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Keywords:

  • trace elements;
  • Barrett's oesophagus;
  • oesophageal adenocarcinoma;
  • selenium;
  • case–control study

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Trace elements have been cited as both inhibitory and causative agents of cancer but importantly exposure to them is potentially modifiable. Our study aimed to examine toenail trace element status and risk of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Toenail clippings from each hallux were obtained from 638 participants of the FINBAR (Factors Influencing the Barrett's Adenocarcinoma Relationship) study comprising 221 healthy controls, 98 reflux oesophagitis, 182 BO and 137 OAC cases. The concentrations of eight toenail trace elements were determined using instrumental neutron activation analysis. Using multivariable adjusted logistic regression analysis, odds ratios (OR) and 95% confidence intervals (CIs) were calculated within tertiles of trace element concentrations. A twofold increased risk of BO was observed, but not OAC, among individuals in the highest tertile of toenail zinc status OR 2.21 (95% CI, 1.11–4.40). A higher toenail selenium status was not associated with risk of OAC OR 0.94 (95% CI, 0.44–2.04) or BO OR 0.89 (95% CI, 0.37–2.12). A borderline significant increased risk of BO was detected with a higher toenail cobalt concentration, OR 1.97 (95% CI, 1.01–3.85). No association was found between toenail levels of chromium, cerium, mercury and OAC or BO risk. This is the first case–control study to investigate a variety of trace elements in relation to OAC and BO risk. Despite antioxidant and proapoptotic properties, no associations were found with selenium. Higher concentrations of toenail zinc and cobalt were associated with an increased BO risk, but not OAC. These findings need confirmation in prospective analysis.

In recent decades, oesophageal adenocarcinoma (OAC) has had the fastest increasing incidence of any malignancy in the developed world, particularly among white men in the USA1 and Europe2; a changing epidemiology which has not been explained by misclassification with gastric cardia adenocarcinoma,3 nor improved diagnostic techniques, as trends differ between sexes.4 In line with the rising incidence of OAC, there appears to have been a concomitant ‘true’ increase in the incidence of Barrett's oesophagus (BO)5, 6; a metaplastic precursor state believed to be acquired through chronic exposure to caustic reflux as a consequence of gastro oesophageal reflux disease (GORD). Five-year survival from OAC has been reported to be as low as 8% in both sexes in the UK7 and <15% in most populations8; therefore, research into modifiable risk factors for the prevention of this cancer is pivotal.

The role of dietary components in the pathogenesis of OAC and BO remains elusive; however, epidemiological research between trace elements and cancer risk is growing.9 Some trace elements are micronutrients that are present in the human body in minute quantities, several of which are essential for a variety of metabolic processes including iron (Fe), zinc (Zn), cobalt (Co), chromium (Cr) and selenium (Se).10 However, exposure to some trace elements, such as mercury (Hg), can be detrimental to health. Trace elements readily bind to the fibrous proteins of hard keratin in toenails and given their slow growth have been shown to be a reliable biomarker for trace element status,11 typically reflecting past year exposure.12 Moreover, in populations who routinely wear socks/shoes they are subjected to less external contamination than fingernails or hair, can be collected noninvasively and are easier to transport and store.13

Se, in particular, has been looked upon as a potentially key anticarcinogenic trace element, given its function as a cofactor of the glutathione peroxidase family of enzymes, each with the biological role of protecting against oxidative stress; furthermore, various Se compounds have been shown to act as antiproliferative and proapoptotic agents14 and have been attributed with antiviral and anticarcinogenic properties.15 To date, only two studies have examined toenail Se status in relation to risk of OAC and BO,16, 17 the principal findings of which have indicated no association with OAC or BO risk. Zn, a cofactor of over 300 catalytically active metalloenzymes,18 plays a crucial role in the regulation, transcription and replication of DNA19 and so like Se, is believed to have both antioxidant and proapoptotic properties18 which may inhibit OAC carcinogenesis. Co, (vitamin B12/cobalamin), is an essential cofactor in the methionine synthase reaction which is integrally involved in DNA biosynthesis, cell division, erythropoiesis and peripheral nerve myelination,20 and hence may play a role in cancer development. Pharmacologically, cerium (Ce) exerts diverse biological effects, given its resemblance to calcium. Although the mechanisms of action remain unclear, Ce has been investigated in vitro for its antiproliferative and antioxidant properties.21, 22 Other elements have been identified as potential causative agents of cancer, for example, hexavalent Cr (VI) can be mutagenic when inhaled23; however, findings from a meta-analysis examining occupational exposure and cancers of the gastrointestinal tract have been inconclusive.24 Similarly, despite the classification of Hg as a potential human carcinogen, there is no robust evidence affirming its role in the aetiology of human cancers.25

