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Fulltext A retrospective clinicopathological study of 59 osteogenic sarcoma of jaw bone archived in a stomatology unit

Ajura AJ, Lau SH

Malays J Pathol, 2010 Jun;32(1):27-34.
PMID: 20614723 MyJurnal

To determine the clinicopathological features of osteogenic sarcomas of the mandible and maxilla.
Ameloblastoma of the jaws: a retrospective analysis of 340 cases in a Malaysian population

Siar CH, Lau SH, Ng KH

J Oral Maxillofac Surg, 2012 Mar;70(3):608-15.
PMID: 21723654 DOI: 10.1016/j.joms.2011.02.039

Ameloblastoma of the human jaw is an uncommon but clinically significant odontogenic epithelial neoplasm. The aim was to analyze the clinicopathologic characteristics of ameloblastoma in a Malaysian population.
Fulltext The use of immunohistochemistry in an oral pathology laboratory

Ajura AJ, Sumairi I, Lau SH

Malays J Pathol, 2007 Dec;29(2):101-5.
PMID: 19108402 MyJurnal

Immunohistochemistry has become part of normal routine diagnostic work in the Stomatology Unit, Institute for Medical Research, Kuala Lumpur. Of 9523 cases received from the year 2000 to 2005, 197 cases (2.1%) required immunohistochemical staining. These cases ranged from benign to malignant lesions. They include lymphomas (n=41), epithelial tumours (n=29), neural lesions (n=21), fibroblastic/myofibroblastic tumours (n=16), small round cell tumour (n=11), vascular tumours (n=4), smooth muscle tumours (n=4), myxomatous tumours (n=4) and skeletal muscle tumours (n=1). In most of the cases (69.5%), immunohistochemical staining was mandatory to reach a definite diagnosis, while 60 cases (30.5%) required immunohistochemistry in confirming the diagnosis. In 32 cases (16.2%), definitive diagnosis could not be made due to the small size of the specimens received or the results of immunohistochemistry were inconclusive. Standardization of techniques, competent medical laboratory technologists and sufficient budget allocation are important in producing a high quality immunohistochemistry service.
Fulltext Clinico-pathological study of malignant odontogenic tumours from a national referral centre

Sathasivam HP, Saw CL, Lau SH

BMC Oral Health, 2021 03 18;21(1):129.
PMID: 33736630 DOI: 10.1186/s12903-020-01365-3

BACKGROUND: Malignant odontogenic tumours are extremely rare tumours occurring within the jaws. Our study was performed to determine the demographic and clinico-pathological features of malignant odontogenic tumours amongst a multi-ethnic Asian population.
METHODS: This was a retrospective cross-sectional study of malignant odontogenic tumours diagnosed at the Institute for Medical Research, Malaysia, from 2009 to 2019. All cases were independently reviewed and reclassified following the criteria set out in the latest edition of the World Health Organization 2017 reference text. Demographic and clinico-pathological data were recorded for each case.
RESULTS: Twenty-four cases of malignant odontogenic tumours were identified. The patients' age ranged from 16 to 79 years with the mean age at diagnosis being 50.8 years (SD = 16.18). There was a male predominance (66.7%) in this cohort of patients. The ethnic distribution appeared to reflect the Malaysian population with most cases seen amongst the Malay ethnic group (66.7%). Ameloblastic carcinoma was the most frequently diagnosed malignant odontogenic tumour (45.8%) and was also predominantly seen in males (90.9%). All patients with clear cell odontogenic carcinoma were females. There was no obvious sex predilection in primary odontogenic carcinoma not otherwise specified (NOS). The mandible (79.2%) was more frequently involved compared to the maxilla.
CONCLUSIONS: Diagnosis and management of malignant odontogenic tumours are challenging due to the rarity of these tumours. Our study has elucidated the clinico-pathological features of malignant odontogenic tumours seen in a multi-ethnic Asian population.
Oral histoplasmosis in Malaysia: A retrospective analysis of cases reported in Stomatology Unit, Institute for Medical Research during 1995-2016

