Browse Articles

Multifunctional Elastic Supramolecular Hydrogels with Self‐Healing, Adhesive, and Ionic Thermoelectric Property for Flexible Sensing and Energy Harvesting

ABSTRACT Supramolecular hydrogels capable of integrating mechanical robustness, strong adhesion, and reliable energy conversion remain highly sought for next‐generation soft electronics. Here, we present a transparent, ultra‐stretchable ionic hydrogel constructed through synergistic host–guest interaction, hydrogen bonding, and electrostatic interactions. The dynamic network exhibits outstanding mechanical performance (2173% strain, 340 kPa strength, 2.88 MJ m − 3 toughness), rapid self‐healing, broad‐substrate adhesion, and potent antibacterial activity. The hydrogel functions as a sensitive strain sensor with stable, multimodal motion detection. It further serves as an efficient electrode for both triboelectric and droplet‐based energy harvesting, powering commercial LEDs. Notably, the material exhibits a high p‐type ionic thermoelectric response, achieving a Seebeck coefficient of 2.95 mV K − 1 and scalable thermovoltage output up to 14.3 mV/K in modular ionic thermoelectric capacitors. This work provides a versatile materials platform toward integrated soft electronics with simultaneous mechanical, sensing, and energy harvesting functionalities.

A nomogram estimates postoperative urinary tract infection risk after upper urinary tract stone surgery with double-J stents

Mechanisms of microRNA Export in Mammalian Cells: From Random Release to Selective Secretion

The association of economic measures and patient outcomes with geographical disparities in access to a UCNS board-certified neuro-oncologist in the United States.

2039 Background: Neuro-oncology is increasingly centralized in academic tertiary centers, potentially creating geographic and economic inequality. This study aims to quantify the national distribution of neuro-oncologists in the United States and evaluate the association between regional economic capacity, metropolitan urbanicity, and population-level clinical outcomes. Methods: We conducted a nationwide cross-sectional ecological analysis using 2025 United Council for Neurologic Subspecialties (UCNS) data, US Bureau of Economic Analysis state-level GDP, and US Census Bureau demographics. Spatial accessibility was modelled for US counties using geodesic distance from population centroids. Outcome measures included CNS tumor mortality and Disability-Adjusted Life Years (DALYs). Results: We identified 323 UCNS board-certified neuro-oncologists distributed across 70 Metropolitan Statistical Areas (MSAs). Workforce distribution was strongly associated with state-level economic magnitude (r=0.930 [95% CI: 0.878–0.960], p<0.0001), with gross domestic product (GDP) explaining 86.4% of variance (R2=0.864). Critically, economic intensity independent of state population was a significant driver, with GDP per capita correlating with specialist density (r=0.344, p=0.014). Specialists were located exclusively within MSAs (𝜒² = 52.28, p < 0.0001), however 81.9% of MSAs lacked local subspecialty presence. Spatial analysis revealed 45.4% of the US population has local access (<20 miles), while 16.5% (55.2 million Americans) live in "Care Deserts" greater than 100 miles from the nearest neuro-oncologist. Increased specialist density predicted lower mortality rates for pediatric (ρ = –0.34 [95% CI: –0.56 to –0.07], p = 0.015) and adult (ρ = –0.352 [95% CI: –0.57 to –0.08], p = 0.011) groups. Similar inverse associations were observed for DALYs in both pediatric (ρ=−0.339 [95% CI: –0.57 to –0.07], p = 0.015) and adult (ρ=−0.347 [95% CI: –0.57 to –0.08], p = 0.013) populations. Conclusions: Distribution of UCNS board-certified neuro-oncologists in the United States is primarily governed by state-level economic prosperity and is critically concentrated in select metropolitan centers. This geographical concentration leaves over 80% of US metro areas without access to a UCNS board-certified neuro-oncologist. Furthermore, higher density of UCNS-certified specialists is significantly associated with reduced mortality and disease burden, suggesting that expanding this workforce may be a lever for improving population-level neuro-oncologic outcomes.

Early lipid-lowering therapy initiation after lorlatinib and clinical outcomes in non–small cell lung cancer: A propensity-matched real-world analysis.

8597 Background: Lorlatinib improves outcomes in NSCLC but commonly causes marked hyperlipidemia, prompting initiation of lipid-lowering therapy (LLT). Beyond lipid control, LLT may be associated with vascular events; however, its association with thromboembolism, healthcare utilization, and mortality among lorlatinib-treated patients has not been characterized in real-world cohorts. Methods: Using TriNetX, we identified adults with NSCLC who received lorlatinib (index = first lorlatinib record). Patients were grouped by early LLT initiation within 30 days of index versus no LLT within 30 days. LLT included statins, ezetimibe, PCSK9 inhibitors, or fibrates. Cohorts were balanced 1:1 using propensity score matching on demographics and baseline comorbidities. Outcomes were assessed through 365 days; patients with prior outcome documentation were excluded. Results: After matching, 387 patients per cohort were analyzed. Early LLT was associated with lower all-cause mortality at 365 days (16.1% vs 26.4%; risk ratio [RR] 0.61, 95% CI 0.46-0.81; p=0.0004) and improved time to death (hazard ratio 0.60, 95% CI 0.44-0.82). Early LLT was also associated with lower venous thromboembolism (6.2% vs 12.1%; RR 0.51, 95% CI 0.30-0.86; p=0.0093) and fewer inpatient hospitalizations (14.6% vs 23.6%; RR 0.62, 95% CI 0.40-0.97; p=0.0320). Emergency department visits were numerically lower (8.3% vs 13.9%; RR 0.59, 95% CI 0.35-1.00; p=0.0467). No significant differences were observed for acute kidney injury or major adverse cardiovascular events. Conclusions: In a real-world propensity-matched cohort of lorlatinib-treated NSCLC patients, LLT initiated within 30 days was associated with lower 1-year mortality, venous thromboembolism, and hospitalization. Given the frequency of lorlatinib-associated dyslipidemia, these findings support early lipid monitoring and timely LLT initiation in practice. Prospective studies are warranted to confirm these associations. 365-day outcomes after matching. Outcome Early LLT (n=387) No early LLT (n=387) RR (95% CI) HR (95% CI) p All-cause mortality 16.1% 26.4% 0.608 (0.458-0.806) 0.597 (0.435-0.818) 0.0004; log-rank 0.001 Venous thromboembolism 6.2% 12.1% 0.509 (0.302-0.857) — 0.0093 Inpatient hospitalization 14.6% 23.6% 0.619 (0.396-0.967) — 0.0320 ED visit 8.3% 13.9% 0.593 (0.352-1.001) — 0.0467 Acute kidney injury 5.4% 7.1% 0.769 (0.429-1.378) — 0.3758 MACE 4.6% 4.6% 1.006 (0.511-1.979) — 0.9868

