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Cardiovascular-related adverse events (CVD-AEs) and echocardiographic (Echo) changes with immunotherapy (IT): A real-world experience.

11185 Background: Immune-checkpoint inhibitors (ICI) are standard of care for many solid tumors but are linked to cardiovascular adverse events (CVD-AEs). Real-world comparative data on CVD-AE incidence between IT & non-IT therapies are limited & no prior studies have evaluated longitudinal Echo changes in IT vs. non-IT patients. Methods: We conducted a retrospective cohort of 5,556 adults with solid malignancies at Cleveland Clinic Ohio (2010–2022). IT patients were compared to non-IT systemic therapy. Cancers included bladder (II-IIIA:476; IV:158), endometrial IV (157), gastric (II-III:797; IV:590), H&N IV (36), renal (III:88; IV:223), melanoma (45) & lung: NSCLC non-squamous (IIIB:206; IV:1609), NSCLC squamous (IIIB:182; IV:366) & SCLC IIIB-IV (623). Follow-up began at therapy start & continued until CVD-AE, last follow-up or death. Data were collected on demographics, CTCAE grade, management & outcomes. Incidence rates per 100 person-years (/100 Py) were estimated using Poisson regression, cumulative incidence (CIR) using Kaplan–Meier methods & adjusted hazard ratios (HRs) using time-dependent Cox models. Echo analyses (n = 418) compared baseline to follow-up studies using multinomial regression. Results: Of the cohort, 1,291 (23%) & 948 (17%) received 1st- & 2nd-line IT. Median age was 66; 38% were female, & 87% were White. ICI accounted for 99.9% of IT. During follow-up, 163 CVD-AEs occurred, including arrhythmias (n = 59), cardiac arrest (n = 35), myocarditis/heart failure (n = 21), pericarditis (n = 10) & acute coronary syndromes (NSTEMI n = 17, STEMI n = 15, unstable angina n = 5). Median follow-up was 14 months (CI 6-35). The CVD-AE CIRs were slightly higher in IT vs. non-IT groups (0.12 vs 0.11 /100 PY). The 4-year CIR was 5% in IT & 3.5% in non-IT (P = 0.4). In time-dependent Cox models, IT was not associated with a significant increase in composite CVD-AEs, though a borderline association with the composite of cardiac dysrhythmia & conduction disorders was observed (HR 1.43, P = 0.06). Echo analyses showed no association between IT & adverse changes in LV/RV systolic function (EF, GLS, TAPSE), pulmonary pressures or diastolic function (E/e’). In contrast, 1st-line IT was associated with increased odds of aortic root dilation (OR 2.95, p = 0.028), mitral valve sclerosis (OR 4.17, P = 0.02) & a trend toward mitral stenosis (OR 3.7, P = 0.05). Abnormal baseline Echo parameters remained the strongest predictors of future worsening. Conclusions: We found that IT was not associated with a significant rise in overall CVD-AEs or myocardial dysfunction, possibly reflecting less use of traditional cardiotoxic agents like anthracyclines. Novel associations with aortic root dilation & mitral valve sclerosis suggest vascular & structural remodeling effects. Findings highlight the need for long-term surveillance of structural heart changes beyond ejection fraction monitoring.

Evaluation of patient-reported gynecomastia following neoadjuvant androgen deprivation therapy and stereotactic body radiotherapy for localized prostate cancer.

e17125 Background: Androgen deprivation therapy (ADT) is commonly combined with stereotactic body radiotherapy (SBRT) for localized prostate cancer. Agents such as leuprolide and relugolix are associated with hormone-related side effects, including gynecomastia. The incidence and severity of bothersome breast tenderness or enlargement following short-course ADT and SBRT remain poorly characterized. This study aimed to assess gynecomastia burden in prostate cancer patients treated with ADT and SBRT, and its association with testosterone recovery. Methods: Institutional IRB approval (IRB#: 2009-510) was obtained for a retrospective review of prospectively collected data. Gynecomastia was measured via Question 13b of the Expanded Prostate Index Composite (EPIC)-26 (EPIC Q13b), which assesses breast enlargement/tenderness. Survey responses and serum testosterone were recorded at ADT initiation and every 3 months, with a median follow-up of 9 months. Follow-up varied due to missed visits or incomplete surveys. EPIC Q13b responses ranged from 0 to 4, and were grouped as 0 (none), 1-2 (mild), and 3-4 (moderate to severe). Results: From 2009 to 2024, 281 localized prostate cancer patients (12 low-risk, 180 intermediate-risk, and 89 high-risk) were treated with short-course ADT (3-6 months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Patients received either leuprolide (n = 166) or relugolix (n = 115). The median age was 72 years, and 42% of patients were non-white. At baseline, 9.8% of men reported mild gynecomastia symptoms, while 2.2% experienced moderate to severe symptoms. The incidence of mild symptoms peaked at 15.4% at 6 months before declining to below baseline by 24 months. Moderate to severe symptoms reached the highest incidence of 5.8% at 12 months and decreased to 0% at 24 months, with a cumulative incidence of 10.3%. There was no significant difference in symptoms between patients treated with leuprolide versus relugolix. Testosterone recovery ( > 230 ng/dL) occurred in approximately 65% of patients by 12 months in those with follow-up. Conclusions: Bothersome gynecomastia occurs at low rates in men treated with neoadjuvant ADT. Resolution of symptoms occurred in most patients within two years after treatment. The temporary nature of gynecomastia may be important to include in patient counseling regarding hormone therapy side effects. Incidence and severity of breast enlargement/tenderness assessed by EPIC Q13b at different follow-up time points. Time Point (months) Total N Grade 0 Grade 1-2 Grade 3-4 0 183 162 (88.5%) 17 (9.3%) 4 (2.2%) 1 133 111 (83.5%) 16 (12%) 6 (4.5%) 3 217 188 (86.6%) 22 (10.1%) 7 (3.2%) 6 221 177 (80.1%) 34 (15.4%) 10 (4.5%) 9 178 156 (87.6%) 16 (9%) 6 (3.4%) 12 156 132 (84.6%) 15 (9.6%) 9 (5.8%) 18 138 121 (87.7%) 15 (10.9%) 2 (1.4%) 24 124 119 (96%) 5 (4%) 0 (0%) 30 78 72 (92.3%) 6 (7.7%) 0 (0%)

