***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: Background Imatinib mesylate , an inhibitor of KIT , ABL protein , and platelet-derived growth factor receptor α ( PDGFRα ) tyrosine kinase , has recently been found to have a dramatic antitumor effect on gastrointestinal stromal tumor ( GIST ) . The aim of this study was to assess the efficacy and safety of imatinib mesylate in Japanese patients with advanced GIST . Methods Patients with measurable lesions were enrolled between April 1 , 2002 , and September 20 , 2002 , using a design based on previous phase II studies in the United States and the European Union . The diagnosis of GIST was proven histologically with positive immunostaining for KIT ( CD117 ) . Imatinib mesylate was administered at a dose of either 400 mg or 600 mg once a day . Pharmacokinetic parameters and mutation analysis of c-kit were also assessed in a subgroup of patients . Results A total of 74 patients ( 28 receiving imatinib mesylate at 400 mg/day ; 46 receiving 600 mg/day ) ; median age , 56.0 years , were enrolled . No patient had a complete response , 51 patients ( 69 % ) had a partial response , and 19 patients ( 26 % ) had stable disease . The median progression-free survival time was 96 weeks . The estimated 3-year overall survival ( Kaplan-Meier ) rate for all patients was 73.6 % . The most frequent adverse effects related to the drug were nausea ( 78 % ) , diarrhea ( 70 % ) , dermatitis ( 62 % ) , facial edema ( 61 % ) , edema of the lower limbs ( 58 % ) , vomiting ( 54 % ) , and eyelid edema ( 51 % ) . Most of the adverse effects were mild and manageable . Conclusion Imatinib mesylate is generally safe and has significant activity in the treatment of advanced GIST in Japanese patients Purpose Gastrointestinal stromal tumours ( GIST ) are mesenchymal neoplasms of the gastrointestinal tract that are unresponsive to st and ard sarcoma chemotherapy . Imaging of GIST patients is done with structural and functional methods such as contrast-enhanced helical computed tomography ( ceCT ) and positron emission tomography ( PET ) with 18F-fluorodeoxyglucose ( FDG ) . The aim of this study was to compare the prognostic power of PET and ceCT and to evaluate the clinical role of PET/CT imaging . Methods All patients with GIST undergoing PET or PET/CT examinations were prospect ively included in this study , and the median overall survival , time to progression and treatment duration were documented . The prognostic significance of PET and ceCT criteria of treatment response was assessed and PET/CT was compared with PET and ceCT imaging . Data for 34 patients ( 19 male , 15 female , 21–76 years ) undergoing PET or PET/CT for staging or restaging were analysed . Results In 28 patients , PET/CT and ceCT were available after introduction of treatment with the tyrosine kinase inhibitor imatinib mesylate ( Gleevec ; Novartis , Basel , Switzerl and ) . Patients without FDG uptake after the start of treatment had a better prognosis than patients with residual activity . In contrast , ceCT criteria provided insufficient prognostic power . However , more lesions were found on ceCT images than on PET images , and FDG uptake was sometimes very variable . PET/CT delineated active lesions better than did the combination of PET and ceCT imaging . Conclusion Both PET and PET/CT provide important prognostic information and have an impact on clinical decision-making in GIST patients .  PET/CT precisely delineates lesions and thus allows for the correct planning of surgical interventions Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity PURPOSE Imatinib is the st and ard treatment of advanced GI stromal tumors ( GISTs ) . It is not known whether imatinib may be stopped in patients in whom disease is controlled . METHODS This prospect i ve , r and omized , multicentric phase III study was design ed to compare continuous ( CONT ) compared with interrupted ( INT ) imatinib beyond 1 year of treatment in patients with advanced GIST . The primary end point was progression-free survival . Secondary end points included overall survival , response rate after reinitiation of imatinib , and quality of life . Early stopping rules in cases of rapid progression of disease were defined , with preplanned interim analyses . RESULTS Between May 2002 and April 2004 , 182 patients with advanced GIST were enrolled . Between May 2003 and April 2004 , 98 patients in response or stable disease under imatinib reached more than 1 year of follow-up . Forty were not eligible for r and omization , and 58 patients were r and omly assigned , 32 and 26 patients in the INT and CONT arms , respectively . As