Petronella G. M. Peer

Age-dependent growth rate of primary breast cancer

Background. Currently, there have been no reports of clear‐cut beneficial effects of regular screening with mammography at a mean screening interval of 2 years in women younger than 50 years of age. It may be that, because of a higher growth rate of breast cancer, more frequent screening is necessary if any effect is to be observed in this age group. However, good quantitative estimates for the growth rate in different age groups are lacking.

Assessment of myocardial velocities in healthy children using tissue Doppler imaging

The objective was to determine the normal range of tissue velocities in paediatric hearts as measured by tissue Doppler imaging. A prospective study was carried out involving 160 healthy children (mean age 10.8 y, range 4.0-17.9 y). Using tissue Doppler imaging (TDI) from parasternal long axis and apical views, peak velocities and peak myocardial velocity differences across the right ventricular anterior wall, interventricular septum and left ventricular posterior wall were assessed during systole, early and late diastole. The existence of transmyocardial velocity differences between the left and right side of the interventricular septum, as well as between the endocardium and epicardium of the left ventricular posterior wall was observed throughout the heart cycle. With range-gated TDI from apical four-chamber view, peak velocities were measured within the basal, mid and apical parts of the interventricular septum, and the left and right free ventricular walls. The highest peak systolic, early and late diastolic velocities were measured within the basal parts of all myocardial walls. The ranges of the calculated velocity ratios (early-to-late diastolic velocity and early diastolic-to-systolic velocity) for the various wall parts appeared to be overlapping. The correlations of peak myocardial tissue velocities and their ratios with age and weight were weak and practically irrelevant. These normal values of peak myocardial velocities, transmyocardial velocity differences and the ratios of peak wall velocities can be used as reference values in future investigations of ventricular dysfunction in this age group.

Age specific sensitivities of mammographic screening for breast cancer

SummaryThe sensitivity of the mammographic screening test in the biennial screening program of Nijmegen is assessed by analyzing the occurrence of interval cancers, i.e. cancers surfacing clinically in the interval between a negative screening examination and the subsequent scheduled examination. The difference between the observed number of interval cancers and the expected number of clinically manifest cancers in the absence of screening for the interval period reflects the number of cancers detected by screening. The expected number should be limited by the number of those cancers that were not detectable at the time of the screening examination because their size was under the threshold of mammographic detectability (5 mm). In contrast to other sensitivity studies we took these ‘fast growing’ cancers into consideration, the numbers of which are estimated in each of the six-month periods of the two-year interval using age-specific tumor volume growth rates for three age groups: < 50, 50–69, and ≥ 70 years. In patients under age 50, the sensitivity was 64% for cancers which would become clinically manifest within one year after screening. This sensitivity was lower than those obtained from the 50–69 and ≥ 70 age groups, being 85% and 80%, respectively. For cancers that would become clinically manifest 12–18 months after screening, sensitivity decreases to 22% in the under age 50 group, and to 56% and 65% in the two above age 50 groups, respectively. We conclude that even when adjusted for growth rate, the mammographic screening test has a poor performance in the under age 50 group.

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.

The effectiveness of cervical screening: A population-based case-control study

The cervical smear histories of 36 women with invasive cervical cancer were compared to those of 120 age-matched controls, drawn from local registrars offices. Of the cases 47% were screened at least once, while for the controls this figure was 68%. The relative risk of getting invasive cervical cancer for women screened at least once compared to women who were never screened was 0.32. The most important confounding factor was age at first intercourse. Contrary to other studies however, it was found that women who were younger when having first intercourse were screened more often. After correcting the relative risk of screened vs unscreened for age at first intercourse, the relative risk became 0.22. When the length of the interval since the last smear was considered, the relative risk was 0.18 when the smear was made between 2 and 5 years earlier and 0.30 when this smear was made more than 5 years earlier. These results support the assumption that screening is effective in the prevention of invasive cancer of the uterine cervix. Even a screening interval of more than 5 years provides considerable protection.

