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The role of coaching in enhancing clinical oncology academic performance.

9040 Background: Oncology faculty in academic medicine navigate a multitude of demands spanning clinical care, research, teaching, and administrative pressures. These forces are the impetus for the implementation of targeted interventions to enhance leadership capabilities. Coaching is a robust intervention and has been recognized as well-suited to meet faculty needs. Despite this recognition and increasing adoption, the impact of coaching on key outcomes in both research and clinical spaces remains underexplored. We leveraged Intentional Change Theory (ICT) to guide our evaluation of an internal coaching program within a large academic hospital in the South-Central United States. ICT articulates how alignment of one’s ideal self with their professional goals yields sustained personal transformation and is a useful guide for professional coaching. Methods: Through this conceptual framework, we employed a quasi-experimental approach to evaluate the impact of coaching on the research outcomes: clinical trials activated and h-index increase, as well as its components (new publications and new citations). Further, we investigated the impact of coaching on the clinical outcomes of Work Adjusted Relative Value Units (RVUs) and patient experience scores (Press Ganey Care Provider Scores). We conducted this study among a sample of clinical oncology faculty who participated in coaching (N = 189) and N = 200 matched peers who were eligible for but had not yet participated in coaching between 2018 and 2022. Results: Analyses revealed coaching positively impacted certain research productivity metrics; notably, faculty who participated in coaching were found to have greater increases in h-index ( F (1, 379) = 7.27, p = .007, η2 = .02, Coached M = 2.52, SD = 4.16; Comparison M = 1.69, SD = 1.77), new publications ( F (1, 318) = 6.26, p = .013, η2 = .02; Coached = M = 10.81, SD = 11.54; Comparison M = 8.06, SD = 10.18), and new citations ( F (1, 379) = 7.43, p = .007, η2 = .02; Coached M = 891.79, SD = 1,598.05; Comparison M = 509.47, SD = 1,054.25) in comparison to faculty who had not engaged with a coach. However, no significant differences were detected between groups in regard to clinical outcomes as measured by Work Adjusted Relative Value Units (RVUs) ( F (1, 304) = 2.06, p = .15, η2 = .007; Coached M = 6,316.48, SD = 3,558.46; Comparison M = 6,352.38, SD = 3,975.66), and patient experience scores ( F (1,150) = 0.91, p = .34, η2 = .006; Coached M = 95.35, SD = 6.41; Comparison M = 96.22, SD = 3.32), or the research outcome of clinical trial activations ( F (1,382) = 0.05, p = .83, η2 = .00; Coached M = .73, SD = 1.62; Comparison M = .49, SD = 1.42). Conclusions: Findings suggest coaching can be an effective intervention to enhance certain research outcomes reliant on self-regulation and individual motivation. Yet, initial evidence suggests coaching may be less well-positioned to influence outcomes prone to institutional constraints and governance.

Randomized phase I/II trial adjuvant CD40.HVAC, an immunotherapy engaging dendritic cells (DC), in patients with HPV16+ oropharyngeal carcinoma (OPC).

6018 Background: Up to 70% of OPCs are HPV-mediated predominantly by HPV16. E6/E7 oncoproteins, constitutively expressed in malignant cells, represent optimal immunotherapeutic targets. We evaluated CD40.HVac, a new DC engager combining a humanized IgG4 monoclonal antibody fused to HPV16 E6/E7, designed to target the CD40 receptor on DCs. Methods: This trial enrolled OPC HPV16⁺ patients (pts) in complete remission 16–22weeks (W) post curative treatment. In cohorts 1 (n=11) and 2 (n=11), pts were randomized (5:1) to receive subcutaneously, Hiltonol (1mg) adjuvanted CD40.HVac, 1 and 3 mg, respectively, or placebo, at W0, 4, 24. Dose-limiting toxicity (DLT) was assessed from W0–W6. Blood E6/E7-specific T cells were assessed 2W post-injection using stimulation of PBMCs with vaccine E6/E7 pools of peptides. CD8+T cells were characterized by expression of Activation Induced Markers (AIM). Immune response was defined as a ≥3-fold increase in HPV specific T cell responses over unstimulated controls after in vitro restimulation, or a net increase of ≥ 0.03% reaching at least 0.05% AIM⁺ T cells compared to baseline. Results: Median age was 58 years (IQR 51; 65), 68% were male, 68% were stage I or II, 32% stage III. At entry, 21 pts were lymphopenic (3 grade 3). All pts received the 3 planned injections. Four pts were randomized to placebo, 18 to CD40.HVac. No DLTs nor grade 3-5 adverse events (AEs) were reported. From W0 to W32, all pts treated with CD40.HVac experienced at least 1 vaccine related AE; 5 (28%) experienced at least 1 grade 2 AE while the 13 others experienced only grade 1 AEs. At W6, 77% of pts treated with CD40.HVac in the both 1 mg and 3 mg cohorts exhibited a 27-fold and 42-fold increase from baseline, respectively, in CD4⁺ T cells producing IL-2, IFNγ and/or TNF. By W26, responses were observed in 100% of pts treated with CD40.HVac in both cohorts, with 35-fold (1 mg) and 83-fold (3 mg) increases from baseline. AIM assays confirmed the induction of HPV specific CD4⁺ and CD8⁺ T cell responses. HPV specific CD8⁺ T cell responses were detected in 50% and 44% of pts treated with CD40.HVac at W6 in the 1 mg and 3 mg cohorts, respectively, and in 71% and 44% at W26. HPV specific CD8⁺ T cells displayed a polyfunctional cytotoxic phenotype, expressing IFNγ, TNF, granzyme B and CD107a, along with PD-1, consistent with an activated state. Both CD4⁺ and CD8⁺ T cell responses were durable and persisted up to1 year post-prime vaccination. Only minimal or no increases in HPV specific responses were observed in pts treated with placebo. After a median follow-up of 1 year, no pt presented disease relapse. HPVct DNA monitoring will be presented at the meeting. Conclusions: The safety and immunogenicity of CD40.HVac support further clinical development of this strategy in pts with HPV16+ OPC. Clinical trial information: NCT06007092 .

