2008 Summer Meeting - Leeds - The Pathological Society of Great ...

S21Sights Unseen, Truths Untold: Pathology and the ModernMedical CurriculumJCE Underwood 11 The University of Sheffield, UKParticularly among pathologists, there is widespread and deep concern aboutthe decline of pathology in modern medical curricula. Until the late 20thcentury, medical students benefited from a wide range of learning opportunitiesin pathology — lectures, tutorials, practical classes, museum collections andautopsy demonstrations. Pathology was regarded as core knowledge, examinedseparately from other subjects and serving as a vital educational bridge betweenthe preclinical sciences and the clinical years.During the last few decades, in the UK and elsewhere, there have beenfundamental changes in medical education: adoption of problem-basedlearning; a shift in emphasis away from science towards clinical andcommunication skills; and curricular organisation aligned with body systemsrather than academic disciplines. Academic departments (where they survive)have ceded their curricular control to curriculum committees. Pathologymuseums (where they survive) are rarely visited by students. Most doctors nowgraduate without learning from autopsies. Where formerly students had to passan examination in pathology before proceeding, the subject is diluted by otherdisciplines and is much less visible.Evidence is now emerging of serious risks to patients, possibly as aconsequence of some of these changes in medical education. Many surgeons areworried about significant gaps in anatomical knowledge. A recent study revealspoor understanding of pathology investigations. Despite all UK medical schoolssatisfying the General Medical Council, recent graduates now differ markedlyin their knowledge according to which medical school they attended.With evidence and advocacy, it is vitally important — for patients — thatpathologists actively engage in curricular organisation and delivery.Pathological knowledge elevates medicine from a caring profession to a curingprofession.S23Molecular prediction: making the most of treatments forbowel cancerMT Seymour 11 Institute of Oncology, St James's University Hospital, LeedsWe now have an increasing range of drug therapies with proven efficacy inbowel cancer. However, each drug typically produces major benefits in lessthan one-third of patients receiving it, whilst the toxicity and costs of treatmentare incurred by all. Predictive biomarkers have the potential to identifysubpopulations of patients with higher or lower probability of benefit or toxicitywith specific drugs. If validated and incorporated into practice, they could allowdrugs to be targeted to patients most likely to benefit, thereby improving bothclinical and cost effectiveness. Ascertainment and validation of predictivebiomarkers requires large, statistically robust studies attached to randomisedclinical trials (RCTs). The UK NCRI and NCRN provide the infrastructure andopportunities for such studies.MRC FOCUS is the largest RCT ever reported in advanced colorectal cancer.We received FFPE tumour material from over 1600 FOCUS patients and haveinvestigated several candidate biomarkers. Topoisomerase-I (Topo1) proteinemerged as a strong candidate predictor of irinotecan and oxaliplatin efficacy,and is now undergoing independent validation. Meanwhile, other trials haveidentified KRAS oncogene status as predictive of benefit from anti-EGFRantibodytherapies. A new NCRI trial, FOCUS-3, will now prospectivelycompare standard therapy or Topo1/KRAS-directed drug choices.S22Genomic Approaches to Understanding Gastric CancerProgressionPTan 11 Duke-NUS Graduate Medical School, SingaporeGastric cancer (GC) is the second highest cause of worldwide cancer mortality,yet comparatively little is known about its underlying genetics and keyoncogenic pathways. In this talk, I will describe our attempts to understand GCfrom a genomics-oriented perspective, in order to better identify cellularinteractions involved in this disease, and potential nodes for pharmacologicintervention. I will present our results in establishing the "gastrome", aconsensus gene co-expression metanetwork of GC derived from hundreds ofgastric tissues and tumours, and describe how a systematic analysis of thismetanetwork can provide unique insights into various topological and systemsproperties of GC. I will further describe how we were able to use the gastrometo uncover a novel cellular pathway for GC invasion and metastasis, involvingthe survival-related gene PLA2G2A.S24Hypoxia as an inducer of leaky microvessels and growth ofatherosclerotic plaquesMDaemen 11 University of MaastrichtAtherosclerosis is considered to be a chronic inflammatory disease with aprominent role for lipids and macrophages. Since atherogenesis is alsoassociated with intraplaque neovascularization, which is thought to bestimulated by hypoxia, the presence of hypoxia and hypoxia-inducibletranscription factors (HIF) was studied in human carotid atherosclerosis.To show hypoxia in atherosclerotic plaques, the hypoxia marker pimonidazolewas infused immediately prior to carotid endarterectomy of 7 symptomaticpatients. Subsequent immunohistochemistry demonstrated the presence ofhypoxia especially in the macrophage-rich centre of the lesions. Hypoxia wasassociated with the presence of a thrombus, neovascularization and expressionof HIF1A, 2A and responsive genes. Microvessels appeared to be very thinwalled, both in the adventitia as well as in the intima, and containedendothelials cells with many membrane blebs and vacuoles, which may explaintheir leaky phenotype.Hypoxia was most prominent in n the macrophage-rich centre and wasassociated with the presence of a thrombus, neovascularization and theexpression of HIF1A, 2A and responsive genes. Also, the expression of proteinsin the HIF pathway was associated with lesion progression and microvesseldensity, suggesting the involvement of the HIF pathway in the response tohypoxia and the regulation of neovascularization in human atherosclerosis.Microvessel (ultra)structure in plaques may explain their leaky phenotype.Summer Meeting (194 th ) 1–4 July 2008 Scientific Programme93