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Cell-free DNA (cfDNA) and cell-free mitochondrial DNA (cf-mtDNA) have been postulated as potential diagnostic and prognostic biomarkers for different human malignancies. Early detection of head and neck malignancies is fundamental for optimal patient management. This study, therefore, aimed to assess the utility of saliva-based liquid biopsy as a noninvasive source of cfDNA and cf-mtDNA for detecting head and neck cancer (HNSCC).One hundred thirty-three patients diagnosed with either oral leukoplakia (OLK) or HNSCC were compared with 137 healthy volunteers. An unstimulated whole saliva sample was collected from each participant. The absolute copy numbers of salivary cf-mtDNA and cfDNA were quantified using Multiplex Quantitative PCR. Two diagnostic indices based on the investigated molecules were assessed for their ability to differentiate between different diagnostic categories.The median scores of cfDNA and cf-mtDNA were statistically significantly higher among HNSCC patients (p 0.05), revealing area under the curve values of 0.758 and 0.826, respectively. The associated accuracy for this test in discriminating HNSCC from other diagnostic categories was 77.37% for the cfDNA-based index and 80.5% for the cf-mtDNA-based index. The median score of cfDNA was statistically significantly higher for patients with severe epithelial dysplasia (OED) compared to those with epithelial keratosis with no OED and mild OED. However, there was no significant difference between controls and OLK individuals.cfDNA and cf-mtDNA showed potential for use as precision medicine tools to detect HNSCC. Further multi-centre prospective studies are warranted to assess the prognostic utility of these molecules.

Circulating tumour cells (CTCs) are cancer cells released by cancer into the peripheral circulation. Haematogenous tumour spread is a hallmark of metastatic malignancy and a key factor in cancer recurrence and prognosis. CTCs have diagnostic and prognostic significance for a number of adenocarcinomas and melanoma. A review of the published peer-reviewed literature was performed to determine the clinical relevance of CTCs as a biomarker in the management of oral squamous cell carcinoma (OSCC). Fourteen studies met the eligibility criteria. With regard to patients with OSCC, this review found the following: (1) CTCs have been detected using multiple techniques; (2) the presence of CTCs does not appear to be related to tumour differentiation or size; (3) CTCs may be detected without lymph node involvement; (4) the detection of CTCs may be prognostic for both disease-free survival and overall survival; (5) quantification of CTCs may reflect the efficacy of therapy; (6) CTCs may be of value for ongoing patient monitoring. Preliminary evidence suggests that CTCs have diagnostic and prognostic potential as a biomarker for oral cancer management and warrant further investigation to determine their appropriate place in the management of OSCC patients.

Background: The global burden of oral squamous cell carcinoma (OSCC) remains formidable. Identifying factors predictive of aggressive tumour behaviour, disease progression and reduced survival time may assist in early identification of “high-risk” patients and appropriately target combination cancer therapies. Methods: A retrospective review of 467 OSCC patients treated over a 19-year period facilitated detailed clinico-pathological database analysis and determination of clinical outcome categories based upon time to progressive disease (loco-regional tumour recurrence and/or distant metastasis), overall death and OSCC-related death (death directly attributable to OSCC). Odds ratio (OR) and hazard ratio (HR) statistical measures were used to investigate relationships between patient demographics and clinico-pathological tumour features with clinical outcome. Results: Older age at presentation (P =.002) and a history of previous non–head and neck cancer (P =.010) increased the risk of overall death. OR for progressive disease development (P =.008) and OSCC-related death (P =.019) was most significant for buccal tumours. HR confirmed advanced-stage disease increased the risk of progressive disease (P

Background: A large number of oral squamous cell carcinomas (OSCCs) are believed to be preceded by oral potentially malignant disorders (OPMD) that have an increased likelihood of malignant transformation compared to clinically normal mucosa. This study was performed to identify differentially expressed genes between OPMDs that underwent malignant transformation (MT) and those that did not, termed “non-transforming” (NT) cases. Methods: Total RNA was extracted from formalin-fixed paraffin-embedded tissue biopsies of 20 OPMD cases with known clinical outcomes (10 MT vs. 10 NT). Samples were assessed for quantity, quality and integrity of RNA prior to sequencing. Analysis for differential gene expression between MT and NT was performed using statistical packages in R. Genes were considered to be significantly differentially expressed if the False Discovery Rate corrected P-value was 1.90). Analysis of RNA-Sequencing outputs revealed 41 genes (34 protein-coding; 7 non-coding) that were significantly differentially expressed between MT and NT cases. The log2 fold change for the statistically significant differentially expressed genes ranged from −2.63 to 2.48, with 23 protein-coding genes being downregulated and 11 protein-coding genes being upregulated in MT cases compared to NT cases. Conclusion: Several candidate genes that may play a role in malignant transformation of OPMD have been identified. Experiments to validate these candidates are underway. It is anticipated that this work will contribute to better understanding of the etiopathogenesis of OPMD and development of novel biomarkers.

Background: The natural history of oral squamous cell carcinoma (OSCC) is complicated by progressive disease including loco-regional tumour recurrence and development of distant metastases. Accurate prediction of tumour behaviour is crucial in delivering individualized treatment plans and developing optimal patient follow-up and surveillance strategies. Machine learning algorithms may be employed in oncology research to improve clinical outcome prediction. Methods: Retrospective review of 467 OSCC patients treated over a 19-year period facilitated construction of a detailed clinicopathological database. 34 prognostic features from the database were used to populate 4 machine learning algorithms, linear regression (LR), decision tree (DT), support vector machine (SVM) and k-nearest neighbours (KNN) models, to attempt progressive disease outcome prediction. Principal component analysis (PCA) and bivariate analysis were used to reduce data dimensionality and highlight correlated variables. Models were validated for accuracy, sensitivity and specificity, with predictive ability assessed by receiver operating characteristic (ROC) and area under the curve (AUC) calculation. Results: Out of 408 fully characterized OSCC patients, 151 (37%) had died and 131 (32%) exhibited progressive disease at the time of data retrieval. The DT model with 34 prognostic features was most successful in identifying “true positive” progressive disease, achieving 70.59% accuracy (AUC 0.67), 41.98% sensitivity and a high specificity of 84.12%. Conclusion: Machine learning models assist clinicians in accessing digitized health information and appear promising in predicting progressive disease outcomes. The future will see increasing emphasis on the use of artificial intelligence to enhance understanding of aggressive tumour behaviour, recurrence and disease progression.

