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Personalized Preventive Medicine of Oral Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Epidemiology and Prevention".

Deadline for manuscript submissions: closed (15 February 2022) | Viewed by 59854

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Special Issue Editors

Dr. Pierre Saintigny

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Guest Editor

1. Department of Medical Oncology, Léon Bérard Center, Lyon 69008, France.
2. Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Cancer Research Center of Lyon, Lyon 69008, France
Interests: head and neck premalignant lesion; head and neck cancer; medical oncology; translational research; biomarker development; molecular classification

Dr. Senada Koljenović

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Guest Editor

Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands
Interests: head and neck cancer; premalignant lesions; translational research; vibrational spectroscopy; Raman spectroscopy

Dr. Paolo Bossi

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Unit of Medical Oncology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, ASST Spedali Civili of Brescia, University of Brescia, Brescia, Italy
Interests: cancer chemotherapy; cancer diagnostics; cancer biology; head and neck cancer; sinonasal cancer; skin cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Jebrane Bouaoud

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Guest Editor

1. Sorbonne University, Department of Maxillo-Facial Surgery, Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris, Paris 75013, France.
2. Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Léon Bérard Center, Cancer Research Center of Lyon, Lyon 69008, France
Interests: head and neck carcinogenesis; premalignant lesion; head and neck cancer; head and neck sarcoma; surgery; pathology; immune microenvironment; translational research

Special Issue Information

Dear Colleagues,

Oral squamous cell carcinoma (OSCC) is the most frequent cancer in the head and neck region. Preneoplastic changes, defined as oral potentially malignant disorders (OPMD), may be diagnosed before and/or after OSCC treatment. These preneoplastic changes may therefore serve as a relevant model and opportunity for preventing subsequent transformation to primary or second primary OSCC.

In this Special Issue, we propose to focus on recent progress made in the study of OPMD, including different aspects: clinical and pathological assessment, epidemiology, screening methods, patient management and trajectories, clinical and pathological diagnosis, biology of the disease, molecular and immunological characterization and classification, biomarkers, preclinical models, and innovative pharmacological strategies for chemoprevention. We expect that this unique effort will facilitate interaction and collaboration between all stakeholders and will pave the road to personalized preventive medicine not only for oral cancer but cancer in general.

Dr. Pierre Saintigny
Dr. Senada Koljenović
Dr. Paolo Bossi
Dr. Jebrane Bouaoud
Guest Editors

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Keywords

preneoplasia
oral potentially malignant disorder
oral leukoplakia
oral dysplasia
risk assessment
malignant transformation
molecular classification
immune characterization
immunoprevention
field cancerization

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Published Papers (13 papers)

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13 pages, 1155 KiB

Open AccessArticle

Identification of a Gene-Expression-Based Surrogate of Genomic Instability during Oral Carcinogenesis

by Eléonore Truchard, Chloé Bertolus, Pierre Martinez, Emilie Thomas, Pierre Saintigny and Jean-Philippe Foy

Cancers 2022, 14(3), 834; https://doi.org/10.3390/cancers14030834 - 7 Feb 2022

Cited by 5 | Viewed by 2424

Abstract

Background: Our goal was to identify a gene-expression-based surrogate of genomic instability (GI) associated with the transformation of oral potentially malignant disorder (OPMD) into oral squamous cell carcinoma (OSCC). Methods: GI was defined as the fraction of genome altered (FGA). Training sets included the CCLE and TCGA databases. The relevance of the enrichment score of the top correlated genes, referred to as the GIN score, was evaluated in eight independent public datasets from the GEO repository, including a cohort of patients with OPMD with available outcome. Results: A set of 20 genes correlated with FGA in head and neck SCC were identified. A significant correlation was found between the 20-gene based GIN score and FGA in 95 esophagus SCC (r = 0.59) and 501 lung SCC (r = 0.63), and in 33 OPMD/OSCC (r = 0.38). A significantly increased GIN score was observed at different stages of oral carcinogenesis (normal–dysplasia –OSCC) in five independent datasets. The GIN score was higher in 10 OPMD that transformed into oral cancer compared to 10 nontransforming OPMD (p = 0.0288), and was associated with oral-cancer-free survival in 86 patients with OPMD (p = 0.0081). Conclusions: The GIN score is a gene-expression surrogate of GI, and is associated with oral carcinogenesis and OPMD malignant transformation. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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16 pages, 1132 KiB

