Brain Tumor and Neuro-Oncology Center - Cleveland Clinic...Letter from the Director The Brain Tumor...

1

BrainTumorandNeuro-OncologyCenter

ANNUALREPORT|2008

Shownabove:Intraoperativeimagingoffirst-evertreatmentofhumanbraintumor(glioblastoma)usingAutoLITT®thermaltherapysystem

2

LETTERFROMTHEDIRECTOR..................................... 1

FACULTYANDKEYPERSONNEL.................................. 2

EXECUTIVESUMMARY................................................ 4

BRAINTUMORANDNEURO-ONCOLOGYCENTER–

OVERVIEW................................................................. 5

ATeamApproachtoIndividualizedCare

CLINICALANDFINANCIALPERFORMANCE–2008....... 6

HigherPatientVolume

LargerMarketShare

FinancialPerformance

RESEARCHREVENUEANDPHILANTHROPY................. 7

ResearchFunding

Philanthropy

BENEFACTORS........................................................... 8

CLINICALPROGRAMS................................................. 9

MedicalNeuro-Oncology

NeurosurgicalOncology

LocalTherapies

RadiationNeuro-Oncology

PediatricandYoungAdultBrainTumorProgram

SectionofMetastaticDisease

Surgery

Radiosurgery

Chemotherapy

SpinalRadiosurgery

CenterforNeurofibromatosis

SectionofSkullBaseSurgery

PituitaryandNeuro-EndocrineCenter(PNEC)

Neuropathology

Neuropsychology

Neuroradiology

Neuro-OncologyNursing

CLINICALRESEARCHPROGRAMS/INNOVATIONS........ 20

BTNCLABORATORYRESEARCH/INNOVATIONS........... 23

BTNCPrimaryLaboratories

CenterforTranslationalTherapeutics–

VogelbaumLaboratory

WeilLaboratory

CollaborativeLaboratories

BTNCCLINICALANDCLINICALRESEARCH

ADMINISTRATION.................................................... 28

PROGRAMDEVELOPMENT........................................ 29

ProfessionalRecruitment

Marketing/Advertising

BTNCintheNews

OUTREACH............................................................... 31

InternationalOutreachServices

EDUCATION.............................................................. 32

ContinuingMedicalEducation/ProfessionalEducation

SupportingPatientEducation

Fellowships

APPENDIXA–CLINICALTRIALS................................ 34

APPENDIXB–PUBLICATIONS................................... 37

APPENDIXC–CHARTSANDSTATISTICS.................... 41

TABLEOFCONTENTS

LetterfromtheDirector

TheBrainTumorandNeuro-OncologyCenter(BTNC)ofClevelandClinicwasestablishedin2001,withanovel

organizationthathashelpedpropelustotheforefrontamongtheleadingbraintumorprogramsinthenation.We

areservingmorepatientsthanever;expandingourservicesandimprovingpatientsatisfaction;attractingworld-

classphysiciansandscientists;makinggiantleapsinresearchanddiscovery;andacquiringmuch-neededfunding,

particularlyphilanthropicsupport.

In2008,amongthehundredsofclinicalstudiesunderway,theBTNCled26newclinicalstudiesthatwere

investigatorinitiated,inpartnershipwithindustryorthroughconsortia.Amongthesewasthefirst-everhumanuse

ofaminimallyinvasivelasertreatmentforglioblastoma–performedaspartofacollaborativetrialwiththeCase

ComprehensiveCancerCenterandUniversityHospitalsCaseMedicalCenter.

CollaboratingwithandbeingintheTaussigCancerInstitute,thelargestcancerprograminOhio,theBTNChas

accesstotheinstitute’sclinicalandresearchresourcesaswellastheopportunitytointeractwithotherhealthcare

professionalswhodealwithcancerpatientsdaily.Usinginnovativetherapyandamultidisciplinarystructure–a

modeloforganizationthatcontinuestoattractnationalandinternationalinterest–weprovideateamapproachto

individualizedcare.Welookforwardtoimprovingcareaswecontinuetomeasureourperformance.

Gene H. Barnett, MD, FACS

Director,BrainTumorand

Neuro-OncologyCenter

BRAINTUMORANDNEURO-ONCOLOGYCENTER

2

FacultyandKeyPersonnel

BrainTumorandNeuro-OncologyCenterFaculty

Neurosurgery

GeneH.Barnett,MD,FACSDirector, Brain Tumor and Neuro-Oncology Center Director, Cleveland Clinic Gamma Knife® Center

LilyanaAngelov,MDHead, Spinal Radiosurgery Head, Primary CNS Lymphoma Program

WilliamBingaman,MD*

XiaoDi,MD*

JoungLee,MDHead, Section of Skull Base Surgery

MarkLuciano,MD,PhD*

PeterRasmussen,MD*

BurakSade,MD

SamuelTobias,MD*

MichaelA.Vogelbaum,MD,PhDDirector, Center for Translational Therapeutics Associate Director, Brain Tumor and Neuro-Oncology Center

RobertWeil,MDHead, Pituitary and Neuro-Endocrine Surgery Associate Director, Basic Laboratory Research

Neurology

BruceCohen,MDCo-Director, Pediatric and Adolescent Brain Tumor Program

GlenH.Stevens,DO,PhDHead, Adult Neuro-Oncology

RadiationOncology

SamuelChao,MD

RogerM.Macklis,MD*

JohnH.Suh,MD*

RadiationPhysics

ChristopherDeibel,PhD*

ToufikDjmel,PhD*

GennadyNeyman,PhD*Head, Gamma Knife Physics

Neuropsychology

MichaelParsons,PhD*

Neuropathology

RichardPrayson,MD*

SusanStaugaitis,MD,PhD*

Endocrinology

AmirHamrahian,MD*

MedicalOncology

DavidPeereboom,MDHead, Medical Oncology Head, Clinical Research

BrianBolwell,MD*

ErnestBorden,MD*

TarekMekhail,MD*

PediatricOncology

KateGowans,MD*

MichaelLevien,MD*

GregoryPlautz,MD*

TanyaTekautz,MDCo-Director, Pediatric and Adolescent Brain Tumor Program

Neuroradiology

ToddEmch,MD*

ThomasMasaryk,MD*

DoksuMoon,MD*

PaulRuggieri,MD*

ToddStultz,MD*

AndrewTievsky,MD*

Research

GeneH.Barnett,MDDirector, Brain Tumor and Neuro-Oncology Center

PeterCohen,MD*

JamesFinke,PhD*

JaharulHaque,MD*

DamirJanigro,PhD*

DavidPeereboom,MDHead, Clinical Research

GregoryPlautz,MD*

BaisakhiRaychaudhuri,PhD

*Denotesjointappointment

2008ANNUALREPORT

3

JeremyRich,MD,PhD*

SusanStaugaitis,MD,PhD*

BruceTrapp,PhD*

RaymondTubbs,DO*

MichaelA.Vogelbaum,MD,PhDDirector, Center for Translational Therapeutics Associate Director, Brain Tumor and Neuro-Oncology Center

IlkaWarshawsky,MD*

RobertWeil,MDAssociate Director, Basic Laboratory Research

Nursing/PhysicianAssistants

MarcellaLupica,RNBTNC Nurse Manager

CathyBrewer,RN

GailDitz,RN,BSN

CarlaDuvall,MSN,CNP

MicheleGavin,MPAS,PA-C

BettyJamison,RN,BSN

KathyLupica,MSN,CNP

MaryMiller,RN,BSN

MaryMurphy,RN

ShelleyOgrin,MSN,RN,CNP

CarolPatton,RN

RachelPerez,RN,BSN

SherrySoeder,MSN,CNP

LauralTuro,RN,BSN

Administration

GeorgeLawrence,MBABTNC Administrator

TheresaNaskaBTNC Workleader

JackieGarciaBTNC Department Coordinator

TeresaMcBrideBTNC Workleader

MarciCiolfi,CCRPResearch Coordinator

KathyRobinsonResearch Coordinator

WendiEvanoff,CCRPResearch/Database Coordinator

MaryMcGrawTissue Bank Coordinator

CharlotteHornerPatient Access Coordinator

JianpingLiSystems Engineer

JasonGrayExecutive Director of Development, Neurological Institute

JamesSaporitoExecutive Director of Development, Taussig Cancer Institute

MillieTorresPatient Access Coordinator

CynthiaFlanaganGamma Knife Surgery Scheduler

ColleenBurkeMarketing Manager

JenniferLynchMarketing Associate

MollyJohnsonMedia Associate

MarthaTobinContinuing Medical Education

AngelaWojtylakReimbursement Specialist

JackieBellMedical Secretary

JanetteCollazoMedical Secretary

PeggyEvansMedical Secretary

CassandraHollidayMedical Secretary

TamikaSmithMedical Secretary

TaussigCancerInstitute

JohnPellecchiaGrant Administrator

DeniseConnorResearch Finance Manager

KristieSummersDivision Research Administrator

DebJohnsonResearch Accountant


4

ClevelandClinicBrainTumorandNeuro-OncologyCenterenjoyedayearofsubstantialaccomplishmentin2008.

Record-SettingClinicalandFinancialPerformance:

•7,943outpatientvisits

•936surgical,GammaKnife®andNovalis®procedures

•Increaseof150%newpatientvisits,366%totaloutpatientvisits,23%surgicalcasesand91%GammaKnifecasessinceprogram’sinceptionin2001

•LargestmarketshareinOhio

•21%increaseinnetrevenueand85%increaseincontributionmarginover2007

SolidResearchRevenueandPhilanthropicSupport:

•Fundingthroughthreefederalgrants

•$1.5Minphilanthropicsupportsince2007and$14.6Msinceinception

Pace-SettingClinicalPrograms:

•World’sfirsthumantreatmentofbraintumorusingAutoLITT®thermaltherapysystem(seecoverfigure)

•AdvancenavigationusingDTIandfMRIplanningandintraoperativevisualizations

•CompactMRIwithdevelopmentofhigh-fieldinterventionalMRIoperatingroom

•Leaderinconvection-enhanceddeliveryofadvancedagentstobraintumors

•SecondGammaKnifePerfexionunitinNorthAmerica–317casesin2008

•Leaderinspinalradiosurgery–74proceduresperformedin2008,andmorethan200casessinceprograminceptionin2004

•Integrationofneuropsychologyintoclinicalprogram

ExecutiveSummary

RobustClinicalResearch:

•CompletingmembershipinNCI-sponsoredNewApproachestoBrainTumorTherapy(NABTT)consortium

•ChartermemberofNCI-sponsoredAdultBrainTumorConsortium(ABTC),commencingin2009

•Leadershipinnationalbraintumororganizations

•Dr.VogelbaumScientificProgramChairof2008SocietyofNeuro-OncologyMeeting

LaboratoryResearch:

•RecruitmentofJeremyRich,MD,asChairofGenomicsInstitute.Dr.Rich,aworld-renownedexpertonbraintumorstemcells,joinedtheprofessionalstaffinSeptember2008.

•RecruitmentofCandeceGladson,PhD,asHeadofBrainTumorLaboratoryResearchintheDepartmentofCancerBiologyofClevelandClinicLernerResearchInstitute.Dr.GladsonjoinedthestaffinJanuary2009.

•Primarylabsandcollaborationsperformingcutting-edgebasicandtranslationalresearch

Education–Local,Regional,NationalandInternationalPresence:

•HostedSecondInternationalSymposiumonStereotacticBodyRadiationTherapyandStereotacticRadiosurgery

•HostedPituitaryDiseaseSymposiuminApril

•HostedjointmeetingwithMexicanNeurosurgicalandNeuro-OncologySocietiesinNovemberatLosCabos,Mexico

•HostedfourGammaKnifehands-oncourses

PublishingOurAccomplishments:

•BTNCstaffpublished38journalarticlesandtwobookchaptersin2008

2008ANNUALREPORT

5

ATeamApproachtoIndividualizedCare

ClevelandClinicBrainTumorandNeuro-OncologyCenter(BTNC)isanationalleaderinthediagnosis,treatmentandresearchofbraintumors.TheuniqueadministrativestructureoftheBTNCallowsourmultidisciplinaryteamofphysiciansandscientiststofocusalmostexclusivelyonbraintumors,facilitatingopportunitiesforourstafftoparticipateininternationalresearchprotocols,shareinformationaboutthelatestdevelopmentsinthefieldandcombinetherapeuticapproachesfromanumberofdisciplines.Theresultistheabilitytobringthemostpromisingnewtreatmentstotheclinicalrealminanenvironmentthatfacilitatesindividualizedpatientcare.

TheBTNChasbeenamemberoftheprestigiousNewApproachestoBrainTumorTherapy(NABTT)consortiumformorethansevenyears.TheprimaryobjectiveoftheNationalCancerInstitute-sponsoredNABTTconsortiumistoimprovethetherapeuticoutcomeforadultswithprimarybraintumorswhilesharinghumanbraintumorspecimensandclinical

andlaboratorydatatofacilitateadditionalresearchpertainingtobasicbiologyandneuro-pharmacologyofnewtreatments.ToqualifyforNABTTmembership,aninstitutionmustpossessstrongclinicalandresearchprogramsforadultbraintumors,expertmultidisciplin-aryclinicalteams,extensivelaboratoryandclinicalresources,andtheabilitytoconducthigh-quality,clinicallyrelevanttrials.In2008,wewerehonoredtobeselectedasachartermemberofthenewAdultBrainTumorConsortium,whichsupersedestheNABTTconsortiumin2009.

BuildingonthestrongtraditionofexcellenceandinnovationestablishedbymembersoftheBTNCteam,thefutureofclinicalapplicationandongoingresearchatClevelandClinicisbothbrightandexciting.Weaimtostreamlinetheprocessofbringingpotentiallygroundbreakingtherapeuticagentsfromthelaboratorytothepatient,makingnewchemotherapeuticagents,radiosurgicaltechniquesandsurgicalproceduresavailablemorequickly,whilemaintainingthehighestscientificstandardsforbothefficacyandsafety.

BrainTumorandNeuro-OncologyCenter–Overview


6

TheBTNCexperiencedanunprecedentedyearofclinicalvolumeandfinancialgrowthin2008.

HigherPatientVolume

Between2001and2008,theBTNCexperiencedanincreaseinnewpatientvolumeof150percent;anincreaseintotaloutpatientvisitsof366percent;anincreaseinsurgicalcasesof32percent;andanincreaseinGammaKnifecasesof92percent.

In2004,BTNCphysiciansbeganperformingNovalisradiosurgery,startingwithonlythreecases.By2008,ourstaffperformed82oftheseprocedures.

Overallin2008,BTNCphysiciansrecorded7,925outpatientvisitsandperformed974surgicalandradiosurgicalprocedures.

LargerMarketShare

TheBTNCmaintainsthehighestmarketshareinthe“CuyahogaCounty,”“21-county”and“stateofOhio”markets,andcontinuestoincreasedominanceoveritsclosestcompetitor.Futureinitiativesfocusonincreasingmarketsharelocally,regionallyandnationally.

FinancialPerformance

Increased Revenue Between2002and2008,grossrevenueincreased178percent;netrevenueincreased111percent;andcontributionmarginincreased79percent.

BTNCFinancialPerformance

ClinicalandFinancialPerformance–2008

2002 2003 2004 2005 2006 2007 2008

n NetRevenues ContributionMargin

ss s s s

s

s

annualized

2008ANNUALREPORT

7

Since2006,generoussupportershavecontributedanadditional$1.6millioninoutrightgifts,pledgesandestatebequests.Ofspecialnoteareanestategiftfromlong-timeBTNCbenefactor,thelateMelBurkhardt,annualgolftournamentfundraisersheldbyKarenWilsonandongoingresearchsupportprovidedbytheWolfFamilyFoundation.ThisfoundationofphilanthropicsupporthasprovencriticaltotheBTNC’seffortstoadvancebraintumortreatmentandresearch.

Inadditiontofinancialsupport,friendsalsocontributetheirtimeandinvaluableserviceasmembersoftheNeurologicalInstituteandTaussigCancerInstituteNationalLeadershipBoards.TheBTNCisgratefulforthecontinuedloyaltyofmanymemberswhoservedontheformerBrainTumorInstituteLeadershipBoard.ManyhavecontinuedtheirserviceononeorbothoftheseboardsasClevelandClinichasmovedtoa

multidisciplinaryinstitutemodelofmedicinewhichpositionstheBTNCaspartoftheNeurologicalInstitutewithstrongcollaborativetiestotheTaussigCancerInstitute.WeareespeciallygratefultoformerBrainTumorInstituteLeadershipBoardChairL.B.McKelveyandmemberKarenWilson,whohavejoinedtheNeurologicalInstituteLeadershipBoard.

AlldevelopmentactivitiessupportingtheBTNCarecoordinatedbyJasonGray,AssociateChairmanofInstituteDevelopment,InstitutionalRelationsandDevelopment,andLauraRobinson,SeniorDirectorofDevelopment,NeurologicalInstitute.IncollaborationwithphysiciansandhealthcareprofessionalsandtheTaussigCancerInstitutedevelopmentteam,thefundraisersandleadershipboardsdriveeffortstoincreaseawarenessandprovideopportunitiesforfriendstosupportpriorityresearchandclinicalinitiatives.

Philanthropy

Our physicians and healthcare professionals, development teams, fundraisers and leadership boards collaborate to increase awareness and provide opportunities to support priority research and clinical initiatives.

The BTNC is grateful to loyal friends who contribute their time and invaluable service as members of the Neurological Institute and Taussig Cancer Institute National Leadership Boards.


8

PartnersinNeuro-Oncology

TheBrainTumorandNeuro-OncologyCenterextendsdeepappreciationtoourPartnersinNeuro-Oncology,eachofwhomhasdonated$1millionormoreovertheirlifetimesinsupportofourprograms.

2008Benefactors

TheBrainTumorandNeuro-OncologyCenterispleasedtoacknowledgethefollowingfriendswhose2008givinginsupportofourmissiontotaled$1,000ormore.

TheJames&CoralieCentofantiCharitableFoundation

CandyandEddieDeBartoloandFamily

ThomasN.Detesco,MD

Mrs.JoyceD.Gagliarducci

Mr.andMrs.RobertR.Houston

Mr.andMrs.ThomasE.HutchJr.

Ms.JeanneJohnston

Kuboff&Associates,Inc.

