The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching

Significance: a mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flow - 'hypoxic vasodilation' - occur in an attempt to restore oxygen supply. Nitric oxide is a major signalling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). Recent advances: this review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of nitric oxide, and mechanisms underlying the involvement of nitric oxide in hypoxic vasodilation. Recent insights into nitric oxide metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite reductases, and release of nitric oxide from storage pools. The processes through which nitric oxide levels are elevated during hypoxia are presented, namely (i) increased synthesis from nitric oxide synthases, increased reduction of nitrite to nitric oxide by heme- or pterin-based enzymes and increased release from nitric oxide stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Critical issues: several reviews covered modulation of energetic metabolism by nitric oxide, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression Future directions: we identify a key position for nitric oxide in the body's adaptation to an acute energy supply-demand mismatc

Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis

Sarah Batson,1 Stephen A Mitchell,1 Ricarda Windisch,2 Elisabetta Damonte,2 Veronica C Munk,2 Noemi Reguart3,4 1DRG Abacus, Bicester, Oxfordshire, UK; 2F Hoffmann-La Roche Ltd, Basel, Switzerland; 3Medical Oncology, Hospital Clinic, 4Translational Genomics and Targeted Therapeutics in Solid Tumors, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Introduction: The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the outlook for patients with advanced non-small-cell lung cancer (NSCLC) with EGFR+ mutations. However, most patients develop resistance, with the result that median progression-free survival (PFS) is ~12 months. Combining EGFR-TKIs with other agents, such as bevacizumab, is a promising approach to prolonging remission. This systematic review and network meta-analysis (NMA) were undertaken to assess available evidence regarding the benefits of first-line combination therapy involving EGFR-TKIs in patients with advanced NSCLC.Methods: Literature searches were performed using relevant search terms. Study-level pseudo-individual patient-level data (IPD) were recreated from digitized Kaplan–Meier curve data, using a published algorithm. Study IPD were analyzed using both the proportional hazards and the acceleration failure time (AFT) survival models, and it was concluded that the AFT model was most appropriate. An NMA was performed based on acceleration factors (AFs) using a Bayesian framework to compare EGFR-TKIs and chemotherapy.Results: Nine randomized controlled trials were identified that provided data for EGFR-TKI therapy in patients with EGFR+ tumors. These included studies of afatinib (n=3), erlotinib (n=3), erlotinib plus bevacizumab (n=1) and gefitinib (n=2). Erlotinib plus bevacizumab produced the greatest increase in PFS compared with chemotherapy, with 1/AF being 0.24 (95% credible interval [CrI] 0.17, 0.34). This combination also produced greater increases in PFS compared with EGFR-TKI monotherapy: 1/AF versus afatinib, 0.51 (95% CrI 0.35, 0.73); versus erlotinib, 0.53 (95% CrI 0.39, 0.72) and versus gefitinib, 0.46 (95% CrI 0.32, 0.66). All three EGFR-TKI monotherapies prolonged PFS compared with chemotherapy; estimates of treatment effect ranged from 1/AF 0.53 (95% CrI 0.48, 0.60) for gefitinib to 1/AF 0.46 (95% CrI 0.40, 0.53) for erlotinib. There was no evidence for differences between EGFR-TKI monotherapies, as all 95% CrIs included the null value.Conclusion: Although data for erlotinib plus bevacizumab came from a single Phase 2 study, the results of the NMA suggest that adding bevacizumab to erlotinib may be a promising approach to improving the outcomes achieved with EGFR-TKI monotherapy in patients with advanced EGFR+ NSCLC. Keywords: bevacizumab, epidermal growth factor receptor tyrosine kinase inhibitor, network meta-analysis, non-small-cell lung cancer, non-squamous, progression-free surviva