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Background: Real-time intraoperative discrimination of malignant tissue during pediatric solid tumor resection is limited, constraining margin optimization; the utility of indocyanine green (ICG) fluorescence in this population remains incompletely defined. Study Design: Prospective, observational, multi-institutional study (2019–2023) of pediatric, adolescent, and young adult patients undergoing resection of intra-abdominal solid malignancies following preoperative ICG administration. The primary endpoint was diagnostic accuracy of ICG fluorescence for tumor-containing specimens; secondary endpoints included association with margin status and surgeon-perceived intraoperative benefit. Results: Forty-three operations in 42 patients yielded 55 specimens, of which 47 (85%) were malignant. Diagnostic performance was highest in hepatic tumors (sensitivity 83%, positive predictive value 83%) and lower in adrenal and heterogeneous tumor types. ICG avidity was not associated with improved negative margin rates (86% vs 75%, p=0.47). Surgeons reported intraoperative benefit in 67% of cases, most commonly improved visualization. No ICG-related adverse events occurred. Conclusions: ICG fluorescence provides reliable tumor identification in hepatic malignancies but does not correlate with margin-negative resection, indicating limited utility for margin guidance. These data support tumor-specific application and further investigation of optimized fluorescence strategies, including dosing, timing, and alternative fluorophores, in pediatric oncologic surgery.

BACKGROUND: Cardiac computed tomography (CT) acquired during the acute stroke imaging protocol is an emerging modality to detect cardiac thrombi. We determined its yield in patients with acute ischemic stroke. METHODS: We performed a 1-stage individual patient data meta-analysis of 4 prospective observational cohorts (AIS of HEARTS [Acute Ischemic Stroke of Heart-Related Embolic Sources Detected on Acute Cardiac CT Scans]), including patients with acute ischemic stroke who underwent ECG-gated or non–ECG-gated cardiac CT between May 2018 and June 2024. We excluded patients with transient ischemic attack or stroke mimics. The primary outcome was the proportion of patients with a thrombus on cardiac CT. Secondary outcomes were additional scan time, radiation dose, comparison with echocardiography, and 90-day outcomes. We performed logistic regression analyses to compare 90-day outcomes between patients with and without thrombus, adjusting for age, sex, history of atrial fibrillation, ischemic heart disease, chronic heart failure, stroke or transient ischemic attack, anticoagulant use, prestroke modified Rankin Scale score, National Institutes of Health Stroke Scale score, large vessel occlusions, and intravenous thrombolysis, as appropriate for each outcome. RESULTS: We included 3919 patients (median age, 74 [interquartile range (IQR), 63–82], 58% male, median National Institutes of Health Stroke Scale score 6 [IQR, 3–12]). Cardiac CT detected a thrombus in 243 (6.2%) patients. Among 1323 patients that underwent both cardiac CT and transthoracic echocardiography, cardiac CT had a higher yield than transthoracic echocardiography (odds ratio, 7.4 [95% CI, 4.0–15.1]; P <0.001). Median additional scan time was 6 minutes (IQR, 5–7) for ECG-gated and 13 seconds (IQR, 12–61) for non–ECG-gated cardiac CT. Median additional radiation dose was 2.9 mSv (IQR, 1.6–4.1). Patients with thrombi had higher 90-day mortality (33% versus 15%, adjusted odds ratio, 1.6 [95% CI, 1.1–2.3]) and worse modified Rankin Scale scores (median modified Rankin Scale score 3 versus 2, adjusted odds ratio, 1.6 [95% CI, 1.2–2.0]), but similar recurrent stroke rates (5% versus 4%, adjusted odds ratio, 1.4 [95% CI, 0.7–2.5]). CONCLUSIONS: Implementing cardiac CT into the acute stroke imaging protocol is feasible, detects thrombi in ≈6% of patients, and has a higher yield than transthoracic echocardiography. Cardiac thrombi were associated with higher mortality, but not higher stroke recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT07165093.

