***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 The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1 * 28 , a variant that reduces the elimination of SN-38 , the active metabolite of irinotecan . We aim ed to identify the maximum-tolerated dose ( MTD ) and dose-limiting toxicity ( DLT ) of irinotecan in patients with advanced solid tumors stratified by the * 1/*1 , * 1/*28 , and * 28/*28 genotypes . PATIENTS AND METHODS Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks . Forty-six percent of the patients had the * 1/*1 genotype , 41 % had the * 1/*28 genotype , and 13 % had the * 28/*28 genotype . The starting dose of irinotecan was 700 mg in patients with the * 1/*1 and * 1/*28 genotypes and 500 mg in patients with the * 28/*28 genotype . Pharmacokinetic evaluation was performed at cycle 1 . RESULTS In patients with the * 1/*1 genotype , the MTD was 850 mg ( four DLTs per 16 patients ) , and 1,000 mg was not tolerated ( two DLTs per six patients ) . In patients with the * 1/*28 genotype , the MTD was 700 mg ( five DLTs per 22 patients ) , and 850 mg was not tolerated ( four DLTs per six patients ) . In patients with the * 28/*28 genotype , the MTD was 400 mg ( one DLT per six patients ) , and 500 mg was not tolerated ( three DLTs per three patients ) . The DLTs were mainly myelosuppression and diarrhea . Irinotecan  clearance followed linear kinetics . At the MTD for each genotype , dosing by genotype result ed in similar SN-38 areas under the curve ( AUCs ; r(2 ) = 0.0003 ; P = .97 ) , but the irinotecan  AUC was correlated with the actual dose ( r(2 ) = 0.39 ; P < .001 ) . Four of 48 patients with disease known to be responsive to irinotecan achieved partial response . CONCLUSION The UGT1A1 * 28 genotype can be used to individualize dosing of irinotecan . Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan Background Systematic review s ( SRs ) are expected to critically appraise included studies and privilege those at lowest risk of bias ( RoB ) in the synthesis . This study examines if and how critical appraisal s inform the synthesis and interpretation of evidence in SRs . Methods All SRs published in March – May 2012 in 14 high-ranked medical journals and a sample from the Cochrane library were systematic ally assessed by two review ers to determine if and how : critical appraisal was conducted ; RoB was summarised at study , domain and review levels ; and RoB appraisal s informed the synthesis process . Results Of the 59 SRs studied , all except six ( 90 % ) conducted a critical appraisal of the included studies , with most using or adapting existing tools . Almost half of the SRs reported critical appraisal in a manner that did not allow readers to determine which studies included in a review were most robust . RoB assessment s were not incorporated into synthesis in one-third ( 20 ) of the SRs , with their consideration more likely when review s focused on r and omised controlled trials . Common methods for incorporating critical appraisal s into the synthesis process were sensitivity analysis , narrative discussion and exclusion of studies at high RoB. Nearly half of the review s which investigated multiple outcomes and carried out study -level RoB summaries did not consider the potential for RoB to vary across outcomes . Conclusions The conclusions of the SRs , published in major journals , are frequently uninformed by the critical appraisal process , even when conducted . This may be particularly problematic for SRs of public health topics that often draw on diverse study design Purpose : Irinotecan ( CPT-11 ) is approved in metastatic colorectal cancer treatment and can cause severe toxicity . The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil ( 5FU ) and CPT-11 adjuvant chemotherapy regimen in a prospect i ve r and omized trial . Experimental Design : Four hundred patients were r and omized in a phase III trial comparing  LV5FU2 to LV5FU2 + CPT-11 .  DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism : 3435C > T for ABCB1 , 6986A > G for CYP3A5 , UGT1A1 * 28 and −3156G > A for UGT1A1 . Results : Genotype frequencies were similar in both treatment arms . In the test arm , no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms . UGT1A1 * 28 homozygous patients showed more frequent severe hematologic toxicity ( 50 % ) than UGT1A1 * 1 homozygous patients ( 16.2 % ) , P = 0.06 . Moreover , patients homozygous for the mutant allele of −3156G > A UGT1A1 polymorphism showed more frequent severe hematologic toxicity ( 50 % ) than patients homozygous for wild-type allele ( 12.5 % ) , P = 0.01 . This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients ( P = 0.043 ) . In a Cox model , the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [ hazard ratio , 8.4 ; 95 % confidence interval , 1.9–37.2 ; P = 0.005 ] . Conclusions : This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity . The −3156G > A polymorphism seems to be a better predictor than the UGT1A1 (TA)6TAA>(TA)7TAA polymorphism Aims : With the increase in the number of systematic review s available , a logical next step to provide decision makers in healthcare with the evidence they require has been the conduct of review s of existing systematic review s. Syntheses of existing systematic review s are referred to by many different names , one of which is an umbrella review . An umbrella review allows the findings of review s relevant to a review question to be compared and contrasted . An umbrella review 's most characteristic feature is that this type of evidence synthesis only considers for inclusion the highest level of evidence , namely other systematic review s and meta-analyses . A methodology working group was formed by the Joanna Briggs Institute to develop method ological guidance for the conduct of an umbrella review , including diverse types of evidence , both quantitative and qualitative . The aim of this study is to describe the development and guidance