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Introduction: The T2-signal intensity (SI) of somatotroph pituitary neuroendocrine tumors (sPitNET) is associated with treatment response and granulation pattern. Our aim was to evaluate SI assessment methods and their clinical implications, including responsiveness to preoperative first-generation somatostatin analogs (SSA). Methods: This single-center, observational study included unselected, consecutive patients with newly diagnosed acromegaly. Out of 109 treatment-naïve patients, 69 were eligible. The qualitative Visual Method involved a visual comparison of the sPitNET with the temporal gray matter. The Three Tissue Method compared the quantified SI of the sPitNET, temporal white matter, and gray matter. The signal intensity ratio of the sPitNET vs. gray matter (GM-SIR) was calculated. Tumors were divided into three groups: hyperintense (HYPER), isointense (ISO), and hypointense (HYPO) according to the Visual Method, Three Tissue Method, and GM-SIR. These groups were compared in terms of demographic, radiological, and biochemical features. The SI assessment methods were investigated for their ability to predict preoperative SSA responsiveness. Results: SI assessment methods classified SI type correspondingly in 58-75.4% of cases. ISO constituted 39-49% of the analyzed sPitNETs. All methods identified significant differences in tumor volume between the SI groups, with HYPO being more biochemically active per tumor volume unit. According to the Three Tissue Method, patients with ISO had the youngest age at diagnosis and onset. According to the Visual Method, ISO had a lower chance of achieving insulin-like growth factor 1 (IGF1) normalization compared to HYPO (odds ratio (OR) 0.089, confidence interval (CI) 0.015-0.538, p= 0.008)), with no differences between HYPER and HYPO. Only the Visual Method predicted the IGF1 normalization after SSA. HYPER and ISO sPitNETs were classified in electron microscopy as both densely and sparsely granulated. Bihormonal tumors presented only as HYPO and ISO. According to the Three Tissue Method, no HYPO was diagnosed with sparse granulation. Discussion: We demonstrated discrepancies between the SI assessment methods. The Visual Method predicted the outcome of preoperative treatment with SSA. Clinically, ISO behaved similarly to HYPER. Further studies are needed to unify SI assessment and improve its clinical applicability in acromegaly. [ABSTRACT FROM AUTHOR]

Background Aims and Methods Results Conclusions Dumping syndrome is a complex of gastrointestinal symptoms originally studied in peptic ulcer surgery patients. At present, it is most prevalent in patients who underwent bariatric, upper gastrointestinal cancer or anti‐reflux surgery. The symptom pattern comprises early and late dumping symptoms. Several management options have been reported including nutritional, pharmacological and surgical approaches.In this study, we aimed to review the current evidence on dumping syndrome definition, diagnosis and treatment, including preliminary data from newer pharmacological studies.Current pathophysiological concepts and analyses of provocative tests has led to a clear definition of dumping syndrome, including both early and late dumping symptoms. The term postbariatric hypoglycemia represents a limited focus on late dumping only. The diagnosis relies on recognition of symptoms and signs in a patient with appropriate surgical history; and can be confirmed by provocative testing or registration of spontaneous hypoglycemia. The initial treatment focuses on dietary intervention, to which meal viscosity enhancers and/or the glycosidase inhibitor acarbose can be added. The most effective therapy is the use of short‐ or long‐acting somatostatin analogues, which is however expensive and entails side effect issues. In case of refractory hypoglycemia, diazoxide or SGLT2 inhibitors can be considered, based on limited evidence. In refractory patients, continuous enteral feeding or (rarely) surgical reinterventions have been advocated, although not supported by solid evidence. Therapies under current evaluation include the broad‐spectrum somatostatin analogue pasireotide, GLP‐1 receptor antagonists, GLP‐1 receptor agonists and administration of stable forms of glucagon are currently under study.Dumping syndrome is a well‐defined but probably under‐diagnosed complication of upper gastrointestinal, especially bariatric, and surgeries. Diagnosis is confirmed by a provocative test and incremental therapies starting with diet, adding meal viscosity enhancers or glycosidase inhibitors and adding somatostatin analogues in refractory cases. A number of emerging therapies targeting intestinal propulsion, peptide hormone effects and hypoglycemic events are under evaluation. [ABSTRACT FROM AUTHOR]

Simple Summary: We present in this study novel data which demonstrates that the most common type of tumor of the salivary glands may be accurately diagnosed using a specific type of radiological imaging. This may be used to help discriminate this tumor or recurrent versions of it amid various types of benign and malignant tumors. Furthermore, this data suggest that new avenues of minimally invasive therapy may be viable for these tumors and potentially even malignant versions of these tumors and should be examined in further studies. Introduction: Currently, the diagnosis of salivary gland tumors using imaging techniques is unreliable. Methods: In this monocentric retrospective study, we examined patients who received a 68Ga-DOTATOC PET/CT and subsequently underwent a salivary gland tumor resection between 1 January 2010 and 31 December 2021. PET/CT image assessment was compared with somatostatin receptor (SSTR) expression and histology. Results: Thirteen patients (five pleomorphic adenoma (PA) and eight other parotid lesions (OPL)) received a 68Ga-DOTATOC PET/CT. Imaging displayed strong focal tracer uptake in all PA except for one with strong tumor to background discrimination. PA revealed higher SUVmax, SUVmean, liver and blood pool quotients than those of Warthin tumors (WT) and of OPL. In comparison to the contralateral parotid, SUVmax (p = 0.02), SUVmean (p = 0.02), liver quotient (p = 0.03) and blood pool quotient (p = 0.03) were all significantly higher. In contrast, WT and OPL showed in relation to the contralateral parotid no significant differences of SUVmax (WT p = 0.79; OPL p = 0.11), SUVmean (WT p = 1.0; OPL p = 0.08), liver quotient (WT p = 0.5; OPL p = 0.08) and blood pool quotient (WT p = 0.8; OPL p = 0.19). Two PA and one granuloma were not available for examination. In the immunohistochemal analysis, all PA demonstrated the highest intensity of SSTR2 expression (grade 3). Furthermore, PA had a high percentage of cells expressing SSTR2 (20%, 80% and 55%). Conclusions: A strong tracer uptake in PA was shown in 68Ga-DOTATOC PET/CT. This may allow physicians to utilize radioligated somatostatin analogue PET CT/MR imaging to accurately diagnose PA. Additionally, it may be possible in the future to treat the PA with a noninvasive peptide receptor radionuclide therapy or with somatostatin analogues. [ABSTRACT FROM AUTHOR]

