Multivariate Cox Regression Model Research Articles

Proton pump inhibitors and all-cause mortality risk among cancer patients

BACKGROUND Proton pump inhibitors (PPIs) are widely used, including among cancer patients, to manage gastroesophageal reflux and other gastric acid-related disorders. Recent evidence suggests associations between long-term PPI use and higher risks for various adverse health outcomes, including greater mortality. AIM To investigate the association between PPI use and all-cause mortality among cancer patients by a comprehensive analysis after adjustment for various confounders and a robust methodological approach to minimize bias. METHODS This retrospective cohort study used data from the TriNetX research network, with electronic health records from multiple healthcare organizations. The study employed a new-user, active comparator design, which compared newly treated PPI users with non-users and newly treated histamine2 receptor antagonists (H2RA) users among adult cancer patients. Newly prescribed PPIs (esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole) users were compared to non-users or newly prescribed H2RAs (cimetidine, famotidine, nizatidine, or ranitidine) users. The primary outcome was all-cause mortality. Each patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence interval (CI). RESULTS During the follow-up period (median 5.4 ± 1.8 years for PPI users and 6.5 ± 1.0 years for non-users), PPI users demonstrated a higher all-cause mortality rate than non-users after 1 year, 2 years, and at the end of follow up (HRs: 2.34-2.72). Compared with H2RA users, PPI users demonstrated a higher rate of all-cause mortality HR: 1.51 (95%CI: 1.41-1.69). Similar results were observed across sensitivity analyses by excluding deaths from the first 9 months and 1-year post-exposure, confirming the robustness of these findings. In a sensitivity analysis, we analyzed all-cause mortality outcomes between former PPI users and individuals who have never used PPIs, providing insights into the long-term effects of past PPI use. In addition, at 1-year follow-up, the analysis revealed a significant difference in mortality rates between former PPI users and non-users (HR: 1.84; 95%CI: 1.82-1.96). CONCLUSION PPI use among cancer patients was associated with a higher risk of all-cause mortality compared to non-users or H2RA users. These findings emphasize the need for cautious use of PPIs in cancer patients and suggest that alternative treatments should be considered when clinically feasible. However, further studies are needed to corroborate our findings, given the significant adverse outcomes in cancer patients.

New Index Demonstrates Association between Social Vulnerability, Environmental Burden, and Kidney Failure Risk among Individuals with Glomerular Disease.

The Centers for Disease Control and Prevention (CDC) Environmental Justice Index Social-Environmental Ranking (EJI-SER) combines a Social Vulnerability Module (SV) with an Environmental Burden Module (EB) to characterize cumulative environmental and social burden at the census tract level. This analysis evaluates the association between EJI-SER and kidney outcomes in glomerular disease (GD) patients. Cure Glomerulopathy (CureGN) is an observational cohort study of adults and children with biopsy-proven GD. EJI-SER is a percentile ranking by census tract, with a higher score indicating a more severe burden. Associations between EJI-SER and its components with kidney failure (initiation of kidney replacement therapy, transplant, or two estimated glomerular filtration rates [eGFRs] <15ml/min/1.73m2) and longitudinal eGFR were tested using multivariable Cox regression and linear mixed models, respectively, adjusted for demographics, histologic diagnosis, eGFR and urine protein to creatinine ratio at enrollment, and time from biopsy to enrollment. Among 1,149 participants with census tract data, the median (IQR) follow-up was 5.4 (3.0-7.0) years, the median (IQR) age at biopsy was 24 (10-48), and self-identified racial distribution was 5% Asian, 18% Black, and 70% White. Median (IQR) EJI-SER was 0.49 (0.26-0.75). EJI-SER scores in the lowest two quartiles were associated with a lower hazard of kidney failure compared to the highest quartile (adjusted HR [95% CI] 0.62 [0.36-1.08] and 0.43 [0.25-0.76] for EJI-SER 0-25% and >25-50% vs. >75%, respectively) and higher eGFR at enrolllment (adjusted mean 90.1 vs. 87.1 ml/min/1.73m2 for 0-25% vs. >75%, p=0.08). As captured by EJI-SER, higher environmental and social burdens are associated with lower eGFR and a higher risk of kidney failure in the CureGN cohort. This first use of the EJI-SER in GD demonstrates the need for additional investigation into social drivers of disparities in GD and policies and resources that address these structural inequities.

Prognostic value of manual versus automatic methods for assessing extents of resection and residual tumor volume in glioblastoma.

