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A sustainable bio-adsorbent from cork oak leaves for methylene blue removal: RSM-BBD optimization, regeneration, DFT/MD insights, and contributions to the SDGs

Alternative probe chemistries for single-molecule analysis of long noncoding RNA

Validation of a tissue-based predictive RNA test for immunotherapy benefit in NSCLC: The PREDAPT study.

e14593 Background: Lung cancer remains the leading cause of cancer mortality worldwide. Immune checkpoint inhibitors targeting PD-1/PD-L1 have significantly improved outcomes in a subset of patients. Methods: OncoPrism, a clinical test employing a multidimensional predictive RNA-based immune biomarker, was evaluated for predicting immune checkpoint inhibitor (ICI) benefit in non-small cell lung cancer (NSCLC) patients. This study included data from 1,487 patients and evaluated OncoPrism across four NSCLC cohorts: one PD-L1 inhibitor cohort (n = 195), one PD-1 inhibitor cohort (n = 89), and two non-ICI cohorts (n = 193 and n = 1,010, respectively). Results: In the PD-L1 inhibitor cohort, OncoPrism predicted progression-free survival (p < 0.0001) and overall survival (p = 0.043). In the PD-1 inhibitor cohort, an observational clinical trial, PREDAPT (NCT04510129) enrolling patients from 17 healthcare systems, OncoPrism predicted overall response rate (p = 0.008), progression-free survival (p = 0.004), and overall survival (p = 0.011). PD-L1 Tumor Proportion Score (TPS) was not predictive of response, progression-free survival, or overall survival. OncoPrism did not predict overall survival across two non-ICI NSCLC cohorts (p = 0.54, p = 0.73), suggesting the test is specifically predictive of ICI benefit rather than being prognostic with more limited clinical utility. Conclusions: Overall, the data show OncoPrism high patients are likely to benefit from a two to three-fold increase in overall response rate, progression-free survival, and overall survival compared to those in other OncoPrism groups. These results underscore the impact of OncoPrism to address the current unmet need for ICI response prediction in NSCLC.

Longitudinal assessment of interfractional geometrical variations of gastrointestinal organs in patients undergoing abdominal radiotherapy.

e16457 Background: Significant anatomical variations of organs-at-risk (OARs), particularly the stomach and duodenum, pose major challenges in abdominal radiotherapy. This study aimed to quantitatively characterize the interfractional geometric stability of these organs during a standard treatment course to provide a scientific basis for adaptive planning and margin optimization. Methods: We retrospectively analyzed 10 patients with abdominal cancer who received radiotherapy. For each patient, diagnostic-quality kV-level fan-beam CT (kV-FBCT) scans were performed daily before each treatment fraction using an integrated linac system (uRT-linac 506). A total of 110 serial scans—including the initial planning CT (pCT) and 10 repeat scans per patient sampled during the treatment course—were retrieved. The stomach and duodenum were manually re-contoured on all scans by senior radiation oncologists. Geometric variations were evaluated using: 1) Volumetric change (ΔV%); 2) Surface-based agreement (MDA and HD); 3) Spatial overlap assessment (DSC). Results: A total of 110 daily kV-FBCT scans were evaluated. The stomach exhibited profound geometric instability, with a mean DSC of 0.62 ± 0.11 and extreme volumetric expansion up to 299.81% (mean ΔV%: 45.08% ± 60.66%). The mean MDA and HD for the stomach were 6.18 ± 3.17 mm and 26.55 ± 12.41 mm, respectively. The duodenum showed even poorer spatial overlap (mean DSC: 0.52 ± 0.12). These geometric variations remained unpredictable and significant throughout the treatment course, with no trend of anatomical stabilization observed. Conclusions: During abdominal radiotherapy, the stomach and duodenum undergo substantial and unpredictable interfractional shifts. The low DSC values and large Hausdorff distances observed via daily kV-FBCT suggest that static planning margins are insufficient. Our quantitative data underscore the necessity of online anatomical assessment and adaptive strategies to ensure safe treatment delivery near gastrointestinal structures.

Disproportionate reporting of hepatic injury with acute leukemia therapies.

e18509 Background: Therapies to treat relapsed/refractory acute leukemia are associated with hepatotoxicity. Cholestatic and hepatocellular injury are adverse drug reactions (ADRs) seen in clinical trials. This pharmacovigilance study uses the FDA Adverse Event Reporting System (FAERS) to evaluate signaling for hepatic ADRs across therapies. Methods: FAERS is a voluntarily reported database to monitor ADRs. Reports for suspected therapies associated with cholestasis, hepatitis, jaundice, graft-versus-host disease (GvHD), and sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were evaluated. The OpenVigil system was used for common therapies- including antibody therapies, tyrosine kinase inhibitors (TKI), hypomethylating agents, and targeted agents. The Reporting Odds Ratio (ROR) was used to determine if these reports were significant. 95% confidence intervals (CI) and p-values were calculated to assess the significance between each drug and ADR. P-values were significant (≤ 0.05), unless stated otherwise. ROR=(positive reports with drug/negative reports with drug)/(positive reports without drug/negative reports without drug). An ROR >1 is considered a potential signal for an ADR. Results: (Table 1) Gilteritinib showed disproportionate reporting for cholestasis (ROR 4.19, 95% CI 2.43-7.22) and hepatitis (ROR 4.54, 95% CI 2.89-7.12). Blinatumomab showed disproportionate reporting for cholestasis (ROR 2.63, 95% CI 1.75-3.96). Imatinib showed signals across all outcomes: cholestasis (ROR 1.41, 95% CI 1.08-1.86), hepatitis (ROR 1.67, 95% CI 1.35-2.08), and jaundice (ROR 2.49, 95% CI 2.09-2.95). Enasidenib showed disproportionate reporting for jaundice (ROR 2.45, 95% CI 1.32-4.57). Dasatinib showed reduced signals across all outcomes: cholestasis (ROR 0.52, 95% CI 0.32-0.83), hepatitis (ROR 0.56, 95% CI 0.38-0.84), and jaundice (ROR 0.66, 95% CI 0.46-0.94). Ponatinib, azacitidine, and midostaurin had insufficient reports for evaluation. There were no reports of GvHD or SOS/VOD. Conclusions: Hepatotoxicity associated with leukemia therapy showed agent-specific differences, notably with gilterinib and imatinib across multiple domains. In contrast, dasatinib and venetoclax had potentially favorable safety profiles. The lack of SOS/VOD and hepatic GvHD signals in FAERS may reflect underreporting and the exclusion of known causes, like gemtuzumab ozogamicin. These findings support further investigation of hepatotoxicity in these patients. ADR signals. Drug Total ADRs ROR, CI (cholestasis) ROR, CI (hepatitis) ROR, CI (jaundice) Blinatumomab 9609 2.63 (1.75-3.96) - - Imatinib 40399 1.41 (1.08-1.86) 1.67 (1.35-2.08) 2.49 (2.09-2.95) Dasatinib 35913 0.52 (0.32-0.83) 0.56 (0.38-0.84) 0.66 (0.46-0.94) Venetoclax 55871 - 0.61 (0.45-0.83) 0.74 (0.56-0.96) Gilteritinib 3420 4.19 (2.43-7.22) 4.54 (2.89-7.12) - Enasidenib 3115 - - 2.45 (1.32-4.57)

