Factors predicting mortality after tips for refractory ascites: a single center experience

Introduction: Transjugular intrahepatic porto-systemic shunt (TIPS) is an accepted indication for treating refractory ascites. Different models have been proposed for the prediction of survival after TIPS; aim of present study was to evaluate the factors associated with mortality after TIPS for refractory ascites. Methods: Seventy-three consecutive patients undergoing a TIPS for refractory ascites in our centre between 2003 and 2008, were prospectively recorded in a database ad were the subject of the study. Mean follow-up was 17±2 months. Forty patients were awaiting liver transplantation (LT) and 12 (16.4%) underwent LT during follow-up. Results: Mean MELD at the moment of TIPS was 15.7±5.3. Overall mortality was 23.3% (n=17) with a mean survival after TIPS of 17±14 months. MELD score (B=0.161, p=0.042), AST (B= 0.020, p=0.090) and pre-TIPS HVPG (B=0.016, p=0.093) were independent predictors of overall mortality. On multivariate analysis MELD (B=0.419, p=0.018) and pre-TIPS HVPG (B=0.223, p=0.060) independently predicted 1 year survival. Patients were stratified into categories of death risk, using ROC curves for the variables MELD and HVPG. Patients with MELD<10 had a low probability of death after TIPS (n=6, 16% mortality); patients with HVPG <16 mmHg (n=6) had no mortality. Maximum risk of death was found in patients with MELD score 19 (n=16, 31% mortality) and in those with HVPG 25 mmHg (n=27, 26% mortality). Conclusions: TIPS increases overall survival in patients with refractory ascites. Liver function (assessed by MELD), necroinflammation (AST) and portal hypertension (HVPG) are independent predictors of survival; patients with MELD>19 and HVPG>25 mmHg are at highest risk of death after TIPS

Phytoremediation by poplar: polyphenols polyamines and oxidative damage in the response to heavy metals in in vitro and in hydroponic cultures.

Poplar is considered a good candidate for phytoremediation, but its tolerance to heavy metals has not been fully investigated yet. In the present work, two different culture systems (in vitro and aeroponic/hydroponic) and two different stress tolerant clones of Populus alba (AL22 and Villafranca) were investigated for their total polyphenol and flavonoid content, individual phenolic compounds, polyamine, lipid peroxidation and hydrogen peroxide levels in response to Cu. In AL22 poplar plants cultured in vitro in the presence or absence of 50 μM Cu, total leaves polyphenol and flavonoid content was higher in treated samples than in controls but unaltered in the roots. Equally the same clone, grown under aeroponic conditions and hydroponically treated for 72 h with 100 μM Cu, displayed increased amount of polyphenols and flavonoids in the leaves, in particular chlorogenic acid and quercetin, and no differences in the roots. In exudates from treated roots total polyphenols and flavonoids, in particular catechin and epicatechin, were more abundant than in controls. Polyamine levels show an increase in conjugated putrescine (Put) and spermidine (Spd) was found. In the Villafranca clone, treated with 100 μM Cu for 6, 24 and 72 h, the pattern of polyphenol and flavonoid accumulation was the same as in AL22; in Cu-treated roots these compounds decreased compared with controls while they increased in root exudates. Free polyamine levels rose at 24 and 72 h while only conjugated Put increased at 24 h. Cu-treated Villafranca plants exhibited a higher malondialdehyde production than controls indicative of membrane lipid peroxidation and, therefore, oxidative stress. An in vitro experiment was carried to investigate the antioxidant effect of the polyamine spermidine (Spd). Exogenous Spd, supplied together with 100 μM Cu, reduced the accumulation of polyphenols and flavonoids, MDA and hydrogen peroxide induced by Cu.

