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DUAL-MODALITYPHOTOACOUSTICANDULTRASOUNDIMAGINGSYSTEMFORNONINVASIVESENTINELLYMPHNODEDETECTIONINPATIENTSWITHBREASTCANCERAlejandroGarcia-Uribe,ToddN.Erpelding,ArieKrumholz,HaixinKe,KonstantinMaslov,CatherineAppleton,JulieA.Margenthaler,LihongV.WangScientificReports|5:15748|DOI:10.1038/srep15748contentsBackgroundResultsanddiscussionMethodsAuthorContributions•Lymphnodesaresmalloval-shapedorgansthatarepartofthebody’slymphaticsystem.Theyarefoundwidelythroughoutthebodyandareconnectedtooneanotherbylymphvessels.•Thesentinellymphnode(SLN)isdefinedasthefirstnodeinthelymphaticsystemthatdrainsatumorsite.•Thesentinellymphnodeconceptisbasedonthefindingthatmethylenebluedye(orotherdyesandradioactiveisotopes)istakenupintothelymphaticsystemsimilartohowtumorcellstravelfromthetumor.•Thus,thedetectionofregionallymphnodemetastasesisimportantincancerstagingasitguidestheprognosisofthepatientandthestrategyfortreatment.BackgroundDetectionsiteaxillarylymphnodeSentinellymphnodedissectionbiopsyUltrasonography(US)examinationVisualization•Signsoverlap•PoordistinctivenessBackgroundtracersradio-labeledsulfurcolloidmethylenebluedyeQuickly(Afewminutes)Slowly(afewhours)However,inthepresentclinicalmedicine,physiciansoftenusebothtwomethodstoidentifytheSLN,whichismostlikelytocontainmetastaticcancercells,andthesurgicalprocedurecauseshighmorbidityandassociatedexpenses.Therefore,theseprovidesgreatinterestandanexcellentopportunityforustoexploreaminimallyinvasivemethod.MorepracticalandsaferSpreadspeedBackgroundInthiswork,wedevelopedadual-modalityphotoacoustictomography(PAT)andUStononinvasivelydetectSLNsbasedontheaccumulationofmethylenebluedye.Ultimately,weaimtoguidepercutaneousneedlebiopsiesandprovideaminimallyinvasivemethodforaxillarystagingofbreastcancer.RelativeUS,PAT&UShassomeadvantagesasfollows:•PATbenefitsfromthetissue’slowacousticscattering;•scatteredlightpresentslessdifficultytoPATbecauseanyabsorbedlightisconvertedtosound;•PATenabledual-modalityimagingwithcomplementarycontrasts;•PATishighlysensitivetothestrongopticalabsorptionofthebluedye.BackgroundFigure1.Schematicofthedual-modalityphotoacousticandultrasonographicimagingsystemandphotographoftheprobe.Theprobefeaturesaflatsurfaceforlightdelivery,andthefiberbundlesareintegratedintotheultrasonictransducerhousingforergonomichandling.BackgroundFigure2.OverviewofPAT-USimagingapproachforminimallyinvasiveSLNstaging.(a)Anatomyshowingtherelevantstructures.(b)Periareolarinjectionofmethylenebluedye,whichiscollectedbylymphaticvesselsanddrainedtothesentinellymphnode.(c)PAT-USimagingpinpointstheSLN.(d)PAT-USimagingguidesaFNABoftheSLNwithhighcontrast.ResultsanddiscussionFigure3.(a)InvivoUSimageofalymphnode.(b)InvivoPATimageofmethylenebluedye.(c)CoregisteredPAT-USimageoftheSLN.(d)RadiographofexvivoSLNshowingthepresenceofthetissuemarkingclip.ResultsanddiscussionMovieS1.Aninvivo,simultaneouslyacquiredPATandUSmovieofalymphnodeinawomanwithbreastcancer.TheleftandmiddlepanelscorrespondtoUSandPAT,respectively.Therightpanelshowsco-registeredPAT-USimagesoftheSLN.Theseimagesweredisplayedinreal-timeduringtheclinicalprocedure.ResultsanddiscussionFigure4.InvivoimagesoftheSLNandtheneedleacquiredusingPAT-US.(a)InvivoUSimageshowingthelymphnodeandneedle.(b)InvivoPATimageoftheSLNandneedle.(c)CoregisteredPAT-USimageoftheSLNandneedle.ResultsanddiscussionMovieS2.Co-registeredPAT(incolor)andUS(ingray)imagesofSLNandaneedleinahumanpatientacquiredinvivo.ThefirstpartofthemovieshowsthelocalizationoftheSLN,thesecondpartshowsthedeploymentofasmalltissuemarker(atitaniumclip)underPAT-USguidanceintothesuspectedSLN.ResultsanddiscussionFigure5.Molarextinctioncoefficientofoxy-hemoglobin(HbO2)anddeoxy-hemoglobin(Hb)aswellasmethyleneblue(MB)dye.ResultsanddiscussionFigure6.Invivo,dual-wavelengthPAT.(a)PATimageacquiredat650nmshowingbothmethylenebluedyeinlymphaticvesselsandhemoglobininbloodvessels.(b)PATimageacquiredat1064nmshowingprimarilyhemoglobininbloodvesselswhilesuppressingthesignalsfrommethylenebluedye.(c)Imagedisplayingthefractionalchange(650nmsignalrelativeto1064nmsignal)convincinglyhighlightsthelocationsofmethylenebluedye.PA650andPA1064:photoacousticamplitudesmeasuredat650nmand1064nm,respectively.ResultsanddiscussionMovieS1.Invivo,dual-wavelengthPATinhumanpatientfollowingmethyleneblueinjection.TheleftpanelshowsthePATimagesacquiredat650nm,whichrepresentsignalsfrombothmethyleneblue(i.e.,lymphaticvessels)andbloodvessels.Themiddlepanel—thePATimagesacquiredat1064nm—showsprimarilysignalsfrombloodvessels.Therightpaneldisplaysthefractionalchange(650nmsignalsrelativeto1064nmsignals),whichhighlightsthelocationsofmethyleneblue.ResultsanddiscussionMethods•Photoacousticimagingsystem;•Participantpopulation;•Patientpreparation.AuthorContributions•L.V.W.designedanddirectedtheproject,discussedtheexperiments,andrevisedthemanuscript.•A.G.-U.performeddataprocessing,carriedoutexperiments,andwrotethemanuscript.•T.N.E.developedcodesfordataacquisition,carriedoutexperiments,andco-wrotethemanuscript.•A.K.andH.K.helpedwiththeexperiments.•K.M.contributedtothesystemdeve