PRESTO 2: An International Survey to Evaluate Patients' Injection Experiences with the Latest Devices/Formulations of Long-Acting Somatostatin Analog Therapies for Neuroendocrine Tumors or Acromegaly.

INTRODUCTION: Real-world data evaluating patients' injection experiences using the latest devices/formulations of the long-acting (LA) somatostatin analogs (SSAs) lanreotide Autogel/Depot (LAN; Somatuline®) and octreotide LA release (OCT; Sandostatin®) are limited. METHODS: PRESTO 2 was a 2020/2021 e-survey comparing injection experience of adults with neuroendocrine tumors (NETs) or acromegaly treated with LAN prefilled syringe versus OCT syringe for > 3 months in Canada, Ireland, the UK and the USA (planned sample size, 304). PRIMARY ENDPOINT: the proportion of patients with injection-site pain lasting > 2 days after their most recent injection, analyzed using a multivariate logistic regression model. Secondary endpoints included interference with daily life due to injection-site pain and technical injection problems in patients with current SSA use for ≥ 6 months. RESULTS: There were 304 respondents (acromegaly, n = 85; NETs, n = 219; LAN, n = 168; OCT, n = 136; 69.2% female; mean age, 59.6 years). Fewer patients had injection-site pain lasting > 2 days after the most recent injection with LAN (6.0%) than OCT (22.8%); the odds of pain lasting > 2 days were significantly lower for LAN than OCT, adjusted for disease subgroup and occurrence of injection-site reactions (odds ratio [95% confidence interval]: 0.13 [0.06-0.30]; p < 0.0001). Injection-site pain interfered with daily life "a little bit" or "quite a bit" in 37.2% and 3.8% (LAN) versus 52.5% and 7.5% (OCT) of patients, respectively. Among patients with ≥ 6 months' experience with current SSA (92.4% of patients), technical injection problems never occurred in 76.8% (LAN) and 42.9% (OCT) of patients. CONCLUSIONS: Compared with OCT, significantly fewer patients using LAN had injection-site pain lasting > 2 days after their most recent injection. Also, fewer LAN-treated patients experienced technical problems during injection. These findings demonstrate the importance of injection modality for overall LA SSA injection experience for patients with acromegaly or NETs.

Patients with neuroendocrine tumors or acromegaly often receive long-term monthly treatment with somatostatin analogs. These injectable drugs stop the body from making an excess of certain hormones. Understanding patients' experiences of these injections helps to provide better care. The PRESTO 2 online study surveyed 304 patients in Canada, Ireland, the UK and the USA with neuroendocrine tumors or acromegaly who were being treated with a somatostatin analog, either lanreotide Autogel/Depot (LAN) or octreotide long-acting release (OCT). The survey asked about injection experience, including injection-site pain lasting > 2 days and how it affected patients' lives, anxiety before injections and technical problems during injections (like syringe blockages). The survey showed fewer patients receiving LAN than OCT had injection-site pain that lasted > 2 days, and fewer said that the pain interfered with their daily lives. There were fewer technical injection problems with LAN than with OCT. However, more patients receiving LAN than OCT felt anxious before their injection. In some countries (including Canada, Ireland and the UK, but not the USA), the patient (or family member/friend) can inject LAN if they are on a stable dose, their doctor agrees, and they received training. A nurse/doctor must inject OCT. In PRESTO 2, about 40% of non-US patients who were eligible injected themselves (or were helped by a family member/friend). This may explain why more patients reported anxiety in the LAN group. PRESTO 2 provides important insights into patients' experiences of receiving somatostatin analogs and helps identify areas for improving patient care.

Bioanalysis of lanreotide in dog plasma using liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study of beagle dogs after single subcutaneous injection.

