Il Nilotinib nella terapia di prima linea della leucemia mieloide cronica

Background: Nilotinib is a potent and selective BCR-ABL inhibitor. The phase 3 ENESTnd trial demonstrated superior efficacy nilotinib vs imatinib, with higher and faster molecular responses. After 24 months, the rates of progression to accelerated-blastic phase (ABP) were 0.7% and 1.1% with nilotinib 300mg and 400mg BID, respectively, significantly lower compared to imatinib (4.2%). Nilotinib has been approved for the frontline treatment of Ph+ CML. With imatinib 400mg (IRIS trial), the rate of any event and of progression to ABP were higher during the first 3 years. Consequently, a confirmation of the durability of responses to nilotinib beyond 3 years is extremely important. Aims: To evaluate the response and the outcome of patients treated for 3 years with nilotinib 400mg BID as frontline therapy. Methods: A multicentre phase 2 trial was conducted by the GIMEMA CML WP (ClinicalTrials.gov.NCT00481052). Minimum 36-month follow-up data for all patients will be presented. Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio <0,1%IS; Complete Molecular Response (CMR): undetectable transcript levels with ≥10,000 ABL transcripts; failures: according to the revised ELN recommendations; events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-to-treat principle. Results: 73 patients enrolled: median age 51 years; 45% low, 41% intermediate and 14% high Sokal risk. The cumulative incidence of CCgR at 12 months was 100%. CCgR at each milestone: 78%, 96%, 96%, 95%, 92% at 3, 6, 12, 18 and 24 months, respectively. The overall estimated probability of MMR was 97%, while the rates of MMR at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. The overall estimated probability of CMR was 79%, while the rates of CMR at 12 and 24 months were 12% and 27%, respectively. No patient achieving a MMR progressed to AP. Only one patient progressed at 6 months to ABP and subsequently died (high Sokal risk, T315I mutation). Adverse events were mostly grade 1 or 2 and manageable with appropriate dose adaptations. During the first 12 months, the mean daily dose was 600-800mg in 74% of patients. The nilotinib last daily dose was as follows: 800mg in 46 (63%) patients, 600mg in 3 (4%) patients and 400mg in 18 (25%), 6 permanent discontinuations. Detail of discontinuation: 1 patient progressed to ABP; 3 patients had recurrent episodes of amylase and/or lipase increase (no pancreatitis); 1 patient had atrial fibrillation (unrelated to study drug) and 1 patient died after 32 months of mental deterioration and starvation (unrelated to study drug). Two patients are currently on imatinib second-line and 2 on dasatinib third-line. With a median follow-up of 39 months, the estimated probability of overall survival, progression-free survival and failure-free survival was 97%, the estimated probability of event-free survival was 91%. Conclusions: The rate of failures was very low during the first 3 years. Responses remain stable. The high rates of responses achieved during the first 12 months are being translated into optimal outcome for most of patients.

Applicazioni industriali e di ricerca della spettroscopia NIR per la valutazione di indici qualitativi di prodotti alimentari

In the present work qualitative aspects of products that fall outside the classic Italian of food production view will be investigated, except for the apricot, a fruit, however, less studied by the methods considered here. The development of computer systems and the advanced software systems dedicated for statistical processing of data, has permitted the application of advanced technologies including the analysis of niche products. The near-infrared spectroscopic analysis was applied to the chemical industry for over twenty years and, subsequently, was applied in food industry with great success for non-destructive in line and off-line analysis. The work that will be presented below range from the use of spectroscopy for the determination of some rheological indices of ice cream applications to the characterization of the main quality indices of apricots, fresh dates, determination of the production areas of pistachio. Next to the spectroscopy will be illustrated different methods of multivariate analysis for spectra interpretation or for the construction of qualitative models of estimation. The thesis is divided into four separate studies that consider the same number of products. Each one of it is introduced by its own premise and ended with its own bibliography. This studies are preceded by a general discussion on the state of art and the basics of NIR spectroscopy.

1963-1968. Dall'avvento dell'amministrazione di Lyndon B. Johnson al Trattato di Non-Proliferazione. gli Stati Uniti, la Francia, la NATO e l'Europa agli esordi della distensione. Storia di una "non-crisi" transatlantica e della riorganizzazione dell'Alleanza.

