Search Results (105)

Background/Objectives: Conventional FDG PET parameters quantify metabolic intensity and volume but not the location of the metabolic hotspot, whose peripheral shift may reflect aggressiveness. In surgically treated oral tongue cancer (OTC), we evaluated two spatial PET metrics—the normalised distance from the hotspot to the tumour centroid (NHOCmax) and perimeter (NHOPmax)—in two parallel analyses: prognosis and measurement reproducibility. Methods: We retrospectively analysed 89 patients with preoperative FDG PET/CT. NHOCmax and NHOPmax were derived alongside conventional PET parameters. Associations with disease-free (DFS) and overall survival (OS) were assessed by uni and multivariable Cox models, and reproducibility was assessed across segmentation methods and by intra-reader repeatability. Results: Over a median 83.4/102.1-month follow-up (DFS/OS), 29 DFS and 25 OS events occurred. In the prognostic analysis, higher NHOCmax (OS HR 1.14, p = 0.032) and lower NHOPmax (DFS HR 0.65, p = 0.017; OS HR 0.65, p = 0.031) were associated with poorer survival upon univariable analysis. In the reproducibility analysis, both were robust to segmentation (intra-class correlation coefficient 0.94 for NHOCmax, 0.78 for NHOPmax); intra-reader repeatability was 0.69 and 0.94, respectively. Both metrics were less reproducible in low-volume tumours. Conclusions: NHOCmax and NHOPmax were associated with poorer survival, though not independently of stage and metabolic tumour volume, and were reproducible except in low-volume tumours; they warrant validation in larger cohorts. Full article

This study aimed to investigate the selective anticancer activity of the curcumin analog PAC (3,5-Bis-4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone). Normal gingival epithelial cells (GECs), cancerous gingival cells (Ca9-22) and tongue squamous carcinoma cells (CAL27) were exposed to increasing concentrations of PAC (0–10 µM) for 24 h. Cell viability and cytotoxicity were evaluated using MTT and LDH assays, while apoptosis and caspase activation were analyzed by Annexin V/PI staining and flow cytometry. Gene-expression profiling was performed using RT² Profiler PCR arrays. PAC significantly inhibited Ca9-22 and CAL27 cell proliferation in a concentration-dependent manner, with an IC₅₀ value of 5 µM, while exerting no noticeable cytotoxic effects on normal GEC. PAC treatment induced significant early and late apoptosis associated with increased caspase activity in both oral cancer cell lines. Transcriptomic analyses revealed extensive modulation of apoptosis-related genes. In Ca9-22 cells, PAC predominantly suppressed anti-apoptotic and survival-associated genes, including BCL2, BIRC3, BIRC5, XIAP, CFLAR, and NFKB1. In contrast, CAL27 cells exhibited a more pronounced pro-apoptotic transcriptional profile characterized by upregulation of TP53, APAF1, CASP1, BID, and TNF. Gene interaction network analyses further demonstrated that PAC targets highly interconnected apoptotic signaling pathways. Collectively, these findings demonstrate that PAC exerts potent selective anticancer activity against OSCC cells through modulation of intrinsic and extrinsic apoptotic pathways. These results further support the therapeutic potential of PAC as a promising multitarget candidate for oral cancer treatment. Full article

Background/Objectives: Oral tongue squamous cell carcinoma (OTSCC) remains clinically challenging because conventional clinicopathological markers do not fully explain variability in recurrence and survival. This systematic review and functional meta-synthesis aimed to identify and critically appraise studies using preoperative magnetic resonance imaging (MRI)-based radiomics, artificial intelligence (AI), deep learning, or quantitative MRI-derived models to predict recurrence and prognostic outcomes in OTSCC. Methods: PubMed, Scopus, and Embase were searched from inception to March 2026. Eligible studies included prognostic model investigations in adults with OTSCC or primary tongue cancer without reported base-of-tongue/oropharyngeal involvement, undergoing preoperative MRI and surgery, with recurrence- or survival-related follow-up. The primary synthesis was a functional meta-synthesis; pooling was not performed because studies were not sufficiently comparable. Results: Seven retrospective studies were included, with a summed descriptive sample of 1287 participants. The evidence base was heterogeneous in MRI sequences, segmentation workflows, model architecture, validation strategy, and endpoint definition. Functional meta-synthesis identified four domains: direct recurrence-oriented modeling, broader prognostic stratification, reported incremental or complementary value over clinical frameworks, and translational maturity/technical implementation. Several studies reported associations between MRI-derived signatures and recurrence- or survival-related outcomes, but findings were interpreted narratively because of differences in primary endpoints, imaging features, model design, validation methods, and outcome definitions. Most studies were judged at high overall risk of bias, and certainty of evidence ranged from low to very low. Conclusions: MRI-based radiomics and AI show preliminary promise for prognostic stratification in OTSCC, particularly recurrence-related risk refinement, but current evidence remains limited by retrospective design, heterogeneity, sparse external validation, and low certainty. Full article