Impact of dual inhibition of iNOS and COX2 on antitumor immunity and response to immune checkpoint blockade in hepatocellular carcinoma.

3153 Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint blockade (ICB) benefits a subset of patients, efficacy is often limited by an immunosuppressive tumor microenvironment. Inducible nitric oxide synthase (iNOS/NOS2) and cyclooxygenase-2 (COX2) are inflammation-associated enzymes implicated in immune regulation. We hypothesized that inhibition of these pathways enhances antitumor immunity and improves responsiveness to immune checkpoint therapy in HCC. Methods: Tumor tissues from 75 patients with resected hepatocellular carcinoma (HCC) were analyzed by immunohistochemistry for NOS2, COX2, and CD8 to assess expression levels and spatial correlations. In parallel, an orthotopic murine HCC model was established by intrahepatic injection of 7.5 × 10⁵ RIL-175 cells (n = 6–10 mice per group). Mice were treated with vehicle control, selective NOS2 inhibition (1400W), COX2 inhibition (celecoxib), anti–PD-L1, or combination regimens including triple therapy. After two weeks of treatment, tumors were harvested for immune profiling, including flow cytometry, spatial imaging, plasma cytokine analysis, and CITE-seq. In vitro, splenocytes isolated from B6 mice were treated with prostaglandin E2 (PGE2) or the nitric oxide donor DETA-NONOate, and expression of CD226 and TIGIT was quantified by flow cytometry. Results: High intratumoral NOS2 expression was associated with inferior overall survival in resected HCC patients (HR 3.65, p=0.0011), with further worsening observed in tumors co-expressing NOS2 and COX2 (HR 9.31, p<0.0001). In murine HCC, combined iNOS and COX2 inhibition significantly reduced tumor burden and promoted intratumoral accumulation of CD8⁺ and CD4⁺ T cells, accompanied by increased B-cell recruitment and elevated circulating IL-2 and IFN-γ. Triple therapy with dual enzyme inhibition plus anti–PD-L1 resulted in superior tumor control and prolonged survival. Single-cell transcriptomic analysis comparing control, dual inhibition, and triple-treatment groups revealed a progressive enhancement of CD8 + T-cell activation states, characterized by increased expression of activation-associated markers and reduced expression of inhibitory receptors. Dual and triple therapy induced upregulation of CD226 and downregulation of TIGIT in CD8⁺ T cells, reflecting enhanced antitumor effector function. In vitro, nitric oxide and prostaglandin E2 directly impaired CD8⁺ T-cell function, as evidenced by reduced CD226 and increased TIGIT expression. Conclusions: iNOS and COX2 cooperatively establish an immunosuppressive inflammatory program in HCC that limits CD8⁺ T-cell–mediated antitumor immunity and response to checkpoint blockade. Dual targeting of these pathways represents a promising strategy to enhance immunotherapy efficacy in HCC.

Real-world outcomes of dual checkpoint blockade versus PD-1/VEGF inhibitor combination as first-line therapy in metastatic renal cell carcinoma.

e16550 Background: Immune-based combinations have upstaged traditional treatment regimens by becoming the first-line therapy for advanced/metastatic renal cell carcinoma. Nivolumab-ipilimumab and PD-1/VEGF inhibitor combinations each have distinct benefits; however, comparative data are limited due to a lack of large-scale clinical trials. This study aims to evaluate the outcomes of the two treatment regimens to refine therapy choices. Methods: We set out to perform a multicenter retrospective cohort study to compare Nivolumab-Ipilimumab with Pembrolizumab-Lenvatinib and Nivolumab-Cabozantinib as first-line therapy in Metastatic/Advanced Renal Cell Carcinoma. We utilized real-world data from the TriNetX database spanning between January 2011 and December 2024. Eligible patients were identified using ICD-10-CM codes related to metastatic RCC and Advanced RCC. Propensity Score matching was used to characterize and balance the cohorts based on age, gender, and ethnicity. We measured the real-world overall and progression-free survival between the compared cohorts using the log-rank test, Kaplan-Meier survival curves, and Cox proportional hazard ratios. Results: Using TriNetX data, we performed two propensity-matched comparative arms. Arm 1 compares the outcomes between the cohorts Nivolumab-Ipilimumab and Pembrolizumab-Lenvatinib, with Arm 2 comparing cohorts Nivolumab-Ipilimumab and Nivolumab-Cabozantinib. After matching, Arm 1 included 965 patients, which showed no significant difference in both overall survival (1,224 vs 1,126 days; hazard ratio 0.919; 95% CI 0.79,1.068, p-value 0.66) and progression-free survival (85 vs 126 days; hazard ratio 1.23; 95% CI 0.932,1.623, p-value 0.927). Arm 2 included 2,498 patients and showed a statistically significant difference in overall survival (1,117 vs 786 days; hazard ratio 0.78; 95% CI 0.719,0.845; p-value < 0.0001) but no significant progression-free survival (100 vs 167 days; hazard ratio 1.18; 95% CI 0.982,1.433; p-value 0.089). Thus, demonstrating a significant overall survival in patients who received Nivolumab-Cabozantinib compared to Nivolumab-Ipilimumab. Conclusions: The treatment landscape of Metastatic/Advanced Renal Cell Carcinoma has evolved significantly with the advent of dual checkpoint inhibitors and PD-1/VEGF inhibitor combinations. In this multicenter retrospective cohort study, Pembrolizumab-Lenvatinib showed no significant change in patients’ overall survival and progression-free survival compared to the Nivolumab-Ipilimumab combination. In contrast, Nivolumab-Cabozantinib had superior overall survival compared to Nivolumab-Ipilimumab, though there was no significant difference in progression-free survival. These findings, projecting from real-world data, would aid clinicians in making effective treatment decisions.

