Background Reactive oxygen species (ROS) play a complex dual role in cancer biology. At physiological levels, ROS act as signaling molecules that drive tumorigenesis, metastasis, and therapy resistance by activating oncogenic pathways, such as NF-κB and PI3K/AKT, and fostering an immunosuppressive microenvironment. Conversely, excessive ROS accumulation overwhelms antioxidant defenses, triggering oxidative stress that can selectively eliminate tumor cells. Consequently, manipulating the delicate redox equilibrium has emerged as a pivotal strategy for cancer treatment. Aim of Review This review systematically examines the multifaceted functions of ROS, bridging the gap between fundamental redox biology and clinical application within the Predictive, Preventive, and Personalized Medicine (3PM) framework. Beyond molecular mechanisms, we evaluated the rationale for utilizing mitochondrial redox signatures as intrinsic biological sensors to identify suboptimal health conditions (SHC) and prevent the health-to-disease transition. Key Scientific Concepts of Review We elucidate the regulatory networks governing ROS production and elimination, highlighting their dual function in promoting genomic instability versus inducing distinct cell death modalities, including apoptosis, autophagy, necroptosis, and ferroptosis. Special attention is given to ROS-mediated remodeling of the tumor microenvironment (TME), where oxidative stress facilitates immunosuppression. Importantly, we provide expert recommendations on integrating digital health monitoring and patient stratification into clinical oncology. By emphasizing mitochondrial rejuvenation and individualised protection, this review discusses how proactive interventions can restore homeostasis and improve long-term outcomes, offering a cost-effective alternative to reactive treatments.

Despite significant advancements in targeted therapy and immunotherapy that have markedly improved the survival of patients with non-small cell lung cancer (NSCLC), challenges such as tumor heterogeneity and therapeutic resistance persist. Ferroptosis, a unique form of iron-dependent programmed cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for cancer treatment. Interleukin-17D (IL-17D), a member of the IL-17 cytokine family, is involved in regulating immune cell responses within the tumor microenvironment. However, its role in ferroptosis remains unclear. In this study, we demonstrated that high IL-17D expression in lung cancer cell lines is significantly associated with ferroptosis resistance and predicts poor prognosis of patients with lung cancer. Mechanistically, IL17D overexpression promotes the expression of ferroptosis resistance-related genes by enhancing the accessibility of nuclear transcription factor Y (NFY) complex binding sites, and reduces intracellular lipid peroxidation levels. Notably, upon treatment with ferroptosis inducers, IL-17D significantly upregulates peroxisome proliferator-activated receptor gamma (PPARγ) expression, promotes cellular lipid droplet accumulation, and elevates ATP levels in lung cancer cells. Importantly, pharmacological inhibition of the PPARγ pathway reverses IL-17D-induced ferroptosis resistance. Collectively, these findings uncover a novel mechanism whereby IL-17D regulates ferroptosis through PPARγ-dependent lipid metabolic reprogramming, highlighting the IL-17D-PPARγ axis as a promising therapeutic target to overcome ferroptosis resistance in lung cancer.

Background: While histopathology is fundamental to cancer diagnosis, its potential for comprehensive molecular profiling remains underexplored. This study aimed to develop an integrated computational pathology pipeline that predicts gene mutations from histopathology images and explores histology-multi-omics correlations. Methods: We analyzed 874 H&E-stained whole-slide images from 647 head and neck squamous cell carcinoma patients across three international cohorts. The pipeline comprised: 1) Cancer-Net, a segmentation model trained on similar to 200,000 annotated image tiles to identify tumor regions; and 2) GEM-Net, an enhanced teacher-student multiple instance learning framework integrating a Transformer architecture for global slide-level feature aggregation, to capture global context for mutation prediction. Sparse canonical correlation analysis (SCCA) was then applied to explore associations between the image features extracted by GEM-Net and transcriptomic/ proteomic pathways. Results: Cancer-Net achieved high tumor segmentation performance (AUC = 0.995). GEM-Net demonstrated robust mutation prediction (AUC = 0.702-0.876), outperforming CNN and Transformer baselines. A clinically relevant dual-thresholding strategy based on GEM-Net outputs demonstrated the potential to reduce theoretical need for molecular testing by 10-26%. Visual explanations from GEM-Net aligned with immunohistochemical staining patterns. SCCA interpreted the morphological features learned by GEM-Net, revealing associations with molecular pathways such as cell cycle dysregulation in TP53-mutant tumors and tight junction disruption in FAT1-mutant cases. Conclusions: This integrated pipeline enables accurate mutation prediction and provides interpretable links between histopathology and multi-omics data, suggesting potential utility for clinical decision support and cancer biology research.