Background: Late-stage presentation of oral cancer remains a major challenge in low- and middle-income countries and contributes substantially to poor clinical outcomes. Data describing oral cancer presentation patterns in Indonesia remain limited. This study aimed to characterize the clinicopathological profile, stage distribution, treatment patterns, and exposure-related characteristics of oral cancer patients treated at a national referral center in Indonesia. Methods: A retrospective study was conducted using medical records of 404 patients with histopathologically confirmed oral malignancies treated between 2021 and 2025. Descriptive analyses were performed to summarize demographic, clinicopathological, staging, treatment-related, and exposure-related characteristics. Results: The mean age at diagnosis was 49.17 ± 14.11 years, with a relatively balanced sex distribution. The tongue was the most common primary tumor site (76.0%), and oral squamous cell carcinoma (OSCC) represented the predominant histopathological diagnosis (81.9%). Late-stage presentation (stage III–IV) was observed in 64.1% of all cases and increased to 70.7% among patients with available staging information, while 29.2% of patients had incomplete or undefined staging data. Surgical treatment, either alone or combined with adjuvant therapies, was the most frequently employed treatment modality. Notably, 21.5% of patients had no documented definitive oncologic treatment during the recorded treatment period. Smoking was reported by 35.4% of patients, alcohol consumption by 4.0%, and a family history of cancer by 24.8%. Conclusions: Advanced-stage oral cancer was highly prevalent in this referral-based cohort. The substantial burden of late-stage disease, together with incomplete staging information and the proportion of patients without documented definitive treatment, highlights challenges related to staging completeness, treatment documentation, and cancer care monitoring. These findings support efforts to strengthen early detection, referral coordination, and cancer care monitoring within the Indonesian healthcare system. Full article

