Objective: Evidence is limited regarding outcome of patients with ectopic Cushing's syndrome (ECS) due to neuroendocrine tumors (NETs). Design: We assessed the prognostic factors affecting the survival of patients with NETs and ECS. Methods: Retrospective analysis of clinicopathological features, severity of hormonal syndrome, treatments from a large cohort of patients with NETs and ECS collected from 17 Italian centers. Results: Our series included 110 patients, 58.2% female, with mean (±s.d.) age at diagnosis of 49.5 ± 15.9 years. The main sources of ectopic ACTH were bronchial carcinoids (BC) (40.9%), occult tumors (22.7%) and pancreatic (p)NETs (15.5%). Curative surgery was performed in 56.7% (70.2% of BC, 11% of pNETs). Overall survival was significantly higher in BC compared with pNETs and occult tumors (P = 0.033) and in G1-NETs compared with G2 and G3 (P = 0.007). Negative predictive factors for survival were severity of hypercortisolism (P < 0.02), hypokalemia (P = 0.001), diabetes mellitus (P = 0.0146) and distant metastases (P < 0.001). Improved survival was observed in patients who underwent NET removal (P < 0.001). Adrenalectomy improved short-term survival. Clinical Study

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Context Signs and symptoms of Cushing’s syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications. Objective The aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis. Data Sources A systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included. Study Selection Clinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question. Data Extraction Data were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were included. Data Synthesis Mean time to diagnosis for patients with CS was 34 months (ectopic CS: 14 months; adrenal CS: 30 months; and pituitary CS: 38 months; P &lt; .001). No difference was found for gender, age (&lt;18 and ≥18 years), and year of diagnosis (before and after 2000). Patients with pituitary CS had a longer time to diagnosis in Germany than elsewhere. Conclusions Time to diagnosis differs for subtypes of CS but not for gender and age. Time to diagnosis remains to be long and requires to be improved.

The apparent paradox of bone fragility in acromegaly patients with a normal BMD can be explained by increased cortical thickness and porosity and reduced trabecular thickness with increased trabecular separation. These structural and microarchitectural abnormalities persist in the controlled phase of acromegaly despite bone turnover normalization. The main determinant of bone disease after hormonal control is severe osteoblastic dysfunction.

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.

Acromegalic patients, characterized by excessive secretion of GH and IGF-1, show a high fracture risk but bone mineral density is a poor predictor for bone fractures in these patients. The effects of an excess of GH/IGF1 on skeleton as well as on osteogenic progenitors, i.e. mesenchymal stem cells, have not been investigated in these patients. We aimed to elucidate the skeletal conditions of acromegalic patients by means of bone microarchitecture analysis and evaluation of MSCs osteogenic commitment. In particular, we performed histomorphometric analyses, and we quantified the expression levels of the osteogenic transcription factor RUNX2 in circulating MSCs. Our results showed an abnormal microarchitecture and demonstrated that bone impairment in acromegalic patients is associated with the upregulation of expression. Furthermore, osteoblastic activity was significantly reduced in patients under pharmacological treatment, compared to untreated patients. In conclusion, this study demonstrates the key role of gene overexpression in causing bone impairment in acromegalic patients. It also suggests a therapeutic approach for the improvement of bone quality, focused on the osteoblastic lineage rather than the inhibition of osteoclastic activity.

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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.