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Abstracts Presented at the 5th Annual Meeting of the North American NeuroEndocrine Tumor Society, October 11–13, 2012, San Diego, California

doi: 10.1097/MPA.0b013e31828543d9
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Laboratory Diagnosis of Gastrinoma Remains Difficult

Joy Ardill,1 Lee Armstrong,1 Brian Johnston,2 David McCance.21NET Group & Regional Regulatory Peptide Laboratory, Royal Victoria Hospital Belfast BT12 6BA, N Ireland, United Kingdom; 2NET Group, Royal Victoria Hospital Belfast BT12 6BA, N Ireland, United Kingdom.

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Background

Clinical diagnosis of gastrinoma remains problematic in a significant number of patients due to other common conditions associated with hypergastrinaemia. Those with excessive circulating gastrin include gastrinoma and those where the negative feedback of gastric acid is absent, specifically patients with atrophic gastritis and those on proton pump inhibitory (ppi) therapy. In addition patients visiting outpatient clinics are not fasted.

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Methods

We have collated data from routine measurement of gastrin in subjects with gastrinoma, auto-immune atrophic gastritis (AIAG), patients ppi therapy, H-pylori (Hp) +ve duodenal ulcer (DU), Hp+ healthy controls, Hp- healthy controls after an overnight fast or post-prandially. Gastrin was assayed in plasma using an antibody (R98) directed towards the C-terminal of gastrin 17 that detects G-17 and G-34 in equimolar quantities. In addition antisera to the N-terminus of G-17 and antisera to the N-terminus of G-34 were used. N=50 in each fasting group and N=25 in each group post-prandially. Post-prandial specimens were collected 2 hours after a standard protein meal. Chromogranin A (CgA) was measured in selected specimens from each group.

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Results

Fasting reference range (RR) for gastrin (R98) is 0–45pmol/L. Results are given in pmol/L as medians (with range). In the gastrinoma group gastrin was 267 (57–31,857) giving complete overlap with AIAG, 545 (55-21,429). 12 % of gastrinoma patients presented with gastrin <70 and 24% with gastrin <200pmol/L, with ppi therapy 41 (7–262) (40%>RR), in DU Hp+ 36 (8–242) (25%>RR), in control Hp+ 24 (10–105) (14%>RR) and in control Hp- 19 (2–38) (all within RR). Use of regional specific antisera did not clarify diagnosis neither did CgA measurement.

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Conclusions

An antiserum which detects G17 and G34 should be used for routine clinical determination of gastrin. Diagnosis of gastrinoma is not confirmed chemically without specific additional information. As interpretation is complex experience is required.

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Neurokinin A is a Sensitive Circulating Biomarker for Neuroendocrine Tumours of the Midgut. Audit of 1000 Consecutive Raised NKA Results in a Routine Regulatory Peptide Laboratory

Joy Ardill,1 Lee Armstrong,1 David McCance,2 Brian Johnston.21NET Group & Regional Regulatory Peptide Laboratory, Royal Victoria Hospital Belfast BT12 6BA, N Ireland, United Kingdom; 2NET Group, Royal Victoria Hospital Belfast BT12 6BA, N Ireland, United Kingdom.

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Background

Chromogranin A (CgA) is the only general circulating biomarker for neuroendocrine tumours (NETs). The breakdown product of serotonin, urinary 5 hydroxy indole acetic acid (5HIAA) is used to confirm tumours of the midgut (MGC) Serotonin and therefore 5HIAA are frequently raised in lung NETs. Dietary precautions are required for measurement of serotonin and 5HIAA. We use circulating Neurokinin A as a diagnostic tool for MGC.

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Methods

One thousand consecutive specimens with raised NKA, from patients were audited. Where CgA had also been measured, results were recorded and where urinary 5HIAA had been measured within 4 weeks of the NKA specimen 5HIAA results were recorded. Diagnosis of NET confirmed by tissue pathology was recorded. All NKA results reported above the reference range (RR) request repeat testing or referral to NET clinic.

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Results

Of the 1,000 specimens, 743 were from patients with confirmed MGC, these corresponded to 124 individuals (Table 1). Of the 200 specimens where diagnosis was unconfirmed, 3 had renal failure, 28 patients had repeat NKA testing falling within the RR and 74 were tested for urinary 5HIAA and were within RR. Remaining specimens related to 45 individuals 6 with NKA >30ng/l. CgA was available for 932 specimens. From NET patients, 29 had CgA within the RR. Urinary 5HIAA was tested in 316 specimens, 38 of these from patients with MGC were within the RR.

TABLE 1

TABLE 1

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Conclusions

NKA is an excellent diagnostic tool for MGC, repeat testing for specimens recording <30ng/l is advised.

Patients with advanced pancreatic NETs may test positive when their tumour is multi-hormone secreting.

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Neurokinin A is a Sensitive Prognostic Indicator for Neuroendocrine Tumours of the Midgut and is Useful to the Clinician When Considering Treatment Options

Joy Ardill,1 Lee Armstrong,1 David McCance,2 Brian Johnston.21NET Group & Regional Regulatory Peptide Laboratory, Royal Victoria Hospital Belfast BT12 6BA, N Ireland, United Kingdom; 2NET Group, Royal Victoria Hospital Belfast BT12 6BA, N Ireland, United Kingdom.

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Background

Endocrine tumours of the midgut (MGC) are the most common NETs comprising 30% of the total. In addition to serotonin they produce tachykinins including neurokinin A (NKA). NKA is readily measured in the circulating. We have published a retrospective study of MGC, in which NKA was the only independent prognostic indicator and the most recent NKA was shown to be the most sensitive prognostic indicator (N=125). Therapeutic options for these patients are increasing and treatments lower circulating NKA, suggesting survival can be improved.

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Methods

Since 2002 at the specialist NET clinic in Belfast all newly diagnosed and referred patients with the diagnosis MGC received standard work up which included measurement of circulating CgA, NKA and 24hour urinary 5HIAA. Treatment options were discussed at the multidisciplinary meeting and best option pathway was followed. NKA and CgA were measured at regular intervals post treatment, timing depending on the therapeutic pathway chosen and stability of disease. Patients continued to receive treatment in response to tumour load, symptoms, and rising NKA as appropriate. Options included surgery, hepatic targeted therapies, systemic therapies including interferon alpha. Somatostatin analogues were used in all patients.

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Results

In the retrospective study median three year survival was 53%. When divided into tertiles according to circulating NKA concentration at presentation, 3 year survival was 88% (NKA <20ng/L), 66% (NKA 20–63ng/L) and 12% (NKA >63ng/L), 5 year survival was,88%, 58% and 0% respectively.

In the ongoing prospective study median three year survival is 70%. When this group was divided as above, 3 year survivals are 100%, 67% and 47% and 5 year survivals 93%, 70% and 49% respectively.

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Conclusions

Circulating NKA is a sensitive prognostic indicator for MGC and is useful for the clinician. This study is showing significant survival improvement when NKA is used in therapeutic decision making.

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Sustained Response to Alpha Interferon in a Patient with an Advanced Metastatic Serotonin Secreting Endocrine Tumour - Case Report

Joy Ardill,1 Lee Armstrong,1 Brian Johnston,2 David McCance.21NET Group & Regional Regulatory Peptide Laboratory, Royal Victoria Hospital Belfast BT12 6BA, N Ireland, United Kingdom; 2NET Group, Royal Victoria Hospital Belfast BT12 6BA, N Ireland, United Kingdom

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Case Report

This 52- year old lady presented in 2001 at a GI clinic complaining of occasional abdominal cramps sometimes severe and prolonged. Symptoms were not associated with diarrhoea or constipation. Weight loss of 4.5Kg over 4 months was noted. Coeliac disease was excluded and a diagnosis of irritable bowel was made.

In January 2002 she represented with further weight loss (total 8Kg), cyclical symptoms of diarrhoea lasting 3–5 days and occasional flushing. Neuroendocrine tumour markers were measured. Urinary 5HIAA was grossly elevated at 637 (Reference Range RR10–47), 5HT 12.05 (RR 0.30–1.30), pancreastatin (PST) >1,000ng/L (RR 0–50) and neurokinin A (NKA), 350ng/L (RR 0–20). CT and Octreotide scintigraphy showed extensive hepatic metastases with para-aortic and iliac lymphadenopathy. No primary tumour was identified. The surgical team considered hepatic disease, inoperable.

Treatment with somatostatin analogues was commenced. Symptoms continued, urinary 5HIAA remained grossly elevated and PST and NKA rose dramatically (9300ng/L and 4500ng/L respectively). Somatostatin analogue dose was increases twice without improvement. Alpha interferon concomitant with somatostatin analogues, was commenced 1.5 MU 3 times weekly increasing to 9MU 3 times weekly. Within 2 months symptoms eased and this regimen was continued. By 6 months symptoms had abated. Urinary 5HIAA settled around the upper limit of normal and 5HT returned within RR. Circulating NKA was secured below 100ng/L within a year and was maintained thereafter at 40–80ng/L. Both PST and Chromogranin A remained >10 times RR. Radiology showed stable/reduced disease.

Due to symptoms of migraine and fatigue, interferon dose was reduced occasionally and the drug was withdrawn for short periods. This resulted in an immediate rise in NKA. In the summer of 2010 the patient decided to discontinue interferon and received three cycled of Yttrium 90 PRRT. She declined gradually and died in June 2011. Survival, post diagnosis was 10 years 5 months.

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An Expert Panel Consensus on Medical Treatment of Non-Midgut Unresectable Neuroendocrine Tumors

Al B. Benson,1 Jonathan R. Strosberg,2 George A. Fisher,3 Jennifer L. Malin,4 Lowell B. Anthony,5 Bulent Arslan,6 John F. Gibbs,7 Edward Greeno,8 Renuka V. Iyer,9 Michelle K. Kim,10 William J. Maples,11 Philip. A. Philip,12 Edward M. Wolin,13 Dasha Cherepanov,14 Michael S. Broder.141Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; 2Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 3Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA; 4David Geffen School of Medicine, University of California, Los Angeles, CA; 5Department of Internal Medicine, Division of Medical Oncology, University of Kentucky Markey Cancer Center, Lexington, KY; 6Rush University Medical Center, Chicago, Illinois; 7Department of Surgery, State University of New York at Buffalo, Buffalo, NY; 8Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN; 9Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY; 10Department of Medicine - Gastroenterology Mount Sinai School of Medicine, New York, NY; 11Mission Health System, Asheville, NC; 12Department of Oncology, Karmanos Cancer Institute, Detroit, MI; 13Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA; 14Partnership for Health Analytic Research, LLC, Beverly Hills, CA.

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Background

Gastrointestinal neuroendocrine tumors (NETs) are rare and current treatment guidelines lack specificity in some clinical areas. We present a panel consensus on medical treatment of well-differentiated (grade 1–2 tumors) unresectable non-pancreatic non-midgut NETs.

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Methods

NET treatment appropriateness ratings were collected using the RAND/UCLA Delphi process. We recruited physician experts (criteria: specialty, geography, practice), reviewed NET treatment literature, and collected 2 rounds of ratings (before and after a face-to-face meeting) from the experts. Experts and the moderator were blinded to the funding source. Patient scenarios (rated on a 1–9 scale indicating appropriateness of various interventions for a given scenario) were labeled as appropriate, inappropriate, or uncertain. Scenarios with >2 ratings from 1–3 and >2 from 7–9 range were considered to have disagreement and were not assigned an appropriateness rating.

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Results

Ten panelists had a mean age of 50.4 years. Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology, and all practices were affiliated with academic institutions. Panelists had practiced between 6–33 years. Among 202 non-midgut rated scenarios, disagreement decreased from 16.2% (32 scenarios) before the meeting to 3% (6) after. In the 2ndround, 42.1% (85 scenarios) were rated inappropriate, 34.2% (69) were uncertain, and 20.8% (42) were appropriate. Consensus statements from the scenarios include:

1) observation is appropriate in patients with no symptoms and low-volume radiographically-stable disease, 2) somatostatin analogs may be appropriate in patients with secretory symptoms, and 3) everolimus or interferon-α can be considered in patients who progressed radiographically or symptomatically on somatostatin analogs.

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Conclusion

We obtained appropriateness ratings of variety medical therapies in NETs from expert physicians. The Delphi process enabled participants to systematically quantify their assessment of the literature in a valid and reliable way while improving overall panel consensus on the appropriateness of medical therapies in non-midgut NETs.

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Microarray Immunoassay Development to Specifically Detect Autoantibodies in Small Intestine Neuroendocrine Tumor (SI-NET) Patients

Joakim Bergstrom,1 Tao Cui,2 Su-Chen Li,2 Kjell Öberg,2,3 Mats Nystrand,4 Valeria Giandomenico2,31Institute of Biotechnology, Uppsala University, Uppsala, Sweden; 2Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 3Endocrine Oncology Clinic, Uppsala University-Hospital, Uppsala, Sweden; 4Mats Nystrand, Phadia AB, Uppsala, Sweden.

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Background

The majority of small intestine neuroendocrine tumor (SI-NET) patients get late diagnosis and metastatic SI-NETs lack of curative treatments. The unmet demand for primary SI-NETs identification requires novel biomarkers. Our study investigated autoantibodies, towards specific SI-NET-associated-antigens to detect potential novel diagnostic circulating serum biomarkers.

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Methods

The ImmunoCAP ISAC platform (Phadia-AB, Uppsala, Sweden) is an allergy diagnostic tool. This relies on multiplexing-technology/protein-microarrays for serum or plasma IgE antibodies detection. Our novel assay to measure SI-NETs autoantibodies uses this platform. We spotted 26 SI-NET-associated-antigens on an activated-glass-chip. Fluorescently-labeled secondary-antibodies towards specific human immunoglobulin-isotypes detected SI-NETs autoantibodies.

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Results

The main finding of this study shows that the ImmunoCAP ISAC is a suitable platform to detect SI-NET patient autoantibodies. The power of this platform is the generation of an immense data amount by using about 30µ1 of serum for each sample. The pilot test confirmed the assay capacity to detect different presence of SI-NET patients autoantibodies compared to healthy donors, by using 20 samples. In addition, it showed that the majority of autoantibodies were IgG1 and IgG4 isotypes. Thus, a randomized and blinded study privileged the study of these isotypes. The study included 120 samples (30 healthy donors and 90 SI-NET patients, at different stage of disease) confirmed the initial findings. The broader analyses showed the presence of differences between healthy donors and patients regarding the presence of protein component specific autoantibodies of the IgG1and IgG4 isotypes. Furthermore, chromogranin A, paraneoplastic antigen Ma2 and several tumor associated antigens displayed high levels of IgG4. Moreover, the presence of IgG4 autoantibodies is specifically observed only in the SI-NET patient group.

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Conclusion

This study investigated whether specific autoantibodies towards SI-NET-associated-antigens are potential circulating biomarkers, by using ImmunoCAP ISAC multiplexing platform. Our findings, support that SI-NET autoantibodies might be developed as novel biomarkers for tumor diagnostics.

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Description of Initial Treatment for Newly Diagnosed Metastatic Carcinoid (cNET) and Pancreatic Neuroendocrine (pNET) Patients

Sarah Bobiack, PhD,1 Michael A. Choti, MD,2 Al B. Benson III, MD,3 Jonathan R. Strosberg, MD,4 P. Mark Bloomston, MD,5 Emily K. Bergsland, MD,6 Carrie C. Zornosa, MSPH,1 Matthew H. Kulke, MD,7 Eric K. Nakakura, MD,6 Manisha H. Shah, MD,5 James C. Yao, MD.81National Comprehensive Cancer Network, Fort Washington, PA 19034; 2The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287; 3Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611; 4H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612; 5The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, Columbus, OH 43210; 6UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143; 7Dana Farber Cancer Institute, Boston, MA 94143; 8The University of Texas MD Anderson Cancer Center, Houston, TX 77030.

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Background

There is limited information on treatment patterns for NET from clinical practice. This analysis describes initial treatment patterns among NET patients.

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Methods

The National Comprehensive Cancer Network (NCCN) Oncology Outcomes Database was queried to identify newly diagnosed patients presenting to seven NCCN institutions with a confirmed metastatic cNET or pNET in 2004–2005. Patients with at least 5-years of follow-up or confirmed death were included. Demographics, clinical characteristics, initial treatment, and 5-year survival were described.

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Results

Among 187 cNET patients, 52% were male, median age at diagnosis was 58, and 51% alive; 58% had a known primary tumor; 65% of which was small bowel. Most cNET patients (85%) presented with symptoms, 33% had carcinoid syndrome. Initial treatment included surgical therapy (43%), drug therapy (41%), and other therapies (16%). 82% had imaging prior to treatment; 79% had a CT and 35% had somatostatin receptor scintigraphy (SRS). CGA was the most common biomarker test; performed in 64 pts, elevated in 53. Of 76 cNET patients receiving drug therapy, 82% were treated with a somatostatin analog (SA). Kaplan-Meier (K-M) curves indicated a 62% 5-year survival among surgery patients and 56% among drug therapy patients. Among 104 pNET patients, 61% were male, median age at diagnosis was 54, and 41% alive. 82% presented with symptoms, among which 25% were hormone related. Among the 84% of patients imaged prior to treatment, CT (79%) and SRS (38%) were most common. pNET patients received drug therapy most often (56%); 60% received SAs; 31% chemotherapy. 25% underwent surgery. K-M curves indicated a 63% 5-year survival among surgical patients compared to 31% for drug therapy patients.

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Conclusions

Initial treatment among the majority of patients was surgery or drug therapy. Among cNET and pNET patients receiving drug therapy, 82% (n=62) and 60% (n=35) respectively, received a SA.

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Resection of Liver Metastasis in Midgut Neuroendocrine Tumors Affects 10-Year Survival

J. Philip Boudreaux, MD,1 Anne E. Diebold, BS,1 Yi-Zarn Wang, MD,1 Eugene A. Woltering, MD.11Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 70112.

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Background

Midgut neuroendocrine tumors (mNETs) are frequently diagnosed after hepatic metastasis occurs, with a 5-year survival of 50%. We hypothesized that surgical cytoreduction of hepatic metastasis would impact survival rates.

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Methods

Review of 1,362 NET patient charts revealed 319 patients with stage IV, well differentiated, mNETs of the jejunum and ileum. Patients with loco-regional disease only were excluded. M1 denoted metastasis confined to either the liver or extra-hepatic sites only (lung, pelvis, bone, ovary, pancreas, diaphragm). M2 denoted extensive metastatic disease to both the liver and other sites. Patients were further stratified based on resection status. Survival data was calculated using the Kaplan-Meier method.

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Results

Of the 319 patients with distant disease, 117 had liver metastasis only, 37 had extra-hepatic metastasis only, and 165 had both (M2). For M1 patient’s liver resected (n=80), liver not resected (n=37), extra-hepatic resected (n=31), extra-hepatic not resected (n=6) the five year survival rates were: 88%, 88%, 84%, and 100% respectively. The ten year survival rates were 79%, 39%, 70%, 67% respectively. For M2 patients that had been resected (n=147) and M2 patients not resected (n=18) the five year survival rates were 82% and 82% respectively. The ten year survival rates were 64% and 55% respectively.

