Gastrointestinal Neuroendocrine Tumors Research Articles

2651 Secrets of the Ampulla: A Rare Neuroendocrine Tumor

INTRODUCTION: Neuroendocrine tumors (NETs) of the ampulla of Vater represent less than 0.3% of gastrointestinal NETs and less than 2% of all periampullary malignancies. There are approximately 139 cases in literature, making this rare condition a diagnostic challenge. Jaundice is the predominant symptom followed by abdominal pain. Acute pancreatitis as the initial presentation has seldom been reported. Herein we report a case of a patient who presented with acute pancreatitis and biliary obstruction secondary to an ampullary NET. CASE DESCRIPTION/METHODS: Case of a 74-year-old male with hypertension who reported burning epigastric pain. Denied fever, vomits, weight loss, diarrhea, flushing or dyspnea. Physical examination with epigastric tenderness. Laboratories showed elevated alkaline phosphatase 398 U/L, total bilirubin 3.4 mg/L, lipase 594 U/L and amylase 216 U/L. Contrast abdominopelvic CT showed a duodenal periampullary mass with common bile duct measuring 1.1 cm and intrahepatic and extrahepatic dilatation. Endoscopic retrograde cholangiopancreatography (ERCP) revealed an irregular, ulcerated ampullary mass. Biopsy showed poorly differentiated carcinoma. Immunostains were positive for chromogranin, synaptophysin, CK7, weakly positive for CDX-2. Negative for TTF-1 and CK20. Octreotide scintigraphy with no uptake. Somatostatin, chromogranin, and 5-hydroxy-in-dole acetic acid were normal. Patient underwent surgical treatment with pancreaticoduodenectomy. DISCUSSION: The rarity of ampullary NETs and its proliferation under an intact mucosa makes it difficult to detect in biopsy. Most of the time the diagnosis is based on histology and preoperative diagnosis may be challenging since they clinically present like adenocarcinoma. The usual presentation of jaundice and abdominal pain places this diagnosis low on the differential. In our case, the unusual morphologic appearance likely facilitated obtaining an assertive pre-operative diagnosis. Our patient presented with obstructive jaundice and acute pancreatitis, which occurs in less than 6% of cases. The clinical picture of ampullary NETs is easily confounded given the associated symptoms and biopsy challenges. A high index of suspicion is paramount to ensure this rare diagnosed is not missed. Pancreaticoduodenectomy has been advocated as the treatment of choice regardless of size due to high risk of occult nodal metastases. Considering this diagnosis within the differential is important given the drastically different outcomes for patients if caught early.

2580 Nothing but NET: A Case of Neuroendocrine Tumor in the Duodenal Bulb

INTRODUCTION: Neuroendocrine tumors (NETs) are rare neoplasms that comprise approximately 2% of all malignant tumors in the gastrointestinal system. The ileum remains the most common site of NETs in the small intestine, making up >70% of small bowel NETs. Duodenal NETs are exceedingly rare, comprising 2-3% of all gastrointestinal NETs and 1-3% of all duodenal tumors. We present a rare case of a patient diagnosed with a duodenal bulb NET. CASE DESCRIPTION/METHODS: A 66-year-old male with a past history of gastroesophageal reflux disease and hypertension presented to the gastroenterology clinic with a chief complaint of intermittent halitosis for the past year. The symptoms were unrelated to food intake. His recent dental examination was normal. He did not have a family history of gastrointestinal malignancies. His physical examination was unremarkable. Laboratory data including Helicobacter pylori antigen was unremarkable. He underwent esophagogastroduodenoscopy which demonstrated a 15 mm nodule in the duodenal bulb (Figure 1). Histopathological examination of the nodule showed a well-differentiated neuroendocrine tumor. Neuroendocrine immunohistochemical stains were positive for chromogranin and synaptophysin. Ki-67 was positive in 1% of tumor cells. CT scan of the abdomen revealed a 1.2 × 0.8 × 0.7 cm well-defined hyperattenuating structure in the posterior wall of the duodenal bulb (Figure 2). On endoscopic ultrasound, the lesion appeared to be located within the deep mucosa and submucosa without invasion of adjacent structures (Figure 3). The patient has been referred to medical oncology. DISCUSSION: The duodenum is an uncommon location for NETs. Duodenal NETs are typically small, single-lesion neoplasms, the majority of which are non-functional and diagnosed during the 6th decade of life. Unlike NETs of the jejunum and ileum that lack a gender preference, duodenal NETs carry a slight male predominance. Metastasis to regional lymph nodes is seen in ∼60% of cases and to the liver in less than 10% of cases. The absence of neuroendocrine clinical syndromes in >90% of duodenal NETs coupled with the rarity of this malignancy creates a noteworthy diagnostic challenge. It is therefore not surprising that the majority of these cases are diagnosed incidentally during work-up for other symptoms. With a rising annual incidence of NETs, it is important for gastroenterologists to keep this diagnosis in mind as a differential for any nodule in the duodenum.