Noratikah AH, Ajura AJ, Lau SH

Trop Biomed, 2018 Dec 01;35(4):1041-1048.
PMID: 33601851

Histoplasmosis is a systemic fungal infection caused by inhalation of Histoplasma capsulatum, which is mainly found in bird and bat droppings. Oral manifestation of histoplasmosis may be the only initial manifestation of the disease or associated with chronic disseminated histoplasmosis. The first review of oral histoplasmosis among Malaysian population from 1967 to 1994 (27 years) revealed the occurrence of 37 cases, reported by Ng and Siar in 1996. This current study is the updated overview of oral histoplasmosis cases in Malaysia. The objective of the study was to review and describe clinical and demographic profile of oral histoplasmosis in Malaysia and to correlate histopathological features of oral histoplasmosis with patient's immunity status. We reviewed oral histoplasmosis cases diagnosed in Stomatology Unit, Institute for Medical Research (IMR), Kuala Lumpur from 1995 until 2016. The data was retrieved from the Oral Pathology Information system (OPIS) Stomatology Unit, IMR, which is the largest oral pathology database in Malaysia. Information regarding patients' sociodemographic data, medical illness, clinical presentation, histopathological features, and referring healthcare institutions was extracted from the clinical information which accompanied the biopsy request form. A total of 39 cases of oral histoplasmosis were identified from 1995-2016. Majority of them were male (89.7%). The age ranges from 29 to 85 years with mean age of 57.8 years. Almost half of them were Malays (51.3%), followed by Chinese (33.3%), Indians (7.7%), and other races (7.7%). The most common sites of oral histoplasmosis were tongue, gingiva, palate, and alveolar ridge. The main clinical presentation was ulcer (61.5%) whereas 38.5% presented clinically as swelling. 17.9% of patients were seropositive for human immunodeficiency virus (HIV), 12.8% had tuberculosis, 10.3% had diabetes mellitus, and 2.6% with hepatitis C. The incidence of oral histoplasmosis should raise suspicion of hidden immunodepression and may be the first manifestation of acquired immunodeficiency syndrome (AIDS). Early recognition and diagnosis is crucial to reduce risk of morbidity and mortality.
Fulltext Modeling Age-Friendly Environment, Active Aging, and Social Connectedness in an Emerging Asian Economy

Lai MM, Lein SY, Lau SH, Lai ML

J Aging Res, 2016;2016:2052380.
PMID: 27293889 DOI: 10.1155/2016/2052380

This paper empirically tested eight key features of WHO guidelines to age-friendly community by surveying 211 informal caregivers and 402 self-care adults (aged 45 to 85 and above) in Malaysia. We examined the associations of these eight features with active aging and social connectedness through exploratory and confirmatory factor analyses. A structural model with satisfactory goodness-of-fit indices (CMIN/df = 1.11, RMSEA = 0.02, NFI = 0.97, TLI = 1.00, CFI = 1.00, and GFI = 0.96) indicates that transportation and housing, community support and health services, and outdoor spaces and buildings are statistically significant in creating an age-friendly environment. We found a statistically significant positive relationship between an age-friendly environment and active aging. This relationship is mediated by social connectedness. The results indicate that built environments such as accessible public transportations and housing, affordable and accessible healthcare services, and elderly friendly outdoor spaces and buildings have to be put into place before social environment in building an age-friendly environment. Otherwise, the structural barriers would hinder social interactions for the aged. The removal of the environmental barriers and improved public transportation services provide short-term solutions to meet the varied and growing needs of the older population.
Fulltext Usability factors predicting continuance of intention to use cloud e-learning application

