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.

Radiation‑induced lung injury (RILI) remains a dose‑limiting and life‑threatening complication of thoracic radiotherapy. The present study aimed to evaluate the therapeutic efficacy and mechanism of the naturally extracted flavonoid, 5,7,8‑trimethoxyflavone (HY‑N7656), in inhibiting RILI. Lung injury in mice was evaluated using micro‑computed tomography, histopathological analysis, enzyme‑linked immunosorbent assay and western blotting. Network pharmacology was conducted to predict the potential therapeutic targets and signaling pathways of HY‑N7656 in RILI. Cell Counting Kit‑8, wound healing, immunofluorescence, reverse transcription‑quantitative (RT‑q) PCR and protein expression analyses were carried out in vitro using TGF‑β‑stimulated A549 cells to evaluate epithelial‑mesenchymal transition (EMT) and signaling activity. Results of the present study revealed that HY‑N7656 markedly alleviated pulmonary inflammation and fibrosis in irradiated mice, leading to a reduction in α‑smooth muscle actin expression. In addition, EMT was effectively reversed following treatment with HY‑N7656 in A549 alveolar epithelial cells treated with TGF‑β, accompanied by restoration of E‑cadherin expression and downregulation of mesenchymal markers, such as N‑cadherin and vimentin. Network pharmacology analysis and molecular docking validation identified the PI3K/Akt pathway as a central target, which was subsequently confirmed via western blot analysis. Moreover, results of the present study demonstrated that HY‑N7656 inhibited radiation‑induced activation of PI3K and Akt. To the best of the authors' knowledge, the present study was the first to demonstrate that HY‑N7656 modulates the PI3K/Akt signaling pathway to suppress the progression of EMT in RILI, establishing HY‑N7656 as a multi‑target inhibitor of RILI. These findings present a potential strategy to enhance the safety of radiotherapy, warranting further preclinical and clinical evaluation.

BackgroundAcute radiation-induced esophagitis (ARIE) is a common complication in non-small cell lung cancer (NSCLC) patients undergoing concurrent chemoradiotherapy (CCRT), negatively impacting their quality of life and treatment outcomes. Jishi Shuanghua Granules (JSG), a Traditional Chinese Medicine formulation, is widely used in clinical practice and has received positive feedback. However, high-quality evidence is still lacking. This study aims to evaluate the efficacy of JSG in reducing ARIE risk and severity and to explore its mechanisms through a multicenter, randomized, double-blind, placebo-controlled trial.MethodsA total of 240 stage III NSCLC patients scheduled to undergo definitive CCRT will be recruited and randomly assigned in a 1:1 ratio to either the JSG or placebo group. The primary efficacy endpoints will be the incidence rates of ARIE (≥Grade 1) and severe ARIE (SARIE, ≥Grade 3) based on the Radiation Therapy Oncology Group (RTOG) criteria. Secondary efficacy endpoints will include time to first occurrence of ARIE and SARIE, ARIE-related pain and dysphagia (assessed using the Numerical Rating Scale), quality of life (measured by the Functional Assessment of Cancer Therapy-Lung questionnaire), short-term lung cancer efficacy (objective response rate and disease control rate), and long-term outcomes (progression-free survival and overall survival). Additionally, the study will explore the mechanisms of JSG through multi-omics analyses, including lymphocyte subsets, inflammatory cytokines, oxidative stress markers, gut microbiota, and metabolomics.DiscussionIf the trial meets its expected outcomes, this study will provide high-quality evidence supporting the use of JSG in preventing and treating ARIE. Furthermore, integrating multi-omics analyses will help elucidate the multi-target mechanisms of JSG, contributing to a more comprehensive evidence base.Clinical trial registrationhttp://itmctr.ccebtcm.org.cn/, identifier [ITMCTR2025000641].

