2021
Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial
Pusztai L, Yau C, Wolf DM, Han HS, Du L, Wallace AM, String-Reasor E, Boughey JC, Chien AJ, Elias AD, Beckwith H, Nanda R, Albain KS, Clark AS, Kemmer K, Kalinsky K, Isaacs C, Thomas A, Shatsky R, Helsten TL, Forero-Torres A, Liu MC, Brown-Swigart L, Petricoin EF, Wulfkuhle JD, Asare SM, Wilson A, Singhrao R, Sit L, Hirst GL, Berry S, Sanil A, Asare AL, Matthews JB, Perlmutter J, Melisko M, Rugo HS, Schwab RB, Symmans WF, Yee D, Van't Veer LJ, Hylton NM, DeMichele AM, Berry DA, Esserman LJ. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Cancer Cell 2021, 39: 989-998.e5. PMID: 34143979, PMCID: PMC11064785, DOI: 10.1016/j.ccell.2021.05.009.Peer-Reviewed Original ResearchConceptsHER2-negative breast cancerTriple-negative breast cancerI-SPY2 trialBreast cancerNeoadjuvant chemotherapyStage II/III HER2-negative breast cancerStage II/III breast cancerGrade 3 adverse eventsPathologic complete response ratePD-L1 inhibitor durvalumabMast cell signaturePaclitaxel neoadjuvant chemotherapyComplete response rateHER2-negative patientsStandard neoadjuvant chemotherapyHER2-negative cancersPARP inhibitor olaparibAdverse eventsGene expression signaturesCare controlSuperior efficacyImmune responseResponse rateCancerInhibitor olaparib
2019
Changing frameworks in treatment sequencing of triple-negative and HER2-positive, early-stage breast cancers
Pusztai L, Foldi J, Dhawan A, DiGiovanna MP, Mamounas EP. Changing frameworks in treatment sequencing of triple-negative and HER2-positive, early-stage breast cancers. The Lancet Oncology 2019, 20: e390-e396. PMID: 31267973, DOI: 10.1016/s1470-2045(19)30158-5.Commentaries, Editorials and LettersConceptsEarly-stage breast cancerHER2-positive breast cancerBreast cancerClinical trialsNeoadjuvant chemotherapyEstrogen receptor-negative breast cancerImproved disease-free survivalReceptor-negative breast cancerParticular chemotherapy regimenResidual invasive cancerNeoadjuvant systemic therapyDisease-free survivalImportant clinical trialsAdo-trastuzumab emtansineNegative breast cancerAdjuvant settingKATHERINE trialOperable diseasePostoperative capecitabineChemotherapy regimenMetastatic diseaseSystemic therapyResidual diseaseInvasive cancerTreatment sequencing
2017
Association of LN Evaluation with Survival in Women Aged 70 Years or Older With Clinically Node-Negative Hormone Receptor Positive Breast Cancer
Chagpar AB, Hatzis C, Pusztai L, DiGiovanna MP, Moran M, Mougalian S, Sanft T, Evans S, Hofstatter E, Wilson LD, Lannin DR. Association of LN Evaluation with Survival in Women Aged 70 Years or Older With Clinically Node-Negative Hormone Receptor Positive Breast Cancer. Annals Of Surgical Oncology 2017, 24: 3073-3081. PMID: 28766195, DOI: 10.1245/s10434-017-5936-x.Peer-Reviewed Original ResearchConceptsBreast cancer-specific survivalLN evaluationPositive breast cancerOverall survivalBreast cancerHormone receptor-positive breast cancerWomen Aged 70 YearsReceptor-positive breast cancerLymph node evaluationCancer-specific survivalLower hazard rateLN surgeryBetter OSPatient ageSEER databasePatient selectionTumor characteristicsSEER dataPatientsNode evaluationHormone receptorsCancerSurvivalTreatment variablesNCDBLong-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype
Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, Walls A, Bousamra A, Ramineni M, Sinn B, Hunt K, Buchholz TA, Valero V, Buzdar AU, Yang W, Brewster AM, Moulder S, Pusztai L, Hatzis C, Hortobagyi GN. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. Journal Of Clinical Oncology 2017, 35: jco.2015.63.101. PMID: 28135148, PMCID: PMC5455352, DOI: 10.1200/jco.2015.63.1010.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsChemotherapy, AdjuvantCyclophosphamideDisease-Free SurvivalDoxorubicinEpirubicinFemaleFluorouracilHumansMiddle AgedNeoadjuvant TherapyNeoplasm, ResidualPaclitaxelPhenotypePrognosisProspective StudiesReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneRisk AssessmentSurvival RateTime FactorsTrastuzumabTumor BurdenConceptsResidual cancer burdenPhenotypic subsetsNeoadjuvant chemotherapyValidation cohortPrognostic riskCancer burdenRCB classBreast cancerRCB indexRelapse-free survival estimatesRelapse-free survival rateHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Hormone receptorsOriginal development cohortGrowth factor receptor 2Clinical-pathologic variablesKaplan-Meier analysisLong-term prognosisLog-rank testIndependent validation cohortBreast cancer subtypesLong-term survivalFactor receptor 2Concurrent trastuzumab