The aim of this proposal is to explain the paradigm of the American foreign policy during the Johnson Administration, especially toward Europe, within the NATO framework, and toward URSS, in the context of the détente, just emerged during the decade of the sixties. During that period, after the passing of the J. F. Kennedy, President L. B. Johnson inherited a complex and very high-powered world politics, which wanted to get a new phase off the ground in the transatlantic relations and share the burden of the Cold war with a refractory Europe. Known as the grand design, it was a policy that needed the support of the allies and a clear purpose which appealed to the Europeans. At first, President Johnson detected in the problem of the nuclear sharing the good deal to make with the NATO allies. At the same time, he understood that the United States needed to reassert their leadeship within the new stage of relations with the Soviet Union. Soon, the “transatlantic bargain” became something not so easy to dealt with. The Federal Germany wanted to say a word in the nuclear affairs and, why not, put the finger on the trigger of the atlantic nuclear weapons. URSS, on the other hand, wanted to keep Germany down. The other allies did not want to share the onus of the defense of Europe, at most the responsability for the use of the weapons and, at least, to participate in the decision-making process. France, which wanted to detach herself from the policy of the United States and regained a world role, added difficulties to the manage of this course of action. Through the years of the Johnson’s office, the divergences of the policies placed by his advisers to gain the goal put the American foreign policy in deep water. The withdrawal of France from the organization but not from the Alliance, give Washington a chance to carry out his goal. The development of a clear-cut disarm policy leaded the Johnson’s administration to the core of the matter. The Non-proliferation Treaty signed in 1968, solved in a business-like fashion the problem with the allies. The question of nuclear sharing faded away with the acceptance of more deep consultative role in the nuclear affairs by the allies, the burden for the defense of Europe became more bearable through the offset agreement with the FRG and a new doctrine, the flexible response, put an end, at least formally, to the taboo of the nuclear age. The Johnson’s grand design proved to be different from the Kennedy’s one, but all things considered, it was more workable. The unpredictable result was a real détente with the Soviet Union, which, we can say, was a merit of President Johnson.

Studio della funzionalità respiratoria in soggetti con sindrome di Turner

The aim of this study is to evaluate the pulmonary function in subjects with diagnosis of Turner Syndrome, in charge at the Syndromology Ward of the Paediatric Clinic of S.Orsola-Malpighi hospital. There are very few datas about lung function in patients with Turner syndrome’s genotype and phenotype in medical literature. Since the thorax of these subjects have peculiar anatomic shape (as “shield” or “overturned triangle”), we presupposed that these subjects could have also a peculiar respiratory function. Moreover we look for the possibility of correlation between pulmonary function and estroprogestinic replacement therapy and/or growth hormone (GH) replacement therapy. Material and methods: we studied 48 patients, with diagnosis of Turner Syndrome; they all made spirometry voluntarily and, when capable, also plethismografy. Results: - the parametres of pulmonary function are a little higher of the predicted values for age and sex but they are a little lower if they're corrected for each patient’s ideal high and weight: so we can conclude that in Turner Syndrme subjects pulmonary function is normal; -there’s not a statistically significant correlation between pulmonary function and GH therapy; -there’s not a statistically significant correlation between GH therapy’s length and pulmonary function except for Total Lung Capacity which increases with the number of years of GH therapy; - there’s not a statistically significant correlation between pulmonary function and estroprogestinic replacement herapy.

Studio dei metodi di valutazione della pericolosità associata ai "debris flow" in ambiente alpino

The present work concerns with the study of debris flows and, in particular, with the related hazard in the Alpine Environment. During the last years several methodologies have been developed to evaluate hazard associated to such a complex phenomenon, whose velocity, impacting force and inappropriate temporal prediction are responsible of the related high hazard level. This research focuses its attention on the depositional phase of debris flows through the application of a numerical model (DFlowz), and on hazard evaluation related to watersheds morphometric, morphological and geological characterization. The main aims are to test the validity of DFlowz simulations and assess sources of errors in order to understand how the empirical uncertainties influence the predictions; on the other side the research concerns with the possibility of performing hazard analysis starting from the identification of susceptible debris flow catchments and definition of their activity level. 25 well documented debris flow events have been back analyzed with the model DFlowz (Berti and Simoni, 2007): derived form the implementation of the empirical relations between event volume and planimetric and cross section inundated areas, the code allows to delineate areas affected by an event by taking into account information about volume, preferential flow path and digital elevation model (DEM) of fan area. The analysis uses an objective methodology for evaluating the accuracy of the prediction and involve the calibration of the model based on factors describing the uncertainty associated to the semi empirical relationships. The general assumptions on which the model is based have been verified although the predictive capabilities are influenced by the uncertainties of the empirical scaling relationships, which have to be necessarily taken into account and depend mostly on errors concerning deposited volume estimation. In addition, in order to test prediction capabilities of physical-based models, some events have been simulated through the use of RAMMS (RApid Mass MovementS). The model, which has been developed by the Swiss Federal Institute for Forest, Snow and Landscape Research (WSL) in Birmensdorf and the Swiss Federal Institute for Snow and Avalanche Research (SLF) takes into account a one-phase approach based on Voellmy rheology (Voellmy, 1955; Salm et al., 1990). The input file combines the total volume of the debris flow located in a release area with a mean depth. The model predicts the affected area, the maximum depth and the flow velocity in each cell of the input DTM. Relatively to hazard analysis related to watersheds characterization, the database collected by the Alto Adige Province represents an opportunity to examine debris-flow sediment dynamics at the regional scale and analyze lithologic controls. With the aim of advancing current understandings about debris flow, this study focuses on 82 events in order to characterize the topographic conditions associated with their initiation , transportation and deposition, seasonal patterns of occurrence and examine the role played by bedrock geology on sediment transfer.

