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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]

Purpose: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [Y]DOTA-TATE and [Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter (Y) and a medium-energy beta/gamma emitter (Lu) in patients with metastatic NET refractory to conventional therapy. Methods: A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [Lu]DOTA-TATE (5.55 GBq) and [Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. Results: Administration of tandem [Y]DOTA-TATE and [Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment Conclusion: The results of our study indicates that combined [Y]DOTA-TATE and [Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach. [ABSTRACT FROM AUTHOR]

This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, irinotecan 240 mg m(-2) day 1; q21) or TEGAFOX (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, oxaliplatin 120 mg m(-2) day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3-4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1-55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6-51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12-23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies. [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]