Lanreotide is similar to a naturally occurring hormone, somatostatin; thus, it may be used to treat acromegaly or metastatic gastroenteropancreatic neuroendocrine tumours. Here, a bioanalytical method coupling ultra-performance liquid chromatography with tandem mass spectrometry to quantify lanreotide and an internal standard (IS) was developed and validated in dog plasma. The plasma samples were extracted using typical protein precipitation processes. The analyte and internal standard were separated on Phenomenex Kinetex® C18 with 0.1% formic acid and acetonitrile in the mobile phase at a flow rate of 0.4 mL/min. The fragmentation of precursor ions to product ions was optimized at m/z 548.8 â†’ 170.0 for lanreotide [M + 2H]2+ and 472.2 â†’ 436.2 for IS [M + H]+. The peak retention times of lanreotide and IS were 1.09 min and 1.22 min, respectively. The calibration curve samples in dog plasma ranged from 0.3 to 1000 ng/mL and showed good linearity, with a correlation coefficient of r2=0.9996. The lower limit of quantitation was 0.3 ng/mL. The intra- and inter-day precision (relative standard deviation) values for each quality control level were < 9.7 % and < 9.3 %, respectively; intra- and inter-day accuracy were < 109.3% and < 110.4%, respectively. Lanreotide in dog plasma was stable in various conditions. The maximum plasma concentration of lanreotide in male beagle dogs after subcutaneous injection of Somatuline® (lanreotide) Autogel 120 mg was 88.1 ng/mL. The half-life (T1/2) of lanreotide in beagle dogs was long, approximately 198.6 h; the area under the plasma-concentration curve from 0 to 840 h (day 35) was 6,995 ng⋅h/mL. This novel quantification method using UPLC-MS/MS was successfully applied to the pharmacokinetic analysis of lanreotide in dog plasma. The results will assist future studies of drug formulation and repurposing.

External Validity of Somatostatin Analogs Trials in Advanced Neuroendocrine Neoplasms: The GETNE-TRASGU Study.

INTRODUCTION: Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs. METHODS: We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs. RESULTS: The dataset contained 535 patients with a median age of 62 years (range: 26-89). The median Ki-67% was 4 (range: 0-20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1-32.0) for octreotide versus 30.1 months (95% CI: 23.1-38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71-1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively. CONCLUSION: Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs.

An unusual complication of tumor surgery: chylous leakage.

PURPOSE: This study was designed to evaluate the effectiveness of conservative treatment for chylous leak after tumor surgery and to propose a management algorithm. METHODS: The data of patients with postoperative chylous leak after tumor surgery in our institution between 2010 and 2019 were retrospectively reviewed. In this study, 469 laparotomies, 89 thoracotomies, and 57 cervical excisions were performed for tumor surgery in our institution. RESULTS: Twelve patients with a median age of 4 (IQR, 3-8) years had postoperative chylous leak. All patients received total parenteral nutrition for a median of 13 days. Five patients had intravenous somatostatin for a median of 14 days (IQR, 9-16) to decrease chyle production. Eventually, chylous leak ceased in all patients with conservative treatment and surgical drains were removed after no leak was observed with enteral feeding. CONCLUSIONS: The incidence of chylous leak in childhood tumor surgery is approximately 2%. Extended tumor resection and lymph node dissection lead to the injury of the delicate structures that drain chyle. Conservative treatment with total parenteral nutrition and somatostatin seems to be effective. In particular, somatostatin may be used in resistant cases. Conservative treatment can take up to 1 month. The algorithm consists of how to manage postoperative chylous leak in childhood.

The Future of Somatostatin Receptor Ligands in Acromegaly.

Currently, the first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot, and nasal octreotide, may improve patients' adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as paltusotine, somatropin, ONO-5788, and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.

Self-Administration of Long-Acting Somatostatin Analogues in NET Patients-Does It Affect the Clinical Outcome?