Associations between early on-treatment weight change and overall survival across targeted therapies in chronic lymphocytic leukemia.

e19001 Background: Targeted therapies for chronic lymphocytic leukemia (CLL) include BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) and the BCL-2 inhibitor venetoclax. We evaluated whether early on-treatment weight change after therapy initiation is associated with overall survival (OS) across agents. Methods: Using the nference nSights federated platform across multiple academic medical centers, we retrospectively identified adults with CLL (ICD-10 C91.1x) initiating ibrutinib, acalabrutinib, venetoclax, or zanubrutinib after diagnosis (>=3 encounters over >=30 days) with baseline weight within 90 days pre-initiation. Percent weight change from baseline was assessed at landmark months 1, 3, 4, and 6 post-initiation (nearest weight within +/-15 days). Cox proportional hazards models were fit by drug and timepoint for OS, adjusting for age, sex, baseline weight, baseline BMI, and diagnosis-to-treatment interval. Results: The cohort included 3,542 patients (ibrutinib 1,398; venetoclax 1,145; acalabrutinib 667; zanubrutinib 332). On-treatment weight gain was associated with improved OS for venetoclax at multiple landmarks (eg, month 3 HR 0.927; p<0.0001) and for ibrutinib at later landmarks (eg, month 6 HR 0.953; p<0.0001). Acalabrutinib and zanubrutinib were not significant at evaluated landmarks. Conclusions: On-treatment weight-trajectory metabotyping may provide a pragmatic clinical decision support signal in CLL, with drug-specific associations between weight gain and OS, strongest for venetoclax. Incorporating early weight-trajectory metabotypes into predictive risk stratification may help identify patients who could benefit from intensified supportive care, closer monitoring, or prognostic enrichment strategies during targeted therapy. Association between on-treatment weight change and OS for CLL patients. Drug Timepoint (Months) Patients C-Index HR (95% CI) p-value Ibrutinib 1 1057 0.606 0.994 (0.962-1.029) 0.747 Ibrutinib 4 889 0.612 0.968 (0.944-0.992) 0.011 Ibrutinib 6 803 0.634 0.953 (0.932-0.974) <0.0001 Acalabrutinib 6 329 0.65 0.979 (0.934-1.027) 0.386 Venetoclax 1 989 0.633 0.962 (0.926-1.000) 0.049 Venetoclax 3 888 0.657 0.927 (0.899-0.956) <0.0001 Venetoclax 4 855 0.641 0.937 (0.908-0.966) <0.0001 Venetoclax 6 678 0.652 0.933 (0.905-0.961) <0.0001 Zanubrutinib 6 178 0.716 0.928 (0.848-1.014) 0.099 HR represents risk per 1% weight change, with HR <1 indicating that weight gain is associated with reduced mortality. Only select rows with p-value<0.05 are shown.

Quality of life in cancer patients treated with anchored interleukin-12 (IL-12) immunotherapy: Results from a first-in-human phase 1 trial of tolododekin alfa (ANK-101).

2593 Background: Anchored immunotherapy is a novel method for retaining high concentrations of anti-tumor drugs in established tumors with limited systemic exposure. The integration of quality-of-life (QOL) assessment in a phase 1 study of anchored IL-12, tolododekin alfa (ANK-101), provided an opportunity to gather baseline QOL data, longitudinally measure patient well-being during drug exposure, identify associations between adverse events and patient well-being, and generate additional clinical benefit information. Methods: All patients enrolled in the phase 1 clinical trial of ANK-101 for patients with advanced/metastatic solid tumors were eligible and provided written informed consent. Patients were treated with direct intratumoral injection every 3 weeks up to 8 cycles over 6 months. QOL was measured by the validated FACT-G survey, which collects scores across a 27-item questionnaire that measures physical, family/social, emotional, and functional well-being. Subjects were asked to complete the FACT-G at baseline every 3 weeks during treatment and at end-of-treatment. QOL scores were evaluated by paired-sample t-tests to evaluate differences in QOL at various time intervals. Data cut-off was on October 21, 2025. Results: 39 of 40 (98%) patients completed at least two FACT-G surveys. The median age was 68 and 44% were female. Patients had a median of 5 lines of prior therapy (range 1-18). The most common cancer types included were melanoma (33%), head and neck (18%), cutaneous squamous cell carcinoma (8%), and colorectal cancer (8%). There were no dose-limiting toxicities but there were 42 grade 2 events in 13 subjects and five grade 3 events in 3 subjects (elevated liver transaminases, abdominal pain, neutropenia, stomatitis). At baseline, the median of QOL score was 80.5 (range 51-106). After two and four cycles, there was no decrease in QOL scores across any of the functional domains. For patients who developed grade 2 or 3 adverse events, there was a trend toward decreased QOL in social well-being (median 25.5 at baseline to 23 after two cycles; median change -2.0; p=0.08) and in physical well-being (median 24 at baseline to 20 after four cycles; median change -5.5; p=0.06 after four cycles). Patients who completed all 8 cycles of treatment demonstrated no change in any QOL measure (p range 0.14-0.70). Conclusions: ANK-101, the first anchored immunotherapy, was associated with QOL scores that were not significantly diminished in heavily pre-treated advanced cancer patients with a non-significant decrease in social and physical well-being among those who developed grade 2 or greater adverse events. Further, patients with visceral tumors had no difference in QOL compared to superficial lesions. Early implementation of QOL data is feasible in phase 1 trials and may be of use to identify drug impact on clinical and safety measures. Clinical trial information: NCT06171750 .

