Detection by fluorescence of pituitary neuroendocrine tumour (PitNET) tissue during endoscopic transsphenoidal surgery using bevacizumab-800CW (DEPARTURE trial):study protocol for a non-randomised, non-blinded, single centre, feasibility and dose-finding trial

INTRODUCTION: Achieving gross total resection and endocrine remission in pituitary neuroendocrine tumours (PitNET) can be challenging, especially in PitNETs with cavernous sinus (CS) invasion, defined as a Knosp grade of 3 or 4. A potential target to identify PitNET tissue is vascular endothelial growth factor A (VEGF-A), which expression is known to be significantly higher in PitNETs with CS invasion.METHODS AND ANALYSIS: The aim of this non-randomised, non-blinded, single centre, feasibility and dose-finding phase 1 trial is to determine the feasibility of intraoperative fluorescence imaging detection of PitNET tissue during endoscopic transsphenoidal surgery using the VEGF-A targeting optical agent bevacizumab-800CW (4, 5, 10 or 25 mg). Nine to fifteen patients with a PitNET with a Knosp grade of 3 or 4 will be included. Secondary objectives are: (1) To identify the optimal tracer dose for imaging of PitNET tissue during transsphenoidal surgery for further development in a phase 2 fluorescence molecular endoscopy trial. (2) To quantify fluorescence intensity in vivo and ex vivo with multidiameter single-fibre reflectance, single-fibre fluorescence (MDSFR/SFF) spectroscopy. (3) To correlate and validate both the in vivo and ex vivo measured fluorescence signals with histopathological analysis and immunohistochemical staining. (4) To assess the (sub)cellular location of bevacizumab-800CW by ex vivo fluorescence microscopy. Intraoperative, three imaging moments are defined to detect the fluorescent signal. The tumour-to-background ratios are defined by intraoperative fluorescence in vivo measurements including MDSFR/SFF spectroscopy data and by ex vivo back-table fluorescence imaging. After inclusion of three patients in each dose group, an interim analysis will be performed to define the optimal dose.ETHICS AND DISSEMINATION: Approval was obtained from the Medical Ethics Review Board of the University Medical Centre Groningen. Results will be disseminated through national and international journals. The participants and relevant patient support groups will be informed about the results.TRIAL REGISTRATION NUMBER: NCT04212793.</p

Labour Productivity and Innovation Performance: The Importance of Internal Labour Flexibility Practices

© 2015, © The Author(s) 2015. This article develops and examines the idea that internal labour flexibility practices are beneficial for labour productivity and innovation performance of companies. This is tested in two studies using unique company level datasets. In Study 1, results obtained from 377 independent companies revealed that internal labour flexibility practices are positively related to objective labour productivity and its growth in the year following, also when controlled for objective labour productivity and objective external labour flexibility from the year before. In Study 2, results obtained from 4271 companies indicated that internal labour flexibility practices were positively related to product innovation and labour productivity. Findings suggest that internal labour flexibility practices benefit both labour productivity and innovation performance of companies. If innovation and labour productivity are considered key to long-term survival, firms and policymakers should consider internal labour flexibility practices.status: publishe

Will 'structural reforms' of labour markets reduce productivity growth? A firm-level investigation

More 'flexible' labour relations significantly reduce labour productivity growth in sectors that tend towards a 'routinised' (other than a 'garage business') innovation regime. We argue that structural reforms that make firing easier will diminish the loyalty and commitment of workers, making accumulation of (tacit) knowledge more difficult. It also reduces training, increases knowledge-leaking to competitors and favours autocratic management and the growth of management and control bureaucracies. Our results are consistent with findings in macro-level studies that wage-cost saving flexibilisation of labour relations and downward wage flexibility reduce labour productivity growth: a 1 per cent wage change causes a ≈ 0.4 per cent change in value added per labour hour

Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student's t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statin

Genomics in Conservation: Case Studies and Bridging the Gap between Data and Application Reply

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