Accurate segmentation of abdominal organs in computed tomography images is essential for disease diagnosis and treatment planning, particularly for tumors and organ abnormalities. However, this task remains challenging due to the intricate anatomical structures and variability in image quality. While convolutional neural networks (CNNs) have been extensively utilized for abdominal organ segmentation, their effectiveness is constrained by a limited receptive field, which hinders the capture of global contextual information. To overcome these limitations, we introduce a novel abdominal organ segmentation framework, the CNN-Transformer Channel and Spatial Attention Network (CTCSANet), which synergistically combines the strengths of CNNs and Vision Transformers. CTCSANet integrates feature maps from different stages through Cross-Stage Feature Fusion, enabling multi-level feature representation. Additionally, considering that redundant information will be generated when combining CNNs and Transformer, an Adaptive Channel-Spatial Attention mechanism is employed to highlighting the organ regions of interest during feature combination. Evaluated on three datasets, CTCSANet achieves performance with 83.32% DSC on Synapse, 94.40% on LiTS17, and 92.68% on MSD_Spleen.

Radiation-induced lung injury (RILI) remains a serious complication of thoracic radiotherapy, with limited treatment options. While reduced glutathione (GSH) has therapeutic potential, its efficacy is hindered by poor pulmonary bioavailability via systemic administration. This study developed a novel glutathione dry powder inhaler (GSH-DPI) through rational formulation optimization. The optimized GSH-DPI exhibited excellent aerosol performance, with a fine particle fraction of 84.48% and sustained release in simulated lung fluid. In a murine RILI model, GSH-DPI (50 mg/kg, intrapulmonary administration) demonstrated superior efficacy in alleviating histopathological damage, restoring immune homeostasis, and reducing oxidative stress and pro-inflammatory cytokine expression compared to equimolar liquid GSH or high-dose oral administration. Mechanistically, analyses of single-cell RNA sequencing data revealed that RILI involves substantial alveolar type II epithelial cell (AT2) loss, compensatory oxidative stress (Nrf2/HO-1 activation), and progressive pyroptosis. GSH-DPI improved the survival of AT2 cells, simultaneously enhancing Nrf2 response and suppressing GSDMD-N-mediated pyroptosis, thereby interrupting the "oxidative stress-pyroptosis-inflammation" vicious cycle. This study highlights GSH-DPI as a promising pulmonary-targeted strategy for RILI, leveraging dual antioxidative and antipyroptotic mechanisms.

IMPORTANCE:Programmed cell death 1 protein (PD-1) or programmed cell death 1 ligand 1 inhibitors plus chemotherapy is the current standard first-line treatment of recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). However, the long-term survival benefits at the 5-year benchmark remain uncertain. OBJECTIVE:To determine whether adding camrelizumab to chemotherapy significantly improved 5-year overall survival (OS) as first-line treatment for RM-NPC, compared with chemotherapy alone. DESIGN, SETTING, AND PARTICIPANTS:The CAPTAIN-1st trial was a randomized, double-blind, phase 3 trial conducted at 28 hospitals in China. Between November 13, 2018, and November 29, 2019, patients with treatment-naive RM-NPC were enrolled. This secondary analysis of the CAPTAIN-1st trial was prespecified. Data analysis was conducted on June 1, 2025. INTERVENTIONS:Patients were randomized (1:1) to receive camrelizumab or placebo in combination with gemcitabine and cisplatin for 4 to 6 cycles, followed by maintenance therapy with camrelizumab or placebo until disease progression, unacceptable toxic effects, or completion of 2 years of treatment. MAIN OUTCOME:The primary end point, progression-free survival per independent review committee, has been reported previously. Herein, the secondary end point of OS is reported as prespecified in the protocol. RESULTS:Among 263 randomized patients (134 in randomized to camrelizumab, 129 to placebo), baseline characteristics were generally balanced between groups, except for age. The mean (SD) age was 49 (11.25) years, and 218 patients (82.9%) were male individuals, 45 (17.1%) were female individuals. With a median survival follow-up of 63.5 (95% CI, 61.2-64.6) months for the camrelizumab group and 63.0 (95% CI, 60.8-64.6) months for the placebo group, 85 (63.4%) and 95 (73.6%) deaths occurred, respectively. Median OS was 34.5 months (95% CI, 29.4-45.7) with camrelizumab vs 26.6 months (95% CI, 19.8-33.5) with placebo (hazard ratio [HR], 0.74; 95% CI, 0.55-0.99; 2-sided P = .047). After adjusting for age imbalance, the HR was 0.65 (95% CI, 0.48-0.89; P = .01). The 5-year OS rates were 37.8% vs 24.2%, reflecting an absolute difference of 13.6% (95% CI, 2.4%-24.8%; P = .02) in favor of camrelizumab. The OS benefits were generally consistent across subgroups. In the camrelizumab group, patients who achieved rapid clearance of Epstein-Barr virus (EBV) DNA had significantly longer OS compared with those without EBV DNA clearance (HR, 0.32; 95% CI, 0.18-0.58; P < .001). CONCLUSIONS AND RELEVANCE:In this secondary analysis of a randomized clinical trial, the addition of camrelizumab to chemotherapy produced statistically significant and clinically meaningful 5-year OS benefits compared with chemotherapy alone in the first-line treatment of RM-NPC. These findings provided the first 5-year evidence supporting the benefit of PD-1-based chemoimmunotherapy in this setting. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03707509.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. This study aimed to develop and validate a regulatory T cell (Treg)-associated magnetic resonance imaging (MRI) radiomics model and assess its prognostic value, cross-species similarity, and interpretability across multicenter cohorts. Tregs retained prognostic significance for patients with GBM under World Health Organization CNS 5 classification. In murine models, Treg depletion suppressed tumor growth and reduced the infiltration of myeloid-derived suppressor cells, tumor-associated macrophages, and exhausted CD8+T cells. The in vitro co-culture of Tregs with GL261 cells significantly reduced radiation-induced apoptosis. We constructed a Treg-associated radiomics model comprising six features and validated the prognostic value of the radiomics score (RS) across multicenter clinical imaging cohorts (First Affiliated Hospital of Fujian Medical University, n = 111, hazard ratio [HR] = 2.178, 95% confidence interval [CI]: 1.269-3.740; Second Affiliated Hospital of Zhejiang University School of Medicine, n = 126, HR = 1.664, 95% CI: 1.049-2.640; The Cancer Genome Atlas, n = 86, HR = 1.811, 95% CI: 1.089-3.010). Treg depletion experiments also confirmed causal associations between two radiomic features and Treg infiltration. RS stratification correlated with hypoxia, glycolysis, interleukin (IL)-2/signal transducer and activator of transcription (STAT) 5, and IL-6/Janus kinase/STAT3 signaling pathways and immune checkpoints and genomic alterations. The MRI radiomics model enables noninvasive prediction of Treg infiltration and serves as a robust, generalizable prognostic biomarker for GBM. These findings provide evidence for biological causal associations and cross-species similarities between radiomics features and Treg infiltration.

