In primary breast cancer the mitotic activity yields similar prognostic information as the histological grade: a study with long-term follow-up.

We evaluated with long-term follow-up, the prognostic value of the mitotic activity index (MAI) and the volume corrected mitotic index (M/V-index) compared with that of the histological grade in breast cancer patients not treated with adjuvant systemic therapy. Of 739 consecutive patients living in the city of Nijmegen, the Netherlands, 477 patients with primary unilateral breast cancer were not treated with adjuvant systemic therapy and eligible for the study. In multivariate survival analyses the MAI and M/V-index showed similar hazard ratios (HRs) compared to HRs of histological grade for overall survival (OS) (HR: 1.45, 1.48, and grade II versus grade I (GII/GI) 1.34, grade III versus grade I (GIII/GI) 1.53, respectively) and for breast cancer specific survival (BCSS) (HR: 1.27, 1.57, and (GII/GI) 1.57 (GIII/GI) 2.32, respectively). Other independent prognostic variables for OS and BCSS were age at diagnosis, tumour size, and number of positive lymph nodes. In the present study with long term follow-up, we compared the prognostic value of mitotic activity with that of histological grade and found no advantage for the mitotic activity in predicting either BCSS or OS and concluded that histological grade and the mitotic activity were equally informative in predicting patient outcome. As histological grade is a well established and widely used prognosticator we do not have arguments to replace the histological grade by the mitotic indices MAI or M/V-index.

Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines.

Identification of genetic copy number changes in glial tumors is of importance in the context of improved/refined diagnostic, prognostic procedures and therapeutic decision-making. In order to detect recurrent genomic copy number changes that might play a role in glioma pathogenesis and/or progression, we characterized 25 primary glioma cell lines including 15 non glioblastoma (non GBM) (I-III WHO grade) and 10 GBM (IV WHO grade), by array comparative genomic hybridization, using a DNA microarray comprising approx. 3500 BACs covering the entire genome with a 1 Mb resolution and additional 800 BACs covering chromosome 19 at tiling path resolution. Combined evaluation by single clone and whole chromosome analysis plus 'moving average (MA) approach' enabled us to confirm most of the genetic abnormalities previously identified to be associated with glioma progression, including +1q32, +7, -10, -22q, PTEN and p16 loss, and to disclose new small genomic regions, some correlating with grade malignancy. Grade I-III gliomas exclusively showed losses at 3p26 (53%), 4q13-21 (33%) and 7p15-p21 (26%), whereas only GBMs exhibited 4p16.1 losses (40%). Other recurrent imbalances, such as losses at 4p15, 5q22-q23, 6p23-25, 12p13 and gains at 11p11-q13, were shared by different glioma grades. Three intervals with peak of loss could be further refined for chromosome 10 by our MA approach. Data analysis of full-coverage chromosome 19 highlighted two main regions of copy number gain, never described before in gliomas, at 19p13.11 and 19q13.13-13.2. The well-known 19q13.3 loss of heterozygosity area in gliomas was not frequently affected in our cell lines. Genomic hotspot detection facilitated the identification of small intervals resulting in positional candidate genes such as PRDM2 (1p36.21), LRP1B (2q22.3), ADARB2 (10p15.3), BCCIP (10q26.2) and ING1 (13q34) for losses and ECT2 (3q26.3), MDK, DDB2, IG20 (11p11.2) for gains. These data increase our current knowledge about cryptic genetic changes in gliomas and may facilitate the further identification of novel genetic elements, which may provide us with molecular tools for the improved diagnostics and therapeutic decision-making in these tumors.

Trends in mortality from malignant cutaneous melanoma in The Netherlands, 1950-1988.

This paper presents an analysis of trends in mortality from malignant melanoma of the skin in The Netherlands, 1950-1988. Statistical analyses show that time period effects are needed to describe the mortality trends in The Netherlands. Because this contrasts with reports from other countries, in which the trends were ascribed to a cohort effect only, log-linear models including the three factors age, time period and birth cohort, were fitted to the data. To be able to separate time period effects from birth cohort effects we assumed a mathematical function for the mortality rates in relation to age. The results obtained in this way indicate that time period effects increased up to 1970. An increase of birth cohort effects is seen for cohorts born between 1900 and 1955. For cohorts born after 1955 the mortality from melanoma seems to decrease. The most plausible explanation for the time period effect probably is improvement in death certification.

