Health and Economic Outcomes of Pembrolizumab in the Treatment of Metastatic Non-small Cell Lung Cancer (mNSCLC) and Melanoma in Italy.

BACKGROUND AND OBJECTIVE: In Italy, the management of metastatic non-small cell lung cancer and melanoma leads to significant healthcare challenges, necessitating cost-effective treatment strategies and offering valuable insights for healthcare policymakers and stakeholders. This study was designed to assess the costs, quality-adjusted life-years (QALYs) and disability-adjusted life-years (DALYs) associated with the health and economic outcomes of (1) pembrolizumab-combined chemotherapy administered as a first-line treatment for metastatic non-squamous and squamous non-small cell lung cancer (NSCLC) where the tumour presents with a programmed death-ligand 1 expression level < 50% and of (2) adjuvant pembrolizumab treatment for stage III melanoma. METHODS: Three cost-effectiveness models developed by MSD were investigated for each treatment indication. A unique model was built to assess the overall effect of pembrolizumab versus chemotherapy or watchful waiting in patients with lung cancer or melanoma, respectively. Theoretical cohorts of patients with metastatic squamous and non-squamous NSCLC were followed over time using a partitioned survival model with weekly cycles. A weekly cycle Markov model was employed for melanoma. The analysis was conducted from the Italian National Health Service perspective, considering a time horizon of 40 years (lifetime). A single closed cohort of treatable patients was followed over time for each indication (4000, 7000 and 900 for NSCLC squamous, non-squamous and melanoma, respectively). The costs evaluated included those for adverse drug events, non-drug disease management, subsequent treatment and terminal care. Drug acquisition and administration costs were excluded. RESULTS: For each treatment indication assessed, pembrolizumab produced downstream direct cost offsets (- €122,498,568, - €133,369,076 and - €32,993,242 for NSCLC squamous, non-squamous and melanoma indications, respectively), increased quality of life (+2088, +5317 and +2307 QALYs for NSCLC squamous, non-squamous and melanoma indications, respectively) and reduced disability (- 2658, - 7202 and - 3029 DALYs for NSCLC squamous, non-squamous and melanoma indications, respectively). Across indications, the total cost offsets of pembrolizumab were - €288,860,885, with 9712 QALYs gained and 12,889 DALYs avoided. CONCLUSIONS: The analysis demonstrated that, compared with chemotherapy, pembrolizumab is more cost effective in Italy as a first-line treatment in patients with metastatic squamous or non-squamous NSCLC and, if compared with watchful waiting, as adjuvant treatment in patients with stage III melanoma. The present analysis suggested that pembrolizumab use could lead to important health benefits for patients while offsetting a portion of cancer care costs.

Predictive Factors for Hemorrhagic Transformation in Acute Ischemic Stroke in the REAL-World Clinical Practice.

BACKGROUND: Few data exists on predictive factors of hemorrhagic transformation (HT) in real-world acute ischemic stroke patients. The aims of this study were: (i) to identify predictive variables of HT (ii) to develop a score for predicting HT. METHODS: We retrospectively analyzed the clinical, radiographic, and laboratory data of patients with acute ischemic stroke consecutively admitted to our Stroke Unit along two years. Patients with HT were compared with those without HT. A multivariate logistic regression analysis was performed to identify independent predictors of HT on CT scan at 24 hours to develop a practical score. RESULTS: The study population consisted of 564 patients with mean age 77.5±11.8 years. Fifty-two patients (9.2%) showed HT on brain CT at 24 hours (4.9% symptomatic). NIHSS score ≥8 at Stroke Unit admission (3 points), cardioembolic etiology (2 points), acute revascularization by systemic thrombolysis and/or mechanical thrombectomy (1 point), history of previous TIA/stroke (1 point), and major vessel occlusion (1 point) were found independent risk factors of HT and were included in the score (Hemorrhagic Transformation Empoli score (HTE)). The predictive power of HTE score was good with an AUC of 0.785 (95% CI: 0.749-0.818). Compared with 5 HT predictive scores proposed in the literature (THRIVE, SPAN-100, MSS, GRASPS, SITS-SIC), the HTE score significantly better predicted HT. CONCLUSIONS: NIHSS score ≥8 at Stroke Unit admission, cardioembolism, urgent revascularization, previous TIA/stroke, and major vessel occlusion were independent predictors of HT. The HTE score has a good predictive power for HT. Prospective studies are warranted.

[Economic burden of diabetic patients with established atherosclerotic cardiovascular disease or risk factors for atherosclerotic cardiovascular disease.] / Analisi dei costi associati ai pazienti con diabete di tipo 2 a rischio di malattia cardiovascolare aterosclerotica o con malattia cardiovascolare aterosclerotica accertata.

