Racial disparities in nephrectomy and mortality among patients with renal cell carcinoma: Findings from SEER.

PURPOSE: To assess racial differences in the receipt of nephrectomy in patients diagnosed RCC in the US. MATERIALS AND METHODS: 2005 to 2015 data from the SEER database was analyzed and 70,059 patients with RCC were identified. We compared demographic and tumor characteristics between black patients and white patients. We applied logistic regression to assess the association between race and the odds of the receipt of nephrectomy. We also applied Cox proportional hazards model to assess the impact of race on cancer-specific mortality (CSM) and all-cause mortality (ACM) in patients diagnosed with RCC in the US. RESULTS: Black patients had 18% lower odds of receiving nephrectomy compared to white patients (p < 0.0001). The odds of the receipt of nephrectomy also reduced with age at diagnosis. In addition, patients with T3 stage had the greatest odds of receiving nephrectomy when compared to T1 (p < 0.0001). There was no difference in the risk of cancer-specific mortality between black patients and white patients; black patients had 27% greater odds of all-cause mortality than white patients (p < 0.0001). Patients who did not receive nephrectomy had a 42% and 35% higher risk of CSM and ACM respectively, when compared to patients who received nephrectomy. CONCLUSIONS: Black patients diagnosed with RCC in the US have a greater ACM risk and are less likely than white patients to receive nephrectomy. Systemic changes are needed to eliminate racial disparity in the treatment and outcomes of RCC in the US.

Increased Levels of the Acrolein Metabolite 3-Hydroxypropyl Mercapturic Acid in the Urine of e-Cigarette Users.

Carcinogen and toxicant uptake by e-cigarette users have not been fully evaluated. In the study reported here, we recruited 30 e-cigarette users, 63 nonsmokers, and 33 cigarette smokers who gave monthly urine samples over a period of 4-6 months. Their product use status was confirmed by measurements of exhaled CO, urinary total nicotine equivalents, cyanoethyl mercapturic acid (CEMA), and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Urinary biomarkers of exposure to the carcinogens acrolein (3-hydroxypropyl mercapturic acid, 3-HPMA), benzene (S-phenyl mercapturic acid, SPMA), acrylonitrile (CEMA), and a combination of crotonaldehyde, methyl vinyl ketone, and methacrolein (3-hydroxy-1-methylpropyl mercapturic acid, HMPMA) were quantified at each visit. Data from subject visits with CEMA > 27 pmol/mL were excluded from the statistical analysis of the results because of possible unreported exposures to volatile combustion products such as secondhand cigarette smoke or marijuana smoke exposure; this left 22 e-cigarette users with 4 or more monthly visits and all 63 nonsmokers. Geometric mean levels of 3-HPMA (1249 versus 679.3 pmol/mL urine) were significantly higher (P = 0.003) in e-cigarette users than in nonsmokers, whereas levels of SPMA, CEMA, and HMPMA did not differ between these two groups. All analytes were significantly higher in cigarette smokers than in either e-cigarette users or nonsmokers. The results of this unique multimonth longitudinal study demonstrate consistent significantly higher uptake of the carcinogen acrolein in e-cigarette users versus nonsmokers, presenting a warning signal regarding e-cigarette use.

Increased acrolein-DNA adducts in buccal brushings of e-cigarette users.

DNA adducts are central in the mechanism of carcinogenesis by genotoxic agents. We compared levels of a DNA adduct of acrolein, a genotoxic carcinogen found in e-cigarette vapor, in oral cell DNA of e-cigarette users and non-users of any tobacco or nicotine product. e-Cigarette users and non-users visited our clinic once monthly for 6 months, and oral brushings and urine samples were collected. For this study, we analyzed oral cell DNA adducts from three monthly visits in e-cigarette users and non-users as confirmed by urinary cyanoethyl mercapturic acid and total nicotine equivalents. DNA was isolated from the oral brushings and analyzed by a validated liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry method for the acrolein DNA adduct 8R/S-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10-(3H)-one (γ-OH-Acr-dGuo). The median value of this DNA adduct in the e-cigarette users was 179 fmol/µmol dGuo (range 5.0 - 793 fmol/µmol dGuo) while that for non-users was 21.0 fmol/µmol dGuo (range 5.0 - 539 fmol/µmol dGuo), P = 0.001. These results demonstrate for the first time that e-cigarette users have elevated levels of a carcinogen-DNA adduct in their oral cells.