Abstract Darier disease (DD) is a rare autosomal dominant genodermatosis. This comprehensive review, developed by the Darier Disease International Task Force (DDITF), consolidates current knowledge on the genetic basis, molecular pathophysiology, clinical presentation, diagnosis and management of DD, offering a global perspective that unites shared expertise. The disease arises from pathogenic variants in the ATP2A2 gene, which encodes sarco/endoplasmic reticulum Ca 2+ ‐ATPase isoform 2 (SERCA2), leading to disrupted calcium homeostasis and impaired desmosomal integrity. Clinically, DD is classified based on lesion type (classic vs. non‐classic) and is often accompanied by significant extracutaneous manifestations. Management remains challenging and requires a multifaceted approach, including topical therapies, systemic retinoids and lifestyle modifications. Emerging treatments that target the underlying molecular mechanisms offer promise for improved outcomes. This review aims to provide an updated reference and practical guidance for clinicians involved in the care and study of DD.

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

Abstract Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45–74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45–74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen’s d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen’s d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P &lt; 0.00001) and an earlier age of first exposure to tackle football (P &lt; 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P &lt; 0.04) and rotational force (P &lt; 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

TPS8124 Background: Immune checkpoint inhibitor (ICI)–based regimens are standard first-line therapy for metastatic non–small-cell lung cancer (NSCLC) without actionable driver mutations; however, most patients experience disease progression within 12 months. A subset develop oligoprogression, defined by progression at a limited number of metastatic sites with otherwise controlled disease. Oligoprogression represents a therapeutic window in which local ablative therapy could be used to prolong disease control. In the prior phase II CURB trial, SBRT was shown to significantly prolong progression-free survival (PFS) in patients with oligoprogressive NSCLC. Methods: CCTG-BR38 is an international, multicenter, open-label, randomized phase III trial conducted through the NCI National Clinical Trials Network. Adults with stage IV NSCLC receiving first-line ICI ± chemotherapy who develop ≤5 extracranial oligoprogressive lesions are randomized 1:1 to: (1) switch to second-line standard systemic therapy or (2) SBRT (30 Gy in 3 fractions) to all oligoprogressive sites followed by continuation of the same first-line systemic therapy. Randomization is stratified by type of first-line systemic therapy (ICI alone vs ICI + chemotherapy), number of oligoprogressive lesions (1–2 vs 3–5), and ECOG performance status (0-1 vs 2). Patients with treated, stable brain metastases are eligible. Primary Endpoints: Dual primary endpoints are PFS and overall survival (OS). Secondary endpoints include safety (CTCAE v5.0), patient-reported adverse events (PRO-CTCAE), quality of life (EORTC QLQ-C30/LC13), and cost-effectiveness (EQ-5D-5L; Canadian sites). Optional blood and tissue collection for exploratory biomarker analyses are planned. Statistical Considerations: A total of 320 patients (160 per arm) will be enrolled. The sample size is based on detecting a HR of 0.7 for OS (an improvement in median OS from 10 to 14.3 months) with 80% power using a 1-sided 2% level test (the overall 1-sided 2.5% type I error will be assigned 2% to OS and 0.5% to PFS). Interim analyses for futility and efficacy are planned. Current Status: The trial was centrally activated on April 3, 2025. Accrual is ongoing across Canadian and US NCTN sites. Clinical trial information: NCT06686771 .

TPS3678 Background: Advanced and metastatic colorectal cancer (CRC) remains an area of significant unmet clinical need, particularly for patients with MSS/MSI-L tumors. In recent years, there have been several advancements in the treatment of solid tumors with T cell engagers. Our ATLAS scRNA-seq based discovery platform identified LY6G6D as a highly-specific tumor-associated antigen in advanced and metastatic CRC. CBI-1214, a CD3 bispecific T cell engager targeting LY6G6D with potent in vitro and in vivo activity even at low LY6G6D expression levels of ~300 copies/cell ( Yigit B et al, AACR 2025 ), is being developed for the treatment of patients with advanced or metastatic MSS/MSI-L CRC. Methods: This ongoing, open-label FIH study (CBI-1214-001) is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of CBI-1214 and to determine the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) in participants with advanced or metastatic MSS/MSI-L CRC who have exhausted at least one prior line of systemic treatment and do not qualify for available targeted treatment options for actionable genomic alterations. Additional eligibility criteria include: at least 18 years of age, measurable disease (as defined by RECIST v1.1), available archival tumor tissue sample or a fresh tumor sample, ECOG PS 0 or 1, as well as adequate hematologic and organ functions. Patients whose CRC tumor tissues have been identified as dMMR or MSI-H are excluded. The study is conducted in two parts: Part 1 dose escalation, which starts with Part 1a as accelerated dose escalation, followed by Part 1b escalation, which is based on a modified toxicity probability interval (mTPI-2) design, and Part 2, which is designed as a randomized dose optimization study to select the final recommended phase 2 dose (RP2D). For both parts of the study, the study intervention is administered as monotherapy, given as an intravenous (IV) infusion, in 21-day treatment cycles, with a step-up option. After an up-to-28-day screening period, eligible patients receive study medication and are followed for their entire treatment period plus a follow-up period of approximately 90 days. The study is open for recruitment in the United States (NCT07321106). Clinical trial information: NCT07321106 .