Over-intake of dietary iron and hereditary iron overload are implicated in colorectal cancer (CRC) carcinogenesis, yet the mechanistic basis of how iron-mediated signaling leads to oncogenesis remains enigmatic. Here we demonstrate that high iron diet augments the regenerative capacity of Hopx+ intestinal stem cells (ISCs) rather than Lgr5+ ISCs to functionally contribute to colon tumor formation. Mechanistically, high iron activates a robust Wnt/β-catenin signaling in ISCs to enhance the proliferation of colonic cells in a Hopx-dependent manner. Furthermore, Wnt/β-catenin induction is attributed to Hopx stabilizing β-catenin protein by directly inhibiting the interaction of β-catenin with UBA52, which targets ubiquitination degradation of β-catenin. This study thus identifies an iron-triggered pathway regulating intestinal tumorigenesis and indicates that iron interventions may complement current prevention and treatment strategies for CRC, and Hopx is a previously unrecognized regulator of β-catenin and a therapeutic target of CRC.

IntroductionRadiotherapy serves as an essential therapeutic modality for head and neck malignancies. However, many patients who undergo head and neck radiation (HNR) frequently experience different severities of xerostomia. Berberine (BBR) has a variety of pharmacological functions and has shown favorable clinical efficacy. However, its therapeutic potential and mechanistic basis in xerostomia have not been explored.MethodsThe histological expressions of Aquaporin 5 (AQP5), Na-K-Cl cotransporter 1 (NKCC1), Muscle intestine stomach expression 1 (MIST1), Proliferating cell nuclear antigen (PCNA), Phospho-GSK-3beta (p-GSK3β) and β-Catenin were examined by immunohistochemistry (IHC). Mucin2 (MUC2), were examined by immunofluorescence. The degree of apoptosis was assessed by TUNEL. The mRNA expression levels of AQP5, NKCC1, PCNA, MUC2, and MIST1 were detected by qRT-PCR assay. The degree of inflammatory was evaluated by detecting the mRNA expression levels of Il1b, Tgfb1, Tnf, and Il10. The Proliferation level was performed by salivary gland organoids.ResultsBBR significantly enhanced saliva secretion in normal physiological conditions and after radiation injury. Mechanistically, BBR upregulated the expression of AQP5, NKCC1 and MIST1. Moreover, BBR conferred its protection via the upregulation of mucin 2 (MUC2) expression, and qPCR analysis revealed elevated Bhlha15 levels. Additionally, BBR preserved cellular proliferation, decreased TUNEL+ apoptotic cells and the inflammatory response in SMG tissues and organoids in HNR-induced xerostomia models.ConclusionIn conclusion, this study demonstrates that BBR can increase saliva secretion in healthy and HNR mice, indicating its potentiality for the treatment of radiation-induced xerostomia.

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

PURPOSE:Radiation therapy (RT) for breast cancer (BC) increases long-term cardiovascular risk; however, the early identification of acute cardiac injury remains critically underexplored. This study aimed to prospectively assess radiation-induced acute cardiac injury after postoperative left-sided BC RT using cardiac magnetic resonance (CMR) strain analysis. METHODS AND MATERIALS:Patients with left-sided BC undergoing RT were prospectively enrolled. Radiation doses to cardiac structures were calculated. CMR scans were performed within 2 weeks before and after RT. RESULTS:Among 64 enrolled patients, 41 received whole-breast RT (40.5 Gy/15 fractions; whole-breast RT [WBRT] group) and 23 received chest wall plus nodal RT (50 Gy/25 fractions; chest wall RT [CWRT] group). The mean cardiac dose in the CWRT group was higher than that in the WBRT group (mean heart dose [MHD]: 8.93 ± 2.67 Gy vs 2.80 [2.25 to 3.61] Gy, P < .001; left ventricle [LV]: 9.50 ± 3.49 Gy vs 2.85 [2.06 to 3.86] Gy, P < .001). The CWRT group demonstrated an increasing gradient of radiation dose from the basal to apical LV layers and a significant reduction in global longitudinal strain (GLS) (-17.50 [-15.73 to -17.85]% vs -15.32% ± 2.58%; P = .020) and global circumferential strain (GCS) (-20.34% ± 1.89% vs -19.22% ± 2.14%; P < .001) after RT, with similar alterations in the apical and middle layers, whereas the WBRT group showed no such changes. Among all patients, cardiac dosimetric parameters were independently associated with decreases in GLS and GCS (P < .05). Moreover, 10 patients (15.6%) developed cancer therapy-related cardiac dysfunction after RT; the combination of cardiac dose and the Systematic Coronary Risk Evaluation 2 risk index accurately predicted cancer therapy-related cardiac dysfunction (area under the curve, [AUC]MHD = 0.931; AUCLV-V5 = 0.925). CONCLUSIONS:High-dose radiation exposure increases susceptibility to acute cardiac injury after left-sided BC RT. CMR-derived myocardial strain is a sensitive indicator of radiation-related acute cardiac dysfunction.

