Displaying publications 1 - 20 of 36 in total

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  1. Chan SW, Kallarakkal TG, Abraham MT
    Asian Pac J Cancer Prev, 2014;15(5):2145-52.
    PMID: 24716948
    BACKGROUND: The survival rate for oral squamous cell carcinoma (OSCC) has remained generally unchanged in the past three decades, underlining the need for more biomarkers to be developed to aid prognostication and effective management. The prognostic potential of E-cadherin expression in OSCCs has been variable in previous studies while galectin-9 expression has been correlated with improved prognosis in other cancers. The aim of the present study was to investigate the expression of galectin-9 and E-cadherin in OSCC and their potential as prognostic biomarkers.

    MATERIALS AND METHODS: E-cadherin and Galectin-9 expression was examined by immunohistochemistry in 32 cases of OSCC of the buccal mucosa (13 with and 19 without lymph node metastasis), as well as 6 samples of reactive lesions and 5 of normal buccal mucosa.

    RESULTS: The expression of E-cadherin in OSCC was significantly lower than the control tissues but galectin-9 expression was conversely higher. Median E-cadherin HSCOREs between OSCCs positive and negative for nodal metastasis were not significantly different. Mean HSCOREs for galectin-9 in OSCC without lymph node metastasis (127.7 ± 81.8) was higher than OSCC with lymph node metastasis (97.9 ± 62.9) but this difference was not statistically significant.

    CONCLUSIONS: E-cadherin expression is reduced whilst galectin-9 expression is increased in OSCC. However, the present results suggest that E-cadherin and galectin-9 expression may not be useful as prognostic markers for OSCC.

  2. Chang SW, Kareem SA, Kallarakkal TG, Merican AF, Abraham MT, Zain RB
    Asian Pac J Cancer Prev, 2011;12(10):2659-64.
    PMID: 22320970
    The incidence of oral cancer is high for those of Indian ethnic origin in Malaysia. Various clinical and pathological data are usually used in oral cancer prognosis. However, due to time, cost and tissue limitations, the number of prognosis variables need to be reduced. In this research, we demonstrated the use of feature selection methods to select a subset of variables that is highly predictive of oral cancer prognosis. The objective is to reduce the number of input variables, thus to identify the key clinicopathologic (input) variables of oral cancer prognosis based on the data collected in the Malaysian scenario. Two feature selection methods, genetic algorithm (wrapper approach) and Pearson's correlation coefficient (filter approach) were implemented and compared with single-input models and a full-input model. The results showed that the reduced models with feature selection method are able to produce more accurate prognosis results than the full-input model and single-input model, with the Pearson's correlation coefficient achieving the most promising results.
  3. 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.
  4. Ghani WMN, Ramanathan A, Prime SS, Yang YH, Razak IA, Abdul Rahman ZA, et al.
    Cancer Invest, 2019;37(7):275-287.
    PMID: 31307249 DOI: 10.1080/07357907.2019.1635614
    Previous studies found that ethnicity influences oral cancer patients' survival; however, most studies were limited to certain ethnic groups particularly from the West, thus of limited relevance to Asians where the disease is most prevalent. We investigated the relationship between ethnicity and patient survival in multi-racial Malaysia. 5-year survival rate was 40.9%. No statistically significant difference was observed in survival between Malays, Chinese, Indians and Indigenous peoples (45.7%, 44.0%, 41.3%, 27.7% respectively). Increased tumor size, lymph node involvement and advanced tumor were predictive of poor survival. We conclude that ethnicity has no effect on survival or its prognostic indicators.
  5. Salahshourifar I, Vincent-Chong VK, Chang HY, Ser HL, Ramanathan A, Kallarakkal TG, et al.
    Clin Oral Investig, 2015 Dec;19(9):2273-83.
    PMID: 25846277 DOI: 10.1007/s00784-015-1467-7
    OBJECTIVES: This study includes the direct sequencing of cornulin (CRNN) gene to elucidate the possible mechanism of CRNN downregulation and explore the genetic imbalances at 1q21.3 across oral squamous cell carcinoma (OSCC) samples.

    MATERIALS AND METHODS: In mutation screening of CRNN gene, gDNA from OSCC tissues were extracted, amplified, and followed by direct sequencing. OSCC samples were also subjected to fragment analysis on CRNN gene to investigate its microsatellite instability (MSI) and loss of heterozygosity (LOH). Immunohistochemistry was performed to validate CRNN downregulation in OSCC samples.