CT Image Analysis of Gastrointestinal Tumors Based on Simple Linear Iterative Cluster Algorithm

Objective: Gastrointestinal cancer is a very common disease at present. The purpose of this experiment is to use CT scanning technology and Simple Linear Iterative Cluster (SLIC) algorithm to analyze and fuse the scanning results, to explore the imaging characteristics of gastrointestinal neuroendocrine tumors by CT scanning and its application value in gastrointestinal tumors. Methods: The medical records of 25 patients with gastrointestinal tumors were selected as samples and analyzed retrospectively. Texture information fusion of CT image based on SLIC algorithm. This algorithm can fuse the texture information in the image, and then propose more targeted treatment for gastrointestinal tumors in different periods. Results: It was found that the diameter of malignant gastrointestinal tumors was more than 5 cm, and most of them occurred in the intestinal tract and the edge. The specific manifestations are blurred or lobulated, uneven density, invasion of surrounding structures and combined transfer rate. Therefore, it can be concluded that there are significant differences in CT features between benign and malignant gastrointestinal tumors. CT examination is helpful to differentiate benign and malignant tumors. Conclusion: Based on CT imaging, it can be found that the main cause of gastric neurosecretory tumors is blood-rich lesions. Gastrointestinal cancer cells of different pathological grades have different CT imaging features. CT imaging has certain value for preliminary judgment of pathological grading of patients.

Diagnostic imaging of gastrointestinal neuroendocrine neoplasms with a focus on ultrasound.

The diagnosis of gastrointestinal neuroendocrine neoplasms represents a significant diagnostic challenge since these tumours have a various, often non-specific clinical presentation. Currently, more than half of gastroenteropancreatic neuroendocrine neoplasms are detected incidentally, usually during surgery, diagnostic imaging studies or endoscopic procedures performed for other indications. Sometimes the first symptom of the disease is the presence of metastatic lesions in the liver. A neuroendocrine tumour is diagnosed based on the clinical presentation, assessment of specific and non-specific biochemical markers, imaging studies and histopathological examination. Focal lesions, both primary and metastatic may be small and often have an atypical location. Diagnostic imaging of neuroendocrine tumours is of fundamental importance for determining the location of the primary lesion, staging of the disease, selection of treatment and monitoring of its effects. In addition, diagnostic imaging make it possible not only to detect tumours, but also to perform therapeutic procedures based on the result. Transabdominal ultrasound is one of the first diagnostic imaging method for neuroendocrine neoplasms. New ultrasound techniques such as ultrasound elastography, contrast-enhanced ultrasound, endoscopic ultrasound, intraductal and intraoperative ultrasound improve the efficacy of ultrasound examination. Endoscopic ultrasound is a fundamental diagnostic tool for the detection of neuroendocrine tumours of the pancreas and the distal part of the colon. Due to the large variety of neuroendocrine tumours and differences in tumour biology, clinical stage and expression of somatostatin receptors, no single imaging method is sufficient; therefore, in order to determine the right diagnosis and select the best treatment, it is recommended that a combined morphological and functional assessment be used.

Prognostic role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with midgut neuroendocrine tumors undergoing resective surgery.

Several studies demonstrated the prognostic value of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and platelet-to-white blood cells ratio (PWR) in different types of tumors. However, there is no information about a possible role of NLR, PLR and PWR as predictor of presence of metastasis or multifocal disease in patients undergoing surgery with curative intent for midgut NET. The aim of our study was to test the role of preoperative NLR, PLR and PWR as predictors of patients undergoing surgery with curative intent for midgut NET. We retrospectively enrolled seven foregut, 35 midgut and six hindgut NET patients with gastrointestinal neuroendocrine tumors operated in our Units from January 2005 to June 2016. Details about preoperative laboratory data, surgical operation, histology and follow-up were retrieved. Non-parametric statistics, ROC curve analysis and survival analysis were used. NLR was significantly higher in patients with distant metastasis (p = 0.04). The ROC curve analysis indicated that a threshold value of NLR of 2.6 predicted the presence of peritoneal metastasis with a specificity of 100% and a sensitivity of 71% and an overall accuracy of AUC = 0.81 (95%CI: 0.59-0.94), p = 0.05. PLR and PWR was not be associated to metastasis but tended to be associated to multifocal disease. In patients with midgut NET, an impaired adaptive immune response, as suggested by a high NLR ratio, was associated to the presence of distant metastasis and in particular of peritoneal metastasis. This information may be helpful when planning the treatment of a patient with a midgut NET.