The extent of resection (EOR) and postoperative residual tumor (RT) volume are prognostic factors in glioblastoma. Calculations of EOR and RT rely on accurate tumor segmentations. Raidionics is an open-access software that enables automatic segmentation of preoperative and early postoperative glioblastoma using pretrained deep learning models. The aim of this study was to compare the prognostic value of manually versus automatically assessed volumetric measurements in glioblastoma patients. Adult patients who underwent resection of histopathologically confirmed glioblastoma were included from 12 different hospitals in Europe and North America. Patient characteristics and survival data were collected as part of local tumor registries or were retrieved from patient medical records. The prognostic value of manually and automatically assessed EOR and RT volume was compared using Cox regression models. Both manually and automatically assessed RT volumes were a negative prognostic factor for overall survival (manual vs automatic: HR 1.051, 95% CI 1.034-1.067 [p < 0.001] vs HR 1.019, 95% CI 1.007-1.030 [p = 0.001]). Both manual and automatic EOR models showed that patients with gross-total resection have significantly longer overall survival compared with those with subtotal resection (manual vs automatic: HR 1.580, 95% CI 1.291-1.932 [p < 0.001] vs HR 1.395, 95% CI 1.160-1.679 [p < 0.001]), but no significant prognostic difference of gross-total compared with near-total (90%-99%) resection was found. According to the Akaike information criterion and the Bayesian information criterion, all multivariable Cox regression models showed similar goodness-of-fit. Automatically and manually measured EOR and RT volumes have comparable prognostic properties. Automatic segmentation with Raidionics can be used in future studies in patients with glioblastoma.

Socioeconomic position and sudden cardiac death: A Danish nationwide study.

The aim of this study was to examine differences in incidence rates of all-cause mortality (ACM) and sudden cardiac death (SCD) in persons of differing socioeconomic position (SEP). All deaths in Denmark from 01-01-2010 to 31-12-2010 (1 year) were included. Autopsy reports, death certificates, discharge summaries and nationwide health registries were reviewed to identify cases of SCD. SEP was measured as either household income or highest achieved educational level and analysed separately. Hazard rates were calculated using univariate and multivariable Cox regression model adjusting for age, sex, and selected comorbidities. A total of 53452 deaths were included of which 6820 were classified as SCDs. Incidence rates of ACM and SCD increased with age and were higher in the lower SEP groups. The greatest difference in SCD incidence was found between the low and high education level groups with an incidence rate ratio of 5.1 (95% CI 3.8-6.8). The hazard ratios for ACM and SCD were significantly higher for low SEP groups independently of comorbidities. Compared with the highest income group, the low-income group had adjusted hazard ratios of ACM and SCD that were 2.17 (2.01-2.34) and 1.72 (1.67-1.76) respectively. We observed an inverse association between both income and education level and the risk of ACM and SCD in the general population, which persisted independently of baseline comorbidities. Our results indicate a need for further research into the mechanisms behind socioeconomic disparities in healthcare and targeted preventative strategies.

The neutrophil–lymphocyte ratio as a risk factor for all-cause mortality among individuals with resolved HBV infection: evidence from the NHANES 1999–2018

BackgroundInflammation is a critical component in the process of resolved hepatitis B virus (HBV) infection. The neutrophil-to-lymphocyte ratio (NLR) serves as a sensitive indicator of systemic inflammation and immune activation. Our study aimed to investigate the correlation between elevated NLR levels and the risk of all-cause mortality in patients with resolved HBV infection. Additionally, we evaluated the potential mediating effect of diabetes mellitus (DM) on this correlation.MethodsOur study enrolled 1,146 adult patients with resolved HBV infection from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. We utilized the Restricted Cubic Splines (RCS) and Maximum Selection Rank Statistical Method (MSRSM) to analyze the relationship between the NLR and the risk of all-cause mortality. The impact of NLR was evaluated using a weighted multivariate Cox regression model, and the model’s predictive accuracy was assessed using time-dependent Receiver Operating Characteristic (ROC) curves. An intermediary analysis was conducted to explore the potential influence of DM on the observed relationship.ResultsDuring follow-up period of 103.54 ± 4.90 months, we recorded 207 deaths among the study participants. The analysis using the RCS method revealed a significant positive correlation between the NLR and the risk of all-cause mortality. Those with elevated NLR levels faced a substantially higher mortality risk compared to those with lower levels, as indicated by a Hazard Ratio (HR) of 1.84, with a 95% Confidence Interval (CI) of 1.17 to 2.89 (p &amp;lt; 0.05). The predictive accuracy of the model was substantial, as evidenced by the Area Under the Curve (AUC) for ROC curves at 3, 5, and 10 years, which were 0.873, 0.870, and 0.862, respectively. Furthermore, mediation analysis indicated that DM significantly influenced the relationship between the NLR and mortality, with a mediation effect of 6.57% (95% Confidence Interval [CI]: 0.64 to 15%; p = 0.02).ConclusionElevated NLR is significantly associated with an increased risk of all-cause mortality in patients with resolved HBV infection. Concurrently, DM acts as a partial mediator of this association.

