Neuroendocrine Tumors: Endocrinology Insights

The Endocrinology of Neuro
ENDOCRINE Tumors
Thomas M. O’Dorisio, MD
HEALING NETs BOOT CAMP
Prepared by Dr. Thomas O'Dorisio, University of Iowa
Special note of thanks to Dr. O’Dorisio:
This presentation has been shared with Mia S. Tepper, MBA C.O.O. of
Inter Science Institute, Inc. (ISI) with written permission from Dr.
Thomas O’Dorisio at The University of Iowa, to copy slides shown here.
   
- November 2020
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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36 y/o male presented with three-year history of constant facial flush, 4-5
“loose stools” daily, R. flank pain, SOB
Liver biopsy (2012) established metastatic NET WHO Grade 1
OctreoScan (2012): Somatostatin receptor (SST2R) avid liver, nodal lesions
Cardiac Echo: (+) tricuspid and (+) pulmonary regurgitation
Surgery of primary tumor (2013): Dr. James R. Howe
CT Scan (5/21/2014): 60% liver tumor burden
S/P four cycles of PRRT (
177
Lu-DOTATATE)
Liver Transplant: 9/23/2017
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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* Mean of three values between January 2015 – April 2018
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Decisions made primarily based on the “Gold Standard” CT, MR,
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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 and sustained later with tumor progression
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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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.
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Prepared by Dr. Thomas O'Dorisio, University of Iowa
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* All functional Tumor Biomarkers are Patho-Hormonal when elevated
** VIP = Vasoactive Intestinal Peptide
PP – Pancreatic Peptide
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Most sensitive, episodic
Collection critical for preservation
Commercially available
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 (5-hydroxy-indoleacetic acid, urine) formed by
metabolism of serotonin by monoamine oxidase
Almost 
NEVER
 elevated without liver METs (usually 15-20% burden)
Plasma 5-HIAA correlates (R=0.8) with urine 5=HIAA
Pancreas 
2013:42(6):937-43
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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E.A. Woltering et al.
Pancreas 
2011;40(7):1000-1005
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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P. Mamikunian…E.A. Woltering.
Pancreas 
2011:40(7);1000-1005
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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TM O’Dorisio, et al. 
Pancreas 
2010:39(5);611-616
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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98 small bowel NETs: 78 pancreatic NETs
Event times estimated by Kaplan-Meier
Pre- and postoperative labs for correlation with outcomes
Multivariant Cox model adjusted for confounders
Sherman SK, Maxwell JE, O’Dorisio MS, O’Dorisio TM,
Howe JR. 
Ann Surg Oncol
 2014; 21:2971
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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98 small bowel NETs: 78 pancreatic NETs
Event times estimated by Kaplan-Meier
Pre- and postoperative labs for correlation with outcomes
Multivariant Cox model adjusted for confounders
Sherman SK, Maxwell JE, O’Dorisio MS, O’Dorisio TM,
Howe JR. 
Ann Surg Oncol
 2014; 21:2971
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Elevated preoperative PAN associated with shorter median PFS
and OS vs normal PAN
PFS 1.7 yrs vs 6.5 yrs vs median not reached
5 yr PFS 14.9% (high prePAN: 59% [normal PAN])
Normalization of post-op pancreastatin significantly improved PFS
and OS (3.9 yrs and 100%)
Elevated post-op pancreastatin, 5 yr PFS dropped to 8.6% and OS
decreased to 6.5 yrs
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Higher pancreastatin levels are significantly associated with
worse PFS and OS in SBNETs and PNETs
Independent of age, primary tumor site, and nodal or
metastatic disease
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Tran C., Sherman S., Scott A., Ear P., Chandrasekharan C.,
Belizzi A., Dillon J., O’Dorisio T., Howe, J.
Annals of Surgical Oncology 
2020
https://doi.org/10.1245/s10434-020-08784-0
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Ann Surg Oncol.
 2020. C. Tran
218 small bowel NETs (92% nodal; 73% metastatic)
Biomarkers: Serotonin (SER), CgA, NKA, Pancreastatin (PAN)
Assessed as categorical (Normal or Elevated) and continuous variable
Progression Free Survival (PFS) and Overall Survival (OS) via Kaplan-
Meier models adjusted for confounders
Serial CT/MR imaging confirmed progression
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Ann Surg Oncol.
 2020. C. Tran
High CgA, PAN, NKA, SER correlated with higher grade and metastatic
disease at presentation (p < 0.05)
Higher levels pre and post surgery of CgA, PAN, NKA, SER correlated
with LOWER PFS and OS (Median F/U 4 yrs)
Using Biomarkers to determine progression:
PAN showed superiority with 79% accuracy 
vs CgA (63% accuracy)
or PAN + CgA (60% accuracy)
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Ann Surg Oncol.
 2020. C. Tran
During long-term F/U, PAN accurately detected progression
PAN should replace CgA for small bowel surveillance
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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T.M. Khan, M. Gary, R. Warner, J.H. Uh, C.M. Divine
Pancreas
, 2015; 45:1032-1035
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77 Patients Retrospective:
 
