Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. Niacin is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that niacin metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10-2.42) and 2.02 (1.29-3.18), respectively; for 4PY: 1.89 (1.26-2.84) and 1.99 (1.26-3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both 2PY and 4PY levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10-18). Moreover, sVCAM-1 levels were significantly correlated with both 2PY and 4PY in a validation cohort (n = 974 total, n = 333 females) (2PY: rho = 0.13, P = 7.7 × 10-5; 4PY: rho = 0.18, P = 1.1 × 10-8). Lastly, treatment with physiological levels of 4PY, but not its structural isomer 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess niacin, 2PY and 4PY, are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and MACE.
BACKGROUND: Heart failure is a common complication after myocardial infarction (MI) and is associated with increased mortality. Whether remote heart failure symptoms assessment after MI can improve risk stratification is unknown. The authors evaluated the association of the 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) with all-cause mortality after MI. METHODS AND RESULTS: Prospectively collected data from consecutive patients hospitalized for MI at a large tertiary heart center between June 2017 and September 2022 were used. Patients remotely completed the KCCQ 1 month after discharge. A total of 1135 (aged 64±12 years, 26.7% women) of 1721 eligible patients completed the KCCQ. Ranges of KCCQ scores revealed that 30 (2.6%), 114 (10.0%), 274 (24.1%), and 717 (63.2%) had scores <25, 25 to 49, 50 to 74, and ≥75, respectively. During a mean follow-up of 46 months (interquartile range, 29-61), 146 (12.9%) died. In a fully adjusted analysis, KCCQ scores <50 were independently associated with mortality (hazard ratio [HR], 6.05 for KCCQ <25, HR, 2.66 for KCCQ 25-49 versus KCCQ ≥50; both P<0.001). Adding the 30-day KCCQ to clinical risk factors improved risk stratification: change in area under the curve of 2.6 (95% CI, 0.3-5.0), Brier score of -0.6 (95% CI, -1.0 to -0.2), and net reclassification improvement of 0.71 (95% CI, 0.45-1.04). KCCQ items most strongly associated with mortality were walking impairment, leg swelling, and change in symptoms. CONCLUSIONS: Remote evaluation of heart failure symptoms using the KCCQ among patients recently discharged for MI identifies patients at risk for mortality. Whether closer follow-up and targeted therapy can reduce mortality in high-risk patients warrants further study.
- MeSH
- hospitalizace MeSH
- infarkt myokardu * komplikace diagnóza MeSH
- kvalita života MeSH
- lidé MeSH
- proporcionální rizikové modely MeSH
- propuštění pacienta MeSH
- srdeční selhání * terapie MeSH
- zdravotní stav MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2- ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population. METHODS: Postmenopausal patients with HR+/HER2- ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan-Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615). RESULTS: At data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50-0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed. CONCLUSIONS: This analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2- ABC.
PURPOSE: To assess the prognostic value of sex for non-muscle-invasive/muscle-invasive bladder urothelial carcinoma (NMIBC/MIBC) treated with radical surgery. METHODS: The PubMed, Web of Science, and Scopus databases were searched in November 2021 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they involved the comparison of the overall, cancer-specific, progression, and recurrence-free survival of patients with NMIBC/MIBC. Formal sex-stratified meta-analyses of these outcomes were performed. RESULTS: Thirty-one studies, which included 32,525 patients with NMIBC, and 63 studies, which included 85,132 patients with MIBC, were eligible for review and meta-analysis. Female sex was associated with worse cancer-specific survival (pooled hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.11-1.31) and overall survival (pooled HR, 1.02; 95% CI, 1.00-1.05) in patients with MIBC. In contrast, however, sex was not associated with cancer-specific survival (pooled HR, 1.01; 95% CI, 0.70-1.46), progression-free survival (pooled HR, 1.04; 95% CI, 0.88-1.24), and recurrence-free survival (pooled HR, 1.06; 95% CI, 0.98-1.16) in patients with NMIBC. CONCLUSIONS: Sex is associated with an increased risk of worse survival outcomes in patients with MIBC but not in those with NMIBC. Given the genetic and social differences between sexes, sex may represent a key factor in the clinical decision-making process.