L’edilizia residenziale popolare pubblica di Milano nei primi tre decenni del XX secolo

Lo stabilirsi di nuovi criteri abitativi nella Lombardia di fine Ottocento e dei primi decenni del XX secolo, ha fatto emergere, nel vasto tema dell’abitazione popolare, componenti meritevoli di essere analizzate nelle loro differenti declinazioni. Nella ricerca sono quindi stati analizzati: gli studi tipologici di quel periodo, l’impiego di differenti materiali edili, il linguaggio compositivo, le interrelazioni dei manufatti architettonici con il contesto urbano, l’apporto delle cooperative alla realizzazione degli interventi, lo sviluppo e l’impiego della prefabbricazione e la tutela, valorizzazione e trasformazione del patrimonio edilizio esistente. Presupposto di quest’analisi è stata l’ampia ricostruzione storiografica delle fasi germinali e del dibattito ottocentesco sulla casa operaia e popolare, che hanno condotto (all’inizio del novecento) alla creazione dell’Istituto Autonomo Case Popolari od Economiche di Milano. Sono state enucleate anche le principali caratteristiche formali e tecnologiche dell’edilizia residenziale popolare milanese di quel periodo. La ricerca inoltre è stata finalizzata alla definizione di strategie gestionali del patrimonio storiografico esistente (documentario, iconografico e bibliografico) rivolto a una migliore fruizione dei beni architettonici considerati e a supporto di conoscenza per la sua valorizzazione, tutela, trasformazione e recupero. Per questa ragione l’analisi delle fonti documentarie e archivistiche, si è basata sull’indagine di alcuni progetti originari (quasi mai in possesso dell’Aler e parzialmente dispersi in archivi comunali e privati). La ricostruzione del patrimonio storico-visuale dell’edilizia residenziale d’inizio secolo, ha dedicato attenzione anche agli aspetti architettonici e di vita degli spazi comuni, dello stato di conservazione e delle trasformazioni delle strutture originarie. Accanto a questi filoni di indagine è stata sviluppata un’attenta analisi della letteratura esistente, studiando sia la pubblicistica sia la letteratura scientifica coeva alle costruzione e gli studi, anche di grande portata, compiuti nei decenni successivi. L’indagine propone anche una periodizzazione delle fasi realizzative dell’edilizia popolare, relazionandole a contesti architettonici e storiografici di più ampio respiro. Si sono indagate, ad esempio, le ragioni del costituirsi di una forte interdipendenza delle varie realtà sociali urbane e si sono posti a confronto gli elementi prettamente architettonici con il quadro tematico connesso al concetto di modernità. La ricerca non ha neppure trascurato gli studi chiarificatori delle istanze sociali, che hanno trovato particolari riferimenti nelle analisi scientifiche (pubblicate su riviste specialistiche, in qualche caso di difficile reperibilità) o nelle ricerche commissionate dal Comune di Milano nel primo decennio del XX secolo. Grande importanza è stata riposta anche nell’analisi delle delibere comunali (verificate e documentate in modo organico e complessivo) che, a partire dal 1861, trattano il tema dell’impegno pubblico nella realizzazione di edilizia operaia a basso costo.

I Responsori della Settimana Santa del Ms 443 dell'Accademia Filarmonica di Bologna

La tesi è dedicata allo studio dei Responsori della Settimana Santa contenuti nel volume manoscritto Musica per la Settimana Santa conservato presso l’Accademia Filarmonica di di Bologna: (I-Baf FA1 443), che la tradizione storiografica fino ad alcuni anni fa attribuiva interamente ad Alessandro Scarlatti. Il volume raccoglie un ampio repertorio di brani musicali appartenenti a generi destinati ai periodi liturgici della Quaresima e del Triduo pasquale. Il lavoro è dedicato ai responsori considerati innanzitutto come progetto compositivo a sé stante e come fonte di rilievo nell’ambito della musica sacra e del genere responsoriale in particolare. Lo studio è suddiviso in due parti: la prima riguarda le ricerche codicologiche sul volume, del quale si riassume anche la storia con nuove ricerche sulla sua acquisizione da parte dell’Accademia Filarmonica. Viene poi esaminato il contesto storico-liturgico della musica per la Settimana Santa e si prendono in esame gli aspetti stilistici del repertorio responsoriale polifonico italiano dalla metà del ‘500 allla prima metà del ’700, in particolare nell’ambito del cosiddetto «stile osservato» del tempo. Nel terzo ed ultimo capitolo della prima parte vengono analizzati nella forma e nello stile i responsori del Ms 443 di Bologna, tenendo conto della teoria musicale e delle consuetudini contrappuntistiche in vigore tra la fine del sec. XVII e l’inizio del sec. XVIII. Nelle rispettive appendici ai capitoli si dànno le Tavole esplicative, con dati di natura codicologica, tecnico-musicale e testuale liturgica e gli elenchi dettagliati delle fonti responsoriali polifoniche rintracciate, manoscritte e a stampa. La seconda parte del lavoro presenta l’edizione critica della musica, con annessa la sua riproduzione in facsimile su CD. Nell’apparato critico la sezione dei Testi restituisce l’edizione filologica dei testi liturgici intonati.