Survival Bias Research Articles

Aortic valve replacement and mortality with left ventricular hypertrophy in setting of normal LVEF

Abstract Background Without symptoms, indications for aortic valve replacement (AVR) in severe aortic stenosis (AS) differ for individuals with normal vs. low/decreasing left ventricular ejection fraction (LVEF). Conceptually, the development of left ventricular hypertrophy (LVH) could also indicate ventricular injury and potential benefit with earlier AVR. However, little is known about the comparative effectiveness of AVR in individuals with LVH. As such, unlike low or dropping LVEF, development of LVH is not in itself an indication for AVR in clinical guidelines. Methods Initially, 1,232,492 echocardiography reports from 12 hospitals were identified from 1 January 2000 to 22 November 2022, and previously validated natural language processing modules were then applied to identify aortic gradients, LVEF, and presence of LVH. These reports were linked to mortality data, key comorbidities with a 2-year lookback covariate window, and date of any AVR. We then isolated echocardiograms demonstrating normal flow severe AS, LVEF ≥ 55% and LVH. Chart reviews were conducted to reduce missing data and outcomes were censored on the date of the chart review (October 4, 2023). To assess the association between AVR and mortality, Cox proportional hazards models considering treatment status (ie, AVR or not) were used with the index echocardiogram as time zero. Covariates used in risk-adjustment were chosen a priori based on conditions and laboratory values used in cardiac surgery mortality risk-adjustment, since those variables could plausibly confound the treatment decision. To address immortal time bias, AVR was considered a time-varying covariate. Multiple additional approaches with propensity scores were performed as sensitivity analyses. Results After application of inclusion and exclusion criteria, 4856 unique patients remained for analysis. Of those, 2043 (42.1%) received AVR with 841/2043 (41.2%) receiving surgical AVR and 1202/2043 (58.8%) receiving transcatheter AVR. Patients who received AVR had lower unadjusted mortality than those who did not receive AVR (33.6% vs. 47.1%, p < 0.001). After adjustment, and accounting for time-dependence of AVR, AVR was associated with reduced mortality (HR 0.81, 95% CI 0.73-0.89, p < 0.0001). The sensitivity analyses were all consistent with the primary analysis. Conclusions AVR was associated with reduced mortality for patients with severe AS, preserved LVEF, and LVH. This association persisted even after accounting for time-dependence, which tends to reduce the observed effectiveness of procedures in observational data. With over a million echocardiograms over more than 20 years, this is the largest known analysis of AVR outcomes in individuals with severe AS and LVH. Our findings suggest LVH may be a high-risk phenotype of individuals with AS, similar to dropping LVEF. As such, these results raise the potential of more proactive AVR clinical guidelines in individuals with LVH, even when LVEF is normal.Survival in AVR Vs No AVR

Clinical outcomes and impact of mitral valve surgery in atrial functional mitral regurgitation: the REVEAL-AFMR registry

Abstract Background The real-world impact and effective treatment strategies of atrial functional mitral regurgitation (AFMR) are poorly understood. The aim of this study was to investigate the prevalence, clinical characteristics, and the effectiveness of mitral valve surgery in AFMR. Methods The REal-world obserVational study for invEstigAting the prevaLence and therapeutic options for Atrial Functional Mitral Regurgitation (REVEAL-AFMR) was a retrospective cohort study conducted across 26 Japanese centers. All transthoracic echocardiography performed in 2019 were reviewed and patients with moderate or severe AFMR defined by preserved left ventricular function, dilated left atrium, and absence of degenerative valvular changes. The primary composite outcomes were heart failure hospitalization and all-cause mortality. Besides traditional multivariable regression analysis, propensity score-based time-zero matching was performed to account for immortal time bias. Results In 177,235 patients who underwent echocardiography, 8,867 had moderate or severe MR. Within this group, 1,007 were diagnosed with AFMR (mean age 78±10, 56% female, 80% atrial fibrillation). Of these, 113 underwent MV surgery, with 81% receiving concurrent tricuspid valve surgery. Patients who underwent surgery were younger but had more severe MR, larger left heart chambers, and a higher prevalence of heart failure than those who remained under medical therapy. During a median follow-up of 1050 days, 28% experienced the primary outcome, and 18% died. Despite a more severe disease status, only the surgical group showed a decrease in natriuretic peptide levels at follow-up and had significantly lower rate of the primary outcome (hazard ratio 0.43 [0.29-0.64], p<0.001 after adjustment for 25 covariates). Propensity score-based time-zero matching also indicated a lower risk of the primary outcome in the surgical group (hazard ratio 0.39 [0.20–0.78], p=0.007). Multiple sensitivity analyses yielded consistent results. Subgroup analysis suggested a significantly greater benefit of surgery for patients with severe MR than those with non-severe MR (p for interaction=0.044). Conclusions Our registry revealed that patients with AFMR are typically old with predominantly with atrial fibrillation, facing poor outcomes. MV surgery was associated with fewer adverse events, a finding that should be validated in future clinical trials.