    RESULTS: No pathogenic mutation was found in CRNN gene, while high frequency of allelic imbalances was found at 1q21.3 region. MSI was found more frequent (25.3 %) than LOH (9.3 %). Approximately 22.6 % of cases had high MSI which reflects higher probability of inactivation of DNA mismatch repair genes. MSI showed significant association with no betel quid chewing (p = 0.003) and tongue subsite (p = 0.026). LOH was associated with ethnicity (p = 0.008) and advanced staging (p = 0.039). The LOH at 1q21.3 was identified to be as an independent prognostic marker in OSCC (HRR = 7.15 (95 % CI, 1.41-36.25), p = 0.018). Downregulation of CRNN was found among MSI-positive OSCCs and was associated with poor prognosis (p = 0.044).

    CONCLUSION: This study showed a significant correlation between LOH/MSI at 1q21.3 with clinical outcomes and that downregulation of CRNN gene could be considered as a prognostic marker of OSCC.

    CLINICAL RELEVANCE: Insights of the downregulation mode of CRNN gene lays the basis of drug development on this gene as well as revealing its prognostic value.

  6. Chher T, Hak S, Kallarakkal TG, Durward C, Ramanathan A, Ghani WMN, et al.
    Ethn Health, 2018 Jan;23(1):1-15.
    PMID: 27781495 DOI: 10.1080/13557858.2016.1246431
    OBJECTIVES: To obtain data on the prevalence of oral mucosal lesions (OMLs) among Cambodians, and to assess the relationship between known risk habits of oral diseases with prevalence of oral potentially malignant disorders (OPMDs).

    DESIGN: This was a population-based, cross-sectional study whereby subjects were adults aged 18 years old and above. A workshop on the identification of OML was held to train and calibrate dental officers prior to data collection in the field. Sociodemographic and risk habits data were collected via face-to-face interview, whilst presence of OML and clinical details of lesions such as type and site were collected following clinical oral examination by the examiners. Data analysis was carried out using the Statistical Package for Social Science (SPSS) version 12.0. The association between risk habits and risk of OPMD was explored using logistic regression analysis.

    RESULTS: A total of 1634 subjects were recruited. Prevalence of OML for this population was 54.1%. Linea alba was the most common lesion seen (28.7%). This study showed an overall OPMD prevalence of 5.6%. The most common type of OPMD was leukoplakia (64.8%), followed by lichen planus (30.8%). Subjects who only smoked were found to have an increased risk for OPMD of almost four-fold (RR 3.74, 95%CI 1.89-7.41). The highest risk was found for betel quid chewers, where the increased risk observed was more than six times (RR 6.75, 95%CI 3.32-13.72). Alcohol consumption on its own did not seem to confer an increased risk for OPMD, however when practiced concurrently with smoking, a significant risk of more than five times was noted (RR 5.69 95%CI 3.14-10.29).

    CONCLUSION: The prevalence of OML was 54.1%, with linea alba being the most commonly occurring lesion. Smoking, alcohol consumption and betel quid chewing were found to be associated with the prevalence of OPMD, which was 5.6%.

