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  1. Dionne KR, Warnakulasuriya S, Zain RB, Cheong SC
    Int J Cancer, 2015 Feb 1;136(3):503-15.
    PMID: 24482244 DOI: 10.1002/ijc.28754
    Despite commendable progress in the prevention, detection, and treatment of a wide variety of solid tumor types, oral squamous cell carcinoma (OSCC) remains a significant health burden across the globe. OSCC carcinogenesis involves accumulation of genetic alterations that coincide with the multistep malignant transformation of normal oral epithelium. OSCC is often first diagnosed at late stages of the disease (advanced regional disease and/or metastasis). Delayed diagnosis precludes successful treatment and favorable outcomes. In clinical practice, opportunities exist to identify patients with oral potentially malignant disorders (OPMDs), which precede the development of cancer. This review addresses the current status of laboratory and clinical research on OPMDs, with emphasis on leukoplakia and erythroplakia. OSF is also presented, though there is a paucity of published studies on this disorder. We focus on findings that could translate into earlier diagnosis and more efficacious treatment of those lesions with significant malignant potential. We explore how markers of OPMD malignant transformation might be implemented into current diagnostic practice to help clinicians objectively stratify patients into treatment/follow-up groups according to relative risk. We provide an overview of recently concluded and ongoing OPMD chemoprevention trials. We describe laboratory OPMD models that can be used to not only to reveal the genetic and molecular intricacies of oral cancer but also to develop novel screening methods and therapeutic approaches. Finally, we call for targeted screening programs of at-risk populations in order to facilitate diagnosis and treatment of OPMD and early OSCC.
  2. Patil S, Warnakulasuriya S, Raj T, Sanketh DS, Rao RS
    J Investig Clin Dent, 2016 Nov;7(4):417-423.
    PMID: 26075572 DOI: 10.1111/jicd.12166
    OBJECTIVE: Exophytic oral verrucous hyperplasia (OVH) is a new entity described by an expert working group from South Asia. First reported in Taiwan, there are no reports so far from an Indian population. The aim was to use the microscopic features described by the expert group to differentiate OVH from other oral verruco-papillary lesions in an Indian archive.

    MATERIALS AND METHODS: In a retrospective multicentre study, using pathology archives, 188 verruco-papillary lesions were retrieved from pathology archives. A proforma listing histopathological criteria for OVH based on published guidelines (Annals of Dentistry, University of Malaya, 2013) was used. Patients' demographic and clinical data were transcribed from patient charts. The Pearson chi-square test was used to determine associations between clinical and histopathological features.

    RESULTS: Of 188 oral verruco-papillary lesions that were evaluated, based on microscopic features the cases were reclassified as OVH (57), verrucous carcinoma (VC) (84), oral squamous cell carcinoma (16), and other verruco-papillary lesions (31). Both OVH (70%) and VC (60%) showed male predominance and commonly affected buccal mucosa (OVH 74% and VC 57%). Absence of downward growth of the hyperplastic epithelium into lamina propria when compared with the level of the basement membrane of the adjacent normal epithelium was a distinct feature in OVH. Keratin plugging, epithelial dysplasia and subepithelial lymphocytic infiltration were found to be significantly different (P 