Background: Oral squamous cell carcinoma (OSCC) is a lethal and deforming disease of rising incidence. With poor 5-year survival rates associated with higher stage disease, there is a need in clinical practice for reliable prognostic determinants to consolidate treatment planning and coordinate therapeutic approaches to improve long-term clinical outcomes for patients. Methods: A retrospective clinicopathological review of 467 OSCC patients with documented clinical outcome and treated in Hong Kong over a 19-year period was undertaken to investigate the potential prognostic role of 4 specific histopathological features of invasive tumour behaviour: perineural invasion (PNI), bone invasion (BNI), lymphovascular invasion (LVI) and extra-nodal extension (ENE) in metastatic neck disease. Results: Histopathological data for PNI, BNI, LVI and ENE, and stratified as zero, one, two, three or four positives, were available for 279 patients. A trend for decreased disease-free status was seen with increasing numbers of positive histopathological features, although this was not statistically significant (P =.1076). The time to onset of further disease (loco-regional recurrence and/or distant metastasis) was statistically significant, however, with progressive disease presenting most rapidly with increasing numbers of positive invasive parameters (P =.000152). Conclusion: PNI, BNI, LVI and ENE, especially when found in combination, show promise as prognostic markers of poor clinical outcome following OSCC treatment. Further, multi-centre prospective studies are required to confirm the predictive value of multi-positive histopathological features in clinical practice and to help improve individualised treatment planning.

Background: Preventive and early diagnostic methods such as health promotion and disease screening are increasingly advocated to improve detection and survival rates for oral cancer. These strategies are most effective when targeted at "high-risk" individuals and populations. Bayesian disease-mapping modelling is a statistical method to quantify and explain spatial and temporal patterns for risk and covariate factor influence, thereby identifying "high-risk" sub-regions or "case clustering" for targeted intervention. Rarely applied to oral cancer epidemiology, this paper highlights the efficacy of disease mapping for the Hong Kong population. Methods: Following ethical approval, anonymized individual-level data for oral cancer diagnoses were obtained retrospectively from the Clinical Data Analysis and Reporting System (CDARS) of the Hong Kong Hospital Authority (HA) database for a 7-year period (January 2013 to December 2019). Data facilitated disease mapping and estimation of relative risks of oral cancer incidence and mortality. Results: A total of 3,341 new oral cancer cases and 1,506 oral cancer-related deaths were recorded during the 7-year study period. Five districts, located in Hong Kong Island and Kowloon, exhibited considerably higher relative incidence risks with 1 significant "case cluster" hotspot. Six districts displayed higher mortality risks than expected from territory-wide values, with highest risk identified for two districts of Hong Kong Island. Conclusion: Bayesian disease mapping is successful in identifying and characterizing "high-risk" areas for oral cancer incidence and mortality within a community. This should facilitate targeted preventive and interventional strategies. Further work is encouraged to enhance global-level data and comprehensive mapping of oral cancer incidence, mortality and survival.

Oral squamous cell carcinoma is one of the commonest head and neck malignancies with approximately 350 000 cases reported annually and a mortality rate of 50% often attributed to late clinical presentation. Due to the close relationship between saliva bio-fluid and tumour lesions, optimizing salivary biomarkers for disease detection and screening provides a major new research direction in diagnostic oral oncology. As inter-tumour heterogeneity and intra-tumour heterogeneity are common within oral cavity neoplasms, it is unlikely that a single diagnostic or "risk-stratifying" saliva biomarker will suffice for universal translation to clinical practice. Therefore, this article highlights a number of promising saliva biomarker combinations for oral cavity cancer detection that require further research and validation to determine their true diagnostic potential.

Impact and efficiency of oral cancer and oral potentially malignant disorders screening are most realized in "at-risk" individuals. However, tools that can provide essential knowledge on individuals' risks are not applied in risk-based screening. This study aims to optimize a simplified risk scoring system for risk stratification in organized oral cancer and oral potentially malignant disorders screening.Participants were invited to attend a community-based oral cancer and oral potentially malignant disorders screening program in Hong Kong. Visual oral examination was performed for all attendees and information on sociodemographic characteristics as well as habitual, lifestyle, familial, and comorbidity risk factors were obtained. Individuals' status of those found to have suspicious lesions following biopsy and histopathology were classified as positive/negative and this outcome was used in a multiple logistic regression analysis with variables collected during screening. Odds ratio weightings were then used to develop a simplified risk scoring system which was validated in an external cohort.Of 979 participants, 4.5% had positive status following confirmatory diagnosis. A 12-variable simplified risk scoring system with weightings was generated with an AUC, sensitivity, and specificity of 0.82, 0.71, and 0.78 for delineating high-risk cases. Further optimization on the validation cohort of 491 participants yielded a sensitivity and specificity of 0.75 and 0.87 respectively.The simplified risk scoring system was able to stratify oral cancer and oral potentially malignant disorders risk with satisfactory sensitivity and specificity and can be applied in risk-based disease screening.

Artificial intelligence could enhance the use of disparate risk factors (crude method) for better stratification of patients to be screened for oral cancer. This study aims to construct a meta-classifier that considers diverse risk factors to identify patients at risk of oral cancer and other suspicious oral diseases for targeted screening.A retrospective dataset from a community oral cancer screening program was used to construct and train the novel voting meta-classifier. Comprehensive risk factor information from this dataset was used as input features for eleven supervised learning algorithms which served as base learners and provided predicted probabilities that are weighted and aggregated by the meta-classifier. Training dataset was augmented using SMOTE-ENN. Additionally, Shapley additive explanations (SHAP) values were generated to implement the explainability of the model and display the important risk factors.Our meta-classifier had an internal validation recall, specificity, and AUROC of 0.83, 0.86, and 0.85 for identifying the risk of oral cancer and 0.92, 0.60, and 0.76 for identifying suspicious oral mucosal disease respectively. Upon external validation, the meta-classifier had a significantly higher AUROC than the crude/current method used for identifying the risk of oral cancer (0.78 vs 0.46; p = 0.001) Also, the meta-classifier had better recall than the crude method for predicting the risk of suspicious oral mucosal diseases (0.78 vs 0.47).Overall, these findings showcase that our approach optimizes the use of risk factors in identifying patients for oral screening which suggests potential clinical application.

Introduction Clinical management of oral potentially malignant disorders relies on accurate histopathological assessment of the presence and grade of oral epithelial dysplasia. Whilst adjunctive laboratory tests have provided useful prognostic information, none are in widespread clinical use. This study was performed to assess the clinical utility of two contemporary oral epithelial dysplasia grading systems. Methods Patients were identified from a clinical database. Oral epithelial dysplasia grading was performed by three oral and maxillofacial pathologists blinded to clinical outcome using the WHO 2017 system and a binary classification. The primary outcome measure was the development of oral squamous cell carcinoma, termed 'malignant transformation'. Results 131 cases satisfied the inclusion criteria, of which 23 underwent malignant transformation. There was substantial inter-rater agreement between the study pathologists for both grading systems, measured using kappa statistics (κ = 0.753-0.784). However, there was only moderate agreement between the consensus WHO 2017 dysplasia grade for the study against the original grade assigned by a pool of six pathologists in the context of the clinical service (κ = 0.491). Higher grade categories correlated with an increased risk of developing cancer using both grading systems. Conclusion This study demonstrates that the WHO 2017 and binary grading systems are reproducible between calibrated pathologists and that consensus reporting is likely to improve the consistency of grading. The WHO and binary systems were prognostically comparable. We recommend that institutions implement consensus oral epithelial dysplasia grading and prospectively audit the effectiveness of risk stratifying their patients with oral potentially malignant disorders. (249 words).

