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BACKGROUD. The B-cell receptor inhibitor ibrutinib has significantly improved treatment and overall management of chronic lymphocytic leukemia (CLL). Although several data derived from clinical ...trials suggest that ibrutinib increases the risk of atrial fibrillation (AF), the incidence of AF in a real-life cohort of CLL patients is unknown. Furthermore, it would be clinically relevant to identify patients at high risk of AF during ibrutinib.
The aim of this study is to report the prevalence and risk factors of AF in ibrutinib-naive CLL, in order to define a predictive model for the development of AF and to test it in a cohort of subjects receiving ibrutinib.
METHODS. We retrospectively analyzed data from 860 ibrutinib-naive CLL patients, referred to the Padua University hospital. Comorbidities, clinical and biological prognostic markers were analyzed using the Mann-Whiney, Fisher exact or Chi-square tests, when appropriated. Time to AF (TTAF) and overall survival (OS) were evaluated with Kaplan-Meier method. Univariate and multivariate Cox models were run to identify independent factors associated with AF. Then, risk values were obtained based on the hazard ratios. The score for AF was calculated as the sum of each risk values. Subsequently, the model was evaluated in a cohort of 354 ibrutinib-treated patients referred from 8 Italian hematological centers.
RESULTS. Among the 860 patients from Padua hospital, 60% were male, 49% were older than 65 years, 73% were Binet A stage at diagnosis and 41% underwent at least one line of treatment. A prior history of AF was present in 21 patients (2.4%) at CLL diagnosis, while, among the remaining 839 patients without a previous history of AF, 47 (5.6%) developed it after a median follow-up of 9.4 years, resulting in an estimated incidence of almost 0.8% cases/year. Moreover, the median OS for patients with AF was significantly shorter than that patients without AF (12 vs 22 years, p<0.0001). Based on univariate and multivariate analysis, variables associated with the risk of AF were: age>65 years (p=0.001, 1 point), male gender (p=0.003, 1 point), valvular hearth diseases (p=0.001, 2 points), cardiopathy (p<0.001, 3 points), hyperthyroidism (p=0.001, 1 point), chronic lung diseases (p=0.001, 1 point), diabetes mellitus (p=0.023, 1 point), severe infections (p=0.019, 1 point). As expected, no clinical and biological prognostic markers (i.e. Binet stage, IGHV mutation, TP53 abnormalities) for CLL were associated with an increased risk of AF. A predictive model was designed based on these factors and it stratified patients into 4 different groups. The estimated TTAF after 15 years of follow-up were 0%, 10%, 19% and 61% for patients with score 0, 1-2, 3-4, and ≥5 respectively (p<0.001, Fig. 1A). Furthermore, it underwent internal validation using the bootstrap method.
Subsequently, we applied our AF model to a cohort of 354 ibrutinib-treated patients, 64% were male, the median age was 69 years, 88 were treatment-naive, 70% U-IGHV and 39% harbored TP53 abnormalities. Forty-four subjects developed AF after a median observation of 25 months, with an estimated 2-year TTAF of 12%. Only 9 out of the 44 patients (20%) discontinued ibrutinib. Sixteen patients (4%) were classified as AF score 0, 218 (62%) score 1-2, 73 (21%) score 3-4 and 46 (13%) at least score 5. Our model was also able to identify patients at a higher risk AF during ibrutinib, in fact the 2-year risk of AF was 0%, 5%, 17% and 40% for patients with score 0, 1-2, 3-4, and ≥5 respectively (p<0.001, Fig. 1B). Patients with a score of 5 or higher have a risk 20 times higher to developed AF than the other subjects (HR 19.6, 95% interval 7-52, p<0.0001). So far, the OS of ibrutinib-treated patients with AF was not inferior to that of patients who did not developed AF (2-years OS 89% and 82%, respectively p=0.1252), but the median follow-up is only 2 years.
CONCLUSIONS. In this study, variables associated with an increased risk of developing AF were identified and recapitulated into a scoring system. Our model proved to be a valid tool to identify patients at a higher risk of developing AF, including ibrutinib-treated patients. Taking these data into account, patients with a score ≥5 should be carefully monitored during ibrutinib treatment given the very high-risk of developing AF or should be considered for alternative therapies.
Visentin:janssen: Consultancy, Honoraria. Mauro:abbvie: Other: board member; janssen: Other: board member. Reda:Janssen and Cilag: Consultancy; ABBVIE: Consultancy; Gilead: Consultancy; Celgene: Consultancy. Molica:Jansen: Other: Advisory board; Gilead: Other: Advisory board; Roche: Other: Advisory board; AbbVie: Other: Advisory board. Rigolin:Gilead: Research Funding. Tedeschi:Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; AbbVie: Consultancy. Cortelezzi:novartis: Consultancy; abbvie: Consultancy; roche: Consultancy; janssen: Consultancy. Coscia:Abbvie, Gilead, Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Karyopharm: Research Funding. Cuneo:Abbvie: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:CELGENE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Trentin:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Gilead: Research Funding; Janssen: Research Funding.
