Gastroenteropancreatic Neuroendocrine Neoplasia Research Articles

Peptide receptor radionuclide therapy for ectopic Cushing’s syndrome caused by metastatic neuroendocrine neoplasia

Background: Metastatic gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) can cause ectopic Cushing’s syndrome (ECS). ECS is highly morbid and medical therapy is complex and can be ineffective. Patients unsuitable for bilateral adrenalectomy (BA) have dismal outcomes. Peptide receptor radionuclide therapy (PRRT) is a rational option for hormone and disease control in ECS caused by NEN with high somatostatin receptor (SSTR) expression. Aim: To describe characteristics and outcomes of patients with ECS treated with PRRT. Methods: Single-centre, retrospective analysis of imaging, biochemistry and outcomes of seven consecutive patients with ECS caused by metastatic GEPNEN treated with PRRT from 2006-2023. Results: Patients were aged 17–75 (female n=6). The primary site was pancreas (5/7) and rectum (2/7). Six patients were on medical therapy for ECS at baseline (one previous BA). A median of 34.4GBq of [177Lu]Lu-DOTA-octreotate was given. [90Y]Y-DOTA-octreotate (one patient) and [111In]In-octreotide (one patient) was also used. Five patients had radiosensitising chemotherapy. Five patients had a flare of ECS within one week of PRRT cycle 1 (PRRT-C1). Following PRRT-C1, 5/7 patients had complete biochemical resolution of ECS at 1.5–6 months (four ongoing; one recurred after 12 months and had elective BA at 18 months). Best metabolic response on [18F]F-FDG PET/CT: Four patients had a complete metabolic response (CMR), one had a partial metabolic response. PFS was 3–208 months. Two patients progressed at first follow-up. The longest ECS remission and CMR continues at >17 years. Conclusion: PRRT can be effective for ECS caused by metastatic SSTR-positive GEPNEN and should be considered in its treatment algorithm.

Gastroenteropancreatic Neuroendocrine Tumors-Current Status and Advances in Diagnostic Imaging.

Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) is a heterogeneous and complex group of tumors that are often difficult to classify due to their heterogeneity and varying locations. As standard radiological methods, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT) are available for both localization and staging of NEN. Nuclear medical imaging methods with somatostatin analogs are of great importance since radioactively labeled receptor ligands make tumors visible with high sensitivity. CT and MRI have high detection rates for GEP-NEN and have been further improved by developments such as diffusion-weighted imaging. However, nuclear medical imaging methods are superior in detection, especially in gastrointestinal NEN. It is important for radiologists to be familiar with NEN, as it can occur ubiquitously in the abdomen and should be identified as such. Since GEP-NEN is predominantly hypervascularized, a biphasic examination technique is mandatory for contrast-enhanced cross-sectional imaging. PET/CT with somatostatin analogs should be used as the subsequent method.

Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy

PurposeGastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) form a rare and remarkably heterogeneous group of tumors. Therefore, establishing personalized therapies is eminently challenging. To achieve progress in preclinical drug development, there is an urgent need for relevant tumor models.MethodsWe successfully established three gastroenteropancreatic neuroendocrine tumor (GEP-NET) cell lines (NT-18P, NT-18LM, NT-36) and two gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) cell lines (NT-32 and NT-38). We performed a comprehensive characterization of morphology, NET differentiation, proliferation and intracellular signaling pathways of these five cell lines and, in addition, of the NT-3 GEP-NET cell line. Additionally, we conducted panel sequencing to identify genomic alterations suitable for mutation-based targeted therapy.ResultsWe found that the GEP-NEN cell lines exhibit a stable neuroendocrine phenotype. Functional kinome profiling revealed a higher activity of serine/threonine kinases (STK) as well as protein tyrosine kinases (PTK) in the GEP-NET cell lines NT-3 and NT-18LM compared to the GEP-NEC cell lines NT-32 and NT-38. Panel sequencing revealed a mutation in Death Domain Associated Protein (DAXX), sensitizing NT-18LM to the Ataxia telangiectasia and Rad3 related (ATR) inhibitor Berzosertib, and a mutation in AT-Rich Interaction Domain 1A (ARID1A), sensitizing NT-38 to the Aurora kinase A inhibitor Alisertib. Small interfering RNA-mediated knock down of DAXX in the DAXX wild type cell line NT-3 sensitized these cells to Berzosertib.ConclusionsThe newly established GEP-NET and GEP-NEC cell lines represent comprehensive preclinical in vitro models suitable to decipher GEP-NEN biology and pathogenesis. Additionally, we present the first results of a GEP-NEN-specific mutation-based targeted therapy. These findings open up new potentialities for personalized therapies in GEP-NEN.

