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1.  Attendance at Cervical Cancer Screening and Use of Diagnostic and Therapeutic Procedures on the Uterine Cervix Assessed from Individual Health Insurance Data (Belgium, 2002-2006) 
PLoS ONE  2014;9(4):e92615.
To assess the coverage for cervical cancer screening as well as the use of cervical cytology, colposcopy and other diagnostic and therapeutic interventions on the uterine cervix in Belgium, using individual health insurance data.
The Intermutualistic Agency compiled a database containing 14 million records from reimbursement claims for Pap smears, colposcopies, cervical biopsies and surgery, performed between 2002 and 2006. Cervical cancer screening coverage was defined as the proportion of women aged 25–64 that had a Pap smear within the last 3 years.
Cervical cancer screening coverage was 61% at national level, for the target population of women between 25 and 64 years old, in the period 2004–2006. Differences between the 3 regions were small, but varied more substantially between provinces. Coverage was 70% for 25–34 year old women, 67% for those aged 35–39 years, and decreased to 44% in the age group of 60–64 years. The median screening interval was 13 months. The screening coverage varied substantially by social category: 40% and 64%, in women categorised as beneficiary or not-beneficiary of increased reimbursement from social insurance, respectively. In the 3-year period 2004–2006, 3.2 million screen tests were done in the target group consisting of 2.8 million women. However, only 1.7 million women got one or more smears and 1.1 million women had no smears, corresponding to an average of 1.88 smears per woman in three years of time. Colposcopy was excessively used (number of Pap smears over colposcopies = 3.2). The proportion of women with a history of conisation or hysterectomy, before the age of 65, was 7% and 19%, respectively.
The screening coverage increased slightly from 59% in 2000 to 61% in 2006. The screening intensity remained at a high level, and the number of cytological examinations was theoretically sufficient to cover more than the whole target population.
PMCID: PMC3972167  PMID: 24690620
2.  EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease 
The EUROGIN 2011 roadmap reviews the current burden of HPV (human papillomavirus)-related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection.
HPV infection causes approximately 600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades.
Randomised trials have demonstrated improved efficacy of HPV-based compared to cytology-based cervical cancer screening. Defining the best algorithms to triage HPV-positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programmes.
HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV-related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, ano-genital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV-related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV.
Key findings in the field of cervical cancer prevention should now be translated in cost-effective strategies, following an organised approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease.
PMCID: PMC3429628  PMID: 22623137
cervical cancer; vulvar cancer; anal cancer; penile cancer; head & neck cancer; genital warts; incidence; mortality; human papillomavirus; HPV; screening; vaccination
3.  Multiple Human Papillomavirus Infections with High Viral Loads Are Associated with Cervical Lesions but Do Not Differentiate Grades of Cervical Abnormalities 
Journal of Clinical Microbiology  2013;51(5):1458-1464.
Multiple human papillomavirus (HPV) genotypes often coexist within cervical epithelia and are frequently detected together in smears of different grades of cervical neoplasia. Describing the association between multiple infections and cervical disease is important in generating hypotheses regarding its pathogenesis. We analyzed the prevalence of multiple HPV infections and their attribution to cervical disease in a screening population of 999 consecutive BD SurePath liquid-based cervical cytology samples enriched with atypical squamous cells of undetermined significance (ASCUS) (n = 100), low-grade squamous intraepithelial lesions (LSIL) (n = 100), and high-grade squamous intraepithelial lesions (HSIL) (n = 97). HPV genotyping was performed only on cytology specimens using a broad-spectrum GP5+/6+-PCR/multiplex HPV genotyping (BSGP5+/6+-PCR/MPG) assay that detects and quantifies 51 HPV genotypes and 3 subtypes. Using a recently defined high viral load cutoff, the quantitative data were scored as high or low viral load. In the 36-month follow-up, 79 histologically confirmed cervical intraepithelial neoplasia grade 2 or greater (CIN2+) cases were identified. In the screening population, there was a trend of having more multiple infections at a younger age. Multiple HPV infections were common. Multiple HPV types were most prevalent in LSIL (75.9% of HPV positives), followed by HSIL (65.5%), ASCUS (64.6%), and negative for intraepithelial lesion or malignancy (NILM) (36.8%). On average, 3.2 and 2.5 HPV types were detected per LSIL and HSIL sample, respectively. Multiple HPV types with high viral loads were most prevalent in LSIL (62.6% of high viral load positives), followed by HSIL (51.9%), ASCUS (40.7%), and NILM (19.3%). Patients with multiple high viral loads showed a 4- to 6-fold-higher risk of having cervical precancerous cytological lesions than did patients with single high viral loads. Compared to NILM, multiple infections, especially with multiple high viral loads, were significantly associated with cytological precancerous lesions. However, the presence of multiple infections did not distinguish low-grade from high-grade cytological lesions.
