Formal Test For Interaction Research Articles

Sex differences in the colorectal tumor immune microenvironment.

283 Background: Males have increased risk and mortality rates of colorectal cancer (CRC) compared to females, but the reasons for these disparities are not well understood. Immune responses differ by sex, and a robust T cell response is an important prognostic indicator in CRC. We hypothesized that females exhibit a stronger CRC-associated T cell response, contributing to reduced mortality in females compared to males. Methods: The study cohort included 2,751 incident CRC patients (1,337 female; 1,414 male) from a population-based case-control study. T cell receptor (TCR) abundance and clonality were quantified using immunoSEQ, and a gastrointestinal pathologist scored tumor-infiltrating lymphocyte counts per high-powered field (TILs/hpf). We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between T cell metrics and sex, adjusting for age, anatomic site, and microsatellite instability (MSI) status. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals for the association between sex and 5-year all-cause and CRC-specific survival, adjusting for known prognostic indicators. We also conducted a formal test for interaction between sex and T cell features in relation to survival outcomes. Results: There were no associations between sex and TCR abundance (OR=1.05, 95% CI=0.98-1.13, p=0.14), TCR clonality (OR=0.99, 95% CI=0.91-1.06, p=0.72), or TILs/hpf (OR=1.05, 95% CI=0.88-1.25, p=0.60). We observed no differences in overall or disease-specific five-year survival between males and females. Further, the associations between T cell responses and survival did not significantly differ by sex. Conclusions: In a well-powered analysis, no robust sex differences were observed in the CRC immune microenvironment or in the relationship between T cell infiltration and CRC outcomes. The high burden of CRC and the emergence of immunotherapy as an important therapeutic approach suggest a need for further research investigating immunological sex differences in the setting of treatment response. Summary of associations between the colorectal tumor T cell response and sex. T cell Features Odds Ratio(Female vs. Male) Lower 95% CI Upper 95% CI P Value TCR Abundance 1.05 0.98 1.13 0.14 TCR Clonality 0.99 0.91 1.06 0.72 TILs/hpf* <2 1.05 0.88 1.25 0.60 *A total of 99 patients (45 female; 54 male) with missing TILs/hpf data were excluded from the regression analysis.

Modifiable risk factors for multiple sclerosis have consistent directions of effect across diverse ethnic backgrounds: a nested case–control study in an English population-based cohort

BackgroundMultiple sclerosis is a leading cause of non-traumatic neurological disability among young adults worldwide. Prior studies have identified modifiable risk factors for multiple sclerosis in cohorts of White ethnicity, such as infectious mononucleosis, smoking, and obesity during adolescence/early adulthood. It is unknown whether modifiable exposures for multiple sclerosis have a consistent impact on risk across ethnic groups.AimTo determine whether modifiable risk factors for multiple sclerosis have similar effects across diverse ethnic backgrounds.MethodsWe conducted a nested case–control study using data from the UK Clinical Practice Research Datalink. Multiple sclerosis cases diagnosed from 2001 until 2022 were identified from electronic healthcare records and matched to unaffected controls based on year of birth. We used stratified logistic regression models and formal statistical interaction tests to determine whether the effect of modifiable risk factors for multiple sclerosis differed by ethnicity.ResultsWe included 9662 multiple sclerosis cases and 118,914 age-matched controls. The cohort was ethnically diverse (MS: 277 South Asian [2.9%], 251 Black [2.6%]; Controls: 5043 South Asian [5.7%], 4019 Black [4.5%]). The age at MS diagnosis was earlier in the Black (40.5 [SD 10.9]) and Asian (37.2 [SD 10.0]) groups compared with White cohort (46.1 [SD 12.2]). There was a female predominance in all ethnic groups; however, the relative proportion of males was higher in the South Asian population (proportion of women 60.3% vs 71% [White] and 75.7% [Black]). Established modifiable risk factors for multiple sclerosis—smoking, obesity, infectious mononucleosis, low vitamin D, and head injury—were consistently associated with multiple sclerosis in the Black and South Asian cohorts. The magnitude and direction of these effects were broadly similar across all ethnic groups examined. There was no evidence of statistical interaction between ethnicity and any tested exposure, and no evidence to suggest that differences in area-level deprivation modifies these risk factor-disease associations. These findings were robust to a range of sensitivity analyses.Conclusions and relevanceEstablished modifiable risk factors for multiple sclerosis are applicable across diverse ethnic backgrounds. Efforts to reduce the population incidence of multiple sclerosis by tackling these risk factors need to be inclusive of people from diverse ethnicities.

