cost effectiveness evaluation of oncological drugs newly marketed in italy

In a previous publication, the incremental overall survival (OS gain vs current therapy) was estimated for the 32 new cancer therapies authorized in Italy between 2010 and 2013.The objective of this article was to quantify the respective incremental costs (including possible regulatory agreements) in order to build incremental cost-effectiveness ratios (ICERs) to be used for economic evaluation.In a first group of 12 therapies, where OS gains were statistically significant (p < 0.05), the ICERs' median value was €53,273 per year gained (range: 3,945 - 179,098) and the mean value was €64,181 (95% CI: 29,302 - 99,060). In the other group, excluding four therapies with negative OS gains, ICERs were calculated for the remaining 16 drugs. The median ICER resulted in €69,568 (range: 3,406 - 308,928) and the mean value was €87,330 (95% CI: 37,024 - 137,636).Assuming a threshold of €5,000 per life-month gained, a total of 14 new cancer therapies met this criterion of economic acceptability (eight out of 12 in the..

Nephrotoxicity of Different Formulations of Amphotericin B: Summarizing Evidence by Network Meta-analysis

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Alpha-Synuclein transgenic mice, h-α-SynL62, display α-Syn aggregation and a dopaminergic phenotype reminiscent of Parkinson's disease

Acknowledgments: The authors acknowledge Mandy Magbagbeolu and Heide Lueck for excellent technical assistance and Anna Thoma for assistance in behavioural testing and maintenance of animals. This work was funded by TauRx Therapeutics Ltd., Singapore. C.R.H. and C.M.W. declare that they are officers in TauRx Therapeutics Ltd.Peer reviewedPublisher PD

MicroRNA profiling of paediatric AML with FLT-ITD or MLL-rearrangements: Expression signatures and in vitro modulation of miR-221-3p and miR-222-3p with BRD4/HATs inhibitors.

Novel therapeutic strategies are needed for paediatric patients affected by Acute Myeloid Leukaemia (AML), particularly for those at high-risk for relapse. MicroRNAs (miRs) have been extensively studied as biomarkers in cancer and haematological disorders, and their expression has been correlated to the presence of recurrent molecular abnormalities, expression of oncogenes, as well as to prognosis/clinical outcome. In the present study, expression signatures of different miRs related both to presence of myeloid/lymphoid or mixed-lineage leukaemia 1 and Fms like tyrosine kinase 3 internal tandem duplications rearrangements and to the clinical outcome of paediatric patients with AML were identified. Notably, miR-221-3p and miR-222-3p resulted as a possible relapse-risk related miR. Thus, miR-221-3p and miR-222-3p expression modulation was investigated by using a Bromodomain‑containing protein 4 (BRD4) inhibitor (JQ1) and a natural compound that acts as histone acetyl transferase inhibitor (curcumin), alone or in association, in order to decrease acetylation of histone tails and potentiate the effect of BRD4 inhibition. JQ1 modulates miR-221-3p and miR-222-3p expression in AML with a synergic effect when associated with curcumin. Moreover, changes were observed in the expression of CDKN1B, a known target of miR-221-3p and miR-222-3p, increase in apoptosis and downregulation of miR-221-3p and miR-222-3p expression in CD34+ AML primary cells. Altogether, these findings suggested that several miRs expression signatures at diagnosis may be used for risk stratification and as relapse prediction biomarkers in paediatric AML outlining that epigenetic drugs, could represent a novel therapeutic strategy for high-risk paediatric patients with AML. For these epigenetic drugs, additional research for enhancing activity, bioavailability and safety is needed

Maternal immune activation impairs endocannabinoid signaling in the mesolimbic system of adolescent male offspring

Prenatal infections can increase the risk of developing psychiatric disorders such as schizophrenia in the offspring, especially when combined with other postnatal insults. Here, we tested, in a rat model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid, whether maternal immune activation (MIA) affects the endocannabinoid system and endocannabinoid-mediated modulation of dopamine functions. Experiments were performed during adolescence to assess i) the behavioral endophenotype (locomotor activity, plus maze, prepulse inhibition of startle reflex); ii) the locomotor activity in response to Δ9-Tetrahydrocannabinol (THC) and iii) the properties of ventral tegmental area (VTA) dopamine neurons in vivo and their response to THC; iv) endocannabinoid-mediated synaptic plasticity in VTA dopamine neurons; v) the expression of cannabinoid receptors and enzymes involved in endocannabinoid synthesis and catabolism in mesolimbic structures and vi) MIA-induced neuroinflammatory scenario evaluated by measurements of levels of cytokine and neuroinflammation markers. We revealed that MIA offspring displayed an altered locomotor activity in response to THC, a higher bursting activity of VTA dopamine neurons and a lack of response to cumulative doses of THC. Consistently, MIA adolescence offspring showed an enhanced 2-arachidonoylglycerol-mediated synaptic plasticity and decreased monoacylglycerol lipase activity in mesolimbic structures. Moreover, they displayed a higher expression of cyclooxygenase 2 (COX-2) and ionized calcium-binding adaptor molecule 1 (IBA-1), associated with latent inflammation and persistent microglia activity. In conclusion, we unveiled neurobiological mechanisms whereby inflammation caused by MIA influences the proper development of endocannabinoid signaling that negatively impacts the dopamine system, eventually leading to psychotic-like symptoms in adulthood

A pilot study on brain plasticity of functional connectivity modulated by cognitive training in mild Alzheimer's disease and mild cognitive impairment

