Effects of somatostatin analogues on muscle sympathetic nerve activity in acromegaly

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Acromegaly is associated with increased cancer risk: A survey in Italy

It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 \uc2\ub1 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 women and 52 men. The SIRs for all cancers was significantly increased compared to the general Italian population (expected: 88, SIR 1.41; 95% CI, 1.18-1.68, P < 0.001). In the whole series, we found a significantly increased incidence of colorectal cancer (SIR 1.67; 95% CI, 1.07-2.58, P = 0.022), kidney cancer (SIR 2.87; 95% CI, 1.55-5.34, P < 0.001) and thyroid cancer (SIR 3.99; 95% CI, 2.32-6.87, P < 0.001). The exclusion of 11 cancers occurring before diagnosis of acromegaly (all in women) did not change remarkably the study outcome. In multivariate analysis, the factors significantly associated with an increased risk of malignancy were age and family history of cancer, with a non-significant trend for the estimated duration of acromegaly before diagnosis. In conclusion, we found evidence that acromegaly in Italy is associated with a moderate increase in cancer risk

Water-Mediated ElectroHydrogenation of CO2 at Near-Equilibrium Potential by Carbon Nanotubes/Cerium Dioxide Nanohybrids

The combination of multiwalled carbon nanotubes (MWCNTs) with undoped CeO2 nanoparticles (NPs) is effective for the direct electrocatalytic reduction of CO2 to formic acid (FA) at acidic pH (0.1 M HNO3), at overpotential as low as \u3b7 = 120.02 V (vs RHE) with Faradic efficiency (FE) up to 65%. Exsitu and operando evidence identifies nonstoichiometric Ce4+/3+O2\u2013x reduced sites as essential for the selective CO2 reduction reaction (CO2RR). The MWCNT-mediated electrochemical reduction of the CeO2 NPs offers a definite advantage with respect to the generally adopted thermochemical cycles (800\u20131500 \ub0C) or deep hydrogenation pretreatments, thus presenting an interesting perspective for the engineering of CeO2 electrocatalysts

Cerium Oxide Nanoparticles Absorption through Intact and Damaged Human Skin

Cerium oxide (CeO2) nanoparticles (NPs) are used in polishing products and absorbents, as promoters in wound healing, and as organopesticide decontaminants. While systemic bioaccumulation and organ toxicity has been described after inhalation, data on CeO2 NPs’ transdermal permeation are lacking. Our study was an in vitro investigation of the permeation of 17-nm CeO2 NPs dispersed in synthetic sweat (1 g L−1) using excised human skin on Franz cells. Experiments were performed using intact and needle-abraded skin, separately. The average amount of Ce into intact and damaged skin samples was 3.64 ± 0.15 and 7.07 ± 0.78 µg cm−2, respectively (mean ± SD, p = 0.04). Ce concentration in the receiving solution was 2.0 ± 0.4 and 3.3 ± 0.7 ng cm−2 after 24 h (p = 0.008). The Ce content was higher in dermal layers of damaged skin compared to intact skin (2.93 ± 0.71 µg cm−2 and 0.39 ± 0.16 µg cm−2, respectively; p = 0.004). Our data showed a very low dermal absorption and transdermal permeation of cerium, providing a first indication of Ce skin uptake due to contact with CeO2

Permeation of platinum and rhodium nanoparticles through intact and damaged human skin

