Browse Articles

The impact of re-adoption of open radical hysterectomy on postoperative outcomes in the United States: An interrupted time series analysis.

5538 Background: The Laparoscopic Approach to Cervical Cancer (LACC) trial, published in 2018, demonstrated inferior disease-free and overall survival outcomes with minimally invasive radical hysterectomy compared to open surgery for cervical cancer, establishing open radical hysterectomy (ORH) as the standard of care. This study evaluates the impact of the rapid adoption of ORH after publication of the LACC trial on postoperative outcomes. Methods: We categorized 2013-2017 as the pre- LACC period, 2019-2022 as the post -LACC period, and 2018 as the washout period. We included patients who underwent radical hysterectomy for cervical cancer in a Commission on Cancer-accredited program with the highest utilization of ORH (top quartile, > 83%) in the post-LACC period. We fit linear probability models with cluster-robust standard errors to estimate the causal association between ORH adoption, postoperative length of stay, 30-day readmission rates, and 90-day mortality, using pre-LACC trends to estimate a counterfactual outcome for 2019 and comparing these with outcomes from the post-LACC period. Results: 2,982 patients were treated in the 107 rapid adopter hospitals. Mean age was 46.5 (SD 12). Most patients were white (67%), followed by Hispanic (14%), and Black (11%). Most patients had grade 1 or 2 (60%) tumors with squamous cell (52%) or adenocarcinoma (40%) histology. Thirty-two percent of patients had positive LVSI and 12% of patients had positive lymph nodes. The proportion or ORH was 45% vs 94% in the pre- vs post-period and ORH utilization was 65 percentage points (p.p.) higher than the estimated 2019 counterfactual ORH utilization. In the pre-period, MIS use increased significantly over time (4.1 p.p. per year, 95% CI 1.9-6.3, p < 0.001) while mean length of postoperative stay declined (0.3 days per year, 95% CI 0.1-0.5, p = 0.003). Rapid adoption of ORH in 2019 (+65.1 p.p., 95% CI 53.4-76.8, p < 0.001) was associated with a 1.7 day (95% CI 1.0-2.5, p < 0.001) increase in the duration of postoperative hospitalization, from 1.5 to 3.3 days. There was no significant association with a change in 30-day readmission rates (3.6% pre vs 1.9% post, 1.7 p.p. decrease, 95% CI -5.3 to +1.8, p = 0.35). Only 13 patients (0.4%) died within 90 days of surgery over the entire study period, precluding analysis of postoperative mortality. Conclusions: Rapid adoption of ORH following the LACC trial was associated with a moderate increase in postoperative length of stay, but no change in 30-day readmission rate.

Association of Schwann cells with immune-cold tumor microenvironment in triple-negative breast cancer.

e12592 Background: Although intratumoral nerves have recently been recognized as a critical regulator of tumor biology, its roles in breast cancer remain poorly understood, largely due to their rarity and technical challenges in transcriptomic profiling, as neuronal cell bodies are absent within tumors. Schwann cells (SCs) ensheath nerve fibers and constitute the most abundant intact cellular component of peripheral nerve system, thus is an ideal target for transcriptomic detection of peripheral nerves. We therefore hypothesized that a SC score will estimate the amount of nerve fibers and reveal its association with tumor biology in triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype. Methods: Spatial transcriptome data was obtained from Zenodo repository. Bulk transcriptome and clinical data of TNBC patients were analyzed in the TCGA (n = 170), METABRIC (n = 335), and SCANB (n = 174) cohorts, as well as cohorts that underwent neoadjuvant chemotherapy (GSE194040, 25066, 163882, 123845, 20271, 230881, and 41998). Signature genes for SC, myelinating SC (mSC), and non-myelinating SC (nmSC) were obtained from PanglaoDB and Tabula Sapiens, and GSVA scores were calculated. Patients were stratified into high- and low-SC score groups using the median. Results: To determine the most appropriate SC score, we compared the PL-SC, TS-SC, TS-mSC, and TS-nmSC scores in ST analyses, and found that the PL-SC score showed the strongest spatial concordance with pathologically annotated nerve fiber regions and was used for all subsequent analyses. The SC score correlated with neuron score defined by xCell algorithm. Across 3 cohorts, high SC scores were associated with lower MKI67 expression, lower Nottingham histological grade, and reduced proliferation scores, accompanied by negative enrichment of cell proliferation-related Hallmark pathways in GSEA. The SC showed no association with genomic instability or homologous recombination deficiency. Although high-SC tumors showed fewer non-silent mutations, no differences in major gene alteration patterns were observed. Consistently, the SC score was negatively associated with multiple immune cell populations, including B cells, CD8⁺ T cells, Th1/2 cells, DCs, and macrophages, while positively associated with stromal cell populations. Immune-related pathways were also downregulated in high-SC tumors. However, the SC score was not associated with pathological complete response in the 8 chemotherapy cohorts. In survival analysis, a high SC score associated with worse disease-specific and overall survival in TCGA, whereas no significant association was observed in the other 2 cohorts. Conclusions: The SC score is associated with a less proliferative, immune-cold tumor microenvironment in TNBC, however, its association with chemotherapy response and prognosis appears to be cohort-dependent.