  7. Auzair LB, Vincent-Chong VK, Ghani WM, Kallarakkal TG, Ramanathan A, Lee CE, et al.
    Eur Arch Otorhinolaryngol, 2016 Jul;273(7):1885-93.
    PMID: 26138391 DOI: 10.1007/s00405-015-3703-9
    Caveolin-1 (Cav-1) and Actin-Related Protein 2/3 Complex, Subunit 1B (ARPC1B) have been implicated in various human cancers, yet its role in tumorigenesis remains controversial. Therefore, this study aims to determine the protein expression of these two genes in oral squamous cell carcinomas (OSCCs) and to evaluate the clinical and prognostic impact of these genes in OSCC. Protein expressions of these two genes were determined by immunohistochemistry technique. The association between Cav-1 and ARPC1B with clinico-pathological parameters was evaluated by Chi-square test (or Fisher exact test where appropriate). Correlation between the protein expressions of these 2 genes with survival was analyzed using Kaplan-Meier and Cox regression models. Cav-1 and ARPC1B were found to be significantly over-expressed in OSCC compared to normal oral mucosa (p = 0.002 and p = 0.033, respectively). Low level of ARPC1B protein expression showed a significant correlation with lymph node metastasis (LNM) (p = 0.010) and advanced tumor staging (p = 0.003). Kaplan-Meier survival analyses demonstrated that patients with over-expression of Cav-1 protein were associated with poor prognosis (p = 0.030). Adjusted multivariate Cox regression model revealed that over-expression of Cav-1 remained as an independent significant prognostic factor for OSCC (HRR = 2.700, 95 % CI 1.013-7.198, p = 0.047). This study demonstrated that low-expression of ARPC1B is significantly associated with LNM and advanced tumor staging whereas high expression of Cav-1 can be a prognostic indicator for poor prognosis in OSCC patients.
  8. Wang C, Zainal NS, Chai SJ, Dickie J, Gan CP, Zulaziz N, et al.
    Front Immunol, 2021;12:763086.
    PMID: 34733290 DOI: 10.3389/fimmu.2021.763086
    HPV-independent head and neck squamous cell carcinoma (HNSCC) is a common cancer globally. The overall response rate to anti-PD1 checkpoint inhibitors (CPIs) in HNSCC is ~16%. One major factor influencing the effectiveness of CPI is the level of tumor infiltrating T cells (TILs). Converting TILlow tumors to TILhigh tumors is thus critical to improve clinical outcome. Here we describe a novel DNA vaccines to facilitate the T-cell infiltration and control tumor growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting two novel antigens were evaluated with or without CPI using a syngeneic model. Most HNSCC patients (43/44) co-expressed MAGED4B and FJX1 and their respective tetramer-specific T cells were in the range of 0.06-0.12%. In a preclinical model, antigen-specific T cells were induced by DNA vaccines and increased T cell infiltration into the tumor, but not MDSC or regulatory T cells. The vaccines inhibited tumor growth and improved the outcome alone and upon combination with anti-PD1 and resulted in tumor clearance in approximately 75% of mice. Pre-existence of MAGED4B and FJX1-reactive T cells in HNSCC patients suggests that these widely expressed antigens are highly immunogenic and could be further expanded by vaccination. The DNA vaccines targeting these antigens induced robust T cell responses and with the anti-PD1 antibody conferring excellent tumor control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner.
  9. Vincent-Chong VK, Karen-Ng LP, Abdul Rahman ZA, Yang YH, Anwar A, Zakaria Z, et al.
    Head Neck, 2014 Sep;36(9):1268-1278.
    PMID: 31615169 DOI: 10.1002/hed.23448
    BACKGROUND: The purpose of this study was to investigate the cause of behavioral difference between tongue and cheek squamous cell carcinomas (SCCs) by verifying the copy number alterations (CNAs).

    METHODS: Array comparative genomic hybridization (aCGH) was used to profile unique deletions and amplifications that are involved with tongue and cheek SCC, respectively. This was followed by pathway analysis relating to CNA genes from both sites.

    RESULTS: The most frequently amplified regions in tongue SCC were 4p16.3, 11q13.4, and 13q34; whereas the most frequently deleted region was 19p12. For cheek SCC, the most frequently amplified region was identified on chromosome 9p24.1-9p23; whereas the most common deleted region was located on chromosome 8p23.1. Further analysis revealed that the most significant unique pathway related to tongue and cheek SCCs was the cytoskeleton remodeling and immune response effect on the macrophage differentiation pathway.

    CONCLUSION: This study has showed the different genetic profiles and biological pathways between tongue and cheek SCCs. © 2013 Wiley Periodicals, Inc. Head Neck 36: 1268-1278, 2014.

