 ) , day 1 ) . Assuming a 45 % improvement in progression-free survival ( PFS ) , 397 patients were required to provide 80 % power to achieve statistical significance at a one-sided level of .025 . RESULTS Enrollment was terminated at 266 patients ( enzastaurin , n = 174 ; lomustine , n = 92 ) after a planned interim analysis for futility . Patient characteristics were balanced between arms . Median PFS ( 1.5 v 1.6 months ; hazard ratio [ HR ] = 1.28 ; 95 % CI , 0.97 to 1.70 ) , overall survival ( 6.6 v 7.1 months ; HR = 1.20 ; 95 % CI , 0.88 to 1.65 ) , and 6-month PFS rate ( P = .13 ) did not differ significantly between enzastaurin and lomustine , respectively . Stable disease occurred in 38.5 % and 35.9 % of patients and objective response occurred in 2.9 % and 4.3 % of patients , respectively . Time to deterioration of physical and functional well-being and symptoms did not differ between arms ( HR = 1.12 ; P = .54 ) . Four patients discontinued enzastaurin because of drug-related serious adverse events ( AEs ) . Eleven patients treated with enzastaurin  died on study ( four because of AEs ; one was drug-related ) . All four deaths that occurred in patients receiving lomustine were disease-related . Grade 3 to 4 hematologic toxicities were significantly higher with lomustine ( 46 events ) than with enzastaurin ( one event ; P < or = .001 ) . CONCLUSION Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma CONTEXT The relative merits of various study design s and their placement in hierarchies of evidence are often discussed . However , there is limited knowledge about the relative citation impact of articles using various study design s. OBJECTIVE To determine whether the type of study design affects the rate of citation in subsequent articles . DESIGN AND SETTING We measured the citation impact of articles using various study design s -- including meta-analyses , r and omized controlled trials , cohort studies , case-control studies , case reports , non systematic review s , and decision analysis or cost-effectiveness analysis --published in 1991 and in 2001 for a sample of 2646 articles . MAIN OUTCOME MEASURE The citation count through the end of the second year after the year of publication and the total received citations . RESULTS Meta-analyses received more citations than any other study design both in 1991 ( P<.05 for all comparisons ) and in 2001 ( P<.001 for all comparisons ) and both in the first 2 years and in the longer term . More than 10 citations in the first 2 years were received by 32.4 % of meta-analyses published in 1991 and 43.6 % of meta-analyses published in 2001 . R and omized controlled trials did not differ significantly from epidemiological studies and non systematic review articles in 1991 but clearly became the second-cited study design in 2001 . Epidemiological studies , non systematic review articles , and decision and cost-effectiveness analyses had relatively similar impact ; case reports received negligible citations . Meta-analyses were cited significantly more often than all other design s after adjusting for year of publication , high journal impact factor , and country of origin . When limited to studies addressing treatment effects , meta-analyses received more citations than r and omized trials . CONCLUSION Overall , the citation impact of various study design s is commensurate with most proposed hierarchies of evidence PURPOSE To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma . PATIENTS AND METHODS Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks . After tumor progression , patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m(2 ) or 125 mg/m(2 ) every 2 weeks , depending on use of enzyme-inducing antiepileptic drugs . Complete patient evaluations were repeated every 4 weeks . RESULTS Forty-eight heavily pretreated patients were accrued to this study .  Thromboembolic events ( 12.5 % ) , hypertension ( 12.5 % ) , hypophosphatemia ( 6 % ) , and thrombocytopenia ( 6 % ) were the most common drug-associated adverse events . Six patients ( 12.5 % ) were removed from study for drug-associated toxicity ( five thromboembolic events , one bowel perforation ) . Thirty-four patients (  
    Output:
    
In general , annual citation rate appeared to gradually increase during the first 2 - 3 years after publication before reaching high levels .
However , areas such as quality of life , side effects , and end-of-life care were underrepresented .