30/4/2016 www.medscape.

com/viewarticle/861715_print

www.medscape.com

EsophagusRegenerationSuccessfulinHumanPatient
JanisC.Kelly April08,2016
USphysicianssuccessfullyregeneratedapatient'sbadlydamagedesophagususingofftheshelfcomponents
approvedbytheUSFoodandDrugAdministrationandautologousplateletrichplasmaadhesivegel.

Sevenyearsafterthesurgeryand3.5yearsafterremovalofthemetalstents,thepatientisabletoeatand
swallownormally.Theepitheliumatthewoundsitenowappearsnormalandcontainsthepropertissuelayers.

KulwinderS.Dua,MD,fromtheDivisionofGastroenterologyandHepatology,MedicalCollegeofWisconsin,
Milwaukee,andcolleaguesreportthelandmarkcaseinapaperpublishedonlineApril8intheLancet.

Thecasereportprovidesproofofconceptthatregrowthoflostesophagusispossiblewithoutcomplextissue
engineering,butthenewapproachrequiresvalidationinanimalstudiesbeforeproceedingtoclinicaltrials.

Thephysiciansundertookthenovelapproachinanattempttosavethelifeofacriticallyill24yearoldpatient
sufferingfroma5cm,fullthicknessholeinhisesophagus.Fiveyearsearlier,thepatienthadbeenrendered
quadriplegicinacaraccidentandundergonecervicalspinestabilizationwithmetalplates.Tissuedeteriorationand
alargeparaspinalabscesscauseddestructionoftheposteriorpharyngealwall,suchthatatthetimeof
presentation,themetalplateinthecervicalspinecouldbeseenwithinthepharynx,andtherewasfree
communicationbetweenthepharynxandthemediastinum.

Theauthorswrite,"Thecervicalspineessentiallycomposedthebackwallofthepharynx.Theanteriorplateswere
removedbyaneurosurgeon,whichresultedinalargeholeintheposteriorwallofthepharynxandpharyngo
esophagealjunctionwithalargecaudaldefect."Thepatient,whohaddysphagia,odynophagia,neckpain,fever,
andchills,wasintubatedandprovidedwithapercutaneousgastrostomyfeedingtube,andhadpurulentfluidsand
phlegmontypedebrisdrainedanddebridedfromtheposteriormediastinum.

Moreconventionalesophagealrepairprocedureswerenotpossiblebecauseofthesizeofthegapandthepatient's
fragilecondition,sothesurgicalteamfirsttriedclosingthedefectwithmultipleinterruptedmattresssuturestobring
thepharyngealwallstogether,inthehopeofreestablishinggastrointestinalcontinuity.Thatdidnotwork,and
imagingduringthenext6weeksshowedsubstantialleakageintothemediastinumandadefectthatcouldnotbe
closeddespitemultiplesurgeries.

Thepatientwasthenreferredtothegastroenterologyservice,wheretheultimatelysuccessfulrepairplanwas
devised.Formalinstitutionalreviewboardwasnotrequiredbecausetheinterventionswerearesultofclinical
necessity,usedonlyproductsalreadyapprovedbytheUSFoodandDrugAdministration,andusedtechniquesthat
werestandardofcareattheinstitute.Thepatientgavewritteninformedconsentforeachintervention.

MultipleAttemptsNeeded

AnattempttogetthelargeoesophagealdefecttohealbyinsertionofanAlimaxxES(MeritMedical)self
expandingmetalstent(18mmdiameter,120mmlong)tomaintainthethreedimensionalshapeoftheesophagus
wasunsuccessfulandwasfollowedby3weeksofspikingfevers,contrastmediumleakingintothemediastinum
alongtheouterwallofthestent,andpartialencirclingofthestentbygranulationtissue.

DrDua'steamthenattemptedregenerationoftheesophagusinvivo,usingcommerciallyavailableAlloDerm
extracellularmatrixandautologousplateletrichplasma(PRP)withstenting.First,takingcaretoavoidplatelet
activation,theyslowlydrew60mLbloodfromthepatient.Thebloodwascentrifuged,andtheresulting3mLPRP
wasmixedwith7mLplateletlowplasmaandtransferredtoa10mLsyringe.Asecond0.1mgsyringecontained
calciumchlorideandtopicalthrombintomakethePRPtensileandadhesive.Bothwereconnectedtoasprayerto
dispensethesolutionsinaratioof10:1.TheuseofautologousPRPmeantnoimmunesuppressionwasneeded.

AlloDerm,derivedfromdonatedhumanskin,isrequiredtotestnegativeforbacterialandfungalpathogensandis
http://www.medscape.com/viewarticle/861715_print 1/3
30/4/2016 www.medscape.com/viewarticle/861715_print

processedaseptically.Cellsareremoved,andthedermalmatrixisretained.Theextracellularmatrixwas
rehydratedinsalineandwrappedcircumferentiallyaroundthestent,withthedermalside(whichreadilyabsorbs
blood)orientedtowardthemediastinumtofacilitatevascularization.Thegraftwassuturedinplaceandsprayed
withtheautologousPRPadhesivegel.Thesternocleidomastoidmusclewasretractedandwrappedoverthegraft.

