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Objectives: To investigate risk factors associated with occult lymph node metastases (ONM) and skip metastasis in early-stage oral tongue squamous cell carcinoma (OTSCC) patients. Meanwhile, to analyze the contribution of metastatic nodes to survival outcomes. Materials and methods: 544 OTSCC patients who were clinically staged T1-T2N0 with pathologic results from May 2018 to January 2024 were enrolled. Those with ONM were divided into subgroups with or without skip metastasis. Clinical, laboratorial, radiological and pathological factors between groups were analyzed by using univariate analysis and multivariate logistic analysis. The association of tumor growth behavior with the metastatic pattern of lymph nodes was summarized. Additionally, disease free survival (DFS) among different groups were compared using Kaplan-Meier analysis. Results: Tumor growth behavior was associated with ONM. Tumor thickness with a threshold of 6.4 mm was not inferior to histological depth of invasion in predicting ONM. Only 1.3% of patients had nodal involvement of neck level IV or V. The DFS of patients with ONM were significantly reduced than those without ONM (P < 0.001). The DFS between patients with and without skip metastasis exhibited no statistical significance(P = 0.246). The 1-year, 2-year recurrence rates of patients with or without ONM were 31.9%, 37.5%, 10.1% and 14.0%, correspondingly. Conclusions: Tumor thickness with a threshold of 6.4 mm could be used as a preoperative predictor for ONM. Elective neck dissection of level I - III might be sufficient for early stage OTSCC patients. OTSCC patients with ONM should be closely observed during the first 2 years after surgery. Clinical relevance: The risk of ONM in early stage OTSCC patients might be predicted by tumor thickness calculated on MR imaging. Elective neck dissection of level I – III could remove micrometastases timely and effectively. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to provide further insights into whether age and/or sex are associated with prognosis in oral tongue squamous cell carcinoma. Methods: This was a retrospective cohort study utilizing hospital registry data from 2006 to 2016 obtained from the National Cancer Database. Identified patients were divided into various cohorts based on age, sex, and staging. A descriptive analysis was performed using chi‐square tests and overall survival rates were estimated using Kaplan–Meier method. Results: A total of 17 642 patients were included in the study. The 5‐year overall survival rates were 82.0% (95% CI: 79.8%–84.0%) in younger patients versus 67.5% (95% CI: 66.7%–68.3%, p‐value <0.0001) older patients. The median overall survival for females was 143.4 months (95% CI: 133.2–NA) versus 129.8 (95% CI: 125.4–138.7, p‐value <0.0001) in males. Conclusions: Our analysis suggests that younger age and female sex are both predictors of improved survival in oral tongue squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Oral tongue squamous cell carcinoma (OTSCC) often presents with aggressive clinical behaviour that may require multimodality treatment based on reliable prognostication. We aimed to evaluate the prognostic ability of five online web‐based tools to predict the clinical behaviour of OTSCC resection and biopsy samples.A total of 135 OTSCC resection cases and 33 OTSCC biopsies were included to predict recurrence and survival. Area under the receiver operating characteristic curves (AUC), χ2 tests, and calibration plots constructed to estimate the prognostic power of each tool.The tool entitled ‘Prediction of risk of Locoregional Recurrences in Early OTSCC’ presented an accuracy of 82%. The tool, ‘Head & Neck Cancer Outcome Calculator’ for 10‐year cancer‐related mortality had an accuracy 77% and AUC 0.858. The other tool entitled ‘Cancer Survival Rates’ for 5‐year mortality showed an accuracy of 74% and AUC of 0.723. For biopsy samples, ‘Cancer Survival Prediction Calculators’ predicted the recurrence free survival with an accuracy of 70%.Web‐based tools can aid in clinical decision making of OTSCC. Three of five online web‐based tools could predict recurrence risk and cancer‐related mortality in resected OTSCC and one tool could help in clinical decision making for biopsy samples. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies have demonstrated that obesity may impact the efficacy of anti‐PD1 therapy, but the underlying mechanism remains unclear. In this study, our objective was to determine the prognostic value of obesity in patients with oral tongue squamous cell carcinoma (OTSCC) treated with pembrolizumab and establish a subtype based on fatty acid metabolism‐related genes (FAMRGs) for immunotherapy. Materials and Methods: We enrolled a total of 56 patients with OTSCC who underwent neoadjuvant anti‐PD1 therapy. Univariate and multivariate Cox regression analyses, Kaplan–Meier survival analysis, and immunohistochemistry staining were performed. Additionally, we acquired the gene expression profiles of pan‐cancer samples and conducted GSEA and KEGG pathway analysis. Moreover, data from TCGA, MSigDB, UALCAN, GEPIA and TIMER were utilized to construct the FAMRGs subtype. Results: Our findings indicate that high Body Mass Index (BMI) was significantly associated with improved PFS (HR = 0.015; 95% CI, 0.001 to 0.477; p = 0.015), potentially attributed to increased infiltration of PD1 + T cells. A total of 91 differentially expressed FAMRGs were identified between the response and non‐response groups in pan‐cancer patients treated with immunotherapy. Of these, 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) were found to affect PD‐1 expression and T cell infiltration in HNSCC, which may impact the efficacy of anti‐PD1 therapy. Conclusion: This study demonstrates that obesity serves as a robust prognostic predictor for patients with OTSCC undergoing neoadjuvant anti‐PD1 therapy. Furthermore, the expression of 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) plays a pivotal role in the context of anti‐PD1 therapy and deserves further investigation. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to compare the radiological tumor (T)-category using multiparametric MRI with the pathological T category in patients with oral tongue squamous cell carcinoma (OTSCC) and to examine which is a better predictor of prognosis. Methods: This retrospective study included 110 consecutive patients with surgically resected primary OTSCC who underwent preoperative contrast-enhanced MRI. T categories determined by maximum diameter and depth of invasion were retrospectively assessed based on the pathological specimen and multiparametric MRI. The MRI assessment included the axial and coronal T1-weighted image (T1WI), axial T2-weighted image (T2WI), coronal fat-suppressed T2WI, and axial and coronal fat-suppressed contrast-enhanced T1WI (CET1WI). Axial and coronal CET1WI measurements were divided into two groups: measurements excluding peritumoral enhancement (MEP) and measurements including peritumoral enhancement. The prognostic values for recurrence and disease-specific survival after radiological and pathological T categorization of cases into T1/T2 and T3/T4 groups were compared. Results: The T category of MEP on coronal CET1WI was the most relevant prognostic factor for recurrence [hazard ratio (HR) = 3.30, p = 0.001] and the HR was higher than the HR for pathological assessment (HR = 2.26, p = 0.026). The T category determined by MEP on coronal CET1WI was also the most relevant prognostic factor for disease-specific survival (HR = 3.12, p = 0.03), and the HR was higher than the HR for pathological assessment (HR = 2.02, p = 0.20). Conclusion: The T category determined by MEP on the coronal CET1WI was the best prognostic factor among all radiological and pathological T category measurements. [ABSTRACT FROM AUTHOR]

Objective: Disease metabolomes have been studied for identifying diagnostic and predictive biomarkers of pathology. Oral tongue squamous cell carcinoma (OTSCC) is one of the most prevalent subtypes of head and neck squamous cell carcinoma, yet the profile and diagnostic value of its tissue metabolite are unclear. Subjects and Methods: Tumor tissue samples and matched normal mucosal tissue samples were collected from 40 OTSCC patients. Untargeted metabolic analysis by liquid chromatography–mass spectrometry/mass spectrometry, in positive and negative ion modes, was used to identify dysregulated metabolites in OTSCC. Further, utilizing LASSO regression and receiver operating characteristic analyses, biomarker metabolites were selected and validated, and a diagnostic model was established. Results: One hundred and ninety metabolites were detected. The OTSCC had a total of 89 dysregulated metabolites, of which 73 were elevated. A diagnostic panel of nine metabolites was subsequently created that could accurately identify OTSCC with 100% sensitivity of 100%, 100% specificity and an AUC of 1.00. Conclusions: This study identified distinct metabolic characteristics of OTSCC and established a diagnostic model. Our research also contributes to the investigation of the pathogenesis of OTSCC. [ABSTRACT FROM AUTHOR]

Photothermal therapy (PTT) and photodynamic therapy (PDT) have been considered as attractive therapeutic treatments for oral tongue squamous cell carcinoma (OTSCC) due to their low toxicity, negligible drug resistance, and minimally invasive properties. Meanwhile, these two treatments can also induce autophagy, which plays an important role in maintaining cellular metabolism and homeostasis through resisting the thermal effect and oxidative stress of PTT and PDT, thus to a certain extent weakening the antitumor efficacy of these two treatments. To improve the antitumor efficiency of PTT/PDT, in this study, we designed a biomimetic nanoparticle treatment system for coloading the photosensitizer and photothermal agent ICG and the autophagy inhibitor hydroxychloroquine (HCQ). Poly-(β-amino ester) (PBAE)/polylactic-co-glycolic acid (PLGA) were regarded as the drugs' carrier materials, and cancer cell membrane (CCM) vesicles extracted from OTSCC further encapsulated the PBAE/PLGA nanocomplex, thus helping to target the delivery of ICG and HCQ to homologous OTSCC cells through efficient self-recognition and cellular uptake. Upon near-infrared laser irradiation, the nanoparticles exhibited significant antitumor efficacy in vitro and in vivo. Accordingly, this study provided a biomimetic nanoparticle that possessed a notable homologous cancer cell drug-delivery ability and significantly amplified PTT/PDT's effects against OTSCC through autophagy inhibition, which is promising to provide new strategies for the clinical treatment of OTSCC. [ABSTRACT FROM AUTHOR]

