Thomas M Attard MD FAAP FACG

1. Improving Outcomes in Hereditary Gastrointestinal Polyposis Syndromes in the Mediterranean Region Thomas M Attard MD FAAP FACG Associate Professor, Pediatrics, Gastroenterology, University of Malta, Malta. Consultant Gastroenterologist Children’s Mercy Hospital, Kansas MO, USA.

2. Content: • Overview: Hereditary Gastrointestinal Polyposis Syndromes in Childhood and Adolescence • PolyposisBurden in Children in the Mediterranean Basin • Obstacles for Management of Childhood Polyposis Syndromes • Pilot Project to Improve Outcomes in Children with Hereditary Gastrointestinal Polyposis Syndromes in the Medicel Forum

3. Genotypic and Phenotypic Heterogeneity in Hereditary Colorectal Cancer Syndromes. AC-I, Amsterdam Criteria I MMR, mismatch repair FAP, familial adenomatouspolyposis AFAP, attenuated familial adenomatouspolyposis; HBCC, hereditary breast and colorectal cancer PJS, Peutz–Jeghers syndrome FJP, familial juvenile polyposis CD, Cowden’s disease BRRS, Bannayan-Ruvalcaba–Riley syndrome. Lynch et al. Cancer 2004;100:53–64

4. Hereditary Gastrointestinal Cancer Syndromes in Childhood • ~ 5% of individuals with colorectal cancer will have a recognizable hereditary gastrointestinal cancer predisposing syndrome • Polyposis syndromes frequently present in the first two decades of life with intestinal / extraintestinal manifestations • Management of hereditary polyposis syndromes includes genetic testing, screening and in many cases surgery during childhood / adolescence

5. Familial Adenomatous Polyposis (FAP 1:8,000) Peutz-Jeghers Syndrome (PJS, 1:15,000) Juvenile Polyposis Syndrome (JPS, 1:35 – 50,000) HNPCC PTEN Hamartoma Syndrome (Cowden’s Syndrome, BRRS) Hereditary Mixed Polyposis Syndrome HMPS MEN IIB MYH-Associated Polyposis (MAP) Hereditary Cancer Syndromes that present in childhood / adolescence

6. Polyposis: Defining the syndrome • (age) • Polyp • Histology • Number • Distribution • Associated Clinical features / findings • Family History

7. Hereditary Cancer Syndromes – polyps by anatomic localization & histology Ψ a significant proportion of syndromic juvenile polyps will harbor areas of adenomatous transformation ¥ Peutz-Jeghers polyps have characteristic - prominent smooth muscle component in the submucosa

8. Hereditary Gastrointestinal Cancer Syndromes: Management modified from Lynch HT, Attard TM, Gastroent. & Hepatology 2005

9. Hereditary colorectal Cancer Syndromes in the Mediterranean Basin • Population specific data is lacking for most countries • InSIGHT membership incl. Italy, Spain*, Israel, Serbia* • Multiple observations on unique disease manifestations and natural history • No significant participation in pediatric chemopreventive trials *Adult Gastroenterology Programs

11. Obstacles for Management of Childhood Polyposis Syndromes • individually these are rare conditions → very different, complex management algorithms: • Genetic testing / Endoscopy / Surgery/ Chemoprevention / Surveillance • need for team approach: • Gastroenterology / Surgery / Adult GI services / Genetic Counseling / Psychology • changing / unclear management algorithms • access to research protocols / chemoprevention

12. Obstacles for Management • Recognizing symptoms and family history at risk. • Access and timely referral for comprehensive services • Long term surveillance planning and follow-up including family screening • Lack of medical guidelines / discrepancy in provider competence

13. FAP PJS JP PTEN - HS Hereditary Gastrointestinal Polyposis Syndromes: Healthcare Provider Training Pediatric residents overall knowledge of gastrointestinal syndromes; proportion of correct answers by syndrome: pathogenesis and clinical features Variation in percent correct response rate by level of training Attard TM et. al submitted J Cancer Edu. 2008

14. Hereditary Colorectal Cancer Registries • National, institutional, regional entity that serves as repository of expertise and academic interest on the group of diseases • Demonstrable patient benefit from belonging to a registry → earlier recognition and treatment • Registries as the only resource able to liase and effect drug (egs. chemoprevention) trials JärvinenHj et al. Gastroenterology. 2000 May;118(5):829-34.

15. STEPWISE MODEL OF THE DEVELOPMENT OF A REGIONAL HEREDITARY GASTROINTESTINAL CANCER REGISTRY Registry Based prospective Chemopreventive Studies Registry Based Family based recommendations Coordination of Epidemiologic / Observational Studies Informational / Educational Cooperation

16. Step 1: Informational / Educational Cooperation • Initial development of a network for individual case consultation • Commitment toward timely, comprehensive – structured consultation • Academic network to pool, study, publish interesting cases • Identification – development of regional / national resources toward Step 2.

17. Step 1: Informational / Educational Cooperation • Multidisciplinary team: • pediatric gastroenterologists + trainee (fellow) based in UoM (Malta, EU), Children’s Mercy Kansas City (MO, USA) • Genetic counselor • Psychologist • e-mail based structured consultation with management plan • De-identified clinical outline retained in dedicated database / Children’s Mercy Hospital, Kansas City (pending IRB approval)

18. Step 1: Informational / Educational Cooperation • structured consultation: • Summary of salient clinical, endoscopic, +/- genetic testing findings • Outline of differential Dx, current diagnostic testing recommendations • Outline long term management incl. surveillance planning

19. Preparing for Step 2 and beyond • How did step 1 go? • Is there a perceived need for more structured resources? • Are communication channels adequate? Does the model work? • Coordinating epidemiologic and observational studies in regional heterogeneity of disease

20. Questions Acknowledgements