Programmed cell death 1 protein (PD-1) or programmed cell death 1 ligand 1 inhibitors plus chemotherapy is the current standard first-line treatment of recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). However, the long-term survival benefits at the 5-year benchmark remain uncertain. To determine whether adding camrelizumab to chemotherapy significantly improved 5-year overall survival (OS) as first-line treatment for RM-NPC, compared with chemotherapy alone. The CAPTAIN-1st trial was a randomized, double-blind, phase 3 trial conducted at 28 hospitals in China. Between November 13, 2018, and November 29, 2019, patients with treatment-naive RM-NPC were enrolled. This secondary analysis of the CAPTAIN-1st trial was prespecified. Data analysis was conducted on June 1, 2025. Patients were randomized (1:1) to receive camrelizumab or placebo in combination with gemcitabine and cisplatin for 4 to 6 cycles, followed by maintenance therapy with camrelizumab or placebo until disease progression, unacceptable toxic effects, or completion of 2 years of treatment. The primary end point, progression-free survival per independent review committee, has been reported previously. Herein, the secondary end point of OS is reported as prespecified in the protocol. Among 263 randomized patients (134 in randomized to camrelizumab, 129 to placebo), baseline characteristics were generally balanced between groups, except for age. The mean (SD) age was 49 (11.25) years, and 218 patients (82.9%) were male individuals, 45 (17.1%) were female individuals. With a median survival follow-up of 63.5 (95% CI, 61.2-64.6) months for the camrelizumab group and 63.0 (95% CI, 60.8-64.6) months for the placebo group, 85 (63.4%) and 95 (73.6%) deaths occurred, respectively. Median OS was 34.5 months (95% CI, 29.4-45.7) with camrelizumab vs 26.6 months (95% CI, 19.8-33.5) with placebo (hazard ratio [HR], 0.74; 95% CI, 0.55-0.99; 2-sided P = .047). After adjusting for age imbalance, the HR was 0.65 (95% CI, 0.48-0.89; P = .01). The 5-year OS rates were 37.8% vs 24.2%, reflecting an absolute difference of 13.6% (95% CI, 2.4%-24.8%; P = .02) in favor of camrelizumab. The OS benefits were generally consistent across subgroups. In the camrelizumab group, patients who achieved rapid clearance of Epstein-Barr virus (EBV) DNA had significantly longer OS compared with those without EBV DNA clearance (HR, 0.32; 95% CI, 0.18-0.58; P < .001). In this secondary analysis of a randomized clinical trial, the addition of camrelizumab to chemotherapy produced statistically significant and clinically meaningful 5-year OS benefits compared with chemotherapy alone in the first-line treatment of RM-NPC. These findings provided the first 5-year evidence supporting the benefit of PD-1–based chemoimmunotherapy in this setting. ClinicalTrials.gov Identifier: NCT03707509

