ThePapanikolaouPrize2018

TheFinalists

DrMyriaGalazi

Title: ErbB activation and heterodimerisation is responsible for resistanceuponPI3K-mTORinhibitioninmetastaticprostatecancer.

My hypothesis is that resistance to PI3K-AKT-mTOR targeting in metastaticprostatecancerinvolvesErbBactivationandheterodimerisation.Currentclinicaltrials are investigating the use of PI3K-AKT-mTOR inhibitors in metastaticcastration-resistantprostatecancer(CRPC).50-70%ofmetastaticCRPCpatientshave genomic aberrations of the PI3K pathway. Upregulation of HER3 waspreviously suggested to be an important resistance mechanism. Within thecontextofthisprojectIhaveappliedbiophysicaltechniquestoquantifyprotein-proteininteractionsi.efluorescencelifetimeimagingmicroscopy(FLIM),agold-standard technique for measuring Forster resonance energy transfer (FRET).ThiswasusedtoevaluateHER3heterodimerisationinprostatecancercellsandmousexenografttissue,alongsidebiochemicalmethodstodemonstratechangesinErbBexpressioninresponsetoPI3K-AKT-mTORinhibition.Inaddition,Iusedthis technology in cell line and patient-derived exosomes. My resultsdemonstrate differential ErbBupregulation invitro in response to PI3K-mTORinhibition,dependingonPTENstatus.ConcomitantupregulationofeitherARorPSMA is also observed. In PTENWT prostate cancer cells, the upregulation ofPSMAisdemonstratedtobeHER2dependentandcanbeinhibitedbylapatinib.The clinical implications of my work propose the use of PI3K-AKT-mTORinhibitorsinthemetastatichormone-sensitivesettingaswell.Inaddition,tissueand/or exosomal ErbB heterodimerisation, together with the use of clinicallyavailablePSMAimagingprobes,mightproveadditionalbiomarkersinresistancedetection and subgroup classification (we show initial PSMA PET imaginganalysesuponPI3K-mTORinhibitioninvivo).

Dr Yunan Gao. Gene Therapy, Centre of Neuroinflammation andNeurodegeneration, Division of Brain Sciences, Faculty of Medicine,ImperialCollegeLondon

Title:Functional improvements followingAAVgenereplacement therapy inmodelsofCDKL5disorder

CDKL5disorderisasevereneurodevelopmentaldisordercausedbymutationsinthe X-linked cyclin-dependent kinase-like 5 (CDKL5) gene. It predominantlyaffects females that typically present severe epileptic encephalopathy,intellectualdisability,autisticfeaturesandmotordysfunction.Currently,thereisno therapyexceptanti-epilepticdrugsprovidingpoor seizuremanagement.Todevelop a gene replacement therapy, we initially characterised the CDKL5isoforms in human brain, neuronal cell lines and primary astrocytes, inwhichhCDKL5_1 and to a lesser extent hCDKL5_2 isoformswere found ubiquitouslyexpressed.We cloned their coding regions downstream of CBh promoter intossAAV2vectorgenomeandproducedhightitrerAAVvectorspseudotypedwithAAV9,AAV-PHP.BandAAV-DJcapsids. IntrajugulardeliveryofAAV-PHP.B-GFPin WT mice transduced neurons and astrocytes throughout the brain moreefficiently than AAV9; and transduced spinal cord, DRGs, kidney and retina.Cdkl5 KO mice were treated with AAV-PHP.B-hCDKL5_1 via intrajugularinjectionatage28-30days,testedbehaviourally1-2monthspost-injectionandanalysed after 3 months. CDKL5-treated KO mice exhibited significant motorimprovements compared to GFP-treated controls. Transgene brain expressionwasmostprominentinCA1hippocampalneuronsandcerebellarPurkinjecells.Correction of PSD95 abnormality was found in cerebellar regions of hightransgene expression. AAV-DJ vectors efficiently transduced CDKL5-mutantiPSC-derived neural progenitors and isogenic controls and subsequentlydifferentiated into neurons. hCDKL5_1 expression in CDKL5-mutant neuronsimproved synaptic contacts whilst hCDKL5_2 ameliorated calcium signallingdefect, implying distinct functions of these isoforms in neurons. This studyprovides the firstevidence thatAAV-mediatedgene therapycanbeeffective intreatingCDKL5disorder.

