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By L. Pedar. Lake Erie College.

Pioglitazone order 50 mg lamictal otc, either alone or in combination with metformin or a sulfonylurea was associated with an increase in weight compared with metformin or a sulfonylurea as 157 monotherapy lamictal 200mg discount. Rosiglitazone did not produce a significant change in weight compared with Thiazolidinediones Page 56 of 193 Final Report Update 1 Drug Effectiveness Review Project 158 159 159 placebo in 1 small study and in an additional poor-quality study buy discount lamictal 200mg on line. Waist-to-hip ratio and 158 waist circumference also did not change with rosiglitazone compared to placebo. For patients with prediabetes or the metabolic syndrome, do thiazolidinediones differ from one another or from placebo in delaying the occurrence of clinical diabetes? Updated Key Question 4: For persons with prediabetes or the metabolic syndrome, do thiazolidinediones differ from one another or from placebo in delaying or preventing the occurrence of type 2 diabetes? There were insufficient data to determine whether pioglitazone and rosiglitazone have different effects on the incidence of diabetes among persons with either prediabetes or the metabolic syndrome. Only 2 relevant studies were identified, both involving monotherapy (Evidence 158, 161 Tables 3 and 10, Table 13). Neither of these studies was designed to investigate the comparative effectiveness of these 2 drugs or to allow a comparison with a placebo group for the outcome of diabetes incidence. A fair-quality, controlled trial compared a no-treatment group with pioglitazone and 158 rosiglitazone groups (both as monotherapy) in 172 persons with impaired glucose tolerance. At 3-year follow-up the incidence rate of diabetes was 3. The study was not powered to compare the 2 thiazolidinediones for this outcome. They noted a reversal to a normal oral glucose tolerance test in 33% of participants taking rosiglitazone (compared with a placebo rate of 13%). One participant in the placebo group developed type 2 diabetes over the course of the study. This small, short-term study was not designed to demonstrate differences between rosiglitazone and placebo for the outcome of new cases of type 2 diabetes. For the updated report we identified 1 new large clinical trial and 1 smaller randomized 59 controlled trial comparing rosiglitazone with placebo in persons with prediabetes the metabolic 160 syndrome. In the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication 161 (DREAM) trial, a large (N=5269), multicenter, international, randomized controlled trial of adults with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) and no preexisting cardiovascular disease, subjects were randomized to rosiglitazone 4 mg daily for 2 months, then 8 mg daily or to placebo. In addition, subjects were also randomized to ramipril 15 mg daily or placebo in a 2x2 factorial design. The primary outcome was a composite of incident diabetes or death: hazard ratio 0. The rates of progression to diabetes over 3 years were 10. The groups had similar frequency of the composite cardiovascular outcome (myocardial infarction, stroke, cardiovascular death, new angina, revascularization procedure, heart failure) and all but 1 of the components of the composite: heart failure (hazard ratio 7. The effects of rosiglitazone were the same in all Thiazolidinediones Page 57 of 193 Final Report Update 1 Drug Effectiveness Review Project regions of the world, with different ethnic groups, in both sexes, and across all ages. For every 1000 people treated with rosiglitazone for 3 years, 144 cases of diabetes would be prevented, with an excess of 4 to 5 cases of congestive heart failure. In a pilot randomized controlled trial (N=200), rosiglitazone was compared with placebo 160 in persons with the metabolic syndrome undergoing percutaneous coronary interventions. Rosiglitazone 4 mg twice daily was given immediately before the intervention and then for 1 year of follow-up. There was no significant difference in rates of death, myocardial infarction, or stroke at 12 months. There were fewer cases of new-onset diabetes in the rosiglitazone group than with placebo, but this did not reach statistical significance (0% compared with 3. For patients with prediabetes or metabolic syndrome, is the use of different thiazolidinediones associated with reversal or slower progression of cardiac risk factors, including lipid levels, central obesity, or elevated blood pressure? Summary of the Evidence • Data are insufficient to determine the comparative effectiveness of Pio and Rosi on cardiovascular risk factors among persons with prediabetes or the metabolic syndrome. Detailed Assessment This question was not included in the updated report. Data are insufficient to determine the comparative effectiveness of pioglitazone and rosiglitazone on cardiovascular risk factors among persons with prediabetes or the metabolic syndrome. There were no data to address comparative effects on blood pressure. One fair-quality head-to-head study demonstrated improved lipid levels with pioglitazone compared to rosiglitazone. Data on both drugs from placebo-controlled trials showed mixed effects on lipid levels. Data on the effect of pioglitazone and rosiglitazone on weight and abdominal obesity are few and, as noted above in Key Question 3, it is not possible to conclude if there is a difference between the 2 drugs for these 2 outcomes. More detailed information on the 6 studies which examined cardiovascular risk factors among persons with prediabetes or the metabolic syndrome are presented in Table 13 and Evidence Tables 2, 9, and 10. Lester 157 and colleagues noted a significant increase in total cholesterol (5. Combined therapy of pioglitazone and either sulfonylurea or metformin produced similar lipid changes to pioglitazone monotherapy. Thiazolidinediones Page 58 of 193 Final Report Update 1 Drug Effectiveness Review Project 158 In a small study, rosiglitazone increased HDL (P=0. Thiazolidinediones Page 59 of 193 Final Report Update 1 Drug Effectiveness Review Project Table 13. U se ofth iaz olidinediones inprediabetes and th e m etabolicsyndrom e C h ange in a Study Population C h ange weigh t,B M I 2 a designTotal Drug,dosage M eanage inblood (kg/m ),or O ccurrence of a Study sam ple siz e C om bination (years) C h ange in pressure C h ange inlipid central clinical a a a Q uality F ollow-up th erapy C om orbidities A 1c(% ) (m m H g) levels (m g/dl) obesity diabetes H ead-to-h ead trials Totalcholesterol: Pio-11;R osi29 (P<0. Thiazolidinediones Page 62 of 193 Final Report Update 1 Drug Effectiveness Review Project Key Question 6. For persons with type 2 diabetes what are the adverse events related to pioglitazone and rosiglitazone, and how do these differ from each other, from placebo, and from other oral hypoglycemic agents? Summary of the Evidence • Adverse events occurring with pioglitazone and rosiglitazone were similar in 3 head-to-head trials. Significantly more female patients who received rosiglitazone experienced fractures than did female patients who received either metformin or glyburide (9. Preliminary analysis of a second, ongoing trial is consistent with this finding. Detailed Assessment Direct evidence comparing pioglitazone to rosiglitazone 67, 68 65 67 Three head-to-head efficacy trials with adverse event data were identified. In 1, 719 patients with both type 2 diabetes and dyslipidemia were randomized to treatment with pioglitazone 30 mg daily for 12 weeks followed by 45 mg for an additional 12 weeks, or rosiglitazone 4 mg daily followed by 8 mg for the same intervals. There were no differences between the drugs in adverse events including weight change (2. Data on the incidence of specific adverse events were not reported.

Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Reportingof attrition discount lamictal 100 mg fast delivery, Nu mber Au th or buy 50mg lamictal, crossov ers buy generic lamictal 25mg line, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled Z "5 3$)LOOc E I! Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Au th or, Eligibility Year, Allocationconcealment Grou pssimilar criteria Ou tcomeassessors Patient Cou ntry Randomizationadeq u ate? Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Reportingof attrition, Nu mber Au th or, crossov ers, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled. Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Class Control Au th or, naïv e grou p Year, patients standard Cou ntry Ex clu sioncriteria Ru n-in/w ash ou t only ofcare Fu nding Relev ance. Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Au th or, Eligibility Year, Allocationconcealment Grou pssimilar criteria Ou tcomeassessors Patient Cou ntry Randomizationadeq u ate? Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Reportingof attrition, Nu mber Au th or, crossov ers, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled. Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Class Control Au th or, naïv e grou p Year, patients standard Cou ntry Ex clu sioncriteria Ru n-in/w ash ou t only ofcare Fu nding Relev ance. Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Au th or, Eligibility Year, Allocationconcealment Grou pssimilar criteria Ou tcomeassessors Patient Cou ntry Randomizationadeq u ate? Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Reportingof attrition, Nu mber Au th or, crossov ers, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled Y%5 3%)*++* E I! Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Au th or, Eligibility Year, Allocationconcealment Grou pssimilar criteria Ou tcomeassessors Patient Cou ntry Randomizationadeq u ate? Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Reportingof attrition, Nu mber Au th or, crossov ers, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled e"G %)LOO, E I! Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Class Control Au th or, naïv e grou p Year, patients standard Cou ntry Ex clu sioncriteria Ru n-in/w ash ou t only ofcare Fu nding Relev ance e"G %)LOO,. Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Au th or, Eligibility Year, Allocationconcealment Grou pssimilar criteria Ou tcomeassessors Patient Cou ntry Randomizationadeq u ate? Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Reportingof attrition, Nu mber Au th or, crossov ers, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled i $(44%U)*++L! Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Au th or, Eligibility Year, Allocationconcealment Grou pssimilar criteria Ou tcomeassessors Patient Cou ntry Randomizationadeq u ate? NCS Page 274 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev idenceTable6. Qu alityassessmentofh ead-to-h eadtrialsinpatientsw ith PAR Reportingof attrition, Nu mber Au th or, crossov ers, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled Z %$9^%& E IE IE I! NCS Page 275 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev idenceTable6. Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR InternalValidity Au th or, Eligibility Year, Allocationconcealment Grou pssimilar criteria Ou tcomeassessors Patient Cou ntry Randomizationadeq u ate? Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR ExternalValidity Reportingof attrition, Nu mber Au th or, crossov ers, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled Ch ervinsky n/n/n/n no yes no fa ir 903/NR/663 2007 US Meltzer n/n/n/n no yes no fa ir 676/NR/471 2007 US Rosenblu t n/n/n/n no yes yes;4pts fa ir 984/NR/810 Mu lticou ntry 2007 Da h l y/y/y/n no yes no g ood 275/NR/262 2005 Denm a rk NCS Page 278 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev idenceTable6a. Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR Class Control Au th or, naïv e grou p Year, patients standard Cou ntry Ex clu sioncriteria Ru n-in/w ash ou t only ofcare Fu nding Relev ance Ch ervinsky Historyof ph ysica lfinding s of na sa lpa th olog y;recentna sa l 7-14da yba seline no yes Alta na P h a rm a yes 2007 biopsy;na sa ltra u m a ;na sa lsu rg ery;a troph icrh initis;rh initis period US m edica m enntosa ;a ctivea sth m a requ iring trea tm entwith corticosteroids orbeta a g onists,known h ypersentivitityto corticosteroids;h istoryof RTIwith in 14da ys of screening visitordevelopm entof respira toryinfection du ring ba seline; u sefo a ntibiotics with in 14da ys of screening visit Meltzer Abnorm a lfinding s inclu ding na sa lpolyps a ndna sa ltra ct 7-14da yba seline no yes Alta na P h a rm a yes 2007 m a lform a tions;rh initis m edica m entosa ;evidenceof a n RTI period US orsig nifica ntm edica ldisorderoth erth a n ARwith in 14da ys of screening ;positivetestforh ep B,h ep CorHIV;a ctive a sth m a requ iring trea tm entwith inh a ledorsystem itc corticosteroids orrou tineu seof beta a g onists;u seof proh ibitedm edica tions du ring wa sh ou tperiods Rosenblu t Anym edica lcondition th a tcou ldinterferewith sa fety 7-14da yba seline no yes Gla xoSm ith KlineR&D yes Mu lticou ntry eva lu a tions,inclu ding severena sa lobstru ction,recentna sa l period 2007 septa lorfa cia lsu rg ery;a sth m a ;rh initis m edica m entosa ; recentRTI;sinu sitis;ca ndida infection of th enoseor oroph a rynx;g la u com a ;ca ta ra cts;ocu la rh erpes sim plex; h istoryof a drena linsu fficiencyora bnorm a lECGorclinica l la btest;INSwith in 4weeks of screening ;corticosteroids with in 6m onth s of screening ;oth erm edica tions th a tcou ld a ffectAR. Da h l pa tients wh o su fferedfrom a sth m a a ndARbeca u seof NR no yes Gla xoSm ith KlineR&D yes 2005 a llerg ens oth erth a n pollen;th osereceiving ch ronic Denm a rk trea tem entwith a ntia sth m a m edica tion ora ny im m u nosu ppressa nts a nd/orim m u noth era pyoverth ela st3 yea rs NCS Page 279 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev idenceTable6a. Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR Au th or, Eligibility Year, Allocationconcealment Grou pssimilar criteria Ou tcomeassessors Patient Cou ntry Randomizationadeq u ate? Gu revich notclea r notclea r yes yes yes yes 2005 USA Mu rph y notclea r notclea r yes yes yes yes 2006 USA Stelm a ch notclea r notclea r yes yes yes yes 2005 Bra zil NCS Page 280 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev idenceTable6a. Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR Reportingof attrition, Nu mber Au th or, crossov ers, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled Gu revich y/y/n/n no yes no fa ir NR/NR/26 2005 USA Mu rph y y/n/n/n no u nclea r no fa ir 407/229/229 2006 USA Stelm a ch y/n/y/n no no yes fa ir NR/NR/74 2005 Bra zil NCS Page 281 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev idenceTable6a. Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR Class Control Au th or, naïv e grou p Year, patients standard Cou ntry Ex clu sioncriteria Ru n-in/w ash ou t only ofcare Fu nding Relev ance Gu revich neg a tiveskin testresponseto a yea r-rou nda llerg en; 1-week ru n-in with no yes Astra Zeneca yes 2005 sea sona la llerg ies;sleep a pnea ;na sa lpolyps;devia ted sa linena sa lspra y USA septu m ;a topicdisea ses oth erth a n AR;non-AR;obesity; onceda ily ch ronicobstru ctivepu lm ona rydisea se;recentu ppera nd 1week wa sh ou t lowera irwa yinfection;u seof ora lorna sa lsteroids with in between stu dya rm s 30d;a nd/oru seof Beta bolckers,tricyclica ntidepressa nts or oth erm edica tions th a ta reknown to a ffectsleep,rh initis a nd da ilyperform a nce Mu rph y a nysig nifica ntch ronicdisea se;a nydisea seorcondition th a tnone no yes Astra Zeneca yes 2006 m ig h ta ffectg rowth ;ch rom osom ea berrra tion;skeleta l USA a bnorm a lities th a ta ffecth eig h t;evidenceof na sa lpolyps; stru ctu ra la bnorm a litites of th enoseca u sing na sa l obstru ction;a clinica llyreleva nta bnora m lityin th eph ysicla exa m ina tion resu lts;a h istoryof su bsta ncea bu se,nenta l illness orreta rda tion;g la u com a orca ta ra a cts,a n a sth m a dia g nosis th a trequ iredtrea tm entwith ora lorinh a led steroids orleu kotrienem odifiers;trea tm entwith ora l, injecta ble,orinh a ledcorticosteroids with in 60dof visit1; insu fficientARsym ptom s to requ ireda ilyth era py;a h istory orevidenceof a bnorm a lg rowth ;a known g esta tiona la g e less th a n 35weeks;g rowth velocitybelowth eth irdpercentile a tth eendof th e6-m onth ba selineperiod;ora nyu seof m edica tion th a tcou lda ffectg rowth Stelm a ch im m u noth era pyorh ospita liza tion du eto a n a sth m a 2-week ru n-in with for3 yes m edica tions a nd yes 2005 exa cerba tion du ring th epreviou s 6m onth s,u seof ora l, pla cebo. Only m onth s pla cebo su ppliedby Bra zil injectedorinh a ledcorticosteroids,no respira toryinfection sa lbu ta m ola nd priorto Fa rm a la b-Ch iesi co. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d Da y Ra nd om ized , Pa tients a ged 6yea rs a nd old er, Intra na sa lb ud esonid e,200 2weeks/NR 1990 d oub le-b lind ,p a ra llel, with p erennia lrhinitis fora tlea st m ea n gra m s twic e d a ilyvs p la c eb o-c ontrolled 2yea rs,c urrentlyrec eiving no p la c eb o trea tm entforrhinitis S tud yp eriod :4weeks Exc lusion:Pregna nc y, tub erc ulosis,resp ira toryinfec tion, a d d itiona ld isea se,ora sthm a req uiring trea tm entwith c ortic osteroid s Fokkens Ra nd om ized , Child ren a ged 6-16yea rs with b ud esonid e a q ueous na sa l NR/NR 2002 d oub le-b lind ,p la c eb o- p erennia la llergic rhinitis fora t sp ra y,128m c g onc e d a ilyvs c ontrolled ,p a ra llel, lea st1yea r,need fortrea tm entof p la c eb o m ultic enter na sa lsym p tom s,m od era te to S tud yp eriod :6weeks severe sym p tom sc ore for b loc ked nose a nd a tlea sta m ild sc ore forrunnynose orsneezing on 4of7d a ys ofrun-in p eriod NCS Page 283 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled Da y terfena d ine,up to two Na sa lsym p tom s 28. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment Da y NR/NR/51 Mea n c ha nge in sym p tom sc ores from b a seline to 4 La b ora torytests,p a tient 1990 weeks;p -va lue=Bvs p la c eb o: self-rep ortofa d verse events Bloc ked nose: Allergic rhinitis:B:-0. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments Da y Noseb leed : NR;NR 1990 Child ren:B:0vs p la c eb o:1 Ad ults:B:4vs p la c eb o:1 S neezing a ftersp ra y: Child ren:B:3vs p la c eb o:2 Ad ults:B:1vs p la c eb o:1 Na sa lirrita tion: Child ren:B:5vs p la c eb o:2 Ad ults:B:4vs p la c eb o:3 Nose d ryness: Child ren:B:1vs p la c eb o:2 Ad ults:B:1vs p la c eb o:1 Coughing: Child ren:B:1vs p la c eb o:3 Ad ults:B:4vp la c eb o:0 H ea d a c he: Child ren:B:7vs p la c eb o:8 Ad ults:B:8vs p la c eb o:5 Fokkens No ofa d verse events rep orted :B:75vs 0;0 2002 p la c eb o:73 Mostfreq uenta d verse events: p ha ryngitis:B:9vs p la c eb o:7 resp ira toryinfec tion:B:7vs p la c eb o:7 vira linfec tion:B;&vs p la c eb o:6 c oughing:B:7vs p la c eb o:4 b lood -tinged sec retion/nose b leed s:B:4vs p la c eb o:6 NCS Page 286 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d H ill Ra nd om ized ,d oub le- Child ren a ged 7-17yea rs,c hronic Intra na sa lb ec lom etha sone NR/NR 1978 b lind ,c ross-over,p la c eb o-m outh-b rea thers with gross d ip rop iona te,300m g/d a yvs c ontrolled hyp ertrop yofna sa lm uc osa a nd p la c eb o single-c enter exc essive rhinorrhea ,fa iling to S tud yp eriod :NR resp ond to a ntihista m ines a nd a d rengic d rugs Na ya k Doub le-b lind ,p la c eb o- Child ren a ged 6-12yea rs with tria m inolone a c etonid e a q ueous NR/NR 1998 c ontrolled a llergic rhinitis,m a les a nd na sa lsp ra y220g onc e d a ilyvs m ultic enter p rem ena rc hea lfem a les 440g onc e d a ily Exc lusion:c linic a llyrelelva nt S tud yp eriod :6weeks d evia tion from norm a lm ed ic a lor la b p a ra m eters,intolera nc e to c ortic osteroid thera p y,a ny m ed ic a lc ond ition c a p a b le of a ltering p ha rm okineti NCS Page 287 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled H ill No d rugs used forrhinitis Da ilysym p tom d ia ryresults 7-17yea rs Assoc ia ted rec urrenta sthm a :12/22 NR/NR/22 1978 a llowed d uring stud yp eriod rec ord ed a tc linic visits 50% Fem a le Evid enc e ofm a rked system ic a llergy Ethnic ityNR to house d ustm ite a nd /orrye gra ss Na ya k NR/NR Ad renoc ortic a lfunc tion 9. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment H ill 0/0/22 Num b erofc hild ren with resp onse: Pa tientd a ilysym p tom d ia ry 1978 Na sa lsym p tom s: Im p roved sc ore:19 Unc ha nged sc ore:0 W orse sc ore:3 Na sa lsigns: Im p roved sc ore:15 Unc ha nged sc ore:7 W orse sc ore:0 Eye sym p tom s: Im p roved sc ore:13 Unc ha nged sc ore:4 W orse sc ore:5 Na ya k 1/0/79 Mea n d ifferenc es in p la sm a c ortisollevels b etween Pa tientrep ort 1998 b a seline a tweek 6: 0hrs: T AA220g:-1. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments H ill None rep orted 0;0 1978 Na ya k Perc enta ge ofp a tients rep orting a d verse 0;0 1998 events: T AA220g/d :54% T AA440g/d :42% Pla c eb o:35% NCS Page 290 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d Neum a n Doub le-b lind , Child ren a ged 9-18yea rs, b ec lom etha sone d ip rop iona te NR/NR 1978 c rossover with p erennia la llergic rhinitis a nd 50g inha led in ea c h nostril,4 d a ilysym p tom s ofsneezing, tim es d a ily rhinorrhoea a nd na sa lob struc tion S tud yp eriod :6weeks fora tlea st5yea rs Nga m p ha ib oon Ra nd om ized d oub le- Child ren a ged 5-11yea rs with m od flutic a sone p rop iona te 100m c g NR/2week wa shoutb etween 1997 b lind ,single d ose, vs p la c eb o trea tm ents T ha ila nd p la c eb o-c ontrolled , S tud yp eriod :4weeks,with 2 p a ra llel weeks a d d itiona lfollowup m ultic enter S a rsfield Ra nd om ized , Child ren with p erennia l Na sa lflunisolid e vs p la c eb o NR/NR 1979 d oub le-b lind ,c rossover a rthritis S tud yp eriod :2m onths stud y T hen 17p a tients resp ond ing wellwith fluc isolid e c ontinued trea tm entfora d d itiona l6m onth, op en p eriod NCS Page 291 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled Neum a n NR Da ilyd ia ryc a rd s, 13. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment Neum a n NR/NR/NR Mea n d a ilyna sa lsym p tom sc ores: Pa tientoutc om e,self-rep ort 1978 W eek 1:BD:1. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments Neum a n None Rep orted NR;NR 1978 Nga m p ha ib oon None rep orted 0;0 1997 T ha ila nd S a rsfield Mostc om m on a d verse events rep orted : 1;1 1979 tra nsientna sa lstinging After6m onth op en-p eriod ,m ea surem ents of0900b lood c ortisolc onc entra tions found no effec t. NCS Page 294 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d S hore Ra nd om ized ,d oub le- Child ren a ged 4-12yea rs, Intra na sa lb ec lom etha sone vs NR/3week wa shoutb etween 1976 b lind ,p la c eb o-c ontrolled ,with p erennia la llergic rhinitis for p la c eb o trea tm ents c ross-over over1yea r,fa ilure to resp ond to S tud yp eriod :4m onths single-c enter sod ium c rom oglyc a te insuffla tion a nd hyp osensitiza tion, p retrea tm entob serva tion a tstud y c linic fora tlea st6m onths, sym p tom a tic a tsc reening, ra d iologic a lstud ies exc lud ing a b norm a lities c a using ob struc tion,ina d eq ua te p revious resp onse to trea tm ent S torm s Ra nd om ized ,d oub le- Pa tients a ged 12-65yea rs,with tria m c inolone a c etonid e na sa l NR/NR 1991 b lind ,p la c eb o-c ontrolled ,p erennia la llergic rhinitis fora t sp ra y,110g vs 220g vs 440g p a ra llel lea st2yea rs,p oorresp onse to onc e d a ilyvs p la c eb o Multi-c enter a ntihista m ines a nd /or S tud yp eriod :12weeks d ec ongesta nts or im m unothera p y,p ostive skin p ric k testfora tlea sta llergin Exc lusion:p regna nc yorla c ta tion, use ofna sa lc rom olyn T od d Ra nd om ized , Child ren with p erennia l fluisolid e na sa lsp ra y50g three NR/NR 1983 d oub le-b lind ,c ross-over rhinitis tim es d a ily,vs p la c eb o S tud yp eriod :8weeks NCS Page 295 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled S hore Pa tients a llowed to Da ilysym p tom d ia ry 8yea rs Allergyto gra ss extra c t:36% NR/NR/46 1976 c ontinue usua la ntihista m ine results rec ord ed a tc linic 78. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment S hore 2/0/44 Results rec ord c a rd s ofb ec lom eta sone: Pa tientd a ilysym p tom d ia ry 1976 S uc c ess:38(86%) Fa ilure:6 S torm s 0/0/305 Mea n Cha nges from Ba seline in S ym p tom s S c ores: Pa tientoutc om e,self-rep ort 1991 W eek 6: Na sa lS tuffiness:110m c g:-0. T od d NR/NR/64 Cha nges in sym p tom a tolgyfrom b a seline to 8weeks- Ind irec tq uestionning a t 1983 p -va lue ofd ifferenc e b etween trea tm enta nd p la c eb o: c linic visits S neezing:p =0. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments S hore None rep orted 2;0 1976 S torm s Ad verse events rep orted : 0;0 1991 H ea d a c he:T 200:16% vs T 400:18% vs T 800:21% vs p la c eb o:18% Up p erresp ira toryinfec tion:T 200:4% vs T 400:5% vs T 800:7% vs p la c eb o:13% Ep ista xis:T 200:3% vs T 400:3% vs T 800: 4% vs p la c eb o:9% T hroa td isc om fort:T 200:1% T od d Na sa lirrita tion:F:12vs p la c eb o:10 NR;NR 1983 Eyes running:F:3vs p la c eb o:1 Nose b leed :F:1vs p la c eb o:1 Itc h:F:2vs p la c eb o:0 Na usea :F:1vs p la c eb o:0 H ea d a c he:F:2vs p a c eb o:2 S leep y:F:0vs p la c eb o:1 Ra sh:F:0vs p la c eb o:1 NCS Page 298 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR InternalValidity R eporting of attrition, Auth or, Alloc ation Elig ibility Outc om e c rossov ers, Year, R and om ization c onc ealm ent Groups sim ilar c riteria assessors Careprov id er Patient ad h erenc e,and Country ad equate? Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR ExternalValidity Auth or, Loss to follow- Intention-to- Post- Num bersc reened / Year, up: treat(ITT) rand om ization Quality elig ible/ Country d ifferential/h ig h analysis exc lusions rating enrolled Exc lusion c riteria R un-in/wash out Day No Ye s No Fair NR/NR/107adults Pre gnancy,tube rculosis,re spiratory 2-w e e k base line pe riod 1990 andchildre n infe ction,additional nasal dise ase or w he re patie nts asthm are quiringtre atm e ntw ith re corde dsym ptom s corticoste roids andre ce ive donly te rfe nadine (60m gup to tw o table ts pe rday Fok k ens No Ye s No Fair NR/NR/202 Pollle n alle rgyin se ason,uppe r 1-w e e k base line pe riod 2002 re spiratoryinfe ction w ithin 2w k s in w hiche fficacy be fore scre e ning,rhinitis variable s w e re m e dicam e ntosaorstructural m e asure dtw ice daily abnorm alitie s sym ptom atice e nough to cause significantnasal obstruction, unstable asthm a,im m unothe rapynot on constantm ainte nance dose ,any othe rsignificantdise ase s,syste m ic corticoste roidthe rapyw ithin 2 m onths,e x te nsive application of topical cutane ous ste roids,topical nasal ste roids w ithin one m onth be fore scre e ning,othe rm e dication possiblyinte rfe ring:antihistam ine s w ithin 3days,crom oglycate w ithin 2 w k s,aste m izole w ithin 1m onth be fore scre e ning Hill No Ye s No Fair NR/NR/22 None re porte d No 1978 NCS Page 300 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR Class Control Auth or, naïv e g roup Year, patients stand ard of Country only c are Fund ing R elev anc e Day No N/A One authoris from Ye s 1990 ABDraco,Lund, Sw e de n Fok k ens No N/A Financial support Ye s 2002 from AstraZe ne ca R&D,LundSw e de n Hill No N/A NR Ye s 1978 NCS Page 301 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR InternalValidity R eporting of attrition, Auth or, Alloc ation Elig ibility Outc om e c rossov ers, Year, R and om ization c onc ealm ent Groups sim ilar c riteria assessors Careprov id er Patient ad h erenc e,and Country ad equate? Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR ExternalValidity Auth or, Loss to follow- Intention-to- Post- Num bersc reened / Year, up: treat(ITT) rand om ization Quality elig ible/ Country d ifferential/h ig h analysis exc lusions rating enrolled Exc lusion c riteria R un-in/wash out Nayak no ye s no fair NR/NR/80 Anyclinicallyre le vantde viation from no 1998 norm al m e dical orlaboratory USA param e te rs,an intole rance to corticoste roidthe rapy,anym e dical condition capable ofalthe ringthe pharm acok intics ofthe drup,acute infe tiors sinusitis,unde rlyingnasal pathologyre sultingin occlusion ofa nostril,visible e vide nce offungal infe ctionn ofthe nose ,throat,or m outh,oran initial m orningplasm a cortisol le ve l outside the range of5to 20m cg/dl.

Infertility in men with SCD has been studied more frequently than infertility in women and appears to have multiple causes buy lamictal 25 mg, Sperm abnormalities including hypogonadism lamictal 25mg overnight delivery, sperm abnormalities order lamictal mastercard, and erectile dys- Sperm abnormalities are frequent in males with SCD, with rates as function (ED) due to priapism. However, up to 24% of men with SCD may develop delayed puberty in males contributes to sperm abnormalities in hypogonadism, a clinical syndrome associated with poor testos- those 25 years of age, these abnormalities improve in older men terone production, infertility, ED, and poor libido. Clinical laboratory findings are low testos- ties are reported even when testosterone, FSH, and LH are normal. It is reprinted with permission from Blood 2014, Volume 124. These high rates may be due to many factors, needed to determine the clinical importance of abnormal sperm including barriers to contraception access, failure of contraception analysis and its impact on male fertility in SCD. Barriers to access may be at the physician level because physicians may be underprescribing hor- ED monal contraceptives. Studies reporting physicians’ prescribing ED occurs frequently in men with SCD, with prevalence rates as patterns for contraception and patient preferences for