Prevalence of depression and associated factors among patients with advanced cancer undergoing comprehensive genomic profiling testing in Japan.

e24108 Background: Comprehensive genomic profiling (CGP) testing is increasingly used in patients with advanced cancer to guide precision oncology. Patients undergoing CGP testing often face limited treatment opportunities and substantial psychological burden; however, the prevalence of depression and its associated factors in this setting remains poorly understood, particularly in Japan. Clarifying the psychological impact of CGP testing is essential to identify high-risk patients and to inform the development of appropriate supportive care strategies. Therefore, this study aimed to evaluate the prevalence of depression and associated factors among patients with advanced cancer undergoing CGP testing in Japan. Methods: This multicenter, prospective cohort study enrolled 712 patients with advanced cancer undergoing CGP testing at seven hospitals in Japan between February 2023 and April 2025. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9) at the time of CGP testing explanation (T1), CGP results explanation (T2), and 6 months after registration (T3). The primary outcome was the prevalence of depression (PHQ-9 ≥ 10) at T1 and T2. Factors associated with depression were analyzed using multivariable logistic regression, adjusting for potential confounders. Results: Among 712 participants, the prevalence of depression was 21.0% (n=148) at T1 and 19.1% (n =99/519) at T2, as measured by PHQ-9 ≥ 10. In multivariable analysis, depression was significantly associated with unemployment (OR 2.04, 95% CI 1.15–3.75, p =0.017) and lower satisfaction with communication (OR [1-unit] 0.95, 95% CI 0.92–0.98, p =0.001). Conclusions: Depression was common among patients with advanced cancer undergoing CGP testing in Japan. Factors such as unemployment and lower satisfaction with communication were independently associated with depression, underscoring the need for psychological support strategies tailored to this population. Clinical trial information: UMIN000049964.

KEYNOTE-811: 6-year median follow-up of pembrolizumab plus trastuzumab and chemotherapy for previously untreated advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma.

4040 Background: At the final analysis of the phase 3 KEYNOTE-811 trial (NCT03615326), first-line (1L) pembrolizumab (pembro) plus trastuzumab and chemotherapy (chemo) showed superior OS and consistently improved PFS and ORR with durable responses vs placebo plus trastuzumab and chemo in participants (pts) with HER2-positive (HER2+) advanced or metastatic gastric or gastroesophageal (G/GEJ) adenocarcinoma, particularly in pts with PD-L1 combined positive score (CPS) ≥1 tumors. Results supported the approval of pembro plus trastuzumab and chemo for 1L treatment of advanced or metastatic HER2+ G/GEJ adenocarcinoma with PD-L1 CPS ≥1. We report results after an additional 20 months of follow-up. Methods: Eligible pts with untreated advanced or metastatic HER2+ G/GEJ adenocarcinoma, measurable disease, and ECOG PS 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or placebo IV Q3W for up to 35 cycles plus trastuzumab 6 mg/kg (after loading dose of 8 mg/kg) and chemo (CAPOX or FP). Dual primary end points were OS and PFS per RECIST v1.1 by BICR. Secondary end points included ORR and DOR (per RECIST v1.1 by BICR), and safety. Data cutoff date was November 12, 2025. Results: Overall, 698 pts were randomly assigned to the pembro group (n = 350) or placebo group (n = 348). Median follow-up was 70.0 months (range, 50.9-84.2). In the intention-to-treat (ITT) population (all randomly assigned pts), median OS was 20.0 months (95% CI, 17.8-22.1) in the pembro group vs 16.8 months (95% CI, 14.9-18.7) in the placebo group. In pts with PD-L1 CPS ≥1, median OS was 20.1 months (95% CI, 17.9-22.9) vs 15.7 months (95% CI, 13.5-18.5). PFS, ORR, and DOR were also consistent between the ITT population and pts with PD-L1 CPS ≥1 (Table). Treatment-related AEs occurred in 341 pts (97.4%; grade ≥3, 206 [58.9%]) in the pembro group and 335 (96.8%; grade ≥3, 177 [51.2%]) in the placebo group. Conclusions: Pembro plus trastuzumab and chemo continued to show improved OS, PFS, and ORR vs placebo plus trastuzumab and chemo after a median study follow-up of 70 months, especially in pts with PD-L1 CPS ≥1. No new safety signals were seen. The findings continue to support pembro plus trastuzumab and chemo as the preferred 1L treatment for advanced or metastatic HER2+ G/GEJ adenocarcinoma. Clinical trial information: NCT03615326 . ITTN = 698 PD-L1 CPS ≥1n = 594 Pembro group n = 350 Placebo group n = 348 Pembro group n = 298 Placebo group n = 296 OS, median (95% CI), months 20.0 (17.8-22.1) 16.8 (14.9-18.7) 20.1 (17.9-22.9) 15.7 (13.5-18.5) HR (95% CI) 0.81 (0.69-0.95) 0.79 (0.66-0.94) PFS, median (95% CI), months 10.0 (8.6-12.2) 8.1 (7.0-8.5) 10.9 (8.5-12.5) 7.3 (6.8-8.4) HR (95% CI) 0.73 (0.61-0.87) 0.72 (0.60-0.87) ORR, % (95% CI) 72.6 (67.6-77.2) 60.1 (54.7-65.2) 73.2 (67.7-78.1) 58.4 (52.6-64.1) DOR, median (range), months 11.3 (1.1+ to 80.0+) 9.5 (1.4+ to 79.6+) 11.3 (1.1+ to 80.0+) 9.6 (1.4+ to 79.6+)

