Search Results (1,730)

Despite advances in multimodal treatment, head and neck squamous cell carcinoma (HNSCC) remains a major clinical problem owing to its high recurrence rate and frequent development of treatment resistance. Abnormal histone modifications, particularly lysine methylation regulated by methyltransferases (KMTs) and demethylases (KDMs), have emerged as key drivers of HNSCC initiation, progression, and cellular plasticity. This review aims to comprehensively evaluate the role of selected KMTs and KDMs in HNSCC biology, with a focus on their contribution to resistance to immunotherapy, radiotherapy, and cytotoxic chemotherapy. We summarize and critically analyze preclinical and clinical studies investigating histone methylation dynamics in HNSCC, with particular emphasis on enzymes such as KMT2C/D, EZH2, NSD1/NSD2, SMYD3, G9a/EHMT2, LSD1, KDM2A/B, KDM3, KDM4, KDM5, KDM6, KDM7, and KDM8. Attention is given particularly to pharmacological approaches targeting these proteins: we discuss small-molecule inhibitors of EZH2, LSD1, KDM4/5/6, and other KMT/KDMs that are currently in preclinical development or in early clinical trials, and we highlight completed and ongoing studies testing EZH1/2 inhibitors and epigenetic combinations in patients with recurrent and metastatic HNSCC. The deregulation of specific KMTs and KDMs reshapes histone methylation at key residues, thereby controlling cell cycle progression, epithelial–mesenchymal transition (EMT), stem cell phenotypes, DNA damage responses, and multiple interactions with the immune system in HNSCC. Targeting disrupted histone methylation pathways may partially reverse the epigenetic reprogramming of HNSCC cells and represents a promising strategy to improve treatment efficacy in patients with advanced disease. We also summarize the preclinical evidence and the currently limited clinical data on targeting histone methylation dynamics in HNSCC and discuss their therapeutic implications. Full article

Background/Objectives: Oral squamous cell carcinoma (OSCC) remains clinically heterogeneous, and prognosis is not always fully explained by conventional clinicopathological parameters. Systemic inflammation and tumor metabolic alterations may provide complementary information on tumor biology. This study aimed to assess associations between preoperative inflammatory markers, isotope ratio mass spectrometry (IRMS)-derived tumor signatures, clinicopathological features, and survival outcomes in OSCC. Methods: This exploratory retrospective secondary analysis included 50 consecutive patients with surgically treated, histologically confirmed OSCC. Preoperative blood-based markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), white blood cell count, lymphocyte count, and C-reactive protein, were retrieved from routine laboratory tests. Matched tumor, surgical margin, and healthy oral mucosa samples were analyzed by IRMS for δ¹³C, δ¹⁵N, carbon and nitrogen content, and [N]/[C] ratio. Associations with clinicopathological variables, nodal status, overall survival (OS), and disease-free survival (DFS) were evaluated using non-parametric tests, Spearman correlations, and Cox regression models. Results: Tumor tissue showed a consistent isotope and elemental phenotype compared with healthy mucosa, including higher nitrogen content, lower carbon content, increased [N]/[C] ratio, lower δ¹⁵N, and less negative δ¹³C values. NLR, PLR, SII, and CRP were not robustly associated with standard clinicopathological features after correction for multiple testing. Correlations between inflammatory and isotope-derived parameters were modest. Higher NLR was associated with worse OS and DFS and remained significant after adjustment for pathologic nodal status. Less negative tumor δ¹³C showed a potential adverse prognostic signal. Conclusions: Systemic inflammatory markers and IRMS-derived tumor signatures appear to reflect partly distinct biological domains in OSCC. NLR may provide accessible prognostic information, while tumor δ¹³C warrants further validation as a metabolic biomarker. Full article

