Treating Thalassemia Patients with Luspatercept: An Expert Opinion Based on Current Evidence

Luspatercept has recently been approved for the treatment of beta-thalassemia and its use in clinical practice has been increasing. As it is the first erythroid maturation drug available for this diagnosis, the expertise about its use is still limited. To address this point, and to promote awareness and guide the clinical use of luspatercept in beta-thalassemia, this paper was developed as a consensus by experts from the Italian Society of Thalassemia and Hemoglobinopathies (SITE). After a brief presentation of the core features of luspatercept, a comprehensive set of questions is addressed, covering relevant aspects for the practical management of this new therapeutic option

Two-year long safety and efficacy of deferasirox film-coated tablets in patients with thalassemia or lower/intermediate risk MDS: phase 3 results from a subset of patients previously treated with deferasirox in the ECLIPSE study

Background: Despite the proven benefits of iron chelation therapy (ICT) in the management of chronic iron overload and related complications, compliance to long-term ICT is challenging. Results from the ECLIPSE study, an open-label, randomized, multicenter, 2-arm, phase 2 study evaluated the safety of deferasirox dispersible tablet and film-coated tablet (FCT) formulations in patients with transfusion-dependent thalassemia (TDT) or very low, low, or intermediate risk myelodysplastic syndrome (MDS) treated over 24 weeks. Methods: The aim of the current study (a 2-year, open-label, multicenter, single-arm, phase 3 study) is to evaluate the long-term safety and efficacy of deferasirox FCT in a subset of patients with TDT or lower/intermediate-risk MDS treated for 2 years after the completion of 24 weeks of treatment with deferasirox in the ECLIPSE phase 2 study. Results: Of 53 patients enrolled, 34 (64.2%) completed treatment and study. Adverse events (AEs) reported in most patients (similar to 70%) were of mild to moderate severity. Headache and diarrhea were the most frequently (> 25%) reported AEs. None of the serious AEs (including 1 death) were considered treatment related. No new safety signal was identified, and long-term safety of deferasirox FCT was consistent with the known safety profile of deferasirox. No major concerns associated with gastrointestinal tolerability, renal safety, or hematological abnormalities (thrombocytopenia/neutropenia) were reported during the 2 years. Patients receiving deferasirox FCT had a treatment compliance (by pill count) of similar to 90% and persistence (continuous use for >= 30 days) of > 95%. Reduction in serum ferritin level was almost consistent starting from week 2 across all post-baseline time points (relative reduction: month 6, 19%; month 12, 29%). Conclusions: The results from this 2-year interventional study suggest that the recommended dosing of deferasirox FCT, with better tolerability, palatability, and compliance, offers a favorable option of ICT for long-term management of iron overload and associated complications in TDT

THE BARILOCHE NEUTRON PHYSICS GROUP CURRENT ACTIVITIES

Our group has evolved around a small accelerator-based neutron source (ABNS), the 25 million electron Volt (MeV) linear electron accelerator at the Bariloche Atomic Centre. It is dedicated to applications of neutronic methods to tackle problems of basic sciences and to technological applications. Among these, the determination of total cross section of a material as a function of neutron energy by means of transmission experiments for thermal and sub-thermal neutrons is very sensitive to the geometric arrangement and movement of the atoms, over distances ranging from the 'first-neighbour scale' up to the microstructural level or 'grain scale'. This also allowed to test theoretical models of calculated cross sections and scattering kernels. Interest has moved from pulsed neutron diffraction towards deep inelastic neutron scattering (DINS), a powerful tool for the determination of atomic momentum distribution in condensed matter and for non-destructive mass spectroscopy. In recent years non-intrusive techniques aimed at the scanning of large cargo containers have started to be developed with this ABNS, testing the capacity and limitations to detect special nuclear material and dangerous substances in thick cargo arrangements. More recently, the use of the ever-present “bremsstrahlung” radiation has been recognized as a useful complement to instrumental neutron activation, as it permits to detect other nuclear species through high-energy photon activation. The facility is also used for graduate and undergraduate students experimental work within the frame of Instituto Balseiro Physics and Nuclear Engineering courses of study, and also MSc and PhD theses work

