Targeting of 3D oral cancer spheroids by αVß6 integrin using near-infrared peptide-conjugated IRDye 680.

BACKGROUND: In the treatment of oral cavity cancer, margin status is one of the most critical prognostic factors. Positive margins are associated with higher local recurrence and lower survival rates. Therefore, the universal goal of oral surgical oncology is to achieve microscopically clear margins. Near-infrared fluorescence guided surgery (FGS) could improve surgical resection using fluorescent probes. αVß6 integrin has shown great potential for cancer targeting due to its overexpression in oral cancers. Red fluorescent contrast agent IRDye 680 coupled with anti-αVß6 peptide (IRDye-A20) represents an asset to improve FGS of oral cancer. This study investigates the potential of IRDye-A20 as a selective imaging agent in 3D three-dimensional tongue cancer cells. METHODS: αVß6 integrin expression was evaluated by RT-qPCR and Western Blotting in 2D HSC-3 human tongue cancer cells and MRC-5 human fibroblasts. Targeting ability of IRDye-A20 was studied in both cell lines by flow cytometry technique. 3D tumor spheroid models, homotypic (HSC-3) and stroma-enriched heterotypic (HSC-3/MRC-5) spheroids were produced by liquid overlay procedure and further characterized using (immuno)histological and fluorescence-based techniques. IRDye-A20 selectivity was evaluated in each type of spheroids and each cell population. RESULTS: αVß6 integrin was overexpressed in 2D HSC-3 cancer cells but not in MRC-5 fibroblasts and consistently, only HSC-3 were labelled with IRDye-A20. Round shaped spheroids with an average diameter of 400 µm were produced with a final ratio of 55%/45% between HSC-3 and MRC-5 cells, respectively. Immunofluorescence experiments demonstrated an uniform expression of αVß6 integrin in homotypic spheroid, while its expression was restricted to cancer cells only in heterotypic spheroid. In stroma-enriched 3D model, Cytokeratin 19 and E-cadherin were expressed only by cancer cells while vimentin and fibronectin were expressed by fibroblasts. Using flow cytometry, we demonstrated that IRDye-A20 labeled the whole homotypic spheroid, while in the heterotypic model all cancer cells were highly fluorescent, with a negligible fluorescence in fibroblasts. CONCLUSIONS: The present study demonstrated an efficient selective targeting of A20FMDV2-conjugated IRDye 680 in 3D tongue cancer cells stroma-enriched spheroids. Thus, IRDye-A20 could be a promising candidate for the future development of the fluorescence-guided surgery of oral cancers.

The prognostic role of single cell invasion and nuclear diameter in early oral tongue squamous cell carcinoma.

BACKGROUND: The clinical significance of single cell invasion and large nuclear diameter is not well documented in early-stage oral tongue squamous cell carcinoma (OTSCC). METHODS: We used hematoxylin and eosin-stained sections to evaluate the presence of single cell invasion and large nuclei in a multicenter cohort of 311 cases treated for early-stage OTSCC. RESULTS: Single cell invasion was associated in multivariable analysis with poor disease-specific survival (DSS) with a hazard ratio (HR) of 2.089 (95% CI 1.224-3.566, P = 0.007), as well as with disease-free survival (DFS) with a HR of 1.666 (95% CI 1.080-2.571, P = 0.021). Furthermore, large nuclei were associated with worse DSS (HR 2.070, 95% CI 1.216-3.523, P = 0.007) and with DFS in multivariable analysis (HR 1.645, 95% CI 1.067-2.538, P = 0.024). CONCLUSION: Single cell invasion and large nuclei can be utilized for classifying early OTSCC into risk groups.

Value of radiological depth of invasion in non-pT4 Oral tongue squamous cell carcinoma: implication for preoperative MR T-staging.