Wang LY, Lew SL, Lau SH, Leow MC

Heliyon, 2019 Jun;5(6):e01788.
PMID: 31198866 DOI: 10.1016/j.heliyon.2019.e01788

In this ever-progressive digital era, conventional e-learning methods have become inadequate to handle the requirements of upgraded learning processes especially in the higher education. E-learning adopting Cloud computing is able to transform e-learning into a flexible, shareable, content-reusable, and scalable learning methodology. Despite plentiful Cloud e-learning frameworks have been proposed across literature, limited researches have been conducted to study the usability factors predicting continuance intention to use Cloud e-learning applications. In this study, five usability factors namely Computer Self Efficacy (CSE), Enjoyment (E), Perceived Ease of Use (PEU), Perceived Usefulness (PU), and User Perception (UP) have been identified for factor analysis. All the five independent variables were hypothesized to be positively associated to a dependent variable namely Continuance Intention (CI). A survey was conducted on 170 IT students in one of the private universities in Malaysia. The students were given one trimester to experience the usability of Cloud e-Learning application. As an instrument to analyse the usability factors towards continuance intention of the application, a questionnaire consisting thirty questions was formulated and used. The collected data were analysed using SMARTPLS 3.0. The results obtained from this study observed that computer self-efficacy and enjoyment as intrinsic motivations significantly predict continuance intention, while perceived ease of use, perceived usefulness and user perception were insignificant. This outcome implies that computer self-efficacy and enjoyment significantly affect the willingness of students to continue using Cloud e-learning application in their studies. The discussions and implications of this study are vital for researchers and practitioners of educational technologies in higher education.
Duplication of lower lip and mandible--a rare diprosopus

Suhaili DN, Somasundaram S, Lau SH, Ajura AJ, Roslan AR, Ramli R

Int J Pediatr Otorhinolaryngol, 2011 Jan;75(1):131-3.
PMID: 21067822 DOI: 10.1016/j.ijporl.2010.10.004

Diprosopus or duplication of the lower lip and mandible is a very rare congenital anomaly. We report this unusual case occurring in a girl who presented to our hospital at the age of 4 months. Surgery and problems related to this anomaly are discussed.
HPV infection and the alterations of the pRB pathway in oral carcinogenesis

Lim KP, Hamid S, Lau SH, Teo SH, Cheong SC

Oncol Rep, 2007 Jun;17(6):1321-6.
PMID: 17487385 DOI: 10.3892/or.17.6.1321

Inactivation of the retinoblastoma (pRB) pathway is a common event in oral squamous cell carcinoma particularly through the aberrant expression of the components within this pathway. This study examines the alterations of molecules within the pRB pathway by looking at the presence of homozygous deletions in p16(INK4A) and the expression patterns of pRB, cyclin D1 and CDK4, as well as the presence of human papillomavirus (HPV) in our samples. In our study, 5/20 samples demonstrated deletions of p16(INK4A) exon 1alpha. pRB overexpression was found in 20/20 samples, the expression was mainly observed in all layers of the epithelia, particularly in the basal layer where cells are actively dividing and aberrant pRB expression was found in 12/20 samples. Cyclin D1 and CDK4 overexpression was detected in 6/20 and 2/20 samples respectively in comparison to hyperplasias where both proteins were either not expressed or expressed at minimal levels (<10%). Strikingly, HPV was found to be present in all of our samples, suggesting that HPV plays a significant role in driving oral carcinogenesis. Notably, 17/20 of our samples showed more than one alteration in the pRB pathway, however, we did not find any significant relationship between the presence of HPV, homozygous deletion of p16(INK4A) and overexpression of pRB, cyclin D1 and CDK4. Collectively, this data demonstrates that alterations in the pRB pathway are a common event and involve the aberration of more than one molecule within the pathway. Furthermore, the involvement of HPV in all our samples suggests that HPV infection may play an important role in oral carcinogenesis.
Alterations of the p14ARF-p53-MDM2 pathway in oral squamous cell carcinoma: MDM2 overexpression is a common event

