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Keywords:

  • epidemiology;
  • esophageal cancer;
  • stomach cancer;
  • fruit;
  • vegetables

Abstract

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

Prospective epidemiologic data on vegetables and fruits consumption and risk of subtypes of esophageal and gastric cancer are sparse. We studied the association between vegetables and fruits consumption and risk of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA) and gastric noncardia adenocarcinoma (GNCA) in the Netherlands Cohort Study. In 1986, 120,852 Dutch men and women aged 55–69 filled out a questionnaire on diet and other cancer risk factors. After 16.3 years of follow-up, 101 ESCC, 144 EAC, 156 GCA, 460 GNCA cases and 4,035 subcohort members were available for case–cohort analysis using Cox proportional hazards models. Multivariable adjusted incidence rate ratios (RRs) were generally below unity. Total vegetable consumption was nonsignificantly inversely associated with EAC and ESCC risk, but not with GCA and GNCA risk. Significant inverse associations were observed for raw vegetables and EAC risk [RR per 25 g/day: 0.81, 95% confidence interval (CI) 0.68–0.98], and Brassica vegetables and GCA risk (RR per 25 g/day: 0.72, 95% CI 0.54–0.95). Total fruit consumption was associated with a nonsignificantly decreased EAC risk. Citrus fruits were inversely associated with EAC and GCA risk (RRs for highest vs. lowest intake: 0.55, 95% CI 0.31–0.98 and 0.38, 95% CI 0.21–0.69, respectively). Specifically for current smokers, vegetables and possibly also fruits intake was inversely associated with ESCC and EAC risk. Consumption of (specific groups of) vegetables and fruits may protect against subtypes of esophageal and gastric cancer.

Vegetables and fruits have been of interest for their possible favorable influence on risk of cancer and other diseases for some decades. These foods contain many substances that are potentially anticarcinogenic, such as vitamins, carotenoids and flavonoids. Possible mechanisms of action include modulation of DNA methylation, protection from and repair of DNA damage, induction of detoxifying phase II enzymes and promotion of apoptosis.1, 2 A recent expert report concluded that consumption of vegetables and fruits probably protects against development of esophageal and gastric cancer.2 Unfortunately, in this report, no distinction was made between the main subtypes of these cancers: esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA) and gastric noncardia adenocarcinoma (GNCA). It is interesting and important to look into subtypes of these cancers, as the evidence is growing that there are differences in risk factors between these cancers.3–5 Case–control studies on vegetables or fruits consumption and ESCC,6–9 EAC,7, 8, 10, 11 GCA7, 8, 12 or GNCA7, 12 mostly reported inverse associations. However, case–control studies are vulnerable for biases because of their retrospective nature. This can specifically be a problem when investigating diet and gastrointestinal cancer.13 Cohort studies are less vulnerable for biases. Cohort studies that reported on ESCC have mostly found inverse associations,14–16 but some cohorts found no association with vegetables16, 17 or fruits17 consumption. For EAC,14, 18 GCA16, 18–21 and GNCA,16, 18–21 mainly null associations have been observed, except for two studies that found inverse associations for fruits consumption and GCA16 and GNCA.20

Using 3.3-22 and 6.313-year follow-up data of the Netherlands Cohort Study (NLCS) on diet and cancer, we have previously reported on the associations between vegetables and fruits consumption and risk of total gastric cancer.13 Only for Allium vegetables, separate results for GCA and GNCA were presented.22

The aim of our study was to prospectively investigate the role of vegetables and fruits consumption in the development of ESCC, EAC, GCA and GNCA. Also, we aimed to study several groups of vegetables and fruits and individual vegetable and fruit items separately, as few studies have performed such comprehensive analyses. For our study, we used 16.3-year follow-up data from the NLCS.

Material and Methods

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

Study design and participants

Our study was conducted within the prospective Netherlands Cohort Study, which started in September 1986 with the inclusion of 58,279 men and 62,573 women aged 55–69 years, who were randomly sampled from Dutch municipal registries.23 At baseline, all subjects completed a self-administered questionnaire on dietary and lifestyle habits and other cancer risk factors.

