BACKGROUND:Target trial emulation (TTE) has emerged as an important framework for generating comparative effectiveness real-world evidence. However, the methodological characteristics and clinical utility of this framework within oncology remained insufficiently analyzed. This study systematically evaluated the characteristics of oncological emulation studies. MATERIALS AND METHODS:We systematically searched PubMed, Embase, and Web of Science Core Collection databases from inception to December 22, 2023, to identify oncology-focused TTE studies. Study characteristics, TTE components, and consistency with corresponding randomized controlled trials (RCTs) were analyzed. Categorical variables were summarized as frequencies and percentages and compared using Chi-square tests in SPSS (version 27.0), with p-values < 0.05 considered statistically significant. RESULTS:A total of 54 TTEs were included. Most were conducted in the United States (22, 40.7%), and publications peaked in 2023 (17, 31.5%). Colorectal cancer (13, 24.1%) was the most frequently investigated cancer type. Studies predominantly used data from national databases (18, 33.3%). While all studies prospectively specified the target trial protocol and emulation procedures, only 1 (1.9%) study was prospectively registered, and most emulation studies (48, 88.9%) did not reference a reporting guideline. Among the 10 RCT-TTE pairs available for comparisons, 6 (60.0%) pairs achieved agreement in both statistical significance and effect estimates. CONCLUSION:This study provides a comprehensive analysis of TTE studies in oncology, highlighting their value for generating higher-quality real-world evidence. Future efforts should prioritize prospective protocol registration and standardize reporting to enhance the credibility and reproducibility of emulation studies.

TPS6130 Background: Epidermal growth factor receptor (EGFR) is highly expressed in approximately 85% of nasopharyngeal carcinoma (NPC) cases and plays a critical role in tumor cell proliferation. Becotatug vedotin (MRG003) is a novel EGFR-targeted antibody-drug conjugate (ADC) with promising anti-tumor activity in NPC. Pucotenlimab is a recombinant humanized programmed cell death protein-1 (PD-1) inhibitor. Although platinum-based chemotherapy combined with a PD-1 inhibitor represents the current standard first-line treatment for recurrent or metastatic (R/M) NPC, treatment-related toxicities and suboptimal efficacy remain significant challenges. Preclinical and early clinical data have demonstrated synergistic anti-tumor activity of MRG003 combined with pucotenlimab in platinum-refractory R/M NPC. However, the efficacy and safety of this platinum-free combination as a first-line therapy for R/M NPC remain uncertain. This study aims to evaluate the efficacy and safety of becotatug vedotin plus pucotenlimab as a novel first-line treatment for patients with R/M NPC. Methods: This is an open-label, single-arm, phase II trial enrolling patients with R/M NPC eligible for first-line systemic therapy. Inclusion criteria include: age 18 to 75 years; ECOG performance status score of 0 or 1; histologically or cytologically confirmed NPC; stage IVB (UICC/AJCC 8th edition) or locoregional recurrence not amenable to curative local therapy; at least one measurable lesion per RECIST v1.1; and adequate organ function. Key exclusion criteria include severe uncontrolled pulmonary disease, active autoimmune disease, or a history of autoimmune disease requiring systemic immunosuppressive therapy. Eligible patients receive becotatug vedotin (2.0 mg/kg, IV, D1, Q3W) and pucotenlimab (200 mg, IV, D1, Q3W) until disease progression, unacceptable toxicity, or death. Dose adjustments are permitted based on toxicities. The primary endpoint is progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death from any cause. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), treatment-related safety, and predictive biomarkers. Research Sponsor: Lepu Biopharma Co., Ltd. Clinical trial information: NCT07381699 .

Breast cancer remains the most common malignancy in women worldwide, and its marked heterogeneity continues to impede effective treatment. Immunotherapy has reshaped the therapeutic landscape, yet only a subset of patients achieves durable benefit, in large part because of immune and metabolic diversity within the tumor microenvironment. Posttranslational modifications are key regulators that couple cellular signaling to metabolic and immune homeostasis. Here, we generated a multiomics immune-metabolic atlas of breast cancer by integrating genomics, transcriptomics, proteomics, lactylomics, and phosphoproteomics from 115 tumor and 99 matched adjacent tissue samples. Using immune infiltration profiling, we defined 3 immune-related breast cancer subtypes with distinct metabolic states, posttranslational modifications cross-talk, and mutational landscapes. Integrated analyses revealed that the interplay between protein lactylation and phosphorylation orchestrates glycolytic reprogramming and immune modulation. Furthermore, we identified subtype-specific histone lactylation patterns and signaling rewiring associated with therapeutic response. This atlas provides a comprehensive framework for dissecting immune-metabolic regulation in breast cancer and yields molecular insights to guide subtype-specific precision immunotherapeutic strategies.