Etentamig in patients (pts) with relapsed/refractory multiple myeloma (RRMM) with prior exposure to B-cell maturation antigen (BCMA)–targeted therapy.

7508 Background: Data on response to BCMA-targeted therapies among BCMA-exposed pts with RRMM are limited. Outcomes after sequential/subsequent anti-BCMA bispecific T-cell engagers (Bs-TCE) are vital to evaluate. Etentamig is a next-generation differentiated BCMA x CD3 Bs-TCE composed of a bivalent BCMA-binding domain with a high-avidity, low-affinity CD3-binding domain potentially reducing cytokine release syndrome (CRS), and a silenced Fc tail for extended half-life and convenient monthly (Q4W) dosing. Phase 1 results of etentamig in RRMM showed robust efficacy and potential best-in-class safety. Methods: Arm B of the open-label, Phase 1b MOVISO study (NCT05650632) evaluated etentamig in pts with RRMM with ≥2 prior lines of therapy (PLT), including triple-class and prior BCMA exposure (antibody-drug conjugate [ADC] >30 days or CAR-T >6 months [mo] after last exposure). Primary safety endpoints were CRS and immune effector cell-associated neurotoxicity syndrome (ICANS); efficacy endpoints included objective response rate (ORR; IMWG 2016), duration of response (DoR), and progression-free survival (PFS). Pts received etentamig (60 mg IV; no step-up dosing [SUD]) on Cycle 1 Day 1 and Q4W thereafter. Results: At cutoff (June 11, 2025), 41 prior BCMA-exposed pts (CAR-T, n=24; ADC, n=17) had been treated; 24 (57%) were male, 38 (93%) were White, median (mdn) (range) age was 68 (43–89) years, 37 (88%) had ECOG PS ≤1, and 34 (81%) were triple-class refractory. Mdn (range) PLT was 6 (3–15). For 21 (51%) pts, the last PLT was BCMA directed; 23 (56%) had previously responded to anti-BCMA therapy (17/24 [71%] for CAR-T and 6/17 [35%] for ADC). Mdn (range) time from last prior CAR-T or ADC to first dose of etentamig was 15 (1–30) and 4 (1–45) mo, respectively. Mdn (range) follow-up was 5.5 (0.2–17.1) mo. Despite no SUD, CRS and ICANS were reported in 24 (57%) and 3 (7%) pts, respectively; all G1/2 events, except 1 G3 ICANS. G3/4 neutropenia and infections were reported in 15 (36%) and 17 (41%) pts, respectively. Efficacy outcomes are detailed in the Table (NE, not estimable). For pts whose last PLT was BCMA directed, MRD negativity (clonoSEQ, 10 –5 ) was seen in 2/3 (67%) evaluable pts, along with robust peak activation and proliferation of CD8+ T cells. Conclusions: Pts treated with etentamig achieved durable responses; rates were higher in pts who received CAR-T as last line. No new safety signals were observed; only low-grade CRS was seen despite no SUD. Clinical trial information: NCT05650632 . All prior BCMA (N=41) Prior BCMA CAR-T (N=24) ORR, n/n (%) [95% CI]  Overall 17/36 (47) [30–65] 11/22 (50) [28–72]  BCMA-directed last PLT 11/19 (58) [34–80] 7/11 (64) [31–89] Mdn DoR, mo [95% CI], No. of pts  Overall 13 [7–NE], N=17 13 [7–NE], N=11  BCMA-directed last PLT 13 [7–NE], N=11 13 [7–NE], N=7 Mdn PFS, mo [95% CI], No. of pts  Overall 3.4 [3–11], N=41 8.3 [2–NE], N=24  BCMA-directed last PLT 9.4 [2–NE], N=21 9.4 [2–NE], N=12

Combining zanidatamab, FOLFOX, and pembrolizumab as first-line therapy for HER2/PD-L1–positive gastroesophageal adenocarcinoma: The phase ll IKF-090/AIO ZANGEA trial with translational analysis.

TPS4244 Background: Gastroesophageal adenocarcinoma (GEA) presents a substantial global health challenge as the number of cases continues to rise. The current standard approach for treating previously untreated, metastatic HER2/PD-L1 positive GEA involves a combination of doublet chemotherapy, which consists of a platinum compound and a fluoropyrimidine, in combination with trastuzumab and pembrolizumab. Recently, the phase 3 HERIZON-GEA-01 trial has shown improved survival for zanidatamab in combination with CAPOX or fluoropyrimidine and cisplatin with the PD-1 inhibitor tislelizumab compared to chemotherapy and trastuzumab. Zanidatamab is a bispecific antibody that targets two distinct HER2 epitopes (domains 2 and 4), thereby crosslinking neighboring HER2 receptors and inducing receptor clustering. This leads to enhanced HER2 internalization, reduced downstream signaling, and increased Fc-mediated immune effector functions, compared with trastuzumab. There is currently insufficient evidence regarding the combination of zanidatamab with the frequently used chemotherapy backbone FOLFOX and no available data on combining this regimen with the PD-1 inhibitor pembrolizumab. Furthermore, biomarkers to predict response and toxicities are lacking. Methods: The ZANGEA study is an open-label, single-arm, multicenter, translational phase II trial designed to assess the efficacy, safety, tolerability and translational aspects of zanidatamab in combination with FOLFOX and pembrolizumab in patients with 1 st line HER2/PD-L1-positive GEA. The primary endpoint is the progression-free survival rate after 12 months. Secondary objectives include safety and tolerability, efficacy in terms of objective response rate, progression-free and overall survival and translational markers, such as blood-based signatures (e.g. inflammatory cytokines), microbiota signatures, dietary patterns or microbiota derived metabolites that may correlate with therapy response or side-effects. In total, 80 patients will be recruited to show an PFS at 12 months of 55% compared to 46% with trastuzumab/pembrolizumab/chemotherapy (KeyNote 811). Enrollment started on 16 Jan 2026. Clinical trial information: NCT07176312 .

