The Mutational Profile of Unicystic Ameloblastoma.

BRAF V600E is the most common mutation in conventional ameloblastoma (AM) of the mandible. In contrast, maxillary AMs appear to harbor more frequently RAS, FGFR2, or SMO mutations. Unicystic ameloblastoma (UAM) is considered a less aggressive variant of ameloblastoma, amenable to more conservative treatment, and classified as a distinct entity. The aim of this study was to characterize the mutation profile of UAM ( n = 39) and to compare it to conventional AM ( n = 39). The associations between mutation status and recurrence probability were also analyzed. In the mandible, 94% of UAMs (29/31, including 8/8 luminal, 6/8 intraluminal, and 15/15 mural subtypes) and 74% of AMs (28/38) revealed BRAF V600E mutations. Among the BRAF wild-type cases, 1 UAM showed a missense SMO mutation (p.L412F), whereas 2 NRAS (p.Q61R), 2 HRAS (p.Q61R), and 2 FGFR2 (p.C383R) activating mutations were identified in AM. Of the 3 maxillary UAMs, only 1 revealed a BRAF V600E mutation. Taken together, our findings demonstrate high frequency of activating BRAF V600E mutations in both UAM and AM of the mandible. In maxillary UAMs, the BRAF V600E mutation prevalence appears to be lower as was shown for AM previously. It could therefore be argued that UAM and AM are part of the spectrum of the same disease. AMs without BRAF V600E mutations were associated with an increased rate of local recurrence ( P = 0.0003), which might indicate that routine mutation testing also has an impact on prognosis.

Assessing the accuracy of autofluorescence, chemiluminescence and toluidine blue as diagnostic tools for oral potentially malignant disorders--a clinicopathological evaluation.

OBJECTIVES: Early detection of oral cancer and their precursors is the key to reducing the high mortality rate attributable to oral cancer. A variety of new chair-side diagnostic tools are currently available that may enhance oral mucosal examination and facilitate the detection of benign and malignant disorders. The aim of this study was to investigate the accuracy of autofluorescence, chemiluminescence and toluidine blue (TBlue) when used in combination against conventional oral examination and surgical biopsy for the detection and assessing risk status of oral potentially malignant disorders. MATERIALS AND METHODS: A total of 126 patients, with white, red and mixed white and red patches were included. Following a comprehensive oral examination, all patients underwent a standard protocol of autofluorescence, chemiluminescence and TBlue examination. A surgical biopsy was performed to assess oral epithelial dysplasia. RESULTS: Seventy patients had leukoplakia/erythroplakia and 44 had epithelial dysplasia. In relation to leukoplakia/erythroplakia, autofluorescence, chemiluminescence and TBlue showed a sensitivity of 87.1, 77.1 and 52.9 % and a specificity of 21.4, 26.8 and 67.9 %, respectively. For dysplasia cases, autofluorescence, chemiluminescence and TBlue showed sensitivity and specificity of 84.1, 77.3 and 56.8 % and 15.3, 27.8 and 65.8 %, respectively. CONCLUSION: While all the three tests were useful in detecting oral mucosal changes, their accuracy in identifying oral potentially malignant disorders (OPMD) is questionable. However, in combination, the tests yielded better results, with improved specificity. CLINICAL RELEVANCE: These research tools are helpful in specialist clinics but further studies are necessary to examine their role in screening in primary care settings.

Eating tasty food to cope. Longitudinal association with BMI.

