Piecewise Cox Regression Research Articles

Allostatic Load/Chronic Stress and Cardiovascular Outcomes in Patients Diagnosed With Breast, Lung, or Colorectal Cancer.

Cardiovascular disease and cancer share a common risk factor: chronic stress/allostatic load (AL). A 1-point increase in AL is linked to up to a 30% higher risk of major cardiac events (MACE) in patients with prostate cancer. However, AL's role in MACE in breast cancer, lung cancer, or colorectal cancer remains unknown. Patients ≥18 years of age diagnosed with the mentioned 3 cancers of interest (2010-2019) and followed up at a large, hybrid academic-community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0-11). Adjusted Fine-Gray competing risks regressions estimated the impact of AL precancer diagnosis on 2-year MACE (a composite of heart failure, ischemic stroke, acute coronary syndrome, and atrial fibrillation). The effect of AL changes over time on MACE was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after cancer diagnosis). Among 16 467 patients, 50.5% had breast cancer, 27.9% had lung cancer, and 21.4% had colorectal cancer. A 1-point elevation in AL before breast cancer diagnosis corresponded to a 10% heightened associated risk of MACE (adjusted hazard ratio, 1.10 [95% CI, 1.06-1.13]). Similar findings were noted in lung cancer (adjusted hazard ratio, 1.16 [95% CI, 1.12-1.20]) and colorectal cancer (adjusted hazard ratio, 1.13 [95% CI, 1.08-1.19]). When considering AL as a time-varying exposure, the peak associated MACE risk occurred with a 1-point AL rise between 6 and 12 months post- breast cancer, lung cancer, and colorectal cancer diagnosis. AL warrants investigation as a potential marker in these patients to identify those at elevated cardiovascular risk and intervene accordingly.

Impact of healthy lifestyle on the incidence and progression trajectory of mental disorders: A prospective study in the UK Biobank

BackgroundHealthier lifestyle decreased the risk of mental disorders (MDs) such as depression and anxiety. However, research on the effects of a comprehensive healthy lifestyle on their progression is lacking. Methods385,704 individuals without baseline MDs from the UK Biobank cohort were included. A composite healthy lifestyle score was computed by assessing alcohol intake, smoking status, television viewing time, physical activity, sleep duration, fruit and vegetable intake, oily fish intake, red meat intake, and processed meat intake. Follow-up utilized hospital and death register records. Multistate model was used to examine the role of healthy lifestyle on the progression of specific MDs, while a piecewise Cox regression model was utilized to assess the influence of healthy lifestyle across various phases of disease progression. ResultsHigher lifestyle score reduced risks of transitions from baseline to anxiety and depression, as well as from anxiety and depression to comorbidity, with corresponding hazard ratios (HR) and 95 % confidence intervals (CI) of 0.94 (0.93, 0.95), 0.90 (0.89, 0.91), 0.94 (0.91, 0.98), and 0.95 (0.92, 0.98), respectively. Healthier lifestyle decreased the risk of transitioning from anxiety to comorbidity within 2 years post-diagnosis, with HR 0.93 (0.88, 0.98). Higher lifestyle scores at 2–4 years and 4–6 years post-depression onset were associated with reduced risk of comorbidity, with HR 0.93 (0.87, 0.99) and 0.92 (0.86, 0.99), respectively. LimitationThe generalizability to other ethnic groups is limited. ConclusionThis study observed a protective role of holistic healthy lifestyle in the trajectory of MDs and contributed to identifying critical progression windows.

Association between ankle-brachial blood pressure index and erectile dysfunction in US adults: a large population-based cross-sectional study.

Erectile dysfunction (ED) is a very common condition among adult men and its prevalence increases with age. The ankle-brachial blood pressure index (ABPI) is a noninvasive tool used to assess peripheral vascular disease (PAD) and vascular stiffness. However, the association between ABPI and ED is unclear. We aimed to explore the association between ABPI and ED in the US population. Our study used data from two separate National Health and Nutrition Examination Survey (NHANES) datasets (2001-2002 and 2003-2004). Survey-weighted logistic regression models were used to explore the association between ABPI as a continuous variable and quartiles with ED. We further assessed the association between ABPI and ED using restricted cubic regression while selecting ABPI thresholds using two-piecewise Cox regression models. In addition, we performed subgroup analyses stratified by BMI, race, marital status, diabetes, and hypertension. ABPI was calculated by dividing the mean systolic blood pressure at the ankle by the mean systolic blood pressure at the arm. Finally, 2089 participants were enrolled in this study, including 750 (35.90%) ED patients and 1339 (64.10%) participants without ED. After adjusting for all confounding covariates, logistic regression analyses showed a significant association between ABPI and ED (OR=0.19; 95% CI, 0.06-0.56, P=0.01); with ABPI as a categorical variable, compared with the lowest quartile, the OR and 95% CI for the second quartile were 0.58 (0.34-0.97; P = 0.04).Besides, splines indicated that there was an L-shaped relationship between ABPI levels and the risk of ED. Piecewise Cox regression demonstrated the inflection point at 1.14, below which the OR for ED was 0.06 (0.02-0.20; P < 0.001), and above which the OR was 2.79 (0.17-4.53; P = 0.469). In our study, lower ABPI was independently associated with ED risk. In addition, the lowest ABPI level associated with ED risk was 1.14, below this level, lower ABPI was associated with higher ED risk.