- MeSH
- karcinom z přechodných buněk * patologie MeSH
- lidé MeSH
- močový měchýř patologie MeSH
- nádory močového měchýře * patologie MeSH
- prognóza MeSH
- proporcionální rizikové modely MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- systematický přehled MeSH
BACKGROUND: Large-scale analyses addressing cancer-specific mortality (CSM) in T1a renal cell carcinoma (RCC) patients treated with local tumor destruction (LTD), relative to partial nephrectomy (PN), are scarce. OBJECTIVE: To compare CSM after LTD versus PN. DESIGN, SETTING, AND PARTICIPANTS: Within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2018), we identified patients with clinical T1a stage RCC treated with LTD or PN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: After 1:1 ratio propensity score matching (PSM) between patients treated with LTD versus PN, competing risks regression (CRR) models addressed CSM, after adjustment for other-cause mortality (OCM) and other covariates (age, tumor size, tumor grade, and histological subtype). RESULTS AND LIMITATIONS: Relative to the 35 984 PN patients, 5936 LTD patients were older and more frequently harbored unknown RCC histological subtype or unknown grade. After 1:1 PSM that resulted in 5352 LTD versus 5352 PN patients, the 10-yr CSM rate was 8.7% versus 5.5%. In multivariable CRR models, LTD was associated with higher CSM, relative to PN (hazard ratio [HR]: 1.58, p < 0.001). Subgroup analyses revealed invariably higher CSM after LTD versus PN in patients with tumor size ≤3 cm (10-yr CSM 7.2% vs 5.3%, multivariable HR: 1.47, p < 0.001) and in patients with tumor size 3.1-4 cm (10-yr CSM 11.4% vs 6.1%, multivariable HR: 1.72, p < 0.001). Lack of information regarding earlier cancer controls, retreatment, tumor location within the kidney, and type of surgery represented limitations. CONCLUSIONS: In T1a RCC patients, LTD is invariably associated with higher CSM relative to PN, even after adjustment for OCM and all available patient and tumor characteristics, and regardless of tumor size considerations. However, the magnitude of CSM disadvantage was more pronounced in LTD patients with tumor size 3.1-4 cm than in those with tumor size ≤3 cm. PATIENT SUMMARY: In patients with small renal masses, we observed higher cancer-specific death rates for local tumor destruction (LTD) than for partial nephrectomy. The LTD disadvantage was more pronounced for patients with tumor size 3.1-4 cm, but was also present in those with tumor size ≤3 cm.
- MeSH
- karcinom z renálních buněk * patologie MeSH
- ledviny chirurgie MeSH
- lidé MeSH
- nádory ledvin * patologie MeSH
- nefrektomie metody MeSH
- proporcionální rizikové modely MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Recently, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published an update on the Global Strategy for Prevention, Diagnosis and Management of COPD, introducing a new classification of chronic obstructive pulmonary disease (COPD). Our aim was to assess the prognostic value of the new GOLD classification system in comparison with the previous GOLD classification systems (GOLD stages I-IV and GOLD groups A-D) and the BODE index. METHODS: We used the data of 784 patients with COPD from the Czech Multicenter Research Database of COPD. Patient survival was analyzed with the use of Kaplan-Meier estimate and Cox model of proportional risks. ROC analysis and area under curve (AUC) were used for comparison of GOLD classifications and BODE index. The analyses were performed with the use of software R (version 4.2.0). RESULTS: We analyzed data of 782 patients with complete data on GOLD classifications. The study population comprised 72.9% of men, 89.1% current or former smokers, with a mean age of 66.6 years, a mean BMI of 27.4 and a mean FEV1 44.9% of predicted. Probability of 5-year survival differed by GOLD classification. Application of the 2023 GOLD classification showed increased risk of death in group B (HR 1.82, 95% CI 1.14-2.92; p = 0.013) and in group E (HR 2.48, 95% CI 1.54-3.99; p˂0.001). The ROC analysis showed that the overall prognostic value of the 2023 GOLD classification was similarly weak to previous A-D GOLD classification schemes (AUCs 0.557-0.576) and was lower compared to the GOLD 1-4 system (AUC 0.614) and even lower when compared to the BODE index (AUC 0.715). CONCLUSION: We concluded that the new GOLD classification system has poor prognostic properties and that specific prediction tools (eg, the BODE index) should be used for mortality risk assessment.
- MeSH
- chronická obstrukční plicní nemoc * diagnóza terapie MeSH
- hodnocení rizik MeSH
- lidé MeSH
- prognóza MeSH
- progrese nemoci MeSH
- proporcionální rizikové modely MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
BACKGROUND: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. METHODS: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. RESULTS: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. CONCLUSIONS: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.
