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As the incidence of neuroendocrine tumors has been rising, gender differences in epidemiology and clinical behavior have emerged, and interest into a gender-driven management of these tumors has grown with the aim to improve survival and quality of life of these patients. Somatostatin Analogues represent the first line of systemic treatment of both functional and non-functional neuroendocrine tumors, through the expression of somatostatin receptors (SSTRs) in the tumor cells, and proved effective in controlling hormonal hypersecretion and inhibiting tumor growth, improving progression-free survival and overall survival of these patients. Aim of the present review is to investigate any differences by gender in efficacy and safety of SSTS-targeted therapies, that represent the mainstay treatment of neuroendocrine tumors, as they emerge from studies of varying design and intent. Although preclinical studies have provided evidence in favor of differences by gender in tumor expression of SSTR, as well as of the role of sex hormones and related receptors in modulating SSTRs expression and function, the clinical studies conducted so far have not shown substantial differences between males and females in either efficacy or toxicity of SSTR-targeted therapies, even if with sometimes inconsistent results. Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.)

Purpose: To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment., Methods: A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety., Results: Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events., Conclusions: HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Octreotide and lanreotide, the first-generation somatostatin analogs, successfully control hormone hyperproduction, and related syndromes, in patients with acromegaly and neuroendocrine tumors. However, their anti-tumor effect, rather evident in large number of pituitary adenomas in acromegalic patients, has been hypothesized for a long time in patients with neuroendocrine tumors as well, although a significant tumor shrinkage has rarely been observed. However, the recent publication of the CLARINET study has strengthened the evidence, already emerged with the PROMID trial, that the long-term treatment with the first-generation long-acting somatostatin analogs may exert an anti-tumor activity on G1 and G2 enteropancreatic neuroendocrine tumors, as well. After the publication, majority of international guidelines have updated their algorithms in line with these results and this class of drugs obtained the indication as anti-tumor agents in the majority of patients with neuroendocrine tumors.

Background/purpose: Somatostatin analogues are the cornerstone of systemic therapy for metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours for both hormonal control and antiproliferative effect. Dose escalation of somatostatin analogues is often utilized in clinical practice, but small studies have yielded mixed results. The aim of this study was to systematically determine the efficacy and safety of escalated-dose somatostatin analogues in the above setting., Methods: Eligible trials (using more than 30 mg octreotide or 120 mg lanreotide/28 days) were identified from MEDLINE, EMBASE, other databases and conference proceedings. Demographics, disease control rate, objective response rate, biochemical response, improvement in symptoms and toxicity were abstracted. Trials were synthesized qualitatively., Results: Eighteen studies (1002 patients) were identified. The risk of bias was moderate for objective response outcomes, but high for the outcomes of symptom control and toxicity due to open-label trial designs. Disease control rates ranged from 30 to 100%, but response rates were modest (at 0-14%). Rates of biochemical improvement (27-100%) and symptom improvement (23-100%) ranged widely depending on the population studied and the definition of response. The most common toxicities were fatigue, diarrhoea, abdominal discomfort and cholelithiasis, with no severe or unexpected toxicities compared to standard-dose somatostatin analogues., Conclusions: The current evidence indicates that escalated-dose somatostatin analogues are well-tolerated in patients with gastroenteropancreatic neuroendocrine tumours, with significant rates of disease control but low rates of tumour response. It was difficult to judge the exact rate of biochemical response or symptomatic improvement. There is a need for large, prospective studies investigating the role of escalated-dose somatostatin analogues in the treatment of metastatic gastroenteropancreatic neuroendocrine tumours.

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

Background: Pancreatic metastases from medullary thyroid carcinoma (MTC) are exceptional. Imaging and treatment based on somatostatin receptors may play a role, though the evidence is unconvincing., Case Presentation: We have, herein, documented a unique case of metastatic MTC, where pancreatic metastasis was identified by 68Ga-PET/CT, with the disease showing very slow progression during treatment with lanreotide autogel. A 51-year-old woman underwent total thyroidectomy for goiter in 2000, with a postoperative diagnosis of MTC. Due to persistent disease, somatostatin analogues (SSA) treatment commenced in 2005, following a positive acute octreotide test. In 2012, a pathology-confirmed pancreatic metastasis was diagnosed via 68Gallium-positron emission tomography (68Ga-PET/CT). The disease progressed very slowly over 17 years of SSA treatment., Conclusion: This uncommon case of pancreatic metastasis from MTC indicates that nuclear medicine techniques might offer valuable additional information. Extended treatment with lanreotide autogel appears to correlate with very slow disease progression in selected patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neuroendocrine tumors (NETs) produce various hormones and bioactive substances and are known to express a large variety of peptide hormone receptors. While these hormones and receptors play a role in the pathophysiology of this heterogeneous group of tumors, they also form an important target for treatment and diagnosis. One of the most well-known target receptors in NETs are somatostatin receptors. On the basis of the expression of functional somatostatin receptors on the cell surface of NET cells, somatostatin analogs have already been used for decades to control symptoms related to hormonal overproduction in patients with NETs. Recent placebo-controlled studies have also demonstrated a significant antitumor activity, both in functioning and nonfunctioning NETs. Moreover, other peptide hormone receptors (e.g. receptors for GLP-1, CCK, GRP, secretin and dopamine) can be expressed at a high density in NETs. As such, these classes of receptors may also form potential targets for diagnosis and treatment. Finally, in recent years novel biotherapies targeting several growth factor systems have been introduced in the treatment of patients with NETs and are being explored for their efficacy in this setting, either as monotherapy or in combination treatment. This chapter aims to give an overview on the above topic., (© 2015 S. Karger AG, Basel.)

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability., (© 2014 Society for Endocrinology.)

Recent studies have shown that G protein-coupled receptors (GPCRs), the largest signal-conveying receptor family, are targets for mutations occurring frequently in different cancer types. GPCR alterations associated with cancer development represent significant challenges for the discovery and the advancement of targeted therapeutics. Among the different molecules that can activate GPCRs, we focused on two molecules that exert their biological actions regulating many typical features of tumorigenesis such as cellular proliferation, survival, and invasion: somatostatin and melatonin. The modulation of signaling pathways, that involves these two molecules, opens an interesting scenario for cancer therapy, with the opportunity to act at different molecular levels. Therefore, the aim of this review is the analysis of the biological activity and the therapeutic potential of somatostatin and melatonin, displaying a high affinity for GPCRs, that interfere with cancer development and maintenance., (© 2020 Wiley Periodicals LLC.)

