Pekka Nieminen

Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting.

BACKGROUND Human papillomavirus (HPV) DNA testing has shown higher sensitivity than cytology for detecting cervical lesions, but it is uncertain whether the higher sensitivity is dependent on the age of the woman being screened. We compared the age-specific performance of primary HPV DNA screening with that of conventional cytology screening in the setting of an organized population-based cervical cancer screening program in Finland. METHODS From January 1, 2003, to December 31, 2005, randomized invitations were sent to women aged 25-65 years for routine cervical cancer screening by primary high-risk HPV DNA testing (n = 54 207) with a Hybrid Capture 2 assay followed by cytology triage for women who were HPV DNA positive or by conventional cytology screening (n = 54 218). In both screening arms, cytology results of low-grade squamous intraepithelial lesion or worse triggered a referral for colposcopy. Relative rates (RRs) of detection to assess test sensitivity, specificity, and positive predictive values (PPVs) with 95% confidence intervals (CIs) were calculated for the histological endpoints of cervical intraepithelial neoplasia (CIN) grade 1 or higher (CIN 1+), CIN grade 2 or higher (CIN 2+), and CIN grade 3 or higher (CIN 3+). All statistical tests were two-sided. RESULTS The overall frequency of colposcopy referrals was 1.2% in both screening arms. Women younger than 35 years were referred more often in the HPV DNA screening vs the conventional screening arm (RR = 1.27, 95% CI = 1.01 to 1.60). The prevalence of histologically confirmed CIN or cancer was 0.59% in the HPV DNA screening arm vs 0.43% in the conventional screening arm. The relative rates of detection for CIN 1, CIN 2, and CIN 3+ for HPV DNA screening with cytology triage vs conventional screening were 1.44 (95% CI = 0.99 to 2.10), 1.39 (95% CI = 1.03 to 1.88), and 1.22 (95% CI = 0.78 to 1.92), respectively. The specificity of the HPV DNA test with cytology triage was equal to that of conventional screening for all age groups (99.2% vs 99.1% for CIN 2+, P = .13). Among women aged 35 years or older, the HPV DNA test with cytology triage tended to have higher specificity than conventional screening. The PPVs for HPV DNA screening with cytology triage were consistently higher than those for conventional screening. In both screening arms, the test specificities increased with increasing age of the women being screening, whereas the highest PPVs were observed among the youngest women being screened. Overall, 7.2% of women in the HPV DNA screening arm vs 6.6% of women in the conventional screening arm were recommended for intensified follow-up, and the percentages were highest among 25- to 29-year-olds (21.9% vs 10.0%, respectively). CONCLUSIONS Primary HPV DNA screening with cytology triage is more sensitive than conventional screening. Among women aged 35 years or older, primary HPV DNA screening with cytology triage is also more specific than conventional screening and decreases colposcopy referrals and follow-up tests.

TOOTH MORPHOGENESIS AND CELL DIFFERENTIATION

The tooth is one of the vertebrate organs in which development at the molecular level is beginning to be understood. Secreted signaling molecules have been identified that mediate sequential and reciprocal inductive interactions between the dental epithelium and mesenchyme. Transcription factors have been found that participate in these signaling cascades. A signaling or organizing center was recently discovered in the dental enamel knot that expresses the same signals as other organizing centers in the embryo, and which presumably regulates tooth shape. It has recently become evident that the signaling networks that operate in the development of mammalian teeth are similar to those that are involved in the development of other vertebrate organs.

Effect of organised screening on cervical cancer incidence and mortality in Finland, 1963–1995: Recent increase in cervical cancer incidence

A nation‐wide screening programme for cervical cancer started in Finland gradually from 1963 onwards. By the beginning of the 1990s, there had been a decrease of 80% both in the age‐adjusted incidence of and mortality from cervical cancer. To describe the recent patterns in cervical cancer incidence and mortality and evaluate their differentials in relation with the organised screening activities, we have updated the material on the cervical cancer incidence and mortality as well as mass‐screening activities up to the year 1995. Based on the files of the Finnish Cancer Registry, there is a striking increase of about 60% in the incidence of cervical cancer during the last 4 years of the study period among women below 55 years of age. The mortality rates are still decreasing. There is no overall decrease over recent years in the coverage of the programme invitations or smears taken. Incidence of invasive cancer and of moderate and severe dysplasia as detected in mass screening have increased. As to the interpretation, changes in the risk factors, such as in sexual behaviour and smoking habits, over the decades might partly explain increasing trends in cervical cancer incidence. As the change in incidence was relatively abrupt, inadequacies or changes in the effectiveness in the screening programme, particularly among young women, may also have contributed. Expanding the coverage of and attendance in the pap‐screening programme among women in young target ages would still be effective. Increasing emphasis on quality assessment in screening is also needed. Int. J. Cancer 83:59–65, 1999.

