Advances in Oral Exfoliative Cytology: From Cancer Diagnosis to Systemic Disease Detection.

Oral exfoliative cytology has emerged as a valuable tool in the early detection of oral cancer and other systemic diseases. This review comprehensively examines the current applications and recent advancements in oral exfoliative cytology techniques. We analyzed published literature from the past decade, focusing on methodological improvements, diagnostic accuracy, and emerging applications. Key findings include: (1) Enhanced cell collection and preparation methods have significantly improved sample quality and diagnostic reliability. (2) Integration of molecular markers and DNA analysis with traditional cytomorphological assessment has increased diagnostic sensitivity and specificity for oral cancer detection. (3) Novel applications in systemic disease detection, including diabetes and iron overload disorders, demonstrate the expanding utility of this technique. (4) Computer-assisted analysis and deep learning algorithms show promise in improving diagnostic accuracy and efficiency. Despite these advancements, challenges remain in standardization and widespread clinical implementation. This review provides a critical evaluation of oral exfoliative cytology's current status and future potential in oral and systemic disease diagnosis.

Serum mRNA levels of cytokeratin-19 and vascular endothelial growth factor in oral squamous cell carcinoma and oral potentially malignant disorders using RT-PCR.

BACKGROUND: Oral cancers, which include tumors of the oral cavity, salivary glands, and pharynx, are becoming increasingly prevalent worldwide. Squamous cell carcinoma accounts for over 90% of malignant oral lesions, with oral squamous cell carcinoma (OSCC) being notably common in the Indian subcontinent and other regions of Asia. This is especially true in South-Central Asia, including Sri Lanka, where it is particularly prevalent among men. This study aims to evaluate the levels of Vascular Endothelial Growth Factor-A (VEGF-A) and Cytokeratin-19 (CK-19) mRNAs in whole blood as a potential method for the early detection of OSCC. METHODS: The study included 40 patients (each from OSCC, Oral Submucous Fibrosis (OSF), Oral Leukoplakia (OLK), Oral Lichen Planus (OLP), and 10 healthy controls. The expression levels of VEGF-A and CK-19 mRNAs were measured from extracellular RNA extracted from whole blood samples using real-time reverse transcription polymerase chain reaction (RT-PCR) with sequence-specific primers. Receiver operating characteristic (ROC) curve analysis was used to evaluate the effectiveness of these biomarkers in detecting OSCC. RESULTS: The results demonstrated a significant increase in blood transcripts of the candidate mRNAs CK-19 and VEGF-A in patients with OSCC, OSF, OLK, and OLP. The Wilcoxon signed-rank test revealed a p-value of 0.002 for each specific comparison between diseased patients and healthy controls (i.e., OSCC vs. HC, OSF vs. HC, OLP vs. HC, OLK vs. HC) for both CK-19 and VEGF-A. When these two biomarkers were used together, they provided a 60% predictive probability for patients with OSCC (p = 0.023). CONCLUSION: This study highlights the efficacy of blood mRNA transcriptome diagnostics in detecting OSCC. This innovative clinical approach has the potential to be a robust, efficient, and reliable tool for early cancer detection. Blood-based transcriptomes could be further explored for their effectiveness in various health contexts and for routine health monitoring.

Proportion trends, cancer stage, and survival of patients with cancer diagnosed through emergency and nonemergency departments: a nationwide cohort study.