Equal Hope's Medicaid breast cancer coordination of care improvement initiative.

e13518 Background: In 2022, there were 11,000 breast cancer diagnoses and 1,600 deaths due to breast cancer in Illinois. Chicago women reporting a mammogram in the past two years was 74.9% however this might be inflated due to self-report data. Studies show that the rate is even lower among individuals with Medicaid or no insurance. Equal Hope is a community-based organization dedicated to eliminating health inequities in the Chicagoland area. The purpose of this initiative was to increase breast cancer screening utilization among Chicago women with Medicaid utilizing Equal Hope’s decentralized patient navigation model. Methods: Five Illinois Medicaid managed care organizations (MCOs) participated in the initiative and sent information for female clients ages 40-64 who did not complete a screening mammogram within the past two years and lived in a west or south side Chicago zip code. By December 2025, a total of 20,494 clients were eligible to participate in the project. Six Equal Hope navigators conducted at least three attempts and assisted in scheduling a mammogram. This is an ongoing project, and this analysis was restricted to clients who received at least one attempt resulting in a final sample size of 14,148. Client demographic and zip code level characteristics were used to describe client outcomes. Results: From February to December 2025, navigators made over 29,000 attempts for 14,148 clients. After excluding 28% of clients due to incorrect contact information, 6,345 were considered unreached, 1,645 reached, 1,423 refused, and 846 enrolled. Clients’ Medicaid MCO, race and ethnicity, and zip code characteristics such as the number of mammography sites, social vulnerability index (SVI), avoidable ED visit rate, rent and transportation burdened, and walkability index showed significant differences in program outcome. MCO D represented the largest enrolled in the initiative (8.8%), MCO C the largest unreached (71.3%), and MCO B the largest refused (20.1%). Clients who lived in a zip code with at least 3 mammography sites (11.0%) had the largest group enrolled. By December, 638 mammograms or ultrasounds were scheduled. Conclusions: Overall, this initiative has proved to be effective in reaching the Medicaid population in Chicago. The primary challenge has been a lack of valid contact information for clients. Regardless, Equal Hope is currently evaluating novel methods to increase collaboration between local clinics to ensure that all individuals have access to quality mammography screening.

Circulating tumor DNA dynamics following molecularly targeted therapy for non–small cell lung cancer.

8652 Background: Biomarkers to guide treatment escalation following suboptimal response to molecular targeted therapy are urgently needed for patients (pts) with non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) has shown promise for monitoring residual disease following definitive treatment, but ctDNA dynamics following targeted therapy response remain understudied. Methods: We examined a real-world, multi-institution cohort of pts with NSCLC undergoing personalized, tumor-informed ctDNA testing (Signatera, Natera, Inc.) and clinical annotations from a deidentified commercial claims dataset (Forian’s Hybrid data ecosystem, CHRONOS). Longitudinal ctDNA results were evaluated before and after targeted therapy initiation and summarized by treatment line, clinical context, and demographic and clinicopathologic features as available. Results: We identified 839 pts (14.0%, 11.1%, 19.4%, and 55.5% with stages I, II, III, and IV) across 395 US institutions, who had ctDNA profiling and were treated with molecularly targeted agents. Median age was 71 years (range 25-93), 67.0% were female, and 85.3% had tumors with adenocarcinoma histology. Pts underwent a median of 4 ctDNA tests/pt (range: 1–58) over a median follow-up of 9 months (range: 0-75). Amongst ctDNA positive tests (n=1705 tests for 408 pts), median ctDNA levels were 1.20 mean tumor molecules/mL (range 0.01–36,599). Pts received osimertinib (58.5%), alectinib (10.7%), sotorasib (5.6%), adagrasib (3.7%), afatinib (3.7%), and capmatinib (3.0%). ctDNA tests prior to targeted therapy (baseline) were available for 336 patients, of which 49.7% (167/336) had detectable ctDNA (“ctDNA(+)”). Among these ctDNA(+) cases, 123 pts had longitudinal ctDNA assessment. ctDNA clearance observed in 38.2% (47/123); 52.1% (25/48) in stage I-III and 29.3% (22/75) in stage IV. Among the 169 pts with baseline ctDNA(-), 115 pts had ctDNA assessed longitudinally. Of these, 89.6% (103/115) remained serially negative, while 10.4% (12/115) had any time ctDNA(+). Among commonly used targeted therapies, ctDNA clearance was observed across multiple agents, and is summarized in table 1. We further analyzed associations between ctDNA dynamics, during different treatment lines, and clinical outcomes. Conclusions: In a multi-institution cohort, ctDNA clearance was observed in pts with NSCLC treated with molecularly targeted therapies. Clearance rates varied by treatment type. The use of ctDNA monitoring to guide treatment escalation in this population warrants further study. Targeted Therapy Pts with ctDNA available pre and post-therapyN Pts with baseline ctDNA(+) N Pts with ctDNA clearanceN (%) osimertinib 128 54 26 (48.1) alectinib 22 7 3 (42.9) sotorasib 15 14 4 (28.6) adagrasib 12 10 2 (20.0) Includes only therapies with more than 10 pts who had pre- and post-treatment ctDNA availability.