Somatostatin (SST) and SST receptors (SS1R, SS2R, SS3R, SS4R and SS5R) appear to play a significant role in the progression of human prostate cancer (PCa), which is associated with heterogeneity of SSRs expression and specific cell localization as we already demonstrated in the LNCaP cell line, an in vitro model of human androgen-dependent PCa. In this study, PC-3 and DU-145 human castration-resistant PCa cells were found to express all SSRs, while LNCaP expressed all but SS4R. A 48-h treatment with BIM-23244 (SS2R/SS5R) or BIM-23926 (SS1R) SST analogs was more effective in inhibiting cell proliferation, compared to BIM-23120 (SS2R), BIM-23206 (SS5R) and BIM-23704 (SS1R/SS2R). BIM-23926 (SS1R) treatment increased the amount of p21 and decreased phosphorylated (p) ERK1/2. BIM-23244 (SS2R/SS5R) led to p21 increment only in PC-3 cells, and to pERK1/2 reduction in both cell lines. SS1R/SS2R and SS2R/SS5R receptor dimers were natively present on cell membrane and their amount was increased by BIM-23704 (SS1R/SS2R) or BIM-23244 (SS2R/SS5R) treatment, respectively. SS1R, SS2R and SS5R were differently distributed among nuclear, lysosomal and microsomal compartment, according to their different recycling dynamics. These results show that, in PC-3, DU-145 and LNCaP cells, activation of SS1R and SS2R/SS5R leads to relevant antiproliferative effects., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr₁/sstr₂, sstr₂/sstr₅, sstr₅/dopamine (DA) type 2 receptor (D₂R), and sstr₂/D₂R dimers. BIM-23704 (sstr₁- and sstr₂-preferential compound) increased the co-immunoprecipitation of sstr₁/sstr₂ and significantly inhibited proliferation (-30.98%). BIM-23244 (sstr₂-sstr₅ selective agonist) significantly increased the co-immunoprecipitation of sstr₂/sstr₅, and induced a -41.36% inhibition of proliferation. BIM-23A760, a new somatostatin/DA chimeric agonist with a high affinity for sstr₂ and D₂R and a moderate affinity for sstr₅, significantly increased the sstr₅/D₂R and sstr₂/D₂R complexes and was the most powerful in inhibiting proliferation (-42.30%). The chimeric compound was also the most efficient in modulating receptor interaction in Calu-6, increasing the co-immunoprecipitation of D₂R/sstr₅ and inhibiting cell proliferation (-30.54%). However, behind BIM-23A760, BIM-53097 (D₂R-preferential compound) also significantly inhibited Calu-6 proliferation (-17.71%), suggesting a key role for D₂R in receptor cross talk and in controlling cell growth. Indeed, activation of monomeric receptors did not affect receptor co-immunoprecipitation, whereas cell proliferation was significantly inhibited when the receptors were synergistically activated. In conclusion, our data show a dynamic ligand-induced somatostatin and DA receptor interaction, which may be crucial for the antiproliferative effects of the new analogues.

Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways. A paradigm of the interactions between the neuroendocrine and immune system is sophisticatedly represented in the thymus. Indeed, receptors for these molecules are heterogeneously expressed in all subsets of thymic cells, and the communications are tuned by feedback circuitries. Herein, we focus on somatostatin (SS), a ubiquitous peptide that regulates several physiological cell processes and acts via five specific receptor (SSR) subtypes (sst(1-5)). Neuronal and accessory cells, so-called neuroendocrine cells, and immune cells, heterogeneously express SSRs. The functional characterization of SSRs in vivo by nuclear medicine techniques opened a complex scenario on the significance of SS/SSR pathway in immune system and related diseases. Several studies have established that SSR scintigraphy may benefit patients with chronic inflammatory and granulomatous diseases, as well as lymphoproliferative diseases. The results are sufficiently promising to warrant larger studies aimed at defining the exact role of these techniques. The development of SS analogs with antisecretory and antiproliferative effects has radically changed the management of neuroendocrine tumors. Moreover, very important recent findings, emerging from in vitro studies on SSR physiology in immune cells, will certainly expand the potential applications of SS analogs for in vivo diagnostic and therapeutic options. Indeed, the anti-inflammatory and analgesic effects of these drugs remain incompletely understood, but may prove useful in a number of autoimmune diseases. Because SS expression is absent in different immune tissues where SSRs are present, the existence of another ligand was hypothesized. In fact, it has been recently demonstrated that human lymphoid tissues and immune cells may express cortistatin (CST). CST is known to bind SSRs and shares many pharmacological and functional properties with SS. However, CST has also properties distinct from SS, and the higher expression of CST in immune cells supports the hypothesis that CST rather than SS may act as a potential endogenous ligand for SSRs in the human immune system.

To study somatostatin/dopamine (SS/D) synergy in a human cell system constitutively expressing SS and D receptors (SSR and DR, respectively), we characterized the expression of SSR and DR subtypes in the non-small-cell lung cancer line Calu-6, and then we evaluated the effect on cell proliferation of SS/D chimeric molecules (BIM-23A387 and BIM-23A370), which bind with high affinity both sst(2) and D(2)R, and compared the results with those obtained by using SS-14 and subtype-selective SS analogs (SSA) and D agonists (DA). Because Calu-6 cells produce insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) peptides, which play a role in the autocrine/paracrine control of cell growth, we also investigated the effects of chimeric compounds on secretion and expression of IGF system components. Relative high levels of sst(2) and the long isoform of the D(2)R were detected by real-time RT-PCR and Western blot in Calu-6, together with sst(5) and to a lesser extent sst(3) and D(4)R. BIM-23A387 and BIM-23A370 significantly inhibited growth of Calu-6, whereas IGF-IGFBP secretion or expression was unaffected, suggesting a direct inhibitory effect. The inhibition of cell growth, measured by both [(3)H]thymidine incorporation and cell count, was significantly lower when individual SSA and DA control peptides or subtype-specific SSA and DA were tested. BIM-23A370 was more potent than BIM-23A387 (P < 0.001). These findings show that SS/D chimeras can inhibit Calu-6 proliferation in an IGF-independent manner and suggest that this enhanced potency might be because of the induction of SSR/DR dimerization. The Calu-6 cell line, constitutively expressing SSR and DR, provides a suitable model to elucidate the mechanism of action of SSA and DA on regulation of cell growth and to characterize the interaction between SSR and DR.

Among hormones and neuropeptides influencing the immune system, somatostatin seems to play a key role not only in inhibiting specific immune cell activities, but also in promoting selected functions of particular immune cell subsets. Indeed, controversial effects have been observed in experimental conditions where somatostatin seems to stimulate certain cell functions, such as secretion of specific products (immunoglobulin, cytokines), cell migration and adhesion to extracellular matrix components. However, interestingly, cortistatin (CST), a neuropeptide that strongly resembles somatostatin, from both the structural and functional points of view, seems to have potential roles in regulating immune responses, as well as other lymphoid cell functions. The unexpected wide distribution of CST in a number of human organs, but particularly in immune cells, points to a broader physiological role of CST than previously presumed. The actions of somatostatin and its synthetic analogs (SSA) are mediated by five membrane G protein-coupled receptors subtypes (SSTR1-5), displaying a tissue specific distribution. The majority of somatostatin-target tissues, including lymphoid tissues, may co-express multiple somatostatin receptor (SSTR). The number of SSTRs in lymphoid cells is significantly lower compared to neuroendocrine tissues. However, the presence of receptors allowed the localization by in vivo SSTR scintigraphy of lymphoproliferative disorders, as well as granulomatous and autoimmune diseases. In specific cases, this technique may contribute to establishing the diagnosis and staging the disease. Recent studies evaluating the specific and quantitative SSTR distribution in lymphoid organs and cells, in both normal conditions and immune disorders, have largely contributed to better understand the phenomenology of in vivo receptor imaging and also the involvement of the different SSTR in determining the uptake of radiolabeled SSAs. Moreover, since lymphomas are highly radiosensitive malignancies, a promising approach in refractory patients with malignant lymphomas may be represented by radionuclide-targeted therapy with radioactive-coupled SSAs combined with gene therapy. This latter technique seems effective in inducing the expression or increasing the number of given SSTR in order to ameliorate the impact of radionuclide-targeted therapy. Medical treatment of lymphoproliferative diseases with currently available synthetic analogs have produced unsatisfactory and conflicting results. This might be due to the affinity of the current available SSAs for specific SSTR. However, the synthesis of new compounds with distinct properties has reopened a challenge in this field. The application of receptor-based localization and anti-tumor strategies should also be taking into account the new knowledge recently emerged on the physiopathology of neuropeptide receptors: firstly, neuropeptide receptor homo- and heterodimerization, which may involve different subtypes of SSTRs, as well as other neuropetide receptors, and secondly, the role of endogenous SSTR ligands, such as CST.

