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Novel medical technologies, like large-panel genomic tumor testing (GTT), offer great promise but also substantial uncertainty regarding their clinical value and appropriate use. The goal of this study was to understand how clinicians' perceived uncertainty about GTT, and uncertainty tolerance (UT), a construct that describes trait-level differences in individuals' responses to uncertainty, influence attitudes and self-efficacy regarding GTT. Community-based oncologists participating in a study of large-panel GTT completed surveys assessing their perceptions of uncertainty about GTT, and their attitudes and self-efficacy regarding GTT. Multivariable regression analyses examined the relationship between oncologists' perceived uncertainty of GTT and their GTT-related attitudes and self-efficacy, and the potential moderating effect of individual differences in UT. Fifty-seven oncologists completed surveys. Greater perceived uncertainty about GTT was associated with more negative attitudes towards it. This association was moderated by UT, such that lower UT was associated with a stronger negative relationship between perceived uncertainty and attitudes. That is, oncologists who perceive GTT as uncertain, tended to have more negative attitudes, particularly if they were low in the trait of uncertainty tolerance. More research is warranted to understand how uncertainty and uncertainty tolerance influence clinicians' responses to GTT and other novel medical interventions. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy relies upon the ability of T cells to infiltrate tumors. The endothelium constitutes a barrier between the tumor and effector T cells, and the ability to manipulate local vascular permeability could be translated into effective immunotherapy. Here, we show that in the context of adoptive T cell therapy, antitumor T cells, delivered at high enough doses, can overcome the endothelial barrier and infiltrate tumors, a process that requires local production of C3, complement activation on tumor endothelium and release of C5a. C5a, in turn, acts on endothelial cells promoting the upregulation of adhesion molecules and T-cell homing. Genetic deletion of C3 or the C5a receptor 1 (C5aR1), and pharmacological blockade of C5aR1, impaired the ability of T cells to overcome the endothelial barrier, infiltrate tumors, and control tumor progressionin vivo, while genetic chimera mice demonstrated that C3 and C5aR1 expression by tumor stroma, and not leukocytes, governs T cell homing, acting on the local endothelium.In vitro, endothelial C3 and C5a expressions were required for endothelial activation by type 1 cytokines. Our data indicate that effective immunotherapy is a consequence of successful homing of T cells in response to local complement activation, which disrupts the tumor endothelial barrier. [ABSTRACT FROM PUBLISHER]