Florian Voss

Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .047). LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856.

Comparative efficacy of fixed-dose combinations of long-acting muscarinic antagonists and long-acting β2-agonists: a systematic review and network meta-analysis

Background: A number of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combinations (FDCs) for treatment of moderate-to-very severe chronic obstructive pulmonary disease (COPD) have recently become available, but none have been directly compared in head-to-head randomized controlled trials (RCTs). The purpose of this study was to assess the relative clinical benefit of all currently available LAMA/LABA FDCs using a Bayesian network meta-analysis (NMA). Methods: A systematic literature review identified RCTs investigating the efficacy, safety and quality of life associated with licensed LAMA/LABA FDCs for the treatment of moderate-to-very severe COPD. RCTs were screened for inclusion in the NMA using prespecified eligibility criteria. Data were extracted for outcomes of interest, including change in trough forced expiratory volume in 1 second (tFEV1) from baseline, St. George Respiratory Questionnaire (SGRQ) percentage of responders, Transition Dyspnea Index (TDI) percentage of responders, change in SGRQ score from baseline, change in TDI focal score from baseline, moderate-to-severe exacerbations, all-cause discontinuation, and discontinuation due to adverse events. Results: Following screening, a total of 27 trials from 26 publications with 30,361 subjects were eligible for inclusion in the NMA. Nonsignificant results were seen in most analyses comparing efficacy, exacerbations and discontinuation rates of included LAMA/LABA FDCs (i.e. aclidinium/formoterol 400/12 µg, glycopyrronium/indacaterol 110/50 µg, tiotropium + olodaterol 5/5 µg, umeclidinium/vilanterol 62.5/25 µg). Meta-regression controlling for post-bronchodilator percentage of tFEV1 predicted at baseline as well as meta-regression adjusting for concomitant use of inhaled corticosteroids at baseline was performed to assess the magnitude of effect modification and produced similar results as observed in the base case analysis. Conclusion: All LAMA/LABA FDCs were found to have similar efficacy and safety. Definitive assessment of the relative efficacy of different treatments can only be performed through direct comparison in head-to-head RCTs. In the absence of such data, this indirect comparison may be of value in clinical and health economic decision-making.

Distributional properties of euclidean distances in wireless networks involving road systems

Stochastic models for hierarchical telecommunication networks are considered, which can be applied to the analysis and planning of large wireless networks. The network geometry is modelled by random geometric graphs, and the locations of network nodes by point processes on the edges of these graphs. In particular, the locations of high-level components (HLC) are modeled by Cox processes concentrated on the edge sets of random graphs, where their serving zones are the cells of Voronoi tessellations induced by these Cox processes. The locations of low-level components (LLC) are either modeled by planar Poisson processes or by Cox processes concentrated on the same edge sets as the HLC. Distributional properties of distances between the locations of network nodes are closely related with the interference geometry and, consequently, the performance of wireless networks. Representation formulas are derived for the distribution function and density of the typical Euclidean connection distance between LLC and HLC. They lead to suitable estimators of these characteristics, which can be computed by Monte Carlo simulation of the typical serving zone and the typical segment system in it, respectively.

SCALING LIMITS FOR SHORTEST PATH LENGTHS ALONG THE EDGES OF STATIONARY TESSELLATIONS

We consider spatial stochastic models, which can be applied to, e.g. telecommunication networks with two hierarchy levels. In particular, we consider Cox processes X L and X H concentrated on the edge set T (1) of a random tessellation T, where the points X L,n and X H,n of X L and X H can describe the locations of low-level and high-level network components, respectively, and T (1) the underlying infrastructure of the network, such as road systems, railways, etc. Furthermore, each point X L,n of X L is marked with the shortest path along the edges of T to the nearest (in the Euclidean sense) point of X H . We investigate the typical shortest path length C * of the resulting marked point process, which is an important characteristic in, e.g. performance analysis and planning of telecommunication networks. In particular, we show that the distribution of C * converges to simple parametric limit distributions if a scaling factor κ converges to 0 or ∞. This can be used to approximate the density of C * by analytical formulae for a wide range of κ.