The differentiated SIRPα–IgG4 Fc fusion protein HCB101 in monotherapy and combination therapy.

2655 Background: The CD47–SIRPα axis is a central innate immune checkpoint that enables tumor immune evasion. No prior CD47-directed program has demonstrated meaningful monotherapy activity, limited by on-target hematologic toxicity, constraining development. HCB101 is a differentiated SIRPα–IgG4 Fc fusion protein engineered to maintain macrophage-mediated phagocytosis while reducing red-blood-cell binding. This study assesses whether HCB101 can overcome historical class limitations by achieving a wide therapeutic safety margin and durable monotherapy antitumor activity, while also serving as a backbone for combination immunotherapy efficacy across standard-of-care (SOC) regimens. Methods: HCB101-101 (NCT05892718) is a first-in-human Phase 1 monotherapy dose-escalation study evaluating weekly IV dosing from 0.08 to 36 mg/kg. HCB101-201 (NCT06771622) is a Phase 1b/2a multi-cohort trial assessing HCB101 combined with SOC agents across 9 solid tumor types, including gastric cancer (GC), triple-negative breast cancer (TNBC), colorectal cancer, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma, ovarian cancer, and small cell lung cancer. Primary endpoints are safety, tolerability, and determination of the recommended Phase 2 dose; secondary and exploratory endpoints include pharmacokinetics (PK), pharmacodynamics, efficacy, and biomarkers. Results: In HCB101-101, 36 mg/kg has been reached. To 09JAN2026, 2 confirmed partial responses (HNSCC: –42% at 5.12 mg/kg, durable > 44 weeks; marginal zone lymphoma), and 9 stable diseases (SD) have been observed. PK was dose-proportional (T 1/2 ~2.9 days) with receptor occupancy plateauing at > 99% by ≥8 mg/kg. In HCB101-201, 2L-GC treated with HCB101 plus ramucirumab and paclitaxel demonstrated 8 PRs and 5 SDs, with two additional patients at 12 mg/kg pending first assessment. In mid-dose cohorts (5.12–8 mg/kg), 8 of 10 subjects achieved PRs and 100% achieved disease control, with regressions up to –78.2%. In 1L HER2+ GC, 4 subjects showed 3 PR (up to –57.6%) and 1 SDs. In 1L-TNBC, 6 of 6 subjects achieved disease control, including 3 PRs. Across cohorts, HCB101 demonstrated manageable safety with reversible cytopenias and no unexpected immune-mediated toxicities. Conclusions: HCB101 demonstrates a class-distinguishing profile for a macrophage checkpoint inhibitor, with durable monotherapy antitumor activity and a wide therapeutic window up to 36 mg/kg, addressing long-standing limitations of CD47-directed therapies. The early and reproducible combination activity across multiple solid tumors, including GC, HER2+ GC, and TNBC, has supported rapid cohort expansion. These data position HCB101 as a next-generation innate immune checkpoint backbone with broad clinical applicability and a clear rationale for future combination-based registrational development. Clinical trial information: NCT05892718 .

Evaluating the role of informal caregivers in metastatic cancer patients treated with oral anticancer therapy: A prospective observational study.

11117 Background: The increasing use of oral anticancer agents (OAAs) in metastatic cancer has shifted treatment management from hospital to home, transferring responsibility for adherence and symptom monitoring to patients and informal caregivers. Evidence on caregiver burden and its impact on patient-reported outcomes in this setting remains limited. Methods: This prospective observational study evaluated patients with metastatic cancer receiving OAAs and their informal caregivers. At baseline and three months, patients completed the EORTC QLQ-C30, MMAS-8, TEMPS-A, and the G8 geriatric screening tool; caregivers completed the Zarit Burden Interview (ZBI), Caregiver Reaction Assessment (CRA), TEMPS-A, and an ad hoc caregiving questionnaire. Statistical analyses were performed using IBM SPSS Statistics (p < 0.05). Results: Sixty-eight patients (median age 67 years; 50% female) were enrolled; among patients aged >70 years, the G8 score indicated a predominance of non-frail patients (68.2%). 66.1% had a caregiver, most commonly a spouse (46.5%) or child (41.9%). Caregivers (mean age 56 years) were involved for >2 years in 76.7% of cases and attended outpatient visits in 69.8%. ZBI showed minimal/no burden in 60.5% and mild-to-moderate burden in 32.6%. CRA scores were highest for self-esteem (4.13±0.62), followed by schedule (3.31±1.36) and health (3.10±0.66). Patients with caregivers reported worse quality of life, physical, role, and emotional functioning, higher symptom burden (fatigue, pain, dyspnea, appetite loss, financial difficulties), and lower adherence compared with those without caregivers (all p<0.05). Caregiver presence was associated with cyclothymic, depressive, and anxious temperaments. Patients cared for by a child showed better role functioning, while spousal caregiving was associated with irritable temperament. At three months (n=22), patients showed significant improvements in adherence, quality of life, physical and role functioning, and symptom burden, suggesting early adaptation to oral therapy despite high baseline caregiving demands. Conclusions: Informal caregivers play a central role in OAA-treated metastatic cancer. Caregiver involvement appears to reflect greater patient vulnerability rather than a causal determinant of poorer outcomes, supporting the need for systematic caregiver assessment and targeted supportive interventions. Caregiver characteristics and associated patient outcomes. Variable Caregiver present No caregiver Patients, % 66.1 33.9 Relationship, % Spouse 46.5 / Child 41.9 – Care duration >2 yrs, % 76.7 – Presence at visits, % 69.8 – ZBI burden, % None/min 60.5; Mild–mod 32.6 – CRA self-esteem (mean±SD) 4.13±0.62 – Quality of life ↓ ↑ Physical functioning ↓ ↑ Symptom burden ↑ ↓ Therapy adherence ↓ ↑

