The 9th international conference of the International Mesothelioma Interest Group September Amsterdam, The Netherlands

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1 ORGANIZATION The9thinternationalconferenceof theinternationalmesotheliomainterestgroup 2527September2008 Amsterdam,TheNetherlands FINALPROGRAM AND ABSTRACTBOOK AMSTERDAM,2527SEPTEMBER,2008 DEMEERVAART,AMSTERDAM

2 ORGANIZATION Organizedby: I.M.I.G. InternationalMesotheliomaInterest Group Localorganizingcommittee: P.Baas,(Amsterdam,TheNetherlands) S.Burgers(Amsterdam,TheNetherlands) ScientificSecretariat: PaulBaas NKI/AVL Plesmanlaan CXAmsterdam(TheNetherlands) SjaakBurgers NKI/AVL Plesmanlaan CXAmsterdam(TheNetherlands) OrganizingSecretariat NKI/AVL Plesmanlaan CXAmsterdam(TheNetherlands) OrganizingFaculty P.Baas S.Burgers W.Strankinga E.VanHezik Y.Tan J.Wagenaar N.van thullenaar N.Schlösser H.Kaajan J.Aerts R.Schrijver M.Koolen H.Schouwink InternationalScientificCommittee S.Albelda S.Armato A.Berns C.Broaddus M.Carbone J.Creaney N.deKlerk D.Fennell R.Gaafar A.Gazdar R.Haas R.Hassan J.Hegmans G.Hillerdal M.C.Jaurand H.Kindler S.Knuutila L.Krug M.Ladanyi R.Lake L.LangLazdunski C.Lee G.Lee M.Metintas B.Mossman S.Mutsaers L.Mutti T.Nakano A.Nowak H.Pass N.Pavlakis J.Peto B.Robinson O.D.Roe R.Stahel J.Steele R.Stephens D.Sterman C.Stevens J.teWaterNaude J.Testa T.Treasure M.Tsuboi J.vanMeerbeeck M.vandeVijver M.vanderWoude N.Vogelzang N.vanZandwijk

3 GENERALINFORMATION CONFERENCEVENUE DEMEERVAART. demeervaart MeerenVaart LEAmsterdam PHONE+31(0) DeMeervaartisawellknownconferencebuildingandtheaterinAmsterdamWest.Itislocatednear ashoppingmall. PARKING QParkparkinggarageOsdorpplein.ComingfromtheLelylaanyoutakearightattheTcrossing.At thesecondstoplightyoutakealeftandyouwillseethegarageonyourlefthandside(placefor500 cars,2minutewalk).atthemeervaartyoucanbuyanexitcoinatareducedrate.withthiscoinyou canexitupto2hoursaftertheshow.theexitcoinalsoservestoopentheentrancedoortothe garage.theparkinggarageisalsoopenonsundaystartingat1hourbeforetheshow.thegaragecan beexited24hoursperday. PUBLICTRANSPORTATIONto DEMEERVAART. Train FromAmsterdamCentralStationorStationCornelisLelylaantaketram1or17. FromStationZuidWTCtakebus63. FromStationSloterdijktakebus192. Tram/bus Tram17towardsOsdorpfromAmsterdamCentralStationstopsinfrontofdeMeervaart,stop Ruimzicht. Tram1towardsOsdorp/deAkerfromAmsterdamCentralStationstopsa5minutewalkawayfrom demeervaart,stop MeerenVaart. Buses19,63and192towardsOsdorp,stop Ruimzicht. Nightbus353towardsAmsterdamCentralStationstop'Ruimzicht'. WALKINGFROMTULIPINNAMSTERDAMCITYWEST TulipInnAmsterdamCityWestislocatedata10minutes walkfromtheconferencevenue De Meervaart.Turnleftwhenyouleavethehotel.Attheendofthestreetturnleftonthe Osdorper Ban.Turnrightimmediatelyacrossthebridge: Hoekenes.Takethethirdturntotheleft: Tussen Meer,thisisastreetwithlotsofshopsandacoveredsidewalk.Wherethemainstreet Tussen Meer turnsleftandright,youcrossthestreetandwalkstraightonintotheshoppingmall.follow thepassagewaythroughthemalluntilyoureachestheroad MeerenVaart.Themainentranceof theconferencecentre DeMeervaart islocatedatyourrighthandsidefacingthelake. 1

4 BUSESFROMHOTELARTEMIS ConferenceBusesareavailableeverymorningat07.00,07.20,07.45and08.000hrstobringyouto theconferencesite.thetransferwilltakeabout15minutes. TransferbacktothehotelArtemis:Thursdaybuseswillbeavailabletobringyoutothehotelat 17.30,19.30,20.00and20.30hrs.FridaybustransferstohotelArtemisareplannedat17.30hrsto thehotelartemisandat17.45hrstothesocialevent.onsaturdaybusesareavailabletothehotel Artemisat12.45hrsand13.30hrs. PUBLICTRANSPORTATIONFROMHOTELARTEMISTOTHECONFERENCESITE. Bus195willbringyoufromhotelArtemisto StationLelylaan.AttheNorthsideofthisstation(1 minutewalk)isthebusstopno63direction OsdorpDeAker.Getoffatthe6 st stop Ruimzicht just before DeMeervaart.Thisridewillcost3 strippen. TAXIS: Canbeorderedatthehoteldesk. TICKETSFORPUBLICTRANSPORTATION Ticketsforpublictransportationwillbeavailableattheregistrationdesk.Thiswillbeforareduced priceof 5,=(normalprice 6,95).Ticketscanbeusedonallbusesandtrams.AfaretoAmsterdam CentralStationcosts3 strippen,whereasthe strippenkaart contains15 strippen.ticketswillbe validthroughoutyourstayinamsterdam. LANGUAGE TheofficiallanguageofthecongressisEnglish.AlllecturesandpresentationswillbeheldinEnglish. REGISTRATION Theregistrationdeskislocatedintheentrancehalloftheconferencecentre.Thedeskwillbeopen onthursdayandfridayfrom7.15amuntil17.00pm. Onsiteregistrationispossibleatthedesk. Atthedesk strippenkaarten (busandtramscards)areavailableatareducedpriceof 5,=. TicketsforthespeciallunchseminarsonThursdayandFridaywillbeavailableatthedesk.Thetickets arefree. Allfeesinclude: participationinthescientificsessions certificateofattendance abstractbook congressbag breakfast,coffeebreaksandlunch welcomereception CASHPOINT Acashpointislocatedatthelefthandsideoftheentranceof DeMeervaart. BREAKFAST OnThursday,FridayandSaturdaybreakfastwillbeservedattheconferencefrom7.00until9.30AM forallregistrants. LUNCH Freelunchwillbeservedattheconferenceinthefoyeratthefirstfloorforallregistrants. Simultaneously,aspecialLUNCHSEMINARwillbeheldinthefoyeronthesecondflooronThursday andfriday.theseluxurylunchesaresponsoredbyfujirebioandmorphotek,respectively. 2

5 Onehundredfreeticketsareavailableforeachseminar,andcanbeobtainedforfreeatthe registrationdeskattheconferencehallandattheboothsoffujirebioandmorphotek.theprogram oftheseseminarsismadeundertheresponsibilityofthesponsors. COFFEEANDTEABREAK Freecoffee,teaandrefreshmentswillbeavailablefrom10.00to17.00h. INFORMATIONFORPRESENTERS Thespeaker sroomislocatedneartheentranceofthe BlueRoom atthesecondfloor.wekindly askthepresentersofposterdiscussions,oralpresentationsandinvitedlecturestouploadthe presentationsbeforethestartofthesession.thetimescheduleofthesessionsistootighttoupload thepresentationsduringthesessions. TIMESCHEDULE Everyeffortshouldbemadetoadherestrictlytothetimeallottedforeachpresentation. POSTERS Theposterscanbeviewedduringthewholeconference.Theywillbeexposedinthreeposterview rooms.theposterswillbedividedintwogroupswhichwilleachbediscussedonthursdayandfriday eveningbyexperts.thewinneroftheposterawardofthatdaywillbeannounced. WeaskyoutoputthepostersontheposterboardsonThursdaymorningbetween7.00and10.00 AM,andremovethepostersonFridayafternoonbetween16.00and18.00PM. AWARDS WAGNERMEDAL TheWagnerMedalaward,foundinhonorofDr.ChrisWagner,whofirstidentifiedtheassociation betweenasbestosexposureandmesothelioma,willbeassignedalsoduringthiseditionofthe Meeting.Theawardwillbepresentedtoanindividualwho,intheopinionoftheIMIGcommittee, hasmadeamajorcontributiontomesotheliomaresearch,eitherclinicalorlaboratory,overa numberofyears.thewinnerwillbeannouncedduringthereceptiononthursdayevening September25 th. YOUNGINVESTIGATOR SAWARD DuringthePosterDiscussionsessiononFridayevening,theYoungInvestigatorAwardswillbe presentedbytherespectivesponsors,internationalbanasbestossecretariat(ibas)andtheasbestos DiseaseAwarenessOrganization(ADOA). Theabstractswereselectedinthreesteps:firstyoushouldhaveindicatedtoyoungerthan40years ofage,whensubmittingtheabstract.next,themeetingchairsshouldhavenominatedyourabstract. Andfinally,aselectionofthefinestiMigboardmembershavechosentheawardswinningabstracts fromthenominatedpreselection. POSTERAWARD Allabstractswhicharepresentedeitherasposterpresentationorasaposterarecandidatesforthe PosterAward.TheabstractswillberatedbythechairsoftheposterdiscussionsessionsThursday andfridayafternoon.eachdayonepriceistobegivenaway:fivehundredeuroandabrandnew2 nd editionofthefamous TEXTBOOKOFPLEURALDISEASES byrichardwlightandycgarylee. 3

6 SOCIALPROGRAM FortheSocialProgramonFridaynight,only120ticketsareavailable:pleasecheckattheregistration deskintheconferencehall.buseswillbereadyattheentranceofthemeervaartfriday17.45h. YouwillbetransportedtotheinnercityofAmsterdamwherewefirsthavedrinksandtapas,(offered bytheasbestslachtofferverenigingnederland)followedbyacanalboattourwhichwilltakeusto oneoftheolderindonesianrestaurantsontherembrandtsquareforanindonesianricetable. Weexpecttoendaround22.15andwillreturntothehotelsbybus. SpecialthankstotheAudiovisualCenteroftheNetherlandsCancerInstituteforprovidingthe picturesonthecover. 4

7 LISTOFSPONSORS Wearetrulyindebtedtothesponsorswhomadeitpossibletoorganizethismeeting. PLATINUMSPONSORS Lilly MSD DavidLawFirm Roche GOLDSPONSORS AsbestslachtofferVerenigingNederland InstituutAsbestSlachtoffers NVALTMesotheliomawerkgroep Fujirebio Morphotek SILVERSPONSORS Bayer Servier Glaxo Amgen KazanLawFirm Pfizer MARF Medapharma BRONZESPONSORS Mundipharma ExtraLifeScienceProductions 5

8 WELCOMEFROMTHEIMIGCHAIR I am delighted to welcome you to Amsterdam, site of the 9 th Meeting of the International Mesothelioma Interest Group. As the leading international organization for physicians and scientists dedicated to mesothelioma research, IMIG is proud to sponsor this conference every two years. This transdisciplinary meeting will gather investigators from around the globe to present scientific information of the highest caliber. It is my hope that this IMIG meeting, like the others that have preceded it, will foster international collaboration, inspire young investigators, generate new ideas, and establish benchmark standards for the diagnosis and treatment of this disease. Hedy Lee Kindler, MD Chicago, USA 6

9 WELCOMEFROMTHEIMIGORGANIZERS Dearparticipant, AwarmwelcometoyouallinAmsterdam.WearehonouredtobeyourhostsontheiMig2009 meeting. Mesotheliomaremainsaglobalproblem.Theincidenceofthisasbestosrelateddiseaseisstillrising. Intheforeseeablefuturethefatalityratemightdropinthedevelopedcountriesbutitissteeply risinginthethirdworld.thisisoneofthemostimportantreasonsforustoorganizethismeeting everyotheryear. Theformatofthecongresswillincludedidacticlecturesfrominternationallyrenownedleaders, debatesanddiscussionsoncontroversialtopics.wehopetoinformyouonallaspectsofmalignant mesothelioma;epidemiology,biology,moleculargenetics,diagnosisandtreatment.specialistshave beenaskedtopreparesessionssummarizingthehottesttopics,theongoingresearchandnew developments.welookforwardstostimulating,opendiscussionsduringthesessionsandhopethat thiswillleadtofruitfulcollaborations. Duringthepreparationofthismeeting,theEuropeanAssociationofCardioThoracicSurgery approacheduswiththerequesttohaveajoinedmeetingduringthisconference.weweremore thanhappytoincludethespecialmeetingwherecliniciansandresearchersofallsortscandiscuss thedirectionweshouldtakeforcombinedtherapyapproaches.thepreviousmeetingshavebeena stimulusforustoprepareaprogramthatfitsbest.inthiscongressbookthesessionsarepresented foreachsubjectbyday,followedbythesubmittedabstractsforyourconvenience. Finally,weareindebtedtooursponsorswhohavemadethiseventpossibleandhopethatinthe nearfuture,togetherwewillbeabletoachieveourgoal:theeradicationofthisdiseaseandfindinga cure! WehopethatyouwillenjoythemeetinginAmsterdam. PaulBaas,MD,PhD SjaakBurgers,MD,PhD TheNetherlandsCancerInstitute Amsterdam,TheNetherlands 7

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12 THURSDAY25SEPTEMBER Thursday Sept,25 Blueroom Room2 Room67 Posterroom Welcome:PaulBaas PresidentsAddress HedyKindler Generalsession: BruceRobinson JulianPeto AntonBerns JosephTesta LauriKazan ChairsBlueRoom: SjaakBurgers NickPavlakis Break Chemotherapy1 Chairs: HedyKindler DeanFennell Imaging Chairs: SamArmato AnnaNowak AnimalModels Chairs: AntonBerns JosephTesta LUNCH SpecialLunchSeminar: Fujirebio Radiotherapy Chairs: RickHaas CraighStevens Pathology1 Chairs: MarcvandeVijver BrookeMossman NovelTargets Chairs: RaffitHassan OlufDimitriRoe Posterdiscussionwith5top ratedposterpresentersand Highlightoftheday Chairs: DeanFennell NicovanZandwijk MARFpresentation M.Hesdorffer WELCOMERECEPTION WagnerPrize POSTERS Posterviewing Rooms1,2and3 10

13 FRIDAY26SEPTEMBER Room1 Friday, Sept26 Blueroom Room2 Room IMIGandEACTSjoint meeting SeeadditionalProgram Break IMIGandEACTSjoint meeting SeeadditionalProgram EarlyDiagnosis Chairs: SteveMutsears JenetteCreaney Asbestosvictims: epidemiology,surveillance, compensationand awareness. Chairs: MachielvanderWoude JamesteWaterNaude LUNCH SpecialLunchSeminar: Morphotek IMIGandEACTSjoint meetingchairs: SeeadditionalProgram ImmunoTherapy Chairs: CourtneyBroaddus JoostHegmans EpidemiologyandCausation Chairs: MuzafferMetintas MicheleCarbone Posterdiscussionwith5top ratedposterpresenterand Highlightoftheday Chairs: BruceRobinson EdvanHezik ADAOPosterAward, IBASPosterAward SPECIALEVENINGTRIPANDBANQUET POSTERSviewing Room1,2and3 11

14 Saturday, SATURDAY27SEPTEMBER Blueroom Room2 Room67 Sept Surgeryand Multimodality Treatment Chairs: RolfStahel MasahiroTsuboi Futuretrends Chairs: RababGaafar DanielSterman MolecularGenetics Chairs: MarcLadanyi MarieClaudeJaurand Break Palliation Pleurodesis Chemotherapy2 MolecularPathology Chairs: Chairs: Chairs: JeremySteele GaryLee NickVogelzang JanvanMeerbeeck LucioMutti SakariKnuuttila LUNCHANDFAREWELL 12

15 LUNCHSESSIONPROGRAM Simultaneouslytothefreelunches,aspecialLUNCHSEMINARwillbeheldinthefoyeronthesecond flooronthursdayandfriday.theseluxurylunchesaresponsoredbyfujirebioandmorphotek, respectively. Onehundredfreeticketsareavailableforeachseminar,andcanbeobtainedforfreeatthe registrationdeskattheconferencehallandattheboothsoffujirebioandmorphotek.theprogram oftheseseminarsismadeundertheresponsibilityofthesponsors. Thursday LunchsessionsponsoredbyFujirebio,ThursdaySeptember25 Time Speaker Title Lee Introduction Pass Mesomarkandtreatmentmonitoring:thediscoveryphase Scherpereel Lee Questions comments Solublemesothelinandmalignantpleuralmesotheliomamanagement:a Frenchgroupfiveyearsexperience LunchsessionsponsoredbyMorphotek,FridaySeptember26 Time Speaker Title Hassan Introduction Robinson ValueofmesothelinSMRPasadiagnosticmarkerinmesothelioma Hassan Morphotek TargetingmesothelinusingMORab009,preclinicalstudiesandresultsof phaseistudy PhaseIIclinicaltrialofMORab009asfrontlinetherapyfor mesothelioma 13

16 GENERALSESSION CHAIRS:NickPavlakisandSjaakBurgers TIME TITLEABSTRACT TYPE abstract number Welcome PaulBaas PresidentialAddress HedyLeeKindler INTERNATIONALMORTALITYTRENDS JulianPeto Invitedspeaker CURRENTSTATUSANDFUTUREDEVELOPMENTSOF TUMORMARKERSINMESOTHELIOMA BruceRobinson Invitedspeaker MODELSYSTEMSFORHUMANMALIGNANT MESOTHELIOMA AntonBerns Invitedspeaker TUMORSUPPRESSIONINMESOTHELIOMA JosephTesta Invitedspeaker INDIA'SASBESTOSTIMEBOMB LaurieKazanAllen Invitedspeaker Break General Session 14

17 CHEMOTHERAPYI CHAIRS:HedyLeeKindlerandDeanFennell TIME TITLEABSTRACT TYPE abstract number GUIDELINESFORTHEMANAGEMENTOFMALIGNANT PLEURALMESOTHELIOMAFROMTHE ERS/ESTS TASKFORCE ArnaudScherpereel Invitedspeaker LATESTDEVELOPMENTSAPOPTOSISANDMESOTHELIOMA CourtneyBroaddus Invitedspeaker INVITROEXTREMECHEMOTHERAPYRESISTANCEASSAY CONFIRMSUTILITYOFCISPLATININTHETREATMENTOF MALIGNANTPLEURALMESOTHELIOMA AneilMujoomdar Oral presentation INHIBITIONOFTRANSLESIONSYNTHESISSENSITIZES MALIGNANTPLEURALMESOTHELIOMACELLSTOCISPLATIN TREATMENT PhilipAlexanderKnobel Oral presentation 9 11,50 NGRHTNF,ANOVELVASCULARTARGETINGAGENT(VTA), ASSECONDLINETHERAPYINMALIGNANTPLEURAL MESOTHELIOMA(MPM):PRELIMINARYRESULTSOFA MULTICENTERPHASEIITRIAL PaoloZucali Oral presentation PHASEIISTUDYOFTHECOMBINATIONOFBEVACIZUMAB PLUSPEMETREXEDANDCARBOPLATINASFIRSTLINE THERAPYINPATIENTSWITHMALIGNANTPLEURAL MESOTHELIOMA(MPM) GiovanniLucaCeresoli Oral presentation NEWDEVELOPMENTSINMESOTHELIOMA HedyLeeKindler Invitedspeaker Lunch Chemotherapy 1 15

18 RADIOTHERAPY CHAIRS:RickHaasandCraigStevens TIME TITLEABSTRACT TYPE abstract number INDICATIONSANDLIMITATIONSOFRTINMPM,SETTINGTHE SCENE CraigStevens Chairperson HYPERTHEMIAANDRTINMPM:RATIONALE,TECHNIQUEAND CLINICALRESULTS J.vanderZee Invited speaker FATALPNEUMONITISASSOCIATEDWITHIMRTINMPM AaronAllen Invited speaker Discussion Chairs Break EXTRAPLEURALPNEUMONECTOMY(EPP)ANDHEMITHORACIC RADIATIONTHERAPY(RT)FORMPM KennethRosenzweig Oral presentation PLEURALINTENSITYMODULATEDRADIATIONTHERAPYIN PATIENTSWITHMPM KennethRosenzweig Oral presentation ADJUVANTHEMITHORACICRADIOTHERAPYFOLLOWINGEPPFOR MPMIMPROVESLOCALCONTROL JohnCho Oral presentation PULMONARYTOXICITYFOLLOWINGINTENSITYMODULATED RADIOTHERAPY(IMRT)AFTEREXTRAPLEURAL PNEUMONECTOMYFORMPM JensBennSrensen Oral presentation IMRTAFTEREXTRAPLEURALPNEUMONECTOMY(EPP)IN PATIENTSWITHMPM:DOESNODALSTATUSMAKETHE DIFFERENCE? MartaScorsetti Oral presentation BORONNEUTRONCAPTURETHERAPYFORMALIGNANT MESOTHELIOMA ChunmanLee Poster discussion SUMMARY Chairs Radiotherapy 16

19 IMAGING CHAIRS:SamuelArmatoandAnnaNowak TIME TITLEABSTRACT TYPE abstract number ASSESSINGPROGNOSISOFMPMBYINCORPORATINGFDG PETPARAMETERSADDSINCREMENTALVALUETO PROGNOSTICMODELSINCORPORATINGCLINICAL INFORMATION AnnaNowak Oral presentation EARLYRESPONSEEVALUATIONINMPMBYTOTAL GLYCOLYTICVOLUME(TGV)ANALYSISOFSERIALFDGPET SCANS GiovanniLucaCeresoli Oral presentation DIFFERENTIATIONBETWEENMALIGNANTMESOTHELIOMA ANDASBESTOSRELATEDBENIGNPLEURALDISEASE HuseyinYildirim Oral presentation THICKNESSANDAREAINTHECTBASEDASSESSMENTOF MESOTHELIOMATUMORRESPONSE SamuelArmato Oral presentation ROLEOF18FDGPETCTINPATIENTSSURVEILLANCEAFTER MULTIMODALITYTHERAPYOFMALIGNANTPLEURAL MESOTHELIOMA CarolTan Oral presentation PRACTICALANDREPRODUCIBLEVOLUMEMEASUREMENT OFMALIGNANTPLEURALMESOTHELIOMAFROM STANDARDCTIMAGES ShinMatsuoka Oral presentation THEINFLUENCEOFTALCPLEURODESISONFDGPET IMAGINGFORMPM. AgathavanderSchaaf Oral presentation CONTINUEDPERMETREXEDANDPLATINBASED CHEMOTHERAPYINPATIENTSWITHMPM:VALUEOF18F FDGPET/CTPARAMETERS N.G.Schaefer Oral presentation SUMMINGUP Chairs LUNCH Imaging 17

20 CHAIRS:MarcvandeVijverandBrookeMossman PATHOLOGY TIME TITLEABSTRACT TYPE OPPORTUNITIESFOROBTAININGHUMANMESOTHELIOMA TISSUESTOCONFIRMTHERELEVANCEOFINVITROANDANIMAL STUDIES BrookeMossman Chairperson abstract number THEDUTCHMESOTHELIOMAREGISTRY MarcvandeVijver Chairperson EVIDENCEOFSTAT1ACTIVATIONINMPMINFORMALINFIXED ANDPARAFFINEMBEDDEDTISSUEUSINGPROTEINLYSATE MICROARRAYS HanneloreKothmaier Oral presentation THEVALUEOFERCC1ASPROGNOSTICMARKERFORMPM IsabelleOpitz Oral presentation 34 Pathology EPIGENETICPROFILESDISTINGUISHPLEURALMESOTHELIOMA FROMADENOCARCINOMAOFTHELUNG BrockChristensen Oral presentation DISCUSSION BREAK DNAMETHYLATIONINTUMORSANDMATCHEDNORMAL TISSUESOFMPMINTHEEGYPTIANPOPULATION AbeerBahnassy EPATHOLOGYANDATYPICALMESOTHELIALHYPERPLASIA (MESODIAGAMH):THEEXPERIENCEOFTHEINTERNATIONAL MESOTHELIOMAPANEL FrançoiseGalateauSallé CRITICALANALYSISOFNUCLEARSIZEASAHISTOLOGIC ASSESSMENTOFPROGNOSISINDIFFUSEMALIGNANT PERITONEALMESOTHELIOMA PaulSugarbaker DELIBERATELYPROVOKINGLOCALINFLAMMATIONDRIVES TUMORSTOBECOMETHEIROWNPROTECTIVEVACCINESITE DeliaNelson Oral presentation Oral presentation Oral presentation Oral presentation DISCUSSION

21 ANIMALMODELS CHAIRS:AntonBernsandJosephTesta TIME TITLEABSTRACT TYPE abstract number THEHETEROGENOUSMICROENVIRONMENTOFMURINE MALIGNANTMESOTHELIOMADURINGTUMOR IMPLANTATION BonnieLau Oral presentation HUMANANDMURINEMESOTHELIOMASHARESIMILAR GENOMICALTERATIONS ElodieManié Oral presentation EXTRACELLULARSIGNALREGULATEDKINASES(ERKS)HAVE DISPARATEROLESINGROWTHANDCHEMORESISTANCEOF HUMANMESOTHELIOMASINVITROANDINAMOUSE XENOGRAFTMODEL ArtiShukla Oral presentation MALIGNANTMESOTHELIOMAMOUSEMODELFORINVIVO ANDINVITROTHERAPEUTICSTRATEGIES JohanJongsma Oral presentation RNAINTERFERENCEBASEDSTRATEGIESDIRECTEDAGAINST BCLXLANDMCL1FORTHETREATMENTOFMALIGNANT PLEURALMESOTHELIOMA EmilieVarin Oral presentation DEPLETIONOFICOSANDTNFR2EXPRESSINGEFFECTOR SUPPRESSORTCELLSPROMOTESTHEERADICATIONOF SUBCUTANEOUSMESOTHELIOMASINMICE RobbertvanderMostRichardLake Oral presentation HIGHFIDELITYPRECLINICALMODELINGINMEXTAG TRANSGENICMICE RichardLake Invited speaker SUMMINGUP Chairs LUNCH Animal Models 19

22 CHAIRS:RaffitHassanandOlufDimitriRoe NOVELTARGETS TIME TITLEABSTRACT TYPE WT1VACCINEINMESOTHELIOMA;ANOVERVIEW LeeKrug Invited speaker abstract number IDENTIFICATIONOFNEWTARGETSBYGENOMEWIDEPROFILING OlufDimitriRe Chairperson REVERSALOFBORTEZOMIBRESISTANCEINMESOTHELIOMABYA MCL1/A1TARGETINGBH3PEPTIDOMIMETIC AlexChacko Oral presentation 49 Novel Targets IDENTIFICATIONOFINTERNALIZINGHUMANANTIBODIES TARGETINGTUMORCELLSURFACEANTIGENSCOMMONLY EXPRESSEDBYALLTYPESOFMESOTHELIOMA ScottBidlingmaier MESOTHELINASTARGETFORMESOTHELIOMA IMMUNOTHERAPY RaffitHassan Oral presentation Chairperson BREAK FREQUENTCOACTIVATIONOFMETANDEGFRINMALIGNANT MESOTHELIOMAASARATIONALEFORCOMBINATIONTARGETED THERAPY ShigekiShimizu PAXILLINISANOVELPOTENTIALMOLECULARTHERAPEUTIC TARGETAGAINSTMESOTHELIOMA RamasamyJagadeeswaran MESOTHELIOMASPHEROIDS,mTOR,MITOCHONDRIAAND MULTICELLULARRESISTANCE DarioBarbone TRANSDUCTIONOFTHEWILDTYPEP53GENEINCOMBINATION WITHANTICANCERAGENTSPRODUCEDANTITUMOREFFECTS ONMESOTHELIOMA YujiTada NOVELTHERAPYFORMPMBASEDONANTIENERGETICEFFECT: ANEXPERIMENTALSTUDYUSING3BROMOPYRUVATEINNUDE MICE XiadongZhang RAPAMYCININTENSIFIESCISPLATINCYTOTOXICTYIN MESOTHELIOMACELLLINES MorLiHartman Oral presentation Oral presentation Oral presentation Poster discussion Poster discussion Poster discussion SUMMARY TheEnd

23 IMIGEACTSJOINTSESSION CHAIRS:HedyKindler,BruceCaseandHarveyPass TIME GENERALSESSION:THESURGICALTRIALS abstract number WELCOME.Chairs IMIG Eacts Joint Session EORTCPaulvanSchil MARSJulianPeto MesoVATSRobertRintoul 142 Friday STATISTICSIN difficulttodo MESOTHELIOMATRIALSRichardStephens DISCUSSION BREAK CHAIRS:DavidWallerandHoukeKlomp TIME CURRENTPRACTICE:SURGEONSandSYMPTOMCONTROL abstract number BESTPALLIATIONOFBREATHLESSNESDUETOFLUID.GaryLee PORTSITERADIOTHERAPY.CraigStevens DECORTICATIONASAMEANOFSYMPTOMRELIEF.DavidWaller APHYSICIAN SPERSPECTIVEONSURGICALOPTIONSFORMESOTHELIOMA. RobertRintoul OVERVIEWANDPANELDISCUSSION.HoukeKlomp LUNCH 21

24 IMIGEACTSJOINTSESSION CHAIRS:TomTreasureandJanvanMeerbeeck TIME MESOTHELIOMA:WHEREAREWEANDWHEREAREWEGOING? abstract number AHISTORICALPERSPECTIVE.EricButchart ANADVOCATE SPERSPECTIVE:ACALLFORADATABASEDAPPROACH. RogerWorthington WHOOWESWHATTOWHOMINCLINICALANDSURGICALRESEARCH? MartynEvans PROPOSALFORBETTERSURGICAL/PATHOLOGICALSTAGING. JohnEdwards 151 TIME MINIDEBATE:SHOULDSURGERYBEAIMINGATCOMPLETERESECTION? abstract number PRO.TomTreasure CON:DavidWaller DOESRADIOTHERAPYADDANYTHINGTOEPP?RezaMehran ESTIMATINGTHESURVIVALBENEFITASSICIATEDWITHRADICAL SURGERY.TomTreasure WHATMIGHTMARS2LOOKLIKE?DavidWaller DIRECTIONSFORFUTURESURGICALRESEARCH.Panel IMIG Eacts Joint Session 22

25 EARLYDIAGNOSIS CHAIRS:SteveMutsearsandJenetteCreaney TIME TITLEABSTRACT TYPE abstract number THEFIBRINOLYTICSYSTEMANDGROWTHOFMALIGNANT PLEURALMESOTHELIOMA StevenIdell Invited speaker CYTOLOGICALDIAGNOSISOFMALIGNANTPLEURAL MESOTHELIOMA AmandaSegal Invited speaker BIOMARKERSFORMALIGNANTPLEURALMESOTHELIOMA: CURRENTSTATUS LaurentGreillier Invited speaker THEDIAGNOSTICACCURACYANDREPRODUCIBILITYOF PLEURALFLUIDLEVELSOFMESOTHELININUNSELECTED PATIENTSWITHPLEURALEFFUSIONS H.E.Davies Oral presentation THEUSEOFMESOTHELINFORMONITORINGPATIENTSWITH MESOTHELIOMA JenetteCreaney Oral presentation EARLYCHANGEINSERUMVEGFANDOSTEOPONTINDURING TREATMENTFORMESOTHELIOMAISPREDICTIVEFOR SURVIVAL. RozelleHarvie Oral presentation GENERALDISCUSSION,includingPOSTERDISCUSSION Chairs Lunch Early Diagnosis 23

26 IMMUNOTHERAPY CHAIRS:CourtneyBroaddusandJoostHegmans TIME TITLEABSTRACT TYPE abstract number ONCOLYTICTYPE5ADENOVIRUSESWITHTYPE35FIBERKNOB STRUCTUREPRODUCEBETTERCYTOTOXICEFFECTSTO MESOTHELIOMACELLSTHATEXPRESSTHETYPE5CELLULAR RECEPTORSATALOWLEVEL MasatoshiTagawa Oral presentation IMMUNOLOGICALCHANGESINMESOTHELIOMAPATIENTSAND THEIREXPERIMENTALDETECTION TakemiOtsuki Oral presentation DENDRITICCELLBASEDIMMUNOTHERAPYFORMPM JoachimAerts Oral presentation LOWDOSECYCLOPHOSPHAMIDESYNERGIZESWITHDENDRITIC CELLIMMUNOTHERAPYINANTITUMORALRESPONSESINA MOUSEMODELFORMESOTHELIOMA JoostHegmans Oral presentation T4ASATUMOURASSOCIATEDANTIGENINMPM SalyAlTaei Oral presentation WILMSTUMOR1(WT1)PEPTIDEVACCINECANELICITIMMUNE RESPONSESINPATIENTSWITHMPM AndrewBrown Oral presentation BREAK IMMUNOCHEMOTHERAPYREDUCESRECURRENCEOF MALIGNANTPLEURALMESOTHELIOMA LucaAmpollini Oral presentation THEEFFECTOFCHEMOTHERAPYONTHEIMMUNESYSTEMIN PATIENTSWITHMALIGNANTMESOTHELIOMA MelanieMcCoy Oral presentation MODULATIONOFTRANSLESIONSYNTHESIS:IMPACTON CHEMOTHERAPYRESISTANCEINMPM? PhilipAlexanderKnobel Oral presentation NONSPECIFICACTIVEIMMUNOTHERAPYINCREASEDSURVIVAL INMALIGNANTMESOTHELIOMA MarieMarthePhilippeaux Oral presentation SUMMINGUP Chairs THEEND Immunotherapy 24

27 ASBESTOSVICTIMS:EPIDEMIOLOGY, SURVEILLANCE,COMPENSATIONANDAWARENESS CHAIRS:MachielvanderWoudeandJamesteWaterNaude TIME TITLEABSTRACT TYPE INTRODUCTION Chairs abstract number INTERNATIONALMORTALITYTENDS Peto Invited speaker THELATROBEVALLEYPOWERINDUSTRYCOHORTSTUDY:A MULTIDISCIPLINARYAPPROACHTOSTUDYINGASBESTOS RELATEDDISEASES AnthonyLaMontagne Oral presentation DISCUSSION THEFRENCHNATIONALPROGRAMFORPOSTOCCUPATIONAL SURVEILLANCEOFSUBJECTSEXPOSEDTOASBESTOS PatrickRolland Oral presentation DISCUSSION APUBLICHEALTHCRITIQUEOFSOUTHAFRICAN MESOTHELIOMACOMPENSATION. JamesteWaterNaude Oral presentation DISCUSSION DUTCHASBESTOSVICTIMSINSTITUTE:ASOCIALRESPONSIBLE SOLUTIONFORACOMPLEXHISTORICALPROBLEM BasdeMol Invited speaker DISCUSSION DEADLYDUST:MITIGATINGTHEIMPACTOFASBESTOS THROUGHEDUCATIONANDPREVENTION,EARLYDETECTION ANDINCREASEDFUNDINGFORRESEARCH LindaReinstein Invited speaker DISCUSSION MESOTHELIOMAINJAPANAFTERTHEENACTMENTOF ASBESTOSRELATEDHEALTHDAMAGERELIEFLAW KenjiMorinaga Oral presentation Asbestos Victims 25

28 EPIDEMIOLOGYandCAUSATION CHAIRS:MuzafferMetintasandMicheleCarbone TIME TITLEABSTRACT TYPE abstract number MESOTHELIOMA:CLINICALCHALLENGESTOADDRESSTHE EPIDEMIOLOGYOFTHISCANCERWORLDWIDE MuzafferMetintas Chairperson CRITERIATOESTABLISHCAUSATIONINHUMANCANCERAND MESOTHELIOMA MicheleCarbone Chairperson REVIEWOFTHEPUBLISHEDEPIDEMIOLOGYLINKINGMINERAL FIBERSTOMESOTHELIOMA GunnarHillerdal Invited speaker ROUNDTABLEDISCUSSION: CAUSATION,EPIDEMIOLOGYANDMESOTHELIOMA BREAK ACASECONTROLSTUDYOFMALIGNANTMESOTHELIOMAIN SUBJECTSWITHNOKNOWNEXPOSURETOASBESTOS NicholasdeKlerk Oral presentation ONCONASEINHIBITSMESOTHELIOMACELLSINVASIONINDUCED BYTNFALPHA. HainingYang Oral presentation PLEURALMESOTHELIOMAASASECONDPRIMARYCANCERPOST THERAPEUTICRADIATIONFORHODGKIN'SANDNONHODGKIN S DISEASE DavidSugarbaker Oral presentation APOPULATIONBASEDSTUDYONRADIOTHERAPY(RT)ASARISK FACTORFORMALIGNANTMESOTHELIOMA EnzoMerler Oral presentation MESOTHELIOMADIAGNOSISINQUÉBEC:PATHOLOGY, EPIDEMIOLOGYANDCOMPENSATION. BruceCase Oral presentation WITTENOOM,WOMENANDMESOTHELIOMA AlisonReid Oral presentation FRENCHNATIONALMESOTHELIOMAREGISTRY[MESONAT]:THE CONTRIBUTIONOFPATHOLOGY NolwennLeStang Oral presentation THEFRENCHNATIONALMESOTHELIOMASURVEILLANCE PROGRAM:ESTIMATESOFTHENATIONALMESOTHELIOMA INCIDENCE PERIOD AnabelleGilgSoitIlg Oral presentation INDIVIDUALCOMPARISONOFINCIDENTCASESOFPLEURAL MESOTHELIOMARECORDEDBYTHEFRENCHNATIONAL MESOTHELIOMASURVEILLANCEPROGRAMANDTHERECORDED CAUSEOFDEATHFORESTIMATINGTHENATIONALINCIDENCE AnabelleGilgSoitIlg Oral presentation MESOTHELIOMASURVIVAL:EFFECTSOFMANAGEMENTAND HISTOLOGICALTYPE WilliamMusk Oral presentation 92 Epidemioly and Causation 26

29 SURGERYandMULTIMODALITYTREATMENT CHAIRS:RolfStahelandMasahiroTsuboi TIME TITLEABSTRACT TYPE abstract number 8.00 EVIDENCEBASEDADJUSTMENTSTOPATHOLOGIC STAGINGOFEPITHELIALMPM DavidSugarbaker Oral Presentation MULTIMODALITYTREATMENT MasahiroTsuboi Invitedspeaker RECENTEXPERIENCEWITHAMODIFIEDCLAGETT'S PROCEDUREINPATIENTSWITHEMPYEMAAND BRONCHOPLEURALFISTULAFOLLOWINGEPPFOR MPM JohnPilling Oral Presentation PREOPERATIVESTAGINGBY18FFDGPETCOMPUTED TOMOGRAPHYFUSEDIMAGINGAND MEDIASTINOSCOPYCOMPAREDTOPATHOLOGICAL FINDINGSAFTEREPP JensBennSrensen Oral Presentation DETECTIONOFN2ADENOPATHYBYCERVICAL MEDIASTINOSCOPYIN175CONSECUTIVEPLEURAL MESOTHELIOMAPATIENTS TamaraTilleman Oral Presentation REDUCEDLUNGVOLUMEMEASUREDBYCTPREDICTS UNRESECTABILITYINMESOTHELIOMAPATIENTS AneilMujoomdar Oral Presentation TRIMODALITYTREATMENTFORMPM:THE HEIDELBERGEXPERIENCE HansHoffmann Oral Presentation CYTOREDUCTIVESURGERYANDHYPERTHERMIC INTRAPERITONEALCHEMOTHERAPYINTHE TREATMENTOFDIFFUSEMALIGNANTPERITONEAL MESOTHELIOMA MarcelloDeraco Oral Presentation CLINICALANDPHARMACOLOGICINFORMATION CONTROLLINGACOMPREHENSIVEMANAGEMENTOF DIFFUSEMALIGNANTPERITONEALMESOTHELIOMA PaulSugarbaker Oral Presentation POSTERSUMMARY Chairs Surgery and Multimodality Treatmant 27

30 CHAIRS:JeremySteeleandGaryLee PALLIATIONANDPLEURODESIS TIME TITLEABSTRACT TYPE WELCOMEandINTRODUCTION Chairs abstract number PALLIATIVECAREISSUESSPECIFICFORMESOTHELIOMA JeremySteele Chairperson 103 Palliation and pleurodesis Saturday PROCONDEBATE: SURGICALPLEURODESISISTHEREFERREDMANAGEMENT FORMALIGNANTEFFUSIONSINMESOTHELIOMA PRO LoïcLangLazdunski CON GaryLee NOVELMANAGEMENTAPPROACHFORMALIGNANT EFFUSIONS:TARGETINGFLUIDFORMATION IoannisKalomenidis UNDERSTANDINGTHEPSYCHOLOGICALISSUES;THE NEGLECTEDASPECTOFMESOTHELIOMACARE HelenClayson Invited speaker Chairperson Invited speaker Invited speaker THEEND

31 CHAIRS:RababGaafarandDanielSterman FUTURETRENDS TIME TITLEABSTRACT TYPE INTRODUCTION RababGaafar TARGETINGCD44WITHHYALURONANFORBNCT:ANOVEL STRATEGYFORMALIGNANTPLEURALMESOTHELIOMA ChunmanLee TARGETINGSURVIVALANDCHEMORESISTANCEINMALIGNANT MESOTHELIOMA GiovanniGaudino Chairperson Oral presentation Oral presentation abstract number TARGETINGOFHUMANMESOTHELIOMACELLSAFTER BIFUNCTIONALIZATIONOFTHESURFACEOFAMORPHOUSSILICA SPHERESWITHTETRAETHYLENEGLYCOL(TEG)ANDAN 8.50 ANTIBODYTOMESOTHELIN KaiCheng CHEMOPREVENTIONOFASBESTOSINDUCEDGENETIC 9.05 INSTABILITY MonicaNeri 9.20 FUTURETRENDS:CANADA ChrisLee 9.40 FUTURETRENDS:JAPAN TakashiNakano SUMMINGUP DanielSterman Oral presentation Oral presentation Invited speaker Invited speaker Chairperson BREAK Future Trends 29

32 CHEMOTHERAPY2 CHAIRS:NickVogelzangandJanvanMeerbeeck TIME TITLEABSTRACT TYPE abstract number RESPONSETOINDUCTIONCHEMOTHERAPYISTHE STRONGESTPREDICTOROFSURVIVALINAMULTICENTER U.S.TRIALOFTRIMODALITYTHERAPYFORRESECTABLE MALIGNANTPLEURALMESOTHELIOMA LeeKrug Oral presentation RISKFACTORSFORACUTEKIDNEYINJURY(AKI)INPATIENTS UNDERGOINGEXTRAPLEURALPNEUMONECTOMY AnnetteMizugushi Oral presentation URINARYKIDNEYINJURYMOLECULE1FORTHEEARLY DETECTIONOFKIDNEYINJURYWITHFOLLOWING CYTOREDUCTIVESURGERYANDINTRACAVITARYCISPLATIN LAVAGEFORMESOTHELIOMA SushrutWaikar Oral presentation NEWCHEMOTHERAPEUTICDRUGSINTHETREATMENTOF ADVANCEDMALIGNANTPLEURALMESOTHELIOMAIN EGYPT RababGaafar Oral presentation CISPLATINANDVINORELBINEFIRSTLINECHEMOTHERAPY INNONRESECTABLEMPM. JensBennSrensen Oral presentation PHASEIISTUDYOFSUNITINIBASSECONDLINETHERAPYIN MPM AnnaNowak Oral presentation SUMMINGUP Chairs THEEND Chemotherapy 2 30

33 MOLECULARGENETICS CHAIRS:MarcLadanyiandMarieClaudeJaurand TIME TITLEABSTRACT TYPE abstract number 8.00 INTEGRATEDGENOMICCHARACTERIZATIONOF MESOTHELIOMATUMORSANDCELLLINES MarcLadanyi Chairperson DISCOVERYOFDIFFERENTIALLYEXPRESSEDALTERNATIVE SPLICINGTRANSCRIPTVARIANTSINMPMUSINGNEXT GENERATIONTRANSCRIPTOMESEQUENCING LingshengDong Oral presentation MICRORNAALTERATIONSINMALIGNANTPLEURAL MESOTHELIOMAASBIOMARKERSOFDISEASE BrockChristensen Oral presentation CELLSURFACEPROTEOMICSREVEALSNEWPROTEINMARKERS FORTHEDISCRIMINATIONOFMPMFROMLUNG ADENOCARCINOMA AnnemarieZiegler Poster discussion GENOMEWIDEPROFILEOFMESOTHELIOMAVERSUSPARIETAL PLEURAMAYEXPLAINITSCHEMOANDRADIORESISTANCE ANDINDICATENEWTARGETS OlufDimitriRe Poster discussion REDOXREGULATIONOFFOXM1INMESOTHELIOMA NicholasHeintz Poster discussion DISCUSSION 9.10 IDENTIFICATIONOFDNAMETHYLATIONMARKERSFOR MESOTHELIOMA JaniceGaller Oral presentation ARGININOSUCCINATESYNTHETASEEXPRESSIONANDSURVIVAL OUTCOMEINPATIENTSWITHMALIGNANTMESOTHELIOMA: MOLECULARANALYSISANDTHERAPEUTICIMPLICATIONS BarbaraDelage Oral presentation CHROMOSOMEXQ27HARBORSAMESOTHELIOMA SUSCEPTIBILITYLOCUSASSOCIATEDWITHPATIENTSURVIVAL. HeatherNelson Oral presentation ASSOCIATIONSTUDYOFTHEXRCC1GENEWITHASBESTOS RELATEDMALIGNANTMESOTHELIOMA(MM) MartaBetti Poster discussion POOLEDANALYSISOFNAT2GENOTYPESASRISKFACTORSFOR ASBESTOSRELATEDMALIGNANTMESOTHELIOMA MartaBetti Poster discussion POSTERDISCUSSION Chairs Molecular Genetics 31

34 MOLECULARPATHOLOGY CHAIRS:LucianoMuttiandSakariKnuutila TIME TITLEABSTRACT TYPE abstract number DETECTIONOFCIRCULATINGTUMORCELLS(CTCS)IN MALIGNANTPLEURALMESOTHELIOMA(MPM) FumihiroTanaka Poster discussion CIRCULATINGENDOTHELIALCELLS(CECS)INTHEDIAGNOSIS OFMALIGNANTPLEURALMESOTHELIOMA FumihiroTanaka Poster discussion PROGNOSTICMARKERFORMALIGNANTPLEURAL MESOTHELIOMA AlexandraSchramm Poster discussion THEROLEOFPLEURALEFFUSIONCYTOLOGYINTHE DIAGNOSISOFMALIGNANTMESOTHELIOMAIN2008 FrançoiseGalateauSalle. Oral presentation ROLEOFTHEMESOTHELINCA125INTERACTIONIN MESOTHELIOMA MitchellHo Oral presentation ANOVELMECHANISMOFLATEGENESILENCINGDRIVESSV40 TRANSFORMATIONOFHUMANMESOTHELIALCELLS MicheleCarbone Oral presentation IDENTIFICATIONOFCELLSWITHSTEMCELL/SELFRENEWAL PROPERTIESINMPM. EmanuelaFellyBosco Oral presentation THESV40LARGETANTIGENP53COMPLEXESBINDAND ACTIVATETHEIGF1PROMOTERSTIMULATINGCELLGROWTH MaurizioBocchetta Poster discussion INCREASEDuPAREXPRESSIONANDVIRULENCEOFREN HUMANMPMCELLS. TorryTucker Poster discussion MECHANISMOFANOIKISRESISTANCEINMESOTHELIOMA CELLS. JulienDaubriac Poster discussion GENOMICANDFUNCTIONALPROFILINGOFMALIGNANT MESOTHELIOMA SakariKnuutila Chairperson NOVELMOLECULARTHERAPEUTICALTARGETSFOR MESOTHELIOMA GiovanniGaudino Invited speaker 139 Molecular Pathology 32

35 POSTERS abstract number TITEL presenter 160. VALPROATESYNERGIZESWITHCISPLATINANDPEMETREXEDTOINDUCE APOPTOSISINMALIGNANTPLEURALMESOTHELIOMACELLS FabianVandermeers 161. INHIBITIONOFTRANSLESIONSYNTHESISSENSITIZESMALIGNANTPLEURAL MESOTHELIOMACELLSTOCISPLATINTREATMENT PhilipAlexanderKnobel 162. MULTIMODALITYTREATMENTVERSUSCHEMOTHERAPYINMALIGNANT PLEURALMESOTHELIOMA. GuntuluAk 163. RETREATMENTWITHPEMETREXEDBASEDCHEMOTHERAPYINPATIENTS WITHMALIGNANTPLEURALMESOTHELIOMA(MPM):ANOBSERVATIONAL STUDY. FabioDeVincenzo 164. IMAGINGFINDINGSOFMALIGNANTPLEURALMESOTHELIOMAINJAPAN. KatsuyaKato 165. LOCALIZEDMALIGNANTMESOTHELIOMA.2NEWCASES. AliciaMorresiHauf FDGPET:ANEWPREDICTIVEANDPROGNOSTICTOOLINPATIENTSWITH MALIGNANTPLEURALMESOTHELIOMA. ArnaudScherpereel 167. THORACOSCOPYUSINGNARROWBANDIMAGING(NBI)AND AUTOFLURORESCENCEIMAGING(AFI)SYSTEMSISANOVELMODALITYFOR THEDETECTIONOFEARLYMESOTHELIOMA. TakashiNakano 168. APROGNOSTICINDEXFORPREOPERATIVEEVALUATIONOFPATIENTSWITH RESECTABLEEPITHELIALMESOTHELIOMA. WilliamRichards 169. EFFECTOFAURORAKINASEINHIBITIONINMESOTHELIOMACELLLINES. ShigekiShimizu Posters 33

36 Posters 170. ENZASTAURIN,APROTEINKINASECBETA(PKCβ)INHIBITORIN MALIGNANTPLEURALMESOTHELIOMA. LeonardoFaoro 171. EXTRAPLEURALPNEUMONECTOMYWITHADJUVANTCHEMORADIOTHERAPY FORTREATMENTOFMALIGNANTPLEURALMESOTHELIOMA. AbdelRahman 172. TRIMODALINITIALVIDEOTHORACOSCOPY,INTRAPLEURALCHEMOTHERAPY ANDP32RADIATIONFORLUNGSPARINGTREATMENTOFPLEURAL MESOTHELIOMA:THECOLUMBIAPROTOCOL. RobertTaub 173. IMPROVEDSAFETYWITHEXTRAPLEURALPNEUMONECTOMYINMALIGNANT PLEURALMESOTHELIOMAPERFORMEDATHIGHVOLUMEHOSPITALWITH HIGHVOLUMESURGEONS. JesperBohsenRavn 174. PROGNOSTICFACTORSACCORDINGTOTREATMENTSCHEDULEIN MALIGNANTPLEURALMESOTHELIOMA. GuntuluAk 175. INDUCTIONCHEMOTHERAPYCONSISTINGOFPEMETREXEDPLUSCISPLATIN FOLLOWEDBYEXTRAPLEURALPNEUMONECTOMYFORMALIGNANTPLEURAL MESOTHELIOMA. KazuyaFukuoka 176. MALIGNANTMESOTHELIOMAOFTHEPLEURAINTHEPROVINCEOFTRIESTE, ITALY, ClaudioBianchi 177. GEOGRAPHYOFMESOTHELIOMA.RELIABLEDATA? ClaudioBianchi 178. CLINICALINVESTIGATIONOFMALIGNANTPLEURALMESOTHELIOMA:A NATIONWIDESURVEYOF502DEATHCASESINJAPAN. KenichiGemba 179. IMMUNOHISTOCHEMISTRYINDISTINGUISHINGMALIGNANTMESOTHELIOMA FROMLUNGADENOCARCINOMA:COMPARISONOFNEWMESOTHELIALAND LUNGADENOCARCINOMAMARKERSANDCONVENTIONALMARKERSIN MALIGNANTMESOTHELIOMA. YasufumiKato 34

37 180. CAVEOLIN1ISANOVELIMMUNOHISTOCHEMICALMARKEROFMALIGNANT MESOTHELIOMAANDDIFFERENTIATESEPITHELIOIDMESOTHELIOMAFROM LUNGADENOCARCINOMA. VishwaJeetAmatya 181. IMPACTOFOESTROGENRECEPTORBETAONPROGNOSISOFHUMAN MALIGNANTPLEURALMESOTHELIOMA. GiuliaPinton 182. MESOTHELIOMAPREVENTIONBYANANTIOXIDANTFOODSUPPORTSAN INVOLVEMENTOFREACTIVEOXYGENSPECIESINASBESTOS CARCINOGENESIS. ShuichiAdachi 183. ASBESTOSINDUCEDMURINEMESOTHELIOMAINDIFFERENTGENETIC BACKGROUND. AnnieRenier 184. C.ELEGANSASAMODELSYSTEMTOEVALUATEGENETICALTERATIONSIN MPM,ANDTHEGENETICENVIRONMENTALINTERACTIONS/EFFECTSOF ASBESTOS. SivakumarLoganathan 185. IDENTIFICATIONOFGENESRELEVANTFORTHEDEVELOPMENTOFMURINE MALIGNANTMESOTHELIOMA. ErwinvanMontfort 186. DIETARYVITAMINAORESUPPLEMENTATIONDOESNOTALTERTHERATEOF DEVELOPMENTOFASBESTOSINDUCEDTUMORSINANACCELERATEDMODEL OFMESOTHELIOMA. CleoRobinson 187. ADENOVIRUSMEDIATEDNK4GENETHERAPYFORMALIGNANT MESOTHELIOMA. LiXiao 188. MEASLESVIRUSINDUCESONCOLYSISOFMESOTHELIOMACELLSANDALLOWS DENDRITICCELLSTOCROSSPRIMETUMORSPECIFICCD8RESPONSE. AnneGauvrit 189. CHEMOIMMUNOTHERAPYINMESOTHELIOMA AnnaNowak 190. MALIGNANTMESOTHELIOMAINJAPANINRELATIONSHIPTOASBESTOS EXPOSURE. TakumiKishimoto Posters 35

38 Posters 191. TOTALANTIOXIDANTCAPACITYINASBESTOSRELATEDDISEASESINPEOPLE EXPOSEDTOCROCIDOLITEINWITTENOOM. AlfonsoHelman 192. ASBESTOSFIBERCONCENTRATIONINLUNGTISSUESRESECTEDFOR MALIGNANTPLEURALMESOTHELIOMA. NoriyasuUsami 193. CLINICALOUTCOME,LUNGASBESTOSBURDEN,ANDDISEASEAREPREDICTED BYEPIGENETICPROFILESINPLEURALMESOTHELIOMA. BrockChristensen 194. ANANATOMOPATHOLOGICALSTUDYOFSPONTANEOUSMALIGNANT MESOTELIOMA(MM)INDOMESTICANIMALS.ITSPOSSIBLEUSEFULNESSIN ENVIRONMENTALMONITORINGFORTHEPROTECTIONOFHUMANHEALTH INASBESTOSPOLLUTED. NarcisoMariani 195. HIGHPREVALENCEOFASBESTOSISASSOCIATEDWITHOCCUPATIONAL ASBESTOSEXPOSUREINWESTERNAUSTRALIA. SveinvanOyen 196. PANELOFTUMORMARKERSFORTHEDIAGNOSISOFMALIGNANTPLEURAL MESOTHELIOMA. MasakiAnraku 197. POTENTIALVALUEOFSOLUBLEMESOTHELINRELATEDPROTEININPLEURAL FLUIDFORDIAGNOSISOFMALIGNANTPLEURALMESOTHELIOMA. NobukazuFujimoto 198. SOLUBLEMESOTHELINRELATEDPEPTIDE(SMRP)INPLEURALEFFUSIONFOR THEDIAGNOSISOFMALIGNANTPLEURALMESOTHELIOMA. TakayukiTerada 199. MEASUREMENTOFPLEURALFLUIDOSTEOPONTINLEVELINDIAGNOSISOF MALIGNANTPLEURALMESOTHELIOMA. KeisukeAoe 200. POTENTIALVALUEOFDNAMETHYLATIONPROFILEINPLEURALFLUIDFOR DIFFERENTIALDIAGNOSISOFMALIGNANTPLEURALMESOTHELIOMAAND ADENOCARCINOMAOFTHELUNG. MasanoriFuji 201. MESOTHELIOMABIOMARKERSINPLEURALEFFUSIONS. KarolaCsürös 36

39 202. REFOCUSINGONTHEHYALURONICACIDCONCENTRATIONINTHEEFFUSION OFMALIGNANTPLEURALMESOTHELIOMA;AROUTINESCREENINGTESTFOR THEEPITHELIALTYPE. HirotaroMiura 203. SERUMMESOTHELINVARIATIONSINPATIENTSWITHADVANCED MALIGNANTPLEURALMESOTHELIOMA(MPM)TREATEDWITH CHEMOTHERAPY:PRELIMINARYRESULTS. ManlioMencoboni 204. SOLUBLEMESOTHELINRELATEDPROTEINANDRENALFAILURE:ACAVEAT. KevinHollevoet 205. PLASMATICOSTEOPONTININSUBJECTSEXPOSEDTOASBESTOSFIBERSAND PATIENTSWITHMALIGNANTMESOTHELIOMA(MME). R.Foddis 206. DIFFERENTIATEMPMFROMOTHERCAUSESUSINGTUMORMARKERS. MichelvandenHeuvel 207. APHARMACOKINETICSTUDYOFPEMETREXEDADMINISTERED INTRAPLEURALLYINANANIMALMODEL. LaurentGreillier 208. VALIDATIONOFTHEBIOMARKERSOSTEOPONTINANDMESOTHELININA MULTICENTERPROSPECTIVETRIAL PRELIMINARYRESULTSOFANONGOING STUDY. HendrikMüllerBerndorff 209. DOWNREGULATIONOFCHEMOKINERECEPTORCXCR3INPERIPHERALT LYMPHOCYTESFROMPATIENTSWITHASBESTOSRELATEDDISEASE. MegumiMaeda 210. IMPAIRMENTINCYTOTOXICITYANDEXPRESSIONOFNKCELLACTIVATING RECEPTORSONHUMANNKCELLSCAUSEDBYEXPOSURETOASBESTOS FIBERS. YasumitsuNishimura 211. ESTABLISHMENTANDCHARACTERIZATIONOFNEWMALIGNANTPLEURAL MESOTHELIOMACELLLINESFROMJAPANESEPATIENTS. TetsuoTaniguchi 212. GENETICALTERATIONSSPECIFICFORMALIGNANTMESOTHELIOMACELLS. KozoKuribayashi Posters 37

40 Posters 213. CELLSURFACEPROTEOMICSREVEALSNEWPROTEINMARKERSFORTHE DISCRIMINATIONOFMALIGNANTPLEURALMESOTHELIOMAFROMLUNG ADENOCARCINOMA. AnnemarieZiegler 214. SELENITEINDUCEDAPOPTOSISSIGNALLINGINDIFFERENTIALLYSENSITIVE MESOTHELIOMACELLLINES. GustavNilsonne 215. ABERRANTSPLICINGANDPROTEASESINVOLVEMENTINMESOTHELIN RELEASEFROMEPITHELIOIDMESOTHELIOMACELLS. CaroleSapedePeroz 216. D240UTILITYFORDIFFERENTIALDIAGNOSISBETWEENPLEURAL SARCOMATOIDMESOTHELIOMAANDLUNGSARCOMATOIDCARCINOMA. YukioTakeshima 217. ANALYSISOFEGFR,PDGFRA,PDGFRBANDRELATEDPATHWAYSIN MALIGNANTPERITONEALMESOTHELIOMAS. FedericaPerrone 218. NOVELSYNTHETICINHIBITORSOFTHEmTORPATHWAYINMALIGNANT MESOTHELIOMA. SaraBusacca 219. OURSURGICALTECHNIQUESOFEXTRAPLEURALPNEUMONECTOMYFOR DIFFUSEMALIGNANTPLEURALMESOTHELIOMA. KazunoriOkabe 220. EARLYDETECTIONOFMALIGNANTPLEURALMESOTHELIOMA. KenzoHiroshima 221. RESULTSOFSURGICALTREATMENTASPARTOFMULTIMODALITY TREATMENTFORMALIGNANTPLEURALMESOTHELIOMA. HoukeKlomp TARGETINGOFSIGNALINGPATHWAYSTHATAREFREQUENTLYIMPLICATED INMALIGNANTMESOTHELIOMA. DeborahAltomare 223. APHASEIII,RANDOMIZED,DOUBLEBLIND,PLACEBOCONTROLLEDTRIALOF VORINOSTATINPATIENTSWITHADVANCEDMALIGNANTPLEURAL MESOTHELIOMA(MPM)PREVIOUSLYTREATEDWITHSYSTEMIC CHEMOTHERAPY. LeeKrug 38

41 224. COMBINEDMODALITYTREATMENTFORMALIGNANTPLEURAL MESOTHELIOMA(MPM). PhilippeNafteux 225. THEINSULINLIKEGROWTHFACTOR(IGF1)PATHWAYINFLUENCES PROLIFERATIONOFSTEMCELLSDERIVEDFROMHUMANMALIGNANT MESOTHELIOMACELLLINES. YongbaekKim 226. SEVERECOMPLICATIONAFTERCYTOREDUCTIVESURGERYAND HYPERTHERMICINTRAPERITONEALCHEMOTHERAPYISAMARKEROFPOOR PROGNOSISINDIFFUSEMALIGNANTPERITONEALMESOTHELIOMA. MarcelloDeraco 227. SIMIANVIRUS40ASAPROGNOSTICFACTORINMALIGNANTPLEURAL MESOTHELIOMA. AbdelRahmanZekri 228. CTDETERMINEDTUMORVOLUMEPREDICTSSURVIVALINEPITHELIALMPM FOLLOWINGEXTRAPLEURALPNEUMONECTOMY. HirotoHatabu 229. MicroRNAMICROARRAYANALYSISOFMALIGNANTMESOTHELIOMA. MohamedGuled Posters 39

42 ABSTRACTS Number:1 Abstracttitle: Internationalmortalitytrends JulianPeto(1),ChristineRake(2),ClareGilham(2),AndrewDarnton(3),JohnHodgson(3) (1)LondonSchoolofHygieneandTropicalMedicine,UK;(2)InstituteofCancerResearch,London,UK; (3)UKHealthandSafetyExecutive Keywords: UK,Australia,mesothelioma,amosite,casecontrol Abstractcontent: By1970theUKhadstoppedusingcrocidoliteandledtheworldinasbestosregulation,yetitnowhas over2,000mesotheliomadeathsperyear,thehighestrateintheworldandfivetimesthatintheus inmenbornbetween1940and1955. WeconductedthefirstUKpopulationbasedstudyofmesotheliomaandthelargestworldwide, interviewing612mesotheliomapatientsand1420controls.wealsocompareddeathrates,asbestos importsandmale:femalemortalityratiosofmesotheliomainothercountriestoassessthe contributionofdifferentasbestostypesonmesotheliomaratesandtoestimatethebackgroundrate intheabsenceofasbestosuse. Ourmainconclusionisthatenduserexposuretoamositewasamajorcauseoftheextraordinary mesotheliomarateinbritishmenborninthe1940s.theukwasthemainimporterofamosite, whichcarriedthesamecontrollimitaschrysotileuntil1983.currentmesotheliomamortalityand historicalpatternsofamositeuseinaustraliaaresimilartothoseintheuk. Otherfindingsinclude:(1)about1in17ofBritishcarpentersand1in50ofplumbers,electricians andpaintersbornbetween1940and1950willdieofmesothelioma;(2)onlyabout1%of mesotheliomaswerecausedbyworkinasbestosfactories;(3)thereappearstobeaworldwide backgroundrateunrelatedtoasbestosproducingalifetimeriskofapproximately1per5,000inboth sexes;(4)theexcessrateabovethisbackgroundinwomenthroughouttheworldisapproximately onetenthofthemalerate;and(5)thelifetimeriskinbritishmenandwomenwhoreportno potentialasbestosexposureisfourtimesthisbackground(almost1per1,000),suggestingthat mesotheliomaswerecausedbyunsuspectedasbestosexposureinawiderangeofoccupationaland nonoccupationalsettings. 40

43 ABSTRACTS Number:3 Abstracttitle: Mesotheliomamousemodels:readyfortestinginterventionstrategies? AntonBerns NetherlandsCancerInstitute,Amsterdam,theNetherlands Abstractcontent: MalignantMesothelioma(MM)isadevastatingdiseasewithpoorprognosisduetoitsrefractoriness tochemotherapy.therefore,thereisanurgentneedformodelsystemsthatcloselymimichuman malignantmesotheliomainwhichnewtherapeuticinterventionscanbeexplored.wehave generatedmousemodelsthatfulfillthisrequirementbythe(conditional)inactivationofconbination ofgenesactinginpathwaysthatarealsofrequentlydisruptedinhumanmesothelioma.these includethenf2tumorsuppressorgene,p19arfandink4a/b.thelatter2actintherbandp53 pathway,respectively.wehavegeneratedsingleandcompound(conditional)knockoutsofthese genesinthemesothelialliningofthethoraciccavityofmicebyinfectionwithadenocrevirusesand monitoredthedevelopmentofmesotheliomas.murinemmdevelopedinaveryhighpercentageof compoundnf2f/f;p53f/f,nf2f/f;ink4aarff/fandink4a;ink4b;p19arfmutantmicewitharelatively shortlatencyperiod,whereassingleknockoutswererefractorytomesotheliomadevelopment.loss ofink4aincombinationwithlossofnf2andp53resultedinoverallmoreinvasivetumorssuggesting thatbesideslossofnf2alsolossofink4amightaugmentinvasivedisease.wehavederivedcelllines andestablishedconditionsinwhichthesemodelscanbeefficientlyusedfortestingintervention strategiesusingcytotoxicdrugsandtargetedtherapies.inspiteofthegeneticuniformityofthese models,tumorcelllinesshowedasignificantvariationinresponsetothevariousdrugs.theutilityof thesemodelsfordesigningnewinterventionstudieswillbediscussed. 41

44 ABSTRACTS Number:5 Abstracttitle: India'sAsbestosTimeBomb LaurieKazanAllen IBAS,UK Keywords: India,asbestos,illness,politics,ban Abstractcontent: India'sAsbestosTimeBomb Historicallytheburdenofindustrialpollutionhasreachedthedevelopingworldmuchfasterthan thefruitsofindustrialgrowth, writesdr.sanjaychaturvedi.thisstatementiswellillustratedbythe evolutionoftheasbestosindustryinindia.inthefranticrushforeconomicdevelopment,therehas beenapervasivelackofconcernforthehealthofworkersandthecontaminationofthe environment.sacrificingthelivesofthefewforthe good ofthemany,theindiangovernmenthas knowinglycolludedinthissadstateofaffairs. \"Itcannotbedisputedthatnodevelopmentispossiblewithoutsomeadverseeffectontheecology andenvironment Thecomparativehardshipshavetobebalancedandtheconvenienceandbenefit toalargersectionofthepeoplehastogetprimacyovercomparativelylesserhardship.\" CumulativeasbestosconsumptioninIndiabetween wasinexcessof7milliontonnes.As thereisnosafelevelofexposuretoasbestosandasevenminimalprecautionshavebeenlacking, phenomenalnumbersofworkershavereceivedhazardousexposures.inindia,neithermesothelioma norasbestosrelatedlungcancerarerecognized.althoughtherearesomeregionalcancerregistries, cancerisnotanotifiablediseaseinindia;agrandtotalof56mesotheliomaswererecordedduring NationalandstategovernmentsinIndiamaintainastonysilenceonthecollateral damagecausedbythewidespreaduseofasbestos;virtuallynothinghasbeendonetoquantifythe effectsofenvironmentalpollutioninthewidercommunity. ThispaperwillexplorethestateofIndia sasbestosmarkets,thepoliticalfavouritismtheindustry enjoys,theconsequencesofhazardousexposuretoworkers,thepublicandtheenvironmentandthe attemptsbygrassrootsactiviststosupporttheasbestosinjuredandimpactonthenationalasbestos debate. 42

45 ABSTRACTS Number:6 Abstracttitle: GuidelinesforthemanagementofMalignantPleuralMesotheliomafromthe ERS/ESTS Taskforce ArnaudScherpereel UniversityofLilleII,France Keywords: mesothelioma,guidelines,management,european,taskforce Abstractcontent: Previouslyconsideredasararetumorwithapoorsurvival,malignantpleuralmesothelioma(MPM) hasbecomeaveryimportantpublichealthissue.mpmincidenceisexpectedtocontinuetoincrease foratleastthenexttenyears,linkedtopreviousasbestosexposure,themainetiologicfactorof MPM.BetweenSeptember2007andJune2008,theEuropeanRespiratorySociety(ERS)andthe EuropeanSocietyofThoracicSurgeons(ESTS)broughttogetherexpertsonmesotheliomatodrawup recommendationsinordertoprovideclinicianswithclear,concise,uptodateguidelineson managementofmpm. ToobtainanearlierandreliablediagnosisofMPMisacrucialissue.Werecommend,exceptincase ofpreoperativecontraindicationorpleuralsymphysis,toperformthoracoscopyforthediagnosisof MPM.StandardstainingproceduresinPathologyareinsufficientin715%ofcases.Thereforewe proposeasetofotherstainingmethodsandimmunologicalmarkersandprefermultiplehistological biopsies.staging:intheabsenceofauniform,robustandvalidatedstagingsystem,weadvicetouse ofthemostrecenttnmbasedclassification,andweproposeathreestepspretreatment assessment.monitoring:performancestatusofthepatientandhistopathologicalsubtypeare currentlytheonlyprognosticfactorsofclinicalimportanceinmanagementofmpm.otherpotential prognosticparametersshouldberecordedatbaselineandreportedinclinicaltrials.treatment: MPMexhibitsahighresistancetochemotherapy;andonlyfewpatientsarecandidateforradical surgery.newtherapeutictoolsorstrategiessuchastargetedtherapies,geneorcelltherapies,and multimodaltreatmenthavebeenreviewedandcommented.becauseoflimiteddataavailableonthe bestcombinationtreatment,weemphasizethatpatientswhoareconsideredcandidatesfora multimodalapproachshouldbeincludedinaprospectivetrialinspecializedcenters.thehighlights oftheers/estsguidelineswillbepresentedduringthemeeting. 43

46 ABSTRACTS Number:8 Abstracttitle: InVitroExtremeChemotherapyResistanceAssayConfirmsUtilityofCisplatinintheTreatmentof MalignantPleuralMesothelioma AneilA.Mujoomdar,MD,TamaraR.Tilleman,MD,PhD,WilliamG.Richards,PhD,RaphaelBueno, MD,DavidJ.Sugarbaker,MD ThoracicSurgery,BrighamandWomen'sHospital,Boston,MA,USA Keywords: ExtremeDrugResistance,Chemotherapy,cisplatin,chemoresistance Abstractcontent: Objective:Inclinicaltrials,cisplatinhasbeenshowntobethemosteffectivesingeagent chemotherapyagentinthetreatmentofmalignantpleuralmesothelioma(mpm).theincidenceof invitrodrugresistancetocisplatin,gemcitabine,orvinorelbineintumorsinpatientswithmpmwas prospectivelyevaluated. Methods:ExtremeDrugResistanceAssays(EDR Assay,Oncotech,Tustin,California)were performedonspecimensfrom126patientsfromjanuary2006untilmay2008.freshtumor specimensintransportsolutionwerecourieredovernighttotheoncotechlaboratoriesintustin, California.Tumorcellswereplatedonagardishesandspecificchemotherapeuticagentsadded. Tritiatedthymidinewasusedtomeasurecellproliferation.Treatedcellswerecomparedto untreatedcontrols.assayresultsaredividedintothreecategories.extremedrugresistanceis definedastumorcellgrowthgreaterthanonestandarddeviationabovethemedian.intermediate drugresistanceisdefinedastumorcellgrowthabovethemedianbutlessthanonestandard deviation.lowdrugresistanceisdefinedastumorcellgrowthlessthanthemedian.drugresistance tocisplatin,gemcitabine,andvinorelbinewascharacterized. Results:TheEDR Assaywasperformedon126MPMtumorspecimensfrom85extrapleural pneumonectomies,27pleurectomies,11thoracotomies,and3chestwallresections.seventyeight (62%)wereepitheliodtypeand30(24%)hadreceivedchemotherapypriortotheassay.Assay resultswereavailablefor105specimens(83%);21hadnoassayresultduetoinsufficienttumor growth.edrtocisplatinwasfoundin11%,gemcitabinein18%andnavelbine30%.idrtocisplatin wasfoundin17%,gemcitabinein15%andnavelbinein31%.ldrtocisplatinwasfoundin72%, gemcitabinein66%andnavelbinein38%.inthosepatientswhohadreceivedchemotherapy, incidenceofedrtocisplatinwas22%versus8%inthosepatientswhohadnot. Conclusions:Aninvitroassessmentoftumorchemoresistancecanbeperformedonamajorityof mesotheliomatumorspecimens.cisplatinhadthelowestincidenceofedrcomparedto gemcitabineandvinorelbine.chemotherapynaïvepatientsalsohadalowerincidenceofedrto cisplatin.correlationwithsurvivalwillberequiredinordertovalidatetheprognosticsignificance. 44