Lim KP, Sharifah H, Lau SH, Teo SH, Cheong SC

Oncol Rep, 2005 Oct;14(4):963-8.
PMID: 16142358 DOI: 10.3892/or.14.4.963

The majority of global incidences of oral cancer occur in Asia, and the aetiology of oral cancer is different in Asia as it is in the West. However, whereas there is a growing understanding of the molecular mechanisms of oral cancer progression in the West, there is little progress in this understanding in Asia. In particular, the role of the p53 pathway in modulating cancer progression in Asian oral cancer remains unclear. In this study, we micro-dissected and analysed 20 well-differentiated oral squamous cell carcinoma specimens for alterations in the p53 pathway. We found that 6/20 samples contained mutations in the p53 gene which occurred in three hotspots, at codon 203, 218 and 296. Furthermore, 6/20 samples had a homozygous deletion of p14ARF, but notably p14ARF deletion and p53 mutation events were often independent and mutually exclusive. Strikingly, MDM2 was upregulated in 20/20 samples, but not in 3/3 normal tissue specimens. Taken together, these data suggest that inactivation of the p53 pathway is a frequent event in oral squamous cell carcinoma, which occurs by an aberration in one of a number of players in the p53 pathway.
A retrospective analysis of oral and maxillofacial biopsied specimens in Malaysian newborns and infants

Binti Shuhairi NN, Bt Abdul Jalil A, Lau SH, Bt Mohd Ghazali S, Kee CC

Int J Paediatr Dent, 2021 Jul;31(4):496-503.
PMID: 32815206 DOI: 10.1111/ipd.12719

BACKGROUND: Globally, research on oral and maxillofacial lesions among newborns and infants remains limited.
AIM: To describe demographic patterns, histopathological findings, and locations of oral and maxillofacial lesions in newborns (birth-1 month) and infants (>1 month-2 years) reported over 51 years.
DESIGN: A retrospective cross-sectional study on histopathological records of newborns and infants was conducted. Patients' demographic characteristics (age, gender, and race), histopathological diagnosis, and lesion's location were gathered. Pearson's chi-square or Fisher's exact test was performed to determine associations between demographic characteristics and different categories of lesions.
RESULTS: Out of 66,546 specimens received, 0.44% (290 specimens) were from patients aged 2 years and younger (27 newborns and 263 infants). The most common category was inflammatory/reactive (44.2%), followed by tumour/tumour-like (42.0%), cystic/pseudocystic (6.6%), and miscellaneous lesions (5.5%). Mucous extravasation cysts (23.4%) and Langerhans cell histiocytosis (7.2%) were the most common histopathological diagnoses. Tumour/tumour-like lesions were significant in newborns (P = .021), and majority were congenital epulis (40.7%). Inflammatory/reactive lesions were significantly higher in male (P = .025) and infants (P =
Gene expression in human oral squamous cell carcinoma is influenced by risk factor exposure

Cheong SC, Chandramouli GV, Saleh A, Zain RB, Lau SH, Sivakumaren S, et al.

Oral Oncol, 2009 Aug;45(8):712-9.
PMID: 19147396 DOI: 10.1016/j.oraloncology.2008.11.002

Oral squamous cell carcinoma (OSCC) is a world health problem and is associated with exposure to different risk factors. In the west, smoking and alcohol consumption are considered to be the main risk factors whilst in India and southeast Asia, betel quid (BQ) chewing is predominant. In this study, we compared the gene expression patterns of oral cancers associated with BQ chewing to those caused by smoking using Affymetrix microarrays. We found that 281 genes were differentially expressed between OSCC and normal oral mucosa regardless of aetiological factors including MMP1, PLAU, MAGE-D4, GNA12, IFITM3 and NMU. Further, we identified 168 genes that were differentially expressed between the BQ and smoking groups including CXCL-9, TMPRSS2, CA12 and RNF24. The expression of these genes was validated using qPCR using independent tissue samples. The results demonstrate that whilst common genes/pathways contribute to the development of oral cancer, there are also other gene expression changes that are specific to certain risk factors. The findings suggest that different carcinogens activate or inhibit specific pathways during cancer development and progression. These unique gene expression profiles should be taken into consideration when developing biomarkers for future use in prognostic or therapeutic applications.
Trigeminal neuralgia: a retrospective multicentre study of 320 Asian patients

Sathasivam HP, Ismail S, Ahmad AR, Basri NN, Muhamad H, Mohd Tahir NF, et al.