2013
Estrogen receptor (ER) mRNA expression and molecular subtype distribution in ER-negative/progesterone receptor-positive breast cancers
Itoh M, Iwamoto T, Matsuoka J, Nogami T, Motoki T, Shien T, Taira N, Niikura N, Hayashi N, Ohtani S, Higaki K, Fujiwara T, Doihara H, Symmans WF, Pusztai L. Estrogen receptor (ER) mRNA expression and molecular subtype distribution in ER-negative/progesterone receptor-positive breast cancers. Breast Cancer Research And Treatment 2013, 143: 403-409. PMID: 24337596, DOI: 10.1007/s10549-013-2763-z.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAnthracyclinesAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsBridged-Ring CompoundsFemaleGene Expression ProfilingHumansKi-67 AntigenMiddle AgedNeoadjuvant TherapyNeoplasm Recurrence, LocalReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneRNA, MessengerSurvival RateTaxoidsYoung AdultConceptsEstrogen receptor mRNA expressionPR-positive patientsTriple-negative cohortER-positive cancersTriple-negative cancersReceptor mRNA expressionProgesterone receptorBreast cancerMolecular subtypesER-negative/PR-positive tumorsProgesterone receptor-positive breast cancerReceptor-positive breast cancerRelapse-free survival rateMRNA expressionAdjuvant endocrine therapyMolecular subtype distributionPR-positive tumorsRoutine clinical assessmentSafe clinical approachLuminal-type cancersExpression of ESR1Adjuvant endocrineEndocrine therapyNeoadjuvant chemotherapyAffymetrix U133A gene chipsA 3-gene proliferation score (TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories
Szekely B, Iwamoto T, Szasz AM, Qi Y, Matsuoka J, Symmans WF, Tokes AM, Kulka J, Swanton C, Pusztai L. A 3-gene proliferation score (TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories. Breast Cancer Research And Treatment 2013, 138: 691-698. PMID: 23504136, DOI: 10.1007/s10549-013-2475-4.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, NeoplasmBreast NeoplasmsCell ProliferationChemotherapy, AdjuvantCohort StudiesDatabases, GeneticDNA Topoisomerases, Type IIDNA-Binding ProteinsFemaleForkhead Box Protein M1Forkhead Transcription FactorsGene Expression Regulation, NeoplasticGenome, HumanHumansKi-67 AntigenPoly-ADP-Ribose Binding ProteinsPredictive Value of TestsPrognosisReceptors, EstrogenSurvival RateTamoxifenConceptsGenomic grade indexGrade 2 cancersPrognostic valueProliferation scoreBreast cancerDistant metastasis-free survival curvesGrade 2Metastasis-free survival curvesER-positive breast cancerSystemic adjuvant therapyHigh expressionCohort of patientsHistological grade 2Intermediate-risk cancerPositive breast cancerSimilar prognostic valueGrade 2 tumorsHigh-risk groupGrade 1 cancersHistological grade groupsNon-significant trendWorse DMFSAdjuvant tamoxifenAdjuvant therapyWorse survival
2011
Response to Neoadjuvant Systemic Therapy for Breast Cancer in BRCA Mutation Carriers and Noncarriers: A Single-Institution Experience
Arun B, Bayraktar S, Liu DD, Barrera A, Atchley D, Pusztai L, Litton JK, Valero V, Meric-Bernstam F, Hortobagyi GN, Albarracin C. Response to Neoadjuvant Systemic Therapy for Breast Cancer in BRCA Mutation Carriers and Noncarriers: A Single-Institution Experience. Journal Of Clinical Oncology 2011, 29: 3739-3746. PMID: 21900106, PMCID: PMC4874218, DOI: 10.1200/jco.2011.35.2682.Peer-Reviewed Original ResearchConceptsNeoadjuvant systemic chemotherapyRelapse-free survivalBreast cancerOS ratesOverall survivalBRCA1 carriersBRCA statusBRCA2 mutationsKaplan-Meier product-limit methodPathologic complete response rateComplete response rateNeoadjuvant systemic therapySingle institution experienceEstrogen receptor negativityBRCA mutation carriersBRCA1 statusIndependent significant predictorsProduct-limit methodMultivariate logistic modelBRCA genetic testingSporadic breast cancerLogistic regression modelsBRCA noncarriersTrastuzumab useSystemic chemotherapyArtificial neural network analysis of circulating tumor cells in metastatic breast cancer patients