Role of residential greenspace in the trajectory of major neurological disorders: A longitudinal study in UK Biobank

BackgroundStroke and dementia are major neurological disorders that contribute significantly to disease burden and are interlinked in terms of risk. Nevertheless, there is currently no study investigating the influence of residential greenspace on the trajectory of these neurological disorders. MethodsThis longitudinal study utilized data from the UK Biobank. Exposure to residential greenspace was measured by the percentage of total greenspace coverage within a 300-meter buffer zone surrounding the participants' residences. A multistate model was employed to illustrate the trajectory of major neurological disorders, and a piecewise Cox regression model was applied to explore the impact of residential greenspace on different time courses of disease transitions. ResultsWith 422,649 participants and a median follow-up period of 12.5 years, 8568 (2.0 %), 5648 (1.3 %), and 621 (0.1 %) individuals developed incident stroke, dementia, and comorbidity of both conditions, respectively. An increase in residential greenspace by one interquartile range was associated with reduced risks of transitions from baseline to stroke, dementia, and death, as well as from stroke to comorbidity. The corresponding hazard ratios (HRs) were 0.967 (95 % CI: 0.936, 0.998), 0.928 (0.892, 0.965), 0.925 (0.907, 0.942), and 0.799 (0.685, 0.933), respectively. Furthermore, the protective effect of residential greenspace on the transition from stroke or dementia to comorbidity was particularly pronounced within the first year and over 5 years after stroke and during the 2 to 3 years after dementia onset, with HRs of 0.692 (0.509, 0.941), 0.705 (0.542, 0.918), and 0.567 (0.339, 0.949), respectively. ConclusionThis study observed a protective role of residential greenspace in the trajectory of major neurological disorders and contributed to identifying critical progression windows. These findings underscore the significance of environment-health interactions in the prevention of neurological disorders.

Improved Overall Survival with Axicabtagene Ciloleucel Vs Standard of Care in Second-Line Large B-Cell Lymphoma Among the Elderly: A Subgroup Analysis of ZUMA-7

