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Milano, Italy

Sala E.,University of Milan | Sala E.,Endocrinology and Diabetology Unit | Ferrante E.,University of Milan | Ferrante E.,Endocrinology and Diabetology Unit | And 20 more authors.
Hormones | Year: 2014

Objective: Transsphenoidal (TNS) surgery remains the primary therapeutic option for GHsecreting pituitary adenomas. The aims of this study were to verify the impact of TNS surgery on treatment of acromegaly before and after identification by a dedicated neurosurgical team and to enumerate diagnostic features of the disease described over three decades. Design: 41 patients (group A) who underwent TNS surgery by a dedicated neurosurgical team (2000- 2008) and 126 patients (group B) operated on by surgeons not specialized in pituitary surgery (1979-1999) were retrospectively analyzed. RESULTS: No significant differences were observed between the two groups in terms of delay of diagnosis, mean basal GH levels and GH nadir values, prevalence of hypopituitarism and hypertension. IGF-I SDS were significantly higher, while prevalence of IGT/diabetes was significantly lower in group B than in group A. Overall remission rate after surgery was 58.5% for group A (75% in microadenomas and 48% in macroadenomas, P=NS) and 37% for group B (P<0.05 vs group A; for microadenomas, 34% vs 75% of group A, P<0.05, for macroadenomas, 36% vs 48% of group A, P=NS). The mean delay of diagnosis was 4.9 and 5.9 years in group A and B, respectively. Conclusions: Our data confirm that a dedicated neurosurgical team is needed in order to improve remission rates in acromegalic patients. No changes in biochemical, clinical and neuroradiological presentation of disease were observed over the last three decades. As the high prevalence of macroadenomas negatively influences surgical cure, earlier diagnosis should be considered as mandatory to achieve a better outcome. Source


Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recombinant therapeutic protein widely used to treat severe neutropenia caused by myelosuppressive drugs in patients with nonmyeloid malignancies. In addition to its role in the regulation of granulopoiesis, treatment with G-CSF is considered the standard approach to mobilize CD34 positive (CD34+) mononuclear cells for reconstituting hemopoietic ability for bone marrow transplantation. An intended biosimilar filgrastim (coded BK0023) was produced in GMP conditions by E.coli fermentation according to an original recombinant process and showed physico-chemical properties and purity profile similar to Neupogen®, a commercial preparation of filgrastim. The aim of the present study was to demonstrate the comparability of BK0023 to Neupogen® in terms of both in vitro biological activities and in vivo toxicology, pharmacokinetics and pharmacodynamics. Cell proliferation and radioligand binding assays were conducted in NFS-60 cells to compare the biological activity and functional interaction with the G-CSF receptor in vitro, while preclinical in vivo studies, including pharmacokinetics and pharmacodynamics after repeated dose were performed in normal and neutropenic rats. A phase I study was carried out in healthy male volunteers treated by multiple-dose subcutaneous administration of BK0023 and Neupogen® to evaluate their pharmacodynamic effects as well as their pharmacokinetic and safety profile and to demonstrate their pharmacodynamic equivalence and pharmacokinetic bioequivalence. The results reported in this work demonstrate that BK0023 is comparable in terms of biological activity, efficacy and safety to Neupogen®. BK0023 has the same pharmacokinetic profile, efficacy and safety as the reference commercial filgrastim Neupogen® and therefore could be further developed to become a convenient option to treat neutropenia in oncological patients. Source


Cicatiello V.,CNR Institute of Neuroscience | Cicatiello V.,Multimedica Group | Apicella I.,CNR Institute of Neuroscience | Tudisco L.,CNR Institute of Neuroscience | And 10 more authors.
Oncotarget | Year: 2015

To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit macrophages migration. iVR1 was able to synergize with irinotecan determining a shrinkage of tumors that became undetectable after three weeks of combined treatment. Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein. Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection. Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts. Source


Yoo S.-A.,Pohang University of Science and Technology | Park J.-H.,Pohang University of Science and Technology | Hwang S.-H.,Pohang University of Science and Technology | Oh S.-M.,Pohang University of Science and Technology | And 11 more authors.
Journal of Immunology | Year: 2015

Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have promigratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. In this study, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with small interfering RNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and neuropilin-1, and upregulating the expression of antiapoptotic molecules, pErk and Bcl2. Knockdown of PlGF transcripts reduced RA-FLS proliferation in a xenotransplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy. Copyright © 2015 by The American Association of Immunologists, Inc. Source


Toini A.,Endocrinology and Diabetology Unit | Toini A.,University of Milan | Dolci A.,University of Milan | Dolci A.,Multimedica Group | And 16 more authors.
European Journal of Endocrinology | Year: 2015

Context: Pituitary incidentalomas (PIs) are commonly encountered in clinical practice. The management of these asymptomatic pituitary lesions is still controversial. Systematic screening for subclinical or mild ACTH-dependent hypercortisolism (AH) is not presently recommended, due to the limited data available thus far on the epidemiological and clinical relevance of this condition in patients with PIs. As subclinical hypercortisolism (SH) was considered to be associated with chronic complications of overt cortisol excess, such as hypertension, diabetes, and osteoporosis, this disorder should be diagnosed at the early stage. Objective: The objective of this study was to evaluate the prevalence of hypercortisolism in a population of subjects with PIs. Design, subjects, and methods: A total of 68 consecutive patients (48 females and 20 males, aged 18-82 years) without clinically overt hypercortisolism, who were referred for evaluation of PIs between January 2010 and March 2013, were prospectively investigated for AH. Pituitary hypercortisolism was diagnosed in the presence of cortisol >50 nmol/l after 1 mg dexamethasone suppression test, non-suppressed ACTH, and the additional finding of one of the following: urinary free cortisol (UFC) >193 nmol/24 h, and midnight serum and salivary cortisol levels >207 and 2.8 nmol/l respectively. Results: Among patients with PIs, we found a 7.3% rate of pituitary hypercortisolism diagnosed with biochemical criteria and a 4.4% rate of histologically confirmed AH. Conclusions: Subclinical or mild hypercortisolism may be more common than generally perceived in patients with PIs. © 2015 European Society of Endocrinology. Source

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