Giordano A, Giuliano M, De Laurentiis M, Eleuteri A, Iorio F, Tagliaferri R, Hortobagyi GN, Pusztai L, De Placido S, Hess K, Cristofanilli M, Reuben JM. Artificial neural network analysis of circulating tumor cells in metastatic breast cancer patients. Breast Cancer Research And Treatment 2011, 129: 451-458. PMID: 21710134, DOI: 10.1007/s10549-011-1645-5.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkers, TumorBreast NeoplasmsFemaleHumansImmunohistochemistryKaplan-Meier EstimateLinear ModelsMiddle AgedNeoplastic Cells, CirculatingNeural Networks, ComputerPrognosisProportional Hazards ModelsReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneRetrospective StudiesRisk AssessmentRisk FactorsSurvival RateTexasTime FactorsConceptsMetastatic breast cancer patientsRisk of deathBreast cancer patientsCTC countMBC patientsPrognostic effectCancer patientsTumor subtypesTumor cellsMD Anderson Cancer CenterConsecutive MBC patientsTriple-negative MBCMetastatic disease sitesAnderson Cancer CenterTumor molecular subtypeNumber of CTCsMolecular tumor subtypesVisceral metastasesOverall survivalCancer CenterHER2 statusProgesterone receptorMolecular subtypesTherapy typePrognostic toolA clinically relevant gene signature in triple negative and basal-like breast cancer
Rody A, Karn T, Liedtke C, Pusztai L, Ruckhaeberle E, Hanker L, Gaetje R, Solbach C, Ahr A, Metzler D, Schmidt M, Müller V, Holtrich U, Kaufmann M. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Research 2011, 13: r97. PMID: 21978456, PMCID: PMC3262210, DOI: 10.1186/bcr3035.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerBasal-like triple-negative breast cancerBreast cancerPrognostic markerMolecular subtypesMultivariate analysisBasal-like molecular subtypeClaudin-low molecular subtypeBasal-like breast cancerAttractive novel therapeutic targetB cell presenceHigh expressionER-positive cancersHigh histological gradeHigher B cellsIL-8 pathwayIL-8 activityNegative breast cancerNew prognostic markerNovel therapeutic targetBiology-based therapiesNon-neoplastic cell populationsRelevant gene signaturesRoutine clinicopathological variablesResultsSeventy-three percent
2010
Impact of Progression During Neoadjuvant Chemotherapy on Surgical Management of Breast Cancer
Caudle AS, Gonzalez-Angulo AM, Hunt KK, Pusztai L, Kuerer HM, Mittendorf EA, Hortobagyi GN, Meric-Bernstam F. Impact of Progression During Neoadjuvant Chemotherapy on Surgical Management of Breast Cancer. Annals Of Surgical Oncology 2010, 18: 932-938. PMID: 21061075, PMCID: PMC4347926, DOI: 10.1245/s10434-010-1390-8.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdultAgedAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsCarcinoma, Ductal, BreastCarcinoma, LobularChemotherapy, AdjuvantCombined Modality TherapyFemaleFollow-Up StudiesHumansLymphatic MetastasisMastectomyMiddle AgedNeoadjuvant TherapyRetrospective StudiesSurvival RateTreatment OutcomeConceptsBreast conservation therapyNeoadjuvant chemotherapyBreast cancerSurgical managementDisease progressionStable diseaseImpact of progressionAdvanced breast cancerEarly-stage diseaseBCT candidatesClinical lymphadenopathyChemotherapy regimensProgressive diseaseStandard therapyComplete responseMedical oncologistsDistant metastasisClinicopathological dataFlap closurePatientsStage ITherapeutic interventionsOperative planEarly identificationMastectomyPrognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer
Bianchini G, Iwamoto T, Qi Y, Coutant C, Shiang CY, Wang B, Santarpia L, Valero V, Hortobagyi GN, Symmans WF, Gianni L, Pusztai L. Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer. Cancer Research 2010, 70: 8852-8862. PMID: 20959472, DOI: 10.1158/0008-5472.can-10-1039.Peer-Reviewed Original ResearchConceptsPathologic complete responseBreast cancerClinical subtypesPredictive valueHigher pathologic complete responseHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Different clinical subsetsDistinct prognostic informationNode-negative patientsGrowth factor receptor 2Different clinical subtypesBreast cancer cell linesFactor receptor 2Subtype-specific inhibitionCancer cell linesNeoadjuvant chemotherapyAdjuvant therapyComplete responseClinical subsetsWorse prognosisPrognostic valuePrognostic informationClinical subgroupsExpression patternsPredictors of Tumor Progression During Neoadjuvant Chemotherapy in Breast Cancer
Caudle AS, Gonzalez-Angulo AM, Hunt KK, Liu P, Pusztai L, Symmans WF, Kuerer HM, Mittendorf EA, Hortobagyi GN, Meric-Bernstam F. Predictors of Tumor Progression During Neoadjuvant Chemotherapy in Breast Cancer. Journal Of Clinical Oncology 2010, 28: 1821-1828. PMID: 20231683, PMCID: PMC2860366, DOI: 10.1200/jco.2009.25.3286.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAnthracyclinesAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsBridged-Ring CompoundsCarcinoma, Ductal, BreastCarcinoma, LobularChemotherapy, AdjuvantDisease ProgressionFemaleHumansMiddle AgedNeoadjuvant TherapyReceptors, EstrogenReceptors, ProgesteroneSurvival RateTaxoidsTreatment OutcomeYoung AdultConceptsHigh Ki-67 scoreNeoadjuvant chemotherapyKi-67 scoreStable diseaseBreast cancerEstrogen receptorMultivariate analysisDistant disease-free survivalER/PR negativityFirst-line surgical approachTumor progressionMost breast cancer patientsDisease-free survivalStandard neoadjuvant chemotherapyCancer clinical stageAmerican Joint CommitteeBreast cancer patientsAfrican American raceAdvanced tumor stagePredictors of responseHigh nuclear gradeHigh tumor gradeNegative estrogen receptorNovel molecular predictorsPR negativity
2009
CXCR4 Expression in Early Breast Cancer and Risk of Distant Recurrence
Andre F, Xia W, Conforti R, Wei Y, Boulet T, Tomasic G, Spielmann M, Zoubir M, Berrada N, Arriagada R, Hortobagyi GN, Hung M, Pusztai L, Delaloge S, Michiels S, Cristofanilli M. CXCR4 Expression in Early Breast Cancer and Risk of Distant Recurrence. The Oncologist 2009, 14: 1182-1188. PMID: 19939894, DOI: 10.1634/theoncologist.2009-0161.Peer-Reviewed Original ResearchConceptsPrimary breast tumorsCXCR4 expressionBone metastasesBreast tumorsClinical characteristicsDistant metastasisPrognostic valueHigh riskLigand stromal cell-derived factor-1Stromal cell-derived factor-1Cell-derived factor-1Bone-targeted agentsEarly breast cancerProspective clinical trialsCox regression modelNovel adjuvant strategyExpression of CXCR4Chemokine receptor 4Early metastatic processOccurrence of metastasesSpecific organ sitesCXCR4 tumorsDistant recurrenceOverall survivalAdjuvant strategies
2008
Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer
Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L. Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer. Journal Of Clinical Oncology 2008, 26: 1275-1281. PMID: 18250347, DOI: 10.1200/jco.2007.14.4147.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsCarcinoma, Ductal, BreastChemotherapy, AdjuvantFemaleHumansMiddle AgedNeoadjuvant TherapyNeoplasm Recurrence, LocalNeoplasm StagingNeoplasm, ResidualNeoplasms, Hormone-DependentPrognosisProspective StudiesReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneSurvival RateConceptsTriple-negative breast cancerPathologic complete response rateNeoadjuvant chemotherapyResidual diseaseBreast cancerProgesterone receptorEstrogen receptorHuman epidermal growth factor receptor 2 (HER2) expressionSurvival rateEpidermal growth factor receptor 2 expressionProgression-free survival ratesM.D. Anderson Cancer CenterComplete response rateOverall survival rateAnderson Cancer CenterReceptor 2 expressionLong-term survivalBone recurrenceNeoadjuvant therapyPostrecurrence survivalVisceral metastasesWorse OSWorse survivalRelapse rateCancer Center
