Exploring the microbiome of oral epithelial dysplasia as a predictor of malignant progression.

A growing body of research associates the oral microbiome and oral cancer. Well-characterized clinical samples with outcome data are required to establish relevant associations between the microbiota and disease. The objective of this study was to characterize the community variations and the functional implications of the microbiome in low-grade oral epithelial dysplasia (OED) using 16S rRNA gene sequencing from annotated archival swabs in progressing (P) and non-progressing (NP) OED. We characterised the microbial community in 90 OED samples - 30 swabs from low-grade OED that progressed to cancer (cases) and 60 swabs from low-grade OED that did not progress after a minimum of 5 years of follow up (matched control subjects). There were small but significant differences between P and NP samples in terms of alpha diversity as well as beta diversity in conjunction with other clinical factors such as age and smoking status for both taxa and functional predictions. Across all samples, the most abundant genus was Streptococcus, followed by Haemophilus, Rothia, and Neisseria. Taxa and predicted functions were identified that were significantly differentially abundant with progression status (all Ps and NPs), when samples were grouped broadly by the number of years between sampling and progression or in specific time to progression for Ps only. However, these differentially abundant features were typically present only at low abundances. For example, Campylobacter was present in slightly higher abundance in Ps (1.72%) than NPs (1.41%) and this difference was significant when Ps were grouped by time to progression. Furthermore, several of the significantly differentially abundant functions were linked to the Campylobacteraceae family in Ps and may justify further investigation. Larger cohort studies to further explore the microbiome as a potential biomarker of risk in OED are warranted.

Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells.

Most human breast cancers have diversified genomically and biologically by the time they become clinically evident. Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRAS(G12D)), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. DNA barcoding of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as 'normal-like'. This system challenges previous concepts that carcinogenesis in normal human epithelia is necessarily a slow process requiring the acquisition of multiple driver mutations. It also presents the first description of initial events that accompany the genesis and evolution of malignant human mammary cell populations, thereby contributing new understanding of the rapidity with which heterogeneity in their properties can develop.

Socioeconomic disparities in head and neck cancer patients' access to cancer treatment centers.

INTRODUCTION: Both socioeconomic status and travel time to cancer treatment have been associated with treatment choice and patient outcomes. An improved understanding of the relationship between these two dimensions of access may enable cancer control experts to better target patients with poor access, particularly in isolated suburban and rural communities. METHODS: Using geographical information systems, head and neck cancer patients across British Columbia, Canada from 1981 to 2009, were mapped and their travel times to the nearest treatment center at their time of diagnosis were modelled. Patients' travel times were analysed by urban, suburban, and rural neighborhood types and an index of multiple socioeconomic deprivation was used to assess the role of socioeconomic status in patients' spatial access. RESULTS: Significant associations between socioeconomic deprivation and spatial access to treatment were identified, with the most deprived quintiles of patients experiencing nearly twice the travel time as the least deprived quintile. The sharpest disparities were observed among the most deprived patient populations in suburban and rural areas. However, the establishment of new treatment centers has decreased overall travel times by 28% in recent decades. CONCLUSIONS: Residence in a neighborhood with high socioeconomic deprivation is strongly associated with head and neck cancer patients' spatial access to cancer treatment centers. Patients residing in the most socioeconomically deprived neighborhoods consistently have longer travel times in urban, suburban, and rural communities in the study area.

Socio-economic deprivation: a significant determinant affecting stage of oral cancer diagnosis and survival.

BACKGROUND: Many factors contribute to socioeconomic status (SES), yet in most survival studies only income is used as a measure for determining SES. We used a complex, composite, census-based metric for socioeconomic deprivation to better distinguish individuals with lower SES and assess its impact on survival and staging trends of oral cancers. METHODS: Oropharyngeal (OPC) and oral cavity cancer (OCC) cases were identified from the British Columbia cancer registry between 1981-2009 and placed into affluent and deprived neighborhoods using postal codes linked to VANDIX (a composite SES index based on 7 census variables encompassing income, housing, family structure, education, and employment). Stage and cancer-specific survival rates were examined by sex, SES, and time period. RESULTS: Approximately 50 % of OPC and OCC cases of both sexes resided in SES deprived neighborhoods. Numbers of cases have increased in recent years for all but OCC in men. The deprivation gap in survival between affluent and deprived neighborhoods widened in recent years for OPC and OCC in men, while decreasing for OPC and increasing slightly for OCC in women. Greater proportions of OCC cases were diagnosed at later stage disease for both sexes residing in deprived neighborhoods, a trend not seen for OPC. CONCLUSION: SES remains a significant independent determinant of survival for both OPC and OCC when using a composite metric for SES. OPC survival rates among men have improved, albeit at slower rates in deprived communities. OCC screening programs need to be targeted towards SES-deprived neighborhoods where greater proportions of cases were diagnosed at a later stage and survival rates have significantly worsened in both sexes.