Mr.andMrs.BenedictW.Lupo

DennisM.Moody,DDS

Mr.andMrs.DonaldL.Oberholtzer

OmegaLaboratories,Inc.

Mrs.JodiO’Neill

Ms.F.L.Rumble

Mr.andMrs.WaylandJ.Russell

Mr.andMrs.EricSeres

Mr.andMrs.JosephSylvester

Mr.andMrs.RobertM.Venrose

TheCarmelM.&JohnG.WhitmanFoundation

Dr.JohnYorkandMs.DeniseDeBartoloYork

MelvinH.*andRoseElla*Burkhardt

RobertW.andKathrynB.Lamborn

Alfred*andNormaLerner

Mr.andMrs.LuciusB.McKelvey

Ms.KarenWilson

Benefactors

*Deceased

TommyDetescoFund

TheBTNCteamisespeciallyindebtedtoDr.ThomasN.Detesco,whoestablishedtheTommyDetescoFundin2007inmemoryofhissonTom,whopassedawayat32yearsoldafteralongbattlewithbraincancer.ThefundsupportsadolescentandyoungadultbraintumorresearchattheBTNC.Sinceitsestablishment,thefundhasreceivedmorethan$350,000ingiftsandpledges,withagoalof$2million.Morethanhalfofthosewhogave$1,000ormoretotheBTNCin2008designatedtheirgiftstosupporttheTommyDetescoFund.

2008ANNUALREPORT

9

TheBTNCofferscomprehensivecareforpatientswithbenignormalignantbraintumors.Ourmultidisciplinaryapproachinvolvesthecloselycoordinatedeffortsofmultiplespecialistsworkingtogetherdaily,mostofwhomtreatonlypatientswithbraintumors.Thisdegreeofsubspecializationhasallowedustocontributetodevelopmentofnew,cutting-edgeinvestigationaltreatments,includingtheuseoftargetedimmunotoxinsandso-called“smallmoleculetherapies”(SMTs)suchaserlotinibandsunitinib.Neweragentsthatcrosstheblood-brainbarrier,suchaspatupilone,arebeingtestedinpatientswithbrainmetastases.These,alongwiththeexpandedroutineuseofmolecularandchromosomaltestingtoguideindividualpatientmanagement,helpputtheBTNCattheforefrontofindividualized careandthemolecular genetic managementofbraintumors.

Methodsforbothsurgicalandnonsurgicaltreatmentsoflife-threateningtumorsareadvancedbymedicalinnovationsintheareaslistedbelow.Amongtheinnovationsistheuseofseveralmodalitiesoftherapyinmultidisciplinary,individualizedcareofthepatientwithabraintumor.

•Advanced Surgical Navigation–computer-guidedsurgeryusingathree-dimensionalsoftwareconfigurationcapableofemployingdiffusiontensorimaging(DTI)andfunctionalmagneticresonanceimaging(fMRI)data

•Intraoperative MRI–navigationalguidanceandmonitoringoftumorresection

•Multiple Radiosurgery Options –GammaKnifeforsingle-sessioncranialstereotacticradiosurgery;NovalisSystemforcranialradiosurgeryinseveralsessionsandspinalradiosurgery

•Fractionated Radiotherapy–widespreadexposureofthebrainandtumortorepeatedlowdosesofradiation

•Brachytherapy–directimplantationofaradiationsource(solidorliquid)withinatumorsite

•Chemotherapy/Growth Modifiers – traditionalanti-tumordrugsaswellastestingofnewagentstargetedatspecifictumormolecules

•Immunotherapy–turningthepatient’simmunesystemagainsttumorcellsorusingimmunologicallytargetedtoxins

•Convection-Enhanced Delivery (CED) – theslow,continuousinfusionofdrugsthroughthebraintotreatcertainbraintumors.Usedbothinthelaboratoryandforpatients,itpermitstreatmentwithagentsthatwouldbetootoxictothebodyifdeliveredconventionally.

•Laser Interstitial Thermal Therapy (LITT) –useofaspecializedlaserprobeto“cook”certainbraintumorsfromtheinside,andmonitoringtheprocedureusingspecialMRItechniques

MedicalNeuro-Oncology

Neuro-oncologists,medicaloncologists,neurosurgicaloncologists,radiationoncologists,neuropathologists,neuroradiologistsandBTNCnursesattenddailyclinicsandtwice-weeklytumorboards.Thiscooperativeapproach,provedinmorethanadecadeofuse,providesforconsensusmanagementplansthatareindividualizedandfocusedonthebestmixofmedical,surgicalandradiotherapytreatmentofpatientswithbothbenignandmalignanttumorsaffectingthebrainandspinalcord.Inadditiontoconventionaltreatments,innovativeclinicalstudies–someofwhichweredevelopedatClevelandClinic–areavailable,andothersareperformedaspartofmulticentertrials.

Membersofthemedicalneuro-oncologyteamalsoprovidelong-termsurveillanceandmedicalmanagementofpatients.Thesespecialistspayparticularattentiontotheneurocognitiveimpactofbraintumors,andplayanimportantroleinthemanagementofanti-seizuremedications.Forexample,Dr.GlenStevensreceived

ClinicalPrograms


10

externalfundingtoevaluateseizurecontrolandsideeffectsassociatedwiththeanticonvulsantlevetiracetaminbraintumorpatients.

NeurosurgicalOncology

Pioneersincomputer-assistedstereotactictechniquesforbraintumorssincethemid-1980s,BTNCsurgeonsextendedthescopeofoperablebraintumorsbyusingtechniquessuchasframeorframelessstereotaxy(toprovideafixedframeofreferencetoassistwithcomputerizednavigationforlocatingbraintumors),lasersurgery,skullbasetechniques,microsurgery,endoscopicsurgery,computer-assistedrehearsalofsurgery,intraoperativeMRI,radiationimplantsandradiosurgery.ThedevelopmentofprecisionsurgicalnavigationsystemsbyClevelandClinic’sCenterforComputer-AssistedNeurosurgeryhasresultedinsubstantialreductionsofwoundandneurologicmorbidity,lengthofsurgery,hospitalcosts,andlengthofstayformanybenignandmalignantbraintumorsurgeries.TheinterestinsurgicalnavigationcontinuesastheDepartmentofNeurosurgeryusesnavigationequipmentfromZ-KAT,Medtronics/StealthandBrainLAB.Theabilitytoplanandnavigateusingspecializedimagingtechniquessuchasdiffusiontensorimaging(DTI)fibertrackingandfunctionalMRI(fMRI)allowsustoseethecriticalbrainpathwaysandsurfaceregions,thusmakingbraintumorsurgeryevensafer,andtoextendwhatistrulyoperable.

TheBTNCcontinuedthepursuitofcutting-edgetechnologywithitsacquisitionofthesecond-generationcompactintraoperativeMRI,thePoleStarN20.Thedeviceweighsonly1,300pounds–afractionoftheweightofconventionalunits.Duringsurgery,thedeviceisstowedbelowtheoperativefield,allowinguseofmanyconventionalsurgicalinstruments.Whenimagingisrequired,themagnetsareraisedintoposition,flankingthepatient’sheadforscansthatrangeintimefromaboutonetosevenminutes.Whennotrequiredduringsurgery,theimagerisplacedinamagnetically

shieldedcageinthecorneroftheroom,allowingfulluseoftheroomforconventionalprocedures.WewereoneofthefirstsitesintheworldtohavethefirstgenerationofthePoleStarsystem,andhavebeenviewedaspioneersintheapplicationofintraoperativeMRItoneurosurgicalprocedures.InconjunctionwiththeradiologicalImagingInstituteandneuroradiology,wearedevelopinganewhigh-field(1.5Tesla)interventionalMRIsuite/operatingroomtoextendwhatcanbedoneandmonitoredwithreal-timeMRItechniques.

LocalTherapies

Malignantgliomasareinvasivetumors.Whiletheportionofthetumorthatformsamasslesioncanoftenberemovedsurgically,surgeryisnotregardedasacurativetreatment,astheinvasiveportionofthetumorinevitablyremainsbehind.Whilethedensityofinvasivetumorcellsmaybegreatestattheresectionmargin,tumorcellscanbefoundcentimetersaway,evenbeyondthelimitsoftheT2/FLAIRabnormalityseenonMRI.Ithasbeenreportedthatasmanyas80percentto90percentoftumorrecurrencesoccurwithintwocentimetersoftheresectioncavity,andtheshrinkingfieldtechniqueofradiationtherapywasdesignedtoprovidethehighestradiationdosetotheareaaroundthetumorcavity.Hence,thereisgreatinterestamongneurosurgicaloncologistsinuseofotherlocalizedandregionalizedtherapiestotreatthemarginsofthetumorresectioncavityaswellasthetumor-infiltratedbraindistantfromthecavity.

TheBTNCwasthefirstintheworldtouseanewlaser-basedsysteminahumanfortheminimallyinvasivetreatmentofabraintumor.ThisAutoLITT(laserinterstitialthermaltherapy)system,developedbyMonterisMedical(Winnipeg,Canada),“cooks”orcoagulatestumorsbyuseofaspeciallaserprobe,preciselydirectedintothetumor,withtheheatingprocessmonitoredbyspecializedsoftwareandthermalMRItechniques(seecoverfigure).Dr.GeneBarnettleadsthistrialincollaborationwithUniversityHospitals

ClinicalPrograms(continued)

2008ANNUALREPORT

11

CaseMedicalCenterandtheCaseComprehensiveCancerCenter.Preliminaryresultssuggestthatthistechnologycouldofferthebenefitsofconventionalsurgerytosomepatientswithinoperabletumorsorsparepatientsmoreinvasiveinterventions.

Arecentlyinvestigatedapproachforbothlocalandregionaldrugdeliveryinvolvesconvection-enhanceddelivery(CED).Incontrasttoimplantedchemotherapywafers,CEDreliesonpositivepressureinfusiontoproduceamorewidespreadanduniformvolumeofdrugdelivery.Thistechniquerequirestheimplantationoftemporarycatheters,whichcanbedirectedtotreatspecificregionsofthebrainsuspectedofbeinginfiltratedbytumor,asdeterminedbyMRI.Novelclassesoftargeteddrugs,whichcannotbeadministeredsystemicallyduetobreakdownortoxicity,havebeendevelopedfordirectdeliverytothebrainviaCED.Whileearlytrialsofthistechniquehaveshownevidenceofefficacy,PhaseIIIevidencedoesnotyetexisttosupportthisapproach.ThefieldofCEDremainsinanearlystageofdevelopment,andnewtypesofbothcathetersanddrugsarebeingdevelopedtooptimizeefficacyofthisapproach.TheBTNChasbeenarecognizedleaderintheclinicaldevelopmentofCED.TheBTNChasparticipatedinseveralCEDmulticenternationalandinternationaltrials,oneofwhichwasdesignedandledbyaBTNCneurosurgeon.Furthermore,theBTNChashostedtheonlyinternationalsymposiafocusedonCED.SeveralnewtrialsarebeingdevelopedandwillbeledbyBTNCneurosurgeons.

RadiationNeuro-Oncology

Radiationoncologists,focusingonthespecificproblemsofbrainandspinalcordtumors,offerbothtraditionalandinnovativetreatmentstoensurepatientsaccesstoanumberoftechnologies.In1989,ClevelandClinic’sradiosurgeryprogramwasthefirstinOhiototreatpatientswithstate-of-the-artnoninvasiveablativetherapy,usingamodifiedlinearaccelerator.Since1997,anumberoftechnologieshavebeenintroduced,including

GammaKnife,intensity-modulatedradiotherapy(IMRT),intraoperativeradiationtherapy(IORT),brachytherapyandimage-guidedradiationtherapy(IGRT).Thesetechnologiesmaycontrollethaltumorsforlongerperiodsthanconventionalradiationtherapy,decreasethepotentialsideeffectsofradiationtherapy,andbenefitpatientswhosegeneralhealthmaynotbesufficienttowithstandaprotractedmicrosurgicalprocedure.

Ateamofpersonnelincludingneurosurgeons,radiationoncologists,radiationphysicistsandradiationtherapistsprovidestreatment.GammaKniferadiosurgerygenerallyrequiresasingleone-totwo-hourtreatmentinwhich192beamsofgammaraysarefocusedatmultiplepointsthroughoutthetarget,withtheaimofmatchingthedeliveredradiationtotheshapeofthetumor.Thus,theradiation’sdestructivepotentialisconcentratedinthetumor,andfalloffinadjacenttissueisexceedinglysteep,minimizingdamagetotissuelyingintheentryorexitpathways.Becauseofthisprecisefocusingability,aggressivehigh-doseradiationcanbedeliveredtostabilize,shrinkordestroysomelesions–eventhosedeepinthecerebralhemispheresorbrainstem.

ThepastyearhasbeenasuccessfulonefortheGammaKnifeCenter.In2007,ourGammaKnifeequipmentwasupgradedtothelatestPerfexionsystem,whichisacompleteredesignofthepreviousGammaKnifeandoffersgreaterflexibilityandsafety.In2008,weperformed317GammaKniferadiosurgerycasesforanumberofindications,whichrepresentedourmostproductiveyearever.Inaddition,wepresentedanumberofpapersatnationalandinternationalmeetings,highlightingourcenter’sresults.

TheGammaKnifeCenterisoneofthreecentersworldwidecertifiedbyElekta(thesolemanufactureroftheGammaKnife)totrainphysiciansnewtoGammaKniferadiosurgery.

TheNovalisSystemfurtherincreasesourcapabilitieswithinradiationoncologyandallowsforradiosurgeryandfractionatedradiosurgerytreatmentsfor


12

neuro-oncologypatients,usingimageguidance.Thistechnologygivesustheabilitytotreatlesionsnearcriticalstructures,suchastheopticnervesandchiasm,aswellasre-treatsomepatientswhohaveundergoneconventionalradiotherapy.Ingeneral,GammaKnifeisusedforsingletreatmentsoffocusedradiationthatconformstotheshapeofsmalltumorsorlesions,whileNovalisdeliversfractionatedconformaltreatmentforlargermalignantorbenigntumors.AlthoughNovaliswasoriginallydevelopedtotreatbraintumors,ClevelandClinicphysiciansrecognizeditspotentialfortreatingextracranialtumors,particularlyprimaryandmetastaticspinaltumorsthataredifficulttotreatduetotheirproximitytocriticalstructures.In2007,webecameoneofthebusiestspineradiosurgeryprogramsinthenationtousetheNovalisplatform.

InadditiontotheGammaKnife,NovalisSystemandlinearaccelerators,weofferIORTwiththeINTRABEAMdevice,a50kVpcontactunitthatisplacedintheresectioncavity.WehaveanongoingPhaseIItrialevaluatingtheuseofINTRABEAMforpatientswithasinglebrainmetastasisthathasbeenresected.

AnumberofclinicaltrialssponsoredthroughtheRadiationTherapyOncologyGroup(RTOG),NABTTandvariouspharmaceuticalcompaniesareofferedhere.Since1998,thedepartmenthasbeenaleaderinradiationsensitizertrialsusingmotexafingadoliniumandefaproxiral.Dr.JohnSuhwastheprincipalinvestigatorfortheinternationalPhaseIIIconfirmatorystudyusingefaproxiralforwomenwithbrainmetastasesfrombreastcancer.Dr.SamuelChao’sresearchinterestincludesradiationnecrosis,apotentialcomplicationofradiationtreatment,andtreatmentofpediatricbraintumors.Bothhavegivenanumberofnationalandinternationaltalksregardingthetreatmentofbraintumorswithradiationtherapyandradiosurgery.

PediatricandYoungAdultBrainTumorProgram

Amultidisciplinaryclinicforchildrenandadolescentswithbraintumorstakesplacetwiceweekly.PatientscanseeDrs.TanyaTekautzandBruceCohenonthesameday,andotherteammembersareconsultedasnecessary.Sedationbyapediatricanesthesiologistforneuro-imagingisroutinelyavailableonallclinicdays.Eachchildhasacarecoordinationteamconsistingofaphysician,anursepractitionerandaregisterednurse.Neurosurgeonsandradiationoncologistsareavailabletoseepatientsasneeded.During2008,therewereatotalof570pediatricoutpatientvisits.

Chemotherapyandradiationtherapyaredeliveredundertheoversightofthecoordinationteam,resultingincontinuityofcare.Thenursepractitioner/RNteamhandlesfollow-upcallsathometoensuretheefficacyofpaincontrolandothermedicalissues,whichresultsinfeweremergencyroomvisits.

Since2004,totalvolumehasmorethandoubled,increasingby138percent.

PediatricOutpatientVisits


600______________________________________________________

300______________________________________________________

0______________________________________________________ 2004 2005 2006 2007 2008

2008ANNUALREPORT

13

SectionofMetastaticDisease

Surgery

Surgery,inadditiontowholebrainradiotherapy,hasbeenshowntobemoreeffectivethanradiotherapyaloneforpatientswithasinglebrainmetastasis.Eveninpatientswithmultiplebrainmetastases,surgicalresectionleadstosurvivalcomparabletothosepatientswithsingleresectedlesions.Pioneersincontemporarycomputer-assistedneurosurgery,BTNCneurosurgeonsroutinelyuseminimalaccesstechniquestoremoveoneormorebrainmetastases,withminimalmorbidityandshorthospitalstays.Also,BTNCclinicalresearchersareinvestigatingtheroleofintraoperativechemotherapyorradiotherapyafterresection,inthehopeofobviatingtheneedforwholebrainradiotherapy.

Today,surgerymaybepartofacomprehensivemanagementplan,withothertechniquesbroughttobearonadditionalbrainmetastasesnotamenabletoradiotherapy.Beyondradiotherapy,stagedtherapyoptionsincludestereotacticradiosurgery,intra-arterialchemotherapywithorwithoutblood-brainbarrierdisruption,andnewersystemicchemotherapies.

Radiosurgery

ClevelandClinic’sradiosurgeryprogramistheoldestinOhioandhasdistinguisheditselfwithitsclinical,educationalandresearchprograms.WeareoneofonlythreecentersintheworldcertifiedbythemanufactureroftheGammaKnifetotrainnewusersofthis“goldstandard”ofradiosurgery.SincewestartedourGammaKnifein1997,wehavetreatedmorethan2,600caseswithvariousmodelsoftheGammaKnife.In2007,webecamethesecondprogramintheUnitedStatestotreatwiththePerfexionunit,andwerecentlystartedanupgradecourseforthoseusingthePerfexionmodel.Inaddition,wehavepublishedextensivelyonourresults,writtennumerouspapersonGammaKniferadiosurgery,andpresentedatmanynationalandinternationalmeetings.