The aim of our study was to, therefore, investigate the association between the states of several toenail trace elements including Se, Zn, Co, Cr, Hg, Ce and risk of OAC and BO, using data from an all-Ireland case–control study, the FINBAR study (Factors INfluencing the Barrett's Adenocarcinoma Relationship study).

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Study design

A detailed description of the FINBAR study, its participation fractions and case exclusions have been published elsewhere26; briefly, this was an all-Ireland case–control study recruiting 227 patients with OAC (131 oesophageal, 92 junctional and 4 unclassified), 224 long segment BO and 260 population-based controls from March 2002 through December 2004. Response rates in FINBAR were 74.2, 82.4 and 41.8% among OAC, BO and population controls, respectively.

Patients aged ≤85 years with a histological diagnosis of adenocarcinoma of the oesophagus (excluding in situ cancers) formed the OAC group. Eligible BO patients were those with ≥3 cm of typical Barrett's mucosa at endoscopy or in which biopsy evidenced the presence of specialised intestinal metaplasia; patients with dysplasia on histological inspection were excluded. Population controls were aged between 35 and 84 years with no prior history of oesophageal/gastrointestinal malignancy or known diagnosis of BO and were selected at random from general practitioner lists throughout Northern Ireland and from four general practices (two urban and two rural) in the Dublin and Cork city areas. All control patients were frequency matched to the cases within 5-year age bands and sex strata.

In Northern Ireland, ethical committee approval was obtained from the Queen's University Belfast research ethics committee. In the Republic of Ireland, consent was obtained from the clinical research ethics committee of the Cork teaching hospitals and the research ethics committee board of St. James Hospital, Dublin.

Exposure assessment

All structured interviews were computerised and conducted by trained researchers. A brief medical history was taken from all subjects and information pertaining to medication usage, medical history, occupation, education and alcohol/smoking history was collected. Anthropometric measurements such as height, weight and waist and hip circumference were taken at the time of consultation. Body mass index (BMI) 5 years prior to interview was assessed by dividing self-reported weight (kg) by height (m2). Dietary intakes were assessed using a semiquantitative food frequency questionnaire; this was a modified version of that used in the European Prospective Investigation into Cancer and nutrition (EPIC).27

Toenail collection and laboratory analysis

Toenail clippings from each hallux were obtained from 638/941 (67.8%) participants comprising 221/260 (85%) controls, 182/224 BO (81.3%) and 137/227 OAC (60.4%). A further 98/230 (42.6%) toenail specimens were collected from a concurrent oesophagitis study in Northern Ireland, however, given the low proportion of toenail specimens available from these reflux oesophagitis cases, their data were not utilised and were excluded from all subsequent analyses. All toenail specimens were placed in labelled resealable plastic pouches and stored at room temperature. In September 2008, these toenail samples were received by staff (JB) at the University of Missouri Research Reactor (MURR, Columbia, MO) for analysis wherein the concentrations of eight elements Se, Fe, Hg, Zn, Co, Cr, scandium (Sc) and Ce were determined by instrumental neutron activation analysis (INAA) using methods which have been described in detail elsewhere.12 It should be noted that toenail concentrations of Sc are not reported herein as this was used as a control element to account for sample contamination from chemicals or glassware prior to irradiation.28 Although toenail Fe concentrations were determined in INAA, they have been published elsewhere with other Fe data in relation to BO and OAC risk.29

