Faculty Bibliography

BACKGROUND: The early detection and excision of potentially malignant disorders (PMD) of the lip and oral cavity that require intervention may reduce malignant transformations (though will not totally eliminate malignancy occurring), or if malignancy is detected during surveillance, there is some evidence that appropriate treatment may improve survival rates. OBJECTIVES: To estimate the diagnostic accuracy of conventional oral examination (COE), vital rinsing, light-based detection, biomarkers and mouth self examination (MSE), used singly or in combination, for the early detection of PMD or cancer of the lip and oral cavity in apparently healthy adults. SEARCH METHODS: We searched MEDLINE (OVID) (1946 to April 2013) and four other electronic databases (the Cochrane Diagnostic Test Accuracy Studies Register, the Cochrane Oral Health Group's Trials Register, EMBASE (OVID), and MEDION) from inception to April 2013. The electronic databases were searched on 30 April 2013. There were no restrictions on language in the searches of the electronic databases. We conducted citation searches, and screened reference lists of included studies for additional references. SELECTION CRITERIA: We selected studies that reported the diagnostic test accuracy of any of the aforementioned tests in detecting PMD or cancer of the lip or oral cavity. Diagnosis of PMD or cancer was made by specialist clinicians or pathologists, or alternatively through follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for relevance. Eligibility, data extraction and quality assessment were carried out by at least two authors independently and in duplicate. Studies were assessed for methodological quality using QUADAS-2. We reported the sensitivity and specificity of the included studies. MAIN RESULTS: Thirteen studies, recruiting 68,362 participants, were included. These studies evaluated the diagnostic accuracy of COE (10 studies), MSE (two studies). One randomised controlled of test accuracy trial directly evaluated COE and vital rinsing. There were no eligible diagnostic accuracy studies evaluating light-based detection or blood or salivary sample analysis (which tests for the presence of bio-markers of PMD and oral cancer). Given the clinical heterogeneity of the included studies in terms of the participants recruited, setting, prevalence of target condition, the application of the index test and reference standard and the flow and timing of the process, the data could not be pooled. For COE (10 studies, 25,568 participants), prevalence in the diagnostic test accuracy sample ranged from 1% to 51%. For the eight studies with prevalence of 10% or lower, the sensitivity estimates were highly variable, and ranged from 0.50 (95% confidence interval (CI) 0.07 to 0.93) to 0.99 (95% CI 0.97 to 1.00) with uniform specificity estimates around 0.98 (95% CI 0.97 to 1.00). Estimates of sensitivity and specificity were 0.95 (95% CI 0.92 to 0.97) and 0.81 (95% CI 0.79 to 0.83) for one study with prevalence of 22% and 0.97 (95% CI 0.96 to 0.98) and 0.75 (95% CI 0.73 to 0.77) for one study with prevalence of 51%. Three studies were judged to be at low risk of bias overall; two were judged to be at high risk of bias resulting from the flow and timing domain; and for five studies the overall risk of bias was judged as unclear resulting from insufficient information to form a judgement for at least one of the four quality assessment domains. Applicability was of low concern overall for two studies; high concern overall for three studies due to high risk population, and unclear overall applicability for five studies. Estimates of sensitivity for MSE (two studies, 34,819 participants) were 0.18 (95% CI 0.13 to 0.24) and 0.33 (95% CI 0.10 to 0.65); specificity for MSE was 1.00 (95% CI 1.00 to 1.00) and 0.54 (95% CI 0.37 to 0.69). One study (7975 participants) directly compared COE with COE plus vital rinsing in a randomised controlled trial. This study found a higher detection rate for oral cavity cancer in the conventional oral examination plus vital rinsing adjunct trial arm. AUTHORS' CONCLUSIONS: The prevalence of the target condition both between and within index tests varied considerably. For COE estimates of sensitivity over the range of prevalence levels varied widely. Observed estimates of specificity were more homogeneous. Index tests at a prevalence reported in the population (between 1% and 5%) were better at correctly classifying the absence of PMD or oral cavity cancer in disease-free individuals that classifying the presence in diseased individuals. Incorrectly classifying disease-free individuals as having the disease would have clinical and financial implications following inappropriate referral; incorrectly classifying individuals with the disease as disease-free will mean PMD or oral cavity cancer will only be diagnosed later when the disease will be more severe. General dental practitioners and dental care professionals should remain vigilant for signs of PMD and oral cancer whilst performing routine oral examinations in practice.