Background and Objectives: Long-acting somatostatin analogues (SSA) (octreotide LAR and lanreotide Autogel) are recommended as first line treatment of locally advanced or metastatic well-differentiated neuroendocrine tumors (NETs) with a good expression of somatostatin receptor (SSTR). Both of these SSAs are usually administered via injections repeated every 4 weeks. The purpose of the study was to compare the route of SSA administration (injection performed by professional medical staff and self-administration of the drug) with progression-free survival. Materials and methods: 88 patients in 2019 and 96 patients in 2020 with locally advanced or metastatic well-differentiated NETs were included in the study. All patients had a good expression of SSTR type 2 and had been treated for at least 3 months with a stable dose of long-acting somatostatin analogue every 4 weeks. All of them had received training on drug self-injections from professional NET nurses at the beginning of the COVID-19 epidemic. Results: The rate of NET progression in the study group in 2020 was higher than in 2019 29.1% vs. 18.1% (28 vs. 16 cases), p = 0.081. Conclusions: The method of administration of long-acting SSA injection performed by professional medical staff vs. self-injection of the drug may significantly affect the risk of NET progression. The unequivocal confirmation of such a relationship requires further observation.

Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results.

INTRODUCTION: This prospective, single-arm, phase 2 study assessed the efficacy and safety of lanreotide autogel (LAN) administered at a reduced dosing interval in patients with progressive neuroendocrine tumours (NETs) after LAN standard regimen. METHODS: Patients had metastatic or locally advanced, grade 1 or 2 midgut NETs or pancreatic NETs (panNETs) and centrally assessed disease progression on LAN 120 mg every 28 days. They were treated with LAN 120 mg every 14 days for up to 96 weeks (midgut cohort) or 48 weeks (panNET cohort). The primary end-point was centrally assessed progression-free survival (PFS). PFS by Ki-67 categories was analysed post hoc. Secondary end-points included quality of life (QoL) and safety. RESULTS: Ninety-nine patients were enrolled (midgut, N = 51; panNET, N = 48). Median (95% CI) PFS was 8.3 (5.6-11.1) and 5.6 (5.5-8.3) months, respectively. In patients with Ki-67 ≤ 10%, median (95% CI) PFS was 8.6 (5.6-13.8) and 8.0 (5.6-8.3) months in the midgut and panNET cohorts, respectively. Patients' QoL did not deteriorate during the study. There were no treatment-related serious adverse events and only two withdrawals for treatment-related adverse events (both in the panNET cohort). CONCLUSIONS: In patients with progressive NETs following standard-regimen LAN, reducing the dosing interval to every 14 days provided encouraging PFS, particularly in patients with a Ki-67 ≤ 10% (post hoc); no safety concerns and no deterioration in QoL were observed. Increasing LAN dosing frequency could therefore be considered before escalation to less well-tolerated therapies.

Cost-Utility of Acromegaly Pharmacological Treatments in a French Context.

Objective: Efficacy of pharmacological treatments for acromegaly has been assessed in many clinical or real-world studies but no study was interested in economics evaluation of these treatments in France. Therefore, the objective of this study was to estimate the cost-utility of second-line pharmacological treatments in acromegaly patients. Methods: A Markov model was developed to follow a cohort of 1,000 patients for a lifetime horizon. First-generation somatostatin analogues (FGSA), pegvisomant, pasireotide and pegvisomant combined with FGSA (off label) were compared. Efficacy was defined as the normalization of insulin-like growth factor-1 (IGF-1) concentration and was obtained from pivotal trials and adjusted by a network meta-analysis. Costs data were obtained from French databases and literature. Utilities from the literature were used to estimate quality-adjusted life year (QALY). Results: The incremental cost-utility ratios (ICUR) of treatments compared to FGSA were estimated to be 562,463 € per QALY gained for pasireotide, 171,332 € per QALY gained for pegvisomant, and 186,242 € per QALY gained for pegvisomant + FGSA. Pasireotide seems to be the least cost-efficient treatment. Sensitivity analyses showed the robustness of the results. Conclusion: FGSA, pegvisomant and pegvisomant + FGSA were on the cost-effective frontier, therefore, depending on the willingness-to-pay for an additional QALY, they are the most cost-effective treatments. This medico-economic analysis highlighted the consistency of the efficiency results with the efficacy results assessed in the pivotal trials. However, most recent treatment guidelines recommend an individualized treatment strategy based on the patient and disease profile.

A randomised, multicentre trial of somatostatin to prevent clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy.

BACKGROUND: Prophylactic 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. METHODS: In 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. RESULTS: Eligible 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). CONCLUSIONS: Prophylactic somatostatin treatment reduced clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy. TRIAL REGISTRATION: NCT03349424.

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Neuroendocrine Tumors in Routine Clinical Practice in Germany and Austria.

BACKGROUND: The long-acting somatostatin analog lanreotide autogel is effective in the treatment of patients with neuroendocrine tumors. OBJECTIVE: To evaluate the long-term treatment response in patients with neuroendocrine tumors receiving lanreotide autogel in routine clinical practice. METHODS: Non-interventional, 24-month study in patients with neuroendocrine tumors treated with lanreotide autogel (NCT01840449). RESULTS: Patients (n=80) from 26 centers in Germany and Austria were enrolled. Neuroendocrine tumors were mainly grade 1/2, metastasized, intestinal, and associated with carcinoid syndrome; 88.9% had received previous neuroendocrine tumor treatment. Of those, 84.4% had previous surgery, 18.7% had received octreotide. The primary endpoint, defined by a <50% chromogranin A increase at month 12 compared with the lowest value between baseline and month 3 was achieved by 89.5% patients. Stable disease according to Response Evaluation Criteria in Solid Tumors 1.1 was observed in 76.9 and 75.0% patients at months 12 and 24 of lanreotide treatment, respectively. Mean change of chromogranin A levels from baseline to month 24 was -0.12 × upper limit of normal (95% CI, -0.22; -0.45). In a post hoc analysis, 38.5% of the subgroup of patients with carcinoid syndrome had daily diarrhea at baseline vs. 21.4% at month 24. At baseline, 27.8% of patients received lanreotide 120 mg every 4 weeks vs. 56.7% at month 24. Quality of life data were heterogeneous. No new safety issues arose and/or required further investigation. CONCLUSIONS: Our study reflects routine lanreotide autogel use in patients with advanced/metastatic neuroendocrine tumors. This analysis shows effectiveness with stabilization of disease-related symptoms and good tolerability of lanreotide autogel in clinical practice.

Outcome of Patients With Metastatic Lung Neuroendocrine Tumors Submitted to First Line Monotherapy With Somatostatin Analogs.

Objective: Antiproliferative activity of somatostatin analogs (SSAs) has been demonstrated in digestive neuroendocrine tumors (NETs), but few data have been published in patients with pulmonary NETs. We therefore conducted a retrospective study to provide additional data on the outcome of patients with metastatic lung NETs submitted to front line SSAs. Research Design and Methods: Patients with metastatic lung NET treated with first line SSA-monotherapy (octreotide or lanreotide) in two different reference Institutions were reviewed. Outcome measures were progression-free survival (PFS) overall survival (OS), overall response rate and safety. We also explored prognostic factors associated with PFS. Methods: The outcome of consecutive patients (pts) with metastatic lung NETs, who underwent first-line treatment with SSAs, recruited from 2014 on 2019 in two Italian reference Institutions, was retrospectively evaluated. Results: Thirty-one patients entered the study: 14 (45.2%) with typical and 17 (54.8%) atypical carcinoid. Six patients (19.4%) had a carcinoid syndrome. 60.0% of patients had Ki-67 ≤ 10%. Two (6.5%) patients obtained a partial response, 24 (77.4%) disease stabilization while 5 (16.1%) had progressive disease. Median progression free survival (PFS) was 28.6 months, median overall survival (OS) was not attained. Ki-67 ≤ 10%, typical carcinoid histotype and non-functioning disease, were associated with a non-significant PFS prolongation. PFS in patients with atypical carcinoids and in those with Ki-67 >10% was greater than 19 months. Conclusions: The long PFS and OS obtained in this case series suggest that SSAs could be effective as first line approach in the management of patients with progressive, metastatic pulmonary NET.

