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Phase 1a study results for IMA203CD8, a PRAME-directed T-cell receptor (TCR) T-cell therapy, in ovarian cancer.

5509 Background: Pts with advanced ovarian cancer (OC) that progresses after platinum-based chemotherapy and subsequent treatment are lacking therapeutic options for durable clinical benefit. TCR T-cell therapies enable immune recognition of intracellular tumor antigens presented by HLA, expanding the therapeutic landscape beyond targets accessible to conventional immunotherapies. PRAME is a cancer-associated antigen expressed across >50 cancers, including OC. IMA203CD8 is a TCR T-cell therapy that engineers CD8+ and CD4+ T cells to detect and destroy PRAME-expressing tumor cells that evade conventional therapeutic approaches. Results from a phase 1a basket trial (NCT03686124) indicated the potential to target several PRAME+ tumors. Here we present updated dose-escalation results for the subset of pts with OC. Methods: Pts were ≥18 y, HLA-A*02:01+, had R/R solid tumors, measurable disease (RECIST 1.1), ECOG PS 0-1, and had exhausted SOC options, including platinum therapy. Following leukapheresis and IMA203CD8 manufacture, pts underwent lymphodepletion (LD) with Cy (500 mg/m 2 × 4 d) and Flu (30 mg/m 2 × 4 d), followed by IMA203CD8 infusion +/- low-dose SUBQ IL-2. Dose escalation is ongoing. Results: As of Oct 27, 2025, 16 heavily pretreated pts with OC were infused with IMA203CD8. Most common TEAEs were LD-related cytopenias (100%). Cytokine release syndrome occurred in 100% of pts and was mostly mild to moderate (G1: 44%, G2: 50%, G3: 6%). Immune effector cell–associated neurotoxicity syndrome occurred in 1 pt (G1: 6%). Tolerability in pts with OC was generally consistent with the known IMA203CD8 safety profile. Eleven pts were efficacy evaluable with ≥1 post-baseline scan (median 4 prior lines of therapy) after treatment with IMA203CD8 across escalating dose levels (median: 2.26×10 9 total TCR T cells; range: 1.4-7.1×10 9 TCR T cells). Tumor reduction was observed in 7 pts with maximum reduction of 74%; 3 responses were >6 mo and durable disease control occurred for up to 12 mo. A dose-dependent signal of activity was observed in pts treated at higher doses (n=5; range: 2.3-7.1×10⁹ TCR T cells), including 2 confirmed partial responses (PRs) with 1 ongoing metabolic complete response (CRs) at 6 mo, and 1 unconfirmed PR. All responses were observed in pts without post-infusion low-dose IL-2. Updated results from ≥20 efficacy-evaluable pts (including several unconfirmed PRs and CRs after data cutoff) with longer follow-up will be presented. Conclusions: In pts with metastatic and/or relapsed OC, IMA203CD8 demonstrated a tolerability profile consistent with prior experience in other solid tumors and encouraging dose-dependent antitumor activity, including durable objective responses according to RECIST. Dose escalation with and without IL-2 at higher doses is currently ongoing to determine RP2D and unlock the full potential of IMA203CD8 in OC. Clinical trial information: NCT03686124 .

Insights from initial scoring in the Health Equity Report Card (HERC) pilot in community oncology settings.

11094 Background: The Health Equity Report Card (HERC) is an innovative tool designed to assess and promote equity in cancer care. Standardized scoring is performed in four domains: Community Engagement, Accessibility of Care and Social Determinants of Health, Addressing Bias in Care Delivery, and Quality and Comprehensiveness of Care. Initial scoring is reported. Methods: Five diverse community oncology sites were recruited to evaluate the HERC's feasibility and usability in this setting. The primary objective is to evaluate the feasibility of implementing the HERC with scoring at community oncology sites. Key metrics include the ability to collect HERC data and complete self- and third-party scores. Baseline scores were calculated using data from prior six months. Quantitative and qualitative feedback was collected via surveys and semi-structured interviews. Results were summarized using descriptive statistics. This study was granted Institutional Review Board exemption by Pearl IRB and sites received funding support. Results: All sites completed self- and third-party scores (Table 1). Average self-scores and third-party scores were similar, with third party scores slightly lower across all domains. There was a wide range in scores across all domains. All sites felt the HERC was easy to understand. Sites requested clarification on four measures and expect the final round of scoring to be easier and faster. 4/5 sites stated collecting sources of evidence was feasible. Key challenges included: a lack of formal documentation and processes not implemented consistently across the practice. Best practices included: 5/5 used tracking logs, 5/5 used a team approach, and 4/5 utilized provided materials to orient staff to the project. All sites stated the HERC was a helpful resource for community practices, was useful to learn about health equity initiatives across the site, and was helpful to identify or prioritize quality improvement projects. All sites felt the HERC would inform changes to site processes and plan to identify improvement strategies based on their baseline scores. Conclusions: Initial implementation of the HERC in community oncology practices was feasible with completion of scoring across all practices. Score variation across sites and domains highlight differences in resources, documentation, and practice. Sites confirmed the HERC is a helpful resource and catalyst for quality improvement. The project remains ongoing. The HERC is a promising tool to foster equitable care delivery for all cancer patients. Summary statistics of baseline self- and third-party scores. Domain Max Score Self-Score Third-Party Score Mean SD Range (Max-Min) Mean SD Range (Max-Min) Community Engagement 4 3 1.1 3 (1-4) 2.2 1.5 4 (0-4) Accessibility 6 3.9 1.7 4.5 (1-5.5) 3.7 1.5 4.5 (1-5.5) Bias 5 1.9 1.3 3 (0.5-3.5) 1.5 1.2 3.5 (0-3.5) Quality of Care 4 2.6 1.7 4 (0-4) 2.4 1.6 4 (0-4)