PURPOSE: Promoter hypermethylation has been recently proposed as mean for HNSCC detection in salivary rinses. In a prospective study of high-risk population, we showed that EDNRB promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy. EXPERIMENTAL DESIGN: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was performed and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by Quantitative methylation-specific PCR. RESULTS: HOXA9, EDNRB and DCC methylation were associated (p=0.012; p<0.0001; p=0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (p=0.0003) or DCC (p=0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (p=0.008; p=0.026; p=0.046) and multivariate analysis (p=0.012; p=0.037; p=0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with similar AUC (0.61, 95%CI=0.60-0.81) when compared to EDNRB and DCC combined AUC (0.60, 95%CI=0.51-0.69), sensitivity of 46% and specificity of 72%. Combination of EDNRB, DCC and CRC was optimal AUC (0.67, 95%CI=0.58-0.76). CONCLUSION: EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available.

Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering "Green" chemoprevention. Cancer Prev Res; 6(5); 410-8. (c)2013 AACR.

This article outlines how to perform a standard comprehensive extraoral and intraoral examination and the existing commercially available adjunctive techniques for the early detection of oral cancer and premalignant lesions. Visualization-based techniques (e.g., autofluorescence and chemiluminescence), toluidine blue vital staining, cytopathologic tests and high-risk human papillomavirus testing are discussed in detail, including the indications and protocols for use, their advantages and disadvantages and clinical cases.

Oral medicine is a specialized area of study within the scope of dental medicine. This discipline is often viewed as the crossroads between medicine and dentistry and has become integral in both pre-and postdoctoral dental education. Oral medicine is recognized as a dental specialty throughout most of the world and currently represents an emerging specialty in the United States. Historically, oral medicine has been loosely defined in the United States without a clear consensus definition. Recent published studies regarding international oral medicine postdoctoral programs and clinical practice have helped to provide more specific information regarding oral medicine from many perspectives. This article will review the literature relevant to defining oral medicine in the United States and present a new definition of this important discipline based on recent studies.

The oral mucosa's accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.

AbstractPurpose. To describe occurrences of oral squamous cell carcinoma (SCC) in patients who had received long-term pegylated liposomal doxorubicin (PLD) for ovarian cancer.Patients and Methods. In our cohort of patients on maintenance PLD for ovarian and related mullerian epithelial malignancies, we encountered two patients with invasive SCC of the oral cavity (one of them multifocal) and one with high-grade squamous dysplasia. Review of patients at our institution receiving PLD for recurrent ovarian cancer identified three additional patients. The duration of treatment, cumulative PLD dose, human papillomavirus (HPV) positivity, BRCA status, stage at diagnosis, outcome, and other characteristics are reviewed.Results. All five cases were nonsmokers with no known risk factors for HPV and four were negative for p16 expression. Four of the patients had known BRCA mutations whereas one tested negative. Cumulative doses of PLD were >1,600 mg/m(2) given over 30-132 months. Three had SCCs staged as T1N0 oral tongue, alveolar ridge (gingival), and multifocal oral mucosa; one had a T2N0 oral tongue; and one had dysplasia. After excision, two were given radiation but recurred shortly thereafter; the others remain well and have had no further exposure to cytotoxic drugs, including PLD.Conclusion. Awareness of this possible long-term complication during PLD treatment should enhance the likelihood of early detection of oral lesions in these patients. Decisions to continue maintenance PLD after complete response of the original cancer should perhaps consider the benefits of delaying ovarian cancer recurrence versus the possible risk for a secondary cancer.