THE BARILOCHE NEUTRON PHYSICS GROUP CURRENT ACTIVITIES

Our group has evolved around a small accelerator-based neutron source (ABNS), the 25 million electron Volt (MeV) linear electron accelerator at the Bariloche Atomic Centre. It is dedicated to applications of neutronic methods to tackle problems of basic sciences and to technological applications. Among these, the determination of total cross section of a material as a function of neutron energy by means of transmission experiments for thermal and sub-thermal neutrons is very sensitive to the geometric arrangement and movement of the atoms, over distances ranging from the 'first-neighbour scale' up to the microstructural level or 'grain scale'. This also allowed to test theoretical models of calculated cross sections and scattering kernels. Interest has moved from pulsed neutron diffraction towards deep inelastic neutron scattering (DINS), a powerful tool for the determination of atomic momentum distribution in condensed matter and for non-destructive mass spectroscopy. In recent years non-intrusive techniques aimed at the scanning of large cargo containers have started to be developed with this ABNS, testing the capacity and limitations to detect special nuclear material and dangerous substances in thick cargo arrangements. More recently, the use of the ever-present “bremsstrahlung” radiation has been recognized as a useful complement to instrumental neutron activation, as it permits to detect other nuclear species through high-energy photon activation. The facility is also used for graduate and undergraduate students experimental work within the frame of Instituto Balseiro Physics and Nuclear Engineering courses of study, and also MSc and PhD theses work

Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with b-thalassemia

b-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with b-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non\u2013transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (\u20214 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for \u20215 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of \u20211.5 g/dL from baseline for \u202114 consecutive days (without RBC transfusions) for non\u2013transfusion-dependent patients or RBC transfusion burden reduction \u202120% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non\u2013transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase \u20211.5 g/dL over \u202114 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved \u202120% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of b-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409

Associations between trace elements and cognitive decline: an exploratory 5-year follow-up study of an elderly cohort

Trace elements (TE) homeostasis is crucial in normal brain functioning. Although imbalances have the potential to exacerbate events leading neurodegenerative diseases, few studies have directly addressed the eventual relationships between TE levels in the human body and future cognitive status. The present study aimed to assess how different TE body-levels relate to cognitive decline. This exploratory research included a study-group (RES) of 20 elderly individuals living in two Portuguese geographical areas of interest (Estarreja; Mértola), as well as a 20 subjects neuropsychological control-group (CTR). Participants were neuropsychologically assessed through the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) and the RES group was biomonitored for TE through fingernail analysis. After 5 years, the cognitive assessments were repeated. Analyses of the RES neuropsychological data showed an average decrease of 6.5 and 5.27 points in MMSE and MoCA, respectively, but TE contents in fingernails were generally within the referenced values for non-exposed individuals. Higher levels of Nickel and Selenium significantly predicted lesser cognitive decline within 5 years. Such preliminary results evidence an association between higher contents of these TE and higher cognitive scores at follow-up, suggesting their contribution to the maintenance of cognitive abilities. Future expansion of the present study is needed in order to comprehensively assess the potential benefits of these TE.This research was supported by the Portuguese Foundation for Science and Technology (Fundação para a Ciência e a Tecnologia (FCT)) — grants SFRH/BPD/71030/2010, IF/01325/2015, SFRH/BD/146680/2019, and UIDB/04035/2020. Funding for this research was also provided by the Labex DRIIHM, French programme “Investissements d’Avenir” (ANR-11-LABX-0010), which is managed by the ANR

Development of a concept and basis for the DEMO diagnostic and control system

An initial concept for the plasma diagnostic and control (D&C) system has been developed as part of European studies towards the development of a demonstration tokamak fusion reactor (DEMO). The main objective is to develop a feasible, integrated concept design of the DEMO D&C system that can provide reliable plasma control and high performance (electricity output) over extended periods of operation. While the fusion power is maximized when operating near to the operational limits of the tokamak, the reliability of operation typically improves when choosing parameters significantly distant from these limits. In addition to these conflicting requirements, the D&C development has to cope with strong adverse effects acting on all in vessel components on DEMO (harsh neutron environment, particle fluxes, temperatures, electromagnetic forces, etc.). Moreover, space allocation and plasma access are constrained by the needs for first wall integrity and optimization of tritium breeding. Taking into account these boundary conditions, the main DEMO plasma control issues have been formulated, and a list of diagnostic systems and channels needed for plasma control has been developed, which were selected for their robustness and the required coverage of control issues. For a validation and refinement of this concept, simulation tools are being refined and applied for equilibrium, kinetic and mode control studies