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Presented at: Neuroendocrine Cancer Regional Conference 2011 Sponsor: The Ohio State Medical Center, CCC-The James Col

Overview of Carcinoid Tumors. Presented at: Neuroendocrine Cancer Regional Conference 2011 Sponsor: The Ohio State Medical Center, CCC-The James Columbus, Ohio December 3, 2011. Presenter Thomas M. O’Dorisio, M.D. Professor of Medicine Director Carcinoid & Neuroendocrine Tumor Program.

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Presented at: Neuroendocrine Cancer Regional Conference 2011 Sponsor: The Ohio State Medical Center, CCC-The James Col

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  1. Overview of Carcinoid Tumors Presented at: Neuroendocrine Cancer Regional Conference 2011 Sponsor: The Ohio State Medical Center, CCC-The James Columbus, Ohio December 3, 2011 Presenter Thomas M. O’Dorisio, M.D. Professor of Medicine Director Carcinoid & Neuroendocrine Tumor Program

  2. Evolution of Neuroendocrine Medical Therapy Dawn Wray Teresa Ruggle © University of Iowa

  3. Siegfried Oberndorfer Coined the term ‘karzinoide’ Frank Z. Pathol 1907;1:425 Modified from IM Modlin & K Oberg, 2007.

  4. Clinical Era Zollinger-Ellison Syndrome 1955 R.M. Zollinger E.H. Ellison Gastrinoma

  5. Era of Gut Peptide Chemistry R.A. Gregory H.J. Tracy V. Mutt J.E. Jorpes

  6. Courtesy of E. Christopher Ellison

  7. SMS 201-995: A Very Potent and Selective Octapeptide Analogue of Somatostatin with Prolonged Action W. Bauer, U. Briner, W. Doepfner, R. Haller, R. Huguenin, P. Marbach, T.J. Petcher & J. Pless Life Sciences. 31(11);113-1140: 1982.

  8. Enrico Solcia University of Pavia, Pavia, Italy Histological Typing of Endocrine Tumors (WHO) Springer 2000; pp1-160

  9. Neuroendocrine Tumors of the Gastrointestinal Tract : Annual Incidence 38.4 cases per million* % Vinik, A.I., Perry, R.R. Neoplasms of the Gastroenteropancreatic Endocrine System, Chapt 103. In: Cancer Medicine, Fourth ed. Vol. 1. Edited by Holland JF, et alBaltimore: Williams & Wilkins, pg. 1605-1641, 1997. Modified by T.M.O. to include Lung Carcinoid * Annals of Surgery 2004. Vol 240 (1): 117-122

  10. Carcinoid: Natural History Diagnosis Irritable Bowel Correct Diagnosis Death Vague abdominal symptoms Diarrhea Flushing Metastases Primary Tumor Growth 0 2 4 6 8 10 12 14 16 18 20 Years Vinik, Moattari Amer J Dig Dis, Sci , 1989;34:14-27.

  11. TTP = 3-5 yrs TTP = 3-4 yrs TTP = 7 mo TTP = 4-5 yrs

  12. IOWA NEUROENDOCRINE DATABASE ( INED ) • Database begun in 1996 with Denise Soble, RN, E.W. Martin, Jr., M.D., and TMO at Ohio State. • Captures Phenotypic Patient Information • 80 Fields of Data • Visits, diagnoses, pathology, radiology, outcomes, survival • Captures Genotype Patient data • FISH, Exome sequencing, GPCR expression https//net.eng.uiowa/mode/add/diagnosis2 Username is “user” Password is “quest”

  13. Problems with Neuroendocrine Tumor Therapeutic Intervention(s) • Decisions made primarily based on the “Gold Standard” CT, MR, Ultrasound demonstration of disease progression • Both “symptomatic” and “asymptomatic” changes are subjective and clinical signs, like art, are often in the eye of the beholder • Tumor-secreting amines and neuropeptides may be episodic initially & sustained later with tumor progression • In U.S., calibrations between neuropeptide plasma markers are sorely lacking between commercial labs

  14. Functioning Neuroendocrine Tumors Basic Principles: • Syndromes and symptoms (e.g., hypoglycemia) are due to sudden or sustained elevations of circulating amines (e.g. serotonin, catecholamine, or neuropeptides (e.g., insulin, VIP). • Documentation of elevated amines and neuropeptides should be done whenever possible.

