Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and is associated with cumulative UV exposure. Studies have shown that prolonged voriconazole use promotes cSCC formation; however, the biological mechanisms responsible for the increased incidence remain unclear. Here, we show that voriconazole directly increases oxidative stress in human keratinocytes and promotes UV‐induced DNA damage as determined by comet assay, 8‐oxoguanine immunofluorescence and mass spectrometry. Voriconazole treatment of human keratinocytes potentiates UV‐induced apoptosis and activation of the p38 MAP kinase and 53BP1 UV stress response pathways. The p38 MAP kinase activation promoted by voriconazole exposure can be mitigated by pretreating keratinocytes with N‐acetylcysteine. Voriconazole increases oxidative stress in keratinocytes by directly inhibiting catalase leading to lower intracellular NADPH levels and the triazole moieties in voriconazole are critical for inhibiting catalase. Furthermore, voriconazole is shown to promote UV‐induced dysplasia in an in vivo model. Together, these data demonstrate that voriconazole potentiates oxidative stress in UV‐irradiated keratinocytes through catalase inhibition. Use of antioxidants may mitigate the pro‐oncogenic effects of voriconazole.
BACKGROUND Carotid endarterectomy (CEA) and carotid artery stenting (CAS) represent options to treat many patients with carotid stenosis. Although randomized trial data are plentiful, estimated rates of morbidity and mortality for both CEA and CAS have varied substantially. OBJECTIVE To evaluate rates of adverse outcomes after CAS and CEA in a large national database. METHODS We analyzed 84 191 adult patients undergoing elective, nonemergent CAS (n = 81 361) or CEA (n = 2830), from 2011 to 2018, in the American College of Surgeons’ National Surgical Quality Improvement Program database. Odds of adverse outcomes (30-d rates of stroke, myocardial infarction (MI), cardiac arrest, prolonged length of stay (LOS), readmission, reoperation, and mortality) were evaluated in propensity-matched (n = 2821) cohorts through logistic regression. RESULTS In the propensity-matched cohorts, CAS had increased odds of periprocedural stroke (odds ratio [OR] 1.97, 95% CI 1.32-2.95) and decreased odds of cardiac arrest (OR 0.33, 95% CI 0.13-0.84) and 30-d reoperation (OR 0.59, 95% CI 0.44-0.80) compared to CEA. Relative odds of MI, prolonged LOS, discharge to destination other than home, 30-d readmission, or 30-d mortality were statistically similar. In the unmatched patient population, rates of adverse outcomes with CEA were constant over time; however, for CAS, rates of stroke increased over time. In both the matched and unmatched patient cohorts, patients 70 yr and older had lower rates of post-procedural stroke with CEA, but not with CAS, compared to younger patients. CONCLUSION In a propensity-matched analysis of a large, prospectively collected, national, surgical database, CAS was associated with increased odds of periprocedural stroke, which increased over time. Rates of MI and death were not significantly different between the 2 procedures.
After propensity matching, two cohorts of 2821 patients who each underwent carotid endarterectomy (CEA) or transfemoral carotid artery stenting (TF-CAS) were generated. TF-CAS had increased odds of periprocedural stroke compared to CEA. Relative odds of myocardial infarction, prolonged length of stay, discharge to destination other than home, 30-day readmission, or 30-day mortality were statistically similar. In the unmatched patient population, rates of adverse outcomes with CEA were constant over time, while rates of stroke increased with TF-CAS over time.Conclusion: In a propensity-matched analysis of a large national database, TF-CAS was associated with increased odds of periprocedural stroke, which increased over time. Rates of myocardial infarction and death were not significantly different between the two procedures.Commentary: I am tired of reviewing CAS articles that do not list the procedure as "trans-femoral carotid artery stenting (TF-CAS)" or "transcarotid artery revascularization (TCAR)" in the title and throughout the article. It was not until the last paragraph of this article that the authors mentioned that most, if not all, of these patients who underwent carotid stenting actually underwent TF-CAS (and not TCAR). Has not TCAR been around for at least 5 years? Should not all clinicians doing carotid interventions make a point of differentiating between the two procedures? Let's all get on the same page and use the same terminology to avoid confusion. For those of you wondering, the authors could not identify patients who were symptomatic or not (the National Surgical Quality Improvement Program does not have this data) and more than 90% of patients who underwent TF-CAS had embolic protection devices used.Pooled analyses of prospective, randomized trials evaluating CEA and TF-CAS demonstrated similar long-term outcomes; however, rates of perioperative 30-day stroke were higher for TF-CAS than for CEA. I know some local cardiologists who insist their own results with TF-CAS are better than these large series and are as good as CEA. Maybe they are right, as long as they are honest and review their own results objectively. Or better yet, they should be part of a registry such as Vascular Quality Initiative. We all need to know our own results in terms of CEA vs TF-CAS vs TCARdand be honest with our patients. I still recommend CEA as the best first-line treatment for the vast majority of my patients. But TCAR is lurking around the corner.
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