  3. Gubod ER, Ramanathan A, Mohamad Zaini Z, Warnakulasuriya S
    Cureus, 2021 Aug;13(8):e17376.
    PMID: 34584786 DOI: 10.7759/cureus.17376
    We present a rare case of ulcerative oral lichen planus that was associated with a thymoma discovered during the management phase, seven months after the initial diagnosis of oral lichen planus. Thymectomy was performed and investigations revealed pure red cell aplasia. Although rare, the association of a thymoma should be considered in recording the medical history of patients presenting with oral lichen planus.
  4. Vohra F, Al-Kheraif AA, Qadri T, Hassan MI, Ahmed A, Warnakulasuriya S, et al.
    Photodiagnosis Photodyn Ther, 2015 Mar;12(1):150-9.
    PMID: 25315968 DOI: 10.1016/j.pdpdt.2014.10.001
    The aim was to systematically review the efficacy of photodynamic therapy (PDT) in the management of oral premalignant lesions.
  5. Zain RB, Ikeda N, Gupta PC, Warnakulasuriya S, van Wyk CW, Shrestha P, et al.
    J Oral Pathol Med, 1999 Jan;28(1):1-4.
    PMID: 9890449
    A variety of betel/areca nut/tobacco habits have been reviewed and categorized because of their possible causal association with oral cancer and various oral precancerous lesions and conditions, and on account of their widespread occurrence in different parts of the world. At a recent workshop in Kuala Lumpur it was recommended that "quid" be defined as "a substance, or mixture of substances, placed in the mouth or chewed and remaining in contact with the mucosa, usually containing one or both of the two basic ingredients, tobacco and/or areca nut, in raw or any manufactured or processed form." Clear delineations on contents of the quid (areca nut quid, tobacco quid, and tobacco and areca nut quid) are recommended as absolute criteria with finer subdivisions to be added if necessary. The betel quid refers to any quid wrapped in betel leaf and is therefore a specific variety of quid. The workshop proposed that quid-related lesions should be categorized conceptually into two categories: first, those that are diffusely outlined and second, those localized at the site where a quid is regularly placed. Additional or expanded criteria and guidelines were proposed to define, describe or identify lesions such as chewer's mucosa, areca nut chewer's lesion, oral submucous fibrosis and other quid-related lesions. A new clinical entity, betel-quid lichenoid lesion, was also proposed to describe an oral lichen planus-like lesion associated with the betel quid habit.
  6. Obade AY, Pandarathodiyil AK, Oo AL, Warnakulasuriya S, Ramanathan A
    Clin Oral Investig, 2021 Sep;25(9):5411-5419.
    PMID: 33629155 DOI: 10.1007/s00784-021-03849-0
    OBJECTIVE: This study aims to examine the ability of optical coherence tomography (OCT) to differentiate ex vivo epithelial structure of benign disorders, dysplastic, and oral squamous cell carcinoma (OSCC) in comparison with the structure of normal marginal mucosa of oral biopsies. As a secondary objective, we examined the inter- and intra-observer variations of OCT measurements of two calibrated assessors.

    MATERIALS AND METHODS: Oral biopsies (n = 44) were scanned using the swept source OCT (SSOCT) and grouped by pathology diagnosis to benign, dysplasia or carcinoma. Two trained and calibrated assessors scored on the five OCT variables: thickness of keratin layer (KL), epithelial layer (EL), homogeneity of lamina propria (LP), basement membrane integrity (BMI), and the degree of reflection of the epithelial layer (Ep Re). Chi-square tests and Fischer's exact method were used to compare the data.

    RESULTS: The OCT images showed breached BM status in all the OSCC samples (100%). Epithelial reflection was noted to be hyper-reflective in all the OSCC and oral dysplasia samples (100%). An increase in KL in 66.67% of the OSCC and 100% of the oral dysplasia samples was found. EL was increased in all the OSCC samples (100%) and 85.72% of the oral dysplasias. Kappa values showed that there was very good agreement (over 0.7) when scoring individual parameters between the two assessors.

    CONCLUSION: The study showed that the BM status was a key parameter in the detection of SCC and for differentiating SCC from oral dysplasia or benign disorders.

    CLINICAL RELEVANCE: OCT is a non-invasive and non-radioactive adjunct diagnostic tool that can provide immediate results on the structure of oral mucosa. The BM status measured ex vivo was a key parameter in the detection of SCC and for differentiating SCC from oral dysplasia or benign disorders.

  7. Pandarathodiyil AK, Ramanathan A, Garg R, Doss JG, Abd Rahman FB, Ghani WMN, et al.
    Asian Pac J Cancer Prev, 2021 Oct 01;22(10):3227-3235.
    PMID: 34710999 DOI: 10.31557/APJCP.2021.22.10.3227
    BACKGROUND: We examined the lactate dehydrogenase (LDH) enzyme levels in the saliva of vapers (e-cigarette users) and compared the data with cigarette smokers and a control group of non-smokers and non-vapers.