Downstream mTOR effectors and VEGFR as biomarkers of malignant stratification in pathologic and genomic heterogeneity of PEComas.

e23527 Background: Perivascular epithelioid cell tumours (PEComas) are rare mesenchymal neoplasms characterized by co-expression of melanocytic and myogenic markers. This spectrum includes typically benign angiomyolipoma (AML), and PEComa-NOS, a diagnostically challenging entity with highly variable malignant potential and no established molecular criteria for stratification. PEComas are classically divided into tumors driven by loss-of-function mutations in TSC1 or TSC2 and a smaller subset harboring TFE3 rearrangements, both converging on activation of the mTORC1 pathway. Although mTOR inhibitors are the standard treatment, clinical resistance is common and may reflect incomplete suppression of downstream translational output. The aim of this study was to evaluate downstream mTOR effectors and VEGFR as biomarkers of malignant stratification in PEComas. Methods: FFPE tissue from 21 tumors was examined, including 8 AML and 13 PEComa-NOS, with central expert confirmation; 5 cases showed clinically and/or pathologically confirmed malignant behavior. Immunohistochemistry was performed for 4E-BP1, phosphorylated 4E-BP1 (p-4E-BP1), eIF4E, and VEGFR, with expression quantified using the H-score method. Targeted next-generation sequencing was performed in 6 PEComa-NOS cases using the Ion Torrent Oncomine Comprehensive Assay v3 on the Genexus System. Results: Expression levels of 4E-BP1, eIF4E, and VEGFR were higher in PEComa-NOS compared with AML (p < 0.001, p = 0.034, and p = 0.003, respectively), whereas no difference was observed for p-4E-BP1 (p = 0.670). High tumor cellularity was associated with increased expression of 4E-BP1 and VEGFR (p = 0.006 and p = 0.007). VEGFR expression showed a negative correlation with mitotic count (R = −0.43, p = 0.053) and was higher in tumors with necrosis than in those without (p = 0.011). Within the PEComa-NOS group, eIF4E expression also correlated negatively with mitotic activity (R = −0.54, p = 0.067). NGS analysis revealed a heterogeneous mutational landscape. Pathogenic loss-of-function mutations in TSC1 or TSC2 were identified in n = 3 cases; notably, all n = 3 TSC-negative malignant tumors harbored pathogenic variants affecting DNA damage response–related genes, including BRCA2 and PMS2 , with additional alterations involving NOTCH pathway components. Conclusions: Increased expression of 4E-BP1, eIF4E, and VEGFR was observed in PEComa-NOS compared with benign AML, suggesting differences in downstream mTOR signaling. Pathogenic alterations in DNA damage response genes identified in TSC-negative malignant cases point to underlying molecular heterogeneity. These findings indicate that combined immunohistochemical and targeted genomic evaluation may provide complementary information for stratifying PEComa beyond canonical mTOR pathway alterations.

Safety and efficacy of eganelisib in adults with higher-risk myelodysplastic syndrome (HR-MDS) or relapsed/refractory (R/R) acute myeloid leukemia (AML).

6507 Background: The gamma isoform of PI3K (PI3Kγ) directs a myeloid-specific signaling node (PI3Kγ-AKT1-PAK1) identified as a core dependency in AML responsible for LSC self-renewal, medullary homing, and resistance to venetoclax and nucleoside analogues (Luo 2024; Gu 2024; Kelly 2024; Qiu 2025). Eganelisib is a highly potent isoform-specific inhibitor of PI3Kγ that demonstrated safety and effective target modulation in solid tumors. Here we report results of a Phase I study of eganelisib monotherapy in R/R AML or HR-MDS using doses previously shown to be biologically active [NCT06533761]. Methods: Eligible patients had ECOG PS <2, R/R AML or IPSS-R Int-Very High risk MDS that was R/R to prior therapy with ≥10% BM blasts. Eganelisib was administered orally in two cohorts of 45 mg and 60 mg QD in 28-day cycles. The primary endpoints were safety and efficacy per ELN 2022 (AML) and IWG 2023 (HR-MDS) and recommended dose for expansion (RDE). Additional endpoints included PK and PD effects assessed by AKT S273 phosphorylation in monocytes. Results: 15 patients have been treated to date (n=7, 45 mg; n=8, 60 mg); patient characteristics are summarized in the table below. There were no DLTs at either dose level. PD studies revealed dose-dependent reduction in AKT phosphorylation of ~90% at the 60 mg dose. Of the 10 patients who completed a 28-day cycle, anti-leukemic activity and evidence of clinical benefit was observed in 4 patients, including a CR in 1 patient at 45 mg. Three patients at 60 mg demonstrated anti-leukemic activity: 1 patient achieved <5% bone marrow blasts by flow cytometry, major cytogenetic response, rapid subclonal clearance, with full trilineage count recovery and low levels of persistent circulating blasts; two patients (both with TP53 mutations) with stable/decreasing marrow blasts had a progressive rise in neutrophils while on therapy. Longest duration of treatment is 5 cycles. Exposure to eganelisib was variable across both dose levels, and both doses showed overlapping plasma concentrations. Conclusions: Eganelisib demonstrates effective inhibition of PI3Kγ with single agent activity in heavily treated, poor-risk patients, validating PI3Kγ as a key vulnerability in MDS and AML. Importantly, eganelisib had no intrinsic hematologic toxicity, consistent with previous studies and pre-clinical observations that PI3Kγ is dispensable for normal hematopoiesis. Given the capacity to potentiate activity of nucleoside analogues and venetoclax, combined therapy in previously untreated HR-MDS & AML patients at the RDE of 60 mg QD is planned. Clinical trial information: NCT06533761 . 45 mg (n=7) 60 mg (n=8) All (n=15) Age (median/range) 78 (71-85) 59 (20-74) 72 (20-85) AML | MDS 7 | 0 7 | 1 14 | 1 Prior MDS or MDS-related changes 6 5 10 Prior therapies(median/range) 2 (1-3) 2 (1-6) 2 (1-6) Adverse-risk ELN 86% 71% 79% TP53 mutation 43% 43% 43% Prior intensive chemo/venetoclax 14%/71% 50%/100% 33%/87%

Clinicogenomic determinants of early progression on first-line osimertinib in <i>EGFR</i> -mutant NSCLC.