Histone deacetylase inhibitors in adult patients with diffuse large b-cell lymphoma relapsed/refractory: a phase II study with Panobinostat

Backgrounds:Treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not eligible to high dose therapy represents an unmet medical need. Panobinostat showed encouraging therapeutic activity in studies conducted in lymphoma cell lines and in vivo in patients with advanced hematologic malignancies.Purpose:FIL-PanAL10 (NCT01523834) is a phase II, prospective multicenter trial of the Fondazione Italiana Linfomi (FIL) to evaluate safety and efficacy of single agent Panobinostat as salvage therapy for R/R DLBCL patients and to evaluate a possible relationships between response and any biological features. Patients and Methods:Patients with R/R DLBCL were included. The treatment plan included 6 induction courses with Panobinostat monotherapy followed by other 6 courses of consolidation. The primary objective was to evaluate Panobinostat activity in terms of overall response (OR); secondary objectives were: CR rate, time to response (TTR), progression-free survival (PFS), safety and feasibility of Panobinostat. We included evaluation of the impact of pharmacogenetics, immunohistochemical patterns and patient’s specific gene expression and mutations as potential predictors of response to Panobinostat as explorative objectives. To this aim a pre-enrollment new tissue biopsy was mandatory. ResultsThirty-five patients, 21 males (60%), were enrolled between June 2011 and March 2014. At the end of induction phase, 7 responses (20%) were observed, including 4 CR (11%), while 28 patients (80%) discontinued treatment due to progressive disease (PD) in 21 (60%) or adverse events in 7 (20%). Median TTR in 9 responders was 2.6 months (range 1.8-12). With a median follow up of 6 months (range 1-34), the estimated 12 months PFS and OS were 27% and 30.5%, respectively. Grade 3-4 thrombocytopenia and neutropenia were the most common toxicities (in 29 (83%) and 12 (34%) patients, respectively. Conclusions The results of this study indicate that Panobinostat might be remarkably active in some patients with R/R DLBCL, showing durable CR

Additive Manufacturing by LPBF and WAAM of metals: correlation between production process, microstructure and mechanical properties

In the most recent years, Additive Manufacturing (AM) has drawn the attention of both academic research and industry, as it might deeply change and improve several industrial sectors. From the material point of view, AM results in a peculiar microstructure that strictly depends on the conditions of the additive process and directly affects mechanical properties. The present PhD research project aimed at investigating the process-microstructure-properties relationship of additively manufactured metal components. Two technologies belonging to the AM family were considered: Laser-based Powder Bed Fusion (LPBF) and Wire-and-Arc Additive Manufacturing (WAAM). The experimental activity was carried out on different metals of industrial interest: a CoCrMo biomedical alloy and an AlSi7Mg0.6 alloy processed by LPBF, an AlMg4.5Mn alloy and an AISI 304L austenitic stainless steel processed by WAAM. In case of LPBF, great attention was paid to the influence that feedstock material and process parameters exert on hardness, morphological and microstructural features of the produced samples. The analyses, targeted at minimizing microstructural defects, lead to process optimization. For heat-treatable LPBF alloys, innovative post-process heat treatments, tailored on the peculiar hierarchical microstructure induced by LPBF, were developed and deeply investigated. Main mechanical properties of as-built and heat-treated alloys were assessed and they were well-correlated to the specific LPBF microstructure. Results showed that, if properly optimized, samples exhibit a good trade-off between strength and ductility yet in the as-built condition. However, tailored heat treatments succeeded in improving the overall performance of the LPBF alloys. Characterization of WAAM alloys, instead, evidenced the microstructural and mechanical anisotropy typical of AM metals. Experiments revealed also an outstanding anisotropy in the elastic modulus of the austenitic stainless-steel that, along with other mechanical properties, was explained on the basis of microstructural analyses.

