Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome.

BACKGROUND: Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods. METHODS: First occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial. RESULTS: In TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3-4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2-3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6-11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7-11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR. CONCLUSION: The time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01677910, NCT02063659.

EndoVascular Occlusion and Tumor Excision (EVOTE): a Hybrid Approach to Small-Bowel Neuroendocrine Tumors with Mesenteric Metastases.

BACKGROUND: Mesenteric metastases from small-bowel neuroendocrine tumors (SBNETs) present a surgical challenge due to encasement of mesenteric vessels. In this study, we evaluate the feasibility and safety of a new, hybrid surgical approach to these mesenteric masses, EndoVascular Occlusion and Tumor Excision (EVOTE). METHODS: From 2014 to 2018, 13 patients underwent the EVOTE procedure after being referred to our institution for primary SBNETs with "unresectable" mesenteric metastases. During stage 1 of the hybrid EVOTE procedure, angiographic evaluation of the mesenteric mass is performed. If adequate collateralization is demonstrated, the encased mesenteric vessel(s) is embolized. Mass excision is performed the following day during stage 2 of the EVOTE procedure. RESULTS: Preoperative embolization was successful in 86% of cases; 2 cases were aborted for persistent abdominal pain following occlusion testing. Complete surgical excision of the mesenteric mass was achieved in 86% of cases. The 30-day overall morbidity and mortality rate was 29% and 0%, respectively. There was one local recurrence at 31.8 months post-op; this patient underwent a repeat EVOTE procedure with successful complete excision. DISCUSSION: EVOTE represents a new technique that aids in preoperative planning and surgical resection of SBNETs with mesenteric metastases.

Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome.

BACKGROUND: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. SUBJECTS, MATERIALS, AND METHODS: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. RESULTS: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. CONCLUSION: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. IMPLICATIONS FOR PRACTICE: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.

Gastric Neuroendocrine Tumor and Duodenal Gastrinoma With Chronic Autoimmune Atrophic Gastritis.

Our group observed the first case of synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis (CAG), in the absence of Helicobacter pylori infection. Demographic, clinical, endoscopic, and pathologic data were abstracted from the electronic medical record at Mount Sinai Hospital from 2013 to 2015. The patient's anonymity was carefully protected, and informed consent was obtained for publication of protected health information. A 53-year-old woman with hypertension presented to Mount Sinai Hospital in June 2013 for a second opinion for management of gastric and duodenal NETs. After evaluation by gastroenterology and surgery, repeat upper endoscopy with ultrasound and fine-needle aspiration revealed multiple diminutive type I gastric NETs and 2 duodenal NETs, against a background of autoimmune CAG, with biopsy pathology negative for H. pylori. She subsequently underwent a transduodenal resection of the duodenal NETs, confirming low-grade, gastrin-positive, stage T2 duodenal NET. On routine follow-up over the next 2 years, clinical, radiographic, and endoscopic surveillance revealed no recurrent or metastatic gastric or duodenal disease. This first report of synchronous duodenal gastrinoma and gastric NET in the setting of autoimmune CAG can broaden our understanding of gastric NET pathophysiology.

Long-term Outcomes of Gastroenteropancreatic Neuroendocrine Tumors.

OBJECTIVES: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare but have been increasing in incidence. Limited data on the long-term outcomes of patients with these tumors are available. METHODS: In this study, we used population-based data from the National Cancer Institute to assess long-term disease-specific survival (DSS) of patients who have undergone surgery for nonmetastatic disease. All patients with NETs of the stomach, small intestine, colon, rectum, appendix, and pancreas diagnosed between 1988 and 2009 were identified from the Surveillance, Epidemiology and End Results registry. Staging was derived from Surveillance, Epidemiology and End Results data using the European Neuroendocrine Tumor Society guidelines. Cases with incomplete staging data were excluded, along with those with stage IV disease, or those who did not undergo surgical resection. RESULTS: Kaplan-Meier analyses were constructed to determine DSS. Analyses were further stratified according to tumor site, stage at diagnosis, and tumor grade. Overall, 13,348 patients with GEP-NETs meeting the inclusion criteria were identified. CONCLUSIONS: There were excellent outcomes for most GEP-NET patients, with a 20-year DSS of greater than 75% across all sites and stages. Pancreatic tumors had the worst outcomes, but DSS remains greater than 50% at 20 years.

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial.

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges-Lehmann estimators of median treatment differences from placebo of -54.0% (95% confidence limits, -85.0%, -25.1%, P < 0.001) and -89.7% (95% confidence limits, -113.1%, -63.9%, P < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).

Lymph Node Metastasis in the Prognosis of Gastroenteropancreatic Neuroendocrine Tumors.