47 ABSTRACTS Number:9 Abstracttitle: Inhibitionoftranslesionsynthesissensitizesmalignantpleuralmesotheliomacellstocisplatin treatment PhilipAlexanderKnobel,EmanuelaFelleyBosco,StefanieKurtz,AlexandraGraf,RolfArnoStahel, ThomasMichaelMarti UniversityHospitalZuerich,Switzerland Keywords: translesionsynthesis,rev3,malignantpleuralmesothelioma,sirna,shrna,cisplatin Abstractcontent: Background: Malignantpleuralmesothelioma(MPM)ismostcommonlytreatedwithamultimodalitytherapy includingtreatmentwithcisplatinorcisplatinanalogues,whichleadtotheformationofinteror intrastranddnaadducts.cisplatinadductscanberepairedor,ifnotrepaired,inducereplicationfork stallingwhichcanbyovercomebyspecifictranslesionpolymerases. Translesionpolymeraseζconsistsoftwosubunits,Rev3isthecatalyticandRev7the structuralsubunit.thetranslesionpolymeraseζisresponsibleforthetranslesionsynthesis (TLS)ofcisplatinbasedadductsandtherepairofDNAinterstrandcrosslinks.Rev3deficient vertebratecelllinesshowthehighestsensitivitytocisplatincomparedtootherrepairdeficientcell lines.rev3inhibitionbyantisensetreatmentconfershighercisplatinsensitivityandlower mutagenicityinimmortalhumanfibroblasts. Workinghypothesis: DownregulationofRev3sensitizesMPMcellstocisplatintreatmentandreducestheformationof cisplatinresistance. Results: WeshowedthattheexpressionofRev3inhumanMPMcellsisdependentoncellcultureconfluency andisalsoaffectedbycisplatintreatmentinatimedependentmanner.functionalinhibitionofrev3 bysirnaincreasedreplicationforkbreakdownasindicatedbyenhancedh2axphosphorylation. REV3expressioninratandhumanMPMcellswassuccessfullyinhibitedbytransienttransfection withplasmidscontainingshorthairpinconstructstargetingrev3. WegeneratedstableHEK293andhumanlungfibroblast(Wi38SV40)celllineswithdecreasedREV3 expression.functionalinhibitionofrev3inthehek293andwi38sv40celllinesresultedin increasedgenotoxicstressasindicatedbyincreasedp53expression,aslowergrowthrateand increasedcisplatinsensitivity. Conclusions: WeshowedthatfunctionalinhibitionoftranslesionpolymeraseζbyshRNAagainstREV3 increasedreplicativestressinmpmcelllinesandincreasedcisplatinsensitivityinhumancells. 45

48 ABSTRACTS Number:10 Abstracttitle: NGRhTNF,anovelvasculartargetingagent(VTA),assecondlinetherapyinmalignantpleural mesothelioma(mpm):preliminaryresultsofamulticenterphaseiitrial. PaoloA.Zucali(1),VanesaGregorc(2),GiovanniL.Ceresoli(1),CristinaNoberasco(3),EmilioBajetta (4),Armando Santoro(1),MariaG.Viganò(2),FedericoCaligarisCappio(2),AntonioLambiase (5),ClaudioBordignon(5) (1)IstitutoClinicoHumanitas,Rozzano,Italy,(2)IstitutoScientificoSanRaffaele,Milan,Italy(3) IstitutoEuropeodiOncologia,Milan,Italy,(4)IRCCSFondazioneIstitutoNazionaledeiTumori,Milan, Italy,(5)MolMed,Milan,Italy Keywords: NGRhTNF,VascularTargetingAgent,Secondlinetherapy Abstractcontent: Background:NGRhTNFisaVTAexploitingatumorhomingpeptide(NGR)thatselectivelybindsto aminopeptidasen/cd13highlyexpressedontumorbloodvessels.ngrhtnfcombinesactivityon tumourvascularpermeabilityanddirectanticanceractivity. Methods:Patients(pts)withadvancedMPMweretreatedwithlowdoseNGRhTNFgivenat0.8 μg/sqmas1hourintravenousinfusionevery3weeks(q3w).thisdosewaspreviouslyselectedina phaseitrialbasedondynamicimagingchangesandpreliminaryclinicalactivity.thetrialhada2 stagedesignwith16and27ptstobeenrolled.progressionfreesurvival(pfs)wastheprimary endpointwithrestagingperformedq6waccordingtompmmodifiedrecistcriteria. Results:FromMay2007toJanuary2008,fortythreeptswithdocumentedprogressivediseaseafter pemetrexed/platinumbasedregimenswereenrolled.globally,41ptsreceived151cycles(median, 2;range,116).Ptscharacteristicswere:medianage64years(range,3480);M/F27/14;histology epithelial/nonepithelial(e/ne)32/9;ps0/1/224/10/7;eortcprognosticscore(eps)good/poor 32/9.Todate,5pts(12%)remainontreatment(range,4.6to11.7months).18pts(44%;95%CI,30 59%)hadstabledisease(SD)asbestresponse.Medianand3monthPFSwere2.8months(95%CI, )and43%(95%CI,2659%),respectively.Inanexploratoryanalysis,therewerenodifferences inpfsbetweenptswithgood/pooreps,e/nehistology,ps01/2andage</ 70years.Forpts achievingsdattheirfirstrestaging(n=18),themedianand6monthpfswere5monthsand44%, respectively.pfsdurationsof11.7and9.5monthswereobservedina70yearoldmaleptwithps2 andinachemorefractorymaleptwithbiphasichistology,respectively.withamedianfollowupof 6.1months(95%CI,5.36.8),31pts(76%)arestillalive.Neithergrade4treatmentrelatedadverse eventsnortoxicityrelateddeathwereobserved.mostcommongrade12toxicitiesperpatientwere transientinfusionrelatedsymptoms,includingchills(63%)andfatigue(24%).currently,an additionalcohortof12ptsistreatedwithaweeklyschedule. Conclusion:NGRhTNFiswelltoleratedandshowsevidenceofdiseasecontrolinchemopretreated MPMpatients.ThedrugwillbefurtherdevelopedinadvancedMPM. 46

49 ABSTRACTS Number:11 Abstracttitle: PHASEIISTUDYOFTHECOMBINATIONOFBEVACIZUMABPLUSPEMETREXEDANDCARBOPLATINAS FIRSTLINETHERAPYINPATIENTSWITHMALIGNANTPLEURALMESOTHELIOMA(MPM) GiovanniLucaCeresoli,PaoloAndreaZucali,FabioDeVincenzo,ManlioMencoboni,Francesco Grossi,MatteoSimonelli,LetiziaGianoncelli,InnaTimofeeva,ArturoChiti,ArmandoSantoro IstitutoClinicoHumanitas,Rozzano(Milan),Italy Keywords: chemotherapy,bevacizumab,pemetrexed,carboplatin Abstractcontent: Background:Thecombinationofpemetrexedandcarboplatinwasfoundtobeactiveandwell toleratedinmpmpatients(pts)inphaseiitrials.vascularendothelialgrowthfactor(vegf)ishighly expressedinmpm;inpreclinicalmodels,antivegfantibodieswereshowntodecreasempmcells growth.thehumanizedantivegfmonoclonalantibodybevacizumabhasshownasynergisticeffect whencombinedwithanumberofchemotherapeutics.aimofthistrialistoassesstheactivityof bevacizumabincombinationwithpemetrexedandcarboplatin(bpcregimen)asfirstlinetherapyin MPMpts. PatientsandMethods:Chemotherapynaiveptswithmeasurablediseaseandadequateorgan function,notcandidatesforcurativesurgery,areeligibletoreceivepemetrexed500mg/m2and carboplatinareaundertheplasmaconcentrationtimecurveof5mg/ml/min,followedby bevacizumab15mg/kg,administeredintravenouslyevery21days.allpatientsreceivefolicacidand vitaminb12supplementation.mainendpointofthestudyistimetodiseaseprogression.responseis evaluatedaccordingtomodifiedrecistcriteria. Results:Thisongoing,multicenter,openlabelphaseIIstudywasdesignedtoincludeupto77pts. UntilMay2008,19ptshavebeenenrolled,anddataof16areavailableforapreliminaryanalysis.Pts characteristicsare:m/f11/5,medianage68yrs(range4777),eortcprognosticscoregood/poor 5/11.Histologywasepithelialinallpts.Apartialresponsewasachievedin6patients,foraresponse rateof37.5%.tenpatientshadstabledisease.withamedianfollowupof6months(range18 months)6ptshaddiseaseprogression;theothersarestillontreatment.noseverehematologicalor nonhematologicaltoxicitywasobserved,exceptforonecaseofbowelperforationpossiblyrelated totreatment.amild,asymptomaticproteinuriawasobservedin6pts.grade2anemiaandfatigue wereregisteredin3and4pts,respectively. Conclusion:FirstlinetreatmentwithBPCregimeninMPMptsseemsfeasible,withacceptable toxicity.bevacizumabrelatedadverseeffectsshouldbestrictlymonitored.inspiteofthelimited numberofenrolledptsandtheshortfollowuptime,preliminaryactivityresultsarepromising.the studyisongoingandupdatedresultswillbepresentedatthismeeting. 47

50 ABSTRACTS Number:14 Abstracttitle: Hyperthermiaandradiotherapyinmalignantpleuralmesothelioma:rationale,techniqueand clinicalresults. CobivanderZee,DanieldenHoed(1) ErasmusMC,(1)CancerCentre,Dept.RadiationOncology,HyperthermiaUnit,Rotterdam,theNetherlands. Symptomaticrecurrencesofmalignantmesotheliomaareoftenpainfulandcouldcausemechanical obstruction.althoughforinterventionsiterecurrencesradiotherapy(rt)isthemosteffective treatment,bothobjectiveandsubjectiveresponseratesaredisappointing.inanattempttoimprove theresultsofradiotherapy,weexploredthecombinationofradiotherapyandhyperthermia(ht)in thesepatients.ht,anincreaseintissuetemperatureto4045 Cforsometimehasatumourspecific cellkillingeffectcomplementarytothatofrt,andisastrongradiosensitiser.tissueheatingcanbe achievedbymicrowaveradiation. Theoutcomein18patientstreatedbyRTincombinationwithHTwascomparedtothatina historicalcontrolgroupof24patientstreatedwithrtalone.theresultsareshowninthetable.all patientspresentedwithapainfulchestwalltumour,hadaperformancestatusofecog2,and weretreatedwitha4gyperfractionscheme,3fractionsweekly,totatotaldoseofmedian40gy. HTwasappliedonceweeklyduringtheperiodofRT.Therelativelylargenumberofpatientswith unknownoutcomereflectsthepoorshorttermsurvivalofthispatientpopulation. RT+HT RTalone Reductioninpain Yes None Unknown Recurrenceofpain(inresponders) None WithinRTfield OutsideRTfield Unknown

51 Tumourresponse Completeresponse Partialresponse(>50%) Nochange Progressivedisease Unknown Tumourprogression(afterinitialresponse) WithinRTfield OutsideRTfield Unknown Nopatientdeveloped>grade2toxicity(RTOG/EORTCradiationmorbidityscore).Thecomparison suggeststhattheadditionofhtimprovedpaincontrol(94vs59%)andobjectivetumourresponse (100vs54%).Furthertheoccurrenceofsubjective(pain)orobjective(tumour)progressionwithin thertfieldwaslessfrequentinthecombinedmodalitygroup. Inourinstitute,thecombinationofRTandHTisthereforeofferedaspalliativetreatmenttothose patientsinarelativelygoodconditionwithasymptomaticrecurrenceataninterventionsite. 49

52 ABSTRACTS Number:16 Abstracttitle: EXTRAPLEURALPNEUMONECTOMY(EPP)ANDHEMITHORACICRADIATIONTHERAPY(RT)FOR MALIGNANTPLEURALMESOTHELIOMA(MPM) KennethRosenzweig,BenjaminLaser,RajaFlores,LeeKrug,ValerieRusch. MemorialSloanKetteringCancerCenter Keywords: hemithoracicradiotherapy Abstractcontent: Purpose:ThetreatmentofMPMremainsatherapeuticchallenge.EvenafterresectionwithEPP thereisalargeriskoftumorrecurrence.wehavethereforetreatedpatientswithpostoperative hemithoracicrtinanefforttoimprovelocalcontrol.thepurposeofthisstudyistoevaluatethe effectivenessofeppandrtforthetreatmentofmpm. Methods:Between1994and2006,89patientswithMPMweretreatedwithEPPfollowedby hemithoracicradiationtherapy.eppwasdefinedasenblocresectionoftheentirepleura,lung,and diaphragm,withorwithoutresectionofthepericardium.theradiationtherapytargetvolumewas theentirehemithorax,includingthepleuralfoldsandthethoracotomyandchesttubeincisionsites. Results:Atotalof89patientsunderwentRTafterEPP.Patientcharacteristicswere:age(median61 years),sex(male74%),laterality(rightsideddisease52%),histology(epithelialin71%andmixedor sarcomatoid29%),stage(i:7%,ii:35%,iii:55%,iv:3%).mediandosewas5400cgy(range2160cgy 5400cGy).Themedianfollowupwas13months(range,099)and28monthsinsurvivors(range,2 99months).Themedianoverallsurvivalwas17.4months.The2yearand5yearoverallsurvivalwas 36%and14%respectively.The2yearand5yearlocalcontrolwas59%and41%respectively.On multivariateanalysisonlytotaldosewassignificantforimprovementinlocalcontrol(p=0.004). Grade2orworsetoxicitywas:esophagitis(25%),pneumonitis(8%),dyspnea(22%),arrythmia(2%), pericarditis(1%),nausea(44%),vomiting(28%),fatigue(47%). Conclusions:Extrapleuralpneumonectomyfollowedbyhemithoracicradiationtherapyistolerable andhasfavorablesurvivalandlocalcontrolinthisaggressivedisease.higherdosesofradiation therapyappeartoimprovelocalcontrol 50

53 ABSTRACTS Number:17 Abstracttitle: PleuralIntensityModulatedRadiationTherapyinPatientswithMalignantPleuralMesothlioma KennethRosenzweig,BenjaminLaser,LeeKrug,EllenYorke,EmilyLevin,ValerieRusch MemorialSloanKetteringCancerCenter,USA Keywords: radiationtherapy,imrt,unrectable Abstractcontent: Purpose:Inpatientswithmalignantpleuralmesothelioma(MPM)whoareunabletoundergoa pneumonectomy,itisdifficulttodelivertumoricidaldosestothepleurawithoutsignificanttoxicity. Wehaveimplementedatechniqueofusingintensitymodulatedradiotherapy(IMRT)totreatthese patients.thisreportassessesthefeasibilityandtoxicityoftreatingpatientswithmpmusingpleural IMRTinpatientswhohavenothadapneumonectomy. MethodsandMaterials:Between2005and2008,18patientswithMPMweretreatedwithpleural IMRTtothehemithoraxwithoutpneumonectomy(mediandose:50.4Gy,range:4550.4Gy)at MemorialSloanKetteringCancerCenter. Results:Patientcharacteristicswere:rightsided(61%),histology(epithelial 72%,sarcomatoid 11%,mixed 16%),stage(I 11%,II 33%,III 22%,IV 33%).Fifteenpatients(83%)received inductionchemotherapy(mostlycisplatinandpemetrexed).surgerywas:pleurectomy/decortication 8patients(44%),pleurectomyalone 2patients(11%),unresectable 8patients(44%).Ofthe18 patients,therewere2casesofacutegrade3dyspnearequiringsteroidsoroxygenand1caseof acutegrade3fatigue.therewerenocasesofacutegrade4or5toxicity.ofthe12patientswith adequatefollowuptoassesslatetoxicity,therewasonecaseofcontinuinggrade3dyspnea.witha medianfollowupof9months,the1yearand2yearoverallsurvivalrateswere92%and52% respectivelywithamedianoverallsurvivalof25.7months.therewasnodifferenceinsurvival betweenpatientsundergoingsurgery(pleurectomy/decorticationorpleurectomyonly)versus patientswithunresectabledisease(p=0.56). Conclusions:TreatingtheintactlungwithpleuralIMRTinpatientswithMPMisasafeandfeasible treatmentoptiontoadoseof50.4gy.wehaveinitiatedaphaseiitrialofinductionchemotherapy withpemetrexedandcisplatinfollowedbypleuralimrtinpatientswithunresectabledisease. 51

54 ABSTRACTS Number:18 Abstracttitle: AdjuvanthemithoracicradiotherapyfollowingEPPforMPMimproveslocalcontrol JohnCho(1),MarcdePerrot(2),AndreaBezjak(1),AnthonyBrade(1),GabrielleKane(1),AlexSun (1) (1)PrincessMargaretHospital,(2)TorontoGeneralHosptial Keywords: mesothelioma;radiotherapy;extrapleuralpneumonectomy;localcontrol Abstractcontent: Objective:Toexaminetheoutcomeofaggressivemultimodalitytherapyformalignantpleural mesotheliomaandtheimpactofadjuvanthemithoracicradiotherapy(rt)followingextrapleural pneumonectomy(epp). Methods:Wereviewed50consecutivepatientsundergoingextrapleuralpneumonectomyfor malignantpleuralmesotheliomainourinstitutionbetweenjanuary1993andmarch2005.epp consistedofenblocremovaloftheparietalpleuraandlungwithexcisionoftheipsilateral hemidiaphragmandpericardium.inductionchemotherapy,ifgiven,consistedof2to3cyclesof platinumbasedregimens.adjuvanthemithoracicrtwasgivento29patientsandconsistedof5054 Gyin2530fractions. Results:Themediansurvivalwas11months,witha3yearsurvivalof24%.Patientsex,histologiccell type,stage,andn2diseasehadsignificantimpactsonsurvivalaccordingtounivariateanalysis.ina multivariateanalysis,however,onlythepresenceofn2diseaseremainedasignificantpredictorof mortality.thepresenceofn2diseasehadnoimpactonthesiteofrecurrence.adjuvant hemithoracicrtsignificantlydecreasedtheriskoflocoregionalrecurrenceto7%(2/29)(p=0.01)but didnotinfluencesurvival.patientsmanagedwitheppwithoutrthadalocoregionalfailurerateof 38%(8/21). Conclusions:Aggressivetrimodalitytherapyisfeasibleinselectedpatientwithmalignantpleural mesothelioma.adjuvanthemithoracicrtappearstosignificantlyreducetheriskoflocoregional recurrence.however,bettersystemictherapiesareneeded. 52

55 ABSTRACTS Number:19 Abstracttitle: PulmonaryToxicityfollowingIntensityModulatedRadiotherapy(IMRT)afterExtrapleural PneumonectomyforMalignantPleuralMesothelioma JensBennSorensen(1),ClausA.Kristensen(1),TrineNoetrup(2),AnneK.Berthelsen(2),Flemming KjaerKristoffersen(2),SvendAa.Engelholm(2) (1)Dept.Oncology,FinsenCentre,Copenhagen,Denmark;(2)Dept.radiotherapy,FinsenCentre, Copenhagen,Denmark Keywords: pneumonitis,imrt,extrapleuralpneumonectomy,doseconstraints Abstractcontent: Introduction:Theintroductionoftrimodalitytreatmentcombiningchemotherapy,surgery,and radiotherapyhasimprovedtheprognosisforpatientswithmalignantpleuralmesothelioma(mpm). Severalstudieshaveindicatedaradiationdoseresponserelationship,andIMRThasallowedforan increaseindosetothepleuralcavityaswellasareductioninradiationdosestoorgansatrisk.even withimrt,unexpectedfatalpulmonarytoxicityhasbeenreported.thepresentstudyreportsthe incidenceoffatalpulmonarytoxicityinpatientstreatedatrigshospitalet,copenhagen,andidentifies lungdoseparametersofimportanceforestablishmentofappropriatelungdoseconstraintsfor futureradiotherapyplanning. Results:TwentysixpatientswithstageT13N0M0MPMwereincludedfromApril2003toApril2006. Inductionchemotherapywiththreecoursesofplatinumbasedcombinationchemotherapywas administeredpreoperativelyatthelocaloncologydepartments.extrapleuralpneumonectomywas subsequentlyperformedandfollowedbyimrtatrigshospitalet,copenhagen.theentirepre operativepleuralsurfaceareawastreatedto50gyandareaswithsuspectedresidualdiseaseor closesurgicalmarginswastreatedto60gyin30fractions.organsatriskwerecontouredandthe IMRTplanswerecalculatedusingCadPlan(Helios)orEclipse/Aria. Themaintoxicitieswerenausea,vomiting,esophagitis,dyspnea,andthrombocytopenia.Fiveoutof 26patientsdevelopedfataltoxicity.Onepatientdiedfromanintracranialhemorrhageduringsevere thrombocytopenia.fourpatients(15%)experiencedgrade5lungtoxicity,i.e.pneumonitiswitha radiographicdiffuseinterstitialinfiltrate1940daysaftercompletionofradiotherapy.patientswith pneumonitishadasignificantlyhigherv10(median:60.3%,range56.4%83.2%)comparedto patientswithoutpneumonitis(median:53.1%,range:25.6%83.2%)(p=0.02).meanlungdose(mld) wasalsosignificantlyhigherinpatientswhodevelopedpneumonitis(median13.9gy,range: Gy)thaninpatientswhodidnot(median=12.4Gy,range:8.4Gy15.4Gy)(p=0.04). Conclusions:SignificantdifferencesinMLDandV10forpatientswithfatalpulmonarytoxicity comparedtopatientswithoutfatallungtoxicityhavebeendemonstrated.basedonthepresented datawehavemodifiedourlungdoseconstraintsinordertoavoidunacceptabletoxicity. 53

56 ABSTRACTS Number:20 Abstracttitle: INTENSITYMODULATEDRT(IMRT)AFTEREXTRAPLEURALPNEUMONECTOMY(EPP)INPATIENTS WITHMALIGNANTPLEURALMESOTHELIOMA(MPM):DOESNODALSTATUSMAKETHEDIFFERENCE? MartaScorsetti,SimonaCastiglioni,GiovanniLucaCeresoli,MarioBignardi,PieraNavarria,Sara Pentimalli,AlfredoMirandola,GaetanoUrso,PaolaLattuada,ArmandoSantoro IstitutoClinicoHumanitas,Rozzano(Milan),Italy Keywords: radiotherapy,imrt,extrapleuralpneumonectomy,nodalstatus Abstractcontent: INTRODUCTION:HemithoracicRThasbeenusedafterEPPtoreducethelocalrecurrencerate.IMRT allowsforsignificantimprovementsindosedelivery,butcanincreaseradiationdosetocontralateral lung.aimofthisdosimetricstudywastocomparetargetcoverageandnormaltissuesparing achievedwithstandard3dconformaltechnique(3dcrt)andimrtinmpmpatients(pts)afterepp. Ptswereanalysedaccordingtodiseasesideandnodalstatusaftersurgery. MATERIALSANDMETHODS:Fifteenptswereincluded:7withleftsidedand8withrightsided disease;6withpn0and9withpn12atpathologicalexamination.3dcrtwasplannedtodelivera totaldoseof54gy/27fractionstotheplanningtargetvolume(ptv)with35orthogonalphoton beamsof618mv.dosecalculationwasperformedbyeclipse(varian)treatmentplanningsystem. IMRTwasplannedtothesamedosagescheme.Seventoninecoplanarbeamswereusedforeach patient.dosecalculationandoptimisationweredoneusinganinversetreatmentplanningsystem (HELIOS,Eclipse,Varian).Dosevolumeconstraintsincluded,forcontralaterallung,ameanlungdose (MLD)<9.5Gy,avolumereceiving 20Gy(V20)<11%,andaV5<60%;forheartV45<30%and V50<20%.Finally,forlivermeanliverdose(MLiD)was<31GyandV30<33%. RESULTS:Inallcases,withbothtechniques,PTVcoveragewasexcellent,withanaverageof95%for targetdose.imrtwasmoreefficientinheartandliversparing.inleftsidedmpm,areductionof about65%wasobservedforheartv45(from72.70+/14.92%to22.58+/10.79%),whilev50was improvedofabout75%(from65.04+/15.94%to11.91+/8.56%).inrightsidedmpm,liverv30was reducedofmorethan50%(from67.40+/22.90%to31.40+/2.24%),andmlidofabout40%(from /10.36to22.89+/4.06Gy).Forcontralaterallung,V20andMLDwerecomparableforboth techniques;v20was2.8+/2.9%and2.3+/3.2%for3dcrtandimrt,whilemldwas4.7+/2.0gy and7.0+/1.5gyrespectively.majordifferencesbetweenthetwotechniqueswerefoundforv5 where,duetofieldsenteringincontralaterallunginimrt,3dcrthadbetterresults(55.9+/14.1vs 19.9+/21.1%).However,inIMRTplansallptswithpN0stagefullyrespecteddoseconstraintsfor contralaterallung.v5was47.7+/5.1%inpn0comparedwith61.3+/12.4%inpn12pts. Regardingcontralateralkidney,spleenandoesophagusbothirradiationmethodsrespectedthedose. ABSTRACTS 54

57 However,inIMRTplansallptswithpN0stagefullyrespecteddoseconstraintsforcontralaterallung. V5was47.7+/5.1%inpN0comparedwith61.3+/12.4%inpN12pts.Regardingcontralateral kidney,spleenandoesophagusbothirradiationmethodsrespectedthedoseconstraints. CONCLUSIONS:LocalcontrolremainsanimportantendpointinMPMptsafterEPP.Doseto contralaterallungiscritical,withhighriskofseverepulmonarytoxicity.datafromourdosimetric studyconfirmthatimrtprovidessuperiordosedistributionincomparisonto3dcrtinptswithout nodalinvolvement.inptswithpn12disease,imrtshouldbeusedwithcaution,andmodified techniqueswithrestrictedfieldsshouldbeconsidered. 55

58 ABSTRACTS Number:21 Abstracttitle: TargetingCD44withhyaluronanforBNCT:Anovelstrategyformalignantpleuralmesothelioma ChunmanLee,HitoshiFujii,ToshiroNishida,MeinoshinOkumura,YasufumiKaneda,YoshikiSawa OsakaUniversity Keywords: BNCT,Hyaluronan,CD44 Abstractcontent: BoronNeutronCaptureTherapy(BNCT)isthetumorselectiveradiotherapywiththealphaparticles producedbybncreactionthatisduetoanuclearreactionbetween10bandthermalneutrons.itis necessaryforeffectivebncttoaccumulate10batomsinthetumorcells,butnotnormalcells.asa prerequisiteforselectiveness,tumorselectivityof10bcompoundsisabsolutelyimperative.we focusedcd44forthetargetingtherapyofmpm,becauselargeamountsofcd44isexpressedonthe MPMcells.WedevelopedHyaluronan(HA)10BconjugateforthetargetingofBNCT.Wealsoused thehemagglutinatingvirusofjapanenvelope(hvje)asavehicleof10b,becauseitpossessesthe immediatecellfusionabilityandcaninduceantitumorimmuneresponses.however,theapplication ofhvjeisrestrictedtothelocaladministrationbecauseofthehemagglutination.sowedeveloped thenovelhvjecompoundswithbiocompatiblepolymertoalleviatethesideeffectofhvje.finally weexaminedbasiccharacteristicsandantitumorefficacyofthefollowingcompounds,cationizedha HVJEconjugatewithSodiumBorocaptate(BSH),CationizedGelatin(CG)HAHVJEwithBSH,andCG HVJEwithBSH.1)Atfirst,weexaminedthehemagglutinationwiththeaboveHVJEcompounds. ThehemagglutinationofHVJEwasinhibitedbyCGHAandotherHVJEcompounds.TheMTDofHVJ e,cghvje,cghahvjefornormalmicewas1,500,2,000,2,500hau(hemagglutinationunit), respectively.theseresultssuggestedpolymerhvjecompoundscouldalleviatethesideeffectof HVJE.2)WeexaminedthebidingabilityofnovelcompoundstotheMPMcells.CGHAHVJEwith luciferaseshowedsignificanthighergeneexpressiontothempmcellscomparingwithcghvje,but nottothetumorcellsexpressinglittlecd44.thesameresultwasconfirmedinthefluorescence microscopyassaywiththefluoresecencelabeledhvjecompounds.theseresultssuggestedcgha HVJEshowedhighaffinityandhighgeneexpressiontotheMPMcells.3)Weexaminedthe cytotoxicityofeachbshcompoundtothempmcellswithbncreactionafteronly30minutes ContactofeachBSHcompound,soCGHAHVJEBSHshowedthestrongestcytotoxicitycomparing withvariousbshcompounds.thecytotoxicityofthecghahvjebshcorrespondswiththatofbsh leftinthewellduringthebncr.4)weexaminedtheantitumorefficacyofeachbshcompound injectedintothepleuralcavityofthempmpleuraldisseminationmousemodel.cghvjebsh showedthemosteffectiveantitumorefficacycomparingwithvariousbshcompounds.theseresults suggestthatthetargetingcd44withcghahvjeistheeffectivemethodforthebnctofmpm. 56

59 ABSTRACTS Number:22 Abstracttitle: BoronNeutronCaptureTherapyforMalignantMesothelioma ChunmanLee(1),HitoshiFujii(1),NagakoSougawa(1),ToruKitagawa(1),HiroshiKomoda(1),Akifumi Matsuyama(1),MinoruSuzuki(2),KojiOno(2),YasufumiKaneda(1),YoshikiSawa(1) (1)OsakaUniversity,(2)KyotoUniversity Keywords: BNCT,CD44,Hyaluronan Abstractcontent: ThetherapyofMMisrequiredthemultidisciplinarytreatment.Inotherwords,eachmonotherapyis incompleteformm.forexample,radiotherapyislimitedutilitybecausetheextensivenessofthe tumorrequireslargefieldsanditisimpossibletoadministertumoricidaldoseswithoutinjuringthe adjacentlungandmediastinalorgans.boronneutroncapturetherapy(bnct)isthetumorselective radiotherapywiththealphaparticlesproducedbyanuclearreactionbetween10bandthermal neutrons.bnctisexpectedtobeabreakthroughstrategyformm,becauseitissuitableforthe therapyofdiffuseandinvasivetumorwithoutinjuringthenormaltissues.however,thesuccessof BNCTdependsontheselectivedeliveryof10B atomstotumorcellstosupplementtheattenuation ofthermalneutronfordeeplesions.wefocusedcd44forthetargetingtherapyofmm,becausea largeamountofcd44isexpressedonthemmcells.wedevelopedhyaluronan(ha)10bconjugate forthetargetingofbnct.wealsousedthehemagglutinatingvirusofjapanenvelope(hvje)asa vehicleof10b,becauseitpossessesthehighcellfusionabilityof10bandkeepthehigh concentrationof10bintumorcells.sowedevelopedthenovelhaandhvjeconjugate(czhahvj E)incorporatingBSHtodiminishthesideeffectofHVJE.Weexaminedthecharacteristicsand antitumorefficacyofczhahvjecompoundformm.1)bindingabilityandgenetransferefficiency ofczhahvjetommcells;czhahvjewithquantumdot655orwithluciferasegeneshowed significanthigherfluorescenceorhighertransfectionefficiencythanhvje,despiteonly30min ContactwithMMcells.Furthermore,thesepreferencestotheMMcellswerediminishedbytheCD44 neutralizingmab.2)cytotoxicityofczhahvjebshtommcellswithbncr;czhahvjebsh showedthehighercytotoxicitythanbshbybncrafteronly30minutescontactofeachbsh compound.3)antitumorefficacyofczhahvjebshformmpleuraldisseminationmodel;czha HVJEBSHefficientlysuppressedthelocalgrowthofMMcellsinvivowithBNCR.Theseresults suggestthatthenovelbnctwithcd44targeteddeliveryof10bisapotentiallyusefulmodalityfor MM. 57

60 ABSTRACTS Number:23 Abstracttitle: Assessingprognosisofmalignantpleuralmesothelioma(MPM)byincorporatingFDGPETparameters addsincrementalvaluetoprognosticmodelsincorporatingclinicalinformation AnnaNowak(1),RoslynFrancis(2),MichaelPhillips(3),MichaelMillward(1),AgathaVanderschaaf (2),JanBoucek(2),MelanieMcCoy(1),AmandaSegal(4),BillMusk(2),MichaelByrne(1) (1)UniversityofWesternAustralia,(2)SirCharlesGairdnerHospital,(3)WesternAustralianInstitute formedicalresearch,(4)pathwest Keywords: Prognosticmodels;FDGPET;pleuradesis;tumorvolume;imaging Abstractcontent: Background:MPMhasapoorprognosis.Prognosticinformationcanbeimportantforindividual patientsandasastratificationfactorinclinicaltrials.sincepreviousscoringsystemsweredeveloped, FDGPETscanninghasbecomeavailable.FDGPETcanquantifymetabolicactivityandtumorvolume, althoughpriorpleuradesismaymakeinterpretationdifficult.weprospectivelyassessedwhether FDGPETscanningaddedinformationtoclinicalprognosticvariableswithorwithoutprior pleuradesis. Methods:Participantswereallconsenting,newlyreferred,untreatedpatientswithaconfirmed diagnosisofmpmatasingletertiaryreferralcentre.patientswerenotexcludedbyageor performancestatus(ps).thestudywasapprovedbytheinstitutionalhumanresearchethics Committee.Allpatientswereassessedatbaselineforclinicalandlaboratoryprognosticfactors. PatientsunderwenthelicalCTscanofthoraxandabdomen,andawholebodyFDGPETscanwithin 28daysofstudyenrolment,withimagingtestswithin14daysofeachother.Asemiautomated regiongrowingalgorithmderivedthetotalglycolyticvolume(tgv),acompositeoftumourvolume andsuv/metabolicactivity(francisetal,jnuclmed(48)144958;2007).patientsweretreatedas clinicallyindicatedandfollowedupforsurvival. Results:97patientswereaccruedfrom2003to2006.4werenotassessableastheydidnothavea PETscan,3wereineligible,and2wereexcludedfromsurvivalanalysesduetoprolongedtimefrom diagnosistostudyentry.ofeligible,assessablepatients,82%weremale,87%hadahistoryof asbestosexposure,and76%hadepithelioidmesothelioma.mostpatientsweresymptomatic,and mosthadanecogpsof01(84%).29of92patientshadundergonepleuradesisbeforestudy enrolment.onunivariateanalysis,significantprognosticfactorswere:tgvonfdgpetinnon pleuradesedpatients(p=0.004),sarcomatoidsubtype(p<0.0001),forcedvitalcapacityas%predicted (p=0.03),weightloss(p=0.04),andeortc good prognosticscore(p=0.03).baselinehightgvwas morepredictiveofsurvivalthantheeortcprognosticscorebothwith(p=0.0005)andwithout (p=0.0008)inclusionofsarcomatoidsubtypesinthemodel. Conclusion:FDGPETderivedparameterscanaddprognosticinformationtostandardclinical variables,evenwhenthestrongestclinicalprognosticfactor,sarcomatoidhistology,isexcluded. 58

61 ABSTRACTS Number:24 Abstracttitle: EARLYRESPONSEEVALUATIONINMALIGNANTPLEURALMESOTHELIOMA(MPM)BYTOTAL GLYCOLYTICVOLUME(TGV)ANALYSISOFSERIALFDGPETSCANS GiovanniLucaCeresoli(1),ArturoChiti(1),LetiziaGianoncelli(1),ElenaLorenzi(1),RoslynFrancis(2), PaoloAndreaZucali(1),MarcelloRodari(1),JanBoucek(2),FabioDeVincenzo(1),ArmandoSantoro(1) (1)IstitutoClinicoHumanitas,Rozzano(Milan),Italy;(2)SirCharlesGairdnerHospital,Nedlands, WesternAustralia,Australia Keywords: PET,responseevaluation,chemotherapy Abstractcontent: Background:Responseevaluationwithconventionalcriteriabasedoncomputedtomography(CT)is challenginginmpmduetoitsdiffusepatternofgrowth.preliminaryreportshavesuggestedthat therapyinducedchangesintumorfluorodeoxyglucose(fdg)uptakeasmeasuredbypositron emissiontomography(pet)maypredictpatient(pt)outcomeearlyinthecourseoftreatment. PatientsandMethods:AretrospectivevolumebasedanalysisofFDGPETuptakewasperformedina previouslyreportedseriesofmpmpatients(ceresolietal,jclinoncol2006)usingasemiautomated 3Dvolumebasedregiongrowingalgorithm(Francisetal.,JNuclMed2007).Ptswerenotcandidates tocurativesurgery,andreceivedchemotherapywithapemetrexedbasedregimen.theywere evaluatedbyfdgpetandctatbaselineandaftertwocyclesoftherapy.totalglycolyticvolume (TGV)wasobtainedfromeachscan.Survivaloutcomesweremeasuredandanalyzedaccordingto TGVchangesafterchemotherapy;metabolicresponse(MR)wasdefinedasanyTGVreductionorasa decreaseof 25%inmaximumstandardizeduptakevalue(SUVmax). Results:Twentypatientswereincludedinthestudy,and17wereassessableforTGVanalysis.After twocyclesofchemotherapy,3ptsachievedapartialresponseatctevaluation,andin11astable diseasewasobserved.tgvvaluefellin11/17pts(65%),withamedianreductionof36%ofbaseline (range,100/+827%).earlymrwassignificantlycorrelatedtotimetotumorprogression(ttp),witha medianttpformetabolicrespondersof15,8monthsversus5,6monthsfornonresponders(p= 0.04).AsimilarresultwasobservedwhenMRwasdefinedaccordingtoSUVmaxvariations(P=0.06). PatientswithaMRhadatrendtowardslongeroverallsurvival;medianOSwas25.4monthsinpts withanytgvreductionvs17.5monthsfornonresponders,butthisdifferencedidnotreach statisticalsignificance(p=0.20). Conclusion:Volumebased(TGV)FDGPETassessmentofresponseseemseffectiveinpredicting patientoutcomeinmpm.however,thesensitivityofthismethodincomparisontoasinglepixel evaluation(suvmax)shouldbeevaluatedinalargerprospectiveseries. 59

62 ABSTRACTS Number:25 Abstracttitle: DIFFERENTIATIONBETWEENMALIGNANTMESOTHELIOMAANDASBESTOSRELATEDBENIGN PLEURALDISEASE: HuseyinYildirim(1),MuzafferMetintas(1),EmreEntok(2),GuntuluAk(1) (1)OsmangaziUniversity,MedicalFaculty,DepartmentofChestDisease,Turkey;(2)Osmangazi University,MedicalFaculty,DepartmentofNuclearMedicine,Turkey Keywords: mesothelioma,asbestosrelatedbenigndisease,pet/ct Abstractcontent INTRODUCTION:Severalstudieshavealreadyaddressedthepotentialroleofanincreasedfluorine 18fluorodeoxyglucose(18FFDG)uptakeinidentificationofpleuralmalignancy. AIM:Wesoughttodefineanaccuratediagnosticapproachfordifferentiatingbenignpleuraldisease frommalignantmesotheliomaonpositronemissiontomography(fdgpet). MATERIALSANDMETHODS:Thestudypopulationcomprised42consecutivepatients(18malignant mesothelioma,15benignasbestospleurisy,9diffusepleuralfibrosis;meanage,59.8years;age range,3982years)whounderwentcombinedwholebodypet/ctscanningforevaluationofknown orsuspectedneoplasmsbetweenjuly2005andapril2008.petimageswerefirstreviewedby nuclearmedicinephysicianswhohadnoclinicalinformation.thoracoscopyorimageguidedpleural needlebiopsyweresystematicallyperformedtorevealpathologicaldiagnosis,and/orclinicalfollow upforatleast2yearforpresenceorabsenceofmalignantpleuraleffusion.rocsanalysesfor standardizeduptakevalueadjustedtobodyweight(suv)werecalculatedbetweenbenignand malignantpleuraldiseases. RESULTS:FDGPETimagingcorrectlydetectedthepresenceofmalignanciesin17of18patientsfor sensitivity,specificity,andaccuracyof94.4%,91.7%,and92.3%,respectively.fdgpetimaging correctlyidentified22of24casesofbenignpleuraldisease.twopatientswithbenignpleural effusionswerereadtobepositiveforpleuraluptakeonpetscans.malignantlesionsaccumulated significantlymorefdgthanthebenignones.themeansuvvalueswere7.8+/3.3and0.4+/0.8, respectively,(p=0.000).whenwecomparedthetwogroupsofpleuraldisease,acutoffvalueof3.0 forsuvgavethebestaccuracywith100%and100%,respectively,forsensitivityandspecificity. CONCLUSION:FDGPETimagingisahighlyaccurateandreliablenoninvasivetesttodifferentiate malignantfrombenignpleuraldisease. 60

63 ABSTRACTS Number:26 Abstracttitle: ThicknessandAreaintheCTBasedAssessmentofMesotheliomaTumorResponse SamuelArmato,MichaelOsborne,RachaelRoberts,WilliamSensakovic,AdamStarkey,Heber MacMahon,HedyKindler TheUniversityofChicago,USA Keywords: tumorresponse,recist,computedtomography(ct),tumorvolume Abstractcontent: Background:Thequantificationofpleuralmesotheliomatumorextentisrequiredtoevaluatethe efficacyofclinicaltrials.themanualacquisitionoflineartumorthicknessmeasurementsoneachof threesectionsacrossaseriesofcomputedtomography(ct)scansisthecurrentstandardfortumor responseassessment.thepurposeofthisstudywastodeterminethecorrelationofresponsebased onlineartumorthicknessmeasurementsandresponsebasedonamorecomplete(buttedious) analysisoftumorarea. Methods:201CTscanswerecollectedfrom42mesotheliomapatientsenrolledinaclinicaltrial. Thesescansrepresentedthecompleteonstudyradiologichistoryofeachpatientbeginningwiththe baselinescan.linearmeasurementsusedfortheclinicalmanagementofeachpatientwere recordedalongwithtumorareaasoutlinedineachsectioninwhichlinearmeasurementshadbeen acquired.patientresponsewasdeterminedfromchangesinthesummedlinearmeasurements basedontheresponseevaluationcriteriainsolidtumors(recist)guidelines,whichdictatethatan increaseinsummedlinearmeasurementsofatleast20%representsprogressivedisease.recistis basedonasphericaltumormodel,forwhicha20%increaseinthelineardiametercorrespondstoa 44%increaseinthecrosssectionalarea.Accordingly,44%wasusedasthecriterionforareabased progressivedisease. Results:Acomparisonofthesumoftumorthicknessmeasurementsandtumorareayieldeda correlationcoefficientof0.54acrossall201scans.withregardtotumorresponse,ofthe28patients whoweredeterminedtohaveprogressivediseasebasedona20%orgreaterchangeinthesumof tumorthicknessmeasurements,only13(46%)demonstratedachangeintotaltumorareathat exceededthemathematicallyexpected44%thresholdrequiredforanareabaseddesignationof progressivedisease;theremaining15patientswouldhavebeenclassifiedasstablediseasebasedon measuredchangesintumorarea. Conclusion:Changesinareabasedmeasurements,apresumablymorecompleteassessmentof tumorburden,exhibiteda46%concordanceratewiththecurrentstandard,changesinlinear measurements.tumorresponseassessmentformesotheliomaisnotconsistentwithspherical modelbasedcriteria. 61

64 ABSTRACTS Number:27 Abstracttitle: Roleof18FDGPETCTinpatientssurveillanceaftermultimodalitytherapyofmalignantpleural mesothelioma. CarolTan,SallyBarrington,SheilaRankin,DavidLandau,JohnPilling,PaulCane,LoicLangLazdunski Guy's&StThomashospital Keywords: PETCT.Multimodalitytherapy.Extrapleuralpneumonectomy.Pleurectomy.Mesothelioma. Abstractcontent(maximal350words,nographs): Objectives:Toinvestigatetheroleof18FDGPETCTinpatientssurveillanceaftermultimodality treatmentofmalignantpleuralmesothelioma. Methods:Retrospectivestudyofpatientshavinghadchemotherapy,radicalsurgeryand radiotherapyformalignantpleuralmesotheliomainourunit.radicalsurgeryincludedextrapleural pneumonectomy(epp)orradicalpleurectomy/decortication(p/d). 18FDGPETCTwasperformedatleast6monthspostoperativelytoevaluateresponsetotreatment orwhendiseaserecurrencewassuspected. 18FDGPETscanswereacquiredfromskullbasetoupperthighstogetherwithlowdoseCTscansfor attenuationcorrectionandimagefusion. Results:ThirtyfivepatientshadEPP(21)orP/D(14)betweenJanuary2004andNovember2007. Eightsymptomaticpatientshad18FDGPETCTdoneforsuspicionofdiseaserecurrenceatamedian of9months(6to16),postoperatively.inthemeantime,8asymptomaticpatientshadasurveillance 18FDGPETCTdoneatamedianof11months(6to26)postoperatively. 18FDGPETCTcorrectlydiagnosedmesotheliomarecurrencein6of8symptomaticpatientsand missedmicroscopicrecurrenceinone. 18FDGPETCTshowedunsuspectedrecurrencesin5outof8asymptomaticpatients. RecurrentmesotheliomashadameanSUVmaxmeasuredat11±5(4to22). Globally,18FDGPETCThadasensitivityof91.6%,specificityof100%andaccuracyof94%. Elevenpatientswerestartedonasecondlinechemotherapybasedon18FDGPETCTfindings. Conclusions:18FDGPETCTisusefulindiagnosingorrulingoutdiseaserecurrenceinasymptomatic andsymptomaticpatientsfollowingmultimodalitytherapyofmalignantpleuralmesothelioma. Werecommendthat18FDGPETCTisperformedinallsymptomaticpatientsandwesuggestthat asymptomaticpatientshaveasurveillance18fdgpetctat12monthspostoperativelyandthen yearly. 62

65 ABSTRACTS Number:28 Abstracttitle: PracticalandReproducibleVolumeMeasurementofMalignantPleuralMesotheliomafromStandard CTImages ShinMatsuoka,MD(1),TamaraR.Tilleman,MD,PhD(2),JordanMueller(2),RituGillRandhawa, MD(1),HirotoHatabu,MD,PhD(1),DavidJ.Sugarbaker,MD(2) (1)DepartmentofRadiology,BrighamandWomen'sHospital,Boston,MA,USA;(2)ThoracicSurgery, BrighamandWomen'sHospital,Boston,MA,USA; Keywords: Tumorvolume,CT Abstractcontent: Rationales/Purpose;CTMeasurementoftumorvolumeofmalignantpleuralmesothelioma(MPM)is challenging.mpmgrowsratherdiffuselyencasingthelung,whichisdifferentfromsphericalgrowth ofothersolidtumors.wehavedevelopedanewmethodofsegmentationandvolumemeasurement ofmpmusingctimages.thismethodusessemiautomaticthresholdtechniquetoisolatethetumor lesionfromothertissuesandstructures,andselectsallpixelsbetween5and150huthatare consideredtumorlesioncanbecalculatedineachctslice.tumorvolumecanbeobtainedas follows;tumorarea;ctslicethickness;numberofslices.however,thisproceduretakestime,sowe hypothesizedthattumorvolumealsocanbeobtainedusingeverysecondorthirdimageswithout significanterror.thus,thisstudywasconductedtotestourhypothesis,andalsoevaluatethe reproducibilityofthismethod. Method;Randomlyselected9patientswithMRMwhounderwentCTscanningwereanalyzed.We calculatedthetumorvolumeusingallctimages(measurement#1),everysecondimages (measurement#2),andeverythirdimages(measurement#3)ineachpatient.correlationswere assessedamongthoseresultsofcalculatedtumorvolumeusinglinerregressionanalysis. Intraobservererrorwasalsotestedusingthesecondmeasurementperformedonemonthafterthe firstsession. Results;Therewerestrongcorrelationsbetweenmeasurement#1andmeasurement#2(r2=.994,p <0.0001),andbetweenmeasurement#1andmeasurement#3(r2=.999,p<0.0001).Themean differencewas1.6%;2.1oftumorvolumebetweenmeasurement#1andmeasurement#2,and 1.2%;1.5oftumorvolumebetweenmeasurement#1andmeasurement#3.Astrongcorrelation wasalsofoundbetweenfirstandsecondsessionoftumorvolumemeasurements(r2=.996,p< ),andthemeandifferencewas2.4%;3.1oftumorvolume. Conclusion;WehaveestablishedpracticalandreproducibletechniqueforMPMvolume measurementusingstandardctimages. 63

66 ABSTRACTS Number:29 Abstracttitle: TheinfluenceoftalcpleurodesisonFDGPETimagingformalignantpleuralmesothelioma(MPM). AgathaAvanderSchaaf(1),AnnaKNowak(2),RoslynJFrancis(1),MichaelPhillips(3),MichaelJ Millward(2),PeterDRobins(1),AW(Bill)Musk(1),JanABoucek(1),MelaineJMcCoy(2),MichaelJ Byrne(2) (1)SirCharlesGairdnerHospital,Australia;(2)UniversityofWesternAustralia;(3)WAInstituteof MedicalResearch,Australia Keywords: FDGPET,Mesothelioma,Pleurodesis Abstractcontent: Aim:FDGPETisanemergingimagingmodalityinMPM.Pleurodesismayaidsymptomcontrol howeverresultinginflammatoryeffectsmayconfoundinterpretationoffdgpetscans.weaimedto describetheeffectofpleurodesisonfdgpetimaginginmpm. Methods:Participantswereconsenting,newlyreferred,untreatedpatientswithaconfirmed diagnosisofmpmatasingletertiaryreferralcentre.patientsunderwentahelicalctscanofthe thorax/abdomen,andawholebodyfdgpetscanwithin14daysofeachother.tumourstagewas derivedforfdgpetandctscansusinguicctnmstaging.fdgpetscanswereanalysedusinga semiautomated3dregiongrowingalgorithm(jnuclmed(48)144958;2007)toderivemeasuresof totalglycolyticvolume(tgv)andsuvmax.patientsweretreatedasclinicallyindicatedandfollowed upforsurvival. Results:97patientswereaccruedfrom2003to2006.3patientswereineligibleand4werenot assessableastheydidnothaveapetscanperformed(n=92).2patientswereexcludedfromsurvival analyses,duetoprolongedtimefromdiagnosistostudyentry.29of92(32%)patientshad undergonepriorpleurodesis.thegroupsweresimilarinage,gender,pathology,performancestatus, FVCandoverallsurvival(p>0.05).Morepleurodesedpatientsreportedchestpain(p=0.02).PETTNM stagedidnotdifferbetweenthegroups(p=0.6).ctstagewassignificantlyhigherinpleurodesed patients(p=0.03),whoweremorelikelytobectdefinedn2orn3(p=0.05).petquantitative analysis:meantgv(nonpleurodesed)506(95%ci302847)vs(pleurodesed)1796(95%ci ),(p=0.003);meanSUVmax(nonpleurodesed)6.7(95%CI5.87.8)vs(pleurodesed)9.1(95%CI ),p=0.02.CoxproportionalhazardsregressionshowsthatbaselineTGVisasignificant prognosticindicatorforbothnonpleurodesed(hr=1.25,p=0.004,c=62.3%)andpleurodesed (HR=1.54,p=0.010,C=70.3%)patients. Conclusion:FDGPETtumourstagingdoesnotdifferfollowingpleurodesis,howeverCTnodalstaging washigherinpatientswithpreviouspleurodesis.quantitativepetparametersaresignificantly higherwithpriorpleurodesis,likelyreflectinginflammatoryeffects.despitetheinflammatoryeffects ofpleurodesis,baselinetgvremainsastrongindependentprognosticfactorinbothpleurodesed andnonpleurodesedpatients. 64

67 ABSTRACTS Number:30 Abstracttitle: ContinuedPemetrexedandPlatinbasedChemotherapyinPatientswithMalignantPleural Mesothelioma(MPM):Valueof18FFDGPET/CTparameters N.G.Schaefer,P.VeitHaiback,J.D.Soyka,H.C.Steinert,R.A.Stahel UniversityHospitalofZurich,Switserland Abstractcontent: Purpose:ToevaluatetheresponsetoPermetrexedandPlatinbasedchemotherapybeyondthethird cycleinpatientswithmalignantpleuralmesothelioma(mpm)usingctandpetcriteria. Methods:BetweenFeb.2002andJun.2004prospectivelyrecruitedpatientswithMPMwere includedinthestudy.responsetotherapyusing18ffdgpet/ct(pet/ct)wasassessedafterevery 3cyclesofPermetrexedandCisplatinorCarboplatin.Patientswithtalcpleurodesiswithin1month priortochemotherapywereexcluded.pettherapyresponseassessmentusedthemaximum standardizeduptakevalue(suvmax)accordingtoeortcguidelines:partialresponse(pr)<25%; Stabledisease(SD)25%+25%;Progressivedisease(PD)>+25%comparedtotheprevious examination.ctbasedtherapyresponseusedmodifiedrecistcriteria:pr<30%;sd30%+20%; PD>+20%comparedtothepreviousexamination.PatientswithPRandSDcomparedtotheprevious examinationweredefinedassequentialresponders(sr),patientswithpdasnonsequential responders(nsr).themeanoverallsurvivalforallgroupswascalculated. Results:42patientswereincluded.Meanage62years(44 74years).Mediansurvivalafterthefirst PET/CTwas461days.Allpatientsbutonediedduringobservation.Survivalafter6cyclesaccording tosrvs.nsr:567dvs.379d(pet)and507dvs.n/a(ct).after9cycles:637dvs.312d(pet)and502d vs.603d(ct).after12cycles:759dvs.317d(pet)and586dvs.465d(ct).after15cycles:875dvs. 135d(PET)and606dvs.608d(CT).After18cycles:890dvs.411d(PET)and698vs.N/A(CT).After21 cycles:1090dvs.362d(pet)and727vs.725d(ct).detailedinformationislistedintable1. Conclusion: PatientswithMPMundergoingcombinedPermetrexedandPlatinchemotherapybenefitfrom treatmentbeyondthethirdcycleifstatedsrintheprecedingpetaccordingtotheeortcguidelines. NosuchcorrelationtosurvivalcanbefoundwithCTifusingmodifiedRECISTcriteria. Table1. 6cycles9cycles12cycles 15cycles 18cycles 21cycles PET(EORTC) 5PR6PR 4PR 1PR 1PR 1PR 16SD 12SD 7SD 6SD 2SD 1SD 7PD 9PD 8PD 4PD 2PD 2PD CT(modifiedRECIST) 1PR 3PR 2PR 1PR 0PR 2PR 30SD 20SD 15SD 8SD 5SD 1SD 0PD 5PD 2PD 2PD 0PD 1PD SRPET 75% 67% 58% 64% 60% 50% SRCT 100% 82% 89% 82% 100% 75% Writtenby:NiklausSchaefer 65

68 ABSTRACTS Number:33 Abstracttitle: EVIDENCEOFSTAT1ACTIVATIONINMALIGNANTPLEURALMESOTHLIOMAINFORMALINFIXEDAND PARAFFINEMBEDDEDTISSUEUSINGPROTEINLYSATEMICROARRAYS HanneloreKothmaier(1),KarlFriedrichBecker(2),HelmutH.Popper(1) (1)InstituteofPathology,MedicalUniversityofGraz;(2)InstituteofPathology,TechnicalUniversityof Munich,Germany, Keywords: STAT1,FFPEtissue,proteinmicroarray,proteomics,cellsignalling Abstractcontent: Background:STAT\'s(signaltransducerandactivatorsoftranscription)arelatentinthecytoplasm untiltheyareactivated.whilestat3andstat5arereferredastheoncogenicstat s,stat1is regardedastumoursuppressor.recently,wehaveshownthatthetumoursuppressorstat1inmpm patientsactssimilartoanoncogene.however,stat1overexpressionconferssometumours resistanceagainstradiationandcisplatintreatment.resistanceagainstcisplatinandradiationbased therapiesisalsofrequentinmpms.theaimofourstudyistoexaminestat1proteinexpressionand activationstatusbycomparingthephosphorylationpatterninmpmtissue. Design.Routinelyprocessedformalinfixedandparaffinembedded(FFPE)tissuefrom14epithelioid MPMpatientswereusedforproteinextractionandcoupledwithproteinlysatemicroarray technology.afterdeparaffinationtissuesweremanuallymicrodissectedfromtheslides.proteins wereextractedaccordingmanufacturesprotocol(qproteomeffpetissuekit).proteinlysateswere spottedwiththemicrocaster(whatman/schleicherandschuell)infourreplicatesontonitrocellulose coatedglassslides.stat1andphosphospecificstat1(pstat1)antibodiesweredetectedby chemiluminiscence,andsignalintensityfromtheantibodystainedslidewasusedforquantitative proteinanalysis,normalizedtothetotalproteinamountasdeterminedbysyprorubystainedslides. Results:Upto15yearoldFFPEmesotheliomacaseswereusedforproteinextraction.Wewereable toextractimmunoreactivestat1andpstat1proteinforanalysis.stat1ishighlyexpressedin14/14 cases.accordingly,weevaluatedpstat1andfoundstat1phosphorylatedonserine727and tyrosine701inmpm.measuredphosphorylationpatternwerealsoassociatedwithsurvivaland couldbelinkedwithpoorpatientoutcome(survival<3years). Conclusion:OurfindingssuggestthatSTAT1signallingplaysacriticalroleinthepathogenesisof MPM.InMPMSTAT1activationseemstobedrivenbyposttranslationalmodifications,suchas phosphorylationonserine727andtyrosine701.proteomicsinarchivedffpemesotheliomatissueis anewpowerfulwaytoanalysetissueswhosepathologicalstatushasbeendeterminedbutwhose proteinmakeupregardingphosphorylationstatusofencodedproteinsislargelyunknownandhas thereforeagreatimpactontranslationalclinicalresearch. 66

69 ABSTRACTS Number:34 Abstracttitle: ThevalueofERCC1asprognosticmarkerforMPM IsabelleOpitz(1),AlexanderSoltermann(2),AlexandraSchramm(1),SvenjaThies(2),Niklaus Schäfer(3),HolgerMoch(2),RolfStahel(3),WalterWeder(1) (1)DivisionofThoracicSurgeryZurich,Switserland;(2)InstituteforSurgicalPathologyZurich, Switserland;(3)LaboratoryforMolecularOncology,ClinicandPolyclinicofOncology,Switserland Keywords: ERCC1,EPP,inductionchemotherapy,prognosticmarker Abstractcontent: Background:Expressionoftheexcisionrepaircrosscomplementationgroup1(ERCC1)protein predictsresponsetoplatinolbasedchemotherapyandsurvivalinlungcancerpatients.therelevance ofercc1expressioninmpmhasnotyetbeenstudied. PatientsandMethods:Threetissuemicroarrays(TMA)withbiopsiesof341MPMpatientswithout standardizedtreatmentwereusedastrainingsetfortheassessmentofimmunohistochemical expressionofercc1.stainingintensitywassemiquantitativelyscored(03)andpercentageof positivestainedcells(0100%)wasmeasured.afinalhscorewascalculatedandcorrelatedtooverall survivalofthisretrospectivedata. OneTMAwithtumourof93MPMpatientswhounderwentinductionchemotherapywith cisplatin/gemcitabine(cis/gem)orcisplatin/pemetrexed(cis/pem)followedbyextrapleural pneumonectomy(epp)wasconstructed.itwillbeassessedforercc1expressionandcorrelatedto prospectivelydocumenteddata.theinfluenceonoverallsurvival,timetorecurrenceandresponse tochemotherapywillbeevaluated. Results: ERCC1wasexpressedin80%ofthecasesinthetrainingTMAset.Mediansurvivalofpatientswith ERCC1Hscore<0.26was8.8(95%CI7.1;10.5)incomparisontopatientswithHscore< months(95%ci8.0;22.9).coxregressionanalysisrevealedthatercc1hscorewastheonly independentmarkerforoverallsurvival. FromMay1999toJanuary2008,139wereintendedtotreatwithinductionchemotherapyfollowed byepp(49%cis/gem;51%cis/pem).toxicitywassignificantlylessfrequentafterchemotherapywith cis/pem(p=0.05).90daymortalitywas6.5%.themediansurvivalofthesepatientswas23months (95%CI:19.9;26.0)incomparisonto9.5months(95%CI:8.1;10.7)ofthepatientswithoutEPP (p=0.0004).therewasnodifferenceinsurvivalbetweenbothchemotherapyregimensapplied. AnalysisofERCC1expressioninthepreoperativebiopsiesandEPPspecimensandcorrelationto survivaldataiscurrentlyongoingandwillbereportedatthemeeting. Conclusion:LossofERCC1expressionseemstobeanindependentprognosticmarkerforpooroverall survivalofmesotheliomapatientsasassessedintheretrospectivedataset.theexactpredictive valueofthismarkerespeciallyinthecontextofplatinolbasedchemotherapyiscurrentlyanalysedin theprospectivetma. 67

70 ABSTRACTS Number:35 Abstracttitle: Epigeneticprofilesdistinguishpleuralmesotheliomafromadenocarcinomaofthelung BrockChristensen(1),E.AndresHouseman(2),JohnGodleski(3),CarmenMarsit(1),Jennifer Longacker(4),HeatherNelson(5),JohnWiencke(6),RaphaelBueno(7),DavidSugarbaker(7),Karl Kelsey(1) (1)BrownUniversity,USA;(2)UniversityofMassachusettsLowell,USA;(3)HarvardSchoolofPublic Health,USA;(4)BostonUniversitySchoolofPublicHealth,USA;(5)UniversityofMinnesota,USA; (6)UniversityofCaliforniaSanFrancisco,USA;(7)BrighamandWomen'sHospitalandHarvard MedicalSchool,USA Keywords: Epigeneticsmethylationdiagnosis Abstractcontent: Alterationsinthecellularepigenomearestableandclearlyimplicatedinthegenesisofhuman cancers,includingpleuralmesotheliomaandlungadenocarcinoma.epigeneticalteration,markedby promoterdnamethylation,canaltergenefunctionleadingtoaberrantgeneexpressionorsilencing. Inordertoevaluatethepotentialforepigenticalterationprofilingtoassistinthedifferential diagnosisofmesotheliomawestudiedthemethylationof1505cpglociassociatedwith803cancer relatedgenesusingtheilluminagoldengate beadarrayin158mesotheliomas,18nontumor pleura,113nonsmallcelllungtumors,and52normallungtissues.applyinganunsupervised mixturemodelingapproachtoclassifyallsamplesbaseduponcpgmethylationprofile,29distinct methylationprofileclassesresulted,significantlydiscriminatingamongmesothelioma,lungtumors, normallung,andnormalpleura(permutationp<0.0001).todeterminetheabilityofcpg methylationtopredictsampletypeweusedarandomforestsclassificationofallsamplesandthe overallsamplemisclassificationerrorwas7.3%(p<0.0001).fourmesotheliomas(3%)were misclassified,andonelungtumor(<1%)wasmisclassified.next,inamixturemodelcontainingonly nonsarcomatoidmesotheliomas(n=153)andlungadenocarcinomas(n=57),14distinctmethylation profileswerehighlysignificantpredictorsoftumortype(permutationp<0.0001).tofollowup,a supervisedrandomforestsclassificationwasperformedonthesetumorsonlyandtheoverall misclassificationerrorwas<1%withonemisclassifiedlungadenocarcinoma(<2%),onemisclassified mesothelioma(<1%),(p<0.0001).finally,comparingmethylationonalocusbylocusbasisusing generalizedlinearmodels,776cpglocihadincreasedmethylation(q<0.05)inlung adenocarcinomascomparedtomesotheliomasafterfalsediscoveryratecorrection,and490cpgloci hadincreasedmethylation(q<0.05)inmesotheliomas.ourresultsshowthatmethylationprofiles candifferentiatemesotheliomafromlungadenocarcinoma.oncevalidatedinaseparatesetof tumors,thismethodwouldbearapid,costeffectivecomplementtoimmunohistochemistrybased diagnostictechniques,acceleratingandincreasingspecificityfordiscriminationofpleural mesotheliomafromlungadenocarcinoma.inaddition,theseprofilesmayaidinidentifying overlappinganddistincttargetsfornoveltreatmentsorpreventativeapproachesforthesediseases. 68

71 ABSTRACTS Number:36 Abstracttitle: DNAmethylationintumorsandmatchednormaltissuesofmalignantpleuralmesothelioma(MPM)in theegyptianpopulation AbeerBahnassy,AbdelRahmanZekri,FatmaElKasem,AbdelRahmanAbdelRahman,NellyHassan, RababGaafar NationalCancerInstitute,Egypte Keywords: DNAmethylation,malignantpleuralmesothelioma,earlydetection,prognosis Abstractcontent: Background:Epigeneticchanges,particularlymethylationareexcellentcandidatestoexplainhow certainenvironmentalfactorsmayincreasetheriskofcancer.malignantpleuralmesothelioma (MPM)isanaggressivedisease,whichiscloselylinkedtoasbestosexposureandassociatedinsome caseswithsv40infection.itisasymptomaticinitsearlystagesandthereforeitisusuallydiscovered late.itwouldbehighlybeneficialtohavemolecularmarkersforearlydetectionofmesothelioma. Methylationsignaturesareapowerfultoolbywhichspecifickindsofcancercouldberecognized. Methods:WeassessedDNAmethylationstatusof23geneson45pairedcancerousand noncanceroustissuesamplesobtainedfromegyptianmpmpatients.twentyfourofthemwere malesand21werefemales(ratio1:1.4),themedianagewas47.6years(range2070),84.4%gavea historyofasbestosexposureand40%werepositiveforsv40bypcr.twentyfourcaseswere epithelioid,16sarcomatoidand5mixed.sixteenpatientswereofstagei,12stageii,10stageiiiand 7stageIV.MethylationspecificPCRwasperformedusingDNAextractedfromformalinfixedparaffin embeddedtissueswithaspecificpanelofselectedgenesthatarefrequentlymethylatedinseveral tumortypes. Results:MethylationofAPC,CCND2,DcR1,HIC1andMLH1wasfrequentlydetectedintumorand noncanceroustissues,suggestingthatthesegenesmaybeearlyeventsinthepreneoplasticstageof MPMandcouldthereforeberelatedtoasbestosexposure.Tengenes(p16,RARB,RASSF1,DcR1and DcR2,CDKN2A,MGMT,RIZ1,HIC1,RRAD)werefoundtobesignificantlymethylatedmorefrequently intumorthaninnoncanceroustissuesamples(p<0.001).methylationofrassfia,dcr1,tms1, CRBP1,HIC1,RRADwassignificantlymorefrequentinSV40positivecases(p=0.023). Conclusions:AberrantmethylationisafrequenteventinMPM.DetectionofAPC,CCND2,DcR1,HIC1 andmlh1methylationmayhelpintheearlydetectionofmpm.moreover,detectionofmethylation oftheaffectedgenesinthebloodofmpmpatientsshouldbeinvestigatedasitmighthelpinfollow upofpatientsforearlydetectionofrecurrenceinearlystagempm. 69

72 ABSTRACTS Number:37 Abstracttitle: Epathologyandatypicalmesothelialhyperplasia(MesoDiagAMH):Theexperienceofthe internationalmesotheliomapanel. FrançoiseGalateauSallé(1),NolwennLeStang(1),VincentVerger(2),MarieBrevet(3),EricBrunet(2), MarcelGoldberg(4) (1)MESONATRegistryCHUCaen,France;(2)CCITICompany,(3)CHUCaen,France;(4)INVSDST, France Keywords: Atypicalmesothelialhyperplasia,mesothelioma,epathology Abstractcontent: Background:Useofvirtualslidessystemandwebbasedtechnologiesinpathologyispromising,but manypathologistsremainsepticregardingthefeasibilityofdiagnosisbasedonanalysisofdigitally scannedslides.sendingslidesfromdifficultandrarecasestoapanelofexpertsworldwideis consumingtimewithariskofdamageorleakageoftheslides.weconductedanevaluationondigital scannedslidesofreactivemesothelialhyperplasia,atypicalmesothelialhyperplasiaofundetermined malignancy[amh]andmesotheliomawithminimalinvasion[mm]toassessreproducibilityofthe diagnosisandifpossibleidentifycriteriathatmightpredictmalignancy. Design:55casesofAMHwereretrievedfromthefilesoftheMesonatregistrybetween andreviewedby5pathologistsfromtheinternationalmesotheliomapanel,and4seniorpulmonary pathologists,plusonefellow.eachpathologistreceivedanapplicationwithamesodiagamhuser manualtodownloadthesystem[cciticompany].theyenterinthesystemwithapersonalloginand password.digitalimageswereretrievedonaserverbasedindijonfrance.theexpertblindly reviewedthevirtualslides.eachexperthastofillascoresheetandtojustifycriteriaonwhichthey maketheirdiagnosisbyselectingregionofinterest(roi)usingadrawingtool.interobservers agreementonthediagnosiswascalculatedaccordingtokappatest.thediagnosiswasthen correlatedtothesurvival. Results:570analysiswereperformed.Therewasageneralmoderateagreementonthediagnosis betweenexpertsfromthecorepanelandfromthoseoutsideofthecorepanel.totalagreementwas observedin30/55cases(21mm/9reactive)anddisagreementin25cases(majorin18and minimalin7).amhwasobservedin11.7%ofthecases.problemsencounteredwiththesoftware andslidesreviewsystemwerediscussed.theuseofroifordiscussionwasextremelyusefulto understanddiscrepancybetweenexperts. Conclusion:Ourresultsshowthatewebbasedpathologyisextremelypromisingandaveryuseful toolfortheinterpretationofmultiplediagnosticvariablesonthereviewofdifficultcasesprovidinga goodstartforthecreationofvirtualslidesexpertisecenter. 70

73 ABSTRACTS Number:38 Abstracttitle: CriticalAnalysisofNuclearSizeasaHistologicAssessmentofPrognosisinDiffuseMalignant PeritonealMesothelioma PaulSugarbaker(1),TristanYan(1),CarlosCerruto(2),DavidChang(3),ThomasGodwin(2) (1)WashingtonCancerInstitute,Washington,DC,USA,(2)DeparmentofPathology,Washington HospitalCenter,Washington,DC,USA,(3)Westat,Rockville,MD,USA Keywords: Peritonealmesothelioma,cytoreductivesurgery,intraperitonealchemotherapy,nucleargrading Abstractcontent: Aims:Nuclearsizehasbeenproposedasasignificantprognosticindicatorforsurvivalafter cytoreductivesurgeryandperioperativeintraperitonealchemotherapyfordiffusemalignant peritonealmesothelioma(dmpm).additionalhistopathologiccriteriausefulinanassessmentof prognosishavenotbeendetermined.thiscurrentstudyassessedthecorrelationsbetweennuclear sizeand12otherhistopathologicparameters. Methods:AreviewofthehistopathologicalfeaturesofDMPMin62patientswhounderwent uniformmanagementofcytoreductivesurgeryandperioperativeintraperitonealchemotherapywas performed.nuclearsizewascategorizedintotwogroups: 30μm(n=35)versus>30μm(n =27).Thecorrelationsbetweennuclearsizeand12histopathologicparametersofDMPMwere determinedbyunivariateanalysis. Results:Patientswithnuclearsize>30μmhadalessfavorableprognosis,ascomparedtopatients withnuclearsize 30μm(p<.001).Nuclearsizewasstatisticallycorrelatedwithhistologic type(p=.012),nuclear/cytoplasmicratio(p<.001),mitoticcount(p=.001),atypicalmitosis(p<.001),tumornecrosis(p<.001),chromatinpattern(p<.001)andnucleolarsize(p<.001). Conclusions:Histopathologicprognosticatorsinadditiontonuclearsizearehistologictype, nuclear/cytoplasmicratio,mitoticcount,atypicalmitosis,tumornecrosis,chromatinpatternand nucleolarsizeinpatientsundergoingcytoreductivesurgeryandperioperativeintraperitoneal chemotherapy.thehistopathologicfeaturestakentogethermayallowthebestcurrentassessment ofprognosis. 71