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) remains a highly aggressive malignancy with poor clinical outcomes. Although poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in tumors with homologous recombination deficiency, their efficacy in BRCA wild-type HNSCC remains limited. Reactive oxygen species (ROS)-induced DNA damage may increase cellular dependence on DNA repair pathways and thereby enhance sensitivity to PARP inhibition. This study investigated whether ROS-mediated DNA damage could sensitize BRCA wild-type HNSCC cells to the PARP inhibitor olaparib. Methods: BRCA wild-type HSC-3 and SCC-25 HNSCC cell lines were exposed to H₂O₂ to induce oxidative stress. Intracellular ROS levels were quantified using DCFDA assays, DNA double-strand breaks were evaluated by γ-H2AX ELISA, PARP activity was assessed by ELISA, and cell viability was determined using MTT assays. Expression levels of DNA repair genes (PARP1, PARP2, BRCA1, BRCA2, RAD51, and MLH1), checkpoint kinases (ATM, ATR, and CHK1), the homologous recombination regulator FANCD2, and redox defense genes (NQO1, GPX4, and SLC7A11) were analyzed by qRT-PCR. Therapeutic selectivity was assessed using HGF-1 normal human gingival fibroblasts as a normal cell control. Apoptosis was measured through caspase-3/7 activity assays, and drug interactions were evaluated using the Chou–Talalay method. Results: H₂O₂ treatment increased intracellular ROS levels in both cell lines, accompanied by significant induction of DNA damage as demonstrated by elevated γ-H2AX levels. ROS induction markedly enhanced olaparib sensitivity, significantly reducing IC₅₀ values in both HSC-3 and SCC-25 cells. Combined H₂O₂ and olaparib treatment produced strong synergistic cytotoxicity, suppressed DNA repair, checkpoint kinase, and redox defense gene expression, and increased caspase-3/7 activity compared with control cells. Importantly, the combination demonstrated selective cytotoxicity toward cancer cells, with normal HGF-1 cells retaining significantly higher viability. Conclusions: ROS-induced DNA damage significantly enhances the anti-tumor activity of olaparib in BRCA wild-type HNSCC cells through a functional synthetic lethal-like interaction involving the simultaneous collapse of DNA repair capacity, checkpoint activation, and oxidative stress buffering, culminating in apoptosis induction. These findings support the rationale for combining ROS-generating therapies with PARP inhibitors in HNSCC treatment. Full article

Oral squamous-cell carcinoma (OSCC) is a prevalent malignancy of the head and neck region. A delay in the diagnosis of OSCC often results in a high metastatic tendency, which is the main reason for the high patient mortality. Dynamic monitoring and management of the onset and progression of OSCC are critical for improving patient survival rates. Liquid biopsy technology—characterized by its non-invasive nature, procedural convenience, and capacity for longitudinal monitoring—is a promising adjunct to histopathological examination for the early diagnosis of OSCC. Epigenetic alterations, characterized by reversibility and long-term stability in physiological fluids, are critical enablers of liquid biopsy and its clinical utility. Advances in detection technologies, including quantitative polymerase chain reaction (qPCR), digital droplet PCR (ddPCR), next-generation sequencing (NGS), and electrochemical biosensors, have significantly facilitated the research and clinical translation of epigenetic biomarkers in oral liquid biopsies. However, translating epigenetic biomarkers from research discovery to clinical practice for OSCC remains hindered by several critical challenges: the scarcity of large-scale, rigorously designed cohort studies, limited multicenter validation, inconsistent preprocessing protocols, and a lack of harmonized analytical platforms. Finally, we propose a conceptual framework to outline potential clinical application models for these biomarkers. Full article