OBJECTIVES: The analysis aimed to quantify the number and costs of patients with type 2 diabetes and atherosclerotic cardiovascular disease or with risk factors for atherosclerotic cardiovascular disease from the Regional Health Service (RHS) perspective of the Marche region. MATERIALS AND METHODS: A cost of illness (COI) model was developed to estimate the economic burden associated with diabetes and established atherosclerotic cardiovascular disease or risk factors for atherosclerotic cardiovascular disease. Data were extrapolated from the administrative database of the Marche region and specific inclusion criteria for enrolling patients were adapted from DECLARE-TIMI 58 clinical trial. RHS perspective (drugs, hospitalizations, monitoring cost) and 1 and 4-year time horizons were considered. RESULTS: The analysis estimated a total number of 92,205 diabetic patients in Marche region in 2014. Of these, 66,306 were patients (5.9% of the resident population) with established atherosclerotic cardiovascular disease (13,104 patients) or risk factors for atherosclerotic cardiovascular disease (53,202 patients). The annual expenditure associated with patients analysed amounted to € 98.8 million (average cost per patient € 1,480) in Marche region. Of these, 52% was associated with hospitalizations. Considering a 4-year time horizon, the overall economic burden rises to over € 301 million per year with an average cost per patient of € 4,545. Stratifying patients between patients hospitalized for heart failure and patients not hospitalized for heart failure, the average annual cost per patient was equal to € 15,896 and equal to € 3,998 respectively. CONCLUSIONS: An important epidemiological and economic burden associated with type 2 diabetes patients were estimated from the analysis due to the disease and the associated comorbidities. The ability to prevent comorbidity risks, especially cardiovascular ones, represents not only a clinical advantage but also a positive reduction in expenditure. Early and effective intervention represents the best strategy to avoid or slow down the evolution of complications of the disease.

Budget Impact Analysis of Dalbavancin in the Treatment of Acute Bacterial Skin and Skin Structure Infections in Three European Countries.

BACKGROUND AND OBJECTIVE: Acute bacterial skin and skin structure infections (ABSSSIs) have been defined by the US Food and Drug Administration (FDA) in 2013 to include a subset of complicated skin and skin structure infections commonly treated with parenteral antibiotic therapy. Inpatient treatment of ABSSSIs involves a significant economic burden on the healthcare system. This study aimed to evaluate the economic impact on the National Health System associated with the management of non-severe ABSSSIs treated in hospitals with innovative long-acting dalbavancin compared to standard antibiotic therapy in Italy, Spain, and Austria. METHODS: A budget impact analysis was developed to evaluate the direct costs associated with the management of ABSSSI from the national public health system perspective. The model considered the possibility of early discharge of patients directly from the Emergency Department (ED), after 1 night in the hospital, or after two or three nights in the hospital. A scenario with Standard of Care was compared with a dalbavancin scenario, where patients had the possibility of being discharged early. The epidemiological and cost parameters were extrapolated from national administrative databases and from a systematic literature review for each country. The analysis was conducted in a 3-year time horizon. A one-way deterministic sensitivity analysis was conducted to examine the robustness of the results. RESULTS: The model estimated an average annual number of patients with non-severe ABSSSI in Italy, Spain, and Austria equal to 5396, 7884, and 1788, respectively. A total annual expenditure of about €9.9 million, €13.5 million, and €3.4 million was estimated for treating the full set of ABSSSI patients in Italy, Spain, and Austria, respectively. Dalbavancin reduced the in-hospital length of stay in each country. In the first year of its introduction, dalbavancin significantly reduced the total economic burden in Italy and Spain (- €352,252 and - €233,991, respectively), while it increased the total economic burden in Austria (€80,769, 0.7% of the total expenditure for these patients); in the third year of its introduction, dalbavancin reduced the total economic burden in each Country (- €1.1 million, - €810,650, and - €70,269, respectively). CONCLUSIONS: The introduction of dalbavancin in a new patient pathway to treat non-severe ABSSSI could generate a significant reduction in hospitalized patients and the overall patient length of stay in hospital.

Cost Estimate of Immune-Related Adverse Reactions Associated with Innovative Treatments of Metastatic Melanoma.

BACKGROUND AND OBJECTIVE: Immuno-oncology therapies represent a new treatment opportunity for patients affected by metastatic melanoma. The purpose of this study was to estimate the costs of immune-related adverse events (irAEs) associated with the new anti-PD1 immuno-oncology therapies, with the anti-CTLA-4 immuno-oncology therapy and with the combined therapy (CTLA4 + anti-PD1) in patients affected by metastatic melanoma. MATERIALS AND METHODS: A probabilistic cost-of-illness (COI) model was developed to estimate the management costs of grade ≥ 3 adverse events associated with the new anti-PD1 therapies (pembrolizumab and nivolumab), the anti-CTLA-4 therapy (ipilimumab) and the combined therapy CTLA4 + anti-PD1 (nivolumab + ipilimumab) for the treatment of patients with metastatic melanoma from the National Health Service (NHS) perspective in Italy. Identification of the epidemiological and cost parameters was carried out through a systematic literature review (SLR). Univariate and probabilistic sensitivity analyses were performed to account for uncertainty and variation in the model results. RESULTS: The model estimated a cost associated with the management of grade ≥ 3 immune-related adverse events in patients with metastatic melanoma equal to €176.2 (95% CI 63.5-335.0) for anti-CTLA-4 therapy, €48.6 (95% CI 40.1-58.5) for the new anti-PDI therapies and €276.8 (95% CI 240.4-316.2) for the combined therapy. Among the innovative therapies for the considered metastatic melanoma, the combined therapy was the most expensive innovative treatment in terms of event management of immune-related grade ≥ 3 adverse events. CONCLUSION: This study may represent a useful tool to understand the economic burden associated with the management of irAEs associated with patients affected by metastatic melanoma.