Association of GLP-1 receptor agonist use with mortality and hospitalization in women with breast cancer and type 2 diabetes: A propensity score–matched cohort study.

e12731 Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used in patients with type 2 diabetes mellitus (T2DM) and have been hypothesized to influence cancer-related outcomes. However, real-world data on survival and hospitalization outcomes among patients with breast cancer and diabetes treated with GLP-1 RAs remain limited. Methods: We conducted a retrospective cohort study using the TriNetX U.S. Collaborative Network. Adult women with non-metastatic breast cancer and T2DM diagnosed between January 1, 2010, and January 1, 2020, were identified. The index event was breast cancer diagnosis. Patients were stratified by GLP-1 RA initiation within one year after breast cancer diagnosis. Patients with metastatic disease or other primary malignancies were excluded. Before matching, 988 patients treated with GLP-1 RAs and 34,228 patients not treated with GLP-1 RAs were identified. Propensity score matching (1:1) was performed based on demographics, comorbidities, diabetes medications (e.g., insulin, metformin), cancer-related therapies, cancer hormonal status, endocrine treatment, and body mass index, resulting in 428 patients in each cohort. Outcomes were assessed up to five years following breast cancer diagnosis. Primary outcomes were all-cause mortality and hospitalization. Results: After propensity score matching, baseline characteristics were well balanced between cohorts, with a mean age of 75.2 years (standard deviation 8.1 years). The median follow-up was 3.8 years. During follow-up, death occurred in 38 patients (8.9%) in the GLP-1 RA cohort compared with 53 patients (12.4%) in the non-GLP-1 RA cohort. GLP-1 RA use was associated with a trend toward reduced mortality (hazard ratio [HR] 0.70, 95% CI 0.46–1.06; log-rank p = 0.09). Hospitalization occurred in 118 patients (27.6%) in the GLP-1 RA cohort and 159 patients (37.1%) in the non-GLP-1 RA cohort. GLP-1 RA use was associated with a statistically significant lower risk of hospitalization (HR 0.67, 95% CI 0.53–0.85; log-rank p = 0.001), with a number needed to treat of 11 to prevent one hospitalization over five years. Conclusions: In this propensity score-matched real-world cohort of women with non-metastatic breast cancer and type 2 diabetes, GLP-1 RA use initiated within one year of breast cancer diagnosis was associated with a significantly lower risk of hospitalization and a trend toward improved overall survival. These findings warrant further prospective investigation into the potential role of GLP-1 RA therapy in this population.

Higher internal locus of control is associated with higher performance in a workplace walking intervention, Global Corporate Challenge®

Background Given the increasing reliance on self-regulation in modern work environments, understanding how psychological characteristics influence physical activity participation can help inform more effective health promotion strategies. This study examines whether individuals with different Locus of Control (LOC) orientations show varying levels of engagement and performance in a workplace pedometer program. Methods We conducted a secondary analysis of 426 office workers in Melbourne, Australia who participated in the 2008 Global Corporate Challenge® (GCC®), a four-month team-based pedometer program encouraging 10,000 steps per day. Internal LOC (ILOC) was assessed at baseline, four months, and 12 months using the Duttweiler Internal Control Index. Baseline ILOC was the primary exposure. Program performance was operationalized as average daily step counts and achievement of the 10,000-step daily goal. Linear regression and logistic regression, adjusted for workplace clustering and covariates, were used to examine associations between ILOC and outcomes. Paired t-tests and descriptive comparisons were used to assess changes in ILOC over time. Results Participants with higher baseline ILOC were older (p < 0.001), more likely to have previously completed the GCC® (p = 0.039), more health-motivated (p = 0.015), met fruit (p = 0.040) and vegetable (p = 0.003) intake guidelines, and reported higher wellbeing and mental health-related quality of life (both p < 0.001). During the program, higher ILOC was associated with higher average daily step counts (β = 46.97, 95% CI [24.62, 69.33]; p = 0.001) and greater likelihood of achieving the 10,000-step goal (OR = 1.02, 95% CI [1.01, 1.03]; p = 0.001). ILOC showed no significant net change overall, but a clear regression-to-the-mean pattern was observed across baseline quartiles. Conclusions Higher ILOC was associated with better performance in the pedometer program, though this did not translate into sustained additional health gains.

BNB/NBN‐Phenalenyl‐2'‐deoxyuridines as a Fluorophore–Quencher Pair in DNA

ABSTRACT Deoxyribonucleic acid (DNA) enables the precise arrangement and positioning of chromophores in order to study their interactions, leading, for example, to through‐space energy transfer processes. BNB‐ and NBN‐doped phenalenyls are electronically complementary fluorophores that are neutral BN/CC isosteres of the phenalenyl cation and anion, respectively. Herein, we present a pair of BNB‐ and NBN‐doped phenalenyl‐extended nucleosides, which we introduced into DNA via phosphoramidite chemistry. The two chromophores act as a donor–acceptor pair in a Förster resonance energy transfer (FRET) process, which results in the quenching of the BNB‐phenalenyl fluorescence due to the nonradiative decay of the charge transfer (CT) state of the NBN‐phenalenyl acceptor in an aqueous environment. The DNA duplex serves as a supramolecular scaffold to control the arrangement of the interacting BNB‐ and NBN‐doped chromophores. The performance of the fluorophore–quencher pair was evaluated in a toehold‐mediated strand displacement (TMSD) experiment, demonstrating its potential for DNA‐based applications.