The goals of this study were to determine if a change in certain motives to eat highly palatable food, as measured by the Palatable Eating Motives Scale (PEMS), could predict a change in body mass index (BMI) over time, to assess the temporal stability of these motive scores, and to test the reliability of previously reported associations between eating tasty foods to cope and BMI. BMI, demographics, and scores on the PEMS and the Binge Eating Scale were obtained from 192 college students. Test-retest analysis was performed on the PEMS motives in groups varying in three gap times between tests. Regression analyses determined what PEMS motives predicted a change in BMI over two years. The results replicated previous findings that eating palatable food for Coping motives (e.g., to forget about problems, reduce negative feelings) is associated with BMI. Test-retest correlations revealed that motive scores, while somewhat stable, can change over time. Importantly, among overweight participants, a change in Coping scores predicted a change in BMI over 2 years, such that a 1-point change in Coping predicted a 1.76 change in BMI (equivalent to a 10.5 lb. change in body weight) independent of age, sex, ethnicity, and initial binge-eating status (Cohen's f(2) effect size = 1.44). The large range in change of Coping scores suggests it is possible to decrease frequency of eating to cope by more than 1 scale point to achieve weight losses greater than 10 lbs. in young overweight adults, a group already at risk for rapid weight gain. Hence, treatments aimed specifically at reducing palatable food intake for coping reasons vs. for social, reward, or conformity reasons, should help achieve a healthier body weight and prevent obesity if this motive-type is identified prior to significant weight gain.

Early dental epithelial transcription factors distinguish ameloblastoma from keratocystic odontogenic tumor.

The aim of the study was to characterize the molecular relationship between ameloblastoma and keratocystic odontogenic tumor (KCOT) by means of a genome-wide expression analysis. Total RNA from 27 fresh tumor samples of 15 solid/multicystic intraosseous ameloblastomas and 12 sporadic KCOTs was hybridized on Affymetrix whole genome arrays. Hierarchical clustering separated ameloblastomas and KCOTs into 2 distinct groups. The gene set enrichment analysis based on 303 dental genes showed a similar separation of ameloblastomas and KCOTs. Early dental epithelial markers PITX2, MSX2, DLX2, RUNX1, and ISL1 were differentially overexpressed in ameloblastoma, indicating its dental identity. Also, PTHLH, a hormone involved in tooth eruption and invasive growth, was one of the most differentially upregulated genes in ameloblastoma. The most differentially overexpressed genes in KCOT were squamous epithelial differentiation markers SPRR1A, KRTDAP, and KRT4, as well as DSG1, a component of desmosomal cell-cell junctions. Additonally, the epithelial stem cell marker SOX2 was significantly upregulated in KCOT when compared with ameloblastoma. Taken together, the gene expression profile of ameloblastoma reflects differentiation from dental lamina toward the cap/bell stage of tooth development, as indicated by dental epithelium-specific transcription factors. In contrast, gene expression of KCOT indicates differentiation toward keratinocytes.

Utility of chemiluminescence (ViziLite™) in the detection of oral potentially malignant disorders and benign keratoses.

BACKGROUND: Oral potentially malignant disorders (OPMD) are known to precede the development of oral cancer. Detection of OPMD allows delivery of interventions that may reduce the evolution of these disorders to malignancy. Following oral examinations, the accuracy of detection of OPMD by chemiluminescence was evaluated using a commercially available detection kit - ViziLite. Data derived were compared in relation to conventional oral examination and surgical biopsy. METHODS: A total of 126 patients, 70 men and 56 women (mean age 58.5 ± 11.9 years) attending Oral Medicine Clinics at King's and Guy's Hospitals, London, with oral white, red, and mixed white and red patches were enrolled. Sixty-one patients were current smokers, 28 were ex-smokers, while 92 were alcohol users. In a detailed investigation, these patients underwent ViziLite examination followed by surgical biopsy. RESULTS: Based on the clinical diagnosis, 70 patients had oral leukoplakia/erythroplakia, 32 had oral lichen planus, nine had chronic hyperplastic candidiasis, and rest had frictional keratosis (13) or oral submucous fibrosis (2). Of 126 lesions, 95 (75.4%) showed aceto-whitening. Most oral leukoplakias had enhanced visibility and sharpness of the lesion when viewed with the ViziLite system. Following biopsy, 44 had oral epithelial dysplasia (29 mild, eight moderate, and seven severe). The sensitivity (se) and specificity (sp) of chemiluminescence for the detection of a dysplastic lesion were 77.3% and 27.8%, respectively. CONCLUSION: While ViziLite has the ability to detect OPMD, it does not accurately delineate dysplastic lesions. The device can be used as a general oral mucosal examination system and may in particular improve the visualization of leukoplakias.

Grading oral epithelial dysplasia: analysis of individual features.