Artificial intelligence and obesity-related factors in breast cancer outcomes: A systematic review and pooled meta-analysis.

e12573 Background: Obesity and excess adiposity are established contributors to breast cancer risk, tumor biology, and treatment-related morbidity, yet their clinical effects are heterogeneous and incompletely captured by conventional risk models. Artificial intelligence (AI), machine learning (ML), and deep learning (DL) enable integrative analysis of obesity-related imaging, molecular, metabolic, and clinical data, offering new opportunities for precision risk stratification and outcome prediction. We systematically evaluated and quantitatively synthesized AI-, ML-, and DL-based models incorporating obesity or weight-related factors across the breast cancer continuum. Methods: A PRISMA-compliant systematic review was conducted using PubMed, Scopus, and Google Scholar through January 2026. Eligible studies applied AI, ML, or DL models to obesity-related exposures, including body mass index, metabolic biomarkers, adiposity-associated gene expression, or body composition–derived imaging features, and reported breast cancer–related outcomes. Outcomes included diagnosis, risk prediction, nodal metastatis, and treatment-related toxicity. Model discrimination metrics were extracted and pooled using a restricted maximum likelihood random-effects model with logit-transformed AUCs. Results: Sixteen models from heterogeneous cohorts were included, ranging from biomarker driven case-control studies to large population based datasets. For diagnosis and risk prediction, pooled discrimination was AUC 0.71 (95% CI 0.64–0.77; 95% prediction interval 0.40–0.90), with heterogeneity evident on forest plots. Imaging-based deep learning and multimodal models incorporating obesity-related variables demonstrated higher discrimination than traditional clinical risk scores. For nodal metastasis and radiotherapy related toxicity prediction, pooled performance across three studies was AUC 0.69 (95% CI 0.62–0.75; 95% prediction interval 0.48–0.84). Gene expression–based and metabolic biomarker models showed high discrimination in selected cohorts, though generalizability was limited by cohort size and validation. Funnel plot suggested possible small-study effects for diagnostic and risk prediction models (Egger p = 0.039). Conclusions: AI-, ML-, and DL-based models incorporating obesity-related factors demonstrate moderate to strong discrimination across breast cancer diagnosis, risk prediction, and selected outcomes, with superior performance in imaging-driven and multimodal models. However, heterogeneity, limited external validation, and inconsistent obesity phenotyping constrain clinical translation. Future studies should prioritize standardized adiposity metrics, harmonized outcomes, and prospective validation to support equitable and clinically actionable implementation of AI driven tools in breast cancer.

Luvometinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: A randomized, double-blind, placebo-controlled, phase 3 trial.

3017 Background: Neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PNs) is associated with significant morbidity, including pain, disfigurement and functional impairment. Surgical treatment for PNs may be limited due to tumor size, location and extent. A randomized, double-blind, placebo-controlled, phase 3 trial (NCT05913037) was conducted to evaluate the efficacy and safety of Luvometinib in adults with inoperable NF1 PN causing significant morbidities. Methods: Adults (≥18 yrs) with NF1 and symptomatic, inoperable PNs were randomized in a 2:1 to receive oral Luvometinib (8 mg daily) or placebo in 28-day cycles, stratified by baseline (BL) NRS-11 tumor pain score (≥2 or＜2). An interim analysis was performed at 16 months after the last patient randomization. The primary endpoint was confirmed objective response rate (ORR) by Blinded Independent Review Committe (BIRC) per REiNS criteria. Key secondary endpoints included ORR by the investigator (INV), duration of response (DOR), time to response (TTR) by BIRC and INV, pain severity and safety. Results: 167 adults were randomized to receive luvometinib (n = 112) or placebo (n = 55). As of the data cutoff on Aug 19, 2025, the median follow-up was 19.7 months(range: 1.4-25.5). The confirmed ORR assessed by BIRC was 43.8%（95% CI, 34.4-53.4）with luvometinib, compared with 10.9%（95% CI, 4.1-22.3）with placebo (p＜0.0001). Luvometinib led to a rapid response (median 3.9 months). The median DOR was 15.1 months (95% CI, 14.8-NE), with a 85.2% rate of DOR ≥12 months with luvometinib. A greater proportion of patients with BL overall tumor pain scores ≥2 experienced a reduction in pain score of at least 2 points with luvometinib compared to placebo (81.0% vs. 53.6%). The most common treatment-emergent adverse events (TEAEs) were folliculitis, increased CPK, mouth ulcer, diarrhea. Serious AEs occurred in 14.3% (luvometinib) versus 7.3% (placebo) of pts. TEAEs led to discontinuation was 1.8% in both groups. Conclusions: Our study demonstrated that luvometinib achieved a statistically significant ORR per BIRC compared with placebo, with rapid and durable response, significant reductions in pain severity, and an overall manageable safety profile. These findings suggest that luvometinib may emerge as a new standard treatment for patients with NF1 and symptomatic, inoperable PNs. Clinical trial information: NCT05913037 .

