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ONS/ONCC CHEMOTHERAPY
IMMUNOTHERAPY CERTIFICATE
Lessonop1:opFoundationsoptoopSetoptheopStageop-opans-- FocusingoponopCellularopStructureopandopFunctionop-opans-- TheopNormalopCellopCycleop-opans--- TheopcellopcycleoprefersoptooptheoporderedopseresopofopprocessesopofopDNAopreplicationop andopmitosis,oporopcellopdivision
Cellopnucleusopregulatesoptheseopprocessesopbyopgatheringopandopprocessingopcomplexe sopmolecularopinformation InterphaseopandopMitoticopPhaseop-opans-- Cellopdivisionopproducesoptwoopidenticalopcellsopthroughoptheseoptwoopmajoropphases Duringopinterphase:op-opans-- CellopgrowsopandopDNAopisopreplicatedopthroughoptheopfollowingopthreeopsteps: 1:opFirstopgrowthopphaseop(G1oporopfirstopgap) 2:opSynthesisopphaseop(Sopphase) 3:MitoticopPhseop(Mopphase) FirstopGrowthopPhaseop(G1oporopfirstopgap)op-opans---cellsopincreaseopinopsize -reproduceopRNA -"qualityopassurance"optestopthatoptheopcellopwillopbeopreadyoptoopsynthesisopDNA -Lengthopofoptimeopisopvariable,opcanopbeopfromophoursoptoopdays SynthesisopPhaseop(Sopphase)op-opans---DNAopreplicates
-ResultsopinoptheopformationopofopidenticaloppairsopofopDNAop(chromatids) -whichopareopattachedopaoptoptheopcentromere -lastsop2-10ophours MitoticopPhaseop(Mopphase)op-opans--- Replicatedopchromosomesopareopaligned,opseparated,opandopmoveopintoop 2 opnew,opidenti calopdaughteropcells -takesopaboutop30-60opminutes Majoroppointsopofopcellopregulationopareopentryopandopexitopfromop-opans---G1opcheckpoint -SopPhase -G2opcheckpoint -Mopphase RestrictionopPointop-opans--- Theoptransitionopfromoptheoprestingopphaseopintoopanopactivelyopdividingopphaseop(G0- G1)opisopaoppointopwhereopcellularoptransformationopcanopoccurop
Duringopthisoptime,opcellsoppassopthroughopaoptransitionopphaseopknownopasopaoprestrictio noppoint
ExtracellularopgrowthopfactorsoptriggeropreentryopintoopG1,opandopGFopareoprequiredoptoop sendoptheopcellsoppastoptheoprestrictionoppoint,oporoptheoppointopofopnoopreturn G0opPhaseop(restingopphase)op-opans--- Afteropmitosis,opcellsopmayopenteropbackopintooptheopG1opphaseoporopgoopintoopaoprestingo pphase,opknownopasopG -MostopcellsopinoptheophumanopbodyopresideopinopG -Exceptionsoptoopthisopareopthoseopthatopareop(RestingopinopG0opphase)op-opans--- Exceptionsoptoopthisopareopthoseopthatopareopmetabollicallyopactive,opsuchopasop -granulocytesop -andoptheopepitheliumopofoptheopGIoptract
DNAopDamageopCheckpointsop-opans--- IfopDNAopdamageopisoppresent,opcellsopareopprogrammedoptoopstopopdividingoporopunderg oopapoptosisop(programmedopcellopdeath) -Theopretinoblastomaopproteinop(Rb),opp53,opandopp21opareopsomeopofoptheopmostopwell- understoodopinhibitoryopproteinsop(IP) Inhibitoryopproteinsopp53op-opans--- LevelsopofopthisopIPopregulateopseveralopimportantoptargetopgenes -WillopincreaseopwhenopDNAopdamageopisoppresent -Protectsopagainstopinappropriateopsignalopproliferation -sometimesopcalledoptheop"suicideopgene" MopPhaseopCheckpointsop-opans-- Whenoptheopcellsopprepareoptoopdivide,optheopchromosomesoplineopupopinoptheopmitoticops pindle. Ifoptheopchromosomesopareopnotopproperlyopaligned,opdivisionopisopnotopallowedoptoopconti nue Immunityop-opans-- CellsopofoptheopImmuneopSystemop-opans-- PluripotentopStemopCellop-opans--- Theopcellsopofoptheopimmuneopsystemopareopcreatedopinoptheopbomeopmarrowopfromopwha topisopknowopasopaop___
