Background Patient-reported outcomes (PROs) are essential for assessing symptomatic adverse events (AEs) from a patient perspective, which significantly impact the quality of life and clinical outcomes in patients with glioma. However, no validated patient-reported outcome measures (PROMs) exist to quantify symptomatic AEs in adult-type diffuse gliomas. Methods The study was conducted in two parts. First, we developed a customised Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) scale for adult-type diffuse gliomas using the Simplified Chinese PRO-CTCAE® item library, informed by initial item screening, patient pilot testing, and a two-round Delphi survey. Delphi experts were recruited through the National Glioma Multidisciplinary Team (MDT) Alliance (NGMA) and invited by email in June 2022 (1st round) and August 2022 (2nd round). We subsequently conducted a multicentre, prospective, observational cohort study (VERONICA) at 13 glioma treatment centres in China between September 2022 and March 2025. Eligible participants were adults aged 18 years or older with a diagnosis of adult-type diffuse glioma, who were able to understand and complete the questionnaires; patients with severe cognitive impairment, severe language dysfunction, or other conditions precluding questionnaire completion were excluded. The primary outcome was the psychometric performance of the customised PRO-CTCAE scale, including test-retest reliability, convergent validity, known-groups validity, and responsiveness, evaluated longitudinally across repeated study visits. VERONICA is registered with ClinicalTrials.gov, NCT05486923. Findings For the Delphi survey, all seven invited experts from six centres participated in 1st round (response rate 100·0%), with moderate agreement in symptom rankings (Kendall's W = 0·415; p < 0·001). In 2nd round, 16 of 20 invited experts from 14 centres participated (response rate 80·0%), with consistent agreement in expert ratings (Kendall's W = 0·351; p < 0·001). The final version of the customised PRO-CTCAE scale comprised 53 items covering 31 symptoms, together with one open-ended free-text item. For VERONICA, 450 participants were enrolled across 13 glioma treatment centres. Mean age was 49·1 years (SD 12·8), and the mean Karnofsky Performance Status (KPS) at baseline (Visit 2) was 72·2 (SD 17·1). 424 provided data eligible for at least one prespecified psychometric analysis. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] ≥0·70 for 47 of 53 items). Convergent validity was supported by correlations in the expected direction with matched European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) domains, with predominantly moderate-to-strong associations (25 items with r ≥ 0·50). Known-groups validity was supported by discrimination between KPS <70 and ≥70 (Cohen's d ≥ 0·20 for 49 of 53 items; p < 0·05 for 43 of 49 items). In Global Impression of Change (GIC)-anchored responsiveness analyses, 37 items showed standardised response means (SRMs) ≥0·20 among participants reporting worsened overall status. Interpretation The customised PRO-CTCAE scale showed robust psychometric performance for adult-type diffuse gliomas. Remote, longitudinal administration supports low-burden quantification of patient-reported symptomatic AEs in clinical trials and routine neuro-oncology practice. Future work should assess implementation in routine care and clinical trials, and extend translation, cultural adaptation, and validation across different languages. Funding Beijing Medical Award Foundation; Shanghai Municipal Health Commission; Department of Science and Technology of Ningxia Hui Autonomous Region; Huashan Hospital, Fudan University (Clinical Research Project).