Higher IL-6 peri-tumoural expression is associated with gastro-intestinal neuroendocrine tumour progression

An association of well-differentiated gastroenteropancreatic neuroendocrine tumours (WD GEP NETs) with metabolic syndrome (MetS) was recently described. Yet no molecular mechanisms linking the two conditions are known. This study's aim was to identify putative molecular signatures linking WD GEP NETs and MetS to gain further insight into potential mechanisms for this association. Patients with WD GEP NETs (n=39), pancreatic (panNET) and gastro-intestinal (GI-NET), were clinically evaluated for presence of MetS. WD GEP NETs immunohistochemistry staining for Forkhead box protein M1 (FOXM1), insulin growth factor 1 receptor (IGF1R), Ki-67 and interleukin 6 (IL-6) was performed and quantified by computerised morphometric analysis. FOXM1, Ki-67, IGF1R or IL-6 expression in WD GEP NETs was not influenced by the presence of MetS. IL-6 peritumoural expression was higher in GI-NETs of patients with low HDL cholesterol (0.018±0.005% vs 0.030±0.005%, p=0.02). In GI-NETs, a higher IL-6 expression was also associated with disease progression (0.026±0.004% vs 0.016±0.002%, p=0.03). In WD GEP-NETs, MetS did not influence FOXM1, IGF1R and IL-6 expression. In GI-NETs, IL-6 expression was influenced by the MetS feature low HDL, and positively associated with disease progression. These data suggest that local and systemic inflammatory status can potentially modulate GI-NET behaviour.

Tumor neuroendocrino relacionado con enfermedad inflamatoria intestinal: a propósito de dos casos

Patients with inflammatory bowel disease (IBD) have a higher risk of developing gastrointestinal tumors, the adenocarcinoma is the most frequently associated, and neuroendocrine tumor (NET) the most rare. We present two patients, one with Crohn's disease and the other with ulcerative colitis, who present nonspecific symptoms, and after resection of an intestinal lesion, a gastrointestinal NET (GINET) is diagnosed. The GINET have an insidious clinic and these can be confused with those of the IBD. There could be an association between both pathologies; an important role of the chronic intestinal inflammatory process is suggested. The best treatment for GINET is the resection.

Comparation of the quantification of the proliferative index KI67 between eyeball and semi-automated digital analysis in gastro-intestinal neuroendrocrine tumors

BackgroundNeuroendocrine tumors (NETs) constitute tumors widely distributed and with heterogeneous biological behavior. For gastrointestinal neuroendocrine tumors (GI-NETs) the following prognostic factors have been identified: location, production of hormones, size and proliferative grade. The latter must be calculated using proliferation index by the number of mitosis or the proportion of tumor cells positive for Ki67 immunostaining. The objective of this study was to use a quantitative tool to calculate the Ki67 index in GI-NETs.Material and methodsWe reviewed 40 cases of GI-NETs diagnosed at the Department of Pathological Sciences, Santa Casa de Misericórdia de São Paulo Hospital between 2004 and 2014 and compared the Ki67 index by manual count using scanned photomicrographs with semi-automated digital analysis (MC) and eyeball estimation (EE) of the histological slide.After Ki67 immunostaining, the slides were scanned with 3DHistech Pannoramic Scanners. Hot spots were selected and exported in a high-resolution image format and the Ki67 index was calculated with semi-automated image analysis software (AxioVision 3.0). Ki67 immunoreactivity was expressed as the percentage of tumor cells with nuclear staining (number of positive tumor cells/a minimum of 500 total tumor cells).ResultsWe compared the classification of the neuroendocrine tumor by using the two methods in the semi-automated method 26 maintained the same grade, while 14 were re-classified, 4 being upgraded and 10 downgraded.ConclusionIn the EE method there was a larger estimate of the percentage of positivity for KI67. As the Ki67 values are the criteria for the classification of neuroendocrine tumors, the semi-automated method can have less error.