8634 Background: With the recent approvals of the FLAURA2 and MARIPOSA regimens in EGFR -mutant non-small cell lung cancer (NSCLC), identifying clinicogenomic features predictive of suboptimal outcomes with first-line osimertinib monotherapy is critical in guiding upfront treatment selections. Methods: This is a multicenter retrospective study enrolling patients (pts) with advanced NSCLC harboring common EGFR mutations (exon 19 deletions [ex19del], L858R) treated with first-line osimertinib monotherapy across 13 centers (Clinical cohort). Comprehensive baseline genomic data on tumor tissue were available for DFCI and MSKCC (Genomic cohort). The association of clinicogenomic features with real-world progression-free survival (rwPFS) was investigated. Time-dependent discrimination for very-early progression (rwPFS &lt; 6 months) was evaluated using Receiver Operating Characteristic (ROC) curve-based Area Under the Curve (AUC). Variable importance was assessed by delta (Δ) AUC after covariate exclusion. Moreover, very-early progression was analyzed with a Cox model censored at 6 months, reporting adjusted hazard ratios (aHR). Results: A total of 1488 pts were enrolled in the clinical cohort; at median follow-up of 43.3 months, median rwPFS was 16.3 months (95%CI 15.3-17.4), median overall survival was 36.7 months (95%CI 34.8-39.4). The strongest predictor of very-early rwPFS in a multivariable model, including, age, sex, EGFR mutations, PD-L1 tumor proportion score (TPS), concurrent TP53 mutations, metastatic sites (brain, bone, liver), performance status, was PD-L1 TPS (aHR 2.75 for ≥50% versus 0%, p &lt; 0.0001), with the largest decrease in the AUC when excluded from the model (ΔAUC = 0.17). Looking at genomic features in the genomic cohort, at median follow up of 38.2 months, loss-of-function mutations in KMT2D (HR 7.1, p &lt; 0.001), TP53 (HR 1.4, p = 0.01), RB1 (HR 1.7, p = 0.01), RBM10 (HR 1.6, p = 0.01), CREBBP (HR 2.7, p = 0.02), ATM (HR 2.1, p = 0.04 ), predicted shorter rwPFS. Next, we investigated the role of concurrent tumor suppressor gene ( TSG ) alterations beyond TP53 , including in this cathegory those with a p &lt; 0.1 for rwPFS and mutated in at least 5 cases (RBM10, CREBBP, ATM, RB1, KMT2D, TSC2, PTEN). TSG MUT had shorter rwPFS compared to TSG WT (aHR 1.5, p = 0.01), specifically in L858R subgroup (aHR 1.7, p = 0.02), while TP53 MUT had shorter rwPFS compared to TP53 WT in ex19del only (aHR 1.7, p = 0.01). Combining TP53 with TSG, pts with TP53 MUT plus at least one TSG MUT and pts with TP53 WT -TSG MUT had shorter rwPFS compared to TP53 WT -TSG WT and TP53 MUT -TSG WT (10.8, 13.1, 21.9, 18.1 months, respectively, p = 0.004). In the genomic cohort, PD-L1 TPS was the strongest predictor of very-early rwPFS (ΔAUC = 0.16), followed by TP53 combined with TSG (ΔAUC = 0.08). Conclusions: In this multicenter real-world cohort, baseline PD-L1 and TP53 combined with TSG predict very-early progression to first-line Osimertinib.

Benefit of adjuvant chemotherapy in resected stage I-IV CRC patients based on ctDNA dynamics across two timepoints: Results from GALAXY study.

102 Background: In current clinical practice, ACT for stages IIB-III CRC is administered as soon as the patient is medically able, and within 8 weeks post-surgery. However, initiation &gt;8 weeks may be appropriate in some patients. The interim analysis of the CIRCULATE-Japan GALAXY showed that patients with ctDNA-negativity during 2-10 weeks post-surgery do not derive benefit from ACT, although a small subset of these ctDNA-negative patients recurred. In this study, we analyzed early ctDNA dynamics to assess if turning ctDNA-positive at 12 weeks identifies the subgroup of initially (4-weeks post-surgery) ctDNA-negative patients who will benefit from ACT. Methods: This analysis included 1,034 patients with stage I-IV CRC undergoing curative-intent surgery from the GALAXY study who were ctDNA-negative at the first timepoint (TP#1; 4 ± 2 weeks post-surgery) and had subsequent ctDNA results available at the second TP (TP#2; 12 ± 2 weeks post-surgery). ctDNA was assessed using a personalized, tumor-informed assay (Signatera, Natera). DFS was assessed between TP#1-negative patients receiving ACT versus observation, stratified by ctDNA dynamics (turned positive at TP#2 or remained negative at both TPs). Analysis was landmarked at the TP#2 (12 weeks ± 2 weeks post-surgery) and Hazard ratios (HRs) were estimated using Cox proportional hazards models. Results: Of the 1,034 patients with ctDNA-negativity at TP#1 included in this analysis, 47.8% were females, and 73.8% had colon cancer, whereas 26.2% had rectal cancer. The pathologic stage distribution included: 11% Stage I / Low Risk Stage II, 72% High Risk Stage II / Stage III, and 17% Stage IV. The median patient age was 69 years (range 25-93) and the median follow-up was 33 months. Median time to ACT initiation was 6.7 weeks (range 3-12) post-surgery. Among patients who became positive at TP#2 (N=36), ACT was associated with significantly improved DFS compared with observation (HR 0.3; p=0.0165). Two-year DFS rates were 45.5% in the ACT group and 9.8% in the observation group, with a median DFS of 22 months and 2.5 months, respectively. In contrast, among patients who remained ctDNA-negative at both TPs (N=998), DFS outcomes were favorable regardless of ACT administration (HR 0.8, p=0.1744), with 2-year DFS rates of 87.1% and 84.1%, respectively, and median DFS was not reached in either group. Conclusions: A statistically significant and clinically meaningful benefit of ACT in resected stage I-IV CRC patients who were ctDNA-negative at 4 weeks but converted to positive at 12 weeks post-surgery was observed. These results underscore the critical role of both the 4- and 12-week post-surgery time points for risk stratification and indicate that early ctDNA dynamics can identify a subgroup of initially ctDNA-negative patients who may benefit from delayed ACT. Clinical trial information: UMIN000039205.