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Conclusions

Debulking of hepatic metastasis had a positive effect on 10-year survival (p<0.0001). Debulking of extra-hepatic disease had little effect on survival. Resection of hepatic metastasis is recommended. However, larger studies are required to assess the impact of debulking in extra-hepatic metastasis.

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Lymph Node Positivity in Patients with Small T1 and T2 Midgut Neuroendocrine Tumors

J. Philip Boudreaux, MD,1 Yi-Zarn Wang, MD,1 Anne E. Diebold, BS,1 Eugene A. Woltering, MD.11Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 70112.

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Background

Midgut neuroendocrine tumors (NETs) ≤ 1 cm (T1) are thought to have a low incidence (0–15%) of positive nodes. T2 lesions (1.1–2 cm) have a 60% incidence of positive nodes. We hypothesize that in a referral practice, the incidence of lymph node positivity from small midgut primaries is much higher than what is seen in the community.

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Methods

The charts of 401 consecutive patients, with well differentiated neuroendocrine NETs of the “small bowel” (midgut) were reviewed. Ninety-six patients with T1 solitary primary tumors (≤ 1 cm) and T2 (1.1–2 cm) were evaluated based on their number of metastatic lymph nodes. The lymph node status was obtained from the pathology report of their initial surgery. The remaining 305 excluded patients had multiple primaries or primaries greater than 2 cm.

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Results

Twenty-nine patients had a primary tumor size of ≤ 1 cm. Eighteen patients (18/29, 62%) presented with nodal metastasis. Sixty-seven patients had a solitary primary tumor size between 1.1 and 2 cm. Sixty-two patients (62/67, 93%) presented with nodal metastasis.

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Conclusions

Based on our review the incidence of lymph node positivity (62–93%) in small midgut NETs is much higher than what is generally accepted. We believe this may be related to an institutional referral bias. Multi-institutional trials are needed to determine the actual incidence of lymph node metastasis in patients with small midgut NETs.

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MK-2206, a Novel AKT Inhibitor, Suppresses Medullary Thyroid Cancer Proliferation

Jocelyn F. Burke, MD,1,2 Logan Schlosser, BS,2 April Harrison, BS,2 Muthusamy cKunnimalaiyaan, PhD,2 Herbert Chen, MD, FACS1,21Division of Endocrine Surgery, Department of Surgery; 2Endocrine Surgery Research Laboratories, University of Wisconsin, Madison, WI 53705..

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Background

Development of targeted therapies for medullary thyroid cancer (MTC) has focused on inhibition of the RET proto-oncogene with minimal success. Akt is a downstream target of RET via the key mediator phosphoinositide-3-kinase. Targeting Akt in MTC may thus be more effective for anti-tumor treatments. MK-2206 is an orally administered allosteric Akt inhibitor that exhibited minimal toxicity in phase 1 trials. We therefore explored the anti-tumor effects of this novel compound in MTC.

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Methods

Human MTC-TT cells were treated with MK-2206 (0-20 μM) for 2, 4, and 6 days. Assays for cell viability were performed at each time point with MTT. Western blot analysis was performed on protein lysates from TT cells treated with MK-2206 (0-10 μM) for 4 days to assess mechanism of action, mechanism of growth inhibition, and production of neuroendocrine tumor markers.

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Results

MK-2206 suppressed MTC cell proliferation in a dose-dependent manner (p≤0.02). Levels of Akt phosphorylated at serine residue 473 declined with increasing doses of MK-2206, indicating successful Akt inhibition. The apoptotic proteins cleaved PARP and cleaved caspase 3 increased in a dose-dependent manner with MK-2206, while survivin, an apoptosis inhibitor, was markedly reduced. Importantly, the anti-tumor effects of MK-2206 were independent of RET, as the levels of RET protein were not blocked.

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Conclusion

The Akt inhibitor MK-2206 significantly suppresses MTC proliferation independent of RET modulation. Given the high oral bioavailability and low toxicity profile, Phase II studies with this drug alone or in combination with RET inhibitors are warranted.

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Preliminary Experience with Intra-Arterial I-131 MIBG Hepatic Infusion for Progressive Metastatic Low Grade Neuroendocrine Tumors: An Ongoing Work-in-Progress

Richard J Campeau, MD, FACNM,1 Adam M Dowling, MD, FACR,1 Eugene A Woltering, MD, FACS,1 J Philip Boudreaux, MD, FACS,1 Yi-Zarn Wang, MD, FACS,1 Maria M Chester, RN, BSN.11Ochsner Medical Center – Kenner Neuroendocrine Tumor Clinic, Radiology, and LSU Health Sciences Center, New Orleans, LA.

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Background

I-131 meta-iodobenzylguanidine (MIBG) is an established treatment modality for well differentiated neuroendocrine tumors (NETs); however, because of the relatively low tumor radiation dose that can be delivered, it is a palliative treatment modality and objective anatomical tumor response is rare. Of the methods employed to increase delivered tumor dose, intra-arterial (IA) MIBG appears promising; however, only one literature report of this use in a mixed NET population could be found. The aim of this work-in-progress is to evaluate the efficacy of IA MIBG in an ongoing heterogeneous group of NET pts demonstrating progressive disease despite standard therapy.

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Methods

From April, 2010 to present, foregut, midgut and hindgut low grade NET patients are being offered IA MIBG for predominant hepatic metastases. 6 patients (5 females, 1 male; mean age, 60.5 yrs) have received a total of 11 hepatic infusions of MIBG. Catheters were placed in the hepatic artery and infusions of 7.4 GBq of I-131 MIBG were given over 30 minutes in a special procedures radiology suite. Clinical, radiographic, and biochemical markers are being followed.

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Results

One pt is stable; 3 pts have expired from progressive disease; 2 pts show progressive disease. Catheterization caused no complications. No carcinoid crisis was observed. Mild reversible thrombocytopenia developed in 3 pts. Mild nausea developed in 1 pt. Side effects were no different than noted in a large group of our NET patients receiving IV MIBG therapy.

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Conclusions

IA MIBG therapy appears to be a safe alternative to standard IV treatment. Despite the theoretically higher mean tumor uptake from IA MIBG, outcomes do not appear to be better thus far in this small group of NET pts than conventional IV MIBG treatment. A larger group of mixed low grade NET pts are being enrolled to assess any potential benefit of IA MIBG therapy.

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Cellular Uptake and Tumor Dosimetry of Ultratrace Iobenguane (MIBG) in a Mouse Model of Pheochromocytoma/Paraganglioma (pheo): Towards 211At-MABG Alpha Therapy

Ann-Marie Chacko,1 Catherine Hou,1 John Mikitsch,1 John Babich,2 Daniel A Pryma11University of Pennsylvania, Philadelphia PA 19104; 2Molecular Insight Pharmaceuticals, Cambridge MA 02142.

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Background

The norepinephrine transporter (NET) is differentially over expressed on the cell surface of most human pheo and provides a highly specific mechanism for directing uptake of NET ligands into tumors. Metaiodobenzylguanidine (MIBG) is one such compound being investigated as a radiotherapeutic for malignant pheo. In an effort to develop 211At-MABG as an alpha therapy for pheo, we have validated Ultratrace125I-MIBG uptake in a mouse model of malignant pheo as a comparator for 211At-MABG.

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Methods

Ultratrace MIBG was synthesized by incubating Ultratrace mBG resin with 125I-NaI and an oxidant, followed by purification by IEC. Radiochemical purity was determined using radioTLC and RP-HPLC. To evaluate the uptake of MIBG we used MPC 4/30PRR cells derived from mouse metastatic pheo (a kind gift from Drs. Powers and Tischler). MIBG uptake in vitro was assessed in the presence desipramine (DMI) blocking and with the HDAC-inhibitor Trichostatin A (TSA). Organ and tumor biodistribution of MIBG was performed in nude mice bearing subcutaneous MPC tumors at 24h post intravenous injection. Digital autoradiography (DAR) was used to confirm microdistribution of MIBG within the tumor.

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Results

In vitro, MPC cells accumulated MIBG to high levels (274 fmol/106 cells at 180min) compared to cells blocked with DMI (73 fmol/106 cells at 60min). TSA pretreatment significantly increased MIBG uptake (511 fmol/106 cells at 180min). MPC tumor xenografts had significant uptake of MIBG (1.06±0.25%ID/g) at 24h (n = 4), with tumor:blood and tumor:muscle ratios 6.24±2.08 and 35.33±14.43, respectively. Tumor DAR revealed that MIBG uptake was concentrated mainly at the tumor periphery.

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Conclusion

The MPC model of metastatic mouse pheo is appropriate to evaluate the targeting of ligands such as MIBG. Furthermore, quantitative MIBG uptake and dosimetry is a promising approach to plan 211At-MABG alpha therapy of pheo.

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Identification and Characterization of Corticotropin Releasing Hormone (CRH) Type 1 System in Human Pancreatic Neuroendocrine Tumors

Monica C. Chen,1 Vay Liang W. Go,2 S. Vincent Wu31Department of Surgery; 2Department of Medicine, David Geffen School of Medicine at UCLA; 3VA Greater Los Angeles Healthcare System, Los Angeles, CA 90095.

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Background

Neuroendocrine peptide hormone corticotropin-releasing hormone (CRH) plays an important role in integrating stress response to restore central and peripheral homeostasis. Potential risk factors for pancreatic endocrine tumor (PET) development are closely associated with chronic stress-induced metabolic disorders and inflammation. This study aims to determine if a local pancreatic CRH system exists in normal versus tumor tissues, and to characterize the function of CRH and urocortin (Ucn) peptides in human carcinoid BON cells and pancreatic cancer (PaCa) cells that are capable of CRH receptor-mediated cell signaling and hormone secretion.

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Methods

Expression of CRH ligand, receptors and binding protein was determined by RT-PCR and qPCR using specific primers in Pancreatic Cancer and Disease Tissue Arrays (Origene) and PaCa cells. Tryptophan hydroxylyase 1 (TPH1) was measured as a marker for 5-HT producing PET. CRH receptor and binding proteins were examined by Western blot probed with specific antibodies. Protein lysates from BON and PaCa cells after CRH/Ucn treatment (10-10-10-6 M, 30 min) were examined for phospho-ERK1/2, p38, CREB and AKT. Immunofluorecent staining was performed on cells and tissue sections were immunostained with CRHR antibodies.

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Results

CRHR and CRHBP with multiple splice variants were detected in human pancreatic cancer tissues and cell lines. CRH and Ucn3, CRHR1a and 1c isoforms and CRHBP were predominantly expressed in the endocrine tumors in which 6/13 also express TPH1 above the normal value. CRH and Ucn-1 stimulated ERK1/2, p38 and CREB, but inhibit AKT phosphorylation via CRHR1 on the BON and PaCa cells.

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Conclusion

Our data show that PET expresses a functional CRH type 1 system, in comparison to normally low or absent in ductal adenocarcinoma tissue. The finding of TPH1 expression in more than 40% of the PET suggests that a nascent CRH-5-HT axis may exist to amply CRH stress signals within and outside the endocrine pancreas.

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Regulation of Corticotropin Releasing Hormone (CRH) and Urocortin Family Peptide Expression in Human Carcinoid BON Cells

Monica C. Chen,1 Vay Liang W. Go,2 Hung Pham,2 Million Mulugeta,2 Sergio Solorzano,3 Martin G. Martin,3 Yvette Taché,2,4 S. Vincent Wu41Department of Surgery; 2Department of Medicine; 3Department of Pediatrics, David Geffen School of Medicine at UCLA; 4VA Greater Los Angeles Healthcare System, Los Angeles, CA 90095..

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Background

CRH plays a key role in integrating stress responses. While CRH neurons in the HPA-axis are well characterized, peripheral expression and function of CRH system are less clear. Understanding the neuroendocrine CRH system will be of clinical relevance in stress-related neuroendocrine tumors.

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Aim

This study was to determine 1) if CRH and urocrotin (Ucn) peptides are expressed and 2) how CRH and Ucn mRNA and peptides are regulated in response to stress hormones in human carcinoid BON cells.

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Methods

BON-4N cells were treated with dexamethasone (Dex, 1-100 nM), 5-HT (0.1-10 μM) and forskolin (Fsk, 1-100 μM) for 1 h for hormone release, and 3-7 days for expression studies. BON-4N was also transfected with human neurogenin (NEUROG)-1 or NEUROG-3 (wild-type, R93L and R107S mutants) for 7 days to modify its growth and differentiation processes. CRH and urocrotin transcripts were analyzed by RT-PCR and qPCR. ProCRH and CRH peptide were detected by Western blot and RIA, respectively.

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Results

BON-4N cells differentially expressed multiple CRH mRNA transcripts in basal and stimulated states. Fsk (10-100 μM) induced CRH and Ucn-1 mRNA increases by 2-5–fold, but reduced Ucn-2 and Ucn-3 expression. ProCRH and CRH were increased in Fsk-stimulated BON-4N cells. Dex at 10-100 nM, inhibited basal and stimulated CRH/Ucn-1 mRNA expression (>50 %). In contrast, 5-HT increased CRH transcripts after 3 days but shown no effects after 7 days. NEUROG-3 induced CRH and Ucn-1, but not Ucn-2 expression. NEUROG3 mutants or NEUROG1 did not show similar effects.

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Conclusion

CRH gene expression is regulated by glucocorticoids, 5-HT and cAMP activators in BON-4N cells. Ectopic expression of NEUROG-3 changed the CRH/Ucn expression profile to a well differentiated 5-HT producing cell phenotype. Thus hormonally and transcriptionally modified BON-4N cells will be useful to unveil the molecular mechanisms underlying CRH gene regulation in neuroendocrine tumors under stress.

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Prevalence of Functional Tumors in Neuroendocrine Carcinoma: An Analysis from the NCCN NET Database

Michael A. Choti, MD,1 Sarah Bobiak, PhD,2 Jonathan R. Strosberg, MD,3 Al B. Benson III, MD,4 P. Mark Bloomston, MD,5 James C. Yao, MD,6 Carrie C. Zornosa, MSPH,2 Emily K. Bergsland, MD,7 Matthew H. Kulke, MD,8 Eric K. Nakakura, MD,7 Manisha H. Shah, MD.51The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287; 2National Comprehensive Cancer Network, Fort Washington, PA 19034; 3H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612; 4Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611; 5The Ohio State University Comprehensive Cancer Center- James Cancer Hospital and Solove Research Institute, Columbus, OH 43210; 6The university of Texas MD Anderson Cancer Center, Houston, TX 77030; 7UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143; 8Dana Farber Cancer Institute, Boston, MA 02215.

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Background

Neuroendocrine tumors (NETs) are increasing in incidence and prevalence. Identification and treatment of specific clinical NET syndromes are established, yet uncertainty exists regarding the prevalence of NET with hormone-related symptoms versus nonfunctional tumors.

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Methods

The National Comprehensive Cancer Network (NCCN) Outcomes Database was queried to identify carcinoid, pancreatic NET (pNET), NET not otherwise specified (NOS), and adrenal cortical carcinoma/pheochromocytoma/paraganglioma (adrenal) patients presenting to 7 NCCN institutions in 2004–2010. This analysis describes demographic and clinical characteristics of NET patients by functional status at diagnosis.

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Results

Among 1497 NET patients, 28% had a functional tumor. Carcinoid syndrome (CS) occurred in 30% of carcinoid patients and 25% of NOS patients, Prevalence of hormonal syndrome (HS) was 23% among pNET patients and 33% among adrenal patients. Among patients with distant disease at diagnosis, 45% of carcinoid patients, 42% of adrenal patients, and 26% of pNET and NOS patients had functional tumors. 15% of carcinoid patients with local/regional disease had CS, most often occurring in the small bowel. Among carcinoid patients with elevated 5-HIAA (n=200), 58% had functional tumors. The majority of functional pNET had an unspecified sub-type, with insulinoma (21%) and gastrinoma (19%) also prevalent. The most common symptoms at diagnosis among functional patients included changed bowel habits, weight loss, abdominal cramping, and nausea. Most patients (84%) with functional tumors and distant disease had metastatic disease in the liver at diagnosis (carcinoid: 84%, pNET: 88%, NOS: 89%).

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Conclusions

Prevalence of CS among carcinoid patients (30%) was slightly higher than the 10% previously reported in the literature. In contrast, the prevalence of HS among pNET patients (23%) was lower than previously reported (42–85%). 15% of carcinoid patients without metastatic disease had CS, warranting further analysis as CS most often occurs in the presence of liver metastasis.

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Ki-67 Index Variability in Neuroendocrine Tumors

Jeffrey Craig,1 Simron Singh,2 Calvin Law,3 Matthew Cheung41Department of Medicine, University Health Network, Toronto, Ontario, Canada; 2Department of Medical Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; 3Department of Surgical Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; 4Department of Hematology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

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Background

The Ki-67 labeling index is well recognized as an integral factor in the identification and treatment of neuroendocrine tumors (NETs). In 2010, the WHO endorsed a grading system of NETs dividing tumors into G1 (Ki-67 <3%), G2 (Ki-67 3-20%), and G3 (Ki-67>20%) classes. Studies have shown that higher Ki-67 scores are associated with greater morbidity, with G3 tumors behaving particularly aggressively. Currently Ki-67 is determined from a single biopsy in a majority of cases and no consensus guidelines exist on taking multiple biopsy specimens through the disease course.

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Aims

To compare Ki-67 variability among multiple biopsy samples taken at different times in individual patients.

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Methods

The Sunnybrook Odette NETs database (n=327) was retrospectively reviewed for patients with a confirmed diagnosis of NET and multiple (>=2) biopsy or surgical pathologic specimens at variable times. Changes in WHO classification between specimens were determined.

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Results

Forty-three patients were identified for inclusion in the analysis. Thirty-nine patients had pathology on their primary tumor as well as a metastatic focus, while 4 had pathology on multiple metastatic foci only. Sixteen of 43 patients (37.2%) were identified who had enough variability between Ki-67 indices resulting in differing WHO classification grades. Twelve of 43 (27.9%) resulted in a second sample that increased the WHO grade by at least one level. Seven of 43 (16.3%) resulted in a new WHO classification of G3.

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Conclusion

The Ki-67 labeling index in NETs may change throughout the disease course, may differ between primary tumor and metastases, and may behave more aggressively later in the disease. Given the reliance on this index for management decisions, multiple biopsies through the disease course may be required to effectively treat these heterogeneous malignancies.

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Neuroendocrine Tumors: A Review of the Sunnybrook Odette Cancer Centre Database

Jeffrey Craig,1 Simron Singh,2 Calvin Law,2 Matthew Cheung.21University Health Network 200 Elizabeth Street Eaton Building 14-217, TORONTO, Ontario, Canada M5G 2C4; 2Department of Medical Oncology Sunnybrook Health Sciences Centre 2075 Bayview Avenue, Suite T2-023, Toronto, Ontario, Canada M4N 3M5.

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Background

Neuroendocrine tumors (NETs) are an uncommon and heterogeneous group of malignancies. A number of reviews have been published attempting to better identify important factors in predicting overall survival, however they are often limited by small sample size and were published before new therapy options came into widespread use.

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Aims

We reviewed our experience at our NETs multidisciplinary reference centre to identify important patient and tumor characteristics associated with improved overall survival.