for the conduct of an umbrella review . Methods : Discussion and testing of the elements of methods for the conduct of an umbrella review were held over a 6-month period by members of a methodology working group . The working group comprised six participants who corresponded via teleconference , e-mail and face-to-face meeting during this development period . In October 2013 , the methodology was presented in a workshop at the Joanna Briggs Institute Convention . Workshop participants , review authors and method ologists provided further testing , critique and feedback on the proposed methodology . Results : This study describes the methodology and methods developed for the conduct of an umbrella review that includes published systematic review s and meta-analyses as the analytical unit of the review . Details are provided regarding the essential elements of an umbrella review , including presentation of the review question in a Population , Intervention , Comparator , Outcome format , nuances of the inclusion criteria and search strategy . A critical appraisal tool with 10 questions to help assess risk of bias in systematic review s and meta-analyses was also developed and tested . Relevant details to extract from included review s and how to best present the findings of both quantitative and qualitative systematic review s in a reader friendly format are provided . Conclusions : Umbrella review s provide a ready means for decision makers in healthcare to gain a clear underst and ing of a broad topic area . The umbrella review methodology described here is the first to consider review s that report other than quantitative evidence derived from r and omized controlled trials . The methodology includes an easy to use and informative summary of evidence table to readily provide decision makers with the available , highest level of evidence relevant to the question posed PURPOSE Predicting efficacy and toxicity could potentially allow individualization of cancer therapy . We investigated putative pharmacogenetic markers of chemotherapy toxicity in a large r and omized trial . PATIENTS , MATERIAL S , AND METHODS Patients were r and omly assigned to different sequences of chemotherapy for advanced colorectal cancer . First-line therapy was fluorouracil ( FU ) , irinotecan/FU ( IrFU ) or oxaliplatin/FU ( OxFU ) . Patients allocated first-line FU had planned second-line irinotecan alone , IrFU , or OxFU . The primary toxicity outcome measure was toxicity-induced delay or dose reduction ; the secondary outcome was Common Terminology Criteria of Adverse Events grade > or= 3 toxicity .  DNA was analyzed in 1,188 patients ; 1,036 were assessable for the primary outcome , including 688 treated with FU , 270 with IrFU ( first or second line ) , 280 with OxFU ( first or second line ) , 184 with irinotecan alone , and 454 with any irinotecan-containing regimen .  Ten polymorphisms were assessed : thymidylate synthase-enhancer region ( TYMS-ER ) , thymidylate synthase 1494 ( TYMS-1494 ) , dihydropyrimidine dehydrogenase ( DPYD ) , methylenetetrahydrofolate reductase ( MTHFR ) , mutL homolog 1 ( MLH1 ) , UDP glucuronyltransferase ( UGT1A1 ) , ATP-binding cassette group B gene 1 ( ABCB1 ) , x-ray cross-complementing group 1 ( XRCC1 ) , glutathione-S-transferase P1 ( GSTP1 ) , and excision repair cross-complementing gene 2 ( ERCC2 ) . Results Using the primary outcome measure , no polymorphism was significantly associated ( P < .01 ) with the toxicity of any regimen or with the difference in toxicity of IrFU or OxFU versus FU alone . Trends ( of doubtful significance ) were seen for associations of XRCC1 , ERCC2 , and GSTP1 with toxicity during irinotecan regimens : XRCC1 , primary end point , any irinotecan-containing regimen ( P = .045 ) ; ERCC2 , secondary end point , irinotecan alone ( P = .003 ) ; GSTP1 , secondary end point ; IrFU ( P = .039 ) ; and irinotecan alone ( P = .05 ) . There was no evidence of association of UGT1A1 * 28 with irinotecan toxicity . CONCLUSION These results do not support the routine clinical use of the evaluated polymorphisms , including UGT1A1 * 28 . Further investigation of XRCC1 , ERCC2 , and GSTP1 as potential predictors of irinotecan toxicity is warranted Irinotecan‐induced severe neutropenia is associated with homozygosity for the UGT1A1 * 28 or UGT1A1 * 6 alleles . In this study , we determined the maximum‐tolerated dose ( MTD ) of irinotecan in patients with UGT1A1 polymorphisms . Patients who had received chemotherapy other than irinotecan for metastatic gastrointestinal cancer were enrolled . Patients were divided into three groups according to UGT1A1 genotypes : wild‐type ( * 1/*1 ) ; heterozygous ( * 28/*1 , * 6/*1 ) ; or homozygous ( * 28/*28 , * 6/*6 , * 28/*6 ) . Irinotecan was given every 2 weeks for two cycles . The wild‐type group received a fixed dose of irinotecan ( 150 mg/m2 ) to serve as a reference . The MTD was guided from 75 to 150 mg/m2 by the continual re assessment method in the heterozygous and homozygous groups . Dose‐limiting toxicity ( DLT ) and pharmacokinetics were evaluated during cycle 1 . Of 82 patients enrolled , DLT was assessable in 79 patients ( wild‐type , 40 ; heterozygous , 20 ; and homozygous , 19 ) . Dose‐limiting toxicity occurred in one patient in the wild‐type group , none in the heterozygous group , and six patients ( grade 4 neutropenia ) in the homozygous group . In the homozygous group , the MTD was 150 mg/m2 and the probability of DLT was 37.4 % . The second cycle was delayed because of neutropenia in 56.3 % of the patients given the MTD . The AUC0–24 
    Output:
    
Both UGT1A1 * 6 and * 28 were reliably demonstrated to be risk factors for irinotecan-induced neutropenia , with tests for both polymorphisms potentially being particularly useful in Asian cancer patients .
UGT1A1 * 6 and * 28 were also related to diarrhoea toxicity ; however , at low doses of irinotecan there was evidence that UGT1A1 * 28 was not .