Introduction: Historically, older patients (pts) with relapsed/refractory large B-cell lymphoma (R/R LBCL) were often deemed ineligible for curative-intent autologous stem cell transplant (ASCT) due to age and concern for increased toxicity related to comorbidities. We previously demonstrated in the pivotal ZUMA-7 study that older pts with R/R LBCL can safely receive axicabtagene ciloleucel (axi-cel) as second-line (2L) therapy with improved event-free survival (EFS), response rate, and quality of life compared with standard of care (SOC) based on results from the primary EFS analysis (Westin, et al. Clin Cancer Res. 2023). At a median follow-up of 47.2 months (mo), results from the ZUMA-7 primary overall survival (OS) analysis demonstrated superior OS in the intention-to-treat (ITT) analysis (hazard ratio [HR], 0.73; 95% CI, 0.54-0.98; stratified two-sided log-rank P=0.03; Westin, et al. N Engl J Med. 2023; NCT03391466). We now report updated efficacy and safety results from the primary OS analysis among ZUMA-7 pts aged ≥65 years (y) and ≥70 y. Methods: Eligible pts were randomized 1:1 to axi-cel or SOC (2-3 cycles of platinum-based chemoimmunotherapy; responding pts proceeded to high-dose chemotherapy with ASCT). The primary OS analysis occurred 5 y after the first pt was randomized (01/25/2018) per protocol. Other endpoints included progression-free survival (PFS) per investigator assessment and safety. A planned subgroup analysis of pts aged ≥65 y was conducted in addition to an analysis for those ≥70 y. Multivariate analyses were performed to examine treatment efficacy with axi-cel compared with SOC after adjusting for multiple covariates, including sex, disease type, molecular subgroup, lactate dehydrogenase (LDH), tumor burden, and age; strata for these analyses included second-line age-adjusted International Prognostic Index (aaIPI), and relapsed vs refractory disease. Exploratory analyses were conducted to determine the association between OS and axi-cel product characteristics for pts aged ≥65 y. Results: A total of 109 pts were included in the analysis (axi-cel: 51 were ≥65 y, 26 of whom were ≥70 y, maximum age was 80 y; SOC: 58 were ≥65 y, 27 of whom were ≥70 y, maximum age was 81 y). Compared with SOC pts at baseline, more axi-cel pts had high-risk features, including aaIPI 2-3, elevated LDH, and high-grade B-cell lymphoma. At a median follow-up of 46.6 mo, OS was prolonged in the axicel vs SOC arm in pts aged ≥65 y (HR, 0.691; 95% CI, 0.401-1.190) and for those ≥70 y (HR, 0.330; 95% CI, 0.135-0.809). Similar results were observed using the piecewise Cox regression model. The median OS for axi-cel and SOC pts was 43.5 mo (95% CI, 20.9-not estimable [NE]) and 19.6 mo (95% CI, 12.3-NE), respectively, among those aged ≥65 y, and 24.7 mo (95% CI, 12.8-NE) and 11.2 mo (95% CI, 6.1-NE), respectively, among those aged ≥70 y. In the SOC arm, 57% and 52% of pts received subsequent cellular immunotherapy off protocol in pts aged ≥65 y and ≥70 y, respectively. Multivariate analyses demonstrated an even greater OS benefit with axi-cel over SOC when adjusting for differences in baseline characteristics in pts aged ≥65 y (HR, 0.526; 95% CI, 0.266-1.041) and in pts aged ≥70 y (HR, 0.184; 95% CI, 0.045-0.755). PFS assessed by investigator confirmed benefit of axi-cel over SOC in pts aged ≥65 y (HR, 0.406; 95% CI, 0.230-0.715) and in pts aged ≥70 y (HR, 0.206; 95% CI, 0.078-0.547). The median PFS for axi-cel and SOC pts was 28.7 mo (95% CI, 5.1-NE) and 5.0 mo (95% CI, 2.8-7.2), respectively, for those aged ≥65 y, and 11.4 mo (95% CI, 4.1-NE) and 2.7 mo (95% CI, 1.7-5.0), respectively, for those aged ≥70 y. No new treatment-related deaths occurred since the primary EFS analysis. There were no manufacturing failures for any pt who underwent leukapheresis. Similar associations between product characteristics and outcomes were observed among the elderly and overall populations, including improved OS associated with a greater (&amp;gt;median) proportion of juvenile or stem memory T-cell phenotype cells (CCR7+CD45RA+ T cells) in the axi-cel product among pts aged ≥65 y (HR, 0.369; 95% CI, 0.138-0.984). Conclusion: Axi-cel as 2L therapy prolonged survival over SOC in pts aged ≥65 y, including in pts aged ≥70 y. These findings confirm that age alone should not be a barrier for consideration of CAR T-cell therapy, supporting the use of axi-cel as a curative-intent 2L therapeutic option for older pts with R/R LBCL.

A U-shaped association between the triglyceride to high-density lipoprotein cholesterol ratio and the risk of incident type 2 diabetes mellitus in Japanese men with normal glycemic levels: a population-based longitudinal cohort study.

Several studies have verified that a high baseline TG/HDL-C ratio is a risk factor for incident type 2 diabetes mellitus (T2DM). However, for low baseline TG/HDL-C levels, the findings were inconsistent with ours. In addition, the association between baseline TG/HDL-C ratio and the risk of incident T2DM in Japanese men with normal glycemic levels is unclear. As a result, our study further investigated the relationship between baseline TG/HDL-C and the risk of incident T2DM in Japanese men with normal glycemic levels. This was a secondary longitudinal cohort study. We selected 7,684 male participants between 2004 and 2015 from the NAGALA database. A standardized Cox regression model and two piecewise Cox regression models were used to explore the relationship between the baseline high-density lipoprotein cholesterol ratio (TG/HDL-C) and incident T2DM. During a median follow-up of 2,282 days, 162 men developed incident T2DM. In the adjusted model, the baseline TG/HDL-C ratio was strongly associated with the risk of incident T2DM, and no dose-dependent positive association was observed between the baseline TG/HDL-C ratio and incidence of T2DM throughout the baseline TG/HDL-C quartiles. Two-piecewise linear regression analysis showed a U-shaped association between baseline TG/HDL-C ratio and incidence of incident T2DM. A baseline TG/HDL-C ratio below 1.188 was negatively associated with incident T2DM (H.R. = 0.105, 95% CI = 0.025, 0.451; P = 0.002). In contrast, a baseline TG/HDL-C ratio >1.188 was positively associated with incident T2DM (H.R. = 1.248, 95% CI = 1.113, 1.399; P<0.001). The best TG/HDL-C threshold for predicting incident T2DM was 1.8115 (area under the curve, 0.6837). A U-shaped relationship between baseline TG/HDL-C ratio and incident T2DM in Japanese men with normal glycemic levels was found.

