Gastrointestinal Neuroendocrine Tumors Research Articles

Advances in Systemic Therapy for Gastroenteropancreatic Neuroendocrine Malignancies.

Neuroendocrine tumors (NETs) are relatively uncommon. They typically arise in the gastrointestinal tract and lungs, and their incidence seems to be rising. Most patients have advanced disease at the time of diagnosis and many more will relapse after surgery. There is thus a great need for improvements in therapy for advanced neuroendocrine tumors. This article reviews the current therapy for both pancreatic NETs and non-pancreatic gastrointestinal NETs, and discusses recent advances in NET management with an emphasis on targeted therapy.

Appendiceal neuroendocrine neoplasms: diagnosis and management.

Gastrointestinal neuroendocrine neoplasms (GI-NENs) are increasingly being recognised, while appendiceal NENs (aNENs) currently constitute the third most common GI-NEN. Appendiceal NENs are generally considered to follow an indolent course with the majority being localised at diagnosis. Thus, the initial surgical approach is not that of a planned oncological resection. Due to the localised nature of the disease in the majority of cases, subsequent biochemical and radiological assessment are not routinely recommended. Histopathological criteria (size, mesoappendiceal invasion, Ki-67 proliferation index, neuro- and angio-invasion) are mainly used to identify those patients who are also candidates for a right hemicolectomy. Goblet cell carcinoids are a distinct entity and should be treated as adenocarcinomas. Despite the absence of any substantial prospective data regarding optimal management and follow-up, recent consensus statements and guidelines have been published. The purpose of this review is to overview the published studies on the diagnosis and management of appendiceal NENs and to suggest a possible management protocol.

The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors.

Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs.SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro. In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo. This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways.This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy.

INSM1: A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and Neuroepithelial Neoplasms

Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms, which are sometimes malignant, although predicting metastasis is difficult. INSM1 is a transcription factor expressed transiently in embryonic neuroendocrine (NE) tissue, thought to coordinate termination of cell division with differentiation of NE and neuroepithelial cells. In adult tissues, INSM1 has been identified in multiple tumors of NE or neuroepithelial origin but has not been thoroughly investigated as a potential neoplastic marker. We evaluated INSM1 as a semiquantitative immunohistochemical (IHC) marker for NE and neuroepithelial neoplasms and as a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) marker for gastrointestinal NENs (GI-NENs). Using IHC, we found in normal adult tissue that INSM1 expression was highly restricted to nuclei of NE cells and tissues. INSM1 was not detected in any adult nonneoplastic, non-NE tissue. In neoplastic tissue, INSM1 was detectable by IHC in 88.3% of 129 NEN specimens. In contrast, INSM1 was detected by IHC in only one of 27 neoplasms without a neuroepithelial or NE component. Using qRT-PCR, we evaluated INSM1 gene expression in 113 GI-NEN specimens. INSM1 expression was significantly increased in neoplastic vs nonneoplastic tissue. Furthermore, among midgut GI-NENs, neoplasms with known metastases showed significantly higher expression than those that had not yet metastasized.

IgG4-Related Disease Presented as a Mural Mass in the Stomach

Isolated gastric IgG4-related disease (IgG4-RD) is a very rare tumefactive inflammatory condition, with only a few cases reported to date. A 48-year-old woman was incidentally found to have a subepithelial tumor in the stomach. Given a presumptive diagnosis of gastrointestinal stromal tumor or neuroendocrine tumor, she underwent wedge resection. The lesion was vaguely nodular and mainly involved the submucosa and proper muscle layer. Microscopically, all classical features of type I autoimmune pancreatitis including lymphoplasmacytic infiltration, storiform fibrosis, obliterative phlebitis, and numerous IgG4-positive plasma cells were seen. She had no evidence of IgG4-RD in other organs. Although very rare, IgG4-RD should be considered one of the differential diagnoses in the setting of gastric wall thickening or subepithelial mass-like lesion. Deep biopsy with awareness of this entity might avoid unnecessary surgical intervention.