Assessment of healthy worker survivor bias among middle-aged manufacturing employees in Korea

Abstract Background Healthy Worker Survivor Bias (HWSB) describes a selection bias where those continuously employed tend to exhibit superior health outcomes compared to their unemployed counterparts. This bias challenges for adjustments due to its time-dependent nature. This study aims to evaluate the extent of HWSB related to changes in employment status among middle-aged manufacturing workers using comprehensive national data from Korea. Methods The study analyzed data from the National Health Insurance Service, targeting individuals aged 40-49 who maintained consistent insurance coverage-either as manufacturing employees or non-employees (self-employed or unemployed)-from 2008 to 2010. The observation period spanned from January 2011 to December 2022, with all-cause mortality as the primary outcome. We employed landmark analysis to quantify HWSB related to employment status by comparing age-standardized mortality ratios between employees and the general population from the initial assessment to the last landmark period (up to 7 years), calculating 95% confidence intervals (CI) using Poisson distribution. Results The cohort included 4,621,983 participants (726,616 manufacturing employees and 3,895,367 (84.3%) non-employees). Throughout an average follow-up of 10.9 years (43.1% male; median age of 44), there were 116,418 deaths (11,530 (1.6%) among manufacturing employees and 104,888 (2.7%) among non-employees). Analysis revealed a consistent linear increase in HWSB over time. Notably, the bias was more pronounced among females (7-year HWSB-ES [95% CI]: 0.27 [0.17-0.37]) compared to males (7-year HWSB-ES [95% CI]: 0.18 [0.14-0.22]). Conclusions This study quantifies the extent of HWSB among middle-aged manufacturing workers in Korea, highlighting its significant impact, notably in females. These findings are vital for occupational health research, emphasizing the necessity to consider HWSB to prevent the underestimation of health risks associated with hazardous exposures. Key messages • Findings suggest HWSB is more pronounced in female manufacturing workers, indicating the need for targeted occupational health interventions. • The study underscores the importance of accounting for HWSB in occupational health studies to avoid underestimating health risks associated with workplace exposures.

Overall survival after CDK4/6 inhibitor dose reduction in women with metastatic breast cancer

BackgroundBreast cancer is the most common cancer in women, and the first-line treatment for patients with hormone-receptor positive/HER2-negative metastatic breast cancer is CDK4/6 inhibitor plus endocrine therapy. Understanding the impact of CDK4/6 inhibitor dose reduction, which occurs in about half of the patients, is important.MethodsThis real-world cohort study is based on electronic health records from Capital Region of Denmark. All women with metastatic breast cancer initiating first-line treatment with CDK4/6 inhibitor between May 2017 and October 2022 were included.ResultsA total of 546 patients were eligible for inclusion in the 12-week landmark analysis and 192 (35%) experienced dose reduction. These patients were older, had worse ECOG PS, more received prior adjuvant endocrine treatment, and more received fulvestrant as the endocrine backbone. Dose reduction was associated with reduced overall survival (39.9 vs. 54.3 months) and shorter treatment duration (18.0 vs. 26.9 months). Adjusted hazard ratio for death was 1.38 (95% CI: 1.01–1.89).ConclusionsDose reduction of CDK4/6 inhibitors within the first 12 weeks of treatment was associated with significantly higher mortality and shorter treatment duration. These findings contrast with previous analyses showing no effect of dose reduction, likely due to considering immortal time bias in this study.

Survival and Treatment Patterns in Stage II to III Esophageal Cancer

Existing clinical trials favor neoadjuvant chemoradiation therapy (NCRT) followed by surgery alone for locally advanced esophageal cancer (EC) and perioperative chemotherapy as the preferred modality for esophageal adenocarcinoma (EAC). However, it is unclear whether these trial findings are reflected in the patterns of care and survival outcomes among patients in the clinical setting. To investigate survival outcomes in the clinical setting among patients with EC after various treatment modalities. This retrospective cohort study examined data from the National Cancer Database maintained by the American College of Surgeons and focused on patients with clinical stage II or III EC, excluding those with gastroesophageal junction cancer, who underwent trimodality therapy (NCRT followed by esophagectomy), definitive chemoradiation therapy (DCRT), radiotherapy (RT) alone, or perioperative chemotherapy from January 2006 to December 2020. Analyses were conducted from December 2023 to August 2024. Perioperative chemotherapy, trimodality therapy, DCRT, and single-modality RT. A Cox proportional hazards regression model was used to compare overall survival (OS) between treatment groups in the entire cohort, among patients with squamous cell carcinoma or adenocarcinoma, and among those older than 65 years. Landmark survival analysis at 6 months was performed to reduce survivorship bias. The study included 57 116 patients (median age, 64 [IQR, 57-72] years; 45 410 [79.5%] male); 21 619 patients (37.9%) received trimodality therapy, 32 493 (57.1%) received DCRT, 2692 (4.7%) received single-modality RT, and 312 (0.5%) received perioperative chemotherapy. In the overall study population, 37 698 patients (66.0%) had EAC, and of the 312 patients that received perioperative chemotherapy, 283 (90.7%) had EAC. In adjusted survival analysis, perioperative chemotherapy (adjusted hazard ratio [AHR], 0.33; 95% CI, 0.28-0.39; P <.001) and trimodality therapy (AHR, 0.45; 95% CI, 0.44-0.46; P < .001) were associated with improved OS compared with DCRT. In contrast, RT alone was associated with worse outcomes compared with DCRT (AHR, 1.37; 95% CI, 1.30-1.45; P < .001). The median OS for perioperative chemotherapy of 66.2 months (95% CI, 43.1-111.9 months; P < .001) was longer compared with that for DCRT alone (18.1 months; 95% CI, 17.8-18.4 months; P < .001). Trimodality therapy was associated with a median OS of 43.9 months (95% CI, 42.8-45.5 months; P < .001), which was shorter than that for perioperative chemotherapy but improved compared with DCRT and RT alone, which was associated with a median OS of 13.5 months (95% CI, 12.8-14.0 months; P < .001). In the subgroup of patients older than 65 years, those who received perioperative chemotherapy had longer median OS (56.7 months; 95% CI, 36.4-115.2 months; P < .001) compared with those receiving other treatment modalities (eg, trimodality therapy: 40.1 months; 95% CI, 38.1-42.0 months; P < .001). Patients who received RT alone had the worst median OS (13.6 months; 95% CI, 12.8-14.4 months; P < .001). In this cohort study of patients with stage II to III EC, trimodality therapy was associated with improved OS compared with DCRT or RT alone for locally advanced EC and perioperative chemotherapy was associated with improved OS for adenocarcinoma.