Impact of Timing of Surgery and Adjuvant Treatment on Survival of Adult IDH–wild-type Glioblastoma: A Single-center Study of 392 Patients

The purpose of our study was to analyze the impact of time interval from referral to surgery and from surgery to adjuvant treatment on survival of adult IDH-wildtype glioblastomas. Data on 392 IDH-wildtype glioblastomas diagnosed at the Tampere University Hospital in 2004-2016 were obtained from the electronic patient record system. Piecewise Cox regression was used to calculate hazard ratios for different time intervals between referral and surgery, as well as between surgery and adjuvant treatments. The median survival time from primary surgery was 9.5 months (interquartile range: 3.8-16.0). Survival among patients with an interval exceeding four weeks from referral to surgery was no worse compared to <2 weeks (hazard ratio: 0.78; 95% confidence interval: 0.54-1.14). We found indications of poorer outcome when the interval from surgery to radiotherapy exceeded 30 days (hazard ratio: 1.42; 95% confidence interval: 0.91-2.21 for 31-44 days and 1.59; 0.94-2.67 for over 45 days). Interval from referral to surgery in the range of 4-10 weeks was not associated with decreased survivals in IDH-wildtype glioblastomas. In contrast, delay exceeding 30 days from surgery to adjuvant treatment may decrease long-term survival.

Allostatic load and cardiovascular outcomes in males with prostate cancer.

Cardiovascular disease (CVD) is the leading cause of death in men with prostate cancer (PC). Accumulated stress plays an important role in CVD development. The cumulative burden of chronic stress and life events can be measured using allostatic load (AL). The initial cohort included males aged 18 years and older diagnosed with PC (2005-2019). AL was modeled as an ordinal variable (0-11). Fine-Gray competing risk regressions measured the impact of precancer diagnosis AL and postdiagnosis AL in 2-year major cardiac events (MACE). The effect of AL changes over time on MACE development was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after PC diagnosis). We included 5261 PC patients of which 6.6% had a 2-year MACE. For every 1-point increase in AL before and within 60 days after PC diagnosis, the risk of MACE increased 25% (adjusted hazard ratio [aHR] =1.25, 95% confidence interval [CI] = 1.18 to 1.33) and 27% (aHR = 1.27, 95% CI = 1.20 to 1.35), respectively. Using AL as a time-varying exposure, the risk of MACE increased 19% (aHR = 1.19, 95% CI = 1.11 to 1.27), 22% (aHR = 1.22, 95% CI = 1.14 to 1.33), 28% (aHR = 1.28, 95% CI = 1.23 to 1.33), and 31% (aHR = 1.31, 95% CI = 1.27 to 1.35) for every 1-point increase in AL before, 2 months after, 6 months after, and 1 year after PC diagnosis, respectively. AL and its changes over time are associated with MACE in PC patients, suggesting a role of a biological measure of stress as a marker of CVD risk among men with PC.

Calf circumference change and all-cause mortality among community-dwelling Chinese older people

Previous studies have described an association between single time point calf circumference (CC) and mortality. Evidence of associations between CC change and mortality is lacking. We aimed to determine the relationship between the CC change over time and all-cause mortality. We conducted a retrospective cohort study of 906 participants in the 2014-2018 Chinese Longitudinal Healthy Longevity Survey (CLHLS). Restricted cubic splines were used to analyze associations between the relative CC change (exposure) and all-cause mortality (primary outcome). When there was evidence of non-linearity, a piecewise Cox regression model was next fitted, adjusting for sociodemographic characteristics, health behaviours, health status and baseline CC. The mean (SD) age was 83.8 (12.2) years old, and 50.2% (455/906) of participants were male. We observed a U-shaped association between the relative CC change (%) and all-cause mortality (P for non-linearity <0.001). Participants with stable CC over time had the lowest risk of death. After adjusting for covariates, when CC decreased over time, the hazard ratio per 10% higher in CC change was 1.32 (1.01-1.69). When CC increased over time, the hazard ratio per 10% higher in CC change was 1.35 (1.10-1.66). Stable CC over time was associated with the lowest mortality risk. Our findings indicate the practical significance of monitoring CC change in older adult.