Retrospective evaluation of an AI-based fusion prioritization agent for oncogenicity assessment in clinical sequencing.

e18558 Background: Categorizing gene fusions as drivers or passengers is a data-intensive challenge requiring manual interventions in all but the most well-established biomarkers. The large numbers of structural variants identified from genomic assays require a combination of tools to prioritize clinically relevant mutations in a timely manner. Recent advances in artificial intelligence (AI) and AI-agents have enabled the summarization of large-scale biological data and are ideally suited for flagging important knowledge quickly and with limited manual intervention. Methods: This work introduces Peryton, a flexible AI-agent capable of analyzing the oncogenic potential of both RNA and DNA fusion events. By integrating genomic breakpoints, gene annotations, literature mining and RNA expression signatures, Peryton generates concise, fully referenced summary of a fusion’s biological function, oncogenic potential, and therapy implications. Peryton incorporates peer-reviewed articles from PubMed Central, publicly available fusion knowledgebases, and internal data (a curated gene fusion database and internal RNA sequencing expression values) to evaluate and prioritize the oncogenic potential of fusions identified within a sample. The chain-of-thought strategy does extensive pre-computation before prompting the large language model (LLM) with data on which protein features are retained or lost in individual gene fusions. A key output is an oncogenicity score, an AI-generated classification of a fusion's cancer-causing potential based on literature review. Results: We benchmarked Peryton against a dataset of 300 known positive events from COSMIC and 300 presumed passenger events. The agent demonstrated high curation accuracy, with an area under the receiver operating characteristic greater than 0.98 across the 600 randomly selected records. In a clinical validation study of 41 non-canonical gene fusions flagged by internal pathologists, which were evaluated for clinical reporting, Peryton correctly prioritized the reportability of 90% of fusions providing evidence for its use supporting non-canonical fusion curation. Furthermore, when applied to all structural variant calls from 2 WGS AML cases (202 and 188 respectively), the agent successfully prioritized with the top score in each of the reported clinical drivers (KMT2A::AFDN and ROCK1::PDGFRA). The next highest fusion events showed prognostic literature evidence further validating its utility in real-world scenarios. Conclusions: Peryton provides a precise assessment of gene fusion events, effectively prioritizing candidate fusions for further clinical and research evaluation. This retrospective analysis demonstrates the agent's potential to streamline fusion curation and ultimately improve patient care.

Outcomes of de novo del(17p) in multiple myeloma.

e19558 Background: Del(17p) (de novo) occurring in up to 10% of newly diagnosed myeloma patients is an independent risk factor for shorter progression free survival (PFS) and overall survival (OS). Current definitions for high-risk myeloma per R-ISS and more recently updated IMS/IMWG consensus support del(17p) as a poor prognostic factor with inferior outcomes. Several studies have evaluated outcomes of patients with de novo del(17p), however, limited data exists on impact of other concomitant cytogenetic abnormalities on outcomes of these patients. In this large retrospective analysis, we present long-term outcomes of patients with de novo del(17p) with concomitant cytogenetic abnormalities. Methods: Among 421 myeloma patients identified with del(17p), 164 patients had de novo del(17p), defined as presence of del(17p) at myeloma diagnosis. Descriptive analyses were performed within the de novo del(17p) cohort, including evaluation of associated abnormalities. Survival outcomes were estimated using Kaplan–Meier method and compared with log-rank tests. Univariate Cox proportional hazards models were used to assess associations with PFS and OS. Statistical analyses performed using SAS version 9.41, with significance set at p < 0.05. Results: In the overall evaluable cohort of del(17p) patients (N = 388), with a median follow-up of 114 months, median PFS was 30 months, and median OS was 74.4 months. For patients with de novo del(17p) (N = 164), 48% were females, 42% were black. With median follow-up of 94.8 months, median PFS was 26.4 months and median OS was 56.4 months. Univariate analysis revealed inferior PFS in del(17p) in combination with gain(1q) [HR 2.24, 95%CI 1.54-3.26], complex karyotype [HR 1.49, 95%CI 1.02-2.18], circulating plasma cells [HR 3.02, 95%CI 1.72-5.28] and extramedullary disease [HR 1.86, 95%CI 1.21-2.86] and superior PFS with hyperdiploidy [HR 0.65, 95%CI 0.45-0.94] and interestingly with autologous stem cell transplant (ASCT) [HR 0.58, 95%CI 0.39-0.88]. Univariate analysis revealed inferior OS in del(17p) in combination with gain(1q) [HR 2.12, 95%CI 1.39-3.24], del(13q) [HR 1.83, 95%CI 1.15-2.93], %plasma cells with del(17p) ≥20 vs < 20% [HR 2.52, 95%CI 1.37-4.63], complex karyotype [HR 1.81, 95%CI 1.18-2.78], circulating plasma cells [HR 3.88, 95%CI 2.16-6.97] and extramedullary disease [HR 2.19, 95%CI 1.38-3.46] and superior OS with hyperdiploidy [HR 0.56, 95%CI 0.37-0.84] and ASCT [HR 0.61, 95%CI 0.38-0.98]. Conclusions: De novo del(17p) combined with gain(1q), complex karyotype, circulating plasma cells, extramedullary disease had inferior PFS and OS while hyperdiploidy and ASCT were associated with superior PFS and OS. Del(13q) and %plasma cells with del(17p) ≥20% were associated with inferior OS. Further evaluation of the dataset might enable us to unfold the differential prognostic outcomes of patients with de novo del(17p) and develop therapeutic strategies to overcome their poor prognostic significance.

