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Introduction: Clinical presentation and genetic profile of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly variable, hampering their management. Sequencing of circulating tumor DNA from liquid biopsy (LB) has been proposed as a less invasive alternative to solid biopsy (SB). Our aim was to compare the mutational profile (MP) provided by LB with that deriving from SB in GEP-NETs., Methods: SB and LB were derived simultaneously from 6 GEP-NET patients. A comparative targeted next-generation sequencing (NGS) analysis was performed on DNA from SB and LB to evaluate the mutational status of 11 genes (MEN1, DAXX, ATRX, MUTYH, SETD2, DEPDC5, TSC2, ARID1A, CHECK2, MTOR, and PTEN)., Results: Patients (M:F = 2:1; median age 64 years) included 3 with pancreatic and 3 with ileal NETs. NGS detected a median number of 55 variants/sample in SB and 66.5 variants/sample in LB specimens (mutational burden: 0.2-1.9 and 0.3-1.8 mut/Mb, respectively). Missense and nonsense mutations were prevalent in both, mainly represented by C>T transitions. ARID1A, MTOR, and ATRX were consistently mutated in SB, and ARID1A, TSC2, MEN1, PTEN, SETD2, and MUTYH were consistently mutated in LB. DAXX mutations were absent in LB. Seventeen recurrent mutations were shared between SB and LB; in particular, MTOR single-nucleotide variants c.G4731A and c.C2997T were shared by 5 out of 6 patients. Hierarchical clustering supported genetic similarity between SB and LB., Conclusions: This pilot study explores the applicability of LB in GEP-NET MP evaluation. Further studies with larger cohorts are needed to validate LB and to define the clinical impact., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Somatostatin and dopamine (DA) receptors have a pivotal role in controlling hormone secretion and cell proliferation in different neuroendocrine neoplasms, including medullary thyroid cancer (MTC). In the present preclinical study, we evaluated the anti-tumor activity of TBR-065 (formerly BIM-23B065), a second-generation somatostatin-DA chimera, in 2 human MTC cell lines., Methods: The effects of lanreotide (LAN) and TBR-065 on cell growth and proliferation, calcitonin (CT) secretion, cell cycle, apoptosis, cell migration, and tumor-induced angiogenesis have been evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, DNA flow cytometry with propidium iodide (PI), Annexin V-FITC/PI staining, electrochemiluminescence immuno assay, wound-healing assay, and zebrafish platform, respectively., Results: TBR-065 exerted a more prominent anti-tumor activity than LAN in both MTC cell lines, as shown by inhibition of cell proliferation (maximal inhibition in TT: -50.3 and -37.6%, respectively; in MZ-CRC-1: -58.8 and -27%, respectively) and migration (in TT: -42.7 and -22.9%, respectively; in MZ-CRC-1: -75.5 and -58.2%, respectively). Only the new chimera decreased significantly the fraction of cells in S phase (TT: -33.8%; MZ-CRC-1: -18.8%) and increased cells in G2/M phase (TT: +13%; MZ-CRC-1: +30.5%). In addition, TBR-065 exerted a more prominent pro-apoptotic effect than LAN in TT cells. A concomitant decrease in CT secretion was observed after 2 days of incubation with both drugs, with a more relevant effect of TBR-065. However, neither LAN nor TBR-065 showed any effect on tumor-induced angiogenesis, as evaluated using a zebrafish/tumor xenograft model., Discussion/conclusion: In MTC cell lines, a second-generation somatostatin-DA analog, TBR-065, exerts a more relevant anti-tumor activity than LAN, through modulation of cell cycle, induction of apoptosis, and reduction in migration. Further studies are required to establish whether TBR-065 has comparable potent inhibitory effects on tumor growth in vivo., (© 2020 S. Karger AG, Basel.)

