***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: 6-Mercaptopurine ( 6MP ) and methotrexate are the backbone of continuation therapy for childhood acute lymphoblastic leukemia ( ALL ) . In studies of oral 6MP and methotrexate , indices of chronic systemic exposure to active metabolites of these agents , namely , red blood cell ( RBC ) concentrations of methotrexate polyglutamates ( MTXPGs ) and thioguanine nucleotides ( TGNs ) have positively correlated with event-free survival ( EFS ) . Our objective was to evaluate whether MTXPGs , TGNs , and the dose intensity of administered methotrexate and 6MP were prognostic in the setting of a treatment protocol in which all treatment was coordinated through a single center , and the weekly doses of methotrexate were given parenterally . On protocol Total XII , 182 children achieved remission and received weekly methotrexate 40 mg/m2 parenterally and daily oral 6MP , interrupted every 6 weeks during the first year by pulse chemotherapy . A total of 709 TGN , 418 MTX-PG , and 267 thiopurine methyltransferase ( TPMT ) measurements , along with complete dose intensity information ( dose received divided by protocol dose per week ) for 19,046 weeks of 6MP and methotrexate , were analyzed . In univariate analyses , only higher dose intensity of 6MP and of weekly methotrexate were significant predictors of overall EFS ( P = .006 and . 039 , respectively ) . The occurrence of neutropenia was associated with worse outcome ( P = .040 ) . In a multivariate analysis , only higher dose intensity of 6MP ( P = .020 ) was a significant predictor of EFS , with lower TPMT activity ( P = .096 ) tending to associate with better outcome .  6MP dose intensity was also associated ( P = .007 ) with EFS  among patients with homozygous wild-type TPMT phenotype . Lower  6MP dose intensity was primarily due to missed weeks of therapy and not to reductions in daily dose . We conclude that increased dose-intensity of oral 6MP is an important determinant of EFS in ALL , particularly among those children with a homozygous wild-type TPMT phenotype . However , increasing intensity of therapy such that neutropenia precludes chemotherapy administration may be counterproductive BACKGROUND Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine , and those with homozygous deficiency in thiopurine S-methyltransferase ( TPMT ) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides . We studied the metabolism , dose requirements , and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes . METHODS We compared , by use of statistical modeling , 6-mercaptopurine  pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children 's Research Hospital Protocol Total XII composed of weekly methotrexate ( 40 mg/m(2 ) ) and daily oral 6-mercaptopurine ( 75 mg/m(2 ) ) given for 2.5 years , interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine . Statistical tests were two-sided . RESULTS Erythrocyte concentrations of thioguanine nucleotides ( pmol/8 x 10(8 ) erythrocytes ) were inversely related to TPMT enzyme activity ( P<.01 ) , with averages ( + /- st and ard deviations ) of 417 ( + /-179 ) , 963 ( + /-752 ) , and 3565 ( + /-1282 ) in TPMT homozygous wild-type ( n = 161 ) , heterozygous ( n = 17 ) , and homozygous-deficient ( n = 2 ) patients , respectively . There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined . There were no sex differences in thioguanine nucleotide concentrations ( P = .24 ) , TPMT enzyme activity ( P = .22 ) , or average weekly prescribed dose of 6-mercaptopurine  ( P=.49 ) . The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT ( 100 % ) , intermediate among heterozygous patients ( 35 % ) , and lowest among wild-type patients ( 7 % ) ( P<.001 ) , with average ( + /- st and ard deviation ) final weekly  6-mercaptopurine doses of 72 ( + /-60 ) , 449 ( + /-160 ) , and 528 ( + /-90 ) mg/m(2 ) , respectively . Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations . CONCLUSION We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity , even among patients who are heterozygous for this trait Thiopurine S‐methyltransferase ( TPMT ) activity exhibits genetic polymorphism . The purpose of this investigation was to identify TPMT mutant alleles in the Saami population as a basis of developing genotyping tests for prediction of TPMT activity . The most predominant allele in Saamis ( n = 194 ) was the TPMT*3C allele ( A719 G mutation ) representing 92 % of the mutant alleles , with an estimated allelic frequency of 3.3 % . The most frequent allele in Caucasians ( n = 66 ) living in the same geographic area was the TPMT*3A ( A719 G and G460A mutations ) representing 91 % of the mutant alleles , with an estimated allelic frequency of 3.4 % . A test for one mutation , A719 G , may prospect ively identify more than 90 % of the Saami individuals who require reduction in thiopurine dose to avoid hematopoietic toxicity . In a Norwegian population , comprising both the major Caucasian population and a minor Saami population , the same genotyping tests ( eg , tests for the A719 G and G460A mutations ) may be used Purpose Important drugs in the treatment of childhood acute lymphoblastic leukaemia ( ALL ) are 6-mercaptopurine ( 6-MP ) and methotrexate ( MTX ) . Thiopurine methyltransferase ( TPMT ) is a polymorphic enzyme causing variability in 6-MP response and toxicity . The aim of this study was to investigate the fluctuation in TPMT enzyme activity over time and the effect of high-dose MTX infusions on TPMT enzyme activity and 6-MP metabolites in paediatric ALL patients . Methods Fifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included