Suburbanisation of oral cavity cancers: evidence from a geographically-explicit observational study of incidence trends in British Columbia, Canada, 1981-2010.

BACKGROUND: Recent studies have demonstrated an elevated risk of oral cavity cancers (OCC) among socioeconomically deprived populations, whose increasing presence in suburban neighbourhoods poses unique challenges for equitable health service delivery. The majority of studies to date have utilised aspatial methods to identify OCC. In this study, we use high-resolution geographical analyses to identify spatio-temporal trends in OCC incidence, emphasising the value of geospatial methods for public health research. METHODS: Using province-wide population incidence data from the British Columbia Cancer Registry (1981-2009, N = 5473), we classify OCC cases by census-derived neighbourhood types to differentiate between urban, suburban, and rural residents at the time of diagnosis. We map geographical concentrations by decade and contrast trends in age-adjusted incidence rates, comparing the results to an index of socioeconomic deprivation. RESULTS: Suburban cases were found to comprise a growing proportion of OCC incidence. In effect, OCC concentrations have dispersed from dense urban cores to suburban neighbourhoods in recent decades. Significantly higher age-adjusted oral cancer incidence rates are observed in suburban neighbourhoods from 2006 to 2009, accompanied by rising socioeconomic deprivation in those areas. New suburban concentrations of incidence were found in neighbourhoods with a high proportion of persons aged 65+ and/or born in India, China, or Taiwan. CONCLUSIONS: While the aging of suburban populations provides some explanation of these trends, we highlight the role of the suburbanisation of socioeconomically deprived and Asia-born populations, known to have higher rates of risk behaviours such as tobacco, alcohol, and betel/areca consumption. Specifically, betel/areca consumption among Asia-born populations is suspected to be a primary driver of the observed geographical shift in incidence from urban cores to suburban neighbourhoods. We suggest that such geographically-informed findings are complementary to potential and existing place-specific cancer control policy and targeting prevention efforts for high-risk sub-populations, and call for the supplementation of epidemiological studies with high-resolution mapping and geospatial analysis.

Population-based incidence trends of oropharyngeal and oral cavity cancers by sex among the poorest and underprivileged populations.

BACKGROUND: Oral cancer is an important health issue, with changing incidence in many countries. Oropharyngeal cancer (OPC, in tonsil and oropharygeal areas) is increasing, while oral cavity cancer (OCC, other sites in the mouth) is decreasing. There is the need to identify high risk groups and communities for further study and intervention. The objective of this study was to determine how the incidence of OPC and OCC varied by neighbourhood socioeconomic status (SES) in British Columbia (BC), including the magnitude of any inequalities and temporal trends. METHODS: ICDO-3 codes were used to identify OPC and OCC cases in the BC Cancer Registry from 1981-2010. Cases were categorized by postal codes into SES quintiles (q1-q5) using VANDIX, which is a census-based, multivariate weighted index based on neighbourhood average household income, housing tenure, educational attainment, employment and family structure. Age-standardized incidence rates were determined for OPC and OCC by sex and SES quintiles and temporal trends were then examined. RESULTS: Incidence rates are increasing in both men and women for OPC, and decreasing in men and increasing in women for OCC. This change is not linear or proportionate between different SES quintiles, for there is a sharp and dramatic increase in incidence according to the deprivation status of the neighbourhood. The highest incidence rates in men for both OPC and OCC were observed in the most deprived SES quintile (q5), at 1.7 times and 2.2 times higher, respectively, than men in the least deprived quintile (q1). For OPC, the age-adjusted incidence rates significantly increased in all SES quintiles with the highest increase observed in the most deprived quintile (q5). Likewise, the highest incidence rates for both OPC and OCC in women were observed in the most deprived SES quintile (q5), at 2.1 times and 1.8 times higher, respectively, than women in the least deprived quintile (q1). CONCLUSION: We report on SES disparities in oral cancer, emphasizing the need for community-based interventions that address access to medical care and the distribution of educational and health promotion resources among the most SES deprived communities in British Columbia.