OBJECTIVE: The prognostic stratification for oral tongue squamous cell carcinoma (OTSCC) is heavily based on postoperative pathological depth of invasion (pDOI). This study aims to propose a preoperative MR T-staging system based on tumor size for non-pT4 OTSCC. METHODS: Retrospectively, 280 patients with biopsy-confirmed, non-metastatic, pT1-3 OTSCC, treated between January 2010 and December 2017, were evaluated. Multiple MR sequences, including axial T2-weighted imaging (WI), unenhanced T1WI, and axial, fat-suppressed coronal, and sagittal contrast-enhanced (CE) T1WI, were utilized to measure radiological depth of invasion (rDOI), tumor thickness, and largest diameter. Intra-class correlation (ICC) and univariate and multivariate analyses were used to evaluate measurement reproducibility, and factors' significance, respectively. Cutoff values were established using an exhaustive method. RESULTS: Intra-observer (ICC = 0.81-0.94) and inter-observer (ICC = 0.79-0.90) reliability were excellent for rDOI measurements, and all measurements were significantly associated with overall survival (OS) (all p < .001). Measuring the rDOI on axial CE-T1WI with cutoffs of 8 mm and 12 mm yielded an optimal MR T-staging system for rT1-3 disease (5-year OS of rT1 vs rT2 vs rT3: 94.0% vs 72.8% vs 57.5%). Using multivariate analyses, the proposed T-staging exhibited increasingly worse OS (hazard ratio of rT2 and rT3 versus rT1, 3.56 [1.35-9.6], p = .011; 4.33 [1.59-11.74], p = .004; respectively), which outperformed pathological T-staging based on nonoverlapping Kaplan-Meier curves and improved C-index (0.682 vs. 0.639, p < .001). CONCLUSIONS: rDOI is a critical predictor of OTSCC mortality and facilitates preoperative prognostic stratification, which should be considered in future oral subsite MR T-staging. CLINICAL RELEVANCE STATEMENT: Utilizing axial CE-T1WI, an MR T-staging system for non-pT4 OTSCC was developed by employing rDOI measurement with optimal thresholds of 8 mm and 12 mm, which is comparable with pathological staging and merits consideration in future preoperative oral subsite planning. KEY POINTS: • Tumor morphology, measuring sequences, and observers could impact MR-derived measurements and compromise the consistency with histology. • MR-derived measurements, including radiological depth of invasion (rDOI), tumor thickness, and largest diameter, have a prognostic impact on OS (all p < .001). • rDOI with cutoffs of 8 mm and 12 mm on axial CE-T1WI is an optimal predictor of OS and could facilitate risk stratification in non-pT4 OTSCC disease.

Ultrasonography use for tongue cancer management: A scoping review.

BACKGROUND: Tongue cancer is associated with debilitating diseases and poor prognostic outcomes. The use of imaging techniques like ultrasonography to assist in the clinical management of affected patients is desirable, but its reliability remains debatable. Therefore, the aim of this study is to investigate the importance of ultrasound use for the clinicopathological management of tongue cancer. METHODS: A scoping review was carried out using specific search strategies in the following electronic databases: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Collected data included bibliographical information, study design, ultrasound equipment, the aim of the ultrasonography use, the timing of ultrasound use during oncological treatment (pre-, trans-, and/or post-operatively), and the advantages and disadvantages of the use of the ultrasound. RESULTS: A total of 47 studies were included in this review after following the selection process. The majority of the studies investigated the use of ultrasound pre-operatively for the investigation of lymph node metastases or to determine the tumor thickness and depth of invasion. The sensitivity, specificity, and accuracy of ultrasound to determine clinical lymph node metastases ranged from 47% to 87.2%, from 84.3% to 95.8%, and from 70% to 86.2%, respectively. The sensitivity and specificity to determine the microscopic depth of invasion were 92.3% and from 70.6% to 82.1%, respectively. CONCLUSION: Ultrasonography seems to be a reliable imaging technique for the investigation of important prognostic parameters for tongue cancer, including depth of invasion and lymph node metastases.

Preoperative sleep-disordered breathing and craniofacial abnormalities are risk factors for postoperative sleep-disordered breathing in patients undergoing skin-flap oropharyngeal reconstruction surgery for oral cavity cancer: a prospective case-control study.