Abstract 4583: Versican accumulation and proteolysis in neuroendocrine tumors

Abstract Introduction: Neuroendocrine tumors (NETs) are a rare, understudied form of human cancer lacking robust preclinical models. Our laboratory has recently demonstrated the importance of the tumor microenvironment (TME) in T-cell exclusion from tumors. Here we examine the accumulation of the immunoregulatory proteoglycan, versican (VCAN), and its immunostimulatory proteolysis product, versikine (Vkine), produced by VCAN cleavage via ADAMTS proteins. Immunotherapeutics are increasingly being studied in NETs and investigation of the immune permissive nature of their TME is warranted. Methods: Human NET tissue microarrays (TMAs) were obtained from the University of Wisconsin Carbone Cancer Center TSB Biobank, containing human NET tissues across a broad spectrum of disease sites including the lung and gastrointestinal (GI) tract among others. Immunohistochemistry was performed using antibodies to VCAN, Vkine, and CD8+ T-cells. VCAN and Vkine levels were measured using a four-tiered relative intensity system (0/1/2/3), while CD8+ T-cell infiltration was measured by counting the CD8+ T-cells per high power field (hpf). Experimental groups were binned as low if VCAN or Vkine scored 0 or 1 and high if VCAN or Vkine scored 2 or 3. Results: Across all samples, high VCAN levels were observed in 20% of samples while high Vkine levels were observed in 55% of samples. Within the lung NET subset, which includes small cell lung cancer, 15% of samples were designated VCAN high and 65% were Vkine high. For the GI NET subset, 34% of samples scored as VCAN high while 50% scored as Vkine high. This study identifies a greater amount of Vkine high tumors present in NETs than we previously observed for colorectal, anal, pancreatic, and breast cancers. The proteolytic predominant phenotype (VCAN low and Vkine high) was present in 55% of lung NETs and 31% of GI NETs. CD8+ T cell infiltration correlated with the VCAN proteolysis predominant phenotype (VCAN low/Vkine High - CD8+ T-cell 16/hpf vs. all other VCAN/Vkine phenotypes 6.5/hpf, p<0.001). This trend persisted across all NET specimen types, including lung and GI primary NETs. Discussion: VCAN accumulation occurs in a subset of NETs, likely leading to immune exclusion and potential resistance to immunotherapies. Excitingly, we demonstrate that a large subset of these cancers has active proteolysis of VCAN in the TME leading to release of the immunostimulatory fragment Vkine. Those NETs with low levels of VCAN and high levels of Vkine are predicted to have a permissive TME for immunotherapies. Further studies are needed to discern the underlying mechanisms resulting in this proteolysis and the signaling consequences with Vkine production. Additionally, this study indicates that VCAN proteolysis should be investigated as a novel biomarker for immunotherapy response for NETs. Citation Format: Christopher P. Babiarz, Philip B. Emmerich, Carley M. Sprackling, Cheri A. Pasch, Linda Clipson, Kristina A. Matkowskyj, Fotis Asimakopoulos, Dustin A. Deming. Versican accumulation and proteolysis in neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4583.

A rare case of duodenal carcinoid presenting as ectopic Cushing’s syndrome

ACTH-dependent Cushing syndrome (CS) due to an ectopic source is responsible for approximately 10-15% cases of Cushing’s syndrome. It is associated with various tumors such as small cell lung cancer and well-differentiated bronchial or gastrointestinal neuroendocrine tumors. Many a times ectopic ACTH production is difficult to manage, and identification of the source may take many years. Hormonal diagnostics include assessments in basic conditions as well as dynamic tests, such as the high-dose dexamethasone suppression test and corticotrophin releasing hormone (CRH) stimulation test. Treatment selection depends on the type of tumor and its extent. In the case of neuroendocrine tumors, the main treatments are surgery and administration of somatostatin analogues or bilateral adrenalectomy in refractory cases and if the source remains unidentified. Here, we report a case who presented with features of Cushing’s syndrome which eventually through workup led us to a diagnosis of duodenal carcinoid producing ectopic ACTH which is extremely rare and was successfully treated.

Impact of gender on multikinase inhibitors (MKIs) toxicity in patients (pts) with advanced pancreatic and gastrointestinal neuroendocrine tumors (NETs): A pooled analysis of two phase II trials with pazopanib and lenvatinib.