Cost-effective analysis of automated programming optimization in cardiac resynchronization therapy: Holistic Markov modelling.

BACKGROUND: Automated optimization algorithm (AdaptivCRT; Medtronic, Mounds View, MN, USA) allowing automated optimization of cardiac resynchronization therapy (CRT), has been introduced. However, little is known concerning its cost-effectiveness. This study aims to evaluate the potential economic benefits of AdaptivCRT of CRT. METHODS: Markov modelling was informed by empirical data sourced from the AdaptivCRT Clinical Trial. Published meta-analyses were used to derive the impact of increasing response to hospitalization and mortality risks. Response was assessed via the clinical composite score. RESULTS: Deterministic results suggested a mean survival of 10.97 years with adaptive algorithms against 10.5 years without (+0.47 in favour of novel algorithms). Heart failure hospitalization costs were modelled to ¥1,382,753 (US $12,686) with novel devices against ¥1,524,747 (US $13,989) with previous technology models. Sensitivity analyses show CRT with Adaptive algorithm was projected to provide cost savings in all scenarios. CONCLUSIONS: The use of AdaptivCRT was projected to improve average patient survival and avoid costs in a Japanese healthcare setting.

The importance of early evaluation after cardiac resynchronization therapy to redefine response: Pooled individual patient analysis from 5 prospective studies.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces mortality and improves outcomes in appropriately selected patients with heart failure (HF); however, response may vary. OBJECTIVE: We sought to correlate 6-month CRT response assessed by clinical composite score (CCS) and left ventricular end-systolic volume index (LVESVi) with longer-term mortality and HF-related hospitalizations. METHODS: Individual patient data from 5 prospective CRT studies-Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD), InSync III Marquis, predictors of response to cardiac resynchronization therapy (PROSPECT), and Adaptive CRT-were pooled. Classification of CRT response status using CCS and LVESVi were made at 6 months. Kaplan-Meier analyses were used to assess time to mortality. Cox proportional hazards regression models were used to compute hazard ratios (HRs) for the 3 levels of CRT response: improved, stabilized, and worsened. Adjusted models controlled for baseline factors known to influence both CRT response and mortality. HF-related hospitalization was compared between CRT response categories using incidence rate ratios. RESULTS: Among a total of 1603 patients, 1426 and 1165 were evaluated in the CCS and LVESVi outcome assessments, respectively. Mortality was significantly lower for patients in the improved (CCS: HR 0.22; 95% confidence interval [CI] 0.15-0.31; LVESVi: HR 0.40; 95% CI 0.27-0.60) and stabilized (CCS: HR 0.38; 95% CI 0.24-0.61; LVESVi: HR 0.41; 95% CI 0.25-0.68) groups than in the worsened group for both measures after adjusting for potential confounders. CONCLUSION: Patients with a worsened CRT response status have a high mortality rate and HF-related hospitalizations. Stabilized patients have a more favorable prognosis than do worsened patients and thus should not be considered CRT nonresponders.

Influence of Histologic Types and Subtypes on Survival Outcomes of Intermediate-High and High-Risk Renal Cell Carcinoma Following Nephrectomy: Findings From the SEER Database.

OBJECTIVE: To understand the influence of histologic subtypes on the survival outcomes of intermediate-high and high-risk renal cell carcinoma (RCC) following nephrectomy. METHODS: This study employed data files from the SEER Program to identify patients diagnosed with intermediate-high or high risk RCC and treated with nephrectomy. Unadjusted Kaplan Meier curves, and multivariable Cox regression analyses were applied to estimate the hazards of histologic types for overall survival (OS) and cancer-specific survival (CSS). RESULTS: OS was higher for chromophobe (HR=0.58, 95% CI 0.47-0.70; P<.0001), similar for papillary (HR=0.90, 95% CI 0.80-1.02; P=.11) and worse for sarcomatoid (HR=3.17, 95% CI 2.70-3.72; P<.0001) subtypes relative to the clear cell subtype. OS was lower in the high-risk disease (HR=2.35, 95% CI 2.01-2.74; P <.0001) versus intermediate-high risk disease. CSS was higher for chromophobe (HR=0.47, 95% CI 0.35-0.63; P<.0001), similar for papillary (HR=0.91, 95% CI 0.77-1.08; P=.28) and worse for sarcomatoid (HR=4.19, 95% CI 3.50-5.02; P<.0001) subtypes relative to the clear cell subtype. CSS was lower for the high-risk disease (HR=2.86, 95%CI 2.39-3.43; P <.0001) relative to intermediate-high risk disease.