Reprogramming tumor-associated immune cells with Z-007, a first-in-class systemic TLR7/8/9 agonist.

e14565 Background: Overcoming tumor-mediated immune suppression is a critical barrier in cancer immunotherapy. Anti-tumor immunity depends on IFN-a, which can be induced using separate mimics of viral GU-rich RNA (TLR7/8 agonist) or CpG DNA (TLR9). We developed Z-007, a first-in-class combined GU-rich RNA/CpG-A DNA hybrid TLR7/8/9 agonist in a non-inflammatory lipid nanoparticle (LNP) for systemic (IV) delivery. Methods: Z-007 activity was evaluated in four species: 1) Ex vivo normal human PBMC (N = 10) and human tumor-associated immune cells from gastrointestinal cancer ascites (N = 5); 2) murine tumor models including i) IV delivery in orthotopic organoid MSS CRC liver metastasis (AKPS) resistant to anti-PD-1; ii) intratumoral (IT) delivery in syngeneic subcutaneous prostate cancer (TRAMPC1-GP); iii) IV in B16 melanoma lung metastasis; and iv) intraperitoneal (IP) delivery in IP MC38 CRC; 3) cynomolgus monkeys 4 week IV safety/PD study (N = 2 Z-007, N = 4 control LNPs) ; and 4) pet dogs with spontaneous tumors (N = 7). Results: Z-007 induced human GI tumor-associated ascites cells to secrete high IFN-α without IL-6 or TNF-α; RNA-seq showed increased IFN-a and IFN-g signatures observed in patients who responded to immune checkpoint blockade in published studies, and reduced immune suppressive and MDSC signatures. R848 (TLR7/8 agonist) induced immune suppressive and MDSC signatures with high IL-6 and TNF-α secretion but minimal IFN-α. CpG-A DNA 2216 induced minimal IFN-a or cytokines. In all murine models, Z-007 demonstrated monotherapy efficacy, driving tumor regression and expanding antigen-experienced CD8+ T cells in the tumor microenvironment. In monkeys, IV Z-007 was well-tolerated up to 100x the projected human equivalent dose without cytokine release syndrome (CRS), but with a "pulse" induction of serum IFN-α (1400 pg/mL) and CXCL10 (40,000 pg/mL) by 6 hr that returned toward baseline by 24 hours, avoiding the sustained signaling associated with T-cell exhaustion. In 3/7 pet dogs, IV or IT Z-007 induced > 30% tumor regression, including a dog with a metastatic hemangiosarcoma who had complete resolution of 13 lung and multiple skin metastases, and 87% regression of a cardiac metastasis during 6 months of weekly IV Z-007 monotherapy with no adverse events or lab changes. Conclusions: Z-007 represents a novel class of innate immune activator that successfully decouples high IFN-a induction from pro-tumorigenic inflammation. Its ability to reprogram human MDSCs and induce tumor regression in multiple murine models and in spontaneous canine tumors without evidence of CRS, fever, or altered liver, kidney, or other organ function, supports its clinical development. Based on the propensity of LNPs to be taken up in the liver, IV Z-007 may reprogram tumor-associated immune cells in patients with liver metastases from a wound healing to antiviral response, inducing systemic anti-tumor CD8+ T cell responses.

A new HLA genotyping algorithm to show accuracy and concordance between tumor and normal samples.

2584 Background: HLA genotyping, specifically HLA-A*02:01 is an actionable marker in uveal melanoma for Tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, with ongoing clinical trials investigating its use in HLA-A*02:01 positive cutaneous and mucosal melanoma. However, prior work has shown a discrepancy in this marker between blood and somatic tumor testing (Seedor R et al ASCO 2023). Given therapeutic implications of these discordances, a better understanding of tumor versus normal HLA testing concordance is critical. Methods: The Tempus HLA genotyping algorithm was run on a cohort of 191 patients, each with a tumor and a normal sample. The reference HLA genotype was determined by an independent lab using the GenDx HLA genotyping kit and long read sequencing of the normal sample. Samples that failed sequencing in either lab were excluded from the analysis. Concordance between tumor and normal samples was additionally evaluated on a cohort of 7,821 solid-tumor samples from a variety of sites, selected from the Tempus multimodal database. Results: The Tempus HLA genotyping algorithm is highly accurate (>98.9% on all HLA genes except DQA1). Specifically, it has an accuracy of 100% on the HLA-A gene, using either the tumor or normal sample. On the larger tumor/normal comparison cohort (7,821 samples), the Tempus HLA genotyping algorithm is highly concordant (>99% for all genes except HLA-DQA1 [94.3%]). For the 183 melanoma samples in this cohort, concordance was similar with 100% for HLA-A and HLA-B and 99.5% (182/183) for HLA-C, further confirming that HLA genotyping can be performed accurately on melanoma tumor samples. Investigation of all discordances on HLA genes for which HLA LOH results were available (HLA-A, -B and -C) shows that 84% (88/105) of those discordant samples have somatically lost the allele responsible for the discordance. Of LOH positive discordant samples, 73% (64/88) had a tumor purity ≥70%. Thus, over half (64/105) of the discordances between tumor- and normal-HLA genotyping are caused by high tumor purity HLA LOH positive samples. On samples meeting these criteria, concordance drops to 86%-89%. Conclusions: The Tempus HLA genotyping algorithm is an extremely accurate laboratory developed test that provides accurate results, regardless of whether the normal or tumor sample is used. Concordance between normal- and tumor-based results is above 99.5% in a large-scale dataset, provided the sample does not have HLA LOH and a tumor purity over 70%. These findings suggest that this test can rapidly screen patients for HLA genotype and match them to appropriate clinical trials but emphasize the importance of a normal sample for high tumor purity specimens. Accuracy (normal) N (normal) Accuracy (tumor) N (tumor) HLA-A 100.0% 189 100.0% 189 HLA-B 99.5% 187 99.0% 189 HLA-C 100.0% 185 98.9% 185 HLA-DQA1 99.5% 182 97.9% 189 HLA-DQB1 100.0% 186 99.5% 187 HLA-DRB1 98.9% 182 98.9% 182

ASTRON (OGSG 2401): A multicenter prospective trial of ferric carboxymaltose without erythropoiesis-stimulating agents for iron deficiency anemia in patients with gastric/colorectal cancer receiving chemotherapy.