Alzheimer's disease (AD) alters the functional connectivity of the default mode network (DMN) but also the topological properties of the functional connectome. Cognitive training (CT) is a tool to slow down AD progression and is likely to impact on functional connectivity. In this pilot study, we aimed at investigating brain functional changes after a period of CT and active control (AC) in a group of 26 subjects with mild AD (mAD), 26 with amnestic mild cognitive impairment (aMCI), and a control group of 29 healthy elderly (HE) people. They all underwent a CT and AC in a counterbalanced order following a crossover design. Resting-state functional MRI and neuropsychological testing were acquired before and after each period. We tested post-CT and post-AC changes of cognitive abilities, of the functional connectivity of the DMN, and of topological network properties derived from graph theory and network-based statistics. Only CT produced functional changes, increasing the functional connectivity of the posterior DMN in all three groups. mAD also showed functional changes in the medial temporal lobe and topological changes in the anterior cingulum, whereas aMCI showed more widespread topological changes involving the frontal lobes, the cerebellum and the thalamus. Our results suggest specific functional connectivity changes after CT for aMCI and mAD

Biosafety in surgical pathology in the era of SARS-Cov2 pandemia. A statement of the Italian Society of Surgical Pathology and Cytology

Surgical pathology units face chemical and biological risks. While chemical risks have been intensely evaluated since the formalin ban, less attention has been drown to biological risks. The actual epidemiologic situation due to the SARS-CoV-2 pandemia has raised a series of questions, which need to be addressed as soon as possible. We have to pursue two lines of action: on one hand we must immediately adopt urgent measures to reduce the risk of SARS-CoV-2 infection of laboratory personnel, and on the other hand, we must address crucial technical and organizational aspects of biological risk reduction, preserving as much as possible the quality of tissue and cell samples. The evaluation of biological risk is an analytical process which involves different steps: a) characterization of the hazard (also known as risk assessment) and b) definition of a risk reduction strategy (also known as risk mitigation) 1. Risk assessment implies a) the identification of the intrinsic biologic characteristics of the infectious agent, and b) the identification of the laboratory procedures related to the agent. The intrinsic biologic characteristics of infectious agents are classified in 4 risk groups (RG) by the laboratory biosafety manual of the WHO 2. The RG range from level 1 (RG1) which includes microorganisms that are unlikely to cause human or animal disease, to level 4 (RG4) which includes pathogens which cause serious diseases, that can be readily transmitted from one individual to another, and for which effective treatment and preventive measures are not usually available. Risk mitigation includes the definition of the appropriate a) level of biosafety of the laboratory, b) type of personal protection equipment (PPE), c) type of infrastructure and equipment, and d) education of involved personnel. Laboratory biosafety is graded in 4 levels (BSL-1 to BSL-4) as exhaustively described in the laboratory biosafety manual of the WHO 2, and these levels are usually also defined by law (in Italy by the D. Lgs. 81/2008). BSL are a series of protections, which include individual safeguards designed to protect laboratory personnel, as well as the surrounding environment and community. The biosafety level required in laboratories derives from the characterization of the risk, and is not automatically derived from the risk group to which the pathogenic agent belongs. It is obvious that the biosafety level for a laboratory which cultivates a RG3 agent, will be higher than the level needed for a laboratory which performs diagnostic tests on inactivated biomaterials on the same agent. Specific checklists, derived from the WHO laboratory biosafety manual, which in Italy are also defined by the National Institute of Labor Safety Insurance (Istituto Nazionale Assicurazione Infortuni sul Lavoro) in its 6th Fascicle published in 2010 3 are necessary to verify the compliance of a given laboratory with the required biosafety level

Therapeutic Value and Innovation of a Drug and Criteria for Evaluation: A Multidisciplinary Experience in the Veneto Region

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Genetic loci linked to Type 1 Diabetes and Multiple Sclerosis families in Sardinia

<p>Abstract</p> <p>Background</p> <p>The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis.</p> <p>Methods</p> <p>To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic.</p> <p>Results</p> <p>In T1D, aside from the HLA locus, we found four regions showing a lod-score ≥1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score ≥1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5).</p> <p>Conclusion</p> <p>This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.</p

Dupilumab in the treatment of severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP): A multicentric observational Phase IV real-life study (DUPIREAL)

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with significant morbidity and reduced health-related quality of life. Findings from clinical trials have demonstrated the effectiveness of dupilumab in CRSwNP, although real-world evidence is still limited. Methods This Phase IV real-life, observational, multicenter study assessed the effectiveness and safety of dupilumab in patients with severe uncontrolled CRSwNP (n = 648) over the first year of treatment. We collected data at baseline and after 1, 3, 6, 9, and 12 months of follow-up. We focused on nasal polyps score (NPS), symptoms, and olfactory function. We stratified outcomes by comorbidities, previous surgery, and adherence to intranasal corticosteroids, and examined the success rates based on current guidelines, as well as potential predictors of response at each timepoint. Results We observed a significant decrease in NPS from a median value of 6 (IQR 5–6) at baseline to 1.0 (IQR 0.0–2.0) at 12 months (p &lt; .001), and a significant decrease in Sino-Nasal Outcomes Test-22 (SNOT-22) from a median score of 58 (IQR 49–70) at baseline to 11 (IQR 6–21; p &lt; .001) at 12 months. Sniffin' Sticks scores showed a significant increase over 12 months (p &lt; .001) compared to baseline. The results were unaffected by concomitant diseases, number of previous surgeries, and adherence to topical steroids, except for minor differences in rapidity of action. An excellent-moderate response was observed in 96.9% of patients at 12 months based on EPOS 2020 criteria. Conclusions Our findings from this large-scale real-life study support the effectiveness of dupilumab as an add-on therapy in patients with severe uncontrolled CRSwNP in reducing polyp size and improving the quality of life, severity of symptoms, nasal congestion, and smell