Terry D. Rees

A review of research on salivary biomarkers for oral cancer detection

Using saliva for disease diagnostics and health surveillance is a promising approach as collecting saliva is relatively easy and non-invasive. Over the past two decades, using salivary biomarkers specifically for early cancer detection has attracted much research interest, especially for cancers occurring in the oral cavity and oropharynx, for which the five-year survival rate (62%) is still one of the lowest among all major human cancers. More than 90% of oral cancers are oral squamous cell carcinoma (OSCC) and the standard method for detection is through a comprehensive clinical examination by oral healthcare professionals. Despite the fact that the oral cavity is easily accessible, most OSCCs are not diagnosed until an advanced stage, which is believed to be the major reason for the low survival rate, and points to the urgent need for clinical diagnostic aids for early detection of OSCC. Thus, much research effort has been dedicated to investigating potential salivary biomarkers for OSCC, and more than 100 such biomarkers have been reported in the literature. However, some important issues and challenges have emerged that require solutions and further research in order to find reliable OSCC salivary biomarkers for clinical use. This review article provides an up-to-date list of potential OSCC salivary biomarkers reported as of the fall of 2013, and discusses those emerging issues. By raising the awareness of these issues on the part of both researchers and clinicians, it is hoped that reliable, specific and sensitive salivary biomarkers may be found soon—and not only biomarkers for early OSCC detection but also for detecting other types of cancers or even for monitoring non-cancerous disease activity.

Effectiveness of a low dose of cyclosporine in the management of patients with oral erosive lichen planus

This study investigated the effectiveness of a low-dose cyclosporine rinse used in the treatment of oral erosive lichen planus. Fourteen patients with oral erosive lichen planus provided seven experimental sites treated with cyclosporine and seven control sites treated with a placebo. Participants rinsed with 5 ml (500 mg) of cyclosporine or 5 ml of a placebo for 5 minutes each day over a period of 4 weeks. Cyclosporine blood levels as well as complete blood cell counts with differential and serial multiple analysis were monitored throughout the study. Weekly quantitative measurements of lesion size and character (ulceration, erythema, and reticulation) were recorded with the use of an intraoral grid. Healing was defined as the transition from ulceration to erythema to reticulation or to complete resolution. Pain assessment with the use of a visual analogue scale and a questionnaire pertaining to any side effects of treatment were completed each week. At 4 weeks, a statistically significant difference was observed in lesion healing between the cyclosporine and placebo groups. All experimental sites demonstrated progressive healing with evidence of reduced erythema and ulceration, increased reticulation, and decreased pain scores. In contrast, control sites exhibited minimal change in lesion size or character, and patients reported unchanged or increased pain scores. No significant side effects were reported. Within the parameters of this investigation, topical cyclosporine proved to an effective alternative therapy to currently available medications used in the treatment of oral lichen planus.

Absorption of a topical steroid and evaluation of adrenal suppression in patients with erosive lichen planus

This study was designed to investigate the absorption of a topical steroid applied to the gingiva and buccal mucosa of patients with erosive lichen planus and to healthy control patients. In addition, adrenal suppression was assessed by measurements of serum and urine cortisol levels. Ten patients with erosive lichen planus and eight control patients provided urine and blood samples at baseline, day 3, and day 21. After establishment of baseline laboratory values, patients were instructed to apply 500 mg of a 0.05% fluocinonide gel to the gingiva and buccal mucosa three times a day for 3 weeks. Measurements of cortisol levels revealed no significant changes in either the disease or the control group. Although procedures were developed to detect fluocinonide, none of the patients showed evidence of the steroid during the study. It was concluded that the topical application of a fluocinonide gel to the gingiva and buccal mucosa over a 3-week period in patients with erosive lichen planus produced no adrenal suppression.

Oral Effects of Drug Abuse

Drug abuse is a major problem in the U.S. and most other countries of the world today. Many studies, surveys, and case reports have described the adverse social and medical effects of drug abuse; yet surprisingly little is known about the specific effects of many of these drugs in the oral cavity. This article reviews the current state of knowledge concerning the systemic and oral effects of drugs of abuse and the dental management of addicted patients.

Oral presentation of pemphigus vulgaris and its response to systemic steroid therapy

This article reviews our experience during a 20-year period with patients with oral lesions of pemphigus vulgaris. Of the 30 patients, 20 were women and 10 were men, with an age range of 24 to 68 years. The soft palate was involved in 80% of cases at initial presentation. Direct immunofluorescence studies were positive for IgG in the intercellular region in all cases where lesional tissue was histologically studied. Systemic steroid therapy alone controlled the disease in 24 patients, one patient was given no treatment, and the remaining five required additional treatment with either azathioprine, cyclophosphamide, or gold. Steroid therapy was continued in the long-term at a reduced dose, but side effects such as diabetes mellitus, hypertension, and duodenal ulcers were observed. Long-term steroid therapy is therefore the treatment of choice for the oral lesions of pemphigus vulgaris, but in some cases alternative treatment options may be required.

Mucous membrane pemphigoid. Treatment experience at two institutions.

The initial oral findings and treatment in 50 cases of mucous membrane pemphigoid are presented. Histologic and immunologic studies were undertaken in each case to confirm the clinical diagnosis. The treatments prescribed are summarized and illustrate that topical steroids are effective, but in some cases systemic steroid therapy with or without other immunologically active drugs is required. A significant number of patients had extraoral manifestations of the disorder.