Overall survival after stereotactic radiosurgery for brain metastases in renal cell carcinoma: A contemporary real-world analysis.

e16598 Background: Brain metastases occur in a substantial proportion of patients with renal cell carcinoma (RCC) and are associated with poor prognosis. Stereotactic radiosurgery (SRS) is frequently used for intracranial disease control; however, contemporary real-world survival outcomes and the influence of systemic therapy exposure and metastatic burden remain incompletely characterized. Methods: We conducted a retrospective observational study using the TriNetX global federated health research network. Adult patients (≥18 years) with RCC and documented brain metastases who underwent stereotactic radiosurgery between January 2013 and December 2023 were identified. The index date was defined as the date of first SRS. Baseline demographics, comorbidities, and prior systemic therapy exposure including immune checkpoint inhibitors and VEGF-targeted therapies within 6 months before SRS were assessed. Metastatic burden was approximated using the number of distinct extracranial metastatic organ sites (single-organ vs multi-organ involvement). Overall survival (OS) was evaluated using Kaplan–Meier methods. Results: A total of 232 patients with RCC and brain metastases treated with SRS were included. Mean age was 61.2 ± 10.6 years, and 72% were male. Common comorbidities included hypertension (53%), diabetes mellitus (30%), chronic kidney disease (28%), and cerebrovascular disease (26%). Prior to SRS, 78% of patients received systemic therapy, including immune checkpoint inhibitors (49%) and VEGF-targeted therapies (46%). Using organ-site count as a proxy for disease burden, 59% demonstrated single-organ extracranial metastatic involvement. During follow-up, 95 patients (40.9%) experienced all-cause mortality. Median overall survival was 967 days (31.8 months). Estimated long-term survival probability at maximum follow-up was 21.2%. Kaplan–Meier analysis demonstrated early survival attrition followed by prolonged survival in a subset of patients. Patients receiving immunotherapy and those with limited extracranial metastatic burden demonstrated more favorable survival patterns. Conclusions: In this large contemporary real-world cohort of RCC patients with brain metastases treated with stereotactic radiosurgery, median overall survival exceeded 2.5 years, providing important modern survival benchmarks. Favorable outcomes were observed among patients receiving systemic immunotherapy and those with limited metastatic burden, supporting the continued role of SRS within multidisciplinary management strategies for selected patients with metastatic RCC.

Arterial and venous thromboembolic events in <i>ALK</i> - and <i>ROS1</i> -positive non–small cell lung cancer (NSCLC): A multicenter real-world analysis.

e23419 Background: Current risk assessment for cancer-associated thrombosis remain suboptimal in NSCLC, likely due to unaccounted tumor-specific biology. Although ALK and ROS1-positive NSCLC share closely related structure and elevated thrombotic risk, real-world data on thromboembolic outcomes remain limited. Methods: This multicenter retrospective study was conducted using TriNetX, a global federated health research network;14 of 113 healthcare organizations contributed to analysis. Adults (≥18 years) with NSCLC ROS1 or ALK from 2012-2025 were included. Index event was defined as the first documented NSCLC diagnosis. Outcomes included cumulative incidence, Kaplan–Meier survival analysis (KMS), and event recurrence for arterial thromboembolism (ATE), deep vein thrombosis (DVT), and pulmonary embolism (PE). Analyses were conducted pre and post-propensity score matching (PSM) adjusted for age and sex. Subgroup analyses evaluated outcomes at 1, 3, 6, and ≥12 months. Results: 3,310 NSCLC patients were identified (ALK n=3,155; ROS1 n=155). Mean age was 73 years, with 52.8% female and 46.2% male; 72.5% White, 12.7% Black, 9.5% Asian; South (49%), Northeast (29%). ALK NSCLC were older than those with ROS1 (mean 68.9 vs 64.6 years, p&lt;0.0001), with similar sex distribution. ROS1 had higher proportion of White (85% vs 72%), while ALK included more Asian and Black. Median follow-up prior to matching was 482 days for ROS1 (post-PSM:482) and 546 days for ALK (post-PSM:601) Incidence proportions in ROS1 NSCLC were 12.3% for ATE, 9.7% for DVT, and 12.9% for PE (vs. ALK: 22.6% for ATE, 12.5% for DVT, 11.8% for PE) For ATE, prior to PSM, ROS1 NSCLC demonstrated a significantly lower risk compared with ALK (16.6% vs 25.0%), with an absolute risk difference of −8.4% (95% CI −14.7 to −2.2; p=0.02) and relative risk of 0.66 (95% CI 0.46–0.96). KMS showed longer ATE-free survival in ROS1 compared to ALK (48.2% vs 44.5%, p=0.01; HR 0.60, 95% CI 0.40–0.91, p=0.04). After PSM, overall ATE risk difference did not reach statistical significance, although ROS1 continued to demonstrate lower risk (16.6% vs 25.8%; risk difference −9.2%, p=0.06). Notably, in the subgroup analyses, this significant risk difference emerged ≥12 months, with improved late ATE-free survival in ROS1(91.1% vs 80.3%, p=0.01). For VTE and PE, no significant differences in risk, survival analyses or recurrence, were observed between ROS1 and ALK before or after PSM (DVT risk: 9.2% vs 9.7% pre-PSM; 9.2% vs 10.1% post-PSM; PE: 11.2% vs 9.9% pre-PSM; 11.2% vs 8.6% post-PSM; all p&gt;0.05). Conclusions: Arterial thromboembolism differed by oncogenic subtype, with higher ATE risk in ALK compared with ROS1-positive NSCLC, particularly ≥12-months. In contrast, no significant difference in venous thromboembolism and pulmonary embolism were observed; further validation in prospective studies is warranted.

