Voriconazole and the Risk of Keratinocyte Carcinomas Among Lung Transplant Recipients in the United States.

Importance: The antifungal medication voriconazole is used to prevent and treat aspergillosis, a major cause of mortality among recipients of lung transplants (hereinafter referred to as lung recipients). Small studies suggest that voriconazole increases risk of cutaneous squamous cell carcinoma (SCC). Objective: To examine associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas (SCC and cutaneous basal cell carcinoma [BCC]) in lung recipients. Design, Setting, and Participants: This population-based cohort study included non-Hispanic white patients (n = 9599) who underwent lung transplant in the United States from January 1, 2007, to December 31, 2016, identified through the national Scientific Registry of Transplant Recipients with data linkable to pharmacy claims. Data were analyzed from March 1, 2018, to February 13, 2019. Exposures: Antifungal medication use, including voriconazole, itraconazole, posaconazole, and other antifungals, was ascertained from pharmacy claims and treated as a time-varying exposure (assessed every 30 days). Cumulative antifungal exposure was calculated as the total number of exposed months. Main Outcomes and Measures: Primary outcomes were the first SCC or BCC reported to the transplant registry by transplant centers. Follow-up began at transplant and ended at SCC or BCC diagnosis, transplant failure or retransplant, death, loss to follow-up, or December 31, 2016. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (AHRs) for each antifungal medication. Results: Among the 9793 lung transplants in 9599 recipients included in the analysis, median age at transplant was 59 (interquartile range [IQR], 48-65) years, 5824 (59.5%) were male, and 5721 (58.4%) reported ever smoking. During a median follow-up of 3.0 (IQR, 1.4-5.0) years after transplant, 1031 SCCs (incidence, 322 per 10 000 person-years) and 347 BCCs (incidence, 101 per 10 000 person-years) were reported. Compared with lung recipients with no observed voriconazole use, those with 1 to 3 months of voriconazole use experienced increased AHR for SCC of 1.09 (95% CI, 0.90-1.31); 4 to 7 months, 1.42 (95% CI, 1.16-1.73); 8 to 15 months, 2.04 (95% CI, 1.67-2.50); and more than 15 months, 3.05 (95% CI, 2.37-3.91). Ever itraconazole exposure was associated with increased SCC risk (AHR, 1.20; 95% CI, 1.00-1.45). For BCC, risk was not associated with voriconazole use but was increased with itraconazole use (AHR, 1.74; 95% CI, 1.27-2.37) or posaconazole use (AHR, 1.55; 95% CI, 1.00-2.41). Conclusions and Relevance: In this study, voriconazole use was associated with increased SCC risk among lung recipients, especially after prolonged exposure. Further research evaluating the risk-benefit ratio of shorter courses or alternative medications in transplant recipients at high risk for SCC should be considered.

The association between body mass index and coronary artery disease severity: a comparison of black and white patients.

INTRODUCTION: Despite known associations between obesity and cardiovascular disease, the relationship between obesity as reflected by body mass index (BMI) and angiographic coronary artery disease (CAD) is not fully understood. Moreover, this relationship has not been adequately defined in black patients, a group demonstrated to have lower rates of angiographic CAD despite higher rates of CAD risk factors, cardiovascular events, and CAD-related mortality. METHODS: Using an angiography database from an academic hospital, we studied patients undergoing first-time, nonemergent coronary angiography. From this cohort, we selected those without previous CAD diagnosis and with complete anthropomorphic measures and outcome data. Using models that controlled for patient demographics and CAD risk factors, we compared rates of angiographic CAD for blacks and whites by BMI. RESULTS: Black patients had higher rates of CAD risk factors, including obesity and morbid obesity. Nevertheless, black patients were less likely to have a significant stenosis than white patients. Morbid obesity was associated with significantly less CAD in both race groups. Controlling for black-white differences in BMI and the prevalence of morbid obesity did not change the odds ratio for CAD among black patients. CONCLUSIONS: Racial differences in BMI and prevalence of morbid obesity do not contribute to black-white differences in CAD detected during elective angiography. The paradoxical association of morbid obesity with a lower burden of atherosclerosis may be attributed in part to the limitations of noninvasive screening in the morbidly obese and subsequent referral of patients without disease for angiography.

Disappearing and reappearing differences in drug-eluting stent use by race.

