Camile S. Farah

The role of alcohol in oral carcinogenesis with particular reference to alcohol-containing mouthwashes

Worldwide, oral cancer represents approximately 5 per cent of all malignant lesions, with over 800 new intra-oral squamous cell carcinomas registered in Australia each year. Despite recent advances in therapy, the five-year survival rate remains around 50 per cent and the sequelae of treatment can be seriously debilitating. It has been long established that smoking and alcohol consumption are risk factors linked to the development of oral cancer. This review assesses the epidemiological evidence, supportive in vitro studies and mechanism by which alcohol is involved in the development of oral cancer. Further, we review the literature that associates alcohol-containing mouthwashes and oral cancer. On the basis of this review, we believe that there is now sufficient evidence to accept the proposition that alcohol-containing mouthwashes contribute to the increased risk of development of oral cancer and further feel that it is inadvisable for oral healthcare professionals to recommend the long-term use of alcohol-containing mouthwashes.

Epithelial to mesenchymal transition (EMT) biomarkers--E-cadherin, beta-catenin, APC and Vimentin--in oral squamous cell carcinogenesis and transformation.

OBJECTIVES To investigate immunohistochemical (IHC) analysis of E-cadherin, β-catenin, APC and Vimentin for prediction of oral malignant transformation. MATERIALS AND METHODS Immunoreactivity for E-cadherin, β-catenin, APC and Vimentin were determined for 100 oral biopsies classified as normal, mild dysplasia, moderate-severe dysplasia or OSCC, using the IHC scoring or label index scoring systems. Co-expression of biomarkers and correlation with histopathological grading was analysed. Vimentin and E-cadherin results were confirmed by RT-PCR and further investigated in vitro using a novel organotypic cell invasion model based on human dermis. RESULTS A trend for decreased E-cadherin expression but increased Vimentin expression that correlated with increased disease severity was observed. Epithelial β-catenin localisation shifted from being membranous to cytoplasmic/nuclear with increased histopathological grade severity. Relative to normal, APC expression was decreased for mild dysplasia but increased for OSCC. Co-expression of β-catenin, APC and Vimentin (Spearman rank correlation) suggests interdependence of these molecules and involvement of the Wnt pathway in oral malignant transformation. Relative mRNA expression of E-cadherin for dysplasia and OSCC were less than 1% of normal tissue values, and mRNA expression of Vimentin was 3.7 times higher for OSCC than normal. After 63 days of organotypic culture neoplastic oral keratinocytes (PE/CA-PJ15) lost expression of E-cadherin and gained expression of Vimentin relative to their non-invasive counterparts in the epithelium. CONCLUSIONS Trends in the expression of EMT markers - E-cadherin, β-catenin, APC and Vimentin - suggest their involvement in oral carcinogenesis via Wnt pathway dysregulation. Aberrant expression of β-catenin, APC and Vimentin are potential markers of malignant transformation.

Innate versus adaptive immunity in Candida albicans infection

Candida albicans is a common opportunistic pathogen, causing both superficial and systemic infection. Clinical observations indicate that mucocutaneous infections are commonly associated with defective cell‐mediated immune responses, whereas systemic infection is more frequently seen in patients with deficiencies in neutrophil number or function. Analysis of mechanisms of host resistance against gastrointestinal and oral infection in mouse models has demonstrated an absolute dependence on CD4+ T cells, although clearance also involves phagocytic cells. Both IL‐12 and TNF‐α appear to be important mediators, but mouse strain‐dependent variations in susceptibility to infection may be related to T‐cell enhancement of production of phagocytic cells by the bone marrow. In murine systemic infection, the role of innate and adaptive responses is less well defined. Studies in immunodeficient and T‐cell‐depleted mice suggest that clearance of the yeast may be predominantly a function of the innate response, whereas the adaptive response may either limit tissue damage or have the potential to cause immunopathology, depending on the host genetic context in which the infection takes place.

T Cells Augment Monocyte and Neutrophil Function in Host Resistance against Oropharyngeal Candidiasis

ABSTRACT The purpose of this study was to identify the cell populations involved in recovery from oral infections with Candida albicans. Monoclonal antibodies specific for CD4+cells, CD8+ cells, and polymorphonuclear leukocytes were used to deplete BALB/c and CBA/CaH mice of the relevant cell populations in systemic circulation. Monocytes were inactivated with the cytotoxic chemical carrageenan. Mice were infected with 108C. albicans yeast cells and monitored for 21 days. Systemic depletion of CD4+ and CD8+ T lymphocytes alone did not increase the severity of oral infection compared to that of controls. Oral colonization persisted in animals treated with head and neck irradiation and depleted of CD4+T cells, whereas infections in animals that received head and neck irradiation alone or irradiation and anti-CD8 antibody cleared the infection in a comparable fashion. The depletion of polymorphonuclear cells and the cytotoxic inactivation of mononuclear phagocytes significantly increased the severity of oral infection in both BALB/c and CBA/CaH mice. High levels of interleukin 12 (IL-12) and gamma interferon (IFN-γ) were produced by lymphocytes from the draining lymph nodes of recovering animals, whereas IL-6, tumor necrosis factor alpha, and IFN-γ were detected in the oral mucosae of both naı̈ve and infected mice. The results indicate that recovery from oropharyngeal candidiasis in this model is dependent on CD4+-T-cell augmentation of monocyte and neutrophil functions exerted by Th1-type cytokines such as IL-12 and IFN-γ.