BackgroundPostoperative depression is a common complication following non-small cell lung cancer (NSCLC) resection, which adversely affects quality of life and may impede long-term survival. Modified Sini Powder (MSNP), a modified traditional Chinese medicine formula derived from classical Sini Powder, has been used in clinical practice to alleviate depressive symptoms. However, comprehensive evidence from well-designed clinical trials remains insufficient. This protocol describes a study designed to evaluate the efficacy and safety of MSNP in managing postoperative mild-to-moderate depression in patients with NSCLC and to characterize its biological mechanisms.MethodsIn this multicenter, randomized, double-blind, placebo-controlled trial, 468 postoperative patients with NSCLC and mild-to-moderate depression will be recruited across nine tertiary medical centers. Participants will be stratified by concomitant paroxetine use and randomized in a 1:1 ratio within each stratum to receive an MSNP-containing intervention or the corresponding placebo control for 6 weeks. The primary outcome is the total effective rate at the end of treatment, defined as a ≥25% reduction in the 17-item Hamilton Depression Rating Scale score from baseline. Secondary outcomes include measures of anxiety, sleep quality, fear of cancer recurrence, quality of life, and survival. Safety will be monitored through adverse event reporting and laboratory examinations. Mechanistic explorations will integrate analyses of inflammatory cytokines, hypothalamic-pituitary-adrenal axis hormones, neurotransmitters, brain-derived neurotrophic factor, serum metabolomics, and gut microbiota profiles.DiscussionThis trial aims to provide robust clinical evidence for the integration of MSNP into the management of postoperative mild-to-moderate depression in patients with NSCLC. Furthermore, multi-omics analyses are expected to elucidate the multi-target and multi-pathway mechanisms of MSNP, offering insights into personalized and integrative therapeutic strategies.Trial RegistrationRegistered on September 1, 2025, at the International Traditional Medicine Clinical Trial Registration Center (https://itmctr.ccebtcm.org.cn/mgt/project/view/1962361959055753216; Identifier: ITMCTR2025001642).

Background The reliability of contrast-enhanced CT (CHCT) as a reference image for MR-based dose calculation in lung stereotactic body radiation therapy (SBRT) with MR-Linac remains uncertain due to contrast-induced electron density (ED) discrepancy. Whether CHCT can be used as a reference image for dose calculation for patients with lung tumors treated with MR-Linac still needs to be explored in further works. Methods This retrospective study included 30 patients with lung metastases treated with SBRT (50 Gy in 5 fractions) on a 1.5 T MR-Linac. Non-contrast CT (pCT) and corresponding CHCT acquired in the same respiratory phase were used to extract mean electron density for targets and organs at risk (OARs). The treatment plans (TP csCT and TP psCT ) based on synthetic CT (sCT) generated by assigning mean ED derived from pCT and CHCT were recalculated without altering parameters. Dosimetric discrepancy were evaluated using dose-volume histogram metrics, conformity indices, gradient indices and gamma analysis. Results Significant differences in mean ED between pCT and CHCT were observed for several structures, most notably the lungs (mean differences > 12%), heart, aorta, and bronchial tree ( p < 0.05), whereas minimal changes were found in bone and spinal cord. Despite these ED variations, dosimetric differences in target coverage were modest, with average discrepancy of 2.21% and 2.31% for TP csCT and TP psCT , respectively. The other dosimetric parameters (D max , D 2% , D 95% , D 98% , D mean , CI and GI) differences for target were generally below 3%. Although statistically significant differences were detected in some OARs dose metrics, all values remained well within clinical tolerance limits (3%). Conclusion Despite significant contrast-induced variations in ED, the using of CHCT as a reference image result in minor dosimetric differences in lung SBRT. Considering the patient's financial capacity and the radiation dose from repeated CT scans, CHCT may be used as a reference image for lung tumor SBRT with MR-Linac when clinical risks are appropriately managed.

