Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

BACKGROUND: Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS: Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS: Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION: Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING: German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

A treatment method for Class II Division 1 patients with extraction of permanent maxillary first molars

Throughout the years, various treatment modalities have been presented for the treatment of Class II Division 1 malocclusions. The goal of this paper is to present a treatment approach that involves the extraction of the maxillary first molars followed by use of fixed appliances with low-friction brackets. This treatment approach has proven to be an efficient treatment modality for Class II Division 1 malocclusions, especially with noncompliant patients.

New means in spinal pedicle hook fixation. A biomechanical evaluation

Pedicle hooks which are used as an anchorage for posterior spinal instrumentation may be subjected to considerable three-dimensional forces. In order to achieve stronger attachment to the implantation site, hooks using screws for additional fixation have been developed. The failure loads and mechanisms of three such devices have been experimentally determined on human thoracic vertebrae: the Universal Spine System (USS) pedicle hook with one screw, a prototype pedicle hook with two screws and the Cotrel-Dubousset (CD) pedicle hook with screw. The USS hooks use 3.2-mm self-tapping fixation screws which pass into the pedicle, whereas the CD hook is stabilised with a 3-mm set screw pressing against the superior part of the facet joint. A clinically established 5-mm pedicle screw was tested for comparison. A matched pair experimental design was implemented to evaluate these implants in constrained (series I) and rotationally unconstrained (series II) posterior pull-out tests. In the constrained tests the pedicle screw was the strongest implant, with an average pull-out force of 1650 N (SD 623 N). The prototype hook was comparable, with an average failure load of 1530 N (SD 414 N). The average pull-out force of the USS hook with one screw was 910 N (SD 243 N), not significantly different to the CD hook's average failure load of 740 N (SD 189 N). The result of the unconstrained tests were similar, with the prototype hook being the strongest device (average 1617 N, SD 652 N). However, in this series the difference in failure load between the USS hook with one screw and the CD hook was significant. Average failure loads of 792 N (SD 184 N) for the USS hook and 464 N (SD 279 N) for the CD hook were measured. A pedicular fracture in the plane of the fixation screw was the most common failure mode for USS hooks.(ABSTRACT TRUNCATED AT 250 WORDS)

Governing individual learning in the transition phase of software maintenance offshoring: a dynamic perspective

Prior studies suggest that clients need to actively govern knowledge transfer to vendor staff in offshore outsourcing. In this paper, we analyze longitudinal data from four software maintenance offshore out-sourcing projects to explore why governance may be needed for knowledge transfer and how governance and the individual learning of vendor engineers inter-act over time. Our results suggest that self-control is central to learning, but may be hampered by low levels of trust and expertise at the outset of projects. For these foundations to develop, clients initially need to exert high amounts of formal and clan controls to enforce learning activities against barriers to knowledge sharing. Once learning activities occur, trust and expertise increase and control portfolios may show greater emphases on self-control.

The bivalency effect represents an interference-triggered adjustment of cognitive control: an ERP study

When bivalent stimuli (i.e., stimuli with relevant features for two different tasks) occur occasionally among univalent stimuli, performance is slowed on subsequent univalent stimuli even if they have no overlapping stimulus features. This finding has been labeled the bivalency effect. It indexes an adjustment of cognitive control, but the underlying mechanism is not well understood yet. The purpose of the present study was to shed light on this question, using event-related potentials. We used a paradigm requiring predictable alternations between three tasks, with bivalent stimuli occasionally occurring on one task. The results revealed that the bivalency effect elicited a sustained parietal positivity and a frontal negativity, a neural signature that is typical for control processes implemented to resolve interference. We suggest that the bivalency effect reflects interference, which may be caused by episodic context binding.

Assimilation of Compliance Software in Highly Regulated Industries: An Empirical Multitheoretical Investigation

In this paper we follow a theory-based approach to study the assimilation of compliance software in highly regulated multinational enterprises. These relatively new software products support the automation of controls which are associated with mandatory compliance requirements. We use institutional and success factor theories to explain the assimilation of compliance software. A framework for analyzing the assimilation of Access Control Systems (ACS), a special type of compliance software, is developed and used to reflect the experiences obtained in four in-depth case studies. One result is that coercive, mimetic, and normative pressures significantly effect ACS assimilation. On the other hand, quality aspects have only a moderate impact at the beginning of the assimilation process, in later phases the impact may increase if performance and improvement objectives become more relevant. In addition, it turns out that position of the enterprises and compatibility heavily influence the assimilation process.

Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naive prostate cancer and are elevated in castration-resistant disease

Patients with advanced prostate cancer (PC) are usually treated with androgen withdrawal. While this therapy is initially effective, nearly all PCs become refractory to it. As hormone receptors play a crucial role in this process, we constructed a tissue microarray consisting of PC samples from 107 hormone-naïve (HN) and 101 castration-resistant (CR) PC patients and analyzed the androgen receptor (AR) gene copy number and the protein expression profiles of AR, Serin210-phosphorylated AR (pAR(210)), estrogen receptor (ER)β, ERα and the proliferation marker Ki67. The amplification of the AR gene was virtually restricted to CR PC and was significantly associated with increased AR protein expression (P<0.0001) and higher tumor cell proliferation (P=0.001). Strong AR expression was observed in a subgroup of HN PC patients with an adverse prognosis. In contrast, the absence of AR expression in CR PC was significantly associated with a poor overall survival. While pAR(210) was predominantly found in CR PC patients (P<0.0001), pAR(210) positivity was observed in a subgroup of HN PC patients with a poor survival (P<0.05). Epithelial ERα expression was restricted to CR PC cells (9%). ERβ protein expression was found in 38% of both HN and CR PCs, but was elevated in matched CR PC specimens. Similar to pAR(210), the presence of ERβ in HN patients was significantly associated with an adverse prognosis (P<0.005). Our results strongly suggest a major role for pAR(210) and ERβ in HN PC. The expression of these markers might be directly involved in CR tumor growth.

Glucose transporter expression in eutopic endometrial tissue and ectopic endometriotic lesions

Endometriosis is an extremely prevalent disorder characterized by the growth of endometrial tissue at ectopic locations. Glycolysis is an energy-producing mechanism that occurs in almost all cells and requires an adequate uptake of glucose mediated by glucose transporter (GLUT) proteins. At present, however, very little is known about their expression in either the endometrium or the endometriotic lesions. The objective of this study was to examine the expression of SLC2A genes in the endometrium of women with and without endometriosis and in the matching ectopic tissue, and to confirm the presence of the GLUT proteins in ectopic lesions. There was a significantly higher expression of SLC2A3 and a significantly lower expression of SLC2A4 in women with endometriosis compared with those without. In women with endometriosis, the ectopic expression of SLC2A3, SLC2A4 and SLC2A5 was significantly higher than that observed in the matching eutopic tissue. GLUT1 protein expression was present in both epithelial and stromal cells and GLUT3 was confined to CD45-positive leukocytes. GLUT4 expression was strong in both ectopic epithelial and stromal cells and localized to the cellular membrane in epithelial cells. These results show that GLUT expression is altered between eutopic and ectopic tissue and between women with and without endometriosis, and that GLUT4 may represent a significant entry route for glucose into the endometriotic epithelial cells. The inducible nature of GLUT4 and its limited cellular expression may make GLUT4 an attractive target for non-hormone-based treatments of endometriosis.