%0 Journal Article %J Microbiol Spectr %D 2024 %T Assessment of the clinical and analytical performance of three Seegene Allplex SARS-CoV-2 assays within the VALCOR framework. %A Pui Yan Jenny Chung %A Sharon Dhillon %A Cindy Simoens %A Lize Cuypers %A Lies Laenen %A Bonde, Jesper %A Philippe Corbisier %A Gerhard Buttinger %A Clementina E Cocuzza %A Steven Van Gucht %A Marc Van Ranst %A M. Arbyn %K Allplex %K COVID-19 %K diagnostics test accuracy %K Quality Control %K reference materials %K RT-PCR %K SARS-CoV-2 %K Seegene %K STANDARD %K Test validation %K VALCOR %X

The coronavirus disease 2019 pandemic has a significant impact on global public health, economies, and societies. As shown through the first phases of the pandemic, accurate and timely diagnosis is crucial for disease control, prevention, and monitoring. Though the pandemic phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has concluded, diagnostic assays remain in demand to monitor SARS-CoV-2 at the individual patient level, regionally, and nationally, as well as to remain an infectious disease preparedness instrument to monitor any new SARS-CoV-2 dissemination across borders using population and wastewater surveillance. The anticipation by WHO and central health care policy entities such as the Center for Disease Control, EMA, and multiple national health authorities is that SARS-CoV-2 will reside as an endemic respiratory disease for years to come. The key strategic consideration is hence shifting from combating a pandemic situation with a high number of patients to instead allowing precise diagnostics of suspected patients with the intention of correct management in a low-prevalence setting.

%B Microbiol Spectr %8 2024 Jan 08 %G eng %R 10.1128/spectrum.02397-23 %0 Journal Article %J Int J Cancer %D 2024 %T Clinical performance of the novel full-genotyping OncoPredict HPV Quantitative Typing assay using the VALGENT framework. %A Clementina Elvezia Cocuzza %A Sharon Dhillon %A Marianna Martinelli %A Chiara Giubbi %A Njoku, Ruth Chinyere %A Bhatia, Ramya %A Cuschieri, Kate %A M. Arbyn %K Adult %K Early Detection of Cancer %K Female %K Genotype %K Genotyping Techniques %K Humans %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K Reproducibility of Results %K Sensitivity and Specificity %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %K Young adult %X

Clinical validation of human papillomavirus (HPV) assays according to international criteria is prerequisite for their implementation in cervical cancer screening. OncoPredict HPV Quantitative Typing (QT) assay (Hiantis Srl, Milan, Italy) is a novel full-genotyping multiplex real-time PCR quantitative assay targeting E6/E7 genes, allowing individual viral load determination of 12 high-risk (HR) HPV types. Quality controls for sample adequacy, efficiency of nucleic acid extraction and PCR inhibition are included in the assay. Clinical performance of OncoPredict HPV QT test was assessed as part of the "Validation of HPV Genotyping Tests" (VALGENT-2) framework, consisting of 1300 cervical liquid-based cytology (LBC) samples of women aged between 20 and 60 years who had originally attended for routine cervical screening in Scotland. The clinical accuracy of the OncoPredict HPV QT (index test) for the detection of CIN2+ was assessed relative to the GP5+/6+ Enzyme ImmunoAssay (GP5+/6+ EIA) (comparator test), using noninferiority criteria. Intra- and interlaboratory reproducibility of the assay was assessed on a subpopulation, comprising 526 samples. The relative sensitivity and specificity for OncoPredict HPV QT vs GP5+/6+-PCR-EIA were 1.01 (95% CI: 0.99-1.03) and 1.03 (95% CI: 1.0-1.06) respectively. The P-values for noninferiority were ≤0.001. The intra- and inter-laboratory reproducibility demonstrated a high concordance (>98.7%) with kappas for individual types ranging from 0.66 to 1.00. OncoPredict HPV QT fulfills the international validation criteria for the use of HPV tests in cervical cancer screening.

%B Int J Cancer %V 154 %8 2024 Feb 01 %G eng %N 3 %R 10.1002/ijc.34754 %0 Journal Article %J Journal of Clinical Virology %D 2024 %T Human papillomavirus negative high grade cervical lesions and cancers: Suggested guidance for HPV testing quality assurance %A Jean Luc Prétet %A Laila Sara Arroyo Mühr %A Cuschieri, Kate %A Fellner, María Dolores %A Rita Mariel Correa %A Picconi, María Alejandra %A Suzanne M. Garland %A Gerald L. Murray %A Monica Molano %A Michael Peeters %A Steven Van Gucht %A Charlotte Lambrecht %A Broeck, Davy Vanden %A Padalko, Elizaveta %A M. Arbyn %A Quentin Lepiller %A Brunier, Alice %A Steffi Silling %A Kristiane Søreng %A Irene Kraus Christiansen %A Poljak, Mario %A Camilla Lagheden %A Emel Yilmaz %A Eklund, Carina %A Hem R. Thapa %A Troy D. Querec %A Elizabeth R. Unger %A Dillner, Joakim %B Journal of Clinical Virology %V 171 %8 Jan-04-2024 %G eng %R 10.1016/j.jcv.2024.105657 %0 Journal Article %J Archives of Public Health %D 2024 %T Methods for meta-analysis and meta-regression of binomial data: concepts and tutorial with Stata command metapreg %A Victoria N Nyaga %A M. Arbyn %K Binomal %K logistic regression %K meta-analyses %K Meta-regressions %K Network Meta-Analysis %K Stata %X

Background

Despite the widespread interest in meta-analysis of proportions, its rationale, certain theoretical and methodological concepts are poorly understood. The generalized linear models framework is well-established and provides a natural and optimal model for meta-analysis, network meta-analysis, and meta-regression of proportions. Nonetheless, generic methods for meta-analysis of proportions based on the approximation to the normal distribution continue to dominate.

Methods

We developed metapreg, a tool with advanced statistical procedures to perform a meta-analysis, network meta-analysis, and meta-regression of binomial proportions in Stata using binomial, logistic and logistic-normal models. First, we explain the rationale and concepts essential in understanding statistical methods for meta-analysis of binomial proportions and describe the models implemented in metapreg. We then describe and demonstrate the models in metapreg using data from seven published meta-analyses. We also conducted a simulation study to compare the performance of metapreg estimators with the existing estimators of the population-averaged proportion in metaprop and metan under a broad range of conditions including, high over-dispersion and small meta-analysis.

Conclusion

metapreg is a flexible, robust and user-friendly tool employing a rigorous approach to evidence synthesis of binomial data that makes the most efficient use of all available data and does not require ad-hoc continuity correction or data imputation. We expect its use to yield higher-quality meta-analysis of binomial proportions.

%B Archives of Public Health %V 82 %8 29/01/2024 %G eng %R https://link.springer.com/article/10.1186/s13690-023-01215-y %0 Journal Article %J Cancers %D 2023 %T Acceptability to Healthcare Professionals of Home-Based HPV Self-Sampling for Cervical Screening: A French Qualitative Study Conducted in an Area with Low Access to Health Services %A Johane Le Goff %A Anne-Sophie Le Duc-Banasz %A Caroline Lefeuvre %A Adeline Pivert %A Alexandra Ducancelle %A H De Pauw %A M. Arbyn %A Aubeline Vinay %A Franck Rexand-Galais %K cancer screening strategies %K cervical cancer %K health professionals %K low physician density %K semi-structured interview %K underscreened women %K urine self-sampling %K vaginal self-sampling %X

Self-sampling may improve participation in cervical cancer secondary prevention programs by women who do not respond or respond irregularly when invited to contact a health professional for the collection of a cervical specimen. It could also help resolve access problems in areas with a low physician density. The present qualitative study examined barriers to screening, effective screening strategies, and the advantages and disadvantages of sending women urine or vaginal self-sampling kits in two medically underserved administrative departments in France (Mayenne and Sarthe) showing low cervical screening coverage. As part of the CapU4 randomized trial, a team of psychologists investigated the attitudes and experiences of 59 healthcare professionals (gynecologists, general practitioners, and midwives) through semi-structured interviews. Results indicated that health professionals believe that self-sampling may address the issues of low physician density and underscreening by removing logistical, organizational, financial, and psychological obstacles. They confirmed trust in the use of vaginal self-sampling, with urine self-sampling as an alternative solution (e.g., for women with vaginismus). The health professionals also identified several limitations of the self-sampling kit that will need to be addressed in future screening campaigns (incomplete kit, complex instructions, poor anatomical knowledge, and obesity).

%B Cancers %V 15 %8 Jan-11-2023 %G eng %N 21 %R 10.3390/cancers15215163 %0 Journal Article %J Br J Cancer %D 2023 %T Accuracy of HPV E6/E7 oncoprotein tests to detect high-grade cervical lesions: a systematic literature review and meta-analysis. %A Laura Downham %A Iman Jaafar %A Mary Luz Rol %A Victoria N Nyaga %A Joan Valls %A Armando Baena %A Zhang, Li %A Marc J Gunter %A M. Arbyn %A Maribel Almonte %K Cervical cardiogenesis %K Cervical lesions %K HPV %X

BACKGROUND:
Cervical carcinogenesis is mediated by the HPV-E6 and E7 oncoproteins, considered as biomarkers usable in managing screen-positive women.

METHODS:
We conducted a systematic review and meta-analysis assessing the accuracy of HPV-E6/E7-oncoprotein tests to detect underlying cervical-precancer and cancer. We included studies reporting data on oncoprotein test accuracy detecting cervical intraepithelial neoplasia grade 3 or worse. Random effects logistic regression models were applied for pooling absolute and relative accuracy.

RESULTS:
Twenty-two studies were included. Sensitivity and specificity estimates ranged from 54.2% (95%CI: 45.2-63.0) to 69.5% (95%CI:60.8-76.9) and from 82.8% (95%CI: 50.4-95.8) to 99.1 (95%CI: 98.8-99.3), respectively in the population irrespective of HPV status. Higher sensitivity estimates ranging from 60.8% (95%CI: 49.6-70.9) to 75.5% (95%CI: 71.7-78.9) but lower specificity estimates ranging from 83.7% (95%CI: 76.1-89.3) to 92.1% (95%CI: 88.5-94.6) were observed in studies enrolling high-risk-HPV-positive women. Studies recruiting only HIV-positive women showed a pooled sensitivity of 46.9% (95%CI: 30.6-63.9) with a specificity of 98.0% (95%CI: 96.8-98.7).

CONCLUSIONS:
The high specificity of oncoprotein tests supports its use for triaging HPV-positive women. However, oncoprotein-negative women would not be recommended to undertake routine screening, requiring further follow-up. Large-scale and longitudinal studies are needed to further investigate the role of E6/E7-oncoprotein detection in predicting the risk of developing cervical pre-cancer and cancer.

%B Br J Cancer %8 2023 Nov 16 %G eng %R 10.1038/s41416-023-02490-w %0 Journal Article %J Virol J %D 2023 %T Assessment of the clinical and analytical performance of the Aptima SARS-CoV-2 assay using the VALCOR protocol. %A Sharon Dhillon %A Cindy Simoens %A Lize Cuypers %A Jannes Bode %A Bonde, Jesper %A Philippe Corbisier %A Clementina E Cocuzza %A Marc Van Ranst %A M. Arbyn %K Clinical Laboratory Techniques %K COVID-19 %K COVID-19 Testing %K Humans %K Molecular Diagnostic Techniques %K Pandemics %K SARS-CoV-2 %K Sensitivity and Specificity %X

BACKGROUND:
The COVID-19 pandemic highlighted the importance of diagnostic testing against curbing the spread of SARS-CoV-2. The urgent need and scale for diagnostic tools resulted in manufacturers of SARS-CoV-2 assays receiving emergency authorization that lacked robust analytical or clinical evaluation. As it is highly likely that testing for SARS-CoV-2 will continue to play a central role in public health, the performance characteristics of assays should be evaluated to ensure reliable diagnostic outcomes are achieved.

METHODS:
VALCOR or "VALidation of SARS-CORona Virus-2 assays" is a study protocol designed to set up a framework for test validation of SARS-CoV-2 virus assays. Using clinical samples collated from VALCOR, the performance of Aptima SARS-CoV-2 assay was assessed against a standard comparator assay. Diagnostic test parameters such as sensitivity, specificity and overall per cent agreement were calculated for the clinical performance of Aptima SARS-CoV-2 assay.

RESULTS:
A total of 180 clinical samples were tested with an addition of 40 diluted clinical specimens to determine the limit of detection. When compared to the standard comparator assay Aptima had a sensitivity of 100.0% [95% CI 95.9-100.0] and specificity of 96.7% [95% CI 90.8-99.3]. The overall percent agreement was 98.3% with an excellent Cohen's coefficient of κ = 0.967 [95% CI 0.929-1.000]. For the limit of detection, Aptima was able to detect all of the diluted clinical samples.

CONCLUSION:
In conclusion. validation of Aptima SARS-CoV-2 assay using clinical samples collated through the VALCOR protocol showed excellent test performance. Additionally, Aptima demonstrated high analytical sensitivity by detecting all diluted clinical samples corresponding to a low limit of detection.

%B Virol J %V 20 %8 2023 Feb 24 %G eng %N 1 %R 10.1186/s12985-023-01986-4 %0 Journal Article %J Nat Med %D 2023 %T Benefits and harms of cervical screening, triage and treatment strategies in women living with HIV. %A Michaela T Hall %A Kate T Simms %A John M Murray %A Adam Keane %A Diep T N Nguyen %A Michael Caruana %A Gigi Lui %A Helen Kelly %A Linda O Eckert %A Santesso, Nancy %A de Sanjosé, Silvia %A Edwin E Swai %A Rangaraj, Ajay %A Owiredu, Morkor Newman %A Cindy Gauvreau %A Owen Demke %A Partha Basu %A M. Arbyn %A Dalal, Shona %A Broutet, Nathalie %A Canfell, Karen %K Acetic Acid %K Cervix Uteri %K Early Detection of Cancer %K Female %K HIV Infections %K Humans %K Papillomavirus Infections %K triage %K Uterine Cervical Neoplasms %X

To support a strategy to eliminate cervical cancer as a public health problem, the World Health Organisation (WHO) reviewed its guidelines for screening and treatment of cervical pre-cancerous lesions in 2021. Women living with HIV have 6-times the risk of cervical cancer compared to women in the general population, and we harnessed a model platform ('Policy1-Cervix-HIV') to evaluate the benefits and harms of a range of screening strategies for women living with HIV in Tanzania, a country with endemic HIV. Assuming 70% coverage, we found that 3-yearly primary HPV screening without triage would reduce age-standardised cervical cancer mortality rates by 72%, with a number needed to treat (NNT) of 38.7, to prevent a cervical cancer death. Triaging HPV positive women before treatment resulted in minimal loss of effectiveness and had more favorable NNTs (19.7-33.0). Screening using visual inspection with acetic acid (VIA) or cytology was less effective than primary HPV and, in the case of VIA, generated a far higher NNT of 107.5. These findings support the WHO 2021 recommendation that women living with HIV are screened with primary HPV testing in a screen-triage-and-treat approach starting at 25 years, with regular screening every 3-5 years.

%B Nat Med %V 29 %8 2023 Dec %G eng %N 12 %R 10.1038/s41591-023-02601-3 %0 Journal Article %J Nat Med %D 2023 %T Benefits, harms and cost-effectiveness of cervical screening, triage and treatment strategies for women in the general population. %A Kate T Simms %A Adam Keane %A Nguyen, Diep Thi Ngoc %A Michael Caruana %A Michaela T Hall %A Gigi Lui %A Cindy Gauvreau %A Owen Demke %A M. Arbyn %A Partha Basu %A Wentzensen, Nicolas %A Beatrice Lauby-Secretan %A Andre Ilbawi %A Raymond Hutubessy %A Maribel Almonte %A de Sanjosé, Silvia %A Helen Kelly %A Dalal, Shona %A Linda O Eckert %A Santesso, Nancy %A Broutet, Nathalie %A Canfell, Karen %K Adult %K Cervix Uteri %K Child, Preschool %K Cost-Benefit Analysis %K Early Detection of Cancer %K Female %K Humans %K Papillomavirus Infections %K triage %K Uterine Cervical Neoplasms %X

In 2020, the World Health Organization (WHO) launched a strategy to eliminate cervical cancer as a public health problem. To support the strategy, the WHO published updated cervical screening guidelines in 2021. To inform this update, we used an established modeling platform, Policy1-Cervix, to evaluate the impact of seven primary screening scenarios across 78 low- and lower-middle-income countries (LMICs) for the general population of women. Assuming 70% coverage, we found that primary human papillomavirus (HPV) screening approaches were the most effective and cost-effective, reducing cervical cancer age-standardized mortality rates by 63-67% when offered every 5 years. Strategies involving triaging women before treatment (with 16/18 genotyping, cytology, visual inspection with acetic acid (VIA) or colposcopy) had close-to-similar effectiveness to HPV screening without triage and fewer pre-cancer treatments. Screening with VIA or cytology every 3 years was less effective and less cost-effective than HPV screening every 5 years. Furthermore, VIA generated more than double the number of pre-cancer treatments compared to HPV. In conclusion, primary HPV screening is the most effective, cost-effective and efficient cervical screening option in LMICs. These findings have directly informed WHO's updated cervical screening guidelines for the general population of women, which recommend primary HPV screening in a screen-and-treat or screen-triage-and-treat approach, starting from age 30 years with screening every 5 years or 10 years.

%B Nat Med %V 29 %8 2023 Dec %G eng %N 12 %R 10.1038/s41591-023-02600-4 %0 Journal Article %J Clin Microbiol Infect %D 2023 %T Can REALQUALITY RQ-HPV screen be considered as a clinically validated HPV test for use in cervical cancer screening? %A M. Arbyn %A Cuschieri, Kate %A Poljak, Mario %A Bonde, Jesper %K Early Detection of Cancer %K Female %K Humans %K Mass Screening %K Papillomaviridae %K Papillomavirus Infections %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %K Vaginal Smears %X

"Can REALQUALITY RQ-HPV screen be considered as a clinically validated HPV test for use in cervical cancer screening?"

%B Clin Microbiol Infect %V 29 %8 2023 Dec %G eng %N 12 %R 10.1016/j.cmi.2023.08.020 %0 Journal Article %J ESGO Textbook of Gynaecological Oncology %D 2023 %T Chapter 10: HPV testing on cervical cancer specimens: which assay can be used in cervical cancer screening. %A M. Arbyn %A P. Rousta %A Sharon Dhillon %A M. Gultekin %A K. Cuschieri %K cervical cancer screening %K gynaecological oncology %K HPV %K HPV screening %X

HPV-based screening offers more effective prevention against cervical cancer than cytology-based screening. Managers of screening programmes need to know which HPV tests are credible and have evidence-based performance in primary screening. Systematic reviews have assessed which high-risk HPV DNA tests are sufficiently reproducible and have non-inferior clinical accuracy compared to standard comparator tests already evaluated in large randomised trials. Other reviews compared the cross-sectional and longitudinal performance of hrHPV mRNA tests with validated DNA tests. These reviews are updated and summarised in this chapter. The assays that can be considered as clinically validated are listed in Text Box 1:

Published by Günes Publishing 2023

%B ESGO Textbook of Gynaecological Oncology %G eng %& 115 %0 Journal Article %J J Mol Diagn %D 2023 %T Clinical Accuracy of Alinity m HR HPV Assay on Self- versus Clinician-Taken Samples Using the VALHUDES Protocol. %A Ardashel Latsuzbaia %A Severien Van Keer %A Vanden Broeck, Davy %A Weyers, Steven %A Gilbert Donders %A Philippe De Sutter %A Wiebren Tjalma %A Jean Doyen %A Alex Vorsters %A M. Arbyn %K Early Detection of Cancer %K Female %K Human Papillomavirus Viruses %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Sensitivity and Specificity %K specimen handling %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %X

The VALHUDES protocol was established to evaluate clinical accuracy of human papillomavirus (HPV) assays to detect cervical precancer on first-void urine (FVU) and vaginal self-samples versus matched clinician-collected cervical samples (CCSs). Here we evaluated clinical performance of Alinity m HR HPV assay in a colposcopy referral population. Home-collected FVU (Colli-Pee FV 5020) 1 day before colposcopy (n = 492), at-clinic collected dry vaginal self-samples [multi-Collect Swab (mC; n = 493), followed by Evalyn Brush (EB; n = 233) or Qvintip (QT; n = 260)] and matched CCSs, were available for the study. Sensitivity to detect cervical intraepithelial neoplasia grade 2 or higher (CIN2) of Alinity testing on FVU (ratio, 0.94; 95% CI, 0.85-1.03), mC (ratio, 1.00; 95% CI, 0.94-1.06), and EB/QT (ratio, 0.92; 95% CI, 0.85-1.00) was not different to CCSs. Specificity on FVU was similar to CCS (ratio, 1.02; 95% CI, 0.95-1.10), whereas specificity on mC was lower (ratio, 0.83; 95% CI, 0.76-0.90), but on EB/QT was higher (ratio, 1.08; 95% CI, 1.01-1.15) than on CCS. Accuracy on EB (sensitivity ratio, 0.96; 95% CI, 0.87-1.05; specificity ratio, 1.18; 95% CI, 1.06-1.31) was slightly better than on QT (sensitivity ratio, 0.88; 95% CI, 0.75-1.03; specificity ratio, 1.00; 95% CI, 0.92-1.09). In conclusion, clinical sensitivity of Alinity assay on all self-sample types was similar to cervical specimens. Adjustment of signal thresholds improved assay's accuracy to detect CIN2 in all self-sample types.

%B J Mol Diagn %V 25 %8 2023 Dec %G eng %N 12 %R 10.1016/j.jmoldx.2023.09.008 %0 Journal Article %J Res Synth Methods %D 2023 %T Comparison and validation of metadta for meta-analysis of diagnostic test accuracy studies. %A Victoria N Nyaga %A M. Arbyn %K Diagnostic Tests, Routine %K Network Meta-Analysis %K Research Design %K SOFTWARE %X

We developed metadta, a flexible, robust, and user-friendly statistical procedure that fuses established and innovative statistical methods for meta-analysis, meta-regression, and network meta-analysis of diagnostic test accuracy studies in Stata. Using data from published meta-analyses, we validate metadta by comparing and contrasting its features and output to popular procedures dedicated to the meta-analysis of diagnostic test accuracy studies; (midas [Stata], metandi [Stata], metaDTA [web application], mada [R], and MetaDAS [SAS]). We also demonstrate how to perform network meta-analysis with metadta, for which no alternative procedure is dedicated to network meta-analysis of diagnostic test accuracy data in the frequentist framework. metadta generated consistent estimates in simple and complex diagnostic test accuracy data sets. We expect its availability to stimulate better statistical practice in the evidence synthesis of diagnostic test accuracy studies.

%B Res Synth Methods %V 14 %8 2023 May %G eng %N 3 %R 10.1002/jrsm.1634 %0 Journal Article %J J Mol Diagn %D 2023 %T Comparison of the Clinical Accuracy of Xpert HPV Assay on Vaginal Self-Samples and Cervical Clinician-Taken Samples within the VALHUDES Framework. %A Ardashel Latsuzbaia %A Vanden Broeck, Davy %A Severien Van Keer %A Weyers, Steven %A Gilbert Donders %A Jean Doyen %A Wiebren Tjalma %A Philippe De Sutter %A Alex Vorsters %A M. Arbyn %K Adult %K Early Detection of Cancer %K Female %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Sensitivity and Specificity %K specimen handling %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %K Vagina %X

The accuracy of high-risk human papillomavirus testing with the Xpert HPV assay on vaginal self-samples was compared with clinician-taken samples within the VALidation of HUman papillomavirus assays and collection DEvices for Self-samples and urine samples (VALHUDES) framework. Five-hundred and twenty-three women were recruited in five Belgian colposcopy clinics, of whom 483 (median age, 40 years; interquartile range, 31 to 49 years) were included in the main analysis (226 collected with Evalyn Brush and 257 collected with Qvintip). Cervical samples were collected with Cervex-Brush. Colposcopy and histology outcomes were considered as the reference standard. The Xpert HPV assay had similar accuracy for cervical intraepithelial neoplasia ≥2 on self-collected versus clinician-collected samples [relative sensitivity, 0.96 (95% CI, 0.91-1.02); and relative specificity, 0.96 (95% CI, 0.89-1.04)]. The relative accuracy slightly differed by vaginal collection device [sensitivity ratios of 0.98 (95% CI, 0.90-1.06) and 0.94 (95% CI, 0.87-1.02) for Evalyn and Qvintip, respectively; specificity ratios of 1.06 (95% CI, 0.95-1.19) and 0.88 (95% CI, 0.80-0.98) for Evalyn and Qvintip, respectively]. No difference in cycle threshold values was observed between vaginal and cervical samples. In conclusion, the sensitivity of Xpert HPV assay for cervical intraepithelial neoplasia ≥2 on vaginal self-samples was similar to that of cervical specimens. The clinical specificity was lower than on clinician-collected samples when self-samples were taken with Qvintip.

%B J Mol Diagn %V 25 %8 2023 Sep %G eng %N 9 %R 10.1016/j.jmoldx.2023.06.004 %0 Journal Article %J Int J Gynecol Cancer %D 2023 %T ESGO Prevention Committee opinion: is a single dose of HPV vaccine good enough? %A Mustafa Onur Kamani %A Kyrgiou, Maria %A Elmar Joura %A Ignacio Zapardiel %A Mihaela Grigore %A M. Arbyn %A Mario Preti %A François Planchamp %A Murat Gultekin %K Cervix Uteri %K Female %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Papillomavirus Vaccines %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %X

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%B Int J Gynecol Cancer %V 33 %8 2023 Apr 03 %G eng %N 4 %R 10.1136/ijgc-2023-004295 %0 Journal Article %J Journal of Medical Virology %D 2023 %T Evaluation of the clinical performance of OncoPredict HPV® SCR assay within the VALGENT‐2 framework %A Sharon Dhillon %A Clementina E. Cocuzza %A Jenny Pui Yan Chung %A Marianna Martinelli %A Chiara Giubbi %A Ruth C. Njoku %A Bhatia, Ramya %A Cuschieri, Kate %A M. Arbyn %K cervical cancer %K HPV genotyping %K human papillomavirus %K OncoPredict HPV® %K test validation. %K VALGENT %X

Human papillomavirus (HPV) assays used in cervical cancer screening should be clinically validated according to international criteria. OncoPredict HPV® Screening (SCR) is a partial genotyping multiplex real-time PCR assay targeting E6/E7 genes of 13 high-risk (hr) HPVs. OncoPredict HPV® SCR (index assay) identifies HPV-16 and HPV-18 separately, 11 other hrHPV in aggregate and includes quality controls for sample adequacy, DNA extraction efficiency and PCR inhibition. 1300 VALGENT-2 study samples (from women aged 20-60 attending the Scottish cervical cancer screening program) were tested with the index assay and the GP5+/6+ PCR enzyme immunoassay (standard comparator assay). Non-inferior accuracy detecting cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) of the index versus comparator was verified. Intra- and interlaboratory reproducibility of the index was evaluated by overall concordance and Cohen's kappa, using a sub-population (n = 526). Relative sensitivity and specificity for CIN2+ of the index versus comparator were 1.01 (95% confidence interval [CI]: 0.99-1.03) and 1.02 (95% CI: 1.0-1.04), respectively. Noninferiority p values were all ≤0.05, except for CIN3+ in patients ≥30 years. Excellent intra- and interlaboratory reproducibility was shown with concordance >98% and kappas >0.95. OncoPredict HPV® SCR fulfills the three international validation criteria for hrHPV DNA tests in cervical cancer screening.

%B Journal of Medical Virology %V 95 %8 Jan-01-2023 %G eng %N 1 %R 10.1002/jmv.28417 %0 Journal Article %J J Med Virol %D 2023 %T Evaluation of the clinical performance of OncoPredict HPV® SCR assay within the VALGENT-2 framework. %A Sharon Dhillon %A Clementina E Cocuzza %A Pui Yan Jen Chung %A Marianna Martinelli %A Chiara Giubbi %A Ruth C Njoku %A Bhatia, Ramya %A Cuschieri, Kate %A M. Arbyn %K Early Detection of Cancer %K Female %K Genotyping Techniques %K Human Papillomavirus Viruses %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Real-Time Polymerase Chain Reaction %K Reproducibility of Results %K Sensitivity and Specificity %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %X

Human papillomavirus (HPV) assays used in cervical cancer screening should be clinically validated according to international criteria. OncoPredict HPV® Screening (SCR) is a partial genotyping multiplex real-time PCR assay targeting E6/E7 genes of 13 high-risk (hr) HPVs. OncoPredict HPV® SCR (index assay) identifies HPV-16 and HPV-18 separately, 11 other hrHPV in aggregate and includes quality controls for sample adequacy, DNA extraction efficiency and PCR inhibition. 1300 VALGENT-2 study samples (from women aged 20-60 attending the Scottish cervical cancer screening program) were tested with the index assay and the GP5+/6+ PCR enzyme immunoassay (standard comparator assay). Non-inferior accuracy detecting cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) of the index versus comparator was verified. Intra- and interlaboratory reproducibility of the index was evaluated by overall concordance and Cohen's kappa, using a sub-population (n = 526). Relative sensitivity and specificity for CIN2+ of the index versus comparator were 1.01 (95% confidence interval [CI]: 0.99-1.03) and 1.02 (95% CI: 1.0-1.04), respectively. Noninferiority p values were all ≤0.05, except for CIN3+ in patients ≥30 years. Excellent intra- and interlaboratory reproducibility was shown with concordance >98% and kappas >0.95. OncoPredict HPV® SCR fulfills the three international validation criteria for hrHPV DNA tests in cervical cancer screening.

%B J Med Virol %V 95 %8 2023 Jan %G eng %N 1 %R 10.1002/jmv.28417 %0 Journal Article %J Lancet Glob Health %D 2023 %T Global and regional estimates of genital human papillomavirus prevalence among men: a systematic review and meta-analysis. %A Bruni, Laia %A Albero, Ginesa %A Jane Rowley %A Alemany, Laia %A M. Arbyn %A Anna R Giuliano %A Markowitz, Lauri E %A Broutet, Nathalie %A Melanie Taylor %K Adult %K Female %K Human Papillomavirus Viruses %K Humans %K Male %K Papillomaviridae %K Papillomavirus Infections %K prevalence %K Sexually Transmitted Diseases %K Uterine Cervical Neoplasms %K Young adult %X

BACKGROUND:
The epidemiology of human papillomavirus (HPV) in women has been well documented. Less is known about the epidemiology of HPV in men. We aim to provide updated global and regional pooled overall, type-specific, and age-specific prevalence estimates of genital HPV infection in men.

METHODS:
We conducted a systematic review and meta-analysis to assess the prevalence of genital HPV infection in the general male population. We searched Embase, Ovid MEDLINE, and the Global Index Medicus for studies published between Jan 1, 1995, and June 1, 2022. Inclusion criteria were population-based surveys in men aged 15 years or older or HPV prevalence studies with a sample size of at least 50 men with no HPV-related pathology or known risk factors for HPV infection that collected samples from anogenital sites and used PCR or hybrid capture 2 techniques for HPV DNA detection. Exclusion criteria were studies conducted among populations at increased risk of HPV infection, exclusively conducted among circumcised men, and based on urine or semen samples. We screened identified reports and extracted summary-level data from those that were eligible. Data were extracted by two researchers independently and reviewed by a third, and discrepancies were resolved by consensus. We extracted only data on mucosal α-genus HPVs. Global and regional age-specific prevalences for any HPV, high-risk (HR)-HPV, and individual HPV types were estimated using random-effects models for meta-analysis and grouped by UN Sustainable Development Goals geographical classification.

FINDINGS:
We identified 5685 publications from database searches, of which 65 studies (comprising 44 769 men) were included from 35 countries. The global pooled prevalence was 31% (95% CI 27-35) for any HPV and 21% (18-24) for HR-HPV. HPV-16 was the most prevalent HPV genotype (5%, 95% CI 4-7) followed by HPV-6 (4%, 3-5). HPV prevalence was high in young adults, reaching a maximum between the ages of 25 years and 29 years, and stabilised or slightly decreased thereafter. Pooled prevalence estimates were similar for the UN Sustainable Development Goal geographical regions of Europe and Northern America, Sub-Saharan Africa, Latin America and the Caribbean, and Australia and New Zealand (Oceania). The estimates for Eastern and South-Eastern Asia were half that of the other regions.

INTERPRETATION:
Almost one in three men worldwide are infected with at least one genital HPV type and around one in five men are infected with one or more HR-HPV types. Our findings show that HPV prevalence is high in men over the age of 15 years and support that sexually active men, regardless of age, are an important reservoir of HPV genital infection. These estimates emphasise the importance of incorporating men in comprehensive HPV prevention strategies to reduce HPV-related morbidity and mortality in men and ultimately achieve elimination of cervical cancer and other HPV-related diseases.

FUNDING:
Instituto de Salud Carlos III, European Regional Development Fund, Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia, and Horizon 2020.

TRANSLATIONS:
For the Spanish and French translations of the abstract see Supplementary Materials section.

%B Lancet Glob Health %V 11 %8 2023 Sep %G eng %N 9 %R 10.1016/S2214-109X(23)00305-4 %0 Journal Article %J Lancet Glob Health %D 2023 %T Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative. %A Deependra Singh %A Jerome Vignat %A Valentina Lorenzoni %A Marzieh Eslahi %A Ophira Ginsburg %A Beatrice Lauby-Secretan %A M. Arbyn %A Partha Basu %A Bray, Freddie %A Salvatore Vaccarella %K Female %K Global Health %K Humans %K incidence %K Malawi %K Uganda %K Uterine Cervical Neoplasms %K World Health Organization %X

BACKGROUND:
Tracking progress and providing timely evidence is a fundamental step forward for countries to remain aligned with the targets set by WHO to eliminate cervical cancer as a public health problem (ie, to reduce the incidence of the disease below a threshold of 4 cases per 100 000 women-years). We aimed to assess the extent of global inequalities in cervical cancer incidence and mortality, based on The Global Cancer Observatory (GLOBOCAN) 2020 estimates, including geographical and socioeconomic development, and temporal aspects.

METHODS:
For this analysis, we used the GLOBOCAN 2020 database to estimate the age-specific and age-standardised incidence and mortality rates of cervical cancer per 100 000 women-years for 185 countries or territories aggregated across the 20 UN-defined world regions, and by four-tier levels of the Human Development Index (HDI). Time trends (1988-2017) in incidence were extracted from the Cancer Incidence in Five Continents (CI5) plus database. Mortality estimates were obtained using the most recent national vital registration data from WHO.

FINDINGS:
Globally in 2020, there were an estimated 604 127 cervical cancer cases and 341 831 deaths, with a corresponding age-standardised incidence of 13·3 cases per 100 000 women-years (95% CI 13·3-13·3) and mortality rate of 7·2 deaths per 100 000 women-years (95% CI 7·2-7·3). Cervical cancer incidence ranged from 2·2 (1·9-2·4) in Iraq to 84·6 (74·8-94·3) in Eswatini. Mortality rates ranged from 1·0 (0·8-1·2) in Switzerland to 55·7 (47·7-63·7) in Eswatini. Age-standardised incidence was highest in Malawi (67·9 [95% CI 65·7 -70·1]) and Zambia (65·5 [63·0-67·9]) in Africa, Bolivia (36·6 [35·0-38·2]) and Paraguay (34·1 [32·1-36·1]) in Latin America, Maldives (24·5 [17·0-32·0]) and Indonesia (24·4 [24·2-24·7]) in Asia, and Fiji (29·8 [24·7-35·0]) and Papua New Guinea (29·2 [27·3-31·0]) in Melanesia. A clear socioeconomic gradient exists in cervical cancer, with decreasing rates as HDI increased. Incidence was three times higher in countries with low HDI than countries with very high HDI, whereas mortality rates were six times higher in low HDI countries versus very high HDI countries. In 2020 estimates, a general decline in incidence was observed in most countries of the world with representative trend data, with incidence becoming stable at relatively low levels around 2005 in several high-income countries. By contrast, in the same period incidence increased in some countries in eastern Africa and eastern Europe. We observed different patterns of age-specific incidence between countries with well developed population-based screening and treatment services (eg, Sweden, Australia, and the UK) and countries with insufficient and opportunistic services (eg, Colombia, India, and Uganda).

INTERPRETATION:
The burden of cervical cancer remains high in many parts of the world, and in most countries, the incidence and mortality of the disease remain much higher than the threshold set by the WHO initiative on cervical cancer elimination. We identified substantial geographical and socioeconomic inequalities in cervical cancer globally, with a clear gradient of increasing rates for countries with lower levels of human development. Our study provides timely evidence and impetus for future strategies that prioritise and accelerate progress towards the WHO elimination targets and, in so doing, address the marked variations in the global cervical cancer landscape today.

FUNDING:
French Institut National du Cancer, Horizon 2020 Framework Programme for Research and Innovation of the European Commission; and EU4Health Programme.

%B Lancet Glob Health %V 11 %8 2023 Feb %G eng %N 2 %R 10.1016/S2214-109X(22)00501-0 %0 Journal Article %J BMC Cancer %D 2023 %T HPV testing in Polish population-based cervical cancer screening programme (HIPPO project)-study protocol of a randomised healthcare policy trial. %A Patrycja Glinska %A Katarzyna Komerska %A Beata Janik %A Julia Olkowicz %A Ilona Jedrzejewska %A Anna Macios %A Paulina Wieszczy %A Michal F Kaminski %A M. Arbyn %A Nowakowski, Andrzej %K Atypical Squamous Cells of the Cervix %K Colposcopy %K Early Detection of Cancer %K Female %K HEALTH POLICY %K Humans %K Mass Screening %K Papillomaviridae %K Papillomavirus Infections %K Poland %K Pregnancy %K Randomized Controlled Trials as Topic %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %K Vaginal Smears %X

BACKGROUND:
An Organised Cervical Cancer Screening Programme (OCCSP) was started in Poland in 2006/2007. Each woman aged 25 to 59 is eligible for a free Pap test every 3 years in OCCSP. Despite implementation of the OCCSP, the age-standardised cervical cancer (CC) incidence and mortality rates in 2019 were 7.3/100 000 and 3.9/100 000 respectively and were still higher than those in Western European countries with well-organised screening programmes. Apart from low coverage of the OCCSP, suboptimal performance of the screening test (conventional cytology) may be partially responsible for this situation. Several countries have already incorporated high risk Human Papillomavirus (hrHPV) testing in CC screening as a more sensitive tool reducing the risk of missing precancerous lesions and allowing for extension of screening intervals. The European Guidelines for Quality Assurance in Cervical Cancer Screening recommend pilot evaluation of a new screening test in country-specific conditions before its implementation.

METHODS:
The HIPPO project (HPV testing In Polish POpulation-based cervical cancer screening program) is a randomised health services study nested in the OCCSP in Poland. The project will randomise 33 000 women aged 30-59 years to cytology or hrHPV testing (ratio: 1:1) with age stratification. In the cytology arm women with repeated Atypical Squamous Cells of Undetermined Significance (ASC-US) or ≥ Low-Grade Squamous Intraepithelial Lesions (LSIL) are referred for colposcopy. In the other arm, hrHPV ( +) women with ≥ ASC-US reflex Liquid-Based Cytology (LBC) are referred for colposcopy. Primary endpoints include detection rates of histologically confirmed high grade intraepithelial lesions or worse (CIN2 +) in each arm.

DISCUSSION:
his pilot randomised healthcare study nested in the OCCSP in Poland will assess and compare the performance of hrHPV testing to current standard-cytology in order to make decisions on implementation of HPV-based screening in the country.

TRIAL REGISTRATION:
This randomised healthcare service study was prospectively registered at https://clinicaltrials.gov/ (identifier: NCT04111835, protocol ID 28/2019) on 19th of September 2019.

%B BMC Cancer %V 23 %8 2023 Nov 17 %G eng %N 1 %R 10.1186/s12885-023-11597-5 %0 Journal Article %J Cancer Epidemiol Biomarkers Prev %D 2023 %T HPV-based Cervical Cancer Screening on Self-samples in the Netherlands: Challenges to Reach Women and Test Performance Questions. %A M. Arbyn %A Stefanie Costa %A Ardashel Latsuzbaia %A Eliane Kellen %A Paolo Girogi Rossi %A Clementina E Cocuzza %A Partha Basu %A Castle, Philip E %K Early Detection of Cancer %K Female %K Humans %K Mass Screening %K Netherlands %K Papillomaviridae %K Papillomavirus Infections %K specimen handling %K Uterine Cervical Neoplasms %X

In 2017, cervical cancer screening in the Netherlands switched from cytology to human papillomavirus (HPV) testing using the validated PCR-based cobas 4800. Women could order and subsequently received a free self-sampling kit (Evalyn Brush) at their home address instead of clinician sampling. In the laboratory, the shipped brush was placed into 20 mL of PreservCyt fluid, before testing. In the first 2 years of the new program, only 7% of screening tests were performed on a self-sample. Those who chose self-sampling versus clinician sampling were more likely to have never been screened previously and differed also with respect to sociodemographic factors. Subsequent more active promotion and increasing the ease to obtain kits increased the proportion opting for self-sampling (16% in 2020). HPV positivity and detection rate of precancer (CIN3+) were lower in the self-sampling compared with the clinician-sampling group (adjusted ORs of 0.65 and 0.86, respectively). Although population differences may partially explain these results, self-samples may have been too dilute, thereby reducing the analytic and clinical sensitivity. The Dutch findings demonstrate the importance of optimizing outreach, specimen handling and testing protocols for self-samples to effectively screen the target population and reach in particular the women at highest risk for cervical cancer. See related article by Aitken et al., p. 183.

%B Cancer Epidemiol Biomarkers Prev %V 32 %8 2023 Feb 06 %G eng %N 2 %R 10.1158/1055-9965.EPI-22-1041 %0 Journal Article %J PLoS One %D 2023 %T Integrating human papillomavirus testing as a point-of care service using GeneXpert platforms: Findings and lessons from a Kenyan pilot study (2019-2020). %A Valerian Mwenda %A Joan-Paula Bor %A Mary Nyangasi %A James Njeru %A Sharon Olwande %A Patricia Njiri %A M. Arbyn %A Weyers, Steven %A Philippe Tummers %A Temmerman, Marleen %K Acetic Acid %K Early Detection of Cancer %K Female %K Human Papillomavirus Viruses %K Humans %K KENYA %K Mass Screening %K Papillomaviridae %K Papillomavirus Infections %K Pilot Projects %K Point-of-Care Systems %K Uterine Cervical Neoplasms %X

BACKGROUND:
Globally, cervical cancer is a major public health problem, with about 604,000 new cases and over 340,000 deaths in 2020. In Kenya, it is the leading cause of cancer deaths, with over 3,000 women dying in 2020 alone. Both the Kenyan cancer screening guidelines and the World Health Organization's Global Cervical Cancer Elimination Strategy recommend human papillomavirus (HPV) testing as the primary screening test. However, HPV testing is not widely available in the public healthcare system in Kenya. We conducted a pilot study using a point of care (POC) HPV test to inform national roll-out.

METHODS:
The pilot was implemented from October 2019 to December 2020, in nine health facilities across six counties. We utilized the GeneXpert platform (Cepheid, Sunnyvale, CA, USA), currently used for TB, Viral load testing and early infant diagnosis for HIV, for HPV screening. Visual inspection with acetic acid (VIA) was used for triage of HPV-positive women, as recommended in national guidelines. Quality assurance (QA) was performed by the National Oncology Reference Laboratory (NORL), using the COBAS 4800 platform (Roche Molecular System, Pleasanton, CF, USA). HPV testing was done using either self or clinician-collected samples. We assessed the following screening performance indicators: screening coverage, screen test positivity, triage compliance, triage positivity and treatment compliance. Test agreement between local GeneXpert and central comparator high-risk HPV (hrHPV) testing for a random set of specimens was calculated as overall concordance and kappa value. We conducted a final evaluation and applied the Nominal Group Technique (NGT) to identify implementation challenges and opportunities.

KEY FINDINGS:
The screening coverage of target population was 27.0% (4500/16,666); 52.8% (2376/4500) were between 30-49 years of age. HPV positivity rate was 22.8% (1027/4500). Only 10% (105/1027) of HPV positive cases were triaged with VIA/VILI; 21% (22/105) tested VIA/VILI positive, and 73% (16/22) received treatment (15 received cryotherapy, 1 was referred for biopsy). The median HPV testing turnaround time (TAT) was 24 hours (IQR 2-48 hours). Invalid sample rate was 2.0% (91/4500). Concordance between the Cepheid and COBAS was 86.2% (kappa value = 0.71). Of 1042 healthcare workers, only 5.6% (58/1042) were trained in cervical cancer screening and treatment, and only 69% (40/58) of those trained were stationed at service provision areas. Testing capacity was identifed as the main challenge, while the community strategy was the main opportunity.

CONCLUSION:
HPV testing can be performed on GeneXpert as a near point of care platform. However, triage compliance and testing TAT were major concerns. We recommend strengthening of the screening-triage-treatment cascade and expansion of testing capacity, before adoption of a GeneXpert-based HPV screening among other near point of care platforms in Kenya.

%B PLoS One %V 18 %8 2023 %G eng %N 5 %R 10.1371/journal.pone.0286202 %0 Journal Article %J J Med Virol %D 2023 %T Intra- and interlaboratory reproducibility of the RIATOL qPCR HPV genotyping assay. %A Sharon Dhillon %A Pui Yan Jen Chung %A Padalko, Elizaveta %A Praet, Marleen %A Ana Rita Pereira %A Nina Redzic %A Vanden Broeck, Davy %A M. Arbyn %K Dna %K Early Detection of Cancer %K Female %K Genotype %K Human Papillomavirus Viruses %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Reproducibility of Results %K Uterine Cervical Neoplasms %X

The implementation of cervical screening based on human papillomavirus (HPV) continues to progress rapidly across countries. Evidence has shown that assays detecting high-risk human papillomavirus (hrHPV) deoxyribonucleic acid (DNA) are more effective than cytology-based screening. Validation of new hrHPV DNA assays requires both noninferior clinical accuracy compared to a standard comparator for cervical precancer and good reproducibility. This study builds upon previous diagnostic accuracy assessments of the RIATOL HPV genotyping qPCR assay and aims to evaluate the international validation criteria for reproducibility. The intra- and interreproducibility of the RIATOL-qPCR assay were assessed using 550 remnant cervical cell material from the cytology archive of the National Reference Center for HPV in Belgium. Specimens were collected in the context of cervical cancer screening and tested in two different laboratories. The international reproducibility criteria include the lower bound of 95% confidence interval of the intra- and interlaboratory agreement regarding the detection of hrHPV DNA exceeding 87% with kappa ≥0.50. The RIATOL-qPCR assay demonstrated excellent intralaboratory reproducibility, achieving an overall agreement of 98.2 (95% CI 96.6-99.1%) and a kappa of 0.96. Interlaboratory testing showed an overall agreement of 98.5 (95% CI 97.1-99.4%) with a kappa of 0.97. The RIATOL-qPCR assay fulfills the third criterion for HPV test reproducibility requirement for use in cervical cancer screening.

%B J Med Virol %V 95 %8 2023 Sep %G eng %N 9 %R 10.1002/jmv.29093 %0 Journal Article %J J Clin Virol %D 2023 %T IPVS policy statement on HPV nucleic acid testing guidance for those utilising/considering HPV as primary precancer screening: Quality assurance and quality control issues. %A Garland, Suzanne M %A Thomas Iftner %A Cuschieri, Kate %A Andreas M Kaufmann %A M. Arbyn %A de Sanjosé, Silvia %A Poljak, Mario %A Dillner, Joakim %A Elizabeth R Unger %K Early Detection of Cancer %K Female %K Humans %K Mass Screening %K nucleic acids %K Papillomaviridae %K Papillomavirus Infections %K POLICY %K Quality Control %K Uterine Cervical Neoplasms %X

We advise that only clinically validated HPV assays which have fulfilled internationally accepted performance criteria be used for primary cervical screening. Further, assays should be demonstrated to be fit for purpose in the laboratory in which they will ultimately be performed, and quality materials manuals and frameworks will be helpful in this endeavor. Importantly, there is a fundamental shortage of well validated, low-cost, low complexity HPV tests that have demonstrated utility in a near-patient setting; representing a significant challenge and focus for future development in order to reach the WHO's goal of eliminating cervical cancer.

%B J Clin Virol %V 159 %8 2023 Feb %G eng %R 10.1016/j.jcv.2022.105349 %0 Journal Article %J J Clin Pathol %D 2023 %T Papilloplex HR-HPV test has non-inferior clinical performance for detection of human papillomavirus infection: assessment using the VALGENT framework. %A Bhatia, Ramya %A Elia Alcaniz Boada %A Bonde, Jesper Hansen %A Wim G V Quint %A Xu, Lan %A Ejegod, Ditte Moller %A Cuschieri, Kate %A M. Arbyn %K Early Detection of Cancer %K Female %K Human Papillomavirus Viruses %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Sensitivity and Specificity %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %X

AIM:
The Papilloplex high-risk human papillomavirus (hrHPV) test (Genefirst, Oxford, UK) is a single tube real-time HPV test which provides multiplex detection and separate identification of 14 hrHPV types. Here, we present the clinical validation of the test in SurePath samples in comparison to a clinically validated reference test, the GP5+/6+Enzyme ImmunoAssay (GP5+/6+EIA) using the VALGENT (VALidation of HPV GENotyping Tests) framework.

METHODS:
Clinical performance was assessed using 998 unselected, cervical screening samples enriched with 297 cytologically abnormal specimens (100 atypical squamous cells of unspecified significance, 100 low-grade squamous intraepithelial lesions, 97 high-grade squamous intraepithelial lesions). Cases were defined as women diagnosed with histologically confirmed cervical intraepithelial neoplasia two or more (≥CIN2, N=119) and controls defined as women with two subsequent negative cytology results (N=834).

RESULTS:
The Papilloplex HR-HPV test has non-inferior sensitivity for detection of cervical precancer (p=0.0001 for ≥CIN2 and p=0.0005 for ≥CIN3) and non-inferior specificity, compared with GP5+/6+EIA (pni=0.0167)). The assay also showed excellent or good agreement for overall hrHPV and nearly all individual HPV types as compared with GP5+/6+EIA/Luminex.

CONCLUSION:
The Papilloplex HR-HPV applied on cervical specimens stored in SurePath medium fulfils the international clinical accuracy criteria for use in cervical cancer screening.

