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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.

Objectives: This study aims to determine the diagnostic test accuracy (DTA) of hypermethylated DNA biomarkers in saliva and oral swabs for oral squamous cell carcinoma (OSCC) detection from the prevalidation studies available. Materials and Methods: Electronic database searching of PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, and LILACS was conducted to identify relevant articles that were published between January 1, 2000, and August 1, 2020. Results: Meta-analysis was conducted based on 11 of 20 studies selected for review. Included studies had high bias concerns on the QUADAS-2 study assessment tool. We found that salivary and oral swab hypermethylation markers had better specificity than sensitivity for oral cancer detection. Summary sensitivity and specificity (95% CI) of hypermethylation panels were 86.2% (60–96.2) and 90.6% (85.9–93.9) while for individual markers, summary sensitivity and specificity (95% CI) were 70% (56.9–80.5) and 91.9% (80.3–96.9), respectively. Respective positive and negative likelihood ratios for combined markers were 9.2 (5.89–14.36) and 0.15 (0.05–0.5), and 8.61 (3.39–21.87) and 0.33 (0.22–0.49) for single-application biomarkers. Conclusion: DNA hypermethylation biomarkers especially in combination have acceptable DTA that warrants further optimization with rigorous biomarker evaluation methods for conclusive determination of their efficacy.

This review sought to determine the range and nature of prospective-sampling and blinding methods for validating nonviral biofluid markers diagnostic of head and neck carcinomas. Electronic database searching was conducted to identify studies published in English from January 1, 2009 to August 1, 2020. Sixteen studies from 17 articles published between 2011 and 2020 were included in this review. We found that about 3 out of 100 studies utilized at least one of the mock testing approaches for biomarker validation. Protein, mRNA, and metabolomic markers also represented the only groups whose validation has been attempted using these methods. Furthermore, studies that utilized both methods were found to have lower bias concerns on the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. Overall, there is a need to include these protocols in research endeavours verifying diagnostic biomarkers for head and neck carcinomas following the preliminary establishment of their classification accuracy.

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.

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 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.

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.

The International Head and Neck Cancer Epidemiology (INHANCE) consortium is a collaboration of research groups leading large epidemiology studies to improve the understanding of the causes and mechanisms of head and neck cancer. The consortium includes investigators of 35 studies who have pooled their data on 25 500 patients with head and neck cancer (i.e., cancers of the oral cavity, oropharynx, hypopharynx, and larynx) and 37 100 controls. The INHANCE analyses have confirmed that tobacco use and alcohol intake are key risk factors of these diseases and have provided precise estimates of risk and dose response, the benefit of quitting, and the hazard of smoking even a few cigarettes per day. Other risk factors include short height, lean body mass, low education and income, and a family history of head and neck cancer. Risk factors are generally similar for oral cavity, pharynx, and larynx, although the magnitude of risk may vary. Some major strengths of pooling data across studies include more precise estimates of risk and the ability to control for potentially confounding factors and to examine factors that may interact with each other. The INHANCE consortium provides evidence of the scientific productivity and discoveries that can be obtained from data pooling projects. © 2015 John Wiley & Sons A/S.

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

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 – 3.09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 – 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels.

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.