Response to venetoclax-containing regimens in patients with relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL).

e18528 Background: Patients (pts) with R/R T-ALL/LBL have poor outcomes with limited approved therapies available to them. Early-phase studies of venetoclax (ven)-based regimens in R/R T-ALL/LBL have shown promising efficacy (Short et al, Blood Adv 2024; Pullarkat et al, Cancer Discov 2021; Cao et al, Lancet Haematol 2025). Given these data, we aimed to characterize the outcomes of pts with R/R T-ALL/LBL treated with ven-based regimens at our institution. Methods: A retrospective review of 19 pts with R/R T-cell disease (13 ALL, 6 LBL) treated with ven-based regimens at the University of Chicago was performed. Five pts had Early T-cell Precursor (ETP) phenotype. Molecular risk stratification was applied using Simonin et al, Blood 2024. The most recent molecular data prior to ven treatment were utilized if available. Response was assessed via European LeukemiaNet (ELN) 2024 criteria. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: The median age at diagnosis was 34.9 years (range 19-74), and 74% of pts were male. In pts with molecular data (n=16), 75% had adverse-risk mutations, while 25% had favorable-risk mutations. The pts were heavily pre-treated prior to ven-based therapy for R/R disease, with 68% receiving ≥ 3 lines of therapy and 42% previously receiving an allogeneic hematopoietic stem cell transplant (allo-HCT). The ven-based regimens utilized are summarized in Table 1. The most common regimens were ven + hypomethylating agent (36.9%), ven + chemotherapy (15.8%), and ven + navitoclax (15.8%). In response to ven-based regimens, 10.5% had a complete remission (CR), 21% had a CR with incomplete count recovery (CRi), 5% had a partial response (PR), and 63.5% had no response or were not evaluable. The CR/CRi rate was 41.6% in those with prior nelarabine exposure (n=12), 0% in those with prior ven exposure (n=3), 31% in those with prior asparaginase exposure (n=13), and 50% in those with prior allo-HCT (n=8). Of the 5 ETP pts, 2 (40%) achieved CR/CRi. Median OS from the time of ven was 6.3 months, 95% CI (3.1 – N/A); 21% of pts proceeded to allo-HCT after ven-based therapy. At the time of data cut-off, 4 patients were alive. Conclusions: In this cohort of R/R T-ALL/LBL patients, responses to ven-based regimens were modest compared to recently reported prospective trials. Especially given the investigation of venetoclax-based therapies in the frontline treatment of T-ALL/LBL, additional novel therapeutic approaches will need to be explored in the R/R setting. Ven-based regimens utilized for R/R T-ALL/LBL (n = 19). Ven monotherapy 2 (10.5%) Ven + hypomethylating agent 7 (36.9%) Ven + chemotherapy 3 (15.8%) Ven + nelarabine 2 (10.5%) Ven + targeted agent 2 (10.5%) Ven + navitoclax 3 (15.8%)

Neutrophil counts as a prognostic biomarker following breast cancer surgery: Insights from a Mayo Clinic platform study.

