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EsophagealCancer
Author:KeithMBaldwin,DO,IMPHChiefEditor:JulesEHarris,MDmore...
Updated:Mar3,2015

PracticeEssentials
Esophagealcancerisadiseaseinepidemiologictransition.Untilthe1970s,themostcommontypeofesophageal
cancerintheUnitedStateswassquamouscellcarcinoma,whichhassmokingandalcoholconsumptionasrisk
factorssincethen,therehasbeenaprogressiveincreaseintheincidenceofesophagealadenocarcinoma,forwhich
themostcommonpredisposingfactorisgastroesophagealrefluxdisease(GERD).Seetheimagebelow.

Cascadeofeventsthatleadfromgastroesophagealrefluxdiseasetoadenocarcinoma.

Signsandsymptoms
Presentingsignsandsymptomsofesophagealcancerincludethefollowing:
Dysphagia(mostcommon)initiallyforsolids,eventuallyprogressingtoincludeliquids
Weightloss(secondmostcommon)
Bleeding
Epigastricorretrosternalpain
Bonepainwithmetastaticdisease
Hoarseness
Persistentcough
Physicalfindingsincludethefollowing:
Typically,normalexaminationresultsunlessthecancerhasmetastasized
Hepatomegaly(fromhepaticmetastases)
Lymphadenopathyinthelaterocervicalorsupraclavicularareas(reflectingmetastasis)
SeeClinicalPresentationformoredetail.

Diagnosis
Laboratorystudiesfocusprincipallyonpatientfactorsthatmayaffecttreatment(eg,nutritionalstatus).
Imagingstudiesusedfordiagnosisandstagingincludethefollowing:
Esophagogastroduodenoscopy(allowsdirectvisualizationandbiopsiesofthetumor)
Endoscopicultrasonography(EUSmostsensitivetestforTandNstaging)
Computedtomographyoftheabdomenandchest(forassessinglungandlivermetastasisandinvasionof
adjacentstructures)
Positronemissiontomography(PET)scanning(forstaging)
Bronchoscopy(tohelpexcludeinvasionofthetracheaorbronchi)
Laparoscopyandthoracoscopy(forstagingregionalnodes)
Bariumswallow(verysensitivefordetectingstricturesandintraluminalmasses,butnowrarelyused)
CurrentTNMclassificationisasfollows(stagingisdetailedinTable1,below):
TisCarcinomainsitu/highgradedysplasia
T1Laminapropriaorsubmucosa
T1aLaminapropriaormuscularismucosae
T1bSubmucosa
T2Muscularispropria
T3Adventitia
T4Adjacentstructures
T4aPleura,pericardium,diaphragm,oradjacentperitoneum
T4bOtheradjacentstructures(eg,aorta,vertebralbody,trachea)
N0Noregionallymphnodemetastasis
N112regionallymphnodes(N1issitedependent)
N236regionallymphnodes
N3Morethan6regionallymphnodes
M0Nodistantmetastasis
M1Distantmetastasis(M1aandM1baresitedependent)
Table1.StagingClassification.(OpenTableinanewwindow)

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StageIA

T1

N0

M0

StageIB

T2

N0

M0

StageIIA T3

N0

M0

StageIIB T1,T2 N1

M0

StageIIIA T4a

N0

M0

N1

M0

T1,T2 N2

M0

T3
StageIIIB T3

N2

StageIIIC T4a

N1,N2 M0

T4b

AnyN M0

AnyT N3
StageIV

M0

M0

AnyT AnyN M1

SeeWorkupformoredetail.

Management
Treatmentofesophagealcancervariesbydiseasestage,asfollows:
StageIConsiderationforendoscopictherapy(eg,mucosalresectionorsubmucosaldissection),particularly
forTisandT1aN0byEUSconsiderationforinitialsurgeryforT1bandanyN
StagesIIIIIConsiderationforchemoradiationfollowedbysurgery(trimodalitytherapy)
StageIVChemotherapyorsymptomaticandsupportivecare
Indicationsforsurgicaltreatmentofesophagealcancerincludethefollowing:
Diagnosisofesophagealcancerinapatientwhoisacandidateforsurgery
HighgradedysplasiainapatientwithBarrettesophagusthatcannotbeadequatelytreatedendoscopically[1,
2]