Plutarch's chemistry of stones and metals: conceptions and explanations. With an appendix on the TheSu XML annotation scheme

This dissertation presents a systematic and analytic overview of most of the information related to stones, minerals, and stone masonry which is found in the corpus of Plutarch of Chaeronea, combined with most of the information on metals and metalworking which is connected to the former. This survey is intended as a first step in the reconstruction of the full landscape of ‘chemical’ ideas occurring in Plutarch’s writings; accordingly, the exposition of the relevant passages, the assessment of their possible interpretations, the discussion on their implications, and their contextualization in the ancient traditions have been conducted with a special interest in the ‘mineralogical’ and ‘metallurgic’ themes developed in the frame of natural philosophy and meteorology. Although in this perspective physical etiology could have come to acquire central prominence, non-etiological information on Plutarch’s ideas on the nature and behaviour of stones and metals has been treated as equally relevant to reach a fuller understanding of how Plutarch conceptualized and visualized them in general, in- and outside the frame of philosophical explanation. Such extensive outline of Plutarch’s ideas on stones and metals is a prerequisite for an accurate inquiry into his use of the two in analogies, metaphors, and symbols: to predispose this kind of research was another aim of the present survey, and this aim has contributed to shape it; moreover, a special attention has been paid to the analysis of analogical and figurative speaking due to the nature itself of a large part of Plutarch’s references to stones and metals, which are either metaphorical, presented in close association with metaphors, or framed in analogies. Much of the information used for the present overview has been extracted —always with supporting argumentation— from the implications of such metaphors and analogies.

Nature in the books of seven metals – Ǧābirian corpus in dialogue with ancient Greek philosophy and Byzantine alchemy –

The Ǧābirian corpus was a receiver of ancient Greek ideas and, at the same time, a source of knowledge for the later Greek-speaking world, in particular for medieval Byzantine alchemy. Both aspects are explored in the dissertation with respect to the notion of nature. After a general introduction to the Corpus and the sciences described in it, particular attention is devoted to a Byzantine anonymous text, The Work of Four Elements, which was probably influenced by the Ǧābirian Books of Seventy. These texts exemplify how, in the theory of the Ǧābirian science, things are constructed from four natures (hot, cold, moist and dry), the balance of which defines what a thing is. By changing the balance of natures, one can transmute any metals into gold that is perfectly proportioned in terms of natures. Ǧābir presents the art of dyeing metals gold in the Books of Seven Metals which, along with chrysopoetic recipes, also include medical recipes and theoretical contents such as the theories of four humours, properties, and talismans. Moreover, Ǧābir postulated a substrate that does not change in itself and continues to exist when natures move in and out of things. Such primary existence is called the fifth nature as an additional principle to the four natures. This key concept for the Ǧābirian theory, which has been underexplored so far, is discussed through the textual and critical analysis of various unedited sources: the Books of Seven Metals and the Book of the Fifth Nature. This study confirms that the fifth nature was probably derived from ancient Greek philosophical concepts such as the Empedoclean particles, the Aristotelian fifth element and the Stoic pneuma. Thus, this research indicates the importance of the Ǧābirian corpus both in the history of alchemy and the history of philosophy.

Green approach to Palladium Cross-Coupling reactions and development of new methodologies based on highly abundant metals

Transition metal catalyzed cross-coupling reactions represent among the most versatile and useful tools in organic synthesis for the carbon-carbon (C-C) bond formation and have a prominent role in both the academic and pharmaceutical segments. Among them, palladium catalyzed cross-coupling reactions are currently the most versatile. In this thesis, the applications, impact and development of green palladium cross-coupling reactions are discussed. Specifically, we discuss the translation of the Twelve Principles of Green Chemistry and their applications in pharmaceutical organometallic chemistry to stimulate the development of cost-effective and sustainable catalytic processes for the synthesis of active pharmaceutical ingredients (API). The Heck-Cassar-Sonogashira (HCS) and the Suzuki-Miyaura (SM) protocols, using HEP/H2O as green mixture and sulfonated phosphine ligands, allowed to recycle and recover the catalyst, always guaranteeing high yields and fast conversion under mild conditions, with aryl iodides, bromides, triflates and chlorides. No catalyst leakage or metal contamination of the final product were observed during the HCS and SM reactions, respecting the very low limits for metal impurities in medicines established by the International Conference of Harmonization Guidelines Q3D (ICH Q3D). In addition, a deep understanding of the reaction mechanism is very important if the final target is to develop efficient protocols that can be applied at industrial level. Experimental and theoretical studies pointed out the presence of two catalytic cycles depending on the counterion, shedding light on the role of base in catalyst reduction and acetylene coordination in the HCS coupling. Finally, the development of a cross-coupling reaction to form aryldifluoronitriles in the presence of copper is discussed, highlighting the importance of inserting fluorine atoms within biological structures and the use of readily available metals such as copper as an alternative to palladium.

