We agree with the commentators on the investigational issues to be resolved to link systemic genotoxicity to cancer risk, and delineate its suitability to monitor and manage this risk in patients with chronic or recurrent intestinal inflammation. However, the commentators might also have noted comparable issues surrounding a more near-term clinical implication—real-time monitoring of intestinal inflammation itself. In chronic inflammatory diseases like inflammatory bowel disease (IBD), inflammation is only one of several multiple mechanisms contributing to abdominal pain and other facets of intestinal dysfunction. Optimal management of anti-inflammatory therapy in this setting is presently impaired by the lack of biomarkers permitting real-time quantification of the inflammatory component of disease. Systemic genotoxicity may offer such an inflammatory readout, and hence potentially address this clinical need for peripheral blood assessment of inflammatory disease activity. However, as the commentators observe, a variety of issues must be evaluated, including the quantitative relationship of oxidative lesions in blood cells and intestinal inflammation in human IBD; the relationship in different modes of acute and chronic intestinal inflammation; and the relationship to nonintestinal modes of inflammation. Indeed, a recent study suggests that systemic genotoxicity is a feature of rheumatoid arthritis, although mechanistically owing to reduced lymphocyte DNA repair rather than increased cytokine-induced genotoxicity (Shao et al, 2009). Moreover, a fuller delineation of the mediators linking inflammation and systemic genotoxicity may be required to assess inflammation by this modality in the context of anti-inflammatory agents. Thus, the importance of the window provided by systemic genotoxicity on both inflammation and inflammation-associated carcinogenesis will require careful analysis in humans of leukocyte genotoxic damage in relation to quantitative measures of these disease states, and whether current therapies (antioxidants, anti-inflammatory agents, probiotics) affect the circulating level of genotoxicity as a disease biomarker. We agree with the commentators on the investigational issues to be resolved to link systemic genotoxicity to cancer risk, and delineate its suitability to monitor and manage this risk in patients with chronic or recurrent intestinal inflammation. However, the commentators might also have noted comparable issues surrounding a more near-term clinical implication—real-time monitoring of intestinal inflammation itself. In chronic inflammatory diseases like inflammatory bowel disease (IBD), inflammation is only one of several multiple mechanisms contributing to abdominal pain and other facets of intestinal dysfunction. Optimal management of anti-inflammatory therapy in this setting is presently impaired by the lack of biomarkers permitting real-time quantification of the inflammatory component of disease. Systemic genotoxicity may offer such an inflammatory readout, and hence potentially address this clinical need for peripheral blood assessment of inflammatory disease activity. However, as the commentators observe, a variety of issues must be evaluated, including the quantitative relationship of oxidative lesions in blood cells and intestinal inflammation in human IBD; the relationship in different modes of acute and chronic intestinal inflammation; and the relationship to nonintestinal modes of inflammation. Indeed, a recent study suggests that systemic genotoxicity is a feature of rheumatoid arthritis, although mechanistically owing to reduced lymphocyte DNA repair rather than increased cytokine-induced genotoxicity (Shao et al, 2009). Moreover, a fuller delineation of the mediators linking inflammation and systemic genotoxicity may be required to assess inflammation by this modality in the context of anti-inflammatory agents. Thus, the importance of the window provided by systemic genotoxicity on both inflammation and inflammation-associated carcinogenesis will require careful analysis in humans of leukocyte genotoxic damage in relation to quantitative measures of these disease states, and whether current therapies (antioxidants, anti-inflammatory agents, probiotics) affect the circulating level of genotoxicity as a disease biomarker. Can Stressed Blood Cells Tell Cancer Risk in Inflammatory Bowel Diseases?GastroenterologyVol. 137Issue 6PreviewWestbrook AM, Wei B, Braun J, et al. (Departments of Molecular Toxicology, Pathology and Laboratory Medicine, and Radiation Oncology, University of California at Los Angeles School of Medicine and School of Public Health, Los Angeles, California). Intestinal mucosal inflammation leads to systemic genotoxicity in mice. Cancer Res 2009;69:4827–4834. Full-Text PDF