High feasibility and antileukemic efficacy of fludarabine, cytarabine, and idarubicin (FLAI) induction followed by risk-oriented consolidation: A critical review of a 10-year, single-center experience in younger, non M3 AML patients

About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m2 (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara-C. Our double induction strategy significantly differs from described fludarabine-containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara-C consolidation is administrated at the reduced cumulative dose of 8 g/m2 per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G-CSF (FLAG-Ida) arm, and, despite higher anti-leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30-day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3-year disease-free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI-5/Ara-C + Ida double induction followed by risk-oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755\u2013762, 2016. \ua9 2016 Wiley Periodicals, Inc

The third-party trademark use

L’obiettivo di questo lavoro è cercare di individuare, alla luce degli ultimi orientamenti giurisprudenziali e dottrinali, quando, e con quali limiti, possa essere considerato lecito l'uso di un marchio altrui e, nel contempo, quanto ampio possa essere l'ambito di protezione per i titolari di un marchio, nel tentativo di contemperare gli interessi, anche dei consumatori, di una libera concorrenza nel mercato e quelli economici delle imprese

Seasonal prediction of mountain snow resources: an application in the Alps

The development of seasonal projections of the state of snow resources in the Alps is of particular interest for the management of water resources and tourism. We present the progress in the development of a modelling chain based on the seasonal forecast variables produced by seasonal prediction systems of the Copernicus Climate Change Service (C3S). Seasonal forecast variables of precipitation, near-surface air temperature, radiative fluxes, wind and humidity are downscaled at three selected instrumented sites, close to five Alpine glaciers, in the North-Western Italian Alps, eventually bias-corrected and finally used as input for a physically-based multi-layer snowpack model (Snowpack; Lehning et al. 2012). A stochastic downscaling procedure is used for precipitation data in order to allow an estimate of uncertainties linked to small-scale variability in the forcing. We evaluate uncertainties affecting the skill of the modelling chain in predicting the evolution of the winter snowpack in hindcast simulations, comparing against historical data of snow depth and snow water equivalent by automatic stations in the study areas. The chain is tested considering seasonal forecast starting dates of November 1st, which are relevant for the snowpack processes. The sensitivity of the snow model to the accuracy of the input variables is discussed

Multifunctional downshifting polymeric coatings for highly stable and efficient organic dye-sensitized solar cells

A new multifunctional polymeric coating for photovoltaic cells is presented in this work, incorporating light-management, UV-protection and easy-cleaning capabilities. Such coating consists of a new photocrosslinkable fluorinated polymer doped with a luminescent Europium complex that acts as luminescent down-shifting (LDS) material to convert UV photons into visible light. By applying this coating onto Ruthenium-free organic dye-sensitized solar cells (DSSCs), a 70% relative increase in power conversion efficiency could be achieved compared with control uncoated devices. To evaluate the photostabilizing effect of the new fluoropolymeric coating, long-term (> 2000 h) weathering tests in real outdoor conditions were conducted on these systems. DSSC devices incorporating the new multifunctional coating exhibited excellent outdoor stability and fully preserved their initial device performance (see Figure below). This behavior was attributed to the combined action of the luminescent material that acts as UVscreen and the highly photostable, hydrophobic fluoropolymeric carrier that further prevents photochemical and physical degradation of the solar cell components. The general approach presented in this study to simultaneously improve performance and outdoor stability of organic DSSC devices may be readily extended to a large variety of sensitizer/luminophore combinations with appropriate spectral match, thus ultimately enabling the fabrication of highly efficient and stable organic DSSCs in an easy and versatile fashion

Standardized EEG analysis to reduce the uncertainty of outcome prognostication after cardiac arrest