Role of [18F]FDG PET/CT in the management of G1 gastro-entero-pancreatic neuroendocrine tumors

PurposeSince the role of [18F]FDG PET/CT in low-grade gastroenteropancreatic (GEP) neuroendocrine neoplasia (NET) is not well established, this study was aimed to evaluate the role of [18F]FDG PET/CT in grade 1 (G1) GEP-NETs.MethodsThis is a retrospective study including patients with G1 GEP-NETs who underwent [18F]FDG PET/CT.Results55 patients were evaluated, including 24 (43.6%) with pancreatic NETs and 31 (56.4%) with gastrointestinal NETs. At the time of diagnosis, 28 (51%) patients had metastatic disease, and 50 (91%) patients were positive by 68-Ga sstr PET/CT. Overall, 27 patients (49%) had positive findings on [18F]FDG PET/CT. Following [18F]FDG PET/CT, therapeutic management was modified in 29 (52.7%) patients. Progression-free survival was longer in patients with negative [18F]FDG PET/CT compared with positive [18F]FDG PET/CT (median PFS was not reached and 24 months, respectively, p = 0.04). This significance was particularly evident in the pancreatic group (p = 0.008).ConclusionsDespite having low proliferative activity, approximately half of GEP-NETs G1 showed positive [18F]FDG PET/CT, with a corresponding negative impact on patients’ clinical outcomes. These data are in favor of a more “open” attitude toward the potential use of [18F]FDG PET/CT in the diagnostic work-up of G1 GEP-NETs, which may be used in selected cases to detect those at higher risk for an unfavorable disease course.

Characterizing Canine Hepatobiliary Neuroendocrine Neoplasia: A Proteomic Approach

Hepatobiliary neuroendocrine neoplasia is an extremely rare cancer in humans and other species. In humans, neuroendocrine neoplasia of the liver and gallbladder represents less than 2% of all gastroenteropancreatic neuroendocrine neoplasia. In the veterinary literature, there is a paucity of information on hepatobiliary neuroendocrine cancer with only a small number of published studies. Improved characterization of these tumors is needed to identify additional biomarkers for diagnosis and generate informed treatment protocols for human and veterinary patients. Here, we applied a proteomics strategy to identify differentially expressed proteins in canine hepatobiliary neoplasia as compared to normal canine adrenal and liver tissue from formalin-fixed paraffin-embedded samples. Our objective was to identify unique protein biomarkers and possible chemotherapeutic targets. Thirty-four up-regulated, differentially expressed proteins were identified in the hepatobiliary neuroendocrine neoplasia samples. Galectin-1, a multivalent carbohydrate binding protein known to play a role in lung and pancreatic neuroendocrine neoplasia development and progression, was among them. Drugs targeting the galectin family have shown promise as anticancer therapeutics in cervical cancer, prostate cancer, lung and pancreatic neuroendocrine neoplasia. Galectin-1 may represent a novel treatment target in hepatobiliary neuroendocrine neoplasia in both humans and dogs.