Aopstemopcellopthatopcanopdifferentiateopintoopanyopcelloptypeopexceptopforopextraembryoti coptissue,opdoesopnotopyetophaveopaopfunction MyeolidopPrecursoropCellsop-opans--Matureopinto: -RBCS -Plts -WBCsop(Granulocytes) LymphoidopPrecursoropCellsop-opans--Matureopinto: -SpecializedopWBCsopcalledoplymphocytesop(Agranulocytes) LinesopofopDefense:opTheopImmuneopSystem'sopResponseoptoopAttackop-opans-- Consistsopofop 2 optypesopofopimmunity:op
1:opInnate 2:opAdaptive InnateopImmunityop-opans---Firstoplineopofopdefenseopagainstopaoppathogen -Doesopnotopretainopmemoryopofoptheopentity -Involvesoptheopfollowing: (skin,opmucousopmembranes,opandopnormalopfloraopofoptheopskinopandopgut) (Cellularopcomponentsopsuchopasopphagocytes,opnaturalopkilleropcells,opgranulocytes,opan dopmacrophages) 1.opPhagocytes 2.opNaturalopKilleropCells 3.opGranulocytes 4.opMacrophagesop-opans--1.Cellsopthatopengulfopandopdestroyopinvader 2.opCellsopthatopsenseopreceptorsoponopselfopandopnon- selfoptoopdetermineopifoptheyopshouldopkilloporopnot 3.opTypeopofopWBCopthatophaveopgranulesop(Neutrophils Eosinophilsop-opparasites Basophilsop-opreleaseophistamineoptoopstimulateopimmuneopresponse) 4.opLargeopphagocyticopcellsopstimulatedopbyopinfection AdaptiveopImmunityop-opans---Stimulatedopifopinnateopimmunityopisopinsufficientop -leadsoptoopimmuneopsystemopmemory -Humoralopimmunity -Cell-mediatedopimmunityop -RegulatoryopT-cells HumoralopImmunityop-opans---B-Cells -MemoryopB-Cells -Plasmaopactoptoopproduceopimmunoglobulinsop(Igs)oporopantibodies B-Cellop-opans---eachoponeopisopprogrammedoptoopmakeoponeopspecificopantibody
Cytokinesop-opans---Secretedopbyoplymphocytes -Taskedopwithopeliminatingoptheopantigen -Multifunctionalopsubsancesophavingopproinflammatory,opanti- inflammatory,opandopregulatoryopfunctionsopinoptheopimmuneopsystem CytokinesopInclude..op-opans---Interferonsop(IFNs) -Tumoropnecrosisopfactors -TransformingopGFs -Interleukinsop(ILop-1,op-2,op-3,op-4,op-6,op-8,op-10,opandop-15)
TheseopcytokinesopregulateopantibodyopproductionopandoptheopfunctionsopofopBopandopTop cellsopasopwellopasopinteractopwithopantigen-presentingopcellsopandopNKCs BenignopTumorsop-opans--- encapsulatedopandopgrowopinopanoporderlyopmanneropwithopsmoothopedges -Doopnotopinvadeopneighboringoptissue -DOopnotopmetastasizeoptoopdistantopsites -theopcellsopwellopdifferentiatedopinopthatoptheyoplookoplikeoptheopparentopcell CharacteristicsopofopCanceropCellsop-opans---Malignantoptumorsopareopnotopencapsulated -Cellopstructureopisopdifferentopfromopparentoptissueop(noopasopwellopdifferentiated) -Cellopdivisionopisopuncontrolled -Cellsopareoplooselyopadherentopwithoutopcontactopinhibition -Cellsopareopableoptoopinvadeopneighboringoptissue -Cellsopcanopmigrateopandopmetastasizeoptoopdistantopsites