PURPOSE: After oropharyngeal reconstruction surgery, excessive flap volume within the oral cavity may increase the risk of pharyngeal obstruction during sleep. This prospective observational study aimed to test a hypothesis that the skin-flap oropharyngeal reconstructive surgery increases nocturnal apnea-hypopnea index (nAHI, primary variable) after surgery. METHODS: Adult patients undergoing oropharyngeal reconstruction surgery participated in this study. The hypothesis was tested by comparing the results of portable type 4 sleep study and craniofacial assessments with lateral head and neck computed tomography scout image before and after surgery. Multiple linear regression analyses were performed to identify predictors for nAHI increase after the surgery. RESULTS: In 15 patients, a postoperative sleep study was performed at 41 (27, 59) (median (IQR)) days after the surgery. nAHI did not increase after the surgery (mean (95% CI), 13.0 (7.2 to 18.7) to 18.4 (10.2 to 26.6) events.hour-1, p = 0.277), while apnea index significantly increased after the surgery (p = 0.026). Use of the pedicle flap for the oropharyngeal reconstruction (p = 0.051), small mandible (p = 0.008), longer lower face (0.005), and larger tongue size (p = 0.008) were independent predictors for worsening of nAHI after surgery. Hospital stay was significantly longer in patients with the pedicle flap (n = 8) than in those with the free flap (n = 7) (p = 0.014), and the period of hospital stay was directly associated with increase of nAHI after surgery (r = 0.788, p < 0.001, n = 15). CONCLUSIONS: Oropharyngeal reconstruction surgery worsens sleep-disordered breathing in some patients with craniofacial and surgical risk factors. TRIAL REGISTRATION: UMIN Clinical Trial Registry (UMIN000036260, March 22, 2019), https://rctportal.niph.go.jp/s/detail/um?trial_id=UMIN000036260.

Impact of dysplasia at resection margin on oncologic outcome after curative resection of oral tongue squamous cell carcinoma: significance of high-grade dysplastic resection margin.

BACKGROUND: This study aimed to compare the oncologic outcomes among negative, close, positive, and dysplasia resection margins (RMs) with oral tongue squamous cell carcinoma (OSCC) and to investigate the impact of dysplastic RMs. METHODS: The 565 patients were retrospectively analyzed and divided into four groups according to RM. Dysplasia was classified into mild, moderate, and severe subgroups. RESULTS: RMs consisted of negative (62.1%), close (27.1%), positive (2.1%), and dysplastic (8.7%). In multivariate analysis, advanced T/N stages and positive RM were significant risk factors for overall survival, while dysplasia at the RM was not a significant risk factor for locoregional recurrence or overall survival. In subgroup analysis of patients with dysplastic margin, RM with severe dysplasia showed higher recurrence than mild and moderate dysplasia. CONCLUSIONS: Dysplastic RM was not a risk factor for recurrence and survival. Severe dysplasia RM should be carefully observed due to higher recurrence compared to other dysplasia RMs.

Global research trends in tongue cancer from 2000 to 2022: bibliometric and visualized analysis.

OBJECTIVES: This study conducts a systematic bibliometric analysis of tongue cancer publications to identify key topics, hotspots, and research distribution. METHODS: We analyzed tongue cancer publications in the Web of Science core collection database, assessing their quantity and quality. We investigated contributors, including countries, affiliations, journals, authors, and categories, within collaborative networks. Additionally, we synthesized key research findings using various analytical techniques, such as alluvial flow, burstness analysis, cluster analysis, co-occurrence network of associations, and network layer overlay. RESULTS: From 2000 to 2022, this bibliometric study covers 2205 articles and reviews across 617 journals, involving 72 countries, 2233 institutions, and 11,266 authors. It shows consistent growth, particularly in 2016. Key contributors include China (499 publications), Karolinska Institute (84 publications), Oral Oncology (144 publications), and Tuula Salo (47 publications). Other notable contributors are the USA (16,747 citations), the National Cancer Institute (NCI) (2597 citations), and the Memorial Sloan-Kettering Cancer Center (MSK) (2231 citations). Additionally, there are significant teams led by Tuula Salo and Dalianis. We have identified six primary clusters: #0 apoptosis, #1 depth of invasion, #2 radiotherapy, #3 hpv, #4 tongue cancer, #5 oral cancer. The top ten highly cited documents primarily pertain to epidemiology, prognostic indicators in early-stage oral tongue cancer, and HPV. Additionally, we observed 16 reference clusters, with depth of invasion (#3), young patients (#4), and tumor budding (#6) gaining prominence since 2012, indicating sustained research interests. CONCLUSIONS: This analysis emphasizes the increasing scholarly interest in tongue cancer research. The bibliometric evaluation highlights pivotal recent research themes such as HPV, depth of invasion, tumor budding, and surgical margins. CLINICAL RELEVANCE: The bibliometric analysis highlights the key topics and studies which have shaped the understanding and management of tongue cancer.

