Search Results (1,562)

Oral cancer is a significant public health concern and is among the most common malignant tumors of the head and neck. Its incidence and mortality rates remain persistently high, especially in regions where smoking and betel nut chewing are prevalent. Due to its high mortality rate, early detection is crucial for improving patient outcomes. However, early symptoms of oral cancer often resemble benign oral lesions, leading to delayed diagnosis. In this study, a vision transformer (ViT) model with Optuna (ViTOPT) is employed to perform classification tasks of identifying oral cancer images. The Optuna is used to determine hyperparameters in ViT. Histological images are obtained from a publicly available dataset. Three classification tasks with histological images namely classifying oral squamous cell carcinoma (OSCC) and leukoplakia (LEUK), classifying the presence of dysplasia, and classifying OSCC and leukoplakia with or without dysplasia are performed in this study. Numerical results reveal that the proposed ViTOPT framework is able to provide satisfactory performance in oral cancer recognition. Thus, the proposed ViTOPT model is a feasible and effective alternative in identifying oral cancer. Full article

Oral squamous cell carcinoma (OSCC), comprising ~90% of oral malignancies, remains a major global health burden with rising incidence despite declining tobacco use. While tobacco and alcohol are classic dominant risk factors, a distinct subgroup of nonsmoking, nondrinking (NSND) patients is increasingly recognized, accounting for 15–35% of OSCC cases in many cohorts, particularly in developed countries. This emerging epidemic shows striking demographic patterns: strong female predominance (often 65–77% of cases), bimodal age distribution with peaks in young adults (<45 years) and elderly individuals (>70 years), and overrepresentation among non-Hispanic White and certain Asian populations. Unlike traditional habit-related OSCC, which favors the floor of the mouth in older males, NSND tumors predominantly arise on the lateral tongue, gingiva, and buccal mucosa. Etiopathogenesis extends far beyond conventional carcinogens and involves multifactorial mechanisms, including chronic mechanical irritation from dental factors, oral microbiome dysbiosis enriched with periodontal pathogens (e.g., Fusobacterium nucleatum and Porphyromonas gingivalis), limited roles for viruses (minimal HPV contribution, possible EBV or “hit-and-run” HSV effects), genetic susceptibilities (e.g., Fanconi anemia and CDKN2A mutations), epigenetic changes, hormonal influences contributing to female bias, metabolic conditions (diabetes and hyperlipidemia), poor oral hygiene, and chronic inflammation. NSND OSCC frequently exhibits a distinct immunological profile with higher tumor-infiltrating lymphocytes and PD-L1 expression, potentially favoring immunotherapy, though prognosis remains heterogeneous—better in some cohorts due to fewer comorbidities, yet worse in young patients with higher recurrence and second primary tumor risks. Delayed diagnosis is common due to low suspicion in “low-risk” individuals. This review underscores NSND OSCC as a unique entity requiring expanded risk assessment, heightened clinical vigilance for persistent oral lesions regardless of habit history, and targeted research into novel prevention and therapeutic strategies. Full article

Background and Objectives: This study aimed to detect and genotype human papillomavirus (HPV) in tissues from oral squamous cell carcinoma (OSCC), oral potentially malignant disorders (OPMD), and healthy individuals. Materials and Methods: The study included 60 patients (31 men and 29 women; median age 60 years, IQR 41.5–69.8) admitted to the Department of Dental, Oral and Maxillofacial Surgery, Medical University of Sofia. Patients were divided into three groups: healthy oral mucosa (n = 20), OPMD (n = 20), and OSCC (n = 20). HPV was tested using punch biopsies with nested PCR and chip technology. Results: Low-risk HPV was found in four (20%) healthy individuals (types 6/11, 43), seven (35%) OPMD patients (types 6/11, 42, 43), and eleven (55%) OSCC patients (types 6/11, 42, 43). Pairwise comparison showed a significant difference in HPV positivity between healthy individuals and OSCC patients (p = 0.022). Among all HPV-positive OPMDs, the virus was detected in two leukoplakia cases (28.6%), three lichen planus cases (42.9%), one lichenoid lesion case (14.3%), and one proliferative verrucous leukoplakia case (14.3%). According to binary logistic regression, OSCC patients were 4.9 times more likely to be HPV-positive compared to healthy individuals (p = 0.027). Conclusions: HPV infection may play a potential role in the pathogenesis of OPMD and OSCC. Full article