BACKGROUND: Circulating tumour cells (CTCs) detected in patient blood samples are relevant as diagnostic and prognostic markers offering insights into tumour behaviour and guiding treatment of cancer at an individualised level. The aim of this study is to ascertain the feasibility of detecting CTCs in oral squamous cell carcinoma (OSCC) using two different methods so as to determine the optimal method for the study of this cancer. METHODS: Comparison of the numbers of CTCs, circulating tumour micro-emboli (CTMs) and circulating tumour endothelial cells (CTECs) was undertaken in forty clinical samples of oral squamous cell carcinoma (OSCC) determined by filtration (ISET®) ) and in-situ fluorescent immunostaining (i-FISH, Cytelligen®) immunostaining and in-situ hybridisation. RESULTS: i-FISH detected CTCs in 80% of samples compared to 40% of samples analysed by microfiltration. i-FISH detected CTCs in a further 40% of samples in which microfiltration did not detect CTCs. No CTC clusters were detected by microfiltration while i-FISH detected CTM in 12.5% of samples. i-FISH analysis detected CTECs in 20/40 samples. CONCLUSION: These results highlight significant differences in detection of CTCs, CTM and CTECs between i-FISH and microfiltration when applied to OSCC samples, suggesting that technologies capable of detecting circulating aneuploidic cells more accurately detect CTCs. i-FISH also detected CTM and CTEC not detected using ISET®. With proven prognostic relevance in adenocarcinomas, accurate enumeration of CTCs, CTMs and CTECs may be a clinically useful tool in the management of OSCC and may aid in the reduction of false negative diagnoses.

Background: Nomograms are graphical calculating devices used to predict risk of malignant transformation (MT) or response to treatment during cancer management. To date, a nomogram has not been used to predict clinical outcome during oral potentially malignant disorder (PMD) treatment. The aim of this study was to create a nomogram for use by clinicians to predict the probability of MT, thereby facilitating accurate assessment of risk and objective decision-making during individual patient management. Methods: Clinico-pathological data from a previously treated cohort of 590 newly presenting PMD patients were reviewed and clinical outcomes categorized as disease free, persistent PMD or MT. Multiple logistic regression was used to predict the probability of MT in the cohort using age, gender, lesion type, site and incision biopsy histopathological diagnoses. Internal validation and calibration of the model was performed using the bootstrap method (n = 1000), and bias-corrected indices of model performance were computed. Results: Potentially malignant disorders were predominantly leukoplakias (79%), presenting most frequently at floor of mouth and lateral tongue sites (51%); 99 patients (17%) developed oral squamous cell carcinoma during the study period. The nomogram performed well when MT predictions were compared with patient outcome data, demonstrating good bias-corrected discrimination and calibration (D = 0.58; C = 0.790), with a sensitivity of 87% and specificity 63%, and a positive predictive value of 32% and negative predictive value 96%. Conclusion: The “Newcastle Nomogram” has been developed to predict the probability of MT in PMD, based on an internally validated statistical model. Based upon readily available and patient-specific clinico-pathological data, it provides clinicians with a pragmatic diagrammatic aid for clinical decision-making during diagnosis and management of PMD.

Background: Oral potentially malignant disorders are a clinical conundrum as there are no reliable methods to predict their behaviour. We combine conventional oral epithelial dysplasia grading with DNA ploidy analysis to examine the validity of this approach to risk assessment in a cohort of patients with known clinical outcomes. Methods: Sections from diagnostic biopsies were assessed for oral epithelial dysplasia using the WHO grading system, and DNA ploidy analysis was performed using established methods. Patients reviewed for a minimum of 5 years who did not develop oral squamous cell carcinoma were classified as “non-transforming” cases. Patients that developed oral squamous cell carcinoma ≥ 6 months after the initial diagnostic biopsy were classified as having “malignant transformation.” Results: Ninety cases were included in the study. Seventy cases yielded informative DNA ploidy results. Of these 70 cases, 31 progressed to cancer. Oral epithelial dysplasia grading and DNA ploidy status were both significantly associated with clinical outcome (P < 0.05). Severe dysplasia had a hazard ratio of 3.50 (CI: 1.46, 8.45; P = 0.005) compared to cases with mild dysplasia. Aneuploidy had a hazard ratio of 2.09 (CI: 1.01, 4.32; P = 0.046) compared to cases with a diploid/tetraploid status. Receiver operating characteristic analysis gave an area under the curve of 0.617 for DNA ploidy status and 0.688 when DNA ploidy status was combined with dysplasia grading. Conclusion: Our findings suggest that combining dysplasia grading with DNA ploidy status has clinical utility which could be used to develop novel management algorithms.

Revisiting the eponymous “Peter Principle,” in this article the author reflects upon a professional lifetime as a clinician, surgeon and researcher, and summarises his efforts to improve contemporary understanding of oral cancer development, refine diagnostic procedure and facilitate efficacious, early treatment intervention to halt the process of carcinogenesis. The author reviews the principles underpinning effective translational research. Utilising his own work in oral epithelial cell science, interventional surgery and potentially malignant disorder patient management and surveillance, a number of significant advances in our knowledge base and their specific clinical application and potential impact are discussed. Research remains an active and ongoing process, however, and the author believes it essential for future relevance that hypotheses should always be initiated, led and mentored by experienced clinical practitioners.

Background Clinically identifiable potentially malignant disorders (PMD) precede oral squamous cell carcinoma development. Oral lichenoid lesions (OLL) and proliferative verrucous leukoplakia (PVL) are specific precursor lesions believed to exhibit both treatment resistance and a high risk of malignant transformation (MT). Methods A retrospective review of 590 PMD patients treated in Northern England by CO2 laser surgery between 1996 and 2014 was carried out. Lesions exhibiting lichenoid or proliferative verrucous features were identified from the patient database and their clinicopathological features and outcome post-treatment determined at the study census date of 31 December 2014. Results One hundred and 98 patients were identified as follows: 118 OLL and 80 PVL, most frequently leukoplakia at ventrolateral tongue and floor of mouth sites, equally distributed between males and females. Most exhibited dysplasia on incision biopsy (72% OLL; 85% PVL) and were treated by laser excision rather than ablation (88.1% OLL; 86.25% PVL). OLL were more common in younger patients (OLL 57.1 year; PVL 62.25 years; P = .008) and more likely than PVL to present as erythroleukoplakia (OLL 15.3%; PVL 2.5%; P = .003). Whilst no significant difference was seen between OLL and PVL achieving disease-free status (69.5% and 65%, respectively; P = .55), this was less than the overall PMD cohort (74.2%). MT was identified in 2 OLL (1.7%) and 2 PVL (2.5%) during follow-up. Conclusion One-third of PMD cases showed features of OLL or PVL, probably representing a disease presentation continuum. Post-treatment disease-free status was less common in OLL and PVL, although MT was infrequent.