Gynaecological infections as risk determinants of subsequent cervical neoplasia.

A longitudinal cohort study was carried out to determine whether gynaecological infections other than human papillomavirus (HPV) are also related to the subsequent increased risk of cervical neoplasia. The study comprised 19114 women attending the organized mass screening in Finland in 1985-1990 with cytologically detected HPV, Actinomyces, herpes simplex, Trichomonas vaginalis, or yeast. The women were followed-up for subsequent preinvasive lesions and invasive cancers until the end of 1994 by linkage to the nation-wide Cancer Registry. Standardized incidence ratios (SIR) with rates for the whole of Finland as reference and 95% confidence intervals (CI) were estimated. Trichomonas vaginalis and HPV were associated with a high relative risk of cervical cancer, SIR 6.4 (CI 3.7-10, preinvasive lesion and invasive cancer combined) and SIR 5.5 (CI 4.2-7.2, preinvasive lesion and invasive cancer combined), respectively. Herpes simplex was rarely detected, but the highest and statistically most significant point estimate was observed (SIR 12, CI 2.4-34, preinvasive lesion and invasive cancer combined). Neither Actinomyces nor yeast was associated with a significantly increased risk of cervical cancer. None of these results could be accounted for by the confounding effect of the other infections. Our results, based on a prospective design, lead us to propose that Trichomonas vaginalis and herpes simplex virus are also predictors for cervical neoplasia.

Ectodysplasin, a protein required for epithelial morphogenesis, is a novel TNF homologue and promotes cell-matrix adhesion.

In the mouse Tabby (Ta) mutant and human X-linked anhidrotic ectodermal dysplasia (EDA) syndrome development of several ectodermal organs such as hair, teeth, and sweat glands is impaired. The gene behind Tabby and EDA has been cloned, and several alternative transcripts have been isolated. The protein product named ectodysplasin had no obvious function or prominent homology to other known gene products apart from a short collagen-like sequence. We have isolated two novel Ta transcripts which are variants of the longest isoform of Tabby, named Ta-A. In situ hybridizations revealed Ta-A to be the major transcript in the developing embryo. It was detected in the endoderm of early embryos and subsequently in specific locations in the neuroepithelium and ectoderm. Unexpectedly, sequence analysis of the most C-terminal domain of Ta revealed that ectodysplasin is a novel member of the tumor necrosis factor (TNF) ligand superfamily. Mouse ectodysplasin was biochemically and functionally characterized, and shown to be a glycosylated, oligomeric type II membrane protein (N-terminus inside), all characteristics typical to TNF-like proteins. Members of the TNF family are critically involved in host defence and immune response often mediating either apoptosis or cell survival. Expression of Ta in several epithelial cell lines did not result in prominent changes in cell morphology and did not promote apoptosis. Instead, it was shown to promote cell adhesion to extracellular matrix, a function consistent with its postulated role in epithelial-mesenchymal interactions regulating the development of ectodermal appendages. Ectodysplasin is the first TNF-like signaling molecule described known to be required for epithelial morphogenesis.

Risk of cervical and other cancers after treatment of cervical intraepithelial neoplasia: retrospective cohort study

Abstract Objective To study the long term risk of cervical and other cancers after treatment for cervical intraepithelial neoplasia. Design Retrospective cohort study. Setting University Hospital, Helsinki, Finland. Participants 7564 women treated for cervical intraepithelial neoplasia during 1974 and 2001 and followed up through the Finnish cancer registry until 2003. Main outcome measures Standardised incidence ratio for cervical cancer and other cancers. Results During follow-up 22 cases of invasive cervical cancer occurred in women treated for cervical intraepithelial neoplasia (standardised incidence ratio 2.8, 95% confidence interval 1.7 to 4.2). The highest risk was during the second decade (10 cases observed: 3.1, 1.5 to 5.7). The standardised incidence ratio for cervical intraepithelial cancer type 1 was 3.1 (1.4 to 6.2) and for type 2 was 3.7 (0.9 to 10.7). Conclusions The risk of cervical cancer in the first 20 years after treatment for cervical intraepithelial neoplasia is higher than in the average population. The risk of smoking related cancers is also increased.

Routine cervical screening with primary HPV testing and cytology triage protocol in a randomised setting.