Tumor Heterogenity in Gastro-Entero-Pancreatic Neuroendocrine Neoplasia

Owing to the rarity and the biological and clinical heterogeneity of gastroenteropancreatic neuroendocrine neoplasia (GEP NEN), the management of these patients may be challenging for physicians. This review highlights the specific features of GEP NEN with particular attention on the role of Ki67 heterogeneity, the potential prognostic role of novel radiological techniques, and the clinical usefulness of functional imaging, including 68Ga-DOTA-SST PET/CT and 18F-FDG PET/CT. Understanding these specific features may help to plan proper and tailored follow-up programs and therapeutic approaches.

Pretreatment Levels of Chromogranin A and Neuron-specific Enolase in Patients With Gastroenteropancreatic Neuroendocrine Neoplasia.

Chromogranin A (CgA) and neuron-specific enolase (NSE) are applied in the diagnosis of neuroendocrine neoplasms (NENs), especially non-functional ones. The aim of this study was to investigate the predictive values of CgA and NSE in long-term survival. Our retrospective analysis included 65 patients with histologically verified gastroenteropancreatic NEN between 2005 and 2019. We performed bivariate and multivariable analyses to evaluate the relationship between CgA and NSE values before histological assessment and overall survival. Distribution of time-to-event was analyzed using Kaplan-Meier survival curves and modelled by Cox regression models. Elevated NSE levels prior to histology were significantly associated with worse survival (HR=1.13, p=0.004) and were associated with low-differentiated NENs (rs=0.321, p=0.0338). CgA was associated with well-differentiated tumors (rs=0.233), but not significantly. Pretreatment serum levels of NSE can serve as a valuable additional predictor of long-term survival in patients with NEN.

Long-term outcome of surgical resection in patients with gastroenteropancreatic neuroendocrine neoplasia: results from a German nation-wide multi-centric registry.

Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy. This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999-2012). It focuses on patients without distant metastases (limited disease, LD, stage I-IIIB). Data of 2239 patients with NEN were recorded. Median age was 59years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p < .001). The resection margins in the LD patients were 76%, 16%, and 3% for R0, R1 and R2, respectively. The 10 ysr was 84%, 59% and 42% for R0, R1 and R2 resections, respectively (p = .021 R0/R1, p < .001 R0/R2). The R0 resection rate was 75% for G1/G2 NET and 67% for G3 NEC. The rate of complete tumour resection (R0) in LD is independent of tumour grading, and R0 resection is the key determinant of long-term survival, as demonstrated by the 10 ysr. of 84%. All NEN patients with limited disease should be considered for operation, if possible, as the best 10-year survival is shown after an R0 resection.

Prognostic value of a three-scale grading system based on combining molecular imaging with 68Ga-DOTATATE and 18F-FDG PET/CT in patients with metastatic gastroenteropancreatic neuroendocrine neoplasias.

We investigated on the added prognostic value of a three-scale combined molecular imaging with 68Ga-DOTATATE and 18F-FDG PET/CT, (compared to Ki-67 based histological grading), in gastroenteropancreatic neuroendocrine neoplasia patients. 85 patients with histologically proven metastatic gastroenteropancreatic neuroendocrine neoplasias, who underwent combined PET/CT imaging were retrospectively evaluated. Highest Ki-67 value available at time of 18F-FDG PET/CT was recorded. Patients were classified according to World Health Organization/European Neuroendocrine Tumor Society histological grades (G1, G2, G3) and into three distinct imaging categories (C1: all lesions are 18F-FDG negative/68Ga-DOTATATE positive, C2: patients with one or more 18F-FDG positive lesions, all of them 68Ga-DOTATATE positive, C3: patients with one or more 18F-FDG positive lesions, at least one of them 68Ga-DOTATATE negative). The primary endpoint of the study was Progression-Free Survival, assessed from the date of 18F-FDG PET/CT to the date of radiological progression according to Response Evaluation Criteria In Solid Tumors version 1.1. Classification according to histological grade did not show significant statistical difference in median Progression-Free Survival between G1 and G2 but was significant between G2 and G3 patients. In contrast, median Progression-Free Survival was significantly higher in C1 compared to C2 and in C2 compared to C3 patients, revealing three distinctive imaging categories, each with highly distinctive prognosis. Our three-scale combined 68Ga-DOTATATE/18F-FDG PET imaging classification holds high prognostic value in patients with metastatic gastroenteropancreatic neuroendocrine neoplasias.

