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Background: Although the embolic stroke of undetermined source (ESUS) construct was proposed as a unifying concept for embolic-appearing strokes without an identified cause, it includes patients with diverse and often unrecognized underlying mechanisms. This study investigates the differential rate of recurrent stroke according to the completeness of neurodiagnostic testing in a diverse multicenter cohort. Methods: This was a retrospective analysis of a multicenter observational cohort study (n=27 sites). Patients with ESUS were categorized into three groups: (1) established mechanism after further work up (ESUS-E), (2) patients who underwent a comprehensive diagnostic workup without an identified etiology (ESUS 2.0), and (3) no advanced workup (ESUS-NAW). The primary outcome of recurrent ischemic stroke was assessed by comparing ESUS 2.0 to both ESUS-E and ESUS-NAW groups using adjusted Cox proportional hazards models. Results: Of the 2,281 patients included, 694 (30%) were classified as ESUS-E, 344 (15%) as ESUS 2.0, and 1,443 (55%) as ESUS-NAW. The ESUS 2.0 group had a significantly lower annualized recurrence rate (1.98 per 100 person-years) compared to both the ESUS-NAW group (7.7 per 100 person-years; aHR 0.27, 95% CI: 0.11–0.62; p=0.002) and the ESUS-E group (6.10 per 100 person-years; aHR = 0.35; 95% CI 0.15–0.85, p=0.020). Within the ESUS-E group, cancer (aHR 5.33; 95% CI: 2.09–13.63; p < 0.001) and non-stenosing atherosclerotic disease or arch atheroma (aHR 3.40; 95% CI: 1.18–9.83; p = 0.023) were associated with significantly increased risk of recurrence when compared to ESUS 2.0. Conclusion: These findings demonstrate a lower risk of recurrent stroke in patients classified as ESUS 2.0, diverging from the 5–6% annual recurrence rates observed in prior ESUS trials. These findings suggest that patients who receive comprehensive diagnostic evaluation without identification of a specific etiology have a lower risk of recurrent stroke, an important consideration for the design of future ESUS studies.

OBJECTIVE The aim of this study was to determine predictors of the minimum clinically important difference (MCID) in the Neck Disability Index (NDI) following cervical spinal deformity surgery. METHODS A retrospective review was performed of a prospective, multicenter adult cervical spinal deformity database. All patients had baseline and 1-year NDI scores. Patients met MCID with an improvement of NDI by 7 points between baseline and 1 year, as previously established. Baseline demographics, comorbidities, and both baseline and 1-year spinopelvic parameters were evaluated for statistical significance in a univariate logistic regression analysis. Significant variables, in addition to baseline NDI, were analyzed in a multivariable logistic regression model by backward selection with Akaike information criterion minimization. RESULTS A total of 122 patients were included with a median age of 62 (IQR 56, 69) years; 62% of patients were female. Of the 122 patients, 72 (59%) achieved NDI MCID at 1 year. Predictors of achieving MCID on univariate analysis included a lower Charlson Comorbidity Index (CCI) total score (OR 0.70, p = 0.03), depression as a comorbidity (OR 2.9, p = 0.02), lower C2 tilt at the 1-year follow-up (OR 0.92, p = 0.02), and a greater difference between 1-year postoperative C2–7 sagittal vertical axis (SVA) and preoperative C2–7 SVA (OR 0.98, p = 0.0495). On multivariable logistic regression analysis, predictors of achieving MCID included a lower CCI (OR 0.62, p = 0.03), depression as a comorbidity (OR 3.1, p = 0.059), a greater change in C2–7 SVA at the 1-year follow-up compared with baseline (OR 0.97, p = 0.055), and baseline NDI (OR 1.02, p = 0.24) with an area under the curve of 0.74. CONCLUSIONS The best-fit multivariable model included higher baseline NDI, a greater change in C2–7 SVA, patient-reported baseline depression, and lower CCI as important factors in predicting NDI MCID.