Widespread HCD-tRNA derived SINEs in bivalves rely on multiple LINE partners and accumulate in genic regions

BackgroundShort interspersed nuclear elements (SINEs) are non-autonomous non-LTR retrotransposons widespread across eukaryotes. They exist both as lineage-specific, fast-evolving elements and as ubiquitous superfamilies characterized by highly conserved domains (HCD). Several of these superfamilies have been described in bivalves, however their overall distribution and impact on host genome evolution are still unknown due to the extreme scarcity of transposon libraries for the clade. In this study, we examined more than 40 bivalve genomes to uncover the distribution of HCD-tRNA-related SINEs, discover novel SINE-LINE partnerships, and understand their possible role in shaping bivalve genome evolution.ResultsWe found that bivalve HCD SINEs have an ancient origin, and they can rely on at least four different LINE clades. According to a “mosaic” evolutionary scenario, multiple LINE partner can promote the amplification of the same HCD SINE superfamilies while homologues LINE-derived tails are present between different superfamilies. Multiple SINEs were found to be highly similar between phylogenetically related species but separated by extremely long evolutionary timescales, up to ~ 400 million years. Studying their genomic distribution in a subset of five species, we observed different patterns of SINE enrichment in various genomic compartments as well as differences in the tendency of SINEs to form tandem-like and palindromic structures also within intronic sequences. Despite these differences, we observed that SINEs, especially older ones, tend to accumulate preferentially within genes, or in their close proximity, consistently with a model of survival bias for less harmful, short non-coding transposons in euchromatic genomic regions.ConclusionHere we conducted a wide characterization of tRNA-related SINEs in bivalves revealing their taxonomic distribution and LINE partnerships across the clade. Moreover, through the study of their genomic distribution in five species, we highlighted commonalities and differences with other previously studied eukaryotes, thus extending our understanding of SINE evolution across the tree of life.

Growth, physical, and cognitive function in children who are born HIV-free: School-age follow-up of a cluster-randomised trial in rural Zimbabwe.