Background/aim: The neuroendocrine tumor (NET) proliferation-based grading system (ENETS/WHO) for gastroenteropancreatic (GEP) tumors has proved reliable for prognostic stratification. To date, concerns exist regarding Ki-67 heterogeneity within the tumor and little is known on whether grade varies between primary and secondary sites. As tumor heterogeneity may have a significant impact on clinical management, our aim was to retrospectively evaluate Ki-67 on a series of GEP NETs in order to establish whether there is variability in different samples of the same lesion or between primary and metastatic disease (local/distant, synchronous/metachronous)., Methods: Sixty patients with multiple samples of tumor were accrued from a total of 338 GEP NETs; 44 of them also had tissue from local/distant metastases and a further 5 had multiple metastatic foci from unknown primary tumors. Immunohistochemistry for Ki-67 was performed on all paraffin blocks from both primary and metastatic tumors., Results: Intratumor Ki-67 heterogeneity sufficient to change grade at first diagnosis was seen in 3/60 cases (5%). Out of 49 patients with primary NETs and/or multiple metastases, discrepancy in grade between sites was identified in 19 (39%) cases and in particular in 11/47 (23%) and in 10/12 (83%) patients with synchronous and metachronous metastases, respectively (p = 0.0002). Change in grade was more frequent in distant compared to locoregional metastases (p = 0.024) and in particular in distant sites other than the liver (p = 0.006)., Conclusions: NETs show frequent differences in grade between primary sites and their synchronous/metachronous metastases; assessment of Ki-67 at all sites may prove to be significant for patient management., (© 2015 S. Karger AG, Basel.)

The recent depiction of dopamine receptors (DRs) in tumors that cause Cushing's syndrome (CS) has renewed the debate about the dopamine control on pituitary-adrenal axis, and opened interesting new perspectives for medical treatment of CS. The new insights arise from the recent accurate characterization of DR subtypes expression within tumors causing CS, the discovery of new mechanisms, such as the dimerization between DRs and other G-protein coupled receptors (CPCRs), including somatostatin receptors (SSTRs), and the recent availability of new agents targeting these receptor subtypes. Corticotropic adenomas express DR subtype 2 (D(2)R), together with different SSTR subtypes (ssts), in particular sst(5). In vitro, activation of D(2)R inhibits ACTH release in the majority of cultures of corticotropic cells, whereas, in vivo, dopaminergic agents display an inhibitory effect on cortisol levels in a subset of patients with CS. In animal models the receptor profile can be deeply modulated in specific environmental conditions, that may resemble the different clinical phases of CS. The new insights about DRs and receptor-targeting drugs may offer different approaches for medical treatment of CS: combination therapies with different types of compounds, treatment with novel molecules (hybrid compounds) with a wider spectrum of activity, or even pretreatment manipulation of receptor profile. Finally, recent studies showed that D(2)R is also significantly expressed in ectopic ACTH-secreting tumors and in both normal and tumoral adrenal tissues. Dopamine-agonists may decrease cortisol levels in a number of these patients, strengthening the current (re)emerging interest in DRs as possible targets for medical treatment of CS., (Copyright © 2010 S. Karger AG, Basel.)

Introduction: In the last decade, GEP-NET nomenclature has been twice reviewed. The 2000 WHO classification had poor prognostic power in well-differentiated (WD) neoplasms which led to the introduction of two new important parameters: grade and stage, by ENETS; the former became part of the new 2010 WHO classification. Aim(s): Considering the recent introduction of grade and stage, their external validation has been called for in the literature. Since these are important tools in the management of patients, our aim was to reclassify retrospectively with grade and stage our series and correlate with follow-up. Materials and methods: From the histopathology archive at our center, 170 GEPNETs (1993-2011) were identified. Until now, 50 patients have been reclassified. Mean age at diagnosis was 56 years, F:M ratio was 1:1.2 and mean follow-up was 56 months (2-196). Results: Correlating differentiation with overall survival (OS), WD NETs had a strikingly better outcome with respect to poorly differentiated ones. However, only grade identified a subgroup of patients with WD lesions with less favorable clinical behavior (OS at 5 yrs: G1 - 96% v. G2 - 50%). Stage was also useful though not statistically significant in our small series. Conclusion: Our series confirms the importance of grade and stage in prognostic stratification. Retrospective classification of patients who may not have been previously graded or staged may influence the choice of therapeutic options in the future. [ABSTRACT FROM AUTHOR]