Meta-analysis of predictive factors for non-sentinel lymph node metastases in breast cancer patients with a positive SLN

AIMS A meta-analysis was performed to identify the clinicopathological variables most predictive of non-sentinel node (NSN) metastases when the sentinel node is positive. METHODS A Medline search was conducted that ultimately identified 56 candidate studies. Original data were abstracted from each study and used to calculate odds ratios. The random-effects model was used to combine odds ratios to determine the strength of the associations. FINDINGS The 8 individual characteristics found to be significantly associated with the highest likelihood (odds ratio >2) of NSN metastases are SLN metastases >2mm in size, extracapsular extension in the SLN, >1 positive SLN, ≤1 negative SLN, tumour size >2cm, ratio of positive sentinel nodes >50% and lymphovascular invasion in the primary tumour. The histological method of detection, which is associated with the size of metastases, had a correspondingly high odds ratio. CONCLUSIONS We identified 8 factors predictive of NSN metastases that should be recorded and evaluated routinely in SLN databases. These factors should be included in a predictive model that is generally applicable among different populations.

Estimating lead time and sensitivity in a screening program without estimating the incidence in the screened group

Early indicators of the effectiveness of a screening test for chronic diseases such as breast cancer are the length of time the diagnosis is advanced by screening, the lead time, and the sensitivity of the screening test. This paper describes a model for simultaneously estimating the mean lead time and the sensitivity when only the number of cancers detected at the successive screenings and the number of cancers occurring in the time interval between the screening examinations are known. This model is particularly useful in assessing the effect of screening when the underlying cancer incidence in the screened group is unknown. The model is fitted to the data of 235 screen-detected breast cancer cases and 146 interval cancers diagnosed across 6 screening rounds of the program in Nijmegen. The maximum likelihood estimate for the mean lead time ranges from 1.3 years in the under age 50 group to 2.2 years in the age 50-65 group, both estimates having large confidence intervals. The corresponding sensitivity estimates are 0.92 and 1.00.

Continuation and maintenance therapy with antidepressive agents. Meta-analysis of research.

The purpose of this study was to ascertain the clinical benefits of long-term antidepressant drug treatment in patients with recurrent major depression. Bibliographic reviews of four textbooks and five review articles, literature searches using MEDLINE (1977–1987) and EXCERPTA MEDICA (1974–1987), hand-searching of the bibliographies of identified papers, and a private set were used for data identification. The most informative, definite research report was selected using explicit criteria for evaluating study design and quality, of each described, randomized, controlled, double-blind trial of long-term antidepressant agent treatment. The trials were started at a specified period after recovery from an affective episode, in patients with major depression. Of the fifty-five originally identified articles, nine were selected that specifically addressed this purpose. The basic data were extracted in the form of 2 x 2 tables comparing the number of patients with an affective relapse to those remaining well and meta-analysed. Six of the selected trials addressed continuation and three addressed maintenance therapy. In two trials of continuation and in one trial of maintenance treatment, antidepressants were significantly more active than a placebo. In none of the trials were antidepressants inferior to a placebo. Continuation therapy with antidepressants (amitriptyline and imipramine) is effective. There are insufficient data to allow any conclusions about the efficacy of maintenance therapy with antidepressants, long-term treatment with antidepressants relative to that with lithium carbonate, or long-term antidepressant treatment in patients with chronic depression.

Prognosis of younger and older patients with early breast cancer

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.

Diverging breast cancer mortality rates in relation to screening? A comparison of Nijmegen to Arnhem and the Netherlands, 1969–1997

Age‐standardised breast cancer mortality rates have been stable for decades. However, rates have started to decline in several Western countries. In countries where population‐based screening programmes for breast cancer were introduced in the late 1980s or early 1990s, the key question now is to what extent screening is responsible for the reported declines in mortality. This study compares breast cancer mortality rates in Nijmegen, where a screening programme for breast cancer was introduced in 1975, to a control city, Arnhem, and to the Netherlands as a whole over a 20‐year period. Age‐standardised breast cancer mortality rates as well as age‐standardised mortality ratios were calculated for successive calendar years from 1969 to 1997. Further, a tailor‐made period‐cohort‐group Poisson regression model was fitted. Figures displaying age‐standardised mortality rates and ratios showed inconclusive patterns with regard to the expected impact of screening. Depending on when mortality rates were allowed to deviate between populations, the period‐cohort‐group analysis indicated a non‐significant 6% to 16% reduction in breast cancer mortality after 2 decades in favour of the Nijmegen female population. Possible explanations are discussed as to why the mortality reductions reported by randomised trials might not be observed in a public health screening programme, such as the Nijmegen programme, evaluated by comparisons of geographical trends.