561 Background: For patients with aHCC, second-line treatment options are not well established. The primary aim of this study was to evaluate the efficacy of Futi, an FGFR 1-4 inhibitor, in combination with Pem as a second line therapy in patients with FGF19-expressing aHCC. Methods: Patients aged ≥ 18 years, with histological/cytological diagnosis or radiological diagnosis of HCC, Child-Pugh (CP) class A-B7, Barcelona Clinic Liver Cancer (BCLC) A, B or C, ECOG performance status of 0-2, and FGF19+, by in-situ hybridization or immunohistochemistry, received Futi 20 mg once daily plus i.v. Pem 200mg every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints include overall survival (OS). The study was designed to enroll 22 evaluable patients to detect PFS6 from 25% (historical control) to 47%, assuming a 1-sided alpha of 0.1 with 80% power. All patients provided written consent. Eligible patients with consent who started treatment are considered evaluable. Results: The study was closed to enrollment early at the request of funding agency due to poor accrual. Between 8/2021 and 3/2024, 14 patients enrolled with 1 patient withdrawing consent before beginning protocol treatment. Among 13 evaluable patients, median age was 72 (range: 60-87) years, 7 (53.8%) were male, 12 CP A (92.3%), 7 BCLC C (53.8%), with 7 (53.8%) having received prior liver directed therapy. Median PFS was 15 weeks (95% confidence interval [CI]: 9.0-Not Estimable) and PFS6 was 23.1% (95% CI: 8.6%, 62.3%). Objective response rate was 0% (95% CI: 0%, 24.71%) and stable disease occurred in 7 (53.9%) of patients. Median OS was 55.7 weeks (95% CI: 47.3-NE). Nine (69.2%) patients experienced at least 1 grade 3+ adverse event (AE), and 2 (15.4%) patients experienced at least a grade 4+ AE. One patient had a grade 5 AE unrelated to study treatment (acute kidney injury). Most commonly reported AEs (occurring in more than 31% of patients) were hyperphosphatemia (76.9%), fatigue (69.3%), diarrhea (61.6%), AST (53.9%) and ALT (46.2%), dry eye (38.5%), nail changes (38.5%), rash-maculo-papular (38.5%), and mucositis oral (38.5%). Conclusions: This prospective study evaluated the use of a targeted treatment in combination with immunotherapy following first line immune-based therapy. This combination had modest activity as a second line therapy for patients with aHCC but did not meet the primary endpoint. The safety profile was acceptable and consistent with prior reports. An optimal second-line regimen remains a critical need. Clinical trial information: NCT04828486 .

Background: There is no consensus scoring system for staging and prognosis in hepatocellular carcinoma (HCC), which is the fourth leading cause of cancer-related mortality worldwide. Commonly used systems include the albumin–bilirubin (ALBI) score, the Barcelona staging classification (Barcelona Clinic Liver Cancer, BCLC), the Model for End-Stage Liver Disease (MELD), and the model to estimate survival in ambulatory HCC patients (MESIAH). Liver secretion of pseudocholinesterase (PCHE) has been linked to liver function but is poorly studied in the natural history of HCC. We evaluated whether serum PCHE level predicts HCC mortality and whether it enhances existing scoring systems. Methods: We conducted a retrospective cohort study of individuals diagnosed with HCC. We collected variables including PCHE level, clinical data used in scoring systems, and time to mortality or liver transplant. We then analyzed the association between these variables and survival using Kaplan–Meier curves, Cox proportional hazards regression models, receiver operating characteristic (ROC) curves, and area under the curve (AUC) calculations. Results: We identified 420 individuals with HCC who were tested for PCHE levels, with a follow-up time of more than 20 years. There was a strong inverse relationship between PCHE level and overall survival, with the lowest quartile having high mortality and poor outcomes. Low PCHE level was associated with hepatitis C virus (HCV) infection, vascular invasion, poor liver function, and a high likelihood of liver transplant. In contrast, the highest quartile was associated with metabolic dysfunction–associated steatotic liver disease (MASLD) as the underlying cause. Compared with validated scoring systems, ALBI, BCLC, MELD 3.0, and MESIAH, the PCHE level was an independent predictor of mortality. PCHE levels could predict 3-month survival as well as or better than the other scoring systems, with an AUC of 0.74. PCHE level could also predict mortality related to hepatectomy. The addition of PCHE level to MESIAH and ALBI scoring systems could further improve the ability to predict overall mortality in HCC. Conclusions: PCHE is a reliable stand-alone biomarker of HCC prognosis. It is an independent predictor of mortality and can improve the accuracy of existing scoring systems. Improved risk stratification could improve outcomes by informing treatment decisions regarding hepatectomy or other interventions.

