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Long-Term Outcome of Fanconi Anemia Patients From the Italian Registry on Behalf of the Marrow Failure Study Group of the AIEOP (Italian Association for Pediatric Haematology-Oncology)
Get PDFWe analyzed 193 Fanconi anemia patients from the Italian Registry, focusing on hematological outcome, cancer risk, and mortality, both in transplanted (n = 130, 67.4% of the cohort) and non-transplanted (n = 63, 36.6% of the cohort) patients. After a median follow-up of 7 years, almost all patients developed cytopenia that was more frequent in patients receiving hematopoietic stem cell transplantation (HSCT). The cumulative overall survival from birth was 91.0% at age 10 years, 71.6% at age 20, and 47.4% at age 30 years; the median survival age was 29.1 years. When stratifying patients by indication for transplantation (moderate vs. severe cytopenia vs. persistent poor prognosis cytogenetic alterations/acute myeloid leukemia), we found a 5-year cumulative mortality higher, though not significantly (p = 0.281) in the last group. Cancers were the second most common cause of death in the whole cohort after infections. Head and neck squamous cell carcinoma was the most frequent cancer, followed by hematologic neoplasms. The cumulative incidence of solid/hematological malignancy remarkably increased after 20 years of age and was 51.7% at age 40 years. The risk of malignancies was greater in subjects who received HSCT (sub-distribution azard ratio 2.9, 95% CI: 1.1–7.5, p = 0.024). We also identified a small group of patients with stable or even improved cytopenia over time without transplant, thus confirming that bone marrow failure is not automatic in all patients and heightening the importance of tight monitoring to surveil on the worsening of hematopoietic function and cancer occurrence. Overall, this study provides important findings that may help to make robust clinical decisions
Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Common Mutations: New Strategies
Get PDFEpidermal growth factor receptor (EGFR) mutations are described in 10–15% of Caucasian patients and in 50% of Asian patients with non-squamous non-small cell lung cancer (NSCLC). The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapeutic scenario and has changed the natural history of the disease. Despite the results obtained with osimertinib, a third-generation TKI, most patients experience disease progression. The search for new therapeutic strategies both to enhance first-line treatment and to ensure adequate second-line therapies represents an unmet medical need, towards which all efforts are being concentrated. In this review, we describe the main strategies identified to improve the prognosis of patients with EGFR-mutated NSCLC
Optimal prediction for quantiles and probabilities
No full textA prediction statement about a future random variable should always be accompanied by a measure of uncertainty and in particular it should be based on a so-called predictive distribution. The choice of a predictive distribution should be driven by the aim of the prediction itself, that usually is to compute predictive quantiles or predictive probabilities. Instead, it is common in the practice to use the same predictive distribution for both targets. The goal of this paper is twofold. First we provide a critical review of some important properties that a predictive distribution should possess, encouraging the correct choice of a predictive distribution in accordance to the predictive goal. Secondly, we propose suitable predictive distribution functions that satisfy the considered properties, to a high order of approximation. These are all in the form of asymptotic corrections of the plug-in distribution function. Some of them are already known in literature and some others are new proposals. In particular we introduce a new predictive distribution that may be useful to obtain calibrated predictions for the probabilities of a future random variable. The computation of the associated asymptotic expansion, when too difficult, can be substituted by simpler bootstrap procedures. The different predictive distribution functions are also compared in terms of mean squared error. As a side result, we show that the predictive distribution that minimises the mean squared error is also optimal with respect to the continuous ranked probability score. Some examples illustrate how to compute the new calibrated predictive distribution. Moreover, several simulation studies clearly show how the performance of different predictive distributions depends on the aim of the prediction and that the improvement can be substantial, in particular for the case of small and medium sample sizes
Early Introduction of Cenobamate in Uncontrolled Focal Epilepsy: Insights from a Structured Controversy