Background: Comparative oncology uses naturally occurring cancers in companion animals to study tumor biology and therapeutic responses relevant to human cancer. Spontaneous feline tumors are increasingly recognized as useful comparative models because they arise in immunocompetent hosts, develop under shared environmental exposures, and can reproduce selected clinical, histopathologic, molecular, and therapeutic features of human malignancies. Methods: This review compares feline oral squamous cell carcinoma (FOSCC) with human head and neck squamous cell carcinoma (HNSCC), and feline mammary carcinoma (FMC) with human breast cancer, emphasizing shared pathologic, molecular, tumor microenvironment, and therapeutic features. Results: Recent immunohistochemical, genomic, transcriptomic, and biomarker studies have identified shared features between feline and human cancers. FOSCC resembles human HNSCC through aggressive local invasion, histologic features, therapeutic resistance, and recurrent alterations of TP53, MYC, and PTEN. FMC shows strong overlap with aggressive human triple-negative breast cancer, including reduced hormone receptor expression, recurrent TP53, PIK3CA, and CXCL12/CXCR4 signaling alterations, and tumor microenvironment features involving immune-checkpoint, inflammatory, and angiogenic pathways. FOSCC clinical trials and emerging clinical investigations into FMC treatments further support the use of cats for translational therapy evaluation. Conclusions: FOSCC and FMC are promising comparative oncology models for human HNSCC and aggressive breast cancer, respectively. Future multicenter studies incorporating standardized tumor classification and grading, predefined stratification criteria, and clinically meaningful endpoints will be essential to strengthen their translational value. Full article

Objective: We aimed to investigate the effects of traditional acupuncture combined with auricular acupressure on quality of life in patients with head and neck squamous cell carcinoma undergoing radiotherapy. Study Design: This is a two-arm, parallel, randomized clinical trial with blinded outcome assessment. The study population comprised 107 patients (55 without intervention and 52 with intervention). Data were collected at Dilson Godinho Hospital in Brazil from March 2017 to June 2018, and all patients provided informed consent and were registered under the UTN U1111-1204-8410/RBR-10v5gcdk. Patients in the intervention group received traditional and auricular acupressure in weekly sessions during their radiotherapy treatment, and patients in the control group received no acupuncture. In addition, quality-of-life assessment data were collected using the WHOQOL-BREF instrument. Results: Analysis of the scores obtained in the WHOQOL-BREF before and after radiotherapy demonstrated that the use of traditional and auricular acupressure had a positive impact on physical, psychological, social, environmental, and overall quality of life. Conclusions: Our findings suggest benefits and provide a context for patients and physicians to decide if acupuncture is a desirable treatment option. However, further studies are required to understand the therapy’s effectiveness better. Full article

Oral diseases, encompassing conditions such as periodontitis, head and neck squamous cell carcinoma, pulpitis, and mucosal infections, remain a major global health burden due to their high prevalence and complex, multifactorial pathophysiology. The unique anatomical structure of the oral cavity, together with persistent microbial challenges and dynamic immune responses, imposes substantial limitations on conventional drug delivery strategies. Biomimetic cell membrane-based materials have recently emerged as a promising class of delivery platforms, leveraging natural biological interfaces to confer inherent biocompatibility, immune evasion, prolonged circulation, specific targeting, and biofilm-interactive capabilities. These features position them as a transformative approach for improving therapeutic precision and efficacy in oral disease management. In this review, we provide a systematic and materials-oriented overview of biomimetic cell membrane-based drug delivery systems. Specifically, we discuss: (1) the biological sources, classification, and physicochemical properties of membrane-coated systems, along with their fabrication and engineering strategies; (2) the mechanistic basis of targeting, immune modulation, and nanobiointerface interactions, and their applications across representative oral diseases; and (3) current challenges, including scalable manufacturing, functional controllability, biosafety, and clinical translation. Furthermore, we highlight emerging directions such as stimuli-responsive membrane systems and multifunctional integrated platforms, aiming to provide a conceptual framework for the rational design and clinical advancement of biomimetic drug delivery systems in complex disease settings. Full article