OBJECTIVES: This study aimed to determine the prognostic use of the extent of lymph node (LN) involvement in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) by analyzing population-based data. METHODS: Patients in the Surveillance, Epidemiology, and End Results registry were identified with histologically confirmed, surgically resected GEP-NETs. We divided patients into 3 lymph node ratio (LNR) groups based on the ratio of positive LNs to total LNs examined: 0.2 or less, greater than 0.2 to 0.5, and greater than 0.5. Disease-specific survival was compared according to LNR group. RESULTS: We identified 3133 patients with surgically resected GEP-NETs. Primary sites included the stomach (11% of the total), pancreas (30%), colon (32%), appendix (20%), and rectum (7%). Survival was worse in patients with LNRs of 0.2 or less (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.2-2.0), greater than 0.2 to 0.5 (HR, 2.0; 95% CI, 1.6-2.5), and greater than 0.5 (HR, 3.1; 95% CI, 2.5-3.9) compared with N0 patients. Ten-year disease-specific survival decreased as LNR increased from N0 (81%) to 0.2 or less (69%), greater than 0.2 to 0.5 (55%), and greater than 0.5 (50%). Results were consistent for patients with both low- and high-grade tumors from most primary sites. CONCLUSIONS: Degree of LN involvement is a prognostic factor at the most common GEP-NET sites. Higher LNR is associated with decreased survival.

Improving survival prognostication of gastroenteropancreatic neuroendocrine neoplasms: Revised staging criteria.

PURPOSE: Current staging criteria for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), while useful, have limitations. In this study, we used a population-based registry to evaluate the prognostic utility of the current staging systems and assess whether evidence-based modifications can improve survival predictions. METHODS: We identified patients with confirmed GEP-NENs from the Surveillance, Epidemiology and End Results registry. We assigned tumour-node-metastasis status according to American Joint Committee on Cancer and European Neuroendocrine Tumor Society criteria. We derived a revised staging classification using Kaplan-Meier methods and Cox regression to assess disease-specific survival and compared the accuracy of potential models based on the Akaike Information Criterion (AIC) and Harrell's C-index. The revised classification was validated in an independent set. RESULTS: We identified 10,268 patients with GEP-NENs. We found that multiple stages, as determined by current criteria, misclassified patients' prognosis. In particular, stage IIIB (T1-4N1) had overlapping survival with stage IIIA (T4N0). A revised system which reclassifies N1 disease into different stages based on T status (T1-2N1, T3N1 and T4N1) had an improved AIC (difference = 38) and C-index (0.86) compared to current staging. These revisions improved predictions in patients with both low and high-grade tumours from all primary sites. Results also were confirmed across all primary sites in the validation set. CONCLUSION: Current staging guidelines misclassify the prognosis of N1 patients. Our results suggest that a revised system could lead to better prognostication for GEP-NEN patients. Further validation followed by implementation of these revisions may improve treatment selection and design of clinical trials.

Patient-Reported Experience of Diagnosis, Management, and Burden of Neuroendocrine Tumors: Results From a Large Patient Survey in the United States.

OBJECTIVES: The aim of this survey was to examine the experience of patients with neuroendocrine tumors (NETs) to raise awareness of the NET-related burden and identify unmet needs. Here, we report data from patients in the United States. METHODS: Patients with NETs participated in a 25-minute anonymous survey, conducted primarily online from February to May 2014. Survey questions captured information on sociodemographics, clinical characteristics, NET diagnostic experience, disease impact/management, interaction with medical teams, and NETs knowledge/awareness. RESULTS: Of 1928 patients who participated globally, the largest percentage was from the United States (39%). Approximately 50% of US patients reported being diagnosed with other conditions before receiving their NET diagnosis, which for 34% took 5 years or more. Patients experienced many symptoms on a daily basis as a result of NETs, which had a substantial negative impact on their work and daily lives. Numerous improvements were suggested by patients, including better access to NET-specific treatments and medical teams/centers and better education for the management of disease-related and treatment-related symptoms. CONCLUSIONS: This survey demonstrated the significant burden of NETs on patients' lives and identified key areas for improvement in diagnosis and long-term management, including better access to NET-specific treatments and specialist medical teams/centers.

Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome.

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Use of Molecular Profiling to Guide Treatment Decisions in Patients with Neuroendocrine Tumors: Preliminary Results.