Impact of shallow whole genome sequencing on diagnostic yield and prognostic precision in myelodysplastic syndromes.

6567 Background: Accurate cytogenetic characterization is critical for risk stratification in myelodysplastic syndromes (MDS). Conventional karyotyping and fluorescence in situ hybridization (FISH) are limited in resolution, target specific loci, and cannot detect copy-neutral loss of heterozygosity (CN-LOH). LeukoPrint, a CE-IVD-marked shallow whole-genome sequencing (sWGS, 1×coverage) test, enables genome-wide detection of copy number alterations (CNAs) and CN-LOH. Previously validated in acute myeloid leukemia and multiple myeloma, it improved CNA detection and prognostic accuracy. This study evaluated its ability to enhance diagnostic yield and refine prognostic precision in a large MDS cohort. Methods: Bone marrow samples from 461 MDS patients were profiled for genome-wide CNA/CN-LOH using LeukoPrint. Results were compared with conventional karyotyping and FISH to assess detection yield and concordance. The impact of additional LeukoPrint findings on Revised International Prognostic Scoring System (IPSS-R) cytogenetic risk stratification and MDS subclassification was evaluated. Results: LeukoPrint detected cytogenetic abnormalities in 63.3% of patients, comprising CNAs in 50.3%, CN-LOH in 23.9%, with 10.8% harboring both. Recurrent CNAs included del(5q) (10.0%), del(20q) (10.0%), +8 (8.9%), and del(7q) (7.8%), among others. CN-LOH frequently affected regions that overlapped common CNA loci, such as 5q (3.7%), 7q (3.7%), and 17p (0.7%). Compared with conventional cytogenetics, LeukoPrint showed 94.4% concordance (κ=0.854) with FISH for five key loci (−5/del(5q), −7/del(7q), +8, del(20q), −Y) and a higher detection rate than karyotyping (65.7% vs 39.2%). For the 11 IPSS-R defined cytogenetic abnormalities (del(3q), del(5q), del(7q), del(11q), del(12p), del(17p), del(20q), +8, +19, -7, and -Y), it identified all karyotype-detected lesions and increased detection yield by 49.4%. These newly identified abnormalities led to IPSS-R cytogenetic risk reclassification in 32.4% (33/102) of comparable cases, predominantly upgrading patients to higher-risk categories. Specifically, 26 patients were reassigned from Good to Intermediate (n = 17), Poor (n = 2), or Very Poor (n = 7); 5 from Intermediate to Poor (n = 4) or Very Poor (n = 1); and 1 from Poor to Very Poor. Furthermore, by detecting additional aberrations such as del(17p) or 17p CN-LOH, LeukoPrint enabled more accurate molecular classification, including the reclassification of one case from MDS-IB1 to MDS-biTP53. Conclusions: sWGS-based LeukoPrint substantially enhances cytogenetic detection in MDS, outperforming conventional karyotyping and FISH. By identifying additional clinically relevant cytogenetic abnormalities, it improves prognostic risk stratification and refines disease classification, supporting its integration into routine MDS cytogenetic assessment.

Heterogeneity of interim PET partial metabolic response in DLBCL: Risk stratification using ΔSUVmax.

e19052 Background: Interim 18 F-FDG PET/CT (iPET) is widely used for response assessment in diffuse large B-cell lymphoma (DLBCL). However, the Lugano classification relies on qualitative metabolic response categories, and the prognostic heterogeneity within Lugano-defined partial metabolic response (PMR) remains poorly characterized. Evidence supporting treatment modification based on iPET findings is also limited. Methods: We retrospectively analyzed 125 newly diagnosed DLBCL patients who underwent 18 F-FDG PET/CT at baseline and after four cycles of first-line therapy. Interim response was assessed according to Lugano criteria and categorized as PMR or no metabolic response (NMR). The relative change in tumor SUVmax between baseline and interim PET (ΔSUVmax) was calculated as a quantitative imaging biomarker. Progression-free survival (PFS) was the primary endpoint. Multivariable Cox regression was used to identify independent prognostic factors. A composite risk score incorporating ΔSUVmax and International Prognostic Index (IPI) group was constructed to stratify patients into risk categories. Interaction analyses explored whether baseline risk modified the association between treatment modification after cycle 4 and PFS. Results: Among 125 patients, 122 (97.6%) were classified as PMR and 3 (2.4%) as NMR by Lugano criteria. During follow-up, 31 PFS events occurred. Unfavorable ΔSUVmax (<= 66%) independently predicted inferior PFS (hazard ratio [HR] 4.56, 95% confidence interval [CI] 2.18–9.54; P<0.001). IPI group was also independently associated with PFS. The final model combining ΔSUVmax and IPI achieved a concordance index of 0.752. Risk stratification based on the composite score demonstrated clear separation of PFS among low-, intermediate-, and high-risk groups (log-rank P<0.001). Formal interaction testing using a Cox model including an interaction term between risk group and treatment change revealed a borderline interaction effect (likelihood ratio test P≈0.10), suggesting that the impact of treatment modification may differ according to baseline risk level. Conclusions: Substantial prognostic heterogeneity exists within Lugano-defined PMR patients. Quantitative assessment using ΔSUVmax refines risk stratification beyond qualitative iPET criteria and may help contextualize treatment decisions following interim PET in DLBCL.

