Wiseman opac2013

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Wiseman opac2013

  1. 1. Martin WisemanMedical and Scientific AdviserWCRF InternationalLondonUKVisiting Professor of Human NutritionUniversity of SouthamptonUKContinuous Update Project -Systematic Review of Mechanistic Evidence
  2. 2. Journal citations - WCRF/AICR Reports0501001502002503003504004505001997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011NumberofcitationsDoll & Peto 19811997 EXPERT REPORT2007 EXPERT REPORT
  3. 3. BreastGlobal variation in cancer incidenceColorectum
  4. 4. Migration data Trends in incidence(Japan)CancerIncidencePer 100,000, world population standard
  5. 5. Systematic reviews• Expert international Task Force for method• Nine centres - USA, UK, NL, Italy• SLR centre coordinator• Test of reproducibility• Standardised search, analysis and display• Epidemiology and mechanisms• Quality assessment• Peer review - protocol, report• Defined expertise required– Nutrition, epidemiology, systematic review, cancer biology, statistics
  6. 6. Inferring causality• Strength• Consistency• Specificity• Timing• Dose Response• Plausibility• Coherence• Experiment• AnalogyBradford Hill
  7. 7. GRADING CRITERIAPredefined requirements for:–Number and types of studies–Quality of exposure and outcome assessment–Heterogeneity within and between study types–Exclusion of chance, bias or confounding–Biological gradient–Evidence of mechanisms–Size of effect
  8. 8. Basis forrecommendations• Convincing• Probable• Limited Evidence – Suggestive• Limited Evidence – No Conclusion• Substantial Effect on Risk UnlikelyGRADING THE EVIDENCE
  9. 9. OBITUARYWylieValeandan elusivestresshormonep.542HISTORYOFSCIENCEDescartes’lost letter trackedusingGooglep.540EARTHSYSTEMSPast climatesgivevaluablecluestofuturewarmingp.537AVIANINFLUENZAShift expertisetotrack mutationswherethey emergep.534Raisestandardsforpreclinical cancer researchC. Glenn Begley and LeeM. Ellisproposehow methods, publicationsandincentivesmust changeif patientsaretobenefit.Manylandmark findings in preclinical oncology researchare not reproducible, inpart because of inadequate cell linesand animal models.S.GSCHMEISSNER/SPLCOMMENT29 MARCH 2012 | VOL 483 | NATURE | 531
  10. 10. OBITUARYWylieValeandan elusivestresshormonep.542HISTORYOFSCIENCEDescartes’lost letter trackedusingGooglep.540EARTHSYSTEMSPast climatesgivevaluablecluestofuturewarmingp.537AVIANINFLUENZAShift expertisetotrack mutationswherethey emergep.534Raisestandardsforpreclinical cancer researchC. Glenn Begley and LeeM. Ellisproposehow methods, publicationsandincentivesmust changeif patientsaretobenefit.Efforts over the past decade tocharacterizethegeneticalterationsinhumancancershaveledtoabetterunderstandingof molecular driversof thiscomplexset of diseases.Althoughweinthecancer fieldhopedthat thiswouldleadtomoreeffectivedrugs,historically,our abilitytotranslatecancer researchtoclinical suc-cesshasbeenremarkablylow1.Sadly,clinicaltrialsinoncologyhavethehighest failureratecomparedwithother therapeuticareas.Giventhehighunmet needinoncology,itisunderstandablethat barrierstoclinicaldevelopment maybelower thanfor otherdiseaseareas,andalarger number of drugswithsuboptimal preclinical validationwillenter oncologytrials.However,thislowsuc-cessrateisnot sustainableor acceptable,andinvestigatorsmust reassesstheir approachtotranslatingdiscoveryresearchintogreaterclinical successandimpact.Manyfactorsareresponsiblefor thehighfailurerate, notwithstandingtheinher-entlydifficult natureof thisdisease. Cer-tainly, thelimitationsof preclinical toolssuch asinadequatecancer-cell-lineandmousemodels2makeit difficult for evenManylandmark findings in preclinical oncology researchare not reproducible, inpart because of inadequate cell linesand animal models.S.GSCHMEISSNER/SPL2 9 M A RC H 2 0 12 | V O L 4 8 3 | N A T U R E | 5 3 1COMMENT© 2012MacmillanPublishersLimited.All rightsreserved29 MARCH 2012 | VOL 483 | NATURE | 531• Reproducibility• Relevance of model• Relevance of exposure• Relevance of dose• Route of administration• Publication bias
  11. 11. Mechanisms Protocol DevelopmentGroupExternal Experts Stephen Hursting (chair) Andrew Dannenberg Johanna Lampe Henry Thompson Steven Clinton Nikki Ford - associate memberWCRF Team Martin Wiseman Susan Higginbotham Rachel Thompson Rachel Marklew Kate Allen Deirdre McGinley-Gieser
  12. 12. HALLMARKS OF CANCERClassic Hallmarks• Sustaining proliferativesignaling• Evading growth suppressors• Resisting cell death• Enabling replicativeimmortality• Inducing angiogenesis• Activating invasion andmetastasisEmerging hallmarks• Deregulating cellularenergetics• Avoiding immunedestructionUnderpinningcharacteristics• Genome instability• InflammationHanahan and Weinberg 2011
  13. 13. MechanismsReviews to be systematic and peerreviewedReviews conducted by exposureFeasibility test of final draft protocol byexternal group, including peer reviewExternal review team should haveexpertise in informatics, stats, cancerbiology, cancer site, nutritionMolecular, cellular, physiological…
  14. 14. Thank you!

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