Background/Objectives: This study aimed to explore the potential value of narrow-band-imaging (NBI)-derived mean optical intensity (MOI) in monitoring the progression of oral squamous cell carcinoma (OSCC), from the normal oral mucosa through epithelial dysplasia to invasive carcinoma. We compared differences in the NBI MOI among distinct pathological stages, so as to provide preliminary evidence for its clinical application in auxiliary diagnosis and progression assessment for OSCC. Methods: A total of 40 human oral mucosal specimens (15 normal, 15 oral leukoplakia, 10 OSCC) were enrolled for NBI image acquisition and MOI measurements. A 4-nitroquinoline-1-oxide (4NQO)-induced mouse OSCC model (n = 34) was used to dynamically record MOI changes across different pathological stages. A syngeneic tongue tumor mouse model (n = 16) was further established to evaluate whether MOI could reflect tumor formation and growth. All MOI values were quantified using ImageJ software with standardized region-of-interest (ROI) selection and background correction. Results: In clinical samples, MOI values decreased progressively from the normal mucosa (129.6 ± 5.991 arbitrary units (a.u.)) to oral leukoplakia (OLK) subgroups, including mild dysplasia (104.6 ± 3.757 a.u.) and moderate-to-severe dysplasia (91.77 ± 4.345 a.u.), and further to OSCC (54.41 ± 14.40 a.u.). In the 4NQO model, the MOI of the lingual mucosa was highest in the healthy control group (167.3 ± 10.05 a.u.) and gradually declined with increasing dysplasia severity, reaching the lowest level at the OSCC stage (48.67 ± 10.07 a.u.). In the syngeneic tumor model, the MOI was significantly lower in tumor-bearing mice than in healthy controls (47.85 ± 10.44 a.u. vs. 119.7 ± 14.20 a.u., p < 0.001). Receiver operating characteristic (ROC) analysis demonstrated good diagnostic performance of the MOI in distinguishing healthy tissue from cancerous lesions. Conclusions: NBI-derived MOI may quantitatively reflect the dynamic alterations of the oral mucosa during oral carcinogenesis and could represent a potential biomarker enabling the non-invasive, repeatable early evaluation and dynamic monitoring of OSCC. 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: 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: Early and accurate diagnosis remains crucial to improving outcomes in oral cancer. Optical coherence tomography (OCT) offers real-time, high-resolution imaging that may support diagnosis and treatment planning in oral squamous cell carcinoma (OSCC). Methods: In this prospective study, preoperative OCT scans were obtained from 68 histologically confirmed OSCC lesions, with 30 paired adjacent mucosa samples from the same patients as histologically negative comparators (diagnostic dataset: 98 lesions). OCT findings were compared with histopathology for diagnostic performance, OCT biomarker patterns by tumour grade, tumour depth measurement, margin assessment, and subsite-specific performance. Results: OCT demonstrated 98.5% sensitivity, 96.7% specificity, and an AUC of 0.98 for detection of invasive OSCC. OCT biomarkers—including abnormal epithelial architecture with variable epithelial thickness, stratification loss, basement membrane disruption, and increased subepithelial reflectivity—varied systematically with tumour differentiation grade. Tumour depth measurements showed acceptable agreement with histology, while margin definition was correct in 80% of cases. Performance was highest in the tongue and the floor of the mouth, with reduced performance in posterior/keratinised subsites. Image artefacts occurred in 5.1% of scans. Conclusions: OCT provides a reproducible, real-time adjunct for diagnosis, margin planning, and lesion stratification in OSCC, with recognised limitations related to light attenuation and operator-dependent factors. Multicentre validation and integration with digital interpretation platforms are warranted. Full article

Background/Objectives: The pattern of invasion describes the arrangement of neoplastic cells along the tumor infiltrative front and refers to the way cancer infiltrates tissue at the tumor/host interface. Accumulating evidence suggested that the Worst Pattern of Invasion (WPOI) represents an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, it is still considered a minor prognostic criterion, and it is recommended as an optional report component in the College of American Pathologists (CAP) guideline. Methods: Therefore, the study aims to extensively review the literature data regarding the prognostic role of the WPOI in OSCC. Results: The WPOI resulted as an independent prognostic factor for locoregional recurrences (LRRs), lymph node metastasis (LMN), overall survival (OS), disease-specific survival (DSS), and bone tissue infiltration, regardless of the oral subsite and the pathological stage. Moreover, several authors suggested the evaluation of the WPOI to lead the postoperative management and to determine the occult LNM in early-stage OSCC. Conclusions: The prognostic relevance of the WPOI in OSCC highlights its evaluation in pathological daily practice. Therefore, the WPOI-detection method and scoring system should be validated based on the tumor stage and site. Full article

Oral cancer, the most common head and neck malignancy, has a high recurrence rate and poor prognosis largely owing to chemotherapy resistance. The adverse effects of conventional therapies have prompted investigations into safer and more effective alternative therapies. Chloroquine (CQ) and hydroxychloroquine (HCQ) have shown potential owing to their roles in autophagy modulation and immune regulation. This study clarifies the selective efficacy of hydroxychloroquine (HCQ) and chloroquine (CQ) in oral squamous cell carcinoma models, emphasizing distinct responses in gingival (Ca9-22) and tongue (SCC-9) carcinoma cells. Non-oncogenic oral epithelial cells (GMSM-K) and oral carcinoma cell lines from the tongue (SCC-9, Cal-27) and gingiva (Ca9-22) were used. Cell viability, cytotoxicity, and colony formation were assessed via MTT, LDH, and crystal violet assays. Flow cytometry was used to measure apoptosis, autophagy, oxidative stress, mitochondrial membrane potential, and DNA damage. The transcriptomic profiles of apoptosis and autophagy-related genes were assessed by qPCR arrays. Bioinformatics analysis allowed estimation of the main gene interaction networks. Pre-screening showed that GMSM-K and Cal-27 cells were non-responsive or exhibited non-specific toxicity at high doses; therefore, subsequent analyses focused on Ca9-22 (GC) and SCC-9 (TC). HCQ significantly reduced viability and colony formation in Ca9-22 cells while moderately affecting SCC-9 cells. Autophagy inhibition was accompanied by compensatory up-regulation of autophagy-related genes, consistent with feedback activation of TFEB and FOXO3a pathways. Gene expression profiling and flow-cytometry analyses revealed cell-type-specific differences in apoptosis, mitochondrial potential, and DNA damage, suggesting HCQ’s selective anti-tumor potential in gingival carcinoma. These findings highlight HCQ as a repurposed adjuvant therapy that modulates autophagy and apoptosis to enhance chemosensitivity in oral cancer. Full article

