Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months

GWTC-2.1: Deep extended catalog of compact binary coalescences observed by LIGO and Virgo during the first half of the third observing run

The second Gravitational-Wave Transient Catalog, GWTC-2, reported on 39 compact binary coalescences observed by the Advanced LIGO and Advanced Virgo detectors between 1 April 2019 15:00 UTC and 1 October 2019 15:00 UTC. Here, we present GWTC-2.1, which reports on a deeper list of candidate events observed over the same period. We analyze the final version of the strain data over this period with improved calibration and better subtraction of excess noise, which has been publicly released. We employ three matched-filter search pipelines for candidate identification, and estimate the probability of astrophysical origin for each candidate event. While GWTC-2 used a false alarm rate threshold of 2 per year, we include in GWTC-2.1, 1201 candidates that pass a false alarm rate threshold of 2 per day. We calculate the source properties of a subset of 44 high-significance candidates that have a probability of astrophysical origin greater than 0.5. Of these candidates, 36 have been reported in GWTC-2. We also calculate updated source properties for all binary block hole events previously reported in GWTC-1. If the 8 additional high-significance candidates presented here are astrophysical, the mass range of events that are unambiguously identified as binary black holes (both objects \geq 3M_\odot) is increased compared to GWTC-2, with total masses from \sim 14M_\odot for GW190924_021846 to \sim 182M_\odot for GW190426_190642. Source properties calculated using our default prior suggest that the primary components of two new candidate events (GW190403_051519 and GW190426_190642) fall in the mass gap predicted by pair-instability supernova theory. We also expand the population of binaries with significantly asymmetric mass ratios reported in GWTC-2 by an additional two events (the mass ratio is less than 0.65 and 0.44 at 90% probability for GW190403_051519 and GW190917_114630 respectively), and find that 2 of the 8 new events have effective inspiral spins \chi_\mathrm{eff} > 0 (at 90\% credibility), while no binary is consistent with \chi_\mathrm{eff} \lt 0 at the same significance. We provide updated estimates for rates of binary black hole and binary neutron star coalescence in the local Universe

Patterns of care and outcome for patients with glioblastoma diagnosed during 2008-2010 in Spain