OurmostcommonindicationforGammaKnifeisbrainmetastases,whichareideallysuitedfortreatmentwithstereotacticradiosurgery.Becausethesetumorsaretypicallysmallandspherical,andbecausetheydisplace,ratherthaninfiltrate,normalbraintissue,theGammaKnifehasbecomeourpreferredstrategytotreatbrainmetastases.Resultsfromradiosurgeryappearcomparabletothoseachievedbysurgerywithradiotherapy,andallowforeffectivetreatmentevenofsurgicallyinaccessibletumors.Radiosurgerymayalsoreducethechanceofleptomeningealspreadasaresultofsurgeryforcertaintumortypes.

So-called“radio-resistant”tumortypes(e.g.,melanoma,renalcellcarcinoma)respondaswelltostereotacticradiosurgeryasdo“radio-sensitive”tumors.NeurologicmorbidityislowwhendosingisprescribedatlevelssetbytheRadiationTherapyOncologyGroup,ofwhichClevelandClinicisanactivemember.Cognitivesideeffectsareminimal,asthetreatmentisconfinedtosmallbrainregions.

InadditiontoGammaKniferadiosurgery,theDepartmentofRadiationOncologyoffersotherstereotacticradiationoptionswiththeNovalisBrainLabunitandSynergy-Sunit.Boththeseunitsprovideprecisionradiationdeliverythroughtheuseofimageguidanceandmicromultileafcollimators.Thedepartmenthasbeendesignateda“centerofexcellence”intheuseofNovalisandhasveryactiveprogramsinspine,brainandlungradiosurgery.

TreatmentwithNovalisisindicatedforthosepatientswhosebraintumorsarenotidealforGammaKniferadiosurgery.Inaddition,Novaliscanbeusedforextracranialsitessuchasmetastaticspinaltumorsandprostateandlungcancers.SinceaddingtheNovalisSystemtoitsarsenalofradiosurgeryprogramsfouryearsago,thedepartmenthastreatedmorethan700patients,withanatomictreatmentsitesincludingthebrain,spine,lung,kidneyandbone.


14

Chemotherapy

Anexcitingareaofinvestigationistheuseofsmalltargetedmoleculestotreatavarietyofmalignancies.Asthemolecularcharacterizationofvarioustumorsimproves,investigationaldrugsthattargetspecificmolecularpathwaysmayplayanincreasingroleinthemanagementofbrainmetastasesandevenleptomeningealdisease.TheuseoftheseagentsandappropriatemodesofdeliveryareandwillcontinuetobeamajorthrustofBTNCclinicalandlaboratoryresearch.

Systemiccancersthatarechemotherapysensitiveoftentakerefugeinthebrain,despitesystemiccontrol,asmostcommonlyusedchemotherapieshavepoorpenetrationthroughtheblood-brainbarrier.Managementofsuchtumorsmaytakeseveralforms.Patientswithmetastaticbreastcancertothebrainwithtumorsthatareestrogen-receptorpositivemayrespondtohormonetherapies.Otheragentsthathaveactivityagainstbreastcancerbrainmetastasesincludecapecitabine,methotrexateandlapatinib.OnemulticenterclinicaltrialledbytheBTNCexaminespatupilone,anepothiloneinwomenwithbreastcancerbrainmetastases.Alternatively,temozolomide,arelativelyneworallyadministeredmethylatingagent,hasexcellentpenetrationintothebrainandmaybeconsideredforsomepatientswithbrainmetastasesfromnon–small-celllungcancerormelanoma.TheBTNCisparticipatinginaclinicaltrialofpatupiloneforpatientswithnon–small-celllungcancerbrainmetastases.Moreintensivetreatmentincludesuseofchemotherapyinjecteddirectlyintothecarotidvertebralarteries,attimesusinghypertonicmannitoltodisrupttheblood-brainbarrierfrompreventingactiveagentsfromreachingadequateconcentrationsinbrainmetastases.

Spinal Radiosurgery

Metastaticbonepainisthemostcommonpainsyndromeencounteredincancerpatients,anddevelopsin60percentto85percentofpatientswithsolidtumors.Ifthemetastasesinvolvethespine,there

canbedisablingpainanddestructionofthevertebralbody,leadingtospinalinstability,compressionofthespinalcordornerverootsand,ultimately,neurologicaldysfunctionandparalysis.Bothearlydetectionandappropriateinterventionareessentialtominimizethesequelaeofspinalmetastases,therebymaximizingpatientfunctionandqualityoflife.

ClevelandClinic’sStereotacticSpineRadiosurgery(SRS)programwasestablishedin2006asthefirstspineradiosurgeryprograminOhio.ItisregardedasoneofthepioneeringprogramsinthecountrytoroutinelyofferthisoutpatienttreatmentmodalityusingNovalisShapedBeamSurgerytechnology.Thistechniqueallowsafocusedradiationdosetobedeliveredselectivelytothetumor,whilesparingtheadjacentnormalstructures.Itresultsinrapidandeffectivepainandtumorcontrolwithminimalriskofsideeffects.Stereotacticspinalradiosurgeryhasthusrevolutionizedthetreatmentofmalignantspinetumorsandmanybenigntumorsaswell.Ourexperiencewithradiosurgery,eitherassingleormultimodaltherapy,demonstratesthatthistreatmentisaneffectiveoptionforpatientswithspinelesions.Todate,wehavetreatedmorethan200spinetumors,withmorethan85percentofpatientswithpainexperiencingclinicallysignificantrelief,andlocaltumorcontrolin90percentofpatientswithasingleoutpatientnoninvasivetreatment.

Spineradiosurgeryis,however,justonecomponentofafullspectrumofstandardandadvancedtreatmentoptionscurrentlyavailableatClevelandClinicforthetreatmentofpatientswithspinetumors.Othersincludeopensurgicalprocedures,minimallyinvasivesurgery,vertebralaugmentation,conventionalchemotherapyandradiationtherapy,surgicalpainmanagementinterventions,palliativecareandavarietyofclinicaltrials.Makingtherighttreatmentrecommendationforspinetumorpatientscanbecomplexandrequiresawell-integratedapproach.UnderthedirectionofDr.LilyanaAngelov,amultidisciplinarySpineTumorBoardwasestablished,includingmembersoftheCenterforSpine


2008ANNUALREPORT

15

Health;theBrainTumorandNeuro-OncologyCenter;departmentsofRadiationOncology,Neuroradiology,Pathology,SurgicalPainManagementandHematology/Oncology;aswellasfellows,residents,nursesandphysicianassistantsfrommultipledisciplines.Thisgroupmeetsweekly,andhasdevelopedacoordinated,multifacetedapproachtospinetumorpatients.Sinceitsinceptiontwoyearsago,theSpineTumorBoardhasprovidedtreatmentrecommendationformorethan550patientswhohavejourneyedtoClevelandClinicfordefinitivemanagementoftheirspinetumors.Weanticipatefurthergrowthinourleading-edgespinetumorprogramoverthecomingyears.

Center for Neurofibromatosis

TheCenterforNeurofibromatosisandBenignTumorshasprovidedmultidisciplinarycaretochildrenandadultswithneurofibromatosis(NF)forthreedecades.PhysiciansinthecenterareexpertsinthediagnosisandtreatmentofNFtypeIandtypeII,aswellasotherlesscommonformsofNF.

MedicalcareiscoordinatedthroughateamofneurologistswhothoroughlyevaluateeachpatientanddeterminewhichoftheotherspecialtyphysiciansandservicesatClevelandClinicarenecessary.Becauseofthelargevolumeofpatientscaredfor,theothermedicalandsurgicalserviceshaveextensiveexperienceintreatingthecomplicationsofNF.Ourphysicianskeepthepatient’sprimarycarephysicianabreastofdevelopmentswitheveryvisit,andoftenworkwiththeprimarycaredoctortoprovidecomprehensivelifelongprincipalcaresothatallthepatient’sspecialtycareisatClevelandClinic.

Membersofthemedicalteamareworld-renownedexpertsinthediagnosisandmanagementofthepediatricbraintumorsfoundinNF1,andhaveparticipatedinanddevelopedclinicaltrialsinvolvingnewdrugtreatmentsforthebraintumorsandplexiformneurofibromasthataffectthelivesofmanypatients.

Often,patientsrequirebrainorspinalsurgeryiftumorsoccur.SurgeonsinourprogramhaveextensiveexperienceincaringforthesecomplicationsofNF.ThesurgeonsintheSectionofSkullBaseSurgeryfocusonmanagementofbenignbraintumorsoftenfoundinNF,includingmeningiomasandschwannomas.SurgeonsintheBTNCandSpineCenterhaveextensiveexperienceinthesurgicalremovalandspinalstabilizationproceduresoftenrequiredbythosewithNF.Useofnewlydevelopedspinalradiosurgerytechniqueshasprovidedanon-invasivemethodoftreatingselecttumors.

Patientsandtheirfamiliescanbeassuredthattheirneedswillbecaredforinacomprehensive,well-coordinatedandcompassionatefashionbyphysiciansandnurseswhoarenationallyrecognizedasleadersinthemanagementofNF.

Section of Skull Base Surgery

AsthesurgicalarmoftheCenterforNeurofibromatosisandBenignTumors,theSectionofSkullBaseSurgeryfocusesonmanagementofbenignbraintumors(e.g.,meningiomasandschwannomas)aswellasskullbasemalignanttumors(sinonasalcarcinomas,chordomas,chondrosarcomas).

ClevelandClinic’sSkullBaseSurgeryProgramwithintheBTNCisinternationallyrecognizedasoneofthelargestprogramsspecializinginthemanagementofmeningiomas,evaluatingmorethan200newmeningiomapatientsannually.Amongthese,approximately50percentofpatientsaretreatedwithsurgeryand15percentwithGammaKniferadiosurgeryorconventionalradiation.

Inadditiontoitslargeclinicalvolume,theSectionofSkullBaseSurgeryisoneofthemostproductiveprogramsinternationallyintheareaofmeningiomaclinicalresearch.Morethan15journalarticlesandbookchapterswerepublishedin2006and2007,with23additionalpublicationsinpressin2008.


16

In2007,furtherexpertiseinendoscopicsurgeryforskullbaseindicationswasprovidedwiththeadditionofDr.BurakSadetotheSkullBaseSurgeryProgram.

BTNCendoscopicneurosurgeonsworkcloselywithendoscopicsinussurgeonsinClevelandClinic’sHeadandNeckInstitutetoprovideminimallyinvasivesurgicalmanagementforskullbasemalignancies,inadditiontopituitaryregiontumors.

PituitaryandNeuro-EndocrineCenter(PNEC)

TheNeuro-EndocrineCenterhasshowncontinuousgrowthsinceitsinceptionin2002,fosteredbyacloseworkingrelationshipamongmembersoftheBTNCandthedepartmentsofEndocrinology,DiabetesandMetabolism;NeurologicalSurgery;Neuro-Ophthalmology;andRadiationOncology.Thecloserelationshiphasledtothedevelopmentofhighlyintegratedclinicalcarepathways,acommonpituitarytumorresearchdatabaseandseveraljointresearchprojects(seebelow).

Clinical Care Pathways

Clinicalcarepathwaysdefinethepre-hospital,perioperativeandpostoperativecareforpatientswithsecretoryandnon-secretorypituitarytumors.Thedevelopmentofnewpathwayshashelpeddecreasepatientlengthofstay,withequalpatientoutcomes.

Academic Activities

AprospectiveIRB-approveddatabasehasbeenestablishedforallpatientswithpituitarytumorsseenintheNeuro-EndocrineCenter.Detailedpreoperativeendocrinetesting,includingCortrosynstimulation,isroutinelyperformedforcomparisontopostoperativefindings.Newclinicalcarepathwayshaveeliminatedtheroutineuseofperioperativesteroids,therebyenablingtheaccuratedeterminationofpostoperativepituitaryadrenalactivity.Severalretrospectiveanalyseshavebeencompletedandarealsoinprogress,includingcomparisonofGammaKnifevs.IMRTfor

subtotallyresectedsomatotrophicpituitaryadenomas,casereviewofpituicytoma,ananalysisoftheimpactofsomatostatinontheefficacyofradiosurgeryforsomatotrophicadenoma,andanevaluationoftheroleofradiosurgeryandpostoperativepituitaryinsufficiency.AdditionalcollaborativeworkwithgroupsoutsideClevelandClinichasfocusedonwhatrolemutationsinthearyl hydrocarbon receptor interacting protein gene (AIP)mayplayintheformationofpituitarytumors,especiallyfamilialacromegaly(excessgrowthhormonesecretionduetoapituitarytumor)orintheearlyonsetofthesetumorsinthesporadicsetting.Thisresultedintwopublicationsin2007-2008:Georgitisietal,Proceedings of the National Academy of Sciences USA (PNAS), 104(10):4101-5,2007andClinical Endocrinology,2008,inpress.

Teachingofresidentsandfellowshassimilarlybeenaugmentedthroughtheestablishmentofthecenter.Endocrineresidentsroutinelyparticipateinoutpatientevaluationwithendocrinologistsandsurgeons.BTNCfellowsareintimatelyinvolvedintheoutpatient,operativeandinpatientcareofallpatients.Neurosurgeryresidentsplayacriticalroleintheinpatientandsurgicalcareofthesepatients,andarefrequentlyabletoattendoutpatientclinics.Ajointconferenceinvolvingendocrinology,neurosurgery,neuro-ophthalmology,neuroradiologyandradiationoncologyisheldonthefirstFridayofeachmonth,duringwhichcasepresentationsandmanagementorvisitinglecturersarepresented.

Inaddition,monthlypathologyreviewsessions,wherethepathologicalfindingsofeachpatientarereviewedjointlybythepathologists,endocrinologistsandneurosurgeons(thePituitaryInterestGroup),continue.ThesesessionsareopentoallinterestedpartiesandareheldthefirstMondayofthemonthinthePathology&LaboratoryMedicineInstitute.AdedicatedAdvancedNeurosurgicalandSpineSkillsandSimulationLaboratory(ANSSSL)hasalsobeendevelopedthroughthePituitaryandNeuro-EndocrineCenter’s


2008ANNUALREPORT

17

leadership,withintheDepartmentofNeurosurgery.Aprimefocusisthetrainingofmedicalstudentsandneurosurgeryresidents,aswellasfellowsandstaff,inopen,minimallyinvasiveandendoscopicapproachestothebrainandskullbase,especiallytheanteriorskullbaseviatransnasalandpara-sellarapproaches.

Neuropathology

NeuropathologistsDr.RichardPrayson,SectionHead,andDr.SusanStaugaitisperforminteroperativeconsultationsandfinalpathologicdiagnosesonmorethan600brainandpituitarytumorspecimenseachyear.Morethan450ofthesespecimenshavebeendigitallycapturedfordiscussionattheBTNCpatientmanagementconferences.Allgliomaspecimensareevaluatedbyapanelofancillaryimmunohistochemicalandmoleculartests.ThestaffoftheBTNChasindicatedthatthefollowingpanelismedicallynecessarybecauseitprovidesadditionalinformationforprognosisand/ortreatmentplanning:

WHO Grade I Glioma

•Ki-67immunohistochemistry(proliferationindex)

WHO Grade II


•P53immunohistochemistry(surrogatemarkerforp53pointmutation)

•Fluorescenceinsituhybridization(FISH)forevaluationofalleliclossofchromosomes1pand19q

•(FISHforevaluationofEpidermalGrowthFactorReceptoramplificationisperformedonWHOGradeIIgliomasbutbilledtoBTNCResearchAccount.)

WHO Grade III-IV


•P53immunohistochemistry(surrogatemarkerforp53pointmutation)

•Fluorescenceinsituhybridization(FISH)forevaluationofalleliclossofchromosomes1pand19q

•FISHforevaluationofEpidermalGrowthFactorReceptoramplification

•Analysisof1pand19qusingLOHbyPCRisperformedonselectedcaseswhenthisprocedureprovidesmoreaccurateoradditionalinformation.

•Duetolowvolumeofrequest,sequencingofTP53isnolongerperformedinhouse,butcanbeperformedona“send-out”basis.

•TestingofMGMTpromotermethylationisalsoofferedasa“send-out”test.

Approximatelyone-thirdofthe1p/19qFISHanalysesperformedareReferenceLaboratoryprocedures(patientsarenotBTNCpatientsatthetimeofrequest).

MolecularDiagnosticTestVolume(ReportingPeriod1/1/2008-12/31/2008)

Specimen Class Total 1p FISH

Total 19q FISH

FISH for EGFR**

1p LOH by PCR

19q LOH by PCR

TP53 SEQ Totals

Routine Surgical (SX)* 166 169 149 8 8 0 500

Surgical Outside Review (SO)* 7 8 1 0 0 0 16

Surgical Reference Lab Consult (SRC) 12 12 2 0 0 0 26

Procedure Only (PRS) 94 93 2 1 1 0 191

Totals 279 282 3 0 0 0

*SpecimenClassesSXandSOarepatientstreatedbyBTNCphysicians.**NumbersdonotincludetestsperformedonWHOGradeIIgliomasbilledtoresearchaccounts.


18

Neuropsychology

NewtotheBTNCistheintegrationoftheneuropsychologyprogramintotheclinicalbraintumorprogram.SpearheadedbyDr.MichaelParsons,primarybraintumorpatients,aswellassomeothers,undergoneuropsychologicalassessmentsbeforeandaftercraniotomyfortumorresection.Theseassessmentsoftenreveallatentcognitivedysfunctionthatmayimpactrecoveryandfunctionalityaftersurgeryandthroughouttheirdiseasemanagement.Patientswithanytypeoftumorwhoexhibitcognitivesymptomscanalsoavailthemselvesoftheseassessmentstoimprovetheirmanagementandlifequalityissues.