PURPOSE:Local recurrence (LR) after reirradiation with intensity-modulated carbon ion therapy (IMCT) in recurrent nasopharyngeal carcinoma (rNPC) may relate to insufficient dose-averaged linear energy transfer (LETd) within the tumor. This study evaluated the prognostic value of LETd metrics for local control (LC) in rNPC. METHODS AND MATERIALS:This retrospective study enrolled 76 patients with rNPC who underwent salvage IMCT reirradiation at Shanghai Proton and Heavy Ion Center (SPHIC) from 2015 to 2019. Clinically, dosimetric and LETd variables were evaluated for association with LC using Cox models with Fine-Gray competing risk analysis accounting for competing risks of death as a sensitivity analysis. Threshold effects were evaluated using restricted cubic spline modeling and time-dependent receiver operating characteristic (time ROC) analysis, with validated by Kaplan-Meier and cumulative incidence function analyses. RESULTS:With a median follow-up of 38.3 months (range, 19.3-72.2), 26 patients developed LR. In long-term survivors, LC patients had significantly higher LETdmean, LETd50, and LETd99. The volume receiving LETd ≥50 keV/μm in gross tumor volume (GTV VL50keV/μm) was nearly 2-fold higher in the LC group than the LR group (57.50% vs 31.75%; P = .013). Multivariate analysis identified GTV LETd99 as a robust independent protective factor for LR.Restricted cubic spline analysis revealed a nonlinear "λ"-shaped association between LETd99 and LR, with a risk inflection point at 39.4 keV/μm. LETd99 showed strongest predictive value at 24 months (area under the curve = 0.77), and LETd99 ≥39.4 keV/μm correlated with improved 2-year LC (94.4% vs 65.3%; P = .003). Interval between the first radiation therapy course and reirradiation emerged as a significant protective factor in the Cox and Fine-Gray model (hazard ratio, subdistribution hazard ratio <1; P < .05). Correlation analysis revealed that tumor volume was the dominant determinant of LETd distribution (r= -0.16 to -0.67), whereas beam angular span primarily affected moderate high-LETd (50-70 keV/μm) volume coverage without influencing LETdmax or LETdmin. CONCLUSIONS:LR in patients with rNPC who underwent reirradiation treated with IMCT is influenced by multiple factors. In addition to biological equivalent dose and tumor volume, a longer interval between radiation therapy courses and higher GTV LETdmin were associated with improved LC. This study provides reference LETd levels and beam arrangement strategies for LET-guided optimization, emphasizing sufficient minimum LETd (>39.4 keV/μm) and broad high-LETd coverage (50-60 keV/μm).

e23537 Background: Radiation-induced sarcoma of the head and neck (RISHN) is a rare but devastating late toxicity of curative radiotherapy (RT). We conducted a single-center cohort study to analyze the clinicopathological characteristics, management, survival, and hemorrhagic risk of RISHN and to identify associated prognostic factors and effective clinical treatments. Methods: We conducted a retrospective analysis of 25 pathologically confirmed RISHN patients treated at Fudan University Shanghai Cancer Center (January 2019 to December 2025), constituting the largest single-institution case series to date. The clinical data include diagnostic age, RT dose, latency, RISHN site, histological subtype, stage, first symptoms and treatment. The survival analysis was estimated by the Kaplan–Meier method. Results: The median age at RISHN diagnosis was 47 years and the median latency was 10.7 months. The most common primary tumor was nasopharyngeal carcinoma (NPC, 21 cases, 84.0%), receiving RT doses ≥66 Gy. RISHN arose chiefly in paranasal sinuses and nasopharynx. Bleeding and nasal congestion were most common presenting symptoms. The Median follow-up time was 24.2 months. The major histological subtypes of RISHN included post-radiation sarcoma (11 cases), undifferentiated sarcoma (4 cases) and osteosarcoma (4 cases). Surgery was the cornerstone of initial management and gross total resection (GTR) was achieved in 11 patients. However, the median EFS was only 10.4 months with the 1-year EFS rate of 41.1%. GTR conferred a significant EFS benefit over nonGTR (incomplete resection or systemic therapy alone), with median EFS times of 12.9 versus 6.9 months (p=0.03; HR=0.34). The median OS was 28.3 months and a numerical advantage in median OS was observed for GTR group (36.9 months) over nonGTR group (20.0 months) (p=0.17, HR=0.40). In 18 patients receiving first-line systemic therapy, the disease control rate (DCR) was 83.4% and the median PFS was 7.7 months. Exploratorily, patients who received immunotherapy had numerically longer PFS (12.7 vs 6.0 months, p=0.53, HR=0.66) and OS (48.9 vs 28.3 months, p=0.99, HR=1.01) than those who did not. Hemorrhage was a notable clinical manifestation especially in anlotinib-treated RISHN patients, whereas none of six patients undergoing prophylactic carotid embolization experienced significant bleeding subsequently. Conclusions: RISHN had a poor prognosis. GTR was an independent prognosis predictor of RISHN, while the EFS was unsatisfactory. Systemic therapy offers an important treatment option. First-line treatment with immunotherapy may improve survival outcomes in RISHN patients. Hemorrhage mitigation, particularly careful use of anti-angiogenic therapy and selective prophylactic endovascular intervention, should be integrated into multidisciplinary care.