Introduction: MCC is a rare cutaneous neuroendocrine neoplasm with aggressive behavior, a high recurrence rate and, generally, poor prognosis. Aim(s): To report histological and clinical features of a series of 12 patients with nodal MCC in the lack of evidence of a primary. Materials and methods: The cases were collected from a multicentric database: mean age at diagnosis was 67 yrs; F:M ratio was 1:1.4; mean follow-up was 54 months. Involved nodal sites were: inguinal (9) and axillar (3). All cases had typical MCC immunoprofile: neuroendocrine (CgA, NSE) and epithelial (CK 20 dot-like) marker positivity. Complete and extensive clinical, dermatologic, radiologic and endoscopic work-up was performed. M1 patients underwent surgery; in one case, chemotherapy, in another case biotherapy and in one further case, radiotherapy was administered. Results: All cases were in stage III of disease, according to UICC. All patients were alive without recurrence at the time of the study. The overall median survival was 52 months. The 4-yr survival was 100%. Conclusion: In patients with nodal metastases of MCC in the absence of a primary lesion, survival seems to be more similar to stage I rather than stage III, since 4-yr survival is reported about 60% for stage III disease in MCC. Regression of a small skin primary with nodal metastases or alternatively a primary nodal MCC might be hypothesized. In conclusion, the unknown primary nodal metastatic skin MCC seems to be associated with a more favorable prognosis. [ABSTRACT FROM AUTHOR]

Introduction: The RNA N6-methyladenosine (m6A) regulators play a crucial role in tumorigenesis and could be indicators of prognosis and therapeutic targets in various cancers. However, the expression status and prognostic value of m6A regulators have not been studied in pancreatic neuroendocrine neoplasms (PanNENs). We aimed to investigate the expression patterns and prognostic value of m6A regulators and assess their correlations with immune checkpoints and infiltrates in PanNENs. Methods: Immunohistochemistry was performed for 15 m6A regulators and immune markers using tissue microarrays obtained from 183 patients with PanNENs. The correlation between m6A protein expression and clinicopathological parameters with recurrence-free survival (RFS) was examined using a random survival forest, Cox regression model, and survival tree analysis. Results: Among the 15 m6A proteins, high expression of YTHDF2 (p < 0.001) and HNRNPC (p = 0.006) was found to be significantly associated with recurrence and served as independent risk factors in multivariate analysis. High YTHDF2 expression was associated with higher number of CD3+ T cells (p = 0.003), whereas high HNRNPC expression was significantly correlated with the expression of PD-L1 (p = 0.039). A YTHDF2-based signature was determined, including five patterns from survival tree analysis: patients with the LNnegYTHDF2high signature had a 5-year RFS rate of 92.1%, whereas patients with LNposTumorSize＜2.5 cm signature had the worst 5-year RFS rate of 0% (p < 0.001). The area under receiver operating characteristic curve was 0.870 (95% confidence interval: 0.762–0.915) for the YTHDF2-based signature. The C-index was 0.978, suggesting good discrimination ability; moreover, the risk score of recurrence served as an independent prognostic factor indicating shorter RFS. Conclusions: YTHDF2 appears to serve as a promising prognostic biomarker and therapeutic target. A YTHDF2-based signature can identify distinct subgroups, which may be helpful to strategize personalized postoperative monitoring. [ABSTRACT FROM AUTHOR]