The enzymatic component of the nitric oxide system in mitochondria of melanoma and skin: What changes occur?

e21537 Background: Malignant melanoma has a multifactorial etiology and a heterogeneous course. Modern concepts about the role of mitochondrial processes in oncogenesis are expanding, and the involvement of the nitric oxide (NO) system in the regulation of mitochondrial function and dynamics has been demonstrated. However, the bimodality of NO effects in carcinogenesis and tumor progression requires close study. The aim of the work was to study the dynamics of inducible nitric oxide synthase (NOS2) and endothelial nitric oxide synthase (NOS3) in mitochondria of tumor and skin cells in female mice of the C57BL/6 line at the growth stages of experimental melanoma B16/F10. Methods: Female C57BL/6 mice (n=84) were divided into two groups: intact controls (n=21) and the main group (n=63), which underwent subcutaneous transplantation of B16/F10 melanoma. Animals were euthanized at 1, 2, and 3 weeks post-implantation. Mitochondria were isolated from melanoma cells and from distal skin (taken at the maximum distance from the tumor) using differential centrifugation. Concentrations of NOS2 and NOS3 in the mitochondrial fraction were determined by enzyme-linked immunosorbent assay (ELISA). All reported data were statistically significant (p<0.05) as determined by nonparametric statistical tests. Results: NOS2 levels in melanoma cell mitochondria progressively decreased throughout tumor growth: by 5.5-fold at week 1, 127.6-fold at week 2, and 192.6-fold at week 3 compared to levels in intact skin mitochondria. Similarly, NOS3 levels in tumor mitochondria declined by 24.4-fold at week 1, 62.5-fold at week 2, and 508.5-fold at week 3. In contrast, mitochondrial NOS2 levels in the skin of tumor-bearing mice showed a significant change only at week 3, decreasing 9.2-fold relative to intact controls and were 7.9-fold lower on average than levels at weeks 1 and 2. Mitochondrial NOS3 content in the skin decreased at all observed time points: by 2.5-fold at week 1, 3.0-fold at week 2, and 20.3-fold at week 3 compared to intact values. At week 3, the skin NOS3 level was 8.0-fold and 6.7-fold lower than at weeks 1 and 2, respectively. Conclusions: Thus, mitochondrial nitric oxide (NO) system dysfunction in melanoma is multifaceted: a pronounced local suppression of NOS2 and NOS3 in tumor mitochondria is accompanied by significant, albeit less marked, alterations in the mitochondria of distant skin. The suppression of NOS3 observed in both tumor and distant skin mitochondria may indicate the involvement of the vascular component in melanoma progression. These findings underscore the significant role of the mitochondrial NO synthase (NOS) pool not only in the autonomous behavior of the tumor but also in the target organ's response. The identified patterns may facilitate the search for potential targets for novel therapeutic strategies.

Phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) ± rituximab (R) + tafasitamab (tafa) in adults with newly diagnosed (ND) Philadelphia chromosome–negative (Ph-) B lymphoblastic leukemia (B-ALL).

6535 Background: For adults with ND Ph- B-ALL, frontline regimens now often include the CD19/CD3 bispecific blinatumomab (blin). However, blin administration is challenging, particularly for less-experienced centers. DA-EPOCH ± R is safe and active in these patients (pts; Cassaday, et al, Leuk Lymphoma , 2023) and easier to deliver. Tafa is a CD19 monoclonal antibody active in B-cell lymphomas. We hypothesized that the addition of tafa to DA-EPOCH ± R will yield higher rates of measurable residual disease negativity (MRD-) without increasing toxicity or administration complexity. Methods: This is a phase II investigator-initiated study (NCT05453500) in adults (>18 years) with ND CD19+ Ph- B-ALL not eligible for a pediatric regimen. DA-EPOCH ± R was given as cited above; tafa 12 mg/kg was given IV on day (d) 1, 8, and 15 of each cycle (C). After blin consolidation was FDA approved, pts could receive this off-study. The primary endpoint was MRD- by multiparameter flow cytometry (MFC) per EuroFlow (~<10 -4 ) after C1 (~d 20); secondary endpoints included MRD- by MFC after C4 (~d 80); non-hematologic adverse events (AEs, CTCAE v5); and relapse-free (RFS) and overall survival (OS). Exploratory endpoints included high-throughput sequencing (HTS; <10 -6 ) by clonoSEQ in marrow and cerebrospinal fluid (CSF). If ³13 of 30 evaluable pts (³43%) are MRD- after C1, the primary endpoint is met (vs 28% with DA-EPOCH ± R alone; 80% power and one-sided α = 0.05). Results: From 3/2023 to 12/2025, 30 pts enrolled: 2 pts did not finish C1 due to grade (G) 4 AST elevation (related) and G5 C. perfringens sepsis (unrelated); 27 were evaluable for response and are the focus here. Median age was 67 (44-84), 70% male, 56% poor risk cytogenetics by NCCN, and 9 received R. Complete response (CR) rate was 85% (23/27); MRD- by MFC after C1 was 44% (12/27) and 80% (20/25) by C4 in pts with sufficient follow-up (f/u). In pts MRD- by MFC, 53% (8/15) were MRD- by HTS. Other G3+ AEs seen in >2 pts: infection (9); febrile neutropenia (8); low fibrinogen (6); hypotension (5); and syncope (4). Initial CSF MFC was positive in 3 pts; HTS was positive in these plus 4 more (7 total). With a median f/u among survivors of 10 mo (1-37), there were 3 relapses: 1 post-HCT and 1 after only 2 treatment cycles; all were CD19+, and 0 involved CNS. Only 2 pts got blin consolidation. 6 pts died: 4 non-relapse causes (3 post-HCT) and 2 from refractory ALL. No deaths were due to study treatment. 1-year RFS and OS were estimated to be 67% and 76%, respectively. Conclusions: DA-EPOCH ± R + tafa yields high rates of MRD-. Follow-up is immature, but early survival rates are comparable to more complex strategies. This study is on pace to reach its primary endpoint, with enrollment ending before the conference. HTS on CSF can identify CNS disease more frequently. Clinical trial information: NCT05453500 .