IntroductionThe T2-signal intensity (SI) of somatotroph pituitary neuroendocrine tumors (sPitNET) is associated with treatment response and granulation pattern. Our aim was to evaluate SI assessment methods and their clinical implications, including responsiveness to preoperative first-generation somatostatin analogs (SSA).MethodsThis single-center, observational study included unselected, consecutive patients with newly diagnosed acromegaly. Out of 109 treatment-naïve patients, 69 were eligible. The qualitative Visual Method involved a visual comparison of the sPitNET with the temporal gray matter. The Three Tissue Method compared the quantified SI of the sPitNET, temporal white matter, and gray matter. The signal intensity ratio of the sPitNET vs. gray matter (GM-SIR) was calculated. Tumors were divided into three groups: hyperintense (HYPER), isointense (ISO), and hypointense (HYPO) according to the Visual Method, Three Tissue Method, and GM-SIR. These groups were compared in terms of demographic, radiological, and biochemical features. The SI assessment methods were investigated for their ability to predict preoperative SSA responsiveness.ResultsSI assessment methods classified SI type correspondingly in 58-75.4% of cases. ISO constituted 39-49% of the analyzed sPitNETs. All methods identified significant differences in tumor volume between the SI groups, with HYPO being more biochemically active per tumor volume unit. According to the Three Tissue Method, patients with ISO had the youngest age at diagnosis and onset. According to the Visual Method, ISO had a lower chance of achieving insulin-like growth factor 1 (IGF1) normalization compared to HYPO (odds ratio (OR) 0.089, confidence interval (CI) 0.015-0.538, p= 0.008)), with no differences between HYPER and HYPO. Only the Visual Method predicted the IGF1 normalization after SSA. HYPER and ISO sPitNETs were classified in electron microscopy as both densely and sparsely granulated. Bihormonal tumors presented only as HYPO and ISO. According to the Three Tissue Method, no HYPO was diagnosed with sparse granulation.DiscussionWe demonstrated discrepancies between the SI assessment methods. The Visual Method predicted the outcome of preoperative treatment with SSA. Clinically, ISO behaved similarly to HYPER. Further studies are needed to unify SI assessment and improve its clinical applicability in acromegaly.

Patients with neuroendocrine tumours located in the gastroenteropancreatic tract (GEP‐NETs) and treatment with somatostatin analogues (SSA's) are at risk of malnutrition which has been reported previously evaluating weight loss or body mass index (BMI) only. The global leadership into malnutrition (GLIM) criteria include weight loss, BMI, and sarcopenia, for diagnosing malnutrition. These GLIM criteria have not been assessed in patients with GEP‐NETs on SSA. The effect of malnutrition on overall survival has not been explored before. The aim of this study is to describe the presence of malnutrition in patients with GEP‐NET on SSA based on the GLIM criteria and associate this with overall survival. Cross‐sectional study screening all patients with GEP‐NETs on SSA's for malnutrition using the GLIM criteria. Body composition analysis for sarcopenia diagnosis were performed. Bloods including vitamins, minerals, and lipid profile were collected. Overall survival since the date of nutrition screening was calculated. Uni‐ and multivariate Cox regression analysis were performed to identify malnutrition as risk factor for overall survival. A total of 118 patients, 47% male, with median age 67 years (IQR 56.8–75.0) were included. Overall, malnutrition was present in 88 patients (75%); based on low BMI in 26 (22%) patients, based on weight loss in 35 (30%) patients, and based on sarcopenia in 83 (70%) patients. Vitamin deficiencies were present for vitamin D in 64 patients (54%), and vitamin A in 29 patients (25%). The presence of malnutrition demonstrated a significantly worse overall survival (p‐value =.01). In multivariate analysis meeting 2 or 3 GLIM criteria was significantly associated with worse overall survival (HR 2.16 95% CI 1.34–3.48, p‐value =.002). Weight loss was the most important risk factor out of the 3 GLIM criteria (HR 3.5 95% CI 1.14–10.85, p‐value =.03) for worse overall survival. A high percentage (75%) of patients with GEP‐NETs using a SSA meet the GLIM criteria for malnutrition. Meeting more than 1 GLIM criterium, especially if there is weight loss these are risk factors for worse overall survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic neuroendocrine tumors are a rare and heterogenous group of neoplasms. Surgical resection is the only curative option. However, there has been an increase in palliative medical options. The aim of this retrospective study was to investigate responses for the most commonly used medical treatments in 192 patients. The current results support the effectiveness of somatostatin analogues in low-grade tumors and showed that it might also be used in patients with Ki-67 ≥ 10%. Treatment with streptozocin and 5-floururacil as first-line treatment showed good efficacy for G2 disease. Due to good efficacy and generally good tolerability PRRT might be considered as first-line treatment for NET G2. The results confirmed poor prognosis in high-grade tumors treated with carboplatin/etoposide or temozolomide. The current results provide valuable knowledge as current treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. Background: Given the rarity and heterogeneity of pancreatic neuroendocrine neoplasms (pNEN), treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. Aim: To investigate overall survival (OS), median progression-free survival (mPFS), and prognostic factors associated with the most common medical treatments for pNEN. Methods: Retrospective single-center study encompassing patients diagnosed and monitored between 2000 and 2020 (n = 192). Results: Median OS was 36 (95% CI: 26–46) months (99 months for grade (G) 1, 62 for G2, 14 for G3, and 10 for neuroendocrine carcinomas). Patients treated with somatostatin analogues (SSA) (n = 59, median Ki-67 9%) had an mPFS of 28 months. Treatment line (HR (first line as reference) 4.1, 95% CI: 1.9–9.1, p ≤ 0.001) emerged as an independent risk factor for time to progression. Patients with a Ki-67 index ≥10% (n = 28) had an mPFS of 27 months. Patients treated with streptozocin/5-fluorouracil (STZ/5FU) (n = 70, first-line treatment n = 68, median Ki-67 10%) had an mPFS of 20 months, with WHO grade serving as an independent risk factor (HR (G1 (n = 8) vs. G2 (n = 57)) 2.8, 95% CI: 1.1–7.2, p-value = 0.031). Median PFS was 21 months for peptide receptor radionuclide therapy (PRRT) (n = 41, first line n = 2, second line n = 29, median Ki-67 8%), 5 months for carboplatin and etoposide (n = 66, first-line treatment n = 60, median Ki-67 80%), and 3 months for temozolomide-based therapy (n = 56, first-line treatment n = 17, median Ki-67 30%). Conclusion: (1) Overall survival was, as expected, highly dependent on grade; (2) median PFS for SSA was around 2.5 years without difference between tumors with Ki-67 above or below 10%; (3) STZ/5FU as first-line treatment exhibited a superior mPFS of 20 months compared to what has historically been reported for targeted treatments; (4) PRRT in G2 pNEN achieved an mPFS similar to first-line chemotherapy; and (5) limited treatment efficacy was observed in high-grade tumors when treated with carboplatin and etoposide or temozolomide. [ABSTRACT FROM AUTHOR]

Purpose: PREF-NET reported patients’ experience of Somatuline® (lanreotide) Autogel® (LAN) administration at home and in hospital among patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Methods: PREF-NET was a multicentre, cross-sectional study of UK adults (aged ≥ 18 years) with GEP-NETs receiving a stable dose of LAN, which comprised of (1) a quantitative online survey, and (2) qualitative semi-structured interviews conducted with a subgroup of survey respondents. The primary objective was the description of overall patient preference for home versus hospital administration of LAN. Secondary objectives included describing patient-reported opinions on the experience and associated preference for each administration setting, and the impact on healthcare utilisation, societal cost, activities of daily living and health-related quality of life (HRQoL). Results: In the primary analysis (80 patients; mean age 63.9 years), 98.7% (95% confidence interval [CI]: 96.1–100.0) of patients preferred to receive LAN at home, compared with 1.3% (95% CI: 0.0–3.9) who preferred the hospital setting. Among participants, over half (60.3%) received their injection from a non-healthcare professional. Most patients (79.5% [95% CI: 70.5–88.4]) reported a positive effect on HRQoL after the switch from hospital to home administration. Qualitative interviews (20 patients; mean age 63.6 years) highlighted that patients preferred home administration because it improved overall convenience; saved time and costs; made them feel more comfortable and relaxed, and less stressed; and increased confidence in their ability to self-manage their treatment. Conclusion: Almost all patients preferred to receive LAN treatment at home rather than in hospital with increased convenience and psychological benefits reported as key reasons for this preference. [ABSTRACT FROM AUTHOR]