Neuroradiology

ThesectionsofNeuroradiologyandMagneticResonanceImagingatClevelandClinicprovideawidearrayofdiagnosticcapabilitiesforroutineimagingstudies,aswellasresearchprojects,insupportoftheBTNC.Duringthelastyear,therehasbeenafurtherintervalincreaseinavailabilityofhigh-fieldimagingwithinClevelandClinichospitalsandsatellites.ThisenhancesthecapabilityofourpatientsandphysicianstoscheduleMRimagingappointmentsatsitesthataremoreconvenientforthepatientsandmoreexpeditiousforpatientmanagement.AllofthesesystemsaremanagedcentrallyatClevelandClinic’smaincampus,andtheimagesaretransmitteddigitallysotheyareimmediatelyavailableforcomparisonwithpriorstudiesonthecentraldigitalarchive.Notonlyaretheimagesimmediatelyavailabletoourdiagnosticneuroradiologystaff,butthefinalizedreportsanddigitalimagesarealsoimmediatelyavailabletoourreferringphysiciansthroughtheelectronicmedicalrecord.ImagesacquiredatoutsideinstitutionshavehistoricallybeenproblematicforNeuroradiology’sreferringphysicians.Werecently

pilotedsoftwareintheirclinicsthatenablethereferringservicestobypassthereviewingsoftwareontheoutsideCDs,reviewtheoutsideimageswithastandardizedprogramanduploadtheimagesontoClevelandClinic’scentralarchiveforfuturereferenceifthepatientistobefollowedlongitudinallybyourphysicians.

Diagnosticimagingcapabilitiesinoursystemincluderoutineimaging,diffusionimagingandhigh-resolutionpreoperativeplanningstudiesatallofourfacilities.Atourmaincampus,wealsohavethecapabilitytoprovideMRperfusionimaging,diffusiontensorimaging,functionalMRIandMRspectroscopyformoreadvancedpreoperativeplanning.ThesedatacannowbefusedwithotherDICOMdatasetsandincorporatedintothestereotacticneurosurgicalplanningsoftware.

TheMRIfacilityislocatedimmediatelyadjacenttotheGammaKnifeCenter,andhasjustcompletedreconstructiontobetteraccommodateadultandpediatricsedationcasesandtoimprovepatientsafety.Adultandpediatricanesthesiologistsadvancetheseeffortsbyroutinelystaffingthefacilityfivedaysperweekandprovidingcontinuedemergencycoverageafterhours.

Inaddition,twonew3.0Teslawhole-bodyMRmachineshavebeeninstalledinthehospitalwithupgradedgradientcapabilities,afullcomplementofphasedarraycoils,andanew32-channelphasedarrayheadcoiltoenhanceourinpatientcapabilitiesinfastimaging,high-resolutionimaging,3DfastspinechoacquisitionsandMRspectroscopy.Thesesystemsnowallowustoperformpreoperativediffusiontensorimagingand,shortly,functionalMRIstudies,whichwerepreviouslyavailableonlyinanoutpatientfacilityatClevelandClinic’sMellenCenterforMultipleSclerosisTreatmentandResearch.


2008ANNUALREPORT

19

Neuro-OncologyNursing

Nurses,physicianassistantsandtechniciansspecializinginthecareofpatientswithbraintumorsareanintegralpartoftheBTNC.Membersofthenursingandphysicianassistantteam,whichincludesCathyBrewer,GailDitz,MicheleGavin,BettyJamison,DebraKangisser,KathyLupica,MaryMiller,CarolPatton,RachelPerez,SherrySoeder,LauralTuro,CarlaDuvall,ShelleyOgrinandMaryMurphy,areoftenthefirstcontactforpatientsseekinganopinionorcomingtotheoutpatientdepartmentforevaluation.TheoutpatientnursingteamisoverseenbyMarcellaLupica.

KathyLupicafacilitatesourmonthlyBrainTumorSupportGroup,whichisattendedbypatients,familiesandfriends.Ms.Lupicapresentedatseveralprofessionalandpatientconferencesin2008,includingalectureon“BrainTumorUpdates”attheNeuroscienceNursingConferenceatClevelandClinicand“BrainTumorPathologyUpdate”aspartofapre-conferenceworkshopattheAmericanAssociationofNeuroscienceNurses’40thAnnualEducationalMeetinginNashville,Tennessee.Shealsoco-presented“BrainTumors:FacingtheChallengeTogether”forpatientsandlovedones,hostedatTheGatheringPlace.

GailDitzpresented“AdvancesinNeuroimaging”aspartofapreponderanceworkshopattheAmericanAssociationofNeuroscienceNurses’40thAnnualEducationalMeeting.Shealsopresentedalectureon“NeuroimagingfortheBedsideNurse”attheNeuroscienceNursingConferenceatClevelandClinic.

CathyBrewerandCarolPattonassistwithpatientsinterestedinparticipatinginorcurrentlyinvolvedinresearchprotocols.BettyJamisonworkswithpatientsundergoingGammaKniferadiosurgery.

Nurse Practitioners

KathyLupica,SherrySoeder,CarlaDuvallandShelleyOgrin

Nurse Clinicians

GailDitz,BettyJamison,RachelPerez,LauralTuro,MaryMiller,MaryMurphy

Research Nurses

CathyBrewer,CarolPatton

Physician Assistants

MicheleGavin,DebraKangisser


20

Becausemanyoftheconditionswetreathavenoknowncures,ortheoptimaltreatmenthasnotyetbeendefined,theBTNCiscommittedtothedevelopmentofnewandinnovativetreatmentsforpatientswithbenignandmalignantbraintumors.Ourpatientsmayelecttoundergoexperimentaltreatmentsortoparticipateinclinicalresearchprojectsrelatedtotheirdiagnoses.VariouschemotherapiesandgrowthmodifiersareamongtheexperimentaldrugprotocolsdevelopedbyBTNCclinicalinvestigators.

TheBTNCwasrecognizedin2004foritsroleasaleaderincutting-edgetreatmentandresearchbybeingselectedasafullmemberoftheprestigiousNewApproachestoBrainTumorTherapy(NABTT)consortium.NABTTisoneofonlytwonationalconsortiafundedbytheNationalCancerInstitutetoconductPhaseIandIItrialsofnewtreatmentsforbraintumors.ThisconsortiumhasnowmergedwiththeNorthAmericanBrainTumorConsortiumtoformtheAdultBrainTumorConsortium(ABTC).TheABTCistheonlyconsortiumfundedbytheNationalCancerInstitutetoconductPhaseIandIItrialsofnewtreatmentsforbraintumors.

TheBTNCparticipatedinseveralotherconsortiaandcooperativegroups,includingRadiationTherapyOncologyGroup(RTOG),Children’sOncologyGroup(COG),AmericanCollegeofSurgeonsOncologyGroup(ACoSOG),InternationalBloodBrainBarrierConsortium(IBBBDC)andSouthWestOncologyGroup(SWOG).Dr.MichaelVogelbaumistheCo-ChairoftheBrainTumorCommitteeandChairoftheNeurosurgeryCommitteeforRTOG.

BTNCphysiciansalsoplayleadershiprolesinothermulticentertrials.BelowareexamplesofsingleandmulticenterclinicaltrialsbeingledbyBTNCphysicians.

•PhaseIItrialofpatupiloneinwomenwithbreastcancerbrainmetastases.Thismulticentertrialtestsanovelepothilonethatcrossestheblood-brainbarrier.ThestudyisheadedbyDr.DavidPeereboom.

•PhaseIItrialofritonavir/lopinavirinpatientswithprogressiveorrecurrenthigh-gradegliomas.ThistrialofanoralagentthatinhibitstumorcellinvasionwasdesignedbyDr.DavidPeereboom.

•PhaseI/IItrialofBMS-247550fortreatmentofpatientswithrecurrenthigh-gradegliomas.Thisclinicaltrialexaminesanepothiloneforpatientswithrecurrenthigh-gradegliomas.Dr.DavidPeereboomisthePIforthisnationaltrialconductedwithintheNCI-sponsoredNABTTCNSConsortium.

•PhaseIIItrialofradiationand/orchemotherapyfornon-1p/19qcodeletedanaplasticgliomas.Dr.MichaelVogelbaumistheU.S.PIforthisinternationaleffortbeingcoordinatedbytheEORTC,aEuropeancooperativetrialgroup.

Additionalclinicalresearchprogramsinclude:

1. Intra-arterial chemotherapy with blood-brain barrier disruption (BBBD) for primary central nervous system lymphoma (PCNSL) and other tumors –Dr.LilyanaAngelovhasdevelopedaconsortium-widedatabaseforthetabulationoftreatmentresultsofthisprocedureforpatientswithPCNSL.ThisefforthasproducedaverylargemulticenterseriesregardingthetreatmentofnewlydiagnosedPCNSLpatientswithosmoticBBBDandintra-arterialchemotherapy–workthathasbeenthesubjectofnumerouspeer-reviewedrequestedpresentationsandmanuscriptsubmissions.Further,theBTNCstaffhascontributedtothewritingofseveralnewprotocolsfortheconsortiumaswellasmakingseveralpresentationsattheconsortium’sannualmeetings.Severalstaffmembershavecontributedtopublicationoftheproceedingsfromthismeeting,aswellasothermeetingsonthistopic.

2. Erlotinib/temozolomide and postoperative radiation for newly diagnosed glioblastoma multiforme (GBM)–Dr.DavidPeereboomledaPhaseIItrialoferlotinibwithtemozolomideandconcurrent

ClinicalResearchPrograms/Innovations

2008ANNUALREPORT

21

radiationtherapypostoperativelyinpatientswithnewlydiagnosedGBM.Thissingle-institutiontrialcompletedaccrualin2007.Thisstudywasthefirsttocombineerlotinibwithstandardtherapyforpatientswithnewlydiagnosedglioblastomas.ThemanuscripthasbeensubmittedtothejournalNeuro-Oncology.

3. Intraoperative radiation therapy for solitary brain metastases –Dr.RobertWeilisconductingaPhaseI/IIstudyutilizinganovelmethodfordeliveringintraoperativeradiationtherapy(INTRABEAM)forthetreatmentofaresectedsolitarybrainmetastasis.Thismethodallowstheprecisedeliveryofradiationtherapydirectlyintothetumorcavityandallowsthepatientwithasolitaryresectablebrainmetastasistopostponetheneedforwholebrainradiation.

4. Convection-enhanced delivery (CED) of anti-tumoral agents– Thisprogramusestheslow,continuousinfusionofagentstargetedtomalignantglioma.Thistechniquehasthepotentialtodeliveragentsthatotherwisecannotbedeliveredtothebrainorthataretootoxictootherorgansforsystemicdelivery.BTNCneurosurgeonshavebeenactivelyinvolvedinseveraltrialsaswellasdevelopmentofnewinvestigations.AmulticenterPhaseItrialofCEDofIL13PE38QQRfornewlydiagnosedGBMwasledbyDr.MichaelVogelbaumandtheresultswerepublishedin2007.Dr.VogelbaumhasalsobeendevelopingnewdrugsanddevicesforCEDintheCenterforTranslationalTherapeutics.Heiscoordinatinganeffort,alongwithClevelandClinicInnovations,tobringanovelCEDcathetertotheFoodandDrugAdministrationinordertomakeitavailableforupcomingCEDtrials.Dr.VogelbaumalsoservesasFoundingPresidentoftheSocietyforCNSInterstitialDeliveryofTherapeutics,thefirstinternationalorganizationdedicatedtoresearchinthistechnique.

5. Laser interstitial thermal therapy –Dr.GeneBarnettisleadingthefirsthumantrialofanewsystemaimedatthermallyablatingbraintumors. Aside-firinglaserisplacedstereotacticallyintoarecurrentglioblastomaandthethermaldamageismonitoredbyreal-timeMRthermometry.Preclinicaltestingwascompletedin2007,andDr.Barnetttreatedthefirstpatientwiththisdevicein2008.

6. Brain metastases trials–TheSectionofMetastaticDiseasehasseveralclinicaltrials.Dr.RobertWeilisClevelandClinic’sprincipalinvestigatorontheDepartmentofDefenseCenterofExcellencegrantfortheeradicationofbreastcancerbrainmetastasis.Aspartofthegrant,heandDr.DavidPeereboomhaveactivatedastudyinwhichabreastcancerchemotherapydrugisgivenpriortoaclinicallyindicatedsurgicalresectionofabreastcancerbrainmetastasis.Thetumorsampleisthenassayedfordrugconcentrationtoassessentryintoapatient’stumor.Dr.Weilwillalsoestablishcelllinesfromtheresectedtissue.Twoclinicaltrialsofpatupiloneinbrainmetastases,oneforbreastcancerandonefornon–small-celllungcancerbrainmetastases,areactivelyaccruingpatientsandhaveshownactivityinthesepatients.ThemulticenterbreastcancerstudywasdevelopedbyDr.DavidPeereboom.AnothermulticentertrialdevelopedbytheBTNCinvolvestheuseofsunitinibwithdelayedwholebrainradiationtherapyforpatientswithonetothreebrainmetastaseswhohavereceivedstereotacticradiosurgery.TheBTNCisactivelyinvolvedinRTOGtrialsforbrainmetastasesaswell.TheBTNCiscompletingaccrualonaPhaseI/IIstudyofthePECintraoperativeradiotherapydeviceforthetreatmentofaresectedsolitarybrainmetastasis,anovelmethodforthedeliveryofintraoperativeradiotherapy.


22

7. Complementary and alternative medicine–Dr.GlenStevenshasreceivedNIHfundingforthefirstBTNCtrialofcomplementaryandalternativemedicine.Histrial,“PhaseIIRandomizedEvaluationof5-LipoxygenaseInhibitionbyDietaryandHerbalComplementaryandAlternativeMedicineApproachComparedtoStandardDietaryControlasanAdjuvantTherapyinNewlyDiagnosedGlioblastomaMultiforme,”seekstominimizebrainedemainpatientswithGBM.

8. National trials led by BTNC investigators–TwoNABTTconsortiumtrialswereledandcoordinatedbyDr.DavidPeereboom:PhaseI/IItrialofixabepiloneinpatientswithrecurrenthigh-gradegliomasandaPhaseIItrialoferlotinibandsorafenibinpatientswithrecurrenthigh-gradegliomas.Dr.MichaelVogelbaumistheU.S.PIforaEuropean-ledPhaseIIItrialofradiationand/orchemotherapyfor1p/19qnon-codeletedanaplasticgliomas.HeisalsotheU.S.co-PIforanotherPhaseIIItrialofradiationand/orchemotherapyfor1p/19qcodeletedanaplasticgliomas.

9. Tumor-treating fields–Dr.RobertWeilisthelocalprincipalinvestigatorofthisnovel,noninvasivemeansofusingappliedelectromagneticfieldsinanefforttotreatrecurrentglioblastoma.

10. Stereotactic radiosurgery – TheBTNCremainsactiveincooperativegroupstudies.Onestudycomparesstereotacticradiosurgeryalonevs.stereotacticradiosurgeryandwholebrainradiationinthemanagementofbrainmetastases(RTOG0574).

11. Primary CNS lymphoma –Thisstudyisassessingtheadditionofrituximab,methotrexateandtemozolomidetothemanagementofprimaryCNSlymphoma(RTOG0227).

12. Brain metastases from non–small-cell lung cancer–TheBTNCisactivelyenrollingpatientsinanRTOGstudytoassesstheroleofchemotherapyinthemanagementofbrainmetastasesfromnon–small-celllungcancer.Theagentsbeinginvestigatedareerlotinibandtemozolomide(RTOG0320).

13. Developing RTOG studies –PhaseIIIstudyusingmemantinetopreventcognitivedysfunctionfromwholebrainradiation(RTOG0614).PhaseIIIstudytoassesstheroleofAvastininthemanagementofglioblastomamultiforme(RTOG0825,Dr.MichaelVogelbaumistheNeurosurgicalChair).

14. Other clinical research interests –Dr.JohnSuhisactivelyinterestedinstudyingtheroleofradiosensitizersinthetreatmentofbraintumors.HehasbeenaninternationalPIforthesestudies.Dr.SamuelChaoisinterestedinthediagnosisandmanagementofradiationnecrosis,acomplicationfollowingradiationtreatment.Heisworkingonprotocolsanddevelopingadatabase.

ClinicalResearchPrograms/Innovations (continued)

2008ANNUALREPORT

23

Basic Research ResearchatClevelandCliniccontinuestogrowandprosperthroughrecruitmentofoutstandingnewstaff,improvementandexpansionoffacilities,developmentofextensiveinfrastructureandsupportservices,andenhancementofeducationprograms.CentraltothesuccessoftheBTNCisadvancingthecareofbraintumorpatientsthroughbetterunderstandingofthecausesandmechanismsoftumordevelopment.Basicscienceresearcheffortsarefocusedonidentifyingthegenetic,cellularandmolecularbiologyofmalignantandbenignbraintumors;investigatingthemechanismoftumorformation;andexploringnewtherapeuticdevelopmentsforbraintumortreatments.

Belowareexamplesofprojectsbeingconductedinthebasicresearchlabs.

•Developmentofimmunotherapyformalignantgliomausingvaccinesformedbyfusingtumorcellswithdendriticcells(Dr.GregoryPlautz)

•Characterizationofthetumorantigenprofileofbraintumorstemcellstodeterminewhethertherearecommongliomaantigens,whichwouldmakeitpossibletodevelopastandardizedgliomavaccine(Dr.GregoryPlautz)

•Theabilityofdendriticcell/tumorcellfusionvaccinesandadoptivetransferoftumor-sensitizedTcellstocureestablishedbraintumors,beingtestedinmousemodelsasapreludetofutureclinicaltrials(Dr.GregoryPlautz)

•InvestigationsintoalterationsinDNArepairmechanismsthatmayimprovethechemo-andradio-sensitivityofmalignantgliomas(Dr.MichaelVogelbaum)

•ExaminationoftheroleofNFkappaBandIL-8indrivingtheinvasionofmalignantgliomas(Dr.MichaelVogelbaumandDr.BaisakhiRaychaudhuri)

•Productionoftumor-specifictoxicityinmalignantgliomasbymodifiedsmallinterferingRNAmolecules(Dr.MichaelVogelbaumandDr.JoseValerio)

•DevelopmentofanovelassayforMGMTfunction(Dr.MichaelVogelbaumandDr.CliffRobinson)

BTNCPrimaryLaboratories

Center for Translational Therapeutics – Vogelbaum Laboratory

TheBTNC’sCenterforTranslationalTherapeutics,directedbyDr.MichaelA.Vogelbaum,performspre-clinicaltestingofthemostpromisinganti-canceragentsthatmaybeofusefortreatingmalignantbraintumors.OnegoaloftheCenterforTranslationalTherapeuticsistoacceleratethelengthyandexpensiveprocessoftestingnewdrugstargetedagainstbraintumorsandtosafelymovethesedrugsintoclinicaltrialsasquicklyaspossibleforthebenefitofpatients.