Background/Objectives: The present study aims to test three different types of PMMA (Fotodent Guide—3D printed (M1), Aidite Temp—milled (M2), Duracryl—self-polymerized (M3) on HFIB-G and on OECM-1. Methods: The two cell types (HFIB-G and OECM-1) were kept in contact with the materials, Fotodent Guide, Aidite Temp, and Duracryl (n = 6), for 24 and 48 h, and subsequently subjected to the following tests: MTT, LDH, NO (according to ISO 10993-5:2009), and immunofluorescent detection of proteins associated with autophagy and apoptosis (mitochondria and caspases 3/7; detection of autophagosomes). Statistical interpretation was made using t-test and ANOVA (* p < 0.05; ** p < 0.01; *** p < 0.001). Results: The MTT assay revealed a reduction in cell viability for all tested materials on gingival fibroblasts compared to control cells, with the most pronounced decrease observed for the 3D-printed material (M1 viability 66.77% for 24 and 52.45% 48 h—p < 0.001), while the self-polymerizing resin (M3 viability 85.92% for 24 h and 85.63% for 48 h) showed the highest level of cellular tolerance (p < 0.001 at 24 h and p < 0.01 at 48 h). Regarding OECM-1 cells, all materials reduced cell viability, particularly M3 after 48 h of incubation (viability 61.79%—p < 0.001). LDH levels generally indicated low membrane damage for all materials. Statistically significant increases in NO levels were recorded for both cell types, suggesting a mild proinflammatory response, especially for M2 OECM-1 48 h—p < 0.05 and M3 (HFIB-G 48 h—p < 0.05, OECM-1 48 h p < 0.05). For both 24 and 48 h, fluorescence analysis demonstrated a significant increase in mitochondrial activity in gingival fibroblasts (p < 0.001), whereas tumor cells exhibited a significantly decreased mitochondrial activity (p < 0.001), particularly for the 3D-printed material M1 (p < 0.001). Caspase-3/7 expression increased in gingival fibroblasts incubated with materials for 24 and 48 h (p < 0.001), while tumor cells showed reduced caspase activity both after 24 and 48 h (p < 0.001). Autophagosome formation decreased initially in fibroblasts at 24 h (p < 0.001) but increased significantly after 48 h (p < 0.001), while tumor cells generally showed enhanced autophagic activity under most experimental conditions (p < 0.001). Conclusions: Our results suggest that all three PMMA-based materials exhibit acceptable biocompatibility profiles, of more than 70%, according to ISO 10993-5:2009, although cellular responses vary depending on the manufacturing technique and the cellular model used. In our study conditions, self-polymerized resin (M3) was the most compatible with gingival fibroblasts, while the 3D-printed and CAD/CAM milled materials (M1 and M2) had a more pronounced impact on cells’ viability and metabolic activity. Full article