%B J Clin Pathol %V 76 %8 March 2023 %G eng %N 3 %R 10.1136/jclinpath-2021-207864 %0 Journal Article %J BMJ Open %D 2023 %T Protocol for a systematic review and meta-analysis of the diagnostic test accuracy of host and HPV DNA methylation in cervical cancer screening and management. %A Sarah J Bowden %A Ellis, Laura Burney %A Kalliala, Ilkka %A Paraskevaidi, Maria %A Jack Tighe %A Konstantinos S Kechagias %A Triada Doulgeraki %A Paraskevaidis, Evangelos %A M. Arbyn %A James Flanagan %A Veroniki, Areti %A Kyrgiou, Maria %K Diagnostic Tests, Routine %K Dna %K DNA Methylation %K Early Detection of Cancer %K Female %K Humans %K Meta-Analysis as Topic %K Papillomavirus Infections %K Sensitivity and Specificity %K Systematic Reviews as Topic %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %X

INTRODUCTION:
Human papillomavirus (HPV) is necessary but not sufficient for cervical cancer development. During cervical carcinogenesis, methylation levels increase across host and HPV DNA. DNA methylation has been proposed as a test to diagnose cervical intraepithelial neoplasia (CIN); we present a protocol to evaluate the accuracy of methylation markers to detect high-grade CIN and cervical cancer.

METHODS AND ANALYSIS:
We will search electronic databases (Medline, Embase and Cochrane Library), from inception, to identify studies examining DNA methylation as a diagnostic marker for CIN or cervical cancer, in a cervical screening population. The primary outcome will be to assess the diagnostic test accuracy of host and HPV DNA methylation for high-grade CIN; the secondary outcomes will be to examine the accuracy of different methylation cut-off thresholds, and accuracy in high-risk HPV positive women. Our reference standard will be histology. We will perform meta-analyses using Cochrane guidelines for diagnostic test accuracy. We will use the number of true positives, false negatives, true negatives and false positives from individual studies. We will use the bivariate mixed effect model to estimate sensitivity and specificity with 95% CIs; we will employ different bivariate models to estimate sensitivity and specificity at different thresholds if sufficient data per threshold. For insufficient data, the hierarchical summary receiver operating curve model will be used to calculate a summary curve across thresholds. If there is interstudy and intrastudy variation in thresholds, we will use a linear mixed effects model to calculate the optimum threshold. If few studies are available, we will simplify models by assuming no correlation between sensitivity and specificity and perform univariate, random-effects meta-analysis. We will assess the quality of studies using QUADAS-2 and QUADAS-C.

ETHICS AND DISSEMINATION:
Ethical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public.

PROSPERO REGISTRATION NUMBER:
RD42022299760.

%B BMJ Open %V 13 %8 2023 Jun 05 %G eng %N 6 %R 10.1136/bmjopen-2022-071534 %0 Journal Article %J BMC Infectious Diseases %D 2022 %T Accuracy of high-risk HPV DNA PCR, p16(INK4a) immunohistochemistry or the combination of both to diagnose HPV-driven oropharyngeal cancer %A Cindy Simoens %A Gheit, Tarik %A Ridder, Ruediger %A Ivana Gorbaslieva %A Holzinger, Dana %A Lucas, Eric %A Rehm, Susanne %A Peter Vermeulen %A Martin Lammens %A Olivier Vanderveken %A Kumar, Rekha Vijay %A Gangane, Nitin %A Alessandro Caniglia %A Maffini, Fausto %A Maria Belén Lloveras Rubio %A Anantharaman, Devasena %A Chiocca, Susanna %A Brennan, Paul %A Madhavan R Pillai %A Sankaranarayanan, Rengaswamy %A Bogers, Johannes %A Pawlita, Michael %A Tommasino, Massimo %A M. Arbyn %K HPV DNA PCR; p16(INK4a) IHC; HPV mRNA; Oropharyngeal carcinoma; HPV-AHEAD %X

Background

The incidence of high-risk human papillomavirus (hrHPV)-driven head and neck squamous cell carcinoma, in particular oropharyngeal cancers (OPC), is increasing in high-resource countries. Patients with HPV-induced cancer respond better to treatment and consequently have lower case-fatality rates than patients with HPV-unrelated OPC. These considerations highlight the importance of reliable and accurate markers to diagnose truly HPV-induced OPC.

Methods

The accuracy of three possible test strategies, i.e. (a) hrHPV DNA PCR (DNA), (b) p16(INK4a) immunohistochemistry (IHC) (p16), and (c) the combination of both tests (considering joint DNA and p16 positivity as positivity criterion), was analysed in tissue samples from 99 Belgian OPC patients enrolled in the HPV-AHEAD study. Presence of HPV E6*I mRNA (mRNA) was considered as the reference, indicating HPV etiology.

Results

Ninety-nine OPC patients were included, for which the positivity rates were 36.4%, 34.0% and 28.9% for DNA, p16 and mRNA, respectively. Ninety-five OPC patients had valid test results for all three tests (DNA, p16 and mRNA). Using mRNA status as the reference, DNA testing showed 100% (28/28) sensitivity, and 92.5% (62/67) specificity for the detection of HPV-driven cancer. p16 was 96.4% (27/28) sensitive and equally specific (92.5%; 62/67). The sensitivity and specificity of combined p16 + DNA testing was 96.4% (27/28) and 97.0% (65/67), respectively. In this series, p16 alone and combined p16 + DNA missed 1 in 28 HPV driven cancers, but p16 alone misclassified 5 in 67 non-HPV driven as positive, whereas combined testing would misclassify only 2 in 67.

Conclusions

Single hrHPV DNA PCR and p16(INK4a) IHC are highly sensitive but less specific than using combined testing to diagnose HPV-driven OPC patients. Disease prognostication can be encouraged based on this combined test result.

%B BMC Infectious Diseases %V 22 %8 06 August 2022 %G eng %R https://doi.org/10.1186/s12879-022-07654-2 %0 Journal Article %J Tumour Virus Res %D 2022 %T HPV and head and neck cancers: Towards early diagnosis and prevention. %A Luisa Galati %A Chiocca, Susanna %A Daria Duca %A Marta Tagliabue %A Cindy Simoens %A Gheit, Tarik %A M. Arbyn %A Tommasino, Massimo %X

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with an increasing trend of its incidence. Alcohol consumption, smoking, and viral infections, such as the mucosal high-risk (HR) human papillomaviruses (HPVs) are major risk factors for HNSCC development. In particular, HR HPVs are mainly associated with a subset of oropharyngeal squamous cell carcinoma (OPSCC), while other head and neck sites are marginally affected by HPV infection. HPV16 is the most frequently HR HPV type associated with HNSCC. In contrast to the cervix, no screening programs or identifiable pre-malignant lesions have been characterized for HPV-related HNSCC. Therefore, identification of general diagnostic algorithms and HPV biomarkers that could facilitate the early diagnosis, disease evolution and recurrence for HPV-driven HNSCCs are urgently needed. We herein review the role of HPV in HNSCC with a focus on epidemiology, biology, applied diagnostic algorithms and available biomarkers in body fluids as early diagnostic tools in HPV-driven HNSCCs.

%B Tumour Virus Res %V 14 %8 2022 Aug 13 %G eng %R 10.1016/j.tvr.2022.200245 %0 Journal Article %J BMC Cancer %D 2022 %T The non-fatal burden of cancer in Belgium, 2004–2019: a nationwide registry-based study %A Vanessa Gorasso %A Geert Silversmit %A M. Arbyn %A Astrid Cornez %A Robby De Pauw %A Delphine De Smedt %A Ian Grant %A Grant M. A. Wyper %A Brecht Devleesschauwer %A Niko Speybroeck %K burden of disease %K Cancer epidemiology %K Disability-Adjusted Life Years %K Years lived with disability %X

Background

The importance of assessing and monitoring the health status of a population has grown in the last decades. Consistent and high quality data on the morbidity and mortality impact of a disease represent the key element for this assessment. Being increasingly used in global and national burden of diseases (BoD) studies, the Disability-Adjusted Life Year (DALY) is an indicator that combines healthy life years lost due to living with disease (Years Lived with Disability; YLD) and due to dying prematurely (Years of Life Lost; YLL). As a step towards a comprehensive national burden of disease study, this study aims to estimate the non-fatal burden of cancer in Belgium using national data.

Methods

We estimated the Belgian cancer burden from 2004 to 2019 in terms of YLD, using national population-based cancer registry data and international disease models. We developed a microsimulation model to translate incidence- into prevalence-based estimates, and used expert elicitation to integrate the long-term impact of increased disability due to surgical treatment.

Results

The age-standardized non-fatal burden of cancer increased from 2004 to 2019 by 6 and 3% respectively for incidence- and prevalence-based YLDs. In 2019, in Belgium, breast cancer had the highest morbidity impact among women, followed by colorectal and non-melanoma skin cancer. Among men, prostate cancer had the highest morbidity impact, followed by colorectal and non-melanoma skin cancer. Between 2004 and 2019, non-melanoma skin cancer significantly increased for both sexes in terms of age-standardized incidence-based YLD per 100,000, from 49 to 111 for men and from 15 to 44 for women. Important decreases were seen for colorectal cancer for both sexes in terms of age-standardized incidence-based YLD per 100,000, from 105 to 84 for men and from 66 to 58 for women.

Conclusions

Breast and prostate cancers represent the greatest proportion of cancer morbidity, while for both sexes the morbidity burden of skin cancer has shown an important increase from 2004 onwards. Integrating the current study in the Belgian national burden of disease study will allow monitoring of the burden of cancer over time, highlighting new trends and assessing the impact of public health policies.

%B BMC Cancer %V 22 %8 Jan-12-2022 %G eng %N 1 %R 10.1186/s12885-021-09109-4 %0 Journal Article %J British Journal of Cancer %D 2022 %T Offering HPV self-sampling kits: an updated meta-analysis of the effectiveness of strategies to increase participation in cervical cancer screening %A Stefanie Costa %A Bo Verberckmoes %A Philip E Castle %A M. Arbyn %K cervical cancer screening %K HPV %K SCREENING %K self-sampling %K self-sampling kits %X

BACKGROUND:
Human papillomavirus (HPV) testing on self-samples represents a great opportunity to increase cervical cancer screening uptake among under-screened women.

METHODS:
A systematic review and meta-analysis on randomised controlled trials (RCTs) were performed to update the evidence on the efficacy of strategies for offering self-sampling kits for HPV testing compared to conventional invitations and to compare different self-sampling invitation scenarios. Four experimental invitational scenarios were considered. Women in the control group were invited for screening according to existing practice: collection of a cervical specimen by a healthcare professional. Random-effects models were used to pool proportions, relative participation rates and absolute participation differences.

RESULTS:
Thirty-three trials were included. In the intention-to-treat analysis, all self-sampling invitation scenarios were more effective in reaching under-screened women compared to controls. Pooled participation difference (PD) and 95% confidence interval (CI) for experimental vs. control was 13.2% (95% CI = 11.0–15.3%) for mail-to-all, 4.4% (95% CI = 1.2–7.6%) for opt-in, 39.1% (95% CI = 8.4–69.9%) for community mobilisation & outreach and 28.1% (23.5–32.7%) for offer at healthcare service. PD for the comparison opt-in vs. mail-to-all, assessed in nine trials, was −8.2% (95% CI = −10.8 to −5.7%).

DISCUSSION:
Overall, screening participation was higher among women invited for self-sampling compared to control, regardless of the invitation strategy used. Opt-in strategies were less effective than send-to-all strategies.

%B British Journal of Cancer %8 14/12/2022 %G eng %R 10.1038/s41416-022-02094-w %0 Journal Article %J Int J Public Health %D 2022 %T Study Protocol: Randomised Controlled Trial Assessing the Efficacy of Strategies Involving Self-Sampling in Cervical Cancer Screening. %A Caroline Lefeuvre %A H De Pauw %A Anne-Sophie Le Duc Banaszuk %A Adeline Pivert %A Alexandra Ducancelle %A Franck Rexand-Galais %A M. Arbyn %K Adult %K Aged %K Early Detection of Cancer %K Female %K Humans %K middle aged %K Randomized Controlled Trials as Topic %K Self Care %K specimen handling %K Uterine Cervical Neoplasms %K Vaginal Smears %X

The cervical cancer screening coverage remains moderate (60%) in France. The aim of the study is to evaluate the efficacy of two experimental invitation strategies (offer of urine or vaginal self-sampling kits) to reach under-screened populations and compare them with the current invitation strategy in rural departments (low medical density and low participation rate) in France. The study is a randomised controlled trial with three arms: a control arm (conventional invitation letter) and two experimental arms (mailing of a urine or vaginal self-sampling kit). The target population includes women aged 30-65 years, who had no screening test recorded since more than 4 years and who did not respond to an invitation letter within 12 months before. The primary outcome measure is the participation rate in each arm. A team of psychologists will also investigate attitudes and experiences by semi-structured/focus-group interviews with voluntary CapU4 participants and with health professionals. CapU4 will identify effective strategies to reach women not responding to current screening invitations and will generate information about acceptance of self-sampling among women and health professionals.

%B Int J Public Health %V 67 %8 2022 %G eng %R 10.3389/ijph.2022.1604284 %0 Journal Article %J Arch Public Health %D 2022 %T VALCOR: a protocol for the validation of SARS-corona virus-2 assays. %A M. Arbyn %A Sharon Dhillon %A Marianna Martinelli %A Cindy Simoens %A Lize Cuypers %A Jannes Bode %A Van Ranst, Marc %A Philippe Corbisier %A Bonde, Jesper %A Clementina Cocuzza %X

BACKGROUND: Testing for SARS-CoV-2, together with vaccination, is one of the most vital strategies in curbing the current COVID-19 pandemic. The pandemic has led to an unprecedented need for diagnostic testing and the rapid emergence of an abundance of commercial assays on the market. Due to the nature of the pandemic and in the interest of health protection, many of these assays received provisional authorisation for emergency use without thorough validation. To limit false negative and false positive results, it is key to define common criteria that SARS-CoV-2 assays need to fulfil. VALCOR or "VALidation of SARS-CORona Virus-2 assays" is a protocol designed to set up a framework for test validation of SARS-CoV-2 virus assays.

OBJECTIVES: VALCOR is a study protocol for the validation of assays used for confirmation of the presence of SARS-CoV-2 in patients with COVID-19 disease or the screening of carriers of SARS-CoV-2 virus by the identification of viral RNA in oropharyngeal and/or nasopharyngeal specimens or other specimens from the human respiratory tract.

METHODS: The VALCOR panel of samples will contain clinical human specimens and standardised artificial specimens. The collection of clinical specimens will include nasopharyngeal or oropharyngeal specimens or other specimens from the respiratory tract obtained from COVID-19 patients and healthy carriers of SARS-CoV-2 as well as specimens from subjects not carrying SARS-CoV-2. Artificial specimens include calibrated amounts of viral RNA of SARS-CoV-2 sequences provided by established competent agencies that produce reference materials for the assessment of the limit of detection of each assay. The panel of samples are sent from a central reference laboratory (having access to biobanks of clinical specimens tested already for SARS-CoV-2 with a reference comparator assay) to participating laboratories for testing with a SARS-CoV-2 index assay that requires evaluation.

DISCUSSION: VALCOR provides a harmonised and standard framework to benchmark the testing performance of SARS-CoV-2 assays that are rapidly evolving. As the pandemic incited an urgent need for testing capacity, there is a gap in the comprehensive validation of SARS-CoV-2 assays. This study will generate comprehensive validation data for assays used for the diagnosis of SARS-CoV-2 and may serve as a basis for other validation protocols.

%B Arch Public Health %V 80 %8 2022 Mar 29 %G eng %N 1 %R 10.1186/s13690-022-00869-4 %0 Journal Article %J Archives of Public Health %D 2022 %T VALCOR: a protocol for the validation of SARS-corona virus-2 assays %A M. Arbyn %A Sharon Dhillon %A Marianna Martinelli %A Cindy Simoens %A Lize Cuypers %A Jannes Bode %A Van Ranst, Marc %A Philippe Corbisier %A Bonde, Jesper %A Clementina Cocuzza %K COVID-19 %K diagnostic test accuracy %K Quality Control %K SARS-CoV-2 %K test validation. %X

Background: Testing for SARS-CoV-2, together with vaccination, is one of the most vital strategies in curbing the current COVID-19 pandemic. The pandemic has led to an unprecedented need for diagnostic testing and the rapid emergence of an abundance of commercial assays on the market. Due to the nature of the pandemic and in the interest of health protection, many of these assays received provisional authorisation for emergency use without thorough validation. To limit false negative and false positive results, it is key to define common criteria that SARS-CoV-2 assays need to fulfil. VALCOR or "VALidation of SARS-CORona Virus-2 assays" is a protocol designed to set up a framework for test validation of SARS-CoV-2 virus assays.

Objectives: VALCOR is a study protocol for the validation of assays used for confirmation of the presence of SARS-CoV-2 in patients with COVID-19 disease or the screening of carriers of SARS-CoV-2 virus by the identification of viral RNA in oropharyngeal and/or nasopharyngeal specimens or other specimens from the human respiratory tract.

Methods: The VALCOR panel of samples will contain clinical human specimens and standardised artificial specimens. The collection of clinical specimens will include nasopharyngeal or oropharyngeal specimens or other specimens from the respiratory tract obtained from COVID-19 patients and healthy carriers of SARS-CoV-2 as well as specimens from subjects not carrying SARS-CoV-2. Artificial specimens include calibrated amounts of viral RNA of SARS-CoV-2 sequences provided by established competent agencies that produce reference materials for the assessment of the limit of detection of each assay. The panel of samples are sent from a central reference laboratory (having access to biobanks of clinical specimens tested already for SARS-CoV-2 with a reference comparator assay) to participating laboratories for testing with a SARS-CoV-2 index assay that requires evaluation.

Discussion: VALCOR provides a harmonised and standard framework to benchmark the testing performance of SARS-CoV-2 assays that are rapidly evolving. As the pandemic incited an urgent need for testing capacity, there is a gap in the comprehensive validation of SARS-CoV-2 assays. This study will generate comprehensive validation data for assays used for the diagnosis of SARS-CoV-2 and may serve as a basis for other validation protocols.

%B Archives of Public Health %V 80 %8 Jan-12-2022 %G eng %N 1 %R 10.1186/s13690-022-00869-4 %0 Journal Article %J Archives of Public Health %D 2021 %T Cervical cancer screening using HPV tests on self-samples: attitudes and preferences of women participating in the VALHUDES study %A H De Pauw %A Gilbert Donders %A Weyers, Steven %A Philippe De Sutter %A Jean Doyen %A Wiebren A.A. Tjalma %A Vanden Broeck, Davy %A Eliana Peeters %A Severien Van Keer %A Alex Vorsters %A M. Arbyn %K ATTITUDES %K cervical cancer %K HPV %K human papillomavirus %K Preferences %K SCREENING %K self-sampling %K urine %K VALHUDES %X

BACKGROUND
Interventions to reach women who do not participate regularly in screening may reduce the risk of cervical cancer. Self-collection of a vaginal specimen has been shown to increase participation. The relative clinical accuracy of human papillomavirus (HPV) testing on first-void urine (with Colli-Pee) and on vaginal self-samples versus on cervical clinician-collected samples is being investigated in the VALHUDES trial. The current study assesses attitudes and experiences regarding self-sampling among women enrolled in VALHUDES.

METHODS
Questionnaires from 515 women (age 25–64 years [N = 498]; < 25 [N = 10], age ≥ 65 [N = 3], enrolled between December 2017 - January 2020) referred to colposcopy because of previous cervical abnormalities and enrolled in VALHUDES (NCT03064087) were analysed.

RESULTS
Of the 515 participants, nearly all women confirmed that self-sampling may help in reaching under-screened women (93%). Nevertheless, 44% of the participants stated before starting collection that a clinician-collected sample is more effective than a self-collected sample. After self-sampling, the large majority of women (> 95%) declared that instructions for self-collection were clear, that collection was easy, and that they were confident about having performed the procedure correctly, for both urine and vaginal collection. However, a proportion of women found self-sampling unpleasant (9.5% [49/515] for urine collection; 18.6% [96/515] and 15.5% [80/515] for vaginal sampling with cotton swabs or plastic brushes, respectively). For their next screening round, 57% would prefer self-sampling whereas 41% opted for collection by a clinician. Among women preferring self-sampling, 53% would choose for urine collection, 38% for vaginal self-collection and 9% had no preference. Age did not modify preferences.

CONCLUSION
We conclude that both urine and vaginal self-sampling are well accepted by women, with a preference for urine sampling. Although the large majority of women are confident in their ability to perform self-sampling, four to five over ten women preferred specimen collection by a clinician.

%B Archives of Public Health %V 79 %8 Jan-12-2021 %G eng %N 1 %R 10.1186/s13690-021-00667-4 %0 Journal Article %J Journal of Clinical Microbiology %D 2021 %T Clinical and analytical evaluation of the Alinity m HR HPV assay within the VALGENT-3 framework %A Sharon Dhillon %A Valenčak, Anja Oštrbenk %A Lan Xu %A Poljak, Mario %A M. Arbyn %X

Only clinically validated human papillomavirus (HPV) tests should be used in cervical cancer screening. VALGENT provides a framework to validate new HPV tests. In the VALGENT-3 study, the clinical accuracy of the recently launched Abbott Alinity m HR HPV assay (Alinity m) to detect cervical precancerous lesions was assessed against the standard comparator test (Hybrid Capture 2; HC2) and additionally against two previously validated alternative comparator tests (Abbott RealTime HR HPV and Roche cobas 4800 assays). Validation was conducted using 1,300 consecutive cervical samples from women attending an organized population-based cervical screening program enriched with 300 cytologically abnormal samples. Overall hrHPV test concordance was assessed by kappa values; the concordance for HPV-16 and HPV-18 was assessed for Alinity m, RealTime, and cobas, and the Linear Array (Roche) was used for more detailed genotyping concordance. In the total study population, the relative sensitivity and specificity for CIN2+ and CIN3+ of Alinity m compared to HC2 was 1.02 (95% CI:0.99–1.06) and 1.03 (95% CI:0.99–1.06), respectively. The relative specificity for ≤ CIN1 was 1.01 (95% CI:1.00–1.02) (all pni ≤ 0.001). Alinity m showed non-inferior clinical accuracy among women 30 years or older when cobas or RealTime were used as comparators. HPV genotype-specific concordance between Alinity m and the three comparator tests showed excellent agreement, with kappa values ranging between 0.82 and 1.00. In conclusion, Alinity m fulfils the international accuracy requirements for use in cervical cancer screening and shows excellent HPV genotype-specific concordance with three clinically validated HPV tests.

%B Journal of Clinical Microbiology %8 May-03-2022 %G eng %R 10.1128/JCM.00286-21 %0 Journal Article %J International Journal of Cancer %D 2021 %T The European response to the WHO call cervical cancer as a public health problem %A M. Arbyn %A Murat Gultekin %A Philippe Morice %A Nieminen, Pekka %A Maggie Cruickshank %A Philip Poortmans %A Daniel Kelly %A Poljak, Mario %A Bergeron, Christine %A David Ritchie %A Dietmar Schmidt %A Kyrgiou, Maria %A Ann Van den Bruel %A Bruni, Laia %A Partha Basu %A Bray, Freddie %A Weiderpass, Elisabete %K cervical cancer screening %K COVID-19 %K elimination of cervical cancer %K Europe %K HPV vaccination %K WHO %X

The age‐standardised incidence of cervical cancer in Europe varies widely (between 3 and 25/100000 women‐years) in 2018. HPV vaccine coverage is low in countries with the highest incidence and screening performance is heterogeneous among European countries. A broad group of delegates of scientific professional societies and cancer organisations endorse the principles of the WHO call to eliminate cervical cancer as a public health problem, also in Europe.
All European nations should, by 2030, reach at least 90% HPV vaccine coverage among girls by the age of 15 years and also boys, if cost‐effective; they should introduce organised population‐based HPV‐based screening and achieve 70% of screening coverage in the target age group, providing also HPV testing on self‐samples for non‐ or under‐screened women; and to manage 90% of screen‐positive women. To guide member states, a group of scientific professional societies and cancer organisations engage to assist in the roll‐out of a series of concerted evidence‐based actions. European health authorities are requested to mandate a group of experts to develop the third edition of European Guidelines for Quality Assurance of Cervical Cancer prevention based on integrated HPV vaccination and screening and to monitor the progress towards the elimination goal. The occurrence of the COVID‐19 pandemic, having interrupted prevention activities temporarily, should not deviate stakeholders from this ambition. In the immediate post‐epidemic phase, health professionals should focus on high‐risk women and adhere to cost‐effective policies including self‐sampling.

%B International Journal of Cancer %V 148 %8 Mar-01-2022 %G eng %N 2 %R 10.1002/ijc.33189 %0 Journal Article %J The Journal of Molecular Diagnostics %D 2021 %T Evaluating Diagnostic Accuracy of Saliva Sampling Methods for Severe Acute Respiratory Syndrome Coronavirus 2 Reveals Differential Sensitivity and Association with Viral Load %A Pieter Mestdagh %A Michel Gillard %A Sharon Dhillon %A Pirnay, Jean-Paul %A J Poels %A Jan Hellemans %A Veronik Hutse %A Celine Vermeiren %A Boutier, Maxime %A Veerle De Wever %A Patrick Soentjens %A Sarah Djebara %A Hugues Malonne %A Emmanuel André %A M. Arbyn %A John Smeraglia %A Vandesompele, Jo %B The Journal of Molecular Diagnostics %V 23 %8 Jan-10-2021 %G eng %N 10 %R 10.1016/j.jmoldx.2021.07.017 %0 Journal Article %J J Mol Diagn %D 2021 %T Evaluating Diagnostic Accuracy of Saliva Sampling Methods for Severe Acute Respiratory Syndrome Coronavirus 2 Reveals Differential Sensitivity and Association with Viral Load. %A Pieter Mestdagh %A Michel Gillard %A Sharon Dhillon %A Pirnay, Jean-Paul %A J Poels %A Jan Hellemans %A Veronik Hutse %A Celine Vermeiren %A Boutier, Maxime %A Veerle De Wever %A Patrick Soentjens %A Sarah Djebara %A Hugues Malonne %A Emmanuel André %A M. Arbyn %A John Smeraglia %A Vandesompele, Jo %K Adult %K Carrier State %K COVID-19 %K COVID-19 Nucleic Acid Testing %K Humans %K Nasopharynx %K Prospective Studies %K Saliva %K specimen handling %K Viral Load %X

Nasopharyngeal swabs are considered the preferential collection method for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostics. Less invasive and simpler alternative sampling procedures, such as saliva collection, are desirable. We compared saliva specimens and nasopharyngeal (NP) swabs with respect to sensitivity in detecting SARS-CoV-2. A nasopharyngeal and two saliva specimens (collected by spitting or oral swabbing) were obtained from >2500 individuals. All samples were tested by RT-qPCR, detecting RNA of SARS-CoV-2. The test sensitivity was compared on the two saliva collections with the nasopharyngeal specimen for all subjects and stratified by symptom status and viral load. Of the 2850 patients for whom all three samples were available, 105 were positive on NP swab, whereas 32 and 23 were also positive on saliva spitting and saliva swabbing samples, respectively. The sensitivity of the RT-qPCR to detect SARS-CoV-2 among NP-positive patients was 30.5% (95% CI, 1.9%-40.2%) for saliva spitting and 21.9% (95% CI, 14.4%-31.0%) for saliva swabbing. However, when focusing on subjects with medium to high viral load, sensitivity on saliva increased substantially: 93.9% (95% CI, 79.8%-99.3%) and 76.9% (95% CI, 56.4%-91.0%) for spitting and swabbing, respectively, regardless of symptomatic status. Our results suggest that saliva cannot readily replace nasopharyngeal sampling for SARS-CoV-2 diagnostics but may enable identification of the most contagious cases with medium to high viral loads.

%B J Mol Diagn %V 23 %8 2021 Oct %G eng %N 10 %R 10.1016/j.jmoldx.2021.07.017 %0 Journal Article %J Cancer Epidemioly %D 2021 %T HPV DNA genotyping, HPV E6*I mRNA detection, and p16INK4a/Ki-67 staining in Belgian head and neck cancer patient specimens, collected within the HPV-AHEAD study %A Cindy Simoens %A Ivana Gorbaslieva %A Gheit, Tarik %A Holzinger, Dana %A Lucas, Eric %A Ridder, Ruediger %A Rehm, Susanne %A Peter Vermeulen %A Martin Lammens %A Olivier Vanderveken %A Kumar, Rekha Vijay %A Gangane, Nitin %A Alessandro Caniglia %A Maffini, Fausto %A Maria Belén Lloveras Rubio %A Anantharaman, Devasena %A Chiocca, Susanna %A Brennan, Paul %A Madhavan R Pillai %A Radhakrishna, Madhavan %A Bogers, Johannes %A Pawlita, Michael %A Tommasino, Massimo %A M. Arbyn %A HPV-AHEAD study group %K Adult %K Aged %K Aged, 80 and over %K Alphapapillomavirus %K Belgium %K Cyclin-Dependent Kinase Inhibitor p16 %K DNA, Viral %K Female %K Genotype %K Head and Neck Neoplasms %K Head and neck neoplasms; Human papillomavirus; Human papillomavirus DNA tests; mRNA; p16(INK4a) %K Humans %K Ki-67 Antigen %K Male %K middle aged %K Oncogene Proteins, Viral %K Papillomavirus Infections %K RNA, Messenger %K Staining and Labeling %X

BACKGROUND: The main risk factors for head and neck cancer (HNC) are tobacco and alcohol use. However, an important fraction of oropharyngeal cancer (OPC) is caused by human papillomaviruses (HPV), a subgroup with increasing incidence in several western countries.

METHODS: As part of the HPV-AHEAD study, we assessed the role of HPV infection in 772 archived tissue specimens of Belgian HNC patients: 455 laryngeal (LC), 106 oral cavity (OCC), 99 OPC, 76 hypopharyngeal (HC), and 36 unspecified parts of the head and neck. All specimens were tested for HPV DNA (21 genotypes); whereof all HPV DNA-positives, all HPV DNA-negative OPCs and a random subset of HPV DNA-negatives of the other HNC-sites were tested for the presence of type-specific HPV RNA and p16 over-expression.

RESULTS: The highest HPV DNA prevalence was observed in OPC (36.4 %), and was significantly lower (p < 0.001) in the other HNCs (OCC:7.5 %, LC:6.6 %). HPV16 was the most common HPV-genotype in all HNCs. Approximately 83.0 % of the HPV DNA-positive OPCs tested HPV RNA or p16-positive, compared to about 37.5 % and 44.0 % in OCC and LC, respectively. Estimation of the attributable fraction of an HPV infection in HNC was very similar for HPV RNA or p16 in addition to DNA-positivity; with 30 % for OPC, and 3 % for OCC and LC.

CONCLUSION: Our study confirms the heterogeneity of HPV DNA prevalence across anatomical sites in HNC, with a predominance of HPV16 in all sites. The estimated proportion of HPV-driven HNC in Belgium, during the period 1980-2014, was 10 times higher in OPC compared to OCC and LC.

%B Cancer Epidemioly %V 72 %8 jun 2021 %G eng %R 10.1016/j.canep.2021.101925 %0 Journal Article %J Lancet Public Health %D 2020 %T Tackling cervical cancer in Europe amidst the COVID-19 pandemic. %A M. Arbyn %A Bruni, Laia %A Daniel Kelly %A Partha Basu %A Poljak, Mario %A Murat Gultekin %A Bergeron, Christine %A David Ritchie %A Weiderpass, Elisabete %K Coronavirus Infections %K COVID-19 %K Europe %K Female %K Humans %K Pandemics %K Pneumonia, Viral %K Uterine Cervical Neoplasms %X

According to estimates for 2018, approximately 33 000 cases of cervical cancer occurred and 15 000 people died from the disease in Europe (see map in appendix). Human papillomavirus (HPV) vaccine coverage is relatively low in countries with the highest incidence and screening performance is heterogeneous among European countries. Cytological screening followed by treatment of screen-detected cervical lesions has resulted in substantial decreases in the burden of cervical cancer in western and northern Europe; but in eastern Europe, cervical cancer incidence and mortality remain comparatively high.

Today, new powerful tools are available for primary and secondary prevention of cervical cancer, among which prophylactic HPV vaccines, and screening using validated HPV tests for women—including some tests that can be applied on self-collected samples, a strategy that might be used to reach underscreened populations.

In May, 2018, the WHO Director General launched a call to eliminate cervical cancer by vaccinating at least 90% of girls by age 15 years, by offering screening at least twice in a lifetime to 70% or more of the target age populations and treat more than 90% of women with screen-detected lesions.

Recently, a large group of experts from diverse professional societies and cancer organisations supporting WHO's call to eliminate cervical cancer, proposed a series of concerted actions to implement organised integrated HPV vaccination and HPV-based screening, and requested European health authorities to endorse the principles of the WHO elimination initiative, mobilise resources to update evidence-based guidelines, and translate them into quantified and monitored preventive activities.

However, in the first half of 2020, due to the dramatic COVID-19 pandemic, cervical cancer prevention activities have been disrupted in many European countries. We are concerned and urge the public health community to maintain sufficient resources to sustain HPV vaccination and cancer screening in the future.

Importantly, the COVID-19 pandemic might also generate opportunities for more efficient prevention, by promoting more cost-effective, evidence-based protocols, by focusing on women who are at high-risk, extending HPV testing on self-collected samples, and discouraging inefficient policies, such as screening with two tests. We welcome the unprecedented collaborations between the cancer and infectious disease communities, who have been working jointly to tackle the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by applying the experience of HPV test evaluation to protocols for comparing and validating SARS-CoV-2 assays and by bringing modellers together in the COVID-19 and Cancer Taskforce Global Modelling Consortium.

%B Lancet Public Health %V 5 %8 2020 Aug %G eng %N 8 %R 10.1016/S2468-2667(20)30122-5 %0 Journal Article %J Eur J Cancer Prev %D 2019 %T Cervical morbidity in Alsace, France: results from a regional organized cervical cancer screening program. %A Baldauf, J-J %A Fender, Murielle %A Bergeron, Christine %A Emilie Marrer %A Michel Velten %A Pierre Pradat %A M. Arbyn %K Adult %K Early Detection of Cancer %K Female %K France %K Humans %K middle aged %K morbidity %K Papillomavirus Vaccines %K REGISTRIES %K Uterine Cervical Neoplasms %X

In 1994, a pilot program of cervical cancer screening was introduced in the Alsace region, France. Women aged 25-65 years were proposed to have one Pap smear every 3 years. The objective was to assess cervical morbidity in Alsace before the human papillomavirus vaccinated population reaches the age of screening. Data on cervical lesions and cancers were collected by EVE for the period September 2008 to August 2011 from existing medical services and cytopathology laboratories in Alsace. Cytological and histological data were completed with data from the two cancer registries covering the region (Bas-Rhin and Haut-Rhin). Cancer incidence rates were computed for the target population (truncated to 25-64 years) and were age standardized according to the world reference population. World standardized incidence rates for the whole female population were obtained from the two cancer registries. During 2008-2011, 565 153 smears were performed in 498 913 women aged 25-64 years, representing an average of 1.13 smears/woman and 1.62 smears/screened woman. The overall screening coverage was 70.1% over the 3-year period. Histologically confirmed high-grade lesions were found in 2303 women (0.5%). Moreover, 215 cervical cancers were reported among women aged 25-64 years (crude and standardized truncated incidence rate of 10.6 and 10.0/100 000 women-years, respectively). The overall screening coverage of 70% at 3 years is higher than the national rate (57%), and the overall cancer incidence of 5.5/100 000 is below the national French level. The EVE database will be useful to assess trends in cervical morbidity over time and to further assess the effect of screening as well as of human papillomavirus vaccination.

%B Eur J Cancer Prev %V 28 %8 2019 Jan %G eng %N 1 %R 10.1097/CEJ.0000000000000415 %0 Journal Article %J Cancer %D 2019 %T Impact of the human papillomavirus status on the development of high-grade cervical intraepithelial neoplasia in women negative for intraepithelial lesions or malignancy at the baseline: A 9-year Swedish nested case-control follow-up study. %A Maria Fröberg %A Östensson, Ellinor %A Karen Belkić %A Anja Oštrbenk %A Poljak, Mario %A Miriam Mints %A M. Arbyn %A Andersson, Sonia %K Adult %K Case-Control Studies %K Female %K Follow-Up Studies %K Human papillomavirus 16 %K Human papillomavirus 18 %K Humans %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K Risk Factors %K Sweden %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %X

BACKGROUND
The causal relation between high-risk human papillomavirus (HPV) and cervical cancer and its precursor lesions has led to the use of sensitive HPV molecular tests for screening. This study examined the impact of the baseline HPV status on the future risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among women with cytology negative for intraepithelial lesions or malignancy (NILM).

METHODS
This was a nested case-control study including women with NILM baseline cytology participating in the Swedish cervical screening program in 2005-2007. Ninety-six cases of CIN2+ and 5 age-matched controls per case were identified through the National Cervical Screening Registry by follow-up through 2014. Baseline liquid-based cytology samples were tested for HPV. Conditional logistic regression analysis was used to calculate odds ratios (ORs) with confidence intervals (CIs).

RESULTS
The risk of future high-grade cervical intraepithelial neoplasia (CIN) was strongly associated with the baseline HPV status. For women younger than 30 years, HPV-16/18 showed a significant association with future risk for CIN2+ (OR, 9.44; 95% CI, 3.37-26.4). Other HPV types were not significantly associated with future CIN2+ in these younger women. For women 30 years old or older, both HPV-16/18 and other HPV subtypes conferred a significant risk.

CONCLUSIONS
The presence of HPV-16/18 among women with NILM cytology is associated with an elevated future risk of high-grade CIN. HPV types other than HPV-16/18 seem to have a greater impact on women 30 years old or older than younger women. Women with NILM cytology and HPV-16/18 need specific follow-up management within screening.

%B Cancer %V 125 %8 2019 Jan 15 %G eng %N 2 %R 10.1002/cncr.31788 %0 Journal Article %J Cancer Cytopathol %D 2019 %T Meta-analysis of the accuracy of p16 or p16/Ki-67 immunocytochemistry versus HPV testing for the detection of CIN2+/CIN3+ in triage of women with minor abnormal cytology. %A Eliana Peeters %A Wentzensen, Nicolas %A Bergeron, Christine %A M. Arbyn %K Atypical Squamous Cells of the Cervix %K Cyclin-Dependent Kinase Inhibitor p16 %K Cytodiagnosis %K Early Detection of Cancer %K Female %K Humans %K immunohistochemistry %K Ki-67 Antigen %K Papillomaviridae %K Papillomavirus Infections %K Sensitivity and Specificity %K Severity of Illness Index %K triage %K Uterine Cervical Diseases %K Uterine Cervical Dysplasia %X

BACKGROUND: Women with atypical squamous cells of undetermined significance (ASC-US) can be triaged accurately with a high-risk human papillomavirus (hrHPV) test to identify those who need a referral. However, the triage of low-grade squamous intraepithelial lesion (LSIL) with hrHPV testing has very low specificity. Overexpression of p16, with or without Ki-67, indicates neoplastic transformation of human papillomavirus-infected cervical cells and may more accurately predict underlying cervical intraepithelial neoplasia of grade 3 or worse (CIN3+).

METHODS: A literature search was conducted in 3 bibliographic databases. Studies were selected if they included women with ASC-US or LSIL who were triaged with dual staining (p16/Ki-67) and/or p16 staining and, if available, with a comparator hrHPV test to detect cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or CIN3+.

RESULTS: Thirty-eight studies were eligible. The sensitivity of p16 staining for CIN3+ was significantly lower than that of hrHPV DNA testing (ratio for ASC-US, 0.87; 95% confidence interval [CI], 0.78-0.97; ratio for LSIL, 0.86; 95% CI, 0.80-0.93). In contrast, the specificity of p16 staining was substantially higher with relative specificities of 1.60 (95% CI, 1.35-1.88) and 2.29 (95% CI, 2.05-2.56) for ASC-US and LSIL respectively. Dual staining was as sensitive as hrHPV DNA testing but was more specific (ratio for ASC-US, 1.65; 95% CI, 1.42-1.92; ratio for LSIL, 2.45; 95% CI, 2.17-2.77).

CONCLUSIONS: This meta-analysis confirms that p16 staining and p16/Ki-67 staining are more specific for CIN2+/CIN3+ than hrHPV DNA testing. Although p16 staining is less sensitive for CIN3+ than hrHPV DNA testing, dual staining has similar sensitivity.

%B Cancer Cytopathol %V 127 %8 2019 Mar %G eng %N 3 %R 10.1002/cncy.22103 %0 Journal Article %J J Infect Dis %D 2019 %T Might Oral Human Papillomavirus (HPV) Infection in Healthy Individuals Explain Differences in HPV-Attributable Fractions in Oropharyngeal Cancer? A Systematic Review and Meta-analysis. %A Mena, Marisa %A Miren Taberna %A Laura Monfil %A M. Arbyn %A de Sanjosé, Silvia %A Francesc Xavier Bosch %A Alemany, Laia %A Bruni, Laia %K Age factors %K Female %K Humans %K Male %K Mouth %K Oropharyngeal Neoplasms %K Papillomaviridae %K Papillomavirus Infections %K prevalence %K Sexual Behavior %K Tobacco Use %X

BACKGROUND: Differences in oral human papillomavirus (HPV) prevalence and contrasts in HPV-attributable fractions (AFs) in oropharyngeal cancer (OPC) have not been evaluated in depth.

METHODS: A systematic review was performed to identify studies in which at least 50 healthy individuals were tested for oral HPV infection. Information on sex, age, tobacco/alcohol consumption, sex practices, specimen collection, HPV detection, and population type was extracted. Prevalences were pooled using random-effects models for meta-analyses of binomial data. Correlations were assessed by the Spearman test.

RESULTS: Forty-eight reports comprising 28 544 individuals fulfilled inclusion criteria. Global oral HPV prevalence was 4.9%. Estimates were highest in Europe, although regional differences were not statistically significant. HPV16 prevalence was 1.0% globally, and regional differences became statistically significant. A lifetime history of >6 sex partners showed a higher risk of oral HPV infection. The age-specific HPV distribution revealed a prevalence of ≥5% over 40 years of age and a lower prevalence at younger ages. There was no association between oral HPV prevalence and HPV-AFs or age-standardized rates (ASRs) of OPC, genital HPV in healthy women, or tobacco use.

CONCLUSIONS: Differences in HPV-AFs or ASRs of OPC cannot be explained by differences in the prevalence of oral HPV infection across healthy populations. Consistent research on determinants of oral HPV prevalence, acquisition, clearance, and persistence is warranted.

%B J Infect Dis %V 219 %8 2019 Apr 19 %G eng %N 10 %R 10.1093/infdis/jiy715 %0 Journal Article %J Gynecologic Oncology %D 2019 %T Pathways to a cancer-free future: A protocol for modelled evaluations to maximize the future impact of interventions on cervical cancer in Australia %A Louiza S. Velentzis %A Megan A. Smith %A Kate T; Simms %A Jie-Bin Lew %A Michaela Hall %A Suzanne Hughes %A Susan Yuill %A James Killen %A Adam Keane %A Katherine Butler %A Jessica Darlington-Brown %A Harriet Hui %A Brotherton, Julia %A Rachel Skinner %A Brand, A %A Lara Roeske %A Stella Heley %A Jonathan Carter %A Deborah Bateson %A Ian Frazer %A Garland, Suzanne M %A Rebecca Guy %A Ian Hammond %A Paul Grogan %A M. Arbyn %A Castle, Philip E %A Marion Saville %A B. Armstrong %A Canfell, Karen %K cervical cancer %K Cervical cancer prevention %K EVALUATION %K Health economics %K Modelling %K Simulation %X

OBJECTIVE
Australia's HPV vaccination and HPV-based cervical screening programs are changing the landscape in cervical cancer prevention. We aim to identify areas which can make the biggest further impact on cervical cancer burden. This protocol describes the first stage of a program of work called Pathways-Cervix that aims to generate evidence from modelled evaluations of interventions across the cervical cancer spectrum.

METHODS
Based on evidence from literature reviews and guidance from a multi-disciplinary Scientific Advisory Committee (SAC), the most relevant evaluations for prevention, diagnosis and treatment were identified.

RESULTS
Priority evaluations agreed by the SAC included: increasing/decreasing and retaining vaccination uptake at the current level; vaccinating older women; increasing screening participation; methods for triaging HPV-positive women; improving the diagnosis of cervical intraepithelial neoplasia (CIN) and cancer; treating cervical abnormalities and cancer; and vaccinating women treated for CIN2/3 to prevent recurrence. Evaluations will be performed using a simulation model, Policy1-Cervix previously used to perform policy evaluations in Australia. Exploratory modelling of interventions using idealised scenarios will initially be conducted in single birth cohorts. If these have a significant impact on findings then evaluations with more realistic assumptions will be conducted. Promising strategies will be investigated further by multi-cohort simulations predicting health outcomes, resource use and cost outcomes.

CONCLUSIONS
Pathways-Cervix will assess the relative benefits of strategies and treatment options in a systematic and health economic framework, producing a list of ‘best buys’ for future decision-making in cervical cancer control.

%B Gynecologic Oncology %V 152 %8 Jan-03-2019 %G eng %N 3 %R 10.1016/j.ygyno.2018.12.019 %0 Journal Article %J Geburtshilfe Frauenheilkd %D 2019 %T Prevention of Cervical Cancer: Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) - Part 1 with Introduction, Screening and the Pathology of Cervical Dysplasia. %A Hillemanns, Peter %A Klaus Friese %A Christian Dannecker %A Stefanie Klug %A Ulrike Seifert %A Thomas Iftner %A Juliane Hädicke %A Thomas Löning %A Lars Horn %A Dietmar Schmidt %A Hans Ikenberg %A Manfred Steiner %A Freitag, Ulrich %A Uwe Siebert %A Gaby Sroczynski %A Willi Sauerbrei %A Matthias W Beckmann %A Marion Gebhardt %A Michael Friedrich %A Karsten Münstedt %A Schneider, Achim %A Kaufmann, Andreas %A K Ulrich Petry %A Axel P A Schäfer %A Pawlita, Michael %A Joachim Weis %A Anja Mehnert %A Mathias Fehr %A Christoph Grimm %A Olaf Reich %A M. Arbyn %A Jos Kleijnen %A Simone Wesselmann %A Monika Nothacker %A Markus Follmann %A Thomas Langer %A Matthias Jentschke %K cervical cancer %K cervical intraepithelial neoplasia (CIN) %K cervical precancerous condition %K HPV %X

AIMS
Annual opportunistic screening for cervical carcinoma has been carried out in Germany since 1971. The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer, as the guideline aims to provide important information and support for planned organized screening for cervical cancer in Germany.

METHODS
With the financial support of German Cancer Aid, 21 professional societies developed evidence-based statements and recommendations (classified using the GRADE system) for the screening, management and treatment of precancerous conditions of the cervix. Two independent scientific institutes compiled systematic reviews for this guideline.

RECOMMENDATIONS
The first part of this short summary presents the pathological basis and considers various questions related to screening for cervical cancer. As also reported in earlier reviews, the meta-analysis by Kleijnen Systematic Reviews showed that HPV-based screening offers better protection against invasive cervical cancer compared to cytology-based screening. The authors of this guideline therefore recommend - in accordance with the guideline of the Joint National Committee of Germany (Gemeinsamer Bundesauschuss, G-BA) - that women aged 35 and above should be examined at regular intervals (at least every 3 years) and undergo HPV-based screening. Co-testing can also be carried out. Women between the ages of 20 and 35 should have cytological screening every 2 years.

%B Geburtshilfe Frauenheilkd %V 79 %8 2019 Feb %G eng %N 2 %R 10.1055/a-0818-5440 %0 Journal Article %J Geburtshilfe Frauenheilkd %D 2019 %T Prevention of Cervical Cancer: Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) - Part 2 on Triage, Treatment and Follow-up. %A Hillemanns, Peter %A Klaus Friese %A Christian Dannecker %A Stefanie Klug %A Ulrike Seifert %A Thomas Iftner %A Juliane Hädicke %A Thomas Löning %A Lars Horn %A Dietmar Schmidt %A Hans Ikenberg %A Manfred Steiner %A Freitag, Ulrich %A Uwe Siebert %A Gaby Sroczynski %A Willi Sauerbrei %A Matthias W Beckmann %A Marion Gebhardt %A Michael Friedrich %A Karsten Münstedt %A Schneider, Achim %A Kaufmann, Andreas %A K Ulrich Petry %A Axel P A Schäfer %A Pawlita, Michael %A Joachim Weis %A Anja Mehnert %A Mathias Fehr %A Christoph Grimm %A Olaf Reich %A M. Arbyn %A Jos Kleijnen %A Simone Wesselmann %A Monika Nothacker %A Markus Follmann %A Thomas Langer %A Matthias Jentschke %K cervical cancer %K cervical intraepithelial neoplasia (CIN) %K cervical precancerous condition %K HPV %X

EN

AIMS
Annual opportunistic screening for cervical carcinoma has been done in Germany since 1971. The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer, as this guideline aims to provide important information and support for planned organized screening for cervical cancer in Germany.

METHODS
With the financial support of German Cancer Aid, 21 professional societies developed evidence-based statements and recommendations (classified using the GRADE system) for the screening, management and treatment of precancerous conditions of the cervix. Two independent scientific institutes compiled systematic reviews for this guideline.

RECOMMENDATIONS
The second part of this short summary deals with the triage, treatment and follow-up care of cervical dysplasia. With regard to those women who do not participate in screening, the guideline authors recommend sending out repeat invitation letters or an HPV self-collection kit. Colposcopy should be carried out for further investigation if cytology findings are Pap II-p and HPV test results are positive or if the results of an HPV 16 or HPV 18 screening test are positive. A single abnormal Pap smear should be triaged and investigated using HPV testing or p16/Ki67 dual staining.

 

FR

OBJECTIFS
dépistage opportuniste annuel pour le cancer du col utérin a été fait en Allemagne depuis 1971. La création de cette ligne directrice S3 répond au besoin important, indiqué dans le Plan national du cancer en ce qui concerne le dépistage du cancer du col de l' utérus, comme cette directive vise à fournir des informations importantes et Soutien au dépistage organisé du cancer du col utérin en Allemagne.

MÉTHODES
avec le soutien financier de German Cancer Aid, 21 sociétés professionnelles ont élaboré des déclarations et des recommandations fondées sur des preuves pour le dépistage, la gestion et le traitement des affections précancéreuses du col de l'utérus. Deux instituts scientifiques indépendants ont compilé des revues systématiques pour cette directive.

RECOMMENDATIONS
La deuxième partie du triage, du traitement et des soins de suivi de la dysplasie cervicale. Lors du dépistage, les auteurs des lignes directrices ou les envoyer à un kit de collecte automatique du VPH. Les tests de dépistage HPP 16 ou HPV 18 sont positifs. Un seul frottis anormal doit être testé et testé avec le test HPV ou la coloration double p16 / Ki67.