    METHODS: Subjects were recruited among those responding to a social media announcement or patients attending the SEGi Oral Health Care Centre between May and December 2019, and among some staff at the centre. Five ml of unstimulated   whole saliva was collected and salivary LDH enzyme activity levels were measured with a LDH colorimetric assay kit. Salivary LDH activity level was determined for each group and compared statistically.

    RESULTS: Eighty-eight subjects were categorized into three groups (control n=30, smokers n=29, and vapers n=29). The mean ± standard deviation (SD) values for salivary LDH activity levels for vapers, smokers, and control groups were 35.15 ± 24.34 mU/ml, 30.82 ± 20.73 mU/ml, and 21.45 ± 15.30 mU/ml, respectively. The salivary LDH activity levels of smoker and vaper groups were significantly higher than in the control group (p = 0.031; 0.017). There was no significant difference of salivary LDH activity level in vapers when compared with smokers (p= 0.234).

    CONCLUSION: Our findings showed higher LDH levels in the saliva of vapers when compared with controls, confirming cytotoxic and harmful effects of e-cigarettes on the oral mucosa.

  8. Fakhruddin KS, Matsubara VH, Warnakulasuriya S, Tilakaratne WM, Ngo HC, Samaranayake LP
    Int Dent J, 2023 Dec 23.
    PMID: 38143163 DOI: 10.1016/j.identj.2023.11.011
    AIM: Mucormycosis is a rare human infection associated with Mucorales, a group of filamentous moulds found in different environmental niches. Its oral manifestations may occur in the mandible and tongue despite being rare. We aimed to systematically review the data on clinical manifestations, risk factors, diagnostic approaches, treatment options, and outcomes of mandibular and tongue mucormycosis.

    METHODS: An electronic search of articles published between January 1975 and November 2022 in PubMed, Web of Science, and EMBASE databases was performed. A total of 22 articles met the inclusion criteria and reported 27 cases of oral mucormycosis in total.

    RESULTS: Fourteen patients had mandibular mucormycosis signs unrelated to COVID-19 infection, 6 had SARS-CoV-2-related mandibular mucormycosis, and 6 had manifestations in the tongue. All published case reports during the COVID-19 pandemic were from India. Patient ages ranged from 4 months old to 82 years, and most patients had important comorbidities, such as blood dyscrasias related to immune deficiency and uncontrolled type 2 diabetes mellitus. The signs and symptoms of mandibular and tongue mucormycosis varied from dental pain, loose teeth, and nonhealing sockets to dysphagia and paraesthesia of the lip. Some patients also reported trismus, draining sinus tract, and facial pain. The diagnosis of oral mucormycosis was based on a combination of clinical, radiographic, and histopathologic findings by demonstrating fungal hyphae in tissue specimens. In most cases, mucormycosis was managed with systemic amphotericin B, strict glycaemic control, and aggressive surgical debridement of infected tissue, minimising the progression of the fungal infection and thus improving the survival rate. In some cases, combined antifungal therapy, antibiotic therapy, and chlorhexidine mouthwashes were used successfully.

    CONCLUSIONS: Recognition of the signs and symptoms by oral care providers is pertinent for the early diagnosis and treatment of tongue and mandibular mucormycosis, and providers should be aware of the possibility of this opportunistic fungal infection in patients with COVID-19. A multidisciplinary approach is recommended for the management of this lethal infection.

  9. Lee CH, Ko AM, Yang FM, Hung CC, Warnakulasuriya S, Ibrahim SO, et al.
    JAMA Psychiatry, 2018 03 01;75(3):261-269.
    PMID: 29417149 DOI: 10.1001/jamapsychiatry.2017.4307
    Importance: Betel-quid (BQ) is the fourth most popular psychoactive agent worldwide. An emerging trend across Asia is the addictive consumption of BQ, which is associated with oral cancer and other health consequences.

    Objective: To investigate the validity and pattern of DSM-5-defined BQ use disorder (BUD) and its association with oral potentially malignant disorder (OPMD) among Asian populations.

    Design, Setting, and Participants: In-person interviews were conducted from January 1, 2009, to February 28, 2010, among a random sample of 8922 noninstitutionalized adults from the Asian Betel-quid Consortium study, an Asian representative survey of 6 BQ-endemic populations. Statistical analysis was performed from January 1, 2015, to December 31, 2016.