Despite diagnostic advancements, the development of reliable prognostic systems for assessing the risk of cancer recurrence still remains a challenge. In this study, we developed a novel framework to generate highly representative machine-learning prediction models for oral tongue squamous cell carcinoma (OTSCC) cancer recurrence. We identified cases of 5- and 10-year OTSCC recurrence from the SEER database. Four classification models were trained using the H2O ai platform, whose performances were assessed according to their accuracy, recall, precision, and the area under the curve (AUC) of their receiver operating characteristic (ROC) curves. By evaluating Shapley additive explanation contribution plots, feature importance was studied. Of the 130,979 patients studied, 36,042 (27.5%) were female, and the mean (SD) age was 58.2 (13.7) years. The Gradient Boosting Machine model performed the best, achieving 81.8% accuracy and 97.7% precision for 5-year prediction. Moreover, 10-year predictions demonstrated 80.0% accuracy and 94.0% precision. The number of prior tumors, patient age, the site of cancer recurrence, and tumor histology were the most significant predictors. The implementation of our novel SEER framework enabled the successful identification of patients with OTSCC recurrence, with which highly accurate and sensitive prediction models were generated. Thus, we demonstrate our framework's potential for application in various cancers to build generalizable screening tools to predict tumor recurrence.

Objectives: To provide a comprehensive characterization of DNA methylome of oral tongue squamous cell carcinoma (OTSCC) and identify novel tumor‐specific DNA methylation markers for early detection using saliva. Material and Methods: Genome‐wide DNA methylation analysis including six OTSCC matched adjacent non‐tumoral tissue and saliva was performed using Infinium MethylationEPIC array. Differentially methylated levels of selected genes in our OTSCC cohort were further validated using OTSCC methylation data from The Cancer Genome Atlas database (TCGA). The methylation levels of a set of tumor‐specific hypermethylated genes associated with a downregulated expression were evaluated in saliva. Receiver operating characteristic (ROC) curves were performed to assess the diagnostic value of DNA methylation markers. Results: A total of 25,890 CpGs (20,505 hypomethylated and 5385 hypermethylated) were differentially methylated (DMCpGs) between OTSCC and adjacent non‐tumoral tissue. Hypermethylation of 11 tumor‐specific genes was validated in OTSCC TCGA cohort. Of these 11 genes, A2BP1, ANK1, ALDH1A2, GFRA1, TTYH1, and PDE4B were also hypermethylated in saliva. These six salivary methylated genes showed high diagnostic accuracy (≥0.800) for discriminating patients from controls. Conclusions: This is the first largest genome‐wide DNA methylation study on OTSCC that identifies a group of novel tumor‐specific DNA methylation markers with diagnostic potential in saliva. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to explore preliminary the performance of radiomics machine learning models based on multimodal MRI to predict the risk of cervical lymph node metastasis (CLNM) for oral tongue squamous cell carcinoma (OTSCC) patients. Methods: A total of 400 patients were enrolled in this study and divided into six groups according to the different combinations of MRI sequences. Group I consisted of patients with T1‐weighted images (T1WI) and FS‐T2WI (fat‐suppressed T2‐weighted images), group II consisted of patients with T1WI, FS‐T2WI, and contrast enhanced MRI (CE‐MRI), group III consisted of patients with T1WI, FS‐T2WI, and T2‐weighted images (T2WI), group IV consisted of patients with T1WI, FS‐T2WI, CE‐MRI, and T2WI, group V consisted of patients with T1WI, FS‐T2WI, T2WI, and apparent diffusion coefficient map (ADC), and group VI consisted of patients with T1WI, FS‐T2WI, CE‐MRI, T2WI, and ADC. Machine learning models were constructed. The performance of the models was compared in each group. Results: The machine learning model in group IV including T1WI, FS‐T2WI, T2WI, and CE‐MRI presented best prediction performance, with AUCs of 0.881 and 0.868 in the two sets. The models with CE‐MRI performed better than the models without CE‐MRI(I vs. II, III vs. IV, V vs. VI). Conclusions: The radiomics machine learning models based on CE‐MRI showed great accuracy and stability in predicting the risk of CLNM for OTSCC patients. [ABSTRACT FROM AUTHOR]

Introduction: The clinical efficacy of CAR-NK cells against CD19-expressing blood cancers has been demonstrated, and they have shown potential for treating solid tumors as well. However, the efficacy of CAR-NK cells for treating human oral tongue squamous cell carcinoma (OTSCC) has not been examined. Methods: We assessed MUC1 expression in human OTSCC tissue and a cell line using immunohistochemistry and immunofluorescence. We constructed NK cells that express CAR targeted to MUC1 from pluripotent stem cells (iPSCderived MUC1-targeted CAR-NK cells) and evaluated their effectiveness against OTSCC in vitro using the xCELLigence Real-Time Cell Analysis system and CCK8 assay, and in vivo by measuring xenograft growth daily in BNDG mice treated with MUC1-targeted CAR-NK cells. As controls, we used iPSC-derived NK cells and NK-free media, which were CAR-free and blank, respectively. Results: MUC1 expression was detected in 79.5% (66/83) of all OTSCC patients and 72.7% (24/33) of stage III and IV. In stage III and IV MUC1 positive OTSCC, 63.6% (21/33) and 48.5% (16/33) patients had a MUC1-positive cancer cell rate of more than 50% and 80%, respectively. The iPSC-derived MUC1-targeted CARNK cells exhibited significant cytotoxicity against MUC1-expressing OTSCC cells in vitro, in a time- and dose-dependent manner, and showed a significant inhibitory effect on xenograft growth compared to both the iPSC-derived NK cells and the blank controls. We observed no weight loss, severe hematological toxicity or NK cell-mediated death in the BNDG mice. Conclusion: The MUC1-targetedCAR-NK cells had significant efficacy against human OTSCC, and their promising therapeutic response warrants further clinical trials. [ABSTRACT FROM AUTHOR]

Background: Oral cancer remains one of the most dreadful diseases in developing nations. Currently, there has been a rise in the prevalence of tongue squamous cell carcinoma (SCC), with a poor prognosis. The use of standard treatment approaches against oral cancer patients brings about several side effects. In recent years, nanomedicine has provided a versatile platform for developing new targeted therapeutic modalities. However, safety remains a concern in the synthesis of nanoparticles (NPs). Therefore, the present study aims to synthesize safer phytoconstituent-mediated gold NPs (AuNPs) utilizing leaf extracts of Annona muricata, where the biochemical components of the plant leaf act as the reducing and capping agents in the synthesis of NPs, and to evaluate its anti-cancer activity against SCC. Materials and Methods: In this in vitro experimental study, AuNPs were synthesized through an effective, simple, and ecologically sound green synthesis method. After characterization of these synthesized AuNPs, in vitro assays such as 3-(4, 5-dimethylthiazole2-yl)-2, 5-biphenyl tetrazolium bromide, wound healing, and clonogenic assays were carried out to investigate the anti-cancer potential of green synthesized AuNPs in the human tongue SCC cell line (SCC-15), and the possible mechanism of action was evaluated through gene and protein expression analysis of Bax, Bcl-2, and p53 genes. The results were expressed as mean ± standard deviation using Statistical Package for Social Sciences (SPSS) 20.0 software and Student's t-test was performed for experimental data. P ≤0.05 were considered statistically significant. Results: The in vitro assays demonstrated that the synthesized AuNPs are exhibiting anti-cancer activity by apoptosis of SCC-15 cells in a dose-dependent manner. Further, it also revealed a highly significant decrease in anti-apoptotic Bcl-2 gene expression, whereas pro-apoptotic genes p53 and Bax revealed a highly significant increase, which is statistically significant compared to the control (P < 0.05). Conclusion: Our findings demonstrated that the AuNPs synthesized from A. muricata leaf extract could act as a novel anticancer agent, particularly against SCC, after further scrutiny. [ABSTRACT FROM AUTHOR]

Lymph node metastasis (LNM) is one of the common features of oral tongue squamous cell carcinoma (OTSCC). LNM is also taken as a sign of advanced OTSCC and poor survival rate. Recently, single‐cell RNA sequencing has been applied in investigating the heterogeneity of tumor microenvironment and discovering the potential biomarkers for helping the diagnosis and prognosticating. Pathogenesis of LNM in OTSCC remains unknown. Specifically, cancer‐associated fibroblasts (CAFs) and epithelial tumor cells could foster the progression of tumors. Thus, in this study, we aimed to comprehensively analyze the roles of subpopulations of CAFs and epithelial tumor cells in lymph node metastatic OTSCC using the integration of OTSCC single‐cell RNA sequencing datasets. Four distinct subtypes of CAFs, namely vascular CAFs, myofibroblast CAFs, inflammatory CAFs, and growth arrest CAFs were successfully discovered in LNM tumor and confirmed the roles of GAS and PTN pathways in the progression of tumor metastasis. In addition, NKAIN2+ epithelial cells and FN1+ epithelial cells specifically exhibited an upregulation of PTN, NRG, MIF, and SPP1 signaling pathways in the metastatic OTSCC. In doing so, we put forth some potential biomarkers that could be utilized for the purpose of diagnosing and prognosticating OTSCC during its metastatic phase and tried to confirm by immunofluorescence assays. [ABSTRACT FROM AUTHOR]

