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62 Background: Both Regorafenib (R) and Trifluridine/Tipiracil (T) ± BEV are widely used treatments for mCRC in later lines. This RW study evaluated optimal sequencing and associated outcomes among patients who initiated R and T in sequential lines of therapy (LOT) between LOT1-LOT6 within community oncology settings in the US. Methods: A retrospective study utilizing electronic medical record data from The US Oncology Network examined adult patients with mCRC who initiated R and T ± BEV sequentially between 09/01/2015 and 11/30/2022 (index date), with follow-up until 05/31/2023. Treatment patterns, overall survival (OS) and time to next treatment (TTNT) after sequence were assessed overall, R first (R-T) and T first (T-R). Multivariable Cox regression adjusting for age, sex, ECOG, tumor stage, and prior medication, assessed the association of factors with OS and TTNT. Results: In total, 308 mCRC patients initiating R and T (R-T, 156 pts [140 R-T and 16 R-T+BEV]; T-R, 152 pts [136 T-R and 16 T+BEV-R]) met study criteria. Baseline demographic (mean age 63 yrs, males 55%) and clinical characteristics (70% colon cancer, 58% ECOG 0-1) were similar between the cohorts. Most patients initiated index therapies at the third line of therapy (LOT3) (49% R-T, 45% T-R). The median (IQR) sequence duration was 7.4 (5.6), 6.7 (4.4), and 7.0 (4.7) months, respectively in patients with R-T, T-R, and overall. The median (95% CI) OS was 12.8 (11.2, 14.1) months among R-T and 10.2 (8.8, 11.9) months among T-R patients. Compared to R-T, the adjusted HR for the T-R sequence was 1.2 (95% CI 0.9–1.6; p=0.2). The median (95% CI) TTNT was 9.3 (8.4, 10.3) and 8.6 (7.8, 9.4) months, for R-T and T-R, respectively; the adjusted HR was 1.1 (95% CI 0.8–1.4; p=0.62). Conclusions: Patients initiating R first appeared to have a longer duration of treatment and survival, although not statistically significant. The one-year median duration of survival in this real-world setting confirms the importance of access to these treatments in patients with mCRC and can inform physicians regarding the choice of medications while sequencing therapies in mCRC. Clinical outcomes among R-T and T-R mCRC patients. Variable Level R-T (± BEV)[N 1 = 156] T (± BEV) -R[N 1 = 152] Adjusted 3,4 HR 5 (95% CI)[R-T Reference] Effect OverallSurvival Months – median (95% CI) 12.8(11.2, 14.1) 10.2(8.8, 11.9) 1.20 (0.91, 1.58) 0.20 TTNT 2 Months – median (95% CI) 9.3(8.4, 10.3) 8.6(7.8, 9.4) 1.07 (0.83, 1.37) 0.62 1 Entire R-T and T-R cohorts are presented since 16 patients in each cohort initiated T+BEV. 2 Time To Next Treatment. 3 Overall Survival adjusting for age, gender, stage at diagnosis, ECOG, prior anti-VEGF treatment. 4 Time To Next Treatment adjusting for age, gender, stage at diagnosis, and line of therapy. 5 Hazard Ratio.

Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed the effects of covariate stratification and interaction on body mass index (BMI) PGS (PGS BMI ) across four cohorts of European (N = 491,111) and African (N = 21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R 2 differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R 2 being nearly double between best- and worst-performing quintiles for certain covariates. Twenty-eight covariates had significant PGS BMI –covariate interaction effects, modifying PGS BMI effects by nearly 20% per standard deviation change. We observed overlap between covariates that had significant R 2 differences among strata and interaction effects – across all covariates, their main effects on BMI were correlated with their maximum R 2 differences and interaction effects (0.56 and 0.58, respectively), suggesting high-PGS BMI individuals have highest R 2 and increase in PGS effect. Using quantile regression, we show the effect of PGS BMI increases as BMI itself increases, and that these differences in effects are directly related to differences in R 2 when stratifying by different covariates. Given significant and replicable evidence for context-specific PGS BMI performance and effects, we investigated ways to increase model performance taking into account nonlinear effects. Machine learning models (neural networks) increased relative model R 2 (mean 23%) across datasets. Finally, creating PGS BMI directly from GxAge genome-wide association studies effects increased relative R 2 by 7.8%. These results demonstrate that certain covariates, especially those most associated with BMI, significantly affect both PGS BMI performance and effects across diverse cohorts and ancestries, and we provide avenues to improve model performance that consider these effects.

