Overall Survival Endpoint in Oncology Clinical Trials: Addressing the Effect of Crossover - The Case of Pazopanib in Advanced Renal Cell Carcinoma

Objective: To identify the issues of using overall survival (OS) as a primary endpoint in the presence of crossover and the statistical analyses available to adjust for confounded OS due to crossover in oncology clinical trials. Methods: An indirect comparison was conducted between pazopanib and sunitinib in advanced renal cell carcinoma. Statistical adjustment methods were used to estimate the true comparative effectiveness of these treatments. Recently, a head-to-head trial comparing pazopanib and sunitinib was completed. This provided the opportunity to compare the OS treatment effect estimated for pazopanib versus sunitinib using indirect comparison and statistical adjustment techniques with that observed in the head-to-head trial. Results: Using a rank-preserving structural failure time model to adjust for crossover in the pazopanib registration trial, the indirect comparison of pazopanib versus sunitinib resulted in an OS hazard ratio (HR) of 0.97, while an unadjusted analysis resulted in an OS HR of 1.96. The head-to-head trial reported a final OS HR of 0.92 for pazopanib versus sunitinib. Conclusion: This case study supports the need to adjust for confounded OS due to crossover, which enables trials to meet ethical standards and provides decision makers with a more accurate estimate of treatment benefit

Influence of STAT4 polymorphism in primary Sjögren's syndrome

Objective. To examine the influence of STAT4 rs7574865 gene polymorphism on patients with primary Sjögren's syndrome (SS). Methods. Two different cohorts were studied: 69 patients with primary SS and 296 controls from Colombia and 108 patients with primary SS and 227 controls from Germany. Samples were genotyped for the STAT4 rs7574865 single-nucleotide polymorphism with a predesigned TaqMan single-nucleotide polymorphism genotyping assay. We carried out a metaanalysis of our results combined with data published to date. Results. Although no significant differences were observed in the allele frequencies of STAT4 rs7574865 gene polymorphism between patients and controls in Colombians (p = 0.28, OR 1.24, 95% CI 0.82-1.87) and Germans (p = 0.08, OR 1.40, 95% CI 0.96-2.02), the metaanalysis disclosed a significant effect of the T allele on disease (p = 4.7 = 10-6, OR 1.40, 95% CI 1.21-1.62). Conclusion. These data reinforce the influence of STAT4 gene on primary SS and as a general autoimmune gene. The Journal of Rheumatology Copyright © 2010. All rights reserved

Computing the first eigenpair of the p-Laplacian via inverse iteration of sublinear supersolutions

We introduce an iterative method for computing the first eigenpair $(\lambda_{p},e_{p})$ for the $p$-Laplacian operator with homogeneous Dirichlet data as the limit of $(\mu_{q,}u_{q})$ as $q\rightarrow p^{-}$, where $u_{q}$ is the positive solution of the sublinear Lane-Emden equation $-\Delta_{p}u_{q}=\mu_{q}u_{q}^{q-1}$ with same boundary data. The method is shown to work for any smooth, bounded domain. Solutions to the Lane-Emden problem are obtained through inverse iteration of a super-solution which is derived from the solution to the torsional creep problem. Convergence of $u_{q}$ to $e_{p}$ is in the $C^{1}$-norm and the rate of convergence of $\mu_{q}$ to $\lambda_{p}$ is at least $O(p-q)$. Numerical evidence is presented.Comment: Section 5 was rewritten. Jed Brown was added as autho

The Influence of Free Quintessence on Gravitational Frequency Shift and Deflection of Light with 4D momentum

Based on the 4D momentum, the influence of quintessence on the gravitational frequency shift and the deflection of light are examined in modified Schwarzschild space. We find that the frequency of photon depends on the state parameter of quintessence $w_q$: the frequency increases for $-1<w_q<-1/3$ and decreases for $-1/3<w_q<0$. Meanwhile, we adopt an integral power number $a$ ($a = 3\omega_q + 2$) to solve the orbital equation of photon. The photon's potentials become higher with the decrease of $\omega_q$. The behavior of bending light depends on the state parameter $\omega_q$ sensitively. In particular, for the case of $\omega_q = -1$, there is no influence on the deflection of light by quintessence. Else, according to the H-masers of GP-A redshift experiment and the long-baseline interferometry, the constraints on the quintessence field in Solar system are presented here.Comment: 12 pages, 2 figures, 4 tables. European Physical Journal C in pres

Holographic Dark Energy Model and Scalar-Tensor Theories

We study the holographic dark energy model in a generalized scalar tensor theory. In a universe filled with cold dark matter and dark energy, the effect of potential of the scalar field is investigated in the equation of state parameter. We show that for a various types of potentials, the equation of state parameter is negative and transition from deceleration to acceleration expansion of the universe is possible.Comment: 11 pages, no figure. To appear in General Relativity and Gravitatio

Top-squark searches at the Tevatron in models of low-energy supersymmetry breaking

We study the production and decays of top squarks (stops) at the Tevatron collider in models of low-energy supersymmetry breaking. We consider the case where the lightest Standard Model (SM) superpartner is a light neutralino that predominantly decays into a photon and a light gravitino. Considering the lighter stop to be the next-to-lightest Standard Model superpartner, we analyze stop signatures associated with jets, photons and missing energy, which lead to signals naturally larger than the associated SM backgrounds. We consider both 2-body and 3-body decays of the top squarks and show that the reach of the Tevatron can be significantly larger than that expected within either the standard supergravity models or models of low-energy supersymmetry breaking in which the stop is the lightest SM superpartner. For a modest projection of the final Tevatron luminosity, L = 4 fb-1, stop masses of order 300 GeV are accessible at the Tevatron collider in both 2-body and 3-body decay modes. We also consider the production and decay of ten degenerate squarks that are the supersymmetric partners of the five light quarks. In this case we find that common squark masses up to 360 GeV are easily accessible at the Tevatron collider, and that the reach increases further if the gluino is light.Comment: 32 pages, 9 figures; references adde

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours

Background: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. Methods: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. Results: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. Conclusions: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. Clinical trial identifier: NCT02157792

Astroparticle Physics with a Customized Low-Background Broad Energy Germanium Detector

The MAJORANA Collaboration is building the MAJORANA DEMONSTRATOR, a 60 kg array of high purity germanium detectors housed in an ultra-low background shield at the Sanford Underground Laboratory in Lead, SD. The MAJORANA DEMONSTRATOR will search for neutrinoless double-beta decay of 76Ge while demonstrating the feasibility of a tonne-scale experiment. It may also carry out a dark matter search in the 1-10 GeV/c^2 mass range. We have found that customized Broad Energy Germanium (BEGe) detectors produced by Canberra have several desirable features for a neutrinoless double-beta decay experiment, including low electronic noise, excellent pulse shape analysis capabilities, and simple fabrication. We have deployed a customized BEGe, the MAJORANA Low-Background BEGe at Kimballton (MALBEK), in a low-background cryostat and shield at the Kimballton Underground Research Facility in Virginia. This paper will focus on the detector characteristics and measurements that can be performed with such a radiation detector in a low-background environment.Comment: Submitted to NIMA Proceedings, SORMA XII. 9 pages, 4 figure