Browse Articles

Phase I/IIa study of DN022150, a novel selective noncovalent small molecule KRAS G12D inhibitor in patients with advanced KRAS G12D–mutant solid tumors.

3007 Background: The KRAS G12D mutation is ranks among the most common RAS mutations across human cancers and is closely linked to poor clinical outcomes. DN022150 is a novel highly selective KRAS G12D inhibitor, that exerts potent antitumor effect by specifically binding to the switch-II pocket of the mutant KRAS G12D protein, this binding mechanism blocks the interaction of GDP and GTP with the mutant protein, thereby abrogating activation of the downstream of the RAS-MAPK signaling pathway. We report preliminary findings from the first-in-human study of DN022150 in patients with advanced KRAS G12D-mutant solid tumors. Methods: This Phase I/IIa study evaluates the safety, tolerability, pharmacokinetics (PK), and efficacy of DN022150 in patients with locally advanced or metastatic solid tumors harboring KRAS G12D mutations who have progressed following prior standard therapies. The study includes three sequential parts: dose escalation, dose expansion, and indication exploration. During dose escalation, patients receive fixed doses of DN022150. Based on integrated analysis of safety, tolerability, PK, and efficacy data from escalation phase, approximately 1-3 dose/frequency cohorts will be selected for the subsequent dose-expansion phase. The primary objective is to evaluate the safety, tolerability, and preliminary antitumor activity of DN022150 in patients with KRAS G12D-mutated advanced solid tumors. Results: As of January 22, 2026, a total of 56 patients were enrolled. Among them, 83.9% (47/56) had an ECOG PS of 1 and 66.1% (37/56) diagnosed with pancreatic cancer. Approximately 80% had received ≥2 prior lines of systemic therapy. Safety analysis included 49 participants (dose levels: 20-650 mg). Notably, no dose-limiting toxicities occurred across all dose levels. Grade ≥3 TEAEs were observed in 44.9% (22/49) of patients, with TRAEs in 30.6% (15/49). No grade 4-5 TRAEs were documented. TRAEs led to dose delays in 14.3% (7/49) of patients and treatment interruptions in 16.3% (8/49). The most common grade ≥3 TRAEs (≥5%) were neutropenia, anemia, and leukopenia. Tumor assessments were conducted every 8 weeks (±7 days). Among the 31 evaluable patients, treated at dose levels of 200 mg to 650 mg, an impressive 96.8% (30/31) achieved target lesion reduction at first post-baseline assessment, including 71% (22/31) with ≥20% reduction. ORR was 37.5% (3/8) at 450 mg and 31.3% (5/16) at 650 mg, with DCR of 87.5% (7/8) and 93.8% (15/16). Conclusions: DN022150 demonstrated favorable safety and tolerability profiles in patients with KRAS G12D-mutated advanced solid tumors, with no dose-limiting toxicities observed and manageable TRAEs. The agent showed potent antitumor activity, confirming its precise targeting of the KRAS G12D mutation. These results position DN022150 as a promising novel therapy for this molecularly defined population. Clinical trial information: CTR20242749.

Photo-thermoelastic diffusive waves with microconcentration in quantum-modified semiconductors

This study presents a general one-dimensional analysis of photo-thermoelastic diffusive wave propagation in quantum-modified semiconductor media that incorporates microconcentration effects. The model extends classical photo-thermoelastic semiconductor theory by introducing a coupled dual-transport mechanism that accounts for quantum-modified carrier diffusion and thermodiffusion associated with microconcentration fields. Quantum transport is represented through a density-gradient formulation, enabling the capture of nonlocal carrier behavior at small length scales, while the microconcentration variable describes additional mass transport induced by temperature gradients. The governing equations for displacement, temperature, carrier density, and microconcentration are formulated within a unified continuum framework and reduced to dimensionless form in a one-dimensional configuration. The resulting system is solved analytically using the Laplace transform, and the physical fields are obtained in the time domain via numerical inversion. The analysis reveals that the interaction between quantum carrier transport and thermodiffusion significantly alters the propagation characteristics, leading to modified attenuation, phase behavior, and wave penetration depth. Furthermore, microconcentration introduces additional coupling that redistributes thermal and mechanical fields within the medium. The proposed formulation provides a comprehensive tool for understanding coupled transport phenomena in semiconductor structures and is relevant to applications in optoelectronic devices, nano-scale thermal management, and laser-driven material systems.