PMCID: PMC3647930  PMID: 23447632
4.  Impact of Genetic Notification on Smoking Cessation: Systematic Review and Pooled-Analysis 
PLoS ONE  2012;7(7):e40230.
This study aimed to evaluate the impact of genetic notification of smoking-related disease risk on smoking cessation in the general population. Secondary objectives were to assess the impact of genetic notification on intention-to-quit smoking and on emotional outcomes as well as the understanding and the recall of this notification.
A systematic review of articles from inception to August 2011 without language restriction was realized using PubMed, Embase, Scopus, Web of Science, PsycINFO and Toxnet. Other publications were identified using hand search. The pooled-analysis included only randomized trials. Comparison groups were (i) high and low genetic risk versus control, and (ii) high versus low genetic risk. For the pooled-analysis random effect models were applied and sensitivity analyses were conducted.
Eight papers from seven different studies met the inclusion criteria of the review. High genetic risk notification was associated with short-term increased depression and anxiety. Four randomized studies were included in the pooled-analysis, which revealed a significant impact of genetic notification on smoking cessation in comparison to controls (clinical risk notification or no intervention) in short term follow-up less than 6 months (RR = 1.55, 95% CI 1.09–2.21).
In short term follow-up, genetic notification increased smoking cessation in comparison to control interventions. However, there is no evidence of long term effect (up to 12 month) on smoking cessation. Further research is needed to assess more in depth how genetic notification of smoking-related disease could contribute to smoking cessation.
PMCID: PMC3394798  PMID: 22808123
6.  High burden of breast cancer in Belgium: recent trends in incidence (1999-2006) and historical trends in mortality (1954-2006) 
In Belgium, breast cancer mortality has been monitored since 1954, whereas cancer incidence data have only been made available for a few years. In this article we update historical trends of breast cancer mortality and describe the recent breast cancer incidence.
Incidence data were extracted from the Belgium Cancer Registry from 2004 to 2006 for the Walloon and Brussels Regions and Belgium, and from 1999 to 2006 for the Flemish Region. The Directorate-general Statistics and Economic information provided the mortality data for the years 1954-1999 and 2004. The regional authorities of the Flemish and Brussels Regions provided the mortality data for the years 2000-2003 and 2005-2006.
In 2004, the World age-standardised breast cancer incidence for the whole of Belgium was 110 per 100, 000 person-years for all ages; and 172, 390 and 345 per 100, 000 person-years for the 35-49, 50-69, and 70+ age groups, respectively. The incidence rate was slightly higher in each age group in the Brussels Region. In Flanders, where the incidence could be observed during a longer period, an increase was observed until 2003 in the 50-69 age group, followed by a decrease. To the contrary, in the oldest age group, incidence continued to rise over the whole period, whereas no change in incidence was observed between 1999 and 2006 in the 35-49 age group.
Mortality increased until the late 1980s and afterwards decreased in all regions and in age groups younger than 70. In women of 70 years and older, the decline began later.