Endoscopic findings and treatment of gastrointestinal neuroendocrine neoplasms

Objective To investigate the endoscopic findings and treatment of gastrointestinal neuroendocrine neoplasms. Methods Endoscopic manifestation and treatment were analyzed retrospectively in 72 patients who were diagnosed as having gastrointestinal neuroendocrine neoplasms by endoscopy and pathology from May 2011 to December 2014. Results In 72 patients of gastrointestinal NEN, rectum was most commonly involved (48 patients, 66.7%), followed by the stomach (16 patients, 22.2%), duodenum, esophagus and the ileocecal valve. There were certain features in rectal neuroendocrine neoplasms under endoscopy, mostly manifested by submucosal tumors. But gastric, esophageal, and small intestine NEN manifestations showed various forms, without specific typical features, and easy to be misdiagnosed. Some patients diagnosed as having NEN G1 or G2 underwent EMR, ESD or laparoscopy combined with endoscopy resection. Patients diagnosed as having NEN G2 or neuroendocrine carcinoma by pathology received surgical resection, chemotherapy or palliative treatment. All 50 patients underwent endoscopic treatment successfully. Perforation occurred in one duodenal bulbar G1 patient during ESD. No bleeding occurred during and after the operation. All patients after treatment were followed up for 15.6+ 13.2 months on average with no recurrence or metastasis. Conclusion Manifestations of gastrointestinal neuroendocrine neoplasms vary under endoscopy.Some tumors that locate in mucosa or submucosa with diameter less than 1cm can be resected through EMR or ESD. Key words: Neuroendocrine tumors; Endoscopy, digestive system; Endoscopic submucosal dissection

Conventional and Nuclear Medicine Imaging in Ectopic Cushing's Syndrome: A Systematic Review.

Ectopic Cushing's Syndrome (ECS) can be a diagnostic challenge with the hormonal source difficult to find. This study analyzes the accuracy of imaging studies in ECS localization. Systematic review of medical literature for ECS case series providing individual patient data on at least one conventional imaging technique (computed tomography [CT]/magnetic resonance imaging) and one of the following: 111In-pentetreotide (OCT), 131I/123I-metaiodobenzylguanidine, 18Ffluoro-2-deoxyglucose-positron emission tomography (FDG-PET), 18F-fluorodopa-PET (F-DOPA-PET), 68Ga- DOTATATE-PET/CT or 68Ga-DOTATOC-PET/CT scan (68Gallium-SSTR-PET/CT). The analysis comprised 231 patients (females, 50.2%; age, 42.617 y). Overall, 52.4%(121/231) had "overt" ECS,18.6% had "occult" ECS, and 29% had "covert" ECS. Tumors were located in the lung (55.3%), mediastinum-thymus (7.9%), pancreas (8.5%), adrenal glands (6.4%), gastrointestinal tract (5.4%), thyroid (3.7%), and other sites (12.8%), and primary tumors were mostly bronchial neuroendocrine tumors (NETs) (54.8%), pancreatic NETs (8%), mediastinum-thymus NETs (6.9%), gastrointestinal NETs (5.3%), pheochromocytoma (6.4%), neuroblastoma (3.2%), and medullary thyroid carcinoma (3.2%). Tumors were localized byCTin66.2%(137/207), magnetic resonance imaging in 51.5% (53/103), OCT in 48.9% (84/172), FDG-PET in 51.7% (46/89), F-DOPAPET in 57.1% (12/21), 131/123I-metaiodobenzylguanidine in 30.8% (4/13), and 68Gallium-SSTRPET/CT in 81.8% (18/22) of cases. Molecular imaging discovered 79.1% (53/67) of tumors unidentified by conventional radiology, with OCT the most commonly used, revealing the tumor in 64%, followed by FDG-PET in 59.4%. F-DOPA-PET was used in only seven covert cases (sensitivity, 85.7%). Notably, 68Gallium-SSTR-PET/CT had 100% sensitivity among covert cases. Nuclear medicine improves the sensitivity of conventional radiology when tumor site identification is problematic. OCT offers a good availability/reliability ratio, and FDG-PET was proven useful. 68Gallium-SSTR-PET/CT use was infrequent, despite offering the highest sensitivity.