Somatostatin and its analogues, known as somatostatin receptor ligands (SRLs), have been reported to attenuate weight gain in some clinical settings. However, their direct effects on preadipocytes are barely investigated. Therefore, this study aimed to evaluate the influence of SRLs on preadipocytes and to further explore the potential mechanisms. Cell Counting Kit-8 assay, Oil Red O staining, triglyceride contents measurements, quantitative polymerase chain reaction (qPCR) and western blot were used to investigate the effects of SRLs on preadipocytes. We found that three SRLs (octreotide, TT232 and pasireotide) inhibited cell viability after 8-48 h but not 4 h. Further western blot results showed that they significantly suppressed activation of PI3K/Akt pathway. Besides, lipid accumulation was also significantly inhibited by these SRLs. Moreover, mRNA levels of some critical adipogenic markers, including Pparg, Cebpa, Fasn, Fabp4, Acaca and Lpl, were downregulated by the treatments of all these SRLs. Consistently, the protein expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα) and fatty acid synthase (FAS) was also suppressed by SRLs. SRLs inhibit the proliferation and lipogenesis in preadipocytes. Their inhibitory effects on cell proliferation may be mediated by the downregulated PI3K/Akt pathway, and the suppressive actions on lipogenesis may be related to the decreased PPARγ and C/EBPα expression., (© 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Simple Summary: Carcinoid syndrome in patients with neuroendocrine tumors is a challenging condition that requires accurate diagnostic and therapeutic management by a multidisciplinary team. Therefore, this review intends to detail all clinical aspects of carcinoid syndrome in order to provide clinicians with a definite overview of the effective approach to carcinoid syndrome. In this way, the review aims to improve patient care and treatment outcomes in this patient population. Carcinoid syndrome (CS) is a rare condition associated with neuroendocrine tumors (NETs), particularly those originating in the gastrointestinal tract, which secrete bioactive substances like serotonin. The management of CS requires a multidisciplinary approach due to its complex clinical manifestations, including flushing, diarrhea, bronchospasm, and carcinoid heart disease. Optimal care involves collaboration between several professional figures like oncologists, endocrinologists, gastroenterologists, surgeons, and dietitians. Currently, a wide range of treatments are available, focused on both symptom control and tumor burden reduction. Somatostatin analogs (SSAs) are the first-line therapy for symptom relief. Still, in patients with progressive disease or refractory CS, other options include targeted therapies, peptide receptor radionuclide therapy (PRRT), liver-directed therapies, and surgical resection, when feasible. Furthermore, management of complications related to prolonged serotonin release and malnutrition as a result of exocrine pancreatic insufficiency, post-surgical conditions, vitamin deficit, and chronic diarrhea often requires early detection to mitigate symptoms and improve the quality of life in these patients. The complexity of CS necessitates individualized care and continuous coordination among specialists to optimize outcomes and enhance patient well-being. [ABSTRACT FROM AUTHOR]

Simple Summary: Somatostatin, a growth hormone-release-inhibiting peptide (SST/SRIF), is a widely distributed multifunctional cyclic peptide that acts by activating G protein-coupled receptors (SSTRs, SST1-5). The diagnostic and prognostic role of these peptides in sporadic CRC remains unclear. The current study showed significant differences in the expression of SST and all SSTRs in the tissue material of sporadic CRC, control colorectal mucosa, and in lymph node metastases from the same patients. A significant dependence of the immunoexpression of SST1-5 on the cellular localization pattern was proved. Differences and/or significant correlations of SRIF system components with clinicopathological data (age, histological subtype of CRC, TNM parameters, Ki-67 antigen, and laboratory tests) were found. Interestingly, only control tissue showed differences in SST1-5 expression depending on the colon segment. The coexpression of all SST1-5 and overexpression of not only SST2 and SST5 in CRC may have applications for future therapy based on the SRIF system in sporadic CRC. Background/Objectives: Colorectal cancer (CRC) is one of the most common human malignancies worldwide. The somatotropin-releasing inhibitory factor/somatostatin (SRIF/SST) acts through activation of five membrane receptors (SSTRs, SST1-5). The diagnostic and prognostic role of these peptides in sporadic CRC remains unclear. This study aimed to determine the role of tissue expression of SST and all SSTRs in the pathogenesis, diagnosis, and prognosis of sporadic CRC. Methods: The expression of SST and all SSTRs was assessed in the tissues of CRC patients, control colorectal mucosa and lymph node metastasis from the same patients using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). Results: Decreased SST (mRNA and peptide) and higher SST2 and SST5 (mRNA and peptide) expression in CRC vs. control was noted. A negative correlation between SST mRNA expression and patient's age in CRC and control groups were observed. IHC study confirmed the coexpression of SSTRs in all tissue groups and significant dependence on the cellular localization. Immunoexpression of SST2 and SST3 showed the most correlations with clinicopathological data in CRC patients. Interestingly, only control tissue showed differences in SST1-5 expression depending on the colon segment. Conclusions: Reduced SST expression in CRC indicates a weakening in its antitumor effect in this cancer in vivo. Overexpression of SST2 and SST5 in CRC suggests that these receptors play an important role in the pathogenesis of this cancer. Analysis of SST1-5 tissue expression allows for differentiation between the mucinous and nonmucinous CRC subtypes. The coexpression of all SST1-5 and overexpression of not only SST2 and SST5 in CRC may have applications for future therapy based on the SRIF system in sporadic CRC. [ABSTRACT FROM AUTHOR]

Somatostatin, a somatotropin release inhibiting factor (SST, SRIF), is a widely distributed multifunctional cyclic peptide and acts through a transmembrane G protein-coupled receptor (SST1-SST5). Over the past decades, research has begun to reveal the molecular mechanisms underlying the anticancer activity of this hormonal peptide. Among gastrointestinal tract (GIT) tumors, direct and indirect antitumor effects of SST have been documented best in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and less well in non-endocrine cancers, including sporadic colorectal cancer (CRC). In the latter, the signaling pathways involved in the antitumor function of SST are primarily MAPK/ERK/AKT and Wnt/β–catenin. Direct (involving the MAPK pathway) and indirect (VEGF production) antiangiogenic effects of SST in CRC have also been described. The anti-inflammatory role of SST in CRC is emphasized, but detailed molecular mechanisms are still being explored. The role of SST in tumor genome/tumor microenvironment (TME)/host's gut microbiome interactions is only partially known. The results of SST analogues (SSAs)' treatment of sporadic CRC in monotherapy in vivo are not spectacular. The current review aims to present the state-of-the-art mechanisms and antitumor activity of endogenous SST and its synthetic analogues in CRC, with particular emphasis on sporadic CRC. [ABSTRACT FROM AUTHOR]