Radiation enteritis is a frequent complication of pelvic radiotherapy, lacking effective pharmacological treatment. The challenge lies in developing therapeutic agents that can maintain specificity, stability, and potency within the dynamic pathological microenvironment of the gastrointestinal tract. We developed an innovative armored probiotic formulation with inflammation-targeting capabilities to improve the efficacy and timing of bacterial therapy for Radiation-Induced Intestinal Injury (RIII). The engineered coating strategy is widely applicable to various probiotic strains and minimally impacts bacterial viability. Notably, probiotics coated with hyaluronic acid-functionalized nanoarmor demonstrate exceptional resilience to harsh intraluminal conditions and exhibit strong mucoadhesive properties. This formulation facilitates specific targeting of inflamed sites via multifaceted interactions, significantly improving therapeutic outcomes in RIII. A key feature is the inflammation-responsive degradation of the nano-armor, ensuring that probiotics are activated and fully functional at the site of injury. The simplicity of preparation and excellent biocompatibility of this cell coating technique offer a promising strategy for enhanced probiotic delivery in biomedical applications.

Objective To identify risk factors for post-radiation xerostomia and to evaluate the tolerance to doses administered to the parotid gland in patients with nasopharyngeal carcinoma (NPC). Methods A total of 462 patients with NPC who received radiotherapy at Nanfang Hospital of Southern Medical University and Sichuan Cancer Hospital from 2012 to 2016 were retrospectively analyzed. Xerostomia was diagnosed according to the Radiation Therapy and Oncology Group (RTOG) grade. Medcalc software and SPSS software were used for statistical analysis, and MATLAB and R software was used for modeling. Results The cut-off values for Dmean (the average dose of parotid), Dmean-L (the average dose of left parotid) and D50-R (dose received at 50% volume of right parotid) were 26.00, 28.30 and 23.93 Gy, above which the risk of long-time xerostomia occurs is increased (P < 0.05). D50, D50-L, D50-R, Dmean, Dmean-L and Dmean-R were 28.66, 23.12, 29.04, 28.00, 28.30 and 35.55 Gy, respectively, but the results showed that this dose was not associated with highest xerostomia grade (HXG) (P > 0.05). The relevant factors were independent risk factors for the development of xerostomia, the same was true for age, T stage, and D-PTV (dose of PTV). Using patient's gender, radiation treatment, number of radiotherapy sessions, T stage, TNM stage, Dmean and D50 (dose received at 50% volume of the parotid glands) to established a prediction model to predict HXG and long-term xerostomia grading (LTG), the results indicated that Training showed R = 0.82. The independent risk factors were included to establish the nomogram prediction model. The results showed that the C-index was 0.671. Conclusion It is feasible to establish a neural network model or a nomogram prediction model using parotid dose parameters to predict the incidence of radiation-induced xerostomia.

BACKGROUND:Outcomes for locally advanced nasopharyngeal carcinoma (LANPC) remain suboptimal despite comprehensive therapy. Preclinical studies demonstrated that low-dose fractionated radiotherapy (LDFRT) could potentiate chemotherapy, warranting further investigation. METHODS:This open-label, randomized phase 2 trial enrolled LANPC patients with advanced nodal stage (N2-N3 with necrosis, extranodal extension, or short axis ≥ 3 cm). Eligible patients were randomized to the LDFRT or control group. All patients received three cycles of induction chemotherapy (IC) followed by concurrent chemoradiotherapy. The LDFRT group received 50 cGy radiation twice daily for 2 days targeting positive lymph nodes during each cycle of IC. The primary endpoint was the overall (nasopharynx and lymph nodes) objective response rate (ORR) after IC, with the secondary endpoints including 2-year survival outcomes and safety. RESULTS:Eighty-two patients (41 per group) were included in the intention-to-treat analysis. After IC, the LDFRT group demonstrated a significantly higher overall ORR (100% vs. 85.4%, p = 0.03) and numerically higher CR rate (14.6% vs. 2.4%, p = 0.11). The LDFRT group achieved greater median lymph node and total tumor volume regression compared to the control group (90.1% vs 53.91%; 77.1% vs 55.1%, respectively; p < 0.001). After a median follow-up of 26.2 months, the 2-year progression-free survival (PFS) and distant metastasis-free survival (DMFS) showed trends favored LDFRT (87.6% vs. 71.9%, p = 0.17; 90.1% vs. 77.1%, p = 0.23, respectively). Acute toxicities were comparable between groups. CONCLUSIONS:In high-risk LANPC, LDFRT with IC improved ORR and tumor volume reduction, and was associated with a potential benefit in PFS and DMFS.