Background: Above-label doses of somatostatin analogs (SSAs) are increasingly utilized in the management of inoperable/metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), progressing on standard 4-weekly regimens. Objective: To evaluate the antiproliferative effect of 3-weekly SSA administration in a retrospective GEP-NET cohort. Methods: Patients with advanced GEP-NET, treated with long-acting release (LAR) octreotide 30 mg or lanreotide Autogel 120 mg at a 3-weekly interval, after disease progression on standard 4-weekly doses, were retrospectively identified. Clinicopathologic and treatment response data were collected. Progression-free survival (PFS; dose escalation to radiographic progression or death) was estimated with the Kaplan-Meier method. Factors associated with PFS were identified with the Cox proportional-hazards model. Results: The inclusion criteria were fulfilled by 105 patients. Octreotide LAR was administered to 60 (57%) and lanreotide Autogel to 45 (43%). Indications for dose escalation were breakthrough carcinoid symptoms (58%), radiographic progression (35%) and/or increasing biomarkers (11%). Diarrheal and/or flushing symptomatic improvement was identified in 37/67 cases (55%) and 30/55 cases (55%) with available data, respectively. The disease control rate (radiographic partial response or stable disease) was achieved in 53 patients (50%). Median PFS was 25.0 months (95% CI 16.9–33.1). Patients with radiographic progression <12 months from 4-weekly SSA initiation had worse PFS after dose escalation (7.0 vs. 17.0 months, p = 0.002). In multivariate analysis, pancreatic NETs, a Ki-67 index ≥5% and multiple extrahepatic metastases were independently associated with inferior PFS. Conclusions: Above-label doses of SSAs may offer a considerable prolongation of PFS and could be utilized as a bridge to other more toxic treatments. Patients with small bowel/colorectal primaries, a Ki-67 index <5% and absence of/limited extrahepatic metastases are more likely to benefit from this approach. [ABSTRACT FROM AUTHOR]

Background: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. Methods: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. Results: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). Conclusions: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs. [ABSTRACT FROM AUTHOR]

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare, heterogeneous group of tumors that originate from the endocrine system of the gastrointestinal tract and pancreas. GEP-NENs are subdivided according to their differentiation into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Since GEP-NENs represent rare diseases, only limited data from large prospective, randomized clinical trials are available, and recommendations for treatment of GEP-NEN are in part based on data from retrospective analyses or case series. In this context, tractable disease models that reflect the situation in humans and that allow to recapitulate the different clinical aspects and disease stages of GEP-NET or GEP-NEC are urgently needed. In this review, we highlight available data on mouse models for GEP-NEN. We discuss how these models reflect tumor biology of human disease and whether these models could serve as a tool for understanding the pathogenesis of GEP-NEN and for disease modeling and pharmacosensitivity assays, facilitating prediction of treatment response in patients. In addition, open issues applicable for future developments will be discussed. [ABSTRACT FROM AUTHOR]

Molecular mechanisms underlying the development and progression of pancreatic neuroendocrine tumors (PanNETs) are still insufficiently understood. Efficacy of currently approved PanNET therapies is limited. While novel treatment options are being developed, patient stratification permitting more personalized treatment selection in PanNET is yet not feasible since no predictive markers are established. The lack of representative in vitro and in vivo models as well as the rarity and heterogeneity of PanNET are prevailing reasons for this. In this study, we describe an in vitro 3-dimensional (3-D) human primary PanNET culture system as a novel preclinical model for more personalized therapy selection. We present a screening platform allowing multicenter sample collection and drug screening in 3-D cultures of human primary PanNET cells. We demonstrate that primary cells isolated from PanNET patients and cultured in vitro form islet-like tumoroids. Islet-like tumoroids retain a neuroendocrine phenotype and are viable for at least 2 weeks in culture with a high success rate (86%). Viability can be monitored continuously allowing for a per-well normalization. In a proof-of-concept study, islet-like tumoroids were screened with three clinically approved therapies for PanNET: sunitinib, everolimus and temozolomide. Islet-like tumoroids display varying in vitro response profiles to distinct therapeutic regimes. Treatment response of islet-like tumoroids differs also between patient samples. We believe that the presented human PanNET screening platform is suitable for personalized drug testing in a larger patient cohort, and a broader application will help in identifying novel markers predicting treatment response and in refining PanNET therapy. [ABSTRACT FROM AUTHOR]

Introduction: Little is known about how pancreatic neuroendocrine tumors (PanNETs) evolve over time and if changes toward a more aggressive biology correlate with prognosis. The purpose of this study was to characterize changes in PanNET differentiation and proliferation over time and to correlate findings to overall survival (OS). Patients and Methods: In this retrospective cohort study, we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were reevaluated with regard to tumor histopathology and Ki-67 index. Results: Forty-six patients with 106 tumor samples (56 available for pathology reevaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1–38%), grade 1 n = 8, grade 2 n = 36, and grade 3 n = 2. The median change in Ki-67 index (absolute value; follow-up – baseline) was +14% (range –11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n = 24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (hazard ratio 3.89, 95% CI 1.91–7.94, p < 0.001). Conclusions: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET. [ABSTRACT FROM AUTHOR]