Open AccessArticle

Deep Learning Predicts the Malignant-Transformation-Free Survival of Oral Potentially Malignant Disorders

by John Adeoye, Mohamad Koohi-Moghadam, Anthony Wing Ip Lo, Raymond King-Yin Tsang, Velda Ling Yu Chow, Li-Wu Zheng, Siu-Wai Choi, Peter Thomson and Yu-Xiong Su

Cancers 2021, 13(23), 6054; https://doi.org/10.3390/cancers13236054 - 1 Dec 2021

Cited by 34 | Viewed by 5755

Abstract

Machine-intelligence platforms for the prediction of the probability of malignant transformation of oral potentially malignant disorders are required as adjunctive decision-making platforms in contemporary clinical practice. This study utilized time-to-event learning models to predict malignant transformation in oral leukoplakia and oral lichenoid lesions. A total of 1098 patients with oral white lesions from two institutions were included in this study. In all, 26 features available from electronic health records were used to train four learning algorithms—Cox-Time, DeepHit, DeepSurv, random survival forest (RSF)—and one standard statistical method—Cox proportional hazards model. Discriminatory performance, calibration of survival estimates, and model stability were assessed using a concordance index (c-index), integrated Brier score (IBS), and standard deviation of the averaged c-index and IBS following training cross-validation. This study found that DeepSurv (c-index: 0.95, IBS: 0.04) and RSF (c-index: 0.91, IBS: 0.03) were the two outperforming models based on discrimination and calibration following internal validation. However, DeepSurv was more stable than RSF upon cross-validation. External validation confirmed the utility of DeepSurv for discrimination (c-index—0.82 vs. 0.73) and RSF for individual survival estimates (0.18 vs. 0.03). We deployed the DeepSurv model to encourage incipient application in clinical practice. Overall, time-to-event models are successful in predicting the malignant transformation of oral leukoplakia and oral lichenoid lesions. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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22 pages, 7859 KiB

Open AccessArticle

Correlation of Soluble CD44 Expression in Saliva and CD44 Protein in Oral Leukoplakia Tissues

by Ingrīda Čēma, Madara Dzudzilo, Regīna Kleina, Ivanda Franckevica and Šimons Svirskis

Cancers 2021, 13(22), 5739; https://doi.org/10.3390/cancers13225739 - 16 Nov 2021

Cited by 9 | Viewed by 3139

Abstract

The aim of this study was to determine whether and how pan-CD44 protein expression in leukoplakia tissues correlates with positive SolCD44 test presence and their role in oral leukoplakia. SolCD44 and total protein expression in saliva were determined using an OncAlert^® Oral Cancer Rapid test. Comparison of paired associations of total protein, SolCD44, mean number of CD44 expressed epithelial layers in leukoplakia tissue, and macrophages below the basement membrane between control group and patients with leukoplakia showed statistically significant results (p < 0.0001). It is shown that the total protein indicates low or elevated risk of possible malignant transformation processes in leukoplakia. Statistically significant differences between higher total protein level and clinical forms of oral leukoplakia (p < 0.0001), as well as CD44-labeled epithelial cell layer decrease (p < 0.0001), were found. This possibly points to the onset of the stemness loss in leukoplakia tissue. CD9 antigen expression in the exosomes of the oral epithelium explained the intercellular flow of SolCD44 and other fluids in the leukoplakia area. We conclude that the OncAlert^® Oral Cancer Rapid test is a valuable screening method in daily clinical practice, in terms of complementing clinical diagnostics methods and to assess the potential for early malignancy. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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18 pages, 3770 KiB