%B Geburtshilfe Frauenheilkd %V 79 %8 2019 Feb %G eng %N 2 %R 10.1055/a-0828-7722 %0 Journal Article %J BMJ Open %D 2018 %T Assessing factors associated with long-term work disability after cancer in Belgium: a population-based cohort study using competing risks analysis with a 7-year follow-up. %A Regine Kiasuwa %A Alina Mioara Nicolaie %A Goetghebeur, Els %A Otter, Renée %A Mortelmans, Katrien %A Sarah Missinnne %A M. Arbyn %A Bouland, Catherine %A De Brouwer, Christophe %K ADOLESCENT %K Adult %K Belgium %K Cancer Survivors %K Disability Evaluation %K Disabled Persons %K Female %K Follow-Up Studies %K Humans %K incidence %K Insurance, Disability %K Kaplan-Meier Estimate %K Male %K middle aged %K Neoplasms %K Quality of Life %K Return to Work %K Young adult %X

OBJECTIVES: The number of workers with cancer has dramatically increasing worldwide. One of the main priorities is to preserve their quality of life and the sustainability of social security systems. We have carried out this study to assess factors associated with the ability to work after cancer. Such insight should help with the planning of rehabilitation needs and tailored programmes.

PARTICIPANTS: We conducted this register-based cohort study using individual data from the Belgian Disability Insurance. Data on 15 543 socially insured Belgian people who entered into the long-term work disability between 2007 and 2011 due to cancer were used.

PRIMARY AND SECONDARY OUTCOME MEASURES: We estimated the duration of work disability using Kaplan-Meier and the cause-specific cumulative incidence of ability to work stratified by age, gender, occupational class and year of entering the work disability system for 11 cancer sites using the Fine and Gray model allowing for competing risks.

RESULTS: The overall median time of work disability was 1.59 years (95% CI 1.52 to 1.66), ranging from 0.75 to 4.98 years. By the end of follow-up, more than one-third of the disabled cancer survivors were able to work (35%). While a large proportion of the women were able to work at the end of follow-up, the men who were able to work could do so sooner. Being women, white collar, young and having haematological, male genital or breast cancers were factors with the bestlikelihood to be able to return to work.

CONCLUSION: Good prognostic factors for the ability to work were youth, woman, white collar and having breast, male genital or haematological cancers. Reviewing our results together with the cancer incidence predictions up to 2025 offers a high value for social security and rehabilitation planning and for ascertaining patients' perspectives.

%B BMJ Open %V 8 %8 2018 Feb 17 %G eng %N 2 %R 10.1136/bmjopen-2016-014094 %0 Journal Article %J BMJ Open %D 2018 %T Assessing factors associated with long-term work disability after cancer in Belgium: a population-based cohort study using competing risks analysis with a 7-year follow-up %A Regine Kiasuwa %A Alina Mioara Nicolaie %A Goetghebeur, Els %A Otter, Renée %A Mortelmans, Katrien %A Sarah Missinnne %A M. Arbyn %A Bouland, Catherine %A De Brouwer, Christophe %K aftercare %K cancer %K EVALUATION %K rehabilitation %X

OBJECTIVES
The number of workers with cancer has dramatically increasing worldwide. One of the main priorities is to preserve their quality of life and the sustainability of social security systems. We have carried out this study to assess factors associated with the ability to work after cancer. Such insight should help with the planning of rehabilitation needs and tailored programmes.

PARTICIPANTS
We conducted this register-based cohort study using individual data from the Belgian Disability Insurance. Data on 15 543 socially insured Belgian people who entered into the long-term work disability between 2007 and 2011 due to cancer were used.

Primary and secondary outcome measures
We estimated the duration of work disability using Kaplan-Meier and the cause-specific cumulative incidence of ability to work stratified by age, gender, occupational class and year of entering the work disability system for 11 cancer sites using the Fine and Gray model allowing for competing risks.

RESULTS
The overall median time of work disability was 1.59 years (95% CI 1.52 to 1.66), ranging from 0.75 to 4.98 years. By the end of follow-up, more than one-third of the disabled cancer survivors were able to work (35%). While a large proportion of the women were able to work at the end of follow-up, the men who were able to work could do so sooner. Being women, white collar, young and having haematological, male genital or breast cancers were factors with the bestlikelihood to be able to return to work.

CONCLUSIONS
Good prognostic factors for the ability to work were youth, woman, white collar and having breast, male genital or haematological cancers. Reviewing our results together with the cancer incidence predictions up to 2025 offers a high value for social security and rehabilitation planning and for ascertaining patients’ perspectives.

%B BMJ Open %V 8 %8 Jan-02-2019 %G eng %N 2 %R 10.1136/bmjopen-2016-014094 %0 Journal Article %J J Clin Virol %D 2018 %T Assessment of the Roche Linear Array HPV Genotyping Test within the VALGENT framework. %A Lan Xu %E Anja Oštrbenk %E Poljak, Mario %X

BACKGROUND: Cervical cancer screening programs are switching from cytology-based screening to high-risk (hr) HPV testing. Only clinically validated tests should be used in clinical practice.

OBJECTIVES: To assess the clinical performance of the Roche Linear Array HPV genotyping test (Linear Array) within the VALGENT-3 framework.

STUDY DESIGN: The VALGENT framework is designed for comprehensive comparison and clinical validation of HPV tests that have limited to extended genotyping capacity. The Linear Array enables type-specific detection of 37 HPV types. For the purpose of this study, Linear Array results were designated as positive only if one of the 13 hrHPV types also included in the Hybrid Capture 2 (HC2) was detected. The VALGENT-3 framework comprised 1600 samples obtained from Slovenian women (1300 sequential cases from routine cervical cancer screening enriched with 300 cytological abnormal samples). Sensitivity for cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) (n=127) and specificity for

RESULTS: The clinical sensitivity and specificity for CIN2+ of the Linear Array in the total study population was 97.6% (95% CI, 93.3-99.5%) and 91.7% (95% CI, 90.0-93.2%), respectively. The relative sensitivity and specificity of Linear Array vs HC2 was 1.02 [95% CI, 0.98-1.05, (p<0.001)] and 1.02 [95% CI, 1.01-1.03, (p<0.001)], respectively The overall prevalence of hrHPV using the Linear Array in the screening population was 10.5% (95% CI, 8.9-12.3%) with HPV16 and HPV18 detected in 2.3% and 0.9% of the samples, respectively. Excellent agreement for presence or absence of HPV16, HPV18 and other hrHPV between Linear Array and RealTime was observed.

CONCLUSIONS: Linear Array showed similar sensitivity with higher specificity to detect CIN2+ compared to HC2. Detection of 13 hrHPV types with Linear Array fulfils the clinical accuracy requirements for primary cervical cancer screening.

%B J Clin Virol %V 98 %8 2018 01 %G eng %R 10.1016/j.jcv.2017.12.001 %0 Journal Article %J JAMA Internal Medicine %D 2018 %T Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women %A Megan A. Clarke %A Beverly J. Long %A Arena Del Mar Morillo %A M. Arbyn %A Jamie N. Bakkum-Gamez %A Wentzensen, Nicolas %K Diagnostic %K Research %X

Importance: As the worldwide burden of endometrial cancer continues to rise, interest is growing in the evaluation of early detection and prevention strategies among women at increased risk. Focusing efforts on women with postmenopausal bleeding (PMB), a common symptom of endometrial cancer, may be a useful strategy; however, PMB is not specific for endometrial cancer and is often caused by benign conditions.

Objective: To provide a reference of the prevalence of PMB in endometrial cancers and the risk of endometrial cancer in women with PMB.

Data sources: For this systematic review and meta-analysis, PubMed and Embase were searched for English-language studies published January 1, 1977, through January 31, 2017.

Study selection: Observational studies reporting the prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB in unselected populations were selected.

Data extraction and synthesis: Two independent reviewers evaluated study quality and risk of bias using items from the Newcastle-Ottawa Quality Assessment Scale and the Quality Assessment of Diagnostic Accuracy Studies tool. Studies that included highly selected populations, lacked detailed inclusion criteria, and/or included 25 or fewer women were excluded.

Main outcomes and measures: The pooled prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB.

Results: A total of 129 unique studies, including 34 432 unique patients with PMB and 6358 with endometrial cancer (40 790 women), were analyzed. The pooled prevalence of PMB among women with endometrial cancer was 91% (95% CI, 87%-93%), irrespective of tumor stage. The pooled risk of endometrial cancer among women with PMB was 9% (95% CI, 8%-11%), with estimates varying by use of hormone therapy (range, 7% [95% CI, 6%-9%] to 12% [95% CI, 9%-15%]; P < .001 for heterogeneity) and geographic region (range, 5% [95% CI, 3%-11%] in North America to 13% [95% CI, 9%-19%] in Western Europe; P = .09 for heterogeneity).

Conclusions and relevance: Early detection strategies focused on women with PMB have the potential to capture as many as 90% of endometrial cancers; however, most women with PMB will not be diagnosed with endometrial cancer. These results can aid in the assessment of the potential clinical value of new early detection markers and clinical management strategies for endometrial cancer and will help to inform clinical and epidemiologic risk prediction models to support decision making.

%B JAMA Internal Medicine %V 178 %8 Jan-09-2018 %G eng %N 9 %R 10.1001/jamainternmed.2018.2820 %0 Journal Article %J JAMA Intern Med %D 2018 %T Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis. %A Megan A. Clarke %A Beverly J Long %A Arena Del Mar Morillo %A M. Arbyn %A Jamie N Bakkum-Gamez %A Wentzensen, Nicolas %K Biopsy %K Endometrial Neoplasms %K Female %K Global Health %K Humans %K Postmenopause %K prevalence %K Risk Factors %K Uterine Hemorrhage %X

IMPORTANCE: As the worldwide burden of endometrial cancer continues to rise, interest is growing in the evaluation of early detection and prevention strategies among women at increased risk. Focusing efforts on women with postmenopausal bleeding (PMB), a common symptom of endometrial cancer, may be a useful strategy; however, PMB is not specific for endometrial cancer and is often caused by benign conditions.

OBJECTIVE: To provide a reference of the prevalence of PMB in endometrial cancers and the risk of endometrial cancer in women with PMB.

DATA SOURCES: For this systematic review and meta-analysis, PubMed and Embase were searched for English-language studies published January 1, 1977, through January 31, 2017.

STUDY SELECTION: Observational studies reporting the prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB in unselected populations were selected.

DATA EXTRACTION AND SYNTHESIS: Two independent reviewers evaluated study quality and risk of bias using items from the Newcastle-Ottawa Quality Assessment Scale and the Quality Assessment of Diagnostic Accuracy Studies tool. Studies that included highly selected populations, lacked detailed inclusion criteria, and/or included 25 or fewer women were excluded.

MAIN OUTCOMES AND MEASURES: The pooled prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB.

RESULTS: A total of 129 unique studies, including 34 432 unique patients with PMB and 6358 with endometrial cancer (40 790 women), were analyzed. The pooled prevalence of PMB among women with endometrial cancer was 91% (95% CI, 87%-93%), irrespective of tumor stage. The pooled risk of endometrial cancer among women with PMB was 9% (95% CI, 8%-11%), with estimates varying by use of hormone therapy (range, 7% [95% CI, 6%-9%] to 12% [95% CI, 9%-15%]; P < .001 for heterogeneity) and geographic region (range, 5% [95% CI, 3%-11%] in North America to 13% [95% CI, 9%-19%] in Western Europe; P = .09 for heterogeneity).

CONCLUSIONS AND RELEVANCE: Early detection strategies focused on women with PMB have the potential to capture as many as 90% of endometrial cancers; however, most women with PMB will not be diagnosed with endometrial cancer. These results can aid in the assessment of the potential clinical value of new early detection markers and clinical management strategies for endometrial cancer and will help to inform clinical and epidemiologic risk prediction models to support decision making.

%B JAMA Intern Med %V 178 %8 2018 Sep 01 %G eng %N 9 %R 10.1001/jamainternmed.2018.2820 %0 Journal Article %J Journal of Clinical Microbioly %D 2018 %T Clinical and Analytical Evaluation of the Anyplex II HPV HR Detection Assay within the VALGENT-3 Framework. %A Oštrbenk, A %A Xu, Lan %A M. Arbyn %A Poljak, Mario %K Adult %K Cervix Uteri %K Early Detection of Cancer %K Female %K Genotype %K Genotyping Techniques %K Humans %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K Reproducibility of Results %K Sensitivity and Specificity %K Slovenia %K Uterine Cervical Neoplasms %X

In 2012, VALidation of human papillomavirus (HPV) GENotyping Tests (VALGENT) was initiated to provide a formalized and uniform study framework for comparison and validation of HPV assays with genotyping capability.
In VALGENT-3, the clinical and analytical performance of Anyplex II HPV HR detection (Anyplex) was compared to that of the Hybrid Capture 2 HPV DNA test (hc2) and the cobas 4800 HPV test (cobas). The panel comprises 1,300 stored samples that were obtained from women 25 to 64 years old who participated in the Slovenian cancer screening program, enriched with 300 samples from women with abnormal cervical cytology. The sensitivity and specificity of Anyplex were noninferior to those of hc2, with a relative sensitivity of 1.01 (95% confidence interval [CI], 0.97 to 1.04) for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and 1.01 (95% CI, 0.97 to 1.06) for CIN3+ and relative specificity of 1.02 (95% CI, 1.00 to 1.03) for a CIN grade of ≤1. The clinical sensitivity of Anyplex for CIN2+ and CIN3+ was comparable to that of hc2 ( values for McNemar test [] of 0.655 and 0.564, respectively), but its specificity was significantly higher ( = 0.008). The sensitivity and specificity of Anyplex were also noninferior to those of cobas, with relative sensitivity of 1.01 (95% CI, 0.98 to 1.04) for CIN2+ and 1.01 (95% CI, 0.99 to 1.04) for CIN3+ and relative specificity of 1.00 (95% CI, 0.99 to 1.01) ( value of >0.05 in all cases). Regardless of the clinical outcome (CIN2+ or CIN3+), age restriction (women ≥30 years old), or comparator test used, Anyplex consistently showed excellent clinical performance and can be considered validated for primary cervical cancer screening.

%B Journal of Clinical Microbioly %V 56 %8 2018 Nov %G eng %N 11 %R 10.1128/JCM.01176-18 %0 Journal Article %J Int J Mol Sci %D 2018 %T Clinical Evaluation of INNO-LiPA HPV Genotyping II Assay Using the VALGENT Framework. %A Lan Xu %A Padalko, Elizaveta %A M. Arbyn %E Anja Oštrbenk %E Poljak, Mario %K Alphapapillomavirus %K Cervical Intraepithelial Neoplasia %K Cervix Uteri %K Diagnostic Tests, Routine %K DNA, Viral %K Early Detection of Cancer %K Female %K Genotyping Techniques %K Humans %K Papillomavirus Infections %K Uterine Cervical Neoplasms %X

In this diagnostic test validation study, we assessed the clinical accuracy and HPV genotyping performance of the INNO-LiPA HPV Genotyping II (INNO-LiPA) within the VALGENT-3 framework. VALGENT is designed to assess the analytical and clinical performance of HPV tests with genotyping capacity. The VALGENT-3 panel comprised 1300 consecutive cervical cell specimens enriched with 300 samples with abnormal cytology obtained from women attending the Slovenian cervical cancer screening programme. The INNO-LiPA allows type-specific detection of 32 HPV types; however, for the clinical accuracy assessment, we considered it as high-risk (hr)HPV positive when at least one of the following HPV types was present: HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, and HPV68. Clinical accuracy for detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was compared between INNO-LiPA and Hybrid Capture 2 (HC2), which is a standard comparator test for HPV tests used in cervical cancer screening. In addition, hrHPV and type-specific detection HPV types were compared between INNO-LiPA and Linear Array HPV Genotyping Test (Linear Array). The prevalence of hrHPV determined by INNO-LiPA was 17.1% (95% CI, 15.0⁻19.2%) in the screening population. HrHPV testing with INNO-LiPA had a sensitivity for CIN2+ of 96.9% (95% CI, 92.1⁻99.1%) which was non-inferior to HC2 (relative sensitivity of 1.01; 95% CI, 0.97⁻1.04; = 0.0002) and a specificity for ≤CIN1 of 85.3% (95% CI, 83.2⁻87.3%) which was inferior to HC2 (relative specificity of 0.95; 95% CI, 0.93⁻0.97; = 0.9998). Genotyping agreement between INNO-LiPA and Linear Array was excellent for hrHPV, HPV16, HPV18, HPV35, HPV45, HPV58 and HPV59, but good or fair for other HPV types. To conclude, INNO-LiPA demonstrated non-inferior clinical sensitivity but lower specificity compared to HC2 in addition to excellent concordance compared to Linear Array for hrHPV and some genotypes.

%B Int J Mol Sci %V 19 %8 2018 Sep 11 %G eng %N 9 %R 10.3390/ijms19092704 %0 Journal Article %J BMJ %D 2018 %T Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses. %A M. Arbyn %A Sara B Smith %A Sarah Temin %A Farhana Sultana %A Philip Castle %K Colposcopy %K Early Detection of Cancer %K Female %K Humans %K incidence %K Intention to Treat Analysis %K Mass Screening %K Papillomaviridae %K Papillomavirus Infections %K Randomized Controlled Trials as Topic %K Sensitivity and Specificity %K specimen handling %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %K Vagina %K Vaginal Smears %X

OBJECTIVE: To evaluate the diagnostic accuracy of high-risk human papillomavirus (hrHPV) assays on self samples and the efficacy of self sampling strategies to reach underscreened women.

DESIGN: Updated meta-analysis.

DATA SOURCES: Medline (PubMed), Embase, and CENTRAL from 1 January 2013 to 15 April 2018 (accuracy review), and 1 January 2014 to 15 April 2018 (participation review).

REVIEW METHODS: Accuracy review: hrHPV assay on a vaginal self sample and a clinician sample; and verification of the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by colposcopy and biopsy in all enrolled women or in women with positive tests. Participation review: study population included women who were irregularly or never screened; women in the self sampling arm (intervention arm) were invited to collect a self sample for hrHPV testing; women in the control arm were invited or reminded to undergo a screening test on a clinician sample; participation in both arms was documented; and a population minimum of 400 women.

RESULTS: 56 accuracy studies and 25 participation trials were included. hrHPV assays based on polymerase chain reaction were as sensitive on self samples as on clinician samples to detect CIN2+ or CIN3+ (pooled ratio 0.99, 95% confidence interval 0.97 to 1.02). However, hrHPV assays based on signal amplification were less sensitive on self samples (pooled ratio 0.85, 95% confidence interval 0.80 to 0.89). The specificity to exclude CIN2+ was 2% or 4% lower on self samples than on clinician samples, for hrHPV assays based on polymerase chain reaction or signal amplification, respectively. Mailing self sample kits to the woman's home address generated higher response rates to have a sample taken by a clinician than invitation or reminder letters (pooled relative participation in intention-to-treat-analysis of 2.33, 95% confidence interval 1.86 to 2.91). Opt-in strategies where women had to request a self sampling kit were generally not more effective than invitation letters (relative participation of 1.22, 95% confidence interval 0.93 to 1.61). Direct offer of self sampling devices to women in communities that were underscreened generated high participation rates (>75%). Substantial interstudy heterogeneity was noted (I>95%).

CONCLUSIONS: When used with hrHPV assays based on polymerase chain reaction, testing on self samples was similarly accurate as on clinician samples. Offering self sampling kits generally is more effective in reaching underscreened women than sending invitations. However, since response rates are highly variable among settings, pilots should be set up before regional or national roll out of self sampling strategies.

%B BMJ %V 363 %8 2018 Dec 05 %G eng %R 10.1136/bmj.k4823 %0 Journal Article %J Expert Rev Vaccines %D 2018 %T Efficacy and safety of prophylactic HPV vaccines. A Cochrane review of randomized trials. %A M. Arbyn %A Lan Xu %K Cervical cancer; HPV vaccines; meta-analysis; randomized clinical trials; safety; systematic review. %X

Introduction: Recently, the evidence on efficacy and safety of prophylactic HPV vaccines derived from randomized trials was published in the Cochrane database of Systematic reviews. A summary of this Cochrane review is presented below.

Areas covered: Only trials involving mono-, bi-, and quadrivalent HPV vaccines were included. Trials evaluating the nonavalent vaccine were excluded since women in the control group received the quadrivalent vaccine. Main efficacy outcomes were: histologically confirmed cervical precancer lesions distinguishing those associated with vaccine HPV types and any cervical precancer. Exposure groups were: women aged: 15-26 or 24-45 years being initially negative for high-risk HPV (hrHPV) or negative for the vaccine types and women unselected by HPV status.

Expert commentary: All evaluated vaccines offered excellent protection against cervical intraepithelial neoplasia of grade 2 or 3 (CIN2 or CIN3) and adenocarcinoma in situ associated with HPV16/18 infection in young women who were not initially infected with hrHPV or HPV16/18. Vaccine efficacy was lower when all women regardless of HPV DNA status at enrollment were included. In young women, HPV vaccination protected also against any cervical precancer but the magnitude of protection was lower than against HPV16/18 associated cervical precancer. Vaccine efficacy was lower in mid-adult (aged 24-45 years) women. No protection against cervical precancer was found in mid-adult women unselected by HPV DNA status at enrollment. Trials were not empowered to address protection against cervical cancer. Occurrence of severe adverse events or adverse pregnancy outcomes was not significantly higher in recipients of HPV vaccines than in women included in the control arms.

%B Expert Rev Vaccines %V 17 %8 2018 Dec %G eng %N 12 %R 10.1080/14760584.2018.1548282 %0 Journal Article %J Cochrane Database Syst Rev %D 2018 %T Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. %A M. Arbyn %A Xu, Lan %A Cindy Simoens %A Martin-Hirsch, Pierre Pl %K ADOLESCENT %K Adult %K Female %K Human papillomavirus 16 %K Human papillomavirus 18 %K Humans %K middle aged %K Papillomavirus Infections %K Papillomavirus Vaccines %K Precancerous Conditions %K Pregnancy %K Pregnancy Outcome %K Randomized Controlled Trials as Topic %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %K Vaccination %K Young adult %X

BACKGROUND: Persistent infection with high-risk human papillomaviruses (hrHPV) types is causally linked with the development of cervical precancer and cancer. HPV types 16 and 18 cause approximately 70% of cervical cancers worldwide.

OBJECTIVES: To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women.

SEARCH METHODS: We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase (June 2017) for reports on effects from trials. We searched trial registries and company results' registers to identify unpublished data for mortality and serious adverse events.

SELECTION CRITERIA: Randomised controlled trials comparing efficacy and safety in females offered HPV vaccines with placebo (vaccine adjuvants or another control vaccine).

DATA COLLECTION AND ANALYSIS: We used Cochrane methodology and GRADE to rate the certainty of evidence for protection against cervical precancer (cervical intraepithelial neoplasia grade 2 and above [CIN2+], CIN grade 3 and above [CIN3+], and adenocarcinoma-in-situ [AIS]), and for harms. We distinguished between the effects of vaccines by participants' baseline HPV DNA status. The outcomes were precancer associated with vaccine HPV types and precancer irrespective of HPV type. Results are presented as risks in control and vaccination groups and risk ratios (RR) with 95% confidence intervals in brackets.

MAIN RESULTS: We included 26 trials (73,428 participants). Ten trials, with follow-up of 1.3 to 8 years, addressed protection against CIN/AIS. Vaccine safety was evaluated over a period of 6 months to 7 years in 23 studies. Studies were not large enough or of sufficient duration to evaluate cervical cancer outcomes. All but one of the trials was funded by the vaccine manufacturers. We judged most included trials to be at low risk of bias. Studies involved monovalent (N = 1), bivalent (N = 18), and quadrivalent vaccines (N = 7). Most women were under 26 years of age. Three trials recruited women aged 25 and over. We summarize the effects of vaccines in participants who had at least one immunisation.Efficacy endpoints by initial HPV DNA statushrHPV negativeHPV vaccines reduce CIN2+, CIN3+, AIS associated with HPV16/18 compared with placebo in adolescent girls and women aged 15 to 26. There is high-certainty evidence that vaccines lower CIN2+ from 164 to 2/10,000 (RR 0.01 (0 to 0.05)) and CIN3+ from 70 to 0/10,000 (RR 0.01 (0.00 to 0.10). There is moderate-certainty evidence that vaccines reduce the risk of AIS from 9 to 0/10,000 (RR 0.10 (0.01 to 0.82).HPV vaccines reduce the risk of any CIN2+ from 287 to 106/10,000 (RR 0.37 (0.25 to 0.55), high certainty) and probably reduce any AIS lesions from 10 to 0/10,000 (RR 0.1 (0.01 to 0.76), moderate certainty). The size of reduction in CIN3+ with vaccines differed between bivalent and quadrivalent vaccines (bivalent: RR 0.08 (0.03 to 0.23), high certainty; quadrivalent: RR 0.54 (0.36 to 0.82), moderate certainty). Data in older women were not available for this comparison.HPV16/18 negativeIn those aged 15 to 26 years, vaccines reduce CIN2+ associated with HPV16/18 from 113 to 6 /10,000 (RR 0.05 (0.03 to 0.10). In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000, (RR 0.30 (0.11 to 0.81), moderate certainty). HPV vaccines reduce the risk of CIN3+ and AIS associated with HPV16/18 in younger women (RR 0.05 (0.02 to 0.14), high certainty and RR 0.09 (0.01 to 0.72), moderate certainty, respectively). No trials in older women have measured these outcomes.Vaccines reduce any CIN2+ from 231 to 95/10,000, (RR 0.41 (0.32 to 0.52)) in younger women. No data are reported for more severe lesions.Regardless of HPV DNA statusIn younger women HPV vaccines reduce the risk of CIN2+ associated with HPV16/18 from 341 to 157/10,000 (RR 0.46 (0.37 to 0.57), high certainty). Similar reductions in risk were observed for CIN3+ associated with HPV16/18 (high certainty). The number of women with AIS associated with HPV16/18 is reduced from 14 to 5/10,000 with HPV vaccines (high certainty).HPV vaccines reduce any CIN2+ from 559 to 391/10,000 (RR 0.70 (0.58 to 0.85, high certainty) and any AIS from 17 to 5/10,000 (RR 0.32 (0.15 to 0.67), high certainty). The reduction in any CIN3+ differed by vaccine type (bivalent vaccine: RR 0.55 (0.43 to 0.71) and quadrivalent vaccine: RR 0.81 (0.69 to 0.96)).In women vaccinated at 24 to 45 years of age, there is moderate-certainty evidence that the risks of CIN2+ associated with HPV16/18 and any CIN2+ are similar between vaccinated and unvaccinated women (RR 0.74 (0.52 to 1.05) and RR 1.04 (0.83 to 1.30) respectively). No data are reported in this age group for CIN3+ or AIS.Adverse effectsThe risk of serious adverse events is similar between control and HPV vaccines in women of all ages (669 versus 656/10,000, RR 0.98 (0.92 to 1.05), high certainty). Mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29 [0.85 to 1.98]; low certainty). The number of deaths was low overall but there is a higher number of deaths in older women. No pattern in the cause or timing of death has been established.Pregnancy outcomesAmong those who became pregnant during the studies, we did not find an increased risk of miscarriage (1618 versus 1424/10,000, RR 0.88 (0.68 to 1.14), high certainty) or termination (931 versus 838/10,000 RR 0.90 (0.80 to 1.02), high certainty). The effects on congenital abnormalities and stillbirths are uncertain (RR 1.22 (0.88 to 1.69), moderate certainty and (RR 1.12 (0.68 to 1.83), moderate certainty, respectively).

AUTHORS' CONCLUSIONS: There is high-certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26. The effect is higher for lesions associated with HPV16/18 than for lesions irrespective of HPV type. The effect is greater in those who are negative for hrHPV or HPV16/18 DNA at enrolment than those unselected for HPV DNA status. There is moderate-certainty evidence that HPV vaccines reduce CIN2+ in older women who are HPV16/18 negative, but not when they are unselected by HPV DNA status.We did not find an increased risk of serious adverse effects. Although the number of deaths is low overall, there were more deaths among women older than 25 years who received the vaccine. The deaths reported in the studies have been judged not to be related to the vaccine. Increased risk of adverse pregnancy outcomes after HPV vaccination cannot be excluded, although the risk of miscarriage and termination are similar between trial arms. Long-term of follow-up is needed to monitor the impact on cervical cancer, occurrence of rare harms and pregnancy outcomes.

%B Cochrane Database Syst Rev %V 5 %8 2018 May 09 %G eng %N 5 %R 10.1002/14651858.CD009069.pub3 %0 Journal Article %J Journal of Clinical Virology %D 2018 %T VALHUDES: A protocol for validation of human papillomavirus assays and collection devices for HPV testing on self-samples and urine samples %A M. Arbyn %A E. Peeters %A Benoy,I. %A D. Vanden Broeck %A Bogers,J. %A P De Sutter %A Donders,G.G. %A W Tjalma %A Weyers,S. %A K. Cuschieri %A Poljak, M %A J. Bonde %A C. Cocuzza %A F.H. Zhao %A S Van Keer %A A Vorsters %K cervical cancer %K diagnostic test accuracy %K SCREENING %K self-sampling %K Test validation %K Urine collection %K VALHUDES %X

BACKGROUND
Systematic reviews have concluded that hrHPV DNA testing using target-amplification tests is as accurate on vaginal self-samples as on clinician-taken specimens for the detection of cervical precancer. However, insufficient evidence is available for specific HPV assay/self-sample device combinations.

OBJECTIVES
The VALHUDES protocol is designed as a diagnostic test accuracy study that aims to compare the clinical sensitivity and specificity of particular hrHPV assay(s) on vaginal self-samples and first-void-urine, collected in agreement with standardized protocols, with hrHPV testing on matched clinician-taken samples.

STUDY DESIGN
Five hundred enrolled women referred to a colposcopy clinic are invited to collect a first-void urine sample and one or more vaginal self-samples with particular devices before collection of a cervical sample by a clinician. Sample sets are subsequently analysed in a laboratory accredited for HPV testing. Disease verification for all enrolled patients is provided by colposcopy combined with histological assessment of biopsies.

RESULTS
A first VALHUDES study has started in Belgium in December 2017 with enrolment from four colposcopy centres. The following assays are foreseen to be evaluated: RealTime High Risk HPV assay (Abbott), cobas-4800 and -6800 (Roche), Onclarity (BD), Xpert HPV (Cepheid) and Anyplex II HPV HR (Seegene).

CONCLUSION
Given empirical evidence that the relative accuracy of HPV-testing on self- vs clinician-samples is robust across clinical settings, the VALHUDES protocol offers a framework for validation of HPV assay/self-sample device combinations that can be translated to a primary screening setting.

%B Journal of Clinical Virology %V 107 %8 Jan-10-2018 %G eng %R 10.1016/j.jcv.2018.08.006 %0 Journal Article %J J Clin Virol %D 2018 %T VALHUDES: A protocol for validation of human papillomavirus assays and collection devices for HPV testing on self-samples and urine samples. %A M. Arbyn %A I Benoy %A D Vanden Broeck %A J Bogers %A P De Sutter %A G Donders %A W Tjalma %A S Weyers %A Cuschieri, K %A Poljak, M %A J Bonde %A C Cocuzza %A F H Zhao %A S Van Keer %A A Vorsters %E E Peeters %K cervical cancer %K diagnostic test accuracy %K SCREENING %K self-sampling %K Test validation %K Urine collection %K VALHUDES %X

BACK GROUND: Systematic reviews have concluded that hrHPV DNA testing using target-amplification tests is as accurate on vaginal self-samples as on clinician-taken specimens for the detection of cervical precancer. However, insufficient evidence is available for specific HPV assay/self-sample device combinations.

OBJECTIVES: The VALHUDES protocol is designed as a diagnostic test accuracy study that aims to compare the clinical sensitivity and specificity of particular hrHPV assay(s) on vaginal self-samples and first-void-urine, collected in agreement with standardized protocols, with hrHPV testing on matched clinician-taken samples.

STUDY DESIGN: Five hundred enrolled women referred to a colposcopy clinic are invited to collect a first-void urine sample and one or more vaginal self-samples with particular devices before collection of a cervical sample by a clinician. Sample sets are subsequently analysed in a laboratory accredited for HPV testing. Disease verification for all enrolled patients is provided by colposcopy combined with histological assessment of biopsies.

RESULTS: A first VALHUDES study has started in Belgium in December 2017 with enrolment from four colposcopy centres. The following assays are foreseen to be evaluated: RealTime High Risk HPV assay (Abbott), cobas-4800 and -6800 (Roche), Onclarity (BD), Xpert HPV (Cepheid) and Anyplex II HPV HR (Seegene).

CONCLUSION: Given empirical evidence that the relative accuracy of HPV-testing on self- vs clinician-samples is robust across clinical settings, the VALHUDES protocol offers a framework for validation of HPV assay/self-sample device combinations that can be translated to a primary screening setting.

%B J Clin Virol %V 107 %8 2018 Oct %G eng %R 10.1016/j.jcv.2018.08.006 %0 Journal Article %J Virol J %D 2018 %T Validation of intra- and inter-laboratory reproducibility of the Xpert HPV assay according to the international guidelines for cervical cancer screening. %A Ajmal Akbari %A Vanden Broeck, Davy %A Benoy, Ina %A Padalko, Elizaveta %A Bogers, Johannes %A M. Arbyn %K Confidence Intervals %K DNA, Viral %K Early Detection of Cancer %K Female %K Genotyping Techniques %K Human Papillomavirus DNA Tests %K Humans %K Mass Screening %K Papillomaviridae %K Papillomavirus Infections %K Practice Guidelines as Topic %K Reproducibility of Results %K Sensitivity and Specificity %K Uterine Cervical Neoplasms %X

BACKGROUND
Cervical cancer screening with assays detecting DNA of high-risk human papillomavirus (hrHPV) types is more effective than cytology-based screening. This study completes the diagnostic accuracy assessment conducted previously within the framework of VALGENT-2 (Validation of HPV genotyping Tests) and aims to determine whether the reproducibility of Xpert HPV is in line with international validation criteria.

METHODS
Validation of new hrHPV DNA assays requires demonstration of good reproducibility and non-inferior clinical accuracy for cervical precancer compared to a standard comparator assay. The international reproducibility criteria are: lower bound of 95% confidence interval of the intra- and inter-laboratory agreement regarding detection of high-risk HPV DNA exceeding 87% with kappa ≥0.5.

RESULTS
The Xpert HPV assay showed high intra-laboratory reproducibility with an overall positivity/negativity agreement of 96.9% and a kappa of 0.925. Inter-laboratory testing showed an agreement of 97.8% with a kappa of 0.948.

CONCLUSIONS
The Xpert HPV assay fulfills the HPV test reproducibility criterion requirement for use in cervical cancer screening.

%B Virol J %V 15 %8 2018 Oct 29 %G eng %N 1 %R 10.1186/s12985-018-1076-6 %0 Journal Article %J BJOG %D 2017 %T Accuracy of combinations of visual inspection using acetic acid or lugol iodine to detect cervical precancer: a meta-analysis. %A Catarino, R %A Schäfer, S %A Vassilakos, P %A Petignat, P %A M. Arbyn %X

BACKGROUND: Visual inspection of the cervix with acetic acid (VIA) or with Lugol's iodine (VILI) have been evaluated for cervical cancer screening in developing countries.

OBJECTIVES: To assess the diagnostic accuracy and clinical utility of visual methods to detect cervical intraepithelial neoplasia grade 2+ (CIN2+) using: (1) VIA alone; (2) VILI alone; (3) co-testing; and (4) VILI as a triage test of a positive VIA result.

SEARCH STRATEGY: PubMed, EMBASE, and the Cochrane Library were searched up to May 2016.

SELECTION CRITERIA: All reports on the accuracy of VIA and VILI, or combinations of VIA/VILI, to detect CIN2+ were identified. Histology and colposcopy when no biopsy was taken were used as the reference standard.

DATA COLLECTION AND ANALYSIS: Selected studies were scored on methodological quality, and sensitivity and specificity were computed. Clinical utility was assessed from the positive predictive value (PPV) and the complement of the negative predictive value (cNPV).

MAIN RESULTS: We included 23 studies comprising 101 273 women. The pooled sensitivity and specificity of VILI was 88 and 86%, respectively. VILI was more sensitive, but not less specific, compared with VIA (relative sensitivity = 1.11; 95% confidence interval, 95% CI, 1.06-1.16; relative specificity = 0.98; 95% CI 0.95-1.01). Co-testing was hardly more sensitive, but significantly less specific, than VILI alone. VILI to triage VIA-POSITIVE women was not less sensitive, but more specific, compared with VIA alone (relative sensitivity = 0.98, 95% CI 0.96-1.01; relative specificity = 1.04, 95% CI 1.02-1.05). The average PPVs were low (range 11-16%), whereas the cNPV varied between 0.3% (VILI, co-testing) and 0.6% (triage).

CONCLUSIONS: Although imperfect, VILI alone appeared to be the most useful visual screening strategy.

TWEETABLE ABSTRACT: VILI alone seems to be the most useful visual screening test for cervical cancer screening.

%B BJOG %8 2017 Jun 12 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28603909?dopt=Abstract %R 10.1111/1471-0528.14783 %0 Journal Article %J Cancer Epidemiol Biomarkers Prev %D 2017 %T Defining optimal triage strategies for hrHPV screen positive women - an evaluation of HPV 16/18 genotyping, cytology and p16/Ki-67 cyto-immunochemistry. %A Stanczuk, Grazyna A %A Baxter, Gwen J %A Currie, Heather %A Forson, William %A Lawrence, James R %A Cuschieri, Kate %A Wilson, Allan %A Patterson, Lynne %A Govan, Lynn %A Black, Janice %A Palmer, Tim %A M. Arbyn %X

BACKGROUND: Several options for the triage of high-risk HPV screen positive (hrHPV+) women were assessed.

METHODS: This study incorporated CIN2+ cases and controls, all of whom tested hrHPV+ and whose results of liquid-based cytology (LBC), HPV16/18 genotyping and p16/Ki67 cyto-immunochemistry were available. Sensitivity and specificity for the CIN2+ of these triage tests were evaluated.

RESULTS: Absolute sensitivities of HPV 16/18 typing, LBC and p16/Ki-67 cyto-immunochemistry for CIN2+ detection were 61.7%, 68.3% and 85.0% for women with hrHPV+ clinician-taken samples. Respective specificities were 70.5%, 89.1% and 76.7%. The absolute accuracy of the triage tests was similar for women with a hrHPV+ self-sample. P16/Ki-67 cyto-immunochemistry was significantly more sensitive than LBC although significantly less specific.

CONCLUSIONS: All three single test triage options, if positive, exceed the threshold of 20% risk at which colposcopy would be indicated. However, none of them conferred a post-test probability of CIN2+ <2%; which would permit routine recall. P16/Ki-67 cyto-immunochemistry on HPV16/18 negative women had a post test probability of CIN2+ of 1.7% and 0.6% if also LBC negative.

IMPACT: This is one of the few studies to directly compare the performance of triage strategies of hrHPV+ women, in isolation and combinations. It is the only study assessing triage strategies in women who test hrHPV+ in self-taken vaginal samples. A combined triage option which incorporated HPV 16/18 typing prior to p16/ki-67 cyto-immunochemistry in HPV 16/18 negative women yielded a post test probability of CIN2+ of >20% while women who tested negative had a probability of CIN2+ of <2%.

%B Cancer Epidemiol Biomarkers Prev %8 2017 Sep 08 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28887297?dopt=Abstract %R 10.1158/1055-9965.EPI-17-0534 %0 Journal Article %J PLoS One %D 2017 %T Development and validation of a protocol for optimizing the use of paraffin blocks in molecular epidemiological studies: The example from the HPV-AHEAD study. %A Mena, Marisa %A Lloveras, Belén %A Tous, Sara %A Bogers, Johannes %A Maffini, Fausto %A Gangane, Nitin %A Kumar, Rekha Vijay %A Somanathan, Thara %A Lucas, Eric %A Anantharaman, Devasena %A Gheit, Tarik %A Castellsagué, Xavier %A Pawlita, Michael %A de Sanjosé, Silvia %A Alemany, Laia %A Tommasino, Massimo %A M. Arbyn %A Cindy Simoens %K Carcinoma %K Europe %K Head and Neck Neoplasms %K Humans %K India %K Molecular Diagnostic Techniques %K Molecular Epidemiology %K Necrosis %K Paraffin %K Paraffin Embedding %K Pilot Projects %K Random Allocation %X

Worldwide use of formalin-fixed paraffin-embedded blocks (FFPE) is extensive in diagnosis and research. Yet, there is a lack of optimized/standardized protocols to process the blocks and verify the quality and presence of the targeted tissue. In the context of an international study on head and neck cancer (HNC)-HPV-AHEAD, a standardized protocol for optimizing the use of FFPEs in molecular epidemiology was developed and validated. First, a protocol for sectioning the FFPE was developed to prevent cross-contamination and distributed between participating centers. Before processing blocks, all sectioning centers underwent a quality control to guarantee a satisfactory training process. The first and last sections of the FFPEs were used for histopathological assessment. A consensus histopathology evaluation form was developed by an international panel of pathologists and evaluated for four indicators in a pilot analysis in order to validate it: 1) presence/type of tumor tissue, 2) identification of other tissue components that could affect the molecular diagnosis and 3) quality of the tissue. No HPV DNA was found in sections from empty FFPE generated in any histology laboratories of HPV-AHEAD consortium and all centers passed quality assurance for processing after quality control. The pilot analysis to validate the histopathology form included 355 HNC cases. The form was filled by six pathologists and each case was randomly assigned to two of them. Most samples (86%) were considered satisfactory. Presence of >50% of invasive carcinoma was observed in all sections of 66% of cases. Substantial necrosis (>50%) was present in <2% of samples. The concordance for the indicators targeted to validate the histopathology form was very high (kappa > 0.85) between first and last sections and fair to high between pathologists (kappa/pabak 0.21-0.72). The protocol allowed to correctly process without signs of contamination all FFPE of the study. The histopathology evaluation of the cases assured the presence of the targeted tissue, identified the presence of other tissues that could disturb the molecular diagnosis and allowed the assessment of tissue quality.

%B PLoS One %V 12 %8 2017 %G eng %N 10 %R 10.1371/journal.pone.0184520 %0 Journal Article %J Int J Cancer %D 2017 %T Diagnostic accuracy of p16(INK4a) immunohistochemistry in oropharyngeal squamous cell carcinomas: A systematic review and meta-analysis. %A Prigge, Elena-Sophie %A M. Arbyn %A von Knebel Doeberitz, Magnus %A Reuschenbach, Miriam %K Biomarkers, Tumor %K Carcinoma, Squamous Cell %K Cell Transformation, Viral %K Cyclin-Dependent Kinase Inhibitor p16 %K DNA, Viral %K Humans %K In Situ Hybridization %K Neoplasm Proteins %K Oncogene Proteins, Viral %K Oropharyngeal Neoplasms %K Papillomaviridae %K Papillomavirus Infections %K polymerase chain reaction %K RNA, Messenger %K RNA, Viral %K Sensitivity and Specificity %X

The accurate diagnosis of human papillomavirus (HPV) causality in oropharyngeal squamous cell carcinomas (OPSCC) is likely to influence therapeutic decisions in affected patients in the near future. We conducted a systematic review and meta-analysis to determine the diagnostic accuracy of p16(INK4a) immunohistochemistry (IHC) to identify HPV-induced OPSCC. We identified all studies that performed p16(INK4a) IHC (index test) and HPV E6/E7 mRNA detection using an amplification-based method (gold standard to indicate a transforming relevance of HPV) in OPSCC. Testing with one or more comparator tests (HPV DNA PCR, HPV DNA in situ hybridization (ISH) and p16(INK4a) IHC/HPV DNA PCR combined testing) was an optional criterion for inclusion. Among 1,636 retrieved studies 24 fulfilled the inclusion criteria. The pooled sensitivity of p16(INK4a) IHC, HPV DNA PCR, HPV DNA ISH and p16(INK4a) IHC/HPV DNA PCR combined testing was 94% (95%-confidence interval (CI) 91-97%), 98% (CI 94-100%), 85% (CI 76-92%) and 93% (CI 87-97%), respectively. The pooled specificity was 83% (CI 78-88%), 84% (CI 74-92%), 88% (CI 78-96%) and 96% (CI 89-100%), respectively. p16(INK4a) IHC/HPV DNA PCR combined testing was as sensitive as either p16(INK4a) IHC or HPV DNA PCR alone but significantly more specific than either separate test. In conclusion, p16(INK4a) IHC is highly sensitive but moderately specific to diagnose HPV-transformed OPSCC when used as a single test. Combined p16(INK4a) IHC and HPV DNA PCR testing significantly enhances specificity while maintaining high sensitivity. This diagnostic test combination thus represents an attractive testing strategy for the reliable diagnosis of HPV-induced OPSCC in the clinical setting and may constitute an inclusion criterion for future therapeutic trials.

%B Int J Cancer %V 140 %P 1186-1198 %8 2017 Mar 01 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27859245?dopt=Abstract %R 10.1002/ijc.30516 %0 Journal Article %J Int J Cancer %D 2017 %T Eurogin 2016 Roadmap: how HPV knowledge is changing screening practice. %A Wentzensen, Nicolas %A M. Arbyn %A Berkhof, Johannes %A Bower, Mark %A Canfell, Karen %A Einstein, Mark %A Farley, Christopher %A Monsonego, Joseph %A Franceschi, Silvia %K Female %K Humans %K Male %K Neoplasms %K Papillomaviridae %K Papillomavirus Infections %K Papillomavirus Vaccines %K Vaccination %X

Human papillomaviruses (HPVs) are the necessary cause of most cervical cancers, a large proportion of other anogenital cancers, and a subset of oropharyngeal cancers. The knowledge about HPV has led to development of novel HPV-based prevention strategies with important impact on clinical and public health practice. Two complementary reviews have been prepared following the 2015 Eurogin Conference to evaluate how knowledge about HPV is changing practice in HPV infection and disease control through vaccination and screening. This review focuses on screening for cervical and anal cancers in increasingly vaccinated populations. The introduction of HPV vaccines a decade ago has led to reductions in HPV infections and early cancer precursors in countries with wide vaccination coverage. Despite the high efficacy of HPV vaccines, cervical cancer screening will remain important for many decades. Many healthcare systems are considering switching to primary HPV screening, which has higher sensitivity for cervical precancers and allows extending screening intervals. We describe different approaches to implementing HPV-based screening efforts in different healthcare systems with a focus in high-income countries. While the population prevalence for other anogenital cancers is too low for population-based screening, anal cancer incidence is very high in HIV-infected men who have sex with men, warranting consideration of early detection approaches. We summarize the current evidence on HPV-based prevention of anal cancers and highlight important evidence gaps.

%B Int J Cancer %V 140 %P 2192-2200 %8 2017 May 15 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/28006858?dopt=Abstract %R 10.1002/ijc.30579 %0 Journal Article %J J Clin Microbiol %D 2017 %T Evaluation of the clinical performance of the HPV-Risk assay using the VALGENT-3 panel. %A Polman, N J %A Oštrbenk, A %A Lan Xu %A Snijders, P J F %A Meijer, C J L M %A Poljak, M %A Heideman, D A M %A M. Arbyn %X

Human papillomavirus (HPV) testing is being increasingly incorporated into cervical cancer screening. VALGENT (VALidation of HPV GENotyping Tests) is a framework designed to evaluate the clinical performance of various HPV tests relative to the validated and accepted comparator test in a formalized and uniform manner. The aim of this study was to evaluate the clinical performance of the HPV-Risk assay within the VALGENT-3 panel, and to compare its performance to the clinically validated Hybrid Capture 2 assay (HC2). The VALGENT-3 panel comprises 1,300 consecutive samples from women participating in the routine cervical cancer screening, enriched with 300 samples from women with abnormal cytology. DNA was extracted from original ThinPrep aliquots and HPV testing was performed using the HPV-Risk assay, blinded to the clinical data. HPV prevalence was analysed and clinical performance for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) and CIN2 or worse (CIN2+) was assessed relative to the performance of the HC2. The sensitivity of the HPV-Risk assay for detection of CIN3+ was similar to that of the HC2 (relative sensitivity: 1.00; 95%CI: 0.95-1.05; p=1.000) with significantly higher specificity (relative specificity: 1.02; 95%CI: 1.01-1.04; p<0.001). For CIN2+, similar results were obtained with relative sensitivity of 0.98; 95%CI: 0.93-1.02 and relative specificity of 1.02; 95%CI: 1.01-1.03. The performance of the HPV-Risk assay for CIN3+ and CIN2+ was non-inferior compared to the HC2, with all p-values ≤0.006. In conclusion, the HPV-Risk assay demonstrated non-inferiority to the clinically validated HC2 through the VALGENT-3 panel for test validation and comparison.

%B J Clin Microbiol %8 2017 Oct 11 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/29021152?dopt=Abstract %R 10.1128/JCM.01282-17 %0 Journal Article %J Ann Intern Med %D 2017 %T Genotyping for Human Papillomavirus Types 16 and 18 in Women With Minor Cervical Lesions: A Systematic Review and Meta-analysis. %A M. Arbyn %A Lan Xu %A Verdoodt, Freija %A Cuzick, Jack %A Szarewski, Anne %A Belinson, Jerome L %A Wentzensen, Nicolas %A Gage, Julia C %A Khan, Michelle J %K Early Detection of Cancer %K Female %K Genotype %K Human papillomavirus 16 %K Human papillomavirus 18 %K Humans %K Papillomavirus Infections %K Precancerous Conditions %K Risk Factors %K Sensitivity and Specificity %K triage %K Uterine Cervical Neoplasms %X

Background: High-risk human papillomavirus (hrHPV) testing to triage women with minor cervical lesions generates many referrals.

Purpose: To evaluate the accuracy of genotyping for HPV types 16 and 18 and its utility as a second triage step after hrHPV testing in women with minor cervical lesions.

Data Sources: Searches of 4 bibliographic databases, without language restrictions, from 1 January 1999 to 1 February 2016.

Study Selection: Studies involving women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) who were triaged with tests for hrHPV and HPV 16/18 to find cervical intraepithelial neoplasia (grade ≥2 [CIN2+] or grade ≥3 [CIN3+]).

Data Extraction: Independent study selection, extraction of data, and quality assessment by 2 reviewers.

Data Synthesis: Twenty-four moderate- to good-quality studies involving 8587 women with ASC-US and 5284 with LSIL were found. The pooled sensitivity of HPV 16/18 genotyping for CIN3+ was about 70% for women with either ASC-US or LSIL. The pooled specificity (with a threshold of grade <2 CIN) was 83% (95% CI, 80% to 86%) for women with ASC-US and 76% (CI, 74% to 79%) for those with LSIL. The average risk for CIN3+ was 17% and 19% in HPV 16/18-positive women with ASC-US and LSIL, respectively, and was 5% in hrHPV-positive but HPV 16/18-negative women with either ASC-US or LSIL.

Limitation: Methodological and technical heterogeneity among studies; insufficient data to assess accuracy of separate assays.