Summary: There are several options for systemic therapy of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), including somatostatin analogues (SSA), molecular-targeted agents, cytotoxic agents, and peptide receptor radionuclide therapy. However, the effectiveness of each agent varies according to the primary site. Although SSA and everolimus are key drugs used for systemic therapy of neuroendocrine tumors arising from the gastrointestinal tract (GI-NET), the optimal strategy for selecting among these modalities remains unexplored. Japanese experts on GI-NET discussed and determined optimal first-line treatment strategies based on the results of previously reported pivotal trials. The consensus was reached that tumor aggressiveness and prognosis can be predicted using hepatic tumor load and Ki-67 labeling index, which are thought to be clinically important factors when selecting systemic therapy for unresectable GI-NET. SSA therapy is considered appropriate for patients with a low hepatic tumor load and low Ki-67 value and everolimus for those with contraindications to SSA therapy. There was also agreement that the treatment strategy should be determined according to whether the origin is in the midgut, considering the biological differences. Based on this strategy, the experts have tentatively created treatment maps and applied them in representative cases of unresectable GI-NET. Japanese experts proposed tentative maps for optimal first-line treatment in patients with unresectable GI-NET. Further investigation is warranted to validate the usefulness of these maps. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumors (pNET) exhibit a wide spectrum of clinical behavior, which makes their assessment and management quite challenging. The purpose of this study was to comprehensively assess the existing treatment landscape for patients with pNET. The study was conducted with the support of the ESSO-EYSAC Research Academy in collaboration with the E-AHPBA. An online survey was distributed via email and social media to surgical networks across Europe and beyond (September 1–30, 2023). Overall, 155 complete responses were obtained. A specialized NET tumor board was present at the institutions of 94 (61 %) of the study participants. The most frequently applied guidelines were from ENETS (n = 97; 63 %), NCCN (n = 74; 48 %), and ESMO (n = 53; 34 %). For resectability, similar criteria as in pancreatic ductal adenocarcinoma were used by 111 (72 %) participants, even though 116 (75 %) participants believed that pNET/pNEC should have their own resectability criteria. Most respondents used somatostatin analogues (n = 126; 81 %) and chemotherapy (n = 85; 55 %) as neoadjuvant treatments, followed by molecularly targeted agents (n = 45; 29 %) and PRRT (n = 37; 24 %). Only 17 (11 %) participants agreed/strongly agreed that the management of pNET/pNEC is sufficiently addressed in surgical education programs. This international survey highlighted areas for improvement in the care of pNET, namely the lack of pNET-specific resectability criteria and educational programs addressing pNET management. [ABSTRACT FROM AUTHOR]

Thyrotoxicosis, which characteristics are increased excitability, emotional lability, tachycardia episodes, increasing of free fractions of tetraiodothyronine (T4) and triiodothyronine (T3) is one of the most common endocrinological syndromes. However, during the interpretation of thyroid status it is very important to take into account the possibility that a patient has TSH-secreting pituitary adenoma. Timely diagnosis of TSH-secreting adenomas plays prominent role in guiding the treatment course since it is associated with an improvement of long-term prognosis and an increase of the patient’s total life expectancy. Needed to underline that in some patients with TSH-secreting adenomas manifestations of the other pituitary hormones hypersecretion (first of all — somatotropin and prolactin) come to the fore, that lead to the development of acromegaly and hyperprolactinemia accordingly. Our work basing on two clinical cases presents main principles of diagnosis and specific clinical manifestations of TSH-secreting pituitary adenomas and demonstrates efficacy of somatostatin analogues in the treatment of this pathology.

A novel HPLC-ESI-MS/MS method for simultaneous gonadotropin-releasing hormone (GnRH) analogs and somatostatin analog quantitation was developed and validated. The developed method was successfully applied to pharmacokinetic studies. The sample preparation process included solid-phase extraction (SPE). Effective chromatographic separation of the analytes and internal standard (dalargin) was achieved with a C18 column, using a gradient elution with two mobile phases: 0.1% v/v formic acid (aqueous solution) and 0.1% v/v formic acid (acetonitrile solution). The linearity of the method was demonstrated within a concentration range of 0.5–20 ng/mL, with correlation coefficients between 0.998–0.999 for goserelin, buserelin, triptorelin, and octreotide, respectively. The relative standard deviation (RSD, %) values for method accuracy and precision did not exceed 20% at the lower level of quantitation (LLOQ) or 15% at other concentration levels. [ABSTRACT FROM AUTHOR]

ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion. Herein we report the first off-label use of pasireotide in a boy with a severe therapy-resistant form of CHI due to a homozygous ABCC8 mutation. After partial pancreatectomy, hyperinsulinism persisted; in an attempt to prevent further surgery, off-label treatment with pasireotide was initiated. Short-acting pasireotide treatment caused high blood glucose level shortly after injection. Long-acting pasireotide treatment resulted in more stable glycemic control. No side effects (e.g., central adrenal insufficiency) were noticed during a 2-month treatment period. Because of recurrent hypoglycemia despite a rather high carbohydrate intake, the boy underwent near-total pancreatectomy at the age of 11 months. In conclusion, pasireotide treatment slightly improved glycemic control without side effects in a boy with severe CHI. However, the effect of pasireotide was not sufficient to prevent near-total pancreatectomy in this case of severe CHI.

We report here a case of a 62-year-old woman with multiple gastric enterochromaffin-like cell neuroendocrine tumor caused by hypergastrinemia due to parietal cell dysfunction that was successfully treated with somatostatin analogue. Esophagogastroduodenoscopy revealed several G1 neuroendocrine tumors, 10 mm in diameter, in the body of the stomach. No evidence of autoimmune gastritis, Helicobacter pylori infection, neuroendocrine neoplasia type 1, or Zollinger–Ellison syndrome was identified. The pattern of immunohistochemical staining of the background gastric mucosa was suggestive of parietal cell dysfunction. She was treated with long-acting release octreotide acetate. Complete response was confirmed after 9 months and was maintained for 22 months. [ABSTRACT FROM AUTHOR]

Pituitary tumours are a significant diagnostic problem in clinical practice. Considering all the rarity of thyrotropic hormone secreting adenoma it is a diagnostic and therapeutic challenge in part due to the lack of the preoperative standards. TSH-oma, besides hyperthyroidism symptoms, might be a cause of other endocrine disorders, most often dysfunction of other tropic axes and may cause neurological symptoms associated with sella expansion. We report a case of a 49-year-old male patient with macroadenoma, overt clinical hyperthyroidism, secondary adrenal insufficiency and hypogonadotropic hypogonadism. The diagnosis of thyrotropinoma was confirmed by blood tests that revealed elevated FT3 and FT4 levels together with high TSH. Thyrotropin-releasing hormone (TRH) test was performed and magnetic resonance imaging (MRI) imaging revealed the presence of macroadenoma. Histopathology examination confirmed the diagnosis of thyrotropic cell pituitary adenoma. The appropriate therapy for thyrotropin pituitary adenoma has not been elaborated in reports of this domain. Preoperatively the patient was prepared by long-acting somatostatin analogue (Sandostatin LAR) injections to reduce tumor size with good therapeutic effect afterwards underwent surgical transsphenoidal treatment successfully. However, specific treatment guidelines for pituitary thyrotropic tumors need to be elaborated more in details.