P2Y12 INHIBITOR MONOTHERAPY OR DUAL ANTIPLATELET THERAPY AFTER PERCUTANEOUS CORONARY INTERVENTION IN PATIENTS WITH HYPERTENSION

Objective: P2Y12 inhibitor monotherapy after a brief period of dual antiplatelet therapy (DAPT, a combination of aspirin and a P2Y12 inhibitor) can reduce bleeding without increasing ischemic harm after percutaneous coronary intervention (PCI). The impact of this approach among patients with hypertension remains unknown. We sought to examine the effect of P2Y12 inhibitor monotherapy versus DAPT among patients with hypertension undergoing PCI. Design and method: This is a post-hock analysis of the hypertension cohort in the SMART-CHOICE trial. The SMART-CHOICE trial was a randomized trial that compared P2Y12 inhibitor monotherapy after 3 months of DAPT with prolonged DAPT (12 months or longer) in patients who underwent PCI. The primary endpoint was Bleeding Academic Research Consortium (BARC) 2 to 5 bleeding. The composite ischemic endpoint was all-cause death, myocardial infarction, or stroke. Treatment effects were estimated according to presence of hypertension with formal interaction testing to assess for effect modification. Results: Patients with hypertension comprised 61.5% (n = 1,840) of the randomized cohort and were characterized by more frequent comorbidities. At 3 years after randomization, patients with hypertension experienced higher rates of all-cause death (3.9% vs 2.5%; p = 0.039), stroke (1.6% vs 0.6%; p = 0.014), or MACCE (6.8% vs 3.8%; p<0.001) but similar BARC types 2 to 5 bleeding (5.4% vs 4.9%; p = 0.601) compared with patients without hypertension. The incidence of BARC 2 to 5 bleeding was 2.9% and 7.8% among patients with hypertension randomized to P2Y12 inhibitor monotherapy versus DAPT [hazard ratio (HR): 0.382; 95% confidence interval (CI): 0.243 to 0.600; p<0.001]. However, P2Y12 inhibitor monotherapy was not associated with an increase in ischemic events compared with DAPT (7.2% vs. 6.5%; HR: 1.135; 95% CI: 0.767 to 1.679; p = 0.527) in patients with hypertension. In the overall trial population, there was no significant interaction between hypertension status and treatment group for the primary bleeding (adjusted p for interaction 0.835) or ischemic endpoints (adjusted p for interaction 0.707). Conclusions: P2Y12 inhibitor monotherapy is associated with significantly lower risk for bleeding events compared with DAPT, without any compromise in ischemic prevention, among patients with history of hypertension undergoing PCI.

0655 Whose Mind after Midnight? Demographic and Clinical Variation in Nocturnal Suicide Risk

Abstract Introduction Although suicides are more prevalent during the day, the risk of suicide is highest at night when adjusted for population wakefulness. It is unclear how nighttime patterns of suicide risk vary by demographic and clinical subgroups. Methods Population wakefulness data were combined with time of fatal injury data for 78,647 suicides from 2003-2017. The primary outcome was number of suicides per hour with wakefulness as an offset/exposure term. Subgroups included sex, race, ethnicity, military service, blood alcohol category and marijuana positive on autopsy, current depressed mood or partner conflict, and prior suicidal ideation or suicide attempts. Formal interaction tests identified significant subgroup variations adjusted for age, sex, race, and ethnicity where appropriate. Groups with significant interactions were subsequently examined using robust Poisson regression models to measure incident risk ratios (IRRs). Results There were subgroup interactions for age (p < 0.001), ethnicity (p = 0.014), blood alcohol level on autopsy (p < 0.001), and current partner conflict at time of fatal injury (p < 0.001). There was a sharp peak in risk around 4AM for individuals aged 15 to 24 (aIRR: 3.11 [2.39, 4.05]) and 25-34 (aIRR 2.15 [1.63, 2.86]), and at 6AM for individuals aged 65 to 74 (aIRR: 1.78 [1.40, 2.25]) and 75+ (aIRR: 2.25 [1.69, 3.00]). Hispanic individuals had an elevated risk between 10PM and 3AM with a maximal 232% increase at 2am (aIRR: 2.32 [1.67, 3.23]). Current partner conflict increased risk from 8PM to11PM and from 1AM to 3AM with a peak risk at 11PM (aIRR: 1.53 [1.24, 1.89]). Individuals with a BAL < 0.08 mg/dL showed a sustained increased risk for suicide between 8PM and 4AM; individuals with a BAL of 0.08 mg/dL or more showed greater risk (aIRR 2.33 [1.88, 2.89] at 1AM) than those with a BAL < 0.08 mg/dL (aIRR: 1.68 [1.40, 2.01] at 12AM). Conclusion Nighttime suicide risk varied significantly by age, ethnicity, blood alcohol level on autopsy, and current partner conflict. Military service was not associated with greater nighttime risk, which contrasts with prior findings. Support (if any)

Abstract WMP108: Genomic Risk Scores And Oral Contraceptive-associated Ischemic Stroke Risk