4109 Background: Retrospective data in some cancer types suggested a possible different toxicity profile with chemotherapy and targeted therapies according to gender. However, data from prospective studies are still very limited, especially in infrequent tumors such as NETs. Methods: Pts with advanced pancreatic and gastrointestinal NETs treated with pazopanib or lenvatinib in the multicenter open-label phase II studies PAZONET and TALENT respectively, were included in the analysis. Both studies were performed by Spanish Task Force Group for Neuroendocrine Tumors (GETNE). All toxicity grades with an incidence higher than 5% were considered for univariate review. Additionally, all grade 3-4 toxicities were analyzed separately. Results: 155 pts (47.7% female) with 1213 adverse events (AEs) (20% G3-4) divided in 121 categories were included. In female patients, liver toxicity, headache, pyrexia, nausea/vomiting, hair/skin disorders and dizziness were significantly more common (table). The only toxicity with higher incidence in men was dysphonia (OR 0.42, 95% CI 0.2-0.9, p 0.02). There were no gender differences in grade 3-4 toxicities. Conclusions: We observed significant differences in toxicity AEs by gender in two prospective phase II studies with MKIs in NETs patients. Potential different approach to manage toxicity may be adopted based on gender. [Table: see text]

Final results of the TALENT trial (GETNE1509): a prospective multicohort phase II study of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and gastrointestinal (giNETs) neuroendocrine tumors (NETs).

4106 Background: Approved systemic therapies for advanced NETs have showed limited tumor shrinkage and no data of activity after progression to prior targeted agents (TA) is available. Lenvatinib, a potent VEGFR1-3 & FGFR1-4 inhibitor may increase efficacy and revert primary and acquired resistance to TA. We report the final results of the TALENT trial. Methods: Two independent cohorts were included: panNETs and giNETs. All pts had baseline documented progression disease (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless of prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT); and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was overall response rate (ORR) by central radiology review. Progression-free (PFS) and overall survival (OS) were assessed by investigator. With 55 pts per arm, our study was powered to identify an ORR ≥25% (90% power, 5% α-error). Results: We recruited 111 pts: 55 panNETs and 56 giNETs (78% from small intestine). Prior therapies were CHT 32%, SSAs 87%, everolimus 70% and sunitinib 30% for panNETs. ORR was 29%, 42.3% for panNETs and 16.3% for giNETs. With a median follow-up of 19 m, PFS and OS for panNETs were 15.5 m (95% CI 11.3-not reached (NR)) and 29.2 m (95% CI 23.2-NR); and 15.4 m (95% CI 11.5-19.4) and NR for giNETs, respectively. Pts who obtained a response by RECIST had a significantly better PFS compared with non-responders (NR vs 11.2 m in panNETs (p=0.004); 37.2 m vs 14.9 m in giNETs (p=0.005). In the subgroup analyses, all pts obtained the same benefit in PFS and ORR, including tumor grade, prior therapies, hormone release, primary location and tumor burden. The most frequent G3/4 adverse events were hypertension (22%), fatigue (11%) and diarrhea (11%). Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. Conclusions: To our knowledge, we report the highest ORR by central radiology assessment with a TA in this setting. Lenvatinib showed a promising PFS and OS in a pretreated population with benefit across subgroups. Further development in advanced NETs is warranted. Clinical trial information: NCT02678780.

Value of SATB2, ISL1, and TTF1 to differentiate rectal from other gastrointestinal and lung well-differentiated neuroendocrine tumors