Abstract Background: SYS6010 is a novel EGFR-targeted ADC, consisting of a humanized anti-EGFR mAb linked to a topoisomerase I inhibitor (JS-1) via a glycine̶̶-glycine-phenylalanine-glycine tetrapeptide linker (DAR = 8). This phase I study (ChiCTR2300072141) evaluated SYS6010 in advanced solid tumors, with NPC cohort results reported here following prior NSCLC data oral presentation on AACR 2025 (25-LB-9831-AACR). Methods: Patients with advanced NPC progressing after ≥1L prior therapy (including PD1 inhibitor and platinum-based chemotherapy) received SYS6010 at 4.2 or 4.8 mg/kg IV every 3 weeks (Q3W) until progression or intolerable toxicity. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Subgroup analyses were conducted by prior EGFR monoclonal antibody treatment and therapy lines. Results: As of September 15, 2025 (data cutoff), 56 patients were enrolled in the safety population (4.2 mg/kg, n=34; 4.8 mg/kg, n=22). Median age was 49.5 years (range, 27-70); 83.9% were male; 19.6% had ECOG PS 0 and 80.4% PS 1; mean BMI was 22.7 ± 3.34; 30.4% had prior EGFR mAb therapy. All patients experienced ≥1 treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs occurred in 64.3% (37/56) of patients, with a comparable incidence between the 4.2 mg/kg (64.7%) and 4.8 mg/kg (63.6%) groups. Most common Grade ≥3 TEAEs were hematological toxicities: white blood cell count decreased (33.9%), neutrophil count decreased (32.1%), and platelet count decreased (28.6%), and their median time of recovering to baseline or grade 1 was 5 days(d), 4 d and 10 d respectively. Non-hematological Grade ≥3 TEAEs were infrequent. As hematological toxicities are well manageable in clinical practice, so the TEAEs led to permanent drug withdrawal in only 7.1% (4/56) of patients, with dose reductions (39.3%) and interruptions (31.6%). In efficacy population (N=54), ORR was 31.5% (17/54), with rates of 28.1% (9/32) in 4.2 mg/kg group and 36.4% (8/22) in 4.8 mg/kg group, including 1 complete response in 4.2 mg/kg group, and DCR was 87.0% (47/54). Median PFS was 7.5 months (mo) (95% CI: 5.49, 8.38) and was consistent across dose groups (4.2 mg/kg: 7.4 mo; 4.8 mg/kg: 7.7 mo). Median OS was not reached, and the 12-mo OS rate was 66.4% (95% CI: 45.01, 81.00). Notably, in EGFR mAb-naive patients receiving ≥2nd line therapy, the ORR was 42.9% (6/14) for the 4.2 mg/kg dose and 50.0% (5/10) for the 4.8 mg/kg dose. The relationship between efficacy and biomarkers (Epstein-Barr virus status, EGFR expression level and so on) will be reported in future conference. Conclusions: SYS6010 demonstrated encouraging antitumor activity and manageable safety profile in advanced NPC patients, supporting further pivotal clinical development. Citation Format: Haiqiang Mai, Linquan Tang, Xicheng Wang, Shaojun Lin, Lei Liu, Runxiang Yang, Song Qu, Kunyu Yang, Yi Gong, Feng Liu, Yanhong Shang, Jinsheng Wu, Shaozhang Zhou, Mengxia Li, Jinheng Hao, Xiugao Yang, Xuechao Wan, Changming Xie, Ying Chen, Jiaxing Hao, Jing Yuan, Kai Zou, Chao Liu, Shun Lu. A first-in-human study result of a novel EGFR-targeted antibody drug conjugate (ADC) in patients with advanced nasopharyngeal carcinoma (NPC) (SYS6010-001-NPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT036.