Canopstimulateoptheopdevelopmentopofopnewopbloodopvesselsoptoopsupplyoptheoptumorop(a ngiogenesis)
Proto-oncogeneop-opans---regulateopnormalopcellopgrowthopandopdivisionop
largeopfamilyopofopgenesopthatopcodeopforopproteinsopandopenzymesopthatopturnoponoptheop cellopcyle Oncogeneop-opans-- whenopmistakesopinopcopiesopofopDNAopcanopoccur,opifopaopmutationopoccursopnextoptoopa opproto-oncogene,opitopcanop"turnopon"opandopbecomeopaop______ Examplesopofoponcogoenesop-opans--1.opEGFRoporopErb- B1op(codesopforopanopepidermalopGFopreceptoropinoptheopreceptor- tyrosineopkinaseopfamilyopadopisopassociatedopwithopheadopandopneckopandopcolorectalopc ancers) -EGFRopinhibitoroptherapiesopareopknownoptoopcauseopcutaneousopreactions 2.opErb-B2oporopHER2/ neuop(codesopforopanopEGFRopproteinopinoptheoptyrosineopkinaseopfamilyopandopisopassoci atedopwithopsomeopbreastopcancers) Tumoropsuppressoropgenesop-opans--- actoplikeopbrakesopinopaopcar,opslowingopdownoporopstoppingopcellopgrowthopandopdivision
inoptheoppresenceopofopmalignancies,optheyopbindoptoopDNAopwithopintentionopofoprepairin goporopactivatingopapoptosis
foropitoptoopbeopturnedoponopitopmustopbeopexpressedoporop"opened"opinoptheopDNAophelixo psoopthatopitopcanopbeoptranscribedoporopcopied p53op-opans---"sucidieopgene"
activatesopapoptosisopwhenoptheopcellopisopdamagedopbeyondoprepairoporoptooopoldoptoopf unction
moreopthanop50%opofopsolidoptumors,optheopgeneopisopmutatedopandopunableoptoopperform opitsopnormalopfunction GrowthopSignalsop-opans--- canceropcellsopareopableoptoopfindoptheiropownopgrowthopsignalsopmakingopthemopself- sufficient
epingopcellsopthatophaveopbeenopexposedoptoopchemotherapyopfromopundergoingopapopto sis -roleopinopangiogenesis phosphoinositideop3-kinasesop(PI3K)op-opans--- transductionopenzymesopthatopactivateopAkt,opleadingoptoopcellopsurvival,opincreasedopcell opproliferation,opandopgrowith NeoadjuvantopTreatmentop-opans--- treatmentopgivenopasopaopfirstopstepoptoopshrinkopaoptumoropbeforeoptheopmainoptreatment, opusuallyopsurgery -examples:opchemo,opradiationoptherapy,ophormoneoptherapy Adjuvantoptherapyop-opans--- additonalopcanceroptreatmentopgivenopafteroptheopprimaryoptreatmentoptooploweroptheoprisk opthatoptheopcanceropcanoprecur
Examples:opchemo,opradiationoptherapy,ophormoneoptherapy,optargetedoptherapy,oporopbi ologicoptherapy Doseopdensityop-opans---refersoptooptheopdrugopdoseopperopunitopofoptime
reductionopofoptimeopbetweenoptreatmentsoptoopachieveophigheropconcentrationopthanopino paopstandardoptreatmentopplan Doseopintensityop-opans---amountopofopdrugopdeliveredopoveroptime -smalleropdosesopofopchemotherapyopgivenopmoreopfrequently Relativeopdoseopintensityop(RDI)op-opans--- calculatedopbyopcomparingoptheopdoseopthatoptheopptopreceivedoptooptheopplannedopdoseo pofoptheopstandardopregimen OralopChemotherapyop-opans--- greateropchallengeoptoopadherenceopbecauseoptheopresponsibilityopfallsoponoptheopptopand opcaregiver Nonadherenceop-opans---ptoptakesoptooopfewoporoptooopmanyoppills
