Personalizzazione del trattamento antivirale nel paziente affetto da epatite C grazie allo studio della dinamica dell'infezione con modello biomatematico

Il trattamento dell’epatite cronica C è in continua evoluzione grazie ai nuovi farmaci ad azione antivirale diretta (DAAs), che tuttavia per gli elevati costi mettono a rischio la sostenibilità economica obbligando a limitarne l'accessibilità a categorie ristrette di pazienti. La possibilità di modulare l’intensità delle terapie in funzione della probabilità di risposta può portare oltre che ad una vera personalizzazione del trattamento anche ad un'ottimizzazione dei costi. Lo studio della dinamica dell'infezione nelle prima 4 settimane di trattamento antivirale con un approccio modellistico biomatematico (basato sulla misura ripetuta di viremia e transaminasi) si è dimostrato in grado di predire con elevata accuratezza diagnostica (90.4%) la risposta virologica sostenuta (SVR) a fine terapia, superiore a quella ottenuta (69.6%) con la valutazione della Risposta Virologica Rapida (RVR: HCV RNA non rilevabile a 4 settimane di terapia con PegIFN+Ribavirina). Nell'intento di una razionalizzazione della spesa sanitaria, la prescrivibilità degli inibitori della proteasi di I generazione per pazienti con epatite cronica C senza fibrosi avanzata è stata limitata ai pazienti senza RVR (quindi con ridotta probabilità di risposta) alla terapia con Peg-Interferone e Ribavirina. Obiettivo dello studio è stato quello di validare una versione semplificata del modello biomatematico originale, più facilmente applicabile nella clinica, e confrontare i costi del trattamento modulato in base alla RVR (guideline-guided, GG) o alla predizione di SVR ottenuta con lo studio della dinamica dell'infezione (model-guided, MG). Il modello semplificato è stato validato in una coorte di 135 pazienti trattati con PegIFN+Ribavirina. I costi delle 2 strategie (GG e MG) cono stati confrontati sviluppando un modello economico analitico-decisionale. Il modello bio-matematico semplificato ha mostrato capacità predittive sovrapponibili all’originale e l’analisi costo-efficacia ha dimostrato un risparmio netto di 3600-3900 € per paziente applicando la strategia MG, che è risultata nel complesso più efficace e meno costosa (dominante). In conclusione, la predizione dopo 4 settimane di duplice terapia dell’SVR mediante modello bio-matematico semplificato migliora il rapporto costo-efficacia della cura, riservando il trattamento con Inibitori delle proteasi di I generazione esclusivamente ai pazienti con minima probabilità di risposta alla duplice terapia. L'applicazione di un tale approccio potrebbe essere considerata anche per un uso personalizzato ed ottimizzato dei nuovi DAAs

Serum levels of VCAM-1 are associated with survival in patients treated with nivolumab for NSCLC

Background High circulating levels of cellular adhesion molecules (CAMs) in non-small cell lung cancer (NSCLC) have been supposed to act as a negative prognostic factor. Here, we explored the predictive role of pre-treatment levels of CAMs in previously treated patients receiving nivolumab for NSCLC. Materials and methods Seventy one patients with advanced NSCLC, treated with nivolumab at the dose of 3 mg/kg every 14 days, were enrolled. Maximum follow-up time was 3 years. Serum levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) were measured at baseline and before each nivolumab administration. Endpoints of the study were a composite outcome of survival >= 2 years or absence of disease progression at the end of the follow-up, and the overall survival. Results Composite outcome and overall survival were positively associated with VCAM-1 baseline levels and with the reduction of VCAM-1 during the treatment. After adjustment for potential confounders, the change in VCAM-1 serum levels during the treatment was an independent predictor of overall survival. Conclusions High baseline serum levels of VCAM-1 are associated with a longer survival in patients treated with nivolumab as second line treatment for NSCLC. Surviving patients experience also a significant reduction in CAMs expression during the treatment. Hence, CAMs might be promising prognostic factors in patients with NSCLC underoing immunotherapy

Statin-Induced Necrotizing Autoimmune Myopathy: Case Report of a Patient under Chronic Treatment

Introduction. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors are widely used worldwide to treat dyslipidaemia and prevent cardiovascular events. Statins can cause a wide variety of muscle injuries ranging from myalgia to severe rhabdomyolysis. In most cases, these symptoms are mild and self-limiting and do not require specific treatment besides drug withdrawal. Statin-induced autoimmune necrotizing myopathy (SINAM) is a rare but potentially fatal complication, characterized by the subacute onset of progressive proximal muscle weakness and considerably high creatine phosphokinase (CK) levels in patients exposed to statins. The diagnosis is supported by the presence of antibodies HMGCR, which allows the differentiation from other forms of necrotizing autoimmune myopathies. Symptoms usually progress even after statin discontinuation and can determine severe muscle damage. Summary. We describe the case of a 77-year-old man who developed SINAM after 5 years of statin use. He suffered from muscle functional impairment mainly involving proximal lower limb muscles which progressed to the point that he almost became bedridden. Initial treatment with prednisone alone was not effective, and he required a combination therapy with steroids, methotrexate, and intravenous immunoglobulins. After 5 months of therapy and rehabilitation, he showed complete laboratory response and muscle strength recovery. Conclusion. Recognizing SINAM is paramount in order to promptly start treatment and avoid permanent muscle damage. Using a combination therapy from the beginning could contribute to a better outcome. Prompt statin cessation, categorization of the muscle disease by autoantibody testing, imaging, and histology, exclusion of malignancy, and anti-inflammatory therapy with corticosteroids, antimetabolites, immunoglobulins, and in some cases rituximab are currently accepted approaches to this entity