Abstract Objectives Previous studies have demonstrated that obesity may impact the efficacy of anti‐PD1 therapy, but the underlying mechanism remains unclear. In this study, our objective was to determine the prognostic value of obesity in patients with oral tongue squamous cell carcinoma (OTSCC) treated with pembrolizumab and establish a subtype based on fatty acid metabolism‐related genes (FAMRGs) for immunotherapy. Materials and Methods We enrolled a total of 56 patients with OTSCC who underwent neoadjuvant anti‐PD1 therapy. Univariate and multivariate Cox regression analyses, Kaplan–Meier survival analysis, and immunohistochemistry staining were performed. Additionally, we acquired the gene expression profiles of pan‐cancer samples and conducted GSEA and KEGG pathway analysis. Moreover, data from TCGA, MSigDB, UALCAN, GEPIA and TIMER were utilized to construct the FAMRGs subtype. Results Our findings indicate that high Body Mass Index (BMI) was significantly associated with improved PFS (HR = 0.015; 95% CI, 0.001 to 0.477; p = 0.015), potentially attributed to increased infiltration of PD1 + T cells. A total of 91 differentially expressed FAMRGs were identified between the response and non‐response groups in pan‐cancer patients treated with immunotherapy. Of these, 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) were found to affect PD‐1 expression and T cell infiltration in HNSCC, which may impact the efficacy of anti‐PD1 therapy. Conclusion This study demonstrates that obesity serves as a robust prognostic predictor for patients with OTSCC undergoing neoadjuvant anti‐PD1 therapy. Furthermore, the expression of 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) plays a pivotal role in the context of anti‐PD1 therapy and deserves further investigation.

Objective: Oral tongue squamous cell carcinoma (OTSCC) frequently harbors non‐functional p53 and depends on G2/M checkpoint mediated by WEE1. WEE1 suppression has been identified as a promising anti‐tumor strategy. This study investigated the capacity of WEE1 kinase inhibitor (MK‐1775) and its underlying mechanisms in enhancing radiation responses of OTSCC cells in vitro. Materials and methods: WEE1 kinase expression and its downstream target (CDK1) were investigated in OTSCC versus normal oral tissue. A synergistic combination of MK‐1775 with radiation on OTSCC cell lines with different p53 statuses was assessed by viability assay. The radio‐sensitizing effects of MK‐1775 on apoptosis, cell cycle, DNA damage, and mitotic entry were also determined. Results: Irradiation enhanced CDK1 expression in all tested cell lines, though the effect was far more pronounced in p53 mutated cell lines. MK‐1775 exhibited inhibitory effects against the survival of all cell lines and enhanced their response to the radiation. These effects were strongly elicited by induction of apoptosis and lethal mitosis, but less likely by abrogation of radiation‐induced G2 arrest. Conclusion: These results demonstrate the efficacy of MK‐1775 in enhancing the radiation effect on OTSCC in vitro associated with a significant apoptotic death rate, identifying WEE1 inhibitor as a potent radiosensitizer in OTSCC irrespective of p53 mutational status. [ABSTRACT FROM AUTHOR]

IntroductionThe clinical efficacy of CAR-NK cells against CD19-expressing blood cancers has been demonstrated, and they have shown potential for treating solid tumors as well. However, the efficacy of CAR-NK cells for treating human oral tongue squamous cell carcinoma (OTSCC) has not been examined. MethodsWe assessed MUC1 expression in human OTSCC tissue and a cell line using immunohistochemistry and immunofluorescence. We constructed NK cells that express CAR targeted to MUC1 from pluripotent stem cells (iPSC-derived MUC1-targeted CAR-NK cells) and evaluated their effectiveness against OTSCC in vitro using the xCELLigence Real-Time Cell Analysis system and CCK8 assay, and in vivo by measuring xenograft growth daily in BNDG mice treated with MUC1-targeted CAR-NK cells. As controls, we used iPSC-derived NK cells and NK-free media, which were CAR-free and blank, respectively.ResultsMUC1 expression was detected in 79.5% (66/83) of all OTSCC patients and 72.7% (24/33) of stage III and IV. In stage III and IV MUC1 positive OTSCC, 63.6% (21/33) and 48.5% (16/33) patients had a MUC1-positive cancer cell rate of more than 50% and 80%, respectively. The iPSC-derived MUC1-targeted CAR-NK cells exhibited significant cytotoxicity against MUC1-expressing OTSCC cells in vitro, in a time- and dose-dependent manner, and showed a significant inhibitory effect on xenograft growth compared to both the iPSC-derived NK cells and the blank controls. We observed no weight loss, severe hematological toxicity or NK cell-mediated death in the BNDG mice. ConclusionThe MUC1-targeted CAR-NK cells had significant efficacy against human OTSCC, and their promising therapeutic response warrants further clinical trials.

Abstract Background 3D culture is increasingly used in cancer research, as it allows the growth of cells in an environment that mimics in vivo conditions. Metastases are the primary cause of morbidity and mortality in cancer patients, and solid tumour metastases are mostly located in lymph nodes. Currently, there are no techniques that model the pre-metastatic lymph node microenvironment in vitro. In this study, we prepared a novel extracellular matrix, Lymphogel, which is derived from lymph nodes, mimicking the tumour microenvironment (TME) of metastatic carcinoma cells. We tested the suitability of the new matrix in various functional experiments and compared the results with those obtained using existing matrices. Methods We used both commercial and patient-derived primary and metastatic oral tongue squamous cell carcinoma (OTSCC) cell lines. We characterized the functional differences of these cells using three different matrices (human uterine leiomyoma-derived Myogel, human pre-metastatic neck lymph node-derived Lymphogel (h-LG), porcine normal neck lymph node-derived Lymphogel (p-LG) in proliferation, adhesion, migration and invasion assays. We also performed proteomic analyses to compare the different matrices in relation to their functional properties. Results OTSCC cells exhibited different adhesion and invasion patterns depending on the matrix. Metastatic cell lines showed improved ability to adhere to h-LG, but the effects of the matrices on cell invasion fluctuated non-significantly between the cell lines. Proteomic analyses showed that the protein composition between matrices was highly variable; Myogel contained 618, p-LG 1823 and h-LG 1520 different proteins. The comparison of all three matrices revealed only 120 common proteins. Analysis of cellular pathways and processes associated with proteomes of each matrix revealed similarities of Myogel with h-LG but less with p-LG. Similarly, p-LG contained the least adhesion-related proteins compared with Myogel and h-LG. The highest number of unique adhesion-related proteins was present in h-LG. Conclusions We demonstrated that human pre-metastatic neck lymph node-derived matrix is suitable for studying metastatic OTSCC cells. As a whole-protein extract, h-LG provides new opportunities for in vitro carcinoma cell culture experiments.

Abstract Objective We aimed to develop a 5-year overall survival prediction model for patients with oral tongue squamous cell carcinoma based on machine learning methods. Subjects and methods The data were obtained from electronic medical records of 224 OTSCC patients at the PLA General Hospital. A five-year overall survival prediction model was constructed using logistic regression, Support Vector Machines, Decision Tree, Random Forest, Extreme Gradient Boosting, and Light Gradient Boosting Machine. Model performance was evaluated according to the area under the curve (AUC) of the receiver operating characteristic curve. The output of the optimal model was explained using the Python package (SHapley Additive exPlanations, SHAP). Results After passing through the grid search and secondary modeling, the Light Gradient Boosting Machine was the best prediction model (AUC = 0.860). As explained by SHapley Additive exPlanations, N-stage, age, systemic inflammation response index, positive lymph nodes, plasma fibrinogen, lymphocyte-to-monocyte ratio, neutrophil percentage, and T-stage could perform a 5-year overall survival prediction for OTSCC. The 5-year survival rate was 42%. Conclusion The Light Gradient Boosting Machine prediction model predicted 5-year overall survival in OTSCC patients, and this predictive tool has potential prognostic implications for patients with OTSCC.