Postoperative surgical draining fluid (SDF) in oral squamous cell carcinoma (OSCC) was reported to contain circulating free DNA and extracellular vesicles (EVs). The potential role of SDF DNA as a cancer biomarker in OSCC patients is investigated. To determine whether EVs contribute to the DNA content of SDF, small EVs (sEVs) were isolated by size exclusion chromatography and compared with those in paired plasma. sEV obtained from a cohort of HPV(+) and HPV(−) patients were evaluated for the endocytic origin, size, vesicular morphology, and the DNA content. The sEV from HPV(+) and HPV(−) SDF were similar. The sEVs from SDF were larger and contained more DNA than the sEV from plasma. Treatments of sEV with the DNase/RNase cocktail established the presence of DNA on the surface and in the sEV lumen. Furthermore, 20 to 30% of the total SDF DNA was associated with sEV. Fragmentomic analyses identified the largest DNA (>10,000 bp) on the vesicle surface. The DNA in the vesicle lumen consisted of smaller (~5000 bp) DNA fragments. Electron microscopy of the enzyme-treated vesicles indicated that surface DNA/RNA may be involved in maintaining vesicular integrity and modulating the vesicle entry into cells. The sEV-carrying surface and luminal DNA emerge as significant contributors to the total SDF DNA and, following validation, might serve as useful biomarkers of disease presence/progression in OSCC. Full article

Oral squamous cell carcinoma (OSCC) is a biologically heterogeneous malignancy with poor clinical outcomes. Hypoxia and lipid metabolic reprogramming are important drivers of OSCC progression and treatment adaptation, and these processes are biologically interconnected. However, prognostic studies integrating hypoxia- and lipid metabolism-related features in OSCC remain limited. Here, transcriptomic data from TCGA-HNSC-OSCC were integrated with curated hypoxia- and lipid metabolism-related genes to identify candidate genes, construct a prognostic signature, and characterize its biological relevance through enrichment analysis, immune profiling, single-cell RNA-sequencing analysis, and RT-qPCR validation. A four-gene signature consisting of STC2, CAV1, ACADL, and PLA2G2D showed stable prognostic performance in the TCGA-HNSC-OSCC cohort and the external validation cohort GSE41613. The risk signature remained significantly associated with overall survival after adjustment for clinicopathological factors and retained prognostic discrimination across stage- and nodal status-defined subgroups. The high- and low-risk groups displayed distinct pathway, immune, mutational, and predicted drug sensitivity features. Notably, PLA2G2D showed the strongest association with differential immune infiltration, whereas single-cell analysis identified endothelial cells as a major CAV1-enriched population with active intercellular communication and dynamic state transitions. These findings define a hypoxia- and lipid metabolism-related prognostic signature and support its relevance to immune remodeling and endothelial cell context in OSCC. Full article

Background/Objectives: Allomyrinasin is a cationic antimicrobial peptide derived from Allomyrina dichotoma larvae with known antibacterial and anti-inflammatory properties; however, its effects on migration-related mechanisms in oral squamous cell carcinoma (OSCC) remain poorly understood. This study investigated the anti-migratory potential of allomyrinasin in OSCC cells, focusing on Na⁺/HCO₃⁻ cotransporter (NBC) activity as a key migratory module. Methods: NBC activity was assessed in YD-38 OSCC cells treated with allomyrinasin. Cell migration was evaluated by wound healing and Transwell assays, and MMP expression. Intracellular reactive oxygen species (ROS), apoptosis-related markers, and lamin A/C expression were analyzed using fluorescence-based assays and gene expression analysis. Results: Allomyrinasin inhibited NBC activity and suppressed cell migration without substantial loss of cell viability. MMP-13 was selectively downregulated among the tested MMPs. Lamin A/C expression was markedly upregulated, suggesting enhanced nuclear stiffness that may restrict confined cell migration. Intracellular ROS levels were elevated, and apoptotic progression was confirmed by increased Annexin V/PI positivity along with downregulation of B-cell lymphoma 2 (BCL2) and upregulation of BCL-2–associated X genes (BAX), through a p53-independent pathway consistent with the TP53-deleted status of YD-38 cells. Conclusions: Allomyrinasin suppresses OSCC cell migration by targeting NBC activity as a key component of the migratory machinery, accompanied by oxidative stress induction and pro-apoptotic signaling. These findings identify allomyrinasin as a potential anti-migratory therapeutic candidate and highlight NBC activity as a promising target for attenuating cancer metastasis. Full article