Biocompatible and ecofriendly selenium nanoparticles in diabetes and wound healing

Multi‐Dimensional Insights Into the Surface and Interfaces of Battery Materials by Time‐of‐Flight Secondary Ion Mass Spectrometry

ABSTRACT Time‐of‐flight secondary ion mass spectrometry (ToF‐SIMS) has emerged as a pivotal analytical technique for characterizing the complex surface and interfacial chemistry of battery materials. This review article comprehensively discusses the fundamental principles and unique attributes of ToF‐SIMS, highlighting its advantages such as ultrahigh surface sensitivity (ppm‐ppb), high spatial resolution (< 50 nm laterally, and < 1 nm in depth), and high mass resolution for hydrogen and isotope study. In the field of battery study, these attributes enable precise, multi‐dimensional characterization of electrode‐electrolyte interphases (EEIs). In the previous works, ToF‐SIMS has been employed to resolve the composition and structures at the nanoscale of EEIs, track the dynamic evolution and degradation of electrode surface, differentiate artificial coating interphases from the bulk materials, and detect isotopes for mechanistic studies. The burgeoning field of in situ liquid ToF‐SIMS for probing the authentic solvation structures and aging mechanism of electrolytes is also highlighted. Challenges of using ToF‐SIMS for battery study, such as the matrix effects, beam‐induced damage, and need for higher sensitivity and depth resolution, are also discussed. In summary, ToF‐SIMS provides multi‐dimensional insights into battery interfaces, which help to establish structure‐property correlations and will continuously guide the rational design of the next‐generation high‐performance energy storage systems.

Matrix Viscoelasticity Regulates Dendritic Cell Migration and Immune Priming

ABSTRACT The tumor microenvironment shapes immune surveillance through its mechanical properties, yet the role of matrix viscoelasticity remains unclear. Here, we used a tunable collagen system that models human tissue viscoelasticity to define how matrix relaxation directs dendritic cell (DC) behavior. Slow‐relaxing, elastic networks restrict actomyosin‐driven remodeling, limiting DC motility and reducing DC‐T cell encounters and activation. Blocking DC migration in fast‐relaxing matrices recapitulated key aspects of the impaired T cell priming seen in elastic networks, identifying migration as a mechanical checkpoint for immune activation. Prolonged confinement in elastic matrices induced a mechanomemory state, locking DCs into a state of reduced motility and altered chromatin accessibility. Studies using patient‐derived ependymoma samples confirmed these findings, establishing viscoelastic relaxation as a key physical regulator of immune priming. Together, this tunable viscoelastic platform provides a defined, human‐relevant model to dissect and model mechanical control of immunity for therapeutic design.

Large‐Area 2D Metasurface‐Based Triboelectric E‐Skin Arrays: Contact & Proximity Tactile Mapping with Broadband Acoustic Readouts

ABSTRACT Recent advances in electromechanically coupled, self‐powered, flexible transducer‐enabled electronic skins are predominantly driven by the capacitive triboelectric nanogenerators (TENGs), which operate intrinsically as multifunctional sensor‐cum‐energy harvester. The resulting TENG's operability in cutting‐edge wearable technologies can be significantly augmented by introducing 2D dielectric metasurfaces, which optimize functionality through enhanced electromechanical coupling. Here, we introduce a 2D metasurface‐TENG e‐skin that unifies tactile (contact and inductive) and acoustic sensing in a single ultrathin platform. Large‐area nanocone (NC) metasurfaces are engineered on 100 µm polydimethoxysilane (PDMS) films via laser‐interference lithography (LIL) and soft molding, which boosts triboelectric charge density and provides optical diffraction cues for strain monitoring. Integrated into a 3 × 3 array, the device delivers real‐time tactile pressure imaging with low crosstalk and non‐contact proximity detection. The NC‐TENG patch also functions as a self‐powered acoustic sensor, in which the sound pressure level (SPL) and frequency response are quantified in both spatial and spectral domains over a broad frequency range (∼50–6400 Hz). Compared to pristine PDMS, the metasurface enhances open‐circuit voltage by ≈46% under identical loading and sustains stable electrical output. By coupling electromechanical and electro‐acoustic transductions with metasurface optics, this work advances multimodal, arrayed e‐skins for next‐generation human‐machine interfaces and wearable sensing.

Interpretable white-box modeling for nitrogen storage in metal–organic frameworks

Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation

Long-term survival outcomes of consolidative local ablative therapy after response to first-line systemic treatment in oligometastatic NSCLC.