Impact of ISUP grade group on cancer-specific mortality in radical prostatectomy-treated prostate cancer patients with organ-confined disease

Introduction: We aimed to test the impact of International Society of Urological Pathology (ISUP) grade group (GG) on cancer-specific mortality (CSM) in organ-confined (pT2) prostate cancer (PCa) at radical prostatectomy (RP). Methods: RP organ-confined prostate cancer (PCa) patients were identified (Surveillance, Epidemiology, and End Results 2004−2015). Cancer-specific survival (CSS) rates were tested in Kaplan-Meier plots and multivariable Cox regression (MCR) models according to GG: 1–3 vs. 4 vs. 5. Sensitivity analyses addressed GG4 and GG5 patients with available primary and secondary Gleason score (GS). Results: Overall, 61 172 patients with RP organ-confined PCa were identified. Of these, 57 715 (94.4%), 2036 (3.3%) and 1421 (2.3%) harbored GG1–3, 4, and 5, respectively. In Kaplan-Meier analyses, seven-years’ CSS estimates were 99.6 vs. 98.2 vs. 93.8% for GG1–3 vs. 4 vs. 5, respectively (p&lt;0.001). In MCR models, GG4 (hazard ratio [HR] 2.72, p&lt;0.001) and 5 (HR 9.95, p&lt;0.001) independently predicted higher CSM, relative to GG1–3. Furthermore, GG5 also independently predicted higher CSM (HR 3.72, p&lt;0.001) vs. GG4. In sensitivity analyses, 1.2, 1.6, and 2.4 CSM events per 1000 person-years of followup were respectively recorded for GS 4+4, 3+5, and 5+3 patients. Conversely, 4.8 vs. 5.3 CSM events per 1000 person-years of followup were respectively recorded for GS 4+5 vs. 5+4/5+5 patients. Conclusions: In organ-confined PCa, at RP, a small proportion of patients harbor GG4–5. These patients exhibit higher CSM than their GG1–3 counterparts. Moreover, detectable mortality rate differences indicate a dose-response effect according to primary and secondary GS. This phenomenon applies in both GG4 and GG5, as well as between GG4 and GG5.

Lutetium-177 PSMA radioligand therapy in taxan-naive first- and second-line metastatic castration resistant prostate cancer after first-line ARPI therapy.

Lutetium-177 Prostate-specific membrane antigen (Lu-PSMA) radioligand therapy is EMA-approved for metastatic castration resistant prostate cancer (mCRPC) after androgen receptor pathway inhibition (ARPI) and taxan-based chemotherapy. However, its effect in taxan-naïve patients is under current investigation. We relied on the FRAMCAP database to elaborate Lu-PSMA therapy outcomes of progression-free (PFS) and overall (OS) in taxan-naïve mCRPC patients after previous ARPI treatment. Comparison was made against current standard of care with ARPI or docetaxel, irrespective of the previous used staging modality. Of 269 patients, 11% received Lu-PSMA in first/second-line mCRPC vs. 57% ARPI vs. 33% docetaxel. Mostly no significant baseline differences between Lu-PSMA and ARPI patients were observed, while Lu-PSMA patients were significantly older, received less systematic treatments and ECOG1-2 proportions were higher, relative to docetaxel patients. In PFS (13.3 vs. 8.2 months, hazard ratio [HR]: 0.70, p = 0.16) and OS analyses (68.9 vs. 39.1 months, HR: 0.64, p = 0.2), Lu-PSMA was numerically more favorable than ARPI. In additional multivariable Cox regression models, Lu-PSMA was significant better regarding PFS and OS, relative to ARPI (both p < 0.05). Compared to docetaxel, also significant better PFS (13.3 vs. 8.1 months, HR: 0.46) and OS (68.9 vs. 27.3 months, HR: 0.34, both p < 0.01) was observed for Lu-PSMA treatment. The OS advantage was also observed after multivariable adjustment (p < 0.01). This retrospective single-center study including a substantial proportion of patients with treatment preference for Lu-PSMA suggests that Lu-PSMA therapy provides significantly more favorable PFS and OS outcomes in taxan-naïve mCRPC patients after previous ARPI treatment, relative to ARPI or docetaxel treatment and may be considered as an early mCRPC treatment option.