Conclusion: Testing for HPV 16/18 to triage women with minor abnormal cytology is poorly sensitive but may be useful as a second triage test after hrHPV testing, with direct referral if the woman is positive for HPV 16/18. Whether colposcopy or repeated testing is recommended for hrHPV-positive but HPV 16/18-negative women depends on local decision thresholds that can be derived from pretest-posttest probability plots.

Primary Funding Source: 7th Framework Programme of the European Commission.

%B Ann Intern Med %V 166 %P 118-127 %8 2017 Jan 17 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27842420?dopt=Abstract %R 10.7326/M15-2735 %0 Journal Article %J Prev Med %D 2017 %T HPV-based cervical cancer screening- facts, fiction, and misperceptions. %A Wentzensen, Nicolas %A M. Arbyn %X

Several randomized trials have demonstrated that HPV-based cervical cancer screening is more effective than cytology-based screening. A pooled analysis of long-term follow-up data from these trials has shown reduced cervical cancer mortality in women screened with HPV compared to cytology. As a consequence, many health systems are currently transitioning to HPV-based screening programs. However, there are several controversies that influence whether and how HPV-based cervical cancer screening is implemented in different settings. Here, we discuss the most important controversies surrounding cervical cancer screening using primary HPV testing in light of published data from clinical trials and large observational studies. Overall, there is strong and uniform evidence for the efficacy of HPV-based screening, and little evidence for the usefulness of adding cytology to primary screening. However, there is currently limited data on optimal triage strategies for HPV-positive women, a critical component of an HPV-based screening program. There will likely be multiple choices for integrated screening programs and implementation may differ depending on risk perception, healthcare funds, assay costs, and available infrastructure, among other factors, in different settings. A particular challenge is the integration of screening and vaccination programs, since increasingly vaccinated populations will have a continuous decrease of cervical cancer risk.

%B Prev Med %V 98 %P 33-35 %8 2017 May %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28279260?dopt=Abstract %R 10.1016/j.ypmed.2016.12.040 %0 Journal Article %J Cochrane Database Syst Rev %D 2017 %T Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test. %A Kyrgiou, Maria %A Kalliala, Ilkka E J %A Mitra, Anita %A Fotopoulou, Christina %A Ghaem-Maghami, Sadaf %A Martin-Hirsch, Pierre Pl %A Cruickshank, Margaret %A M. Arbyn %A Paraskevaidis, Evangelos %K Cervical Intraepithelial Neoplasia %K Colposcopy %K Female %K Humans %K Papillomaviridae %K Patient Compliance %K Precancerous Conditions %K Randomized Controlled Trials as Topic %K Referral and Consultation %K Time Factors %K Vaginal Smears %K Watchful Waiting %X

BACKGROUND: A significant number of women are diagnosed with minor cytological abnormalities on cervical screening. Many authorities recommend surveillance as spontaneous regression might occur. However, attendance for cytological follow-up decreases with time and might put some women at risk of developing invasive disease.

OBJECTIVES: To assess the optimum management strategy for women with minor cervical cytological abnormalities (atypical squamous cells of undetermined significance - ASCUS or low-grade squamous intra-epithelial lesions - LSIL) at primary screening in the absence of HPV (human papillomavirus) DNA test.

SEARCH METHODS: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, 2016), MEDLINE (1946 to April week 2 2016) and Embase (1980 to 2016 week 16).

SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing immediate colposcopy to cytological surveillance in women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis).

DATA COLLECTION AND ANALYSIS: The primary outcome measure studied was the occurrence of cervical intra-epithelial neoplasia (CIN). The secondary outcome measures studied included default rate, clinically significant anxiety and depression, and other self-reported adverse effects.We classified studies according to period of surveillance, at 6, 12, 24 or 36 months, as well as at 18 months, excluding a possible exit-examination. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using a random-effects model with inverse variance weighting. Inter-study heterogeneity was assessed with I(2) statistics.

MAIN RESULTS: We identified five RCTs with 11,466 participants that fulfilled the inclusion criteria. There were 18 cases of invasive cervical cancer, seven in the immediate colposcopy and 11 in the cytological surveillance groups, respectively. Although immediate colposcopy detects CIN2+ and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN2+: 3 studies, 4331 women; 17.9% versus 18.3%, RR 1.14, CI 0.66 to 1.97; CIN3+: 3 studies, 4331 women; 10.3% versus 11.9%, RR 1.02, CI 0.53 to 1.97). The inter-study heterogeneity was considerable (I(2) greater than 90%). Furthermore, the inclusion of the results of the exit examinations at 24 months, which could inflate the CIN detection rate of cytological surveillance, may have led to study design-derived bias; we therefore considered the evidence to be of low quality.When we excluded the exit examination, the detection rate of high-grade lesions at the 18-month follow-up was higher after immediate colposcopy (CIN2+: 2 studies, 4028 women; 14.3% versus 10.1%, RR 1.50, CI 1.12 to 2.01; CIN3+: 2 studies, 4028 women, 7.8% versus 6.9%, RR 1.24, CI 0.77 to 1.98) both had substantial inter-study heterogeneity (I(2) greater than 60%) and we considered the evidence to be of moderate quality).The meta-analysis revealed that immediate referral to colposcopy significantly increased the detection of clinically insignificant cervical abnormalities, as opposed to repeat cytology after 24 months of surveillance (occurrence of koilocytosis: 2 studies, 656 women; 32% versus 21%, RR 1.49, 95% CI 1.17 to 1.90; moderate-quality evidence) incidence of any CIN: 2 studies, 656 women; 64% versus 32%, RR 2.02, 95% CI 1.33 to 3.08, low-quality evidence; incidence of CIN1: 2 studies, 656 women; 21% versus 8%, RR 2.58, 95% CI 1.69 to 3.94, moderate-quality evidence).Due to differences in trial designs and settings, there was large variation in default rates between the included studies. The risk for default was higher for the repeat cytology group, with a four-fold increase at 6 months, a six-fold at 12 and a 19-fold at 24 months (6 months: 3 studies, 5117 women; 6.3% versus 13.3%, RR 3.85, 95% CI 1.27 to 11.63, moderate-quality evidence; 12 months: 3 studies, 5115 women; 6.3% versus 14.8%, RR 6.39, 95% CI 1.49 to 29.29, moderate-quality evidence; 24 months: 3 studies, 4331 women; 0.9% versus 16.1%, RR 19.1, 95% CI 9.02 to 40.43, moderate-quality evidence).

AUTHORS' CONCLUSIONS: Based on low- or moderate-quality evidence using the GRADE approach and generally low risk of bias, the detection rate of CIN2+ or CIN3+ after two years does not appear to differ between immediate colposcopy and cytological surveillance in the absence of HPV testing, although women may default from follow-up. Immediate colposcopy probably leads to earlier detection of high-grade lesions, but also detects more clinically insignificant low-grade lesions. Colposcopy may therefore be the first choice when good compliance is not assured. These results emphasize the need for an accurate reflex HPV triage test to distinguish women who need diagnostic follow-up from those who can return safely to routine recall.

%B Cochrane Database Syst Rev %V 1 %P CD009836 %8 2017 01 26 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28125861?dopt=Abstract %R 10.1002/14651858.CD009836.pub2 %0 Journal Article %J Int J Cancer %D 2017 %T Immediate referral to colposcopy versus cytological surveillance for low-grade cervical cytological abnormalities in the absence of HPV test: A systematic review and a meta-analysis of the literature. %A Kyrgiou, Maria %A Kalliala, Ilkka %A Mitra, Anita %A Ng, Ka Ying Bonnie %A Raglan, Olivia %A Fotopoulou, Christina %A Martin-Hirsch, Pierre %A Paraskevaidis, Evangelos %A M. Arbyn %K Atypical Squamous Cells of the Cervix %K Colposcopy %K Cytodiagnosis %K Disease Management %K Female %K Humans %K Population Surveillance %K Randomized Controlled Trials as Topic %K Referral and Consultation %K Sensitivity and Specificity %K Squamous Intraepithelial Lesions of the Cervix %K triage %K Vaginal Smears %K Watchful Waiting %X

We performed a systematic review and meta-analysis to explore the optimum management strategy for women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis) cytological abnormalities at primary screening in the absence of HPV DNA test. We searched MEDLINE, EMBASE and CENTRAL and included randomised controlled trials comparing immediate colposcopy to cytological surveillance in women with ASCUS/LSIL. The outcomes of interest were occurrence of different histological grades of cervical intraepithelial neoplasia (CIN) and default rates during follow-up. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effect model and with inverse variance weighting. Interstudy heterogeneity was assessed using I(2) statistics. Six RCTs were included. Immediate colposcopy significantly increased detection of unimportant abnormalities as opposed to repeat cytology (koilocytosis: 32 vs. 21%, RR: 1.49, 95% CI = 1.17-1.90); CIN1: 21 vs. 8%, RR: 2.58, 95% CI = 1.69-3.94). Although immediate colposcopy detected CIN2, CIN2+, and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN3+: 10.3 vs.11.9%, RR: 1.02, 95% CI = 0.53-1.97), with significant interstudy heterogeneity (p < 0.001, I(2)  = 93%). Default risk was significantly higher for repeat cytology (6 months: 6.3 vs. 13.3%, RR: 3.85, 95% CI = 1.27-11.63; 12 months: 6.3 vs. 14.8%, RR: 6.39, 95% CI = 1.24-32.95; 24 months: 0.9 vs. 16.1%, RR: 19.1, 95% CI = 9.02-40.4). Detection of CIN2+ for cytological surveillance over two years is similar to that of immediate colposcopy, although patients may default. Colposcopy may be first choice when good compliance is not assured, but may increase detection of insignificant lesions. This emphasizes the need for a reflex triage test to distinguish women who need diagnostic work-up from those who can return to routine recall.

%B Int J Cancer %V 140 %P 216-223 %8 2017 Jan 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27603593?dopt=Abstract %R 10.1002/ijc.30419 %0 Journal Article %J J Gynecol Obstet Hum Reprod %D 2017 %T Impact of anaesthesia mode on evaluation of LEEP specimen dimensions. %A Mercuzot, A %A Chevreau, J %A Sevestre, H %A Muszynski, C %A M. Arbyn %A Sergent, F %A Gondry, J %X

OBJECTIVES: To study the influence of anaesthesia (local by cervical block vs. general or spinal anaesthesia) on height and volume of resection specimens in case of conization treatment for cervical intraepithelial neoplasia (CIN).

METHODS: Prospective observational study of all patients who underwent a first treatment by loop electrosurgical excision procedure (LEEP) for CIN. Height of fresh resection specimens was first measured by the operator and then by the pathologist after formaldehyde fixation. Volume of fresh specimens was measured in a measuring cylinder by fluid displacement.

RESULTS: One hundred patients were included and 35% of LEEP were performed under local anaesthesia. There was a significant difference in height of specimens depending on anaesthesia mode: after fixation, the average height was 11.2mm in the general or spinal anaesthesia group vs. 8.8mm in the local anaesthesia group (P=0.002). There was also a difference in terms of volume depending on anaesthesia mode: 1.6mL in local anaesthesia group vs. 2.3mm in general and spinal anaesthesia group (P=0.01).

CONCLUSIONS: Anaesthesia mode has an impact on height and volume of LEEP specimens. In our experience, local anaesthesia could reduce LEEP specimen height.

%B J Gynecol Obstet Hum Reprod %V 46 %P 339-342 %8 2017 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28643661?dopt=Abstract %R 10.1016/j.jogoh.2016.12.006 %0 Journal Article %J Diagn Cytopathol %D 2017 %T Introduction of liquid-based cytology and human papillomavirus testing in cervical cancer screening in Luxembourg. %A Ardashel Latsuzbaia %A Hebette, Gaëtan %A Fischer, Marc %A M. Arbyn %A Weyers, Steven %A Vielh, Philippe %A Schmitt, Fernando %A Mossong, Joel %K Adult %K Aged %K Atypical Squamous Cells of the Cervix %K Carcinoma, Squamous Cell %K Cervical Intraepithelial Neoplasia %K Colposcopy %K cross-sectional studies %K DNA, Viral %K Early Detection of Cancer %K Female %K Humans %K Luxembourg %K middle aged %K Neoplasm Grading %K Papillomaviridae %K Papillomavirus Infections %K Practice Guidelines as Topic %K Pregnancy %K prevalence %K Squamous Intraepithelial Lesions of the Cervix %K Uterine Cervical Neoplasms %K Vaginal Smears %X

BACKGROUND: In 2014, liquid-based cytology with HPV triage replaced conventional cytology. The aim of our study was to compare conventional and liquid-based cytology (LBC), estimate the prevalence of abnormal cervical cytology and high risk HPV (hrHPV) infection and their correlation, among screened women in Luxembourg.

METHODS: Between the first January 2013 and 31st December 2015, 315,868 cervical samples from 150,815 women (mean age 42.2 years) were investigated by the national cytology laboratory. Slides were prepared and screened according to European Guidelines. All cytological results were classified according to the Bethesda 2001 system terminology.

RESULTS: The prevalence of abnormal cervical lesions was as follows: atypical squamous cells of undetermined significance (ASC-US), 1.3%; low-grade squamous intraepithelial lesion (LSIL), 1.9%; high-grade squamous intraepithelial lesion (HSIL), 0.4%. The detection rate of cytological lesions was significantly higher with LBC than with conventional cytology. Based on 11,838 samples with concomitant cytology and HPV testing, hrHPV was detected in 9.5, 45.3, 70.0, and 92.6% of women with negative cytology, ASC-US, LSIL, and HSIL, respectively.

CONCLUSION: More cervical lesions were identified using LBC compared to conventional cytology. HrHPV infection was correlated with the severity of intraepithelial lesions. The current findings provide important information to evaluate the prevention of cervical cancer in Luxembourg and for monitoring the future impact of HPV vaccination. Diagn. Cytopathol. 2017;45:384-390. © 2017 Wiley Periodicals, Inc.

%B Diagn Cytopathol %V 45 %P 384-390 %8 2017 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/28247516?dopt=Abstract %R 10.1002/dc.23678 %0 Journal Article %J Eur J Obstet Gynecol Reprod Biol %D 2017 %T Pregnancy outcome after cervical conisation: A 2nd retrospective cohort study in the Leuven University Hospital. %A van Velthoven, Kim %A Poppe, Willy %A Verschuere, Hannah %A M. Arbyn %X

OBJECTIVE: To evaluate whether the dimensions of the cones removed during large loop excision of the transformation zone have decreased over time. Secondly, whether these changes were associated with a lower risk of obstetrical harms on a subsequent pregnancy.

STUDY DESIGN: A retrospective matched cohort study was performed in a tertiary referral unit in Belgium. A total of 97 women were identified from a database of women who underwent excisional treatment for cervical precancer between January 1st, 2004 and December 31st, 2012, and delivered before December 31st, 2014. The control group consisted of 120 non-treated women who had no history of cervical intra-epithelial neoplasia. Data on smoking status; gestational age at delivery; number of conisations; time interval between treatment and pregnancy; dimensions of the cone; severity of the lesion; and the extra resection of endocervical tissue were collected. These data were compared with those from a previous similar study at the University Hospital of Leuven in 2009, which database we enriched with information on the cone dimensions. Main outcome variables were gestational age at delivery, birthweight and neonatal condition at birth.

RESULTS: Only a significant lower birthweight could be found in the treated group compared to the control group (3364g [95% CI 3094-3290] versus 3364g [95% CI 3253-3475], P=0.023). The current study showed no increase in preterm birth rate after conisation and no relationship between volume or depth of the cone and preterm birth could be found. Over the period 1999-2014, a significant decrease in all dimensions was observed: on average -0.3mm, -0.3mm, -0.4mm and -132mm(3) per year, for the depth, anteroposterior and transverse diameter and the volume, respectively.

CONCLUSIONS: Our two successive studies showed a significant trend towards smaller cones which was accompanied by a decrease in preterm birth after excisional treatment. The clinician could limit the size of the cone to avoid obstetrical harms, but needs to be aware of the oncological safety as well.

%B Eur J Obstet Gynecol Reprod Biol %V 216 %P 224-231 %8 2017 Sep %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28822944?dopt=Abstract %R 10.1016/j.ejogrb.2017.06.043 %0 Journal Article %J Int J Cancer %D 2017 %T Role of mucosal high-risk human papillomavirus types in head and neck cancers in central India. %A Gheit, Tarik %A Anantharaman, Devasena %A Holzinger, Dana %A Alemany, Laia %A Tous, Sara %A Lucas, Eric %A Prabhu, Priya Ramesh %A Pawlita, Michael %A Ridder, Ruediger %A Rehm, Susanne %A Bogers, Johannes %A Maffini, Fausto %A Chiocca, Susanna %A Lloveras, Belén %A Kumar, Rekha Vijay %A Somanathan, Thara %A de Sanjosé, Silvia %A Castellsagué, Xavier %A M. Arbyn %A Brennan, Paul %A Sankaranarayanan, Rengaswamy %A Madhavan R Pillai %A Gangane, Nitin %A Tommasino, Massimo %K Adult %K Aged %K Cyclin-Dependent Kinase Inhibitor p16 %K Female %K Head and Neck Neoplasms %K Humans %K India %K Male %K middle aged %K Papillomaviridae %K Papillomavirus Infections %X

Mucosal high-risk (HR) human papillomaviruses (HPV) cause a subset of head and neck cancers (HNC). The HPV-attributable fraction of HNC varies substantially between countries. Although HNC has a very high incidence in the Indian subcontinent, information on the contribution of HPV infection is limited. Here, we evaluated the HPV-attributable fraction in HNC (N = 364) collected in a central region of India. HNC from three different anatomical subsites were included, namely, oral cavity (n = 252), oropharynx (n = 53) and hypopharynx/larynx (n = 59). In this retrospective study, HPV-driven HNC were defined by presence of both viral DNA and RNA. Overexpression of p16(INK4a) was also evaluated. HR-HPV DNA was detected in 13.7% of the cases; however, only 2.7% were positive for both HPV DNA and RNA. The highest percentage of HPV DNA/RNA double positivity was found in oropharynx (9.4%), followed by larynx (1.7%) and oral cavity (1.6%) (p = 0.02). More than half of HPV DNA/RNA-positive cases were p16(INK4a) -negative, while a considerable number of HPV RNA-negative cases were p16(INK4a) -positive (17.9%). HPV16 was the major type associated with HNC (60.0%), although cases positive for HPV18, 35 and 56 were also detected. Our data indicate that the proportion and types of mucosal HR-HPV associated with HNC in this central Indian region differ from those in other (developed) parts of the world. This may be explained by differences in smoking and/or sexual behaviour compared with North America and northern Europe. Moreover, we show that p16(INK4a) staining appeared not to be a good surrogate marker of HPV transformation in the Indian HNC cases.

%B Int J Cancer %V 141 %P 143-151 %8 2017 Jul 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28369859?dopt=Abstract %R 10.1002/ijc.30712 %0 Journal Article %J BMJ %D 2016 %T Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. %A Kyrgiou, Maria %A Athanasiou, Antonios %A Paraskevaidi, Maria %A Mitra, Anita %A Kalliala, Ilkka %A Martin-Hirsch, Pierre %A M. Arbyn %A Bennett, Phillip %A Paraskevaidis, Evangelos %K Adult %K Cervical Intraepithelial Neoplasia %K Cervix Uteri %K conization %K Delivery, Obstetric %K Female %K Humans %K Obstetric Labor, Premature %K Pregnancy %K Pregnancy Complications, Neoplastic %K Pregnancy Outcome %K Premature Birth %K Risk Factors %K Uterine Cervical Neoplasms %X

OBJECTIVE:  To assess the effect of treatment for cervical intraepithelial neoplasia (CIN) on obstetric outcomes and to correlate this with cone depth and comparison group used.

DESIGN:  Systematic review and meta-analysis.

DATA SOURCES:  CENTRAL, Medline, Embase from 1948 to April 2016 were searched for studies assessing obstetric outcomes in women with or without previous local cervical treatment.

DATA EXTRACTION AND SYNTHESIS:  Independent reviewers extracted the data and performed quality assessment using the Newcastle-Ottawa criteria. Studies were classified according to method and obstetric endpoint. Pooled risk ratios were calculated with a random effect model and inverse variance. Heterogeneity between studies was assessed with I(2) statistics.

MAIN OUTCOME MEASURES:  Obstetric outcomes comprised preterm birth (including spontaneous and threatened), premature rupture of the membranes, chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage, and cervical stenosis. Neonatal outcomes comprised low birth weight, admission to neonatal intensive care, stillbirth, APGAR scores, and perinatal mortality.

RESULTS:  71 studies were included (6 338 982 participants: 65 082 treated/6 292 563 untreated). Treatment significantly increased the risk of overall (<37 weeks; 10.7% v 5.4%; relative risk 1.78, 95% confidence interval 1.60 to 1.98), severe (<32-34 weeks; 3.5% v 1.4%; 2.40, 1.92 to 2.99), and extreme (<28-30 weeks; 1.0% v 0.3%; 2.54, 1.77 to 3.63) preterm birth. Techniques removing or ablating more tissue were associated with worse outcomes. Relative risks for delivery at <37 weeks were 2.70 (2.14 to 3.40) for cold knife conisation, 2.11 (1.26 to 3.54) for laser conisation, 2.02 (1.60 to 2.55) for excision not otherwise specified, 1.56 (1.36 to 1.79) for large loop excision of the transformation zone, and 1.46 (1.27 to 1.66) for ablation not otherwise specified. Compared with no treatment, the risk of preterm birth was higher in women who had undergone more than one treatment (13.2% v 4.1%; 3.78, 2.65 to 5.39) and with increasing cone depth (≤10-12 mm; 7.1% v 3.4%; 1.54, 1.09 to 2.18; ≥10-12 mm: 9.8% v 3.4%, 1.93, 1.62 to 2.31; ≥15-17 mm: 10.1% v 3.4%; 2.77, 1.95 to 3.93; ≥20 mm: 10.2% v 3.4%; 4.91, 2.06 to 11.68). The choice of comparison group affected the magnitude of effect. This was higher for external comparators, followed by internal comparators, and ultimately women with disease who did not undergo treatment. In women with untreated CIN and in pregnancies before treatment, the risk of preterm birth was higher than the risk in the general population (5.9% v 5.6%; 1.24, 1.14 to 1.35). Spontaneous preterm birth, premature rupture of the membranes, chorioamnionitis, low birth weight, admission to neonatal intensive care, and perinatal mortality were also significantly increased after treatment. :

CONCLUSIONS:  Women with CIN have a higher baseline risk for prematurity. Excisional and ablative treatment further increases that risk. The frequency and severity of adverse sequelae increases with increasing cone depth and is higher for excision than for ablation.

%B BMJ %V 354 %P i3633 %8 2016 Jul 28 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/27469988?dopt=Abstract %R 10.1136/bmj.i3633 %0 Journal Article %J Diagn Microbiol Infect Dis %D 2016 %T Analytical performance evaluation of Anyplex II HPV28 and Euroarray HPV for genotyping of cervical samples. %A Ardashel Latsuzbaia %A Tapp, Jessica %A Nguyen, Trung %A Fischer, Marc %A M. Arbyn %A Weyers, Steven %A Mossong, Joel %K ADOLESCENT %K Adult %K Aged %K Cervix Uteri %K Female %K Genotyping Techniques %K Humans %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K Young adult %X

Analytically accurate human papillomavirus (HPV) genotyping methods are required to assess the impact of HPV vaccination. The aim of this study was to evaluate the analytical performance of Anyplex II HPV28 (Seegene, Korea) and Euroarray HPV (Euroimmun, Germany) genotyping kits, for conducting a future HPV vaccine efficacy monitoring study in Luxembourg. A total number of 150 cervical swabs were collected from women with mean age 31.4 years. Agreements for detecting any HPV between Aptima/Anyplex (88.0%) and Aptima/Euroarray (90.7%) were similar. Agreement of Anyplex/EuroArray with Aptima was higher for Genotypes 16, 18 or 45 than for the other 11 HPVs. The average number of HPV genotypes detected per sample was similar with 2.6 and 2.5, for Anyplex and EuroArray, respectively. In conclusion, Anyplex and Euroarray showed high agreement in general and in particular for detecting genotypes contained in HPV vaccines.

%B Diagn Microbiol Infect Dis %V 85 %P 318-322 %8 2016 Jul %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27156793?dopt=Abstract %R 10.1016/j.diagmicrobio.2016.04.011 %0 Journal Article %J Stat Methods Med Res %D 2016 %T ANOVA model for network meta-analysis of diagnostic test accuracy data. %A Victoria N Nyaga %A Aerts, Marc %A M. Arbyn %X

Procedures combining and summarising direct and indirect evidence from independent studies assessing the diagnostic accuracy of different tests for the same disease are referred to network meta-analysis. Network meta-analysis provides a unified inference framework and uses the data more efficiently. Nonetheless, handling the inherent correlation between sensitivity and specificity continues to be a statistical challenge. We developed an arm-based hierarchical model which expresses the logit transformed sensitivity and specificity as the sum of fixed effects for test, correlated study-effects to model the inherent correlation between sensitivity and specificity and a random error associated with various tests evaluated in a given study. We present the accuracy of 11 tests used to triage women with minor cervical lesions to detect cervical precancer. Finally, we compare the results with those from a contrast-based model which expresses the linear predictor as a contrast to a comparator test. The proposed arm-based model is more appealing than the contrast-based model since the former permits more straightforward interpretation of the parameters, makes use of all available data yielding shorter credible intervals, and models more natural variance-covariance matrix structures.

%B Stat Methods Med Res %8 2016 Sep 20 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/27655805?dopt=Abstract %R 10.1177/0962280216669182 %0 Journal Article %J Syst Rev %D 2016 %T Barriers and opportunities for return-to-work of cancer survivors: time for action--rapid review and expert consultation. %A Regine Kiasuwa %A Otter, Renée %A Mortelmans, Katrien %A M. Arbyn %A Herman Van Oyen %A Bouland, Catherine %A De Brouwer, Christophe %K Age factors %K Antineoplastic Agents %K Combined Modality Therapy %K dépression %K Educational Status %K Fatigue %K Humans %K Income %K Neoplasm Staging %K Neoplasms %K pain %K Protective Factors %K Referral and Consultation %K Return to Work %K Risk Factors %K sick leave %K Social Support %K Survivors %K Workload %X

BACKGROUND: The spread of early detection and the improvement of cancer treatment have led to an increased prevalence of cancer survivors, including in the working age population. Return-to-work (RTW) of cancer survivors has become a key issue for national cancer control plans. This study aims (1) to identify the factors that have an impact on RTW of cancer survivors and to draw a risk profile supporting health professionals in the screening of those at risk for barriers of RTW and (2) to sharpen these results with input from health, social security and academic Belgian experts and to provide evidence-based recommendations that facilitate RTW of cancer survivors.

METHODS: A rapid review was conducted, based on the methodology elaborated by The Knowledge to Action Research Programme and researchers from the University of York, including a quality assessment of retained studies. Next, the Delphi method was used to organize a consultation with experts in order to discuss, validate and complement the results.

RESULTS: Forty-three out of 1860 studies were included. We identified nine risk factors grouped into four categories: socio-demographic, disease and treatment-related, work-related, and personal and subjective factors. Experts suggested dividing them into two even groups: factors which are modifiable and those which are not. The awareness of health professionals regarding the identified factors, a better assessment of work capacities, clarity on the rights and obligations of employers and workers alike, and the setup of a positive discrimination employment policy for cancer survivors were acknowledged as factors facilitating RTW of cancer survivors.

CONCLUSIONS: The awareness of health professionals regarding barriers of RTW may improve the early identification of cancer survivors at risk for prolonged time to RTW and may allow early supportive intervention. Social and employment policies should be better tailored to support both employers and cancer survivors in the RTW process, providing incentives to positively discriminate cancer survivors on prolonged sick leave.

%B Syst Rev %V 5 %P 35 %8 2016 Feb 24 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26912175?dopt=Abstract %R 10.1186/s13643-016-0210-z %0 Journal Article %J J Clin Virol %D 2016 %T Clinical and analytical performance of the PapilloCheck HPV-Screening assay using the VALGENT framework. %A Heard, I %A Cuschieri, K %A Geraets, D T %A Quint, W %A M. Arbyn %X

BACKGROUND: The benefit of HPV testing for cervical cancer screening and disease management has been shown in many recent studies and is part of several new evidence-based guidelines. Assessment of emerging HPV tests in this context is essential, using well-annotated samples, such as those generated via the Validation of Genotyping Tests-HPV (VALGENT) framework.

OBJECTIVE: Our aim was to assess the PapilloCheck HPV assay in terms of absolute and relative accuracy for primary cervical cancer screening, using a standard comparator test (GP5+/6+EIA)already validated in randomised trials.

STUDY DESIGN: Type-specific HPV prevalence was stratified by age and cytology grade and compared with the luminex typing assay incorporating a GP5+6+ PCR (GP5+/6+ LMNX Assay). Clinical outcomes were compared with GP5+/6+EIA.

RESULTS: Prevalence of hrHPV types (high-risk HPV) increased with severity of cytology. The concordance between PapilloCheck and the GP5+/6+ LMNX Assay was excellent when assessed at the qualitative hrHPV presence/absence level also at the type-specific level in the whole population and in women over 30 years of age. Absolute clinical sensitivity and specificity of the PapilloCheck was high and ranged between 95.5% and 98.2% for sensitivity and between 82.7% and 91.6% for specificity, depending on the outcome and population.

CONCLUSION: The sensitivity and specificity of this assay for the outcomes of CIN2+ were similar to those of the standard comparator assay, GP5+/6+ EIA.

%B J Clin Virol %V 81 %P 6-11 %8 2016 Aug %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/27262102?dopt=Abstract %R 10.1016/j.jcv.2016.05.004 %0 Journal Article %J BMJ Open %D 2016 %T Clinical validation of hrHPV testing on vaginal and urine self-samples in primary cervical screening (cross-sectional results from the Papillomavirus Dumfries and Galloway-PaVDaG study). %A Stanczuk, Grazyna %A Baxter, Gwendoline %A Currie, Heather %A Lawrence, James %A Cuschieri, Kate %A Wilson, Allan %A M. Arbyn %K Cervical Intraepithelial Neoplasia %K Cervix Uteri %K Early Detection of Cancer %K Female %K Human Papillomavirus DNA Tests %K Humans %K Papillomavirus Infections %K Predictive Value of Tests %K Reproducibility of Results %K Scotland %K specimen handling %K Urinalysis %K Vagina %X

OBJECTIVES: Papillomavirus Dumfries and Galloway (PaVDaG) assessed the performance of a high-risk human papillomavirus (hrHPV) PCR-based assay to detect high-grade cervical intraepithelial neoplasia (CIN2+) in self-collected vaginal and urine samples.

SETTING: Women attending routine cervical screening in primary care.

PARTICIPANTS: 5318 women aged 20-60 years provided self-collected random urine and vaginal samples for hrHPV testing and a clinician-collected liquid-based cytology (LBC) sample for cytology and hrHPV testing.

INTERVENTIONS: HrHPV testing. All samples were tested for hrHPV using the PCR-based cobas 4800 assay. Colposcopy was offered to women with high-grade or repeated borderline/low-grade cytological abnormalities; also to those who were LBC negative but hrHPV 16/18 positive.

PRIMARY AND SECONDARY OUTCOME MEASURES: The self-tests' absolute sensitivity and specificity for CIN2+ were assessed on all biospecimens; also, their relative sensitivity and specificity compared with clinician-taken samples. Interlaboratory and intralaboratory performance of the hrHPV assay in self-collected samples was also established.

RESULTS: HrHPV prevalence was 14.7%, 16.6% and 11.6% in cervical, vaginal and urine samples, respectively. Sensitivity for detecting CIN2+ was 97.7% (95% to 100%), 94.6% (90.7% to 98.5%) and 63.1% (54.6% to 71.7%) for cervical, vaginal and urine hrHPV detection, respectively. The corresponding specificities were 87.3% (86.4% to 88.2%), 85.4% (84.4% to 86.3%) and 89.8% (89.0% to 90.7%). There was a 38% (24% to 57%) higher HPV detection rate in vaginal self-samples from women over 50 years compared with those ≤29 years. Relative sensitivity and specificity of hrHPV positivity for the detection of CIN2+ in vaginal versus cervical samples were 0.97 (0.94 to 1.00) and 0.98 (0.97 to 0.99); urine versus cervical comparisons were 0.53 (0.42 to 0.67) and 1.03 (1.02 to 1.04). The intralaboratory and interlaboratory agreement for hrHPV positivity in self-samples was high (κ values 0.98 (0.96 to 0.99) and 0.94 (0.92 to 0.97) for vaginal samples and 0.95 (0.93 to 0.98) and 0.90 (0.87 to 0.94) for urine samples).

CONCLUSIONS: The sensitivity of self-collected vaginal samples for the detection of CIN2+ was similar to that of cervical samples and justifies consideration of this sample for primary screening.

%B BMJ Open %V 6 %P e010660 %8 2016 Apr 25 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27113237?dopt=Abstract %R 10.1136/bmjopen-2015-010660 %0 Journal Article %J J Clin Microbiol %D 2016 %T Correction for Geraets et al., Clinical Evaluation of a GP5+/6+-Based Luminex Assay Having Full High-Risk Human Papillomavirus Genotyping Capability and an Internal Control. %A Geraets, D T %A Cuschieri, K %A de Koning, M N C %A van Doorn, L J %A Snijders, P J F %A Meijer, C J L M %A Quint, W G V %A M. Arbyn %B J Clin Microbiol %V 54 %P 1927 %8 2016 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/27343293?dopt=Abstract %R 10.1128/JCM.00753-16 %0 Journal Article %J J Clin Virol %D 2016 %T Direct comparison of two vaginal self-sampling devices for the detection of human papillomavirus infections. %A Jentschke, M %A Chen, K %A M. Arbyn %A Hertel, B %A Noskowicz, M %A Soergel, P %A Hillemanns, P %X

BACKGROUND AND OBJECTIVES: Two devices for vaginal self-sampling of dry cell material (Evalyn Brush, Rovers Medical Devices; Qvintip, Aprovix) were compared using the Abbott RealTime High Risk HPV test.

STUDY DESIGN: Both self-sampling devices (change of order with every patient) including instructions for use and a questionnaire were handed to 146 patients in a colposcopy clinic prior to scheduled colposcopies with collection of cervical reference specimens by gynaecologists using a broom-like device. Matched self-collected and physician collected specimens were transferred to ThinPrep medium and tested for the presence of hr-HPV. Biopsies were taken if indicated by colposcopy.

RESULTS: Evaluation of 136 patients with complete data (136/146; 93.2%) showed high agreement of overall hr-HPV detection rates between self-collected and clinician-collected specimens (Evalyn: 91.2% [kappa 0.822]; Qvintip: 89.0% [kappa 0.779]). Colposcopy and histological evaluation revealed 55 women without cervical intraepithelial neoplasia (CIN), 32 CIN1, 34 CIN2, 14 CIN3 and one adenocarcinoma in situ. Hr-HPV testing detected all CIN3+ cases on the clinician-taken or Evalyn self-samples (14/14) and 93% of them on the Qvintip samples (13/14). There was no significant difference regarding the sensitivity for CIN2+ or CIN3+ and specificity of hr-HPV testing on self- vs. clinician samples and on Evalyn vs. Qvintip. Based on signal intensities of β-globin, the observed DNA concentration with Evalyn samples (mean CN: 22.0; 95%-CI: 21.5-22.6) was found to be significantly higher compared to that of Qvintip samples (mean CN: 23.8; 95%-CI 23.2-24.4), regardless of the order of self-sampling (p<0.0001). Most women considered self-sampling easy and comfortable. Qvintip was considered easier than the Evalyn Brush to understand (p<0.001) and to use (p=0.002).

DISCUSSION: This study confirms that hr-HPV testing with a clinically validated PCR-based HPV assay is as accurate on self-samples as on clinician-samples without significant difference between both self-sampling devices.

%B J Clin Virol %V 82 %P 46-50 %8 2016 Sep %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/27434147?dopt=Abstract %R 10.1016/j.jcv.2016.06.016 %0 Journal Article %J Cancer Epidemiol %D 2016 %T Enrolment of young women attending cervical cancer screening to survey effectiveness of HPV vaccination. %A M. Arbyn %A Vanden Broeck, Davy %A Bogers, Johannes %A Van Damme, Pierre %A Temmerman, Marleen %A Weyers, Steven %B Cancer Epidemiol %V 45 %P 178-179 %8 2016 Dec %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/27847177?dopt=Abstract %R 10.1016/j.canep.2016.10.017 %0 Journal Article %J Int J Cancer %D 2016 %T High-risk HPV testing in the management of atypical glandular cells: A systematic review and meta-analysis. %A Verdoodt, Freija %A Jiang, Xuezhi %A Williams, Mark %A Schnatz, Peter F %A M. Arbyn %K Adenocarcinoma %K Cervical Intraepithelial Neoplasia %K Early Detection of Cancer %K Female %K Humans %K Papillomavirus Infections %K Uterine Cervical Neoplasms %X

Whereas the utility of high-risk HPV (hrHPV) testing is widely accepted in triage of women with atypical squamous lesions, its role in managing atypical glandular cells (AGC) is not fully elucidated. A systematic review and meta-analysis were performed to evaluate the accuracy of hrHPV testing in the management of women with AGC to detect underlying high-grade intraepithelial neoplasia or worse, and adenocarcinoma in situ or worse (AIS+). Additionally, the diagnosis of extra-cervical cancer was considered as an outcome in this review. A bibliographic database search (PubMed, EMBASE, CENTRAL) identified twelve eligible studies. The occurrence of cervical intraepithelial neoplasia grade two or worse including AIS+ (CIN2+/AIS+), was 19.8% among women with AGC, and 55.7% among women with AGC and concurrent squamous lesions (atypical squamous cells of undetermined significance or worse, ASC-US+). The pooled sensitivity and specificity of hrHPV-testing with Hybrid Capture 2 (HC2) to detect CIN2+/AIS+ in women with AGC was 90.0% (95% CI = 85.1-93.4%) and 75.1% (95% CI = 64.8-83.2%), respectively. Women who were hrHPV-negative, demonstrated an increased risk for extra-cervical malignancy (endometrium, fallopian tube, ovary). In women of 50y and older, a hrHPV-negative result was linked with a 18.0% chance of extra-cervical malignancy, while the chance of cervical pre-cancer and cancer was 0.4 and 0.0%, respectively. In conclusion, given the high risk of underlying CIN2+/AIS+, women with AGC should be referred directly to colposcopy. However, hrHPV test results in combination with the age, appears to improve the diagnostic process by distinguishing the risk for cervical versus non-cervical lesions.

%B Int J Cancer %V 138 %P 303-10 %8 2016 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25583258?dopt=Abstract %R 10.1002/ijc.29424 %0 Journal Article %J J Clin Virol %D 2016 %T HPV testing in the context of post-treatment follow up (test of cure). %A Cuschieri, Kate %A Bhatia, Ramya %A Cruickshank, Margaret %A Hillemanns, Peter %A M. Arbyn %K Biomarkers, Pharmacological %K Cervical Intraepithelial Neoplasia %K DNA, Viral %K Female %K Follow-Up Studies %K Genotyping Techniques %K Human Papillomavirus DNA Tests %K Humans %K Mass Screening %K Papillomaviridae %K Papillomavirus Infections %K Sensitivity and Specificity %K Treatment Outcome %K Uterine Cervical Neoplasms %X

BACKGROUND: Women treated for cervical lesions are at higher risk of subsequent disease compared to the general population. Consequently, post treatment surveillance strategies are required to ensure the success of treatment, so called "test of cure". The high sensitivity and negative predictive value of HPV assays can enhance post-treatment strategies.

OBJECTIVES: To provide an overview of the current data on test of cure strategies with a particular focus on HPV testing and to identify knowledge gaps and areas for further research.

RESULTS: HPV testing is sensitive for the detection of residual or recurrent disease post treatment for CIN2+ and is more sensitive than cytology alone. Co-testing increases sensitivity, marginally and there is a lack of consensus regarding the efficiency and safety to release negative women. Most test of cure studies have applied HPV DNA tests and post treatment positivity rates vary widely depending on assay and potentially, treatment type.

CONCLUSIONS: Globally, an increasing number of test of cure algorithms now incorporate HPV testing although there is heterogeneity of practice with respect to assay, number of post treatment tests, testing intervals, follow up time. While type specific persistence identified through genotyping may identify those at greater risk of disease there is no consensus as to how this may be applied, clinically. Data on HPV testing in women treated for glandular lesions would be welcome as would the performance of different HPV assays and associated biomarkers in this context.

%B J Clin Virol %V 76 Suppl 1 %P S56-S61 %8 2016 Mar %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26525202?dopt=Abstract %R 10.1016/j.jcv.2015.10.008 %0 Journal Article %J Nat Rev Clin Oncol %D 2016 %T HPV-FASTER: broadening the scope for prevention of HPV-related cancer. %A Bosch, F Xavier %A Robles, Claudia %A Diaz, Mireia %A M. Arbyn %A Baussano, Iacopo %A Clavel, Christine %A Ronco, Guglielmo %A Dillner, Joakim %A Lehtinen, Matti %A Petry, Karl-Ulrich %A Poljak, Mario %A Kjaer, Susanne K %A Meijer, Chris J L M %A Garland, Suzanne M %A Salmerón, Jorge %A Castellsagué, Xavier %A Bruni, Laia %A de Sanjosé, Silvia %A Cuzick, Jack %K Adult %K Early Detection of Cancer %K Female %K Human papillomavirus 16 %K Human papillomavirus 18 %K Humans %K Mass Screening %K middle aged %K Papillomavirus Infections %K Papillomavirus Vaccines %K Sensitivity and Specificity %K Uterine Cervical Neoplasms %K Vaccination %K Young adult %X

Human papillomavirus (HPV)-related screening technologies and HPV vaccination offer enormous potential for cancer prevention, notably prevention of cervical cancer. The effectiveness of these approaches is, however, suboptimal owing to limited implementation of screening programmes and restricted indications for HPV vaccination. Trials of HPV vaccination in women aged up to 55 years have shown almost 90% protection from cervical precancer caused by HPV16/18 among HPV16/18-DNA-negative women. We propose extending routine vaccination programmes to women of up to 30 years of age (and to the 45-50-year age groups in some settings), paired with at least one HPV-screening test at age 30 years or older. Expanding the indications for HPV vaccination and much greater use of HPV testing in screening programmes has the potential to accelerate the decline in cervical cancer incidence. Such a combined protocol would represent an attractive approach for many health-care systems, in particular, countries in Central and Eastern Europe, Latin America, Asia, and some more-developed parts of Africa. The role of vaccination in women aged >30 years and the optimal number of HPV-screening tests required in vaccinated women remain important research issues. Cost-effectiveness models will help determine the optimal combination of HPV vaccination and screening in public health programmes, and to estimate the effects of such approaches in different populations.

%B Nat Rev Clin Oncol %V 13 %P 119-32 %8 2016 02 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26323382?dopt=Abstract %R 10.1038/nrclinonc.2015.146 %0 Journal Article %J J Clin Microbiol %D 2016 %T Performance of a Cartridge-Based Assay for Detection of Clinically Significant Human Papillomavirus (HPV) Infection: Lessons from VALGENT (Validation of HPV Genotyping Tests). %A Cuschieri, Kate %A Geraets, Daan %A Cuzick, Jack %A Cadman, Louise %A Moore, Catherine %A Vanden Broeck, Davy %A Padalko, Elisaveta %A Quint, Wim %A M. Arbyn %K ADOLESCENT %K Adult %K Aged %K Early Detection of Cancer %K Female %K Genotyping Techniques %K Humans %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K Reproducibility of Results %K Sensitivity and Specificity %K United Kingdom %K Uterine Cervical Neoplasms %K Young adult %X

The Validation of Human Papillomavirus (HPV) Genotyping Tests (VALGENT) studies offer an opportunity to clinically validate HPV assays for use in primary screening for cervical cancer and also provide a framework for the comparison of analytical and type-specific performance. Through VALGENT, we assessed the performance of the cartridge-based Xpert HPV assay (Xpert HPV), which detects 14 high-risk (HR) types and resolves HPV16 and HPV18/45. Samples from women attending the United Kingdom cervical screening program enriched with cytologically abnormal samples were collated. All had been previously tested by a clinically validated standard comparator test (SCT), the GP5+/6+ enzyme immunoassay (EIA). The clinical sensitivity and specificity of the Xpert HPV for the detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and CIN3+ relative to those of the SCT were assessed as were the inter- and intralaboratory reproducibilities according to international criteria for test validation. Type concordance for HPV16 and HPV18/45 between the Xpert HPV and the SCT was also analyzed. The Xpert HPV detected 94% of CIN2+ and 98% of CIN3+ lesions among all screened women and 90% of CIN2+ and 96% of CIN3+ lesions in women 30 years and older. The specificity for CIN1 or less (≤CIN1) was 83% (95% confidence interval [CI], 80 to 85%) in all women and 88% (95% CI, 86 to 91%) in women 30 years and older. Inter- and intralaboratory agreements for the Xpert HPV were 98% and 97%, respectively. The kappa agreements for HPV16 and HPV18/45 between the clinically validated reference test (GP5+/6+ LMNX) and the Xpert HPV were 0.92 and 0.91, respectively. The clinical performance and reproducibility of the Xpert HPV are comparable to those of well-established HPV assays and fulfill the criteria for use in primary cervical cancer screening.

%B J Clin Microbiol %V 54 %P 2337-42 %8 2016 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/27385707?dopt=Abstract %R 10.1128/JCM.00897-16 %0 Journal Article %J Cancer %D 2016 %T Reply to HPV test results provide useful risk stratification information in women with ASC-H Pap test findings. %A M. Arbyn %A Lan Xu %A Wentzensen, Nicolas %B Cancer %V 124 %P 754-755 %8 2016 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/27336222?dopt=Abstract %R 10.1002/cncy.21754 %0 Journal Article %J Cancer Epidemiol %D 2016 %T Surveillance of effects of HPV vaccination in Belgium. %A M. Arbyn %A Broeck, Davy Vanden %A Benoy, Ina %A Bogers, Johannes %A Depuydt, Christophe %A Praet, Marleen %A Sutter, Philippe De %A Hoorens, Anne %A Hauben, Esther %A Poppe, Willy %A Van Ranst, Marc %A Delvenne, Philippe %A Gofflot, Stéphanie %A Pétein, Michel %A Engelen, Frans %A Vanneste, Alain %A Beeck, Lode Op De %A Damme, Pierre Van %A Temmerman, Marleen %A Weyers, Steven %K ADOLESCENT %K Adult %K Belgium %K Biopsy %K Female %K Human papillomavirus 16 %K Human papillomavirus 18 %K Humans %K middle aged %K Papillomavirus Infections %K Papillomavirus Vaccines %K Uterine Cervical Neoplasms %K Vaccination %K Young adult %X

BACKGROUND: Early effects of HPV (human papillomavirus) vaccination are reflected by changes observable in young women attending cervical cancer screening.

SUBJECT AND METHODS: The SEHIB study included HPV geno-typing of ∼6000 continuous and 650 pathological cervical cell specimen as well as biopsies, collected from women in Belgium in 2010-2014. Data were linked to vaccination status.

RESULTS: HPV vaccination offered protection among women aged <30years against infection with HPV16 (vaccine effectiveness [VE]=67%, 95% CI: 48-79%), HPV18 (VE=93%, 95% CI: 52-99%), and high-risk HPV (VE=16%, 95% CI: 2-29%). Vaccination protected also against cytological lesions. Vaccination protected against histologically confirmed lesions: significantly lower absolute risks of CIN1+ (risk difference [RD]=-1.6%, 95% CI: -2.6% to -0.7%) and CIN3+ associated with HPV16/18 (RD=-0.3%, 95% CI -0.6% to -0.1%). Vaccine effectiveness decreased with age. Protection against HPV16 and 18 infection was significant in all age groups, however no protection was observed against cytological lesions associated with these types in age-group 25-29.

CONCLUSION: The SEHIB study demonstrates the effectiveness of HPV vaccination in Belgian young women in particular in age group 18-19. Declining effectiveness with increasing age may be explained by higher tendency of women already exposed to infection to get the vaccine.

%B Cancer Epidemiol %V 41 %P 152-8 %8 2016 Apr %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26895623?dopt=Abstract %R 10.1016/j.canep.2015.12.011 %0 Journal Article %J Cancer Cytopathol %D 2016 %T Triage of ASC-H: A meta-analysis of the accuracy of high-risk HPV testing and other markers to detect cervical precancer. %A Lan Xu %A Verdoodt, Freija %A Wentzensen, Nicolas %A Bergeron, Christine %A M. Arbyn %K Atypical Squamous Cells of the Cervix %K Early Detection of Cancer %K Female %K Human Papillomavirus DNA Tests %K Humans %K Neoplasm Invasiveness %K Neoplasm Staging %K Papillomavirus Infections %K Precancerous Conditions %K Sensitivity and Specificity %K Squamous Intraepithelial Lesions of the Cervix %K triage %K Uterine Cervical Neoplasms %K Vaginal Smears %X

BACKGROUND: Women with a cytological diagnosis of atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) are usually immediately referred for colposcopy. However, triage may reduce the burden of the diagnostic workup and prevent overtreatment.

METHODS: A meta-analysis was conducted to assess the accuracy of high-risk human papillomavirus (hrHPV) testing and testing for other molecular markers for the detection of grade 2 cervical intraepithelial neoplasia or worse (CIN2+) or grade 3 cervical intraepithelial neoplasia or worse (CIN3+) in women with ASC-H. An additional question that was assessed was whether triage would be useful in light of the relatively high pretriage probability of underlying precancer.

RESULTS: The pooled absolute sensitivity and specificity of the Hybrid Capture 2 (HC2) assay for CIN2 + (derived from 19 studies) were 93% (95% confidence interval [CI], 89%-95%) and 45% (95% CI, 41%-50%), respectively. p16(INK4a) staining (only 3 studies) had similar sensitivity (93%; 95% CI, 75%-100%) but superior specificity (specificity ratio, 1.69) to HC2 for CIN2+. Testing for paired box 1 gene methylation (only 1 study) showed a superior specificity of 95% (specificity ratio, 2.08). The average pretest risk was 34% for CIN2 + and 20% for CIN3+. A negative HC2 result decreased this to 8% and 5%, respectively, whereas a positive result upgraded the risk to 47% and 28%, respectively.

CONCLUSIONS: Because of the high probability of precancer with a diagnosis of ASC-H, the utility of triage is limited. The usual recommendation for referring women with ASC-H for colposcopy is not altered by a positive triage test, whatever test is used. A negative hrHPV DNA or p16(INK4a) test may allow repeat testing, but this recommendation will depend on local decision thresholds for referral.