Introduction: To reduce mortality, the Taiwan government has vigorously promoted free cancer screening and preventive health screening services. Cancers are usually advanced by the time they are discovered in the emergency department. Through this study, we aimed to understand the characteristics of cancer patients diagnosed through the emergency department and thus identify high-risk populations by comparing cancer staging and survival rates in patients diagnosed in the emergency department and those diagnosed in the non-emergency department. Methods: The retrospective study enrolled a total of 389,043 patients over the age of 20 who were newly diagnosed with one of the five major cancers (including lung cancer, colorectal cancer, breast cancer, prostate cancer, and oral cancer) between 2008 and 2017 and analyzed their diagnostic pathway, cancer stage at diagnosis, and survival time. Results: Of the study participants, 59,423 patients (about 15.3%) were diagnosed with cancer through the emergency department. We found that a sizable proportion of older people and patients with low education and low incomes were diagnosed through emergency department visits, and those with a health condition comorbidity severity of 3 had the highest proportion diagnosed by the emergency department, advanced stages at diagnosis, and risk of death. These can be classified as high-risk groups. In addition, 76.4% of patients diagnosed in the emergency department had advanced cancer, and the risk of death was 1.46 times higher than that of patients diagnosed in the non-emergency department. Although cancer screening is available, it does not reduce the proportion of patients with advanced cancer who are diagnosed through or at the time of diagnosis in the emergency department. Conclusions: The present study found that the government's cancer screening did not affect the proportion or number of cancers diagnosed through emergency department visits. Therefore, the government should focus on more cancer screening, health education in high-risk groups, and strengthening the link between emergency and oncology departments to reduce the risk of death for patients diagnosed through emergency department visits.

STAT3 interactome predicts presence of proteins that regulates immune system in oral squamous cell carcinoma.

OBJECTIVES: Signal transducer and activator of transcription 3 (STAT3) is one of the key proliferation mechanism-related proteins that helps in oral squamous cell carcinoma (OSCC) progression. Immune evasion by STAT3 is mediated by the JAK2/STAT3/PDL1 signaling axis. Based on previous findings, we hypothesized that STAT3-binding partners participate in the inhibition of anti-tumor activity in OSCC. METHODS: A 3D cancer-immune co-culture model was constructed using oral cancer cell lines SCC4, SCC9, SCC25, and CAL27 and normal oral cell line OKF6. The cells were co-cultured with natural killer (NK-92) and Jurkat cells. The target protein STAT3 was chosen based on SWATH data, and co-immunoprecipitation (Co-IP)-based proteomics was conducted. The Co-IP LC-MS/MS output was analyzed to determine the protein interaction network, gene ontology, pathway analysis, and protein cluster annotation. RESULTS: STAT3 in oral cancer cell lines interacts with the epidermal growth factor receptor (EGFR) and other proteins that participate in proliferation and immune mechanisms. Proteome analysis showed that some STAT3-binding proteins found in this study are known immune system regulators. CONCLUSION: Overall, STAT3 interactive proteins regulate the immune system in oral squamous cell carcinoma cells.

Risk factors and incidence of oral tumors: Findings from a longitudinal population-based study.

OBJECTIVE: This study investigated risk factors contributed to benign and malignant oral tumors using longitudinal cohort big data. MATERIALS AND METHODS: We included individuals aged ≥40 years who participated in the National Health Examination in South Korea between 2003 and 2004. National Health Insurance claims data after 16 years were used to determine the incidence of oral tumors and the related risk factors. Hazard ratios were calculated using the Cox proportional hazard regression. RESULTS: A total of 5,992,671 participants were included. The incidence of oral cancer was significantly higher in men and increased with age, whereas that of benign tumors was unaffected by sex and decreased with age. Periodontal disease was associated with the incidence of oral cancer but not benign tumors. Soft tissue diseases were associated with both benign and malignant tumors. Various systemic diseases influence the development of oral tumors. Light alcohol consumption reduced the incidence of oral tumors, whereas heavy alcohol consumption increased the incidence of malignant tumors only. Smoking increased the incidence of benign but not malignant tumors. CONCLUSION: Recognized risk factors such as sex, age, comorbidities, and dental diseases were associated with oral tumors. Alcohol consumption and smoking were not significantly associated with malignant tumors.

Early identification of people at high risk of oral cancer-A review of existing risk prediction models.