Acute radiation-induced lung injury (RILI) remains a major dose-limiting complication of thoracic radiotherapy with limited therapeutic options. Here, we develop an inhalable nanoformulation of the traditional Chinese medicine Huaxian Formula (NHXF) with favorable physicochemical stability and enhanced pulmonary delivery properties. In vitro and in vivo studies demonstrate that NHXF attenuates radiation-induced alveolar epithelial injury, accompanied by reductions in oxidative stress and apoptosis. NHXF also suppresses secondary inflammatory responses, as evidenced by decreased pro-inflammatory cytokine production and neutrophil infiltration, which may contribute to its protective effects against acute RILI. Importantly, NHXF displays a favorable safety profile throughout treatment. Transcriptomic analysis highlights ferroptosis-related pathways associated with NHXF-mediated protection. Our findings indicate that NHXF treatment is associated with the attenuation of ferroptosis-related alterations in iron homeostasis and lipid peroxidation. Pharmacological activation of ferroptosis significantly diminishes the protective effects of NHXF against radiation-induced injury, further supporting a functional contribution of ferroptosis modulation to NHXF-mediated protection, while acknowledging that additional direct mechanistic evidence is warranted to establish causal dependency. Collectively, these findings support NHXF as a potential inhalable nanotherapeutic for acute RILI and highlight pulmonary delivery of nanoformulated traditional Chinese medicine combined with ferroptosis modulation as a promising strategy for RILI management.

12125 Background: To explore the early intervention timing of recombinant human thrombopoietin (rhTPO) for cancer treatment-induced thrombocytopenia (CTIT) in cervical squamous cell carcinoma (CSCC) patients during concurrent chemoradiotherapy. Methods: Patients with stage I-IVa CSCC who developed CTIT during radical concurrent chemoradiotherapy were prospectively enrolled in our study. rhTPO intervention was used at the first presentation of G1 or G2 CTIT during concurrent chemotherapy respectively. The key indexes, including nadir platelet count, platelet recovery time, platelet transfusion and incidence of G3-5 CTIT were recorded in two groups. χ² test was used for the effective analysis, and univariate and multivariate analyses logistic regression analysis was used to predict the potential factors for the G3-5 CTIT. Results: From February 2021 to June 2024, 204 CSCC patients who developed CTIT during radical chemoradiotherapy at Sichuan Cancer Hospital were prospectively enrolled. 75 patients who occurred G1 and G2 CTIT at the first presentation during concurrent chemoradiotherapy received rhTPO intervention. They were included in the intent-to-treat (ITT) population analysis. According to the timing of the rhTPO intervention, the patients were divided into G1 group (100×10 9 /L>PLT>75×10 9 /L) and G2 group (75×10 9 /L>PLT>50×10 9 /L). For effective analysis, the nadir platelet count in G1 group was greater than that in G2 group (67 × 10 9 /L vs. 54 × 10 9 /L, p = 0.000), and the platelet recovery time in G1 group was shorter than that in G2 group (8 days vs. 14 days, p = 0.003). Moreover, patients in G1 group had a significantly lower incidence of G3-5 CTIT than that in G2 group (14.3% vs. 35%, p = 0.04). In two groups, only 1 patient in G2 group received 4 apheresis platelet units transfusion. Univariate and multivariate analysis showed the early intervention of the rhTPO was a substantial factor for decreasing the incidence of G3-5 CTIT. The sensitivity was 0.67 and the specificity was 0.74. Conclusions: For CSCC patients received with radical concurrent chemoradiotherapy, the early intervention of rhTPO was a substantial factor for decreasing the incidence of G3-5 CTIT. It could significantly improve the nadir platelet count, shorten the platelet recovery time, and reduce the incidence of G3-5 CTIT, thereby ensuring the uninterrupted continuation of treatment. Platelet recovery time and the degree of CTIT. Data Baseline platelet count(×10 9 /L) Days with platelet count recover ≥100×10 9 (Days) Minimal mean platelet count（×10 9 /L） Incidence of G3-5 CTIT(%) G1 group 172±64.92 8±5.86 67±15.81 14.3 G2 group 166±78.43 14±9.59 54±14.37 35 P value 0.76 0.003* 0.000* 0.04* *Statistically significant.