To minimise systematic differences that may have arisen in the way specimens were handled, case and control specimens were analysed in a random order together in batches of 100 by laboratory staff who were blinded to their case–control status. All toenail clippings were thoroughly washed with deionised water and 10% nitric acid using a sonicator, prior to being freeze dried and placed in precleaned high-density polyethylene vials. For Se determination, specimens were irradiated with neutrons and transferred to a high-resolution γ-ray spectrometer where the γ-ray from the decay of 77mSe was quantified and Se concentrations were determined. Samples were coanalysed with NIST SRM 1577b (Bovine liver) quality controls which have a certified Se value of 1.1 ± 0.1 μg/g. The average (mean ± SD) Se value across the samples was 1.07 ± 0.3 μg/g which agreed well with the certified controls. Out of the 638 samples available for Se analysis, 236 (37%) had sufficient mass to run the analysis with a duplicate sample to check for sample homogeneity and reproducibility; three samples were found to have inconsistent Se concentrations and were subsequently excluded from Se analysis. For further multielement determinations, the toenail samples were irradiated for 50 hr, allowed to decay for 6–10 days and similarly quantified by a γ-ray spectrometer. In total, 73/638 samples were of sufficient mass to allow duplicates to be primed and analysed. Observed and accepted mean values between the coanalysed toenail samples and the quality control materials NIST SRM 1577b (bovine liver), NIST SRM 1571 (orchid leaves) and NCS DC 73347 (human hair) were satisfactorily comparable. Toenail samples from two subjects (one BO and one control) were mixed together during multielement determination and were excluded from subsequent analyses. Additionally, 41/638 toenail samples analysed had a very low mass (<0.01 g) and were excluded from all subsequent analyses.

Statistical analysis

Differences in demographic characteristics between cases and controls were examined using a t-test for continuous variables and χ2 test for categorical data (all tests were two-tailed and α = 0.05). A natural logarithmic (loge) transformation of all toenail element concentrations was undertaken prior to analysis to approximate a normal distribution. Multivariate logistic regression analysis was then used to investigate the association between tertiles of toenail trace element concentrations and risk of OAC and BO vs. controls to attain odds ratios (ORs) and 95% confidence intervals (95% CIs). Using a parsimonious backwards elimination approach, the ORs of confounders identified as statistically significantly affecting an association (α ≤ 0.05%) were entered into the final models. A range of available confounders were considered including BMI 5 years prior to the date of interview (kg/m2), alcohol intake (g/day), total energy intake (Kcal), manual/nonmanual work, gastro oesophageal reflux (GOR) symptoms, that is, symptoms of heartburn or acid reflux experienced at least once weekly 5 years prior to the interview date (ever/never), Helicobacter pylori infection seropositivity (+ve/−ve), Nonsteroidal anti-inflammatory drug use at least once weekly for ≥6 months or more (ever/never), education (years), location (Republic of Ireland/Northern Ireland), vitamin C intake (mg/day). Although data on waist to hip ratio were available, there was no material difference to the effect estimates if this was substituted for BMI in multivariate models. Where data were available, adjustment for other metals which could affect the uptake, transport, metabolism and physiological activity of the element under investigation (antagonistic elements) was undertaken, that is in the analysis of Se, Zn and copper were initially included in the multivariate model. Age (years), gender and smoking status (current, former and never) were retained in the models, irrespective of significance, given their potential moderating effects on toenail trace element concentrations.13, 30, 31

Tertile cut-points were derived using toenail concentrations from the controls as the reference population. In the analysis of Ce and Cr, 67.1% (345/514) and 75.7% (389/514) of subjects, respectively, had a toenail concentration that was at or below the limit of detection (LOD). To minimise any resultant bias,32 analysis was confined to just two categories of above LOD (>0.015 and >0.4 μg/g for Ce and Cr, respectively) and at or below the LOD (≤0.015 and ≤0.4 μg/g for Ce and Cr, respectively), ensuring that those individuals with the lowest trace element exposure were placed in the lowest category. Although unplanned, subgroup explorations (limited to the analysis of Se) were undertaken to enable comparison with the only other studies which have investigated toenail Se status and OAC and BO risk.16, 17 Upon post hoc subgroup analysis, resultant regression models failed to achieve convergence because the number of OAC and BO cases in relation to explanatory variables was small.33 To test for linear trends across the trace element tertiles, the element was entered as a continuous variable in the regression models. Tests for interaction were performed using the log-likelihood ratio statistic. All statistical analyses were conducted using STATA version 11.0 (StataCorp LP, College Station, TX).