To establish consensus recommendations and standardized protocols for the clinical assessment and management of radiation-induced hearing loss (RIHL), a common yet potentially serious complication in nasopharyngeal carcinoma (NPC) patients receiving radiotherapy, for which effective treatments remain limited. A two-round Delphi survey was conducted with 19 Chinese experts from diverse specialties, including radiation oncology, medical oncology, radiology, and otorhinolaryngology. Utilizing a detailed items questionnaire that addressed diagnosis, prevention, and treatment aspects of RIHL, the panel formulated consensus recommendations. Additionally, the final recommendations were formulated based on the findings of the Delphi survey, in conjunction with evidence appraised using the GRADE system. During radiotherapy planning, the implementation of dose constraints for key auditory structures—namely the tympanic cavity, internal auditory canal and cochlea—was emphasized to preserve auditory function. Diagnostic evaluations were advised to comprise comprehensive assessments such as pure tone and speech audiometry, tympanometry, otoacoustic emissions, auditory evoked potentials, otoscopic examination, and CT/MRI imaging, with classification guided by the 2021 WHO grading criteria for type and severity. Therapeutic approaches should be customized based on disease stage and underlying etiology, incorporating strategies like Eustachian tube function restoration, management of otitis media with effusion, and tailored auditory rehabilitation. However, consensus on the applicability of most interventions was limited due to insufficient or conflicting evidence, underscoring the need for further research. This consensus provides a structured framework to standardize clinical assessment and management of RIHL, while laying a groundwork for future studies focused on optimizing patient outcomes.

BackgroundThis study aimed to systematically characterize genetically links and Mediation mechanism between glioma susceptibility and brain microstructure, cross-compartment metabolic profiles, and region-specific gene expression, followed by functional validation.MethodsUsing GWAS data from 12,488 glioma cases and 18,169 controls, we performed two-sample MR (TSMR) and summary data-based MR (SMR) analyses. We evaluated 587 brain imaging-derived phenotypes (IDPs) from diffusion and structural MRI; levels of 962 brain tissue metabolites, 440 cerebrospinal fluid (CSF) metabolites, and 1,400 plasma metabolites; and eQTL based gene expression across 13 brain regions. A two-step MR design was employed for mediation analysis, and the key gene identified, HEATR3, underwent clinical correlation and in vitro functional validation.ResultsTSMR identified 6 IDPs significantly associated with all glioma subtypes. Specifically, elevated intracellular volume fraction (ICVF) in the corpus callosum and cingulum increased risk, while increased mean diffusivity (MD) in the posterior limb of the right internal capsule was protective. Integrated SMR and TSMR revealed that elevated HEATR3 expression across all 13 brain regions significantly increases glioma risk. Functional experiments confirmed HEATR3 is upregulated in glioma, correlates with poor patient prognosis, and promotes malignant progression in vitro. Mediation analysis showed that HEATR3’s effect on glioma risk is partially mediated by specific white matter IDPs. Metabolic analysis revealed that higher levels of orotate—a product of de novo pyrimidine synthesis—in plasma, CSF, and brain tissue significantly increase GBM risk. Mediation analysis suggested that the effect of plasma orotate on glioma risk is partially mediated by the ICVF in the right cingulum hippocampus. Enrichment analyses indicated that significant regional genes are heavily involved in DNA metabolism and cell cycle pathways.ConclusionThis study provides robust multi-layered evidence for the causal roles of white matter microstructural abnormalities, metabolic dysregulation, and regional gene expression in glioma development. These findings offer novel genetic insights and potential therapeutic targets for precision medicine in glioma.

This study examined regulatory T cell (Treg) dynamics in radiation-induced lung injury (RILI), focusing on miRNA/mRNA-mediated differentiation mechanisms to identify therapeutic targets. Temporal Treg changes in irradiated mouse lungs were analyzed via single-cell RNA sequencing (scRNA-seq) and flow cytometry. Treg ablation via anti-CD25 antibodies assessed their regulatory roles in neutrophil and monocyte infiltration. High-throughput sequencing identified miRNAs/mRNAs governing Treg differentiation. Plasma miRNA profiles from GSE147242 were enrolled to validate the differential expression of miR-223-3p in RILI. Additionally, machine learning methods were used to construct most predictive miRNA signature post- radiotherapy alterations. Dual-luciferase assays validated miR-223-3p binding to leukemia inhibitory factor (Lif). In vivo/in vitro experiments evaluated METTL3’s impact on miR-223-3p maturation and Treg differentiation. Treg infiltration increased in RILI and bleomycin-induced fibrosis, interacting with epithelial, endothelial, and fibroblast cells. miR-223-3p directly targeted Lif to regulate Treg differentiation, while METTL3 suppressed miR-223-3p maturation via m6A modification. METTL3 inhibition reduced Treg accumulation and alleviated lung injury. Additionally, plasma miRNA analysis confirmed marked differential expression of miR-223-3p post-radiotherapy. A predictive model, integrating miR-223-3p, miR-150-5p, and miR-34a-5p via JMI and SVM-RFE machine learning methods, achieved an AUC of 0.997 (five-fold cross-validation AUC: 0.973), highlighting its high predictive efficacy. scRNA-seq revealed resting Tregs differentiating into Th2-like subsets (marked by KLRG1 and GATA3) with altered m6A levels, implicating epitranscriptional control of Treg plasticity. Tregs mediate multicellular interactions in irradiated lungs. METTL3 promotes miR-223-3p maturation via m6A and drives Treg differentiation through Lif. The METTL3/miR-223-3p/Lif axis regulates Treg-mediated fibrosis, highlighting METTL3 as a therapeutic target for RILI.