Background/Objectives: Oral cavity squamous cell carcinoma (OSCC) remains a major global health burden, with outcomes strongly dependent on stage at diagnosis. Although the oral cavity is directly accessible to clinical examination, many cases are still detected at advanced stages. This narrative review aimed to summarize current trends in OSCC diagnosis and early monitoring, with emphasis on non-invasive and minimally invasive techniques and biomarkers. Methods: A semi-systematic narrative literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science using predefined combinations of OSCC-, early-detection-, imaging-, cytology-, liquid-biopsy-, salivaomics-, artificial-intelligence-, and biosensor-related terms. English-language systematic reviews, meta-analyses, reviews of reviews, translational studies, and clinically relevant original articles were prioritized, with explicit attention to oral cavity-specific evidence and clearly identified extrapolation from broader head-and-neck or oropharyngeal cancer settings. Results: Conventional oral examination and histopathological assessment of biopsy specimens remain the diagnostic foundation. Adjunctive methods may support lesion triage, biopsy-site selection, risk stratification, and early monitoring, but cannot replace tissue diagnosis. Narrow-band imaging, optical coherence tomography, and molecular brush cytology appear particularly promising for specialist assessment and surveillance. Liquid biopsy and saliva-based biomarker platforms offer translational potential, particularly for repeatable monitoring, but clinical implementation is limited by methodological heterogeneity, pre-analytical variability, inconsistent thresholds, and insufficient external validation. Artificial intelligence and biosensor platforms remain promising but largely developmental. Conclusions: Progress in early OSCC diagnosis and monitoring will most likely depend on integrated diagnostic models combining clinical examination, adjunctive imaging, minimally invasive sampling, molecular biomarkers, and computational decision-support tools, validated in prospective multicenter studies. Full article

Background/Objectives: Human papillomavirus (HPV) is a well-established prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC); however, the short-term treatment response remains heterogeneous, particularly among HPV-positive patients. Given the high prevalence of malnutrition in head and neck cancer, this study examined whether baseline nutritional status, body composition and functional status were associated with early treatment response in OPSCC according to HPV status. Methods: A prospective observational multicenter cohort study of newly diagnosed OPSCC patients eligible for curative-intent treatment was conducted at three tertiary hospitals in Barcelona, Spain. Baseline assessments comprised anthropometry, computed tomography (CT)-based body composition at L3, functional performance tests, systemic inflammatory biomarkers and nutritional diagnosis by the Patient-Generated Subjective Global Assessment (PG-SGA). Early treatment response, assessed around 12 weeks post-therapy, was classified as complete remission (CR) or non-complete remission (NCR). Classification tree analyses were performed separately by HPV status. Results: Of 101 enrolled patients, 97 completed post-treatment assessment, of whom 51% were HPV-positive. Among HPV-positive patients, PG-SGA score was the main discriminating variable for early response within the classification tree model, with CR achieved in 74% of patients scoring <6 versus 33% of those scoring ≥6 (AUC 0.68, 95% CI 0.55–0.82). Conversely, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and age were the primary discriminating variables in HPV-negative patients (AUC 0.81, 95% CI 0.70–0.93). In both HPV subgroups, body composition and inflammatory markers were not retained in the analysis once nutritional and functional status were considered. Conclusions: PG-SGA-defined nutritional status was associated with early treatment response in HPV-positive patients, while functional status was the main variable retained in HPV-negative patients. These findings support the potential clinical value of standardized nutritional assessment in OPSCC and suggest that early identification of poor nutritional status or functional impairment may help refine supportive care planning at treatment initiation. Full article

Head and neck cancer (HNC), particularly oral squamous cell carcinoma (OSCC), remains a major clinical challenge due to its aggressive behavior, high recurrence rates, and frequent resistance to conventional therapies. Natural compounds, especially curcumin and its derivatives, have gained increasing attention as potential anticancer agents due to their ability to target multiple molecular pathways involved in tumor progression. This review critically evaluates the current preclinical and translational evidence supporting curcumin and its derivatives as monotherapeutic agents in HNC, with particular emphasis on oral cancer. We integrate the available evidence to assess the biological rationale, therapeutic potential, and current limitations of curcumin-based approaches. The molecular mechanisms underlying their antitumor activity are discussed, including modulation of EGFR/ERK and PI3K/Akt signaling pathways, inhibition of NF-κB and STAT3 activation, induction of apoptosis, regulation of oxidative stress, and suppression of epithelial–mesenchymal transition and tumor invasiveness. In addition, we address the impact of curcumin on the tumor microenvironment and its role in overcoming intrinsic cellular resistance mechanisms. The review also highlights advances in drug delivery strategies, such as nanoformulations, that are designed to improve curcumin’s bioavailability and therapeutic efficacy. By critically integrating current evidence, this review highlights both the promise and the challenges associated with curcumin-based monotherapy in HNC, emphasizing the need for more robust and clinically relevant studies to support future translation. Full article