e12691 Background: Breast cancer prognosis is influenced not only by tumor-specific factors but also by systemic inflammatory responses. Elevated circulating neutrophils after surgery may reflect one such systemic inflammatory response that promotes a pro-tumorigenic environment. Neutrophil extracellular traps (NETs) have been recognized as promoters of cancer activity. However, there have been no studies looking at neutrophil count alone as an independent inflammatory marker in cancer. Clinical prognostic significance of post-operative neutrophil counts remains incompletely understood. If proven significant, neutrophil count is a simple, widely available measure to predict post-operative outcomes in patients with breast cancer. Methods: Data from the Mayo Clinic Platform were retrospectively analyzed, including only breast cancer patients with normal BMI and neutrophil counts recorded within one week after breast surgery. Patients who underwent radical mastectomy were excluded. Patients were stratified into two groups based on neutrophil count: high (&gt;7×10⁹/L) and normal (1.7–7×10⁹/L). Clinical outcomes assessed included age distribution and 5-year overall survival. Age differences were evaluated using Cohen’s D, and Kaplan-Meier survival curves and hazard ratio estimation were performed using the Mayo Clinic Platform's tool. Results: A total of 899 patients were included in the study cohort: 303 in the high neutrophil group (Cohort A) and 596 in the normal neutrophil group (Cohort B). Age distributions were comparable between groups (Cohort A mean 59.2 ± 13.1 years; Cohort B mean 59.1 ± 14.3 years; Cohen's d = 0.0079). High neutrophil counts were significantly associated with reduced 5-year survival (77.8% vs. 84.5%) and an increased risk of mortality (HR 1.63; 95% CI: 1.16–2.29; P = 0.0041). Conclusions: Recent literature supports that surgery-induced NET formation may drive metastatic progression. Findings from this retrospective analysis at Mayo Clinic suggest that elevated neutrophil counts after breast cancer surgery are associated with poorer survival and may reflect systemic inflammation. While markers like NLR and NPAR have prognostic value, neutrophil count alone is a practical, accessible biomarker for clinical use. Limitations of this study include potential confounding factors such as lifestyle and comorbidities, and lack of subgroup analysis by breast cancer type, stage, and other treatments in addition to surgery. Further prospective studies are still needed for validation. Five-year survival rate comparison. Statistic High Neutrophil counts Normal Neutrophil counts Patient Count 303 596 1 Month Survival 99% 99.8% 5 Month Survival 97% 99.3% 10 Month Survival 94.4% 97.3% 30 Month Survival 85.4% 91.9% 60 Month Survival 77.8% 84.5% Hazard Ratio* 1.63 (95% CI: 1.16–2.29) P = 0.0041.

Phase I study of BL-M05D1, a novel Claudin18.2-directed antibody-drug conjugate (ADC), in patients with locally advanced or metastatic Claudin18.2–expressing solid tumors.

3030 Background: BL-M05D1 is a novel Claudin18.2-directed ADC with a potent topoisomerase I inhibitor Ed-04. Results for safety and efficacy data from a phase I study on BL-M05D1 in patients (pts) with locally advanced or metastatic (LA/M) Claudin18.2-expressing solid tumors are presented. Methods: Pts who had LA/M solid tumors enrolled in dose escalation and dose expansion phase, and treated with BL-M05D1 at 0.66, 2.0, 3.0, 4.0 or 5.0mg/kg on Day 1 every 3 weeks (D1 Q3W). Gastric cancer/gastroesophageal junction cancer (GC/GEJ), biliary tract cancer (BTC), and pancreatic cancer (PanC) patients with Claudin18.2-expressing enrolled in dose expansion phase were treated at 2.0, 3.0 or 4.0mg/kg D1 Q3W. Results: As of Nov 30, 2025, a total of 245 pts were enrolled (87 GC/GEJ, 53 BTC, 104 PanC) and 1 other). The most frequent grade≥3 TRAEs were all hematological, including thrombocytopenia (33.9%), neutropenia (32.7%), leukopenia (31.8%) and anemia (14.3%); non-hematologic TRAEs were relatively low. One pt at 5.0mg/kg group experienced grade 3 febrile neutropenia as a DLT. No treatment-related deaths or ILD were reported. In PanC, BL-M05D1 has demonstrated a promising efficacy with an ORR of 35.7% and mPFS of 5.6 mo at 4.0mg/kg in CLDN18.2-positive pts; in the second line pts, ORR was 50.0% with a mPFS of 5.7 mo. Furthermore, BL-M05D1 has shown promising efficacies in CLDN18.2-positive GC and BTC with an ORR of 39.2% and 37.9%, and mPFS of 5.4 mo and 5.9 mo, respectively, at 4.0mg/kg. Efficacy results are summarized below. Conclusions: BL-M05D1 has demonstrated a promising antitumor activity with a tolerable safety profile in pts with pretreated Claudin18.2-positive PanC, GC, and BTC. 4.0mg/kg D1 Q3W was chosen as RP2D. The data support further development of BL-M05D1 in Claudin18.2-positive PanC, GC, and BTC. Phase III studies are in preparation. Clinical trial information: NCT06349811 . PanC-Total * PanC CLDN 18.2 + # 4.0 mg/kg PanC CLDN 18.2 + # 1 Prior Chemo in 4.0mg/kg GC-Total * GC CLDN 18.2 + # 4.0 mg/kg GC CLDN 18.2 + # 1 Prior Chemo in 4.0 mg/kg BTC-Total * BTC CLDN 18.2 + # 4.0 mg/kg BTC CLDN 18.2 + # 1 Prior Chemo in 4.0 mg/kg N = 81 N = 28 N = 16 N = 79 N = 51 N = 29 N = 40 N = 29 N = 20 Median prior LoT (range) 2 (1-4) 2 (1- 3) / 2 (1-4) 1 (1-3) / 1 (1-3) 1 (1-3) / ORR, % (95% CI) 17.3 (9.8-27.3) 35.7 (18.6-55.9) 50.0 (24.7-75.3) 35.4 (25.0-47.0) 39.2 (25.8-53.9) 44.8 (26.4-64.3) 37.5 (22.7-54.2) 37.9 (20.7-57.7) 45.0 (23.1-68.5) DCR, % (95% CI) 74.1 (63.1-83.2) 89.3 (71.8-97.7) 100 (79.4-100) 88.6 (79.5-94.7) 88.2 (76.1-95.6) 86.2 (68.3-96.1) 92.5 (79.6-98.4) 93.1 (77.2-99.2) 90.0 (68.3-98.8) mFU for PFS (mo) 2.8 5.5 4.2 4.4 4.4 4.3 2.8 2.7 2.7 mPFS (mo) 4.0 5.6 5.7 4.4 5.4 7.7 6.9 5.9 5.9 * Efficacy analysis included all pts who received at least one dose of BL-M05D1 and with at least one post baseline scan. # PanC CLDN 18.2 +: IHC 2+/3+ ≥ 50%; GC CLDN 18.2 +: IHC 2+/3+ ≥ 40%; BTC CLDN 18.2 +: IHC1+/2+/3+≥30%.