This study aimed to investigate whether hippocampal avoidance (D40 < 15 Gy) could reduce anxiety incidence in patients with nasopharyngeal carcinoma (NPC) undergoing intensity modulated radiation therapy (IMRT), and to dynamically assess the anxiety incidence at 3 and 6 months after radiotherapy. A single-center, single-arm prospective clinical trial was conducted, enrolling eligible NPC patients who underwent hippocampal-sparing IMRT with the hippocampal D40 < 15 Gy. The Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety, and the Mini-Mental State Examination (MMSE) was applied to evaluate cognitive function. Assessments were conducted at pre-radiotherapy, end of radiotherapy, 3- and 6-month post-radiotherapy. All 37 enrolled patients met the criterion of hippocampal D40 ≤ 15 Gy. The incidence of anxiety was 0% (0/37) at the end of radiotherapy, which was lower than the 30.8% observed in the historical control group with hippocampal D40 > 15 Gy (p = 0.001). At 3 months post-radiotherapy, no patients developed anxiety (0/34, 0%), and the incidence was 3.0% (1/33) at 6 months. The median MMSE score remained 29 from pre-radiotherapy to the end of radiotherapy, and no significant decline in MMSE scores was observed at 3-and 6-month post-radiotherapy compared with pre-radiotherapy levels. Dosimetric evaluation confirmed acceptable target coverage, conformity, and homogeneity index. Collectively, hippocampal avoidance with bilateral D40 < 15 Gy was associated with a low incidence of anxiety in NPC patients undergoing IMRT without compromising target dose or cognitive function, providing a novel approach to improve quality of life.

BackgroundRegulatory T cells (Tregs) contribute significantly to immune suppression and therapy resistance in isocitrate dehydrogenase (IDH)-wild-type glioblastoma (GBM), a highly aggressive brain tumor with poor prognosis.MethodsIn this study, we developed an artificial intelligence (AI)-powered pathomics model to predict Treg infiltration and stratify prognosis in GBM patients undergoing radiotherapy. Using high-dimensional features extracted from hematoxylin and eosin-stained biopsies, we constructed a pathomics score (PS) via gradient boosting after feature selection with Minimum Redundancy Maximum Relevance (mRMR) and Relief algorithms.ResultsThe model demonstrated strong predictive performance across multi-center cohorts (n > 300), where high PS was significantly associated with elevated Treg levels and reduced overall survival (TCGA: HR = 2.16; validation cohort: HR = 1.706). Gene set enrichment analysis linked high PS to immune-evasive pathways, including Notch and IL-6/JAK/STAT3 signaling, along with increased expression of DNA repair gene RAD50, suggesting a potential association with radiotherapy response.ConclusionThis AI-based pathomics framework offers a robust and interpretable tool for immunoprofiling and outcome prediction, paving the way for precision radiotherapy and Treg-targeted therapeutic strategies in glioblastoma.

Purpose: To investigate the impact of Intensity-Modulated Radiation Therapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT) on hippocampal radiation dosage and psychological status in patients newly diagnosed with nasopharyngeal carcinoma Patients and Methods: A retrospective analysis was conducted on 269 NPC patients who received initial treatment between January 2013 and April 2022. Patients were categorized into the IMRT group and the VMAT group based on the radiotherapy technique employed. The differences in hippocampal doses for NPC patients at different stages between the two groups were analyzed. The Hospital Anxiety and Depression Scale (HADS) was used to assess patients' anxiety and depression states. Before radiotherapy, patients with anxiety scores (HADS-A) between 0 and 10 points were included to analyze the differences in anxiety occurrence rates between IMRT and VMAT techniques. Similarly, patients with depression scores (HADS-D) between 0 and 10 points were included to analyze the differences in depression occurrence rates between the two radiotherapy techniques. Results: In patients with T1-2 stage, those treated with IMRT had significantly higher hippocampal doses compared to those treated with VMAT. Furthermore, after radiotherapy, the occurrence rates of anxiety (HADS-A >= 11) and depression (HADS-D >= 11) in the IMRT group were 27.3% and 19.5%, respectively, while in the VMAT group, they were 9.5% and 7.4%, both showing significant statistical differences (P=0.010, P=0.035). However, there was no significant correlation between the radiotherapy technique and anxiety or depression occurrence rates in patients with T3-4 stage. Additionally, age and gender exhibited certain influences on psychological status. Conclusion: In the absence of hippocampal protection, opting for a VMAT treatment plan over IMRT may potentially reduce the incidence of anxiety and depression. This perspective offers new insights for optimizing treatment strategies and improving quality of life.

ObjectiveIdiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by fibroblast activation and extracellular matrix deposition. Although mechanical forces are known to influence critical processes such as tissue remodeling and cellular differentiation, the specific role of mechanosensitive genes in IPF pathogenesis remains poorly understood.MethodsThis study applied mechanical force-related scoring to IPF and control samples. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify IPF-specific genes associated with mechanical force-related scores, which were subsequently subjected to enrichment analysis. Core genes were screened through univariate Cox regression analysis and machine learning algorithms. Independent prognostic genes were determined using stepwise multivariate Cox regression analysis, which informed the construction of a nomogram integrating key clinicopathological variables. The core genes were further analyzed through single-cell RNA sequencing (scRNA-seq) and Connectivity Map (CMap) analyses to investigate molecular subtypes and identify potential therapeutic targets.ResultsIPF samples exhibited significantly higher scores related to mechanical-related genes (MRGs). Moreover, these samples demonstrated notable heterogeneity, with distinct patterns of high and low mechanical force-associated scores. Core gene analysis revealed two distinct molecular subtypes among idiopathic IPF samples. The C2 subtype was characterized by pronounced inflammatory responses, activation of mechanotransduction pathways, and more severe pathological features. CMap analysis identified nifekalant, which targets AGTR2, as a potential therapeutic agent for the C2 subtype. CD24, PPP1R14C, DSP, and CC2D2A were identified as diagnostic biomarkers, among which CD24, PPP1R14C, and CC2D2A also served as independent prognostic indicators. scRNA-seq demonstrated elevated expression of CD24 and CC2D2A in IPF samples, predominantly within ciliated cells. Pseudotime trajectory analysis revealed two distinct cell fate trajectories in IPF samples. Differentiation toward cell fate 1 was associated with enhanced protein synthesis and secretion, whereas cell fate 2 and the branching point origin region exhibited increased cell adhesion and activation of the p38 MAPK signaling pathway.ConclusionCD24, PPP1R14C, and CC2D2A were identified as prognostic genes associated with MRGs, functioning as markers for molecular subtyping in IPF. These genes may contribute to the pathogenesis of IPF by modulating mechanotransduction processes within epithelial cell subpopulations.

BACKGROUND:Brain and central nervous system (CNS) cancers pose a significant global health challenge, with marked regional variations. Updated evidence is essential to optimize resource allocation and inform targeted interventions. METHODS:Data from the Global Burden of Disease 2021 were systematically analyzed, including incidence, mortality, and disability-adjusted life years (DALYs), along with their corresponding age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and age-standardized DALY rate (ASDR). Temporal trends were evaluated using Joinpoint regression, health disparities were assessed with inequality metrics, and burden contributors were identified through decomposition analysis. Future trends were projected using Bayesian age-period-cohort models. RESULTS:Over the past 30 years, CNS cancer incidence rose by 106.52%, DALYs by 49.59%, and mortality by 89.87%. High-Socio-Demographic Index (SDI) regions (e.g., Europe, North America, East Asia) reported the highest ASIR, with aging as the primary driver of increasing DALYs and mortality. In low-SDI regions (e.g., Africa, Latin America), population growth was the leading contributor to the rising burden. Although ASDRs and ASMRs have declined in high-SDI regions, significant increases have been detected among individuals aged 65 years and more. Low-SDI regions continue to bear a heavy disease burden, particularly among those aged more than 10 years. Disparities across SDI levels are projected to widen, especially in low-income areas. Nonetheless, advances in neuroscience suggest declines in ASIR, ASDR, and ASMR over the next 15 years. CONCLUSIONS:The growing CNS cancer burden highlights the urgent need for targeted interventions. Enhancing healthcare access and bolstering prevention and treatment in underserved regions are critical priorities.

PURPOSE:To elucidate the role of lysine-specific demethylase 4 C (KDM4C), characterized by its upregulation in glioblastoma (GBM) cells following X-ray irradiation (IR), in GBM radiosensitivity. MATERIALS AND METHODS:KDM4C overexpression in GBM cell lines U87 and U251 was investigated to determine its impact on radiosensitivity by assessing clonogenic survival, DNA damage responses, and apoptosis rates following X-ray IR. Transcriptional changes associated with KDM4C upregulation were also analyzed in U251 cells after IR exposure. Furthermore, U251-derived xenograft models were utilized to evaluate the effect of KDM4C on radiosensitivity in vivo. RESULTS:KDM4C overexpression in GBM cells U87 and U251 resulted in increased clonogenic survival rates, diminished DNA damage responses, and reduced apoptosis rates after IR exposure. Treatment with the KDM4C inhibitor SD70 effectively counteracted these effects. Upregulation of KDM4C induced substantial transcriptional remodeling in U251 cells following IR exposure. In vivo, KDM4C overexpression decreased IR-induced upregulation of Cleaved-Caspase 3 in U251-derived xenografts. CONCLUSION:These findings highlight the critical role of KDM4C in reducing GBM radiosensitivity, suggesting that a therapeutic strategy combining radiotherapy with KDM4C inhibition may provide a promising approach to enhance treatment outcomes in GBM.