The aim of the study was to evaluate percutaneous penetration of platinum and rhodium nanoparticles (PtNPs: 5.8 \ub1 0.9 nm, RhNPs: 5.3 \ub1 1.9 nm) through human skin. Salts compounds of these metals are sensitizers and some also carcinogenic agents. In vitro permeation experiments were performed using Franz diffusion cells with intact and damaged skin. PtNPs and RhNPs, stabilized with polyvinylpyrrolidone, were synthesized by reduction of Na2PtCl6 and RhCl3\ub73H2O respectively. Suspensions with a concentration of 2.0 g/L of PtNPs and RhNPs were dispersed separately in synthetic sweat at pH 4.5 and applied as donor phases to the outer surface of the skin for 24 h. Measurements of the content of the metals in the receiving solution and in the skin were performed subsequently. Rhodium skin permeation was demonstrated through damaged skin, with a permeation flux of 0.04 \ub1 0.04 \u3bcg cm 122 h 121 and a lag time of 7.9 \ub1 1.1 h, while no traces of platinum were found in receiving solutions. Platinum and rhodium skin-analysis showed significantly higher concentrations of the metals in damaged skin. Rh and Pt applied as NPs can penetrate the skin barrier and Rh can be found in receiving solutions. These experiments pointed out the need for skin contamination prevention, since even a minor injury to the skin barrier can significantly increase penetration

Effects on glucose metabolism of high-dose octreotide LAR in patients with acromegaly inadequately controlled by conventional somatostatin analog therapy

The effects of conventional somatostatin analog (SSA) regimens on glucose homeostasis seem to have minor clinical impact in acromegaly. Recently, we performed a trial showing that high dose octreotide LAR significantly reduces IGF1 in acromegalic patients uncontrolled with conventional SSA doses. In this post-hoc analysis, we evaluated the effects of high doses versus high frequency octreotide LAR on glucose homeostasis (HbA1c, FPG, HOMA-R) in patients with acromegaly enrolled in this trial. After approval by ethical committee and informed consent, 26 patients (14 F, 12 M, median age 51 years, range: 27–78) with uncontrolled acromegaly were randomly treated with high-dose (11 patients: 60 mg/28 days) or high-frequency (15 patients: 30 mg/21 days) octreotide LAR for 6 months. At study entry, seven patients had diabetes mellitus and eight impaired fasting glucose (IFG). After 6-month treatment, glucose metabolism was impaired in six patients (23.1%), improved in two patients (7.7%) and unchanged in the remaining 18 patients (69.2%). Rate of impairment in glucose homeostasis was similar in high doses versus high frequency octreotide LAR (27.3 vs 20.0%; P=0.44). In all six patients with impaired glucose homeostasis, serum IGF1 and/or GH values remained high during treatment, whereas significant decrease (>20%) in serum IGF-I or GH values was observed in 75% of patients in whom glucose homeostasis did not impair (P=0.03). Impairment of glucose homeostasis occurred in 26.7% of patients with pre-existing diabetes mellitus or IFG and in 18.2% of patients with pre-existing normal glucose metabolism (P=0.35). In conclusion, the increase in octreotide LAR doses or frequency did not produce negative effects on glucose metabolism in the majority of patients. In the minority of patients who experienced impairment of glucose homeostasis, this event occurred more frequently in those with persistently uncontrolled acromegaly and it seems to be not dependent on the pre-existing abnormalities of glucose metabolism

Water-Mediated ElectroHydrogenation of CO2 at Near-Equilibrium Potential by Carbon Nanotubes/Cerium Dioxide Nanohybrids

The combination of multiwalled carbon nanotubes (MWCNTs) with undoped CeO2 nanoparticles (NPs) is effective for the direct electrocatalytic reduction of CO2 to formic acid (FA) at acidic pH (0.1 M HNO3), at overpotential as low as \u3b7 = -0.02 V (vs RHE) with Faradic efficiency (FE) up to 65%. Ex situ and operando evidence identifies nonstoichiometric Ce4+/3+O2-x reduced sites as essential for the selective CO2 reduction reaction (CO2RR). The MWCNT-mediated electrochemical reduction of the CeO2 NPs offers a definite advantage with respect to the generally adopted thermochemical cycles (800-1500 \ub0C) or deep hydrogenation pretreatments, thus presenting an interesting perspective for the engineering of CeO2 electrocatalysts