Radiotherapy augments immunotherapy, yet conventional 2 Gy x-ray fractions largely induce apoptosis, whereas robust immunogenic cell death (ICD) is more commonly associated with higher-dose irradiation regimens. Here, we reveal a dose-independent, high-LET-specific paradigm: a physical dose of 2 Gy of carbon ions provokes antitumor immunity. Carbon ions redirect death wiring to MLKL-dependent necroptosis and trigger an NF-κB-driven inflammatory cascade (IL1A/B, CXCL1/2/3), surpassing 8 Gy x-rays in immunogenicity despite lower direct tumor cell-killing capacity. Multi-omics analyses identify clustered DNA damage-driven super-enhancer remodeling as an epigenetic switch that suppresses cIAP1/2-caspase-8-mediated apoptosis while licensing inflammatory necroptosis. Pharmacologic inhibition of MLKL abolishes these responses to carbon ion radiotherapy (CIRT). In vivo, 2 Gy CIRT drives abscopal response with increased CD8 + T cell infiltration and function. Together, these findings establish CIRT as a feasible, immune-stimulatory radiotherapy converting local exposure into systemic control via super-enhancer-mediated reprogramming of death and inflammation, providing a mechanistic rationale to integrate carbon ions into next-generation radio-immunotherapy.

This study evaluates the dosimetric feasibility of carbon-ion radiation therapy (CIRT) for ocular melanoma (OM) using a local effect model-I-based treatment planning system (TPS) combined with pencil beam scanning delivery. Cube-shaped targets were designed based on the experience of CIRT for OM at the National Institutes for Quantum Science and Technology (QST). Treatment plans used the local effect model-I-based TPS (Syngo® V13C, SIEMENS, Germany) prescribing an absorbed dose consistent with values reported in the literature. A conversion factor (CF) was established to convert the QST dose to LEM based relative biological effectiveness (RBE)-weighted dose. The physical doses were verified by an in-house Monte Carlo program and measurement. The CF for the LEM, equivalent to the QST RBE-prescribed dose of 70 Gy (RBE) over 5 fractions, was established as 0.65. The 3D gamma passing rate between TPS and MC was ≥94% using 3%-3 mm criteria. Mean dose deviations between the TPS and measurement were ≤±1.61% for all targets sizes except the smallest one (7 mm). Mean distance-to-agreement was <1 mm for all plans except one with a range shifter (distance-to-agreement = 2.92 mm). Phantom cases showed a lateral penumbra of 5.4-6.2 mm, and distal dose fall-off measures 3.6 and 5.6 mm. The results underscore the need for RBE-weighted dose conversion when applying QST's CIRT experience to OM treatment.