Prediction plays a ubiquitous role in cancer care. At every stage of the illness, the patient, the physician, and the family must make numerous decisions. Utilizing epidemiological, clinical, biological, lifestyle, and genetic factors, a cancer-specific risk assessment model calculates the likelihood of developing cancer. In India, oral cancer ranks as the fourth most common cancer, affecting nearly 3,000,00 individuals annually. Because it is in the premalignant stage, oral cancer is easily detectable in the oral cavity. Prompt identification of this lesion can result in better outcomes and a higher standard of living. Advanced statistical techniques have been used to develop prediction algorithms or risk scores that identify individuals with a high risk of developing oral cancer. With the aid of these risk assessment models, specific individuals can be screened to aid in the early detection of the disease, which may result in better outcomes and lifestyle modifications. Finding the best model among the current risk models for oral cancer may be aided by a thorough examination of all these models. Finding and assessing the risk model that primary care physicians can use and easily apply in clinical practice will be made easier with a succinct and straightforward comparison of the models. This review compares the current models to determine which has the best performance metrics, which could lead to a better understanding of the advantages and disadvantages of various risk prediction models of oral cancer.

Andrographolide demonstrates anti-proliferative activity in oral cancer by promoting apoptosis, the programmed cell death process.

Objectives: Andrographolide has been studied on different types of human cancer cells, but very few studies have been conducted on oral cancer. The study aimed to evaluate the anticancer potential of Andrographolide on an oral cancer cell line (KB) through in-silico network analysis and in vitro assays. Materials and Methods: The in-silico analysis involved the determination of drug-likeness prediction, prediction of common targets between oral cancer and andrographolide, Protein-Protein Interactions (PPI), hub genes, top 10 associated pathways by Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway, gene ontology (GO), and molecular docking experiments. In vitro assays comprised MTT assay, apoptosis assay, cell cycle analysis, intracellular reactive oxygen species (ROS) measurement, mitochondrial membrane potential (MMP), anti-migration activity, and gene expressions using polymerase chain reaction (PCR). Results: Fifteen common genes were obtained and were seen to be involved in cellular proliferation, regulation of apoptosis, migration of cells, regulation of MAPK cascade, and regulation of cell cycle. The most common genes involved in the top 10 pathways were MAPK1, MAPK8, MAPK14, and IL6 which were seen to be associated with the MAPK signaling pathway which may be the key pathway through which andrographolide may aid in treating oral cancer. In vitro assays showed anti-proliferative properties, late apoptosis, and anti-migratory properties. Conclusion: According to the results obtained, andrographolide has shown anticancer properties and has the potential to be used as a chemotherapeutic drug. The in-silico approach used in the present study can aid as a model for future research in developing efficient cancer treatments.

Establishment of Chemotherapy Prediction Model Based on Hypoxia-Related Genes for Oral Cancer.

Purpose: Identify the hypoxia genes related to chemotherapy resistance of oral cancer, and construct a chemotherapy response model by machine learning algorithm. Methods: 72 oral cancer patients with complete chemotherapy records and chemotherapy reactions were screened from the Cancer Genome Atlas (TCGA) database. According to the chemotherapy reactions, they were divided into chemotherapy sensitive group and chemotherapy resistant group. The differential genes were screened by Limma package. Then the chemotherapy response gene were screened by univariate analysis. Based on the gene expression profile of chemotherapy response, four machine learning algorithms were used to construct the prediction model of chemotherapy response. The core genes were screened by lasso regression analysis. Finally, the prognosis and immune infiltration of the core genes were analyzed. The results were verified by immunohistochemistry (IHC). Results: We obtained 22 hypoxia related differential genes. Univariate analysis found 6 Chemotherapy response genes. Machine learning algorithms show that XGBoost have the best predictive performance for chemotherapy response. ALDOA is the core gene of chemotherapy resistance. Conclusions: Successfully constructed a chemotherapy prediction model for oral cancer by machine learning algorithm. Under hypoxia, the high expression of ALDOA is associated with chemotherapy resistance in oral cancer.

Surgical Factors and Progression of Osteoradionecrosis of Mandible: An Institutional Experience and Recommendations.