Dr George Vassiliou, Reader in Haematological Malignancies at theUniversityofCambridgeandSeniorFellowOFCancerResearchUK.Title:Predictionofacutemyeloidleukaemiariskinhealthyindividuals

The incidence of acute myeloid leukaemia (AML) increases with age andmortality exceeds90%whendiagnosedafter age65.Most cases arisewithoutany detectable early symptoms and patients usually present with the acutecomplicationsofbonemarrow failure.Theonsetof suchdenovoAMLcases istypically preceded by the accumulation of somatic mutations in preleukaemichaematopoieticstemandprogenitorcells(HSPCs)thatundergoclonalexpansion.However, recurrentAMLmutationsalsoaccumulate inHSPCsduringageingofhealthyindividualswhodonotdevelopAML,aphenomenonreferredtoasage-relatedclonalhaematopoiesis(ARCH).Hereweusedeepsequencingtoanalysegenes that are recurrentlymutated in AML to distinguish between individualswho have a high risk of developing AML and those with benign ARCH. Weanalysed peripheral blood cells from 95 individuals that were obtained onaverage 6.3 years before AML diagnosis (pre-AML group), together with 414unselectedage-andgendermatchedindividuals(controlgroup).Pre-AMLcasesweredistinctfromcontrolsandhadmoremutationspersample,highervariantallele frequencies, indicatinggreater clonal expansion, andshowedenrichmentofmutationsinspecificgenes.Geneticparameterswereusedtoderiveamodelthat accurately predicted AML-free survival; this model was validated in anindependentcohortof29pre-AMLcasesand262controls.BecauseAMLisrare,we also developed an AML predictive model using a large electronic healthrecord database that identified individuals at greater risk. Collectively ourfindingsprovideproof-of-concept that it ispossible todiscriminateARCHfrompre-AML many years before malignant transformation. This could in futureenableearlierdetectionandmonitoring,andmayhelptoinformintervention.

DrGeorgiosSotiropoulos,BartsThoraxCentre,Londo,UKandNationalandKapodistrianUniversityofAthens,Greece

Title:Chemerinasanovelbiomarkerinresectablelungcancer

Objectives: Chemerin is an emerging adipocytokine involved inflammation,chemotaxis, thrombosis, fibrinolysisandmetabolism.Ouraimsweretoexplorecirculating chemerin in resectable non-small cell lung cancer (NSCLC),to studyits diagnostic potential, to assess its associations with clinicopathologicalfeaturesofNSCLC.

Materials andMethods: In a large case-control study, serum chemerin, insulinresistance and lipid parameters, classic adipocytokines, inflammatory,coagulation, fibrinolysis and tumor biomarkers were determined in 110consecutive patientswith resectableNSCLC and110healthy controlsmatchedonagegenderanddateofblooddraw

Results: NSCLC cases exhibited significantly elevated circulating chemerincompared to controls (p < 0.001). In NSCLC cases, chemerin was positivelyassociated with Homeostasis model assessment score of insulin resistance(HOMA-IR), fibrinogen, plasminogen activity, tumor and inflammatorybiomarkers,adiponectin,numberofinfiltratedlymphnodesandNSCLCstage.Incontrol participants, circulating chemerin was positively correlated withsomatometric, metabolic, lipid, hemostatic and inflammatory biomarkers, andleptin. Serum chemerin was independently associated with NSCLC, above andbeyond NSCLC risk. In cases, hemostatic parameters (platelet count andplasminogen activity), HOMA-IR, CYFRA 21-1, creatinine and plant foodconsumption emerged as independent predictors of circulating chemerin (p <0.05).Serumchemeringreaterthan220μg/L(cut-offpoint)yieldedasensitivityand a specificity of 63% and 91.8% respectivelywith amodest discriminativeability(AUC=0.72,95%C.I.0.64-0.79)forthediagnosisofNSCLC.

Conclusion: Chemerinmay represent a potentially useful biomarker in NSCLCintegrating tumor-promoting networks, inflammatory and hemostaticmechanisms,andcancer-relatedmetabolicpathways.