Background: Gastric neuroendocrine neoplasms (NENs) are very heterogeneous, ranging from mostly indolent, atrophic gastritis-associated, type I neuroendocrine tumors (NETs), through highly malignant, poorly differentiated neuroendocrine carcinomas (pdNECs), to sporadic type III NETs with intermediate prognosis, and various rare tumor types. Histologic differentiation, proliferative grade, size, level of gastric wall invasion, and local or distant metastases are used as prognostic markers. However, their value remains to be tailored to specific gastric NENs. Methods: Series of type I NETs (n = 123 cases), type III NETs (n = 34 cases), and pdNECs (n = 43 cases) were retrospectively collected from four pathology centers specializing in endocrine pathology. All cases were characterized clinically and histopathologically. During follow-up (median 93 months) data were recorded to assess disease-specific patient survival. Results: Type I NETs, type III NETs, and pdNECs differed markedly in terms of tumor size, grade, invasive and metastatic power, as well as patient outcome. Size was used to stratify type I NETs into subgroups with significantly different invasive and metastatic behavior. All 70 type I NETs < 0.5 cm (micro-NETs) were uneventful. Ki67-based grading proved efficient for the prognostic stratification of type III NETs; however, grade 2 (G2) was not associated with tumor behavior in type I NETs. Although G3 NETs (2 type I and 9 type III) had a very poor prognosis, it was found that patient survival was longer with type III G3 NETs compared to pdNECs. Conclusions: Given the marked, tumor type-related behavior differences, evaluation of gastric NEN prognostic parameters should be tailored to the type of neoplastic disease. [ABSTRACT FROM AUTHOR]

Biomarkers have been the mainstay in the diagnosis and follow-up of patients with neuroendocrine tumors (NETs) over the last few decades. In the beginning, secretory products from a variety of subtypes of NETs were regarded as biomarkers to follow during diagnosis and treatment: serotonin for small intestinal (SI) NETs, and gastrin and insulin for pancreatic NETs. However, it became evident that a large number of NETs were so-called nonfunctioning tumors without secreting substances that caused hormone-related symptoms. Therefore, it was necessary to develop so-called "general tumor markers." The most important ones so far have been chromogranin A and neuron-specific enolase (NSE). Chromogranin A is the most important general biomarker for most NETs with a sensitivity and specificity somewhere between 60 and 90%. NSE has been a relevant biomarker for patients with high-grade tumors, particularly lung and gastrointestinal tract tumors. Serotonin and the breakdown product urinary 5-hydroxyindoleacetic acid (U-5-HIAA) is still an important marker for diagnosing and follow-up of SI NETs. Recently, 5-HIAA in plasma has been analyzed by high- performance liquid chromatography and fluorometric detection and has shown good agreement with U-5-HIAA analysis. In the future, we will see new tests including circulating tumor cells, circulating DNA and mRNA. Recently, a NET test has been developed analyzing gene transcripts in circulating blood. Preliminary data indicate high sensitivity and specificity for NETs. However, its precise role has to be validated in prospective randomized controlled trials which are ongoing right now. [ABSTRACT FROM AUTHOR]

The European Neuroendocrine Tumor Society (ENETS) proposed standard of care guidelines for pathology in 2009. Since then, profound changes in the classification have been made, dividing neuroendocrine neoplasia (NEN) into well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC) in the 2010 WHO classification. The 7th edition of the TNM classification (2009) included NEN for the first time, widely adapting ENETS proposals but with some differences for NEC and for NET of the pancreas and the appendix. Therapy guidelines for gastroenteropancreatic NET were updated in 2016. The need for an update of the standards of care prompted the ENETS to organize a consensus conference which was held in Antibes in 2015; a working group was designated to propose pathological standards of care. [ABSTRACT FROM AUTHOR]

Abstracts from the 13th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease held in Barcelona, Spain on March 9-11 2016 are presented including "Are elFs Ingredients for Neuroendocrine Tumorigenesis?" by N. Gantenbein and colleagues, "The MEN2B Due to de Novo Mutation M918T at Algiers" by A. Chikouche and "Neuroendocrine Cancer Patient Experience Survey" by C. Bouvier and colleagues.

