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.

SummaryInsulin autoimmune syndrome (IAS), a rare cause of autoimmune hyperinsulinaemic hypoglycaemia, is relatively well known in Japan. The incidence in Caucasians is less than one-fifth of that reported in Japanese people, but it is becoming increasingly recognised worldwide in non-Asians as well. Drugs containing sulphydryl groups are known to be associated with the disease in genetically predisposed individuals. Moreover, several recent reports showed a direct association between the onset of IAS and the consumption of dietary supplements containing alpha-lipoic acid (LA). Insulinoma remains the most prevalent cause of hypersulinaemic hypoglycaemia in Caucasians. Consequently, primary investigation in these patients is generally focused on localisation of the pancreatic tumour, often with invasive procedures followed by surgery. We described a case of an Italian woman presenting to us with severe recurrent hypoglycaemia associated with high insulin and C-peptide levels and no evidence of pancreatic lesions at imaging diagnostic procedures. She had taken LA until 2 weeks before hospitalisation. After an evaluation of her drug history, an autoimmune form of hypoglycaemia was suspected and the titre of insulin autoantibodies was found to be markedly elevated. This allowed us to diagnose LA-related IAS, thus preventing any unnecessary surgery and avoiding invasive diagnostic interventions.Learning points:IAS is a rare cause of hyperinsulinaemic hypoglycaemia that typically affects Asian population, but it has been increasingly recognised in Caucasian patients.It should be considered among the differential diagnosis of hyperinsulinaemic hypoglycaemia to avoid unnecessary diagnostic investigations and surgery.It should be suspected in the presence of very high serum insulin levels (100–10  000  μU/mL) associated with high C-peptide levels.There is a strong association with administration of drugs containing sulphydryl groups included LA, a dietary supplement commonly used in Western countries to treat peripheral neuropathy.

The introduction of immunomodulatory drugs such as lenalidomide combined with dexamethasone (Len/Dex) has improved the outcome of patients with relapsed/refractory multiple myeloma (RRMM). Few data are currently available which investigate whether paraprotein relapse represents an indication for starting a new treatment. The aim of our retrospective, single-center study was to analyze the impact of disease status (relapsed/refractory) and type of relapse (clinical/paraprotein) on response rate and time-to-next-treatment (TNT). We included 74 patients (median age 70 years) with RRMM treated with Len/Dex until progression or unacceptable toxicity from 2008 to 2012. Age and disease status were not factors affecting overall response rate (ORR) and median TNT, but TNT was significantly longer in patients with asymptomatic compared to clinical relapse (34 vs. 19 months, p<0.008). In conclusion, Len/Dex represents an effective treatment with satisfactory ORR and outcomes in RRMM, especially for patients starting therapy in asymptomatic relapse.

SommarioL’insulinoma maligno è un tumore neuroendocrino pancreatico estremamente raro ed è associato a una severa sindrome ipoglicemica che impatta negativamente sulla qualità di vita e sulla sopravvivenza dei pazienti affetti. La gestione terapeutica dell’insulinoma maligno è complessa sia per il controllo delle crisi ipoglicemiche, sia per il controllo della crescita tumorale. La sindrome ipoglicemica rappresenta una sfida terapeutica per l’endocrinologo in quanto spesso non è responsiva alla terapia medica sintomatica, in particolare al diazossido utilizzato in monoterapia o associato agli analoghi della somatostatina. Everolimus ha un ruolo nel trattamento delle crisi ipoglicemiche refrattarie da insulinoma maligno sia per l’azione di inibizione del rilascio di insulina che di insulino-resistenza. La chirurgia con approccio curativo dell’insulinoma maligno è raramente perseguibile a causa della diffusione metastatica, mentre la chirurgia a scopo di debulking può essere presa in considerazione in casi selezionati sia per il controllo sintomatico sia perché può aumentare l’efficacia delle terapie sistemiche o locoregionali. La terapia radiometabolica con analoghi caldi della somatostatina rappresenta un’opzione terapeutica nei pazienti con tumori a elevata espressione dei recettori della somatostatina sia per il controllo della sintomatologia che della crescita tumorale, sebbene l’esperienza negli insulinomi maligni sia piuttosto scarsa. Data la rarità della malattia, sono disponibili in letteratura solo descrizioni di singoli casi o studi condotti su casistiche limitate; pertanto, è difficile stabilire la sequenza terapeutica più efficace in questi casi. Recentemente è stato condotto uno studio multicentrico italiano, in 13 centri di riferimento, focalizzato sulle caratteristiche clinico-patologiche, sulle modalità di trattamento e sui fattori prognostici che condizionano decorso ed esito dell’insulinoma maligno allo scopo di individuare una strategia terapeutica mirata basata su criteri razionali ed evidenze cliniche. In questa rassegna verranno descritti i principali risultati dello studio che comprende una casistica tra le più ampie finora pubblicate.

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Introduction: management of malignant insulinoma is challenging due to the need to control both hypoglycemic syndrome and tumor growth. Literature data is limited to small series. Aim of the study: to analyze clinical-pathological characteristics, treatment modalities and prognosis of patients with malignant insulinoma. Materials and methods: Multicenter retrospective study on 31 patients (M 61.3%) diagnosed between 1988 and 2017. Results: The mean age at diagnosis was 48 ± 15 years. In 5 cases (16.1%) the hypoglycemic syndrome occurred after 46 ± 35 months from the diagnosis of NET, in 26 (83.9%) cases it led to the diagnosis of NET, of which 11 cases (42.3%) with mean diagnostic delay of 32.7 ± 39.8 months. The majority ​​of the NET were G2 (70.8 %) and in the pancreatic body-tail (78.6%). The mean NET diameter was 41 ± 31 mm. Metastases were widespread in 40.7%, only hepatic in 37%, only lymph nodal in 18.5%..Surgical treatment was performed in 21/31 (67.7%) with hypoglycemic control in 42.9%. Except for 2 patients with curative surgery, the others underwent further different lines of therapies including somatostatin analogues (SA), Peptide Receptor Radionuclide Therapy (PRRT), everolimus, chemotherapy, TAE/TACE/RFA, radiotherapy. PRRT was performed in 14/31 (45.1%) with complete (42.9 %) or partial (50%) syndrome control. The median follow-up was 60 months. The 5-year survival rate was 62%. The median overall survival (OS) was 40 months. No significant difference in OS was observed according to the site of primary tumour and its dimension. A trend towards increased survival was found according to grading (5-year OS 100% for G1, 77% for G2, 33% for G3). Patients with Ki-67 ≤ 10% had a significant higher survival rate compared to patient with Ki-67 &gt;10% (5-year OS rate 87% vs 43%, p: 0.03). As regards the type of treatment, patients who underwent surgery had a higher survival rate than those who did not (5-year OS 76% vs 31.7%, p= 0.006). Moreover, patients receiving PRRT as II line treatment had a better prognosis than those who underwent it in further lines, although the 5-year OS was not significantly different (80% vs 25% respectively, p=0.057). Conclusions: Our study includes the largest series of patients with malignant insulinomas up to now reported. The hypoglycemic syndrome may occur after years in initially non-functioning NETs, or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 &lt;10% are prognostic factors associated with better survival. PPRT seems to be promising in the control of hypoglycemic syndrome.