Immunotherapy for uncommon <i>EGFR</i> mutations in lung adenocarcinoma.

e20613 Background: While common EGFR mutations (ex19del/L858R) are associated with poor response to immune checkpoint inhibitors (IO) in lung adenocarcinoma (LUAD), data on IO efficacy in uncommon EGFR mutations remains limited . We evaluated the clinicogenomic features and outcomes of individuals with uncommon EGFR- mutant LUAD treated with IO-based therapy. Methods: Using next-gen sequencing data, we identified patients with uncommon (non-ex19del/L858R) EGFR- mutant LUAD seen at Indiana University Health from Jan 1 st 2018 to Dec 31 st 2025. Uncommon mutations excluding ex20ins were categorized as atypical. Endpoints were collected retrospectively through chart review for individuals with advanced disease. Kaplan-Meier was used to assess progression-free survival (PFS) and overall survival (OS). Results: Among 1497 patients with LUAD identified, 56 (3.7%) had uncommon EGFR mutations, including 49 (89%) with Stage IV disease. Median age was 69, 39% were male, 86% were White (86%), 65% had tobacco use history (median pack-years: 20), 25% had brain metastases, and 10% had ≥3 metastatic sites. Median tumor mutation burden (TMB) was 4.5 mut/Mb (range, 0-14). PD-L1 TPS were &lt; 1%,1-49%, and &gt; 50% in 39%, 44%, and 17% of cases. EGFR atypical mutations (most commonly G719X, S768I, and L961Q) comprised of 34 (69%) uncommon cases. Among 40 patients undergoing systemic therapy for metastatic disease, 14 received IO-based therapy. First-line (1L) treatments included IO-based +/- chemotherapy (33%), targeted based with tyrosine kinase inhibitor +/- chemotherapy or amivantamab/chemotherapy (62%), or chemotherapy alone (5%). Detailed outcomes of 1L IO-based and targeted based therapies were illustrated in Table 1, with trend towards favoring targeted-based therapies. Median OS for IO-treated and IO-naïve patients was 31.5 mo vs 61 mo (IO-treated (n = 14) vs IO-naïve (n = 26)) in uncommon and 40.9 vs 61 mo (IO-treated (n = 7) vs IO-naïve (n = 21)) in atypical mutant group. Among IO-treated patients with available PD-L1 data, mOS seemed to improve with higher PD-L1 levels (26 mo, &lt; 1%, n = 3; 24 mo, 1-49%, n = 5; 35 mo, ≥50%, n = 4). Response was independent of TMB status and smoking history. Notably, one patient with EGFR G719A and PD-L1 TPS 100% demonstrated a complete response to pembrolizumab after three cycles. Conclusions: While 1L targeted therapy trended toward longer survival, the small sample size limits interpretation. Immunotherapy could be a beneficial option for select patients with atypical EGFR mutations (especially if high PD-L1). Given its rare incidence, prospective evaluation of IO in this patient population warrants further evaluation through multi-institutional consortium studies. 1L therapy Median PFS (mo) 3-year OS (%) Uncommon (n=40)IO-based (n=13)Targeted based (n=25) 9.931.4 4068.9 Atypical (n=27)IO-based (n=7)Targeted based (n=20) 630.1 62.574.7

Performance of the NutriPal nutritional screening algorithm in advanced cancer palliative care: A multicenter study.