BACKGROUND:The optimal reconstructive approach following neoadjuvant immunochemotherapy (NICT) and surgery for locally advanced oral squamous cell carcinoma (OSCC) remains debated. This study compared pedicled submental island flap (SIF) and free flap (FF) reconstruction in this contemporary treatment setting. METHODS:We conducted a retrospective comparative study of 212 consecutive patients with locally advanced OSCC treated with NICT followed by surgery. Propensity score matching (1:1) yielded a balanced cohort of 54 SIF and 54 FF patients. Outcomes included disease-free survival (DFS), overall survival (OS), operative time, complications, recovery milestones, and patient-reported quality of life (QoL) assessed via EORTC QLQ-C30/H&N35 at baseline, 3, 6, and 12 months. RESULTS:Operative time and hospital stay were significantly shorter for SIF (4.5 ± 1.1 vs. 6.3 ± 1.4 h, p < 0.001; 8.1 ± 2.5 vs. 11.8 ± 3.1 days, p < 0.001). Flap survival and major complication rates were comparable (p > 0.05). Median follow-up was 38.5 months. No significant differences were observed in DFS (HR = 0.90, 95% CI: 0.41-1.98, p = 0.796) or OS (HR = 0.83, 95% CI: 0.34-2.00, p = 0.678). However, QoL recovery was superior in the SIF group, with significantly greater improvements in Global QoL (81.5 ± 8.2 vs. 73.9 ± 10.1, p < 0.001), physical and social functioning, and head and neck-specific symptoms (swallowing, speech) at 12 months. Linear mixed models confirmed a favorable SIF trajectory over time (time-by-group interaction p < 0.001). CONCLUSION:In patients with locally advanced OSCC undergoing NICT, SIF reconstruction offers comparable oncologic safety to FF while facilitating faster surgical recovery and yielding superior long-term functional and quality of life outcomes.

Betel nut chewing (BNC) is a prevalent risk factor for oral squamous cell carcinoma (SCC) in South and Southeast Asia, yet its influence on response to neoadjuvant immunochemotherapy remains unexplored. This study aimed to evaluate the association between BNC and pathologic response in oral SCC patients receiving neoadjuvant immunochemotherapy. We retrospectively reviewed 192 patients with primary oral SCC who received neoadjuvant immunochemotherapy (docetaxel, cisplatin, and PD-1 inhibitors) followed by surgery between January 2020 and October 2024. Pathologic complete response (pCR), major pathologic response (mPR), objective response rate (ORR), clinical to pathological downstaging, adverse pathologic features, and disease-free survival (DFS) were compared between BNC (n = 42) and no-BNC (n = 150) groups. BNC patients demonstrated significantly lower pCR (16.7