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Methods

The Sunnybrook Odette Cancer Centre NETs Database was retrospectively reviewed. All patients with a pathologically confirmed diagnosis of NET were included in the analysis. Patient characteristics, tumor markers and pathology, treatment, and response to treatment were recorded. Univariate and multivariate Cox-regression analyses were performed.

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Results

A total of 327 patients were included in the analysis. In univariate analysis, factors associated with improved overall survival included local/regional disease at presentation (p<0.001), lower Ki67 index (P<0.001), normal chromogranin A at presentation (p=0.008), urinary 5-hydroxyindoleacetic acid drop following treatment (p=0.024), symptom response to treatment (p<0.001), surgery on primary tumor (P<0.001), surgery on metastases (p=0.003), having multiple surgeries (p<0.001), and treatment with long-acting somatostatin (LAS) (P=0.029). In multivariate analysis, treatment with LAS (p<0.001, HR 0.141, 95%CI 0.064–0.31) and having multiple surgeries (p=0.045, HR 0.591, CI 0.354–0.988) were shown to be independent predictors of improved overall survival.

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Conclusions

Treatment with long-acting somatostatin and having multiple surgeries were shown to be independent predictors of improved overall survival in NETs. This data further supports the use of aggressive medical and surgical intervention in a multi-modal approach for advanced NETs. This may be best achieved in the setting of NETs multidisciplinary reference centres.

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The Risk of Adenocarcinoma of the Stomach in Type I Carcinoid

Michelle Cramblitt, RN,1 Matthew M. Eves, MD, FACG.21Mobile Infirmary Medical Center, Mobile, Al 36604; 2Mobile Infirmary Medical Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604.

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Background

The progression from atrophic gastritis to gastric adenocarcinoma or Type I Carcinoid is the accepted paradigm for considering the risk of atrophic gastritis.1 This paradigm may underestimate the true risk of Type I Carcinoid. The rate of metastasis from Type I Carcinoid is less than 5%.2 Gastric adenocarcinoma and Type I Carcinoid are not exclusive. Type I Carcinoid may be a very important marker for the development of gastric adenocarcinoma.

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Methods

Patients from a data base of a therapeutic endoscopy practice identified as having either anti parietal cell antibodies or anti intrinsic factor antibodies were reviewed. The database was evaluated from 2009 through 2011. Development of Type I Carcinoid was documented as was the development of adenocarcinoma of the stomach. Gastrin levels were also available for most patients.

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Results

16 patients were found to have gastric antibodies. Of these, 5 patients were also noted to have Type I Carcinoid. Of these 5, 3 developed gastric adenocarcinoma. Although sample size is small, this represents a greater than 50% risk factor for the development of an aggressive cancer.

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Conclusions

If the risk of metastasis from Type I Carcinoid is on the order of 5%, is the 5% really Type I or rather misdiagnosed Type II or III. Carcinoid tumors are in general among the most poorly diagnosed tumors in medicine. Even if correctly diagnosed as Type I’s, on average, metastatic carcinoid is more treatable than gastric adenocarcinoma. Rather than focusing on the metastatic risk of these tumors, more attention should be given to the risk of gastric adenocarcinoma. Recommendations for endoscopic surveillance should reflect this.

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Olfactory Receptor 51E1 is a Potential Novel Tissue Biomarker for the Diagnosis of Small Intestine Neuroendocrine Tumors

Tao Cui,1,2 Apostolos V. Tsolakis,1,3 Janet Cunningham,4 Su-Chen Li,1,2 Thomas Lind,5 Kjell Öberg,1,2,3 Valeria Giandomenico1,2,3*1Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden; 2Science for Life Laboratory, Uppsala, Sweden; 3Center of Excellence for Endocrine Tumors, Uppsala University-Hospital, Uppsala, Sweden; 4Department of Neurosciences, Psychiatry, Uppsala University-Hospital, Uppsala, Sweden; 5Department of Medical Sciences, Osteoporosis and Clinical Pharmacogenetics, Uppsala University, Uppsala, Sweden.

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Background

Small intestine neuroendocrine tumor (SI-NET) patients get late diagnosis. We have previously reported olfactory receptor 51E1 (OR51E1) as a novel SI-NET mRNA marker. We aimed at understanding whether, OR51E1 protein may be developed as a novel diagnostic marker.

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Methods

OR51E1 coding sequence was cloned by using total RNA from human NET cells and patient specimens. Laser capture microdissection (LCM) isolated SI-NE tumor and normal cells. OR51E1 mRNA expression was investigated in CNDT2.5, KRJ-1, different cancer and fibroblast cell lines, and normal liver cells and tissue by using QRT-PCR. OR51E1 protein expression was investigated on paraffin-embedded sections from 70 SI-NET patients (43 primary tumors, 28 mesentery metastases and 18 liver metastases) by using conventional immunohistochemistry. Adjacent tumor mucosa and tumor material was investigated by using double immunofluorescence [OR51E1, vesicular-monoamine-transporter-1 (VMAT1)].

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Results

OR51E1 coding sequence analysis showed absence of mutation in tumor cells from established NET cell lines and from patient specimens. CNDT2.5 and KRJ-1 cells are OR51E1-negative. OR51E1 expression in LCM SI-NET cells is higher than in the stroma cells. Normal human liver tissue and a panel of normal human hepatic cells do not express OR51E1. Moreover, we detected OR51E1 protein expression both in the primary and in the metastatic tumor cells. Cytoplasmic, perinuclear and membranous OR51E1 expression was detected. Primary tumors (42%), mesentery metastases (25%) and liver metastases (33%) show over 50% OR51E1 positive cells. OR51E1 and VMAT1 co-localize in a minority of EC cells in the adjacent tumor SI-mucosa, whereas they co-localize in the majority of SI-NE tumor cells from patients at different stage of disease.

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Conclusion

OR51E1 protein is a novel potential diagnostic SI-NET biomarker. Its role in the pathophysiology in SI-NETs has to be further characterized. Moreover, it may retain a proper specificity to be developed as therapeutic target.

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Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTA Octreotate for Somatostatin Receptor-expressing Neuroendocrine Tumors: The First U.S. Experience

Ebrahim S. Delpassand,1,2 Amin Samarghandi,1 Sara Zamanian,2 Jack Erion,3 Jim Somone,4 Robert Wolfangel,5 Edward M. Wolin,6 Gregory D. Espenan.71Excel Diagnostics and Nuclear Oncology Center, Houston, TX, United States; 2RadioMedix, Inc., Houston, TX, United States; 3BioSynthema, St Louis, MO and Advanced Accelerator Applications, St. Genis Pouilly, France; 4IsoTherapeutics Groups, LLC. Angleton, TX, United States; 5Clinical and Regulatory Services, LLC. Manchester, MO, United States; 6Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States; 7Physics Services Inc., Metairie, LA, United States

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Aim

To study the safety and effectiveness of peptide receptor radionuclide therapy (PRRT) with 177Lu- Octreotate (DOTATATE) in patients with somatostatin receptor-expressing neuroendocrine tumors (NET).

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Background

At this time, the only approved systemic therapies for NET in the United States are streptozocin, everolimus, and sunitinib for pancreatic NET. PRRT with radio-labeled somatostatin analogues is a novel method of treatment in patients with inoperable and/or metastatic neuroendocrine tumors expressing high levels of somatostatin receptors. We are reporting the first U.S. experience on 177Lu-DOTATATE PRRT under FDA approved IND, at our institution.

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Methods

177Lu- DOTA Octreotate (200 mCi (7.4GBq) per cycle) was administered to 39 patients diagnosed with disseminated NET. Co-infusion of 15% Clinisol was used as a kidney radioprotectant.

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Results

Response to treatment (PR+MR) and stable disease (SD) were seen in 29.4% and 47% of evaluable patients, respectively. PR was significantly associated with the lower burden of disease in the liver. No significant acute toxicity was observed during or immediately following the treatment. Hematological and hepatic toxicity grade III was seen in 12.9% and 9.67%, respectively. Also, a significantly longer PFS was seen in patients who completed all four cycles of treatment vs. those who received one cycle. An impressive improvement of Karnofsky performance status and also overall quality of life was seen after 177Lu-DOTATATE therapy.

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Conclusion

The first U.S. experience with 177Lu-DOTATATE PRRT suggests that this agent is an effective and a rather safe method of treatment for patients with progressive, disseminated neuroendocrine tumors. Our preliminary results confirm the information published by other investigators in Europe and Australia.

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Management of Breast Metastases from Gastroenteropancreatic Neuroendocrine Tumor Origin

Jeremiah L. Deneve, DO,1 Larry Kvols, MD,2 Marilyn M. Bui, MD,3 Jonathan R. Strosberg, MD,2 John V. Kiluk, MD,1 Christine Laronga, MD,1 Marie C. Lee, MD,1 Nazanin Khakpour, MD.11Department of Women’s Oncology; 2Department of Medical Oncology; 3Department of Pathology, Moffitt Cancer Center Tampa, FL, United States.

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Background

Solid tumor metastases to the breast are rare. Of these, neuroendocrine tumors (NET) metastatic to the breast have been rarely reported. We describe our single-institution experience managing breast metastases from gastroenteropancreatic NETs.

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Methods

Moffitt Cancer Center tumor registry and pathology queries were conducted searching for NET metastases to the breast. Breast carcinoma with neuroendocrine features, bronchial NETs and primary breast NETs were excluded. Descriptive statistics were performed.

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Results

Seventeen patients (median age 52 years) were identified with pathologically confirmed gastroenteropancreatic NET metastases to the breast. (Table 1) The majority (88%) initially presented with stage IV disease. Five patients (29%) had synchronous breast metastases and were initially misdiagnosed as primary breast carcinomas. Twelve patients (71%) had metachronous metastases; median 28 months from initial diagnosis (range 3–200 months). Breast metastases were managed with excision in 13 (76%, median tumor size 1.0 cm) for diagnosis or palliation. Symptomatic ovarian metastases were resected in 4 (36%). Carcinoid syndrome was present in 16 patients (94%), all managed with octreotide therapy. At a median follow up of 68 months (range 16–250 months) from diagnosis, 13 patients (76%) remained alive while 4 (24%) had died of disease.

TABLE 1

TABLE 1

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Conclusion

Breast metastases from gastroenteropancreatic NETs are rare. A diagnosis of breast cancer in the setting of NET warrants consideration of metastatic disease. Excision may be considered for definitive diagnosis or palliation. Long-term survival is possible despite advanced stage at diagnosis.

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A Single Fasting Plasma 5-HIAA Value Correlates with 24-Hour Urinary 5-HIAA Values and Other Biomarkers in Midgut Neuroendocrine Tumors (NETs)

Anne E. Diebold, BS,1 Maria R. Tellez, PhD,2 Gregg Mamikunian, MS,2 Vay Liang W. Go, MD,3 Thomas M. O’Dorisio, MD,4 Aaron I. Vinik, MD, PhD,5 Eugene A. Woltering, MD.11Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 70112; 2Inter Science Institute, Inglewood, CA 90302; 3Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095; 4Department of Medicine, University of Iowa, Iowa City, IA52242; 5Strelitz Diabetes Institute, Eastern Virginia Medical School, Norfolk, VA 23501.

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Background

5-hydoxyindoleacetic acid (5-HIAA) is used for the evaluation of neuroendocrine tumors (NETs), however the current 5-HIAA assay requires a twenty-four hour urine collection which is inconvenient.

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Methods

We developed a gas chromatography-mass spectroscopy (GC-MS) based plasma 5-HIAA assay. We compared 24-hour urine 5-HIAA values with single fasting plasma 5-HIAA values in 115 mixed variety NET patients, a subset of 72 patients with only small bowel NETs, and another subset of 47 patients with small bowel NETs with liver metastasis. We also compared the information gained from urinary and plasma 5-HIAA values with other biomarkers of midgut NET activity in order to determine the plasma assay’s clinical implications.

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Results

In a group of 115 patients with all types of NETS, in a subgroup of 72 midgut NET patients and in another subgroup of 47 mid gut NETS with liver metastasis, the correlation between the urine and fasting plasma 5-HIAA values were highly statistically significant (<0.0001, p<0.0001, p<0.0001). Comparison of the proportions of normal or abnormal urinary and plasma.

5-HIAA values to the proportions of chromogranin, serotonin, neurokinin or pancreastatin values that were in the normal or abnormal range yielded essentially identical information.

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Conclusions

Plasma fasting 5-HIAA values are proportional to urinary 5-HIAA values and provide similar clinical correlation with other biomarkers.

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Development and Preclinical Evaluation of the New Pan-Somatostatin PET Imaging Probe 68Ga-DOTA-SOM230 (SOMscan®)

Melpomeni Fani,1 Eleni Gourni,1 Friederike Braun,1 Anika Mann,2 Andrea Kliewer,2 Jens Kaufmann,3 Angela Dreykluft,3 Wolfgang A. Weber,1 Hakim Bouterfa,3 Stefan Schulz,2 Helmut R. Maecke11University Hospital Freiburg, Germany; 2University Hospital Jena, Germany; 3OctreoPharm Sciences GmbH, Berlin, Germany.

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Background

Imaging of somatostatin receptor (sst)-positive tumors using 68Ga-labeled somatostatin analogs such as the sst2 subtype-specific 68Ga-DOTA-TOC or 68Ga-DOTA-TATE is current clinical standard. Analogs targeting more receptor subtypes, such as 68Ga-DOTA-NOC, may improve detection of heterogeneous tumors. We aim to develop and evaluate a new 68Ga-labeled PET imaging probe based on SOM230 (Pasireotide) highly affine for sst1, 2, 3 and 5.

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Methods

SOM230 was conjugated to DOTA and labeled with 68Ga. In vitro evaluation included stability studies in human serum, determination of lipophilicity, sst-subtype binding profile and internalization. In vivo studies were performed in sst1, 2, 3 and 5 tumor xenografts using small animal PET imaging. 68Ga-DOTA-TATE and 68Ga-DOTA-NOC were used as control.

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Results

68Ga-DOTA-SOM230 was prepared in radiochemical purity >95% and specific activity ∼50 MBq/nmol. 68Ga-DOTA-SOM230 had logD = −0.93±0.15 and was highly stable in human serum up to 2 h with no metabolites determined. In vitro binding studies revealed high affinity for sst1, 2, 3 and 5 and internalization profiles were observed. 68Ga-DOTA-SOM230 clearly visualized sst-expressing tumors in PET images within 1 h p.i. Biodistribution studies exhibited relatively high blood pool activity (∼4 %IA/g), kidney and liver uptake (∼30 and 12 %IA/g, respectively) at 1 h p.i. At 2 h p.i., tumor uptake remained high while tumor-to-background ratios and image contrast were improved. The specificity of the radiotracer was confirmed with blocking experiments, in both biodistribution and PET imaging studies. 68Ga-DOTA-SOM230 compares reasonably well with the control radiotracers. The sst2-tumor uptake is not significantly higher for 68Ga-DOTA-TATE than for 68Ga-DOTA-SOM230 (17.8±2.2 and 14.1±4.5 %IA/g, respectively, p > 0.05) while the uptake in sst5 is significantly higher for 68Ga-DOTA-SOM230 than for 68Ga-DOTA-NOC (11.4±1.3 and 7.7±1.5 %IA/g, respectively, p < 0.05), 1 h p.i. with similar tumor-to-background contrast.

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Conclusion

The preclinical evaluation of 68Ga-DOTA-SOM230 (SOMscan®) reveals its potentiality as PET imaging probe of a broad spectrum of somatostatin receptors.

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Outcomes after Liver Resection and Multidisciplinary Management of astroenteropancreatic Neuroendocrine Tumour Liver Metastases

Adam Fehr,1 Pankaj Bhatia,1 Daryl Gray,1 Walter Kocha,1 Robin Reid,1 James Elliott,1 Amol Mujoomdar,1 Christopher Howlett,1 Douglas Quan.11Departments of Surgery, Oncology, Nuclear Medicine, Radiology and Pathology, The University of Western Ontario, London, Canada.

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Background

Metastatic liver disease from neuroendocrine tumours (mNETs) has a significant impact on prognosis. Although complete surgical resection remains the only potentially curative therapy, a multimodal approach is becoming the standard by which it is managed.

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Aims

To describe outcomes after liver resection (LR) of mNETs in patients with and without a multimodal approach.

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Methods

Retrospective analysis of patients undergoing LR for mNET at London Health Sciences Centre between 2004 and 2010.

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Results

We performed 35 LR in 30 patients for mNET to the liver. The median age of the patients was 56.5 years. 19 (63.3%) had a primary intestinal NET, 6 (20%) had a primary pancreatic NET, 3 (10%) had a primary of NET of unknown origin. There was no perioperative mortality. Postoperative morbidity was 36%. Of the 30 patients who underwent LR 25 (83.3%) are alive with a mean followup of 53 months. 15 of the procedures resulted in an R0 resection; 10 of these went on to recurrence with the median time of 16 months to recurrence. 10 patients received preoperative treatment with systemic chemotherapy, TACE, or PRRT. Compared to those who received no preoperative treatment, there was a trend to increasing R0 resection but this was not significant nor was postoperative morbidity.

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Conclusion

Liver resection for metastatic NET shows a favourable outcome for this contemporaneous group of patients. There was no clear advantage to multimodality therapy but this concept needs further research.

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Expert Panel Consensus Statements on the Medical Treatment of Unresectable Pancreatic Neuroendocrine Tumors

George A. Fisher,1 Jonathan R. Strosberg,2 Al B. Benson,3 Jennifer L. Malin,4 Lowell B. Anthony,5 Bulent Arslan,6 John F. Gibbs,7 Edward Greeno,8 Renuka V. Iyer,9 Michelle K. Kim,10 William J. Maples,11 Philip. A. Philip,12 Edward M. Wolin,13 Dasha Cherepanov,14 Michael S. Broder.141Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA; 2Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 3Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; 4David Geffen School of Medicine, University of California, Los Angeles, CA; 5Department of Internal Medicine, Division of Medical Oncology, University of Kentucky Markey Cancer Center, Lexington, KY; 6Rush University Medical Center, Chicago, Illinois; 7Department of Surgery, State University of New York at Buffalo, Buffalo, NY; 8Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN; 9Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY; 10Department of Medicine - Gastroenterology Mount Sinai School of Medicine, New York, NY; 11Mission Health System, Asheville, NC; 12Department of Oncology, Karmanos Cancer Institute, Detroit, MI; 13Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA; 13Partnership for Health Analytic Research, LLC, Beverly Hills, CA.

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Background

Neuroendocrine tumors (NETs) of the pancreas (PNETs), a major subtype of gastrointestinal NETs, are rare neoplasms that lack some specificity in current treatment guidelines. We describe a physician expert panel consensus on medical treatment of well-differentiated (grade 1–2) unresectable PNETs.

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Methods

PNET treatment appropriateness ratings were collected using the RAND/UCLA Delphi process: recruited physician experts (e.g., by specialty, geography, practice), reviewed treatment literature, and collected 2 rounds of ratings (before and after a face-to-face meeting) from the experts. Experts and the moderator were blinded to the funding source. Patient scenarios (rated on a 1–9 scale indicating appropriateness of interventions for a given scenario) were labeled as appropriate, inappropriate, or uncertain. No appropriateness rating was assigned to a scenario in presence of disagreement: >2 ratings from 1–3 and >2 from 7–9 range.