Objective: To evaluate whether a genomic risk score for ischemic stroke (IS) modifies oral contraceptive (OC)-associated IS risk. Background: OCs are generally safe but vascular risk factors are known to increase OC-associated IS risk. If a genomic risk score could identify a subset of women with substantially increased risk of OC-associated IS, this could influence prescribing guidelines and reduce stroke events. Methods: In the Genetics of Early-Onset Stroke (GEOS) study, there were 340 premenopausal women (143 IS cases and 197 controls) with data on OC use within 30 days prior to index event for cases or prior to interview for controls. Using a previously validated genomic risk score (metaGRS) for IS based on 19 polygenic risk scores of vascular events and risk factors, we stratified our sample into tertiles of genomic risk and calculated the association between OC use and IS within each tertile. We tested if the association between OC use and IS depended on genomic risk of stroke using logistic regression with an OC use*metaGRS interaction term. Results: Among all women, OC use was significantly associated with IS (odds ratio = 2.4, p = 0.002). The odds ratio for IS associated with OC use decreased from 3.9 in the tertile with highest genomic risk of IS to 1.5 in the tertile with lowest genomic risk (see Table). The formal test of interaction was consistent with our hypothesis (p = 0.07) that the genomic risk score modifies the association of OC use with IS. Conclusions: The results of our exploratory analysis support the need for international collaboration to generate sufficient sample sizes to determine whether a genomic risk score could be clinically useful in reducing OC-associated IS.

Clinical impact of influenza vaccination after ST- and non-ST-segment elevation myocardial infarction - insights from the IAMI trial

Influenza vaccination early after myocardial infarction (MI) improves prognosis but vaccine effectiveness may differ dependent on type of MI. A total of 2,571 participants were prospectively enrolled in the Influenza vaccination after myocardial infarction (IAMI) trial and randomly assigned to receive in-hospital inactivated influenza vaccine or saline placebo. The trial was conducted at 30 centers in eight countries from October 1, 2016 to March 1, 2020. Here we report vaccine effectiveness in the 2,467 participants with ST-segment elevation MI (STEMI, n=1,348) or non-ST-segment elevation MI (NSTEMI, n=1,119). The primary endpoint was the composite of all-cause death, MI, or stent thrombosis at 12 months. Cumulative incidence of the primary and key secondary endpoints by randomized treatment and NSTEMI/STEMI was estimated using the Kaplan-Meier method. Treatment effects were evaluated with formal interaction testing to assess for effect modification. Baseline risk was higher in participants with NSTEMI. In the NSTEMI group the primary endpoint occurred in 6.5% of participants assigned to influenza vaccine and 10.5% assigned to placebo (hazard ratio [HR], 0.60; 95% CI, 0.39-0.91), compared to 4.1% assigned to influenza vaccine and 4.5% assigned to placebo in the STEMI group (HR, 0.90; 95% CI, 0.54-1.50, P=.237 for interaction). Similar findings were seen for the key secondary endpoints of all-cause death and cardiovascular death. The Kaplan-Meier risk difference in all-cause death at one year was more pronounced in participants with NSTEMI (NSTEMI: HR, 0.47; 95% CI 0.28-0.80, STEMI: HR, 0.86; 95% CI, 0.43-1.70, interaction P=.028). The beneficial effect of influenza vaccination on adverse cardiovascular events may be enhanced in patients with NSTEMI compared to those with STEMI.

Subgroup analyses in randomized phase III trials of systemic treatments in patients with advanced solid tumours: a systematic review of trials published between 2017 and 2020

Subgroup analyses of randomized controlled trials are very common in oncology; nevertheless, the methodological approach has not been systematically evaluated. The present analysis was conducted with the aim of describing the prevalence and methodological characteristics of the subgroup analyses in randomized controlled trials in patients with advanced cancer. A systematic literature search using PubMed was carried out to identify all phase III randomized controlled trials conducted in adult patients affected by locally advanced or metastatic solid tumours, published between 2017 and2020. Overall, 253 publications were identified. Subgroup analyses were reported in 217 (86%) publications. A statistically significant association of presence of subgroup analysis with study sponsor was observed: subgroup analyses were reported in 157 (94%) for-profit trials compared with 60 (70%) non-profit trials (P < 0.001). Description of the methodology of subgroup analysis was completely lacking in 82 trials (38%), only cited without methodological details in 100 trials (46%) and fully described in 35 trials (16%). Forest plot of subgroup analyses for the primary endpoint was available in 195 publications (77%). Among publications with reported forest plots, the median number of subgroups for primary endpoint was 19 (range 6-78). Out of the 217 publications with subgroup analyses, authors discuss the heterogeneity of treatment effect among different subgroups in 173 publications (80%), although a formal test for interaction for subgroup analysis of primary endpoint was reported for at least one variable only in 60 publications (28%). Correction for multiplicity was explicitly carried out only in nine trials (4%). The very high prevalence of subgroup analyses in published papers, together with their methodological weaknesses, makes advisable an adequate education about their correct presentation and correct reading. More attention about proper planning and conduction of subgroup analysis should be paid not only by readers, but also by authors, journal editors and reviewers.