74 ABSTRACTS Number:39 Abstracttitle: Deliberatelyprovokinglocalinflammationdrivestumorstobecometheirownprotectivevaccinesite DeliaNelson(1),ConnieJackaman(2),BruceRobinson(2) (1)CurtinUniversity,Australia;(2)UniversityofWesternAustralia Keywords: Immunotherapy,memory,neutrophils Abstractcontent: AnticAnticancerimmunotherapiesaimtogenerateresolutionofallexistingtumors,including inaccessibleones,andprovidelongtermprotectionagainstrecurrence.thisisrarelyachieved.thus, weaimedtodetermineifthetumormicroenvironmentcouldbeturnedintoapotent self vaccine site.ourtargetwastoeradicatelargertumorburdens.ourmodelsrespondtosingleagent immunotherapieshowever,theyfailatapreciselydefined cutoff tumorburden.thus,thissystem wasusedtodefinetheimmunemechanismsrequiredtomediateregressionoflargertumorsthat areresistanttomonoimmunotherapies.wereportthatdirectinjectionofil2withagonistanti CD40antibodyintothetumorbedresultedinpermanentresolutionoftreatedanduntreateddistal tumors.tumorinfiltratingcd8+tcellsandneutrophilscollaboratedtoeradicatetreatedtumors, IFNγwasnotcritical,andprotectivememorywaspreserved.Thisapproachreliedonlyon tumorantigensexpressedwithinthetumormicroenvironment.italsoavoidedsystemictoxicities, didnotrequirechemotherapyorsurgery,andisclinicallyusefulbecauseonlyonetumorsitehasto beaccessiblefortreatment.weconcludethatprovokingintratumoralinflammationskewsthetumor microenvironmentfromtumorigenictoimmunogenic,resultingintheresolutionoftreatedand untreateddistaltumors,aswelllongtermprotectivememory. 72

75 ABSTRACTS Number:40 Abstracttitle: Theheterogenousmicroenvironmentofmurinemalignantmesotheliomaduringtumorimplantation BonnieLau,NathanMiselis,NormaMessier,AgnesKane BrownUniversity Keywords: tumormicroenvironment,immunocompetentmurinemodel,hostcellrecruitment,chemokines, growthfactors Abstractcontent: Immunocompetentmurinemodelsformalignantmesotheliomaarevaluableforstudyingthehost responsetotumorimplantation.whilethetumorsfromamurinemodelusingintraperitoneal injectionofmesotheliomacellshasbeenpreviouslydescribedtorecapitulatethehistopathologyand molecularalterationsofthehumandisease,thedynamictimecourseofhostcellsbeingrecruitedto thetumorsandthecorrespondingexpressionofchemokinesandgrowthfactorsforrecruitmentof hostcells,hasnotbeenevaluated.wehypothesizetherearemultiplecelltypesbeingrecruitedat differentratesandtimesthroughouttheprogressionofmalignantmesothelioma.wedescribe tumorprogressionastumorspheroidgrowthandlocalinvasion,andassolidtumorinvasionand metastasis.multiplecelltypes,includingtumorassociatedmacrophages,endothelialcells,dendritic cells,myeloidderivedsuppressorcells,tlymphocytesandstem/progenitorcellsareidentifiedinthe stromaofbothtumorspheroidsandsolidmesotheliomatumors.thedynamicsanddistributionof hostderivedstromalcellschangeovertime.thisdynamictimecourseisalsoreflectedbyupand downregulationofgenesinvolvedinrecruitmentofstromalcells,asdeterminedbyrealtimepcr arrays.elucidatingthedynamicsofhostcellrecruitmenttomalignantmesotheliomacanprovide noveltargetsfortherapy. ThisworkisfundedbytheNationalInstitutesofHealthNIEHSgrantR01ES03721(Kane)andNRSA grantf30es013639(lau). 73

76 ABSTRACTS Number:41 Abstracttitle: Humanandmurinemesotheliomasharesimilargenomicalterations ElodieManié(1),AnnieRenier(2),JocelyneFleuryFeith(2),CélineLecomte(2),PascalAndujar(3), MarcoGiovannini(2),MarcHenriStern(1),MarieClaudeJaurand(2) (1)INSERMU830InstitutCurieParis,(2)INSERMU674Paris,(3)INSERMU841Créteil Abstractcontent: Mesotheliomaisaseveredisease,whichfrequencyhasdramaticallyincreasedduetothelargeuseof asbestosfibers.togaininsightinitsphysiopathology,amodelwasdevelopedinwildtype(wt)and hemizygousnƒ2ko3/+miceexposedtofibers(asbestosandrefractoryceramicfibers),which developedmesotheliomaandtumoralascites(ta)9to24monthsafterexposure.seventeenta,4 and13inwtandnƒ2ko3/+backgrounds,respectively,werecharacterizedbyarraycomparative genomichybridization(cgha)andcomparedtodnaprofilingobtainedfromaseriesof34human mesotheliomas. CGHawasperformedonthegenomewideCITM3Musmusculus1KBACarrayandanalyzedusing thevampinterface.asyntenicconversiontoolwasdevelopedtovisualizethe humanized profile ofmurinetumorsandtofacilitatecomparisonwithhumanprofiles.themostfrequentaberration was aninterstitialdeletionofmurinechromosome4in14/17tumors,withfrequentbiallelic deletions(9/17).theminimalregionofdeletioncontainedthecdkn2a/2bgenes.otheralterations includedrecurrentgainsofchromosomes15,19and6,andlossesofchromosomes7and14,most frequentlyimplicatingwholechromosomes.however,aninterstitialdeletionofchromosome14was definedin12/17tumors.fivehighlevelgainswereobservedin2tumors,implicatingregions containingmet,mycandbrafascandidatetargetgenes. Genomicprofileofhumanmesotheliomasischaracterizedbyfrequentgainsofchromosomes5p,7p and20,andlossesofchromosomes1p,3p,4,6q,9p,13,18and22.after humanizing murine tumorgenomicprofiles,similaritiesanddifferenceswereeasilyevidenced.strikingly,themost frequentdeletioninhumandiseaseandmousemodelsisthedeletionofcdkn2a/2b,frequentlyby biallelicdeletion.othersharedaberrationsarethedeletionof1p,ofchromosome13andgainof5p. However,thefrequentdeletionof3pinhumantumorswasnotfoundinmurinetumors. Acknowlegements:MurineCGHawasperformedattheCITplatformatInstitutCuriebyCBlanchard. HumanCGHawasperformedattheCITplatformatIGBMC.WearegratefultoAJanin,FGalateau Sallé,CDanel,IAbdAlsamad,PAstoul,IMonnet,JCPairon,FLePimpecBarthes. Affiliations:AR,CL,MGandMCJ:INSERMU674,IFR105,CEPH,IUH,75010Paris;PA:INSERMU841 IMRBCreteil;AMandMHS:INSERMU830InstitutCurie,75248Paris. Grants:fromtheLigueNationaleContreleCancerCIT1andCIT2programs;INSERM;Ministèresde l Emploi,delaSolidaritéetdel Environnement;CancéropôleIledeFranceandtheLegsPoix. 74

77 ABSTRACTS Number:42 Abstracttitle: ExtracellularSignalRegulatedKinases(ERKs)haveDisparateRolesinGrowthandChemoresistanceof HumanMesotheliomasInVitroandinaMouseXenograftModel ArtiShukla(1),JeddM.Hillegass(1),MaximilianB.MacPherson(1),MariaE.RamosNino(1),HarveyI. Pass(2),MicheleCarbone(3),JosephR.Testa(4),DeborahA.Altomare(4),NicholasH.Heintz(1), BrookeT.Mossman(1) (1)UniversityofVermontCollegeofMedicine,USA;(2)NewYorkUniversityMedicalCenter,USA; (3)CancerResearchCenterofHawaii,USA;(4)FoxChaceCancerCenter,USA Keywords: MalignantMesothelioma,ExtracellularSignalRegulatedKinases,Chemoresistance,CellGrowth Abstractcontent: Malignantmesothelioma(MM)isafatalcancerassociatedhistoricallywithoccupationalexposures toasbestos.extracellularsignalregulatedkinases(erks)arederegulatedinapproximatelyonethird ofallhumancancersandactivatedbyasbestos;however,littleisknownregardingtheirrole(s)in MM.Initially,weusedseveralpleuralMMcelllines(MO,ME12,ME26andME27)invitrotoassess theroleoferk1/2inmigration,invasion,andgeneexpressioninthepresenceorabsenceofa MEK1/2inhibitor,U0126(10and20μM)oritsinactiveanalog,U0124(20μM).Cell migrationandinvasionweregreatestintheonlysarcomatoidmmline(mo)andinhibitedbyu0126 butnotu0124.additionofdoxorubicin(dox)(ld50~25μm)causedlossofviabilityaswellas ERK1/2activationinall4MMcelllines.UseofU0126inhibitedDox inducederk1/2activationand modifiedcellviability,suggestingaprosurvivalroleforerk1/2.todissecttheindividualrolesof ERK1,ERK2andERK5,aERKfamilymemberrecentlylinkedtoFra1regulationandMMviability (RamosNinoetal.,AmJRespirCellMolBiol.38:20917,2008),inMMgrowthandchemoresistance, wecreatedstablesherklinesusingammcellline(hmeso)givingrisetotumorsaftersubcutaneous (sc)injectionintoscidmice.selectiveinhibitionofapproximately8090%oferk1,erk2orerk5was achievedinindividualcloneswithoutcompensatoryincreasesinothererkfamilymembers.these clones,untransfected,andcontrolvectortransfected(shnc)lineswereinjectedintomice(n=4sc injectionsite/4mice/group)andassayedfortheirchemoresistancetodoxinvitro.incomparisonto allothergroups,miceinjectedwithsherk2cellsshoweddecreasedornotumordevelopment whereassherk5cellsshowedincreasedviabilityinresponsetodoxadditioninvitro.these observationsarepresentlybeingconfirmedinothersherkmodifiedhumanmmcelllines.data demonstratethaterk2playsanimportantroleinmmcellgrowthwhereaserk5governsdox resistance.supportedbyp01ca

78 ABSTRACTS Number:43 Abstracttitle: Malignantmesotheliomamousemodelforinvivoandinvitrotherapeuticstrategies JohanJongsma(1),ErwinvanMontfort(1),JohnZevenhoven(1),MarcVooijs(2),PaulKrimpenfort(1), MartinvanderValk(1),MarkvandeVijver(1),SjaakBurgers(1),AntonBerns(1) (1)NKI/AvL,Amsterdam,theNetherlands;(2)HubrechtInstitutefordevelopmentalbiologyandstem cellresearch,utrecht,thenetherlands Keywords: mesotheliomamodel,tumorigenesis,therapy,invitro,bioluminescence Abstractcontent: Wehavedevelopedamurinemodelforhumanmalignantmesotheliomawhereweinducesite specificlossofnf2,ink4a/arf,andp53byusingthecreloxsysteminnf2loxp/loxp, Ink4a/ArfloxP/loxP,p53loxP/loxP,Nf2loxP/loxP;Ink4a/ArfloxP/loxP,Nf2loxP/loxP;p53loxP/loxP,and Nf2loxP/loxP;Ink4a*/*;p53loxP/loxP.Murinemesotheliomasdevelopedoneithervisceralpleuraof lungsandheartand/oronparietalpleuraofdiaphragmandthoracicchestwall.weareabletofollow tumorgrowthnoninvasivelywithaconditionalluciferasereporter.nexttoourinvivomodel,we alsodevelopedseveralinvitrocelllineswithorwithouttheluciferasereporterfrommurine mesotheliomasfromdifferentgeneticbackgrounds.fromtheluciferasereporterpositivecelllines wehavesuccessfullyderivedorthotopictranplantationmodelswhichgivesustheopportunityto quicklysetuplargeinvivoexperiments. Ageneticapproachbybothexpression/oligoandCGHBacarraytechnologytofurthervalidatethe mousemodelforhumanmesotheliomaisongoinginthemurinetumorsandcelllinesaswellasin patientmaterialtosearchforparallelgeneticaberrations.theresultsofthisdetailedgenetic validationshouldyieldusinformationastowhichgeneticaberrationsoccurmostfrequent,what expressionprofilesareconcomitantwiththesespecificgeneticaberrationsandtowhatextentwe caninterferewithpathwaystostoptumorgrowthinrelationtospecificaberrations. Inthismodelweperformbasicandpreclinicalresearch.Thebasicresearchconsistsonstudyofearly eventsinmurinemesotheliomadevelopmentandtheroleoflossofink4ainmurinemesothelioma development.thepreclinicalpartfocusesoncomparativetreatmentinthemousemodel,bothin vivoandinvitro,withdifferenttherapeuticoptionsrangingfromuseofcytostatics(e.g.cisplatinum, doxorubicinorgemcitabine),biologicalcompounds(e.g.pemetrexed,thalidomide,orgefitinib), radiationandimmunologicalintervention(e.g.il2ordc)orcombinationsoftheabove. 76

79 ABSTRACTS Number:44 Abstracttitle: RNAinterferencebasedstrategiesdirectedagainstBclxLandMcl1forthetreatmentofmalignant pleuralmesothelioma EmilieVARIN(1),ChristopheDENOYELLE(1),EmilieBROTIN(1),EdwigeLEMOISSON(1),Florence GIFFARD(1),PhilippeICARD(1),LaurentPOULAIN(2) (1)GRECANEA1772,France;(2)Servicechirurgiethoraciqueetcardiovasculaire,CHUCaen Keywords: Chemoresistance,RNAinterference,BclxL,Mcl1 Abstractcontent: Malignantpleuralmesothelioma(MPM)isahighlyaggressivetumourwithpoorprognosisand limitedresponsetostandardcombinedchemotherapy(i.e.pemetrexedpluscisplatin).altered expressionofantiapoptoticproteinshavebeenpreviouslydescribedtocontributeto chemoresistance,andamongthem,bclxlseemstoplayanimportantroleinmpm.different strategieshavebeendevelopedtoimpedeitsactivity(bh3mimetics)oritsexpression(antisense oligonucleotides).interestingly,sinceitbasedonthehighlyspecificandefficientsilencingofatarget gene,rnainterference(rnai)representsoneofthemostpromisinginnovatingapproachestobe combinedtoconventionaltherapies.inourstudy,abclxlspecificrnainterferenceapproach(sixl1) wasusedtoinhibitbclxlexpressioninmesotheliomacelllinesforevaluatingbothitsantitumor effectanditspotentialtosensitizemesotheliomacellstostandardchemotherapy.weshowedthat sixl1inducedadrasticinhibitionofbclxlexpressionbothatthemrnaandproteinlevelsin differentmpmcelllines.wecharacterizedtheresponseofchemoresistantncih28cellstosixl1, aloneorassociatedtocisplatin.sixl1alonecauseddeathofafractionofthepopulation(about20%), themajorityofcellsbeingonlytransientlyarrestedinthecellcycleforfewdays.notably,the combinationofsixl1andcisplatinresultedinasupraadditiveeffectwithnearlycomplete annihilationofthepopulation,whereasneithercisplatinalonenorcisplatinassociatedtocontrol sirnainducedcelldeathinthesecells.moreover,itwasrecentlydemonstratedthatthe neutralizationofbothbclxlandmcl1sufficesforefficientbakmediatedapoptosis.wethus evaluatedtheinterestofthesixl1/simcl1combinationandshowedthatthisassociationissufficient toinduceasignificantcelldeath.theinterestofsuchsirnasassociationcombinedtostandard chemotherapyforthepreventionoflongtermrecurrenceisunderinvestigation.finally,preclinical studieswillbeperformedinnudemicetoprecisethetherapeuticpotentialofsuchapproachesfor thetreatmentofmpm.insummary,thesefindingshighlightthatsirnastrategyaimedatdown regulatingbothbclxlandmcl1maybeusedasnovelandhighlyeffectivetool,withthepotential forfuturetargetedtherapyofmalignantpleuralmesothelioma. 77

80 ABSTRACTS Number:45 Abstracttitle: DepletionofICOSandTNFR2expressingeffectorsuppressorTcellspromotestheeradicationof subcutaneousmesotheliomasinmice RobbertGvanderMost,SathishMahendran,AnnaK.NowakandRichardALake TumourImmunologyGroup,NationalResearchCentreforAsbestosRelatedDiseases,Universityof WesternAustralia Abstractcontent: TumorgrowthiscloselylinkedtoimmunosuppressionandCD25+regulatoryTcellsplayakeyrolein thisprocess.here,wereportthatthechemotherapeuticdrugcyclophosphamideeradicates establishedmesotheliomasinmiceinacd8tcelldependentfashionandthatdepletionofan effectorsuppressorpopulationoftcellsisanecessarypartoftheprocess.ourstudymakesfour points.first,cyclophosphamidedepletesallcycling(ki67hi)tcells,butpreferentiallytargetsfoxp3+ CD4Tcells.Second,cyclingregulatoryCD4TcellsexpresshighlevelsofTNFR2andICOSconsistent withthispopulationincludingthemaximallysuppressiveregulatorytcells.third,reconstitutionof cyclophosphamidetreatedmicewithcd4+cd25+tcellsfromuntreatedtumorbearingmice resultedinrapidtumorgrowth,showingthatdepletionofregulatorytcellswasessentialfortumor eradication.however,depletionofregulatorytcellsperse(bytargetingthecd25+population)had noeffectontumorgrowth.fourth,combinationofthecytotoxicdruggemcitabine,whichasasingle agentdoesnotcuremice,withcd25depletioncured75%ofmice.thus,theinteractionbetween tumorcellapoptosisandregulatorytcelldepletionyieldsasignificantbenefit.ourdatashowthat cyclophosphamidecuresmicebecauseitpreferentiallydepleteseffectorsuppressortcells.the synergybetweengemcitabineandcd25+cd4regulatorytcelldepletionsuggeststhatcombinations oftherapiesmayofferbenefittopatientswithmesothelioma. 78

81 ABSTRACTS Number:47 Abstracttitle: Wilmstumor1(WT1)peptidevaccinecanelicitimmuneresponsesinpatientswithmalignantpleural mesothelioma AndrewBrown,LeeKrug,PeterMaslak,WilliamTravis,SaraBekele,TaoDao,LeslieTyson,David Scheinberg MemorialSloanKetteringCancerCenter,USA Keywords: Vaccines,Immunotherapy Abstractcontent: BACKGROUND:Thetranscriptionfactor,WT1,ishighlyoverexpressedinmalignantpleural mesothelioma(mpm)suchthatimmunohistochemicalstainsforwt1areroutinelyusedtoaidinits diagnosis.forthisreason,wt1isanattractivetargetforimmunotherapy.usingcomputer predictionanalysiswedesignedanalogpeptidesderivedfromwt1sequencesbysubstitutingamino acidsatkeyhlaa0201bindingpositions.onepeptide(wta1)wascapableofstimulatingcd8t cellsforkillingofhlamatchedtumorcells.amodifiedversionoftheprotein(wt1122a1)created byaddingflankingaminoacidstothecoresequence,generatedcd4responsesaswell.two additionalpeptidesweregenerated(wt1427&wt1331)whichwerecapableofrecruitingcd4t cellresponseacrossmultiplehladrsubtypes.thesefourpeptidesadministeredtogetherwith adjuvantmontanideandgmcsfcomprisethevaccine. METHODS:Wetestedthesafety,activityandimmunogenicityofWT1vaccineinpatientswith myeloidandthoracicneoplasms.patientswithmpmwererequiredtohavetumorsexpressingwt1 byimmunohistochemistryandtreatedwithnomorethanonepriorchemotherapyregimen.immune responseswereevaluatedbydth,cd4tcellproliferation,cd4andcd8tcellinterferonrelease, andwt1peptidetetramerstaining. RESULTS:TwentypatientshavebeenenrolledincludingeightwithMPM(4withrelapseafter combinedmodalitytherapy,3withonepriorchemotherapyregimenforadvanceddisease,andone previouslyuntreated).fivempmpatientsdiscontinuedvaccinesbecauseofprogression,twoare active,andonehasnoprogression7monthsaftercompletionof12vaccinations.preliminaryresults showcd4responsein7/9patientsoveralland2/3mpmpatients,cd8responsein5/6overalland 1/2MPMpatients,andDTHresponsesin4/14overalland1/3MPMpatients.InoneMPMpatient, WT1peripheralbloodlevelwasundetectableafter3vaccines.Toxicitieswerelimitedtomild injectionsitereactionsandonegrade2urticaria.conclusions:thisanalogwt1peptidevaccineis welltoleratedandimmuneresponsescanbeelicitedinpatientswithmpm.arandomizedtrial testingthisvaccineasadjuvanttherapyinmpmisplanned.supportedbynihpo123766,innovive Pharmaceuticals,MARF,TheExperimentalTherapeuticsCenterandtheBakerStreetFoundation. 79

82 ABSTRACTS Number:49 Abstracttitle: ReversalofBortezomibResistanceinMesotheliomabyaMCL1/A1targetingBH3Peptidomimetic AlexChacko(1),DarioBarbone(2),NyreeCrawford(1),PatrickJohnston(1),LucianoMutti(3), V.CourtneyBroaddus(2),GiovanniGaudino(4),DeanA.Fennell(1) (1)Queen'sUniversityBelfast,UK;(2)UniversityofCaliforniaSanFrancisco,USA;(3)Lab.diOncologia Clinica,Borgosesia,Italia;(4)DISCAFF,UniversityofPiemonteorientale"A.Avogadro",Italia Keywords: apoptosis,bcl2family,proteasomeinhibition,bortezomib,obatoclax, Abstractcontent: Basedonpromisingpreclinicaldata,bortezomib(bz)iscurrentlyunderinvestigationintwophaseII clinicaltrialsinmesothelioma.however,themoleculardeterminantsofsensitivityandresistanceto bzareunknown,warrantinganalysisofitsproapoptoticpharmacodynamics.bzisknownto modulatebothproandantiapoptoticbcl2familyproteins.accordingly,theirregulationwas exploredinmesotheliomacells.bzupregulatedtheproapoptoticbh3onlyproteinandmcl1/a1 antagonistnoxa,insensitiverencellsandxenografts,butnotinresistantmpp89orrenspheroids. KnockdownofNOXAbysiRNAinhibitedbzinduceddeathofRENcells.DespitethelackofNOXA upregulationinmpp89cells,directtargetingofmcl1/a1witheitherexogenousbh3noxaorwith obatoclax,abh3peptidomimetictargetingmcl1/a1,wassufficienttoreducempp89viability. Furthermore,combinationofobatoclaxandbzexhibitedpotentsynergyinthesecells.Bzefficacyis thereforecharacterizedbynoxaupregulation,whichisabsentinresistantcells.antagonismofmcl 1/A1issufficienttoinduceapoptosisirrespectiveofbzsensitivity.Thepromisingpotencyobserved withbzplusobatoclaxsuggestsanoveltherapeuticstrategywithpotentialtoreversebzresistancein mesothelioma. 80

83 ABSTRACTS Number:50 Abstracttitle: Identificationofinternalizinghumanantibodiestargetingtumorcellsurfaceantigenscommonly expressedbyalltypesofmesothelioma ScottBidlingmaier(1),FengAn(1),YongWang(1),DarylDrummond(2),DmitriKirpotin(2),Steven Nishimura(1),CourtneyBroaddus(1),BinLiu(1) (1)UniversityofCaliforniaSanFrancisco,USA;(2)HermesBiosciences Keywords: Internalizinghumansinglechainantibodies.MCAM,alltypesofmesothelioma Abstractcontent: Mesotheliomaisadeadlydiseasecausedbymalignanttransformationofthemesothelium,the protectiveliningsurroundingmostofbody sinternalorgans.therearethreemaintypesof mesothelioma:epithelioid,sarcomatoid,andmixed.epithelioidmesotheliomaisthemostcommon form,comprisingbetween5070%ofmesotheliomacases,andisthemostlikelytorespondto treatment.sarcomatoidmesotheliomaaccountsfor1020%ofmesotheliomacasesandrarely respondstotreatment.approximately2035%ofmesotheliomacasesaremixedtype,which containsbothepithelioidandsarcomatoidfeaturesandhasanintermediateoutlook.currently,very fewmesotheliomaassociatedcellsurfaceantigensthatareexpressedbyalltypesofthisdiseaseare known.forexample,mesothelin,acellsurfaceglycoprotein,hasbeenshowntobeausefulmarker forepithelioidmesothelioma,butitisnotexpressedbysarcomatousmesothelioma.toidentifycell surfaceantigensthatareexpressedbyalltypesofmesothelioma,wehaveprobedthecellsurface epitopespaceofvarioustypesofmesotheliomabymonoclonalantibodies.wehaveselecteda500 millionmemberphageantibodydisplaylibraryonepithelioidandsarcomatoidmesotheliomacell lines,andhaveidentifiedapanelofinternalizinghumansinglechainantibodiesthatbindtoboth typesofmesotheliomacells.wehavefurtherexploitedtheinternalizingfunctionoftheseantibodies tospecificallydeliverlethaldosesofliposomeencapsulatedsmallmoleculedrugstobothepithelioid andsarcomatoustypesofmesotheliomacells.toidentifyantigensboundbythosenoveltumor targetingantibodies,wescreenedbyflowcytometrytheentirehumanproteomedisplayedonthe surfaceofyeast.wehaveidentifiedmcam/muc18/cd146asoneofthetargetantigens. ImmunohistochemistryanalysisofmesotheliomatissuemicroarraysconfirmedthatMCAMiswidely expressedbyepithelioid,sarcomatousandmixedtypesofmesotheliomatumorcellsinsitubutnot bynormalmesothelialcells.thus,wehaveidentifiedacellsurfaceantigenexpressedbyalltypesof mesothelioma,makingmcamacandidatefortherapeutictargeting. 81

84 ABSTRACTS Number:52 Abstracttitle: FrequentCoActivationOfMETAndEGFRInMalignantMesotheliomaAsARationaleFor CombinationTargetedTherapy ShigekiShimizu,PeterIllei,FernandoLopezRios,AdamOlshen,ValerieRusch,MarcLadanyi MemorialSloanKetteringCancerCenter,NewYork,NY,USA Abstractcontent: Background:Toidentifynewtherapeutictargetsinmalignantmesothelioma(MM),weperformeda screenforactivatedreceptortyrosinekinases(rtks)inmesothelioma. ExperimentalDesign:Westudied14MMcelllinesand70primarytumors.Expressionof phosphorylatedrtkswasanalyzedbywesternblottingandamembranebasedantibodyarray (ProteomeProfiler,R&DSystems).Screeningformutationswasperformedbydirectsequencingof exonsencodingthekinase,semaphorin,andjuxtamembranedomainsofmetandthekinasedomain ofegfr.met,hgf,andegfrexpressionwerestudiedbywesternblotting,immunohistochemistry, ELISA(HGF),andatthetranscriptlevelinAffymetrixexpressionmicroarraydataorbyQRTPCR.Cell proliferationwasmeasuredbymttassays. Results:Profilingofthephosphorylationstatusof42RTKsinMMcelllinesshowedprominent expressionofbothphosphometandphosphoegfrin8/14(57%).twommcelllinesshowed nonsynonymoussequencealterationsinmet(r988c,t1010i)andnoneshowedegfrmutations.no somaticmutationsofmetwerefoundin70primarytumors.treatmentwiththemetinhibitor,pha (giftofPfizer),identifiedJMNasthemostsensitivecelllineandthiswasalsotheonlylineto showautocrinehgfproduction.notably,metinhibitionbypha665752injmnandothermmlines inhibitednotonlythephosphorylationofmetbutalsothatofegfr.knockdownofmetbyrna interferencealsoreducedegfrphosphorylation.conversely,stimulationwithhgfincreasedboth phosphometandphosphoegfr.combinationtherapywithpha665752andtheegfrinhibitor, erlotinib,suppressedcellgrowthmorethaneitheragentalonein3/6(50%)celllines. Conclusion:MMfrequentlycoexpressphosphorylatedMETandphosphorylatedEGFRwithevidence ofcrossactivation.combinationtargetingofmetandegfrmaybemoreeffectivethaneither inhibitoraloneinasubsetofmm. 82

85 ABSTRACTS Number:53 Abstracttitle: PaxillinisaNovelpotentialMoleculartherapeuticTargetAgainstMesothelioma RamasamyJagadeeswaran,SoheilYala,VijayMohan,HedyKindler,RaviSalgia DepartmentofMedicine,UniversityofChicago,USA Keywords: Paxillin,mutation,geneamplification,Mesothelioma Abstractcontent: MalignantPleuralMesothelioma(MPM)cellsmigratealongthepleuralsurface,areinvasive,andcan metastasizetolymphnodes.thesemechanismscanpotentiallyinvolvethecytoskeleton.wehave recentlyidentifiedthatpaxillin,afocaladhesionprotein,isanimportantactivecytoskeletalprotein inmpm.wefirstfounduniquepaxillin(pxn)genemutationsidentifiedinbetweenldmotifsand withinlimdomainsinmesotheliomadnasamples.paxillinisanimportantdownstreamtargetof receptortyrosinekinases,suchascmet.weexaminedtheexpressionofpaxillinandcmetin mesotheliomacelllinesusingstandardimmunoblottingwiththe5h11paxillinmonoclonalantibody andpolyclonalanticmetantibody.therewassignificantoverexpressionofpaxillinandcmetin mostofthempmcelllines(4outof5)examinedwhencomparedtomet5a(normalmesothelial cells).wefoundoverexpressionofpaxillin(2+to3+)inarchivalmesotheliomatumortissues.a numberofmesotheliomatissueshadhighexpressionofpaxillininmpmsubtypes,inparticular89% ofsarcomatoid(score2+to3+)comparedtoepithelioid(54%)andmixedtype/biphasic(60%). Statisticallysignificantdifferencesbetweenepithelialandsarcomatoidtumorswereobservedfor paxillin(p<0.01).specificstainingofthemesotheliomatumortissuewasevidentwithnegative stainingseeninthesurroundingstromaltissues.expressionofpaxillinintumortissueswasidentified asbothnuclearandcytoplasmicinepithelioidtypeandpredominantlymembranouslocalizationin sarcomatoidtypeofmesotheliomapatients.geneamplificationofpaxillin(pxn)andcmetwas analyzedbymethodsofqpcrandfishinapanelofmesotheliomacelllines.therewasincreased copynumbersofthepaxillingeneidentifiedinh2461andh2691cells.atotalgenomicgainofpxnin mesotheliomacelllineswasabout33%(3outof9).oneofthemostfrequentlyoccurringpaxillin mutants(a127t)foundinmpmwasagainoffunctionmutantthatconferredcellsurvivaladvantage, enhancedcellmotility/migration,andangiogenesis.sirnainhibitorystrategywasusedtotarget againstpaxillinmrnatotestandvalidatethepotentialoftherapeuticinhibitionofpaxillin.sirna duplexestargetingpaxillinmrnawastransfectedintocellstoachievepaxillingenesilencing.paxillin proteinexpressionwassuccessfullyinhibitedby7090%over72h.sirnadownregulationofpaxillin proteinresultedinreducedcellviability.therefore,paxillinwouldbeanimportanttherapeutictarget inmpm,andrationalinhibitorydrugdesignshouldbeconsideredagainstthisimportantcytoskeletal molecule. 83

86 ABSTRACTS Number:54 Abstracttitle: Mesotheliomaspheroids,mTOR,mitochondriaandmulticellularresistance DarioBarbone(1),TsungMingYang(1),LucianoMutti(2),GiovanniGaudino(3),VCBroaddus(1) (1)LungBiologyCenter,UCSF,USA;(2)Lab.diOncologiaClinica,Borgosesia,Italy;(3)DISCAFF, UniversityofPiemonteorientale"A.Avogadro",Italy Keywords: Apoptosis,biomarker,TRAIL,S6K,threedimensional Abstractcontent: Mesotheliomaprogressesfromatwodimensional(2D)layerofnormalmesothelialcellsintoathree dimensional(3d)thicktumormass.thisstructuraltransitionmayitselfaccountforsomeofthe characteristicpropertiesofthetumorsuchaschemoresistance.wefoundthat,whengrownas3d spheroids(multicellularspheroids),mesotheliomacelllinesacquireapronouncedresistancetoa widearrayofchemotherapeuticscomparedtotheir2dmonolayercounterparts,apropertytermed multicellularresistance.proapoptotictreatmentsincludedcombinationsoftrail,gemcitabine,the proteasomeinhibitormg132andhistonedeacetylaseinhibitorstrichostatinaandsodiumbutyrate. Wehaveinvestigatedthemechanismsthatdrivemulticellularresistancein3Dusingboth mutlicellularspheroidsgeneratedfrommesotheliomacelllinesandtumorfragmentspheroidsgrown fromhumanmesotheliomatumor.inbothmodels,wehavefoundthatthepi3k/akt/mtoraxisand particularlymtorsignalingcontributetomulticellularresistance;infact,inhibitionofs6k,a downstreamtargetofmtor,effectivelyreducedbymorethan40%theapoptoticresistanceinthe 3Dspheroidsbutnotinmonolayers.Furthermore,tumorfragmentspheroidresponsivenessto mtor/s6kinhibitioncorrelatedwithpositivestainingforphosphos6k,butnotforphosphoakt. Stainingoftissuemicroarrayscontaining37mesotheliomasfurtherdemonstratedthatphosphoS6K correlatesonlyweaklywithphosphoakt,suggestingtheexistenceofanaktindependentregulation ofmtor.theactualtargetsofthemtor/s6ksignalsthatconfermulticellularresistancearenotyet identifiedbutappeartoconvergeatthemitochondria,whereapoptoticsignalsareknowntobe integratedandamplified. WeproposethatmTOR/S6Kmediatessurvivalsignalsinmanymesotheliomatumorsasrevealedby itscontributiontotheacquiredapoptoticresistanceofmesotheliomacellsin3dbutnotin2d cultures.wesuggestthat3dspheroidsreflectamoreclinicallyrelevantinvitrosettinginwhich mtorelicitsantiapoptoticproperties,modelingthechemoresistanceseeninvivo.inhibitionof mtormayprovideanontoxicadjuncttotherapydirectedagainstmalignantmesothelioma, especiallyintumorswithhighbaselineexpressionofphosphos6k. ResearchwassupportedbyNIHRO1CA95671(VCB)andtheBuzziUNICEMFoundation(GGandDB). 84

87 ABSTRACTS Number:55 Abstracttitle: Transductionofthewildtypep53geneincombinationwithanticanceragentsproducedantitumor effectsonmesothelioma YujiTada(1),TaroUeyama(2),KenzoHiroshima(3),HideakiShimada(4),YuichiTakiguchi(5),Koichiro Tatsumi(5),TakayukiKuriyama(5),MasatoshiTagawa(2) (1)DepartmentofRespirology,SchoolofMedicine,ChibaUniversity;(2)DivisionofPathology,Chiba CancerCenterResearchInstitute;(3)DepartmentofDiagnosticPathology,SchoolofMedicine,Chiba University;(4)DivisionofGastroenterologicalSurgery,ChibaCancerCenter;(5)Departmentof Respirology,SchoolofMedicine,ChibaUniversity Keywords: genetherapy,adenovirus,p53,cellcycle,chemotherapy Abstractcontent: Malignantmesotheliomaisoneoftheintractablediseasesandtheprognosisremainspoordespite multimodaltreatments.weexaminedapossibletherapeuticstrategywithadenovirus(ad)mediated transductionofthewildtypep53geneincombinationwithanticanceragents,gemcitabineand pemetrexed.mostofmesotheliomacellsaredevoidofp14/p16genesandsubsequentlythep53 mediatedsignalpathwaysarefunctionallyinactivated.restorationofthepathwayscouldbea strategytoinducednadamageinducedapoptosisandtoincreasethesensitivitytoanticancer agents.transductionofhumanmesotheliomacellswithadbearingthecytomegaloviruspromoter linkedthep53gene(adp53)suppressedthesurvivaldependingontheadamountswhereasthead expressingbetagalactosidasegenedidnot.theadp53mediatedcytotoxicitywasinfluencedby expressionlevelsoftype5adreceptors,coxsackievirusandadenovirusreceptor(car)molecules,on targetcells.cellcycleanalysesshowedthattransductionwithadp53inducedg1phasearrest whereasgemicitabineandpemetrexeddidsphasearrest.bothadp53andtheagentsincreased subg1fractionsthereafter.combinatorytreatmentsofadp53andeithergemicitabineor pemetrexedproducedadditivecytotoxiceffectsinparticularonmesotheliomaexpressingcarata highlevel.cellcycleanalysessuggestedthataprecedenttreatmentofmesotheliomacellswith pemetrexedbeforeadp53administrationincreasedthesubg1populationcomparedwithother combinationschedules.cytotoxicassaysalsosupportedthescheduledependenteffects.thesedata collectivelyimplythattransductionwithadp53isapossibletreatmentmodalityformesothelioma andenhancedcytotoxicitybycombinationofanticanceragentsisanothertherapeuticoption. 85

88 ABSTRACTS Number:56 Abstracttitle: Noveltherapyformalignantpleuralmesotheliomabasedonantienergeticeffect:anexperimental studyusing3bromopyruvateinnudemice XiadongZhang(1),EmilieVarin(1),MélanieBriand(1),StéphaneAllouche(2),NatachaHeutte(1), LaurentSchwartz(3),LaurentPoulain(1),PhilippeIcard(4) (1)GRECANEA1772,Caen,France;(2)Laboratoiredebiochimie,CHUCaen,France;(3)Ecole polytechnique,saclay,france;(4)servicedechirurgiethoraciqueetcardiovasculaire,chucaen, France Keywords: mesothelioma,nudemice,glycolysis,energeticmetabolism,chemotherapy Abstractcontent: Purpose:Mostcancercellsexhibitincreasedaerobicglycolysisandusethismetabolicpathwayfor thegenerationofatpasamainsourceofenergy.thisimpairedmetabolismofglucose,leadingto thesecretionoflacticacideveninthepresenceofoxygen,isnamedthe Warburgeffect.Because cancercellsarepartlyormainlydependentonsuchpathwaytogenerateatp,inhibitionofglycolysis mayslowdowntheproliferationorkillcells. Experimentaldesign:Wetestedtheeffectof3Bromopyruvate(3BrPA)aloneorassociatedto cisplatinonnudemicepresentingintraperitonealcarcinomatosisdevelopedafterintraperitoneal injectionofhumanmesotheliomacells(msto211h). Results:3BrPAprolongedverysignificantlysurvivalofanimals.Combinedwithcisplatin,it demonstratedsignificantbenefitonsurvivalwhereascisplatinalonehasnoormildeffect. Conclusions:3BrPAmaythusconstituteaninterestingnovelanticancerdrugthatcouldbetestedin humans. 86

89 ABSTRACTS Number:57 Abstracttitle: Rapamycinintensifiescisplatincytotoxicityinmesotheliomacelllines MorLiHartman,MD(1),JohnM.Esposit(1),BeowY.Yeap(2),DavidJ.Sugarbaker(1) (1)NovelTherapeuticsLaboratory,DivisionofThoracicSurgery,BrighamandWomen'sHospital, Boston,MA,USA;(2)HematologyOncologyUnit,DepartmentofMedicine,MassachusettsGeneral Hospital,USA Keywords: mtor,rapamycin,cisplatin,dephosphorylation,pi3k/aktpathway,cytotoxicty Abstractcontent: Malignantpleuralmesothelioma(MPM)isanaggressivecancerthatrespondspoorlytostandard chemotherapeuticapproaches,withfiveyearsurvivallessthan1%.cisplatinisthe chemotherapeuticagentmostcommonlyused;however,itsmoderatetherapeuticimpactjustifies thesearchforadditionalagentstoenhanceitstherapeuticeffect.thephosphatidylinositol3kinase (PI3K)/Aktpathway,oftenactivatedinMPM,hasbeenimplicatedintheaggressivebehaviorofthis tumor,putativelybymediatingcellsurvivalandreducingsensitivitytochemotherapy.rapamycinis anestablishedinhibitoroftheakt/mtorpathway.wesoughttodeterminewhethercombined therapywithrapamycin+cisplatinwouldenhancecelldeathinmpm. HumanMPMcelllineswereincubatedwithrapamycinorcisplatinaloneorincombinationand assayedforcellviabilityovertime.aktanddownstreamproteinsofthemtorpathway,p70s6 kinaseand4ebp1,wereanalyzedatdifferentphosphorylationsites,tocharacterizethe dephosphorylationeffectsofdifferenttreatmentregimens. MPMcellsexhibitedarangeofsensitivitytoeachdrug.Rapamycin+cisplatinsignificantly(p=0.029) increasedcelldeathcomparedwitheitherdrugalone.combinedtreatmentcausedgreater dephosphorylationof4ebp1thaneitherdrugalone.inaddition,combinedtreatmentcaused dephosphorylationofaktandp70s6kinase.inatleastonecellline,h2052(cisplatinsensitivecell line),24hourpretreatmentwithrapamycincausedgreatercelldeathcomparedwithcombined treatmentalone.rapamycin+cisplatin. RapamycinappearstoenhancethesensitivityofcisplatininMPMcelllinesviathemTORpathway. Theresultsprovideabasisforclinicalevaluationofcombinedrapamycin+cisplatinchemotherapy. 87

90 ABSTRACTS Number:58 Abstracttitle: Thefibrinolyticsystemandgrowthofmalignantpleuralmesothelioma StevenIdell TheUniversityofTexasHealthCenteratTyler,Tyler,Texas,USA Abstractcontent: Malignantmesothelioma(MM)isalethalneoplasmforwhichcurrenttherapyisunsatisfactory, promptingthesearchfornewtherapeutictargets.thefibrinolyticsystemandtheurokinase plasminogenactivatorreceptor(upar)inparticularareimplicatedinthepathogenesisofanumber ofsolidneoplasmsbuttheirroleinthepropagationofmmisatpresentunclear.wefoundthatren humanpleuralmmcellsexpressed>10foldmoreoftheurokinasereceptorthanms1orm9kcells ormet5ahumanpleuralmesothelialcells.overexpressionofuparrelatestoinabilitytointernalize thereceptorandrencellslacklrpbutuparmrnaisstabilizedinthesecells.inaneworthotopic murinemodelofpleuralmm,thekineticsofrencelltumorigenesiswasacceleratedversusms1or M9Kcells,thatRENinstillatesgeneratedlargertumorsandcausedearliermortality.REN,MS1and M9KtumorsareallassociatedwithprominentextravascularfibrindepositionandexcisedRENtumor homogenateswerecharacterizedbymarkedlyincreaseduparexpressionatboththemrnaand proteinlevels.proliferativecapacityofrencellsrencellstraversedthreedimensionalfibringels whilems1,m9kandmet5acellswereimmotileinthissystem.uparsilencingoruparblocking antibodiesdecreasedrencellmigrationandinvasioninthissystemandinchamberanalyses,while upaandserumaugmentedtheeffects.upawasabsentinculturedrencellsbutwasdetectablein tumorhomogenatesandintherenderivedtumorsbyimmunohistochemistry.theseobservations linkupartothepathogenesisofmalignantpleuralmesotheliomaandsuggestthatthisreceptor contributes to accelerated tumor growth in part through interactions with upa. 88

91 ABSTRACTS Number:59 Abstracttitle: Cytologicaldiagnosisofpleuralmalignantmesothelioma(MM) Segal A(1), Whitaker D(1), Sterrett GF(1), Frost FA(1), Robinson BWS(2,3), Olsen N(3,4), Musk AW(2,3,4),CreaneyJ(2). (1)Path Laboratory Medicine, QEII Medical Centre, Western Australia; (2)National Centre for Asbestos Related Diseases, University of Western Australia; (3)Dept of Respiratory Medicine, Sir CharlesGairdnerHospital,WesternAustralia;(4)SchoolofPopulationHealth,UniversityofWestern Australia Abstractcontent: BACKGROUND:Cytologicalexaminationofeffusionspecimensprovidesanopportunitytoestablisha diagnosisofmmsometimesatanearlystageofdiseasepriortoadetectablemasslesion.however cytologicaldiagnosisiscontroversial(churgajsp2000),andisnotacceptedbysomepathologists andclinicians.toexaminetheroleofcytologyinthisdiagnosticsettingweconductedanauditof pleuralcytologyspecimensovera20yearperiod( ). MATERIALSANDMETHODS:PleuralspecimensreceivedatPathWestQEIIwereextractedfromthe databaseandanalysedtoidentifymmcases,anddeterminethenumberofcasesdiagnosedby cytologyandthefrequencywithwhichcytologybasedmmdiagnosiswasconfirmedbyadditional pathologyorbythewamesotheliomaregistry. RESULTS:9985pleuralsampleswerereceived(1740biopsy,8245cytology)from6198individuals. 801individualshadafinaldiagnosisofMM.544ofthesehadcytologicalmaterialexamined,and425 (78%)receivedacytologicaldiagnosisofMM.Followupinformationwasobtainedin404(95%).In 318casesthediagnosiswasconfirmedbybiopsy,electronmicroscopy(EM),and/ornecropsy.In86 casesmmwasconfirmedbywamesotheliomaregistrydata.twentyonecaseshadcytological diagnosisalone.thereweretwoincorrectdiagnosesofmminpatientswithmetastaticmalignancy tothepleura;bothoccurredpriortoavailabilityofspecificmesothelialmarkers.119patientswitha biopsydiagnosisofmmhadacytologyspecimenwhichwasnotdiagnosticofmm;49were diagnosedasatypicalorsuspiciousand70asnegativeformalignancy.ofthecasesnotestablished bycytology,40(34%)weresarcomatoidonbiopsy.positivepredictivevalueofacytological diagnosisofmmwas99.8%andpredictivevalueofamalignantdiagnosisinmmcaseswas100%. Absolutesensitivitywas78%;completesensitivity87%,andspecificity99.9%. CONCLUSION:ThevalueofcytologyinthediagnosisofpleuralepithelioidMMisunquestionable. Cytologyprovidesarapid,cheapandminimallyinvasivediagnosticmodality,andmayenableearly diagnosis.effusioncytologyisrarelyhelpfulinthediagnosisofsarcomatoidmm,andtherearesome casesofepithelioid/biphasicmmwhichrequirebiopsytoestablishadefinitivediagnosis. 89

92 ABSTRACTS Number:60 Abstracttitle: Biomarkersformalignantpleuralmesothelioma:currentstatus LaurentGreillier(1),PaulBaas(2),AlexandrePassioukov(1) (1)EORTCHeadquarters,Brussels,Belgium;(2)TheNetherlandsCancerInstitute,Amsterdam,The Netherlands Keywords: Biologicalmarkers,Diagnosticbiomarkers,Prognosticbiomarkers,Predictivebiomarkers,Malignant PleuralMesothelioma Abstractcontent: Malignantpleuralmesotheliomaisanaggressivetumor,whosemainetiologyistheexposureto asbestosfibers.theincidenceofmalignantmesotheliomaisanticipatedtoincreaseduringthefirst halfofthiscentury,bothindevelopedanddevelopingcountries.theprognosisofmalignantpleural mesotheliomapatientsispoor,withamedianoverallsurvivalwithouttreatmentoflessthan12 months.forvariousreasons,malignantpleuralmesotheliomaisdifficulttodiagnoseandthisdisease isnotoriouslyrefractorytomostoftreatments.however,twoactivechemotherapyregimenswere recentlydemonstratedtosignificantlyincreasemalignantpleuralmesotheliomapatients survival, andseveraltherapeuticagentsandstrategiesarecurrentlyunderevaluation. Fortwentyyears,therehasbeengreatenthusiasminthesearchformoleculesthatmayserveas biomarkersformalignantpleuralmesothelioma.indeed,biomarkerswouldbehelpfulinthree differentstepsofclinicalmanagementofmesotheliomapatients:earlydiagnosis,prognosis,and treatmentoutcomeprediction.theaimofthepresentreviewwastosummarizethepublishedand recentlypresenteddataonmalignantpleuralmesotheliomabiomarkers,todrawthecurrentstatus ofscientificknowledgeinthisdomainandtoidentifyperspectivesforfuturetranslationalresearch projects. 90

93 ABSTRACTS Number:61 Abstract title: The Diagnostic Accuracy and Reproducibility of Pleural Fluid Levels of Mesothelin in Unselected Patients with Pleural Effusions HEDavies(1),RSSadler(2),CEManners(1),RJODavies(1),BLFerry(2),YCGLee(1) (1)OxfordCentreforRespiratoryMedicine,ChurchillHospital,Oxford,UK;(2)Departmentof Immunology,ChurchillHospital,Oxford,UK Keywords: Mesothelioma,pleuraleffusion,pleuralfluidmesothelin,diagnosis,pleuralfluidcytology Abstractcontent: Pleuralfluidmesothelinlevelsareelevatedineffusionsfrommesothelioma.Thevalueofpleuralfluid mesothelinoverexistingdiagnostictestsandthereproducibilityofpleuralfluidmesothelinlevelshavenot beenestablished. Aim:To(i)assessthediagnosticvalueofpleuralfluidmesothelinlevelsinpatientswithundiagnosedpleural effusions;and(ii)determinevariationofpleuralfluidmesothelinlevelsovertimeinpatientswithpersistent effusions. Methods:Mesothelinconcentrationsweredeterminedin306pleuralfluidsamplesbyELISA(CISBio,France). Pleuralfluidwasprospectivelycollectedfrom139patientspresentingtoatertiarypleuralunitwitha previouslyundiagnosedpleuraleffusion,includingeffusionsfrommesothelioma(n=18),metastaticcarcinomas (n=57)andbenigncauses(n=64).serialsamplesofpleuralfluidwereobtainedfrompatientswhoreceivedan indwellingpleuralcatheter(n=19)orrepeatedthoracentesis(n=15). Results:Pleuralfluidmesothelinconcentrationsweresignificantlyhigher[median(range)42.8( ) nm/l]inthemesotheliomagroupcomparedwithmetastaticcarcinomas[5.95(086.7)nm/l]andbenign effusions[5.79(082.0)nm/l],p< Attheoptimalcutoffof20nM/L,thediagnosticsensitivityandspecificityofpleuralfluidmesothelinlevelsfor mesotheliomawere78%and87%respectively.allfalsenegativecasesweremesotheliomasofthesarcomatoid subtype. Pleuralfluidmesothelinmeasurementprovidedadditionalvalueovercytologicalanalysis.Ineffusionsnegative formalignantcellsoncytologicexamination(86of125),measurementofpleuralfluidmesothelinlevels offeredasensitivityandspecificityof70%and95%respectivelyforthediagnosisofmesothelioma. Importantly,pleuralfluidmesothelinlevelscorrectlyidentifiedallfourcasesofmesotheliomainpleuralfluids suspicious butnotdefiniteformalignantcells(n=7). Intraindividualreproducibilitywasexcellent.Inpairedpleuralfluidsamplesobtainedwithinsevendays,mean (±SD)variationofmesothelinwas0.11(±8.42)nM/Linmesotheliomapatients,and0.76(±6.02)nM/Linnon mesotheliomacases.pleuralfluidmesothelinlevelsincreasedsignificantlywithtime(r=0.595,p<0.0001)in mesotheliomapatients,reflectingdiseaseprogression. Conclusion:Pleuralfluidmesothelinprovidesadditionaldiagnosticvalueformesotheliomaovercytologic examination.mesothelinmeasurementsarehighlyreproducibleintheshortterm(<7days)butincreaseover timeinpatientswithmesothelioma. 91

94 ABSTRACTS Number:62 Abstracttitle: Theuseofmesothelinformonitoringpatientswithmesothelioma JenetteCreaney(1),AmandaSegal(2),AnnaNowak(1),RosFrancis(3),JohnAlveraz(4),BillMusk(1), BruceRobinson(1) (1)NRCARD,Australia;(2)PathWest,Australia;(3)UWA,Australia;(4)SCGH,Australia Keywords: mesothelin Abstractcontent: Numerousstudieshavedemonstratedthesensitivityandspecificityofthebiomarkermesothelinfor diagnosingmalignantmesotheliomabothinserumandineffusionsamples.thecurrentstudy examinedtheutilityofmesothelinformonitoringofpatients,bothduringthecourseofnatural diseaseprogressionandinresponsetotherapy. Longitudinalserumsampleswerecollectedfrommesotheliomapatientsduringthecourseof theirroutinestandardcare,andmesothelinconcentrationsweredeterminedusingthemesomark assay(fujirebiodiagnosticincorporated,malvernpa). Therewasgoodcorrelationbetweenmesothelinlevelandtumourstage,asdefinedbythe IMIGTNMstagingsystem)(r=0.579;p<0.05).Furthermore,mesothelinlevelswerecorrelatedin41 patientswithtumourburdenasmeasuredbypositronemissiontomography(pet).usingbaseline measures,therewasapositivecorrelationofmesothelinlevelswithtotalglycolyticvolume(tgv; r=0.4;p=0.01)andmaximumstandardizeduptakevalue(suvmax;r=0.34;p<0.05).changesin mesothelinlevelalsoreflectreductionintumourburdenasevidencedbythefindingthatanaverage 50%reductionofpresurgerymesothelinconcentrationwasobservedin14patientsfollowing extrapleuralpneumonectomy.in35patientswhounderwentpartialdebulkingsurgeryareductionin mesothelinlevelwasalsoobservedthoughtheaveragereductionwasapproximately15%of baseline.inover70%of52patientswhoreceivedchemotherapy(variousregimes)therewas concordancebetweenpatientresponse,atspecifiedtimepoints,asdefinedbyradiologicalmeasures andpercentchangeinmesothelinconcentration. Further,morecomplexanalyseoflongitudinalchangesinmesothelinlevelsisunderway however,atpresentweareconfidentthatthebiomarkermesothelinhasavaluableroletoplayin theclinicalmanagementofmesotheliomapatients. 92

95 ABSTRACTS Number:63 Abstracttitle: EarlychangeinserumVEGFandosteopontinduringtreatmentformesotheliomaispredictivefor survival. RozelleHarvie,FlorianPaturi,ZoltanZerestes,RossDavey,NickPavlakis BillWalshCancerResearchLaboratories,UniversityofSydney,Australia Keywords: VEGFosteopontinserumpredictivetreatmentsurvival Abstractcontent: Weevaluatedapanelofpotentialserummarkersfortheirpredictivevalueinacohortofpatients treatedwiththalidomidein2previouslyreportedphaseiitrials(n=62).serumlevelsofvascular endothelialgrowthfactor(vegf),osteopontin,creactiveprotein(crp),mesothelin,interlukin6and solubleil6receptorweremeasuredpretreatmentandafter8weeksusingelisamethod.survival correlationsweremadeusingunivariateanalyseswithmedianlevelsusedascutoff.onlyvegfand CRPshowedasignificantrelationshipbetweenpretreatment(baseline)levelandsurvival.Patients withvegf<medianhadameansurvivalof70weekscomparedto31weeksforthosewith>median VEGFlevels(P<0.05).MeansurvivalwhenCRP<medianwas62weekscomparedto31weekswith CRP>median(P<0.05).Thechangebetweenbaselineand8weekVEGFandosteopontinwasalso prognosticofsurvival.decreasingvegfwasassociatedwithameansurvivalof79weekscompared to39weeksforincreasingvegf(p<0.05).decreasingosteopontinwasassociatedwithamean survivalof108weekscomparedto47weeksforincreasedlevels(p<0.05).vegfchangeon treatment(increasingordecreasing)waspredictiveregardlessofbaselinevegf.patientswithhigh baselinevegfanddecreasingvegfhadameansurvivalof56weekscomparedto26weeksfor thosewithincreasingvegf(p<0.05).likewise,osteopontinchangeontreatment(increasingor decreasing)waspredictiveinpatientswithbothhighorlowbaselinevegf:patientswithhigh baselinevegfanddecreasingosteopontinhadameansurvivalof92weekscomparedto45weeks forthosewithincreasingosteopontinlevels(p=0.05).changeinosteopontinlevelwasalso prognosticinthepatientgroupwithlowpretreatmentvegf:patientswithdecreasingosteopontin hadameansurvivalof125weekscomparedto62weeksforthosewithincreasingosteopontin (P<0.05).ThesefindingssuggestthatthechangesinVEGFandosteopontinduringtreatmentmaybe moreusefulaspredictivemarkersthantheirpretreatmentlevels.changesinvegfandosteopontin mayprovideameansofmonitoringtreatmentresponseinmesotheliomaandshouldbeevaluated prospectively. 93

96 ABSTRACTS Number:64 Abstracttitle: Oncolytictype5adenoviruseswithtype35fiberknobstructureproducebettercytotoxiceffectsto mesotheliomacellsthatexpressthetype5cellularreceptorsatalowlevel MasatoshiTagawa(1),KiyokoKawamura(1),GuangyuMa(1),QuanhaiLi(1),YujiTada(2),Taro Ueyama(2),YuichiTakiguchi(2),KoichiroTatsumi(2),HideakiShimada(3),KenzoHiroshima(4) (1)DivisionofPathology,ChibaCancerCenterResearchInstitute,Chiba,Japan;(2)Dept.of Respirology,GraduateSchoolofMed.,ChibaUni.,Chiba,Japan;(3)DivisionofGastroenterological Surgery,ChibaCancerCenter,Chiba,Japan;(4)Dept.ofDiag.Path.,GraduateSchoolofMed.,Chiba Univ.,Chiba,Japan Keywords: genetherapy,adenovirus,coxsackievirusandadenovirusreceptor,cd46,e1a,tumorpromoter Abstractcontent: Weinvestigatedapossibleapplicationofadenoviruses(Ad)mediatedcelldeathtomesothelioma treatments.thee1ageneofadencodesatranscriptionalfactorthatregulatestheviralreplication andsphaseentryofcellcycleintheinfectedcells.adinwhichthee1aexpressionisregulatedwith anexogenouspromoterreplicatedependingonthepromoterspecificityandcanproduce cytotoxicitytotheinfectedcellsaccordingly.controllede1aexpressionwithtumorspecificity therebyrenderstheadcytotoxictotheinfectedtumors.weexaminedtranscriptionalactivitiesof regulatoryregionsofthemidkine,survivingandcyclooxygenase2genesandfoundthatthese putativetumorpromoterscouldactivateareportergeneinmesotheliomacells.wedevelopedtype 5Ad(Ad5)byintegratingtheputativetumorpromoterslinkedwiththeE1AandE1Bgenes.TheseAd poweredbythepromotersachievedcytotoxiceffectstohumanmesotheliomacelllinesand producedoncolyticactivitieswithminimaltoxicitytonormalcells.theseoncolyticadhoweverdid notproducesignificantantitumoreffectsinsomecelllines.infectivityofad5tocellsisprimarily mediatedbytheinteractionbetweentheadfibersknobregionandthecoxsackievirusand adenovirusreceptor(car).downregulatedcarexpression,oftenfoundinhumantumors, hamperedad5mediatedgenetransfer.thecarexpressionlevelofmesotheliomacellswasvariable andtheinfectivityofad5tocarlowexpressingcellstherebydiminished.thedecreasedantitumor effectswithoncolyticad5couldbeattributabletothedownregulatedcarexpression.type35ad usecd46moleculesastheircellularreceptorsandexpressionlevelsofcd46ontumorswerenot downregulated.chimericad5inwhichthefiberknobstructurewassubstitutedwiththatofthe type35(ad5f35)wouldinfecthumancellsinadifferentmannerfromad5.wefoundthatad5f35 infectedmesotheliomacellsbetterthanad5andthatoncolyticad5withthefiberknobreplacement producedgreaterantitumoreffectsthanunmodifiedad5particularlytocarlowexpressing mesotheliomacells.thesedatasuggestthatthefiberknobmodifiedad5poweredbyputativetumor promotersareapotentialtherapeuticmodalitytomostofmesotheliomaandcouldbeafeasible strategyincombinationwithconventionalchemotherapy. 94

97 ABSTRACTS Number:65 Abstracttitle: Immunologicalchangesinmesotheliomapatientsandtheirexperimentaldetection TakemiOtsuki(1),YoshieMiura(1),YIngChen(1),MegumiMaeda(1),ShukoMurakami(1),Naoko Kumagai(1),HiroakiHayashi(1),KozoKuribayashi(2),KazuyaFukuoka(2),TakashiNakano(2),Takumi Kishimoto(3),YasumitsuNishimura(1) (1)DepartmentofHygiene,KawasakiMedicalSchool,Japan;(2)DepartmentofRespiratoryMedicine, HyogoMedicalCollegeofMedicine,Japan;(3)OkayamaRosaiHospital,Japan Keywords: mesothelioma,immunology,tumorimmunity,apoptosis,cytokine Abstractcontent: Itiscommonknowledgethatasbestosexposurecausesasbestosrelateddiseasessuchasasbestosis, lungcancerandmalignantmesothelioma(mm)notonlyinpeoplewhohavehandledasbestosinthe workenvironment,butalsoinresidentslivingnearfactoriesthathandleasbestos.thesefactshave beenanenormousmedicalandsocialprobleminjapansincethesummerof2005.toanalyzethe possibilitythatimmunologicalalterationinasbestosrelateddiseases(ards)suchasasbestosis(asb) andmalignantmesothelioma(mm)mayaffecttheprogressionofcancers,ahumanadulttcell leukemiavirusimmortalizedtcellline(mt2org)wascontinuouslyexposedto10g/mlofchrysotile B(CB),anasbestos.Afteratleast8monthsofexposure,therateofapoptosisinthecellsbecame verylowandtheresultantsublinewasdesignatedmt2rst.themt2rstcellswerecharacterizedby (i)enhancedexpressionofbcl2,withregainofapoptosissensitivitybyreductionofbcl2bysirna, (ii)excessil10secretionandexpression,and(iii)activationofstat3thatwasinhibitedbypp2,a specificinhibitorofsrcfamilykinases.theseresultssuggestedthatthecontactbetweencellsand asbestosmayaffectthehumanimmunesystemandtriggeracascadeofbiologicaleventssuchas activationofsrcfamilykinases,enhancementofil10expression,stat3activationandbcl2 overexpression.thisspeculationwaspartiallyconfirmedbythedetectionofelevatedbcl2 expressionlevelsincd4+peripheralbloodtcellsfrompatientswithmmcomparedwiththosefrom patientswithasborhealthydonors.furtherstudieswillberequiredtoverifytheroleoftcellswith enhancedbcl2expressionintumorprogressioninducedbyasbestosexposure.inaddition,high plasmaconcentrationsofinterleukin(il)10andtransforminggrowthfactor(tgf)ß,andmultiple overrepresentationoftcellreceptor(tcr)vßinperipheralcd3+tcellsfoundinmmpatients.we alsodetailanexperimentallongtermexposuretcellmodel.analysisoftheimmunologicaleffects ofasbestosmayhelpourunderstandingofthebiologicaleffectsofasbestos. 95

98 ABSTRACTS Number:66 Abstracttitle: Dendriticcellbasedimmunotherapyformalignantpleuralmesothelioma JoachimAerts(1),JorisVeltman(1),MargarethaLambers(1),BartLambrecht(2),HenkHoogsteden(1), JoostHegmans(1) (1)ErasmusMedicalCenter,Rotterdam,theNetherlands;(2)UniversityofGhent,Belgium Keywords: dendriticcells,immunotherapy,phaseistudy Abstractcontent: Introduction: Dendriticcells(DCs)areextremelypotentantigenpresentingcellsspecializedforinducingactivation andproliferationofcd8+cytotoxictlymphocytesandotherlymphocytes.exploitingthese immunostimulatorycapacitiesofdcsholdsgreatpromiseforcancerimmunotherapy.dcscanbe generatedinlargeamountsinvitro,intheabsenceofthesuppressingtumormicroenvironment,and subsequentlyinjectedinamaturestatetoinduceantitumorresponses.aphaseiclinicaltrialwas initiatedtodefinethesafetyandtoxicityoftumorlysatepulseddcsinjectedinpatientswith mesotheliomaafterchemotherapy.secondaryendpointsincludeimmuneresponsesbyskindelayed typehypersensitivityreactionsonmesotheliomacelllysatesandthecontrolantigenkeyholelimpet hemocyanin(klh)bothinvivoandinvitro. Methods: Patientswithenoughtumorcells(>150x10e6tumorcells)intheirpleuraleffusionattimeof diagnosiswereincludedinthestudy.tumorcelllysatesweregeneratedbyrepeatedfreezethaw cyclesandirradiation.afterchemotherapy,patientsunderwentleukapheresis.monocyteswere isolatedbyelutriationanddcscouldbeculturedinsufficientamountusinggmcsfandil4.after5 daysinculture,dcwerepulsedwithautologoustumorlysateandklh.acytokinecocktailinduced thefinalmaturationstepatday8.themorphologyandphenotypeofculturedcellswasconsistent withdendriticcells.ninepatientsreceivedthethreeplanneddcvaccinationsandarecurrently followed. 96

99 ABSTRACTS Results: ThisstudyshowedthatinjectionofDCswasoverallwelltoleratedwithoutsystemictoxicity,withthe exceptionofalowgradeflulikesymptoms:fever,rigors,andatemporarilylocalskinreactionafter DCinjection(mildgrade1or2).LocalaccumulationofTcellswerefoundatthevaccinationsites.All participantsthusfarexperiencednorashorlymphadenopathyordevelopedanyclinicalevidenceof autoimmunityorrheumatoiddisease.dthandstrongantibodyimmuneresponses(igmandigg)on KLHwereseeninallpatientsindicatingthatimmuneresponsesweregenerated.Itisimportantto emphasizethatseverallaboratorytestsneedtobeperformedtoallowfirmconclusions(e.g.invitro assaysoflymphocytefunction). Discussion&conclusion: FirstresultsfromourphaseIclinicaltrialindicatethatDCimmunotherapyissafeandfeasiblefor mesotheliomapatients. 97

100 ABSTRACTS Number:67 Abstracttitle: Lowdosecyclophosphamidesynergizeswithdendriticcellimmunotherapyinantitumoralresponses inamousemodelformesothelioma JoostHegmans(1),MargarethaLambers(1),JorisVeltman(1),SanneDeJong(1),BartLambrecht(2),HenkHoogsteden(1), JoachimAerts(1) (1)ErasmusMedicalCenter,Rotterdam,theNetherlands;(2)UniversityofGhent,Belgium Keywords: dendriticcells,immunotherapy,regulatorytcells,cyclophosphamide Abstractcontent: Introduction: Malignantmesothelioma(MM)isacancerwithdismalprognosis.Currentlyweareinvestigatingdendriticcell basedimmunotherapyinpatientswithmmafterchemotherapy.furtheroptimizationinmiceisrecommended toexploitthefulltherapeuticpotentialofdendriticcells.itisknownthattumorcellscreatean immunosuppressiveenvironmentthatcanleadtoadownregulationoftheantitumorimmunity.onetypeof suppressivecells,theregulatorytcells(tregs)seemsinstrumentalinallowingagrowingcancertoevade immunologicalattack.thesecellsmaycontributetotheimpairedtcellfunctionfrequentlyobservedin mesotheliomapatients.thegoalofthisstudyistoinvestigatemeasuresthatcanovercomethesuppressive functionofregulatorytcellsincombinationwithdcimmunotherapytoincreasethesuccessrateoftumor eradication. Materials&Methods: Atday0,immunocompetentBALB/cmicewereinoculatedwithalethaldoseofAB1mesotheliomatumorcells. TumorlysatepulsedDCswereadministratedintraperitoneallyatday10.CTXwasaddedtothedrinkingwater fromday3tillday10and/orfromday14tillday21.micewerekilledifprofoundlyill,andscoreddeathin survivalanalysis.tumors,bloodandlymphnodeswereexcisedandanalyzedfortregsusing immunohistochemicalstainingsandflowcytometry. Results: IncreasednumbersofTregswerefoundwithintheblood,draininglymphnodes,andtumorsofmicewith mesothelioma.administrationoflowdosectxpreventedtheinductionoftregsleadingtoanincreased survival.notoxicsideeffectswereobservedinmicereceivinglowdosectx. Discussion&conclusion: Wedemonstrateinamousemodelthatimmunotherapyusingstimulateddendriticcellsisapowerfultoolto controlmmoutgrowth.wefoundthatlowdosecyclophosphamideinducedbeneficialimmunomodulatory effectsbyreducingthelevelsoftregs.itimprovesdcbasedimmunotherapyleadingtoanincreaseinmedian andoverallsurvival.futurestudieswilldemonstratetheusefulnessofthiscombinationtreatmentin mesotheliomapatients. 98

101 ABSTRACTS Number:68 Abstracttitle: 5T4asatumourassociatedantigeninmalignantpleuralmesothelioma SalyAlTaei(1),SeamusLinnane(2),MalcolmMason(1),ZsuzsannaTabi(1) (1)VelindreHospital,CardiffUniversity,UK;(2)LLandoughHospital,UK Keywords: MalignantPleuralMesothelioma,Immunotherapy,5T4 Abstractcontent: Malignantpleuralmesothelioma(MPM)isamalignancyofthelungmesotheliumwithlatediagnosis andresistancetoconventionaltreatments.alternativestrategiesareneededtoimprovedisease prognosis.preclinicalmodelsofmpmhaverespondedfavourablytoimmunotherapeutic approachesbutcancervaccinedesignishamperedbytherelativelackofmpmassociatedtumour antigens.5t4isa72kdaoncofoetalantigen,highlyexpressedonawiderangeoftumours;the cancervaccinetrovax (modifiedvacciniavirusankaraencoding5t4)ispresentlyundergoingphase IIIclinicaltrialsinrenalcancer.Theaimofourprojectwastoassessif5T4mayserveasan immunologicaltargetinmpm.wehavestudiedtheexpressionof5t4inmesotheliomacelllinesand alsointhecellularfractionofpleuralfluidsamplesobtainedfrommpmpatients.varyinglevelsof 5T4cellsurfaceexpressionwasidentifiedbyflowcytometryin19outof19celllinesandin6outof6 pleuralfluidsampleswheretumourcellswereidentifiableinthecellularfractionbyflowcytometry. Thefindingswereconfirmedbywesternblotting.5T4specificCD4+memoryTcellresponseshave beendetectedinapatientwith5yeardiseasefreesurvivalfollowingpneumonectomy.ongoing workisfocusingonscreeningmpmpatientsfor5t4memorytcellresponsesandcharacterisingt cellswiththerelevantspecificities.takentogether,wereporthereforthefirsttimethe overexpressionof5t4onmesotheliomacells,indicatingthat5t4isapotentialnewtargetantigenfor theimmunotherapyofmpm. 99

102 ABSTRACTS Number:69 Abstracttitle: Immunochemotherapyreducesrecurrenceofmalignantpleuralmesothelioma LucaAmpollini(1),AlexSolteramnn(2),EmanuelaFelleyBosco(3),DididerLardinois(1),Stephan Arni(1),RobertoSpeck(4),WalterWeder(1),IsabelleOpitz(1) (1)DivisionofThoracicSurgery,Zurich,Switserland;(2)InstituteofSurgicalPathologyZurich, Switserland;(3)LaboratoryofMolecularOncology,Zurich,Switserland;(4)DivisionofInfectious DiseasesandHospitalEpidemiologyZurich,Switserland Keywords: ImmunotherapycisplatinintrapleuraltolllikereceptorsCpGODN Abstractcontent: Objective:Toassesstheeffectofimmunochemotherapyontheextentoflocaltumourrecurrencein anestablishedratmodelofmalignantpleuralmesothelioma(mpm). Methods:SixdaysaftersubpleuralinoculationofasyngeneicMPMcellline(IL45),tumournodule wasresectedafterleftsidedpneumonectomy.animalswererandomizedinto4treatmentsgroups forintrapleuraltherapy:control(n=6),500;gcpgodn(cytosinephosphateguanosine oligodeoxynucleotide)(n=6),cisplatinfibrin(n=6),cisplatinfibrin+500;gcpg(n=6).6dayslaterthe volumeoftumourrecurrencewasassessed,whichwastheprimaryendpoint.secondaryendpoints werethesrygene(sexdeterminingregiony)expressionforquantificationoftheratiohost/tumour cellsinthelocalrecurrenceandcytokineexpressionprofileinthetumourtissuebyqpcr.t lymphocytesubpopulationsinthetumourrecurrencetissuewereevaluatedby immunohistochemistry.treatmentrelatedtoxicitywasassessedbyrepeatedbloodsampling. Results:Thevolumeoftumourrecurrencewassignificantlyreducedfrom610mm3inthecontrol groupto11.7mm3inthecisplatinfibringroup(p=0.004)andto21.8mm3inthecisplatinfibrin+cpg group(p=0.004).proinflammatorycytokines(ifn,il6,il12)wereincreasedaftertreatmentwith cisplatinfibrin+cpgincomparisontocisplatinfibrinalonebutdifferenceswerenotstatistically significant.thedeterminationofsrygenebyqpcrtechniqueshowedahigherratioofhost/tumour cellsinthecisplatinfibrin+cpggroup(45/55%)comparedtothecisplatinfibringroup(27/73%).in comparisontothecontrolgroup,animalstreatedwithcisplatinfibrin+cpgshowedastatistically significanthighernumberofcd8+cellsinthetumourtissue(p<0.05).nosignificanttreatment relatedtoxicitywasobserved. Conclusions:Adjuvanttreatmentwithchemoorchemoimmunotherapyleadstosignificant reductionofmesotheliomarecurrenceaftersurgeryinthisratmpmmodel.chemoimmunotherapy resultedinanincreasedrecruitmentofinflammatorycellstothesiteoftumourigenesisandelicited higherleveloftumourgrowthinhibitingcytokines. 100