Abstract Rationale Mucus plugs occur in chronic obstructive pulmonary disease (COPD), but little is known about their size and airway location or whether these mucus plug features change as emphysema worsens. Methods Computed tomographic lung scans from 31 participants with COPD from the SubPopulations and InteRmediate Outcomes In COPD Study (SPIROMICS) cohort were analyzed to quantify mucus plug size and airway location and extent of emphysema. Radiologist annotations of mucus plugs were incorporated in an image processing pipeline to generate size and location information. Emphysema was quantified as the percentage of voxels less than -950 Hounsfield units. Measurements and Main Results The length distribution of 563 annotated mucus plugs varied from 2 to 50 mm. The distribution was multimodal, and an 11-mm length defined short (“stubby,” ≤11 mm) and long (“stringy,” &gt;11 mm) plug phenotypes, with stubby plugs being most common (64%). Mucus plugs localized predominantly to airway generations 6 to 9, and their prevalence was highest in lower lobes. On a lobar basis, the mucus plug number decreased as emphysema percentage increased, whereas average mucus plug volume tended to increase. Conclusion COPD is characterized by mucus plugs of varying size and shape, and emphysematous lung regions may be differentially susceptible to formation of these plugs. The location of mucus plugs in segmental and subsegmental airways in COPD makes them amenable to treatment with inhaled medications or bronchoscopy.

Abstract Background Gastrointestinal (GI) cancer remains a major global health challenge. This study provides updated 2022 estimates of GI cancer incidence and mortality worldwide, along with projections of incident cases and deaths through 2050 to inform cancer control strategies. Methods In this population‐based study, data from the GLOBOCAN 2022 database were used to examine incidence and deaths associated with GI cancer. By using global demographic projections, this study estimated the projected number of incident cases and deaths until the year 2050. Results By 2050, the global burden of GI cancer is projected to reach 9.06 million incident cases (+85%) and 6.42 million deaths (+93%) from 2022. Increases in incidence are projected for both females (+87%) and males (+83%), as are increases in mortality for both females (+97%) and males (+91%). Whereas the Western Pacific region will have the highest absolute burden, with 3.88 million new cases and 2.79 million deaths, the greatest relative increase is expected in Africa, with incidence and deaths rising by 157% and 160%, respectively. As measured by the Human Development Index (HDI), the steepest increases are projected in low (+151% incidence; +152% deaths) and medium (+112% incidence; +114% deaths) HDI countries. Overall, all GI cancer types are projected to increase, led by pancreatic cancer in incidence (+95%) and colorectal cancer in deaths (+103%). Conclusions GI cancer incidence and deaths are expected to nearly double by 2050, with increases across sexes, cancer types, and regions, especially in lower HDI countries.

ABSTRACT Enzalutamide and abiraterone are hormonal treatments that improve survival in metastatic castration‐resistant prostate cancer. Identifying genetic variants associated with the clearance of these drugs may aid in improved dosing and outcomes. We performed genetic association studies of enzalutamide and abiraterone oral clearance in the Alliance A031201 clinical trial. Genome‐wide genotyping was performed with the primary analysis limited to European‐descent participants. Pharmacogene metabolic phenotypes were estimated using PyPGx and Stargazer. Associations of metabolic activity groups for CYP3A4 , CYP3A5 , CYP2C19 and SLCO1B1 with enzalutamide clearance ( N = 706) and CYP3A4 , SLCO2B1 and UGT1A4 with abiraterone clearance ( N = 323) were tested by linear regression. Targeted SNP associations were assessed for abiraterone clearance at loci proximal to major metabolizing genes. Full genome‐wide association studies were performed for both sets of clearance values. No significant associations were identified between metabolic phenotypes and enzalutamide or abiraterone oral clearance SNPs in the SULT2A1 5′ flanking region were significantly associated with lower abiraterone clearance, (rs296373, minor allele frequency = 0.15, β = −0.457, p = 3.2E‐06). Liver protein and liver and adrenal gland gene expression QTL databases indicated significantly lower SULT2A1 expression patterns for individuals carrying associated alleles, likely explaining the lower abiraterone oral clearance. CYP2C8*3 was associated with higher enzalutamide clearance ( p = 0.012), but this was not significant after correction for multiple testing. This study is the first to identify the genetic association of SULT2A1, known to be involved in the metabolism of steroids in the liver and adrenal glands, with abiraterone clearance. Genetic variation in SULT2A1 may be useful to inform personalized dosing of abiraterone. ClinicalTrials.gov Identifier: NCT01949337