BackgroundThe modest neoadjuvant response in early-stage HR+/HER2- breast cancer necessitates novel treatment intensification strategies. While radiotherapy can enhance systemic efficacy via immune modulation, the optimal fractionation for integration with immunochemotherapy remains unknown. This multicenter phase II study aims to evaluate the feasibility, safety, and preliminary efficacy of Toripalimab combined with chemotherapy and tumor-directed radiotherapy, specifically investigating three distinct fractionation schedules.MethodsThis prospective, multicenter, three-cohort exploratory study enrolls treatment-naïve patients with early-stage HR+/HER2- breast cancer. Participants receive neoadjuvant Toripalimab plus chemotherapy alongside image-guided radiotherapy restricted to the primary tumor. Cohorts are differentiated by fractionation regimen: Arm 1 (8 Gy × 3 fractions, total 24 Gy); Arm 2 (16 Gy single fraction); Arm 3 (0.5 Gy twice daily for 8 cycles, cumulative 8 Gy). A total of 45 patients (15 per cohort) will be enrolled. The primary endpoint is pathological complete response (pCR). Secondary endpoints include objective response rate, recurrence, survival outcomes (OS, EFS, DMFS, IDFS, IBTR), and safety.ConclusionsThis exploratory study will provide feasibility, tolerability, and preliminary efficacy data for a novel multimodal neoadjuvant strategy combining different radiotherapy fractionation patterns with immunotherapy and chemotherapy. Given the descriptive analytical framework, findings are expected to be hypothesis generating and will inform the selection of radiotherapy schedules for future larger-scale randomized trials aimed at improving outcomes in HR+/HER2- breast cancer.Clinical trial registrationhttp://www.chictr.org.cn, identifier NCT06639672.

TPS657 Background: Early-stage triple-negative breast cancer (TNBC) carries a high risk of locoregional recurrence and distant metastasis. The KEYNOTE-522 trial established that adding an immune checkpoint inhibitor to neoadjuvant chemotherapy in high-risk early-stage TNBC yields a pathologic complete response (pCR) rate of 64.8%. However, nearly 40% of patients still fail to achieve pCR. Radiotherapy not only directly eradicates tumor cells but also can induce systemic immunomodulatory effects, such as promoting tumor antigen release and enhancing T-cell infiltration. Therefore, combining radiotherapy with immune checkpoint inhibitors and chemotherapy represents a promising strategy to improve outcomes in early-stage TNBC. Preliminary data from small-sample, single-arm studies suggest that neoadjuvant stereotactic body radiotherapy (SBRT) combined with an anti-PD-L1 antibody and chemotherapy can increase pCR rate to 90%(Liu C., et al., Elife , 2023). However, this therapeutic modality lacks large-scale clinical data to further confirm the radiosensitizing effect of radiotherapy on immune checkpoint inhibitors. This phase III, randomized, controlled, multicenter study aims to evaluate the efficacy and safety of toripalimab (an anti-PD-1 monoclonal antibody) plus chemotherapy with or without SBRT in treatment-naïve TNBC patients. Methods: Eligible patients are treatment-naïve, non-metastatic TNBC with clinical stage cT1cN1-2M0 or cT2N0-2M0 (AJCC 8th edition). Patients are randomized 1:1 to receive toripalimab (240 mg, intravenously, every 3 weeks for 8 cycles) plus nab-paclitaxel (260 mg/m², intravenously, every 3 weeks for cycles 1-4) and carboplatin (AUC=5, intravenously every 3 weeks for cycles 1-4) and epirubicin (90-100 mg/m², intravenously, every 3 weeks for cycles 5-8) and cyclophosphamide (600 mg/m², intravenously every 3 weeks for cycles 5-8), with or without SBRT (8 Gy × 3 fractions). All patients undergo surgery 4-8 weeks after completing neoadjuvant therapy. The primary endpoint is investigator-assessed pCR. Secondary endpoints include breast conservation rate, ipsilateral breast recurrence or locoregional recurrence, overall survival (OS), and safety. Sample size was calculated assuming a pCR rate of 64.8% in the control arm (based on KEYNOTE-522) and 80% in the experimental (SBRT) arm. With a one-sided α of 0.025, 80% power, 1:1 allocation, and accounting for a 20% dropout rate, 159 patients per arm (total N=318) are enrolled. The study was initiated in November 2024. Clinical trial information: NCT06627712 .