    Main Outcomes and Measures: Participants were evaluated for BUD using DSM-5 criteria for substance use disorder and for OPMD using a clinical oral examination. Current users of BQ with 0 to 1 symptoms were classified as having no BUD, those with 2 to 3 symptoms as having mild BUD, those with 4 to 5 symptoms as having moderate BUD, and those with 6 or more symptoms as having severe BUD.

    Results: Among the 8922 participants (4564 women and 4358 men; mean [SD] age, 44.2 [0.2] years), DSM-5 symptoms showed sufficient unidimensionality to act as a valid measure for BUD. The 12-month prevalence of DSM-5-defined BUD in the 6 study populations was 18.0% (mild BUD, 3.2%; moderate BUD, 4.3%; and severe BUD, 10.5%). The 12-month proportion of DSM-5-defined BUD among current users of BQ was 86.0% (mild BUD, 15.5%; moderate BUD, 20.6%; and severe BUD, 50.0%). Sex, age, low educational level, smoking, and drinking were significantly associated with BUD. Among individuals who used BQ, family use, high frequency of use, and amount of BQ used were significantly linked to moderate to severe BUD. Compared with individuals who did not use BQ, those who used BQ and had no BUD showed a 22.0-fold (95% CI, 4.3-112.4) risk of OPMD (P 