This case series demonstrates the potential of molecular profiling to improve selection of antitumor therapies in the treatment of patients with neuroendocrine and carcinoid tumors. Carcinoid tumors resected at one institution over a 3-year period were sent for molecular profiling to guide choice of treatment. Potentially beneficial therapies were identified based on the measured expression of 20 proteins and oncogenes and a comprehensive review of the chemotherapy response literature. The clinical charts of 41 patients were reviewed retrospectively, and 12 were selected as representatives of the range of effects molecular profiling has on carcinoid treatment. Their presentation, molecular profile results, treatment, and disease progression is reviewed in the following case series. A total of nine patients were treated with drugs identified as potentially beneficial by molecular profile reports. These include capecitabine, 5-fluorouracil, temozolomide, oxaliplatin, and gemcitabine. Based on clinical symptoms, serum markers of disease, and radiographic evidence five of nine patients responded to treatment, two had mixed responses, and two did not respond to treatment. At this early juncture, our critique of molecular profiling for neuroendocrine tumors is favorable, as a significant number of our patients responded to drugs identified by molecular profiling as potentially beneficial.

Laparoscopic antrectomy: a safe and definitive treatment in managing type 1 gastric carcinoids.

BACKGROUND: Treatment for type 1 gastric carcinoid (T1GC) includes esophagogastroduodenoscopy (EGD), polypectomy, and antrectomy, but few studies compare outcomes. This study assessed risk-benefit ratio to determine the most effective treatment for T1GC. METHODS: A retrospective review of 52 T1GC patients (ages 30 to 88 years; 77% female) presenting to Mount Sinai Medical Center between 2004 and 2012 was conducted. Patient demographics, procedures, and outcomes were reviewed, and patient satisfaction was assessed using a phone-administered validated questionnaire. Data were analyzed using SPSS version 20 software. RESULTS: Average EGDs needed per follow-up year was significantly lower for antrectomy than polypectomy or EGD surveillance (.395 vs 1.038 vs 1.380, P = .002). Antrectomy patients exhibited decreased recurrence risk than polypectomy patients (11% vs 44%, P = .049), despite longer follow-up time (6.10 vs 4.39 years, P = .023). CONCLUSIONS: Antrectomy treats T1GC with lower recurrence risk and less postintervention monitoring, whereas allowing patients to avoid the discomfort of repeated EGD surveillance and anxiety over a lingering condition.

Differential Protein Expression in Small Intestinal Neuroendocrine Tumors and Liver Metastases.

OBJECTIVE: Small intestinal neuroendocrine tumors (SI-NETs) are often detected after they have become metastatic. Using a novel protein array, we identified pathways important in SI-NET metastasis development in surgically resected patients. METHODS: Paired primary tumors and liver metastases from 25 patients undergoing surgical resection for metastatic SI-NETs were harvested. Extracted proteins were separated by sodium dodecyl sulfate gel and multiplex immunoblots were performed with 136 antibodies. Significant Analysis of Microarray was used to select for differentially expressed proteins. A tissue microarray was constructed from 27 archived specimens and stained by immunohistochemistry. RESULTS: Comparing primary SI-NETs with matched normal small-bowel mucosa, 9 proteins were upregulated and cyclin E was downregulated. The SI-NET liver metastases demonstrated upregulation of P-ERK and p27 but downregulation of CDK2 and CDC25B. When comparing primary SI-NET with their paired liver metastases, cyclin E demonstrated a significant upregulation in the liver metastasis. Tissue microarray demonstrated higher p38 expression and lower Cdc 25b expression in SI-NETs versus liver metastases and confirmed higher expression of p27 in liver metastases versus normal liver. CONCLUSIONS: Few studies have compared protein expression in paired primary and metastatic SI-NETs. Our findings reveal changes in a limited number of proteins, suggesting that these may be targets for therapy.

Elevated Serum Pancreastatin Is an Indicator of Hepatic Metastasis in Patients With Small Bowel Neuroendocrine Tumors.

OBJECTIVES: Serum pancreastatin is a sensitive and specific diagnostic biomarker in neuroendocrine tumors (NETs). Elevated pancreastatin levels are associated with worse progression-free survival and overall survival in small bowel and pancreatic NETs. In this study, we investigated the clinical significance of elevated serum pancreastatin in identifying metastatic disease to the liver. METHODS: Retrospective chart review of patients with NET managed at a single institution was performed. The site of primary tumor, laboratory data, and presence of metastatic disease were reviewed. The sensitivity, specificity, and positive and negative predictive values for pancreastatin as indicator of liver metastasis were ascertained. RESULTS: Data were abstracted from 77 patient records. Small bowel was the primary tumor site in 44 patients (57%), and 49 patients had metastasis to the liver (64%). Sensitivity and specificity of serum pancreastatin was 85.7% and 66.7%, respectively, which compared with 61.5% and 43.8% for chromogranin A, in identifying liver metastasis in patients with primary tumors of the small bowel. CONCLUSIONS: Elevated serum pancreastatin is a sensitive and specific assay for detecting the incidence of liver metastasis in patients with small-bowel NET. Routine measurement of pancreastatin in patients with NET, especially in patients with small bowel primaries, is supported.

The Prognostic Significance of Lymph Node Ratio in Carcinoid Tumors.