Physicians,researchersandscientistsinvolvedinthiscenterworkwithpharmaceuticalcompaniesandothermedicalinstitutionstoidentify,obtainandtestnewcompounds.Thecenter’sefforts,includinganinternationalsearchforallpotentialbraintumor-relevanttherapies,haveyieldedseveralpromisingagentsfortesting.Testingofnewagentsinvolvesevaluatingthetoxicityandefficacyofthesecompoundsinthelaboratoryandinanimalsthathavebraintumors.Inaddition,weareinvestigatingtheoptimalrouteofdeliveryofthesedrugs.

Becausemanynewtherapeuticagentscannotpenetratethecentralnervoussystem,centerresearchersareexploringalternativedeliverymethods.Inadditiontoinvestigatingtheefficacyoforaldelivery,researchersevaluatetheefficacyoftheagentswhendeliveredintracerebrally–directlyintothebrain–viaaspecializedneurosurgicaltechniquecalledconvection-enhanceddelivery(CED).Furthermore,incollaborationwithinvestigatorsintheDepartmentofBiomedicalEngineeringofLernerResearchInstitute(LRI),weareevaluatingalternativeformulationsusingnanotechnology,whichmayenhancedistributionofpotentialtherapeuticswithinthebrain.

Thecenterhasstartedresearchprojectswithanumberofpharmaceuticalandbiotechnologycompaniesranginginsizefromsmallstartupfirmstosomeofthelargest

BTNCLaboratoryResearch/Innovations


24

publiclytradedcompanies.Whatthesecompanieshaveincommonarenoveldrugsthatareclosetoorinclinicaltrial,andthatarerationallydesignedtobeeffectiveagainstmalignantgliomasgiventhemolecularandgeneticmakeupofthesetumors.ThesedrugsaretargetedagainstmoleculessuchasEGFR,mTOR/Akt,STAT3andRaf-1kinase.OurfirsttranslationalclinicaltrialiswithTarceva/OSI-774,aselectiveEGFRkinaseinhibitorsmall-moleculedrug.ThisPhaseIItrialshowedanencouragingrateoftumorresponsesanddiseasestabilization.Incombinationwithworkdoneinourpreclinicalmodels,thisclinicaltrialraisedimportantquestionsregardingtheabilityofthedrugtopenetratetheblood-brainbarrier.Asaresultoftheseobservations,welaunchedafollow-uptrialinwhichpatientsundergoatumorbiopsywhilereceivingthedrug.ByanalyzingtheeffectsofTarcevaonthetumortissues,wewillbeabletodeterminewhetherresponsetothisdrugdependsprimarilyuponitsabilitytoreachitsintendedtargetinthetumor.

ThecenterhasalsoworkedcloselywithotherlaboratoriesatClevelandClinictohelpdevelopnoveltherapeuticsthatmayhaveapplicationforpatientswithmalignantbraintumors.Wehaveevaluatedmethodsforimprovingimmuneresponsetogliomas(incollaborationwithJamesFinke,PhD,oftheDepartmentofImmunologyinLRI),understandingtheroleofNFkBinregulatinggliomacellmigrationandexploringtheuseofanewdrugthatmaysensitizegliomastotemozolomide(incollaborationwithStantonGerson,MD,DirectoroftheCaseComprehensiveCancerCenter).Oureffortshaveincludedcollaborationswithinvestigatorswhohavetraditionallyworkedoutsidethefieldofmalignantbraintumors,includingQingWang,PhD(DepartmentofMolecularCardiology,LRI),withwhomweareinvestigatingtheroleofanewlydefinedtumorangiogenesisgene.

Weil Laboratory

Gliomas and GlioblastomasTheWeilLaboratorycontinuesitsworkingenomicandproteinprofilingof

braintumors.Thisisverytime-consuming,laboriouswork–onetumoratatime–butitisrewardingintermsofgainingaricherandmorenuancedunderstandingofhowthesetumorsmaydevelop,progressandrespondtotherapy,especiallywithrespecttofindingnewtargets.

Additionalworkcontinuesondecipheringtheinternalgeneticandproteindifferencesofmalignantgliomas,usingavarietyofmoleculargeneticandproteomicmethods.Thisisalong-termprojectthatwillproceedoveranumberofyears,gainingstrengthandnuanceasmoretissuesarestudiedandvariationsaccountedfor.

Forexample,KhatriRG,NavaratneK,WeilRJ.“TheRoleofaSingleNucleotidePolymorphismofMDM2inGlioblastoma.”Journal of Neurosurgery,November2008,detailshowasingle-nucleotidepolymorphism(SNP),whichisanormalvariantintheDNAsequenceencodingaprotein,canleadtoalteredsignalingofthatorotherproteins.Inthiscase,theGalleleisexpressedmorecommonlyinpatientswithglioblastomamultiforme(GBM),andthisleadstohigherlevelsofMDM2,irrespectiveofthelevelsofTp53,whichnormallycontrolsMDM2.HigherlevelsofMDM2,whichactsasanoncogene(atumor-promotinggene),areknowntoenhancetumorgrowthinmanycancers,includingGBM.ThisworksuggeststhatacommonSNPvariant,whichanyonemayhave,andwhichwouldnotcauseproblemsinthenormalcell,mayenhancecancerinthosepatientswhodevelopaGBM.

Brain MetastasisMetastatictumorstothebrain,whichoccurinupto200,000peopleperyear,representasignificantsourceofneurologicaldebilityandprematuredeath,andareasecondclinicalandresearchfocusofthislaboratoryeffort.

SupportfromtheBurkhardtChairpermittedpreliminaryworkinproteomicsofbreastcancermetastasisthatsupportedasuccessfulgrantapplication.Dr.RobertWeilisClevelandClinic’sprincipalinvestigatoronarecentlyawardedDepartmentofDefenseCenterofExcellence(COE)grant,fiveyearsinlengthand

BTNCLaboratoryResearch/Innovations(continued)

2008ANNUALREPORT

25

involvingapproximately10centers,tostudytheprocessofCNSmetastasisinbreastcancerpatients.Overall,itisa$17millionaward(directandindirectcosts),withnearly$2.7millioncomingtoClevelandClinictofundaclinicaltrial,themajoritytofundproteomicsresearchontheidentificationofproteinsthatgowiththeprocessofbrainmetastasis.PatriciaSteeg,theheadoftheWomen’sCancersSectionattheNationalCancerInstitute,istheleadPrincipalInvestigatorfortheCOE.Workonproteomicprofiling,comparingbreastcancersfromwomenwhohaveneverdevelopedabrainmetastasiswiththosewhohave,isongoing.Thegoalistoidentifyasetofgenesandproteinsintheoriginalbreastcancerthatmaysuggestwhichwomenmaybeatriskofdevelopingbreastcancerthatwillmetastasizetothebrain,bothtodevelopsurveillancemethodstofindsuchtumorsearlyand,moreimportantly,todevisestrategiesandtreatmentsthatmaypreventthemfromdeveloping.

Pituitary TumorsThisisanareaofclinicalinterestinwhichseveralimportantpublicationshaveresultedfromworkdonetogetherwithLauriAaltoneninFinland,showingthatmutationsinthearylhydrocarbonreceptorinteractingproteingene(AIP)mayplayaroleintheformationofpituitarytumors,especiallyfamilialacromegaly(excessgrowthhormonesecretionduetoapituitarytumor)orearlyonsetofthesetumorsinthesporadicsetting.Thishasresultedintwopublicationsinprestigiousjournals,includingProceedings of the National Academy of SciencesUSA(PNAS),104(10):4101-5,2007andClinical Endocrinology,inpress.

Collaborative Laboratories

Jeremy Rich, MD, PhD *

Dr.RichjoinedClevelandClinicasChairoftheGenomicsInstituteinSeptember2008.Heisaworld-renownedexpertonbraintumorstemcellsaswellasbeingaclinicalneuro-oncologist.Dr.Richwillcarryonhiscutting-edgebraintumorstemcellresearchincollaborationwithBTNCcliniciansandscientists.

Jaharul Haque, PhD *

Dr.Haque’slaboratoryinvestigatestheroleofthetranscriptionfactorSTAT3todrivethemalignantbehaviorofgliomas.IncollaborationwithDr.MichaelVogelbaum,thisprojectobtainedNIHfunding:“CytokineSignalinginGlioblastomaCells.”NIHR01CA95006-01(MAVco-PI;10%effort;PI:JaharulHaquePhD;6/1/03–5/31/08,totaldirectcosts:$1.6million)andgeneratedmultiplepeer-reviewedpublications.Afollow-upfundingproposalhasbeensubmittedtoNIHforreview.

Susan Brady-Kalnay, PhD

Dr.Brady-Kalnay’slaboratoryhasinvestigatedtheroleofanovelphosphataseinregulatingtheinvasionandmigrationofmalignantgliomacells.IncollaborationwithDr.MichaelVogelbaum,thisprojectobtainedNIHfunding:“PTPµSuppressesBrainTumorCellMigrationandDispersal.”NIHR01NS051520-01A1(MAVcollaborator,5%effort;PI:SusanBrady-KalnayPhD;6/1/2006–5/31/2011,totaldirectcosts:$1.9million).Overthecourseofthisgrantingperiod,wehaveperformedinvivostudiestoevaluatehowalterationsinthefunctioningofPTPµaffecttheabilityofhumangliomaxenograftstoinvadeinrodentbrains.

James Finke, PhD *

Dr.Finkehasbeeninvolvedwithinvestigationoftheimmunobiologyofgliomas. Priorstudiesofmalignantgliomashaveshownthatgliomasareimmunosuppressive,asevidencedbydecreasedTcellfunctionandthepresenceofapoptosisinasubsetoflymphocytesfrompatients’blood.GBMsareknowntooverexpressseveraldifferentgangliosidesthatcanbeshedfromthetumorandpromoteTcelldysfunction.Morerecently,ithasalsobeenclearthatthetumormicroenvironmentcanpromotetheaccumulationofimmunecellswithsuppressiveactivitythatcanpreventthedevelopmentofanti-tumorimmunity.ThisincludestheT-regulatorypopulationaswellasmyeloidderivedsuppressorcells(MDSC).Understanding

*DenotesClevelandClinicphysicianorscientist.


26

therolethatGBM-derivedgangliosides,aswellasimmunesuppressivecells,playindampeningtheTcellresponsetothistumorisimportant–asisdefiningtheirmechanismsofaction.WeandothersproposethateffectiveimmunotherapywilllikelybeachievedbycombiningeithervaccineoradoptiveTcelltherapywithagentsthatcanreducetheimmunesuppression.

Tothisend,wehavebeenevaluatingtheimmunosuppressivepropertiesofgangliosidesisolatedfromGBMcelllines.Previously,wereportedthathumangliolastomacelllinesandisolatedgangliosidesinduceapoptosisinperipheralbloodTcells.Morerecently,weexaminedthemechanismbywhichGBMlinesandgangliosidesinduceapoptosis.PeripheralbloodTcellsactivatedwithanti-CD3(OKT3)/anti-CD28antibodieswereculturedeitherwithGBMcelllinesorwithGBMcelllinederived-gangliosides(10-20mg/ml)for48to72hourspriortoassessingapoptosis(nuclearblebbingdetectedbyDAPIstaining),caspase(-3,-8,-9)activation,andchangesintheexpressionoftheanti-apoptoticproteinsBcl-2andRelA.WhencomparedwithTcellsco-culturedwithmediaalone,thoseco-culturedwithallthreeGBMcelllines(CCF52,CCF4andU87)showedapoptoticblebbingandreducedexpressionofRelAandBcl-2butnotb-actinasacontrolprotein.Thereductionintheexpressionoftheanti-apoptoticproteinslikelycontributestothepromotionofTcelldeathfollowingexposuretoGBMcelllines.Caspases,whichareproteinscriticalforinitiatingthedeathsequenceforapoptosis,werealsoactivatedinTcellsbyexposuretotumorcelllines,asdemonstratedbytheappearanceofcleavedcaspase-3and-8fragmentsandthereductionincaspase-9proform.

ThatgangliosidesderivedfromtheGBMcellsareimportantforinductionofTcelldeathissupportedbythedemonstrationthatgangliosidesderivedfromtheGBMlinescanmimictheapoptoticeventsinducedbytheRCClines.Gangliosidesisolatedfromthethree

GBMcelllinescontainedsignificantlevelsofGM2,GM1andGD1aasdeterminedbyHPTLCandELISAanalysis.TheseGBMcellline-derivedgangliosidesinducedRelAdegradationalongwithTcelldeathin72hours.ItwasalsodemonstratedthatexposureofTcellstoGBM-derivedgangliosidesinducedtheformationofreactiveoxygenspecies(ROS)within12to18hours,whichwasfollowedbymitochondrialdamage.Westernblottingdemonstratedthatgangliosidesfromallthreecelllinesinducedmitochondrialdamageasevidentbythereleaseofcytochrome-cintothecytosol.Additionally,mitochondrialpermeabilitytransition(MPT)wasobservedasdetectedbyreduceduptakeofthemitochondrialdyeDiOC6inTcellstreatedwiththegangliosidescomparedwiththeuntreatedcells.GBM-derivedgangliosidesalsoresultedintheactivationoftheeffectorcaspase-3alongwithbothinitiatorcaspases(-9and-8).Theadditionofcaspase-8or-9inhibitorstothecellculturesdemonstratedthatthecaspase-8inhibitorwasmoreeffectiveatprotectingTcellsfromapoptosis(60percentprotection)thanwasthecaspase-9inhibitor(25percentprotection).Interestingly,boththecaspase-8and-9inhibitorswereequallyeffectiveatblockingcaspase-8andcaspase-3activation.ThesefindingsshowthatGBM-derivedgangliosidesinduceTcelldeathbyreducingtheexpressionofkeyanti-apoptoticproteins(RelAandBcl-2)andbyinducingROSformationmitochondrialdamagealongwithcaspaseactivation.Thisstudyalsoshowsthatcaspase-8,whichistypicallyassociatedwithdeathreceptor-mediatedapoptosis(Fas,TNFa),isclearlycriticalforganglioside-mediatedapoptosis.

WehavealsostartedexaminingperipheralbloodTcellsfromGBMpatientsfortheirstainingwithantibodiestogangliosidesthataretypicallynotdetectedonTcellsfromhealthydonors,butareexpressedbyGBMs.ThissamekindofstudyhasshownthatthegangliosidesGM2andGD2aredetectedonTcellsfrompatientswithrenalcancer,butnotnormaldonorTcells.The

BTNCLaboratoryResearch/Innovations(continued)

2008ANNUALREPORT

27

GM2/GD2positivecellsareclearlymoreapoptoticthantheGM2/GD2negativeTcellsfromthesamepatient.WhetherweobservethesamefindingswithTcellsfromGBMpatientswillbeexamined.Aspartofthesestudies,wewillalsotestwhethertheperipheralbloodfromGBMpatientscontainsasignificantnumberofMDSCwhencomparedwithbloodfromhealthydonors.IncreasednumberofMDSChasbeenobservedinperipheralbloodofcancerpatients,althoughtherehavebeennostudiesinGBMpatients.IfMDSCareincreasedinnumber,wewillassessthattheysuppressactivityinvitroandifthetyrosinekinaseinhibitorsunitinibcaninhibittheirsuppressiveactivityorinduceapoptosisinthesecells.

Stanton Gerson, MD, and Lili Liu, PhD

Dr.GersonandDr.LiuarerecognizedauthoritiesregardingtheroleofDNArepairenzymesinmediatingresistanceoftumorcellstochemotherapy.IncollaborationwithDr.MichaelVogelbaum,theyareevaluatingtherolesoftheMGMTandbaseexcisionrepairpathwaysinmediatingthechemoresistanceofgliomas.Multiplelaboratoryprojectsareongoingandafundingproposalisbeingdeveloped.

Damir Janigro, PhD *

Since2007,theCenterforCerebrovascularResearch,directedbyDr.Janigro,hasbeeninvestigatingproteomicmarkersforbrainmetastasesinpatientsinitiallydiagnosedwithlungcancer.ThisstudyhasbeenperformedinconjunctionwithDr.PeterMazzonefromtheDepartmentofPulmonaryMedicineandDr.TarekMekhailfromtheDepartmentofHematology/Oncology,aswellasDr.ThomasMasarykfromtheSectionofNeuroradiology.Thestudyinitiallycenteredonthewell-knownmarkerofblood-brainbarrierintegrity,S-100bbut,liketheCSFcounterpartmarker,transthyretinmonomer(alsoknownasprealbuminmonomer),hasbeenfoundtobefalselyelevatedbythepresenceofsmallvesselischemicdisease(SVID),whichismost

prevalentintheelderlyandthosewithdiabetesmellitusand/orhypertension.

ArecentprospectivestudycompletedbymedicalresidentDr.J.MichaelTaylor,performingresearchinDr.Janigro’slabandpresentingattheShowCASE2008conferenceatCaseWesternReserveUniversity,foundthatofmorethan550lungcancercasesfollowedatClevelandClinicoverthepastfiveyears,themajorityofthesepatients(358,or65percent)werefoundtohaveSVIDbyMRI.AnauxiliaryfindingfromthestatisticalanalysisofthesepatientswasthatthepresenceofSVIDappearedtocorrelatewithadecreasedincidenceofbrainmetastases(14.0percent)whencomparedwiththosewhodidnothavefindingsofSVIDbyMRI(33.7percent;P<0.01).EarlierworkperformedbyVincentFazio,MS,basedonDr.Janigro’scollaborationwithDrs.MazzoneandMekhail,uncoveredalungcancerpatientwhooninitialpresentationwasnegativeforbrainmetastasesbut,uponasecondaryMRIperformed16monthslater,presentedwithmultiplebrainmetastases.Althoughthisfindingwasunfortunateforthepatient,thecomparisonofthesetwoserumsamplesfromthesamepatienthelpedtoeliminatenon-metastaticrelatedvariationsbetweenlungcancerpatientswithandwithoutthedevelopmentofbrainmetastases.