Abstract Background Patients with metastatic small-intestinal neuroendocrine tumours (NET) have been shown to have a reduced quality of life compared to the general population and many have disabling symptoms during somatostatin analogue (SSA) treatment. The aim of this prospective study was to document the patient-reported symptoms, coping and quality of life during SSA treatment and to measure patients’ fat-soluble vitamin levels. Methods Patients with metastatic small-intestinal NET on treatment with long-acting SSA were included. Data on patient characteristics, blood samples, questionnaires (EORTC-QLQ-C30 and GI.NET-21) and structured patient interviews were collected at inclusion and after 1 year. Results Eighty-eight patients were included, 77 (88%) attended 1 year follow-up. Approximately 50% of patients reported symptoms, the most common symptoms at baseline and after 1 year follow-up were diarrhoea, flatulence, fatigue, abdominal discomfort and sore injection lumps. Diarrhoea and fatigue were reported as their main complaint, 23% had > 5 daily episodes of diarrhoea and 59% reported fatigue. However, patients reported a high perceived quality of life, high daily activity, coped with their symptoms and managed their daily life well. Deficiency of vitamin D (27%) and A (13%) were observed. Conclusions Patients with metastatic small-intestinal NET on SSA treatment reported a high frequency of symptoms. Minor improvements were seen after 1-year of follow-up, illustrating that many symptoms might be difficult to improve, or may not be recognised by the health service. Patients, however, generally reported a high quality of life. Care for NET patients on SSA treatment should include a regular systematic symptom registration and vitamin measurements.

ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion. Herein we report the first off-label use of pasireotide in a boy with a severe therapy-resistant form of CHI due to a homozygous ABCC8 mutation. After partial pancreatectomy, hyperinsulinism persisted; in an attempt to prevent further surgery, off-label treatment with pasireotide was initiated. Short-acting pasireotide treatment caused high blood glucose level shortly after injection. Long-acting pasireotide treatment resulted in more stable glycemic control. No side effects (e.g., central adrenal insufficiency) were noticed during a 2-month treatment period. Because of recurrent hypoglycemia despite a rather high carbohydrate intake, the boy underwent near-total pancreatectomy at the age of 11 months. In conclusion, pasireotide treatment slightly improved glycemic control without side effects in a boy with severe CHI. However, the effect of pasireotide was not sufficient to prevent near-total pancreatectomy in this case of severe CHI. [ABSTRACT FROM AUTHOR]

Introduction: Well-differentiated neuroendocrine pulmonary tumours (NETp) are morphologically classified as typical carcinoid (TC) and atypical carcinoid (AC). There are limited data on systemic treatment for metastatic disease. Objective: Our study evaluated the median progression-free survival of patients with metastatic tumours, comparing TC and AC status for different treatments. Methods: Retrospective series of patients with metastatic NETp treated from 2002 to 2019 in a large cancer centre were analysed. Our primary endpoint was progression-free survival according to morphological classification (TC vs. AC). All patients received at least one treatment modality (e.g., somatostatin analogue [SSA], chemotherapy [ChP], and everolimus [Eve]). Variables were analysed using the chi-square test, median progression-free survival (mPFS) rates (months), with comparisons evaluated by the log-rank test. Results: Twenty-seven patients were included: 44% with TC and 56% with AC. TC patients were on average 58-years-old, 83.3% were female, and 33.3% received more than one treatment. AC patients were on average 61-years-old, 66.7% were female, and 20% received more than one treatment. All patients were treated more frequently with SSA (TC: 75% vs. AC: 80%, p=0.756). Cisplatin and etoposide were the most frequent ChP regimen (TC: 75% vs. AC: 30%, p=0.248). Patients with TC and AC treated with SSA had higher mPFS in months (TC mPFS SSA: 14.5, Eve: 2.50, ChP: 4.0, SSA + Eve: 4.50; AC mPFS SSA: 7.50, Eve: 4.50, ChP: 7.50, SSA + Eve: 7.00). Conclusion: Although the statistical analyses did not show a significant difference between treatment, numerically, more patients with TC or AC experienced tumor control with SSAs, where the mPFS pairs showed a possible tendency to differentiate themselves from the other regimes (Eve and ChP).

Abstract 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.

A novel HPLC-ESI-MS/MS method for simultaneous gonadotropin-releasing hormone (GnRH) analogs and somatostatin analog quantitation was developed and validated. The developed method was successfully applied to pharmacokinetic studies. The sample preparation process included solid-phase extraction (SPE). Effective chromatographic separation of the analytes and internal standard (dalargin) was achieved with a C18 column, using a gradient elution with two mobile phases: 0.1% v/v formic acid (aqueous solution) and 0.1% v/v formic acid (acetonitrile solution). The linearity of the method was demonstrated within a concentration range of 0.5–20 ng/mL, with correlation coefficients between 0.998–0.999 for goserelin, buserelin, triptorelin, and octreotide, respectively. The relative standard deviation (RSD, %) values for method accuracy and precision did not exceed 20% at the lower level of quantitation (LLOQ) or 15% at other concentration levels.

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. [ABSTRACT FROM AUTHOR]

Introduction Acromegaly is a chronic disease of increased growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels induced by a pituitary adenoma. HMGA2 (high mobility group A2) and AIP (aryl hydrocarbon receptor-interacting protein) expression levels are related to GH-secreting adenomas, and also a response to Somatostatin Analogs (SSAs). We studied SNPs in miR-107 and miR-23b that related with AIP and HMGA2 genes respectively and control their expression, and also SNP in the 3'UTR of HMGA2 gene. Our aim was to investigate genotype distributions of the studied SNPs, as well as the possible relationship between disease and/or response to SSAs treatment in patients with acromegaly. Material and Methods Genotypes were determined by qRT-PCR method from DNA materials obtained blood samples of acromegaly patients (141) and healthy individuals (99). The genotype distributions of patients and healthy groups, as well as the relationship between the clinical data of the disease and genotypes were statistically compared. Results In acromegaly patients with T-allele, p53 expression (p=0.049) was significantly higher. In patients with CT+TT genotype and T-allele who were responder to SSA-treatment Ki-67 index (respectively p=0.019, p=0.020 respectively) was higher. We did not observe the genotypes for miR-23b and miR-107 polymorphisms in the patients and control group of Turkish population. Conclusion The genetic variations of the miRNAs genes related with HMGA2 and AIP genes were not seen in our study. Although there is no relationship between HMGA2-rs1351394 polymorphism and acromegaly disease, T allele was associated with some clinical features related to adenoma in patients with acromegaly. [ABSTRACT FROM AUTHOR]

