Mammography screening in three Finnish residential areas: comprehensive population-based study of breast cancer incidence and incidence-based mortality 1976-2009.

BACKGROUND: The aim of this study was to evaluate the effectiveness of a large-scale screening programme for breast cancer (BC) in Turku, Finland. Incidence and incidence-based mortality (IBM) figures were compared with the areas applying different screening policies. METHODS: Deaths and person-time of women aged 40-84 were assessed for the period 1976-1986 (prescreening era) and the periods 1987-1997 and 1998-2009 (screening periods) using incidence and IBM by age at diagnosis and at death. There was a total of 40.7 million women-years, 83 497 invasive BCs obtained from the Finnish Cancer Registry; 17 508 BC deaths were linked with the data from Statistics Finland. RESULTS: In Turku, a significant (> 20%) reduction in IBM occurred during 1987-2009 among women aged 60-74 years at diagnosis compared with Helsinki (IBMRR: 0.75, 95% CI: 0.57-1.00), and in women aged 75-84 years at death compared with the rest of Finland (IBMRR: 0.72, 95% CI: 0.53-0.96). CONCLUSIONS: The wide mammography screening programme in Turku was effective in decreasing BC mortality in the elderly age groups. These results support the implementation of BC screening from age 50 up to 74 years.

Overdiagnosis due to breast cancer screening: updated estimates of the Helsinki service study in Finland.

BACKGROUND: Overdiagnosis is the most important adverse event of breast cancer screening with the estimates ranging from 0% to 40-50% depending on invitational age and methods. We updated the estimates of overdiagnosis in Helsinki service screening study in Finland by comparing the observed and expected cumulative incidence of all breast carcinomas and invasive breast carcinomas. METHODS: Women aged 50-59 years have been invited to Helsinki service screening since 1986. The incidence of breast carcinoma in the first invited birth cohorts born in 1935-1939 was compared with older, non-invited cohorts. The minimum follow-up time of the invitees after the last screening round was 14 years. Expected cumulative incidence rates were estimated with two alternative approaches. RESULTS: For both any breast carcinoma and invasive breast carcinoma, the estimates of overdiagnosis varied from 5% (95% CI=-1, 11%) to 7% (95% CI=1, 13%) depending on the approach. CONCLUSIONS: Our estimates of overdiagnosis are of the same magnitude than other plausible estimates in Europe. Both alternative approaches produced similar estimates for the expected cumulative incidence, which increased the confidence in the estimates of overdiagnosis.

Type- and age-specific distribution of human papillomavirus in women attending cervical cancer screening in Finland.

BACKGROUND: Large-scale data on type-specific HPV prevalences and disease burden are needed to monitor the impact of HPV vaccination and to plan for HPV-based cervical screening. METHODS: 33 043 women (aged 25-65) were screened for HPV by a Hybrid Capture 2 (HC2) in a population-based programme. HPV-positive women (n=2574) were triaged by cytology and HPV genotyped using PCR-Luminex. Type-specific prevalence of HPV infection and its correlation to findings in cytology triage and histology as well as Population Attributable Fractions for a referral to colposcopy and findings in histology were calculated. RESULTS: Among HC2-positive women, 61.5% had normal, 23.1% had ASC-US and 15.5% had LSIL or more severe (LSIL+) results in cytology. Out of HC2-positive samples, 57% contained the 13 Group 1/2A HPV types, which were targeted by the HC2, 15% contained Group 2B types, 8.5% Group 3 types and 30% were found to be negative in HPV genotyping. The proportion of samples positive for HPV by the HC2, but negative in HPV genotyping increased with age and decreased with increasing cytological abnormality. The most frequent types were HPV 16 (0.9% of screened women and 12.1% of the HC2-positive women), HPV 31 (0.7% and 8.9%, respectively) and HPV 52 (0.5% and 6.3%, respectively). The prevalence of Group 1/2A HPV types increased with increasing CIN grade and attributed 78.3% (95% CI 53.4-89.9) of the CIN 3+ lesions, while HPV 16 attributed 55.8% (40.0-67.5) of them. CONCLUSION: The type-specific prevalence of HPV were slightly lower than the average in international meta-analyses. Genotyping for HPV 16 better identified women with CIN 3+ than cytology triage at the threshold of LSIL+. The high proportion of women that were HC2-positive but HPV-negative in genotyping suggests that HPV genotyping may be useful also for validation of results in HPV screening. The large-scale HPV genotyping data were found to be directly useful for planning further preventive efforts for cervical cancer.