8601 Background: The role of consolidative local ablative therapy (LAT) for patients (pts) with oligometastatic non-small cell lung cancer (NSCLC) who have responded to first line (1L) systemic treatment remains controversial especially after negative results from the NRG LU002 phase II/III trial. Data on long-term survival outcomes remain limited. Methods: We retrospectively collected data from EMR records of pts with oligometastatic NSCLC treated with 1L systemic treatment at the University of Pennsylvania Health System (2015–2025). Oligometastasis was defined as ≤4 distant metastases. Eligible pts had either genuine synchronous or induced oligometastatic disease and had achieved partial response (PR) or stable disease (SD) after 1L systemic treatment. We hypothesized that LAT would be associated with improved PFS and OS using time-dependent Cox regression analysis. Results: We identified 187 eligible pts. 53% were female; median age was 67 yrs and 31% had PD-L1 expression > 50%. At diagnosis, 90% had genuine oligometastatic disease: 45% with one metastatic lesion, 24% with two, 15% with three, and 11% with four lesions. Median follow- up time was 81 mos. (Reverse Kaplan-Meier). Of 187 pts, 21 received consolidative LAT in addition to maintenance therapy (LAT+) while 166 received maintenance therapy alone (LAT-). The LAT+ group was less likely to have bone metastasis (4.8% vs 34%, P = 0.007) and more likely to have adrenal metastasis (38% vs 19%, P = 0.049). In the LAT+ group, 67% had received chemo-immunotherapy as 1L and 19% had received immunotherapy alone, compared with 58% and 17% in the LAT− group, respectively (P = 0.80, Chi-square). In the LAT+ group, 76% achieved PR and 24% had SD to 1L therapy, compared with 65% and 35% in the LAT− group, respectively (P = 0.30, Chi-square). Median time from diagnosis to LAT delivery was 6 mos. (range, 2 – 24 mos.). The most common LAT modality was radiation (82%). The most common site of LAT was lung (68%). Median PFS was 28 vs 12 mos. and median OS was 98 vs 24 mos. in the LAT+ and LAT− groups, respectively. In time-dependent Cox models treating LAT as time-varying exposure, LAT+ was associated with improved PFS (P = 0.045) and OS (P = 0.003). A multivariable model confirmed the benefit of LAT after adjusting for PD-L1 status, treatment response, brain metastasis, bone metastasis, and nodal status (PFS: HR = 0.38, P = 0.004; OS: HR = 0.27, P = 0.002). Adverse events grade ≥3 were similar in both groups. Conclusions: LAT was associated with significantly improved PFS and OS in pts with oligometastatic NSCLC with an objective response or stable disease following 1L systemic treatment. Prospective studies are warranted to define pt characteristics that predict the greatest benefit from and optimal timing of LAT.

Chemoablation with oral erdafitinib in recurrent <i>FGFR3</i> -altered non–muscle-invasive bladder cancer: A phase II window-of-opportunity trial.

4623 Background: Non-muscle invasive bladder cancer (NMIBC) frequently recurs despite intravesical treatments, necessitating repeated transurethral resections of bladder tumors (TURBT). FGFR3 alterations are common in NMIBC and may be a potential therapeutic target. Erdafitinib, a pan-FGFR inhibitor, is approved for metastatic urothelial cancer, but its efficacy as a chemoablative agent in recurrent NMIBC is not yet established. This trial evaluates the efficacy of oral erdafitinib as a chemoablative treatment in patients with recurrent FGFR3-altered NMIBC. Methods: Patients with recurrent NMIBC and FGFR3 alterations detected with MSK-IMPACT were given oral erdafitinib (6 mg daily) for ~28 days before TURBT. Tumor response was assessed using RECIT-Bladder criteria, and tissue, blood, and urine samples were collected for pharmacodynamic analyses and biomarker exploration. Toxicities were graded using CTCAE v5.0. Results: A total of 20 patients with recurrent NMIBC and confirmed FGFR3 mutations were enrolled in the study. The most common mutations were S249C (n=12), Y373C (n=3), and R248C (n=3). Most patients (70%) had a history of low-grade Ta (LG Ta) tumors. All patients had received at least one prior intravesical therapy, with 55% having undergone multiple courses of BCG, gemcitabine, mitomycin, or combination regimens. The objective response rate (ORR) was 75% (15/20), with complete response (CR) achieved in 11 patients (55%). No grade ≥3 toxicities were observed. Conclusions: Oral erdafitinib demonstrated efficacy in reducing tumor burden in select FGFR3-altered NMIBC in this window-of-opportunity trial. Clinical trial information: NCT04917809 .

HIPEC combined with NIPS and tislelizumab for conversion therapy in gastric cancer with peritoneal metastasis (P0CY1 or PCI ≤10): A prospective, single-arm, phase II study.

TPS4240 Background: Peritoneal metastasis, which is common, difficult to diagnose early, and associated with a poor prognosis, is a leading cause of death in pts with advanced gastric cancer. Due to the peritoneal-plasma barrier, traditional systemic chemotherapy is often ineffective for gastric cancer patients with peritoneal metastasis. In recent years, combined systemic and intraperitoneal therapy has gained increasing recognition. The RATIONALE-305 study demonstrated that tislelizumab (TIS) significantly improves outcomes in these patients. This study combines hyperthermic intraperitoneal chemotherapy (HIPEC), normothermic intraperitoneal and systemic chemotherapy (NIPS), and PD-1 inhibitor, exploring a novel conversion therapy regimen for pts with gastric cancer peritoneal metastasis. Methods: This is a prospective, single-center, single-arm phase II study aims at evaluate the efficacy and safety of HIPEC combined with NIPS and tislelizumab as conversion therapy for gastric cancer pts with peritoneal metastasis who are either cytology-positive only without macroscopic peritoneal deposits (P0CY1) or Peritoneal Carcinomatosis Index (PCI) ≤10. Key inclusion criteria are: 1) age 18-75 years; 2) ECOG performance status 0-1; 3) HER2-negative confirmed by IHC, and PD-L1 CPS≥1; 4) either P0CY1 or PCI ≤10 without other distant metastases confirmed by laparoscopy; 5) adequate function of major organs. Pts undergo diagnostic laparoscopy for PCI scoring and peritoneal cytology examination. Upon confirmation of eligibility, pts receive three sessions of HIPEC followed by 4 cycles of NIPS combined with systemic therapy. The HIPEC regimen consists of paclitaxel at a dose of 75 mg/m² administered on D1, 3, and 5. After a two-week rest, NIPS combined TIS is initiated. The NIPS regimen includes paclitaxel (20 mg/m², ip, D1,8, Q3W and 50 mg/m², iv, D1,8, Q3W) ,S-1 (40-60mg based on BSA, po, D1-14, Q3W). The dosage and administration of TIS is 200 mg, iv, D1, Q3W. Radiological evaluations are performed every 2 cycles during conversion therapy. Upon completion of conversion therapy, pts undergo a second laparoscopic exploration with peritoneal cytology examination to re-evaluate disease status. Operable pts who achieve R0 resection receive postoperative adjuvant therapy with the same regimen (paclitaxel + S-1 + TIS) for 4 cycles. For inoperable pts or those not achieving R0 resection, subsequent treatment is determined by a multidisciplinary team (MDT). The primary endpoint is the surgical conversion rate. Secondary endpoints include the 1-year progression-free survival (PFS) rate, 2-year overall survival (OS) rate, PFS, OS, and safety. Exploratory endpoints aim to investigate the correlation between efficacy prediction and biomarkers such as PD-L1 expression, CLDN18.2 expression, and microsatellite instability (MSI) status. Clinical trial information: NCT07304258 .