12045 Background: Iron deficiency anemia (IDA) during chemotherapy for patients with gastrointestinal cancer worsens quality of life (QoL) and may compromise treatment continuity. Ferric carboxymaltose (FCM) enables high-dose intravenous iron supplementation; however, prospective data without concomitant erythropoiesis-stimulating agents (ESAs) remain limited. We conducted a multicenter prospective trial to evaluate intravenous FCM without concomitant ESAs or red blood cell (RBC) transfusion support. Methods: This was a multicenter prospective single-arm study. Key eligibility criteria included unresectable or recurrent gastric or colorectal cancer, ongoing chemotherapy, hemoglobin (Hb) <10.0 g/dL, and transferrin saturation (TSAT) <20%. FCM was administered as three 500 mg doses at ≥7-day intervals (total 1500 mg), with all doses completed within 29 days of the first infusion (Day 1). The primary endpoint was Hb improvement rate at week 8, defined as an Hb increase ≥1.0 g/dL from baseline without RBC transfusion. The improvement rate was tested against a threshold of 18% using a one-sided exact binomial test (α=0.05). QoL (FACT-An and EQ-5D-5L) was analyzed using linear mixed-effects models. Results: Fifty-two patients were enrolled; 51 received FCM. Median age was 72 years (range 45–90). Primary tumors were gastric (71.2%) and colorectal (28.8%); ECOG PS 0/1/2 was 50.0%/46.2%/3.8%. Disease status was unresectable in 55.8% and postoperative recurrence in 44.2%. The primary tumor was present in 40.4%. Most patients (90.4%) were receiving cytotoxic chemotherapy. Baseline median Hb was 9.15 g/dL (IQR 8.50–9.50), TSAT 8.55% (IQR 5.77–12.80), and ferritin 37.6 ng/mL (IQR 17.1–179.0). The week-8 Hb improvement rate was 72.5% (37/51; 95% CI 58.3–84.1; p<0.001). Hb improvement rates at weeks 4 and 12 were 58.8% (30/51) and 76.5% (39/51), respectively. FACT-An total score improved at week 8 (mixed-model estimate +4.93; 95% CI 0.23–9.62; p=0.040). EQ-5D also improved at week 8 (estimate +6.72; 95% CI 0.98–12.46; p=0.022). Planned protocol treatment was completed in 49/52 patients (94.2%). No treatment-related serious adverse events or deaths were observed. Conclusions: FCM achieved an Hb improvement rate of 72.5% and improved QoL in patients with gastric or colorectal cancer and IDA receiving chemotherapy, with high protocol completing and no treatment-related serious adverse events. These findings support FCM as an effective and feasible option for managing IDA during chemotherapy without ESAs. Clinical trial information: jRCTs051240288.

First-line rilvegostomig (R) + chemotherapy (CTx) in advanced biliary tract cancer (BTC): Updated analysis of GEMINI-Hepatobiliary substudy 2 cohort A.

4105 Background: Addition of PD-(L)1 inhibitors to CTx has transformed advanced BTC treatment but survival is limited for most patients (pts). R is a monovalent, Fc-reduced PD-1xTIGIT bispecific antibody that delivers coordinated and synchronous PD-1 and TIGIT blockade on immune effector cells. The primary analysis of substudy 2 Cohort A of GEMINI-Hepatobiliary (NCT05775159), a global phase 2 study evaluating R + CTx in pts with advanced BTC, demonstrated promising efficacy and a manageable safety profile. We report updated analyses after ≥18 months of follow-up for the last enrolled pt. Methods: Pts ≥18 years with previously untreated unresectable/metastatic BTC and ECOG PS 0/1 received intravenous R every 3 weeks (Q3W; ≤2 years) + gemcitabine 1000 mg/m 2 + cisplatin 25 mg/m 2 on days 1 and 8 Q3W (≤8 cycles). Coprimary endpoints were 6-month progression-free survival (PFS) and safety/tolerability. Secondary endpoints included median PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and overall survival (OS). Response and progression were investigator-assessed per RECIST v1.1. Results: As of Oct 24, 2025, the median follow-up for OS was 16.2 months (IQR 10.4–21.5); 6 pts (20.0%) received ≥20 cycles of R. Median OS was 16.8 months (95% confidence interval [CI] 11.0–not calculable [NC]) overall; 18-month OS was 44.8% (95% CI 26.5–61.6). Median OS was > 13 months across all subgroups based on age ( < 65/≥65 years), ECOG PS (0/1), geography, initially unresectable/recurrent disease at enrollment, and primary tumor location (gallbladder or bile duct). Two unconfirmed responses were identified after > 85 weeks follow-up: one complete and one partial response. The safety profile was consistent with the primary analysis. The most common treatment-related adverse events (AEs) were anemia (53.3%), neutrophil count decreased (50.0%), and platelet count decreased (43.3%). Detailed efficacy and safety data are in the Table. Conclusions: R + CTx demonstrated promising efficacy and a manageable safety profile. This study and phase 3 studies of R in BTC (ARTEMIDE-Biliary01, ARTEMIDE-Biliary02, DESTINY-BTC01) are ongoing. Clinical trial information: NCT05775159 . N=30* PFS Events, n (%) 6-month, % (95% CI) 12-month, % (95% CI) Median (95% CI), months 25 (83.3)73.0 (53.2–85.5)25.6 (11.4–42.6)8.2 (6.7–11.1) Confirmed ORR, % (95% CI) 31.0 (15.3–50.8) Best objective response, n (%) Partial response Stable disease Progressive disease 9 (31.0)18 (62.1)2 (6.9) DCR, % (95% CI) 93.1 (77.2–99.2) DoR, median (95% CI), months 6.9 (2.8–NC) OS Events, n (%) 12-month, % (95% CI) 18-month, % (95% CI) Median (95% CI), months 19 (63.3)65.5 (45.4–79.7)44.8 (26.5–61.6)16.8 (11.0–NC) Any / R-related AEs, n (%) Grade ≥3 Serious Led to R discontinuation Led to death 30 (100) / 22 (73.3)27 (90.0) / 5 (16.7)14 (46.7) / 3 (10.0)2 (6.7) / 1 (3.3) † 2 (6.7) / 0 * N=29 for responses. † Hepatic function abnormal.

Deciphering the heterogeneity and cellular interactions of cancer-associated fibroblasts in extrahepatic cholangiocarcinoma by spatial transcriptomics.