Association between somatostatin analogues and diabetes mellitus in gastroenteropancreatic neuroendocrine tumor patients: A Surveillance, Epidemiology, and End Results-Medicare analysis of 5235 patients.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are increasingly common malignancies and tend to have favorable long-term prognoses. Somatostatin analogues (SSA) are a first-line treatment for many NETs. Short-term experiments suggest an association between SSAs and hyperglycemia. However, it is unknown whether there is a relationship between SSAs and clinically significant hyperglycemia causing development of diabetes mellitus (DM), a chronic condition with significant morbidity and mortality. AIM: In this study, we aimed to compare risk of developing DM in patients treated with SSA vs no SSA treatment. METHODS AND RESULTS: Using the Surveillance, Epidemiology, and End Results (SEER) database and linked Medicare claims (1991-2016), we identified patients age 65+ with no prior DM diagnosis and a GEP-NET in the stomach, small intestine, appendix, colon, rectum, or pancreas. We used χ2 tests to compare SSA-treated and SSA-untreated patients and multivariable Cox regression to assess risk factors for developing DM. Among 8464 GEP-NET patients, 5235 patients had no prior DM and were included for analysis. Of these, 784 (15%) patients received SSAs. In multivariable analysis, the hazard ratio of developing DM with SSA treatment was 1.19, which was not statistically significant (95% CI 0.95-1.49). Significant risk factors for DM included black race, Hispanic ethnicity, prior pancreatic surgery, prior chemotherapy, tumor size >2 cm, pancreas tumors, and higher Charlson scores. CONCLUSION: DM was very common in GEP-NET patients, affecting 53% of our cohort. Despite prior studies suggesting an association between SSAs and hyperglycemia, our analysis found similar risk of DM in SSA-treated and SSA-untreated GEP-NET patients. Further studies are needed to better understand this relationship. As NET patients have increasingly prolonged survival, it is crucial to identify chronic conditions such as DM that these patients may be at elevated risk for.

Somatostatin administration following pancreatoduodenectomy: a case-matched comparison according to surgical technique, body mass index, American Society of Anesthesiologists' score and Fistula Risk Score.

PURPOSE: This study evaluated the controversial role of somatostatin after pancreatoduodenectomy (PD), stratifying patients for the main risk factors using the most recent postoperative pancreatic fistula (POPF) classification and including only patients who had undergone PD with the same technique of pancreatojejunostomy. METHODS: Between November 2010 and February 2020, 218 PD procedures were carried out via personal modified pancreatojejunostomy (mPJ-PD). Somatostatin was routinely administered between 2010 and 2016, while from 2017, 97 mPJ-PD procedures without somatostatin (WS) were performed. The WS group was retrospectively compared with a control (C) group obtained with one-to-one case-control matching according to the body mass index, American Society of Anesthesiologists' score, and Fistula Risk Score (FRS). RESULTS: A total of 144 patients (72 WS group versus 72 C group) were compared. In the WS group. 6 patients (8.3%) developed clinically relevant POPF, compared with 8 patients (11.1%) in the C group (p = 0.656). In addition, on analyzing the subgroup of high-risk patients according to the FRS, we did not note any significant differences in POPF occurrence. Furthermore, no marked differences in the morbidity or mortality were found. Digestive bleeding and diabetes onset rates were higher in the WS group than in the control group, but not significantly so. CONCLUSIONS: The results of the present study confirm no benefit with the routine administration of somatostatin after PD to prevent POPF, even in high-risk patients. However, a possible role in the prevention of postoperative digestive bleeding and diabetes was observed.