Contraindicationsforsurgicaltreatmentincludethefollowing:
MetastasistoN2(celiac,cervical,supraclavicular)nodesorsolidorgans(eg,liver,lungs)
Invasionofadjacentstructures(eg,recurrentlaryngealnerve,tracheobronchialtree,aorta,pericardium)
Severeassociatedcomorbidconditions(eg,cardiovasculardisease,respiratorydisease)
Impairedcardiacorrespiratoryfunction
Surgicaloptionsincludethefollowing:
Transhiatalesophagectomy(THE)
Transthoracicesophagectomy(TTE)
Minimallyinvasiveesophagectomy
Endoscopicmucosalresection(EMR)
Neoadjuvanttherapyforesophagealcancerisasfollows:
Combinationofradiotherapyandchemotherapy
Usuallyadministeredovera45dayperiod,withesophagealresectionafterapproximately4weeks
Mostchemotherapyagentsforesophagealcancerareusedofflabel
Palliativecareoptionsforpatientswhoarenotcandidatesforsurgeryareasfollows:
Chemotherapy
Radiotherapy
Lasertherapy
Stents
SeeTreatmentandMedicationformoredetail.

Background
Esophagealcancerisadevastatingdisease.Althoughsomepatientscanbecured,thetreatmentforesophageal
cancerisprotracted,diminishesqualityoflife,andislethalinasignificantnumberofcases.
Theprincipalhistologictypesofesophagealcanceraresquamouscellcarcinomaandadenocarcinoma.As
squamouscellslinetheentireesophagus,squamouscellcarcinomacanoccurinanypartoftheesophagusitoften
arises,however,intheupperhalfoftheesophagus.Adenocarcinomatypicallydevelopsinspecializedintestinal
metaplasia(Barrettmetaplasia)thatdevelopsasaresultofgastroesophagealrefluxdisease(GERD)thus,
adenocarcinomatypicallyarisesinthelowerhalfofthedistalesophagus.(SeePathophysiologyandEtiology.)

Diagnosis
Themostcommonpresentingsymptomofesophagealcancerisdysphagia(seePresentation).
Esophagogastroduodenoscopyallowsdirectvisualizationandbiopsiesofthetumor,whileendoscopic
ultrasonographyisthemostsensitivetestfordeterminingthedepthofpenetrationofthetumorandthepresenceof
enlargedperiesophageallymphnodes.Inpatientswhoappeartohavelocalizedesophagealcancer,positron
emissiontomography(PET)scanningmaybeusefulaspartofthebaselinestaging.Otherimagingstudiesmaybe
valuableinselectedpatients.(SeeWorkup.)

Treatment
Surgeryhastraditionallybeenthetreatmentforesophagealcarcinoma.Thefirstsuccessfulresectionwasperformed

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in1913byTorek. [3]Inthe1930s,OhsawainJapanandMarshallintheUnitedStateswerethefirsttoperform
successfulsinglestagetransthoracicesophagectomieswithcontinentreconstruction. [4,5]Nonoperativetherapyis
usuallyreservedforpatientswhoarenotcandidatesforsurgerybecauseofclinicalconditionsoradvanceddisease.
(SeeTreatment.)
Theidealtreatmentforlocalizedesophagealcancerissometimesdebatedacrosspracticeculturesand
subspecialties.Defendantsofsurgicaltreatmentarguethatresectionistheonlytreatmentmodalitytooffercurative
intentdefendantsofthenonsurgicalapproachclaimthatesophagectomyhasaprohibitiveindexofmortalityand
thatesophagealcancerisanincurabledisease.

Differentials
Esophageallesionsotherthancancercancausedysphagia.Theseincludepepticstricturesfromgastroesophageal
refluxandbenignesophagealtumors(principallyesophagealleiomyoma).Imagingstudieshelptodifferentiate
theselesionsfromesophagealcancer.Otherdifferentialsincludethefollowing
Achalasia
Esophagealstricture
Gastriccancer

Patienteducation
Forpatienteducationinformation,seetheHeartburnandGERDCenterandEsophagealCancer(Cancerofthe
Esophagus).