Comparative analysis of volumetric changes between resection volume of oral tongue cancer and post operative volume of radial forearm flaps.

OBJECTIVES: This study investigates the relationship between the total volume of oral tongue cancer pre-operatively and the RFFF volume post-operatively. MATERIALS AND METHODS: A total of 52 DICOM imaging datasets (CT or MRI) of 26 patients were included in this study. The volume of the desired structure was quantified using semi-automatic segmentation using the software ITK-SNAP. All extracted measurements were validated by two further clinicians at separate instances. RESULTS: The variation of MeanVolTu can be predicted by MeanVolFlap moderately reliable with 59.1% confidence (R-Qua: 0.591). ANOVA Testing to represent how well the regression line fits the data, resulted in the overall regression model being statistically significant in predicting the MeanVolTu (p < 0.001). The flap volume may be predicted using the following algorithm: MeanVolFlap0 = 3241,633 + 1, 322 * MeanVolTu. CONCLUSION: The results of this study show positive correlation between tumor volume and flap volume, highlighting the significance of efficient flap planning with increasing tumor volume. A larger extraction volume of the radial forearm free flap from the donor site compromises the forearm more, thus increasing the probability of post-operative complications. CLINICAL RELEVANCE: Radial forearm free flap design in accordance with its corresponding 3D tumor volume.

The prognostic role of MRI-based radiomics in tongue carcinoma: a multicentric validation study.

PURPOSE: Radiomics is an emerging field that utilizes quantitative features extracted from medical images to predict clinically meaningful outcomes. Validating findings is crucial to assess radiomics applicability. We aimed to validate previously published magnetic resonance imaging (MRI) radiomics models to predict oncological outcomes in oral tongue squamous cell carcinoma (OTSCC). MATERIALS AND METHODS: Retrospective multicentric study on OTSCC surgically treated from 2010 to 2019. All patients performed preoperative MRI, including contrast-enhanced T1-weighted (CE-T1), diffusion-weighted sequences and apparent diffusion coefficient map. We evaluated overall survival (OS), locoregional recurrence-free survival (LRRFS), cause-specific mortality (CSM). We elaborated different models based on clinical and radiomic data. C-indexes assessed the prediction accuracy of the models. RESULTS: We collected 112 consecutive independent patients from three Italian Institutions to validate the previously published MRI radiomic models based on 79 different patients. The C-indexes for the hybrid clinical-radiomic models in the validation cohort were lower than those in the training cohort but remained > 0.5 in most cases. CE-T1 sequence provided the best fit to the models: the C-indexes obtained were 0.61, 0.59, 0.64 (pretreatment model) and 0.65, 0.69, 0.70 (posttreatment model) for OS, LRRFS and CSM, respectively. CONCLUSION: Our clinical-radiomic models retain a potential to predict OS, LRRFS and CSM in heterogeneous cohorts across different centers. These findings encourage further research, aimed at overcoming current limitations, due to the variability of imaging acquisition, processing and tumor volume delineation.

Occupation and tongue cancer in Nordic countries.

PURPOSE: Almost 200,000 tongue cancers were diagnosed worldwide in 2020. The aim of this study was to describe occupational risk variation in this malignancy. METHODS: The data are based on the Nordic Occupational Cancer (NOCCA) study containing 14.9 million people from the Nordic countries with 9020 tongue cancers diagnosed during 1961-2005. The standardized incidence ratio (SIR) of tongue cancer in each occupational category was calculated using national incidence rates as the reference. RESULTS: Among men, the incidence was statistically significantly elevated in waiters (SIR 4.36, 95% confidence interval (CI) 3.13--5.92), beverage workers (SIR 3.42, 95% CI 2.02-5.40), cooks and stewards (SIR 2.55, 95% CI 1.82-3.48), seamen (SIR 1.66, 95% CI 1.36-2.00), journalists (SIR 1.85, 95% CI 1.18-2.75), artistic workers (SIR 2.05, 95% CI 1.54-2.66), hairdressers (SIR 2.17, 95% CI 1.39-3.22), and economically inactive persons (SIR 1.57, 95% CI 1.42-1.73). Among women, the SIR was statistically significantly elevated only in waitresses (SIR 1.39, 95% CI 1.05-1.81). Statistically significant SIRs ≤ 0.63 were observed in male farmers, gardeners, forestry workers and teachers, and in female launderers. CONCLUSIONS: These findings may be related to consumption of alcohol and tobacco, but the effect of carcinogenic exposure from work cannot be excluded.