AI-powered assessment of tertiary lymphoid structures (TLS) from H&amp;E whole-slide images as a prognostic tool in HNSCC.

6024 Background: Tertiary lymphoid structures (TLS) are recognized prognostic markers in Head and Neck Squamous Cell Carcinoma (HNSCC), yet manual assessment from H&amp;E whole-slide images (WSI) remains subjective and labor-intensive, limiting clinical utility. This highlights the need for a reproducible and objective AI-based approach to TLS assessment using routine H&amp;E slides. Methods: We conducted an integrative analysis by combining transcriptomic and histopathologic data. TCGA HNSCC mRNA expression data (n = 566) were analyzed using xCell to compute enrichment scores for B cells, T cells (CD4+ and CD8+), and dendritic cells. A TLS enrichment score was calculated by averaging the z-standardized aggregate scores of these lineages. Patients in the top and bottom quartiles were labeled ‘TLS enriched’ and ‘non-enriched,’ respectively; these labels were used to train a foundation model-based AI using Imagene’s OI Suite powered by CanvOI with a 3:1 train–test split. Survival analyses were performed at the patient level in 443 evaluable patients with high-quality H&amp;E whole-slide images and definitive AI-predicted TLS enrichment status. Univariable and multivariable Cox regression evaluated AI-predicted TLS enrichment as an independent predictor of overall survival. Results: The AI model demonstrated robust performance for TLS assessment, achieving an AUC of 0.77 in the training set (n = 332, 75%) and AUC of 0.85 in the test set (n = 111, 25%). Kaplan–Meier analysis showed that among 443 patients, the AI-predicted TLS-enriched (TLS+) group (n = 146, 33%) demonstrated improved overall survival compared with the TLS-non-enriched (TLS-) group (n = 297, 67%), with median OS 57.9 vs 35.4 months (HR 0.72; 95% CI 0.53–0.98; log-rank P = 0.039). After adjustment for age, sex, and stage, AI-predicted TLS enrichment remained independently associated with improved overall survival (HR, 0.73; 95% CI, 0.54–1.00; P = 0.0499). These findings suggest that the AI model successfully translates molecular TLS signatures into histological predictors, capturing critical tumor microenvironment (TME) features that refine risk stratification beyond standard clinicopathologic factors. Conclusions: AI-based H&amp;E WSI analysis helps identify TLS enrichment as a potential predictor of overall survival in HNSCC. This unbiased computational approach provides a reproducible and objective methodology using H&amp;E slides alone, without the need for additional molecular or immunohistochemical assays, thereby supporting immune risk stratification for precision immunotherapy, particularly in resource-limited settings.

Analytical validation of a plasma-based cfDNA NGS assay (Guardant360 Liquid CDx) for comprehensive solid tumor profiling.