Background: Lesions of the submandibular gland represent a pleomorphically diverse group in which benign and malignant pathologies are difficult to differentiate from each other. Accurate diagnosis and surgical intervention relies upon clinical presentation, examination and investigations to guide appropriate management. The current series aimed to identify the roles of preoperative cytology and imaging with subsequent histopathology in the management of these lesions. Methods: Between 1998 and 2008, 54 patients of median age 54 years (range 25-94), with a male:female ratio of 1:3.5 were identified, of which, 50 patients underwent 52 excisions of the submandibular gland. Demographic data were recorded. The utility of imaging and cytology were analysed, and the accuracy of cytology correlated with histology. Results: Pathologies of resected specimens were sialadenitis 17 (32%), pleomorphic adenomas nine (17%), calculi eight (15%), lymphoma five (10%), squamous cell carcinoma two (4%), adenoid cystic carcinoma one (2%) and other 10 (20%). Twenty-eight patients (52%) underwent fine-needle aspiration cytology/core biopsies, of which 25 (89%) were correlated with histology. The accuracy, sensitivity and specificity of the fine-needle aspiration cytology correlation with histology were 88.0%, 71.4% and 94.4%, respectively. Overall, the complication rate was 9.6%; involving five temporary nerve palsies of the marginal mandibular branch of the facial nerve, including one temporary lingual nerve palsy. Conclusion: This series demonstrates histological outcomes in patients specific to the submandibular salivary gland. The malignancy rate was low compared to current published literature. The transcervical surgical approach to submandibular gland pathology is a safe and effective method with minimal morbidity when performed by experienced surgeons. No single investigative modality can be solely aligned with diagnosing a specific lesion of the submandibular gland. © 2010 The Authors. ANZ Journal of Surgery

The assessment of competence in clinical skills has become more frequent in published healthcare curricula and syllabuses recently. There are agreed mechanisms for the assessment of competence in the post-graduate environment, but no consensus within the undergraduate curriculum. This paper seeks to develop an agreed generic checklist for the assessment of competence in forceps exodontia.Materials and methods: A modified Delphi process was undertaken with representatives from all UK dental schools (n = 13) to develop a generic checklist for the assessment of competence in forceps exodontia. A content analysis of the assessments employed by each school was used to help discussion and inform the Delphi process.Results: Seven schools currently employ a summative assessment of competence in forceps exodontia, with the majority employing a structured clinical objective test (n = 6). From the seven assessments, there were a total of 29 putative items and 10 putative domains identified for a generic checklist. These were reduced to five domains and 19 items through the content analysis and Delphi process, and a generic overarching checklist was created.Conclusion: Using this generic checklist, it may now be possible to pool data inter-institution to perform more powerful analyses on how our students obtain, or fail to obtain competence in forceps exodontia. © 2010 John Wiley & Sons A/S.

Introduction: Competence based education is becoming more important in dentistry and medicine. In dentistry clinical skills are assessed using longitudinal assessments or structured objective clinical tests. We have previously presented the assessment of competence in surgical extractions however the success rate for this was poor. The opportunity to alter staffing levels and timetabling arose and we present the influence of this on the achievement of competence. Methods: The competence assessments and portfolios of two consecutive years of dental undergraduates were examined after completing their surgical extraction course. The first cohort received 9 sessions of teaching spread over 2 years with one staff supervisor per session. The second cohort received 10 sessions with varying numbers of staff supervisors. Results: The first cohort required 210 staff sessions and performed 275 surgical extractions (mean 4), and 23% achieved competence. The second cohort required 240 staff sessions and performed 403 surgical extractions (mean 6), and 66% achieved competence. Thirty six extra sessions were provided for students in the second cohort who failed to complete their competence during the allocated blocks and following this 99% of the second cohort achieved competence. These differences are significant (P

Percutaneous tracheostomy is an effective method of airway management in the critically ill patient, avoiding an open exposure of the trachea. This method is time and cost-efficient and is used in many intensive care units. However, we would like to draw attention to one serious potential complication of this technique. This case report describes a case of complete tracheal stenosis above the level of tracheostoma as a direct result of the procedure. The aetiology of the stenosis as well as the surgical and postoperative managements is discussed.

Accurate, predictive assessment of the behaviour and progression of oral cancers and precancers remains elusive in clinical practice. Archival tissue specimens from 10 previously treated patients with oral lesions of known clinical outcome (3 years post-treatment) were re-examined histopathologically, and proliferative cell labelling indices (LIs) determined for Ki67, cyclin A and histone mRNA cell cycle markers. While histone mRNA labelling ultimately proved unreliable, both Ki67 and cyclin A LIs demonstrated a clear trend for enhanced labelling to occur in increasingly dysplastic and neoplastic tissue, with particular emphasis on suprabasal labelling in abnormal tissue. Perhaps of greatest significance was the observation of increased LIs and suprabasal labelling in lesions with poor clinical outcome, such as patients developing recurrent disease or cervical lymph node metastasis. Measurement of cell proliferative activity in individual oral epithelial dysplastic lesions or invasive squamous cell carcinomas may thus provide unique, predictive information on clinical outcome.

