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Objective: To investigate the six-month recommended follow-up after mass screening of Pap smears because of the absence of endocervical columnar cells (ECC-) or ECC+ smears with atypical squamous or glandular cells of undetermined origin (ASCUS/AGUS) or low-grade squamous or glandular intraepithelial lesions (LSIL/LGIL) in a Dutch mass screening cervical cancer programme., Methods: Data were extracted from computerised medical records of national representative Dutch general practices. We have studied the attendance at and the outcome of the subsequent Pap smears after a 6-month recommendation., Results: The six-month follow-up was linked to 8.7% of the Pap smears (n = 1,002); 77.6% were without endocervical columnar cells (ECC-). Clear differences were found between the follow-up of ECC+ and ECC- smears; after 36 weeks of follow-up of 43.5% the women had an ECC- smear and 66.9% had other conditions. For initial ECC- Pap smears, 84.1% had no abnormalities in the subsequent Pap smear; for initial ECC+ Pap smears, in about 64% of the cases no abnormalities were found (p < 0.0001)., Conclusions: Repeating ECC- smears has a low follow-up rate but also lacks evidence-based necessity. However, for the other 6-month recommended Pap smears, one in five women had still not responded within one year, so improvement is necessary.

Background: There is still only limited understanding of whether and why interventions to facilitate the implementation of guidelines for improving primary care are successful. It is therefore important to look inside the 'black box' of the intervention, to ascertain which elements work well or less well., Aim: To assess the associations of key elements of a nationwide multifaceted prevention programme with the successful implementation of cervical screening guidelines in general practice., Design of Study: A nationwide prospective cohort study., Setting: A random sample of one-third of all 4,758 general practices in The Netherlands (n = 1,586)., Method: General practitioners (GPs) in The Netherlands were exposed to a two-and-a-half-year nationwide multifaceted prevention programme to improve the adherence to national guidelines for cervical cancer screening. Adherence to guidelines at baseline and after the intervention and actual exposure to programme elements were assessed in the sample using self-administered questionnaires., Results: Both baseline and post-measurement questionnaires were returned by 988 practices (response rate = 62%). No major differences in baseline practice characteristics between study population, non-responders, and all Netherlands practices were observed. After the intervention all practices improved markedly (P<0.001) in their incorporation of nine out of 10 guideline indicators for effective cervical screening into practice. The most important elements for successful implementation were: specific software modules (odds ratios and 95% confidence intervalsfor all nine indicators ranged from OR = 1.85 [95% CI = 1.24-2.77] to OR = 10.2 [95% CI = 7.58-14.1]); two or more 'practice visits' by outreach visitors (ORs and 95% CIs for six indicators ranged from OR = 1.46 [95% CI= 1.01-2.12] to OR = 2.35 [95% CI = 1.63-3.38]); and an educational programme for practice assistants (ORs and 95% CIs for four indicators ranged from OR = 1.57 [95% CI = 1.00-1.92] to OR = 1.90 [95% CI = 1.25-2.88])., Conclusion: A multifaceted programme targeting GPs, including facilitating software modules, outreach visits, and educational sessions for PAs, contributes to the successful implementation of national guidelines for cervical screening.

Background: The effectiveness of three different organizational approaches to cervical cancer screening (community based, family practice based, and a combination) was evaluated in nationally representative family practices., Method: We selected 122 family practices with a computerized sex-age register from a database of 1, 251 family practices, representative of all 4,758 family practices in The Netherlands. Approximately 40 practices were linked with each approach. We measured the attendance, the reasons for nonattendance, and the influence of a reminder on the attendance of women invited for cervical screening in September, October, and November 1996. The patients were grouped according to age. A cross-sectional design was used for the study., Results: For younger women, the total attendance rate, coverage (percentage of women "protected" against cervical cancer), and control rate (percentage of women with medical reasons for nonattendance or postponement of the smear) were highest in practices using the family practice-based approach (68, 77, and 90%, respectively) and lowest in practices with the community-based approach (53, 62, and 68%, respectively). For older women, the family practice-based approach and the combination approach were associated with attendance rates significantly higher than those for the community-based approach (approximately 60, 80, and 80% vs 47, 67, and 70%, respectively). A reminder sent by the family physician to women not responding to an initial invitation increased the attendance rate by 7 to 11% in both age categories, depending on who had sent the first invitation., Conclusion: A family practice-based cervical screening approach appeared to be the most effective at a national level, achieving the highest attendance rate, coverage, and control rate., (Copyright 2000 American Health Foundation and Academic Press.)