Anatomy
Theesophagusisamusculartubethatextendsfromthelevelofthe7thcervicalvertebratothe11ththoracic
vertebra.Theesophaguscanbedividedintothefollowinganatomicparts:
Cervicalesophagus
Thoracicesophagus
Abdominalesophagus
Thebloodsupplyofthecervicalesophagusisderivedfromtheinferiorthyroidartery,whilethebloodsupplyforthe
thoracicesophaguscomesfromthebronchialarteriesandtheaorta.Theabdominalesophagusissuppliedby
branchesoftheleftgastricarteryandinferiorphrenicartery.
Venousdrainageofthecervicalesophagusisthroughtheinferiorthyroidvein,whilethethoracicesophagusdrains
viatheazygousvein,thehemiazygousvein,andthebronchialveins.Theabdominalesophagusdrainsthroughthe
coronaryvein.
Theesophagusischaracterizedbyarichnetworkoflymphaticchannelsinthesubmucosathatcanfacilitatethe
longitudinalspreadofneoplasticcellsalongtheesophagealwall.Lymphaticdrainageistocervicalnodes,
tracheobronchialandmediastinalnodes,andgastricandceliacnodes.

Pathophysiology
TheprogressionofBarrettmetaplasiatoadenocarcinomaisassociatedwithseveralchangesingenestructure,
geneexpression,andproteinstructure. [6,7,8]TheoncosuppressorgeneTP53andvariousoncogenes,particularly
erbb2,havebeenstudiedaspotentialmarkers.
CassonandcolleaguesidentifiedmutationsintheTP53geneinpatientswithBarrettepitheliumassociatedwith
adenocarcinoma. [9]Inaddition,alterationsinp16genesandcellcycleabnormalitiesoraneuploidyappeartobe
someofthemostimportantandwellcharacterizedmolecularchanges.

Etiology
Theetiologyofesophagealcarcinomaisthoughttoberelatedtoexposureoftheesophagealmucosatonoxiousor
toxicstimuli,resultinginasequenceofdysplasiatocarcinomainsitutocarcinoma.InWesterncultures,
retrospectiveevidencehasimplicatedcigarettesmokingandchronicalcoholexposureasthemostcommonetiologic
factorsforsquamouscellcarcinoma.Highbodymassindex,GERD,andresultantBarrettesophagusareoftenthe
associatedfactorsforesophagealadenocarcinoma. [10]
Nutritionaldeficiencieshavebeenrecognizedascontributingfactors.InhighriskregionssuchaspartsofChinaand
Iran,deficienciesinvitamins(eg,riboflavin)ormicronutrientsmayplayaroleincausation.
Avarietyofotherfactorsmaypromoteesophagealcancer.Theseincludethefollowing:
Causticinjuries
Certainfoodstuffs(eg,betelnut)
Drinkingscaldinghotliquids
Environmentalcontributors(eg,nitrosaminesinsoil)
Certainfungi,molds,oryeasts
Acquiredconditions(eg,achalasia)
AgenomewideassociationstudybyWuetalidentifiedsevensusceptibilitylocionchromosomes5q11,6p21,
10q23,12q24,and21q22,suggestingtheinvolvementofmultiplegeneticlociandgeneenvironmentinteractionin
thedevelopmentofesophagealcancer. [11]Individualswiththegeneticdisordertylosispalmarisetplantarisareat
veryhighriskforesophagealcancer.PlummerVinsonsyndromealsoincreasesitsrisk.
Bisphosphonateusecanresultinesophagitisandhasbeensuggestedasariskfactorforesophagealcarcinoma.
However,alargestudyfoundnosignificantdifferenceinthefrequencyofesophagealorgastriccancersbetween
thebisphosphonatecohortandthecontrolgroup. [12]