Abstract 119: P2Y12 Inhibitor With Or Without Aspirin In Patients With Hypertension Undergoing Percutaneous Coronary Intervention

Background: P2Y12 inhibitor monotherapy after a brief period of dual antiplatelet therapy (DAPT) can reduce bleeding without increasing ischemic harm after percutaneous coronary intervention (PCI). We sought to examine the effect of P2Y12 inhibitor monotherapy vs. prolonged DAPT among patients with hypertension undergoing PCI. Methods: This is a post-hoc analysis of the SMART-CHOICE trial, in which patients undergoing PCI were randomly assigned to either P2Y12 inhibitor monotherapy after 3-month DAPT (n=1495) or DAPT for 12 months or longer (n=1498). The primary endpoint was Bleeding Academic Research Consortium (BARC) 2~5 bleeding. The composite ischemic endpoint was all-cause death, myocardial infarction, or stroke. Treatment effects were estimated according to the presence of hypertension with formal interaction testing. Results: Patients with hypertension comprised 61.5% of the randomized cohort, and were characterized by more frequent comorbidities, a higher PRECISE-DAPT score, and a higher prevalence of the multivessel disease. At 3 years, patients with hypertension experienced higher rates of all-cause death (3.9% vs 2.5%; p=0.039), stroke (1.6% vs 0.6%; p=0.014), or a composite ischemic endpoint (6.8% vs 3.8%; p&lt;0.001), but similar BARC 2~5 bleeding (5.4% vs 4.9%; p=0.601) compared with patients without hypertension. The incidence of BARC 2~5 bleeding was 2.9% and 7.8% among patients with hypertension randomized to P2Y12 inhibitor monotherapy versus DAPT [hazard ratio (HR), 0.382; 95% confidence interval (CI), 0.243 to 0.600; p&lt;0.001]. However, P2Y12 inhibitor monotherapy was not associated with an increase in ischemic events compared with DAPT (7.2% vs. 6.5%; HR: 1.135; 95% CI: 0.767 to 1.679; p=0.527) in patients with hypertension. In the overall population, there was no significant interaction between hypertension and treatment for the primary bleeding (adjusted p for interaction 0.835) or ischemic endpoints (adjusted p for interaction 0.707). Conclusions: P2Y12 inhibitor monotherapy is associated with a significantly lower risk for bleeding events compared with DAPT, without any compromise in ischemic prevention, among patients with hypertension undergoing PCI.

Transurethral prostate surgery in prostate cancer patients: A population-based comparative analysis of complication and mortality rates

ObjectiveProstate cancer (PCa) patients might experience lower urinary tract symptoms as those diagnosed with benign prostatic hyperplasia (BPH). Some of them might be treated for their lower urinary tract symptoms instead of PCa. We aimed to test the effect of PCa versus BPH on surgical outcomes after transurethral prostate surgery, namely complication and mortality rates. MethodsWithin the American College of Surgeons National Surgical Quality Improvement Program database (2011–2016), we identified patients who underwent transurethral resection of the prostate, photoselective vaporization, or laser enucleation. Patients were stratified according to postoperative diagnosis (PCa vs. BPH). Univariable and multivariable logistic regression models evaluated the predictors of perioperative morbidity and mortality. A formal test of interaction between diagnosis and surgical technique used was performed. ResultsOverall, 34 542 patients were included. Of all, 2008 (5.8%) had a diagnosis of PCa. The multivariable logistic regression model failed to show statistically significant higher rates of postoperative complications in PCa patients (odds ratio: 0.9, 95% confidence interval: 0.7–1.1; p=0.252). Moreover, similar rates of perioperative mortality (p=0.255), major acute cardiovascular events (p=0.581), transfusions (p=0.933), and length of stay of more than or equal to 30 days (p=0.174) were found. Additionally, all tests failed to show an interaction between post-operative diagnosis and surgical technique used. ConclusionPatients diagnosed with PCa do not experience higher perioperative morbidity or mortality after transurethral prostate surgery when compared to their BPH counterparts. Moreover, the diagnosis seems to not influence surgical technique outcomes.

Greater Body Fatness Is Associated With Higher Protein Expression of LEPR in Breast Tumor Tissues: A Cross-Sectional Analysis in the Women's Circle of Health Study.