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

In comparison to individuals providing a toenail specimen, a higher proportion of those who were not recruited from the Republic of Ireland (among population controls only) had a high waist to hip ratio. There were no statistically significant differences between individuals who provided or did not provide a toenail specimen in terms of age, gender, smoking status, BMI or frequency of GOR symptoms (Supporting Information Table 1).

Table 1. Characteristics of OAC and BO cases and population controls who provided a toenail specimen
inline image

The characteristics of cases and controls who returned a toenail sample are summarised in Table 1. There were no significant differences between case and control groups by age or gender. OAC cases had a higher average BMI and a greater proportion were current smokers than population controls. BO cases had a significantly higher energy intake and both alcohol intake and years of education were significantly lower among OAC cases in comparison to population controls. Almost half of the OAC cases (46%) and over 70% of BO cases reported experiencing GOR symptoms more frequently than controls (18%), a difference which was significant. A higher proportion of controls had tested positive for H. pylori infection in comparison to either OAC or BO cases. Both BO and OAC cases had a lower mean toenail Se concentration than controls p = 0.001 and 0.019, respectively. Toenail concentrations of Zn were also observed to be significantly higher among BO cases than population controls p = 0.017. There were no other statistically significant differences in mean toenail trace element concentrations across the case groups (Table 2).

Table 2. Toenail trace element concentrations among OAC and BO cases and healthy controls
inline image

Se and Zn

In multivariate logistic regression analyses, no association was observed between risk of OAC and BO comparing the lowest tertile of toenail Se to the highest, OR 0.94 (95% CI, 0.44–2.04) and OR 0.89 (95% CI, 0.37–2.12) for OAC and BO cases, respectively (Table 3). Confounders in the multivariate model that account most for the transition from a protective association observed in minimally adjusted models are GOR symptoms, H. pylori infection, smoking status, alcohol and years of education. In unplanned subgroup analysis, those individuals in the highest tertile of toenail Se and who were current smokers had a twofold greater risk of OAC OR 2.83 (95% CI, 1.10–7.28; p interaction = 0.01). Conversely, although not significant, higher toenail Se status was associated with an increased risk of BO among never smokers (Table 4). In multivariable models, no association was observed between those cases in the highest tertile of toenail Zn concentrations and risk of OAC OR 0.92 (95% CI, 0.50–1.69); however, a consistent significantly higher risk of BO was detected in univariate and multivariate models OR 2.21 (95% CI, 1.11–4.40) (Table 3).

Table 3. Risk of OAC & BO according to tertiles of toenail trace element concentrations
inline image
Table 4. Toenail Se status and BO and OAC risk by gender, smoking status and BMI
inline image

Hg and Co

Multivariable analysis showed no statistically significant association between tertiles of toenail Hg and risk of OAC OR 0.76 (95% CI, 0.36–1.62) or BO OR 0.72 (95% CI, 0.33–1.57) (Table 3). A borderline significant increased risk of BO OR 1.97 (95% CI, 1.01–3.85) was observed with higher toenail concentration of Co in relation to population controls. Although insignificant, a weaker positive association was also observed among OAC cases OR 1.54 (95% CI, 0.84–2.85) (Table 3).

Ce and Cr

In multivariable analysis, there was no association between those individuals with a detectable toenail Ce concentration and risk of OAC OR 0.73 (95% CI, 0.36–1.47) or BO OR 1.53 (95% CI, 0.77, 3.03) in comparison to individuals who had little or no exposure to this element (Table 3). Similar results were observed among the highest toenail Cr concentrations and risk of OAC OR 0.82 (95% CI, 0.39–1.73) and BO OR 1.21 (95% CI, 0.56–2.60) (Table 3).

Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

To the authors' knowledge, this is the first case–control study to investigate the association between a variety of toenail trace elements and OAC and BO risk. No association was found between higher toenail concentrations of Se and risk of BO or OAC. BO, but not OAC, was positively associated with a higher toenail concentration of Zn and Co. No associations were found between higher concentrations of toenail Cr, Ce or Hg and either OAC or BO risk.