Direction-selective enhancement of terahertz emission in Py/Ni/Pt via stacking-dependent angular momentum transport

Spintronic terahertz (THz) emitters based on ferromagnet/heavy-metal heterostructures provide a compact platform for broadband THz generation. Here, we demonstrate a direction-selective enhancement of THz emission in Permalloy (Py)/Ni/Pt trilayers associated with spin-orbital transport. We find that the Py/Ni/Pt configuration produces a significantly stronger THz signal than Ni/Py/Pt, far exceeding the sum of bilayer contributions, with an enhancement factor of up to ∼17. Thickness-dependent measurements, interface engineering, and material substitution reveal that this behavior is closely linked to the stacking-sequence-dependent role of the Ni layer. In the Py → Ni → Pt sequence, Ni not only provides an intrinsic orbital contribution but also facilitates spin-to-orbital conversion via spin–orbit coupling, enabling additional transport pathways toward Pt. However, this pathway is largely suppressed in the reversed stacking, resulting in a near-additive response. These results highlight stacking-sequence-dependent angular momentum transport as a key factor governing THz emission and establish ferromagnetic-layer engineering as an effective strategy for optimizing spintronic THz emitters.

Integrated in silico network pharmacology and β-cyclodextrin nanosponge based delivery of nafithromycin: Mechanistic insights, controlled release, and enhanced antimicrobial activity

3D‐Printing Starfish‐Inspired Gas‐Evolving Electrode Scaffolds Enable Ampere‐Level Alkaline Water Electrolysis

ABSTRACT Alkaline water electrolysis (AWE) mitigates the high cost and immaturity of polymer electrolyte membrane‐based water electrolysis (PEMWE) for green hydrogen production. However, its industrial application at ampere‐level current densities (ACDs) remains challenging. Conventional disordered gas‐evolving electrode (GEE) scaffolds endow with sluggish bubble detachment kinetics and mechanical instability, preventing operation at high ACDs, while rational scaffold designs for accelerating bubble detachment remain rarely explored. Inspired by starfish scaffolds, we design and fabricate a biomimetic GEE with conical sieve‐plate hole scaffolds via 3D printing. Combined COMSOL simulations and in situ bubble behavior analyses reveal that like the breath and mass exchange of starfish, the sieve plate optimizes bubble force balance to accelerate detachment, while the conical structure conducts bubbles rapidly into the electrolyte. Such starfish‐inspired GEE design yields a 21‐fold lower mass‐transfer overpotential vs. current density slope than that of common flat round‐hole scaffold. Consequently, champion lowest overpotentials of 159 and 430 mV among all the well‐documented state‐of‐the‐art GEEs are achieved at the ACD of 1000 mA cm −2 for HER and OER, respectively. Moreover, our starfish‐inspired GEE sustains ACDs operation with ≈100% Faraday efficiency for over 150 h, demonstrating its potential for practical AWE applications.

Longitudinal cognitive assessment using the Cumulus NeuLogiq platform in amyotrophic lateral sclerosis and frontotemporal dementia

Platelet CLEC-2 activation leads to GPIb⍺ shedding: Implications for doxorubicin chemotherapy and thrombosis

PRIME-ROSE: A blueprint for implementing precision cancer medicine in Europe.

11086 Background: Precision Cancer Medicine (PCM) is limited by increasingly small patient subgroups defined by tumor type and biomarker, producing rare cohorts even within common cancers. This is demonstrated by several European national PCM platform trials like DRUP (NL), IMPRESS-Norway (NO) and ProTarget (DK). From our experiences, we identify four essential requirements for successful, scalable PCM implementation: i) integration of platform trials with national healthcare systems via molecular tumor boards for efficient screening by comprehensive molecular profiling and accrual; ii) cross-national data merging; iii) scalable networks to onboard new countries; and iv) clear decision pathways linked to outcome data for reimbursement. Methods: PRIME-ROSE links national PCM implementation platforms through a robust data sharing framework that retains national/regional data governance while enabling harmonised statistical analyses and standardised endpoints for decision-makers. Predictable implementation pathways provide multiple, pre-defined decision points for industry, health technology assessment (HTA) bodies and payers, and integrate risk-sharing and responder-only reimbursement options with existing data collection. A scalable, transparent network facilitates rapid expansion to additional European partners. Results: We have developed and tested an operational data-sharing framework, with defined protocols for minimal datasets and harmonised merging procedures. Patient-level data from multiple national cohorts (1100 patients in 400 cohorts) have been aggregated, and analyses of five filled cohorts are in progress. PRIME-ROSE uses a staged implementation model to detect initial efficacy signals (industry-financed drugs) to confirm and expand on prior evidence, facilitating predictable scale-up. Risk-sharing is operationalised via responder-only reimbursement after 16 weeks of treatment and a defined transition from trial to commercial supply. In 2025, PRIME-ROSE expanded partnerships, secured the first and second multi-trial industry access contracts, and expanded payer commitment to make reimbursement decisions after Stage III. Conclusions: PRIME-ROSE translates lessons from platform trials into a practical, scalable blueprint that preserves national governance, accelerates evidence generation and reduces payer uncertainty – thereby lowering barriers to equitable, continent-wide PCM adoption. Aligned with initiatives such as Basket of Baskets and ROME, PRIME-ROSE is positioned for further scale-up through member state collaboration under the Joint Action on Personalised Cancer Medicine.