Valve Sparing Aortic Root Replacement in the Resternotomy Setting.

While valve-sparing aortic root replacement (VSRR) has demonstrated satisfactory outcomes, its utility in a reoperative sternotomy setting remains uncertain. This study evaluates the perioperative safety and long-term durability of reoperative sternotomy VSRR. All consecutive VSRR at two centers from 2005-2020 were included. Reoperative VSRR was defined as prior sternotomy for any reason. Time-dependent outcomes were compared between groups after balancing of covariates with inverse probability of treatment weighting. Multivariable Cox regression and Fine-Gray sub-distribution hazard model were used to identify factors associated with 10-year survival and aortic valve (AV) reintervention, respectively. Of 778 VSRR, 69 (8.9%) were reoperative sternotomies. Compared to primary, reoperative VSRR patients were younger (43 [34-54] vs 51 [39-61] years, p<0.001) and had less aortic insufficiency (33.3% vs 48.5%, p=0.02). Cardiopulmonary bypass times were longer in reoperative VSRR with similar rates of circulatory arrest. Reoperative VSRR had a higher incidence of postoperative acute kidney injury (10.1% vs 3.2%, p=0.01) and prolonged ventilation (24.6% vs 9.9%, p<0.001); operative mortality was higher in reoperative VSRR (2.9% (2/69) vs 1.4% (10/709)) although not significantly (p=0.66). Ten-year survival was 82.0% [70.0-96.0] and AV reintervention rate was 11.8% [2.3-19.4] after reoperative VSRR. After IPTW adjustment, survival and AV reintervention rates were not different. Reoperative sternotomy was not associated with long-term mortality (p=0.13) or AV reintervention (p=0.77) on multivariable analysis. Although complex, reoperative sternotomy VSRR can be performed with low operative mortality in carefully selected patients. Ten-year survival and AV reintervention rates were acceptable and comparable to primary VSRR.

Sex Differences in the Association Between Cardiovascular Autonomic Neuropathy and Mortality in Patients With Type 2 Diabetes: The ACCORD Study.

Cardiovascular autonomic neuropathy (CAN) is a severe complication of type 2 diabetes. Significant sex-related differences have been observed in type 2 diabetes consequences such as mortality. However, the effect of sex on the association between CAN and mortality in patients with type 2 diabetes is currently unknown. We assessed 7866 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, including 4730 men and 3136 women. CAN was diagnosed using a combination of heart rate variability and QT interval index, which has 3 different definitions. There were 1364 cases of all-cause mortality and 452 cases of cardiovascular disease mortality during a median follow-up of 9.7 years. We used multivariable Cox regression models to assess the association between different CAN definitions and mortality. In women, various CAN measures were statistically significant associated with an increased risk of all-cause mortality (CAN1: hazard ratio [HR], 1.64 [95% CI, 1.28-2.09]; CAN2: HR, 1.58 [95% CI, 1.17-2.15]; CAN3: HR, 1.78 [95% CI, 1.20-2.65]) and mortality (CAN1: HR, 2.25 [95% CI, 1.44-3.52]; CAN 2: HR, 2.22 [95% CI, 1.28-3.87]; CAN3: HR, 3.31 [95% CI, 1.67-6.57]). CAN was not significantly associated with mortality in men. A significant multiplicative interaction of CAN and sex was observed on both mortality outcomes (P<0.01). Significant sex-related differences were observed in CAN and its associated mortality. In terms of mortality risk prevention, CAN should be given greater consideration in women with type 2 diabetes.

Chronic kidney disease as a predictor of long-term adverse cardiovascular outcomes in patients with aortoiliac disease: a prospective cohort study.