Background: Changes in Caveolin-1 (CAV-1) expression are related to tumorigenesis. The aim of this study was to evaluate the role of CAV-1 in tumor progression in oral squamous cell carcinoma (SCC) tissue samples and the effect of CAV-1 silencing on two oral tongue SCC (OTSCC) cell lines (SCC-25, from a primary tumor, and HSC-3 from lymph node metastases). Methods: Mycroarray hybridization, mRNA expression, and immunohistochemistry were performed on OSCC tissue samples and corresponding non-tumoral margin tissues. The effects of CAV-1 silencing (siCAV-1) on cell viability, membrane fluidity, on the expression of epithelial to mesenchymal transition (EMT) markers and on cell migration and invasion capacity of OTSCC cell lines were evaluated. Results: Microarray showed a greater CAV-1 expression (1.77-fold) in OSCC tumors than in non-tumoral tissues and 2.0-fold more in less aggressive OSCCs. However, significant differences in CAV-1 gene expression were not seen between tumors and non-tumoral margins nor CAV-1 with any clinicopathological parameters. CAV-1 protein was localized both in carcinoma and in spindle cells of the tumor microenvironment (TME), and CAV-1 positive TME cells were associated with smaller/more aggressive tumors, independent of the carcinoma cells' expression. Silencing of CAV-1 increased cell viability only in SCC-25 cells. It also stimulated the invasion of HSC-3 cells and increased ECAD and BCAT mRNA in these cells; however, the protein levels of the EMT markers were not affected. Conclusion: Decreased expression of CAV-1 by tumor cells in OSCC and an increase in the TME were associated with increased cell invasiveness and tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Background: 3D culture is increasingly used in cancer research, as it allows the growth of cells in an environment that mimics in vivo conditions. Metastases are the primary cause of morbidity and mortality in cancer patients, and solid tumour metastases are mostly located in lymph nodes. Currently, there are no techniques that model the pre-metastatic lymph node microenvironment in vitro. In this study, we prepared a novel extracellular matrix, Lymphogel, which is derived from lymph nodes, mimicking the tumour microenvironment (TME) of metastatic carcinoma cells. We tested the suitability of the new matrix in various functional experiments and compared the results with those obtained using existing matrices. Methods: We used both commercial and patient-derived primary and metastatic oral tongue squamous cell carcinoma (OTSCC) cell lines. We characterized the functional differences of these cells using three different matrices (human uterine leiomyoma-derived Myogel, human pre-metastatic neck lymph node-derived Lymphogel (h-LG), porcine normal neck lymph node-derived Lymphogel (p-LG) in proliferation, adhesion, migration and invasion assays. We also performed proteomic analyses to compare the different matrices in relation to their functional properties. Results: OTSCC cells exhibited different adhesion and invasion patterns depending on the matrix. Metastatic cell lines showed improved ability to adhere to h-LG, but the effects of the matrices on cell invasion fluctuated non-significantly between the cell lines. Proteomic analyses showed that the protein composition between matrices was highly variable; Myogel contained 618, p-LG 1823 and h-LG 1520 different proteins. The comparison of all three matrices revealed only 120 common proteins. Analysis of cellular pathways and processes associated with proteomes of each matrix revealed similarities of Myogel with h-LG but less with p-LG. Similarly, p-LG contained the least adhesion-related proteins compared with Myogel and h-LG. The highest number of unique adhesion-related proteins was present in h-LG. Conclusions: We demonstrated that human pre-metastatic neck lymph node-derived matrix is suitable for studying metastatic OTSCC cells. As a whole-protein extract, h-LG provides new opportunities for in vitro carcinoma cell culture experiments. [ABSTRACT FROM AUTHOR]

Objective: We aimed to develop a 5-year overall survival prediction model for patients with oral tongue squamous cell carcinoma based on machine learning methods. Subjects and methods: The data were obtained from electronic medical records of 224 OTSCC patients at the PLA General Hospital. A five-year overall survival prediction model was constructed using logistic regression, Support Vector Machines, Decision Tree, Random Forest, Extreme Gradient Boosting, and Light Gradient Boosting Machine. Model performance was evaluated according to the area under the curve (AUC) of the receiver operating characteristic curve. The output of the optimal model was explained using the Python package (SHapley Additive exPlanations, SHAP). Results: After passing through the grid search and secondary modeling, the Light Gradient Boosting Machine was the best prediction model (AUC = 0.860). As explained by SHapley Additive exPlanations, N-stage, age, systemic inflammation response index, positive lymph nodes, plasma fibrinogen, lymphocyte-to-monocyte ratio, neutrophil percentage, and T-stage could perform a 5-year overall survival prediction for OTSCC. The 5-year survival rate was 42%. Conclusion: The Light Gradient Boosting Machine prediction model predicted 5-year overall survival in OTSCC patients, and this predictive tool has potential prognostic implications for patients with OTSCC. [ABSTRACT FROM AUTHOR]

Background: Oral tongue squamous cell carcinoma tends to metastasize to cervical lymphatic nodes early which leads to a 50% drop of survival rate. CXCL1 could be secreted by LNMTca8113 cell induced lymphatic endothelial cells and promoted LNMTca8113 cell migration. The current study aimed to further explore the effect of CXCL1 on the proliferation and migration abilities of tongue cancer cells and the prognostic value of serum CXCL1 in oral tongue squamous cell carcinoma. Methods: Cell proliferation and migration ability were analysed by CCK8 assays and transwell migration assays. Immunofluorescence technique was used to show cytoskeleton. GST pull‐down assay was applied to quantify the activation of GTPases. Blood samples of patients were collected and clinicopathological characteristics were analysed. Results: CXCL1 could promote cancer cell proliferation in appropriate concentration by PI3K/AKT pathway. It also regulated the activation of Rho GTPases to mediate the rearrangements of cytoskeleton to promote tumour cell migration. Level of plasma CXCL1 could predict the possibility of early lymphatic metastasis and had a predictive value in progression‐free survival and overall survival. Conclusions: CXCL1 could promote oral cancer cell proliferation, migration and invasion in vitro and contributed theoretical knowledge for the target selection in molecular targeted therapy. Level of plasma CXCL1 might serve as a biomarker for prognosis in oral tongue squamous cell carcinoma patients. [ABSTRACT FROM AUTHOR]

Objectives: c-Met, a receptor tyrosine kinase, is involved in the growth, invasion and metastasis of a variety of cancers. In a set of cell lines from several solid tumors, a five-fold increase in c-Met expression after irradiation has been reported. This study aimed to assess if c-Met is likewise abundantly expressed in oral tongue squamous cell carcinoma (OTSCC) upon exposure to irradiation, followed by a Met-induced biological response. Materials and methods: Six OTSCC cell lines were exposed to gamma radiation doses of 2, 4, and 6 Gray. The changes in c-Met protein levels were assessed by western blot and flow cytometry. c-Met gene expression, cell migration, proliferation and cell cycle assays were performed as phenotypic readouts. Results: Irradiation resulted in upregulation of c.Met in all cell lines with different time kinetics. On average the cells displayed minimal c-Met expression on their surface ranging from 5 to 30% of total protein. Abrupt downregulation of c-Met surface expression occurred one hour after radiation but recovered 48 h post-radiation. Intracellularly, the highest level of expression was found on day 5 after radiation exposure. Irradiation induced aggressive invasive potential of the cells as determined in cell migration assays, particularly in cell lines with the highest c-Met expression. Conclusions: These results provide novel insights into both intracellular and extracellular dynamics of c-Met expression profiles upon irradiation of OTSCC cells in vitro. It might also suggest that radiation enhances cell migration, indicative of invasiveness, through c-Met up-regulation, at least for certain types of OTSCC cells. [ABSTRACT FROM AUTHOR]

This retrospective study addressed the role of oral potentially malignant disorders and the presence of intraepithelial Candida hyphae in the carcinogenesis of the oral tongue squamous cell carcinoma and its association with smoking, alcohol consumption, and oral inflammatory burden. The medical records of 183 subjects diagnosed with oral tongue squamous cell carcinoma at the Helsinki University Hospital were investigated. Preceding oral lichen planus, lichenoid reaction, and leukoplakia diagnosis were recorded. Further, the data on Candida hyphae in histological samples as an indicator of oral candidiasis, oral inflammatory burden, smoking, and alcohol consumption were recorded and analyzed. The histopathological diagnosis of oral lichen planus/lichenoid reaction (p < 0.001) and the presence of Candida hyphae (p = 0.005) were associated significantly with female gender. Oral lichen planus/lichenoid reaction patients were less often smokers than patients without these lesions. Candida hyphae were more often recorded in patients without alcohol use (p = 0.012). Oral lichen planus/lichenoid reaction and Candida hyphae in histological samples were associated with female gender and lower levels of typical risk factors, such as alcohol use and smoking, in oral tongue squamous cell carcinoma patients. Therefore, these patients should be well monitored despite a potential lack of the classical risk factors of oral carcinoma. [ABSTRACT FROM AUTHOR]

Background: Tongue tumors show intra and inter-tumoral heterogenicity with high incidence, relapse and mortality rates necessitating further research. Recurrence/metastasis that occurs after surgical resection of primary cancer is often the reason for poor survival in these patients. Lymph nodes are the most common site of metastasis in tongue tumors. Therefore, premetastatic molecular changes can be best evaluated in lymph nodes which may epitomize the earliest events in the metastasis cascades. The presence of circulating tumor cells(CTCs) in the absence of nodal disease (N0) may represent tumor aggressiveness, suggesting an immune escape which may have high metastatic potential. This trial was developed to investigate the earliest pre-metastatic changes which may regulate tumor dormancy and predict metastasis. A better understanding of organotropism or pre-metastatic changes can help in theragnostic, thereby preventing the outbreak of overt metastasis. Methods: A single-institutional prospective observational cohort study. This trial will be conducted at a tertiary care Centre (Amrita Institute of Medical Sciences Kochi). Eligible patients will be enrolled after obtaining informed consent. The dissected lymph nodes will be subjected to histopathological and immunohistochemical analyses for premetastatic niche (PMN) formation. In addition, circulating tumor cells will be evaluated before treatment and 6 months after treatment. The patients will be followed up for a period of two years to correlate the findings with the recurrence-free survival. Expected results: The pre-metastatic changes, if detected will be a predictive biomarker. It may help to define future drug targets for metastasis chemoprevention . CTCs may define the tumor aggressiveness ,there by prognostication and helps in better disease management. Ethics and dissemination: The study has received the following approval: Ethics Committee of Amrita School of Medicine (ECASM-AIMS-2022-048).Trial Registered Prospectively( CTRI/2022/03/041256 ) on 22/03/2022 under Clinical Trial Registry of India

