The management of patients with brain metastases has become a major issue due to the increasing frequency and complexity of the diagnostic and therapeutic approaches. In 2014, the European Association of NeuroOncology (EANO) created a multidisciplinary Task Force to draw evidence-based guidelines for patients with brain metastases from solid tumors. Here, we present these guidelines, which provide a consensus review of evidence and recommendations for diagnosis by neuroimaging and neuropathology, staging, prognostic factors, and different treatment options. Specifically, we addressed options such as surgery, stereotactic radiosurgery/stereotactic fractionated radiotherapy, whole-brain radiotherapy, chemotherapy and targeted therapy (with particular attention to brain metastases from non-small cell lung cancer, melanoma and breast and renal cancer), and supportive care. Key wordsbrain metastases | chemotherapy | neuroimaging | neuropathology | stereotactic radiosurgery/stereotactic fractionated radiotherapy | supportive care | surgery | targeted therapy | whole-brain radiation therapy

Immune checkpoint inhibitors (ICPI), such as ipilimumab [anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody] and nivolumab or pembrolizumab [anti-programmed cell death protein-1 (PD-1) antibodies], improve survival in several cancer types. Since inhibition of CTLA-4 or PD-1 leads to non-selective activation of the immune system, immune-related adverse events (irAEs) are frequent. Enterocolitis is a common irAE, currently managed with corticosteroids and, if necessary, anti-tumor necrosis factor-α therapy. Such a regimen carries a risk of serious side-effects including infections, and may potentially imply impaired antitumor effects. Vedolizumab is an anti-integrin α4β7 antibody with gut-specific immunosuppressive effects, approved for Crohn’s disease and ulcerative colitis. We report a case series of seven patients with metastatic melanoma or lung cancer, treated with vedolizumab off-label for ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October 2016. Clinical, laboratory, endoscopic, and histologic data were analyzed. Patients initially received corticosteroids but were steroid-dependent and/or partially refractory. One patient was administered infliximab but was refractory. The median time from onset of enterocolitis to start of vedolizumab therapy was 79 days. Following vedolizumab therapy, all patients but one experienced steroid-free enterocolitis remission, with normalized fecal calprotectin. This was achieved after a median of 56 days from vedolizumab start, without any vedolizumab-related side-effects noted. The patient in whom vedolizumab was not successful, due to active ulcerative colitis, received vedolizumab prophylactically. This is the first case series to suggest that vedolizumab is an effective and well-tolerated therapeutic for steroid-dependent or partially refractory ICPI-induced enterocolitis. A larger prospective study to evaluate vedolizumab in this indication is warranted.

Summary: Cardiotoxicity is a serious side effect of treatment of malignant diseases with 5-fluorouracil (5-FU). The underlying pathophysiologic mechanism remains unclear but clinical data suggest that the endothelium of coronary arteries may be involved. Experimental studies indicate that the endothelium is especially susceptible to 5-FU and support the hypothesis that a thrombogenic effect of 5-FU, secondary to its direct toxic effect on the endothelium, is one of the pathophysiologic mechanisms behind 5-FU-induced cardiotoxicity. In the present study we evaluate the role of antithrombotic treatment with dalteparin as protection against the thrombogenic effect of 5-FU on the vascular endothelium in a rabbit model. The effects on the vascular endothelium of 5-FU, dalteparin, and the combination of these two substances were evaluated with scanning electron microscopy 1, 3, 7, 14, and 30 days after treatment and compared with a control group. Very severe damage to the endothelium was seen in 5-FU-treated animals, often leading to intima disruption and denudation of underlying structures, with accompanying platelet accumulation and fibrin formation. The most extensive damage was observed on Day 3 after treatment. The cytotoxic effect of 5-FU was partly reversible. The combination of 5-FU and dalteparin gave lower scores on Day 3 because of less evidence of thrombotic events. However, the reversibility of the endothelial damage was poorer in this group, as well as in the group that received dalteparin alone. The findings support the hypothesis that antithrombotic treatment with dalteparin can protect against the thrombogenic effect of 5-FU, secondary to its direct toxic effect on the vascular endothelium. However, the study indicates that dalteparin per se has a toxic effect on the endothelium that is different from that of 5-FU.

Cardiotoxicity is a serious side effect of cancer treatment with the commonly used drug 5-fluorouracil (5-FU). The pathophysiology of this is unclear. Experimental studies show a thrombogenic effect of 5-FU, secondary to a direct toxic effect on the endothelium, possibly mediated by radical generation. Probucol is a lipid-lowering drug with strong antioxidant properties. The aim of this study was to evaluate the possibility of using probucol treatment to protect against the toxicity of 5-FU on vascular endothelium of the central artery in the ears of rabbits. Five groups of rabbits were treated with 1) 5-FU, 2) saline, 3) probucol high-dose and saline, 4) probucol high-dose and 5-FU, 5) probucol low-dose and 5-FU. Damage to the arterial endothelium was evaluated by scanning electron microscopy. Damage to the endothelium in 5-FU + probucol-treated animals was minimal and comparable to that of the control group. Intima disruption or thrombus formation was seen with 5-FU only. The results of the study indicate that treatment with probucol prevents 5-FU-induced endothelial injury.