During the past decade, the role of inflammation in the pathophysiology of arterial thrombosis has been elucidated. However, comparatively little is known about the relationship between inflammation and venous thrombosis. The aim of this study was to perform a systematic review of clinical studies that have examined the association between inflammation and venous thrombosis, specifically: (1) the value of inflammatory markers in predicting the future development of venous thrombosis; (2) test characteristics of markers of inflammation in the diagnosis of acute venous thrombosis; and (3) effect of venous thrombosis on blood levels of inflammatory markers. Using keywords venous thrombosis, venous thromboembolism, inflammation, acute phase markers, C-reactive protein (CRP), interleukin (IL)-6, IL-8, and monocyte chemotactic protein (MCP)-1, PubMed and Medline computerized databases were searched for English language articles published after 1980. Search results were restricted to clinical studies in humans that used study designs that were appropriate to address the above objectives. Results show that plasma CRP levels do not appear to predict risk of future venous thrombosis (two studies; N = 41,308). Four studies (N=562) have examined the utility of plasma CRP in the diagnosis of venous thrombosis; pooled positive and negative predictive values were 53% (95% CI:47%,59%) and 85% (95% CI: 81%, 89%), respectively. A two- to six-fold increase in the risk of deep vein thrombosis (DVT) is associated with elevations in plasma levels of CRP, IL-6, IL-8, MCP-1 or TNF-alpha (three studies). We can conclude that the nature of the relationship between inflammation and clinical venous thrombosis is not yet established. CRP does not appear to be useful in predicting future venous thrombosis or in the diagnosis of acute venous thrombosis. While several markers of inflammation are elevated in acute venous thrombosis, further research is needed to determine the precise relationship between these markers and venous thrombosis. The identification and elucidation of inflammatory markers relevant to venous thrombosis could provide targets for future therapy.
Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.
Nivolumab (Opdivo) is a monoclonal antibody classified as an immune modulator. A case is presented of nivolumab-induced myositis, an unlisted side effect.
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