Background Patients with advanced neuroendocrine tumors (NETs) have multiple treatment options. Ideally, treatment decisions are shared between physician and patient; however, previous studies suggest that oncologists and patients place different value on treatment attributes such as adverse event (AE) rates. High-quality information on NET patient treatment preferences may facilitate patient-centered decision making by helping clinicians understand patient priorities. Methods This study used 2 discrete choice experiments (DCE) to elicit preferences of NET patients regarding advanced midgut and pancreatic NET (pNET) treatments. The DCEs used the "potentially all pairwise rankings of all possible alternatives" (PAPRIKA) method. The primary objective was to determine relative utility rankings for treatment attributes, including progression-free survival (PFS), treatment modality, and AE rates. Ranking of attribute profiles matching specific treatments was also determined. Levels for treatment attributes were obtained from randomized clinical trial data of NET treatments. Results One hundred and 10 participants completed the midgut NET DCE, and 132 completed the pNET DCE. Longer PFS was the highest ranked treatment attribute in 64.5% of participants in the midgut NET DCE, and in 59% in the pNET DCE. Approximately, 40% of participants in both scenarios prioritized lower AE rates or less invasive treatment modalities over PFS. Ranking of treatment profiles in the midgut NET scenario identified 60.9% of participants favoring peptide receptor radionuclide therapy (PRRT), and 30.0% somatostatin analogue dose escalation. Conclusion NET patients have heterogeneous priorities when choosing between treatment options based on the results of 2 independent DCEs. These results highlight the importance of shared decision making for NET patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The tissue expression of somatostatin receptor (SSTR) subtypes in neuroendocrine tumors (NETs) holds paramount significance with far-reaching diagnostic and therapeutic implications. SSTRs contribute significantly to localizing NETs, aiding in advanced imaging techniques such as somatostatin receptor scintigraphy and PET scans. Elevated SSTR expression often aligns with less aggressive tumors, impacting tumor grading and influencing treatment decisions. Therapeutically, SSTRs serve as pivotal targets for treatments like targeted radiotherapy and synthetic somatostatin analogs (e.g., octreotide), commonly employed to inhibit hormone secretion and suppress tumor growth. Tailoring treatment strategies based on SSTR subtype expression enhances therapeutic efficacy. SSTR expression serves as a valuable prognostic indicator, predicting treatment response. While challenges like tumor heterogeneity persist, ongoing research explores promising avenues, including combination therapies. In conclusion, a nuanced understanding of SSTR expression in NETs is indispensable for precise diagnosis and the development of tailored therapeutic interventions, offering the potential for improved patient outcomes. Neuroendocrine tumors (NETs) arise from neuroendocrine cells and manifest in diverse organs. Key players in their regulation are somatostatin and its receptors (SSTR1–SSTR5). Understanding receptor–ligand interactions and signaling pathways is vital for elucidating their role in tumor development and therapeutic potential. This review highlights SSTR characteristics, localization, and expression in tissues, impacting physiological functions. Mechanisms of somatostatin and synthetic analogue binding to SSTRs, their selectivity, and their affinity were analyzed. Upon activation, somatostatin initiates intricate intracellular signaling, involving cAMP, PLC, and MAP kinases and influencing growth, differentiation, survival, and hormone secretion in NETs. This review explores SSTR expression in different tumor types, examining receptor activation effects on cancer cells. SSTRs' significance as therapeutic targets is discussed. Additionally, somatostatin and analogues' role in hormone secretion regulation, tumor growth, and survival is emphasized, presenting relevant therapeutic examples. In conclusion, this review advances the knowledge of receptor–ligand interactions and signaling pathways in somatostatin receptors, with potential for improved neuroendocrine tumor treatments. [ABSTRACT FROM AUTHOR]

Neuropeptides are among the most abundant chemical messengers produced in the brain that can function as neurotransmitters or hormones. Neuropeptides are synthesized and used by a neuron. There are over one hundred known neuropeptides, representing the largest and most diverse class of signaling molecules in the nervous system. Neuropeptides are often co-released with other neuropeptides and neurotransmitters in a single neuron, yielding a multitude of effects. The focus of this review is their role in cancer in general and mainly sarcomas. Neuropeptides and their receptors are no exception when it comes to their pro or antitumorigenic diverse functions defined by cellular and disease content. The molecular targets, pathways, and epigenetic regulation of sarcoma growth by neuropeptides are highlighted to better understand the importance of these molecules and suggest future alternative therapies for this challenging disease with unmet cancer needs. [ABSTRACT FROM AUTHOR]

Simple Summary: Few therapies are available for patients with aggressive or metastatic pituitary neuroendocrine tumours (PitNETs). Peptide receptor radionuclide therapy (PRRT), widely used to treat gastroenteropancreatic neuroendocrine tumours, has been emerging as a potential option for aggressive or metastatic PitNETs if other treatment approaches are not feasible or failed in controlling the disease progression. However, the data regarding the use of PRRT in this setting is scarce, and mainly derives from few case reports or small series of cases. Here, we review the published data regarding the effectiveness and safety of PRRT in the management of aggressive or metastatic PitNETs, as well as the effects of PRRT on the pituitary function in other cancer patients. Pituitary neuroendocrine tumours (PitNETs) are usually benign and slow-growing; however, in some cases, they may behave aggressively and become resistant to conventional treatments. Therapeutic options for aggressive or metastatic PitNETs are limited, and currently mainly consist of temozolomide, with little experience of other emerging approaches, including peptide receptor radionuclide therapy (PRRT). Somatostatin receptor expression in PitNETs explains the effectiveness of somatostatin analogues for treating PitNETs, particularly those hypersecreting pituitary hormones, such as growth hormone or adrenocorticotropic hormone. The expression of such receptors in pituitary tumour cells has provided the rationale for using PRRT to treat patients with aggressive or metastatic PitNETs. However, the PRRT efficacy in this setting remains unestablished, as knowledge on this today is based only on few case reports and small series of cases, which are reviewed here. A total of 30 PRRT-treated patients have been thus far reported: 23 aggressive PitNETs, 5 carcinomas, and 2 of malignancy status unspecified. Of the 27 published cases with information regarding the response to PRRT, 5 (18%) showed a partial response, 8 (30%) had stable disease, and 14 (52%) had progressive disease. No major adverse effects have been reported, and there is also no increased risk of clinically relevant hypopituitarism in patients with pituitary or non-pituitary neuroendocrine tumours following PRRT. PRRT may be regarded as a safe option for patients with aggressive or metastatic PitNETs if other treatment approaches are not feasible or have failed in controlling the disease progression, with tumour shrinkage occurring in up to a fifth of cases, while about a third of aggressive pituitary tumours may achieve stable disease. Here, the data on PRRT in the management of patients with aggressive pituitary tumours are reviewed, as well as the effects of PRRT on the pituitary function in other PRRT-treated cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine tumours, recently reclassified as neuroendocrine neoplasms (NENs), are a heterogeneous group of tumours with variability in their disease course and outcome. Complex mechanisms involving spatial and temporal changes in tumour biology affect their treatment response and survival. Treatment strategies are often based on information regarding tumour stage and grade. Tumour heterogeneity, however, is a common phenomenon in NENs, and it is not uncommon for these neoplasms to show intra- and inter-tumour heterogeneity that may lead to incomplete understanding of their tumour biology and behaviour. This review summarises the available evidence on gastroenteropancreatic NEN heterogeneity and its impact on diagnosis and clinical management. Tumour heterogeneity is a common phenomenon in neuroendocrine neoplasms (NENs) and a significant cause of treatment failure and disease progression. Genetic and epigenetic instability, along with proliferation of cancer stem cells and alterations in the tumour microenvironment, manifest as intra-tumoural variability in tumour biology in primary tumours and metastases. This may change over time, especially under selective pressure during treatment. The gastroenteropancreatic (GEP) tract is the most common site for NENs, and their diagnosis and treatment depends on the specific characteristics of the disease, in particular proliferation activity, expression of somatostatin receptors and grading. Somatostatin receptor expression has a major role in the diagnosis and treatment of GEP-NENs, while Ki-67 is also a valuable prognostic marker. Intra- and inter-tumour heterogeneity in GEP-NENS, however, may lead to inaccurate assessment of the disease and affect the reliability of the available diagnostic, prognostic and predictive tests. In this review, we summarise the current available evidence of the impact of tumour heterogeneity on tumour diagnosis and treatment of GEP-NENs. Understanding and accurately measuring tumour heterogeneity could better inform clinical decision making in NENs. [ABSTRACT FROM AUTHOR]