Abstract Introduction: The Duffy null variant (genotype or phenotype) is associated with lower circulating absolute neutrophil counts (ANC) without increased risk for infection. It is found in ~66% of people identifying as Black or African American vs &lt;1% of people of Asian or European ancestry. Many ANC reference intervals (RI) are not representative of the Duffy null population. There are no adult Duffy null WBC RI and no pediatric Duffy null ANC or WBC RI. Thus, we aimed to assess Duffy null ANC and WBC distributions as well as develop WBC and ANC RI for adults and pediatrics. Methods: Twenty-three sites across the United States collected samples with all sites excluding participants with conditions or medications that could impact ANC or WBC. Only Duffy null participants were included. Sex, race, ethnicity, age, sample collection type, practice setting, Duffy testing method, ANC, and WBC were recorded. The non-parametric method for determining lower limit of normal (LLN), upper limit of normal (ULN), and 90% confidence intervals (CI) around the limits was performed according to the Clinical and Laboratory Standards Institute guidelines. Specific ULN and LLN are not reported as these are preliminary data. The Mann-Whitney U test was used to compare sex and prior data; differences by age groups were assessed with Kruskal-Wallis test. Results: 316 participants 18+ years-old (y/o) were assessed of whom 62.3% (n=197) are female, 97.5% (n=308) identified as Black or African American, and 94.9% (n=300) identified as non-Hispanic. Median age was 47 y/o (IQR: 32-60.5). Median ANC was 2600/uL (IQR: 1860-3530; range: 400-7400); 28.6% (n=90) of participants had ANC &lt;2000/uL, 13.6% (n=43) had ANC &lt;1500/uL, and 2.5% (n=8) had &lt;1000/uL. The 90% CI around the LLN was 810-1070/uL and 5570-7130/uL around the ULN. Consistent with prior data, there was a difference in median ANC by sex (male: 2400/uL; female: 2710/uL; p=0.02). There was no significant difference between this ANC data and previously published Duffy null ANC data (p=0.28). Median WBC was 5.4x109/L (IQR: 4.4-6.5; range: 2.10-11.64) with 4.1% (n=13) of participants with WBC &lt;3.0x109/L. The 90% CI around the LLN is 3.68-4.30x109/L and 11.02-12.97x109/L around the ULN. 515 participants between 0-17 y/o were assessed with 51.8% (n=267) females, 94.8% (n=488) identified as Black or African American, and 94.0% (n=484) identified as non-Hispanic. Among pediatric participants, 56.8% (n=291) had ANC &lt;2000/uL, 38.7% (n=198) had ANC &lt;1500/uL, and 14.4% (n=74) had ANC &lt;1000/uL. For those &lt;1 y/o (n=29), median ANC was 950/uL (IQR: 840-1360; range: 111-3910). There are currently too few samples to predict ULN and LLN. Median WBC was 8.85x109/L (IQR: 7.03-10.16; range: 4.17-13.53). For those 1-5 y/o (n=143), median ANC was 1735/uL (IQR: 1100-2550; range: 207-5810) with a 90% CI around the LLN of 207-820/uL and 4020-5810/uL around the ULN. Median WBC was 6.72x109/L (IQR: 5.64-8.25; range: 3.68-12.97). For those 6-11 y/o (n=128), median ANC was 1590/uL (IQR: 1090-2470; range: 420-5490) with a 90% CI around the LLN of 420-910/uL and 4340-5490/uL around the ULN. Median WBC was 5.42x109/L (IQR: 4.45-6.70; range: 2.80-10.50). For those 12-17 y/o (n=215), median ANC was 2190/uL (IQR: 1460-2930; range: 204-5850) with a 90% CI around the LLN of 540-930/uL and 4350-5510/uL around the ULN. Median WBC was 5.06x109/L (IQR: 4.26-6.20; range of 2.04-9.91). There is a significant difference in ANC by age category (p&lt;0.0001). Conclusion: This is the first report of healthy pediatric Duffy null ANC and WBC data and the first large-scale verification of adult Duffy null ANC and WBC data. Final RI are expected in September 2025. Among adults with the Duffy null phenotype, ANC LLN are likely between 810-1070/uL. Pediatric ANC LLN are likely as low as 207-820/uL (1-5 y/o), 420-910/uL (6-11 y/o), and 540-930/uL (12-17 y/o). These findings redefine “normal” as a significant proportion of healthy participants have ANC or WBC below current RI or below thresholds typically defined as disease. Limitations include heterogeneous sample populations and collection methods. Future analyses will assess differences between collection sites or methods. Ultimately, this work lays the foundation for a more scientifically sound and equitable approach to medical care by ensuring that RI accurately reflects health for the entire community. Healthcare systems are strongly encouraged to adopt Duffy null-specific ANC and WBC RI.