BACKGROUND:Carbon-ion rotating gantries use is limited by its large size, weight, and high cost. Gantry-free modality enables the reduction of the overall size, weight, and cost. Among them, upright treatment, which utilizes fixed ion beamlines, in combination with a treatment chair capable of 360° rotation and adjustable pitch angle (enabling non-coplanar beam delivery), provides a wider range of beam entry angles compared to conventional couch-based setups and has already been applied in particle radiotherapy for head and neck cancer patients. PURPOSE:In this study, we analyzed clinical data from the Shanghai Proton and Heavy Ion Center (SPHIC) to quantify residual setup errors across various regions of interest (ROIs) for both upright and supine treatments. METHODS:A total of 402 treatment fractions from 28 patients (median 5 fractions, range: 5-16 fractions per posture per patient) were enrolled in this study. All these patients were immobilized and scanned in supine posture and received both supine and upright radiotherapy. Three rectangular-shaped ROIs were delineated based on bone structures, encompassing the mandible, orbit, and neck vertebrae C1-C3. Box-based registration, focusing solely on the anatomical structures within the specific ROIs was performed to subtract the correction vector used in treatment, thereby obtaining the residual setup error for each ROI. Margins for each ROIs were calculated. RESULTS:For both postures, the median values of residual setup error for all translational directions were less than 1 mm. The median values did not exceed 0.2 degrees for rotational errors. More than 78% of the fractions for upright treatment fell within the 1 mm/° threshold, while 94% were within the 2 mm/° threshold. In contrast, for supine treatment, over 61% fell within the 1 mm/° threshold, while 86% were within the 2 mm/° threshold. The maximum margin was 3.3 mm in the AP direction of the C1-C3 region for the supine posture. CONCLUSIONS:Upright treatments demonstrated comparable residual setup errors to supine treatments, with most errors falling within clinically acceptable thresholds. This study provides valuable clinical evidence for the continued development and implementation of upright radiotherapy.

Tumor radioresistance and severe toxicity make reirradiation for recurrent nasopharyngeal carcinoma (NPC) a significant clinical challenge. This study aims to investigate the ability of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib to sensitize recurrent NPC cells irradiated with photon or carbon ion (C-ion), and to explore the underlying mechanism of the synergistic promotion of cell death by olaparib and ionizing radiation. The results show that olaparib has significant X-ray and C-ion radiosensitization effects on recurrent NPC cells and the associated HK-RR photon-resistant model. Radiation, particularly C-ion exposure, induces a homologous recombination (HR)-deficient gene signature in HR-proficient NPC cells, potentially increasing their sensitivity to PARP inhibition. C-ion and X-ray irradiation induces similar modes of cell death, and multiple cell death pathways [including apoptosis, necrosis, ferroptosis, senescence, and autophagic cell death (ACD)] contribute to the cytotoxic effects of radiation combined with olaparib, with ACD being the dominant pathway. Both the pharmacological and genetic inhibition of autophagy significantly attenuate the radiosensitization effect of olaparib. In conclusion, olaparib effectively sensitizes recurrent NPC cells to both X-ray irradiation and C-ion irradiation, with autophagy playing a central role in mediating this effect.

Increasing evidence highlights the role of aberrant circadian rhythm gene expression in glioblastoma (GBM) progression, but the impact of the circadian rhythm gene network on GBM molecular profiles and prognosis remains unclear. A total of 1042 GBM samples from six public datasets, TCGA and CGGA, were analyzed, with GBM samples stratified into three circadian core-gene patterns using unsupervised clustering based on the expression profiles of 17 circadian rhythm genes. The Limma R package identified differentially expressed genes (DEGs) among the three patterns, and a secondary clustering system, termed circadian-related gene pattern, was established based on DEGs. A circadian risk score was constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm, and the efficiency of these patterns and the circadian risk score in distinguishing molecular profiles and predicting prognosis was systematically analyzed. The relationship between the circadian risk score and response to immune or targeted therapy was examined using the GSE78200 and IMvigor210 datasets. The results showed that GBM patients were clustered into three circadian core-gene patterns based on the expression profiles of 17 core circadian genes, with distinct molecular profiles, malignant characteristics, and patient prognoses among the patterns. Thirty-two DEGs among these patterns were identified and termed circadian-related genes, and secondary clustering based on these 32 DEGs classified GBM samples into two circadian-related gene patterns, which also predicted molecular profiles and prognosis. A circadian risk scoring system was established, allowing the calculation of individual risk scores based on the expression of 10 genes, where GBM patients with lower circadian risk scores had prolonged overall survival and less aggressive molecular subtypes, while higher circadian risk scores correlated with better responses to MAPK-targeted therapy. In conclusion, this study established two clustering patterns based on 17 circadian rhythm genes or 32 circadian-related genes, enabling the rapid classification of GBM patients with distinct molecular profiles and prognoses, while the circadian risk scoring system effectively predicted survival, molecular profiles, and therapeutic responses for individual GBM patients, demonstrating that the circadian rhythm gene network can distinguish molecular profiles and prognosis in GBM.