2006
Bortezomib (VELCADE®) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits
Yang CH, Gonzalez-Angulo AM, Reuben JM, Booser DJ, Pusztai L, Krishnamurthy S, Esseltine D, Stec J, Broglio KR, Islam R, Hortobagyi GN, Cristofanilli M. Bortezomib (VELCADE®) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Annals Of Oncology 2006, 17: 813-817. PMID: 16403809, DOI: 10.1093/annonc/mdj131.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBone NeoplasmsBoronic AcidsBortezomibBreast NeoplasmsDisease ProgressionDisease-Free SurvivalFemaleHumansMaleMaximum Tolerated DoseMiddle AgedPleural NeoplasmsProtease InhibitorsPyrazinesReceptors, EstrogenReceptors, ProgesteroneSoft Tissue NeoplasmsSurvival RateTreatment OutcomeConceptsMetastatic breast cancerBreast cancerPlasma interleukin-6 levelsCommon grade 3Limited clinical activityClinical response ratePhase II studyInterleukin-6 levelsMedian survival timeWeek of restBroad antitumor activityStable diseaseII studyObjective responseSkin rashClinical effectsClinical benefitDisease progressionClinical activityGrade 3Pharmacodynamic dataSurvival timeMean inhibitionSingle agentResponse rate
2005
The Nuclear Transcription Factor κB/bcl-2 Pathway Correlates with Pathologic Complete Response to Doxorubicin-Based Neoadjuvant Chemotherapy in Human Breast Cancer
Buchholz TA, Garg AK, Chakravarti N, Aggarwal BB, Esteva FJ, Kuerer HM, Singletary SE, Hortobagyi GN, Pusztai L, Cristofanilli M, Sahin AA. The Nuclear Transcription Factor κB/bcl-2 Pathway Correlates with Pathologic Complete Response to Doxorubicin-Based Neoadjuvant Chemotherapy in Human Breast Cancer. Clinical Cancer Research 2005, 11: 8398-8402. PMID: 16322301, DOI: 10.1158/1078-0432.ccr-05-0885.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsBcl-2-Associated X ProteinBreast NeoplasmsCell NucleusChemotherapy, AdjuvantCyclophosphamideCytoplasmDoxorubicinFemaleFluorouracilHumansMiddle AgedNeoadjuvant TherapyNeoplasm StagingNF-kappa BProto-Oncogene Proteins c-bcl-2Signal TransductionSurvival RateTreatment OutcomeConceptsPathologic complete responseHuman breast cancerNF-kappaBNeoadjuvant chemotherapyComplete responseNeoadjuvant doxorubicinBcl-2Poor responseBreast cancerAnthracycline-based neoadjuvant chemotherapyNF-kappaB.Bcl-2-positive tumorsHuman breast cancer samplesBreast cancer responseClinical outcome dataTranscription factor NF-kappaBBreast cancer pathologistNuclear factor-kappaBBreast cancer samplesPCR ratePositive tumorsChemotherapy responseTumor stainingImmunohistochemical stainingCancer response
2001
Factors predictive of outcome in patients with breast cancer refractory to neoadjuvant chemotherapy.
Buchholz T, Hill B, Tucker S, Frye D, Kuerer H, Buzdar A, McNeese M, Singletary S, Ueno N, Pusztai L, Valero V, Hortobagyi G. Factors predictive of outcome in patients with breast cancer refractory to neoadjuvant chemotherapy. The Cancer Journal 2001, 7: 413-20. PMID: 11693900.Peer-Reviewed Original ResearchConceptsEstrogen receptor-negative diseaseReceptor-negative diseaseLocal-regional recurrenceLocal-regional recurrence ratePositive lymph nodesNeoadjuvant chemotherapyLymph nodesOverall survivalProgressive diseaseRecurrence rateLymph node-negative diseaseSignificant poorer overall survivalEstrogen receptor-positive diseaseBreast cancer refractoryInvolved lymph nodesNegative lymph nodesReceptor-positive diseaseNode-negative diseasePostoperative radiation therapyInitial clinical stageCox regression analysisBreast cancer patientsPoor overall survivalAdjuvant chemotherapyCancer refractory
1998
Discouraging news for high-dose chemotherapy in high-risk breast cancer
Pusztai L, Hortobagyi G. Discouraging news for high-dose chemotherapy in high-risk breast cancer. The Lancet 1998, 352: 501-502. PMID: 9716049, DOI: 10.1016/s0140-6736(05)79310-7.Peer-Reviewed Original Research