Tatiana V. Macfarlane

Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals

BACKGROUND Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens. METHODS We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies. RESULTS Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96-1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39-2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23-1.38, P = 1 x 10(-18)), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19-1.35, P = 5 x 10(-13)). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01-1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour. CONCLUSIONS This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.

Population attributable risk of tobacco and alcohol for upper aerodigestive tract cancer.

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.

Orofacial pain: just another chronic pain? Results from a population-based survey

&NA; Features of somatisation have been shown to predict the onset of widespread body pain. This study aims to determine to what extent persons with orofacial pain syndromes share these features and to what extent they are uniquely related to oral mechanical factors. We have conducted a population‐based cross‐sectional survey in the South‐East Cheshire area of the United Kingdom involving 2504 individuals aged 18–65 years. All participants completed a postal questionnaire which enquired about the occurrence of both orofacial pain and widespread body pain. It also enquired about potential risk factors for one or both conditions. In total, 473 subjects (23%) reported orofacial pain only, 123 (6%) widespread pain only, while 85 (4%) reported both. The number reporting both was significantly higher than would be expected if the symptoms were independent (P<0.001). Several oral mechanical factors were significantly associated with both orofacial pain and widespread body pain (grinding teeth, clicking jaw, missing teeth), while two (facial trauma, locking jaw) were specifically related to orofacial pain. Both pain syndromes were associated equally with high levels of psychological distress, indicators of somatisation and maladaptive response to illness. These results suggest that orofacial pain syndromes may commonly be a manifestation of the process of somatisation and the excess reporting of some local mechanical factors amongst persons with these symptoms, may not be uniquely associated with pain in the orofacial region.

Oral lichenoid lesions related to dental restorative materials

Objectives To determine the effectiveness of replacing restorations considered to be the cause of an oral lichenoid lesion (oral lichenoid reaction)(OLL).Design Clinical intervention and nine-month follow up.Setting The study was carried out in the University Dental Hospital of Manchester, 1998-2002.Subjects and methods A total of 51 patients, mean age 53 (SD 13) years, who had oral lesions or symptoms suspected to be related to their dental restorations were investigated. Baseline patch tests for a series of dental materials, biopsies and photographs were undertaken. Thirty-nine out of 51 (76%) of patients had their restorations replaced.Results The clinical manifestations of OLL were variable; the majority of OLL were found to be in the molar and retro molar area of the buccal mucosa and the tongue. Twenty-seven (53%) patients had positive patch test reactions to at least one material, 24 of them for one or more mercury compound. After a mean follow up period of nine months, lesions adjacent to replaced restorations completely healed in 16 (42%) patients (10 positive and 6 negative patch tests). Improvement in signs and symptoms were found in 18 (47%) patients (11 positive and 7 negative patch tests).Conclusion OLLs may be elicited by some dental restorations. Replacing restorations adjacent to these lesions is associated with healing in the majority of cases particularly when lesions are in close contact with restorations. A patch test seems to be of limited benefit as a predictor of such reactions.

Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 european countries: The ARCAGE project

Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus and account for 6.4% of all new cancers in Europe. In the context of a multicenter case-control study conducted in 14 centers within 10 European countries and comprising 1,511 cases and 1,457 controls (ARCAGE study), 115 single nucleotide polymorphisms (SNP) from 62 a priori-selected genes were studied in relation to UADT cancer. We found 11 SNPs that were statistically associated with UADT cancers overall (5.75 expected). Considering the possibility of false-positive results, we focused on SNPs in CYP2A6, MDM2, tumor necrosis factor (TNF), and gene amplified in squamous cell carcinoma 1 (GASC1), for which low P values for trend (P trend<0.01) were observed in the main effects analyses of UADT cancer overall or by subsite. The rare variant of CYP2A6 -47A>C (rs28399433), a phase I metabolism gene, was associated with reduced UADT cancer risk (P trend=0.01). Three SNPs in the MDM2 gene, involved in cell cycle control, were associated with UADT cancer. MDM2 IVS5+1285A>G (rs3730536) showed a strong codominant effect (P trend=0.007). The rare variants of two SNPs in the TNF gene were associated with a decreased risk; for TNF IVS1+123G>A (rs1800610), the P trend was 0.007. Variants in two SNPs of GASC1 were found to be strongly associated with increased UADT cancer risk (for both, P trend=0.008). This study is the largest genetic epidemiologic study on UADT cancers in Europe. Our analysis points to potentially relevant genes in various pathways.

Diet and upper-aerodigestive tract cancer in Europe: The ARCAGE study

There is suggestive, but inconclusive, evidence that dietary factors may affect risk of cancers of the upper aerodigestive tract (UADT). In the context of the alcohol‐related cancers and genetic susceptibility in Europe study, we have examined the association of dietary factors with UADT cancer risk. We have analyzed data from 2,304 patients with UADT cancer and 2,227 control subjects recruited in 14 centers in 10 European countries. Dietary data were collected through a semi‐quantitative food frequency questionnaire that also assessed preferred temperature of hot beverages. Statistical analyses were conducted through multiple logistic regression controlling for potential confounding variables, including alcohol intake and smoking habits. Consumption of red meat (OR per increasing tertile = 1.14, 95% CI: 1.05–1.25), but not poultry, was significantly associated with increased UADT cancer risk and the association was somewhat stronger for esophageal cancer. Consumption of fruits (OR per increasing tertile = 0.68, 95% CI: 0.62–0.75) and vegetables (OR per increasing tertile = 0.73, 95% CI: 0.66–0.81) as well as of olive oil (OR for above versus below median = 0.78, 95% CI 0.67–0.90) and tea (OR for above versus below median = 0.83, 95% CI 0.69–0.98) were significantly associated with reduced risk of UADT cancer. There was no indication that an increase in tea or coffee temperature was associated with increased risk of UADT overall or cancer of the esophagus; in fact, the association was, if anything, inverse. In conclusion, the results of this large multicentric study indicate that diet plays an important role in the etiology of UADT cancer.