Background: Accurate response evaluation in patients with neuroendocrine liver metastases (NELM) remains a challenge. Radiomics has shown promising results regarding response assessment. Purpose: To differentiate progressive (PD) from stable disease (SD) with radiomics in patients with NELM undergoing somatostatin analogue (SSA) treatment. Material and Methods: A total of 46 patients with histologically confirmed gastroenteropancreatic neuroendocrine tumors (GEP-NET) with ≥1 NELM and ≥2 computed tomography (CT) scans were included. Response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST1.1). Hepatic target lesions were manually delineated and analyzed with radiomics. Radiomics features were extracted from each NELM on both arterial-phase (AP) and portal-venous-phase (PVP) CT. Multiple instance learning with regularized logistic regression via LASSO penalization (with threefold cross-validation) was used to classify response. Three models were computed: (i) AP model; (ii) PVP model; and (iii) AP + PVP model for a lesion-based and patient-based outcome. Next, clinical features were added to each model. Results: In total, 19 (40%) patients had PD. Median follow-up was 13 months (range 1–50 months). Radiomics models could not accurately classify response (area under the curve 0.44–0.60). Adding clinical variables to the radiomics models did not significantly improve the performance of any model. Conclusion: Radiomics features were not able to accurately classify response of NELM on surveillance CT scans during SSA treatment. [ABSTRACT FROM AUTHOR]

Background: Type 1 gastric neuroendocrine tumors (GC-1) represent an uncommon subtype of neoplasms. Endoscopic resection has been proposed as the treatment of choice; active surveillance may be performed in those smaller than 1 cm, while gastric surgery may be performed for those with frequent recurrences. The antiproliferative effect of somatostatin analogues (SSA) is well known, and their action on GC-1s has been postulated as a chronic treatment to reduce recurrence. Methods: A two-centered, retrospective, observational study that included nine patients (55.6% women) diagnosed with GC-1, receiving long-term treatment with SSA, with a median follow-up from baseline of 22 months, was undertaken. Endoscopic follow-up, extension study, and analytical values of chromogranin A (Cg A) and gastrin were collected. Results: In total, 88.9% of patients presented partial or complete response. Treatment with SSA was the only independent factor with a trend to prevent tumor recurrence (Odds Ratio 0.054; p = 0.005). A nonsignificant tendency toward a decrease in CgA and gastrin was observed; lack of significance was probably related to concomitant treatment with proton pump inhibitors in some patients. Conclusions: Chronic treatment with SSA is a feasible option for recurrent GC-1s that are difficult to manage using endoscopy or gastrectomy. Randomized clinical trials to provide more scientific evidence are still needed. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. Methods: A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. Results: A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52–0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52–0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. Conclusions: We estimate there is a 67–68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced neuroendocrine tumors originating in the intestinal tract and pancreas are treated with biologics that activate somatostatin receptors (lanreotide and octreotide), small molecule drugs that target the mTOR (everolimus) and VEGF and other signaling pathways (sunitinib), chemotherapies (temozolomide, capecitabine, fluorouracil, platinums), and receptor-targeted radionuclides (Lu177-DOTATATE). These treatments eventually fail to control tumor progression, but the mechanisms for therapeutic resistance are poorly understood. We will review preclinical and early clinical studies that provide insight into potential etiologies and new therapies and combinations that may address this resistance. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising. [ABSTRACT FROM AUTHOR]

Background: The antiproliferative activity of a high dose of somatostatin analogs (HD-SSA) in treating gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) remains under debate. Methods: A systematic review and proportion meta-analysis were made. The primary endpoint was the efficacy measured as incidence density ratio (IDR) at one year. The secondary endpoints were the disease control rate (DCR) and severe adverse events (SAEs). The heterogeneity (I2), when high (>50%), was interpreted by performing a univariate metaregression analysis, analyzing as covariates: type and design of the study, location (Europe or USA), sample size, grading according to 2017 WHO, the metastatic disease rate, previous therapy including surgery, and quality of the study. Results: A total of 11 studies with 783 patients were included. The IDR was 62 new progressions of 100 patients treated with HD-SSA every one year. The heterogeneity was high. The study's year, type and design, primary tumor, grading, previous treatments, and quality of the studies did not influence the IDR. The IDR was significantly higher in USA centers and studies with more than 50 patients. The IDR was lower when a high rate of metastatic patients was present in the studies. The DCR was 45%. The heterogeneity was high. The DCR was lower in USA studies and in prospective trials. Conclusion: Given the limited efficacy of HD-SSA in preventing the disease progression in unresectable GEP-NENs after failure of standard dose SSA, the use of this therapeutic approach is advisable in selected cases when other antiproliferative treatments are not feasible. [ABSTRACT FROM AUTHOR]

Malignant insulinomas are functional neuroendocrine tumors of the pancreas and the primary cause of tumor-related hypoglycemia. Malignant insulinoma is rare and has a poor prognosis. We report a case of metastatic malignant insulinoma in a 64-year-old female patient with severe and refractory hypoglycemia. After several ineffective locoregional and systemic therapeutic lines for the secretory disease, the introduction of pasireotide, a second-generation somatostatin analog, provided an improved clinical and secretory evolution both quickly and sustainably, with an excellent safety profile. Pasireotide is an effective and well-tolerated therapy in the treatment of refractory hypoglycemia in metastatic insulinoma. [ABSTRACT FROM AUTHOR]