Radiotherapy followed by CAPOX plus tislelizumab in microsatellite-stable rectal cancer with synchronous resectable metastases: Updated results of the MIRACLE-1 study.

e15555 Background: Microsatellite-stable (MSS) tumors comprise ~95% of metastatic colorectal cancer cases and show low response to immunotherapy. Emerging evidence suggests combining radiotherapy with chemotherapy and PD-1 inhibitors may yield promising responses in locally advanced rectal cancer (RC). The MIRACLE-1 study evaluated this combination as upfront treatment for MSS RC with synchronous resectable metastases. Methods: MIRACLE-1 was a prospective, single-arm, phase II study. Inclusion criteria included MSS RC with primary tumor ≤10 cm from anal verge on MRI and limited liver/lung metastases deemed resectable. Patients received upfront radiotherapy: hypofractionated radiotherapy (HFRT) for primary lesion and HFRT or stereotactic body radiotherapy (SBRT) for metastases. Subsequently, six cycles of CAPOX plus Tislelizumab were administered. Tumor response was assessed after the third and sixth cycles. Further management included primary tumor resection and metastasectomy/local ablative therapies for metastases. For patients unable to preserve anal sphincter, a watch-and-wait (WW) strategy was considered if clinical complete response (cCR) of primary tumor was achieved. For patients achieving no evidence of disease (NED), adjuvant Tislelizumab was continued for up to 1 year postoperatively. Other patients received investigator-determined subsequent therapy. Primary endpoint: 1-year NED rate. Secondary endpoints: objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and safety. Results: As of December 31, 2025, efficacy data were available for 50 patients (37 males, 74.0%; median age 60 years, range 28-71). Among these, 62.0% had liver metastases, 20.0% lung metastases, and 18.0% both liver and lung metastases. RAS/BRAF mutations were detected in 62.0% of primary tumors. Upon reassessment, 38 patients (76.0%) achieved partial response (PR), 10 (20.0%) stable disease (SD), and 2 (4.0%) progressive disease (PD). ORR was 76.0%. Additionally, 54% (27/50) attained NED. Median follow-up duration was 18.7 months (95% CI: 15.5-21.9). Median PFS was 17 months (95% CI: 8.7-25.3), and 1-year PFS rate was 61.2%. Median OS was not reached, with 1-year OS rate of 83.5%. One treatment-related death occurred due to immunotherapy-induced hepatitis. All-grade treatment-related adverse events (TRAEs): thrombocytopenia (93.8%), lymphopenia (81.3%), and anemia (77.1%). Grade 3/4 TRAEs: thrombocytopenia (39.6%), lymphopenia (14.6%), and neutropenia (12.5%). Conclusions: In MSS RC patients with synchronous resectable metastases, radiotherapy combined with CAPOX plus Tislelizumab demonstrated promising antitumor efficacy and manageable safety profile. While initial findings are encouraging, longer follow-up is needed to assess durable outcomes. Clinical trial information: NCT05359393 .

Blood-derived small extracellular vesicle-based liquid biopsy for repeatable genomic and transcriptomic monitoring in adult-type diffuse glioma.

e14081 Background: Adult-type diffuse glioma is an aggressive primary brain tumor characterized by profound spatial and temporal heterogeneity. Although, clinical decision-making relies primarily on tissue biopsy, pathologic examination of resected tumor typically involves only a small portion of the heterogeneous tumor mass, limiting molecular interpretation. Moreover, repetitive sampling of intracranial tissue is not feasible. Small extracellular vesicles (sEV), released by all cell types and detectable in circulation, can carry nucleic acids originating from intracranial tumors, capable of crossing the blood–brain barrier. Since sEV can be isolated from blood repeatedly and non-invasively, they represent a promising platform for longitudinal genomic and transcriptomic profiling. Methods: DNA isolated from plasma sEV of glioma patients was sequenced and processed through a standardized variant calling and hard-filtering workflow (depth, mapping quality, genotype quality, strand-bias metrics). Variant recurrence across plasma-derived sEV (n=5) and concordance with matched solid tumor DNA (n=3) were assessed. RNA was also isolated from plasma sEV (n=5 healthy; n=3 glioma) and analyzed by capture-based whole-transcriptome sequencing. Results: Across sEV-DNA samples, we detected ~30–70 high-confidence variants per patient after filtering, with multiple loci recurrent across individuals. A subset of these variants was shared across all samples, supporting technical reproducibility. In matched sEV–solid biopsy datasets, more than 200 shared variants were observed in a representative paired analysis, demonstrating measurable overlap between sEV and tissue DNA while also indicating that sEV profiles contain additional variants not captured by single-site biopsy sampling. Importantly, sEV RNA whole-transcriptome sequencing detected expression of >9,000 genes and identified ~500 dysregulated genes in glioma sEV relative to healthy controls. sEV from glioma patients broadly showed transcriptional suppression compared to healthy controls, with 13 transcripts uniquely detected in glioma sEV and 43 were exclusive to controls. Notably, several recurrent sEV-DNA variants, including those annotated to WBP1L, ATXN1, and MLLT3, were consistently detected across all five glioma sEV-DNA samples, and their corresponding transcripts also showed altered expression in sEV-RNA profiling. This concordance between DNA-level variation and transcriptomic signal strengthens confidence in the sEV-derived mutation calls and highlights their potential for uncovering previously unrecognized molecular alterations relevant to glioma biology. Conclusions: Combined sEV- DNA and -RNA profiling provides a feasible, non-invasive, and repeatable approach to capture complementary genomic and transcriptomic features of glioma.