Oral squamous cell carcinoma (OSCC) is a lethal disease, with rising incidence. There were 6767 new OSCC cases and 2056 deaths in the UK in 2011. Cancers are preceded by oral potentially malignant disorders (PMDs), recognizable mucosal diseases harbouring increased SCC risk, offering clinicians a 'therapeutic window' to intervene. Contemporary practice remains unable to predict lesion behaviour or quantify malignant transformation risk. No clear management guidelines exist and it is unclear from the literature whether early diagnosis and intervention prevents cancer. Between 1996 and 2014, 773 laser treatments were performed on 590 PMD patients in Newcastle maxillofacial surgery departments. The efficacy of the intervention was examined by review of the clinicopathological details and clinical outcomes of the patients (mean follow-up 7.3 years). Histopathology required up-grading in 36.1% on examining excision specimens. Seventy-five percent of patients were disease-free, mostly younger patients with low-grade dysplasia; 9% exhibited persistent disease and were generally older with proliferative verrucous leukoplakia. Disease-free status was less likely for erythroleukoplakia (P=0.022), 'high-grade' dysplasia (P

Objectives:\ud \ud To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer.\ud Materials and Methods:\ud \ud Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease.\ud Results:\ud \ud Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent.\ud Conclusions:\ud \ud If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients.

Objective: To assess the efficacy of scaffold-mediated localized chemotherapy in cancer. Methods: Databases including PubMed, Cochrane Library, and SCOPUS were searched for articles reporting the use of scaffold-mediated localized drug delivery in cancer. Essential data including scaffold fabrication material and methods, drug dosage and release duration and its effect on the cancer cells were extracted. Results: 15 articles out of 60 screened, fulfilled the eligibility criteria. Among the 15 studies, 5 studies included only cell lines and 2 studies were on mouse models, while 8 studies involved a combination of cell lines and mouse models. Scaffold materials included both synthetic polymers such as poly-lactide, polycaprolactone and natural materials including d-periosteum and human micro-fragmented adipose tissueA wide number of other variables included the fabrication procedure, drugs used, and the methods used to assess the effects on cancer. As a result, it was not possible to make any direct comparison of the efficacy of the therapeutic strategy used in each of these studies. Conclusion: Irrespective of the many variables, a common consensus in all the included studies was that scaffold mediated localized drug delivery effectively reduced cancer cell viability by increasing drug bioavailability to the target tissue, while its localized effect reduced the risk of systemic toxicity.

Objectives: \ud This study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as interacting continuous exposures.\ud \ud Materials and Methods: \ud We pooled individual-level data from 33 case-control studies (18,260 HNC cases and 29,844 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. In bivariate regression spline models, exposures to cigarette smoking intensity and duration (compared with never smokers) were modeled as a linear piecewise function within a logistic regression also including potential confounders. We jointly estimated the optimal knot locations and regression parameters within the Bayesian framework.\ud \ud Results: \ud For oral-cavity/pharyngeal (OCP) cancers, an odds ratio (OR) >5 was reached after 30 years in current smokers of ∼20 or more cigarettes/day. Patterns of OCP cancer risk in current smokers differed across strata of alcohol intensity. For laryngeal cancer, ORs >20 were found for current smokers of ≥20 cigarettes/day for ≥30 years. In former smokers who quit ≥10 years ago, the ORs were approximately halved for OCP cancers, and ∼1/3 for laryngeal cancer, as compared to the same levels of intensity and duration in current smokers.\ud \ud Conclusion: \ud Referring to bivariate spline models, this study better quantified the joint effect of intensity and duration of cigarette smoking on HNC risk, further stressing the need of smoking cessation policies.

Background: Oral squamous cell carcinoma (SCC) is a lethal and deforming disease of rising incidence and global significance; 600 000 new cases are seen each year, including 40 000 in China. Despite advances in management, 50% of patients die within 5 years of diagnosis. Cancer is the leading cause of death in Hong Kong, with the Hong Kong Cancer Registry (HKCR) confirming a 2% increase in new cases each year, and oral SCC the tenth leading cause of cancer death in males. Strategies to improve clinical outcome require identification and early intervention in the “high-risk” population. Unfortunately, demographic information is limited in HKCR making it difficult to undertake accurate population-based studies. This study aimed to profile contemporaneous demographics of oral cancer within the Hong Kong population. Methods: Following local ethical approval, the Hong Kong Hospital Authority (HA) database was accessed to identify new cases of oral SCC diagnosed and treated during an 18-year period (January 2000 to December 2017). Results: A total of 6706 oral cavity SCC cases were identified: 4291 male and 2415 female patients (with a mean age of 64.14 years). A trend for increasing number of cases each year was seen, with most patients presenting to hospitals on the Kowloon Peninsula and Hong Kong Island. The tongue was the most commonly affected oral site in 3168 patients, with tonsil (863), buccal mucosa (539) and floor of mouth (409) less common. Mean survival time between initial diagnosis and death was 1.95 years; patients with hard palate and oropharyngeal SCC survived the shortest period, whilst labio-buccal and vestibular cases exhibited significantly longer survival (P < 0.0001). Conclusion: Whilst useful HA data are available regarding age, sex, site and outcome, there is a need for further improvement in demographic profiling to characterise the “high-risk” oral cancer population in Hong Kong and to facilitate targeted early therapeutic intervention.

Background: Programmed death-ligand 1 (PD-L1) is an immune checkpoint that is primarily located on the surface of tumor cells. PD-L1 expression detected by immunohistochemistry (IHC) assays has been widely studied to predict survival outcomes in head and neck squamous cell carcinoma (HNSCC) recently. We aimed to review comprehensively the prognostic role of PD-L1 expression for survival in HNSCC. Methods: We systematically searched PubMed, Embase, Web of Science, Cochrane Library and Scopus to identify studies investigating the prognostic role of PD-L1 expression in HNSCC. All studies published before March 31, 2018 were screened. Included studies were assessed using the Quality in Prognosis Studies (QUIPS) tool. Data were extracted and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), disease-specific survival (DSS) were combined and presented as hazard ratios (HR) with 95% confidence interval (CI) using the generic inverse-variance method. Results: Twenty-three studies with 3105 patients were analysed. The overall positive rate of PD-L1 in HNSCC was 0.42 (95% CI: 0.36–0.48). There was no significant difference between PD-L1-positive and -negative HNSCC patients in OS (HR: 0.98; 95% CI: 0.71–1.37; p = 0.93), DFS (HR: 1.07; 95% CI: 0.68–1.70; p = 0.76), and DSS (HR: 0.90; 95% CI: 0.63–1.29; p = 0.56). An improved PFS was observed in patients with positive PD-L1 expression (HR: 0.71; 95% CI: 0.55–0.93; p = 0.01). In patients with low CD8+ tumor-infiltrating T cells, a poorer OS was detected in patients with positive PD-L1 expression (HR: 1.90; 95% CI: 1.07–3.36; p = 0.03). Patients with HPV-positive HNSCC were associated with increased PD-L1 expression (OR: 1.99; 95% CI: 1.50–2.64; p < 0.001). However, PD-L1 expression showed no significant benefit on OS in HPV-positive HNSCC (HR: 1.04; 95% CI: 0.65–1.65; p = 0.88). Conclusions: PD-L1 expression detected by IHC was not recommended to predict survival in HNSCC patients. However, the positive PD-L1 expression might predict better PFS in patients with advanced HNSCC. The combined effects of PD-L1 expression and CD8+ tumor-infiltrating T cells should be further elucidated.