Oral Surg Oral Med Oral Pathol Oral Radiol, 2017 Jan;123(1):51-57.
PMID: 27727102 DOI: 10.1016/j.oooo.2016.08.005

This study was performed to obtain the clinicodemographic data regarding patients with trigeminal neuralgia (TN) treated at oral-maxillofacial medicine clinics, as there is a paucity of such information in the Asian setting.
Four-protein signature accurately predicts lymph node metastasis and survival in oral squamous cell carcinoma

Zanaruddin SN, Saleh A, Yang YH, Hamid S, Mustafa WM, Khairul Bariah AA, et al.

Hum Pathol, 2013 Mar;44(3):417-26.
PMID: 23026198 DOI: 10.1016/j.humpath.2012.06.007

The presence of lymph node (LN) metastasis significantly affects the survival of patients with oral squamous cell carcinoma (OSCC). Successful detection and removal of positive LNs are crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the LNs, where up to a third of clinically diagnosed metastasis-negative (N0) patients actually have metastasis-positive LNs in the neck. We developed a molecular signature in the primary tumor that could predict LN metastasis in OSCC. A total of 211 cores from 55 individuals were included in the study. Eleven proteins were evaluated using immunohistochemical analysis in a tissue microarray. Of the 11 biomarkers evaluated using receiver operating curve analysis, epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2/neu), laminin, gamma 2 (LAMC2), and ras homolog family member C (RHOC) were found to be significantly associated with the presence of LN metastasis. Unsupervised hierarchical clustering-demonstrated expression patterns of these 4 proteins could be used to differentiate specimens that have positive LN metastasis from those that are negative for LN metastasis. Collectively, EGFR, HER-2/neu, LAMC2, and RHOC have a specificity of 87.5% and a sensitivity of 70%, with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated that the LN signature could independently predict disease-specific survival (P = .036). The 4-protein LN signature validated in an independent set of samples strongly suggests that it could reliably distinguish patients with LN metastasis from those who were metastasis-free and therefore could be a prognostic tool for the management of patients with OSCC.
Fulltext Co-Expression of TWIST1 and ZEB2 in Oral Squamous Cell Carcinoma Is Associated with Poor Survival

Kong YH, Syed Zanaruddin SN, Lau SH, Ramanathan A, Kallarakkal TG, Vincent-Chong VK, et al.

PLoS One, 2015;10(7):e0134045.
PMID: 26214683 DOI: 10.1371/journal.pone.0134045

Oral squamous cell carcinoma (OSCC) is an aggressive disease accounting for more than 260,000 cancer cases diagnosed and 128,000 deaths worldwide. A large majority of cancer deaths result from cancers that have metastasized beyond the primary tumor. The relationship between genetic changes and clinical outcome can reflect the biological events that promote cancer's aggressive behavior, and these can serve as molecular markers for improved patient management and survival. To this end, epithelial-mesenchymal transition (EMT) is a major process that promotes tumor invasion and metastasis, making EMT-related proteins attractive diagnostic biomarkers and therapeutic targets. In this study, we used immunohistochemistry to study the expression of a panel of transcription factors (TWIST1, SNAI1/2, ZEB1 and ZEB2) and other genes intimately related to EMT (CDH1 and LAMC2) at the invasive tumor front of OSCC tissues. The association between the expression of these proteins and clinico-pathological parameters were examined with Pearson Chi-square and correlation with survival was analyzed using Kaplan Meier analysis. Our results demonstrate that there was a significant differential expression of CDH1, LAMC2, SNAI1/2 and TWIST1 between OSCC and normal oral mucosa (NOM). Specifically, CDH1 loss was significantly associated with Broder's grading, while diffused LAMC2 was similarly associated with non-cohesive pattern of invasion. Notably, co-expression of TWIST1 and ZEB2 in OSCC was significantly associated with poorer overall survival, particularly in patients without detectable lymph node metastasis. This study demonstrates that EMT-related proteins are differentially expressed in OSCC and that the co-expression of TWIST1 and ZEB2 could be of clinical value in identifying patients with poor survival for appropriate patient management.
Establishment and characterization of Asian oral cancer cell lines as in vitro models to study a disease prevalent in Asia

Hamid S, Lim KP, Zain RB, Ismail SM, Lau SH, Mustafa WM, et al.