%B Cancer Cytopathol %V 124 %P 261-72 %8 2016 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26618614?dopt=Abstract %R 10.1002/cncy.21661 %0 Journal Article %J J Clin Virol %D 2016 %T Triage of HPV positive women in cervical cancer screening. %A Wentzensen, Nicolas %A Schiffman, Mark %A Palmer, Timothy %A M. Arbyn %K Cervical Intraepithelial Neoplasia %K Colposcopy %K DNA Methylation %K DNA, Viral %K Early Detection of Cancer %K Female %K Genotype %K Genotyping Techniques %K Human Papillomavirus DNA Tests %K Humans %K Mass Screening %K Papillomaviridae %K Papillomavirus Infections %K Risk Factors %K triage %K Uterine Cervical Neoplasms %X

Despite HPV vaccines, screening will remain central for decades to control cervical cancer. Recently, HPV testing alone or with cytology was introduced as an alternative to cytology screening. However, most HPV infections are harmless and additional tests are required to identify women with progressing infections or precancer. With three options for primary screening, and without clear strategies for triage of screen-positive women, there is great confusion about the best approach. Also, increasing HPV vaccination coverage will lead to lower disease prevalence, and force new screening approaches. Currently recommended triage strategies for primary HPV screening include HPV genotyping for HPV16 and HPV18 and cytology. Other alternatives that are currently evaluated include p16/Ki-67 dual stain cytology, host methylation, and viral methylation testing. Clinical management of women with cervical cancer screening results is moving to use risk thresholds rather than individual test results. Specific risk thresholds have been defined for return to primary screening, repeat testing, referral to colposcopy, and immediate treatment. Choice of test algorithms is based on comparison of absolute risk estimates from triage tests with established clinical thresholds. Importantly, triage tests need to be evaluated together with the primary screening test and the downstream clinical management. An optimal integrated screening and triage strategy should reassure the vast majority of women that they are at very low risk of cervical cancer, send the women at highest risk to colposcopy at the right time, when disease can be colposcopically detected, and minimize the intermediate risk group that requires continued surveillance.

%B J Clin Virol %V 76 Suppl 1 %P S49-S55 %8 2016 Mar %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26643050?dopt=Abstract %R 10.1016/j.jcv.2015.11.015 %0 Journal Article %J J Clin Virol %D 2016 %T VALGENT: A protocol for clinical validation of human papillomavirus assays. %A M. Arbyn %A Depuydt, Christophe %A Benoy, Ina %A Bogers, Johannes %A Cuschieri, Kate %A Schmitt, Markus %A Pawlita, Michael %A Geraets, Daan %A Heard, Isabelle %A Gheit, Tarik %A Tommasino, Massimo %A Poljak, Mario %A Bonde, Jesper %A Quint, Wim %K Adult %K Cervical Intraepithelial Neoplasia %K Early Detection of Cancer %K Female %K Genotyping Techniques %K Human Papillomavirus DNA Tests %K Humans %K Mass Screening %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K Reagent Kits, Diagnostic %K Uterine Cervical Neoplasms %K Vaginal Smears %K Validation Studies as Topic %X

BACKGROUND: Testing for high-risk HPV is more effective in primary cervical cancer screening than the cytological examination of a Pap smear. Separate genotyping may be useful for triage in both HPV-based and cytology-based screening. Only clinically validated tests should be used in clinical practice.

OBJECTIVES: VALGENT is a study framework for test comparison and validation of HPV assays in general and HPV genotyping tests in particular according to clinically relevant outcomes and for clinical applications endorsed by scientific evidence.

STUDY DESIGN: VALGENT involves the collation of fresh or archived cervical cell specimen from women attending routine screening supplemented with cytologically abnormal samples. Multiple aliquots of residual material are sent from a central laboratory to participating laboratories for testing with novel HPV assays with limited, extended or full genotyping capacity. Outcomes are derived from screening and pathology registries. Each VALGENT panel includes an assay already validated for screening. A series of accuracy and concordance statistics were generated.

RESULTS: Currently, two VALGENT study rounds, originated from laboratories in Antwerp (Belgium) and Edinburgh (Scotland), were completed. Two new assays (G5+/6+ PCR-LMNX and Xpert HPV) were validated for screening by showing similar accuracy for cervical precancer as the standard comparator test. For two other tests (BD Onclarity, PapilloCheck) validation was confirmed. Inter-test agreement was high although certain type-specific discordances were observed which warrant further analysis.

CONCLUSION: VALGENT extends current guidelines for high-risk HPV test validation in cervical cancer screening and has produced a large study resource for test comparison. More robust procedures of sample selection and handling and integration with the global WHO reference laboratory network focusing on analytical accuracy, may result in the generation of an international standard and a formalized system for clinical validation of HPV assays and quality control in HPV-based screening.

%B J Clin Virol %V 76 Suppl 1 %P S14-S21 %8 2016 Mar %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26522865?dopt=Abstract %R 10.1016/j.jcv.2015.09.014 %0 Journal Article %J Cancer Cytopathol %D 2016 %T Why follow-back studies should be interpreted cautiously: The case of an HPV-negative cervical lesion. %A Rossi, Paolo Giorgi %A Ronco, Guglielmo %A Dillner, Joakim %A K Miriam Elfström %A Snijders, Peter J F %A M. Arbyn %A Berkhof, Johannes %A Carozzi, Francesca %A Del Mistro, Annarosa %A de Sanjosé, Silvia %A Bosch, Xavier %A Petry, Karl Ulrich %A Poljak, Mario %A Naldoni, Carlo %A Meijer, Chris J L M %K Early Detection of Cancer %K Female %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Uterine Cervical Neoplasms %B Cancer Cytopathol %V 124 %P 66-7 %8 2016 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26356132?dopt=Abstract %R 10.1002/cncy.21622 %0 Journal Article %J Int J Gynaecol Obstet %D 2016 %T World Health Organization Guidelines for treatment of cervical intraepithelial neoplasia 2-3 and screen-and-treat strategies to prevent cervical cancer. %A Santesso, Nancy %A Mustafa A Reem %A Schünemann, Holger J %A M. Arbyn %A Blumenthal, Paul D %A Cain, Joanna %A Chirenje, Michael %A Denny, Lynette %A De Vuyst, Hugo %A Eckert, Linda O'Neal %A Forhan, Sara E %A Franco, Eduardo L %A Gage, Julia C %A Garcia, Francisco %A Herrero, Rolando %A Jeronimo, José %A Lu, Enriquito R %A Luciani, Silvana %A Quek, Swee Chong %A Sankaranarayanan, Rengaswamy %A Tsu, Vivien %A Broutet, Nathalie %K Cervical Intraepithelial Neoplasia %K Colposcopy %K conization %K Cryosurgery %K Cryotherapy %K Early Detection of Cancer %K Female %K Humans %K Neoplasm Staging %K Patient Preference %K Randomized Controlled Trials as Topic %K Uterine Cervical Neoplasms %K World Health Organization %X

BACKGROUND: It is estimated that 1%-2% of women develop cervical intraepithelial neoplasia grade 2-3 (CIN 2-3) annually worldwide. The prevalence among women living with HIV is higher, at 10%. If left untreated, CIN 2-3 can progress to cervical cancer. WHO has previously published guidelines for strategies to screen and treat precancerous cervical lesions and for treatment of histologically confirmed CIN 2-3.

METHODS: Guidelines were developed using the WHO Handbook for Guideline Development and the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. A multidisciplinary guideline panel was created. Systematic reviews of randomized controlled trials and observational studies were conducted. Evidence tables and Evidence to Recommendations Tables were prepared and presented to the panel.

RESULTS: There are nine recommendations for screen-and-treat strategies to prevent cervical cancer, including the HPV test, cytology, and visual inspection with acetic acid. There are seven for treatment of CIN with cryotherapy, loop electrosurgical excision procedure, and cold knife conization.

CONCLUSION: Recommendations have been produced on the basis of the best available evidence. However, high-quality evidence was not available. Such evidence is needed, in particular for screen-and-treat strategies that are relevant to low- and middle-income countries.

%B Int J Gynaecol Obstet %V 132 %P 252-8 %8 2016 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26868062?dopt=Abstract %R 10.1016/j.ijgo.2015.07.038 %0 Journal Article %J PLoS One %D 2015 %T Barriers to and facilitators of compliance with clinic-based cervical cancer screening: population-based cohort study of women aged 23-60 years. %A Östensson, Ellinor %A Alder, Susanna %A K Miriam Elfström %A Sundström, Karin %A Zethraeus, Niklas %A M. Arbyn %A Andersson, Sonia %K Adult %K Cohort Studies %K Costs and Cost Analysis %K Female %K Humans %K Mass Screening %K middle aged %K Patient Compliance %K Patient Education as Topic %K Socioeconomic Factors %K Surveys and Questionnaires %K Sweden %K Uterine Cervical Neoplasms %X

OBJECTIVE: This study aims to identify possible barriers to and facilitators of cervical cancer screening by (a) estimating time and travel costs and other direct non-medical costs incurred in attending clinic-based cervical cancer screening, (b) investigating screening compliance and reasons for noncompliance, (c) determining women's knowledge of human papillomavirus (HPV), its relationship to cervical cancer, and HPV and cervical cancer prevention, and (d) investigating correlates of HPV knowledge and screening compliance.

MATERIALS AND METHODS: 1510 women attending the clinic-based cervical cancer screening program in Stockholm, Sweden were included. Data on sociodemographic characteristics, time and travel costs and other direct non-medical costs incurred in attending (e.g., indirect cost of time needed for the screening visit, transportation costs, child care costs, etc.), mode(s) of travel, time, distance, companion's attendance, HPV knowledge, and screening compliance were obtained via self-administered questionnaire.

RESULTS: Few respondents had low socioeconomic status. Mean total time and travel costs and direct non-medical cost per attendance, including companion (if any) were €55.6. Over half (53%) of the respondents took time off work to attend screening (mean time 147 minutes). A large portion (44%) of the respondents were noncompliant (i.e., did not attend screening within 1 year of the initial invitation), 51% of whom stated difficulties in taking time off work. 64% of all respondents knew that HPV vaccination was available; only 34% knew it was important to continue to attend screening following vaccination. Age, education, and income were the most important correlates of HPV knowledge and compliance; and additional factors associated with compliance were time off work, accompanying companion and HPV knowledge.

CONCLUSION: Time and travel costs and other direct non-medical costs for clinic-based screening can be considerable, may affect the cost-effectiveness of a screening program, and may constitute barriers to screening while HPV knowledge may facilitate compliance with screening.

%B PLoS One %V 10 %P e0128270 %8 2015 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26011051?dopt=Abstract %R 10.1371/journal.pone.0128270 %0 Journal Article %J JAMA Intern Med %D 2015 %T Cervical cancer screening by human papillomavirus testing followed by cytology triage. %A Giorgi-Rossi, Paolo %A M. Arbyn %A Meijer, Chris J L M %K Alphapapillomavirus %K Early Detection of Cancer %K Female %K Humans %K Mass Screening %K Papanicolaou Test %K Papillomavirus Infections %K Uterine Cervical Neoplasms %X

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2293482

%B JAMA Intern Med %V 175 %P 1068 %8 2015 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/26030858?dopt=Abstract %R 10.1001/jamainternmed.2015.0592 %0 Journal Article %J KCE Report %D 2015 %T Cervical cancer screening program and Human Papillomavirus (HPV) testing, part II: Update on HPV primary screening. %A M. Arbyn %A A. Haelens %A A. Desomer %A F. Verdoodt %A N. Thiry %A J. Francart %A G. Hanquet %A J. Robays %K cancer screening %K cervical cancer %K HPV %X

Key Findings
 

%B KCE Report %G eng %0 Journal Article %J J Clin Microbiol %D 2015 %T Clinical and Analytical Performance of the Onclarity HPV Assay Using the VALGENT Framework. %A Cuschieri, K %A Geraets, D T %A Moore, C %A Quint, W %A Duvall, E %A M. Arbyn %K ADOLESCENT %K Adult %K Aged %K Cervical Intraepithelial Neoplasia %K Early Detection of Cancer %K Female %K Genotyping Techniques %K Humans %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K Sensitivity and Specificity %K Young adult %X

As the demand for human papillomavirus (HPV)-related cervical screening increases, emerging HPV tests must be evaluated robustly using well-annotated samples, such as those generated in the Validation of HPV Genotyping Tests (VALGENT) framework. Through VALGENT, we assessed the performance of the BD Onclarity HPV assay, which detects 14 high-risk (HR) types and resolves six individual types and three groups of types. Consecutive samples from a screening population (n = 1,000), enriched with cytologically abnormal samples (n = 300), that had been tested previously with the GP5+/6+ PCR enzyme immunoassay (EIA) and the GP5+/6+ PCR LMNX assay (Diassay) were tested with the Onclarity assay. Type-specific HPV prevalences were analyzed according to age and cytological result. The accuracy of the Onclarity assay for the detection of cervical intraepithelial neoplasia grade 2+ (CIN2+) and CIN3+ was assessed relative to the GP5+/6+ EIA results by using noninferiority criteria. Overall agreement and type-specific agreement between the Onclarity assay and the GP5+/6+ LMNX assay were assessed. The prevalence of HPV types 16, 18, 31, and 45 increased with the severity of cytological results (P for trend, <0.05). For the detection of CIN2+, the Onclarity assay had a relative sensitivity of 1.02 (95% confidence interval [CI], 0.99 to 1.05; P < 0.001 for noninferiority) and a relative specificity of 0.99 (95% CI, 0.97 to 1.00; P = 0.186 for noninferiority). The kappa for agreement between the Onclarity assay and the GP5+/6+ LMNX assay for HR-HPV was 0.92 (95% CI, 0.89 to 0.94), and values for the six individual types ranged from 0.78 (95% CI, 0.68 to 0.87) for HPV-52 to 0.96 (95% CI, 0.93 to 0.99) for HPV-16. These data suggest that the Onclarity assay offers applications for clinical workstreams while providing genotyping information that may be useful for risk stratification beyond types 16 and 18.

%B J Clin Microbiol %V 53 %P 3272-9 %8 2015 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26246482?dopt=Abstract %R 10.1128/JCM.01366-15 %0 Journal Article %J Eur J Obstet Gynecol Reprod Biol %D 2015 %T Colposcopy training and assessment across the member countries of the European Federation for Colposcopy. %A Moss, E L %A Redman, C W E %A M. Arbyn %A Dollery, E %A Petry, K U %A Nieminen, P %A Myerson, N %A Leeson, S C %K Accreditation %K Clinical Competence %K Colposcopy %K Curriculum %K Delphi Technique %K Educational Measurement %K Europe %K Humans %K Population Density %K Societies, Medical %K Surveys and Questionnaires %X

OBJECTIVES: Colposcopy training and assessment is not uniform across Europe with individual countries determining their own required standards and regulations. In light of the significant changes in colposcopic practice that have occurred over the past decade and the expansion of the European Federation for Colposcopy (EFC) membership, a study was conducted firstly, to assess the current requirements for training in each of the member countries and secondly, to review an EFC-approved core training curriculum for colposcopy.

STUDY DESIGN: A questionnaire survey of the EFC representatives from all member countries investigating their country's current practices/requirements with regard to training, assessment and accreditation for colposcopy. A two-round Delphi consultation with representation from the full, associate and three potential member countries was conducted using a 5-point Likert scale for scoring opinions. The results were analysed with respect to each country's population size and World Bank economic classification.

RESULTS: For the questionnaire survey, responses were received from 31/34 countries invited to participate. Training programmes were reported to be in place in 21 of the 31 countries but only 17 of the 21 countries had a committee overseeing the training programme. An assessment was part of the training programme in 20 countries with multiple choice questions and portfolios the most common assessment tools. Countries with a population size less than 2 million have a statistically significant lower probability of having a structured training/assessment programme, 1/5 compared to 20/26 for a populations greater than 2 million, p=0.013. For the Delphi study, responses were received from 34/39 countries invited to participate. Of the 51 competencies previously identified only 2 did not receive full support: 'perform bacterial swabs' and 'provide data to national body'. There was no significant difference in the responses given by member, associate member or potential member countries.

CONCLUSIONS: There is considerable variation in colposcopy training and assessment across Europe. This study has enabled consensus opinion with the EFC on the contents of an EFC core curriculum. The revised curriculum has a mandate from the EFC member countries to be implemented across Europe as the standard for colposcopic training.

%B Eur J Obstet Gynecol Reprod Biol %V 188 %P 124-8 %8 2015 May %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25839437?dopt=Abstract %R 10.1016/j.ejogrb.2015.03.012 %0 Journal Article %J Eur J Cancer Prev %D 2015 %T Early effects of human papillomavirus vaccination in Belgium. %A Merckx, Mireille %A Vanden Broeck, Davy %A Benoy, Ina %A Depuydt, Christophe %A Weyers, Steven %A M. Arbyn %K ADOLESCENT %K Adult %K Belgium %K Cohort Studies %K Early Detection of Cancer %K Female %K Human papillomavirus 16 %K Human papillomavirus 18 %K Humans %K Papanicolaou Test %K Papillomavirus Infections %K Papillomavirus Vaccines %K Poisson Distribution %K prevalence %K regression analysis %K Retrospective Studies %K Uterine Cervical Neoplasms %K Vaginal Smears %K Young adult %X

Human papillomavirus (HPV) vaccination has been reimbursed in Belgium since 2007 for girls (12-15 years), extended to girls up to 18 years in 2008. This study assesses the trend of HPV 16/18 infections in women less than 25 years of age participating in opportunistic cervical cancer screening. A significant reduction in the prevalence of HPV 16 [relative risk (RR)=0.61, 95% confidence interval=0.39-0.95] and a nonsignificant reduction in HPV 18 (RR=0.65, 95% confidence interval=0.29-1.48) was found in the youngest group (15-19 years). The prevalences in the older age group did not change significantly. These findings show the early effects of HPV vaccination and confirm the effectiveness of immunization in a real-life setting.

%B Eur J Cancer Prev %V 24 %P 340-2 %8 2015 Jul %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25117724?dopt=Abstract %R 10.1097/CEJ.0000000000000067 %0 Journal Article %J BMC Cancer %D 2015 %T The implementation of an organised cervical screening programme in Poland: an analysis of the adherence to European guidelines. %A Nowakowski, Andrzej %A Cybulski, Marek %A Śliwczyński, Andrzej %A Chil, Arkadiusz %A Teter, Zbigniew %A Seroczyński, Przemysław %A M. Arbyn %A Ahti Anttila %K Adult %K Colposcopy %K Early Detection of Cancer %K Female %K Humans %K Mass Screening %K middle aged %K Poland %K Pregnancy %K Uterine Cervical Neoplasms %K Vaginal Smears %X

BACKGROUND: Well-organised quality-controlled screening can substantially reduce the burden of cervical cancer (CC). European guidelines (EuG) for quality assurance in CC screening provide guidance on all aspects of an organised screening programme. Organised CC screening in Poland was introduced in 2007. The purpose of our study was to analyse: (i) adherence of the programme to EuG; (ii) programme process and performance indicators; (iii) impact of the programme on the incidence of and mortality from CC.

METHODS: Available data on the policy, structure and functioning of the Polish programme were compared with the major points of the EuG. Data on the process, and available performance indicators were drawn from the screening database and other National Health Fund (NHF) systems. Joinpoint regression was used to assess changes in CC incidence and mortality trends.

RESULTS: The Polish programme adheres partially to EuG in terms of policy and organisation. Only a limited set of performance indicators can be calculated due to screening database incompleteness or lack of linkage between existing databases. The screening database does not include opportunistic smears collected within NHF-reimbursed or private care. The organised programme coverage rate fluctuated from 21% to 27% between 2007-2013. In 2012 the coverage reached 35% after combining both organised and opportunistic smears reimbursed by the NHF. In 2012 the number of smears reimbursed by NHF was 60% higher in opportunistic than in organised screening with significant overlap. Data from the private sector are not recorded. Depending on years, 30-50% of women referred for colposcopy/biopsy because of abnormal Pap smears were managed within the programme. The age-standardised CC incidence and mortality dropped linearly between 1999 and 2011 without evidence of a period effect.

CONCLUSIONS: The Polish organised cervical screening programme is only partially adherent to evidence-based EuG. Its implementation has not influenced the burden of CC in the country so far. Changes with special focus on increasing coverage, development of information systems and assessment of quality are required to increase programme adherence to EuG and to measure its effectiveness. Our findings may be useful to improve the Polish programme and those implemented or planned in other countries.

%B BMC Cancer %V 15 %P 279 %8 2015 Apr 14 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25879466?dopt=Abstract %R 10.1186/s12885-015-1242-9 %0 Journal Article %J Cancer Epidemiol Biomarkers Prev %D 2015 %T Offering Self-Sampling Kits for HPV Testing to Reach Women Who Do Not Attend in the Regular Cervical Cancer Screening Program. %A M. Arbyn %A Castle, Philip E %K Female %K Humans %K Mass Screening %K Papillomaviridae %K Papillomavirus Infections %K specimen handling %K Uterine Cervical Neoplasms %X

In 2016, the Netherlands will switch, as first European country, from cytology-based to HPV-based cervical cancer screening, with cytology triage for those with a positive HPV test. The new Dutch program includes sending self-sampling devices to women who do not respond to an invitation to have a cervical sample taken by their general practitioner. The cost-effectiveness of this additional strategy will depend on its capacity to recruit nonscreened women and in particular those at increased risk of cervical (pre)cancer, the possible switch of previous responders to self-sampling, the accuracy and cost of the HPV assay-self-sampler combination, and the compliance of women being self-sample HPV-positive with further follow-up. Validated PCR-based assays, detecting high-risk HPV DNA, are as accurate on self-samples as on clinician-collected samples. On the contrary, HPV assays, based on signal amplification, are less sensitive and specific on self-samples. The introduction of self-sampling strategies should be carefully prepared and evaluated in pilot studies integrated in well-organized settings before general rollout. Opt-in procedures involving a request for a self-sampler may reduce response rates. Therefore, an affordable device that can be included with the invitation to all nonattendees may yield a stronger effect on participation.

%B Cancer Epidemiol Biomarkers Prev %V 24 %P 769-72 %8 2015 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/25713024?dopt=Abstract %R 10.1158/1055-9965.EPI-14-1417 %0 Journal Article %J Eur J Cancer %D 2015 %T Reaching women who do not participate in the regular cervical cancer screening programme by offering self-sampling kits: a systematic review and meta-analysis of randomised trials. %A Verdoodt, F %A Jentschke, M %A Hillemanns, P %A Racey, C S %A Snijders, P J F %A M. Arbyn %K Early Detection of Cancer %K Female %K Health Services Accessibility %K Humans %K Intention to Treat Analysis %K Patient Participation %K Postal Service %K Predictive Value of Tests %K Self Care %K Uterine Cervical Neoplasms %K Vaginal Smears %X

INTRODUCTION: Population coverage for cervical cancer screening is an important determinant explaining differences in the incidence of cervical cancer between countries. Offering devices for self-sampling has the potential to increase participation of hard-to-reach women.

METHODS: A systematic review and meta-analysis were performed to evaluate the participation after an invitation including a self-sampling device (self-sampling arm) versus an invitation to have a sample taken by a health professional (control arm), sent to under-screened women.

RESULTS: Sixteen randomised studies were found eligible. In an intention-to-treat analysis, the pooled participation in the self-sampling arm was 23.6% (95% confidence interval (CI)=20.2-27.3%), when self-sampling kits were sent by mail to all women, versus 10.3% (95% CI=6.2-15.2%) in the control arm (participation difference: 12.6% [95% CI=9.3-15.9]). When women had to opt-in to receive the self-sampling device, as used in three studies, the pooled participation was not higher in the self-sampling compared to the control arm (participation difference: 0.2% [95% CI=-4.5-4.9%]).

CONCLUSION: An increased participation was observed in the self-sampling arm compared to the control arm, if self-sampling kits were sent directly to women at their home address. However, the size of the effect varied substantially among studies. Since participation was similar in both arms when women had to opt-in, future studies are warranted to discern opt-in scenarios that are most acceptable to women.

%B Eur J Cancer %V 51 %P 2375-85 %8 2015 Nov %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/26296294?dopt=Abstract %R 10.1016/j.ejca.2015.07.006 %0 Journal Article %J Clinical Microbiology and Infection %D 2015 %T Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening? %A M. Arbyn %A Snijders, Peter J F %A C. J.L.M. Meijer %A Berkhof, J %A K. Cuschieri %A B.J. Kocjan %A Poljak, M %K cervical cancer %K cervical cancer screening %K diagnostic test accuracy %K human papillomavirus %K meta-analysis %K systematic review %K validation of tests %X

Several countries are in the process of switching to high-risk human papillomavirus (hrHPV) testing for cervical cancer screening. Given the multitude of available tests, validated assays which assure high-quality screening need to be identified.
A systematic review was conducted to answer the question which hrHPV tests fulfil the criteria defined by an international expert team in 2009, based on reproducibility and relative sensitivity and specificity compared to Hybrid Capture-2 or GP5+/6+ PCR–enzyme immunoassay. These latter two hrHPV DNA assays were validated in large randomized trials and cohorts with a follow-up duration of 8 years or more. Eligible studies citing the 2009 guideline were retrieved from Scopus (http://www.scopus.com) and from a meta-analysis assessing the relative accuracy of new hrHPV assays versus the standard comparator tests to detect high-grade cervical intraepithelial neoplasia or cancer in primary screening.
The cobas 4800 HPV test and Abbott RealTime High Risk HPV test were consistently validated in two and three studies, respectively, whereas the PapilloCheck HPV-screening test, BD Onclarity HPV assay and the HPV-Risk assay were validated each in one study. Other tests which partially fulfil the 2009 guidelines are the following: Cervista HPV HR Test, GP5+/6+ PCR-LMNX, an in-house E6/E7 RT quantitative PCR and MALDI-TOF (matrix assisted laser desorptionionization time-of-flight).
The APTIMA HPV assay targeting E6/E7 mRNA of hrHPV was also fully validated. However, the cross-sectional equivalency criteria of the 2009 guidelines were set up for HPV DNA assays. Demonstration of a low risk of CIN3+ after a negative APTIMA test over a longer period is awaited to inform us about its utility in cervical cancer screening at 5-year or longer intervals

%B Clinical Microbiology and Infection %V 21 %8 Jan-09-2015 %G eng %N 9 %R 10.1016/j.cmi.2015.04.015 %0 Journal Article %J Clin Microbiol Infect %D 2015 %T Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening? %A M. Arbyn %A Snijders, P J F %A Meijer, C J L M %A Berkhof, J %A Cuschieri, K %A Kocjan, B J %A Poljak, M %K Early Detection of Cancer %K Female %K Genotyping Techniques %K Humans %K Molecular Diagnostic Techniques %K Papillomaviridae %K Reproducibility of Results %K Sensitivity and Specificity %K Uterine Cervical Neoplasms %X

Several countries are in the process of switching to high-risk human papillomavirus (hrHPV) testing for cervical cancer screening. Given the multitude of available tests, validated assays which assure high-quality screening need to be identified. A systematic review was conducted to answer the question which hrHPV tests fulfil the criteria defined by an international expert team in 2009, based on reproducibility and relative sensitivity and specificity compared to Hybrid Capture-2 or GP5+/6+ PCR-enzyme immunoassay. These latter two hrHPV DNA assays were validated in large randomized trials and cohorts with a follow-up duration of 8 years or more. Eligible studies citing the 2009 guideline were retrieved from Scopus (http://www.scopus.com) and from a meta-analysis assessing the relative accuracy of new hrHPV assays versus the standard comparator tests to detect high-grade cervical intraepithelial neoplasia or cancer in primary screening. The cobas 4800 HPV test and Abbott RealTime High Risk HPV test were consistently validated in two and three studies, respectively, whereas the PapilloCheck HPV-screening test, BD Onclarity HPV assay and the HPV-Risk assay were validated each in one study. Other tests which partially fulfil the 2009 guidelines are the following: Cervista HPV HR Test, GP5+/6+ PCR-LMNX, an in-house E6/E7 RT quantitative PCR and MALDI-TOF (matrix-assisted laser desorption-ionization time-of-flight). The APTIMA HPV assay targeting E6/E7 mRNA of hrHPV was also fully validated. However, the cross-sectional equivalency criteria of the 2009 guidelines were set up for HPV DNA assays. Demonstration of a low risk of CIN3+ after a negative APTIMA test over a longer period is awaited to inform us about its utility in cervical cancer screening at 5-year or longer intervals.

%B Clin Microbiol Infect %V 21 %P 817-26 %8 2015 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/25936581?dopt=Abstract %R 10.1016/j.cmi.2015.04.015 %0 Journal Article %J J Clin Virol %D 2015 %T WITHDRAWN: Comparative evaluation of two vaginal self-sampling devices for the detection of human papillomavirus infections. %A Jentschke, M %A Chen, K %A M. Arbyn %A Hertel, B %A Noskowicz, M %A Soergel, P %A Hillemanns, P %X

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

%B J Clin Virol %8 2015 Aug 28 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26358862?dopt=Abstract %R 10.1016/j.jcv.2015.08.011 %0 Journal Article %J Lancet Oncol %D 2014 %T Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis. %A M. Arbyn %A Verdoodt, Freija %A Snijders, Peter J F %A Verhoef, Viola M J %A Suonio, Eero %A Dillner, Lena %A Minozzi, Silvia %A Bellisario, Cristina %A Banzi, Rita %A Zhao, Fang-Hui %A Hillemanns, Peter %A Ahti Anttila %K Biopsy %K Cervical Intraepithelial Neoplasia %K Colposcopy %K Female %K Humans %K Mass Screening %K Papillomaviridae %K Papillomavirus Infections %K Predictive Value of Tests %K Reproducibility of Results %K Self Care %K specimen handling %K Uterine Cervical Neoplasms %X

BACKGROUND: Screening for human papillomavirus (HPV) infection is more effective in reducing the incidence of cervical cancer than screening using Pap smears. Moreover, HPV testing can be done on a vaginal sample self-taken by a woman, which offers an opportunity to improve screening coverage. However, the clinical accuracy of HPV testing on self-samples is not well-known. We assessed whether HPV testing on self-collected samples is equivalent to HPV testing on samples collected by clinicians.

METHODS: We identified relevant studies through a search of PubMed, Embase, and CENTRAL. Studies were eligible for inclusion if they fulfilled all of the following selection criteria: a cervical cell sample was self-collected by a woman followed by a sample taken by a clinician; a high-risk HPV test was done on the self-sample (index test) and HPV-testing or cytological interpretation was done on the specimen collected by the clinician (comparator tests); and the presence or absence of cervical intraepithelial neoplasia grade 2 (CIN2) or worse was verified by colposcopy and biopsy in all enrolled women or in women with one or more positive tests. The absolute accuracy for finding CIN2 or worse, or CIN grade 3 (CIN3) or worse of the index and comparator tests as well as the relative accuracy of the index versus the comparator tests were pooled using bivariate normal models and random effect models.

FINDINGS: We included data from 36 studies, which altogether enrolled 154 556 women. The absolute accuracy varied by clinical setting. In the context of screening, HPV testing on self-samples detected, on average, 76% (95% CI 69-82) of CIN2 or worse and 84% (72-92) of CIN3 or worse. The pooled absolute specificity to exclude CIN2 or worse was 86% (83-89) and 87% (84-90) to exclude CIN3 or worse. The variation of the relative accuracy of HPV testing on self-samples compared with tests on clinician-taken samples was low across settings, enabling pooling of the relative accuracy over all studies. The pooled sensitivity of HPV testing on self-samples was lower than HPV testing on a clinician-taken sample (ratio 0·88 [95% CI 0·85-0·91] for CIN2 or worse and 0·89 [0·83-0·96] for CIN3 or worse). Also specificity was lower in self-samples versus clinician-taken samples (ratio 0·96 [0·95-0·97] for CIN2 or worse and 0·96 [0·93-0·99] for CIN3 or worse). HPV testing with signal-based assays on self-samples was less sensitive and specific than testing on clinician-based samples. By contrast, some PCR-based HPV tests generally showed similar sensitivity on both self-samples and clinician-based samples.

INTERPRETATION: In screening programmes using signal-based assays, sampling by a clinician should be recommended. However, HPV testing on a self-sample can be suggested as an additional strategy to reach women not participating in the regular screening programme. Some PCR-based HPV tests could be considered for routine screening after careful piloting assessing feasibility, logistics, population compliance, and costs.

FUNDING: The 7th Framework Programme of the European Commission, the Belgian Foundation against Cancer, the International Agency for Research on Cancer, and the German Guideline Program in Oncology.

%B Lancet Oncol %V 15 %P 172-83 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24433684?dopt=Abstract %R 10.1016/S1470-2045(13)70570-9 %0 Journal Article %J J Pathol %D 2014 %T Are 20 human papillomavirus types causing cervical cancer? %A M. Arbyn %A Tommasino, Massimo %A Depuydt, Christophe %A Dillner, Joakim %K Female %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Uterine Cervical Neoplasms %X

In 2012, the International Agency for Research on Cancer concluded that there was consistent and sufficient epidemiological, experimental and mechanistic evidence of carcinogenicity to humans for 12 HPV types (HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58 and HPV59) for cervical cancer. Therefore, these types were considered as 1A carcinogens. They all belong to the family of the α-Papillomaviridae, in particular to the species α5 (HPV51), α6 (HPV56), α7 (HPV18, HPV39, HPV45, HPV59) and α9 (HPV16, HPV31, HPV33, HPV35, HPV52, HPV58). Less evidence is available for a thirteenth type (HPV68, α7), which is classified as a 2A carcinogen (probably carcinogenic). Moreover, seven other phylogenetically related types (HPV26, HPV53, HPV66, HPV67, HPV68, HPV70 and HPV73) were identified as single HPV infections in certain rare cases of cervical cancer and were considered possibly carcinogenic (2B carcinogens). Recently, Halec et al [7] demonstrated that the molecular signature of HPV-induced carcinogenesis (presence of type-specific spliced E6*| mRNA; increased expression of p16; and decreased expression of cyclin D1, p53 and Rb) was similar in cervical cancers containing single infections with one of the eight afore-mentioned 2A or 2B carcinogens to those in cancers with single infections with group 1 carcinogens. Ninety six percent of cervical cancers are attributable to one of the 13 most common HPV types (groups 1 and 2A). Including the additional seven HPV types (group 2B) added 2.6%, to reach a total of 98.7% of all HPV-positive cervical cancers. From recently updated meta-analyses, it was shown that HPV68, HPV26, HPV66, HPV67, HPV73 and HPV82 were significantly more common in cancer cases than in women with normal cervical cytology, suggesting that for these HPV types, an upgrading of the carcinogen classification could be considered. However, there is no need to include them in HPV screening tests or vaccines, given their rarity in cervical cancers.

%B J Pathol %V 234 %P 431-5 %8 2014 Dec %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25124771?dopt=Abstract %R 10.1002/path.4424 %0 Journal Article %J PLoS One %D 2014 %T 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). %A M. Arbyn %A Fabri, Valérie %A Temmerman, Marleen %A Cindy Simoens %K Adult %K Age factors %K Belgium %K Biopsy %K Cervix Uteri %K Colposcopy %K conization %K Early Detection of Cancer %K Female %K Humans %K Hysterectomy %K incidence %K Insurance, Health %K middle aged %K Papanicolaou Test %K Socioeconomic Factors %K Uterine Cervical Neoplasms %X

OBJECTIVE: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

%B PLoS One %V 9 %P e92615 %8 2014 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24690620?dopt=Abstract %R 10.1371/journal.pone.0092615 %0 Journal Article %J J Clin Microbiol %D 2014 %T Clinical evaluation of a GP5+/6+-based luminex assay having full high-risk human papillomavirus genotyping capability and an internal control. %A Geraets, D T %A Cuschieri, K %A de Koning, M N C %A van Doorn, L J %A Snijders, P J F %A Meijer, C J L M %A Quint, W G V %A M. Arbyn %K Adult %K Cervical Intraepithelial Neoplasia %K Cervix Uteri %K Early Detection of Cancer %K Female %K Humans %K middle aged %K Molecular Diagnostic Techniques %K Oligonucleotide Probes %K Papillomaviridae %K Papillomavirus Infections %K Reference Standards %K Sensitivity and Specificity %K Young adult %X

The LMNX genotyping kit HPV GP (LMNX) is based on the clinically validated GP5+/6+ PCR, with a genotyping readout as an alternative for the more established enzyme immunoassay (EIA) detection of 14 targeted high-risk human papillomavirus (HPV) types. LMNX is additionally provided with an internal control probe. Here, we present an analysis of the clinical performance of the LMNX using a sample panel and infrastructure provided by the international VALGENT (Validation of Genotyping Tests) project. This panel consisted of cervical specimens from approximately 1,000 women attending routine screening, "enriched" with 300 women with abnormal cytology. Cases were defined as women classified with cervical intraepithelial neoplasia (CIN) grade 2+ (CIN2+) (n = 102) or CIN3+ (n = 55) within the previous 18 months. Controls were women who had normal cytology results over two subsequent screening rounds at a 3-year interval (n = 746). The GP5+/6+-PCR EIA (EIA) was used as a comparator assay and showed sensitivities of 94.1% and 98.2% for CIN2+ and CIN3+, respectively, with a clinical specificity of 92.4% among women aged ≥ 30 years. The LMNX demonstrated clinical sensitivities of 96.1% for CIN2+ and of 98.2% for CIN3+ and a clinical specificity of 92.6% for women aged ≥ 30 years. The LMNX and EIA were in high agreement (Cohen's kappa = 0.969) for the detection of 14 hrHPVs in aggregate, and no significant difference was observed (McNemar's P = 0.629). The LMNX internal control detected 0.6% inadequate specimens. Based on our study results, we consider the LMNX, similarly to the EIA, useful for HPV-based cervical cancer screening.

%B J Clin Microbiol %V 52 %P 3996-4002 %8 2014 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/25210073?dopt=Abstract %R 10.1128/JCM.01962-14 %0 Journal Article %J Oncohémato %D 2014 %T Deelname aan cervixkankerscreening in België - Participation au dépistage du cancer du col en Belgique %A M. Arbyn %A Cindy Simoens %A Fabri, Valérie %B Oncohémato %8 24/11/2014 %G eng %N 8 %0 Journal Article %J Lancet %D 2014 %T Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. %A Ronco, Guglielmo %A Dillner, Joakim %A K Miriam Elfström %A Tunesi, Sara %A Snijders, Peter J F %A M. Arbyn %A Kitchener, Henry %A Segnan, Nereo %A Gilham, Clare %A Giorgi-Rossi, Paolo %A Berkhof, Johannes %A Peto, Julian %A Meijer, Chris J L M %K Adult %K Cervical Intraepithelial Neoplasia %K Colposcopy %K Cytological Techniques %K Early Detection of Cancer %K Europe %K Female %K Follow-Up Studies %K Humans %K incidence %K middle aged %K Multicenter Studies as Topic %K Neoplasm Invasiveness %K Papillomavirus Infections %K Precancerous Conditions %K Randomized Controlled Trials as Topic %K Uterine Cervical Neoplasms %K Young adult %X

BACKGROUND: In four randomised trials, human papillomavirus (HPV)-based screening for cervical cancer was compared with cytology-based cervical screening, and precursors of cancer were the endpoint in every trial. However, direct estimates are missing of the relative efficacy of HPV-based versus cytology-based screening for prevention of invasive cancer in women who undergo regular screening, of modifiers (eg, age) of this relative efficacy, and of the duration of protection. We did a follow-up study of the four randomised trials to investigate these outcomes.

METHODS: 176,464 women aged 20-64 years were randomly assigned to HPV-based (experimental arm) or cytology-based (control arm) screening in Sweden (Swedescreen), the Netherlands (POBASCAM), England (ARTISTIC), and Italy (NTCC). We followed up these women for a median of 6·5 years (1,214,415 person-years) and identified 107 invasive cervical carcinomas by linkage with screening, pathology, and cancer registries, by masked review of histological specimens, or from reports. Cumulative and study-adjusted rate ratios (experimental vs control) were calculated for incidence of invasive cervical carcinoma.

FINDINGS: The rate ratio for invasive cervical carcinoma among all women from recruitment to end of follow-up was 0·60 (95% CI 0·40-0·89), with no heterogeneity between studies (p=0·52). Detection of invasive cervical carcinoma was similar between screening methods during the first 2·5 years of follow-up (0·79, 0·46-1·36) but was significantly lower in the experimental arm thereafter (0·45, 0·25-0·81). In women with a negative screening test at entry, the rate ratio was 0·30 (0·15-0·60). The cumulative incidence of invasive cervical carcinoma in women with negative entry tests was 4·6 per 10(5) (1·1-12·1) and 8·7 per 10(5) (3·3-18·6) at 3·5 and 5·5 years, respectively, in the experimental arm, and 15·4 per 10(5) (7·9-27·0) and 36·0 per 10(5) (23·2-53·5), respectively, in the control arm. Rate ratios did not differ by cancer stage, but were lower for adenocarcinoma (0·31, 0·14-0·69) than for squamous-cell carcinoma (0·78, 0·49-1·25). The rate ratio was lowest in women aged 30-34 years (0·36, 0·14-0·94).

INTERPRETATION: HPV-based screening provides 60-70% greater protection against invasive cervical carcinomas compared with cytology. Data of large-scale randomised trials support initiation of HPV-based screening from age 30 years and extension of screening intervals to at least 5 years.

FUNDING: European Union, Belgian Foundation Against Cancer, KCE-Centre d'Expertise, IARC, The Netherlands Organisation for Health Research and Development, the Italian Ministry of Health.

%B Lancet %V 383 %P 524-32 %8 2014 Feb 08 %G eng %N 9916 %1 http://www.ncbi.nlm.nih.gov/pubmed/24192252?dopt=Abstract %R 10.1016/S0140-6736(13)62218-7 %0 Journal Article %J BMJ %D 2014 %T Fertility and early pregnancy outcomes after treatment for cervical intraepithelial neoplasia: systematic review and meta-analysis. %A Kyrgiou, Maria %A Mitra, Anita %A M. Arbyn %A Stasinou, Sofia Melina %A Martin-Hirsch, Pierre %A Bennett, Phillip %A Paraskevaidis, Evangelos %K Cervical Intraepithelial Neoplasia %K Cervix Uteri %K conization %K Female %K Fertility %K Humans %K Models, Statistical %K Postoperative Complications %K Pregnancy %K Pregnancy Complications %K Pregnancy Outcome %K Pregnancy Rate %K Uterine Cervical Neoplasms %X

OBJECTIVE: To determine the impact of cervical excision for cervical intraepithelial neoplasia on fertility and early pregnancy outcomes.

DESIGN: Systematic review and meta-analysis of cohort studies.

DATA SOURCES: Medline and Embase.

ELIGIBILITY CRITERIA: Studies assessing fertility and early pregnancy outcomes in women with a history of treatment for cervical intraepithelial neoplasia versus untreated women. We classified the included studies according to treatment type and fertility or early pregnancy endpoint.

ANALYSIS: Pooled relative risks and 95% confidence intervals using a random effect model, and interstudy heterogeneity with I(2) statistics.

RESULTS: 15 studies fulfilled the inclusion criteria and were included. The meta-analysis did not provide any evidence that treatment for cervical intraepithelial neoplasia adversely affected the chances of conception. The overall pregnancy rate was higher for treated women than for untreated women (four studies; 43% v 38%, pooled relative risk 1.29, 95% confidence interval 1.02 to 1.64), although the heterogeneity between studies was high (P<0.0001). Pregnancy rates did not differ between women with an intention to conceive (two studies; 88% v 95%, 0.93, 0.80 to 1.08) and the number requiring more than 12 months to conceive (three studies, 15% v 9%, 1.45, 0.89 to 2.37). Although the rates for total miscarriages (10 studies; 4.6% v 2.8%, 1.04, 0.90 to 1.21) and miscarriage in the first trimester (four studies; 9.8% v 8.4%, 1.16, 0.80 to 1.69) was similar for treated and untreated women, cervical treatment was associated with a significantly increased risk of miscarriage in the second trimester. The rate was higher for treated women than for untreated women (eight studies; 1.6% v 0.4%, 16,558 women; 2.60, 1.45 to 4.67). The number of ectopic pregnancies (1.6% v 0.8%; 1.89, 1.50 to 2.39) and terminations (12.2% v 7.4%; 1.71, 1.31 to 2.22) was also higher for treated women.

CONCLUSION: There is no evidence suggesting that treatment for cervical intraepithelial neoplasia adversely affects fertility, although treatment was associated with a significantly increased risk of miscarriages in the second trimester. Research should explore mechanisms that may explain this increase in risk and stratify the impact that treatment may have on fertility and early pregnancy outcomes by the size of excision and treatment method used.

%B BMJ %V 349 %P g6192 %8 2014 Oct 28 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25352501?dopt=Abstract %R 10.1136/bmj.g6192 %0 Journal Article %J J Low Genit Tract Dis %D 2014 %T The future role for colposcopy in Europe. %A Leeson, Simon C %A Alibegashvili, Tamar %A M. Arbyn %A Bergeron, Christine %A Carriero, Carmine %A Mergui, Jean-Luc %A Nieminen, Pekka %A Prendiville, Walter %A Redman, Charles W E %A Rieck, Gudrun C %A Quaas, Jens %A K Ulrich Petry %K Cervical Intraepithelial Neoplasia %K Colposcopy %K Early Detection of Cancer %K Europe %K Female %K Humans %K Uterine Cervical Neoplasms %X

Improvements in the performance of cervical screening may be limited by the diagnostic performance of colposcopy. Nonetheless, colposcopy remains the best available tool to assess women considered at high risk for having or developing cervical cancer. The provision and role of colposcopy across Europe is variable. Introduction of vaccination against human papillomavirus (HPV) types 16 and 18 as well as the possible switch to HPV-based screening is likely to change the profiles of women presenting to colposcopy services and provide management difficulties for the colposcopist.The standard of colposcopy in Europe can be maintained or improved despite a variable availability of screening. The prevalence of cervical intraepithelial neoplasia grade 3 may decrease for women having had HPV vaccination. The incidence of cervical intraepithelial neoplasia grade 3 and cervical cancer in second and subsequent rounds of HPV-based screening are likely to decrease compared to cytology-based screening. In HPV-based screening, the numbers of women with no detectable or minor abnormalities at colposcopy and with screen-detected glandular disease are likely to increase. We have considered how these issues will affect states that have varying implementation of organized cervical screening programs and varying degrees of implementation of HPV testing or vaccination.The development of quality assurance across Europe accompanying these program changes is discussed.

%B J Low Genit Tract Dis %V 18 %P 70-8 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23774077?dopt=Abstract %R 10.1097/LGT.0b013e318286b899 %0 Journal Article %J Lancet Oncol %D 2014 %T HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. %A Ndiaye, Cathy %A Mena, Marisa %A Alemany, Laia %A M. Arbyn %A Castellsagué, Xavier %A Laporte, Louise %A Bosch, F Xavier %A de Sanjosé, Silvia %A Trottier, Helen %K Carcinogenesis %K Cyclin-Dependent Kinase Inhibitor p16 %K DNA, Viral %K Head and Neck Neoplasms %K Human papillomavirus 16 %K Humans %K Oncogene Proteins, Viral %K Papillomavirus E7 Proteins %K Papillomavirus Infections %K Repressor Proteins %K RNA, Messenger %X

BACKGROUND: We aimed to provide updated information about the global estimates of attributable fraction and type distribution of human papillomavirus (HPV) in head and neck squamous cell carcinomas by doing a systematic review and meta-analysis.

METHODS: We did a literature search on PubMed to identify studies that used PCR for detection of HPV DNA in head and neck squamous cell carcinomas with information about HPV genotype distribution. We included studies that tested 20 or more biopsies per cancer site and were published between July 15, 1990, and Feb 29, 2012. We collected information about sex, risk factors, HPV detection methods, and biomarkers of potentially HPV-induced carcinogenesis (E6/E7 mRNA and p16(INK4a)). If it was not possible to abstract the required information directly from the paper, we contacted the authors. We did a meta-analysis to produce pooled prevalence estimates including a meta-regression to explore sources of heterogeneity.

FINDINGS: 148 studies were included, contributing data for 12 163 cases of head and neck squamous cell carcinoma from 44 countries. HPV DNA was detected in 3837 cases. HPV16 accounted for 82·2% (95% CI 77·7-86·4) of all HPV DNA positive cases. By cancer site, pooled HPV DNA prevalence estimates were 45·8% (95% CI 38·9-52·9) for oropharynx, 22·1% (16·4-28·3) for larynx (including hypopharynx), and 24·2% (18·7-30·2) for oral cavity. The percent positivity of p16(INK4a) positive cases in HPV-positive oropharyngeal cancer cases was 86·7% (95% CI 79·2-92·9) and of E6/E7 mRNA positive cases was 86·9% (73·2-96·8). The estimate of HPV attributable fraction in oropharyngeal cancer defined by expression of positive cases of E6/E7 mRNA was 39·8% and of p16(INK4a) was 39·7%. Of subsites, tonsils (53·9%, 95% CI 46·4-61·3) had the highest HPV DNA prevalence. HPV DNA prevalence varied significantly by anatomical site, geographic region, but not by sex or tobacco or alcohol consumption.

INTERPRETATION: The contribution of HPV prevalence in head and neck squamous cell carcinoma and in particular that of HPV16 in the oropharynx shows the potential benefit of prophylactic vaccines.

FUNDING: European Commission.

%B Lancet Oncol %V 15 %P 1319-31 %8 2014 Nov %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/25439690?dopt=Abstract %R 10.1016/S1470-2045(14)70471-1 %0 Journal Article %J The Lancet Oncology %D 2014 %T HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis %A Ndiaye, Cathy %A Mena, Marisa %A Alemany, Laia %A M. Arbyn %A Castellsagué, Xavier %A Laporte, Louise %A Bosch, F Xavier %A de Sanjosé, Silvia %A Trottier, Helen %K HPV DNA %K meta-analyses %K neck cancer %X

BACKGROUND
We aimed to provide updated information about the global estimates of attributable fraction and type distribution of human papillomavirus (HPV) in head and neck squamous cell carcinomas by doing a systematic review and meta-analysis.

METHODS
We did a literature search on PubMed to identify studies that used PCR for detection of HPV DNA in head and neck squamous cell carcinomas with information about HPV genotype distribution. We included studies that tested 20 or more biopsies per cancer site and were published between July 15, 1990, and Feb 29, 2012. We collected information about sex, risk factors, HPV detection methods, and biomarkers of potentially HPV-induced carcinogenesis (E6/E7 mRNA and p16INK4a). If it was not possible to abstract the required information directly from the paper, we contacted the authors. We did a meta-analysis to produce pooled prevalence estimates including a meta-regression to explore sources of heterogeneity.

