First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer: a network meta-analysis

Marscha S Holleman,1,2 Harm van Tinteren,3 Harry JM Groen,4 Maiwenn J Al,1,2 Carin A Uyl-de Groot1,2 1Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, the Netherlands; 2Institute for Medical Technology Assessment, Erasmus University Rotterdam, Rotterdam, the Netherlands; 3Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands; 4Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands Background: EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib have proven efficacy in terms of progression-free survival (PFS) in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, an overall view for comparing efficacy and toxicity on a meta-level is lacking. This study compared efficacy and toxicity of first-line treatment with five different EGFR-TKIs by conducting a network meta-analysis (NMA). Methods: A systematic review was performed, aiming to find eligible literature. Data of PFS, overall survival (OS), objective response rate (ORR), and adverse events were extracted. An NMA based on Bayesian statistics was established to synthesize the efficacy and toxicity of all treatments. Results: Thirteen randomized controlled trials, including data from 3,539 patients with EGFR-mutated NSCLC, were analyzed. Rank probabilities showed that osimertinib had a potentially better efficacy in terms of PFS and OS compared to all other TKIs. For ORR, afatinib and osimertinib showed a trend of superiority compared to the other four TKIs. Furthermore, there was a high risk of diarrhea and rash for patients treated with afatinib or dacomitinib as well as a moderate risk for treatment with erlotinib, gefitinib, and osimertinib. Conclusion: Our study showed a favorable efficacy of osimertinib in terms of PFS and OS compared to all other EGFR-TKIs in patients with NSCLC harboring activating EGFR mutations. Furthermore, gefitinib, erlotinib, and osimertinib were associated with fewer toxicities compared to the other TKIs. Therefore, osimertinib is indicated as a preferable first-line TKI in patients with activating EGFR-mutated NSCLC. Keywords: EGFR-TKI, gefitinib, erlotinib, afatinib, osimertinib, network meta-analysi

First solid-state NMR analysis of uniformly 13C-enriched major light-harvesting complexes from Chlamydomonas reinhardtti and identification of protein and cofactor spin clusters

The light-harvesting complex II (LHCII) is the main component of the antenna system of plants and green algae and plays a major role in the capture of sun light for photosynthesis. The LHCII complexes have also been proposed to play a key role in the optimization of photosynthetic efficiency through the process of state 1\u2013 state 2 transitions and are involved in down-regulation of photosynthesis under excess light by energy dissipation through non-photochemical quenching (NPQ). We present here the first solid-state magic-angle spinning (MAS) NMR data of the major light-harvesting complex (LHCII) of Chlamydomonas reinhardtii, a eukaryotic green alga. We are able to identify nuclear spin clusters of the protein and of its associated chlorophyll pigments in 13C\u201313C dipolar homonuclear correlation spectra on a uniformly 13C-labeled sample. In particular, we were able to resolve several chlorophyll 131 carbon resonances that are sensitive to hydrogen bonding to the 131-keto carbonyl group. The data show that 13C NMR signals of the pigments and protein sites are well resolved, thus paving the way to study possible structural reorganization processes involved in lightharvesting regulation through MAS solid-state NMR

Mortality after major amputation in elderly patients with critical limb ischemia

Sanne Klaphake,1,2 Kevin de Leur,1 Paul GH Mulder,1,3 Gwan H Ho,1 Hans G de Groot,1 Eelco J Veen,1 Hence JM Verhagen,2 Lijckle van der Laan1 1Department of Surgery, Amphia Hospital, Breda, 2Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, 3Amphia Academy, Amphia Hospital, Breda, the Netherlands Background: Owing to the aging population, the number of elderly patients with critical limb ischemia (CLI) has increased. The consequence of amputation is immense. However, at the moment, information about the mortality after amputation in the elderly vascular patients is unknown. For this reason, this study evaluated mortality rates and patient-related factors associated with mortality after a major amputation in elderly patients with CLI.Methods: From 2006 to 2013, we included patients aged >70 years who were treated for chronic CLI by primary or secondary major amputation within or after 3 months of initial therapy (revascularization or conservative management). Outcome measurements were mortality after major amputation and factors associated with mortality (age, comorbidity and timing of amputation).Results: In total, 168/651 patients (178 legs; 26%) underwent a major amputation. Patients were stratified by age: 70–80 years (n=86) and >80 years (n=82). Overall mortality after major amputation was 44%, 66% and 85% after 1, 3 and 5 years, respectively. The 6-month and 1-year mortality in patients aged 80 years or older was, respectively, 59% or 63% after a secondary amputation <3 months versus 34% and 44% after a secondary amputation >3 months. Per year of age, the mortality rate increased by 4% (P=0.005). No significant difference in mortality after major amputation was found in the presence of comorbidity or according to Rutherford classification.Conclusion: Despite developments in the treatment of CLI by revascularization, amputation rates remain high and are associated with tremendous mortality rates. Secondary amputation after a failed attempt of revascularization causes a higher mortality. Further research concerning timing of amputation and patient-related outcome is needed to evaluate if selected patients might benefit from primary amputation. Keywords: peripheral arterial disease, aged, limb ischemia, primary amputation, octogenarians, patient selectio

Spin tunneling in junctions with disordered ferromagnets

We provide compelling evidence to establish that, contrary to one's elementary guess, the tunneling spin polarization (TSP) of amorphous CoFeB is larger than that of highly textured fcc CoFeB. First principles atomic and electronic structure calculations reveal striking agreement between the measured TSP and the predicted s-electron spin polarization. Given the disordered structure of the ternary alloy, not only do these results strongly endorse our communal understanding of tunneling through AlOx, but they also portray the key concepts that demand primary consideration in such complex systems.Comment: To be published in Physical Review Letters. 5 double-column pages with 3 figure