Opinion Statement: Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies with rising incidence and prevalence. Outcome and therapy of small bowel neuroendocrine tumours (SBNETs) is variable, depending on the grade, differentiation, tumour burden, as well as the site of the tumour origin. Because of this, multidisciplinary approach is essential. Large randomized clinical trials, with somatostatin analogues (PROMID, CLARINET) or with peptide receptor radionuclide therapy (PRRT) with 177-lutetium (NETTER-1 trial) as well as the mammalian target of rapamycin inhibitor (mTOR) everolimus (RADIANT trials), represent milestones for the medical management of unresectable grade 1 and 2 SBNETS over the last decade. Novel therapies, such as tyrosine kinase inhibitors (TKI), are on the cutting edge. However, multiple unsolved questions remain. This review provides a comprehensive review of the main systemic therapeutic options for advanced SBNETs and discusses the latest guideline recommendations for palliative treatment. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease. An increased expression of somatostatin receptor subtype 2 in patients with IPF was identified and lung fibroblasts expressed somatostatin receptors in vitro. In addition, somatostatin analogue inhibits the expression of transforming growth factor-β, insulin-like growth factor (IGF) −1, platelet-derived growth factor, and basic fibroblast growth factor. Therefore, we examined the effects of somatostatin analogue on bleomycin-induced pulmonary fibrosis in mice. In a similar model, it has been reported that administration of high-dose somatostatin analogs suppressed acute inflammation and subsequent pulmonary fibrosis. However, it was clarified that the same effect can be obtained even at the dose used in clinical practice. C57BL/6 mice received a single tracheal instillation of bleomycin. After randomly allocated, mice were treated with subcutaneous injection of either normal saline or somatostatin analogue. Somatostatin analogue reduced the number of neutrophils and lymphocytes in bronchoalveolar lavage (BAL) and IGF-1 level in serum and BAL fluid and attenuated weight loss. The hydroxyproline content of the lung homogenates in somatostatin analogue treatment group was significantly lower than in that of normal saline treatment group. These results suggest that somatostatin analogue may attenuate pulmonary fibrosis after bleomycin treatment at the dose used in clinical practice. [ABSTRACT FROM AUTHOR]

A fifty-one-year-old male patient with a history of recurring abdominal pains and signs of subileus, without carcinoid syndrome signs, underwent a laparatomy with a resection of the small intestine segment. Histopathology revealed a well- -differentiated neuroendocrine neoplasm of the small intestine. Due to the lack of hormonal activity and low malignancy potential the patient was not qualified for adjuvant therapy. The yearly computed tomography did not indicate a recurrence of the neoplasm. The patient did not report any “red flag” symptoms. After a few years in remission [68Ga]-DOTATATE PET/CT revealed a dynamic development of the illness. The patient was qualified for palliative treatment with long-acting somatostatin analogue. Due to the treatment’s ineffectiveness and further progression of the disease, the patient received Peptide Receptor Radionuclide Therapy (PRRT). In spite of the therapy his condition did not improve and progression was observed. The patient died because of a malfunction of the cardiac conduction system caused by metastases in the heart. [ABSTRACT FROM AUTHOR]

Background: No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled trials are lacking. In vivo somatostatin receptor assessment with 68 Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68 Ga-DOTATATE PET-positive NFPMA., Methods: The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10 mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68 Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120 mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22., Findings: Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68 Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 [50%]) or placebo (22 [50%]). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was +1·2 (2·5) mm with lanreotide and +1·3 (1·5) mm with placebo; adjusted mean difference versus placebo -0·1 mm (95% CI -1·3 to 1·2, p = 0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events., Interpretation: Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68 Ga-DOTATATE PET-positive NFPMA., Funding: Ipsen Farmaceutica BV., Competing Interests: MLD was independent chair and organiser of the Dutch Neuro-endocrine Symposium 2021, funded by Ipsen Farmaceutica BV. JH was invited lecturer at this same symposium. CBLMM has received several unrelated grants paid to the institution in the past 36 months, namely from CVON/Dutch Heart Foundation, the European Commission, Healthcare Evaluation Netherlands, TWIIN Foundation, and Stryker; and further owns a minority interest in Nicolab. No other potential conflicts of interest have been declared., (© 2024 The Author(s).)

VIPoma is an unusual neuroendocrine neoplasm that autonomously secretes VIP. It is associated with secretory diarrhea and electrolyte disturbances. Herein we report a case of a male patient, who was hospitalized in the Department of Endocrinology in Hedi Chaker Hospital, Sfax, Tunisia. He presented VIPoma syndrome, with hepatic metastases at diagnosis. He had a history of chronic, watery diarrhea. He was dehydrated with many electrolytic disorders as hypokalemia, hyponatremia and metabolic acidosis. Abdominal CT scan showed a heterogeneous mass in the pancreatic head with multiple hepatic lesions. A high VIP hormone level was found. Histological study of a liver biopsy revealed hepatic metastases of neuroendocrine carcinoma. The patient received analogues of somatostatin and systemic chemotherapy, with a transient symptomatic relief. Sadly the patient was lost to follow-up.

A number of therapeutic agents have been reported to be clinically useful for the management of the patients with unresectable pancreatic neuroendocrine tumors (PanNETs) including somatostatin analogues, molecular-targeted agents and cytotoxic agents. However, the optimal strategy for selection among those treatment modalities above in these patients has remained unexplored. Japanese experts for PanNET discussed and determined the optimal treatment strategies according to the results of previously reported studies. The tumor volume of liver metastases and the Ki-67 labeling index were unanimously accepted as indicators of the tumor burden and tumor aggressiveness, respectively, which are two most clinically pivotal factors for determining the strategy of systemic treatment for unresectable PanNETs. In addition, for those with a relatively small tumor burden and slow disease progression, somatostatin analogues were selected as the first-line treatment agents. For those with a relatively large tumor burden and rapid tumor progression, cytotoxic agents were selected, possibly aiming at tumor shrinkage. For those of intermediate tumor volume and/or growth rate, molecular-targeted agents were selected as the first choice. Based on this strategy discussed among the experts, we tentatively prepared a MAP for proposing optimal treatment strategy and examined its validity in some patients with unresectable PanNETs. Results validated the usefulness of this MAP proposed for patients harbouring unresectable PanNETs. We herein propose a tentative MAP for optimal treatment selection for the patients harbouring unresectable PanNETs. Further large scale studies are, however, warranted to validate the usefulness of this MAP proposed in this study. [ABSTRACT FROM AUTHOR]

Background: Patients with metastatic small-intestinal neuroendocrine tumours (NET) have been shown to have a reduced quality of life compared to the general population and many have disabling symptoms during somatostatin analogue (SSA) treatment. The aim of this prospective study was to document the patient-reported symptoms, coping and quality of life during SSA treatment and to measure patients' fat-soluble vitamin levels.Methods: Patients with metastatic small-intestinal NET on treatment with long-acting SSA were included. Data on patient characteristics, blood samples, questionnaires (EORTC-QLQ-C30 and GI.NET-21) and structured patient interviews were collected at inclusion and after 1 year.Results: Eighty-eight patients were included, 77 (88%) attended 1 year follow-up. Approximately 50% of patients reported symptoms, the most common symptoms at baseline and after 1 year follow-up were diarrhoea, flatulence, fatigue, abdominal discomfort and sore injection lumps. Diarrhoea and fatigue were reported as their main complaint, 23% had > 5 daily episodes of diarrhoea and 59% reported fatigue. However, patients reported a high perceived quality of life, high daily activity, coped with their symptoms and managed their daily life well. Deficiency of vitamin D (27%) and A (13%) were observed.Conclusions: Patients with metastatic small-intestinal NET on SSA treatment reported a high frequency of symptoms. Minor improvements were seen after 1-year of follow-up, illustrating that many symptoms might be difficult to improve, or may not be recognised by the health service. Patients, however, generally reported a high quality of life. Care for NET patients on SSA treatment should include a regular systematic symptom registration and vitamin measurements. [ABSTRACT FROM AUTHOR]