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Results

Ten panelists (mean age: 50.4 years) from the northeast, midwest, south, and west census regions convened for a 1 day meeting. Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the meeting to 1% (2) after. In the 2ndround, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: 1) it is appropriate to use somatostatin analogs (SA) as 1stline therapy in patients with hormonally functional tumors, 2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as 1stline therapy in patients with symptomatic or progressive tumors, and 3) beyond 1stline, these same agents can be used as can octreotide LAR (in patients with uncontrolled secretory symptoms) in doses up to 60 mg every 4 weeks or up to 40 mg every 3 or 4 weeks.

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Conclusion

We systematically obtained appropriateness ratings for a variety of medical therapies in PNETs from a group of physician experts. The Delphi process allowed the experts to reliably quantify complex qualitative data in order to arrive at consensus on the appropriateness of medical therapies for the treatment of PNETs.

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KI-67 Heterogeneity in Gastro-Entero-Pancreatic Neuroendocrine Tumors

Federicca Grillo,1 Manuela Albertelli,2 Paola Calamaro,1 Borra Tiziana,1 Sara Bruno,1 Luca Mastracci,1 Roberto Fiocca,1 Diego Ferone.21Histopathology, DISC, University of Genova, Genova, Italy; 2Endocrinology, DIMI and Center of Excellence for Biomedical Research CEBR, University of Genova, Genova, Italy.

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Background

The neuroendocrine tumor (NET) proliferation-based grading system (ENETs) has proved reliable for prognostic stratification, however concerns exist on Ki67 heterogeneity. Our aim was to evaluate intratumor Ki67 index heterogeneity in primary and metastatic sites.

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Methods

A total of 170 GEP-NETs (between 1993–2011) were identified, 50 of them with clinical follow-up (mean follow up was 59 months, range 2–168 months). Twenty-five cases had multiple paraffin blocks on which Ki67 immunohistochemistry was performed.

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Results

Thirteen out of 21 (62%) primary sites presented exactly the same Ki67 percentage and therefore the same grade in each paraffin block. Six (29%) tumors presented different Ki67 indices between paraffin blocks, but with no change in grade. Two (10%) tumors showed Ki67 index discrepancy (7% vs 2% and 4% vs 2%) which was enough to change grade (G1 to G2). Out of 14 patients with primary NET and synchronous metastases, 9 (64%) presented exactly the same Ki67 index between sites while 2 (14%) showed variability in their Ki67 index, but not in grade. Three (21%) cases showed discrepancy between primary tumor and metastases. In particular two cases showed an increase in proliferation index in nodal metastases (1% vs 5% and 17% vs 31%) and one case showed increased Ki67 index in a mesenteric localization (1% vs 5%). One case with multiple hepatic metastases showed discrepancy between each metastasis (7% vs 1%). Six patients underwent surgical excision of metachronous metastases during follow up. Three (50% - 1 nodal and 2 hepatic metastases) patients showed an increase in Ki67 rate in the metastatic site and a change in grade, from G1 to G2 (1% vs 10%; 2% vs 5%; 1% vs 7%).

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Conclusion

Differences in grade between primary and synchronous/metachronous metastatic sites are important and evaluation of Ki67 at all sites may be significant for patient management.

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Multi-Center Phase II Trial of Temsirolimus (TEM) and Bevacizumab (BEV) in Pancreatic Neuroendocrine Tumor (PNET): Results of a Planned Interim Efficacy Analysis

Timothy Hobday, MD,1 Rui Qin, PhD,1 Diane Reidy, MD,2 Malcolm Moore, MD,3 Jonathan Strosberg, MD,4 Andreas Kaubisch, MD,5 Manisha Shah, MD,6 Hedy Kindler, MD,7 Heinz-Joseph Lenz, MD,8 Helen Chen, MD,9 Charles Erlichman, MD.11Mayo Clinic College of Medicine, Rochester, MN (Mayo Phase 2 Consortium (P2C); 2Memorial Sloan-Kettering Cancer Center (MMSK), New York, NY (MMSK P2C); 3Princess Margaret Hospital, Toronto, ON (Princess Margaret P2C); 4H Lee Moffit Cancer Center, Tampa, Fl (Southeast P2C); 5Montefiore Medical Center, Bronx, NY (Montefiore P2C); 6Ohio State University, Columbus, OH (Ohio State P2C); 7University of Chicago, Chicago, Il (University of Chicago P2C); 8University of Southern California, Los Angeles, CA (California Cancer P2C); 9National Cancer Institute, Rockville MD. Supported by NCI N01 Contracts: 662205, 62203, 62208, 62209, 62206, 62204, 62207, 62201.

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Background

PNET has long had few effective therapies other than chemotherapy. Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are still <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy.

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Methods

We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 patients, with interim analysis for futility after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0–1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed.

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Results

Confirmed PR was documented in 13 of the first 25 (52%) evaluable patients. 21 of 25 (84%) patients were progression-free at 6 months. Both endpoints exceeded the protocol-defined criteria to continue enrollment. For 36 evaluable patients, the most common grade 3–4 adverse events attributed to therapy were hypertension (14%), leukopenia (11%), lymphopenia (11%), hyperglycemia (11%), mucositis (8%), hypokalemia (8%), and fatigue (8%).

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Conclusion

The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 52%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 84% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing.

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G3 Neuroendocrine Neoplasms (G3 NENs) with Deceptively Well-Differentiated Histologic Features Have a Poor Outcome

Lily Jih, MD,1 Richard Mertens, MD, PhD,1 Run Yu, MD, PhD,2 Edward Wolin, MD,3 Deepti Dhall, MD11Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048; 2Division of Endocrinology and Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048; 3Division of Oncology and Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048.

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Background

The 2010 WHO classification stratifies NENs into 3 tiers based on cellular proliferation. The G3 NENs (mitotic count >20/10 HPF and/or Ki-67 index >20%) are classified as neuroendocrine carcinomas (NECs). G3 NENs and poorly-differentiated NECs (PDNECs) are categorized the same. PDNECs exhibit small cell (SC) or large cell (LC) morphology with severe nuclear atypia, necrosis and high mitotic activity. G3 NENs may show features similar to well-differentiated NENs, except for high Ki-67 index. This study evaluates the clinicopathological features of G3 NENs with well-differentiated histology (G3-WD).

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Methods

Gastroenteropancreatic G3-WD and PDNECs were retrieved from the anatomic data base from 2000 to 2011. Outcome data was obtained from the tumor registry.

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Results

9 cases of G3-WD (6 pancreatic, 3 gastrointestinal) were identified. The tumor cells were uniform and largely arranged in an organoid pattern. None could be classified as NEC of SC or LC type. 3 had oncocytoid appearance; 5 had focal higher grade cytologic features; 4 had prior diagnosis or current foci of low or intermediate grade NEN. 5 PDNECs (all gastrointestinal with SC morphology) were used as controls. Patient demographics, tumor characteristics and follow-up are detailed in Table 1.

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Conclusion

G3-WD have a poor clinical outcome, although fare slightly better compared to PDNECs. G3-WD may represent transformation from prior low or intermediate grade NENs. When such transformation occurs, aggressive treatment may be warranted.

TABLE 1

TABLE 1

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Bone Metastases in Well-to-Moderately Differentiated Neuroendocrine Tumors: A Review of Clinical Characteristics, Hormone Levels, and Survival

Juraj Kavecansky, MD,1 Lai Wei,2 Lisa Caronia,3 Mark Bloomston, MD,4 Manisha Shah, MD.51Wexner Medical Center of the Ohio State University, Department of Internal Medicine, Columbus, OH 43210; 2Wexner Medical Center of the Ohio State University, Center for Biostatistics, Columbus, OH 43221; 3The Ohio State University College of Medicine, Columbus, OH 43210; 4Wexner Medical Center of the Ohio State University, Department of Surgery, Division of Surgical Oncology, Columbus, OH 43210; 5Wexner Medical Center of the Ohio State University, Department of Internal Medicine, Division of Medical Oncology, Columbus, OH 43210.

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Background

Metastatic neuroendocrine tumors, specifically those with bone metastases, are rare and not yet comprehensively researched. In this study we look at the clinical features associated with bone metastasis in patients with well-to-moderately differentiated neuroendocrine tumors (NETs), specifically primary tumor characteristics, spinal cord compression, pathologic fractures, elevated hormone levels, and survival.

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Methods

A retrospective study was performed on all patients treated at our hospital for well-to-moderately differentiated NETs diagnosed from 2000 to 2010 who were found to have bone metastases. A control group of patients with metastatic NETs was matched with regards to age, gender, primary site, and date of diagnosis for comparison.

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Results

40 patients with well to moderately differentiated NETs were found with bone metastases. Patients with bone metastases had larger primary tumors than matched controls (47.5 mm vs 33 mm diameter, p= 0.024). Among patients with bone metastases, 8 patients were found with spinal cord compression (20%), 6 patients with pathologic fractures (15%), 18 patients with carcinoid syndrome (45%), and 36 patients with an elevated pancreastatin (90%) on diagnosis. Patients with bone metastases also had shorter survival (52 months) compared to the control group (98 months, p=0.024); among only those with bone metastases, patients had a shorter survival if they had non-resectable disease (32 vs 76 months, p=0.005). Cord compression, pathologic fracture, carcinoid syndrome, and elevated pancreastatin were not associated with shorter survival among patients with bone metastases.

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Conclusion

Our study suggests that patients with well to moderately differentiated NETs metastatic to bone have larger tumors, more frequently elevated pancreastatin, and shorter survival than patients without bone metastases.

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Effect of Short-Term Proton Pump Inhibitor Treatment and Its Discontinuation on Chromogranin A in Healthy Subjects

Walter Kocha, MD,1 Hala H. Mosli, MBBS, FRCP(c), ABIM, ABEM, Cert Endo,2,5 Alan Dennis, PhD, FCACB, MBA,3 Linda J. Asher, RN,2 Stan H.M. Van Uum, MD PhD, FRCP(c).2,41London Health Science Centre; 2Department of Medicine, Schulich School of Medicine and Dentistry, Western University; 3London Laboratory Services Group; 4Lawson Health Research Institute, Western University, London, Ontario, Canada; 5Department of Medicine, King Abdulaziz University Hospital, Jeddah Saudi Arabia.

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Background

Chromogranin A (CgA) is used as a generic tumor marker for neuroendocrine tumors. Proton Pump Inhibitors (PPIs) are known to increase CgA, but it is not clear to what extent, and there is little information on how long PPIs need to be discontinued before the effect of PPIs has disappeared. Further, is it not known if this PPI effect is dependent on the CgA assay used. The objective of the study was to To determine the effect of 7 day treatment with a PPI and its discontinuation on CgA in serum and plasma comparing 4 CgA assays.

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Methods

17 healthy subjects took lansoprazole 30 mg at bedtime for 7 days, and blood samples for CgA were obtained at baseline, day 7 of PPI use, and 1, 2, 4, and 7 days after discontinuation of the PPI. In all samples, CgA was measured using the following assays: Alpco (serum and plasma), Cis-Bio (serum and plasma), DAKO and Cis-Bio Radioisotope assay.

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Results

When using the same assay, CgA was higher in plasma then in serum. Treatment with a PPI for one week resulted in a significant (about 2.5 fold) increase in CgA with significant interindividual variation. After discontinuation of PPI, serum CgA gradually declined with a half-life of 4–5 days.

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Conclusion

Short term PPI use results in a significant increase of CgA in serum and plasma, an effect that is largely independent of the assay used. PPIs need to be discontinued for 2 weeks to fully eliminate their effect on CgA. This effect of PPIs needs to be considered when interpreting results of CgA measurements.

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Response to Chemotherapy Necessary in G2 and G3 Neuroendocrine Carcinomas

Walter I. Kocha.11London Regional Cancer Center, London Ontario, Canada N6A 4L6.

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Background

Although approaches to treatment of G1 and G3 neuroendocrine carcinomas are generally agreed upon, treatment of G2 and G3 disease is problematic. Therapy should initially be directed to the highest proliferating component with chemotherapy. Residual disease could sequentially be treated with the modalities relevant to that G1 tumor such as peptide receptor radioisotope therapy (PRRT). What degree of response therefore should be expected utilizing chemotherapy depending on the proportion of the rapidly proliferating component?

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Methods

A simple mathematical model of tumor volume related to tumor diameter was considered assuming that the perfectly spherical tumor was the least sensitive case. Varying the total fraction of tumor volume that was of high proliferation and assuming that all of the actively proliferating tumor compartment was eradicated by chemotherapy, the expected change in tumor diameter was calculated as defined and utilized by the RECIST criteria.

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Results

Based on the RECIST criterion of a decrease in diameter of greater than 30% required classification as response, the model predicts that the threshold for partial response could not be satisfied unless the initial proliferative fraction is 40% or greater.

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Conclusion

Patients with G2 and low G3 disease should have at least stable disease to consider transitioning to treat residual disease as G1 disease.

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A Multi-Institutional Phase II Open-Label Study of AMG 479 in Advanced Carcinoid and Pancreatic Neuroendocrine Tumors

Matthew H. Kulke,1 Jennifer A. Chan,1 David P. Ryan,2 Jeffrey A. Meyerhardt,1 Charles S. Fuchs,1 Thomas Abrams,1 Eileen Regan,1 Rachel Brady,1 Jill Weber,3 Tiffany Campos,3 Larry K. Kvols,3 Jonathan R. Strosberg.31Dana-Farber Cancer Institute, Boston, MA 02215; 2Massachusetts General Hospital, Boston, MA 02114; 3Moffitt Cancer Center, Tampa, FL 33612.

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Background

The IGF pathway has been implicated in neuroendocrine tumor (NET) progression. We therefore investigated AMG 479, a human monocolonal antibody against IGF1-R, in patients with metastatic progressive carcinoid and pancreatic NETS.

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Methods

This phase II study enrolled patients (≥18 yrs) with metastatic low and intermediate-grade carcinoid and pancreatic NETs. Inclusion criteria included evidence of progressive disease (by RECIST) within 12 months of enrollment, ECOG PS 0–2, and fasting blood sugar <160mg/dL. Prior treatments were allowed and concurrent somatostatin analog therapy was permitted as long as patients remained on a stable dose. The primary endpoint was objective response rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety.

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Results

60 patients (30 carcinoid, 30 pancreatic NET) were treated with AMG 479 18mg/kg every 3 weeks and 54 patients were evaluable for response. There were no objective responders by RECIST. When best response to therapy was evaluated, 10/27 (37%) evaluable carcinoid patients and 8/26 (31%) evaluable pancreatic NET patients appeared to have experienced some degree of tumor shrinkage, while 17/27 (63%) of the carcinoid patients and 15/26 (58%) of the pancreatic NET patients appeared to experience continued tumor growth. Median PFS was 6.3 months (95% CI 4.2–12.6) for the entire cohort; 10.5 months for carcinoid patients and 4.2 months for pancreatic NET patients. The OS rate at 12 months was 70% (55%–81%) for the entire cohort. Median OS has not been reached. Treatment related grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%) and infusion reaction (1%).

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Conclusions

While well-tolerated, treatment with AMG 479 was not associated with major tumor responses among patients with metastatic low-intermediate grade carcinoid or pancreatic NET. Subgroup analysis to identify characteristics of patients who may have benefited from therapy with AMG 479 is ongoing.

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B12Global MicroRNA Profiling of Small Intestine Neuroendocrine Tumors (SI-NETs) and Establishment of a Method to Study Serum MicroRNA Expression From the Same Tumors

Su-Chen Li,1 Cécile Martijn,2 Ahmed Essaghir,3 Ricardo V. Lloyd,4 Jean-Baptiste Demoulin,3 Kjell Öberg,1,5 Valeria Giandomenico1,51Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 2Department of Surgical Sciences, Anaesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden; 3Université Catholique de Louvain, de Duve Institute, Brussels, Belgium; 4Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison Wisconsin, United States; 5Endocrine Oncology Clinic, Uppsala University Hospital, Uppsala, Sweden..

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Background

MicroRNAs (miRNAs) are important post-transcriptional regulators in biological processes and they function either as tumor suppressors or oncogenes. This study aims at providing exclusive miRNAs profile and identifying serum miRNA expression from SI-NET patients’ serum.

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Methods

We used frozen SI-NET specimens to perform Affymetrix miRNA-arrays. QRT-PCR analysis validated our in silico results. Moreover, human NET cells and serum samples were involved in the study.

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Results

Global miRNA profile shows the expression of significantly altered nine miRNAs between primary tumors and metastases. Furthermore, QRT-PCR analysis from laser-capture microdissected (LCM) tumor cells detected upregulated miR-96, -182, -183, 196a and 200a expression in LCM tumor cells versus LCM normal enterochromaffin (EC) cells from two independent specimen sets. Whereas, miR-31, -129-5p, -133a and -215 were downregulated in LCM tumor cells versus LCM normal EC cells. In addition, the five upregulated miRNAs are significantly more expressed in LCM primary tumor cells than in LCM stroma cells. Whereas, two downregulated miRNAs out of four are significantly less expressed in LCM primary tumor cells than in LCM stoma cells. The nine deregulated miRNAs are expressed at different level on five human NET cell lines. Moreover, the potential miRNA target genes list is the results of miRNA online software programs search combined to our published results from SI-NETs microarray analysis by Leja et al., 2009. In addition, we established a technical method to isolate miRNAs from serum samples. Total RNA, which includes miRNAs, was isolated from 3 healthy donors, 3 primary SI-NETs, 3 lymph node metastases and 3 liver metastases. Then, QRT PCR analysis was used to prove method reliability by detecting miR-16, an internal control.

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Conclusion

The SI-NET miRNA profile provides potential pivotal miRNAs, which may be involved in tumor progression and having a role to develop novel therapeutic targets. Moreover, we may implement the study using patient’s serum.

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The Prevalence of Over the Counter Medication Use Among Patients with Mid-Gut Neuroendocrine Tumors

Erika B. Lindholm, MD,1 Maneesh K. Gupta, MD,1 Anne Diebold, BS,1 JP Boudreaux, MD,1 Yi Z. Wang, MD,1 Eugene A. Woltering, MD.11Department of Surgery, Louisiana State University, New Orleans, Louisiana 70130.

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Background

Recent increases in the use of over the counter (OTC) medicines partnered with under reporting the use of these medications to physicians has sparked interest in the number and types of “supportive” therapies used by patients with neuroendocrine tumors. Patients with NETS are of special interest due to the potential interactions/interferences between tumor -associated peptide and amine production and the use of these supplements.

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Methods

A retrospective analysis of patients with primary ileal or jejunal carcinoid between 1998–2012 was conducted to define and catalog each patient’s prescription and OTC medications at each clinic visit. The most recently recorded patient medications were used for this analysis.

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Results

362 patients with small bowel primary NETS were studied. 187 patients (51.6%) were taking nutritional supplements. Of these taking supplements, the percent of patients taking 1, 2, 3, or >3 supplements is 28.3%, 24.1%, 22.5% and 25.1% respectively. Females (n=109) were more likely to take supplements in comparison to male (n=78), p = 0.037. The most popular supplement types were vitamins [162 patients (44.7%)], followed by elemental supplements [107 patients (29.5%)], botanical [28 (7.7%)] and amino acid [3 patients (0.8%)]. 51 patients (14.1%) took OTC proton pump inhibitors and 31 patients (8.6%) took Loperamide.