Two prior prospective investigations,16, 17 both conducted within the Netherlands Cohort Study, have examined toenail Se status in relation to OAC and BO risk, respectively. In their first article, Steevens et al.16 found no clear association with higher toenail Se status and risk of OAC RR 0.76 (95% CI, 0.41–1.40); a finding affirmed in this case–control analysis. The authors reported a significant inverse association between toenail Se and OAC risk among never smokers RR 0.74 (95% CI, 0.64–0.86), and although based on small numbers, among women RR 0.72 (95% CI, 0.61–0.84). It is conceivable that a high dietary intake of Se (and hence correlated higher toenail Se status) may counteract the negative oxidative damage induced by smoking; however, in unplanned stratified analysis of Se and smoking status from the FINBAR study, there was a significant twofold increased risk of OAC among current smokers and a nonsignificant decreased risk among never smokers; perhaps, reflecting the inability of Se to completely counteract the oxidative stress induced by smoking, especially as many of the anticarcinogenic effects of Se are observed at supranutritional doses.34

In a subsequent examination, Steevens et al.17 found no evidence of an association between BO risk and toenail Se status RR 1.06 (95% CI, 0.71–1.57; p trend = 0.99), nor in subgroup analyses defined by sex, smoking status, BMI or antioxidant intake. Mean Se levels in the FINBAR study were 0.49 and 0.48 μg/g among OAC and BO cases, respectively, and 0.52 μg/g among population controls, the median toenail Se level in the Netherlands Cohort study was 0.55 μg/g; concentrations which lie in the mid-range of those reported elsewhere in Europe (μg/g): 0.45 in Germany (Berlin), 0.57 in Scotland (Edinburgh) and 0.83 in Finland (Helsinki).35 It is worth noting that one previous cross-sectional study has examined serum Se levels as a marker for neoplastic progression of BO,36 finding that higher levels were associated with a reduced risk of high-grade dysplasia in patients with BO, OR 0.5 (95% CI, 0.3–0.9).

In our study, a higher toenail Zn concentration was associated with a twofold increased risk of BO; however, no association was observed with OAC. Mean toenail Zn concentrations were 70.72, 74.7 and 70.11 μg/g among OAC and BO cases and population controls, respectively. These levels appear to be lower in comparison to other levels in Europe (μg/g): Berlin, 108.3; Edinburgh, 112.93; Helsinki, 102.8; Malaga, 102.9 and Moscow, 103.8.37 There have been no further studies which have examined OAC or BO in relation to toenail Zn status. Notably, however, toenail Zn has been shown to correlate well with dietary Zn intake, even in healthy populations with little Zn deficiency and high Zn supplementation rates.38 Importantly, Zn metalloenzymes, such as metallothionein, are powerful antioxidants and scavengers of hydroxyl radicals39, 40 and may therefore have associated anticancer effects. However, to date, the nutritional contribution to BO and OAC is largely unknown41; a previous analysis of the dietary intake of Zn from the FINBAR study42 found no association between the higher intakes and the risk of BO or OAC. This incongruence with our findings of an increased risk of BO may be because of the different dietary assessment methods utilised, that is the use of toenails as a biomarker of dietary Zn intake may avoid measurement errors incurred through self-reported dietary intakes on the food frequency questionnaires.

Interestingly, Abnet et al.43 observed that individuals with oesophageal dysplasia (a precursor lesion to oesophageal squamous cell carcinoma [OSCC]) had higher tissue Zn concentrations in their oesophageal tissue than those with no oesophageal dysplasia or OSCC. Although histologically disparate, this may lend support to our study findings of higher Zn deposition in toenail tissue observed in the premalignant lesion BO than either controls or patients with OAC. Similar findings have been observed in prostate cancer in which Zn levels in the malignant vs. normal prostate tissue are often 60–70% lower.44, 45 It would, therefore, be useful for prospective studies to further examine toenail Zn concentrations in relation to BO and OAC risk. No studies, to date, have examined the role of other toenail trace elements and OAC or BO risk for comparison with the present findings.