Abstract 10355: Allostatic Load and Cardiovascular Outcomes in Males With Prostate Cancer

Introduction: Prostate cancer (PC) is the leading type of newly diagnosed cancer in males. Cardiovascular disease (CVD) is the leading cause of death in men with PC. Accumulated stress, which is triggered by multiple environmental factors and life events, plays an important role in CVD development. The cumulative burden of chronic stress and life events can be measured using allostatic load (AL). Hypothesis: We hypothesize that AL is associated with the development of major cardiac events (MACE) after the diagnosis of PC. Methods: Data were obtained from a Cleveland area integrated health care systems informatics platform. The initial cohort included males ≥18 years diagnosed with PC between 2005 and 2019. AL was modeled as an ordinal variable from 0 to 11. Fine and Gray competing risk regression model accounting for the competing risk of all-cause mortality were used to calculate the impact of pre-cancer diagnosis AL and post-diagnosis AL in 2-year major cardiac events (MACEs). The effect of AL variation over time on MACEs development was calculated via the piecewise Cox Regression model where the time periods considered were before PC diagnosis, 2 months after, 6 months after and 1-year after PC diagnosis. Results: We analyzed 5,261 (19,840 person-years) PC adenocarcinoma patients, of which 6.6% (N=347) had a 2-year MACE. For every 1 point increase in AL before PC diagnosis and within 60 days after PC diagnosis the risk of MACE increased 25% (adjusted Hazards Ratio [aHR] =1.25, 95% Confidence Interval [CI] = 1.18-1.33), and 27% (aHR=1.27; 95% CI = 1.20-1.35), respectively. Using AL as a time varying exposure, the risk of MACE increased 19% (aHR=1.19, 95% CI 1.11-1.27), 22% (aHR=1.22, 95% CI 1.14-1.33), 28% (aHR=1.28, 95% CI 1.23-1.33), and 31% (aHR=1.31, 95% CI 1.27-1.35) for every 1 point increase in AL before PC diagnosis, 2 months after, 6 months after and 1-year after PC diagnosis, respectively. Conclusion: AL and its variation over time are associated with MACE in PC patients, suggesting a role of a biological measure of stress as a marker of CVD risk among men with PC. Preventive measures to minimize AL may require collaboration between cancer control and cardio-oncology.

The duration of protection against clinical malaria provided by the combination of seasonal RTS,S/AS01E vaccination and seasonal malaria chemoprevention versus either intervention given alone

BackgroundA recent trial of 5920 children in Burkina Faso and Mali showed that the combination of seasonal vaccination with the RTS,S/AS01E malaria vaccine (primary series and two seasonal boosters) and seasonal malaria chemoprevention (four monthly cycles per year) was markedly more effective than either intervention given alone in preventing clinical malaria, severe malaria, and deaths from malaria.MethodsIn order to help optimise the timing of these two interventions, trial data were reanalysed to estimate the duration of protection against clinical malaria provided by RTS,S/AS01E when deployed seasonally, by comparing the group who received the combination of SMC and RTS,S/AS01E with the group who received SMC alone. The duration of protection from SMC was also estimated comparing the combined intervention group with the group who received RTS,S/AS01E alone. Three methods were used: Piecewise Cox regression, Flexible parametric survival models and Smoothed Schoenfeld residuals from Cox models, stratifying on the study area and using robust standard errors to control for within-child clustering of multiple episodes.ResultsThe overall protective efficacy from RTS,S/AS01E over 6 months was at least 60% following the primary series and the two seasonal booster doses and remained at a high level over the full malaria transmission season. Beyond 6 months, protective efficacy appeared to wane more rapidly, but the uncertainty around the estimates increases due to the lower number of cases during this period (coinciding with the onset of the dry season). Protection from SMC exceeded 90% in the first 2–3 weeks post-administration after several cycles, but was not 100%, even immediately post-administration. Efficacy begins to decline from approximately day 21 and then declines more sharply after day 28, indicating the importance of preserving the delivery interval for SMC cycles at a maximum of four weeks.ConclusionsThe efficacy of both interventions was highest immediately post-administration. Understanding differences between these interventions in their peak efficacy and how rapidly efficacy declines over time will help to optimise the scheduling of SMC, malaria vaccination and the combination in areas of seasonal transmission with differing epidemiology, and using different vaccine delivery systems.Trial registrationThe RTS,S-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT03143218

Racial and Ethnic Disparities in Incidence and Prognosis of Perioperative Stroke Among Pediatric Cardiac Transplant Recipients.