e20761 Background: The prognostic role of serial circulating tumor DNA (ctDNA) dynamics during osimertinib treatment has been described mainly in Asian and European populations; however, it remains poorly defined in Hispanic patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC). Our aim was to determine whether serial plasma EGFR testing identifies patients at high risk of early mortality. Methods: This multicenter, retrospective study included 64 Hispanic patients with stage IIIB–IV EGFR-mutant NSCLC treated with first-line osimertinib between 2018 and 2023. Tumor tissue genotyping was performed using hybrid-capture next-generation sequencing. Plasma EGFR mutations were assessed at baseline, week 8, and week 24. Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox models adjusted for p53 status, RAF-pathway alterations, and metastatic burden. Results: The cohort had a median age of 61 years, with 65.6% of patients being female and 56.2% being never-smokers. Sensitizing EGFR mutations consisted mainly of exon 19 deletion (59.4%) and L858R (39.1%). Relevant co-mutations were identified in TP53 (29.7%) and RAF-pathway genes (6.2%). Plasma ctDNA remained positive in 42.2% of patients at week 8 and 22.0% at week 24. Week-8 ctDNA persistence was strongly associated with an inferior OS (HR 9.36, 95% CI 3.80–23.03, p < 0.001) after multivariable adjustment. Week-24 positivity also predicted worse OS (HR 3.34, 95% CI 1.13–9.89, p = 0.02). ctDNA status at week 8 or 24 was not significantly associated with PFS. Patients with TP53 or RAF pathway mutations demonstrated higher rates of molecular persistence. Conclusions: In Hispanic patients receiving Osimertinib, ctDNA positivity at 8-24 weeks is able to identify patients with poor survival outcomes. ctDNA monitoring may provide an early, non-invasive biomarker to guide treatment intensification and trial enrollment in EGFR-mutant NSCLC.