ThewinneroftheStudentScholarship

DimitriosKarponisBSc(Hons),5thYearMedicalStudent,ImperialCollegeLondon School of Medicine (ICSM) and Institute of Biomaterials andBioengineering,Tokyo,Japan,

Title:Evaluationofapneumaticsurgicalrobotwithdynamicforcefeedback

Robot-assisted surgery is limited by the lack of haptic feedback and increasedoperating times. Force scaling adjusts feedback transmitted to the operatorthrough the use of scaling factors. Herein, we investigate how force scalingaffectsforcesexertedinroboticsurgeryduringsimpleandcomplextasks,usingapneumaticsurgicalrobot,IBISVI.Secondaryobjectivesweretotesttheeffectsofforcescalingonoperatingtime,depthofneedleinsertionandusersatisfaction.Two novice males performed simple (modified block transfer) and complex(needle insertion) tasksunder fourscaling factors:0.0,0.5,1.0and2.0.Single-blind experimentswere repeated five times,with alternating scaling factors inrandom order. Increasing the scaling factor from 0.0 to 2.0 reduces forces inblock transfer (p = 0.04). All feedback conditions reduce forces in needleinsertion compared to baseline (0.5: p < 0.001, 1.0: p = 0.001, 2.0: p = 0.001).Timetocompleteblock transfer isshorter forscaling factor0.5(p=0.02),butnot for1.0 (p=0.05)or2.0 (p=0.48), compared tobaseline.Depthofneedleinsertion decreases consistently with incremental scaling factors (p < 0.001).Furtherreductionsareobserveduponaugmentingfeedback(0.5-2.0:p=0.02).Usersatisfactioninblocktransferishighestforintermediatescalingfactors(0.0-1.0: p = 0.01), but no change is observed in needle insertion (p = 0.99).Incrementsinscalingfactorreduceforcesexerted,particularlyintasksrequiringprecision.Depthofneedleinsertionfollowsasimilarpattern,butoperatingtimeandusersatisfactionareimprovedbyintermediatescalingfactors.Insummary,dynamic adjustment of force feedback can improve operative outcomes andadvancesurgicalautomation.

TheContestants

EpaminondasMarkosValsamisMBBChir,MA(Cantab),MRCS,PGCertMedEd,BrightonandSussexUniversityHospitalsNHSTrust

Title: Predictors of mortality in elderly patients with fractures of theodontoidprocess:canweuseestablishedhipfracturescoringsystems?

Fractures of the odontoid process (OP) in the elderly are associated withmortality rates akin to hip fractures. Currently there are no scoring systemsspecifictothesefractures, whichmayidentifyhigherriskpatients.Establishedhipfracturescoringsystemsmaybebeneficialaspredictorsofmortalityinthesepatients.We conducted a retrospective review of patients presentingwith OPfracture at two institutions. Data collected included demographics, medicalhistory, residence, mobility status, admission blood tests, abbreviated mentaltestscore,presenceofother injuriesandneurologicaldeficit.Allpatientsweretreated with rigid cervical orthoses. Multivariate analysis was performed toidentifypredictorsofmortalityat30daysand1year.Ninetypatients(meanage83)wereidentified.Mortalitywas16.8%at30daysand36%at1year.Throughlogisticregressionanalysisstatisticallysignificantindependentpredictorsof30-day mortality included the presence of neurological deficit (p=0.0010), theNottinghamHip Fracture Score (NHFS) (p=0.0089), presence of other injuries(p=0.0141) and the presence of other spinal injuries (p=0.0361). Independentpredictors for 1-year mortality included the presence of other injuries(p=0.0040)andtheNHFSscore(p=0.0044).ROCcurveanalysisdemonstratedanoptimalcutoffvalueofNHFSof5asapredictorofmortality(AUC=0.694for30days and 0.686 for 1 yearmortality). In conclusion, theNHFSmay be used toidentifyhigh-riskpatientswithfracturesoftheOP.Thismayhelptoguidemulti-disciplinarymanagementandinformpatients.

Dr. Maria Pantelidou, Academic Clinical Fellow and Specialist Registrar,DepartmentofRadiology,CambridgeUniversityHospitals

Title: Robotic-assisted partial nephrectomy versus percutaneousradiofrequencyablationforthetreatmentofsmallrenalcellcarcinoma

Purpose: A single center comparison of Radio-frequency ablation (RFA) withRobotic assisted PartialNephrectomy (RPN) for the treatment of T1 renal cellcarcinoma(RCC)intermsofoncologicalandfunctionaloutcomes.