The role of high-risk human papillomavirus (hrHPV) testing in primary cervical screening has not been established. We generated a randomised evaluation design ultimately to clarify whether primary hrHPV testing implemented into routine screening can bring increase in the programme effectiveness. The aim of the present report on first-year results was to assess the cross-sectional relative validity parameters for routine hrHPV screening, in comparison with conventional screening. An equal number of women invited to routine screening was randomly allocated to primary hrHPV screening (n=7060) and to cytological screening (n=7089). In the hrHPV screening arm, after a single positive hrHPV test result, the need of colposcopy referral was determined by a cytological triage test. Compared with the conventional arm, more colposcopy referrals were made in the hrHPV screening arm (relative risk 1.51, confidence interval 95% 1.03–2.22). Specificity of the primary screening with sole hrHPV test (91.5–92.1%) was much lower than that with the cytology triage (98.7–99.3%), which was not quite as specific as screening with conventional cytology (99.2–99.6%). Compared with conventional cytology, primary screening with hrHPV test results in increased cross-sectional relative sensitivity at the level of all positive lesions at the cost of substantial loss in specificity. With cytology triage, the specificity improves to the level of conventional cytology.

Self-sample HPV Tests As an Intervention for Nonattendees of Cervical Cancer Screening in Finland: a Randomized Trial

Background: Attendance in screening is an important determinant of cervical cancer. Previous experience on high-risk human papillomavirus (hrHPV) DNA testing on patient-obtained samples suggests a good effect among nonattendees of screening. We assessed the effects of self-sampling on attendance in the Finnish screening program. Methods: Nonattendees after the primary invitation in one municipality (Espoo) were randomized to receive either a self-sampling kit (2,397 women) or an extra invitation (6,302 women). One fourth (1,315 women) of reminder letter arm nonattendees also received a self-sampling kit as a third intervention. Main outcomes were increases in screening attendance and coverage. Results: The adjusted relative risk for participation by self-sampling as a second intervention in comparison to a reminder letter arm was 1.21 (95% CI: 1.13–1.30). Total attendance increased from 65% to 76% by self-sampling and from 65% to 74% with a reminder letter. Combining the interventions (reminder letter and then self-sampling) increased total attendance from 63% to 78%. One fifth of the participants in all three groups increased screening coverage (previous Pap smear ≥5 years ago or never). Self-obtained samples were more often HPV positive than provider-obtained ones (participants after primary invitation and reminder letter), 12% to 13% versus 7%. Conclusions: Self-sampling is a feasible option in enhancing the attendance at organized screening, particularly as an addition to a reminder letter. Impact: If self-sampling is used as a third intervention after two written invitations, the overall attendance in Finland could most likely reach the desired 80% to 85%. Cancer Epidemiol Biomarkers Prev; 20(9); 1960–9. ©2011 AACR.

Gene defect in hypodontia: exclusion of MSX1 and MSX2 as candidate genes

Hypodontia, congenital lack of one or a few teeth, is an autosomally inherited dominant trait. Homeobox genes MSX1 and MSX2 are expressed in presumptive dental tissues at the stage of initiation of tooth development. Recently, tooth development was shown to be inhibited in transgenic mice lacking a functional Msx1 gene. Here, we studied the relationship of the MSX1 and MSX2 genes to familial hypodontia in five Finnish families with a total of 20 affected individuals, by linkage analysis. The pairwise lod-scores regarding the intragenic microsatellites in the MSX1 and MSX2 genes at a recombination fraction of 0.0 were -3.1 and -3.0, respectively, thus excluding these genes as causative loci for hypodontia in these families.

Gene Defect in Hypodontia: Exclusion of EGF, EGFR, and FGF-3 as Candidate Genes:

Hypodontia, congenital absence of one or a few permanent teeth without any systemic disorders, is regarded as an autosomally inherited dominant condition with varying expression and incomplete penetrance. Many studies have reported that the prevalence of hypodontia varies from 5% to 10% among European and Asian populations. The teeth most often missing are second premolars, upper lateral incisors, and lower central incisors. Consequently, we call this trait incisor-premolar hypodontia. Peg-shaped or strongly mesio-distally reduced upper lateral incisors demonstrate variation in the expression of the trait. The gene or genes causing incisor-premolar hypodontia are not known. We have begun the genetic mapping of hypodontia by using linkage analyses in seven Finnish three-generation families with 77 individuals, 31 affected with incisor-premolar hypodontia. As the first step, we studied the possibility of linkage between hypodontia and some candidate genes which have been suggested to have important functions during tooth development. Here we report the exclusion of EGF, EGFR, and FGF-3 loci as possible sites for gene mutation causing incisor-premolar hypodontia in our family material. Because of the close location of the FGF-3 and FGF-4 genes, the results also suggest the exclusion of the FGF-4 locus.