The severe complication in oral cancer patients receiving radiation therapy is osteoradionecrosis. The reported incidence of ORN is highly variable, ranging from 0 to 37.5%. Diverse treatment protocols underscore the complexity of managing ORN. This study aims to address the surgical factors and their association with the formation of ORN in patients with oral squamous cell carcinoma undergoing surgery. Data of 17 patients who received definitive surgery and post-operative adjuvant radiotherapy (using the 3D CRT technique alone) to the head and neck from January 2016 to December 2023 presented with post-operative changes, which shows clinical evidence of ORN confirmed by radiographic investigations collected. Among 17 patients, 10 patients (58.8%) had posterior segmental mandibulectomy and seven patients (41.1%) had undergone marginal mandibulectomy with coronoidectomy respectively. Only two patients (11.7%) had regional flap reconstruction using PMMC flap, and for one patient (5.8%), surgical defect closed primarily; the remaining 14 (82.3%) patients underwent free flap reconstruction. Among free flaps, six patients (35.2%) had fibula and seven patients had radial forearm (41.1%) reconstruction. Only one patient (5.8%) underwent reconstruction using an anterolateral thigh flap. Along with consideration of radiation dose, dental extraction, oral hygiene, etc. do anticipate ORN and contemplate surgical risk factors during surgical planning in the management of head and neck cancer.

Alcohol-Containing Mouthwash and the Risk of Oral Cancer: Exploring the Association.

Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both. Mouthwashes are liquid antiseptic solutions that decrease the microbial load in the oral cavity. Alcohol is often used in mouthwashes for its antiseptic functions and as a carrier for some active ingredients, including menthol or thymol, helping them penetrate the plaque. There is some evidence for alcohol-containing mouthwash use which is associated with the potential risk of developing carcinoma of oral cavity. The results are inconclusive, as actual mouthwash use patterns may be inconsistent and cannot be easily quantified. Based on the available data, there is no sufficient evidence to accept the proposition that the use of mouthwashes containing alcohol can influence the development of oral cancer.

The relationship between salivary cytokines and oral cancer and their diagnostic capability for oral cancer: a systematic review and network meta-analysis.

BACKGROUND: Oral cancer (OC) is a common malignancy in clinical practice. Saliva testing is a convenient and noninvasive early diagnostic technique for OC. Several salivary cytokines have been identified as potential biomarkers for OC, including IL-8, IL-6, TNF-α, IL-1ß, and IL-10. Nonetheless, the optimal cytokine for OC diagnosis remains inconclusive and highly contentious. METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were comprehensively retrieved to collect all case-control studies on OC. A meta-analysis was performed to compare the levels of salivary IL-8, IL-6, IL-10, TNF-α, and IL-1ß in OC patients and healthy controls. Network meta-analysis (NMA) was carried out to probe into the accuracy of these salivary cytokines in diagnosing OC. RESULTS: This analysis included 40 studies, encompassing 1280 individuals with OC and 1254 healthy controls. Significantly higher levels of salivary IL-8, IL-6, TNF-α, IL-1ß, and IL-10 were observed in patients with OC in comparison to healthy controls. The results of NMA showed that TNF-α had the highest diagnostic accuracy for OC, with a sensitivity of 79% and a specificity of 92%, followed by IL-6 (sensitivity: 75%, specificity: 86%) and IL-8 (sensitivity: 80%, specificity: 80%). CONCLUSION: This study suggests that IL-8, IL-6, IL-10, TNF-α, and IL-1ß may be potential diagnostic biomarkers for OC. Among them, TNF-α, IL-6, and IL-8 are highly accurate in the diagnosis of OC. Nevertheless, further studies that eliminate other confounding factors are warranted, and more standardized procedures and large-scale studies are needed to support the clinical use of saliva testing.

Evaluation of the Prevalence and Potential Impact of HPV Vaccines in Patients with and Without Oral Diseases: A Ten-Year Retrospective Study.