103 ABSTRACTS Number:70 Abstracttitle: Theeffectofchemotherapyontheimmunesysteminpatientswithmalignantmesothelioma Melanie.J.McCoy,RobbertGvanderMost,AnnaK.Nowak&RichardA.Lake TumourImmunologyGroup,NationalResearchCentreforAsbestosRelatedDiseases,Universityof WesternAustralia Abstractcontent: Chemotherapyandimmunotherapyhavehistoricallybeenconsideredantagonistictreatment modalitiesduetothevariablelymphopaeniaexperiencedasasideeffectofmanycytotoxicdrugs. Recentlyhowever,researchusinganimalmodelshasdemonstratedthatcertainchemotherapy drugs,despitecausingdecreasesinlymphocytenumbers,canactuallyenhancetheanticancer immuneresponse,possiblyviatheinductionof immunogenic tumourcelldeath.wearecurrently undertakingastudytodeterminetheeffectofdifferentchemotherapyregimesontheantitumour immuneresponseinpatientswithmesothelioma.thegenerationofaneffectiveimmuneresponse againstatumourinvolvesthepresentationofantigentocd8+effectortcells,whichareabletokill tumourcellsdirectly.tregulatorycells(tregs),ontheotherhand,havebeenshowntoexerta suppressiveeffect.theeffectofchemotherapyonthesetwocelltypesisthereforebeingspecifically assessed.onceknown,thiswillhavemajorimplicationsforthedevelopmentofcombinedchemo immunotherapytreatmentprotocols.patientswithhistologicallyorcytologicallyconfirmed mesotheliomawhoaretobeginchemotherapyaspartofusualcarearebeinginvitedtotakepartin thestudy.bloodsamplesaretakenfrompatientspriortocommencementofchemotherapyand thenat3timepointsacrossthecourseoftreatment.ourworkconfirmsthefeasibilityofusing8 parameterflowcytometrytoperformlongitudinalanalysesofchangesinthenumber,activation statusandproliferationofcd8+tcellsandtregs. 101

104 ABSTRACTS Number:71 Abstracttitle: Modulationoftranslesionsynthesis:Impactonchemotherapyresistanceinmalignantpleural mesothelioma ThomasMichaelMarti,EmanuelaFelleyBosco,StefanieKurtz,AlexandraGraf,RolfArnoStahel, PhilipAlexanderKnobel UniversityHospitalZuerich,Switzerland Keywords: translesionsynthesis,rev3,malignantpleuralmesothelioma,sirna,shrna,cisplatin Abstractcontent(maximal350words,nographs): Background:Malignantpleuralmesothelioma(MPM)ismostcommonlytreatedwithamultimodality therapyincludingtreatmentwithcisplatinorcisplatinanalogues,whichleadtotheformationof interorintrastranddnaadducts.cisplatinadductscanberepairedor,ifnotrepaired,induce replicationforkstallingwhichcanbyovercomebyspecifictranslesionpolymerases. Translesionpolymeraseζconsistsoftwosubunits,Rev3isthecatalyticandRev7the structuralsubunit.thetranslesionpolymeraseζisresponsibleforthetranslesionsynthesis (TLS)ofcisplatinbasedadductsandtherepairofDNAinterstrandcrosslinks.Rev3deficient vertebratecelllinesshowthehighestsensitivitytocisplatincomparedtootherrepairdeficientcell lines.rev3inhibitionbyantisensetreatmentconfershighercisplatinsensitivityandlower mutagenicityinimmortalhumanfibroblasts. Workinghypothesis:DownregulationofRev3sensitizesMPMcellstocisplatintreatmentand reducestheformationofcisplatinresistance. Results:WeshowedthattheexpressionofRev3inhumanMPMcellsisdependentoncellculture confluencyandisalsoaffectedbycisplatintreatmentinatimedependentmanner.functional inhibitionofrev3bysirnaincreasedreplicationforkbreakdownasindicatedbyenhancedh2ax phosphorylation.rev3expressioninratandhumanmpmcellswassuccessfullyinhibitedby transienttransfectionwithplasmidscontainingshorthairpinconstructstargetingrev3. WegeneratedstableHEK293andhumanlungfibroblast(Wi38SV40)celllineswithdecreasedREV3 expression.functionalinhibitionofrev3inthehek293andwi38sv40celllinesresultedin increasedgenotoxicstressasindicatedbyincreasedp53expression,aslowergrowthrateand increasedcisplatinsensitivity. Conclusions:WeshowedthatfunctionalinhibitionoftranslesionpolymeraseζbyshRNA againstrev3increasedreplicativestressinmpmcelllinesandincreasedcisplatinsensitivityin humancells. 102

105 ABSTRACTS Number:72 Abstracttitle: NONSPECIFICACTIVEIMMUNOTHERAPYINCREASEDSURVIVALINMALIGNANTMESOTHELIOMA MarieMarthePhilippeaux(1),JeanClaudePache(1),ClaudeIrle(2),JeanLucMagnenat(3),John Robert(1),AnastaseSpiliopoulos(1) (1)GenevaUniversityHospital,Switserland;(2)GenevaLaTourHospital,Switserland ;(3)Geneva ClinicalCarouge,Switserland Keywords: Nonspecificactiveimmunotherapymacrophagesimmunitytherapy Abstractcontent: Introduction: Immunizationwithaninactivatedbacteriavaccineisawaytocreateimmunityagainstcertain diseases.theinjectionof* Pneumovax23 priortothesurgicaltreatmentofmalignant mesothelioma(mm)isatooltotagettumorcells(tc)bymountinganimmuneresponse.the successofthisapproachdependsupontheabilitytostimulateeffectivelyboththecellmediatedand theantibodymediatedimmunity,whichmustworkinconcerttoovercometcgrowth.inthisreport, weexaminedthepossibilitytoactivatetheimmunesysteminordertoslowdowntcproliferationor tomaintainthecellsinadormantstateallowingthedevelopmentofanappropriatetreatment.* [Pneumococcalpolysaccharidevaccine(PPV)] MethodsandResults Threepatientsacceptedtodonate50mlofperipheralbloodcellstoevaluatetheircellmediated immunereactivityafterpneumopleurectomy.peripheralbloodcellswereseparatedbygradient centrifugationandcultivatedoncollageninthepresenceofagram+bacteriavaccine(ppv)andtc supernatant. Resultsdemonstratedtheproliferationoflargegranularlymphocytes,Bcellsandmacrophages(Mø). Theseindicateastimulatingeffectanddifferentiationofmonocyticcells.ACytotoxicassay demonstratedthatactivatedmacrophages(am)wereabletokilltc. Twopatientsdiedsomemonthslaterwithoutanyvaccination.TheThirdone,whoreceivedagram+ vaccine3monthsbeforethesurgicaltherapy,continuedthechemotherapyandwasclinicallyfitand abletoreturntoworkat40%.hedidnotreceiveanyothertherapyfor4yearsbeforeexperiencinga recurrence,provenbypathologicalanalysis.monocyticcellproliferationwasnotobservedinvitro. Thepatientwasimmediatelyreboostedwith Prevenar7 **.Thisinjectionwasassociatedwith peripheralbloodcellproliferation.twoyearslater,thisresponsedisappearedagain. 103

106 ABSTRACTS Thisobservationsuggestedthatsuccessiverevaccinationshouldbeprovidedwheneveradecreasein theimmuneresponseoccurs,whichmaylastaslongas2years.hereceivedanewinjectionofpcvin June2008.**[Pneumococcalconjugatevaccine(PCV)] PerspectiveandConclusion: Inafutureassay,treatmentbasedonthetransfertofautologousAMbyadoptiveimmunotherapy willbeusedasanotherarmagainsttc. Thisstudyreportsforthefirsttimemarkedprolongationofsurvivalwithagoodqualityoflifeforthe patienttreatedwithassociatedtherapies,includingnonspecificactiveimmunotherapy. Thisisasingleinformativeandundergoingcasereportwithanunusuallylongsurvivalofalmost7 yearsaftertheonsetofmm.futurestudiesofthecorrelationbetweenthevaccinationresponseand clinicalevolutionarewarranted. 104

107 ABSTRACTS Number:73 Abstracttitle: Internationalmortalitytrends JulianPeto(1),ChristineRake(2),ClareGilham(2),AndrewDarnton(3),JohnHodgson(3) (1)LondonSchoolofHygieneandTropicalMedicine,UK;(2)InstituteofCancerResearch,London,UK; (3)UKHealthandSafetyExecutive Keywords: UK,Australia,mesothelioma,amosite,casecontrol Abstractcontent: By1970theUKhadstoppedusingcrocidoliteandledtheworldinasbestosregulation,yetitnowhas over2,000mesotheliomadeathsperyear,thehighestrateintheworldandfivetimesthatintheus inmenbornbetween1940and1955. WeconductedthefirstUKpopulationbasedstudyofmesotheliomaandthelargestworldwide, interviewing612mesotheliomapatientsand1420controls.wealsocompareddeathrates,asbestos importsandmale:femalemortalityratiosofmesotheliomainothercountriestoassessthe contributionofdifferentasbestostypesonmesotheliomaratesandtoestimatethebackgroundrate intheabsenceofasbestosuse. Ourmainconclusionisthatenduserexposuretoamositewasamajorcauseoftheextraordinary mesotheliomarateinbritishmenborninthe1940s.theukwasthemainimporterofamosite, whichcarriedthesamecontrollimitaschrysotileuntil1983.currentmesotheliomamortalityand historicalpatternsofamositeuseinaustraliaaresimilartothoseintheuk. Otherfindingsinclude:(1)about1in17ofBritishcarpentersand1in50ofplumbers,electricians andpaintersbornbetween1940and1950willdieofmesothelioma;(2)onlyabout1%of mesotheliomaswerecausedbyworkinasbestosfactories;(3)thereappearstobeaworldwide backgroundrateunrelatedtoasbestosproducingalifetimeriskofapproximately1per5,000inboth sexes;(4)theexcessrateabovethisbackgroundinwomenthroughouttheworldisapproximately onetenthofthemalerate;and(5)thelifetimeriskinbritishmenandwomenwhoreportno potentialasbestosexposureisfourtimesthisbackground(almost1per1,000),suggestingthat mesotheliomaswerecausedbyunsuspectedasbestosexposureinawiderangeofoccupationaland nonoccupationalsettings. 105

108 ABSTRACTS Number:74 Abstracttitle: TheLatrobeValleyPowerIndustryCohortStudy:Amultidisciplinaryapproachtostudyingasbestos relateddiseases AnthonyLaMontagne(1),DeborahVallance(1),JenetteCreaney(2),RichardLake(2),Andrew Holloway(3) (1)UniversityofMelbourne,Australia;(2)UniversityofWesternAustralia;(3)PeterMacCallum CancerCentre,Australia Keywords: cohortstudy Abstractcontent: TheLatrobeValleyhasbeenthesiteofelectricitygenerationfortheStateofVictoria,Australia,since the1920 s.largeamountsofasbestoswereusedintheconstructionandmaintenanceofpower stations,andsignificantasbestosexposureshavebeendocumented.themortalitydueto mesotheliomainthelatrobevalleyisthehighestinvictoria,at4.6timesthestateaverage.this concentrationofcases,plusthefactthattheformerstateelectricitycommission(sec),a governmentbodyresponsibleforconstructionandoperationofthepowerstations,wasthe dominantemployerofahighlyunionisedworkforcemakesthelatrobevalleyanidealplaceto recruitandstudyacohortofhighlyasbestosexposedindividuals.anestimated55,000currentor formersecworkerswerestillalivein2003. WehaveusedacombinationofalocalCommunityGroupandrelevantTradeUnionstoassistwith therecruitmentofapproximately900(outofananticipatedtotalof1,000)currentorformerpower industryworkersintothestudy.allparticipantsareaskedtodonateabloodsampleeachyearfor threeyearsandtodate,morethan300bloodsampleshavebeencollected.eachparticipantisalso askedtocompleteadetailedquestionnairefromwhichwewillcalculatelikelyasbestosexposure, andcollectotherdemographicandhealthrelatedinformation.wehavealsocommenced determinationofmesothelinlevelsinthebloodsamplestoquantitatethenaturalvariationinthis protein slevelsinanotherwisehealthyasbestosexposedpopulation.wearealsoofferingatailored smokingcessationprogramtoanysmokersinthecohort.whereaparticipanthasconsented,all samplescollectedareavailabletootherresearchersconductingethicallyapprovedresearchinto asbestos. Wewillpresentourconsiderationsaroundthedesignofthestudy,someanalysisofthecohortto date,andpreliminaryresultsofmesothelintesting.wewillalsodiscusshowresearchersmayuse thisresourceintheirresearch. 106

109 ABSTRACTS Number:75 Abstracttitle: TheFrenchnationalprogramforpostoccupationalsurveillanceofsubjectsexposedtoasbestos PatrickRolland(1),MatthieuCarton(2),JulieHomère(1),MelissaNachtigal(2),AlexisGaignon(2), SophieBonnaud (2),SabyneAudignon(3),PatrickBrochard(3),EllenImbernon(4),MarcelGoldberg(5) (1)InstitutdeVeillesanitaireDépartementSantéTravailEssatBordeaux,France;(2)EquipeRisques postprofessionnelscohortesinsermu687villejuif,france;(3)universitébordeauxispedlste EssatBordeaux,France;(4)InstitutdeVeillesanitaireDépartementSantéTravailSaintMaurice, France;(5)InVSDSTSaintMaurice&EquipeRPPCInsermU687Villejuif,France Keywords: occupationalasbestosexposure,retiredworkers,medicalsurveillance,epidemiologicalsurveillance, cancers Abstractcontent: Backgroundandaims:TheFrenchnationalInstitutesforPublicHealthSurveillance(InVS)andfor MedicalResearch(Inserm)haveestablishedasurveillanceprogramforretiredsubjectsexposedto asbestosduringtheirworkinglife.itsobjectivesaretoidentifyexposedworkersandtopropose themamedicalsurveillance,todescribepastexposuresandtheirlongtermhealtheffects,andto assesstheprogramintermsofbenefitsforhealthandcompensation. Methods:Since2005,twoprospectivecohortsofretiredworkershavebeensetupamongformer malesalariedworkers( Spirale cohort)andselfemployedcraftsmen( Espri cohort).in2008,both cohortscover31french départements (coveringonethirdofthepopulation).eachyear,a questionnaireismailedtonewretiredworkers(50000salariedworkersand4500craftsmen)to detectpastoccupationalasbestosexposure.theexposureassessmentismadebymedicaland industrialhygieneexperts.themedicalsurveillanceisproposedtosubjectsaccordingtospecific exposurecriteria.thefrenchnationalmedicaldatabasesareusedforthecohortfollowup. Results:Duringthepilotstage( ),theparticipationratewas24%forsalariedworkers (withoutreminder)and67%forcraftsmen(withonereminder).heavyexposureswerefoundfor occupationsinconstruction,shipbuildingandfabricationofmetalproducts,andalsoformotor vehiclemechanics.firstestimatesofthelifelongprevalenceofoccupationalasbestosexposure indicatedthanaboutonehalfofretiredcraftsmenhavebeenexposedduringtheirworkinglife, versusonequarterofthesalariedworkers.amongcraftsmenwhohadachestctscan,aboutone quartershowedasbestosrelatedabnormalitiesorpathologies,essentiallypleuralplaques. 107

110 ABSTRACTS Discussionandconclusions:ThefirstresultsfromtheFrenchnationalprogramforpostoccupational surveillancehighlightedtheexpectationofretiredworkersforsurveillanceofpastoccupational exposures.itsexpansiontothewholeterritoryisplannedandwillincludearound250000male salariedworkersretiringeachyearand17000selfemployedcraftsmen.theassessmentofthe impactoftheprogramonbenefitsforhealthandcompensationduringthecohortfollowupwill provideguidanceforpublicpolicyaboutsurveillanceofworkersexposedtocarcinogenicagents. 108

111 ABSTRACTS Number:76 Abstracttitle: ApublichealthcritiqueofSouthAfricanmesotheliomacompensation JimteWaterNaude,AsbestosReliefTrust,SouthAfrica Keywords: Compensation,Publichealth,Healthpromotion Abstractcontent: Introduction TherehavebeenfivebroadavenuesinSouthAfricaformesotheliomavictimstoachieve compensation.theseare: 1.Thestatutorycompensationlawforminers,theOccupationalDiseasesinMinesandWorksActof 1973,whichofferscompensationforalldustdiseasessufferedbyminersinSouthAfrica.Thisis fundedbyongoingstatutoryminelevies,andminersarepaid 7200formesothelioma. 2.TheCapePLCcaseof2002,wherelitigationeventuatedinajudgementforcompensation,which wasappealedandareducedfundworth 7Millionwassetup. 3.TheAsbestosReliefTrustof2003,whichwasestablishedinaoutofcourtsettlementbetween asbestossufferersandtheminingcompaniesmsauli,gefcoandtheirparentcompanygencor,which wasintheprocessofdissolving.thesethreecompaniesagreedtosetaside 42Millionto compensateexworkerswhohadworkedinsouthafricanminesforallasbestosrelatedconditions. 4.TheKgalagadiReliefTrustof2006,whichwassetupinavoluntarysettlementwiththesuccessors ofpreviouslyeternitownedmines,wherecompensationwasguaranteedforallincidentcases.this settlementisestimatedtobeworth 9Million,and 5.Privateindividuallitigationsettlementsinourcourts,whichoccuroccasionally.Theseare estimatedtobeworth 90000each. Method Theactivitiesofthesecompensationavenuesweremeasuredagainstanidealizedpublichealth approach thepreventionofdisease,promotionofhealthandprolongationoflifethroughthe organizedeffortsofsociety. Results Avenues1,2and5haveremainedcompensationschemes.TheTrusts(avenues3and4)haveby contrastdistinguishedthemselvesbyadoptingamoreholisticapproachtomesothelioma,andhave performedattheprimary,secondaryandtertiarylevelsofprevention,aswellasinhealth promotion.thetrustshaveengagedgovernmentindifferentsectorstoimprovepublicpolicies; improvedthediagnosis,managementandpalliationofmesotheliomainprevalentareas;funded communityorganizationsthatcreateawarenessofmesotheliomaandsupportvictims. Discussion Compensationschemesmakeapublichealthimpactiftheyalsoworkdevelopmentally,withaffected communitiesinmind. 109

112 ABSTRACTS Number:77 Abstracttitle: "DutchAsbestosVictimsInstitute :asocialresponsablesolutionforacomplexhistoricalproblem Abstract B.deMol AMC,Amsterdam,theNetherlands Abstractcontent: The"DutchAsbestosVictimsInstitute"isanexampleofthefamous"poldermodel".Government, employers,insurancecompanies,tradeunionsandvictimsorganisationsfoundan,forallparties, acceptablesolutionregardingthecompensationofmesotheliomavictims.currently,financial compensationisrestrictedtocaseswithprovenmesotheliomaandoccupationalasbestosexposure. Thecornerstonesofasuccesfulclaimaresufficientmedicalevidenceand"reasonable"exposure rates.therefore,medicalscienceandexpertiseareindispensableinordertoexcecuteany compensationscheme.professordemolwillgiveaninsightintothebackgroundoftheinstituteand theprocedureitworkswith.inthesecondparthewillpayattentiontothemedicalresearch programmetheinstituteisgoingtofulfilinthecomingyears. 110

113 ABSTRACTS Number:78 Abstracttitle: DeadlyDust:MitigatingtheImpactofAsbestosThroughEducationandPrevention,EarlyDetection, andincreasedfundingforresearch LindaReinstein AsbestosDiseaseAwarenessOrganization Abstractcontent: Althoughsheisneitherdoctornorscientist,MrsLindaReinsteincofoundedtheAsbestosDisease AwarenessOrganizationwhichisdedicatedtoprovidingresources,support,andadvocacyfor asbestosvictimsandtheirlovedones,worldwide. MrsLindaReinsteinwillfocusonmitigatingtheimpactofasbestosrequiringathreeprongapproach: preventioninbothoccupationalandnonoccupationalsettings,improvementinearlydetectionand diagnosis,andincreasedresearchfunding. Occupationaldustrelateddiseaseisonthedecline(e.b.,silicosis,bysinosis,CWP)intheUnited States,exceptforasbestosexposurewhichremainsontherise.Nonoccupationalasbestosexposure continues,andisbecomingmoreprevalent,resultinginexposureinmoreunusualsettingsandtoa lesstypicalpopulationthatisyoungerandfemale.theadao(asbestosdiseaseawareness Organization)hasbeenworkingforincreasedproducttesting,recognitionandjusticeforvictimsof asbestosexposure,theworldhealthorganization(who)andinternationallabororganization(ilo) bothhaveadoptedpoliciestoeliminateallasbestosrelateddisease.yet,workplaceexposures continuewhiletheasbestosindustryarguesthatchrysotileisthesafeformofasbestos.earlier diagnosisisthefirststeptoimprovingtreatmentforvictimsofasbestosrelateddiseases. Recognitionofearlywarningsignsbycliniciansandconsumers,alongwithidentificationofhighrisk patientsbyoccupationalandexposurehistoryisessential.thepatientprofileofthosewithasbestos relateddiseaseischangingasunsuspectedsourcesofexposureincrease.inaccuracyofreportingof asbestosrelateddiseaseanddeathsisanotherbarriertoimprovedcareandtreatment.increased attentionisneededtoimprovenonoccupationalreporting.deathcertificateinaccuraciesin reportingmesotheliomaasanunderliningcauseofdeathandcodesforreportingofpleuraland peritonealmalignanciesarenecessaryformoreaccuratedataonwhichtodeveloppolicies. Advocacyworktoincreaseresearchfundingthroughregistriesandvalidstatisticsmustoccurifwe aretomoveclosertoeliminatingasbestosrelateddisease. Anunderlyingthemeofthispresentationwillbetheurgentimportanceofcommunicationand cooperationbetweenscientists,doctors,governments,laborgroups,andtheworldwidecommunity ofvictims. 111

114 ABSTRACTS Number:79 Abstracttitle: MesotheliomainJapanaftertheenactmentofAsbestosRelatedHealthDamageReliefLaw KenjiMorinaga(1),HirotaroMiura(2),MitsutoshiSakatani(3),FumikazuSakai(4),Norihiko Kohyama(5),TakumiKishimoto(6),KoukiInai(7),YuichiIshikawa(8),MasanoriAkira(3),Yasushi Shinohara(9) (1)NationalInstituteofIndustrialHealth;(2)YokosukaUwamachiHospital;(3)NationalKinkiChest DiseaseCenter;(4)InternationalMedicalCenter,SaitamaMedicalCollage;(5)ToyoYuniversity; (6)OkayamaRousaiHospital;(7)SchoolofMedicine,HirosimaUniversity;(8)TheCancerInstitute; (9)NationalInstituteofIndustrialHealth Keywords: mesothelioma,occupation,relief,compensation Abstractcontent: InJapan,theAsbestosRelatedHealthDamageReliefLawwasenteredintoforceon27March2006, andanewreliefsystemstartedforthepatientsofmesotheliomaandasbestosrelatedlungcancer. Thislawcoversvictimsofthesetwomalignancies,whoarenotcompensatedbyworker sinsurance schemesuchasneighborsaroundasbestosfactories,asbestosworkers families,andselfemployed workers. FromApril2006toMarch2008,1,925sufferersproposedtogetthisrelief,and1,152mesothelioma patientswererecognizedbythislawand181wererefusedbecauseofincorrectdiagnosisof mesothelioma.asforlungcancer,789sufferersproposedbutonly289patientswererecognized. 202wererefusedaccordingtothecriteriaforasbestosrelatedlungcancer.. Duringthefirstyearoftheenactmentofthislaw,631casesofpleuralmesotheliomawererelieved. 414weremales,and158werefemales.Therewere45peritonealmesothelioma(males28,females 17),and14caseswerepericardiumandothers.Amongthesepleuralmesotheliomas,mostwere constructionworkers,andengagedinmanufacturing,but11caseswereteachers.residencehistory wasobtainedbyselfquestionnairebypatientsorhis/herfamilies.therewere50pleural mesotheliomaswhohadthehistoryofresidenceinamagasakicity,wherealargescaleofasbestos factorywaslocated,thathadbeenmanufacturingasbestoscementpipebetween1954and1975 usingcrocidoliteandchrysotile. Duringthesameperiod(fromApril2006toMarch2007),1,007mesotheliomaand790lungcancer werecompensatedasoccupationalcancerbyworker sinsurancescheme. Japanhasnowencounteringtheepidemicofasbestosrelatedcancers. 112

115 ABSTRACTS Number:83 Abstracttitle: Acasecontrolstudyofmalignantmesotheliomainsubjectswithnoknownexposuretoasbestos NicholasdeKlerk,SoeTun,AlisonReid,HelmanAlfonso,NolaOlsen,JanSleith,RobinMina,A WilliamMusk UniversityofWesternAustralia Keywords: aetiology,nonasbestosrelatedmesothelioma,occupation,environment Abstractcontent: Background Malignantmesothelioma(MM)isarareandusuallyfatalcancer,generallycausedbyasbestos. However,inmanyseries,uptoathirdofcasesappeartohavehadnoasbestosexposure. Aims Toidentifysourceswherebypeoplehavebeenunknowinglyexposedtoasbestosandtoidentify othermaterialswhichmaybeleadtomm. Methods Amatchedcasecontrolstudydesignwasused.CaseswereselectedfromtheWesternAustralian MesotheliomaRegisterwithoccupationalandenvironmentalhistoriesbutwithnoknownexposure toasbestos.twosetsof2controlspercasewereselectedfrompatientshospitalisedforconditions unrelatedtoasbestos:(a)specificcancers(mainlybreastandlymphomas),and(b)generalmedical conditions(mainlyaccidentsandorthopaedic),matchedforage,sex,postcode,andyear. Occupationalandenvironmentalhistorieswereobtainedbyquestionnaireandcodedbyanexpert industrialhygienistastonature,likelihood,quantityanddurationofexposureto57substances.data wereanalysedusingconditionallogisticregression. Results Eligiblecaseswithoutasbestosexposurewerefarfewerthananticipated.After9yearstherewere39 MMcases,71cancerand76medicalcontrolsrecruited.RiskofMMwaselevated,butnot significantlyso,afteranyexposure(probableordefinite)toasbestos,silica,pesticides,welding fumes,otherfumes,toxicmetals,andothersubstances.therewerealsoincreasingrisks(againnot significant)withincreasingquantityanddurationofexposuretoasbestos,wooddust,silica, pesticides,otherfumes,syntheticmineralfibres,andtoxicmetals. DiscussionandConclusions Veryfewpeoplehaveneverbeenexposedtoasbestosandcarefulelucidationofoccupationaland environmentalhistoriesusuallyuncoversexposuressufficienttocausemm.itseemslikelythatmost casesofmminpeoplewithnoknownexposuretoasbestosoccur,ataverylowrate,amongthe hugenumbersofpeoplewhohavehadsmallamountsofasbestosexposure. 113

116 ABSTRACTS Number:84 Abstracttitle: OnconaseinhibitsmesotheliomacellsinvasioninducedbyTNFalpha. HainingYang,MicheleCarbone CancerCenter,UniversityofHawaii,USA. Abstractcontent: Background:OnconaseisamemberofthepancreaticRNaseAsuperfamilyofribonucleases.Ithas antitumoractivityandiscurrentlyinclinicaltrialforthetreatmentofunresectablemalignant mesothelioma.previously,wereportedthattnfalphaplaysacriticalroleinasbestosinduced oncogenesisandmesotheliomadevelopment.wefoundthattnfalphainhibitsasbestosinduced cytotoxicityandincreasesthepoolofasbestosdamagedhumanmesothelialcells(hm)thatare susceptibletomalignanttransformation.here,byusingmalignantmesotheliomacelllines,we furtherstudiedtheeffectoftnfalphaontheprocessoftumorprogressionandmesotheliomacells invasion.theinhibitiveeffectofonconaseoncellinvasionwasalsoanalyzed. Methods:Cytotoxicitywasmeasuredbylactatedehydrogenase(LDH)andMTTassays.Westernblot andelectrophoreticmobilityshiftassay(emsa)wereusedtochecknfkbpathway.metalloprotease (MMP)9expressionandactivityweremeasuredbyWesternblotandzymographyassay.Cell invasionwasmeasuredbyinvasionassayusingmatrigelinvasionchamber. ResultsandConclusions:WefoundthatTNFalphaactivatedNFkBpathwayinmesotheliomacells. TheactivationofNFkBinducedtheexpressionandactivityofMMP9,whichpromotedtumorcell migrationandinvasion.wereportthatonconaseinhibitednfkbactivityinducedbytnfalphain mesotheliomacells,anditsuppressedtumorcellsinvasionbyinhibitingmmp9expressionand activity. 114

117 ABSTRACTS Number:85 Abstracttitle: PleuralmesotheliomaasasecondprimarycancerposttherapeuticradiationforHodgkin'sandnon Hodgkin sdisease. DavidJ.Sugarbaker,MD(1),JordanMueller(1),TamaraR.Tilleman,MD,PhD(1),LambrosZellos,MD, MPH(1),WilliamG.Richards,PhD(1),JohnJ.Godleski,MD(2) (1)ThoracicSurgery,BrighamandWomen'sHospital,Boston,MA,USA;(2)PathologyDepartm, BrighamandWomen'sHospital,Boston,MA,USA Keywords: therapeuticradiation,hodgkin\'sandnonhodgkin slymphoma,survival Abstractcontent: Asbestosexposureisthedominantetiologyformesothelioma.Therapeuticradiationimproved survivalespeciallyinchildhoodmalignancies,yetitmaybecarcinogenictothepleuraand peritoneumresultinginsecondaryneoplasms.wereviewed1875medicalrecordsofmpmpatients identifyingthosewithreportedhistoryoftherapeuticradiation(tr)forhodgkin\'sandnon Hodgkin slymphoma(hl,nhl).survivalwasestimatedusingkaplanmeierwithlogrankcomparison. Wereportdemographic,clinical,pathologicfeaturesandoutcomeofthesepatients. RESULTS: Twentyfourpatients,19maleand5femalewithamedianageof45(27 79)yearswereidentified. Twelvepatientshadleftsideddisease,11hadrightsided,andsitewasundocumentedinone patient.celltypewasepithelialin19(79%)patients,mixedin4(17%)patients,andsarcomatoidin1 (4%)patient.LatencyfromTRtodiagnosiswas21.4(1.6 43)years.Twentypatients(83%)had radiationforhl,while4patients(17%)hadfornhl.surgericalresectionwasperformedin14outof the24patients;extrapleuralpneumonectomy(epp)(7:29%)andpleurectomy(7;29%).ofthe resected,11wereepithelialand3weremixedtype.themedianageofresectedpatientswas44 years.medianpreoperativelabvalueswere:wbc10.3(k/ul),rbc4.3(m/ul),andplt340.5(k/ul). Surgicalstagingwasavailableforthe7patientswhounderwentEPP:2werestageIIand5were stageiii(ajcc6thedition).mediansurvivalforallpatientswas16months.mediansurvivalfor14 patientswhounderwentresectionwas32.6monthsversus12.5monthsfor10patientsthathadno resection(p=0.046).themedianasbestosbodycountin4resectedspecimenswas35.5(12108) ppg. CONCLUSIONS: Patientswithpleuralmesotheliomasecondarytoradiationareyoungerandhaveasurvival advantagecomparedtohistoricalcontrols.thesepatientsmaybenefitfromsurgicalresection. Theatypicaldemographicandhistologicaldistributionofthissubgroupsupportradiationtherapyas anadditionaletiologyorariskfactorformpm. 115

118 ABSTRACTS Number:86 Abstracttitle: ApopulationbasedstudyonRadiotherapy(RT)asariskfactorforMalignantMesothelioma(MM) EnzoMerler(1),SaraRoberti(2) (1)VenetianMesotheliomaRegistry,SPISALAULSS16,Padua,Italy;(2)DeptofStatisticalSystem, VenetoRegion,Venice,Italy Keywords: secondcancer,radiation,epidemiology,mesotheliomaregistry Abstractcontent: Background: AnincreasedriskofMMwasobservedamongsubjectsfollowedupafteradsorbeddosesofradiation (Thorotrast)(Andersson,1995)orwhounderwentRTfortesticularcancers(Travis,2005),HDand NHL(Tward,2006;Teta,2007;Hodgson,2007). WeestimatedtheoccurrenceofMMduetoRTinapopulationfollowedbyaMesotheliomaRegistry. Methods: Weinvestigated1177newcasesofMM,diagnosedbymeansofamorphologicalexamination, occurredamongthepopulationofthevenetoregion(northeastofitaly,4.5millionsofresidents) between1987and2005(843casesamongmales;1063pleural,107peritoneal).disease classificationandexposureassessmentfollowedpredefinedcriteria.afacetofaceinterviewwith patientsorrelativeswasthemainstrategytocollectinformationbutpreviousdiseasesand treatmentswerealsoassessedthroughtheexaminationofclinicalrecords. Astandardizedincidence(standard:Europeanpopulation)wascomputedfortheperiod Results. Differentdegreeofprobabilityofasbestosexposurecouldbeattributedin946MMcases(83%of thetotal)andveryhighpercentagesofmmwereconsideredtohavebeenexposedtoasbestos, becauseofworkorfamiliaranddomesticexposures. 8MMcases,allpleural,underwentRTforthetreatmentofHD(6cases),reticulosarcoma,orNHL (onecase,respectively). TheseMMarosealwaystimeafteraRTwithnolessthan20Gy,homolaterallytothesideof treatment,insidetheirradiatedarea,evenamongsubjectsnottreatedwithchemotherapyand withoutasbestosexposure.themeanageatdiseaseonsetformmduetortisyoungerthantheage ofallmmcases,andlatencyisshorterthantheoneforasbestosexposure. TheMMincidenceamongthegeneralpopulationwas20.5(95%IC18.922)and6,4( );17.4 ( )and3.7(3.4.3)amongMMduetoasbestos;0,084(00.181)and0.126(00.251)x106 amongmmassociatedwithrt,amongmalesandfemales,respectively. Conclusion.WeconfirmthatlongsurvivorsofsomeprimarycancerstreatedwithRT,especially thosetreatedwithfieldmantle,candevelopamm.theincidenceofthesemminthegeneral populationishoweverdefinitivelylow. 116

119 ABSTRACTS Number:87 Abstracttitle: MesotheliomadiagnosisinQuébec:Pathology,EpidemiologyandCompensation. BruceCase(1),FranceLabrèche(2),GastonOstiguy(3),JeanChalaoui(4) (1)McGillUniversity,Canada;(2)InstitutnationaldesantépubliqueduQuébec,Canada;(3)McGill UniversityHospitalCentre/MontrealThoracicInst,Canada;(4)CentreHospitalierdel Universitéde Montréal,Canada Abstractcontent: Arecentstudyshowed22%concordanceofQuebecTumourRegistry(QTR)incidentmesothelioma casesfrom1982to1996(n=832)tocasescompensated(n=184)bytheresponsibleprovincialboard (CSST).Weassessedpossibleoverdiagnosisbyascertaining incidentQTRcases.All187 incidentcaseshadsummarymedicalchartreview;64%gaveconsentforpathologyreevaluation. Respectively8.6%,10%,and18%refusedconsent,didnotreply,orwereuntraceable.Pathology sampleswereobtainedfor89%of119consenting.118hadmedicalimagingforreview.charts indicatedoccupationwassoughtinmost(87%)cases;questionsaboutpastasbestosexposurewere askedin64%.40%ofchartsmentionedthepossibilityofreferringpatientsforcompensation.new reviewofpathologyandclinicaldiagnosesofmesotheliomawereratedalongfivecategories: definite/probable,possible,unlikely,definitelynot,orunclassifiable.clinically,51%hada preliminaryratingofdefinite/probableand24%possible,with18%unlikelyordefinitelynot mesothelioma.rateper100,000forclinicallydefinite/probableandpossiblecaseswas1.61formen and0.35forwomen;overdiagnosisofabout34%comparedto unvalidated QTRrates. Pathologically,forthefirst64cases,55%wereconsidereddefinite/probable,23%possible,and17% unlikelyordefinitelynotmesothelioma;5%hadinadequatetissue.morethanhalfof possible caseshadalternativediagnoseswhichclinicalcorrelationmayresolve,andimmunostainsunavailable in2001/2002mayhelp.overallpathologicalclinicalcorrelationhastodatebeenverygood(80%for adjacentprobabilitycategories),andpathologyreducesapparentclinicaloverdiagnosisfurther. Overall,weestimatependingfurtherstudyQTRoverdiagnosisatapproximately20%.This overdiagnosismayhoweverbemodifiedbyotherunderascertainedmesotheliomaincidentcases (suchasmisclassifiedlungcancers).wecannotestimatethetrueproportionofcompensable incidentqtrcases,becauseothercsstcriteriaarealsoinvolved,butif100%ofprobableordefinite caseswerecompensableitwouldexceed50%andincludingallpossiblecaseswouldleadittoexceed 70%.Overdiagnosisexists,butisprobablynottheprincipalreasonforfailureofconcordanceof compensationcaseswithqtrdiagnoses.possiblesolutionswhichhaveworkedelsewhereinclude directreportingofcasesfromthecancerregistriestothoseconcerned. 117

120 ABSTRACTS Number:88 Abstracttitle: Wittenoom,WomenandMesothelioma AlisonReid,GeoffreyBerr(1),JanHeyworth,NickdeKlerk,NolaOlsen,JanSleith,JaniceHansen, RobinMina,HelmanAlfonso,Arthur(Bill)Musk UniversityofWesternAustralia,UniversityofSydney(1) Keywords: women,mesothelioma,crocidolite Abstractcontent: Introduction:Mostofwhatweknowepidemiologicallyaboutmesotheliomahasbeendetermined throughtheexaminationofcohortstudiesofmenexposedtoasbestosintheirworkplace.however, mostwomenhavebeenexposedtoasbestosnonoccupationally.therefore,wedonotknowifthese studiesofmencharacterisetherisksadequatelyforwomen.theaimofthisstudyistodescribe mesotheliomapatternsamongthewittenoomwomenandtopredictfuturemesotheliomasto2030. Methods:2968womenandgirlslivedandworkedatthecrocidoliteminingtownshipofWittenoom, inwesternaustralia,between1943and workedfortheaustralianblueasbestos Company(ABA),and2,552werethereasthewivesordaughtersofABAworkers.Quantitative asbestosexposuremeasurementswerecalculatedforeachindividualbasedontheirplaceand durationofworkortheirperiodanddurationofresidence.modelsincorporatingparametersfor timesincefirstexposure,competingrisksofmortalityfromothercausesandanamountforthe annualclearanceoffibresfromthelungwereusedtopredictmesotheliomamortalityto2030. Results:47incidentmesotheliomasoccurredbetween1960and2005,36amongtheresidentsand 11amongtheABAworkers.StandardisedIncidenceRatioswere:forAllwomen77(95%CI57103); Workers83(95%CI41148);andResidents77(95%CI54106)comparedwiththefemaleWestern Australianpopulation.Exposureresponserelationshipswereconfirmedseparatelyforwomen exposedenvironmentallyor=2.7f/mlyear(95%ci1.93.8)andoccupationallyor=1.7f/mlyear (95%CI1.12.8).WomenwholivedwithOR=2.6(95%CI1.06.8)orwashedtheclothesofanABA workeror=1.7(95%ci0.94.3)hadanonstatisticallysignificantincreasedriskofmesothelioma comparedwithwomenwhodidnotlivewithorwashtheclothesofanabaworker.between66and 87furthermesotheliomas,manymorethanhavearisenalready,werepredictedtooccurbytheend of2030. Conclusion:ThebriefperiodoftheWittenoomcrocidoliteindustrywillcontinuetoexerta detrimentalimpactwellintothefuture. 118

121 ABSTRACTS Number:89 Abstracttitle: FRENCHNATIONALMESOTHELIOMAREGISTRY[MESONAT]:THECONTRIBUTIONOFPATHOLOGY. NolwennLeStang(1),AnabelleGilgsoitIlg(2),PatrickBrochard(3),JeanClaudePairon(4),Philippe Astoul(5),PatrickRolland(3),EllenImbernon(2),MarcelGoldberg(2),GuyLaunoy(6),Francoise GalateauSalle(1) (1)MesonatRegistryCHUCaen,France;(2)INVSDST;(3)ISPEDESSAT;(4)IIMTPIF;(5)CHUMarseille, France;(6)ERI3INSERM Keywords: Mesothelioma,Registry,pathology, Abstractcontent: Background:FrenchNationalMesotheliomaRegistry(MESONAT)hasbeencreatedin1998to supporttheresearchactivitiesofthefrenchnationalmesotheliomasurveillanceprogram(pnsm). MESONATisbasedonanexhaustiveregistrationofallincidentalpleuralmesotheliomacasesin specifiedgeographicalzones.thesedistrictswerechosentoberepresentativeoffrance (employementandeconomicactivitycaracteristics).theregistry,whichistoday,byitspopulation (30%ofthefrenchpopulationin2007)anditsquality,oneofthemostimportantinternational systemsofmesotheliomaregistration.allcasesarevalidatedaccordingtoastandardisedprocedure ofpathologicaldiagnosiscertificationperformedbythefrenchgroupofpathologistsexpertinthe fieldsofmesothelioma(mesopathgroup).theaimsofthisprocedureistoimprovethe exhaustivenessofcasesandascertainabetterknowledgeofthedisease. Design:FromthefilesoftheMESONATregistry,1680casesofsuspectedpleuralmalignant mesothelioma,validatedaccordingtothefrenchprocedureofpathologicaldiagnosiscertification, werecollectedbetween threeexperts,blindlyreviewedtheslides(h&e,plus immunohistochemicalanalysiswithapanelofantibodies;twopositiveandtwonegativemarkersfor thediagnosisofmesothelioma)withouttheknowledgeofasbestosexposureorclinicalinformation. TheyhadtoclassifyeachcaseaccordingtotheWHO2004classification,ascertain,uncertain (unclassifiabletumorsorbecauseofinadequatematerials)anddefinitivelyexcludedfrom mesotheliomadiagnosis.incaseofdisagreementbetweenoneoftheexperts,thecasewasreviewed collectivelyduringaconsensusmeetingwithaquorumofatleast11mesopathmembersandwas classifiedasabove. 119

122 ABSTRACTS Results:Amongthese1680cases,1287(76%)weremesothelialtumors(1274malignant mesothelioma,12welldifferentiatedsuperficialpapillarymesotheliomaand1adenomatoid tumors),263(16%)wereuncertainand130(8%)wereexcludedfrommesotheliomadiagnosis(80 metastasis,18othersprimitivetumors,6pseudomesotheliomatousadenocarcinomaand26other diagnosis).pleuralmesotheliomasdevelopedmainlyinmen(80%)andtheaverageagewas70 years,range[2796yearsold].epithelioidsubtypewaspredominant(77%),followedbythebiphasic subtype(13%).sarcomatoidanddesmoplasticsubtypeswererarelyobserved(respectively8%and2 %).Mediansurvivaltimesincefirstbiopsywas12monthsforepithelioidsubtype,8monthsfor biphasic,4monthsforsarcomatoidand5monthsfordesmoplastic.165casesofunusual mesotheliomavariantswereobserved,notably40casesofpleomorphicmesotheliomaand20cases oflymphohistiocytoidmesothelioma.mediansurvivaltimesincefirstbiopsywas7monthsfor pleomorphicand11monthsforlymphohistiocytoid. Conclusion:Ourresultsshowtheimportantcontributionofastandardisedpathologicalprocedureof certificationinaspecializedregistry.mesopathgroupinvolvementallowstoexcludecases(8%) frommesotheliomadiagnosis.ourresultsshowthattheprocedurefacilitatestheclassificationofthe histologicalsubtypes,mandatoryinsurvivalanalysis. 120

123 ABSTRACTS Number:90 Abstracttitle: TheFrenchNationalMesotheliomaSurveillanceProgram:Estimatesofthenationalmesothelioma incidence Period AnabelleGilgSoitIlg(1),EllenImbernon(1),PatrickRolland(2),StéphaneDucamp(2),JeanClaude Pairon(3),PhilippeAstoul(4),FrançoiseGalateauSallé(5),PatrickBrochard(6),MarcelGoldberg(1) (1)InstitutdeVeilleSanitaireDépartementSantéTravailSaintMaurice,France;(2) Institutde VeilleSanitaireDépartementSantéTravailEssatBordeaux,France;(3)IIMTPIFParis&INSERM U841Créteil,France;(4)HôpitalSainte Marguerite&UPRES3287Marseille,France; (5)Laboratoired'AnatomiePathologiqueMesopathGroupInsermERI3Caen,France; (6)UniversitéBordeaux2IspedLSTEEssatBordeaux,France Keywords: mesothelioma;epidemiologicalsurveillance;occupationaldisease Abstractcontent: Objectives:Duetothelackofobserveddata,mostpreviousestimatesofmesotheliomaincidencein Francewerebasedontheoreticalmodels.TheFrenchNationalMesotheliomaSurveillanceProgram (PNSM)wasestablishedin1998bytheNationalInstituteforHealthSurveillance(InVS)inorderto provideanestimateofthetrendsinmesotheliomanationalincidence. Methods:ThePNSMrecordsincidentpleuraltumoursin22Frenchdistricts(approximately30%of thefrenchpopulation).astandardizedprocedureofpathologicandclinicaldiagnosisascertainment isused.thedataonmesotheliomaincidencecollectedbythepnsmiscomparedtothemalignant pleuralcancermortality.incidence/mortalityratios(i/m)ratioswerecomputedineachdisctrict,and; geographicaldisparitieswereanalyseddifferenthypothesisregardingthenationali/mratiowere consideredinordertoprovideestimatesofthenationalmesotheliomaincidence. Results:Amongthe1,823reportedincidentcases(years ),pathologyreviewconfirmed theinitialpathologist\'sdiagnosisin78%ofcases,ruleditoutin8%,andleftituncertainforthe others;forhalfofthelatter,theclinicalfindingsstronglysupportedamesotheliomadiagnosis.mean ageofthenonexcludedcaseswas71forwomenand70formen(80%ofallcases).overthe period,takingintoaccounttheheterogeneityintheI/Mratioforpleuralcancer,weestimated themeanannualincidencetovaryfrom525to630casesamongmen(incidencerate:1.8to2.2per 100,000),andfrom150to200forwomen(incidencerate:0.5to0.75per100,000). Conclusions:Theestimatednumberofincidentcasesofpleuralmesotheliomaareclosetotheothers nationalestimatesmadebytheinsermexpertadvisorypanelorbasedonmodellingofthedataof thefrancimnetworkofcancerregisters,thedifferencebeingmainlyduetothefactthatmorethan 10%ofthecasesregularlyregisteredwereexcludedbythePNSMdiagnosisascertainment procedure.asreportedinpreviouspublications,mesotheliomaepidemicshouldcontinuetodevelop infranceforatleasttwoorthreemoredecades.theanalysisofthepnsmdataontheperiod doesnotshowanyparticulartrend. 121

124 ABSTRACTS Number:91 Abstracttitle: IndividualcomparisonofincidentcasesofpleuralmesotheliomarecordedbytheFrenchNational MesotheliomaSurveillanceProgramandtherecordedcauseofdeathforestimatingthenational incidence AnabelleGilgSoitIlg(1),EllenImbernon(1),PatrickRolland(2),StéphaneDucamp(2),JeanClaude Pairon(3),PhilippeAstoul(4),FrançoiseGalateauSallé(5),PatrickBrochard(6),MarcelGoldberg(1) (1)InstitutdeVeilleSanitaireDépartementSantéTravailSaintMaurice,France;(2)InstitutdeVeille SanitaireDépartementSantéTravailEssatBordeaux,France;(3)IIMTPIFParis&InsermU841 Créteil,France;(4)HôpitalSainte Marguerite&UPRES3287Marseille,France;(5)Laboratoire d'anatomiepathologiquemesopathgroupinsermeri3caen,france;(6)universitébordeaux2 IspedLSTEEssatBordeaux,France Keywords: Pleuralmesothelioma;deathcertificate;InternationalClassificationofDiseases Abstractcontent: Objectives:Inmostcountries,estimatesofthenationalincidenceofpleuralmesotheliomarelyof deathcertificates.theobjectiveofthisstudyistoestimatetheproportionofdeathcertificates codedc4509(icd10threvision)whicharereallypleuralmesotheliomas,andthefractionofpleural mesotheliomawhicharecorrectlycoded. Methods:InafirststepweindividuallymatchedthedeathcertificatescodedC4509in2005inthe districtscoveredbythenationalmesotheliomasurveillanceprogram(pnsm)withtheincidentcases ofpleuralmesotheliomatoestimatethepartofmesotheliomadeathsunknownbythepnsm.ina secondstep:weindividuallymatchedtheincidentpleuralmesotheliomacasesregisteredbythe PNSMin2000withthedeathscodedC459from2000to2005toestimatethepartoftruepleural mesotheliomanotcodedc45.inthethirdstep,wecomputedanincidence/mortality(i/m)ratio, andappliedittothenationalmortality(c4509)toestimatethenationalpleuralmesothelioma incidence. Results:Firststep:65%oftheC4509deathcertificateswereknownaspleuralmesotheliomasbythe PNSM;5%wereexcludedbythecertificationprocedureandshouldnothavebeencodedC4509;for the30%codedc4509in2005whichwereunknownbythepnsm,wemadetwoextreme hypothesis:i)thepnsmmisssescasesandallaretruemesotheliomaii)noneofthesedeathsshould havebeencodedc

125 ABSTRACTS Secondstep:about20%oftheincidentcaseswhodiedwerenotcodedC4509.Thirdstep:according tothetwohypotheses,thei/mratiovariedfrom80%(73%amongwomen)to120%,andtheannual nationalpleuralmesotheliomaincidencevariesfrom520to780amongmenandfrom150to240 amongwomen. Conclusions:Thosecomparisonsshowedthat:i)anonnegligiblepartofthedeathscodedC4509are unknownbythepnsmandapartofthemshouldnothavebeencodedasmesotheliomas;weplanto reviewthemedicalrecordsofthesedeathsinordertochecktherealdiagnosis;;ii)aboutonefifthof thepleuralmesotheliomacasesarenotcodedc4509ondeathcertificatesastheyshouldhavebe. Thesystematiccomparisonofincidentascertainedcasesandmortalitydataisofgreatimportance fortheestimationofnationalincidencerates. 123

126 ABSTRACTS Number:92 Abstracttitle: MesotheliomaSurvival:EffectsofManagementandHistologicalType A.WilliamMusk(1),NolaOlsen(1),HelmanAlfonso(1),AlisonReid(1),RobinMina(1),JanSleith(1), TimThrelfall(2),NicholasdeKlerk(1) (1)UniversityofWesternAustralia;(2)DepartmentofHealth,WA,Australia Keywords: survival,treatment,mesotheliomaregister,site,histology Abstractcontent: Background Malignantmesotheliomaofthepleuraandperitoneumisauniversallyfataldiseaseattracting increasingmedicalinterventionsandescalatinghealthcarecostsasnoveltreatmentsaretried. Sincethefirstclinicaltrialofgemcitibineandcisplatinumshowingpartialresponseratesof3040% andsimilarstablediseaseratesandthedemonstrationofsignificantlyprolongedsurvivalwith pemetrexedandcisplatinummorepatientsaresubmittingtoactivetreatmentregimes.trimodality therapywithradicalpleuropneumonectomy,radiotherapyandchemotherapystillattractssome peoplewith\"early\"disease.reportsofgenetherapyandimmunotherapytrialsaboundin conferenceproceedingsandreports.cancerisanotifiablediseaseinwesternaustraliaandall incidentcasesofmesotheliomainthestate,sincethefirstcasein1961,areformallyreviewedbya committeetoconfirmthediagnosisanddocumentdatesandmethodsofdiagnosis,site,anddateof death,aswellasasbestosexposurestatus. Aims Toexaminethechangesinsurvivalandthefactorsaffectingsurvivalofallpatientseverdiagnosed withmalignantmesotheliomainwesternaustraliaoverthepastfivedecades. Methods PatientswereidentifiedfromtheCancerRegistry.Dateandmethodofdiagnosis,siteofdiseaseand histologicaltypewererecorded.survivalanalysiswasexaminedseparatelyforeach5and10year periodsusingcoxregression.caseswithaconfirmeddiagnosisuptotheendof2004wereincluded. Followupfordeathswascensoredattheendof

127 ABSTRACTS Results survivalwasinverselyrelatedtoage,worseformales(hr1.495%ci1.21.6)andworsefor peritonealmesothelioma(hr1.495%ci1.11.7).survivalimprovedafterthe1970sandhasmade incrementalimprovementssincethen(mediansurvivalbydecadeindayswithinterquartilerange were64(0198),177(48350),221(97504),238(108502),and301(134611). Discussion despiteincreasingresourcesandtreatmentcostsofmalignantmesotheliomaoverthepast40years therehavebeenonlymodestimprovementsinsurvivalandnocompleteremissions.earlier diagnosiswithconcomitantincreasedapparentsurvivalmaybeoneexplanationandimprovements intreatmentanother.preventionofexposuretoasbestosstillremainstheurgentpriorityfor mesotheliomaprevention. 125

128 ABSTRACTS Number:95 Abstracttitle: Preoperativestagingofmesotheliomaby18Ffluoro2deoxyDglucosePositronEmission TomographyComputedTomographyfusedimagingandmediastinoscopycomparedtopathological findingsafterextrapleuralpneumonectomy JensBennSorensen(1),JesperRavn(2),AnnikaLoft(3),JoernBrenoe(2),AnneKiilBerthelsen(4) (1)DeptOncology,FinsenCentre,Copenhagen,Denmark;(2)Dept.ThoracicSurgery,Rigshospital, Copenhagen,Denmark;(3)PET6CyclotronUnit,Rigshospital,Copenhagen,Denmark;(4)Dept. radiotherapy,rigshospital,copenhagen,denmark Keywords: Staging,PETCTScan,mediastinoscopy,extrapleuralpneumonectomy Abstractcontent: Objectives:Extrapleuralpneumonectomy(EPP)inMPMmaybeconfinedwithbothmorbidityand mortalityandcarefulpreoperativestagingidentifyingresectablepatientsisimportant.stagingis difficultandtheaccuracyofpreoperativectscan,18ffdgpet/ctscan(pet/ct),and mediastinoscopyisunclear.theobjectivesweretocomparethesestagingtechniquestoeachother andtosurgicalpathologicalfindings. Methods:PatientshadepithelialsubtypeMPM,age 70years,andlungfunctiontest allowingpneumonectomy.preoperativestagingafter36coursesofinductionchemotherapy includedconventionalctscan,pet/ct,andmediastinoscopy.surgicalpathologicalfindingswere comparedtopreoperativefindings. Results:42consecutivepatientswerewithoutT4orMonCTscan.PET/CTshowedinoperabilityin12 patients(29%)duetot4(7patients)andm1(7pts).among30patientswithsubsequent mediastinoscopy,including10withn2/n3onpet/ct,n2werehistologicallyverifiedin6(20%). Among24resectedpatients,T4occurredin2patients(8%),andN2in4(17%),allbeingPET/CT negative.pet/ctaccuracyoft4andn2/n3comparedtocombinedhistologicalresultsof mediastinoscopyandeppshowedsensitivity,specificity,pos.predictivevalue,neg.predictivevalue, andpos.andneg.likelihoodratiosof78%and50%,100%and75%,100%and50%,94%and75%, notapplicableand5.0,and0.22and0.67,respectively. Conclusions:Noncurativesurgeryisavoidedin29%outof42MPMpatientsbypreoperativePET/CT andinfurther14%bymediastinoscopy.eventhoughbothproceduresarevaluable,therearefalse negativefindingswithboth,urgingforevenmoreaccuratestagingprocedures. 126

129 ABSTRACTS Number:96 Abstracttitle: DetectionofN2adenopathybycervicalmediastinoscopyin175consecutivepleuralmesothelioma patients. TamaraR.Tilleman,MD,PhD,AneilA.Mujoomdar,MD,ChristopherT.Ducko,MD,MichaelT. Jaklitsch,MD,LambrosZellos,MD,PhD,JordanMueller,AnnaWinterkorn,RaphaelBueno,MD, DavidJ.Sugarbaker,MD ThoracicSurgery,BrighamandWomen'sHospital,Boston,MA,USA Keywords: CervicalMediastinoscopy,N2Adenopathy,Resectability,Survival,ProgressionFreeSurvival Introduction:Extrapleurallymphnodemetastasisiswellestablishedasastrongpredictorofpoor prognosisinmalignantpleuralmesothelioma(mpm)patients. Objective:Todeterminetheeffectivenessofcervicalmediastinoscopy(cMED)indetectingN2 adenopathyinpatientswithmpm. Methods:Aretrospectivereviewof175cMEDperformedbetweenJanuary2004andJune2006in MPMpatients. Results:Themedianageofthe175patientswas63years(range2783),142patientsweremale (81%)and33werefemale(19%).Histologywasepithelialfor114(65%)andsarcomatoid/mixedfor 61(35%).TwentysevenpatientshadpositiveN2nodesbymediastinoscopy(15.4%). Ofthe148patientswithnopositiveN2nodesatcMED(84.6%),98underwentEPPand84patients wereresectable(86%),allowingcompleteevaluationofn2nodes.resectabilityrateforepithelial patientswas82%andforthesarcomatoid/mixedwas92%.positiven2nodeswerefoundin26 patientsatthetimeofepp(31%).n2nodelocationwasundefinedforfourpatients. ThemajorityofpositivenodeswereinthelowerstationsthatarenotaccessibleduringcMED (5,6,8,9,low7,n=22patients). Resectability Positivelymph nodesatepp Upper Nodes(2,4) LowerNodes (5,6,7,8,9,IM) Upper and Lower Epithelial 49/60(82%) 18/49(37%) NonEpithelial 35/38(92%) 8/35(23%) Total 84/98(86%) 26/84(31%)

130 ABSTRACTS Overallmediansurvivalforthe84patientsresectablebyEPPandwithnegativecMEDwas12.9 months.mediansurvivalforpatientswithpositiven2nodesateppwas9.7monthsversus15 monthsforthe58patientswithoutpositiveextrapleuralnodes(notsignificant).progressionfree survival(pfs)was10.5months.medianpfsforpatientswithpositiven2nodesateppwas6.7 monthsversus11.6monthsforthepatientswithnegativenodes(p=0.046). Conclusions: cmedcorrectlyidentifynegativen2nodesin69%ofmesotheliomapatientswhounderwentepp. Nonepithelialmesotheliomaishighlyresectable(92%)whenthepreoperativecMEDisnegative. OtherstagingproceduressuchasEndoscopicandEndobronchialUltrasoundsshouldbenvestigated toenhancepreoperativelyidentificationofn2diseaseinthelowermediastinalstations. 128

131 ABSTRACTS Number:97 Abstracttitle: ReducedlungvolumemeasuredbyCTpredictsunresectabilityinmesotheliomapatients AneilA.Mujoomdar,M.D(1),ShinMatsuoka,M.D.(2),HirotoHatabu,M.D.,P.hD.(3),LambrosZellos, M.D.MPH(1),JordanMueller(1),BeowY.Yeap,Sc.D(4),TamaraR.Tilleman,M.D.,P.hD.(1),Raphael Bueno,M.D.(1),DavidJ.Sugarbaker(1) (1)ThoracicSurgery,BrighamandWomen'sHospital,Boston,MA,USA;(2)RadiologyDepartment, BrighamandWomen'sHospital,Boston,MA,USA;(3)RadiologyDepartment,BrighamandWomen's Hospital,Boston,MA,USA;(4)DivisionofHematology/Oncology,DepartmentofMedicine, MassachusettsGeneralHospital,USA Keywords: unresectability,extrapleuralpneumonectomy,lungvolume,volumetricanalysis,predictor Abstractcontent: Introduction:Resectabilityapproaches85%inpatientswithmalignantpleuralmesothelioma(MPM) evaluatedforextrapleuralpneumonectomy(epp).preoperativeidentificationofunresectable patientscanavoidunnecessaryoperationandcontributetothepatient squalityoflife. Objective:ToidentifypreoperativevariablescontributingtounresectabilityinMPMpatients. Methods:Aretrospectivereviewof64mesotheliomapatientswhounderwentexplorativeoperation withintenttoperformeppintheyear2007.thereviewincludeddemographicvariables,clinical symptomsandvolumetricanalysisofthetumorandthelung.categoricalvariablesweretestedfor significanceusingfisher sexacttestwhilecontinuousvariablesweretestedusingwilcoxonrank sum. Results:Ofthe64patients,52weremaleand12werefemale.Themedianagewas62years(3181), 48hadepithelialhistologyand52wereresectable(52/64,81%resectability).Twelvewere unresectableduetotumorinvolvementofchestwall(9),svcoraorta(5)orthespine(2).formatted CTimageswereavailablefor12unresectablepatientsandfor42resectablepatients. Nonepithelialtumorsweremorelikelytobeunresectablethanepithelialtumors,44%(7/16)versus 10%(5/48),respectively(p=0.0068).Unresectabletumorshadlargertumorvolume(median= cc;range= )comparedtoresectablepatients(median=588.5cc;range= )(p= ).Unresectablepatientshadsmallernormalizedlungvolume(22.2%;091.7)comparedto patientswithresectabletumors(42.3%;081.1)(p=0.0436). Therewerenosignificantdifferencesbetweensex,age,tumorsite,weightloss,smokinghistory,pain ortakingpainmedications. Conclusions: Reducedlungvolumeisapredictorofunresectabilityinmesotheliomapatients. Nonepithelialtypeisalsoassociatedwithlowresectability. Preoperativevolumetricanalysisofthetumorandthelungmayhelpassessingrespectability andavoidingunnecessaryoperationsinmesotheliomapatients. Aprospectivestudyisrequiredtovalidatetheseparameters. 129

132 ABSTRACTS Number:98 Abstracttitle: TRIMODALITYTREATMENTFORMPM:THEHEIDELBERGEXPERIENCE HansHoffmann(1),KonstantinaStorz(1),ThomasMuley(1),HelgeBischoff(1),MichaelThomas(1), ChristianThieke(2),MarkMünter(2),PhilippSchnabel(3),FelixHerth(1),HendrikDienemann(1) (1)Thoraxklinik;(2)Radioonkologie;(3)Pathologie Keywords: Chemotherapy,ExtrapleuralPneumonectomy,Intensitymodulatedradiotherapy Abstractcontent: Purpose: Toinvestigatecombinedmodalitytreatmentwithneoadjuvantchemotherapyfollowedby extrapleuralpneumonectomyandintensitymodulatedradiotherapyinpatientswithstageiiii(imig) malignantpleuralmesothelioma(mpm)inaprospectivestudy. PatientsandMethods: BetweenJanuary2003andDecember2006,50patientswithMPMstageIIII(IMIG)consideredtobe completelyresectableandecogperformancestatus 1wereenrolledinthestudy. Neoadjuvantchemotherapyconsistedofacombinationofcisplatinandpemetrexedorcisplatinand gemcitabine.extrapleuralpneumonectomy(epp)wasperformedasanenblocresectionofthe pleura,thelung,ipsilateralhemidiaphragm,andpericardium.postoperativeinverseplanned intensitymodulatedradiationtherapy(imrt)withamediantargetdoseof50to54gywasapplied in2gyfractions. Results: 50patientswereenrolledinthestudyandunderwentextrapleuralpneumonectomy(EPP).Forty sevenpatientsreceived2ormorecyclesofneoadjuvantsystemicchemotherapyand31ofthese patientsreceivedimrtasintended.therewere2postoperativedeaths(4%).withamedianfollow upof30.3monthsthemediansurvivalfortheentiregroupof50patientswas22.9months(95% confidenceinterval, ).Forthe31patientswhocompletedthetrimodalitytreatment protocolasintended,mediansurvivalwas27.3months. Conclusion: TheresultsofthistrialsuggestthatcombinedmodalitytreatmentofpatientswithMPMisfeasible andeffectiveinachievinglongersurvival. 130

133 ABSTRACTS Number:99 Abstracttitle: Cytoreductivesurgeryandhyperthermicintraperitonealchemotherapyinthetreatmentofdiffuse malignantperitonealmesothelioma MarcelloDeraco,ShigekiKusamura,DarioBaratti,DomenicoSabia FondazioneIRCCSIstitutoNazionaleTumoriMilano,Italy Keywords: peritonealmesothelioma,localregionaltherapy Abstractcontent: Background:diffusemalignantperitonealmesothelioma(DMPM)isaveryrarediseasewithapoor prognosis.intheformertimestheconditionwasconsideredterminalandamenableonlytopalliative interventions.themediansurvivalwasapproximately1yearaftersystemicchemotherapy.the emergenceofacombinedmodalityofcytoreductivesurgeryandhyperthermicintraperitoneal chemotherapy(crs+hipec)seemstohavechangedpositivelytheoutcomeofdmpmpatients.inthe presentstudyweproposetoreporttheexperienceofnciofmilaninthetreatmentofdmpmwith CRS+HIPECfocusingresultsintermsofsurvivalandmorbidity. Methods:Fromadatabaseof86casesofperitonealmesotheliomaweselected66patients (30M/36F)withDMPMhistologysubmittedtoCRS+HIPECwithacurativeintent.CRSwasperformed usingperitonectomyprocedures.hipecthroughtheclosedabdomentechniquewasconductedwith cisplatin(25mg/m2/lofperfusate)+mitomycinc(3.3mg/m2/lofperfusate)orcisplatin(43mg/lof perfusate)+doxorubicin(15.25mg/lofperfusate),at42.5 C.Wetestedtheprognosticsignificanceof thefollowings:age,sex,carcinomatosisextension,completenessofcytoreduction(cc)andhipec drugschedule.thesurvivalwascalculatedfromthedateofoperationuntilthedateofdeathorof thelastcontact.themedianfollowupwas30.5months(range:1118).theadverseeventswere gradedaccordingtoncictcaev3criteria.thesurvivalcurvedistributionwascalculatedbythe KaplanMeiermethod.TheLogranktestwasusedtoassessthesignificanceofsurvivaldistributions. RESULTS:FiveyearOSandPFSwere45%and21%,respectively.Thecompletenessofcytoreduction impactedtheosandtheage>52impactedonthepfs.thepostoperativesurgicalmorbidityg35and systemictoxicityg35rateswere31%and36%,respectively. CONCLUSIONS:Unfortunatelytherarityofthediseaserepresentsthemajordrawbackforthe conductionofaprospectiverandomizedstudy,inacceptabletimeframe,toconfirmthesepromising resultsintermsofsurvival.notwithstandingtheperitonealsurfacemalignancyprogramofnciof Milanisalsoexertingeffortsinthemolecularbiologyfield,inordertoobtainabetterunderstanding oftheunderliningtumorkinetics,identifynewprognosticmarkersandtrytovalidatenewtargeted therapies. 131

134 ABSTRACTS Number:100 Abstracttitle: ClinicalandPharmacologicInformationControllingaComprehensiveManagementofDiffuse MalignantPeritonealMesothelioma PaulSugarbaker,TristanYan,OswaldStuart,LanaBijelic,ThomasGodwin(1) WashingtonCancerInstitute,Washington,DC,USA(1)DepartmentofPathology,Washington HospitalCenter,Washington,DC,USA Keywords: Peritonealmesothelioma,cytoreductivesurgery,peritonectomy,intraperitonealchemotherapy Abstractcontent: Aims:Inthepast,diffusemalignantperitonealmesothelioma(DMPM)hasbeenregardedasa terminalcondition.thelengthofthesurvivalwasdependentupontheaggressiveversusindolent biologyoftheneoplasm,neverthelesscurewasnotconsideredasareasonableexpectationandthe overallmediansurvivalwasapproximatelyoneyear. Methods:Clinicalinformationandpharmacologicdataaccumulatedovertwodecadeshavebeen usedtoformulatethecurrenttreatmentstrategyfordmpm. Results:Todate116patientshavebeenmanagedusingcytoreductivesurgeryandperioperative intraperitonealchemotherapy.pharmacologicstudieswereusedtodesignthehyperthermic intraoperativeintraperitonealchemotherapytreatmentswithcisplatinanddoxorubicin.also,early perioperativeintraperitonealpaclitaxelisroutinelyusedforthefirst5postoperativedays.long termbidirectionalchemotherapywithintraperitonealpemetrexedandintravenouscisplatinhas beeninitiatedasanadjuvanttreatmentasaresultofpharmacologicdata.morbidityofthe comprehensivemanagementplanis14%andperioperativemorbidity3%.survivalanalysisshowsa medianof80months. Conclusions:Thecurrentstandardofcareatourinstitutionhasevolvedfromaseriesof pharmacologicprotocols.increasedperioperativedoseintensityandlongtermadjuvanttreatment hasconverteddmpmintoachronicdiseaseformostpatients. 132

135 ABSTRACTS Number:101 Abstracttitle: EvidencebasedadjustmentstopathologicstagingofepithelialMPM DavidSugarbaker(1),JordanMueller(1),CarlAlsup(1),JohnGodleski(1),LucianChirieac(1),Joseph Corson(1),AneilMujoomdar(1),BeowYeap(2),RaphaelBueno(1),WilliamRichards(1) (1)BrighamandWomen'sHospital,Boston,MA,USA;(2)MassachusettsGeneralHospital,USA Keywords: pathologicstaging,extrapleuralpneumonectomy,surgery Abstractcontent: Cancerstagingsystemspredictoutcomeforagiventumorbiologybasedonaconsistenttherapeutic intervention.severalpathologicstagingsystemsformalignantpleuralmesothelioma(mpm)have beenpublished,butnoneoptimallystratifiessurvivalamongpatientstreatedwithsurgery.existing systemsfailtoidentifymanypatientswitheitherfavorableandunfavorableoutcome,categorizing mostpatientsasstageiii.tumorhistologyhasbeenshowntoprofoundlyaffectoutcomeinmpm andmaycontributetoinconsistencyofcurrentstagingsystems.similarly,interpretationofprior studiescorrelatingpathologicfactorswithoutcomehasbeenconfoundedbyinclusionofpatients withdifferingsurgicalproceduresandtumorhistology. Weexaminedallpublishedtumorstaging(T)factorsinrelationtooutcomeamongpatients undergoingextrapleuralpneumonectomy(epp)forepithelialsubtypempm.logrankcomparisonsof survivalamongpatientswithandwithouteachtfactorguidedadjustmentstoajcctstagecriteria accordingtoobjectiverules.kaplanmeieranalysisofadjustedtstagestratifiedbylymphnode(n) stageguidedadjustmentstostagegroupings. Of473patientswithepithelialmesotheliomaundergoingsurgicalexplorationforplannedEPP,365 wereresectablebythatprocedurewith5%operativemortality.medianagewas57years;72%were male.overallmediansurvivalwas20months.twohundredfortyseven(68%)and202(55%) patientswerestageiiibyajccandbrighamcriteria,respectively.combiningcriteriafromboth systemsbasedonlogrankstatisticresultedinimprovedstagedistributionandsurvivalstratification (Table). DatadrivenadjustmentofAJCCTstagingandstagegroupingcriteriaresultedinimproved stratificationofsurvivalinthiscohortofpatientswithepithelialtumorhistologywhoreceived definitivesurgicaltherapybyepp.thisrevisedtnmstagingsystemmayprovidethebasisformore accurateprognosticationandallowformoreappropriateselectioncriteriaforadjuvanttherapy. Adjusted N Median 1yr 2yr 3yr 5yr TNMStage StageI % 79% 63% 38% StageII % 56% 43% 22% StageIII % 37% 22% 11% StageIV % 21% 10% 0% 133

136 ABSTRACTS Number:102 Abstracttitle: RecentexperiencewithamodifiedClagett'sprocedureinpatientswithempyemaandbronchopleural fistulafollowingextrapleuralpneumonectomyformalignantmesothelioma. JohnPilling,CarolTan,StuartMarshall,LoicLangLazdunski Guy's&StThomashospital Keywords: Mesothelioma.Extrapleuralpneumonectomy.Empyema.Openwindowthoracostomy.Clagett. Abstractcontent: Objectives:Tostudytheoutcomeofpatientswithmalignantmesotheliomatreatedbyamodified Clagett'sprocedureforempyemaandbronchopleuralfistula(BPF)occuringafterextrapleural pneumonectomy(epp).methods:prospectivestudyofallpatientspresentingwithempyemaandbpf followingeppandtreatedatourinstitutionsince2003.themodifiedclagett'sprocedureconsisted ofalargeopenwindowthoracostomywithstagedremovalofthediaphragmaticmeshinallpatients. 18FDGPETCTwasusedroutinelytoguidetherapeuticdecision. Results:ThreepatientshadamodifiedClagett'sproceduredone80,102,and210days,respectively, afterrightepp.allpatientshadreceivedinductionchemotherapyandhadbpfdocumentedat bronchoscopy.histopathologyshowedoneepithelioidandtwobiphasicmesotheliomasstage pt3n2m0,pt3n0m0andpt3n0m0,respectively.allpatientshadremovalofthediaphragmatic mesh3weeksfollowingtheopenwindowthoracostomy.antibioticswereadministeredfora minimumof2weeksfollowingthisprocedureandcavitydressingswerechangeddailyandthen everyalternateday,dependingonthegranulationofthecavity.nopatientreceivedadjuvant radiotherapyorchemotherapy.inhospitalstaywas75+/29days.18fdgpetctdoneat9,11and 13months,respectivelyshowedmesotheliomarecurrenceinthemediastinum,chestwalland contralaterallungofthefirstpatient.biopsiesofthepleuralcavitiesshowedinflammatorycell infiltrateswithoutmalignancyinall3patients.bpffailedtocloseinthefirstpatient,butdidclosein thelasttwopatientswhoareawaitingchestwallreconstructionandclosure.thefirstpatientdiedat 13monthsofdiseaseprogressionandtheothertwopatientsarealiveanddiseasefreeat15and16 months,respectively. Conclusions:ThemodifiedClagett'sprocedureisasafeoptionwhenpatientspresentwithempyema andbpffollowingepp.inthissituation,18fdgpetctisusefultoexcludemesotheliomarecurrence andhelpplanchestwallreconstruction. 134