FINDINGS
148 studies were included, contributing data for 12 163 cases of head and neck squamous cell carcinoma from 44 countries. HPV DNA was detected in 3837 cases. HPV16 accounted for 82·2% (95% CI 77·7–86·4) of all HPV DNA positive cases. By cancer site, pooled HPV DNA prevalence estimates were 45·8% (95% CI 38·9–52·9) for oropharynx, 22·1% (16·4–28·3) for larynx (including hypopharynx), and 24·2% (18·7–30·2) for oral cavity. The percent positivity of p16INK4a positive cases in HPV-positive oropharyngeal cancer cases was 86·7% (95% CI 79·2–92·9) and of E6/E7 mRNA positive cases was 86·9% (73·2–96·8). The estimate of HPV attributable fraction in oropharyngeal cancer defined by expression of positive cases of E6/E7 mRNA was 39·8% and of p16INK4a was 39·7%. Of subsites, tonsils (53·9%, 95% CI 46·4–61·3) had the highest HPV DNA prevalence. HPV DNA prevalence varied significantly by anatomical site, geographic region, but not by sex or tobacco or alcohol consumption.

INTERPRETATION
The contribution of HPV prevalence in head and neck squamous cell carcinoma and in particular that of HPV16 in the oropharynx shows the potential benefit of prophylactic vaccines.

FUNDING
European Commission.

%B The Lancet Oncology %V 15 %8 Jan-11-2014 %G eng %N 12 %R 10.1016/S1470-2045(14)70471-1 %0 Journal Article %J J Low Genit Tract Dis %D 2014 %T HPV testing and vaccination in Europe. %A Leeson, Simon C %A Alibegashvili, Tamar %A M. Arbyn %A Bergeron, Christine %A Carriero, Carmine %A Mergui, Jean-Luc %A Nieminen, Pekka %A Prendiville, Walter %A Redman, Charles W E %A Rieck, Gudrun C %A Quaas, Jens %A K Ulrich Petry %K Early Detection of Cancer %K Europe %K Female %K Human Papillomavirus DNA Tests %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Papillomavirus Vaccines %K Uterine Cervical Neoplasms %K Vaccination %X

Current cytology-based screening has a moderate sensitivity to detect cervical intraepithelial neoplasia grade 3 (CIN 3) and cervical cancer even in those states providing rigorous quality control of their cervical screening programs. The impact of vaccination against human papillomavirus (HPV) types 16 and 18 as well as the incorporation of HPV testing on the detection of CIN 3 and cancer is discussed. HPV testing used as a triage for atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions, test of cure after treatment, and HPV-based primary screening may improve current cervical screening programs.HPV testing as a triage test for ASCUS seems to offer an improved sensitivity, with a similar specificity as compared to repeat cytology for diagnosing high-grade CIN and has been recommended throughout most EU states. HPV testing as a triage test for low-grade squamous intraepithelial lesions has a low specificity and is not recommended in most member states. HPV test of cure offers an improved sensitivity compared to cytology for women with persistent cervical precancer after treatment. HPV-based cervical cancer screening is more effective than screening with cytology. The effects of HPV-based screening depend on the organization of the program and on adherence to algorithms for screening triage. Otherwise, it is likely that HPV-based screening will increase the referral rate to colposcopy including more women with no detectable cervical lesion. HPV vaccination will require many years to evaluate any beneficial effects on cervical cancer incidence and mortality.

%B J Low Genit Tract Dis %V 18 %P 61-9 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23774078?dopt=Abstract %R 10.1097/LGT.0b013e318286b8d3 %0 Journal Article %J BMJ %D 2014 %T Long term outcomes for women treated for cervical precancer. %A M. Arbyn %A Kyrgiou, M %A Gondry, J %A Petry, K U %A Paraskevaidis, E %K Cervical Intraepithelial Neoplasia %K Female %K Humans %K Uterine Cervical Neoplasms %K Vaginal Neoplasms %B BMJ %V 348 %P f7700 %8 2014 Jan 14 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24423750?dopt=Abstract %R 10.1136/bmj.f7700 %0 Journal Article %J Arch Public Health %D 2014 %T Metaprop: a Stata command to perform meta-analysis of binomial data. %A Victoria N Nyaga %A M. Arbyn %A Aerts, Marc %X

BACKGROUND: Meta-analyses have become an essential tool in synthesizing evidence on clinical and epidemiological questions derived from a multitude of similar studies assessing the particular issue. Appropriate and accessible statistical software is needed to produce the summary statistic of interest.

METHODS: Metaprop is a statistical program implemented to perform meta-analyses of proportions in Stata. It builds further on the existing Stata procedure metan which is typically used to pool effects (risk ratios, odds ratios, differences of risks or means) but which is also used to pool proportions. Metaprop implements procedures which are specific to binomial data and allows computation of exact binomial and score test-based confidence intervals. It provides appropriate methods for dealing with proportions close to or at the margins where the normal approximation procedures often break down, by use of the binomial distribution to model the within-study variability or by allowing Freeman-Tukey double arcsine transformation to stabilize the variances. Metaprop was applied on two published meta-analyses: 1) prevalence of HPV-infection in women with a Pap smear showing ASC-US; 2) cure rate after treatment for cervical precancer using cold coagulation.

RESULTS: The first meta-analysis showed a pooled HPV-prevalence of 43% (95% CI: 38%-48%). In the second meta-analysis, the pooled percentage of cured women was 94% (95% CI: 86%-97%).

CONCLUSION: By using metaprop, no studies with 0% or 100% proportions were excluded from the meta-analysis. Furthermore, study specific and pooled confidence intervals always were within admissible values, contrary to the original publication, where metan was used.

%B Arch Public Health %V 72 %P 39 %8 2014 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25810908?dopt=Abstract %R 10.1186/2049-3258-72-39 %0 Journal Article %J Am J Clin Pathol %D 2014 %T p16INK4a immunohistochemistry in cervical biopsy specimens: A systematic review and meta-analysis of the interobserver agreement. %A Reuschenbach, Miriam %A Wentzensen, Nicolas %A Dijkstra, Maaike G %A von Knebel Doeberitz, Magnus %A M. Arbyn %K Biomarkers, Tumor %K Cervical Intraepithelial Neoplasia %K Cyclin-Dependent Kinase Inhibitor p16 %K Female %K Humans %K immunohistochemistry %K Observer Variation %K Uterine Cervical Neoplasms %X

OBJECTIVES: The interpretation of cervical biopsy specimens guides management of women with suspected cervical cancer precursors. However, morphologic evaluation is subjective and has low interobserver agreement. Addition of p16(INK4a) immunohistochemistry may improve interpretation.

METHODS: We performed a systematic review and meta-analysis of published data on interobserver agreement of p16(INK4a) positivity using p16(INK4a) immunohistochemistry and of cervical intraepithelial neoplasia grade 2 (CIN2+) and CIN grade 3 (CIN3+) classification using H&E morphology in conjunction with p16(INK4a) in comparison with H&E morphology alone.

RESULTS: The literature search revealed five eligible articles. The results show strong agreement of pathologists' interpretation of cervical biopsy specimens as p16(INK4a) positive or negative (pooled κ = 0.90; 95% confidence interval [CI], 0.88-0.92) and significantly higher agreement for a CIN2+ diagnosis with H&E morphology in conjunction with p16(INK4a) (κ = 0.73; 95% CI, 0.67-0.79) compared with H&E morphology alone (κ = 0.41; 95% CI, 0.17-0.65). Also, a slightly higher agreement for CIN3+ can be observed (κ = 0.66; 95% CI, 0.39-0.94 for H&E morphology in conjunction with p16(INK4a) and κ = 0.61; 95% CI, 0.44-0.78 for H&E morphology alone), but this difference was not statistically significant.

CONCLUSIONS: The published literature indicates improved interobserver agreement of the diagnosis of CIN2+ with the conjunctive use of H&E morphology with p16(INK4a) immunohistochemistry compared with H&E morphology alone.

%B Am J Clin Pathol %V 142 %P 767-72 %8 2014 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25389329?dopt=Abstract %R 10.1309/AJCP3TPHV4TRIZEK %0 Journal Article %J Cancer Cytopathol %D 2014 %T Reply to triage of women with minor abnormal cervical cytology: Meta-analysis of the accuracy of an assay targeting messenger ribonucleic acid of 5 high-risk human papillomavirus types. %A M. Arbyn %A Verdoodt, Freija %A Cuschieri, Kate %K Cervical Intraepithelial Neoplasia %K Female %K Humans %K Papillomavirus Infections %K RNA, Messenger %K triage %K Uterine Cervical Neoplasms %B Cancer Cytopathol %V 122 %P 77-8 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24170382?dopt=Abstract %R 10.1002/cncy.21359 %0 Journal Article %J Eur J Cancer %D 2014 %T Trends in corpus uteri cancer mortality in member states of the European Union. %A Weiderpass, Elisabete %A Jérôme Antoine %A Bray, Freddie I %A Oh, Jin-Kyoung %A M. Arbyn %K Adult %K Age Distribution %K Aged %K Aged, 80 and over %K Cohort Studies %K Europe %K European Union %K Female %K Humans %K middle aged %K mortality %K Uterine Neoplasms %X

OBJECTIVES: The burden of corpus uteri cancer varies in the European Union (EU). We analysed trends in corpus uteri cancer mortality in 26 EU member states from 1970 onward.

METHODS: Population numbers and number of uterine cancer deaths were extracted from the World Health Organisation mortality database. Corpus uteri cancer mortality rates were corrected for certification problems using different reallocation rules for deaths registered as uterine cancer not otherwise specified, or using mixed disease codes. Join point regression was used to study the annual percentage change of age-standardised corpus uteri cancer mortality rates. Changes in corpus uteri cancer mortality rates by calendar period and standardised cohort mortality ratios were also estimated.

RESULTS: In 2008, 12,903 women died from corpus uteri cancer in the EU. Corrected age-standardised corpus uteri cancer mortality rates have decreased significantly over the past decades in most member states, with exception of Malta and Bulgaria, where rates increased; Greece, where rates remained low but stable; and Sweden, where rates have been stable since 1970. Original member states showed a steeper decrease than newer member states. The standardised cohort mortality ratios indicated that corpus uteri cancer mortality does not decrease further, nor does it increase, among women born after 1940, although these birth cohorts may still be too young for corpus uteri cancer incidence to be fully evaluated.

CONCLUSION: Our corrected corpus uteri cancer mortality rates showed a decrease in most EU member states among women born before 1940.

%B Eur J Cancer %V 50 %P 1675-84 %8 2014 Jun %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24656568?dopt=Abstract %R 10.1016/j.ejca.2014.02.020 %0 Journal Article %J B.J.O.G. %D 2013 %T Accuracy of colposcopy-directed punch biopsies %A E.L Moss %A C.W.E. Redman %A M. Arbyn %K abstract %K accuracy %K Belgian Foundation Against Cancer %K Biopsy %K cancer %K cervix %K cit_Marbyn %K Colposcopy %K Comment %K diagnostic test accuracy %K hospital %K hospitals %K IARC %K PREHDICT %K punch biopsy %K REVIEW %K UK %K Universities %K university %K university hospital %X Abstract not available %B B.J.O.G. %V 120 %P 903 - 903 %8 1/7/2013 %G eng %N 7 %1 34702 %& 903 %R http://dx.doi.org/10.1111/1471-0528.12161 %0 Journal Article %J Int J Cancer %D 2013 %T The APTIMA HPV assay versus the Hybrid Capture 2 test in triage of women with ASC-US or LSIL cervical cytology: a meta-analysis of the diagnostic accuracy. %A M. Arbyn %A Roelens, Jolien %A Cuschieri, Kate %A Cuzick, Jack %A Szarewski, Ann %A Ratnam, Sam %A Reuschenbach, Miriam %A Belinson, Suzanne %A Belinson, Jerome L %A Monsonego, Joseph %K Adult %K Cervical Intraepithelial Neoplasia %K DNA, Viral %K Early Detection of Cancer %K Female %K Human Papillomavirus DNA Tests %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Sensitivity and Specificity %K triage %K Uterine Cervical Neoplasms %K Young adult %X

Testing for DNA of 13 high-risk HPV types with the Hybrid Capture 2 (HC2) test has consistently been shown to perform better in triage of women with cervical cytology results showing atypical squamous cells of undetermined significance (ASC-US) but often not in triage of low-grade squamous intraepithelial lesions (LSIL) detected in cervical cancer screening. In a meta-analysis, we compared the accuracy of the APTIMA HPV test, which identifies RNA of 14 high-risk HPV types, to HC2 for the triage of women with ASC-US or LSIL. Literature search-targeted studies where the accuracy of APTIMA HPV and HC2 for detection of underlying CIN2/3+ was assessed concomitantly including verification of all cases of ASC-US and LSIL. HSROC (Hierarchical Summary ROC) curve regression was used to compute the pooled absolute and relative sensitivity and specificity. Eight studies, comprising 1,839 ASC-US and 1,887 LSIL cases, were retrieved. The pooled sensitivity and specificity of APTIMA to triage ASC-US to detect underlying CIN3 or worse was 96.2% (95% CI = 91.7-98.3%) and 54.9% (95% CI = 43.5-65.9%), respectively. APTIMA and HC2 showed similar pooled sensitivity; however, the specificity of the former was significantly higher (ratio: 1.19; 95% CI = 1.08-1.31 for CIN2+). The pooled sensitivity and specificity of APTIMA to triage LSIL were 96.7% (95% CI = 91.4-98.9%) and 38.7% (95% CI = 30.5-47.6%) for CIN3+. APTIMA was as sensitive as HC2 but more specific (ratio: 1.35; 95% CI = 1.11-1.66). Results were similar for detection of CIN2 or worse. In both triage of ASC-US and LSIL, APTIMA is as sensitive but more specific than HC2 for detecting cervical precancer.

%B Int J Cancer %V 132 %P 101-8 %8 2013 Jan 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22610699?dopt=Abstract %R 10.1002/ijc.27636 %0 Generic %D 2013 %T Cervical cancer screening using mRNA HPV tests. %A M. Arbyn %K at %K cancer %K cancer screening %K Cervical %K cervical cancer %K cervical cancer screening %K CERVICAL-CANCER %K cervix %K conference %K diagnostic test accuracy %K HPV %K meta-analysis %K mRNA %K primary screening %K Research %K Rna %K SCREENING %K Test %K tests %B EUROGIN Conference "HPV at a crossroads: 30 years of research and practice" %I NA %C NA %8 30/6/2013 %G eng %N EUROGIN %1 35321 %2 03-06/11/2013 %0 Government Document %D 2013 %T Chairman of session: HPV screening and management. %A M. Arbyn %E EUROGIN %K at %K cancer %K cervix %K conference %K HPV %K management %K primary screening %K Research %K SCREENING %K triage %8 30/6/2013 %G eng %1 35185 %0 Journal Article %J Vaccine %D 2013 %T Comprehensive control of human papillomavirus infections and related diseases. %A Bosch, F Xavier %A Broker, Thomas R %A Forman, David %A Moscicki, Anna-Barbara %A Gillison, Maura L %A Doorbar, John %A Stern, Peter L %A Stanley, Margaret %A M. Arbyn %A Poljak, Mario %A Cuzick, Jack %A Castle, Philip E %A Schiller, John T %A Markowitz, Lauri E %A Fisher, William A %A Canfell, Karen %A Denny, Lynette A %A Franco, Eduardo L %A Steben, Marc %A Kane, Mark A %A Schiffman, Mark %A Meijer, Chris J L M %A Sankaranarayanan, Rengaswamy %A Castellsagué, Xavier %A Kim, Jane J %A Brotons, Maria %A Alemany, Laia %A Albero, Ginesa %A Diaz, Mireia %A de Sanjosé, Silvia %X

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters.

%B Vaccine %V 31 Suppl 7 %P H1-31 %8 2013 Dec 31 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24332295?dopt=Abstract %R 10.1016/j.vaccine.2013.10.003 %0 Journal Article %J Eur.J.Obstet.Gynecol.Reprod.Biol. %D 2013 %T European Federation of Colposcopy quality standards Delphi consultation %A E.L Moss %A M. Arbyn %A Dollery,E. %A Leeson,S. %A Petry,K.U %A Dvorak,V. %A Nieminen,P. %A C.W.E. Redman %K * %K ALL %K an %K cancer %K Case %K Cervical %K Cervical Intraepithelial Neoplasia %K cervix %K cit_Marbyn %K Colposcopy %K consultation %K Countries %K cytology %K data %K Design %K documentation %K EFC %K Europe %K European %K identify %K Indicator %K Indicators %K International %K LEVEL %K List %K Monitoring %K need %K Objective %K ON %K Order %K performance %K performance indicators %K Practice %K PROGRAM %K Quality %K QUALITY ASSURANCE %K Quality Control %K RANGE %K result %K results %K standards %K study %K study design %K Target %K Targets %K treatment %X OBJECTIVE: %B Eur.J.Obstet.Gynecol.Reprod.Biol. %V 170 %P 255 - 258 %8 1/9/2013 %G eng %1 34698 %& 255 %R http://dx.doi.org/10.1016/j.ejogrb.2013.06.032 %0 Generic %D 2013 %T Evidence for clinical applications of HR HPV testing. %A M. Arbyn %K application %K applications %K at %K cancer %K cervix %K Clinical %K conference %K evidence %K Evidence-Based Medicine %K follow-up after treatment %K HPV %K meta-analysis %K primary screening %K Research %K triage %B EUROGIN Conference "HPV at a crossroads: 30 years of research and practice", %I NA %C NA %8 30/6/2013 %G eng %N EUROGIN %1 35320 %2 06/11/2013 %0 Journal Article %J J.Clin.Epidemiol. %D 2013 %T A framework provided an outline toward the proper evaluation of potential screening strategies %A Adriaensen,W.J. %A Mathei,C. %A F.J. Buntinx %A M. Arbyn %K accuracy %K an %K analysi %K analysis %K AS %K Awareness %K Belgium %K Benefit %K benefits %K cancer %K care %K Cervical %K cervical cancer %K CERVICAL-CANCER %K Clinical %K Cost effectiveness %K Cost-effectiveness %K Design %K diagnostic accuracy %K electronic %K EVALUATION %K general %K General practice %K Harm %K health %K Impact %K implementation %K IS %K journal %K Lead %K LEVEL %K levels %K longitudinal %K Objective %K objectives %K ON %K Patient %K POPULATION %K Practice %K precursor %K primary care %K public %K public health %K Public-health %K result %K results %K SCREENING %K screening test %K SENSITIVITY %K Sensitivity and Specificity %K specificity %K Strategies %K Strategy %K study %K study design %K Test %K tests %X OBJECTIVES: Screening tests are often introduced into clinical practice without proper evaluation, despite the increasing awareness that screening is a double-edged sword that can lead to either net benefits or harms. Our objective was to develop a comprehensive framework for the evaluation of new screening strategies. STUDY DESIGN AND SETTING: Elaborating on the existing concepts proposed by experts, a stepwise framework is proposed to evaluate whether a potential screening test can be introduced as a screening strategy into clinical practice. The principle of screening strategy evaluation is illustrated for cervical cancer, which is a template for screening because of the existence of an easily detectable and treatable precursor lesion. RESULTS: The evaluation procedure consists of six consecutive steps. In steps 1-4, the technical accuracy, place of the test in the screening pathway, diagnostic accuracy, and longitudinal sensitivity and specificity of the screening test are assessed. In steps 5 and 6, the impact of the screening strategy on the patient and population levels, respectively, is evaluated. The framework incorporates a harm and benefit trade-off and cost-effectiveness analysis. CONCLUSION: Our framework provides an outline toward the proper evaluation of potential screening strategies before considering implementation %B J.Clin.Epidemiol. %V 66 %P 639 - 647 %8 6/2/2013 %G eng %N 6 %1 35306 %& 639 %R http://dx.doi.org/ %0 Journal Article %J Int.J.Cancer %D 2013 %T High-risk HPV testing on self-sampled versus clinician-collected specimens: A review on the clinical accuracy and impact on population attendance in cervical cancer screening %A Snijders,P.J. %A Verhoef,V.M. %A M. Arbyn %A Ogilvie,G. %A Minozzi,S. %A Banzi,R. %A van Kemenade,F.J. %A Heideman,D.A. %A C.J. Meijer %K 2012 %K access %K accuracy %K additional %K an %K Area %K Areas %K AS %K at %K cancer %K cancer screening %K Cervical %K cervical cancer %K cervical cancer screening %K Cervical Intraepithelial Neoplasia %K CERVICAL-CANCER %K Clinical %K Combination %K comparing %K Countries %K cytology %K Database %K detection %K developed countries %K electronic %K HPV %K Human %K identify %K im %K Impact %K improve %K IS %K IT %K journal %K Laboratories %K Less %K Literature %K medical %K Netherlands %K ON %K pathology %K performance %K POPULATION %K PROGRAM %K Programs %K Recall %K response %K REVIEW %K risk %K Sample %K Samples %K SCREENING %K SCREENING PROGRAM %K Search %K self-sampling %K specific %K Strategies %K Strategy %K study %K Test %K tests %K The Netherlands %K Universities %K university %K use %K variation %K variations %K WOMEN %X This review elaborates on the accuracy and feasibility of human papillomavirus (HPV) self-sampling, i.e., offering self-sampling of (cervico-)vaginal cell material by women themselves in nonclinical settings for high-risk HPV (hrHPV) detection in the laboratory, for cervical screening. To that end a bibliographic database search (PubMed) was performed to identify studies (published between January 1992 and January 2012) that compared clinical accuracy of HPV testing on self-sampled material with that of cytology or HPV testing on clinician-taken samples, and studies comparing response to offering HPV self-sampling with a recall invitation. Overall, hrHPV testing on self-samples appeared to be at least as, if not more, sensitive for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) as cytology on clinician-obtained cervical samples, though often less specific. In most studies, hrHPV testing on self- and clinician-sampled specimens is similarly accurate with respect to CIN2+ detection. Variations in clinical performance likely reflect the use of different combinations of collection devices and HPV tests. Because it is known that underscreened women are at increased risk of cervical cancer, targeting non-attendees of the screening program could improve the effectiveness of cervical screening. In developed countries offering self-sampling has shown to be superior to a recall invitation for cytology in re-attracting original non-attendees into the screening program. Additionally, self-testing has shown to facilitate access to cervical screening for women in low resource areas. This updated review of the literature suggests that HPV self-sampling could be an additional strategy that can improve screening performance compared to current cytology-based call-recall programs %B Int.J.Cancer %V 132 %P 2223 - 2236 %8 15/5/2013 %G eng %N 10 %1 35602 %& 2223 %R http://dx.doi.org/10.1002/ijc.27790 %0 Generic %D 2013 %T HPV testing on self-samples. %A M. Arbyn %K at %K cancer %K cervix %K conference %K diagnostic test accuracy %K HPV %K meta-analysis %K ON %K Research %K self-sampling %B EUROGIN Conference "HPV at a crossroads: 30 years of research and practice" %I NA %C NA %8 30/6/2013 %G eng %N EUROGIN %1 35323 %2 03/11/2013 %0 Journal Article %J Vaccine %D 2013 %T Human papillomavirus prevalence and type-distribution, cervical cancer screening practices and current status of vaccination implementation in Russian Federation, the Western countries of the former Soviet Union, Caucasus region and Central Asia. %A Rogovskaya, Svetlana I %A Shabalova, Irina P %A Mikheeva, Irina V %A Minkina, Galina N %A Podzolkova, Nataly M %A Shipulina, Olga Y %A Sultanov, Said N %A Kosenko, Iren A %A Brotons, Maria %A Buttmann, Nina %A Dartell, Myassa %A M. Arbyn %A Syrjänen, Stina %A Poljak, Mario %K Adult %K Aged %K Asia, Central %K Early Detection of Cancer %K Europe, Eastern %K Female %K Genotype %K Humans %K Male %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K Papillomavirus Vaccines %K prevalence %K Russia %K Uterine Cervical Neoplasms %K Vaccination %K Young adult %X

Limited data are available on the burden of human papillomavirus (HPV) and its associated diseases in the Russian Federation, the Western Countries of the former Soviet Union (Belarus, Republic of Moldova, Ukraine), the Caucasus region and Central Asia (Armenia, Azerbaijan, Georgia, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan). Both the incidence and mortality rate of cervical cancer are higher in these countries than in most Western European countries. In this article, we review available data on HPV prevalence and type distribution in women with normal cytology, women from the general population, cervical precancerous lesions and cervical cancer, as well as data on national policies of cervical cancer screening and HPV vaccination initiatives in these countries. Based on scarce data from the 12 countries, the high-risk HPV (hrHPV) prevalence among 5226 women with normal cytology ranged from 0.0% to 48.4%. In women with low-grade cervical lesions, the hrHPV prevalence among 1062 women varied from 29.2% to 100%. HrHPV infection in 565 women with high-grade cervical lesions ranged from 77.2% to 100% and in 464 invasive cervical cancer samples from 89.8% to 100%. HPV16 was the most commonly detected hrHPV genotype in all categories. As the HPV genotype distribution in cervical diseases seems to be similar to that found in Western Europe the implementation of HPV testing in screening programs might be beneficial. Opportunistic screening programs, the lack of efficient call-recall systems, low coverage, and the absence of quality assured cytology with centralized screening registry are major reasons for low success rates of cervical cancer programs in many of the countries. Finally, HPV vaccination is currently not widely implemented in most of the twelve countries mainly due to pricing, availability, and limited awareness among public and health care providers. Country-specific research, organized nationwide screening programs, registries and well defined vaccination policies are needed. This article forms part of a Regional Report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Central and Eastern Europe and Central Asia Region" Vaccine Volume 31, Supplement 7, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

%B Vaccine %V 31 Suppl 7 %P H46-58 %8 2013 Dec 31 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24332297?dopt=Abstract %R 10.1016/j.vaccine.2013.06.043 %0 Journal Article %J Vaccine %D 2013 %T Human papillomavirus prevalence and type-distribution, cervical cancer screening practices and current status of vaccination implementation in Central and Eastern Europe. %A Poljak, Mario %A Seme, Katja %A Maver, Polona J %A Kocjan, Boštjan J %A Cuschieri, Kate S %A Rogovskaya, Svetlana I %A M. Arbyn %A Syrjänen, Stina %K Early Detection of Cancer %K Europe, Eastern %K Female %K Genotype %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Papillomavirus Vaccines %K prevalence %K Uterine Cervical Neoplasms %K Vaccination %X

We present a review of current cervical cancer screening practices, the implementation status of vaccination against human papillomaviruses (HPV) and available data concerning the burden of HPV infection and HPV type-specific distribution in 16 Central and Eastern European countries: Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia and the Former Yugoslav Republic (FYR) of Macedonia. Since published data were relatively scarce, two detailed surveys were conducted during August-October 2011 and in January 2013 to obtain relevant and updated information. The mean prevalence of HPV infection in 8610 women with normal cervical cytology from the region was 12.6%, with HPV16 being the most frequent HPV type. The overall HPV DNA prevalence in women with high-grade cervical lesions was 78.1%. HPV DNA was found in 86.6% of cervical cancers; the combined prevalence of HPV16/18 among HPV positive cases was 87.5%. The overall HPV DNA prevalence in genital warts and laryngeal papillomas was 94.8% and 95.2%, respectively, with HPV6 and HPV11 being the most frequent types. Opportunistic and organized cervical screening, mainly based on conventional cytology, is performed in nine and seven countries in the region, respectively, with the proposed age of the start of screening ranging from 20 to 30 years and the estimated coverage ranging from a few percent to over 70%. At least one of the current HPV prophylactic vaccines is registered in all Central and Eastern European countries except Montenegro. Only Bulgaria, Czech Republic, FYR Macedonia, Latvia, Romania and Slovenia have actually integrated HPV vaccination into their national immunization programme and currently provide routine vaccination free of charge to the primary target population. The key reasons for lack of implementation of HPV vaccination into the national immunization programme are high vaccine cost and negative public perception. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Central and Eastern Europe and Central Asia Region" Vaccine Volume 31, Supplement 7, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

%B Vaccine %V 31 Suppl 7 %P H59-70 %8 2013 Dec 31 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24332298?dopt=Abstract %R 10.1016/j.vaccine.2013.03.029 %0 Journal Article %J Cochrane Database Syst Rev %D 2013 %T Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions. %A M. Arbyn %A Roelens, Jolien %A Cindy Simoens %A Buntinx, Frank %A Paraskevaidis, Evangelos %A Martin-Hirsch, Pierre P L %A Prendiville, Walter J %K Cervical Intraepithelial Neoplasia %K DNA, Viral %K Female %K Humans %K Papillomaviridae %K Papillomavirus Infections %K Sensitivity and Specificity %K triage %K Uterine Cervical Neoplasms %K Vaginal Smears %X

BACKGROUND: Atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intra-epithelial lesions (LSIL) are minor lesions of the cervical epithelium, detectable by cytological examination of cells collected from the surface of the cervix of a woman.Usually, women with ASCUS and LSIL do not have cervical (pre-) cancer, however a substantial proportion of them do have underlying high-grade cervical intra-epithelial neoplasia (CIN, grade 2 or 3) and so are at increased risk for developing cervical cancer. Therefore, accurate triage of women with ASCUS or LSIL is required to identify those who need further management.This review evaluates two ways to triage women with ASCUS or LSIL: repeating the cytological test, and DNA testing for high-risk types of the human papillomavirus (hrHPV) - the main causal factor of cervical cancer.

OBJECTIVES: Main objective To compare the accuracy of hrHPV testing with the Hybrid Capture 2 (HC2) assay against that of repeat cytology for detection of underlying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+) in women with ASCUS or LSIL. For the HC2 assay, a positive result was defined as proposed by the manufacturer. For repeat cytology, different cut-offs were used to define positivity: Atypical squamous cells of undetermined significance or worse (ASCUS+), low-grade squamous intra-epithelial lesions or worse (LSIL+) or high-grade squamous intra-epithelial lesions or worse (HSIL+).Secondary objective To assess the accuracy of the HC2 assay to detect CIN2+ or CIN3+ in women with ASCUS or LSIL in a larger group of reports of studies that applied hrHPV testing and the reference standard (coloscopy and biopsy), irrespective whether or not repeat cytology was done.

SEARCH METHODS: We made a comprehensive literature search that included the Cochrane Register of Diagnostic Test Accuracy Studies; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (through PubMed), and EMBASE (last search 6 January 2011). Selected journals likely to contain relevant papers were handsearched from 1992 to 2010 (December). We also searched CERVIX, the bibliographic database of the Unit of Cancer Epidemiology at the Scientific Institute of Public Health (Brussels, Belgium) which contains more than 20,000 references on cervical cancer.More recent searches, up to December 2012, targeted reports on the accuracy of triage of ASCUS or LSIL with other HPV DNA assays, or HPV RNA assays and other molecular markers. These searches will be used for new Cochrane reviews as well as for updates of the current review.

SELECTION CRITERIA: Studies eligible for inclusion in the review had to include: women presenting with a cervical cytology result of ASCUS or LSIL, who had undergone both HC2 testing and repeat cytology, or HC2 testing alone, and were subsequently subjected to reference standard verification with colposcopy and colposcopy-directed biopsies for histologic verification.

DATA COLLECTION AND ANALYSIS: The review authors independently extracted data from the selected studies, and obtained additional data from report authors.Two groups of meta-analyses were performed: group I concerned triage of women with ASCUS, group II concerned women with LSIL. The bivariate model (METADAS-macro in SAS) was used to assess the absolute accuracy of the triage tests in both groups as well as the differences in accuracy between the triage tests.

MAIN RESULTS: The pooled sensitivity of HC2 was significantly higher than that of repeat cytology at cut-off ASCUS+ to detect CIN2+ in both triage of ASCUS and LSIL (relative sensitivity of 1.27 (95% CI 1.16 to 1.39; P value < 0.0001) and 1.23 (95% CI 1.06 to 1.4; P value 0.007), respectively. In ASCUS triage, the pooled specificity of the triage methods did not differ significantly from each other (relative specificity: 0.99 (95% CI 0.97 to 1.03; P value 0.98)). However, the specificity of HC2 was substantially, and significantly, lower than that of repeat cytology in the triage of LSIL (relative specificity: 0.66 (95% CI 0.58 to 0.75) P value < 0.0001).

AUTHORS' CONCLUSIONS: HPV-triage with HC2 can be recommended to triage women with ASCUS because it has higher accuracy (significantly higher sensitivity, and similar specificity) than repeat cytology. When triaging women with LSIL, an HC2 test yields a significantly higher sensitivity, but a significantly lower specificity, compared to a repeat cytology. Therefore, practice recommendations for management of women with LSIL should be balanced, taking local circumstances into account.

%B Cochrane Database Syst Rev %P CD008054 %8 2013 Mar 28 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23543559?dopt=Abstract %R 10.1002/14651858.CD008054.pub2 %0 Generic %D 2013 %T Intensity of cervical cancer screening in Belgium. %A M. Arbyn %K Belgium %K cancer %K cancer screening %K Cervical %K cervical cancer %K cervical cancer screening %K CERVICAL-CANCER %K cervix %K Colposcopy %K conization %K cytology %K Flemish %K health %K Obstetrics %K Participation %K SCREENING %K screening coverage %K Societies %K Society %B 18th Colloquium for Ethics and Health Economy of the Flemish Society of Gynaecology and Obstetrics %I NA %C NA %8 30/6/2013 %G eng %N Flemish Society of Gynaecology and Obstetrics %1 35179 %2 20/04/2013 %0 Journal Article %J Cancer Epidemiol. %D 2013 %T Inter-laboratory variability in the presence of human papillomavirus in normal and abnormal cervical cytology samples %A Weyn,C. %A Garbar,C. %A Noel,J.C. %A Weynand,B. %A Verhest,A. %A M. Arbyn %K an %K ASCUS %K at %K behaviour %K Belgian Foundation Against Cancer %K Belgium %K Brussels %K Bruxelles %K cancer %K cells %K Cervical %K cervix %K CI %K cit_Marbyn %K cytology %K cytovirological correlation %K de %K detection %K Development %K disease %K Dna %K Faculty %K HPV %K Human %K IARC %K INFECTION %K IS %K Laboratories %K LSIL %K method %K methods %K microbiology %K ON %K PREHDICT %K prevalence of HPV %K reproduction %K Research %K result %K results %K risk %K Sample %K Samples %K study %K time %K treatment %K Type %K VARIABILITY %X Introduction: Treatment of cervical carcinoma is affected by the stage of the disease, being most likely curable with early detection. High-risk human papillomavirus (HPV) infection and persistency are necessary to the development of precancerous and cancerous lesions leaving the possibility to detect in time cells progressing in at risk behaviour. Methods: This study documents the proportion of HPV DNA positivity in 906 samples with cytological result negative for intraepithelial lesion and malignancy (NILM), 220 atypical squamous cells of undetermined significance (ASC-US) samples and 211 low grade intraepithelial lesions (LSIL) samples collected from various pathological laboratories in Brussels, Belgium. Results: The proportion of samples harbouring one or more HPV types was 10.8% (95% confidence interval, 95% CI: 8.8-12.8) in NILM, 34.5% (95% CI: 27.6-40.3) in ASC-US, 54.3% (95% CI: 47.5-61.1) in LSIL, with significant variability of HPV proportion in ASC-US and LSIL between laboratories. Conclusion: This study provides an on-site picture, confirming an added value of HPV DNA detection %B Cancer Epidemiol. %V 37 %P 457 - 461 %8 26/4/2013 %G eng %N 4 %1 35619 %& 457 %R http://dx.doi.org/10.1016/j.canep.2013.03.016 %0 Generic %D 2013 %T IPD-meta-analysis: dose-effect relation between cone size and risk of preterm delivery. 2 nd EFC Workshop on treatment of CIN: how to determine obstetrical and oncological safety ranges? %A M. Arbyn %E European Federation for Colposcopy and Cervical Pathology %K Cervical %K CIN %K Colposcopy %K Congresses %K delivery %K EFC %K European %K IPD meta-analysis %K meta-analysis %K obstetrical outcomes %K ON %K pathology %K RANGE %K risk %K SAFETY %K Size %K treatment %K treatment of CIN %B 6 th European Congress of the European Federation for Colposcopy and Cervical Pathology %8 7/9/2013 %G eng %N European Federation for Colposcopy and Cervical Pathology %1 35317 %2 05/09/2013 %0 Generic %D 2013 %T Keynote lecture: HPV testing on self-samples vs cytology or HPV testing on clinician samples: a meta-analysis of the diagnostic test accuracy. %A M. Arbyn %E Hellenic Society for Colposcopy and Cervical Pathology %K accuracy %K cancer %K Cervical %K cervix %K Colposcopy %K Congresses %K cytology %K diagnostic test accuracy %K HPV %K meta-analysis %K ON %K pathology %K Sample %K Samples %K self-sampling %K Test %B 7 th Hellenic and 3 rd Turkish Joint Congress on Colposcopy and Cervical Pathology %8 11/10/2013 %G eng %N Hellenic Society for Colposcopy and Cervical Pathology %1 35319 %2 11/10/2013 %0 Generic %D 2013 %T Meta-analysis of the accuracy of 5-type mRNA-testing in the triage of women with ASC-US or LSIL. %A Verdoodt,F. %A Halfon,P. %A Szarewski,A. %A Cuschieri,K. %A M. Arbyn %E Ronco,G. %E Monsonego,J. %K accuracy %K ASCUS %K at %K cancer %K cervix %K conference %K HPV %K LSIL %K meta-analysis %K triage %K WOMEN %B EUROGIN-2013 Conference: HPV at a crossroads %8 6/11/2013 %G eng %N Ronco,G., Monsonego,J. %1 35617 %2 02/11/2013 %0 Journal Article %J J.Clin.Microbiol. %D 2013 %T Multiple HPV infections with high viral loads are associated with cervical lesions but do not differentiate grades of cervical abnormalities %A Schmitt,M. %A Depuydt,C. %A Benoy,I. %A Bogers,J. %A Jérôme Antoine %A M. Arbyn %A Pawlita,M. %K additional %K age %K AS %K ASCUS %K association %K at %K cancer %K Case %K Cervical %K Common %K cutoff %K cytology %K data %K disease %K electronic %K Follow up %K FOLLOW-UP %K Genome %K Genotype %K Germany %K HPV %K Human %K im %K INFECTION %K infections %K IS %K IT %K journal %K LSIL %K Multiple %K multiple infections %K ON %K Patient %K patients %K POPULATION %K prevalence %K PROGRAM %K Research %K risk %K Sample %K Samples %K SCREENING %K trend %K Type %K Viral Load %X Multiple human papillomavirus (HPV) genotypes often co-exist within the cervical epithelium and are frequently detected in smears of different grades of cervical neoplasia. Describing the association of multiple infections with cervical disease is important to generate 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 additional ASC-US (n=100), LSIL (n=100) and HSIL (n=97). HPV genotyping was performed on cytology specimens only using BSGP5+/6+-PCR/MPG that detects and quantifies 51 HPV genotypes and 3 subtypes. Using a recently defined high viral load cutoff, the quantitative data was scored as high or low viral load. In the 36 month follow-up, 79 histologically confirmed 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%), ASC-US (64.6%) and NIL/M (36.8%). In 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%), ASC-US (40.7%) and NIL/M (19.3%). Patients with multiple high viral loads showed a 4- to 6-fold increased risk of having cervical precancerous cytological lesions than patients with single high viral loads.Compared to NIL/M, multiple infections, especially with multiple high viral loads, were significantly associated with cytological precancerous lesions. However, the presence of multiple infection did not distinguish low-grade from high-grade cytological lesions %B J.Clin.Microbiol. %V 51 %P 1458 - 1464 %8 27/2/2013 %G eng %N 5 %1 35600 %& 1458 %R http://dx.doi.org/10.1128/JCM.00087-13 %0 Generic %D 2013 %T p16/Ki67 immuno-cytochemistry in triage ASC-US & LSIL. %A M. Arbyn %K ASCUS %K at %K cancer %K cervix %K conference %K diagnostic test accuracy %K HPV %K Ki67 %K LSIL %K meta-analysis %K molecular markers %K p16 %K Research %K triage %B EUROGIN Conference "HPV at a crossroads: 30 years of research and practice" %I NA %C NA %8 6/11/2013 %G eng %N EUROGIN %1 35322 %2 03/11/2013 %0 Journal Article %J Vaccine %D 2013 %T Patterns and trends in human papillomavirus-related diseases in Central and Eastern Europe and Central Asia. %A Bray, Freddie %A Lortet-Tieulent, Joannie %A Znaor, Ariana %A Brotons, Maria %A Poljak, Mario %A M. Arbyn %K Asia, Central %K Europe, Eastern %K Humans %K incidence %K Neoplasms %K Papillomavirus Infections %K prevalence %K Survival Analysis %X

This article provides an overview of cervical cancer and other human papillomavirus (HPV)-related diseases in Central and Eastern Europe (Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia, and the Former Yugoslav Republic [FYR] of Macedonia) and Central Asia (Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Republic of Moldova, the Russian Federation, Tajikistan, Turkmenistan, Ukraine and Uzbekistan). Despite two- to three-fold variations, cervical cancer incidence rates are high in many countries in these two regions relative to other populations on the European and Asian continents. In Central and Eastern Europe, Romania and the FYR of Macedonia had the highest rates in 2008 alongside Bulgaria, Lithuania and Serbia, while in Central Asia, rates are elevated in Kyrgyzstan (the highest rates across the regions), Kazakhstan and Armenia. In each of these countries, at least one woman in 50 develops cervical cancer before the age of 75. The high cervical cancer burden is exacerbated by a lack of effective screening and an increasing risk of death from the disease among young women, as observed in Belarus, Tajikistan, Kyrgyzstan, Armenia, Azerbaijan, Ukraine, the Russian Federation and Kazakhstan. In several countries with longstanding cancer registries of reasonable quality (Belarus, Estonia and the Russian Federation), there are clear birth cohort effects; the risk of onset of cervical cancer is increasing in successive generations of women born from around 1940-50, a general phenomenon indicative of changing sexual behaviour and increasing risk of persistent HPV infection. There are limited data for other HPV-related cancers and other diseases at present in these countries. While options for reducing the HPV-related disease burden are resource-dependent, universal HPV vaccination with enhanced screening would maximally reduce the burden of cervical cancer in the countries within the two regions. It is hoped that the expanded second edition of the European Guidelines will finally kick-start effective interventions in many of these countries that still lack organised programmes. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Central and Eastern Europe and Central Asia Region" Vaccine Volume 31, Supplement 7, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

%B Vaccine %V 31 Suppl 7 %P H32-45 %8 2013 Dec 31 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24332296?dopt=Abstract %R 10.1016/j.vaccine.2013.02.071 %0 Journal Article %J Int.J.Cancer %D 2013 %T Prevalence and viral load of 51 genital human papillomavirus types and three subtypes %A Schmitt,M. %A Depuydt,C. %A Benoy,I. %A Bogers,J. %A Jérôme Antoine %A M. Arbyn %A Pawlita,M. %K an %K Analyses %K ASCUS %K Belgian %K cancer %K Cervical %K cytology %K data %K differences %K Dna %K electronic %K Frequency %K Genome %K Germany %K health %K HPV %K Human %K im %K Increase %K INFECTION %K infections %K IS %K journal %K LSIL %K n %K POPULATION %K Populations %K prevalence %K PROGRAM %K Research %K Sample %K Samples %K SCREENING %K series %K study %K Type %K Viral Load %K WOMEN %X Of the 120 known human papillomaviruses (HPV), 51 HPV types infect the genital mucosa. Very little is known about the prevalence and viral load of the majority of these low-risk (Lr-) HPV types in screening populations. We determined the prevalence of 51 HPV types and three subtypes in 999 consecutive BD-SurePath liquid-based cervical cytology samples collected during routine gynecological health checks from Belgian women. This series of screening samples was enriched with ASC-US (n = 100), low-grade squamous intraepithelial lesion LSIL (n = 100) and high-grade squamous intraepithelial lesion (HSIL) (n = 97) and analyzed by BSGP5+/6+-PCR/MPG assay for 51 HPV types and three subtypes. In consecutive screening samples, any of the 54 genital HPV (sub)types was found in 37.1%; Hr-HPV types were detected more frequently (26.8%) than the 31 Lr-HPV types (16.4%) and the six possibly high-risk types (6.6%). High viral load infections were present in 17.0% of the screening population. Among the women with cytological abnormalities, the prevalence of high viral loads of Hr-HPV types increased from negative for intraepithelial lesion or malignancy (NIL/M) over ASC-US, LSIL to HSIL (5.3, 47.1, 84.2 and 91.8%, respectively). The prevalence of possibly Hr and Lr-HPV types increased from NIL/M to LSIL but declined to HSIL. From NIL/M to HSIL, Hr-HPV infections showed an increasing frequency of high viral loads compared to total DNA positivity, but the increase between LSIL and HSIL was small. Type-specific analyses revealed substantial differences between individual HPV types in these groups. Our study provides quantitative data for the whole spectrum of genital HPV in a Belgian screening population and in a representative set of women with cervical abnormalities %B Int.J.Cancer %V 132 %P 2395 - 2403 %8 15/5/2013 %G eng %N 10 %1 35599 %& 2395 %R http://dx.doi.org/10.1002/ijc.27891 %0 Generic %D 2013 %T Prevention and treatment of disease related to infection with human papillomaviruses. Opportunities for a specific Cochrane collaboration. %A M. Arbyn %K cancer %K cervix %K cochrane %K Cochrane Review %K disease %K health %K HPV %K Human %K incidence %K INFECTION %K Institute %K meta-analysis %K mortality %K prevention %K public %K public health %K Public-health %K SCREENING %K specific %K systematic review %K treatment %K Vaccination %B Tuesday Seminaries of the Scientific Institute of Public Health %I NA %C NA %8 5/2/2013 %G eng %N WIV-ISP %1 35316 %2 05/02/2013 %0 Journal Article %J Cochrane Database Syst.Rev. %D 2013 %T Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors (Protocol) %A M. Arbyn %A Bryant,A. %A Lan Xu %A Cindy Simoens %A L. Markowitz %K a1 %K abstract %K Adenocarcinoma %K age %K ALL %K antibodies %K AS %K assessment %K at %K Belgian Foundation Against Cancer %K cancer %K Categories %K Cervical %K cervical cancer %K CERVICAL-CANCER %K cervix %K CIN %K Clinical %K cochrane %K CoHeahr %K Dna %K ECCG %K Evaluating %K EVALUATION %K Female %K Females %K Follow %K HPV %K Human %K INFECTION %K IS %K IT %K objectives %K outcome %K outcomes %K precursor %K PREHDICT %K protocol %K REVIEW %K SAFETY %K serology %K status %K systematic review %K time %K Type %K Vaccination %K vaccine %K vaccines %K WOMEN %X This is the protocol for a review and there is no abstract. The objectives are as follows:To evaluate the immunogenicity, clinical efficacy, and safety of prophylactic HPV vaccines in females. The assessment of clinical efficacy will address protection against HPV infection (for homologous and heterologous HPV types), against re-infection, against cervical cancer and its precursors (high-grade CIN (grade 2 or grade 3), adenocarcinoma in situ) in women previously not exposed to HPV infection (negative at enrolment for both HPV DNA and antibodies against the vaccine HPV types). We will assess clinical effectiveness by evaluating outcomes in all women, irrespective of the HPV DNA or serology status at enrolment. Evaluation by fine age and time since sexual debut categories is also planned. %B Cochrane Database Syst.Rev. %V 12 %P 1 - 15 %8 30/12/2013 %G eng %N CD009069 %1 31608 %& 1 %R http://dx.doi.org/ %0 Journal Article %J Vaccine %D 2013 %T Recommendations for cervical cancer prevention in Central and Eastern Europe and Central Asia. %A Poljak, Mario %A Rogovskaya, Svetlana I %A Kesić, Vesna %A Bray, Freddie %A Berkhof, Johannes %A Seme, Katja %A Brotons, Maria %A Castellsagué, Xavier %A Syrjänen, Stina %A M. Arbyn %A Bosch, F Xavier %K Asia, Central %K Early Detection of Cancer %K Europe, Eastern %K Female %K Humans %K Papillomavirus Infections %K Uterine Cervical Neoplasms %B Vaccine %V 31 Suppl 7 %P H80-2 %8 2013 Dec 31 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24332300?dopt=Abstract %R 10.1016/j.vaccine.2013.04.038 %0 Journal Article %J Eur.J.Cancer Prev. %D 2013 %T Transmission of carcinogenic human papillomavirus types from mother to child: a meta-analysis of published studies %A Merckx,M. %A Liesbeth Wildero-Van Wouwe %A M. Arbyn %A Meys,J. %A Weyers,S. %A Temmerman,M. %A D. Vanden Broeck %K a1 %K Adult %K adults %K an %K at %K Belgian Foundation Against Cancer %K Belgium %K birth %K Brussels %K cancer %K cervix %K Child %K CHILDREN %K Clinical %K Control %K criteria %K data %K differences %K effect %K effects %K Engineering %K epidemiology %K Explanation %K Faculty %K health %K hospital %K HPV %K Human %K INFECTION %K Institute %K IS %K IT %K Literature %K Mathematics %K meta-analysis %K Mode %K MODEL %K Mother %K mothers %K nursing %K Objective %K Obstetrics %K ON %K Pregnancies %K Pregnancy %K PREHDICT %K PROCESSES %K public %K public health %K Public-health %K report %K Research %K risk %K Science %K Selection %K study %K Transmission %K Type %K Universities %K university %K university hospital %X Currently, human papillomavirus (HPV) research focuses on HPV infection in adults and sexual transmission. Data on HPV infection in children are slowly becoming available. It is a matter of debate whether mother-to-child transmission of HPV is an important infection route and whether children born to HPV-positive mothers are at a higher risk of HPV infection compared with children born to HPV-negative mothers. The objective of this meta-analysis is to summarize the published literature on the extent to which genital HPV infection is vertically transmitted from mother to child. Medline, Web of Science, and CINAHL were searched for eligible reports published before January 2011. Differences in the risk of HPV infection between newborns from HPV-positive and HPV-negative mothers were pooled using a random-effects model. Twenty eligible studies, including 3128 women/children pairs, fulfilled the selection criteria. High heterogeneity could be found (I=96%). The overall estimated risk difference was 33% (95% confidence interval: 22-44%). On restricting to high-risk HPV-positive mothers only (n=4; women=231), the difference in risk was 45% (95% confidence interval: 33-56%). The heterogeneity was found to be low (I=15%). This meta-analysis indicates a significantly higher risk for children born to HPV-positive mothers to become HPV positive themselves. Plausible explanations include vertical transmission of HPV during pregnancy and/or birth or a higher infection rate during early nursing from mother to child. More research is required to gain an insight into the precise mode of transmission and the clinical effects of infection on the child %B Eur.J.Cancer Prev. %V 22 %P 277 - 285 %8 1/5/2013 %G eng %N 3 %1 32813 %& 277 %R http://dx.doi.org/10.1097/CEJ.0b013e3283592c46 %0 Journal Article %J Cancer Cytopathol %D 2013 %T Triage of women with minor abnormal cervical cytology: meta-analysis of the accuracy of an assay targeting messenger ribonucleic acid of 5 high-risk human papillomavirus types. %A Verdoodt, Freija %A Szarewski, Anne %A Halfon, Philippe %A Cuschieri, Kate %A M. Arbyn %K Adult %K Cervical Intraepithelial Neoplasia %K Early Detection of Cancer %K Female %K Humans %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K RNA, Messenger %K RNA, Viral %K Sensitivity and Specificity %K triage %K Uterine Cervical Neoplasms %K Vaginal Smears %X

BACKGROUND: High-risk human papillomavirus (hrHPV) DNA detection is generally accepted for the triage of women with a cytologic diagnosis of atypical squamous cells of undetermined significance (ASC-US). However, no consensus has been reached on the optimal management of low-grade squamous intraepithelial lesions (LSIL).

