Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines.

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts.

Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase 3 Randomized Clinical Trial.

Importance: DCVAC/PCa is an active cellular immunotherapy designed to initiate an immune response against prostate cancer.

Objective: To evaluate the efficacy and safety of DCVAC/PCa plus chemotherapy followed by DCVAC/PCa maintenance treatment in patients with metastatic castration-resistant prostate cancer (mCRPC).

Design, Setting, And Participants: The VIABLE double-blind, parallel-group, placebo-controlled, phase 3 randomized clinical trial enrolled patients with mCRPC among 177 hospital clinics in the US and Europe between June 2014 and November 2017.

Blood Pressure Recovery After Dobutamine Antagonism: Partial With Landiolol, None With Esmolol.

We investigated the hemodynamic effects of 2 short-acting β -blockers, landiolol and esmolol, in the continuous presence of dobutamine in a prospective, single-center, randomized, crossover study in 16 healthy White volunteers. Dobutamine was infused at a rate sufficient to increase the heart rate by at least 30 beats per minute, followed by a 60-minute infusion of 50 μg/kg/min esmolol or 10 μg/kg/min landiolol on top of the unchanged dobutamine infusion. Concentrations of β-blockers and their metabolites in blood, heart rate, and blood pressure were followed for 180 minutes.

Autologous dendritic cell-based immunotherapy (DCVAC/LuCa) and carboplatin/paclitaxel in advanced non-small cell lung cancer: A randomized, open-label, phase I/II trial.

Purpose: To investigate the efficacy and safety of an active cellular immunotherapy (DCVAC/LuCa) and chemotherapy in patients with stage IV non-small cell lung cancer (NSCLC).

Patients And Methods: SLU01 was a multicenter, open-label, parallel-group, randomized, phase I/II trial. NSCLC patients were randomized in a ratio of 1:1:1 to receive: DCVAC/LuCa and chemotherapy (carboplatin and paclitaxel; Group A); DCVAC/LuCa, chemotherapy, pegylated interferon-α2b, and hydroxychloroquine (Group B); or chemotherapy alone (Group C).

Dobutamine Alters the Pharmacokinetic and Pharmacodynamic Behavior of Esmolol.

Background and objective This study involved an investigation into the pharmacokinetic and pharmacodynamic behavior of esmolol in the presence of dobutamine in healthy subjects of European ancestry. Methods We conducted a single-center, prospective randomized study of 16 healthy subjects with each receiving an infusion of dobutamine sufficient to increase heart rate (HR) by 30 beats per minute (bpm) followed by a 60-minute infusion of 50 µg/kg/min esmolol. Pharmacokinetics, HR, and blood pressure were evaluated for 180 minutes.

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults.

Background: To study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry.

Methods: We conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 μg/kg/min landiolol.

Results: Dobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started.

Open-Label Two-Dose Pilot Study of Landiolol for the Treatment of Atrial Fibrillation/Atrial Flutter in Caucasian Patients.

Background: We investigated for the first time the suitability of landiolol, an ultra-short-acting β1-specific β-blocker, for the treatment of atrial fibrillation/atrial flutter (AF/AFL) in Caucasian patients.

Methods and results: The 20 study patients received landiolol as a continuous infusion (starting dose 40 µg/kg/min) with (B+CI) or without (CI) a preceding bolus dose (100 µg/kg/min administered over 1 min) in a prospective open-label study. The primary endpoint was the proportion of patients with sustained heart rate (HR) reduction ≥20% or to <90 beats/min within 16 min of starting the CI.

Landiolol in patients with septic shock resident in an intensive care unit (LANDI-SEP): study protocol for a randomized controlled trial.

Background: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting.

Pharmacokinetics and Pharmacodynamics of Low-, Intermediate-, and High-Dose Landiolol and Esmolol During Long-Term Infusion in Healthy Whites.

The pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of esmolol and landiolol, a new fast-acting cardioselective β-blocker, were compared for the first time in Caucasian subjects in a prospective clinical trial. Twelve healthy volunteers received landiolol and esmolol by continuous infusion for 24 hours in a randomized crossover study using a dose-escalation regimen. Blood concentrations of drugs and metabolites, heart rate, blood pressure, ECG parameters, and tolerability were observed for 30 hours and compared.