Cervical lymph node metastasis is the strongest prognostic factor in oral tongue carcinoma, yet current clinical guidelines rely primarily on depth of invasion to guide elective neck dissection. This approach results in unnecessary surgery in up to 70% of patients. Cancer-testis antigens (CTAs) are a family of genes associated with tumor aggressiveness and may serve as predictive biomarkers for nodal spread. A multi-step analysis integrating large-scale public datasets, including microarray (GSE78060), bulk RNA-seq emerging from the cancer genome atlas (TCGA), and single-cell RNA-seq (GSE103322), was employed to identify CTA genes active in oral tongue cancer. Selected genes were validated using NanoString nCounter RNA profiling of 16 patients undergoing curative glossectomy with elective neck dissection. Machine learning algorithms, including decision trees, t-distributed stochastic neighbor embedding (t-SNE), and convolutional neural networks (CNN), were applied to assess predictive power for nodal metastasis. Computational analysis initially identified 40 cancer-active CTA genes, of which four genes (LY6K, MAGEA3, CEP55, and ATAD2) were most indicative of nodal spread. In our patient cohort, NanoString nCounter profiling combined with machine learning confirmed these four genes as highly predictive. We present a proof-of-concept CTA-based genetic diagnostic tool capable of discriminating nodal involvement in oral tongue cancer. This approach may reduce unnecessary neck dissections, minimizing surgical morbidity. Full article

Oral tongue squamous cell carcinoma (OTSCC) is a common type of oral cancer influenced by genetic, epigenetic, and environmental factors like exposure to environmental toxins. These environmental toxins can decrease the effectiveness of established chemotherapy drugs, such as Irinotecan, used in OTSCC treatment. Bioinformatics, drug discovery, and machine learning techniques were employed to investigate the impact of Irinotecan on OTSCC patients by identifying targets and signaling pathways, including those that positively influence protein phosphorylation, protein tyrosine kinase activity, the PI3K-Akt (Phosphatidylinositol 3-kinase- Protein Kinase B) signaling system, cancer pathways, focal adhesion, and the HIF-1 (Hypoxia-Inducible Factor 1) signaling pathway. Later, the protein–protein interactions (PPIs) network, along with twelve cytoHubba approaches to finding the most interacting molecule, was employed to find the important proteins BCL2 and EGFR. Drugs related to BCL2 and EGFR were extracted from the DGIdb database for further molecular docking. Molecular docking revealed that Docetaxel, Paclitaxel, Imatinib, Ponatinib, Ibrutinib, Sorafenib, and Etoposide showed more binding affinity than Irinotecan (i.e., −9.8, −9.6). Of these, Paclitaxel (−10.3, −11.4) and Imatinib (−9.9, −10.4) are common in targeting BCL2 and EGFR. Using these identified candidate genes and pathways, we may be able to uncover new therapeutic targets for the treatment of OTSCC. Furthermore, molecular dynamics (MD) simulations were performed for selected ligand–receptor complexes, revealing stable binding interactions and favorable energetic profiles that supported the docking results and strengthened the reliability of the proposed drug repurposing strategy. Full article