Objective: The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs). Methods: We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR. Results: SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription. Conclusions: The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

An author index for Volume 92, Supplement 1, 2010 issue of the journal "Neuroendocrinology" is presented.

The article presents abstracts presented at the 9th Annual European Neuroendocrine Tumor Society (ENETS) Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, including "Expression of UCH-L1 in PETs and Its Implications," "Activation of Hedgehog Pathway in Neuroendocrine Tumor," and "Alterations of Global and Gene-Specific DNA Methylation in Midgut Carcinoids."

Dopamine (DA) agonists are the primary treatment choice for prolactinoma, effectively suppressing prolactin expression and reducing tumour size. However, the intracellular pathway(s) through which either DA or its agonists impact on proliferation or lead to tumour shrinkage are incompletely understood. To identify the mediators in the apoptotic cascades after DA or DA agonist challenges we used a well-characterized model system, the rodent somatolactotroph cell line GH3. In these cells, we show that apoptosis induced by the DA agonist bromocriptine (BC), but not DA, is initiated through activation of the JNK pathway. However, both DA and BC activate the terminal effector caspase, caspase-3. Kinetic studies and chemical inhibitor co-incubation experiments support a role for JNK activation preceding caspase-9 activation in BC challenged cells, however, engagement of these mediators was not apparent in DA challenge cells. These studies suggest that apoptosis induced by BC or DA is mediated through distinct and independent pathways that converge with activation of the terminal caspase, caspase-3. These observations were further reinforced by our findings that DA and BC, in co-incubation experiments, synergistically induce apoptosis. These findings raise the possibility that drugs acting through the same pathway as DA may be clinically beneficial when combined with BC. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: Somatostatin and dopamine receptors are both G-protein-coupled receptors. Somatostatin receptor (SSTR) expression in neuroendocrine tumours has been well characterised, and there is evidence of dopamine receptor expression in neuroendocrine tumours. In this study, we examined expression of D2R, SSTR-2 and SSTR-5 using immunohistochemistry in patients with neuroendocrine tumours. Methods: Consecutive samples of formalin-fixed paraffin-embedded tumour tissue were available from 56 patients with a histologically confirmed diagnosis of neuroendocrine tumour (NET). The study population was divided into low-grade (n = 29), intermediate-grade (n = 18) and high-grade NET (n = 9). Immunohistochemical evaluation was performed for the expression of SSTR-2a, SSTR-5 and D2 receptors (D2R). Results: Both SSTR-2 and SSTR-5 were expressed in 100% of low-grade, 94.4% of intermediate-grade and 66.7% of high-grade NET. D2R was expressed in 93.1% of low-grade, 77.8% of intermediate-grade and 44.4% of high-grade tumours. Co-expression of all 3 receptors was present in 93.1% of low-grade tumours. There was an inverse correlation of SSTR-2 (r = –0.380, p < 0.005) and SSTR-5 (r = –0.472, p < 0.0001) with tumour grade. D2R was positively correlated with SSTR-2 (r = 0.269, p = 0.041) and SSTR-5 (r = 0.267, p = 0.045). Also, D2R expression was inversely correlated with grade of tumour (r = 0.395, p = 0.006). Octreoscan correlated with SSTR-2, SSTR-5 and D2R expression. Conclusion: D2R is expressed in the majority of low and intermediate grade tumours. It is co-expressed with SSTR-2 and SSTR-5 in the majority of cases. The advent of new chimeric molecules that bind both somatostatin and dopamine receptors may provide a new therapeutic option in the management of neuroendocrine patients. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: Y90-DOTATATE and Y90-DOTATOC are established treatments for patients with advanced neuroendocrine tumours. Outcomes associated with improved survival following therapy are still unclear. Aim(s): To determine clinical, biochemical and radiological response rates to Y90 therapy and their possible association with improved survival. Materials and methods: A retrospective case note analysis was conducted on 60 patients who had received Y90. Clinical response was assessed subjectively. Biochemical and radiological response were assessed using WHO and RECIST criteria, respectively. Survival curves were constructed for responders (stable/regression) v. non-responders (progression). Results: Sixty patients received a total of 146 treatments of Y90 DOTATOC/DOTATATE (median 3, range 1-3). During a median follow-up of 21 (range 1-91) months, 25 (41.6%) patients died with a median survival time of 51 months se+/- 5.2 (range 40-61 months). Eighty-three percent were clinical responders (46.5% improved and 35.5% stable), 76% were radiological responders (24% improved and 52% stable) and 69% were biochemical responders (23% improved and 46% stable). A clinical and radiological response (stable disease or regression post therapy) was associated with improved survival (51 months se+/-5.2 v. 10 +/-5.5; p=0.001 and 56 v. 18+/- 2.8; p=0.001, respectively) compared with no response. Conclusion: A significant survival benefit in clinical and radiological responders has important implications in selecting patients for re-treatment with targeted therapy. [ABSTRACT FROM AUTHOR]