Open AccessArticle

RARβ Expression in Keratinocytes from Potentially Malignant Oral Lesions: The Functional Consequences of Re-Expression by De-Methylating Agents

by Raghu Radhakrishnan, Hannah L. Crane, Marc Daigneault, Kanaka Sai Ram Padam and Keith D. Hunter

Cancers 2021, 13(16), 4064; https://doi.org/10.3390/cancers13164064 - 12 Aug 2021

Cited by 1 | Viewed by 2509

Abstract

Loss of RARβ2 expression by promoter methylation is an early event in oral carcinogenesis. Understanding the mechanisms and consequences of RARβ loss may aid in understanding the disappointing results of retinoid chemoprevention trials. This study aimed to describe the effects of all-trans retinoic acid (ATRA) and the de-methylating agent 5-Aza-2′ deoxycytidine (5-AZA-CdR) on a panel of immortal potentially malignant oral lesion (PMOL) cell cultures. RARβ expression was assessed in PMOL tissues by immunohistochemistry. Cells were treated with ATRA ± 5-AZA-CdR, and the effects on the cell cycle and senescence were assessed. In PMOL tissues, RARβ expression was variable, but lower in biopsies which gave rise to immortal cell cultures. Treatment of iPMOL cells with ATRA resulted in little change in RARβ expression, but the addition of 5-AZA-CdR resulted in significant increases. The effects on the cell cycle and senescence were variable and may be related to 5-AZA-CdR, as this has wider effects on the cell cycle. Overall, the response of iPMOL cells to ATRA and 5-AZA-CdR treatment was variable and is dependent on several factors, including RARβ-promoter methylation. These findings may help to explain the lack of consistent effect of retinoids in PMOLs seen in chemoprevention trials. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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27 pages, 4712 KiB

Open AccessArticle

Genetic and Proteinic Linkage of MAO and COMT with Oral Potentially Malignant Disorders and Cancers of the Oral Cavity and Pharynx

by Ping-Ho Chen, Yen-Yun Wang, Ting-Hsun Lan, Leong-Perng Chan and Shyng-Shiou Yuan

Cancers 2021, 13(13), 3268; https://doi.org/10.3390/cancers13133268 - 29 Jun 2021

Cited by 2 | Viewed by 2383

Abstract

Betel quid (BQ), a group I human carcinogen, strongly contributes to an increased risk of oral potentially malignant disorders (OPMD) and cancers of the oral cavity and pharynx. This study was conducted to discover whether monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) variants play a potential role in the risk assessment of oral cavity and pharynx cancers and OPMD, particularly among BQ users. We applied a case–control study to confirm the polymorphism of MAO and COMT using single-nucleotide polymorphisms. We used qRT-PCR, Western blotting, and immunohistochemistry (IHC) to determine MAO and COMT expression. Carriers of the MAOA rs6323 G-allele, MAOB rs6324 G-allele, and COMT rs4633 C/C-genotype had a prominently increased risk of oral cavity and pharynx cancers (AOR = 56.99; p < 0.001). Compared to adjacent noncancerous tissues, a significant downregulation of MAO and COMT expression was exhibited in cancerous tissues (p < 0.01). Furthermore, in different cell models, MAO and COMT expression was significantly downregulated with an increased dose of arecoline (p < 0.01). In personalized preventive medicine for oral and pharyngeal cancers, our findings are the first to demonstrate the potential role of lower MAO and COMT expression levels, with the risk polymorphisms utilized as clinical biomarkers. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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13 pages, 2119 KiB