METHODS: In this meta-analysis, the diagnostic accuracy of nucleic acid sequence-based amplification (NASBA) detection of messenger ribonucleic acid (mRNA) of 5 hrHPV types (the PreTect HPV-Proofer and NucliSENS EasyQ tests) for detecting grade 2 cervical intraepithelial neoplasia or worse (CIN2+) and CIN3+ was assessed in women who had a diagnosis of ASC-US and LSIL. The results were compared with the Hybrid Capture-2 (HC2) assay, which detects the DNA of 13 hrHPV types. A bivariate random-effect model that incorporated the intrinsic correlation between the true-positive and false-positive rates was used for a pooled meta-analysis.

RESULTS: Considering underlying CIN2+, the pooled absolute sensitivity of the 10 included studies was 75.4% (95% confidence interval [CI], 68.1%-82.7%) and 76.2% (95% CI, 68.3%-76.9%) for the triage of ASC-US and LSIL, respectively. The pooled absolute specificity to exclude CIN2+ was 77.9% (95% CI, 70.1%-85.7%) and 74.2% (95% CI, 69.5%-78.8%) in women with ASC-US and LSIL, respectively. Five studies allowed direct comparison of the mRNA assays with HC2. Considering CIN2+ in women with ASC-US and LSIL, mRNA testing was substantially more specific than the HC2 assay (ratio: 1.98 and 3.36, respectively; P < .001) but was less sensitive (ratio: 0.80 and 0.74, respectively; P < .001).

CONCLUSIONS: HPV assays for detecting the mRNA of 5 hrHPV types may reduce the over-diagnosis of women who have minor cytologic abnormalities. However, given the lower sensitivity, women with negative mRNA test results cannot be considered free of CIN2+ and require further surveillance.

%B Cancer Cytopathol %V 121 %P 675-87 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23881840?dopt=Abstract %& 675 %R 10.1002/cncy.21325 %0 Journal Article %J Cancer Epidemiol.Biomarkers Prev. %D 2013 %T Viral load of high-risk human papillomaviruses as reliable clinical predictor for the presence of cervical lesions %A Schmitt,M. %A Depuydt,C. %A Benoy,I. %A Bogers,J. %A Jérôme Antoine %A M. Arbyn %K accuracy %K Antwerp %K AS %K at %K Belgium %K Biomarkers %K Brussels %K cancer %K Case %K cause %K cells %K Cervical %K cervical cancer %K CERVICAL-CANCER %K Clinical %K cytology %K detection %K Diagnostics %K Dna %K electronic %K epidemiology %K Follow up %K FOLLOW-UP %K Genome %K Germany %K health %K healthcare %K HPV %K Human %K identify %K INFECTION %K infections %K Institute %K IS %K journal %K LSIL %K n %K ON %K Order %K p %K PCR %K precursor %K PROGRAM %K public %K public health %K Public-health %K qPCR %K Quantitative real-time PCR %K real time PCR %K Real-time PCR %K Research %K result %K results %K Sample %K Samples %K scale %K SCREENING %K SENSITIVITY %K specificity %K Test %K tests %K threshold %K thresholds %K transformation %K Type %K Viral Load %X BACKGROUND: Infections with high-risk human papillomaviruses (Hr-HPV) can cause malignant transformation of the human cervical epithelium. HPV DNA tests generally are very sensitive to detect cervical neoplastic lesions but also identify transient HPV infections. As a consequence, the specificity and positive predictive value are low.METHODS: We analyzed viral load of Hr- and possibly Hr-HPV types more than seven orders of magnitude (on a log10 scale) in 999 consecutive BD-SurePath liquid-based cervical cytology samples from routine cervical screening enriched with atypical squamous cells of undetermined significance (n = 100), low-grade squamous intraepithelial lesions (LSIL; n = 100), and high-grade squamous intraepithelial lesions (HSIL; n = 97) using type-specific multiplex quantitative real-time PCR and the BSGP5+/6+-PCR/MPG assay. In the 36-month follow-up, 79 histologically verified CIN2+ and 797 double-negative cytology cases were identified.RESULTS: Viral loads in LSIL and HSIL were significantly increased compared with no intraepithelial lesion or malignancy in both the quantitative PCR (qPCR) and BSGP5+/6+-PCR/MPG assay (P < 0.0001). The mean viral loads in LSIL and HSIL were not significantly different. Using a newly determined high viral load cut off for 14 Hr-HPV types, the sensitivity for prevalent CIN3+ remained at 100% for both assays compared with the minimal detection threshold. The specificity (corresponding to double-negative cytology at subsequent screening episodes) increased substantially (qPCR, from 91.1% to 95.7%; BSGP5+/6+-PCR/MPG, from 79.8% to 96.2%).CONCLUSIONS: Compared with DNA positivity alone, high Hr-HPV viral loads could reduce the amount of false positive results detected by the BSGP5+/6+-PCR/MPG and qPCR by 81.4% and 52.1%, respectively.Impact: Quantitative type-specific HPV DNA assays show high flexibility in defining thresholds that allow optimizing clinical accuracy for cervical cancer precursors. Cancer Epidemiol Biomarkers Prev; 1-9. (c)2013 AACR %B Cancer Epidemiol.Biomarkers Prev. %V 22 %P 406 - 414 %8 12/2/2013 %G eng %1 35601 %& 406 %R http://dx.doi.org/10.1158/1055-9965.EPI-12-1067 %0 Generic %D 2013 %T Which HPV tests can be used? Meta-analyses of performance of different HPV tests in primary screening. %A M. Arbyn %E European Federation for Colposcopy and Cervical Pathology %K cancer %K Cervical %K cervix %K clinical validation %K Colposcopy %K Congresses %K European %K Guidelines %K HPV %K pathology %K performance %K primary screening %K SCREENING %K Test %K tests %B 6 th European Congress of the European Federation for Colposcopy and Cervical Pathology %8 7/9/2013 %G eng %N European Federation for Colposcopy and Cervical Pathology %1 35318 %2 05/09/2013 %0 Journal Article %J BJOG %D 2012 %T Adverse obstetrical outcomes after treatment of precancerous cervical lesions: a Belgian multicentre study. %A Cindy Simoens %A Goffin, F %A Simon, P %A Barlow, P %A Jérôme Antoine %A Foidart, J-M %A M. Arbyn %K Adult %K Belgium %K Cervical Intraepithelial Neoplasia %K conization %K Female %K Humans %K Infant, Newborn %K Infant, Small for Gestational Age %K Precancerous Conditions %K Pregnancy %K Pregnancy Complications, Neoplastic %K Pregnancy Outcome %K Premature Birth %K Uterine Cervical Neoplasms %X

OBJECTIVE: To assess the impact of cervical intraepithelial neoplasia (CIN) treatment on the risk of (spontaneous) preterm delivery (PD) and small for gestational age (SGA) at birth.

DESIGN: A multicentre cohort study.

SETTING: Maternity wards of four academic hospitals in Belgium.

POPULATION: Ninety-seven exposed pregnant women (with a CIN treatment history) and 194 nonexposed pregnant women (without a history of CIN treatment).

METHODS: A questionnaire and check of obstetrical files included socio-demographic characteristics, risk factors for PD, obstetrical history for all women and characteristics of the CIN treatment for exposed women. Pregnancy outcomes were recorded after delivery. The influence of previous treatment of CIN on pregnancy outcomes, adjusted for confounding variables, was assessed by Cox regression and lifetables (for the outcome gestational age at birth) and by logistic regression (for the outcomes PD and SGA at birth).

MAIN OUTCOME MEASURES: Occurrence of PD and SGA at birth.

RESULTS: Seventy-nine per cent of the women in the database were multiparous; 16.3% of women with a previous excisional treatment spontaneously delivered preterm, compared with 8.1% of unexposed women [odds ratio (OR), 2.19; 95% confidence interval (CI), 0.97-4.99]. When adjusting for confounding factors (ethnicity, HIV status, education, age, smoking and parity), the OR for PD was 2.33 (95% CI, 0.99-5.49). Excisional treatment did not have an impact on SGA at birth (OR, 0.94; 95% CI,0.41-2.15). The depth of the cone was >10 mm in 63.5% of the documented cases. Large cones, more than 10 mm deep, were associated with a significantly increased risk of PD (adjusted OR, 4.55; 95% CI, 1.32-15.65) compared with untreated women, whereas smaller cones (≤ 10 mm) were not significantly associated with PD (OR, 2.77; 95% CI, 0.28-27.59). The associations seen for PD with respect to the cone size did not hold for SGA at birth.

CONCLUSIONS: There was an increased risk of (spontaneous) PD after excision of CIN, in particular when the cone depth exceeded 10 mm.

%B BJOG %V 119 %P 1247-55 %8 2012 Sep %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/22804838?dopt=Abstract %R 10.1111/j.1471-0528.2012.03429.x %0 Government Document %D 2012 %T Analyse des données individuelles des organismes assureurs sur les frottis de col de l'uterus, les colposcopies, les biopsies cervicales et la chirurgie du col de l'uterus (Belgique, 2002-2006) %A M. Arbyn %A Cindy Simoens %A Fabri,V. %K Belgique %K Biopsy %K cancer %K Colposcopy %K de %K ET %K LE %X Not available %B Epi-Scoop %C Brussels %V 12 %P 4 - 4 %8 0/2/2012 %G eng %1 35307 %& 4 %0 Government Document %D 2012 %T Analyse van individuele sociale zekerheidsgegevens over uitstrijkjes, colposcopieën, biopsieën en chirurgische ingrepen op de baarmoederhals (België, 2002-2006) %A M. Arbyn %A Cindy Simoens %A Fabri,V. %K België %K cancer %K de %B Epi-Scoop %C Brussel %V 12 %P 4 - 4 %8 0/2/2012 %G eng %1 32273 %& 4 %0 Journal Article %J Arch.Pathol.Lab Med %D 2012 %T Causes and relevance of unsatisfactory and satisfactory but limited smears of liquid-based compared with conventional cervical cytology %A Siebers,A.G. %A Klinkhamer,P.J.J.M. %A Vedder,J.E.M. %A M. Arbyn %A Bulten,J. %K an %K AS %K at %K Belgian Foundation Against Cancer %K cervix %K cit_Marbyn %K conventional %K cytology %K detection %K differences %K ECCG %K endocervical cells %K Follow up %K FOLLOW-UP %K Hand %K Increase %K monolayer cytology %K Netherlands %K ON %K PREHDICT %K quality of smear %K RATES %K RCT %K Register %K result %K results %K risk %K study %K Test %K The Netherlands %K WOMEN %X Context.-Recent randomized controlled trials have shown a significant decrease in unsatisfactory rates for liquid-based cytology (LBC) compared with conventional Papanicolaou test (CP). The underlying causes and relevance of unsatisfactory results for LBC and CP have never been compared within the setting of a randomized controlled trial. Objective.-To examine differences in causes and relevance of unsatisfactory and satisfactory but limited by (SBLB) results for LBC and CP. Design.-Data from the Netherlands ThinPrep Versus Conventional Cytology (NETHCON) trial were used, involving 89 784 women. Causes and relevance of unsatisfactory and SBLB results were analyzed. Results.-The primary cause for unsatisfactory results for CP and LBC was scant cellularity. Other causes for unsatisfactory CPs were virtually eliminated with LBC. The same was true for SBLB subcategories, with the exception of SBLB absence of transformation zone component and SBLB scant cellularity. The SBLB absence of transformation zone component showed a statistically significant 22% and SBLB scant cellularity a 12% nonsignificant increase with LBC. The detection rates of abnormalities found during 18 months of follow-up of unsatisfactory test results did not differ significantly between the 2 study arms, nor did they differ from the initial test positivity rates from the NETHCON trial. Conclusions.-Liquid-based cytology shows an almost complete elimination of most causes for unsatisfactory CP, with scant cellularity remaining as the sole cause for unsatisfactory LBC. On the other hand, with LBC a significant increase of smears without a transformation zone component was noted. Women with an unsatisfactory test result are not at increased risk for cervical abnormalities either with LBC or with CP. Trial Registration.-Nederlands Trial Register, NTR1032, www.trialregister.nl %B Arch.Pathol.Lab Med %V 136 %P 76 - 83 %8 0/1/2012 %G eng %N 1 %1 31264 %& 76 %R http://dx.doi.org/10.5858/arpa.2011-0113-OA %0 Generic %D 2012 %T Cervical cancer screening in the European Union: burden & screening coverage %A M. Arbyn %E Instituto Nazionale Tumori %K cancer %K cancer screening %K Cervical %K cervical cancer %K cervical cancer screening %K CERVICAL-CANCER %K Coverage %K European %K European Union %K health %K Health indicator %K Indicator %K SCREENING %K screening coverage %K symposium %B Symposium of the European Cancer Health Indicator Project %8 26/2/2012 %G eng %N Instituto Nazionale Tumori %1 35313 %2 26/02/2012 - 27/02/2012 %0 Generic %D 2012 %T Cochrane Review: Cervical Cancer Screening in developing countries %A M. Arbyn %E University of Helsinki %E University of Tampere %E Finnish Medical Society %K cancer %K cancer screening %K Cervical %K cervical cancer %K cervical cancer screening %K CERVICAL-CANCER %K cochrane %K Cochrane Review %K Countries %K developing %K Developing Countries %K HPV %K ON %K REVIEW %K SCREENING %K symposium %K Vaccination %B Fourth Helsinki Symposium on HPV Vaccination %8 12/1/2012 %G eng %N University of Helsinki, University of Tampere, Finnish Medical Society %1 35311 %2 12/01/2012 %0 Generic %D 2012 %T Cochrane Review: Safety, immunogenecity and efficacy of prophylactic HPV vaccines %A M. Arbyn %E University of Tampere %E University of Helsinki %E Finnish Medical Society %K cochrane %K Cochrane Review %K HPV %K ON %K REVIEW %K SAFETY %K symposium %K Vaccination %K vaccine %K vaccines %B Fourth Helsinki Symposium on HPV Vaccination %8 12/1/2012 %G eng %N University of Tampere, University of Helsinki, Finnish Medical Society %1 35312 %2 12/01/2012 %0 Journal Article %J J.Low Genit.Tract.Dis. %D 2012 %T Is the colposcopically-directed punch biopsy a reliable diagnostic test in women with minor cytological lesions? %A E.L Moss %A Hadden,P. %A Douce,G. %A Jones,P.W. %A M. Arbyn %A C.W.E. Redman %K Agreement %K an %K ASCUS %K at %K Biopsy %K cancer %K cells %K cervix %K Change %K Changes %K CI %K conization %K cutoff %K cytology %K diagnostic test accuracy %K epub %K IS %K LEVEL %K LLETZ %K LSIL %K method %K methods %K Objective %K Order %K outcome %K parameters %K result %K results %K Sample %K Samples %K SENSITIVITY %K study %K Test %K UK %K WOMEN %X OBJECTIVE: %B J.Low Genit.Tract.Dis. %V 16 %8 4/6/2012 %G eng %N 4 %1 32242 %R http://dx.doi.org/ %0 Journal Article %J BMJ %D 2012 %T Effect of screening on deaths from cervical cancer in Sweden %A M. Arbyn %A Weiderpass,E. %A Capocaccia,R. %K Belgian Foundation Against Cancer %K Belgium %K Brussels %K cancer %K cervical cancer %K cervix %K ECCG %K effect %K epidemiology %K epub %K EUROCHIP %K EUROCOURSE %K health %K incidence %K Institute %K mortality %K ON %K PREHDICT %K public %K public health %K Public-health %K SCREENING %K survival %K Sweden %K trend %B BMJ %V 344 %P e804 %8 1/3/2012 %G eng %1 32277 %& e804 %R http://dx.doi.org/10.1136/bmj.e804 %0 Journal Article %J Int J Cancer %D 2012 %T EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease. %A M. Arbyn %A de Sanjosé, Silvia %A Saraiya, Mona %A Sideri, Mario %A Palefsky, Joel %A Lacey, Charles %A Gillison, Maura %A Bruni, Laia %A Ronco, Guglielmo %A Wentzensen, Nicolas %A Brotherton, Julia %A Qiao, You-Lin %A Denny, Lynnette %A Bornstein, Jacob %A Abramowitz, Laurent %A Giuliano, Anna %A Tommasino, Massimo %A Monsonego, Joseph %K Anus Neoplasms %K Early Detection of Cancer %K Female %K Head and Neck Neoplasms %K Humans %K Male %K Papillomaviridae %K Papillomavirus Infections %K Papillomavirus Vaccines %K Penile Neoplasms %K Primary Prevention %K Secondary Prevention %K Uterine Cervical Neoplasms %K Vulvar Neoplasms %X

The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)-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 ~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. Randomized 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 programs. 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, anogenital 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 organized 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.

%B Int J Cancer %V 131 %P 1969-82 %8 2012 Nov 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22623137?dopt=Abstract %R 10.1002/ijc.27650 %0 Journal Article %J Vaccine %D 2012 %T Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. %A M. Arbyn %A Ronco, Guglielmo %A Ahti Anttila %A Meijer, Chris J L M %A Poljak, Mario %A Ogilvie, Gina %A Koliopoulos, George %A Naucler, Pontus %A Sankaranarayanan, Rengaswamy %A Peto, Julian %K Early Detection of Cancer %K Female %K Humans %K Molecular Diagnostic Techniques %K Papillomavirus Infections %K Secondary Prevention %K Uterine Cervical Neoplasms %K virology %X

More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods. A summary is given from recent meta-analyses and systematic reviews on 3 possible clinical applications of human papillomavirus (HPV) testing: triage of women with equivocal or low-grade cytologic abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer. Consistent evidence is available indicating that HPV-triage with the Hybrid Capture(®) 2 assay (Qiagen Gaithersburg, Inc., MD, USA [previously Digene Corp.] (HC2) is more accurate (higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. Several other tests show at least similar accuracy but mRNA testing with the APTIMA(®) (Gen-Probe Inc., San Diego, CA, USA) test is similarly sensitive but more specific compared to HC2. In triage of low-grade squamous intraepithelial lesions (LSIL), HC2 is more sensitive but its specificity is substantially lower compared to repeat cytology. The APTIMA(®) test is more specific than HC2 without showing a loss in sensitivity. Identification of DNA of HPV types 16 and/or 18, or RNA from the five most carcinogenic HPV types allow selecting women at highest risk for CIN3+ but the sensitivity and negative predictive value of these markers are lower than full-range high-risk HPV (hrHPV) testing. After conservative treatment of cervical pre-cancer, HPV testing picks up more quickly, with higher sensitivity and not lower specificity, residual or recurrent high-grade CIN than follow-up cytology. Primary screening for hrHPV generally detects more CIN2, CIN3 or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASC-US) or LSIL, but is less specific. Combined HPV and cytology screening provides a further small gain in sensitivity at the expense of a considerable loss in specificity if positive by either test is referred to colposcopy, in comparison with HPV testing only. Randomised trials and follow-up of cohort studies consistently demonstrate a significantly lower cumulative incidence of CIN3+ and even of cancer, in women aged 30 years or older, who were at enrollment hrHPV DNA negative compared to those who were cytologically negative. The difference in cumulative risk of CIN3+ or cancer for double negative (cytology & HPV) versus only HPV-negative women is small. HC2, GP5+/6+ PCR (polymerase chain reaction), cobas(®) 4800 PCR (Roche Molecular Systems Inc., Alameda, CA, USA) and Real Time PCR (Abbott Molecular, Des Plaines, IL, USA) can be considered as clinically validated for use in primary screening. The loss in specificity associated with primary HPV-based screening can be compensated by appropriate algorithms involving reflex cytology and/or HPV genotyping for HPV16 or 18. There exists a substantial evidence base to support that HPV testing is advantageous both in triage of women with equivocal abnormal cytology, in surveillance after treatment of CIN lesions and in primary screening of women aged 30 years or older. However, the possible advantages offered by HPV-based screening require a well organised program with good compliance with screening and triage policies. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

%B Vaccine %V 30 Suppl 5 %P F88-99 %8 2012 Nov 20 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/23199969?dopt=Abstract %R 10.1016/j.vaccine.2012.06.095 %0 Generic %D 2012 %T Highlights of the 27th International Papillomavirus Conference and Clinical Workshop (Berlin, 17-22 September 2011) - Part 3: Epidemiology and Public Health %A M. Arbyn %A Gissmann,L. %E Schneider,A. %E Gissman,L. %E A.M. Kaufmann %K cancer %K Clinical %K cochrane %K conference %K ECCG %K epidemiology %K health %K HPV %K HPV-AHEAD %K International %K PREHDICT %K public %K public health %K Public-health %B 27th International Papillomavirus Conference and Clinical Workshop %S Future Virol. %V 7 %P 127 - 133 %8 0/2/2012 %G eng %N Schneider,A., Gissman,L., Kaufmann,A. %1 31899 %2 17-22/09/2011 %& 127 %R http://dx.doi.org/10.2217/fvl.11.131 %0 Generic %D 2012 %T Highlights of the 27th International Papillomavirus Conference and Clinical Workshop (Berlin, 17-22 September 2011) - Part 2: Applied Clinical Science %A M. Arbyn %A Gissmann,L. %E Schneider,A. %E Gissman,L. %E A.M. Kaufmann %K antibodies %K assessment %K cancer %K cervical cancer %K cervix %K Clinical %K conference %K disease %K Dna %K ECCG %K health %K HPV %K HPV-AHEAD %K immunology %K INFECTION %K International %K Laboratories %K ON %K precursor %K PREHDICT %K prevention %K public %K public health %K Public-health %K questions %K report %K REVIEW %K Role %K Science %K SCREENING %K Secondary %K standards %K Test %K treatment %K Vaccination %K VALGENT %K WHO %X The 27th International Papillomavirus Conference and Clinical Workshop, held in Berlin (17-22 September 2011), brought together more than 2000 scientists, clinicians and public health experts who shared new findings in the knowledge of the HPV and the prevention and treatment of HPV-related disease. In this second of three reports of the conference, the applied clinical science sessions are summarized, which focused on immunology, new HPV tests, benign HPV infections, noncervical HPV-related disease, primary and secondary prevention of cervical cancer by HPV-based screening and prophylactic HPV vaccination and treatment of HPV-induced disease. The clinical workshops discussed possible alternative schedules of prophylactic HPV vaccination, prevention of anal cancer and anal precancer, validation of HPV genotyping assays, establishment of standards and laboratory proficiency in testing for HPV DNA and anti-HPV antibodies through the WHO LabNet, and currently heavily debated questions on the role of colposcopy in the assessment of cervical cancer precursors. %B 27th International Papillomavirus Conference and Clinical Workshop %S Future Virol. %V 7 %P 19 - 24 %8 0/1/2012 %G eng %N Schneider,A., Gissman,L., Kaufmann,A. %1 31860 %2 17-22/09/2011 %& 19 %0 Journal Article %J Future Virol. %D 2012 %T Highlights of the 27th International Papillomavirus Conference and Clinical Workshop (Berlin, 17-22 September 2011) - Part 2: Applied Clinical Science %A M. Arbyn %A Schneider,A. %A Gissmann,L. %A A.M. Kaufmann %K alternative %K anal %K antibodies %K assessment %K cancer %K Cervical %K cervical cancer %K CERVICAL-CANCER %K cervix %K Clinical %K Colposcopy %K conference %K disease %K Dna %K ECCG %K health %K HPV %K HPV-AHEAD %K immunology %K INFECTION %K infections %K International %K Laboratories %K ON %K precursor %K PREHDICT %K prevention %K public %K public health %K Public-health %K questions %K report %K REVIEW %K Role %K Science %K SCREENING %K Secondary %K standards %K Test %K tests %K treatment %K Vaccination %K VALGENT %K VALIDATION %K WHO %X The 27th International Papillomavirus Conference and Clinical Workshop, held in Berlin (17-22 September 2011), brought together more than 2000 scientists, clinicians and public health experts who shared new findings in the knowledge of the HPV and the prevention and treatment of HPV-related disease. In this second of three reports of the conference, the applied clinical science sessions are summarized, which focused on immunology, new HPV tests, benign HPV infections, noncervical HPV-related disease, primary and secondary prevention of cervical cancer by HPV-based screening and prophylactic HPV vaccination and treatment of HPV-induced disease. The clinical workshops discussed possible alternative schedules of prophylactic HPV vaccination, prevention of anal cancer and anal precancer, validation of HPV genotyping assays, establishment of standards and laboratory proficiency in testing for HPV DNA and anti-HPV antibodies through the WHO LabNet, and currently heavily debated questions on the role of colposcopy in the assessment of cervical cancer precursors. %B Future Virol. %V 7 %P 19 - 24 %8 0/0/2012 %G eng %N 1 %1 35308 %& 19 %R http://dx.doi.org/ %0 Book %B Gynaecologie %D 2012 %T Hoofdstuk 15: Optimale afname van cellen van de baarmoederhals voor cervixscreening %A F.J. Buntinx %A van der Putten,H.W.H.M. %A M. Arbyn %E Essed,G.G.M. %K cancer %K cervix %K cit_Marbyn %K de %K GENERAL PRACTITIONER %K GP %K Guidelines %K Netherlands %K quality of smear %K SCREENING %B Gynaecologie %7 277 %I Bohn Stafleu van Loghum (Springer) %C Houten (the Netherlands) %P 277 %8 0/0/2012 %@ 9789031382668 %G eng %9 Praktische Huisartsgeneeskunde %1 32156 %& 199 %0 Conference Proceedings %D 2012 %T Impact of genetic notification on smoking cessation: Pooled analysis %A de Viron,S. %A Johan Van der Heyden %A Ambrosio,E. %A M. Arbyn %A Brand,A. %A Herman Van Oyen %E Johan Peeters %K analysi %K analysis %K Cessation %K Genetic %K Impact %K Notification %K ON %K pooled analysis %K report %K SMOKING %K Smoking cessation %K WIV-ISP %I WIV-ISP %C Brussels %P 45 - 47 %8 0/0/2012 %G eng %1 36386 %& 45 %0 Journal Article %J PLoS One %D 2012 %T Impact of genetic notification on smoking cessation: systematic review and pooled-analysis. %A de Viron, Sylviane %A Johan Van der Heyden %A Ambrosino, Elena %A M. Arbyn %A Brand, Angela %A Herman Van Oyen %K Confidence Intervals %K Follow-Up Studies %K Genetic Predisposition to Disease %K Humans %K Publication Bias %K Randomized Controlled Trials as Topic %K Risk Factors %K SMOKING %K Smoking cessation %X

OBJECTIVES: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.

%B PLoS One %V 7 %P e40230 %8 2012 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/22808123?dopt=Abstract %& e40230 %R 10.1371/journal.pone.0040230 %0 Journal Article %J Cancer Causes Control %D 2012 %T Liquid-based cervical cytology using ThinPrep technology: weighing the pros and cons in a cost-effectiveness analysis %A de Bekker-Grob,E.W. %A de Kok,I.M. %A Bulten,J. %A van Rosmalen,J. %A Vedder,J.E.M. %A M. Arbyn %A Klinkhamer,P.J.J.M. %A Siebers,A.G. %A van Ballegooijen,M. %K Advantages %K alternative %K an %K Analyses %K AS %K at %K Belgian Foundation Against Cancer %K cancer %K cancer screening %K Cervical %K cervical cancer %K cervical cancer screening %K CERVICAL-CANCER %K cervix %K Change %K cit_Marbyn %K conditions %K conventional %K Cost %K Cost effectiveness %K Cost-effectiveness %K COSTS %K cytology %K data %K ECCG %K EU %K EUROCHIP %K EUROCOURSE %K Evaluating %K Follow up %K FOLLOW-UP %K HPV %K Human %K implementation %K IS %K Less %K Life %K method %K methods %K MODEL %K monolayer cytology %K Netherlands %K ON %K PREHDICT %K Quality %K Quality of Life %K RCT %K Research %K result %K results %K SCREENING %K SENSITIVITY %K Strategies %K Strategy %K System %K Test %K threshold %K triage %K values %K WOMEN %X PURPOSE: %B Cancer Causes Control %V 23 %P 1323 - 1331 %8 17/6/2012 %G eng %N 8 %1 32195 %& 1323 %R http://dx.doi.org/ %0 Journal Article %J Cancer Cytopathol %D 2012 %T p16INK4a immunocytochemistry versus human papillomavirus testing for triage of women with minor cytologic abnormalities: a systematic review and meta-analysis. %A Roelens, Jolien %A Reuschenbach, Miriam %A von Knebel Doeberitz, Magnus %A Wentzensen, Nicolas %A Bergeron, Christine %A M. Arbyn %K Cervical Intraepithelial Neoplasia %K Cervix Uteri %K Cyclin-Dependent Kinase Inhibitor p16 %K DNA, Viral %K Female %K Human Papillomavirus DNA Tests %K Humans %K immunohistochemistry %K Papillomaviridae %K Sensitivity and Specificity %K triage %K Uterine Cervical Neoplasms %X

The best method for identifying women who have minor cervical lesions that require diagnostic workup remains unclear. The authors of this report performed a meta-analysis to assess the accuracy of cyclin-dependent kinase inhibitor 2A (p16(INK4a)) immunocytochemistry compared with high-risk human papillomavirus DNA testing with Hybrid Capture 2 (HC2) to detect grade 2 or greater cervical intraepithelial neoplasia (CIN2+) and CIN3+ among women who had cervical cytology indicating atypical squamous cells of undetermined significance (ASC-US) or low-grade cervical lesions (LSIL). A literature search was performed in 3 electronic databases to identify studies that were eligible for this meta-analysis. Seventeen studies were included in the meta-analysis. The pooled sensitivity of p16(INK4a) to detect CIN2+ was 83.2% (95% confidence interval [CI], 76.8%-88.2%) and 83.8% (95% CI, 73.5%-90.6%) in ASC-US and LSIL cervical cytology, respectively, and the pooled specificities were 71% (95% CI, 65%-76.4%) and 65.7% (95% CI, 54.2%-75.6%), respectively. Eight studies provided both HC2 and p16(INK4a) triage data. p16(INK4a) and HC2 had similar sensitivity, and p16(INK4a) has significantly higher specificity in the triage of women with ASC-US (relative sensitivity, 0.95 [95% CI, 0.89-1.01]; relative specificity, 1.82 [95% CI, 1.57-2.12]). In the triage of LSIL, p16(INK4a) had significantly lower sensitivity but higher specificity compared with HC2 (relative sensitivity, 0.87 [95% CI, 0.81-0.94]; relative specificity, 2.74 [95% CI, 1.99-3.76]). The published literature indicated the improved accuracy of p16(INK4a) compared with HC2 testing in the triage of women with ASC-US. In LSIL triage, p16(INK4a) was more specific but less sensitive.

%B Cancer Cytopathol %V 120 %P 294-307 %8 2012 Oct 25 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/22700382?dopt=Abstract %R 10.1002/cncy.21205 %0 Journal Article %J Infect.Dis.Obstet.Gynecol. %D 2012 %T Prevention of human papillomavirus-related malignancies of the female genital tract %A Koliopoulos,G. %A M. Arbyn %K cancer %K cervix %K cit_Marbyn %K epub %K Female %K HPV %K Human %K prevention %K REVIEW %B Infect.Dis.Obstet.Gynecol. %V 2011 %8 5/4/2012 %G eng %1 32221 %R http://dx.doi.org/ %0 Journal Article %J BMJ %D 2012 %T Primary screening for human papillomavirus compared with cytology screening for cervical cancer in European settings: cost effectiveness analysis based on a Dutch microsimulation model %A de Kok,I.M. %A van Rosmalen,J. %A Dillner,J. %A M. Arbyn %A Sasieni,P. %A Iftner,T. %A van Ballegooijen,M. %K age %K Analyses %K analysis %K Belgian Foundation Against Cancer %K cancer %K Case %K cervical cancer %K cervix %K cit_Marbyn %K Combination %K Cost %K Cost-effectiveness %K COSTS %K Countries %K cytology %K Design %K ECCG %K epub %K Europe %K European %K European countries %K health %K HPV %K Human %K IS %K LEVEL %K levels %K Life %K measure %K measures %K medical %K MODEL %K Netherlands %K objectives %K ON %K outcome %K POLICIES %K POLICY %K POPULATION %K PREHDICT %K prevalence %K primary screening %K public %K public health %K Public-health %K Quality %K Ratio %K Ratios %K result %K results %K risk %K SCREENING %K SENSITIVITY %K situation %K Strategies %K Strategy %K Term %K Test %K threshold %K triage %K Universities %K university %K variables %K WOMEN %X 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 %B BMJ %V 344 %P e670 %8 5/3/2012 %G eng %1 32291 %& e670 %R http://dx.doi.org/10.1136/bmj.e670 %0 Generic %D 2012 %T Publications of the EUROCHIP-3 project on cervical cancer in Romania, Bulgaria, Estonia, Lithuania and Latvia %A M. Arbyn %E Instituto Nazionale Tumori %K Bulgaria %K cancer %K Cervical %K cervical cancer %K CERVICAL-CANCER %K EUROCHIP-3 %K European %K health %K Health indicator %K Indicator %K ON %K publication %K symposium %B Symposium of the European Cancer Health Indicator Project %8 27/2/2012 %G eng %N Instituto Nazionale Tumori %1 35314 %2 26/02/2012 - 27/02/2012 %0 Journal Article %J BJOG. %D 2012 %T The thickness and volume of LLETZ specimens can predict the relative risk of pregnancy-related morbidity %A Khalid,S. %A Dimitriou,E. %A Conroy,R. %A Paraskevaides,E. %A Kyrgiou,M. %A Harrity,C. %A M. Arbyn %A Prendiville,W. %K age %K an %K analysis %K AS %K association %K at %K Belgium %K birth %K Brussels %K cancer %K Case %K cervix %K CI %K cit_Marbyn %K complications %K criteria %K data %K Design %K effect %K FNRS %K health %K hospital %K HPV %K Increase %K Infant %K Infants %K Institute %K Ireland %K LLETZ %K Logistic %K logistic regression %K Logistic-regression %K M %K measure %K measures %K method %K methods %K morbidity %K Objective %K obstetrical outcomes %K ON %K outcome %K Paper %K physical %K POPULATION %K population health %K Pregnancies %K Pregnancy %K PREHDICT %K premature %K public %K public health %K Public-health %K RATES %K regression %K relative %K Relative risk %K report %K result %K results %K risk %K S %K Science %K Service %K SMOKING %K study %K teaching %K Term %K time %K treatment %K treatment of CIN %K UK %K Universities %K university %K WHO %K WOMEN %X Objective %B BJOG. %V 119 %P 685 - 691 %8 0/5/2012 %G eng %N 6 %1 32241 %& 685 %R http://dx.doi.org/10.1111/j.1471-0528.2011.03252.x %0 Journal Article %J Methods Mol Biol %D 2011 %T Cervical cytology biobanks as a resource for molecular epidemiology. %A M. Arbyn %A Andersson, Kristin %A Bergeron, Christine %A Bogers, John-Paul %A von Knebel-Doebertitz, Magnus %A Dillner, Joakim %K Biological Specimen Banks %K Cervix Uteri %K Female %K Humans %K Molecular Epidemiology %K Papanicolaou Test %K Papillomavirus Infections %K Vaginal Smears %X

A cervical cytology biobank (CCB) is an extension of current cytopathology laboratory practice consisting in the systematic storage of Pap smears or liquid-based cytology samples from women participating in cervical cancer screening with the explicit purpose of facilitating future scientific research and quality audit of preventive services. A CCB should use an internationally agreed uniform cytology terminology, be integrated in a national or regional screening registry, and linked to other registries (histology, cancer, and vaccination). Legal and ethical principles concerning personal integrity and data safety must be respected strictly. Biobank-based studies require approval from ethical review boards. A CCB constitutes a nearly inexhaustible resource to perform fundamental and applied biologic research. In particular, it can contribute in answering questions on the natural history of HPV infection and HPV-induced lesions and cancers, screening effectiveness, exploration of new biomarkers, and surveillance of short- and long-term effects of the introduction of HPV vaccination. To understand the limitations of CCB, more studies are needed on quality of samples in relation to sample type, storage procedures, and duration of storage.

%B Methods Mol Biol %V 675 %P 279-98 %8 2011 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/20949396?dopt=Abstract %R 10.1007/978-1-59745-423-0_15 %0 Journal Article %J Eur J Cancer Prev %D 2011 %T Cytological screening for cervical cancer in the province of Limburg, Belgium. %A M. Arbyn %A An Van Nieuwenhuyse %A Bogers, Johannes %A De Jonge, Eric %A De Beeck, Lode Op %A Matheï, Catharina %A Buntinx, Frank %K Adult %K Belgium %K Female %K Humans %K Mass Screening %K middle aged %K Neoplasms, Squamous Cell %K Papanicolaou Test %K REGISTRIES %K Uterine Cervical Neoplasms %K Vaginal Smears %X

Cervical cancer screening in Belgium is mainly opportunistic with periodic attempts to organize it according to the European guidelines. In the province of Limburg (north-east Belgium), a cervical cytology registry was set up in collaboration with local cytopathological laboratories, provincial health authorities and the Limburg Cancer Registry. Laboratories regularly communicated coded results of Pap smears from women residents in Limburg to the provincial cytological registry. All individual records contained a virtually unique identifying code allowing the study of longitudinal histories and linkage with the cancer registry. The screening coverage (percentage of women with a Pap smear in a defined period), the prevalence and incidence of squamous intraepithelial lesions and changes over time and geographical area were evaluated using a database of more than 600 000 Pap smear interpretations between 1996 and 2005. In 2000, 47% of women aged between 25 and 64 years had at least one Pap smear recorded in the last 3 years, and the average number of smears screened for each woman was 1.5. On account of incomplete registration, the coverage was 8% lower than estimated from health insurance data. The modal screening interval was in the range of 12-14 months; the first quartile, median and third quartile were 355, 440 and 676 days, respectively. Over the 10 years, 82% of the target population had their Pap smear recorded. The prevalence of cytological abnormalities was 3.7% (atypical squamous cells of undetermined significance: 2.2%, atypical glandular cells of undetermined significance: 0.1%, low-grade squamous intraepithelial lesion: 1.1%, high-grade squamous intraepithelial lesion or more serious lesions: 0.4%), but varied substantially among laboratories. The prevalence of atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion increased significantly over time. Pathologists from Limburg have pioneered cytology registration in the context of opportunistic screening in Belgium. The estimated screening coverage was slightly underestimated. Obligatory registration, use of a uniform terminology and linkage with population and follow-up data are needed to give a cytology registry its full role in an organized screening programme.

%B Eur J Cancer Prev %V 20 %P 18-24 %8 2011 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20805755?dopt=Abstract %R 10.1097/CEJ.0b013e32833ecbc6 %0 Report %D 2011 %T Prevention of Cervical Cancer in Belgium: Anno 2011 %A M. Arbyn %A Viviane Van Casteren %A Van Hoof,E. %K Belgium %K cancer %K cervical cancer %K cervix %K HPV %K incidence %K mortality %K prevention %K SCREENING %K Vaccination %I WIV-ISP %C Brussels %V 2010/010 %P 118 %8 0/0/2011 %@ D/2011/2505/79 %G eng %1 35170 %& 1 %0 Journal Article %J Cochrane Database Syst Rev %D 2011 %T Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. %A M. Arbyn %A L Xu %A Cindy Simoens %A Martin-Hirsch, Pierre Pl %A Bryant, Andrew %A Beutels, Philippe %A Paraskevaidis, Evangelos %A van Hoof, Elke %A Steben, Marc %A Qiao, Youlin %A Zhao, Fang-Hui %A Schneider, Achim %A Kaufmann, Andreas %A Dillner, Joakim %A Markowitz, Lauri %A Hildesheim, Allan %K clinical efficacy %K immunogenicity %K prophylactic HPV vaccines %X

This is the protocol for a review and there is no abstract. The objectives are as follows: To evaluate the immunogenicity, clinical efficacy, and safety of prophylactic HPV vaccines in females. The assessment of clinical efficacy will address protection against HPV infection (for homologous and heterologous HPV types), against re-infection, against cervical cancer and its precursors (high-grade CIN (grade 2 or grade 3), adenocarcinoma in situ) in women previously not exposed to HPV infection (negative at enrolment for both HPV DNA and antibodies against the vaccine HPV types). We will assess clinical effectiveness by evaluating outcomes in all women, irrespective of the HPV DNA or serology status at enrolment. Evaluation by fine age and time since sexual debut categories is also planned.

%B Cochrane Database Syst Rev %V 2011 %8 2011 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25267916?dopt=Abstract %R 10.1002/14651858.CD009069 %0 Report %D 2011 %T Prophylactic vaccination of girls and female adolescents against human papilomavirus infection (Belgium, 2007-2009) %A M. Arbyn %A Cindy Simoens %A Fabri,V. %A Béatrice Swennen %K ADOLESCENT %K Adolescents %K Belgium %K cancer %K cervix %K Female %K Girls %K HPV %K Human %K INFECTION %K Vaccination %K vaccination coverage %I WIV-ISP; Agence Intermutualiste/Intermutualistisch Agentschap (AIM/IMA) %C Brussels %P 50 %8 0/0/2011 %G eng %1 35171 %& 1 %0 Journal Article %J BJOG %D 2011 %T Treatment of cervical cancer precursors: influence of age, completeness of excision and cone depth on therapeutic failure, and on adverse obstetric outcomes. %A M. Arbyn %A Cindy Simoens %A Goffin, F %A B Noehr %A F Bruinsma %K Adult %K Age factors %K Female %K Humans %K Pregnancy %K Premature Birth %K Treatment Outcome %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %B BJOG %V 118 %8 2011 Sep %G eng %N 10 %R 10.1111/j.1471-0528.2011.03068.x %0 Journal Article %J Int J Cancer %D 2011 %T Trends in cervical cancer incidence and mortality in the Baltic countries, Bulgaria and Romania. %A M. Arbyn %A Jérôme Antoine %A Mägi, Margit %A Smailyte, Giedre %A Stengrevics, Aivars %A Suteu, Ofelia %A Valerianova, Zdravka %A Bray, Freddie %A Weiderpass, Elisabete %K Adult %K Age factors %K Aged %K Baltic States %K Bulgaria %K Cohort Studies %K Female %K Humans %K incidence %K middle aged %K Neoplasm Invasiveness %K Prognosis %K Risk Factors %K Romania %K Survival Rate %K Uterine Cervical Neoplasms %K Young adult %X

The burden of cervical cancer varies considerably in the European Union (EU). In this article, we describe trends in incidence of and mortality from this cancer in the two most affected areas: the Baltic countries (Estonia, Latvia and Lithuania) and Southeast Europe (Bulgaria and Romania). Incidence data were obtained from the national cancer registries. Data on population and number of deaths from uterine cancers were extracted from the World Health Organization mortality database. Mortality rates were corrected for inaccuracies in the death certification of not otherwise specified uterine cancer. Joinpoint regression was used to study the annual variation of corrected and standardized incidence and mortality rates. Changes were assessed by calendar period and age group, whereas the evolution by birth cohort was synthesized by computing standardized cohort incidence/mortality ratios. Joinpoint regression revealed rising trends of incidence (in Lithuania, Bulgaria and Romania) and of mortality (in Latvia, Lithuania, Bulgaria and Romania). In Estonia, rates were rather stable. Women born between 1940 and 1960 were at continuously increasing risk of both incidence of and mortality from cervical cancer. Although some quality issues in the registration of cancer and causes of death cannot be ignored, the trends indicate increased exposure to human papillomavirus infection and absence of effective screening programs. Rising trends of cervical cancer in the most affected EU member states reveal a worrying pattern that warrants urgent preventive actions.

%B Int J Cancer %V 128 %P 1899-907 %8 2011 Apr 15 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/20568103?dopt=Abstract %R 10.1002/ijc.25525 %0 Journal Article %J Ann Oncol %D 2011 %T Worldwide burden of cervical cancer in 2008. %A M. Arbyn %A Castellsagué, X %A de Sanjosé, S %A Bruni, L %A Saraiya, M %A Bray, F %A Ferlay, J %K Alphapapillomavirus %K Female %K Humans %K incidence %K Papillomavirus Infections %K prevalence %K Uterine Cervical Neoplasms %X

BACKGROUND: The knowledge that persistent human papillomavirus infection is the main cause of cervical cancer has resulted in the development of assays that detect nucleic acids of the virus and prophylactic vaccines. Up-to-date and reliable data are needed to assess impact of existing preventive measures and to define priorities for the future.

MATERIALS AND METHODS: Best estimates on cervical cancer incidence and mortality are presented using recently compiled data from cancer and mortality registries for the year 2008.

RESULTS: There were an estimated 530,000 cases of cervical cancer and 275,000 deaths from the disease in 2008. It is the third most common female cancer ranking after breast (1.38 million cases) and colorectal cancer (0.57 million cases). The incidence of cervical cancer varies widely among countries with world age-standardised rates ranging from <1 to >50 per 100,000. Cervical cancer is the leading cause of cancer-related death among women in Eastern, Western and Middle Africa; Central America; South-Central Asia and Melanesia. The highest incidence rate is observed in Guinea, with ∼6.5% of women developing cervical cancer before the age of 75 years. India is the country with the highest disease frequency with 134,000 cases and 73 000 deaths. Cervical cancer, more than the other major cancers, affects women <45 years.

CONCLUSIONS: In spite of effective screening methods, cervical cancer continues to be a major public health problem. New methodologies of cervical cancer prevention should be made available and accessible for women of all countries through well-organised programmes.

%B Ann Oncol %V 22 %P 2675-86 %8 2011 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21471563?dopt=Abstract %R 10.1093/annonc/mdr015 %0 Report %D 2010 %T Analysis of individual health insurance data pertaining to pap smears, colposcopies, biopsies and surgery on the uterine cervix (Belgium 2002-2006) %A M. Arbyn %A Cindy Simoens %A Fabri,V. %K analysis %K Belgium %K Biopsy %K cervix %K Colposcopy %K data %K health %K insurance %K ON %K surgery %I WIV-ISP %C Brussels %P 125 %8 0/9/2010 %@ D/2010/2505/42 %G eng %1 33823 %2 2010-021 %0 Journal Article %J Int J Biol Markers %D 2010 %T Cervical cytology biobanking in Europe. %A M. Arbyn %A Evert-Ben Van Veen %A Andersson, Kristin %A Bogers, Johannes %A Boulet, Gaëlle %A Bergeron, Christine %A von Knebel-Doeberitz, Magnus %A Dillner, Joakim %K Alphapapillomavirus %K Biological Specimen Banks %K Cervix Uteri %K Dna %K Europe %K Female %K Guidelines as Topic %K Humans %K Medical Record Linkage %K Molecular Diagnostic Techniques %K Papanicolaou Test %K Papillomavirus Infections %K Papillomavirus Vaccines %K REGISTRIES %K Rna %K specimen handling %K Terminology as Topic %K Uterine Cervical Neoplasms %K Uterine Cervicitis %K Vaginal Smears %X

A cervical cytology biobank (CCB) is an extension of current cytopathology laboratory practice consisting in the systematic storage of Pap smears or liquid-based cytology samples from women participating in cervical cancer screening with the explicit purpose to facilitate future scientific research and quality audit of preventive services. A CCB should use an internationally agreed uniform cytology terminology, be integrated in a national or regional screening registry, and be linked to other registries (histology, cancer, vaccination). Legal and ethical principles concerning personal integrity and data safety must be respected strictly. Biobank-based studies require approval of ethical review boards. A CCB is an almost inexhaustible resource for fundamental and applied biological research. In particular, it can contribute to answering questions on the natural history of HPV infection and HPV-induced lesions and cancers, screening effectiveness, exploration of new biomarkers, and surveillance of the short- and long-term effects of the introduction of HPV vaccination. To understand the limitations of CCB, more studies are needed on the quality of samples in relation to sample type, storage procedures, and duration of storage.

%B Int J Biol Markers %V 25 %P 117-25 %8 2010 Jul-Sep %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20872354?dopt=Abstract %0 Journal Article %J Ann Oncol %D 2010 %T European Guidelines for Quality Assurance in Cervical Cancer Screening. Second edition--summary document. %A M. Arbyn %A Anttila, A %A Jordan, J %A Ronco, G %A Schenck, U %A Segnan, N %A Wiener, H %A Herbert, A %A von Karsa, L %K Cervical Intraepithelial Neoplasia %K Europe %K Female %K Humans %K Mass Screening %K Quality Assurance, Health Care %K Uterine Cervical Neoplasms %X

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.

%B Ann Oncol %V 21 %P 448-58 %8 2010 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20176693?dopt=Abstract %R 10.1093/annonc/mdp471 %0 Journal Article %J BJOG %D 2010 %T Human papillomavirus-based triage of women showing a cervical cytology result of borderline or mild dyskaryosis. %A M. Arbyn %A Martin-Hirsch, P %A Wentzensen, N %K Adult %K Cervical Intraepithelial Neoplasia %K cross-sectional studies %K Female %K Humans %K middle aged %K Papillomavirus Infections %K triage %K Uterine Cervical Dysplasia %K Uterine Cervical Neoplasms %K Young adult %B BJOG %V 117 %P 641-4 %8 2010 May %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/20383875?dopt=Abstract %R 10.1111/j.1471-0528.2010.02521.x %0 Journal Article %J Evid Based Med %D 2010 %T Immediate colposcopy referral in women with low-grade abnormal results on cervical cytology detects more CIN2 or worse lesions than cytological surveillance in primary care, but might lead to overtreatment. %A M. Arbyn %A Martin-Hirsch, Pierre %A Buntinx, Frank %B Evid Based Med %V 15 %P 13-4 %8 2010 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20176871?dopt=Abstract %R 10.1136/ebm.15.1.13 %0 Journal Article %J Gynecol Obstet Invest %D 2010 %T Introduction of human papillomavirus vaccination in Belgium, Luxembourg and the Netherlands. %A M. Arbyn %A Cindy Simoens %A Van Damme, P %A Scharpantgen, A %A Meijer, C J L M %A Beutels, P %K ADOLESCENT %K Belgium %K Child %K Female %K HEALTH POLICY %K Humans %K Luxembourg %K Mass Vaccination %K Netherlands %K Papillomavirus Infections %K Papillomavirus Vaccines %K Reimbursement Mechanisms %K Uterine Cervical Diseases %K Uterine Cervical Neoplasms %X

AIMS: To document progress with human papillomavirus (HPV) vaccine introduction in three closely related European countries, one with organized (the Netherlands) and two with opportunistic cervical cancer screening (Belgium and Luxembourg).