BACKGROUND: Assessing epithelial dysplasia to predict malignant transformation remains problematic in many tissues because grading systems are poorly structured and individual features poorly defined. Dysplasia grading is criticised for lack of reproducibility and poor predictive value. Grading systems for upper aerodigestive tract dysplasia have evolved over several decades and are not supported by good outcome experimental data. METHODS: This study analysed the individual features of dysplasia in 86 oral dysplastic lesions and determined the reproducibility of scoring for each, and correlated them with other features and clinical factors using complex clustering analyses. RESULTS: A uniform pattern of dysplasia was found in 37 lesions, focal dysplasia in 36 and in 13 lesions dysplasia formed complex discontinuous patterns. There was wide variation in reproducibility of scoring of individual features and many, including thickness, some types of rete morphology, basaloid cell anisonucleosis, basal dyscohesion, and dyskeratosis as deep single cells correlated with sub-sites. Rete morphology, type of keratinisation, hyperchromatism of the basaloid compartment, prickle cell anisonucleosis and extension down salivary ducts correlated with smoking. Conventional grading and oral intraepithelial neoplasia (OIN) grading by 'thirds affected' showed strong correlation overall but scores obtained with the OIN system tended to a higher grade at all sites except soft palate/fauces. There was poor correlation between the systems for moderate dysplasia and also severe dysplasia at some sites. Individual features could not be shown to cluster to form distinct patterns of dysplasia. CONCLUSIONS: These variations may account in part for the lack of reproducibility and poor predictive value of the grading systems in current use and could inform the design of future grading systems.

Evaluation of an autofluorescence based imaging system (VELscope™) in the detection of oral potentially malignant disorders and benign keratoses.

Early detection of oral cancer is crucial in improving survival rate. Identification and detection of oral potentially malignant disorders (OPMD) allow delivery of interventions to reduce the evolution of these disorders to malignancy. A variety of new and emerging diagnostic aids and adjunctive techniques are currently available to potentially assist in the detection of OPMD. The objective of the present study was to evaluate the accuracy of autofluorescence against conventional oral examination and surgical biopsy. A total of 126 patients, 70 males and 56 females (mean age 58.5±11.9 years) who presented to the Oral Medicine Clinics at King's and Guy's Hospitals, London with oral white and red patches suspicious of OPMD were enrolled. Following a complete visual and autofluorescence examination, all underwent an incisional biopsy for histopathological assessment. Seventy patients had oral leukoplakia/erythroplakia, 32 had oral lichen planus, 9 chronic hyperplastic candidiasis and rest frictional keratosis (13) or oral submucous fibrosis (2). Of 126 lesions, 105 (83%) showed loss of fluorescence. Following biopsy 44 had oral epithelial dysplasia (29 mild, 8 moderate and 7 severe). The sensitivity (se) and specificity (sp) of autofluorescence for the detection of a dysplastic lesion was 84.1% and 15.3% respectively. While VELscope was useful in confirming the presence of oral leukoplakia and erythroplakia and other oral mucosal disorders, the device was unable to discriminate high-risk from low-risk lesions.

Suicides by jumping from iconic bridges in Hong Kong.

BACKGROUND: Three bridges in Hong Kong have become iconic sites for suicide since their openings 11 years ago. AIMS: This retrospective record-based study aimed to examine suicides by jumping from a group of three iconic bridges in Hong Kong, and to explore potential preventive strategies on these bridges to prevent future suicide. METHODS: We examined the Coroner's files of 12 people who killed themselves by jumping from the bridges between 1997 and 2007. We also examined the Coroner's files of other suicides in 2003, and compared them with the bridge suicides. RESULTS: The majority of the suicides were male, middle-age (40-59 years), married or cohabiting, not living alone, employed or self-employed, and in financial difficulty. None of these cases had a reported psychiatric diagnosis or psychiatric care history, and only one case had a history of suicidal attempt. Compared with other suicides in Hong Kong, the bridge jumpers were more likely to be younger, holding a job, indebted, free from a psychiatric and attempt history, and to leave a suicide note (p < .05). The bridge suicide cases in Hong Kong also appeared to be different from the profiles of bridge jumpers in other countries. CONCLUSIONS: Erection of an effective safety barrier has been found to prevent bridge suicides in many countries. Given the different characteristics of bridge jumpers in Hong Kong and the technical difficulties, more innovative ways may be needed to prevent suicides by such means. Potential prevention measures are discussed and, hopefully, will better inform the future design and development of bridges of significance.