Gastroenteropancreatic Neuroendocrine Neoplasia Characterization in Portugal: Results from the NETs Study Group of the Portuguese Society of Endocrinology, Diabetes and Metabolism.

Background The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has been increasing in the last five decades, but there is no large-scale data regarding these tumours in Portugal. We conducted a cross-sectional, multicentric study in main Portuguese centers to evaluate the clinical, pathological, and therapeutic profile of GEP-NENs. Methods From November, 2012, to July, 2014, data from 293 patients diagnosed with GEP-NENs from 15 centers in Portugal was collected and registered in an online electronic platform. Results Median age at diagnosis was 56.5 (range: 15-87) years with a preponderance of females (54.6%). The most frequent primary sites were the pancreas (31.1%), jejunum-ileum (24.2%), stomach (13.7%), and rectum (8.5%). Data regarding hormonal status was not available in most patients (82.3%). Stratified by the tumour grade (WHO 2010 classification), we observed 64.0% of NET G1, 24.7% of NET G2, and 11.3% of NEC. Poorly differentiated tumours occurred mainly in older patients (p = 0.017), were larger (p < 0.001), and presented more vascular (p = 0.004) and lymphatic (p = 0.001) invasion. At the time of diagnosis, 44.4% of GEP-NENs presented metastatic disease. Surgery (79.6%) and somatostatin analogues (30.7%) were the most frequently used therapies of GEP-NENs with reported grading. Conclusion In general, Portuguese patients with GEP-NENs presented similar characteristics to other populations described in the literature. This cross-sectional study represents the first step to establish a national database of GEP-NENs that may aid in understanding the clinical and epidemiological features of these tumours in Portugal.

Role of Combined [68Ga]Ga-DOTA-SST Analogues and [18F]FDG PET/CT in the Management of GEP-NENs: A Systematic Review.

Gastro-entero-pancreatic neuroendocrine neoplasia (GEP-NENs) are rare tumors, but their frequency is increasing. Neuroendocrine tumors normally express somatostatin (SST) receptors (SSTR) on cell surface, especially G1 and G2 stage tumors, but they can show a dedifferentiation in their clinical history as they become more aggressive. Somatostatin receptor imaging has previously been performed with a gamma camera using [111In]In or [99mTc]Tc-labelled compounds, while [68Ga]Ga-labelled compounds and PET/CT imaging has recently become the gold standard for the diagnosis and management of these tumors. Moreover, in the last few years 18F-fluorodeoxyglucose ([18F]FDG) PET/CT has emerged as an important tool to define tumor aggressiveness and give relevant prognostic information, particularly when coupled with [68Ga]Ga-labelled SST analogues PET/CT. This review focuses on the importance of combined imaging with [68Ga]Ga-labelled SST analogues and [18F]FDG for the management of GEP-NENs.

P-095 - Gastroenteropancreatic neuroendocrine neoplasia G3 according to 2019 WHO classification: a comprehensive clinicopathological characterization including mismatch repair proteins and PDL1 expression in a large cohort of patients

P-095 - Gastroenteropancreatic neuroendocrine neoplasia G3 according to 2019 WHO classification: a comprehensive clinicopathological characterization including mismatch repair proteins and PDL1 expression in a large cohort of patients

BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma.

To determine the role of BRAFV600E mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAFV600E mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAFV600E mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAFV600E mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAFV600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAFV600E mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAFV600E mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAFV600E positive NEC xenografts. High frequencies of BRAFV600E mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs.

Investigation of receptor radionuclide therapy with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index.