Somatostatin is an inhibitory peptide, which regulates the release of several hormones, and affects neurotransmission and cell proliferation via its five Gi protein-coupled receptors (SST1-5). Although its endocrine regulatory and anti-tumour effects have been thoroughly studied, little is known about its effect on the vascular system. The aim of the present study was to analyse the effects and potential mechanisms of somatostatin on endothelial barrier function. Cultured human umbilical vein endothelial cells (HUVECs) express mainly SST1 and SST5 receptors. Somatostatin did not affect the basal HUVEC permeability, but primed HUVEC monolayers for thrombin-induced hyperpermeability. Western blot data demonstrated that somatostatin activated the phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt) and p42/44 mitogen-activated protein kinase (MAPK) pathways by phosphorylation. The HUVEC barrier destabilizing effects were abrogated by pre-treating HUVECs with mitogen-activated protein kinase kinase/extracellular signal regulated kinase (MEK/ERK), but not the Akt inhibitor. Moreover, somatostatin pre-treatment amplified vascular endothelial growth factor (VEGF)-induced angiogenesis (3D spheroid formation) in HUVECs. In conclusion, the data demonstrate that HUVECs under quiescence conditions express SST1 and SST5 receptors. Moreover, somatostatin primes HUVECs for thrombin-induced hyperpermeability mainly via the activation of MEK/ERK signalling and promotes HUVEC proliferation and angiogenesis in vitro. [ABSTRACT FROM AUTHOR]

Objectives. To analyze and summarize the effect of SSA treatment on EAS due to p-NETs (EAS-p-NETs). Methods. Thirteen patients with EAS-p-NETs treated with SSAs at our center or described in the literature were included in this study. Clinical characteristics, laboratory data, imaging studies, histopathologic results, the effect of SSA treatment, and the prognosis of these EAS-p-NET patients were evaluated. Results. Four males and 9 females with an average age of 42.9 years were included in the study. The mean duration of follow-up was 38.8 ± 28.2 months. As one of the combined treatment measures, SSAs controlled the levels of ACTH and cortisol in 9 of the 13 patients (69.2%). Partial response was observed in 3 patients (23.1%), stable disease in 2 patients (15.4%), and progressive disease in 6 patients (46.2%). The median time to tumor progression was 24 months, and the median overall survival was 61 months. The side effects of SSA treatment included temporary mild abdominal pain, diarrhea, gallstones, and cholecystitis. Conclusions. As a supplemental therapy, SSA treatment led to clinical and biochemical improvement with a good safety profile in patients exhibiting EAS-p-NET with metastasis. However, tumor progression was inhibited by SSA treatment in only a few patients. Combined with other treatments, SSAs may improve the prognosis of patients with EAS-p-NETs. [ABSTRACT FROM AUTHOR]

Somatostatin exhibits an inhibitory effect on pituitary hormone secretion, including inhibition of growth hormone and adrenocorticotropic hormone (ACTH), and it can have antisecretory and antitumor effects on neuroendocrine tumors (NETs) that express somatostatin receptors. Although the precise mechanism remains unclear, the finding that glucocorticoids downregulate somatostatin receptor subtype 2 (SSTR2) expression has been used to explain the lack of efficacy of traditional SSTR2-targeting analogs in patients with ACTH-secreting NETs. Glucocorticoid receptor (GR) antagonism with mifepristone has been shown to reverse the glucocorticoid-induced downregulation of SSTR2; however, the effects of GR modulation on SSTR2 expression in ACTH-secreting NETs, particularly corticotroph pituitary tumors, are not well known. The current study presents new insight from in vitro data using the highly selective GR modulator relacorilant, showing that GR modulation can overcome dexamethasone-induced suppression of SSTR2 in the murine At-T20 cell line. Additional data presented from clinical case observations in patients with ACTH-secreting NETs suggest that upregulation of SSTR2 via GR modulation may re-sensitize tumors to endogenous somatostatin and/or somatostatin analogs. Clinical, laboratory, and imaging findings from 4 patients [2 ACTH-secreting bronchial tumors and 2 ACTH-secreting pituitary tumors (Cushing disease)] who were treated with relacorilant as part of two clinical studies (NCT02804750 and NCT02762981) are described. In the patients with ectopic ACTH secretion, SSTR2-based imaging (Octreoscan and 68Ga-DOTATATE positron emission tomography) performed before and after treatment with relacorilant showed increased radiotracer uptake by the tumor following treatment with relacorilant without change in tumor size at computed tomography. In the patients with Cushing disease who received relacorilant prior to scheduled pituitary surgery, magnetic resonance imaging after a 3-month course of relacorilant showed a reduction in tumor size. Based on these findings, we propose that GR modulation in patients with ACTH-secreting NETs upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects. The effect of relacorilant on pituitary corticotroph tumors is being investigated in an ongoing phase 3 study (NCT03697109; EudraCT 2018-003096-35). [ABSTRACT FROM AUTHOR]

Both somatostatin (SST) and somatostatin receptors (SSTRs) are proteins with important functions in both physiological tissue and in tumors, particularly in neuroendocrine tumors (NETs). NETs are frequently characterized by high SSTRs expression levels. SST analogues (SSAs) that bind and activate SSTR have anti-proliferative and anti-secretory activity, thereby reducing both the growth as well as the hormonal symptoms of NETs. Moreover, the high expression levels of SSTR type-2 (SSTR2) in NETs is a powerful target for therapy with radiolabeled SSAs. Due to the important role of both SST and SSTRs, it is of great importance to elucidate the mechanisms involved in regulating their expression in NETs, as well as in other types of tumors. The field of epigenetics recently gained interest in NET research, highlighting the importance of this process in regulating the expression of gene and protein expression. In this review we will discuss the role of the epigenetic machinery in controlling the expression of both SSTRs and the neuropeptide SST. Particular attention will be given to the epigenetic regulation of these proteins in NETs, whereas the involvement of the epigenetic machinery in other types of cancer will be discussed as well. In addition, we will discuss the possibility to target enzymes involved in the epigenetic machinery to modify the expression of the SST-system, thereby possibly improving therapeutic options. [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]