BackgroundOral squamous cell carcinoma (OSCC) represents a common malignancy characterized by significant morbidity and mortality rates, highlighting the critical necessity for novel therapeutic approaches. Consequently, investigating differentially expressed genes linked to inflammation and pyroptosis may identify potential prognostic biomarkers and therapeutic targets.MethodsTo address this research gap, our study utilized an extensive bioinformatics approach by analyzing the Cancer Genome Atlas Head and Neck Squamous Cell Carcinoma (TCGA-HNSC) dataset through differential expression analysis to identify genomic features associated with OSCC. Subsequent analyses included Gene Ontology and pathway enrichment assessments, along with survival analyses using Cox regression models, to evaluate the prognostic significance of the identified differentially expressed genes. Furthermore, immune infiltration analysis and somatic mutation assessments were conducted to elucidate the relationship between immune cell types and key prognostic genes. Additionally, copy number variation analysis was performed to highlight genomic alterations associated with immune-related and prognostic-related differentially expressed genes(DEGs).ResultsOur analysis identified a total of 3,495 differentially expressed genes, among which 53 immune-related and prognosis-related differentially expressed genes demonstrated a significant correlation with the prognosis of OSCC. Immune infiltration analysis further revealed the presence of 28 immune cell types within OSCC samples, with a notable prevalence of activated CD8 T cells and regulatory T cells, underscoring their association with critical prognostic genes. Additionally, pathway analysis highlighted the activation of cytokine signaling pathways and their associations with processes relevant to systemic lupus erythematosus. A prognostic risk model derived from these findings effectively stratified patients based on overall survival, identifying four key genes—CTSG,HKDC1,PTX3 and SPP1—as crucial prognostic indicators. This analysis may uncover potential prognostic biomarkers and therapeutic targets.ConclusionThis study established a novel OSCC prognostic risk model based on inflammation- and pyroptosis-related interactive genes. CTSG, HKDC1, PTX3 and SPP1 were validated as independent prognostic biomarkers, and the risk score was closely associated with tumor microenvironment features, metabolic activity, and therapeutic sensitivity. This work may provides substantial references for the exploration of novel biomarkers for OSCC treatment and facilitates clinical decision-making.

Neoadjuvant immunochemotherapy (NICT) has transformed the treatment of locally advanced oral squamous cell carcinoma (OSCC), yet the prognostic reliability of the eighth-edition American Joint Committee on Cancer (AJCC) pathologic nodal staging in this context remains unclear. This study sought to develop a ypN staging system for post-NICT OSCC. This retrospective study analyzed 559 patients with locally advanced OSCC who received NICT followed by radical surgery across two centers (training cohort, n = 226; external validation cohort, n = 333). A proposed ypN staging system integrating viable node burden and macro- extranodal extension (ENE) status was developed and externally validated. Model performance was compared with the eighth-edition AJCC staging using Harrell’s C-index, the Akaike Information Criterion, and decision curve analysis. Three prognostic groups emerged (0, 1–2, and ≥3 viable metastatic lymph nodes). Multivariate analysis showed that micro-ENE did not add significant risk (hazard ratio, 1.12; P = 0.79), whereas macro-ENE independently predicted recurrence. The proposed staging framework, which categorizes patients into ypN0 (0 viable nodes), ypN1 (1 to 2 viable nodes without macroscopic ENE), ypN2 (≥3 viable nodes without macroscopic ENE), and ypN3 (≥1 viable nodes with macroscopic ENE), produced a clearly distinct prognostic gradient, with 3-year disease-free survival rates of 84.1, 61.2, 31.8, and 9.1

Abstract Fibroblast growth factor 2 (FGF2) is frequently induced during ischemic retinal injury and has traditionally been considered a pro-angiogenic factor based largely on studies using exogenous FGF2 administration. However, its endogenous cellular origin and physiological role remain incompletely understood. Here, we used single-cell transcriptomic analysis combined with spatial validation and rod photoreceptor-specific genetic approaches to define the endogenous role of FGF2 during oxygen-induced retinopathy (OIR). We identify rod photoreceptors as a major cellular source of ischemia-induced FGF2. Notably, Fgf2 expression remained elevated during the regression of pathological neovascularization, revealing a temporal dissociation between neuronal stress responses and vascular remodeling. Single-cell analysis further showed that Fgf2 induction occurred within a coordinated photoreceptor stress-response program involving endothelin 2 ( Edn2 ) and B-cell lymphoma 3 ( Bcl3 ). This transcriptional signature was independently reproduced in the N-methyl-N-nitrosourea (MNU)-induced photoreceptor degeneration model. Rod-specific deletion of Fgf2 markedly increased photoreceptor apoptosis, indicating that endogenous FGF2 contributes to photoreceptor survival under ischemic stress. In contrast, neither genetic depletion nor overexpression of FGF2 altered pathological neovascularization or vaso-obliteration. Bidirectional manipulation of FGF2 further modulated the expression of representative stress-associated genes Edn2 and Bcl3, supporting FGF2 involvement in this injury-response program. Finally, receptor expression analysis revealed relatively limited endothelial expression of Fgfr1-Fgfr4 compared with VEGF receptors, suggesting a cellular basis for the distinct effects of endogenous FGF2 and VEGF signaling. Together, these findings identify endogenous retinal FGF2 as a photoreceptor-derived survival factor that is induced during stress but is insufficient to drive pathological angiogenesis. These results support a model in which neuronal adaptation and vascular remodeling represent partially distinct responses during ischemic retinal injury.

