Effect of early administration of tetracosactide on mortality and host response in critically ill patients requiring rescue surgery: a sensitivity analysis of the STOPSHOCK phase 3 randomized controlled trial.

BACKGROUND: Undifferentiated shock is recognized as a criticality state that is transitional in immune-mediated topology for casual risk of lethal microcirculatory dysfunction. This was a sensitivity analysis of a drug (tetracosactide; TCS10) targeting melanocortin receptors (MCRs) in a phase 3 randomized controlled trial to improve cardiovascular surgical rescue outcome by reversing mortality and hemostatic disorders. METHODS: Sensitivity analysis was based on a randomized, two-arm, multicenter, double-blind, controlled trial. The Naïve Bayes classifier was performed by density-based sensitivity index for principal strata as proportional hazard model of 30-day surgical risk mortality according to European System for Cardiac Operative Risk Evaluation inputs-outputs in 100 consecutive cases (from August to September 2013 from Emilia Romagna region, Italy). Patients included an agent-based TCS10 group (10 mg, single intravenous bolus before surgery; n = 56) and control group (n = 44) and the association with cytokines, lactate, and bleeding-blood transfusion episodes with the prior-risk log-odds for mortality rate in time-to-event was analyzed. RESULTS: Thirty-day mortality was significantly improved in the TCS10 group vs. control group (0 vs. 8 deaths, P < 0.0001). Baseline levels of interleukin (IL)-6, IL-10, and lactate were associated with bleeding episodes, independent of TCS10 treatment [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.39-2.79; OR = 1.53, 95%CI 1.17-2.12; and OR = 2.92, 95%CI 1.40-6.66, respectively], while baseline level of Fms-like tyrosine kinase 3 ligand (Flt3L) was associated with lower bleeding rates in TCS10-treated patients (OR = 0.31, 95%CI 0.11-0.90, P = 0.03). For every 8 TCS10-treated patients, 1 bleeding case was avoided. Blood transfusion episodes were significantly reduced in the TCS10 group compared to the control group (OR = 0.32, 95%CI 0.14-0.73, P = 0.01). For every 4 TCS10-treated patients, 1 transfusion case was avoided. CONCLUSIONS: Sensitivity index underlines the quality target product profile of TCS10 in the runway of emergency casualty care. To introduce the technology readiness level in real-life critically ill patients, further large-scale studies are required. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT Number: 2007-006445-41 ).

Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study.

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67-0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.

Efficacy and retention rate of adalimumab in rheumatoid arthritis and psoriatic arthritis patients after first-line etanercept failure: the FEARLESS cohort.

Few studies have compared the efficacy of switching from etanercept to adalimumab in the real-life setting in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This study evaluated the 2-year retention rate and 12-month efficacy of adalimumab in RA and PsA patients, previously treated with etanercept. RA and PsA patients from 11 Italian Rheumatology Units received adalimumab after first-line etanercept failure. Two-year adalimumab retention rate was calculated by the Kaplan-Meier method and Cox proportional hazard models were developed to examine predictors of drug persistence. Univariate and multivariate logistic regression analyses were developed to examine potential predictors of 12-month DAS-28 remission. The study population included 117 RA (disease duration of 10.1 ± 7.7 years and baseline DAS28-ESR of 4.97 ± 1.3) and 102 PsA (disease duration of 7.1 ± 5.1 years and baseline DAPSA of 24.6 ± 11.8). The 2-year retention rate was 48.2% in RA and 56.5% in PsA patients. Concomitant methotrexate treatment was not associated with increased drug survival in both groups. Similarly, cause of etanercept discontinuation or treatment duration was not associated with retention rate. 12-month remission and low disease activity were achieved, respectively, in 27.3% and 23.9% of RA patients and 27.4% and 23.5% PsA of patients. In multivariate models, etanercept discontinuation due to inefficacy (OR 0.27, 95% CI 1.03-0.73; p = 0.009) and baseline DAS-28 (OR 0.45, 95% CI 0.29-0.69; p < 0.001) remained significant negative predictors of remission in RA patients. No variable was associated with remission in PsA patients. Adalimumab after etanercept failure was highly effective and safe in both RA and PsA patients.

HLA-C*06:02 Does Not Predispose to Clinical Response Following Long-Term Adalimumab Treatment in Psoriatic Patients: A Retrospective Cohort Study.