Real-world survival and safety outcomes of tarlatamab in patients with extensive stage small cell lung cancer.

e20168 Background: Tarlatamab, a DLL-3 targeted bispecific T cell engager targeting Delta-Like ligand 3 has shown promising clinical activity in relapsed, refractory extensive-stage small cell lung cancer (ES-SCLC). Toxicities included cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias. However, real-world data on survival and safety remains limited. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network Database. Patients with SCLC treated with tarlatamab were identified. Lung cancer diagnosis codes were combined with SCLC-specific histologic classifications. The index date was the first recorded tarlatamab administration. The primary outcome was overall survival (OS) and was assessed using Kaplan-Meier methods, with survival probabilities estimated at 6 months, 1 year, and 2 years. Treatment-related toxicities were evaluated in secondary analyses and included CRS, ICANS, pyrexia, and neutropenia. Results: 682 patients with ES-SCLC treated with tarlatamab were identified. Kaplan–Meier–estimated survival probabilities were 68.8% at 6 months, 54.6% at 1 year, and 46.2% at 2 years. The Kaplan–Meier survival curve did not cross the 50% threshold during the available follow-up period, and therefore median overall survival was not reached. The median observed survival time at 2 years was 417 days. Given the relatively short median follow-up compared with the 2-year survival horizon, longer-term survival estimates should be interpreted with caution. Treatment-related adverse events were evaluated within prespecified post-treatment time windows. Within the first 30 days following treatment initiation, pyrexia or CRS occurred in 287 patients (42.1%). ICANS was identified in 69 patients (10.1%), and neutropenia occurred in 52 patients (7.6%). Lower observed rates of CRS and neutropenia alongside a higher incidence of ICANS may be related to monitoring intensity and systematic toxicity assessment in trial settings. Conclusions: In this real-world large database analysis, tarlatamab demonstrated clinically meaningful overall survival and a manageable toxicity profile. These findings support the clinical effectiveness of tarlatamab outside of trial settings and underscore the importance of real-world evidence concerning novel bispecific therapies. Longer-term follow-up is needed to assess the durability of survival and late toxicities.

SGLT2 inhibitor use and long-term outcomes in anthracycline-treated breast cancer: A real-world retrospective cohort study.

e12707 Background: Anthracycline-based chemotherapy remains a cornerstone of breast cancer treatment but is limited by dose-dependent cardiotoxicity. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardioprotective effects across diverse populations. Preclinical models suggest they may mitigate anthracycline-induced cardiotoxicity. However, clinical data evaluating this association remain limited. Methods: We conducted a retrospective cohort study using the TriNetX real world data platform, including adults with breast cancer who received anthracycline within one year of diagnosis. Patients were stratified by SGLT2i use within one year of diagnosis into the SGLT2i group and the non-SGLT2i group. Propensity score matching (PSM) was performed to balance baseline demographics and comorbidities. Outcomes included 3-year all-cause mortality, heart failure, myocardial infarction, atrial fibrillation, mean left ventricular ejection fraction (LVEF), mean Troponin I, and mean brain natriuretic peptide level (BNP), analyzed using risk ratios (RR) and Kaplan-Meier survival analysis. Results: After PSM, 2912 patients were included in each group, with a mean follow-up of 630.3 days in SGLT2i group and 756.7 days in non-SGLT2i group. Mean age was 61.5 years vs 62.3 years (SGLT2i group vs non-SGLT2i group), with more than 98% of females in both groups. Most patients were White (49.0% in SGLT2i group and 48.6% in non-SGLT2i group), followed by African American (23.7% vs. 23.4%), unknown races (14.0% vs 14.0%), and Asian (9.5% vs. 9.8%). At baseline, the SGLT2i group had lower mean LVEF (53.4% vs 61.9%), higher mean Troponin I (0.992 vs 0.0849), and higher mean BNP levels (778 vs 240). SGLT2i group was associated with significantly lower 3-year all-cause mortality (Hazard ratio 0.52, 95% CI 0.44–0.61). Heart failure incidence (9.5% vs 6.0%; p = 0.0005) was significantly higher in the SGLT2i group. Mean LVEF in SGLT2i group was significantly lower (51.7% vs 58.9; p < 0.0001) and mean BNP level was significantly higher in SGLT2i group (685.5 vs 383.0; p = 0.0336). No significant differences were observed in myocardial infarction (3.9% vs 3.4%; p = 0.4459), atrial fibrillation (3.4% vs 4.5%; p = 0.0799), and mean troponin I (0.085 vs 0.113, p = 0.5191). Conclusions: In this real-world cohort, SGLT2i use was associated with lower 3-year all-cause mortality despite higher rates of heart failure. Notably, patients receiving SGLT2i had worse baseline cardiac function yet demonstrated more favorable trends in cardiac biomarkers, including smaller declines in LVEF, reductions in BNP, and lower mean troponin I levels, suggesting a slower progression of cardiac dysfunction. These findings support a potential cardioprotective and survival benefit of SGLT2i in patients with breast cancer receiving anthracycline therapy and warrant confirmation in future studies.