Squamous cell carcinoma arising from oral mucosal epithelium remains a lethal and deforming disease due to tumour invasion, oro‐facial destruction, cervical lymph node metastasis and ultimate blood‐borne dissemination. Worldwide, 300 000 new cases are seen each year, with a recent and significant rise in incidence affecting particularly the young. To rationalize perspectives on preventive strategies in oral cancer management, this study addresses a number of fundamental questions regarding carcinogenesis: proliferation—what epithelial cell changes precede tumour development? Position—why are certain oral sites so predisposed to cancer? Progression—why do some precursor lesions progress to invasive carcinoma and others do not? Prediction—how can we predict individual patient and/or lesion behaviour to prevent disease progression? By improving our understanding of oral carcinogenesis, can we thereby facilitate more effective primary, secondary and tertiary preventive strategies and ultimately reduce the global burden of oral squamous cell carcinoma (OSCC)?

Oral potentially malignant disorders (PMD) are recognisable mucosal conditions that have an unpredictable risk of transformation to squamous cell carcinoma (SCC), a lethal and deforming disease of rising incidence. Contemporary management is based on clinical recognition of suspicious lesions and incisional biopsy to enable histopathological assessment and grading of dysplasia, together with excision of high-risk lesions and long-term surveillance. However, it is impossible to predict clinical outcome or risk of malignant transformation. Our aim was to evaluate the relevance of previously identified oral precursor lesions for the development of SCC and staging of disease. We therefore retrospectively reviewed 1248 cases of SCC diagnosed in oral and maxillofacial surgery units at Newcastle upon Tyne and Sunderland hospitals between 1996 and 2009. Of them, 58 identifiable precursor lesions became malignant but only 25 had been dysplastic on initial biopsy; 19 of 33 non-dysplastic lesions exhibited lichenoid inflammation only. SCC arose most often on the ventrolateral tongue and floor of the mouth, with a mean transformation time of 29.2 months. Transformation time was significantly shorter in men (p=0.018) and those over 70 years of age (p=0.010). Patients who consumed more than 21 units of alcohol/week and those who had had interventional laser surgery to treat precursor lesions, had higher-staged tumours (p=0.048). Although retrospective, this study shows that the results of incisional biopsy and grading of dysplasia have limited use as predictive tools, and supports the view that cancer may arise in the absence of recognisable epithelial dysplasia. Our findings confirm the importance of clinical vigilance and active surveillance in the management of all patients with clinically suspicious oral lesions, irrespective of the histological findings.

Introduction A national follow‐up survey was undertaken to determine whether dental graduates from 2009 perceived that their undergraduate oral surgery education had equipped them for general dental practice 4 years after graduating. Materials and Methods Graduates from the same 13 United Kingdom dental schools who had taken part in the original survey were invited to take part in this follow‐up online survey. Their contact details were identified via the general dental council register, social media and alumni groups. Results In total, 161 responded (2009b) which represents 16% of the graduates of the original survey in 2009a. A similar percentage of these respondents perceived that the teaching in oral surgery had given them sufficient knowledge to undertake independent practice (83% and 79% in 2009a and 2009b, respectively). Most respondents (99% in both years) reported confidence in undertaking simple forceps exodontia. Confidence in surgical exodontia was poor in both surveys, but one area that appeared improved in the follow‐up related to the sectioning of teeth (84% in 2009b compared with 49% in 2009a). Areas of weakness identified in 2009 were reported to be improved in the follow‐up. Conclusion This follow‐up survey supports the findings of the original survey. Future longitudinal studies would allow institutions to identify possible weaknesses in their curriculum and to track the career development of their graduates and facilitate robust data collection.

Objectives HPV16-positive oropharyngeal cancer (OPC) patients experience better outcomes compared to HPV16-negative patients. Currently, strategies for treatment de-escalation are based on HPV status, smoking history and disease stage. However, the appropriate cut-point for smoking and the role of other non-clinical factors in OPC survival remains uncertain. Materials and Methods We examined factors associated with OPC outcome in 321 patients recruited in a large European multi-center study. Seropositivity for HPV16 E6 was used as a marker of HPV16 positive cancer. Hazard ratios (HR) and confidence intervals (CI) were estimated using Cox proportional models adjusted for potential confounders. Results Overall 5-year survival following OPC diagnosis was 50%. HPV16-positive OPC cases were at significantly lower risk of death (aHR = 0.51, 95% CI: 0.32–0.80). A significant effect on OPC survival was apparent for female sex (aHR 0.50: 95% CI: 0.29–0.85) and being underweight at diagnosis (aHR: 2.41, 95% CI: 1.38–4.21). A 10 pack year smoking history was not associated with overall survival. Higher stage at diagnosis appeared as the only factor significantly associated with OPC recurrence (aHR: 4.88, 95% CI: 2.12–11.21). Conclusion This study confirms that HPV16 status is an independent prognostic factor for OPC survival while female sex lowers risk of death and being underweight at diagnosis increases the risk of death. Smoking was not an independent predictor of OPC survival.

Contemporary potentially malignant disorder management is based upon provisional histological diagnosis followed by interventional surgery to excise or ablate 'high-risk' mucosal lesions. Although the majority of patients achieve disease-free status post-treatment, others develop further or persistent disease unresponsive to intervention. A detailed, retrospective clinico-pathological review of treatment resistant potentially malignant lesions, from a 590 patient cohort treated by CO2 laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was determined at study census date (31 December 2014). A total of 87 patients (15%) exhibited PMD disease resistant to treatment: 34 (6%) became disease free following further treatment, whilst 53 (9%) had persistent disease despite intervention. Disease-free patients were younger, changed lesion appearance from erythroleukoplakia to leukoplakia (P = .004), developed further lesions at new sites, demonstrated reduction in dysplasia severity with time and required multiple treatments to achieve disease-free status (P = .0005). In contrast, persistent disease patients were older, male, often presented with proliferative verrucous leukoplakia (PVL) on gingival and alveolar sites, displayed less severe dysplasia initially and underwent laser ablation rather than excision (P = .027). Despite clinico-pathological profiling of treatment resistant patients, the precise inter-relationship between the inherent nature of potentially malignant disease and the external influence of treatment intervention remains obscure.