ERBB receptors in developing, dysplastic and malignant oral epithelia.

Some oral squamous cell carcinomas (OSCCs) overexpress epidermal growth factor receptor (EGFR) but little is known about the receptor system overall during oral carcinogenesis. We studied all four ERBB receptors (EGFR, ERBB2-4) in developing (n=2), normal (n=7), dysplastic (n=23) and malignant (n=26) oral epithelia by means of immunohistochemistry. The investigations were supplemented by conducting reverse transcription-polymerase chain reactions in relation to 13 OSCC samples. All four ERBB receptors were detected in developing oral epithelium and, to a lesser degree, in mature oral epithelium. An increase in EGFR immunoreactivity was seen in 61% and 54% of dysplasias and OSCCs, respectively. The corresponding percentages for ERBB2 were 48 and 12, for ERBB3 48 and 43. ERBB4 nuclear staining was increased in 30% of dysplasias and 26% of OSCCs. Changes in ERBB receptor mRNA levels were not statistically significant. The results show that ERBB receptor profiles are specific to each tumour. Increased nuclear translocation of ERBB4 in some OSCCs may alter transcription of target genes and be associated with cancer progression. This information may be useful for clinicians as EGFR inhibitors are becoming treatment options in modern oncology.

Genetic changes in sporadic keratocystic odontogenic tumors (odontogenic keratocysts).

Little is known about the genetic background of keratocystic odontogenic tumors (KCOT, odontogenic keratocysts). Our aim was to characterize genomic aberrations in sporadic KCOT using cDNA-expression arrays and array-comparative genomic hybridization. For cDNA-expression arrays, 10 KCOT specimens and 20 fetal tooth germs were studied. Quantitative real-time reverse-transcription/polymerase chain-reaction and immunohistochemical studies were also undertaken. Several genes were over-expressed in 12q13, including cytokeratin 6B (KRT6B) ( approximately 10-fold), epidermal growth factor receptor ERBB3 (approximately 4.7-fold), and glioma-associated oncogene homologue 1 (GLI1) (approximately 5- to 12-fold). One amplicon (approximately 0.7 Mega base pairs [Mbp]), covering several genes involved in the regulation of cell growth, was found in 12q13.2. Deletions were found in 3q13.1, 5p14.3, and 7q31.3, including the cell-adhesion-related gene cadherin 18 (CDH18) and leukocyte cell adhesion molecule (ALCAM, MEMD). Over-expressed and amplified genes in 12q13, also reported in several other tumors and cell lines, may contribute to the persistent growth characteristics of KCOT.

DNA ploidy in proliferative verrucous leukoplakia.

Proliferative verrucous leukoplakia (PVL) is a clinicopathologically distinctive form of oral leukoplakia presenting with multifocal flat, nodular and verrucous lesions that progress inexorably to squamous carcinoma. The aims of this investigation were to describe the clinical and histopathological features of six cases of PVL and to determine whether lesional epithelium demonstrates DNA ploidy anomalies prior to malignant transformation. The clinical and pathological features of six patients were reviewed and all biopsy specimens were subjected to image-based DNA ploidy analysis. The female:male ratio was 5:1 and the average age on first biopsy was 66 years. Only one patient reported both tobacco smoking and alcohol intake. The most frequently affected sites were alveolar ridge and/or gingiva (6/6), buccal mucosa (3/6), palate (3/6), tongue (2/6), buccal sulcus (2/6), and lip (1/6). Three patients developed multiple primary carcinomas, either invasive or verrucous. A ploidy anomaly at any oral site would have predicted malignant transformation in four cases and probably in a fifth for whom DNA ploidy failed to meet diagnostic criteria but was suspicious of aneuploidy. The site of transformation was predicted by ploidy and histopathology for three carcinomas and a further carcinoma showed severe dysplasia and a suspicious ploidy result in adjacent tissue. Both conventional histopathology and DNA ploidy proved effective in predicting the site of transformation in this limited series.

Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren's syndrome.

OBJECTIVE: Ectopic lymphoneogenesis can occur in the salivary glands of Sjögren's syndrome (SS) patients and is associated with local antigen-driven B cell responses, autoantibody formation, and potential lymphomatous transformation. CXCL13 and CCL21 have been identified in salivary glands, but their role in ectopic lymphoneogenesis in SS remains unclear. This study aimed to evaluate the microanatomic association between CXCL13 and CCL21 expression and the acquisition of lymphoid features in periductal foci. METHODS: Salivary glands from 37 SS patients and 9 chronic sialadenitis patients were analyzed by immunohistochemistry for T cell/B cell segregation, CD21+ follicular dendritic cell networks, and peripheral lymph node addressin (PNAd)-positive high endothelial venules (HEVs) in relationship to the size of the aggregates and the expression of CXCL13 and CCL21 within infiltrating cells, epithelium, and endothelium. RESULTS: Grade 1 aggregates (10-50 lymphocytes) demonstrated predominance of nonorganized CD3+ cells, while grade 2 (>50 lymphocytes) and grade 3 (>50 with germinal centers) showed a progressive increase in CD20+ B cells and T cell/B cell segregation. This higher degree of lymphoid organization was significantly related to an increased expression of CXCL13 within infiltrating cells and PNAd+ HEV-associated CCL21-producing cells. Conversely, no association between lymphoid organization and lymphoid chemokine expression by epithelial cells was observed. CONCLUSION: The acquisition of lymphoid features by inflammatory foci in SS is critically associated with the enlargement of the inflammatory foci and with the expression of CXCL13 and CCL21 within the infiltrate, but is not associated with their expression by epithelial cells. These data strongly support an active participation of CXCL13 and CCL21 in regulating the progressive organization and maintenance of periductal foci.

Congenital sialolipoma of the parotid gland first reported case and review of the literature.

Tumours of the parotid gland in children are uncommon, and represent only 1.3% of all benign salivary tumours. Lipomas of the parotid are also rare, and account for 0.5% of all parotid gland tumours. Sialolipoma is a new variant of salivary gland lipoma, consisting of adipose and glandular tissue that was first proposed by Nagao et al. in 2001. Ten cases of parotid gland lipoma associated with glandular elements have been previously reported in the literature. All have been in adults and none in children. We present the first reported case of congenital sialolipoma that had developed in a female infant. It was managed successfully by superficial parotidectomy undertaken at ten weeks of age.

Expression of keratins in normal, immortalized and malignant oral epithelia in organotypic culture.

Keratins have been extensively studied in tissues and cultured keratinocytes but limited information is available on epithelia reconstructed in vitro. The aim of this study was to examine keratin expression in organotypic epithelia with normal (NOK), immortalized (SVpgC2a) and malignant (SqCC/Y1) human buccal cells. Organotypic epithelia were derived from 10 days of culture at the air-liquid interface of collagen gels containing human oral fibroblasts using a standardized serum-free medium. Sections were stained immunohistochemically with selected mono-specific antibodies to a range of keratins. Organotypic epithelia showed sharp differences in keratin expression and distribution. K4/K13, K1/K10, K6/K16 were variably expressed in NOK and SqCC/Y1 but were not detected in SVpgC2a. K5 was expressed in all organotypic epithelia but K14 was absent in SVpgC2a. K7 and K8 showed variable expression while K18 was expressed uniformly in all epithelia. K19 was expressed consistently in NOK and K20 was distributed heterogeneously in SVpgC2a. Overall, organotypic cultures of normal keratinocytes express many of the same keratins as buccal mucosa. Further, the loss of keratins in SVpgC2a and their retention in SqCC/Y1 have several features in common with the respective keratin profile of oral epithelial dysplasia and well-differentiated oral squamous cell carcinoma. Although qualitative and quantitative differences exist compared to keratin expression in vivo, these cell lines in organotypic culture may serve in studies of the multi-step progression of oral cancer.