Impact of facility type on outcomes for elderly patients (≥ 75 years) with Burkitt lymphoma: Real-world data of academic vs community cancer programs.

e19059 Background: Burkitt lymphoma (BL) is an aggressive B-cell malignancy characterized by rapid proliferation. While highly curable in children and young adults, prognosis remains inferior in the elderly due to poor tolerance for intensive chemotherapy and higher baseline comorbidities which presents as a significant treatment challenging. This is the first real-world study to compare demographic characteristics, treatment patterns, and survival outcomes for patients aged 75 and older treated at Academic Cancer Programs (ACP) versus Community Cancer Programs (CCP). Methods: A retrospective analysis using the National Cancer Database was conducted on 1,618 patients (ACP n=837; CCP n=781) diagnosed with BL between 2004 and 2022 was carried out. ACP included academic and National Cancer Institute-designated research centers; CCP included community, comprehensive community, and integrated network cancer programs. Kaplan-Meier and Cox regression models were used to compare overall survival (OS), adjusting for: age, race/ethnicity, insurance status, Charlson-Deyo comorbidity score, and distance from treating facility. Results: ACP demonstrated significantly superior OS outcomes compared to CCP [p=0.004]. Patients at ACP were slightly younger with a median age of 80 vs 81 years [p=0.001]. No difference in sex, race or ethnicity was noted in both groups. Although most patients had Medicare, almost 10% for both groups had private insurance. Patients treated at ACP were more likely from the Metropolitan area, 83% vs 77% in CCP [p=0.016], with the median distance in miles was 9.2 vs 8.1, respectively. ACP had a higher proportion of Stage IV disease, 50% vs 43%, [p=0.029]. Treatment was more frequently administered at ACP with 58% vs 52% [p=0.001], and when administered it was initiated faster than CCP with median of 12 vs 14 days [p=0.018]. Median follow-up time was longer in the ACP cohort with 5.4 months vs 3.1 months, [P&lt;0.001]. Two, five, and ten-year survival probabilities were higher at ACP than CCP: 36% vs 28%, 26% vs 21%, and 14% vs 11%, respectively. The adjusted median OS was 0.48 years for ACP and 0.27 years for CCP. Conclusions: Among patients aged ≥75 years with BL, treatment at ACP was associated with a statistically significant and clinically meaningful improvement in OS compared with CCP (log-rank p=0.004). Patients treated at ACP were more likely to receive therapy and experienced shorter time to initiation of treatment, despite also having a higher proportion of patients with more advanced-stage disease. These findings highlight the persistent vulnerability of elderly patients with BL and reinforce the need for integrated ACP-CCP care models. Such system-level strategies are essential to early referral, timely treatment delivery, risk-adapted strategies to mitigate toxicity, and provide robust supportive care for this population.

Expression of Concern: Construction of a high-density genetic map and QTL analysis for yield, yield components and agronomic traits in chickpea (Cicer arietinum L.)

Outside Front Cover: Polyfluoroalkyl‐Tagged Cell‐Penetrating Peptide‐Additives Enhance Intracellular Protein Delivery via Sustained Monomeric Lipid Interaction (Angew. Chem. Int. Ed. 23/2026)

Strategies Toward Accessing Enantioenriched (Hetero)Benzo‐Fused 5‐ and 6‐ Membered Rings via Intermolecular Carbometalation

ABSTRACT Enantioenriched benzofused 5‐ and 6‐ membered rings continue to be found as notable motifs in important molecules such as pharmaceuticals and natural products. A key synthetic strategy towards accessing these structures is via a metal‐catalyzed intermolecular carbometalation step across a substituted olefin or alkyne. This review emphasizes recent advances towards accessing enantioenriched benzofused 5‐ and 6‐ membered rings via intermolecular carbometalation strategy, catalyzed by late and early transition metals. Through covering the key mechanistic investigations and computed conformational analyses, this review hopes to allow for a more unified understanding of how asymmetric control is attained across a diverse array of metals and ligands, and to highlight significant advances made in the past decade.

Quantum optics in photocatalytic hydrogen production: Light-matter interaction at the quantum scale

Thermally activated paint-sludge as potential sustainable adsorbent for pollutant removal with insights from isotherms kinetics thermodynamics and response surface methodology

Impact of heme on the therapeutic efficacy of anti-CD20 antibodies

A two-axis machine learning framework for cell-of-origin inference in AML: A proof-of-concept study.