Liquid Chromatography-Nanoelectrospray Ionization-High-Resolution Tandem Mass Spectrometry Analysis of Apurinic/Apyrimidinic Sites in Oral Cell DNA of Cigarette Smokers, e-Cigarette Users, and Nonsmokers.

Cigarette smoking is an established risk factor for oral cancer. The health effects of e-cigarettes are still under investigation but may disturb oral cavity homeostasis and cause lung and cardiovascular diseases. Carcinogens and toxicants in tobacco products and e-cigarettes may damage DNA, resulting in the formation of apurinic/apyrimidinic (AP) sites and initiation of the carcinogenic process. In this study, we optimized a liquid chromatography-nanoelectrospray ionization-high-resolution tandem mass spectrometry method to analyze AP sites in buccal cell DNA of 35 nonsmokers, 30 smokers, and 30 e-cigarette users. AP sites in e-cigarette users (median 3.3 per 107 nts) were significantly lower than in smokers (median 5.7 per 107 nts) and nonsmokers (median 6.0 per 107 nts). AP sites in smokers were not significantly different from nonsmokers (p > 0.05). The e-cigarette vaporizing solvents propylene glycol and glycerin were tested and did not protect against AP site formation in in vitro control and carcinogen exposed rat liver homogenates. However, propylene glycol may inhibit bacteria in oral cells, resulting in reduced inflammation and related effects, and reduced AP site levels in e-cigarette user DNA. This is the first study to examine AP site formation in e-cigarette users and to evaluate AP sites in human oral cell DNA.

Association between preoperative prostate-specific antigen levels and mortality in high- and intermediate-grade prostate cancer patients who received radical prostatectomy: Findings from the SEER database.

BACKGROUND: The degree of expression of prostate-specific antigen (PSA) has been applied for the purpose of screening and monitoring the progression of prostate cancer. The goal of this study was to evaluate the association between preoperative PSA levels and mortality outcomes in men with high- and intermediate-grade prostate cancer who received radical prostatectomy. METHODS: The 2004-2014 files of the Surveillance, Epidemiology, and End Result database were analyzed. A total of 97,357 patients with non-metastatic high- and intermediate-grade adenocarcinoma of the prostate who received radical prostatectomy were identified. Using Kaplan-Meier estimates and multivariable Cox proportional hazard models, the relationship between preoperative PSA values and cancer-specific mortality outcomes in men with high- and intermediate-grade prostate cancer who received radical prostatectomy was tested. RESULTS: Of 97,357 patients with high- and intermediate-grade prostate cancer who received radical prostatectomy from 2001 to 2014, there were 983 cancer-specific deaths, and the average follow-up time for the cohort was 85.0 (34.6) months. Preoperative PSA values > 10 ng/ml were associated with greater risk of cancer-specific mortality (hazard ratio 2.3, P < 0.0001) when compared to the referent/normal values for preoperative PSA (<4 ng/ml). Individuals with preoperative PSA values 4-10 ng/ml had lower risk of prostate cancer-specific mortality (hazard ratio 0.80, P = 0.03) when compared to individuals with normal preoperative PSA values. CONCLUSIONS: Individuals with preoperative PSA values 4-10 ng/ml had 20% lower risk of prostate cancer-specific mortality when compared to individuals with preoperative PSA values of <4 ng/dl. The findings from this study suggest that low or normal preoperative PSA values may not always mean that prostate cancer is indolent, and more work needs to be done to better classify risk in men with prostate cancer.

Relationships Between Race, Gender, and Spot Urine Levels of Biomarkers of Tobacco Exposure Vary Based on How Creatinine Is Handled in Analyses.