Background: Oral cancer remains one of the most dreadful diseases in developing nations. Currently, there has been a rise in the prevalence of tongue squamous cell carcinoma (SCC), with a poor prognosis. The use of standard treatment approaches against oral cancer patients brings about several side effects. In recent years, nanomedicine has provided a versatile platform for developing new targeted therapeutic modalities. However, safety remains a concern in the synthesis of nanoparticles (NPs). Therefore, the present study aims to synthesize safer phytoconstituent-mediated gold NPs (AuNPs) utilizing leaf extracts of Annona muricata, where the biochemical components of the plant leaf act as the reducing and capping agents in the synthesis of NPs, and to evaluate its anti-cancer activity against SCC. Materials and Methods: In this in vitro experimental study, AuNPs were synthesized through an effective, simple, and ecologically sound green synthesis method. After characterization of these synthesized AuNPs, in vitro assays such as 3-(4, 5-dimethylthiazole2-yl)-2, 5-biphenyl tetrazolium bromide, wound healing, and clonogenic assays were carried out to investigate the anti-cancer potential of green synthesized AuNPs in the human tongue SCC cell line (SCC-15), and the possible mechanism of action was evaluated through gene and protein expression analysis of Bax, Bcl-2, and p53 genes. The results were expressed as mean ± standard deviation using Statistical Package for Social Sciences (SPSS) 20.0 software and Student's t-test was performed for experimental data. P ≤0.05 were considered statistically significant. Results: The in vitro assays demonstrated that the synthesized AuNPs are exhibiting anti-cancer activity by apoptosis of SCC-15 cells in a dose-dependent manner. Further, it also revealed a highly significant decrease in anti-apoptotic Bcl-2 gene expression, whereas pro-apoptotic genes p53 and Bax revealed a highly significant increase, which is statistically significant compared to the control (P < 0.05). Conclusion: Our findings demonstrated that the AuNPs synthesized from A. muricata leaf extract could act as a novel anticancer agent, particularly against SCC, after further scrutiny.

Background: Tongue tumors show intra and inter-tumoral heterogenicity with high incidence, relapse and mortality rates necessitating further research. Recurrence/metastasis that occurs after surgical resection of primary cancer is often the reason for poor survival in these patients. Lymph nodes are the most common site of metastasis in tongue tumors. Therefore, premetastatic molecular changes can be best evaluated in lymph nodes which may epitomize the earliest events in the metastasis cascades. The presence of circulating tumor cells(CTCs) in the absence of nodal disease (N0) may represent tumor aggressiveness, suggesting an immune escape which may have high metastatic potential. This trial was developed to investigate the earliest pre-metastatic changes which may regulate tumor dormancy and predict metastasis. A better understanding of organotropism or pre-metastatic changes can help in theragnostic, thereby preventing the outbreak of overt metastasis. Methods: A single-institutional prospective observational cohort study. This trial will be conducted at a tertiary care Centre (Amrita Institute of Medical Sciences Kochi). Eligible patients will be enrolled after obtaining informed consent. The dissected lymph nodes will be subjected to histopathological and immunohistochemical analyses for premetastatic niche (PMN) formation. In addition, circulating tumor cells will be evaluated before treatment and 6 months after treatment. The patients will be followed up for a period of two years to correlate the findings with the recurrence-free survival. Expected results: The pre-metastatic changes, if detected will be a predictive biomarker. It may help to define future drug targets for metastasis chemoprevention . CTCs may define the tumor aggressiveness ,there by prognostication and helps in better disease management. Ethics and dissemination: The study has received the following approval: Ethics Committee of Amrita School of Medicine (ECASM-AIMS-2022-048).Trial Registered Prospectively( CTRI/2022/03/041256 ) on 22/03/2022 under Clinical Trial Registry of India

Background: Oral tongue squamous cell carcinoma (OTSCC) is a common malignancy of the oral cavity with poor survival rates. The aim of this project is to investigate the relationship between certain histopathological factors such as Worst Pattern of Invasion (WPOI) and Extranodal Extension (ENE) in patients with oral tongue squamous cell carcinoma (OTSCC) who underwent surgical resection at Loyola University Medical Center. Methods: This was a retrospective cohort study at a tertiary care academic medical center. All patients that underwent primary surgical resection of OTSCC between 1/1/2015 and 1/1/2022 were reviewed. Patients were identified using the Cerner CoPath Laboratory Information System. Results: A total of 82 patients met inclusion criteria and were included in the study. Higher grades of WPOI (WPOI 5) were not significantly associated with the presence of ENE in our study (P = 0.82), regardless of the presence of major or minor ENE. WPOI 5 was associated with a higher incidence of local recurrence (P = 0.011). Conclusions: Higher grades of WPOI were not found to correlate with the presence of ENE, a common histopathological factor that is used as an important prognostic indicator in OTSCC. It is important for clinicians to consider these factors separately when determining whether a patient is high-risk and would benefit from aggressive multimodal treatment. [ABSTRACT FROM AUTHOR]

Introduction: Oral tongue squamous cell carcinoma (OTSCC) is the most common cancer of the oral cavity. Contradictory results have been observed on the involvement of herpes simplex virus 1 (HSV-1) in oral squamous cell carcinomas. Here, we aimed to study the predominance of HSV-1 or HSV-2 in oral HSV infections and to investigate the presence of HSV-1 in OTSCC and its effect on carcinoma cell viability and invasion. Methods: The distribution of HSV types one and two in diagnostic samples taken from suspected oral HSV infections was determined from the Helsinki University Hospital Laboratory database. We then analysed 67 OTSCC samples for HSV-1 infection using immunohistochemical staining. We further tested the effects of HSV-1 using six concentrations (0.00001-1.0 multiplicity of infection [MOI]) on viability and two concentrations (0.001 and 0.1 MOI) on invasion of highly invasive metastatic HSC-3 and less invasive primary SCC-25 OTSCC cell lines using MTT and Myogel-coated Transwell invasion assays. Results: Altogether 321 oropharyngeal samples were diagnosed positive for HSV during the study period. HSV-1 was the predominant (97.8%) HSV type compared with HSV-2 (detected in 2.2% of samples). HSV-1 was also detected in 24% of the OTSCC samples and had no association with patient survival or recurrence. OTSCC cells were viable even after 6 days with low viral load (0.00001, 0.0001, 0.001 MOI) of HSV-1. In both cell lines, 0.001 MOI did not affect cell invasion. However, 0.1 MOI significantly reduced cell invasion in HSC-3 cells. Discussion: HSV-1 infection is predominant compared with HSV-2 in the oral cavity. HSV-1 is detected in OTSCC samples without clinical significance, and OTSCC cell survival or invasion was not affected at low doses of HSV-1. [ABSTRACT FROM AUTHOR]

Objective: The objectives of this study were to estimate the prognostic value of the tumour‐stroma ratio (TSR) and tumour budding (TB) in oral tongue squamous cell carcinoma (OTSCC) and to establish a reliable model to predict the outcome of OTSCC patients. Methods: A total of 103 patients surgically treated at our hospital were enrolled in this study. Chi‐square tests, Kaplan–Meier analyses and Cox proportional hazards regression models were performed for statistical analysis. Results: Fifty‐six patients were categorized as stroma‐rich, and 47 patients were categorized as stroma‐poor. Only pathological grade was associated with the TSR (p = 0.017). Kaplan–Meier analysis showed that stroma‐rich, high‐intensity budding and high risk groups were associated with worse prognosis. The Cox regression model showed that the TSR was an independent risk factor for OTSCC patients prognosis, and the high risk group was also related to poor prognosis (p < 0.05). TB was significantly associated with poor prognosis but was not an independent risk factor. Conclusions: We found that patients in the stroma‐rich group had a worse long‐term prognosis. The TSR is an independent risk factor for OTSCC patients' outcome. In addition, a risk model that combined the TSR and TB proved to be valuable for predicting OTSCC patients' outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: The present study evaluates the reliability of depapillation surrounding oral tongue squamous cell carcinomas (OTSCC) as a perineural invasion predictor and how it could affect narrow-band imaging performance. Our retrospective study was conducted on seventy-six patients affected by OTSCC submitted to radical surgery. The presence of depapillation, clinicopathological variables and narrow-band imaging vascular patterns were analyzed. Our results report that peritumoral depapillation is a reliable feature for perineural invasion in OTSCC, and narrow-band imaging margin detection is not impaired by depapillation. A recent study reported that the occurrence of depapillated mucosa surrounding oral tongue squamous cell carcinomas (OTSCC) is associated with perineural invasion (PNI). The present study evaluates the reliability of depapillation as a PNI predictor and how it could affect narrow-band imaging (NBI) performance. This is thus a retrospective study on patients affected by OTSCC submitted to radical surgery. The preoperative endoscopy was evaluated to identify the presence of depapillation. Differences in distribution between depapillation and clinicopathological variables were analyzed. NBI vascular patterns were reported, and the impact of depapillation on those was studied. We enrolled seventy-six patients. After evaluation of the preoperative endoscopies, 40 (53%) patients had peritumoral depapillation, while 59 (78%) had a positive NBI pattern. Depapillation was strongly correlated to PNI, 54% vs. 28% (p = 0.022). Regarding the NBI pattern, there was no particular association with depapillation-associated tumors. The presence of depapillation did not affect the intralesional pattern detected by the NBI, while no NBI-positive pattern was found in the depapillation area. Finally, the NBI-guided resection margins were not affected by depapillation. Peritumoral depapillation is a reliable feature for PNI in OTSCC. NBI margin detection is not impaired by depapillation. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the impact of a change in macroscopic/surgical margin width upon histological margins and loco-regional failure in early oral tongue squamous cell carcinoma (OTSCC). In 2009, the surgical margin protocol was increased from 10 mm to 15 mm. A retrospective review was performed of all patients who underwent treatment for early OTSCC between 2009 and 2016 with a 15-mm surgical margin (n = 142), and these patients were compared to those treated between 1999 and 2008 with a 10-mm surgical margin (n = 78). There was a significant increase in the rate of clear histological margins (P < 0.001). The rates of close (P = 0.002) and involved (P < 0.001) histological margins decreased significantly. There were significant reductions in local (P < 0.001) and regional (P < 0.001) recurrence rates. This study demonstrated that a surgical margin of 15 mm delivered significantly lower rates of close/involved histological margins and improved local and regional disease recurrence in early OTSCC when compared with a surgical margin of 10 mm. [ABSTRACT FROM AUTHOR]