6540 Background: Leukemogenesis mirrors hematopoietic differentiation yet proceeds through dysregulated programs. Multiparameter flow cytometry (MFC) allows leukemia immunophenotypes projection onto normal myeloid ontogeny. Here, we apply machine-learning (ML) models trained on MFC data to reconstruct a preliminary data-driven representation of inferred cell-of-origin (COO). Additionally, we explore integration of monocytic differentiation into canonical COO framework to identify dysregulated commitment programs not explained by developmental maturity alone. Methods: After IRB approval, MFC data from 261 AML patients were aligned to immunophenotypic signatures of normal myeloid ontogeny (HSC, MPP, CMP, GMP, GP, MP) as previously described (Simoes et al. , Blood Neoplasia , 2024; Vergez et al. , Blood Cancer Journal , 2022). Probabilistic COO states were inferred from core markers (CD34, HLA-DR, MPO, CD33, CD117) using ensemble Random Forest classifiers with gradient boosting [Training/Validation=70/30]. Because canonical COO algorithms omit monocytic features, we implemented a secondary Mono-Risk Layer trained on monocytic markers (CD14, CD64) and stemness/invasiveness surrogates (CD56, reflecting adhesion, migration propensity) and CD123, to generate complementary phenotypic labels. Models were trained with cross-validation in Python, and mutation enrichment was projected onto inferred COO states. Results: Mean age was 63.8 years. 114/261(44%) were male. 123/261 (47.1%) of cases produced multidimensional P-COO achieving “Ensembled (RF+ Boosting Gradient)" AUC=0.74. Confusion matrix revealed a structured pattern of misclassification predominantly between adjacent COO states, consistent with a continuous differentiation manifold (Recall for MPP, CMP, GMP, GP, MP, 50% 83%, 62%, 65%, 76%, respectively). Mono-Risk-Layer (MRL) improved discriminatory ability for MP (AUC 0.94, Recall 86%, F1 0.75). NPM1 was mapped to GMP (60%), MP (34%) and CMP (27%), p= 2.61e-09, FLT3 ITD GMP (43.3%), CMP (32.4%) and MP (12.3%), p =4.72 e-05, TP53 HSC (50%), MPP (24.3%) and GMP (16%), p =3.6e-04, RUNX1 MPP (26.1%), HSC (25%) and MP (13%), p =7.7 e-03, RAS MP (35%), MPP (19%) and HSC (13%), p =5.18 e-03. Conclusions: Machine-learning–based probabilistic cell-of-origin inference from routine flow cytometry is feasible and biologically informative in AML. Incorporation of a monocytic risk layer improves resolution of monocytic programs not captured by canonical COO and reveals distinct mutation–differentiation relationships. NPM1 and FLT3-ITD are enriched in GMP/MP-like states, TP53 in primitive HSC/MPP compartments, RUNX1 in early progenitors, and RAS in monocytic-skewed trajectories. These findings link genomic drivers to specific developmental niches and establish a scalable framework for biologically grounded AML classification and therapeutic modeling.

Lung cancer incidence and PM _2.5 : Evaluating the association with varying spatial scales and durations of exposure estimates.

10600 Background: Particulate matter with a diameter of 2.5 µm or less (PM 2.5 ) is classified as an IARC group 1 carcinogen based on decades of research. However, little is known about how the association between PM 2.5 and lung cancer incidence is impacted by varying spatial and temporal methods of estimating exposure. Methods: We performed a nested case-control analysis using the Department of Veterans Affairs (VA) Clinical Data Warehouse. Patients were eligible for inclusion if they had a recorded date of birth, smoking data, and quarterly location data for 40 or more quarters between 2009 and 2021. Cases were required to have at least 10 years of location data prior to diagnosis; diagnoses and diagnosis dates were identified using the VA Central Cancer Registry. Controls were matched in a 4:1 ratio on age (by birth quarter), smoking status (self-reported, defined as “Smoker” vs. “Never Smoker”), and the specific calendar quarters contributing to the PM 2.5 average. Modeled daily PM 2.5 estimates at a spatial resolution of 1 km 2 for the entire contiguous United States (US) were aggregated to quarterly estimates at three US Census geography levels (block group, census tract, and county). After case-control matching, we evaluated the impact of different spatial and temporal measures of PM 2.5 exposure on the association between PM 2.5 and lung cancer incidence. Specifically, we evaluated estimates at the block group, census tract, and county level with both 5-year and 10-year averages. Associations were evaluated using conditional logistic regression; model fit was assessed using the Akaike Information Criterion (AIC). Results: Approximately 4.7 million veterans met our inclusion criteria. Of these, 8451 veterans developed incident lung cancer at least 10 years after the observation period began; 33,150 matched controls were selected. All models showed a statistically significant increase in the risk of lung cancer with increasing PM 2.5 exposure, with odds ratios (ORs) ranging from 1.06 (95% CI 1.04-1.09) to 1.13 (95% CI 1.10-1.17) and p-values &lt; 0.001 for all models. In both the 5-year and 10-year analyses, models with larger spatial units (county &gt; census tract &gt; block group) had higher ORs and superior model fit by AIC. All models with 10-year averages had higher ORs and lower AIC values compared to models with 5-year averages. Conclusions: Our findings add to the considerable body of research that demonstrates an epidemiologic association between PM 2.5 and lung cancer incidence. Furthermore, our results demonstrate that this association is robust to various methods of estimating patient PM 2.5 exposure. Finally, these data suggest that using county-level PM 2.5 estimates and an estimate duration of at least 10 years may be preferable to finer spatial scales and shorter estimate durations in future studies.