European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview and introduction to the full supplement publication.

Population-based screening for early detection and treatment of colorectal cancer (CRC) and precursor lesions, using evidence-based methods, can be effective in populations with a significant burden of the disease provided the services are of high quality. Multidisciplinary, evidence-based guidelines for quality assurance in CRC screening and diagnosis have been developed by experts in a project co-financed by the European Union. The 450-page guidelines were published in book format by the European Commission in 2010.  They include 10 chapters and over 250 recommendations, individually graded according to the strength of the recommendation and the supporting evidence. Adoption of the recommendations can improve and maintain the quality and effectiveness of an entire screening process, including identification and invitation of the target population, diagnosis and management of the disease and appropriate surveillance in people with detected lesions. To make the principles, recommendations and standards in the guidelines known to a wider professional and scientific community and to facilitate their use in the scientific literature, the original content is presented in journal format in an open-access Supplement of Endoscopy. The editors have prepared the present overview to inform readers of the comprehensive scope and content of the guidelines.

Pregnancy incidence and outcome among patients with cervical intraepithelial neoplasia: a retrospective cohort study.

OBJECTIVE: To investigate the effect of cervical intraepithelial neoplasia (CIN) treatment on incidence of pregnancy and pregnancy outcome. DESIGN: Retrospective cohort study. SETTING: Helsinki University Central Hospital, Finland, the sole reference centre in the Helsinki-Uusimaa region for women referred for colposcopy. POPULATION: A cohort of 6179 women treated for CIN between 1974 and 2001, and a randomly selected, age- and municipality-matched, reference population of 30,436 women. METHODS: Based on nationwide registers, all women were followed-up for pregnancy outcomes until death, emigration, sterilization, or until the end of 2004. MAIN OUTCOME MEASURES: Incidence of any pregnancy, livebirths, miscarriages, extrauterine pregnancies, molar pregnancies, and terminations of pregnancies (TOPs) before and after CIN treatment, estimated by calculating hazard ratios (HRs) with stratified Cox regression and Poisson regression. RESULTS: After CIN treatment, both incidence of pregnancy (HR 1.20; 95% CI 1.15-1.26; P < 0.001) and incidence of livebirths (HR 1.12; 95% CI 1.06-1.18; P < 0.001) were higher among the treated women than among the reference population. Before treatment, only incidence of pregnancy had been elevated among those treated (HR 1.06; 95% CI 1.04-1.09; P < 0.001). The incidence of extrauterine pregnancies and of TOPs was significantly elevated among those treated both before and after CIN treatment. CONCLUSIONS: No clear evidence emerged of adverse effects resulting from the CIN treatment itself, because the women treated had more pregnancies and more children than their reference population. TOPs and extrauterine pregnancies were more common among the treated women already before the CIN treatment.

Large performance variation does not affect outcome in the Finnish cervical cancer screening programme.

OBJECTIVE: Cytology screening for prevention of cervical cancer can reduce incidence and mortality by more than 80% in settings with good organization and rigorous quality control. Audit studies are essential for reaching and maintaining a high quality of screening. The aim of this study was to evaluate variation in performance indicators by screening laboratory and assess the impact on the effectiveness of screening as indicated by cervical intraepithelial neoplasia grade 3 and above (CIN3+) rates after a negative screen. METHODS: Seven cytology screening laboratories operating during 1990-1999 with a total of 953 610 screening tests performed were included in the study. By linking screening and cancer register files, all cases of CIN3+ diagnosed in the screened population were identified. For 395 CIN3+ cases with a preceding negative screen and 787 controls, a re-evaluation of smears was undertaken to uncover false negative screening tests. Performance parameters and rates of CIN3+ after a negative screen were analysed for interlaboratory heterogeneity. RESULTS: The rates of follow-up recommendations and referrals varied by up to 3.6- (2.8-10.2%) and 4.0-fold (0.03-0.12%), respectively. CIN1, CIN2 and CIN3+ screen detection rates differed by up to 8.5- (0.02-0.17%), 5.4- (0.05-0.25%) and 3.3-fold (0.05-0.18%). False negative rates determined by re-evaluation showed up to 2.1-fold differences (29-62%). Rates of CIN3+ after a negative screen (0.023-0.048%) and as a proportion of total CIN3+ (15-31%) in the screened population were low and did not vary significantly. CONCLUSIONS: There were large variations in the sensitivity-specificity trade-off between laboratories, reflected in all performance indicators as well as in the test validity estimates of the re-evaluation phase, but not in screening effectiveness. Even though performance variations do not always have an impact on the effectiveness of screening, they lead to variations in cost, treatment and psychological burden, and should be addressed.