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Conclusion

OTC supplement use is prevalent and is used by 50% of our patients with primary small bowel NETS. Over a third of our patients reported using three or more over the counter medicines daily. These medicines have the potential to interact with the metabolism of prescribed medicines, modify ability to clot during surgery and can potentially exacerbate NET symptoms. Given the prevalence of over the counter medication use and their potential actions it is important to carefully catalog and track their use.

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Activation of EGFR and c-Met Signaling Pathways in Well-Differentiated Neuroendocrine Tumors of the Small Intestine

E. Liu,1 K. Mikhitarian,1 F. Revetta,1 C. Shi11Vanderbilt University Medical Center, Nashville, TN..

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Background

Well-differentiated neuroendocrine tumors of the small intestine (SI-NETs) are the second most common malignancy of the gastrointestinal tract only after colorectal carcinoma. Little is known about molecular mechanisms underlying the tumor growth. The purpose of this study is to explore the role of EGFR and c-Met signaling pathways in the pathogenesis of SI-NETs.

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Methods

A tissue microarray of primary and metastatic SI-NETs was evaluated by immunohistochemistry for expression of amphiregulin, Her2/neu, EGFR, phosphorylated –EGFR (p-EGFR), c-Met and phosphorylated c-Met (p-c-Met). The microarray contains 9 cases with primary SI-NET and liver metastasis, 20 with primary tumor only, and 6 with liver metastasis only. Activation of EGFR and c-Met was compared between the primary tumors and liver metastases. The correlation of the activation of these two signaling pathways and liver metastatic status was also assessed. Fisher’s exact test was used to calculate p values.

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Results

Amphiregulin was diffusely expressed in all primary and metastatic SI-NETs. EGFR expression was not detected in any of the tumors. Weak membranous Her2/neu labeling was observed in 18 of 35 (51%) cases. Eleven of 35 (31%) cases were labeled with p-EGFR (activated EGFR). Cytoplasmic and membranous labeling of c-Met was found in almost all cases. However, activation of c-Met (p-c-Met) was only present in 13 of 35 (37%) cases. The activation of c-Met and EGFR was not associated with increased or decreased liver metastasis (p>0.05). In addition, there was no significant difference in p-EGFR and p-c-Met labeling between the primary SI-NETs and liver metastases (see table 1, p>0.05), indicating that the activation of EGFR and c-Met may not play a key role in the different growth pattern of metastatic SI-NETs in the liver.

TABLE 1

TABLE 1

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Conclusions

Activation of EGFR and c-Met signaling pathways may be involved in tumorigenesis of SI-NETs. However, activation of EGFR and c-Met signaling pathways does not appear to account for the extensive growth pattern of liver metastases from these tumors.

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Expression of Serotonin, FGF2, β-Catenin, E-Cadherin and Cadherin 17 in Primary and Metastatic Well-Differentiated Neuroendocrine Tumors of the Small Intestine

E. Liu,1 K. Mikhitarian,1 F. Revetta,1 C. Shi11Vanderbilt University Medical Center, Nashville, TN..

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Background

While most primary well-differentiated neuroendocrine tumors of the small intestine (SI-NETs) remain small and asymptomatic, they can spread to regional lymph nodes and to the liver where they can grow extensively, causing small bowel obstruction and liver failure. Mechanisms underlying the different local behavior of the primary and metastatic tumors have not been elucidated. In this study, we investigate the expression of serotonin, FGF2, β-catenin, E-cadherin and cadherin 17 in primary and metastatic SI-NETs.

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Methods

A tissue microarray of primary SI-NETs (n=28) and lymph node metastases (LN-mets, n=24) was assessed by immunohistochemistry for expression of serotonin, FGF2, β-catenin, E-cadherin and cadherin 17. The expression of these molecules was compared between the primary tumors and their corresponding LN-mets. The relationship between their expression in the primary tumors and liver metastatic status was also analyzed.

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Results

Serotonin was expressed in a majority of primary SI-NETs (Table 1), with most cases showing a decrease in the LN-Met. FGF2 was expressed in 57% of primary tumors, with LN mets from FGF2-positive primaries showing decreased expression. In addition, 8 of 12 (67%) cases of FGF2-negative primary tumors had liver metastases, whereas only 4 of 16 (25%) cases of FGF2-positive primary tumors had liver metastases (p=0.05, Fisher’s exact test). All the primary SI-NETs had β-catenin cytoplasmic and nuclear labeling, with most showing decreased β-catenin labeling in the LN-mets compared to their corresponding primary tumors. The expression of E-cadherin was present in almost all primary SI-NETs but was variable in the LN-mets. Cadherin-17 was strongly expressed in all primary and metastatic SI-NETs. There was no association between liver metastatic status and the expression of serotonin, β-catenin, E-cadherin or cadherin 17 in the primary tumors.

TABLE 1

TABLE 1

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Conclusion

Loss of FGF2 expression in primary SI-NETs may be associated with an increased risk for liver metastasis. Decreased serotonin, FGF2 and β-catenin expression was observed in the LN-mets in the majority of the SI-NETs. All SI-NETs and their LN-mets expressed cadherin 17, which is also known to mark other GI carcinomas.

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Loss of Succinate Dehydrogenase (SDHB) Expression in Midgut Carcinoids as Prognostic Factor: A New Marker of Personalized Cancer Medicine in Neuroendocrine Tumors?

Massimo Milione,1 Sara Pusceddu,2 Roberto Buzzoni,3 Angela Damato,3 Emanule Meroni,4 Alfonso Marchianò,5 Barbara Formisano,2 Ettore Seregni,6 Filippo G. de Braud,2 Jorgelina C. Coppa,7 Vincenzo Mazzaferro,7 Giuseppe Pelosi11Pathology Unit; 2Medical Oncology Unit; 3Day Hospital Unit; 4Endoscopic Unit; 5Radiologic Unit; 6Nuclear Medicine Unit; 7Surgery and Liver Transplantation Unit, Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan, Italy for the ENETS Center of Excellence.

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Background

Gene mutations of SDH complex have been involved in the pathogenesis of cancer cells. These mutations are often associated with loss of activity of SDH subunity B and overexpression of HIF-1α, which play a central role in angiogenesis.

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Aims

To investigate the expression of SDHB levels in carcinoids as prognostic marker.

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Methods

31 carcinoid tumors were analyzed. Immunohistochemical (IHC) results for SDHB were assessed according to the staining intensity scored as 1 (low) or 2 (high).

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Results

The IHC loss of SDHB expression has been reported to be a surrogate marker of malignancy in pheochromocytomas and paragangliomas, via activation of hypoxia signals. All patients had G1 tumors with stage IV for synchronous liver metastases. 25/31 patients underwent primary surgery. IHC evaluation of the SDHB and MIB1 expression was carried out in 19 primary tumors (T) and 19 liver metastases (M). In 11 patients, SDHB and MIB1 were tested in both T and M. High (2+) positivity for SDHB, with clear cytoplasmatic mitochondrial reactivity, was found in 14/19 (77%) T, while loss of SDHB expression (1+) was detected in 17/19 (90%) M. The combined analysis (T+M) confirmed the loss of SDHB expression in 9/11 (82%) M compared to 2/11 (18%) T. These findings were inversely proportional to MIB1 distribution, that was 1,5% in the metastatic sites and 0.7% in the primary ones, respectively. The intensity of SDHB staining in tumor cells was associated significantly with the site of tumors and Ki67 labeling index, as primary lesions bearing a proliferative activity ≤ 1.3% showed over 50% immunoreactive tumor cells. Likewise, significant associations were found among the site of tumors (p<0.0001) or Ki-67 labeling index (p<0.0001) and SDHB intensity. No further associations were found.

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Conclusions

This analysis suggests a possible correlation among SDHB expression loss, MIB1 increase and biological aggressiveness of advanced midgut carcinoids.

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Surveillance of Small Rectal Carcinoid Tumors in the Absence of Metastatic Disease

Sara E. Murray, MD,1 Rebecca S. Sippel, MD, FACS,1 Ricardo Lloyd, MD, PhD,2 Herbert Chen, MD, FACS.11Section of Endocrine Surgery, Department of Surgery, University of Wisconsin, Madison, WI; 2Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI.

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Background

The incidence of rectal carcinoids is rapidly increasing, typically presenting as small (<1.0 cm) localized tumors. While the evaluation of rectal carcinoids on presentation is well standardized, surveillance following resection has not been well established.

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Methods

A prospective database documented patients with rectal carcinoids at our institution between January 1995 and September 2011. Information collected included patient and tumor characteristics, treatment method, surveillance schedule, recurrence, and survival.

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Results

Twenty-eight patients with rectal carcinoid were identified. Ten patients were excluded for tumors >1 cm, known metastases, <6 months follow-up, or previous resection. The mean age of the remaining patients was 56±3 years and 61% were female. All patients were diagnosed on endoscopy, with 50% diagnosed incidentally on screening endoscopy. Treatment methods included endoscopic therapy (n=13, 72%), transanal excision (n=3, 17%), and transanal endoscopic microsurgery (n=1, 5.5%). One patient (5.5%) received no additional invasive therapy after diagnostic endoscopy. The mean tumor diameter was 4.6±0.5 mm. The average length of follow-up was 5.4±0.9 years, with a median number of 2 follow-up endoscopies (range 0–6). Two patients (11%) died within the follow-up period from non-carcinoid causes. Importantly, no surviving patients developed local or distant recurrence with up to 12.3 years of follow-up.

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Conclusion

Based on this experience, patients presenting with small (≤1.0 cm), non-metastatic rectal carcinoids are unlikely to develop local or distant recurrence after resection. Aggressive surveillance with repeat endoscopies or other imaging studies after resection may be unnecessary in this patient population.

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Telotristat Etiprate Produces Clinical and Biochemical Responses in Patients with Carcinoid Syndrome: Update of a Phase 2, Multicenter, Open-Label, Serial-Ascending, European Study

Marianne Pavel,1 Bertram Wiedenmann,1 Martyn Caplin,2 Dieter Hoersch,3 Joel Freiman,4 Linda Law,4 Phillip Banks,4 Kenny Frazier,4 Jessica Jackson,4 Brian Zambrowicz.41Charité - Universitätsmedizin, Berlin Germany; 2Royal Free London NHS Foundation Trust, London, United Kingdom; 3Zentralink Bad Berka GmbH, Bad Berka, Germany; 4Lexicon Pharmaceuticals, Inc., The Woodlands, TX United States.

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Background

Excess serotonin (5-HT) may cause gastrointestinal (GI) symptoms (eg, diarrhea) in carcinoid syndrome (CS) patients. Telotristat etiprate is an oral serotonin synthesis inhibitor (tryptophan hydroxylase inhibitor) designed to reduce peripheral 5-HT levels and alleviate GI distress.

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Methods

This study evaluated the safety and tolerability of intrapatient dose escalation (150, 250, 350, and 500 mg tid) of telotristat etiprate in CS patients, averaging ≥4 bowel movements (BMs)/day, with or without background somatostatin analog therapy. Dose strength was increased following every 2 weeks of therapy with no dose-limiting toxicity (DLT). The maximum dose for each patient was extended for an additional 4 weeks. Objectives included evaluation of symptomatic response (including number of BM/day, and flushing episodes), global assessment of symptoms, and biochemical response (urinary 5-hydroxyindole acetic acid [5-HIAA]).

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Results

15 patients enrolled with a mean baseline BMs/day of 5.9, flushing 2.8/day, and urinary 5-HIAA of 127.8 mg/24 hrs. 12/15 patients escalated to 500 mg tid. Data collected during the final 4 wks of therapy demonstrated that 11 (73%) had mean reductions of ≥30% and 5 (33%) had ≥50% reduction in BMs/day; 11 of 15 patients had baseline flushing and 5 (45%) had mean reductions of ≥30% in flushing/day. 5-HIAA levels decreased an average of 54% from baseline. There were no drug-related SAEs and no dose-limiting toxicities.

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Conclusion

Telotristat etiprate (≤500 mg tid) produced clinically relevant biochemical and clinical responses in patients with carcinoid syndrome. Telotristat etiprate was safe and well tolerated through 12 weeks of therapy. The program will be advanced into further clinical studies.

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Interim Results of an Open-Label, Single-Arm Trial of Ultratrace I-131-Iobenguane in Patients with Metastatic Pheochromocytoma/Paraganglioma (Pheo)

Daniel A Pryma,1 R Edward Coleman,2 Richard Noto,3 Rodolfo F Perini,4 Camilo Jimenez,5 Miguel Pampalon,6 Aldo Serafini,7 Richard Wahl,8 Lale Kostakoglu,9 Perry W. Grigsy,10 Julie Schwarz,10 Kathy Ford,11 Jennifer Conley,11 Norman LaFrance,11 John Barrett,11 John Babich.111University of Pennsylvania, Philadelphia PA 19104; 2Duke University Medical Center, Durham NC 27710; 3Rhode Island Hospital, Providence RI 02903; 4Hospital of the University of Pennsylvania, Philadelphia PA 19104; 5MD Anderson Cancer Center, Houston TX 77030; 6UCSF, San Francisco CA 94143; 7University of Miami, Miami FL 33136; 8Johns Hopkins School of Medicine, Baltimore MD 21205; 9Mount Sinai School of Medicine, New York, NY 10029; 10Washington University, St. Louis, MO 63110; 11Molecular Insight Pharmaceuticals, Cambridge MA 02142.

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Background

The primary aim of this study was to evaluate the therapeutic efficacy of no carrier added (nca) I-131-MIBG in pheo as measured by >50% reduction of all antihypertensives for ≥6 months. Secondarily, to evaluate safety and assess for objective and biomarker responses.

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Methods

Patients with metastatic pheo causing hypertension were treated with up to two 500 mCi doses of 131I-nca-MIBG 3–6 months apart. Administered dose was limited by pretreatment organ dosimetry (Emami 1991). Response and toxicity were evaluated for at least 1 year or until death.

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Results

41 patients (16–72 years) received at least one treatment (full analysis; FA); 34 patients received 2 treatments (per protocol; PP). All patients were followed at least 1 year or until death. The primary endpoint of sustained reduction in antihypertensives was achieved in 35% (PP) and 32% (FA). 25/41 subjects who received at least 1 treatment had ≥50% reduction in antihypertensives, mean duration 8.3±6.9 months (range 0.1–22.1 months). Objective PR was seen in 41% (PP) and 34% (FA). 56% of PP had at least objective MR. All PP subjects and 90% in FA had at least stable disease. At 8 months there was a 53±31% reduction in ChromograninA from baseline in PP. Median survival to date is 31 months.

Primary toxicity was myelosupression: Grade 3 (27%), Grade 4 (30%). Grade 3 GI disorders were 36%. Biomarker response correlated to objective and antihypertensive responses. Thrombocytopenia was the most common treatment-emergent SAE (n=4) related to study drug. No other treatment-emergent SAE was related to study drug in >2 subjects.

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Conclusions

12 of 34 in PP in this study met the primary endpoint, which correlated with objective and biomarker responses in this disease with no approved, efficacious therapies. Toxicity for all patients was tolerable and predominantly limited to myelosupression.

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Expression of MTOR Pathway Components and Association With Clinical Outcomes in Neuroendocrine Tumors

Zhi Rong Qian,1 Monica Ter-Minassian,1,3 Jennifer A. Chan,1 Yu Imamura,1 Susanne M. Hooshmand,1 Aya Kuchiba,1 Teppei Morikawa,1 Lauren K. Brais,1 Anastassia Daskalova,1 Rachel Heafield,1 Xihong Lin,2 David C. Christiani,3,4,5 Charles S. Fuchs,1,6 Shuji Ogino,1,4,7 Matthew H. Kulke11Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 2Department of Biostatistics; 3Department of Environmental Health; 4Department of Epidemiology, Harvard School of Public Health, Boston; 5Massachusetts General Hospital, Harvard Medical School, Boston, MA; 6Channing Laboratory, Department of Medicine; 7Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

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Background

Clinical studies have implicated the MTOR pathway in the regulation of neuroendocrine tumor growth. We investigated whether immunohistochemical expression of mTOR pathway components have prognostic significance in NET patients.

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Methods

We evaluated expression of the mTOR pathway components PIK3CA, PIK3R1, PDPK1, AKT, p-AKT, TSC1, TSC2, MTOR, p-MTOR, p-RPS6KB1, p-RPS6, and p-EIF4EBP1, in a cohort of archival neuroendocrine tumors. We correlated expression levels with clinical outcomes, after adjusting for other clinical prognostic variables.

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Results

We evaluated 196 cases with the following clinical characteristics: small bowel/pancreas/other: 125/19/52; M/F: 94/102, mean age 56 yrs, localized (Stage 1-3)/metastatic (stage 4): 96/95; Ki 67 ≤20%/>20%: 173/12. In the overall cohort, high expression of p-RPS6KB1, a downstream target of mTOR, was associated with both shorter DFS (HR 3.34, p=0.019) and OS (HR 2.80, p=0.02) in a multivariate analysis. In the subgroup of resected small bowel NET (n=47), high expression of mTOR was associated with shorter DFS in both univariate (HR 3.73, p=0.036) and multivariate (HR 11.7, p=0.016) analysis. In metastatic small bowel NET (n=76), univariate analysis revealed that high expression of mTOR (HR 2.48, p=0.029), p-RPS6 (HR 3.37, p=0.01 and p-EIF4EBP1 (HR 2.64, p=0.022) was associated with shorter OS. In multivariate analysis, high expression of p-RPS6KB1 (HR 3.02, p=0.03) and p-EIF4EBP1 (HR 2.77, p=0.037) was associated with shorter OS in metastatic pts.

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Conclusion

Expression of MTOR and its downstream effectors, including p-RPS6KB1 and/or p-EIF4EBP1 appear to be associated with clinical outcomes in patients with NET. In addition to studies confirming these observations, specific studies investigating whether these markers may also be associated with response to MTOR inhibitors are warranted.

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Use of a 92-gene Molecular Classifier to Predict the Site of Origin for Primary and Metastatic Tumors with Neuroendocrine Differentiation

Catherine A. Schnabel, PhD,1 Sarah E. Kerr, MD,2 Peggy Sullivan, MD,3 Yi Zhang, PhD,1 Veena Singh, MD,1 Brittany Carey,4 Mark G. Erlander, PhD,1 W. Edward Highsmith, PhD,2 Elena F. Brachtel, MD,4 Sarah M. Dry, MD31bioTheranostics, Inc., San Diego, CA, United States; 2Mayo Clinic, Rochester, MN, United States; 3University of California at Los Angeles, Los Angeles, CA, United States; 4Massachussetts General Hospital, Boston, MA, United States.

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Background

A diagnosis of neuroendocrine carcinoma (NEC) is typically straight-forward using a combination of morphology and immunohistochemical stains (eg. synaptophysin, chromogranin), however, the tumor site of origin may remain elusive in a metastatic presentation. Neuroendocrine tumor subtyping has important implications for staging and management. This study describes the use of a 92-gene molecular cancer classifier for neuroendocrine tumor subtyping.