Globally, over 16 million children were exposed to HIV during pregnancy but remain HIV-free at birth and throughout childhood by 2022. Children born HIV-free (CBHF) have higher morbidity and mortality and poorer neurodevelopment in early life compared to children who are HIV-unexposed (CHU), but long-term outcomes remain uncertain. We characterised school-age growth, cognitive and physical function in CBHF and CHU previously enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. The SHINE trial enrolled pregnant women between 2012 and 2015 across 2 rural Zimbabwean districts. Co-primary outcomes were height-for-age Z-score and haemoglobin at age 18 months (clinicaltrials.gov NCT01824940). Children were re-enrolled if they were aged 7 years, resident in Shurugwi district, and had known pregnancy HIV-exposure status. From 5,280 pregnant women originally enrolled, 376 CBHF and 2016 CHU reached the trial endpoint at 18 months in Shurugwi; of these, 264 CBHF and 990 CHU were evaluated at age 7 years using the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox. Cognitive function was evaluated using the Kaufman Assessment Battery for Children (KABC-II), with additional tools measuring executive function, literacy, numeracy, fine motor skills, and socioemotional function. Physical function was assessed using standing broad jump and handgrip for strength, and the shuttle-run test for cardiovascular fitness. Growth was assessed by anthropometry. Body composition was assessed by bioimpedance analysis and skinfold thicknesses. A caregiver questionnaire measured demographics, socioeconomic status, nurturing, child discipline, food, and water insecurity. We prespecified the primary comparisons and used generalised estimating equations with an exchangeable working correlation structure to account for clustering. Adjusted models used covariates from the trial (study arm, study nurse, exact child age, sex, calendar month measured, and ambient temperature). They also included covariates derived from directed acyclic graphs, with separate models adjusted for contemporary variables (socioeconomic status, household food insecurity, religion, social support, gender norms, caregiver depression, age, caregiver education, adversity score, and number of children's books) and early-life variables (length-for-age-Z-score) at 18 months, birthweight, maternal baseline depression, household diet, maternal schooling and haemoglobin, socioeconomic status, facility birth, and gender norms. We applied a Bonferroni correction for the 27 comparisons (0.05/27) with threshold of p < 0.00185 as significant. We found strong evidence that cognitive function was lower in CBHF compared to CHU across multiple domains. The KABC-II mental processing index was 45.2 (standard deviation (SD) 10.5) in CBHF and 48.3 (11.3) in CHU (mean difference 3.3 points [95% confidence interval (95% CI) 2.0, 4.5]; p < 0.001). The school achievement test score was 39.0 (SD 26.0) in CBHF and 45.7 (27.8) in CHU (mean difference 7.3 points [95% CI 3.6, 10.9]; p < 0.001); differences remained significant in adjusted analyses. Executive function was reduced but not significantly in adjusted analyses. We found no consistent evidence of differences in growth or physical function outcomes. The main limitation of our study was the restriction to one of two previous study districts, with possible survivor and selection bias. In this study, we found that CBHF had reductions in cognitive function compared to CHU at 7 years of age across multiple domains. Further research is needed to define the biological and psychosocial mechanisms underlying these differences to inform future interventions that help CBHF thrive across the life-course. ClinicalTrials.gov The SHINE follow-up study was registered with the Pan-African Clinical Trials Registry (PACTR202201828512110). The original SHINE trial was registered at NCT https://clinicaltrials.gov/study/NCT01824940.

Effectiveness of remdesivir in patients with COVID-19 and severe renal insufficiency: a nationwide cohort study in Japan

Background The effectiveness of remdesivir in patients with coronavirus disease 2019 (COVID-19) and severe renal insufficiency remains underexplored. Objectives To evaluate whether remdesivir reduces the risk of mortality or invasive mechanical ventilation/extracorporeal membrane oxygenation (IMV/ECMO) in this population. Methods This retrospective observational study utilising the COVID-19 Registry Japan (COVIREGI-JP) included noncritical patients with COVID-19 and severe renal insufficiency (defined as serum creatinine levels ≥3 mg/dL, on maintenance dialysis, or kidney transplant recipients) admitted to Japanese hospitals within 7 days of symptom onset between January 1, 2020 and May 8, 2023. Patients were classified into the remdesivir group if remdesivir was initiated within the first 2 days of admission. We estimated the multivariable-adjusted hazard ratio (HR) for mortality and initiation of IMV/ECMO using landmark analysis to address immortal time bias. Results Among the 1,449 patients included in the landmark analysis (median age, 74 years [interquartile range 62–84 years]; 992 [68.5%] were male), 272 initiated remdesivir within the first 2 days of admission. During the 28 days from the landmark timepoint, 19 (7.0%) and 136 (11.6%) patients in the remdesivir and control groups, respectively, had an outcome. The remdesivir group had a lower risk of mortality or IMV/ECMO initiation than the control group (adjusted HR, 0.44; 95% confidence interval, 0.23–0.83). Conclusions In noncritical patients with COVID-19 and severe renal insufficiency at admission, initiating remdesivir early after disease onset, within the first 2 days of admission, led to a lower risk of mortality or IMV/ECMO initiation, compared with non-initiation of remdesivir.

Impact of SGLT2-Inhibitor Therapy on Survival in Patients with Transthyretin Amyloid Cardiomyopathy: Analysis of a Prospective Registry Study.

Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) represent a high-risk heart failure population with continued unmet therapeutic needs. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction, and first evidence regarding their safety and effectiveness in patients with ATTR-CM is arising. This study investigates the association between SGLT2i therapy and clinical outcomes in these patients. Methods: This is an analysis of a prospective registry conducted at a referral centre for hypertrophic cardiomyopathies including 116 patients with confirmed ATTR-CM. Fifty-one patients (44%) were treated with SGLT2i while 65 patients (56%) remained SGLT2i-naïve. Results: During a median follow-up of 2.6 (1.7-3.7) years, 38 patients (33%) died, of whom 11 patients (9%) received SGLT2i treatment and 27 patients (23%) were treatment-naïve. SGLT2i therapy was significantly associated with lower mortality (HR 0.457, 95%CI 0.227-0.922, p = 0.029). This association persisted after adjusting for age and sex (HR 0.479, 95%CI 0.235-0.977, p = 0.043) and after additional adjustment for eGFR, NT-proBNP, LVEF, and concomitant therapy with tafamidis (HR 0.328, 95%CI 0.141-0.760, p = 0.009). However, when potential immortal time bias was considered, this association lost statistical significance (HR 1.075, 95%CI 0.524-2.206, p = 0.843). No significant associations between SGLT2i therapy and worsening heart-failure hospitalization or cardiovascular mortality were observed. Conclusions: In crude analysis, SGLT2i therapy associates with better survival in patients with ATTR-CM. However, after adjustment for immortal time, this association becomes statistically insignificant. Hence, to draw final conclusions on the effectiveness of SGLT2i therapy in these patients, a randomized controlled trial is warranted.

