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Janne P.A.,Belfer Institute for Applied Cancer Science | Shaw A.T.,Massachusetts General Hospital | Pereira J.R.,Instituto Brasileiro Of Cancerologia Toracica | Jeannin G.,Service de pneumologie | And 8 more authors.
The Lancet Oncology | Year: 2013

Background: No targeted therapies are available for KRAS-mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS-mutant NSCLC. Methods: Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB-IV KRAS-mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0-1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m2 on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov, number NCT00890825. Findings: Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS-mutation positive. Median overall survival was 9·4 months (6·8-13·6) in the selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in the placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6-6·4) in the selumetinib group and 2·1 months (95% CI 1·4-3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3-4 adverse events were neutropenia (29 [67%] of 43 patients in the selumetinib group vs 23 [55%] of 42 patients in the placebo group), febrile neutropenia (eight [18%] of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one [2%] of 44 patients in the selumetinib group vs five [12%] of 42 in the placebo group), and asthenia (four [9%] of 44 patients in the selumetinib group vs none in the placebo group). Interpretation: Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS-mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS-mutant NSCLC. Funding: AstraZeneca. © 2013 Elsevier Ltd.

Reboldi G.,University of Perugia | Gentile G.,University of Perugia | Angeli F.,Hospital S Maria della Misericordia | Verdecchia P.,Hospital of Assisi
Current Atherosclerosis Reports | Year: 2011

Diabetes and its micro- and macrovascular complications represent a worldwide epidemic that will place an enormous financial burden on poorer countries in the years to come. In patients with diabetes and hypertension, the main determinant of the cardiovascular and renal benefits of antihypertensive drugs is the blood pressure (BP) level achieved under treatment. Quite recently, the paradigm of a BP target <130/80 mm Hg in these patients has been questioned by a number of trials, including data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure-lowering arm and from the diabetic cohort of International Verapamil SR-Trandolapril Study (INVEST). At the same time, even if the key role of BP control is unquestionable, a growing number of published trials suggest that different antihypertensive combinations may offer specific cardio-, vasculo-, and renoprotective advantages that go beyond BP reduction per se. The present review focuses on the most recent and important literature that explored the "optimal" antihypertensive therapy in patients with type 2 diabetes and concomitant hypertension, and it discusses in detail the various areas of uncertainty, including the specific renoprotective effects of renin-angiotensin system blocking agents and the long-term effects of angiotensin-converting enzyme/angiotensin receptor blocker combinations on the progression of diabetic nephropathy. © Springer Science+Business Media, LLC 2011.

Sepe V.,University of Naples Federico II | Distrutti E.,Hospital S Maria della Misericordia | Limongelli V.,University of Naples Federico II | Limongelli V.,University of Lugano | And 2 more authors.
Future Medicinal Chemistry | Year: 2015

Bile acids (BAs) are experiencing a new life. Next to their ancestral roles in lipid digestion and solubilization, BAs are today recognized signaling molecules involved in many physiological functions. These signaling pathways involve the activation of metabolic nuclear receptors, mainly the BA sensor FXR, and the dedicated membrane G protein-coupled receptor, GPBAR1 (TGR5). As a consequence, the discovery of GPBAR1/FXR selective or dual modulators represents an important answer to the urgent demand of new pharmacological opportunity for several human diseases including dyslipidemia, cholestasis, nonalcoholic steatohepatitis, Type 2 diabetes and inflammation. Targeted oriented discovery of natural compounds and medicinal chemistry manipulation have allowed the development of promising drug candidates. © 2015 Future Science Ltd.

Reboldi G.,University of Perugia | Gentile G.,University of Perugia | Manfreda V.M.,Nephrology and Dialysis Unit | Angeli F.,Hospital S Maria della Misericordia | Verdecchia P.,Hospital of Assisi
Current Cardiology Reports | Year: 2012

Blood pressure (BP) targets in diabetic patients stills represent the object of a major debate, fueled by the recent publication of post hoc observational analyses of the INVEST and the ONTARGET trials, suggesting an increased risk of cardiovascular events with tighter control, the J-curve effect, and by the results of the ACCORD trial, showing no improvements in the composite primary outcome of nonfatal myocardial infarction, stroke, or cardiovascular death in the intensive BP-lowering arm (<120/80 mmHg). In the present review, we focus on existing evidence about different BP targets in diabetic subjects and we present the results of our recent meta-analysis, showing that tight BP control may significantly reduce the risk of stroke in these patients without increasing the risk of myocardial infarction. Therapeutic inertia (leaving diabetic patients with BP values of 140/90 mmHg or higher) should be avoided at all costs, as this would lead to an unacceptable toll in terms of human lives, suffering, and socioeconomic costs. © 2011 Springer Science+Business Media, LLC.

Angeli F.,Hospital S Maria della Misericordia
Obstetrics and Gynecology | Year: 2010

Objective: High white blood cell and neutrophil counts identify patients at increased cardiovascular risk in various clinical settings. However, the prognostic value of white blood cell and neutrophil counts in hypertensive postmenopausal women is unknown. We tested the independent prognostic value of total white blood cell and neutrophil counts for cardiovascular events in hypertensive postmenopausal women. Methods: We examined 298 initially untreated postmenopausal women with essential hypertension who were part of Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA). Mean duration of follow-up was 8 years (range 1-20 years). Treatment was tailored to each individual. Results: Mean age at entry was 59 years. Diabetic women comprised 9.1% of the group, and current smokers comprised 17.5% of the group. During follow-up, 31 new major cardiovascular events occurred. In univariable analyses, age, diabetes, serum creatinine, blood pressure, left ventricular hypertrophy, and neutrophil count showed an association with the risk of events (all P<.05). In a multivariable Cox analysis, after adjustment for traditional cardiovascular risk factors, for each 1.25×10 (1 standard deviation) increase in neutrophil count there was a 67% higher risk of cardiovascular events (hazard ratio 1.67, 95% confidence interval 1.32-2.07; P<.001). Furthermore, neutrophil count showed robust incremental predictive value for cardiovascular events, in addition to traditional risk factors. Total white blood cell count did not show any association with cardiovascular events. Conclusion: A high peripheral neutrophil count identifies postmenopausal hypertensive women at increased risk of cardiovascular disease. Such relation appears to be independent of traditional risk factors. © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.

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