The burden of breast cancer in Belgium is very high. In 2004, Belgium ranked first for the age-standardised incidence rate in Europe for all ages combined and in the 35-49 and 50-69 age groups. The impact of the known risk factors and of mammographic screening should be further studied. The mortality rate in Belgium ranked lower than incidence, suggesting favourable survival. Plausible explanations for the discrepancy between incidence and mortality are discussed.
PMCID: PMC3436615  PMID: 22958447
7.  HPV E6/E7 mRNA Testing Is More Specific than Cytology in Post-Colposcopy Follow-Up of Women with Negative Cervical Biopsy 
PLoS ONE  2011;6(10):e26022.
In Norway, women with negative or low-grade cervical biopsies (normal/CIN1) are followed up after six months in order to decide on further follow-up or recall for screening at three-year intervals. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures whereas a low risk of high-grade disease among triage negative women assures safety.
Materials and Methods
At the University Hospital of North Norway, cytology and the HPV mRNA test PreTect HPV-Proofer, detecting E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45, are used in post-colposcopy follow-up of women with negative or low-grade biopsy. In this study, women with negative biopsy after high grade cytology (ASC-H/HSIL) and/or positive HPV mRNA test in the period 2005–2009 were included (n = 520). Histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) was used as study endpoint.
Of 520 women with negative or low-grade biopsy, 124 women (23.8%) had CIN2+ in follow-up biopsy. The sensitivity and specificity of the HPV mRNA test were 89.1% (95% CI, 80.1–98.1) and 92.5% (95% CI, 88.2–96.7), respectively. The ratios of sensitivity, specificity and PPV of HPV mRNA testing compared to repeat cytology for finding CIN2+ was 1.05 (95% CI: 0.92–1.21), 1.21 (95% CI: 1.12–1.32), and 1.49 (95% CI: 1.20–1.86), respectively. The PPV of mRNA was 77.3% (95% CI, 59.8–94.8) in women aged 40 or older.
Women with negative cervical biopsy require follow-up before resumption of routine screening. Post-colposcopy HPV mRNA testing was as sensitive but more specific than post-colposcopy cytology. In addition, the HPV mRNA test showed higher PPV. A positive mRNA test post-colposcopy could justify treatment in women above 40 years.
PMCID: PMC3188582  PMID: 21998748
8.  Triage of Women with Low-Grade Cervical Lesions - HPV mRNA Testing versus Repeat Cytology 
PLoS ONE  2011;6(8):e24083.
In Norway, women with low-grade squamous intraepithelial lesions (LSIL) are followed up after six months in order to decide whether they should undergo further follow-up or be referred back to the screening interval of three years. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures.
Materials and Methods
At the University Hospital of North Norway, repeat cytology and the HPV mRNA test PreTect HPV-Proofer, detecting E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45, are used in triage of women with ASC-US and LSIL. In this study, women with LSIL cytology in the period 2005–2008 were included (n = 522). Two triage methods were evaluated in two separate groups: repeat cytology only (n = 225) and HPV mRNA testing in addition to repeat cytology (n = 297). Histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) was used as the study endpoint.
Of 522 women with LSIL, 207 had biopsies and 125 of them had CIN2+. The sensitivity and specificity of repeat cytology (ASC-US or worse) were 85.7% (95% confidence interval (CI): 72.1, 92.2) and 54.4 % (95% CI: 46.9, 61.9), respectively. The sensitivity and specificity of the HPV mRNA test were 94.2% (95% CI: 88.7, 99.7) and 86.0% (95% CI: 81.5, 90.5), respectively. The PPV of repeat cytology was 38.4% (95% CI: 29.9, 46.9) compared to 67.0% (95% CI: 57.7, 76.4) of the HPV mRNA test.
HPV mRNA testing was more sensitive and specific than repeat cytology in triage of women with LSIL cytology. In addition, the HPV mRNA test showed higher PPV. These data indicate that the HPV mRNA test is a better triage test for women with LSIL than repeat cytology.