Clinicogenomic characterization of MUC16 and MUC17 in small cell lung cancer.

e20165 Background: Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapies and poor survival. Transmembrane mucins, like MUC16 (CA125) and MUC17, regulate tumor progression, immune evasion, and treatment response. MUC16 mutations are associated with poor prognosis in non–small cell lung cancer but favorable outcomes in gastric cancer, highlighting the need for disease-specific evaluation. The combined role of MUC16 and MUC17 has not been systematically examined. We investigated the clinicogenomic context and prognostic relevance of MUC16 and MUC17 in SCLC. Methods: Clinicogenomic data from four publicly available SCLC cohorts in cBioPortal (n = 239) were analyzed. MUC16 and MUC17 were assessed for mutational patterns, tumor mutational burden (TMB), overall survival (OS), and progression-free survival (PFS). Results: MUC16 was identified in 64 patients (26.8%), MUC17 in 54 (22.5%), and both in 25 (10.5%), ranking seventh and tenth most common mutations. Mutational characteristics of MUC16 and MUC17 are summarized in Table 1. Patients with MUC16/MUC17 had higher rates of TP53 (93.1% vs. 58.5%) and RB1 (66.7% vs. 47.6%) mutations (both p < 0.01) and a significantly higher median TMB (11.2 vs. 3.7 mutations/Mb, p < 0.01) compared with unaltered patients. Median OS was shorter in patients with MUC16 (22.0 vs. 27.0 months; HR 1.18, 95% CI 0.74–1.89), MUC17 (22.0 vs. 27.0 months; HR 1.17, 95% CI 0.64–2.11), or both alterations (23.0 vs. 27.0 months; HR 1.21, 95% CI 0.71–1.65) compared with unaltered group. Median PFS was also shorter in patients with MUC16 (10 vs. 18 months, p = 0.21), MUC17 (7 vs. 10.5 months, p = 0.02), or both alterations (10 vs. 18 months, p = 0.18). Conclusions: MUC16 / MUC17 alterations are relatively common in SCLC and are associated with high TMB and frequent TP53/RB1 co-mutations, warranting further mechanistic investigation. These mutations are predominantly missense and extracellular, consistent with long-gene passenger mutagenesis rather than oncogenic drivers, suggesting a potential role as immunogenic subset biomarkers. Although survival differences were not statistically significance, differences may be noted with comparison to wild type mutations. The association with worse survival trends with elevated TMB prognostic relevance may evolve with increasing immunotherapy use. While mutation and expression are distinct yet correlated, emerging targeted and personalized therapies may hold future relevance. Study limitations include cohort heterogeneity and lack of expression-level data. Prospective studies integrating genomics and treatment response are needed to determine the therapeutic potential of MUC16 / MUC17 in SCLC. Mutational profile of MUC16 and MUC17 . MUC16 MUC17 Mutation Type Missense 180 61 Nonsense 5 4 Frameshift 2 4 Splice 5 0 In Frame 0 0 Fusion 0 0 Mutation Location Extracellular (non-SEA) 178 64 Extracellular (SEA) 14 4 Transmembrane 0 0 Cytoplasmic 0 1

Whole slide imaging–based prediction of immunohistochemistry markers and surgical pathological features.