4237 Background: Cholangiocarcinoma (CCA) is a rare and lethal malignancy characterized by a desmoplastic stroma. containing cancer-associated fibroblasts (CAFs). Although CAFs have been widely studied in intrahepatic CCA, their impact on TME remodeling and chemo-immunotherapy (CIT) efficacy in extrahepatic (e) CCA is not fully elucidated. A compressive characterization of the spatial orchestration of the eCCA TME and of the interaction between CAFs and adjacent tumor cells is needed for the identification of therapies able to improve CIT efficacy, that, so far, is limited in these patients. Methods: We employed spatial transcriptomics on tumor specimens from 8 patients with advanced distal (d) or perihilar (p) CCA treated with durvalumab + cisplatin/gemcitabine. 126 microregions were analyzed with the GeoMx Digital Spatial Profiler and classified according to pan-CK and ACTA2/αSMA straining, as follow: CK + αSMA - tumor, CK - αSMA + distant and peritumor CAF-enriched stroma, or CK - αSMA - peritumor stroma. Results: αSMA staining showed a high degree of stromal heterogeneity in all eCCA, with some tumor nests surrounded by a dense CAF-enriched stroma and others by αSMA - cells within the same sample. Based on CD45 staining all samples were classified as immune-desert or -excluded, as no immune cells were found intratumorally. Tumor-adjacent CAFs exhibited a distinct extracellular matrix (ECM) remodeling signature marked by the expression of COL11A1 , MMP11 and TGFB family members. GSEA showed a positive enrichment of epithelial-mesenchymal transition (EMT) transcripts linked to the downregulation of signatures of immune activation and IFN response, in both peritumoral CAF-enriched regions and adjacent tumor cells. Confirming this data, receptor-ligand interaction modeling performed using the CellChat tool confirmed that CAF-enriched regions exhibited strong interactions with adjacent tumor cells, throughout the secretion of several factors involved in ECM-remodeling and immunosuppression. Intriguingly, a higher expression of EMT-related genes linked to a higher downregulation of pathways of immune activation was observed in dCCA vs pCCA samples, with dCCA patients experiencing a shorter progression-free survival (PFS) from CIT compared to pCCA patients (PFS ranging from 7-12 and 10-24 months, respectively). Conclusions: Our findings suggest that COL11A1 + MMP11 + CAFs might limit CIT efficacy in eCCA by promoting eCCA EMT and, at the same time, by forming a collagen-dense physical barrier that hampers the intratumoral recruitment of immune cells, thus offering novel insights into potential therapeutic targets for interventions. A deeper characterization of CAF features and CAF-tumor interactions is ongoing.

Efficacy and safety of larotrectinib in patients with non-primary central nervous system <i>TRK</i> fusion cancer: An updated analysis.

3145 Background: Larotrectinib (laro) is the first-in-class, highly selective TRK inhibitor approved for tumor-agnostic use in patients (pts) with TRK fusion cancer based on a robust and durable objective response rate in pts with various cancers. Here, we report updated long-term efficacy and safety in adult and pediatric pts treated with laro with non-primary central nervous system (CNS) TRK fusion cancer. Methods: Pts from 3 clinical trials (NCT02637687 [SCOUT], NCT02576431 [NAVIGATE], NCT02122913) were included. Laro was administered at 100 mg twice daily (BID) and 100 mg/m 2 (max 100 mg) BID in most adult and pediatric pts, respectively. Responses were independent review committee-assessed (RECIST v1.1). Pts enrolled in SCOUT could stop laro in the absence of on-treatment progression (“wait-and-see”) and remain on trial. If pts were re-treated due to progression, response was assessed by investigators. Data cutoff: July 20, 2025. Results: In total, 304 pts were treated; 25 had baseline CNS metastases. There were 28 tumor types, including soft tissue sarcoma (24%), infantile fibrosarcoma (16%), lung (11%), and thyroid (10%). NTRK gene fusions were detected by next-generation sequencing (NGS) in 266 (88%) pts. Overall response rate was 65% (95% confidence interval [CI] 59–70) with 61 (20%) complete responses (CR), 18 (6%) pathological CR, 118 (39%) partial responses (PR), 55 (18%) stable disease (SD), 32 (11%) progressive disease (PD), and 20 (7%) not evaluable/undefined. Median duration of treatment was 19 months ([mo] range 0–111). At data cutoff, 52 pts (17%) remained on trial (either on treatment or in “wait-and-see”). Median time to response was 1.8 mo (range 0.9–80.3). Median duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were 42 mo (95% CI 31–59), 26 mo (95% CI 19–35), and not reached (95% CI 89–not estimable), respectively, at median follow-ups of 54, 52, and 65 mo. The 5-year rates for DoR, PFS, and OS were 41% (95% CI 33–49), 33% (95% CI 27–40), and 61% (95% CI 55–67), respectively. Fifty-seven pediatric pts entered a first “wait-and-see” period (median duration 24 mo [range 0–75+]). Of these, 38 exited the “wait-and-see” period. By investigator assessment, 20 pts had PD and resumed treatment (with 6 CR, 5 PR [including 2 pending confirmation], 7 SD, 2 unevaluable/undefined). The other 18 pts discontinued laro permanently but were all alive at data cutoff. Treatment-related adverse events (TRAEs) were mainly worst Grade 1/2 (n=189; 62%). Worst Grade 3/4 TRAEs occurred in 72 (24%) pts. Five (2%) pts discontinued due to TRAEs. Conclusions: Laro continues to demonstrate rapid and durable responses, extended survival, clinical benefit, and a favorable safety profile in pts with TRK fusion cancer. These data support the wider adoption of NGS panels that include NTRK gene fusions to identify pts who may benefit from TRK inhibitor therapy. Clinical trial information: NCT02637687 , NCT02576431 , NCT02122913 .