Background:Osteosarcoma (OS) is a highly aggressive primary bone malignancy in adolescents, with poor prognosis due to limited diagnostic and therapeutic strategies. Mitochondrial dysfunction is a hallmark of cancer, and mitophagy, the selective clearance of damaged mitochondria, critically maintains cellular homeostasis. However, the specific role of mitophagy in shaping the OS tumor microenvironment (TME) at single-cell resolution remains poorly understood. This study aims to systematically characterize mitophagy patterns within the OS TME and investigate their impact on intercellular communication, tumor progression, and patient prognosis. Methods:We analyzed single-cell RNA sequencing data from OS samples using non-negative matrix factorization to cluster cells based on mitophagy-related genes. We characterized distinct mitophagy-associated subtypes of TME cells. Pseudotime trajectory, cell-cell communication), gene regulatory network, and functional enrichment analyses were performed. Prognostic significance was evaluated using GSVA and Cox regression in bulk RNA-seq cohort. Immunotherapy response was predicted using the TIDE algorithm. Results:We identified diverse mitophagy-activated cellular subtypes within the TME. Mitophagy-active CAFs and macrophages exhibited enhanced angiogenic signaling to endothelial cells. Mitophagy-associated CD8+ T cells displayed marked exhaustion features, while macrophages showed metabolic reprogramming. Clinically, higher infiltration of these mitophagy-related subtypes was consistently associated with poorer overall survival. TIDE analysis indicated that mitophagy patterns potentially correlate with immune checkpoint blockade response. Conclusions:Our findings reveal that mitophagy drives complex intercellular crosstalk in the OS TME, promoting angiogenesis and immunosuppression. Mitophagy-related signatures serve as robust prognostic biomarkers. These insights suggest that targeted inhibition of mitophagy, rather than activation, represents a promising therapeutic strategy, providing a novel framework for improving OS patient outcomes.

6091 Background: Neoadjuvant immunotherapy combined with chemotherapy is a promising strategy for resectable LAHNSCC. While most regimens employ single-target PD-1 inhibitors, dual-target agents (PD-1/CTLA-4 or PD-1/VEGF) have shown superior efficacy in recurrent/metastatic HNSCC. Building on our preliminary data (ASCO 2025) which suggested high pathological response rates, this ongoing randomized phase II trial aims to compare single- versus dual-target NAI regimens in an expanded cohort to identify the optimal treatment strategy. Methods: This is an ongoing randomized, open-label, phase II trial. Eligible pts were randomized (1:1:1) to receive 3 cycles of neoadjuvant therapy as follows: Cohort 1 will receive ivonescimab (PD-1/VEGF bispecific antibody, 10 mg/kg every 3 weeks), Cohort 2 will receive cadonilimab (PD-1/CTLA-4 bispecific antibody, 6 mg/kg every 3 weeks), and Cohort 3 will receive penpulimab (PD-1 antibody, 200 mg every 3 weeks), all in combination with cisplatin and nab-paclitaxel. After neoadjuvant treatment, Surgery was performed with the surgical margins based on pre-treatment (baseline) evaluation. Pts with pCR received adjuvant immunotherapy for up to 16 cycles. Pts without pCR received adjuvant radiotherapy or chemoradiotherapy, followed by 16 cycles of adjuvant immunotherapy. Results: Up to Dec. 2025, all 59 pts completed 3 cycles of neoadjuvant therapy and were evaluable, with a median follow-up of 12 months. The pCR rates were 60% (12/20) in Cohort 1, 42.1% (8/19) in Cohort 2, and 40% (8/20) in Cohort 3. The major pathologic response (MPR) rates were 75% (15/20), 57.9% (11/19), and 55% (11/20) in Cohort 1, 2, and 3, respectively. The ORR was 95% in Cohort 1 (CR: 8/20, PR: 11/20) and 84.2% in Cohort 2 (CR: 5/19, PR: 11/19), while Cohort 3 had an ORR of 80% (CR: 4/20, PR: 12/20). To date, pts have received a median of 6 cycles of adjuvant immunotherapy. The most common treatment-related adverse events (TRAEs) (>20%) were: leukopenia, anemia, neutropenia, thrombocytopenia, lymphocytopenia, hypothyroidism, hypertriglyceridemia, radiation dermatitis, stomatitis, vomiting, decreased appetite, and fatigue. Conclusions: Neoadjuvant dual-target (PD-1/VEGF) immunotherapy combined with chemotherapy demonstrated a higher pCR rate compared to dual-target (PD-1/CTLA-4) and single-target PD-1 regimens in resectable LAHNSCC. The treatment was well-tolerated, with all pts completing the intended neoadjuvant therapy and the observed most common TRAEs consistent with expected chemotherapy and radiotherapy profiles. Further analyses are ongoing with continued enrollment. Clinical trial information: NCT06444009 . RECIST and pathologic response. RECIST Pathologic Response CR PR SD PD pCR MPR pPR pNR (RVT=0) (0 （RVT:10-49%） (RVT:≥50%) Cohort 1 (n=20) 8 11 1 12 3 2 3 Cohort 2 (n=19) 5 11 3 8 3 2 6 Cohort 3 (n=20) 4 12 4 8 3 0 9