  10. Kallarakkal TG, Ramanathan A, Zain RB
    Int J Dent, 2013;2013:298249.
    PMID: 24223590 DOI: 10.1155/2013/298249
    Verrucous papillary lesions (VPLs) of oral cavity are diagnostically challenging as they include a spectrum of benign, potentially malignant, and frankly malignant lesions. A majority of the benign VPLs have viral aetiology and include commonly occurring squamous papilloma along with verruca vulgaris, focal epithelial hyperplasia, and condyloma. Current understanding of potentially malignant VPLs is perplexing and is primarily attributed to the use of confusing and unsatisfactory terminology. Clinically and histologically oral verrucous hyperplasia, a potentially malignant disorder, resembles oral verrucous carcinoma and may be indistinguishable from one another. The most reliable way to separate these entities on routine haematoxylin-eosin stained tissue sections is to recognize the exophytic growth patterns of oral verrucous hyperplasia from the combined exophytic and endophytic growth patterns associated with verrucous carcinoma. A review of the literature showed that there is a lot of confusion regarding the current clinical and histopathological guidelines to diagnose this potentially malignant entity. The criteria elaborated by different authors in establishing the diagnosis of oral verrucous hyperplasia are discussed in detail. A brief overview of the treatment modalities adopted is also discussed. The need for establishing a clear understanding of this potentially malignant entity is stressed as it may have far reaching implications on its management.
  11. Lee CE, Vincent-Chong VK, Ramanathan A, Kallarakkal TG, Karen-Ng LP, Ghani WM, et al.
    Int J Med Sci, 2015;12(12):937-45.
    PMID: 26664254 DOI: 10.7150/ijms.11605
    Collagen Triple Helix Repeat Containing 1 (CTHRC1) is a protein often found to be over-expressed in various types of human cancers. However, correlation between CTHRC1 expression level with clinico-pathological characteristics and prognosis in oral cancer remains unclear. Therefore, this study aimed to determine mRNA and protein expression of CTHRC1 in oral squamous cell carcinoma (OSCC) and to evaluate the clinical and prognostic impact of CTHRC1 in OSCC.
  12. Chan SW, Liew LH, Wong GR, Kallarakkal TG, Abraham MT, Ramanathan A, et al.
    Int. J. Surg. Pathol., 2016 Aug;24(5):401-9.
    PMID: 27006298 DOI: 10.1177/1066896916639372
    BACKGROUND: Turnaround time (TAT) is the benchmark to assess the performance of a laboratory, pathologists, and pathology services, but there are few articles on TAT of surgical pathology, particularly in relation to oral or head and neck specimens. This study investigates the TAT for oral histopathology reporting in an academic institution's training laboratory and offers recommendations to achieve better overall quality of diagnostic services.

    METHODS: This study examined data obtained from biopsy request forms for specimens received from the Oro-Maxillofacial Surgery Department of Hospital Tengku Ampuan Rahimah Klang in the Oral Pathology Diagnostic Laboratory of the Faculty of Dentistry, University of Malaya, over a period of 3 years between January 2012 and October 2014.

    RESULTS: TAT for surgical and decalcified specimens were increased significantly compared to biopsies. Additional special handling did not influence TAT, but increased specimen volume resulted in greater TAT. Slide interpretation was the most time-consuming stage during histopathology reporting. Overall, mean TAT was acceptable for most specimens, but the TAT goals were less than satisfactory.

    CONCLUSION: A TAT goal appropriate for this laboratory may hence be established based on this study. Collective efforts to improve the TAT for various specimens are essential for better laboratory performance in the future.
  13. Zain RB, Pateel DGS, Ramanathan A, Kallarakkal TG, Wong GR, Yang YH, et al.
    J Cancer Educ, 2020 Aug 21.
    PMID: 32821988 DOI: 10.1007/s13187-020-01814-1
    Early diagnosis of oral cancer results in less aggressive treatment and improves the quality of life and overall 5-year survival rate. Well-trained dental professionals can play a crucial role in the early detection of oral cancers. The present study aims to determine the effectiveness of the training program "OralDETECT", a spaced repetitive, test-enhanced learning tool with a corrective feedback mechanism for early detection of oral cancer. Thirty-two dentists and 259 dental students from three Malaysian dental schools were involved in this study. All participants were trained and calibrated to recognize oral potentially malignant disorders (OPMD) and oral cancer using "OralDETECT", which is comprised of a series of pre-test, lecture, post-tests and review sessions. The percentage of correct answers (scores) for each test given by the participants was calculated and analysed using a paired t test. It was found that the overall percentage of diagnostic accuracy for both dental professionals and student groups increased to above 80% from the pre-tests to the final post-tests. There was a significant improvement in overall scores between the pre-tests and all three post-tests for the dental professional groups and the student groups. The diagnostic accuracy for individual OPMD and lesions suspicious of oral cancer also increased to above 80% for both groups. The results of our study demonstrate that the "OralDETECT" is an efficient and effective competency tool which can be used to train dental professionals and students for the early detection of OPMD and oral cancer.
  14. Ng SW, Syamim Syed Mohd Sobri SN, Zain RB, Kallarakkal TG, Amtha R, Wiranata Wong FA, et al.
    PMID: 35068209 DOI: 10.1177/13558196211053110
    OBJECTIVE: Oral cancer is amenable to early detection but remains a prominent cause of mortality in the Asia Pacific region. This study aimed to identify barriers to early detection and management of oral cancer in the Asia Pacific region.

    METHODS: A mixed-methods approach was employed triangulating findings from a survey and focus groups. The survey was conducted among seven representative members of the Asia Pacific Oral Cancer Network (APOCNET) across six countries. Focus groups were conducted to gain deeper insights into the findings of the survey.