contraception high as 21%–35% reported. Management of ED due to priapism depends on the extent of penile tissue fibrosis. Contraception choices for women with SCD Penile implants have been used successfully, but multiple complica- 21,22 Combined hormonal contraceptive agents. A general clinical philosophy is that prevention monal contraceptive use in patients with SCD has been fraught with is better than treatment because of the relatively poor outcomes of concerns regarding thrombotic complications and increased pain. Therapeutic Theoretical concerns are related to the underlying pathophysiology strategies to limit the duration of priapism events and to prevent of SCD and its “prothrombotic” state. Abnormal RBC rheology, priapism recurrences should be used aggressively. These factors may lead to increased venous stasis, studies have addressed this topic prospectively using standard clotting, and pain in women with SCD receiving estrogen. Although the studies are small, 150 individual patients may reproductive years as a surrogate for fertility. Thrombotic rates of patients with SCD and healthy controls have been com- events have been reported to occur in a small number of pa- pared, the lower number of pregnancies in women with SCD has tients. Presently, we understand that many factors other than infertility may have influenced the number of pregnancies per patient. Progestin-only con- supported by studies finding similar conception rates in women with traceptives should be a good choice in women with SCD due to a SCD and healthy controls. One of the biggest menstrual bleeding in women with SCD is its association with an barriers to progesterone-only medication is its side effect profile, increased SCD-related pain rate. These progesterone- women, increased SCD-related pain occurs at different stages of the only compounds have changed over the years to narrow the side menstrual cycle and this pattern may be related to fluctuations in the effects, and this limits the ability to compare data between levels of estrogen and progesterone. Progesterone used as daily oral or As mentioned in earlier sections, progesterone was reported to depot preparations decreases SCD-related painful events in a subset decrease the frequency of acute pain in women with SCD as early of women. After preliminary studies of progesterone and testoster- one demonstrated decreased sickling, investigators performed a Sexuality and reproductive choices in women with SCD crossover study in 28 women treated with progesterone and 16 Information on sexuality in women with SCD is limited. Although results were prelimi- the well-described data on delayed puberty and adverse outcomes nary, they reported an 80% reduction in pain in the treated group. However, attitudes regarding contraception and unplanned placebo either before or after depot medroxyprogesterone acetate pregnancy suggest that women with SCD are interested in avoiding (DMPA). In addition, hemoglobin, fetal hemoglobin, and general population. This led to the Unplanned pregnancy and SCD conclusion that improved RBC survival may be due to the Unplanned pregnancy remains high globally and contraceptive use increased survival of RBCs containing higher concentrations of varies widely by country, age, and race/ethnicity. Finally, de Abood et al reported 43 women SCD, unplanned pregnancy rates have been high historically and with SCD who had pain in the last year and were nonrandomly remain high. Hematology 2014 419 Use of implantable progesterone-only containing compounds has although 2 women had successful pregnancies, 1 after preimplanta- been reported in small prospective studies in women with SCD. In 2004, the World unpredictable risk of infertility, patients may opt for procedures to Health Organization released recommendations on the use of preserve fertility before HSCT regardless of conditioning regimens. Although experience is limited, patients with IUDs outweighed the risks associated with the increased morbidity SCD have success with procedures and therapies that preserve and mortality associated with pregnancy. Cryopreservation options have expanded and depend Eligibility Criteria for Contraceptive Use 2010 continues to support 49 on stage of pubertal development. Combined hormonal contraceptives are pubertal males is standard and improvement of sperm banking classified as level 2, meaning that “the advantages of using the techniques and increased use of intracytoplasmic sperm injection method generally outweigh the theoretical or proven risks. Cryopreservation of testicular terone-only containing pills are classified as level 1, meaning that tissue, considered experimental, is an option in prepubertal boys, these agents can be used without restrictions. However, it is but is waiting for the development of technology and procedures for concerning that these recommendations are based primarily on the 63 restoring human fertility. It should be noted, however, that reduced SCD-related morbidity. However, as utilization of these women with SCD are at risk for thromboses67 and increased acute therapies increases, more attention is drawn to their associated pain while being exposed to increased estrogen levels during adverse effects and toxicities. Issues have been raised regarding HU ovarian stimulation. Successful oocyte preservation after controlled use, abnormal sperm production, and teratogenic effects. In addi- ovarian stimulation in a 19-year-old woman with SCD has been tion, fertility preservation after HSCT