TALENT: A randomized phase 2 study of talazoparib with or without enzalutamide in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) alterations after progression on abiraterone acetate.

TPS5145 Background: The phase 3 TALAPRO-2 study (NCT03395197) demonstrated superior efficacy with enzalutamide plus talazoparib vs. enzalutamide plus placebo for pts with mCRPC with tumors harboring HRR mutations. Only 8% of HRRm pts enrolled in TALAPRO-2 had prior exposure to abiraterone acetate with prednisone, and none had received an androgen receptor inhibitor. Given the evolving treatment landscape of metastatic hormone sensitive prostate cancer (mHSPC), many patients now receive ADT in combination with abiraterone acetate and prednisone until progression. It is unknown whether the synergistic effects of inhibiting PARP alongside potent AR inhibition will be maintained in those patients with tumors that have demonstrated resistance to an androgen biosynthesis inhibitor such as abiraterone. The TALENT study (NCT06844383) will address this unanswered question by randomizing pts with HRR-mutated mCRPC following progression on abiraterone acetate with prednisone to receive talazoparib in combination with enzalutamide versus talazoparib alone. We hypothesize that synergy between PARP and AR inhibition will be demonstrated in this contemporary patient population. Methods: TALENT will enroll approximately 126 pts with mCRPC with prior disease progression while receiving abiraterone acetate for HSPC or locally advanced disease and a confirmed mutation in one of twelve HRR genes. ATM mutations will be limited to 15%. Prior exposure to docetaxel in the mHSPC setting will be included as a stratification factor. Pts will be randomized in a 1:1 fashion to either talazoparib and enzalutamide or talazoparib alone administered along with ADT. Pts will continue treatment until disease progression, unacceptable toxicity, treatment delay &gt; 60 days of talazoparib, protocol violation, withdrawal of consent, physician decision, study termination by the Sponsor, loss to follow-up, or death. Patients will be monitored using RECIST 1.1 and PCWG3 criteria for bone disease. The primary endpoint is investigator-assessed radiographic progression free survival (rPFS). Secondary endpoints include time to PSA50 response, time to PSA progression, overall survival, and patient reported outcomes capturing quality of life. Exploratory analyses will evaluate rPFS by HRR gene (BRCA vs non-BRCA, individual genes, and gene clusters). Pt recruitment is planned at approximately 15 sites in the US . As of January 27, 2026, 0 pts have been enrolled. Clinical trial information: NCT06844383 .

Management of first recurrence from IDH-wildtype glioblastoma with re-resection or stereotactic radiosurgery: A retrospective, international, multicenter study.

2063 Background: Optimal management of recurrent glioblastoma remains ill-defined. While re-resection is frequently provided as local salvage therapy, stereotactic radiosurgery (SRS) might represent a treatment approach for small, focal recurrences. We comparatively evaluated outcomes after re-resection and SRS for first recurrence of IDH-wildtype glioblastoma. Methods: Adult patients with first radiographic recurrence of IDH-wildtype glioblastoma (WHO 2021 classification) were identified. Information on patients managed with re-resection were collected through the international eight-center database of the RANO resect group, and patients managed with SRS were collected by twelve centers from the IRRF study group. Survival after recurrence was analyzed using Kaplan–Meier estimates and Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was applied to mitigate baseline imbalances. Results: Overall, 567 patients were included (re-resection: n = 310; SRS: n = 257). Compared with SRS, patients managed with re-resection were younger and had larger contrast-enhancing recurrence volumes. Despite those baseline differences, overall survival did not differ between treatment modalities (10.2 [95%CI 9.3–11.7] vs. 11.1 [10.3–12.8] months; HR 1.12, 95%CI 0.93–1.35; p = 0.231). Also, no survival differences between treatment groups were observed when effects of potential baseline confounders including tumor volume were minimized using IPTW. Notably, among patients typically not considered SRS candidates due to tumor volumes &gt;10 cm³ ( n = 234), maximal re-resection of the enhancing tumor (RANO class 1–2) was associated with survival comparable to SRS-treated low-volume tumors ≤10 cm³ (9.1 [7.7–11.5] vs. 11.0 [9.9–12.8] months; HR 1.27, 0.95–1.69; p = 0.106) whereas incomplete re-resection (RANO class 3) was associated with less favourable survival. In the subgroup of patients with focal recurrences in whom local physicians from the IRRF consortium perceived clinical equipoise between treatment modalities but eventually performed SRS ( n = 112), IPTW-adjusted analyses demonstrated no significant difference in overall survival compared with re-resected patients (HR 0.90, 0.65–1.25; p = 0.539). Conclusions: While complete re-resection is prognostic in recurrent glioblastoma, SRS might represent a reasonable therapeutic approach for selected individuals with small low volume tumor recurrence. Given substantial baseline differences between patients treated with re-resection and SRS and potential treatment provider bias, prospective trials are warranted to guide nuanced decision-making.