In the 2010 WHO classification, a Ki-67 proliferation index of 20% is the cut-off between intermediate-grade and high-grade gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN). However, in clinical practice, tumours with a Ki-67 index of >15% are often considered high grade and treated with chemotherapy. In 40-70% of high-grade NENs, somatostatin receptors are overexpressed, enabling peptide receptor radionuclide therapy (PRRT) to be performed. We investigated the role of PRRT with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index. A total of 33 patients with advanced GEP-NENs, positive somatostatin receptor imaging (SRI+) and a Ki-67 proliferation index ranging from 15% to 70% were treated with Lu-PRRT. A cumulative activity of 18.5GBq or 27.8GBq of 177Lu-DOTATATE was administered in four or fivecycles. Receiver operating characteristic (ROC) curve analysis was used to determine the best threshold of Ki-67 expression to predict disease progression. All patients completed the intended treatment. The median follow-up was 43months (range 3-69months). Two patients (6%) achieved a partial response and 21 (64%) showed stable disease, giving a disease control rate (DCR) of 70%. The median progression-free survival (PFS) was 23months (95% CI 14.9-31.0months) and the median overall survival was 52.9months (95% CI 17.1-68.9months). ROC curve analysis at 23months revealed that the best Ki-67 index cut-off was 35%. In 23 patients (70%) the Ki-67 index was ≤35% and in 10 patients (30%) the Ki-67 index was in the range 36-70%. The DCR in the former group was 87% and 30% in the latter. The median PFS was 26.3months (95% CI 18.4-37.7months) and 6.8months (95% CI 2.1-27months), respectively (p = 0.005). Lu-PRRT showed antitumour activity in SRI+ GEP-NENs of intermediate and high-grade. DCR and PFS were significantly better in patients with a Ki-67 index of ≤35% than in those with a Ki-67 index of >35%. On the basis of these results, PRRT should be considered as a therapeutic option in patients with high-grade SRI+ GEP-NENs, in particular those with a Ki-67 proliferation index of ≤35%.

Abstract B22: High prevalence of TSC2 germline missense mutations in nontuberous sclerosis patients with gastroenteropancreatic neuroendocrine neoplasia

Abstract Background: Neuroendocrine neoplasias (NENs) are sporadic diseases, with only a few cases occurring in patients with predisposing syndromes, such as multiple endocrine neoplasia type 1 and type 2, von Hippel-Lindau disease, neurofibromatosis, and tuberous sclerosis. Nevertheless, epidemiologic researches have demonstrated that, even for previously healthy people, there is a higher risk for developing gastroenteropancreatic (GEP) NENs when a relative is affected by these neoplasms. The molecular basis to explain this familial pattern is, however, still unrecognized. We examined germline genes of GEP NEN nonsyndromic patients and looked for mutations that could justify this genetic susceptibility. Methods: Patients with GEP NEN who were in medical care between March to November 2015 at Hospital Sírio-Libanês or Instituto do Câncer do Estado de São Paulo (both in São Paulo, Brazil) were invited to participate of the study. We excluded patients with previously known mutation in any gene surveyed in this study (MEN1, RET, VHL, NF1, TSC1, and TSC2). All participating patients signed the written informed consent form. Targeted next-generation sequencing of the coding region of the 6 genes which are associated with NEN physiopathology was performed in germline DNA. Only mutations with damaging impact by SIFT or PolyPhen2 functional predictors; with minor allele frequency (MAF) lower than 0.1% and with confirmed analysis by Sanger sequencing, were considered for the results. Enrichment of mutations in the evaluated genes in GEP NEN patients was verified by Fisher's exact test, contrasting the results of the GEP NEN group with the ExAC populational database. Results: Ninety-three patients were included in the study (54.8% males) with the median age at diagnosis of 52 years. No patients had clinical phenotype of any syndromes related to NENs predisposition. The majority of patients had neoplasia grades 1 and 2 (38.7% and 41.9%), with primary site in pancreas (44.1%) or small bowel (35.5%) and were not associated with functional syndrome (74.2%). Eight patients (8.6%) have germline missense mutations in the TSC2 gene, and 1 patient (1.1%) in RET. There were no clear differences on age at diagnosis, neoplasia differentiation, site of the primary tumor, or diagnosis of functional syndrome when comparing patients with or without mutations. Populational analysis have shown an odds ratio of 3.8 (IC95% 1.42-7.42; p-value=0.004) for detecting TSC2 mutation in GEP NEN patients comparing with ExAC database. All mutations detected in the TSC2 are not diagnostic for tuberous sclerosis by consensus criteria. No association was seen in RET mutation (OR=1.00). Conclusion: GEP NEN patients without clinical phenotype of any syndrome related to NENs susceptibility are significantly enriched for germline damaging missense mutation in the TSC2 gene. There is no enrichment of mutations in other evaluated genes. Taking into account the increasingly consistent evidence about hereditary predisposition in GEP NEN, as well as the already established relationship of truncated tuberin protein with predisposition of NENs, these findings strongly suggest that TSC2 damaging missense mutation is implicated in the genesis of GEP NEN in some nonsyndromic patients. Although these mutations are not associated with classical phenotype of tuberous sclerosis, this condition could be considered a new feature of a mild tuberous sclerosis. Funding: This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and by Ludwig Institute for Cancer Research São Paulo. Citation Format: Rudinei Diogo Marques Linck, Paula Fontes Asprino, Jônatas Eduardo da Silva Cesar, Florêncio Porto Freitas, Fernanda Christtanini Koyama, Rachel Simões Pimenta Riechelmann, Pedro Alexandre Favoretto Galante, Frederico Perego Costa, Paulo Marcelo Gehm Hoff, Diogo Meyer, Anamaria Aranha Camargo, Jorge Sabbaga. High prevalence of TSC2 germline missense mutations in nontuberous sclerosis patients with gastroenteropancreatic neuroendocrine neoplasia [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B22.

