EXOCRINE: 93% Acinar Cells Duct Cells. ENDOCRINE: 5% Alpha Cells Beta Cells Delta Cells Others

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2 EXOCRINE: 93% Acinar Cells Duct Cells Digestive Enzymes Trypsin: Digests Proteins Lipases: Digests Fats Amylase: Digest Carbohydrates ENDOCRINE: 5% Alpha Cells Beta Cells Delta Cells Others Hormones Glucagon Insulin Somatostatin Gastrin, VIP

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5 Y1973 Y1975 Y1977 Y1979 Y1981 Y1983 Y1985 Y1987 Y1989 Y1991 Y1993 Y1995 Y1997 Y1999 Y2001 Y2003 Y2005 Y2007 Y2009 Y2011 Y2013 Incidence per 100K Age-adjusted Neuroendocrine Tumor Incidence with Trend Projection Line, SEER 18 Year Yao et al. J Clin Oncol 2008; 26:

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7 Vague abdominal symptoms Death Diarrhea Flushing Metastases Primary tumor Time Vinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.

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9 Localized Distant Regional Flushing No sweating First sip of alcohol 27% 24% 50% Diarrhea Especially nocturnal Wheezing Irritable bowel syndrome Bloating Yao JC et al. J Clin Oncol. 2008;26:

10 Std Arterial Venous Delayed

11 CT & MRI The ability to pick up extrapancreatic Dz

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13 General NET markers Chromogranin A Affected by somatostatin analogues, proton pump inhibitors, kidney function, liver function Neuron-specific enolase Midgut (small bowel, appendix, cecum) 5 HIAA (24-hr urine collection) Serotonin (blood, more variable) 5-HIAA = 5-hydroxyindoleacetic acid

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15 Fasting measurements when possible Gastrinoma Glucagonoma Insulinoma VIPoma Insulin Gastrin Glucagon Pro-insulin Vasoactive intestinal peptide C-peptide

16 Gastrinoma Triangle

17 Lots of markers; expression can change over time Chromogranin B and C, pancreastatin, substance P, neurotensin, neurokinin A, pancreatic polypeptide Take large panel of markers at key points Diagnosis or relapse Follow a few elevated markers over time Not necessary to check every marker at each visit

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20 Gagandeep Singh, MD Yuman Fong, MD Susanne Warner, MD Laleh Melstrom, MD Lucille Leong, MD Daneng Li, MD Vincent Chung, MD Joseph Chao, MD Marwan Fakih, MD John Williams, PhD David Colcher, PhD Jack Shively, PhD Paul Yazaki, PhD James Lin, MD Donald David, MD John Park, MD Jonathan Kessler, MD Aram Lee, MD YJ Chen, MD Jeff Wong, MD N Vora, MD

21 The first question we ask ourselves is- are the tumors surgically resectable?" SURGERY IS THE GOLD STANDARD WHEN POSSIBLE Somatostatin analogs mtor inhibitors Chemotherapy for pancreatic NETs Regional therapy approaches

22 Locate and resect primary p/net or Carcinoid Imaging & Tumor Markers Resect Mesenteric Nodal Masses Resecting Liver Metastases Remove the Gall Bladder Be prepared for Carcinoid Crisis

23 Distal Pancreatectomy with Splenectomy 30% Central Pancreatectomy Total Pancreatectomy 5% Whipple Pancreatoduodenectomy 65% Classic Pylorus Preserving

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30 R e s e c t i o n o f P r i m a r y T u m o r U n r e s e c t a b l e M e t a s t a s e s Retrospective review of 84 patients with abdominal carcinoids and proven liver mets 60 patients had removal of primary alone Median PFS 56 months in resected vs. 26 months in unresected (p<0.001) Median OS not reached in resected vs. 47 months in unresected (p<0.001) Givi and Pommier, Surgery, 2006

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33 Presented at Society of Surgical Oncology 2016 n= 864 Stage 4 California Cancer Registry Primary Removed Survival by Primary Site without Liver Treatment Primary Removed Primary Untouched Primary Untouched PTR Primary Removed Primary Removed Primary Untouched Primary Untouched Aaron Lewis, MD, Michael White MD Gagandeep Singh MD

34 Presented at Society of Surgical Oncology 2016 n= 864 Stage 4 California Cancer Registry Primary Removed Primary Untouched A Lewis, M White G Singh MD

35 LIVER FAILURE- from tumor burden Irresolvable bowel obstruction

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37 March 12 th, 2007

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44 Disease progression pnet Functional Nonfunctional Carcinoid syndrome Octreotide LAR + chemotherapy Chemotherapy Octreotide LAR Liver Directed Therapies Hepatic artery embolization Investigational agents Carcinoid Midgut No syndrome Non-midgut No syndrome No standard No standard (No approved therapies available) LAR = long-acting release; pnet = pancreatic NET

45 9-39% Response Rate

46 5 years later s/p Distal Pancreatectomy Radioembolization x2

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48 Presented at Society of Surgical Oncology 2016 Overall Survival by Treatment Type n= 3919 California Cancer Registry p< A Lewis, M White, J Kessler, G Singh

49 Somatostatin receptor Peptide receptor radiotherapy (PRRT) Angiogenesis Inhibitors mtor Inhibitors mtor = mammalian target of rapamycin

50 Somatostatin receptors highly expressed by NETs Targeting SST receptors can provide symptom and disease control New targets could change treatment paradigm mtor, PI3K, VEGF inhibitors Other antiangiogenic agents High potential for combinations PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor

51 111 In pentetreotide Systemic radiotherapy targeting somatostatin receptors 111 In DTPA-CO-NH-D-Phe-Cys S Phe D-Trp S Lys Thr(ol)-Cys Thr 90 Y DOTATOC Compounds vary by isotope and carrier molecule RR from (N = 90): 4.4%- 24% 90 Y DOTA-CO-NH-D-Phe-Cys S S Thr(ol)-Cys Tyr Thr D-Trp Lys 177 Lu DOTATATE 177Lu DOTATATE1 and 90Y DOTATOC2: promising results in phase 2 studies 177 Lu DOTA-CO-NH-D-Phe-Cys S S Thr-Cys Tyr Thr D-Trp Lys 177 Lu-DOTATATE: 177 Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid 0 (DOTA), Tyr 3 -octreotate; 90 Y DOTATOC: [90Y-DOTA]-D- Phe1-Tyr3-octreotide. 1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26: Waldherr C et al. Ann Oncol. 2001;12:

52 N = GBq in 4 cycles Efficacy in 310 pts, NOT ITT RR: 30% Median TTP: 40 months PRRT clearly active; strong need for rigorous phase 3 study- in progress ITT = intent-to-treat; RR = response rate; TTP = time to progression Imaging studies property of James Yao, MD. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:

53 SURGERY IS THE GOLD STANDARD DEBULK WHEN POSSIBLE- Definite Survival Advantage Somatostatin analogs effective in controlling hormonal syndrome PROMID suggests octreotide LAR controls tumor growth in midgut carcinoids Confirmatory phase 3 RADIANT Trials have established the Efficacy of Everolimus in Advanced NETs Look Forward to the Results of PRRT

EXOCRINE: 93% Acinar Cells Duct Cells. ENDOCRINE: 5% Alpha Cells Beta Cells Delta Cells Others

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