Background Oral potentially malignant disorders harbour variable and unpredictable risk for squamous carcinoma development. Whilst current management strategies utilise histopathological diagnoses, dysplasia grading and targeted intervention for ‘high risk’ lesions, clinicians are unable to predict malignant potential. Methods Detailed, retrospective clinico-pathological analysis of potentially malignant lesions undergoing malignant transformation, from a 590 patient cohort treated by interventional laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was documented at study census date (31 December 2014). Results 99 patients (16.8%) developed cancer: 71 (12%) seen ‘unexpectedly’ upon excision and 28 (4.8%) progressing to malignancy at a median of 87.3 months post-surgery. 30 ‘unexpected’ excisions were micro-invasive (42.3%) arising primarily in severely dysplastic precursors (75%) at ventro-lateral tongue and floor of mouth sites (54.5%); 1 patient (1.4%) had a cancer-related death, whilst 58 (81.7%) were disease free. 19 of 28 ‘progressive’ cancers (67.9%) arose at new sites, with erythroleukoplakia a significant predictor of malignancy (p=0.0019). 9 (32.1%) developed at the same precursor site, with 6 (77.7%) on the ventro-lateral tongue and floor of mouth. 3 (10.7%) were micro-invasive, 9 patients (32.1%) died from metastatic disease and 12 (42.9%) were disease free (p

Background Oral potentially malignant disorders (PMD) harbour unpredictable risk for squamous cell carcinoma development. Current management requires tissue biopsy for histopathology characterisation, dysplasia grading and targeted intervention to “high-risk” lesions, although evidence-based guidelines are limited and diagnoses subjective. This study investigated the use of adjunctive oral brush biopsy techniques during the management of PMD in a UK hospital population. Methods Retrospective review of a 310 PMD patient cohort presenting to Maxillofacial Surgery in Newcastle upon Tyne with new, single-site lesions between December 2009 and May 2014. Patients underwent Orcellex® brush biopsy and liquid-based cytology examination in addition to conventional biopsy techniques, with management proceeding along established care pathways. Patient demographics, cytology data, most significant histopathology diagnoses and clinical outcome were all documented at the study census date (31.12.15). Results A total of 170 male & 140 female patients (age range 18-91 years), exhibiting primarily leukoplakia (86.5%) at floor of mouth and ventrolateral tongue sites (44.9%), were identified. Management comprised: observation (49.7%), laser surgery (44.9%), antifungal treatment (3.5%) and Head & Neck clinic referral following cancer diagnosis (1.9%). Clinical outcomes were as follows: disease free (51.3%), persistent PMD (42.3%) and malignant transformation (6.4%). Histology and cytology diagnoses strongly correlated (r = .305). Treatment modality, lesion site, histology and cytology diagnoses were the best predictors of clinical outcome. Conclusions Orcellex® brush cytology provides reliable diagnoses consistent with conventional histopathology and offers less invasive, adjunctive assessment appropriate for long-term monitoring of patients in specialist clinics.

Potentially malignant disorders (PMD) are recognisable mucosal conditions preceding invasive squamous carcinoma development. Established oral cancer remains a lethal and deforming disease, with a rising incidence. Management techniques for identifiable oral precursor lesions have traditionally been polarised between observational and interventional surgical techniques. By defining salient management goals for treating potentially malignant disease, and examining the evidence supporting the efficacy of treatment intervention, this paper presents the case for interventional laser surgery as a definitive diagnostic and treatment modality.

Background: A national survey was undertaken to establish a baseline of our final year students’ perception of how their undergraduate oral surgery education has equipped them for key areas of general dental practice. Materials and Methods: Questionnaires were distributed to the 13 UK schools with final year students, towards the end of the academic year in 2009. The questionnaires were completed anonymously and were optically scanned. Results: In total, 632 questionnaires were returned, which represents 66% of the students of the graduating year. The majority (83%) of the respondents perceived that the teaching in oral surgery had given them sufficient knowledge to undertake independent practise. Most respondents (99%) felt confident to perform forceps exodontia, but confidence in the various aspects of surgical exodontia was lower. A majority (83%) had experience of an outreach scheme performing forceps exodontia (75%) and surgical exodontia (16%) in this environment. Twenty per cent indicated a desire to undertake a career in oral surgery, 6% in oral and maxillofacial surgery and 35% in another speciality. Conclusion: This survey suggests that the majority of the students perceive that the oral surgery education has prepared them well for key areas of general practice. It also suggests that there is, however, a need to provide further improvement in the delivery of surgical skills and knowledge.

Alcohol is known to be a risk factor for oral precancerous lesions, but evidence has been weakened by subjective estimates of alcohol intake from patients, and confounded by their use of tobacco. Red cell macrocytosis, assessed by calculation of mean corpuscular volume (MCV), may be a useful objective indicator of chronic alcohol intake. The aim of this study was to compare subjective and objective measures of alcohol intake in patients with oral precancerous lesions and assess the use of reported alcohol intake and MCV on assessing the degree of dysplasia at presentation and their role as markers of the behaviour of such lesions by assessing clinical outcome after treatment. Fifty-four new patients were recruited. All were smokers and had histologically confirmed single dysplastic oral precancerous lesions, but had had no previous treatment. Subjective data about their alcohol consumption were recorded, and blood samples taken for the assessment of MCV. All patients had laser excision of their lesions, which were assessed histopathologically for signs of dysplasia. Patients were followed up for 2 years. The significance of differences was assessed using Fisher's exact test. Alcohol intake of more than 28 units/week and MCV of over 100 were associated with increased dysplasia at presentation (p=0.01 and p=0.03, respectively). Thirty-six patients were disease-free at 2 years, but 18 developed further disease, often at new sites. Alcohol intake of more than 28 units/week was significantly associated with an increased risk of further disease (p=0.03), particularly recurrence at the same site (p=0.02).

Oral precancerous lesions may be solitary or multifocal, the latter being difficult to manage because of extensive field change. The aim of this study was to characterise differences in clinicopathological features, proliferative labelling indexes for cyclin A, cyclin B1, and Ki67, and clinical outcome 5 years after laser resection in a group of patients presenting with single and multiple oral precancerous lesions. Ninety-six patients with 132 lesions (78 single and 18 multiple) were recruited, and there were no significant differences between those with single and multiple lesions with respect to age, sex, smoking, or alcohol consumption, although multiple lesions were significantly more common in smokers who ate little fruit and vegetables (p = 0.02). Clinically, most lesions were leukoplakia, with ulcerated or exophytic lesions appearing singly. There were significant differences in site, single lesions being most common on the floor of the mouth and the ventrolateral tongue, and multiple lesions preferring the buccal mucosa (p = 0.0002). The most severe dysplasia was seen in single lesions (p = 0.001) with labelling indexes for cyclin A and Ki67 being significantly higher in these (p = 0.04 and p = 0.01, respectively). Oral squamous cell carcinoma developed in 3/78 single lesions and 4/18 multiple ones. There are distinct differences between single and multiple lesions that have implications for the prophylaxis and management of oral cancer.