‌To identify factors influencing margins, re-excision rates, and prognosis in breast-conserving surgery (BCS) patients, and compare the accuracy of ultrasonography (US), mammography (MG), and magnetic resonance imaging (MRI) in assessing tumor size, axillary lymph node status and margins using pathology as the gold standard.‌ A retrospective analysis was conducted on 2775 consecutive invasive breast cancer patients who receive BCS between June 2014 and June 2024. All patients underwent preoperative US, MG, and MRI. The positive margin rate was 18.2% (506/2775).‌ Independent predictors of margin status included pT, lymphovascular invasion (LVI), extensive intraductal component (EIC), US-measured tumor size, MRI-based abnormal enhancement extent, fibroglandular tissue (FGT), background parenchymal enhancement (BPE), non-mass-like enhancement (NME), and axillary lymph node metastasis (ALNM). Factors influencing margin status varied significantly across MRI tumor size subgroups and molecular subtypes. US demonstrated the highest accuracy for preoperative tumor size assessment, while MRI outperformed other modalities in evaluating resection margin status and ALNM. Among 2,450 patients who successfully underwent BCS, the reoperation rate was independently associated with HER2, EIC, MRI abnormal enhancement extent, FGT, BPE, and ALNM. The local-regional recurrence (LRR) rate was 2.5%, with independent predictors including age, molecular subtype, LVI, EIC, MRI abnormal enhancement extent, BPE, ductal pattern orientation, and radiotherapy status.‌ Preoperative imaging and molecular subtyping provide critical insights into margin status and recurrence risk in BCS patients. Tailored surgical planning and adjuvant therapy based on these factors may optimize clinical outcomes and reduce recurrence rates.

The current reliance on wet-lab experiments for evaluating the efficacy and adverse effects of natural products remains a major obstacle in new drug discovery. We propose KAN-PROSPECT, a novel deep learning framework that integrates transfer learning with Kolmogorov-Arnold Networks (KAN). This model can simultaneously predict the efficacy and adverse effects of natural products based solely on molecular SMILES representations, thereby addressing the limited generalizability of existing models in predicting these aspects for natural products. Beyond methodological advances, KAN-PROSPECT also contributes to more sustainable and resource-efficient drug discovery. Leveraging a cross-modal transfer learning strategy pretrained on approximately 3,800 drugs and fine-tuned on 400 natural products, KAN-PROSPECT consistently outperforms baseline models in dual-label prediction tasks. Notably, it demonstrates exceptional robustness in addressing data scarcity, excelling particularly in few-shot and zero-shot scenarios. Through the transfer learning strategy, the model partially alleviates the data scarcity issue commonly encountered in natural product prediction tasks. In addition, the incorporation of KAN layers enhances the ability to model complex nonlinear relationships between molecular structures and associated pharmacological or adverse reaction profiles, contributing to improved predictive performance. Furthermore, the framework demonstrates strong generalization ability, enabling high-accuracy predictions for the efficacy and adverse effects of entirely new natural products. KAN-PROSPECT was further applied to comprehensively predict natural products from the MEC and NPASS databases, with Icaritin from Epimedium used as a representative case study. Overall, KAN-PROSPECT is the first framework to unify transfer learning with the KAN architecture for dual-label prediction of natural products, showing great potential for large-scale bioactivity and toxicity prediction, new drug development, and drug repositioning of natural products.

Chronic infection with Helicobacter pylori (H. pylori) is a major environmental risk factor for gastric carcinogenesis. Malignancy is largely driven by variations within the virulence factor CagA, with East Asian lineages exhibiting higher oncogenic potential than Western ones. However, how these variants modulate cellular crosstalk remains poorly understood. We integrated molecular dynamics (MD) simulations with single-cell transcriptomics across progressive disease stages, including chronic atrophic gastritis, intestinal metaplasia, and gastric cancer. Local niche remodeling was evaluated via cell–cell communication profiling among epithelial, stromal, and immune circuits, while simulations of MARK2 kinase bound to distinct CagA lineages determined binding affinities. Single-cell analysis revealed that H. pylori toxicity progressively dampens epithelial–stromal crosstalk, marked by severe epithelial polarity aberrations that disrupt neuroendocrine-like secretory and synaptic pathways during malignant transformation. Mechanistically, MD simulations and MM/GBSA calculations demonstrated that East Asian CagA lineages exhibit higher binding affinity toward host MARK2 than Western lineages. Specific East Asian amino acid substitutions dramatically tighten the protein interface, driving stronger signaling perturbations. This study bridges atomistic structural virulence with microenvironmental shifting, establishing geographic CagA toxicity divergence as a critical determinant for pathogen-driven gastric cancer risk.