Objective: To assess the effects of a Dutch national prevention programme, aimed at general practitioners (GPs), on the adherence to organizational guidelines for effective cervical cancer screening in general practice. To identify the characteristics of general practices determining success., Design: A prospective questionnaire study with pre- and post-measurement (before and 15 months after the introduction of the national programme)., Setting and Study Participants: A random sample of one-third of all 4758 Dutch general practices. One GP was asked to participate per practice., Intervention: A national GP prevention programme to improve population-based prevention of cervical cancer combining various methods for quality improvement in general practice, performed on a national, district and practice level. Outreach visitors were a key strategy in bringing about behavioural changes., Main Outcome Measures: The proportion of practices adhering to 10 recommendations (in four guidelines) to organize effective cervical cancer screening., Results: After 15 months, all Dutch practices showed significant improvement in adherence to nine out of 10 recommendations. Two recommendations, in particular 'identifying women who should be medically excluded from screening' and 'sending a reminder to non-compliers' showed the largest absolute increases of 26% and 33%, respectively. Besides more intensive support of outreach visitors, practice characteristics such as 'computerization' and 'delegation of many clinical tasks to the practice assistant' were important in improving the adherence to guidelines., Conclusion: The national programme, with a combination of various methods for quality improvement, appeared to be effective in improving the organization of cervical screening in general practice. Computerization and, to a lesser extent, delegation of many clinical tasks to the practice assistant and more intensive support to practices, positively influenced the effectiveness of the national programme.

Background: Well-organized cervical screening has been shown to be effective in the reduction of both morbidity and mortality from cancer of the uterine cervix. In The Netherlands, the GP plays an important role in the cervical screening. The question is whether the general practices are able to organize an effective cervical cancer screening., Objectives: We explored the extent to which Dutch general practices adhere to organizational guidelines for effective population-based prevention of cervical cancer and which practice characteristics are important for this adherence., Methods: A postal survey was conducted in a random sample of one-third of all 4758 Dutch general practices. Two sets of information were collected: practice characteristics and adherence to four organizational guidelines for effective cervical screening concerning inviting the women, monitoring attendance and sending reminders, organizing the taking of the smear and follow-up monitoring., Results: A total of 1251 (79%) general practices returned a questionnaire; 90 questionnaires were excluded from analyses owing to missing data. The 1161 practices were representative of the Netherlands. A minority of the practices adhered to the four guidelines (in total, ten recommendations). The presence of the practice characteristics 'a general practice-based inviting system', 'a high delegation index' (delegating many tasks to the assistants) and a 'computerized patient information recording system' were positively associated with the adherence to most of the guidelines., Conclusion: This study showed that most of the Dutch general practices are not yet ready to organize an effective cervical cancer screening system. A general practice-based inviting system, a high delegation index and a computerized patient information recording system proved to be important for the adherence to the guidelines. In order to organize a cervical screening programme to achieve optimal effectiveness, emphasis should be placed on the adherence to the four guidelines described in this study and on stimulating a general practice-based inviting system, delegation to the practice assistant and computerization.

Cervical cancer is the most prevalent tumor in developing countries and the second most frequent cancer among females worldwide. Specific human papillomaviruses (HPVs) and, most notably, HPV types 16 and 18 are recognized as being causally associated with this malignancy. Antibodies against early HPV proteins E6 and E7 have been found more often in patients with tumors than in controls. Existing peptide enzyme-linked immunosorbent assays (ELISAs) for the detection of anti-E6 and anti-E7 antibodies in human sera have low levels of sensitivity and specificity and thus are not suitable for use as diagnostic tools. Based on highly purified recombinant native proteins, we developed four sandwich ELISAs for the detection of antibodies against HPV type 16 and 18 E6 and E7 proteins. We demonstrate their sensitivities and high degrees of specificity for cervical cancer. Among a total of 501 serum specimens from unselected patients with invasive cervical cancer, 52.9% reacted positively in at least one of the four assays. In contrast, among 244 serum specimens from control subjects without cervical cancer, only 2 reactive serum specimens (0.8%) were found. For 19 of 19 antibody-positive patients, the HPV type indicated by seroreactivity was identical to the HPV DNA type found in the tumor, which also indicates a high degree of specificity for antibody detection with respect to HPV type. In a direct comparison of 72 serum specimens from patients with cervical cancer, 56% of the specimens reacted in at least one of the four protein ELISAs, whereas 40% reacted in at least one of seven peptide ELISAs covering the four antigens. These assays could be of value for the detection of invasive cervical cancer in settings in which cytology-based early tumor screening is not available, for the clinical management of patients diagnosed with cervical cancer, and for the immunological monitoring of E6 and E7 vaccination trials.