Enhancing deep learning classification performance of tongue lesions in imbalanced data: mosaic-based soft labeling with curriculum learning.

BACKGROUND: Oral potentially malignant disorders (OPMDs) are associated with an increased risk of cancer of the oral cavity including the tongue. The early detection of oral cavity cancers and OPMDs is critical for reducing cancer-specific morbidity and mortality. Recently, there have been studies to apply the rapidly advancing technology of deep learning for diagnosing oral cavity cancer and OPMDs. However, several challenging issues such as class imbalance must be resolved to effectively train a deep learning model for medical imaging classification tasks. The aim of this study is to evaluate a new technique of artificial intelligence to improve the classification performance in an imbalanced tongue lesion dataset. METHODS: A total of 1,810 tongue images were used for the classification. The class-imbalanced dataset consisted of 372 instances of cancer, 141 instances of OPMDs, and 1,297 instances of noncancerous lesions. The EfficientNet model was used as the feature extraction model for classification. Mosaic data augmentation, soft labeling, and curriculum learning (CL) were employed to improve the classification performance of the convolutional neural network. RESULTS: Utilizing a mosaic-augmented dataset in conjunction with CL, the final model achieved an accuracy rate of 0.9444, surpassing conventional oversampling and weight balancing methods. The relative precision improvement rate for the minority class OPMD was 21.2%, while the relative [Formula: see text] score improvement rate of OPMD was 4.9%. CONCLUSIONS: The present study demonstrates that the integration of mosaic-based soft labeling and curriculum learning improves the classification performance of tongue lesions compared to previous methods, establishing a foundation for future research on effectively learning from imbalanced data.

Genetic Features of Tongue Cancer Recurrence in Young Adults.

To identify genetic alterations associated with tongue cancer recurrence in young adults, whole exome sequencing of the primary tumor, recurrence, and whole blood samples from young patients with tongue cancer was performed. A frameshift mutation in the TP53 gene was detected in the primary tumor and recurrence tumor tissue. A mutation in the EPHB6 gene was detected in the recurrence and was absent in the primary tumor. In addition, the primary tumor and recurrence tongue cancer tissue harbored amplification of the 20p13 region containing C20orf96, DEFB125, DEFB126, DEFB127, DEFB128, DEFB129, DEFB132, and ZCCHC3 genes. Thus, genetic alterations have been identified that are associated with tongue cancer recurrence in young adults.

PRI-724 and IWP-O1 Wnt Signaling Pathway Inhibitors Modulate the Expression of Glycolytic Enzymes in Tongue Cancer Cell Lines.

The dysregulation of energetic metabolism is one of the hallmarks of cancer cells. Indeed, the growth of head and neck squamous cell carcinoma (HNSCC) cells depends heavily on glycolytic activity, which can be considered a potential therapeutic target. Wnt signaling is one of the pathways that undergoes upregulation in HNSCC. Our previous studies have shown that Wnt signaling inhibitors-PRI-724 and IWP-O1-attenuate tongue SCC survival and reduce glucose uptake and lactate release. The aim of this research was to further evaluate the possible mechanisms of the previously observed effects. We assessed the effect of PRI-724 and IWP-O1 on the expression of selected glycolytic enzymes: phosphofructokinase M, pyruvate kinase M2, and lactate dehydrogenase. Relative transcript expression was assessed by real-time PCR, and protein levels by Western blot. Moreover, clinical data concerning mRNA and protein expression, gene promoter methylation, and HNSCC patients' survival time were analyzed by the UALCAN tool, and protein-protein interaction was assessed using the STRING database. Experimental and bioinformatic data confirmed the relation between Wnt signaling and glycolytic enzymes in tongue cancer cells and HNSCC clinical samples. Overall, the inhibition of glucose metabolism by Wnt signaling inhibitors is a promising mode of action against tongue cancer cells.