OBJECTIVES: Nodal metastases are an important prognostic factor in survival for patients with carcinoid tumors. However, it is unclear if the current American Joint Committee on Cancer's gastrointestinal carcinoid staging guidelines, which look only at presence or absence of regional metastases (N1/N0), are fully utilizing lymph node data. Some research has indicated that lymph node ratios (LNRs) are powerful predictors of survival. In our study, we evaluated LNR in carcinoid tumors. METHODS: Eleven thousand one hundred eighty-nine carcinoid tumors recorded in the Surveillance, Epidemiology, and End Results database between 1988 and 2011 were evaluated. Receiver operating characteristic curves and the area under the receiver operating characteristic curve (AUC) were used to evaluate the ability of nodal involvement or LNR to predict 10-year survival. All analyses were performed using STATA and SAS version 9.3. RESULTS: Receiver operating characteristic curve analysis indicated that LNR and node positivity were both predictive of 10-year survival, AUC = 0.734, P < 0.0001; AUC = 0.7048, P < 0.0001. Lymph node ratio was 88% specific and 50% sensitive in predicting 10-year survival. N1 was 88% specific and 49% sensitive in predicting 10-year survival. CONCLUSIONS: Our study indicated that LNR is an independent predictor of survival for patients with carcinoid tumors but was no better than N1/N0 for 10-year survival.

Prognostic significance of lymph node metastases in small intestinal neuroendocrine tumors.

BACKGROUND/AIMS: Current staging guidelines for small intestinal neuroendocrine tumors (SI-NETs) differentiate between the presence (N1) and absence (N0) of lymph node (LN) metastases. However, the prognostic significance of the extent of LN involvement remains unknown. In this study, we used data from a population-based cancer registry to examine whether involvement of a higher number of LNs is associated with worse survival. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with histologically confirmed, surgically resected SI-NETS diagnosed between 1988 and 2010. Patients were classified into three groups by the LN ratio (number of positive LNs/number of total LNs examined, LNR): ≤0.2, >0.2-0.5, and >0.5. We used the Kaplan-Meier method and Cox models to assess NET cancer-specific survival differences (up to 10 years from diagnosis) according to LNR status. RESULTS: We identified 2,984 surgically resected patients with stage IIIb (N1, M0) SI-NETs with detailed LN data. More than half of the NETs were located in the ileum. A higher LNR was significantly associated with worse NET cancer-specific survival (p < 0.0001). Ten-year NET-specific survival was 85, 77, and 74% for patients in the ≤0.2, >0.2-0.5, and >0.5 LNR groups, respectively. In stratified analyses, higher LNR groups had worse survival only in early tumor (T1, T2) disease (p < 0.0001). CONCLUSIONS: The extent of LN involvement provides independent prognostic information on patients with LN-positive SI-NETs. This information may be used to identify patients at high risk of recurrence and inform decisions about the use of adjuvant therapy.

Management and disease outcome of type I gastric neuroendocrine tumors: the Mount Sinai experience.

BACKGROUND AND AIM: The incidence of gastric neuroendocrine tumors (NETs) has increased tenfold since the 1970s. Our aim was to describe the clinicopathologic profile, management, and outcomes of type I gastric NETs at The Mount Sinai Hospital. METHODS: From existing databases of the Mount Sinai Division of Gastrointestinal Pathology and the Carcinoid Cancer Foundation, we identified 56 patients with type I gastric NETs seen at The Mount Sinai Hospital from 1993 to 2012. We generated a comprehensive dataset encompassing demographic, clinical, endoscopic, and pathologic factors. Survival information was determined from medical records and the Social Security Death Index. Tumor-node-metastasis staging was conducted, and tumors were graded based on mitotic counts and Ki67 index. RESULTS: Median NET size was 3.0 mm; 55.8 % displayed multifocal disease. Stages I, II, III, and IV disease were observed in 83.8, 10.8, 5.4, and 0 %, respectively. Tumors were either low (69.7 %) or intermediate (30.3 %) grade. Furthermore, 3.6 % of patients developed gastric dysplasia, and 5.5 % had gastric adenocarcinoma. Patients underwent endoscopy every 15 months, while 28.6 % underwent polypectomy, 32.7 % somatostatin therapy, and 46.4 % surgical resection. 5- and 10-year disease-specific survival was 100 %. CONCLUSIONS: Most patients received annual endoscopic surveillance, with a minority undergoing surgical resection, though outcomes remained excellent independent of therapeutic approach. We identified a very low but real rate of loco-regional spread, despite the generally indolent behavior of type I gastric NETs. Several patients demonstrated concurrent dysplasia or adenocarcinoma, underscoring the efficacy of regular endoscopic management not only for gastric NETs, but also for dysplasia and adenocarcinoma.