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Methods

Seventy-five (44 metastatic and 31 primary) formalin-fixed, paraffin-embedded tumor samples were selected after a 3-pathologist adjudicated review. Clinicopathologic diagnoses were classified as follows for comparison to the molecular classifier output: Intestinal NEC (n=12), high-grade pulmonary NEC (small cell or large cell, n=11), low-grade pulmonary NEC (pulmonary carcinoid, n=11), Merkel cell carcinoma (n=10), pancreatic NEC (n=10), pheochromocytoma/paraganglioma (n=10), and medullary thyroid carcinoma (n=11). Samples were tested in a blinded fashion using the CancerType ID 92-gene classifier (bioTheranostics, Inc), which makes tumor type predictions based upon expression measurement of 87 gene targets and 5 reference genes by quantitative PCR. The top classifier prediction was compared to the reference diagnosis.

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Results

The classifier correctly predicted the reference subtype diagnosis in 71 of 75 cases (95%). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for predicting individual subtypes are shown in Table 1. Three of the 4 incorrectly predicted cases were correctly predicted to the neuroendocrine carcinoma level, but were assigned an incorrect subtype.

TABLE 1

TABLE 1

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Conclusion

The 92-gene classifier demonstrated excellent accuracy for subtyping tumors with neuroendocrine differentiation. While this study did not adjust for subtype prevalence in practice, these results show promise for use in classifying neuroendocrine tumors of unknown primary site.

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Factors Associated with Octreotide LAR Use Among Elderly Patients with Carcinoid Syndrome: A Population-Based Analysis

Chan Shen,1 Ying Xu,1 Colleen C. Leary,1 James C. Yao,1 Ya-Chen Tina Shih.21University of Texas M. D. Anderson Cancer Center, 1515 Holcombe, Houston Texas 77030; 2University of Chicago, 5841 S. Maryland Ave., MC 5000, Office W306, Chicago IL 60637.

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Background

Octreotide LAR is indicated for the treatment of carcinoid syndrome, diarrhea related to VIPoma, and may delay tumor growth in neuroendocrine tumors (NETs). The pattern of octreotide LAR use in clinical practice has not been well documented.

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Methods

Using the SEER-Medicare database, we identified patients diagnosed with NETs from July 1999 to Dec 2007. We then excluded those patients with poorly differentiated histology, under age 65 at diagnosis, enrolled in HMOs, and who did not have continuous Part A & B enrollment within 12 months of diagnosis. We further identified patients with potential indication for octreotide LAR use as those having two or more claims indicating carcinoid syndrome, flushing, diarrhea, or malignant islet cell neoplasm within the first year of NETs diagnosis, with the first claim occurring within 6 months of diagnosis. HCPCS codes, J2352 and J2353, were used to identify octreotide LAR use. Multivariate logistic regression analysis was performed to ascertain factors associated with octreotide use; covariates included age, race, region, comorbidity score, urban/rural status, tumor characteristics, neighborhood socioeconomic status and year of diagnosis.

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Results

Of the 2000 NETs patients with potential indication for octreotide LAR use, 478 (23.9%) were started on octreotide LAR within 6 months of diagnosis. Multivariate analysis showed that older age (≥ 80) (OR=0.61, 95 CI=0.44 – 0.86), southern region (OR =0.67; 95% CI =0.44 – 1.00) and tumor of undetermined grade (OR=0.71, 95% CI=0.52 – 0.98) were associated with lower odds of octreotide use while the odds was positively associated with advanced stage and more recent diagnosis years. By primary site, no clear pattern was identified.

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Conclusions

Our analyses suggest only a small (< 25%) fraction of patients with eligible diagnoses are receiving indicated therapy with octreotide LAR. Further studies and improved education are needed to improve the management of carcinoid syndrome.

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Clinical, Pathologic, and Biologic Characterization of WHO Grade 3, Non Small Cell and Non Large Cell Neuroendocrine Carcinoma of the Pancreas

Chanjuan Shi,1 Jesse Wright,2 Frank Revetta,1 Eric Liu,2 Alex Parikh†,2 Kay Washington,1 Nipun Merchant.2,31From the Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232; 2From the Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232; 3From the Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232.

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Background

WHO has classified pancreatic neuroendocrine tumors (PanNETs) into 3 grades based on Ki-67 and mitosis: grade 1 (Ki-67≤2% and mitosis<2/10 HPF), grade 2 (Ki-67=3–20% and/or mitosis=2–20/10 HPF), and grade 3 (Ki-67>20% and/or mitosis>20/10 HPF). Little is known about a small percentage of grade 3 PanNETs that have a morphology indistinct from grade 1–2 PanNETs, but with a Ki-67>20% and/or mitosis>20/10 HPF. This study explores their clinical, pathologic and biological features.

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Methods

Review of 94 resected PanNET patients from 2002 to 2011 identified 10 WHO grade 3 PanNETs that were neither small cell carcinoma nor large cell NET. These tumors had morphology very similar to grade 1–2 PanNETs, but had mitosis >20/10 HPF (n=5) and/or a Ki-67>20% (n=10). Clinical history and pathologic features were reviewed. Specimens were immunohistochemically labeled with Ki67, her2/neu, c-Met, and EGFR.

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Results

Of the 10 cases, 60% were male and ages ranged from 38–78 years. 3 pts had a hereditary syndrome: 2 with MEN1 and 1 with Von Hippel–Lindau. Tumor size ranged from 2.4 to 26.0 cm. 5 pts presented with stage IV disease, 4 with stage II and 1 with stage I. Overall survival for these pts was significantly worse than that of grade 1 and 2 PanNET pts. Focal necrosis, lymphovascular invasion (LVI), and perineural invasion (PNI) were observed in 50%, 70%, and 30% of cases, respectively. All cases were diffusely and strongly labeled with c-Met; 6 had weak Her2/neu membranous labeling and 4 had expression of EGFR.

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Conclusion

Grade 3 PanNETs account for ∼10% of PanNETs and can occur in pts with or without a hereditary syndrome. Most pts present with advanced disease and have worse prognosis. The tumors are always associated with high risk pathologic features (necrosis, LVI, PNI, and thickened fibrotic septa) and express other growth factor receptors such as c-Met, Her2/neu or EGFR, which may provide a clue towards further understanding their biology to identify novel targeted therapies.

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Zollinger-Ellison Syndrome is Best Managed by Surveillance in Multiple Endocrine Neoplasia-1 and Surgery in Eligible Sporadic Cases

Maneesh H. Singh, MD,1 Douglas L. Fraker, MD,2 David C. Metz, MD.1,31Department of Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104; 2Department of Surgery, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104; 3Division of Gastroenterology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104.

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Background

Zollinger-Ellison syndrome (ZES) management remains controversial because few institutions see sufficient patients to allow for comprehensive post-intervention analysis. We investigated surgical outcomes of ZES patients to determine the best approach to management of this population.

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Methods

A retrospective chart review of 49 ZES patients seen at a tertiary care center since 1994 was performed. Cox proportional hazards modeling was used for survival comparisons between similar groups based on Multiple Endocrine Neoplasia-1 (MEN-1) and surgical status. Differences between variables were compared using the unpaired t-test and Fisher’s exact test when appropriate.

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Results

Of 49 ZES patients, 34 underwent surgery (9 with MEN-1). Compared to sporadic ZES patients, MEN-1-associated patients present earlier (34.9 vs. 45.7yrs; p<0.05), are diagnosed earlier (39.3 vs. 49.7yrs; p<0.01); yet, die at the same age (55.9 vs. 55.1yrs; p=0.91) with no MEN-1 deaths due to progressive disease (0% vs. 86%; p<0.05). Lymph node involvement at surgery likely increases risk of liver metastasis in the setting of the natural history of gastrinoma (Figure 1; p=0.13) and was significantly associated with lack of postoperative cure (p=0.01). Surgery decreased all-cause (HR 0.11 [0.2–0.6]; p=0.011) and disease-related mortality (HR 0.14 [0.2–0.84]; p=0.032) in sporadic, but not MEN-1, patients.

FIGURE 1

FIGURE 1

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Conclusions

The presence of MEN-1 predicts earlier onset and diagnosis of ZES but a more benign clinical course rarely characterized by disease-related death in support of deferring surgery early on. However, sporadic ZES is associated with disease-related mortality that is reduced by early surgical intervention. Lymph node involvement at surgery likely increases the risk of liver metastases which, in almost all cases, occurred within 2 years of diagnosis. In addition, lymph node involvement decreased the likelihood of postoperative cure further supporting surgical intervention soon after diagnosis in eligible sporadic patients.

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Epidemiology of Neuroendocrine Tumors in Ontario: A 15-year Population-Based Study

Simron Singh,1 Refik Saskin,2 Ning Lin,2 Moises Cukier,1 Calvin Law.1,21Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Canada; 2Institute for Clincial Evaluative Sciences, Toronto, Canada.

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Background

A recent study of the SEER database in the United States showed a 5-fold increase in neuroendocrine tumours (NETs) over the last 30 years. Conflicting reports of incidence trends have been reported worldwide. The objective of our study is to describe the incidence and anatomical distribution of NETs in Ontario, Canada.

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Methods

A population based study was initiated using the Ontario Cancer Registry, cross-linked with the Registered Persons Database and the Canadian Institute of Health Information Discharge Abstract Database. All cases of NETs were identified in Ontario (> 13 million persons) from 1994 to 2009. Baseline demographic, clinical and outcomes data were abstracted.

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Results

A total of N = 5619 cases were identified. The incidence rate increased from 2.46/ 100,000 (95% CI, 2.13–2.83) in 1994 to 5.86/ 100,000 (95% CI, 5.40 – 6.35) in 2009. The median age was 62 with 50.5% female cases. Bronchopulmonary NETs where the most common (22%), then jejunum/ileum (17%) and rectal (16%). The absolute increase was most pronounced for pNETs (6-fold), rectal (5-fold) and gastric (5-fold) NETs. Metastatic disease was documented in 45% of cases.

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Conclusions

There appears to be a significant increase of reported cases of NETs in Ontario, Canada, particularly pancreas, rectum and gastric NETs. This supports much of the population-based reports worldwide. Further research is required to understand the impact of this cancer previously perceived to be rare but clearly increasing.

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Patterns of Care of Neuroendocrine Cancer in Ontario: Health Services Delivery

Simron Singh,1 Refik Saskin,2 Ning Lin,2 Moises Cukier,1 Calvin Law1,21Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Canada; 1Institute for Clinical Evaluative Sciences, Toronto, Canada.

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Background

Delayed diagnosis and treatment of NETs may result in increased health care utilization, medical costs and patient distress. Patients may be treated by different specialists and modalities.The aim of this study is to analyze health care utilization of NETs patients in Ontario and variations in treatments.

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Methods

Using the Ontario Cancer Registry (cross-linked with the Registered Persons Database and the Canadian Institute of Health Information Discharge Abstract Database), all cases of NETs were identified in Ontario (> 13 million persons) from 1994 to 2009. Baseline demographic, clinical and outcomes data were abstracted.

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Results

A total of N = 5619 cases were identified. Two years, 1 year and 60 days prior to diagnosis, 60.3%, 52.3% and 35.3% of patients visited a hospital emergency room and 83.1%, 78.0% and 65.4% had a radiological investigation. Within 60 days pre-diagnosis 98% of patients visited a physician with family practice (83%), general surgeon (44%), cardiologist (25%) and gastroenterologist (22%) being the most common. Only 4% of patients visited an endocrinologist. Post diagnosis 26% of patients had chemotherapy and 8% had radiotherapy while 64% of patients had a major surgical procedure and 12% had an embolization procedure.

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Conclusions

NETs patients have large health care utilization prior to diagnosis likely due to diagnosis delays. Treatment varies significantly with most patients receiving surgery. Further follow up on patient outcomes in relation to the treatments is warranted.

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Survival of Patients with Neuroendocrine Cancers in Ontario Over Last 15 Years

Simron Singh,1 Refik Saskin, Ning Lin,2 Moises Cukier,1 Calvin Law1,21Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Canada; 2Institute for Clinical Evaluative Sciences, Toronto, Canada.

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Background

There has been increased incidence of neuroendocrine tumours (NETs) in Ontario, Canada over the last 15 years but little is known about trends in survival. The aim of this study is to examine the survival and associated prognostic factors of NET patients in Ontario.

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Methods

A population based study was initiated using the Ontario Cancer Registry, cross-linked with the Registered Persons Database and the Canadian Institute of Health Information Discharge Abstract Database. All cases of NETs were identified in Ontario (> 13 million persons) from 1994 to 2009. Baseline demographic, clinical and outcomes data were abstracted. A multivariate cox proportional hazards analysis was performed.

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Results

A total of N = 5619 cases were identified. Probability of recurrence free survival/overall survival at one, five and ten years was 0.81, 0.71 and 0.65 vs 0.81,0.61 and 0.47 respectively. Probability of recurrence was 0.40 years and 0.21 at 5 and 10 years. Significant predictors of death included male sex (HR=1.30), age at diagnosis (HR=1.04), rural resident (HR=1.135) and lowest income quintile (HR=1.24). Pancreas primary (HR=1.38) was most associated with death and rectum (HR= 0.34) and small bowel (HR=0.61) were least.

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Conclusions

Poor outcome factors include male sex, age of diagnosis and pancreas primary. Rural residence and low income were also associated with poor survival, perhaps due to less access to specialized NETs care. This issue requires further examination as does causes for decreased survival among men with NETs.

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Review of 126 High Grade Neuro-Endocrine Carcinomas of the Colon and Rectum

James D. Smith,1 Diane L. Reidy,2 Martin Weiser,1 Larissa K. Temple,1 Jose G. Guillem,1 Philip B. Paty,1 Garrett M. Nash11Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065; 2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.

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Background

High grade neuroendocrine carcinoma’s (NEC) of the colon and rectum are rare tumors, constituting less then 1% of colorectal cancers. The purpose of this review is to identify the natural history and oncologic outcomes of this disease, the role of surgery and to determine the clinical and pathological factors associated with outcomes.

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Methods

Following IRB approval patients with high grade NEC were identified from our institutional database. Patient charts and pathology reports were analyzed retrospectively for clinical and pathological factors.

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Results

126 patients with a median follow up of 9 months were identified. The median survival was 13.2 months. 85 (67%) of patients had metastatic disease at diagnosis. The 3 year overall survival (OS) was 5% and 18% for patients with and without metastatic disease respectively. Factors associated with improved OS on multivariable analysis were absence of metastatic disease and presence of an adenocarcinoma component within the tumor. For metastatic disease alone, response to chemotherapy was the only factor associated with survival. For localized disease, presence of an adenocarcinoma component within the tumor was the only factor associated with survival. Resection of the tumor was not statistically associated with survival in localized tumors or metastatic disease.

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Conclusion

High grade colorectal NEC are extremely aggressive tumors with a poor prognosis. Patients appear to have a marginally better prognosis is they present without metastatic disease, have a component of adenocarcinoma within their tumor or respond to chemotherapy. Surgery, particularly in the presence of metastatic disease, may not offer a survival benefit for the majority of patients with this disease.

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Targeting Achaete-scute Complex-like1 (ASCL1): A Regulator of Carcinoid Growth and Phenotype

Yash Somnay, BS,1 Jake Eide, BS,1 Renata Jaskula-Sztul, PhD,1 April Harrison, BS,1 Kevin Simon, BS,1 Selvi Kunnimalaiyaan, MS,1 Herbert Chen, MD, FACS,1 Muthusamy Kunnimalaiyaan, PhD,11Endocrine Surgery Research Laboratories (ESRL), Department of Surgery, University of Wisconsin School of Medicine and Public Health, 3028 Wisconsin Institutes for Medical Research, 1111 Highland Avenue, Madison, WI, 53705.

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Background

Achaete-scute complex-like1 (ASCL1), a basic helix-loop-helix transcription factor of early neuroendocrine development, is abundantly expressed among neuroendocrine tumors, including carcinoids, but absent in normal adult tissues. We’ve reported that Raf-1 or Notch pathway activation, or AKT pathway inhibition suppresses carcinoid growth and hormone production. Importantly, this correlates with significantly reduced ASCL1 levels. Thus, we sought to determine firstly, ASCL1’s role in carcinoid proliferation and bioactive hormone production, and secondly, its expression following treatment with select small-molecule compounds.

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Methods

Human pancreatic BON, and pulmonary H727 carcinoid cells were transfected with either ASCL1-siRNA to suppress ASCL1, or non-specific no target siRNA as a negative control. The effect of siRNA was assessed by Western analysis for ASCL1. BON and H727 were also treated for 4 days with MK-2206, a novel small-molecule compound developed by Merck® for treating solid tumors, after which ASCL1 levels were determined. Levels of bioactive hormones chromogranin A and synapotphysin, and cell cycle arrest markers were also assessed. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) rapid colorimetric assay measured cell viability.

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Results

ASCL1-siRNA treatment suppressed ASCL1 expression in both cell lines, while non-specific no target siRNA showed no effect. ASCL1 depletion reduced cell proliferation and levels of chromogranin A and synaptophysin. Notably, cell viability gradually recovered as ASCL1-siRNA-induced suppression diminished and ASCL1 expression was restored. ASCL1 depletion increased p21 and p27 and reduced cyclin B1 and D1 expression, suggesting cell cycle arrest. Furthermore, ASCL1 expression declined following MK-2206 treatment, also inhibiting chromogranin A expression and cell proliferation.

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Conclusions

ASCL1-knockdown experiments suggest ASCL1 is necessary for carcinoid bioactivity and viability. Furthermore, agents like MK-2206 may be effective for treating carcinoids given their ability to reduce ASCL1 expression and inhibit growth and tumor marker expression. Understanding the regulatory role of ASCL1 in carcinoid pathogenesis and clinical course may help identify molecular targets for novel treatments.

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Ki-67 Proliferative Index Predicts Response to Chemotherapy and Survival in 252 Patients with High-Grade Gastrointestinal Neuroendocrine Carcinoma (WHO G3)

Halfdan Sorbye,1 Staffan Welin,2 Seppo Langer,3 Lena Vestermark,4 Nanna Holt,5 Pia Osterlund,6 Svein Dueland,7 Eva Hofsli,8 Marianne Guren,9 Katarina Ohrling,10 Elke Birkemeyer,11 Espen Thiis-Evensen,12 Matteo Biagini,13 Henning Gronbaek,14 Leena-Maija Soveri,6 Ingrid Holst Olsen,15 Birgitte Federspiel,16 Jurg Assmus,17 Eva Tiensuu Janson,2 Ulrich Knigge151Department of Oncology, Haukeland University Hospital, Bergen, Norway; 2Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 3Department of Oncology, Rigshospitalet, University of Copenhagen, Denmark; 4Department of Oncology, Odense University Hospital, Denmark; 5Department of Oncology and Medical V, Aarhus University Hospital, Denmark; 6Department of Oncology, Helsinki University Central Hospital, Finland; 7Department of Oncology, Radium Hospital, Oslo University Hospital, Norway; 8Department of Oncology, St Olavs Hospital, University of Trondheim, Norway; 9Department of Oncology, Ullevål Hospital, Oslo University Hospital, Norway; 10Department of Oncology, Karolinska University Hospital, Stockholm, Sweden; 11Department of Oncology, Stavanger University Hospital, Stavanger, Norway; 12Department of Medicin, Oslo University Hospital, Rikshospitalet, Norway; 13Department of Pathology, Odense University Hospital, Denmark; 14Department of Medical V, Aarhus University Hospital, Denmark; 15Depart.of Surgery C, Rigshospitalet, University of Copenhagen, Denmark; 16Depart. of Pathology, Rigshospitalet, University of Copenhagen, Denmark; 17Center for Clinical Research, Haukeland University Hospital, Bergen, Norway.