Aortoiliac disease poses a significant cardiovascular (CV) risk, especially in individuals with chronic kidney disease. This study aimed to assess the predictive role of chronic kidney disease in long-term major adverse CV events in patients submitted to aortoiliac revascularization due to severe aortoiliac atherosclerotic disease. From 2013 to 2023, patients who underwent aortoiliac revascularization for TASC II type D lesions, including those with chronic kidney disease, were selected from a prospective cohort study. Demographic, clinical, and postoperative data were collected. Prognostic factors were evaluated for their independent impact on outcomes using survival analysis with a multivariate Cox regression model. The study included 135 patients, 93.3% male, with a mean age of 62.39±9.20 years. Chronic kidney disease was associated with higher prevalence of short-term myocardial injury after noncardiac surgery (54.5%, P=0.014) and was a long-term predictor of acute heart failure (Hazard Ratio=4.884; 95% confidence interval 2.377-22.802; P=0.007), major adverse CV events (HR 2.992; 95% CI 1.498-5.975, P=0.002) and all-cause mortality (HR 3.296; 95% CI 1.626-6.682, P<0.001). The multivariable analysis revealed significant associations between major adverse CV events and the following predictors: chronic kidney disease (adjusted HR=2.416, 95% CI 1.171-4.984, P=0.017) and congestive heart failure (adjusted HR=2.633, 95% CI 1.233-5.623, P=0.012). Chronic kidney disease is a recognized CV risk factor and an independent predictor of long-term acute heart failure, major adverse CV events, and all-cause mortality. These findings underscore the importance of early identification of CV complications and stricter long-term follow-up for chronic kidney disease patients undergoing aortoiliac revascularization.

Plasma Hepatic Transaminases and Incidence of Metabolic Syndrome Before Midlife in Military Adults: A CHIEF Cohort Study.

Plasma AST and ALT may reflect the nonalcoholic fatty liver disease (NAFLD) severity and have been associated with the risk of MetS in middle- or old-aged individuals. This study aimed to examine the associations of plasma hepatic aspartate and alanine transaminases (AST and ALT) levels with incident metabolic syndrome (MetS) in young adults, which have not been verified before. The goal of this study was to identify the association between plasma hepatic transaminases and the incidence of new-onset MetS among young adults. There were 2,804 military men and women, with ages of 18-39 years, free of baseline MetS and any viral hepatitis in Taiwan in 2014. Incident MetS were followed in the annual military health examinations from baseline till the end of 2020. The definition of MetS was made using the criteria of the International Diabetes Federation. Plasma concentrations of AST and ALT were checked at baseline. A Multivariable Cox regression model with adjustments for sex, age, each component of MetS, body mass index, substance use status, and physical activity at baseline was performed to determine the associations. Subgroup analyses were performed according to sex and each MetS component. During a median follow-up of 5.8 years, 644 incident MetS (23.0%) developed. ALT and AST levels (each 10 U/L increase) were respectively associated with 5% and 11% increased risk of incidence of MetS (hazard ratios (HRs) and 95% confidence intervals (CIs): 1.05 (1.01-1.09) and 1.11 (1.04-1.19), respectively). In subgroup analyses, the risk of incidence of MetS with ALT and AST levels respectively increased 75% and 114% in women (HRs: 1.75 (1.07-2.87) and 2.14 (1.35-3.41), respectively), and 7% and 14% in those free of central obesity (HRs: 1.07 (1.02-1.11) and 1.14 (1.06-1.23), respectively) which were higher than their counterparts (p-values for interaction by sex: 0.06 and 0.001, respectively; and by central obesity: 0.04 and 0.07, respectively). Plasma hepatic transaminase levels were positively associated with incident MetS among young adults. The individual role of central obesity and sex on the association of ALT and AST with incident MetS should be further clarified.

Pre-treatment Pulmonary Function Testing Has Limited Utility In B-cell Lymphoma Treated with CD19 CAR T-cells.

Pulmonary function tests (PFT) are recommended for hematopoietic cell transplantation (HCT) evaluation. However, their prognostic value in chimeric antigen receptor T-cell (CAR-T) therapy remains unclear. We assessed the predictive significance of PFTs and pulmonary comorbidity classifications, per the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), in B-cell lymphoma patients undergoing autologous CD19-CAR-T therapy. Single-center retrospective analysis encompassing 192 patients with relapsed/refractory (R/R) B-cell lymphoma, treated with commercial and point-of-care CD19-directed CAR-T therapy. Pre-therapy PFT were conducted, and patients were stratified into 3 HCT-CI-based pulmonary comorbidity grades, utilizing forced expiratory volume in 1 second (FEV1) and single-breath diffusing capacity for carbon monoxide (DLCO). Outcomes and toxicities were evaluated using univariate and multivariable Cox regression, logistic regression, Kaplan-Meier method, and spline models. Pulmonary comorbidity measures were not correlated with overall response rates or immune-toxicities, including cytokine release syndrome grade>2 and immune effector cell-associated neurotoxicity grade>2. Categorical FEV1, DLCO, and pulmonary comorbidity level did not correlate with overall survival (p=0.3, p=0.4, p=0.6, respectively) or progression free survival (PFS) (p=0.058, p>0.9, p=0.2, respectively). FEV1 as continuous measure was associated with reduced PFS in a multivariable model (HR 0.87 [95% CI 0.78-0.96], p=0.007). Spline modeling demonstrated a linear correlation between FEV1 and PFS. Categorical FEV1, DLCO, and pulmonary comorbidity level failed to predict therapy efficacy or toxicity. FEV1 as continuous measure was the sole PFT measure associated with PFS, independent of OS or severe toxicities.