Influence of fluorescence on screening decisions for oral mucosal lesions in community dental practices.

BACKGROUND: Quality of oral screening examinations is dependent upon the experience of the clinician and can vary widely. Deciding when a patient needs to be referred is a critical and difficult decision for general practice clinicians. A device to aid in this decision would be beneficial. The objective of this study was to to examine the utility of direct fluorescence visualization (FV) by dental practitioners as an aid in decision-making during screening for cancer and other oral lesions. METHODS: Dentists were trained to use a stepwise protocol for evaluation of the oral mucosa: medical history, head, neck and oral exam, and fluorescent visualization exam. They were asked to use clinical features to categorize lesions as low (LR), intermediate (IR), or high (HR) risk and then to determine FV status of these lesions. Clinicians made the decision of which lesions to reassess in 3 weeks and based on this reassessment, to refer forward. RESULTS: Of 2404 patients screened over 11 months, 357 initially had lesions with 325 (15%) identified as LR, 16 (4.5%) IR, and 16 (4.5%) HR. Lesions assessed initially as IR and HR had a 2.7-fold increased risk of FV loss persisting to the reassessment appointment versus the LR lesions. The most predictive model for lesion persistence included both FV status and lesion risk assessment. CONCLUSION: A protocol for screening (assess risk, reassess, and refer) is recommended for the screening of abnormal intraoral lesions. Integrating FV into a process of assessing and reassessing lesions significantly improved this model.

Gender- and ethnicity-specific survival trends of oral cavity and oropharyngeal cancers in British Columbia.

INTRODUCTION: A shift in etiology of oral cancers has been associated with a rise in incidence for oropharyngeal cancers (OPC) and decrease for oral cavity cancers (OCC); however, there is limited information about population-based survival trends. We report epidemiological transitions in survival for both OPC and OCC from a population-based cancer registry, focusing upon gender and ethnic differences. METHODS: All primary oral cancers diagnosed between 1980 and 2005 were identified from the British Columbia Cancer Registry and regrouped into OPC and OCC by topographical subsites, time periods (1980-1993 and 1994-2005), stage at diagnosis, and ethnicity. Cases were then followed up to December 2009. Using gender-based analysis, actuarial life tables were used to calculate survival rates, which were compared using Kaplan-Meier curves and log-rank tests. RESULTS: For OPC, survival improved, significant for tonsil and base of tongue in men and marginally significant at base of tongue in women. This improvement occurred in spite of an increase in late-stage diagnosis for OPC in both genders. Interestingly, there was no difference in survival for early- and late-stage disease for OPC in men. For OCC, there was a decrease in survival for floor of mouth cancers in both genders although significant in women only. South Asians had the poorest survival for OCC in both genders. CONCLUSION: Survival for OPC improved, more dramatically in men than women, in spite of late-stage diagnosis and increasing nodal involvement. Given the poor survival rates and need for early detection, targeted OCC screening programs are required for South Asians.

Ultrasensitive rapid cytokine sensors based on asymmetric geometry two-dimensional MoS2 diodes.

The elevation of cytokine levels in body fluids has been associated with numerous health conditions. The detection of these cytokine biomarkers at low concentrations may help clinicians diagnose diseases at an early stage. Here, we report an asymmetric geometry MoS2 diode-based biosensor for rapid, label-free, highly sensitive, and specific detection of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine. This sensor is functionalized with TNF-α binding aptamers to detect TNF-α at concentrations as low as 10 fM, well below the typical concentrations found in healthy blood. Interactions between aptamers and TNF-α at the sensor surface induce a change in surface energy that alters the current-voltage rectification behavior of the MoS2 diode, which can be read out using a two-electrode configuration. The key advantages of this diode sensor are the simple fabrication process and electrical readout, and therefore, the potential to be applied in a rapid and easy-to-use, point-of-care, diagnostic tool.

Canadian Optically-guided approach for Oral Lesions Surgical (COOLS) trial: study protocol for a randomized controlled trial.