Cost-effectiveness of switching from trivalent to quadrivalent inactivated influenza vaccines for the at-risk population in Italy.

Seasonal influenza is caused by two subtypes of influenza A and two lineages of influenza B. Although trivalent influenza vaccines (TIVs) contain both circulating A strains, they contain only a single B-lineage strain. This can lead to mismatches between the vaccine and predominant circulating B lineages, a concern especially for at-risk populations. Quadrivalent influenza vaccines (QIVs) containing a strain from both B lineages have been developed to improve protection against influenza. Here, we used a cost-utility model to examine whether switching from TIV to QIV would be cost-effective for the at-risk population in Italy. Costs were estimated from the payer and societal perspectives. The discount rate for outcomes was 3.0%. Univariate and probabilistic sensitivity analyses were performed to examine the effects of variations in parameters. Switching from TIV to QIV in Italy was estimated to increase quality-adjusted life-years (QALYs) and produce cost savings, including €1.6 million for hospitalization and approximately €2 million in productivity. The incremental cost-effectiveness ratio was €23,426 per QALY from a payer perspective and €21,096 per QALY from a societal perspective. Switching to QIV was most cost-effective for individuals ≥ 65 years of age (€19,170 per QALY). Probabilistic sensitivity analysis showed that the switching from TIV to QIV would be cost-effective for > 91% of simulation at a maximum willingness-to-pay threshold of €40,000 per QALY gained. Although the model did not take herd protection into account, it predicted that the switch from TIV to QIV would be cost-effective for the at-risk population in Italy.

PrPc activation induces neurite outgrowth and differentiation in PC12 cells: role for caveolin-1 in the signal transduction pathway.

Cellular prion protein (PrP(c)) is a ubiquitous glycoprotein, whose physiological role is poorly characterized. It has been suggested that PrP(c) participates in neuritogenesis, neuroprotection, copper metabolism, and signal transduction. In this study we detailed the intracellular events induced by PrP(c) antibody-mediated cross-linking in PC12 cells. We found a Fyn-dependent activation of the Ras-Raf pathway, which leads to a rapid and transient phosphorylation of extracellular regulated kinases. In addition, this activation cascade relies on the engagement of integrins, and involves focal adhesion kinase activation. We demonstrated the tyrosine phosphorylation of caveolin-1 as a consequence of PrP(c) stimulation, and showed that phosphocaveolin-1 scaffolds and coordinates protein complexes involved in PrP(c)-dependent signaling. Moreover, we found that caveolin-1 phosphorylation, is a mechanism for recruiting the C-terminal Src kinase and inactivating Fyn, so as to terminate cell signaling. Furthermore our data support a significant role for PrP(c) as a response mediator in neuritogenesis and cell differentiation.

Low molecular weight protein tyrosine phosphatase and caveolin-1: interaction and isoenzyme-dependent regulation.

Low molecular weight protein tyrosine phosphatases (LMW-PTPs) are small enzymes that are ubiquitous in many organisms. They are important in biological processes such as cell proliferation, adhesion, migration, and invasiveness. LMW-PTP is expressed in mammalian cells as two isoforms (IF1 and IF2) originating through alternative splicing. We have previously shown that IF2 targets lipid rafts called caveolae and interacts with caveolin-1, their major structural protein. Caveolae are cholesterol- and sphingolipid-rich membrane microdomains that have been implicated in a variety of cellular functions, including signal transduction events. Caveolin-1 contains a scaffolding region that contributes to the binding of the protein to the plasma membrane and mediates protein omo- and etero-oligomerization. Interaction of many signaling molecules with the scaffolding domain sequesters them into caveolae and inhibits or suppresses their activities. Caveolin-interacting proteins usually have a typical sequence motif, also present in all the LMW-PTPs, which is characterized by aromatic or large hydrophobic residues in specific positions. We have examined here the interaction of the LMW-PTP isoforms with caveolin-1 and its molecular mechanism, together with the consequences for their tyrosine phosphatase activities. We found that IF1 and IF2 are both capable of interacting with defined regions of caveolin-1 and that their putative caveolin binding sequence motif is not responsible for the association. The formation of LMW-PTP/caveolin-1 complexes is accompanied by modulation of the enzyme activities, and the inhibitory effect elicited against IF1 is stronger than that against IF2. The caveolin scaffolding domain is directly involved in the observed phenomena.