Introduction:Butyric acid is a major gut microbiota metabolite that exhibits many biological functions, including the suppression of colorectal cancer (CRC) growth. However, previous studies have mainly been conducted using cell lines, which do not recapitulate the genuine three-dimensional spatial characteristics of CRC. In this study, we explored the therapeutic outcome and precise molecular targets of butyrate with sodium butyrate (NaB) using tumor organoids of CRC. Methods:Firstly, we examined the influence of butyrate on CRC subcutaneous allografts. And then the biological effects of butyrate were mainly determined using CRC organoids derived from KPC mice and Caco-2 cells. The morphological characteristics of butyrate-treated CRC organoids were analyzed, and multiple experimental assays were employed to determine the biological and molecular influences of butyrate. Finally, the inhibitor of HDAC2 was used to mimic the biological effects of butyrate on CRC organoids. Results:It was observed that butyrate significantly suppressed the growth of CRC allografts. Importantly, butyrate could apparently inhibit the proliferation, disrupt epithelial integrity, and induce apoptosis in CRC organoids. Transcriptomic analyses revealed that butyrate acts as an epigenetic modulator, targeting HDAC2 and selectively repressing its transcription. This led to inhibition of cyclin D1, CDK4/6, and upregulation of p21 expression, suggesting cell cycle arrest. The selective HDAC2 inhibitor similarly recapitulated the influences of butyrate on CRC organoids. Discussion:Butyrate exerts the definitive blocking effects on cell cycle progression in CRC organoids, and HDAC2 is one of the important targets. Butyrate modulates cell cycle via targeting HDAC2, constituting a novel therapeutic pathway for CRC. This study provides new evidence for gut microbial metabolites as a potential means for the prevention and treatment of colorectal cancer.

Radiation-induced intestinal injury involves catastrophic loss of intestinal stem cells (ISCs), but the mechanisms enabling their rescue remain elusive. Here, we demonstrated that melatonin, a potent mitigator of mitochondrial oxidative stress, robustly promoted the regeneration of intestinal crypts and organoids following irradiation. Using in vivo lineage tracing with Lgr5CreERT2;Rosa26-tdTomato, Mist1CreERT2;Rosa26-tdTomato, and Bmi1CreER;Rosa26-tdTomato models, we pinpointed Bmi1+ cells as the source of the melatonin-induced proliferating cells responsible for regeneration. Genetic ablation of Bmi1+ lineages abolished the regenerative benefits of melatonin. Mechanistically, melatonin was associated with a shift in mitochondrial metabolism in Bmi1+ ISCs, in part through the suppression of Ca2+/CaMKⅡ-driven phosphorylation of DRP1, which contributed to reduced reactive oxygen species (ROS) production. This attenuation of oxidative stress subsequently reduced DNA damage and cell cycle arrest, while enhancing mitochondrial oxidative phosphorylation. Crucially, pharmacological inhibition of p-DRP1 phenocopied the effects of melatonin, promoting Bmi1+ ISC-mediated regeneration. In conclusion, our work revealed that melatonin acts as a guardian of Bmi1+ ISCs and promotes regeneration by imposing a critical checkpoint on CaMKII/DRP1-dependent metabolic dysfunction. Targeting this pathway with melatonin or specific p-DRP1 inhibitors represents a novel and highly promising therapeutic strategy for radiation-induced intestinal injury.