3077 Background: NGS-based profiling of circulating cell-free DNA (cfDNA) enables accurate and sensitive tumor genotyping from blood. Guardant360 Liquid CDx is intended as a companion diagnostic for comprehensive tumor mutation profiling across &gt;700 genes in patients with malignant neoplasms. Analytical performance was evaluated per FDA IVD standards and guidelines across five variant classes: single-nucleotide variants (SNVs), insertions/deletions (indels), gene rearrangements, gene amplifications (CNA), and copy-number losses (CNLs) – with emphasis on accuracy, precision, specificity (limit of blank [LoB]), and limit of detection (LoD). Methods: Analytical Validation tested &gt;4000 samples from nearly 2,000 unique patients across 29 cancer types, as well as contrived materials. Concordance was evaluated against FDA-approved Guardant360 CDx and an externally developed ctDNA assay, where applicable. Primary endpoints were positive percent agreement (PPA) and negative percent agreement (NPA) by variant class and category (clinically significant vs panel-wide). LoD was established at both low and high input levels. No minimum cfDNA ng input cutoff was required; low-input performance was evaluated at minimum molecule coverage (QC threshold). Precision was assessed across workflow components and blood collection tube (BCT) lots. Specificity was assessed using healthy donor cfDNA sequenced with multiple replicates at high input. Results: Clinical samples demonstrated a high QC pass rate of 99.1%. Clinically significant variants showed high concordance: SNV PPA 94.9% with NPA 99.86%, and indel PPA 96.24% with NPA 99.98%. Panel-wide specificity was near-perfect (SNV NPA 99.99966%; indel NPA 99.99991%). Rearrangements achieved PPA 94.64% and NPA 99.76%; CNA PPA 91.67% and NPA 99.97% ; CNL PPA 100% and NPA 97.56%. High-input LoD was established in silico and confirmed with clinical samples: 0.2% mutant allele frequency (MAF) for all clinically relevant SNVs, indels and most rearrangements, with selected variant LoD as low as 0.1% (KRAS G12C). At the minimum input, panel-wide LoD was 1.0% for clinically relevant SNVs and 0.9% for indels; 0.5-1.6% for rearrangements, 2.3-2.4 copies for CNAs, and 22.7% tumor fraction for CNL. Precision studies showed ≥98.6% agreement across conditions at near-LoD variant levels; within-lot and between-lot BCT precision yielded &gt;97% analytical positive/negative agreement (targeted variants ≥1× LoD). In LoB, no false positive variants were detected in any healthy donor replicates (0% FPR per sample and per variant), validating in-silico CHIP detection methods. Conclusions: The assay demonstrates high accuracy, precision and specificity across all reportable variant classes, with LoD at or below 0.2% MAF for key variant types. These data support its use for comprehensive, pan-cancer tumor genomic profiling in routine oncology practice.

Induction chemotherapy plus camrelizumab followed by concurrent chemoradiotherapy for unresectable locally advanced esophageal squamous cell carcinoma (ImpactCRT): Long-term outcomes of a single-arm phase II trial.

4059 Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for unresectable locally advanced esophageal squamous cell carcinoma (ESCC), with 3-year overall survival (OS) approximately 30%. Induction chemoimmunotherapy followed by CCRT appears promising, but long-term efficacy remains unclear. In the ImpactCRT study, induction chemotherapy plus camrelizumab followed by CCRT has shown promising efficacy in patients with unresectable locally advanced ESCC. Here, we reports long-term outcomes with ≥3-year follow-up. Methods: ImpactCRT was a prospective, single-arm, phase II study at the First Affiliated Hospital of Sun Yat-sen University. Eligible patients were aged 18–75 years with untreated, unresectable locally advanced ESCC (cT1–4bN0–3M0 or M1 limited to supraclavicular nodes). Patients received two 21-day cycles of induction therapy with albumin-bound paclitaxel (260 mg/m²), carboplatin (AUC 5), and camrelizumab (200 mg) on day 1, followed by two 28-day cycles of fluorouracil (750 mg/m² per 24 h for 5 days) and cisplatin (75 mg/m² on day 1) administered concurrently with radiotherapy (50–63 Gy in 25–28 fractions). The primary endpoint was the 1-year OS rate in the per-protocol set (PPS). The trial was registered with ChiCTR (ChiCTR2000034304). Results: Between July 12, 2020, and October 14, 2022, 49 patients were enrolled; all completed induction chemoimmunotherapy, and 46 received CCRT and comprised the PPS. As of January 1, 2026, median follow-up among surviving patients was 53.7 months (range 41.1–65.5). In the PPS, the 1-, 2-, 3-, and 4-year OS rates were 87.0% (95% CI 77.7–97.3), 73.9% (95% CI 62.3–87.8), 65.2% (95% CI 52.8–80.5), and 60.9% (95% CI 48.3–76.7), respectively. Corresponding PFS rates were 71.7% (95% CI 59.8–86.0), 63.0% (95% CI 50.5–78.7), 56.5% (95% CI 43.9–72.8), and 50.0% (95% CI 37.5–66.8). Median OS was not reached (95% CI 40.7 months–not reached), and median PFS was 45.5 months (95% CI 26.7–not reached). Disease progression occurred in 17 patients (37.0%), all within 3 years after treatment (median 6.1 months; range 2.9–35.2): locoregional failure in 7 (15.2%), distant metastasis in 5 (10.9%), and simultaneous locoregional and distant failure in 5 (10.9%). During follow-up, 20 patients (43.5%) died, including 12 (26.1%) due to disease progression. Grade 3 late toxicities occurred in three patients, all esophageal strictures; no grade ≥3 late toxicities were observed in the lung, heart, or other organs. Conclusions: Induction chemotherapy plus camrelizumab followed by CCRT showed improved long-term survival and acceptable late toxicity in unresectable locally advanced ESCC. Median PFS exceeded three years and appeared superior to previous reports. This regimen warrants further evaluation in randomized controlled trials. Clinical trial information: ChiCTR2000034304.