Socio-economic inequality of utilization of cancer testing in Europe: A cross-sectional study.

There are currently screening programmes for breast, cervical and colorectal cancer in many European countries. However, the uptake of cancer screening in general may vary within and between countries. The aim of this study is to assess the inequalities in testing utilization by socio-economic status and whether the amount of inequality varies across European regions. We conducted an analysis based on cross-sectional data from the second wave of the European Health Interview Survey from 2013 to 2015. We analysed the use of breast, cervical, and colorectal cancer testing by socio-economic position (household income, educational level and employment status), socio-demographic factors, self-perceived health and smoking behaviour, by using multinomial logistic models, and inequality measurement based on the Slope index of inequality (SII) and Relative index of inequality (RII). The results show that the utilization of mammography (Odds Ratio (OR) = 0.55, 95% confidence interval (95%CI):0.50-0.61), cervical smear tests (OR = 0.60, 95%CI:0.56-0.65) and colorectal testing (OR = 0.82, 95%CI:0.78-0.86) was overall less likely among individuals within a low household income compared to a high household income. Also, individuals with a non-EU country of birth, low educational level and being unemployed (or retired) were overall less likely to be tested. The income-based inequality in breast (SII = 0.191;RII = 1.260) and colorectal testing utilization (SII = 0.161;RII = 1.487) was the greatest in Southern Europe. For cervical smears, this inequality was greatest in Eastern Europe (SII = 0.122;RII = 1.195). We concluded that there is considerable inequality in the use of cancer tests in Europe, with inequalities associated with household income, educational level, employment status, and country of birth.

Urodynamic assessment of children treated with botulinum toxin A injections for urge incontinence: a pilot study.

OBJECTIVE: This study aimed to investigate changes in urodynamic findings and symptoms after detrusor injections of botulinum toxin A (BTX-A) in children with idiopathic detrusor overactivity (IDO) and urge incontinence. MATERIAL AND METHODS: Eight girls and five boys, aged 7-19 years, who had urge incontinence refractory to scheduled voiding and anticholinergics, were included this prospective study. Urodynamic studies showed postoperative IDO in 12 patients. A dose of 50-100 IU (1.3 -- 4.8 IU/kg) BTX-A was primarily administered at 15-20 detrusor sites. A control urodynamic study was performed within 3 months after the injections. Seven patients had a repeated procedure 16 (range 6-24) months on the average after the first one. RESULTS: Eleven of the 13 patients had daily incontinence and two had incontinence a couple of times a week in association with urge symptoms. Postoperatively, no patient had urinary retention, but one girl had a urinary tract infection 4 months after the therapy. Five patients had a full response, seven partial responses and one no response 1-3 months after the first treatment. After 1 year, three of nine patients still have full response. Maximum cystometric capacity increased after the first treatment from a median of 227 ml to 379 ml (p = 0.005) and the number of patients with uninhibited detrusor contractions more than 30 cmH2O during the filling phase decreased from eight to two out of 13 (p = 0.041). CONCLUSIONS: Intradetrusor BTX-A injections effectively reduce day-time wetting, significantly increase bladder volume and decrease detrusor overactivity in children with urge incontinence refractory to scheduled voidings and anticholinergics.

European Guidelines for Quality Assurance in Cervical Cancer Screening. Second edition--summary document.