BackgroundThe mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their receptors in breast tumors might play a role.MethodsIn a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index (FMI), and percent body fat with protein expression (log-transformed, n = 722) and gene expression (log2-transformed, n = 148) of leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons.ResultsIn multivariable models, we found that increasing BMI (β = 0.0529, 95% CI: 0.0151, 0.0906) and FMI (β = 0.0832, 95% CI: 0.0268, 0.1397) were associated with higher LEP gene expression, corresponding to 34.5% and 38.3% increases in LEP gene expression for a standard deviation (SD) increase in BMI and FMI, respectively. Increasing BMI (β = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (β = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (β = 0.0015, 95% CI: 0.0007, 0.0024), and FMI (β = 0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These associations equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for a 1-SD increase in BMI, waist circumference, hip circumference, and FMI, respectively. Further, these associations were stronger among White and postmenopausal women and ER+ cases; formal tests of interaction yielded evidence of effect modification by race. No associations of body fatness with LEP protein expression, LEPR gene expression, or protein or gene expression of ADIPOQ, ADIPOR1, and ADIPOR2 were found.ConclusionsThese findings support an association of increased body fatness – beyond overall body size measured using BMI – with higher LEP gene expression and higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine and adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step.

Abstract P182: Large Scale Analyses Of Gene-by-smoking Interaction On Cardiovascular Disease

Introduction: Cardiovascular disease risk is determined by both genetic susceptibility and lifestyle factors such as smoking. However, gene-by-smoking interactions have been understudied in this context. The objective of this study was to leverage large-scale individual level data to carry out a genome-wide gene-by-smoking interaction analysis on cardiovascular outcomes including coronary heart disease (CHD), stroke and peripheral artery disease (PAD). Methods: Our study sample included 401,384 unrelated, European-ancestry participants of the UK Biobank study. CHD, stroke, and PAD outcomes were based on data from baseline questionnaires and linked data from inpatient admissions and death registries. Smoking status (ever vs never) was based on self-report at baseline. Gene-environment interaction analyses were carried out using GEM (https://github.com/large-scale-gxe-methods/GEM), a new, computationally efficient software tool developed for biobank scale data. Using generalized linear models, we carried out a test of the genetic main effect adjusted for smoking status, a formal test for gene-by-smoking interaction, and a joint test of the main genetic and interaction effects. Single nucleotide polymorphisms with a minor allele frequency less than 1% were excluded from analyses. Results: The formal interaction test revealed a novel genome-wide significant (GWS) gene-by-smoking signal for PAD within the IREB2 gene (p=2.0x10 -8 ), which has been previously associated with smoking intensity and lung disease. The joint test has been shown to increase power for genetic discovery, which we observed here. The joint test for PAD identified 10 additional loci reaching genome-wide significance (p&lt;5x10 -8 ) that were not revealed in the main effect analyses. Several of these loci are in genes linked with measures of body composition in earlier studies ( PNLIP, CDH4, STAT5A, PRKCE ). We did not detect any GWS gene-by-smoking interactions for CHD or stroke. However, for CHD, two novel loci within the ARSG and SARS1 genes were identified using the joint test but had no GWS main effects. Both genes have been associated with LDL-cholesterol levels in prior genome-wide studies. Although our analyses did not yield any signals that exceeded the GWS threshold for stroke, we did identify 25 and 47 independent loci that reached genome-wide suggestive significance (p&lt;1x10 -5 ) for the formal interaction and joint tests, respectively. We are augmenting the current analyses to include additional data from approximately 120,000 trans-ethnic ancestry individuals. Conclusion: The analysis of gene-by-smoking interactions can provide novel insights into the genetic architecture and pathophysiology of cardiovascular disease.

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis

Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups. For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855. Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group. Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended. University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.

Abstract PO-107: Racial differences in survival among advanced-stage non-small cell lung cancer patients who received immunotherapy: An analysis of the U.S. National Cancer Database (NCDB)

