***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: Until 1990 , the survival of children with acute lymphoblastic leukaemia ( ALL ) in Russia was below 10 % . To establish a protocol feasible under conditions there , ALL-MB 91 was design ed to avoid prolonged bone marrow aplasia , thereby reducing needs for extensive supportive care , blood transfusions , long-lasting hospitalization and costs . High-dose therapies were avoided , anthracycline use was limited and CNS radiation therapy only foreseen in high-risk patients ( about 30 % ) . This was r and omized against a modified BFM protocol . From 1995 to 2002 , 834 patients of age up to 18 years were registered in 10 centres and 713 received after central r and omization the allocated risk-stratified treatment . After a median follow-up of 7 years , the event-free survival ( EFS ) was 67±3 % on ALL-MB 91 ( N=358 ) vs 68±3 % on ALL-BFM 90 m ( N=355 ) . The overall survival ( OS ) was 71±3 % vs 74±2 % , respectively . Anaemia , thrombocytopenia , agranulocytosis > 10 days and hospitalization ( median 35 vs 68 days ) were lower on ALL-MB 91 ( P<0.01 , N=197 ) . While EFS and OS were similar with both protocol s , ALL-MB 91 significantly incurred fewer toxicity and re source requirements and , therefore , has been increasingly used across Russia In a series of 40 patients treated with L-asparaginase for various neoplastic diseases , 6 patients had generalized anaphylactic reactions to L-asparaginase .  Each of these reactors had antibodies detectable by passive hemagglutination , but precipitins were detectable in only one of this group of six patients . That patient had received two courses of the enzyme . 1 wk after the anaphylactic reaction , complement-fixing antibodies were present in all the patients that were studied . Specific reagin antibodies ( IgE ) were demonstrated in one patient by the release of histamine from his leukocytes after incubation in vitro with L-asparaginase . Binding of L-asparaginase to serum antibodies after incubation in vitro was detected by selective precipitation of the complexes with 30 % ammonium sulfate or by ultracentrifugation . Total inactivation of the enzyme did not occur even at optimal proportions or at antibody excess . Passive hemagglutinating antibodies to L-asparaginase  were present in all patients who had an allergic reaction at least 1 day before the reaction occurred , when that sample was available , and were absent in all patients who did not manifest clinical allergy . Titration of antibodies by passive hemagglutination may thus provide a means of predicting impending anaphylaxis in this system , particularly when coupled with a sudden decrease in circulating levels of L-asparaginase activity BACKGROUND l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia , and is usually administered intramuscularly . Pegylated Escherichia coli asparaginase ( PEG-asparaginase ) has a longer half-life and is potentially less immunogenic than the native Escherichia coli ( E coli ) preparation , and can be more feasibly administered intravenously . The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05 - 001 ( DFCI 05 - 001 ) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E colil-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia . METHODS DFCI 05 - 001 enrolled patients aged 1 - 18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada . Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy . Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a r and omised comparison of intravenous PEG-asparaginase ( 15 doses of 2500 IU/m(2 ) every 2 weeks ) or intramuscular native E colil-asparaginase ( 30 doses of 25 000 IU/m(2 ) weekly ) , beginning at week 7 after study entry . R and omisation ( 1:1 ) was unmasked , and was done by a statistician-generated allocation sequence using a permuted blocks algorithm ( block size of 4 ) , stratified by final risk group . The primary endpoint of the r and omised comparison was the overall frequency of asparaginase-related toxicities ( defined as allergy , pancreatitis , and thrombotic or bleeding complications ) . Predefined secondary endpoints were disease-free survival , serum asparaginase activity , and quality of life during therapy as assessed by PedsQL surveys . All analyses were done by intention to treat . This study is registered with Clinical Trials.gov , number NCT00400946 . FINDINGS Between April 22 , 2005 , and Feb 12 , 2010 , 551 eligible patients were enrolled . 526 patients achieved complete remission after induction , of whom 463 were r and omly assigned to receive intramuscular native E colil-asparaginase ( n=231 ) or intravenous PEG-asparaginase ( n=232 ) . The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities ( 65 [ 28 % ] of 232 patients in the intravenous PEG-asparaginase group vs 59 [ 26 % ] of 231 patients in the intramuscular native E colil-asparaginase group , p=0·60 ) , or in the individual frequency of allergy ( p=0·36 ) , pancreatitis ( p=0·55 ) , or thrombotic or bleeding complications ( p=0·26 ) . Median follow-up was 6·0 years ( IQR 5·0 - 7·1 ) . 5-year disease-free survival was 90 % ( 95 % CI 86 - 94 ) for patients assigned to intravenous PEG-asparaginase and 89 % ( 85 - 93 ) for those assigned to intramuscular native E colil-asparaginase ( p=0·58 ) . The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E colil-asparaginase . Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparaginase group . Scores for other domains were similar between the groups . The most common grade 3 or worse adverse events were bacterial or fungal infections ( 47 [ 20 % ] of 232 in the intravenous PEG-asparaginase group vs 51 [ 22 % ] of 231 patients in the intramuscular E colil-asparaginase group ) and asparaginase-related allergic reactions ( 14 [ 6 % ] vs 6 [ 3 % ] ) . INTERPRETATION Intravenous PEG-asparaginase was not more toxic than , was similarly efficacious to , and was associated with decreased anxiety compared with intramuscular native E colil-asparaginase , supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia . FUNDING National Cancer Institute and Enzon Pharmaceuticals Much progress has been made in the biological characterization of acute lymphoblastic leukemia ( ALL ) . Many biologic features with prognostic significance have been used together with clinical factors to define patient groups for risk-adapted therapy . However , it is well recognized that the prognostic significance of virtually all variables depends on the type and intensity of treatment . The differences in risk classification , eligibility ( eg upper or lower age limit ) and composition of ethnic or racial population have made it difficult to compare results between study groups . The comparison is further complicated by the inclusion of only subsets of patients in some publications . In October 1985 , an international workshop ( organized by R Mastrangelo ) was held in Rome during which recommendations were made to report study results by common , easily available criteria ( age and presenting leukocyte count ) ; to collect prospect ively information on organ involvement , immunphenotype , genetics and treatment response ; and to use st and ard statistical methods to analyze data .4 Despite this effort , different risk classifications continue to be used , and a large number of clinical trials had been conducted on subgroups of ALL , especially in the USA . In 1993 , the US National Cancer Institute organized a workshop for the US cooperative study groups and major institutions to develop uniform risk criteria . The recommendations published in 19965 were more widely accepted . The major groups defined by age and leukocyte count were identical to that of the Rome workshop ( Table 1 ) . While the importance of cytogenetics and molecular genetics were recognized , they were not included in the risk criteria because the tests were not widely available at that time . BACKGROUND Minimal residual disease ( MRD ) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia ( ALL ) during remission . We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification . METHODS Between Oct 1 , 2003 and June 30 , 2011 , consecutive children and young adults ( aged 1 - 25 years ) with ALL from the UK and Irel and were recruited . Eligible patients were categorised into clinical st and ard , intermediate , and high risk groups on the basis of a combination of National Cancer Institute ( NCI ) criteria , cytogenetics , and early response to induction therapy , which was assessed by bone marrow blast counts taken at days 8 ( NCI high-risk patients ) and 15 ( NCI st and ard-risk patients ) after induction began . Clinical st and ard-risk and intermediate-risk patients were assessed for MRD . Those classified as MRD low risk ( undetectable MRD at the end of induction [ day 29 ] or detectable MRD at day 29 that became undetectable by week 11 ) were r and omly assigned to receive one or two delayed intensification courses . Patients had received induction , consolidation , and interim maintenance therapy before they began delayed intensification . Delayed intensification consisted of pegylated asparaginase on day 4 ; vincristine , dexamethasone ( alternate weeks ) , and doxorubicin for 3 weeks ; and 4 weeks of cyclophosphamide and cytarabine . Computer r and omisation was done with stratification by MRD result and balancing for sex , age , and white blood cell count at diagnosis by method of minimisation . Patients , clinicians , and data analysts were not masked to treatment allocation . The primary outcome was event-free survival ( EFS ) , which was defined as time to relapse , secondary tumour , or death . Our aim was to rule out a 7 % reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses . Analyses were by intention to treat . This trial is registered , number IS RCT N07355119 . FINDINGS Of 3207 patients registered in the trial overall , 521 MRD low-risk patients were r and omly assigned to receive one ( n=260 ) or two ( n=261 ) delayed intensification courses . Median follow-up of these patients was 57 months ( IQR 42 - 72 ) . We recorded no significant difference in EFS between the group given one delayed intensification ( 94·4 % at 5 years , 95 % CI 91·1 - 97·7 ) and that given two delayed intensifications ( 95·5 % , 92·8 - 98·2 ; unadjusted odds ratio 1·00 , 95 % CI 0·43 - 2·31 ; two-sided p=0·99 ) . The difference in 5-year EFS between the two groups was 1·1 % ( 95 % CI -5·6 to 2·5 ) . 11 patients ( actuarial relapse at 5 years 5·6 % , 95 % CI 2·3 - 8·9 ) given one delayed intensification and six ( 2·4 % , 0·2 - 4·6 ) given two delayed intensifications relapsed ( p=0·23 ) . Three patients ( 1·2 % , 0 - 2·6 ) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification ( p=0·08 ) . We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects ; however , the second delayed intensification course was associated with one ( < 1 % ) treatment-related death , and 74 episodes of grade 3 or 4 toxic effects in 45 patients ( 17 % ) . INTERPRETATION Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy . FUNDING Medical Research Council and Leukaemia and Lymphoma Research BACKGROUND To evaluate if dissolution of asparaginase in lidocaine can relieve pain of an intramuscular injection in children without changes in bioavailability . PROCEDURE The study was design ed as a double-blinded study , 
    Output:
    
The fixed effects pooled odds ratio after adjusting for publication bias was 2.49 ( 95 % CI 1.62 - 3.83 ) , indicating a significantly higher risk of hypersensitivity for IV over IM PEG-ASP .
Although administering PEG-ASP through IV is preferable for patients , it poses a significantly higher risk of hypersensitivity when compared with IM administration , especially for HR patients .