12062 Background: Malnutrition is highly prevalent in advanced cancer and is closely associated with functional decline, systemic inflammation, symptom burden, and impaired quality of life (QoL). Although several nutritional screening tools exist, none were specifically developed for patients with advanced cancer receiving palliative care. The NutriPal nutritional screening algorithm, which integrates the Patient-Generated Subjective Global Assessment short form and the Glasgow Prognostic Score, was recently developed for this population; however, evidence of its performance outside the development cohort remains limited. The objective was to evaluate the performance of the NutriPal nutritional screening algorithm in identifying nutritional risk among patients with advanced cancer receiving palliative care in a multicenter clinical setting and its association with functional status, inflammation, muscle strength, and QoL. Methods: This multicenter, cross-sectional study included adults with locally advanced or metastatic cancer receiving palliative care in four private oncology centers in Brazil from June 2024 to November 2025. Nutritional risk was classified using NutriPal in degrees 1 (lower) to 4 (greater nutritional risk). Karnofsky Performance Status (KPS), handgrip strength (HGS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and QoL (EORTC QLQ-C15-PAL) were evaluated as independent variables. Associations with worsening nutritional risk were examined using ordinal logistic regression. Results: A total of 165 patients were included (60% women; 70% ≥60 years). NutriPal classified 54% as degree 1, 25% degree 2, 10% degree 3, and 11% degree 4 nutritional risk. Worse nutritional risk was independently associated with KPS &lt; 60% (OR 2.67; 95% CI 1.17 - 6.07), low HGS in women ( &lt; 22 kg; OR 2.69; 95% CI 1.19 - 6.12) and men ( &lt; 32 kg; OR 2.06; 95% CI 1.02 - 5.44), NLR ≥2.78 (OR 2.02; 95% CI 1.18–3.15), and PLR ≥171.95 (OR 2.09; 95% CI 1.12 - 3.89). Poorer scores across all QoL domains (except insomnia) were significantly associated with higher nutritional risk (OR range 1.14 - 7.68), including global QoL (OR 4.08; 95% CI 2.14 - 7.61). Conclusions: NutriPal effectively discriminated nutritional risk severity and identified clinically relevant profiles characterized by functional impairment, systemic inflammation, and poorer QoL among patients with advanced cancer receiving palliative care in private oncology centers. These findings support its clinical utility as a targeted and pragmatic nutritional screening tool in real-world palliative oncology practice settings.

Association of clonal hematopoiesis driven by mosaic chromosomal alterations with epigenetic age in the PLCO trial.

10556 Background: Mosaic chromosomal alterations (mCAs) are age-associated clonal events detectable in peripheral blood and have been linked to hematologic malignancy risk and adverse clinical outcomes. Whether mCAs are associated with accelerated biological aging, as measured by DNA methylation–based epigenetic clocks, remains poorly understood. Methods: We analyzed peripheral blood DNA methylation data generated using the Illumina EPIC array from 482 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. mCAs were identified from SNP array data and classified by subtype, including autosomal copy-neutral loss of heterozygosity (CN-LOH), gains, losses, and loss of the sex chromosome . Epigenetic age was estimated using six established DNA methylation clocks: Hannum, Horvath pan-tissue/skin and blood, PhenoAge, GrimAge &amp; DunedinPACE. Associations between mCA presence, mCA subtype, clonal burden, and epigenetic age acceleration were evaluated using multivariable linear regression models adjusted for age, sex, smoking status, body mass index, and genetic ancestry. Results: Among 482 participants, 261 were mCA-free and 221 had at least one detectable mCA. Individuals with any detectable mCA exhibited higher epigenetic age acceleration than mCA-free individuals across multiple clocks, with the most consistent effect sizes across mCA subtypes observed for GrimAge. Although age acceleration was directionally higher among individuals with mCAs across all non–rate-based clocks, statistically significant differences were observed only for the Hannum, PhenoAge, and GrimAge clocks. For GrimAge, estimated effects for mCA-positive individuals were uniformly positive, except for gain-only events, with effect sizes ranging from 1.2 to 1.9 years of age acceleration. Age acceleration increased with clonal burden: participants with multiple mCAs (n = 51) exhibited greater age acceleration than those with a single mCA (n = 170), particularly for GrimAge and PhenoAge. Higher cellular fraction was also associated with increased age acceleration, with significant associations observed for GrimAge (β = 2.97, 95% CI 0.82–5.12, p = 0.007) and Hannum (β = 4.25, 95% CI 1.14–7.37, p = 0.008) clocks. Conclusions: Mosaic chromosomal alterations, particularly CN-LOH and higher clonal burden states, are associated with accelerated biological aging in peripheral blood leukocytes. Epigenetic age acceleration was most consistently observed using GrimAge, a mortality- and healthspan-associated clock, with more variable and less consistent associations observed for chronological age-trained and rate-based clocks. These findings suggest that epigenetic age acceleration may represent a clinically relevant feature of clonal hematopoiesis, warranting further investigation in aging populations. Funded by NCI Contract No. 75N91019D00024.

Human versus AI in audiological practice: A comparative evaluation of ChatGPT and physician treatment decisions in idiopathic sudden sensorineural hearing loss

Purpose Artificial Intelligence (AI) is increasingly being applied in the field of audiology, demonstrating potential to support screening, diagnosis, and rehabilitation in auditory and vestibular disorders. However, its effectiveness in guiding complex therapeutic decisions—such as those for idiopathic sudden sensorineural hearing loss (ISSNHL)–remains uncertain. This study aimed to compare treatment recommendations for ISSNHL made by medical doctors (MDs) with those proposed by an AI system (ChatGPT, GPT-4o model). The goal was to evaluate the concordance between human and AI decision-making, particularly regarding the administration of corticosteroids and adjunctive therapies, and to assess AI’s potential in clinical practice. Methods This study is a retrospective observational analysis. Data from 86 patients diagnosed with ISSNHL were retrospectively analysed. Treatment decisions by MDs were compared with those generated by ChatGPT using anonymized patient datasets and a series of sequential prompts simulating multidisciplinary discussion. Agreement between AI and MDs was assessed using Cohen’s Kappa coefficient. Results Overall, poor to fair agreement was observed between AI and clinician treatment decisions. ChatGPT did not recommend oral corticosteroids in 26 cases where MDs prescribed them (Kappa = 0.029) and recommended intravenous corticosteroids in 20 patients who were not treated with this approach by MDs (Kappa = 0.393). Discrepancies were also evident in recommendations for intratympanic steroids (Kappa = −0.044) and adjunctive therapies (Kappa = 0.035). These differences likely stem from the AI’s rigid adherence to generalized treatment protocols and limited contextual understanding. Conclusion While ChatGPT (GPT-4o) shows promise in generating structured, protocol-driven suggestions, its clinical decision-making capabilities for ISSNHL remain inferior to those of experienced physicians. The AI’s lack of individualized reasoning and context sensitivity resulted in frequent discordance with physician-led care. Thus, AI should currently be viewed as a supportive tool in audiological practice, with its integration requiring careful oversight and further validation in real-world clinical environments.