A retrospective audit of 1079 2-week referrals between 1 January 2004 and 31 December 2006 was undertaken. The aims of this audit were to assess compliance of referrals with Department of Health (DoH) guidelines; the effectiveness of the 2-week referral route in detecting head and neck cancers, and to determine whether this route identified more early stage cancers. Of 1079 2-week referrals, 71.5% conformed to DoH criteria. DoH guidelines were found to have a high sensitivity of 83.9% (75.5-89.7%, 95% CI) for head and neck cancer, but a low positive predictive value of 12.8% (10.5-15.3%) and a specificity of 30.0% (27.2-33.1%). Only 10.9% of 2-week referrals were diagnosed with a head and neck cancer. The cancer detection rate was higher amongst referrals that conformed to DoH guidelines (12.8%) compared to those that did not 6.2%. This was statistically significant (Chi square, p

Prediction of the behaviour of oral precancerous lesions (OPLs) is unreliable in clinical practice. The aim of this study was to analyse the efficacy of cell cyclin markers A and B1, and the proliferative marker Ki67, in predicting clinical outcome for patients with OPLs. A cohort of previously-treated patients with single OPLs were retrieved from the MaxilloFacial Dysplasia database and reviewed. All had dysplastic lesions excised by laser and were followed up for 5 years post-treatment. Outcome was determined as no recurrence or further disease. Excision specimens were re-examined immunohistochemically and labelling indices (LIs) for cyclin A, B1 and Ki67 determined. Forty patients, aged between 31 and 91 years, were recruited. There were no differences in age or sex. OPLs were predominantly leukoplakias on the floor of mouth or ventro-lateral tongue (65%), most of which exhibited moderate or severe dysplasia. Cyclin A LIs ranged from 3.9% to 31.3%, B1 0 to 28.3% and Ki67 3.5% to 54.5%. Using median LIs as 'cut off points' (12% cyclins; 22% Ki67) Kaplan-Meier survival analysis showed a significant risk of further progression of disease in patients with OPL LIs exceeding median values (Cyclin A p=0.02, Cyclin B1 p=0.01, Ki67 p=0.025). By combining analysis of both Cyclin A and B LI, the significance of the difference was increased (p

Smoking is the commonest risk factor for oral cancer and precancer. The objective of this study was to characterize smoking behaviour and attitude in a cohort of oral precancer patients in Newcastle upon Tyne, UK, and to determine changes in behaviour during diagnosis, treatment and follow-up. Twenty-seven consecutive, smoking patients with dysplastic oral lesions were recruited to the study and a detailed smoking history obtained, quantifying types and numbers of cigarettes smoked, length of smoking history, and changes in smoking behaviour during treatment episodes and long-term follow-up. All patients underwent an interventional management protocol comprising risk-factor education, histopathological diagnosis by incisional biopsy and laser excision of lesions. Patients were followed up for 5 years. Whilst there was a significant decrease in the number of cigarettes smoked at patients' most recent follow-up compared with initial presentation (p < 0.001), 74% continued to smoke. Patients received advice from a smoking cessation adviser on support available to them from the local NHS (National Health Service) Stop Smoking services. Six out of 10 patients who set a 'quit date' and attended a programme had quit at the 4-week follow-up but only 5 remained non-smokers. Smoking remains a considerable problem in oral precancer patients even after interventional treatment, with the risk of further precancerous lesions and malignant transformation.

Accurate, predictive assessment of the behaviour of oral cancers and precancers remains elusive. Increasing dysregulation of cell proliferation is a feature of carcinogenesis, and alterations in cyclin proteins regulating cell cycle progression are involved in enhanced cell proliferation. The authors of the present study have previously demonstrated increased proliferative activity in oral dysplastic lesions and poorly differentiated carcinomas, and hypothesize that cell proliferation can be used as a predictive agent in clinical management. In this preliminary study, immunohistochemical quantification of cyclin A expression was carried out for 33 excised oral lesions (ranging from mild dysplasia to invasive squamous cell carcinoma, SCC). Clinical outcome was determined as: no disease after 2 years follow-up, persistent disease, or further disease presentation. Labelling Indices (LIs) ranged from 5.5 to 32.1%, and whilst a trend to increased labelling in increasingly dysplastic and neoplastic tissue was seen, this was not statistically significant (P = 0.06). High LIs were related to poor clinical outcome (P = 0.003), suggesting a definite role for cyclin A measurement as a predictive tool in clinical management.

Previous studies have emphasised the lack of relevant medical history information available for patients attending for surgery. The records of 57, consecutive patients attending the nurse-led Pre-Admission Clinic (PAC) at the Oral Surgery Day Case Unit at Newcastle Dental Hospital were reviewed to determine whether nurses or clinicians were best at identifying potential medical problems. For 22 patients, nurse-led PAC interview revealed additional information not recorded by clinicians, most frequently cardiovascular disorders (9), arthritis (5) and drug allergies (2). Pancreatitis, epilepsy, recurrent epistaxis and a history of a fractured mandible were other conditions only identified following nurse consultation. Medical history taking by nurses at PAC thus provides an important screening function prior to successful ambulatory surgery.

Patients with oral squamous cell carcinoma (OSCC) are at risk of developing second or multiple primary cancers as a result of field cancerization in the upper aerodigestive tract. In order to quantify the incidence of field change observable in oral mucosa, 26 consecutive new (untreated) patients presenting with a unilateral OSCC (18) or a premaligant lesion (eight) underwent 'mirror image' biopsies from clinically normal-looking mucosa at corresponding anatomical sites. A total of 15 patients (58%) demonstrated histologically abnormal tissue upon microscopic examination: six showed reactive change/cellular atypia associated with chronic irritation, seven exhibited frank dysplasia, whilst two displayed carcinoma-in-situ (CIS) or microinvasive SCC. Although not statistically significant, there was an observable trend for the lateral/ventral tongue and floor of mouth to display increased vulnerability to dysplastic change.