Get PDFIntroduction: Drug-resistant focal epilepsy, as defined by the International League Against Epilepsy (ILAE), is characterized by the failure to achieve seizure control despite the use of at least two appropriately chosen and adequately dosed antiseizure medications (ASMs). This condition affects approximately 30% of patients and represents a significant clinical challenge. Cenobamate, a novel ASM with a unique dual mechanism of action—enhancing inhibitory GABAergic currents and attenuating persistent sodium currents—has emerged as a promising therapeutic option for drug-resistant focal epilepsy. Methods: This expert consensus document was developed using a structured controversy methodology, integrating real-world experience and a narrative review of the literature focusing on the role of cenobamate in the management of drug-resistant focal epilepsy. This manuscript synthesizes current evidence on cenobamate and provides clinical recommendations for its integration into epileptological practice. Results: The expert panel findings support the early use of cenobamate following the failure of two ASMs, emphasizing its efficacy in achieving substantial seizure reduction and increasing the likelihood of seizure freedom. Early prescription of cenobamate may offer a valuable therapeutic opportunity for patients with refractory focal epilepsy, potentially reducing seizure-related complications and improving quality of life. Identified challenges include limited long-term safety data in specific populations and regional disparities in drug access. Conclusion: Cenobamate represents a significant advancement in the treatment of drug-resistant focal epilepsy. Its early adoption in clinical practice has the potential to enhance patient outcomes. The expert panel provides recommendations that underscore individualized treatment planning, close monitoring during titration, and advocacy for improved accessibility. Continued research and policy initiatives are essential to fully realize the therapeutic potential of cenobamate
The Challenges of the National Recovery and Resilience Plan and of Asymmetric Regionalism: A Resilience Opportunity for Italian Regions?
No full textMore than twenty years after the constitutional reform aimed at enhancing
territorial autonomy in Italy, the relations between the State and the Regions are still
based on an architecture that, in various sectors of the legal system, does not seem
updated to the new framework. In particular, the State has not fully reconciled
decentralization with equity of access to essential levels of services (ELS) concerning
civil and social rights that must be guaranteed throughout the national territory. The
implementation of fiscal autonomy of territorial governments is partial and not
homogeneous. These critical issues must now be understood in light of the mandatory
provisions of the National Recovery and Resilience Plan (NRRP) aimed at enacting
fiscal federalism and the will expressed by the Parliament to implement asymmetric
regionalism but only after the determination of the ELS. The obligations stemming from this framework make clear the implementation of the constitutional framework
can no longer be postpone
Guido Calogero, Scuola, dialogo, riforma sociale, a cura di Andrea Mariuzzo, Scholé, Brescia, 2024,
Get PDFRemodeling of Mitochondria–Endoplasmic Reticulum Contact Sites Accompanies LUHMES Differentiation
Get PDFNeural progenitor cells (NPCs) are often used to study the subcellular mechanisms underlying differentiation into neurons in vitro. Works published to date have focused on the pathways that distinguish undifferentiated NPCs from mature neurons, neglecting the earlier and intermediate stages of this process. Current evidence suggests that mitochondria interaction with the ER is fundamental to a wide range of intracellular processes. However, it is not clear whether and how the mitochondria-ER interactions differ between NPCs and their differentiated counterparts. Here we take advantage of the widely used NPC line LUHMES to provide hints on the mitochondrial dynamic trait changes that occur during the first stage of their maturation into dopaminergic-like neurons. We observed that the morphology of mitochondria, their interaction with the ER, and the expression of several mitochondria-ER contact site resident proteins change, which suggests the potential contribution of mitochondria dynamics to NPC differentiation. Further studies will be needed to explore in depth these changes, and their functional outcomes, which may be relevant to the scientific community focusing on embryonic neurogenesis and developmental neurotoxicity
Dynamics and dissipation in 2D fluid foams: The foamy continuum model
No full textThe paper establishes the governing equations of the dynamics of a foamy continuum, in the sense of Davini and Podio-Guidugli, which is expected to mimic the behavior of a monodisperse fluid foam. We model this special continuum as a dissipative ordered fluid, following the lead by Sonnet and Virga. Attention to both regular and topological transformations is taken