Kawasaki disease shock syndrome (KDSS) is a severe phenotype of Kawasaki disease (KD) characterized by hemodynamic instability and systemic inflammation. Early identification of children at risk for KDSS remains challenging. N-terminal pro-B-type natriuretic peptide (NT-proBNP) reflects cardiovascular stress and has been associated with severe manifestations of KD; however, its interpretation in children is complicated by age dependency. This study aimed to evaluate the predictive utility of baseline NT-proBNP, compare raw NT-proBNP concentrations with age-adjusted NT-proBNP z-scores, and assess their performance relative to other routinely available laboratory biomarkers for KDSS prediction. A total of 588 KD patients were finally enrolled in this prospective cohort study between January 2015 and March 2021. The demographic/clinical characteristics and laboratory data were compared between the patients with KDSS (KDSS group, n = 35) and those without (KD group, n = 553). NT-proBNP concentrations were analyzed as both raw values and age-adjusted z-scores calculated using established pediatric reference ranges. Multivariable logistic regression models were constructed using baseline variables, with log10-transformed NT-proBNP and NT-proBNP z-score evaluated in separate models. Receiver operating characteristic (ROC) analyses were performed to compare predictive performance among NT-proBNP-related parameters and other candidate biomarkers. Children in the KDSS group were older than those in the non-KDSS group (66.11 ± 47.06 vs. 31.36 ± 23.57 months, P < 0.001). KDSS patients had significantly higher rates of coronary artery lesions (40.0% vs. 11.6%, P < 0.001) and intravenous immunoglobulin (IVIG) resistance (51.5% vs. 12.5%, P < 0.001), while classic clinical manifestations such as bilateral conjunctival injection (74.3% vs. 92.8%, P = 0.001) and oral mucosal erythema (77.1% vs. 93.1%, P = 0.004) were less frequent. Regarding laboratory parameters, KDSS patients exhibited significantly higher neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), creatinine, and NT-proBNP, but significantly lower lymphocyte-to-C-reactive protein ratio (LCR), hemoglobin, platelet count, hematocrit, sodium, and potassium levels compared with non-KDSS patients. Multivariate logistic regression identified older age, higher NT-proBNP (both raw and age-standardized Z-score), lower platelet, hemoglobin, and rates of erythema of oral and pharyngeal mucosa as independent predictors of KDSS. ROC analysis showed that the raw NT-proBNP cutoff of 1354 pg/mL gave an AUC of 0.71 (95% CI 0.61-0.81), with sensitivity of 74.3% and specificity of 64.2%, and age-standardized NT-proBNP Z-score had an AUC of 0.73 (95% CI 0.63-0.83), with an optimal cutoff of ≥ 3.3 yielding a sensitivity of 74.3% and specificity of 65.8%. CONCLUSION:NT-proBNP might be a complementary laboratory marker for the prediction of KDSS in KD. WHAT IS KNOWN:• NT-proBNP concentrations are age-dependent in children, but most previous studies of KDSS have relied on absolute NT-proBNP concentrations without age-standardized interpretation. WHAT IS NEW:• Baseline NT-proBNP was independently associated with KDSS, and age-adjusted NT-proBNP z-scores showed comparable predictive performance, supporting NT-proBNP as an adjunctive marker for early KDSS risk stratification after consideration of age dependency.

BACKGROUND:Tumor metastasis is a key factor in cancer progression, yet its molecular mechanisms are not fully understood. ERBB2-positive lung cancer exhibits aggressive behavior, and the role of miR-139 in its metastasis requires investigation. OBJECTIVES:This study aimed to explore the function of miR-139 in ERBB2-positive lung cancer and its underlying molecular mechanism involving the ERBB2/Rac1/NF-κB signaling axis. METHODS:The study utilized A549 lung cancer cells and tissue samples from 106 lung cancer patients. Methods included RT-PCR, bioinformatics analysis, dual-luciferase reporter assay, Western blot, cell migration/invasion assays, wound healing tests, Rac1 activity assays, and rescue experiments using Rac1-Q61L. RESULTS:MiR-139 expression was significantly downregulated in lung cancer tissues, especially in lymph node metastases (P<0.01). MiR-139 directly targeted the 3'UTR of ERBB2 and inhibited its expression (P<0.01). Overexpression of miR-139 reduced Rac1 activity (P<0.01) without affecting RhoA or Cdc42, and decreased NF-κB signaling activity in ERBB2-positive tissues. MiR-139 overexpression significantly suppressed cell migration and invasion (P<0.01), an effect partially reversed by Rac1-Q61L. CONCLUSION:MiR-139 inhibits lung cancer cell migration and invasion by targeting ERBB2, suppressing Rac1 activity, and downregulating NF-κB signaling. Its downregulation promotes metastasis through the ERBB2/Rac1/NF-κB axis.