Nasopharyngeal carcinoma (NPC) diagnosis and routine follow-up for recurrence typically rely on contrast-enhanced MRI. This study introduces a deep learning model for diagnosing NPC using only non-contrast MRI, reducing the need for gadolinium-based contrast agents (GBCA). This approach helps avoid safety concerns related to GBCA deposition, while also shortening scan times and reducing costs. In this study, we propose an innovative deep learning model for NPC diagnosis using only non-contrast MRI, reducing the need for gadolinium-based contrast agents (GBCA). This approach not only mitigates potential safety concerns associated with residual GBCA deposition but also reduces scan time and examination costs. The study consisted of three phases. Firstly, a novel knowledge distilled modality fusion model is developed using a cohort of 854 cases and tested its performance on an internal set (257 cases, AUC = 0.95) and an independent external set (277 cases, AUC = 0.86). Secondly, the proposed method was compared with: (1) Non-contrast MRI without model improvement (Baseline 1) and (2) current virtual-contrast enhancement-based NPC diagnosis using three state-of-the-art methods (Baselines 2-4). The proposed model consistently outperformed Baselines 1 on both internal dataset (AUC: 0.95 vs. 0.93) and external test set (AUC: 0.86 vs. 0.82). Additionally, it surpassed Baselines 2-4, achieving performance gains of 6.7%, 69.8%, and 28.6% in AUC, over three state-of-the-art methods. Thirdly, the effectiveness of this model was evaluated through a fully crossed multi-reader, multi-case study involving 13 readers from 6 hospitals. The results showed that with AI assistance, readers could diagnose NPC using only non-contrast MRI, achieving results that were not inferior to contrast-enhanced imaging (AUC: 0.90 vs. 0.93, p<0.01). In conclusion, this study demonstrated the model’s potential as a safe, cost-effective, and GBCA-free option for NPC diagnosis in clinical practice.

Nasopharyngeal carcinoma (NPC) exhibits unique radiosensitivity, yet radioresistance remains a major therapeutic challenge. This study investigates the role of RAC2 in hypoxia-induced radioresistance through reactive oxygen species (ROS) regulation. Radiation effectiveness was demonstrated through dose-dependent DNA damage, proliferation inhibition, and ROS elevation in NPC cells, while hypoxic conditions attenuated these effects. Mechanistically, RAC2 was identified as a crucial mediator of hypoxia-induced radioresistance by modulating NADPH oxidase-derived ROS production. The findings reveal that RAC2 drives hypoxia-associated radioresistance in NPC by amplifying ROS production, suggesting its potential as a therapeutic target for radiosensitization. This research provides new insights into overcoming hypoxia-mediated radioresistance in NPC treatment.