BACKGROUND:Processing methods for fine-needle aspiration biopsy (FNA) samples mainly include conventional smears (CS) and liquid-based preparations (LBP). There is still debate as to which method is better and the diagnostic value and necessity of combining the two methods remains unclear. The objective of the current study was to compare the diagnostic performance of the two methods and their combined use in thyroid nodules. METHODS:We analyzed thyroid cytopathology data from 16 medical centers between June 2010 and November 2025, comparing nondiagnostic and indeterminate nodules rates across preparation methods. For histologically confirmed samples, diagnostic performance metrics were calculated. Cases with separate CS and LBP descriptions (multi-diagnoses group) were analyzed for diagnostic consistency and performance. RESULTS:In total, 89,392 thyroid FNA cases were included (49,309 CS, 13,161 LBP, and 26,922 combined). The rate of indeterminate nodules was 10.3% (CS), 10.9% (LBP), and 14.8% (combined), while nondiagnostic rate was lowest in the combined group (7.3% vs. 10.5% for CS and 17.9% for LBP). LBP demonstrated higher sensitivity (98.1% vs. 95.0%) and accuracy (97.0% vs. 93.7%) than CS, while combined use provided no significant advantage over LBP alone. In the multi-diagnoses group, CS-LBP concordance among diagnostic samples was 92.9%, with comparable diagnostic performance across all methods. CONCLUSIONS:LBP demonstrated superior diagnostic performance compared with CS, but combined use of both methods provided no significant advantage over LBP alone.

ObjectiveTo elucidate the clinicopathological characteristics and survival trajectories of patients with head and neck squamous cell carcinoma (HNSCC) who developed brain metastasis (BM).MethodsThis retrospective analysis enrolled patients diagnosed with HNSCC and BM from three tertiary care institutions. Survival following the diagnosis of BM and the patterns of BM were examined.ResultsA total of 201 HNSCC patients with BM were analyzed, revealing an incidence rate of 1.1%. The median interval from the initiation of treatment to the diagnosis of BM was determined to be 2.5 years. The distribution of intracranial metastases was as follows: one metastasis in 65 cases, two or three in 84 cases, and four or more in 52 patients. Brain metastases were predominantly localized to the supratentorial region in 130 patients, while involvement of both supratentorial and infratentorial regions occurred in 56 patients. The majority of patients reported significant discomfort. All patients succumbed within two years of the initial BM diagnosis, with the median survival time of 3 months. In Cox model analyses, patients receiving whole-brain radiotherapy or stereotactic radiosurgery alone or those undergoing surgical intervention in conjunction with post-operative radiotherapy exhibited a reduced mortality risk compared to those receiving no treatment, with hazard ratios of 0.72 (95% confidence interval: 0.53-0.98) and 0.64 (95% confidence interval: 0.43-0.95), respectively.ConclusionBrain metastasis in patients with head and neck squamous cell carcinoma is a rare occurrence, often correlated with lung metastasis. Local therapy for brain metastases, primarily involving whole-brain radiotherapy, whether administered alone or alongside surgical interventions, was found to be associated with modest prolonged survival durations.

Abstract Cancer immunotherapy benefits remain limited, even among “hot” tumors with high killer lymphocyte infiltration. Here, we investigated the population-level architecture of killer cells based on nearly 5,000 pan-cancer scRNA-seq samples, together with orthogonal validation by spectral cytometry and spatial transcriptomics. Unlike the prevailing “hot-cold” paradigm, which assumes coordinated infiltration of multiple cytotoxic lineages, we uncovered a conserved framework wherein terminal cytotoxic immunity in individuals or malignancies diverges into states dominated by either exhausted CD8+ T cells (Tex) or CD56 dim CD16 hi NK (NK1) cells. Despite the complexity of the tumor microenvironment, Tex-NK1 divergence governs the primary axis of tumor-intrinsic and tumor-extrinsic variance. Distinct from the conventional view that NK cells positively contribute to immunotherapy efficacy, NK1-skewed tumors, although highly cytolytic, are refractory to current immune checkpoint blockade regimens. This killer divergence defines a foundational axis of cancer immunity and provides a resource for prioritizing next-generation targets for NK-directed immunotherapy.