Background Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a crucial biological process in suppressing tumor growth. Accumulating evidence suggests that the dysregulation of ferroptosis is closely linked to the progression and therapeutic resistance of breast cancer (BC). However, the specific mechanisms driving ferroptosis in BC progression remain to be fully elucidated. Objectives This study aims to elucidate the mechanisms underlying BC progression. Methods Proteomic data from the CPTAC database (PDC000120) were analyzed to identify differentially expressed proteins (DEPs). Ferroptosis-related genes were obtained from the GeneCard database, and an intersection with DEPs was performed to obtain common targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to characterize these targets. Weighted gene co-expression network analysis (WGCNA) was employed to identify clinical modules, and their intersection with the common targets yielded core targets. Furthermore, machine learning algorithms were utilized to screen for hub genes. The tumor immune microenvironment was evaluated using the CIBERSORT algorithm. Finally, in vitro experiments, including Western blotting, EdU assays, flow cytometry, and biochemical measurements, were performed to validate the function of the selected gene. Results A total of 76 ferroptosis-related DEPs were identified. WGCNA identified the “red” and “turquoise” modules as the most clinically significant, and 39 core targets were obtained by intersecting module genes with the DEPs. Through machine learning algorithms, BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) and lysine-specific demethylase 5C (KDM5C) were identified as candidate hub genes. Immune infiltration analysis revealed that BUB1B and KDM5C expression was significantly correlated with various immune cells, including NK cells and macrophages. Pan-cancer analysis indicated that BUB1B exhibited more extensive differential expression compared to KDM5C and was upregulated in BC tissues and cell lines. Functional experiments demonstrated that silencing BUB1B significantly inhibited BC cell proliferation, promoted apoptosis, and induced ferroptosis, evidenced by increased Fe2+, malondialdehyde, and lipid reactive oxygen species levels, as well as decreased glutathione levels. Further assays revealed that BUB1B knockdown inhibited GPX4 and promoted ACSL4 protein expression in BC cells. Conclusion This study systematically identified BUB1B as a key ferroptosis-related gene associated with BC progression. BUB1B promoted tumor malignancy by regulating cell proliferation, apoptosis, and ferroptosis. These findings suggest that BUB1B holds promise as a potential therapeutic target for BC.

The prediction of drug response would significantly improve the treatment of lung cancer. Tumor heterogeneity and complex signal transduction pathways lead to varied treatment effects among patients, but traditional computational approaches struggle to model the nonlinear, high-dimensional relationship between genes and drug responses. In order to develop a Generative Adversarial Network (GAN)-based model that can predict drug-induced gene expression profiles from lung cancer cell lines, we developed GRIP-Lung (Generative Model of Response to Drug-Induced Perturbation in Lung Cancer). By making use of biologically informed embeddings of cell line identity as well as drug treatment conditions, this model is able to gain a fairly good understanding of cell types and their transcriptional perturbations induced by different drugs. The GRIP-Lung model displayed reasonably good prediction ability in terms of predictive accuracy and showed high concordance between the predicted and experimental expression profiles. We not only predicted transcriptional changes induced by drug therapy but also used single-sample Gene Set Enrichment Analysis (ssGSEA) to classify post-treatment response states based on characteristic molecular biomarkers, offering a means for selecting effective drugs to target specific heterogeneity within lung tumors. The proposed GRIP-Lung framework faithfully reproduces drug-induced transcriptional perturbations in lung cell line models. By integrating biologically informed embeddings and adversarial learning, the model advances drug response prediction. This makes it a flexible computational tool for drug repositioning.