Neuroendocrine tumors of the abdomen

Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) are aheterogeneous group of complex tumors, which is often difficult to classify due to heterogeneity and varying locations. Ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and positron-emission tomography computed tomography (PET/CT) are available for the localization of NEN as well as for the staging. In particular, nuclear medical examination methods with somatostatin analogues are of great importance since radioactively labeled receptor ligands make tumors visible with high sensitivity. CT and MRT have high detection rates for GEP-NEN and have been further improved by developments such as diffusion weighted imaging. The nuclear medical methods, however, are superior in detection, especially in gastrointestinal NEN ACHIEVEMENTS: It is important for the radiologist to become acquainted with the NEN as they can occur ubiquitously in the abdomen and should be identified as such. Since GEP-NEN are predominantly hypervascularized, abiphasic examination technique is obligatory for contrast-enhanced cross-sectional imaging. PET/CT with somatostatin analogs should be used for further diagnosis.

Preclinical assesement of survivin and XIAP as prognostic biomarkers and therapeutic targets in gastroenteropancreatic neuroendocrine neoplasia

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) represent a rare and heterogenous tumor entity. Importantly, the highly proliferative subgroup of neuroendocrine carcinoma (GEP-NEC) is characterized by high resistance to conventional chemotherapy. Consequently, there is an urgent need to identify novel therapeutic targets, especially for GEP-NEC. Thus, we focused on Inhibitor of apoptosis protein (IAP) family members survivin and XIAP that orchestrate inhibition of apoptosis, induce resistance against chemotherapeutics and facilitate tumor metastasis. Copy number gains (CNGs) could be detected by microarray comparative genomic hybridization for survivin and XIAP in 60 % and 26.7 % of all GEP-NENs, respectively. Immunohistochemical staining of tissue specimens from 77 consecutive patients with GEP-NEN demonstrated increased survivin protein expression levels in tissue specimens of highly proliferative GEP-NEC or GEP-NEN located in the stomach and colon. In contrast, XIAP overexpression was associated with advanced tumor stages. Knockdown of survivin and XIAP markedly reduced cell proliferation and tumor growth. In vitro, YM155 induced apoptotic cell death accompanied by a reduction in cell proliferation and inhibited GEP-NEC xenograft growth. Taken together, our data provide evidence for a biological relevance of these IAPs in GEP-NEN and support a potential role of survivin as therapeutic target especially in the subgroup of aggressive GEP-NEC.