    RESULTS: The identified barriers were a lack of national cancer control strategies and cancer registries and the limited availability of trained health care professionals. Overcoming these challenges in the Asia Pacific region where resources are scarce will require collaborative partnerships in data collection and novel approaches for continuous professional training including eLearning. Further, to overcome the lack of trained health care professionals, innovative approaches to the management of oral potentially malignant lesions and oral cancer including telemedicine were suggested.

    CONCLUSION: The findings of this study should be taken into account when charting national cancer control plans for oral cancer and will form the basis for future collaborative studies in evaluating effective measures to improve oral cancer detection and management in low- and middle-income countries.

  15. Tegginamani AS, Shivakumar VH, Kallarakkal TG, Ismail SM, Abraham MT, Bin Zamzuri AT
    J Oral Maxillofac Pathol, 2020 09 09;24(2):400.
    PMID: 33456258 DOI: 10.4103/jomfp.JOMFP_272_19
    Background: Oral potentially malignant disorders have a risk for malignant transformation but are difficult to reliably identify and predict which patients are at the risk for malignant transformation. OCT4 has been hypothesized to play a key oncogenic driver in a variety of solid tumors. A deeper understanding of the aberrant molecular pathways which lead to carcinogenesis needs to be identified by the potential markers.

    Aims: To assess the OCT4 stemness factor in oral leukoplakia for its potential risk to malignant transformation.

    Settings and Design: 20 cases of oral leukoplakia were obtained from archives at Oral Cancer Research & Coordinating center (OCRCC) Malaysia Subjects and Methods: 20 cases of oral leukoplakia were assessed by OCT4 immunohistochemically. Oral squamous cell carcinoma was used as a control.

    Result: no expression of OCT 4 was observed in any cases of oral leukoplakia.

    Conclusion: The molecular mechanisms of Oct4 regulation and in particular of its switch on and off in tissues depends upon its microenvironment, which makes it challenging in fundamental and applied research fields of regenerative medicine and cancer therapy. It's better that patients should undergo multiple biopsies for the early detection of malignant transformation with close follow-up during the first two to three years, a large amount of work remains to be done with multi-marker panel investigation, as cure rates have remained constant over three decades.

  16. Kazakydasan S, Rahman ZA, Ismail SM, Abraham MT, Kallarakkal TG
    J Oral Pathol Med, 2016 Jul 15.
    PMID: 27417330 DOI: 10.1111/jop.12476
    Lymph node metastasis in oral squamous cell carcinoma (OSCC) is a well-known independent prognostic factor. However, the identification of occult tumour cells within the lymph nodes has remained a challenge for the pathologist as well as the clinician.
  17. Kallarakkal TG, Zaini ZM, Ghani WMN, Karen-Ng LP, Siriwardena BSMS, Cheong SC, et al.
    J Oral Pathol Med, 2024 Jan;53(1):53-60.
    PMID: 38081145 DOI: 10.1111/jop.13501
    INTRODUCTION: A major pitfall of many of the established oral epithelial dysplasia (OED) grading criteria is their lack of reproducibility and accuracy to predict malignant transformation. The main objective of this study was to determine whether calibration of practicing oral pathologists on OED grading could improve the reproducibility of the WHO 2017 and the binary OED grading systems.

    METHODS: A nationwide online exercise was carried out to determine the influence of calibration on the reproducibility of the WHO 2017 and the binary OED grading systems.

    RESULTS: A significant improvement was observed in the inter-observer agreement for the WHO 2017 OED grading system (K 0.196 vs. 0.448; Kw 0.357 vs. 0.562) after the calibration exercise. The significant difference (p = 0.027) in the level of agreement between those with five or more years and less than 5 years of experience was no more observed (p = 0.426) after the calibration exercise. The percent agreement for binary grading was significantly higher (91.8%) for buccal mucosal lesions as compared to lesions on the tongue after the calibration exercise.

    CONCLUSION: This study validates the significance of calibration in improving the reproducibility of OED grading. The nationwide exercise resulted in a statistically significant improvement in the inter-observer agreement for the WHO 2017 OED grading system among a large number of oral pathologists. It is highly recommended that similar exercises should be organized periodically by professional bodies responsible for continuing education among oral pathologists to improve the reliability of OED grading for optimal treatment of oral potentially malignant disorders.

  18. Tegginamani AS, Kallarakkal TG, Vanishree HS, Muttalib KBA
    J Coll Physicians Surg Pak, 2019 Jul;29(7):688.
    PMID: 31253228 DOI: 10.29271/jcpsp.2019.07.688
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