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Background

Gastrointestinal neuroendocrine carcinoma (GI-NEC) are aggressive tumors and usually metastatic at diagnosis. GI-NEC have a high proliferation rate with a Ki-67 index >20% by definition, but it is often higher (>75%). Treatment of patients with gastrointestinal neuroendocrine carcinoma remains a challenge for the clinician, as published data are very limited on this subgroup of neuroendocrine tumors. We retrospectively reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients.

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Methods

Epidemiological, biochemical, histopathological, treatment and survival data were registered for advanced GI-NEC patients treated with chemotherapy during 2000-2009 at 12 Nordic university hospitals.

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Results

252 patients were included. Response rate to 1st-line chemotherapy was 31%, 33% had stable disease, and median survival was 11 months. Ki-67<55% was by ROC analysis the best cut-off value concerning correlation to response rate. Response rate to 1st-line platinum-based chemotherapy was lower in patients with Ki-67<55% (14% vs. 44%, p<0.001). Response rate for 84 patients given 2nd-line chemotherapy was 18%, whereas 33% achieved SD. The most important negative prognostic factors for survival were poor performance status, primary colorectal tumors, and elevated platelets or lactate dehydrogenase (LDH) levels at baseline. Survival and response rates did not differ between the different platinum chemotherapy schedules (cisplatin-based vs. carboplatin-based) or morphological subtypes. Patients with Ki-67<55% had longer median survival (15 months) than patients with Ki-67≥55% (10 months) (p<0.001).

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Conclusions

GI-NEC patients with Ki-67<55% had significantly longer survival than patients with higher Ki-67, but were much less responsive to platinum-based chemotherapy. Platinum-based chemotherapy may not be the optimal chemotherapy schedule when Ki-67<55%. Our data indicate that it might not be correct to consider all GI-NEC as one single disease entity (WHO G3) as in the present WHO classification.

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Does the ENETS TNM Staging Criteria Predict Survival in Patients with Small Bowel Neuroendocrine Tumours?

Rajaventhan Srirajaskanthan,1,2 Adil Ahmed,1 John K. Ramage*‡.1,31Kings College Hospital, London, United Kingdom; 2University Hospital Lewisham, London, United Kingdom; 3Hampshire Hospitals Foundation Trust, Hampshire, United Kingdom.

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Background

A TNM staging system was designed by ENETS to stage small bowel NETs. This study aims to retrospectively stage patients with known small bowel primary NETs and see whether survival is dependent on stage and grade of disease and finally to identify cause of death.

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Methods

138 patients with small bowel NETs were identified from Kings College Hospital. Primary site: Duodenal 2.1% (3), Jejunal 2.9% (4), ileal 95% (131). Mean duration of follow-up of 5 years. Median age 61 years (range 24–84).

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Results

TNM staging and follow-up data was available in 118 cases. Due to low numbers of Stage 2 and 3 tumours these were group together for comparison. There were four cases with stage 2, 23 cases with Stage 3 and 91 cases with stage 4 small bowel NETs. Kaplan- Meier plots were constructed these demonstrated a significant difference in survival between patients with different stage of disease (P=0.03). There was no significant difference in survival between stage 2 and stage 3 disease. There was a significant survival difference between G1 (Ki67 ≤2) vs. G2 (Ki67 3-20) p=0.049. There was a significant survival benefit in patients whom underwent resection of primary tumour compared to those who did not (120 vs 56 months, p<0.005). The overall 5 year and 10 year survival was 79.5% and 48.5% respectively for all patients independent of stage of disease. Of the patients that died the median time to death from diagnosis was 3 years (range 0-14). The cause of death was related to tumour burden in 50% (22 patients), carcinoid heart disease in 11.3% (5 patients), post intervention (1 case surgery, 1 case post-embolization) 4.5%, small bowel obstruction or perforation 13.6% (6 patients) and non-tumour related deaths in 24.5% (9) patients.

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Conclusion

This study demonstrates the ENETS TNM staging prognosticates survival. Overall survival has improved compared to the published SEER data.

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Medical Treatment Consensus in Unresectable Midgut Gastrointestinal Neuroendocrine Tumors

Jonathan R. Strosberg,1 George A. Fisher,2 Al B. Benson,3 Jennifer L. Malin,4 Lowell B. Anthony,5 Bulent Arslan,6 John F. Gibbs,7 Edward Greeno,8 Renuka V. Iyer,9 Michelle K. Kim,10 William J. Maples,11 Philip A. Philip,12 Edward M. Wolin,13 Dasha Cherepanov,14 Michael S. Broder.141Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA; 3Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; 4David Geffen School of Medicine, University of California, Los Angeles, CA; 5Department of Internal Medicine, Division of Medical Oncology, University of Kentucky Markey Cancer Center, Lexington, KY; 6Rush University Medical Center, Chicago, Illinois; 7Department of Surgery, State University of New York at Buffalo, Buffalo, NY; 8Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN; 9Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY; 10Department of Medicine - Gastroenterology Mount Sinai School of Medicine, New York, NY; 11Mission Health System, Asheville, NC; 12Department of Oncology, Karmanos Cancer Institute, Detroit, MI; 13Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA; 14Partnership for Health Analytic Research, LLC, Beverly Hills, CA.

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Background

Neuroendocrine tumors (NETs) comprise mostly carcinoid or pancreatic NETs and are rare with symptoms that may be difficult to control. Current treatment guidelines lack some specificity. We summarize an expert panel consensus on medical treatment of well-differentiated unresectable midgut NETs.

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Methods

Consensus statements were developed via RAND/UCLA Delphi process, which involved a diverse group of physician experts (e.g., by specialty, geography, practice) developing comprehensive clinical patient scenarios and rating the scenarios on the appropriateness of various medical therapies before and after a face-to-face meeting. Experts and moderator were blinded to funding source. Scenarios were rated on a 1–9 scale and were labeled as appropriate, inappropriate, or uncertain. Scenarios with >2 ratings in 1–3 and >2 in 7–9 range were considered to have disagreement and were not assigned an appropriateness rating.

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Results

Panelists (age: 38-63 years) were from the northeast, midwest, south, and west regions. Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean 15.5 years (range: 6–33). Panelists rated 202 scenarios. The proportion for which there was disagreement decreased from 11.7% (23 scenarios) before the meeting to 4.5% (9) after. Post-meeting, 49% (99 scenarios) were rated inappropriate, 29.7% (60) were uncertain, and 16.8% (34) were appropriate. Consensus statements from the scenarios included: 1) it is appropriate to use somatostatin analogs (SA) as 1st-line therapy in all patients, 2) it is appropriate to increase the dose/frequency of octreotide-LAR as 2nd-line therapy in patients with uncontrolled symptoms up to 60 mg every 4 weeks or up to 40 mg every 3 or 4 weeks for refractory carcinoid syndrome. Other treatment options may also be appropriate in 2nd-line.

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Conclusion

Treatment consensus obtained in this study is concordant with NCCN recommendations. The Delphi process allowed quantification of ratings in a systematic and reliable way while improving consensus in a group of physicians on the appropriateness of medical therapies in midgut NETs.

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Prognostic Validity of the American Joint Committee on Cancer (AJCC) Staging Classification for Midgut Neuroendocrine Tumors

Jonathan Strosberg, MD,1 Jill Weber, MPH,1 Max Feldman, MD,1 Larry Kvols, MD.11H. Lee Moffitt Cancer Center, 12902 Magnolia Dr, Tampa FL 33612.

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Background

The American Joint Committee on Cancer (AJCC) staging manual has introduced a TNM staging classification for jejunal-ileal (midgut) neuroendocrine tumors (NETs). This classification has not been validated in a population consisting solely of midgut NETs.

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Methods

Patients with jejunal and ileocecal NETs treated at the Moffitt Cancer Center between 2000 and 2010 were assigned stages (I-IV) based on TNM staging classification. Kaplan-Meier analyses for overall survival (OS) were performed based on TNM stage and pathologic grade using log-rank tests. Survival time was measured from time of initial diagnosis until date of last contact or date of death. Multivariate modeling was performed using Cox proportional hazards regression.

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Results

We identified 691 patients with histologically-proven jejunal and ileocecal NETs. The AJCC classification in aggregate was highly prognostic for overall survival (P<0.00001). 5-year overall survival (OS) rates for stages I, II, III and IV were 100%, 100%, 91% and 72% respectively. The survival difference between stages III and IV was significant (p<0.00001); the difference between stages I/II versus III was not statistically significant (p=0.1). Among patients with stage IIIB tumors, 5-year survival rates were 95% for resectable tumors versus 78% for unresectable mesenteric tumors (P=0.02).

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Conclusions

Stages I and II midgut NETs are associated with identical survival rates and are unlikely to be prognostically distinct. Stage IIIB tumors are heterogeneous, with significant differences in survival observed between resectable mesenteric lymph nodes versus unresectable masses in the root of the mesentery. Revisions to the current AJCC staging classification may therefore be warranted.

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Treatment of Metastatic Neuroendocrine Tumors of the Thymus with Capecitabine and Temozolomide: A Case Series

Jonathan Strosberg, MD,1 Vita Saranga-Perry, MD,1 Brian Morse, MD,1 Barbara Centeno, MD,1 Larry Kvols, MD.11H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa FL 33612.

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Background

Metastatic neuroendocrine tumors of the thymus are exceedingly rare with an annual incidence of approximately 0.2 per 1,000,000. They are highly resistant to therapy, and there have been no reports of an objective radiographic response to treatment.

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Methods

The authors retrospectively evaluated three patients with progressive, metastatic neuroendocrine tumors of the thymus who were treated with a combination of capecitabine and temozolomide. Radiographic scans were evaluated and response assessed using RECIST criteria.

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Results

One patient experienced a partial radiographic response, another patient experienced a minor response and the third patient experienced stable disease as the best response to treatment.

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Conclusion

The combination of capecitabine and temozolomide appears to be active in a rare neuroendocrine malignancy that is generally refractory to systemic therapy. Prospective multicenter trials are needed to validate this strategy.

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Duration and Type of Presenting Symptoms in Patients with Neuroendocrine Tumor (NET)

Monica Ter-Minassian,1,2 Jennifer A. Chan,1 Susanne M. Hooshmand,1 Lauren K. Brais,1 Anastassia Daskalova,1 Rachel Heafield,1 Laurie Buchanan,1 Zhi Rong Qian,1 Xihong Lin,3 David C. Christiani,2 Matthew H. Kulke.11Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; 2Department of Environmental Health; 3Department of Biostatistics, Harvard School of Public Health, Boston MA 02115.

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Background

Delayed diagnoses are reported to be common in NET patients (pts). Few studies have prospectively characterized the type and duration of presenting symptoms in this pt population.

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Methods

Of 937 NET pts enrolled in a prospective study, 717 completed questionnaires regarding the type and duration of symptoms prior to diagnosis. We summarized symptoms in the cohort overall and in subgroups of pts with small bowel carcinoid (SBC), pancreatic NET (panNET), or other NET. Estimation of time from symptom onset to diagnosis was based on analysis of 213 symptomatic patients who completed questionnaires within 6 months of diagnosis.

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Results

The cohort comprised 289 SBC, 158 panNET and 270 other NET; 400 pts had localized and 316 had metastatic disease. 76% (67% localized and 84% metastatic) of the pts were symptomatic prior to diagnosis. Abdominal pain was the most common single complaint, and led to diagnosis in 39% SBC, 27% panNET, and 17% of other NET pts. Diarrhea and flushing were reported in only 12% and 7% of SBC and 13% and 0% of panNET patients, respectively. 24% (20% SBC, 20% panNET, 30% other NET) had incidental diagnoses. Incidental diagnosis was more common in pts with localized disease (33%) than in those with metastases (16%).The median duration of symptoms prior to diagnosis was 2.69 months (2.92 mos SBC, 3.41 mos panNET, 2.10 mos other NET). However, the reported range was broad, and the mean duration of symptoms was 11.3 mos (14.1 mos SBC, 10.9 mos panNET and 7.8 mos other NET).

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Conclusion

Our study suggests that abdominal pain is the most common symptom leading to diagnosis of gastrointestinal NET. While the majority of NET patients appear to be diagnosed less than 3 months after symptom onset, prolonged symptom duration prior to diagnosis remains a prominent feature of this disease.

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Diagnostic Performance of Dual Tracer PET/CT in Staging Neuroendocrine Tumors of the Lung

Giorgio Treglia,1 Antonella Stefanelli,1 Giuseppe Cardillo,2 Filippo Lococo,3 Guido Rindi,4 Vittoria Rufini.11Institute of Nuclear Medicine, Catholic University of the Sacred Heart, Rome, Italy; 2Department of Thoracic Surgery, San Camillo-Forlanini Hospital, Rome, Italy; 3Department of Thoracic Surgery, Catholic University of the Sacred Heart, Rome, Italy; 4Institute of Pathology, Catholic University of the Sacred Heart, Rome, Italy.

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Background

Different positron emission tomography/computed tomography (PET/CT) tracers may be useful in staging lung neuroendocrine tumors (LNETs). The aim of this study was a) to calculate the diagnostic accuracy of PET/CT using two different tracers (Fluorine-18-fluorodeoxyglucose [FDG], a glucose analogue and Gallium-68-DOTANOC, a somatostatin analogue) in a series of patients with suspected LNETs and b) to correlate histology with PET findings to assess which is the best PET tracer for staging LNETs.

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Methods

Twenty-nine patients (14 male/15 female; mean age: 64 y.o.) with suspected LNETs based on radiological and/or biochemical findings underwent PET/CT with FDG and Gallium-68-DOTANOC for presurgical staging. Detection rates of LNETs on a per patient-based analysis were calculated. Histology was used as reference standard. An exact Fisher’s test was used to correlate histology and PET findings.

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Results

FDG-PET/CT was true positive in 12 cases, true negative in 6, false negative in 11. Gallium-68-DOTANOC-PET/CT was true positive in 18 cases, true negative in 6, false negative in 5. No false positive results were found. Pathology showed 12 typical carcinoids, 11 atypical carcinoids and 6 benign pulmonary lesions. Overall and histology-based detection rates are shown in Table 1. Discordant findings using both PET tracers were found in 69% of LNETs. Combining both PET methods, the detection rate was 100%. A significant association between histological type and PET findings with the two tracers was found (p<0.05).

TABLE 1

TABLE 1

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Conclusions

Overall, the diagnostic performance of Gallium-68-DOTANOC-PET/CT is superior compared to FDG-PET/CT in staging LNETs, particularly in typical carcinoids. Nevertheless, FDG-PET/CT seems to be more useful in detecting atypical carcinoids compared to Gallium-68-DOTANOC-PET/CT. Both PET/CT methods should be performed when the histological subtype of LNETs is unknown.

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Obturator Canal Lymph Node Metastasis from Rectal Carcinoid Tumor-Total Mesorectal Excision May be Insufficient for Some Rectal Carcinoids

Yi-Zarn Wang, DDS, MD,2 Michael Hall, MD, MS.21New Orleans Louisiana Neuroendocrine Tumor Specialists (NOLANETS), Ochsner Clinic Foundation, Ochsner Medical Center- Kenner, Kenner, LA 70065; 2Department of Surgery, Louisiana State University Health Science Center, New Orleans, LA 70112.

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Background

The optimal treatment option for rectal carcinoid tumor remains unsettled. It is generally accepted that small tumors (< 1-2 cm in size) without lymph node involvement can be treated with trans-anal excision. Larger tumors, and those with lymph node metastasis, however, are usually treated via low anterior resection with total mesorectal excision (TME). Mid gut carcinoid tumors have been found to have the tendency to obstruct lymphatic flow, subsequently developing a detour of lymphatic passage. We hypothesize that rectal carcinoid may have the same potential in developing an alternative lymphatic pathway outside of the mesorectal envelope, thus escaping surgical removal with traditional TME.

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Methods

A retrospective review of 22 consecutive rectal carcinoid patients who underwent radical LAR with TME was undertaken, in order to determine if any extra-mesorectal metastasis had occurred.

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Results

22 patients under went LAR with TME for rectal carcinoid. 18 patients had radio-guided surgery (RGS). 13 of which, were injected with TC-99 intra-operatively and 5 had a preoperative injection of In-111 for Octreo-scan. 6 of the 22 patients (27%) were found to have obturator canal lymph node metastasis, confirmed by final pathologic review. Of these 6 patients, 5 had the nodal metastasis to the right side. Of note, 3 of the 6 patients complained of debilitating foot pain on the ipsilateral side of the metastatic obturator lymph node metastasis and all had symptom resolution after surgical excision.

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Conclusions

Up to 27% of rectal carcinoid patients have extra-mesorectal lymph node metastasis that would easily be missed by the traditional TME. Preoperative octreotide scanning with In-111 injection or intra-operative Tc-99 peri-tumor injection, with concomitant RGS can easily identify and remove such metastasis. Symptomatic improvement can be accomplished with its removal. The effect of such extra-mesorectal metastasis on patients’ long term or disease survival is yet to be determined.

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Surgical Treatment Options for Rectal Carcinoid Cancer: Trans-Anal Excision versus Low Anterior Resection with Total Mesorectal Excision

Yi-Zarn Wang, DDS, MD,1,2 Anne Diebold, BS,1,2 Philip Boudreaux, MD,1,2 Daniel Raines, MD,1,3 Richard Campeau, MD,1,4 Lowell Anthony, MD,5 Eugene Woltering, MD.1,21New Orleans Louisiana Neuroendocrine Tumor Specialists (NOLANETS), Ochsner Clinic Foundation, Ochsner Medical Center- Kenner, Kenner, LA 70065; 2Department of Surgery, Louisiana State University Health Science Center, New Orleans, LA 70112; 3Department of Medicine, Louisiana State University Health Science Center, New Orleans, LA 70112; 4Department of Radiology, Louisiana State University Health Science Center, New Orleans, LA 70112; 5Department of Medicine, The University of Kentucky, Lexington, KY 40506.

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Background

The biological behavior of rectal carcinoids has yet to be fully appreciated due to the rarity of the disease and thus, the optimal surgical treatment remains controversial. Oftentimes, primary tumors less than 2 cm are assumed to be indolent and treated by trans-anal excision. We hypothesized that rectal carcinoids are more malignant than previously described and small tumors warrant more aggressive surgery than what has been traditionally recommended.

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Methods

The charts of 62 consecutive rectal carcinoid patients seen at our institution between 10/2006-8/2011 were retrospectively reviewed. The primary tumor size, extent of disease, surgical history, and basic survival data was collected for analysis.

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Results

Thirty-two patients had localized disease and three patients had lymph node metastasis without distant metastasis. All 35 patients are alive. Twenty-seven patients had distant disease. Four patients had only a local excision of their rectal carcinoid; two of these patients have died. Nine patients had an initial local excision, followed by a radical excision; one patient has died. Twelve patients had an initial radical resection; five of these patients have died. Two patients did not undergo any surgical procedures; both have died. The primary tumor size and chances of lymph node metastases for all 32 patients are as follows: <1 cm: 2/26 (8%); 1.1–2 cm: 9/13 (69%); 2.1-3 cm: 4/5 (80%) and >3 cm: 7/12 (58%).