Smokingandalcoholuse
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TheNetherlandsCohortStudy,aprospectivestudyin120,852participants,demonstratedthecombinedeffectsof
smokingandalcoholconsumptiononriskofsquamouscellcarcinomaoftheesophagus. [13]Amongparticipantswho
drank30gormoreofethanoldaily,themultivariableadjustedincidencerateratio(RR)foresophagealsquamous
cellcarcinomawas4.61comparedwithabstainers.TheRRforcurrentsmokerswhoconsumedmorethan15g/day
ofethanolwas8.05whencomparedwithnonsmokerswhoconsumedlessthan5g/dayofethanol.
Noassociationswerefoundbetweenalcoholconsumptionandesophagealadenocarcinoma.
Incontrast,theriskofsquamouscellcarcinomaandadenocarcinomaoftheesophaguswasincreasedamong
currentsmokers. [13]
AstudybySteevensetalfoundthatamongcurrentsmokers,increasedconsumptionofspecificgroupsof
vegetablesandfruitswereinverselyassociatedwithesophagealsquamouscellcarcinomaandesophageal
adenocarcinomarisk. [14]Totalvegetableconsumptionnonsignificantlyreducedtheriskforbothesophagealcancer
types.Consumptionofrawvegetablesandofcitrusfruitswasinverselyassociatedwithriskforesophageal
adenocarcinoma.

Infections
Humanpapillomavirus(HPV)infectionhasbeenrecognizedasacontributingfactortoesophagealcancer.However,
Sitasetalreportedlimitedserologicevidenceofanassociationbetweenesophagealsquamouscellcarcinomaand
HPVinastudyofmorethan4000subjects.ThestudycouldnotexcludethepossibilitythatcertainHPVtypesmay
beinvolvedinasmallsubsetofcancers,althoughHPVdoesnotappeartobeanimportantriskfactor. [15]
Helicobacterpyloriinfection,whichcancausestomachcancer,hasnotbeenassociatedwithesophagealcancer.

AdenocarcinomaandGERD
GERDisthemostcommonpredisposingfactorforadenocarcinomaoftheesophagus.Adenocarcinomamay
representthelasteventofasequencethatstartswithirritationcausedbytherefluxofacidandbileandprogresses
tospecializedintestinal(Barrett)metaplasia,lowgradedysplasia,highgradedysplasia,andfinallyadenocarcinoma.
Approximately1015%ofpatientswhoundergoendoscopyforevaluationofGERDsymptomsarefoundtohave
Barrettepithelium.(Seethechartbelow.)

Cascadeofeventsthatleadfromgastroesophagealrefluxdiseasetoadenocarcinoma.

In1952,MorsonandBelcherpublishedthefirstdescriptionofapatientwithadenocarcinomaoftheesophagus
arisinginacolumnarepitheliumwithgobletcells. [16]In1975,Naefetalemphasizedthemalignantpotentialof
Barrettesophagus. [17]TheriskofadenocarcinomaamongpatientswithBarrettmetaplasiahasbeenestimatedto
be3060timesthatofthegeneralpopulation.
AnationwidepopulationbasedcasecontrolstudyperformedinSwedenfoundanoddsratioof7.7for
adenocarcinomaamongpersonswithrecurrentsymptomsofreflux,ascomparedwithpersonswithoutsuch
symptoms,andanoddsratioof43.5amongpatientswithlongstandingandseveresymptomsofreflux. [10]
AlthoughtheannualriskofdevelopingesophagealadenocarcinomainpeoplewithGERDhasbeenreportedat
0.5%,somestudieshavefoundlowerrisk.DatafromtheNorthernIrelandBarrettEsophagusRegister,whichisone
ofthelargestpopulationbasedregistriesintheworld,foundthatthemalignantprogressionamongpatientswith
Barrettesophaguswas0.22%peryear.Thissuggeststhatcurrentsurveillanceapproachesmaynotbecost
effective. [18]
AstudybyHvidJensenetalexaminedalargeDanishregistry(11,028patientsoveramedianof5.2y)andfound
theincidenceofesophagealadenocarcinomatobe1.2casesper1000personyears(or0.12%annualrisk).Low
gradedysplasiadetectedonindexendoscopywasassociatedwithanincidencerateof5.1casesper1000person
years,comparedwith1per1000personyearsamongthosewithoutdysplasia. [19]