Real-world evidence on changes in uptake, sepsis, and costs with dual immunotherapy for first-line NSCLC.

e20701 Background: The addition of immunotherapy to platinum-based chemotherapy regimens has transformed first-line treatment of non-small cell lung cancer (NSCLC), as demonstrated by KEYNOTE-407. Subsequently, CHECKMATE 9LA showed improved overall survival (OS) with a tolerable safety profile when dual immunotherapy was combined with chemotherapy. This study aimed to provide comprehensive real-world evidence on the utilization, adverse events, and healthcare costs associated with first-line chemo-immunotherapy regimens compared to non-immunotherapy regimens in NSCLC. Methods: We conducted a retrospective analysis of the Highmark claims database from January 2020 through May 2025. Adult patients diagnosed with NSCLC of any stage who initiated first-line chemotherapy with either singlet immunotherapy, doublet immunotherapy, or no immunotherapy were included. Key outcomes assessed included time to treatment discontinuation (TTD), incidence of adverse events (AEs), healthcare costs estimated as per-member-per-month (PMPM), and overall survival (OS) determined from recorded deaths. Results: A total of 3,117 patients met inclusion criteria: 1,560 (50.0%) received chemotherapy alone, 957 (30.7%) received chemotherapy with singlet immunotherapy, 37 (1.2%) received chemotherapy with doublet immunotherapy, and 563 (18.1%) received other regimens. Median TTD was 96 days [IQR 55-143] for chemotherapy only, 93 [IQR 51-134] days for chemotherapy with singlet immunotherapy, and a notably shorter 55 [IQR 49-68] days for chemotherapy used with doublet immunotherapy. PMPM cost increased significantly at follow-up for all patients, with patients receiving chemotherapy and doublet immunotherapy seeing the largest increase from $6,895 at baseline to $75,348 at follow-up. Adverse events were similar across all arms; however, sepsis occurred more frequently in the doublet immunotherapy group (18.9%) compared with the singlet immunotherapy group (7.4%) or the chemotherapy alone group (8.9%). Among 945 patients with recorded deaths, 1- and 3- year OS rates were 79.2% and 58.8% for chemotherapy alone, 73.8% and 44.0% for the singlet immunotherapy arm, and 74.9% and 62.4% for the doublet immunotherapy arm, respectively. Conclusions: This real-world analysis reveals a substantial gap between clinical trial data and routine clinical practice for first-line NSCLC treatment. Dual immunotherapy regimens were remarkably underutilized, associated with an increased incidence of sepsis, and incurred significantly higher healthcare costs. While acknowledging the limitations of a retrospective, claims-based study, these findings underscore critical real-world challenges related to utilization, safety, and economic burden. These insights are vital for informing treatment guidelines, payer policies, and future research to optimize value-based care in NSCLC.

Predictors of low- and high-grade ICANS after CAR-T: A nationwide analysis.

7036 Background: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a leading cause of morbidity following chimeric antigen receptor T-cell (CAR-T) therapy. However, the real-world predictors of severity remain incompletely defined. We evaluated whether ICANS risk differs between multiple myeloma (MM) and other CAR-T indications. Methods: CAR-T hospitalizations were identified using ICD-10-PCS procedure codes. ICANS was identified using ICD-10-CM grade-specific codes (G92.00–G92.05) and severity was graded as none, low-grade (1–2), or high-grade (3–5). The 2022–2023 Healthcare Cost and Utilization Project National Inpatient Sample (HCUP NIS) with discharge weights was used for this analysis. Multivariable multinomial (nominal) regression (reference outcome: no ICANS) estimated adjusted odds ratios (aORs) for low- and high-grade ICANS. Cancer type was modeled with MM as a reference and compared with lymphomas, leukemias, solid/metastatic malignancies, and unspecified/other malignancies, adjusting for prespecified comorbidities including dementia, diabetes, and substance use diagnoses. Results: Among 10,105 weighted CAR-T hospitalizations, the risk of high-grade ICANS varied significantly by cancer type. Relative to MM, high-grade ICANS was significantly higher in leukemia (aOR 5.23 (95% CI 3.81–7.16), p < 0.001); lymphoma (aOR 3.91 (95% CI 3.07–5.00), p < 0.001); solid/metastatic malignancy (aOR 1.92 (95% CI 1.30–2.83), p = 0.001); and unspecified/other malignancy (aOR 6.34, 95% CI 4.98–8.07, p < 0.001). For low-grade ICANS, lymphoma was associated with increased odds compared with MM (aOR 1.53, 95% CI 1.31–1.78; p<0.001). Comorbidity signals were dominated by baseline neurologic vulnerability and metabolic disease. Dementia was the strongest predictor of high-grade ICANS (aOR 7.54, 95% CI 4.13–13.78; p<0.001). Drug abuse was associated with increased odds of low-grade ICANS (aOR 2.68, 95% CI 1.45–4.97; p=0.002). Diabetes with complications was associated with both low-grade (aOR 1.49, 95% CI 1.24–1.79; p<0.001) and high-grade ICANS (aOR 1.63, 95% CI 1.33–1.99; p<0.001). Conclusions: In a nationally representative inpatient cohort, multiple myeloma (MM) was associated with significantly lower odds of high-grade ICANS compared with other CAR-T indications, especially leukemia and lymphoma. Dementia and complicated diabetes were highly predictive of high-grade ICANS across all cancer types. These findings identify a clinically actionable risk profile that may inform future risk-stratified monitoring and early intervention strategies as CAR-T use expands. Limitations include reliance on administrative ICD-10 coding, which may misclassify ICANS severity, the possibility of clinical confounding, and a lack of product-specific and other clinical granularity.

