Respiratory-related death in individuals with incident asthma and COPD: a competing risk analysis

Background Distinguishing between mortality attributed to respiratory causes and other causes among people with asthma, COPD, and asthma-COPD overlap (ACO) is important. This study used electronic health records in England to estimate excess risk of death from respiratory-related causes after accounting for other causes of death. Methods We used linked Clinical Practice Research Datalink (CPRD) primary care and Office for National Statistics mortality data to identify adults with asthma and COPD from 2005 to 2015. Causes of death were ascertained using death certificates. Hazard ratios (HR) and excess risk of death were estimated using Fine-Gray competing risk models and adjusting for age, sex, smoking status, body mass index and socioeconomic status. Results 65,021 people with asthma and 45,649 with COPD in the CPRD dataset were frequency matched 5:1 with people without the disease on age, sex and general practice. Only 14 in 100,000 people with asthma are predicted to experience a respiratory-related death up to 10 years post-diagnosis, whereas in COPD this is 98 in 100,000. Asthma is associated with an 0.01% excess incidence of respiratory related mortality whereas COPD is associated with an 0.07% excess. Among people with asthma-COPD overlap (N = 22,145) we observed an increased risk of respiratory-related death compared to those with asthma alone (HR = 1.30; 95% CI 1.21–1.40) but not COPD alone (HR = 0.89; 95% CI 0.83–0.94). Conclusions Asthma and COPD are associated with an increased risk of respiratory-related death after accounting for other causes; however, diagnosis of COPD carries a much higher probability. ACO is associated with a lower risk compared to COPD alone but higher risk compared to asthma alone.

Antithymocyte globulin exposure in CD34+ T-cell depleted allogeneic hematopoietic cell transplantation

Traditional weight-based dosing results in variable rabbit anti-thymocyte-globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+IR) leading to higher mortality. In a retrospective, pharmacokinetic (PK)/pharmacodynamic analysis of patients undergoing their first CD34+ T-cell depleted (TCD) Allogeneic Hematopoietic Cell Transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area-under-the-curve (AUC;AU*d/L) using a validated population-PK model. We related rATG exposure to non-relapse mortality (NRM), CD4+IR (CD4+ ≥50/µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute-graft versus host disease (GVHD) to define an optimal rATG-exposure. Cox-proportional hazard models, and multi-state competing risk models were used. 554 patients were included (age 0.1-73 years). Median post-HCT rATG exposure was 47AU*d/L (range 0-101). Low post-HCT AUC (<30AU*d/L) was associated with lower risk of NRM (p<0.01) and higher probability of achieving CD4+IR (p<0.001). Patients who attained CD4+IR had a 7-fold lower 5-year NRM (p<0.0001). Probability of achieving CD4+IR was 2.5-fold and 3-fold higher in the <30AU*d/L-group, compared to 30-55AU*d/L and ≥55AU*d/L-groups, respectively. In multivariable analyses, post-HCT rATG-exposure ≥55AU*d/L was associated with an increased risk of NRM (HR 3.42,95%CI 1.26-9.30). In the malignancy subgroup (n=515) a 10-fold and 7-fold increased NRM, was observed in the >55AU*d/L and 30-55AU*d/L groups, respectively, compared to <30AU*d/L group. Post-HCT rATG exposure ≥55AU*d/L was associated with higher risk of acute GVHD (HR 2.28,95%CI 1.01-5.16). High post-HCT rATG-exposure is associated with higher NRM secondary to poor CD4+IR after TCD-HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.

Clofarabine-fludarabine-busulfan in HCT for pediatric leukemia: an effective, low toxicity, TBI-free conditioning regimen

We prospectively studied CloFluBu-conditioning in allogeneic Hematopoietic Cell Therapy (HCT) for lymphoid- and myeloid malignancies, and hypothesized that CloFluBu provides a less toxic alternative to conventional conditioning regimens, with adequate anti-leukemic activity. All patients receiving their first HCT, from 2011-2019, were included and received CloFluBu. Primary endpoint was Event Free Survival (EFS). Secondary endpoints were Overall Survival (OS), Graft-versus-Host-Disease (GvHD)-Relapse-Free Survival (GRFS), Treatment Related Mortality (TRM), Cumulative Incidence of Relapse (CIR), acute and chronic GvHD, and veno-occlusive disease (VOD). Cox Proportional Hazard- and Fine and Gray competing-risk models were used for data analysis. 155 Children were included; 60 acute lymphoid leukemia (ALL), 69 acute myeloid leukemia (AML), and 26 other malignancies (mostly MDS-EB). Median age was 9.7 (0.5-18.6) years. Estimated 2-yr EFS was 72.0% ± 6.0 in ALL, and 62.4% ± 6.0 in AML patients. TRM in the whole cohort was 11.0% ± 2.6, incidence of aGvHD III-IV at 6 months was 12.3% ± 2.7, extensive chronic GvHD at 2-yr was 6.4% ± 2.1. Minimal residual disease-positivity prior to HCT was associated with higher CIR, both in ALL and AML. CloFluBu showed limited toxicity and encouraging EFS. CloFluBu is a potentially less toxic alternative to conventional conditioning regimens. Randomized prospective studies are needed.