The Importance of Real-World Data in Evaluating the Safety of Biosimilars: A Descriptive Study of Clinical Practice in an Oncohematological Italian Population.

The clinical safety and efficacy of rituximab biosimilars compared to the reference rituximab (Mabthera) have been well established in randomized trials. However, concerns persist regarding the safety of changing from the reference product to biosimilars, and particularly between different biosimilars. This prospective multicenter observational study was conducted in 13 oncohematology units of eight Italian regions. The study included 800 patients with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) who received rituximab between March 2018 and June 2022. To minimize survivorship bias, only newly diagnosed patients (i.e., those without prior rituximab treatment) were included in the analysis of adverse drug reactions (ADRs). Thus, this study focused on 505 incident cases (79.8% of the initial cohort) from 13 centers. A total of 3681 rituximab infusions were administered, and 16.8% of the patients experienced at least one ADR. These were observed most frequently during the first infusion (44 patients, 52%) and the second infusion (17 patients, 20%). The most frequent reactions were general disorders and administration site conditions (n. 50, 8% serious). These findings support the clinical safety of rituximab biosimilars and suggest that switching between biosimilars does not increase the risk of adverse events. This evidence may alleviate concerns about biosimilar use, potentially leading to broader acceptance and reduced healthcare costs.

Survival Analysis of Conversion Surgery in Borderline Resectable and Locally Advanced Unresectable Pancreatic Ductal Adenocarcinoma Addressing Selection and Immortal Time Bias: A Retrospective Single-Center Study.

The purpose of this study was to provide a detailed evaluation of the oncological advantages of surgery following neoadjuvant chemotherapy (NAC) for patients with borderline resectable (BR) or unresectable (UR) pancreatic ductal adenocarcinoma (PDAC), with a focus on minimizing biases. Recently, NAC has become the standard care for BR or UR locally advanced (UR-LA) PDAC, however, many studies have assessed survival benefits and favorable variables without consideration for biases, particularly immortal time bias. This study included patients diagnosed with BR or UR-LA PDAC at Juntendo University Hospital from 2019 to 2022. To mitigate bias, we applied methods such as propensity score matching (PSM), time-dependent covariate Cox proportional hazard regression analysis (TDC), landmark analysis, and multivariable Cox proportional hazards regression model. The study analyzed 124 patients, dividing them into a surgery group (n = 57) and a chemotherapy-only group (n = 67). After PSM, there were 21 matched pairs. Survival analysis using TDC analysis showed that the surgery group had significantly better overall survival compared with the chemotherapy-only group in both the entire cohort and the matched pairs. Cox regression analysis of the entire cohort also revealed a similar superiority of surgery, while the landmark analysis showed varying results depending on the landmark setting. After careful adjustment for selection and immortal time biases, surgery following NAC appears to significantly extend survival in patients with BR or UR PDAC.

Exposure misclassification: an “immortal time” bias in observational studies of training load and injury

Several observational studies of the relationship between training load and injury have found increased risks of injury at low loads. These associations are expected because load is often assessed at the end of the injury follow-up period. As such, athletes who get injured earlier in the follow-up period will have systematically lower loads than athletes who get injured later in the follow-up period. In this commentary, we identify this problem as a type of exposure misclassification occurring from the misalignment of exposure measurement and start of follow-up. This methodological issue has previously been recognized in other areas of epidemiology as “immortal time bias”. We discuss how this bias can be prevented by aligning the measurement of load with the start of follow-up for injury.

Inclusion of Surgery in Multimodality Treatment is Predictive of Better Survival in Stage IIIA Non-small Cell Lung Cancer: an Inverse Probability Treatment-Weighting Analysis