Impact of an artificial intelligence–based management model on psychological and behavioral outcomes in breast cancer patients undergoing home CDK4/6 inhibitor therapy: A multicenter randomized controlled trial.

633 Background: Patients receiving CDK4/6 inhibitors (CDK4/6i) often face significant psychological and physical challenges. This study evaluated the multi-dimensional impact of an AI-based management model (Group A), a customized active follow-up model (Group B), and conventional care (Group C) on the psychological status, quality of life (QoL), and biological indicators of patients with HR+/HER2- breast cancer and their primary caregivers . Methods: In this randomized controlled trial (2024–2025), 140 patient-caregiver dyads were enrolled and randomized into Group A (n=47), Group B (n=45), or Group C (n=48) . Longitudinal assessments were conducted using the Self-Rating Anxiety/Depression Scales (SAS/SDS), EORTC QLQ-C30, and PRO-CTCAE . Statistical analyses included mixed-design ANOVA for longitudinal changes, multiple correspondence analysis (MCA) for caregiver coping patterns, and Pearson correlation for psychological and serological indicators . Results: Baseline characteristics were balanced across groups (P &gt; 0.05) . Mixed-design ANOVA revealed significant time-by-group interaction effects for anxiety (F=5.961, P &lt; 0.001) and depression (F=4.931, P &lt; 0.001) . During follow-up, Groups A and B showed significantly better psychological stability and depression relief compared to Group C; Group C’s psychological status deteriorated over treatment cycles, peaking at T3 (16 weeks), while Groups A and B remained stable or improved (P &lt; 0.001) . Regarding QoL, Groups A and B significantly outperformed Group C in cognitive, emotional, social functioning, and global health (P &lt; 0.05), with Group A showing superior cognitive function scores . MCA identified a strong clustering between the AI-based model and "positive coping strategies" among caregivers, whereas Group C was associated with "severe psychological stress" . Pearson analysis showed SAS/SDS scores positively correlated with ALT (r=0.178, P &lt; 0.05) and glucose (r=0.221, P &lt; 0.05) . Furthermore, Group A achieved a higher capture rate of adverse events via AI monitoring, effectively mitigating high-grade toxicity risks . Conclusions: AI-based management and customized follow-up significantly improve psychological outcomes and QoL in breast cancer patients on CDK4/6i. The correlation between psychological stress and physiological markers (ALT, Glucose) highlights the necessity of a "bio-psycho-social" approach in oncology management. These findings support integrating AI models into precision survivorship care .

Efficacy and safety of brentuximab vedotin in relapsed or refractory diffuse large B-cell lymphoma: A systematic review and meta-analysis.

e19065 Background: Relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge, with a significant proportion of patients failing standard R-CHOP therapy. While CAR T-cell therapy has transformed outcomes for eligible patients, its use is limited by cost, logistics, and toxicity. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, has shown activity in CD30-positive lymphomas. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of BV in r/r DLBCL. Methods: Embase, PubMed, Cochrane, and ClinicalTrials.gov were searched through December 2025. Five studies comprising 260 patients were included. Pooled analyses of complete response rate (CRR), overall response rate (ORR), hematologic toxicity, peripheral neuropathy, treatment discontinuation, and mortality were performed using random-effects models in R 4.5.2 using the “metafor” package. Heterogeneity was quantified using I² statistics, and leave-one-out sensitivity analyses were conducted to explore variability. Results: The pooled CRR was 0.42 (95% CI: 0.17–0.72; I² = 84.8%), and ORR was 0.72 (95% CI: 0.40–0.91; I² = 54.1%), indicating meaningful clinical activity. Grade 3/4 hematologic toxicities included neutropenia (0.40; 95% CI: 0.32–0.48), thrombocytopenia (0.12; 95% CI: 0.01–0.61), and anemia (0.13; 95% CI: 0.02–0.57). Severe adverse events occurred in 76% of patients (95% CI: 0.54–0.90; I² = 84.3%). Grade 3/4 peripheral neuropathy was low (0.06; 95% CI: 0.03–0.12), and treatment discontinuation due to toxicity occurred in 17% (95% CI: 0.08–0.34). All-cause mortality was 6% (95% CI: 0.01–0.24). Conclusions: BV shows meaningful clinical activity in r/r DLBCL, with nearly three-quarters of patients achieving an objective response and a substantial proportion achieving complete remission. Hematologic toxicity and treatment discontinuation are notable, but severe neurotoxicity is rare. These findings support BV as a therapeutic option in r/r DLBCL.