Somatostatin (SST) and somatostatin receptors (SSTRs) play an important role in the brain and gastrointestinal (GI) system. SST is produced in various organs and cells, and the inhibitory function of somatostatin-containing cells is involved in a range of physiological functions and pathological modifications. The GI system is the largest endocrine organ for digestion and absorption, SST-endocrine cells and neurons in the GI system are a critical effecter to maintain homeostasis via SSTRs 1-5 and co-receptors, while SST-SSTRs are involved in chemo-sensory, mucus, and hormone secretion, motility, inflammation response, itch, and pain via the autocrine, paracrine, endocrine, and exoendocrine pathways. It is also a power inhibitor for tumor cell proliferation, severe inflammation, and post-operation complications, and is a first-line anti-cancer drug in clinical practice. This mini review focuses on the current function of producing SST endocrine cells and local neurons SST-SSTRs in the GI system, discusses new development prognostic markers, phosphate-specific antibodies, and molecular imaging emerging in diagnostics and therapy, and summarizes the mechanism of the SST family in basic research and clinical practice. Understanding of endocrines and neuroendocrines in SST-SSTRs in GI will provide an insight into advanced medicine in basic and clinical research. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogs (SSAs) are the frontline antitumor therapy in advanced well‐differentiated gastroenteropancreatic neuroendocrine tumors (GEP‐NETs). A subset of patients demonstrate early disease progression on SSA therapy, yet the currently known predictors for treatment failure lack specificity to affect therapeutic decision. SSAs target tumor somatostatin receptors, the level of which can be quantitatively assessed with 68Ga‐DOTATATE positron emission tomography‐computed tomography (PET/CT). We investigated the ability of 68Ga‐DOTATATE PET/CT to predict response to SSA therapy. Materials and Methods: The records of 108 consecutive patients with well‐differentiated grade 1–2 GEP‐NETs on SSA monotherapy who received 68Ga‐DOTATATE PET/CT scans were retrospectively reviewed to obtain baseline characteristics, 68Ga‐DOTATATE maximum standardized uptake value (SUVmax), and progression‐free survival (PFS) data. The optimal SUVmax cutoff for patient stratification was obtained with receiver operating characteristic curve analysis. PFS in the high versus low SUVmax groups was compared with Kaplan‐Meier survival analysis. The effects of baseline characteristics and SUVmax on PFS were examined with univariate and multivariate Cox regression. Results: 68Ga‐DOTATATE SUVmax predicted therapeutic failure with sensitivity and specificity of 39% and 98%, respectively. SUVmax of <18.35 was associated with shorter PFS, which was reproduced in the subgroup analysis of SSA‐naïve patients. Low SUVmax was the only predictor of early treatment failure (hazard ratio, 6.85) in multivariate analysis, as well as in the subgroup analysis of grade 2 GEP‐NETs. Conclusion: Low SUVmax on 68Ga‐DOTATATE PET/CT independently predicts early failure on SSA monotherapy in patients with well‐differentiated grade 1–2 GEP‐NET. Patients with lack of expected benefit from SSA therapy can be readily identified using routine 68Ga‐DOTATATE PET/CT with very high specificity. Implications for Practice: Based on 68Ga‐DOTATATE positron emission tomography‐computed tomography imaging, clinicians can better inform patients on the expected benefit of somatostatin analog therapy for gastroenteropancreatic neuroendocrine tumors, especially when access to the therapy is difficult, and offer proactive discussion on alternative management options. Somatostatin analogs (SSAs) are the frontline antitumor therapy for patients with advanced well‐differentiated gastroenteropancreatic neuroendocrine tumors. This study investigated the ability of 68Ga‐DOTATATE PET/CT to predict response to SSA therapy. [ABSTRACT FROM AUTHOR]

Background Headache is a common complaint in growth hormone (GH)-secreting pituitary adenoma and considered to be relieved after tumor removed. However, some headache could be resistant after surgery, which is rare and intractable. This article summarized the clinical characteristics and diagnosis and treatment of intractable headache combined with GH-secreting pituitary adenoma. Methods and Results Four intractable headache combined with GH-secreting pituitary adenoma patients hospitalized in Peking Union Medical College Hospital from Febuary 2014 to July 2017 were reviewed. All the 4 patients received transsphenoidal surgery again and took long-acting somatostatin analogs (SSTAs) to control headache symptoms after admission. The serum GH, insulin-like growth factor-1 (IGF-1) and GH in Oral Glucose Tolerance Test (OGTT) before surgery were (5.80 ± 2.86), (644 ± 249) and (3.12 ± 1.37) μg/L, (3.50 ± 2.91), (362.25 ± 160.11) and (3.28 ± 2.99) μg/L in 7 days after surgery, and (3.10 ± 2.14), (357 ± 165) and (1.54 ± 1.24) μg/L 3 months after surgery. Numeric Rating Scale (NRS) was (7.50 ± 0.58), (1.75 ± 0.50) and (3.75 ± 1.50) score in different timepoints. Conclusions Long-acting SSTAs can be effective to intractable headache combined with GH-secreting pituitary adenoma, further studies are needed. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogs (SSAs) are the mainstay of neuroendocrine tumor (NET) treatment. Biliary stone disease is reported as a common side effect of SSAs, with a frequency ranging from 10% to 63%. Studies on SSA‐treated patients for acromegaly report an increased incidence of biliary stone disease compared with the general population, whereas data on patients with NETs are few. Guidelines are based on weak evidence, thus resulting in conflicting recommendations. The aim of the study is to evaluate biliary stone disease incidence, complications, and risk factors in a large population of SSA‐treated patients with NETs. Materials and Methods: A retrospective analysis of a prospectively collected database was performed. Patients with a diagnosis of NET in seven dedicated centers from 1995 to 2017 were included at the time of SSA start. Results: A total of 754 SSA‐treated patients were evaluated. Patients with history of cholecystectomy or with known biliary stone disease were excluded; 478 patients were included. Among them, 118 patients (24.7%) received prophylactic ursodeoxycholic acid (UDCA). During the study period, 129 patients (27.0%) developed biliary stone disease; of them, 36 (27.9%) developed biliary complications. On multivariate analysis, primary gastrointestinal (GI)‐NET (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were independent risk factors for biliary stone disease. Conclusion: We report a high incidence of biliary stone disease particularly in GI‐NET or GI surgery. UDCA prophylaxis does not seem to have a protective role. Our data suggest that all patients with primary GI‐NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy; no conclusion could be drawn on the indication of prophylactic cholecystectomy in patients with primary pancreatic or thoracic NET for whom abdominal surgery is not planned. Implications for Practice: The results of this study confirm an increased rate of gallstones development and related complications in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointestinal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI‐NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA‐related biliary stone disease. Biliary stone disease is a common side effect of somatostatin analog treatment for neuroendocrine tumors. This article evaluates incidence, complications, and risk factors for biliary stone disease in a large population of patients treated with somatostatin analogs. [ABSTRACT FROM AUTHOR]

Advanced adrenocortical carcinoma (ACC) is an aggressive disease with poor prognosis, and the current therapeutic options, such as mitotane or platinum‐based chemotherapy regimens, often offer limited efficacy. Here, we present the first report, to the author's knowledge, of metastatic ACC with positive octreoscan scintigraphy that was successfully treated with octreotide long‐acting release (LAR). A patient with metastatic ACC who showed poor tolerance to mitotane received octreotide LAR because of positive octreoscan scintigraphy. She obtained major partial response to the somatostatin analog. Interestingly, the expression of somatostatin receptor 2 from the previous local recurrence lesion was negative. The next‐generation sequencing‐based circulating tumor DNA analysis in the patient was performed and failed to identify any alterations. These findings suggest that octreotide LAR may be a good option for the treatment of metastatic ACC in selected patients. New therapies for advanced adrenocortical carcinoma are urgently needed. This brief communication describes the case of a patient with metastatic adrenocortical carcinoma with positive scintigraphy, which was successfully treated with octreotide LAR. [ABSTRACT FROM AUTHOR]

Somatostatin analogs have an important role in the medical therapy of neuroendocrine tumors (NETs). Octreotide and lanreotide, both somatostatin analogs binding with high affnity for the somatostatin receptor (SSTR)2, can control symptoms in functional NETs. In addition, these compounds, because of their antiproliferative effects, can stabilize growth of well-differentiated NETs. Pasireotide is a novel multireceptor-targeted somatostatin analog with high affnity for SSTR1, 2, 3, and 5. This review provides an overview of the state of the art of pasireotide in the treatment of NETs, with the aim of addressing clinical relevance and future perspectives for this molecule in the management of NETs. [ABSTRACT FROM AUTHOR]