Socioeconomic factors associated with risk of upper aerodigestive tract cancer in Europe.

INTRODUCTION In the European Union, there are 180,000 new cases of upper aerodigestive tract (UADT) cancer cases per year--more than half of whom will die of the disease. Socioeconomic inequalities in UADT cancer incidence are recognised across Europe. We aimed to assess the components of socioeconomic risk both independently and through their influence on the known behavioural risk factors of smoking, alcohol consumption and diet. PATIENTS AND METHODS A multicentre case-control study with 2198 cases of UADT cancer and 2141 controls from hospital and population sources was undertaken involving 14 centres from 10 countries. Personal interviews collected information on demographics, lifetime occupation history, smoking, alcohol consumption and diet. Socioeconomic status was measured by education, occupational social class and unemployment. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using unconditional logistic regression. RESULTS When controlling for age, sex and centre significantly increased risks for UADT cancer were observed for those with low versus high educational attainment OR=1.98 (95% CI 1.67, 2.36). Similarly, for occupational socioeconomic indicators--comparing the lowest versus highest International Socio-Economic Index (ISEI) quartile for the longest occupation gave OR=1.60 (1.28, 2.00); and for unemployment OR=1.64 (1.24, 2.17). Statistical significance remained for low education when adjusting for smoking, alcohol and diet behaviours OR=1.29 (1.06, 1.57) in the multivariate analysis. Inequalities were observed only among men but not among women and were greater among those in the British Isles and Eastern European countries than in Southern and Central/Northern European countries. Associations were broadly consistent for subsite and source of controls (hospital and community). CONCLUSION Socioeconomic inequalities for UADT cancers are only observed among men and are not totally explained by smoking, alcohol drinking and diet.

Gait analysis as an objective measure in a chronic pain model.

The aim of this study was to investigate objective characterisation of gait as a marker of the chronic pain of adjuvant arthritis (AA). Video recorded images of spontaneous rat ambulations were analysed to quantify various temporal and spatial parameters and compare these between the AA and control groups. Changes were also recorded after the administration of a single dose of buprenorphine (15 ?g). Individual temporal parameters were significantly reduced (velocity (P=0.05), stride length (P=0.007), single stance time (P<0.001), swing time (P=0.001)), or increased (dual stance time (P<0.001)) at 10 days in the AA group compared to control. The rear paws showed reduced ground contact and the fore paws an increase in proximal pad and decrease in digit area, although these changes were not all statistically significant. Some of the gait parameters showed significant reversal following administration of buprenorphine (velocity (P<0.001) and stride length (P<0.001) were increased and single stance time (P=0.014) reduced). It is proposed that changes in gait are a marker of AA chronic pain in this model. These behavioural changes were significant at a very early stage (day 10), before the development of physical deformities and increase in paw volume and might permit an earlier detection of pain than other models.

The Effect of an Apex Locator on Exposure to Radiation During Endodontic Therapy

The objective of this study was to investigate whether the use of an electronic apex locator results in a reduction in X-ray exposure during endodontic therapy. Fifty, sound, extracted, single-rooted canine and incisor teeth were selected and randomly divided into two groups (A and B) of 25 teeth. The working length was determined radiographically with (group B) and without (group A) adjunctive use of an apex locator by one operator. After working length determination, the teeth were sectioned and the actual working length measured for comparison. For group A, 14 retake radiographs were required to determine the working length, whereas group B required no retake radiographs; this difference was highly significant (p < 0.001). The electronic apex locator was extremely accurate in locating the apical foramen with all teeth tested within 0.5 mm of the anatomical apex and 11 (44%) teeth at the apical foramen. In contrast, 15 (60%) teeth tested using radiographs alone were within 0.5 mm of the anatomical apex and only 4 (16%) teeth were actually at the anatomical apex. It was concluded that using an electronic apex locator as an aid to endodontic therapy could potentially reduce the number of diagnostic radiographs required for working length determination. Location of the apical foramen using a combination of an electronic apex locator and radiographs to determine working length is more accurate than using radiographs alone.

Alcohol-related cancers and genetic susceptibility in Europe: the ARCAGE project: study samples and data collection.

Cancers of the upper aerodigestive tract (UADT) include those of the oral cavity, pharynx (other than nasopharynx), larynx, and esophagus. Tobacco smoking and consumption of alcoholic beverages are established causes of UADT cancers, whereas reduced intake of vegetables and fruits are likely causes. The role of genetic predisposition and possible interactions of genetic with exogenous factors, however, have not been adequately studied. Moreover, the role of pattern of smoking and drinking, as well as the exact nature of the implicated dietary variables, has not been clarified. To address these issues, the International Agency for Research on Cancer initiated in 2002 the alcohol-related cancers and genetic susceptibility (ARCAGE) in Europe project, with the participation of 15 centers in 11 European countries. Information and biological data from a total of 2304 cases and 2227 controls have been collected and will be used in a series of analyses. A total of 166 single nucleotide polymorphisms of 76 genes are being studied for genetic associations with UADT cancers. We report here the methodology of the ARCAGE project, main demographic and lifestyle characteristics of the cases and controls, as well as the distribution of cases by histology and subsite. About 80% of cases were males and fewer than 20% of all cases occurred before the age of 50 years. Overall, the most common subsite was larynx, followed by oral cavity, oropharynx, esophagus and hypopharynx. Close to 90% of UADT cancers were squamous cell carcinomas. A clear preponderance of smokers and alcohol drinkers among UADT cases compared with controls was observed.