Fusarium wilt caused by Fusarium oxysporum f.sp. melonis (FOM) is a devastating disease of melon worldwide. Pathogenicity tests performed with F. oxysporum isolates obtained from Italian ...melon‐growing areas allowed to identify thirty‐four FOM isolates and the presence of all four races. The aims of this work were to examine genetic relatedness among FOM isolates by race determination and to perform phylogenetic analyses of identified FOM races including also other formae speciales of F. oxysporum of cucurbits. Results showed that FOM race 1,2 was the most numerous with a total of eighteen isolates, while six and nine isolates were identified as race 0 and 1, respectively, and just one isolate was assigned to race 2. Phylogenetic analysis was performed by random amplified polymorphic DNA (RAPD) profiling and by translation elongation factor‐1α (TEF‐1α) sequencing. The analysis of RAPD profiles separated FOM races into two distinct clades. Clade 1, which included races 0, 1 and 1,2, was further divided into ‘subclade a’ which grouped almost all race 1,2 isolates, and into ‘subclade b’ which included race 0 and 1 isolates. Clade 2 comprised only race 2 isolates. The phylogenetic analysis based on TEF‐1α separated FOM from the other formae speciales of F. oxysporum. Also with TEF‐1α analysis, FOM races 0, 1 and 1,2 isolates grouped in one single clade clearly separated from FOM race 2 isolates which grouped closer to F. oxysporum f.sp. cucumerinum. RAPD technique was more effective than TEF‐1α in differentiating FOM race 1,2 isolates from those belonging to the closely related races 0 and 1. Both phylogenetic analyses supported the close relationship between the three different FOM races which might imply the derivation from one another and the different origin of FOM race 2.
Rising temperature, drought and more-frequent extreme climatic events have been predicted for the next decades in many regions around the globe. In this framework, soil water availability plays a ...pivotal role in affecting vegetation productivity, especially in arid or semi-arid environments. However, direct measurements of soil moisture are scarce, and modeling estimations are still subject to biases. Further investigation on the effect of soil moisture on plant productivity is required. This study aims at analyzing spatio-temporal variations of a modified temperature vegetation wetness index (mTVWI), a proxy of soil moisture, and evaluating its effect on gross primary production (GPP) in forests. The study was carried out in Europe on 19 representative tree species during the 2000–2010 time period. Results outline a north–south gradient of mTVWI with minimum values (low soil water availability) in Southern Europe and maximum values (high soil water availability) in Northeastern Europe. A low soil water availability negatively affected GPP from 20 to 80%, as a function of site location, tree species, and weather conditions. Such a wetness index improves our understanding of water stress impacts, which is crucial for predicting the response of forest carbon cycling to drought and aridity.
Type I interferons (IFNs) represent a group of cytokines that act through a common receptor composed by two chains (IFNAR-1 and IFNAR-2). Several in vitro and in vivo studies showed a potent ...antitumor activity induced by these cytokines. IFN-α, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. IFN-α, is currently the most used cytokine in the treatment of cancer. However, the potential anti-tumour activity of IFN-α is limited by the activation of tumour resistance mechanisms. This article reviews the current knowledge about the antitumor activity of type I IFNs, focusing on new potential strategies able to strengthen the antitumor activity of these cytokines.
First, to assess the appropriateness of requests for albumin using current guidelines; second, to evaluate physicians' compliance with this protocol.
Descriptive, prospective study.
'Paolo Giaccone' ...University Hospital in Palermo (Italy).
The six departments with the highest orders for albumin.
An experimental, pharmacist-driven process for daily orders of albumin was activated over a period of 1 month. Pharmacy personnel handed out order forms on six different wards. Physicians were required to select one of a number of intended uses listed on the form.
Data on albumin and serum protein levels; number of vials and grams of albumin requested/day; number of vials and grams of albumin/day needed to normalize serum albumin levels; informed consent; indications and appropriateness of use.
A total of 126 forms were collected. Mean serum albumin and protein levels of patients in the different wards were close to normal (2.5 and 5 g/dl, respectively). The albumin doses requested by the various wards were 2 to 7 times higher than expected. 37.3% of the requests were for appropriate indications, 40.5% were for occasionally appropriate indications and 18.2% were inappropriate. According to current guidelines, 83.3% of requests were appropriate. 45% of orders from the Intensive Care ward were for inappropriate indications.
The introduction of a well-defined, flexible pharmacist-driven ordering process for albumin could reduce omissions in albumin indications and aid request assessment. It would allow pharmacists to collaborate with physicians in verifying whether requests are appropriate and whether prescriptions comply with current guidelines.