137 ABSTRACTS Number:104 Abstracttitle: Novelmanagementapproachformalignanteffusions:Targetingfluidformation I.Kalomenidis,Md Athens,Greece Abstractcontent: Malignantpleuraleffusion(MPE)occursinthecourseofvariousmalignancies,signalingincurability, shortenedlifeexpectancy,andseverelycompromisedqualityoflife.treatmentofmpemainlyaims totherelievedyspneacausedbythepleuralfluid(pf).thisisaccomplishedbyremovingand preventingthereaccumulationofthepf.currenttreatmentmodalitiesareofsuboptimalefficacy andassociatedwith(evenlifethreatening)sideeffects.thus,novel,effectiveandsafetherapeutic measuresareurgentlyneededinthemanagementofpatientswithmpe.ithasbeenbelievedthat understandingthepathogenesisofmpewillleadtothedevelopmentoftherapeutictoolsthat specificallyblockpfaccumulationwhenthepleuralcavityisinvadedbytumorcells.severallinesof evidencesuggestthatexcesspleuralfluidproductionistheresultofincreasedpleuralvascular permeabilityandresultantplasmaextravassationinducedbyavarietyofmediatorswhichare releasedinthepleuralcavitybytumor,inflammatoryandmesothelialcells. Recently,invivostudiesusinganimalmodelsofMPEprovidedimportantinsightsintothe pathogenesisofthediseaseandunveilthecrucialroleofcertainmediatorsincludingvascular EndothelialGrowthFactor,Interleukin6,TumorNecrosisFactoalpha,MonocyteChemotactic Protein1,osteopontinandangiopoieitins.Thesestudiesnotonlyunderscoredtheimportanceof vascularhyperpermeabilityinmpeformationbutalsodemonstratedthatpleuralvascularleakageis closelyassociatedwithangiogenesisandpleuralspaceinfiltrationbyinflammatorycells.theabove findingssuggestthattargetingcertainhyperpermeability/angiogeneticfactorsinvolvedinmpe progressionmayprovetobebeneficialinpatientswithmpe. However,itislikelythataspecificantagonistagainstasinglemediatorwillnotbesimilarlyeffective ineverypatientwithmpecausedbytumorofanyhistologicaltype,meaningthatsurrogatemarkers ofsensitivitytospecificagentswillberequiredtodirecttreatment.inaddition,drugsthatinhibit severalstepsofmpepathogenesisrepresentanattractivealternativestrategy.inconnectiontothis, zolendronicacid,anaminobiophosphonate,suppressesmurinempeprogressionthroughinhibition oftumorangiogenesis,vascularhyperpermeabilityandpleuralspacemacrophageaccumulation,the aboveeffectsbeingassociatedwithpreventionofrasandrhoproteinprenylation. 135

138 Number:105 Abstracttitle: Understandingthepsychologicalissues;theneglectedaspectofmesotheliomacare H.Clayson, HospiceofSt.MaryofFurness,Ulverston,CumbriaUK Abstractcontent: ABSTRACTS Thediagnosisofmesotheliomaisassociatedwithspecificandoftenparticularlydifficult psychologicalissues.theseareadditionaltotheacknowledgedproblemsforpatientsfacingdeath frommalignantdiseaseandthosealsoknowntoaffecttheirfamilies. AqualitativeinterviewstudyofpatientsinNorthernEnglandsufferingfrommesotheliomarevealed thattheirparticularproblemscouldbedescribedunderthefollowingheadings:anticipatoryanxiety (thedamocles syndrome),reactionstothediagnosis,attribution,copingwithseveresymptomsand rapidphysicaldeterioration,andthestressrelatedtopursuingacivilclaimfornegligentexposureto asbestosbypreviousemployers.patientstendedtodevelopa narrativeofcoping asameansof minimisingemotionaldistressandmaintainingsomecontrol.however,thisstrategypreventedsome patientsfromaccessingthesupportthatthey,andtheirclosefamily,required.areviewofthe medicalnotesof80patientswhodiedfrommesotheliomarevealedarecordofpsychoemotional symptomsin46%. Afocusgroupstudydemonstratedthat,duringtheillness,familymembersfollowedtheleadsetby patientsinmostcasesbutmanysufferedsevereandenduringdistressinbereavement. Retrospectiveaccountsfromrelativescontrasteddramaticallywiththemainlystoicalaccountsfrom patients.additionalsufferingexperiencedbyfamilymembersrelatedtothemedicolegalprocedures afterdeathandalsotothecivilcompensationclaimsproceduresthatwereoftennotcompleted beforethedeathofthepatient,bothoftheseledtoasenseof noclosure.bereavedfamily membersoftenexperiencedpersistingangerandoutrage;someregardedthedeathsdueto mesotheliomaas massmurder. Theroleofsupportgroupsforpatientswithmesotheliomaandtheirfamilieshasnotbeenpreviously reported.thispaperwillincludeabriefdescriptionofauniquesupportgroupthatwasdeveloped afterconsultingthepublicinatownwithahighincidenceofmesothelioma. 136

139 ABSTRACTS Number:106 Abstracttitle: TARGETINGSURVIVALANDCHEMORESISTANCEINMALIGNANTMESOTHELIOMA GiovanniGaudino(1),PietroBertino(1),SaraBusacca(1),FedericoComoglio(1),LorisDeCecco(2), SerenaGermano(1),BrunoMurer(3),LucianoMutti(4),MarcoPierotti(5),MaurizioRinaldi(1) (1)University"A.Avogadro",DISCAFF,Novara,Italy;(2)MolCancerGeneticsGroup,IFOM&Deptof ExpOncologyINTMilan,Italy;(3)DepartmentofPathology,MestreHospital,Mestre,Italy;(4)Deptof Medicine,LocalHealthUnit11,Piemonte,Italy;(5)DeptofExperimentalOncology,IstitutoNaz Tumori,Milan,Italy Keywords: malignantmesothelioma,akt,chemoresistance,microrna,microarray Abstractcontent: Malignantpleuralmesothelioma(MMe)isanasbestosrelated,highlyaggressivemalignancy.The increaseinmmeincidenceisrecognizedworldwideandispredictedtopersistuntilthenexttwo decades.cellsurvivalrescueshumanmesothelialcells(hmc)cellsfromasbestosdamagesaspartof themultistepprocessleadingtoneoplastictransformationandtumorchemoresistance,whichisa majordrawbackinmmetherapy.recently,weshowedthatthecombinedtreatmentofthepdgfr inhibitorimatinibwithgemcitabinesynergizesininducingmmecelldeathinvitroandinvivo. TumorspecificmiRNA(smallRNAmoleculescontrollingthetranslationoftargetmRNAs)are dysregulatedinseveralcancerstheirgenesmayfunctionaspotentialoncogenesortumorsuppressor genes,contributingtocelltransformationandtumorigenesis.duringapreliminarysurveyby microarrayanalysisofmicrornaexpression,confirmedbyrealtimequantitativereverse TranscriptionPCR(qRTPCR),wefoundthatspecificmiRNAsweredifferentiallyexpressedinMMe cellscomparedtohmc.moreover,bycombiningmirnaexpressionanalysiswithgeneexpression profiles,followedbyacomputationalanalysis,weattainedanaccuratepredictionofgenes potentiallytargetedbydysregulatedmirnas.amongthepredictedgenesseveralareinvolvedinthe developmentandprogressionofmalignantmesothelioma(btg1,cdkn1b,hgf,mecp2),suggesting thatmirnasmaybekeyplayersinmesotheliomaoncogenesis. Furthermore,weinvestigatedmiRNAexpressionbyqRTPCRonapanelof24mesothelioma specimens,representativeofthethreehistotypes(epithelioid,biphasicandsarcomatoid)and noteworthytheupregulationofsevenmirnaswassignificantlyassociatedwithabetterpatient survival. OurdataremarkablyhighlightmiRNAsasdiagnosticandprognosticmarkersofmesotheliomaand usefultoolsfordevelopmentofnoveltherapeuticapproachesforthismalignancy. 137

140 ABSTRACTS Number:107 Abstracttitle: TargetingofHumanMesotheliomaCellsafterBifunctionalizationoftheSurfaceofAmorphousSilica SphereswithTetraethyleneGlycol(TEG)andanAntibodytoMesothelin KaiCheng,StevenR.Blumen,MaximilianB.MacPherson,DanielJ.Weiss,TedA.James,Christopher C.Landry,BrookeT.Mossman UniversityofVermontCollegeofMedicine,USA Keywords: Mesothelioma,AmorphousSilicaSpheres,Mesothelin Abstractcontent: Therearenoeffectivetreatmentregimensformalignantmesothelioma(MM),atumorassociated withexposuretoasbestosinwhichpatientsexhibitanaverage10monthsurvivalperiodafter diagnosis.intravenousadministrationofchemotherapeuticdrugsisproblematicduetothedrug resistanceofmmsandconsequentsystemictoxicity.herewedescribeauniquestrategyfor modifyingtheexternalsurfaceofhighlyporousamorphoussilicaspheres(apms)(originally describedbyblumenetal.,amjrespircellmolbiol,33:333342,2007)thatcanbeloadedwith chemotherapeuticdrugs,smallinterferingrnasormolecularconstructs.apmsmodifiedwiththe surfacefunctionalities,tetraethyleneglycol(teg)andamonoclonalantibodytomesothelin(affinity Bioreagents),aproteinoverexpressedinhumanMMs,aretakenuppreferentiallybyhumanMM cellsincontrasttoparticlesmodifiedwiththegenericprotein,bovineserumalbumin(bsa).using confocalscanninglasermicroscopyandflowcytometry,weverifiedthatmaximalcelluptakewas achievedusingapmsteg.incontrast,apmsmesothelinwasnottakenupbyhumanmm.the combinationofapmstegmesothelinallowedtargetedandmaximalassociationofparticleswith MMcellswhereasalungcancercellline(A549)didnotshowapreferenceforeithertypeofmodified particle.apmstegmodifiedwithmmspecificantibodiesallowingtargeteddeliveryoftheirloaded cargo drugswillbeinvaluableintherapeuticapproachestomm.supportedbyagrantfrommarf andasttrgrantfromthenationalcancerinstitute. 138

141 ABSTRACTS Number:108 Abstracttitle: Chemopreventionofasbestosinducedgeneticinstability MonicaNeri NationalCancerResearchInstituteGenoa Italy Keywords: chemoprevention;asbestos;clinicaltrial Abstractcontent: Chemopreventionofasbestosinducedgeneticinstability Exposuretoasbestosfiberscanleadtoneoplasticdiseasessuchasmalignantpleuralmesothelioma (MM),lungcancer(LC)andtoseverenoncancerconditionssuchasasbestosis.Asbestoshasbeen usedextensivelyinmanufacturesandbuildingduetoitsresistancetoheat;inthelastdecadesithas beenbannedinanumberofcountries.becauseofthelonglatencyofthesetumors,especiallymm, subjectsoccupationallyorenvironmentallyexposedtoasbestosarestillatincreasedriskevenwhere thepresenceofasbestosintheenvironmentisprogressivelydecreasing.theincidenceofmmis particularlyhighinareascharacterizedbythepresenceofasbestosassociatedindustrialand shippingactivities.intheseareasworkerswithanoccupationalhistoryofasbestosexposureare invitedtoenterprogramsofmedicalsurveillance.however,theseprogramsaresubstantially inefficientinreducingcancerriskormortalityrates.smokingcessationreduceslcriskbutis ineffectiveindecreasingmmrisk.anappropriateapproachmaybechemoprevention,i.e.,theuseof specificagentstoprevent,arrestorreverseeithertheinitiationphaseofcarcinogenesisorthe progressionofneoplasticcellstocancer.fewchemopreventiontrialshavebeenconductedtodatein asbestosexposedsubjects.giventherelativelylowincidenceoflcandespeciallyofmm,verylarge andexpensivetrialswouldberequiredtoproperlytesttheeffectofchemopreventivetreatment.on theotherhand,theuseofbiomarkersassurrogateendpointsisincreasinglyreportedinthe literatureasasuitableapproachtotesttreatmentactivityinshortandcheapstudies.amechanism knowntomediateasbestostoxicityandcarcinogenicityisthegenerationofreactiveoxygenor nitrogenspecies,whoseconsequencesincludegenomicinstability.aphaseiibrandomizedclinical trialisproposed,aimedatevaluatingtheactivityofantioxidantdrugsinsubjectswithdocumented occupationalexposuretoasbestos.theextentofgenomicinstabilitywillbeevaluatedusing biomarkersofnuclearandmitochondrialdnadamage. 139

142 ABSTRACTS Number:109 Abstracttitle: malignantmesotheliomaincanada ChristopherLee BCCancerAgencyFraserValleyCentre,Canada Keywords: FutureTrends:Canada Abstractcontent: TheincidenceofmalignantmesotheliomainCanadahasincreaseddramaticallysincethe1960s, althoughitisexpectedtoplateaufollowingtheintroductionofsafetyguidelinesintheworkplace andadeclineinthedomesticuseofasbestos.thelatestdataavailablefromthecanadiancancer Registryisthattherewere406newcasesofmesotheliomadiagnosedin2004.Aggressivesurgical managementofthediseaseisrestrictedtoafewspecializedthoracicsurgeryprogramsacrossthe country.treatmentwithchemotherapyisnowaroutineconsideration,althoughreimbursementof drugcostsisanissueinsomeprovinces.anationalclinicalresearchstrategyisfocusingonnewdrug developmentandestablishmentofamesotheliomaregistryandtumourbank.effortstoimprove accesstocompensationforpatientshaveincludedautomaticreminderstoprimaryhealthcare providerstofilereportswithworkers compensationboards. 140

143 ABSTRACTS Number:111 Abstracttitle: ResponsetoinductionchemotherapyisthestrongestpredictorofsurvivalinamulticenterU.S.trialof trimodalitytherapyforresectablemalignantpleuralmesothelioma LeeKrug(1),HarveyPass(2),ValerieRusch(1),HedyKindler(3),DavidSugarbaker(4),Kenneth Rosenzweig(1),JosephFriedberg(5),KathyPisters(6),ColemanObasaju(7),NicholasVogelzang(8) (1)MemorialSloanKetteringCancerCenter,(2)NewYorkUniversity,(3)MemorialSloanKettering CancerCenter,(4)BrighamandWomen\'sHospital,(5)UniversityofPennsylvaniaMedicalCenter, (6)MDAndersonCancerCenter,(7)EliLillyandCompany,(8)NevadaCancerInstitute Keywords: Multimodalitytherapy,extrapleuralpneumonectomy Abstractcontent: Background:Anaggressivesurgicalapproachisfrequentlyofferedtofitpatientswithearlystage mesothelioma,butthevariablenaturalhistorymakesitdifficulttodeterminewhichpatientsare mostlikelytobenefit.thecurrentanalysisexplorespatternsofsurvivalwithinpatientsubgroupsina multicenterfeasibilitystudyoftrimodalitytherapy.methods:eligibilitycriteriaincludedstaget13 N02,postoppredictedFEV1>35%,PS01.Patientsreceivedpemetrexed500mg/m2pluscisplatin 75mg/m2withvitaminsupplementationfor4cycles.Patientswithoutdiseaseprogression underwentextrapleuralpneumonectomyfollowedbyhemithoracicradiation(54gy).theprimary endpointwaspathologiccompleteresponserate.univariatecomparisonsofsurvivalweremade withinpatientsubgroups.enrollmentwascompletedinmarch,2006. Results:77patientswereenrolled.83%receivedall4cyclesofinductionchemotherapy.Medianage =63.0(range3478),M:F=56:21,ClinicalstageI:II:III:IV=6:33:35:1,epithelial:other=62:15,ECOG PS0:1:2=28:47:2.Responsetochemotherapywas1.3%CR,31.2%PR,46.8%SD.3patientshada pathologiccr.mediansurvivalfortheittpopulationwas16.8m(95%ci=13.6,23.2),1year survival65.2%,2yearsurvival37.2%.forpatientsundergoingepp(n=57),mediansurvivalwas21.9 m(95%ci=16.8,29.1),andforpatientscompletingalltherapy(throughrt,n=40),mediansurvival was29.1m(19.3,ne)and2yearsurvivalwas61.2%.withintheittpopulation,mediansurvivalwas 17.4mforepithelialhistologyvs13.8mforother;17.1mforN0vs16.1mforN1orN2;26.0mfor CRorPRvs13.9mforSDorPD(Pforcomparison.05);16.8mformalesvs.17.3mfor females;and17.3forclinicalstageioriivs.16.8mforstageiiioriv.survivaldifferenceswithin patientsubgroupswerenotsignificantfortheepporrtcompletedpopulations. Conclusions:WithintheITTpopulation,differencesinsurvivalweresignificantbyresponseto chemotherapybutnotbyhistology,nodalstatus,gender,orstage.patientswhowereableto completealltherapyhadanexcellent2yearsurvivalrate.sponsoredbyelililly&company. 141

144 ABSTRACTS Number:112 Abstracttitle: RISKFACTORSFORACUTEKIDNEYINJURY(AKI)INPATIENTSUNDERGOINGEXTRAPLEURAL PNEUMONECTOMY AnnetteMizuguchi,PeterIreland,CostasGioules,AyaMitani,SushrutWaikar,JosephBonventre, DavidSugarbaker,GyorgyFrendl BrighamandWomen'sHospital,HarvardMedicalSchool,USA Keywords: acutekidneyinjury,cisplatin,extrapleauralpneumonectomy,mesothelioma Abstractcontent: Background:Thesurvivalofpatientsundergoingtherapyformesotheliomahasimprovedwith extrapleuralpneumonectomy(epp)incombinationwithintraoperative,intracavitaryheatedcisplatin chemotherapy(iohc).however,eppisassociatedwith2.7%incidenceofrenalfailure,ariskfurther increasedwiththeadditionofcisplatinchemotherapy.inordertominimizetheriskofacutekidney injury(aki)ourobjectivewastoidentifymodifiableperioperativeriskfactorsofaki,andtodevelop strategiesfortheearlyrecognitionofakitopreventrenalfailure. Methods:AnalysisofperioperativeriskfactorsofAKIusingadatabaseofacohortof227patients whounderwentepp,pleurectomy,orexploratorythoracotomywith(n=114)orwithout(n=113) IOHC.Wehypothesizedthatpreoperativefactors(decreasedestimatedglomerularfiltrationrate, lowhematocrit,prioruseofnsaids)orintraandpostoperativevariables(amountofredbloodcells received,needforvasopressors)maycontributetoaki(definedasa0.3mg/dlincreaseofserum creatininefrombaseline).apredictionmodelwascreatedusingmultiplestepwiselogisticregression. Results:TheoverallincidenceofAKI(withthestrictestdefinitionofa0.3mg/dlriseinserum creatininefrombaseline)intheentirepopulationwas50.22%,64.9%forpatientswhoreceivediohc and35.4%forthosewhodidnot(rr:1.84[ci95%: ]).amultivariatestepwiselogistic regressionmodel,builtonthefindingsoftheunivariateanalysis,indicatedthatiohcwasthe strongestpredictorofaki(or:3.81[ci95%: ])thefollowingadditionalfactorsshowed statisticallysignificantcorrelationwiththedevelopmentofaki:needfortheuseofvasopressors(or: 2.49[CI95%: ]);reoperation(OR:1.99[CI95%: ]).Atrendofcorrelationwas observedforageover60(or:1.45[ci95%: ]);andageover70(or:1.75[ci95%: ]). Ouranalysisalsosuggestedthatfemalegendermaybeprotective(OR:0.53[CI95%:0/241.15]). Conclusions:OurpreliminaryanalysisindicatesthatIOHCandpostoperativeuseofvasopressorsare thestrongestpredictorsofpostoperativeakiinpatientsundergoingeppandiohc.reoperationand ageover60mayalsocontributetoaki.furtheranalysis,encompassingallourmesothelioma patients,isplannedtoconfirmthesefindingsandtoidentifyadditionalmodifiableriskfactors. 142

145 ABSTRACTS Number:113 Abstracttitle: Urinarykidneyinjurymolecule1fortheearlydetectionofkidneyinjurywithfollowingcytoreductive surgeryandintracavitarycisplatinlavageformesothelioma SushrutS,Waikar,MD,MPH(1),VishalS.Vaidya,PhD(1),CostasGioules,BS(1),KelseySunderland, BA(1),ColleenHession,BA(1),FitzB.Collings,BS(1),GaryC.Curhan,MD,ScD(1),GyorgyFrendl,MD, PhD(2),DavidJ.Sugarbaker,MD(3),JosephV.Bonventre,MD,PhD(1) (1)RenalDivision,BrighamandWomen'sHospital,Boston,MA,USA;(2)DeptofAnesthesiology, BrighamandWomen'sHospital,Boston,MA,USA;(3)3DivisionofThoracicSurgery,Brighamand Women'sHospital,Boston,MA Keywords: Acuterenalfailure,biomarkers,cisplatinnephrotoxicity Abstractcontent: Body:Acutekidneyinjury(AKI)isacommonanddevastatingpostoperativecomplicationinpatients undergoingcytoreductivesurgeryandintracavitarycisplatinlavageforpleuralmesothelioma.serum creatinine(scr)isthegoldstandardforthediagnosisofakibuttakesmorethan24htorise significantlyevenaftersevereinjury,leadingtodelayeddiagnosis.kidneyinjurymolecule1(kim1) isatype1transmembraneproteinthatisnotdetectableinnormalkidneytissuebutexpressedat highlevelsindedifferentiatedproximaltubuleepithelialcellsinhumanandrodentkidneysafter ischemicortoxicinjury.thekim1ectodomainisshedintotheurineandcanbedetectedinhumans withakiasanearlyandsensitivebiomarkerofaki. WemeasuredpreoperativeandpostoperativeurinaryKIM1in30patientsundergoingtreatmentfor pleuralmalignantmesothelioma.thesurgicalapproachinvolvesextrapleuralpneumonectomyor pleurectomy,aswellas1hofintraoperativeintracavitaryhyperthermiccisplatinlavage(225mg/m2) inmostpatients.meanagewas64y(range,50to78y)andmeanpreoperativescrwas0.9mg/dl (range,0.5to1.6mg/dl). 12patients(40%)developedAKIasdefinedbya0.5mg/dLincreaseinSCr.Therewasnodifference inpreoperativekim1levelsbetweenthosewhodidanddidnotdevelopaki(0.5ng/mgcreatin both).at24,48,and72hpostoperatively,meankim1levelsroseto3.6,6.5and4.7ng/mginthose whowentontodevelopakiand1.7,2.0,and1.8ng/mginthosewhodidnotdevelopaki(p=0.02, 0.02,and0.15,respectively).Theareasunderthereceiveroperatingcharacteristicscurve(AUCROC) were0.80,0.82,and0.71at24,48,and72h.thediagnosisofakiwasmadebyscrat24hin4of12 patientsandnotuntil72hin8of12patients. WeconcludethaturinaryKIM1levels24hpostoperativelycanprovideearlyandaccurate identificationofaki,enablingthepromptinstitutionofrenalprotectivestrategiesthatwould otherwisebesignificantlydelayedusingserumcreatininefordiagnosis. 143

146 ABSTRACTS Number:114 Abstracttitle: NewChemotherapeuticDrugsintheTreatmentofAdvancedMalignantPleuralMesotheliomain Egypt RababGaafar,MohamedEmara,YasserSallam,HananEzzat,GehanRisk,AsmaaAbourabia,Maha Helal,NellyAlieldin,NadiaMokhtar,HusseinKhaled NationalCancerInstitute,Cairo Keywords: mesothelioma,chemotherapy,newdrugs Abstractcontent: Purpose: Patientswithmalignantpleuralmesothelioma,arapidlyprogressivemalignancywithamedian survivalof6to9months,arewellknowntohavepoorresponsetochemotherapy.theaimofthis workwastoevaluatetheefficacyandsafetyofnewchemotherapeuticagentsforthetreatmentof EgyptianMPMpatients. Patientsandmethods Thefirststudywasanonrandomized,openlabeltrial(partofanInternationalCompassionatetrial). Itincluded34eligiblepatientsthatwereassignedtoreceiveeithercisplatin/pemetrexedor pemetrexedaloneifcisplatinwascontraindicated.theregimenconsistedofpemetrexed500mg/m2 IVfollowedbycisplatin75mg/m2IVorpemetrexed500mg/m2IVonday1ofeach21daycyclesfor amaximumof8cycles.inthesecondtrial21chemonaivepatientswithhistologicallyproven advancedmpmwereincluded.eligibilityincludedwhoperformancestatus(ps)0to2,adequate hematological,renal,andhepaticfunction.theyreceivedcisplatinandraltitrexedaspartofeortc 08983protocol.Theregimenconsistedofraltitrexed3mg/m2IVfollowedbyCisplatinatadoseof 80mg/m2IVonday1ofeach21daycyclesforamaximumof6cycles. Results: Inthefirsttrial,themedianagewas43.5years(range25 69),theresponseratewas(37.5%),and theclinicalbenefit(responseplusstabledisease)wasevidentin28patients(87.5%).themedian timetoprogressionandoverallsurvivalfromthestartoftherapywas7and14monthsrespectively. Survivalat1yearwas64.7%. Notoxicitywasobservedin17.6%ofpatients,grade34toxicitywasevidentin11.8%(neutropenia), 8.8%(anemia),and2.9%(vomitinganddiarrhea). Inthesecondtrial,themedianagewas46years(range1971),theoverallresponseratewas28.6%, includingonecompleteremission.stablediseasewasnoticedin13patients(61.9%). 144

147 ABSTRACTS Themediantimetoprogressionandoverallsurvivalfromthestartoftherapywas6and12months respectively.survivalat1yearwas51.6%. Conclusion: Bothcisplatin/pemetrexedandcisplatin/raltitrexedareeffectiveandsaferegimensforthe treatmentofmpm. 145

148 ABSTRACTS Number:115 Abstracttitle: CisplatinandVinorelbinefirstlinechemotherapyinnonresectableMalignantPleuralMesothelioma (MPM). JensBennSorensen(1),HannaFrank(2),TorbenPalshof(3) (1)DepartmentOncology,FinsenCentre/NationalUniversityHospital,Copenhagen,Denmark; (2)DepartmentOncology,AalborgUniversityHospital,Denmark;(3)DepartmentOncology,Aarhus UniversityHospital,Denmark Keywords: chemotherapy,vinorelbine,firstline Abstractcontent: Aim:Theaimwastoevaluatetheactivityofcisplatinandvinorelbineinpreviouslyuntreated, inoperablepatientshavinghistologicallyverifiedmpm,normalorganfunctionandperformance status02. Methods:Treatmentwasvinorelbine25mg/m2i.v.weeklyandcisplatin100mg/m2i.v.everyfour weekswithhydrationandstandardprophylacticantiemetictreatment.patientsgavewritten informedconsent. Results:Characteristicsof54consecutivepatientswere:Males85%,epithelialsubtype74%,IMIG stagesiiiandiv35%and46%,performancestatus0,1,and226%,69%,and6%,andmedianage63 years(3178years).ctcgrade3or4toxicityoccurredwithrespecttoleucocytopenia(48%ofpts, grade4in13%),nausea(13%),neurotoxicity(11%),nephrotoxicity(4%),andothertoxicities(9%). Therewerenotoxicdeaths.Medianno.ofcycleswas4.Thefractionofpatientsaliveat1,2,and3 yrswere61%,31%,and4%,respectively,andmediansurvivalandmediantimetoprogressionwere 16.8months( months)and7.2months( months).ThereweretwoCRsand14PRs (responserate29.6%). Conclusions:CisplatinandintraveneousvinorelbineisahighlyactiveregimeninMPMwitha responserateandsurvivalcomparabletothemostactiveregimenssofarreported. 146

149 ABSTRACTS Number:116 Abstracttitle: PhaseIIstudyofsunitinibassecondlinetherapyinmalignantpleuralmesothelioma(MPM) AnnaNowak(1),MichaelMillward(1),RoslynFrancis(2),AgathaVanderschaaf(2),BillMusk(2), AmandaSegal(3),MichaelByrne(2) (1)UniversityofWesternAustralia;(2)SirCharlesGairdnerHospital,Australia;(3)Pathwest,Australia Abstractcontent: Background: ThereisnostandardsecondlinetherapyforprogressiveMPMfollowingfirstlinechemotherapy. SunitinibisamultitargetedtyrosinekinaseinhibitorofVEGFR,PDGFR,cKitandFlt3.VEGFRand PDGFRarepotentialtargetsinMPM.Weexaminedthesafetyandefficacyofsunitinibassecondline treatmentinmpm. Methods: EligiblepatientshadprogressiveMPMduringorafterfirstlinechemotherapywithplatinumandan antimetabolite,ecogps01,adequateorganfunction,measurabledisease,andgaveinformed consent.treatment:sunitinib50mg/dayx28dq6weeks.primaryendpointwasobjectiveresponse definedbyeithera).modifiedrecistcriteria(mrc)onctscanorb)metabolicresponseonfdgpet inpatientswithoutpriortalcpleuradesis(francisetal,jnucmed(48)144958;2007).imagingwas performedatbaselineandaftercycles1,2,andevery2cyclesthereafter.simon s2stagedesign required2responsesin23patients(stagei)togiveα=0.05,β=0.1assumingatruerr of20%tobeofinterest.stageiisreportedhere. Results: FromMay2006toOctober200723patientswereaccrued:22wereradiologicallyassessablefor response.demographics:m/f(18:5);medianage65(range4981);histology epithelial/sarcomatoid/mixed/unknown(16:0:2:5).ecogps0/1(4:19).priorplatinum/pemetrexed 57%,priorplatinumgemcitabine43%.BestMRCresponse:CR0;PR4(18%);SD11(55%);PD7 (32%).MetabolicresponseonPET:3of11assessable(27%),1alsowithMRCresponse.Total protocoldefinedresponse6/22(27%,95%ci5%40%).medianfollowupis15months(range724 months).medianoswas8.2months(95%ci ).medianttpwas3.7months(95%ci2.94.5). Totalcyclesgivenis64.Adverseevents(%ofallcycles):Grade4,thrombocytopenia1%;Grade3, fatigue17%,anorexia3%,diarrhea3%.7/23requireddosereduction.therewasonepossible treatmentrelateddeathfrompulmonaryinfiltratesandrespiratoryfailure.fourpatientsdeveloped increasingpleuraleffusionsorasciteswithoutotherradiologicalevidenceofpd.treatmentwas otherwisewelltolerated. Conclusions: SunitinibhasactivityinpreviouslytreatedMPM.StageIIcontinuestoaccruetoaplanned51 patients. 147

150 ABSTRACTS Number:118 Abstracttitle: DiscoveryofDifferentiallyexpressedalternativesplicingtranscriptvariantsinMalignantPleural Mesothelioma(MPM)usingnextgenerationtranscriptomesequencing LingshengDong(1),RoderickJensen(2),GavinGordon(1),DavidSugarbaker(1),RaphaelBueno(1) (1)BrighamandWomen'sHospital,Boston,MA,USA;(2)VirginiaBioinformaticsInstitute,USA Abstractcontent: Background: AlternativesplicingofpremRNAistightlyregulatedduringdevelopment.Differenttissuetypesas wellasdiseaseprocessesincludingtumorscaneffectchangesinpremrnasplicingpatterns. Recently,weadoptedwholetranscriptomeshotgun454pyrosequencingtocharacterizethe transcriptomesof4pleuralmesotheliomatumors,1lungadenocarcinomaand1normallung.we hypothesizedthatalternativesplicingprofilesshouldbepreservedinthesesequencingdataforthe expressedgenes. Methods: Wedevelopedasoftwarepipelinetomapalltranscriptomereadsequencesofeachtumoronto knownexonjunctionsequencesinaceviewandcounthowmanyreadsmaptoeachjunction.the exonjunctionexpressionindex(ejei)wascalculatedforeachexonjunctionpersampletorepresent thepurealternativesplicingregulationeffectonexonjunctionexpression.tenexonjunctionswith thebiggestejeidifferencebetweenthe4mesotheliomaand1normallungsampleswerethen examinedfordifferentialexpressionusingaqrtpcrplatforminthefivesequencedsamples.two oftheexonjunctions(actg2.aaug05.547andcdk4.aaug )werefurthervalidatedwithqrt PCRplatforminadditional18mesotheliomaand18normallungspecimens. Result: Amongthe10identifieddifferentiallyexpressedexonjunctions,6wereconfirmedbyQRTPCRto havethesameejeitrendasinitiallydiscoveredbythe454sequencingplatforminatleast4ofthe5 specimens.ejeiofactg2.aaug05.547andcdk4.aaug byqrtpcrplatformcansuccessfully classifymesotheliomaandnormallungspecimenswithhighsensitivity(89%or16/18and100%or 18/18respectively)andSpecificity(89%or16/18and78%or14/18respectively). Conclusion: Wholetranscriptomeshotgunsequencinganddownstreambioinformaticspipelinearepowerful toolsfortheidentificationofdifferentiallyexpressedexonjunctionsresultingfromalternative splicingvariants.unlikeexonarrayswhicharelimitedtoknownsplicevariants,newgeneration sequencingcanbeusedtoprovideanunbiasedanalysisofdifferentiallyexpressedalternative splicingvariantswhichmaybeinvolvedincancerpathobiology. 148

151 ABSTRACTS Number:119 Abstracttitle: MicroRNAAlterationsinMalignantPleuralMesotheliomaasBiomarkersofDisease CarmenMarsit(1),MicheleAvissar(1),HeatherNelson(2),RaphaelBueno(3),DavidSugarbaker(3), KarlKelsey(1),BrockChristensen(1) (1)BrownUniversity,(2)UniversityofMinnesotaCancerCenter,(3)BrighamandWomen\'sHospital Keywords: mirna,differentialdiagnosis,adenocarcinoma,biomarker Abstractcontent: TheinvolvementofmicroRNAs(miRNAs)incarcinogenesisisbecomingincreasinglyappreciated,as thesesmallnoncodingrnaspecieshavetheabilitytoalterthetranslationofmaturemrnaand havebeenshowntoactfunctionallyasbothoncogenesandtumorsuppressors.inmanysolid tumors,alterationsofthesemirnahavebeendemonstratedtopossessgreatpotentialas biomarkersofdiseasepresence,pathologicdiagnosis,treatmentefficacy,andsurvival.alterationsof mirnainmalignantpleuralmesotheliomahavebeenlesswellcharacterized.thus,wesoughtto identifymirnasalteredinmpmandtoexaminewhetherthisprofilecanactasdiseasebiomarkers oraidindifferentialdiagnosis.mpmsampleswereobtainedfrompatientstreatedthroughthe InternationalMesotheliomaProgramatBrighamandWomen shospitalinboston,whilelung adenocarcinomatumorswereobtainedfrompatientsinvolvedinaretrospectivecasecontrolstudy ofnonsmallcelllungcanceratmassachusettsgeneralhospital.totalrnawasisolatedfrom15 freshfrozenmpmsrepresentingallhistologies,4freshfrozenlungadenocarcinomas,and2non tumorigenicmesothelialcelllines.mirnaprofilingwascarriedoutbyasuragenservicesusingthe mirvanamirnabioarraysv2platform(ambion,inc.)aftermanufacturerindicatedmirna fractionation,labeling,andhybridizationprocedures.theresultingdatawasanalyzedusing SignificanceAnalysisofMicroarrays(SAM)andPredictionAnalysisofMicroarrays(PAM)approaches andafalsediscoveryratecutoffof5%.astrikingdifferenceinmirnaexpressionwasobserved betweenmpmtumorsandnontumorigeniccelllines,with116mirnassignificantlyupregulatedin tumorscomparedtocelllines,and4mirnassignificantlydownregulated.wealsoidentified7 mirnasdifferentiallyexpressedbetweenepithelioidandsarcomatoidmpmhistologies,but surprisingly,only1mirnadifferentiallyexpressedbetweenmpmandlungadenocarcinoma.a numberofthesemirnashavepreviouslybeenidentifiedasoncogenicortumorsuppressive,and thusitissuggestedthatthesemirnasplayacriticalroleinthegenesisofthisdisease.theseresults, consistentwiththeliterature,suggestthatalthoughcelllinesmayhavesignificantusein understandingthemechanisticaspectsofmirnafunction,theymaynotbeappropriateinthe identificationofclinicallyrelevantmirnabiomarkers. 149

152 ABSTRACTS Continuingworkinthelaboratoryisfocusedonconfirmingtheseresultsandexaminingtheirclinical utilityandrelationshiptoetiologiccontributorsinalargerseriesofmpmandnormalpleurasamples. Thisworkaimstodefinenovelandclinicallyusefulbiomarkersandtoidentifynewpathwaysand targetsforadvanced,potentiallypatientspecifictherapies. 150

153 ABSTRACTS Number:120 Abstracttitle: CellSurfaceProteomicsrevealsnewproteinmarkersforthediscriminationofmalignantpleural mesotheliomafromlungadenocarcinoma AnnemarieZiegler(1),FerdinandoCerciello(1,2),DamarisBauschFluck(1,3),EmanuelaFelley Bosco(2),ColetteBigosch(2),AlexSoltermann(4),HolgerMoch(4),RolfStahel(2),RuediAebersold(1), BerndWollscheid(1,3) (1)InstituteofMolecularSystemsBiology,ETHZurich,Switserland;(2)LaboratoryofMolecular Oncology,ClinicandPoliclinicforOncology,UniversityHopitalZurich,Switserland;(3)NCCRNeuro CenterforProteomics,Zurich,Switserland;(4)InstituteofSurgicalPathology,UniversityHospital Zurich,Switserland Keywords: malignantpleuralmesothelioma;lungadenocarcinoma;cellsurfacecapturin;cellsurface glycoproteins;classificationmarker Abstractcontent: Introduction Thecorrectdiagnosisofmalignantpleuralmesothelioma(MPM)isstillamajorproblemforclinicians aswellasforthepathologists.thehistopathologicalapproachiscomplicatedbyabroaddifferential diagnosisandcurrently,apanelofhistopathologicalmarkerareneededtodiscriminatempmfrom anatomicallyrelatedmalignancieslikelungadenocarcinoma.therefore,wesetouttoidentifycell surfaceproteinpatternsviamassspectrometry(ms)whichwouldallowforthediscriminationof MPMfromlungadenocarcinomaattissuelevel. Methods WeinvestigatedthecellsurfacesubproteomeofoneepithelialMPMcellline(ZL55)incomparisonto oneadenocarcinomacellline(calu3)viathecellsurfacecapturing(csc)technology.relative quantificationoftheidentifiedcellsurfaceproteinswasachievedbysilac(stableisotopelabeling byaminoacidsincellculture)labeling.differentiallyexpressedcellsurfaceproteinswerefurther investigatedonthemrnalevelbylowdensitymicroarrayrtpcronacollectionofmpmand adenocarcinomacelllines.confirmedclassificationmarkercandidateswerefurthervalidatedbyihc stainingsoncelllinesandfrozentissuesamplesfrompatientsaffectedbylatestagempmorlung adenocarcinoma. Results Over130bonafidecellsurfaceglycoproteinswereidentifiedandquantifiedviaCSCtechnology, amongthem37cdannotatedproteins.62cellsurfaceglycoproteinswerefoundtobedifferentially expressedbetweenthetwocelllinesatleasttwofold.rtpcranalysisof29differentiallyexpressed proteincandidateson15epithelialmpmand6adenocarcinomacelllinesrevealedtwoglycoproteins aspotentiallygooddiscriminationmarkersbetweenmpmandadenocarcinoma. 151

154 ABSTRACTS ThesetwoclassificationmarkercandidateswerefurtherinvestigatedinantibodybasedIHC experimentsonpatientsamples.acommerciallyavailableantibodyagainstoneoutofthetwotarget cellsurfaceglycoproteinsdiscriminatedmpmfromadenocarcinomainclinicalrelevantihcstainings onbiopsiesfromselectedpatients. Conclusion Byusingcellsurfacecapturingtechnologyinaquantitativeproteomicsapproachwewereableto identifycellsurfaceglycoproteinswhicharedifferentiallyexpressedbetweenmesotheliomaand adenocarcinomacells.initialvalidationoftwoselectedproteinsonpatientsamplesindicatetheir potentialforaidinginthecorrectclassificationofmpmincontrasttoadenocarcinoma. 152

155 ABSTRACTS Number:121 Abstracttitle: Genomewideprofileofmesotheliomaversusparietalpleuramayexplainitschemoandradio resistanceandindicatenewtargets. OlufDimitriRøe(1,2),EndreAnderssen(2),HelmutSandeck(3),ToneChristensen(2),ErikLarsson(4), SteinarLundgren(1,2) (1)Dept.ofOncology,St.OlavsUniversityHospital;(2)NorwegianUniversityofScienceand Technology(NTNU)Dept.ofCancerResea,Norway;(3)Dept.ofPathologyandMoleculrGenetics,St. OlavsUniversityHospital,Norway;(4)Dept.ofLaboratoryMedicine,Children sandwomen shealth, Trondheim,Norway Keywords: Chemoresistance,DNArepair,Drugtarget,Fanconianemia,Homologousrecombination,Radiation resistance Abstractcontent: Background:Malignantmesotheliomaisatumourhighlyresistanttomostchemotherapeuticand irradiationregimens.littleisknownaboutitsmolecularbasis.methods:needlebiopsiesfromfive patientswithmesotheliomawereobtainedandsnapfrozen.normalvisceralandparietalpleura samples,wereobtainedbyvideoassistedthoracoscopyfromsixcancerfreepatientswith spontaneouspneumothorax,anatomicallydissectedandsnapfrozen.adjacenttissuewasformalin fixedandhematoxylineosinsafran(hes)stainedforanalysisofcelltypes.rnawasextractedand analyzedwiththeaffymetrixhumangenomeu133plus2.0chipoligoarrayof38500genes. DifferentiallyexpressedgenesweredetectedusingaBayesianlinearmodelandgeneswithcorrected Pvaluessmallerthan0.05weretakenassignificant.Thelistsofsignificantgenesweretestedfor overrepresentedkeggpathways,andgeneontologytermsusingfishersexacttest.cellspecific expressionofproteinsencodedbysomeoftheoverexpressedgenesweredetectedby immunohistochemistry.resultsandconclusion:parietal,visceralpleuraandmesotheliomahad distinctexpressionprofiles.whenparietalpleuraandtumorwerecompared,targetgenesofchemo (e.g.top2a,birc5/survivinandproteasome)andradiotherapy(e.g.brca2,fanca,fancd2,ccnb1 andrad50)wereoverexpressed.wediscoveredacloserelationbetweengeneprofileandresistance towardstopoisomerasepoisons,antitubulines,antifolates,platinumcompoundsandradiation therapy.leukocytetransendothelialdownregulationcouldbeapartofthetumourdefence.the Fanconianemia/BRCA2pathwayresponsibleforhomologousrecombinationalDNArepairmaybea keypathwayinmesotheliomachemoandradioresistance.commonexpressionfeatureswithother resistantcancersrelatedtodnarepairandreplicationcouldindicatethatthesefindingsmayserve asageneralmodeloftumourresistance. 153

156 ABSTRACTS Targetedsuppressionofsomeofthesekeygenes/pathwayscombinedwithchemotherapyor radiationcouldimproveoutcomeofmesothelioma.weproposechek1,rad21,fancd2andranas newcotargetsformesotheliomatreatment.bothaggf1mrnaandproteinwerehighlyover expressedinalltumoursandmayserveasatargetforantiangiogenictreatment.overexpressionof NQO1mayrendermesotheliomasensitivetothenovelcompoundbetaLapachone. 154

157 ABSTRACTS Number:122 Abstracttitle: RedoxRegulationofFoxM1inMesothelioma KhengNewick(1),HarveyI.Pass(2),,BrookeT.Mossman(1),ArtiShukla(1),JackL.Arbiser(3),Nicholas H.Heintz(1) (1)UniversityofVermontCollegeofMedicine,USA;(2)NewYorkUniversityMedicalCenter,USA; (3)EmoryUniveristySchoolofMedicine,USA Keywords: Mesothelioma,RedoxRegulation,NAPDHOxidase Abstractcontent: Targetedmicroarrayswereusedtoassesstheexpressionlevelsof96genesinvolvedredox metabolismisfourmalignantmesothelioma(mm)celllines.thelp9mesothelialcellline immortalizedwithhtertwasusedascontrol.cytoglobin(astressresponsefactor),duox1(dual oxidase),duox2(dualoxidase),dusp1(mapkphosphatase1),peroxiredoxin4(secreted2cys peroxidase),ptgs1and2(prostoglandinendoperoxidases),sod2(mitochondrialmnsuperoxide dismutase)werealldownregulated,whereasccl5(ccmotifchemokine5),foxm1(g2/m transcriptionfactor)gpx5(glutathioneperoxidase5),gpx6(glutathioneperoxidase6),gpx7 (glutathioneperoxidase7),lpo(lactoperoxidase),msra(methioninesulfoxidereductase),ncf2 (p67phox),nme5(nucleosidediphosphatekinase),nox4(nadphoxidase4),nox5(nadphoxidase 5),NUDT1(8oxoguanineDNAglycosylase),PRDX5(peroxiredoxin5),STK25(STE20homolog,yeast), andtxnrd2(mitochondrialthioredoxinreductase)wereallupregulatedinall4mmcelllines. Thesechangesingeneexpressionareindicativeenhancedproductionofreactiveoxygenspecies (ROS),acommonpropertyoftumorcellswithconstitutivelyactivemitogenicsignaling.All4MMcell linesexpressedisoformsofthefoxm1transcriptionfactorthatactivatetranscriptionofgenes requiredfortheg2/mtransitionofthecellcycle,and3of4mmcelllinescontinuedtoexpress FoxM1intheabsenceofgrowthfactors.InhibitorsofNADPHoxidaseactivitymarkedlyreduced expressionoffoxm1,whichcorrelatedwithdosedependentdecreasesinmmcellproliferationand viability.thiostrepton,aninhibitoroffoxm1,showedsimilardosedependenteffectsonmmcell viability.thesestudiesindicatethatalteredoxidantmetabolismthatsupportsexpressionoffoxm1 mayrepresentausefultherapeutictargetinthetreatmentofmm. 155

158 ABSTRACTS Number:123 Abstracttitle: IdentificationofDNAMethylationMarkersforMesothelioma JaniceGaller(1),IrisDautzenberg(1),MichaelKoss(1),AnilWali(2),HarveyPass(3),IteLaird Offringa(1) (1)UniversityofSouthernCalifornia,USA;(2)WayneStateUniversity,USA;(3)NewYorkUniversity, USA; Keywords: Epigenetics,Earlydiagnosis,DNAmethylation,MethyLight,Illumina Abstractcontent: StudiesoftheDNAmethylationpatternsfoundincancercellsareimportantfortworeasons.Onthe onehand,identificationofcpgislandsthatarespecificallymethylatedinagiventypeofcancercan leadtotheidentificationoftumorsuppressorgenesthataresilencedinthesecancers.identifying thetumorssuppressorgenesinactivatedinmesotheliomaiscriticaltounderstandingthemultistep pathwaythatunderliesthedevelopmentandprogressionofthisdisease.secondly,methylation patternscanbeusedaspowerfulsignaturestoidentifyparticularkindsofcancers.assuch, mesotheliomaspecificdnamethylationsignaturescouldbeinvaluabletoolsfortheaccurate diagnosisofmesothelioma,especiallyincaseswherethedistinctionbetweenmesotheliomaand othermalignantorbenignconditionsisdifficult.ourobjectivehasbeentoidentifydnamethylation markersforearlydetectionofmesothelioma.tothisend,wehaveusedamultitudeofapproaches, includingapplicationofthequantitativemethylighttechnologyinacandidategeneapproach,cpg islandmicroarraysandtheilluminagoldengateassay.forcomparison,wehaveanalyzedlung adenocarcinoma,nontumoradjacentlungfromlungadenocarcinomapatients(sincethisformsa verystringentcomparisonduetoexpectedhighmethylationbackground),andnontumorpleura. Wehavealsocomparedmesotheliomamethylationprofilestothosefromavarietyofothercancer types.wenotethatdnamethylationappearstobelessfrequentinmesotheliomacomparedto manytypesofcancer.however,withtheexaminationofsufficientloci,wehavebeenabletoidentify anumberofgenesthatshowhighlysignificanthypermethylationcomparedtolungadenocarcinoma, nontumorlungandnontumorpleura.herewereportonourtopmarkergenes. 156

159 ABSTRACTS Number:124 Abstracttitle: Argininosuccinatesynthetaseexpressionandsurvivaloutcomeinpatientswithmalignant mesothelioma:molecularanalysisandtherapeuticimplications BarbaraDelage(1),MichaelSheaff(1),FernandoLópezRíos(2),LynnCawkwell(3),MichaelLind(3), DeanFennell(4),TimCrook(5),NickLemoine(1),PeterSzlosarek(1) (1)Barts,QMUL,UK;(2)HospitalUniversitario12deOctubre,Madrid,Spain;(3)HullYorkMedical School,UK;(4)CCRBC,Belfast,UK;(5)ImperialCollege,London,UK Keywords: argininosuccinatesynthetase,malignantpleuralmesothelioma,survival,argininedepletion Abstractcontent: Malignantpleuralmesothelioma(MPM)isanincreasinghealthburdeninmanypartsoftheworld, andremainstherapeuticallychallengingwithamediansurvivaloflessthan12months.novel approachesareneededtogobeyondthecurrentstandardofantifolateandplatinumbased chemotherapy.tumoralexpressionoftheratelimitingenzymeforargininebiosynthesis, argininosuccinatesynthetase(ass)isabsentinhalfofpatientswithmpm.wehavepreviouslyshown thatargininedeprivationtriggersapoptosisofassnegativempmandthisstrategyisbeingtestedin aclinicaltrialofthearginineloweringagent,pegylatedargininedeminaseinpatientswithmpmin theuk(clincancerres2006).here,wehaveassessedwhetherexpressionofassislinkedtoclinical outcomeinmpm,applyingimmunohistochemistrytomesotheliomaarchivaltissuewithsurvival followupdata.analysisofampmtissuemicroarraywithfortyonetumoursampleseachintriplicate withappropriatecontrols(32epithelioid;3biphasic;3sarcomatoid;2desmoplastic;1uncertain) revealedaworseprognosisintheass lowexpressor groupwithamediansurvivalof5months comparedto12monthsintheass highexpressor group(p=0.001).validationofassasaprognostic markeriscurrentlybeingperformedusingasecondindependentcohortofeightypatientswith MPM.WeareemployingASSoverexpressionandsiRNAwithgeneexpressionprofilingtoelucidate theroleofassinmpmbiology.amolecularlytargetedapproachbasedonassexpressionmay becomeanoptioninthemanagementofpatientswithmpminthefuture. 157

160 ABSTRACTS Number:125 Abstracttitle: ChromosomeXq27harborsamesotheliomasusceptibilitylocusassociatedwithpatientsurvival HeatherNelson(1),JenniferLongacker(2),BrockChristensen(3),MichaelMcClean(3),James Hammond(4),CarmenMarsit(3),RaphaelBueno(5),DavidSugarbaker(5),KarlKelsey(3) (1)UniversityofMinnesota,(2)BostonUniversity,(3)BrownUniversity,(4)NorthDakotaState University(5)BrighamandWomen\'sHospital Keywords: geneticsusceptibility,polymorphism Abstractcontent: Epidemiologicdatafromregionsofendemicasbestosexposurehaveprovidedevidenceofgenetic susceptibilitytomesothelioma.todate,candidategeneapproacheshaveresultedinfairlyweak associationsbetweengeneticpolymorphismsanddiseaserisk.weusedamodifiedwholegenome associationstudytoidentifynewgeneregionsassociatedwithmesotheliomasusceptibility.casesof malignantpleuralmesotheliomawereidentifiedthroughtheinternationalmesotheliomaprogramat BrighamandWomensHospital,Boston,MA(USA).Controlswerecancerfreeresidentsderivedfrom theboston,maregion,includingbothasbestosexposedandunexposedindividuals.fiftycasesand 25controlsweregenotypedusingtheAffymetrix500Kgenotypingarray.Candidatelocifromthis screeningeffortthatwereassociatedwiththediseaseaftercontrolforfalsediscoverywere subsequentlygenotypedintheentirestudypopulation(143casesand502controls).twosnps mappingtochromosomexq27.3wereassociatedwitha2.5foldincreasedriskofmesotheliomain men(p<0.0001).wefurtherinvestigatedthesexchromosomesnpsinrelationtopatientsurvival. Inthiscontext,thesesamepolymorphismswereassociatedwitha50%improvementinpatient survival(hr0.5,95%ci ).Thesedatahighlightanovelsusceptibilitylocusthatisalso predictiveofpatientoutcomeandprovidenewinsightintothegeneticandbiologicbasisof mesothelioma. 158

161 ABSTRACTS Number:126 Abstracttitle: AssociationstudyoftheXRCC1genewithasbestosrelatedmalignantmesothelioma(MM) MartaBetti(1),DanielaFerrante(1),MarinellaBertolott(1),DarioMirabelli(1),MarinaPadoan(1),Mara Giordano(2),CorradoMagnani(1),IrmaDianzani(1) (1)LaboratoriodiPatologiaGenetica,DipartimentodiScienzeMediche,UniversitàdelPiemonte Orientale,Novara,Italy;(2)LaboratoriodiGeneticaUmana,DipartimentodiScienzeMediche, UniversitàdelPiemonteOrientale,Novara,Italy Keywords: DNArepairgene;SingleNucleotidePolymorphism;Haplotype Abstractcontent: Background.PolymorphismsinDNArepairgenesmaybeassociatedwithdifferencesinDNArepair capacity,therebyinfluencingtheindividualsusceptibilitytocancer.inapreviousstudywe investigatedtheassociationofdnarepairgeneswithmmofthepleurain81patientsand110 controlslivinginasmallpiedmontesetownexposedtoasbestospollution(dianzanietal.2006).our datashowedanassociationofmmwithxrcc1399qinasbestosexposedindividuals. Methods&Results.Usingunconditionalmultivariatelogisticregressionadjustedforageandgender toestimateoddratios(or)and95%confidenceintervals(cis),weconfirmedtheassociation betweenxrcc1399qandmmriskinadifferentpanelof52patientsand72controls(or=1.5095% CI0.82.8inasbestosexposedindividuals).Analysisoftheentirepanelof151patientsand252age andsexmatchedcontrolsshowedasignificantassociationinasbestosexposedindividuals(adjusted OR=2.08;95%CI= ).Toevaluatewhether399Qwasdirectlyresponsibleoftheassociationor whetheradifferentchangecouldhavearole,wedecidetogenotypefurther9snpsreportedinthe HAPMAPdatabaseastheXRCC1tagSNPs(i.e.SNPsthatallowtodetectallthehaplotypic combinationsatthelocus).todatethehaplotypefrequencywasestimatedfromthegenotypedata offiveoftheselectedsnps(rs t>cexon1,rs g>tivs2,rs c>givs3, rs a>givs4,rs c>givs10)usingthemaximumlikelihoodestimation(haploview software4.1).noneofthesesnpswasassociatedtomm,butthehaplotypetggaagwasfound morefrequentlyinpatientsascomparedtocontrols(crudefrequencies0.342vs0.264,2=4.546,p value=0.033)amongthesubjectsexposedtoasbestos(131cases,194controls).thehaplotype associationwasslightlyhigherthanthatshownby399qalone,thussuggestingthepresenceofa differentresponsiblevariationonthishaplotypiccombination.toevaluatethishypothesisthexrcc1 genewassequencedin30patientshomozygousfortheassociatedhaplotype.severalchangeswere identified,buttheirroleneedstobeevaluated. Conclusion.OurdatasupportthehypothesisthatXRCC1polymorphismisariskfactorforMMin subjectsexposedtoasbestos. 159

162 ABSTRACTS Number:127 Abstracttitle: PooledanalysisofNAT2genotypesasriskfactorsforasbestosrelatedmalignantmesothelioma MartaBetti(1),MonicaNeri(2),DanielaFerrante(3),StefanoLandi(4),FedericaGemignani(4),Dario Mirabelli(3),MarinaPadoan(3),StefanoBonassi(2),CorradoMagnani(3),IrmaDianzani(1) (1)DipartimentodiScienzeMediche,UniversitàdelPiemonteOrientale,Novara,Italy; (2)DipartimentodiEpidemiologiaMolecolare,NationalCancerResearchInstitut,Italy;(3)Unitàdi StatisticaMedicaedEpidemiologia&CPOPiemonte,Italy;(4)DipartimentodiBiologia,Universitàdi Pisa,Pisa,Italy Keywords: NAcetyltransferase;OxidativeStress;SingleNucleotidePolymorphism Abstractcontent: Background.Themostimportantcausalfactorforthedevelopmentofmalignantmesothelioma (MM)isoccupationalexposuretoasbestos.Differentlinesofevidencesuggestaroleofgenetic backgroundinmmdevelopment,asforothercancers.twopublishedstudiesobservedan associationbetweenmmandnacetyltransferase2(nat2)polymorphisms.first,afinnishstudy observedthatthenat2slowacetylatorphenotypewasassociatedwithanincreasedriskofmm. Conversely,MMriskwashigherinItaliansubjectscarryingtheNAT2fastacetylatorphenotypes.The conflictingresultsobtainedinfinlandanditalycouldbeascribedtorandomchance,consideringthe smallpanelofpatientsandcontrolsinthetwostudies,butalsoethnicorotherdifferencesmayhave beenimportant. Method.ToascertaintheroleofNAT2genotypeweperformedastudyon252MMpatientsand262 controlsrecruitedintwonorthernitalyareasthatwerecharacterizedbyhighasbestosexposure, duetointenseindustrialactivities(anasbestoscementfactoryincasalemonferrato,mainly shipyardsandrefineriesinliguria).unconditionalmultivariatelogisticregressionwasusedto estimateoddsratios(ors)and95%confidenceintervals(cis). Results.NAT2fastacetylatorphenotypesshowedanincreasedOR,althoughnotstatistically significant,bothinasbestosexposedsubjects(or=1.47;95%ci= )andintheentire population(or=1.38;95%ci= ). Conclusion.TheseresultssuggestthatNAT2polymorphismsdonotexertastrongeffectonindividual susceptibilitytomm. 160

163 ABSTRACTS Number:128 Abstracttitle: Detectionofcirculatingtumorcells(CTCs)inmalignantpleuralmesothelioma(MPM) FumihiroTanaka,KazueYoneda,MasakiHashimoto,TeruhisaTakuwa,NobuyukiKondo,Yoshitomo Okumura,SeikiHasegawa,KozoKuribayashi,KazuyaFukuoka,TakashiNakano HyogoCollegeOfMedicine,Japan Keywords: Circulatingtumorcell,CTC,Diagnosis,Mesothelioma Abstractcontent: CellSearchTM isanautomatedquantitativeevaluationsystemofcirculatingtumorcell(ctc) capturedwithanantiepcamantibody,andthectctesthasbeenestablishedandapprovedasa clinicalmarkerforbreastcancerinusa.asexpressionofepcam,amarkerofepithelium,was positivein55%ofmalignantpleuralmesothelioma(mpm)tissuesinourpreliminaryexperiment,we examinedthediagnosticvalueofctcinthepresentstudy;7.5mlofperipheralbloodwastakenfrom atotalof77consecutivepatientspresentedatourinstitutewithsuspicionordiagnosisofmpm(final diagnosis,mpmin55andnonmalignantdiseasesin22patients),andctcswasevaluatedwith CellSearchTM withoutknowledgeoffinaldiagnosis.therewasnodifferenceinpatient characteristicsbetweenmpmandnonmalignantgroups(meanage,64.6vs64.3years;female percentage,31.0%vs13.6%).formpmgroup,ctccount(/7.5ml)was0in36patients(62.1%),1in 12(20.7%),2in5(8.6%),3in2(3.4%),and5,6and27inoneeachpatient(1.7%),andtherewasno significantdifferencebetweenctccountandtumorprogression.fornonmalignantgroup,ctc countwas0inmostpatients(19/22,86.4%),but1intwo(9.1%)and2inonepatient(4.5%).when 1 (cell/7.5ml)wasusedasacutoffvalueofthectctestforthediagnosisofmpm,thesensitivity, specificity,positivepredictivevalue(ppv),negativepredictivevalue(npv),andaccuracywere37.9%, 86.4%,88.0%,34.5%,and53.2%,respectively.When 3 (cells/7.5ml)wasusedasthecutoff,the specificityandppvwere100%butthesensitivitywasonly9.1%(ppvandaccuracy,29.3%,and 34.5%,respectively).Inconclusion,CTCscanbedetectedinperipheralbloodofMPMpatients,and canbeausefultoolforthediagnosiswithhighspecificityandppv.however,thecurrentctctest usingantiepcamantibodyprovideslowsensitivityandnpvforthediagnosisofmpm,whichsuggest aneedformoreeffectivectcdetectionsystem. 161

164 ABSTRACTS Number:129 Abstracttitle: Circulatingendothelialcells(CECs)inthediagnosisofmalignantpleuralmesothelioma(MPM) FumihiroTanaka,KazueYoneda,MasakiHashimoto,TeruhisaTakuwa,NobuyukiKondo,Yoshitomo Okumura,SeikiHasegawa,KozoKuribayashi,KazuyaFukuoka,TakashiNakano HyogoCollegeOfMedicine,Japan Keywords: Circulatingendothelialcell,angiogenesis,malignantpleuralmesothelioma Abstractcontent: Malignantpleuralmesothelioma(MPM)isamalignanttumorwithaggressiveangiogenicbehavior, andangiogenesiscanbeadiagnosticandtherapeutictargetofmpm.circulatingendothelialcell (CEC)ispotentialsurrogateofangiogenesis,whichcanbequantitativelyevaluatedbythe CellSearchTM systemwherececswerecapturedwithananticd105antibody.inthepresent study,therefore,weassessedthediagnosticvalueofcecinmpm.atotalof67consecutivepatients withsuspicionordiagnosisofmpm(finaldiagnosis,mpmin50andnonmalignantdiseasesin17 patients)wereincluded,andceccountin4.0mlofperipheralbloodwasevaluatedwith CellSearchTM withoutknowledgeoffinaldiagnosis.therewasnodifferenceinpatient characteristicsbetweenmpmandnonmalignantgroups.themeanceccountformpmgroupwas 90.9(range,13302),whichwasmarginallyhigherthanthatfornonmalignantgroup(mean,53.0 [range,9194];p=0.071).formpmgroup,themeanceccountsinstagei,ii,iii,andivdiseaseswere 42.0,74.9,67.9,and117.2,respectively(p=0.068forallstageandp=0.049forstageIIIIvsstageIV). When 35 (cells/4.0ml)wasusedasacutoffvaluefordistinguishingmpmfromnonmalignant diaseses,thesensitivity,specificity,positivepredictivevalue(ppv),negativepredictivevalue(npv), andaccuracywere76.0%,52.9%,82.6%,42.9%,and68.7%,respectively(p=0.036).when 50 (cells/4.0ml)wasusedasthecutoff,thespecificityandppvwereashighas70.6%and85.3%,but thesensitivityandnpvwereaslowas58.0%and36.4%.inconclusion,ceccountisanusefulclinical markerinthediagnosisofmpm,andpatientswithhigherceccount(35ormore)maybecandidates forfurtherexaminationincludingsurgicalproceduresforthediagnosisofmpm.inaddition,cec countmaybesurrogateoftumorprogression,andalsocanbeamarkeroftherapeuticeffect. 162

165 ABSTRACTS Number:130 Abstracttitle: PrognosticmarkerforMalignantPleuralMesothelioma AlexandraSchramm(1),IsabelleSchmittOpitz(1),AlexanderSoltermann(2),MartinAbaecherli(3), PeterVogt(2),NicoleProbstHensch(2),HolgerMoch(2),RolfA.Stahel(3),WalterWeder(1) (1)DepartmentofThoracicSurgeryUniversityHospitalZurich,Switserland;(2)InstituteforSurgical Pathology,DepartmentPathology,Zurich,Switserland;(3)LaboratoryforMolecularOncology,Clinic andpolyclinicofoncology,universityhospitalzurich,switserland Keywords: MalignantPleuralMesothelioma TissueMicroarray prognosticmarker immunohistochemistry Survival Abstractcontent: Objective:ToassesstheimpactofmarkerexpressionsuchasthetumoursuppressorPTEN,the oncogeneegfr,p27(cellcycleinhibtor)andtheexcisionrepaircrosscomplementationgroup1 (ERCC1)protein alsorelevantforsurvivalandresponsetoplatinolchemotherapyinnsclcpatients onoverallsurvivalofmesotheliomapatientsaswellasthecorrelationtoestablishedprognostic markerashistologicalsubtypeinatissuemicroarraybased(tma)basedstudy.patientsand Methods:Quadriplepunchesof341MPMwerestudiedfortheexpressionofPTEN,EGFR,p27and ERCC1byimmunohistochemistryusingdifferentantibodies.Stainingintensitywassemi quantitativelyscored(03)andforercc1percentageofpositivestainedcells(0100%)was additionallymeasured.afinalhscorewascalculatedbysummingupintensitiesorbymultiplication ofintensitywithpercentage(ercc1).thishscorewascorrelatedtooverallsurvival. Results:Morethan50%ofthebiopsiesshowedabiphasicgrowthpatternofmesothelioma,34% wereanepitheloidsubtypeand13%asarcomatoidsubtype.ptenexpressionwaslostin62%ofthe cases;ercc1wasexpressedin80%,egfrin90%andp27in53%ofthesecases.stepwisecox regressionanalysisrevealedthategfrexpressiononlycorrelatestoepitheloidsubtype.survivaltime wascorrelatedtomarkerexpressionin126caseswithcompletefollowupdata.univariateanalysis revealedage(p=0.02),histologicalsubtype(p=0.01),treatment(nonewithtrimodalitytherapy)(p= )andPTENHScore(p= ),HScoreERCC1(p=0.0004)andp27asprognosticmarker. StepwisecoxregressionanalysisrevealedPTENandERCC1Hscoreastheonlyindependentmarker foroverallsurvival(p=0.001andp=0.02,respectively). Conclusion:EGFRexpressioncorrelateswithepitheloidgrowthpatterninmesotheliomapatients. OverallsurvivalisindependentlypredictedbyproteinexpressionofERCC1andPTEN,whichwillbe furtheranalysiedinaprospectivelydocumenteddatabaseofmpmpatientsundergoingcisplatin chemotherapy. 163

166 ABSTRACTS Number:131 Abstracttitle: Theroleofpleuraleffusioncytologyinthediagnosisofmalignantmesotheliomain2008. FrancoiseGalateauSalle(1)NolwennLeStang(1),MariaPaciencia(2),VirginieSaguet(2),Arnaud Scherpereel(3),MarieClaudeJaurand(4) (1)Mesonatregisitry,(2)CHUCAEN,(3)CHULille,(4)IFR105CEPHIUHINSERMU674 Keywords: mesothelioma,atypicalmesothelialhyperplasia,cytology,fish,homozygousdeletioncdkn2a Abstractcontent: Background:Itiswellknownthatadefinitivediagnosisofmesotheliomabasedonconventional effusioncytologyiscontroversial.thisisduetothefactthatbenignreactivemesothelialcellsmay havecytologicfeaturesthatmimicmalignanciesandmalignantmesotheliomaisagreatmimickerof benignormalignantdisease.theliterature,10yearsagoshowedthatthediagnosticaccuracyof effusioncytologywasunsatisfactorywithalowsensitivityof30%infavorofthediagnosisof malignantmesothelioma.moreover,thediagnosisprovidedbyeffusioncytologyhadtobe confirmedbythoracoscopyorsurgicalbiopsyanduntilnow,generallynotherapywasinstituted basedoncytologydiagnosisalone.theaimofthisstudywastoevaluatethediagnosticaccuracyof conventionalpleuraleffusioncytologyinthediagnosisofmalignantmesotheliomaandtoassessthe usefulnessofp16/cdkn2adeletionbyfishasadiagnosticmarkerforthedistinctionbetween benignreactiveandmalignantmesothelialcells. Design:Aseriesof16710patientswereretrievedfromthedepartmentofpathologyinCHUCaen fromjanuary1998tomay2008periodoftime.amongthem3483exfoliativepleuralcytology specimenswerecollected.4slideseithersmearsorcytospinsweresystematicallyanalyzedand comparedwithclinicalandor/histologicalfollowup.additionnally,aseriesof143patientswitha diagnosisofmesotheliomamadeeitherbycytologyand/orbyabiopsywereretrievedaccordingto thefrenchsystemofcodificationadicapcode:m7p*,m4p0,m0p*,0c82,c082.thediagnosisof malignantmetheliomaweresystematicallyvalidatedaccordingtothestandardizedprocedureof certificationofthemesopathgroup.adualcolorfishforp16/cdkn2aandchromosome9 centromerewasperformedeitheronfrozenorparaffinembeddedcellblocksfrom11reactive mesothelialhyperplasiaand9cytologicallypositiveeffusions(allhistologicallycertified mesotheliomabythemesopathgroup). Results:Fromthe3483pleuraleffusionspecimens,adiagnosisofmalignancywasperformedin12% (n=411),andofnonmalignantdiseasein88%(n=3072).amongthe411patientswithapositive cytologyforcanceradiagnosisofmesotheliomawasobservedin9%ofcases,ofothercancers (carcinomas)in84%andoflymphomain7%.fromtheseriesof143patientswithadiagnosisof mesotheliomamadeeitherbycytologyand/orbiopsy,thediagnosisofmesotheliomawasmadeby thoracoscopyorsurgicalbiopsyin50%ofcases(n=71),bycytologyalonein3%(n=5)andby thoracoscopywithcytologyin47%(n=67).thesensitivityofourcytologicaldiagnosisonpleural effusionswas30%withapositivepredictivevalue[ppv]of86%.amongthe45negativecytology specimenswithapositivebiopsyformesothelioma,thecytologicaldiagnoseswere;definitively malignantin29%(n=13),suspiciousformalignancyin11%(n=5),definitivelyreactivein33%(n=13) andinadequatein27%(n=12).falsenegativeresultswereobservedin33%ofthecases. 164

167 ABSTRACTS Duetotheoverlapfeatures,whenthecellsweretrulymalignantin9/13,thepathologistwasnot abletodecideifthemalignantcellswerefromamalignantmesotheliomaoffroman adenocarcinomaorigin.whenwecomparetheperiodoftimefromjanuary1998todec2003andthe periodoftimefromdec2003tomay2008,thesensitivitityandppvwererespectively15%(n=65) withappvof80%and39%(n=78)withappvof88%.homozygousdeletioncdkn2awasdetected byfishin2/9mesotheliomacasesandinnoneoftheatypicalreactivemesothelialhyperplasia( 0/11). Conclusion:Ourresultsshowthatthediagnosticaccuracyofpleuraleffusioncytologyisstill unsatisfactory(lowsensitivity39%)butisimprovingwithabetterdefinitionofcriteriaforthe diagnosisofmalignantmesothelialcellsandtherecognitionofpitfalls.moreoverthedetectionof homozygouscdkn2adeletionbyfishcouldbeextremelyusefulforthediagnosisofmesothelioma overatypicalreactivemesothelialhyperplasia.geneticmolecularcouldbeagooddriverfor screeningandresearchforinnovativetherapies. 165