Epidemiology and demographic patterns of mucosal lentiginous melanoma: A retrospective NCDB cohort.

e21608 Background: Mucosal lentiginous melanoma (MLM) arises from melanocytes in mucosal surfaces and is one of the rarest forms of melanoma, accounting for approximately 1–1.4% of all melanoma cases. It frequently follows an aggressive clinical course with poor long-term survival. Diagnosis is often delayed, and treatment guidance remains limited due to the scarcity of large studies. Broader epidemiologic data are needed to clarify its presentation and clinical context, prompting the use of the National Cancer Database (NCDB) to examine demographic patterns in patients with MLM. Methods: A retrospective cohort study using the 2004–2020 NCDB identified 330 patients with histologically confirmed MLM (ICD-O-3 Code 8746). Demographic variables included age, sex, race, Hispanic origin, facility type, urban status, income quartile, and Charlson-Deyo score. Treatment modalities and tumor characteristics were also analyzed. Descriptive statistics summarized patient features, and incidence trends were evaluated through regression analysis. Results: The incidence of MLM remained stable from 2004 to 2020 (R² = 0.515). Patients were primarily older adults (mean 64.9 years), female (71.8%), non-Hispanic (92.4%), and White (91.8%). Most had a Charlson-Deyo score of 0 (79.1%) and lived in metropolitan areas (85.3%), with 42.4% in the highest income quartile. The vulva (26.7%) and perianal skin (12.4%) were the most common primary sites. Surgical resection was performed in 79.0% of cases, with 58.2% achieving negative margins. Radiation, immunotherapy, and chemotherapy were administered to 24.8%, 19.4%, and 12.5% of patients, respectively, while hormone therapy was rarely used (0.9%). Palliative care was uncommon, with 95.5% of patients not receiving symptom-directed interventions. Patients traveled a mean of 73.6 miles (SD = 161.5) for treatment, most commonly at academic/research programs (66.3%). Early mortality was low (0.8% at 30 days; 1.5% at 90 days). Tumors averaged 39.0 mm, and mean overall survival reached 78.7 months, with survival rates of 66.2% at two years, 44.7% at five years, and 28.2% at ten years. Conclusions: This NCDB study provides the first population-level characterization of MLM. It predominantly affects older, non-Hispanic White females most commonly arising on the vulva and perianal skin. Most patients underwent surgical resection, and over half achieved complete tumor removal, with low early mortality. Radiation and immunotherapy were the most frequently used treatments, while palliative care was uncommon. Socioeconomic findings revealed that patients were more likely to reside in metropolitan areas, belong to the highest income quartile, and receive care at academic centers. These results underscore the need for further investigation into how demographic, socioeconomic, and treatment-related factors contribute to variability in outcomes for this rare melanoma subtype.

Efficacy of chimeric antigen receptor T-cell therapy in diffuse large B-cell lymphoma (DLBCL): A meta-analysis.

e19005 Background: Diffuse Large B- Cell Lymphoma (DLBCL) is an aggressive lymphoma; while R-CHOP has improved outcomes, 30-40% of patients often experiencing poor prognoses. CD19 CAR T-cell therapy has revolutionized treatment in this group but failure to achieve optimal outcomes in some patients prompted the development of dual target (CD19 &amp; CD20) CAR T-cell therapy. Given the lack of recent comprehensive data on combined therapeutic outcomes, this meta analysis aims to evaluate the overall efficacy of CAR T-cell therapy in DLBCL. Methods: A systematic search of PubMed, Embase, and Cochrane databases identified 483 studies, from which 9 clinical trials (n=376) evaluating CAR T-cell therapy efficacy in DLBCL were included. Chang et al. (2018) reported efficacy of both single and dual target CAR T-cell therapy separately and they were included as separate data sets. Primary outcomes were pooled proportions of overall response rates (ORR) and complete response (CR) rates using random-effects models with 95% confidence intervals (CI). Results: A total of 376 patients across 9 studies were included. The median age ranged from 48 to 65 years across 7 studies. The median number of prior therapies were reported in six studies ranging from 2 to 5. The pooled proportion of ORR under a random-effects model was 0.74 (95% CI: 0.58–0.88). There was significant heterogeneity across the studies (I² = 84%, p &lt; 0.0001), indicating considerable variability between the studies. Among the reported studies, the dual target CAR T-cell therapy studied in Chang et al. 2018 reported the highest response rate (0.91). All the ten studies reported complete response rates. The pooled proportion of CR was 0.45 (95% CI: 0.38–0.51) under the random-effects model. There was no significant evidence of between-study heterogeneity (I² = 6.9%, p = 0.38). Conclusions: This meta-analysis demonstrates that CAR T-cell therapy is an effective treatment for relapsed or refractory DLBCL, achieving a high pooled ORR of 74%, which was statistically significant despite high heterogeneity. While the CR rate was lower at 45%, the lack of significant heterogeneity in the CR results suggests consistent efficacy across different patient cohorts. These findings support the continued use and development of CAR T-cell therapies, with dual targeting approaches showing particular promise for improving clinical outcomes. Limitation: The generalizability of these findings may be constrained by the relatively small aggregate study population. Additionally, the pooled results may have been disproportionately influenced by a single large scale study (Kwon et al.), which possessed a significantly larger cohort compared to the other included trials.

Sex-stratified outcomes, hormone receptor expression, and treatment utilization in neuroendocrine carcinoma of the breast: A population-based analysis.

e12757 Background: Neuroendocrine carcinoma of the breast (NECB) is a rare malignancy with limited contemporary population-level data describing sex-stratified clinicopathologic features, treatment utilization, and survival outcomes. Given the rarity of NECB in men, descriptive population-based benchmarks are needed to contextualize outcomes in this understudied subgroup. Methods: We performed a retrospective population-based analysis of patients diagnosed with NECB using SEER Research Plus. Demographics, treatment utilization (surgery and chemotherapy), and hormone receptor expression were summarized by sex. Progesterone receptor (PR) status was evaluated due to greater completeness relative to other receptor variables in earlier diagnosis years. Observed overall survival was summarized descriptively by sex overall and stratified by receipt of surgery and chemotherapy, with survival estimates reported at 12 to 60 months. Given the rarity of NECB in men, analyses were descriptive and hypothesis-generating, and no formal comparative modeling was performed. Results: A total of 398 patients with NECB were included in the survival cohort, of whom 396 (99.5%) were female and 2 (0.5%) were male. In the PR-annotated subset (n = 350), 345 patients were female and 5 were male. PR positivity was observed in 54.2% of female patients (187/345) and 80.0% of male patients (4/5), though estimates among men were limited by small sample size. Among female patients, observed overall survival was 81.5% at 12 months (95% CI, 77.3–85.0) and 56.8% at 60 months (95% CI, 51.5–61.7). Observed overall survival for the combined cohort was 81.6% at 12 months and 57.0% at 60 months. Male patients demonstrated no observed death events during available follow-up; however, confidence intervals were not estimable due to sparse event counts. In analyses stratified by receipt of surgery and chemotherapy, female patients demonstrated expected declines in survival over time, while sex-stratified estimates among men remained limited. Conclusions: In this population-based cohort, NECB in men was exceedingly rare, limiting definitive sex-based outcome comparisons. Sex-stratified descriptive analyses demonstrated a high prevalence of hormone receptor expression and substantial heterogeneity in survival outcomes. These findings are hypothesis-generating and provide population-level descriptive benchmarks, highlighting the need for pooled multi-registry efforts to better characterize sex-specific biology, treatment patterns, and outcomes in NECB.