Evaluation of treatment regimens to cure Helicobacter pylori infection--a meta-analysis.

OBJECTIVE: To assess effectiveness of treatment to cure Helicobacter pylori infection. DATA SYNTHESIS: Meta-analysis of 666 manuscripts (full papers, abstracts, letters to the editor) identified through Medline and a manual search (1986 to January 1998). Data were overviewed by regression analysis with weighted random effects models. SUBJECTS: 53 228 patients with H. pylori infection. INTERVENTIONS: Patients were treated with 132 different medication combinations. MAIN OUTCOME MEASURE: Cure of H. pylori infection per protocol and intention-to-treat basis at least 28 days after treatment. RESULTS: The nationality of the patients and therapeutic regimen have a significant impact on the results, after correction for the heterogeneity in the precision of the cure rate caused by different study sizes and random effect for study. On the basis of the original sample size, cure rates of 80-85% were achieved using combinations of a proton-pump inhibitor or ranitidine bismuth citrate with two antibiotics including clarithromycin, amoxycillin and metronidazole or tinidazole. Comparable cure rates were also achieved using a combination of a proton-pump inhibitor or H2-receptor antagonist with bismuth subcitrate or tripotassium dicitrato bismuthate, metronidazole and tetracycline. The dose of clarithromycin influenced cure rates. Treatment duration did not influence the outcome. CONCLUSION: Several therapeutic regimens are eligible to cure H. pylori infection. However, none of the medication combinations were able to cure H. pylori infection in more than 85% of the patients assessed by intention-to-treat. The countries in which the studies were performed also had a significant impact on eradication rates.

Shortcut method to calculate the sample size in trials of screening for chronic disease.

One of the first questions arising in the planning of a randomized trial to evaluate mortality reduction by screening concerns the sample size of the trial required to detect an expected mortality reduction in the study group for given significance level alpha, and power 1 - beta. If estimates exist of the underlying average annual incidence rate of the disease ra and the annual mortality rate delta a or survival data for patients in the population under consideration before screening started, then a simple formula for the probability of dying from the disease within T years after entry into the trial can be given for the control group. Standard formulas may then be used for sample size calculations in randomized trials, which compare the risk of death from the disease in the control and the study group accrued at T years after entry. A simple correction for loss of follow-up, due to mortality from other causes or, for instance, migration is possible.

Generalizability of trial results based on randomized versus nonrandomized allocation of OME infants to ventilation tubes or watchful waiting.

The objective was to study the generalizability of trial results by comparing randomized patients to eligible but nonrandomized patients who received the same management. Implementation of trial results is only justifiable when the results can be generalized to the total domain population. The design was a multicentre randomized controlled trial on the effect of early screening and treatment with ventilation tubes on infants with otitis media with effusion. Randomized (n = 187) and nonrandomized eligible patients (n = 133) were followed up. The study population comprised children who were detected by auditory screening at the age of 9-12 months and who were subsequently diagnosed with persistent bilateral otitis media with effusion for 4-6 months. A significant difference was found in the distribution of some prognostic factors: more randomized children had older siblings, did not attend day care and had mothers with a lower educational level than the nonrandomized children. These factors, however, did not modify the outcome. No differences were found in mean hearing levels between the randomized and nonrandomized children: in both the randomized and nonrandomized children ventilation tubes improved the hearing level, especially after 6 months. However, in the long term (12 months), the hearing levels were equal again. The results of the randomized and nonrandomized patients were comparable. The results of this trial appear to be generalizable to the total domain population. The procedure of following up both randomized and nonrandomized patients is recommended when there is concern about selective participation and reduced generalizability.

Mortality trend from cancer of the gastric cardia in The Netherlands, 1969-1994.

BACKGROUND: Time trends of cancer of the gastric cardia differ between populations and the reasons are not fully understood. The object of this study was to investigate the occurrence of cancer of the gastric cardia in descriptive relation to age at death, calendar period, birth cohort and gender in the Netherlands between 1969 and 1994. METHODS: Data on the number of people with cancer of the gastric cardia as the underlying cause of death from 1969 to 1994 were obtained from annual publications by the National Causes of Death Registry of Statistics Netherlands. To estimate the separate effects of age, calendar period and birth cohort on the trend in mortality, a simultaneous analysis of these factors was performed using a log-linear Poisson model. RESULTS: In 1969, the mortality rates from cancer of the gastric cardia for males and females per 100,000 people were 2.1 and 1.1; in 1994 the mortality rates were 1.5 and 0.7, respectively. Examination of the time trend suggested that mortality for cancer of the gastric cardia may reflect a period phenomenon, although a cohort effect may have also contributed to the observed time trend. Furthermore, more males than females died from cancer of the gastric cardia. The difference was most striking in the younger age categories. CONCLUSION: In this Dutch population, the age-period-cohort-gender analysis indicated that the mortality rates decreased after the period 1975-1979 which might be explained by a decrease in exposure to risk factor(s) or an increase in exposure to protective factor(s).