Abstract Background: Lung cancer is the most common cause of cancer death among men and women in the United States, with 85% of all cases characterized as non-small cell lung cancer (NSCLC). These cancers are often diagnosed at advanced stage due to inapparent clinical symptoms. In 2015, the Food and Drug Administration approved the first use of immunotherapy for NSCLC, and it has since become a standard modality for treatment among advanced-stage NSCLC patients. Although significant racial disparities have been documented in overall NSCLC survival, it is unclear whether these disparities persist upon equal utilization of immunotherapy. The purpose of this study was to evaluate the association between race and all-cause mortality among advanced-stage non-small cell lung (NSCLC) cancer patients who received immunotherapy. Methods: We obtained data from the 2016 National Cancer Database on patients diagnosed with advanced-stage (III-IV) NSCLC from 2015-2016. The NCDB is a joint project of the American Cancer Society and the Commission on Cancer of the American College of Surgeons, and captures 70% of all patients with newly diagnosed cancer in the United States. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) by race/ethnicity. Additionally, we evaluated the interaction of race/ethnicity with Charlson-Deyo comorbidity score and area-level median income using stratified models and formal tests of interaction. Results: A total of 3,068 patients were included. NH-Black patients had a lower risk of death relative to NH-White patients (HR 0.85; 95% CI 0.74, 0.98) after adjusting for sociodemographic, clinical, and treatment factors. Formal tests of interaction evaluating race with Charlson-Deyo comorbidity score and race with area-level median income were nonsignificant. However, in stratified analyses, NH-Black vs. NH-White patients had a lower risk of death in models adjusted for sociodemographic factors among those with at least one comorbidity (HR 0.76; 95% CI 0.59, 0.98), and those living in regions within the two lowest quartiles of median income (HR 0.82; 95% CI 0.69, 0.98). Conclusions: Among advanced-stage NSCLC patients who received immunotherapy, NH-Black patients experienced higher survival compared to NH-White patients. We urge the implementation of policies and interventions that seek to equalize access to care as a means of addressing differences in overall NSCLC survival by race. Citation Format: Anjali Gupta, Tomi Akinyemiju. Racial differences in survival among advanced-stage non-small cell lung cancer patients who received immunotherapy: An analysis of the U.S. National Cancer Database (NCDB) [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-107.

Racial Differences in Survival Among Advanced-stage Non-small-Cell Lung Cancer Patients Who Received Immunotherapy: An Analysis of the US National Cancer Database (NCDB).

Lung cancer is the most common cause of cancer death among men and women in the United States, with significant racial disparities in survival. It is unclear whether these disparities persist upon equal utilization of immunotherapy. The purpose of this study was to evaluate the association between race and all-cause mortality among non-small-cell lung cancer (NSCLC) patients who received immunotherapy. We obtained data from the 2016 National Cancer Database on patients diagnosed with advanced-stage (III-IV) NSCLC from 2015 to 2016. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) by race/ethnicity. A total of 2940 patients were included. Non-Hispanic (NH)-Black patients had a lower risk of death relative to NH-White patients (HR: 0.85; 95% CI: 0.73, 0.98) after adjusting for sociodemographic, clinical, and treatment factors. Formal tests of interaction evaluating race with Charlson-Deyo comorbidity score and race with area-level median income were nonsignificant. However, in stratified analyses, NH-Black versus NH-White patients had a lower risk of death in models adjusted for sociodemographic factors among those with at least 1 comorbidity (HR: 0.75; 95% CI: 0.57, 0.97), and those living in regions within the 2 lowest quartiles of median income (HR: 0.82; 95% CI: 0.68, 0.99). Among advanced-stage NSCLC patients who received immunotherapy, NH-Black patients experienced higher survival compared with NH-White patients. We urge the implementation of policies and interventions that seek to equalize access to care as a means of addressing differences in overall NSCLC survival by race.

Achieved blood pressure post-acute kidney injury and risk of adverse outcomes after AKI: A prospective parallel cohort study

BackgroundThere has recently been considerable interest in better understanding how blood pressure should be managed after an episode of hospitalized AKI, but there are scant data regarding the associations between blood pressure measured after AKI and subsequent adverse outcomes. We hypothesized that among AKI survivors, higher blood pressure measured three months after hospital discharge would be associated with worse outcomes. We also hypothesized these associations between blood pressure and outcomes would be similar among those who survived non-AKI hospitalizations.MethodsWe quantified how systolic blood pressure (SBP) observed three months after hospital discharge was associated with risks of subsequent hospitalized AKI, loss of kidney function, mortality, and heart failure events among 769 patients in the prospective ASSESS-AKI cohort study who had hospitalized AKI. We repeated this analysis among the 769 matched non-AKI ASSESS-AKI enrollees. We then formally tested for AKI interaction in the full cohort of 1538 patients to determine if these associations differed among those who did and did not experience AKI during the index hospitalization.ResultsAmong 769 patients with AKI, 42 % had subsequent AKI, 13 % had loss of kidney function, 27 % died, and 18 % had heart failure events. SBP 3 months post-hospitalization did not have a stepwise association with the risk of subsequent AKI, loss of kidney function, mortality, or heart failure events. Among the 769 without AKI, there was also no stepwise association with these risks. In formal interaction testing using the full cohort of 1538 patients, hospitalized AKI did not modify the association between post-discharge SBP and subsequent risks of adverse clinical outcomes.ConclusionsContrary to our first hypothesis, we did not observe that higher stepwise blood pressure measured three months after hospital discharge with AKI was associated with worse outcomes. Our data were consistent with our second hypothesis that the association between blood pressure measured three months after hospital discharge and outcomes among AKI survivors is similar to that observed among those who survived non-AKI hospitalizations.

Risk of intracerebral haemorrhage from hypertension is greatest at an early age.