INTRODUCTION: We illustrate the differential impact of common analysis approaches to handling urinary creatinine, a measure for urine dilution, on relationships between race, gender, and biomarkers of exposure measured in spot urine. METHODS: In smokers, spot urine levels of total nicotine equivalents (TNE, sum of total nicotine, total cotinine, and total 3'-hydroxycotinine) and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) overall and per cigarette were examined. Relationships between race (African Americans [AA] n = 373, Whites n = 758) or gender (males n = 629, females n = 502) and TNE or NNAL were examined using the following approaches to handling creatinine: (1) unadjusted/unstandardized; (2) standardization; (3) adjustment as a covariate. Significance was considered at p < .05. RESULTS: Creatinine was higher in AA versus Whites (1.19 vs. 0.96 mg/mL; p < .0001) and in males versus females (1.21 vs. 0.84 mg/mL; p < .0001). Independent of how creatinine was handled, TNE was lower among AA than Whites (TNE ratios AA vs. Whites: 0.67-0.84; p's < .05). Unadjusted TNE per cigarette was higher among AA versus Whites (ratio 1.12; p = .0411); however, the relationship flipped with standardization (ratio 0.90; p = .0360) and adjustment (ratio 0.95; p = .3165). Regarding gender, unadjusted TNE was higher among males versus females (ratio 1.13; p = .0063), but the relationship flipped with standardization (ratio 0.79; p < .0001) or adjustment (ratio 0.89; p = .0018). Unadjusted TNE per cigarette did not differ across gender (ratio 0.98; p = .6591), but lower levels were found in males versus females with standardization (ratio 0.68; p < .0001) and adjustment (ratio 0.74; p < .0001). NNAL displayed similar patterns. CONCLUSIONS: Relationships between race, gender, and spot urine levels of biomarkers of exposure can vary greatly based on how creatinine is handled in analyses. IMPLICATIONS: Lack of appropriate methods can lead to discrepancies across reports on variability of urinary biomarkers by race and gender. We recommend that for any analyses of biomarkers of exposure measure in spot urine samples across race, gender, or other population subgroups that differ in urinary creatinine levels, sensitivity analyses comparing the different methods for handling urinary creatinine should be conducted. If methods result in discrepant findings, this should be clearly noted and discussed.

Cigarette Smokers Versus Cousers of Cannabis and Cigarettes: Exposure to Toxicants.

INTRODUCTION: Cannabis and tobacco couse is common and could expose users to higher levels of toxicants. No studies have examined biomarkers of toxicant exposure in cousers of cannabis and cigarettes, compared with cigarette smokers (CS). AIMS AND METHODS: Adult daily CS were recruited from 10 US sites for a study of reduced nicotine cigarettes. In this analysis of baseline data, participants were categorized as either cousers of cannabis and tobacco (cousers; N = 167; urine positive for 11-nor-9-carboxy-Δ 9-tetrahydrocannnabinol and self-reported cannabis use ≥1×/week), or CS (N = 911; negative urine and no self-reported cannabis use). Participants who did not meet either definition (N = 172) were excluded. Self-reported tobacco and cannabis use and tobacco and/or combustion-related biomarkers of exposure were compared between groups. RESULTS: Compared to CS, cousers were younger (couser Mage = 38.96, SD = 13.01; CS Mage = 47.22, SD = 12.72; p < .001) and more likely to be male (cousers = 67.7%, CS = 51.9%, p < .001). There were no group differences in self-reported cigarettes/day, total nicotine equivalents, or breath carbon monoxide, but cousers had greater use of non-cigarette tobacco products. Compared to CS, cousers had higher concentrations of 3-hydroxypropylmercapturic acid, 2-cyanoethylmercapturic acid, S-phenylmercapturic acid, 3-hydroxy-1-methylpropylmercapturic acid (ps < .05), and phenanthrene tetraol (p < .001). No biomarkers were affected by number of cannabis use days/week or days since last cannabis use during baseline (ps > .05). CONCLUSIONS: Cousers had higher concentrations of biomarkers of exposure than CS, but similar number of cigarettes per day and nicotine exposure. Additional studies are needed to determine whether cannabis and/or alternative tobacco products are driving the increased toxicant exposure. IMPLICATIONS: Cousers of cannabis and tobacco appear to be exposed to greater levels of harmful chemicals (ie, volatile organic compounds and polycyclic aromatic hydrocarbons), but similar levels of nicotine as CS. It is unclear if the higher levels of toxicant exposure in cousers are due to cannabis use or the increased use of alternative tobacco products compared with CS. It is important for studies examining biomarkers of exposure among CS to account for cannabis use as it may have a significant impact on outcomes. Additionally, further research is needed examining exposure to harmful chemicals among cannabis users.