Purpose Post-resuscitation guidelines recommend a multimodal algorithm for outcome prediction after cardiac arrest (CA). We aimed at evaluating the prevalence of indeterminate prognosis after application of this algorithm and providing a strategy for improving prognostication in this population. Methods We examined a prospective cohort of comatose CA patients (n = 485) in whom the ERC/ESICM algorithm was applied. In patients with an indeterminate outcome, prognostication was investigated using standardized EEG classification (benign, malignant, highly malignant) and serum neuron-specific enolase (NSE). Neurological recovery at 3 months was dichotomized as good (Cerebral Performance Categories [CPC] 1-2) vs. poor (CPC 3-5). Results Using the ERC/ESICM algorithm, 155 (32%) patients were prognosticated with poor outcome; all died at 3 months. Among the remaining 330 (68%) patients with an indeterminate outcome, the majority (212/330; 64%) showed good recovery. In this patient subgroup, absence of a highly malignant EEG by day 3 had 99.5 [97.4-99.9] % sensitivity for good recovery, which was superior to NSE < 33 mu g/L (84.9 [79.3-89.4] % when used alone; 84.4 [78.8-89] % when combined with EEG, both p < 0.001). Highly malignant EEG had equal specificity (99.5 [97.4-99.9] %) but higher sensitivity than NSE for poor recovery. Further analysis of the discriminative power of outcome predictors revealed limited value of NSE over EEG. Conclusions In the majority of comatose CA patients, the outcome remains indeterminate after application of ERC/ESICM prognostication algorithm. Standardized EEG background analysis enables accurate prediction of both good and poor recovery, thereby greatly reducing uncertainty about coma prognostication in this patient population

How to tailor recommendations on the treatment of multi-drug resistant Gram-negative infections at country level integrating antibiotic stewardship principles within the GRADE-ADOLOPMENT framework

: Promoting the optimal use of antibiotics through evidence-based recommendations should be regarded as a crucial step in the global fight against antimicrobial resistance. Within this scope, several guidelines and guidance documents for antibiotic therapy have been published in recent years. All documents underline the limitations of existing evidence and remark on the need for tailoring recommendations at the national level, based on local epidemiology, availability of diagnostics and drugs, and antimicrobial stewardship principles. The GRADE-ADOLOPMENT methodology is an evidence-based methodology that allows the adoption, adaptation, and update of existing recommendations to specific settings without performing de novo systematic reviews and grading of the evidence. However, procedures to integrate this evidence with stewardship principles, countries' surveillance data, and capacity in terms of diagnostics and antibiotics' availability have never been defined. This Personal View provides the first example of a country's calibration of international evidence-based guidance documents on treating infections caused by multidrug-resistant bacteria. A panel of experts convened by the Italian Medicine Agency (AIFA) used the GRADE methodology for systematically extracting and evaluating 100 recommendations on the treatment of infections due to multidrug-resistant Gram-negative bacteria from 11 guidance documents and 24 systematic reviews. The ADOLOPMENT procedure was used to calibrate the existing recommendations to the national context, leading to the adoption of 64, the adaptation of 27, and the rejection of nine recommendations. We discuss the technical details of the GRADE-ADOLOPMENT application, the calibration process, and the human resources required to support such an effort. This Personal View also covers the challenges of integrating antibiotic stewardship principles in evidence-based recommendations for treating infections with very limited therapeutic and diagnostic options. The details presented here could support the easy transferability of the methodology to other countries and settings, particularly where the incidence of antibiotic-resistant infections is high

MiR-9 and miR-200 regulate PDGFRβ-mediated endothelial differentiation of tumor cells in triple negative breast cancer

Organization of cancer cells into endothelial-like cell lined structures to support neovascularization and fuel solid tumors is a hallmark of progression and poor outcome. In triple negative breast cancer (TNBC), PDGFRβ has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of microRNAs as therapeutic approach to inhibit PDGFRβ–mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200. In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted or inhibited, respectively, the formation of vascular-like structures in vitro. Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFRβ signaling, promoted significant vascular-sprouting of TNBC cells in part by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFRβ through the direct suppression of ZEB1. Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA- MB-231 stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, immunohistochemistry and immunofluorescence analyses in TNBC specimens indicated that PDGFRβ expression marked tumor cells engaged in vascular lacunae. In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFRβ, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR- 200 to inhibit the process of vascular lacunae formation in TNBC