Furtherstudiesofserumfromlungcancerpatientspresentingwithorwithoutbrainmetastases,andforwhichthepresenceofSVIDbyMRIwasdeterminedthroughcollaborationwithDr.MasarykfromNeuroradiology,identifiedtheproteinProapolipoproteinA1asamarkerofbrainmetastasesthatwasnotfoundtobeelevatedduringthepresenceofSVID.Thisworkwasvalidatedbytwo-dimensionalWesternblottingofthisvariantforApolipoproteinA1performedbyMr.FaziooveranexpandedisoelectricrangefrompI4.7-5.9.ThisworkhasrecentlybeenpublishedinworkbyNicolaMarchi,PhD,etal.,Cancer2008;112:1313–24.

*DenotesClevelandClinicphysicianorscientist.


28

Establishedin2001,ClevelandClinic’sBrainTumorandNeuro-OncologyCenter(formerlyBrainTumorInstitute)isamongtheleadingprogramsintheUnitedStatesforthediagnosisandtreatmentofprimaryandmetastatictumorsofthebrain,spineandnervesandtheireffectsonthenervoussystem.NowpartofthenewlyestablishedClevelandClinicNeurologicalInstitute,theBrainTumorandNeuro-OncologyCentercloselycollaborateswithTaussigCancerInstitutetoprovideinnovativesolutionsforthesecomplexproblems,utilizingthelatesttechnology.

UnderthedirectionofGeneBarnett,MD;MichaelVogelbaum,MD,PhD,AssociateDirector;GeorgeLawrence,Administrator;andTheresaNaska,Manager,successcontinuedin2008,withmorepatientsthaneverbeingserved,andmorethanaquarterofnewpatientscomingfromoutsideOhio.Weexpandedourservices,improvedpatientsatisfaction,attractedworld-classphysiciansandscientiststoourstaff,madesignificantadvancesinbasicandclinicalresearch,andofferedabroadarrayofeducationalexperiences,includinginternationalforums.

TheBTNC’sclinicalresearchinfrastructureisfullyintegratedwiththatofClevelandClinicTaussigCancerInstitute.Allclinicalprotocolsandcorrespondences,includingIRBsubmissions(e.g.,protocolamendments,safetyreports),protocolbudgetcreation,nursingassignmentandstudystart-up,arefunneledintotheBTNCthroughTheresaNaskaandprocessedthroughBTNCstudycoordinatorsKathyRobinsonandMarciCiolfi.Materialisdispersedfromthiscentralresourcetoallappropriateparties.TheBTNChastwodedicatedresearchnurses,CathyBrewerandCarolPatton,who

manageallclinicaltrials,includingpatientconsent,monitoringandfollow-up.ThesenursesarepartoftheTaussigCancerInstituteprogramandarebackedupbyotherTaussigCancerInstituteresearchnurses.Theprogramoverseesandmanagesallregulatorymatters,IRBsubmissionsandalldatacollection/CRFtranscriptionresponsibilitiesthroughthededicatedBTNCstudycoordinators.

ClevelandClinicTaussigCancerInstituteisaffiliatedwithCaseWesternReserveUniversityandUniversityHospitalsCaseMedicalCenter.ThisrelationshipprovidestheopportunitytointegrateanoutstandinggroupofcancerresearchersandalargecancerreferralnetworkaspartofNorthernOhio’sonlyNationalCancerInstitute-designatedComprehensiveCancerCenterbasedatCase.

TheCaseComprehensiveCancerCentercombines,underasingleleadershipstructure,thecancerresearchactivitiesofthelargestbiomedicalresearchandhealthcareinstitutionsinOhio–CaseWesternReserveUniversity,ClevelandClinicandUniversityHospitalsofCleveland–intoaunifiedcancerresearchcenter.Withthisintegration,theCaseComprehensiveCancerCenterhasstrengtheneditsscientificprograms,expandedopportunitiesfordisease-focusedresearch,andenhancedaccessandabilitytoservetheentirepopulationofNortheastOhio.

TheClevelandcommunityhasfullyembracedthisexceptionalopportunitytojointheregion’stwopre-eminenthealthcaredeliverysystemsandCase,theiracademicpartner,intoasingleNCI-designatedComprehensiveCancerCenter.

BTNCClinicalandClinicalResearchAdministration

2008ANNUALREPORT

29

ProfessionalRecruitment

TheadditionofDr.JeremyRichtoClevelandClinicasChairmanofitsGenomicsInstitutewasamajorcoupfortheinstitutionandtheBTNC.Dr.Richisaninternationallyrecognizedexpertinthefieldofbraintumorstemcells–bothapotentialcauseaswellastreatmentforcertainbraintumors.Dr.Rich,aneuro-oncologist,willbeworkingcloselywithBTNCclinicalandresearchstaffinhispursuitofnewinsightsandtherapiesforbraintumors.

TheBTNCalsoparticipatedinthesuccessfulrecruitmentofDr.CandeceGladson.Dr.Gladsonisasenior,fundedscientistinbraintumorresearch.Dr.Gladson’sinterestsincludemolecularmechanismsinvolvedinmalignantastrocytomacellmigration,invasionandproliferation;celladhesionreceptorsmechanisms;determiningthesignalsgeneratedbyengagementofspecificintegrinsandhowthesesignalspromotecellproliferationandmigration;andbraintumorcellinvasion,proliferationandtheirquantification.ShejoinedthestaffofClevelandClinicinJanuary2009.

TheBTNCisactivelyrecruitinganadditionaladultneuro-oncologisttohelpmeettheclinicalneedsofourever-increasingpatientpopulation.

Marketing/Advertising

ManymarketingandadvertisinginitiativeswereimplementedtocreateawarenessoftheBTNCin2008.Becausebraintumorpatientsareinformationsavvyandseekoutthelatestinmedicaloptionsfortheircondition,theBTNCwebsiteisaparticularlyimportantmarketingtool.Aprimaryfocusin2008hasbeenonredesigningtheBTNCwebpagesandupdatingthecontent.ThecontentwillbestrategicallyoptimizedtoincreasethenaturalrankingsoftheBTNCwebpageson

searchengines.

Specific BTNC 2008 Marketing/Advertising Initiatives

National physician mailing–Toincreasegeographicreachofphysicianreferrals,aletterandfactsheetweremailedtopotentialreferringphysiciansacrossthecountry.Themailingwasexecutedinthefall,andsuccesswillbemeasuredbasedonreferralactivityoverthenextsixmonths.

Web banner advertising campaign–DevelopedtoofferconsumersaccesstoBTNCpatientinformationalwebcastsonthefollowingtopics:

•Advances in surgery for brain tumors,GeneBarnett,MD

•Intraoperative imaging for brain tumor surgery,GeneBarnett,MD

•Chemotherapy for brain tumors,DavidPeereboom,MD

Thecampaignisaimedatdrawingappointmentsfromoutsidethelocalmarket.Thecurrentclick-throughrateis.08percentcomparedwithanindustryaverageof.05percent.

NI Publications

BTNCarticleswerefeaturedinnearlyalloftheNeurologicalInstitutepublications,includingNeuroscience Pathways,whichismailedtoneurologistsandneurosurgeonsnationallyandtoprimarycarespecialistsregionally.TheBTNCwasfeaturedinthefollowingarticles:

Spring2008

•T Cell Immunotherapy for Malignant Brain Tumors,GregoryPlautz,MD

•AnumberofBTNCclinicaltrials

Fall2008

•Making the Inoperable Operable: Subcortical Navigation for Brain Tumors,GeneBarnett,MD


ProgramDevelopment


30

TheNIannualreport,whichismailedtoasimilaraudienceasNeuroscience Pathways,prominentlyfeaturedtheBTNC,withpresenceinthefollowingareas:

•ClinicalPrograms

•Neuro-Oncology

•NeurosurgicalOncologyandRadiationNeuro-Oncology

•Fellowships

•ClinicalResearch

•LaboratoryResearch

•Outcomes

•PatientSuccessStory–JoeCase

•CMECourses

TheBTNCwasalsofeaturedinthespring2008issueofSpinal Column,whichismailedtoneurologists,neurosurgeons,chiropractors,orthopaedicsurgeons,rheumatologistsandsportsmedicine,familypractice,internalmedicineandgeriatricphysiciansinOhioandsixcontiguousstates.TheBTNCwasfeaturedinthefollowingarticle:

•Stereotactic Spine Radiosurgery,LilyanaAngelov,MD

Other Publications

Taussig Cancer Institute publications–SpringeditionofCancer Consult includedanumberofBTNCclinicaltrialsandthefalleditionincludedthefollowing:

•Making the Inoperable Operable: Subcortical Navigation for Brain Tumors,GeneBarnett,MD

•T Cell Immunotherapy for Malignant Brain Tumors,GregoryPlautz,MD


BTNC clinical trials mailer–Mailersenttoneurologists,neurosurgeons,oncologists,hematologists,andfamilypracticeandinternalmedicinephysiciansinOhioandsixcontiguousstatesinearlyOctober2008thatincludedthefollowingtrials:

•Celldex(RT/Temozolomide)IRBCC311

•RTOG0277Methotrexate,Rituximab,TemodarIRBCC238

•CCFIRBCC526MONT1307

Website enhancements–CurrentlyworkingonredesigningthelayoutoftheBTNCwebsiteandupdatingcontent.

Other

ABTA–Displayatpatientconference

ASCOdisplay–BTNCinformationalmaterialswereofferedashandouts

VirualTrials.org–Websitesponsorshipandbanneradplacement

Pituitary.org–HospitalmembershipandphysicianmembershipforDr.RobertWeil

GammaKnifeumbrellas–NewGammaKnifegolfumbrellasorderedfortheGammaKnifetrainingsessioninlate2008

BTNCintheNews

Print

USA Today, Plain Dealer, The Boston Globe, WebMD – Dr.MichaelVogelbaumcommentsonSen.EdwardKennedy’sbraintumordiagnosis.5/22/2008

Plain Dealer, The Times-Picayune–TwoClevelandhospitalsareembarkingonanexperimentalprocedureusinglaserheatto“cook”braintumors,offeringhopeofimprovedsurvivalofoneofthemostdifficult-to-treatcancers.9/25/2008,10/11/2008

ProgramDevelopment (continued)

2008ANNUALREPORT

31

Kalamazoo Gazette, The Boston Globe – Dr.DavidPeereboomcommentsonclinicaltrials. 6/15/2008

Plain Dealer – Dr.MichaelVogelbaumcommentsontheroleclinicaltrialsplayintreatingbraincancer.5/22/2008

Broadcast

MSNBC News Live, network affiliates–Drs.GeneBarnett,JohnSuhandMichaelVogelbaumcommentonbraintumordiagnosisandtreatments.

The Diane Rehm Show–Dr.MichaelVogelbaumcommentsonbraintumorsandtreatments.5/22/2008

Various national network affiliates–Dr.JohnSuhcommentsonPerfexion,anewwaytodeliverradiation.4/2/2008

WYTV (Youngstown)–Dr.ThomasDetesco’ssonwasdiagnosedwithabraintumorandisraisingmoneyforbraintumorresearchatClevelandClinic.5/08/2008

WYTV (Youngstown)–ClevelandClinicdoctorssaythereisnooverallincreasedriskofbraintumorsamongcellphoneusers.7/29/2008

Outreach

International Outreach Services

BTNCphysiciansworkcloselywithneurosurgeonsinClevelandClinicFloridatoprovideservicesforpatients.Out-of-statepatientscantakeadvantageofClevelandClinic’sMedicalConciergeprogram,acomplimentaryservicethatoffersfacilitationandcoordinationofmultiplemedicalappointments;accesstodiscountsonairlineticketsandhotels,whenavailable;helpinmakinghotelreservationsorhousingaccommodations;andarrangementofleisureactivities.BTNCandGammaKnifeCenterspecialistsalsotreatpatientsfromoutsidetheUnitedStates.ThespecialrequirementsofinternationalpatientsarehandledthroughClevelandClinic’sGlobalPatientServicesprogram.TheprofessionalswithinGlobalPatientServicesprovidetheassistanceandservicesourinternationalpatientsneedtohelpthemfeelathomewhiletheyarebeingtreatedhere.Weemployalargemultilingualstaff,andinterpretersareavailabletoassistpatients.Ourstaffhelpscoordinateallthedetailsofavisit,fromschedulingmedicalappointmentsandmakinghotelandtransportationarrangementstotransferringand

translatingmedicalrecords.


32

ContinuingMedicalEducation/ProfessionalEducation

Supporting Professional EducationAspartofourmissiontoadvancebraintumortreatmentandresearchthroughcollaborationandeducation,theBTNCandtheDepartmentofNeurosurgerycoordinatedandhostedtwomajorsymposiain2008,includingtheSecondInternationalSymposiumonStereotacticBodyRadiationTherapyandStereotacticRadiosurgery,heldinFebruaryinOrlando,Florida.Thesymposiumfeaturednationalandinternationalleadersinbrain-,spine-andbody-targetedstereotacticradiationmodalitiesandtechniques.Thissuccessfuleventbroughttogethermorethan150participantswhospentthreedaysdiscussingadvancesinthetreatmentofbenignandmalignanttumorsinvolvingmultipleorgansites.TheBTNCalsohostedadualsymposiuminClevelandonpituitarydiseasemanagementforphysiciansandforpatientsinApril,attractingmorethan125participants.InNovember,theBTNCwasajointsponsorwithMexicanneurosurgicalandneuro-oncologysocietiesinLosCabos,Mexico.

TheBTNC’sGammaKnifeCenter,underthedirectionofDr.JohnSuh,continuestobeamajorthrustfortheBTNC.Tosupporteducation,ClevelandClinichadfourhands-onGammaKniferadiosurgerytrainingcoursesformorethan30peoplethroughDecember2008.

SupportingPatientEducation

TheBTNCwasaproudsponsoroftheAmericanBrainTumorAssociation’s(ABTA)regionalpatientmeetinginMay2008inChicago.Patientsandtheirfamilymembers,healthcareprovidersandvolunteersgatheredtolearnaboutvarioustopics,fromthebiologyofbraintumorstochoosingbetweenstandardtherapyandaclinicaltrial.KathyLupica,MSN,

CNP,andMaryMurphy,RN,BSN,aswellasMarketingManagerColleenBurke,madeinformationavailabletopatients.KathyLupicaalsopresentedaconcurrentworkshoptopatientstitled“TheCaregiverJourney.”Amonthlybraintumorsupportgroupforpatients,familiesandfriendsisfacilitatedbyKathyLupica.

Fellowships

TheBTNChastwoneurosurgicaloncologyfellowshipprograms.Oneisatwo-year,combinedclinicalandlaboratoryresearchfellowshipprogram,whichprovidesexposuretothedesignandoperationofclinicaltrialsaswellasopportunitiestocontributetotheneuro-oncologyliterature.Fellowsareexpectedtoparticipateinthedesign,IRBapplicationprocessandmanagementofnewclinicaltrialsduringthisfellowship,andtoproduceclinicalpresentationsandreports.

ThesecondfellowshipisrunbytheSectionofSkullBaseSurgery.Bycombiningthehighlyspecializedtechniquesofinterventionalneuroradiology,otolaryngology,neurosurgery,ophthalmologyandplasticsurgery,theprincipalgoalofskullbasesurgeryistoaccessdeep-seated,difficult-to-reachlesionsbyanatomicdisplacementorextensiveremovalofthebaseoftheskull.Thesetechniquesreduceoreliminatetheneedforbrainretraction,therebyminimizinginjurytothebrain,cranialnervesandbloodvessels.

Skullbasesurgerytechniquesarecommonlyusedtotreatvariouslesionsinoraroundtheparanasalsinusesandtheflooroftheanteriorfossa,orbit,infratemporalfossa,sella,clivus,cavernoussinus,temporalbone/petrousapex,posteriorfossaandtheforamenmagnumregion.