Efficacy and safety results of a first-in-class PRMT1 inhibitor CTS2190 in patients (pts) with immune checkpoint inhibitor (ICI)–insensitive advanced solid tumors.

e15164 Background: Immuno-cold tumors remain low response rate to ICIs. The treatment options and efficacy are limited for patients after PD-(L)1 inhibitors-based therapy. CTS2190 specifically inhibits arginine methyltransferase 1 (PRMT1) and modulate immune microenvironment by epigenetic gene regulation. Here we present clinical data of CTS2190 (NCT06224387) to demonstrate promising safety and efficacy of CTS2190 in heavily pretreated pts with advanced solid tumors including those ICI-insensitive NSCLC, TNBC and mCRPC. Methods: In Phase I/II study of CTS2190, for dose escalation part, in addition to 60~300 mg regimens (QD, 2 weeks on and 1 week off, 5 days on and 2 days off), the safety and tolerability of 120 mg BID were explored. Results: As of 19 Jan, 2026, 71 pts received CTS2190 treatment (1 at 60 mg, 1 at 120 mg QD, 30 at 180 mg, 29 at 240 mg, 2 at 300 mg, and 6 at 120 mg BID). DLT events of grade (G) 4 platelet count decreased occurred in 1 pt at 240 mg and 2 pts at 300 mg. The most common ≥ G3 TRAE was platelet count decreased (32%). The incidence rates in 180 mg QD and 120 mg BID were 33% and 17%, significant less than that in the 240 mg dose level (41%). Exploratory analysis of median PFS was conducted among various subgroups stratified by clinicopathological features. In 60 response-evaluable pts, there was a trend toward improved median PFS among ICI-insensitive pts compared with ICI-sensitive pts（HR = 0.35, P = 0.001）. A similar trend was observed in the PD-(L)1 primarily resistant NSCLC subgroup（HR = 0.34, P = 0.009).There are no differences in median PFS among subgroups of other features (gender, age, ECOG or prior lines of therapies). In 31 response-evaluable ICI-insensitive pts at active dose, The ORR was 12.9% and disease control rate (DCR) was 68%. Of note, in the subgroup of PD-(L)1 primarily resistant NSCLC pts, the ORR was 19% and the DCR was 75%. 25% ORR was observed in mCRPC pts. In the preliminary overall survival (OS) analysis, the median OS was 663 days for pts with PD-(L)1 primarily resistant NSCLC, for ICI-insensitive all comer pts 663-day cumulative survival rate by Kaplan Meier was 54%.Among 16 pts with available PD-L1 expression data, 9 exhibited PD-L1 expression below 5% and showed more favorable responses compared with those having higher expression. Of these 9 patients, 7 were identified as primarily resistant to PD-(L)1 inhibitors. Conclusions: CTS2190 has shown superior safety and promising efficacy in heavily pretreated pts with advanced solid tumors to achieve the clinical proof-of-concept. More patients are being enrolled at RP2Ds in current phase IIa cohort expansion study in NSCLC, mCRPC, TNBC, PDAC and other indications of interest. Studies to combine CTS2190 with SoCs in solid tumors are being planned. Meanwhile, biomarker exploration on PRMT1, PD-L1 expression, MTAP-null and related DDR genes are ongoing. Clinical trial information: NCT06224387 .

Primary care (PCP) and oncology (ONC) provider perspectives on primary care involvement in cancer clinical trial discussions in a safety-net health system.

e13592 Background: A collaborative model of care between PCPs and ONCs within safety-net systems may be needed to increase representative enrollment in cancer clinical trials. We evaluated provider attitudes toward PCP involvement in early clinical trial discussions, alignment and misalignment between PCP and ONC expectations. Methods: A cross-sectional survey of PCPs and ONCs at a safety-net healthcare system affiliated with a Comprehensive Cancer Center assessed attitudes, communication, and behaviors about clinical trials, barriers and facilitators to accrual, and utility of various supportive strategies. Two clinical vignettes (Spanish vs. English speaking patients) assessed provider approaches to communication and enrollment support using mixed-effects ordinal regression. Results: Respondents included 78 PCPs and 57 ONCs (35% and 39% attending physicians, 51% and 23% trainees, and 6% and 30% advanced practice providers, respectively). For the vignettes, there was no difference in responses between PCPs and ONCs (p &gt; .05). Among vignette response choices (multiple allowed), most PCPs (64%) strongly agreed with referring patients to ONCs for further trial discussion whereas 52% reported indifference to recommending trial participation. Most ONCs strongly agreed with discussing trials themselves (58%) and referring patients to research staff (75%). Both PCPs and ONCs identified similar patient-, trial-, and system-level barriers and facilitators to trial discussions (Table). PCPs agreed they have an important role in informing patients about trials (56%), especially for increasing representative enrollment (73%). Although ONCs agreed that PCPs play an important role in patients’ cancer care (81%) and in enhancing trial diversity (56%), most (53%) reported that PCPs should not initiate trial discussions. In ranking strategies to support PCP-led trial discussions, PCPs and ONCs both prioritized access to centralized, up-to-date trial information. Incentive-based strategies ranked lowest among PCPs and mid-tier for ONCs. Conclusions: We identified provider-endorsed system-level strategies to normalize trial conversations and support equitable trial accrual that may be feasible and scalable across primary care and oncology settings. The absence of language effects suggests that these supports may be broadly applicable in safety-net settings. Provider-reported barriers and facilitators to cancer clinical trial discussions (Percent endorsing “strongly agreed”). Domain PCP (%) ONC (%) Facilitators Coverage of non-standard procedures 76 68 In-person interpreters 64 65 Research navigation NA 63 Financial support 60 58 Transportation 53 60 Barriers Personal knowledge of trial opportunities 85 NA Time constraints 53 14 Patient fear of research participation 44 28 Health literacy 41 23 NA: Not Applicable.

Advancing value-based breast cancer screening in a safety-net health system: A multimodal approach to improving population health and system sustainability.