44 (57%) Primary small bowel
 
49 (64%) Metastasis to liver
Metastatic Markers: Pancreastatin (PAN) and CgA
Sensitivity (%), Specificity (%)
Positive (%)/Negative (%) Predictive Value (PV)
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PAN
 
87% Sensitivity
 
(+) PV = 71%
 
(-) PV = 83%
CgA
 
62% Sensitivity
 
(+) PV = 64%
 
(-) PV = 41%
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ELEVATED SERUM PANCREASTATIN:
Sensitive and specific assay for detecting incidence of
metastatic small bowel NETs
Routine measurement of PAN in small bowel NETs is
supported
B
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M
A
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K
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CgA levels can reflect total tumor burden (when metastatic) for
both pancreatic and mid-gut (ileal) N/E tumors
Neurokinin A is a 
predictor
 for aggressive mid-gut (ileal) tumors
Pancreastatin may be a very 
early
 marker for liver tumor activity
and predicts 
PFS, OS, and Progression
Prepared by Dr. Thomas O'Dorisio, University of Iowa
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Delve into the complex world of neuroendocrine tumors (NETs) through a detailed presentation prepared by Dr. Thomas O'Dorisio from the University of Iowa. Explore case reports, therapeutic interventions, and the challenges associated with managing these tumors. Gain valuable insights into the functioning of NETs and their impact on patients.

  • Neuroendocrine Tumors
  • Endocrinology
  • Oncology
  • Medical Imaging
  • Therapeutic Interventions

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  1. The Endocrinology of Neuro ENDOCRINE Tumors Thomas M. O Dorisio, MD HEALING NETs BOOT CAMP Prepared by Dr. Thomas O'Dorisio, University of Iowa

  2. Special note of thanks to Dr. ODorisio: This presentation has been shared with Mia S. Tepper, MBA C.O.O. of Inter Science Institute, Inc. (ISI) with written permission from Dr. Thomas O Dorisio at The University of Iowa, to copy slides shown here. - November 2020 Prepared by Dr. Thomas O'Dorisio, University of Iowa

  3. PATIENT M.D.G. PATIENT M.D.G. 36 y/o male presented with three-year history of constant facial flush, 4-5 loose stools daily, R. flank pain, SOB Liver biopsy (2012) established metastatic NET WHO Grade 1 OctreoScan (2012): Somatostatin receptor (SST2R) avid liver, nodal lesions Cardiac Echo: (+) tricuspid and (+) pulmonary regurgitation Surgery of primary tumor (2013): Dr. James R. Howe CT Scan (5/21/2014): 60% liver tumor burden S/P four cycles of PRRT (177Lu-DOTATATE) Liver Transplant: 9/23/2017 Prepared by Dr. Thomas O'Dorisio, University of Iowa

  4. CASE REPORT CASE REPORT PT. M.D.G. PT. M.D.G. 36 y/o, M: Carcinoid tumor syndrome with METs to liver Pre-Liver Transplant* Post-Liver Transplant* 3/3/2020 Serotonin 1,975 249 217 CgA 2,111 118 160 (Nl < 160) Pancreastatin 15,251 61 95 NK A 953 28 31 Subst P 1,292 109 198 * Mean of three values between January 2015 April 2018 Prepared by Dr. Thomas O'Dorisio, University of Iowa

  5. PROBLEMS WITH NEUROENDOCRINE TUMOR PROBLEMS WITH NEUROENDOCRINE TUMOR THERAPEUTIC INTERVENTION(S) 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 and sustained later with tumor progression Prepared by Dr. Thomas O'Dorisio, University of Iowa

  6. FUNCTIONING NEUROENDOCRINE TUMORS 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. Prepared by Dr. Thomas O'Dorisio, University of Iowa

  7. BIOMARKERS AND NEUROENDOCRINE TUMORS BIOMARKERS AND NEUROENDOCRINE TUMORS TUMOR BIOMARKERS [Serotonin] CgA Pancreastatin Neurokinin A (Substance P) [CgA] Pancreastatin Serotonin (3-5%) Substance P (?) PP [CgA Pancreastatin] Carcinoid, Sm. Intest (Mid-Gut) Carcinoid, Lung (Fore-Gut) N/E Pancreas (Fore-Gut) Non-functional (70%) Functional (30%) PP, Calcitonin Serotonin (?) Insulin, Gastrin, etc Prepared by Dr. Thomas O'Dorisio, University of Iowa