Synthesis of magnetite nanoparticles from steel iron oxide waste as a resource recovery strategy: An optimization and characterization study

The mechanistic basis and cellular functions of UFMylation

Dual‐Site Catalytic Interfaces Synergistically Boost Desolvation and Redox Kinetics in Zinc‐Ion Batteries

ABSTRACT Aqueous zinc‐bromine batteries hold significant promise for large‐scale energy storage owing to their intrinsic safety, high operating voltage and low cost. Their deployment, however, is limited by sluggish Zn 2 + desolvation at the anode/electrolyte interface and sluggish redox kinetics of bromine species at the cathode. In this work, we developed a dual‐site catalytic interface that selectively accelerates interfacial kinetics without altering the bulk electrolyte. On the anode‐facing side, the indium acetylacetonate molecules provide soft Lewis acid In 3 + sites that weakly coordinate with water and interact with solvated Zn 2 + , effectively lowering Zn 2 + desolvation energy and enabling uniform, dendrite‐free zinc deposition. On the cathode‐facing side, the copper acetylacetonate molecules offer redox‐active Cu 2 + /Cu + sites that catalyze the Br 0 /Br − conversion, accelerating reaction kinetics and improving reversibility. As a result, the desolvation energy barrier decreases by approximately 21% (from 39.69 to 31.25 kJ·mol −1 ). The zinc‐bromine battery with dual‐site interface delivers a high specific capacity exceeding 293.8 mAh·g −1 at 0.2 A·g −1 , which reaches approximately 87.5% of the theoretical capacity of pure bromine (335.5 mAh·g −1 ). Our findings reveal that targeted interfacial catalysis can overcome kinetic bottlenecks in zinc batteries while preserving the intrinsic properties of the electrolyte, offering a general strategy for high‐performance energy storage systems.

Geospatial modelling of seawater intrusion risk in coastal aquifer systems of Southern Malabar Coast, Kerala using GALDIT index and hydrogeochemical analysis

Electrostatic tuning of the pyridoxal-5′-phosphate cofactor site defines pH dependence in type I cystathionine β-lyases

Multiple myeloma incidence, prevalence, and mortality burden in the United States: Retrospective epidemiological trends and burden (1990–2023) with machine learning-based projections to 2050.

e19546 Background: Multiple myeloma, a plasma cell malignancy, imposes a substantial disease burden in the United States, with improvements in survival driven by novel therapies yet persistent challenges in incidence and long-term outcomes. This study examined age-standardized rates (ASRs) of DALYs, deaths, incidence, and prevalence from 1990 to 2023, quantified trends via estimated annual percentage change (EAPC), and projected future burden to 2050 through ARIMA time-series forecasting. Methods: Age-standardized rates per 100,000 population were extracted from the Global Burden of Disease 2023 database for the United States, stratified by sex (Both, Female, Male). Historical trends (1990–2023) were evaluated using EAPC from linear regression on log-transformed ASRs. Future projections (2024–2050) were generated with ARIMA models fitted to historical time series, providing point estimates and 95% prediction intervals (PI). Results: From 1990 to 2023, age-standardized DALYs (Both sexes) declined from 74.26 (95% UI: 68.16–81.47) to 55.94 (95% UI: 50.99–60.56), with an EAPC of -1.06% (95% CI: -1.18 to -0.94); females showed a steeper reduction (EAPC -1.19%, 95% CI: -1.34 to -1.05) than males (EAPC -1.03%, 95% CI: -1.13 to -0.93). Age-standardized death rates decreased from 3.24 to 2.72 (EAPC -0.69%, 95% CI: -0.80 to -0.58), with stronger declines in females (EAPC -0.83%) than males (EAPC -0.67%). Incidence fell modestly from 4.33 to 3.95 (EAPC -0.47%, 95% CI: -0.63 to -0.30), while prevalence remained nearly stable (EAPC -0.08%, 95% CI: -0.34 to 0.18), reflecting substantial survival gains from therapeutic advances. ARIMA forecasts indicate accelerated declines in age-standardized DALYs (Both: from 55.07 in 2024 toward ~32.55 by 2050, with widening intervals at extended horizons), deaths (to ~1.76), and incidence (to ~2.68), while prevalence shows gradual erosion or stabilization. Conclusions: Age-standardized burden of multiple myeloma in the US decreased substantially from 1990–2023 across DALYs, mortality, and incidence, with more pronounced improvements in females and notable survival-driven gains. Projections to 2050 anticipate continued reductions in key metrics, underscoring the impact of therapeutic innovations, though persistent absolute cases due to aging populations emphasize the need for sustained research into prevention and equitable access to care. Measure Sex EAPC Lower 95%CI Upper 95%CI DALYs Both -1.06 -1.18 -0.94 DALYs Female -1.19 -1.34 -1.05 DALYs Male -1.03 -1.13 -0.93 Deaths Both -0.69 -0.8 -0.58 Deaths Female -0.83 -0.97 -0.69 Deaths Male -0.67 -0.77 -0.58 Incidence Both -0.47 -0.63 -0.3 Incidence Female -0.61 -0.8 -0.42 Incidence Male -0.42 -0.57 -0.27 Prevalence Both -0.08 -0.34 0.18 Prevalence Female -0.28 -0.56 -0.01 Prevalence Male 0.06 -0.2 0.31

Real-world outcomes with atezolizumab versus durvalumab plus chemotherapy for extensive-stage small cell lung cancer: A TriNetX propensity-matched analysis.

