Body mass index may predict the response to ipilimumab in metastatic melanoma: An observational multi-centre study.

INTRODUCTION: Immunotherapy is a well-established treatment option in patients with metastatic melanoma. However, biomarkers that can be used to predict a response in these patients have not yet been found, putting patients at risk of severe side effects. METHODS: In this retrospective analysis, we investigated the association between the body mass index and ipilimumab treatment response in patients with metastatic melanoma. Patients with metastatic melanoma who received a monotherapy of up to 4 doses of ipilimumab (3 mg/kg) every 3 weeks from 2011 to 2014 in three major hospitals in Austria were included. Patients were classified into two groups: normal group (BMI<25) and overweight group (BMI≥25). RESULTS: 40 patients had a normal BMI, and 36 had a BMI above normal. Patients with a BMI that was above normal showed significantly higher response rates (p = 0.024, χ2), and lower likelihood of brain metastases (p = 0.012, χ2). No differences were found between both groups with respect to gender (p = 0.324, χ2), T-stage (p = 0.197, χ2), or the occurrence of side effects (p = 0.646, χ2). Patients with a BMI above normal showed a trend towards longer overall survival (p = 0.056, Log-Rank), but no difference was found regarding progression-free survival (p = 0.924, Log-Rank). CONCLUSIONS: The BMI correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients.

The angiogenesis inhibitor thrombospondin-1 inhibits acute cutaneous hypersensitivity reactions.

There is increasing evidence that vascular remodeling and endothelial cell activation promote acute and chronic inflammation. Thrombospondin 1 (TSP-1) is a potent endogenous angiogenesis inhibitor thought to play an important role in maintaining cutaneous vascular quiescence. We first investigated TSP-1 expression in human and contact hypersensitivity (CHS) reactions and found that TSP-1 was upregulated in the inflamed skin of patients and in mice. To elucidate the function of TSP-1 in cutaneous inflammation, we induced CHS reactions in the skin of mice with targeted epidermal TSP-1 overexpression in TSP-1-deficient mice and in wild-type mice. We found decreased edema formation, angiogenesis, and inflammatory infiltrate in the inflamed skin of TSP-1 transgenic mice. Conversely, TSP-1-deficient mice exhibited an enhanced and prolonged inflammation, characterized by increased edema formation, enhanced vascular remodeling, and increased neutrophilic infiltrate, when compared with wild-type mice. Moreover, we found strong upregulation of the proinflammatory cytokines IL-1beta, macrophage inflammatory protein 2, and tumor necrosis factor-alpha in the inflamed skin of TSP-1-deficient mice. Our results indicate that TSP-1 downregulates cutaneous delayed-type hypersensitivity reactions by acting on several distinct pathways mediating skin inflammation.

Novel anti-inflammatory properties of the angiogenesis inhibitor vasostatin.

Endothelial cells are critically involved in the pathogenesis of inflammation, which is characterized by vasopermeability, plasma leakage, leukocyte recruitment, and neovascularization. Therefore, inhibitors of endothelial cell function could reduce inflammation. In this study, we evaluated the effects of the angiogenesis inhibitor vasostatin on inflammations induced by contact hypersensitivity reactions in mouse ears. Vasostatin-treated mice revealed significantly reduced edema formation, resulting from lower plasma leakage and inhibition of inflammation-associated vascular remodeling. Intravital microscopy studies of inflamed ears showed a decrease in the fraction of rolling leukocytes in vasostatin-treated mice, and Lycopersicon esculentum lectin-perfused ears revealed fewer leukocytes adherent to the vessel wall. The inflammatory infiltrate from vasostatin-treated mice was characterized by fewer CD8+ T cells, neutrophils, and macrophages compared to the saline-treated animals. In a modified Miles assay, vasostatin inhibited vascular endothelial growth factor-A-induced permeability, and inflamed ear tissues from vasostatin-treated mice expressed significantly reduced levels of the vascular destabilizer angiopoietin-2. These results reveal a previously unrecognized anti-inflammatory property of the angiogenesis inhibitor vasostatin, and suggest that vasostatin is a potential candidate drug for the treatment of inflammation.