Somatostatin analogs (SSA) are well-established antisecretory drugs in functionally active neuroendocrine tumors (NET). Two placebo-controlled trials have recently demonstrated significant improvement of progression-free survival under SSA treatment. Furthermore, somatostatin receptor (SSTR) overexpression in NET has also been utilized for diagnostic imaging and peptide receptor radionuclide therapy (PRRT). However, PRRT in NET is associated mostly with partial and minor remission, while other radionuclide therapies reach complete remissions in up to 75% of cases. This study assessed a potential radiosensitizing effect of SSA treatment in five established NET cell line models: BON, QGP-1, LCC-18, H727, and UMC-11. Irradiation was found to significantly inhibit proliferation, while no additional effect by octreotide treatment was observed. Intriguingly, no impact of SSA treatment alone was found in any of these NET cell lines when systematically analyzing cell viability, proliferation, and cell cycle distribution. Investigation of the causes for this octreotide resistance led to demonstration of low octreotide binding and scarce SSTR, specifically SSTR2 expression as compared to levels found in human NETs. The resistance toward SSA treatment in viability and proliferation assays could not be overcome by re-expression of SSTR2 in two of the cell lines. These results provide systematic evidence for a lack of authentic, tumor-like SSTR expression, and function in five frequently used NET cell line models and point to the need for more physiologic tumor model systems. [ABSTRACT FROM AUTHOR]

Purpose: Analyze the role of somatostatin analogues (SSAs) in the treatment of sporadic and MEN1-related gastrinomas, trying to define whether recent trials have changed the landscape of gastrinoma therapy.Methods: We evaluate the rationale of SSA use in the treatment of gastrinomas, summarize the current literature concerning the effect of SSAs on the control of Zollinger-Ellison syndrome (ZES) and gastrinomas tumor progression and discuss their role in the most recent guidelines.Results: The medical treatment of gastrinoma and related ZES is aimed at controlling acid hypersecretion and tumor progression, in inoperable patients. The use of proton pump inhibitors (PPIs) to control the syndrome is a cornerstone in the ZES therapy. SSAs are not usually indicated for antisecretory purpose, because PPIs are considered the treatment of choice, due to their long lasting high efficacy and oral availability. The antiproliferative effect of SSAs has been established by two placebo-controlled trials that have clearly demonstrated a significant increase in progression free survival in patients affected by non-functioning well-differentiated advanced neuroendocrine tumors (NETs). The recent ENETS guidelines recommend the use of SSAs in advanced well differentiated NETs as antiproliferative agents.Conclusions: The high sstr-expression in gastrinomas make them highly responsive to SSAs and support the use of such drugs to counteract the tumour growth in patients not amenable to surgical cure. Unfortunately, limited data, mainly case reports or small series, support the use of SSAs in advanced gastrinomas, therefore, it is difficult to quantify their ability to control tumour growth and disease progression. [ABSTRACT FROM AUTHOR]

Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response. [ABSTRACT FROM AUTHOR]

Background. Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research. Methods. Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016. Results. Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full-length publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)-NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET. Conclusion. Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. [ABSTRACT FROM AUTHOR]

Interactions between intestinal neuroendocrine peptides/amines and the immune system appear to have an important role in the pathophysiology of inflammatory bowel disease (IBD). The present study investigated the effects of activator protein (AP)-1 and nuclear factor (NF)-κB inhibitors on inflammation-induced alterations in enteroendocrine cells. A total of 48 male Wistar rats were divided into the following four groups (n=12 rats/group): Control, trinitrobenzene sulfonic acid (TNBS)-induced colitis only (TNBS group), TNBS-induced colitis with 3-[(dodecylthiocarbonyl)-methy l]-glutarimide (DTCM-G) treatment (DTCM-G group), and TNBS-induced colitis with dehydroxymethylepoxyquinomicin (DHMEQ) treatment (DHMEQ group). A total of 3 days following administration of TNBS, the rats were treated as follows: The control and TNBS groups received 0.5 ml vehicle (0.5% carboxymethyl cellulose; CMC), respectively; the DTCM-G group received DTCM-G (20 mg/kg body weight) in 0.5% CMC; and the DHMEQ group received DHMEQ (15 mg/kg body weight) in 0.5% CMC. All injections were performed intraperitoneally twice daily for 5 days. The rats were sacrificed, and tissue samples obtained from the colon were examined histopathologically and immunohistochemically. Inflammation was evaluated using a scoring system. In addition, the sections were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP) and somatostatin, and immunostaining was quantified using image-analysis software. The density of cells expressing CgA, PYY and PP was significantly lower in the TNBS group compared with in the control group, whereas the density of cells expressing serotonin, oxyntomodulin and somatostatin was significantly higher in the TNBS group compared with in the control group. None of the endocrine cell types differed significantly between the control group and either the DTCM-G or DHMEQ groups. All of the colonic endocrine cell types were affected in rats with TNBS-induced colitis. The expression density of these endocrine cell types was restored to control levels following treatment with AP-1 or NF-κB inhibitors. These results indicated that the immune system and enteroendocrine cells interact in IBD. [ABSTRACT FROM AUTHOR]

A combination of basic research observations concerning the interaction of somatostatin (SST) and dopamine (DA) receptors, and clinical reports of enhanced efficacy of combined SST and DA analogue treatment in suppressing GH hypersecretion, lead to the concept of creating chimeric molecules combining structural features of both compound classes. The resulting SST/DA chimeras retain the ability to interact with receptors of both families and display greatly enhanced potency and efficacy, as compared with that of individual SST or DA receptor agonists. In vitro studies with pituitary adenoma cells from acromegalic patients have demonstrated that the chimeric molecules have exceptional activity with regard to suppression of GH and prolactin secretion. Similarly, potent suppression of ACTH secretion from Cushing's-causing corticotroph tumors, and suppression of nonfunctioning pituitary adenoma proliferation has been observed. The chimeric SST/DA compounds are also quite potent and efficacious in suppressing both GH and IGF1 in vivo when tested in nonhuman primates, with no effect on either insulin secretion or glycemic control. Initial clinical studies examining acute, subcutaneous administration of the chimeric SST/ DA compound, BIM-23A760, revealed both prolonged circulating half-life and extended duration of biological effect. With chronic administration, however, BIM-23A760 was found to produce a metabolite with dopaminergic activity that gradually accumulates and interferes with the activity of the parent compound. Consequently, efforts are currently underway to produce a second-generation chimera for treatment of neuroendocrine disease. [ABSTRACT FROM AUTHOR]

Background: Ingested immunoactive proteins type I interferon, soluble immune response suppressor peptide 1-21 and melanocyte-stimulating hormone inhibit clinical attacks and inflammation in acute experimental autoimmune encephalomyelitis (EAE). Objective: We examined whether another immunoactive protein, somatostatin (SST), would have similar anti-inflammatory effects on EAE after oral administration. Design/methods: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or SST during ongoing disease. Splenocytes from mock-fed or SST-fed mice were adoptively transferred into active MOG peptide 35-55-immunized recipient mice during ongoing disease. Results: In actively fed mice, increased Th2-like cytokines in both the spleen and the central nervous system (CNS) inhibited active disease. In recipients of donor cells from SST-fed donors, reduction of Th1 and Th17 and induction of Th2-like IL-4 cytokines in both the spleen and CNS inhibited disease. Treg cells were increased threefold in actively fed spleen cells that are responsible for protection against disease after adoptive transfer. Conclusions: Ingested (orally administered) SST can inhibit clinical disease, inhibit CNS inflammation by decreasing Th17 and Th1-like cytokines and increasing Th2-like cytokines in the CNS via induction of Treg cells. [ABSTRACT FROM AUTHOR]