The principal strengths of the FINBAR study are its population-based design, rapid case ascertainment and stringent inclusion criteria for BO (specialised intestinal metaplasia, length, ≥3 cm). Additionally, it was possible to adjust for a range of potential confounders including H. pylori seropositivity and symptoms of GORD. However, both GORD and BMI were ascertained in the 5-year period prior to the interview date in cases and controls raising the potential for recall bias of these exposures. A high proportion of BO patients' report having no reflux symptoms prior to diagnosis; consequently, the overall prevalence of BO remains low.46 Therefore, the associations observed in our study may have been attenuated by the absence of BO diagnosis in asymptomatic controls. Participation rates in FINBAR were 74.2 and 82.4% among OAC and BO cases, respectively. Control response rates were much lower at 41.8%, raising a potential issue with selection bias.47 As published previously, however,26 controls were similar to the general population with regard to the symptoms of GORD, mean weight and BMI. This suggests that respondents largely reflect (on important covariates) the population from which they were drawn. However, in the 2001 Northern Ireland health and social wellbeing survey,48 23.6% of males (55 years or more) were current smokers, 53.1% former smokers and 23.3% never smokers. In our study, 83% of control respondents were male and 16, 41 and 43% were current, former and never smokers, respectively. Therefore, the percentage of current smokers may be slightly underrepresented and the number of nonsmokers overrepresented in this study in comparison to the general population, leading to the potential overestimation of a positive association of cigarette smoking and OAC/BO, particularly in subgroup analyses of this exposure. There is no comparable population-based data on the average concentration of selected toenail trace elements in Northern Ireland/Ireland. However, trace element concentrations for Se, for example (0.52 μg/g), appear to be in line with similar control populations in the UK49 (0.59 μg/g) and Europe17 (0.54 μg/g).

The overall response rate for toenail collection was 67.8% and was highest among population controls (85%). Failure to return samples by post was the main reason for not having complete toenail specimens across the case groups studied; moreover, out of the 90 OAC cases recruited as hospital inpatients, 76.7% had habitually clipped their toenails prior to admission, which was problematic for procurement of a nail sample. A further limitation of this case–control study is that the samples were collected postdiagnosis, making it impossible to distinguish if the exposure changed as a consequence of the disease process itself (reverse causation). For example, preclinical anorexia and weight loss in combination with individual-level factors such as age, gender, smoking status and alcohol consumption; as well as extraneous influences such as warmer weather (i.e., the season in which the nails were cut) and toe length (proportional to nail bed growth) are known determinants of trace element deposition.13, 30, 31 The imperfect measurement of smoking status in our analysis may have been insufficient to remove its confounding effect; therefore, residual confounding by smoking status and other unmeasured variables remains a possibility. As has been previously discussed, post hoc subgroup explorations in this case–control study were limited to the analysis of Se for comparison with extant literature; however, a statistical issue which frequently arises upon tests for interactions is that of multiple testing, resulting in an uncontrolled type 1 error rate.50

In summary, too few studies have been conducted in this field to enable any robust conclusions to be drawn. Only one prospective study has examined toenail levels of Se in relation to OAC and BO risk; findings of this prospective study and the analysis from this case–control study have both shown inconclusive results. The presented subgroup analyses of Se should be interpreted with caution, given that they were not prespecified and the small sample size involved increases the chances of a spurious finding. This study observed a twofold increase in risk of BO among individuals in the highest tertile of toenail Zn; however, no association was observed with OAC. Higher toenail concentrations of Co were associated with a borderline significant increased risk of BO but not OAC. Given the number of statistical tests performed, these findings may have occurred by chance; these associations should be confirmed in further prospective analyses.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

The authors appreciate the contributions made by the study participants and their families. The authors thank the clinicians who were contacted throughout the study period and their secretaries for administrative support. The authors acknowledge the contribution of Miss Siobhan Reynolds, Ms. Majella Gallagher, Ms. Carol Anderson and Mr. Martin McAnaespie and Dr. Damian McManus. Thanks to the Ulster Cancer Foundation, the Northern Ireland Cancer Registry and the National Cancer Registry Ireland for their support and involvement in the research. This study was supported in part by the intramural research program of the NIH (National Cancer Institute).

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  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

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