Computer simulation has been carried out to help to determine the cell-proliferative mechanisms underlying data gathered from a double-labelling experiment on the dorsal tongue of the mouse. Good fits to the data have been obtained by assuming that there is a high degree of synchrony in the stem cells, which have a 24-h cell cycle time, and that daughters of these cells undergo two further divisions, with mean cell cycle times of 48 h, before differentiating. This results in one-seventh of proliferative cells being stem cells, which ties in well with the concept of epidermal proliferative units. There is no need to assume that S-phase duration changes diurnally. The administration of epidermal growth factor seems to increase the degree of synchrony. In such systems, the influx to S-phase and the efflux from it have very sudden short peaks, which it is impossible to observe unless observations are taken very frequently. There are therefore implications for the designs of experiments that attempt to study diurnal rhythms or the effect of factors that disturb the normal proliferative pattern of cells.

A family of finite end filters is constructed using a minimum revisions criterion and based on a local dynamic model operating within the span of a given finite central filter. These end filters are equivalent to evaluating the central filter with unavailable future observations replaced by constrained optimal linear predictions. Two prediction methods are considered: best linear unbiased prediction and best linear biased prediction where the bias is time invariant. The properties of these end filters are determined. In particular, they are compared to X-11 end filters and to the case where the central filter is evaluated with unavailable future observations predicted by global ARIMA models as in X-11-ARIMA or X-12-ARIMA. Copyright © 2002 John Wiley & Sons, Ltd.

A non-linear dynamic model is introduced for multiplicative seasonal time series that follows and extends the X-11 paradigm where the observed time series is a product of trend, seasonal and irregular factors. A selection of standard seasonal and trend component models used in additive dynamic time series models are adapted for the multiplicative framework and a non-linear filtering procedure is proposed. The results are illustrated and compared to X-11 and log-additive models using real data. In particular it is shown that the new procedures do not suffer from the trend bias present in log-additive models. Copyright © 2002 John Wiley & Sons, Ltd.

An off-line technique is described for the preparation of H(2) from water prior to analysis of delta(2)H by dual-inlet isotope ratio mass spectrometry. H(2) is produced from sample water by reaction with LiAlH(4). This provides a rapid and inexpensive method for the analysis of delta(2)H in small (10 microL) samples of water. Precision was +/- 4.2 to 8.0 (1sigma(n), n = 8) delta(2)H(VSMOW) for samples between 428 and 1500 delta(2)H(VSMOW), +/- 14.5 delta(2)H(VSMOW) for water enriched to 3750 delta(2)H(VSMOW) and +/- 26.0 delta(2)H(VSMOW) for water enriched to 6100 delta(2)H(VSMOW). Accuracy was +/- 1.1 to 4.2 delta(2)H(VSMOW) for water standards from natural abundance to 1000 delta(2)H(VSMOW) (the highest enrichment at which water of accepted delta(2)H is currently available). This method for delta(2)H determination is most appropriate for use with small (