The phenotypic plasticity of epithelial cells along the epithelial–mesenchymal (E-M) axis, or epithelial–mesenchymal transition (EMT), is a critical aspect of tumour progression and therapeutic resistance. During EMT, epithelial cells gradually acquire mesenchymal traits, facilitating vital functions in embryogenesis, wound healing, fibrosis, and tumour metastasis. This review article investigates the potential interplay between hyperglycaemia-induced metabolic stress and EMT in the context of therapeutic resistance. The study examines a complex, multifaceted network of molecular mechanisms regulating EMT, including specialised transcription factors and signalling pathways as well as growth factors, integrins, and matrix metalloproteinases in various epithelial carcinomas. Emerging findings have demonstrated the existence of EMT hybrid states along the continuum, possessing heightened metastatic potential and distinctive metabolic signatures that play critical roles in the development of therapeutic resistance in cancer cells. Hyperglycaemia has been particularly highlighted for its potential to promote EMT-driven therapeutic resistance through various interconnected mechanisms. Elevated glucose levels induce the increased production of reactive oxygen species (ROS), activation of EMT-promoting transcription factors, and a metabolic shift towards glycolysis. This hyperglycaemic stress involves upregulation of glucose transporters and glycolytic enzymes, creating feed-forward loops that support drug efflux mechanisms and help maintain the mesenchymal phenotype. Clinical data also indicate that hyperglycaemia in OSCC patients is associated with more advanced tumour stages, more extended hospital stays, less effective treatments, and higher rates of local recurrence and distant metastasis. Overall, these insights reveal a deleterious feed-forward loop in which hyperglycaemia promotes EMT-driven therapeutic resistance, with the strongest clinical evidence in oral squamous cell carcinoma (OSCC) and supportive data from pancreatic and breast cancers. Although glycaemic control represents a promising low-risk adjunctive approach, its clinical benefit remains to be validated in prospective interventional studies. Full article

Background: The optimal role of induction chemotherapy (IC) in the management of oral cavity squamous cell carcinoma (OCSCC) remains controversial. This study compared oncologic outcomes between IC followed by surgery and concurrent chemoradiotherapy (CCRT) and upfront surgery followed by adjuvant CCRT. Methods: We retrospectively analyzed 98 patients with OCSCC treated between 2011 and 2017. Overall survival (OS), cancer-specific survival (CSS), and local control (LC) were evaluated using Kaplan–Meier survival analysis and Cox proportional hazards models to identify prognostic factors. Results: Fifty patients received IC and 48 underwent upfront surgery. With a median follow-up of 77.8 months, no significant differences in OS, CSS, or LC were observed between treatment groups (OS: HR 1.31, p = 0.415; CSS: HR 1.36, p = 0.421; LC: HR 1.29, p = 0.475). Positive surgical margins independently predicted inferior OS, CSS, and LC, while extracapsular spread was independently associated with inferior CSS. Although tumor downstaging was frequently observed after IC, it did not translate into survival benefit. Conclusions: IC followed by surgery was associated with no statistically significant differences in oncologic outcomes compared with upfront surgery followed by adjuvant CCRT. Prognosis was primarily determined by pathological risk factors rather than treatment sequence. Full article