IntroductionStage IIIA non-small cell lung cancers (NSCLC) are treated with surgical based multimodality approach or definitive chemoradiation therapy plus durvalumab consolidation. It is not clear whether surgery-based multimodality therapy has any survival advantage over definitive chemoradiation plus immunotherapy consolidation. MethodNational Cancer Database (NCDB) was used to identify NSCLC patients at stage IIIA (AJCC8, T3N1/T4N0-1 or T1N2/T2N2) who are treated with surgery-based multimodality approach or definitive chemoradiation plus durvalumab. Survival between groups were compared using inverse probability of treatment weighting (IPTW)-adjusted Kaplan Meier curves and Cox proportional hazards regression analysis. Results were independently confirmed by Landmark Inverse and Clone Censor Weight analyses to address immortal time bias. ResultsFrom 2017 to 2019, 24,170 patients are identified as potentially resectable stage IIIA (T3N1, T4N0-1, T1N2/T2N2). Among them, 2,615 (10.8%) received surgery-based multi-modality therapy and 2,985 (12.4%) received definitive chemoradiation plus durvalumab. Surgery based multimodality approach had significant survival advantage over definitive chemoradiation plus durvalumab (HR 0.74; 95% CI 0.69-0.79, P<0.001). The median overall survival (mOS) for the definitive chemoradiation plus durvalumab group was 48.59 m whereas mOS was not reached for surgery-based multimodality group. This trend persisted in both N2 negative and positive tumors. Neoadjuvant chemotherapy was just as effective as adjuvant chemotherapy and delay of immunotherapy consolidation to 12 weeks after initiation of chemoradiation did not negatively affect survival outcome. ConclusionFor stage IIIA NSCLC patients, surgery-based multimodality treatment outperformed chemoradiation plus durvalumab in survival. DisclosureZH reports grant from Bayer Inc, BMS, Merck, AMG, Legend biotech, BeiGene, Novartis and OncC4. No disclosure from all other authors. MicroAbstractResectable stage IIIA non-small cell lung cancer treated with multi-disciplinary approach with surgical resection survive longer than those who were treated with concurrent chemoradiation therapy plus consolidation durvalumab. Chemotherapy can be given as adjuvant or as neoadjuvant with no survival difference. Delay of immunotherapy consolidation to more than 12 weeks after starting radiation does not compromise survival outcome.

Self-Rated Health Predicts Mortality -- But It Depends on Your Age

While self-rated health (SRH) has long been known to predict mortality in adult populations, the age of respondents plays an interesting and complex role in both explaining and modifying the association. The objective of this study is to test for differences by age in the association of SRH with all-cause mortality. Because much of the research has been conducted with older samples, a wider age range of adults may show that some age groups have more predictive SRH than others. We estimated Cox proportional hazards models to determine if SRH in 1999 predicted survival to 2021 differently based on age, using data from the Panel Study of Income Dynamics. The sample consisted of 5,843 respondents aged 25 to 97 who were interviewed in 1999 and followed for survival until 2021. We included demographic and socioeconomic factors, physical health and mental health indicators, and health risk behaviors as covariates to assess their potential mediating role in the predictive ability of SRH. The results showed a significant interaction between SRH and age, with larger and more significant hazards for those aged 40-54 and 55-74. There were no significant effects at all for the youngest group and virtually none for the oldest group. For example, for individuals aged 40-54, there were significant HRs for poor health (2.49, 95% CI 1.05, 5.89) and fair health (1.95, 95% CI 1.11, 3.42) compared to excellent health in the fully adjusted models. Our findings suggest that age group differences in the predictiveness of SRH may reflect an absence of health knowledge and experience for younger respondents, and a survivor bias for the oldest age group due to the lifetime elimination of those with poor health.

The association of azole antifungals with overall survival in patients with non-small cell lung cancer receiving immune checkpoint inhibitors.

Preclinical data suggest antifungal azole derivatives have antitumor efficacy that may modulate response to immune checkpoint inhibitors (ICIs). We aimed to evaluate the association of azole drugs with overall survival (OS) in a population of patients with non-small cell lung cancer (NSCLC) treated with ICI within the Veterans Health Administration (VHA). In this retrospective study, the VA Corporate Data Warehouse was queried for patients diagnosed with NSCLC and treated with ICI from 2010 to 2018. Concomitant oral azole use was defined as dispensation by a VA pharmacy within 90 days of the first ICI infusion. Patients who received azole after 30 days were excluded from the analysis to mitigate immortal time bias. OS was measured from the start of ICI. Cox regression and propensity score matching were used to adjust for confounders. We identified 3413 patients with NSCLC receiving ICI; 324 (9.5%) were exposed to concomitant azoles. As a group, azole use was not associated with OS (hazard ratio [HR] = 0.96; 95% CI, 0.84-1.09; P = .51). After stratification by azole type, clotrimazole had an association with better OS on univariable (HR = 0.75; 95% CI, 0.59-0.96; P = .024) and multivariable analysis (HR = 0.71; 95% CI, 0.56-0.91; P = .007). Propensity score matching of patients who received clotrimazole vs no azole yielded 101 patients per matched cohort. Clotrimazole was associated with improved OS, although this did not meet the threshold for statistical significance (HR = 0.74; 0.54-1.01; P = .058). This observational study demonstrated an association between clotrimazole and OS among patients with advanced NSCLC receiving ICI. These findings build upon preclinical evidence and support further investigation into the potential for clotrimazole as a repurposed FDA drug to improve cancer outcomes.