Donafenib plus immune checkpoint inhibitors with or without oral fluorouracil chemotherapy drugs (S-1/capecitabine) for patients with resected high-risk biliary tract tumor: A multi-center retrospective study.

4236 Background: Chemotherapy combined with Immune Checkpoint Inhibitors (ICIs) and donafenib showed promising efficacy and safety in advanced biliary tract cancer (BTC). Oral fluorouracil chemotherapy drugs S-1 or capecitabine are used as standardized adjuvant therapy for BTC. This study aimed to evaluate the efficacy and safety of donafenib plus ICIs with or without oral fluorouracil chemotherapy drugs as adjuvant therapy in BTC patients with high-risk recurrence factors after radical resection. Methods: This multi-center retrospective study enrolled BTC patients with high-risk recurrence factors who underwent surgical resection at Hunan Provincial People's Hospital, Sichuan Provincial People's Hospital, The First Affiliated of Zhengzhou University, Sir Run Run Shaw Hospital and Jiangsu Provincial People's Hospital from Aug 2022 to Nov 2025. All patients exhibited at least one of the following high-risk recurrence factors: macrovascular invasion, lymph node metastasis, satellite lesion, nerve invasion and the maximum diameter of tumors≥5cm. Patients received adjuvant therapy of donafenib plus ICIs with or without S-1/capecitabine after surgery. The primary endpoint was RFS and secondary endpoints included OS and safety. Results: A total of 50 patients were enrolled, with a median age of 60.5, included 21 Intrahepatic, 18 hilar cholangiocarcinoma and 11 others. Tumor stage I/II/III/IV, 8/10/25/7; R0/R1 resection, 44/6. All patients exhibited a high risk factor of recurrence at least, the rate of macrovascular invasion, lymph node metastasis, satellite lesion, nerve invasion and the maximum diameter of tumors≥5cm are 40.0%, 42.0%, 6.0%, 70.0% and 34.0%. 20 patients received the adjuvant therapy of S-1/ capecitabine plus donafenib with ICIs, and the other 30 patients were treated with donafenib and ICIs. The median follow-up time was 15.2 months (95%CI: 11.17-18.46), 16 patients relapsed. The median RFS was 14.0 months (95% CI: 11.07-NA), and the one-year RFS rate was 63.8%, two-year RFS rate was 45.1%. T staging of tumor is an independent influencing factor on disease recurrence in the multivariate analysis. The RFS in stage T1/2 patients was significantly higher than stage T3/4. The incidence of grade 3 TEAEs stood at 26.0%, including hand-foot syndrome (44%), anaemia (16%), diarrhea (16%) and rash (12%). No patients encountered grade 5 TRAEs. Conclusions: The combination of donafenib plus ICIs with or without oral fluorouracil chemotherapy drugs (S-1/capecitabine) appears to be a promising adjuvant therapy for patients with high-risk biliary tract tumor. Furthermore, no significant safety concerns were observed.

Efficacy and safety of capivasertib-based combination therapy in PTEN-deficient advanced or metastatic prostate cancer: A systematic review and meta-analysis.

e17058 Background: In advanced and metastatic prostate cancer, PTEN loss is a frequent change that activates the PI3K–AKT pathway and causes resistance to conventional treatments. Capivasertib, a selective AKT inhibitor, was tested in conjunction with routine therapies to improve results in this molecularly characterized cohort. Methods: For adult patients with PTEN-deficient advanced or metastatic prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC) we conducted a systematic review and meta-analysis of randomized controlled trials comparing capivasertib-based combination therapy versus matched standard-of-care regimens without AKT inhibition. Abiraterone acetate (with or without prednisolone), enzalutamide, or docetaxel with prednisolone, were used as background treatments. Radiographic or Composite progression-free survival (PFS), overall survival (OS), Prostate Specific Antigen (PSA)-related outcomes, treatment termination due to adverse events (AEs), grade ≥3 diarrhea, and grade ≥3 exhaustion were the outcomes evaluated. Random-effects models were used to pool risk ratios (RRs) and hazard ratios (HRs). Results: There were three randomized studies. Capivasertib-based combination therapy improved PFS considerably compared to control (HR 0.83; 95% CI, 0.70-0.98; I² = 0%). A positive trend toward better OS was noted (HR 0.76; 95% CI, 0.57-1.00; I2= 47%). Capivasertib combinations also improved PSA-related outcomes (RR 0.78; 95% CI, 0.63-0.98; I2= 0%). Nevertheless, capivasertib was linked to an increased probability of discontinuing therapy due to adverse events (RR 3.21; 95% CI, 2.25-4.56; I2= 0%). While grade ≥3 fatigue was similar acrossgroups (RR 0.92; 95% CI, 0.71-1.19; I2= 0%), grade ≥3 diarrhea was numerically greater but extremely diverse among trials (RR 4.45; 95% CI, 0.37–54.04; I² = 92%). Conclusions: Capivasertib-based combination therapy offers a slight but noteworthy increase in PFS and PSA-related outcomes in patients with PTEN-deficient advanced or metastatic prostate cancer, with a signal toward OS benefit. Increased treatment dropout due to adverse events offsets these efficacy gains, emphasizing the significance of careful patient selection and toxicity management. AKT inhibition is a promising targeted therapy in this molecularly chosen population that should be further optimized in future trials.