Analysis of efficacy and safety of CAR T-cell therapy in relapsed/refractory lymphomas: current indications and future perspectives

In the last few years, the introduction of chimeric antigen receptor (CAR) T-cell therapy into clinical practice has revolutionized the approach to patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), whose outcome used to be dismal with median overall survival (OS) of approximately 6 months with standard salvage therapy. At our Institute, we started treating diffuse large B-cell lymphoma (DLBCL) patients with CAR T-cell products in August 2019 and they received either axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) as per regulatory indications. This research project presents the 2-year follow-up of the first 53 treated patients. Our first aim is to investigate the feasibility of this treatment strategy in a real-world setting, although the reimbursement criteria set by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) are very similar to the inclusion criteria of clinical trials and stricter than those established by the regulatory authorities of many foreign countries. One month after infusion, the ORR was 66% with 19 patients already in CR (38%). Restaging at 3, 6 and 12 months post-infusion shows that early CRs tend to be maintained over time and, moreover, that a considerable number of PRs and a few SDs can improve into a CR. The safety data were consistent with what is reported in the literature; toxicity was generally manageable, largely due to the increasing expertise in handling the specific adverse events related to CAR T-cell therapy. Our results confirms that CAR T-cell therapy is both safe and effective in a real-life setting and that it represents a crucial weapon in a subset of patients who were previously doomed to an inevitably severe prognosis.

Rhodium clusters: investigation of the reactivity towaeds phosphines and selected d- and p-metals

During my PhD we focused on different research projects concerning the synthesis and characterization of new rhodium carbonyl clusters. More specifically, we studied the reactivity between Rh4(CO)12 and different bidentate phosphines, obtaining seven different species: Rh4(CO)10(dppe), Rh4(CO)8(dppe)2, Rh4(CO)10(dppf), {Rh4(CO)10(dpp-hexane)}2, {Rh4(CO)10(t-dppe)}2, Rh2(CO)2(dppf)2 and Rh4(CO)9(μ2-dppe)(μ1-dppeO). The reactivity of [Rh7(CO)16]3- with [AuCl4]- and Au(Et2S)Cl led to the formation of seven bimetallic clusters, of which four new ones, namely [Rh16Au6(CO)36]6-, [Rh10Au(CO)26]3-, [Rh16Au6(CO)36]4-, [Rh16Au6(CO)36]5-, [Rh22Au3(CO)47]5-, [Rh19Au5(CO)40]4- and [Rh20Au7(CO)45]5-. The reactivity of [Rh16Au6(CO)36]6- and [Rh10Au(CO)26]3- was studied as well. The reactivity of [Rh7(CO)16]3- with AgBF4, AgNO3 and with Pt(Et2S)2Cl2 was investigated, yielding only to the already known [Rh6N(CO)15]-, [PtRh5(CO)15]- and [PtRh4(CO)14]2- compounds. [Rh7(CO)16]3- war reacted with SnCl2·2H2O in acetone obtaining [Rh7Sn4Cl10(CO)14]5-, and [Rh12Sn(CO)23Cl2]4- was reacted with H+ obtaining [Rh18Sn3Cl2(CO)44]4-. Reactivity of [Rh7(CO)16]3- with InCl3 resulted in the isolation of [Rh12In(CO)28]3- and [Rh11In3(CO)25Cl2]3-, already known in our research lab, and the new [HRh11In(CO)26]3-. Moreover, a more straightforward synthesis for [Rh6InCl3(CO)15]2- was found, and this also led to the isolation of the [Rh6InCl2(DMF)(CO)15]-. The recover or rhodium as valuable carbonyl compound was also studied, and starting from a mixture of by-products it was possible to obtain the starting material [Rh7(CO)16]3-.