BackgroundManagement of neuroendocrine tumors (NETs) depends on the primary site, but the location of many well-differentiated (WD) NETs is elusive. Organ-specific markers are required for pathological diagnosis from biopsy. Transcription factors with good organ specificity include TTF1 (thyroid transcription factor 1; lung), CDX2 (caudal type homeobox transcription factor 2; midgut), and ISL1 (ISL LIM homeobox 1) and PAX8 (paired box 8) for the pancreas and rectum. SATB2 (SATB homeobox 2) has shown high sensitivity and specificity in colorectal adenocarcinoma. This study determined the viability of SATB2 and other transcription factors as markers, single or in combination, for WD-NETs of various sites. MethodsImmunohistochemical staining of 81 WD-NETs from 8 organ sites was performed to identify SATB2, TTF1, CDX2, ISL1, and PAX8. Receiver operating characteristic (ROC) curves were constructed for different combinations of the 5 markers to determine sensitivity and specificity. ResultsAmong the WD-NETs, SATB2 was predominantly found in those of the rectum; TTF1 in the lung, larynx, and esophagus; and ISL1 in the duodenum and rectum. PAX8 and CDX2 showed poor organ specificity. ROC profiles showed 50% sensitivity and 96% specificity to lung for TTF1+ ISL1–; and 65% sensitivity and 100% specificity to rectum for SATB2+ ISL1– TTF1–. ISL1+ SATB2– TTF1– showed 83% sensitivity and 85% specificity to the duodenum, and 44% sensitivity and 87% specificity to the pancreas. A literature search showed that there was no significant difference in the expression rates of the five transcription factors (TTF1, CDX2, SATB2, PAX8 and ISL1) between primary and metastatic WD-NETs at the same organ when there was a large sample size. ConclusionAmong the 5 transcription factors tested, SATB2 may be a viable marker of WE-NETs of the rectum. The combination of SATB2, ISL1, and TTF1 may help estimate the locations of WD-NETs of unknown origin.

Efficacy of Detoxsan® powder on diarrhea caused by gastrointestinal neuroendocrine tumors.

BACKGROUNDPatients with neuroendocrine tumors (NETs) of the gastrointestinal tract suffer frequently from chronic diarrhea. A well characterized medical advice containing zeolite (Detoxsan® powder) was applied to patients suffered from therapy-refractory diarrhea either by its frequency or by watery stool, despite receiving standard pharmacotherapy according to the guidelines for carcinoid syndrome and comorbidities. Detoxsan® powder acts as an adsorbent and might reduce significantly symptoms of diarrhea in patients suffering from NETs.AIMTo overcome the therapy-refractory diarrhea of patients with NETs by the zeolite containing medical advice Detoxsan® powder.METHODSA total of 20 patients (12 female and 8 male) suffering from diarrhea either by its frequency or from watery stool caused by NETs were included. In each patient, the diagnosis had been confirmed by histology and somatostatin receptors expression proven by positron emission tomography/computed tomography using Ga-68-labeled somatostatin analogs. All patients received standard-of-care pharmacotherapy and were additionally given Detoxsan® powder as an extemporaneous drug containing 90% natural Cuban zeolite and 10% magnesium aspartate. Recommended daily dosage ranges between 3 g once to three times per day. Each day dose and bowel movements were documented by the patients themselves in a pre-defined table. Additionally to the bowel movements quantitative determinations of serotonin, urea, creatinine and single ions were performed within the serum of the patients by commercially available equipment used as a matter of routine in the clinic.RESULTSAll patients enrolled in this pilot study did not only suffer from NETs, but also from comorbidities and treatment-resistant diarrhea. There was insufficient control of diarrhea, most probably due to the secretion of hormones like serotonin produced by the slowly growing and highly differentiated NETs. All patients only took Detoxsan® powder as an antidiarrheal drug. In general, response effects need several days to become perceptible and require an intake of Detoxsan® powder for an extended time period or intermittently, if persisting stabilization of bowel movements could not be achieved. A correlation between NET grade, part and size of bowel resection and functionality of the tumor could not be demonstrated. Therefore, diarrhea seemed to be based on the metabolic activity of the well-differentiated NETs, which eventually led to treatment resistance. In summary, 14 out of the 20 patients (70%) declared to be very content with using Detoxsan® powder and observed a significant reduction of diarrhea, while the effective dose and intake period that resulted in a symptom relief varied individually.CONCLUSIONDetoxsan® powder is able to reduce significantly symptoms of NET-related diarrhea in the majority of patients. The duration of taking Detoxsan® powder and its dosage vary individually.

Tu1660 – Increasing Inpatient Admissions, Costs, and Mortality Associated with Gastrointestinal Neuroendocrine Tumors: Analysis of a Nationwide Inpatient Sample

Tu1660 – Increasing Inpatient Admissions, Costs, and Mortality Associated with Gastrointestinal Neuroendocrine Tumors: Analysis of a Nationwide Inpatient Sample

Determination of thresholds values for platelet serotonin and urinary 5-HIAA concentrations for the biological diagnosis of digestive neuroendocrine tumors