Open AccessArticle

Automated Detection and Classification of Oral Lesions Using Deep Learning to Detect Oral Potentially Malignant Disorders

by Gizem Tanriver, Merva Soluk Tekkesin and Onur Ergen

Cancers 2021, 13(11), 2766; https://doi.org/10.3390/cancers13112766 - 2 Jun 2021

Cited by 77 | Viewed by 9914

Abstract

Oral cancer is the most common type of head and neck cancer worldwide, leading to approximately 177,757 deaths every year. When identified at early stages, oral cancers can achieve survival rates of up to 75–90%. However, the majority of the cases are diagnosed at an advanced stage mainly due to the lack of public awareness about oral cancer signs and the delays in referrals to oral cancer specialists. As early detection and treatment remain to be the most effective measures in improving oral cancer outcomes, the development of vision-based adjunctive technologies that can detect oral potentially malignant disorders (OPMDs), which carry a risk of cancer development, present significant opportunities for the oral cancer screening process. In this study, we explored the potential applications of computer vision techniques in the oral cancer domain within the scope of photographic images and investigated the prospects of an automated system for detecting OPMD. Exploiting the advancements in deep learning, a two-stage model was proposed to detect oral lesions with a detector network and classify the detected region into three categories (benign, OPMD, carcinoma) with a second-stage classifier network. Our preliminary results demonstrate the feasibility of deep learning-based approaches for the automated detection and classification of oral lesions in real time. The proposed model offers great potential as a low-cost and non-invasive tool that can support screening processes and improve detection of OPMD. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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18 pages, 3802 KiB

Open AccessArticle

Epithelial Mutant p53 Promotes Resistance to Anti-PD-1-Mediated Oral Cancer Immunoprevention in Carcinogen-Induced Mouse Models

by Jin Wang, Yuan Hu, Vicente Escamilla-Rivera, Cassandra L. Gonzalez, Lin Tang, Bingbing Wang, Adel K. El-Naggar, Jeffrey N. Myers and Carlos Caulin

Cancers 2021, 13(6), 1471; https://doi.org/10.3390/cancers13061471 - 23 Mar 2021

Cited by 9 | Viewed by 4021

Abstract

Oral squamous cell carcinoma (OSCC) develops through the multistep malignant progression of squamous epithelium. This process can be prevented by PD-1 blockade in a mouse model for oral carcinogenesis. OSCCs exhibit a high incidence of p53 mutations that confer oncogenic gain-of-function (GOF) activities that promote resistance to standard therapies and poor clinical outcomes. To determine whether epithelial p53 mutations modulate anti-PD-1-mediated oral cancer immunoprevention, we generated mouse models for oral carcinogenesis by exposing mice carrying epithelial-specific p53 mutations to the carcinogen 4NQO. Consistent with the oncogenic functions of mutant p53, mice with OSCCs expressing the p53^R172H GOF mutation developed higher metastasis rates than mice with loss-of-function (LOF) p53 deletion or with wild-type p53. Throughout oral cancer progression, pre-invasive and invasive lesions showed a gradual increase in T-cell infiltration, recruitment of immunosuppressive regulatory T-cells (Tregs), and induction of PD-1/PD-L1 immune checkpoint proteins. Notably, while PD-1 blockade prevented the development of OSCCs in mice with wild-type p53 or p53 deletion, GOF p53^R172H abrogated the immunopreventive effects of anti-PD-1, associated with upregulation of IL17 signaling and depletion of exhausted CD8 cells in the microenvironment of the p53^R172H tumors. These findings sustain a potential role for p53 profiling in personalized oral cancer immunoprevention. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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Review

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16 pages, 364 KiB

Open AccessReview

Unmet Needs and Perspectives in Oral Cancer Prevention

by Jebrane Bouaoud, Paolo Bossi, Moshe Elkabets, Sandra Schmitz, Léon C. van Kempen, Pierre Martinez, Sankar Jagadeeshan, Ingrid Breuskin, Gerwin J. Puppels, Caroline Hoffmann, Keith D. Hunter, Christian Simon, Jean-Pascal Machiels, Vincent Grégoire, Chloé Bertolus, Ruud H. Brakenhoff, Senada Koljenović and Pierre Saintigny