The combination of volumetric arc radiation therapy and boost high-dose rate interstitial brachytherapy for T3N2c tongue cancer: a technical report.

Currently, tongue cancers are primarily managed by surgery, and interstitial brachytherapy is only recommended for a selected group of early state T1-2N0 patients who refuse surgery or are medically inoperable. In this report, a case with T3N2cM0 tongue cancer who has been effectively treated by the combination of concurrent chemoradiotherapy involving volumetric arc therapy and boost high-dose rate interstitial brachytherapy is presented. Of course, surgery remains the main treatment strategy for tongue cancer patients; however, the authors believe that if volumetric arc therapy is carefully planned to reduce the mandible dose as much as possible and high-dose rate interstitial brachytherapy with a mouthpiece that protects the mandible is combined, it is possible to treat T3N2 disease, and this can be considered for patients who want to preserve organ function.

Three-dimensional assessment of tongue cancer prognosis by preoperative MRI.

PURPOSE: To obtain the relative volume by measuring the tongue volume and the lesion volume, and further explore its relationship with the prognosis of patients, hoping to supplement the TNM staging with a new index. METHODS: ITK-SANP software was used to outline the patients' MRI. After MRI reconstruction and measurement, slicer software was used to estimate tumor volume. RESULTS: A total of 64 patients with tongue cancer who met the inclusion criteria were included in the study. The estimated tumor volume after MRI reconstruction revealed a significant and robust correlation with tumor stage (p < 0.05, Rs = 0.6207) and a substantial and medium correlation with early lymph node metastasis (p < 0.05, Rs = 0.4873). CONCLUSIONS: We classified tongue cancer into three grades based on tumor volume (Stage I, tumors smaller than 1500 mm³; Stage II, tumors 1500-9000 mm³; and Stage III, tumors larger than 9000 mm³), and such grading could be used as a reference for tumor staging, lymph node metastasis, and patient prognosis to a certain extent.

Epidemiology of tongue squamous cell carcinoma: A retrospective cohort study.

OBJECTIVE: To analyze the epidemiological profile and the specific survival of patients diagnosed with tongue squamous cell carcinoma at the National Cancer Institute (INCA). MATERIALS AND METHODS: Hospital Cancer Registry System Data and Mortality Information from 2007 to 2009 were retrieved in a retrospective cohort study of patients diagnosed with tongue squamous cell carcinoma. Specific survival was estimated using the Kaplan-Meier method. The association between independent variables and the risk of death was explored in a Cox proportional hazards regression model. RESULTS: A total of 346 patients were eligible, mostly male (77.5%), smokers (87.6%), with alcohol consumption (80.9%), with low education (65.6%), advanced staging at the time of diagnosis (71.1%), and presenting a high mortality rate (72.5%). In total, 44.5% of patients underwent a surgical approach alone or associated with another treatment modality, of which 85.1% of patients underwent neck dissection and 90.1% had free surgical margins. Specific survival was 40.6% in two years and 31.2% in five years. CONCLUSION: The 5-year specific survival was considered worse in individuals over 60 years, and who did not undergo surgical treatment or had surgery associated with another treatment, compared to patients undergoing isolated surgery.

Oral mucosal disease recognition based on dynamic self-attention and feature discriminant loss.

OBJECTIVES: To develop a dynamic self-attention and feature discrimination loss function (DSDF) model for identifying oral mucosal diseases presented to solve the problems of data imbalance, complex image background, and high similarity and difference of visual characteristics among different types of lesion areas. METHODS: In DSDF, dynamic self-attention network can fully mine the context information between adjacent areas, improve the visual representation of the network, and promote the network model to learn and locate the image area of interest. Then, the feature discrimination loss function is used to constrain the diversity of channel characteristics, so as to enhance the feature discrimination ability of local similar areas. RESULTS: The experimental results show that the recognition accuracy of the proposed method for oral mucosal disease is the highest at 91.16%, and is about 6% ahead of other advanced methods. In addition, DSDF has recall of 90.87% and F1 of 90.60%. CONCLUSIONS: Convolutional neural networks can effectively capture the visual features of the oral mucosal disease lesions, and the distinguished visual features of different oral lesions can be extracted better using dynamic self-attention and feature discrimination loss function, which is conducive to the auxiliary diagnosis of oral mucosal diseases.