168 ABSTRACTS Number:132 Abstracttitle: RoleofthemesothelinCA125interactioninmesothelioma MitchellHo,OsamuKaneko,IraPastan NationalCancerInstitute Keywords: Mesothelioma,mesothelin,CA125,MUC16,antibody,ovariancancer Abstractcontent: MesothelinisaGPI anchoredglycoproteinpresentonthecellsurface.mesothelinisoverexpressed inavarietyofcancersincludingmalignantmesotheliomaandovariancancer,makingmesothelinan idealtargetforanticanceragents.wehaveshownthatmesothelinisshedfromtumorcells.shed serummesothelinhasbeenapprovedbyfdaasanewdiagnosticbiomarkerinmesothelioma.we havefoundthatantibodiesspecificformesothelinareelevatedintheseraofpatientswith mesotheliomaandovariancancer,andthatthiselevationisassociatedwithhighexpressionof mesothelinintumors. SeveralgroupsincludingourshaveshowedthatmesothelinbindsCA125(alsoknownasMUC16), andthattheinteractionofmesothelinandca125maymediatetumorcelladhesion.ithasbeen suggestedthatthismaycontributetothemetastasisoftumorstotheperitoneum.ca125,whichwas originallyfoundasabiomarkerinovariancancer,isexpressedby88%ofmalignantmesothelioma. MesotheliomahasthesecondhighestcoexpressionofCA125andmesothelinafterovariancancer.It hasbeenshownthatca125asscociatednglycansarerequiredforbindingtomesothelin.the mesothelinca125interactionmayrepresentanovelbiologicalmechanismincelladhesion. ToidentifytheCA125bindingdomainofmesothelin,wehavegeneratedtruncatedmutantsof mesothelinandassessedtheirbindingcapabilitytoca125.althoughfulllengthmesothelincontains 622aminoacids,afragmentconsistingofonly65aminoacidsmaintains100%bindingtoCA125. SmallerfragmentsfromwithinthisregionshownobindingtoCA125.Furthermore,ourstudieshave indicatedcriticalaminoacidsinvolvedinthemesothelinca125interaction.characterizingthe mesothelinca125interactionwillallowabetterunderstandingoftheprogressionofmesothelioma inperitonealcavityandmayalsoleadtotherapeuticsthatcanpreventorreversetumormetastasis. ThisworkissupportedbyNCIIntramuralResearchProgram.M.Hoistherecipientof2007 MesotheliomaAppliedResearchFoundationGrantinHonorofCraigKozicki. 166

169 ABSTRACTS Number:133 Abstracttitle: AnovelmechanismoflategenesilencingdrivesSV40transformationofhumanmesothelialcells. MicheleCarbone(1),AntonioPannuti(1),LeiZhang(1),JosephTesta(2),MaurizioBocchetta(3) (1)UniversityofHawaii,USA;(2)FoxChaseCancerCenter,USA;(3)LoyolaUniversityChicago,USA Keywords: carcinogenesis,sv40,dnatumorviruses,antisensecontrolofgeneexpression,oncogenes,tumor antigens,viraltranformationandcarcinogenesis Abstractcontent: Suppressionofthelategeneexpression,usuallybyintegrationoftheviralDNAintothehost genome,isacriticalstepindnatumorvirusescarcinogenesis.simianvirus40(sv40)induceshigh ratesoftransformationininfectedprimaryhumanmesothelialcells(shm)intissueculture,leading totheformationofimmortalcelllines(shml).thestudiesdescribedhereweredesignedto elucidatetheunusualsusceptibilityofprimaryhumanmesothelialcells(hm)tosv40carcinogenesis. WefoundthatSHMLcontainedwildtype,mostlyepisomalSV40DNA.Inthesecellstheearlygenes thatcodefortheviraloncogenesareexpressed,athesametime,thesynthesisofthelategenes capsidproteinsissuppressedandshmlarenotlysed.lategenessuppressionisachievedthrough theproductionofantisensernamolecules.theseantisensernamoleculesoriginateintheearly regionofthesv40circularchromosomeandproceedinantisenseorientationintothelategene region,leadingtotheformationofhighlyunstabledoublestrandrnathatisrapidlydegraded.our resultsrevealanovelbiologicalmechanismresponsibleforthesuppressionoflateviralgene products,animportantstepinviralcarcinogenesisinhumans. 167

170 ABSTRACTS Number:134 Abstracttitle: Identificationofcellswithstemcell/selfrenewalpropertiesinmalignantpleuralmesothelioma ClaudiaFrei(1),IsabelleOpitz(2),StefanieKurtz(1),WalterWeder(2),RolfStahel(1),EmanuelaFelley Bosco(1) (1)LaboratoryofMolecularOncology,UniversityHospitalofZurich,Switserland;(2)Divisionof ThoracicSurgery,UniversityHospitalZürich,Switserland Keywords: chronicinjury,tissuerepair,hedgehogpathway,sidepopulation Abstractcontent: Mesotheliomatumorigenesisisfelttobebasedonchronictissuerepaircausedbytheaccumulations offibersinthepleuralspace.theexpressionofstemcellrenewalgenessuchasbmi1hasbeen showntobeinverselycorrelatedwithsurvivalinmesotheliomapatients(glinskyetal,jci115:1503, 2005).Bmi1isadownstreamtargetofthestemcellsignalingHedgehogpathway.Wemadethe hypothesisthatinmesotheliomaafractionofcellswithselfrenewal/stemcellsignalingpropertiesis present.thereforewetestedwhetherhedgehogsignalingisactiveinmesotheliomaandwhethera subpopulationofcellswithselfrenewalpropertiescouldbedetected.epithelialmesotheliomahada significantlyhigherexpressionofgli1comparedtonormalpleura,indicatingthehedgehogpathway tobeindeedactiveintumors.toinvestigatewhetherthispathwayisinvolvedincellgrowth,twenty fourprimarymesotheliomacellcultures,establishedfromsurgicalspecimen,wereinvestigated. Cyclopamine,aninhibitoroftheHedgehogsignalingpathway,significantlyinhibitedcellgrowthin 50%oftheprimarycultures.Tomatidine,whichwasusedascontrol,hadnoeffect.Furthermore, GANT61,aninhibitorofHedgehogpathwayactingdownstreamofSmo,inhibitedcellgrowthin66% ofthecultures.theseeffectswereaccompaniedbyinhibitionoftheexpressionofgenes downstreamhedghogsignaling.inordertofurthercharacterizethestemcellcomponentoftumors weusedafunctionalapproachbasedontheabilityofstemcellstoeffluxhoechst33342.thesecells canbeidentifiedbyfacsasnotstainedcellsandarecalled sidepopulation.usingthisfunctional approachwewereabletoisolateasidepopulationfromzl55cellswhichrepresented3.8±1.7%of cells(mean±sd,n=12).wecouldshowthatthesortedzl55sidepopulationagaingaverisetoasmall sidepopulationfractionandanonsidepopulationfraction,suggestingthatthesidepopulation indeedincludescellswithselfrenewalproperties.ontheotherhandthezl55nonsidepopulation onlygaverisetothenonsidepopulationfraction.similarresultswereobtained,fortwooutofthree primarymesotheliomacultures.takentogethertheseresultsindicatethatcellswithstemcell renewalpropertiesarepresentinmesothelioma. 168

171 ABSTRACTS Number:135 Abstracttitle: TheSV40largeTantigenp53complexesbindandactivatetheIGF1promoterstimulatingcellgrowth MaurizioBocchetta(1),SandraEliasz(1),MelissaArakelianDeMarco(1),JenniferRudzinski(1),Lei Zhang(2),HainingYang(2),MicheleCarbone(2)i (1)LoyolaUniversityChicago,USA;(2)UniversityofHawaii,USA Keywords: SV40LargeTantigen,DNAtumorviruses,p53,IGF1,celltransformation,cancer,mesothelioma Abstractcontent: Inactivationofcellularp53isacrucialstepincarcinogenesis.Accordingly,p53isinactivatedinmost humancancersbydifferentmechanisms.incellsinfectedwithdnatumorviruses,p53isboundto theviraltumorantigens(tags).thecurrent dogma viewsthetagp53complexesasawayof sequesteringandinactivatingp53.usingprimaryhumancellsandsv40transformedhumancells,we showthatinadditionofinactivatingp53tumorsuppressoractivities,thetagp53complexhas growthstimulatoryactivitiesthatarerequiredformalignantcellgrowth.wefoundthatinhuman cells,tag/p53complexesregulatetranscriptionoftheigf1genebybindingtotheigf1promoter togetherwithprbandp300.depletionofp53leadstostructuralrearrangementsofthismulti proteincomplex,resultinginigf1promotertranscriptionalrepressionandgrowtharrest.ourdata provideanovelmechanisticandbiologicalinterpretationofthep53/tagscomplexesandofdna tumorvirustransformationingeneral.inthemodelwepropose,p53isnotapassiveinactive partneroftag.insteadthep53/tagcomplexpromotesmalignantcellgrowththroughitsabilityto activatetheigf1signalingpathway. 169

172 ABSTRACTS Number:136 Abstracttitle: IncreaseduPARExpressionandVirulenceofRENHumanMalignantPleuralMesotheliomaCells. TorryTucker(1),CandiceDean(1),KathyKoenig(1),AndreyKomissariv(1),SreeramaShetty(1),Barry Starcher(1),AndrewMazar(2),StevenIdell(1) (1)TheUniversityofTexasHealthScienceCenteratTyler,USA;(2)TheTexasLungInjuryInstituteand Attenuon,LLC.,USA. Keywords: Malignantmesothelioma,UrokinaseReceptor,Urokinase Abstractcontent: Malignantpleuralmesothelioma(MPM)isalethalneoplasmforwhichcurrenttherapyislargely ineffective.toassessdifferencesinthegrowthofmpmcellsinvivo,wedevelopedanorthotopic modelofmpminwhichms1,m9korrencellswereadministeredbyintrapleuralinjectioninnude mice.aswaspreviouslyreportedinmpminhumans,prominentextravascularfibrindeposition characterizedalloftheneoplasmsandencapsulatedthetumors.renderivedtumorswerelargerat 2,3and4weeksafterintrapleuralinjectionandexhibitedmorerapidgrowthandlethalityinvivo. Theurokinaseplasminogenactivatorreceptor;uPAR,hasbeenimplicatedinthepathogenesisofa numberofsolidneoplasmsincludingmalignantmesothelioma.wethereforesoughtevidenceofa linkbetweenthelevelofuparexpressionandvirulenceoftheren,ms1andm9kcelllinesinthe orthoptopicmodel.rentumorsandthecellsculturedinvitrowerefoundtooverexpressuparat boththemrnaandproteinlevels.asopposedtotheothercelllines,renhadnodetectablelrpat thecellsurface,suggestingthatimpairedinternalizationcouldcontributetotheoverexpressionof cellsurfaceupar.excisedrentumorsandimmunohistochemicalanalysesdemonstratedupa antigenwhilenoupaproteinormessagewasdetectableinculturedcells.murineupawasfoundto bindhumansuparorrencellsinvitro.rencellsexhibitedincreasedmigrationinthreedimensional fibringelanalysesandtheeffectwasblockedbyantibodiesthatpreventedthebindingofupato upar.tracesofupaantigenandactivityweredetectableinthefetalcalfserumcomponentofthe mediaandanantibodytoupaalsoblockedrencellmigrationinthefibringelsystem.uparorupa blockingantibodiesalsodecreasedrencellmigrationandinvasivenessinboydenchamberanalyses. uparsilencingsignificantlyreducedrencellmigrationandinvasiveness.thesestudiessuggestthat uparexpressionandassociationwithhostupamaycontributetothemalignantpotentialofmpm andsuggestapotentiallypromisingtargetforfuturetherapeuticintervention.supportedbynihpo 1HL076406(SI,TT,CD,KK,AK),TheGinaSabatasseResearchGrantAward,TheTexasLungInjury InstituteandAttenuon,LLC.TheUniversityofTexasHealthScienceCenteratTyler. 170

173 ABSTRACTS Number:137 Abstracttitle: Mechanismofanoikisresistanceinmesotheliomacells JulienDaubriac(1),JocelyneFleuryFeith(1),LaurenceKheuang(1),AnnieRenier(1),Marco Giovannini(1),Françoise(2),GalateauSallé(1),MarieClaudeJaurand(1) (1)INSERMU674,Paris,France,(2)ERI3INSERM,CHUCaen,France Keywords: mesothelioma;anoikis;apoptosis;micropapillary;signalingpathways Abstractcontent: Pleuralfluid(PF)accumulationisafrequentclinicalobservationindiffusemalignantpleural mesothelioma.thecytologicalanalysisofpfoftenrevealedthepresenceofspheroidalclustersof malignantcells(micropapillaries),addressingthequestionoftheabilityofnonadherenttumorcells tosurviveandtodevelopnewtumorfociinthepleuralcavity.asanoikisisthemechanismwhereby cellsdiefollowinglossofmatricialanchorage,theaimofthepresentworkwastodeterminewhether mesotheliomacellsareresistanttoanoikis. Tostudyanoikisresistanceofmalignantmesothelioma(MM)cells,threemesotheliomacelllinesand thenontumoralmesothelialcelllinemet5awereculturedonpoly2hydroxyethylmethacrylate (polyhema)coatedplates.cellcyclewasevaluatedbystudyingki67antigenexpressioncoupledto PIstaining,andcelldeathwasdeterminedbyassessingDNAfragmentation,byflowcytometry. ContributionoftheSAPK/JNKpathwayandoftheproapoptoticproteinsBimandcaspase9to anoikiswasevaluatedusingchemicaleffectorsandrnainterferencestrategy.expressionof phosphosapk/jnk,bimandofthecleavedformsofthecaspase9andcaspase3wereestimatedby westernimmunoblot. Innonadherent(NA)condition,MMcellsformmicropapillarylikestructurescomposedofviable cells.whilethepi3k/akt,erkandsapk/jnksignalingpathwaysareactivatedinadherentmmcells, lossofanchorageresultsinaninactivationofthesepathways.accordingly,mmcellsin micropapillariesentering0phaseearlierthanadherentcells.incomparison,met5acellsenter anoikisinasapk/jnk,bimandcaspase9dependentpathway.resistancetoanoikisinmmcellscan bereversedbyactivatingsapk/jnkwithanisomycin,accordingtoabimandcaspase9dependent pathway.finally,wefoundthatblockingmicropapillaryassemblybyculturingcellsunderspinning activatedsapk/jnkandbim,andmademmcellstoenteranoikis.theseresultspointoutthe importanceofcellclusteringintheanoikisresistanceofmmcells. 171

174 ABSTRACTS Number:138 Abstracttitle: Genomicandfunctionalprofilingofmalignantmesothelioma SakariKnuutila UniversityofHelsinki,HaartmanInstitute,DepartmentofPathology,Finland Keywords: microarray,geneprofiling Abstractcontent: Beforenormalmesothelialcellsofpleuratransformtoneoplasticandmalignantcells,numerous geneticchangesareneeded.inmalignantmesotheliomaadistinctchromosomalinstabilityisa characteristicfeaturevisualizedbykaryotypic(chromosomeandarraycghincluded)analyses.what arethecausesoftheinstability?doinheritedcongenitalgeneticchangesinadditiontotheasbestos fiberburdenhaveanyroleinthemalignanttransformation?whatistheroleoftheinflammation? Furthermore,dothechangesserveasdiagnostic,prognostic,predictiveortherapeuticmarkersin malignantmesothelioma?sofarverylittleisknownaboutalltheissuesrelatedtothequestions.the novelgenomewideprofilinghas,however,openedanewerafortheunderstandingof mesotheliomatotheextentthatwecanfindclinicallyandtherapeuticallyrelevantmarkersforthis fataldisease. Mypresentationreviewstheresultsofstudiesrelatedtothegenomicandfunctionalprofilingof malignantmesothelioma.ourrecentpublications(1,2)andthesoonappearingbookchapter(3)give additionalinformationforthesubject. 1.MustiM,KettunenE,DragonieriS,LindholmP,CavoneD,SerioG&KnuutilaS:Cytogeneticand moleculargeneticchangesinmalignantmesothelioma.areview.cancergenetcytogenet170:915, LindholmPM,SalmenkiviK,VauhkonenH,NicholsonAG,AnttilaS,KinnulaV&KnuutilaS:Gene copynumberanalysisinmalignantpleuralmesotheliomausingoligonucleotidearraycgh.cytogenet GenomeRes119:4652,2007.(EpubDec14,2007). 3.NymarkP,KettunenE&KnuutilaS:Tumorsoftherespiratorytract.InCancerCytogenetics. ChromosomalandMolecularGeneticAberrationsinTumorCells.3rdedition,HeimS&MitelmanF (eds.).inpress. 172

175 ABSTRACTS Number:139 Abstracttitle: NOVELSYNTHETICINHIBITORSOFTHEmTORPATHWAYINMALIGNANTMESOTHELIOMA SaraBusacca(1),GianCesareTron(1),GiovanniBattistaGiovenzana(1),LucianoMutti(2),Giovanni Gaudino(1) (1)DISCAFF,Novara,Italy;(2)DepartmentofMedicine,LocalHealthUnit11,Piemonte,Italy Keywords: malignantmesothelioma,mtor,kinaseactivity,p70s6k,4ebp1 Abstractcontent: MalignantMesotheliomaisanaggressivecancerwithpoorprognosisandlowmediansurvival, refractorytocurrenttherapies.mammaliantargetofrapamycin(mtor)promotesuncontrolled proliferation,throughcellcycleprogression,regulationofproteinsynthesisandproteindegradation, playingacriticalroleintumorcellsurvivalandresistancetochemotherapy.themtorpathway becomesactivatedinmosthumantumors,includingmalignantmesothelioma.rapamycinandits derivativesareknownasmtorinhibitors,howeverweaimedattestingnovelsmallmolecules, synthetizedbythesplitugimulticomponentreaction,asselectiveinhibitorsofthisenzymeactivity, todevelopeffectivestrategiesforthetreatmentofthisneoplasm.weevaluatedcytotoxicityofthe synthesizedcompoundsonthreemesotheliomacelllines:mpp89,msto211handren.after preliminaryscreeningsweobservedamarkeddecreaseofcellviabilityinallthreecelllinesfortwo outoftencompounds,whichdisplayedic50valuesaboutof15μm.moreover,theyinhibited theautophosphorylationofmtoronser2481aswellasthephosphorylationoftwomtor downstreameffectors70kdaribosomalproteins6kinase1(p70s6k)andtheeukaryotictranslation initiationfactor4e(eif4e)bindingprotein1(4ebp1).conversely,noinhibitiononakt(ser473)and mtor(ser2448)phosphorylationwasobserved. Interestingly,theinhibitionofmTORkinaseactivityofbothp70S6Kand4EBP1wasobservedinMPP 89cells,whileinMSTO211Hcellswasinhibitedonlythephosphorylationofp70S6K,whichwas slightlyaffectedinrencells.thesepreliminarydatahighlightthesecompoundsasnewinhibitorsof themtorpathway,exertingcytotoxiceffectsonallmesotheliomacellsexaminedandsuggest selectiveeffects,dependentonthedifferentcellphenotypes. 173

176 ABSTRACTS Number:140 Abstracttitle: EORTC08031 P.VanSchil,B.Hasan,A.Maat,M.vandePol,R.Gaafar,S.Dussenne,J.Welch,J.VanMeerbeeck,P.Baas onbehalfoftheeortclungcancergroup Abstractcontent: Malignantpleuralmesothelioma(MPM)isahighlylethaldiseaseandoptimaltreatmenthasnot beendeterminedyet.theuseofradicalsurgeryinthetreatmentofpotentiallyresectablempm remainscontroversial.themediansurvivalforpatientsundergoingextrapleuralpneumonectomy (EPP)isapproximately12months.Surgeryisseldomradicalduetodiffusethoracicinvolvement.In experiencedcentresoperativemortalityis<10%butpostoperativemorbidityremainshigh[1]. NeoadjuvantchemotherapyisanewtherapeuticoptioninMPMandpromisingresultsofa multicenterphaseiitrialwererecentlyreported[2].intotal,58patientscompletedinduction chemotherapyconsistingof3cyclesofcisplatinandgemcitabine.forthe45patientsundergoing EPPmediansurvivalwas23months.PemetrexedisalsoanactiveagentforthetreatmentofMPM. In2005theEORTCinitiatedaphaseIIfeasibilitytrialconsistingofinductionchemotherapywith cisplatinandpemetrexedfollowedbyeppandpostoperativeradiotherapy(eortc08031).the generaloutlineisdepictedinfigure1.theprimaryendpointis successoftreatment whichis definedasapatientwhoreceivedthefullprotocoltreatment,isstillalive90daysaftertheendof protocoltreatmentwithoutprogressionandwithoutevidenceofgrade34toxicityat90daysafter theendofprotocoltreatment.thesecondaryendpointsincludetoxicityofthistrimodality treatment,overallsurvivalandprogressionfreesurvival.inpatientswithpreoperativepetscan,the valueofpetscanforstagingisalsoconsideredasasecondaryendpoint.translationalresearchwill alsobeperformed.totalnumberofpatientsrequiredwas52.thestudywasinitiatedinjuly2005 andclosedinaugust2007when59patientswereregistered.demographicdataareavailableon55 patientsand44ofthemweremen.agerangewasfrom26to67yearswiththemedianof57years. Thirtyonepercentofpatientshadassociatedchronicdisease.Allpatientsunderwent mediastinoscopy,ct1/t2/t364%/27%/9%,cn0/n198%/2%,performancestatus0/136%/64%and2 hadfocalchestwallinfiltration.finalresultswillbeavailableearly2009.ifthetrimodalitytreatment inthiseortc08031studyprovestobefeasible,itwillbeusedasexperimentalarminafuture randomizedclinicaltrial. References 1. SugarbakerDJ,JaklitschMT,BuenoRetal.Prevention,earlydetection,andmanagementof complicationsafter328consecutiveextrapleuralpneumonectomies.jthoraccardiovascsurg2004; 128: WederW,StahelRA,BernhardJetal.Multicentertrialofneoadjuvantchemotherapy followedbyextrapleuralpneumonectomyinmalignantpleuralmesothelioma.annoncol2007; 18:

177 ABSTRACTS Number:142 Abstracttitle: MesoVATSstudy RobertRintoul DeptofThoracicOncologyPapworthHospital,Cambridge,UK Abstractcontent: TheMesoVATSstudyisarandomisedcontrolledstudytocomparetheeffectivenessoftalc pleurodesisagainstvatscytoreductivepleurectomyinsuspectedorconfirmedmalignant mesothelioma.theprimaryoutcomemeasureissurvivalatoneyear.secondaryoutcomesare controlofpleuraleffusion,symptomsandqualityoflifeat3,6and12months,assessmentof procedurerelatedcomplicationsineacharmandcosttothehealthserviceintermsofresources usedforprocedures,hospitalbedusageandcosttoprimaryandsecondarycarefor12monthsfrom timeofrandomisation.forinclusion,patientsmusthaveconfirmedorsuspectedmesothelioma,a pleuraleffusionandbeclinicallyfitandsuitableforavatspleurectomyortalcpleurodesisviaan intercostalchestdrain.basedondataavailableatthetimeofsetup,thestudyispoweredtodetect a22%differenceinsurvivalatoneyearbetweenthetwoarms.thennumberis196patients.to date70patientshavebeenrandomisedalthough151havebeenscreened.themainreasonsfor exclusionareeithernotmeetinginclusioncriteria(69cases)orthepatientdeclinedtoparticipate(12 cases).inaddition7patients,whowouldotherwisehavebeensuitable,wereenteredintothe MesotheliomaandRadicalSurgery(MARS)study.Slowrecruitmenthasledtoexpansionfroma singlecentrestudytoamulticentrestudy.fivesurgicalcentreswithintheukarenowopen. Similarly,recentchangesinthepreferredmanagementofmalignantpleuraleffusionhaveledtothe studybeingmodifiedtoincludemedicalthoracoscopybothasameansofobtainingbiopsiesandfor instillationoftalc.itishopedthatthesechangeswillincreaserecruitmentoverthecomingmonths. 175

178 ABSTRACTS Number:149 Abstracttitle: AnAdvocate sperspective:acallforadatabasedapproach RogerG.Worthington TheLawOfficeofRogerG.Worthington,P.C.,SanPedro,California,US Abstractcontent: Mesoclientssufferfromalackofinformationabouttreatment.ThankstotheInternet,patientsare beginningtoaskfrankquestions.thequestionsprovokeconflictinganswersreflectedbyconfusion withinthemedicalcommunityaboutmesothelioma.asanadvocate,itisimportanttobeableto providethumbnailanswersinordertoreferclientstothebesttreaters.alackofconsensuson researchprioritiesandotherissuesareexacerbatedbyacripplinglackofaccessibledata.froman advocate sperspective,withoutthisdataclientscannotmakeinformeddecisionsabouttreatment, whichaffectstheviabilityoftheirlawsuitandultimatefinancialcompensation.aquestionnairesent outtothemostwellknownsurgeonsintheu.s.whotreatmesopatientsreceivedadisappointing response.onewaytoaddressthisproblemisaglobalmesodatabasethatwouldtakeadvantageof theextraordinarymedicaldatageneratedbylitigation.uploadingmedicalrecords,films,charts, prescriptions,exposureinformation,andpatientsurveysintoaconfidential,webbased,multilingual databasewouldhelpprovidecriticallyneededdata.theproblemofdataaccessibilityoccursin tandemwithmesoremaininggrosslyunderfundeddespitebillionsofdollarschanginghandsin asbestoslitigation.recentlitigationchangeshaveprovidedindustrywithanestimated$60billion windfallthathasnot,andwillnot,finditswayintoresearchcoffers.theu.s.congresscoulduse moneyheldinasbestossettlementtrustfundsforresearch.thevalueofthesetrustsisbetween$40 and$60billionusd,andasmallpercentageofthosefundsdedicatedtomesoresearchwouldgoa longwaytofinallyjumpstartingresearchintopreventionandtreatmentforanasbestosrelated cancerknownsincethelate1940 s. 176

179 ABSTRACTS Number:150 Abstracttitle: Whooweswhattowhominclinicalandsurgicalresearch?(Humanisticperspective futureresearch incardiothoracicsurgery) H.M.Evans DurhamUniversity,UK Abstractcontent: Whatobligationsariseinclinicalresearch,andtowhom andbywhom aretheyowed? Theelaborationofclinicalresearchethicshasfocusedonprotectingvulnerableresearchsubjects fromexploitation,mostvisiblybyensuringvoluntaryparticipationthroughmechanismsofconsent. Significantly,consentisitselfprecededbyconsiderationofwhetherresearchwouldbeethicalin termsofpermissiblelevelsofharm,evenifthoseharmswereundergonevoluntarily.these obligationsareowedbyresearcherstoresearchsubjectparticipants,topatientsgenerally,andto societyaswhole. Theseimportantprotectionsarosewhentheresearchsubject svulnerabilitywasrecognisedand takenseriously thingswerenotalwaysthus.however,hasthependulumswungtoofartheother way?ingeneralterms,probablynot;buttherearetwoimportantaspectsofethicalobligationthat areusuallyoverlooked,butthatneedthemselvestobetakenseriously. First,patientsaccessingtreatmentsprovidedbypubliclyfundedhealthcarehaveageneralobligation tocontributetodevelopingbettertreatmentsforfuturepatients astheythemselvesbenefitfrom researchcarriedoutonpatientsinthepast.notallmoralobligationsareowedbysocietyto individuals;someobligationsareowedintheotherdirection,somethingthatwerecogniseclearly enoughintermsoflawabidingconductandthepaymentoftaxes.whyshouldhealthcarebeany different? Second,researchersandclinicianshaveanobligationtoreducetheuncertaintywithinwhichthey providetreatmenttopatients,especiallyintermsofsafetyandefficacy.thismeansacommitment toundertakingresearchtoimprovefuturetreatment,especiallywherewearelessthancertain aboutthebenefitsandharmsofwhatwecurrentlydo anobligationowedtobothpresentand futurepatients. Togetherthesetwoobligationsconstituteacompellingmoralargumentinfavourofincludingfar moreexistingtreatmentepisodeswithintherubricofclinicaltrialsprotocols,withallthatthat entails,especially andmostcontentiouslyforindividualclinicians thesubjectionoftreatment allocationchoicestorandomisationwherethisisscientificallyappropriate. Thispaperwillconsiderthischallengingsuggestiononitsmeritsandinthelightofobviousobjections toit. 177

180 ABSTRACTS Number151 Abstracttitle: IASLC/IMIGMesotheliomaStagingProject MrJohnGEdwardsPhDFRCS(C/Th) Sheffield,UnitedKingdom Abstractcontent: TheInternationalAssociationfortheStudyofLungCancer/InternationalMesotheliomaInterest GroupMesotheliomaStagingProjectaimstocollectdataretrospectivelyandprospectivelyto exploreandvalidateclinicalandpathologicalstagingcriteria.theprojectwaslaunchedatthe SocietyofThoracicSurgeonsannualmeetinginJanuary2008.DataarebeingcollectedbyCancer ResearchandBiostatistics(Seattle,USA)bytheteamwhoanalysedtheIASLCLungCancerStaging Projectdata.DrValerieRusch(NewYork,USA)andMrJohnEdwards(Sheffield,UK)aretheproject cochairs,withsupportfromprofpetergoldstraw(london,uk),drjohncrowley(crab)and numerousleadingsurgeonsandphysicians. TheProjectwillhavethreephases: PhaseIa: Reviewofretrospectivelycollecteddatafromcurrentlyidentifiedmajorsurgicalunits PhaseIb: Reviewofretrospectivelycollecteddatafromoncologytrialdatasets. PhaseII: Retrospectivedatareviewfromthewidersurgicalandoncologicalcommunity PhaseIII: ProspectiveDataCollection WorkisunderwaytoidentifyandapproachunitswillingtosharedatafortheprojectforphasesIand II.Theprospectivedatasetisunderdevelopment.Itishopedthatdatacollectionwillstarton1 January2009andcontinueuntil31December2014,allowinguptotwoyearsfordatatomatureand tobeanalysedinadvanceofsubmissionofthe8 th EditionoftheAJCCManual. FundingforretrospectivedatacollectionandanalysishasbeenreceivedfromtheMesothelioma AppliedResearchFoundation.Furtherfundingwillbesoughtfromcharitableorganisationsand industry. 178

181 ABSTRACTS Number:154 Abstracttitle: DoesRadiotherapyAddAnythingToExtrapleuralPneumonectomy? DavidRice DepartmentofThoracicandCardiovascularSurgery,TheUniversiyofTexas,USA Abstractcontent: Malignantpleuralmesothelioma(MPM)remainsachallengingdiseasefromthesurgicalperspective. Itsdiffusenaturewithinvolvementofthelung,pericardiumanddiaphragm,theinabilitytoreliably obtainnegativemargins,thesignificantmorbidityandmortalityassociatedwithradicalresection, andmostimportantly,thehighrecurrencerateaftersurgery,allcontributetothenihilisticattitude withwhichmostcliniciansviewthisdisease.despitemajorimprovementsinoperativemortalityover thelasttwodecades,whichisnowbetween2%and8%atmostcenters,surgeryaloneisassociated withhighratesoflocalfailure.forthisreason,adjuvantandneoadjuvantmodalitieshavebeen integratedintothesurgicalmanagementofmpm.inmostcenterstodayaggressivetherapeutic approachesinvolveatrimodalityregimenincludingextrapleuralpneumonectomy(epp),radiation therapyandchemotherapy. ThereisarationaleforusingofradiationtherapyafterEPP.First,despitetraditionalbeliefs, mesotheliomacellsareradiationsensitive,atleasttodosesgreaterthan40gy.theproblemhas beenindeliveringtherapeuticradiationdosestotheinvolvedhemithoraxwhileavoidingradiation sensitiveorganssuchasthelung,liver,heartandspinalcord.forthisreasonradiationtherapyasa primarymodalityhasfailed.however,afterepptheipsilaterallungnolongerisalimitingfactor,and withmodernradiationtechniquesthecomplextargetareaofthepostpneumonectomyspacecan usuallybesafelycovered.second,ateppmicroscopicallynegativemarginsarenotoriouslydifficultto achieve.thus,localrecurrenceratesareashighas50%aftereppalone.furthermoreintrapleural adjuvanttherapiessuchasphotodynamictherapy,heatedchemotherapyandimmunotherapyhave nothadanymajorimpactonlocalrecurrence. WhatdataexisttosupporttheuseofradiationtherapyafterEPP?DaVallewasfirsttodescribethe useofadjuvantradiationaftereppinasmallseriesofpatientswithmpm(davalle,1986). Throughoutthelate80 sand90 sthebrighamgroupemployedatrimodalityregimenwhichincluded adjuvantchemotherapyandradiationof30.6gytothehemithorax(40gytothemediastinum)anda boosterdoseof50gytoareasthoughttobeathighriskforrecurrence.in1999,sugarbaker reportedoutcomesof183patientstreatedinthisfashion,anddemonstratedfeasibilityofthe multimodalityapproachandanenviable5yearsurvivalof46%forepithelioid,nodenegative, patientswhowerecompletelyresected(sugarbaker,1999).detailsoftheradiationtreatmentofa subsetofthesepatientswhoreceivedtheirtreatmentatthebrighamwerereportedbybaldiniand colleagues(baldini,1997).11of35patients(31%)whoreceivedtrimodalitytherapydeveloped tumorrecurrencewithintheipsilateralchest.despitethehighrateoflocoregionalfailure,the3year survivalwas34%. 179

182 ABSTRACTS TheBrighamgrouprecentlyreportedpatternsoffailureofamorerecentgroupofpatientswhohad undergoneeppandradiation.someweretreatedwithmediumdosehemithoracicradiationtherapy (MDRT)to30Gy,whileothersreceivedhigherdoseradiation(HDRT)to54Gy(Allen,2007).Local failureremainedasignificantproblemandoccurredin50%(12of24)patientstreatedwithmdrt butinonly27%(4of15)patientswhoreceivedhdrt,suggestingthathigherdosehemithoracic radiationmaybemoreefficacious. In2001theMemorialSloanKetteringgroupreportedencouragingresultsfromamultiinstitutional phaseiitrial(rusch,2001).patientswithmpmunderwenteppandthenreceivedadjuvant high dose radiationtotheipsilateralhemithorax.nochemotherapywasgiven.thetechniqueemployed photonradiationtoadoseof54gyin30fractions.radiationsensitiveorganssuchastheliver,heart andspinalcordwereshieldedusingcustomizedblocksaftertheyhadreceivedtheirthresholddose limit.thechestwallandpleuraintheshieldedregionswerethenirradiatedwithmatchedelectron fields,whichhaveshallowerpenetrancethanphotons.of54patientswhounderwenteppand adjuvantradiation,only7(13%)hadlocoregionalrecurrence.despiteexcellentlocalcontrol,30 patients(56%)recurreddistally.asubsequentreportbythesameinvestigatorsdetailedradiation administeredto35patientswhoweretreatedatmskcc(yajnik,2003).localrecurrencedeveloped in13of35patients(37%),andinthemajorityofcasesfailureoccurredattheinferiorposteriorand medialmarginsregionsnotoriouslydifficulttotreatwith3dconformalradiation.itshouldbenoted thatradiationwasgenerallywelltoleratedandnomajorpulmonaryrelatedeventsoccurred. In2004,Wederandcolleaguesreported13patientswhounderwentneoadjuvantchemotherapy, EPPandadjuvantradiationtherapyto(Weder,2004).Radiationtherapyincludedeitherhemithoracic photonbeamtherapyto30gywithbooststo50gyinareasdefinedasbeingathighriskfor recurrence(n=6),or involvedfield localradiationto48gyto60gy(n=7).8(62%)patients developedrecurrenceswithinthefieldofradiation.theauthorssubsequentlyreportedresultsofa phaseiistudyusingasimilarregimen,inwhich45patientsunderwentneoadjuvantchemotherapy followedbyepp(weder,2007).36patientsreceivedadjuvantradiation.mediansurvivalwas23 monthsand38patients(84%)developedrecurrence,howeverthespecificpatternsoffailurewere notdescribed. Becauseofthedifficultyinadequatelytargetingtheentirepostpneumonectomyspacewith conventionalradiation,severalcentershaveevaluatedtheuseofintensitymodulatedradiation therapy(imrt).imrtisanadvancedmethodofdelivering3dimensionaltreatmentusingmultiple fluctuatingradiationbeamintensitiestomaximizetheintendeddosetothetumoraltargetwhile minimizingunwantedradiationdosetonormaltissues.ithasbeenshowntoimproveplanning targetvolumecoverageaftereppcomparedto3dconformalradiation(krayenbuehl,2007).using thistechnique,thegroupatm.d.andersonrecentlypublishedoutcomesin63patients(mediandose 45Gy)(Rice,2007).Themajorityofpatients(87%)werestageIII/IV.LiketheMSKCCseries, locoregionalrecurrencesoccurredin13%ofpatients,howeveronly3ofthesehad infield failure. Unfortunatelydistantrecurrenceswerefrequent(54%)andlimitedsurvivalinthisgroupofadvanced stagepatients(mediansurvival14months).morerecently,thedukeuniversitygrouppublished resultsofimrtin13patientsafterepp(70%stageiii/iv)andreportedahigherincidenceoflocal recurrences(46%)(miles,2008). TherehasbeenrecentdebateregardingthesafetyofIMRTafterEPP.TheBrighamgroup 180

183 ABSTRACTS reportedfatalradiationpneumonitisin6of13patients(46%)treatedwithimrttoamediandoseof 54Gy(Allen,2006).Wereviewedpulmonaryrelateddeathsin63patientswhounderwentIMRT aftereppatm.d.andersoncancercenter(rice,2007).6patients(10%)diedofpulmonarycauses within6monthsofinitiationofimrt,andofthese,2clearlyhadradiationpneumonitis.analysisof multipledosimetricparametersrevealedthatpatientswhodiedfrompulmonaryrelatedevents receivedsignificantlymoreradiationtotheremaininglungthansurvivorsdid.however,in comparisontothebrighamseries,overallradiationdosestothecontralaterallungweremuchlower. Inaddition,neithertheDuke(n=13)northeHeidelberg(n=11)groupsreportedsignificantpulmonary toxicitywithimrt(miles,2008;münter,2005). IncontrasttostandardhemithoracicradiationusingAP/PAbeamgeometry,whereverylittleofthe contralaterallungreceivesanyradiation,imrtresultsinarelativelylargeproportionofthe contralateralhemithoraxreceivingasmalldoseofradiation.inourseries,themedianpercentageof lungthatreceivedatleast5gywas75%.itisthereforenotunexpectedthattheremightbemore pulmonaryrelatedeventsassociatedwithimrtcomparedwithstandardhemithoracicradiation. Howeverusingstrictdosimetricconstraintsfornormaltissueandcarefultreatmentplanning,IMRT canusuallybeadministeredsafelyafterepp.thetradeoffforthisincreasedriskappearstobebetter coverageoftheatrisktargetvolumeandpossiblyimprovedlocalcontrol. Insummary,hemithoracicradiationto45Gyorhigherappearstobeeffectiveinreducing locoregionalrecurrenceofmesotheliomaafterepp.both3dconformalandimrtappeartobe acceptabletechniques.ifimrtisused,strictadherencetonormaltissueconstraintsmustbe employed,andcareshouldbegiventolimittheradiationdosetothecontralaterallung.despite improvedlocalcontrol,distantrecurrencesremainasignificantproblemanduntilbettersystemic therapybecomesavailable,adjuvantradiationmaynotaddmuchintermsofoverallsurvival. 181

184 ABSTRACTS Number:155 Abstracttitle: Estimatingthesurvivalbenefitassociatedwithradicalsurgery MartinUtley,FrancescaFiorentino,TomTreasure ClinicalOperationalResearchUnit,UniversityCollegeLondon,UK. Keywords: Surgery Abstractcontent: Theroleofradicalsurgeryinthetreatmentofmesotheliomaiscontentious.Intheabsenceofdata fromrandomisedcontrolledstudies,wehaveexploredthepossibilityofusingdatafrompublished observationalandfollowupstudiestoestimatethemagnitudeofanysurvivalbenefitassociated withthispractice,whetherinconjunctionwithadjuvanttreatmentoralone.selectionbiasis inevitablewhenmakingcomparisonsbetweentreatmentgroupsincontextswhereallocationto treatmentisinfluencedbyclinicalconsiderationsastothefitnessandsuitabilityofthepatient.for thisreason,wehavelimitedourselvestoestimatingtheupperboundofanysurvivalbenefit.given theburdensomenatureofthesurgery,itcouldbearguedthateventhemostoptimisticestimateof anysurvivalbenefitismeagre. 182

185 ABSTRACTS Number:156 Abstracttitle: MARS2 DavidWaller GlenfieldHospital,Leicester,UK. Abstractcontent: MARS(MesotheliomaAndRadicalSurgery)isastudyofthefeasibilityofacomparisonof chemotherapyversuschemotherapyandextrapleuralpneumonectomywithadjuvantradical hemithoraxirradiation. Theinclusioncriteriahaveincludednonsarcomatoidhistologyandnegativemediastinoscopy. Theinitialcriticismoftheprotocolincludedthesuggestionthatpatientswithearlyepithelioid diseasewouldnotwanttoforegothechanceofcurebynotreceivingepp. Inrealitythetrialhasnotrecruitedasfastaspredictedforthefollowingreasons: 1. manypatientsdonothavesufficientcardiorespiratoryreservetotolerateepp 2. ageatpresentationisincreasingandperformancestatusisdecreasing Chapman,Thorax2008;63: manypatientspresentlatewithmediastinalnodemetastases 4. patientsarereluctanttosufferthelossinlungfunctionandthereforequalityoflifeafterepp withnopromiseoflongtermsurvival 5. patientsmaybemoreinclinedtoundergolungsparingsurgeryifanacceptablesymptom freeintervalcanbeoffered Theroleofsurgeryinprolongingsurvivalinmesotheliomastillneedstobeconfirmedintheeyesof manycliniciansthereforearandomisedtrialisneeded. InMARS2theobjectiveofsurgeryintheexperimentalarmshouldbe: toobtainmacroscopictumourclearancewiththeleastanatomicalresectionrequired Thiswouldpermitradicalpleurectomy/decorticationandthuswidenthepotentialstudypopulation tothosewithpoorerlungfunctionleadingtoincreasedrecruitmentitwouldalsoencouragepatients whoarereluctanttosignificantlyrisktheirqualityoflife. Selectioncriteriacouldprobablyberelaxedtoomitmediastinoscopybutanyradicalsurgeryin sarcomatoidmesotheliomaseemsdifficulttojustify. Thecontrolarmofthestudyshouldcontinuetooffermaximumactivesymptomcontrolincluding VATSpleurodesisbutthoracoscopicdebulkingshouldnotbeperformed.Thechoiceofchemotherapy regimeshouldbelefttothediscretionoftherespectiveoncologist. 183

186 ABSTRACTS Number:160 Abstracttitle: Valproatesynergizeswithcisplatinandpemetrexedtoinduceapoptosisinmalignantpleural mesotheliomacells FabianVandermeers(1),PascaleHubert(2),MathieuBoxus(1),ArnaudScherpereel(3),Thierry Berghmans(4),CélineMascaux(4),ArsèneBurny(1),PhilippeDelvenne(2),JeanPaulSculier(4),Luc Willems(1) (1)CellularandMolecularBiology,FNRSFUSAGx;(2)ResearchCenterinExperimentalCancerology ULg;(3)CalmetteHospital,CHURLille;(4)JulesBordetInstitute Keywords: HDACinhibitors,apoptosis Abstract: Thefirstlinetreatmentformalignantpleuralmesothelioma(MPM)includesaregimenof pemetrexedandcisplatin.themajorissuesofthischemotherapyareacutetoxicity,lowoverall responserateandfrequentrelapse.wehypothesizedthattherapeuticefficacyislimitedby inadequategeneexpressionintumorcells.therefore,weevaluatedtheactivityofvalproate(vpa),a histonedeacetylase(hdac)inhibitorknowntoactivategenetranscription. WeshowthatVPAsynergizeswithpemetrexedandcisplatintoinduceapoptosisinmesothelioma celllines(m14k,m38kandzl34)andinbiopsiesfrommpmpatients.onsetofapoptosisinvolves bothextrinsicandintrinsicpathwaysrequiringenzymaticactivitiesofcaspase8andcaspase9, respectively.incontrasttosaha,vpaefficientlystimulatesproductionofreactiveoxygenspecies (ROS)and,interestingly,thefreeradicalscavengerNacetylcystein(NAC)inhibitsapoptosis, indicatingthatrosaremajormediatorsofvpaactivity.asexpected,vpaaloneorcombinedwith pemetrexedandcisplatintriggershyperacetylationofhistoneh3.vpastimulatesreleaseof cytochromecfrommitochondria,cleavageofbidandoverexpressionofp21andfas.finally,vpa combinedwithpemetrexedandcisplatinpreventstumorgrowthinscidmiceengraftedwithm14k cells. TheseobservationssupportapotentialnewregimenofVPAcombinedwithpemetrexedand cisplatinforfirstlinetreatmentofmpm. 184

187 ABSTRACTS Number:161 Abstracttitle: Inhibitionoftranslesionsynthesissensitizesmalignantpleuralmesotheliomacellstocisplatin treatment PhilipAlexanderKnobel,EmanuelaFelleyBosco,StefanieKurtz,AlexandraGraf,RolfArnoStahel, ThomasMichaelMarti UniversityHospitalZuerich,Switzerland Keywords: translesionsynthesis,rev3,malignantpleuralmesothelioma,sirna,shrna,cisplatin Abstract: Background: Malignantpleuralmesothelioma(MPM)ismostcommonlytreatedwithamultimodalitytherapy includingtreatmentwithcisplatinorcisplatinanalogues,whichleadtotheformationofinteror intrastranddnaadducts.cisplatinadductscanberepairedor,ifnotrepaired,inducereplicationfork stallingwhichcanbyovercomebyspecifictranslesionpolymerases. Translesionpolymeraseζconsistsoftwosubunits,Rev3isthecatalyticandRev7the structuralsubunit.thetranslesionpolymeraseζisresponsibleforthetranslesionsynthesis (TLS)ofcisplatinbasedadductsandtherepairofDNAinterstrandcrosslinks.Rev3deficient vertebratecelllinesshowthehighestsensitivitytocisplatincomparedtootherrepairdeficientcell lines.rev3inhibitionbyantisensetreatmentconfershighercisplatinsensitivityandlower mutagenicityinimmortalhumanfibroblasts. Workinghypothesis: DownregulationofRev3sensitizesMPMcellstocisplatintreatmentandreducestheformationof cisplatinresistance. Results: WeshowedthattheexpressionofRev3inhumanMPMcellsisdependentoncellcultureconfluency andisalsoaffectedbycisplatintreatmentinatimedependentmanner.functionalinhibitionofrev3 bysirnaincreasedreplicationforkbreakdownasindicatedbyenhancedh2axphosphorylation. REV3expressioninratandhumanMPMcellswassuccessfullyinhibitedbytransienttransfection withplasmidscontainingshorthairpinconstructstargetingrev3. WegeneratedstableHEK293andhumanlungfibroblast(Wi38SV40)celllineswithdecreasedREV3 expression.functionalinhibitionofrev3inthehek293andwi38sv40celllinesresultedin increasedgenotoxicstressasindicatedbyincreasedp53expression,aslowergrowthrateand increasedcisplatinsensitivity. Conclusions: WeshowedthatfunctionalinhibitionoftranslesionpolymeraseζbyshRNAagainstREV3 increasedreplicativestressinmpmcelllinesandincreasedcisplatinsensitivityinhumancells. 185

188 ABSTRACTS Number:162 Abstracttitle: MULTIMODALITYTREATMENTVERSUSCHEMOTHERAPYINMALIGNANTPLEURALMESOTHELIOMA GuntuluAk(1),MuzafferMetintas(1),HuseyinYildirim(1),HasanBatirel(2),CumhurSivrikoz(1),Emine Dundar(1) (1)ESOGÜMedicalFacultyDepartmentofPathologyEskisehir,Turkey;(2)MarmaraUniversity MedicalFacultyDepofChestSurgeryIstanbul,Turkey Keywords: mesothelioma;chemotherapy;multimodalitytherapy Abstract: Objectives: Formalignantpleuralmesothelioma(MPM)treatment,multimodalitytherapyisdeclaredtobethe besttreatment.however,thismultimodalitytherapycanonlybeappliedtothechosengroupof patients.thecriteriausedforchoosingthepatientsforthistreatmentarealsogoodprognostic factors.inthisstudy,weaimedtocomparethesurvivalofmultimodalitytherapyappliedmpm patientsandchemotherapyappliedpatientswithsimilarcharacteristics. Methods: Extrapleuralpneumonectomywasperformedto21ofourpatients.Fourofthem(19%)diedbecause ofprocedurerelatedtocomplications.therefore4patientswereexcluded.forthisstudy,basedon age,gender,stageofmultimodalitytherapyapplied17patientsarandomlychosencontrolgroup wasformedamongchemotherapyappliedpatients.thepatientsofcontrolgrouprefusedsurgical therapy.themediansurvivalofthesetwogroupswascompared. Results: Twentyofthepatients(58.8%)weremaleand14ofthem(41.2%)werefemale.Themeanagewas 52,4±9,1(33 69)years.Therewasnoanydifferencebetweentwogroupsaboutage,gender, asbestosexposure,durationofasbestosexposure,smokinghistory,karnofskyperformancestatus, durationofsymptoms,symptoms,histologicsubtype,andstage.however,inthemultimodality therapygroupleftsidetumorwasmorefrequentthanthechemotherapygroup.themediansurvival formultimodalitytherapygroupwas21,0±4,1months,forchemotherapygroupwas15,0±1,9 months(logrank=2,883;p=0,090).themultimodalitytherapygrouphadalongersurvivalthan chemotherapygroup,whencomparedexcludingpatientswithextrapleurallymphnodemetastasis (22,0monthsvs.15,0months;p=0,037). Conclusion: Weconcludedthatmultimodalitytherapyprovidesabettersurvivalforsuitablepatients,when performedbyexperiencedcenters. 186

189 ABSTRACTS Number:163 Abstracttitle: RETREATMENTWITHPEMETREXEDBASEDCHEMOTHERAPYINPATIENTSWITHMALIGNANT PLEURALMESOTHELIOMA(MPM):ANOBSERVATIONALSTUDY FabioDeVincenzo,PaoloAndreaZucali,GiovanniLucaCeresoli,MatteoSimonelli,LetiziaGianoncelli, ElenaLorenzi,ArmandoSantoro IstitutoClinicoHumanitas,Rozzano(Milan),Italy Keywords: secondline,chemotherapy,pemetrexed Abstract: Background:Secondlinechemotherapyinpatients(pts)withMPMisbeingincreasinglyusedin clinicalpractice,butitsroleiscurrentlyundefined.recentcaseserieshavesuggestedapossiblerole ofretreatmentwithpemetrexedbasedchemotherapy(pbc)inthissetting(razak,lungcancer 2008).Aimofthisobservationalstudywastoevaluatethistherapeuticoptioninaconsecutiveseries ofptspreviouslytreatedwithfirstlinepbc. Methods:Ptswhohadpartialresponse(PR)orstabledisease(SD)foratleast3monthsafterfirst linepbcwereeligibleforthestudy.ptsreceivingretreatmentwithpbceitherassecondline(2l)or furtherline(>2l)therapywereconsideredforanalysis. Results:Eighteenptswereevaluated(9treatedin2L,9in>2Lsetting).Therewere13malesand5 females.medianagewas66(range4780).histologywasepithelialin15,mixedin3.eortc prognosticscorewaspoorin13,goodin5.foursdand2prwereobserved,allin2lsetting,foran overalldiseasecontrolrateof33%.twelveptshaddiseaseprogression(9/9ptstreatedin>2l). Grade3/4haematologicaltoxicitywasobservedin2pts(11%),with1caseoffebrileneutropenia. Nonhematologicaltoxicitywasgenerallymild,withonly1caseofgrade3constipation.Mediantime toprogression(mttp)was3.5mos(range mos).ptsreceivingpbcas2ltherapyhada longermttpincomparisontothosetreatedwith>2ltherapy(5.6vs2.8mos).outcomeafterre treatmentwithpbcwascorrelatedtottpachievedwithfirstlinepbc(5.2vs2.4mosinptswith firstlinettp;or<12mos,respectively). Conclusion:RetreatmentwithPBCseemstobeapossibleoptioninthesecondlinesettinginpts withmpmachievingadurablediseasecontrolwithfirstlinetreatment.furtherevaluationina prospectivetrialiswarranted. 187

190 ABSTRACTS Number:164 Abstracttitle: ImagingFindingsofMalignantPleuralMesotheliomainJapan KatsuyaKato(1),TakumiKishimoto(2),KenichiGemba(2),KoukiInai(3),YukioTakeshima(3),Keisuke Aoe(4),Shinichi,Fujimoto(2),SusumuKanazawa(5) (1)Dept.ofRadiology,OkayamaUniversityMedicalSchool;(2)OkayamaRosaiHospital;(3)Hiroshima UniversityMedicalSchool;(4)SanyoHospital;(5)OkayamaUniversityMedicalSchool Keywords: malignantpleuralmesothelioma,ct,diagnosticimaging,pleuralplaque Abstract: Purpose:OurpurposeistofindtheradiologicalfindingswhichcanbethekeytoimproveMPM diagnosisbyreviewingtheimagesofmpmcasesinjapan. MethodsandMaterials:Among2742mesotheliomadeathcasesextractedby VitalStatisticsof Japan2003to2005,Wereviewed211MPMcases(182men,29women;meanage,69years)in whichthechestctandxpwereobtained.theaccuracyofdiagnosisofmpmwasdeterminedinall casesbydiscussionwiththeclinicalandradiologicalmaterials. 1.WereviewedhavingpleuralplaqueornotoneachCTandXP.Thepresenceofapleuraleffusion andasbestosiswerealsoevaluated. 2.AbnormalfindingsinthepleuraonCTimageswereevaluated,withcategorizationasfollows, Category1(nothickening),Category2(smooththickening),Category3(irregularthickening)and Category4(massformation).ThecategoriesofeachcasewascomparedwithTstageaccordingto IMIG. 3.Wereviewedlocalizationofthepleuralirregularity.Wefocusedonthreeplacesasfollows, mediastinal,fissuralandbasalpleura. Results 1. Inall211cases,pleuralplaquewerepresentin37%casesonCTandin12%casesonXP.Each pleuraleffusionandasbestosiswaspresentin93%and3%cases. 2. Theratioofeachcategoryofpleurawasasfollows,Cat1;5%cases,Cat2;17%cases,Cat3;35% cases,cat4;43%cases.asforcorrelationwithtstage,themajorityofpatientsogcat1and Cat2wereT12(91%),Cat3andCat4wereT34(85%) 3. Locationofpleuralthickeningwasmediastinalin78%cases,fissural47%cases,andbasalin73% cases. 188

191 ABSTRACTS Conclusion Theseresultsshowthatdegreeofthepleuralirregularitywasmildin22%casesofMPM,andTstage waslowinthesecases.mostofmpmcaseswereaccompaniedwithpleuraleffusion.therefore, whenthediagnoseunidentifiedpleuraleffusion,mpmshouldbesuspectedinthecaseofpleural plaqueandmediasitinal,fissuralandbasalpleuralirregularity. ForearlydiagnosisoftheMPM,itisnecessarytopayattentiontomediastinal,fissuralandbasal pleuralirregularityandpleuralplaqueinunidentifiedpleuraleffusioncase. 189

192 ABSTRACTS Number:165 Abstracttitle: LocalizedMalignantMesothelioma.2newcases AliciaMorresiHauf,SabineSchottHildebrand,HaukeWinterandMichaelLindner.Departmentof PathologyandThoracicSurgery.AsklepiosFachklinikenMünchenGauting. Keywords: LocalizedMalignantMesotheliomaDiagnosis Abstractcontent: Wepresent2newcasesoflocalizedmalignantmesothelioma(LMM)anddiscussthemostimportant aspectsofthediagnosisofthisveryuncommonvarietyofmalignantmesothelioma. Case1: A49yearoldwomanwithoutahistoryofasbestosexposurepresentedwithahistoryofseverechest painfor3months.thechestctrevealedaleftparavertebralpleuraltumor. Thediagnosisofaneurinomawasconsidered.Atsurgeryasessile3x2,5x2cmtumorwithout infiltrationoftheneighbouringstructureswasfoundatthedorsalchestwallandresected. Microscopicallythereweretubularstructureswithfocaladenoidcharacterandthetypical immunohistochemicalfindingsofmesothelioma. Case2: A65yearoldelectricianpresentedwithahistoryofchestpainforsomemonths. ThechestCTshowedatumorintherightanteriorchestwallwithdestructionofthe5thribwithout anyevidenceofdiffusegrowth. Thetumorwascompletelyresectedtogetherwiththeadjacentchestwallandawedgeoftheupper lunglobe.thepathologicalexaminationrevealedamesotheliomaofpredominantepitheloidtype. Theimmunohistochemicalfindingsconfirmedthemesothelialnatureoftheneoplasm. InbothcasesthediagnosisofaLMMwasestablished.Theclinicalcourseaftersurgerywas uneventful.thepatientsunderwentalocalradiotherapy6weeksaftertheoperation. Discussion: LMMareveryrare.Lessthan50caseshavebeenreported. LMMsisdefinedby a)themicroscopicappearanceofamalignantmesothelioma b)thelackofdiffuseormulticentricspread Thusaverythoroughradiologicandmacroscopicexaminationiscrucialforthediagnosis. DiffusemalignantmesotheliomawithadominantmasscanbeconfusedwithLMMandisthemost importantdifferentialdiagnosis.theanalysisoftheliteratureonlmmisdifficult,mainlydueto earlierdenominationssuchas benigne or localised mesotheliomaforsolitaryfibroustumor. 190

193 ABSTRACTS ThepublishedcasesofLMMdemonstratethatalsolocalisedneoplasmswithgrosslybenign appearanceshouldbehistologicallyexaminedwithoutdelay. TheroleofasbestosexposureintheaetiologyorLMMisnotwellestablished. TheseparationofLMMfromDMMiscrucialbecauseLMMseemstobeassociatedwithabetter prognosisaftercompleteresection. 191

194 ABSTRACTS Number:166 Abstracttitle: 18FDGPET:anewpredictiveandprognostictoolinpatientswithmalignantpleuralmesothelioma ArnaudScherpereel,AmandineBeron,ClaudeHosseinFoucher,MassimoConti,HenriPorte,Bachar Chahine,JeanJacquesLafitteandXavierMarchandise Abstractcontent: Introduction:FDGPETseemstobeapromisingtoolinmalignantpleuralmesothelioma(MPM)but itsinterestinthestagingandinthemonitoringofthepatientsisnotreallyproved.wewantedto evaluatetheusefulnessoffdgpetfordiagnosisofmpmandassessmentoftheresponseto treatment. Materialandmethod:46MPMpatients(sexratioM/F=35/11;meanage=61years(3979))were retrospectivelystudied.preliminaryresultsincluded32ofthese46patients.fordiagnosisand staging,fdgpetfindingswerecomparedwithcomputedtomography(ct)andpathologydata. InternationalMesotheliomaInterestGroupStagingclassificationdistinguishedthepatients:stageI: n=3,ii:n=13,iii:n=11,iv:n=5).thirteenpatientsweretreatedbychemotherapythensurgery(epp) andradiotherapy,17patientshadchemotherapyandpalliativechestradiotherapy,and2patients receivedonlybestsupportivecare. Results:allpatientshadabnormalpleuraluptake(SUVmax:range= g/mL,mean=9.5g/mL, median=7.75g/ml).nodalinvolvementwaspotentiallyunderestimatedbyfdgpetin10(31%) patientscomparedtoct.pathologicalfindingsonsurgerysamplesconfirmedthatpetandct underestimatednodalinvolvementin6/13patients.petdiagnoseddistantmetastasisinfour patients,missedonct. Metabolicresponseassessmentafterchemotherapy(6cyclesofcisplatinpemetrexed)waspossible for13patients.fdgpetpredictedtherapeuticresponseabout3monthsearlierthanctin4of13 patients.presenceofametabolicresponseafterchemotherapyvisualizedonfdgpetseemedtobe associatedwithalongertimetoprogression(19monthsagainst11monthswhenprogression). TherewasnosignificantstatisticalcorrelationbetweenSUVmeasurementsandnodalinvolvement. However,SUVmaxvaluewascorrelatedwiththesurvivalofthepatients(p=0.016). Conclusion:FDGPETseemedtobeausefultoolfordetectionofdistantmetastasisofMPM,butits evaluationoflocaltumorextensionandnodalinvolvementwasratherdisappointing.fdgpetcould beinterestingtoassessthepatients prognosisandtomonitorthemetabolicresponseto chemotherapy.furtherstudyofourotherpatientsisongoingtovalidatethesepreliminaryresults. 192

195 ABSTRACTS Number:167 Abstracttitle: Thoracoscopyusingnarrowbandimaging(NBI)andautoflurorescenceimaging(AFI)systemsisa novelmodalityforthedetectionofearlymesothelioma TakashiNakano,kihiroYasumitsu,KozoKuribayashi,KazuyaFukuoka,HyogoCollegeofMedicine Japan Keywords: Thoracoscopy,Diagnosis, Abstract: INTRODUCTION: Narrowbandimaging(NBI)isanewendoscopictechnique,whichimprovesvisualizationofvascular architectureusingspeciallydesignedopticalfilters.and,theuseofautofluorescenceimaging(afi)in conjunctionwithconventionalwhitelight(wl)endoscopyhassignificantlyimprovedtheendoscopic diagnosisofpreneoplasticlesionandearlycancer.weevaluatedthenbiandafisystemsinthe detectionofpreinvasiveandsmalllesionsofthepleurainpatientswithearlystageofmesothelioma. MATERIALSandMETHODS: 19ptswithatypicalorsuspiciouscellsinpleuralfluidsorradiologicalsuspicionofmesothelioma wereevaluatedbythoracoscopyunderlocalanesthesia.pleurawasfirstscreenedwithconventional WL,andthenwasexaminedbyNBI(OlympusLTF240)andAFI(OlympusBF260)fordetectionof additionallesions.thedeviceofnbiandafisystemshasafunctionoftwomodalities,whicheasily switchesbetweenwlobservationandnbi,wlandafi,respectively. Allsuspiciousareas detectedbynbi,afiorbothwerebiopsiedandcomparedwithpathologicaldiagnosis. RESULTS: NBIenabledclearvisualizationofvasculararchitectureinthepleuracomparingwithconventional WL,whichcoulddistinguishsuperficialbloodvesselsfromdeeperones,i.e.,bloodvesselsnearthe pleuralsurfaceweredisplayedinbrownishtones,andthickvesselsinthedeeperlayerwereshown incyantones.tortuousandirregulardilatedvesselsandshortbranchvesselscouldbevisualized clearlyintheinvolvedpleura.afidisclosedthatnormalmesotheliumofthepleuraappearedgreena little,andthatneoplasticareasappearedmagenta.smallnoduleoft1amesotheliomaappeared brownonnbiandmagentaonafi,withhighvascularizationonandsurroundingthenodule,wherea pathologicaldiagnosiswasmadebybiopsy. CONCLUSIONS: AdvancedimagingmodalitiesofNBIandAFImayallowthedetectionofearlylesionsofmalignant pleuralmesothelioma.and,magnifiednbiisfeasiblefordetectingsubmesothelialvascularizationin theearlystageofmesothelioma. 193

196 ABSTRACTS Number:168 Abstracttitle: Aprognosticindexforpreoperativeevaluationofpatientswithresectableepithelialmesothelioma WilliamRichards(1),JordanMueller(1),CarlAlsup(1),JohnGodleski(1),LucianChirieac(1),Joseph Corson(1),AneilMujoomdar(1),BeowYeap(2),RaphaelBueno(1),DavidSugarbaker(1) (1)BrighamandWomen'sHospital,Boston,MA,USA;(2)MassachusettsGeneralHospital,USA Keywords: Extrapleuralpneumonectomy,Surgery,Epithelial,Prognosis Abstract: TheuseofprognosticfactorsindependentofTNMstagemayaidintheappropriateselectionof patientsforaggressivetreatmentstrategies.publishedstudiesexaminingprognosticfactorsin mesotheliomahavelackedconsensusonwhicharesignificant.mosthavelackedstatisticalpowerto stratifyforimportantfactorssuchastreatmentandhistologicsubtype.ourobjectivewastoidentify preoperativefactorsrelatedtopooroutcomefollowingsurgerybasedmultimodaltherapy.to minimizevariability,onlypatientswithepithelialtumorswhounderwentextrapleural pneumonectomy(epp)wereanalyzed.epithelialmesotheliomaismoreamenabletotreatmentwith multimodalityregimensthanmixedorsarcomatoidhistologies. Of473patientswithepithelialmesotheliomawhounderwentsurgicalexplorationforplannedEPP, 365wereresectablebyEPP.Amongthese,72%weremale,themedianagewas57yearsandthe30 dayorinhospitalmortalitywas5%.factorsthatweremeasurablepreoperatively,weresignificantly relatedtoprognosisinatleast2priorreportsandcouldbedocumentedforamajorityofthispatient cohortwereconsidered.continuousvariablesweredichotomized,andfactorswithunivariate logrankpvalueslessthan0.01wereanalyzedinastepupproportionalhazardsmodel. Plateletcount>350K/uL(RR1.97),whitecellcount>10K/dL(RR1.63),hemoglobin<11g/dL(RR 1.71),malegender(RR1.56)andage>57(RR1.52)remainedhighlysignificantateachiterationof themodel,indicatingtheirindependentprognosticvalue.theoverallsimilarityofrelativeriskamong thefactorspermittedtheiradditivecombinationasaprognosticindexforeachpatient,which significantlystratifiedoutcome(seetable).asacomponentofpreoperativeassessment,this prognosticindexmayidentifyasubgroupofpatients(index3:4or5factorspositive)whowould benefitminimallyfromeppandforwhomalternativemanagementshouldbeconsidered. Index Factors N Median 1-yr 2-yr 3-yr 5-yr mo 85% 66% 50% 31% mo 64% 31% 18% 5% mo 26% 5% 0% 0% 194

197 ABSTRACTS Number:169 Abstracttitle: Effectofaurorakinaseinhibitioninmesotheliomacelllines ShigekiShimizu,FernandoLópezRíos,AdamOlshen,LeeKrug,MaureenZakowski,ValerieRusch, MarcLadanyi MemorialSloanKetteringCancerCenter,NewYork,NY Keywords: AuroraKinase Abstract: Background:Aurorakinasesregulatechromosomemicrotubuleattachmentsduringcelldivisionand providemitoticcheckpointcontrol.amplificationoroverexpressionofaurorakinasesisassociated withaneuploidy,aggressivephenotype,andpoorprognosisinseveralcancers.ourpreviousgene expressionprofilingstudyshowedthatmoreaggressivemesotheliomasexpresshigherlevelsof AurorakinasesA(AURKA)andB(AURKB).Therefore,weexaminedthesensitivityofmesothelioma celllinestothepanaurorakinaseinhibitor,ve465(giftofmerck). Methods:Westudiedthesensitivityof14mesotheliomacelllinestoVE465byMTTassaysat96 hours.aurkaandaurkbtranscriptlevelswereexaminedbyqrtpcrandinaffymetrixu133plus 2.0microarrayhybridizationdata.Westernblottingforp53,p21,totalRb,phosphoRb,phospho histoneh3,andactinwasperformed. Results:TheHMesocelllinewasverysensitivetoVE465(IC50:2nM).Othermesotheliomacelllines wererelativelylesssensitive,withic50valuesrangingfrom2umto20um.therewasasignificant correlationbetweenic50valuesandphosphohistoneh3(p=0.045);phosphohistoneh3washighly expressedinhmeso(themostsensitiveline).ve465decreasedtheexpressionofphosphohistone H3insensitivelines.TherewasnosignificantcorrelationbetweenIC50valuesandmRNAlevelsof AURKAorAURKBorproteinexpressionofAURKA,AURKB,p53,p21,orphosphoRb. Conclusions:Inthisstudy,1/14mesotheliomacelllinesshowedexquisitesensitivitytoaurorakinase inhibitionbyve465andmoderatesensitivitywasseeninseveralotherlines.phosphohistoneh3 expressionmaybeusefulasapredictiveandapharmacodynamicmarkerinthissetting.the therapeuticpotentialofaurorakinaseinhibitioninasubsetofmesotheliomapatientswarrants furtherinvestigation. 195

198 ABSTRACTS Number:170 Abstracttitle: Enzastaurin,aProteinkinaseCbeta(PKCβ)inhibitorinmalignantpleuralmesothelioma Keywords: Abstract: 196

199 ABSTRACTS Number:171 Abstracttitle: ExtrapleuralpneumonectomywithadjuvantChemoRadiotherapyforTreatmentofMalignantPleural Mesothelioma AbdelRahman,RababGaafar,FatmaKassem,HodaBaky,HishamHoseiny NCI,CairoUniversityEgypt Keywords: Extrapleuralpneumonectomy,chemoradiotherapy,mesothelioma Abstract: Background Surgicalresectionhasbeenconsideredthemainstayoftreatmentformalignantpleural mesotheliomabysome.however,itisimpossibletoachievemicroscopicallycompleteresectionwith surgeryalone. Methods Between ,33patientswereoperateduponasapartofmultimodaltherapyforMPM.Pre operativeworkupincluded:computedtomography,pulmonaryfunctiontests,pleuralbiopsy,full laboratoryinvestigations,echocardiographyinpatientsover50years.otherinvestigationsasmri chest,bonescanbrainctandventilationperfusionscanweredonewhenindicated. IMIGstagingsystemwasusedtostageourpatients.Extrapleuralpneumonectomywithmediastinal nodaldissectionorsamplingwasdoneforallpatients.sixcyclesofcarboplatin,holoxanwereadded postoperativelytoallpatientsexcept3withchestradiationinadoseof4500to6000cgy. Results Therewere14malesand19female,agerangewas2365y.Allpatientshadasbestosexposurewith adurationofexposurethatrangedbetween1246y.threepatientshadpositivefamilyhistoryofthe disease.twentypatientshadrightsideddiseaseand13hadleftsideddisease. ByCTscan,twentypatientshadunilateralpleuraleffusionand13haddiffusepleuralthikening. Preoperativestagingrevealed9patientswithstageIand24withstageII.Postoperativestaging showed5patientswithstagei,12withstageiiand16withstageiiidisease.majormorbidity developedinonepatient,minorcomplicationsoccurredin7patients.twopatientsdiedafter surgery.epithelialhistologywasfoundin24patients,8withmixedhistologyandonewith sarcomatiodtype.therewere5patientswithn2disease,onewithbothn1andn2diseaseand2 withn1diseaseonly.recurrentdiseasedevelopedin21patients,11withlocalrecurrence,5with peritoneal,contralateralhemithoraxin3,contralateralaxillain1andbonemetastasesinone.the Overalloneyearsurvivalwas84.8%,overall2yearssurvivalwas51.5%,overall3yearssurvivalwas 18.2%andoverall4yearssurvivalwas12.12%. Conclusion MultimodalitytreatmentappearstobenefitasubgroupofhighlyselectedpatientswithMPM. 197

200 ABSTRACTS Number:172 Abstracttitle: TrimodalInitialVideothoracoscopy,IntrapleuralChemotherapyandP32RadiationforLungSparing TreatmentofPleuralMesothelioma:TheColumbiaProtocol RobertTaub(1),JoshuaSonnett(1),MarkGinsburg(1),RashidFawwaz(1),CarolineVisser(1),Elethea Hare(1),JoshuaLeinwand(1),MaryHesdorffer(2) (1)ColumbiaUniversity,USA;(2)MesotheliomaAppliedResearchFoundation,USA Keywords: intrapleuralchemotherapy,p32,lungsparing Abstract: Background:Wehavedevelopedatrimodalregimenforintracavitarytreatmentofpatientswith StageI(IMIGT1T2)malignantpleuralmesothelioma,incorporatingrepeatedoutpatientcoursesof intrapleural(ip)chemotherapyplusipradiationwithp32toselectedpatientswithmalignantpleural mesotheliomawhowereunwillingorunabletoundergoextirpativesurgery. Methods:Ptsunderwentinitialexploratoryvideothoracoscopy(VATS)toconfirmthepresenceof disease,andtheaccessibilityofthepleuralspacetointracavitarytreatment.twoipcatheterswere placed,anteriorlyalongthepericardialborderuptotheipsilaterallungapex,andposteriorlyalong andintothediaphragmaticsulcus.eachcatheterwasattachedproximallytoasubcutaneous mediportchamberplacedovertheipsilaterallowerribs.overthenext612weeksat12weekly intervals,cisplatin2040mg,doxorubicin20mg,orgammainterferon(1,000micrograms)influid volumesupto200mlwasinjectedintobothportstoperfusetheentirepleuralspace.the distributionofinjectatewasverifiedbyintracavitaryiohexolctimaging.thefluidwasnotremoved butallowedtoremainandbeabsorbed.additionalintravenouspemetrexedplusciplatin chemotherapywasgiventoselectedpatients.atweek812insuitablepatients,thepleuralcavity wasimagedwithradioactivetechnetiumlabelledsulfurcolloid;ifuniformlydistributed,15mciof radioactivep32chromicphosphatesulfurcolloidwasinjected,therebydelivering4,0006,000cgyto accessiblepleuralsurfaces.asecondlookexploratoryvatswasperformed,thecathetersand mediportswereremoved,andthepleuralsurfaceswereinspectedandbiopsied. Results:8malesand5femaleptsaged4679weretreated,sixwithbothperitonealandpleural involvement,otherswithunresectablediseaseorwhorefusedsurgery.8ptsreceivedipp32,oneto bothleftandrightpleuralcavities.theaboveprocedureswerewelltoleratedwithoutearlyorlate complications.afteruptotwoyearsoffollowup(asofjan2008)2patientsshownoovertdiseaseat 21and26months.5patientsarealive withdisease;onehasundergonepleurectomy/decortication(p/d)and onehasundergoneextrapleuralpneumonectomy(epp);surgicalp/dorepp remainpossibleoptionsin3others.6patientshavedied,5ofprogressivepleuraldisease. Conclusions:Thisretrospectiveanalysisallowsthehypothesisthatlungsparingrepeatedintrapleural chemotherapycombinedwithintrapleuralp32radiotherapymaybesafelyusedinpatientswith malignantpleuralmesothelioma.thisregimendeservesongoingprospectivestudyastooverall efficacyandpotentialincorporationintopresentdaytreatmentparadigms. 198