For reasons of efficiency, the case–cohort approach was used for data processing and analysis.24, 25 Cases were derived from the entire cohort, and the number of person-years at risk for the entire cohort was estimated from a subcohort of 5,000, who were randomly sampled from the total cohort at baseline. The subcohort has been followed up by contacting the participants and using data from municipal population registries.23 Person-years at risk were calculated from the start of the study until esophageal or gastric cancer diagnosis, death, emigration, loss to follow-up or end of follow-up, whichever occurred first. Only one male subcohort member was lost to follow-up after 16.3 years.

Follow-up for cancer incidence was performed by record linkage26 to the Netherlands Cancer Registry (NCR) and PALGA, the nationwide network and registry of histopathology and cytopathology in the Netherlands.27 Data of 16.3 years of follow-up (baseline to December 31, 2002) were used. The completeness of cancer follow-up is ≥96%.28 The following numbers of incident, microscopically confirmed, primary carcinomas were identified: 130 ESCC29 (ICD-O-3 C15), 181 EAC29 (C15), 206 GCA (C16.0) and 594 GNCA (C16.1-C16.9) (Fig. 1). The group of GNCA included cancers with a lesion with overlapping subsites of the stomach (C16.8, n = 160) and some gastric, not otherwise specified cancers (C16.9, n = 75), raising the possibility that some cardia cancers might be included in the noncardia category. However, as we found risk estimates to be similar in separate analyses of gastric cancers of specified sites (C16.1-C16.5) and other gastric cancers (C16.6-C16.9) (data not shown), we combined the groups in the analysis.

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Figure 1. Flow diagram of subcohort members and cases on whom the analyses were based. *PALGA: Nationwide Network and Registry of Histopathology and Cytopathology in the Netherlands; ESCC: esophageal squamous cell carcinoma; EAC: esophageal adenocarcinoma; GCA: gastric cardia adenocarcinoma; GNCA: gastric noncardia adenocarcinoma.

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We excluded subjects who reported having prevalent cancer other than skin cancer at baseline. Also, excluded were cases and subcohort members with incomplete or inconsistent dietary data.30 Figure 1 shows the selection and exclusion steps that resulted in the numbers of case subjects and subcohort members that were included in the analyses. Further details on the design of the study and methods of follow-up have been published previously.23, 26 The Medical Ethics Committee of Maastricht University, The Netherlands, has approved the study.

Questionnaire data

The self-administered questionnaire included a 150-item Food Frequency Questionnaire (FFQ). The FFQ concentrated on the habitual consumption of foods and beverages during the year preceding the start of the study.

With regard to vegetables consumption, subjects were asked to report their frequency of consumption of a number of vegetables (listed in Table 2), both in summer and in winter. They could choose one of six categories, ranging from “never or less than 1× per month” to “3–7× per week.” Subjects were asked about usual serving sizes only for string beans and cooked endive; the mean of these values served as an indicator to derive the serving sizes of all cooked vegetables, according to a vegetable-specific algorithm based on results of a pilot study. For onions and tomatoes, participants were asked to report their consumption in number per week; for sweet peppers per month and for mushrooms the number of 250-g boxes per month. Subjects with inconsistent vegetable data were excluded from analysis.13, 30

With regard to fruits consumption, subjects were asked to report the frequency and amount of consumption of a number of fruits (listed in Table 2). Categories ranged from “never or less than 1× per month” to “6–7× per week.” Using household units, these frequencies and amounts have been converted to consumption in grams/day.

The choice of items in the questionnaire was such that it covered almost all vegetables and fruits eaten regularly, with the exception of chicory, red cabbage and cucumber. Furthermore, in an open-ended question, participants could fill in other foods they consumed regularly as well as the frequency and amount consumed on each occasion.

Questionnaire data were key entered and processed in a standardized manner, blinded with respect to case/subcohort status to minimize observer bias in the coding and interpretation of the data.