Overadherenceop-opans--- whenopaopptopbelievesopaopdoseopwasopmissedoporopthatop"moreopisopbetter",optooopmucho pmedicationopmayopbeoptaken,opleadingoptoopincreasedoptoxicity Factoropaffectingopadherenceop-opans---provideroprelationship -sideopeffects -necessity -routinization -support -lifestyleopfit -cost -medicationopknowledge -pillopburden -regimentopcomplexity Lessonop2:opAlkylatingopAgentsop-opans-- AlkylatingopAgentsop-opans--- functionopbyopcausingopaopbreakopinoptheopDNAophelixopstrand,opcausingopinterferenceopw ithopDNAopreplication,opwhichopresultsopinopcellopdeath AlkylatingopAgentopSubgroupsop-opans--- Nitrogenopmustardsop(cyclophosphamide{Cytoxin},opifosfamide{Ifex},opbendamustine{Tre anda}) -Platinum- basedop(cisplatin{Planitol},opcarboplatin{Paraplatin}):opdoopnotoppossessopanopalkylopgrou p -nitrosoureas Nitrosoureasop-opans---subgroupopofopalkylatingopagents -ableoptoopcrossoptheopblood- brainopbarrierop(effectiveopinoptreatingopsomeopbrainoptumors,opmelanomas,oplymphomas) -Carmustineop(BiCNU) -Lomustineop(CeeNu) -Streptozocinop(Zanosar) -pulmonaryopmonitoringoprecommended Carboplatinop(Paraplatin)op-opans---Alkylazingopagent
-onlyopMTXopandopcytarabineopviaopthisoproute -ITophydrocortisoneopisopoftenopgivenopatoptheopsameoptimeoptoopreduceopinflammation -MUSTopbeoppreservativeopfreeoptoopavoidopCNSopirritation Chemotherapy-InducedopN/Vop(CINV)opRiskopfactorsop-opans---younger -haveopaophxopofoplowoporopnoopalcoholopconsumption -areopfemale -hxopofopmorningopsickness -proneoptoopmotionopsickness -haveophadopchemooppreviously TypesopofopCINVop-opans---Acute:opoccurringopwithinop 24 ophours -Delayed:opfromop 24 ophourop-op 5 opdaysopafter -Breakthrough:opOccurringopdespiteoptreatment -Anticipatory:optriggeredopbyoptaste,opodor,opmemories,opvisions,opanxietyopr/topchemo
Refractory:opoccurringopdespiteopsubsequentopcyclesopwhenoptreatmentopfailedopinopearli eropcycles Prevention/Treatmentopofophandopfootopsyndromeop-opans--- limitopexposureopofophandsopandopfeetoptoophotopwater -takeopcoolopshowers
avoidopexposureoptoopsourcesopofopheat,opsuchopasopusingopsaunasoporopsittingopinoptheop sun
avoidopactivitiesopthatopcauseopunnecessaryopforceoporopfrictionoponoptheophandsoporopfeet ,opsuchopasoprunningoporopaerobics
avoidopcontactopwithopharshopchemicalsopusedopinopdetergentsopandophouseholdopcleanin gopproducts -avoidopactivitiesopthatoprequireopyouoptooppressopyourophandopagainstopaophardopsurface
-elevateopyourophandsopandopfeetopwhenopsittingoporoplyingopdown -gentlyopapplyopskinopcareopcreamsoptoopkeepophandsopmoist -wearoploose-fitting,opwellopventilatedopshoes Nadirop-opans--- pointopatopwhichopbloodopcellopcountsopareopatoptheiroplowestopfollowingoptreatment -typically,opbutopnotopalways,opoccursop7-10opdaysopafteroptheopcycleopisopadministered Neutropeniaop-opans---ANCopofoplessopthanop500/mm3oporop -lessopthanop1000/ mm3opwithoptheopexpectationopthatoptheopcountopwillopdropopbelowop 500 opinoptheopnextop 4 8 ophours NeutopeniaopRFop-opans---olderopthanop 65 -hxopofopneutropeniaopwithoppreviousopchemo -previousopchemooporopradiation -hematologicopmalignancy,opuncontrolledoporopadvancedopcancer,oporoplungopcancer