6022 Background: Immunohistochemistry (IHC) marker testing and identification of pathological features are essential tasks in surgical pathology following resection of head and neck cancers. However, IHC testing is time-consuming, and identifying pathologic features typically requires examination of multiple slides. We hypothesized that imaging features from a single H&E-stained whole slide image (WSI) could predict this information using machine learning. Methods: We utilized data from the publicly available HANCOCK dataset for machine learning model development and testing. All patients had undergone surgical resection for locoregional head and neck cancer. Image features (embeddings extracted by TITAN, a pretrained vision-language pathology foundation model) from each primary tumor's H&E-stained WSI served as model inputs. Four machine learning algorithms (XGBoost, support vector machine, multilayer perceptron, and random forest) were trained to predict seven IHC markers (CD3, CD8, CD56, CD68, CD163, MHC-I, PD-L1) and three surgical pathological features (tumor grading, lymphovascular invasion, and perineural invasion). IHC marker positivity was determined using DeepLIIF-derived percent-positive staining, with non-PD-L1 markers binarized by median split and PD-L1 positivity defined using a 10% threshold. Surgical pathological features were binary except for tumor grade, which included four classes. All models underwent nested stratified five-fold cross-validation with hyperparameter tuning. Performance was assessed using AUC and F1 score for binary tasks (IHC markers, lymphovascular invasion, perineural invasion), and balanced accuracy and macro-F1 score and for tumor grading. Results: Between 685 and 699 cases were available for model development depending on the prediction task. Support vector machine (SVM) was the best-performing model for five tasks, followed by XGBoost (XGB) for three tasks and random forest (RF) for two tasks. Performance metrics for the best-performing models are detailed in the table. Conclusions: Our findings demonstrate that IHC markers and surgical pathological features can be predicted with reasonable accuracy from image features extracted from a single H&E-stained WSI. Future work will focus on external validation of these models in independent cohorts and exploration of advanced foundational models to further improve prediction performance. Task Best Model Metrics CD3 XGB AUC: 0.78 ± 0.04 F1: 0.72 ± 0.03 CD8 SVM AUC: 0.73 ± 0.03 F1: 0.67 ± 0.04 CD56 XGB AUC: 0.66 ± 0.03 F1: 0.67 ± 0.02 CD68 SVM AUC: 0.75 ± 0.03 F1: 0.70 ± 0.04 CD163 SVM AUC: 0.71 ± 0.05 F1: 0.67 ± 0.04 MHC1 SVM AUC: 0.68 ± 0.05 F1: 0.66 ± 0.03 PDL1 SVM AUC: 0.73 ± 0.06 Macro F1: 0.54 ± 0.04 Grading RF Balanced Acc: 0.71 ± 0.04 Macro F1: 0.70 ± 0.03 Lymphovascular Invasion RF AUC: 0.82 ± 0.02 Macro F1: 0.70 ± 0.02 Perineural Invasion XGB AUC: 0.78 ± 0.03 Macro F1: 0.67 ± 0.03

Sintilimab plus anlotinib and chemotherapy as first-line treatment for advanced malignant pleural mesothelioma (SACH-MPM): A prospective, single-arm, phase II trial.

8050 Background: Standard first-line treatments for advanced malignant pleural mesothelioma (MPM) include platinum-pemetrexed with bevacizumab or nivolumab plus ipilimumab. While the addition of atezolizumab to chemotherapy and bevacizumab improved PFS in the BEAT-meso trial (9.2 vs. 7.6 m, HR 0.72), it failed to show an OS benefit. Anlotinib is a multi-target TKI targeting VEGFR, FGFR, and PDGFR. We investigated the efficacy and safety of sintilimab (anti-PD-1) combined with anlotinib and chemotherapy as first-line treatment for advanced MPM. Methods: This open-label, dual-center, single-arm Phase II study (NCT05188859) enrolled systemic treatment-naive pts with unresectable locally advanced or metastatic MPM. Pts received sintilimab (200 mg D1) and anlotinib (12 mg D1-14) plus chemotherapy (pemetrexed 500 mg/m² with cisplatin 75 mg/m² or carboplatin AUC 5, D1) Q3W for 4-6 cycles, followed by maintenance sintilimab, anlotinib, and pemetrexed until disease progression, intolerable toxicity, or up to 24 months. Primary endpoint was ORR per modified RECIST (mRECIST) 1.1 for mesothelioma. A Simon’s two-stage design (H0 = 41.3%, H1 = 60%, α = 0.1) planned for 23 evaluable pts, requiring ≥12 responses. Results: From Sep 2024 to Jan 2026, 30 pts were enrolled (median age 58.5 y; 76.7% epithelioid, 80% stage IIIB). At data cutoff, 29 pts were evaluable. Median follow-up was 7.4 months (m). The primary endpoint was met, with a confirmed ORR of 65.5% (95% CI: 45.7-82.1). DCR was 100%. Median time to response was 1.4 m; median DoR was not reached (0.7+-8.4+ m). PFS and OS were not mature. The 6- and 12-m PFS rates were 100% and 67.5%, respectively. OS rate was 100% at cutoff. Grade ≥3 TRAEs (36.7%) included neutrophil count decreased (13.3%), platelet count decreased (10.0%), pulmonary embolism (6.7%), diarrhea (6.7%), and hypertension (3.3%; any grade 10.0%). Bleeding events were Grade 1-2 (epistaxis 13.3%). TRAEs led to anlotinib dose reduction or discontinuation in 20.0%. No Grade 5 events occurred. Conclusions: Sintilimab plus anlotinib and chemotherapy demonstrated superior ORR compared to historical controls with a manageable safety profile. The study met its primary endpoint, and the high 12-month PFS rate suggests a potential survival benefit. These findings support integrating a multi-target TKI with PD-1 blockade and chemotherapy as a potent first-line strategy for advanced MPM. Clinical trial information: NCT05188859 .

A phase 2 pivotal study of savolitinib in patients with <i>MET</i> -amplified gastric cancer or gastroesophageal junction adenocarcinomas.