  10. Lee CH, Ko AM, Yen CF, Chu KS, Gao YJ, Warnakulasuriya S, et al.
    Br J Psychiatry, 2012 Nov;201(5):383-91.
    PMID: 22995631 DOI: 10.1192/bjp.bp.111.107961
    Despite gradual understanding of the multidimensional health consequences of betel-quid chewing, information on the effects of dependent use is scant.
  11. Zain RB, Kallarakkal TG, Ramanathan A, Kim J, Tilakaratne WM, Takata T, et al.
    Asian Pac J Cancer Prev, 2016 01 09;17(9):4491.
    PMID: 27865210 DOI: 10.7314/APJCP.2016.17.(9).4491
    Verruco-papillary lesions (VPLs) of the oral cavity described in the literature involve a spectrum of conditions
    including squamous papilloma, verruca vulgaris, focal epithelial hyperplasia, condyloma, proliferative verrucous
    leukoplakia and verrucous carcinoma. A majority of the VPLs are slow growing, benign in nature and have a
    viral aetiology. Virus associated benign mucosal outgrowths are not too difficult to diagnose either clinically or
    by microscopy. Apart from virus-associated lesions, VPLs harboring malignant potential or behaviour such as
    verrucous carcinoma, proliferative verrucous leukoplakia, oral verrucous hyperplasia (OVH), oral papillary
    squamous cell carcinoma (PSCC) and oral conventional squamous cell carcinoma with papillary features (CSCC)
    need to be further clarified for better understanding of their predictable biologic behavior and appropriate
    treatment. Current understanding of potentially malignant VPLs is perplexing and is primarily attributed to
    the use of confusing and unsatisfactory terminology. In particular, the condition referred to as oral verrucous
    hyperplasia (OVH) poses a major diagnostic challenge. OVH represents a histopathological entity whose clinical
    features are not well recognised and is usually clinically indistinguishable from a verrucous carcinoma and a
    PSCC or a CSCC. A consensus report published by an expert working group from South Asia as an outcome of
    the ‘First Asian Regional Meeting on the Terminology and Criteria for Verruco-papillary Lesions of the Oral
    Cavity’ held in Kuala Lumpur, Malaysia, recognised the clinical description of these OVH as a new entity named
    ‘Exophytic Verrucous Hyperplasia’. Previously described clinical features of OVH such as the ‘blunt’ or ‘sharp’
    variants; and the ‘mass’ or ‘plaque’ variants can now collectively fall under this newly described entity. This paper
    discusses in detail the application of the standardized criteria guidelines of ‘Exophytic Verrucous Hyperplasia’
    as published by the expert group which will enable clinicians and pathologists to uniformly interpret their pool
    of OVH cases and facilitate a better understanding of OVH malignant potential.
  12. Mehrtash H, Duncan K, Parascandola M, David A, Gritz ER, Gupta PC, et al.
    Lancet Oncol, 2017 12;18(12):e767-e775.
    PMID: 29208442 DOI: 10.1016/S1470-2045(17)30460-6
    Betel quid and areca nut are known risk factors for many oral and oesophageal cancers, and their use is highly prevalent in the Asia-Pacific region. Additionally, betel quid and areca nut are associated with health effects on the cardiovascular, nervous, gastrointestinal, metabolic, respiratory, and reproductive systems. Unlike tobacco, for which the WHO Framework Convention on Tobacco Control provides evidence-based policies for reducing tobacco use, no global policy exists for the control of betel quid and areca nut use. Multidisciplinary research is needed to address this neglected global public health emergency and to mobilise efforts to control betel quid and areca nut use. In addition, future research is needed to advance our understanding of the basic biology, mechanisms, and epidemiology of betel quid and areca nut use, to advance possible prevention and cessation programmes for betel quid and areca nut users, and to design evidence-based screening and early diagnosis programmes to address the growing burden of cancers that are associated with use.
  13. Lee CH, Chiang SL, Ko AM, Hua CH, Tsai MH, Warnakulasuriya S, et al.
    Addiction, 2014 Jul;109(7):1194-204.
    PMID: 24650227 DOI: 10.1111/add.12530
    Betel-quid (BQ) contains biologically psychoactive ingredients; however, data are limited concerning the symptoms and syndrome of BQ dependence among chewers. The aims of this study were to evaluate the ingredients-associated BQ dependence syndrome and country-specific chewing features and behaviour for BQ dependence among chewers from six Asian communities.
  14. Lee CH, Ko AM, Warnakulasuriya S, Ling TY, Sunarjo, Rajapakse PS, et al.
    Am J Public Health, 2012 Mar;102(3):e17-24.
    PMID: 22390524 DOI: 10.2105/AJPH.2011.300521
    We investigated the population burden of betel quid abuse and its related impact on oral premalignant disorders (OPDs) in South, Southeast, and East Asia.
  15. Lee CH, Ko AM, Warnakulasuriya S, Yin BL, Sunarjo, Zain RB, et al.
    Int J Cancer, 2011 Oct 1;129(7):1741-51.
    PMID: 21128235 DOI: 10.1002/ijc.25809
    Health risks stemming from betel-quid (BQ) chewing are frequently overlooked by people. Updated epidemiological data on the increased BQ use among Asian populations using comparable data collection methods have not been widely available. To investigate the prevalence, patterns of practice and associated types of oral preneoplastic disorders, an intercountry Asian Betel-quid Consortium study (the ABC study) was conducted for Taiwan, Mainland China, Malaysia, Indonesia, Nepal and Sri Lanka. A random sample of 8,922 subjects was recruited, and the data were analyzed using survey-data modules adjusted for the complex survey design. Chewing rates among men (10.7-43.6%) were significantly higher than women (1.8-34.9%) in Taiwan, Mainland China, Nepal and Sri Lanka, while women's rates (29.5-46.8%) were higher than that for men (9.8-12.0%) in Malaysia and Indonesia. An emerging, higher proportion of new-users were identified for Hunan in Mainland China (11.1-24.7%), where Hunan chewers have the unique practice of using the dried husk of areca fruit rather than the solid nut universally used by others. Men in the Eastern and South Asian study communities were deemed likely to combine chewing with smoking and drinking (5.6-13.6%). Indonesian women who chewed BQ exhibited the highest prevalence of oral lichen planus, oral submucous fibrosis and oral leukoplakia (9.1-17.3%). Lower schooling, alcohol drinking and tobacco smoking were identified as being associated with BQ chewing. In conclusion, the ABC study reveals the significant cultural and demographic differences contributing to practice patterns of BQ usage and the great health risks that such practices pose in the Asian region.
  16. Bouvard V, Nethan ST, Singh D, Warnakulasuriya S, Mehrotra R, Chaturvedi AK, et al.
    N Engl J Med, 2022 Nov 24;387(21):1999-2005.
    PMID: 36378601 DOI: 10.1056/NEJMsr2210097
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