BACKGROUND: The prevalence of oral human papillomavirus (HPV) in the healthy population and patients with oral diseases such as oral squamous cell carcinoma (OSCC), oral potentially malignant disorders (OPMDs), and oral benign lesions (BL), is not consistently described in the literature, with scarce and often heterogeneous data. In addition, the efficacy of HPV prophylactic vaccines in preventing HPV-related oral disorders has been scarcely investigated. METHODS: The prevalence of HPV and the potential impact of vaccines were analyzed in 1,415 oral rinse specimens, collected over 10 years and grouped into four categories based on histological/clinical diagnosis. RESULTS: HPV prevalence in OSCC, OPMD, and BL patients and in healthy individuals potentially exposed to HPV (HPE) was comparable (12.7 vs. 27.2% vs. 13.5 vs. 9%). Statistical analysis of the vaccine impact involved calculating high and low estimates and showed a significant difference only for the low effect. The nonavalent vaccine had higher low estimates than the bivalent vaccine in OSCC and HPE patients (29.6 vs. 51.9%, p < 0.05; 18.2 vs. 42.4%, p < 0.05), while for OPMD and BL, the frequency of bivalent low estimates was lower than that of quadrivalent and nonavalent (48.6 vs. 68.6%, p < 0.05 and 48.6 vs. 77.1%, p < 0.05; 23.9 vs. 50.7%, p < 0.05, and 23.9 vs. 63.4%, p < 0.05). CONCLUSIONS: This study provided new insights into the prevalence of oral HPV and showed that the nonavalent vaccine may provide better protection than the other vaccines in the presence of an OSCC diagnosis. Conversely, the quadrivalent vaccine may be sufficient to prevent OPMD and BL.

Is long-term administration of PLD-pegylated liposomal doxorubicin able to induce oral cancer?

Leukoplakia, a potentially malignant oral condition, manifests as a nonremovable white lesion that is often linked to risk factors such as smoking, alcohol, and HPV. Pegylated liposomal doxorubicin (PLD), which is used in cancer treatment, has been associated with secondary oral cancers, particularly in patients with leukoplakia. A case study revealed the development of squamous cell carcinoma (SCC) on the tongue following PLD treatment, suggesting a potential link between the drug and malignant transformation. Despite the benefits of PLD in reducing cardiac toxicity, long-term oral monitoring is essential due to the persistent risk of oral cancer posttreatment.

Genetics Affecting the Prognosis of Dental Treatments.

Genetics plays a significant role in determining an individual's susceptibility to dental diseases, the response to dental treatments, and the overall prognosis of dental interventions. Here, the authors explore the various genetic factors affecting the prognosis of dental treatments focusing on dental caries, orthodontic treatment, oral cancer, prosthodontic treatment, periodontal disease, developmental disorders, pharmacogenetics, and genetic predisposition to faster wound healing. Understanding the genetic underpinnings of dental health can help personalize treatment plans, predict outcomes, and improve the overall quality of dental care.

Antihypertensive agent losartan promotes tongue squamous cell carcinoma cell proliferation via EGFR/ERK1/2/cyclin D1 signaling axis.

OBJECTIVE: To study the effects of losartan, an angiotensin II receptor blocker, in the SCC4 and SCC25 human tongue squamous cell carcinoma cell lines. METHODS: Cell proliferation was measured by MTS/PMS activity and trypan blue exclusion assays. The levels of the cell proliferation marker, cyclin D1, were analyzed by western blotting. Apoptosis was assessed by caspase-3 activation and Annexin V-FITC/propidium iodide double staining. Activation of epidermal growth factor receptor (EGFR) and ERK1/2 was validated by western blotting. RESULTS: Moderate concentrations of losartan enhanced the proliferation of SCC4 and SCC25 cells. However, high losartan concentrations induced apoptosis in SCC4 cells. Losartan activated the EGFR/ERK1/2/cyclin D1 signaling axis, which in turn promoted cell proliferation. Afatinib (EGFR inhibitor) and U0126 (ERK1/2 inhibitor) abolished losartan-induced cell proliferation. In contrast, UC2288 (p21 inhibitor) enhanced it. CONCLUSIONS: Losartan exhibited dual effects on tongue squamous cell carcinoma cells. Moderate losartan concentrations facilitated cell proliferation, whereas high concentrations induced cytotoxicity in tongue carcinoma cells.