Association between lifestyle risk factors and mortality in the Mexico City prospective study

Unhealthy lifestyles risk factors, such as smoking, alcohol consumption, physical inactivity, poor diet, and obesity, have been associated with a higher risk of all-cause and cause-specific mortality. However, composite score of these unhealthy behaviours has not been considered, particularly in Latin American populations. Herein, we examined the association of lifestyle risk factors score with all-cause and cause-specific mortality in Mexican adults. A total of 159,517 adults from the Mexico City Prospective Study (MCPS) were included. Data on sociodemographic, lifestyle risk factors and medical histories was collected through a self-reported baseline questionnaire in a census-style door-to-door interviews. Lifestyle risk factors assessment was based on five modifiable lifestyle risk factors and their respective cut-off points according to current health recommendations, including obesity, physical inactivity, tobacco, alcohol consumption and fruits and vegetables intake. Multivariable Cox regression models were used to estimate the associations of lifestyle risk factor score (ranging from 0 to 5) with all-cause and cause-specific mortality (cardiovascular disease, renal or hepatobiliary diseases, diabetes, respiratory diseases, cancer and all-cause mortality). We excluded the first 2, 5, 10, and 15 years of follow-up to account for reverse causation bias. We found a high prevalence (77%) of Mexican adults, with two or more lifestyle risk factors. Hazard ratio for respiratory diseases and renal or hepatobiliary diseases were 1.86 (95%CI: 1.45–2.39) and 2.00 (95%CI: 1.60–2.52) comparing participants with 4–5 lifestyle risk factors vs. those with none. For all-cause mortality, participants with 4–5 lifestyle risk factors had a 49% (HR: 1.49; 95%CI: 1.03–2.16) higher risk as compared to participants with none. The magnitude of the associations increased as the exclusion of follow-up time increased after 2, 5, 10 and 15 years. There was a positive association between the number of lifestyle risk factors and all-cause and cause-specific mortality, showing the highest rate of respiratory, renal or hepatobiliary and all-cause mortality among participants with 4–5 lifestyle risk factors. After accounting for reverse causation, associations were stronger.

Defining the Optimal Radiation-induced Lymphopenia Metric to Discern Its Survival Impact in Esophageal Cancer.

A detrimental association between radiation-induced lymphopenia (RIL) and oncologic outcomes in patients with esophageal cancer has been established. However, an optimal metric for RIL remains undefined but is important for the application of this knowledge in clinical decision-making and trial designs. The aim of this study was to find the optimal RIL metric discerning survival. Patients with esophageal cancer treated with concurrent chemoradiation therapy (CRT; 2004-2022) were selected. Studied metrics included absolute lymphocyte counts (ALCs) and neutrophil counts-and calculated derivatives-at baseline and during CRT. Multivariable Cox regression models for progression-free survival (PFS) and overall survival (OS) were developed for each RIL metric. The optimal RIL metric was defined as the one in the model with the highest c-statistic. Among 1339 included patients, 68% received photon-based and 32% proton-based CRT (median follow-up, 24.9 months). In multivariable analysis, the best-performing models included "ALC in week 3 of CRT" (corrected c-statistic 0.683 for PFS and 0.662 for OS). At an optimal threshold of <0.5 × 103/μL (ie, grade ≥3 RIL), ALC in week 3 was significantly associated with PFS (adjusted hazard ratio, 1.64; 95% CI, 1.27-2.13) and OS (adjusted hazard ratio, 1.56; 95% CI, 1.15-2.08), with 5-year PFS of 29% vs 40% and OS of 38% vs 51%, respectively. Reaching grade ≥3 RIL in week 3 of CRT for esophageal cancer is the strongest RIL metric to distinguish survival outcomes. We suggest that this metric should be the target for lymphopenia-mitigating strategies and propose this metric to be included in future trials.

Rhythm Control Better Prevents Stroke than Rate Control in Patients with Concomitant Hypertrophic Cardiomyopathy and Atrial Fibrillation: A Nationwide Population Based Cohort Study with Long-Term Follow-Up.

