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2.  Effect of mammographic breast density on breast cancer screening performance: a study in Nijmegen, The Netherlands 
STUDY OBJECTIVE: To study the implications of breast density on mammographic screening performance. DESIGN: Screening outcomes of women with dense breast patterns were compared with those of women with lucent breast patterns (dense > 25% densities, lucent < or = 25% densities); the women were screened in different periods (before/after improvement of the mammographic technique in 1982). SETTING: Nijmegen, the Netherlands, 1977-1994. PARTICIPANTS: Between 1977 and 1994, 73,525 repeat screenings were performed in 19,152 participants (aged 50-69 years) in the Nijmegen breast cancer screening programme (repeat screenings were defined as mammographic examinations that were preceded by an examination in the previous screening round). Participants were screened biennially with mammography. There were 258 screen detected and 145 interval cancers. MAIN RESULTS: Before 1982 (rounds 2-4) the predictive value of a positive screening test (PV+) was lower in women with dense breasts than in those with lucent breasts (dense 29% v lucent 52%, p = 0.003). Also, the ratio of screen detected cancers to the total number of screen detected plus interval cancers (as a proxy for sensitivity) was lower in this group (based on a one year interval: dense 63% v lucent 92%, p = 0.001 and based on a two year interval: dense 41% v lucent 68%, p = 0.002). Moreover, the survival rate was less favourable for those with dense breasts (p = 0.07). In rounds 5- 10, there were no important differences with respect to PV+ (dense 66% v lucent 62%, p = 0.57) or survival (p = 0.48). Moreover, sensitivity based on a one year interval was nearly as high in women with dense breasts as in those with lucent breasts (85% v 86%, p = 0.75). However, based on a two year interval sensitivity was lower (dense 59% v lucent 72%, p = 0.04). CONCLUSIONS: In the early screening years (rounds 2-4) high breast density had an unfavourable effect on screening performance. Nowadays, the situation has improved with respect to PV+, survival and detecting tumours in dense breasts with a lead time of up to one year, but little improvement has occurred in the detection of tumours with a lead time greater than one year.
 
PMCID: PMC1756693  PMID: 9616416
3.  Interval cancers in the Dutch breast cancer screening programme 
British Journal of Cancer  1999;81(5):912-917.
The nationwide breast cancer screening programme in The Netherlands for women aged 50–69 started in 1989. In our study we assessed the occurrence and stage distribution of interval cancers in women screened during 1990–1993. Records of 0.84 million screened women were linked to the regional cancer registries yielding a follow-up of at least 2.5 years. Age-adjusted incidence rates and relative (proportionate) incidences per tumour size including ductal carcinoma in-situ were calculated for screen-detected and interval cancers, and cancers in not (yet) screened women, comparing them with published data from the UK regions North West and East Anglia. In total 1527 interval cancers were identified: 0.95 and 0.99 per 1000 woman-years of follow-up in the 2-year interval after initial and subsequent screens respectively. In the first year after initial screening interval cancers amounted to 27% (26% after subsequent screens) of underlying incidence, and in the second year to 52% (55%). Generally, interval cancers had a more favourable tumour size distribution than breast cancer in not (yet) screened women. The Dutch programme detected relatively less (favourable) invasive cancers in initial screens than the UK programme, whereas the number of interval cancers confirms UK findings. Measures should be considered to improve the detection of small invasive cancers and to reduce false-negative rates, even if this will lead to increasing referral rates. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690786
PMCID: PMC2374303  PMID: 10555768
breast cancer; interval cancer; proportionate incidence; population-based screening; evaluation