Diagnostic approach used by US general dental practitioners following discovery of oral lesions suspicious for malignancy/premalignancy: findings from the National Dental Practice-Based Research Network.

Oral cancer examinations seek to clinically identify early oral cancers and discover premalignancies prior to their progression to invasive cancer. A cross-sectional study was conducted between April and August 2017 to explore and quantify the diagnostic approach used by United States (U.S.) general dentists (GDs) following discovery of an oral lesion suspicious for malignancy/premalignancy. U.S. licensed GDs who were clinically-active members of the U.S. National Dental Practice-Based Research Network were eligible to participate. Data for analysis were obtained via two questionnaires. The majority of participants were males, practiced full-time, had a suburban primary practice, were born during the 1950s, and graduated dental school in the 1980s or 2000s. After identifying an oral lesion suspicious for premalignancy/malignancy, the next action of most GD respondents (65.4%) was to refer the patient for consultation/biopsy. Most GDs (87.2%) referred to an oral and maxillofacial surgeon; 22% of GDs reported personally biopsying suspicious lesions. There was a relatively weak association between completing an AEGD or GPR residency and subsequently personally performing biopsies on patients with oral lesions suspicious for malignancy/premalignancy (OR 1.33, p=0.06). Most written referrals take place electronically and often include information, including lesion location (87.0%), lesion sign/symptoms (85.3%), lesion history (83.9%), radiographs (59.3%), medical history (50.6%), dental history (48.8%), and photographs (42.4%). When a referral biopsy was performed, referring clinicians were most frequently informed of the findings via a written report (96.7%,when positive for malignancy/premalignancy and 95.4% when negative). We present a snapshot of current actions taken by U.S. GDs following the discovery of oral abnormalities suspicious for premalignancy/malignancy.

Let-7 reduces the proliferation and migration of oral cancer cells via PI3K/AKT signaling pathway.

The involvement of let-7 in the occurrence and progression of various cancers has been well-documented. However, the precise molecular mechanisms underlying its impact on oral cancer development remain unclear. In this study, we aimed to elucidate the role of let-7 in oral cancer progression and investigate its underlying molecular mechanisms. The expression of let-7 and high mobility group A2 (HMGA2) mRNA was assessed using the quantitative reverse transcription polymerase chain reaction. Western blot analysis was employed to detect the expression of key proteins in the PI3K/AKT signaling pathway as well as HMGA2 protein levels. The targeting relationship between let-7 and HMGA2 was predicted through bioinformatics methods and confirmed via luciferase reporter gene assay. The effects of let-7 and HMGA2 on the functionality of oral cancer cells were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation assay, Transwell assay, wound healing assay, and Annexin V/PI apoptosis assay. Additionally, the impact of let-7 on the growth of oral cancer cells in vivo was investigated by inducing subcutaneous tumor formation in nude mice. Let-7 effectively suppresses the proliferation, migration, and invasion of oral cancer cells by inhibiting the activation of the PI3K/AKT signaling pathway. HMGA2, a downstream target gene of let-7, exhibits high expression in oral cancer. However, overexpression of HMGA2 diminishes the inhibitory effects induced by let-7 overexpression on the proliferation, migration, and invasion of oral cancer cells. The occurrence and progression of oral cancer cells are inhibited by Let-7 through the downregulation of HMGA2, potentially mediated by the inhibition of PI3K/AKT signaling pathway activation.

Role of midline raphe in compartmental surgery for squamous cell carcinoma of the tongue.