Cancers 2022, 14(7), 1815; https://doi.org/10.3390/cancers14071815 - 2 Apr 2022

Cited by 20 | Viewed by 4905

Abstract

Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

11 pages, 3018 KiB

Open AccessReview

Leukoplakia in the Oral Cavity and Oral Microbiota: A Comprehensive Review

by Giacomo Pietrobon, Marta Tagliabue, Luigi Marco Stringa, Rita De Berardinis, Francesco Chu, Jacopo Zocchi, Elena Carlotto, Susanna Chiocca and Mohssen Ansarin

Cancers 2021, 13(17), 4439; https://doi.org/10.3390/cancers13174439 - 3 Sep 2021

Cited by 19 | Viewed by 3702

Abstract

We reviewed the current published literature on the impact of oral microbiota on oral cavity leukoplakia (OLK), aiming at clarifying its role in disease transformation. The analysis unveiled that bacterial richness and diversity in the oral cavity tend to be decreased in OLK compared to healthy controls, with a reduction in the prevalent commensals, such as Streptococci, and elevation of anaerobes. Moreover, Fusobacterium nucleatum, Porphyromonas gingivalis and Prevotella intermedia are recurrent findings, and they already have been linked to periodontal disease. These microbial community changes may also represent a marker for the transition from OLK to oral squamous cell carcinoma. Unfortunately, the reviewed studies present several limitations, making an objective comparison difficult. To overcome these biases, longitudinal studies are necessary. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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22 pages, 1864 KiB

Open AccessReview

Ethanol-Induced Cell Damage Can Result in the Development of Oral Tumors

by Lore Hoes, Rüveyda Dok, Kevin J. Verstrepen and Sandra Nuyts

Cancers 2021, 13(15), 3846; https://doi.org/10.3390/cancers13153846 - 30 Jul 2021

Cited by 11 | Viewed by 4142

Abstract

Alcohol consumption is an underestimated risk factor for the development of precancerous lesions in the oral cavity. Although alcohol is a well-accepted recreational drug, 26.4% of all lip and oral cavity cancers worldwide are related to heavy drinking. Molecular mechanisms underlying this carcinogenic effect of ethanol are still under investigation. An important damaging effect comes from the first metabolite of ethanol, being acetaldehyde. Concentrations of acetaldehyde detected in the oral cavity are relatively high due to the metabolization of ethanol by oral microbes. Acetaldehyde can directly damage the DNA by the formation of mutagenic DNA adducts and interstrand crosslinks. Additionally, ethanol is known to affect epigenetic methylation and acetylation patterns, which are important regulators of gene expression. Ethanol-induced hypomethylation can activate the expression of oncogenes which subsequently can result in malignant transformation. The recent identification of ethanol-related mutational signatures emphasizes the role of acetaldehyde in alcohol-associated carcinogenesis. However, not all signatures associated with alcohol intake also relate to acetaldehyde. This finding highlights that there might be other effects of ethanol yet to be discovered. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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18 pages, 325 KiB

Open AccessReview

Early-Phase Interventional Trials in Oral Cancer Prevention

by Caroline McCarthy, Stefano Fedele, Christian Ottensmeier and Richard J. Shaw

Cancers 2021, 13(15), 3845; https://doi.org/10.3390/cancers13153845 - 30 Jul 2021