4011 Background: MET amplification is a poor prognosis for survival in patients (pts) with gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJa). Currently no approved targeted therapy is available for MET-amplified GC/GEJa. Savolitinib is a potent and highly selective oral MET-TKI. Here we reported the primary analysis results from a pivotal phase 2 trial investigating savolitinib in MET-amplified GC/GEJa, conducted with registration intent (NCT04923932). Methods: Eligible pts had locally advanced or metastatic GC/GEJa with MET amplification (gene copy number ≥10 by FISH) and had failed ≥2 lines of prior standard therapy. Pts received savolitinib 200 mg (BW &lt; 50 kg) or 300 mg (BW ≥50 kg) BID. The primary endpoint was ORR assessed by an Independent Review Committee (IRC) per RECIST 1.1, with a pre-specified efficacy threshold defined as the lower limit of the 95% CI of ORR exceeding 15%. Secondary endpoints mainly included DCR, DoR, TTR, PFS, OS and safety. An exploratory OS analysis was conducted in pts with MET-amplified GC/GEJa, who had previously received first-line, second-line, or later-line standard therapies, but were ineligible for study enrollment and did not receive the study drug. Plasma samples were also collected at baseline and end of treatment (EOT) for comprehensive genomic profiling using a 671-gene sequencing panel (Benrui GCP, OrigiMed). Results: As of Oct 8, 2025, 65 eligible pts were enrolled and received savolitinib. Baseline characteristics were: median age of 57.4 years, ECOG PS of 0 (13.8%) or 1 (86.2%), primary tumor sites of GC (84.6%) or GEJa (15.4%), and baseline ctDNA MET-positive rate of 64.6% (42 pts). Per the IRC assessment, ORR was 32.3% (95%CI: 21.2%, 45.1%), which exceeded the pre-specified efficacy threshold; in baseline ctDNA MET-positive pts (42 pts), IRC-assessed ORR was 45.2% (95%CI: 29.8%, 61.3%). IRC-assessed secondary efficacy endpoints were: DCR of 63.1%; mTTR of 1.4 months; mDoR of 9.7 months; and mPFS 4.0 of months. mOS was 6.9 months in the 65 treated pts, versus 4.8 months in 139 pts who received alternative treatments rather than the study drug in the exploratory OS analysis. Savolitinib-related TEAEs of Grade ≥3 occurred in 23 pts (35.4%). Exploratory ctDNA biomarker analysis showed that pts (N = 14) harboring baseline alterations in FGFR2, EGFR, PIK3CA, BRAF, or KRAS had lower ORR (14.3%, 2/14) and shorter mPFS (1.4 months). Additionally, in pts (N = 26) who provided PD/EOT samples, 12 pts developed alterations in these genes that were identified as putative acquired resistance mechanisms, and 4 pts had acquired MET mutations. Conclusions: Savolitinib showed clinical efficacy and a tolerable safety profile in pts with MET-amplified GC/GEJa who had received ≥2 lines of prior therapy, supporting it to be a future treatment option for this genetically defined population. Clinical trial information: NCT04923932 .

Multimodal profiling of STIC lesions to identify precursor states with genomic features of high grade serous ovarian cancer.

10581 Background: High-grade serous ovarian cancer (HGSC) is a lethal gynecologic malignancy characterized by near-universal TP53 inactivation, chromosomal instability (CIN), and frequent whole-genome doubling. Because population screening is ineffective, risk-reducing salpingo-oophorectomy (RRSO) remains the only proven risk-reduction strategy. Nonetheless, some individuals develop primary peritoneal carcinoma (PPC), and identification of serous tubal intraepithelial carcinoma (STIC) at RRSO is associated with &gt; 30-fold higher PPC risk. We sought to define the molecular steps required for HGSC initiation and identify features of high-risk STIC. Methods: We assembled a 201-patient cohort spanning stages of HGSC development, including normal fallopian tube epithelium, p53 signatures, STIC, and early- and advanced-stage HGSC. All specimens underwent multiplex immunofluorescence (mpIF). Forty-five samples from 36 patients were profiled using Visium HD spatial transcriptomics ( &gt; 20 million 8-µm bins). We analyzed epithelial state transitions using unsupervised clustering and trajectory inference. Copy-number variation (CNV) was inferred using spatial inferCNV; CNV calls were validated with matched formalin-fixed paraffin-embedded (FFPE) single-cell whole-genome sequencing. Results: mpIF demonstrated lesion-to-lesion variability in cyclic GMP–AMP synthase (cGAS) staining within STIC, consistent with evolving tolerance to CIN before invasion. Spatial transcriptomic clustering identified distinct, reproducible STIC epithelial programs that mapped to histologic features. STIC programs were enriched for NFκB and TGF-β signaling and lacked evidence of the JAK/STAT activation observed in advanced HGSC. CNV inference showed that normal fallopian tube and p53 signature lesions were chromosomally stable, whereas STIC displayed broad, genome-wide alterations resembling advanced HGSC, including losses encompassing TP53 , BRCA1 , and BRCA2 and amplifications of MYC and CCNE1 . In a germline BRCA2 carrier, we identified polyclonal STIC with distinct CNV profiles; trajectory analysis suggested early CNV changes within an expanded secretory population, followed by loss of chromosome 17 ( TP53 ), loss of chromosome 13 ( BRCA2 ), and subsequent oncogene amplifications (e.g., MYC ). As lesions became invasive, spatial CNV profiling revealed neighborhoods of clonally related invasive cells with distinct microenvironments, including differences in fibroblast states and vascularization. Conclusions: A multimodal atlas of fallopian tube transformation supports a model in which TP53 loss precedes BRCA1/2 inactivation and indicates that STIC is genomically similar to advanced HGSC. These findings provide a framework to study early HGSC evolution, stratify STIC risk after RRSO, and inform early-interception strategies.