Many meteorological datasets are mixtures in which components correspond to particular physical phenomena, the accurate identification of which are important from a meteorological standpoint. In particular, rainfall is generated by at least two processes—one convection, the other frontal systems—each characterised by its own distribution of rain rates and durations. The breakpoint data format, in which the timings of rain-rate changes and the steady rates between changes are recorded, captures the information required to parameterise these phenomena. Rainfall data has only recently become available in breakpoint format, which is both more compact and contains more information than older sources such as the fixed amount and fixed interval representation commonly used. Techniques such as the EM algorithm can be used to decompose the breakpoint data into its components. However, the quality of the currently available breakpoint data is poor for low rates and short durations and these portions of the data need to be discarded, or screened out, and the EM algorithm modified. In this paper, the EM algorithm is extended to deal with datasets in which data screening has taken place. The unified approach adopted appears new and, although tailored to a particular and important application, the method should have much wider application. Furthermore, in this paper the extension is applied to a large scale breakpoint dataset of about 56,000 observations with univariate and bivariate normal mixtures being fitted after censoring or truncation below a point or line respectively. The procedure was also applied to simulated breakpoint data which showed that the procedure was relatively robust and gave excellent results in the majority of cases. For the actual data, the results at low truncation agreed with applications of the EM algorithm to non-truncated data, but a different picture arose at moderate truncation. An analysis of the dry times between periods of precipitation is also given as an example of censoring. Overall, four components were required to adequately represent the wet data and another four for the dry data, giving a total of 34 parameters to model the 56,000 breakpoints. Copyright © 1998 John Wiley & Sons, Ltd.

We show how the concept of hidden Markov model may be accommodated in a setting involving multiple sequences of observations. The resulting class of models allows for both interrelationships between different sequences and serial dependence within sequences. Missing values in the observation sequences may be handled in a straightforward manner. We also examine a group of methods, based upon the observed Fisher Information matrix, for estimating the covariance matrix of the parameter estimates. We illustrate the methods with both real and simulated data sets. Nous montrons comment le concept du modele de Markov cache peut etre accommode a un environnement impliquant des sequences multiples d'observations. La classe de modeles en resultant permet des inter-relations entre differentes sequences et la dependance en serie au sein des sequences. Nous soulignons que les valeurs manquantes dans les sequences d'observations peuvent etre manipulees de facon simple. Nous examinons egalement un groupe de methodes fonde sur la matrice d'information de Fisher observee, afin d'estimer la matrice de covariance des estimations de parametres. Nous illustrons les methodes avec des ensembles de donnees reelles et simulees.

Although previous studies on tobacco and alcohol and the risk of upper-aerodigestive-tract (UADT) cancers have clearly shown dose-response relations with the frequency and duration of tobacco and alcohol, studies on addiction to tobacco smoking itself as a risk factor for UADT cancer have not been published, to our knowledge. The aim of this report is to assess whether smoking addiction is an independent risk factor or a refinement to smoking variables (intensity and duration) for UADT squamous cell carcinoma (SCC) risk in the multicenter case–control study (ARCAGE) in Western Europe. The analyses included 1,586 ever smoking UADT SCC cases and 1,260 ever smoking controls. Addiction was measured by a modified Fagerstrom score (first cigarette after waking up, difficulty refraining from smoking in places where it is forbidden and cigarettes per day). Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for UADT cancers with addiction variables were estimated with unconditional logistic regression. Among current smokers, the participants who smoked their first cigarette within 5 min of waking up were two times more likely to develop UADT SCC than those who smoked 60 min after waking up. Greater tobacco smoking addiction was associated with an increased risk of UADT SCC among current smokers (OR = 3.83, 95% CI: 2.56–5.73 for score of 3–7 vs. 0) but not among former smokers. These results may be consistent with a residual effect of smoking that was not captured by the questionnaire responses (smoking intensity and smoking duration) alone, suggesting addiction a refinement to smoking variables.