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Conclusions

Rectal carcinoids are more malignant than previously portrayed. Primary tumors greater than 1 cm have a much higher rate of lymph node metastasis than previously reported. We believe that tumors larger than 1 cm should have a Low Anterior Resection (LAR) with Total Mesorectal Excision (TME) as their initial definitive treatment. For tumors less than 1 cm, surgical treatment should be individualized.

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Above-Label Doses of Octreotide-LAR in Patients with Metastatic Small Intestinal Carcinoid Tumors

Jill Weber, MPH,1 Max Feldman, MD,2 Larry Kvols, MD,3 Jonathan Strosberg, MD.31Allied Healthcare Representative, Portland, OR 97202; 2University of South Florida, Tampa, FL 33612; 3H. Lee Moffitt Cancer Center, Tampa FL 33612.

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Background

Octreotide LAR is indicated for treatment of the malignant carcinoid syndrome, and has been studied at doses of 10-30mg intramuscularly every 4 weeks. It has also been proven to delay time to progression of metastatic midgut carcinoid tumors at a dose of 30mg every 4 weeks. In clinical practice, higher doses are often prescribed for patients who experience refractory carcinoid syndrome (flushing and/or diarrhea) or tumor growth while on the maximal labeled dose. We performed a retrospective, longitudinal review of octreotide LAR administration at a tertiary institution to determine the frequency of ‘above-label’ dosing and outcomes.

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Methods

A retrospective chart-review was performed using a database of patients with metastatic small-bowel carcinoid tumors treated at the Moffitt Cancer Center between the years 2000 and 2010. Data included the maximal dose of octreotide LAR administered, reasons for change in dose or frequency (above the labeled dose of 30mg every 4 weeks), and clinical responses to dose change.

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Results

337 patients were considered evaluable, among whom 99 patients (27%) underwent at least one increase in dose or frequency of octreotide-LAR above the standard labeled dose. The most common maximal doses were 40mg every 4 weeks (37 patients), 60mg every 4 weeks (34 patients), and 30mg every 3 weeks (17 patients). The indications for dose increase were worsening carcinoid syndrome (60 patients), radiographic progression (33 patients) and rising urine 5-HIAA (6 patients). Among patients whose doses were increased for refractory carcinoid syndrome, 62% experienced improvement in diarrhea and 56% experienced improvement in flushing.

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Conclusions

In clinical practice, octreotide LAR is commonly prescribed in doses or schedules above the labeled dose and frequency. Patients with refractory carcinoid syndrome appear to experience a clinical benefit from the change. Prospective data is needed to evaluate this strategy.

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Effect of Open-Label Everolimus in Patients with Advanced Neuroendocrine Tumors After Disease Progression on Somatostatin Analog: A RADIANT-2 Analysis

Edward M. Wolin,1 John D. Hainsworth,2 Dieter Hörsch,3 Gabriele Luppi,4 Valentine Jehl,5 Marc Peeters.61Cedars-Sinai Medical Center, Los Angeles, CA, 90048, United States; 2Sarah Cannon Research Institute, Nashville, Tennessee, 37203, United States; 3Klinik für Innere Medizin, Gastroenterologie und Endokrinologie, Zentrum für Neuroendokrine Tumore, Zentralklinik Bad Berka GmbH, Bad Berka, 99437, Germany; 4Azienda Ospedaliero-Universitaria, Modena, 41124, Italy; 5Novartis Pharma AG, Basel, CH-4002, Switzerland; 6Department of Oncology, Antwerp University Hospital, Edegem, 2650, Belgium.

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Background

In the RADIANT-2 study (NCT00412061), everolimus + octreotide LAR (E+O) resulted in a clinically meaningful increase in median progression-free survival (PFS; by adjudicated central review) of 5.1 months versus placebo + octreotide LAR (P+O) in patients with advanced NET with a history of carcinoid syndrome. Investigator-assessed PFS was 12.0 months for E+O compared with 8.6 months for P+O, respectively. Upon radiological disease progression (as per investigator assessment), P+O patients could cross over to open-label E+O. Here we present the outcomes of P+O patients who crossed over to open-label E+O.

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Methods

429 patients were randomly assigned: 216 to E (10 mg/d) + O (30 mg IM q 28 d) and 213 to P+O.

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Results

Upon radiological disease progression per investigator assessment, 124 P+O patients crossed over to open-label E+O. Median duration of treatment with open-label E+O was 26.3 weeks (range, 1–133); 34 patients (27.4%) received open-label E+O for ≥12 months. Median time from randomization to crossover to open-label E+O was 14.1 months. Median PFS in the open-label E+O group, calculated from time of crossover and assessed by local investigators, was 10.1 months (95% CI, 8.0–13.5). Adverse events were similar to those reported for the E+O arm during the double-blind phase of the study.

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Conclusions

Patients with NET enrolled in the RADIANT-2 study who received open-label E+O after progressing on P+O had median PFS of 10.1 months with no unexpected adverse events.

Supported by Novartis

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Comparison of Yttirum-90 Microspheres and Transarterial Chemoembolization in the Treatment of Inoperable Metastatic Neuroendocrine Tumors

Yuhsin V. Wu, MD,1 Garin Tomaszewski, MD,2 Adrienne E. Groman, MS,3 Renuka V. Iyer, MD,4 Boris W. Kuvshinoff, MD, MBA.11Department of Surgical Oncology, Roswell Park Cancer Institute Buffalo, NY 14263; 1Department Angio-Interventional and Diagnostic Radiology, Roswell Park Cancer Institute, Buffalo, NY 14263; 1Department of Biostatistics, Roswell Park Cancer Institute Buffalo, NY 14263;§Department of Medicine, Roswell Park Cancer Institute Buffalo, NY 14263.

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Background

There are limited treatment modalities for inoperable liver neuroendocrine (NET) metastases. The study compares the efficacy and safety of yttrium-90 microspheres (SIR) to transarterial embolization (TACE).

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Methods

Medical records and axial imaging studies were retrospectively reviewed for all patients with NET liver metastases treated with SIR or doxorubicin based TACE at our institution from Jan, 2001-Dec, 2010. The demographics, immediate effects, and time to radiologic progression were compared.

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Results

89 liver directed procedures were performed on 18 SIR and 23 TACE patients. Median follow-up was 26 mos (range 4–120). Patient age, performance status, type of primary NET, and systemic therapy were similar. Pts in the SIR group did not require liver-directed therapy as quickly (SIR 43.7 mos vs. TACE 18.2 mos, p<0.001) and had less liver burden than TACE patients (65% vs. 33% with <25% liver burden respectively). Immediate treatment response was measured using the product of WHO times EASL. SIR achieved total benefit of 97% (9.1% complete response (CR), 48.5% partial response (PR), 39.4% stable disease (SD) verses 83.3% for TACE (0% CR, 37.5% PR, 45.8% SD) (p=0.05). At 26 mos, SIR had a longer radiologic response than TACE (10 mos) (p=0.035). SIR patients underwent less treatments (95% with < 2 treatments) than TACE patients (70% with < 2 treatments) (p=0.045). Both treatments were well tolerated with minimal side effects. With only 10/41 deaths, there was no statistically significant difference in overall survival between the two groups.

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Conclusion

Liver metastasis from NETs can be successfully treated with yttrium-90 radioembolization. Earlier intervention using SIR allows fewer treatments with more durable responses. Prospective studies controlling for rate of disease progression and disease burden are needed to validate these findings.

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Dosing Patterns of Octreotide LAR Among Elderly Patients with Neuroendocrine Tumors: Analysis of the SEER-Medicare Database

Ying Xu,1 Ya-Chen Tina Shih,2 Colleen C. Leary,1 Chan Shen,1 James C. Yao.11University of Texas M. D. Anderson Cancer Center, 1515 Holcombe, Houston Texas 77030; 2University of Chicago, 5841 S. Maryland Ave., MC 5000, Office W306, Chicago IL 60637.

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Background

Octreotide LAR is used for treatment of hormonal syndromes associated with NETs and may delay tumor progression. Although various dosages and schedules of administration have been reported, a systematic analysis has not been performed.

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Methods

Using the SEER-Medicare database, we identified patients diagnosed with NETs between July 1999 and December 2007. We then excluded those patients with poorly differentiated histology, under age 65 at diagnosis, enrolled in HMOs, and who did not have continuous Part A & B enrollment between NET diagnosis and the end of 12 months after the initial octreotide LAR use. HCPCS codes, J2352 and J2353, were used to identify octreotide LAR from Medicare claims. For each patient, mean octreotide LAR dose per month was calculated and classified into five dosing categories, ≤ 10, 11–20, 21–30, 31–40, >40 mg, for the initial 3 months and every subsequent 3 months during the first year.

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Results

A total of 3,543 octreotide LAR treatments were observed among 355 patients during their first year of therapy. Dose given on a single day ranged from 10 mg to 90 mg. 86 (24.2%) patients required a ≥ 30% escalation in dose during the first year of therapy. The distributions of the mean monthly doses by dosing categories for the initial 3 months and the highest use 3 months during the first year are included in the Table 1 below. 134 (37.7%) patients required doses greater than 30 mg per month.

TABLE 1

TABLE 1

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Conclusions

Our analyses showed that patients frequently required the escalation of octreotide LAR dose during their course of illness. A substantial number of patients required doses greater than the FDA approved dose of 30 mg per month.

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RADIANT-4: A Randomized, Double-blind, Multicenter, Phase III Study of Everolimus Versus Placebo in the Treatment of Patients With Advanced Non-functional NET of GI or Lung Origin

James C Yao,1 Marianne E Pavel,2 Nicola Fazio,3 Matthew Kulke,4 Simron Singh,6 Gaurav Shah,6 Judith Klimovsky,6 Jonathan Strosberg.71The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, United States; 2Charité Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, 10117, Germany; 3European Institute of Oncology, via Ripamonti, Milan, 20141, Italy; 4Dana-Farber Cancer Institute, Boston, Massachusetts, 02215, United States; 5Sunnybrook Odette Cancer Center, Toronto, Ontario, M4N 3M5, Canada; 6Novartis, Florham Park, New Jersey, 07932, United States; 7Moffitt Cancer Center, Tampa, Florida, 33612, United States.

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Background

In the phase III RADIANT-3 study, everolimus significantly improved PFS compared with placebo (11 vs 4.6 months, P<.001) in patients with advanced pancreatic NET. In the phase III RADIANT-2 study, everolimus added to octreotide provided some evidence of efficacy based on PFS in patients with advanced functional (carcinoid) NET compared to octreotide alone; the difference was not statistically significant. RADIANT-4 was designed to test everolimus in patients with advanced non-functional NET of GI or lung origin, a group not evaluated in either RADIANT-2 or RADIANT-3.

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Methods

RADIANT-4 is a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase III study with a target of 285 adults with histologically confirmed well-differentiated (G1 or G2) advanced NET of GI or lung origin, with no history of and no active symptoms related to carcinoid syndrome, and with radiologic progression in the last 6 months. Patients will be randomized (2:1) to receive either everolimus 10 mg qd or matching placebo. Both arms will receive best supportive care. Randomization will be stratified by prior somatostatin analog exposure, tumor origin, and WHO performance status. The primary objective of RADIANT-4 is to evaluate PFS as per modified RECIST 1.0. Secondary objectives include evaluating overall survival, safety, quality of life, and overall response rates.

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Results

Enrollment began in May 2012 with completion expected in October 2013. An interim analysis (expected 21 months from the start) is planned when approximately 140 (80%) of the planned 176 PFS events are reached. If the primary endpoint is met at either the interim or final analysis, the DMC may recommend unblinding and crossover for all patients receiving placebo.

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Conclusions

RADIANT-4 will provide important efficacy and safety information on everolimus in a large cohort of patients with advanced non-functional NET of GI or lung origin.

ClinicalTrials.gov Identifier: NCT01524783

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The VEGF Pathway in Pancreatic Neuroendocrine Tumors: Prognostic and Predictive Capacity of Baseline Biomarker Levels on Efficacy of Everolimus Analyzed From the RADIANT-3 Study

James C. Yao,1 Manisha Shah,2 Ashok Panneerselvam,3 David Chen,3 Sotirios Stergiopoulos,3 Tetsuhide Ito,4 Marianne Pavel51The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, United States; 2Ohio State University, Columbus, Ohio, 43210, United States; 3Novartis Pharmaceuticals Corporation, Florham Park, New Jersey, 09732, United States; 4Kyushu University, Fukuoka, 812-8581, Japan; 5Charité Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, 10117, Germany.

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Background

RADIANT-3, a phase III study, investigated the effect of the mTOR inhibitor everolimus on PFS in patients with advanced pancreatic neuroendocrine tumors. Everolimus significantly improved PFS compared with placebo (11 vs 4.6 months; HR=0.35; 95% CI, 0.27 to 0.45; P<.001). Here we investigate the predictive and prognostic effect of soluble VEGF pathway biomarkers among patients treated in this study.

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Methods

Baseline plasma levels of VEGF-A, PlGF, sVEGFR1, and sVEGFR2 were determined by ELISA using multiplexed MSD platform. The optimal cutoffs for these markers were explored using the “survival tree analysis” method. Interaction of treatment and baseline marker status (< or ≥ cutoff) was analyzed using a Cox proportional hazards model to assess predictive effects of these markers. P values and hazard ratios for prognostic effects were obtained using stratified log rank test and Cox proportional hazards model, stratified by treatment.

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Results

Significant improvement in PFS was observed in patients receiving everolimus compared with patients receiving placebo, regardless of baseline marker levels (P<.001, Table). Significantly longer PFS was seen in those with lower levels of VEGF-A, PlGF, and sVEGFR1, regardless of treatment. A trend for longer PFS was also observed for lower sVEGFR2 (Table 1).

TABLE 1

TABLE 1

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Conclusions

These exploratory analyses demonstrated consistent everolimus efficacy in all patients with advanced pNET irrespective of their baseline VEGF pathway biomarker levels, suggesting that the levels of the markers are not predictive of the efficacy of everolimus. Lower baseline levels of VEGF-A, PlGF, and sVEGFR1 are potential prognostic factors for pNET progression.

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Is There a Role for Radiation for Neuroendocrine Neoplasm Hepatic Metastases?

Rebecca Zener, MD,1 Michael Lock, MD,2 Walter Kocha, MD,3 Robert Reid, MD,1 Daryl Gray, MD.41Department of Medical Imaging, London Health Sciences Centre, London, ON, Canada, N6A 4L6; 2Department of Radiation Oncology, London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada, N6A 4L6; 3Department of Medical Oncology, London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada, N6A 4L6; 4Department of General Surgery, London Health Sciences Centre, London, ON, Canada N6A 4L6.

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Background

The liver is the most common metastatic site for neuroendocrine neoplasms (NEN). Its presence is a major prognostic factor. While stereotactic body radiotherapy (SBRT) and standard external beam radiotherapy have been successful in treating non-neuroendocrine hepatic metastases, it has not been incorporated into NEN hepatic metastases management. This study investigates radiation’s potential role in treating NEN hepatic metastases.

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Methods

Four patients with hepatic metastases from advanced gastrointestinal NEN were prospectively identified and treated with SBRT. Radiation treatment method consisted of respiratory-gated simulation and treatment, individualized dosing with radiobiological calculation of normal tissue complication probability.

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Results

One patient with hepatic metastases from a gallbladder primary was only able to receive low-dose radiation (3000 cGy/10). She died of in-field recurrence 5 months post-SBRT. Two patients, one with hepatic metastases from a functional, well-differentiated, 5-HIAA positive, neuroendocrine small bowel carcinoma, and another with hepatic metastases from a well-differentiated, non-functional, pancreatic neuroendocrine carcinoma achieved progression-free, stable disease after being treated with 4200 cGy/6, and 5574 cGy/6 of SBRT, respectively. Both remain alive 3.5 years post-SBRT. The fourth patient was treated with SBRT for hepatic metastases from esophageal NEN without major toxicity, and remains alive more than 2 years post-SBRT. However, status of his disease and local control are unknown, as he was lost to imaging follow-up. Overall, no grade 2, 3, or 4 toxicities were observed.

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Conclusion

External beam radiation for NEN liver metastases appears to be well tolerated, and may achieve disease stability for a substantial period of time. While it is a small case series with a heterogeneous patient group, this represents the first case series of SBRT for NEN hepatic metastases, and the results are encouraging. The effectiveness of SBRT for NEN hepatic metastases, progression-free survival, control of tumor functionality, and determination of selection criteria warrants further investigation.

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Baseline Demographics of Neuroendocrine Tumor Patients Presenting to Seven National Comprehensive Cancer Network (NCCN) Institutions: Development of a Multi-Institutional Outcomes Database

Carrie C. Zornosa, MSPH,1 Michael A. Choti, MD,2 Sarah Bobiak, PhD,1 Matthew H. Kulke, MD,3 James C. Yao, MD,4 Emily K. Bergsland, MD,5 Eric K. Nakakura, MD,5 P. Mark Bloomston, MD,6 Al B. Benson III, MD,7 Manisha H. Shah, MD,6 Jonathan R. Strosberg, MD.81National Comprehensive Cancer Network, Fort Washington, PA 19034; 2The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287; 3Dana Farber Cancer Institute, Boston, MA 02215; 4The University of Texas MD Anderson Cancer Center, Houston, TX 77030; 5UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143; 6The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, Columbus, OH 43210; 7Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611; 8H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612.

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Background

Diagnostic strategies, management paradigms, and clinical outcomes of patients with neuroendocrine tumors (NETs) are diverse and poorly characterized. The National Comprehensive Cancer Network (NCCN) created a comprehensive database to characterize patients treated for NETs at seven participating institutions. Preliminary results from the database are reported.

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Methods

Member IRB approval was obtained to identify patients at least 18 years of age presenting to each of seven NCCN institutions between 2004 and 2007 with pathologically confirmed newly or previously diagnosed NETs via hospital medical records. Eligible patients included those with carcinoid (any site); goblet cell or adenocarcinoid; composite carcinoid; poorly differentiated gastrointestinal small cell tumor; pancreatic NET; NET of unknown primary site; pheochromocytoma; and paraganglioma. Baseline demographic characteristics were summarized for this analysis.

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Results

Among the 2,798 patients identified with a NET diagnosis, patients most frequently presented with carcinoid tumor (53%), pancreatic NET (26%) and NET of unknown primary site (8%). Median age at diagnosis was 56 (SD=14). Fifty-three percent of patients were female. Most (86%) were Caucasian and 8% were African American. Thirty percent of patients were diagnosed with NET before presenting to the NCCN. Among these, the median time between initial NET diagnosis and presentation to the NCCN was 2 years (SD=6). Significant differences in provider specialty referral patterns were observed between institutions. The institutional point of entry for the majority of patients was medical oncology (institutional range: 17–93%) or surgery (institutional range: 3–62%).

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Conclusions

The baseline demographic characteristics of NET patients in this new database are consistent with those previously reported in population-based registries. The database will provide a valuable resource for further exploration of patterns of diagnosis, treatment, and consistency with established guidelines, as well as clinical outcomes in patients with this condition.

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