201 ABSTRACTS Number:173 Abstracttitle: ImprovedsafetywithExtrapleuralPneumonectomyinMalignantPleuralMesotheliomaperformedat highvolumehospitalwithhighvolumesurgeons. JesperBohsenRavn,JørnBrenøe,SusanneSchmidt,AnnikaLoft,AnneKiilBertelsen,JensBenn Sørensen Rigshospitalet,Denmark Keywords: extrapleuralpneumonectomy,learningcurve,highvolumesurgery Abstract: Background:Fewpatientswithmalignantpleuralmesothelioma(MPM)arecandidatesforintended curativesurgerybyextrapleuralpneumonectomy(epp)whichisthusarareproceduretoperformin mostdepartmentsofthoracicsurgery.selectionandcorrectstagingisofoutmostimportancebut stillthesurgicalprocedureofeppforearlystagesofmpmisconfinedwithconsiderablemorbidity andalsoa30dayperioperativemortalityratearound3%to5%inrecentseries.onewayof reducingthemorbidityandmortalityofeppinmpmmaybetoconfinethishighrisksurgical proceduretofewexperiencedcentres. Methods:TheNordicMesotheliomaGroupdecidedin2003tocentralizethehighriskEPPoperation andpreoperativestagingforpotentiallyresectablempminonemesotheliomaresearchunitatthe NationalUniversityhospitalinCopenhagen,Denmark,coveringthethreeScandinaviancountries(18 mill.inhabitants).thisstudyaimstoexaminethelearningcurveforthecliniciansandtheimproved safetyexperiencedinthefirst4cohortsof10patientseach(totally40patients)undergoingepp duringthiscentralizedprogramme.endpointsaredurationofoperativeprocedures,surgical complications,andperioperative30daysand90daysmortality. Results:Fourcohortsof10patientseachhadEPPafter36coursesofplatinumbasedinduction chemotherapyfromoct2003tosept2007.therewere33males,27hadrighthemithorax malignancy,andmedianagewasoverall62years(range4569years)withoutanydifferences betweencohorts.ten%ofpatientshadpatchproblemsand10%hadfistulationsamongthefirst2 cohortscomparedto0%and0%amongthesubsequent2cohorts,respectively.thedurationofthe surgicalproceduredeclinedfrommedian355minutesinthefirstcohortto220minutesinthefourth cohort.the30daysand90daysperioperativemortalitywas0%inallcohorts. Conclusions:CentralizationofEPPleadtoasharplearningcurvewithdiminishedcomplicationsand shortenedtimespendonthesurgicalprocedurewithoutanyperioperativemortality.potential explanationsforthisfavorableoutcomesmaybethathighvolumesurgeonsandhighvolume hospitalsmayoptimizepatientselection,minimizetechnicalerrors,andimproveexpertiseincritical caremedicineandsophisticateddiagnosticandtreatmentservices 199

202 ABSTRACTS Number:174 Abstracttitle: PROGNOSTICFACTORSACCORDINGTOTREATMENTSCHEDULEINMALIGNANTPLEURAL MESOTHELIOMA GuntuluAk,SelmaMetintas,MuzafferMetintas,HuseyinYildirim,SinanErginel,FusunAlatas,Emel Kurt,OmerCadirci ESOGUMedicalFacultyDepartmentofChestDiseasesEskisehir,Turkey Keywords: mesothelioma;prognosis;survival Abstract: Objectives: Inthisstudyweaimedtoinvestigateaccordingtotreatmentschedulethefactorseffectedthe survivalofpatientswithmalignantpleuralmesothelioma(mpm). Methods: 235MPMpatientswhohaddiagnosedinourclinicbetweenJanuary1991andJune2008were evaluated.thepatientswereclassifiedintothreegroupsaccordingtotheirtreatmentschedule:the bestsupportivecaregroup(71patients),thechemotherapygroup(147patients)and,the multimodalitytherapygroup(17patients).prognosticfactorsweredetectedforallpatients,thebest supportivecaregroup,thechemotherapygroupandthemultimodalitytherapygroupbyunivariate/ multivariateanalyses. Results: Afterthecorrectionsweremadeaccordingtotherapy,non epithelialsubtype,karnofsky PerformanceStatus(KPS)70,stage3 4disease,rightsidetumor,serumLDH500IU1werefound asworseprognosticfactorsforallpatients.thenon epithelialsubtype,stage3 4disease,KPS70 werefoundasworseprognosticfactorsforthebestsupportivecaregroup.theworseprognostic factorforthechemotherapygroupwasonlykps70.histologicsubtypeandstagewerenotrelated toprognosis.thenon epithelialsubtypeandrightsidetumorwerefoundasworseprognostic factorsforthemultimodalitytherapygroup. Conclusions: Thatisjustlikeexpected,thepatients,whohadepithelialsubtype,goodKPS,andearlystagetumor, hadbetterprognosis,eveniftheydonothaveanytreatment.chemotherapyshouldbegivento patientswiththebestperformancestatus,regardlesstheirhistologicsubtypeandstage.forthe patientswhohadmixedorsarcomatoussubtypemultimodalitytherapycannotbegoundermulti modaltherapy. 200

203 ABSTRACTS Number:175 Abstracttitle: InductionChemotherapyConsistingofPemetrexedplusCisplatinFollowedbyExtrapleural PneumonectomyforMalignantPleuralMesothelioma KazuyaFukuoka(1),KozoKuribayashi(1),TakayukiTerada(1),TakashiNakano(1),SeikiHasegawa(2), FumihiroTanaka(2),TohruTsujimura(3),NoriakiTsubota(2) (1)DepartmentofRespiratoryMedicine,HyogoCollegeofMedicine,Japan;(2)Departmentof ThoracicSurgery,HyogoCollegeofMedicine,Japan;(3)DepartmentofMolecularPathology,Hyogo CollegeofMedicine,Japan; Keywords: Inductionchemotherapy,pemetrexed,apoptosis Abstract: Background:Malignantpleuralmesothelioma(MPM)isanunfavorableintractabletumorcausedby asbestosexposure.aslocaltreatment,suchassurgicalresectionorradiotherapy,isoflimited efficacy,establishmentofmultimodalitytreatmentincludingsystemicchemotherapy,playsan importantroleinimprovementoftreatmentoutcome.inthisstudy,weretrospectivelyevaluatethe efficacyandsafetyofinductionchemotherapyconsistingofpemetrexed(pem)pluscisplatin(cis) followedbyextrapleuralpneumonectomy(epp). Results:Between01/2005and12/2007,inductionchemotherapywasadministeredto13patients, allofthemunderwentepp.ofthe13patients,8patientsreceivedthecombinationchemotherapy withpempluscis.characteristicsofthese8patientsareasfollows;patients(7malesand1female) wereaged49to71(mean63)years.sevenpatientshadapsof0/1,andonepatientapsof2.all patientshadepithelioidhistology.fourpatientshadstageidisease,onepatientstageii,onepatient stageiii,and2patientsstageiv(t4).threecyclesofinductionchemotherapywereadministeredin allpatients.overallresponseratewas37%,with3partialresponses.astablediseasewasobserved in5patients,withanoveralldiseasecontrolrateof100%.toxicitywasmildwithgrade3/4 neutropeniainonepatient,andnograde3/4nonhematologicaltoxicitywasobserved.histological examinationsofresectedspecimensrevealedthatapoptosiswasinducedinsometumortissues, althoughpathologicalcompleteresponsewasnotachieved. Conclusion:InductionchemotherapyconsistingofPemplusCiswaswelltoleratedagainstthe patientswithmpm,underwentepp.aprospectivemultiinstitutionalstudyisnowongoinginjapan toevaluatethefeasibilityofinductionchemotherapyconsistingofpempluscis,followedbyeppand postoperativehemithoracicradiationinpatientswithpotentiallyrespectablempm. 201

204 ABSTRACTS Number:176 Abstracttitle: MALIGNANTMESOTHELIOMAOFTHEPLEURAINTHEPROVINCEOFTRIESTE,ITALY, ClaudioBianchi,TommasoBianchi,MauroTommasi., CenterfortheStudyofEnvironmentalCancerandThoracicSurgeryUnit,Monfalcone,Italy Keywords: pleura,asbestosexposure,triesteprovince,shipbuilding,portactivity,maritimetrades,domestic exposure,latencyperiod Abstract: Background.TheProvinceofTriesteisasmallcoastaldistrict,locatedinNorthEasternItaly,witha populationofabout240,000inhabitants.studiesconductedsince1971showedaveryhighincidence ofasbestosrelatedmesotheliomaofthepleurainthisarea.objectives.thepresentstudywas carriedouttoobtaindataonthetrendofmesotheliomaepidemicintheprovinceoftrieste,during thelastsevenyears,aswellastocharacterizethecasesintermsofasbestosexposure.methods. PleuralmesotheliomasdiagnosedattheThoracicSurgeryUnitoftheTriesteUniversity,intheperiod Jan2001Dec2007,werereviewed.Thehistologicaldiagnosiswasgenerallybasedonmaterial obtainedatthoracoscopyandatsurgery.inthreecasesthepathologicaldiagnosiswasmadeby biopsyofthethoracicwall,andinonecasebycytologicalexaminationofpleuralfluid.necropsywas carriedoutin54cases.detailedoccupationalhistorieswereobtainedfromthepatientsthemselves atthetimeoftheirfirstadmission.results.thegroupincluded124menand12women,aged between43and89years(mean69.2years,median69.0).amajorityofpatientshadbeenemployed inmarinework,includingshipbuilding(67cases),portactivity(17cases),andmaritimetrades(10 cases).sixteenpeoplehadworkedinotherindustries(ironindustry,petrochemical,etc.).afurther 16patientshadbeenemployedinavarietyofoccupations(cinemaprojectionist,firefighter,lift mechanic,pastryworker,telephonetechnician,etc.).threemenhadworkedasinsulators.seven womenhadhistoriesofexposuretoasbestosathome,havingcleanedworkclothespollutedby asbestos.amajorityofpatientshadtheirfirstexposuretoasbestosbefore1960.latencyperiods (timeintervalselapsedbetweenfirstexposuretoasbestosanddiagnosisofmesothelioma)ranged from25to71years(mean48.7,median48.0).onepatienthadahistoryofpriorthoracicirradiation forhodgkin sdisease.conclusions.intheprovinceoftriestethemesotheliomaepidemicdoesnot showsignsofabatement.marinework,andinparticularshipbuilding,remaintheprincipalcauseof pleuralmesotheliomainthisarea.however,avarietyofotheroccupationsarealsoassociatedwith thetumor. 202

205 ABSTRACTS Number:177 Abstracttitle: Geographyofmesothelioma.Reliabledata? ClaudioBianchi,TommasoBianchi CenterfortheStudyofEnvironmentalCancer,Monfalcone,Italy Keywords: mesothelioma,geography,asbestosexposure,incidence,mortality,diagnosis,registration,necropy Abstractcontent: Background.Adramaticincreaseinmesotheliomaincidencehasbeenobservedinmany industrializedcountriesduringthelastdecades[bianchic,bianchit.indhealth2007;45:379387]. Arelationshipbetweenmesotheliomaincidenceatanationallevelandpreviousconsumptionof asbestoshasbeendetectedinseveralstudies.sinceinalargepartoftheworldexposuretoasbestos continues,itwouldbeopportunethatreliableepidemiologicaldataonmesotheliomawereavailable. Methods.Inthepresentstudywereviewedthedatareportedonmesotheliomaepidemiologyin ,aswellasthoseobtainedatourCenter,byinterviewingresearchersofnumerouscountries. Results.Dataareavailableforabout15%onlyoftheworldpopulation.Threegroupsofcountries maybeidentified.thefirstgroupwithestimatedannualcrudeincidenceratesof30casespermillion ormoreincludesaustralia,belgium,andgreatbritain.thesecondgroupwithratescomprised between11and23permillionincludesalargepartofeurope(france,germany,italy,scandinavian countries,thenetherlands),newzealand,andus.rateslowerthan11permillionhavebeen reportedforothercountries,includingjapan(7permillion).verymarkedvariationsinthe incidence/mortalityfromoneareatoanotherareobservedinvariouscountries(e.g.croatia,italy, Sweden,TheNetherlands,GreatBritain). Comments.1)ThelackofdataforenormouscountriessuchasChina,India,andRussiarepresentsa seriousobstacleintheknowledgeonmesotheliomageography.2)themarkeddifferencesin incidencebetweensomehighlyindustrializedcountriessuchasaustraliaandgreatbritain,andother countriessuchjapanandus,areinsomewayunexpected.3)theverylowincidenceof mesotheliomainsomeeuropeancountriessuchasgreeceandinlargeportareassuchashongkong andsingaporeissurprising.4)doubtsonthereliabilityoftheavailabledataaresuggestedbyvarious elements:a)majordifficultiesareoftenencounteredinthediagnosisaswellasintheregistrationof mesothelioma;b)inpracticethepercentageofnecropsiesisverylow;c)inmanycountries mesotheliomaepidemiologyislargelyorexclusivelybasedonmortalitydata. 203

206 ABSTRACTS Number:178 Abstracttitle: Clinicalinvestigationofmalignantpleuralmesothelioma:anationwidesurveyof502deathcasesin Japan KenichiGemba(1),NobukazuFujimoto(1),KatsuyaKato(2),KeisukeAoe(3),KoukiInai(4),Takumi Kishimoto(1) (1)OkayamaRosaiHospital,Japan;(2)OkayamaUniversityHospital,Japan;(3)NHOSanyoHospital, Japan;(4)HiroshimaUniversityGraduatedSchool,Japan Keywords: asbestos,epp,systemicchemotherapy Abstract: Background:Clinicalfeaturesofmalignantmesothelioma(MM)havenotbeenfullyinvestigatedin Japan.ThisstudyisanationwidesurveyofMMcasesselectedonVitalStatisticsofJapan.Methods: Therewere2742deathcasesofMMbetween2003and2005,ontheVitalStatistics.Weexamined clinicalfeaturesincludingdiagnosticprocedure,treatmentoutcome,oroccupationalasbestos exposureinmalignantpleuralmesothelioma(mpm)cases,basedoninformedconsentsfromtheir familymembers.results:weselected502mpmcaseswithconfirmedpathologicaldiagnosis(m/f: 418/84,meanageatdiagnosis:67yearold),inwhichthemedicalinformationwasavailable. Histologicalsubtypeswereepithelioidin190,sarcomatoidin95,biphasicin65,andothersin4cases. Asadiagnosticprocedure,thoracoscopy,percutaneousneedlebiopsy,andthoracotomywere performedin155,152,and98cases,respectively.sixtythreecaseswerediagnosedwithcytological examinationofpleuralfluidand14wereatautopsy.tnmstaging(imig)wasstageioriiin104,iiiin 152,andIVin114cases.Curativeresectionwasperformedin94casesand179casesundergone systemicchemotherapy.mediansurvivaltimefromdiagnosiswas7.8months.logranktestrevealed thatpatientslessthan70yearold,withnosymptomsatdiagnosis,stageioriidisease,orwho undergoneextrapleuralpneumonectomy(epp)orplatinumbasedsystemicchemotherapy(pbsc), hadapreferableoutcome.coxregressionmultivariateanalysisindicatedthatnosymptomsat diagnosis,stageioriidisease,orbeingundergoneepporpbscasapreferableprognosticfactors. Conclusion:TheusefulnessofEPPorPBSCwasindicated,buttheprognosisofMPMisextremely poor.developmentofearlydiagnostictoolsorestablishmentofadvancedtreatmentstrategyis urgentlyneeded. 204

207 ABSTRACTS Number:179 Abstracttitle: Immunohistochemistryindistinguishingmalignantmesotheliomafromlungadenocarcinoma: comparisonofnewmesothelialandlungadenocarcinomamarkersandconventionalmarkersin malignantmesothelioma YasufumiKato,NaobumiTochigi,AkikoMiyagiMaeshima,ShunichiWatanabe,HisaoAsamura,Koji Tsuta NationalCancerCenterHospital,Tokyo,Japan Keywords: TTF1,NapsinA,Calretinin,malignantpleuralmesothelioma,lungadenocarcinoma Abstract: Aim:Distinctionbetweenprimarylungadenocarcinomaandmalignantpleuralmesotheliomacanbe amajorchallenge.thepresentstudyanalyzedtheutilityofnewmarkers(podoplanin,monoclonal Calretinin,newTTF1 scloneofspt24,andnapsina)fordifferentialdiagnosisofmalignantpleural mesothelioma(mpm)andcomparedthemwiththeconventionalpositiveandnegativempm markers. Materials:Thematerialsforthepresentstudywereextractedfromcasesdepositedinthepathology filesofthenationalcancercenterhospital,tokyo,between1971and2005.thisstudywas composedof48casesofmpmand40casesofprimaryadenocarcinomaofthelung. Methods:Theantibodiesusedinthisstudywerecalretinin(polyclonalandDAKCalret1),Podoplanin (D240),WT1(6FH2),surfactantapoproteinA(PE10),thyroidtranscriptionfactor1(8G7G3/1and SPT24),andNapsinA(TMUAd02).Immunohistochemicalstainingwasscoredindependentlybytwo observers(y.k.andk.t). Results:ThepositiveimmunostainingrateofpolyclonalcalretininandDAKCalret1wereboth93.8% inmpms,whereastherateswereonly40%and32.5%inadenocarcinomasofthelung,respectively. ImmunostainingbyPodoplaninwasobservedin87.5%ofMPMs,whereasinonly2.5%ofthe adenocarcinomas.immunostainingbywt1wasobservedin75%ofmpm,butin0%ofthe adenocarcinomas. Immunostainingforthenegativemarkers,SPAandNapsinAwereobservedin0%ofMPMs,butin 47.5%and95%oftheadenocarcinomas,respectively.ImmunostainingbySPT24and8G7G3/1were observedin92.5%and87.5%oftheadenocarcinomas,respectively.howevernoimmunostaining whateverwasobservedinanympmswithspt24and8g7g3/1. Conclusion:Thepresentstudyrevealedthatmostsensitivemesothelialmarkeriscalretinin(DAK Calret1),andthemostspecificmarkerisWT1.Alllungadenocarcinomamarkerswerenegativefor MPM.ThemostsensitivemarkerforadenocarcinomawasNapsinA. 205

208 ABSTRACTS Number:180 Abstracttitle: Caveolin1isanovelimmunohistochemicalmarkerofmalignantmesotheliomaanddifferentiates epithelioidmesotheliomafromlungadenocarcinoma. VishwaJeetAmatya,YukioTakeshima,HidekazuKohno,KeiKushitani,TaketoYamada,Chikao Morimoto,KoukiInai.DepartmentofPathology,KeioUniversity,DivisionofClinicalImmunology, UniversityofTokyoand DeptofPathology,HiroshimaUniversity,Japan Keywords: caveolin1;immunohistochemistry;mesothelioma;lungadenocarcinoma Abstract: Theincidenceofmesotheliomaisincreasing,andsurgicalpathologistsaremoreandmorefrequently facingwiththediagnosticproblemindistinguishingepithelioidmesotheliomafromlung adenocarcinomainvolvingpleura.theuseofimmunohistochemicalpanelthatshouldincludeboth positiveandnegativemesothelialmarkersisbecomingageneralrule.however,the immunohistochemicalprofileofthetumorinallcasesisnotalwaysdefinitive,leadingthecontinual searchfornewpositivemesothelialmarkers.caveolin1,whichisexpressedinendothelialcells, alveolartypeipneumocytes,andmesothelialcells,seemstobeoneofsuchnovelmarkers.we analyzedtheexpressionofcaveolin1in130casesofmalignantmesothelioma,including80casesof epithelioidmesothelioma,30casesofsarcomatoidmesotheliomaand20casesofbiphasic mesothelioma.wefoundcaveolin1expressioninallcasesexceptone.sixtythreecasesshowed caveolin1expressioninmorethan50%oftumorcells,55caseswith550%oftumorcellsand12 caseswithlessthan5%.thecaveolin1expressionwasalsoidentifiedinnonneoplasticmesothelial cells,fromflattenedmesothelialcelltoreactivemesothelialcells.wealsostudiedexpressionof caveolin1expressionin80casesoflungadenocarcinoma.only6cases(7.5%)oflung adenocarcinomashowedweakornegligibleexpressionandnomorethan1%oftumorcells.we foundthatthesensitivityandspecificityofcaveolin1expressionfordifferentiatingepithelioid mesotheliomafromlungadenocarcinomawascomparableorevensuperiortothatofcurrently availablepositivemarkers.theinclusionofthisnovelmarkerofmesotheliomainthe immunohistochemicalpanelusedforthedifferentiationofepithelioidmesotheliomafromlung adenocarcinomaishighlyrecommended. 206

209 ABSTRACTS Number:181 Abstracttitle: IMPACTOFOESTROGENRECEPTORBETAONPROGNOSISOFHUMANMALIGNANTPLEURAL MESOTHELIOMA GiuliaPinton(1),ElisaBrunelli(1),BrunoMurer(2),RiccardoPuntoni(3),MatteoPuntoni(4),Giovanni Gaudino(1),LucianoMutti(3,5),LauraMoro(1) (1)DiscaffUniversityofPiemonteOrientale,NovaraItaly;(2)DepartmentofAnatomicPathology, MestreItaly;(3)GIMEItaly;(4)MedicalOncologyUnit,GallieraHospital,GenoaItaly;(5)S.Pietroe PaoloHospital,BorgosesiaItaly Keywords: Oestrogenreceptorbeta,malignantpleuralmesothelioma,genderdifference,survival Abstract: MalignantPleuralMesothelioma(MMe)isanasbestosrelatedneoplasmwithpoorprognosis, refractorytocurrenttherapies,whoseincidenceisexpectedtoraiseinthenextdecades.female genderwasidentifiedasapositiveprognosticfactoramongotherclinicalandbiologicalprognostic markersformme,yetaroleofoestrogenreceptors(ers)hasnotbeenstudied.ourgoalwasto investigateersexpressioninmmeandtoassesswhethertheirexpressioncorrelateswithprognosis. ImmunohistochemicalanalysisrevealedintensenuclearERstaininginnormalpleurathatwas reducedintumourtissues.conversely,neithertumours,nornormalpleurastainedpositiveforer. Multivariateanalysisof78MMepatientswithpathologicalstage,histologicaltype,therapy,sexand ageatdiagnosis,indicatedthaterexpressionisanindependentprognosticfactorofbettersurvival. Moreover,studiesinvitroconfirmedthattreatmentwith17oestradiolledtoanERmediated inhibitionofmmecellproliferationaswellasp21cip1andp27kip1upregulation.consistentlycell growthwassuppressedbyeroverexpression,causingag2/mphasecellcyclearrest,paralleledby cyclind1andsurvivindownregulation.ourdatasupportthenotionoferactingasatumour suppressor,andarepotentiallyrelevanttopredictionofdiseaseprogressionandtotherapeutic responseofmmepatients. 207

210 ABSTRACTS Number:182 Abstracttitle: Mesotheliomapreventionbyanantioxidantfoodsupportsaninvolvementofreactiveoxygenspecies inasbestoscarcinogenesis ShuichiAdachi(1),MihoMizoi(2),KenKawamura(3),KazuakiKawai(4),HiroshiKasai(4),Kazuro Iwai(5) (1)DeptPublicHealth,SagamiWomen'sUniversity,Japan;(2)ResearchCenterforPreventionof AsbestosHazards,SagamiWomen'sUniversity,Japan;(3)DeptPublicHealth,KagawaNutrition University,Japan;(4)OccupationalOncology,UniversityOccupationalEnvironHealth,Japan; (5)ResearchCenterforPreventionofAsbestosHazards,SagamiWomen'sUniversity,Japan Keywords: prevention,boysenberry,antioxidant,8ohdg,rat Abstract: Ithasbeenwellrecognizedthatthedietaryhabitsaffecttheincidenceofmalignantneoplasms, exceptmesothelioma.theaimofthestudywastoinvestigatethepossibilitytolowertheriskof asbestosinducedmesotheliomabyingestionofboysenberrywhichisknownasthehighcontentsof antioxidantsandotherprotectivesubstances.femalef344ratsweredividedintothe6groups(n=20 each):asbestosi.p.+standarddiet(as);asbestosi.p.+2%boysenberrydiet(a2b);asbestosi.p.+1% Boysenberrydiet(A1B);asbestosi.p.+5%beeffatdiet(ABF);salinei.p.+2%Boysenberrydiet(S2B); salinei.p.+5%beeffatdiet(sbf)andsalinei.p.+standarddiet(ss).afteri.p.administrationof chrysotileasbestos(2mg/mlinsaline,10mg/rat),ratswerefollowedfor2years.thefirstcaseof mesotheliomawasdissectedatday211intheabf,atday239intheas,atday248inthe248inthe A1Bandatday292intheA2B.Nomesotheliomawasdevelopedinratsadministeredsalineinstead ofchrysotileintheexperimentalperiod.overthe2years,survivalrateofa2bwassignificantly extendedincomparisonwiththecontrol(aa).incontrast,survivalrateofabfwastheworstinall groupswithastatisticalsignificancevs.a2b.twopercentboysenberrydietcorrespondedtoa humandailyintakeof160gofboysenberryjuice.thisresultsupportsthehypothesisthatnaturally occurringantioxidantsandotherprotectivesubstancesinboysenberrycandelayandreducetherisk todevelopasbestosinducedmesothelioma.inadditiontothispreventiveeffect,serum8ohgua andurinary8ohdgsupportthattheasbestoscarcinogenesisinvolvesreactiveoxygenspeciesand itsderivedoxidativednadamage. 208

211 ABSTRACTS Number:183 Abstracttitle: ASBESTOSINDUCEDMURINEMESOTHELIOMAINDIFFERENTGENETICBACKGROUND AnnieRenier(1),JocelyneFleuryFieth(1),CélineLecomte(2),AudreySaintAlbin(1),Laurence Kheuang(3),AnneJanin(4),MarcoGiovannini(1),MarieClaudeJaurand(2) (1)INSERMU674,CEPHIUHIFR105,Paris,F75010,France;(2)UPRESEA3222,LEHAVRE,F76058, France;(3)INSERMU841,UniversitéParis12,FacultédeMédecine,IFR10,Créteil,F94000,France; (4)INSERMU728,Paris,F75010,France Keywords: Asbestosmesothelioma,tumorsuppressorgenes Abstract: Tobetterunderstandtheroleoftumorsuppressorgenes(TSGs)inmalignantmesothelioma(MM) wehavedevelopedmodelsofmm.survivalandmmcharacteristicswerestudiedin3groups(204 mice)offvb/nmutantmiceinjectedintraperitoneallywith5mgofcrocidolitefibres(crmice)or salinectrlmice),in3independantstudies.therewere25nf2+//p16+/mice,67nf2+/and53wt Crmice,and8,27and24Ctrlmicerespectively.Miceweresacrificedwhensignsofillnesswere detected.geneticanalyseswereperformedonearlyculturesof22tumourascitesfrom7nf2+/ /P16+/mice,11Nf2+/and4WTmice. Survivalofallmice,postinjection,wassignificantlydifferentbetweenthe3groups(p=0.0033),with thenf2+//p16+/micehavingtheshortersurvival.survivalofcrmicewasshorterthanthatofctrl miceinallgroups((p=0.0126,0.0001and0.0001innf2+//p16+/,nf2+/andwt)butnotdifferent betweengroupsofcrmice.mmwasobservedin25%,38.2%and15.7%ofcrnf2+//p16+/,cr Nf2+/andCrWTmicerespectively(p=0.02).TwoMMwereobservedinCtrlNf2+//P16+/mice. Nosignificantdifferencewasfoundinthedelayoftumouroccurrencebetweenthe3groupsofCro mice(p=0.16).the3mainsubtypesofmmwereobservedwithasimilardistributioninthe3groups ofcrmice(p=0.55).sarcomatoidformwaspredominant.therewasalinkbetweenascitesformation andmmoccurrenceinallgroups.genomicanalysesshowednf2lohinallbutoneofbothnf2+/ /P16+/andCrNf2+/culturesfromtumourascites.Trp53wasmutatedin1CrNf2+//P16+/,1Cr Nf2+/and1CrWT.Incontrast,genesattheINK4locuswereinactivatedinmostcellculturesfrom CrNf2+/andCrWTmice,althoughlessinCrNf2+//P16+/cultures(3outof7). InterestinglytherewereexclusivemutationbetweenTrp53andthesegenes. Inconclusion,mutationsaffectingtheTSGsNf2andP16increasethefrequencyofMM,butdonot alterthepathologicalfeaturesofcrocidoliteinducedmmobservedwtmice,andmimicshuman MM.ThegenomicsimilaritiesbetweenhumanandmurineMMunderlinetheroleoftheseTSGsin asbestosinducedmm. 209

212 ABSTRACTS Number:184 Abstracttitle: C.elegansasamodelsystemtoevaluategeneticalterationsinMPM,andthegeneticenvironmental interactions/effectsofasbestos SIVAKUMARLOGANATHAN,ShahidSiddiqui,HedyKindler,RaviSalgia UniversityofChicago,USA Keywords: C.eleganstransgenics,cMetreceptortyrosinekinase,juxtamembranedomainmutations,asbestos exposure Abstract: TherearealargenumberofgeneticabnormalitiesthatoccurinMPM.Wehaverecentlyshownthat themetreceptortyrosinekinaseisoverexpressed,sometimesmutatedand/oramplifiedinmpm tumortissuesandcelllines.inordertotestthefunctionalityofkinases,suchasmet,wehave developeda highthroughput systeminthemulticellularmicroscopicorganismc.elegans. Chrysotilehasbeenusedmorethananyothertypeandaccountsforabout95%oftheasbestos foundinbuildingsintheus.first,wehaveexaminedthetoxiceffectofthisfiberincontrol(n2)c. elegans.c.eleganswasculturedinm9mediumfor2weekswithorwithoutchrysotilefibers (asbestos),afterwhichsurvivalandratesofdevelopmentaldefectswereestimated.chrysotile reducedsurvivalandinducedlocomotiondefects(asmeasuredbytimelapsevideomicroscopy).to examinetheeffectofhumanmetgeneexpressioninc.elegans,cdnaconstructsofhumanmet withthemammaliancmvpromoterweremicroinjectedintothegonadsyncytium.wildtypemet cdnaandmutantmet(t1010i,juxtamembranedomain)cdnawereinjected.controlanimals(n2) wereinjectedwithvectoralone.progenieswereisolatedandexaminedforvisiblemorphological abnormalitiessuchasdefectsinvulvalformation,bodymorphologyandlocomotion.individually clonedtransgenicanimalswerefurtheranalyzedforfecundityandviability.expressionofhuman wildtypemetcdnainc.eleganstransgenicanimalsinduceddevelopmentalabnormalitiessuchas vulvadefects,uncoordinatedlocomotion,andeffectsonviabilityoftheprogeny.arangeof abnormalitiesinvulvaldevelopmentwereobserved,suchasvulvaless,multivulva,protrudingvulva, andectopicvulvalphenotypes.inordertoconfirmthattransgenicanimalswithabnormal phenotypesexpressedthehumanmetgene,metexpressionwasexaminedattheproteinlevelby immunoblottingwholeanimalproteinextractsagainstantibodiesspecifictohumanmetprotein.an increaseindevelopmentaldefects(vulva)wasobservedint1010imutantmettransgenicanimals whencomparedtowildtypemetandn2control(p<0.0001).currently,ourstudiesonthevarious mutantsofmetandtheeffectsofasbestosareongoing.ultimately,thiswillserveasanew paradigmforhighthroughputanalysisofanygene(withorwithoutmutations)andinteractionswith theenvironment(asbestos)inamulticellularorganism. 210

213 ABSTRACTS Number:185 Abstracttitle: Identificationofgenesrelevantforthedevelopmentofmurinemalignantmesothelioma ErwinvanMontfort,JohanJongsma,JohnZevenhoven,JosJonkers,AntonBerns NetherlandsCancerInstitute,Amsterdam,theNetherlands Keywords: Mousemodel,arrayCGH,expressionarray Abstract: Littleisknownaboutthegeneticlesionscontributingtothedevelopmentofmalignant mesothelioma.inasubsetoftumorsinman,inactivationoftumorsuppressorgenessuchasthe neurofibromatosistype2gene(nf2),ink4aandtp53hasbeenreported.werecentlypublisheda mousemodelformalignantmesotheliomausingconditionalknockoutmouse(1).mesothelioma developedathighincidenceinnf2;ink4a/arfandnf2;p53conditionalknockoutmiceandthetumors closelymimickedhumanmalignantmesothelioma.uponfunctionalink4alossinthelattermice, survivalwassignificantlyreducedandalltumorswerehighlyinvasive. Weanalyzedthesemurinemesothelioma switharraycghtoidentifygenesthatcontributetotumor progressioninthismodel.conditionalnf2;p53mesotheliomasrevealedmultiplerecurring chromosomalgainsandlosses,themostcommonaberrationbeinggainofchromosome15.afew small,highlevelamplificationspointtotheinvolvementofcmycencmetinthedevelopmentof thesetumors.arraycghanalysisofthemesotheliomasinthenf2;ink4a/arfandnf2;p53;ink4amice showedamorestablegenomeinthesetumorswithfewergeneticaberrations. Wearecurrentlyanalyzingarepresentativesubsetofthesetumorswithexpressionarrays,tofurther investigategenesthatarerelevantfortumordevelopmentinthismodel. (1)JongsmaJ,vanMontfortE,VooijsM,ZevenhovenJ,KrimpenfortP,vanderValkM,vandeVijver M,BernsA.(2008)AConditionalMouseModelforMalignantMesothelioma.CancerCell.2008 March;13(3):

214 ABSTRACTS Number:186 Abstracttitle: DietaryvitaminAorEsupplementationdoesnotaltertherateofdevelopmentofasbestosinduced tumorsinanacceleratedmodelofmesothelioma CleoRobinsonAnnaK.NowakRichardA.Lake TumourImmunologyGroup,NationalResearchCentreforAsbestosRelatedDiseases,Universityof WesternAustralia Abstract: Epidemiologicalstudiessuggestthatdietaryintakeof carotenecanreducetheriskoflung cancer.thefindingofaninverserelationshipbetweenserum carotenelevelsandriskof lungcancerstrengthenedthevalidityoftheobservation.vitaminaandotherretinoidshavebeen testedinclinicaltrials,andalltransretinoicacidisnowanacceptedtreatmentforacute promyelocyticleukemia.similarly,vitaminehasbeenscrutinizedforitspotentialtoreducetherisk ofdeveloping cancerandinonestudy, tocopherylsuccinate,asemisyntheticvitamineanalogue increasedsurvival>3foldcomparedtountreatedanimalsinanexperimentalmodelofperitoneal mesothelioma.theresultsfrominterventionstudies,however,havebeenmuchlessconvincing. Alfonsoandcolleaguesrecentlyreportedthattherewerenosignificantassociationsbetween caroteneorvitamineconcentrationsandincidenceofmesotheliomainacohortofatriskindividuals inwesternaustralia.here,weconfirmthesefindingsinatransgenicanimalmodelofmesothelioma inwhichsv40expressionisdirectedtothemesothelialcompartment.untreatedanimalsremain diseasefree,butinoculationofasbestosleadstoacceleratedtumourdevelopmentwithamedian survivalof32weeks.animalsfedvitaminsupplementeddietshadidenticalsurvival,demonstrating thatdietaryvitaminaoresupplementationdoesnotaltertherateofdevelopmentofasbestos inducedtumors. 212

215 ABSTRACTS Number:187 Abstracttitle: AdenovirusmediatedNK4genetherapyformalignantmesothelioma LiXiao,JosephTesta,GuangHuiXiao FoxChaseCancerCenter,Philadelphia,Pennsylvania,USA Abstract: Malignantmesothelioma(MM)isahighlyinvasiveandmetastaticmalignancy.Despitediverse therapeuticapproachessuchassurgery,radiotherapyorchemotherapy,mmcontinuetohaveavery poorprognosis.thus,newtherapeuticmodalitiesareurgentlyneededforpatientswithmm. Hepatocytegrowthfactor(HGF)anditsreceptorMetplayacriticalroleinthepathogenesisofMM, andtargetinghgf/metsignalingcouldbetherapeuticallyimportant.nk4,ahgfantagonistand angiogenesisinhibitor,composesthenterminalhairpindomainandfourkringledomainsofthe chainofhgf.thetherapeuticpotentialofnk4hasbeendemonstratedinothertumor types.inthisstudy,wegeneratedanadenovirusmediatednk4deliveringsystemfortargeted therapyagainsthgf/metinmm.ourresultsshowedthatnk4significantlyinhibitedmmcellgrowth inculturedishes.nk4alsomarkedlyreducedthenumberofmmcellsthatinvadedthroughmatrigel, anddecreasedtherateofcellmigrationinwoundhealingassays.furthermore,ourpilotexperiments showedthatmmcellsinfectedwithnk4adenovirusdevelopedtumorsmuchslowerthanmmcells infectedwithcontroladenovirusdidinmice.theseresultssuggestthatmoleculartargetingof HGF/MetbyNK4couldbeaneffectivetherapeuticapproachforpatientswithMM. 213

216 ABSTRACTS Number:188 Abstracttitle: MeaslesVirusInducesOncolysisofMesotheliomaCellsandAllowsDendriticCellstoCrossPrime TumorSpecificCD8Response AnneGauvrit,SamanthaBrandlern(1),CaroleSapedePeroz,NicolasBoisgerault,FrédéricTangy(1), MarcGregoire INSERM,(1)InstitutPasteur, Keywords: Mesotheliomameaslesvirusvirotherapycancervaccine Abstractcontent: Despiteconventionalmedicalandsurgicaltreatments,malignantpleuralmesothelioma(MPM) remainsincurable.oncovirotherapy(i.e.,theuseofreplicationcompetentvirusforcancer treatment)iscurrentlyexploredinclinicaltrials.inthisstudy,weinvestigatedtheantineoplastic potentialofanewoncolyticviralagent,aliveattenuatedmeaslesvirus(mv)strainderivedfromthe Edmonstonvaccinelineage(Schwarzstrain).Weevaluatedbothoncolyticactivityand immunoadjuvantpropertiesofthemvvaccinestrainonmesotheliomatumorcells.infectivity, syncytiumformation,andcytolyticactivityofmvwerestudiedonapanelofmesotheliomacells derivedfrompleuraleffusionsofmpmpatients.weobservedthatmvinfectedpreferentiallympm celllinesincomparisonwithnontransformedmesothelialcells,leadingtoanefficientkillingofa significantfractionoftumorcells.acytoreductiveactivitywasalsoevidencedthroughformationof multinuclearcellularaggregates(syncytia).thesusceptibilityofmpmcelllinestomeaslesinfection wasassessedbytheanalysisofcellsurfaceexpressionofthemvvaccinereceptor(cd46).wealso evaluatedwhethermvinfectionofmesotheliomacellscouldelicitanautologousantitumorimmune response.weshowedthatmvschwarzstraininducedapoptoticcelldeathofinfectedmesothelioma cells,whichwereefficientlyphagocytosedbydendriticcells(dc).loadingofdcswithmvinfected MPMcellsinducedDCspontaneousmaturation,asevidencedbytheincreasedexpressionofMHC andcostimulatorymoleculesalongwiththeproductionofproinflammatorycytokines.primingof autologoustcellsbydcsloadedwithmvinfectedmpmcellsledtoasignificantproliferationof tumorspecificcd8tcells.altogether,thesedatastronglysupportthepotentialofoncolyticmvas anefficienttherapeuticagentformesotheliomacancer. 214

217 ABSTRACTS Number:189 Abstracttitle: Chemoimmunotherapyinmesothelioma AnnaNowak,SathishMahendran,RobbertvanderMost,RichardLake UniversityofWesternAustralia Keywords: cisplatin,pemetrexed,immunotherapy,murine,cd40 Abstract: Wepreviouslydemonstratedsynergybetweengemcitabineandimmunotherapyinsmallsyngeneic murinemesotheliomatumors.sincethen,cisplatinandpemetrexedhasbecometheclinicalstandard ofcareinmesothelioma.weaimedtoinvestigatecombinationsofcisplatinandpemetrexedwith immunotherapy.themurinemesotheliomacelllineab1hawasgeneratedthroughperitoneal asbestosinoculationandtransfectedwiththehemagglutinin(ha)neoantigentoallowanalysisof antigenspecificantitumorresponsesusingcd4+orcd8+lymphocytesfromhaspecifictcr transgenicmice.invitrogrowthinhibitionwasassessedbymttassays.invivotumorgrowthwas assessedusingasubcutaneousflankmodelinathymicnudeandwildtype(wt)balb/cmice. Chemotherapywasgiveni.p.atthepreviouslydeterminedMTD.FGK45(activatingantiCD40 antibody)wasgiven3timesi.v.starting2daysaftertheendofchemotherapy.ab1hawas approximately5foldmoresensitivetogemcitabinethanpemetrexedinvitro.invivoinathymic nudemice,gemcitabinedecreasedtumoroutgrowthascomparedwithuntreatedcontrolmice(p <0.001)butcisplatinandpemetrexeddidnot(p=NS).However,inwtmice,bothgemcitabine (p<0.001)andcisplatinandpemetrexed(p=0.01)decreasedtumoroutgrowth,suggestingaroleof intactadaptivecellularimmunityintheobservedinvivoefficacyofcisplatinandpemetrexed.the adoptivetransferofhaspecificcd8+tcellsrestoredthewtphenotypeofathymicnudemice treatedwithchemotherapy.nolongtermsurvivalwasobservedwithchemotherapyalone.despite modestinvivoefficacyofchemotherapyalone,thecombinationofcisplatin,pemetrexed,andcd40 ligationwithfgk45resultedinlongtermsurvivalandresistancetorechallengein40%ofmicewith largeestablishedtumorsatthestartofimmunotherapy(5x5mm).thiscontrastedwith0%long termsurvivalinmicetreatedwithgemcitabineandfgk45whenimmunotherapywasstartedatthe sametumoursize(5x5mm),althoughthiscombinationcuredsmallertumours(2x2mm).in conclusion,thisstudysupportsanimmunemodulatoryeffectofcisplatinandpemetrexedanda rationaleforcombinationstudiesofthisregimenwithcd40activatingimmunotherapyinhuman clinicaltrials. 215

218 ABSTRACTS Number:190 Abstracttitle: MalignantmesotheliomainJapaninrelationshiptoasbestosexposure TakumiKishimoto,KenichiGemba,NobukazuFujimoto,IkujiUsami StudyGroupofAsbestosrelatedDiseasesofRosaiHospitalsinJapan Keywords: occupationalasbestosexposure,diagnosis,therapy,survival Abstractcontent: TheclinicalfeaturesandtherapyofmalignantmesotheliomainJapanwereinvestigatedin relationshiptoasbestosexposure. (Materialandmethod)Retrospectivestudyofmalignantmesotheliomapatientsfrom2000to2007 treatedin27rosaihospitals,japanwasperformed.gender,ages,primarysites,diagnosticmotives, methodologicalproceduresfordiagnosis,histologicaltypes,clinicalstagesofimigclassification, therapyandprognosis,occupationalhistoriesandradiologicalfindingsofasbestosrelatedchanges wereexamined.thenumberofasbestosbodiesinthelungwasalsocounted. (Results) Total237caseswereexaminedand221werediagnosedofmalignant mesotheliomaandother16caseswerenotdiagnosedasmalignantmesothelioma.twohundredand twentyonepatientsconsistedof185maleand36femalewiththemedianageof67years.one hundredandeightyfouroriginatedfrompleuraand29fromperitoneum,4frompericardiumand2 fromtunicavaginalis.onehundredandthirtyfivepatientswerediagnosedbythechiefcomplaints andother27patientswerediagnosedbyregularhealthcheckupetc.onehundredninetyfive patientswerediagnosedbythehistologicalexaminationsand17patientswerebycytological examinations. Asforthehistology,112patientsexhibitedepithelioidtype,52forsarcomatoidtypeand30for biphasictype.accordingtotheclinicalstage,40patientswerestagei,13patientsstageii,64 patientsstageiiiand62patientswereclassifiedtostageiv. Fiftypatientsweredonebysurgery,99bychemotherapy,71patientsforbestsupportivetherapy. Overallsurvivalof221caseswas7.1monthsSurvivaltermforpleuralmesotheliomawasmedianof 7.5monthsandperitonealmesotheliomawas5.4months.Forpleuralmesothelioma,stageI+IIwere themedianof9.7monthssurvival,stageiiiwere9.4monthsandstageivwere5.2months. Eightyfourpercentof201patientshadoccupationalexposuretoasbestos.Thirtysevenpatientshad occupationalhistoriesofshipyardwork,22patientshadinconstructionworks,19patientswere insulators,andtheremainderswerealsoemployedintheasbestosrelatedworks.themedian durationofasbestosexposurewas30yearsandthemedianlatentperiodfromthefirstasbestos exposuretotheappearanceofmalignantmesotheliomawas43years. Fortheradiographicalfindingsofasbestosrelatedchanges,9patientsexhibitedasbestosis,106 pleuralplaques,2roundedatelectasisand6showeddiffusepleuralthickening.eightythreepercent of45patientshadmorethan1,000asbestosbodiesper1gofdrylungtissue. (Conclusion)MorethaneightypercentofmalignantmesotheliomainJapanwasinducedbythe occupationalexposuretoasbestos. 216

219 ABSTRACTS Number:191 Abstracttitle: TotalantioxidantcapacityinasbestosrelateddiseasesinpeopleexposedtocrocidoliteinWittenoom HelmanAlfonso,SimonChing,JonHall,JohnBeilby,AlisonReid,NicholasdeKlerk,BillMusk. VarianAustraliaPtyLtd,Belmont,WesternAustralia,SchoolPopulationHealth,UWAandDep ClinicalBiochemistry,UWA Keywords: antioxidant;vitamins;retinol;betacarotene;crocidolite;mesothelioma;lungcancer Abstract: Background Recentreportshaveshownincreasedmortalityrisksassociatedwithintakeofantioxidantvitamin supplements.asbestosrelateddiseases(ard)havebeenassociatedwithanincreaseofoxidative activity.vitaminahasbeensupplementedtopeoplepreviouslyexposedtocrocidoliteatwittenoom inanattempttopreventard. Methods: UsingplasmacollectedintheVitaminAProgramfromworkersexposedtocrocidoliteatWittenoom, wehavecomparedtaclevelsinthosewhosubsequentlydevelopedmesothelioma(n=63),orlung cancer(n=50)against200controlworkers.wehavealsoexaminedtherelationshipsbetweentac levelsandplasmalevelsofantioxidantvitaminspreviouslymeasuredintotheprogram. Results:Therewere3,107measurementsover11.7yearsoffollowup,onaverage.Afteradjustment forageandsmoking,plasmataclevelswerestatisticallysimilaramongcasesofmesotheliomaand lungcancer,comparedwithcontrols(p 0.13andp 0.85respectively).Therewasa significantincreaseofplasmataclevelsovertimeinthenondiseased(0.011units/year,p=0.05), whiletaclevelsinthemesotheliomaandlungcancergroupsshowednoanysignificanttrendover timepriortodevelopingdisease. Inamultivariateanalysis,apositiveassociationwasfoundbetweenplasmaTAClevelsandplasma retinollevels(p=0.08)andvitaminelevels(p<0.01).aninverseassociationbetweenbetacarotene andtacwasfound(p<0.01).thesignificanteffectofplasmaretinollevelsontacwaslostafter adjustmentforplasmatotalalbuminlevels(p=0.75). Conclusions: PlasmaTAClevelsmeasuredbyAIORmethodwasnotstatisticallyassociatedwiththedevelopment ofmesotheliomaorlungcancerinthisstudy.severalreasonsmayexplainthisfinding,includingthe lackofadjustmentfordietandotherlifestylefactors.thepositiveassociationbetweenretinoland vitamineandtaclevelsisinagreementwiththeirprotectiveassociationwithardandlungfunction previouslyobservedinthiscohort.thenegativeassociationbetweenbetacaroteneandtaclevels mayhelpexplainpreviousobservationsofdeleteriouseffectofbetacarotenesupplementation.this studysuggeststhatmeasuringtheoxidativecapacityofsupplementalvitaminsmayclarifytheir functionalroleinpreventingthesediseases. 217

220 ABSTRACTS Number:192 Abstracttitle: AsbestosFiberConcentrationinLungTissuesResectedforMalignantPleuralMesothelioma NoriyasuUsami(1),KiyoshiSakai(2),TetsuyaMizuno(1),NoriakiSakakura(1),NorihisaOohata(1), TetsuoTaniguchi(1),KoheiYokoi(1) (1)DivisionofThoracicSurgery,NagoyaUniversityGraduateSchoolofMedicine,Japan;(2)Nagoya CityPublicHealthResearchInstitute,Japan Keywords: Asbestosconcentration,Analyticalelectronmicroscopy Abstract: BackgroundAlthoughtheassociationbetweenasbestosexposureandthedevelopmentof malignantpleuralmesothelioma(mpm)iswellrecognized,therelationshipbetweenasbestos contentsbyfibertypeandthedevelopmentformpmremainsunclear. MethodsAsbestosfibercontentsinthelungtissuesandtumorwereanalyzedin4patientswith MPMbytransmissionelectronmicroscopywithenergydispersiveXrayanalysisusingalow temperatureashingprocedure.thegeometricmeancontentoftotalasbestos,crysotileand amphiboleasbestosinthecontrolsubjectswithoutasbestosexposurewereusedasreference,which was1.8,0.5and1.0(x106fibers/gdrylung),respectively.(reference:sakaiketal.asbestos ConcentrationandFiberSizeinLungsoftheUrbanResidents.JapaneseJournalofPublicHealth, 1991;38:762770) ResultsFourpatientswereanalyzedinthisstudy,whichwereCase1:50M,biphasictype, pt3n2m0,case2:54m,biphasictype,pt2n0m0,case3:56m,epithelialtype,pt4n0m0andcase4: 65M,epithelialtype,pT3N2M0.Allpatientshadahistoryofasbestosexposureandunderwentan extrapleuralpneumonectomywithcurativeintent.asbestosfiberswerenotdetectedinthetumor tissuesinall.thegeometricmeancontentoftotalasbestosinlungtissueswere1.8(x106fibers/g drylung),54.2,6.5and1.6inthecase1,2,3and4,whichratiosofcasetocontrolwere1.0,29.6,3.6 and0.9,respectively.ratiosofcasetocontrolofchrysotile scontentwere2.8,58.2,1.8and0.8,and thoseofamphiboleasbestoswere0.4,25.1,5.6and1.2inthecase1,2,3and4,respectively. ConclusionsCase1and4hadMPMwithouthighlevelexposureoftotalasbestos.Ontheother hand,case2and3showedhigherconcentrationoftotalasbestosfiberinthelungtissuesthan controlsubject,whichevidencedthehighlevelexposureofasbestos.thosetwopatientsalsohada largeproportionofamphiboleasbestos,whichmightbeassociatedwiththedevelopmentofmpm. Toelucidatetherelationbetweenthepulmonaryasbestosfibercontentsbyfibertypeand developmentofmpm,furtherinvestigationisconsiderednecessary. 218

221 ABSTRACTS Number:193 Abstracttitle: Clinicaloutcome,lungasbestosburden,anddiseasearepredictedbyepigeneticprofilesinpleural mesothelioma BrockChristensen(1),E.AndresHouseman(2),JohnGodleski(3),CarmenMarsit(1),Jennifer Longacker(4),HeatherNelson(5),JohnWiencke(6),RaphaelBueno(7),DavidSugarbaker(7),Karl Kelsey(1) (1)BrownUniversity,USA;(2)UniversityofMassachusettsLowell,USA;(3)HarvardSchoolofPublic Health,USA;(4)BostonUniversitySchoolofPublicHealth,USA;(5)UniversityofMinnesota,USA; (6)UniversityofCaliforniaSanFrancisco,USA;(7)BrighamandWomen'sHospitalandHarvard MedicalSchool,USA Keywords: Survival,prognosis,asbestosburden,epigenetics,methylation Abstract: Mechanismsofactionofnonmutageniccarcinogenssuchasasbestosremainpoorlycharacterized. Aspleuralmesotheliomaisknowntohavelimitednumbersofgeneticmutations,weaimedto characterizetherelationshipsamonggenelocusspecificmethylationalterations,diseasestatus, asbestosburden,andsurvivalinthisrapidlyfatalandcostlyasbestosassociatedtumor.methylation of1505cpglociassociatedwith803cancerrelatedgeneswerestudiedin158pleural mesotheliomasand18normalpleura.afterfalsediscoveryratecorrection,969cpglociwere independentlyassociatedwithdiseasestatus(qvalue<0.05).classifyingsamplesbaseduponcpg methylationprofilewithamixturemodelapproach,methylationclassesdiscriminatedtumorfrom normalpleura(permutationtestp<0.0001).inarandomforestsclassificationtheoverall misclassificationerrorratewas3.4%,with<1%(n=1)oftumorsmisclassifiedasnormal(p<0.0001). Amongtumors,methylationclassmembershipwassignificantlyassociatedwithlungtissueasbestos bodyburden(p<0.03),andsignificantlypredictedsurvival(likelihoodratiotestp<0.01).consistent withpriorwork,asbestosburdenwasassociatedwithanincreasedriskofdeath(hr=1.4,95%ci, ).Ourresultshaveshownthatmethylationprofilespowerfullydifferentiatediseasedpleura fromnontumorpleura,thatasbestosburdenandmethylationprofilesareindependentpredictorsof mesotheliomapatientsurvival,andthatcellularepigeneticdysregulationisacriticalmodeofaction forasbestosintheinductionofpleuralmesothelioma.importantly,thesefindingsholdgreatpromise fortheuseofepigenticprofilinginthediagnosisandprognosisofhumancancersingeneral. 219

222 ABSTRACTS Number:194 Abstracttitle: ANANATOMOPATHOLOGICALSTUDYOFSPONTANEOUSMALIGNANTMESOTELIOMA(MM)IN DOMESTICANIMALS.ITSPOSSIBLEUSEFULNESSINENVIRONMENTALMONITORINGFORTHE PROTECTIONOFHUMANHEALTHINASBESTOSPOLLUTED NarcisoMariani,PaolaBarbieri,PaolaRe,SaraOrecchia,MichelaSalvio,ElenaArnolfo,Roberta Libener,PierGiacomoBetta ASOAlessandria,Italy Keywords: mesothelioma,environment,domesticanimals Abstract: SixteenyearsafterthebanontheindustrialuseofasbestosinItaly,therearestillsomegeographic areaswithahighincidenceofmmderivingfromenvironmentalexposuretofibres.inthese territorialcontextsitwouldnowbenecessarytoacquiredataconcerningasbestosrelatedtumour riskresultingfromexposureschronologicallycloserthanthetraditionalonesofoccupationaltype, whichcausemminhumanswithinductionlatencytimesof2040years.forthispurposethestudy ofspontaneousmmindomesticanimalsandpets,particularlydogs,hasbeensuggested:mmwould beanindicatorofasbestospollution,especiallyintheindoorenvironment.onthisbasisa preliminaryanatomopathologicalstudyhasbeencarriedout,preparatorytotherealizationofa methodologicallystructuredinvestigationwiththerecruitmentofastatisticallyadequatenumberof smalldomesticanimalsinanareawithhighmmincidence,suchasthedistrictofcasalem.to.the aimwastodefinethegrossandmicroscopiccharacteristicsofspontaneousmminalimitedseriesof smalldomesticanimals,suchasdogs(n=8)andcats(n=2),whichhadbeenlivingincasalem.toand, whilestillalive,hadshownpleuropulmonarydiseasesuggestingmmonthebasisoftheclinico radiologicalandlaboratorydata.thekeygross(multiplenodules,localgrowthwithinvasionof submesothelialtissuesbycontinuityandmetastasestolocoregionallymphnodes,butveryrarely withsystemicspreadviathebloodstream)andmicroscopeimages(epitheloidpatternmore frequentthanbiphasic,ferruginousbodiesinthelungtissue)andtheimmunoreactivity (coexpressionofcytokeratinandvimentinwithstronganddiffusecytoplasmicstaining)have suggestedaclosemorphobiologicalsimilaritybetweenspontaneouslyoccurringmminanimalsand humans.thankstotheshorterinductionlatencytimeof89years,thestudyofspontaneousmmin domesticanimalscanactasacomparativemodelinenvironmentalhealthsurveys.moregenerally, thestudyoftheenvironmentveterinarypathologyprobablydoesnotprovidedatawhichcanbe usedastheonlydeterminingfactorinassessmentofrisktohumanhealthduetoenvironmental pollutants.however,itmaybeusefulassupportforfurtherbiologicalevidenceinmonitoring programmesofenvironmentaldecontamination. 220

223 ABSTRACTS Number:195 Abstracttitle: HighPrevalenceofAsbestosisAssociatedwithOccupationalAsbestosExposureinWesternAustralia SveinCvanOyen(1),HelmanAlfonso(1),AlisonReid(1),NicholasHdeKlerk(1,3),LinFritschi(4),AW (Bill)Musk(1,2) (1)OccupationalRespiratoryEpidemiology,SchoolofPopulationHealth,UniversityofWestern Australia;(2)DepartmentofRespiratoryMedicine,SirCharlesGairdnerHospital,Perth,Western Australia;(3)TelethonInstituteofChildhoodResearch,Perth,WesternAustralia;(4)Western AustralianInstituteforMedicalResearch Abstract: Background WesternAustralia(WA)hasthehighestnationalrateofmalignantmesotheliomain Australia.Howeverlimitedinformationisavailableontheoccupationalrisksoflungcancerand asbestosisintheworkforce. Objectives Toexaminetheriskofasbestosrelateddisease(ARD)fromoccupationalasbestos exposuretoasbestosinwausingjobtitleasasurrogateforexposure Methods Participantswereselectedfromacancerpreventionprogramforpeopleexposedto asbestos.acohortof1399malesoccupationallyexposedtoasbestosotherthanatthewittenoom crocidoliteminewerefollowedupfrom1990to2005.malignantmesotheliomaandlungcancer incidence,andmortalitywithradiographicasbestosisrepresentedardwithinthestudy.rateratios (RR)compareddiseaserateswithinthecohortovertimeandbyindustryandoccupation. Results Onehundredandtwodeathswithasbestosis,28incidentcasesofmalignantmesothelioma (21pleuraland7peritoneal)and48incidentcasesoflungcancerwereobserved.Fortypercentof thecohort(570cases)hadsomelevelofasbestosis.deathscodedasasbestosisrepresented2%of totalasbestosisprevalence.ardincidencestatisticallyincreasedoverfollowup(p=0.0085).asbestos manufacturingrepresentedthegreatestriskofardforindustryandoccupationsfollowedbythe marineindustryandoccupations,shipyardindustry,processoperatorsandfiremen.resultswere limitedbytheselectivenatureofthecohortandriskestimatescouldnotbegeneralizedtothewa workforce. Conclusion Thepresentationofoccupationalasbestosiswasfoundtobefarabovethatofany malignantardwithinthecohort.examiningradiographicasbestosisaswellasmalignant mesotheliomaandlungcancermayallowamuchbetterpredictionoftheextentanddurationofard inaustralia.occupationalriskestimatesprovidedpreliminaryevidencetowardsjobtitleswhere asbestosdiseaseandexposuremaybeapriority. 221

224 ABSTRACTS Number:196 Abstracttitle: PanelofTumorMarkersfortheDiagnosisofMalignantPleuralMesothelioma MasakiAnraku,ApurvaPatel,ZhihongYun,GeoffreyLiu,PaulWheatleyPrice,ShafKeshavjee, MichaelJohnston,MarcdePerrotTorontoGeneralHospital Keywords: tumormarker,earlydetection,elisa Abstract: OBJECTIVE: Mostmalignantpleuralmesothelioma(MPM)patientspresentwithadvancedstageofdiseasewhen therapeuticoptionsarelimited.tumormarkersthatdefinehighriskpatientswouldenhance diagnosticcapabilitiesandhaveclinicalbenefitfordetectionofmpm.inthecurrentstudy,plasma concentrationsofsmrp,osteopontin,ca125,andtransforminggrowthfactorβ(tgfβ) inpatientswithmpmwerecomparedagainstthosefromasbestosexposedcontrolstodetermine theroleofthesemarkersindetectionofmpm. METHODS: ProspectiveevaluationofplasmaSMRPandosteopontinwasconductedonpatientswithMPM(n= 38)andasbestosexposedmatchedcontrols(n=64).Matchedfactorsweregender,age,and smokinghistory.enzymelinkedimmunosorbent(elisa)assayswereusedtodeterminethevalues. RESULTS: MedianSMRP,osteopontin,andCA125werehigherintheuntreatedMPMpatientscomparedto thoseinasbestosexposedcontrols(4.6±5.7vs.1.4±1.0nm,p=0.02;500.1±521.6vs.241.6±94.8 ng/ml,p=0.02;37.3±39.8vs.9.1±8.0u/ml,p<0.001,respectively),whiletgfβshowedno statisticaldifferencebetweentwogroups(10.2±8.9vs.14.8±10.2ng/ml,p=0.1).inreceiver operatingcurveanalysis,thesensitivityandspecificityofsmrpindifferentiatingthecontrolsfrom untreatedmpmpatientswere94%and75%(cutoff,1.9nm),thoseofosteopontinwere100%and 54%(cutoff,247ng/ml),andthoseofCA125were100%and43%(cutoff,7.1U/ml),respectively. Among17patentswhohadtheirtumormarkersmeasuredbeforeanytypeoftherapy,16ofthem hadallthreemarkers(smrp,osteopontin,andca125)abovetheircutoffvalues(sensitivity,94%). Ontheotherhand,only4of68asbestosexposedcontrolsdemonstratedhighervaluesthantheir cutoffvaluesforallthreemarkers(specificity,94%). CONCLUSIONS: Thepanelofthreemarkers(SMRP,osteopontin,andCA125)isvaluableinsuggestingthediagnosisof MPM,andpotentiallyusefulinscreeninghighriskasbestosexposedpopulationsforMPM. 222

225 ABSTRACTS Number:197 Abstracttitle: Potentialvalueofsolublemesothelinrelatedproteininpleuralfluidfordiagnosisofmalignantpleural mesothelioma NobukazuFujimoto,KenichiGemba,ShinjiOzaki,KatsuichiroOno,SaeWada,TakumiKishimoto. OkayamaRosaiHospitalJapan Keywords: mesothelin,diagnosticmarker,benignasbestospleurisy Abstractcontent: Malignantpleuralmesothelioma(MPM)isahighlyaggressiveneoplasmstronglyassociatedwith asbestosexposure,primarilyarisingfromthesurfaceserosalcellsofthepleura.patientswithmpm oftendeveloppleuralfluidasinitialpresentation.however,cytologicaldiagnosiswithpleuralfluidis usuallydifficultandhaslimitedutility.usefulmolecularmarkerfordifferentialdiagnosisespecially withlungcancer(lc)isurgentlyneeded.theaimofthepresentstudyistoinvestigatethediagnostic valueofsolublemesothelinrelatedprotein(smrp)inpleuralfluid.pleuralfluidswerecollectedfrom 23patientswithMPM,38withLC,26withbenignasbestospleurisy(BAP),5withtuberculous pleurisy(tp),and4withcongestiveheartfailure(chf),andsmrpconcentrationwasdetermined.all datawereanalyzedbyusingnonparametrictwosidedstatisticaltests.themeanconcentrationof SMRPinMPM,LC,BAP,TB,andCHFwere20.96±23.99(range, ),7.13±6.66(range, ),6.36±2.83(range, ),and3.79±2.25(range, ),and2.05±0.69 (range, )nmol/L,respectively.SMRPconcentrationwassignificantlyhigherinMPMthan inotherdiseases(p=0.001).theareaundertheroccurve(auc)valuesofmpmdiagnosiswas0.75 fordifferentialdiagnosisfromothergroups.basedonthecutoffvalueof8nmol/l,thesensitivity andspecificityfordiagnosisofmpmwere70.0and68.4,respectively.theseresultsindicatethat SMRPconcentrationinpleuralfluidwouldbeausefulmarkerfordiagnosisofMPM. 223

226 ABSTRACTS Number:198 Abstracttitle: Solublemesothelinrelatedpeptide(SMRP)inpleuraleffusionforthediagnosisofmalignantpleural mesothelioma TakayukiTerada,SyusaiYamada,KazuyaFukuoka,KozoKuribayashi,TakashiNakano HyogoCollegeofMedicine,Japan Keywords: Solublemesothelinrelatedpeptide,SMRP,pleuraleffusion Abstractcontent: Background:Wehavedemonstratedthatsolublemesothelinrelatedpeptide(SMRP)inserumis highlyspecificandmoderatelysensitivebiomarkerformalignantpleuralmesothelioma(mpm).since mostpatientswithmpmpresentwithfluidretention,weinvestigatewhetherlevelsofsmrpwere raisedinpleuraleffusions. Methods:Pleuralfluidwascollectedfrom80patientswithMPM.SMRPlevelsineffusionwere determinedbyadoubledeterminantelisausingtwoantibodies(ov569and4h3). Results:AccordingtoeachhistologicsubtypeofMPM,themeanlevelsofSMRPshowedasfollows; 75.9nMinepithelioid,18.9nMinsarcomatoid,43.8nMinbiphasic,and36.6nMindesmoplastic, respectively.themeanlevelsofsmrpineffusionofepithelioidsubtypeweresignificantlyhigher thanthoseofnonepithelioidsubtypes.accordingtoeachstageofmpm,themeanlevelsofsmrp showedasfollows;48.1nminstagei,48.6nminstageii,63.6nminstageiii,and77.1nminstageiv patients.smrplevelsineffusionswereelevatednotonlyinadvancedstage,butalsoinearlystage. Conclusions:MeasurementofSMRPlevelsinpluraleffusionmaycontributetomakeanearly diagnosisofmpm. 224

227 ABSTRACTS Number:199 Abstracttitle: Measurementofpleuralfluidosteopontinlevelindiagnosisofmalignantpleuralmesothelioma KeisukeAoe(1),AkioHiraki(2),NobukazuFujimoto(3),KenichiGemba(3),TomoyukiMurakami(1), HiroshiUeoka(1),TakumiKishimoto(3) (1)NHOSanyoNationalHospital,Japan;(2)OkayamaUniversityHealthServiceCenter,Japan; (3)OkayamaRosaiHospital,Japan Keywords: pleuralfluid,osteopontin Abstract: Previousstudiesreportedthatserumosteopontinlevelswereelevatedinpatientswithpleural mesothelioma,indicatingthatosteopontincanbeausefulbiomarkerinpleuralmesothelioma.we examinedpleuralfluidosteopontinlevelsin26patientswithpleuralmesothelioma(pm),15with asbestospleurisy(ap),37matastaticplreuritis(mp)and28withvariousnonmalignantdiseases (NM).Averagepleuralfluidosteopontinlevelwas17907ng/ml,15550ng/ml,15126ng/mland7332 ng/mlinpm,ap,mpornm,respectively.therewasasignificantdifferencebykruskalwallistest(p =0.0003).Receiveroperatingcharacteristics(ROC)analysisshowedanareaundercurve(AUC)of 0.641betweenPMandtheothers.Atacutoffvalueof8530ng/ml,thesensitivityandspecificity were84.6%and40.0%,respectively.rocanalysisshowedanaucof0.805betweenpmandnm. ButROCanalysisshowedAUCsof0.479betweenPMandAPand0.585betweenPMandMP, respectively.averagepleuralfluidosteopontinlevelswere17272ng/ml,9568ng/ml,36412ng/mlin epithelioid,sarcomatoidandbiphsictype,respectively.measurementofpleuralfluidosteopontin levelisusefulindifferentiatingpmfromnm,hardindifferentiatingpmfromapormp.plueralfluid osteopontinlevelinpatientswithsarcomatoidtypemesotheliomaislowerthanthatwithepithelioid orbiphasictypemesothelioma. 225

228 ABSTRACTS Number:200 Abstracttitle: PotentialvalueofDNAmethylationprofileinpleuralfluidfordifferentialdiagnosisofmalignant pleuralmesotheliomaandadenocarcinomaofthelung MasanoriFujii(1),NobukazuFujimoto(2),AkioHiraki(3),KenichiGemba(2),KeisukeAoe(4),Shigeki Umemura(1),HidekiKatayama(4),KatsuyukiKiura(1),MitsuneTanimoto(1),TakumiKishimoto(2) (1)DepartmentofHematology,Oncology,andRespiratoryMedicine,OkayamaUniversity,Japan; (2)DepartmentofOccupationalPulmonaryDiseases,OkayamaRosaiHospital,Japan;(3)Health ServiceCenter,OkayamaUniversity,Okayama,Japan;(4)DepartmentofMedicalOncology,NHO SanyoHospital,Ube,Japan Keywords: DNAmethylation,Pleuralfluid,Malignantpleuralmesothelioma Abstract: Malignantpleuralmesothelioma(MPM)isahighlyaggressiveneoplasmstronglyassociatedwith asbestosexposure,primarilyarisingfromthesurfaceserosalcellsofthepleura.patientswithmpm oftendeveloppleuralfluidasinitialpresentation.however,cytologicaldiagnosiswithpleuralfluidis usuallydifficultandhaslimitedutility.usefulmolecularmarkerfordifferentialdiagnosisespecially withadenocarcinomaofthelung(ac)isurgentlyneeded.theaimofthepresentstudyisto investigatethediagnosticvalueofdnamethylationprofilesinpleuralfluid.pleuralfluidswere collectedanddnawasextractedfrom38patientswithmpm,24withac,14withtuberculous pleurisy(tb),and27withbenignasbestospleurisy(bap).themethylationstatusofrasassociation domainfamily1a(rassf1a)andp16ink4awasexaminedwithmethylationspecificpolymerase chainreaction(msp).therelativeleveloftwomethylatedgenesineachsamplewasdeterminedas theratioofmspamplifiedtwogenestoßactin(actb),areferencegene.themeanratiosofmsp amplifiedrassf1atoactbinmpm,ac,tb,andbapwere0.94(range, ),0.21(range, ),1.50(range, ),and1.05(range, ),respectively.Themeanratiosof MSPamplifiedp16INK4atoACTBinMPM,AC,TBandBAPwere1.73(range, ),0.27 (range,0 4.62),2.00(range, ),and1.62(range, ),respectively.In RASSF1A/ACTBandp16INK4a/ACTBmethylationratio,wefoundstatisticallysignificantdifferences betweenmpmandac(p=.002;.007,respectively).theseresultsindicatethepotentialusefulnessof methylationanalysisofpleuralfluiddnaasatoolfordifferentialdiagnosisofpulmonarydiseases presentingpleuralfluidsincludingmpmandac. 226

229 ABSTRACTS Number:201 Abstracttitle: MesotheliomaBiomarkersinPleuralEffusions KarolaCsürös,FilipMundt,KatalinDobra,AndersHjerpe KarolinskaIntitutet,Sweden Keywords: mesothelioma,biomarkers,pleuraleffusion Abstract: Theanalysisofhyaluronanineffusionshaslongbeenausefuladjunctforthediagnosisofa mesothelioma[1],givingdiagnosticvaluesinlessthan60%ofthecases.morerecentlymesothelin[2] andosteopontin[3]havebothbeenrecommendedasmesotheliomabiomarkerswhenanalyzing effusionsand/orserum. Theseanalyseswereperformedon270effusionsupernatants,includingfluidsfrom35patientswith mesothelioma.logisticregressionanalysisclearlydemonstratedthathyaluronanandmesothelin werediagnosticallyuseful,whileosteopontinhadnoadditionalinformationofdiagnosticvalue.the analysisalsoprovidedaninterpretationalgoritmfortheevaluationofthecombinedhyaluronan mesothelinanalysistoimprovediagnosticsensitivityandspecificity. Thestudyisnowextendedtothetestingoffurthercandidatebiomarkers.Fortheupcomingmeeting wehopealsotopresentpreliminarydataregardingtheutilityofanalyzingsyndecan1and thioredoxinineffusionsupernatants 227