BACKGROUND: Oral cancer is a major health problem worldwide. The 5-year survival rate ranges from 30-60%, and has remained unchanged in the past few decades. This is mainly due to late diagnosis and high recurrence of the disease. Of the patients who receive treatment, up to one third suffer from a recurrence or a second primary tumor. It is apparent that one major cause of disease recurrence is clinically unrecognized field changes which extend beyond the visible tumor boundary. We have previously developed an approach using fluorescence visualization (FV) technology to improve the recognition of the field at risk surrounding a visible oral cancer that needs to be removed and preliminary results have shown a significant reduction in recurrence rates. METHOD/DESIGN: This paper describes the study design of a randomized, multi-centre, double blind, controlled surgical trial, the COOLS trial. Nine institutions across Canada will recruit a total of 400 patients with oral severe dysplasia or carcinoma in situ (N = 160) and invasive squamous cell carcinoma (N = 240). Patients will be stratified by participating institution and histology grade and randomized equally into FV-guided surgery (experimental arm) or white light-guided surgery (control arm). The primary endpoint is a composite of recurrence at or 1 cm within the previous surgery site with 1) the same or higher grade histology compared to the initial diagnosis (i.e., the diagnosis used for randomization); or 2) further treatment due to the presence of severe dysplasia or higher degree of change at follow-up. This is the first randomized, multi-centre trial to validate the effectiveness of the FV-guided surgery. DISCUSSION: In this paper we described the strategies, novelty, and challenges of this unique trial involving a surgical approach guided by the FV technology. The success of the trial requires training, coordination, and quality assurance across multiple sites within Canada. The COOLS trial, an example of translational research, may result in reduced recurrence rates following surgical treatment of early-stage oral cancer with significant impacts on survival, morbidity, patients' quality of life and the cost to the health care system. TRIAL REGISTRATION: Clinicaltrials.gov NCT01039298.

Visual Analytics: A Method to Explore Natural Histories of Oral Epithelial Dysplasia.

Risk assessment and follow-up of oral potentially malignant disorders in patients with mild or moderate oral epithelial dysplasia is an ongoing challenge for improved oral cancer prevention. Part of the challenge is a lack of understanding of how observable features of such dysplasia, gathered as data by clinicians during follow-up, relate to underlying biological processes driving progression. Current research is at an exploratory phase where the precise questions to ask are not known. While traditional statistical and the newer machine learning and artificial intelligence methods are effective in well-defined problem spaces with large datasets, these are not the circumstances we face currently. We argue that the field is in need of exploratory methods that can better integrate clinical and scientific knowledge into analysis to iteratively generate viable hypotheses. In this perspective, we propose that visual analytics presents a set of methods well-suited to these needs. We illustrate how visual analytics excels at generating viable research hypotheses by describing our experiences using visual analytics to explore temporal shifts in the clinical presentation of epithelial dysplasia. Visual analytics complements existing methods and fulfills a critical and at-present neglected need in the formative stages of inquiry we are facing.

Predicting Progression of Low-Grade Oral Dysplasia Using Brushing-Based DNA Ploidy and Chromatin Organization Analysis.

Most oral cancers arise from oral potentially malignant lesions, which show varying grades of dysplasia. Risk of progression increases with increasing grade of dysplasia; however, risk prediction among oral low-grade dysplasia (LGD), that is, mild and moderate dysplasia can be challenging as only 5%-15% transform. Moreover, grading of dysplasia is subjective and varies with the area of the lesion being biopsied. To date, no biomarkers or tools are used clinically to triage oral LGDs. This study uses a combination of DNA ploidy and chromatin organization (CO) scores from cells obtained from lesion brushings to identify oral LGDs at high-risk of progression. A total of 130 lesion brushings from patients with oral LGDs were selected of which 16 (12.3%) lesions progressed to severe dysplasia or cancer. DNA ploidy and CO scores were analyzed from nuclear features measured by our in-house DNA image cytometry (DNA-ICM) system and used to classify brushings into low-risk and high-risk. A total of 57 samples were classified as high-risk of which 13 were progressors. High-risk DNA brushing was significant for progression (P = 0.001) and grade of dysplasia (P = 0.004). Multivariate analysis showed high-risk DNA brushing showed 5.1- to 8-fold increased risk of progression, a stronger predictor than dysplasia grading and lesion clinical features. DNA-ICM can serve as a non-invasive, high-throughput tool to identify high-risk lesions several years before transformation. This will help clinicians focus on such lesions whereas low-risk lesions may be spared from unnecessary biopsies.Prevention Relevance: DNA ploidy and chromatin organization of cells collected from oral potentially malignant lesions (OPMLs) can identify lesions at high-risk of progression several years prior. This non-invasive test would enable clinicians to triage high-risk (OPMLs) for closer follow-up while low-risk lesions can undergo less frequent biopsies reducing burden on healthcare resources.