Traditional American Joint Committee on Cancer (AJCC) staging exhibits critical limitations when assessing oral squamous cell carcinoma (OSCC) treated with neoadjuvant immunochemotherapy (NICT). This study proposed using the percentage of residual viable tumor (

Optimal management of the clinically node-negative (cN0) neck in early-stage (cT1-2) lip squamous cell carcinoma (SCC) remains controversial. Sentinel lymph node biopsy (SLNB) offers a minimally invasive staging alternative to observation or elective neck dissection, but its diagnostic accuracy, lymphatic mapping patterns, and survival impact in lip SCC are not well-established. We conducted a retrospective study of 101 patients with cT1-2N0 lip SCC treated at a tertiary cancer center (2005–2022), comparing SLNB-guided management (n = 46) to observation (n = 55). Diagnostic performance of SLNB was evaluated against final histopathology. Lymphatic mapping was performed using lymphoscintigraphy/SPECT and gamma probe. Survival outcomes were analyzed using Kaplan–Meier and Cox regression, with sensitivity analysis using inverse probability of treatment weighting (IPTW). SLNB achieved a 100

This study evaluated the clinical utility of C-reactive protein (CRP) and homocysteine (Hcy) as biomarkers for injury severity assessment and prognostic prediction in traumatic brain injury (TBI). A retrospective cohort study included 103 TBI patients (February 2020 to February 2023) stratified by Glasgow Coma Scale (GCS) scores into mild (n = 20), moderate (n = 32), and severe (n = 51) injury groups, alongside 20 healthy controls. Serum and cerebrospinal fluid (CSF) CRP and Hcy levels were measured serially over 14 days post-injury. Prognostic outcomes were assessed using 3-month Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) scores. Severe TBI patients exhibited significantly higher serum and CSF CRP levels than moderate/mild groups (p < 0.01), peaking within 72 h and remaining elevated through day 14. Serum Hcy levels increased rapidly post-injury, with severe cases sustaining prolonged elevations (> 7 days vs. ≤3 days in mild/moderate groups). CRP and Hcy levels inversely correlated with admission GCS scores (r = - 0.756, 0.756 and - 0.652, respectively; p < 0.001) and positively correlated with intracranial pressure (r = 0.829, 0.779 and 0.633). The initial CRP and Hcy levels were negatively correlated with GOS and positively correlated with mRS at 3 months post-injury, indicating their potential as biomarkers for assessing injury severity and predicting prognosis in TBI patients. CRP (serum/CSF) and serum Hcy are reliable biomarkers for assessing injury severity and predicting prognosis in TBI patients.

e16180 Background: Sequential hepatic artery infusion chemotherapy (HAIC) and transarterial chemoembolization (TACE) may synergistically increase the drug concentration within the hepatocellular carcinoma(HCC). Moreover, anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors and immune checkpoint inhibitors are widely used in advanced HCC patients. This study aims to evaluate the efficacy and safety of sequential HAIC and TACE combined with targeted therapy and immunotherapy as quadruple first-line treatment for advanced HCC. Methods: This retrospective single-center study recruited data from advanced HCC patients at Zhongshan Hospital, Fudan University, from January 1, 2023 to October 31, 2024. Enrolled patients were treated by sequential FOLFOX-HAIC and TACE combined with anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors (including apatinib in 4 cases, bevacizumab in 4 cases, donafenib in 2 cases, and lenvatinib in 28 cases) and immune checkpoint inhibitors (including PD-1 antibody in 34 cases and PD-L1 antibody in 4 cases). The primary outcome was objective response rate (ORR), evaluated according to RECIST v1.1 and mRECIST criteria. Secondary outcomes included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: A total of 38 patients (35 [92.1%] men and 3 [7.9%] women) with advanced HCC were enrolled. At the end of this study (November 30, 2024), the ORR was 73.7% (28/38; 95%CI:59.8%-87.6%), and the disease control rate (DCR) was 92.1% (35/38; 95% CI:83.5%-100.0%) based on the RECIST v1.1 criteria. Similarly, according to the mRECIST criteria, the ORR was 86.8% (33/38; 95%CI:76.0%-97.6%), and the DCR was 94.7% (36/38 ;95% CI:87.6%-100.0%). Eleven patients with advanced HCC were down-staged and subsequently achieved curative treatment. With the middle follow-up of 13.0 months, the 12-months OS rate was 84.2%. The median OS and median PFS have not been reached. No grade 5 adverse events were observed in this study. The grade 3/4 adverse events included elevated aminotransferase levels (50.0%), abdominal pain (42.1%), hyperbilirubinemia (36.8%), thrombocytopenia (13.2%), leukopenia (7.9%), rash (5.3%), diarrhea (5.3%), hypokalemia (2.6%), vomiting (2.6%). Conclusions: Sequential hepatic artery infusion chemotherapy and transarterial chemoembolization combined with anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors and immune checkpoint inhibitorsachieved encouraging outcomes with accepted adverse events in advanced HCC patients. These findings warrant further validation in a large randomized clinical trial.