The FFQ was validated against a 9-day diet record.30 The Spearman correlation coefficients were 0.38 for total vegetables consumption and 0.60 for total fruits consumption. On an average, vegetables consumption appeared to be slightly overestimated and fruits consumption to be underestimated by the FFQ when compared to the diet records.

Statistical analysis

We checked for possible influence of preclinical cancer at baseline on the consumption of vegetables and fruits.13 This was done by comparing the mean consumption of vegetables and fruits for cases that were diagnosed during the first 2 years of follow-up with the mean consumption for cases diagnosed later in follow-up. An independent samples t-test was used to test for statistical significance of differences, after a square-root transformation was applied to normalize the distribution of the vegetables and fruits variables. Vegetables consumption was statistically significantly lower among early vs. late GCA (difference 43 g/day, p = 0.04) and GNCA (difference 22 g/day, p = 0.02) cases, whereas fruits consumption was lower among early vs. late ESCC cases (difference 74 g/day, p = 0.01). On the basis of these observations, we decided to exclude the first 2 years of follow-up from all analyses to prevent bias caused by reversed causation due to preclinical cancer (Fig. 1).

Analyses were performed for total vegetables consumption, cooked and raw vegetables, several vegetable subgroups and the most frequently consumed individual vegetables. Furthermore, we analyzed total fruits consumption, citrus fruits and the most frequently consumed individual fruits. The composition of each vegetable and fruit group can be found in Table A1. For categorical analyses, vegetables and fruits consumption levels were categorized into quintiles according to the distribution in the subcohort. For continuous analyses, an increment of 25 g/day was chosen.

The following confounders were included in all models because they changed the incidence rate ratios (RRs) by more than 5%: age (years), sex, cigarette smoking (current yes/no, number of cigarettes smoked daily and number of smoking years) and consumption of alcohol (g/day), red meat (g/day) and fish (g/day). The following variables were considered potential confounders but were not included in the models because they did not change the RRs by more than 5%: consumption of tea, consumption of meat products, nonoccupational physical activity, body mass index (BMI), highest educational level, family history of esophageal or gastric cancer, long-term use of nonsteroidal anti-inflammatory drugs or aspirin or lower esophageal sphincter relaxing medication.31, 32 Analyses of vegetables were adjusted for fruits consumption and vice versa. For exact model specifications, see the table footnotes.

Cox proportional hazards models were used to estimate age- and sex-adjusted and multivariable adjusted RRs and corresponding 95% confidence intervals (CIs).33 Standard errors were estimated using a robust covariance matrix estimator to account for increased variance due to sampling from the cohort.24 The proportional hazards assumption was tested using the scaled Schoenfeld residuals.34 Tests for dose-response trends were assessed by fitting ordinal exposure variables as continuous terms.

Because of the limited numbers of cases, specifically female cases, all analyses were carried out for both sexes combined. Nevertheless, analyses stratified by sex were performed for total vegetables and fruits consumption using continuous variables. We also investigated possible interaction between vegetables and fruits consumption and cigarette smoking status (current, former and never) by performing stratified analyses. p values for interaction were assessed by including a cross-product term in the models.

All analyses were done using Stata 9.2 statistical software package (StataCorp, College Station, TX). The significance level α was set at 0.05. All reported p values are two sided.

Results

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

Characteristics of the study population

Baseline characteristics of the subcohort and case groups are presented in Table 1. The most striking difference is the high percentage of men among EAC (78%) and GCA cases (85%) compared to the subcohort (49% men). Furthermore, cases were more likely current cigarette smokers than subcohort members and among ever smokers, cases smoked longer and more cigarettes than did subcohort members. Ethanol intake was also higher in all case groups than in the subcohort, particularly among ESCC cases. EAC cases had a higher BMI than the subcohort. A family history of esophageal or gastric cancer was reported by a higher percentage of ESCC, GCA and GNCA cases compared to the subcohort. Nonoccupational physical activity was especially higher among GCA cases than among subcohort members.