Summary: Background: Previous cost evaluation studies reported either no increase or cost-saving using pasireotide in patients undergoing pancreaticoduodenectomy. We examined the likelihood and magnitude of cost-saving when using pasireotide at our institution to determine the generalizability of prior reports. Methods: Cost data were obtained for a cohort of 440 patients undergoing pancreaticoduodenectomy at a single institution during 2009–2016. A statistical model was used to simulate the cost of patient care had they received pasireotide. Sensitivity analyses were performed to assess the impact of pasireotide price and pancreatic fistula rate on cost. Results: With a fistula rate of 10.2% and a current price for pasireotide of $1257, the likelihood of cost-saving is 60%. When cost-saving does occur, the mean cost-saving per patient is $1442, 2.5–97.5% quantile difference (QD): $69–3756. At the same pasireotide price but with a fistula rate of 30%, the likelihood of cost-saving increases to 91% with a mean cost-saving of $4030, 2.5–97.5% QD: $402–8511. At the same fistula rate but with a pasireotide price of $1000, the likelihood of cost-saving increases to 65% with a cost-saving of $1566, 2.5–97.5% QD: $75–3979. Conclusion: At its current price, and with the fistula rate at our institution, pasireotide is more likely to pay for itself than not, but there is a significant probability that it will not be cost-saving. Negotiating a better price (i.e., to the lowest found in the literature) will reduce the likelihood of pasireotide not being cost-saving by 5%. [ABSTRACT FROM AUTHOR]

Introduction: Acromegaly and gigantism entail increased morbidity and mortality if left untreated, due to the systemic effects of chronic GH and IGF-1 excess. Guidelines for the diagnosis and treatment of patients with GH excess are well established; however, the presentation, clinical behavior and response to treatment greatly vary among patients. Numerous markers of disease behavior are routinely used in medical practice, but additional biomarkers have been recently identified as a result of basic and clinical research studies. Areas covered: This review focuses on genetic, molecular and genomic features of patients with GH excess that have recently been linked to disease progression and response to treatment. A PubMed search was conducted to identify markers of disease behavior in acromegaly and gigantism. Markers already considered as part of routine studies in clinical care guidelines were excluded. Literature search was expanded for each marker identified. Novel markers not included or only partially covered in previously published reviews on the subject were prioritized. Expert opinion: Recognizing the most relevant markers of disease behavior may help the medical team tailoring the strategies for approaching each case of acromegaly and gigantism. This customized plan should make the evaluation, treatment and follow up process more efficient, greatly improving the patients' outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Somatostatin analogues are used to treat symptoms and slow tumour progression in patients with neuroendocrine tumours (NETs) and carcinoid syndrome and to reduce hormone secretion and pituitary tumour volume in patients with acromegaly. A new syringe for lanreotide autogel/depot (LAN) was developed following feedback from a human factors study to improve ease of injection compared with previous syringes. PRESTO aimed to assess preferences of nurses between the LAN new syringe and the octreotide long-acting release (LAR) syringe.Methods: PRESTO, a multinational, multicentre, prospective, noninterventional, simulated-use study, enrolled nurses with ≥ 2 years' experience injecting LAN and/or octreotide LAR in patients with NETs and/or acromegaly. Nurses administered injections into pads using the LAN new syringe and octreotide LAR syringe in a randomised sequence. In an anonymous web-based questionnaire, nurses reported their overall preference ('strong' or 'slight'; primary endpoint) and rated and ranked the importance of nine attributes for each syringe (1 [not at all] to 5 [very much]).Results: Overall, 90 nurses attended sessions and completed valid questionnaires. Most nurses (97.8%) expressed a preference (85.6% 'strong', 12.2% 'slight') for the LAN new syringe versus the octreotide LAR syringe (P < 0.0001). Attribute performance ratings (1 [not at all] to 5 [very much]) were consistently higher for the LAN new syringe versus the octreotide LAR syringe, with the greatest differences in 'fast administration' and 'confidence the syringe will not be clogged' (mean difference [SD]: 2.6 [1.2] and 2.3 [1.5], respectively; P < 0.0001). The attribute ranked most important was 'confidence the syringe will not be clogged' (24.4%); least important was 'convenience of syringe format, including packaging, from preparation to injection' (34.4%).Conclusions: Nurses preferred the user experience of the LAN new syringe compared with the octreotide LAR syringe, with a particular preference for attributes related to product delivery with the LAN new syringe. [ABSTRACT FROM AUTHOR]

Purpose: The antiproliferative properties of lanreotide autogel (LAN) in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) were demonstrated in the CLARINET study. However, there is limited literature regarding factors that affect progression-free survival (PFS) in patients with GEP NENs treated with LAN. Methods: We identified a total of 191 treatment-naive patients with advanced GEP NENs and positive SSTR uptake on imaging (Octreoscan or 68Gallium DOTATATE Positron Emission Tomography [68GaPET]) who received first-line LAN monotherapy, albeit at various starting doses (60, 90 or 120 mg/month). A group of 102 patients who initiated treatment at the standard dose of 120 mg/month were included in the study and further evaluated by univariate and multivariate analyses to identify predictors of PFS. Results: The location of tumour primary was in the small bowel in 63 (62%), pancreas in 31 (30%) and colon/rectum in 8 patients (8%). The tumours were well-differentiated, and the majority were grade 1 (52%), or 2 (38%). About 60% of cases had progressive disease at the time of treatment initiation. Most patients with available pretreatment nuclear medicine imaging (Octreoscan or 68Ga PET) had a Krenning score of 3 (44%) or 4 (50%). The median PFS for the entire cohort was 19 months (95% CI 12, 26 months). The univariate analysis demonstrated that grade 2 tumours, progressive disease at baseline and metastatic liver disease were associated with a significantly shorter PFS, while other evaluated variables did not affect PFS at a statistically significant level. However, at multivariate analysis only the tumour grade remained statistically significant. Conclusions: The current study showed that, of many evaluated variables, only the tumour grade was predictive of PFS duration and this should be considered during patient selection for treatment. [ABSTRACT FROM AUTHOR]