in the study . TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment . TPMT and 6-MP metabolites were measured before the initiation of high-dose MTX ( HD-MTX ) infusions and at 66 h post-infusion . The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukaemic cell line . Results Forty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity according to genotype at the time of diagnosis . TPMT activity had decreased significantly 66 h after the start of HD-MTX infusions ( −9.2 % ; p = 0.013 ) . MTX bound to recombinant TPMT protein severely inhibiting TPMT enzyme activity ( remaining activity 16 % ) . Conclusions Our results show that TPMT genotyping should be performed in children with ALL , since 40 % of the children in our study who carried the wild-type TPMT gene were at risk of initial underdosing of 6-MP in cases where only TPMT enzyme activity was determined . MTX inhibits the TPMT enzyme activity after HD-MTX infusions due to protein binding Thiopurine methyltransferase ( TPMT ) catalyzes thiopurine S-methylation , an important metabolic pathway for drugs such as 6-mercaptopurine .  Erythrocyte ( RBC ) TPMT activity  was measured in blood sample s from 298 r and omly selected subjects . Of the subjects , 88.6 % were included in a subgroup with high enzyme activity ( 13.50 + /- 1.86 U , mean + /- SD ) , 11.1 % were included in a subgroup with intermediate activity ( 7.20 + /- 1.08 U ) , and 0.3 % had undetectable activity . This distribution conforms to Hardy-Weinberg predictions for the autosomal codominant inheritance of a pair of alleles for low and high TPMT activity , TPMT(L ) and TPMT(H ) , with gene frequencies of .059 and .941 , respectively . If RBC TPMT activity is inherited in an autosomal codominant fashion , then subjects homozygous for TPMT(H ) would have high enzyme activity , subjects heterozygous for the two alleles would have intermediate activity , and subjects homozygous for TPMT(L ) would have undetectable activity . The segregation of RBC TPMT activity among 215 first-degree relatives in 50 r and omly selected families and among 35 members of two kindreds and one family selected because they included prob and s with undetectable RBC enzyme activity were also compatible with the autosomal codominant inheritance of RBC TPMT . For example , in eight matings between subjects with intermediate activity ( presumed genotype TPMT(L)TPMT(H ) ) and subjects with high activity ( presumed genotype TPMT(H)TPMT(H ) ) , 47 % ( 8/17 ) of the offspring had intermediate activity . This value is very similar to the 50 % figure expected on the basis of autosomal codominant inheritance ( chi(2 ) ( [ 1 ] ) = .059 ) . Further experiments are required to determine whether this genetic polymorphism for an important drug metabolizing enzyme may represent one factor in individual variations in sensitivity to thiopurines Background : Research into adverse events ( AEs ) has highlighted the need to improve patient safety . AEs are unintended injuries or complications result ing in death , disability or prolonged hospital stay that arise from health care management . We estimated the incidence of AEs among patients in Canadian acute care hospitals . Methods : We r and omly selected 1 teaching , 1 large community and 2 small community hospitals in each of 5 provinces ( British Columbia , Alberta , Ontario , Quebec and Nova Scotia ) and review ed a r and om sample of charts for nonpsychiatric , nonobstetric adult patients in each hospital for the fiscal year 2000 .  Trained review ers screened all eligible charts , and physicians review ed the positively screened charts to identify AEs and determine their preventability . Results : At least 1 screening criterion was identified in 1527 ( 40.8 % ) of 3745 charts . The physician review ers identified AEs in 255 of the charts . After adjustment for the sampling strategy , the AE rate was 7.5 per 100 hospital admissions ( 95 % confidence interval [ CI ] 5.7– 9.3 ) . Among the patients with AEs , events judged to be preventable occurred in 36.9 % ( 95 % CI 32.0%–41.8 % ) and death in 20.8 % ( 95 % CI 7.8%–33.8 % ) . Physician review ers estimated that 1521 additional hospital days were associated with AEs . Although men and women experienced equal rates of AEs , patients who had AEs were significantly older than those who did not ( mean age [ and st and ard deviation ] 64.9 [ 16.7 ] v. 62.0 [ 18.4 ] years ; p = 0.016 ) . Interpretation : The overall incidence rate of AEs of 7.5 % in our study suggests that , of the almost 2.5 million annual hospital admissions in Canada similar to the type studied , about 185 000 are associated with an AE and close to 70 000 of these are potentially preventable BACKGROUND Azathioprine ( aza ) therapy is beneficial in the treatment of inflammatory bowel disease , but 10%-30 % of patients can not tolerate aza therapy because of adverse drug reactions . Thiopurine S-methyltransferase ( TPMT ) deficiency predisposes to myelotoxicity , but its association with other side effects is less clear . Inosine triphosphatase ( ITPA ) mutations are other pharmacogenetic polymorphisms possibly involved in thiopurine metabolism and tolerance . METHODS We analyzed data from a 6-month prospect i ve study including 71 patients with Crohn disease undergoing first-time aza treatment with respect to aza intolerance . Patients were genotyped for common TPMT and ITPA mutations and had pretherapy TPMT activity measured . 
    Output:
    
Clinical decision-makers require high- quality evidence of clinical validity and clinical utility of TPMT genotyping to ensure appropriate use in patients