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Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development

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Final presentation given by Ileana Lulic and Ivor Kovic at the end of Scientific research in gastro-intestinal & liver diseases …

Final presentation given by Ileana Lulic and Ivor Kovic at the end of Scientific research in gastro-intestinal & liver diseases
Sunday, July 8 - Friday, August 3, 2007
Amsterdam, Academisch Medisch Centrum


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  • 1. Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development Ileana Lulic, Ivor Kovic
  • 2. Definition “... a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy ...” American College of Gastroenterology
  • 3. Characteristics • Caucasian males – middle age • Rapidly rising incidence in Western countries • Around 150x higher risk of esophageal adenocarcinoma compared to general population • 0.5% of BE patients will develop EAC • Overall survival rate of EAC = 20-25%
  • 4. Progression Squamous esophageal epithelium Intestinal metaplasia Dysplasia Esophageal adenocarcinoma
  • 5. Progression Squamous esophageal epithelium GERD Intestinal metaplasia Dysplasia Esophageal adenocarcinoma
  • 6. Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Esophageal adenocarcinoma
  • 7. Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Low grade High grade Esophageal adenocarcinoma
  • 8. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology
  • 9. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology http://www.gastrointestinalatlas.com/
  • 10. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology
  • 11. Surveillance problems Endoscopy Pathology • • Intra-observer variability Difficulty of identifying early neoplastic lesions • Inter-observer variability • Sampling errors • Expensive and time consuming
  • 12. Surveillance problems Endoscopy Pathology • • Intra-observer variability Difficulty of identifying early neoplastic lesions • Inter-observer variability • Sampling errors • Expensive and time consuming Questionable cost-effectiveness
  • 13. Potential of genetic markers • Prediction of risk for disease progression in endoscopic surveillance program • Early detection of high grade dysplasia and invasive adenocarcinoma • Staging and prognosis • Prediction of chemosensitivity • Novel targets for anticancer therapies
  • 14. Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q
  • 15. Genetic markers p16/9p-loss No dysplasia p53/17p-loss Low grade dysplasia Y chromosome loss Aneuploidy/tetraploidy High grade dysplasia Losses - 3p, 4p, 7q, 12q,17q Esophageal adenocarcinoma Gains – 2p, 8q, 20q
  • 16. Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q
  • 17. Genetic markers p16/9p-loss Fluorescent in situ hybridization p53/17p-loss Y chromosome loss Image cytometry Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q
  • 18. Procedure Image cytometry Brush cytology Slides preparation FISH
  • 19. FISH • Fluorescent probe • Fluorescent microscopy
  • 20. FISH • Numerical chromosomal changes: aneuploidy • Locus specific losses: tumor suppressor genes • Amplifications: oncogenes and growth factor
  • 21. Image cytometry • DNA ploidy analysis • Aneuploidy – from 2N to 4N, DNA index • Measurement of optical density
  • 22. FISH results Cep1 p16 p53 Patient Hystology loss gain loss gain loss gain + + 1 LGD + 2 LGD + + + 3 HGD + + 4 HGD + + + 5 HGD + + 6 HGD Total 2 3 5 0 3 0
  • 23. Image cytometry results
  • 24. Image cytometry results
  • 25. Results LGD HGD 6 5 4 3 2 1 0 Cep 1 gain p16 loss p53 loss
  • 26. Results from 151 patients (n=114) (n=24) (n=13)
  • 27. Conclusion • p53 loss and aneuploidy are promising markers for dysplasia development in BE • Ongoing follow up study to demonstrate the true predictive value of these markers
  • 28. Agnieszka Rygiel Francesca Milano Sheila Krishnadath Wendy Bruins Willemijn van Dop