RATIONALE, AIMS AND OBJECTIVES: Drug-eluting coronary stents (DES) rapidly dominated the marketplace in the United States after approval in 2003, but utilization rates were initially lower among African American patients. We assess whether racial differences persisted as DES diffused into practice. METHODS: Medicare claims data were used to identify coronary stenting procedures among elderly patients with acute coronary syndromes (ACS). Regression models of the choice of DES versus bare mental stent controlled for demographics, ACS type, co-morbidities and hospital characteristics. Diffusion was assessed in the short run (2003-2004) and long run (2007), with the effect of race calculated to allow for time-varying effects. RESULTS: The sample included 381,887 Medicare beneficiaries treated with stent insertion; approximately 5% were African American. Initially (May 2003-February 2004), African American race was associated with lower DES use compared to other races (44.3% versus 46.5%, P < 0.01). Once DES usage was high in all patients (March-December 2004), differences were not significant (79.8% versus 80.3%, P = 0.45). Subsequent concerns regarding DES safety caused reductions in DES use, with African Americans having lower use than other racial groups in 2007 (63.1% versus 65.2%, P < 0.01). CONCLUSIONS: Racial disparities in DES use initially disappeared during a period of rapid diffusion and high usage rates; the reappearance of disparities in use by 2007 may reflect DES use tailored to unmeasured aspects of case mix and socio-economic status. Further work is needed to understand whether underlying differences in race reflect decisions regarding treatment appropriateness.

SOSTDC1 differentially modulates Smad and beta-catenin activation and is down-regulated in breast cancer.

Sclerostin domain containing 1 (SOSTDC1) protein regulates processes from development to cancer by modulating activity of bone morphogenetic protein (BMP) and wingless/int (Wnt) signaling pathways. As dysregulation of both BMP and Wnt signaling has been observed in breast cancer, we investigated whether disruption of SOSTDC1 signaling occurs in breast cancer. SOSTDC1 mRNA expression levels in breast tissue were examined using a dot blot. Affymetrix microarray data on SOSTDC1 levels were correlated with breast cancer patient survival using Kaplan-Meier plots. Correlations between SOSTDC1 protein levels and clinical parameters were assessed by immunohistochemistry of a breast cancer tissue microarray. SOSTDC1 secretion and BMP and Wnt signaling were investigated using immunoblotting. We found that SOSTDC1 is expressed in normal breast tissue and this expression is reduced in breast cancer. High levels of SOSTDC1 mRNA correlated with increased patient survival; conversely, SOSTDC1 protein levels decreased as tumor size and disease stage increased. Treatment of breast cancer cells with recombinant SOSTDC1 or Wise, a SOSTDC1 orthologue, demonstrated that SOSTDC1 selectively blocks BMP-7-induced Smad phosphorylation without diminishing BMP-2 or Wnt3a-induced signaling. In conclusion, SOSTDC1 mRNA and protein are reduced in breast cancer. High SOSTDC1 mRNA levels correlate with increased distant metastasis-free survival in breast cancer patients. SOSTDC1 differentially affects Wnt3a, BMP-2, and BMP-7 signaling in breast cancer cells. These results identify SOSTDC1 as a clinically important extracellular regulator of multiple signaling pathways in breast cancer.

The contribution of hypertension to black-white differences in likelihood of coronary artery disease detected during elective angiography.

BACKGROUND: Black patients in the United States undergoing angiography for suspected coronary artery disease (CAD) have consistently been found to have less disease than whites. As the effects of hypertension are greater in blacks than whites, and hypertensive heart disease may mimic CAD and lead to catheterization, we examined the association between race and hypertension as an explanation for the disparities in angiographic CAD. METHODS: Using an academic hospital's institutional database, we studied patients undergoing first-time elective angiography from 2001 to 2008. Using multivariable logistic regression with data on patient demographics, CAD risk factors, and coronary stenoses, we compared rates of angiographic disease for blacks and whites, creating models separately for patients with and without hypertension. We then tested the significance of an interaction term between race and hypertension on angiographic findings. RESULTS: We identified 1,203 black and 2,538 white patients who underwent initial elective angiography. Black patients were less likely to have a significant stenotic lesion (≥50% stenosis in the left main artery or ≥70% stenosis elsewhere) than whites (adjusted risk ratio 0.65; 95% confidence interval (CI) 0.55-0.75). Among patients with hypertension this difference was exaggerated (adjusted risk ratio 0.60; 95% CI 0.51-0.71). However, among patients without hypertension, the risk of having a significant lesion was similar in blacks and whites (adjusted risk ratio 0.97; 95% CI 0.67-1.37). The interaction term for race and hypertension was confirmed as statistically significant. CONCLUSIONS: Among patients electively referred for angiography, hypertension, and its effects may contribute to the lower rate of CAD found in blacks compared to whites.