and the endocrine abnormali- described using a protocol to avoid hyperstimulation and incorporat- ties associated with transfusional iron overload remain concerns. In addition, successful pregnan- contraception counseling is paramount to decreasing unplanned cies in women with SCD after ovarian tissue preservation have been pregnancies. Hormonal contraceptive use is controversial in SCD 61,62 reported. For girls who are 18 years of age, particularly those primarily due to the theoretical increased risk for venous thrombo- 12 years, ovarian tissue preservation is an option, although embolism and risk for acute pain events. When counseling pediatric 68 outcomes in SCD are not clear. Transfusional iron overload and infertility Patterns of transfusional iron overload in patients with SCD seem to HSCT and fertility preservation be different from those in patients with thalassemia. HSCT remains the sole cure for SCD, with event- free survival rates averaging 85%–90% for allogeneic transplanta- Transfusional iron overload, if untreated, may lead to infertility tions. Gonadal failure in patients with SCD on outcomes such as endocrine dysfunction and impaired fertility are chelation therapy occurs at similar rates in those with SCD without iron overload. If the toxicity of conditioning regimens could be decreased while maintaining low rates of graft rejection, delayed in patients with SCD receiving chronic transfusion therapy HSCT may be considered more often in patients with SCD before compared with patients with thalassemia major. Generally, focus is severe acute complications and major end-organ damage occur. In women with Myeloablative conditioning regimens before HSCT for SCD cause thalassemia major, biomarkers have been used to assess reproduc- infertility, particularly in females. Young children who receive SCD receiving HU is impressive. Its impact on reducing acute HU appear to have normal growth,75 but information on pubertal complications and improving survival suggests that HU may development is less clear. However, 2 reproductive issues loom have a positive effect at limiting SCD-related organ dysfunction with the use of HU in both the pediatric and adult populations: long term. Furthermore, some clinicians suggest that HU’s abnormal spermatogenesis and teratogenic effects.

For example purchase lamictal 200mg free shipping, these patients may be eligible preemptive testing for thiopurine methyltransferase status will for phase 2 or 3 studies order lamictal without a prescription, which would include novel drugs that have likely decrease the risk of mercaptopurine-induced toxicities associ- already gone through early phases of clinical development in adults proven lamictal 100 mg. This, in turn, might reduce An example of a rare subpopulation specifically identified in the likelihood of acute myelosuppression (without compromising relationship with a targeted therapy is that of Ph ALL patients, disease control) and the risk for the development of mercaptopurine- accounting for only 3% of the ALL population. However, the increased risk of developing hepatic venoocclusive disease. It is sample size needed in the framework of a traditional study is possible that, in the near future, genetic guidance might ensure a difficult to achieve in a reasonable time frame considering that 616 American Society of Hematology high-risk leukemias often represent a small subset and that, in controlled trials should only be considered when completely general, lymphoblastic leukemia is not regarded as a common unavoidable and justified. For this reason, mainly in childhood leukemia, many countries have developed national study groups that design and run A final consideration is concerning the clinical use of MRD multicenter clinical trials. In addition to that, they have developed assessment. Although we can assume that MRD provides relevant international collaborations to address therapeutic questions in trials additional information on the activity of new drugs because it for rare subgroups, including Ph ALL. Formal validation of a surrogate end point is that is sufficient for driving changes in treatment practice. Further- usually carried out by performing a meta-analysis of all of the more, it should be taken into account that relatively large trials are randomized trials in which a new drug (or a class of drugs) was also needed to optimize treatment modalities by aiming at modest studied, with the aim of assessing whether the treatment effects on differences that nonetheless are clinically important for outcome MRD are strongly related to the treatment effects on the clinical improvement (efficacy), together with a more efficient definition of benefit end point. This would be necessary before using MRD as a therapeutic strategies that use existing chemotherapeutic agents. These studies are generally powered to detect less than 10% Conclusions absolute increase (or difference) in EFS in a subpopulation of The remarkable advances in the treatment of childhood ALL have patients, usually of relevant size, who have a relatively good become a paradigm of success in modern oncology. In childhood ALL, these studies typically address the still have to deal with a treatment failure rate of 10%-15% and the so-called intermediate-risk patients, accounting for approximately need to minimize long-term health complications in a large popula- 50% of the ALL population, who have a 4-year EFS of 70% to 80%. To face these challenges and to keep These studies may ask