Influence of genomic and clinical high-risk features on outcomes after BCMA-directed bispecific antibody therapy in relapsed/refractory multiple myeloma.

7534 Background: The definition of high-risk (HR) multiple myeloma (MM) is broad and encompasses established molecular features such as gain(1q) and del(17p), and the presence of extramedullary disease (EMD), plasma cell leukemia (PCL), and focal lesions (FLs), particularly when located in the humeri and femora. While the prognostic relevance of these factors has been widely studied, most data were generated in the pre–T-cell–redirecting therapy era. Their role in patients treated with bispecific antibodies (bsAb) remains poorly defined. Here, we investigated the prognostic value of FL and other high-risk features in relapsed/refractory (RR) MM patients receiving BCMA-directed bsAB therapy. Methods: We included 152 RRMM patients (59% male) with a median age of 72 years at bsAb initiation, and a median of 5 (2-12) prior lines of therapy. All patients received at least one full cycle of BCMA targeting bsAb therapy. Functional imaging (PET and/or DWI) was performed within 3 months of bsAb initiation. HR status was defined according to the IMS/IMWG consensus. Progression free (PFS) and overall survival (OS) were estimated using Kaplan Meier analysis. To address the combined impact of prognostic factors, we calculated conditional inference trees. Results: Patients with FLs involving the appendicular skeleton (humeri/femora/ribs/shoulders, n=85) showed a trend toward shorter median PFS (20 months, p=0.061) and significantly shorter median OS (20 months, p=0.01), compared to patients without FLs (n=54) or with FLs confined to the spine and/or pelvis (n=13, median PFS and OS not reached [NR]). EMD and PCL were observed in 41 (27%) and 10 (7%) patients, respectively. Patients with PCL had the poorest outcomes, with both median PFS and OS &lt;2 months. EMD was also strongly prognostic, with significantly shorter PFS (11 vs 28 months) and OS (17 months vs NR) compared to patients without EMD. Similarly, HR disease as defined by IMS/IMWG criteria was associated with worse outcomes (PFS 14 months, OS 19 months). Conditional inference tree analyses for PFS identified PCL, EMD and del(17p) as the most relevant prognostic variables. For OS, PCL again emerged as the strongest predictor, whereas EMD was only prognostic in the presence of gain(1q). Notably, gain(1q) also modified the impact of other clinical parameters: both a higher number of prior therapy lines (&gt;5) and prior BCMA exposure were prognostic only in patients without gain(1q). Conclusions: Here, we show that EMD, PCL, and FLs of the appendicular skeleton are associated with inferior outcomes in RRMM patients treated with BCMA-directed bsAbs. Notably, the prognostic impact of these tumor growth patterns appears to be strongly influenced by the presence of genomic HR features, underscoring the central role of chromosomal aberrations as key modifiers of clinical risk even in the era of T-cell–redirecting immunotherapies.

Incidence, risk factors, and survival of secondary primary CNS tumors following hematologic malignancies: A population-based SEER study (2000-2022).

e19047 Background: Survivors of hematologic malignancies face an increased risk of secondary cancers, but the incidence and outcomes of primary central nervous system (CNS) tumors following hematologic malignancies remain poorly defined. Methods: Using the SEER 17 registries (2000–2022), we identified 830,018 patients with a first primary hematologic malignancy. Of these, 813 (0.1%) subsequently developed a primary CNS tumor. For comparison, a cohort of 122,270 patients with a first primary CNS tumor and no prior malignancy was constructed. We evaluated demographics, incidence, survival, temporal trends, and risk stratification by clinical and demographic factors. Standardized incidence ratios (SIRs) were calculated to compare secondary CNS tumor risk against the general population. Results: Patients with secondary CNS tumors were older at hematologic diagnosis, more frequently male (64%) and White (90%), and most commonly presented with nodal NHL (31%) or CLL (19%). Their CNS tumors predominantly arose in the brain (95%), with a median latency of 4.5 years, peaking within the first 5 years. Survival after secondary CNS tumor diagnosis was extremely poor (median OS: 6 months; 85% mortality). Even after adjustment for age, sex, race, and income, secondary CNS tumors conferred the worst overall survival, though cancer-specific survival was paradoxically higher than for primary CNS tumors without prior malignancy. The risk of secondary CNS tumors was significantly elevated compared with the general population (SIR = 1.17), rising sharply over time and peaking in 2022 (SIR = 8.57). Risk was highest among Asian/Pacific Islanders (SIR = 3.98), Black patients (SIR = 1.47), females (SIR = 1.55), adolescents (ages 15–19, SIR = 4.32), and those diagnosed within the first year after hematologic malignancy (SIR = 4.29). Extranodal NHL (SIR = 3.96) and acute lymphocytic leukemia carried the strongest associations, whereas Hodgkin lymphoma, CLL, and myeloma were associated with reduced risk. Radiation (SIR = 2.22) and chemotherapy (SIR = 1.36) significantly amplified risk. Anatomically, excess risks were profound for brain regions including cerebrum (SIR = 136.88), frontal (SIR = 105.51), temporal (SIR = 121.32), and parietal lobes (SIR = 102.05), with overlapping brain lesions (SIR = 208.76) showing the highest excess. Conclusions: Survivors of hematologic malignancies, particularly those with extranodal NHL, ALL, or prior radiation/chemotherapy, are at significantly elevated risk for aggressive secondary CNS tumors with dismal survival outcomes. These findings highlight the need for heightened surveillance, risk-adapted follow-up, and future studies on prevention and early detection strategies in this vulnerable population.