Background/Objectives: Oral squamous cell carcinoma (OSCC) is the most common oral cancer, progressing from hyperplasia to dysplasia, carcinoma in situ (CIS), and finally invasive squamous cell carcinoma (ISCC). Developing an animal model that mimics both early and advanced OSCC stages has been challenging. The 4-Nitroquinoline 1-oxide (4NQO) model is considered one of the most suitable, as it represents all stages of OSCC. Nevertheless, thoroughly understanding the properties of the 4NQO model is essential for preclinical testing of novel therapeutics. Methods: We aimed to characterize the 4NQO rat model using two application methods—drinking water and topical application—over eight months. Monthly sacrifices allowed histopathological analysis and ex vivo magnetic resonance imaging (MRI) to track tumor progression. Results: CIS was observed at three months in the drinking water group, evolving into ISCC by six months, while topical application induced CIS at eight months without ISCC formation. The tongue was divided into three regions and histological properties, lesion size, and invasion depth were analyzed. In the drinking water group, particularly in the body of the tongue, we saw earlier CIS development, larger lesions, and deeper invasion. Additionally, assessment of proliferative properties showed an increased cell division in dysplastic lesions that reduced upon invasion. MRI was able to show macroscopic tumoral lesions, in concordance with histology. Conclusions: Overall, the drinking water method closely mimics human OSCC, validating the 4NQO model for translational OSCC research. Full article

RNA-binding proteins (RBPs) critically regulate post-transcriptional gene networks, yet their roles and mechanisms in oral squamous cell carcinoma (OSCC) remain underexplored. Dysregulated RBPs were identified through integrated analysis of RNA-seq and single-cell RNA-seq. The oncogenic functions of IGF2BP2 were evaluated through tissue microarrays, CCK-8, transwell assays, mouse xenografts, and Igf2bp2-deficient mouse models of tongue SCC (TSCC). Subsequently, we utilized RNA-seq, RIP-seq, RIP/MeRIP-qPCR, and dual-luciferase reporter assays to investigate IGF2BP2-target genes. Furthermore, cell co-culture system and mouse TSCC models were used to validate the therapeutic effect of the IGF2BP2 inhibitor. IGF2BP2 was the most markedly upregulated RBP in OSCC cells and cancer-associated fibroblasts (CAFs), correlating with unfavorable prognosis. IGF2BP2 deprivation significantly impaired human OSCC proliferation and metastasis, and delayed mouse TSCC onset. Mechanistically, IGF2BP2 stabilized EGFR and PIK3R1 mRNA via m6A-dependent interactions, thereby sustaining activation of the EGFR/PI3K/AKT oncogenic axis. Pharmacological inhibition of IGF2BP2 exhibited anti-OSCC efficacy in vivo and in vitro by concurrently suppressing EGFR and PI3K/AKT pathway activity, overcoming anti-EGFR resistance resulting from cell-intrinsic PI3K/AKT hyperactivation and CAF-secreted factors. Our findings identified IGF2BP2 as a master regulator of OSCC progression and a promising therapeutic target, offering an alternative strategy for OSCC patients suffering anti-EGFR resistance. Full article

Tumor budding (TB) occurs at the deepest site of tumor invasion and is a significant prognostic indicator of cervical metastasis in oral squamous cell carcinoma (OSCC). The mechanism of TB, however, remains unclear. This study investigated the roles of the tumor microenvironment and partial epithelial–mesenchymal transition (p-EMT) in TB expression using molecular and cellular physiological analyses. We established oral metachronous carcinoma cell lines (gingival carcinoma: 020, tongue carcinoma with high TB expression: 020G) from two cancers with pathologically different TB in the same patient and subjected them to exome analysis to detect gene mutations related to carcinogenesis and malignancy. Differences in EMT expression induced by transforming growth factor-β (TGF-β) between 020 and 020G were analyzed by Western blotting and reverse transcription polymerase chain reaction, and TGF-β-induced changes in cell morphology, proliferation, migration, and invasive ability were also examined. TGF-β expression was observed in the deepest tumor invasion microenvironment. TGF-β also induced the expression of several p-EMT markers and increased the migration and invasive abilities of 020G compared with 020 cells. In conclusion, TGF-β in the deep-tumor microenvironment can induce p-EMT in tumor cells, expressed as TB. Full article