Investigation of cardiac fibroblasts using myocardial slices

Aims: Cardiac fibroblasts (CFs) are considered the principal regulators of cardiac fibrosis. Factors that influence CF activity are difficult to determine. When isolated and cultured in vitro , CFs undergo rapid phenotypic changes including increased expression of \u3b1-SMA. Here we describe a new model to study CFs and their response to pharmacological and mechanical stimuli using in vitro cultured mouse, dog and human myocardial slices. Methods and Results: Unloading of myocardial slices induced CF proliferation without \u3b1-SMA expression up to 7 days in culture . CFs migrating onto the culture plastic support or cultured on glass expressed \u3b1SMA within 3 days. The cells on the slice remained \u3b1SMA(-) despite TGF-\u3b2 (20ng/mL) or angiotensin II (200\ub5M) stimulation. When diastolic load was applied to myocardial slices using A-shaped stretchers, CF proliferation was significantly prevented at day 3 and 7 (P\u2009<\u20090.001). Conclusions: Myocardial slices allow the study of CFs in a multicellular environment and may be used to effectively study mechanisms of cardiac fibrosis and potential target

Baseline serum levels of osteopontin predict clinical response to treatment with nivolumab in patients with non-small cell lung cancer

reserved20noTreatment with nivolumab improves survival and response rate in non-small cell lung cancer (NSCLC). Nevertheless, due to its high financial cost, identifying predictors of response to treatment has become an urgent need. Here, we focused on serum osteopontin (OPN), a pleiotropic protein overexpressed in lung cancer and involved in the immune response. A cohort of NSCLC patients (n = 72) treated with nivolumab was enrolled. Blood samples were collected at the time of first five nivolumab administrations. OPN and high-sensitivity C-reactive protein (hs-CRP) were assayed at each time point. The primary endpoint was to assess the predictive value of baseline serum levels of OPN towards overall survival (OS). Secondary endpoints included the potential association between OPN, hs-CRP and response to nivolumab. OPN and hs-CRP correlate with each other, with neutrophil count and biochemical markers of metastatic disease. At baseline, serum OPN increased with increasing Eastern Cooperative Oncology Group scale of Performance Status (ECOG PS). When Eastern Cooperative Oncology Group scale of Performance Status) (RECIST) criteria were considered, high baseline OPN levels were associated with a worse response to nivolumab. Cox hazard regression further confirmed baseline serum OPN as a predictor of mortality with the best predictive accuracy for serum levels above 37.7 ng/mL. Patients above the cut-off value had a higher mortality rate as compared to low serum OPN levels during follow up. Serum OPN may have a predictive role in NSCLC patients treated with nivolumab. Although larger confirmatory studies are needed, measuring serum OPN levels at baseline can be a clinically useful tool in a near future.mixedCarbone, Federico; Grossi, Francesco; Bonaventura, Aldo; Vecchié, Alessandra; Minetti, Silvia; Bardi, Nicholas; Elia, Edoardo; Ansaldo, Anna Maria; Ferrara, Daniele; Rijavec, Erika; Dal Bello, Maria Giovanna; Biello, Federica; Rossi, Giovanni; Tagliamento, Marco; Alama, Angela; Coco, Simona; Spallarossa, Paolo; Dallegri, Franco; Genova, Carlo; Montecucco, FabrizioCarbone, Federico; Grossi, Francesco; Bonaventura, Aldo; Vecchié, Alessandra; Minetti, Silvia; Bardi, Nicholas; Elia, Edoardo; Ansaldo, Anna Maria; Ferrara, Daniele; Rijavec, Erika; Dal Bello, Maria Giovanna; Biello, Federica; Rossi, Giovanni; Tagliamento, Marco; Alama, Angela; Coco, Simona; Spallarossa, Paolo; Dallegri, Franco; Genova, Carlo; Montecucco, Fabrizi

Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study

Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (<\u200995 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9\u2009<\u200995 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results

Investigation of cardiac fibroblasts using myocardial slices

Aims: Cardiac fibroblasts (CFs) are considered the principal regulators of cardiac fibrosis. Factors that influence CF activity are difficult to determine. When isolated and cultured in vitro , CFs undergo rapid phenotypic changes including increased expression of α-SMA. Here we describe a new model to study CFs and their response to pharmacological and mechanical stimuli using in vitro cultured mouse, dog and human myocardial slices. Methods and Results: Unloading of myocardial slices induced CF proliferation without α-SMA expression up to 7 days in culture . CFs migrating onto the culture plastic support or cultured on glass expressed αSMA within 3 days. The cells on the slice remained αSMA(-) despite TGF-β (20ng/mL) or angiotensin II (200µM) stimulation. When diastolic load was applied to myocardial slices using A-shaped stretchers, CF proliferation was significantly prevented at day 3 and 7 (P < 0.001). Conclusions: Myocardial slices allow the study of CFs in a multicellular environment and may be used to effectively study mechanisms of cardiac fibrosis and potential target