This study examines the bioaccumulation of 17 trace elements (including aluminum, arsenic, cadmium, copper, and zinc, among others) in the muscle tissue of the blackmouth catshark (Galeus melastomus) ...from various locations in the Mediterranean Sea. This research focuses provides insights into the distribution and accumulation patterns of these elements in G. melastomus and sheds light on the potential risks posed by chemical contamination in the Mediterranean Sea. The study underscores the significance of investigating the impacts of pollutants on marine organisms, particularly sharks, to develop effective conservation and management strategies. The data contribute to our understanding of trace element bioaccumulation in elasmobranch species, thus highlighting the importance of protecting these key ecological players in marine ecosystems. Environmental pollution, particularly in the marine environment, has become a significant concern due to the increasing presence of pollutants and their adverse effects on ecosystems and human health. This study focuses on the bioaccumulation of trace elements in the muscle tissue of the blackmouth catshark (Galeus melastomus) from different areas in the Mediterranean Sea. Trace elements are of interest due to their persistence, toxicity, and potential for bioaccumulation. This research aims to assess the distribution and accumulation of trace elements in the muscle tissue of G. melastomus and investigate their potential impact on the deep-sea environment of the Mediterranean. The focused areas include the Ligurian Sea, the northern and central Tyrrhenian Sea, the southern Tyrrhenian Sea, the Ionian Sea, the Pantelleria Waters, and the Gela Waters. Samples were collected following established protocols, and trace element analysis was conducted using inductively coupled plasma mass spectrometry. The study provides data on the concentrations of 17 trace elements, namely aluminum, arsenic, cadmium, cobalt, copper, manganese, molybdenum, nickel, zinc, selenium, strontium, lead, chromium, iron, barium, bismuth, and uranium. The findings contribute to a better understanding of trace element bioaccumulation patterns in elasmobranch species, specifically G. melastomus, and highlight the potential risks associated with chemical contamination in the Mediterranean Sea. This research emphasizes the importance of studying the impacts of pollutants on marine organisms, particularly those occupying key ecological roles, like sharks, to support effective conservation and management strategies.
Medullary thyroid cancer (MTC) is a tumor highly resistant to chemo‐ and radiotherapy. Drug resistance can be induced by epigenetic changes such as aberrant DNA methylation. To overcome drug ...resistance, we explored a promising approach based on the use of 5‐aza‐2′‐deoxycytidine (AZA), a demethylating agent, in combination with the mTOR inhibitor everolimus in MTC cells (MZ‐CRC‐1 and TT). This combined treatment showed a strong synergistic antiproliferative activity through the induction of apoptosis. The effect of everolimus and/or AZA on genome‐wide expression profiling was evaluated by Illumina BeadChip in MZ‐CRC‐1 cells. An innovative bioinformatic pipeline identified four potential molecular pathways implicated in the synergy between AZA and everolimus: PI3K‐Akt signaling, the neurotrophin pathway, ECM/receptor interaction, and focal adhesion. Among these, the neurotrophin signaling pathway was most directly involved in apoptosis, through the overexpression of NGFR and Bax genes. The increased expression of genes involved in the NGFR‐MAPK10‐TP53‐Bax/Bcl2 pathway during incubation with AZA plus everolimus was validated by western blotting in MZ‐CRC‐1 cells. Interestingly, addition of a neutralizing anti‐NGFR antibody inhibited the synergistic cytotoxic activity between AZA and everolimus. These results open a new therapeutic scenario for MTC and potentially other neuroendocrine tumors, where therapy with mTOR inhibitors is currently approved.
Drug resistance is a problem in the treatment for medullary thyroid cancer (MTC). We explored a synergistic treatment, combining the demethylating agent 5‐aza‐2′‐deoxycytidine with the mTOR inhibitor everolimus in MTC cell lines. This combined treatment showed a strong synergistic antiproliferative activity through the induction of apoptosis, through the overactivation of the NGFR‐MAPK10‐TP53‐Bax pathway. Thus, this combined treatment opens a new therapeutic scenario for MTC.
Introduction
Safinamide is a recent antiparkinsonian drug that modulates both dopaminergic and glutamatergic systems with positive effects on motor and nonmotor symptoms of Parkinson’s disease (PD). ...Here, we aimed to describe the efficacy and safety of safinamide in the Italian PD patients in real-life conditions.
Methods
We performed a sub-analysis of the Italian cohort of the SYNAPSES study, a multi-country, multi-center, retrospective-prospective cohort observational study, designed to investigate the use of safinamide in routine clinical practice. Patients received for the first time a treatment with safinamide and were followed up for 12 months. The analysis was conducted on the overall population and in subgroups of interest: i) patients > 75 years, ii) patients with relevant comorbidities and iii) patients affected by psychiatric symptoms.
Results
Italy enrolled 616/1610 patients in 52 centers, accounting for 38% of the entire SYNAPSES cohort. Of the patients enrolled, 86.0% were evaluable at 12 months, with 23.3% being > 75 years, 42.4% with psychiatric conditions and 67.7% with relevant comorbidities.
Safinamide was effective on motor symptoms and fluctuations as measured through the Unified PD rating scale III and IV scores, and on the total score, without safety issues in none of the subgroups considered.
Conclusion
The SYNAPSES data related to Italian patients confirms the good safety profile of safinamide even in special groups of patients. Motor fluctuations and motor impairment improved at the follow-up suggesting the significant role of safinamide in managing motor symptoms in PD patients.
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