11145 Background: First-line treatment for extensive-stage small cell lung cancer (ES-SCLC) consists of platinum-etoposide plus an immune checkpoint inhibitor (ICI), either atezolizumab or durvalumab. No head-to-head randomized trials have compared these regimens. We evaluated real-world outcomes associated with these ICIs using a large multi-institutional database. Methods: We performed a retrospective cohort study using the TriNetX Global Collaborative Network. Adults with ES-SCLC treated with platinum-etoposide plus atezolizumab or durvalumab were included. The index date was initiation of platinum, etoposide, and ICI therapy. Cohorts were matched 1:1 using propensity scores based on age, sex, race, tobacco use, and comorbidities. The primary outcomes were overall survival (OS) and real-world progression-free survival (rwPFS), defined as time to second-line therapy or death. Survival was analyzed using the Kaplan-Meier method and cox proportional hazards models. Secondary endpoints were immune-related adverse events (irAEs) and hospitalization rates and evaluated by z-test. The study protocol was created and reviewed by the authors prior to implementation and did not require IRB approval. Results: Among 750 eligible patients (677 atezolizumab, 73 durvalumab), 69 matched pairs were identified. Median follow-up was 13.4 months for atezolizumab and 8.6 months for durvalumab. Median OS was significantly longer with durvalumab compared with atezolizumab (23.2 vs 9.1 months; Hazard Ratio [HR] 0.58, 95% CI 0.47–0.93; p=0.021). No significant difference in rwPFS was observed (8.6 vs 6.7 months; HR 0.72, 95% CI 0.47–1.11; p=0.14) as shown in Table 1. Atezolizumab was associated with higher rates of hematologic adverse events (35 vs 22 events; p=0.025) and a trend toward increased hospitalizations (34 vs 24; p=0.085). No significant differences were observed in other irAE categories. Conclusions: This retrospective real-world analysis found that durvalumab-based first-line therapy was associated with longer OS compared to atezolizumab in patients with ES-SCLC, although no significant difference in rwPFS was observed. Interpretation is limited by shorter follow-up duration in the durvalumab cohort, which may contribute to observed survival differences. Due to the observational study design, potential residual confounding, and limited sample size, these results should be regarded as hypothesis-generating. These findings underscore the need for additional comparative effectiveness research to clarify optimal immunotherapy selection in ES-SCLC. Outcomes in propensity-matched cohort. Outcomes Atezolizumab Durvalumab Effect Estimate Patients (n) 69 69 Median OS (months) 9.1 23.2 HR 0.58 (95% CI 0.47–0.93) Median rwPFS (months) 6.7 8.6 HR 0.72 (95% CI 0.47–1.11)

A global multicenter, open-label, randomized, phase 3 registrational study of lisaftoclax (APG-2575) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): GLORA trial in progress.

TPS7101 Background: Patients with high-risk CLL/SLL not achieving a complete response (CR) after ≥ 12 months of BTK inhibitor (BTKi) monotherapy remain at risk for early progression due to residual disease and BTKi resistance. A BCL-2 inhibitor (BCL-2i) introduces a complementary, BCR-independent apoptotic mechanism that may deepen responses and prolong progression-free survival (PFS). Lisaftoclax, a selective oral BCL-2i with a short half-life (4-6 h), enables once-daily dosing and is approved in China as second-line CLL therapy. Lisaftoclax monotherapy has demonstrated overall response rates (ORRs) of 67% in relapsed/refractory CLL and 62.5% in BTKi-refractory disease, including del(17p)/ TP53 -mutated cases. Lisaftoclax combined with acalabrutinib achieved ORRs &gt;97% with favorable tolerability. This study evaluates whether lisaftoclax plus BTKi (acalabrutinib, zanubrutinib, or ibrutinib) improves PFS and/or overall survival (OS) (vs continued BTKi monotherapy) in patients with CLL/SLL and residual disease after prolonged BTKi treatment. Methods: This study will enroll approximately 440 patients randomly allocated to receive lisaftoclax plus BTKi or BTKi alone. Eligible patients have CLL/SLL and, after ≥12 months of BTKi monotherapy (lines 1-3), have achieved neither CR nor progressive disease (PD). Randomization is stratified by del(17p)/ TP53 status. Key inclusion criteria include age ≥18 years, ECOG PS 0-2, and residual disease with either high-risk features (del(17p)/ TP53 mutation, unmutated IGHV , or complex karyotype [≥5 abnormalities]), or measurable residual disease with lymph nodes ≥2.5 cm in the absence of high-risk features. Exclusion criteria include prior BCL-2i therapy or Richter transformation. Patients in the investigational arm will undergo a 5-day oral lisaftoclax ramp-up to 400 mg once daily plus physician's choice of BTKi in 28-day cycles until progression or toxicity. Control patients continue their current BTKi monotherapy. Safety and disease assessments (CT/MRI) will occur regularly. The primary endpoint is PFS by independent review committee (iwCLL 2018); key secondary endpoint OS; and other secondary endpoints, PFS by investigator, ORR, duration of response, MRD negativity, and safety. Enrollment is ongoing across 126 sites in 18 countries (ClinicalTrials.gov ID: NCT06104566). Clinical trial information: NCT06104566 .