NeutropenicopFeverop-opans---tempopofop38.3oporopgreateroponeoptime -tempopofop 38 oplastingop 1 ophour AbsoluteopNeutrophilopCountop-opans---op(%segsop+op%bands)opxop(WBC)op/op 100 Mucositisop-opans--- inflammationopofoptheopmucousopmembraneopliningoptheopdigestiveoptractopfromopmouthop toopanus -affectsop40-100%opofoppts Stomatitisop-opans---specificallyopinflammatoryopconditionsopofoptheopmouth Xerostomiaop-opans--- drynessopofoptheopmouthopcausedopbyopdamageoptooporopdysfunctionopofoptheopsalivaryopg lands
Irritantop-opans--- causesopinflammation,oppain,opandopburningopbutoprarelyopcausesoptissueopnecrosis Vesicantsop-opans--- causesopblisteringopandopsignificantoppainopandoptissueopdamageopandopdestruction,oplea dingoptooptissueopdeath VesicantsopinopPIVsop-opans---DoopnotopuseopIVopinophand,opwrist,opACopareas -DoopNOTopplaceoptheopIVopbelowopaoprecentopventipunctureopsiteopusedop(<24ophours) -UseopaopflexibleopIVopcatheter Whenopaopvesicantopextravasationopoccursoporopisopsuspected,optakeoptheopfollowingopste ps:op-opans--1.opImmediatelyopSTOPopadministeringoptheopvesicantopandopIVopfluids 2.opDisconnectoptheopIVoptubingopfromoptheopIVopdevice.opDoopnotopremoveoptheopIVopdevi ceoporopnoncoringopportopneedle 3.opAttemptoptoopaspirateopresidualopvesicantopfromoptheopIVopdeviceoporopportopneedlingo puseopaopsmallop(1-3opmL)opsyringe 4.opRemoveoptheopperipheralopIVopdeviceoporopportopneedle 5.opInitiateopappropriateopmanagementopmeasures ManagingopNon-DNAopBindingopVesicantopExtravasationop-opans--- VincaopAlkaloidsop(vincristine,opvinblastine)
DoopnotopbindoptoopDNAopinophealthyopcellsopwhenoptheyopextravasateopintooptissue.opIndi rectopeffectoponophealthyoptissue
Treatopwithopheat,opelevation,opandophyaluronidaseoplocalopinjectionop(spreadsoptheopvesi cantopthroughoptheoptissueopforopfasteropmetabolismopofoptheopvesicantopagent) -Usuallyopresultsopinoplessoptissueopdamage -Improvesopoveropaopshortopperiodopofoptimeop(daysoptoopweeks( ManagementopofopDNA-BindingopVesicantopExtravasationop-opans---- Anthracyclinesop(doxorubicin,opepirubicin,opdaunorubicin,opidarubicin) -BindsoptoopDNAopinophealthyopcellsopwhenoptheyopextravasateopintooptissue
Whenopnotopimmediatelyoptreatedopwithopdexrazoxane,optheopvesicantopremainsopinoptheo ptissueopandopinvadesopadjacentophealthyoptissue -Likelyoptoopresultopinopmoreoptissueopdamage
Leftopuntreated,opextravasationsopbecomeoplargeropandopdeeper,opworseningopoveroptime op(weeksoptoopmonths) Lessonop11:opTargetedopTherapyop-opans-- Howoptargetedoptherapyopandopchemoopdifferop-opans--- targetedoptherapiesopactoponopspecificopmolecularoptargetsoponoporopwithinoptheopcellsopth atopareopassociatedopwithopcancer,opwhereasopstandardopchemoopactoponopalloprapidlyopdi vidingopcells -chemoophasopmoreopSEs
targetedoptherapyopaeopchosenopandopdesignedoptoopinteractopwithoptheiroptargetoponoporo pwithinoptheopcells,opwhereasopchemoopwereopIDedopbecausedoptheyopkillopcells