Seit einigen Jahren unterliegt der Bereich der Ingenieurgeodäsie einem starken Wandel, da sich diese Disziplin generell den stetig weiterentwickelnden, anwendungsbezogenen Problemstellungen widmet. Unter diesen Aspekten ist insbesondere die flächenhafte Erfassung von Objekten und ihrer Geometrien – bis hin zur ganzheitlichen Raumkontinuisierung – in den Fokus der Ingenieurgeodäsie geraten. In diesem Kontext ergründet diese Dissertation, inwieweit die Konfiguration bei der Approximation von Oberflächen, die räumlich ungleichmäßig abgetastet wurden, analysiert und gegebenenfalls auch optimiert werden kann. Die zugrunde liegenden Messungen basieren auf Nivellements und terrestrischen Laserscans. Deren Oberflächenabtastung ist jeweils ungleichmäßig. Bei Nivellements liegt die Ursache in der Wirtschaftlichkeit und Siedlungsstruktur der Untersuchungsgebiete, beim terrestrischen Laserscanning (TLS) kann dies messtechnisch mit der polaren Abtastung begründet werden. In beiden Fällen dienen die Messpunkte häufig zur Approximation von Oberflächen, um flächenkontinuierliche Aussagen treffen zu können. Gängige Anwendungen sind z.B. die Analyse von Bodenbewegungen beim Nivellement oder die Deformationsanalyse beim TLS. Obwohl bei diesen Anwendungen im Allgemeinen eine ausreichend große Anzahl an Messpunkten zur Verfügung steht, führt die ungleichmäßige Punktverteilung dennoch oftmals zu einer ungünstigen Konfiguration des Ausgleichs. Diese kann in Kombination mit dem oft nur limitiert vorhanden Modellwissen bei der Flächenmodellierung zu verzerrten Parameterschätzungen führen. Diese Konfiguration gilt es demnach zu analysieren und ggf. auch zu optimieren. Auf Basis dieser methodischen Analysen können schwerpunktmäßig vier Aspekte herausgestellt werden: 1) Anhand der Redundanzanteile sowie anhand von relativen Redundanzanteilunterschieden kann gezeigt werden, dass die ungleichmäßige Punktverteilung in Kombination mit limitiertem Modellwissen zu einer suboptimalen Konfiguration bei der Approximation von Oberflächen führt. Die Redundanzanteile vereinen sowohl die geometrische Verteilung der Messpunkte, die Objektgeometrie als auch das stochastische Modell der Beobachtungen zur Beurteilung der Zuverlässigkeit und der Konfiguration. 2) Zur Optimierung der Konfiguration bei der Approximation flächenhafter Nivellements wird ein Algorithmus aufgestellt, der die Messpunktverteilung im Bezug zur Komplexität der Bodensenkungen objektiv bewertet. Die existierenden Messpunkte werden hinsichtlich ihrer Wichtigkeit für die Approximation – auf Basis der Konfiguration – selektiert. Zusätzlich ist es in der Netzausgleichung erstmals möglich, die Positionen und die Anzahl zusätzlich benötigter Messpunkte zu bestimmen. 3) Die Approximationen gescannter Oberflächen sind oft verzerrt und abhängig vom Standpunkt. Dies kann anhand einer Konfigurationsanalyse unter Betrachtung der Redundanzanteile quantifiziert und analysiert werden. Ferner kann durch eine Punktausdünnung – also durch die Herstellung einer gleichmäßigen Abtastung – eine Minimierung der Standpunktabhängigkeit erzeugt werden. Dies zeigt sich auch in Form einer verbesserten Konfiguration. 4) Ein weiterentwickeltes Konzept zur scannerbasierten Deformationsuntersuchung integriert die beschriebenen Aspekte der Konfigurationsanalyse und -optimierung anhand eines konkreten Beispiels. Ferner wird der Aspekt der Scannerkalibrierung hervorgehoben und in die Deformationsanalyse integriert. Insgesamt bedeuten diese Maßnahmen einen großen Fortschritt für die Nutzung terrestrischer Laserscanner zur zuverlässigen und genauen Deformationsanalyse. Diese Ergebnisse sind unmittelbar relevant für alle flächenhaften Approximationen mit hohen Genauigkeitsanforderungen. Im Gesamten stellt diese Dissertation also eine Grundlage zur verbesserten Analyse, Bewertung und Interpretation von Approximationen auf Basis ungleichmäßig abgetasteter Oberflächen dar. Eingebettet in ebenfalls erwähnte, weiterführende methodische Untersuchungen ist diese Dissertation damit bei der für die Ingenieurgeodäsie angestrebten ganzheitlichen Raumkontinuisierung von großem NutzenAnalysis of the configuration at approximating irregularly sampled surfaces based on levellings and terrestrial laser scans Since several years, the field of engineering geodesy has been subject to change. This is due to the fact that engineering geodesy generally attends to applied problem statements. Based on these aspects, especially the area-based acquisition of objects and their geometries – up to an integrated space continualization – got into focus of engineering geodesy. In this context, this dissertation fathoms the possibility of analyzing and optimizing the configuration at approximation surfaces that are spatially irregularly sampled. The underlying measurements are based on levellings and terrestrial laser scans, which both sample the surface irregularly. With levellings, the reason for the irregular sampling is caused by cost effectiveness and the settlement structure of the investigated areas. With terrestrial laser scanning (TLS), the reason is caused by its polar sampling due to its measurement technology. In both cases, the sampling points are often used for approximating surfaces in order to gain area-based conclusions. Established applications are, e.g., the analysis of ground subsidence with levellings or the area-based deformation analysis with TLS. The configuration of approximation suffers from the irregular spatial distribution of the sampling points even if these sampling points are of sufficient quantity. In combination with limited model knowledge, this can result in biased parameter estimates when modelling surfaces. Hence, the configuration needs to be analyzed and – if necessary – also optimized. Based on these methodical analyses, four aspects can be highlighted with emphasis: 1) It can be exposed that the irregular distribution of sampling points in combination with limited model knowledge results in a suboptimal configuration at approximating surfaces. This analysis rests on partial redundancies and relative differences in partial redundancies. Partial redundancies combine the geometric distribution of the sampling points, the object geometry and the stochastic model of the observations for evaluating the reliability and configuration. 2) For optimizing this configuration at approximating area-based levellings, an algorithm is developed. This algorithm objectively evaluates the spatial distribution of the sampling points dependent on the complexity of the ground subsidence. Existing sampling points are selected based on their importance for the approximation – judged by the configuration analysis. Furthermore, the number and position of additionally required sampling points can be determined for the first time in geodetic network optimization. 3) The parameter estimates of scanned surfaces are often biased and due to the station of the laser scanner. This can be quantified and analyzed based on a configuration analysis considering the partial redundancies. A data reduction – which equals a thinning of the point cloud to gain a regular sampling – minimizes the dependence of the parameter estimates on the laser scanner station. This can also be seen in the improved configuration. 4) An advanced concept for laser scanner based deformation analyses integrates the described aspects of configuration analysis and optimization for a concrete application. In this context, also the aspect of laser scanner calibration is pointed out and integrated into this deformation analysis. These steps altogether imply an immense progress at using terrestrial laser scanners for reliable and accurate deformation analyses. These results are instantaneously relevant for all surface-based approximations demanding high accuracy. Overall, this thesis builds up a fundament for an improved analysis, evaluation and interpretation of area-based approximations based on irregularly sampled surfaces. Embedded in other mentioned methodical aspects, this thesis is of great benefit for the integrated space continualization aspired in engineering geodesy