BACKGROUND: To assess the association between of type and number of D'Amico high-risk criteria (DHRCs) with rates of cancer-specific mortality (CSM) in prostate cancer (PCa) patients treated with external beam radiotherapy (RT). METHODS: In the Surveillance, Epidemiology, and End Results database (2004-2016), we identified 34,908 RT patients with at least one DHRCs, namely prostate-specific antigen (PSA) >20 ng/dL (hrPSA), biopsy Grade Group (hrGG) 4-5, clinical T stage (hrcT) ≥T2c. Multivariable Cox regression models (CRM), as well as competing risks regression (CRR) model, which further adjust for other cause mortality, tested the association between DHRCs and 5-year CSM. RESULTS: Of 34,908 patients, 14,777 (42%) exclusively harbored hrGG, 5641 (16%) hrPSA, 4390 (13%) had hrcT. Only 8238 (23.7%) harbored any combination of two DHRCs and 1862 (5.3%) had all three DHRCs. Five-year CSM rates ranged from 2.4% to 5.0% when any individual DHRC was present (hrcT, hrPSA, hrGG, in that order), versus 5.2% to 10.5% when two DHRCs were present (hrPSA+hrcT, hrcT+hrGG, hrPSA+hrGG, in that order) versus 14.4% when all three DHRCs were identified. In multivariable CRM hazard ratios relative to hrcT ranged from 1.07 to 1.76 for one DHRC, 2.20 to 3.83 for combinations of two DHRCs, and 5.11 for all three DHRCs. Multivariable CRR yielded to virtually the same results. CONCLUSIONS: Our study indicates a stimulus-response effect according to the type and number of DHRCs. This indicates potential for risk-stratification within HR PCa patients that could be applied in clinical decision making to increase or reduce treatment intensity.
- MeSH
- biopsie MeSH
- lidé MeSH
- nádory prostaty * patologie MeSH
- proporcionální rizikové modely MeSH
- prostatektomie * metody MeSH
- prostatický specifický antigen MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
- MeSH
- chronicko-progresivní roztroušená skleróza * MeSH
- imunoterapie MeSH
- lidé MeSH
- proporcionální rizikové modely MeSH
- recidiva MeSH
- relabující-remitující roztroušená skleróza * MeSH
- roztroušená skleróza * terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
CONTEXT: Immune checkpoint inhibitors (ICIs) are widely used in the management of patients with advanced urothelial carcinoma (aUC). However, its performance in aUC patients with poor performance status (PS) remains unknown. OBJECTIVE: We aimed to assess the impact of patients' performance status on the oncologic outcomes in patients with aUC treated with ICIs. EVIDENCE ACQUISITION: We searched PubMed, Web of Science, and Scopus from inception until July 2022 to identify studies assessing the association between the Eastern Cooperative Oncology Group (ECOG) PS and the oncologic outcomes in patients with aUC treated with ICIs in randomised (RCTs) and nonrandomised (NRCTs) control studies according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The outcomes of our interests were overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and objective response rate (ORR). EVIDENCE SYNTHESIS: Overall, six RCTs comprising 5428 patients and 32 NRCTs comprising 6069 patients were included. The meta-analysis of the RCTs revealed that patients with ECOG PS = 0 and PS ≥1 had a trend towards better OS with ICIs compared with those treated with chemotherapy (pooled hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.71-1.04, and HR: 0.74, 95% CI: 0.53-1.03, respectively). There was no significant difference in terms of response to ICIs between patients with poor and good PS (I2 = 0%, p = 0.46). The meta-analysis of the NRCTs revealed that patients with PS ≥2 had significantly worse OS than those with PS <2 (pooled HR: 2.52, 95% CI: 2.00-3.17), as well as worse CSS (pooled HR: 3.35, 95% CI: 1.90-5.91), PFS (pooled HR: 2.89, 95% CI: 1.67-5.01), and ORR (pooled odds ratio: 0.47, 95% CI: 0.27-0.82). Similarly, patients with PS ≥1 had significantly worse oncologic outcomes than those with PS = 0. CONCLUSIONS: In the NRCTs, poor PS was correlated with worse oncologic outcomes in aUC patients treated with ICIs. In the RCTs, ICIs performed better than chemotherapy across all PS categories. These findings should be interpreted with caution due to the high heterogeneity across the studies and patient populations. More RCTs including poor PS are needed to assess the impact of PS on ICI therapy outcomes. PATIENT SUMMARY: Immune therapy for patients with urothelial carcinoma should not be restricted on the grounds of performance status. However, patients with poor performance status should be considered for other factors such as life expectancy and comorbidities.
- MeSH
- inhibitory kontrolních bodů terapeutické užití MeSH
- karcinom z přechodných buněk * farmakoterapie MeSH
- lidé MeSH
- nádory močového měchýře * farmakoterapie MeSH
- proporcionální rizikové modely MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- systematický přehled MeSH