The risk of intracerebral haemorrhage (ICH) associated with hypertension (HTN) is well documented. While the prevalence of HTN increases with age, the greatest odds ratio (OR) for HTN as a risk for ischemic stroke is at an early age. We sought to evaluate if the risk for ICH from HTN was higher in the youngest patients of each race. The Ethnic/Racial Variations of ICH (ERICH) study is a prospective multicenter case-control study of ICH among whites, blacks, and Hispanics. Participants were divided into age groups based on race-specific quartiles. Cases in each race/age group were compared to controls using logistic regression (i.e., cases and controls unmatched). The probability of ICH among cases and controls for each race were compared against independent variables of HTN, quartile of age and interaction of quartile and age also using logistic regression. Overall, 2033 non-lobar ICH cases and 2060 controls, and 913 lobar ICH cases with 927 controls were included. ORs were highest in the youngest age quartile for non-lobar haemorrhage for blacks and Hispanics and highest in the youngest quartile for lobar haemorrhage for all races. The formal test of interaction between age and HTN was significant in all races for all locations with the exception of lobar ICH in whites (p = 0.2935). Hypertension is a strong independent risk factor for ICH irrespective of location among persons of younger age, consistent with the hypothesis that first exposure to HTN is a particularly sensitive time for all locations of ICH.

Abstract 13195: Race, Body Mass Index, and the Risk of Atrial Fibrillation: The Multi-Ethnic Study of Atheroclerosis

Introduction: Higher body mass index (BMI) is associated with an increased risk of incident atrial fibrillation (AF), but it is not known if this relationship varies based on race/ethnicity. Hypothesis: The relationship between BMI and incident AF will vary by race/ethnicity. Methods: Eligible MESA participants had no AF at baseline. The risk of incident AF as a function of baseline BMI was modelled using Cox proportional hazards. Formal tests of interaction by race/ethnicity were performed. Restricted cubic splines models were used to explore non-linear relationships. Results: Among 6,739 participants, 0.8% were underweight, 27.8% had normal BMI, 39.0% were overweight, 21.1% had grade I obesity, 7.6% had grade II obesity, and 3.7% had grade III obesity. Over 79,860 person-years of follow-up (median 13.8), 991 participants (14.7%) had new-onset AF. With BMI modeled as a categorical variable, only those with grade II and grade III obesity had an increased risk of AF (HR 1.48, 95% CI 1.13 - 1.94, p = 0.005 for grade II obesity and HR 2.21, 95% CI 1.11 - 4.40, p = 0.02 for grade III obesity ). The relationship between BMI and AF risk was non-linear, best characterized as J-shaped. However, the risk of AF as a function of BMI varied substantially by race/ethnicity (p-value for interaction = 0.02), with Chinese-American participants having a much higher risk of AF with higher BMI and African-American participants having minimal increased risk of AF with higher BMI (Figure 1). Conclusions: Obesity is associated with an increased risk of incident AF. The relationship between BMI and the risk of AF is J-shaped and this relationship differs by race/ethnicity, such that Chinese-Americans have a more pronounced increased risk of AF with higher BMI, while African-Americans have minimal increased risk. Further exploration of the differential effects of BMI by race/ethnicity on cardiovascular outcomes is needed.

Little Evidence of Modified Genetic Effect of rs16969968 on Heavy Smoking Based on Age of Onset of Smoking.

Tobacco smoking is the leading cause of preventable death globally. Smoking quantity, measured in cigarettes per day, is influenced both by the age of onset of regular smoking (AOS) and by genetic factors, including a strong effect of the nonsynonymous single-nucleotide polymorphism rs16969968. A previous study by Hartz et al. reported an interaction between these two factors, whereby rs16969968 risk allele carriers who started smoking earlier showed increased risk for heavy smoking compared with those who started later. This finding has yet to be replicated in a large, independent sample. We performed a preregistered, direct replication attempt of the rs16969968 × AOS interaction on smoking quantity in 128 383 unrelated individuals from the UK Biobank, meta-analyzed across ancestry groups. We fit statistical association models mirroring the original publication as well as formal interaction tests on multiple phenotypic and analytical scales. We replicated the main effects of rs16969968 and AOS on cigarettes per day but failed to replicate the interaction using previous methods. Nominal significance of the rs16969968 × AOS interaction term depended strongly on the scale of analysis and the particular phenotype, as did associations stratified by early/late AOS. No interaction tests passed genome-wide correction (α = 5e-8), and all estimated interaction effect sizes were much smaller in magnitude than previous estimates. We failed to replicate the strong rs16969968 × AOS interaction effect previously reported. If such gene-moderator interactions influence complex traits, they likely depend on scale of measurement, and current biobanks lack the power to detect significant genome-wide associations given the minute effect sizes expected. We failed to replicate the strong rs16969968 × AOS interaction effect on smoking quantity previously reported. If such gene-moderator interactions influence complex traits, current biobanks lack the power to detect significant genome-wide associations given the minute effect sizes expected. Furthermore, many potential interaction effects are likely to depend on the scale of measurement employed.