Real-world treatment patterns and outcomes during and after treatment with CDK4/6 inhibitors for HR-positive and HER2-negative metastatic breast cancer.

e13052 Background: The purpose of this multicenter study was to investigate treatment patterns and real-world outcomes among patients with hormone receptor-positive and human epidermal growth factor 2 receptor-negative (HR+/HER2-) metastatic breast cancer (MBC) treated with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in northwest China. Methods: Patients with HR+/HER2- MBC who received CDK4/6i for the first time between July 2017 and December 2024 at 11 centers were retrospectively included. Results: A total of 605 women were eligible for analysis, including 398 (67.2%), 126 (21.3%), and 68 (11.5%) who received CDK4/6i therapy as first-, second-, and third- or later-line treatment, respectively. The median PFS was 22.9 months (95% CI, 19.6-26.7 months). The earlier the CDK4/6i was used, the longer the mPFS was achieved (first-line 26.6 vs second-line 21.0 vs later-line 11.0 months, P = 0.00014). The data on at least two consecutive lines’ treatment after progression on CDK4/6i were available for 225 patients. The first post-CDK4/6i regimen was chemotherapy (CT), endocrine therapy (ET), or antibody–drug conjugates (ADC) in 121 (53.8%), 88 (39.1%), and 16 (7.1%) patients, respectively, with different mPFSb observed among the three group (CT 5.67 vs ET 9.20 vs ADC 10.03 months, P = 0.00029). Among all different sequential treatment combinations, there was a statistically significant difference in mPFS3 across different treatment regimens in the cohort that selected ET after progression on CDK4/6i (CDK4/6i→ET→ET 32.93 vs CDK4/6i→ET→CT 23.53 vs CDK4/6i→ET→ADC 33.67 months, P = 0.0017). Conclusions: Our findings support the early initiation of CDK4/6i plus ET in patients. After progression on CDK4/6i, ET should be preferred for patients maintaining endocrine sensitivity, otherwise ADC especially for HER2-low patients, whereas CT should be delayed as much as clinical feasible, as it seems that CT may weaken the efficacy of its subsequent ET or ADC. Patterns of post-progression therapy with CDK4/6i in different lines. All patients (n = 225) 1st line (n = 144) 2nd line (n=55) ≥ 3rd line (n=26) P CT 121 (53.8) 70 (48.6) 35 (63.6) 16 (61.7) 0.027 Taxanes 75 (33.3) 47 (32.6) 23 (41.8) 5 (19.3) Three-bines* 17 (7.6) 9 (6.3) 6 (10.9) 2 (7.7) Utidelone/Eribulin/others 29 (12.9) 14 (9.7) 6 (10.9) 9 (34.7) ET 88 (39.1) 64 (44.4) 16 (29.1) 8 (30.7) 0.041 Single SERD 11 (4.8) 6 (4.1) 4 (7.3) 1 (3.8) ET + overline CDK4/6i Palbociclib 11 (4.8) 8 (5.7) 2 (3.6) 1 (3.8) Abemaciclib 25 (11.1) 15 (10.4) 5 (9.1) 5 (19.3) Ribociclib 17 (7.6) 15 (10.4) 2 (3.6) 0 (0.0) Dalpiciclib 17 (7.6) 13 (9.0) 3 (5.5) 1 (3.8) PAM inhibitor* + FUL/AI 7 (3.2) 7 (4.8) 0 (0.0) 0 (0.0) ADC 16 (7.1) 10 (7.0) 4 (7.3) 2 (7.6) 0.73 *three-bines including Gemcitabine, Vinorelbine, or Capecitabine *PAM inhibitor including PI3K inhibitors, AKT inhibitors, mTOR inhibitors, etc.

Synthetic data generation from breast cancer patients to enable PSM on wide and multidimensional real-world populations.

e12574 Background: In several surgical oncology domains randomized controlled trials are no longer feasible due to ethical and acceptability constraints. Evidence generation therefore relies on real-world data (RWD), which are intrinsically affected by strong selection bias. Propensityscore matching (PSM) improves comparability but, in highly multidimensional datasets, often causes substantial loss of sample size. Synthetic data generation may enable expansion of matched cohorts while preserving real-world structure. We tested this methodology in the historical setting of breast conservation and radiotherapy vs. mastectomy. Methods: SEER-based RWD were used to compare PSM performance between real and synthetic cohorts. A synthetic cohort was generatedusing a conditional generative adversarial network, preconditioned on the same covariates used for propensity score estimation, to preserve the full multidimensional joint distribution of clinical, demographic, and socioeconomic variables, including rare and extreme treatment patterns. Fidelity, correlation structure, utility, and privacy were validated using the Synthetic Validation Framework (SAFE). Propensity scores were estimated via logistic regression including 12 covariates. Stratified nearest-neighbor PSM was applied using distances computed in a whitened covariate space (Mahalanobis-equivalent). Matching quality was assessed using standardized mean differences (SMD; &lt; 0.1 optimal, &lt; 0.2 acceptable). Identical matching parameters were applied to real and synthetic datasets, followed by caliper sensitivity analyses. Results: When PSM was applied to RWD alone (22,405 patients), only 7.5% of MX-RT patients (601) were matched, despite excellent balance (mean SMD 0.02; all SMD &lt; 0.2). The synthetic cohort (137,782 patients) substantially increased matching yield. Using identical parameters, 33.7% of MX-RT patients (17,383) were matched with preserved balance (mean SMD 0.037). After caliper optimization (c = 2.6), matching efficiency increased to 46.1% (23,753 patients), while maintaining acceptable balance (mean SMD 0.056; all SMD &lt; 0.2). The treated-to-control ratio remained stable (~1:1.4). Overall, synthetic data enabled up to a six-fold increase in matched patients, allowing exploration of clinically relevant subgroups. Conclusions: Synthetic data generation, validated with SAFE, enables recovery of sample size lost to PSM in highly multidimensional RWD while preserving covariate balance and structural complexity. This approach does not generate new clinical evidence but enables adequately powered exploratory and subgroup analyses in observational settings where randomization is no longer feasible.