11114 Background: Evaluation of breast cancer screening (BCS) adherence in our large safety-net health system revealed wide variability and late-stage diagnosis rates that exceeded national benchmarks. A multidisciplinary taskforce (primary care, radiology, cancer center, and patient advocates) identified barriers, co-designed, and implemented a multi-pronged intervention to address screening uptake and adherence. Methods: Mixed-methods evaluation across 18 primary care sites revealed wide variability in BCS rates (60-82%); lack of systematic management of screening bottlenecks (ordering, scheduling, no-shows/cancellations); and unmet patient needs (transportation, screening hesitancy). We co-developed and implemented a phased intervention from March–December 2025 to address identified barriers through: (1) radiology navigator outreach to primary care patients at low-performing sites (March), (2) electronic medical record patient portal self-scheduling (July), (3) AI-assisted rescheduling after no-shows/cancellations (December), and (4) assessment and navigation of social needs and screening hesitancy (March). Outcomes measured were outreach, engagement, and screening completion. We performed multivariate regression to examine demographic predictors of screening. Results: Of 57, 041 HEDIS-eligible patients, 15,971 (28%) were overdue at baseline (mean age 58 yo, 77% Hispanic or non-Hispanic Black, 74% Medicaid or Dual). Overall, the intervention resulted in 1,610 additional screens over 9 months, improving systemwide BCS rates from 72 to 76%. Of the additional screens, radiology navigator achieved 452 screens (29%), patient portal self-scheduling achieved 1,097 screens (70%), and AI-assisted outreach of no-show/cancelled achieved 61 screens (4%). Engagement and show rates varied: navigator outreach had the highest scheduling engagement (74%) but lower show rates (46%); patient portal self-scheduling showed moderate engagement (44%) with higher show rates (76%); and AI-assisted outreach had low engagement (4%) with moderate show rates (56%). Demographics did not predict screening outcomes. Screening hesitancy (37%) and transportation (10%) were the most common barriers, addressed through social and peer navigation, respectively. Revenue from additional screenings fully offset navigator costs. Conclusions: A coordinated, resource-efficient screening outreach strategy combining digital tools, human navigation, and AI assistance—co-designed with patients and clinical stakeholders—improved BCS adherence, addressed unmet needs of underserved populations, and proved itself financially sustainable across a safety net health system. Future efforts will focus on further scaling of population health approaches to cancer screening programs.

Prognostic impact of ASXL1 somatic mutation on patients with chronic myeloid leukemia: A systemic review and meta-analysis.

e18596 Background: Outcomes in chronic myeloid leukemia (CML) remain heterogeneous despite effective BCR::ABL1 tyrosine kinase inhibitors (TKIs). Somatic mutations in epigenetic regulators, particularly ASXL1, have been implicated in adverse prognosis, but their clinical impact in CML has not been systematically defined. Methods: A systematic review was conducted using CINAHL, EMBASE, MEDLINE Ultimate, and PubMed from inception through August 2025. A total of 1,339 records were identified; after duplicate removal and screening, 11 studies met inclusion criteria and were included in qualitative synthesis and meta-analysis. Eligible studies included adult and pediatric patients with chronic and advanced phase (accelerated or blast) CML with ASXL1 mutation status assessed using validated molecular methods. Outcomes included molecular response, cytogenetic response, survival, and treatment resistance. Random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CI). Statistical heterogeneity was assessed using the I² statistic. Results: At 12 months, ASXL1-mutated patients had significantly lower odds of achieving major molecular response (MMR) compared with ASXL1–wildtype patients (OR 0.29; 95% CI 0.16–0.51; p&lt;0.0001; I²=30%). No statistically significant difference was observed in complete cytogenetic response (CCyR) (OR 0.30; 95% CI 0.02–5.31; p=0.41; I²=68%). Compared with patients harboring other non-ASXL1 somatic mutations, ASXL1 mutation was not associated with a significant difference in MMR (OR 0.49; 95% CI 0.23–1.05; p=0.067; I²=0%). Conclusions: ASXL1 mutations are associated with inferior molecular response to TKI therapy in CML, supporting their role as an adverse prognostic biomarker. These findings highlight the potential value of incorporating myeloid mutation profiling into future CML risk-stratification strategies.

Trastuzumab deruxtecan (T-DXd) + bevacizumab (BEV) as first-line (1L) maintenance therapy in patients (pts) with human epidermal growth factor receptor 2 (HER2)–expressing ovarian cancer (OC): Results from the DESTINY-Ovarian01 (DO-01/ENGOT-ov89/GOG-3112/APGOT-OV13) safety run-in (SRI).

5554 Background: HER2 immunohistochemistry (IHC) expression scores of 3+, 2+, or 1+ occur in up to ~6%, ~28%, and ~21% of OC cases, respectively. In DESTINY-PanTumor02, T-DXd, a HER2-directed antibody–drug conjugate, showed clinically meaningful antitumor activity in pts with heavily pretreated HER2-expressing OC, establishing HER2 as a targetable biomarker. BEV + chemotherapy, followed by maintenance BEV ± poly (ADP-ribose) polymerase inhibitors (PARPi), is a recommended 1L treatment; however, an unmet need remains for PARPi-ineligible pts with HER2-expressing OC. We report the SRI results from DO-01 (NCT06819007), a randomized, open-label, phase 3 trial evaluating T-DXd + BEV vs BEV alone as 1L maintenance therapy in pts with HER2-expressing OC. Methods: Pts with newly diagnosed, advanced, high-grade, locally or centrally determined HER2-expressing (IHC 3+/2+/1+) epithelial OC, with no disease progression after 1L chemotherapy + BEV, and ineligible for PARPi, were enrolled and received T-DXd 5.4 mg/kg + BEV 15 mg/kg intravenously every 3 weeks. Pts were treated for ≥2 cycles. Preliminary safety of T-DXd + BEV was assessed by dose-limiting toxicity (DLT; ~30% maximum acceptable rate) and the frequencies of treatment-emergent adverse events (TEAEs) and TEAEs of special interest. Results: At data cutoff (DCO; October 23, 2025), 21 pts received a median of 4 cycles (range, 2-8) of T-DXd + BEV; no pt withdrew before cycle 2. Median age was 57 years (range, 22-71) and 19 pts (90.5%) were Asian; 7 (33.3%) and 14 pts (66.7%) had FIGO stages III and IV at baseline, respectively. Median treatment duration was 3.0 mo (range, 1.4-5.5). At DCO, 20 pts (95.2%) completed DLT evaluation and remained on treatment; 1 withdrew after the DLT evaluation period. DLTs occurred in 2 pts (10.0%). TEAEs are shown in the Table. Grade ≥3 drug-related TEAEs occurred in 9 pts (42.9%). Drug-related TEAEs led to dose reduction in 5 pts (23.8%) and dose delay in 6 pts (28.6%). No drug-related TEAEs led to discontinuation or death. Most common drug-related TEAEs (&gt;50%) were nausea (76.2%), leukopenia (52.4%), and neutropenia (52.4%). No cases of adjudicated drug-related interstitial lung disease or left ventricular dysfunction were reported. Conclusions: The preliminary safety profile of T-DXd + BEV was consistent with the known safety profiles of the individual agents, and no new safety signals were identified, supporting continued investigation of T-DXd + BEV in DO-01. Clinical trial information: NCT06819007 . Pts with events, n (%) T-DXd + BEVN = 21 Drug-related TEAEs 21 (100) Drug-related grade ≥3 TEAEs 9 (42.9) Drug-related TEAEs leading to discontinuation 0 Drug-related TEAEs leading to dose reduction 5 (23.8) Drug-related TEAEs leading to dose delay 6 (28.6) TEAEs with outcome of death 0