European Guidelines for Quality Assurance in Cervical Cancer Screening have been initiated in the Europe Against Cancer Programme. The first edition established the principles of organised population-based screening and stimulated numerous pilot projects. The second multidisciplinary edition was published in 2008 and comprises approximately 250 pages divided into seven chapters prepared by 48 authors and contributors. Considerable attention has been devoted to organised, population-based programme policies which minimise adverse effects and maximise benefits of screening. It is hoped that this expanded guidelines edition will have a greater impact on countries in which screening programmes are still lacking and in which opportunistic screening has been preferred in the past. Other methodological aspects such as future prospects of human papillomavirus testing and vaccination in cervical cancer control have also been examined in the second edition; recommendations for integration of the latter technologies into European guidelines are currently under development in a related project supported by the European Union Health Programme. An overview of the fundamental points and principles that should support any quality-assured screening programme and key performance indicators are presented here in a summary document of the second guidelines edition in order to make these principles and standards known to a wider scientific community.

European guidelines for clinical management of abnormal cervical cytology, part 2.

The current paper presents the second part of chapter 6 of the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. The first part of the same chapter was published in a previous issue (Cytopathology 2008;19:342-54). This part provides guidance on how to manage and treat women with histologically confirmed cervical intraepithelial neoplasia. The paper describes the characteristics, indications and possible complications of excisional and ablative treatment methods. The three options to monitor the outcome after treatment (repeat cytology, HPV testing and colposcopy) are discussed. Specific recommendations for particular clinical situations are provided: pregnancy, immuno-suppression, HIV infection, post-menopause, adolescence and cyto-colpo-histological disparity. The paper ends with recommendations for quality assurance in patient management and some general advice on how to communicate screening, diagnosis and treatment results to the woman concerned. Finally, a data collection form is attached.

European guidelines for quality assurance in cervical cancer screening: recommendations for clinical management of abnormal cervical cytology, part 1.

The current paper presents the first part of Chapter 6 of the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. It provides guidance on how to manage women with abnormal cervical cytology. Throughout this article the Bethesda system is used for cervical cytology terminology, as the European guidelines have recommended that all systems should at least be translated into that terminology while cervical intraepithelial neoplasia (CIN) is used for histological biopsies (Cytopathology 2007; 18:213-9). A woman with a high-grade cytological lesion, a repeated low-grade lesion or with an equivocal cytology result and a positive human papillomavirus (HPV) test should be referred for colposcopy. The role of the colposcopist is to identify the source of the abnormal cells and to make an informed decision as to whether or not any treatment is required. If a patient requires treatment the colposcopist will decide which is the most appropriate method of treatment for each individual woman. The colposcopist should also organize appropriate follow-up for each woman seen. Reflex testing for high-risk HPV types of women with atypical squamous cells (ASC) of undetermined significance with referral for colposcopy of women who test positive is a first option. Repeat cytology is a second possibility. Direct referral to a gynaecologist should be restricted to special circumstances. Follow-up of low-grade squamous intraepithelial lesion is more difficult because currently there is no evidence to support any method of management as being optimal; repeat cytology and colposcopy are options, but HPV testing is not sufficiently selective, unless for older women. Women with high-grade squamous intraepithelial lesion (HSIL) or atypical squamous cells, cannot exclude HSIL (ASC-H) should be referred without triage. Women with glandular lesions require particular attention. In a subsequent issue of Cytopathology, the second part of Chapter 6 will be presented, with recommendations for management and treatment of histologically confirmed intraepithelial neoplasia and guidance for follow-up of special cases such as women who are pregnant, postmenopausal or immunocompromised.

Service screening mammography reduces breast cancer mortality among elderly women in Turku.

OBJECTIVES: The aim of this study was to assess the effects of service screening mammography on breast carcinoma incidence and refined mortality among women aged 55-69 at entry in three cities employing different screening policies. METHODS: Since 1987, the city of Turku, Finland, has provided service screening mammography for women aged 55-69 at entry (in 1987), and Tampere provided screening for women aged 55-59 at entry, whereas Helsinki did not screen any of these age groups. The incidence of breast carcinoma during the screening period 1987-97 in women born in 1918-32 (1918-22, 1923-27, 1928-32) was compared with incidence during the pre-screening period 1976-86 in women born in 1907-21 (1907-11, 1912-16, 1917-21) in each city. The follow-up for mortality was four years longer. RESULTS: Breast carcinoma incidence was 31-38% higher in the screening period in all three cities irrespective of screening. In breast carcinoma mortality, no significant changes were seen in Helsinki or Tampere. In Turku, a 36% mortality reduction (relative risk [RR] 0.64; 95% confidence interval [CI] 0.47-0.88; P=0.007) in the whole study population and a 47% reduction in women aged 65-69 at entry (RR 0.53; 95% CI 0.28-0.99; P=0.047) were seen. CONCLUSIONS: The incidence of breast carcinoma increased in all study cities irrespective of screening. The comprehensive screening programme in Turku including women aged 55-69 at entry was associated with a significant reduction in breast carcinoma mortality. The pronounced decrease in mortality in the oldest age group (65-69 years at entry) also indicated that women of this age group greatly benefit from mammography screening.