Introduction: Oral tongue squamous cell carcinoma (OTSCC) is the most common cancer of the oral cavity. Contradictory results have been observed on the involvement of herpes simplex virus 1 (HSV-1) in oral squamous cell carcinomas. Here, we aimed to study the predominance of HSV-1 or HSV-2 in oral HSV infections and to investigate the presence of HSV-1 in OTSCC and its effect on carcinoma cell viability and invasion.Methods: The distribution of HSV types one and two in diagnostic samples taken from suspected oral HSV infections was determined from the Helsinki University Hospital Laboratory database. We then analysed 67 OTSCC samples for HSV-1 infection using immunohistochemical staining. We further tested the effects of HSV-1 using six concentrations (0.00001–1.0 multiplicity of infection [MOI]) on viability and two concentrations (0.001 and 0.1 MOI) on invasion of highly invasive metastatic HSC-3 and less invasive primary SCC-25 OTSCC cell lines using MTT and Myogel-coated Transwell invasion assays.Results: Altogether 321 oropharyngeal samples were diagnosed positive for HSV during the study period. HSV-1 was the predominant (97.8%) HSV type compared with HSV-2 (detected in 2.2% of samples). HSV-1 was also detected in 24% of the OTSCC samples and had no association with patient survival or recurrence. OTSCC cells were viable even after 6 days with low viral load (0.00001, 0.0001, 0.001 MOI) of HSV-1. In both cell lines, 0.001 MOI did not affect cell invasion. However, 0.1 MOI significantly reduced cell invasion in HSC-3 cells.Discussion: HSV-1 infection is predominant compared with HSV-2 in the oral cavity. HSV-1 is detected in OTSCC samples without clinical significance, and OTSCC cell survival or invasion was not affected at low doses of HSV-1.

Background: The extent of neck dissection for tongue SCC is unclear owing to the potential presence of occult level IV metastasis. We aim to assess the incidence of occult level IV nodal metastasis for tongue SCC patients treated in our centre over a 20 year period. Methods: A retrospective analysis of data collected from 1999 to 2019 was performed. Patients diagnosed with oral tongue SCC treated primarily with surgery and a neck dissection fulfilled the inclusion criteria. Results: A total of 124 patients were included in our study. Sixty‐one patients were N0 with no occult level IV metastasis. About 17.3% of clinically node positive patients had level IV metastasis. Length of hospital stay and complication rates were comparable for patients who received levels I–III and I–IV neck dissections. Conclusion: Occult level IV metastasis in N0 tongue SCC patients are exceedingly rare, we would therefore suggest consideration for a level I–III neck dissection. In patients who are clinically node positive, a level I–IV neck dissection would be recommended. [ABSTRACT FROM AUTHOR]

The surgical management of the clinical negative neck node in early oral tongue squamous cell carcinoma (OTSCC) has been the topic of debate since few decades. As the occult cervical lymph node metastasis is considered to be the prime prognostic factor in early OTSCC, this meta-analysis has been carried out to find the risk of regional nodal recurrence, disease specific survival and overall survival rates in outcome of Elective neck dissection (END) versus patients under observation. The articles were electronically retrieved from Ovid Medline, PubMed, Cochrane and Scholar for comparison of END versus Observation in early OTSCC. The search strategy identified 37 relevant review articles from April 1979 to April 2020 from different search engines. A total of 11,973 patients from 32 retrospective analysis, 4 prospective and 1 randomised control trial were included in this meta-analysis. Statistical analysis revealed Overall test (OR: 5.31 95% CI: − 2.132–14.698) with t-test 1.919 and p value 0.113 which is not statistically significant but the readings says that there is always better Disease specific survival with END patients rather than patients kept on observation. Overall test revealed (OR: 13.02 95% CI: 1.360–17.154) with t test 2.382 and p value 0.023 which is statistically significant and showed that End significantly reduced the risk of regional nodal recurrence. Overall test revealed (OR: 7.93 95% CI: − 15.461–4.238) with t test − 1.347 and p value 0.220 which is statistically insignificant and but showed that to some extent Overall survival improves in patient with END than the patients kept on observation. This meta-analysis find that there is statistically significant relationship when Elective neck dissection was performed which reduced the risk of regional nodal recurrence. This analysis didn't statistically find any significance in Disease specific survival and Overall survival with Elective neck dissection patients rather than patients kept on observation but however showed good prognosis when elective neck dissection was performed. [ABSTRACT FROM AUTHOR]

This retrospective study addressed the role of oral potentially malignant disorders and the presence of intraepithelial Candida hyphae in the carcinogenesis of the oral tongue squamous cell carcinoma and its association with smoking, alcohol consumption, and oral inflammatory burden. The medical records of 183 subjects diagnosed with oral tongue squamous cell carcinoma at the Helsinki University Hospital were investigated. Preceding oral lichen planus, lichenoid reaction, and leukoplakia diagnosis were recorded. Further, the data on Candida hyphae in histological samples as an indicator of oral candidiasis, oral inflammatory burden, smoking, and alcohol consumption were recorded and analyzed. The histopathological diagnosis of oral lichen planus/lichenoid reaction (p < 0.001) and the presence of Candida hyphae (p = 0.005) were associated significantly with female gender. Oral lichen planus/lichenoid reaction patients were less often smokers than patients without these lesions. Candida hyphae were more often recorded in patients without alcohol use (p = 0.012). Oral lichen planus/lichenoid reaction and Candida hyphae in histological samples were associated with female gender and lower levels of typical risk factors, such as alcohol use and smoking, in oral tongue squamous cell carcinoma patients. Therefore, these patients should be well monitored despite a potential lack of the classical risk factors of oral carcinoma.

Abstract Background Oral tongue squamous cell carcinoma (OTSCC) is a prevalent malignant disease that is characterized by high rates of metastasis and postoperative recurrence. The aim of this study was to establish a nomogram to predict the outcome of OTSCC patients after surgery. Methods We retrospectively analyzed 169 OTSCC patients who underwent treatments in the Cancer Hospital of Shantou University Medical College from 2008 to 2019. The Cox regression analysis was performed to determine the independent prognostic factors associated with patient’s overall survival (OS). A nomogram based on these prognostic factors was established and internally validated using a bootstrap resampling method. Results Multivariate Cox regression analysis revealed the independent prognostic factors for OS were TNM stage, age, lymphocyte-to-monocyte ratio and immunoglobulin G, all of which were identified to create the nomogram. The Akaike Information Criterion and Bayesian Information Criterion of the nomogram were lower than those of TNM stage (292.222 vs. 305.480; 298.444 vs. 307.036, respectively), indicating a better goodness-of-fit of the nomogram for predicting OS. The bootstrap-corrected of concordance index (C-index) of nomogram was 0.784 (95% CI 0.708–0.860), which was higher than that of TNM stage (0.685, 95% CI 0.603–0.767, P = 0.017). The results of time-dependent C-index for OS also showed that the nomogram had a better discriminative ability than that of TNM stage. The calibration curves of the nomogram showed good consistency between the probabilities and observed values. The decision curve analysis also revealed the potential clinical usefulness of the nomogram. Based on the cutoff value obtained from the nomogram, the proposed high-risk group had poorer OS than low-risk group (P

Despite diagnostic advancements, the development of reliable prognostic systems for assessing the risk of cancer recurrence still remains a challenge. In this study, we developed a novel framework to generate highly representative machine-learning prediction models for oral tongue squamous cell carcinoma (OTSCC) cancer recurrence. We identified cases of 5- and 10-year OTSCC recurrence from the SEER database. Four classification models were trained using the H2O ai platform, whose performances were assessed according to their accuracy, recall, precision, and the area under the curve (AUC) of their receiver operating characteristic (ROC) curves. By evaluating Shapley additive explanation contribution plots, feature importance was studied. Of the 130,979 patients studied, 36,042 (27.5%) were female, and the mean (SD) age was 58.2 (13.7) years. The Gradient Boosting Machine model performed the best, achieving 81.8% accuracy and 97.7% precision for 5-year prediction. Moreover, 10-year predictions demonstrated 80.0% accuracy and 94.0% precision. The number of prior tumors, patient age, the site of cancer recurrence, and tumor histology were the most significant predictors. The implementation of our novel SEER framework enabled the successful identification of patients with OTSCC recurrence, with which highly accurate and sensitive prediction models were generated. Thus, we demonstrate our framework’s potential for application in various cancers to build generalizable screening tools to predict tumor recurrence.