Salivary endothelin-1 potential for detecting oral cancer in patients with oral lichen planus or oral cancer in remission.

Endothelin-1 (ET-1) is a potent vasoconstrictor involved not only in vascular biology but also in carcinogenesis. Results of a study in 2007 suggested salivary ET-1 as a potential biomarker for oral squamous cell carcinoma (OSCC), but a later study showed conflicting results. The purpose of our pilot study was to investigate feasibility of using salivary ET-1 as a biomarker for OSCC in two groups: oral lichen planus (OLP) patients and patients with OSCC in remission. Saliva samples were collected from five groups of subjects: patients with newly diagnosed, active OSCC (Group A); patients with OSCC in remission (Group B); patients with active OLP lesions (Group C); patients with OLP in remission (Group D); and normal controls (Group E). Salivary ET-1 levels were determined by enzyme-linked immunosorbent assay, and the results were analyzed by the Mann-Whitney U test. The mean salivary ET-1 level in Group A was significantly higher than that found in Group C (p=0.001), Group D (p=0.015) or Group E (p=0.004). There were no significant differences (p>0.05) in the mean salivary ET-1 levels between Groups A and B; Groups B and C; Groups B and D; Groups B and E; Groups C and D; Groups C and E; or Groups D and E. Salivary ET-1 could be a good biomarker for OSCC development in OLP patients regardless of the degree of OLP disease activity. However, it appeared not to be a good biomarker for detecting recurrence of OSCC in patients in remission.

Evaluation of major parotid glycoproteins in patients with burning mouth syndrome

OBJECTIVE This study was to investigate the potential role of salivary glycoproteins in burning mouth syndrome. STUDY DESIGN This study compared major parotid glycoproteins in a group of patients with burning mouth syndrome and age-, sex-, race-matched healthy controls. RESULTS By use of a glycoprotein detection kit, saliva from both patients and controls exhibited three major parotid glycoprotein banding patterns consisting of either one or two bands, molecular weights 58 kDa and 77 kDa. The strong lectin reactivity of major parotid glycoproteins with Ricinus communis agglutinin suggests that galactose is the most prevalent terminal sugar. In addition, major parotid glycoproteins were shown to express blood group antigen H. On the basis of metachromatic characteristics and immunologic reactivity, major parotid glycoproteins appear to be members of the proline rich protein multigene family, proline rich glycoprotein, genetic polymorphism G1. No qualitative difference was observed in major parotid glycoprotein banding patterns between patients and controls. CONCLUSION These findings do not support a role for major parotid glycoproteins in burning mouth syndrome.

Salivary Interleukin-6 and -8 in Patients With Oral Cancer and Patients With Chronic Oral Inflammatory Diseases

BACKGROUND Previous research has indicated that salivary interleukin (IL)-6 and IL-8 are potential biomarkers for oral squamous cell carcinoma (OSCC). However, their levels have been found to be significantly elevated in patients with chronic periodontitis (CP) or oral lichen planus (OLP). The data also showed wide variations in levels among the different studies, and no standardization procedure was ever performed. Therefore, the objective of this study is to determine whether CP or OLP confounds the use of IL-6 or IL-8 for OSCC detection. METHODS Saliva samples were collected from five groups: OSCC before treatment (n = 18); CP (n = 21); disease-active OLP (n = 21); disease-inactive OLP (n = 20); and healthy controls (n = 21). IL-6 and IL-8 concentrations (determined by enzyme-linked immunosorbent assays) were compared, using total salivary protein-standardized levels to validate the data. The Kruskal-Wallis test (α = 0.05) followed by pairwise Mann-Whitney U (post hoc) tests with Bonferroni adjustments (α = 0.00625) were used for statistical analysis. RESULTS Salivary IL-6 levels were significantly higher in patients with OSCC than in patients with CP (P <0.001), disease-active OLP (P = 0.001), disease-inactive OLP (P <0.001), and healthy controls (P <0.001). Salivary IL-8 levels were significantly higher in patients with OSCC than in patients with CP (P <0.001), but only marginally significantly higher than in healthy controls (P = 0.014). Statistical results of standardized IL-6 and IL-8 levels were consistent with the non-standardized levels in all pairs except one. CONCLUSION Salivary IL-6 may be a useful biomarker in the detection of OSCC, unconfounded by CP or OLP.

Salivary basic fibroblast growth factor in patients with oral squamous cell carcinoma or oral lichen planus

OBJECTIVE The objective of this study was to gather preliminary data concerning the feasibility of using salivary basic fibroblast growth factor (bFGF) for detecting development of oral squamous cell carcinoma (OSCC) in patients with oral lichen planus (OLP), and in patients with OSCC whose disease was in remission. STUDY DESIGN Saliva samples were collected from 5 patient groups: patients with newly diagnosed OSCC, patients with OSCC whose disease was in remission, patients with OLP in disease-active state, patients with OLP in disease-inactive state, and healthy controls. Salivary bFGF levels were determined by enzyme-linked immunosorbent assay, and data were analyzed using the Mann-Whitney U test. RESULTS Salivary bFGF levels were significantly elevated in patients with newly diagnosed OSCC compared with patients with OSCC in remission, patients with disease-active OLP, and healthy controls. No significant difference was found between patients with newly diagnosed OSCC and patients with disease-inactive OLP. CONCLUSIONS Our results suggested that salivary bFGF might be a potential biomarker for detecting OSCC development in patients with OSCC in remission, but not in patients with OLP.