Platelet serotonin and its urinary metabolite 5-HIAA (5-hydroxyindolacetic acid) are the main biomarkers measured for the detection of neuroendocrine tumors (NET). We observe in our laboratory many false positives or false negatives for the 2 assays using threshold values given by the manufacturer. We aim to determine our own local threshold values for a better detection of gastrointestinal NETs. We studied patients with measurement of platelet serotonin and/or urinary 5-HIAA in University Hospital of Tours between January 2005 and June 2016. We established an «index» cohort with 75% of patients to determine local threshold value for the 2 parameters. A "validation" cohort constituted with 25% of remaining patients allowed us to compare the performances of manufacturer's values with local threshold values. Two hundred ninety patients were included, with 19 suffering from NETs. Local threshold value for platelet serotonin was determined at 5.13 amol/platelet, the one for urinary 5-HIAA at 3.60 μmol/mmol urinary creatinine. Platelet serotonin specificity was better with local threshold value for identical sensibility (0.75). Urinary 5-HIAA sensibility was improved with local threshold value (1 vs 0.667) for identical specificity (0.902). Using our local threshold value for platelet serotonin and urinary 5-HIAA improved diagnostic performances of these biochemical markers to detect NETs.

Targeted next-generation sequencing of well-differentiated rectal, gastric, and appendiceal neuroendocrine tumors to identify potential targets

Rectal neuroendocrine tumors (NETs) are the most common gastrointestinal (GI) NETs with an uncertain malignant potential despite their small size. There are limited data about driver mutations in rectal NETs, which may explain the tumors' unexpected behavior or common histologic morphology with other GI-NETs. Here, we investigated the clinically and pathologically relevant mutations of rectal and nonrectal NETs and compared the frequency and clinical significance of detected mutations between them. We sequenced 84 primary GI-NETs (69 rectal, 7 gastric, 5 appendiceal, and 3 sigmoid colon NETs) and 3 metastatic GI-NETs using targeted next-generation sequencing. Twenty-one rectal NETs (30.4%) showed at least 1 mutation in 24 cancer-related genes; the most common mutations were TP53 (10.1%) and FBXW7 (7.2%), of which 73% were pathogenic/likely pathogenic mutations. TP53 (p.R337C and p.R213*), PTEN (p.W111*, p.Q214*), CDKN2A (p.W110*), FBXW7 (p.R465H), and AKT1 (p.R23Q) were repetitive mutations found exclusively in rectal NETs, whereas SMAD4 (p.R361C) and STK11 (p.D176N) were repetitive mutations found only in gastric NETs. PTEN (p.G129K), EGFR (p.E709K), and KIT (p.V555I) were shared mutations between rectal and appendiceal NETs, whereas SMAD4 (p.R361C), ALK (p.G1202R), VHL (p.Q132*), and IDH1 (p.R132H) were concurrently detected between rectal and gastric NETs. GI-NETs with higher histologic grades, lymphovascular invasion, or recurrence tended to have higher numbers of mutation variants than other tumors; however, there was no significant difference. In conclusion, rectal NETs commonly carried pathogenic/likely pathogenic mutations. Because most mutations were identified in nonhotspot positions, next-generation sequencing is useful in identifying potential drug targets in rectal NETs.

Efficacy and safety of endoscopic submucosal dissection for gastrointestinal neuroendocrine tumors: a 10-year data analysis of Northern China

Objective: Endoscopy is the main method to treat gastrointestinal neuroendocrine tumors (GI-NETs), but the specific indications are still controversial. We aim to investigate the clinical outcomes of GI-NETs patients who experienced endoscopic submucosal dissection (ESD).Methods: We retrospectively reviewed the clinical features and prognosis of 65 GI-NETs patients who underwent ESD between 2008 and 2018.Results: A total of 65 patients diagnosed with GI-NETs pathologically, bearing 75 lesions, were found by endoscopy incidentally for other symptoms. The locations of these lesions were stomach (n = 24), duodenal bulb (n = 4) and rectum (n = 47). The diameter of 75 tumors were as follows: size ≤ 1 cm (78.7%), 1 cm < size ≤ 2 cm (17.3%), 2 cm < size ≤ 3.5 cm (4.0%). Endoscopic ultrasonography (EUS) suggested that 72 lesions were confined to submucosa and 3 lesions invaded into muscularis propria. The rates of en bloc resection and complete resection were all 100% and the rates of intraoperative bleeding and perforation were 2.7% and 1.3%, respectively. None of the 65 patients had lymph nodes and distant metastasis during the period of study.Conclusion: For GI-NETs without lymph nodes and distant metastases, the lesion confined to submucosa with the diameter ≤1 cm is absolute indication of ESD. For rectal neuroendocrine tumors limited in submucosa with the diameter between 1 and 2 cm, and Type 1 gastric neuroendocrine tumors predicted to be T2, ESD should be prioritized to preserve gastrointestinal volume and function at initial treatment.