Effectiveness of Cabergoline Treatment in Patients with Acromegaly Uncontrolled with SSAs: Experience of a Single Tertiary Center.

PURPOSE: To evaluate the effectiveness of cabergoline and the parameters affecting cabergoline response as add-on treatment to somatostatin analaogues (SSA) in patients with acromegaly uncontrolled with SSAs. MATERIAL AND METHOD: One hundred and twenty-nine acromegalic patients uncontrolled with SSA who had cabergoline added to their treatment were included in this retrospective study. Patients were divided into the SSAs + cabergoline-responsive (group 1) and non-responsive groups (group 2), and biochemical, pathologic, and radiologic parameters were assessed. RESULTS: IGF-1 normalization was achieved in 75 of 129 patients (58%) when cabergoline was added to the SSA treatment. Female patients were significantly higher in group 1 compared to group 2 (p=0.006). Group 1 had significantly smaller pre- and post-cabergoline tumor size (p=0.011, p=0.007 respectively), lower levels of IGF-1 in pre-and post-operative period (p=0.040, p=0.001), and lower levels of IGF-1 in pre- and post-cabergoline treatment (p<0.001). Cavernous invasion on sellar magnetic resonance imaging, dural invasion in pathologic examination were not significantly different between the groups. Sellar invasion in pathologic examination was significantly higher in group 1 (p=0.011). No significant difference was found in proliferation indices between two groups. The presence of fibrous bodies was significantly lower in group 1 (p=0.010). CONCLUSION: Cabergoline can be added to the treatment of acromegalic patients uncontrolled with SSAs due to its ease of use and low economic cost, especially in patients with acromegaly who have small adenomas and no fibrous bodies.

Paracrine regulation of somatostatin secretion by insulin and glucagon in mouse pancreatic islets.

AIMS/HYPOTHESIS: The endocrine pancreas comprises the islets of Langerhans, primarily consisting of beta cells, alpha cells and delta cells responsible for secretion of insulin, glucagon and somatostatin, respectively. A certain level of intra-islet communication is thought to exist, where the individual hormones may reach the other islet cells and regulate their secretion. Glucagon has been demonstrated to importantly regulate insulin secretion, while somatostatin powerfully inhibits both insulin and glucagon secretion. In this study we investigated how secretion of somatostatin is regulated by paracrine signalling from glucagon and insulin. METHODS: Somatostatin secretion was measured from perfused mouse pancreases isolated from wild-type as well as diphtheria toxin-induced alpha cell knockdown, and global glucagon receptor knockout (Gcgr-/-) mice. We studied the effects of varying glucose concentrations together with infusions of arginine, glucagon, insulin and somatostatin, as well as infusions of antagonists of insulin, somatostatin and glucagon-like peptide 1 (GLP-1) receptors. RESULTS: A tonic inhibitory role of somatostatin was demonstrated with infusion of somatostatin receptor antagonists, which significantly increased glucagon secretion at low and high glucose, whereas insulin secretion was only increased at high glucose levels. Infusion of glucagon dose-dependently increased somatostatin secretion approximately twofold in control mice. Exogenous glucagon had no effect on somatostatin secretion in Gcgr-/- mice, and a reduced effect when combined with the GLP-1 receptor antagonist exendin 9-39. Diphtheria toxin-induced knockdown of glucagon producing cells led to reduced somatostatin secretion in response to 12 mmol/l glucose and arginine infusions. In Gcgr-/- mice (where glucagon levels are dramatically increased) overall somatostatin secretion was increased. However, infusion of exendin 9-39 in Gcgr-/- mice completely abolished somatostatin secretion in response to glucose and arginine. Neither insulin nor an insulin receptor antagonist (S961) had any effect on somatostatin secretion. CONCLUSIONS/INTERPRETATION: Our findings demonstrate that somatostatin and glucagon secretion are linked in a reciprocal feedback cycle with somatostatin inhibiting glucagon secretion at low and high glucose levels, and glucagon stimulating somatostatin secretion via the glucagon and GLP-1 receptors. Graphical abstract.