230 ABSTRACTS Number:202 Abstracttitle: Refocusingonthehyaluronicacidconcentrationintheeffusionofmalignantpleuralmesothelioma;a routinescreeningtestfortheepithelialtype HirotaroMiura(1),HisanoriMatsushita(1),ShiroTsujimoto(1),NaohikoInase(2),ShinsukeAida(3) (1)YokosukaGeneralHospitalUwamachi,Japan;(2)TokyoMedicalandDentalUniversity,Japan; (3)NationalDefenseMedicalCollege,Japan Keywords: hyaruronicacid,epithelialmesothelioma,cytology,pleuraleffusion Abstract: [Purpose]:Itiswellknownthathyaluronicacid(HA)concentrationinpleuraleffusionofmalignant pleuralmesothelioma(mpm)ishigherthanintheotherdisease.buteveryeffusionofmpmmaynot alwayshavehighconcentration.thereasonofthisdifferencehasnotbeenwellknown.[method]: TheHAconcentrationsinthepleuraleffusionatthefirstthoracentesisofMPMwereinvestigated retrospectivelyaccordingtothecytologyofthesamesampleandthehistologicaltype.ha concentrationwasmeasuredbysandwichbindingproteinassay(sbpa),whichisawidespread methodinjapantomeasuretheserumhafordiagnosingliverfibrosisofchronichepatitispatient (serumnormalrange;upto50ng/ml).theeffusionhalevelwassohighthatthesamplewasdiluted beforemeasurement.[result]:therewere34definitempmpatientsfittingabovecriteria( ).Atotalof22epithelialand7biphasictypehadsignificantlyhighermeanlevelof383.7mg/l (s.d.=463.3)and232.7mg/l(s.d.=257.6)respectivelythan5sarcomatoustype,meanlevelof27.1 mg/l(s.d.=11.0),p<0.05.atotalof16cytologicalpositive(papanicolaou sclass5;epithelial12, biphasic4)caseshadhighermeanlevelof511.6mg/l(range ,s.d.=469.0)thantheother ones,112.2mg(range ,s.d.=218.6),whichincludedallofsarcomatoustype,p<0.05. [Conclusion]:TheHAconcentrationofMPMeffusionhavingepithelialcomponentishigherthanthe otherone.cytologicallypositivecasesshowatendencytohighereffusionhaconcentration.ifthe pleuraleffusionhashighhaconcentrationandpositivecytology,thereisastrongprobabilityof MPM,especillyepithelialtype.TheSBPAmethodformeasuringHAismoreconvenientandhaslower costperformancethantheothermethods.theroutineanalysisofthepleuraleffusionatthefirst thoracentesisisrecommendedforearlydetectionofepithelialmesothelioma. 228

231 ABSTRACTS Number:203 Abstracttitle: SERUMMESOTHELINVARIATIONSINPATIENTSWITHADVANCEDMALIGNANTPLEURAL MESOTHELIOMA(MPM)TREATEDWITHCHEMOTHERAPY:PRELIMINARYRESULTS ManlioMencoboni(1),GiovanniLucaCeresoli(2),RosangelaFiliberti(3),PaoloAndreaZucali(2),Fabio Spigno(4),InnaTimofeeva(2),MariaSerra(1),PaolaMarroni(3),MarinaBergaglio(1),Armando Santoro(2) (1)OspedaleVillaScassi,Sampierdarena,Italy;(2)IstitutoClinicoHumanitas,Rozzano(Milan), Italy;(3)NationalInstituteforCancerResearch,Genova,Italy;(4)UniversityofGenova,Genova,Italy; Keywords: chemotherapy,response,mesothelin Abstract: Background:ThedifficultiesinassessingresponsetotherapyinMPM,andthelargevariationsofthe prognosticfactors,makethepotentialavailabilityofserumtumormarkersveryuseful.mesothelinis acellsurfaceglycoproteinoverexpressedinmpm.aimofthisstudywastoexploretheroleof serummesothelin(sm)aspredictorofresponsetochemotherapy(cht)inpatients(pts)with advancedmpm. Methods:PtswithhistologicallyprovenMPM,treatedwithpemetrexedbasedChTintwodifferent centers,wereeligibleforthisstudy.smlevelsweremeasuredatbaselineandaftertwocyclesofcht, usinganelisaassay(mesomark ).RadiologicalresponsewasmeasuredbyspiralCTscan accordingtompmmodifiedrecistcriteria.diseasecontrolrate(dc)wasdefinedascomplete response(cr)+partialresponse(pr)+stabledisease(sd). Results:Twentyeightpts(23male,5female)havebeenevaluated.Medianagewas66(range63 78).Histologywasepithelialin26,sarcomatoidin1,unspecifiedin1pts.FifteenSDand7PRwere observed,foranoveralldcrateof79%.sixptshaddiseaseprogression.medianbaselinesmvalue was1.8nm(range );itwas1.79inptsachievingdcand1.71nmincaseswithprogression (p=ns).postchemotherapysmwasavailablefor25pts.afterchemotherapy,mediansmvaluewas 1.53nM(range ),andwassimilarinptswithdiseaseprogressionandinthoseachievingDC (1.53vs1.47nM,p=ns).Mesothelinlevelsdroppedin13/25pts(52%),withameanreductionof 44%ofbaselinevalue.Inparticular,sMvaluewasreducedafterchemotherapyin55%ofpts achievingdcandin40%ofnonresponders(p=0.6). Conclusion:TheusesMlevelsintheassessmentoftreatmentefficacyinMPMappearspromising. However,nosignificantcorrelationwithradiologicalresponsewasobservedinthisseries.Our preliminaryobservationsneedtobeconfirmedinalargernumberofpts,withacorrelationwith survivaloutcomes. 229

232 ABSTRACTS Number:204 Abstracttitle: SOLUBLEMESOTHELINRELATEDPROTEINANDRENALFAILURE:ACAVEAT KevinHollevoet,VeroniqueStove,JanPvanMeerbeeck,JorisDelanghe UniversityHospitalGent,Belgium Keywords: SMRP,mesothelin,renalfailure Abstract: BACKGROUND:Thelowmolecularweightprotein(LWMP)solublemesothelinrelatedprotein (SMRP)(40kDa),asassessedbymeansoftheELISAassayMESOMARKTM,hasbeenshowntobe increasedintheserumofmalignantmesothelioma(mm)patients[robinson,2003].therefore,it mightbeusedasabiomarkerfor(early)diagnosisofmminhighriskasbestosexposedindividuals andpatients,monitordiseaseprogressionandresponsetotreatment.oneofthelimitationsofthe assayisitsdependencyofrenalfunction.theglomerularfiltrationrate(gfr)canconfoundthe relationshipbetweensmrpandmm,giventhatlmwpsaccumulateinrenalfailure.gfralso declineswithage,andsincemmpatientshaveamedianageof65years,theirkidneyfunctioncanbe impairedleadingtofalselyelevatedsmrplevels.wehaveinvestigatedtheimpactofrenalfunction onsmrplevelsinserumofpatientswithdifferentgradesofrenalfailure. METHODS:18cancerpatientsand2nontransplantkidneypatients,referredfor51CrEDTA clearancewereincludedinthisstudy.renalfunctionwasassessedbydeterminationofcystatinc andβ tracelevelsinsera.withtheexceptionofsmrp,allmeasurementswereperformed usingcommercialreagents(rochediagnostics,dadebehring). RESULTS:SerumSMRPwasfoundtocorrelatewithrenalfunctionmarkers51CrEDTAclearance (p=0,014),cystatinc(p=0,054)andβ traceprotein(p=0,041). CONCLUSION:TheaccumulationofserumSMRPinrenalfailuremightcauseacaveatforthe applicationofthemesomarkassayasabiomarkerformesothelioma.updateddatawillbepresented atthemeeting Thisstudywasmadepossiblebyanunrestrictedgrantofthe BelgianFoundationagainstCancer 230

233 ABSTRACTS Number:205 Abstracttitle: PlasmaticosteopontininsubjectsexposedtoasbestosfibersandpatientswithMalignant Mesothelioma(MMe) R.Foddis(1),S.Simonini(1),A.Bonotti(1),S.Perretta(1),A.Vivaldi(1),G.Guglielmi(1),L.Mutti(2),A. Cristaudo(1) (1)OccupationalMedicine,S.ChiaraUniversityHospital,Pisa,Italia;(2)S.PietroePaoloHospital,ASL Vercelli,Italia Keywords: MalignantMesothelioma;PasmaticOsteopontin;EarlyDiagnosis Abstract: Serumosteopontin(sOPN)andserummesothelin(SMRPhavebeenreportedaspromisingmarkers ofincreasedriskand/orearlydiagnosisofmme. AlthoughthemostimportantdataregardingtheroleofOPNinMMscomeoutfromtheirdosagein serasamples,themajorityofthelaboratorykits,commerciallyavailable,forosteopontinassay,are suitableforplasmaticdosageonly. We,therefore,measuredosteopontinin93plasmasamples(pOPN;30MMepatients,45healthy workerspreviouslyexposedtoasbestos,5benignpleuraldiseases;bpd)to: a)validatetheirroleinpreventionanddiagnosis b)todiscloseifanyfactor,i.eage,tobaccosmoking,durationofasbestosexposure,caninterfere withdosagesofpopn. WealsomeasuredSMRPinthesamesamplesinordertoevaluateanycorrelationbetweenthetwo markersinthepopulationaunderinvestigation. popnlevelsinbothmmeandbpdweresignificantlyhigherthaninhealthycontrolgroup(p<0.0001, p=0.048respectively),butnostatisticallysignificantdifferencewasfoundbetweenmmeandbpd (p=0.070). TheapplicationofaROCcurvefortheperformanceofpOPNresultedinaAUCvalueof0.65witha bestcutoffof995.02ng/ml,associatedwith56.3%ofsensitivityand80.6%ofspecificity. AsignificantpositivecorrelationwasobservedbetweenageandpOPN(p=0.002,Rsquare=0.102), butnocorrelationwasfoundwitheitherdurationofasbestosexposureorwithsmokinghabit.a positivesignificantcorrelationwasseenbetweenplasmaticosteopontinandserummesothelin dosages(p=0.001,rsquare=0.195). AlthoughbasedonasmallsizedpopulationthesepreliminarydatasuggestthatpOPNmaybeuseful inclinicalandpreventiveapplicationandfurtherinvestigationsareworthtobeperformed. 231

234 ABSTRACTS Number:206 Abstracttitle: DifferentiateMPMfromothercausesusingtumormarkers MichelvandenHeuvel,TinyKorse,HansBonfrer,PaulBaas NKI/AvL,Amsterdam,theNetherlands Keywords: smrp;cea;cyfra211;mpm;nsclc Abstract: Serummarkershavebeentestedinpatientswithmalignanteffusionsfortheirabilitytodifferentiate malignantpleuralmesotheliomafromothercauses.wehaveexaminedthreedifferentserum markers(solublemesothelinrelatedprotein(smrp),cyfra21.1,andcarcinoembryonicantigen (CEA))inaseriesofpatientswithdifferentthoracicmalignanciesandahealthycontrols. Thisretrospectivestudyconsistsof179patientsand50healthycontrolswhovisitedourhospital. Seventyfourpatientshadaconfirmedmesothelioma,and106patientshadnonsmallcelllung cancer(nsclc),55hadadenocarcinoma. Cyfra21.1wasthebestsinglemarkerdiscriminatinghealthyfromanymalignantdisease(AUC)0.92, 95%confidenceinterval(CI) Bycombiningallthreemarkersthediscriminatorypower improvedmarginally(auc0.95,ci ,p=0.015).thecombinationofceaandsmrpwasmost accurateindifferentiatingmesotheliomafromnsclc(auc0.94,95%ci )andcorrectly identify152of179(85%)cases. Conclusions:Byusing2serummarkers(CEAandSMRP)wewereabletodiscriminatemesothelioma fromnsclcwithhighsensitivity,whilecyfra21.1isusefulinthediscriminationofnormalvs. malignancy. Table:Resultsoflogisticregressionmodelstodistinguishmalignantpleuralmesotheliomafrom malignantlungdiseasewiththetumormarkersaspredictorvariables Tumormarker OR 95%CI pvalue Univariateanalysis: Cyfra21.1(μg/l) SMRP(nmol/l) <0.001 CEA(μg/l) <0.001 Multipleanalysis: SMRP(nmol/l) CEA(μg/l) <

235 ABSTRACTS Number:207 Abstracttitle: Apharmacokineticstudyofpemetrexedadministeredintrapleurallyinananimalmodel LaurentGreillier,SuzanneMonjanelMouterde,JulienBouvenot,AnneFraticelli,BénédicteDevictor Pierre,PhilippeAstoul AssistancePubliqueHôpitauxdeMarseille,UniversitédelaMéditerranée Keywords: Chemotherapy;Intrapleuraladministration;Mesothelioma;Pemetrexed,Pharmacokinetics;Toxicity Abstract: Background:Pemetrexedisakeydrugforthetreatmentofmalignantpleuralmesothelioma.The intrapleuraladministrationofpemetrexedmightincreaseitsefficacyanddecreaseitstoxicityin comparisonwithintravenousadministration.theaimofthisstudywastoassessinananimalmodel thepharmacokineticsofpemetrexedadministeredintrapleurallycomparedtointravenously. Methods:ThirtyWistarratswererandomizedintofourgroupsaccordingtotherouteof administration(intravenousorintrapleural)andthedoseofpemetrexed(10or100mg/kg).during theexperiments,bloodsampleswereharvestedusingastandardizedprotocol.pemetrexed concentrationsinplasmawereanalyzedbyhighperformanceliquidchromatography.thestudied pharmacokineticsparameterswerethemaximumplasmaconcentration(cmax),theareaunderthe plasmaconcentrationtimecurve(auc),andthetotalbodyclearance(cl). Results:Whenpemetrexedwasdeliveredat10mg/kg,neithertheAUCnortheCLsignificantly differedaccordingtotherouteofadministration,butthecmaxwassignificantlylowerafter intrapleuraladministrationthanafterintravenousadministration(14.36μg/mlversus29.83μg/ml; P=0.008).Similarresultswerefoundwhenpemetrexedwasdeliveredat100mg/kg(Cmaxafter intrapleuraladministration,70.64μg/ml;cmaxafterintravenousadministration,218.64μg/ml; P=0.001). Conclusions:WhileintravenousandintrapleuraladministrationofpemetrexedyieldedsimilarAUC andcl,thelatterachievedsignificantlylowercmax.ascmaxisadeterminantofpemetrexed toxicity,intrapleuraladministrationmightofferameansofwideningtheeffectivetherapeuticindex ofthedrugbyimprovingtolerability.futurestudiesareneededtoconfirmthishypothesisin malignantpleuralmesotheliomapatients. 233

236 ABSTRACTS Number:208 Abstracttitle: Validationofthebiomarkersosteopontinandmesothelininamulticenterprospectivetrial Preliminaryresultsofanongoingstudy HendrikMüllerBerndorff,PeterBrand,MichaelFelten,LarsKnoll,ThomasSchettgen,ThomasKraus InstituteandOutpatientClinicforOccupationalandSocialMedicine,RWTH,Germany Keywords: asbestos,exposureassessment,riskmodelling,biomarkers Abstract: Purpose: Formerlyasbestosexposedworkersinthepowerindustryareatriskofdevelopingasbestosrelated diseases,especiallylungcancerandmalignantmesothelioma.recentreportssuggestthatthe biomarkerslikeosteopontinandmesothelinmightcontributetoearlydiagnosisofmesothelioma. Design: Inanongoingsurveyof8632formerlyorstillactiveemployeesofamajorproviderofelectrical poweringermany,generalmedicalandoccupationalhistory,auscultationofthethorax,lung functiontestingandastandardchestxrayisperformed.forhighriskindividualsthesurveillance includedannuallowdosespiralct(ldsct)andsputumcytology.since10/2005osteopontinin plasmaandmesothelininserumsamplesismeasured..cutoffpointsweredefinedas900ng/mlfor osteopontinand1,4nm/lformesothelin. Preliminaryresults: In342(4%)highriskindividualscompletedatainclusiveLDSCTareavailablein06/2008.Themedian agewas65years(range44to81years).mediannumberofpackyearswas26.mediancumulative exposurewas15fibreyears.inamultiplelinearregressionmodeltherewasasignificantassociation ofosteopontinwithbenignasbestosrelatedfindingsinldsct(parenchymalp=0.006;pleuralp= 0.001)andage(p<0.0001),whilemesothelindidnotshowsignificantresultswiththeabove mentionedpotentialconfoundingfactors. Medianconcentrationswere350ng/ml(range16to2204ng/ml)forosteopontinand0,589nM/L (range0,036to4nm/l)formesothelin.11(4%)resp.18(5%)casesexceededthecutoffvaluesfor osteopontinresp.mesothelin.sofaronepersondevelopedmalignantmesotheliomawhileanother wasalreadyundertreatmentatthefirstexaminationwithinthestudy.bothcaseshadbiomarker valuesbelowthecutoff.intheincidentmesotheliomacasethebloodsamplewastaken16months beforediagnosis. 234

237 ABSTRACTS Conclusions: Ourpreliminaryresultsin342highriskemployeessuggestthatonlyosteopontinlevelsincontraryto mesothelinlevelsarecorrelatingwithbenignparenchymalandpleuralchangesinctscan.moreover osteopontinconcentrationsareagedependent.thereforeageand/ordiseasestatusdependentcut offvaluesshouldbeconsideredforthisbiomarker,toreduce falsepositives.fortheinterpretation ofmesothelinconcentrationsthefactorsconsideredinourstatisticalanalysisdon`tseemtohave influenceonmesothelinlevels. Thepredictivevaluesofbothbiomarkersshouldnotbecalculatedsofaronthebasisoftwocases. Duetotheprospectivedesignofourstudyitwillbepossibletodescribethevalueofboth biomarkersinthesurveillanceofasbestosworkers. 235

238 ABSTRACTS Number:209 Abstracttitle: DownregulationofchemokinereceptorCXCR3inperipheralTlymphocytesfrompatientswith asbestosrelateddisease MegumiMaeda,YasumitsuNishimura,ShukoMurakami,NaokoKumagai,HiroakiHayashi,Ying Chen,YoshieMiura,TakashiNakano,TakumiKishimoto,TakemiOtsuki. Dept.ofRespiratoryMed.,HyogoCollegeofMed,OkayamaRosaiHospital,Dept.ofHygiene, KawasakiMed.SchoolandEppleyInst.forCancerRes.,Univ.ofNebraskaMed.Center Keywords: Asbestos,Tcell,CXCR3,IFNγ Abstract: [Introduction]Asexposuretoasbestoscauseslungcancerandmalignantmesothelioma(MM)aftera longincubationperiodevenifonlyslightly,weassumethatanattenuationofantitumorimmunity inducedbyimmunecellsexposedtoasbestosisinvolvedinthedevelopmentofthesediseases.to elucidatetheinfluenceofasbestosonthecd4 Tcells,whichactivatetumorimmunity,we examinedthegeneexpressionprofileofhumanadulttcellleukemiavirusimmortalizedtcellline (MT2Org)exposedtochrysotileBofasbestosusingDNAmicroarraymethod.[Methods]Six asbestosinduced,apoptosisresistantsublines(mt2rst)wereestablishedbyalongtermexposure (morethan8months)toalowconcentrationofchrysotileb(10μg/ml).totalrnafromallcell lineswereusedforthemicroarrayanalyses.theclustering,pathwayandnetworkanalyseswere performedusinggenespringandmetacoreasbioinformaticstools.peripheralbloodcd4 T cellsfromhealthydonorswereexpandedbycd3/cd28stimulationexvivo,culturedinthepresence ofil2andexposuredto50μg/mlchrysotilebforfourweeks.theexpressionofchemokine receptorcxcr3inexpandedcd4 TcellsandCD4 Tcellsfromperipheralblood mononuclearcells(pbmc)ofasbestosrelatedpleuralplaqueormalignantmesotheliomapatients wereexaminedbyflowcytometry.[resultsanddiscussions]thednamicroarrayanalysesrevealed analterationoftheexpressionof162genes,102geneswereupregulatedand60genesweredown regulatedrespectively,wasinducedbyalongterm,lowconcentrationexposuretoasbestos. Additionallyaclusteringanalysisshowedgeneexpressionprofilesofallasbestosinducedapoptosis resistantsublines(mt2rst)tobeverysimilar.pathwayandnetworkanalysissuggestedthatdown regulatedchemokinereceptorcxcr3inmt2rstisinvolvedinifnγsignaling.furthermore, expandedcd4 TcellsexposedtochrysotileBexhibitedadecliningtrendofCXCR3 expression.finally,theresultsshowedthatthecxcr3expressionincd4 Tcellsfrom PBMCdecreasedinpatientswithasbestosrelatedpleuralplaqueormalignantmesothelioma.These findingssuggestthatadecreasedcxcr3expressioncausedbyacontinuousexposuretoasbestos mayreducethecapacityofifnγproduction,whichmayplayaroleintumorimmunity enhancement. 236

239 ABSTRACTS Number:210 Abstracttitle: ImpairmentincytotoxicityandexpressionofNKcellactivatingreceptorsonhumanNKcellscausedby exposuretoasbestosfibers YasumitsuNishimura,MegumiMaeda,ShukoMurakami,NaokoKumagai,HiroakiHayashi,Yoshi Miura,KazuyaFukuoka,TakashiNakano,TakemiOtsuki. Dept.ofHygiene,KawasakiMedicalSchool,EppleyInstituteforCancerResearch Univ.of NebraskaMedicalCenterandDept.ofRespiratoryMedicine,HyogoCollegeofMedicine Keywords: tumorimmunity,nkcell,cytotoxicity,nkcellactivatingreceptor Abstract: Malignantmesotheliomacanresultfromexposuretoasbestos,butthedevelopmentofthisdisease requiresalongperiodafterexposuretoasbestos,suggestingthatasbestosmightgraduallyaffect antitumorimmunity.cytotoxicityofnaturalkiller(nk)cellsagainsttumorcellsiscontrolledbynk activatingreceptorssuchasnkg2d,2b4andnkp46,andinvolvescomponentsincytotoxicgranules suchasgranzymeandperforin.thepresentstudyexploredtheeffectofasbestosexposureonnk cellsbyexaminingfeaturesofyta1humannkcellsexposedtochrysotileb(cb)asbestos,nkcells frompatientswithmalignantmesothelioma(mm),andnkcellsinpbmcsculturedwithcbbyflow cytometry.yta1cellswerecontinuouslyculturedwithorwithout5μg/mlofcb,namedytcb5and YTOrg,respectively.BothsublinesshowedsimilarcytotoxicitiesamonthafterexposuretoCB. However,ataround5monthsafterexposuretoCB,thecytotoxicitiesofYTCB5againstK562cells andanti2b4antibodycoatedp815cellsdecreasedcomparedwithytorg.furthermore,ytcb5 exhibitedsignificantdecreasesincellsurfacenkg2d,2b4andintracellulargranzymea.the degradationsstimulatedwithantinkg2dandanti2b4antibodiesalsodecreasedinytcb5.pbmcs frompatientswithmmexhibiteddecreasedcytotoxicityagainstk562,thepercentageofnkcells, andtheexpressionofnkp46,butnotnkg2dor2b4,innkcells.pbmcsculturedwithcbshoweda significantdecreaseintheexpressionofnkp46onnkcells.incontrast,glasswool,whichisa representativeasbestossubstitute,didnotinduceadecreasedexpressionofnkp46.theseresults indicatethatexposuretoasbestoshasthepotentialtoimpairthecytotoxicityofnkcells,andalter theexpressionofnkcellactivatingreceptorsandperforin/granzymes.nkp46seemstobe particularlyremarkablebecauseitslowexpressionwascommontobothnkcellsofpatientswith MMandNKcellsexposedtoasbestos.FuturestudiesconcerningimpairmentinexpressionsofNK cellactivatingreceptorsonnkcellsexposedtoasbestoswillcontributetothepreventionofthe developmentofmalignantmesothelioma. 237

240 ABSTRACTS Number:211 Abstracttitle: EstablishmentandcharacterizationofnewmalignantpleuralmesotheliomacelllinesfromJapanese patients TetsuoTaniguchi,HidekiMurakami,MakikoFujii,NoriyasuUsami,KoheiYokoi,YoshitakaSekido. AichiCancerCenterResearchInstitute,NagoyaUniversityGraduateSchoolofMedicine Keywords: arraycomparativegenomichybridization(cgh)analysis,celllineestablishment Abstract: Malignantpleuralmesothelioma(MPM)isanasbestosrelatedmalignancythatishighlyresistantto currenttherapeuticmodalities.inadditionto4celllinesthatwereportedinthepreviousmeeting, weestablishedanother8celllines(ymeso9,ymeso11b,ymeso12,ymeso14,ymeso21,y MESO22,YMESO25,andYMESO26B)fromJapaneseMPMpatients.Mutationandexpression analysesdemonstratedthatthenf2tumorsuppressorgene,whichisknowntobeoneofthemost frequentlyinactivatedinmpm,ismutatedordeletedinymeso9,ymeso12,ymeso14,ymeso 22,andYMESO26B,anddownregulatedinYMESO11BandYMESO21.Wedetectedhomozygous deletionofp16ink4a/p14arfin11of12celllines.however,mutationsofthetp53tumor suppressorgeneandotheroncogenes,includingkras,nras,braf,werenotfoundinthese12cell lines.wealsoperformedarraycomparativegenomichybridization(cgh)analysisandfoundnovel genomicalterationregions.ournewmpmcelllinesareusefulasnewmodelsforstudyingvarious aspectsofthebiologyofhumanmpmaswellasmaterialsforthedevelopmentoffuturetherapies. 238

241 ABSTRACTS Number:212 Abstracttitle: Geneticalterationsspecificformalignantmesotheliomacells KozoKuribayashi(1),KazuyaFukuoka(1),SyusaiYamada(1),ChiharuTabata(1),TakayukiTerada(1), YoshieYoshikawa(2),TomokoTamaoki(2),TohruTujimura(3),NoriakiTsubota(4),TakashiNakano(1) (1)DivisionofRespiratoryMedicine,HyogoCollegeofMedicine,Japan;(2)Departmentof Genetics,HyogoCollegeofMedicine,Japan;(3)DepartmentofMolecularPathology,HyogoCollegeof Medicine,Japan;(4)DepartmentofThoracicOncology,HyogoCollegeofMedicine,Japan Keywords: geneticalterations,p16,malignantmesothelioma(mm) Abstract: Toelucidatethegeneticalterationsspecificformalignantmesothelioma(MM),weconductedarray CGHanalysisof14humanMMcelllinesestablishedinourlaboratory.Homozygousdeletionswere detectedinvariousregionsof9q21ofallcelllines.homozygousorheterozygousdeletionswerealso detectedin22qregionsof12celllines.theminimumdeletionof9q21commontoallcelllineswas 20kb,involvingthep16gene,andseveralbreakpointhotspotswerenoted.Wethenanalyzed deletionofthep16geneatasinglecelllevelbyfishmethod.homozygousdeletionsweredetected in70%ofthecelllinesusedthatweredi,tri,ortetraploid.p16deletionscouldnotbedetectedin 30%,whichmaybeduetothelargesize(350kb)ofthep16probenotsuitablefordetectingsmall deletions.basedontheseresults,p16deletionsintumorcellsobtainedfromthepleuralbiopsyand pleuraleffusionwereanalyzedbyrealtimepcrtargetingseveralregionsof9q21.homozygousand heterozygousdeletionsofthep16geneweredetectedinallsamples,indicatingthatthismethodis usefulfordiagnosisofmm,althoughheterozygousdeletionsmaybeascribedtocontaminationof normalcells. 239

242 ABSTRACTS Number:213 Abstracttitle: CellSurfaceProteomicsrevealsnewproteinmarkersforthediscriminationofmalignantpleural mesotheliomafromlungadenocarcinoma AnnemarieZiegler(1),FerdinandoCerciello(1,2),DamarisBauschFluck(1,3),EmanuelaFelley Bosco(2),ColetteBigosch(2),AlexSoltermann(4),HolgerMoch(4),RolfStahel(2),RuediAebersold(1), BerndWollscheid(1,3) (1)InstituteofMolecularSystemsBiology,ETHZurich,Switserland;(2)LaboratoryofMolecular Oncology,ClinicandPoliclinicforOncology,UniversityHopitalZurich,Switserland;(3)NCCRNeuro CenterforProteomics,Zurich,Switserland;(4)InstituteofSurgicalPathology,UniversityHospital Zurich,Switserland Abstract: Introduction:Thecorrectdiagnosisofmalignantpleuralmesothelioma(MPM)isstillamajor problemforcliniciansaswellasforthepathologists.thehistopathologicalapproachiscomplicated byabroaddifferentialdiagnosisandcurrently,apanelofhistopathologicalmarkerareneededto discriminatempmfromanatomicallyrelatedmalignancieslikelungadenocarcinoma.therefore,we setouttoidentifycellsurfaceproteinpatternsviamassspectrometry(ms)whichwouldallowfor thediscriminationofmpmfromlungadenocarcinomaattissuelevel. MethodsWeinvestigatedthecellsurfacesubproteomeofoneepithelialMPMcellline(ZL55)in comparisontooneadenocarcinomacellline(calu3)viathecellsurfacecapturing(csc)technology. RelativequantificationoftheidentifiedcellsurfaceproteinswasachievedbySILAC(StableIsotope LabelingbyAminoAcidsinCellCulture)labeling.Differentiallyexpressedcellsurfaceproteinswere furtherinvestigatedonthemrnalevelbylowdensitymicroarrayrtpcronacollectionofmpm andadenocarcinomacelllines.confirmedclassificationmarkercandidateswerefurthervalidatedby IHCstainingsoncelllinesandfrozentissuesamplesfrompatientsaffectedbylatestageMPMor lungadenocarcinoma.results:over130bonafidecellsurfaceglycoproteinswereidentifiedand quantifiedviacsctechnology,amongthem37cdannotatedproteins.62cellsurfaceglycoproteins werefoundtobedifferentiallyexpressedbetweenthetwocelllinesatleasttwofold.rtpcr analysisof29differentiallyexpressedproteincandidateson15epithelialmpmand6adenocarci nomacelllinesrevealedtwoglycoproteinsaspotentiallygooddiscriminationmarkersbetweenmpm andadenocarcinoma.thesetwoclassificationmarkercandidateswerefurtherinvestigatedin antibodybasedihcexperimentsonpatientsamples.acommerciallyavailableantibodyagainstone outofthetwotargetcellsurfaceglycoproteinsdiscriminatedmpmfromadenocarcinomainclinical relevantihcstainingsonbiopsiesfromselectedpatients.conclusion:byusingcellsurface capturingtechnologyinaquantitativeproteomicsapproachwewereabletoidentifycellsurface glycoproteinswhicharedifferentiallyexpressedbetweenmesotheliomaandadenocarcinomacells. Initialvalidationoftwoselectedproteinsonpatientsamplesindicatetheirpotentialforaidinginthe correctclassificationofmpmincontrasttoadenocarcinoma. 240

243 ABSTRACTS Number:214 Abstracttitle: Seleniteinducedapoptosissignallingindifferentiallysensitivemesotheliomacelllines GustavNilsonne,EricOlm,AdamSzulkin,FilipMundt,AgnesStein,BrancaKocic,AnnaKlaraRundlöf, AristiFernandes,MikaelBjörnstedt,KatalinDobra KarolinskaInstitutet,Sweden Keywords: malignantmesothelioma,selenite,apoptosis Abstract: Malignantmesotheliomacellsmaydifferentiateintoanepithelioidorasarcomatoidphenotype.The latterisusuallymoreresistanttochemotherapy,andwehavepreviouslyfoundthatseleniteis selectivelytoxictosarcomatoidcells.seleniteisknowntoinduceoxidativestressandapoptosis.in thispaperweinvestigatewhichpathwaysofapoptosissignallingareactivatedbyselenite. Treatmentwithselenitecausedlossofmitochondrialmembranepotential.AnnexinPIanalysiswas usedtogetherwithjc1toexaminetheeffectofinhibitionofsignallingenzymes.chemicalinhibition experimentsshowedthatjnkhadanantiapoptoticrole,whilep38hadsomemediatoryeffectin sarcomatoidbutnotinepithelioidcells.inhibitionofp53madenodifference.seleniteinduced nucleartranslocationofp53.however,lessp53wasfoundinitsactivednabindingformafter selenitetreatment.levelsofthioredoxindecreasedconsiderablyinsarcomatoidcellsafterselenite treatment,indicatingthatp53maybeinactivated.cathepsinbbutnotdandeshowedproapoptotic activitythatcouldbeabrogatedbychemicalinhibition,althoughthisdidnotincreasetheviabilityof thecells.activationofcaspase3waslimited.asanalternative,wesearchedforautophagicvesicles, butfoundnone.baxwasupregulatedonlyinsarcomatoidcellsandbclxlwasdownregulated particularlyinepithelioidcells.thesephenotypicdifferencesmaypartiallyexplainthediffering sensitivityofmesotheliomacellstoselenite. 241

244 ABSTRACTS Number:215 Abstracttitle: Aberrantsplicingandproteasesinvolvementinmesothelinreleasefromepithelioidmesothelioma cells. CaroleSAPEDEPEROZ,AnneGAUVRIT,IsabelleBARBIEUX,MartinePADIEU,LaurentCELLERIN, ChristineSAGAN,ArnaudSCHERPEREEL,GérardDABOUIS,MarcGREGOIRE INSERM,LilleHospitalPulmonary&ThoracicOncology,NantesHospital Pulmonaryand Anatomopathology Keywords: MesotheliomaSolubleMesothelinMetalloproteasesDiagnosis Abstract: Elevatedamountsofsolublemesothelinrelatedproteins(SMRP)havealreadybeenreportedinsera orpleuraleffusionsfrommesotheliomapatients,providingausefuldiagnosticmarkerformalignant pleuralmesothelioma(mpm).however,theoriginofsmrpisnotyetunderstood.productionof SMRPcouldberelatedtoanabnormalsplicingeventleadingtosynthesisofasecretedprotein (release)ortoanenzymaticcleavagefrommembraneboundmesothelin(ectodomainshedding).to testthesehypotheses,weusedapanelofmesotheliomacellsestablishedinculturefrompleural effusionsofmpmpatients.ourinvitroresultsconfirmedspecificmesothelinexpressionandsmrp productioninsupernatantsfromepithelioidmpmcelllines,thusprovidingarelevantcellularmodel tostudysolublemesothelinproductionmechanisms.expressionofmesothelinencodingrna variantswasscreenedbyrtpcrexperiments.proteasesinvolvementinmesothelincleavagefrom cellularsurfacewasinvestigatedbytreatmentofmpmcellswithgm6001,abroadspectrummmps andadamsfamiliesinhibitor.gm6001treatmentsignificantlyimpairedsmrpproductionbympm celllines,infavourofanenzymaticmediatedsheddingprocess.inaddition,asplicevariant transcriptofmesothelin(variant3)wasdetectedinthesempmcelllines,inaccordancewiththe releaseofasecretedpartoftheprotein.so,ourresultsindicatethatbothmechanismscouldbe implicatedinsolublemesothelinproductionbyepithelioidmesotheliomacells. 242

245 ABSTRACTS Number:216 Abstracttitle: D240UtilityforDifferentialDiagnosisbetweenPleuralSarcomatoidMesotheliomaandLung SarcomatoidCarcinoma YukioTakeshima,JeetVAmatya,KeiKushitani,MayumiKaneko,KoukiInai Dept.ofPathol,HiroshimaUniversity,Dept.ofPathol,HiroshimaCityAsaHospital,Japan Keywords: D240,Immnohistochemistry,Sacrcomatoidmesothelioma,Sarcomatoidcarcinoma Abstract: [OBJECTIVES] Thedifferentialdiagnosisofpleuralsarcomatoidmesothelioma(SM)fromlungsarcomatoid carcinoma(lsc)invadingparietalpleuraandchestwallischallengingissue.thepurposeofthisstudy istoelucidatetheusefulantibodiesfordifferentialdiagnosis. [MATERIALS&METHODS] FortyfivepleuralSMsand27LSCswereimmunohistochemicallyanalyzedusing15commercially availableantibodies,includingd240,calretinin,thrombomodulin,wt1,cea,napsina,ttf1, pancytokeratin,cam5.2,ema,berep4,moc31,αsmoothmuscleactin,hcaldesmonand desmin. [RESULTS] OnlyD240positivity(86.7%)amongpleuralSMwassignificantlyhigherthanthatofLSC(25.9%).The proportionofstaininggradeofd240inpleuralsmwerealsohigherthanthatoflsc.thepositivity of adenocarcinomamarkers,includingcea,napsinaandttf1waslow.eveninlsc. [CONCLUSION] Theseresultsindicatedthatevaluationofpositiverateandpositivedegreeofwellknown mesothelialmarker, D240,wasapplicabletodifferentiatepleuralSMfromsarcomatoid componentoflscalongwithclinicalandradiologicalinformation. 243

246 ABSTRACTS Number:217 Abstracttitle: AnalysisofEGFR,PDGFRA,PDGFRBandrelatedpathwaysinmalignantperitonealmesotheliomas. FedericaPerrone,GennyJocollè,SilviaBrich,AntonelloCabras,MarcelloDeraco,DarioBaratti, SilvanaPilotti FondazioneIRCCSIstitutoNazionaleTumoriMilano,Italy Keywords: EGFR;PDGFRA;PDGFRB;PI3KCA Abstract: Purpose.Littleisknownaboutreceptortyrosinekinase(RTK)activationinmalignantperitoneal mesotheliomas(mpm),thusweperformedegfr,pdgfraandpdgfrbanalysistoascertainif deregulationofrtkcouldofferusefulalternativetherapeutictargetsinthistumor. Experimentaldesign.EGFR,PDGFRAandPDGFRBexpressionandphosphorylationwere immunohistochemicallyandbiochemicallyanalysedin15mpmwhoseformalinfixedparaffin embeddedandsurgicalfrozenmaterialwasavailable.thetyrosinekinasedomain(exons1821)of theegfrgenewereautomaticallysequenced,aswellastheextracellular(exon10)and juxtamembraneregions(exon12)andthetyrosinekinasedomain(exons14and18)ofpdgfraand PDGFRB.ThecognateligandexpressionwasinvestigatedbyrealtimePCR.Additionally,weexplored thestatusofrtkdownstreampathwaysthroughmutationalandbiochemicalanalysisofpi3kca gene(exons9and20)/pten/akt,anderk,alongwithmtoranditseffectors6. Results.Immunohistochemicalandimmunoprecipitation/westernblotanalysesshowedEGFR, PDGFRAandPDGFRBexpressionandactivationinthemostofthecases.InparticularEGFRand PDGFRAresultedmorefrequentlyphosphorylatedthanPDGFRB.Autocrineloopactivationofthese receptorswassuggestedinallthecasesbytheexpressionoftherelatedcognateligandstgfα, PDGFAandPDGFB,inabsenceofreceptorgainoffunctionmutations.NoPI3KCAmutationswere found,whileallthempmsshowedexpressionofptenandexpression/activationofakt,erk,aswell asofmtorands6. Conclusions.EGFR,PDGFRAandPDGFRBseemtobepromisingmoleculartargetsfortailored treatmentsinmpm.furthermore,thestrongactivationofthedownstreamsignallingpointsouta roleofmtorinhibitorsoranalogousinmpmtreatment. 244

247 ABSTRACTS Number:218 Abstracttitle: NOVELSYNTHETICINHIBITORSOFTHEmTORPATHWAYINMALIGNANTMESOTHELIOMA SaraBusacca(1),GianCesareTron(1),GiovanniBattistaGiovenzana(1),LucianoMutti(2),Giovanni Gaudino(1) (1)DISCAFF,Novara,Italy;(2)DepartmentofMedicine,LocalHealthUnit11,Piemonte,Italy Keywords: malignantmesothelioma,mtor,kinaseactivity,p70s6k,4ebp1 Abstract: MalignantMesotheliomaisanaggressivecancerwithpoorprognosisandlowmediansurvival, refractorytocurrenttherapies.mammaliantargetofrapamycin(mtor)promotesuncontrolled proliferation,throughcellcycleprogression,regulationofproteinsynthesisandproteindegradation, playingacriticalroleintumorcellsurvivalandresistancetochemotherapy.themtorpathway becomesactivatedinmosthumantumors,includingmalignantmesothelioma.rapamycinandits derivativesareknownasmtorinhibitors,howeverweaimedattestingnovelsmallmolecules, synthetizedbythesplitugimulticomponentreaction,asselectiveinhibitorsofthisenzymeactivity, todevelopeffectivestrategiesforthetreatmentofthisneoplasm.weevaluatedcytotoxicityofthe synthesizedcompoundsonthreemesotheliomacelllines:mpp89,msto211handren.after preliminaryscreeningsweobservedamarkeddecreaseofcellviabilityinallthreecelllinesfortwo outoftencompounds,whichdisplayedic50valuesaboutof15μm.moreover,theyinhibited theautophosphorylationofmtoronser2481aswellasthephosphorylationoftwomtor downstreameffectors70kdaribosomalproteins6kinase1(p70s6k)andtheeukaryotictranslation initiationfactor4e(eif4e)bindingprotein1(4ebp1).conversely,noinhibitiononakt(ser473)and mtor(ser2448)phosphorylationwasobserved. Interestingly,theinhibitionofmTORkinaseactivityofbothp70S6Kand4EBP1wasobservedinMPP 89cells,whileinMSTO211Hcellswasinhibitedonlythephosphorylationofp70S6K,whichwas slightlyaffectedinrencells.thesepreliminarydatahighlightthesecompoundsasnewinhibitorsof themtorpathway,exertingcytotoxiceffectsonallmesotheliomacellsexaminedandsuggest selectiveeffects,dependentonthedifferentcellphenotypes. 245

248 ABSTRACTS Number:219 Abstracttitle: OurSurgicalTechniquesofExtrapleuralPneumonectomyforDiffuseMalignantPleuralMesothelioma KazunoriOkabe,EisukeMatsuda,HiroyukiTao,SeikiKobayashi,KatsutoshiHirasawa,KazuroSugi SanyoNationalHospital,Ube,Japan Keywords: extrapleuralpneumonectomy,malignantpleuralmesothelioma,mesothelioma,surgery Abstract: Background:Multimodalitytherapywhichincludessurgery,radiotherapyandchemotherapyis neededtotreatearlystagediffusemalignantpleuralmesothelioma.manyexpertsurgical techniquesarerequiredforexcellentextrapleuralpneumonectomytokeeppatientconditiongood enoughforradiotherapyandchemotherapy.oursurgicaltechniquesofextrapleural pneumonectomyfordiffusemalignantpleuralmesotheliomaarepresented. Surgicaltechniques:1.Anasogastrictubeisplacedtoconfirmtheesophagusandtoprevent aspirationpneumonia.2.extendedposterolateralincisionalongthe6thribismade,andoldincision siteforthepleuralbiopsyisremoved.the6thribisresected,andtheextrapleuraldissectionis started.3.bloodlossisreducedbyhypotensiveanesthesiaanddilutedepinephrine.systolicblood pressureiskeptaround90mmhg.towelswhicharesoakedin500mlsalinewith0.5mlof epinephrinearepackedinthedissectedextrapleuralspace.4.thecostalarchisdividedtocreate widerexposure.5.thediaphragmincisionisinitiatedatitsanteriormargin.theperitoneumis preservedwhendissectingthediaphragm.6.thepericardiumincisionisstartedattheapexcordis. 7.Thepulmonaryveinsandarteryaredividedintrapericardiallybystaplers.8.Themainbronchusis dividedbyastapler.9.themediastinallymphnodesareresected.10.thethoracicductisligatedat thelevelofdiaphragmintherightsidecase.11.dualmeshbiomaterial(20cmx30cmx1mm,w.l. Gore&Associates,Inc.,AZ,USA)forthediaphragmreconstructionandprecludepericardial membrane(15cmx20cmx0.1mm,w.l.gore&associates,inc.,az,usa)aresoakedinantibiotics solution.12.whenthediaphragmisreconstructed,multiplesuturesaretiedoutsidetheintercostal space.someofthemshouldbestitchedaroundthe9thor10thrib.13.thepericardiumis reconstructedtopreventcardiacherniation.14.achesttubeisplacedthroughtheposterolateral incision. Conclusion:Oursurgicaltechniquesofextrapleuralpneumonectomyfordiffusemalignantpleural mesotheliomaarepresented.manyexperttechniquesarerequiredtoperformexcellent extrapleuralpneumonectomytokeeppatientconditiongoodenoughforradiotherapyand chemotherapy. 246

249 ABSTRACTS Number:220 Abstracttitle: Earlydetectionofmalignantpleuralmesothelioma KenzoHiroshima,ChibaUniversity,ToshikazuYusa,ChibaRosaiHospital,ToruKameyaShizuoka CancerCenter,ChikabumiKadoyamaSaitamaRedCrossHospital,YukioSaitohNaritaRedCross Hospital,TakekazuIwata,ChibaEastHospital,YujiTada,ChibaUniversity,HideakiShimada,Chiba CancerCenter,MasatoshiTagawa,ChibaCancerCenter,YukioNakataniChibaUniversity Keywords: mesothelioma,pathology,earlydiagnosis,extrapleuralpneumonectomy,thoracosopy, immunohistochemistry Abstract: Background.Pleuraleffusionistheonlyroentgenographicalabnormalfindinginpatientswithearly stagemalignantpleuralmesothelioma(mpm),inwhichnonodulesweredetected roentgenographically.computedtomographyshowspleuraleffusionwithslightpleuralthickening. Histopathologicalfindingofpleuralbiopsywiththoracoscopeistherebycrucialforthediagnosisof mesothelioma.however,pathologicaldiagnosisofmesotheliomawithsmallbiopsiesisoften difficult,becausespecificimmunohistochemicaltestorothermarkersthatdiscriminatebetween hyperplasticandneoplasticmesotheliumarecurrentlyunavailable.althoughapapillaryarchitecture andnecrosisofmesothelialcellsfavorsmesotheliomainthepleura,invasionisthemostdecisive indicatorofmesothelioma.theaimofthisstudywastoelucidatetheclinicaldataandthe pathologicalfindingsonthoracoscopicbiopsiesofearlystagempm.design.weinvestigatedeight extrapleuralpneumonectomy(epp)casesofmpmwithoutgrosslyvisibletumor.weevaluatedthe clinicaldataandthepathologicalfindingsofthoracoscopicbiopsiesperformedbeforeepp.results. Levelsofhyaluronicacidwereextremelyhigh(>90,000ng/ml)infivecasesandmoderatelyhigh (>40,000ng/ml)inonecase.Cytologicalexaminationofpleuraleffusionrevealedmalignantcellsin sixcasesandsuspiciousofmalignancyintwocases.multiplesmallmaculasornoduleswith diameterlessthanafewmillimeterswereobservedonthoracosopyinsomecases.however,there wasnoabnormalfindingintwocases.invasionintofattissuewasobservedinthreecases,papillary structurewasobservedintwocases,andexpansilestromalnoduleswereobservedinonecasein thoracoscopicbiopsies.mesotheliomacellsproliferatedbothontheparietalandvisceralpleurae andinvadedthemineppspecimens.theyproliferatedinsolitary,trabecular,papillary,orsolid patternsinepithelioidmesothelioma,andinpatternlesspatterninsarcomatoidmesothelioma.the lesionswerediscontinuousandmultifocal.conclusions.pathologicalfindingsofstromalinvasion wereobservedinlessthanhalfofthecases.papillaryproliferationandexpansilestromalnodules areimportantpathologicalfindingsforthediagnosisofearlystagempm.clinicaldata,suchaslevels ofhyaluronicacid,cytologicalexamination,andthoracoscopicfindings,arehelpfulindiagnosing MPMinwhichthoracoscopicbiopsieslackthefindingsofstromalinvasion. 247

250 ABSTRACTS Number:221 Abstracttitle: Resultsofsurgicaltreatmentaspartofmultimodalitytreatmentformalignantpleuralmesothelioma. HoukeKlomp,JohannavanSandick,IngridKappers,SjaakBurgers,MichelWouters,RickHaas,Paul Baas TheNetherlandsCancerInstituteNKIAVLAmsterdamTheNetherlands. Keywords: surgery,multimodality,radiotherapy,chemotherapy,earlystage Abstract: Background.Aminorityofpatientswithmalignantpleuralmesotheliomaarecandidatesforsurgical treatment.itisvirtuallyimpossibletoachieveamicroscopicallyradicalresection.therefore,surgical therapyhasbeencombinedwithothertreatmentmodalities.themosteffectivecombinationis unknown.theobjectiveofthisstudywastoevaluatetheresultsofsurgicaltherapyaspartofthree differenttherapeuticregimensinourinstitute. Patients.Thesegroupsformconsecutiveseriesofpatientsingoodcondition(WHO01,noweight loss>10%)withlowvolumempm(stageiii,nohemithoracicretraction,epitheloidormixedtype). BetweenJanuary1999andDecember2001,20patientsunderwentacombinationofcytoreductive surgerypleurectomy(12)orextrapleuralpneumonectomy(epp)(8)andintraoperative hyperthermicintrathoracicchemotherapy(hithoc),followedbyradiotherapytothethoracotomy scaranddrainagetracts(24gy).betweenjanuary2002andseptember2005,15mpmpatientswere treatedwitheppandpostoperativehemithoracicradiation(54gy).betweenseptember2005and October2007,17MPMpatientsweretreatedwithinductionchemotherapy(PC=pemetrexed, cisplatin),followedbyeppandpostoperativehemithoracicradiation(54gy).mediandurationof postoperativefollowupwas14(880)monthsforhithocpatients,30(871)monthsforepp+rt patients,and14(532)monthsforpc+epp+rtpatients. Results.Thethreegroupswerecomparableregardingage,sex,performancestatus,pulmonary function,andtumorhistology.mediandurationofhospitalstaywas15vs14vs10days(p=0.02), medianicustaywas4vs2vs1day(p=0.01).allbutonehithocpatientreceivedradiotherapy accordingtoprotocol.hemithoracicradiotherapywasdeliveredasplannedin12of15epp+rt patients.fourpatientsinthepc+epp+rtgroupdidnotundergosurgicalresectionduetoprogression oremboliccomplicationsduringinductionchemotherapy.hemithoracicradiotherapywasdelivered asplannedin9of13operatedpc+epp+rtpatientsmedianrecurrencefreesurvivalwas11months forhithocpatients,23monthsforepp+rtpatientsand16monthsforpc+epp+rtpatients(0.09). Themediantimetolocaltumorrecurrencewas12vs39vs19months(p=0.008).Follow upistoo shortforevaluationofoverallsurvival. Conclusions.Theuseofcytoreductivesurgerywithintraoperativechemoperfusioninthe managementofmpmisnotsupported.localoncologicresultsofextrapleuralpneumonectomywith adjuvanthemithoracicradiotherapyareencouraging.inourhands,inductionpcchemotherapyisnot associatedwithimproved(locoregional)diseasecontrol. 248

251 ABSTRACTS Number:222 Abstracttitle: TARGETINGOFSIGNALINGPATHWAYSTHATAREFREQUENTLYIMPLICATEDINMALIGNANT MESOTHELIOMA DeborahA.Altomare,LiliZhang,JosephR.Testa. HumanGeneticsProgram,FoxChaseCancerCenter,Philadelphia,PA19111,USA Keywords: Mesothelioma,AKT,ERK Abstract: Malignantmesothelioma(MM)ishighlyresistanttoconventionaltherapies.Activatedkinasesthat arepartofgrowthfactorstimulatedsignalingpathways,suchaspi3k/akt/mtorandraf/mek/erk, arelikelytocontributetoahighrateoftumorgrowth,progressionandresistancetotreatment.our hypothesisisthattheeffectivenessofmmtherapymaybeimprovedthroughanticanceragentsthat targetmultipleproteinsinkeysignalingpathwaystoincreasecelldeath.wearefocusingondrugs thathavebeenreportedtoblocktheenzymaticactivityofaktorerk.weusedapdk1/akt/fltdual pathwayinhibitordesignatedkp3721,aknownexperimentalinhibitorofmekkinasenamedu0126 andapharmaceuticalcurrentlyinclinicaltrialscalledsorafenib(nexavar;bayerpharmaceuticals) thattargetsseveralkinasesinvolvedintumorproliferationandprogressionincludingraf,vegfr,and othergrowthfactorreceptors.analysisofphosphorylatedproteinsdownstreamintherespective pathwaysshowedthatsorafenibwaseffectiveatinhibitingerkactivityinourpanelofhumanmm celllines,whereaskp3721didnotinducethepredictedeffects.sorafenibalsoinhibitedthesurvival ofhumanmmcellsinmttassays.moreover,facsanalysisanddnafragmentationassaysshowed thatsorafenibinducedmmcelldeath.testingofsorafenibinmousemodelsofmmshowed promise,delayingmmtumorprogression.studiesarenowunderwaywithanothermousemodel thatdevelopsasbestosinducedmmstodetermineifsorafenibisefficaciousinthispreclinicalmodel. Overall,insightsderivedfromthesestudiesareexpectedtoprovideimportantcluesforthedesignof atherapeuticstrategytargetingspecificsignaltransductionpathwaysinmm. 249

252 ABSTRACTS Number:223 Abstracttitle: APhaseIII,Randomized,DoubleBlind,PlaceboControlledTrialofVorinostatinPatientswith AdvancedMalignantPleuralMesothelioma(MPM)PreviouslyTreatedwithSystemicChemotherapy LeeKrug(1),MaurizioMarangolo(2),HedyKindler(3),ChristianManegold(4),PaulBaas(5),Hilary Calvert(6),GregLubiniecki(7),CesarSanzRodriguez(7),JoséGarciaVargas(7) (1)MemorialSloanKetteringCancerCenter,USA;(2)AziendaUSI,Italy;(3)UniversityofChicago,USA; (4)UniversityofHeidelberg,Germany;(5)TheNetherlandsCancerInstitute,theNetherlands; (6)NewcastleUniversity,UK;(7)MerckResearchLaboratories Keywords: Vorinostat,HDACinhibitor,advancedmesothelioma Abstract: Background:Malignantpleuralmesothelioma(MPM)isanuncommoncancerassociatedwith asbestosexposurethathasagenerallypoorprognosis.currenttreatmentshavealimitedeffecton survival.thestandardfirstlinechemotherapyregimenispemetrexedandcisplatinwhichimproved mediansurvivalovertreatmentwithcisplatinalonefrom9to12months.nostandardsecondline therapyexistsandthebenefitsofchemotherapyforpatientswithprogressionaftertreatmentwith pemetrexed/cisplatinareunknown.inapriorphaseitrialoftheoralhistonedeacetylase(hdac) inhibitor,vorinostat,responsesanddiseasestabilizationwereobservedinseveralpatientswith previouslytreatedmpm,promptingfurtherstudy. Methods:ThisPhaseIII,randomized,doubleblind,placebocontrolled,multicenterstudyaimsto assesswhethertreatmentwithvorinostatimprovessurvivalforpatientswithadvancedmpmand progressivediseaseafterpriorchemotherapy.eligibilitycriteriainclude:pathologicallyconfirmed diagnosisofepithelial,sarcomatoid,ormixedhistologympm,whichhasprogressedorrelapsed followingtreatmentwithpemetrexedandeithercisplatinorcarboplatin;nomorethan2prior systemictherapies(pemetrexedmusthavebeenpartofthemostrecentregimen);measurable disease;andkarnofskyperformancescalestatus;70%.patientsarerandomized1:1toreceive vorinostatplusbestsupportivecare(bsc)orplaceboplusbsc.patientsaretreatedwith300mgoral vorinostattwicedailyfor3consecutivedaysevery7days,repeatedweeklyina21daycycle.the primaryobjectivesaretocomparetheoverallsurvivalofpatientstreatedwithvorinostatplusbscto thatachievedinpatientstreatedwithplaceboplusbsc,andtoassessthesafetyandtolerabilityof vorinostat.secondaryobjectivesincludecomparisonofoverallobjectiveresponserate;progression freesurvival;dyspneascore;andpercentchangeinforcedvitalcapacity. Results:Patientaccrualisunderwayandapproximately660patientswillbeenrolledtoachieve540 eventsforthesurvivalanalysis.thetrialhaspassedthesecondinterimanalysisandcurrent recruitmentstatuswillbepresented. Discussion:ThisisthelargesttrialeverconductedinpatientswithpreviouslytreatedMPM.If successful,vorinostatwouldfillanunmetneedforthisgroupofpatients. 250

253 ABSTRACTS Number:224 Abstracttitle: COMBINEDMODALITYTREATMENTFORMALIGNANTPLEURALMESOTHELIOMA(MPM) PhilippeNafteux,JohnnyMoons,KristiaanNackaerts,YolandeLievens,JohanVansteenkiste,Marc Decraemer,WalterVandenBogaert,ToniLerut UniversityHospitalsLeuven,Belgium Keywords: combinedmodality,extrapleuralpneumonectomy,pemetrexed, Abstract: Purpose: GuidelinesforthetreatmentofMPMdonotadvocateeitherradiotherapyorsurgeryonly.Since newerandmoreactivechemotherapybecameavailableformpm,combinedmodalitytreatmentfor MPMbyincludingneoadjuvantoradjuvantchemotherapyandpostoperativeradiotherapy,hasbeen studiedmorefrequently.wealsostartedafeasibilitystudyofcombinedmodalitytreatment(cmt) formpmpatients,combiningneoadjuvantchemotherapy,surgeryandpostoperativeradiotherapy. Patientsandmethods: AllconsecutiveMPMpatients,selectedforCMTbetweenMarch2003andDecember2007were included.treatmentconsistedofinductionchemotherapy(ic)withcisplatinpemetrexed(3cycles,q 3wks),extendedpleuropneumonectomy(EPP),andradiotherapy(mostlybyIMRT,intensity modulatedradiotherapy;54gy/1.8gy).inclusioncriteriawere:age<65years,whoperformance Status 1,medicallyfitforpneumonectomy,stagingofcT2N2M0orless(epithelialsubtypes) andct2n1m0orless(otherhistologicsubtypes). Results: Atotalof39MPMpatientswereselectedforCMT.Histologicsubtypeswere:epithelial(n=28); desmoplastic(n=2);sarcomatous(n=1);mixed(n=8).fivepatientswereeitherprogressiveaftericor estimatedirresectable.twentysixpatientsunderwentepp(20withr0resection;6withr1 resection)while7patientshadanexploratorythoracotomy(irresectablempmduetochestwallor oesophagealinvasion)and1patientrefusedsurgery.postsurgicalcomplicationsincluded: postoperativemortality(n=3or11%),rethoracotomyforbleeding(n=1),atrialfibrillation(n=8), ARDS(n=2),DVT(n=1)andempyema(n=1).Because1patientwasestimatedineligiblefor irradiation(uniquekidney)andanotherdevelopedbonemetastases,21patientsstarted postoperativeradiotherapy.onepatientdidn tcompleteradiotherapyandanotherdiedafterending radiotherapy(boop).attheend,20/39patientscompletedcmt.mediansurvival(aftermpm diagnosis)forall39patientswhostartedcmtandforthe20patientswhocompletedcmt,was24.7 monthsand31.2months,respectively. Conclusions: ThisstudydemonstratedthatCMTwithneoadjuvantchemotherapy,EPPandpostoperative radiotherapyisfeasibleinourcentrebutforselectedmpmpatientsonly.themediansurvivalfor thosepatientswhocompletedcmtispromising,butvalidationoftheseresultsinfuturerandomized controlledtrialswillbeofinterest. 251

254 ABSTRACTS Number:225 Abstracttitle: TheInsulinLikeGrowthFactor(IGF1)PathwayInfluencesProliferationofStemCellsDerivedfrom HumanMalignantMesotheliomaCellLines. YongbaekKim,KiyonoriKai,SusanD'Costa,ArnoldBrody NorthCarolinaSt.Univ Keywords: Insulinlikegrowthfactor;cancerstemcells;malignantmesothelioma Abstract: Stemcellsexhibitextensiveselfrenewalcapacityandtheabilitytodifferentiateintoawidevariety ofcelltypes.thepotentialroleofstemcellsinneoplasiahasbeenalongstandingresearchtopic,but inthelastfewyears,agrowingbodyofevidencesupportsthepostulatethattumorsareorganizedin ahierarchyofheterogeneouscellpopulationswithdifferentbiologicpropertiesandthatthecapacity tosustaintumorformationandgrowthresidesexclusivelyinasmallproportionofcellscalledcancer stemcells(cscs).thecscisdefinedashavingtheabilitytoselfrenew,givingrisetoanother malignantstemcellaswellascellsthatdevelopsintocancercellswithdiversephenotypesand genotypes.humanmalignantmesothelioma(hmm)isaninvariablylethaltumorofthepleuraor peritoneumcausedprimarilybyexposuretoasbestosfibers.hmmremainsweaklyresponsiveto standardmodalitiesoftherapy.theinsulinlikegrowthfactor(igf)signalingpathwayisimportantin theregulationofcellproliferation,survivalandapoptosis.thebiologicalactivitiesofigf1are mediatedthroughtheigf1receptor.ithasbeenshownthattheigf1pathwayandrelatedgenesare dysregulatedinhmmandtheblockingofthispathwaysuppressesmesotheliomacellgrowthinvitro andinvivo.herewehaveusedhoechst33342stainingtoidentifycscsbyflowcytometryattwo emissionwavelengths(redandblue).lowfluorescentcellsappearedasa sidepopulation (SP)well separatedfromthenonsidepopulation(nsp)ofhighfluorescentcells.stemcellswere predominantlyfoundinthespfractionandwereseparatedfromthreehmmcelllines.abreast cancerlinewasincludedasapositivecontrol. Stemness genessuchasnotch1andpou5f1were expressed35foldinspcellsovernspcells.treatmentofthehmmcellswithseveralspecifickinase inhibitorsblockedtheigf1rpathwayandshoweddosedependentreductionofcellsinthesp fraction,whilecisplatintreatmentincreasedthepercentageofspcells.weproposethatfurther studiesonthebiologyofcscsinthespsofhmmcellscouldprovidenewinformationonthe responseofthesecellstopotentialtherapeuticapproaches. 252

255 ABSTRACTS Number:226 Abstracttitle: Severecomplicationaftercytoreductivesurgeryandhyperthermicintraperitonealchemotherapyisa markerofpoorprognosisindiffusemalignantperitonealmesothelioma MarcelloDeraco,ShigekiKusamura,DarioBaratti,DomenicoSabia FondazioneIRCCSIstitutoNazionaleTumoriMilano,Italy Keywords: peritonealmesothelioma,prognosticfactors,localregionaltherapy Abstract: Background:Thecytoreductivesurgeryandhyperthermicintraperitonealchemotherapy(CRS+HIPEC) isactuallyconsideredthetreatmentofchoicefordiffusemalignantperitonealmesothelioma (DMPM).Patientselectionfortheprocedureshouldpursuenotonlymaximumbenefitintermsof survivalandqualityoflifebutalsotheidentificationoflowriskgroupsformajormorbidity.we assessedthecorrelationbetweenprocedurerelatedmorbidityandriskofdiseaseprogression,2 adverseeventsthatareusuallytakenasindependentphenomenainthedecisionmakingfor procedureindication. Methods:SixtythreeDMPMpatients(27M/36F)submittedtoCRS+HIPECwithacurativeintent.We considered2maindependentvariablessurgicalmorbidityg35andsystemictoxicityg35afterthe procedure.theadverseeventsweregradedaccordingtoncictcaev3criteria.weassessedthe correlationofthesevariableswithoverallandprogressionfreesurvivals(os/pfs).wealsotestedthe prognosticsignificanceofthefollowings:previoussurgicalscore,age,sex,carcinomatosisextension, completenessofcytoreduction(cc).thesurvivalwascalculatedfromthe14thpostoperativeday untilthedateofdeathorofthelastcontact.themedianfollowupwas22.2months(range:1118). RESULTS:ThepostoperativesurgicalmorbidityG35andsystemictoxicityG35rateswere32%and 33%,respectively.MedianOSandPFSwere39monthsand22months,respectively.After multivariateanalysisccandsurgicalmorbidityg35wereproventobeindependentlycorrelated withashorteros.accordinglyage,surgicalmorbidityg35weresignificantlyandindependently correlatedwithashorterpfs. CONCLUSIONS:Theindicationoftheprocedureinhighriskgroupforseveremorbidityshouldbe carefullytailoredasoutcomebenefitisunlikelytobeobtainedinsuchcircumstance.fromaanother pointofview,thisdatacouldmeanthatoncethedmpmpatientistreated,theemergenceofa seriousmorbiditycouldbeasignofaworseprognosis.theunderliningmechanismsresponsiblefor thecorrelationbetweenthetreatmentmorbidityandpooroutcomeisunknown. 253

256 ABSTRACTS Number:227 Abstracttitle: Simianvirus40asaprognosticfactorinmalignantpleuralmesothelioma AbdelRahmanzekri,AbeerBahnassy,WaleedMohamed,NellyHassan,AbdelRahmanAbdel Rahman,FatmaKassem,RababGaafar NationalCancerInstitute,CairoUniversity,Egypte Keywords: SV40,Mesothelioma,Prognosticfactors,Biologicalmarkers Abstract: Background:MalignantMesotheliomaisahighlyaggressiveneoplasm.Inthepast50years,the incidenceofmalignantpleuralmesothelioma(mpm)hasbeenincreasingespeciallyindeveloping countries,alongwithindustrialdevelopment.theassociationbetweensimianvirus(sv40)and malignantpleuralmesothelioma(mpm)suggestsanetiologicalroleforsv40.however,exact pathogenicmechanismsandpossibleprognosticvaluearenotclear. Methods:Freshtumortissueswereobtainedfrom40MPMEgyptianpatients.Allcasesdiagnosedas MPMwerepositiveformesotheliomamarkers(calretinine,mesotheliomaantigen,keratin5/6)and negativeforepithelialmembraneantigenand/orcytokeratinand/orcea.sarcomatoidcaseswere diagnosedbybeingpositiveformesotheliomaantigenandnegativeforvimentin.thesampleswere alsoinvestigatedforthepresenceofsv40dna,alteredrbexpressionandp53genestatususing immunohistochemistryandmoleculartechniques.therelationbetweensv40,asbestosexposure, Rb,p53andtheircontributiontoclinicopathologiccharacteristicsandoverallsurvival(OS)were assessed. Results:Theagerangedfrom20to69years(mean=45),21weremalesand19werefemales.SV40 DNAwasdetectedin20/40casesandasbestosexposurein31cases;18ofthemwereSV40positive. Alteredp53andRbexpressionweredetectedin57.5%and52.5%respectivelywithnop53mutation. TherewasastatisticallysignificantcorrelationbetweenthepresenceofSV40viralsequencesandthe pathologicaltypeofthetumorsince13outofthe20sv40positivecases(65%)wereofthe sarcomatoid/mixedvariantscomparedto7(35%)oftheepithelioidvariant(p.=0.03).similarly,there wasastatisticallysignificantcorrelationbetweenthepresenceofsv40viralsequencesandapositive historyofasbestosexposure(p.=0.03).multivariateanalysisshowedthatwhensv40andasbestos exposurewereconsideredtogether,onlycombinedpositivityofbothisanindependentprognostic factoraffectingtheos(p=0.001). Conclusion:SV40andasbestosexposurearecommoninEgyptianMPMdenotingapossible etiologicalroleandasynergisticeffectforbothagents.ourresultsprovethatcombinedpositivityfor SV40andasbestosexposureisanindependentprognosticfactorinMPMhavingadetrimentaleffect onos. 254

257 ABSTRACTS Number:228 Abstracttitle: CTdeterminedtumorvolumepredictssurvivalinepithelialMPMfollowingextrapleural pneumonectomy HirotoHatabu,WilliamRichards,ShinMatsuoka,JordanMueller,CarlAlsup,LambrosZellos,Aneil Mujoomdar,MichaelJaklitsch,RaphaelBueno,DavidSugarbaker BrighamandWomen'sHospital,Boston,MA,USA Abstract: Passetal(JThoracCardiovascSurg1998;115:310318)reportedanassociationoftumorvolumewith survivalinsurgicallytreatedmalignantpleuralmesothelioma(mpm)patientswithvaryinghistology andextentofresection.giventheclinicalimportanceofpreoperativefactorspredictiveofoutcome, wesoughttoreplicatethisanalysisusingupdatedvolumetricmeasurementtechniques.tominimize competinginfluencesonoutcomewestudiedahomogeneouscohortofpatientswithepithelial MPMtreatedwithextrapleuralpneumonectomy(EPP). DICOMfilesofCTimagesofthehemithoraxwereanalyzedusingasemiautomaticimageprocessing thresholdtechniquetoisolatethetumorfromothertissuesandstructures(imagejver.1.39; Pixelsbetween5to150HUwithinsegmentedareasweresummedbythesoftwareandmultipliedby 15forconventionalCT(sliceinterval5mm)orby11.16forPETCT(sliceinterval3.72).Tumor volumeestimateswereobtainedbyintegrationacrossslices.apicaldiseasewasevaluatedvisually andscoredaspresentorabsent. EightythreepatientswithepithelialtumorswhounderwentEPPandforwhomDICOMimageswere availablewereevaluated.amongthese,58weremaleandmedianagewas59yrs.mediantumor volumewas423cc(range14236cc).thirtyeightpatientswithtumorvolume<500ccexperienced significantlylongersurvivaldurationthan45patientswith>500cctumorvolume(37versus17 months;p<.0001).fortypatientswithradiographicevidenceoftumorintheapexofthechesthad significantlyshortersurvivalthan42patientswithout(19versus27months;p=.0147). Weconcludethatpreoperativeradiographicestimationoftumorvolumeshouldbeincludedin prognosticevaluationofpatientsbeingconsideredforprimarysurgeryforepithelialmpm.if volumetricanalysisisunavailable,evidenceofapicaldiseaseinvolvementmaybeareasonable surrogate. 255

258 ABSTRACTS Number:229 Abstracttitle: MicroRNAmicroarrayanalysisofmalignantmesothelioma MohamedGuled(1),PamelaLindhomlm(1),KaisaSalmenkivi(1),AndrewG.Nicholson(2),Sakari Knuutila(1,3) (1)HaartmanInstitute,universityofHelsinki,Finland;(2)RoyalBromptonhospital,;(3)Helsinki UniversityCentral,Finland Keywords: mirna,microarray,malingnantmesothelioma Abstract: MicroRNAMicroarrayAnalysisofMalignantMesothelioma Background.MicroRNAshavegeneratedstronginterestinthefieldofcancerresearchasa consequenceofrecentfindingsabouttheirfunction.theyhavebeenshowntoregulategene expressionatthelevelofmrna.thesesmallandnoncodingrnascanaffectthestabilityofthe mrnasandcanalsoinitiateand/orinhibittheprocessoftranslationintoproteins.morethan1000 mirnasareknowntodaywiththerapidlyincreasingnumber.mirnahasavarietyoffunctions startingfromcelldeathregulationtoantiviraldefensesinalllivingorganisms.itismainlyinvolvedin posttranscriptionalgeneregulationwherebyitbindstothecomplementarysequenceofthetarget mrna.ithasbeenspeculatedthatmirnascouldregulate~30%ofthehumangenome.mirnashave beenfoundtoberesponsibleforthefineregulationofgeneexpressionandadjustingcellular phenotypeduringvitalprocesses,suchasdevelopmentanddifferentiation. MiRNAarefoundtobeconservedthroughoutthemammaliangenomewhichfurtherreaffirmstheir involvementinessentialprocesses.thereforemirnagenemutations(inherited,somaticmutations, amplifications,deletions,epigeneticsilencing)arelikelytocausecertaincancerswhileincreasing susceptibilitytoothers.furthermore,significantamountmirnasareshowntobeincancer associatedgenomicregions. Aim.LittleisknownabouttheexpressionofmiRNAsinmalignantmesotheliomas.Theaimofthis studyistogainmoreinsightintothepossibleroleandfunctionofthesenovelregulatorsofgene expressioninthisparticularcancer. ItisbecomingmoreevidentthatmiRNAsplayanessentialroleintheregulationofpathwaysthatare involvedintumorigenesisofvarioustumors.itisthereforeessentialtocombinepotentialmirna datafromthisstudywithexistinggenomicandexpressionprofilesofmm.analysisofintegrateddata canfurtherassistinunderstandingthefundamentalmechanismsinthedevelopmentandthe progressionofmm. MaterialsandMethods.Freshfrozensamplesfrom23MMpatientswereusedinthisstudy.Before extractingrna,tumorcontentofeachsamplewasdetermined.totalrnawasextractedusing Agilent smirneasyminikitandmicroarrayexperimentswereperformedusingagilent smirna microarraysystem. Finalresultsofthestudywillbepresentedattheconference. 256

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