Increased risk of fatal prostate cancer may explain the rise in mortality in The Netherlands.

BACKGROUND: Several lines of evidence suggest that, as a result of improved diagnostic techniques, the increase in incidence of prostate cancer is due largely to increased detection of subclinical cases. Between 1971 and 1989, a considerable increase in incidence was found in Southeastern Netherlands among men aged under 60 years without an improvement in prognosis. We hypothesized that in addition to the increase due to increased detection, a genuine increase in incidence has occurred in the last two decades and that this should be reflected in national mortality rates. METHODS: Age-specific and age-adjusted mortality rates were calculated to determine whether mortality due to prostate cancer continued to increase after 1990. Using log-linear Poisson modelling according to Clayton and Schifflers, we estimated the contribution of period and cohort effects to prostate cancer mortality between 1955 and 1994. RESULTS: The age-adjusted mortality increased from 22 in 1955-1959 to 33 per 10(5) in 1990-1994 (European standardized rate). For men under 65, the rates stabilized after 1989. The age-cohort model fitted the data better than the age-period model. Therefore, the increase in mortality can be explained largely by the increasing risk for successive birth cohorts for men born until 1930. However, more frequent reporting of prostate cancer as the underlying cause of death (partly attributable to a decline in competing causes of death) may have occurred as well. CONCLUSIONS: Our findings suggest an increased risk of fatal prostate cancer in The Netherlands between 1955 and 1994.

The capture-recapture method for estimation of cancer registry completeness: a useful tool?

BACKGROUND: In this paper we investigated whether the capture-recapture method is useful for a cancer registry to monitor its completeness of case ascertainment on a routine basis. METHODS: The capture-recapture method was used to estimate the completeness of case ascertainment in three regional cancer registries in the Netherlands, which are based on case finding by pathology laboratories and hospitals. RESULTS: Completeness was estimated to be 98.3%. The estimate of completeness was dependent on age and cancer site, with lower estimates of completeness for skin cancer and lymphatic and haematopoietic malignancies and for the age group > or = 75 years. CONCLUSIONS: A major drawback of the capture-recapture method is its inability to estimate the number of cases that are not routinely notified to the registry by one or both notification sources. Another limitation is the lack of statistical power to detect incompleteness in an early stage. It is concluded that the capture-recapture method is not useful for everyday surveillance of completeness in cancer registration.

Analysis and presentation of data on the natural course of otitis media with effusion in children.

Methods of analysing and presenting longitudinal data on health characteristics that have a fluctuating course are by no means standard. Several possibilities are discussed and tried out on longitudinal data on Otitis Media with Effusion (OME) in Dutch children. If the purpose of a study is descriptive, a graphical presentation based on an idea from Fiellau-Nikolajsen is preferred. For estimation purposes on the other hand, hazard functions are the most suitable. Further reduction of the data does not lead to a clear view into the complex nature of the course of a disease such as OME.

Evaluation of overdiagnosis of breast cancer in screening with mammography: results of the Nijmegen programme.

After 12 years of screening for breast cancer in Nijmegen (1975-86), during which period six mammographic examination rounds were carried out, the extent of overdiagnosis was evaluated. Overdiagnosis is defined as a histologically established diagnosis of invasive or intraductal breast cancer that would never have developed into a clinically manifest tumour during the patient's normal life expectancy if no screening examination had been carried out. The whole 12-year period shows an excess of 11% of breast cancer cases in Nijmegen, compared with the neighbouring city of Arnhem, where no mass screening was performed. The incidence of breast cancers in Nijmegen in the period 1975-78 is higher, compared with the incidence rates in Arnhem; the rate ratio is 1.30. For the time-intervals 1979-82 and 1983-86 the rate ratios are 1.03 and 1.01 respectively with (0.89; 1.18) and (0.86; 1.16) as 95% confidence intervals. This leads to the conclusion that there is no evidence that screening programmes using modern mammography constitute a significant risk for overdiagnosis of breast cancers.