The risk and prognosis of secondary primary malignancy in lung cancer: a population-based study

Aim: To assess and predict risk and prognosis of lung cancer (LC) patients with second primary malignancy (SPM). Methods: LC patients diagnosed from 1992 to 2016 were obtained through the Surveillance, Epidemiology, and End Results database. Standardized incidence ratios were calculated to evaluate SPM risk. Cox regression and competing risk models were applied to assess the factors associated with overall survival, SPM development and LC-specific survival. Nomograms were built to predict SPM probability and overall survival. Results & conclusion: LC patients remain at higher risk of SPM even though the incidence declines. Patients with SPM have a better prognosis than patients without SPM. The consistency indexes for nomograms of SPM probability and overall survival are 0.605 (95% CI: 0.598–0.611) and 0.644 (95% CI: 0.638–0.650), respectively.

Association Between Patient Survival and Clinician Variability in Treatment Rates for Aortic Valve Stenosis

Background Patients with symptomatic severe aortic stenosis (ssAS) have a high mortality risk and compromised quality of life. Surgical/transcatheter aortic valve replacement (AVR) is a Class I recommendation, but it is unclear if this recommendation is uniformly applied. We determined the impact of managing cardiologists on the likelihood of ssAS treatment. Methods and Results Using natural language processing of Optum electronic health records, we identified 26 438 patients with newly diagnosed ssAS (2011–2016). Multilevel, multivariable Fine‐Gray competing risk models clustered by cardiologists were used to determine the impact of cardiologists on the likelihood of 1‐year AVR treatment. Within 1 year of diagnosis, 35.6% of patients with ssAS received an AVR; however, rates varied widely among managing cardiologists (0%, lowest quartile; 100%, highest quartile [median, 29.6%; 25th–75th percentiles, 13.3%–47.0%]). The odds of receiving AVR varied >2‐fold depending on the cardiologist (median odds ratio for AVR, 2.25; 95% CI, 2.14–2.36). Compared with patients with ssAS of cardiologists with the highest treatment rates, those treated by cardiologists with the lowest AVR rates experienced significantly higher 1‐year mortality (lowest quartile, adjusted hazard ratio, 1.22, 95% CI, 1.13–1.33). Conclusions Overall AVR rates for ssAS were low, highlighting a potential challenge for ssAS management in the United States. Cardiologist AVR use varied substantially; patients treated by cardiologists with lower AVR rates had higher mortality rates than those treated by cardiologists with higher AVR rates.

On Progressive Censored Competing Risks Data: Real Data Application and Simulation Study

Competing risks are frequently overlooked, and the event of interest is analyzed with conventional statistical techniques. In this article, we consider the analysis of bi-causes of failure in the context of competing risk models using the extension of the exponential distribution under progressive Type-II censoring. Maximum likelihood estimates for the unknown parameters via the expectation-maximization algorithm are obtained. Moreover, the Bayes estimates of the unknown parameters are approximated using Tierney-Kadane and MCMC techniques. Interval estimates using Bayesian and classical techniques are also considered. Two real data sets are investigated to illustrate the different estimation methods, and to compare the suggested model with Weibull distribution. Furthermore, the estimation methods are compared through a comprehensive simulation study.

Surgical Options for Localized Renal Cell Carcinoma, A Retrospective Clinical Study Based on Tumor Size

PurposeAlthough many studies have explored the options of radical nephrectomy (RN) and nephron sparing surgery (NSS) for localized renal cell carcinoma (RCC), the answer to this question remains unclear. This study aims to compare the long-term prognostic differences between RN and NSS among different sizes of localized RCC.MethodsThis study retrospectively included 80,439 T1-T4 N0 M0 patients who underwent RN or NSS based on the Surveillance, Epidemiology, and End Results database. We calculated the 10-year overall survival (OS) and cancer specific survival of patients with RCC. We also evaluated the risk of cardiovascular death in patients using competing risk models for RN and NSS.ResultsOur analysis showed that patients who underwent NSS had a more prolonged OS of 5 and 10 years when the tumor size was less than 8.5cm and 7.2cm. Compared to RN, NSS does not appear to improve OS in large (> 7.2cm) RCC patients. And stratified analysis showed that NSS for RCC less than 9.2cm may be more likely to benefit from long-term OS in younger patients (<60 years), while RCC above 7.3cm may be more suitable for RN in older patients (>=60 years). The gender-stratified results suggested male and female patients may be more suitable for NSS for RCC below 6.4 and 7.7cm, respectively. Besides, competing risk models showed patients receiving RN have higher cumulative cardiovascular mortality.ConclusionsFor large RCC, NSS may be very carefully selected unless there are clear indications such as isolated congenital kidney and bilateral kidney cancer.