Simulation of the typical Poisson–Voronoi–Cox–Voronoi cell

We consider stationary Poisson–Voronoi tessellations (PVT) in the Euclidean plane and study the properties of Voronoi tessellations induced by linear Poisson processes on the edges of the PVT. We are especially interested in simulation algorithms for the typical cell. Two different simulation algorithms are introduced. The first algorithm directly simulates the typical cell, whereas the second algorithm simulates cells from which distributional properties of the typical cell can be obtained. This second algorithm can also be used for simulating the typical cell of other Cox–Voronoi tessellations. The implementation of both algorithms is tested for their correctness using random software tests. Then different cell characteristics are studied by simulation and compared with the typical cell of PVT and Cox–Voronoi tessellations based on linear Poisson processes on the lines of Poisson line processes. Our results can be applied, for example, in the analysis of telecommunication networks and vesicle paths on cytoskeletal networks.

Parametric distributions of connection lengths for the efficient analysis of fixed access networks

The access network displays an important particularity that the locations of the network components strongly depend on geometrical features such as road systems and a city’s architecture. This paper deals with the distributions of point-to-point connection lengths that play a major role in current problems in the analysis and planning of networks. Using the mathematical framework of stochastic geometry to model both the road system and the locations of network nodes, we derive analytical formulas for distributions of connection lengths. These formulas depend explicitly on a few parameters that can be computed easily and fast avoiding time-consuming reconstructions. We validate the approach by a comparison with actual network data and show its adaptability by considering several policies for nodes location and examples of use.

Densities of Shortest Path Lengths in Spatial Stochastic Networks

We consider a spatial stochastic model for telecommunication networks, the stochastic subscriber line model, and we investigate the distribution of the typical shortest path length between network components. Therefore, we derive a representation formula for the probability density of this distribution which is based on functionals of the so-called typical serving zone. Using this formula, we construct an estimator for the density of the typical shortest path length and we analyze the statistical properties of this estimator. Moreover, we introduce new simulation algorithms for the typical serving zone which are used in a numerical study in order to estimate the density and moments of the typical shortest path length for different specific models.

Myc Regulates Embryonic Vascular Permeability and Remodeling

Previous work has shown that c-Myc is required for adequate vasculogenesis and angiogenesis. To further investigate the contribution of Myc to these processes, we conditionally expressed c-Myc in embryonic endothelial cells using a tetracycline-regulated system. Endothelial Myc overexpression resulted in severe defects in the embryonic vascular system. Myc-expressing embryos undergo widespread edema formation and multiple hemorrhagic lesions. They die between embryonic days 14.5 and 17.5. The changes in vascular permeability are not caused by deficiencies in vascular basement membrane composition or pericyte coverage. However, the overall turnover of endothelial cells is elevated as is revealed by increased levels of both proliferation and apoptosis. Whole-mount immunohistochemical analysis revealed alterations in the architecture of capillary networks. The dermal vasculature of Myc-expressing embryos is characterized by a reduction in vessel branching, which occurs despite upregulation of the proangiogenic factors vascular endothelial growth factor-A and angiopoietin-2. Thus, the net outcome of an excess of vascular endothelial growth factor-A and angiopoietin-2 in the face of an elevated cellular turnover appears to be a defect in vascular integrity.

Efficacy and Safety of Faldaprevir, Deleobuvir, and Ribavirin in Treatment-Naive Patients with Chronic Hepatitis C Virus Infection and Advanced Liver Fibrosis or Cirrhosis

ABSTRACT Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n = 362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.)

ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir, Deleobuvir, and Ribavirin for HCV Infection

Background & Aim Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin. Methods HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression. Results In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12. Conclusions The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes. Trial Registration ClinicalTrials.gov: NCT01132313