Table 1. Characteristics of cases and subcohort members in The Netherlands Cohort Study on Diet and Cancer (NLCS), 1986–2002
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Baseline vegetables and fruits consumption

Baseline intakes of the individual vegetables and fruits that were listed in the questionnaire are presented as Supporting Information Table 1. Because the vegetables and fruits had a right-skewed distribution, we present medians and interquartile ranges. The vegetables and fruits are ranked by increasing percentage of nonconsumers in the subcohort. The median daily consumption of the subcohort was 179 g of vegetables and 157 g of fruits. The most frequently eaten vegetables in our population were string beans, cauliflower and lettuce, whereas raw carrots, gherkins and vegetable juices were only consumed by a small number of subjects. When we look at the median daily consumption among consumers, the vegetables eaten in the largest amounts were tomatoes, onions and string beans. Apples and pears, strawberries and oranges had the highest percentage consumers. The fruits eaten in the largest amounts were apples and pears, and oranges.

Main analyses

Results of the multivariable Cox regression analyses on total vegetables and fruits and subgroups of vegetables and fruits are shown in Table 2. The results from the age- and sex-adjusted analyses are presented in Supporting Information Table 2 because of limited space. These results were comparable with the multivariable adjusted results.

Table 2. Multivariable-adjusted1 associations between vegetables and fruit consumption and risk of esophageal and gastric cancer subtypes; Netherlands Cohort Study on Diet and Cancer (NLCS( 1986–20022
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For total vegetables consumption, we observed that subjects in quintiles 2–5 had lower risks of esophageal and gastric cancers when compared to quintile 1. The clearest inverse association was observed for EAC (RR for Q5 vs. Q1: 0.59, 95% CI 0.33–1.06), whereas the association was weakest for GNCA (RR for Q5 vs. Q1: 0.90, 95% CI 0.64–1.26). RRs or trends were not statistically significant for any tumor type.

For specific groups of vegetables, we can see that the majority of the RRs observed were below unity. These inverse associations, however, mostly did not reach statistical significance. No clear associations were observed for cooked vegetables, whereas for raw vegetables we found a significant inverse trend (p = 0.05) for EAC risk (RR per 25 g/day increment: 0.80, 95% CI 0.68–0.98). Decreased risks associated with raw vegetables were also observed for ESCC and GCA, but these were not statistically significant. A quite strong, but not statistically significant, inverse association was observed between consumption of legumes and pulses and ESCC risk, whereas for GCA and GNCA these associations were weaker, and no apparent association was present for EAC. Consumption of Brassica vegetables was associated with a statistically significantly decreased risk of GCA (RR per 25 g/day: 0.72, 95% CI 0.54–0.95, p-trend = 0.01) and slightly decreased risk of EAC (RR per 25 g/day: 0.85, 95% CI 0.49–1.48), whereas Brassicas were not clearly associated with risk of ESCC or GNCA. No clear associations were seen for consumption of Allium vegetables or cooked leafy vegetables and any tumor type, whereas for raw leafy vegetables inverse associations were seen for ESCC and EAC.

Table 2 also shows the RRs for consumption of total fruits and citrus fruits. Total fruits consumption was nonsignificantly inversely associated with ESCC risk (RR for Q5 vs. Q1: 0.62, 95% CI 0.32–1.22), whereas RRs only slightly below unity were seen for EAC, GCA and GNCA. Citrus fruits were quite consistently associated with a decreased risk of all tumors: for ESCC, the RR for Q5 vs. Q1 was 0.54 (95% CI 0.27–1.07), for EAC this RR was 0.55 (95% CI 0.31–0.98), for GCA 0.38 (95% CI 0.21–0.69) and finally for GNCA this RR was 0.80 (95% CI 0.56–1.15).