Purpose:Bone and soft tissue tumors present unique therapeutic challenges due to their heterogeneity and poor prognosis to standard treatments. Particle therapy offers improved dose distribution and potentially higher relative biological effectiveness, however, its immunological effects in patients remain poorly understood. Investigating peripheral immune cell changes could offer valuable insights for integrating immunotherapies and optimizing treatment outcomes. Methods:In this observational study, we enrolled 12 patients with head and neck bone and soft tissue tumors treated at our center between November 1, 2022, and November 1, 2024. Treatment modalities included proton or carbon-ion radiotherapy, with or without chemotherapy, targeted therapy, or immunotherapy. Peripheral blood samples were collected both before and after the completion of radiotherapy. Hematologic assessments were conducted, including total lymphocyte counts and immunophenotyping of CD3+, CD4+, CD8+, and other lymphocyte subsets. Statistical analyses, including paired Student's t-test, Wilcoxon signed-rank tests and univariate analysis, were performed to investigate associations between lymphocyte changes and clinical factors. Results:Minor reductions were noted in CD3+ and CD4+ T cell subsets, accompanied by a small increase in CD3+CD4-CD8- subsets. Even after excluding the patient who received immunotherapy, the observed trend in lymphocyte counts and subset changes remained consistent. This finding suggests that, compared with conventional photon radiotherapy, particle therapy may better preserve immune function. Remarkably, all patients were alive and showed no evidence of disease progression during the study period. Conclusion:Particle therapy in patients with head and neck bone and soft tissue tumors induces modest immunological alterations, suggesting it may preserve immune function more effectively than conventional photon radiotherapy. These preliminary findings from our small cohort support further research into combining particle therapy with immunomodulatory strategies, potentially enhancing clinical outcomes and expanding therapeutic options for these challenging malignancies.

Carbon ion radiotherapy (CIR) has emerged as a promising therapeutic modality for photon-resistant malignancies due to its unique physical depth-dose distribution and enhanced radiobiological effectiveness. Nevertheless, treatment resistance persists in certain recurrent or refractory head and neck squamous cell carcinoma (HNSCC) cases, underscoring the need for novel combinatorial strategies. Here, we demonstrated the sensitizing effect of targeting discoidin domain receptor 1 (DDR1) in HNSCC for CIR. MOC1 and and Cal27 cell lines along with tumor-bearing C57BL/6 mice were used for in vitro and in vivo studies. DDR1 was knocked down via lentivirus. Cell viability and proliferation were assessed by CCK-8 and colony formation assays. Immunogenicity and tumor-infiltrating lymphocytes were measured via flow cytometry and immunofluorescence. Tumor suppression mechanisms were investigated using RNA sequencing and bioinformatics. Ferroptosis markers (lipid peroxidation, iron, ROS) were detected using MDA, BODIPY 581/591 C11, FerroOrange, and DCFH-DA probes. Upstream ferroptosis mechanisms were analyzed by Western blot, co-immunoprecipitation, key molecule modulator administration, and SCD1 overexpression. We demonstrated that targeting DDR1 potentiated CIR by triggering ferroptosis-mediated immunogenic cell death, which in turn enhanced antitumor immunity. Mechanistically, DDR1 sustained tumor cell survival by forming 14–3-3-mediated assembly of a DDR1/14–3-3/Akt ternary complex, thereby activating the Akt/mTORC1/SREBP1/SCD1 axis to promote monounsaturated fatty acid (MUFA) biosynthesis and suppress ferroptosis. Silencing DDR1 disrupted this complex, alleviating MUFA-mediated ferroptosis inhibition and subsequently increasing tumor immunogenicity. This immunogenic shift facilitated CD8 + T cell infiltration and cytotoxicity, amplifying CIR-induced tumor suppression. Furthermore, pharmacological inhibition of DDR1 using the small-molecule inhibitor 7rh recapitulated these effects, demonstrating potent anti-proliferative and ferroptosis-inducing capabilities, enhancing CIR sensitivity to better control tumor progression. Our findings positioned DDR1 targeting as a therapeutic strategy to potentiate CIR through immunogenic ferroptosis induction in HNSCC.