Rationale: Oral squamous cell carcinoma (OSCC) carries a poor prognosis despite advances in multimodal therapy. Nanomedicine represents a compelling strategy to enhance targeted drug delivery and improve therapeutic outcomes. Here, we investigated sEV-mediated delivery of curcumin as a novel therapeutic approach for OSCC. Methods: Small extracellular vesicles (sEVs) were isolated from Jurkat cells by size-exclusion chromatography and loaded with curcumin via sonication to generate JCsEV. Functional effects were assessed in vitro using wound healing, transwell invasion, and metabolic activity assays across multiple cancer cell lines. Therapeutic efficacy in vivo was evaluated in the 4-nitroquinoline 1-oxide (4-NQO) immunocompetent murine model of oral carcinogenesis. Female C57BL/6J mice received intraperitoneal treatment for four weeks with PBS, free curcumin, unloaded JsEV, or JCsEV. Tumor number, tumor burden, and body weight changes were assessed at the experimental endpoint. Results: In vitro, JCsEV significantly inhibited tumor cell migration, invasion, and metabolic activity compared with controls (p < 0.05). In vivo, treatment with JCsEV significantly reduced tumor number and tumor burden in the 4-NQO model (p < 0.01). In addition, body weight loss was reduced in JCsEV-treated mice compared with controls. Conclusion: sEV-mediated delivery of curcumin effectively suppresses tumor progression in experimental OSCC. These findings establish proof-of-concept for sEV-based nanomedicine as a therapeutic strategy for OSCC and provide a compelling rationale for further translational investigation of sEVs as drug delivery platforms. Full article

Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, their functional significance in OSCC remains poorly understood. Methods: Immunohistochemical analysis was performed using surgically resected human tongue OSCC specimens and a tissue microarray (TMA) cohort. In parallel, four TAS2R agonists were evaluated in SCC7 cells to assess intracellular calcium responses. RNA sequencing was conducted to analyze transcriptional changes following diphenidol treatment, and functional assays, including proliferation, migration, and apoptosis analyses, were performed in vitro. Antitumor effects were further evaluated in a syngeneic SCC7 mouse model, followed by TUNEL staining and flow cytometry to assess apoptosis and immune cell infiltration. Results: TAS2R38 expression was markedly upregulated in dysplastic and invasive OSCC lesions with predominant nuclear localization and was associated with histological grade and clinical stage, indicating an early and sustained alteration during tumor progression. Among the agonists tested, diphenidol most strongly induced IP₃-dependent intracellular Ca²⁺ elevation. RNA sequencing revealed upregulation of Il1rl1 and Lzts2. Functionally, diphenidol significantly suppressed SCC7 cell proliferation and migration and induced apoptosis in vitro. In vivo, diphenidol reduced tumor volume and weight and increased apoptotic activity. Flow cytometry demonstrated a marked reduction in tumor-infiltrating CD4⁺CD25⁺Foxp3⁺ regulatory T cells, indicating modulation of the tumor immune microenvironment. Conclusions: TAS2R activation by diphenidol suppresses tumor growth through both tumor-intrinsic mechanisms and modulation of the tumor immune microenvironment in OSCC. These findings define TAS2R-mediated calcium signaling as a novel axis linking tumor progression and immunoregulation. Given that diphenidol is a clinically approved drug with an established safety profile, our results provide a strong rationale for TAS2R-targeted drug repurposing strategies in cancer therapy. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) remains a global public health challenge with significant morbidity and mortality. Emerging epidemiological data indicate a rising global incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). Serology for early HPV antigens has been highlighted as a relevant biomarker for HPV-associated OPSCC. This study aimed to determine the seroprevalence of HPV16 E6 antibodies in HNSCC patients in the state of Espírito Santo, Brazil. Methods: This is a prospective longitudinal cohort study in which 287 patients with HNSCC were enrolled, recruited from two oncology centers in Espírito Santo between 2011 and 2018, along with 68 cancer-free individuals. Serum samples were analyzed using the HPV16 E6 GST Capture ELISA assay. Statistical analysis was performed using SPSS. Binary logistic regression was employed to identify independent predictors of seropositivity. Results: The overall seroprevalence of HPV16 E6 antibodies was 7.3%. Seropositivity was observed in tumors of the oral cavity (6.2%) and oropharynx (13.3%). Patients with OPSCC demonstrated a significantly higher likelihood of seropositivity compared to those with tumors of the oral cavity, larynx, and hypopharynx (OR = 2.96, 95% CI: 1.21–7.28, p = 0.018). The highest frequency of HPV16 E6-positive cases occurred in tumors of the palatine tonsils (OR = 6.00; 95% CI: 1.58–22.89; p < 0.009). No seropositive cases were observed in hypopharyngeal or laryngeal tumors. Among patients with OPSCC and oral cavity squamous cell carcinoma (OCSCC), HPV16 E6 serostatus did not significantly correlate with sociodemographic, behavioral, or clinical tumor characteristics. Conclusions: Our findings reinforce the predilection of HPV-associated carcinogenesis for the oropharynx, more specifically in the palatine tonsils. In addition, this study highlights HPV16 E6 serology as a potential biomarker for HPV-driven OPSCC and underscores Brazil’s epidemiological heterogeneity, warranting standardized clinical validation. Full article