Abstract 2744: Familial multiple metastatic small intestine neuroendocrine tumors: searching for genetic susceptibility

Abstract Small intestinal neuroendocrine tumors (SI-NETs) originating from the enterochromaffin cells of the intestinal mucosa are among the most common tumors in the small intestine. In the past few decades the incidence of SI-NETs has increased more than four-fold in the Western countries. Although SI-NETs are usually well differentiated and indolent with low mitotic activity, multiple discontinuous tumors are present in up to 1/3 of the patients and metastases are found in the majority of the patients at diagnosis. Previous studies have described significantly elevated risk for gastrointestinal NETs in family members of affected individuals. Our recent nationwide registry-based analyses also showed high familial enrichment for SI-NETs. MEN1 syndrome (MIM#131100) patients are often affected by foregut NETs, but no genetic predisposition factor is known for SI-NETs. We have studied a Finnish family of five affected individuals with multiple SI-NETs. The affected individuals had also been diagnosed with numerous adenomas of the colon. The family exhibits autosomal dominant inheritance of SI-NETs with affected individuals in two generations. To identify the possible genetic predisposing factor, we performed genome-wide SNP genotyping and linkage analysis followed by exome and genome sequencing. In addition, we have studied the somatic alterations of the tumors by genome-wide copy number analysis and exome sequencing. We have identified candidate chromosomal regions and genetic variants in this family. Currently we are functionally validating the pathogenicity of the variants and screening the variants in additional familial and sporadic cases with SI-NETs, including a Swedish family of three affected individuals in three generations and Finnish familial and sporadic cases identified through Finnish Cancer Registry. Increased understanding of tumor susceptibility is of great importance in creating tools for better diagnosis and management of the patients. Characterization of novel tumor susceptibility conditions and identification of the associated gene defects also enable studies on gene's biological function and role in other relevant phenotypes or associated tumor types. Citation Format: Mervi Aavikko, Eevi Kaasinen, Iikki Donner, Kaisa Lehti, Erika Gucciardo, Bideep Shrestha, Jukka-Pekka Mecklin, Järnhult Johannes, Kalle Landerholm, Eero Pukkala, Camilla Schalin-Jäntti, Ari Ristimäki, Pia Vahteristo, Lauri A. Aaltonen. Familial multiple metastatic small intestine neuroendocrine tumors: searching for genetic susceptibility. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2744. doi:10.1158/1538-7445.AM2015-2744

Retrospective analysis of the clinicopathological characteristics of gastrointestinal neuroendocrine neoplasms.

The aim of the present study was to analyze and summarize the clinicopathological characteristics and factors affecting prognosis for patients with gastrointestinal neuroendocrine neoplasms (GINENs). Retrospective analysis was conducted on the clinicopathological data of 74 patients who were diagnosed with GINEN, and immunohistochemical methods were used to detect the expression levels of relevant markers [synaptophysin (Syn), chromogranin A (CgA) and Ki-67]. Among the 74 cases with GINEN, there were 39 males and 35 females, with an average age of 56.9 years. There were 32 neoplasms in the rectum, 29 in the stomach, 6 in the colon, 2 in the small intestine and 5 in the appendix. All 74 cases underwent surgical resection. According to the World Health Organization Classification of Tumors of the Digestive System (2010), the diagnosis of the 74 cases showed 41 cases (55.4%) of neuroendocrine tumor (NET; 25 cases of G1 and 16 cases of G2), 21 cases (28.4%) of neuroendocrine carcinoma (NEC) and 12 cases (16.2%) of mixed adenoneuroendocrine carcinoma (MANEC). Additionally, 19 cases had metastasis to lymph nodes. During 10-34 months of follow-up, 15 patients had distant metastasis and 24 patients succumbed, and the accumulative survival rate in 1 or 2 years was 87.8 and 74.3%, respectively. Six factors, namely neoplasm size, depth of invasion, lymph node metastasis, distant metastasis, pathological type and the expression or lack of expression of CgA, significantly affected the survival time of patients. Definitive diagnosis of GINEN mainly relies on pathological diagnosis. GINENs with different histopathological types and grading have different clinicopathological characteristics and prognosis: NETs are mainly early lesions with a good prognosis, whereas NECs and MANECs have high malignancy and strong invasion with a worse prognosis.

Gemcitabine and oxaliplatin or alkylating agents for neuroendocrine tumors: Comparison of efficacy and search for predictive factors guiding treatment choice.