e19503 Background: The anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) belantamab mafodotin is approved in the USA and EU for relapsed/refractory multiple myeloma (RRMM). Understanding treatment options and patient outcomes following ADC failure is clinically important. This study describes post-ADC treatment patterns and clinical outcomes in real-world patients with RRMM. Methods: Adult patients with MM who received an ADC and initiated ≥1 subsequent line of therapy (LOT) were included. The index date was the start of the first post-ADC LOT. Data were obtained from chart reviews at International Myeloma Foundation International Myeloma Working Group (IMF IMWG) academic sites, and US electronic health records from largely community sites (COTA and Guardian Research Network [GRN]). Patient characteristics and index regimens were summarized descriptively. Time to next treatment (TTNT) and overall survival (OS) were estimated with the Kaplan-Meier estimator. Results: The IMF IMWG cohort (n=40) had a mean age of 70.8 years, median of 7 prior LOTs and 82.5% were triple-class refractory (TCR). Overall, 85% received ADC monotherapy (70% belantamab mafodotin) and 15% combination therapy. Pre-ADC and not considering corticosteroids, patients were commonly exposed to lenalidomide (R; 100%), bortezomib (V; 92.5%), daratumumab (D) and pomalidomide (P; 90% each). Over a median follow-up of 26 months after index date, 29 unique index post-ADC regimens were reported, frequently selinexor (27.5%) and bispecific antibodies (15%). CAR T-cell therapy was administered to 5%, with 60% re-treated with a pre-ADC drug class (PI/IMiD/anti-CD38) after ADC. Median (95% CI) TTNT and OS were 10.8 (7.0–20.6) and 19.0 (13.4–25.1) months, respectively. The COTA-GRN cohort (n=39) had a mean age of 67.5 years, median of 8 prior LOTs, and 51.3% were TCR. Overall, 56% received ADC monotherapy (belantamab mafodotin) and 44% combination therapy. Pre-ADC and not considering corticosteroids, patients were commonly exposed to D and R (97.4% each), and carfilzomib, V and P (94.9% each). Over a median follow-up of 9.2 months, 32 unique index post-ADC regimens were reported, frequently selinexor (23.1%) and venetoclax (17.9%) based; 0% received CAR Ts and 54% were re-treated with a pre-ADC drug class (PI/IMiD/anti-CD38) after ADC. Median (95% CI) TTNT and OS were 4.9 (2.8–non-estimable [NE]) and 12.0 (4.9–NE) months, respectively. Conclusions: Findings highlight that most patients with heavily pretreated BCMA-ADC exposed MM were re-treated with similar classes. Academic centers used novel therapies (ie, CAR T, bispecific antibodies) more often and their patients had longer survival than those treated at community sites. However, clinical outcomes remained sub-optimal, emphasizing the unmet need for effective, accessible post-ADC treatments.

e16535 Background: RMC is a rare and highly aggressive malignancy that predominantly affects young individuals with sickle hemoglobinopathies. Due to its rarity, no validated prognostic models exist to guide clinical decision-making. We aimed to develop and internally validate a prognostic model for patients with RMC using routinely available clinical and laboratory variables. Methods: We analyzed a single-institution cohort of patients with RMC. Candidate variables were identified based on biological plausibility and represented in a directed acyclic graph. Missing data were handled via multiple imputation by chained equations ( m = 50). Variables were ranked using elastic net Cox regression ( α = 0.5, λ = λ min ) with stability selection derived from 100 bootstrap resamples per imputed dataset. Predictors achieving > 60% selection frequency were retained for a nested parsimony analysis. Bootstrap internal validation ( B = 2000) estimated optimism-corrected discrimination and calibration performance, with the calibration slope applied as global shrinkage to penalize final coefficients for overfitting. Clinical utility was evaluated via decision curve analysis (DCA) at 18- and 24-month horizons. Results: Among 180 patients (median age 29; IQR 23–37), 142 deaths occurred with a median follow-up of 12.4 months. The final model included four predictors (Table). The optimism-corrected c-index was 0.667 (optimism = 0.009), and the calibration slope was 0.964, indicating minimal overfitting. Calibration plots showed excellent predicted-observed agreement at 12, 18, 24, and 36 months. DCA showed net benefit across threshold probabilities of 10%–75% at 18 months and 10%–80% at 24 months compared to default strategies. In sensitivity analysis, inclusion of TP53 mutation status improved discrimination ( c -index 0.686) and model fit ( ΔAIC −10.6). An interactive web-based risk calculator was developed to facilitate clinical implementation. Conclusions: This study presents the first internally validated prognostic model for RMC, demonstrating acceptable discrimination and excellent calibration using routinely available variables. By stratifying patients into distinct risk groups, this model may inform treatment intensity—guiding escalation to multi-agent regimens or sequential chemotherapy cycling in high-risk patients, while identifying lower-risk patients who may benefit from de-escalation strategies such as metastasis-directed therapy for oligometastatic disease or consideration of cytoreductive nephrectomy. External validation is warranted. Variable Time Ratio 95% CI p value ECOG performance status 0.64 0.53–0.77 <0.001 Distal (non-retroperitoneal) lymph node metastases 0.69 0.52–0.92 0.011 Neutrophil-to-lymphocyte ratio 0.98 0.94–1.02 0.25 Corrected calcium (mg/dL) 0.77 0.56–1.06 0.10 Sensitivity Analysis Only TP53 Mutation 0.63 0.36-1-10 0.10