Radiomics has the potential to improve risk stratification in head and neck squamous cell carcinoma (HNSCC), but clinical adoption is limited by inconsistent performance across institutions. A key source of variability is how radiomic features are generated, preprocessed, and selected prior to model development. This multicenter study evaluated how radiomics parameterization and feature selection strategies affect external model performance, feature stability, and time-to-event risk stratification. We studied pre-treatment CT scans from 752 patients with primary HNSCC from three hospitals. For each scan, 1648 radiomic features were computed using 20 different preparation methods that varied in scaling, outlier removal, and gray-level bin width. We compared five feature selection methods: Graph-FS with connected components, Boruta, Lasso, RFE-RF, and mRMR. The classification models used were Random Forest, XGBoost, CatBoost, and Logistic Regression. We measured performance using external ROC-AUC, bootstrap confidence intervals, Brier score, and RobustScore. Stability of feature selection was assessed using the Kuncheva and Jaccard indices. Cox proportional hazards models confirmed time-to-event results, and consensus SHAP analysis helped explain the models. Radiomics parameterization influenced model performance, and no single configuration was optimal across all analyses. Radiomics-only models outperformed clinical-only models, while clinical–radiomics models achieved the highest overall performance. mRMR and Lasso produced the highest average external AUCs, while Graph-FS showed the greatest stability. The best classification model achieved an external AUC of 0.817. In Cox validation, the best clinical–radiomics configuration achieved an external C-index of 0.662 and separated high- and low-risk patients in the external cohort. Full article

Supportive care is essential during chemotherapy for head and neck cancer, yet the role of traditional Japanese medicine (kampo) remains unclear; therefore, we investigated whether Ninjin’yoeito (NYT) could reduce adverse events during cisplatin-based chemotherapy. We retrospectively analyzed 47 patients treated between June 2022 and June 2024, dividing them into an NYT group and a control group. Hematological toxicities, including decreases in white blood cells, neutrophils, hemoglobin, and platelets, as well as gastrointestinal disorders such as nausea, were evaluated. Compared with controls, patients receiving NYT showed significantly lower incidences of decreased white blood cell counts (p = 0.04), decreased hemoglobin levels (p = 0.03), and gastrointestinal disorders (p = 0.04). Trends toward reduced neutropenia and thrombocytopenia were also observed, although these did not reach statistical significance. These findings suggest that NYT may help mitigate hematological and gastrointestinal toxicities associated with cisplatin-based chemotherapy in patients with head and neck cancer. However, given the retrospective design and limited sample size, prospective studies are needed to confirm the efficacy and safety of NYT in this setting. Full article