The alkylating agents (ALKYs) streptozotocin, dacarbazine, and temozolomide currently are the main drugs used in systemic chemotherapy for neuroendocrine tumors (NETs). The promising activity shown by gemcitabine and oxaliplatin (GEMOX) in previous studies prompted this study 1) to confirm the use of GEMOX in a larger population of NET patients, 2) to compare its efficacy with that of ALKYs, and 3) to explore whether the O(6) -methylguanine-DNA methyltransferase (MGMT) status could help in selecting the chemotherapy regimen. One hundred four patients with metastatic NETs (37 pancreatic NETs, 33 gastrointestinal NETs, 23 bronchial NETs, and 11 NETs of other/unknown origin) were treated with GEMOX between 2004 and 2014. Among these patients, 63 also received ALKYs. MGMT promoter gene methylation was assessed via pyrosequencing in 42 patients. Patients received a median of 6 courses of GEMOX. Twenty-four (23%) had an objective response (OR). The median progression-free survival (PFS) and overall survival were 7.8 and 31.6 months, respectively. In the 63 patients treated with both ALKYs and GEMOX, the ORs (22% and 22%) and the PFSs (7.5 and 7.3 months) were similar. The response was concordant in 53% of the patients. Promoter gene methylation of MGMT was associated with better outcomes with ALKYs (P = .03 for OR and P = .04 for PFS) but not GEMOX. GEMOX is effective against NETs; its activity is comparable to that of ALKYs, and it is not influenced by the MGMT status. Our data suggest that GEMOX might be preferred for patients with unmethylated MGMT tumors. Cancer 2015;121:3435-43. © 2015 American Cancer Society.

Neuroendocrine tumors of the luminal gastrointestinal tract.

Neuroendocrine tumors (NETs) of the gastrointestinal tract have been recognized for more than a century. Despite histologic similarities between different sites in the tract, behavior varies between areas. All of these tumors have malignant potential, but determination of exact risk is difficult. To review the diagnosis of luminal gastrointestinal NETs, including a discussion of grading. Grading by mitotic index/activity, in conjunction with tumor size/stage, has been found to be the strongest predictor of behavior. Literature review of luminal gastrointestinal NETs was performed and the results summarized. Our understanding of these lesions is incomplete and continues to evolve.

Non-L-cell immunophenotype and large tumor size in rectal neuroendocrine tumors are associated with aggressive clinical behavior and worse prognosis.

According to the 2010 World Health Organization classification, all gastrointestinal neuroendocrine tumors (NETs) are classified as malignant except for L-cell-type (glucagon-like peptide [GLP] and peptide YY [PYY]-producing) NETs. However, L-cell immunophenotype in rectal NETs has not been widely studied previously. Immunohistochemical labeling of L-cell markers with GLP1 and PYY was performed in 208 surgically or endoscopically resected rectal NET cases with tissue microarrays and was compared with clinicopathologic features and patient survival. Rectal NETs with non-L-cell immunophenotype and large tumor size (>1 cm) were associated with increased tumor grading, advanced T category, lymphovascular and perineural invasions, and lymph node and distant metastases (P<0.001, each). Rectal NET patients with non-L-cell phenotype and measuring >1 cm had significantly worse survival outcome than other groups by univariate (P<0.001) and multivariate (P<0.001) analyses. In summary, non-L-cell immunophenotype and large tumor size are associated with increased tumor grading and staging, concurrently indicating that they are independently poor prognostic indicators in rectal NET patients. Therefore, combining L-cell phenotype and tumor size can demonstrate the clinical behavior of rectal NETs more precisely than use of L-cell immunophenotype alone.

Neoplasms of the disseminated neuroendocrine cell system of the gastrointestinal tract

The classification of neuroendocrine neoplasms (NEN) of the gastrointestinal tract and also the pancreas is based on the World Health Organization (WHO) classification from 2010, the site-related TNM stage classification and the clinicopathological characterization. This allows a classification of NEN that is adapted to the individual patient, is of high prognostic relevance and serves the needs of an adequate treatment. This article summarizes the current knowledge on the clinical pathology of gastrointestinal NEN, in order to enable a rapid diagnostic orientation.