AbstractCholecystectomy is the standard treatment for acute cholecystitis, but it may not be suitable for all patients. For those who cannot undergo surgery, a percutaneous cholecystostomy tube (PCT) and ERCP-guided transpapillary gallbladder drainage are viable options. We aimed to perform a nationwide study to assess 30-day readmission rates, adverse events (AEs), and mortality rates in these two cohorts.We conducted a nationwide cohort study using data from the Nationwide Readmissions Database (NRD) from 2016 to 2019. We identified patients with acute cholecystitis during the index admission who underwent either PCT or ERCP-guided gallbladder drainage. Propensity score matching along with multivariable regression was used to compare cohorts.During the study period, 3,592 patients (average age 63.0 years) underwent endoscopic drainage, whereas 80,372 patients (average 70.8 years) underwent Interventional Radiology drainage. Utilizing multivariate Cox regression analysis, compared with ERCP, PCT had a higher risk for 30-day readmission (adjusted hazard ratio [aHR] 1.47; 95% confidence interval [CI] 1.27 to 1.71; P < 0.001). The PCT group had a significantly higher rate of readmission for acute cholecystitis compared with the ERCP group (2.72% vs 0.86%; P < 0.005). Cox proportional hazard ratio showed a 3.41-fold increased risk (95% CI 1.99 to 5.84) for readmission in the PCT group. ERCP was consistently associated with lower rates of post-procedural AEs compared with PCT including acute hypoxemic respiratory failure (P < 0.001), acute renal failure (P < 0.001), shock (P < 0.001), and need for blood transfusions (P < 0.001).Our nationwide analysis revealed that ERCP-guided gallbladder drainage should be the preferred approach for managing acute cholecystitis when unfit for surgery.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide criteria for selecting individuals for screening and offer recommendations for evaluating and managing lung nodules detected during initial and subsequent annual screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

AbstractBackgroundWomen with suspected coronary microvascular dysfunction (CMD) may be at higher risk of experiencing cognitive decline due to cerebral small vessel disease, a known contributor to Alzheimer’s disease and related dementias (ADRD). A potential underlying mechanism that could accelerate this cognitive decline is the accumulation of brain tissue iron, which has been previously linked to changes in brain function potentially caused by oxidative stress and cell death. Therefore, we aim to elucidate whether a similar mechanism could affect women with suspected CMD by investigating the potential role of iron deposition on the brain’s functional organization and its effect on cognition using advanced magnetic resonance imaging (MRI).Material and MethodsTwenty‐seven women with suspected CMD [Age; median (range) = 54 (29‐76)], drawn from ongoing cohorts (3R01HL146158‐04S1,3U54AG065141‐04S1), underwent a 3T MRI protocol, including submillimeter T2* 3‐dimensional echo‐planar‐imaging for assessing iron deposition with high‐resolution quantitative susceptibility mapping (QSM) and resting‐state fMRI (rs‐fMRI). Iron content was quantified by total‐generalized‐variation based QSM analysis. Functional integrity was determined via graph theoretical approach (i.e., nodal degree). Cognitive assessment was also performed using the NIH Toolbox. Mediation analysis was conducted using Python Statsmodels.ResultsMost of the women with suspected CMD showed lower performance in processing speed, working memory, executive function, and attention (Figure 1A). We found a significant association between elevated iron levels in paracentral gyrus and lower functional connectivity in left hippocampus (p=0.005, adjusted‐r2=0.19) (Figure 1B). Elevated iron level in the paracentral gyrus showed an impact on cognitive performance in the domains of executive function and attention (p<0.0001, coefficient=531.09) as well as language functions and crystalized abilities (p=0.036, coefficient=362.45), mediated by functional connectivity in the left hippocampus (indirect effect on executive function / language: p = 0.034 / 0.038, coefficient = ‐254.54 /‐ 213.06) (Figure 1C).ConclusionsOur results suggest that changes in hippocampal functional organization are associated with cortical iron deposition and mediate its impact on cognitive performances. These changes may increase the risk of cognitive decline/ADRD or in women with suspected CMD. Future research in a larger cohort with a longitudinal design is necessary to validate and expand upon these findings.