  15. Carcinoid Tumors • Serotonin EOTA (Plasma + ascorbic acid) • most sensitive, episodic • Collection critical for preservation • 5-HIAA (5-hydroxy-indoleacetic acid, urine) formed by metabolism of serotonin by monoamine oxidase • Best measured by HPL (measure Creat as well) • Almost NEVER elevated without liver METS (usually 15-20% burden)

  16. Serotonin and Carcinoids • Mid-gut carcinoids are rich in serotonin containing granules and are frequently associated with carcinoid syndrome • Foregut carcinoids (Stomach, Lungs) have few serotonin granule • Hind-gut carcinoids have very few serotonin granules Modified: AC Deacon. Ann Clin Biochem 1994:31;215-232

  17. Chromogranin A (CgA) • Acidic, water soluble, secretory glycoprotein (ng/ml) • Stored in matrix of secretory granules of nervous & neuroendocrine cells / tumors • Cleared by prohormone convertase I (PC-1) to pancreastatin (pg/ml) • An accurate “marker” of neurocrine tumor burden and metastasis

  18. “Pearls” on Chromogranin A (CgA) • Try and stay with the same lab (five in US) • Is very helpful when you know you have a N/E tumor. • May be elevated when there is no actual N/E tumor • Severe hypertension • Gastric acid suppression (PPI’s) • Renal insufficiency

  19. Development of a Highly Sensitive and Specific Carboxy-terminal Human Pancreastatin Assay to Monitor Neuroendocrine Tumor Behavior TM O’Dorisio1, SR Krutzik2, EA Woltering3, E Lindholm3, S Joseph3, Y-Z Wang3, JP Boudreaux3, AI Vinik4, VLW Go5, JR Howe1, T Halfdanarson1, MS O’Dorisio1, G Mamikunian2 PANCREAS 39(5):611-616, 2010 University of Iowa Neuroendocrine Tumor Program

  20. 700 600 500 400 Marker in Appropriate Units 5-HIAA CGA Pancreastatin 300 200 100 0 4/13/2005 2/13/2007 2/13/2008 6/13/2005 4/13/2007 6/13/2007 8/13/2007 8/13/2005 4/13/2008 6/13/2008 8/13/2008 8/13/2006 2/13/2006 4/13/2006 6/13/2006 12/13/2007 10/13/2007 10/13/2008 10/13/2005 12/13/2005 10/13/2006 12/13/2006 12/13/2008 Date Results Sequential Marker Measurement PANCREAS 39(5):611-616, 2010

  21. Results Comparison of ISI vs URL Pancreastatin Values 1000000 ISI URL 100000 10000 Pancreastatin Value (pg/ml) 1000 100 10 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Subject Number PANCREAS 39(5):611-616, 2010

  22. Validation of Neurokinin A (NKA) Assays in the U.S. and Europe P. Mamikunian, J.E. Ardill, T.M. O’Dorisio…E.A. Woltering et al. Pancreas 2011;40(7):1000-1005

  23. Kaplan-Meier Survival Curve 1.0 0.5 0.0 NKA < 50 ng/L NKA > 50 ng/L Cumulative survival probability 0 24 48 72 96 Survival (Months) P. Mamikunian..E.A. Woltering Pancreas 2011, In press

  24. Biomarkers • CgA levels can reflect total tumor burden (when metastatic) for both pancreatic and mid-gut (ileal) N/E tumors • Neurokinin A may be a predictor for aggressive mid-gut (ileal) tumors • Pancreastatin may be a very early marker for liver tumor activity

  25. Evolution of Neuroendocrine Medical Therapy Dawn Wray Teresa Ruggle © University of Iowa

  26. Theranostics “Molecular targeting of VECTORS which can be used for both therapies and diagnosis, when modified accordingly… (it) embodies both molecular and personalized medicine.” Rosch, F, Baum R.P. Generator-based PET radiopharmaceuticals for molecular imaging of tumours: On the way to THERANOSTICS. Dalton Trans 2011; 40:6104-11.

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