Locations of Adolescent Physical Activity in an Urban Environment and Their Associations with Air Pollution and Lung Function.

Rationale: Physical activity while being exposed to high concentrations of air pollution may lead to greater inhalation of pollutant particles and gases. Thus, owing to features of the built city environment, specific locations where physical activity take place may put individuals at increased risk for harmful inhaled exposures leading to decrements in lung function.Objectives: The objectives were to determine locations throughout an urban landscape where children engage in moderate to vigorous activity (MVA). We hypothesized that outdoor activity would be associated with increased exposure to air pollution and reduced lung function.Methods: Children aged 9-14 years living in New York City (NYC) (n = 151) wore global positioning system devices and wrist accelerometers for two 24-hour periods. Time-stamped global positioning system points and accelerometer data were aggregated and mapped using ArcGIS to determine locations where children engaged in MVA. Location-specific particulate matter <2.5 microns and nitrogen dioxide (NO2) was determined based on land use regression models of street-level pollution. Temporal air pollution exposure was determined based on daily concentrations collected at one central site in NYC. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF25-75) were collected following each 24-hour period. Data were analyzed using multivariable linear regression models to examine associations between MVA time and both lung function and air pollution in separate models. Additionally, a multiplicative interaction term (MVA time × season) was included to test whether the association between MVA time and lung function outcomes varied by warmer versus colder months.Results: On average, children spent less MVA time outdoors (38.2 ± 39.6 min/d) compared with indoors (71.9 ± 74.7 min/d, P < 0.01), regardless of season. The majority of outdoor MVA occurred along sidewalks and roadbeds (30.2 ± 33.3 min/d, 76.9% of outdoor) where annual average concentrations of NO2 were relatively high. Interquartile range (IQR) increase in outdoor MVA time (44 min) was associated with higher levels of annual average NO2 (P < 0.01) but not particulate matter <2.5 microns. In warmer months, for IQR increase in outdoor MVA time, children had 1.41% lower FEV1/FVC (95% confidence interval [95% CI], -2.46 to -0.36) and 4.40% lower percent predicted FEF25-75 (95% CI, -8.02 to -0.78). These results persisted even after adjustment for location-specific annual average concentrations of NO2. No association was observed between MVA time and lung function in colder months (P > 0.05), and a formal test for interaction (MVA time × season) was significant (P value for interaction = 0.01 and 0.03 for FEV1/FVC and FEF25-75, respectively).Conclusions: Children in NYC spent less time active outdoors compared with indoors. Outdoor activity was greatest near traffic sources and associated with higher annual average concentrations of NO2. In warmer months, outdoor activity was associated with lower lung function, but this association did not appear to be mediated by higher exposure to outdoor pollution during exercise.

High Mean Platelet Volume Associates with In-Hospital Mortality in Severe Pneumonia Patients.

Background Although mean platelet volume (MPV) appears to be associated with poor outcome of pneumonia, the relationship between MPV and in-hospital mortality is unclear in severe pneumonia (SP) patients. Methods In this retrospective cohort study, 115 SP patients from June 1st, 2016, to September 29th, 2019, were included and divided into two groups. The primary outcome was in-hospital mortality. The receiver operating characteristic (ROC) curve was performed to assess the predictive ability for in-hospital mortality. Kaplan-Meier cumulative incidence curves were applied to observe the incidence of mortality. Multivariable Cox regression analyses were used to evaluate the hazard ratios (HRs). Besides, a formal test for interaction was investigated to analyze the relationship between MPV and sex. Results During the course of hospitalization, 63 cases of mortality were recorded. ROC analysis suggested that MPV had a modest power for predicting in-hospital mortality (AUC = 0.723, 95% CI: 0.628-0.818, P < 0.001). Yet the cutoff value of MPV was 10.5 (sensitivity = 73.02%; specificity = 73.08%). Compared to the low-MPV group, the high-MPV group had significantly increased in-hospital mortality (log-rank test = 13.501, P < 0.001), while the adjusted Cox model indicated that the high-MPV group was associated with an elevated risk of in-hospital mortality (HR: 2.267, 95% CI: 1.166-4.406, P = 0.016). Moreover, analyses of in-hospital mortality suggested a significant interaction between optimal MPV level and sex (P = 0.011). In a multivariate Cox model which included females only, a high MPV level was associated with increased risk of in-hospital mortality (HR: 11.387, 95% CI: 1.767-73.380, P = 0.011). Conclusion High MPV level is an independent risk factor for in-hospital mortality in patients with SP.