A novel 18F-radiolabeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, was synthesized and evaluated for positron emission tomography (PET) imaging of Neuroendocrine tumors (NETs). [Al18F]NODA-MPAA-HTA was designed and synthesized by conjugating 18F nuclide with a modified KE108 peptide, a somatostatin analog with high affinity for all five subtypes of somatostatin receptors (SSTR 1–5), through coupling a bifunctional chelator (NODA) to target somatostatin receptor (SSTR) positive tumors. The amino group of KE108 peptide, a SSTRs-targeting pharmacophore, was conjugated with the carboxyl group of NODA by a condensation reaction to obtain the labeling precursor of [Al18F]NODA-MPAA-HTA, in which its precursor was obtained through Fmoc solid-phase methods. A novel methodology for Al18F labeling of chelating agent-biomolecule conjugates was used to synthesize [Al18F]NODA-MPAA-HTA. In vitro stabilities of [Al18F]NODA-MPAA-HTA were evaluated by incubating it in saline or bovine serum for 2 h. Ex vivo biodistribution and in vivo imaging of [Al18F]NODA-MPAA-HTA were further investigated to evaluate its SSTRs targeting ability and feasibility for the diagnosis of NETs using PET imaging. [Al18F]NODA-MPAA-HTA was synthesized using a one-step 18F-AlF labeling procedure resulting in moderate radiochemical yield (60–80 %, non-decay corrected) and high radiochemical purity (>95 %). It exhibited good hydrophilicity and excellent stability in vitro, with a molar activity of 122 GBq/μmol. At 30 min and 60 min, the uptake of [Al18F] NODA-MPAA-HTA by HEK293-SSTR2 cells was 5.47 ± 0.97 %/105 cells and 12.11 ± 0.32 %/105 cells, respectively. The affinity of [Al18F]NODA-MPAA-HTA for SSTR2 was determined to be 8.77 ± 1.14 nM. In micro-PET imaging of HEK293-SSTR2 tumor-bearing mice, [Al18F]NODA-MPAA-HTA showed high tumor uptake of radioactivity and a high tumor-to-muscle ratio. Biodistribution results confirmed that radioactivity uptake in the tumor was significantly higher than that in the muscle by more than five-fold (P<0.001). Furthermore, the relatively low bone uptake of [Al18F]NODA-MPAA-HTA suggested that defluorination did not occur in vivo. These preliminary results provide experimental evidence for further study of Al18F-labeled somatostatin analogues as tumor probes for PET imaging of NETs. Fluorine-18 is widely used as a radionuclide for the production of radiopharmaceuticals for positron emission tomography (PET). Due to its short half-life (T1/2,109.8 min), its ease of production will facilitate the widespread dissemination of this radiopharmaceutical. A high-quality [Al18F]NODA-MPAA-HTA was synthesized with satisfactory yield. This radiopharmaceutical demonstrated higher tumor uptake and better tumor-to-muscle contrast, resulting to excellent image quality. These findings suggest that the novel 18F-labeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, is a promising tool for PET imaging of NETs. [Display omitted] [ABSTRACT FROM AUTHOR]

Veldoreotide, a somatostatin analogue, binds to the somatostatin receptors (SSTR) 2, 4, and 5. The current aim was to assess its pharmacological activity as an SSTR4 agonist. G-protein signaling was assessed using a fluorescence-based membrane potential assay in human embryonic kidney 293 (HEK293) cells stably co-expressing G-protein-coupled inwardly rectifying potassium 2 channels and the individual SSTR2, SSTR4, and SSTR5, and in human BON-1 cells stably expressing these SSTRs. Veldoreotide effects on chromogranin A (CgA) secretion and cell proliferation were examined in BON-1 cells. In HEK293 transfected cells, veldoreotide showed a high efficacy for activating the SSTR4; octreotide and pasireotide had little activity (Emax, 99.5% vs. 27.4% and 52.0%, respectively). Veldoreotide also activated SSTR2 and SSTR5 (Emax, 98.4% and 96.9%, respectively). In BON-1 cells, veldoreotide activated SSTR2, SSTR4, and SSTR5 with high potency and efficacy. CgA secretion was decreased to a greater degree in the BON-1 cells expressing SSTR4 versus the cells expressing SSTR2 and SSTR5 (65.3% vs. 80.3% and 77.6%, respectively). In the BON-1 cells expressing SSTR4, veldoreotide inhibited cell proliferation more than somatostatin SS-14 (71.2% vs. 79.7%) and to a similar extent as the SSTR4 agonist J-2156 in the presence of SSTR2 and SSTR5 antagonists. Veldoreotide is a full agonist of SSTR2, SSTR4, and SSTR5.

Hanford Yau,1 Mustafa Kinaan,2 Suzanne L Quinn,3 Andreas G Moraitis3 1Division of Endocrinology, Diabetes, and Metabolism, University of California, San Francisco (Fresno Division), Fresno, CA, USA; 2Division of Internal Medicine, University of Central Florida College of Medicine, Orlando, FL, USA; 3Division of Endocrinology, Diabetes, and Metabolism, Orlando VA Medical Center, Orlando, FL, USA Abstract: Over the past three decades, the incidence and prevalence of neuroendocrine tumors have gradually increased. Due to the slow-growing nature of these tumors, most cases are diagnosed at advanced stages. Prognosis and survival are associated with location of primary lesion, biochemical functional status, differentiation, initial staging, and response to therapy. Octreotide, the first synthetic somatostatin analog, was initially used for the management of gastrointestinal symptoms associated with functional carcinoid tumors. Its commercial development over time led to long-acting repeatable octreotide acetate, a long-acting version that provided greater administration convenience. Recent research demonstrates that octreotide’s efficacy has evolved beyond symptomatic management to targeted therapy with antitumoral effects. This review examines the history and development of octreotide, provides a synopsis on the classification, grading, and staging of neuroendocrine tumors, and reviews the evidence of long-acting repeatable octreotide acetate as monotherapy and in combination with other treatment modalities in the management of non-pituitary neuroendocrine tumors with special attention to recent high-quality Phase III trials. Keywords: carcinoid, everolimus, neuroendocrine tumor, octreotide LAR, somatostatin analog, ITMO, NETTER-1, PROMID, RADIANT-2

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a large and very diverse group of neoplasms. Clinical presentation of NETs depends on the site of the primary tumor and whether the tumor is functioning (i.e., secreting peptides or neuroamines that produce symptoms). The diagnosis of GEP-NET is further complicated by symptomatic differences that occur depending on the type of secreted peptide or neuroamine. Due to their heterogeneity and unique characteristics, early diagnosis of GEP-NETs is difficult, which increases the likelihood of metastatic disease and reduces the scope of therapeutic possibilities. Thus, a multidisciplinary approach for the treatment of GEP-NETs is necessary. This review is the result of presentations that were delivered during an expert meeting on the treatment of GEP-NETs supported by Ipsen. We summarize the current knowledge on the epidemiology, incidence, diagnosis, and treatment of GEP-NETs. We examined the role of the somatostatin analog (SSA) lanreotide and the impact of the data from the recently published, randomized, double-blind, placebo -controlled CLARINET study (Controlled study of Lanreotide Antiproliferative Response In Neuroendocrine Tumors) on disease management. We also review the recent treatment options and recommendations for GEP-NETs.

Abstract Background Treatment of severe diffuse congenital hyperinsulinism (CHI) without sufficient response to diazoxide is complicated by the lack of approved drugs. Therefore, patients are often hospitalized long-term or have to undergo pancreatic surgery if episodes of severe hypoglycaemia cannot be prevented. A long-acting somatostatin analogue, octreotide, has been reported to be an effective treatment option that prevents severe hypoglycaemia in children with CHI, and its off-label use is common in CHI. However, octreotide requires continuous i.v. or s.c. infusion or multiple daily injections. Here, we report our experiences with the use of a monthly application of a long-acting somatostatin analogue, lanreotide autogel® (LAN-ATG), in early infancy. Results The mean blood glucose concentration within 7 days before the first LAN-ATG administration were compared to 7 days after the first LAN-ATG administration and increased by 0.75 mmol/L (range 0.39–1.19 mmol/L). In the following weeks intravenous glucose infusions, octreotide, and glucagon treatment could be successfully stopped in all patients 3–20 days after the first LAN-ATG injection without substantial worsening of the hypoglycaemia rate. Increased carbohydrate requirements could be normalized with an average reduction in the carbohydrate-intake of 7 g/kg body weight/d (range 1.75–12.8 g/kg body weight/d). Over a total of 52 treatment months, no serious adverse effects occurred. Conclusion Long-term LAN-ATG treatment improved blood glucose concentrations, lowered the frequency of hypoglycaemia or allowed for normalization of oral carbohydrate intake in infants with CHI younger than 6 months of age. No severe side effects were observed. LAN-ATG might be an alternative treatment option in infants with severe CHI who lack risk factors for necrotizing enterocolitis and are not responding to current treatment regimens as an alternative to surgery after careful individual evaluation.