AbstractBackgroundTwo main risk factors of Alzheimer’s disease (AD) are aging and APOE‐ε4. However, some individuals remain cognitively normal despite having these risk factors. They are considered “cognitively resilient”. This study aimed to identify molecular factors that confer cognitive resilience in APOE‐ε4 carriers ≥ 80 years of age and may serve as biomarkers.MethodWe applied weighted gene co‐expression network analysis (WGCNA) to generate consensus co‐expression networks from blood of participants in two antemortem cohorts, the Mayo Clinic Study of Aging (MCSA, n=105), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=91), using RNA‐sequencing and microarray data, respectively. We associated these networks with resilience (resilient vs non‐resilient), cognitive endophenotypes and hippocampal volume. Preservation between consensus networks from blood and those derived from postmortem brain tissues of AD and control donors from AMP‐AD (n=1174) was evaluated. We validated the human findings in four AD mouse models. Finally, machine learning models were utilized to discriminate cases (AD+mild cognitive impairment (MCI)) from controls in MCSA, ADNI and ANMerge antemortem cohorts.ResultFour consensus networks were significantly correlated with a memory phenotype (logical memory delayed recall=LMDR) and hippocampal volume in both MCSA and ADNI. Among these, blood expression module M3 was most preserved with the brain transcriptome. M3 was enriched with NDUF hub genes that are involved in the mitochondrial respiratory chain. Expression levels of M3 and many blood NDUFs had significant associations with better LMDR and hippocampal volume. In brain, NDUFs were upregulated in controls compared to AD, and their expression levels were associated with better global cognition and decreased AD neuropathology. Many NDUFs were significantly downregulated in the hippocampus or cortex of AD mice compared to wild‐types. Lastly, models that included blood NDUFs improved diagnostic accuracy of AD+MCI compared to models that only included demographic and risk variables (age, sex, APOE‐ε4) in MCSA, ADNI and ANMerge. In MCSA and ADNI, adding NDUFs’ expression to models that included established blood biomarkers (Aβ42/40, ptau181, NFL) further improved diagnostic accuracy.ConclusionOur results suggest that mitochondrial NDUFs are centrally‐linked peripheral molecular signatures that may be resilience factors against AD and serve as both therapeutic targets and novel diagnostic biomarkers.

AbstractBackgroundWomen with suspected coronary microvascular dysfunction (CMD) may be at higher risk of experiencing cognitive decline due to cerebral small vessel disease, a known contributor to Alzheimer’s disease and related dementias (ADRD). A potential underlying mechanism that could accelerate this cognitive decline is the accumulation of brain tissue iron, which has been previously linked to changes in brain function potentially caused by oxidative stress and cell death. Therefore, we aim to elucidate whether a similar mechanism could affect women with suspected CMD by investigating the potential role of iron deposition on the brain’s functional organization and its effect on cognition using advanced magnetic resonance imaging (MRI).Material and MethodsTwenty‐seven women with suspected CMD [Age; median (range) = 54 (29‐76)], drawn from ongoing cohorts (3R01HL146158‐04S1,3U54AG065141‐04S1), underwent a 3T MRI protocol, including submillimeter T2* 3‐dimensional echo‐planar‐imaging for assessing iron deposition with high‐resolution quantitative susceptibility mapping (QSM) and resting‐state fMRI (rs‐fMRI). Iron content was quantified by total‐generalized‐variation based QSM analysis. Functional integrity was determined via graph theoretical approach (i.e., nodal degree). Cognitive assessment was also performed using the NIH Toolbox. Mediation analysis was conducted using Python Statsmodels.ResultsMost of the women with suspected CMD showed lower performance in processing speed, working memory, executive function, and attention (Figure‐1A). We found a significant association between elevated iron levels in paracentral gyrus and lower functional connectivity in left hippocampus (p = 0.005, adjusted‐r2 = 0.19) (Figure‐1B). Elevated iron level in the paracentral gyrus showed an impact on cognitive performance in the domains of executive function and attention (p<0.0001, coefficient = 531.09) as well as language functions and crystalized abilities (p = 0.036, coefficient = 362.45), mediated by functional connectivity in the left hippocampus (indirect effect on executive function / language: p = 0.034 / 0.038, coefficient = ‐254.54 /‐ 213.06) (Figure‐1C).ConclusionsOur results suggest that changes in hippocampal functional organization are associated with cortical iron deposition and mediate its impact on cognitive performances. These changes may increase the risk of cognitive decline/ADRD or in women with suspected CMD. Future research in a larger cohort with a longitudinal design is necessary to validate and expand upon these findings.

Abstract BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 (“MORPHO”) was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD–mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.