Head and neck squamous cell carcinoma (HNSCC) remains one of the most aggressive and heterogeneous malignancies worldwide, characterized by high rates of locoregional recurrence, metastatic dissemination, and therapeutic resistance. Angiogenesis plays a central role in tumor progression by supporting vascular remodeling, hypoxia adaptation, invasion, immune evasion, and metastatic spread. In HNSCC, angiogenic activation is regulated through complex interactions involving hypoxia-inducible factors, vascular endothelial growth factor (VEGF) signaling, stromal remodeling, inflammatory pathways, and epigenetic mechanisms within the tumor microenvironment. Recent evidence has also highlighted the role of non-coding RNAs, particularly microRNAs, and exosome-mediated communication in modulating angiogenic and immune-related signaling pathways. Although antiangiogenic therapies, including monoclonal antibodies and tyrosine kinase inhibitors, have demonstrated biological activity in HNSCC, their clinical efficacy remains limited by tumor heterogeneity, adaptive resistance mechanisms, toxicity, and the lack of validated predictive biomarkers. Several emerging therapeutic strategies are under preclinical or early clinical investigation in HNSCC, including miRNA-based approaches, nanoparticle-assisted delivery systems, vascular normalization concepts, and combinations with immune checkpoint inhibitors; however, robust clinical evidence for most of these strategies remains limited, and their translation to routine practice requires further validation. This review provides a comprehensive overview of the molecular mechanisms regulating angiogenesis in HNSCC and critically discusses current and emerging pharmacological strategies targeting these pathways. Particular emphasis is placed on VEGF/VEGFR signaling, the integration of miRNA and exosome biology, resistance mechanisms, and translational perspectives for biomarker-guided personalized therapy. The novelty of this review lies in the systematic integration of miRNA- and exosome-mediated angiogenic regulation, therapeutic resistance pathways, and precision medicine strategies into a unified pharmacological framework, addressing gaps not fully covered by prior reviews focused primarily on VEGF-targeted agents. Full article

Background: Spread through air spaces (STAS) is a recognized histologic pattern of invasion associated with poor prognosis in non-small-cell lung cancer (NSCLC), particularly adenocarcinoma. However, its presence in pulmonary squamous cell carcinoma (SCC), whether primary or metastatic, remains largely unexplored. Given the limited available evidence, this study was designed as an exploratory analysis to evaluate the prevalence and potential prognostic significance of STAS in pulmonary SCC. Material and Methods: In this exploratory retrospective study, we analyzed 57 patients who underwent surgical resection for pulmonary squamous cell carcinoma (P-SCC) at the Department of Thoracic Surgery at the University Hospital Erlangen between 2008 and 2020. The cohort included both primary lung SCC and metastatic SCC to the lung from extrapulmonary sites, primarily from ear, nose, and throat (ENT) tumors. Histological slides were reviewed to assess the presence of STAS, as defined by established morphological criteria. The Chi-square test was used to investigate the presence of STAS. Disease-free survival (DFS) and overall survival (OS) was evaluated using Kaplan–Meier analysis, and the prognostic impact of STAS along other variables were assessed using Cox proportional hazards regression. Results: A total of 57 patients with squamous cell carcinoma (SCC), 22 (39%) had primary lung SCC and 35 (61%) had metastatic SCC from head and neck tumours (ENT). Spread through air spaces (STAS) was detected in 20 patients (35%). Disease-free survival (DFS) differed according to primary tumour location (p-value of 0.009), with higher 1-, 3-, and 5-year DFS in patients with primary lung SCC (86.4%, 77.3%, 63.3%) than in those with head and neck SCC (54.3%, 31.4%, 22.2%). DFS was also significantly higher in patients undergoing solitary resections compared with multiple resections (78.6%, 64.3%, 49.5% vs. 33.3%, 6.7%, not estimable; p-value < 0.001). DFS was slightly longer in STAS-negative patients compared with STAS-positive patients (1-, 3-, 5-year DFS: 64.9%, 51.4%, 40.5% vs. 70%, 45%, not estimable), (median DFS 36 vs. 25 months; p-value of 0.776). Overall survival (OS) was significantly longer in patients with primary lung SCC (median OS 125 months) than in those with head and neck SCC (27 months; p-value of 0.039). STAS-negative patients had also a longer OS than STAS-positive patients (median OS 46 vs. 38 months; HR = 1.11, 95% CI 0.56–2.20; p-value of 0.771). Conclusions: STAS was identified in metastatic pulmonary SCC lesions as well as in primary lung SCC, occurring in approximately one-third of cases. However, due to the limited cohort size and the exploratory univariate design of the study, the prognostic significance of STAS could not be definitively established and requires further investigation in larger, adequately powered studies. Full article