Accurate, predictive assessment of the clinical behaviour and progression of individual oral cancers and premalignant lesions requires reproducible and quantitative analyses of diseased tissue. In this paper we describe the use of in vitro double labelling (sequential tritiated thymidine and bromodeoxyuridine staining of proliferating epithelial cells) to calculate S phase labelling indices (LIs), estimation of S phase duration (tS), and measurement of variables of flux to and from S for excised specimens of oral squamous cell carcinoma, premalignant lesions, and clinically normal mucosa from patients with oral cancer. There was a significant increase in mean LIs in buccal mucosa leukoplakias (14.5%) compared with normal mucosa (10.3%); P = 0.03. LIs were also increased in patients with cancers of the floor of mouth and ventral tongue but neither these changes nor alterations in flux parameters or S Phase durations were significant. Twenty-one kinetic profiles of dysplastic and malignant tissue were compared with conventional histopathological results, however, and these showed a 2.2% increase in LIs with each increase in grade of dysplasia (P = 0.004) and a 12% increase in LIs with each reduction in tumour differentiation (P = 0.02).

Our aim was to characterize epithelial cell proliferative activity within the oral cavity and to find out if there were differences between sites with high and low incidence of cancer. A total of 105 samples of clinically normal mucosa were harvested from various intra-oral sites. Excised specimens were incubated in vitro with tritiated thymidine and bromodeoxyuridine to 'double label' cells undergoing DNA synthesis, and enable calculation of the duration of S phase and estimation of variables of cell flux to and from S. Mean labelling indices (percentage of cells within the S phase of the cell cycle) were highest in the floor of mouth (12.3%) and ventral tongue (10.1%), while activity was lowest in the dorsum of tongue (4.3%) and the palate (7.2%), P

Objective We aimed to assess the association of oral health (OH), dental care (DC) and mouthwash with upper-aerodigestive tract (UADT) cancer risk, and to examine the extent that enzymes involved in the metabolism of alcohol modify the effect of mouthwash. Materials and methods The study included 1963 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1993 controls. Subjects were interviewed about their oral health and dental care behaviors (which were converted to scores of OH and DC respectively), as well as smoking, alcohol drinking, diet, occupations, medical conditions and socio-economic status. Blood samples were taken for genetic analyses. Mouthwash use was analyzed in relation to the presence of polymorphisms of alcohol-metabolizing genes known to be associated with UADT. Adjusted odds ratios (ORs) and 95%-confidence intervals [CI] were estimated with multiple logistic regression models adjusting for multiple confounders. Results Fully adjusted ORs of low versus high scores of DC and OH were 2.36[CI = 1.51–3.67] and 2.22[CI = 1.45–3.41], respectively, for all UADT sites combined. The OR for frequent use of mouthwash use (3 or more times/day) was 3.23[CI = 1.68–6.19]. The OR for the rare variant ADH7 (coding for fast ethanol metabolism) was lower in mouthwash-users (OR = 0.53[CI = 0.35–0.81]) as compared to never-users (OR = 0.97[CI = 0.73–1.29]) indicating effect modification (pheterogeneity = 0.065) while no relevant differences were observed between users and non-users for the variant alleles of ADH1B, ADH1C or ALDH2. Conclusions Poor OH and DC seem to be independent risk factors for UADT because corresponding risk estimates remain substantially elevated after detailed adjustment for multiple confounders. Whether mouthwash use may entail some risk through the alcohol content in most formulations on the market remains to be fully clarified.

Tobacco and alcohol are major risk factors for upper aerodigestive tract (UADT) cancer and significant variation is observed in UADT cancer rates across Europe. We have estimated the proportion of UADT cancer burden explained by tobacco and alcohol and how this varies with the incidence rates across Europe, cancer sub-site, gender and age. This should help estimate the minimum residual burden of other risk factors to UADT cancer, including human papillomavirus. We analysed 1981 UADT cancer cases and 1993 controls from the ARCAGE multicentre study. We estimated the population attributable risk (PAR) of tobacco alone, alcohol alone and their joint effect. Tobacco and alcohol together explained 73% of UADT cancer burden of which nearly 29% was explained by smoking alone, less than 1% due to alcohol on its own and 44% by the joint effect of tobacco and alcohol. Tobacco and alcohol together explained a larger proportion of hypopharyngeal/laryngeal cancer (PAR=85%) than oropharyngeal (PAR=74%), esophageal (PAR=67%) and oral cancer (PAR=61%). Tobacco and alcohol together explain only about half of the total UADT cancer burden among women. Geographically, tobacco and alcohol explained a larger proportion of UADT cancer in central (PAR=84%) than southern (PAR=72%) and western Europe (PAR=67%). While the majority of the UADT cancers in Europe are due to tobacco or the joint effect of tobacco and alcohol, our results support a significant role for other risk factors in particular, for oral and oropharyngeal cancers and also for UADT cancers in southern and western Europe.

Interventional carbon dioxide laser surgery is the preferred method to treat oral precancerous lesions and early invasive squamous cell carcinomas (SCCs). Little is known, however, about the complications that patients experience after such treatment. We retrospectively reviewed the hospital records of 82 patients with new dysplastic oral lesions or early invasive oral SCCs treated by laser surgery in the maxillofacial unit at Newcastle General Hospital. The most common postoperative complications were pain for more than two weeks after operation (n = 28), bleeding (n = 4), difficulties with speech (n = 5), paraesthesia of the lingual nerve (n = 17), difficulty swallowing (n = 2), obstructive swelling of the submandibular gland (n = 22), and tethering of the tongue (n = 10). Overall, 78% of patients had one or more complication. In the absence of randomised controlled trials, this study provides the best available evidence for complication rates following interventional surgery. In addition to aiding in the preoperative counselling of patients, the data will help to inform and advise patients particularly during the immediate postoperative period.

Management of oral precancerous lesions remains polarised between interventional surgery and conservative treatment. We have previously shown the efficacy of carbon dioxide laser excision for both diagnosis and treatment of oral precancerous lesions. The aim of this study was to review the clinicopathological details of a group of patients in whom pre-existing but occult invasive carcinoma was diagnosed histopathologically in specimens excised by laser. We retrospectively reviewed 169 patients who attended the Maxillofacial Dysplasia Clinic at Newcastle General Hospital with single, new oral premalignant lesions over a 5-year period (2004-2008). They were all treated by laser excision of lesions that were confirmed to be dysplastic from examination of preoperative incisional biopsy specimens. There was a significant correlation between the results of diagnostic incisional, and laser excision, biopsy specimens (p < 0.01), but 15 patients had signs of occult invasive carcinoma in the excision specimens (9%). In all cases the carcinomas were completely excised by the laser. Carbon dioxide laser excision is not only an effective treatment of precancerous lesions, but also facilitates early diagnosis and management of oral carcinoma at a stage when it is otherwise clinically undetectable.

A case is reported of a central venous catheter that was placed inadvertently into the internal jugular vein during the anaesthetic preparation for surgery. The catheter tip was sectioned during surgery and was feared to have embolised into the central circulation but it was subsequently identified in the pathological specimen. A summary of the complications associated with central venous catheterisation is reported and a simple protocol is proposed to avoid a similar complication.