PMCID: PMC3168878  PMID: 21918682
9.  Age-Specific Patterns of Unsatisfactory Results for Conventional Pap Smears and Liquid-Based Cytology: Data from Two Randomized Clinical Trials 
To investigate the rate of unsatisfactory cervical cell samples in liquid-based (LBC) versus conventional cytology (CC) by age.
randomised clinical trials.
population-based cervical cancer screening in the Netherlands and Italy
Population and sample
asymptomatic women invited for screening enrolled in two randomised trials: NETHCON (Netherlands ThinPrep vs. Conventional Cytology, 39,010 CC, 46,064 LBC) and NTCC (New Technologies in Cervical Cancer Screening, 22,771 CC, 22,403 LBC).
Comparison of categorical variables using Pearson’s chi2 test, logistic regression and trend tests.
Main outcomes
proportion of unsatisfactory samples, ratio LBC versus CC, variation by 5-year group.
In NETHCON, a lower percentage of LBC samples were called unsatisfactory compared to CC (0.33% vs. 1.11%). There was no significant trend in unsatisfactory results by age group for conventional cytology (ptrend = 0.54) but there was a trend towards an increasing percentage of unsatisfactory results with increasing age for LBC (ptrend < 0.001). In NTCC, a lower percentage of LBC samples were called unsatisfactory compared to conventional cytology (2.59% vs. 4.10%). There was a decrease in the unsatisfactory results by age group with conventional cytology (ptrend < 0.001) and with LBC (ptrend = 0.01), although the latter trend was due just to the 55–60 years age group (ptrend = 0.62 when excluding this group).
The clinical trial in which the results were collected and the cytologic method used were the most important determinants of unsatisfactory cytology. In all situations, the proportion of unsatisfactory samples was lower in LBC compared to CC. The effects of age depended on the criteria used to define unsatisfactory results.
PMCID: PMC2915792  PMID: 20604775
cervical cancer screening; liquid-based cytology; conventional cytology; Pap smear; specimen adequacy
10.  Human Papillomavirus Genotype Distribution in Czech Women and Men with Diseases Etiologically Linked to HPV 
PLoS ONE  2011;6(7):e21913.
The HPV prevalence and genotype distribution are important for the estimation of the impact of HPV-based cervical cancer screening and HPV vaccination on the incidence of diseases etiologically linked to HPVs. The HPV genotype distribution varies across different geographical regions. Therefore, we investigated the type-specific HPV prevalence in Czech women and men with anogenital diseases.
We analyzed 157 squamous cell carcinoma samples, 695 precancerous lesion samples and 64 cervical, vulvar and anal condylomata acuminate samples. HPV detection and typing were performed by PCR with GP5+/6+ primers, reverse line blot assay and sequencing.
Thirty different HPV genotypes were detected in our study, HPV 16 being the most prevalent type both in precancerous lesions (45%) and squamous cell carcinomas (59%). In benign lesions, HPV 6 (72%) was the most common type. Altogether, 61% of carcinoma samples and 43% of precancerous lesion samples contained HPV 16 and/or 18. The presence of HPV types related to the vaccinal ones (HPV 31, 45, 33, 52, 58) were detected in 16% of carcinoma samples and 18% of precancerous lesion samples. HPV 16 and/or 18 were present in 76% of cervical cancer samples, 33% of CIN1, 43% CIN2 and 71% of CIN3 samples. HPV types 6 and/or 11 were detected in 84% samples of condylomata acuminate samples.
The prevalence of vaccinal and related HPV types in patients with HPV-associated diseases in the Czech Republic is very high. We may assume that the implementation of routine vaccination against HPV would greatly reduce the burden of HPV-associated diseases in the Czech Republic.