Long term effects of treatment with dabrafenib (D) and/or trametinib (T) in pediatric patients with MAPK pathway-activated tumors.

10031 Background: Studies have shown the clinical benefits of D and T, in combination and as monotherapy, to treat adult and pediatric patients with BRAF V600 mutation-positive cancers. Here, we report the interim results from a long-term, follow-up study for patients from previously completed clinical trials that assessed the use of D and/or T in pediatric patients with MAPK pathway-activated tumors. Methods: This ongoing, global, open-label, multi-center study evaluated the long-term effects (general health, growth and development) of D and/or T in pediatric patients with tumors with MAPK pathway activation from previous studies that assessed (1) safety, tolerability and pharmacokinetics of D in solid tumors (NCT01677741); (2) pharmacodynamics and clinical activity of T or D+T in cancer or plexiform neurofibromas (NCT02124772); and (3) safety and efficacy of D+T in glioma (NCT02684058). The patients in this study followed the same treatment as at the end of the parent study. The duration of this study is 7 years after the first patient first visit (FPFV) (November 2019). The primary objective is to assess the long-term safety of the treatment. Results: Of a total 165 patients, 157 received the study treatment (D [n=28], T [n=21], D+T [n=108]) and 8 patients were for observation only. Most patients with low-grade glioma (LGG) and high-grade glioma (HGG) had BRAF V600 mutation (n=129). The median duration of exposure was approximately 21 months. From FPFV to the data cut-off (October 2024), most of the patients (94.3%) experienced at least one adverse event (AE) with 28% patients experiencing serious AEs. The most common AE was pyrexia (36.9%). AEs leading to treatment discontinuation occurred in 3.8% of total patients (D [3.6%], T [9.5%], D+T [2.8%]). One on-treatment death was reported in the D+T arm due to convulsion (not related to the study treatment). No clinically meaningful changes were observed in hematological or biochemical parameters in the D+T arm. Grade ≥ 3 abnormalities were infrequent and were reported in &lt;2% of patients, except creatine kinase increase (5.7%). Assessment of vital signs, growth, electrocardiography, bone age and Tanner staging did not reveal any new safety signals. In the D+T arm, as per investigator assessment, overall response (complete + partial) was 27.7% for patients with BRAF V600E mutation positive LGG (stable disease: 63.9% patients) and 41.2% for patients with BRAF V600E mutation positive HGG. The median progression-free survival and median overall survival were not reached. Conclusions: In this long-term study, reported AEs were in line with established safety profile of D and/or T. Except more than normal increase in weight, no significant impact of D and/or T was observed on growth, sexual maturation and skeletal development. The benefit-risk remained favorable toward D and/or T therapy in pediatric patients with MAPK pathway-activated tumors. Clinical trial information: NCT03975829 .

Ultra-hypofractionated versus hypofractionated radiotherapy in breast cancer: Real-world toxicity, efficiency, and implementation patterns.

e12722 Background: Hypofractionated regimens are standard for breast-conserving therapy due to equivalent efficacy and reduced treatment burden. Ultra-hypofractionated regimens have demonstrated non-inferior outcomes in randomized trials; however, real-world data on safety, efficiency, and implementation remain limited, particularly in Latin America. Methods: We conducted a retrospective cohort study including patients with breast cancer treated with curative or adjuvant external beam radiotherapy at a comprehensive cancer center in Colombia. Patients received hypofractionated or ultra-hypofractionated regimens. Clinicopathological variables, treatment duration, and RT-associated toxicity were collected. Comparisons between regimens were performed using bivariate analyses. Results: A total of 121 patients were included, of whom 97 (80.1%) received hypofractionated and 24 (19.8%) ultra-hypofractionated radiotherapy. RT-related toxicity was infrequent and comparable between regimens (9.3% vs 4.2%), limited to skin toxicity. Ultra-hypofractionated RT was associated with a shorter treatment duration (5 vs 15 days). Ultra-hypofractionation was implemented across age groups, disease stages, and molecular subtypes, with no significant differences between regimens. A non-significant trend toward higher lobular histology was observed in the ultra-hypofractionated group. Three-year overall survival was high in both groups (98.9% vs 100%); survival analyses were descriptive due to a low number of events. Conclusions: Ultra-hypofractionated whole-breast radiotherapy demonstrated a safety profile comparable to hypofractionated regimens, with low rates of RT-related toxicity. Ultra-hypofractionation was implemented across a broad range of clinical characteristics, suggesting feasibility in routine practice. Survival outcomes were high in both groups and should be interpreted in the context of the limited number of events. These findings support ultra-hypofractionated radiotherapy as an efficient and safe strategy that may optimize quality of care and resource utilization in breast cancer. Baseline characteristics and outcomes by radiotherapy regimen. Variable Hypofractionated (n=97) Ultra-hypofractionated (n=24) Age, years 53.9 59.4 AJCC stage I–II, n (%) 76 (80.0) 19 (82.6) AJCC stage III, n (%) 18 (20.0) 4 (17.4) Invasive lobulillar carcinoma, n (%) 8 (8.2) 7 (29.2) Invasive ductal carcinoma, n (%) 79 (81.4) 14 (58.3) Any RT-related toxicity, n (%) 9 (9.3) 1 (4.2)