Abstract A041: Assessing the impact of neighborhood structural racism on survival for African American men with prostate cancer; a population-based cancer registry study across eight US states

Abstract Background: African American (AA) men are more than twice as likely to die of prostate cancer (PC) compared to non-Hispanic White men in the US. Among AA men, we examined survival after PC diagnosis by neighborhood-level structural racism and whether its effects are mediated by neighborhood socioeconomic status (nSES). Methods: We pooled data for 133,241 AA men diagnosed with PC from 2000-2013 from ten population-based cancer registries across eight states (CA, Detroit, FL, GA, LA, NJ, NY, TX) of the RESPOND Study (Research on Prostate Cancer among African American Men). Residential addresses at PC diagnosis were geocoded and appended to census block-group measures of structural racism (contemporary redlining, racial/ethnic segregation typology, and racial bias in mortgage lending) and nSES, an index comprising measures of income, education, occupation, employment, and housing. We used Cox models and the %mediation SAS macro for causal mediation to assess overall and PC- specific survival according to structural racism and to quantify the extent to which survival differences were mediated by nSES. Models were adjusted for diagnosis year and age, state of residence, and marital status. Results: There were 46,830 deaths overall with 12,272 PC-specific deaths among the study population. Greater mortality risk was observed among AA men residing in neighborhoods in the highest compared to lowest quartile of redlining (total effect) for both overall survival (Hazards ratio [HR]=1.26; 95% CI=1.22, 1.31) and PC-specific survival (HR=1.30; 95% CI=1.21-1.39). Neighborhood SES mediated 59% and 47% of the effect of redlining, resulting in natural direct effects of HR=1.11 (95% CI=1.05, 1.17) and HR=1.16 (95% CI=1.04, 1.29) for overall and PC-specific survival, respectively. Compared to predominantly White neighborhoods, AA men residing in neighborhoods with all other racial/ethnic typologies had greater overall and PC-specific mortality risk, with largest risk for neighborhoods with predominantly AA or mixed with Hispanic and AA residents. Neighborhood SES completely mediated the effect of racial/ethnic typology on survival for all typologies except that of mixed Hispanic and Black residents (37% and 25% mediation by nSES for overall and PC-specific survival, respectively). There was no association between racial bias in mortgage lending and survival. Results from models additionally adjusted for prognosis (Prostate Cancer Cohort Consortium [PC3] classification of aggressive disease) and treatment (receipt of surgery, radiation, chemotherapy, or hormone therapy) were similar. Conclusions: Neighborhood SES explains substantial portions of the impact of redlining and racial/ethnic typology on overall and PC-specific survival among AA men across eight states in the US. Remaining survival differences for the most redlined neighborhoods and neighborhoods with a mix of Hispanic and Black residents independent of nSES suggest alternative pathways for the impact of neighborhood structural racism on mortality risk for AA men with PC. Citation Format: Mindy C. DeRouen, Meera Sangaramoorthy, Katherine Lin, Annie Vu, Dan Meltzer, Pushkar Inamdar, Yuhong Zhou, Kevin Ward, Xiao-Cheng Wu, Antoinette Stroup, Jennifer Beebe-Dimmer, Anshu Shrestha, Aaron P. Thrift, Margaret Gates-Kuliszewski, Peter Kanetsky, Tamara Lotan, Anthony Colombo, David Conti, Christopher Haiman, Ann Hamilton, Kirsten Beyer, Joseph Gibbons, Iona Cheng, Salma Shariff-Marco, Scarlett Gomez. Assessing the impact of neighborhood structural racism on survival for African American men with prostate cancer; a population-based cancer registry study across eight US states [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A041.

Analysis of Brain Age Gap across Subject Cohorts and Prediction Model Architectures.

Background: Brain age prediction from brain MRI scans and the resulting brain age gap (BAG)-the difference between predicted brain age and chronological age-is a general biomarker for a variety of neurological, psychiatric, and other diseases or disorders. Methods: This study examined the differences in BAG values derived from T1-weighted scans using five state-of-the-art deep learning model architectures previously used in the brain age literature: 2D/3D VGG, RelationNet, ResNet, and SFCN. The models were evaluated on healthy controls and cohorts with sleep apnea, diabetes, multiple sclerosis, Parkinson's disease, mild cognitive impairment, and Alzheimer's disease, employing rigorous statistical analysis, including repeated model training and linear mixed-effects models. Results: All five models consistently identified a statistically significant positive BAG for diabetes (ranging from 0.79 years with RelationNet to 2.13 years with SFCN), multiple sclerosis (2.67 years with 3D VGG to 4.24 years with 2D VGG), mild cognitive impairment (2.13 years with 2D VGG to 2.59 years with 3D VGG), and Alzheimer's dementia (5.54 years with ResNet to 6.48 years with SFCN). For Parkinson's disease, a statistically significant BAG increase was observed in all models except ResNet (1.30 years with 2D VGG to 2.59 years with 3D VGG). For sleep apnea, a statistically significant BAG increase was only detected with the SFCN model (1.59 years). Additionally, we observed a trend of decreasing BAG with increasing chronological age, which was more pronounced in diseased cohorts, particularly those with the largest BAG, such as multiple sclerosis (-0.34 to -0.2), mild cognitive impairment (-0.37 to -0.26), and Alzheimer's dementia (-0.66 to -0.47), compared to healthy controls (-0.18 to -0.1). Conclusions: Consistent with previous research, Alzheimer's dementia and multiple sclerosis exhibited the largest BAG across all models, with SFCN predicting the highest BAG overall. The negative BAG trend suggests a complex interplay of survival bias, disease progression, adaptation, and therapy that influences brain age prediction across the age spectrum.