Introduction: A recent study of a small series of patients with appendiceal neuroendocrine tumors (ANETs) fulfilling various criteria for right hemicolectomy (RHC) revealed that approximately 25% may harbor identifiable extra-appendiceal disease. The residual disease might not have been detected using the latest European Neuroendocrine Tumors Society (ENETS) revised pathological criteria. Aim(s): To evaluate the pathological criteria for RHC in an extended series of patients with ANETs. Materials and methods: The medical files of 27 consecutive patients who underwent RHC for ANETs were retrospectively assessed. Results: In 8/27 patients with tumor diameter less than 1 cm, the indications for RHC included: tumor presence in surgical margins (3), extensive mesoappendiceal invasion (EMI) (5), vascular invasion (VI) (2), Ki-67 ≥2% (3); residual disease was present in one patient. In 12/27 patients with tumor diameter of 1-2 cm, RHC followed tumor presence in surgical margins (1), EMI (10), VI (2), Ki-67 ≥2% (2); residual disease was present in two patients. In 7/27 patients with tumor diameter ≥2 cm, tumor was present in surgical margins in three patients, in seven patients there was EMI, in five patients VI was demonstrated, and Ki-67 ≥2% was found in five patients; residual disease was present in two patients. Conclusion: In the subgroup of patients with a primary tumor size between 1-2 cm (the "gray zone"), the risk of residual disease is high. Using the latest criteria for RHC, residual disease may be missed in 7% of ANETs patients. [ABSTRACT FROM AUTHOR]

Introduction: Everolimus is a treatment option for patients with pancreatic NETs, while its use in patients with gastrointestinal NETs still remains to be defined. Aim(s): To test the efficacy and side effects of Everolimus in six patients with differentiated NET refractory to other therapies. Materials and methods: Everolimus (10 mg/day; compassionate use) was administered until disease progression or unacceptable toxicity. Three patients had metastases of ileal neuroendocrine carcinoma; one of typical lung carcinoid; one of ovary carcinoid and one of pancreatic insulinoma. Results: Two patients showed stable disease at imaging after six and 12 months of treatment. One patient showed biochemical remission. Two patients discontinued treatment due to adverse events. One patient did not reach the six months followup. Side effects were: stomatitis (2); thrombocytopenia (2); nausea (2); fatigue (2) that in one case determined definitive therapy discontinuation after eight months; skin infected lesions (1) leading to definitive discontinuation after three months of therapy. In one case, Everolimus was discontinued after 17 months for severe tricuspid valve insufficiency. Finally, one patient discontinued therapy after three months for worsening dyspnea. The only patient currently under treatment had no side effects. During therapy, lipid and glucose profile did not show significant alterations. Conclusion: Everolimus induces disease stabilization but may have several side effects which should be monitored. [ABSTRACT FROM AUTHOR]