Excess seasonality of births among patients with schizophrenia and seasonal ovopathy.

In this study we examined whether the well-known winter excess of schizophrenic births exists among Dutch schizophrenia patients when statistical artifacts such as the age-incidence and age-prevalence effects are avoided and, if so, whether the seasonal preovulatory release of overripe ovum (SPrOO) hypothesis, that is, seasonally bound ovopathy, might be an explanation for this excess. We analyzed the month-of-birth distribution of 1,037 Dutch schizophrenia patients born between 1962 and 1966 and first admitted to a psychiatric hospital between 1978 and 1990 by the so-called window analysis to avoid the artifacts mentioned. The results show a winter excess of births among Dutch schizophrenia patients, even when statistical artifacts are avoided, and that the SPrOO hypothesis might be an explanation for this excess. Further research is needed to support the hypothesis that ovopathy, either seasonally bound or not, could be involved in the etiology of schizophrenia.

Changes in mammographic breast density and concomitant changes in breast cancer risk.

Among participants of the biennial Nijmegen breast cancer screening programme, we examined whether diminution of mammographic breast density lowered breast cancer risk. Post-menopausal breast cancer cases (n = 108), who had to have participated in all the five screening rounds prior to their diagnosis, were matched to 400 controls on year of birth and screening history. Controls had to be free of breast cancer at the time of the case's diagnosis. Changes in breast density were measured over a 10-year period, by a fully computerized method. Women in whom 5-25% or >25% of the breast was composed of fibro-glandular density showed a threefold increased 10-year risk compared to women with <5% density. In women with 5-25% density initially, we observed a trend of decreasing risk with diminishing density: when women with <5% density throughout the whole period formed the reference category, the odds ratio (OR) for those who decreased from 5-25% to <5% density was 1.9 [95% confidence interval (CI) = 0.6-6.1] in contrast to the OR of 5.7 (95% CI = 2.2-15.2) for those with persisting 5-25% density. In women who increased from 5-25% density to >25% density the OR was 6.9 (95% CI = 2.1-22.9). In women with >25% density initially, diminishing density was not clearly associated with lowering risk, which may be partly explained by the low number of women who decreased to <5% (n = 12). Due to the limited size of the study these results have to be interpreted with caution. Although the results are not conclusive, they could indicate a trend of decreasing risk with diminishing breast density. Should this effect be real, it may have great implications for the primary prevention of breast cancer or for the identification of high-risk groups who would benefit by more frequent screening. Therefore, large-scale, long-term follow-up studies on the effects of changes in breast density are needed.

Studying seasonality by using sine and cosine functions in regression analysis.

STUDY OBJECTIVE: A statistical test that allows for adjustment of confounding can be helpful for the study of seasonal patterns. The aim of this article is to supply a detailed description of such a method. An example of its application is given. DESIGN: A statistical test is presented that retains the information on the connection of time periods by describing the seasonal pattern as one sine and one cosine function. Such functions can be included into a regression model. The resulting form of the seasonal pattern follows a cosine function with variable amplitude and shift. MAIN RESULTS: The test is shown to be applicable to test for seasonality. Not only one cosine function per time period, but also a mixture of cosine functions can be used to describe the seasonal pattern. Adjustment for confounding effects is possible. CONCLUSIONS: This method for studying seasonal patterns can be applied easily in a regression model. Adjusted prevalences and odds ratios can be calculated.

Cancer incidence: life table risk versus cumulative risk.

STUDY OBJECTIVE: To study differences between various methods of estimating cancer risk in individuals. DESIGN: Information was obtained from a cancer registry. Lifetime risk was calculated using the life table method, taking competing causes of death into account and using well recognised methods such as the cumulative rate and risk. SETTING: Regional cancer registry of the Comprehensive Cancer Centre IKL, located in Maastricht, The Netherlands. PATIENTS: Patients with a first primary malignancy in 1989-90 in the catchment area of the cancer registry. MAIN RESULTS: The lifetime risk of developing cancer was estimated to be 34.8% for males and 30.4% for females. In males, especially, the risk estimates were considerably higher when the cumulative risk was used. CONCLUSIONS: The life table method is convenient for estimating the probability that a person will develop cancer during a defined period or during his or her lifetime. The other estimates overestimate the risk of the disease under investigation, especially in the very elderly.