Pharmacodynamic and -kinetic Behavior of Low-, Intermediate-, and High-Dose Landiolol During Long-Term Infusion in Whites.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of landiolol, a fast-acting cardioselective β-blocker, were investigated for the first time in white subjects in a prospective clinical trial. Blood concentrations of landiolol and its metabolites, heart rate (HR), blood pressure (BP), and electrocardiogram parameters were studied in 12 healthy volunteers receiving continuous infusions of a new 12-mg/mL formulation of landiolol using a dose-escalation regimen (10 μg/kg BW/min for 2 hours, 20 μg/kg BW/min for 2 hours, 40 μg/kg BW/min for 20 hours, 6 hours follow-up). Landiolol blood concentrations were dose proportional.

Intravenous thrombolysis for ischemic stroke in the golden hour: propensity-matched analysis from the SITS-EAST registry.

As there are scarce data regarding the outcomes of acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT) within 60 min from symptom onset ("golden hour"), we sought to compare outcomes between AIS patients treated within [GH(+)] and outside [GH(-)] the "golden hour" by analyzing propensity score matched data from the SITS-EAST registry. Clinical recovery (CR) at 2 and 24 h was defined as a reduction of ≥10 points on NIHSS-score or a total NIHSS-score of ≤3 at 2 and 24 h, respectively. A relative reduction in NIHSS-score of ≥40% at 2 h was considered predictive of complete recanalization (CREC).

Bolus application of landiolol and esmolol: comparison of the pharmacokinetic and pharmacodynamic profiles in a healthy Caucasian group.

Purpose: The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective β1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages.

Materials And Methods: We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.

Incidence of Hospitalized Stroke in the Czech Republic: The National Registry of Hospitalized Patients.

Background: Contemporary stroke incidence data are not available in some countries and regions, including in Eastern Europe. Based on previous validation of the accuracy of the National Registry of Hospitalized Patients (NRHOSP), we report the incidence of hospitalized stroke in the Czech Republic (CR) using the NRHOSP.

Methods: The results of the prior validation study assessing the accuracy of coding of stroke diagnoses in the NRHOSP were applied, and we calculated (1) the overall incidence of hospitalized stroke and (2) the incidence rates of hospitalized stroke for the three main stroke types: cerebral infarction (International Classification of Diseases Tenth Revision, CI I63), subarachnoid hemorrhage (SAH I60), and intracerebral hemorrhage (ICH I61).

Real-World Outcomes in Fingolimod-Treated Patients with Multiple Sclerosis in the Czech Republic: Results from the 12-Month GOLEMS Study.

Background And Objective: Once-daily oral fingolimod is approved in the EU as escalation treatment for adult patients with highly active relapsing multiple sclerosis (MS). The efficacy and safety profiles of fingolimod have been well established in a large clinical development programme and several papers reflecting the experience with fingolimod in real-world settings have been published to date. The GOLEMS study was designed to evaluate the efficacy, safety and tolerability of fingolimod and the impact of fingolimod treatment on disability progression and work capability in patients with MS in routine clinical practice in the Czech Republic.

Single-Phase Versus Multiphase CT Angiography in Middle Cerebral Artery Clot Detection-Benefits for Less Experienced Radiologists and Neurologists.

Objectives: CT angiography (CTA) is recommended as a standard of stroke imaging. We investigated accuracy and precision of standard or single-phase CTA as compared with novel technique or multiphase CTA in clot detection in the middle cerebral artery.

Methods: Twenty single-phase CTA and twenty multiphase CTA with prevailing M2 occlusion were assessed by 10 radiologists and 10 neurologists blinded to clinical information (7 less experienced and 3 experienced).

Pharmacokinetics and pharmacodynamics of two different landiolol formulations in a healthy Caucasian group.

Background: To date, no data have been reported on the pharmacokinetic and pharmacodynamic properties of landiolol, a fast-acting cardioselective β1-adrenergic antagonist, in non-Asian subjects. The aim of this study was to compare two landiolol formulations in healthy Caucasian subjects.