BACKGROUND:This retrospective study report the clinical experience of eye-preserving treatment follow by particle beam radiotherapy (IMPT or CIRT) for orbital malignancies. And to evaluate prognostic factors for orbital and lacrimal gland tumors. METHODS:Sixty-two patients with orbital malignancies were identified in the records of a single center between 2015 and 2021. Sixty-one patients met inclusion criteria. All of the patients received eye-preserving treatment before PBRT. Majority of the patients (91.8%) were treatment with CIRT. Clinical data, treatment modality, local control, metastases and survivals and visual outcomes, as well as associated prognostic indicators were were assessed. RESULTS:Sixty-one patients were followed with a median of 40.7 months (44.3 months for surviving patients). The 3- and 5-year DSS and LC rates were 88.1% and 69.9%, and the 3- and 5-year DMC rates were 77.5% and 74.2% for entire orbital malignancies. For lacrimal gland carcinoma, the 5-year DSS, LC, DMC, and PFS rates were 83.3%, 64.8%, 66.8%, and 53.4%. Tumor size, T stage, extraorbital invasion, and bone invasion influenced survivals. No grade 3 or higher acute toxicities were observed. A total of 8 patients experienced grade 3-4 visual impairment. CONCLUSIONS:Particle radiotherapy following eye-preserving treatment provided a favorable local control and survivals with moderate acute and late toxicities, even in patients with unresectable disease. Particle radiotherapy was a promising strategy for management of orbital tumors.

Glioblastoma (GBM), the most prevalent and lethal primary malignancy of the central nervous system, remains refractory to conventional photon radiotherapy due to inherent limitations in dose distribution. Although carbon ion radiotherapy offers distinct advantages, including its characteristic Bragg peak deposition and superior relative biological effectiveness, its clinical application is constrained by high costs and increased toxicity. This study explores the radiobiological interactions underlying a mixed carbon ion-photon irradiation regimen, a promising strategy in advanced particle therapy. Our findings demonstrate that combined irradiation exerts synergistic cytotoxic effects in GBM models. Mechanistic analysis reveals that this combination induces clustered DNA double-strand breaks, leading to the cytoplasmic accumulation of double-stranded DNA (dsDNA) fragments. This, in turn, activates the cGAS-STING-mediated cytosolic DNA sensing pathway, which facilitates NCOA4-FTH1 axis-driven ferritinophagy and ultimately triggering iron-dependent ferroptosis. These findings offer a new mechanistic perspective on optimizing combined particle therapy regimens for GBM treatment, with significant implications for translational applications in clinical radiation oncology.

INTRODUCTION:Despite significant advances in the comprehensive treatment of nasopharyngeal carcinoma (NPC), local recurrence or distant metastasis still occurs in a considerable proportion of patients, leading to poor outcomes and posing a significant clinical challenge. The current therapeutic agent, Triptonide (TN), has shown potential efficacy in modulating cellular autophagy, suggesting its therapeutic promise for treating NPC. However, the precise molecular targets and mechanisms underlying TN's role in NPC remain to be elucidated. METHODS:Initially, relevant targets for TN in the treatment of NPC were identified through public databases. Next, network pharmacology and bioinformatics analyses were employed to pinpoint the top 15 hub targets and critical signaling pathways involved in TN's therapeutic action. Finally, experimental validation, including a range of molecular assays, was conducted to investigate the cellular effects of TN treatment, such as apoptosis induction, migration inhibition, Caspase-3 activation, mitochondrial dysfunction, autophagy-related gene expression, and TFAM level detection, thereby confirming the essential genes and pathways. RESULTS:A total of 31 potential molecular targets for TN in NPC were identified, with 27 genes confirmed through autophagy-related gene analysis. Among these, the top 15 hub genes included RELA, CASP8, NFKBIA, PPARG, PTGS2, MAPK14, MAPK8, HDAC1, ERBB2, CASP1, TERT, AR, CDK1, PGR, and HDAC6. TN was found to activate the MAPK signaling pathway. In vitro, TN induced NPC cell apoptosis via increased ROS, MAPK14 activation, and Caspase-3 cleavage. It disrupted mitochondrial function (reduced membrane potential, decreased copy number, enhanced fission), inhibited mTOR and RELA phosphorylation, and promoted autophagy. TN also caused S-phase arrest, reduced CDH3, and increased CDH1. Lipoic acid partially reversed TN-induced cytotoxicity. DISCUSSION:TN exerts anti-NPC effects primarily through MAPK pathway activation and autophagy induction. Key targets mediating these effects include RELA, CASP8, PPARG, MAPK14, MAPK8, HDAC1, ERBB2, and CASP1. The reversal by lipoic acid implicates ROS in TN's mechanism. The disruption of mitochondrial function represents a critical facet of its action. CONCLUSION:TN demonstrates potential as a therapeutic agent for NPC, primarily through activation of the MAPK signaling pathway and autophagy. Key targets, including RELA, CASP8, PPARG, MAPK14, MAPK8, HDAC1, ERBB2, and CASP1, have been identified as critical mediators of TN's effects, highlighting its role in promoting autophagy and enhancing NPC treatment.