Validity of process indicators of screening for breast cancer to predict mortality reduction.

The aim of the study was to empirically assess the acceptable levels of process indicators as described in the European Community Guidelines using materials from the mammography service screening programmes. The Finnish programme was evaluated for effectiveness with a prior estimate of 0.74 for RR in Finland and 0.81 in Helsinki. Hence, the Finnish programme was likely to be somewhat less effective in terms of reduction in mortality than implied on the basis of early randomized trials, but probably approaching the same level of effectiveness. Finland therefore provides background data on the applicability of the process indicators that are indicators of performance and surrogates for effectiveness. The performance data on 10 Finnish screening centres at subsequent screens were used. These centres invited 687,000 women aged 50-64 years in 1991-2000. The mean compliance was 93% and the corresponding recall rate was 2.3%. The benign to malignant biopsy ratio was 0.43:1. The average breast cancer detection rate was 0.36%, 2.1 compared with the background incidence. The proportion of screen-detected stage II+ cancers was 26%. Most, but not all, of these process indicators met the desirable reference values of the European Community. The specific criteria of the European Community on stage distribution, rates of screen-detected cancers by stage and detection rate to background incidence may need reconsideration.

Effectiveness of screening for colorectal cancer with a faecal occult-blood test, in Finland.

BACKGROUND: Screening for colorectal cancer (CRC) with guaiac-based faecal occult-blood test (FOBT) has been reported to reduce CRC mortality in randomised trials in the 1990s, but not in routine screening, so far. In Finland, a large randomised study on biennial FOB screening for CRC was gradually nested as part of the routine health services from 2004. We evaluate the effectiveness of screening as a public health policy in the largest population so far reported. METHODS: We randomly allocated (1:1) men and women aged 60-69 years to those invited for screening and those not invited (controls), between 2004 and 2012. This resulted in 180 210 subjects in the screening arm and 180 282 in the control arm. In 2012, the programme covered 43% of the target age population in Finland. RESULTS: The median follow-up time was 4.5 years (maximum 8.3 years), with a total of 1.6 million person-years. The CRC incidence rate ratio between the screening and control arm was 1.11 (95% CI 1.01 to 1.23). The mortality rate ratio from CRC between the screening and control arm was 1.04 (0.84 to 1.28), respectively. The CRC mortality risk ratio was 0.88 (0.66 to 1.16) and 1.33 (0.94 to 1.87) in males and females, respectively. CONCLUSIONS: We did not find any effect in a randomised health services study of FOBT screening on CRC mortality. The substantial effect difference between males and females is inconsistent with the evidence from randomised clinical trials and with the recommendations of several international organisations. Even if our findings are still inconclusive, they highlight the importance of randomised evaluation when new health policies are implemented. TRIAL REGISTRATION: 002_2010_august.

Glycophorin A somatic cell mutation frequencies in Finnish reinforced plastics workers exposed to styrene.