Intestinal occlusion by gynecological cancers treated by percutaneous endoscopic gastrostomy and lanreotide: an Aviano National Cancer Institute experience.

The Commentary reports on our experience in Centro di Riferimento Oncologico IRCCS Aviano about the integrated and combined treatment with percutaneous endoscopic gastrostomy and lanreotide in patients with bowel obstructions by ovarian cancer and peritoneal carcinomatosis. We treated patients with gynecological cancers and bowel obstruction with percutaneous endoscopic gastrostomy and, when patients were partially responsive, with lanreotide. We registered a constant overall benefit for the quality of life and for the control of symptoms, which is very important especially during the home care follow-up of terminal patients.

Medical Therapy of Acromegaly in Germany 2019 - Data from the German Acromegaly Registry.

CONTEXT: Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion from pituitary adenomas in most cases. If neurosurgical therapy is contraindicated or not sufficient, medical therapy is the second line therapy. OBJECTIVE: To describe current medical therapy in acromegaly. DESIGN & METHODS: Retrospective data analysis from 2732 patients treated in 69 centers of the German Acromegaly Registry. 749 patients were seen within the recent 18 months, of which 420 were on medical therapy (56.1%). RESULTS: 73% of medically treated acromegalic patients had normal/low IGF-1 levels. 57% of patients with non-normalized IGF-1 levels had an IGF-1 value between 1- and 1.25-fold above the upper limit of normal. Most patients (55%) received somatostatin analogs as monotherapy, 12% GH receptor monotherapy, and 9% dopamine agonist therapy. Doses of each medical therapy varied widely, with 120 mg lanreotide LAR every 4 weeks, 30 mg octreotide LAR every 4 weeks, 140 mg pegvisomant per week and 1mg cabergoline per week being the most frequent used regimens. A combination of different medical regimens was used in almost 25% of the patients. CONCLUSION: The majority of German acromegalic patients receiving medical therapy are controlled according to normal IGF-1 levels.

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Acromegaly in Routine Clinical Practice in Germany, Austria and Switzerland.

BACKGROUND: Evidence from controlled trials has shown that lanreotide autogel is effective in achieving biochemical and symptom control in patients with acromegaly. However, it is important to better understand the real-world patient population receiving lanreotide autogel treatment. METHODS: In this non-interventional study the long-term treatment response to lanreotide autogel in adult patients with acromegaly from office-based centers or clinics in Germany, Austria and Switzerland was studied. Assessments included growth hormone and insulin-like growth factor-I levels, symptoms, quality of life, lanreotide plasma levels and tumor somatostatin receptor subtype expression. The primary endpoint was achievement of full biochemical control, defined as growth hormone ≤2.5 µg/L and insulin-like growth factor I normalization at month 12. RESULTS: 76 patients were enrolled from 21 sites. 7/51 (13.7%) patients of the efficacy population had full biochemical control at baseline, 15/33 (45.5%) at month 12 and 10/26 (38.5%) at month 24 of treatment. At 12 months of treatment higher rates of biochemical control were observed in the following subgroups: older patients (>53 years [median]), females, treatment-naïve patients, and patients with a time since diagnosis of longer than 1.4 years (median). No clinically relevant differences in acromegaly symptoms or quality of life scores were observed. Median fasting blood glucose and glycated hemoglobin levels remained unchanged throughout the study. No new safety signals were observed. Overall tolerability of treatment with lanreotide autogel was judged by 80.8% of the enrolled patients at month 12 as 'very good' or 'good'. CONCLUSION: Treatment with lanreotide autogel in a real-world setting showed long-term effectiveness and good tolerability in patients with acromegaly.