Incidence patterns of neuroendocrine neoplasms in California.

242 Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors that typically account for &lt; 5% of tumors arising in any organ site. Both the low incidence and heterogeneity contribute to the paucity of epidemiologic data regarding risk factors. However, evidence suggests that incidence rates in the U.S. are rising. We aimed to further characterize the burden of NENs in California. Methods: Using data from the California Cancer Registry (CCR), we identified all newly diagnosed NENs arising from pulmonary (including SCLC) and gastrointestinal (GI) sites from 1992-2015. We estimated age-adjusted incidence rates (AIR) standardized to the 2000 U.S. census population. We calculated annual percent change (APC) in AIRs using Joinpoint regression and compared AIRs by sex, race-ethnicity, primary tumor site, and county of residence categorized as urban, suburban or rural using SEER∗Stat. Results: From 1992-2015, 97,398 NENs were reported, with 40,099 GI (not lung or bronchus). Overall AIR was 12.5 per 100,000 person-years. Most NENs were of pulmonary (AIR 7.6) or colorectal (AIR 1.3) origin. Females had lower AIR with IR ratio (IRR) vs. males (0.80 95% CI 0.79-0.81). However, females had higher rates of gastric (IRR 1.22 95% CI 1.12-1.32) and appendiceal (IRR 1.19 95% CI 1.07-1.33) primaries vs. males. Compared to non-Hispanic (NH) whites, NH blacks had an IRR of 1.06 (95% CI 1.03-1.09), Asian/Pacific Islanders had an IRR of 0.46 (95% CI 0.45-0.48), and Hispanics had an IRR of 0.57 (95% CI 0.56-0.58). For all NEN subtypes, we estimated lower rates for residents of urban counties (IRR 0.83 95% CI 0.80-0.86) and suburban counties (IRR 0.94 95% CI 0.90-0.97) vs. rural counties. However for GI NENs, we estimated higher rates for residents of suburban counties (IRR 1.11 95% CI 1.03-1.18) and urban counties (IRR 1.10 95% CI 1.03-1.18) vs. rural counties. We found that rates of pulmonary NENs decreased since 1992 (APC -2.6), but rates increased in colorectal (APC 3.9) and all other GI primaries (all APCs ≥ 2.8). Conclusions: Based on these results we conclude that incidence rates for GI NENs reported to CCR steadily increased from 1992-2015. Residence in a suburban or urban county was associated with increased incidence of GI NENs. Additional analyses are ongoing.

Everolimus for the treatment of advanced gastrointestinal or lung nonfunctional neuroendocrine tumors in East Asian patients: a subgroup analysis of the RADIANT-4 study.

BackgroundIn RADIANT-4, everolimus showed an improvement of 7.1 months in median progression-free survival (PFS) vs placebo among patients with advanced, well-differentiated, nonfunctional neuroendocrine tumors (NETs) of gastrointestinal (GI) or lung origin. The present analysis focuses on the effect of everolimus on the East Asian-subgroup population of the RADIANT-4 study.MethodsPatients were randomized to receive everolimus 10 mg/day or matching placebo. The primary end point was PFS (central review). Secondary end points were overall response rate, safety, and tolerability.ResultsAmong 302 patients enrolled in RADIANT-4, 46 were included in the East Asian subgroup (everolimus, n=28; placebo, n=18) analysis. Everolimus was associated with an 82% reduction in the relative risk of disease progression or death (HR 0.18, 95% CI 0.09–0.38). The median PFS (central review) in this subgroup was 11.2 months with everolimus vs 3.1 months with placebo. Adverse events (AEs) occurred in all 28 patients treated with everolimus and ten patients receiving placebo. The majority of these AEs were grade 1 or 2. Most commonly reported ($30% of incidence) drug-related AEs of any grade included stomatitis (75%, n=21) and rash (43%, n=12) in the everolimus arm.ConclusionEverolimus demonstrated a clinically meaningful PFS benefit in the East Asian population. The safety findings were consistent with the known safety profile of everolimus. These results support the use of everolimus in the East Asian population with advanced, nonfunctional NETs of GI or lung origin.