10.3760/cma.j.issn.1673-422X.2015.04.019

Gastrointestinal neuroendocrine tumor (GI-NET) originates from peptide neurons and neuroendocrine cells in gastrointestinal tract, and secrets peptide hormones, leading to carcinoid syndrome which rarely happens in clinical practice. Because of the improvement of diagnostic method and understanding of this rare disease, the morbidity is rising in recent years. The main treatments of GI-NET are surgery and comprehensive therapy, consisting of chemotherapy and targeted therapy. Key words: Gastrointestinal tract; Neuroendocrine tumors; Diagnostic evaluation; Therapeutics

Tu1922 Expression of Somatostatin Receptor to Cell Membrane May Possibly Be Relevant to Therapeutic Efficacy by Octreotide in Gastrointestinal Neuroendocrine Tumor

Tu1922 Expression of Somatostatin Receptor to Cell Membrane May Possibly Be Relevant to Therapeutic Efficacy by Octreotide in Gastrointestinal Neuroendocrine Tumor

Evaluation of newly developed histone deacetylase inhibitors for the treatment of solid tumors

The inhibition of histone deacetylases (HDACs) with small‐molecule inhibitors is a new and promising approach for innovative cancer treatment. Histones are of importance for the organization of DNA in the form of chromatin. Transcriptional regulation comprises of a complex machinery of histone modifications, DNA‐methylation as well as acetylation and deacetylation of the chromatin. Dysregulation of acetylation and deacetylation of histones plays an important role in the development and progression of cancer and is often associated with an overexpression or upregulated activity of HDACs. HDAC inhibitors (HDACi) are highly versatile, and have effects on cell cycle, DNA‐repair, DNA‐damage, mitosis, apoptosis and angiogenesis. Here we investigated the suitability of newly synthesized HDACi with enhanced antitumor efficacy as compared to the already established HDACi, such as SAHA.Studies on a set of different cancer cell models (urological cancer cells with or without cisplatin resistance, neuroendocrine gastrointestinal tumor cells and esophageal cancer cells) revealed pronounced growth inhibitory and apoptosis‐inducing effects – starting at nanomolar concentrations (180nM – 1.6µM). Moreover, in vivo tests using the CAM assay method revealed antiangiogenic effects and a concomitant reduction of tumor growth of inoculated urological tumors. Further investigations will focus on the underlying mode of action of the new HDACi in terms of apoptosis, attenuation of subtype‐specific HDAC‐activity and cell cycle regulation.

P53, KI-67, CD117 expression in gastrointestinal and pancreatic neuroendocrine tumours and evaluation of their correlation with clinicopathological and prognostic parameters.

Gastrointestinal and pancreatic neuroendocrine tumors (GEPNETs) originate from the cells of the endocrine system. Their molecular genetic mechanism of development and progression is complex and remains largely unknown. The purpose of this study was to review the gastrointestinal and pancreatic neuroendocrine tumors and to evaluate p53, Ki-67 and CD 117 expressions with their clinicopathological correlations. Twenty-one patients were reviewed and classified as having well-differentiated neuroendocrine neoplasm (WDET, Grade I), well-differentiated neuroendocrine carcinoma (WDEC, Grade II) and poorly differentiated neuroendocrine carcinoma (PDEC, Grade III). We performed immunohistochemical tests to characterize the expession of the immunoreactivity for synaptophysin, chromogranin, p53, Ki67 and CD 117. Median age of 21 patients was 43 years. Thirteen (61.9%) patients were male and eight (38.1%) patients were female. Tumors were located in the stomach (38.1%), appendix (38.1%), duodenum (4.8%), ileum (4.8%), colon (9.5%), and pancreas (4.8%). There was a statistically significant difference between well-differentiated endocrine neoplasm (Grade I), and well-differentiated endocrine carcinoma (WDEC, Grade II) and PDEC for Ki-67 >20% (p<0.001) (Pearson chi-square test). There was a statistically significant difference between WDET (Grade I), WDEC (Grade II) and PDEC (Grade III) for p53 positivity (p<0.05) (Pearson chi-square test).

Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation.

Gallium 68 ((68)Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE, GaTate) positron emission tomography (PET)/computed tomography (CT) is an imaging technique for detecting and characterizing neuroendocrine tumors (NETs). GaTate, a somatostatin analog, has recently been accorded orphan drug status by the U.S. Food and Drug Administration, thereby increasing interest in and availability of this radiotracer. GaTate PET/CT allows whole-body imaging of cell surface expression of somatostatin receptors (SSTRs) and is rapidly evolving as the new imaging standard of reference for the detection and characterization of NETs. The authors discuss the normal appearance at GaTate PET/CT and the utility of this modality in a variety of these tumors, including gastrointestinal, pancreatic, and bronchial NETs as well as pheochromocytoma, paraganglioma, meningioma, and oncogenic osteomalacia. In addition, they discuss potential causes of false-positive findings, including pancreatic uncinate process activity, inflammation, osteoblastic activity, and splenosis. They also highlight the complementary role of 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) PET/CT, including the advantages of using both GaTate PET/CT and FDG PET/CT to evaluate sites of well- and poorly differentiated disease. The use of GaTate PET/CT together with FDG PET/CT allows identification of tumor heterogeneity, which provides prognostic information and can be pivotal in guiding biopsy. It also allows optimal patient management, including theranostic application of peptide receptor radionuclide therapy, and the restaging of patients following therapy.