Material and Methods: RPN was performed using the DaVinci robot and RFAunder CT-guided radiofrequency electrodes. Data collected included baselinedemographics,P.A.D.U.Ascoreandtumorsize.Peri-operativecomplicationsandoncologicaloutcomeswerecompared.

Results: In total, 126 cases were audited. Baseline demographics were well-matchedbutcomorbidconditionsweremorepronounced inRFA.Tumoursizewas greater in the RPN group (2.88cm vs. 2.11, p= 0.0003) but PADUA scoreshowedno significantdifference (7.38RPNvs. 7.27RFA).More singlekidneysweretreatedwithRFA(15/63vs.1/63,p=0.0002).Therewerenoconversionstoopensurgeryandnobloodtransfusions.Follow-upwaslongerinRFAduetoarecentcommencementofRPN(4vs.0.5years,p=<0.0001).Lengthofstaywassignificantly shorter in the RFA group (1 vs. 3 days, p= <0.0001).Moreminorcomplications were recorded in RPN (10/63 vs. 4/63, p=0.15) but localrecurrence was more frequent in RFA (6/63 vs. 1/63, p=0.11). Disease-freesurvival(DFS)wasnotsignificantlydifferent inthetwogroups(HRratio=0.91,p=0.92).TumoursizehadasignificanteffectonDFS(HR=1.7;95%Cl:1.1-2.6;p=0.02).

Conclusion: Both RPN and RFA offer excellent oncological outcomes for thetreatmentofT1RCCwithlowperi-operativemorbidity.RFAwasassociatedwithlessperioperativecomplications,whereasRPNhadalowerlocalrecurrencerate.RFAshouldbeofferedalongsideRPNforselectedcases.

Maria-Angeliki Gkini, MD, MSc, PhD, Specialist Registrar in DermatologyBartsHealthNHSTrust

Title:Aredermatologistsatriskofmajorcomplaintsandbeingstalked?

Patientswithdelusional infestation (DI)usually seekhelp fromdermatologistsand deny firmly referral to psychiatrists. Psychiatrists and related healthcarestaff are at risk of complaints, abuse and being stalked, but so are otherspecialties.InasurveyofcosmeticsurgeonsinAustralasia,20%reportedhavingbeenharassedbypatients.Norelevantdataareavailablefordermatologists.

ObjectivesofourstudyweretoassessthenumberofdermatologistswhotreatpatientswithDI and their approach and to evaluate the volumeandnature ofcomplaints,abuseand/orstalkingforwhichdermatologistsarethetargetfromthisgroupofpatients.

A 10-item questionnaire was sent to dermatologists [members ofPsychodermatology UK (n=152) and European Academy of Dermatology andPsychiatry(n=161)]throughaSurveymonkey.

44 dermatologists responded. 50% of them referred patients with DI topsychiatry,while75%admittedfeelingstressedwhendealingwiththiscategoryofpatients. Intotal,48%ofphysicians,whoregularlyseepatientswithDI,hadreceivedcomplaints,wereverballyabusedorwerethreatenedwithdefamation.Nobody reported physical abuse or stalking. Internet abuse (trolling) wasbecomingmoreofarisk.

Thisstudyisthefirsttoevaluatetheprevalenceandnatureofcomplaintsamongdermatologists,whomanagepatientswithpsycho-cutaneousdisease. Ourdataindicate that managing such patients could invoke significant risks todermatologists’ personal and professional wellbeing. A multidisciplinaryapproachthroughapsychodermatologyclinicshouldbeencourageforboththepatientandtheclinician.

DrKonstantinosC.Fragkos,ClinicalFellowinGastroenterology,GIServices,UniversityCollegeLondonHospitalsNHSFoundationTrust,London

Title:HomeParenteralNutritioninAdvancedCancer

Background: Home parenteral nutrition (HPN) in advanced cancer patientsremains controversial in the UK.We exploredmany aspects of this treatmentwithoriginalresearchofprimaryandsecondarydata.