of October 15 , 2005 , eight of 26 patients in the CONT group and 26 of 32 patients in the INT group had documented disease progression ( P < .0001 ) . Twenty-four of 26 patients with documented progression in the INT arm responded to imatinib re introduction . No differences in overall survival or imatinib resistance were observed between the two arms . Quality of life evaluated 6 months after r and om assignment using the 30-item Quality of Life Question naire was not significantly different between the two groups of r and omly assigned patients . CONCLUSION Imatinib interruption results in rapid progression in most patients with advanced GIST , and can not be recommended in routine practice unless patient experience significant BACKGROUND No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available . We did a r and omised , double-blind , placebo-controlled , multicentre , international trial to assess tolerability and anticancer efficacy of sunitinib , a multitargeted tyrosine kinase inhibitor , in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib . METHODS Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment . The primary endpoint was time to tumour progression . Intention-to-treat , modified intention-to-treat , and per- protocol analyses were done . This study is registered at Clinical Trials.gov , number NCT00075218 . FINDINGS 312 patients were r and omised in a 2:1 ratio to receive sunitinib ( n=207 ) or placebo ( n=105 ) ; the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib . Median time to tumour progression was 27.3 weeks ( 95 % CI 16.0 - 32.1 ) in patients receiving sunitinib and 6.4 weeks ( 4.4 - 10.0 ) in those on placebo ( hazard ratio 0.33 ; p<0.0001 ) . Therapy was reasonably well tolerated ; the most common treatment-related adverse events were fatigue , diarrhoea , skin discolouration , and nausea . INTERPRETATION We noted significant clinical benefit , including disease control and superior survival , with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab . Tolerability was acceptable A recent r and omized EORTC phase III trial , comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours ( GISTs ) , reported dose dependency for progression-free survival . The current analysis of that study aim ed to assess if tumour mutational status correlates with clinical response to imatinib . Pre-treatment sample s of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA . Mutation types were correlated with patients ' survival data . The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib  , increasing the relative risk of progression by 171 % ( P<0.0001 ) and the relative risk of death by 190 % ( P<0.0001 ) when compared with KIT exon 11 mutants . Similarly , the relative risk of progression was increased by 108 % ( P<0.0001 ) and the relative risk of death by 76 % ( P=0.028 ) in patients without detectable KIT or PDGFRA mutations . In patients whose tumours expressed an exon 9 KIT oncoprotein , treatment with the high-dose regimen result ed in a significantly superior progression-free survival ( P=0.0013 ) , with a reduction of the relative risk of 61 % . We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs . Our findings suggest the need for differential treatment of patients with GISTs , with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug In the EORTC-ISG-AGITG trial 946 patients with advanced gastro-intestinal stromal tumours ( GIST ) were r and omised to receive 400 or 800 mg of imatinib daily . An increase in progression free survival ( PFS ) was demonstrated for patients r and omised to the high-dose arm . Patients r and omised to low-dose could cross-over to high-dose upon progression . We evaluated the feasibility , safety and efficacy of this policy . Of the 241 patients available for follow-up , 133 patients ( 55 % ) crossed over to high-dose imatinib according to the protocol . Of these patients , 92 % had not had a prior dose reduction . The cumulative incidence of subsequent dose reductions after cross-over was 17 % after six months with 51 % discontinuing therapy without requiring a dose reduction . The extent of anaemia and fatigue increased significantly after cross-over , whilst neutropenia was less severe than during low-dose treatment . Objective responses after cross-over included three patients ( 2 % ) with a partial response and 36 ( 27 % ) with stable disease . The median PFS after cross-over was 81 days , although 18.1 % of patients were still alive and progression free one year after cross-over . We conclude that a cross 
    Output:
    
The statistical likelihood of response may depend on exon mutational status .