Exploring phosphatase and tensin homolog (PTEN) loss via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) as a potential predictive marker for response to everolimus in patients (pts) with neuroendocrine tumors (NET).

333 Background: Identification of pts with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Exceptional responders to everolimus in NET including pancreatic (PNET) were observed in our cohort of pts. PTEN is a key negative regulator of the phosphatidylinositol 3-kinase(PI3K)/Akt and mammalian target of rapamycin (mTOR) pathway. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to PI3K/Akt/mTOR pathway activation. Inthis study, we explored the role of PTEN as a potential predictive marker of everolimus in pts with NET including PNET. Methods: Between 2010 and 2014, pts with well-differentiated unresectable and metastatic gastrointestinal NET treated at our institution with everolimus were identified. 17 patients had pathology specimens available for testing. PTEN loss detection by FISH was carried out using a commercially available probe for cytoband 10q23, and by IHC using a commercially available antibody. Patients’ response to everolimus was evaluated through August 2014. The primary outcome was PFS and PTEN status was correlated with PFS for any potential association. Results: The median age was 59 years (range 45-78); 7 were male; 8 had PNET (2 gastrinomas, 1 insulinoma and 5 non-functional); 7 had small bowel NET and 2 unknown primary. All pts received everolimus starting at 10mg daily and octreotide LAR. Of the pts with PNETs, 3 had PTEN loss by FISH. Of those, one did not tolerate everolimus. The PFS for the other two pts was 8 and 24 months respectively. Among the 4 pts with intact PTEN; PFS was 14, 26, 3 and 12 months. 1 patient had insufficient tumor for testing. PTEN FISH is ongoing in the 9 non-pancreatic NET pts. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusions: Testing for PTEN loss by FISH is feasible. Due to the small sample size, the role of PTEN loss could not be defined as a predictive marker in PNET. Testing on additional cases is ongoing and will be presented at the meeting.

Role of double-balloon enteroscopy in malignant small bowel tumors.

To assess the double-balloon enteroscopy (DBE) role in malignant small bowel tumors (MSBT). This is a retrospective descriptive study performed in a single center. All consecutive patients who underwent a DBE with final diagnosis of a malignant neoplasm from 2004 to 2014 in our referral center were included. Patient demographic and clinical pathological characteristics were recorded and reviewed. MSBT diagnosis was achieved either by DBE directed biopsy with multiple tissue sampling, endoscopic findings or histological analysis of surgical specimen. We have analyzed double-balloon enteroscopy impact in outcome and clinical course of these patients. Of 627 patients, 28 (4.5%) (mean age = 60 ± 17.3 years) underwent 30 procedures (25 anterograde, 5 retrograde) and were diagnosed of a malignant tumor. Patients presented with obscure gastrointestinal bleeding (n = 19, 67.9%), occlusion syndrome (n = 7, 25%) and diarrhea (n = 1, 3.6%). They were diagnosed by DBE biopsy (n = 18, 64.3%), histological analysis of surgical specimen (n = 7, 25%) and unequivocal endoscopic findings (n = 2, 7.1%). Gastrointestinal stromal tumor (n = 8, 28.6%), adenocarcinoma (n = 7, 25%), lymphoma (n = 4, 14.3%), neuroendocrine tumor (n = 4, 14.3%), metastatic (n = 3, 10.7%) and Kaposi sarcoma (n = 1, 3.6%) were identified. DBE modified outcome in 7 cases (25%), delaying or avoiding emergency surgery (n = 3), modifying surgery approach (n = 2) and indicating emergency SB partial resection instead of elective approach (n = 2). DBE may be critical in the management of MSBT providing additional information that may be decisive in the clinical course of these patients.