Ferroptosis induced by plasma-activated Ringer's lactate solution prevents oral cancer progression.

OBJECTIVE: This study aimed to investigate the effect of plasma-activated Ringer's lactate solution (PAL) on oral squamous cell carcinoma (OSCC) cells and carcinogenic processes with a particular focus on iron and collagenous matrix formation. MATERIALS AND METHODS: We used three OSCC cell lines, one keratinocyte cell line, and two fibroblast lines, and cell viability assays, immunoblotting, flow cytometry, and transmission electron microscopy were performed to evaluate the effect and type of cell death. The effect of PAL treatment on lysyl oxidase (LOX) expression was investigated in vitro and in vivo. Tamoxifen-inducible Mob1a/b double-knockout mice were used for the in vivo experiment. RESULTS: PAL killed OSCC cells more effectively than the control nontumorous cells and suppressed cell migration and invasion. Ferroptosis occurred and the protein level of LOX was downregulated in cancer cells in vitro and in vivo. Additionally, PAL improved the survival rate of mice and suppressed collagenous matrix formation. CONCLUSIONS: We demonstrated that PAL specifically kills OSCC cells and that ferroptosis occurs in vitro and in vivo. Furthermore, PAL can prevent carcinogenesis and improve the survival rate of oral cancer, especially tongue cancer, by changing collagenous matrix formation via LOX suppression.

Modified submandibular mandibulotomy approach versus lip-splitting approach in tongue cancer surgery: a retrospective paired-cohort study.

OBJECTIVES: The surgical approach for resection and reconstruction of tongue cancer (TSCC) with or without the lip-splitting incision is controversial. This study introduced a modified approach without lip-splitting and the clinical results were assessed. METHODS: Sixty-eight TSCC patients underwent surgery using the modified submandibular mandibulotomy (MSMM) approach without lip-splitting, and another matched 68 patients using lip-splitting mandibulotomy (LSM) approach were enrolled in this study. The clinical results including intraoperative relevance and surgical morbidities, survival status, facial appearance and scar scores, function of lower lip, and quality of life (QOL) were evaluated. RESULTS: The primary tumors were en bloc resected through the MSMM approach with excellent tumor exposure and R0 resection margins as LSM approach. The survival status and complications were similar in both groups. The function of lower lip was better in patients of MSMM group at 1 month after surgery. The MSMM approach was associated with significantly better facial appearance and recreation compared to LSM approach by scar scores and QOL assessment. CONCLUSION: The MSMM approach without lip-splitting achieves similar tumor control, better aesthetic results, and QOL compared to LSM approach. It is a safe and effective surgical approach for patients with TSCC. CLINICAL RELEVANCE: The MSMM approach without lip-splitting is oncological safety in tongue cancer surgery and is scrutinized as one part of the treatment concept for better aesthetic results.

Alterations of posterior pharyngeal wall movement during swallowing in postoperative tongue cancer patients: assessment with a videofluoroscopic swallowing study.

This study aimed to determine the association between the progressive contraction of the posterior pharyngeal wall and dysphagia in postoperative patients with tongue cancer. A videofluoroscopic swallowing study (VFSS) was performed in 34 patients after tongue cancer surgery. Images were analyzed using a two-dimensional video measurement software. Cases in which the processes on the posterior pharyngeal wall moved downward from the 2nd to 4th vertebral regions were defined as "normal type", other cases were defined as "abnormal type". Twenty-four patients showed normal movement of the posterior pharyngeal wall, whereas 10 patients showed the abnormal type. The results showed that there was a significant difference in dysphagia scores between the postoperative swallowing type and swallowing dysfunction score. This implies that dysphagia is related to the movement of the posterior pharyngeal wall after tongue cancer surgery. Furthermore, the extent of resection and stage were significantly different between the normal and abnormal groups in the posterior pharyngeal wall movement. There was also a significant difference between the two groups in terms of the following: whether the tongue base was included in the excision range (p < 0.01), whether neck dissection was performed (p < 0.01), or whether reconstruction was not performed (p < 0.01). VFSS results showed that posterior pharyngeal wall movement was altered after surgery in patients with tongue cancer who had severe dysphagia.