A purification protocol was developed to obtain human papillomavirus (HPV) type 16 E7 protein expressed in the yeast Schizosaccharomyces pombe. Only three chromatographic steps were necessary to purify the unfused HPV 16 E7 protein to homogeneity (95-99%) as shown by silver staining after polyacrylamide gel electrophoresis. Approximately 0.8 mg of highly purified E7 was obtained from 5 x 10(10) yeast cells. The purified HPV 16 E7 phosphoprotein (Ser 31/32) was refolded and assayed for functionality. Binding to the proteins Rb1 and p107 in vitro and induction of DNA synthesis after microinjection into serum-deprived NIH 3T3 cells suggest that the E7 protein retains some of its biological activities. Most importantly, the purification strategy is also applicable for different HPV 16 E7 mutants and for E7 proteins from other HPV types such as HPV 18 and 11.

In this study we show, by immunofluorescence and electron microscopy immuno-gold labelling, that the major transforming protein of Human Papillomavirus type 16 E7 is associated with the nucleolus of cells derived from the HPV16-positive cervical carcinoma line CaSki. The E7 nucleolar staining appeared to be cell cycle dependent, being considerably reduced in the G2 phase. The total level of the protein in the cell, however, remained constant during all phases. We also show that the cellular protein Rb1, which is targeted by E7, is localised in the nucleus and nucleolus in CaSki cells. Thus, it is possible that the presence of E7 in the nucleolus correlates with a hypothetical function(s) of Rb1 in this particular intranuclear compartment. The nucleolar localisation of HPV16 E7 protein was also observed in the fission yeast Schizosaccharomyces pombe, suggesting that a targeting mechanism of HPV16 E7 protein into the nucleolus is common to both mammalian and yeast systems. Nucleolar localisation of HPV16 E7 protein may be independent from Rb1 since no Rb1 related proteins have been identified in fission yeast.

Growth of cervical carcinoma cells depends on continuous expression of high risk type human papillomavirus oncogenes E6 and E7. E6 destabilizes p53, a tumor-suppressive transcription factor, which activates expression of the inhibitor of cell cycle progression p21 and other genes. E6-mediated p53 degradation can therefore result in cell cycle deregulation. It has, however, not yet been determined whether p53 inactivation is sufficient to provoke cell cycle progression in established cervical carcinoma cells. Moreover, it has not yet been clarified whether E6 confers additional p53-independent growth stimuli in cancer cells. To address these questions, we analysed p53 functions in SW 756 cervical cancer cells in which the expression of endogenous HPV 18 E6-E7 genes can be downregulated by dexamethasone. This results in significantly increased p53 levels and subsequent cell cycle arrest in the Gz phase. Surprisingly, p53 activities were suppressed rather than enhanced in these cervical cancer cells. However, if high risk papillomavirus type 16 E6 genes, including a mutant which does not degrade p53, were expressed in dexamethasone-treated SW 756 cells with suppressed endogenous HPV type 18 E6-E7 expression, the cells reentered the cell cycle even in the absence of a cooperating viral E7 gene. In contrast, the non oncogenic papillomavirus type 6 E6 gene did not release the cells from growth arrest under these conditions. These data indicate that suppression of p53 functions is not sufficient to provoke cell cycle progression in E6-E7-depleted cervical cancer cells and point to a p53-independent mitotic activity to oncogenic papillomavirus type E6 genes in cervical carcinoma cells.