Basement membrane degeneration is common in lichenoid mucositis with dysplasia.

Background: Two subtypes of lichenoid mucositis (LM) with oral epithelial dysplasia have been proposed, with differing risks of malignant transformation. However, no research has been done to authenticate this hypothesis. The study objective was to determine whether there are 2 subcategories within this entity, one with primary lichenoid and secondary dysplastic features (L1D2), and the other with primary dysplastic and secondary lichenoid features (D1L2), and to compare the proportion of malignant progression in these groups. Methods: Patients with a diagnosis of lichenoid mucositis with low-grade (mild/moderate) oral epithelial dysplasia, no history of head and neck cancer, and who had at least 5 years of follow-up were eligible to participate in this nested case-control study. Cases (n = 10) were defined as lesions that progressed to severe dysplasia, carcinoma in situ or squamous cell carcinoma; controls (n = 32) were defined as those that did not progress. Immunohistochemistry was performed to assess for basement membrane (BM) degeneration using collagen IV-an integral BM protein. Results: Lesions that progressed to cancer exhibited a similar proportion of BM degeneration at baseline (70%) compared to non-progressors (78%), with no statistically significant difference between groups (p = 0.69). Conclusion: BM degeneration is frequently seen in LM with dysplasia and alone does not appear to be a predictor of malignant progression in lesions with both lichenoid and low-grade dysplastic features. Dysplasia should not be discounted in the presence of LM. Lesions that display any degree of dysplasia warrant clinical follow-up and continued monitoring.

Contexte: Deux sous-types de mucosites lichénoïdes (ML) avec dysplasie épithéliale buccale ont été proposés, avec des risques différents de transformation maligne. Cependant, aucune recherche n'a été faite pour valider cette hypothèse. L'objectif de l'étude était de déterminer s'il y a 2 sous-catégories au sein de cette entité, la première avec des caractéristiques lichénoïdes primaires et dysplasiques secondaires (L1D2), et l'autre avec des caractéristiques dysplasiques primaires et lichénoïdes secondaires (D1L2), et de comparer la proportion de progression maligne dans ces groupes. Méthodologie: Les patients ayant reçu un diagnostic de mucosite lichénoïde avec une dysplasie épithéliale buccale de faible intensité (faible/modérée), qui n'avaient aucun antécédent de cancer de la tête et du cou, et qui avaient eu au moins 5 ans de suivi, étaient admissible à participer à cette étude de cas-témoins emboîtés. Les cas (n = 10) étaient définis comme des lésions qui ont progressé à la dysplasie sévère, un carcinome in situ ou un carcinome squameux; les contrôles (n = 32) étaient définis comme ceux qui n'ont pas progressé. L'immunohistochimie a été effectuée pour évaluer s'il y avait eu une dégénérescence de la membrane basale (MB) en utilisant du collagène IV, une protéine MB intrinsèque. Résultats: Les lésions qui ont évolué en cancer ont présenté une proportion semblable de dégénérescence de MB au début (70 %) par rapport aux non-progresseurs (78 %), et aucune différence statistiquement significative entre les groupes (p = 0,69). Conclusion: La dégénérescence des MB est fréquemment constatée dans les ML avec dysplasie et seule, ne paraît pas être une variable explicative de l'évolution maligne dans les lésions à caractéristiques à la fois lichénoïdes et dysplasiques de faible intensité. Il ne faut pas sous-estimer la dysplasie en présence de ML. Les lésions qui présentent de la dysplasie, peu importe son étendue, exigent un suivi clinique et une surveillance continue.

Intraoral Photography Recommendations for Remote Risk Assessment and Monitoring of Oral Mucosal Lesions.