Diagnostic performance, safety, and biodistribution of [ ⁶⁸ Ga]Ga-OncoACP3 for PET imaging in prostate cancer: A phase I clinical trial.

3074 Background: Acid Phosphatase 3 (ACP3) is an emerging promising theranostic target in prostate cancer (PCa), expressed on PCa cells across most primary and metastatic lesions. ACP3 shows higher, more homogeneous expression than PSMA in low- and high-ISUP-grade tumours and in metastases, while not being expressed in healthy organs such as salivary glands, kidneys, and gastrointestinal tract. We present data from a multicentre, prospective phase I clinical trial investigating safety, dosimetry, pharmacokinetics, and diagnostic performance of [ 68 Ga]Ga-OncoACP3, a high-affinity ligand of ACP3 discovered from DNA-Encoded Chemical Libraries, in PCa. Methods: Twenty patients with a confirmed diagnosis of PCa were planned for enrolment in the study in two cohorts: Cohort A, 5 patients with primary tumour only; Cohort B, 15 patients with or without metastatic disease. Each patient received a single intravenous injection of [ 68 Ga]Ga-OncoACP3. PET/CT acquisitions were performed at 0, 10, 60 and 120 minutes after the injection with multiple blood and urine samples collections for pharmacokinetic and dosimetric analysis. Adverse events were recorded and graded according to CTCAE v5.0. [ 68 Ga]Ga-OncoACP3 PET findings were compared with PSMA PET (performed by all patients, according to clinical practice) and, when available, with follow-up data and histopathological findings. Results: All 20 patients completed [ 68 Ga]Ga-OncoACP3 PET imaging: 8 for initial staging, 10 for biochemical relapse, and 2 for advanced disease evaluation. No adverse events occurred. The tracer showed mixed hepatobiliary/renal excretion, with no uptake in salivary glands. PET-positive lesions showed rapid and selective tumour uptake shortly after injection, with increasing signal intensity at 60 and 120 minutes. All confirmed PSMA-positive lesions were evident at [ 68 Ga]Ga-OncoACP3 PET, in most cases with a higher tumour-to-background compared to PSMA PET. In three cases, [ 68 Ga]Ga-OncoACP3 PET detected additional PCa lesions, all confirmed by follow-up data or histopathology. No area of unspecific bone uptake at PSMA PET was evident at [ 68 Ga]Ga-OncoACP3. Conclusions: [ 68 Ga]Ga-OncoACP3 has an excellent safety profile and favourable pharmacokinetics, as well as promising tumour-targeting properties in PCa. [ 68 Ga]Ga-OncoACP3 may outperform current PSMA-targeting modalities across the whole natural history of the disease, and particularly in theranostic applications. Clinical trial information: NCT06840535 .

RNA expression signatures as predictors of prognosis in thin and thick primary cutaneous melanoma.

e21602 Background: Risk stratification of primary cutaneous melanoma based on Breslow thickness remains clinically imperfect, particularly in thin tumors (≤1 mm), where a subset progresses unexpectedly. Previously, targeted RT-PCR analyses of established tissue RNA markers demonstrated prognostic utility mainly in thick melanoma, with no robust markers identified for thin tumors, prompting an unbiased RNA sequencing approach to address this gap.Objectives: Identify RNA expression signatures associated with prognosis in thin (≤1 mm) and thick (≥4 mm) primary cutaneous melanoma. Methods: RNA-seq was performed on primary tumor tissue from 51 thin and 65 thick melanomas after hybrid-capture library preparation and deep sequencing (NovaSeq 6000, S4). Expression was quantified for 18,146 genes, including full coding regions of 17,702 protein-coding genes (54,142 transcripts), using a standardized four-step pipeline with stringent filtering. Analyses were performed by clinical outcome (regional recurrence and/or distant metastases and/or death) and to build classifiers distinguishing thin vs thick melanoma. Results: In thin melanoma, 69 genes were differentially expressed by outcome; a 10-marker panel (BAIAP2L1, DMRT3, ENSG00000305404, HOXA11-AS, MGP, MIR1183, MUC6, NBPF17P, NANOS3, TMEM191C) showed the best prognostic performance (AUROC 0.835). In thick melanoma, 26 prognostic genes were identified; a 6-marker panel (EEF1A1P16, HSPA8P5, IBSP, MEX3B, MMP3, VAMP2) achieved AUROC 0.93. A shared 4-marker signature (MMP3, RGS1, SPP1, VAMP2) performed consistently across thin and thick tumors (AUROC 0.80). A 5-marker classifier (ALOX12, COL22A1, KRT10-AS1, S100B, SPP1) distinguished thin vs thick melanomas (AUROC 0.96), supporting distinct transcriptional programs linked to thickness and progression biology. Conclusions: RNA profiling reveals substantial prognostic heterogeneity within thin melanoma and identifies multigene signatures that may refine risk stratification beyond Breslow thickness. Divergent prognostic panels in thin vs thick tumors suggest distinct mechanisms of progression and support development of clinically deployable RNA-based assays for risk-adapted management.These signatures identify biologically aggressive subsets within thin melanoma that may warrant intensified surveillance or consideration of adjuvant strategies.