Effects of Very Low Nicotine Content Cigarettes on Smoking Behavior and Biomarkers of Exposure in Menthol and Non-menthol Smokers.

INTRODUCTION: Because 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy. METHODS: In a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence. RESULTS: At baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition. CONCLUSIONS: Although menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers. IMPLICATIONS: Results of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes.

Effects of immediate versus gradual nicotine reduction in cigarettes on biomarkers of biological effects.

AIM: A previous study showed significantly greater reductions in number of cigarettes smoked and biomarkers of toxicant and carcinogen exposure in smokers assigned to immediate reduction of nicotine in cigarettes to very low levels versus gradually over time or continued smoking of normal nicotine content cigarettes. This study examines the effects of these approaches on selected biomarkers associated with harmful biological effects. DESIGN: Three-arm, randomized controlled trial. SETTING: Ten United States academic institutional sites. PARTICIPANTS: Daily smokers uninterested in quitting smoking with a mean age of 45.1 [standard deviation (SD) = 13.4)] years and smoking 17.1 (SD = 8.5) cigarettes/day; 43.9% (549 of 1250) female; 60.6% (758 of 1250) white ethnicity. INTERVENTIONS: (1) Smoking cigarettes where nicotine content was immediately reduced to very low levels (n = 503); (2) smoking cigarettes where nicotine content was gradually reduced, with dose changes occurring monthly (n = 498); and (3) continued smoking with normal nicotine content cigarettes (n = 249). MEASUREMENTS: Smokers were assessed at baseline while smoking their usual brand cigarettes, and again at 4, 8, 12, 16 and 20 weeks. Outcomes were areas under the concentration time curve (AUC) for the period of study of biomarkers of inflammation, oxidative stress and hematological parameters. FINDINGS: No consistent significant differences were observed across groups (Bayes factors showing data to be insensitive), with the only exception being red blood cell size variability, which was observed to be lower in the immediate versus gradual nicotine reduction [mean difference =  -0.11; 95% confidence interval (CI) = -0.18, -0.04, P = 0.004] and normal nicotine control groups (mean difference = - 0.15, 95% CI = -0.23, -0.06, P = 0.001). CONCLUSION: It remains unclear whether switching to very low nicotine cigarettes leads to a short-term reduction in biomarkers of tobacco-related harm.

Racial Disparities in the Presentation, Early Definitive Surgical Treatment, and Mortality Among Men Diagnosed with Poorly Differentiated/Undifferentiated Non-metastatic Prostate Cancer in the USA.

OBJECTIVE: To assess the influence of race on presentation of poorly differentiated/undifferentiated prostate cancer, use of radical prostatectomy (RP) as primary treatment and survival outcomes. METHODS: Using the 2004-2014 files of the Surveillance, Epidemiology, and End Results (SEER) data, we identified 244,167 black and white men diagnosed with poorly differentiated/undifferentiated prostate cancer. Demographic and tumor characteristics of study patients were compared by race. Logistic regression was used to evaluate the influence of race on receipt of RP. Cox proportional hazard models were fitted to determine the impact of RP and race on cancer-specific mortality (CSM) and all-cause mortality (ACM). RESULTS: Compared to white men, black men were diagnosed of prostate cancer at a younger age (64.2 years versus (vs) 67.5 years, p < 0.0001) and presented with higher median prostate-specific antigen, PSA (24.4 ng/ml vs 22.1 ng/ml, p < 0.0001) but lower disease stage. Lower proportion of black men received RP compared to white men (33.9% vs 42.6%; p < 0.0001). The odds of receipt of RP were 2 times higher in white men relative to black men. The risks of CSM and ACM were over 2 times and 3 times respectively higher in patients who did not receive RP vs patients who received RP in the study population and in each race. CONCLUSION: Despite the younger age at diagnosis of poorly differentiated/undifferentiated prostate cancer and higher PSA at diagnosis in black men, white men had significantly higher odds of receipt of RP relative to black men.