Oral cancer is a global health issue with substantial morbidity and a high mortality rate mainly because of late-stage diagnosis. Cancerous lesions are often preceded by potentially malignant lesions that may be detected during routine dental examinations. Not only is the oral cavity easily accessible for screening, but the clinical risk factors of the disease are also known. However, patients may not always be able to access screening services or receive follow-up for diagnosed lesions. In these circumstances, intraoral photos are crucial for timely triage, risk assessment, and monitoring of oral lesions. Further, photos form an integral part of a patient's records, facilitate patient education and communication between health care providers, and provide important information during the referral process. To ensure that intraoral photos are of good quality and standardised there is a need to establish recommendations regarding intraoral photography in oral mucosal screening. This article recommends methods to help health professionals and patients obtain interpretable intraoral photographs. Suggestions to achieve ideal lighting, mirror placement, camera angle, and retraction have been discussed. These recommendations are adaptable to easily available smartphone or point-and-shoot cameras and may be further used to develop future teledentistry platforms.

Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions.

BACKGROUNDThe aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention.METHODSIndividuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3-12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing.RESULTSTwenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses (P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological (P = 0.04) and clinical (P = 0.01) responses.CONCLUSIONTo our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent.TRIAL REGISTRATIONNCT02581137FUNDINGNIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870.

Exploring Knowledge and Perspectives of South Asian Children and Their Parents Regarding Healthy Cardiovascular Behaviors: A Qualitative Analysis.

South Asian children and parents have been shown to have a higher risk for cardiovascular disease (CVD) relative to white individuals. To design interventions aimed at addressing the comparatively higher burden in South Asians, a better understanding of attitudes and perspectives regarding CVD-associated behaviors is needed. As a result, we sought to understand knowledge about CVD risk in both children and parents, and attitudes toward physical activity and diet in both the children and parents, including potential cultural influences. In-depth interviews were conducted with 13 South Asian child-and-parent dyads representing a range of child body mass index (BMI) levels, ages, and with both sexes. South Asian children and parents demonstrated good knowledge about CVD prevention; however, knowledge did not always translate into behavior. The influence of social and cultural dynamics on behavior was also highlighted. To ensure that interventions aimed at this population are effective, an understanding of the unique social dynamics that influence diet and physical activity-related behaviors is needed.

Effect of Fluorescence Visualization-Guided Surgery on Local Recurrence of Oral Squamous Cell Carcinoma: A Randomized Clinical Trial.

Importance: High local recurrence rates with aggressive disease remain the main concern in oral cancer survival. Use of a translational device using fluorescence visualization (FV) approved by the US Food and Drug Administration and Health Canada, has shown a marked reduction in the 3-year local recurrence rate of high-grade oral lesions in a single-center observational study. Objective: To determine whether FV- guided surgery can improve local control rates in the treatment of in situ or T1 to T2 category oral squamous cell carcinoma (OSCC). Design, Setting, and Participants: A multicenter randomized clinical trial was conducted in a surgical setting. A total of 457 patients were enrolled between January 18, 2010, and April 30, 2015. Data analysis of the intention-to-treat population was performed from April 3, 2019, to March 20, 2020. Patients with histologically confirmed high-grade dysplasia/carcinoma in situ or T1 to T2 category OSCC were randomized to receive traditional peroral surgery or FV-guided surgery. Intervention: Fluorescence visualization during surgery. Main Outcomes and Measures: The primary outcome was local recurrence of OSCC. Secondary outcomes were failure of the first-pass margin, defined as a histologically confirmed positive margin for severe dysplasia or greater histologic change of the main specimen (ie, not the margins taken from the resection bed), regional or distant metastasis, and death due to disease. Results: Of the 457 patients enrolled in the study, 443 patients (264 [59.6%] men; mean [SD] age, 61.5 [13.3] years) completed the randomized treatment: 227 FV-guided and 216 non-FV guided surgery. The median follow-up was 52 (range, 0.29-90.8) months. In total, 45 patients (10.2%) experienced local recurrence. The 3-year local recurrence rate was 9.4% in the FV-guided group and 7.2% in the non-FV group (difference, 2.2%; 95% CI, -3.2% to 7.4%). Other similarities between the FV vs non-FV groups included failure of first-pass margin (68/227 [30.0%]) vs 65/216 [30.1%]), regional failure (39/227 [17.2%] vs 37/216 [17.1%]), disease-specific survival (23/227 [10.1%] vs 19/26 [8.8%]), and overall survival (41/227 [18.1%] vs 38/216 [17.6%]) were also similar between groups. No adverse events were judged to be related to the intervention. Conclusions and Relevance: In this randomized clinical trial, FV-guided surgery did not improve local control rates in the treatment of patients with in situ or T1 to T2 category oral cancer. Under a controlled environment, FV-guided surgery did not have an evident effect in reduction of local recurrence for localized OSCC. This result suggests that attention be directed to strategies other than improving definitions of nonapparent disease at clinical margins to identify the sources of local recurrence. Trial Registration: ClinicalTrial.gov Identifier: NCT01039298.