Identifying Factors Affecting Cancer-related Death in Patients with Adenocarcinoma Gastric Cancer; An Analysis in the Presence of Competing Risks

Background: Adenocarcinoma is the most common type of gastric cancer that has shorter survival than other types of gastric cancer. The death of patients with this type of cancer may be due to the progression of cancer or other related causes. Objectives: The aim of this study is to determine the factors affecting death due to the cancer progression in gastric cancer patients with the diagnosis of adenocarcinoma, using competing risk models. Methods: This retrospective cohort study was performed on 306 gastric cancer patients diagnosed with adenocarcinoma referring to Imam Khomeini clinic in Hamadan from 2002 to 2017. Death due to the cancer progression was considered an interest event and death due to without progression as a competing event. To determine the effect of covariates on hazard, the cause-specific and subdistribution hazard regression models were used. Data analysis was performed, using R3.6.1 software and cmprsk and survival packages. Results: The mean (SD) age of patients was 62.3 (12.5) years and 74.3% were male. The effect of the stage, the number of involved lymphomas, and the type of treatment were significant on the hazard of death due to the disease progression in both cause-specific and subdistribution hazard models. Conclusions: The results showed that most deaths occur in the first 3 years of follow-up. The higher stage and higher number of lymph nodes have increased the hazard of death but supplementary treatment significantly decreased the hazard of death due to cancer progression in adenocarcinoma gastric cancer patients in both competing risk models.

Extubation Failure in Critically Ill COVID-19 Patients: Risk Factors and Impact on In-Hospital Mortality

Purpose: We sought to identify clinical factors that predict extubation failure (reintubation) and its prognostic implications in critically ill COVID-19 patients. Materials and Methods: Retrospective, multi-center cohort study of hospitalized COVID-19 patients. Multivariate competing risk models were employed to explore the rate of reintubation and its determining factors. Results: Two hundred eighty-one extubated patients were included (mean age, 61.0 years [±13.9]; 54.8% male). Reintubation occurred in 93 (33.1%). In multivariate analysis accounting for death, reintubation risk increased with age (hazard ratio [HR] 1.04 per 1-year increase, 95% confidence interval [CI] 1.02 -1.06), vasopressors (HR 1.84, 95% CI 1.04-3.60), renal replacement (HR 2.01, 95% CI 1.22-3.29), maximum PEEP (HR 1.07 per 1-unit increase, 95% CI 1.02 -1.12), paralytics (HR 1.48, 95% CI 1.08-2.25) and requiring more than nasal cannula immediately post-extubation (HR 2.19, 95% CI 1.37-3.50). Reintubation was associated with higher mortality (36.6% vs 2.1%; P < 0.0001) and risk of inpatient death after adjusting for multiple factors (HR 23.2, 95% CI 6.45-83.33). Prone ventilation, corticosteroids, anticoagulation, remdesivir and tocilizumab did not impact the risk of reintubation or death. Conclusions: Up to 1 in 3 critically ill COVID-19 patients required reintubation. Older age, paralytics, high PEEP, need for greater respiratory support following extubation and non-pulmonary organ failure predicted reintubation. Extubation failure strongly predicted adverse outcomes.

Sex Differences in the Risk of 30-Day Death After Acute Ischemic Stroke

Objective:To examine sex differences in early stroke deaths according to cause of death.Methods:We investigated 30-day deaths in acute ischemic stroke patients enrolled in a multicenter stroke registry between 2007 and 2019 in Fukuoka, Japan. We estimated the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of cause-specific deaths for women vs. men using Cox proportional hazards models and competing risk models. The risk of acute infections during hospitalization and the associated case fatality rates were also compared between the sexes.Results:Among 17,956 acute ischemic stroke patients (women: 41.3%), the crude 30-day death rate after stroke was higher in women than men. However, adjusting for age and stroke severity resulted in a lower risk of death among women (HR [95% CI]: 0.76 [0.62–0.92]). Analyses using competing risk models revealed that women were less likely to die from acute infections (subdistribution HR [95% CI]: 0.33 [0.20–0.54]). Further analyses showed that women were associated with a lower risk of acute infections during hospitalization (odds ratio [95% CI]: 0.62 [0.52–0.74]), and a lower risk of death due to these infections (subdistribution HR [95% CI]: 052 [0.33–0.83]).Conclusions:When adjusting for confounders, the female sex was associated with a lower risk of 30-day death after stroke, which could be explained by a female survival advantage in poststroke infections. Sex-specific strategies are needed to reduce early stroke deaths.Classification of Evidence:This is a Class I prognostic study because it is a prospective population based cohort with objective outcomes. Female gender appears to be protective for 30 mortality and post stroke infections.