Atrial fibrillation (AF) increases the risks of stroke and mortality. It remains unclear whether rhythm control reduces the risk of stroke in patients with AF concomitant with hypertrophic cardiomyopathy (HCM). We identified AF patients with HCM who were ≥ 18 years old in the Taiwan National Health Insurance Database. Patients using antiarrhythmic medications for ≥ 30 defined daily doses (DDDs) or receiving catheter ablation for AF constituted the rhythm control group. Patients using rate control medications for ≥ 30 DDDs constituted the rate control group. A multivariable Cox regression model was used to evaluate the hazard ratio (HR) for adverse cardiovascular events. We enrolled a total of 178 patients with both AF and HCM without pre-existing cardiovascular diseases. Among them, 99 were in the rhythm control group and 79 were in the rate control group. After a follow-up period of 6.47 ± 0.98 years, the rhythm control group had a lower risk of stroke than the rate control group (adjusted HR: 0.380, p = 0.031) after adjusting for covariates including use of antithrombotic agents. After excluding patients receiving catheter ablation, the rhythm control group still had a lower risk of stroke than the rate control group (adjusted HR: 0.380, p = 0.037). In patients with AF and HCM, rhythm control with mainly pharmacological treatment better prevented stroke than rate control in long-term follow-up. The beneficial effect of lowering stroke risk through rhythm control was independent of oral anticoagulant use.

Association between early ondansetron use and the risk of sepsis in intensive care unit patients: a secondary data of the Medical Information Mart for Intensive Care IV database

ObjectiveThis study planned to analyse the association between ondansetron use within 24 hours before intensive care unit (ICU) admission to within 48 hours after ICU admission and the risk of...

Genome-wide meta-analysis associates donor-recipient non-HLA genetic mismatch with acute cellular rejection post-liver transplantation.

Acute cellular rejection (ACR) remains a common complication causing significant morbidity post-liver transplantation. Non-human leukocyte antigen (non-HLA) mismatches were associated with an increased risk of ACR in kidney transplantation. Therefore, we hypothesized that donor-recipient non-HLA genetic mismatch is associated with increased ACR incidence post-liver transplantation. We conducted an international multicenter case-control genome-wide association study of donor-recipient liver transplant pairs in 3 independent cohorts, totaling 1846 pairs. To assess genetic mismatch burden, we calculated sum scores for single-nucleotide polymorphism (SNP) mismatch based on all non-HLA functional SNPs, specifically SNPs coding for transmembrane or secreted proteins as they more likely affect the immune system. We analyzed the association between the non-HLA mismatch scores and ACR in a multivariable Cox regression model per cohort, followed by a weighted meta-analysis. During the first year post-transplantation, 90 of 689 (13%), 161 of 720 (22%), and 48 of 437 (11%) recipients experienced ACR in cohorts 1-3, respectively. Weighted meta-analyses showed that higher mismatch in functional non-HLA SNPs was associated with an increased incidence of ACR (HR 5.99; 95% CI: 1.39-20.08; p=0.011). Moreover, we found a larger effect of mismatch in SNPs coding for transmembrane or secreted proteins on ACR (HR 7.54; 95% CI 1.95-28.79; p=0.003). Sensitivity analyses showed that imputed HLA mismatch did not affect the associations between both non-HLA mismatch scores and ACR. Donor-recipient mismatch of functional non-HLA SNPs overall and, especially, of SNPs encoding transmembrane or secreted proteins correlated with 1-year ACR post-liver transplantation. Identifying high-risk immunological burdens between pairs may prevent early graft rejection and aid in personalizing immunosuppressive therapy. Future studies are, however, needed to validate our findings using a genotyped HLA cohort.

Efficacy outcomes of CDK4/6 inhibitors in combination with endocrine therapy treatment in hormone receptor-positive/HER2-negative advanced breast cancer according to PAM50 intrinsic subtype: Primary results of SOLTI-1801 CDK-PREDICT study.