Int J Mol Med, 2007 Mar;19(3):453-60.
PMID: 17273794

We have established 3 cell lines ORL-48, -115 and -136 from surgically resected specimens obtained from untreated primary human oral squamous cell carcinomas of the oral cavity. The in vitro growth characteristics, epithelial origin, in vitro anchorage independency, human papilloma-virus (HPV) infection, microsatellite instability status, karyotype and the status of various cell cycle regulators and gatekeepers of these cell lines were investigated. All 3 cell lines grew as monolayers with doubling times ranging between 26.4 and 40.8 h and were immortal. Karyotyping confirmed that these cell lines were of human origin with multiple random losses and gains of entire chromosomes and regions of chromosomes. Immunohistochemistry staining of cytokeratins confirmed the epithelial origin of these cell lines, and the low degree of anchorage independency expressed by these cell lines suggests non-transformed phenotypes. Genetic analysis identified mutations in the p53 gene in all cell lines and hypermethylation of p16INK4a in ORL-48 and -136. Analysis of MDM2 and EGFR expression indicated MDM2 overexpression in ORL-48 and EGFR overexpression in ORL-136 in comparison to the protein levels in normal oral keratinocytes. Analysis of the BAT-26 polyadenine repeat sequence and MLH-1 and MSH-2 repair enzymes demonstrated that all 3 cell lines were microsatellite stable. The role of HPV in driving carcinogenesis in these tumours was negated by the absence of HPV. Finally, analysis of the tissues from which these cell lines were derived indicated that the cell lines were genetically representative of the tumours, and, therefore, are useful tools in the understanding of the molecular changes associated with oral cancers.
Fulltext In vitro evaluation of dual-antigenic PV1 peptide vaccine in head and neck cancer patients

Chai SJ, Fong SCY, Gan CP, Pua KC, Lim PVH, Lau SH, et al.

Hum Vaccin Immunother, 2019;15(1):167-178.
PMID: 30193086 DOI: 10.1080/21645515.2018.1520584

Peptide vaccines derived from tumour-associated antigens have been used as an immunotherapeutic approach to induce specific cytotoxic immune response against tumour. We previously identified that MAGED4B and FJX1 proteins are overexpressed in HNSCC patients; and further demonstrated that two HLA-A2-restricted 9-11 amino acid peptides derived from these proteins were able to induce anti-tumour immune responses in vitro independently using PBMCs isolated from these patients. In this study, we evaluated the immunogenicity and efficacy of a dual-antigenic peptide vaccine (PV1), comprised of MAGED4B and FJX1 peptides in HNSCC patients. We first demonstrated that 94.8% of HNSCC patients expressed MAGED4B and/or FJX1 by immunohistochemistry, suggesting that PV1 could benefit the majority of HNSCC patients. The presence of pre-existing MAGED4B and FJX1-specific T-cells was detected using a HLA-A2 dimer assay and efficacy of PV1 to induce T-cell to secrete cytotoxic cytokine was evaluated using ELISPOT assay. Pre-existing PV1-specific T-cells were detected in all patients. Notably, we demonstrated that patients' T-cells were able to secrete cytotoxic cytokines upon exposure to target cells expressing the respective antigen post PV1 stimulation. Furthermore, patients with high expression of MAGED4B and FJX1 in their tumours were more responsive to PV1 stimulation, demonstrating the specificity of the PV1 peptide vaccine. Additionally, we also demonstrated the expression of MAGED4B and FJX1 in breast, lung, colon, prostate and rectal cancer suggesting the potential use of PV1 in these cancers. In summary, PV1 could be a good vaccine candidate for the treatment of HNSCC patients and other cancers expressing these antigens.
Fulltext Transcriptional analysis highlights three distinct immune profiles of high-risk oral epithelial dysplasia

Gan CP, Lee BKB, Lau SH, Kallarakkal TG, Zaini ZM, Lye BKW, et al.

