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Introduction: Management of malignant insulinomas is challenging due to the need to control both hypoglycaemic syndrome and tumor growth. Literature data is limited to small series. Aim of the study: To analyze clinico-pathological characteristics, treatments and prognosis of patients with malignant insulinoma. Materials and methods: Multicenter retrospective study on 31 patients (male: 61.3%) diagnosed between 1988 and 2017. Results: The mean age at diagnosis was 48 years. The mean NET diameter was 41 ± 31 mm, and 70.8% of NETs were G2. Metastases were widespread in 38.7%, hepatic in 41.9% and only lymph nodal in 19.4%. In 16.1% of the cases, the hypoglycaemic syndrome occurred after 46 ± 35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of the cases it led to the diagnosis of NET, of which 42.3% with a mean diagnostic delay of 32.7 ± 39.8 months. Surgical treatment was performed in 67.7% of the cases. The 5-year survival rate was 62%. Overall survival was significantly higher in patients with Ki-67 ≤10% (P = 0.03), insulin level <60 µU/mL (P = 0.015) and in patients who underwent surgery (P = 0.006). Peptide Receptor Radionuclide Therapy (PRRT) was performed in 45.1%, with syndrome control in 93% of patients. Conclusions: Our study includes the largest series of patients with malignant insulinoma reported to date. The hypoglycaemic syndrome may occur after years in initially non-functioning NETs or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 ≤10% are prognostic factors associated with better survival. PPRT proved to be effective in the control of hypoglycaemia in majority of cases. [ABSTRACT FROM AUTHOR]

Introduction: Everolimus is a treatment option for patients with pancreatic NETs, while its use in patients with gastrointestinal NETs still remains to be defined. Aim(s): To test the efficacy and side effects of Everolimus in six patients with differentiated NET refractory to other therapies. Materials and methods: Everolimus (10 mg/day; compassionate use) was administered until disease progression or unacceptable toxicity. Three patients had metastases of ileal neuroendocrine carcinoma; one of typical lung carcinoid; one of ovary carcinoid and one of pancreatic insulinoma. Results: Two patients showed stable disease at imaging after six and 12 months of treatment. One patient showed biochemical remission. Two patients discontinued treatment due to adverse events. One patient did not reach the six months followup. Side effects were: stomatitis (2); thrombocytopenia (2); nausea (2); fatigue (2) that in one case determined definitive therapy discontinuation after eight months; skin infected lesions (1) leading to definitive discontinuation after three months of therapy. In one case, Everolimus was discontinued after 17 months for severe tricuspid valve insufficiency. Finally, one patient discontinued therapy after three months for worsening dyspnea. The only patient currently under treatment had no side effects. During therapy, lipid and glucose profile did not show significant alterations. Conclusion: Everolimus induces disease stabilization but may have several side effects which should be monitored. [ABSTRACT FROM AUTHOR]

Introduction: Medical treatment of metastatic insulinoma is debated. Aim(s): To test the efficacy of Everolimus on insulin secretion by liver metastases of a pancreatic insulinoma. Materials and methods: The patient (66 yrs old) was admitted due to hypoglycemic crises. Glucose=35 mg/dl, insulin =94.9 mUI/l, HbA1c= 4.5% and C peptide = 11.1 ng/ml suggested an insulinoma. Abdominal CT showed a 1.5 cm nodule of the head of the pancreas and six metastatic liver nodules. Liver biopsy showed metastases of well-differentiated neuroendocrine carcinoma, G2. The patient underwent a total pancreasectomy with removal of a portion of the gastric wall, spleen, duodenum, gallbladder, right liver lobe. Histology showed a pancreatic well-differentiated neuroendocrine carcinoma, Ki-67= 4%, infiltrating the peri-pancreatic adipose tissue, with metastases to the gastric lymphodes and to the liver. One month after angio-US showed the presence of at least six liver mestastases in the residual left liver, not suitable for radiofrequency ablation. Hypoglycemia recurred, indicating the persistence of insulin production by the metastatic liver in keeping with measurable insulin and C-peptide plasma levels. The patient then started compassionate treatment with Everolimus (10 mg/day). Results: Ten days after the patient became diabetic needing insulin administration. She developed hypertrygliceridemia and hypercholesterolemia, with improvement in liver function and no serious adverse events. Conclusion: Everolimus controls insulin secretion in metastatic insulinoma. [ABSTRACT FROM AUTHOR]

Introduction: It has been demonstrated that mTOR inhibitors have potent anti-proliferative effects in a human Medullary Thyroid Carcinoma (MTC) cell line. We here explore the possible role of roTOR inhibitors, Everolimus and BEZ235 (which also inhibits the PI3K pathway) on the effects of Insulin-like Growth Factor-1 (IGF-1) in human MTC primary cultures. Aim(s): To this purpose, 20 MTCs were dispersed in primary cultures, treated without or with 1uM Everolimus, 10nM-1uM BEZ235, and/or 50nM IGF-1. Materials and methods: Cell viability and apoptosis were evaluated after 48 h. We observed the phosphorylation of p70s6k by ELISA. Results: Everolimus and Bez 235 significantly reduced MTC cell viability, respectively, by 30% and 40 %, while IGF-1 enhanced cell viability, an effect completely blocked by mTOR inhibitors. Co-incubation with an IGF-1R blocking antibody enhanced the antiproliferative effects of mTOR inhibitors. Phosphorylation of p70S6K, a down-stream effector in the PI3K/Akt pathway of mTOR was as well-enhanced by IGF-1 and reduced by Everolimus and BEZ235 indicating that IGF-1 exerts its proliferative effects by inducing this pathway, which, in turn, can be effectively blocked by mTOR inhibitors. Conclusion: In conclusion, mTOR inhibitors reduced MTCs cell viability by inducing apoptosis, with a mechanism likely involving IGF-I signalling, suggesting that it might represent a possible medical treatment for persistent/recurrent MTCs. [ABSTRACT FROM AUTHOR]