Ultra-high dose rate radiotherapy (FLASH-RT) has emerged as a promising technology in recent years. Unlike conventional radiotherapy (CONV-RT), FLASH-RT delivers radiation at an ultra-high dose rate over a very short duration. This approach not only greatly shortens the treatment time, but also exhibits the “FLASH effect”, which significantly spares healthy tissues while maintaining antitumor efficacy comparable to that of CONV-RT. Radiotherapy ignites immunity, fueling the radioimmunotherapy boom. However, even the most advanced radiotherapy techniques inevitably expose healthy tissue, immune organs, vasculature, and circulating or infiltrated lymphocytes to radiation-induced toxicity, limiting the synergistic effect of radioimmunotherapy. Notably, FLASH-RT offers a considerable alternative by protecting the immune system, converting the immunosuppressive tumor microenvironment (TME) into a moderately immune-infiltrated TME, and reducing immunosuppressive responses, thereby enhancing antitumor immunity. A growing number of studies have demonstrated that this combination shows synergistic antitumor effects even in drug-resistant tumor models. Despite these encouraging findings, the combination of FLASH-RT with immunotherapy remains in its early stages and has yet to reach clinical implementation. In this review, we present the current status, underlying mechanisms, and future prospects of FLASH-RT, with a particular focus on its immunomodulatory abilities and potential as a future platform for cancer radioimmunotherapy.

AbstractBackground: Lattice spatially fractionated radiotherapy (Lattice SFRT) is a promising modality for advanced solid tumors, but optimal treatment parameters (e.g., fractionation schedule, dose contrast) and patient stratification criteria remain unclear. This study aimed to systematically investigate these parameters and identify the patient population most likely to benefit.Methods: A retrospective cohort of 135 patients with pathologically confirmed solid tumors who received Lattice SFRT at Sichuan Cancer Hospital (2021–2024) was analyzed. Relationships between tumor characteristics (size, location, histology), treatment parameters (dose contrast, fractionation schedule), and clinical outcomes (objective response rate [ORR], disease control rate [DCR]) were evaluated. Subgroup analyses stratified by tumor burden were performed to explore interactions with fractionation regimens.Results: The overall DCR was 93.3% and ORR was 20.7%. Tumor burden was the only factor significantly associated with DCR (P=0.044), with higher DCR in larger tumors. In medium-sized tumors (3–6 cm), once-daily (qd) and once-weekly (qw) fractionation yielded 100% DCR, significantly superior to every-other-day (qod) regimens (P=0.021). Dose contrast (>4 vs. 2–4) was not associated with DCR (P=0.678). No variables were significantly associated with ORR.Conclusions: Lattice SFRT achieves high disease control in advanced solid tumors. Optimal application requires stratification by tumor burden; qd/qw fractionation is superior to qod for medium-sized tumors. Moderate dose contrast (2–4-fold) is sufficient for efficacy, lowering technical barriers to clinical implementation, providing evidence for individualized treatment planning.

Background:Epstein-Barr virus (EBV) DNA is a well-established biomarker in nasopharyngeal carcinoma (NPC), but its integration into artificial intelligence (AI)-based prognostic tools remains limited. This study aimed to develop and validate AI models incorporating EBV DNA load levels to predict progression-free survival (PFS) in patients with advanced NPC treated with concurrent chemoradiotherapy (CRT). Methods:A retrospective multicenter cohort of 503 patients was divided into training (n = 301) and validation (n = 202) sets. Four machine learning algorithms-Cox regression, LASSO, RSF, and GBM-were applied to predict 1- and 1.5-year PFS in patients with advanced NPC. Model performance was evaluated using the concordance index (C-index), time-dependent receiver operating characteristic (ROC), decision curve analysis (DCA), and interpretability tools such as SHAP values and partial dependence plots (PDP). Results:The 1-, 3-, and 5-year PFS rates were 100.0%, 91.5%, and 88.6% in the EBV = 0 group; 99.4%, 91.2%, and 88.5% in the > 0 and < 1500 group; and 92.3%, 81.0%, and 75.7% in the ≥ 1500 group, respectively, with statistically significant differences among the three groups (P = 0.0024). The RSF model outperformed other models with the highest C-index (0.778) and area under the ROC curve of 0.810 and 0.634 at 1 and 1.5 years, respectively. EBV DNA emerged as the most influential predictor across all interpretability analyses. Patients with EBV DNA ≥1500 copies/ml had the poorest predicted survival, showing a distinct threshold effect in the PDP. Conclusions:High EBV DNA levels were associated with poorer PFS in advanced NPC. Among the models evaluated, the RSF model demonstrated the best predictive performance and interpretability. EBV-informed AI modeling represents a promising approach for enhancing individualized risk prediction and clinical decision-making in NPC.