Introduction: Parathyroids are derived from third and fourth branchial pouches and neuroendocrine C-cells originate for neighboring fifth branchial pouch. A close ontogenic relation between these embryonal pouches is illustrated in DiGeorge syndrome wherein there is an absence of parathyroid glands and C-cells. It is not known for certain if normal parathyroids contain NE cells. However, NETs of the parathyroid have been reported in two other cases (Medline search: 1966-2011). Aim(s): We report a third case along with treatment given and follow-up course. Materials and methods: A 61-year-old woman presented with respiratory distress. She had outside surgery for an 8 cm "parathyroid tumor," adherent to strap muscles and trachea. Our Investigations: Serial serum Ca++,PTH, Vitamin D, ALKptase, albumin. Histopathology, immunostains, US/CT Neck, CT Chest, PET-CT, Bone scan. Results: Histology: invasive NET, w/multiple vascular emboli, Ki-67 index 5%. Immunostains: chromogranin+, synaptophysin + PTH weak +, thyroglobulin-, TTF1-, p53-. Serum Ca++, PO4-, PTH were persistently normal 3-yrs. Imaging studies showed multiple locally invasive soft tissue masses w/an exophytic lesion infiltrating and obstructing tracheal lumen, lyric vertebral metastases of C4& C6 and mukiple lung lesions. Bronchoscopic radio-fulguration of tracheal lesion done. XRT given for vertebral lesions. Pt. is alive 3 yrs. w/progression of lung lesions and no stigmata of MEN syndrome. Conclusion: NET of parathyroid gland is rare. It should be distinguished from parathyroid adenoma/carcinoma/metastatic to ensure proper management. [ABSTRACT FROM AUTHOR]

Introduction: B-Lymphocyte Stimulator (BLyS) was recently involved in the regulation of malignant cell survival cancers. Aim(s): To test BLyS as a new serological marker in the follow-up of patients with neuroendocrine tumors (NET). Materials and methods: Eighty-one consecutive patients with NET and 56 sex-matched controls enrolled in the study. Patients were classified in two subgroups according to clinical course: evidence of persistent but stable disease or in remission (n=45) and patients with evidence of recurrent disease (n=36). BLyS and Chromogranin A (CgA) serum levels were analyzed by ELISA. Results: BLyS levels were more elevated in NET patients than in controls (1153±529 pg/ml v. 655±158 pg/ml; p<0.0001) and correlated with tumor differentiation (1058±398 pg/ml in gastroenteric G1 - typical lung carcinoid v. 1325±640 pg/ml in gastroenteric G2 - atypical lung carcinoid; p=0.026). Stable/remission patients displayed significant lower BLyS levels than patients with recurrent disease (889±251 pg/ml v. 1461±623 pg/ml; p<0.0001). BLyS levels did not change in patients who remained stable after 6.6±2.8 months (from 864±283 pg/ml to 809±235 pg/ml; p=ns), but increased in patients with disease progression (from 1575±810 pg/ml to 1887±1163 pg/ml; p=0.045). CgA levels, instead, showed conflicting changes. Conclusion: Elevated BLyS levels characterized more aggressive NET cases. BLyS appears as a new potential prognostic marker in the follow-up. [ABSTRACT FROM AUTHOR]

Introduction: Whereas an array of treatment modalities have evolved for management of pancreatic NETs, there has been a lack of information regarding a clear algorithm of optimal treatment or an appropriate sequence in which different treatment modalities can be applied to a given patient for optimal results. Aim(s): We report a young woman with an invasive pancreatic NET that disseminated to regional lymph node and vertebra. We suggested and planned for her a treatment algorithm consisting of Whipple's procedure, followed by concurrent use of radionucleide and Everolimus w/XRT for the skeletal lesion. Materials and methods: A 20-year-old female was referred to us post-Whipple procedure for a pancreatic NET. We undertook histological examination of the tumor tissue, 1-131 MIBG scan, CT abdomen. Octreoscan, PET-CT. serum CGA & genetic studies are pending. Results: The tumor was 8 cm, with lymphovascular, duodenal wall, adjacent liver tissue and metastatic celiac lymph node invasion. Imaging results: destructive lesion of L2 vertebral body with avid uptake of MIBG. Rx plans include 1-131 MIBG with consideration for use of Everolimus and XRT to vertebral lesion. Conclusion: Pancreatic NETs are diagnosed at an advanced stage with about 65% of pts. presenting with metastases. Treatment options are limited for these pts. Recently evidence has emerged with favorable outcome using Everolimus. Whether Everolimus monotherapy suffices for advanced cases remains to be determined. We suggest a multimodal approach in such cases. [ABSTRACT FROM AUTHOR]