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.

Efficacy of hydroquinine in preventing frequent ordinary muscle cramp outlasts actual administration.

In order to compare the efficacy of a daily dose of 300 mg hydroquinine hydrobromide and placebo in preventing frequent ordinary muscle cramp, we designed a randomized, double-blind, placebo-controlled study of three consecutive 2-week periods viz. a qualification period, a medication period and a wash-out period. Twenty healthy adult volunteers experiencing at least 3 muscle cramps a week (6 men, 14 women aged 38-78 yrs) were enrolled into this study, and 19 of them completed it. Hydroquinine hydrobromide (300 mg/day) was administered to group 1 (10 women) and placebo to group 2 (4 women, 6 men). The frequency, severity, duration and location of muscle cramps as well as short-term adverse drug effects were recorded in daily diaries. Compared with placebo the decrease in the mean number of muscle cramps (16.1 or 58%) in the active drug treatment group during the medication period was highly significant (Wilcoxon test p = 0.004). During the wash-out period this decrease partly persisted (8.9 or 33%). In this study a daily dose of 300 mg hydroquinine hydrobromide was effective in preventing frequent ordinary muscle cramp in healthy female volunteers. The effects of hydroquinine outlasted its administration. The drug was well tolerated.

Sample size determination for a trial of breast cancer screening under age 50: population versus case mortality approach.

OBJECTIVE: To determine the efficacy of screening for breast cancer in women aged 40 to 49. METHODS: A large number of women will have to be enrolled to ensure adequate statistical power. Attention will be restricted to the deaths from breast cancer that occur among comparable groups of patients with breast cancer rather than to an analysis in which all women entering into the trial are considered at risk of dying from breast cancer (population mortality analysis). As the new trial is likely to be conducted in regions where screening has been established for all women from age 50 onward, comparability may be reached by including the breast cancers detected at the routine screening examination at age 50. CONCLUSIONS: When comparability of cases can be reached, such a case mortality analysis requires 15-30% fewer women to be enrolled than a population approach.

Comparison of the CAPAS and Ewing tests for screening of hearing in infants.

OBJECTIVE: To study the similarities and differences between the non-automated labour intensive Ewing hearing test and the less labour intensive automated CAPAS (Compact Amsterdam Paedo-Audiometrical Screening) hearing test. SETTING: A multicentre study in which all the children born in the eastern part of the Netherlands between 1 January 1996 and 1 April 1997 were routinely screened for hearing impairment at 9 months of age. METHODS: Differences and similarities between the two methods were described for the proportion of children who failed every test, the percentage of referred children, the yield of bilateral and unilateral otitis media with effusion (OME), the positive predictive value of the third test result, and the yield of persistent OME after 4-6 months' follow up at an ENT department. RESULTS: 12,603 infants were screened with the CAPAS test and 17,496 with the Ewing test. There were differences between the CAPAS and Ewing tests respectively in the proportions of children lost to follow up (10.1% v 15.2%), the proportions of children referred diagnosed with OME (59% v 81%), the yield of bilateral otitis media with effusion (2.4% v 3.0%), and the yield of persistent OME after 4-6 months' follow up (1.1% v 1.6%). CONCLUSIONS: The CAPAS test is more practical than the Ewing test, but the non-automated Ewing test seems to be more reliable and valid for detecting conductive hearing loss.

High mammographic breast density and its implications for the early detection of breast cancer.

OBJECTIVES: Women with high mammographic breast density are at increased risk of breast cancer. This study explores whether these women should receive intensified screening (more frequent screening or screening with alternative techniques that increase the length of the preclinical detectable phase) to reduce further breast cancer mortality. METHODS: Mathematical models were used to estimate the effects of intensified screening in women with high breast density. The effects were expressed as a reduction in the number of interval cancers. RESULTS: If women with > 25% breast density (comprising about one fifth of all women) are screened annually instead of biennially, an 18% reduction in the total number of interval cancers can be expected. Screening these women with alternative screening techniques biennially may produce the same reduction, provided that these techniques double the mean lead time. CONCLUSIONS: By screening women with dense breasts more intensively, many more breast cancers can theoretically be detected at an early stage. The results provide an early indication of what may be expected from screening strategies. Next, cost-benefit analyses are needed.