Background In the general population, Black children have a higher incidence of stroke and all-cause mortality after stroke than White children. Beginning 6 months following cardiac transplantation, Black children have higher mortality than White children. However, whether there are racial and ethnic disparities in incidence and all-cause mortality following perioperative stroke among pediatric cardiac transplant recipients is unknown. Methods and Results Using the Scientific Registry of Transplant Recipients, we studied children who underwent their first heart transplant in the United States between January 1994 and September 2019. Using multivariable logistic regression, we assessed the association between race and ethnicity and perioperative stroke. We used multivariable piecewise Cox regression to examine the association between race and ethnicity and mortality among survivors of perioperative stroke. Among 8224 children who had a first cardiac transplant, 255 (3%) had a perioperative stroke. Black children had 32% lower odds of perioperative stroke compared with White children (adjusted odds ratio, 0.68 [95% CI, 0.46-0.996]). Following perioperative stroke, mortality rates were similar for Black and White children in the first 6months (adjusted hazard ratio [HR], 0.99 [95% CI, 0.44-2.26]). However, Black children had a higher mortality rate than White children beyond 6 months (adjusted HR, 3.36 [95% CI, 1.22-9.22]). Conclusions Among pediatric cardiac transplant recipients, Black children have a lower incidence of perioperative stroke than White children. Among survivors of perioperative stroke, mortality is initially similar by race and ethnicity, but beyond 6 months, Black children have over a 3-fold higher mortality rate than White children. Identifying and intervening on potential differences in care is essential to addressing these disparities.

A comprehensive analysis of SNPs and CNVs identifies novel markers associated with disease outcomes in colorectal cancer.

We aimed to examine the associations of a genome‐wide set of single nucleotide polymorphisms (SNPs) and 254 copy number variations (CNVs) and/or insertion/deletions (INDELs) with clinical outcomes in colorectal cancer patients (n = 505). We also aimed to investigate whether their associations changed (e.g., appeared, diminished) over time. Multivariable Cox proportional hazards and piece‐wise Cox regression models were used to examine the associations. The Cancer Genome Atlas (TCGA) datasets were used for replication purposes and to examine the gene expression differences between tumor and nontumor tissue samples. A common SNP (WBP11‐rs7314075) was associated with disease‐specific survival with P‐value of 3.2 × 10−8. Association of this region with disease‐specific survival was also detected in the TCGA patient cohort. Two expression quantitative trait loci (eQTLs) were identified in this locus that were implicated in the regulation of ERP27 expression. Interestingly, expression levels of ERP27 and WBP11 were significantly different between colorectal tumors and nontumor tissues. Three SNPs predicted the risk of recurrent disease only after 5 years postdiagnosis. Overall, our study identified novel variants, one of which also showed an association in the TCGA dataset, but no CNVs/INDELs, that associated with outcomes in colorectal cancer. Three SNPs were candidate predictors of long‐term recurrence/metastasis risk.

A new model outperforming RPA and DS-GPA scores for individualized survival prediction of patients following whole brain irradiation for brain metastasis

PurposeSurvival after whole brain radiation therapy (WBRT) in patients with multiple brain metastases (BM) is currently predicted by group-based scoring systems with limited usability for decision. We aimed to develop a more relevant individualized predictive model than Radiation Therapy Oncology Group – Recursive Partitioning Analysis (RTOG-RPA) and Diagnosis – Specific Graded Prognostic Assessment (DS-GPA) for patients with limited life-expectancy. MethodsBased on a Discovery cohort of patients undergoing WBRT, multivariable piecewise Cox regression models with time cut-offs at 1 and 3 months were developed to predict overall survival (OS). A final parsimonious model was defined, and an external validation cohort was used to assess its discrimination and calibration at one, six, and 12 months. ResultsIn the 173-patient Discovery cohort, the majority of patients had primary lung cancer (56%), presence of extracranial disease (ECD) (75%), Eastern Cooperative Oncolgy Group - Performance Status (ECOG-PS) score 1 (41%) and no intracranial hypertension (ICH) (74%). Most patients were classified as the RPA class II (48%). The final piecewise Cox model was based on primary site, age, ECD, ECOG-PS and ICH. An external validation of the model was carried out using a cohort of 79 patients. Individualized survival estimates obtained with this model outperformed the RPA and DS-GPA scores for overall survival prediction at 1-month, 6-months and 12- months in both Discovery and Validation cohorts. A R/Shiny web application was developed to obtain individualized predictions for new patients, providing an easy-to-use tool for clinicians and researchers. ConclusionOur model provides individualized estimates of survival for poor prognosis patients undergoing WBRT, outperforming actual scoring systems.