a randomized question on intensification or making progress against childhood ALL, we need new drugs and inclusion of new formulations of existing drugs such as, for transnational collaborations across large and well-characterized example, pegylated L-asparaginase instead of the native product. Treatment optimization may also be achieved by testing strategies that are at least as efficacious as those currently used, but carry a Acknowledgments lower burden of toxicity and complications. Typically, this gener- This work was supported by the Associazione Italiana Ricerca sul ates studies of noninferiority targeted to subpopulations of patients Cancro (IG-8666 to A. We thank Maria EFS, for whom the attempt is to de-intensify certain therapy Grazia Valsecchi and Valentino Conter for conceiving, writing, and elements with known short- or long-term side effects without revising the manuscript. In addition, in these 2 settings, international cooperation is needed in addition to innovative ap- proaches of study design and conduct. Tettamanti progressive availability of new targeted therapy will make the ONLUS. With that in mind, we should always consider the possibility of conducting international Correspondence collaborative traditional trials to maximize recruitment, even if this Andrea Biondi, Department of Pediatrics and Centro Ricerca would cause a significant increase in the organizational and Tettamanti, University of Milano-Bicocca, S. To this end, alternative statistical approaches Fondazione MBBM, 20900, Monza, Italy; Phone: 0039-039- may be needed. It is also essential to give more emphasis on the 2333513; Fax: 39-039-2301646; e-mail: abiondi. References The use of a Bayesian approach to the study design has also been 1. Pediatric proposed, because this enables information gathered from previous acute lymphoblastic leukemia: where are we going and how do studies to contribute to the estimation process. Acute lymphoblastic heavily on the accuracy of the prior information. Biology, risk Research institutions and medicine regulatory agencies have issued stratification, and therapy of pediatric acute leukemias: an guidelines on how to run clinical trials in small populations for drug update. The Pediatric Cancer methods for the design and analysis of these trials, they agree to the Genome Project. Risk- and response- cal approaches if they are useful to improve the study. In the based classification of childhood B-precursor acute lymphoblas- regulatory approval process, deviations from standard randomized tic leukemia: a combined analysis of prognostic markers from Hematology 2013 617 the Pediatric Oncology Group (POG) and Children’s Cancer pediatric Philadelphia negative B-cell precursor acute lympho- Group (CCG). Identification and from independent studies by the Children’s Cancer Group molecular characterization of recurrent genomic deletions on (CCG) and Pediatric Oncology Group (POG) associating 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1- favorable prognosis with combined trisomies 4, 10, and 17 in positive acute lymphoblastic leukemia patients: on behalf of children with NCI Standard-Risk B-precursor Acute Lympho- Gruppo Italiano Malattie Ematologiche dell’Adulto Acute blastic Leukemia: a Children’s Oncology Group (COG) initia- Leukemia Working Party (GIMEMA AL WP). Cazzaniga G, Valsecchi MG, Gaipa G, Conter V, Biondi A. Defining the correct role of minimal residual disease tests in the J Clin Oncol. Prognostic value of genetic and adolescents with B-cell precursor acute lymphoblastic alterations in children with first bone marrow relapse of leukemia: results in 3184 patients of the AIEOP-BFM ALL childhood B-cell precursor acute lymphoblastic leukemia. Genetic alterations childhood acute lymphoblastic leukemia is predicted by flow activating kinase and cytokine receptor signaling in high-risk cytometric measurement of residual disease on day 15 bone acute lymphoblastic leukemia. Mutations and deletions response determines relapse risk overall and in subsets of of the TP53 gene predict nonresponse to treatment and poor childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 outcome in first relapse of childhood acute lymphoblastic study. The genomic P2RY8-CRLF2 fusion but not for CRLF2 over-expression in landscape of hypodiploid acute lymphoblastic leukemia. Nat children with intermediate risk B-cell precursor acute lympho- Genet. Chemotherapy in relapsed acute lymphoblastic leukaemia. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A comparison by genetic randomisation in an international prospec- subtype of childhood acute lymphoblastic leukaemia with poor tive study. Application of genomics for risk stratification of Oncol. Molecular genetics of B-precursor acute lympho- blastic leukaemia. The molecular basis of T cell cogenetics Implementation Consortium. Nordic status discriminates for outcome in Imatinib-treated BCR- Society for Paediatric Haematology and Oncology. Children’s Oncology blastic leukemia: results from the NOPHO ALL-92 study. Deletion of IKZF1 and prognosis in acute lymphoblas- Blood. Imatinib after blastic leukemia treated according to the ALL-BFM 2000 induction for treatment of children and adolescents with protocol. What is the mia (EsPhALL): a randomised, open-label, intergroup study. Pritchard-Jones K, Dixon-Woods M, Naafs-Wilstra M, Valsec- domised clinical trials in rare cancers. Improving recruitment to clinical trials for cancer in 49.

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