BACKGROUND: The genetic basis of predisposition to psoriasis is recognised; however, the response to psoriasis treatment in patients with different genetic predisposition is poorly understood. OBJECTIVE: To analyse the presence of the HLA-C*06:02 polymorphism in psoriatic patients treated with adalimumab. METHODS: Genomic DNA was extracted from whole blood of 122 patients with moderate-to-severe psoriasis treated with adalimumab for 3 years. Genotyping was performed using PCR. Disease severity was assessed by the Psoriasis Area and Severity Index (PASI) at day 0 and after 1, 3, 6, 12, 24 and 36 months. Logistic regression was used to evaluate the association between dependent variables (including HLA-C*06:02 status) and achievement of PASI 50, 75 and 90. RESULTS: No difference was observed after adalimumab treatment between C*06:02 positive (HLA-C*06:02-POS) patients (n = 46) and C*06:02 negative (HLA-C*06:02-NEG) patients (n = 76) over the 3-year follow-up period in terms of PASI response or time-course when PASI response was achieved. However, a small, but non-statistically significant difference was noted between genotypes for PASI 50 at 1 month (HLA-C*06:02-NEG: 44.7% vs. HLA-C*06:02-POS: 56.5%) and at 3 months (HLA-C*06:02-NEG: 71.1% vs. HLA-C*06:02-POS: 80.4%). Simple logistic regression analysis did not reveal an association between independent variables (including C*06:02 status) and PASI response; however, multivariate regression revealed that gender (females better than males) was associated with achievement of PASI 50 at month 1 (OR 0.34, 95% CI 0.16-0.72, p = 0.005) and of PASI 75 at 3 months (OR 0.36, 95% CI 0.16-0.8, p = 0.012). CONCLUSION: Adalimumab reduced long-term severity in patients with moderate-severe psoriasis, independent of their HLA-C*06:02 status.

Impact of training on concordance among rheumatologists and dermatologists in the assessment of patients with psoriasis and psoriatic arthritis.

OBJECTIVE: To evaluate the impact of training on the reliability among dermatologists and rheumatologists in the assessment of psoriatic arthritis (PsA) patients. METHODS: Overall, 9 hospital-based rheumatologists and 8 hospital-based dermatologists met in Reggio Emilia, Italy on October 2015 to assess 17 PsA patients. After 1 month, physicians underwent a 3-h training session by 4 recognized experts and then assessed 19 different PsA patients according to a modified Latin square design. Measures included tender (TJC) and swollen joint count (SJC), dactylitis, enthesitis, Schober test, psoriasis body surface area (BSA), Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), and static physician's global assessment of PsA disease activity (sPGA). Variance components analyses were performed to estimate the intraclass correlation coefficient (ICC). RESULTS: TJC and enthesitis-measured pre-training by dermatologists or rheumatologists revealed moderate-substantial agreement (ICC: 0.4-0.8). In contrast, SJC and Schober test showed fair (ICC: 0.2-0.4) and moderate agreement, respectively (ICC: 0.4-0.6), while poor agreement (ICC: 0-0.2) was represented by dactylitis. Moderate-substantial (ICC: 0.4-0.8) agreement was observed for most skin measures by dermatologists and rheumatologists, apart from BSA, where fair agreement (ICC: 0.2-0.4) was observed. Agreement levels were similar before and after training for arthritis measures. In contrast, levels of agreement after training for 3 of the 4 skin measures were increased for dermatologists and all 4 skin measures were increased for rheumatologists. CONCLUSIONS: Substantial to excellent agreement was observed for TJC, enthesitis, PASI, and sPGA. Rheumatologists benefited from training to a greater extent.

Pathophysiology and pharmacological targets of VEGF in diabetic macular edema.

Diabetic macular edema (DME) is a serious condition that can cause blindness in diabetic patients suffering from diabetic retinopathy (DR). Although vascular endothelial growth factor (VEGF) is known to play a role in the development of DME, the pathological processes leading to the onset of this disease are highly complex and the exact sequence in which they occur is still not completely understood. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of this disease. However, it still remains to be clarified whether angiogenesis following VEGF over-expression is a cause or a consequence of inflammation. Here, we provide an overview of the current data available in the literature focusing on VEGF, angiogenesis, inflammation, DR and DME. Our analysis suggests that angiogenesis and inflammation act interdependently during the development of DME. VEGF is a critical player in the molecular crosstalk occurring between these two processes, reinforcing the use of anti-VEGF agents for the treatment of DME.

Epoetin beta for the treatment of chemotherapy-induced anemia: an update.

