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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]

Background Functional well-differentiated neuroendocrine tumours (NET) with liver metastases represent a therapeutic challenge with few alternative options in guidelines. In these patients, the role of surgical resection of the primary tumour is controversial. Patients and methods From a regional registry collecting somatostatin analogue (SSA)-treated tumours from 1979 to 2005, a series of 139 patients presenting with symptomatic, liver-metastatic, well-differentiated NET (G1–G2, mitoses: ≤20, Ki-67: ≤20%) was prospectively collected and retrospectively analysed. Surgery on either the primary tumour or liver metastases was chosen: 1) when low perioperative risk was predictable; 2) in presence of an impending risk of obstruction, bleeding, or perforation; or 3) if liver metastases were suitable of curative or subtotal (>90%) tumour removal. Impact of the most relevant clinico-pathological parameters on survival was studied. Results Median follow-up was 127 months and median survival was 94 months, with 138 vs. 37 months in resected vs. non-resected primary NET (p < 0.001), respectively. In the univariate analysis, prolonged survival was significantly associated with primary tumour resection (p < 0.001), resection of liver metastases (p = 0.002), site of primary (carcinoid vs. pancreatic, p = 0.018), basal chromogranin-A (CgA) <200 ng/mL (p = 0.001), and absence of diarrhea (p = 0.012). Multivariate analysis showed that primary tumour resection was an independent positive prognostic factor (HR = 3.17; 95% CI: 1.77–5.69, p < 0.001), whereas diarrhea, basal CgA ≥200 ng/mL, and high tumour load were independent negative prognostic factors. Also, in 103 patients with non-resectable liver metastases, primary tumour resection was significantly associated with prolonged survival (median 137 vs. 32 months, p < 0.0001). Conclusions Primary tumour resection may improve survival in functional well-differentiated NET with liver metastases. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the fi fth most common malignancy worldwide with approximately 500,000 new cases per year, ranking as the third cause of cancer deaths. Until the very recent past no systemic therapy was available for patients with advanced HCC. However, advances achieved in the understanding of the molecular cancer biology and the subsequent introduction of molecularly targeted agents have disclosed promising and interesting possibilities for the treatment of this highly vascularized tumor in which the inhibition of angiogenesis is likely to represent the main potential therapeutic target. In this regard, sorafenib, an oral multikinase inhibitor endowed with signifi cant activity against several tyrosine-kinase receptors involved in blood vessel development, has shown to be very active in the treatment of advanced HCC. This review makes a survey of pharmacology, mode of action, pharmacokinetics, clinical value and safety of sorafenib when employed in the treatment of advanced HCC. [ABSTRACT FROM AUTHOR]

Introduction: Recently, gene mutations (SDH complex) involved in the pathogenesis of familial P/P have been discovered. These mutations are often associated with SDHB activity loss and activation of hypoxia signals. Aim(s): SDHB IHC expression in sporadic P/P with limited or advanced disease. Materials and methods: Eleven P/P treated from 1999 to 2009 were identified: median age 62 yrs (range 34-78), males/females = 4/7.28% were in stage IV, with syncronous and metachronous mts in 33% and 37%, respectively. SDHB IHC expression were carried out in all primary tumor tissues using a semiquantitative scale, considering staining intensity (score 0-3). The staining for SDHB was optimized employing micro-slices of normal myocardial atrial muscle as positive control. So as to ensure antibody specificity, consecutive sections were incubated in the absence of primary antibody. Results: Loss of SDHB expression (0) was found only in 2/11 pts with advanced disease, whilst high positivity (3+), with a clear cytoplasmic mitochondrial reactivity, was found in 100% (3/3) and 40% (2/5) of PIP with synchronous and metachronous liver metastases, respectively. One-third (33%) of non-metastatic pts demonstrated a high positivity. Conclusion: These data, even if on a limited number of cases of sporadic P/P, do not support the association between loss of SDHB and malignancy advocated for familial P/P. On the contrary, our findings could suggest a possible correlation between a higher incidence of SDHB IHC intensity (score 3+) and advanced disease. [ABSTRACT FROM AUTHOR]

