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Background In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs. Materials and Methods SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN. Results Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication. Conclusions LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile. Drugs that control tumor growth and/or inhibit hormone release are a mainstay of management of neuroendocrine tumors. This study investigated the combined treatment with lanreotide, a drug derived from the naturally occurring inhibitory hormone somatostatin, and the chemotherapeutic agent temozolomide.

BackgroundProphylactic somatostatin to reduce the incidence of clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy remains controversial. We assessed the preventive efficacy of somatostatin on clinically relevant postoperative pancreatic fistula in intermediate-risk patients who underwent pancreaticoduodenectomy at pancreatic centres in China.MethodsIn this multicentre, prospective, randomised controlled trial, we used the updated postoperative pancreatic fistula classification criteria and cases were confirmed by an independent data monitoring committee to improve comparability between centres. The primary endpoint was the rate of clinically relevant postoperative pancreatic fistula within 30 days after pancreaticoduodenectomy.ResultsEligible patients (randomised, n = 205; final analysis, n = 199) were randomised to receive postoperative intravenous somatostatin (250 μg/h over 120 h; n = 99) or conventional therapy (n = 100). The primary endpoint was significantly lower in the somatostatin vs control group (n = 13 vs n = 25; 13% vs 25%, P = 0.032). There were no significant differences for biochemical leak (P = 0.289), biliary fistula (P = 0.986), abdominal infection (P = 0.829), chylous fistula (P = 0.748), late postoperative haemorrhage (P = 0.237), mean length of hospital stay (P = 0.512), medical costs (P = 0.917), reoperation rate (P > 0.99), or 30 days’ readmission rate (P = 0.361). The somatostatin group had a higher rate of delayed gastric emptying vs control (n = 33 vs n = 21; 33% vs 21%, P = 0.050).ConclusionsProphylactic somatostatin treatment reduced clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy.Trial registrationNCT03349424.

Pasireotide (Signifor ® , Signifor ® LAR) is a somatostatin analogue recently approved for the treatment of acromegaly. Unlike the first-generation agents, octreotide and lanreotide, which bind preferentially to somatostatin receptor (SSTR)-2, pasireotide binds to multiple SSTRs. This article reviews the clinical use and summarizes the pharmacological properties of intramuscular pasireotide in the treatment of acromegaly. The efficacy of pasireotide 40 mg every 28 days was superior to that of intramuscular octreotide 20 mg every 28 days with regard to biochemical control in a 12-month, phase III trial in medically naive patients. Similarly, in a 6-month, phase III trial in patients with acromegaly inadequately controlled with somatostatin analogues for at least 6 months, the efficacy of pasireotide 40 or 60 mg was superior to that of continued octreotide 30 mg or lanreotide autogel 120 mg (each drug was administered once every 28 days) with regard to biochemical control. The tolerability profile of intramuscular pasireotide is generally similar to that of first-generation agents, except for a higher incidence of hyperglycaemia-related adverse events with pasireotide. In clinical trials, the risk of developing pasireotide-associated hyperglycaemia was numerically greater in patients categorized as diabetic or prediabetic at baseline than in those with normal glucose tolerance. Careful monitoring of glycaemic status is required prior to and during pasireotide treatment and antidiabetic therapy should be commenced as indicated. Thus, in the treatment of acromegaly, pasireotide may be a more effective somatostatin analogue than other approved agents of the same class; however, the increased risk of hyperglycaemia needs to be considered and proactively managed.

