A Cancer Paradox: Machine-Learning Backed Propensity-Score Analysis of Coronary Angiography Findings in Cardio-Oncology.

OBJECTIVES: Cancer has been proposed as a cardiovascular risk factor. We aimed to assess the cardiovascular risk profile and coronary angiography (CA) findings of cancer patients and compare them to those of patients without cancer. METHODS: A retrospective case-control analysis was conducted on randomly enrolled cancer and non-cancer patients from a high-volume cardio-oncology center and a tertiary cardiology center, respectively, who underwent CA from April 2008 to June 2018. Baseline demographics, laboratory findings, cancer status and treatment, and current and prior CA findings were collected by chart review. Coronary artery disease (CAD) burden was assessed with machine-learning (neural-network) guided propensity-score adjusted multivariable regression, controlling for known CAD confounders. RESULTS: Of the 480 enrolled patients, a total of 240 (50%) had cancer. Fewer cancer vs non-cancer patients had clinically significant lesions on the left anterior descending artery (25.00% vs 39.17%, respectively; P<.01) and left circumflex artery (15.83% vs 30.00%, respectively; P<.001). Left main and right coronary artery disease prevalence was similar. Subjects with cancer were less likely to have multivessel CAD (odds ratio, 0.53; 95% confidence interval, 0.29-0.98; P=.04) and significant left circumflex artery lesions (odds ratio, 0.47; 95% confidence interval, 0.26-0.85; P=.01), independent of known CAD confounders. CONCLUSIONS: Patients with cancer have a lower burden of angiographically detected coronary atherosclerosis. Cancer patients are more likely than non-cancer patients to undergo CA for reasons other than suspicion of CAD. Further studies should prospectively analyze the impact of cancer on the development of CAD.

SDF-1α mediates wound-promoted tumor growth in a syngeneic orthotopic mouse model of breast cancer.

Increased growth of residual tumors in the proximity of acute surgical wounds has been reported; however, the mechanisms of wound-promoted tumor growth remain unknown. Here, we used a syngeneic, orthotopic mouse model of breast cancer to study mechanisms of wound-promoted tumor growth. Our results demonstrate that exposure of metastatic mouse breast cancer cells (4T1) to SDF-1α, which is increased in wound fluid, results in increased tumor growth. Both, wounding and exposure of 4T1 cells to SDF-1α not only increased tumor growth, but also tumor cell proliferation rate and stromal collagen deposition. Conversely, systemic inhibition of SDF-1α signaling with the small molecule AMD 3100 abolished the effect of wounding, and decreased cell proliferation, collagen deposition, and neoangiogenesis to the levels observed in control animals. Furthermore, using different mouse strains we could demonstrate that the effect of wounding on tumor growth and SDF-1α levels is host dependent and varies between mouse strains. Our results show that wound-promoted tumor growth is mediated by elevated SDF-1α levels and indicate that the effect of acute wounds on tumor growth depends on the predetermined wound response of the host background and its predetermined wound response.

Up-regulation of human prostaglandin reductase 1 improves the efficacy of hydroxymethylacylfulvene, an antitumor chemotherapeutic agent.

Prostaglandin reductase 1 (PTGR1) is a highly inducible enzyme with enone reductase activity. Previous studies demonstrated the role of rat PTGR1 in the activation of acylfulvene analogs, a class of antitumor natural product derivatives. Of these, hydroxymethylacylfulvene (HMAF) was in advanced clinical development for the treatment of advanced solid tumors, including prostate, ovarian, and pancreatic cancers. However, the efficiency of human PTGR1 in activating acylfulvenes and its potential to enhance therapeutic efficacy have remained uncharacterized. In this study, human PTGR1 was polymerase chain reaction-cloned and purified. Conversion of HMAF to its cellular metabolite by the purified enzyme proceeded at a 20-fold higher rate than with the rat variant of the enzyme. The Km was 4.9 µM, which was 40-fold lower than for the rat variant and similar to the therapeutic dose. Human cell lines, including colon cancer lines, were transfected with a vector containing rat PTGR1 or human PTGR1, and cell viability was examined after dosing with HMAF. New data obtained in this study suggest that transfection with human PTGR1, or its induction in colon and liver cancer cell lines with 1,2-dithiol-3-thione, enhances susceptibility to the cytotoxic influences of HMAF by 2- to 10-fold. Furthermore, similar or enhanced enzyme induction and HMAF toxicity results from preconditioning cancer cells with the bioactive food components curcumin and resveratrol. The functional impact of PTGR1 induction in human cells and chemical-based strategies for its activation can provide important knowledge for the design of clinical strategies involving reductively activated cytotoxic chemotherapeutics.