Impact of variant topography of <i>NPM1</i> mutations in acute myeloid leukemia.

6536 Background: NPM1 is a frequent driver mutation in AML and conveys favorable prognosis in the absence of FLT3 mutations. Currently, NPM1 subtypes (Type A, B, D and non-ABD) are approached uniformly. A granular analysis evaluating NPM1 subtypes (ST) is essential to improve molecular risk stratification in AML. We seek to evaluate the molecular intricacies of NPM1 variants and genomic architecture to determine how these influence outcomes in AML. Methods: The cohort had patient data from Karmanos Cancer Institute, meta-analytic cohorts (Awada et al., 2021; Kewan et al., 2023), cBioPortal, and AACR GENIE (v17) (Cerami et al., 2012; Gao et al., 2013; de Bruijn et al., 2023). Clinical and genomic characteristics of NPM1 MT AML were reviewed. Insertions between nucleotides 863 and 864 determined the ST classification: TCTG (A), CATG (B), CCTG (D) and others (non-ABD). Stratification of NPM1 by VAF was performed by quartiles from the median. Clonal hierarchy was defined as a difference in VAF ≥5% and differences &lt;5% were designated as codominant. Results: Of 7653 patients with AML, 5342 (84.2%) had de novo AML. NPM1 MT was present in 1570. Type A was most common (73%), followed by non-ABD (18%), B (5%) and D (4%). Median age was 66 years (IQR 53.8-73.7) and was similar across groups. Females more frequently had non-ABD than B or D (67% vs 45% and 53%, p=0.0008 and 0.04, respectively). Non-ABD had the least proliferative bone marrow compared to A, B or D (blast percentage 54 vs 79, 75.5, 70, p&lt;0.0001, p=0.0015, p=0.02). Type A had lower VAF than other ST (29% vs 34%, p&lt;0.0001), while B and D had higher VAF than other ST (38% vs 30%, p&lt;0.0001 and 33% vs 30% p=0.0004). The most common co-mutation with NPM1 was DNMT3A (48%). Type A was enriched for DNMT3A compared to other ST (54% vs 34%, p&lt;0.00001). Type A and D had more IDH1 , IDH2 , and NRAS mutations than B and non-ABD (17% vs 10%, p=0.01; 23% vs 9%, p&lt;0.00001; 16% vs 10%, p=0.03, respectively). B and non-ABD were more enriched in WT1 compared to A and D (12% vs 4%, p=0.00002). Non-ABD was more enriched for FLT3 mutations than other ST (39% vs 24%, p=0.00012). DNMT3A R882 was enriched in high VAF (HV) compared to low VAF (LV) NPM1 (54% vs 46%, p=0.01). FLT3 was more common in HV NPM1 (34% vs 17%, p&lt;0.0001). NPM1 was often a subclone (82%), but was more likely to be dominant in B (29%, p=0.001). The median OS of NPM1 MT AML was 19 mo, similar across ST (A: 18 vs B: 14 mo, p=0.3896). OS was numerically higher in D (26 mo) and non-ABD (25 mo). LV NPM1 (Q1 ≤ 22.8%) had significantly better OS than HV (Q3 ≥ 38%): 21 vs 10 mo (p&lt;0.0001). This trend was most pronounced in D and non-ABD (D: 58 vs 10 mo, p=0.009; non-ABD: 29 vs 7 mo, p=0.005). Conclusions: As survival differences between NPM1 mutation subtypes were numerically different, enrichment of Type A and D for IDH1/2 and NRAS , non-ABD for FLT3 , B and D for WT1 probes the question of the impact of these co-mutations and VAF on NPM1 outcomes. Further work will evaluate the impact of NPM1 ST on de novo and therapy-related AML.

Expression of Concern: InDel markers: An extended marker resource for molecular breeding in chickpea

Nano-hydroxyapatite (n-HAp) and its composites for heavy metal removal from water: A comprehensive review

Intelligent Acousto‐Electrical Metamaterials (IAM) for Sound Source Detection (Adv. Mater. 36/2026)

Magnetically Induced Ordered Structure‐Assisted Defect Engineering Strategy for High‐Performance All‐Pseudocapacitive Film Supercapacitors

ABSTRACT Film supercapacitors, due to their light weight and good flexibility, are ideal power sources for wearable electronic devices. However, due to the limited research on pseudocapacitive film electrode materials, achieving high energy density for film supercapacitor remains a challenge. Here, the film anode (Fe@Fe 3 O 4 /CNTs) and cathode (NiCo‐NiCo compound/CNTs) were prepared by the vacuum filtration technology. Density functional theory calculations combined with experimental results revealed that oxygen vacancies can induce the formation of dense localized charge aggregation regions at the Fe/Fe 3 O 4 interface, significantly enhancing the charge transfer rate in electrochemical reactions, enabling the anode to achieve a specific capacity of 7.88 F cm −2 (749.1 C g −1 ) at a high mass loading of 16.7 mg cm −2 . Meanwhile, after introducing oxygen vacancies, the adhesion energy at the interface significantly increased, enhancing the binding strength between Fe and Fe 3 O 4 , making it less prone to peeling due to current shock during long‐term charge and discharge cycles, thereby improving the cycling stability of the Fe‐based anode (76% capacitance retention after 20 000 cycles). The all‐pseudocapacitive film supercapacitor successfully assembled obtains an excellent energy density of 1.362 mWh cm −2 (122.5 Wh kg −1 ) at a total mass loading of 27.8 mg cm −2 , far exceeding previously reported values.

SRM-CSR: unsupervised aspect category detection based on semantic-aware relevance modeling and contextual sentence representation