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Second-line treatments have also been designed over the past few years, including regorafenib (antiangiogenesis) (Bruix et al., 2017), nivolumab [against the programed cell death-1 (PD1) immune checkpoint] (El-Khoueiry et al., 2017), and ramucirumab (against VEGFR2) (Zhu et al., 2019)

Seiwerth and colleagues (Inflammopharmacology, 1999) documented effects on angiogenic growth factor pathway signalling, and subsequent work has expanded characterisation to include VEGF receptor 2 upregulation, endothelial cell migration in capillary-formation assays, and improved healing in ischemia-reperfusion preparations