Epidemiology
UnitedStatesstatistics
Esophagealcanceristheseventhmostcommoncauseofcancerdeathinmales. [20]The5yearsurvivalratefrom
2001to2007was19%. [21]
TheAmericanCancerSocietyestimatesthat17,990newcasesofesophagealcancer(14,440inmenand3,550in
women)willoccurintheUnitedStatesin201315,210persons(12,220menand2,990women)areexpectedtodie
ofthedisease.
TheincidencerateofadenocarcinomaoftheesophagusintheUnitedStatesshowedanaverageannualincreaseof
1.7%inmenand1.9%inwomenfrom1999to2008. [21]Theincidenceofesophagealcarcinomaisapproximately3
6casesper100,000persons,althoughcertainendemicareasappeartohavehigherpercapitarates.Theage
adjustedincidenceis5.8casesper100,000persons.
TheepidemiologyofesophagealcarcinomahaschangedmarkedlyoverthepastseveraldecadesintheUnited
States. [22]Untilthe1970s,squamouscellcarcinomawasthemostcommontypeofesophagealcancer(9095%).It
waslocatedinthethoracicesophagusandmostfrequentlyaffectedAfricanAmericanmenwithalonghistoryof
smokingandalcoholconsumption.

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Overthelast4decades,theincidenceofadenocarcinomaofthedistalesophagusandgastroesophagealjunction
hasincreasedprogressively.Currently,itaccountsformorethan70%ofallthenewcasesofesophagealcancer.

Internationalstatistics
Esophagealcanceristheseventhleadingcauseofcancerdeathworldwide.Insomeregions,suchasareasof
northernIran,someareasofsouthernRussia,andnorthernChina,theincidenceofesophagealcarcinomamaybe
ashighas800casesper100,000population.UnlikeintheUnitedStates,squamouscellcarcinomaisresponsible
for95%ofallesophagealcancersworldwide.

Sexandagerelateddemographics
Esophagealcancerisgenerallymorecommoninmenthaninwomen.Themaletofemaleratiois34:1.
Esophagealcanceroccursmostcommonlyduringthesixthandseventhdecadesoflife.Thediseasebecomesmore
commonwithadvancingageitisabout20timesmorecommoninpersonsolderthan65yearsthanitisin
individualsbelowthatage.

Prognosis
Survivalinpatientswithesophagealcancerdependsonthestageofthedisease.Squamouscellcarcinomaand
adenocarcinoma,stagebystage,appeartohaveequivalentsurvivalrates.
Lymphnodeorsolidorganmetastasesareassociatedwithlowsurvivalrates.In20012007,theoverall5year
survivalrateforesophagealcancerwas19%. [21]Patientswithoutlymphnodeinvolvementhaveasignificantlybetter
prognosisand5yearsurvivalratethanpatientswithinvolvedlymphnodes.StageIVlesionsareassociatedwitha
5yearsurvivalrateoflessthan5%.(Seethetablebelow.)

FiveyearsurvivalforesophagealcancerbasedonTNMstage.

Areportof1085patientswhounderwenttranshiatalesophagectomyforcancershowedthattheoperationwas
associatedwitha4%operativemortalityrateanda23%5yearsurvivalrate.Abetter5yearsurvivalrate(48%)was
identifiedinasubgroupofpatientswhohadacompleteresponse(ie,disappearanceofthetumor)following
preoperativeradiationandchemotherapy(ie,neoadjuvanttherapy). [23]
Transhiatalandtransthoracicesophagectomieshaveequivalentlongtermsurvivalrates. [24,25]

Imagingandprognosis
Suzukietalfoundthatahigherinitialstandardizeduptakevalueonpositronemissiontomography(PET)scanning
isassociatedwithpooreroverallsurvivalamongpatientswithesophagealorgastroesophagealcarcinomareceiving
chemoradiation.TheauthorssuggestedthatPETscanningmaybecomeusefulforindividualizingtherapy. [26]
AstudybyGilliesetalalsofoundthatPETcomputedtomography(CT)scanningcanbeusedtopredictsurvivalin
thisstudy,thepresenceoffluorodeoxyglucose(FDG)avidlymphnodeswasanindependentadverseprognostic
factor. [27]

HER2andprognosis
AstudybyPrinsetalofhumanepidermalgrowthfactor2(HER2)proteinoverexpressionandHER2gene
amplificationinesophagealcarcinomasfoundthatHER2positivityandgeneamplificationareindependently
associatedwithpoorsurvival.Intheirstudy,whichinvolved154patientswithesophagealadenocarcinoma,HER2
positivitywasseenin12%ofthesepatientsandoverexpressionwasseenin14%ofthem. [28]