Epidemiology and classification of gastroenteropancreatic neuroendocrine neoplasms using current coding criteria.

BackgroundThe lack of uniform criteria for coding of gastroenteropancreatic neuroendocrine neoplasia (GEP‐NEN) has hampered previous epidemiological studies. The epidemiology of GEP‐NEN was investigated in this study using currently available criteria.MethodsAll patients diagnosed with GEP‐NEN between January 2003 and December 2013 in a well defined Norwegian population of approximately 350 000 people were included. Age‐ and sex‐adjusted incidence rates were calculated. The current 2010 World Health Organization criteria, European Neuroendocrine Tumour Society classification and International Union Against Cancer (UICC) classification were used.ResultsA total of 204 patients (114 male, 55·9 per cent) were identified. The median age at diagnosis was 61 (range 10–94) years. The annual overall crude incidence was 5·83 per 100 000 inhabitants, with an increasing trend (P = 0·033). The most frequent location was small intestine (60 patients, 29·4 per cent) followed by appendix (48 patients, 23·5 per cent) and pancreas (33 patients, 16·2 per cent). Grade 1 tumours were more common in gastrointestinal (100 patients, 58·5 per cent) than in pancreatic (9 patients, 27 per cent) NEN. According to the UICC classification, 77 patients (37·7 per cent) had stage I, 17 patients (8·3 per cent) stage II, 37 patients (18·1 per cent) stage III and 70 patients (34·3 per cent) had stage IV disease. No patient with stage I disease had grade 3 tumours; advanced tumour grade increased with stage.ConclusionA high crude incidence of GEP‐NEN, at 5·83 per 100 000 inhabitants, was noted together with a significant increasing trend over time.

GNA15 expression in small intestinal neuroendocrine neoplasia: Functional and signalling pathway analyses

Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) comprises a heterogeneous group of tumours that exhibit widely divergent biological behaviour. The identification of new targetable GPCR-pathways involved in regulating cell function could help to identify new therapeutic strategies. We assessed the function of a haematopoietic stem cell heterotrimeric G-protein, Gα15, in gut neuroendocrine cell models and examined the clinical implications of its over expression. Functional assays were undertaken to define the role of GNA15 in the small intestinal NEN cell line KRJ-I and in clinical samples from small intestinal NENs using quantitative polymerase chain reaction, western blot, proliferation and apoptosis assays, immunoprecipitation, immunohistochemistry (IHC) and automated quantitative analysis (AQUA). GNA15 was not expressed in normal neuroendocrine cells but was overexpressed in GEP-NEN cell lines. In KRJ-I cells, decreased expression of GNA15 was associated with inhibition of proliferation, activation of apoptosis and differential effects on pro-proliferative ERK, NFκB and Akt pathway signalling. Moreover, Gα15 was demonstrated to couple to the ß1 adrenergic receptor and modulated proliferative signals through this GPCR. Transcript and protein levels of GNA15 were significantly elevated in primary and metastatic tumours compared to normal mucosa and were particularly increased in low Ki-67 expressing tumours. IHC and AQUA revealed that a higher Gα15 expression was associated with a poorer survival. GNA15 may have a pathobiological role in SI-NENs. Targeting this signalling mediator could provide an opportunity for the development of new therapeutic strategies for this tumour type.

Quantitative detection of survivin protein in the serum of gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) patients – a promising new biomarker?

Background: The anti-apoptotic and pro-mitotic protein survivin is a powerful prognostic marker in gastroenteropancreatic neuroendocrine neoplasias (GEP-NENs) as measured by immunohistochemical methods in tumor tissues. The present study was conducted to investigate if survivin can also be detected in the serum of GEP-NEN patients.