Background: The treatment response to radiotherapy of hepatocellular carcinoma (HCC) primary tumors and different types of tumor thrombus under identical radiation doses remains uncertain. Objectives: This multicenter study aimed to evaluate and compare the radiotherapy responses of primary tumors (PT), portal vein tumor thrombus (PVTT), and hepatic vein tumor thrombus (HVTT) in HCC patients and to establish a prediction model for treatment response. Design: This multicenter retrospective cohort study analyzed the treatment response of 242 HCC patients with macrovascular tumor thrombus who received radiotherapy combined with systemic therapy from five hospitals. Methods: The objective response rate (ORR) was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 and modified RECIST (mRECIST) criteria. Independent factors of treatment response were identified by logistic regression analysis and used to create a nomogram. Model performance was evaluated through the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCA). Results: Among the entire cohort, the ORRs evaluated by RECIST were 51.65% for PT, 56.32% for PVTT, and 81.93% for HVTT; the ORRs evaluated by mRECIST were 55.79% for PT, 62.63% for PVTT, and 87.95% for HVTT. Both criteria demonstrated that HVTT exhibited significantly higher response rates than PT and PVTT ( p < 0.001). Multivariate logistic regression analysis identified irradiated primary tumor size, biologically effective dose, and tumor thrombus type as independent predictors of response in the radiation-field lesions. The developed nomogram showed good discriminative ability with an AUC of 0.788 in the training cohort and 0.736 in the external validation cohort. Calibration and DCA indicated that the model provided reliable predictions and substantial clinical benefit. Conclusion: Under identical radiation doses, macrovascular tumor thrombus, especially HVTT, is associated with a higher response rate to radiotherapy compared to HCC primary tumors. The nomogram demonstrated good predictive performance, but prospective validation in larger cohorts is still warranted.

Conventional fractionated radiotherapy (CFRT) for hepatocellular carcinoma (HCC) is limited by intrinsic radioresistance. In this study, we investigated the radiosensitizing potential of maraviroc, a chemokine receptor 5 (CCR5) antagonist, and its mechanistic basis in HCC. A murine HCC model was established by subcutaneous implantation of H22 cells into the hind limbs of mice. Tumor-bearing mice received CFRT with or without maraviroc, and tumor growth kinetics were evaluated. Systemic levels of myeloid-derived suppressor cells (MDSCs) in peripheral blood and plasma chemokine ligand 5 (CCL5) were longitudinally monitored post-irradiation. In vitro mechanistic studies utilized maraviroc combined with conditioned media from 2 Gy-irradiated H22 cells to dissect its radiosensitizing effects. H22 cell viability, proliferation and migration were assessed following irradiation with or without maraviroc. Flow cytometry was employed to quantify polymorphonuclear MDSC (PMN-MDSC) proliferation, differentiation and immunosuppressive capacity via T-cell proliferation assays. Compared to monotherapy with either CFRT or maraviroc alone, maraviroc combined with CFRT significantly inhibited HCC growth in the mouse model. In vitro, maraviroc did not directly enhance irradiation-induced H22 cell death or suppress proliferation but reversed PMN-MDSC-mediated immunosuppression by attenuating PMN-MDSC migration and abrogating PMN-MDSC suppression of T-cell proliferation. Maraviroc combined with CFRT significantly inhibited the differentiation of bone marrow cells into PMN-MDSCs. In conclusion, the synergistic application of CCR5 antagonist with CFRT significantly enhanced radiosensitivity in HCC, primarily through suppression of PMN-MDSCs differentiation and migration, coupled with blockade of their T-cell proliferation inhibitory functions.