We have used the glycophorin A (GPA) in vivo somatic cell mutation assay to assess the genotoxic potential of styrene exposure in 47 reinforced plastics workers occupationally exposed to styrene and 47 unexposed controls matched for age, gender, and active smoking status. GPA variant erythrocyte frequencies (Vf), reflecting GPA allele loss (phi/N) and allele loss and duplication (N/N) somatic mutations arising in vivo in the erythroid progenitor cells of individuals of GPA M/N heterozygous genotype, were flow cytometrically determined in peripheral blood samples from these subjects. Measurements of styrene exposure of the workers at the time of blood sampling showed a mean 8-h time-weighted average (TWA8-h) styrene concentration of 155 mg/m3 (37 ppm) in the breathing zone. Mean urinary concentrations of the styrene metabolites mandelic acid (MA) and mandelic acid plus phenyl glyoxylic acid (MA+PGA) were 4.4 mmol/liter (after workshift) and 2.1 mmol/liter (next morning), respectively. Multivariate analysis of covariance on log-transformed GPA Vf data with models allowing adjustment for age, gender, smoking status, and styrene exposure showed that N/N Vf were nearly significantly increased among all of the exposed workers (adjusted geometric mean, 6.3 per million versus 5.0 in the controls; P = 0.058) and were statistically significantly elevated (adjusted geometric mean, 6.8 versus 5.0 in the controls; P = 0.036) among workers classified into a high-exposure group according to personal TWA8-h concentration of styrene in the breathing zone of > or = 85 mg/m3 (20 ppm; Finnish threshold limit value). Women in this high exposure group showed especially elevated N/N Vf (adjusted geometric mean 8.5 versus 5.3 in control women; P = 0.020); this elevation was also significant if urinary MA+PGA of > or = 1.2 mmol/liter was used as the basis of classification (adjusted geometric mean, 8.3; P = 0.030). The occupational exposure could not be shown to influence phi/N Vf. Cigarette smoking was associated with significantly elevated GPA Vf among active smokers (P = 0.042 for phi/N and P = 0.020 for N/N) and among active and ex-smokers combined (P = 0.014 for N/N). Its influence on phi/N Vf was especially clear among active smokers in the control group (P = 0.005). An effect of smoking, nearly statistically significant, was also observed for the phi/N Vf of control ex-smokers (P = 0.055) and of all active and ex-smokers combined (P = 0.050). Thus, the two characterized chemical exposures experienced by this group of workers and controls appear to produce differential effects on the two independent classes of GPA variants enumerated in the assay. This result suggests that the genotoxicity of these agents is mediated, at least in part, by different genetic mechanisms. Styrene exposure is associated with a specific increase in GPA N/N Vf; these allele loss and duplication variants reflect predominantly somatic recombination mechanisms in erythroid progenitor cells. Tobacco smoke exposure in active and ex-smokers is also associated not only with an increase in N/N Vf but also with an increase in phi/N Vf, reflecting the induction of GPA gene-inactivating mutations, including point mutations and deletions. This finding is consistent with a broad mechanistic spectrum of tobacco smoke genotoxicity associated with this complex mixture of chemical mutagens. Finally, there was no detectable effect of age on phi/N Vf; however, a highly significant (P = 0.0002) increase in N/N Vf with age, even after adjustment for other variables, was observed.

Cervical cancer screening programme in Finland.

In Finland, the organised screening programme for the prevention of cervical cancer has been run for over 30 years and has contributed to a 70-80% decrease in the age-adjusted cervical cancer incidence, as well as a reduction in mortality rates. In this article, we describe the operational details of the organised programme - how the target population is defined, how the invitations are done, how smear tests are collected and analysed, how referrals to confirmation and treatment are conducted, and we also provide recent data on the extent and main screening results. The Finnish programme has led to net savings when assessed for its cost-effectiveness. The results encourage the continuation of the screening programme. By introducing modern screening technologies and more systematic quality control activities in the programme, and by expanding the coverage and compliance we expect to further increase the impact of the programme.

Process indicators from ten centres in the Finnish breast cancer screening programme from 1991 to 2000.

The aim of this study was to evaluate the quality of the Finnish mammography programme by assessing process indicators from 10 screening centres using data from the first and subsequent screens. We compared these screen-specific indicators with European standards and results from countries with similar screening protocols. Ten Finnish centres invited approximately 1,000,000 women from 1991-2000. Women were mainly 50-64 years old. Mean compliance amongst this age group was 90% at the first and 93% at subsequent screens. The corresponding recall rates were 4.6% and 2.3%, respectively. The average breast cancer detection rates were 0.44% and 0.36%, respectively. The positive predictive values (PPVs) of mammography at the first and subsequent screens were 10% (range 7-20%) and 16% (range 12-31%), and the corresponding benign to malignant (B:M) biopsy ratios were 1:1 (range 0.5-1.8:1) and 0.4:1 (range 0.3-0.8:1). The PPV of mammography increased significantly during the study period, and the average process indicators fulfilled the criteria of the European community for the most part. However, the variation in PPVs was wide, as has been seen for other European mammography programmes, indicating meaningful differences in diagnostic criteria and potential adverse effects.

Overview of important cervical cancer screening process values in European Union (EU) countries, and tentative predictions of the corresponding effectiveness and cost-effectiveness.