Purpose: To investigate the effects of preoperative somatostatin analogue (SSA) treatment on the annual cost of all acromegaly treatment modalities and on remission rates. Methods: The medical records of 135 patients with acromegaly who were followed at endocrinology clinic of Cerrahpasa Medical Faculty for at least 2 years after surgery between 2009 and 2016 were reviewed. Results: The mean follow-up time was 50.9 ± 25.7 months. Early remission was defined according to 3rd month values in patients who didn't achieve remission, and 6th month values in patients who achieved remission at the 3rd month after surgery. The early and late remission rates of the entire study population were 40% and 80.7%, respectively. The early remission of the preoperative SSA-treated group (61.5%) was significantly higher than SSA-untreated group (31.2%) (p = 0.002). The early remission of the preoperative SSA-treated patients with macroadenomas (52.2%) was also significantly higher than the SSA-untreated group (23.5%) (p = 0.02). In the subgroup analysis; this difference was much more pronounced in invasive macroadenomas (p = 0.002). There were no differences between the groups in terms of late remission.The median annual cost of all acromegaly treatment modalities in study population was €3788.4; the cost for macroadenomas was significantly higher than for microadenomas (€4125.0 vs. €3226.5, respectively; p = 0.03). Preoperative SSA use in both microadenomas and macroadenomas didn't alter the cost of treatment. The increase in the duration of preoperative medical treatment had no effect on early or late remissions (p = 0.09; p = 0.8). Conclusions: Preoperative medical treatment had no effect on the costs of acromegaly treatment. There was a benefical effect of pre-operative SSA use on early remission in patients with macroadenomas; however, this effect didn't persist long term. [ABSTRACT FROM AUTHOR]

Summary: Lanreotide autogel is a long-acting somatostatin analogue with proven efficacy and safety in patients with well-differentiated (WD) gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) in a prior randomized phase III trial (CLARINET). However, the CLARINET study only enrolled patients with Ki-67 index <10%, and few patients of Asian ethnicity were included. We retrospectively analyzed the efficacy and safety of lanreotide in Korean patients with GEP-NETs in the daily practice setting. Between January 2015 and May 2018, 64 patients with metastatic WD GEP-NETs received lanreotide at Asan Medical Center, Seoul, Korea. Of them, 45 (70.3%) patients who received lanreotide as monotherapy were included in the current analysis. The most common primary tumor site was the pancreas (n = 22, 48.9%), followed by the rectum (10, 22.2%) and the small bowel (7, 15.6%). According to RECIST v1.1, a partial response was achieved in one patient (2.2%) and stable disease was achieved in 40 patients (88.9%). The median progression-free survival (PFS) was 16.4 months (95% confidence interval, 9.5–23.3 months). There were no differences in PFS according to the primary tumor site (p = 0.77). Hepatic tumor volume > 25% and prior systemic therapy were significantly associated with poorer PFS in the multivariate analysis. Lanreotide is well-tolerated and effective for Korean patients with GEP-NETs in the daily practice setting. [ABSTRACT FROM AUTHOR]

Abstract Purpose Somatostatin analogues (SSAs) can slow down the growth of neuroendocrine tumors. However, the mechanism remains unclear. Recent studies on patients with acromegaly suggest that SSAs may induce apoptosis, increase autophagy, and decrease cell proliferation of pituitary adenoma. Ki-67-labeling index is a marker of cellular proliferation; therefore, decreased levels are associated with inhibition of proliferation. The aim of this study was to evaluate and compare the Ki-67-labeling index of GH-secreting pituitary adenoma tissues in patients who had undergone pituitary surgery twice due to residual or recurrent tumors and had received SSA treatment between the two surgeries. Method Thirty acromegaly patients who met the above criteria were identified and evaluated for the demographic, clinical and radiological features retrospectively. Surgical pathology samples of each operation were stained for Ki-67 and evaluated blindly by a staff pathologist specialized in pituitary diseases. Results Among patients who received SSA treatment between the first and second operations, the Ki-67 index of the adenoma at the second operation was significantly lower than the Ki-67 index at the first operation. There were no differences in clinical and radiological prognostic markers between the groups with decreased and unchanged Ki-67 index. Conclusion We concluded that SSA treatment appears to decrease Ki-67 proliferation index independent of tumor features, SSA type, dose and treatment duration. This result suggests that SSA treatment may decrease cellular proliferation, supporting the previous studies. Highlights • SSA's appears to decrease Ki-67 independent of tumor features, treatment dose and duration. • Higher dose and longer treatment duration were associated with higher radiologic response. • Radiologic response rate was higher in patients with decreased Ki67 index. [ABSTRACT FROM AUTHOR]

Background: A long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form of congenital hyperinsulinism (CHI). However, no reports of its use in patients with the focal form of CHI exist. Case 1: A 1-month-old boy diagnosed with diazoxide-unresponsive CHI due to a paternal heterozygous ABCC8 gene mutation showed partial response to octreotide. 18F-DOPA-PET/CT scan revealed a focal lesion in the pancreatic head. Surgical removal of the lesion was unsuccessful. He was switched to monthly lanreotide treatment at the age of 11 months, which stabilised his blood glucose over a 12-month period. Case 2: A 1-month-old boy with diazoxide-unresponsive CHI due to a paternal heterozygous KCNJ11 gene mutation was partially responsive to octreotide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. Over 6 months, he underwent 3 lesionectomies and afterwards responded to octreotide. At the age of 9 months, treatment was switched to monthly lanreotide. Currently, he is aged 3, with stable glycaemia, and improved fasting tolerance. Case 3: A 3-week-old girl with a paternal heterozygous ABCC8 gene mutation was unresponsive to diazoxide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. She responded to octreotide, and her parents preferred to avoid pancreatic surgery. At the age of 20 months, treatment was switched to monthly lanreotide, resulting in euglycaemia over the last 7 months. Conclusion: CHI patients with focal pancreatic head lesions are challenging, especially if not surgically amenable. Conservative treatment is preferable, and lanreotide might be an option. The therapeutic impact of lanreotide treatment in patients with the focal forms of CHI should be confirmed in prospective studies with close monitoring of the side effects. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the serial changes of GH and IGF-1 in seven patients with naïve, active acromegaly following presurgical treatment of the somatostatin analog pasireotide long-acting release (LAR) and octreotide LAR. The patients were treated with pasireotide LAR with or without octreotide LAR for two years and underwent transsphenoidal adenomectomy. After treatment with the somatostatin analogs, the surgical cure rate was similar to that in patients who underwent transsphenoidal surgery alone. Diabetes insipidus was not identified in any patients after the operation. Pasireotide LAR was effective on GH as well as IGF-1 suppression and tumor size decreasing when used as the primary therapy. Future large-population studies to investigate the surgical curative rate after presurgical treatment with somatostatin analogs in patients with acromegaly and macroadenomas close to the cavernous sinus are warranted. However, that hyperglycemia developed following pre-surgical treatment with pasireotide should take into consideration.