ContributorInformationandDisclosures
Author
KeithMBaldwin,DO,IMPHAssistantProfessorofSurgery,BostonUniversitySchoolofMedicineEndocrine
andSurgicalOncologist,DepartmentofGeneralSurgery,RogerWilliamsCancerCenter
KeithMBaldwin,DO,IMPHisamemberofthefollowingmedicalsocieties:AmericanAssociationofEndocrine
Surgeons,AmericanCollegeofSurgeons,AmericanHepatoPancreatoBiliaryAssociation,Societyof
InternationalHumanitarianSurgeons,andSocietyofSurgicalOncology
Disclosure:Nothingtodisclose.
Coauthor(s)
NJosephEspat,MD,MS,FACSHaroldJWaneboProfessorandChiefofSurgicalOncology,Director,Adele
RDecofCancerCenter,ViceChairofDepartmentofSurgery,RogerWilliamsMedicalCenter,BostonUniversity
SchoolofMedicine
NJosephEspat,MD,MS,FACSisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,American
AssociationforCancerResearch,AmericanCollegeofSurgeons,AmericanHepatoPancreatoBiliary
Association,AmericanMedicalAssociation,AmericanSocietyforParenteralandEnteralNutrition,American
SocietyofClinicalOncology,AssociationforAcademicSurgery,CentralSurgicalAssociation,ChicagoMedical
Society,InternationalHepatoPancreatoBiliaryAssociation,PancreasClub,SigmaXi,SocietyforLeukocyte

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Biology,SocietyforSurgeryoftheAlimentaryTract,SocietyofAmericanGastrointestinalandEndoscopic
Surgeons,SocietyofSurgicalOncology,SocietyofUniversitySurgeons,SoutheasternSurgicalCongress,
SouthernMedicalAssociation,andSurgicalInfectionSociety
Disclosure:Nothingtodisclose.
FernandoAMHerbella,MD,PhD,TCBCAffiliateProfessor,AttendingSurgeoninGastrointestinalSurgery,
EsophagusandStomachDivision,DepartmentofSurgery,FederalUniversityofSaoPaulo,BrazilPrivate
PracticeMedicalExaminer,SaoPaulo'sMedicalExaminer'sOfficeHeadquarters,Brazil
FernandoAMHerbella,MD,PhD,TCBCisamemberofthefollowingmedicalsocieties:SocietyforSurgeryof
theAlimentaryTract
Disclosure:Nothingtodisclose.
MarcoGPatti,MDProfessorofSurgery,Director,CenterforEsophagealDiseases,UniversityofChicago
PritzkerSchoolofMedicine
MarcoGPatti,MDisamemberofthefollowingmedicalsocieties:AmericanAssociationfortheAdvancementof
Science,AmericanCollegeofSurgeons,AmericanGastroenterologicalAssociation,AmericanMedical
Association,AmericanSurgicalAssociation,AssociationforAcademicSurgery,PanPacificSurgicalAssociation,
SocietyforSurgeryoftheAlimentaryTract,SocietyofAmericanGastrointestinalandEndoscopicSurgeons,
SouthwesternSurgicalCongress,andWesternSurgicalAssociation
Disclosure:Nothingtodisclose.
ChiefEditor
JulesEHarris,MDClinicalProfessorofMedicine,SectionofHematology/Oncology,UniversityofArizona
CollegeofMedicine,ArizonaCancerCenter
JulesEHarris,MDisamemberofthefollowingmedicalsocieties:AmericanAssociationforCancerResearch,
AmericanAssociationfortheAdvancementofScience,AmericanAssociationofImmunologists,American
SocietyofHematology,andCentralSocietyforClinicalResearch
Disclosure:Nothingtodisclose.
AdditionalContributors
PhilipSchulman,MDChief,MedicalOncology,DepartmentofMedicine,MemorialSloanKetteringCancer
Center
PhilipSchulman,MD,isamemberofthefollowingmedicalsocieties:AmericanAssociationforCancer
Research,AmericanCollegeofPhysicians,AmericanSocietyofHematology,andMedicalSocietyoftheState
ofNewYork
Disclosure:Nothingtodisclose.
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollege
ofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:MedscapeSalaryEmployment

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