Thisstoppedtheleakintothemediastinalcavity,andthepatientwasallowedoralintake,whichtheuseofmetal
stentsmadepossible.However,4weekslater,granulationtissueblockedthelowerendofthestent,andthe
patientdevelopeddysphagia.Anattempttofixthisproblembytelescopinganotherselfexpandingmetalstentinto
thefirstonefailedbecausethetwostentsmigratedproximallytothepointofoverhangingthelarynx,producing
throatdiscomfortandstridor,sothesetwostentswereremovedandreplacedwiththreestents,all18mm
diameter,alignedwiththeproximalstentacrosstheupperesophagealsphincterandtheupperendoftheproximal
stentattheleveloftheinterarytenoidfoldstoavoidinterferingwiththeepiglottisduringswallowing,andthelower
endofthedistalstentabovetheloweresophagealsphinctertopreventrefluxintothehypopharynx.

Thisthirdstentattemptworked,andthepatientwaseatingsoftfoodsbythetimeofdischarge,supplementedby
gastrictubefeeding.

Themedicalteamhadintendedtoremovethestentat12weeksafterinsertion,buthavingregainedtheabilityto
eat,thepatientwasnotwillingtoriskleakageorstricturedevelopingafterremoval.Thissituationcontinuedfor3
yearsuntilstentinducedgranulationtissueagainobstructedthelowerendofthedistalstent.Partialablationofthe
granulationwastemporarilyeffective,butthepatientdecidedtohavethestentsremovedafterrecurrentproblems.
Thiswasdonebyendoscopy.

Eightweekslater,endoscopyshowed"normalsquamousmucosawithnostrictureorfistula."At1yearafterstent
removal,thepatienthadnormalappearingsquamousepitheliumcoveringtherepairedsiteshowingfivelayers:
mucosa,muscularismucosa,submucosa,muscularispropria,andadventitia.Swallowingwasnormal,aswas
peristalsisintherepairedesophagusandbolustransitintothestomach.By4yearsafterstentremoval,thepatient
waseatingnormally,maintainingnormalweight,andnolongerneedingsupplementalgastrictubefeeding.

Inanaccompanyingeditorial,MartinBirchall,MD,fromtheRoyalNationalThroat,NoseandEarHospitaland
UniversityCollege,London,andPaoloDeCoppi,fromGreatOrmondStreetforChildrenNHSFoundationTrust
andUniversityCollegeLondon'sInstituteforChildHealth,UnitedKingdom,write,"Theendoscopicultrasounddata
arecrucialtounderstandingthecontributionoftheimplantedgraftmaterial.Thesedataseemtoconfirmcomplete
regenerationofalllayersoftheoesophaguswithacellfreeengineeredconstruct,aremarkablefindinggiventhe
presumedcomplexityofthisorgan."

Theauthorsnotethattheextendeddelay(3.5years)beforestentremovalmeanttheywerenotabletodetermine
thetimerequiredforregeneration,whichhastakenupto1yearinanimalstudies.Ifthetechniquesarereplicated,
"thismethodmighthavesubstantialeffectsonthetreatmentofpatientswhoneedconduitsafteroesophageal
resection,"theauthorsconclude.

Inapressrelease,DrDuasaid,"Thisisafirstinhumanoperationandonethatweundertookasalifesaving
measureoncewehadexhaustedallotheroptionsavailabletousandthepatient.Theuseofthisprocedurein
routineclinicalcareisstillalongwayoffasitrequiresrigorousassessmentinlargeanimalstudiesandphase1and
2clinicaltrials.Theapproachweusedisnovelbecauseweusedcommerciallyavailableproductswhicharealready
approvedforuseininthehumanbodyandhencedidn'trequirecomplextissueengineering."

Thestudyauthorsandtheeditorialistsallwarnedagainstviewingthiscaseasashortcuttoclinicaltrials.DrBirchall
andDeCoppisaidmuchcanbelearnedfromtheearlyuseoncompassionategroundsofnewtechnologiesin
patientsforwhomnoconventionaltreatmentsaresuitable,butadded,"[S]uchseriouslyillpatientsarenotusually
typical,havinghighlydisorderedphysiologyand,inpatientswithsurgicaldisorders,anatomy,andscepticsargue
thattheunderlyingmechanismsforsuccessorfailurecannotbeunderstoodonthebasisofdatafromsuch
patients.Instead,welldesignedanimalstudiesarethemostappropriateprecedentstoearlyphaseclinicaltrials."

Theauthorsandeditorialistshavedisclosednorelevantfinancialrelationships.

http://www.medscape.com/viewarticle/861715_print 2/3
30/4/2016 www.medscape.com/viewarticle/861715_print

Lancet.PublishedonlineApril8,2016.

FormoregastroenterologynewsjoinusonTwitter:@MedscapeGastro

MedscapeMedicalNews2016WebMD,LLC

Sendcommentsandnewstipstonews@medscape.net.

Citethisarticle:EsophagusRegenerationSuccessfulinHumanPatient.Medscape.Apr08,2016.

ThiswebsiteusescookiestodeliveritsservicesasdescribedinourCookiePolicy.Byusingthiswebsite,youagreetothe
useofcookies.
close

http://www.medscape.com/viewarticle/861715_print 3/3