This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.

Objective: Despite the contribution of national registries and population-based reports, data concerning the epidemiology of acromegaly is scanty. In addition, the role of the environmental context has not been investigated. Design: Epidemiology of acromegaly was studied in the province of Messina (Sicily, Italy), focusing on the influence of environmental factors. Methods: Four zones, characterized by different degrees of exposition to environmental toxins due to industrial pollution, were identified in the province: area A (76 338 inhabitants), area B (287 328 inhabitants), area C (243 381 inhabitants), and area D (47 554 inhabitants) at low, middle-low, middle, and high industrial density respectively. We identified all acromegalics who were born and resided in the province of Messina, among patients either referred to our endocrine unit or referred elsewhere but recorded in the archives of the provincial healthcare agency.

The ligand/receptor hepatocyte growth factor (HGF)/c-met signaling system promotes cellular growth and angiogenesis through PI3K/phosphor-Akt and STAT3/phosphor-STAT3 downstream effectors. In this study, we have evaluated the expression of molecules of the HGF/c-met pathway in pituitary adenomas (PA). The expression of HGF, c-met, PI3K (p85αsubunit) pAkt, STAT3, and pSTAT3 was analyzed by immunohistochemistry in an archival series of 30 PA (12 non-functioning and 18 functioning; 25 macroadenomas and 5 microadenomas). PAs expressed all six proteins in tumor epithelial cells. The proportion of c-met(+ve) cells was greater than HGF(+ve) cells (49 ± 19 vs 34 ± 17 %, P < 0.01), the pAkt(+ve) cells greater than PI3K(+ve) cells (39 ± 16.0 vs 1.3 ± 0.5 %, P < 0.001), and the STAT3(+ve) cells greater than active pSTAT3(+ve) cells (14 ± 8 vs 7 ± 6 %, P < 0.01). Furthermore, endothelial Akt immunostaining was detected on the vascular surface area of 17 PAs, in macroadenomas more frequently than in microadenomas (82 vs 18 %). The percentage of immunostained endothelial cells was greater in macro than in microadenomas (19 ± 7 and 7 ± 3 %; P < 0.05). In conclusion, HGF and c-met are widely expressed in PA, and correlate with pAkt expression. These data, together with the finding of pAkt immunostaining on microvascular areas related to tumor size, suggest a major role of the pAKT signaling in tumor growth and angiogenesis. There might be practical implications for the targeted therapy of PA.

Genetic variants potentially inducing functional abnormalities of the aryl hydrocarbon receptor (AHR) pathway are associated with a more severe acromegaly, increased pituitary tumor size, and somatostatin analog resistance in patients living in HR areas.

PEGV effectiveness improves when up titration is appropriate. Higher PEGV doses at start and a more rapid up-titration are necessary in patients with obesity and/or IGF-1 > 2.7 × ULN.

Prediction of ischemic cardiovascular events (ICE) in acromegalic patients stratified accordingly with Framingham (FS) and Agatston score (AS). 32 patients with active (group A (0)) and 20 with controlled (group B (0)) acromegaly have been enrolled. During the 5-year follow-up, 19 out of 32 patients in group A (0) reached disease control. At entry, FS and AS, by an eight-slice MDCT scanner, were calculated in all patients. ICE were diagnosed by autopsy, if lethal, and by electrocardiography and/or echocardiography, if non-lethal. Overall, 9.6 % of patients died for lethal ICE. AS >400, but not high FS at entry, was associated with increased risk of lethal ICE. Lethal ICE had occurred in two patients of group A (0) and three of group B (0) (p NS), while a non-lethal ICE had occurred in two cases of the former and in other two of the latter group (p NS). Either FS or AS was correlated with the risk for ICE overall (p < 0.02), but only AS correlated with that of lethal ICE (p < 0.0003). Survival analysis demonstrated reduced life expectancy in patients with high FS (p < 0.02). In acromegalics, AS >400 is associated with increased risk of lethal ICE, while high FS is associated with reduced life expectancy, regardless of disease control.

Context: Hepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome. Objective: To determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment. Design and setting: Multicenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy. Patients: A total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled. Interventions: Clinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping. Results: No differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratioZ1.25; PZ0.04) and the number of concomitant medications, other than SSTa (BZ3.9; PZ0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found. Conclusions: UGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.

In this cohort of acromegalic patients, CRT risk is increased in 677TT MTHFR patients with low plasma folate levels. Smoking, high HbA1c levels, dyslipidaemia and disease activity were also associated with increased CRT risk.