Cited by 8 | Viewed by 2883

Abstract

The increasing breadth of molecular targets, promise of immune-targeted therapies and repurposed agents have heightened interest in cancer prevention. While, to date, testing of oral cancer chemoprevention strategies has failed to deliver therapeutic agents for routine clinical practice, there remains an urgent need for further clinical research to overcome this hurdle. Patients at the greatest risk of disease stand to benefit the most from inclusion in clinical trials; therefore, there is a need to carefully define this population using validated clinical and molecular markers. Safety, tolerability and the efficacy of interventions is assessed through carefully selected endpoints. These endpoints may include pharmacodynamic, clinical, histological and on-target molecular modifications as an individual or as a composite endpoint. Early-phase trials provide an area of opportunity to explore novel and repurposed agents in the setting of oral cancer chemoprevention, eventually leading to phase III trials with clinical endpoints such as transformation and clinical outcome; these studies are large, lengthy and expensive and should be reserved for the most promising of agents. This paper will explore current evidence in oral cancer chemoprevention, drug repurposing, selection of appropriate endpoints for early-phase trials and novel therapeutic angles in oral cancer chemoprevention. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

16 pages, 12971 KiB

Open AccessReview

Overview of Oral Potentially Malignant Disorders: From Risk Factors to Specific Therapies

by Luigi Lorini, Coro Bescós Atín, Selvam Thavaraj, Urs Müller-Richter, Margarita Alberola Ferranti, Jorge Pamias Romero, Manel Sáez Barba, Alba de Pablo García-Cuenca, Irene Braña García, Paolo Bossi, Paolo Nuciforo and Sara Simonetti

Cancers 2021, 13(15), 3696; https://doi.org/10.3390/cancers13153696 - 23 Jul 2021

Cited by 45 | Viewed by 9548

Abstract

Oral squamous cell carcinoma (OSCC) is a very aggressive cancer, representing one of the most common malignancies worldwide. Oral potentially malignant disorders (OPMDs) regroup a variegate set of different histological lesions, characterized by the potential capacity to transform in OSCC. Most of the risk factors associated with OSCC are present also in OPMDs’ development; however, the molecular mechanisms and steps of malignant transformation are still unknown. Treatment of OSCC, including surgery, systemic therapy and radiotherapy (alone or in combination), has suffered a dramatic change in last years, especially with the introduction of immunotherapy. However, most cases are diagnosed during the advanced stage of the disease, decreasing drastically the survival rate of the patients. Hence, early diagnosis of premalignant conditions (OPMDs) is a priority in oral cancer, as well as a massive education about risk factors, the understanding of mechanisms involved in malignant progression and the development of specific and more efficient therapies. The aim of this article is to review epidemiological, clinical, morphological and molecular features of OPMDs, with the purpose to lay the foundation for an exhaustive comprehension of these lesions and their ability of malignant transformation and for the development of more effective and personalized treatments. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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11 pages, 14692 KiB

Open AccessCommentary

The 4P: Preventing Preneoplasia through Patients Partnership

by Angélique Virgone and Sara Badreh

Cancers 2021, 13(17), 4408; https://doi.org/10.3390/cancers13174408 - 31 Aug 2021

Viewed by 2268

Abstract

The early diagnosis and management of oral potentially malignant disorders (OPMD) represent a unique opportunity to develop strategies that will prevent malignant transformation. Despite a high prevalence, awareness remains low, patient outcomes poor, and quality of life highly affected. How can patient advocacy groups (PAGs) bring more awareness to preneoplasia preceding oral cancers and help patients after the identification of a suspicious oral leukoplakia presented as white patches in the mouth? PAGs are today involved with awareness campaigns, lobbying, and education of both health care systems as well as the survivor and the newly diagnosed. PAGs are a link between the clinician and the patient, making sure that the medical terminology used is explained in layman language and that psychological support is available during and after treatment. This review outlines the actions that could be deployed by PAGs to successfully complete OPMD prevention challenge. The added value of researchers and patient representatives working together is the increased awareness of the problem. To know at which angle to best approach it for encouraging early diagnosis, improved education of disease signs and symptoms will condition effective prevention from the beginning. Full article

(This article belongs to the Special Issue Personalized Preventive Medicine of Oral Cancer)

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