Materials And Methods: We conducted a single-center, prospective, double-blinded, randomized study in two cross-over periods with 12 healthy subjects (7 women and 5 men) each receiving three doses (0.

Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera.

In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) α-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients.

Safety of Statin Pretreatment in Intravenous Thrombolysis for Acute Ischemic Stroke.

Background And Purpose: A recent meta-analysis investigating the association between statins and early outcomes in acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT) indicated that prestroke statin treatment was associated with increased risk of 90-day mortality and symptomatic intracranial hemorrhage. We investigated the potential association of statin pretreatment with early outcomes in a large, international registry of AIS patients treated with IVT.

Methods: We analyzed prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST) registry on consecutive AIS patients treated with IVT during an 8-year period.

Validation of Stroke Diagnosis in the National Registry of Hospitalized Patients in the Czech Republic.

Background: Stroke is a common cause of mortality and morbidity in Eastern Europe. However, detailed epidemiological data are not available. The National Registry of Hospitalized Patients (NRHOSP) is a nationwide registry of prospectively collected data regarding each hospitalization in the Czech Republic since 1998.

Earlier identification of risks: cumulative probability analysis of time to safety alerts for therapeutic monoclonal antibodies.

Objective: Previous analysis of US FDA Medwatch safety alerts for monoclonal antibody therapeutics demonstrated that premarketing clinical trials can predict more than half of safety concerns. We expanded this analysis to assess whether the predictable alerts are detected sooner than the unpredictable alerts.

Methods: Times to alert were compared using Mann-Whitney test, Kolmogorov-Smirnov test, and using curves displaying cumulative frequencies of alerts over time.

Midlife Alcohol Consumption and Risk of Dementia Over 43 Years of Follow-Up: A Population-Based Study From the Swedish Twin Registry.

Background: Midlife alcohol consumption (beer, wine, and spirits) was examined in relation to dementia incidence over 43 years.

Methods: Participants were 12,326 members of the population-based Swedish Twin Registry born during 1907-1925 who responded to items about alcohol consumption in 1967/1970, subsequently classified as nondrinking (0 grams of ethanol per day), light (1-5g/d), moderate (5-12g/d), heavy (12-24g/d), and very heavy (>24g/d) drinking. Dementia was identified from the National Patient and Cause of Death Registries.

Alcohol consumption at midlife and risk of stroke during 43 years of follow-up: cohort and twin analyses.

Background And Purpose: Although alcohol-stroke association is well known, the age-varying effect of alcohol drinking at midlife on subsequent stroke risk across older adulthood has not been examined. The effect of genetic/early-life factors is also unknown. We used cohort and twin analyses of data with 43 years of follow-up for stroke incidence to help address these gaps.

Hyperdense cerebral artery computed tomography sign is associated with stroke severity rather than stroke subtype.

Background: The hyperdense cerebral artery sign (HCAS) on unenhanced computed tomography (CT) in acute ischemic stroke is a valuable clinical marker, but it remains unclear if HCAS reflects clot composition or stroke etiology. Therefore, variables independently associated with HCAS were identified from a large international data set of patients treated with intravenous thrombolysis.

Methods: All stroke patients undergoing intravenous thrombolysis from the Safe Implementation of Treatments in Stroke-EAST (SITS-EAST) database between February 2003 and December 2011 were analyzed.

Factors influencing door-to-imaging time: analysis of the safe implementation of treatments in Stroke-EAST registry.

Background: Brain imaging is logistically the most difficult step before thrombolysis. To improve door-to-needle time (DNT), it is important to understand if (1) longer door-to-imaging time (DIT) results in longer DNT, (2) hospitals have different DIT performances, and (3) patient and hospital characteristics predict DIT.

Methods: Prospectively collected data in the Safe Implementation of Treatments in Stroke-EAST (SITS-EAST) registry from Central/Eastern European countries between 2008 and 2011 were analyzed.

Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study.

Objective: Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation.

Design: Multicenter, double-masked, randomized, placebo-controlled phase III study.