The novel insulin-mimetic adipocytokine visfatin has been linked to the metabolic syndrome, but its regulation has not been characterised to date. Since insulin-mimetic actions of visfatin may be part of the feedback regulation of glucose homeostasis, we hypothesised that visfatin concentrations are influenced by glucose or insulin blood levels in humans. In this randomised, double-blind, placebo-controlled crossover study, nine healthy male subjects (age 26+/-6 years) attended three different study days. On each day, systemic glucose concentrations of 5.0, 8.3 and 11.1 mmol/l were attained by stepwise increases in i.v. infusions of glucose, representing fasting and postprandial conditions. Visfatin plasma concentrations were studied during concomitant exogenous hyperinsulinaemia, inhibition of endogenous insulin production by somatostatin infusion, and placebo time control. Additionally, human adipocytes were cultured to study visfatin release and mRNA expression in vitro. Glucose concentrations of 8.3 and 11.1 mmol/l increased circulating visfatin from baseline concentrations of 0.5+/-0.0 ng/ml to 0.9+/-0.1 and 2.1+/-0.3 ng/ml, respectively (p<0.01). Glucose-induced elevation of visfatin was prevented by co-infusion of insulin or somatostatin (p<0.05). Cultured subcutaneous and visceral adipocytes released an equivalent amount of visfatin upon glucose-concentration- and time-dependent stimulation. Visfatin secretion involved the phosphatidylinositol 3-kinase (PI3-kinase) and protein kinase B (AKT) pathways. The mRNA expression pattern of visfatin was consistent with this altered protein release. Circulating visfatin concentrations are increased by hyperglycaemia. This effect is suppressed by exogenous hyperinsulinaemia or somatostatin infusion. Glucose signalling for visfatin release in adipocytes involves the PI3-kinase/AKT pathway.

Ghrelin plasma concentrations increase during fasting and fall rapidly after nutrient ingestion. We hypothesized that insulin or glucose could regulate ghrelin secretion by a feedback mechanism. In this randomized, double-blind, placebo-controlled crossover study, three different study days were carried out in nine healthy volunteers (age 26 +/- 6 years). On each day, stepwise increasing systemic glucose concentrations of 5.0, 8.3, and 11.1 mmol/l were attained by intravenous infusion of glucose, representing fasting and postprandial conditions. Ghrelin plasma concentration was studied during concomitant exogenous hyperinsulinemia, inhibition of endogenous insulin production by somatostatin infusion, and placebo time control, respectively. Elevated glucose concentrations increased circulating insulin to 612 +/- 85 pmol/l (P < 0.01), but they did not affect ghrelin concentrations. Prolonged hyperinsulinemia by exogenous infusion resulted in circulating insulin of 1,602 +/- 261 pmol/l (P < 0.01) and suppressed plasma ghrelin to 49.6% of baseline (P < 0.01). During administration of somatostatin, insulin concentration remained constant, but an even greater decrease in ghrelin to 39.5% of baseline was noted (P < 0.01). Hyperglycemia does not decrease ghrelin, and a reduction in ghrelin is only seen at supraphysiological insulin concentrations. In contrast, systemic ghrelin concentrations are decreased by somatostatin. The meal-related suppression of ghrelin appears not directly regulated by glucose or insulin.

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.

Cardiac 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography preceded by extended fasting is used to demonstrate active cardiac sarcoidosis. However, physiological insulin-dependent myocardial 18F-FDG uptake often obscures 18F-FDG uptake in sarcoid lesions. We therefore aimed to completely suppress physiological myocardial 18F-FDG uptake by pharmaceutically blocking endogenous insulin secretion while elevating free fatty acids (FFAs). Six patients with suspected cardiac sarcoidosis were studied in a randomized cross-over design: (1) 12 hours fasting followed by 2 hours saline infusion (SALINE), and (2) 12 hours fasting followed by 2 hour infusions of somatostatin (300 μg/hour) and heparin (70 mIE/kg/minutes) (SOMA). 18F-FDG PET scans were performed post-infusion. Glucose, insulin, and FFA levels were measured and left ventricle SUV-values were recorded. During the SALINE infusion, insulin, glucose, and FFAs remained stable. By design, the SOMA infusions rapidly (<60 minutes) suppressed insulin completely, while FFA levels peaked at 1.13 ± 0.23 mM. However, SOMA infusions only suppressed cardiac 18F-FDG uptake insignificantly globally [SUVmean (g/mL): 4.0 ± 3.3 (SALINE) vs 2.4 ± 1.2 (SOMA), P = .15] and regionally. Complete insulin suppression combined with markedly increased circulating FFAs does not completely suppress physiological myocardial 18F-FDG uptake and thus conveys no extra diagnostic value compared with extended fasting.