High-dose octreotide LAR in patients with acromegaly inadequately controlled by conventional somatostatin analogue therapy: a randomized, controlled trial

Objective: In acromegaly, 25–50% of patients remain uncontrolled with conventional somatostatin analogue (SA) therapy. Evidence suggests that response may be improved by increasing the dose or frequency of administration of SAs. This study evaluated the efficacy and safety of octreotide LAR administered at a high dose or high frequency in patients with acromegaly. Methods: This was a 24-week prospective, multicenter, randomized, open-label trial in patients with active acromegaly despite ≥6 months’ conventional maximal-dose SA therapy. Patients had baseline GH>2.0 μg/l, elevated IGF-I for age/sex-matched controls and had a ≥50% reduction in GH during previous SA treatment. Patients were randomized to receive high-dose (60 mg/28 d; n=11) or high-frequency (30 mg/21 d; n=15) octreotide LAR for 24 weeks. The primary endpoint was change from baseline in GH and IGF-I at week 24. Secondary endpoints included IGF-I normalization, tumor shrinkage, safety and tolerability. Results: In the high-dose group only, a significant change from baseline was seen for mean GH (−28%; P=0.046) and IGF-I (−27%; P=0.023). In the high-frequency group, changes from baseline in mean GH (+6.4%) and IGF-I (−4.7%) were not statistically significant. Significantly more patients in the high-dose group achieved a reduction in IGF-I at week 24 than those in the high-frequency group (91 vs 53%; P<0.05). IGF-I normalization or GH<2 μg/l occurred with only the high-dose regimen (IGF-I 36 vs 0%, P=0.022; GH 27 vs 0%, P=0.06). The proportion of patients experiencing tumor shrinkage was similar in the high-frequency and high-dose groups (14 vs 11%). Both regimens were well tolerated. Conclusion: High-dose octreotide LAR (60 mg/28 d) is effective and well tolerated in patients with active acromegaly inadequately controlled with conventional SA therapy. These results suggest that in selected patients uncontrolled on conventional doses of SAs, high-dose octreotide LAR should be tried before switching to other treatment modalities

High-dose and high-frequency lanreotide autogel in acromegaly: A randomized, multicenter study

Context: Increase in drug frequency or dose is recommended for acromegaly patients with partial response to long-acting somatostatin receptor ligands (SRLs). However, the efficacy and safety data with lanreotide (LAN) Autogel (LAN-ATG) at high dose (HD) or high frequency (HF) are still scanty. Objective: To evaluate the biochemical efficacy and safety of HF and HD LAN-ATG in patients with active acromegaly. Design: Twenty-four-week prospective, multicenter, randomized, open-label trial. Patients and Interventions: Thirty patients with active acromegaly, partial responders to SRLs, were randomized to HF (120 mg/21 days; 15 patients) or HD (180 mg/28 days; 15 patients) LAN-ATG. Outcomes: Normalization of serum insulin-like growth factor-I (IGF-I) and reduction in random growth hormone (GH) values ,1.0 mg/L, reduction in serum IGF-I and GH from baseline, differences in biochemical response between HF and HD LAN-ATG, adverse events. Results: IGF-I decreased significantly (P = 0.007) during the 24-week treatment, with greater decrease in HD (P = 0.03) vs HF group (P = 0.08). Normalization in IGF-I values occurred in 27.6% of patients (P = 0.016 vs baseline), without a significant difference between HF and HD groups (P = 0.59). The decrease in serumIGF-I significantly correlated with serumLAN values (P = 0.04), and normalization of IGF-I was predicted by baseline IGF-I values (P = 0.02). Serum GH values did not change significantly (P = 0.22). Overall, 19 patients (63.3%) experienced adverse events, all being mild to moderate and transient, without differences between the two therapeutic arms. Conclusion: HF and HD LAN-ATG regimens are effective in normalizing IGF-I values in about onethird of patients with active acromegaly inadequately controlled by long-term conventional SRLs therapy