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Introduction: Telotristat ethyl is indicated for use in combination with somatostatin analogs (SSAs) to treat carcinoid syndrome (CS) diarrhea uncontrolled by SSAs alone in adults, but long-term safety and efficacy data beyond 48 weeks are needed., Objectives: The aims of the study were to evaluate the long-term safety and tolerability of telotristat ethyl and its effect on quality of life (QOL) in patients with CS., Methods: In this phase 3, nonrandomized, multicenter, open-label, long-term extension study (TELEPATH), patients who participated in phase 2 or 3 trials of telotristat ethyl continued treatment at their present dose level (250 or 500 mg thrice daily) for 84 weeks. Safety and tolerability, the primary endpoint, were assessed by monitoring adverse events (AEs), serious AEs, AEs of special interest (AESIs; including liver-related AEs, depression, and gastrointestinal AEs), and deaths. The secondary objective was to evaluate changes in patients' QOL using validated cancer questionnaires and a subjective global assessment of CS symptoms., Results: In 124 patients exposed to telotristat ethyl for a mean of 102.6 ± 53.2 weeks, the type and frequency of AEs were consistent with those reported in previous trials. The occurrence of AESIs was not related to dosage or duration of therapy. Most AEs were mild to moderate in severity, and no deaths were related to telotristat ethyl. QOL scores remained stable, and the majority of patients reported adequate symptom relief throughout the study., Conclusions: Safety results of TELEPATH support the long-term use of telotristat ethyl in patients with CS diarrhea. Telotristat ethyl was well-tolerated and associated with sustained improvement in QOL scores (NCT02026063)., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies., (© 2020 S. Karger AG, Basel.)

Background/aims: Lung carcinoids (LCs) are often diagnosed at an early stage and surgical intervention becomes the next phase of treatment. To date, there is lack of long-term follow-up data after surgery and prognostication based on WHO classification criteria and evolving prognostic markers, particularly the expression of somatostatin receptors (SSR)., Methods: We included 102 consecutive patients (72 women; age at baseline 51 ± 16 years [mean ± SD]) with LCs, who underwent thoracic surgery (n = 99) and/or laser treatment (n = 8). Hospital charts were reviewed for clinico-pathological parameters. Immunohistochemical (IHC) expression of SSR1-5 and other novel markers were studied with regard to their prognostic value., Results: Five- and 10-year overall survival (OS) was 96 and 83% respectively; relative survival (RS) was 101 and 93% respectively; and event-free survival (EFS) was 80 and 67% respectively. Independent prognostic factors for OS, RS and/or EFS were age at diagnosis, histopathological type and the presence of ipsilateral mediastinal subcarinal lymph node metastases. Macro-radicality of resective surgery and its extent were associated with increased OS and EFS. The IHC expression of SSR1-5 and other novel markers was not associated with OS or EFS., Conclusion: The long-term outcome of surgically treated patients with LCs is favourable. Age, histopathological type and ipsilateral mediastinal subcarinal lymph node status at baseline were independent prognostic factors for survival and disease recurrence or progression. The extent of surgery and operative macro-radicality also had an impact on prognosis. None of the IHC markers tested appeared to be associated with disease prognosis., (© 2018 S. Karger AG, Basel.)

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies with a very variable clinical expression and progression. They present unique properties that are important to consider for radiological and nuclear imaging, such as APUD-characteristics (amine precursor uptake and dearboxylation), as well as the expression of somatostatin receptors. The most common localizations are the lungs, gastrointestinal tract and pancreas. The only curative treatment is surgery, but more than 50% present metastatic disease at the time of diagnosis. The systemic treatment includes chemotherapy and targeted agents, as well as peptide receptor radiotherapy. The diagnosis and follow-up of these tumors necessitate a large number of different imaging methods, such as CT, MRI, US, SRS and PET. Ultrasonography offers the possibility to take guided biopsies from different lesions. Somatostatin receptor scintigraphy was developed in the 1990s and nowadays presents the standard of care for NETs in most countries. The procedure offers a total body examination and a better staging of the disease. However, it has been replaced in most centers by PET/CT with 68Ga-DOTA-somatostatin analogues with a superior spatial resolution and faster imaging (one-stop procedure). Another tracer used for PET/CT is 18FDG, particularly for high-grade tumors. Other more specific tracers are 18F-L-DOPA, 11C-L-DOPA and 11C-5-hydroxytryptophan, which have demonstrated excellent imaging results. The new targeted agents present a challenge in the evaluation procedure of treatment and, therefore, new imaging techniques and an improvement of currently available techniques are mandatory., (© 2016 S. Karger AG, Basel.)

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.)

Background/aims: The phase III placebo-controlled RADIANT-2 trial investigated the efficacy of everolimus plus octreotide long-acting repeatable (LAR) in patients with advanced neuroendocrine tumors (NET) associated with carcinoid syndrome. Here we report a secondary analysis based on the previous somatostatin analogue (SSA) exposure status of patients enrolled in RADIANT-2., Methods: Patients were randomly assigned to receive oral everolimus 10 mg/day plus octreotide LAR 30 mg intramuscularly (i.m.) or to receive matching placebo plus octreotide LAR 30 mg i.m. every 28 days. SSA treatment before study enrollment was permitted. Patient characteristics and progression-free survival (PFS) were analyzed by treatment arm and previous SSA exposure status., Results: Of the 429 patients enrolled in RADIANT-2, 339 were previously exposed to SSA (95% received octreotide); 173 of 339 patients were in the everolimus plus octreotide LAR arm. All patients had a protocol-specified history of secretory symptoms, but analysis by type showed that more patients who previously received SSA therapy had a history of flushing symptoms (77%), diarrhea (86%), or both (63%) compared with SSA-naive patients (62, 62, and 24%, respectively). Patients who received everolimus plus octreotide LAR had longer median PFS regardless of previous SSA exposure (with: PFS 14.3 months, 95% confidence interval, CI, 12.0-20.1; without: 25.2 months, 95% CI, 12.0-not reached) compared with patients who received placebo plus octreotide LAR (with: 11.1 months, 95% CI, 8.4-14.6; without: 13.6 months, 95% CI, 8.2-22.7)., Conclusion: Everolimus in combination with octreotide improves PFS in patients with advanced NET associated with carcinoid syndrome, regardless of previous SSA exposure., (© 2015 S. Karger AG, Basel.)

Introduction: Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value., Materials and Methods: All patients with progressive metastatic bronchial carcinoid treated with temozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1., Results: There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11 (52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxicities grade 3-4 were noted in 4 patients, thrombocytopenia (n = 3) and leukopenia (n = 1)., Conclusion: Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining temozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients., (Copyright © 2013 S. Karger AG, Basel.)