This study aims to detect Mycobacterium tuberculosis complex (MTBC) DNA in intraocular fluid from clinically suspected tuberculous uveitis patients using multiplex polymerase chain reaction (PCR) and investigate the diagnostic utility of multiplex PCR for tuberculous uveitis. Primers targeting three specific genes (MPB64, CYP141, and IS6110) within the MTBC genome were designed. Multiplex PCR was conducted using DNA from the H37Rv strain as well as DNA extracted from fluids of confirmed tuberculosis patients to assess primer specificity and method feasibility. Intraocular fluid samples were collected during the initial visit for multiplex PCR detection of MTBC DNA. The results of multiplex PCR tests were correlated with intraocular fluid findings and clinical profiles of patients clinically diagnosed with tuberculous uveitis who underwent standard antituberculosis therapy. Multiplex PCR was employed to detect MTBC DNA in intraocular fluid samples from 15 patients clinically suspected of having tuberculous uveitis, with no amplification bands observed in the DNA lanes for the three target genes. T-cell spot test (T-SPOT) results were positive in 11 patients (100

[This corrects the article DOI: 10.3389/fonc.2022.807597.].

Background:An observational approach in the management of the cervical region in instances of maxillary squamous cell carcinoma (SCC) results in appreciable treatment failure, necessitating a more efficacious neck intervention. Our objective was to compare the efficacy of sentinel lymph node biopsy (SLNB) versus observation regarding regional control (RC) in patients diagnosed with cT1/2N0 maxillary SCC. Methods:Patients who underwent SLNB or observation for neck management in primary cT1/2N0 maxillary SCC were retrospectively enrolled. SLNB was performed one day before surgery using 99mTc-nanocolloid, with the decision to proceed with neck dissection guided by intraoperative sentinel lymph node pathology. Primary outcome variable was 5-year RC. Impact of neck management on RC was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards modeling. Results:A total of 145 patients were included, with SLNB performed in 46 necks and observation applied to 99 cases. Sentinel lymph nodes were successfully identified in all instances. In comparison, regional recurrence was observed in eight patients within the SLNB cohort, of whom six had previously exhibited a metastatic sentinel lymph node, as opposed to 21 patients in the observational group. In the Cox model, SLNB was associated with a relative 28% reduction in the risk of neck failure compared to observation (p=0.021). Occult lymph node metastasis was more prevalent in tumors possessing a diameter exceeding 2cm or a depth of invasion surpassing 4mm, subgroup analysis revealed that the positive impact of SLNB on outcomes became statistically significant only for tumors larger than 2.0 cm (p=0.041, hazard ratio=0.23, 95% confidence interval: 0.05-0.98) or with a depth of invasion greater than 4.0 mm (p=0.042, hazard ratio=0.22, 95% confidence interval: 0.02-0.95). Conclusion:SLNB demonstrated superior RC compared to observation in patients diagnosed with cT1/2N0 maxillary SCC. These results support reconsidering SLNB as a standard approach among those with tumors exceeding 2.0 cm in size or a depth of invasion surpassing 4.0 mm.