Front Immunol, 2022;13:954567.
PMID: 36119104 DOI: 10.3389/fimmu.2022.954567

Oral potentially malignant disorders (OPMD) are precursors of oral squamous cell carcinoma (OSCC), and the presence of oral epithelial dysplasia (OED) in OPMD confers an increased risk of malignant transformation. Emerging evidence has indicated a role for the immune system in OPMD disease progression; however, the underlying immune mechanisms remain elusive. In this study, we used immune signatures established from cancer to delineate the immune profiles of moderate and severe OED, which are considered high-risk OPMD. We demonstrated that moderate and severe OEDs exhibit high lymphocyte infiltration and upregulation of genes involved in both immune surveillance (major histocompatibility complex-I, T cells, B cells and cytolytic activity) and immune suppression (immune checkpoints, T regulatory cells, and tumor-associated macrophages). Notably, we identified three distinct subtypes of moderate and severe OED: immune cytotoxic, non-cytotoxic and non-immune reactive. Active immune surveillance is present in the immune cytotoxic subtype, whereas the non-cytotoxic subtype lacks CD8 immune cytotoxic response. The non-immune reactive subtype showed upregulation of genes involved in the stromal microenvironment and cell cycle. The lack of T cell infiltration and activation in the non-immune reactive subtype is due to the dysregulation of CTNNB1, PTEN and JAK2. This work suggests that moderate and severe OED that harbor the non-cytotoxic or non-immune reactive subtype are likely to progress to cancer. Overall, we showed that distinct immune responses are present in high-risk OPMD, and revealed targetable pathways that could lead to potential new approaches for non-surgical management of OED.
Fulltext Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies

Fadlullah MZ, Chiang IK, Dionne KR, Yee PS, Gan CP, Sam KK, et al.

Oncotarget, 2016 May 10;7(19):27802-18.
PMID: 27050151 DOI: 10.18632/oncotarget.8533

Emerging biological and translational insights from large sequencing efforts underscore the need for genetically-relevant cell lines to study the relationships between genomic alterations of tumors, and therapeutic dependencies. Here, we report a detailed characterization of a novel panel of clinically annotated oral squamous cell carcinoma (OSCC) cell lines, derived from patients with diverse ethnicity and risk habits. Molecular analysis by RNAseq and copy number alterations (CNA) identified that the cell lines harbour CNA that have been previously reported in OSCC, for example focal amplications in 3q, 7p, 8q, 11q, 20q and deletions in 3p, 5q, 8p, 18q. Similarly, our analysis identified the same cohort of frequently mutated genes previously reported in OSCC including TP53, CDKN2A, EPHA2, FAT1, NOTCH1, CASP8 and PIK3CA. Notably, we identified mutations (MLL4, USP9X, ARID2) in cell lines derived from betel quid users that may be associated with this specific risk factor. Gene expression profiles of the ORL lines also aligned with those reported for OSCC. By focusing on those gene expression signatures that are predictive of chemotherapeutic response, we observed that the ORL lines broadly clustered into three groups (cell cycle, xenobiotic metabolism, others). The ORL lines noted to be enriched in cell cycle genes responded preferentially to the CDK1 inhibitor RO3306, by MTT cell viability assay. Overall, our in-depth characterization of clinically annotated ORL lines provides new insight into the molecular alterations synonymous with OSCC, which can facilitate in the identification of biomarkers that can be used to guide diagnosis, prognosis, and treatment of OSCC.
Fulltext DNA Vaccines Targeting Novel Cancer-Associated Antigens Frequently Expressed in Head and Neck Cancer Enhance the Efficacy of Checkpoint Inhibitor

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.

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