The objective was the evaluation of the (cost-)effectiveness of cervical cancer screening in the European Union (EU) countries. Data were collected on recommended screening age ranges and intervals, coverage, proportion of non-negative smears and smear use. Estimates reported by representatives of each participating Member State were compared, and used as input for model based on (using the MISCAN simulation model for cancer screening) effectiveness and cost-effectiveness calculations. Differences in coverage from below 50 to 82% resulted in more or less proportional differences in expected percentage life-years lost reduction, almost regardless of differences in 7-50+ smears recommended in a lifetime. Differences in screening intensity (resulting from the recommended number of smears per lifetime and the number of excess smears on top of these recommendations) resulted in more than 2-fold difference in the expected number of smears per percentage life-years lost reduction. (Cost-)effectiveness predictions would have greatly improved if estimates of long-term coverage had also been available. To conclude, estimates for a restricted set of well defined parameters - a few for short and long-term coverage and one for the total number of smears - are quite useful for country-specific (cost-)effectiveness evaluations. The main, and to some extent, unsolvable problem for further improvement of the analysis is the lack of reliable country-specific estimates for the background risk of cervical cancer in women eligible for screening in the near future.

Prospects for phase III-IV HPV vaccination trials in the Nordic countries and in Estonia.

BACKGROUND: oncogenic, i.e. high risk human papillomavirus (hrHPV) types are the major cause of invasive cervical cancer (ICC). Putatively licensable vaccines against the hrHPVs have been developed and are approaching clinical phase III trials that use persistent HPV infection as end point. Direct extension of the phase III trials towards long-term end points (ICC and its immediate precursors: carcinoma in situ and severe dysplasia, i.e. cervical intraepithelial neoplasia grade III, CINIII) is important, to avoid early contamination of the target population by opportunistic use of licensed HPV vaccines. Country-wide registration on population and health events in a stable population of 25 million make Estonia and the Nordic countries a unique venue for long-term evaluation of cervical cancer control measures. Mass-screening programmes exist in all Nordic countries, but not in Estonia. AIM: design of phase III-IV trials for evaluation of protection against ICC and CINIII by preventive HPV vaccines based on cancer registry follow-up. RESULTS: in the Nordic countries, population based randomisation of all 15-year-old women to the vaccination (vaccine and placebo) and reference cohorts entering conventional Pap-smear screening after a clinical phase III trial would assure comparability of the cohorts. Enrollment of 10094 vaccinees +10094 placebo vaccinees +30282 other hrHPV negative women without vaccination at the age of 16 would give 80% power for the demonstration of 70% vaccine efficacy (VE) against ICC in 20 years by cancer registry follow-up. On the other hand, vaccination of 8303 Estonian hrHPV negative women among the entire 15-year-old female birth cohort (about 10000 women) with an already licensed HPV vaccine would enable demonstration of 70% VE against ICC by 20 years of registry follow-up of these and comparable 16606 women identified among the 16-19-year-old birth cohorts. CONCLUSIONS: evaluation of the protective effect of an HPV vaccine against ICC is possible both in countries with or without mass-screening. The effects of vaccination on spread of different HPVs in the population would need to be monitored, especially in Estonia. Ethical aspects, cost-benefit evaluation and comparisons with other new means of cervical cancer control warrant further investigation.

Benign response to particles of diamond and SiC: bone chamber studies of new joint replacement coating materials in rabbits.

Wear particles from total joint replacements are thought to accelerate prosthetic loosening. Diamond coating may improve the smoothness and wear characteristics of the femoral head component of total hip replacements, and thus increase their longevity. The brittleness of a thin diamond coat may be overcome by using an SiC-whisker diamond composite. This study describes the reactions of regenerating bone tissue to phagocytosable particles of diamond and SiC, using implanted bone harvest chambers in rabbits. The particles were dispersed in hyaluronan and introduced into a canal transversing the implant. The tissue that entered the canal during the following 3 weeks was then harvested. In previous studies using this model, particles of high density polyethylene, bone cement and chromium-cobalt all caused an inflammatory reaction and a marked decrease in the amount of ingrown bone. In the present study, neither the diamond nor the SiC particles caused any decrease in bone formation. It appears that particles of diamond and SiC are comparatively harmless.