Objectives: To determine whether quantitative parameters derived from dual-energy computed tomography (DECT) were predictive of the aggressiveness of oral tongue squamous cell carcinoma (OTSCC) including the pathologic stages, histologic differentiation, lymph node status, and perineural invasion (PNI). Methods: Between August 2019 and March 2021, 93 patients (mean age, 54.6 ± 13.8 years; 66 men) with pathologically diagnosed OTSCC were enrolled in this prospective study. Preoperative DECT was performed and quantitative parameters (e.g., slope of the spectral Hounsfield unit curve [λHu], normalized iodine concentration [nIC], normalized effective atomic number [nZeff], and normalized electron density [nRho]) were measured on arterial phase (AP) and venous phase (VP) DECT imaging. Quantitative parameters from DECT were compared between patients with different pathologic stages, histologic differentiation, lymph node statuses, and perineural invasion statuses. Logistic regression analysis was utilized to assess independent parameters and the diagnostic performance was analyzed by the receiver operating characteristic curves (ROC). Results: λHu and nIC in AP and λHu, nZeff, and nIC in VP were significantly lower in stage III–IV lesions than in stage I–II lesions (p < 0.001 to 0.024). λHu in VP was an independent predictor of tumor stage with an odds ratio (OR) of 0.29, and area under the curve (AUC) of 0.80. λHu and nIC were higher in well-differentiated lesions than in poorly differentiated lesions (p < 0.001 to 0.021). The nIC in VP was an independent predictor of histologic differentiation with OR of 0.31, and AUC of 0.78. λHu and nIC in VP were lower in OTSCCs with lymph node metastasis than those without metastasis (p < 0.001 to 0.005). λHu in VP was the independent predictor of lymph node status with OR of 0.42, and AUC of 0.74. No significant difference was found between OTSCCs without PNI and those with PNI in terms of the quantitative DECT parameters. Conclusion: DECT can be a complementary means for the preoperative prediction of the aggressiveness of OTSCC. [ABSTRACT FROM AUTHOR]

ObjectiveThe rising incidence of oral tongue squamous cell carcinoma (OTSCC) in patients who have never smoked and the paucity of knowledge of its biological behavior prompted us to develop a new cell line originating from a never-smoker.Materials and methodsFresh tumor tissue of keratinizing OTSCC was collected from a 44-year-old woman who had never smoked. Serum-free media with a low calcium concentration were used in cell culture, and a multifaceted approach was taken to verify and characterize the cell line, designated UCSF-OT-1109.ResultsUCSF-OT-1109 was authenticated by STR DNA fingerprint analysis, presence of an epithelial marker EpCAM, absence of human papilloma virus (HPV) DNA, and SCC-specific microscopic appearance. Sphere-forming assays supported its tumorigenic potential. Spectral karyotype (SKY) analysis revealed numerical and structural chromosomal abnormalities. Whole-exome sequencing (WES) identified 46 non-synonymous and 13 synonymous somatic single-nucleotide polymorphisms (SNPs) and one frameshift deletion in the coding regions. Specifically, mutations of CDKN2A, TP53, SPTBN5, NOTCH2, and FAM136A were found in the databases. Copy number aberration (CNA) analysis revealed that the cell line loses chromosome 3p and 9p, but lacks amplification of 3q and 11q (as does HPV-negative, smoking-unrelated OTSCC). It also exhibits four distinctive focal amplifications in chromosome 19p, containing 131 genes without SNPs. Particularly, 52 genes showed >3- to 4-fold amplification and could be potential oncogenic drivers.ConclusionWe have successfully established a novel OTSCC cell line from a never-smoking patient. UCSF-OT-1109 is potentially a robust experimental model of OTSCC in never-smokers.

ObjectivesTo determine whether quantitative parameters derived from dual-energy computed tomography (DECT) were predictive of the aggressiveness of oral tongue squamous cell carcinoma (OTSCC) including the pathologic stages, histologic differentiation, lymph node status, and perineural invasion (PNI).MethodsBetween August 2019 and March 2021, 93 patients (mean age, 54.6 ± 13.8 years; 66 men) with pathologically diagnosed OTSCC were enrolled in this prospective study. Preoperative DECT was performed and quantitative parameters (e.g., slope of the spectral Hounsfield unit curve [λHu], normalized iodine concentration [nIC], normalized effective atomic number [nZeff], and normalized electron density [nRho]) were measured on arterial phase (AP) and venous phase (VP) DECT imaging. Quantitative parameters from DECT were compared between patients with different pathologic stages, histologic differentiation, lymph node statuses, and perineural invasion statuses. Logistic regression analysis was utilized to assess independent parameters and the diagnostic performance was analyzed by the receiver operating characteristic curves (ROC).ResultsλHu and nIC in AP and λHu, nZeff, and nIC in VP were significantly lower in stage III–IV lesions than in stage I–II lesions (p < 0.001 to 0.024). λHu in VP was an independent predictor of tumor stage with an odds ratio (OR) of 0.29, and area under the curve (AUC) of 0.80. λHu and nIC were higher in well-differentiated lesions than in poorly differentiated lesions (p < 0.001 to 0.021). The nIC in VP was an independent predictor of histologic differentiation with OR of 0.31, and AUC of 0.78. λHu and nIC in VP were lower in OTSCCs with lymph node metastasis than those without metastasis (p < 0.001 to 0.005). λHu in VP was the independent predictor of lymph node status with OR of 0.42, and AUC of 0.74. No significant difference was found between OTSCCs without PNI and those with PNI in terms of the quantitative DECT parameters.ConclusionDECT can be a complementary means for the preoperative prediction of the aggressiveness of OTSCC.

A recent study reported that the occurrence of depapillated mucosa surrounding oral tongue squamous cell carcinomas (OTSCC) is associated with perineural invasion (PNI). The present study evaluates the reliability of depapillation as a PNI predictor and how it could affect narrow-band imaging (NBI) performance. This is thus a retrospective study on patients affected by OTSCC submitted to radical surgery. The preoperative endoscopy was evaluated to identify the presence of depapillation. Differences in distribution between depapillation and clinicopathological variables were analyzed. NBI vascular patterns were reported, and the impact of depapillation on those was studied. We enrolled seventy-six patients. After evaluation of the preoperative endoscopies, 40 (53%) patients had peritumoral depapillation, while 59 (78%) had a positive NBI pattern. Depapillation was strongly correlated to PNI, 54% vs. 28% (p = 0.022). Regarding the NBI pattern, there was no particular association with depapillation-associated tumors. The presence of depapillation did not affect the intralesional pattern detected by the NBI, while no NBI-positive pattern was found in the depapillation area. Finally, the NBI-guided resection margins were not affected by depapillation. Peritumoral depapillation is a reliable feature for PNI in OTSCC. NBI margin detection is not impaired by depapillation.

The appropriate surgical management of early-stage oral tongue squamous cell carcinoma (OTSCC) remains a debated topic. The aim of this study is to investigate the role of the pre-treatment neutrophil to lymphocyte ratio (NLR) and tumor depth of invasion (DOI) in predicting the presence of occult neck metastases in early-stage OTSCC. A retrospective analysis of patients affected by early-stage (cT1-T2 cN0) OTSCC who were submitted to elective neck dissection (END) was performed. Tumors were classified retrospectively according to the 8th TNM classification, the DOI was assessed on the pre-operative magnetic resonance imaging, and the pre-treatment NLR was calculated for each patient. A logistic regression model to estimate the probability π (x) of cervical metastases by studying the NLR and DOI was carried out. Next, the correlation between the two variables, the NLR and DOI, was preliminarily studied. A cohort of 110 patients was analyzed (mean age, 62 years old; male to female ratio 1.2:1). The patients were staged as cT1 in 53 cases and cT2 in 57 cases. A DOI greater than 5.4 mm and a NLR greater than 2.93 are associated with an increased risk of presenting occult cervical metastases. Furthermore, the variables NLR and DOI are linearly associated with a positive correlation, proved by Spearman's rank correlation coefficient rho of 0.64, with a unitary increase in the DOI of 1 mm directly associated with an increase of 0.47 in the NLR. The DOI and NLR can be effectively used to predict the occurrence of occult neck metastasis and therefore to plan an END in early-stage OTSCC. [ABSTRACT FROM AUTHOR]

Objectives: To compare the correlation of depth of invasion (DOI) measured on multiple magnetic resonance imaging (MRI) sequences and pathological DOI, in order to determine the optimal MRI sequence for measurement. Methods: A total of 122 oral tongue squamous cell carcinoma (OTSCC) patients were retrospectively analyzed, who had received preoperative MRI and surgical resection. DOIs measured on fat-suppressed T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), dynamic enhanced-T1 high-resolution insotropic volume examination (e-THRIVE), and contrast-enhanced fat-suppressed T1WI (CE-T1WI) were respectively compared to those measured in pathologic specimens. The cutoff value of the best correlated MRI sequence was determined, and the T staging accuracy of MRI-derived DOI was evaluated. Results: DOI derived from e-THRIVE showed the best correlation (r = 0.936, p < 0.001) with pathological DOI. The area under the curve values of MRI-derived DOI distinguishing T1 stage from T2 stage and distinguishing T2 stage from T3 stage were 0.969 and 0.974, respectively. The T staging criteria of MRI-derived DOI were 6.2 mm and 11.4 mm, with a staging accuracy of 86.9% compared to pathological DOI criteria of 5 mm and 10 mm. Conclusion: E-THRIVE was the optimal MR sequence to measure the MR-derived DOI, and DOI derived from e-THRIVE could serve as a potential cut-off value as a clinical T staging indicator of OTSCC. Key Points: • Multiparametric MRI helps radiologists to assess the neoplasm invasion in patients with oral tongue squamous cell carcinoma. • Retrospective study indicated that measurement was most accurate on enhanced-T1 high-resolution insotropic volume examination dynamic contrast enhancement images. • T staging of oral tongue squamous cell carcinoma was accurate according to the dynamic contrast enhancement MRI-derived depth of invasion. [ABSTRACT FROM AUTHOR]