PURPOSE: In the present study, we investigated how tumor distance from midline (TDFM) and depth of invasion (DOI) may affect survival outcomes after compartmental tongue surgery (CTS) for oral tongue squamous cell carcinoma (OTSCC). METHODS: A retrospective series of cT2-T3 OTSCC treated with upfront CTS at our Department from 2010 to 2021 was evaluated. Radiological and pathological DOI and TDFM were correlated. The main outcomes were overall (OS) and loco-regional recurrence free survival (LRRFS). The linear relationship between DOI and TDFM with 2-year OS and LRRFS was tested. Survival estimates were obtained by the Kaplan-Meier method. Univariate analysis was performed for variables of interest, and results expressed in terms of hazard ratios and 95% confidence intervals. RESULTS: A total of 64 patients underwent CTS and neck dissection. No significant difference was found between pathological (pDOI) and radiological DOI (rDOI) (p = 0.321) or between pathological (pTDFM) and radiological TDFM (p = 0.435). Two- and 5-year OS and LRRFS were 85.7% and 70.4%, 84.3% and 76.1%, respectively. A linear and significant relationship with OS (p = 0.020) and LRRFS (p = 0.013) was found for pDOI; although linear, the relationship between pTDFM was not statistically significant for either survival outcomes. Once categorized, the ideal cut-off for pDOI according to OS was set at 10 mm (p = 0.023). CONCLUSION: In patients undergoing CTS for primary OTSCC, magnetic resonance-derived rDOI represents an accurate estimate of pDOI, In contrast, TDFM was not associated with OS suggesting that the median raphe is a safe deep margin for CTS. PROTOCOL N: BS/231,009 retrospectively registered.

Causal inference of the effect of plasma proteins on the incidence of oral cancer: two-sample Mendelian randomization.

OBJECTIVE: This study is aimed to investigate the causal relationship between plasma proteins and oral cancer risk using two-sample MR (Mendelian randomization). METHODS: Summary-level GWAS (genome-wide association study) data on plasma protein levels (4,907 proteins) and oral cancer (6,034 cases, 6,585 controls) of European ancestry were utilized. SNPs (single nucleotide polymorphisms) associated with proteins at genome-wide significance were selected as instrumental variables. Multiple MR methods including IVW (inverse-variance weighted), MR-Egger, weighted median, simple mode and weighted mode were applied to estimate causal effects. Sensitivity analyses were conducted. RESULTS: Eight plasma proteins (CCDC167, MID2, NDRG4, PEAR1, PIAS4, RCAN1, SAMHD1 and TNMD) were identified to have significant causal associations with oral cancer risk. NDRG4, RCAN1, SAMHD1 and TNMD were associated with increased oral cancer risk while PEAR1 was associated with decreased risk. The causal estimates were consistent across different methods. Sensitivity analyses indicated the results were robust without significant heterogeneity or horizontal pleiotropy. Multivariable MR adjusting for smoking, alcohol intake and periodontal disease showed CCDC167, MID2, NDRG4, PEAR1, PIAS4 and SAMHD1 still had direct effects on oral cancer. CONCLUSION: This two-sample MR study provides evidence for potentially causal effects of several plasma proteins on oral cancer risk. The identified proteins may serve as biomarkers and shed light on biological mechanisms underlying oral carcinogenesis. Further research is warranted to validate and extend these findings.

PREVALENCE OF OCCULT CERVICAL LYMPH NODES METASTASIS IN CN0 IN ORAL SQUAMOUS CELL CARCINOMA (OSCC).

Occult metastasis is not easily detected clinically or radiographically. Various methods have been applied for neck control for clinically N0 via elective neck dissection (END), wait and watch (W&W) and sentinel lymph node biopsy (SLNB). The main aim of this study is to investigate the prevalence of occult cervical lymph nodes metastasis in cN0 in oral squamous cell carcinoma, to investigate and compare the disease-free state and overall survival rate between occult metastasis and the non-occult group that presented at the oral and maxillofacial surgery clinic, Faculty of Dentistry, Universiti Malaya. This is a retrospective study involving 48 patients with complete data from 2008 to 2019. Data collected includes socio-demographic and clinicopathologic factors. Descriptive analysis was performed and Kaplan-Meier analysis was used to compare disease-free status and overall survival period between occult and non-occult metastases groups. The prevalence of occult metastasis in oral squamous cell carcinoma (OSCC) was low at 8.3% but it became 100% on OSCC tongue. The main tumor site for occult metastasis originated from the oral tongue with T2 size. Non-occult group had better overall survival rate comparing to occult metastasis group and the advanced group. Therefore, END is recommended particularly for N0 OSCC tongue.