  8. BIOMARKERS, REGULATORY FUNCTION, ACUTE BIOMARKERS, REGULATORY FUNCTION, ACUTE- -CHRONIC EXCESS CHRONIC EXCESS BIOMARKER FUNCTION* ACUTE EXCESS CHRONIC EXCESS Serotonin Hormone Hypotension, Tinnitus, Flush Diarrhea, Perspiration Subst P Neuro-Mod Flush, Hypotension Secret Diarrhea Gastrin Hormone Flush, Reflux Atyp Ulcers, Rugal Thick Insulin Hormone Sympt Hypoglyce Neuroglycopenia Glucagon Hormone Hyperglycemia Dermopathy, Wt Loss, DVT VIP** Neuro-Mod Hypotension, Flush Watery Diarrhea Syndrome PP Hormone None None Somatostatin Multi-Regul None/hypoglyce Fat Malab, Gallstones * All functional Tumor Biomarkers are Patho-Hormonal when elevated ** VIP = Vasoactive Intestinal Peptide PP Pancreatic Peptide Prepared by Dr. Thomas O'Dorisio, University of Iowa

  9. CARCINOID TUMORS CARCINOID TUMORS Small Bowel (mid gut) Small Bowel (mid gut) Serotonin EDTA (Plasma + ascorbic acid) Most sensitive, episodic Collection critical for preservation Commercially available 5-HIAA (5-hydroxy-indoleacetic acid, urine) formed by metabolism of serotonin by monoamine oxidase Almost NEVER elevated without liver METs (usually 15-20% burden) Plasma 5-HIAA correlates (R=0.8) with urine 5=HIAA Pancreas 2013:42(6):937-43 Prepared by Dr. Thomas O'Dorisio, University of Iowa

  10. VALIDATION OF NEUROKININ A (NKA) ASSAYS VALIDATION OF NEUROKININ A (NKA) ASSAYS IN THE U.S. AND EUROPE 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 Prepared by Dr. Thomas O'Dorisio, University of Iowa

  11. KAPLAN KAPLAN- -MEIER SURVIVAL CURVE MEIER SURVIVAL CURVE 1.0 NKA < 50 ng/L NKA > 50 ng/L Cumulative survival probability 0.5 0.0 0 24 48 72 96 P. Mamikunian E.A. Woltering. Pancreas 2011:40(7);1000-1005 Survival (Months) Prepared by Dr. Thomas O'Dorisio, University of Iowa

  12. SEQUENTIAL MARKER SENSITIVITY OF PANCREASTATIN SEQUENTIAL MARKER SENSITIVITY OF PANCREASTATIN 700 Marker in Appropriate Units 600 500 400 5-HIAA CGA Pancreastatin 300 200 100 0 12/13/2007 4/13/2005 12/13/2008 10/13/2007 2/13/2007 10/13/2008 2/13/2008 6/13/2005 8/13/2008 4/13/2007 6/13/2007 8/13/2007 10/13/2005 12/13/2005 10/13/2006 12/13/2006 8/13/2005 4/13/2008 6/13/2008 8/13/2006 2/13/2006 4/13/2006 6/13/2006 Date TM O Dorisio, et al. Pancreas 2010:39(5);611-616 Prepared by Dr. Thomas O'Dorisio, University of Iowa

  13. PANCREASTATIN PREDICTS SURVIVAL IN PANCREASTATIN PREDICTS SURVIVAL IN NEUROENDOCRINE TUMOR PATIENTS NEUROENDOCRINE TUMOR PATIENTS 98 small bowel NETs: 78 pancreatic NETs Event times estimated by Kaplan-Meier Pre- and postoperative labs for correlation with outcomes Multivariant Cox model adjusted for confounders Sherman SK, Maxwell JE, O Dorisio MS, O Dorisio TM, Howe JR. Ann Surg Oncol 2014; 21:2971 Prepared by Dr. Thomas O'Dorisio, University of Iowa

  14. PANCREASTATIN PREDICTS SURVIVAL IN PANCREASTATIN PREDICTS SURVIVAL IN NEUROENDOCRINE TUMOR PATIENTS NEUROENDOCRINE TUMOR PATIENTS 98 small bowel NETs: 78 pancreatic NETs Event times estimated by Kaplan-Meier Pre- and postoperative labs for correlation with outcomes Multivariant Cox model adjusted for confounders Sherman SK, Maxwell JE, O Dorisio MS, O Dorisio TM, Howe JR. Ann Surg Oncol 2014; 21:2971 Prepared by Dr. Thomas O'Dorisio, University of Iowa