4.  Long term breast cancer screening in Nijmegen, The Netherlands: the nine rounds from 1975-92. 
STUDY OBJECTIVE: To assess the performance of breast cancer screening in different age categories over two decades. DESIGN: Important determinants of reduced breast cancer mortality such as attendance, mammography performance, cancer detection, and disease stage were recorded. SETTING: Nijmegen, The Netherlands, 1975-92. SUBJECTS: Since 1975 more than 40,000 women aged 35 years and older have been invited biennially for breast screening in a population based project in Nijmegen. MAIN RESULTS: Rates of attendance, referral, detection, and disease stage were calculated, as well as the specificity of screening mammography and the predictive value of referral and biopsy. From round 3 onwards, the attendance rate of women younger than 50 years stabilised at 70%, in women of 50-69 years it was 62%, and in women aged 70 and over it was 22%. In these three age categories, the referral rates of a positive screening mammography per 1000 screened women were 4.9, 6.2, and 11.8, respectively. Specificity rates were between 99% and 100%. Current predictive values of referral were high: in the specific age categories 39%, 59%, and 68% of the referred women had cancer. Detection rates remained fairly stable over the rounds 4-9, at 1.9, 3.6, and 8.0 cancers per 1000 screened women. In the two year period between screening the numbers of interval cancers per 1000 screened women were 2.2, 2.2, and 2.9, for the three age categories respectively. With regard to invasive cancers detected during screening, the percentage of small tumours (< or = 20 mm on the mammogram) was 84% in each age category. For women younger than 50 years, the proportion of intraductal carcinoma in all the cancers detected at screening was 40%, while it was 15% in the other age categories. CONCLUSION: Throughout the nine rounds, the screening outcomes were found to be adequate, particularly considering the high specificity rate and the predictive value of referral without the interference of a low detection rate. Although the occurrence of interval cancers seemed high, it was similar to other screening programmes. Despite a relatively low referral rate, the ratios of screen detected versus interval cancer cases were favourable. Well organised screening programmes can achieve good mammography results without too many false positives. It is important that women continue to participate in a screening programme because cancer can still be detected even after several successive negative screening examinations.
PMCID: PMC1060295  PMID: 8935470
5.  A proposal for short-term quality control in breast cancer screening. 
British Journal of Cancer  1991;63(2):261-264.
Current proposals for a monitoring and evaluation system in breast cancer screening programmes focus on mortality reduction. Here emphasis is laid on the prevention of too high a number of false-positive screening results, i.e. no subsequent demonstration of malignancy. By comparing the specificity of the screening test, the positive predictive value and the detection rate with reference values, the screening performance can be measured in a very early phase of the programme, even before the registration results on interval cancers become available. The proposed average reference values for the first screening round are 99.2%, 40% and 5.4/1000, respectively. Measures specifically for the age groups 45-49, 50-59 and 60-69 will be given, thus allowing improvements to be made if necessary.
PMCID: PMC1971772  PMID: 1997104
6.  The occurrence of interval cancers in the Nijmegen screening programme. 
British Journal of Cancer  1989;59(6):929-932.
Since January 1975 a population-based screening programme for the early detection of breast cancer has been carried out in the city of Nijmegen. During five interscreening periods of 2 years each a total of 158 so-called interval cancers were diagnosed. Careful revision of all screening and diagnostic mammograms was executed. Of all interval cancers 26% were 'missed' at the previous screening examination (due to technical or observer error), 16% were radiographically occult at the time of diagnosis and 58% were 'true' interval cancers. Interval cancers were regarded as 'true' when an obvious lesion was observed on the diagnostic mammogram while no suspect signs were seen on the previous screening mammogram. The prevalence of 'missed' cancers did not decline in the course of the screening programme. Radiographically occult tumours were localised, mostly in Wolfe's P2/DY breast parenchyma (83%), 33% were lobular invasive and 25% ductal non-invasive. 'True' interval cancer cases (58%) showed the same overall survival as control breast cancer patients, diagnosed in a non-screening situation. Shortening the screening interval would reduce interval cancer rates and probably further decrease breast cancer mortality in a screened population. However, from the present series of interval cancers 63% would not have been prevented by an annual screening examination. As regards women under age 50 annual screening would still leave 66% of all interval cancers in this age group undetected. Probably more benefit will be gained by searching for new imaging techniques to reduce numbers of 'missed' cancers and to detect lobular invasive and ductal non-invasive cancers in dense breast parenchyma.