Genomic imbalances in precancerous tissues signal oral cancer risk.

Oral cancer develops through a series of histopathological stages: through mild (low grade), moderate, and severe (high grade) dysplasia to carcinoma in situ and then invasive disease. Early detection of those oral premalignant lesions (OPLs) that will develop into invasive tumors is necessary to improve the poor prognosis of oral cancer. Because no tools exist for delineating progression risk in low grade oral lesions, we cannot determine which of these cases require aggressive intervention. We undertook whole genome analysis by tiling-path array comparative genomic hybridization for a rare panel of early and late stage OPLs (n = 62), all of which had extensive longitudinal follow up (>10 years). Genome profiles for oral squamous cell carcinomas (n = 24) were generated for comparison. Parallel analysis of genome alterations and clinical parameters was performed to identify features associated with disease progression. Genome alterations in low grade dysplasias progressing to invasive disease more closely resembled those observed for later stage disease than they did those observed for non-progressing low grade dysplasias. This was despite the histopathological similarity between progressing and non-progressing cases. Strikingly, unbiased computational analysis of genomic alteration data correctly classified nearly all progressing low grade dysplasia cases. Our data demonstrate that high resolution genomic analysis can be used to evaluate progression risk in low grade OPLs, a marked improvement over present histopathological approaches which cannot delineate progression risk. Taken together, our data suggest that whole genome technologies could be used in management strategies for patients presenting with precancerous oral lesions.

Multiple pathways in the FGF signaling network are frequently deregulated by gene amplification in oral dysplasias.

Genetic alteration in oral premalignant lesions (OPLs), the precursors of oral squamous cell carcinomas (OSCCs), may represent key changes in disease initiation and development. We ask if DNA amplification occurs at this early stage of cancer development and which oncogenic pathways are disrupted in OPLs. Here, we evaluated 50 high-grade dysplasias and low-grade dysplasias that later progressed to cancer for gene dosage aberrations using tiling-path DNA microarrays. Early occurrences of DNA amplification and homozygous deletion were frequently detected, with 40% (20/50) of these early lesions exhibiting such features. Expression for 88 genes in 7 recurrent amplicons were evaluated in 5 independent head and neck cancer datasets, with 40 candidates found to be overexpressed relative to normal tissues. These genes were significantly enriched in the canonical ERK/MAPK, FGF, p53, PTEN and PI3K/AKT signaling pathways (p = 8.95 x 10(-3) to 3.18 x 10(-2)). These identified pathways share interactions in one signaling network, and amplification-mediated deregulation of this network was found in 30.0% of these preinvasive lesions. No such alterations were found in 14 low-grade dysplasias that did not progress, whereas 43.5% (10/23) of OSCCs were found to have altered genes within the pathways with DNA amplification. Multitarget FISH showed that amplification of EGFR and CCND1 can coexist in single cells of an oral dysplasia, suggesting the dependence on multiple oncogenes for OPL progression. Taken together, these findings identify a critical biological network that is frequently disrupted in high-risk OPLs, with different specific genes disrupted in different individuals.

Areca nut and betel quid chewing among South Asian immigrants to Western countries and its implications for oral cancer screening.

The South Asian community is the largest and one of the fastest growing minority groups in Canada, according to the 2006 census. These immigrants bring to Canada talents and skills that can promote Canada's economy and cultural diversity, but they also bring lifestyle habits that may lead to serious health issues. Chewing areca nut and betel quid (paan, with and without tobacco) is a known risk factor for oral cancer. This habit is common in the Indo-Canadian population, as evidenced by its sales in local Indian markets and restaurants. In this article, we present an overview of the sociocultural beliefs, knowledge and practices regarding betel quid/areca nut chewing, and discuss its implications for oral cancer screening among this immigrant population.