Purpose: Oral squamous cell carcinoma (OSCC) carries a substantial burden in low- and middle-income countries as well as underserved subpopulations within high-income settings, where structural barriers contribute to worse outcomes. While evidence supports targeted screening of high-risk groups, practical guidance for designing organized, quality-assured programs remains limited. This review proposes a framework to translate contemporary cancer-screening principles into operational criteria for OSCC. Methods: A review following the Scale for the Assessment of Narrative Review Articles was conducted. Conceptual papers, international evaluations, implementation studies, and programmatic guidance were included. The evidence was synthesized narratively, with emphasis on contemporary cancer-screening principles, implementation frameworks, and their applicability to OSCC. Results: Clinical oral examination can improve the detection of OSCC in early stages and reduce mortality among high-risk groups when embedded in coordinated care pathways. Effective programs require governance structures, screening policies, risk-stratified approaches, and robust information systems capable of call-recall, referral tracking, and quality monitoring. Dental schools and academic clinics might play a role as regional hubs and represent feasible anchors for programs within mixed health systems. Conclusions: Aligning core OSCC-screening principles with operational enablers offers a practical pathway to develop context-appropriate programs that strengthen capacity, promote equity, and generate evidence for responsible scale-up. Full article

Background/Objectives: Oral squamous cell carcinoma (OSCC) exhibits substantial biological heterogeneity, and current clinicopathological risk stratification incompletely reflects tumor metabolic behavior. Stable isotope ratio mass spectrometry enables the quantitative assessment of carbon and nitrogen isotopic composition, potentially capturing cumulative metabolic reprogramming associated with tumor aggressiveness. This study evaluated whether isotopic signatures of tumor tissue and surgical margins are associated with lymph node metastasis and survival outcomes in OSCC. Methods: In this prospective study, 54 consecutive patients undergoing primary surgical treatment for OSCC were enrolled. Paired samples derived from tumor tissue and surgical margins were analyzed using isotope ratio mass spectrometry to determine the relative abundance of nitrogen-15 and carbon-13 isotopes. The primary endpoint was pathological lymph node metastasis. Secondary endpoints included disease-free survival and overall survival. Paired comparisons were performed using Wilcoxon signed-rank tests with false discovery rate correction. Logistic regression models for nodal metastasis were constructed using Firth penalization with bootstrap internal validation, while survival outcomes were evaluated using Cox proportional hazards models with model complexity restricted according to the number of events. Results: Tumor tissues demonstrated significantly lower δ¹³C and δ¹⁵N values and higher nitrogen-to-carbon ratios compared with surgical margins (all adjusted p < 0.05). In multivariable analysis, tumor δ¹⁵N was independently associated with lymph node metastasis and modestly improved model discrimination. However, it was not independently associated with disease-free or overall survival. Exploratory analyses indicated that higher δ¹³C values in surgical margins were independently associated with shorter disease-free survival. Conclusions: These findings suggest that isotope ratio mass spectrometry-based isotopic profiling identifies reproducible metabolic differences between tumor and margin tissues in OSCC. Tumor δ¹⁵N is associated with lymph node metastasis, whereas margin δ¹³C may reflect recurrence risk and potentially capture metabolic field effects. These findings are hypothesis-generating and warrant validation in larger, independent cohorts. Full article