The prognostic value of PAM50 intrinsic subtypes (IS), cell cycle, and immune-related gene expression in HR+ /HER2- advanced breast cancer (BC) treated with CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) in a first-line metastatic setting is unclear. This study evaluates these biomarkers in metastatic biopsies from patients diagnosed with HR+ /HER2- advanced BC. CDK-PREDICT study is a multicentric, ambispective observational cohort study conducted in six Spanish hospitals. It included patients diagnosed with HR+ /HER2- advanced BC treated in the first-line setting with CDK4/6i and ET. Baseline biopsies were obtained prior to treatment to determine research-based PAM50 IS, cell cycle and immune-related gene expression. The primary objective was to evaluate progression-free survival (PFS) differences among PAM50 IS using uni- and multivariable Cox regression models. Secondary objectives included overall survival (OS), overall response rate (ORR), and correlating cell cycle and immune response gene expression with PFS. A total of 185 patients were included, with a median follow-up of 38.5 months. PAM50 luminal subtypes were predominant (82.7 %). Non-luminal subtypes showed significantly shorter median PFS (10.2 vs. 25.7 months; HR, 2.50; p < 0.001) and OS (32.3 vs. 58.1 months; HR, 2.54; p < 0.001) than luminal subtypes. Higher cell cycle and immune-related genes expression, such as CCNE1 and PDCD1, as well as tumor infiltrating lymphocytes were associated with poorer outcomes. This study confirms the independent prognostic value of PAM50 IS in HR+ /HER2- advanced BC treated with CDK4/6i and ET. Non-luminal subtypes exhibited the worst prognosis, underscoring the need for novel therapeutic strategies in this population.

The impact of specialist cardiology inpatient care on the long-term outcomes of non-ST-segment elevation myocardial infarction (NSTEMI): A nationwide cohort study.

Specialist cardiac care has been shown to reduce inpatient mortality following non-ST segment myocardial infarction (NSTEMI), but whether this benefit extends beyond index admission is unclear. Using the linked Myocardial Ischaemia National Audit Project (MINAP) registry, and Office for National Statistics mortality recording, we included 425,205 NSTEMI patients admitted to UK hospitals, between January 2005 and March 2019 that survived to discharge. 217,964 (52 %) were admitted to a specialty cardiac ward. Multivariable Cox-regression models were applied to imputed data to estimate Hazard Ratios for mortality over our study period. Patients admitted to specialty cardiology wards were younger (70 years vs. 75), less often female (32 % vs. 40 %) but more often received statins (86 % vs. 84 %) or beta-blockers (83 % vs. 77 %) (all P < 0.001). One-year (aHR:0.84, 95 % CI 0.83-0.86), and ten-year mortality (aHR: 0.88, 95 % CI 0.87-0.89) were lower in patients admitted to specialty cardiac wards, compared to admitted elsewhere (all P < 0.001). There was significant geographic variation in the proportion admitted to speciality cardiac wards (London 59 % vs. East of England 43 %), with over 1700 deaths potentially avoided if the MINAP target of 80 % was reached. Patients admitted to a cardiac ward had significantly lower mortality compared to alternate wards persisting up to ten-years. There is wide regional variation in the proportion of patients who received specialist cardiology care during their admission and an opportunity exists for lives saved if the proportion of NSTEMI patients admitted to a cardiac ward were to reach the MINAP target of 80 %.

Association Between Artificial Liver Support System and Prognosis in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

The artificial liver support system (ALSS) has been recruited as an available method for patients with acute-on-chronic liver failure (ACLF), but its impact on the outcome of ACLF remains controversial. This study aimed to investigate the association between ALSS treatment and short-term prognosis of hepatitis B-related ACLF (HBV-ACLF). This was a retrospective observational cohort study, and data were obtained from the Center of Infectious Diseases, West China Hospital of Sichuan University, between Mar 2015 and December 2021. The primary outcome was 28-day transplant-free mortality and the secondary outcomes were 60- and 90-day transplant-free mortality. Patients were divided into standard medical therapy (SMT) and ALSS groups. Kaplan-Meier survival analysis curves show the 28-day, 60-day and 90-day transplant-free mortality. Based on the feature selection result of univariate logistic, univariate Cox and Boruta algorithm, the univariate and multivariate logistic and COX regression models were used to investigate the association of ALSS with 28-day, 60-day and 90-day outcomes in patients with HBV-ACLF. Subgroup analyses were conducted to test the robustness of the results. A total of 589hBV-ACLF patients were enrolled in this study (median age, 48.00 years [IQR,44.00-55.00 years]; 70 [11.9%] female). The 28-day, 60-day and 90-day transplant-free mortality rates were 25.6%, 35.8% and 38.9%, respectively. In the univariate and Kaplan-Meier survival analysis, ALSS could significantly reduce 28-day, 60-day and 90-day transplant-free mortality compared to SMT. Furthermore, an in-depth analysis of our study revealed that the therapeutic benefits of the ALSS were observed exclusively within the end-stage (PT-INR ≥ 2.5) subgroup of HBV-ACLF patients. Compared to SMT, ALSS demonstrated efficacy primarily in enhancing the short- term prognosis of end-stage HBV-ACLF patients, rather than across the entire spectrum of HBV-ACLF patients.