BACKGROUND:Major salivary gland tumors (MSGTs) are rare and pose significant treatment challenges. This study investigates the efficacy and safety of particle beam radiotherapy (PBRT) for patients with newly-diagnosed MSGTs. METHODS:We conducted a retrospective analysis of 82 patients treated at the Shanghai Proton and Heavy Ion Center (SPHIC) between August 2015 and March 2022. The cohort received various radiotherapy regimens based on surgical history and pathological risk factors. We evaluated survival outcomes, treatment toxicity, and potential prognostic factors. RESULTS:Our findings revealed promising 3-year survival rates: 94.3% for overall survival (OS), 81.3% for progression-free survival (PFS), 97.2% for locoregional control (LRC), and 82.6% for distant metastasis-free survival (DMFS). Acute and late toxicities were generally mild to moderate, with a favorable safety profile. Distant metastasis was the primary mode of treatment failure, emphasizing the need for early risk assessment. CONCLUSION:As a potentially safe and efficient treatment option for newly-diagnosed MSGTs, proton and carbon ion radiation offers an excellent alternative for traditional methods. More investigation is required to determine the long-term results and relative efficacy of various treatment modality for major salivary gland cancer when compared to photon therapy.

Due to the advantageous depth dose profile of carbon ion beams, carbon ion therapy is commonly applied in the form of intensity modulated particle therapy (IMPT) with few treatment fields. Carbon ion arc therapy (C-Arc) has recently been proposed to improve dose conformity and increase the dose-averaged linear energy transfer (LETd) inside the target to levels relevant for overcoming tumor radioresistance. In this work, we investigate different energy selection approaches for C-Arc, including a novel greedy energy layer refinement strategy. Robust biologically optimized C-Arc plans were generated for six head neck cancer patient previously treated at the Shanghai Proton and Heavy Ion Center (SPHIC). Different heuristic approaches for mono- and dual-energy C-Arc were implemented, and compared to carbon IMPT pans. A novel greedy energy layer refinement was developed, acting directly on the dose influence matrix, rather than on an iterative plan optimization. A key challenge in C-Arc with few energy layers per angle is the sharpness of the carbon ion Bragg peak, which is challenging for plan robustness. To improve robustness and plan quality, we propose the use of a 6 mm ripple filter instead of the typical 3 mm ripple filter used for carbon IMPT. Most mono-energetic C-Arc plans were able to meet the established clinical goals, but some of the heuristic energy selection schemes were not universally applicable with low plan quality in some patients. The developed energy layer refinement strategy delivered high quality plans even for complex cases. Mono-energetic C-Arc plans presented an average increase between 10 _50% compared to the IMPT carbon ion plans. C-Arc plans with 2 energies per treatment angle, for the employed energy selection heuristic, improved dosimetric quality compared to mono-energetic C-Arc plans, but did not provide the same natural improvement in LETd compared to IMPT. For small, centrally located targets C-Arc demonstrates the greatest potential, but feasible plans could also be achieved for more complex cases in this work. Further development is necessary for improving C-Arc delivery efficiency and plan quality toward possible clinical application.