BackgroundEpithelial-myoepithelial carcinoma (EMCa) is a low-grade malignant tumor that occurs primarily in the salivary glands. Its occurrence in the nasopharynx is exceedingly rare. Due to its scarcity, there is currently a lack of standardized treatment protocols, and robust prognostic data remain limited.MethodsWe report a case series of two patients with histopathologically confirmed nasopharyngeal EMCa, supplemented by a systematic literature review to summarize its clinicopathological characteristics, treatment modalities, and prognostic factors.ResultsThe two cases exhibited strikingly divergent outcomes. The first patient (Case 1) underwent surgical resection followed by adjuvant radiotherapy, achieving a complete clinical response and remaining disease-free at 31 months. In contrast, the second patient (Case 2) presented a markedly more aggressive profile, characterized by younger age, neurological symptoms, and an atypically high 18F-FDG uptake on PET/CT, a notable deviation from the typically non-significant avidity reported for EMCa. Despite aggressive multimodal therapy, the disease progressed rapidly with extensive metastases. Subsequent institution of a combined chemotherapy and immunotherapy regimen successfully achieved disease stabilization.ConclusionOur cases illustrate the heterogeneous clinical behavior of nasopharyngeal EMCa, ranging from indolent disease to aggressive progression. Our observations suggest that high 18F-FDG uptake may serve as a critical biomarker for an aggressive phenotype. Given this variability, individualized treatment strategies may be warranted, and further studies are needed to better define optimal management for this rare tumor.

6025 Background: Inhibition of PD-1 is an important part of standard of care treatment options for patients (pts) with recurrent/metastatic (R/M) HNSCC, but prognosis remains poor and there is a need for novel regimens to improve outcomes. Dual PD-(L)1 and CTLA-4 inhibition has shown a trend towards improved survival vs the EXTREME regimen as first-line (1L) therapy in PD-L1-expressing R/M HNSCC. Volrustomig, a monovalent, bispecific, humanized IgG1 monoclonal antibody, inhibits PD-1 and CTLA-4, with increased CTLA-4 blockade on PD-1-positive activated T cells compared to PD-1-negative resting peripheral T cells. We report safety and efficacy from the planned interim analysis of substudy 2 of the phase 2 eVOLVE-02 (NCT06535607) study, investigating volrustomig monotherapy in pts with R/M HNSCC. Methods: Eligible pts had histologically or cytologically confirmed R/M HNSCC of the hypopharynx, oral cavity, larynx, or oropharynx (HP, OC, LX, OP), had ECOG performance status (PS) 0/1, and were either treatment-naïve in the 1L setting with confirmed PD-L1 positivity or had disease progression (PD) on/after a 1L platinum-containing regimen. Pts received IV volrustomig until PD (RECIST v1.1)/discontinuation criteria were met. Primary endpoints: safety and confirmed objective response rate (cORR). Secondary endpoints include progression-free survival (PFS) and overall survival. Data cutoff (DCO): August 15, 2025. Results: 23 pts with recurrent (n=12) or metastatic (n=11) HNSCC (7 HP, 8 OC, 4 LX, 4 OP) received volrustomig as 1L (n=12) or 2L (n=11) treatment. Median age was 61 years; 16 pts (69.6%) had PS 1; 19 (82.6%) had a PD-L1 combined positive score (CPS) ≥1. Median duration of exposure was 2.1 months (range 0.7–6.4). Treatment-emergent adverse events (TEAEs) were reported in 91.3% of pts (30.4% grade 3/4, 34.8% serious TEAEs); treatment-related AEs per investigator were reported in 82.6% (8.7% grade 3/4, 4.3% serious AEs). No pts discontinued treatment due to AEs. Grade 5 AEs were reported in 13.0% of pts (none considered related to treatment). At DCO, median follow-up was 5.4 months. In pts with CPS ≥1: 5 had partial responses (3 LX, 1 HP, 1 OC); cORR was 26.3%; disease control rate was 52.6%. Median time to response was 2.6 months (IQR 1.4–2.8); responses were ongoing in 60% of responders at DCO. Blood RNA seq showed increased CTLA-4-associated immune proliferation/activation (Ki67/ICOS gene expression) with volrustomig on cycle 1, day 8 vs at baseline. Conclusions: Volrustomig monotherapy showed an acceptable safety profile and encouraging activity in pts with R/M HNSCC, warranting further clinical development. Volrustomig is under investigation in combination with chemotherapy as 1L treatment for R/M HNSCC in the phase 2 eVOLVE-02 substudy 3, and as consolidation monotherapy in locally advanced HNSCC after concurrent chemoradiotherapy in the phase 3 eVOLVE-HNSCC (NCT06129864) study. Clinical trial information: NCT06535607 .