List of Contributors Preface Acknowledgements 1. Introduction General Introduction Epidemiology Prevention Treatment Strategies Terminology Summary References 2. Structure and Function of Oral Mucosa Introduction Applied Anatomy of the Oral Cavity Function of the Oral Mucosa The Microanatomy of Oral Mucosa Regional Variation of Oral Mucosa Oral Epithelial Cell Kinetics Oral Epithelial Cell Proliferative Activity Anatomical Site Predilection for Oral Carcinogenesis Summary References 3. Oral Carcinogenesis Introduction Oral Cancer and Precancer The Progression Model for Oral Cancer Aetiology and Risk Factors Patient and Risk Factor Profiling Summary References 4. Clinical Presentation of Oral Precancer Introduction Clinical Terminology Precancerous (Premalignant) Lesions Precancerous (Premalignant) Conditions Multiple Lesion Disease Summary References 5. Diagnostic Methods Introduction Screening Clinical Examination Techniques Vital Tissue Staining Light Based Detection Systems Brush Biopsy and Exfoliative Cytology Clinical Diagnosis in Practice Summary References 6. Pathological Aspects of Oral Precancer Introduction Biopsy Techniques The Role of the Pathologist Histopathological Features of Oral Potentially Malignant Disorders Grading of Dysplasia Limitations in Conventional Pathological Techniques Summary References 7. Management of Oral Precancer Introduction Risk Factor Modification Observation versus Intervention Medical Treatment Surgical Treatment Interventional Laser Surgery Combined Treatment Modalities Patient Follow Up and Surveillance Summary References 8. Clinical Outcome Introduction Clinical Outcome Studies Patient Cohort Studies Definitions of Clinical Outcome Newcastle Patient Cohort Studies Patient Follow Up Prediction of Clinical Outcome Summary References 9. Malignant Transformation and Oral Cancer Development Introduction The Risk of Progression to Oral Carcinoma Malignant Transformation versus Oral Cancer Development Interventional Laser Surgery and Oral Cancer Prevention The Newcastle 10 Year Follow Up Study High and Low Risk Patients Clinical Signs of Oral Squamous Cell Carcinoma Diagnosis and Management of Unexpected Malignancy Prognosis for the Transformed Patient Summary References 10. The Future Introduction Prevention of Oral Precancer Early Diagnosis of Potentially Malignant Disease Interventional Management Strategies in the Future Individualised Patient Treatments Biomarkers and Targeted Chemoprevention Future Research Directions Summary References 11. Case Histories Introduction Diagnosis of Unexpected Malignancy Multiple Lesion Disease Responding to Conservative Management Multiple Lesion Disease Requiring Repeated Laser Treatments Proliferative Verrucous Leukoplakia Localised Oral Lichenoid Reaction Multiple Oral Lichenoid Reactions Widespread Dysplastic Oral Lichenoid Reactions An Immunosuppressed Patient Chronic Hyperplastic Candidosis Tobacco Associated Hyperkeratosis Malignant Transformation in Longstanding Non-erosive Lichen Planus Summary 12. Conclusions Oral Cancer Potentially Malignant Disorders Clinical Management Patient Care Pathways Public Health Strategies Future Directions Index

A new method is proposed for forecasting electricity load-duration curves. The approach first forecasts the load curve and then uses the resulting predictive densities to forecast the load-duration curve. A virtue of this procedure is that both load curves and load-duration curves can be predicted using the same model, and confidence intervals can be generated for both predictions. The procedure is applied to the problem of predicting New Zealand electricity consumption. A structural time-series model is used to forecast the load curve based on half-hourly data. The model is tailored to handle effects such as daylight savings, holidays and weekends, as well as trend, annual, weekly and daily cycles. Time-series methods, including Kalman filtering, smoothing and prediction, are used to fit the model and to achieve the desired forecasts of the load-duration curve.

The novel gene encoding Clone 4, previously isolated through the Serological screening of recombinant expression cDNA library (SEREX) in chronic myeloid leukaemia (CML), was characterized. It is localized to chromosome 7 at q22, occupies approximately 4.5 kb of DNA and comprises 4 exons. Three single nucleotide polymorphisms and a 13 base deletion/insertion polymorphism have been identified. The mRNA transcript was approximately 2.4 kb and contained a long 5'-untranslated region of almost 1 kb before the candidate open reading frame. Northern blot analysis and multiple tissue expression array indicated a restricted normal tissue distribution. Our findings provide a platform for future investigations into the role of the gene product in CML.