Long-Term Follow-Up of Mortality and Heart Failure Hospitalisation in Patients With Intracardiac Device-Related Tricuspid Regurgitation

Tricuspid regurgitation (TR) is a known complication of cardiac implantable electronic devices (CIED). Abetter understanding of the patient population affected by this complication and their outcomes is needed. The aims of our study were to: 1) describe the incidence of CIED-related tricuspid regurgitation; 2) identify patient characteristics conferring risk; 3) assess the long-term risk of hospitalisation for heart failure and mortality in patients with this complication. This was a retrospective cohort study of 2,265 patients that had a de novo device implantation at a tertiary referral centre between January 2010 and December 2017. Patients with echocardiograms prior to and at least 3 months after device implantation were included. Patients with moderate or severe TR at baseline were excluded. Following screening of medical records, 165 patients were analysed. Forty-four (44) (27%) patients developed new-onset moderate or severe device-related TR, without a significant difference between patients with permanent pacemaker (PPM) and implantable cardioverter-defibrillator (ICD). Patients with CIED-related tricuspid regurgitation had a higher rate of hospitalisation for heart failure than those without (63.6% vs 34.7%, p=0.001) during a median follow-up of 29 months (IQR 13-60 months). Subsequent analyses showed that the association between CIED-related TR and heart failure hospitalisation only became significant in the period beyond 12 months following CIED implantation. Piecewise Cox regression analysis stratified at 12 months of follow-up showed that CIED-related TR was associated with an increased risk of heart failure hospitalisation beyond 12 months after adjustment for differences in baseline characteristics (HR 1.99, 95% CI 1.05-3.76, p=0.03). There was a higher mortality rate in the group with CIED-related TR; however, this did not reach significance (36.3% vs 22.3%, p=0.09). CIED-related TR is common and clinically significant with serious implications for long-term outcomes, especially congestive heart failure.

A Retrospective Cohort Study on Pretreated Neutrophil-to-Lymphocyte Ratio and Prognosis of Small Cell Lung Cancer: Evidence of Effect Modification by Chemotherapy Regimen.

PurposeNeutrophil-to-lymphocyte ratio (NLR) has been suggested as an independent risk factor for progression-free survival (PFS) and overall survival (OS) in small cell lung cancer (SCLC). However, it is still unknown whether there is a linear relationship between the NLR and the risk of death in SCLC. The objective of this study is to provide further results.Patients and MethodsA retrospective cohort study was performed among a total of 251 participants with SCLC. Smooth curve fitting and piecewise Cox regression model were used to determine the linear relationship between NLR and mortality risk. A multivariable Cox regression model was used to estimate the effects of NLR on OS. Interaction and stratified analyses were conducted according to covariates.ResultsThe analysis indicated no significant nonlinear relationship or threshold effect between NLR and hazard of death. Multivariate analysis revealed that every unit increase in NLR was associated with a 10% increase in mortality risk. High NLR (>3.5) at baseline was associated with poor OS (hazard ratio [HR]=1.97, P=0.009). The difference in median OS duration between the high and low NLR groups was statistically significant (9.1 months vs 14.6 months, P=0.0067). Furthermore, interaction analysis identified the chemotherapy regimen to play an interactive role in the association between NLR and hazard of death.ConclusionNLR was identified as an independent risk factor for OS in SCLC and the linear correlation was observed between them. Administration of etoposide plus cisplatin (EP) regimen in patients with low NLR resulted in better long-term outcome than that of etoposide plus carboplatin (EC) regimen, while administration of the EC regimen conferred longer OS than that of the EP regimen in patients with high NLR.

Zoster Vaccine Effectiveness Against Incident Herpes Zoster and Post-Herpetic Neuralgia In Elderly In The UK

Herpes zoster (HZ) is a painful skin rash that occurs most frequently in older adults and is caused by reactivation of latent varicella zoster virus (VZV). Its most common complication is post-herpetic neuralgia (PHN). The UK introduced zoster vaccination in the national immunization program in 2013. The vaccine was routinely offered to 70 year-olds and, as part of the catch-up, to 79 year-olds. This study assessed the vaccine effectiveness (VE) against HZ and PHN in elderly within the total population. This retrospective cohort study included subjects from birth cohorts 1943-1946 (routine) and 1934-1937 (catch-up) in the UK Clinical Practice Research Datalink (CPRD). Vaccinated subjects were compared to unvaccinated subjects using piecewise Cox regression model. HZ outcomes in community setting were analyzed, including HZ, PHN and other HZ complications (i.e. neurological but not PHN, ocular, disseminated and other). For the routine birth cohorts (79274 subjects), we found a VE for HZ of 76.4% (95% CI: 70.6%-81.1%) and for PHN of 68.3% (95% CI: 7.4%-89.1%) for the first 2 years of vaccination. For the subsequent 2+ years, the VE estimates of HZ was 56.1% (95% CI: 29.2%-72.7%). For the catch-up cohorts (48193 subjects), the VE estimates were comparable. We found insufficient evidence to determine the VE for other HZ complications. Within the total population, the HZ vaccine provided protection against HZ and PHN, but its protection declined over time. Immunosuppressed conditions need to be taken into account.