  15. RESULTS (2) RESULTS (2) ( (Ann Surg Oncol Ann Surg Oncol 2014; 21:2971) 2014; 21:2971) Elevated preoperative PAN associated with shorter median PFS and OS vs normal PAN PFS 1.7 yrs vs 6.5 yrs vs median not reached 5 yr PFS 14.9% (high prePAN: 59% [normal PAN]) Normalization of post-op pancreastatin significantly improved PFS and OS (3.9 yrs and 100%) Elevated post-op pancreastatin, 5 yr PFS dropped to 8.6% and OS decreased to 6.5 yrs Prepared by Dr. Thomas O'Dorisio, University of Iowa

  16. CONCLUSION CONCLUSION ( (Ann Surg Oncol Ann Surg Oncol 2014; 21:2971) 2014; 21:2971) Higher pancreastatin levels are significantly associated with worse PFS and OS in SBNETs and PNETs Independent of age, primary tumor site, and nodal or metastatic disease Prepared by Dr. Thomas O'Dorisio, University of Iowa

  17. IT IS TIME TO RETHINK BIOMARKERS FOR IT IS TIME TO RETHINK BIOMARKERS FOR SURVEILLANCE OF SMALL BOWEL NETs SURVEILLANCE OF SMALL BOWEL NETs Tran C., Sherman S., Scott A., Ear P., Chandrasekharan C., Belizzi A., Dillon J., O Dorisio T., Howe, J. Annals of Surgical Oncology 2020 https://doi.org/10.1245/s10434-020-08784-0 Prepared by Dr. Thomas O'Dorisio, University of Iowa

  18. SUBJECTS AND METHODS SUBJECTS AND METHODS Ann Surg Oncol. 2020. C. Tran 218 small bowel NETs (92% nodal; 73% metastatic) Biomarkers: Serotonin (SER), CgA, NKA, Pancreastatin (PAN) Assessed as categorical (Normal or Elevated) and continuous variable Progression Free Survival (PFS) and Overall Survival (OS) via Kaplan- Meier models adjusted for confounders Serial CT/MR imaging confirmed progression Prepared by Dr. Thomas O'Dorisio, University of Iowa

  19. RESULTS RESULTS Ann Surg Oncol. 2020. C. Tran High CgA, PAN, NKA, SER correlated with higher grade and metastatic disease at presentation (p < 0.05) Higher levels pre and post surgery of CgA, PAN, NKA, SER correlated with LOWER PFS and OS (Median F/U 4 yrs) Using Biomarkers to determine progression: PAN showed superiority with 79% accuracy vs CgA (63% accuracy) or PAN + CgA (60% accuracy) Prepared by Dr. Thomas O'Dorisio, University of Iowa

  20. CONCLUSION CONCLUSION Ann Surg Oncol. 2020. C. Tran During long-term F/U, PAN accurately detected progression PAN should replace CgA for small bowel surveillance Prepared by Dr. Thomas O'Dorisio, University of Iowa

  21. ELEVATED SERUM PANCREASTATIN IS AN INDICATOR ELEVATED SERUM PANCREASTATIN IS AN INDICATOR OF HEPATIC METASTASIS IN PATIENTS WITH SMALL OF HEPATIC METASTASIS IN PATIENTS WITH SMALL BOWEL NEUROENDOCRINE TUMORS BOWEL NEUROENDOCRINE TUMORS T.M. Khan, M. Gary, R. Warner, J.H. Uh, C.M. Divine Pancreas, 2015; 45:1032-1035

  22. PATIENTS AND METHODS PATIENTS AND METHODS 77 Patients Retrospective: 44 (57%) Primary small bowel 49 (64%) Metastasis to liver Metastatic Markers: Pancreastatin (PAN) and CgA Sensitivity (%), Specificity (%) Positive (%)/Negative (%) Predictive Value (PV) RESULTS RESULTS PAN CgA 87% Sensitivity 62% Sensitivity (+) PV = 71% (+) PV = 64% (-) PV = 83% (-) PV = 41%

  23. CONCLUSION CONCLUSION ELEVATED SERUM PANCREASTATIN: Sensitive and specific assay for detecting incidence of metastatic small bowel NETs Routine measurement of PAN in small bowel NETs is supported

  24. BIOMARKERS BIOMARKERS CgA levels can reflect total tumor burden (when metastatic) for both pancreatic and mid-gut (ileal) N/E tumors Neurokinin A is a predictor for aggressive mid-gut (ileal) tumors Pancreastatin may be a very early marker for liver tumor activity and predicts PFS, OS, and Progression Prepared by Dr. Thomas O'Dorisio, University of Iowa

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