The ratio of levels of insulin signaling system factors and diabetes markers in the blood of patients with non-muscle-invasive bladder cancer in the absence and presence of type 2 diabetes mellitus.

e16609 Background: Components of the insulin signaling system (ISS) are involved in oncogenesis, and type 2 diabetes mellitus (T2DM) is known to influence cancer development. However, data on ISS alterations in non-muscle-invasive bladder cancer (NMIBC) are contradictory, and changes associated with the co-occurrence of NMIBC and T2DM remain largely unexplored. This study aimed to investigate the levels of ISS factors and markers of diabetes mellitus in the blood of patients with NMIBC, both with and without comorbid T2DM. Methods: The study included 20 patients with primary NMIBC, 20 patients with NMIBC and comorbid T2DM (age 49-72 years, both sexes), 12 patients with T2DM without cancer, and 10 age- and sex-matched healthy donors. Blood levels of insulin-like growth factors (IGF-1, IGF-2), insulin-like growth factor-binding protein 1 (IGFBP-1), glucose, glycated hemoglobin (HbA1c), insulin, and C-peptide were measured by enzyme-linked immunosorbent assay (ELISA) prior to anticancer treatment. Statistical analysis was performed using the Mann-Whitney test (with Bonferroni correction), coefficient of variation, and Spearman's rank correlation coefficient. Only statistically significant differences (p &lt; 0.05) are reported. Results: Blood levels of ISS factors in patients with NMIBC exhibited high variability (coefficient of variation up to 273%). Despite normal insulin levels, a sharp decrease in C-peptide (3.6–21-fold lower than the minimum donor value) and a 3.5-fold average increase in IGFBP-1 were observed. In patients with comorbid T2DM, these differences from donors were 2–6 times less pronounced. Unlike patients with NMIBC-only or T2DM-only, those with both conditions showed relatively low levels of IGF-1 and IGF-2, similar to donor values. Among patients receiving effective metformin therapy for T2DM, IGF-1 levels were the lowest across all groups. A strong negative correlation between C-peptide and glucose levels was found exclusively in the NMIBC+T2DM group (r = -0.845). In the metformin-treated subgroup of this cohort, a strong positive correlation was observed between IGF-1 and glucose levels (r = +0.803). Conclusions: Blood levels of ISS factors in NMIBC patients are highly variable. The presence of comorbid T2DM shifts the profile toward lower IGF-1 and IGF-2 levels. Normoinsulinemia in NMIBC is accompanied by decreased C-peptide and elevated IGFBP-1, alterations that are attenuated in patients with T2DM. The minimal IGF-1 levels in normoglycemic patients on metformin, coupled with the positive IGF-1/glucose correlation, suggest a potential antitumor mechanism of metformin mediated through IGF-1 suppression.

Integrative in silico prioritization of tumor-associated antigen pairs to support bispecific antibody-drug conjugate design in solid tumors.

e15036 Background: Antibody–drug conjugates (ADCs) are an established therapeutic modality in solid tumors, although tumor heterogeneity and antigen loss can limit response durability. Bispecific ADCs targeting two tumor-associated antigens (TAAs) represent a promising strategy to improve tumor selectivity and potentially mitigate resistance mechanisms, and integrative in silico analyses may help inform the prioritization of biologically plausible TAA pairs. Methods: TAAs corresponding to ADCs approved by the FDA and/or EMA for solid tumors were selected as reference targets, including HER2, TROP2, NECTIN4, Tissue Factor, FOLR1 and c-MET. Gene expression correlations with an extended panel of clinically relevant TAAs were assessed using TIMER 3.0 across TCGA solid tumors. High-confidence associations were defined using a Spearman correlation coefficient ≥0.7, with tumor types annotated using standard TCGA nomenclature. Results: High-confidence co-expression patterns were identified between selected reference TAAs and an extended panel of TAAs across TCGA solid tumors; correlations observed in more than one tumor type were considered recurrent and are summarized in Table 1. HER2 showed recurrent high-confidence co-expression with ERBB3, together with additional tumor-specific associations. TROP2 and NECTIN4 displayed overlapping recurrent co-expression patterns with multiple partner antigens, alongside additional tumor-specific correlations. In contrast, Tissue Factor and FOLR1 exhibited exclusively tumor-specific high-confidence associations. c-MET demonstrated recurrent co-expression with several partner antigens, together with tumor-specific associations. Conclusions: This integrative in silico analysis identifies high-confidence co-expression patterns between clinically relevant TAAs across solid tumors, enabling the prioritization of biologically plausible TAA pairs. The identification of both recurrent and tumor-specific associations highlights distinct co-expression landscapes that may help inform pan-tumoral and indication-driven bispecific ADC design. TAA co-expression patterns supporting bispecific ADC design (r ≥ 0.7). Reference TAA Recurrent correlated TAAs Tumor-specific correlated TAAs TCGA tumor types HER2 ERBB3 B7-H3, TPBG, PTK7 PAAD, BLCA, THYM, KIRP, THCA TROP2 NECTIN4, ERBB3, FUT3, LYPD3, MUC1, NaPi-2b ITGB6, EGFR, FGFR2/3, Tissue Factor, CEACAM5, B7-H4 ESCA, SKCM, THCA, UCS, THYM, KIRP, HNSC, CESC NECTIN4 TROP2, LYPD3, ERBB3, FUT3 c-MET, EFNA4, EGFR, CDH3, B7-H4, SLC44A4, Tissue Factor ESCA, SKCM, THCA, UCS, PAAD, THYM Tissue Factor – AXL, ITGB6, LYPD3, NECTIN4, ROR1, TROP2 THYM, SKCM, TGCT FOLR1 – NaPi-2b, RORC, B7-H4, ROR2 LUSC, PRAD, UVM c-MET ADAM9, AXL, CD46, EGFR ERBB3, ITGB6, NaPi-2b, FGFR2, TPBG, CD71 LIHC, STAD, THCA, PRAD, UVM, KIRP, KICH, THYM