Epoetin beta belongs to the class of erythropoiesis-stimulating agents (ESAs) that are currently available to treat anemic patients receiving chemotherapy. Chemotherapy-induced anemia affects a high percentage of cancer patients and, due to its negative effects on disease outcome and the patient's quality of life, should be treated when first diagnosed. Initial trials with ESAs have shown efficacy in improving quality of life and reducing the need for blood transfusions in patients with chemotherapy-induced anemia. However, recent meta-analyses have provided conflicting data on the impact of ESAs on survival and tumor progression. Here we provide an overview of these recent data and review the role of epoetin beta in the treatment of chemotherapy-induced anemia over the past 20 years.

Potential therapeutic use of deferoxamine and mesenchymal stem cells in type-1 diabetes: assembling another piece of the jigsaw, in what is a complex puzzle.

Mesenchymal stem cells (MSCs) are recognized for their potential in regenerative medicine. Due to long-term negative effects associated with insulin administration and difficulty with pancreas transplantation, patients with type-1 diabetes could significantly benefit from organ-targeted cell-based therapy. Although several pharmacological agents increase the homing capacity of MSCs, the mechanisms regulating this process are still poorly understood. In this issue, Najafi et al. have demonstrated that pre-treatment of bone marrow-derived MSCs with the iron chelator and hypoxia mimetic, deferoxamine, can increase homing to the pancreas in a rat model of diabetes. This effect appears to be driven through specific chemokines in addition to hypoxia-inducing factor 1-alpha. Results from this study provide important clues in our endeavour to solve a complex process. Further studies will help determine whether these findings may offer potential therapeutic benefit to patients with diabetes.

Levels of circulating CXCR4-positive cells are decreased and negatively correlated with risk factors in cardiac transplant recipients.

The association between levels of circulating endothelial progenitor cells (EPCs) and heart transplant recipients (HTX) with cardiac allograft vasculopathy (CAV) is under debate. The chemokine receptor CXCR4 plays an important role in the mobilization of progenitor cells and is implicated in pathological conditions, including cardiovascular disease. This study aims to evaluate the association between EPCs and CXCR4-positive cells in HTX patients. Peripheral blood mononuclear cells (PBMCs) from 34 HTX patients and 25 control participants were analyzed by flow cytometry for CXCR4-positive cells and EPCs. Endothelial progenitor cells were defined by the expression of a range of hematopoietic and endothelial lineage markers in different combinations. The ability to form endothelial cell colonies in vitro was also assessed by colony-forming unit (CFU) assay. Phenotypic analysis of EPCs by flow cytometry revealed similar levels in HTX patients compared to controls. In addition, no difference was observed between levels of EPCs or CFU number in patients with and without CAV. By contrast, CFU assay revealed a reduced number of CFUs in HTX patients compared to controls (3.3% ± 0.95 and 13.3% ± 4.5%, respectively, P = 0.014). Likewise, levels of CXCR4-positive cells were significantly reduced (15.9 ± 1.4 in patients vs 24.8 ± 3.3% in controls, P < 0.01), negatively correlated with Framingham risk score (rho = -0.4, P = 0.02) and the number of risk factors (rho = -0.3, P = 0.049). Levels of CXCR4-positive cells were also correlated with CFU number (r = 0.65, P = 0.0005). These findings further develop our understanding of the role of EPCs and endothelial CFUs in cardiovascular disease, in addition to highlighting the potential importance of CXCR4 in heart transplantation.

Reduced levels of putative endothelial progenitor and CXCR4+ cells in coronary artery disease: kinetics following percutaneous coronary intervention and association with clinical characteristics.

Levels of circulating endothelial progenitor cells (EPCs) and CXCR4-positive cells are decreased in patients with coronary artery disease (CAD); however, their ability to change in response to acute vascular injury remains to be elucidated. Progenitor and CXCR4-positive cells were analysed by flow cytometry from the peripheral blood of 23 healthy controls and 23 patients with CAD, of which 13 patients underwent angiogram and 10 patients received percutaneous coronary intervention (PCI) with stent implantation. Baseline levels of progenitor and CXCR4-positive cells were substantially reduced in CAD patients compared to controls, although they were still capable of increasing in response to vascular injury. Levels of progenitor and CXCR4-positive cells were increased to a greater extent in the PCI group compared to angiogram patients. At presentation, levels of putative endothelial progenitor and CXCR4-positive cells were found to be negatively correlated with disease severity. A one-year follow-up revealed that out of the cell populations examined, only levels of CXCR4-positive cells were positively correlated with angina frequency in the PCI group, but not in patients receiving angiogram. Baseline levels of progenitor cells are differentially increased depending upon the severity of vascular injury incurred, regardless of a significant deficit in baseline levels in CAD patients. Levels of putative EPCs and CXCR4-positive cells were negatively correlated with disease severity at presentation, however, only CXCR4-positive cells were associated with patient condition in a one-year follow-up.