6004 Background: The addition of PD-1 inhibitor to gemcitabine and cisplatin (GP) showed promising activity as first-line therapy for R/M NPC. Here, we first report the PD-L1 inhibitor Tagitanlimab (KL-A167) plus GP compared with placebo plus GP in a randomized phase 3 study (KL167-Ⅲ-08, NCT05294172). Methods: Eligible patients (pts) with previously untreated R/M NPC were in 2:1 ratio randomly assigned to receive tagitanlimab or placebo (1200 mg, D1) in combination with cisplatin (80 mg/m 2 , D1) and gemcitabine (1000 mg/m 2 , D1 and D8) every 3 weeks (Q3W) for up to 6 cycles followed by tagitanlimab or placebo monotherapy Q3W until disease progression, unacceptable toxicity, or withdrawal of consent. After disease progression, pts from the placebo arm could crossover to receive tagitanlimab monotherapy. The primary endpoint was progression-free survival (PFS) assessed by the blinded independent central review (BICR) according to RECIST version 1.1. Results: Between Jun 16, 2022, and May 27, 2023, 295 pts were assigned to tagitanlimab plus GP arm (n = 197) or placebo plus GP arm (n = 98). The median age was 52 years, and 79.7% were male. As of Feb 4, 2024, 47.2% of pts in tagitanlimab plus GP arm vs 23.5% of pts in placebo plus GP arm were still on treatment, 36.7% of pts in placebo plus GP arm were crossed to receive tagitanlimab monotherapy after disease progression. The median follow-up time was 11.7 months. The PFS per BICR was met at the prespecified interim analysis with a 53% reduction in risk of progression or death (HR 0.47; 95% CI, 0.33 to 0.66; one-sided P <0.0001). The median PFS was not reached (95% CI, 10.9-NE) in tagitanlimab plus GP arm and 7.9 months (95% CI, 6.9-8.3) in placebo plus GP arm; the 12-month PFS rate was 56.7% vs 26.7%. The objective response rate (ORR) per BICR was 81.7% (95% CI, 75.6-86.9) in tagitanlimab plus GP arm and 74.5% (95% CI, 64.7-82.8) in placebo plus GP arm, with a median duration of response (DoR) of 11.7 months (95% CI, 8.2-NE) and 5.8 months (95% CI, 5.6-6.9; HR 0.48, 95% CI, 0.32-0.70), respectively. The overall survival (OS) benefit was observed in tagitanlimab plus GP arm vs placebo plus GP arm (median OS not reached for either arm; HR 0.62, 95% CI 0.32-1.22). The most common ≥ grade 3 treatment-related adverse events (tagitanlimab plus GP arm vs placebo plus GP arm) were neutrophil count decreased (57.9% vs 49.0%), white blood cell count decreased (52.8% vs 46.9%), and anemia (38.6% vs 40.8%). Conclusions: The addition of tagitanlimab to GP demonstrated superior PFS efficacy compared to GP alone, supporting that tagitanlimab, as a PD-L1 inhibitor, could be the new standard of treatment for pts with R/M NPC in the first-line setting. The safety profile of tagitanlimab combined with GP was manageable and consistent with previous reports, with no new safety signals identified. Clinical trial information: NCT05294172 .

BACKGROUND:People with recurrent or metastatic nasopharyngeal carcinoma that progressed after chemotherapy and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors have few treatment options and a poor prognosis. We therefore aimed to investigate the efficacy and safety of the bispecific antibody-drug conjugate izalontamab brengitecan (iza-bren) in heavily pretreated individuals with recurrent or metastatic nasopharyngeal carcinoma. METHODS:This multicentre, randomised, open-label, phase 3 study was conducted at 55 hospitals in China. Eligible participants were aged 18-75 years with histologically or cytologically confirmed recurrent or metastatic nasopharyngeal carcinoma that had progressed after at least two lines of systemic chemotherapy including at least one platinum-containing regimen and PD-1 or PD-L1 inhibitors. Participants were randomly assigned (1:1) to receive either iza-bren at 2·5 mg/kg intravenously on days 1 and 8 of each 3-week cycle or chemotherapy. Random assignment was done through an interactive web-based response system, stratified by baseline Eastern Cooperative Oncology Group performance status (0 vs 1), liver metastases, and previous lines of platinum-based chemotherapy (one line vs two or more lines), with a variable block size. The dual primary efficacy endpoints were objective response rate (ORR) assessed by masked independent central review as per Response Evaluation Criteria in Solid Tumours version 1.1 criteria, and overall survival. Progression-free survival, duration of response, and safety were the secondary endpoints. This report is the first planned interim analysis. This trial is registered with ClinicalTrials.gov (NCT06118333) and is ongoing. FINDINGS:From Dec 4, 2023, to Feb 21, 2025, 522 patients were screened, of whom 386 were enrolled and randomly assigned to receive either iza-bren (n=191) or chemotherapy (n=195). At a median follow-up of 7·66 months for the iza-bren group and 7·10 months for the chemotherapy group, the ORR by masked independent central review was 54·6% (95% CI 45·2-63·8%) with iza-bren and 27·0% (19·1-36·0%) with chemotherapy (difference 27·9%, 95% CI 15·5-39·4%; p<0·0001). Overall survival data were not mature at data cutoff. Grade 3 or higher treatment-related adverse events occurred in 80% of patients receiving iza-bren and 62% of those receiving chemotherapy. The most common grade 3 or higher treatment-related adverse events in the iza-bren group were haematological, including anaemia (50% vs 10%), decreased white blood cell count (43% vs 44%), decreased platelet count (43% vs 7%), and decreased neutrophil count (38% vs 41%). Non-haematological treatment-related adverse events in the iza-bren group were mostly grade 1 or 2. Serious treatment-related adverse events occurred in 43% of patients receiving iza-bren and 27% of those receiving chemotherapy. Four (2%) treatment-related deaths occurred in the iza-bren group. INTERPRETATION:Iza-bren significantly improved the ORR compared with chemotherapy in individuals with heavily pretreated recurrent or metastatic nasopharyngeal carcinoma, with a manageable safety profile. These findings suggest iza-bren might represent a new therapeutic standard for this population. Further analysis will help to fully understand the benefit of this new therapy. FUNDING:Baili-Bio (Chengdu) Pharmaceutical.