Results: 1. Systematic review: Eighteen studies met inclusion criteria. Overallsurvival was 3.8±1.4 months. Variation in clinical practice exists betweencountries.Aculturalchangeandeducationofprofessionalsisrequiredtoensureearly access to HPN for appropriate patients. 2. Retrospective cohort (107patients,UKlargest):Mainindicationswerebowelobstruction(74.3%)andhighoutput ostomies (14.3%). Cancer cachexia was present in 87.1% of patients.Performance status, prognostic scoring and HPN requirements predictedsurvivalinCoxregression.Mostpatientspassedawayintheirhomesorhospice(77.9%).3.Nomograms:Basedon theCox regression,patientswhoscoreover150units inthe3-monthandover100units inthe12-monthnomograms,hadless than 20% survival probability, respectively. Internal validation confirmednomogramresults.4.Readmissions:Hospitalreadmissionsreducequalityoflifeinthiscohort.Whilstthemediannumberofreadmissionswasthree,themedianpercentage of readmission days to overall survival was 19%. Readmissionreasons were mainly oncology-related (over 70%) versus HPN-related. 5.Standard bags: The use of standard (instead of bespoke) HPN bagsmay offertime and costs savings in this sensitive cohort of patients. Comparisons of thedischarge HPN scripts with 29 standard bags were conducted. Standard bagscouldnotbesafelyappliedtothiscohort,however,maybeapplicabletoasub-setbasedoncaloriesandelectrolytesrequirements.

DrSavvasVlachos,TheDepartmentofIntensiveCareMedicine,GuysandStThomasHospital,London,UK

Title:TheUtilityofICUReadmissionasaQualityIndicatorandtheEffectofSelection

Objectives: Intensivecare readmissionratesareused to signalquality,yet it isunclearwhether they representpoorquality in the transitionof care from theICUtotheward,patientfactors,ordifferencesinsurvivaloftheinitialadmission.This study aims to measure the selection effect of surviving the initial ICUadmissiononreadmissionrates.

Design: Retrospective cohort study of adult patients admitted to ICUsparticipatingintheCaseMixProgramdatabasefromtheIntensiveCareNationalAuditResearchCentre.Thestudyincludes262ICUsintheUnitedKingdom.Thestudyincludes682,975patientsadmittedtoICUsbetween2010and2014.

MeasurementsandMainResults:Thestudyincludes682,975patientsadmittedtoICUsintheUnitedKingdom.Therewere591,710patientsdischargedalive,ofwhich9,093(1.53%)werereadmittedwithin the first2daysof ICUdischarge.Post-ICU admission hospital mortality and ICU readmission were poorlycorrelated (r = 0.130). The addition of a selectionmodel resulted in aweakercorrelation(r=0.082).

Conclusions: ICU readmission performed poorly as a performancemetric. Theselectionprocessbywhichonlypatientswhosurvivetheirindexadmissionareeligible for readmission has a significant effect on ICU readmission rankings,particularlythehigherrankedICUs.FailuretoconsiderthisselectionbiasgivesmisleadingsignalsaboutICUperformanceandleadstofaultydesignofincentiveschemes.

Dr Andreas Panagiotopoulos, Institute of Orthopaedics andMusculoskeletalScience,UniversityCollegeLondonandtheRoyalNationalOrthopaedicHospital,Stanmore,London,UK

Title:DamagePatternsat theHead-StemTaper JunctionHelpsUnderstandtheMechanismsofMaterialLoss.

BACKGROUND:

Totalhipreplacement isaverycommonoperation in theNHS.Material lossatthetaperjunctionofmetal-on-metaltotalhiparthroplastieshasbeenimplicatedintheirearlyfailure.Themechanismsofmateriallossarenotfullyunderstood;analysis of the patterns of damage at the taper can help us better understandwhymateriallossoccursatthisjunction.

METHODS:

Wemappedthepatternsofmateriallossinaseriesof155metal-on-metaltotalhiparthroplasties receivedatour centerby scanning the taper surfaceusingaroundness-measuring machine. We examined these material loss maps todevelop a 5-tier classification system based on visual differences betweendifferentpatterns.Wecorrelatedthesepatternstosurgical,implant,andpatientfactorsknowntobeimportantforhead-stemtaperdamage.

RESULTS:

Wefoundthat63implantshad"minimaldamage"atthetaper(materialloss<1mm3),andtheremaining92implantscouldbecategorizedby4distinctpatternsoftapermaterialloss.Wefoundthat(1)headdiameterand(2)timetorevisionwerekeysignificantvariablesseparatingthegroups.

CONCLUSION:

These material loss maps allow us to suggest different mechanisms thatdominate the cause of the material loss in each pattern: (1) corrosion, (2)mechanically assisted corrosion, or (3) intraoperative damage or poor sizetolerancesleadingtotogglingoftrunnionintaper.