PMCID: PMC2246722  PMID: 2736229
8.  The predictive value of positive test results in screening for breast cancer by mammography in the Nijmegen programme. 
British Journal of Cancer  1987;56(5):667-671.
After 10 years of screening for breast cancer by mammography in Nijmegen, the predictive value of positive screening results (PV+) was evaluated. The percentage of women with breast cancer in the group of referred women (PV+) for women under age 50 was 16-26%, regardless of the number of screening examinations they had. The percentage of women with breast cancer in the group of women who were biopsied was 25-40%, regardless of the number of examinations. For women aged 50 and over the predictive value was 34-57% and 58-90% respectively. It was further evaluated whether characteristics such as age, Quetelet index, parity, and Wolfe-classification could be used to increase the PV+ in women who were identified as positive by mammography. A logistic regression model analysis showed that true-positive and false-positive cases differ significantly only in terms of age and breast complaints. Although the model had a good fit, it could not be used to distinguish false-positive from true-positive test results.
PMCID: PMC2001909  PMID: 3426934
9.  Children on hunger strike: child abuse or legitimate protest? 
BMJ : British Medical Journal  1996;312(7029):501-504.
The issue of children on hunger strike (voluntary total fasting) has not been reported before. The World Medical Association Declaration of Tokyo 1975 and the Declaration of Malta 1991 (revised 1992) provide clinicians with guidelines for the management of adult patients on hunger strike but do not mention children. We report the management of 14 Vietnamese children, aged 1 to 12 years, who took part in a hunger strike at a refugee detention centre in Hong Kong.
PMCID: PMC2349980  PMID: 8597690
10.  Prognosis of younger and older patients with early breast cancer. 
British Journal of Cancer  1996;73(3):382-385.
The use of mammography in recent years has resulted in an increase in the detection of small breast cancers. The beneficial effects of early detection on breast cancer mortality seem to differ with age. To obtain more insight into this matter we studied the long-term prognosis of patients with early invasive breast cancers (T1) in three age groups: 144 patients of age 40-49, 402 patients of age 50-69 and 192 patients 70 years or older at diagnosis. In all age groups, patients with a tumour of 1 cm or less have a longer breast cancer specific survival than patients with a tumour larger than 2 cm. The survival advantage in the case of tumours of a size rounded to 1.5 cm compared with tumours larger than 2 cm in the under age 50 group was marginal (and not significant). However, older patients with tumours of this size do have a significantly improved survival. It is more difficult to improve survival in younger patients through early detection, partly because of an apparent early metastatic potential of their tumours. A reduction in breast cancer mortality might be expected in women younger than 50 years of age only if a substantial proportion of the invasive cancers are detected before their size exceeds 1 cm.
PMCID: PMC2074432  PMID: 8562346
11.  Identification of F11 fimbriae on chicken Escherichia coli strains. 
Infection and Immunity  1993;61(3):800-806.
Fimbriae were purified from Escherichia coli strains isolated from chickens with septicemia or colibacillosis. When grown on solid media, these strains expressed fimbriae with an apparent subunit molecular mass of 18 kDa. Morphological, biochemical, serological, functional, and molecular characterization revealed that these 18-kDa fimbriae are identical to F11 fimbriae, which were previously found to be involved in the pathogenesis of human urinary tract infection. Screening of a large strain collection showed that 78% of chicken E. coli strains expressed F11 fimbriae, whereas this percentage increased to 96% when the only strains taken into account were those with the serotypes most commonly encountered in avian colibacillosis (O1:K1, O2:K1, O35, and O78:K80). The prevalence of F11 fimbrial expression appeared to be independent of the country of isolation of the strains, except for the United States, where the prevalence seemed higher. Expression of F11 fimbriae by chicken E. coli strains could not be correlated with adherence to chicken tracheal or pharyngeal cells.
Images
PMCID: PMC302804  PMID: 8094382
12.  ABC of sleep disorders. Sleep disorders in children. 
BMJ : British Medical Journal  1993;306(6878):640-643.
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PMCID: PMC1676915  PMID: 8461819

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