5540 Background: Clinical findings on onatasertib (ATG-008), an oral TORC1/2 inhibitor, showed promising anti-tumor efficacy and manageable safety when used in combination with toripalimab, an anti-PD-1 monoclonal antibody, in treatment-naïve cervical cancer (CC) patients who had not received prior anti-PD-(L)1 therapy. Here, we present results from the anti-PD-(L)1 therapy treated CC cohort of the TORCH-2 study who had at least prior 1 line of anti-PD-(L)1 therapy with the combination of onatasertib and tori. Methods: The TORCH-2 study is a phase 1/2 open-label, dose escalation and expansion trial of onatasertib in combination with tori in patients (pts) with advanced solid tumours (NCT04337463). Eligibility criteria included at least one measurable lesion, ECOG 0-1 and adequate organ function. Pts with prior PI3K/AKT/mTOR inhibitor therapy were excluded. CC pts with at least prior 1 line of anti-PD-(L)1 therapy and 1 line of platinum chemotherapy regardless of PD-L1 expression, were enrolled and received onatasertib 15mg orally once a day (QD) in combination with tori 240 mg, once every 21 days (Q3W). Efficacy assessments were reported based on RECIST1.1 criteria and the endpoints included overall response rate (ORR), disease control rate (DCR), duration of response (DOR), progression free survival (PFS) and overall survival (OS). Results: As of Nov 25, 2024, 30 advanced CC pts who had at least prior 1 line of anti-PD-(L)1 therapy and 1 line of platinum chemotherapy were enrolled. Median age was 56.5 years. Baseline ECOG scores were 0 (26 pts) and 1 (4 pts). There were 14 and 16 pts who had received 1 and ≥2 prior lines of systemic therapy, respectively. Additionally, 16 pts had prior abraxane treatment and 11 pts had prior bevacizumab therapy. The median time since initial diagnosis was 37 months(m). The efficacy-evaluable population (27 CC pts) had an ORR of 22.2% (6/27, all confirmed). The DCR was 85.2%. The median time to response was 1.7 m (1.4, 4.2) and median DOR was 5.7 m (95% CI: 2.7, NE). Median PFS and median OS was 4.2 m (95% CI: 3.3, 5.8) and 21.4 m (95% CI: 15.5, NE), respectively. The ORRs of PD-L1 positive and PD-L1 negative populations were 30% (3/10) and 33.3% (2/6), respectively. Thirty pts (100%) had ≥ 1 TEAEs; 22 (73.3%) pts had grade ≥ 3 TRAEs. The most common all grade TRAEs included hyperglycaemia (56.7%), rash (43.3%) and white blood cell decreased (43.3 %). No TEAE led to death. Conclusions: Onatasertib in combination with tori is tolerable with encouraging response rate and disease stabilisation in advanced CC pts with prior anti-PD-(L)1 therapy, regardless of PD-L1 expression. The expansion cohorts are ongoing. Clinical trial information: NCT04337463 .

Objective:To evaluate and compare the impact of surgery versus radiotherapy on local control rates in Kimura disease (KD). Methods:A retrospective analysis was conducted on 26 patients diagnosed with KD at the First Affiliated Hospital of Fujian Medical University from January 2001 to January 2024. Patients were categorized into four treatment groups: Primary Surgery (PS), Primary Radiotherapy (PR), Salvage Surgery (SS), and Salvage Radiotherapy (SR) following recurrence. Data on demographics, tumor characteristics, eosinophil counts (EO), disease duration, and radiation dose were collected. Univariate and multivariate analyses were performed to identify factors influencing local control rates. Results:The cohort had a mean age of 42.2 ± 17.7 years, with 24 male patients. Kaplan-Meier analysis revealed that radiotherapy provided superior local control compared to surgery, with significant differences between PS and PR (p = 0.047) and SS and SR (p < 0.001). No significant difference was found between PR and SR (p = 0.816). Multivariate analysis identified treatment modality as the strongest predictor of recurrence (HR: 0.062). Additionally, factors such as radiotherapy, bilateral involvement, and longer disease duration were associated with improved local control. Among radiotherapy patients, age, tumor number, tumor size, pre-treatment eosinophil count, radiotherapy dose, and disease duration significantly influenced prognosis. Conclusion:Radiotherapy is more effective than surgery in achieving local control of Kimura disease. Higher radiation doses may negatively impact outcomes, suggesting that a tailored, moderate-dose approach is optimal. Radiotherapy should be prioritized, particularly for recurrent or multifocal cases, offering a more reliable long-term treatment strategy than surgery.