Education

2008ANNUALREPORT

33

Fellows,2002–Present

Program Start End Fellow

Neurosurgical Oncology 07/01/2002 06/30/2003 VitalySiomin,MD

07/01/2002 06/30/2005 NarendraNathoo,MD,PhD

10/01/2002 11/30/2003 LilyanaAngelov,MD

10/20/2003 06/30/2004 AbhayVarma,MD

08/20/2004 08/19/2005 DaeLee,MD

07/01/2005 06/30/2006 TinaThomas,MD

08/01/2006 07/31/2007 RongshengCai,MD

01/01/2007 JoseValerio-Pascua,MD

07/01/2007 06/30/2008 ZhiyuanXu,MD

07/01/2008 SacitOmay,MD

Skull Base Surgery 08/25/2003 08/19/2004 DaeLee,MD

08/01/2004 07/31/2007 BurakSade,MD

10/22/2007 10/21/2008 JaeSungPark,MD

11/01/2008 SoichiOya,MD


34

IRB COOPERATIVE GROUP TITLE PI

3669 ProtocolA:CombinationChemotherapy(Methotrexate,Procarbazine,&CCNU),IntraventricularCytarabine&Methotrexate,+/–Intra-OcularChemotherapyforPatientswithPrimaryCentralNervousSystemLymphoma(PCNSL)&ProtocolB:CombinationChemotherapy(Methotrexate,Cyclophosphamide&EtoposidePhosphate)DeliveredinConjunctionwithOsmoticBlood-BrainBarrierDisruption(BBBD),withIntraventricularCytarabine+/–Intra-OcularChemotherapy,inPatientswithPrimaryCentralNervousSystemLymphoma(PCNSL)

Barnett

CC296CASE1307

OhioBrainTumorStudy(OBTS) Barnett

CC375MDCC1307

GLIOGENE:AnInternationalBrainTumorLinkageConsortiumStudy Barnett

CC526MONT1307

AProspectiveFirst-inMan(FIM)SafetyTrialoftheAutoLITTLaserTreatmentofRecurrent/ProgressiveBrainTumors Barnett

CC582BRMY1308

PhaseIOpenLabel,Multi-CenterStudytoEvaluatetheSafetyandTolerabilityofCT-322AdministeredinCombinationwithFocalBrainRadiotherapyandTemozolomidetoSubjectswithNewlyDiagnosedGlioblastomaMultiforme

Barnett

CC248 RTOG NCCTGRTOG0574:PhaseIIIRandomizedTrialoftheRoleofWholeBrainRadiationTherapyinAdditiontoRadiosurgeryinPatientswithOnetoThreeCerebralMetastases

Chao

4204 PhaseIITrialofContinuousDoseTemozolomideinPatientswithNewlyDiagnosedAnaplasticOligodendrogliomasandMixedOligoastrocytoma

Peereboom

4347 NABTT PhaseI/IIStudyofOralProcarbazineintheTreatmentofRecurrentHighGradeAstrocytomas Peereboom

4348 NABTT PhaseI/IIStudyofCol-3AdministeredonaContinuousDailyOralScheduleinPatientswithRecurrentHighGradeAstrocytoma

Peereboom

7749 NABTT PhaseITrialofBay43-9006forPatientswithRecurrentorProgressiveMalignantGlioma Peereboom

7936 NABTT ASafetyRun-In/RandomizedPhaseIITrialofEMD121974inConjunctionwithRadiationTherapyinPatientswithNewlyDiagnosedGlioblastomaMultiformeNCI#:NABTT0306PI:Nabors

Peereboom

8314 NABTT PhaseIITrialofTalampanelinConjunctionwithRadiationTherapywithConcurrentandAdjuvantTemozolomideinPatientswithNewlyDiagnosedGlioblastomaMultiforme

Peereboom

CASE1308 PhaseIITrialofSunitinibasMaintenanceTherapyAfterStereotacticRadiosurgeryinPatientswith1-3NewlyDiagnosedBrainMetastases

Peereboom

CC011 NABTT NABTT0402IdentificationofHypermethylatedSerumTumorDNAinHighGradeGliomaPatientsandCorrelationwithMagneticResonanceImagingFinding

Peereboom

CC038 PhaseI/IIStudyofPatientswithNewlyDiagnosedPrimaryCentralNervousSystemLymphomaTreatedwithMethotrexate/BBBD,andAddingRituximab(anantiCD-20Antibody)andCarboplatin,totheTreatmentRegimen

Peereboom

CC050 NABTT PhaseIITrialofRadiationPlusTemozolomideFollowedbyAdjuvantTemozolomideandPoly-ICLCinPatientswithNewlyDiagnosedGlioblastomaMultiforme

Peereboom

CC140 NABTT Open-LabelPhaseI/PhaseIIStudyofIntravenousInfusionofTetra-o-MethylNordihydroguaiareticAcid(EM-1421)inSubjectswithRecurrentHighGradeGlioma

Peereboom

CC141 NABTT PhaseIITrialofErlotinib(OSI-774)andSorafenib(BAY43-9006)forPatientswithProgressionorRecurrentGlioblastomaMultiforme

Peereboom

CC185 PhaseIITrialofPatupiloneinPatientswithBrainMetastasesfromBreastCancer Peereboom

CC190 PhaseIandII,Open-LabelMulti-CenterTrialsofPazopanibinCombinationwithLapatinibinAdultPatientswithRelapsedMalignantGlioma(PhaseII)

Peereboom

CC222 NABTT AFeasibilityAssessmentandaPhaseI/IITrialofMLN518forTreatmentofPatientswithRecurrentGlioblastoma Peereboom

CC243 NABTT PhaseI,OpenLabelStudyofAT-101PlusRadiotherapy&Temozolomide&ofAT-101PlusAdjuvantTemozolomideforPatientswithNewly-DiagnosedGlioblastomaMultiforme

Peereboom

CC258 NABTT NABTT2201PHASEIIStudyofANTI-CD-20MonoclonalAntibody(Rituximab)TherapyforPatientswithRefractoryorRelapsedPrimaryCenteralNervousSystemLymphoma(PCNSL)

Peereboom

AppendixA–ClinicalTrials(Adult)

2008ANNUALREPORT

35

CC279 PhaseIb/IIa,Multicenter,Open-labelStudyofAQ4NinCombinationwithRadiationTherapyandTemozolomide,toEvaluatetheSafety,Tolerability,andEfficacyinSubjectswithNewlyDiagnosedGlioblastomaMultiforme

Peereboom

CC396NOVA1507

AnOpen-label,Multicenter,PhaseIIStudytoEvaluatetheActivityofPatupilone(EPO906),intheTreatmentofRecurrentorProgressiveBrainMetastasesinPatientswithNSCLC

Peereboom

CC432 NABTT PhaseI/IIofHydroxychloroquineinConjunctionw/RT Peereboom

CC436 NABTT PhaseIIStudyofR-(-)-gossypol(Ascenta’sAT-101)inRecurrentGlioblastomaMultiforme Peereboom

CC492CASE2307

PhaseIITrialofRitonavir/LopinavirinPatientswithProgressiveorRecurrentHigh-GradeGliomas Peereboom

NVCA1306 PhaseII,Multicenter,OpenLabelCaseControlled(Part1),Randomized,ActiveControlled(Part2)StudyofAQ4NinCombinationwithXRTandTemozolomideforSafety,Tolerability,andActivityinSubjectswithNewlyDiagnosedGBM

Peereboom

6253 PhaseIIStudyforPatientswithRelapsedPrimaryCentralNervousSystemLymphoma Stevens

6385 PhaseIIClinicalTrialofPatientswithHigh-GradeGliomaTreatedwithIntra-arterialCarboplatin-basedChemotherapy,RandomizedtoTreatmentwithorwithoutDelayedIntravenousSodiumThiosulfateasaPotentialChemoprotectantagainstSevereThrombocytopenia

Stevens

7348 PhaseIIRandomizedEvaluationofSelective,5-LipoxygenaseInhibitionbyBoswelliaserrataHerbalMedicineApproachComparedtoControlasanAdjuvantTherapyinNewlyDiagnosedandRecurrentHighGradeGliomas;NIHGrantNo.1R21CA107277-01

Stevens

CC052 EvaluationofaStressReductionPrograminPatientswithMalignantBrainTumorsandTheirFamilyCaregivers Stevens

CC541UCSF2308

LivedExperienceofaLongTermSurvivorwithaHighlyMalignantBrainTumor Stevens

4106 RTOG PhaseIIIComparisonofBiafine(r)toDeclaredInstitutionalPreferenceforRadiationInducedSkinToxicityinPatientsUndergoingRadiationTherapyforAdvancedSquamousCellCarcinomasoftheHeadandNeck(RTOG99-13)

Suh

6795 APhase3Randomized,Open-labelComparativeStudyofStandardWholeBrainRadiationTherapywithSupplementalOxygen,withorwithoutConcurrentRSR13(efaproxiral),inWomenwithBrainMetastasesfromBreastCancer

Suh

7791 RTOG RTOG0320;APhaseIIITrialComparingWholeBrainRadiationandStereotacticRadiosurgeryAloneVersuswithTemozolomideorGefitinibinPatientswithNon–Small-CellLungCancerand1-3BrainMetastases

Suh

7992 ProspectiveAnalysisofWellnessFollowingGammaKnifeforNon-MalignantIndications Suh

8053 PhaseIITrialofMotexafinGadoliniumwithWholeBrainRadiationTherapyFollowedbyStereotacticRadiosurgeryBoostintheTreatmentofPatientswithBrainMetastases

Suh

8078 ProspectiveStudyontheShort-termAdverseEffectsfromGammaKnifeRadiosurgery Suh

8208 RTOG PhaseIIStudyofTemozolomide-BasedChemotherapyRegimenforHighRiskLow-GradeGliomas Suh

CC081 RTOG RTOG0525;PhaseIIITrialComparingConventionalAdjuvantTemozolomidewithDose-IntensiveTemozolomideinPatientswithNewlyDiagnosedGlioblastoma

Suh

CC238 RTOG PhaseI/IIStudyofPre-IrradiationChemotherapywithMethotrexate,Rituximab,TemozolomideandPost-IrradiationTemozolomideforPrimaryCentralNervousSystemLymphoma

Suh

CC559 RTOG ARandomized,PhaseIII,Double-Blind,Placebo-ControlledTrialofMemantineforPreventionofCognitiveDysfunctioninPatientsReceivingWhole-BrainRadiotherapy

Suh

CC559 RTOG ARandomized,PhaseIII,Double-Blind,Placebo-ControlledTrialofMemantineforPreventionofCognitiveDysfunctioninPatientsReceivingWhole-BrainRadiotherapy

Suh

4369 NABTT PhaseIGliadelandEscalatingDosesofIntravenousO6-BenzylguanineTrialinPatientswithRecurrentMalignantGliomas

Vogelbaum

5472 ACOSOG PhaseIIIRandomizedTrialoftheRoleofWholeBrainRadiationTherapyinAdditiontoRadiosurgeryintheManagementofPatientswithOnetoThreeMetastases

Vogelbaum

5478 PhaseIITrialofTarcevaInPatientswithRecurrent/ProgressiveGlioblastomaMultiforme Vogelbaum



36

7161 PhaseIStudyofConvectionEnhancedDelivery(CED)OfIL13-PE38QQRInfusionafterResectionFollowedbyRadiationTherapywithorwithoutTemozolomideinPatientswithNewDiagnosedSupratentorialMalignantGlioma

Vogelbaum

CC311CLDX1307

PhaseII/IIIRandomizedStudyofCDX-110withRadiation&TemozolomideinPatientswithNewlyDiagnosedGBM Vogelbaum

CC429 PhaseII,Multicenter,ExploratoryStudy,EvaluatingtheTreatmentEffectofSurgeryPlusGLIADELWaferinPatientswithMetastaticBrainCancer

Vogelbaum

MGI1307 PhaseII,Multicenter,ExploratoryStudy,EvaluatingtheTreatmentofSurgeryPlusGLIADELWaferinPatientswithMetastaticBrainCancer

Vogelbaum

7003 PhaseI/IIStudyUtilizingthePECIntraoperativeRadiotherapyDevicefortheTreatmentofaResectedSolitaryBrainMetastasis

Weil

CC126 AProspective,Multi-centerTrialofNovoTTF-100AComparedtoBestStandardofCareinPatientswithProgressiveorRecurrentGBM

Weil

CC385CASE4107

ClinicalStudytoAssessEntryofChemotherapeuticAgentsintoBrainMetastasesinWomenwithBreastCancer Weil

PROTOCOL TITLE PI

ACNS0232 Radiotherapyvs.ChemotherapyinCNSGerminoma TekautzT;WiersmaS

ACNS0331 RTandChemotherapyinMedulloblastoma TekautzT.

ACNS0423 PhaseIIRxRadiationandTemozolomideandTemozolomideandCCNUinHighGradeGliomas TekautzT;WiersmaS

ACNS0334 PhaseIIIRandomizedTrialfortheTreatmentofNewlyDiagnosedSupratentorialPNETandHighRiskMedulloblastomainChildren<36monthsoldwithIntensiveInductionChemotherapywithMethotrexatefollowedbyConsolidationwithStemCellRescuevs.theSameTherapywithoutMethotrexate

TekautzT;WiersmaS

ANBL0531 ResponseandBiology-BasedTherapyforIntermediate-riskNeuroblastoma TekautzT;WiersmaS

ANBL0421 Irinotecan+TemozolomideinNeuroblastoma WiersmaS;TekautzT

ACNS0121 ConformalRTTreatmentforEpendymoma WiersmaS;TekautzT

ACNS0122 NeoadjuvantChemotherapyChemo+/-SurgeryforNGGCT WiersmaS;TekautzT

ACNS0223 Carboplatin,VincristineandTemozolomideinGliomas WiersmaS;TekautzT

ACNS0221 ConformalRTinGliomas WiersmaS;HildenJ;BurkeM

ACNS0222 PhaseIIStudyofMotexafin-Gadolinium(NSC659238,IND#55583)andInvolvedFieldRadiationTherapyforInstrinsicPontineGliomaofChildhood

TekautzT;WiersmaS

ACNS0332 EfficacyofCarboplatinAdministeredConcomitantlywithRadiationandIsotretinoinasPro-ApoptoticAgentinOtherThanAverageRiskMedulloblastoma/PNETPatients

WiersmaS;TekautzT

AppendixA–ClinicalTrials(Adult) (continued)

PediatricTrials:COG(Children’sOncologyGroup)


2008ANNUALREPORT

37

AppendixB–Publications

synergizetoinduceT-cellapoptosis.Cancer Res2008Mar15;68(6):2014-2023.

ElkassabanyNM,BhatiaJ,DeogaonkarA,BarnettGH,LottoM,MaurtuaM,EbrahimZ,SchubertA,FerenceS,FaragE.Perioperativecomplicationsofbloodbrainbarrierdisruptionundergeneralanesthesia:aretrospectivereview.J Neurosurg Anesthesiol2008Jan;20(1):45-48.

FinkeJH,GoelM.T-cellunresponsivenessinrenalcellcarcinomapatients.In:BukowskiRM,NovickAC,eds.Clinical management of renal tumors. Totowa,NJ:HumanaPress;2008.Chapter7.p.115-130.

FinkeJH,RiniB,IrelandJ,RaymanP,RichmondA,GolshayanA,WoodL,ElsonP,GarciaJ,DreicerR,BukowskiR.Sunitinibreversestype-1immunesuppressionanddecreasesT-regulatorycellsinrenalcellcarcinomapatients.Clin Cancer Res2008Oct15;14(20):6674-6682.

FitzgeraldDP,PalmieriD,HuaE,HargraveE,HerringJM,QianY,Vega-ValleE,WeilRJ,StarkAM,VortmeyerAO,SteegPS.Reactivegliaarerecruitedbyhighlyproliferativebrainmetastasesofbreastcancerandpromotetumorcellcolonization.Clin Exp Metastasis2008;25(7):799-810.

FuP,vanHeeckerenWJ,WadhwaPD,BajorDJ,CregerRJ,XuZ,CooperBW,LaughlinMJ,GersonSL,KocON,LazarusHM.Time-dependenteffectofnon-Hodgkin’slymphomagradeondisease-freesurvivalofrelapsed/refractorypatientstreatedwithhigh-dosechemotherapyplusautotransplantation.Contemp Clin Trials2008Mar;29(2):157-164.

GeorgeS,HutsonTE,MekhailT,WoodL,FinkeJ,ElsonP,DreicerR,BukowskiRM.PhaseItrialofPEG-interferonandrecombinantIL-2inpatientswithmetastaticrenalcellcarcinoma.Cancer Chemother Pharmacol2008Jul;62(2):347-354.

GeorgitsiM,DeMenisE,CannavoS,MakinenMJ,TuppurainenK,PaulettoP,CurtoL,WeilRJ,PaschkeR,ZielinskiG,WasikA,LubinskiJ,VahteristoP,KarhuA,AaltonenLA.Arylhydrocarbonreceptorinteractingprotein(AIP)genemutationanalysisinchildrenandadolescentswithsporadicpituitaryadenomas.Clin Endocrinol (Oxf )2008Oct;69(4):621-627.

GibsonSE,ZengWF,WeilRJ,PraysonRA.AuroraBkinaseexpressioninependymalneoplasms.Appl Immunohistochem Mol Morphol2008May;16(3):274-278.

GrossmanSA,CarsonKA,PhuphanichS,BatchelorT,PeereboomD,NaborsLB,LesserG,HausheerF,SupkoJG.PhaseIandpharmacokineticstudyofkarenitecininpatientswithrecurrentmalignantgliomas.Neuro Oncol2008Aug;10(4):608-616.

JournalPublications

AngelovL.Stereotacticspineradiosurgery.Spinal Column2008Spring;14-15.

BainM,MoheetAM,RasmussenP.Whichpatientsbenefitfromcarotidstenting?Whatrecenttrialsshow.Cleve Clin J Med2008Oct;75(10):714-720.

BalmacedaC,PeereboomD,PannulloS,CheungYKK,FisherPG,AlaviJ,SistiM,ChenJ,FineRL.Multi-institutionalphaseIIstudyoftemozolomideadministeredtwicedailyinthetreatmentofrecurrenthigh-gradegliomas.Cancer2008Mar1;112(5):1139-1146.

BratDJ,ParisiJE,Kleinschmidt-DemastersBK,YachnisAT,MontineTJ,BoyerPJ,PowellSZ,PraysonRA,McLendonRE.Surgicalneuropathologyupdate:areviewofchangesintroducedbytheWHOclassificationoftumoursofthecentralnervoussystem,4thedition.Arch Pathol Lab Med2008Jun;132(6):993-1007.

BratDJ,PraysonRA,RykenTC,OlsonJJ.Diagnosisofmalignantglioma:roleofneuropathology.J Neurooncol2008Sep;89(3):287-311.

BuattiJ,RykenTC,SmithMC,SneedP,SuhJH,MehtaM,OlsonJJ.Radiationtherapyofpathologicallyconfirmednewlydiagnosedglioblastomainadults.J Neurooncol2008Sep;89(3):313-337.

ChamberlainWA,PraysonRA.FocalcorticaldysplasiatypeII(malformationsofcorticaldevelopment)aberrantlyexpressesapoptoticproteins.Appl Immunohistochem Mol Morphol2008Oct;16(5):471-476.

ChaoST,BarnettGH,VogelbaumMA,AngelovL,WeilRJ,NeymanG,ReutherAM,SuhJH.Salvagestereotacticradiosurgeryeffectivelytreatsrecurrencesfromwhole-brainradiationtherapy.Cancer2008Oct15;113(8):2198-2204.

DaneshvarH,NelmsJ,MuhammadO,JacksonH,TkachJ,DavrosW,PetersonT,VogelbaumMA,BruchezMP,TomsSA.Imagingcharacteristicsofzincsulfideshell,cadmiumtelluridecorequantumdots.Nanomed2008Feb;3(1):21-29.

DasT,SaG,Paszkiewicz-KozikE,HilstonC,MoltoL,RaymanP,KudoD,BiswasK,BukowskiRM,FinkeJH,TannenbaumCS.RenalcellcarcinomatumorsinduceTcellapoptosisthroughreceptor-dependentandreceptor-independentpathways.J Immunol2008Apr1;180(7):4687-4696.