To study the effects of a specific glucagon receptor antagonist (Bay 27-9955), on plasma glucose concentrations and rates of glucose production in response to hyperglucagonaemia in humans. The study was conducted as a two-dose [Low Dose Bay 27-9955 70 mg, (n = 6), High Dose Bay 27-9955 200 mg, (n = 8)], double blind, placebo controlled, crossover study. Basal glucose production was measured after an overnight fast with [6,6-2H]. At 0 min Bay 27-9955 or placebo was administered and at 120 min an infusion of somatostatin [0.1 microg x (kg x min)(-1)], insulin [24 pmol x (m2 x min)(-1)] and glucagon [3 ng x (kg x min)(-1)] was initiated. Basal plasma glucose concentrations were about 5 mmol/l and basal rates of glucose production were about 13 micromol x (kg x min)(-1). During the hyperglucagonaemic period, plasma glucagon concentrations doubled to 100 pg/ml, plasma glucose concentration increased by 75 % to a peak of about 10 mmol/l and glucose production doubled to about 23 micromol x (kg x min)(-1) (p < 0.0001 vs basal). In the High Dose Group these effects of glucagon were markedly blunted, plasma glucose concentrations were 7.6 +/- 1.1 mmol/l (p = 0.012 vs placebo) and rates of glucose production increased minimally to 15.3 +/- 1.9 micromol x (kg-min)(-1) (p < 0.0003 vs placebo]. In the Low Dose Group, there was a proportional decrease in the effects of Bay 27-9955 on these parameters. Bay 27-9955 is an effective and safe glucagon antagonist in humans. Given the potentially important role of glucagon in increasing glucose production and gluconeogenesis in patients with Type II (non-insulin-dependent) diabetes mellitus this agent could represent an innovative class of therapeutic agents for the disease.

Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst or sst knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst or sst but not sst or sst receptor agonists produced rapid and sustained inhibition of HPA axis. sst agonists selectively produced anxiolytic-like behaviors whereas both sst and sst agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sst KO mice and depressive-like behaviors observed in both sst KO and sst KO strains. Both hippocampal sst and sst receptors selectively inhibit stress-induced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.

The response to first-generation somatostatin receptor ligands (SRLs) treatment in acromegaly correlates with expression of somatostatin receptor subtype 2 (SSTR2). However, pasireotide shows the highest binding affinity for SSTR subtype 5 (SSTR5). It has been suggested that in acromegaly, SSTR5 expression is better at predicting the response to pasireotide long-acting release (PAS-LAR) treatment than SSTR2 expression. To investigate in patients with active acromegaly whether response to SRL treatment correlates to PAS-LAR treatment and to what extent SSTR2 and SSTR5 expression are correlated to the response to PAS-LAR treatment. We included 52 patients from a cohort that initially received SRL treatment, followed by SRL and pegvisomant combination treatment, and finally PAS-LAR treatment. The long-term response to PAS-LAR was evaluated using a PAS-LAR score. In 14 out of 52 patients, somatotroph adenoma tissue samples were available to evaluate SSTR2 and SSTR5 expression using a previously validated immunoreactivity score (IRS). The percentage IGF-I (times the upper limit of normal) reduction, which was observed after SRL treatment, correlated with PAS-LAR response score during follow-up (r = 0.40; P = 0.003; n = 52). After exclusion of SRL-pretreated patients, SSTR2 IRS was positively correlated to PAS-LAR score (r = 0.58; P = 0.039; n = 9), whereas SSTR5 IRS showed no relation (r = 0.35; P = 0.36; n = 9). In a cohort of patients partially responsive to SRLs, the IGF-I-lowering effects of PAS-LAR treatment correlated with the effect of SRL treatment and seemed to be mainly driven by SSTR2 expression instead of SSTR5.