Oral fungal infections: an update for the general practitioner

Oral candidosis is the most common fungal infection encountered in general dental practice. It manifests in a variety of clinical presentations which may mimic more sinister diseases, and can occasionally be refractory to treatment requiring the attention of an oral medicine specialist. Management of oral candidosis should always include a thorough investigation of underlying predisposing conditions, as the disease often presents when the patient is systemically compromised. This update highlights the pathogenesis, clinical presentation, and management strategies of oral Candidal lesions commonly encountered in dental practice.

Primary Role for CD4 T Lymphocytes in Recovery From Oropharyngeal Candidiasis

ABSTRACT Oropharyngeal candidiasis is associated with defects in cell-mediated immunity and is commonly seen in human immunodeficiency virus positive individuals and AIDS patients. A model for oral candidiasis in T-cell-deficient BALB/c and CBA/CaH nu/nu mice was established. After inoculation with 108Candida albicans yeasts, these mice displayed increased levels of oral colonization compared to euthymic control mice and developed a chronic oropharyngeal infection. Histopathological examination of nu/nu oral tissues revealed extensive hyphae penetrating the epithelium, with polymorphonuclear leukocyte microabscess formation. Adoptive transfer of either naive or immune lymphocytes into immunodeficient mice resulted in the recovery of these animals from the oral infection. Reconstitution of immunodeficient mice with naive CD4+ but not CD8+ T cells significantly decreased oral colonization compared to controls. Interleukin-12 and gamma interferon were detected in the draining lymph nodes of immunodeficient mice following reconstitution with naive lymphocytes. This study demonstrates the direct requirement for T lymphocytes in recovery from oral candidiasis and suggests that this is associated with the production of cytokines by CD4+ T helper cells.

Efficacy of tissue autofluorescence imaging (velscope) in the visualization of oral mucosal lesions

Technology that highlights potentially malignant oral lesions in a highly sensitive and specific manner will aid clinicians in early diagnosis of these conditions. This study assessed the efficacy of direct tissue autofluorescence imaging Visually Enhanced Lesion Scope (VELScope) in the detection of oral mucosal lesions.

Oral mucosal malignancy and potentially malignant lesions: an update on the epidemiology, risk factors, diagnosis and management

An oral examination for the assessment for malignant and potentially malignant oral mucosal lesions is routine in general dental practice. It may be uncommon for general dental practitioners to encounter oral cancer, with anecdotal reports suggesting that this occurs about once every 10 years in a busy general dental practice. However, potentially malignant oral mucosal lesions are relatively common, occurring in about 2.5% of the population. This update highlights the epidemiology, risk factors, diagnosis and management of these oral mucosal lesions.

The assessment of diffused light illumination and acetic acid rinse (Microlux/DL™) in the visualisation of oral mucosal lesions

Oral examination alone cannot always distinguish benign from premalignant and malignant lesions, thereby resulting in delayed patient referral and poorer prognosis. Thus, any non-invasive technology which highlights oral premalignant and malignant lesions in a highly sensitive and specific manner will undoubtedly aid clinicians in early diagnosis and treatment of these conditions. The aim of this study was to assess the efficacy of acetic acid mouthwash and diffused light illumination (Microlux/DL) as a diagnostic aid in the visualisation of oral mucosal lesions and its ability to highlight malignant and potentially malignant lesions. Fifty patients referred for assessment of an oral white lesion were initially examined under routine incandescent operatory light. The location, size, ease of visibility, border distinctness and presence of satellite lesions were recorded. Clinical examination was repeated using the Microlux/DL diffused light illumination kit. An incisional biopsy was performed to provide a definitive histopathological diagnosis. Microlux/DL examination enhanced the visibility of 34 lesions, however, it did not help uncover any clinically undetected lesions, change the provisional diagnosis, or alter the biopsy site. Microlux/DL showed a sensitivity of 77.8% and a specificity of 70.7%, with a positive predictive value of 36.8%. Although Microlux/DL appears useful at enhancing lesion visibility, it is a poor discriminator for inflammatory, traumatic and malignant lesions.

Role of complement C5 and T lymphocytes in pathogenesis of disseminated and mucosal candidiasis in susceptible DBA/2 mice

The aims of the study were to compare the pathogenesis of Candida albicans infection in various organs and anatomical regions of C5-deficient (DBA/2) and C5-sufficient (BALB/c) mice, and to evaluate the importance of complement C5 and T lymphocytes as factors that determine host susceptibility or resistance. The kidneys of DBA/2 mice showed higher colonisation and more severe tissue damage than those of BALB/c, but infection at other sites, including oral and vaginal mucosa, was generally similar in the two strains. Passive transfer of C5-sufficient serum into DBA/2 mice decreased the fungal burden in the kidney, and prolonged survival of the reconstituted animals. Depletion of CD4(+) and/or CD8(+) cells did not exacerbate either systemic or mucosal infection when compared to controls, and passive transfer of splenocytes from infected donors caused only a small and transient reduction in numbers of yeasts recovered from the kidney of sub-lethally infected recipients. It is concluded that the acute susceptibility of the kidneys in this mouse strain is due to C5 deficiency expressed on a susceptible genetic background. T lymphocytes, however, appear to have minimal influence on recovery from systemic infection with this isolate of C. albicans.