DasT,SaG,HilstonC,KudoD,RaymanP,BiswasK,MoltoL,BukowskiR,RiniB,FinkeJH,TannenbaumC.GM1andtumornecrosisfactor-alpha,overexpressedinrenalcellcarcinoma,


38

AppendixB-Publications (continued)

GrossmanSA,OlsonJ,BatchelorT,PeereboomD,LesserG,DesideriS,YeX,HammourT,SupkoJG.Effectofphenytoinoncelecoxibpharmacokineticsinpatientswithglioblastoma.Neuro Oncol2008Apr;10(2):190-198.

GuoS,ChaoST,ReutherAM,BarnettGH,SuhJH.Reviewofthetreatmentoftrigeminalneuralgiawithgammakniferadiosurgery.Stereotact Funct Neurosurg2008;86(3):135-146.

HaasRH,ParikhS,FalkMJ,SanetoRP,WolfNI,DarinN,WongLJ,CohenBH,NaviauxRK.Thein-depthevaluationofsuspectedmitochondrialdisease.Mol Genet Metab2008May;94(1):16-37.

HartsellWF,DeSilvioM,BrunerDW,ScarantinoC,IvkerR,RoachM,III,SuhJ,DemasWF,MovsasB,PetersenIA,KonskiAA.Canphysiciansaccuratelypredictsurvivaltimeinpatientswithmetastaticcancer?AnalysisofRTOG97-14.J Palliat Med2008Jun;11(5):723-728.

Hernandez-RodriguezJ,MolloyES,CalabreseLH,PraysonRA,LangfordCA.Arteriovenousmalformationofthebrainmimickingprimarycentralnervoussystemvasculitis.Scand J Rheumatol2008Nov;37(6):481-484.

HollanI,PraysonR,SaatvedtK,AlmdahlSM,NossentHC,MikkelsenK,LiangMH,KvelstadIL,AamodtG,ForreOT.Inflammatorycellinfiltratesinvesselswithdifferentsusceptibilitytoatherosclerosisinrheumaticandnon-rheumaticpatients.Circ J2008Dec;72(12):1986-1992.

HousriN,WeilRJ,ShalowitzDI,KoniarisLG.Shouldinformedconsentforcancertreatmentincludeadiscussionabouthospitaloutcomedisparities?PLoS Med2008Oct21;5(10):e214.

JehiLE,LudersHO,NaugleR,RuggieriP,MorrisH,FoldvaryN,WyllieE,KotagalP,BingamanB,DinnerD,PraysonR,DiehlB,AlexopoulosA,BautistaJ,BuschR.Temporallobeneoplasmandseizures:howdeepdoesthestorygo?Epileptic Disord2008Mar;10(1):56-67.

JohnsonMD,SadeB,MilanoMT,LeeJH,TomsSA.Newprospectsformanagementandtreatmentofinoperableandrecurrentskullbasemeningiomas.J Neurooncol2008Jan;86(1):109-122.

JulianoJJ,CodyRL,SuhJH.Metastaticadrenocorticaloncocytoma:Acasereport.Urol Oncol2008Mar-Apr;26(2):198-201.

KangTY,JinT,ElinzanoH,PeereboomD.Irinotecanandbevacizumabinprogressiveprimarybraintumors,anevaluationofefficacyandsafety.J Neurooncol2008Aug;89(1):113-118.

KellyME,RasmussenPA,MasarykTJ.Intracranialaneurysmsandsubarachnoidhemorrhage.In:MasarykTJ,ed.Endovascular techniques in the management of cerebrovascular disease. London:InformaHealthcare;2008.Chapter7.p.111-132.

KhatriRG,NavaratneK,WeilRJ.TheroleofasinglenucleotidepolymorphismofMDM2inglioblastomamultiforme.J Neurosurg2008Nov;109(5):842-848.

KimSH,WeilRJ,ChaoST,TomsSA,AngelovL,VogelbaumMA,SuhJH,BarnettGH.Stereotacticradiosurgicaltreatmentofbrainmetastasesinolderpatients.Cancer2008Aug15;113(4):834-840.

KimSH,ChaoST,TomsSA,VogelbaumMA,BarnettGH,SuhJH,WeilRJ.Stereotacticradiosurgicaltreatmentofparenchymalbrainmetastasesfromprostateadenocarcinoma.Surg Neurol2008Jun;69(6):641-646.

KruserTJ,ChaoST,ElsonP,BarnettGH,VogelbaumMA,AngelovL,WeilRJ,PelleyR,SuhJH.Multidisciplinarymanagementofcolorectalbrainmetastases:aretrospectivestudy.Cancer2008Jul1;113(1):158-165.

LevyEI,HopkinsLN,TurkAS,FiorellaDJ,RasmussenPA,MasarykTJ,AlbuquerqueFC,McDougallCG,PrideGL,Jr.,WelchBG,PurdyPD,WooHH,NiemannDB,Aagaard-KienitzB.Responsetothecommentary“howdowespinwingspan?”.AJNR Am J Neuroradiol2008Sep;29(8):e67-e68.

LiJ,YinC,OkamotoH,BalgleyBM,LeeCS,YuanK,IkejiriB,GlaskerS,VortmeyerAO,OldfieldEH,WeilRJ,ZhuangZ.Identificationofanovelproliferation-relatedprotein,WHSC14a,inhumangliomas.Neuro Oncol2008Feb;10(1):45-51.

LoSS,FakirisAJ,AbdulrahmanR,HendersonMA,ChangEL,SuhJH,TimmermanRD.Roleofstereotacticradiosurgeryandfractionatedstereotacticradiotherapyinpediatricbraintumors.Expert Rev Neurother2008Jan;8(1):121-132.

LoSS,ChaoST,SuhJH.3DconformalRT.In:JeremicB,PitzS,eds.Primary optic nerve sheath meningioma. NewYork,NY:Springer;2008.Chapter8.p.85-94.

MarkoNF,TomsSA,BarnettGH,WeilR.Genomicexpressionpatternsdistinguishlong-termfromshort-termglioblastomasurvivors:apreliminaryfeasibilitystudy.Genomics2008May;91(5):395-406.

MasarykTJ,RasmussenPA,WooH,FiorellaD.Endovascular techniques in the management of cerebrovascular disease. London:InformaHealthcare;2008.184p.

2008ANNUALREPORT

39

ParikhS,CohenBH,GuptaA,LachhwaniDK,WyllieE,KotagalP.Metabolictestinginthepediatricepilepsyunit.Pediatr Neurol2008Mar;38(3):191-195.

ParisiJE,MillerDV,BoyerPJ,BratDJ,CochranEJ,CohenML,DemastersBK,DolinakD,McCombRD,McLendonRE,PowellSZ,PraysonRA,VintersHV,YachnisAT.Protocolfortheexaminationofspecimensfrompatientswithtumorsofthebrain/spinalcord.Arch Pathol Lab Med2008Jun;132(6):907-912.

PineyroMM,MakdissiA,FaimanC,PraysonRA,ReddySK,MaybergMC,WeilRJ,HamrahianAH.Poorcorrelationofserumalpha-subunitconcentrationandmagneticresonanceimagingfollowingpituitarysurgeryinpatientswithnonfunctionalpituitarymacroadenomas.Endocr Pract2008May;14(4):452-457.

PlesecTP,RuizA,McMahonJT,PraysonRA.Ultrastructuralabnormalitiesofrespiratorycilia:a25-yearexperience.Arch Pathol Lab Med2008Nov;132(11):1786-1791.

PraysonB,McMahonJT,PraysonRA.Fastfoodhamburgers:whatarewereallyeating?Ann Diagn Pathol2008Dec;12(6):406-409.

PraysonBE,McMahonJT,PraysonRA.Applyingmorphologictechniquestoevaluatehotdogs:whatisinthehotdogsweeat?Ann Diagn Pathol2008Apr;12(2):98-102.

PraysonRA.Ki-67immunoreactivityintypeIImalformationsofcorticaldevelopment.Appl Immunohistochem Mol Morphol2008Jul;16(4):357-361.

PraysonRA.Neuropathology review. 2nd ed. Totowa,NJ:HumanaPress;2008.252p.

PraysonRA.Pathologyofepileptogenicneoplasms.In:LudersHO,ed.Textbook of epilepsy surgery. London:InformaCare;2008.Chapter145.p.1373-1383.

RasmussenPA.Thedecision-makingprocess:treatmentplanningforcerebrovasculardisease.In:MasarykTJ,ed.Endovascular techniques in the management of cerebrovascular disease. London:InformaHealthcare;2008.Chapter10.p.171-180.

SadeB,LeeJH.Highincidenceofopticcanalinvolvementinclinoidalmeningiomas:rationaleforaggressiveskullbaseapproach.Acta Neurochir (Wien)2008Nov;150(11):1127-1132.

SerhalD,WeilRJ,HamrahianAH.Evaluationandmanagementofpituitaryincidentalomas.Cleve Clin J Med2008Nov;75(11):793-801.

SharmaP,ChakrabortyR,WangL,MinB,TremblayML,KawaharaT,LambethJD,HaqueSJ.Redoxregulationofinterleukin-4signaling.Immunity2008Oct;29(4):551-564.

SikerML,DonahueBR,VogelbaumMA,TomeWA,GilbertMR,MehtaMP.Primaryintracranialneoplasms.In:HalperinEC,PerezCA,BradyLW,eds.Perez and Brady’s Principles and practice of radiation oncology. 5th ed. Philadelphia,PA:WoltersKluwerHealth/LippincottWilliams&Wilkins;2008.Chapter32.p.717-750.

StevensG,AngelovL.Evaluatinganddiagnosingspinetumors.Spinal Column2008Spring;19-20.

SuhJH,BarnettGH,RegineWF.Brainmetastasis.In:ChinLS,RegineWF,eds.Principles and practice of stereotactic radiosurgery. NewYork,NY:Springer;2008.Chapter14.p.181-191.

TomsSA,WeilRJ,GuptaA,BoulisNM,PraysonR,LangFF.Clinicalproblem-solving:islandintruder.Neurosurgery2008Apr;62(4):920-928;discussion928-929.

TurkAS,LevyEI,AlbuquerqueFC,PrideGL,Jr.,WooH,WelchBG,NiemannDB,PurdyPD,Aagaard-KienitzB,RasmussenPA,HopkinsLN,MasarykTJ,McDougallCG,FiorellaD.Influenceofpatientageandstenosislocationonwingspanin-stentrestenosis.AJNR Am J Neuroradiol2008Jan;29(1):23-27.

TurnerRD,ByrneJV,KellyME,MitsosAP,GonuguntaV,LallooS,RasmussenPA,FiorellaD.Delayedvisualdeficitsandmonocularblindnessafterendovasculartreatmentoflargeandgiantparaophthalmicaneurysms.Neurosurgery2008Sep;63(3):469-474.

UgokweK,ChahlaviA,BingamanW,GuptaA,PraysonR,BoulisNM,MontesJ.Clinicalproblemsolving:seizetheday.Neurosurgery2008Feb;62(2):481-487;discussion487-488.

VideticGMM,RiceTW,MurthyS,SuhJH,SaxtonJP,AdelsteinDJ,MekhailTM.UtilityofpositronemissiontomographycomparedwithmediastinoscopyfordelineatinginvolvedlymphnodesinstageIIIlungcancer:insightsforradiotherapyplanningfromasurgicalcohort.Int J Radiat Oncol Biol Phys2008Nov1;72(3):702-706.

WebbC,PraysonRA.Pediatricpituitaryadenomas.Arch Pathol Lab Med2008Jan;132(1):77-80.

WeilRJ.Incorporatingmoleculartoolsintoearly-stageclinicaltrials.PLoS Med2008Jan22;5(1):e21.

WeissmanJR,KelleyRI,BaumanML,CohenBH,MurrayKF,MitchellRL,KernRL,NatowiczMR.Mitochondrialdiseaseinautismspectrumdisorderpatients:acohortanalysis.PLoS ONE2008;3(11):e3815.


40

WesaAK,HerremCJ,MandicM,TaylorJL,VasquezC,KawabeM,TatsumiT,LeibowitzMS,FinkeJH,BukowskiRM,BruckheimerE,KinchMS,StorkusWJ.EnhancementinspecificCD8+TcellrecognitionofEphA2+tumorsinvitroandinvivoaftertreatmentwithligandagonists.J Immunol2008Dec1;181(11):7721-7727.

Yee-GuardinoS,GowansK,Yen-LiebermanB,BerkP,KohnD,WangFZ,nziger-IsakovL,SabellaC,WorleyS,PellettPE,GoldfarbJ.Beta-herpesvirusesinfebrilechildrenwithcancer.Emerg Infect Dis2008Apr;14(4):579-585.

ZafereoME,FakhriS,PraysonR,BatraPS,LeeJ,LanzaDC,CitardiMJ.Esthesioneuroblastoma:25-yearexperienceatasingleinstitution.Otolaryngol Head Neck Surg2008Apr;138(4):452-458.

Zamanian-DaryoushM,MarquesJT,GantierMP,BehlkeMA,JohnM,RaymanP,FinkeJ,WilliamsBRG.DeterminantsofcytokineinductionbysmallinterferingRNAinhumanperipheralbloodmononuclearcells.J Interferon Cytokine Res2008Apr;28(4):221-233.

BookChapters

SikerML,DonahueBR,VogelbaumMA,TomeWA,GilbertMR,MehtaMP.Primaryintracranialneoplasms.In:HalperinEC,PerezCA,BradyLW,eds.Perez and Brady’s Principles and practice of radiation oncology. 5th ed. Philadelphia,PA:WoltersKluwerHealth/LippincottWilliams&Wilkins;2008.Chapter32.p.717-750.

SuhJH,BarnettGH,RegineWF.Brainmetastasis.In:ChinLS,RegineWF,eds.Principles and practice of stereotactic radiosurgery. NewYork,NY:Springer;2008.Chapter14.p.181-1

ParkBJ,KimHK,Sade B,LeeJH.Epidemiology.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

LeeJH,Sade B. Meningiomasofthecentralneuraxis:uniquetumors.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

LeeJH,Sade B. Managementoptionsandsurgicalprinciples:Anoverview.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

LeeJH, Sade B. Operativeoutcomefollowingmeningiomasurgery:Apersonalseriesof600cases.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

Sade B,LeeJH.Thefactorsinfluencingoutcomeinmeningiomasurgery.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

Sade B,LeeJH.Thenovel“CLASS”algorithmicscaleforsurgicaldecisionmakinginmeningiomasurgery:Itsvalidityandutility.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

KumarPP,Sade B. Brachytherapyformeningiomas.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

LeeJH,Sade B. Anteriorclinoidalmeningiomas.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

Sade B,LeeJH.Cavernoussinusmeningomas.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

Sade B,LeeJH.Petrousmeningiomas.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

LeeJH,Sade B. Duralreconstructioninmeningiomasurgery.In:LeeJH,ed.Meningiomas.London:Springer-Verlag;2008,inpress.

Sade B,HughesG,LeeJH.Petrousmeningiomas.In:Garcia-IbanezE,HuyPTB,eds.Proceedings of the 5th International Conference on Vestibular Schwannoma and Other CPA Lesions. 2008,inpress.

MazzoneP,Chao S,SuhJ.“NeurologicalComplicationsinLungCancer.”In:BillerJ,ed.The Interface of Neurology and Internal Medicine.6thedition.Chicago:LippincottWilliamsandWilkins,2008.

MazzonePI,ChaoST,SuhJH.RadiationTherapyforBrainMetastases.In:BillerJ,ed.The Interface of Neurology and Internal Medicine,6thedition.Lippincott,WilliamsandWilkins.Pp.139-150,2008.

SuhJH,BarnettGH,RegineGH.Roleofstereotacticradiosurgeryforbrainmetastases.In:ChinL,RegineWF,eds.Principles and Practice of Stereotactic Radiosurgery.Springer.Pp181-192,2008.

KniselyJ,TsienC,SuhJH.OverviewofCNSmalignancies.In:HaftyBG,WilsonLD,eds.Handbook of Radiation Oncology. JonesandBartlett,pp.221-250,2008.

LoSS,ChaoST,SuhJH.3D-conformalradiationtherapyforopticnervesheathmeningioma.In:JeremicB,ed.Primary Optic Nerve Sheath Meningioma.pp.85-94,2008.

Angelov,L.,Golubic,M.,Molecularbasisofmeningiomatumorigenesisandprogression.In:LeeJ,ed.Meningiomas.Springer,2008,inpress.

AppendixB-Publications (continued)

2008ANNUALREPORT

41

BTNCProceduralVolume

0

200

400

600

800

1,000

1,200

Novalis Cases

GK CasesTotal Cases

Surgical Cases

20082007200620052004200320022001

TheBrainTumorandNeuro-OncologyCenter(BTNC)con-tinuestogrowinvolumeofprocedures.401stereotacticradiosurgery(GammaKnifeandNovalis)and573surgicalprocedureswereperformedin2008,whichisacombined62percentincreasecomparedwith2001.

BTNCPatientVisits

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

Total Outpatient Visits

New Outpatient Visits

20082007200620052004200320022001

Totaloutpatientvisitsincreasedby366percentoverthepasteightyears.Newpatientvisitshavemorethandoubledsince2001.

BTNCPatientEnrollment

0

20

40

60

80

Therapeutic Trials

20082007200620052004200320022001

Therapeutictrialenrollmenthasleveledoffatanaverage55patientsenrolledperyear.

AppendixC–ChartsandStatistics

TheNeurologicalInstituteisoneof26institutesatClevelandClinicthatgroupmultiplespecialties

togethertoprovidecollaborative,patient-centeredcare.Theinstituteisaleaderintreatingthe

mostcomplexneurologicaldisorders,advancinginnovationssuchasdeepbrainstimulation,epilepsy

surgery,stereotacticspineradiosurgeryandblood-brainbarrierdisruption.Annually,ourstaffof

morethan220specialistsserves140,000patientsandperforms7,500surgeries.ClevelandClinic

isanonprofitmultispecialtyacademicmedicalcenter,consistentlyrankedamongthetophospitals

inAmericabyU.S.News & World Report.Foundedin1921,itisdedicatedtoprovidingquality

specializedcareandincludesanoutpatientclinic,ahospitalwithmorethan1,000staffedbeds,

aneducationinstituteandaresearchinstitute.

09-NEU-065

Brain Tumor and Neuro-Oncology Center - Cleveland Clinic...Letter from the Director The Brain Tumor...

Documents

Transcript of Brain Tumor and Neuro-Oncology Center - Cleveland Clinic...Letter from the Director The Brain Tumor...