targetedoptherapiesopareopoftenopcytostaticop(theyopblockoptumoropcellopproliferation)opwh ereasopchemoopagentsopareopcytotoxicop(killoptumoropcells) Goalsopofoptargetedoptherapyop-opans--- diseaseopcureopwhenopusedopasopprimaryoporopadjuvantoptherapy -improvingopoverallopresponseoporopincreaseopdisease- freeopsurvivalopwhenopusedopinopcombinationopwithopconventionaloptherapies -controllingoporopstabilizingopdisease -maintainingoporopenhancingopqualityopofoplife -decreasingoptheopseverityopofoptoxicitiesopfromopotheroptherapies Receptorop-opans--- moleculeopinsideoporoponoptheopsurfaceopofopaopcellopthatopbindsoptoopaopspecificopsubstan ceopcausesopaopspecificopeffectopinopthatopcell
Twoopwaysopthatopangiogenesisopinhibitorsopworkop-opans-- 1.opsomeopintergereopwithopactionopofopVEGFopwhichopstimulatesopnopewopbloodopvesselo pformation 2.opothersoptargetoptheiropmoleculesopthatopstimulateopnewopbloodopvesselopgrowth SmallopMoleculeopCompoundopTargetedopTherapiesop-opans---endopinop-ib
targetsoplocatedopinsideoptheopcellopbecauseoptheseopgentsopareopableoptoopenteropcellsop moreopeasily -intracellular -mostopgivenoporally MonoclonalopAntibodyopTargetedopTherapyop-opans---opendopinop-mab -relativelyoplargeopinopsizeopandopthereforeopusuallyopcannotopenteropcells -extracellularoporoptransmembrane
manopmadeopversionopofopantibodiesopthatopareopdesignedoptoopattackopaopveryopspecifico ptargetoponopcanceropcells -usuallyopfromopmice Lessonop12:opImmunotherapyop-opans-- Immunotherapyopworksopbyop-opans--- stoppingoporopslowingoptheopgrowthopofopcanceropcells -stoppingopcanceropfromopspreadingoptoopotheroppartsopofoptheopbody
helpingoptheopimmuneopsystemoprecognizeopcanceropcellsopandopincreaseopitsopeffectiven essopatopeliminatingopcanceropcells PassiveopImmunotherapyop-opans--- initateopanopantitumoropeffectopbutopdoopnotopresultopinopanyopimmunologicopmemory -requireoprepeatedopadministrationoptoopbeopeffective -includesopmonoclonalopantibodiesopandopcytokines
ActiveopImmunotherapyop-opans--- capitalizeoponoptheopimmuneopsystem'sopabilityoptooprememberopaopforeignopinvade
mountopanopimmuneopresponseopagainstoptheoptumoropandophopefullyoprememberoptheopc anceropcellsoplongopafteroptreatmentophasopstopped -includesopcanceropvaccines SpecificopImmunotherapyop-opans--- capitalizeoponoptumoropmarkersoptoopspecificallyoptargetopandopkillopcanceropcells -examplesopareopmAbsopandopcanceropvaccines NonspecificopImmunotherapyop-opans--- doopnooptargetopcanceropcellsopaloneopbutopratheropstimulateopaoplargeopimmuneoprespon se -givenopadjuvantlyoptoopotheropanticanceroptreatmentopdrugs -examplesopareopcytokines,opinterleukins,opandopcheckpointopinhibitors Lessonop13:opSafeopHandlingop-opans-- HierarchyopofopHazardopControlsopaimedopatopreducingopworkeropexposureop-opans-- 1.opElininationopofoptheopHazard 2.opEngineeringopControls: 3.opAdministrativeopControls 4.opPPE: 1.opEliminationopofoptheopHazard:op-opans--- highestoplevelopofopprotectionopfromopaophazardousopexposure -substituteopaoplessoptoxicopsubstanceopforoptheophazardousopmaterial -notopfeasibleopwithopdrugoptherapy 2.opEngineeringopControlsop-opans---secondophighestoplevelopofopprotection