Insomnia predicts long-term all-cause mortality after acute myocardial infarction: A prospective cohort study

BackgroundSleep impairment such as insomnia is an established risk factor for the development of cardiovascular disease and acute myocardial infarction (AMI). The aim of the current study was to examine the association between insomnia and all-cause mortality among AMI patients. MethodsThis prospective cohort study used data on n=732 patients recruited from September 2006 to May 2011 as part of the Västmanland Myocardial Infarction Study (VaMIS), a prospective cohort study of AMI patients living in Västmanland County, Sweden. Participants were followed up for all-cause mortality until December 9, 2015. The outcome of interest was time-to-death (TTD), with the presence of insomnia being the risk factor of main interest. Data were analyzed using a piecewise Cox regression model with change point for insomnia at two years of follow-up, adjusted for socioeconomic, lifestyle and clinical risk factors. ResultsIn total, n=175 (23.9%) of the participants suffered from insomnia. During a mean (SD) follow-up time of 6.0 (2.5) years (4392person–years), a total of n=231 (31.6%) participants died, n=77 (44.0%) in the insomnia group and n=154 (27.6%) in the non-insomnia group (log-rank test p<0.001). In a multiple adjusted piecewise Cox regression model, insomnia did not imply a higher risk of death during the first two years after AMI (HR 0.849; 95% CI 0.508–1.421; p=0.534). During the period after the first two years, however, insomnia implied a 1.6 times higher risk of death (HR 1.597; 95% CI 1.090–2.341; p=0.016). ConclusionsInsomnia implies a higher risk of death among AMI patients in the long term.

The Temporal Risk of Heart Failure Associated With Adjuvant Trastuzumab in Breast Cancer Patients: A Population Study.

The late cardiac effect of adjuvant trastuzumab and its potential interaction with anthracycline have not been well-studied on a population level. In this retrospective population-based cohort study, female breast cancer patients in Ontario, diagnosed between 2003 and 2009, were identified by the Ontario Cancer Registry and linked to administrative databases to ascertain demographics, cardiac risk factors, comorbidities, and use of adjuvant trastuzumab and other chemotherapy. Patients with pre-existing heart failure (HF) were excluded. The main endpoint was new diagnosis of HF. Analyses included Kaplan-Meier (KM) survival analysis, multivariable piecewise Cox regression, and competing risk and propensity score analyses. All statistical tests were two-sided. Nineteen thousand seventy-four women with breast cancer treated with adjuvant chemotherapy were identified, of whom 3371 (17.7%) also received adjuvant trastuzumab. Anthracycline use was 84.9% overall. After a median follow-up of 5.9 years, patients treated with trastuzumab and chemotherapy were more likely to develop HF than patients on chemotherapy alone (5-year cumulative incidences of 5.2% vs 2.5%; log-rank P < .001). After adjusting for confounders, adjuvant trastuzumab remained independently associated with incident HF in the first 1.5 years (HR = 5.77, 95% CI = 4.38 to 7.62, P < .001), but not thereafter (HR = 0.87, 95% CI = 0.57 to 1.33, P = .53). Anthracycline use did not increase the risk of HF with trastuzumab synergistically, neither within (P interaction = .92) nor beyond 1.5 years (P interaction = .23). Adjuvant trastuzumab was associated with increased risk of new incidence of HF in breast cancer survivors during the period of adjuvant treatment but not thereafter. Routine intensive monitoring may not be necessary after completing adjuvant therapy.

Long-term risk of heart failure associated with adjuvant trastuzumab in breast cancer patients.

9504 Background: The late cardiac effect of adjuvant trastuzumab (T) and its potential interaction with anthracycline in the general population have not been well studied. The purpose of this retrospective population-based cohort study was to determine the long-term risk of heart failure (HF) associated with adjuvant T and chemotherapy, compared to chemotherapy alone. Methods: Female breast cancer patients in Ontario, diagnosed between 2003 and 2009 were identified by the Ontario Cancer Registry and linked to administrative databases to ascertain demographics, cardiac risk factors, comorbidities, and use of adjuvant T and other chemotherapy. Patients with pre-existing HF were excluded. The main endpoint was new diagnosis of HF, obtained using an algorithm of admission and physician claims data. Group differences were assessed by the Kaplan-Meier (KM) method and multivariable piecewise Cox regression. Competing risk analysis using the Fine and Gray method and propensity score matching analysis were perform...