ctDNA kinetics throughout first-line AI and palbociclib using a tumor-informed structural variant-based ctDNA assay: Retrospective analysis of PADA-1 samples.

3050 Background: With standard assays (Limit of Detection [LoD95] at or &gt;100 PPM), most patients with ER+/HER2- mBC show ctDNA "clearance" within a few weeks after initiating first- line AI+CDK4/6i, with ctDNA becoming detectable again only at or shortly before progression. To gain a more comprehensive view of ctDNA kinetics in response to therapy, we analyzed serial plasma samples from PADA-1 using a tumor-informed assay with a 100-1,000-fold higher sensitivity (LoD95 &lt;10PPM). Methods: PADA-1 allowed the collection of plasma at baseline and every two months during first-line AI+palbociclib (PAL). A total of 489 serial plasma samples from 45 patients in PADA-1 were analyzed using an ultrasensitive structural variant-based ctDNA assay. WGS was performed on tumor material from archival primary or metastatic biopsies, and personalized multiplex dPCR assays tracking up to 16 somatic structural variants were used for ctDNA monitoring. Results: At baseline, before AI+PAL start, ctDNA was detected in N=40/41 evaluable patients (98%). ctDNA remained detectable in 381/489 (78%) samples during therapy. ctDNA was persistently detectable and quantifiable (i.e. detected at all timepoints) throughout first-line therapy in most initially positive patients (24/40, 60%). With this ultra-sensitive assay, we report, for the first time, that ctDNA follows a recurrent kinetic pattern: (1) a steep decrease during the first 6 months of treatment, (2) a nadir reached at 6–12 months, and (3) a continuous increase until radiological disease progression (or discontinuation of follow-up). In some patients (15/40, 38%), ctDNA became undetectable at some point during therapy despite the high sensitivity of the assay, with sustained ctDNA clearance associated with no risk of impending tumor progression. Conclusions: Serial analyses with a highly sensitive ctDNA test uncover the molecular trajectory of tumor response to first line AI+PAL. The presence of an early ctDNA nadir, followed with a later slow and continuous increase of ctDNA, prior to radiological progression, highlights the dynamic nature of ER+ HER2- mBC response to therapy. This approach can complement imaging-based disease monitoring, extends the clinical utility of ctDNA monitoring beyond individual mutations, and opens new perspectives of therapeutic interventions and treatment adaptation. Clinical trial information: NCT03079011 .

Trends in lung cancer mortality among adults younger than 55 years: A CDC WONDER analysis.

e20770 Background: Lung cancer remains the leading cause of cancer-related death in the United States, with risk increasing substantially with age. Most cases occur in adults aged 65 years or older, yet trends among younger patients are less well described. We evaluated long-term patterns in lung cancer mortality among individuals younger than 55 years. Methods: Mortality data were obtained from the CDC WONDER database using ICD-10 codes for lung cancer. Deaths among individuals younger than 55 years were analyzed from 1999 to 2020. Age-adjusted mortality rates (AAMRs) per 100,000 population were examined by sex and race. Results: From 1999 to 2020, a total of 269,823 lung cancer–related deaths occurred among individuals younger than 55 years. Over the study period, lung cancer mortality declined steadily in both sexes. Among females, AAMRs decreased from 9.85 in 1999 to 4.40 in 2020. A similar pattern was observed in males, with AAMRs falling from 14.53 to 4.92. Although mortality rates remained higher in males throughout the study period, the absolute decline was greater among males than females. Race-stratified analyses showed decreasing AAMRs across all racial groups. African American individuals experienced the highest mean AAMR but also the steepest decline, with rates decreasing from 19.4 to 5.1 over the study period. Conclusions: Despite lung cancer remaining a leading cause of cancer-related mortality, deaths among individuals younger than 55 years have declined substantially over the past two decades. This trend likely reflects reductions in smoking prevalence, increased use of low-dose CT screening, and advances in systemic therapies. Persistent sex- and race-based differences highlight the importance of continued efforts in prevention, early detection, and equitable access to care.