In Table 3, we present multivariable adjusted results for the individual vegetable and fruit items that were most frequently consumed in our cohort. Again, the age- and sex-adjusted results can be found in the Supporting Information (i.e., Supporting Information Table 3). None of the individual vegetable or fruit items was statistically significantly associated with risk of ESCC or EAC. For GCA, we observed inverse associations for cauliflower (RR per 25 g/day increment: 0.58, 95% CI 0.35–0.96), and oranges and fresh orange juices (RR per 25 g/day: 0.86, 95% CI 0.77–0.95). Positive associations were observed for tomato consumption and GNCA risk (RR per 25 g/day: 1.13, 95% CI 1.00–1.28), for spinach consumption and GCA risk (RR per 25 g/day: 1.77, 95% CI 1.04–3.02) and for apples and pears consumption and GCA risk (RR per 25 g/day: 1.05, 95% CI 1.00–1.09).

Table 3. Multivariable adjusted1 associations between consumption of individual vegetable and fruit items and risk of esophageal and gastric cancer subtypes; Netherlands Cohort Study on Diet and Cancer (NLCS) 1986–20022
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Interaction analyses

Results of analyses stratified by sex and smoking status are presented in Table 4 (multivariable adjusted) and Supporting Information Table 4 (age- and sex-adjusted). Adjustment for confounding variables did not change the RRs.

Table 4. Multivariable-adjusted1 associations between consumption of individual vegetable and fruit items and risk of esophageal and gastric cancer subtypes, stratified by sex and cigarette smoking status; Netherlands Cohort Study on Diet and Cancer (NLCS(, 1986–20022
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Total vegetables consumption was associated with risk of ESCC only in men (RR per 25 g/day increment: 0.90, 95% CI 0.80–1.00, p-interaction = 0.04), whereas for EAC an inverse association was observed in women only (RR per 25 g/day: 0.86, 95% CI 0.75–0.97, p-interaction = 0.06). For GCA and GNCA, no clear sex differences were observed. In current cigarette smokers only, we found significant inverse associations between vegetables consumption and risk of ESCC (RR per 25 g/day: 0.90, 95% CI 0.81–0.99, p-interaction = 0.03) and EAC (RR per 25 g/day: 0.85, 95% CI 0.75–0.97, p-interaction = 0.08). We found no interaction between vegetables consumption and smoking for GCA and GNCA.

An inverse association between consumption of fruits and ESCC was present in men (RR per 25 g/day: 0.91, 95% CI 0.83–1.00), but the interaction with sex was not statistically significant (p-interaction = 0.24). For women, a positive association between fruits consumption and GCA risk was observed (RR per 25 g/day: 1.08, 95% CI 1.02–1.14, p-interaction = 0.003). No significant interactions between smoking status and fruits consumption were observed, although for ESCC, EAC and GCA the risk estimates were further below 1 for current smokers than for never and former smokers.

Discussion

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

In the Netherlands Cohort Study, we found mostly inverse associations between vegetables and fruits consumption and risk of esophageal and gastric cancer subtypes. Most RRs were not statistically significant. Overall vegetable intake was associated with a not statistically significantly decreased risk of ESCC and EAC, and overall fruits intake was associated with a not statistically significantly decreased risk of EAC. However, our extensive questions on specific vegetables and fruits allowed us to study these foods in more detail. We identified significant inverse associations for raw vegetables and EAC risk, Brassicas and GCA risk and citrus fruits and EAC and GCA risk. Associations were generally stronger inverse in current smokers, but the interaction tests were not always statistically significant.

The current evidence from case–control and cohort studies does not clearly point to any specific group of vegetables that is responsible for the observed inverse associations. For ESCC, significant inverse associations have been observed with Cruciferous vegetables in one cohort study15 and with cooked vegetables,35 raw vegetables,7, 36 tomatoes37 and spinach37 in case–control studies. The few studies on EAC found significant inverse associations with raw and cooked spinach,14 dark green vegetables,7 dark yellow vegetables7, 38 and raw vegetables.7 Only one study found significant inverse associations with GCA for dark green vegetables and beetroot.39 Beetroot, carrots, Allium vegetables,39 dark green, light green and yellow vegetables40 have shown significant inverse associations with GNCA in two studies. This diversity of vegetables, for which significant inverse association has been observed, may be due to differences in vegetable consumption habits among continents, countries and populations with respect to the amount and types eaten.