Abstract Background To assess the feasibility of tongue conservation treatment with induction chemotherapy (ICT), tongue conservation surgery, and risk‐adapted postoperative adjuvant therapy in oral tongue squamous cell carcinoma (OTSCC). Methods Patients with newly diagnosed OTSCC cT2‐4 N0‐2 M0 were recruited. The ICT with a regimen of docetaxel, cisplatin, and oral tegafur/uracil (DCU) was administrated every 21 days. After the first cycle of ICT (DCU1), patients with a more than 30% decrease in the longest diameter of primary tumor underwent a second cycle of ICT (DCU2). Tongue conservation surgery was performed after ICT, and risk‐adapted adjuvant therapy was organized based on pathological features. Results From July 2011 to December 2015, a total of 23 patients were enrolled, 87% of whom were classified as stage III–IV. Clinical responders to DCU1 and DCU2 were determined in 90.5% (19/21) and 88.2% (15/17) of patients. Tongue conservation surgery was performed in 16 responders to ICT. Only one patient had a positive margin (6.3%), and a complete pathologic response was achieved in eight patients (50%). Only one patient developed local recurrence after a median follow‐up of 58.6 months (range, 7.9–105.2). The 5‐year overall survival (0% vs. 87.5%, P = 0.001) and disease‐specific survival (0% vs. 93.3%, P = 0.000) were significantly different between the DCU1 nonresponders and responders. Conclusion Tongue conservation treatment with ICT, followed by conservation surgery and risk‐adapted adjuvant therapy, is feasible for patients with OTSCC who are good responders to ICT. However, the outcomes of nonresponders are dismal. Further study in a larger patient population is warranted.

Background: Oral tongue squamous cell carcinoma (OTSCC) is a prevalent malignant disease that is characterized by high rates of metastasis and postoperative recurrence. The aim of this study was to establish a nomogram to predict the outcome of OTSCC patients after surgery. Methods: We retrospectively analyzed 169 OTSCC patients who underwent treatments in the Cancer Hospital of Shantou University Medical College from 2008 to 2019. The Cox regression analysis was performed to determine the independent prognostic factors associated with patient's overall survival (OS). A nomogram based on these prognostic factors was established and internally validated using a bootstrap resampling method. Results: Multivariate Cox regression analysis revealed the independent prognostic factors for OS were TNM stage, age, lymphocyte-to-monocyte ratio and immunoglobulin G, all of which were identified to create the nomogram. The Akaike Information Criterion and Bayesian Information Criterion of the nomogram were lower than those of TNM stage (292.222 vs. 305.480; 298.444 vs. 307.036, respectively), indicating a better goodness-of-fit of the nomogram for predicting OS. The bootstrap-corrected of concordance index (C-index) of nomogram was 0.784 (95% CI 0.708–0.860), which was higher than that of TNM stage (0.685, 95% CI 0.603–0.767, P = 0.017). The results of time-dependent C-index for OS also showed that the nomogram had a better discriminative ability than that of TNM stage. The calibration curves of the nomogram showed good consistency between the probabilities and observed values. The decision curve analysis also revealed the potential clinical usefulness of the nomogram. Based on the cutoff value obtained from the nomogram, the proposed high-risk group had poorer OS than low-risk group (P < 0.0001). Conclusions: The nomogram based on clinical characteristics and serological inflammation markers might be useful for outcome prediction of OTSCC patient. [ABSTRACT FROM AUTHOR]

Ran Yang,1 Yusen Shui,2 Shoushan Hu,2 Kun Zhang,2 Yuru Wang,2 Yiran Peng1 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, Sichuan, People’s Republic of China; 2Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, People’s Republic of ChinaCorrespondence: Yiran PengDepartment of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, 14 Renmin South Road Third Section, Chengdu 610041, Sichuan, People’s Republic of ChinaTel/ Fax +86-28-85503527Email Drpeng1021@163.comBackground: Oral tongue squamous cell carcinoma (OTSCC) represents oral epithelial cell damage. Myeloblastosis (MYB) is involved in OTSCC. This study tried to probe roles of MYB in OSCC with potential axis.Methods: Expression of MYB and miR-130a in OTSCC was detected. Western blot analysis was utilized to determine epithelial–mesenchymal transition-related protein levels. Dual-luciferase reporter gene assay certified the target relation between miR-130a and CYLD. Moreover, xenograft tumors in nude mice were applied to confirm the in vitro experiments.Results: Both MYB and miR-130a were highly expressed in OTSCC, which promoted cell growth. Meanwhile, silenced miR-130a discouraged cell development enhanced by overexpressed MYB. CYLD was poorly expressed in OTSCC and targeted by miR-130a. Additionally, MYB knockdown activated CYLD to suppress OTSCC by downregulating miR-130a.Conclusion: Our experiment supported that silenced MYB suppressed OTSCC malignancy by inhibiting miR-130a and activating CYLD. This investigation may provide novel insights for OTSCC treatment.Keywords: oral tongue squamous cell carcinoma, MYB, microRNA-130a, CYLD, epithelial–mesenchymal transition, proliferation

Abstract We investigated whether a unique immune response was instigated with the development of oral tongue squamous cell carcinomas (OTSCC), with/without nodal involvement, with/without recurrent metastatic disease, or within tumor involved nodes. One hundred and ten formalin‐fixed paraffin‐embedded samples were collected from a retrospective cohort of 67 OTSCC patients and 10 non‐cancerous tongue samples. Targets including CD4, CD8, FOXP3, PD‐L1, and PD‐1 were analyzed by immunohistochemistry. The Nanostring PanCancer Immune Profiling Panel was used for gene expression profiling. Data were externally validated in the The Cancer Genome Atlas (TCGA) head and neck (HNSCC), melanoma and lung squamous cell carcinoma (LSCC) cohorts. A 24‐immune gene signature was identified that discriminated more aggressive OTSCC cases, and although not prognostic in HNSCC was associated with survival in other TCGA cohorts (improved survival for melanoma, P

Strong evidence has indicated that upregulation of chemokine (CC motif) ligand-2 (CCL2) expression and the presence of an inflammatory tumor microenvironment significantly contribute to the migratory and invasive properties of oral squamous cell carcinoma, specifically oral tongue squamous cell carcinoma (OTSCC). However, the precise epigenetic mechanism responsible for enhanced CCL2 expression in response to the inflammatory mediator tumor necrosis factor alpha (TNF-α) in OTSCC remains inadequately elucidated. We have demonstrated that the production of CCL2 can be induced by TNF-α, and this induction is mediated by the chromatin remodel protein BRG1. Through the use of a chromatin immunoprecipitation (ChIP) assay, we have found that BRG1 was involved in the recruitment of acetylated histones H3 and H4 at the CCL2 promoter, thereby activating TNF-α-induced CCL2 transcription. Furthermore, we have observed that recruitment of NF-κB p65 to the CCL2 promoter was increased following BRG1 overexpression and decreased after BRG1 knockdown in OTSCC cells. Our Re-ChIP assay has shown that BRG1 knockdown completely inhibits the recruitment of both acetylated histone H3 or H4 and NF-κB to the CCL2 promoter. In summary, the findings of our study demonstrate that BRG1 plays a significant role in mediating the production of CCL2 in OTSCC cells in response to TNF-α stimulation. This process involves the cooperative action of acetylated histone and NF-κB recruitment to the CCL2 promoter site. Our data suggest that BRG1 serves as a critical epigenetic mediator in the regulation of TNF-α-induced CCL2 transcription in OTSCC cells., (© 2024 Wiley Periodicals LLC.)

Aims: The 8th edition of the American Joint Committee on Cancer (AJCC) Staging introduced depth of invasion (DOI) into the pT category of oral cavity squamous cell carcinoma. However, we noted multiple practical obstacles in accurately measuring DOI histologically in our daily practice. Methods and results: To compare the prognostic effects of DOI and tumour thickness (TT), a meticulous pathology review was conducted in a retrospective cohort of 293 patients with AJCC 7th edition pT1/T2 oral tongue squamous cell carcinoma. Overall survival (OS) and nodal metastasis rate at initial resection were the primary and secondary outcomes, respectively. We found that TT and DOI were highly correlated with a correlation coefficient of 0.984. The upstage rate was only 6% (18 of 293 patients) when using TT in the pT stage compared with using DOI. More importantly, DOI and TT, as well as pT stage using DOI and pT stage using TT, performed identically in predicting risk of nodal metastasis and OS. Conclusions: We therefore propose to replace DOI, a complicated measurement with many challenges, with TT in the pT staging system. [ABSTRACT FROM AUTHOR]