Introduction: CS is characterized by flushing, diarrhea and carcinoid heart disease (CHD) alone or in association. Aim(s): To assess the incidence, clinical features and survival of WDNETs pts with CS. Materials and methods: We retrospectively analyzed 700 NET pts, between 1979 to 2009. One-hundred and ten pts with Typical (T) or Atypical (A) CS were identified. Results: Incidence of CS was 15.7%, with a prevalence of 7.5/700 cases. Median age was 55.5 years, male/female = 59/51. All pts were WDNETs and 83% were GEP: Carcinoids/pNET= 66%/34%; Midgut/Foregut/ Hindgut= 44%/35.5%/3.3%. Liver involvement was found in 96%: synchronous (42%); metacronous (68%). Primary tumor resection was performed in 67% of midgut and in 33% of foregut. TCS was evident in 92/110 (83.3%), whilst ACS in 2/110 (2.2%). The most common symptoms were flushing/diarrhea/CHD in 72 %/64%/12 % of pts. CgA/NSE/HIAA levels were pathologic in 78%/22%/50%, respectively, mOS was 90 months (range 2-274), 5- and 10-year survival rates were 58% and 43% respectively. Significant difference in mOS was found between male/female 114/90 months; midgut/foregut 114/74 months; carcinoids/pNET 131/74 months (p<0.05). Primary tumor resection may be correlated with survival amelioration. Conclusion: The advanced stage and, in particular, the liver involvement could be the main factor related to the CS appearance. The status of functional or nonfunctional NET could be mostly correlated to tumor load involvement rather than to primary tumor site, which still remains the main prognostic factor. [ABSTRACT FROM AUTHOR]

Introduction: The immunoistochemical (IHC) loss of SDHB expression was reported as a surrogate marker of malignancy in sporadic and familial pheocromocytomas/paragangliomas. SDHB loss is supposed to be tumorigenic (activation hypoxia signals). Aim(s): SDHB levels evaluation in advanced midgut carcinoids and its potential role as a prognostic marker. Materials and methods: Thirty-one midgut carcinoids were identified: 78% males, 22% females, median age 55.5 yrs (range 19-75). All pts were NET G1, stage IV synchronous liver metastases. 25/31 underwent surgical primary resection. 70% were up front treated with somatostatin analogues. SDHB and MIB1 expression were carried out in 19 primary tumors (T) and in 19 liver metastasis (M). In eleven pts, SDHB and MIB1 were tested both in T and in M. SDHB was evaluated with a semiquantitative scale considering staining intensity score 1 (low), 2 (high). Results: SDHB (2+), with a clear cytoplasmatic mitochondrial reactivity, was found in 77% (14/19) T, whilst loss of SDHB expression (1+) was detected in 90% (17/19) M. In eleven pts, the combined analysis (T+M), confirmed a loss of SDHB expression in 82% (9/11) M, compared to 18% (2/11) T. These data are inversely proportional to Mib-1% value that, on the contrary, increased in metastatic lesions: median (T) MIB1:0.7% v. median (M) MIB1: 1.54%. Conclusion: Our findings support a correlation between a loss of SDHB expression, increase of MIB1 and malignancy in advanced midgut carcinoids. A prospective evaluation is mandatory to clarify a possible correlation wth survival. [ABSTRACT FROM AUTHOR]

In this preplanned sub-analysis, a patient-relevant endpoint of health-related quality of life (HRQOL) deterioration-free survival (QFS) was evaluated in relation to the typically used clinical endpoint, progression-free survival (PFS). QFS was reported as (1) median QFS time in months and (2) QFS rates (ie, percentage of patients who had deteriorated at 6 and 12 months). Median QFS and QFS rates were qualitatively compared with median PFS and PFS rates, respectively. [Extracted from the article]