For fruit groups, the evidence is more consistent than for vegetable groups. Citrus fruits have been shown to be inversely associated with risk of ESCC,14, 35, 36 EAC,38 GCA18 and GNCA18, 39 by a considerable number of studies. Some other fruits that showed significantly lower risks were Rosaceae (apples, peaches, nectarines, plums, pears and strawberries) for ESCC,14 fruit juices for GCA and GNCA39 and apples and pears for GNCA.39

Our data suggest that for current smokers, decreased risks of EAC and ESCC associated with vegetables and fruits consumption were more apparent than for never and former smokers. This finding is consistent with three case–control studies,6, 8, 36 which found inverse associations between vegetables consumption and ESCC only6 or most strongly8, 36 in smokers. Cohort studies found no interactions for ESCC,14, 15 EAC,14 GCA19 or GNCA.19 Smoking causes oxidative stress and DNA damage in the body.41 Substances in vegetables and fruits that have anticarcinogenic properties (e.g., vitamin C, carotenoids, flavonoids and folate) could counteract these effects. Smokers could, therefore, benefit most from consuming vegetables and fruits.

Case–control studies have generally found stronger and more often statistically significant associations compared to cohort studies. An explanation may be reversed causation. Individuals who are diagnosed with gastrointestinal cancer may already have experienced intestinal complaints quite some time before the diagnosis. This may have caused them to change their dietary habits, including consumption of vegetables and fruits, leading to biased measurement of the diet as it was before the onset of the disease.13 Asking about dietary habits long before the diagnosis will not solve this problem, as reporting past diet is influenced by current diet.42 Cohort studies have fewer problems with reversed causation thanks to their prospective nature. Additionally, we minimized the influence of reversed causation on our results by excluding early cases. On the other hand, measurement of vegetables and fruits in cohort studies is not perfect either. It is very difficult for persons to accurately report their intake, specifically of vegetables. This is reflected in the relatively low correlations in validation studies.43 A consequence of these low correlations is attenuation of risk estimates. Thus, the true associations may have been stronger than we observed, strengthening our conclusion of protective effects of some vegetables and fruits on esophageal and gastric cancers. Information on tumor types was received from the cancer registries, and this may have caused misclassification, especially between EAC and GCA. The NCR collects its information actively and has access to medical files and pathology records. Cancer registry data with respect to topography and histology were reported to be of high accuracy.44 Besides the attenuation of RRs, another explanation for the nonsignificance of the results is the limited power. Even though one strength of the NLCS is its large size, the number of ESCC, EAC and GCA cases is limited because of the relative rareness of these diseases in the Netherlands. The large size of the study combined with a long follow-up did allow for separate analysis of ESCC vs. EAC and GCA vs. GNCA. A strength of our study was the ability to check for confounding by several important risk factors (see Material and Methods) and to make adjustments if necessary. One factor that we did not measure and may have confounded the associations with GNCA in particular is infection with Helicobacter pylori, which is a risk factor for GNCA and may protect against GCA. It is not clear whether adjustment for H. pylori infection would have changed our results. One study that made this adjustment45 found no effect on the estimates. Two studies did not find any interaction between vegetable and fruit intake and H. pylori infection.18, 45

In conclusion, we observed significant inverse associations between some specific vegetables and fruits and risk of ESCC, EAC, GCA and GNCA. Most other observed associations were inverse, but not statistically significant. Consumption of fruits and vegetables may specifically help protect smokers from developing ESCC, EAC and GCA.

Acknowledgements

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

The authors thank the participants of this study; the Netherlands Cancer Registry and the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA); Dr. A. Volovics and Dr. A. Kester for statistical advice; S. van de Crommert, H. Brants, J. Nelissen, C. de Zwart, M. Moll, W. van Dijk, M. Jansen and A. Pisters for assistance and H. van Montfort, T. van Moergastel, L. van den Bosch, R. Schmeitz and J. Berben for programing assistance.

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

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