PMCID: PMC3135602  PMID: 21765924
11.  How to evaluate emerging technologies in cervical cancer screening? 
Excellent recommendations exist for studying therapeutic and diagnostic questions. We observe that good guidelines on assessment of evidence for screening questions are currently lacking. Guidelines for diagnostic research (STARD), involving systematic application of the reference test (gold standard) to all subjects of large study populations, are not pertinent in situations of screening for disease that is currently not yet present. A five-step framework is proposed for assessing the potential use of a biomarker as a screening tool for cervical cancer: 1) correlation studies establishing a trend between the rate of biomarker expression and severity of neoplasia; 2) diagnostic studies in a clinical setting where all women are submitted to verification by the reference standard; 3) biobank-based studies with assessment in archived cytology samples of the biomarker in cervical cancer cases and controls; 4) prospective cohort studies with baseline assessment of the biomarker and monitoring of disease; 5) randomised intervention trials aiming to observe reduced incidence of cancer (or its surrogate, severe dysplasia) in the experimental arm at subsequent screening rounds.
The 5-phases framework should guide researchers and test developers in planning assessment of new biomarkers and protect clinicians and stakeholders against premature claims for insufficiently evaluated products.
PMCID: PMC2790915  PMID: 19626591
cervical cancer screening; human papillomavirus; HPV; biomarker; evaluation of diagnostic test; guidelines; health technology assessment
12.  Visual inspection with acetic acid as a cervical cancer test: accuracy validated using latent class analysis 
The purpose of this study was to validate the accuracy of an alternative cervical cancer test – visual inspection with acetic acid (VIA) – by addressing possible imperfections in the gold standard through latent class analysis (LCA). The data were originally collected at peri-urban health clinics in Zimbabwe.
Conventional accuracy (sensitivity/specificity) estimates for VIA and two other screening tests using colposcopy/biopsy as the reference standard were compared to LCA estimates based on results from all four tests. For conventional analysis, negative colposcopy was accepted as a negative outcome when biopsy was not available as the reference standard. With LCA, local dependencies between tests were handled through adding direct effect parameters or additional latent classes to the model.
Two models yielded good fit to the data, a 2-class model with two adjustments and a 3-class model with one adjustment. The definition of latent disease associated with the latter was more stringent, backed by three of the four tests. Under that model, sensitivity for VIA (abnormal+) was 0.74 compared to 0.78 with conventional analyses. Specificity was 0.639 versus 0.568, respectively. By contrast, the LCA-derived sensitivity for colposcopy/biopsy was 0.63.
VIA sensitivity and specificity with the 3-class LCA model were within the range of published data and relatively consistent with conventional analyses, thus validating the original assessment of test accuracy. LCA probably yielded more likely estimates of the true accuracy than did conventional analysis with in-country colposcopy/biopsy as the reference standard. Colpscopy with biopsy can be problematic as a study reference standard and LCA offers the possibility of obtaining estimates adjusted for referent imperfections.
PMCID: PMC2018715  PMID: 17663796
15.  Primary screening for human papillomavirus compared with cytology screening for cervical cancer in European settings: cost effectiveness analysis based on a Dutch microsimulation model 
Objectives To investigate, using a Dutch model, whether and under what variables framed for other European countries screening for human papillomavirus (HPV) is preferred over cytology screening for cervical cancer, and to calculate the preferred number of examinations over a woman’s lifetime.
Design Cost effectiveness analysis based on a Dutch simulation model. Base case analyses investigated the cost effectiveness of more than 1500 different screening policies using the microsimulation model. Subsequently, the policies were compared for five different scenarios that represent different possible scenarios (risk of cervical cancer, previous screening, quality associated test characteristics, costs of testing, and prevalence of HPV).
Setting Various European countries.
Population Unvaccinated women born between 1939 and 1992.
Main outcome measures Optimal screening strategy in terms of incremental cost effectiveness ratios (costs per quality adjusted life years gained) compared with different cost effectiveness thresholds, for two levels of sensitivity and costs of the HPV test.
Results Primary HPV screening was the preferred primary test over the age of 30 in many considered scenarios. Primary cytology screening was preferred only in scenarios with low costs of cytology and in scenarios with a high prevalence of HPV in combination with high costs of HPV testing.
Conclusions Most European countries should consider switching from primary cytology to HPV screening for cervical cancer. HPV screening must, however, only be implemented in situations where screening is well controlled.
PMCID: PMC3293782  PMID: 22391612

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