Survival benefits of radiotherapy in locally advanced unresectable and metastatic pancreatic cancer: a single-institution cohort and SEER database analysis.

Chemotherapy (CT) remains the primary treatment for locally advanced unresectable pancreatic cancer (LAUPC) and metastatic pancreatic cancer (MPC). The role of radiotherapy (RT) in these conditions remains unclear. This study compares the outcomes of CT alone versus CT combined with RT (combined-modality therapy [CMT]) in LAUPC and MPC patients. We conducted a retrospective analysis of LAUPC and MPC patients treated with either CT or CMT from a single institution and Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier curves and Cox hazards models evaluated the association between treatment modalities and overall survival (OS). Propensity score matching (PSM) ensured balanced comparisons. Landmark analysis addressed immortal time bias. Subgroup analyses were based on clinical characteristics. eXtreme Gradient Boosting (XGBoost) and Shapley Additive Explanations (SHAP) assessed outcome prediction and influence of significant predictors. The study included 102 patients receiving CMT and 155 receiving CT at single institution, along with 1733 CMT and 9310 CT patients from the SEER dataset. In the single-institution cohort, CMT showed superior survival compared to CT both before (median OS: 20.5 vs. 11.5 months, hazard ratio [HR]: 0.47, 95% CI: 0.34-0.65, P=0.001) and after PSM (median OS: 22.2 vs. 11.8 months, HR: 0.49, 95% CI: 0.30-0.79, P=0.003). Multivariate analyses confirmed that CMT was independently associated with improved OS both before (HR: 0.54, 95% CI: 0.38-0.77, P=0.001) and after PSM (HR: 0.45, 95% CI: 0.27-0.73, P=0.001). Landmark analysis indicated better OS for patients receiving CMT compared to CT alone. Subgroup analysis revealed an OS benefit for CMT across most subgroups. SHAP value analysis indicated that CMT was the most significant contributor to survival outcomes. SEER database validation confirmed these findings. This study demonstrates that CMT significantly improves OS in LAUPC and MPC patients compared to CT alone. Integrating RT with CT could be beneficial for treating LAUPC and MPC.

Women entrepreneurs in rural Nigeria: formal versus informal credit schemes

PurposeThis study examines why low-wealth women entrepreneurs forgo mobile enabled money services and government supported micro finance for informal, community-based revolving loans in rural Nigeria.Design/methodology/approachThematic analysis of 25 interviews with women in rural, south-west Nigeria. Entrepreneurial ecosystem theory, in the gendered context of micro finance and community-based lending, is employed.FindingsThis study explains the paradox of forgoing seemingly accessible mobile enabled credit, and formal credit schemes (e.g. micro-finance programs) for informal, one-on-one borrowing. Convenience and trust-based relationships with respected community members ease the burden of time scarcity and vulnerability associated with formal capital. Flexible terms, autonomy, self-reliance and knowing who one is dealing with make Esusu a preferred source of finance. Findings are discussed in the context of gendered entrepreneurial ecosystems in which participants conduct business.Research limitations/implicationsThe sample is not representative of women entrepreneurs in rural Nigeria. Survivorship bias is acknowledged. Further research is needed on the psychological risks of informal capital and the benefits of community-based lending.Practical implicationsMeasures to scale mobile enabled credit, without commensurate interventions to address time management and other structural issues that confront women traders, limit their utility and impacts. Power differentials between women traders and lenders must also be considered in the design of lending products. Training of women traders and formal lenders should incorporate curricula about gender gaps in capital markets and systematic gender challenges to support entrepreneurs who seek to grow beyond subsistence enterprises.Originality/valueThis study documents decision criteria that motivate informal rural women traders to employ community-based revolving credit or Esusu. Findings inform measures to increase women entrepreneurs' access to capital in a rural sub-Saharan Africa contexts.

Can Machine Learning Overcome the 95% Failure Rate and Reality that Only 30% of Approved Cancer Drugs Meaningfully Extend Patient Survival?

Despite implementing hundreds of strategies, cancer drug development suffers from a 95% failure rate over 30 years, with only 30% of approved cancer drugs extending patient survival beyond 2.5 months. Adding more criteria without eliminating nonessential ones is impractical and may fall into the "survivorship bias" trap. Machine learning (ML) models may enhance efficiency by saving time and cost. Yet, they may not improve success rate without identifying the root causes of failure. We propose a "STAR-guided ML system" (structure-tissue/cell selectivity-activity relationship) to enhance success rate and efficiency by addressing three overlooked interdependent factors: potency/specificity to the on/off-targets determining efficacy in tumors at clinical doses, on/off-target-driven tissue/cell selectivity influencing adverse effects in the normal organs at clinical doses, and optimal clinical doses balancing efficacy/safety as determined by potency/specificity and tissue/cell selectivity. STAR-guided ML models can directly predict clinical dose/efficacy/safety from five features to design/select the best drugs, enhancing success and efficiency of cancer drug development.