METHODS: Experts involved in cervical cancer screening and national immunization programs from the three countries were contacted to provide information on the decision-making process concerning the introduction of HPV vaccine. Sales statistics were obtained from Intercontinental Marketing Services.

RESULTS: Advisory boards in all three countries advised organized HPV vaccination of girls of 12 years with variable catch-up policies. In Belgium, the national health authority partially reimburses the HPV vaccine for girls of 12-15 years (recently extended until 18 years). In Luxembourg, 12-year-old girls are invited for free vaccination, but the HPV vaccine is also free of charge for female adolescents of 13-17 years. The number of vaccines reimbursed in Belgium in December 2007 to May 2008 corresponds with the amount required to fully vaccinate 29% of the female population aged 12-15 years. In Luxembourg, between March and November 2008, the immunization program delivered a quantity of HPV vaccines which theoretically covered 29% of females aged 12-17 years. In the Netherlands, nationwide HPV vaccination of girls of 12 years will start in September 2009. The sales of HPV vaccines (all ages combined) were by far the lowest in the Netherlands.

CONCLUSION: Up to the end of 2008, HPV vaccination efforts reached less than a third of the target population in Belgium and Luxembourg. If the latest trend continues, the current policy is expected to reach to most half of the target population. Well-planned introduction of vaccination combined with an organized screening program and active surveillance are crucial for the program to achieve and monitor its desired aims. Such surveillance should include linkage between vaccination, screening and cancer registries.

%B Gynecol Obstet Invest %V 70 %P 224-32 %8 2010 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21051840?dopt=Abstract %R 10.1159/000314010 %0 Journal Article %J Prev Med %D 2009 %T Analysis of 13 million individual patient records pertaining to Pap smears, colposcopies, biopsies and surgery on the uterine cervix (Belgium, 1996-2000). %A M. Arbyn %A Cindy Simoens %A Herman Van Oyen %A Foidart, Jean-Michel %A Goffin, Frédéric %A Simon, Philippe %A Fabri, Valérie %K Adult %K Belgium %K Biopsy %K Colposcopy %K Female %K Humans %K Medical Audit %K middle aged %K Papanicolaou Test %K Uterine Neoplasms %K Vaginal Smears %X

OBJECTIVE: Cervical cancer screening by surveys overestimate coverage because of selection and reporting biases.

METHODS: The prepared Inter-Mutualistic Agency dataset has about 13 million records from Pap smears, colposcopies, cervical biopsies and surgery, performed in Belgium between 1996 and 2000. Cervical cancer screening coverage was defined as the proportion of the target population (women of 25-64 years) that has had a Pap smear taken within the last 3 years. Proportions and incidence rates were computed using official population data of the corresponding age group, area and calendar year.

RESULTS: Cervical cancer screening coverage, in the period 1998-2000, was 59% at national level, for the target age group 25-64 years. Differences were small between the 3 regions. Variation ranged from 39% to 71%. Coverage was 64% for 25-29 year old women, 67% for those aged 30-39 years, 56% for those aged 50-54. The modal screening interval was 1 year. In the 3-year period 1998-2000, 3 million smears were taken from the 2.7 million women in the age group 25-64. Only 1.6 million women of the target group got one or more smears in that period and 1.1 million women had no smears, corresponding to an average of 1.88 smears per woman.

CONCLUSION: Coverage reached only 59%, but the number of smears used was sufficient to cover more than 100% of the target population. Structural reduction of overuse and extension of coverage is warranted.

%B Prev Med %V 48 %P 438-43 %8 2009 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/19272405?dopt=Abstract %R 10.1016/j.ypmed.2009.02.021 %0 Journal Article %J Eur J Cancer %D 2009 %T The challenges of organising cervical screening programmes in the 15 old member states of the European Union. %A M. Arbyn %A Rebolj, Matejka %A De Kok, Inge M C M %A Fender, Murielle %A Becker, Nikolaus %A O'Reilly, Marian %A Andrae, Bengt %K Adult %K Aged %K Cervical Intraepithelial Neoplasia %K Cost-Benefit Analysis %K Europe %K European Union %K Female %K Forecasting %K Humans %K Mass Screening %K middle aged %K Prognosis %K Quality-Adjusted Life Years %K Uterine Cervical Neoplasms %X

Cervical cancer incidence and mortality can be reduced substantially by organised cytological screening at 3 to 5 year intervals, as was demonstrated in the Nordic countries, the United Kingdom, the Netherlands and parts of Italy. Opportunistic screening, often proposed at yearly schedules, has also reduced the burden of cervical cancer in some, but not all, of the other old member states (belonging to the European Union since 1995) but at a cost that is several times greater. Well organised screening programmes have the potential to achieve greater participation of the target population at regular intervals, equity of access and high quality. Despite the consistent evidence that organised screening is more efficient than non-organised screening, and in spite of the Cancer Screening Recommendations of the European Council, health authorities of eight old member states (Austria, Belgium, France, Germany, Greece, Luxembourg, Portugal and Spain) have not yet started national organised implementation of screening for cervical cancer. A decision was made by the Irish government to extend their pilot programme nationally while new regional programmes commenced in Portugal and Spain. Introduction of new methods of prevention, such as HPV screening and prophylactic HPV vaccination, can reduce the burden further, but this will require a high level of organisation with particular attention needed for the maximisation of population coverage, compliance with evidence-based guidelines, monitoring of data enabling continued evaluation and improvement of the preventive programmes.

%B Eur J Cancer %V 45 %P 2671-8 %8 2009 Oct %G eng %N 15 %1 http://www.ncbi.nlm.nih.gov/pubmed/19695867?dopt=Abstract %R 10.1016/j.ejca.2009.07.016 %0 Journal Article %J Archives of Public Health %D 2009 %T Description of cervical cancer mortality in Belgium using Bayesian age-period-cohort models. %A Raifu, A O %A M. Arbyn %K age-cohort-period modelling %K Bayesian analysis %K cervical cancer %K mortality %K trend analysis %X

OBJECTIVE: 
To correct cervical cancer mortality rates for death cause certification problems in Belgium and to describe the corrected trends (1954-1997) using Bayesian models.

METHOD: 
Cervical cancer (cervix uteri (CVX), corpus uteri (CRP), not otherwise specified (NOS) uterus cancer and other very rare uterus cancer (OTH) mortality data were extracted from the WHO mortality database together with population data for Belgium and the Netherlands.

Different ICD (International Classification of Diseases) were used over time for death cause certification. In the Netherlands, the proportion of not-otherwise specified uterine cancer deaths was small over large periods and therefore internal reallocation could be used to estimate the corrected rates cervical cancer mortality. In Belgium, the proportion of improperly defined uterus deaths was high. Therefore, the age-specific proportions of uterus cancer deaths that are probably of cervical origin for the Netherlands was applied to Belgian uterus cancer deaths to estimate the corrected number of cervix cancer deaths (corCVX).

A Bayesian loglinear Poisson-regression model was performed to disentangle the separate effects of age, period and cohort.

RESULTS:
The corrected age standardized mortality rate (ASMR) decreased regularly from 9.2/100 000 in the mid 1950s to 2.5/100,000 in the late 1990s. Inclusion of age, period and cohort into the models were required to obtain an adequate fit. Cervical cancer mortality increases with age, declines over calendar period and varied irregularly by cohort.

CONCLUSION:
Mortality increased with ageing and declined over time in most age-groups, but varied irregularly by birth cohort. In global, with some discrete exceptions, mortality decreased for successive generations up to the cohorts born in the 1930s. This decline stopped for cohorts born in the 1940s and thereafter. For the youngest cohorts, even a tendency of increasing risk of dying from cervical cancer could be observed, reflecting increased exposure to risk factors. The fact that this increase was limited for the youngest cohorts could be explained as an effect of screening.

Bayesian modeling provided similar results compared to previously used classical Poisson models. However, Bayesian models are more robust for estimating rates when data are sparse (youngest age groups, most recent cohorts) and can be used to for predicting future trends.

%B Archives of Public Health %V 67 %8 Jan-12-2009 %G eng %N 3 %R 10.1186/0778-7367-67-3-100 %0 Journal Article %J Int J Cancer %D 2009 %T How to evaluate emerging technologies in cervical cancer screening? %A M. Arbyn %A Ronco, Guglielmo %A Cuzick, Jack %A Wentzensen, Nicolas %A Castle, Philip E %K Clinical Trials as Topic %K Diagnostic Tests, Routine %K Female %K Humans %K Mass Screening %K Uterine Cervical Neoplasms %X

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: i) correlation studies establishing a trend between the rate of biomarker expression and severity of neoplasia; ii) diagnostic studies in a clinical setting where all women are submitted to verification by the reference standard; iii) biobank-based studies with assessment in archived cytology samples of the biomarker in cervical cancer cases and controls; iv) prospective cohort studies with baseline assessment of the biomarker and monitoring of disease; v) 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.

%B Int J Cancer %V 125 %P 2489-96 %8 2009 Dec 01 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/19626591?dopt=Abstract %R 10.1002/ijc.24774 %0 Journal Article %J Cancer Lett %D 2009 %T International agreement to join forces in synthesizing evidence on new methods for cervical cancer prevention. %A M. Arbyn %A Cuzick, Jack %K Carcinoma in Situ %K Female %K Humans %K Meta-Analysis as Topic %K Papillomavirus Infections %K Precancerous Conditions %K Randomized Controlled Trials as Topic %K risk %K Societies, Medical %K Uterine Cervical Neoplasms %X

Recently published baseline results of randomised controlled trials, comparing cytology with HPV-based cervical cancer screening, consistently show increased detection of high-grade cervical intraepithelial neoplasia (CIN) in the HPV-arm. These results are in line with the pooled estimates of the relative sensitivity derived from cross-sectional studies. From two randomised trials, also the longitudinal outcomes observed at the second screening round were reported. HPV-negative women, had a relative risk of developing CIN3 in the next 3 to 5 years, compared to cytology-negative women, of 0.53 (95% CI: 0.29-0.92) and 0.45 (95% CI: 0.28-0.67), respectively in the Swedish and Dutch trial. Consensus was reached at the Cochrane Workshop on Cervical Cancer Prevention, organized at the occasion of the 24th Conference of the International Papillomavirus Society, to join forces to conduct future meta-analyses of the HPV screening trials and to synthesize evidence on new methods for cervical cancer prevention.

%B Cancer Lett %V 278 %P 1-2 %8 2009 Jun 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/18930588?dopt=Abstract %R 10.1016/j.canlet.2008.09.002 %0 Journal Article %J Euro Surveill %D 2009 %T Introduction of human papillomavirus (HPV) vaccination in Belgium, 2007-2008. %A Cindy Simoens %A Martine Sabbe %A Van Damme, P %A Beutels, P %A M. Arbyn %K ADOLESCENT %K Adult %K Belgium %K Carcinoma, Squamous Cell %K Child %K Female %K Guideline Adherence %K HEALTH POLICY %K Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 %K Humans %K Insurance, Health, Reimbursement %K Mass Vaccination %K Papillomavirus Infections %K Papillomavirus Vaccines %K Practice Guidelines as Topic %K School Health Services %K Uterine Cervical Neoplasms %K Young adult %X

This paper documents the progress of human papillomavirus (HPV) vaccine introduction in Belgium. Information on vaccine use is based on sales statistics and reimbursement claims. From November 2007 to November 2008, the National Institute for Health and Disability Insurance reimbursed the HPV vaccine for girls aged between 12-15 years. In December 2008, the age limit was extended to include girls up to the age of 18. In November 2008, the total number of HPV vaccines sold exceeded 530,000 doses. The number of vaccines reimbursed in Belgium, for the period November 2007-November 2008, corresponds to the amount required to fully vaccinate 44% of all girls aged between 12-15 years. However, the trend was decreasing over the last 10 months. By the current reimbursement policy, we can expect that maximum half of the target population can be reached. In Flanders (one of the three Communities in Belgium), the intention is to start, from September 2010, with a free school-based HPV immunisation for girls in the first year of secondary school (12 years of age), complemented with vaccination by a physician of choice. This strategy ensures a higher HPV vaccine coverage which is expected to be as high as the current coverage in the hepatitis B vaccination programme (approximately 80%) offered to boys and girls in the same age group and under the same circumstances.

%B Euro Surveill %V 14 %8 2009 Nov 19 %G eng %N 46 %1 http://www.ncbi.nlm.nih.gov/pubmed/19941796?dopt=Abstract %0 Journal Article %J Cancer Epidemiol Biomarkers Prev %D 2009 %T Prevaccination distribution of human papillomavirus types in women attending at cervical cancer screening in Belgium. %A M. Arbyn %A Benoy, Ina %A Cindy Simoens %A Bogers, Johannes %A Beutels, Philippe %A Depuydt, Christophe %K ADOLESCENT %K Adult %K Aged %K Aged, 80 and over %K Analysis of Variance %K Belgium %K Chi-Square Distribution %K cross-sectional studies %K Early Detection of Cancer %K Female %K Humans %K middle aged %K Papillomaviridae %K Papillomavirus Infections %K Papillomavirus Vaccines %K prevalence %K Reverse Transcriptase Polymerase Chain Reaction %K Uterine Cervical Neoplasms %X

INTRODUCTION: Before the introduction of vaccination against human papillomaviruses (HPV) as a new strategy of combating cervical cancer, it is required to describe the baseline prevalence of HPV infection as well as the distribution of the different HPV types in the population and among women with cervical lesions.

MATERIALS AND METHODS: Approximately 10,000 liquid cervical cell samples from women, resident of Flanders (North Belgium) and participating in cervical cancer screening, were assessed cytologically and virologically with a multiplex real-time PCR using primers targeting the E6/E7 genes of 16 HPV types. Correlations of HPV infection with age, geographic area, and occurrence of cytologic lesions were assessed.

RESULTS: The prevalence of cytologic abnormalities was atypical squamous cells of undetermined significance (ASC-US), 1.6%; atypical glandular cells (AGC), 0.2%; low-grade squamous intraepithelial lesion (LSIL), 2.6%; atypical squamous cells, HSIL cannot be excluded (ASC-H), 0.3%; and high-grade squamous intraepithelial lesion (HSIL), 1.2%. The frequency of high-risk HPV infections was 11% in women without cytologic abnormalities, 77% in ASC-US, 32% in AGC, 85% in LSIL, and 93% in ASC-H and HSIL. The prevalence of high-risk HPV infection was highest in women of ages 20 to 24 years (29%) and decreased progressively with age. The percentage of women with HSIL in the entire study population attributable to infection with a particular type (AR(pop) %) was highest for HPV16 (32%), followed by HPV31 (22%), HPV39 (11%), and HPV52 (11%). HPV18 was responsible for 7% of the HSIL lesions. Elimination of HPV16 and HPV18 is expected to reduce the prevalence of ASCUS with 24%, AGC with 19%, LSIL with 29%, ASC-H with 31% and HSIL with 37%.

DISCUSSION: Compared to other West European studies, the prevalence of HPV infection was considerably higher in cytologically negative women but similar in women with cervical lesions. These differences could be due to the use of a PCR with high analytic sensitivity. These data are relevant for estimating the expected and theoretical levels of vaccine protection offered as vaccinated girls gradually age into the groups from which our observations stem. Further periodic laboratory-based surveys, including genotyping of cervical cell samples and linkage with vaccine registries, are an important resource to address pending questions of the effect of HPV vaccination. Research is warranted to disentangle the causal role of individual HPV types in case of multiple infections.

%B Cancer Epidemiol Biomarkers Prev %V 18 %P 321-30 %8 2009 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/19124515?dopt=Abstract %R 10.1158/1055-9965.EPI-08-0510 %0 Journal Article %J Eur J Cancer %D 2009 %T Trends of cervical cancer mortality in the member states of the European Union. %A M. Arbyn %A Raifu, Amidu O %A Weiderpass, Elisabete %A Bray, Freddie %A Ahti Anttila %K Adult %K Age Distribution %K Aged %K Aged, 80 and over %K Europe %K European Union %K Female %K Humans %K middle aged %K mortality %K Uterine Cervical Neoplasms %K Young adult %X

BACKGROUND: Cervical cancer mortality can be avoided to a large extent by screening and treatment of screen-detected cervical lesions. However, in 2004, more than 16,000 women died from cervical cancer in the European Union (EU). In the current paper, we analyse cervical cancer mortality trends in the 27 member states since 1970 and, subsequently, try to explain how screening and other factors have driven changes.

METHODS: Data on number of deaths from uterine cancers and overall female populations from EU member states were extracted from the World Health Organisation mortality database. Three different reallocation rules were applied to correct cervical cancer mortality for inaccuracies in certification of cause of death of not otherwise specified uterine cancer. Joinpoint regression was used to study annual variation of corrected cervical cancer mortality in all member states. We distinguished the 15 old from the 12 new member states, which acceded to the EU in 2004 or later. For Finland, France and Romania, age-specific trends by calendar period and the standardised cohort mortality ratios by birth cohort were analysed.

RESULTS: Corrected age-standardised cervical cancer mortality rates have decreased significantly over the past decades in the old member states. Member states in Eastern Europe and also the Baltic states showed mortality rates that decreased at a lower intensity (Czech Republic, Poland), remained constant at a high rate (Estonia, Slovakia) or even increased (Bulgaria, Latvia, Lithuania, Romania). The standardised cohort mortality ratio indicated that mortality does not decrease further or even increase among women born after 1940.

CONCLUSION: Remarkable contrasts were observed on cervical cancer mortality, in particular, between the old and new member states of the EU, which might probably be explained by differences in preventive strategies. This contrast might increase in the future, unless adequate preventive measures are adopted.

%B Eur J Cancer %V 45 %P 2640-8 %8 2009 Oct %G eng %N 15 %1 http://www.ncbi.nlm.nih.gov/pubmed/19695864?dopt=Abstract %R 10.1016/j.ejca.2009.07.018 %0 Journal Article %J J Cell Mol Med %D 2009 %T Triage of women with equivocal or low-grade cervical cytology results: a meta-analysis of the HPV test positivity rate. %A M. Arbyn %A Martin-Hirsch, Pierre %A Buntinx, Frank %A Van Ranst, Marc %A Paraskevaidis, Evangelos %A Dillner, Joakim %K ADOLESCENT %K Adult %K Aged %K Female %K Humans %K middle aged %K Papillomaviridae %K Roc Curve %K triage %K Vaginal Smears %X

Consistent evidence underlines the utility of human papillomavirus (HPV) DNA testing in the management of women with equivocal cervical cytological abnormalities, but not in case of low-grade lesions. We performed a meta-analysis including studies where the high-risk probe of the Hybrid Capture-II is used to triage these two cytological categories. The triage test-positivity rate reflects the colposcopy referral workload.Data were pooled on the HPV test positivity rate in women with atypical squamous cells of undetermined significance (ASCUS/ASC-US) or low-grade squamous intraepithelial lesions (LSIL), derived from different cytological classification systems. The meta-analysis was restricted to studies, published between 1991 and 2007. A random-effect model was applied for meta-analytical pooling and the influence of covariates on the HPV positivity rate was analyzed by meta-regression. The variation by age was assessed within individual studies since age strata were not defined uniformly. On an average, 43% (95% CI: 40-46%) of women with ASCUS/ASC-US were high-risk HPV positive (range 23-74%). In women with LSIL, the pooled positivity rate was 76% (95% CI: 71-81%; range 55-89%). In spite of considerable inter-study heterogeneity, the difference in HPV positivity between the two triage groups was large and highly significant: 32% (95% CI: 27-38%). HPV rates dropped tremendously as age and cutoffs of test positivity increased. Other factors (cytological classification system, country, continent, collection method and year of publication) had no statistically significant impact, except in LSIL triage where HPV positivity was significantly lower in European compared to American studies. Women with LSIL, especially younger women, have high HPV positivity rates suggesting limited utility of reflex HPV triaging these cases. Research is needed to identify more specific methods to triage women with low-grade squamous cervical lesions.

%B J Cell Mol Med %V 13 %P 648-59 %8 2009 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/19166485?dopt=Abstract %R 10.1111/j.1582-4934.2008.00631.x %0 Journal Article %J Obstet Gynecol %D 2008 %T Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. %A M. Arbyn %A Bergeron, Christine %A Klinkhamer, Paul %A Martin-Hirsch, Pierre %A Siebers, Albertus G %A Bulten, Johan %K Cervical Intraepithelial Neoplasia %K Colposcopy %K Female %K Humans %K Mass Screening %K Randomized Controlled Trials as Topic %K Sensitivity and Specificity %K specimen handling %K Uterine Cervical Neoplasms %K Vaginal Smears %X

OBJECTIVE: To compare test performance characteristics of conventional Pap tests and liquid-based cervical cytology samples.

DATA SOURCES: Eligible studies, published between 1991 and 2007, were retrieved through PubMed/EmBase searching and completed by consultation of other sources.

METHODS OF STUDY SELECTION: Studies were selected if a conventional and a liquid-based sample were prepared from the same woman or when one or the other type of sample was taken from a separate but similar cohort. The current systematic review and meta-analysis is restricted to studies where all subjects were submitted to gold standard verification, based on colposcopy and histology of colposcopy-targeted biopsies, allowing computation of absolute and relative test validity for cervical intraepithelial neoplasia grade 2 or worse. Randomized trials were selected as well if all test-positive cases were verified with the same gold standard, allowing computation of the relative sensitivity. Impact of study characteristics on accuracy was assessed by subgroup meta-analyses, meta-regression, and summary receiver operating characteristic curve regression.

TABULATION, INTEGRATION, AND RESULTS: The relative sensitivity, pooled from eight studies, with complete gold standard verification and from one randomized clinical trial, did not differ significantly from unity. Also, the specificity, considering high-grade and low-grade squamous intraepithelial lesions as cutoff, was similar in conventional and liquid cytology. However, a lower pooled specificity was found for liquid-based cytology when presence of atypical squamous cells of undetermined significance was the cutoff (ratio 0.91, 95% confidence interval 0.84-0.98). Differences in study characteristics did not explain interstudy heterogeneity.

CONCLUSION: Liquid-based cervical cytology is neither more sensitive nor more specific for detection of high-grade cervical intraepithelial neoplasia compared with the conventional Pap test.

%B Obstet Gynecol %V 111 %P 167-77 %8 2008 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/18165406?dopt=Abstract %R 10.1097/01.AOG.0000296488.85807.b3 %0 Journal Article %J BMJ %D 2008 %T Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. %A M. Arbyn %A Kyrgiou, M %A Cindy Simoens %A Raifu, A O %A Koliopoulos, G %A Martin-Hirsch, P %A Prendiville, W %A Paraskevaidis, E %K Cervical Intraepithelial Neoplasia %K Female %K Humans %K Infant, Low Birth Weight %K Infant, Newborn %K Obstetric Labor, Premature %K Obstetric Surgical Procedures %K Perinatal Mortality %K Pregnancy %K Pregnancy Complications, Neoplastic %K Pregnancy Outcome %K Risk Factors %K Uterine Cervical Neoplasms %X

OBJECTIVE: To assess the relative risk of perinatal mortality, severe preterm delivery, and low birth weight associated with previous treatment for precursors of cervical cancer.

DATA SOURCES: Medline and Embase citation tracking from January 1960 to December 2007. Selection criteria Eligible studies had data on severe pregnancy outcomes for women with and without previous treatment for cervical intraepithelial neoplasia. Considered outcomes were perinatal mortality, severe preterm delivery (<32/34 weeks), extreme preterm delivery (<28/30 weeks), and low birth weight (<2000 g, <1500 g, and <1000 g). Excisional and ablative treatment procedures were distinguished.

RESULTS: One prospective cohort and 19 retrospective studies were retrieved. Cold knife conisation was associated with a significantly increased risk of perinatal mortality (relative risk 2.87, 95% confidence interval 1.42 to 5.81) and a significantly higher risk of severe preterm delivery (2.78, 1.72 to 4.51), extreme preterm delivery (5.33, 1.63 to 17.40), and low birth weight of <2000 g (2.86, 1.37 to 5.97). Laser conisation, described in only one study, was also followed by a significantly increased chance of low birth weight of <2000 g and <1500 g. Large loop excision of the transformation zone and ablative treatment with cryotherapy or laser were not associated with a significantly increased risk of serious adverse pregnancy outcomes. Ablation by radical diathermy was associated with a significantly higher frequency of perinatal mortality, severe and extreme preterm delivery, and low birth weight below 2000 g or 1500 g.

CONCLUSIONS: In the treatment of cervical intraepithelial neoplasia, cold knife conisation and probably both laser conisation and radical diathermy are associated with an increased risk of subsequent perinatal mortality and other serious pregnancy outcomes, unlike laser ablation and cryotherapy. Large loop excision of the transformation zone cannot be considered as completely free of adverse outcomes.

%B BMJ %V 337 %P a1284 %8 2008 Sep 18 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/18801868?dopt=Abstract %R 10.1136/bmj.a1284 %0 Journal Article %J Int J Cancer %D 2008 %T Pooled analysis of the accuracy of five cervical cancer screening tests assessed in eleven studies in Africa and India. %A M. Arbyn %A Sankaranarayanan, Rengaswamy %A Muwonge, Richard %A Keita Namory %A Dolo, Amadou %A Mbalawa, Charles Gombe %A Nouhou, Hassan %A Sakande, Boblewende %A Wesley Ramani %A Somanathan, Thara %A Sharma, Anjali %A Shastri, Surendra %A Basu, Parthasarathy %K Africa %K Alphapapillomavirus %K Cervical Intraepithelial Neoplasia %K Coloring Agents %K DNA, Viral %K Female %K Humans %K India %K Iodides %K Mass Screening %K Papanicolaou Test %K Reagent Kits, Diagnostic %K Sensitivity and Specificity %K Tumor Virus Infections %K Uterine Cervical Neoplasms %K Vaginal Smears %X

Cervical cancer is the main cancer among women in sub-Saharan Africa, India and other parts of the developing world. Evaluation of screening performance of effective, feasible and affordable early detection and management methods is a public health priority. Five screening methods, naked eye visual inspection of the cervix uteri after application of diluted acetic acid (VIA), or Lugol's iodine (VILI) or with a magnifying device (VIAM), the Pap smear and human papillomavirus testing with the high-risk probe of the Hybrid Capture-2 assay (HC2), were evaluated in 11 studies in India and Africa. More than 58,000 women, aged 25-64 years, were tested with 2-5 screening tests and outcome verification was done on all women independent of the screen test results. The outcome was presence or absence of cervical intraepithelial neoplasia (CIN) of different degrees or invasive cervical cancer. Verification was based on colposcopy and histological interpretation of colposcopy-directed biopsies. Negative colposcopy was accepted as a truly negative outcome. VIA showed a sensitivity of 79% (95% CI 73-85%) and 83% (95% CI 77-89%), and a specificity of 85% (95% CI 81-89%) and 84% (95% CI 80-88%) for the outcomes CIN2+ or CIN3+, respectively. VILI was on average 10% more sensitive and equally specific. VIAM showed similar results as VIA. The Pap smear showed lowest sensitivity, even at the lowest cutoff of atypical squamous cells of undetermined significance (57%; 95% CI 38-76%) for CIN2+ but the specificity was rather high (93%; 95% CI 89-97%). The HC2-assay showed a sensitivity for CIN2+ of 62% (95% CI 56-68%) and a specificity of 94% (95% CI 92-95%). Substantial interstudy variation was observed in the accuracy of the visual screening methods. Accuracy of visual methods and cytology increased over time, whereas performance of HC2 was constant. Results of visual tests and colposcopy were highly correlated. This study was the largest ever done that evaluates the cross-sectional accuracy of screening tests for cervical cancer precursors in developing countries. The merit of the study was that all screened subjects were submitted to confirmatory investigations avoiding to verification bias. A major finding was the consistently higher sensitivity but equal specificity of VILI compared with VIA. Nevertheless, some caution is warranted in the interpretation of observed accuracy measures, since a certain degree of gold standard misclassification cannot be excluded. Because of the correlation between visual screening tests and colposcopy and a certain degree of over-diagnosis of apparent CIN2+ by study pathologists, it is possible that both sensitivity and specificity of VIA and VILI were overestimated. Gold standard verification error could also explain the surprisingly low sensitivity of HC2, which contrasts with findings from other studies.

%B Int J Cancer %V 123 %P 153-60 %8 2008 Jul 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/18404671?dopt=Abstract %R 10.1002/ijc.23489 %0 Journal Article %J Ann Oncol %D 2007 %T Burden of cervical cancer in Europe: estimates for 2004. %A M. Arbyn %A Raifu, A O %A Autier, P %A Ferlay, J %K Adult %K Aged %K Cost of Illness %K Europe %K Female %K Humans %K incidence %K middle aged %K Time Factors %K Uterine Cervical Neoplasms %K Uterine Neoplasms %X

The European Council recommends that organised cervical cancer screening be offered in all member states. In order to evaluate the impact of existing and new prevention methods, regularly updated information on the burden of cervical cancer is needed. The best estimates of mortality and incidence rates were applied to the 2004 projected population of 40 European countries using methods developed by the International Agency for Research on Cancer. Using the absolute number of cases and deaths, the standardised and cumulative rates (up to age of 74 years) were computed for individual countries, and aggregated for the 15 old (EU15) and the 10 new member states (EU10) of the European Union (EU25). For the 28 countries (25 belonging to the EU25 and three others), deaths from not otherwise specified uterine cancer were reallocated to cervix or corpus uteri cancer using age-specific rules described in GLOBOCAN 2002. The burden of cervical cancer deaths in the whole of Europe was assessed by analysing uterus cancer mortality in women aged <45 years. In 2004, approximately 31,000 women in the EU25 developed cervical cancer and almost 14,000 died from the disease. A striking contrast is noted between the 15 old and 10 new EU member states: world age-standardised incidence rates (per 10(5) women-years) of 9.5 versus 16.7; standardised mortality rates of 4.9 versus 10.7; cumulative mortality rate of 0.27% versus 0.71%. The burden was lowest in Finland (cumulative incidence and mortality rate of 0.38% and 0.12%, respectively) and highest in Lithuania (cumulative incidence and mortality of 1.64% and 0.94%, respectively). The mapping of uterine cancer mortality among women aged <45 years indicates that the burden of cervical cancer is particularly high across the whole of Eastern Europe. Cervical cancer still constitutes a considerable public health problem in Europe. The dramatic contrast between West and East European states merits particular attention from the health authorities of the countries concerned and the EU as a whole. The European Commission should maintain cervical cancer control in future action plans and increase support to the most affected member states.

%B Ann Oncol %V 18 %P 1708-15 %8 2007 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/17369600?dopt=Abstract %R 10.1093/annonc/mdm079 %0 Journal Article %J Coll Antropol %D 2007 %T The burden of cervical cancer in south-east Europe at the beginning of the 21st century. %A M. Arbyn %A Primic-Zakelj, Maja %A Raifu, Amidu O %A Grce, Magdalena %A Paraskevaidis, Evangelos %A Diakomanolis, Emanuel %A Kesić, Vesna %A Nicula, Florian A %A Suteu, Ofelia %A von Karsa, Lawrence %K Europe %K Female %K History, 21st Century %K Humans %K incidence %K Uterine Cervical Neoplasms %X

The situation of cervical cancer prevention in South-East Europe is hardly documented, in spite of the fact that it encloses the most affected countries of Europe. We estimated the number of cases of cervical cancer, the number of deaths from this malignancy and the corresponding rates for 11 countries located in South-East Europe, in the period 2002-2004. Each year, approximately 9,000 women develop cervical cancer and about 4,600 die from the disease in this subcontinent. The most affected country is Romania with almost 3,500 cases and more than 2,000 deaths per year High world-age standardised mortality rates (> 7.5 [expressed per 100,000 women-years]) are observed in 7 countries: FYROM (7.6), Moldova (7.8), Bulgaria (8.0), Bosnia & Herzegovina (8.0), Albania (9.8), Serbia & Montenegro (10.1) and Romania (13.0). A matter of concern is the increasing mortality rate, in younger women, in the countries with the highest burden of cervical cancer. Thus, appropriate cervical cancer prevention programmes should be set up without delay in this part of Europe.

%B Coll Antropol %V 31 Suppl 2 %P 7-10 %8 2007 Apr %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/17600932?dopt=Abstract %0 Journal Article %J Cytopathology %D 2007 %T European guidelines for quality assurance in cervical cancer screening: recommendations for collecting samples for conventional and liquid-based cytology. %A M. Arbyn %A Herbert, A %A Schenck, U %A Nieminen, P %A Jordan, J %A Mcgoogan, E %A Patnick, J %A Bergeron, C %A Baldauf, J-J %A Klinkhamer, P %A Bulten, J %A Martin-Hirsch, P %K Europe %K Female %K Humans %K Mass Screening %K Papanicolaou Test %K Quality Assurance, Health Care %K specimen handling %K Uterine Cervical Neoplasms %K Vaginal Smears %X

The current paper presents an annex in the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. It provides guidance on how to make a satisfactory conventional Pap smear or a liquid-based cytology (LBC) sample. Practitioners taking samples for cytology should first explain to the woman the purpose, the procedure and how the result will be communicated. Three sampling methods are considered as acceptable for preparing conventional Pap smears: (i) the cervical broom; (ii) the combination of a spatula and an endocervical brush; and (iii) the extended tip spatula. Smear takers should take care to sample the entire circumference of the transformation zone, to quickly spread the cellular material over a glass slide, and to fix the preparation within a few seconds to avoid drying artefacts. According to local guidelines, one of these three methods may be preferred. Sampling with a cotton tip applicator is inappropriate. Similar procedures should be followed for sampling cells for LBC, but only plastic devices may be used. The collected cells should be quickly transferred into a vial with fixative liquid according to the instructions of the manufacturer of the LBC system. Subsequently, the slide or vial and the completed request form are sent to the laboratory for cytological interpretation.

%B Cytopathology %V 18 %P 133-9 %8 2007 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/17573762?dopt=Abstract %R 10.1111/j.1365-2303.2007.00464.x %0 Journal Article %J J Clin Virol %D 2007 %T Review of current knowledge on HPV vaccination: an appendix to the European Guidelines for Quality Assurance in Cervical Cancer Screening. %A M. Arbyn %A Dillner, Joakim %K ADOLESCENT %K Adult %K Alphapapillomavirus %K Child %K Clinical Trials, Phase II as Topic %K Clinical Trials, Phase III as Topic %K Female %K Humans %K Male %K Papillomavirus Infections %K Papillomavirus Vaccines %K Practice Guidelines as Topic %K Uterine Cervical Neoplasms %X

The recognition of a strong etiological relationship between infection with high-risk human papillomavirusses and cervical cancer has prompted research to develop and evaluate prophylactic and therapeutic vaccines. One prophylactic quadrivalent vaccine using L1 virus-like particles (VLP) of HPV 6, 11, 16 and 18 is available on the European market since the end of 2006 and it is expected that a second bivalent vaccine containing VLPs of HPV16 and HPV18 will become available in 2007. Each year, HPV16 and HPV18 cause approximately 43,000 cases of cervical cancer in the European continent. Results from the phase-IIb and III trials published thus far indicate that the L1 VLP HPV vaccine is safe and well-tolerated. It offers HPV-naive women a very high level of protection against HPV persistent infection and cervical intra-epithelial lesions associated with the types included in the vaccine. HPV vaccination should be offered to girls before onset of sexual activity. While prophylactic vaccination is likely to provide important future health gains, cervical screening will need to be continued for the whole generation of women that is already infected with the HPV types included in the vaccine. Phase IV studies are needed to demonstrate protection against cervical cancer and to verify duration of protection, occurrence of replacement by non-vaccine types and to define future policies for screening of vaccinated cohorts. The European Guidelines on Quality Assurance for Cervical Cancer Screening provides guidance for secondary prevention by detection and management of precursors lesions of the cervix. The purpose of the appendix on vaccination is to present current knowledge. Developing guidelines for future use of HPV vaccines in Europe, is the object of a new grant offered by the European Commission.

%B J Clin Virol %V 38 %P 189-97 %8 2007 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/17258503?dopt=Abstract %R 10.1016/j.jcv.2006.12.009 %0 Journal Article %J Vaccine %D 2006 %T Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. %A M. Arbyn %A Sasieni, Peter %A Meijer, Chris J L M %A Clavel, Christine %A Koliopoulos, George %A Dillner, Joakim %K DNA, Viral %K Europe %K Female %K Humans %K Mass Screening %K Molecular Diagnostic Techniques %K Papillomaviridae %K Papillomavirus Infections %K Sensitivity and Specificity %K Treatment Outcome %K United States %X

BACKGROUND: More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods.

MATERIAL AND METHODS: A summary is given from recently published meta-analyses on three possible clinical applications of human papillomavirus (HPV)-DNA testing: triage of women with equivocal or low-grade cytological abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer.

RESULTS: Consistent evidence is available indicating that HPV-triage with the Hybrid Capture-2 assay (HC2) is more accurate (significantly higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. When triaging women with low-grade squamous intraepithelial lesions (LSIL), a reflex HC2 test does not show a significantly higher sensitivity, but a significantly lower specificity compared to a repeat Pap smear. After treatment of cervical lesions, HPV testing easily detects (with higher sensitivity and not lower specificity) residual or recurrent CIN than follow-up cytology. Primary screening with HC2 generally detects 23% (95% confidence interval, CI: 13-23%) more CIN-2, CIN-3, or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASCUS) or LSIL, but is 6% (95% CI: 4-8%) less specific. By combined HPV and cytology screening, a further 4% (95% CI: 3-5%) more CIN-3 lesions can be identified but at the expense of a 7% (95% CI: 5-9%) loss in specificity, in comparison with isolated HC2 screening.

CONCLUSIONS: Sufficient evidence exists to recommend HPV testing in triage of women with atypical cytology and in surveillance after treatment of CIN lesions. In the United States, recently reviewed knowledge has resulted in the approval of combined cytology and HC2 primary screening in women older than 30 years. However, in Europe, cytology-based screening still remains the standard screening method. The European screening policy will be reviewed based on the longitudinal results of randomised population trials which are currently underway.

%B Vaccine %V 24 Suppl 3 %P S3/78-89 %8 2006 Aug 31 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/16950021?dopt=Abstract %R 10.1016/j.vaccine.2006.05.117 %0 Journal Article %J Gynecol Oncol %D 2005 %T Clinical utility of HPV-DNA detection: triage of minor cervical lesions, follow-up of women treated for high-grade CIN: an update of pooled evidence. %A M. Arbyn %A Paraskevaidis, E %A Martin-Hirsch, P %A Prendiville, W %A Dillner, J %K Carcinoma, Squamous Cell %K Cervical Intraepithelial Neoplasia %K DNA, Viral %K Female %K Humans %K Papillomaviridae %K Papillomavirus Infections %K triage %K Uterine Cervical Neoplasms %X

OBJECTIVE: Human papilloma virus (HPV) testing and repeat cytology are both proposed as methods to triage women with minor cytological cervical lesions. By triage, those women can be identified who need referral for diagnostic exploration with colposcopy and/or biopsy.

METHODS: We conducted meta-analyses of reported studies on the accuracy to detect high-grade cervical intra-epithelial neoplasia or worse disease (CIN2+) in women with ASCUS or LSIL. We also performed meta-analyses to examine the best predictor of recurrence of CIN after treatment for CIN2 or CIN3.

RESULTS: We found that HPV testing using the Hybrid Capture II test is more effective (more sensitive, equally specific) than cytology for the triage of patients with ASCUS Pap smears. Because of the high rate of HPV positivity, this is not the case for patients with LSIL. Studies concerning post-treatment follow-up were heterogeneous. In general, HPV testing performed better than follow-up cytology to predict success or failure of treatment (significantly higher sensitivity, not significantly lower specificity).

CONCLUSIONS: Overall, in comparison with follow-up cytology, HPV DNA testing is more sensitive and equally specific for triage of ASCUS cases and for predicting recurrence of CIN in women treated for high-grade CIN.

%B Gynecol Oncol %V 99 %P S7-11 %8 2005 Dec %G eng %N 3 Suppl 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/16154623?dopt=Abstract %R 10.1016/j.ygyno.2005.07.033 %0 Journal Article %J J Natl Cancer Inst %D 2004 %T Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia. %A M. Arbyn %A Buntinx, Frank %A Van Ranst, Marc %A Paraskevaidis, Evangelos %A Martin-Hirsch, Pierre %A Dillner, Joakim %K ADOLESCENT %K Adult %K Aged %K Aged, 80 and over %K Bias (Epidemiology) %K Carcinoma, Squamous Cell %K Cervical Intraepithelial Neoplasia %K Cervix Uteri %K Confidence Intervals %K DNA, Viral %K Female %K Humans %K middle aged %K ODDS RATIO %K Papanicolaou Test %K Papillomaviridae %K Papillomavirus Infections %K Practice Guidelines as Topic %K Predictive Value of Tests %K prevalence %K Reproducibility of Results %K Sensitivity and Specificity %K triage %K Tumor Virus Infections %K United States %K Uterine Cervical Neoplasms %K Vaginal Smears %X

BACKGROUND: The appropriate management of women with minor cytologic lesions in their cervix is unclear. We performed a meta-analysis to assess the accuracy of human papillomavirus (HPV) DNA testing as an alternative to repeat cytology in women who had equivocal results on a previous Pap smear.

METHODS: Data were extracted from articles published between 1992 and 2002 that contained results of virologic and cytologic testing followed by colposcopically directed biopsy in women with an index smear showing atypical cells of undetermined significance (ASCUS). Fifteen studies were identified in which HPV triage and the histologic outcome (presence or absence of a cervical intraepithelial neoplasia of grade II or worse [CIN2+]) was documented. Nine, seven, and two studies also documented the accuracy of repeat cytology when the cutoff for abnormal cytology was set at a threshold of ASCUS or worse, low-grade squamous intraepithelial lesion (LSIL) or worse, or high-grade squamous intraepithelial lesion (HSIL) or worse, respectively. Random-effects models were used for pooling of accuracy parameters in case of interstudy heterogeneity. Differences in accuracy were assessed by pooling the ratio of the sensitivity (or specificity) of HPV testing to that of repeat cytology.

RESULTS: The sensitivity and specificity were 84.4% (95% confidence interval [CI] = 77.6% to 91.1%) and 72.9% (95% CI = 62.5% to 83.3%), respectively, for HPV testing overall and 94.8% (95% CI = 92.7% to 96.9%) and 67.3% (95% CI = 58.2% to 76.4%), respectively, for HPV testing in the eight studies that used the Hybrid Capture II assay. Sensitivity and specificity of repeat cytology at a threshold for abnormal cytology of ASCUS or worse was 81.8% (95% CI = 73.5% to 84.3%) and 57.6% (95% CI = 49.5% to 65.7%), respectively. Repeat cytology that used higher cytologic thresholds yielded substantially lower sensitivity but higher specificity than triage with the Hybrid Capture II assay. The ratio of the sensitivity of the Hybrid Capture II assay to that of repeat cytology at a threshold of ASCUS or worse pooled from the four studies that used both triage tests was 1.16 (95% CI = 1.04 to 1.29). The specificity ratio was not statistically different from unity.

CONCLUSION: The published literature indicates that the Hybrid Capture II assay has improved accuracy (higher sensitivity, similar specificity) than the repeat Pap smear using the threshold of ASCUS for an outcome of CIN2+ among women with equivocal cytologic results. The sensitivity of triage at higher cytologic cutoffs is poor.

%B J Natl Cancer Inst %V 96 %P 280-93 %8 2004 Feb 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/14970277?dopt=Abstract %0 Journal Article %J Cancer %D 2003 %T Metaanalysis of the accuracy of rapid prescreening relative to full screening of pap smears. %A M. Arbyn %A Schenck, Ulrich %A Ellison, Erin %A Hanselaar, Anton %K False Negative Reactions %K Female %K Humans %K Laboratories %K Mass Screening %K Observer Variation %K Papanicolaou Test %K Predictive Value of Tests %K Quality Control %K Sensitivity and Specificity %K Time Factors %K Uterine Cervical Neoplasms %K Vaginal Smears %X

BACKGROUND: Efficient quality assurance and improvement measures are essential ingredients in a well organized cytology-based program for cervical carcinoma screening. Various pap smear review procedures, aiming for optimization of accuracy, are described throughout the literature. Evaluation and synthesis of those methods are needed. In a previous study, we pooled data on the diagnostic quality of rapid reviewing (RR) of cervical smears initially reported as normal or unsatisfactory. We now focus on rapid prescreening (RPS) of unreported smears.

METHODS: Six published studies on the accuracy of RPS relative to subsequent full screening were pooled using metaanalytic methods. Individual and pooled sensitivity, specificity, and predictive values were assessed using forest plots. Random effect pooling methods were used for interstudy heterogeneity. Variation in sensitivity according to influencing factors was explored by metaregression.

RESULTS: The pooled average sensitivity of RPS was 64.9% (95% confidence interval [CI] 50.7-79.1%) for all abnormalities, 72.6% (95% CI 60.6-85.2%) for low-grade lesions or more severe, and 85.7% (95% CI 77.8-93.6%) for high-grade lesions or more severe. The pooled specificity was estimated at 96.8% (CI 95.8-97.8%). The sensitivity increased significantly with duration of screening and decreased with workload. Almost 3% of all abnormal slides were detected only by RPS (2.8%; CI 0.0-5.8%). This is comparable to the proportion of false-negative smears detectable by RR.

CONCLUSIONS: Rapid prescreening has a high yield for severe dysplasia and shows diagnostic properties that support its use as a quality control procedure in cytologic laboratories. We showed previously that RR is superior to full reviewing of a 10% random sample of negative slides (10% FR). Because the yield of additional abnormalities found by RR and RPS is comparable, we expect RPS to be more efficient than 10% FR as well.

%B Cancer %V 99 %P 9-16 %8 2003 Feb 25 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/12589640?dopt=Abstract %R 10.1002/cncr.10921 %0 Journal Article %J Lancet Oncol %D 2002 %T Belgian Parliament calls for organised cervical cancer screening and HPV research throughout Europe. %A M. Arbyn %A Temmerman, Marleen %K Belgium %K Female %K Humans %K Mass Screening %K National Health Programs %K Papillomaviridae %K Papillomavirus Infections %K Primary Prevention %K Research %K Tumor Virus Infections %K Uterine Cervical Neoplasms %B Lancet Oncol %V 3 %P 74 %8 2002 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/11902526?dopt=Abstract %0 Journal Article %J Int J Cancer %D 2002 %T Trend of cervical cancer mortality in Belgium (1954-1994): tentative solution for the certification problem of unspecified uterine cancer. %A M. Arbyn %A Geys, Helena %K Adult %K Age factors %K Aged %K Aged, 80 and over %K Belgium %K Death Certificates %K Female %K Humans %K middle aged %K Risk Factors %K Uterine Cervical Neoplasms %K Uterine Neoplasms %X

We investigated the evolution of mortality from cervical cancer in Belgium between 1954 and 1994 in terms of absolute number of deaths, and standardised and age-specific mortality rates. Changes over generations were summarised using the standardised cohort mortality ratio. Trend studies of cervical cancer mortality were hampered by certification problems. The number of deaths due to cancer of the uterine cervix is not known exactly since a substantial proportion of death causes are coded as cancer of the uterus without specifying the anatomic site: cervix or corpus uteri. This inaccuracy in codification has been corrected using distribution tables derived from countries where this certification problem is minimal. Trends in mortality from certified and corrected cervical cancers were compared. The corrected age-standardised mortality rate decreased continuously over the last 4 decades, from over 14 to 5 per 100,000 woman-years (slope -0.26/100,000 woman-years, 95% CI -0.28 to -0.24). Its slope is 3.1 times (95% CI 2.9-3.5) more important than for the rate of mortality from certified cervical cancer. In addition to the almost linear decrease, substantial nonlinear cohort influences were observed in certified and corrected mortality rates. The tendency of increasing mortality in women born after 1935 required particular attention. Nevertheless, the slope of the corrected recent cohort effect remained limited in Belgium, probably as a consequence of screening.

%B Int J Cancer %V 102 %P 649-54 %8 2002 Dec 20 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/12448009?dopt=Abstract %R 10.1002/ijc.10761 %0 Report %D 2001 %T Cervical cancer screening in the Flemish Community. A technical guideline: collection of adequate PAP smears of the uterine cervix. %A M. Arbyn %A De Cock, R. %K cancer %K cancer screening %K cervical cancer %K cervix %K Flemish %K report %K SCREENING %X

Not available

%I Ministry of the Flemish Community %C Brussels %P 53 %8 0/0/2001 %G eng %M D/2001/2505/31 %1

33875

%2

2000-004

%0 Journal Article %J Eur J Cancer %D 2000 %T Cervical cancer screening in Belgium. %A M. Arbyn %A Herman Van Oyen %K Adult %K Belgium %K Costs and Cost Analysis %K Data collection %K Female %K Health Personnel %K Humans %K incidence %K Interprofessional Relations %K Mass Screening %K middle aged %K Patient Acceptance of Health Care %K Practice Guidelines as Topic %K Quality Assurance, Health Care %K REGISTRIES %K Uterine Cervical Neoplasms %X

A description is given of the burden of cervical cancer and the status of screening in Belgium until 1998. Screening is essentially opportunistic and generally performed at yearly intervals. A programme for organised screening - promoting one cervical smear every 3 years for women aged between 25 and 64 years - is being set up in the Flemish Region alone. Important progress has been made concerning the development of technical guidelines on the collection of an adequate Papanicolaou (Pap) smear, uniform terminology for the cytological report and the follow-up of positive tests. The implementation of the programme is confined to the provinces that are instructed to make women and physicians aware of the screening policy. The establishment of a screening register, allowing for individualised invitation of women, was hampered by strict privacy laws and by the heterogeneity of software used for data entry in cytological laboratories. The impact of the Flemish programme was further limited since the reimbursement of smear taking by a gynaecologist or a general practitioner (GP) and the cytological reading are not conditioned by the respect of guidelines. This is due to the fact that the organisation of preventive healthcare and the financing of medical activities concerns distinct authorities. The coverage of the target population is good in Flanders (82.3% according to certain estimates), but is achieved at the expense of an important amount of over-screening. The coverage is lower in the Walloon and the Capital Region. Rationalisation of the policy regarding cancer screening involving all concerned authorities of the country is necessary.

%B Eur J Cancer %V 36 %P 2191-7 %8 2000 Nov %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/11072203?dopt=Abstract %0 Journal Article %J Acta Cytol %D 2000 %T Detection of false negative Pap smears by rapid reviewing. A metaanalysis. %A M. Arbyn %A Schenck, U %K Cell Biology %K False Negative Reactions %K Female %K Humans %K Laboratories %K Mass Screening %K Papanicolaou Test %K Quality Control %K Uterine Cervical Neoplasms %K Vaginal Smears %X

OBJECTIVE: To explore the diagnostic validity of rapid reviewing (RR) as a quality control method in cytologic laboratories.

STUDY DESIGN: Fourteen studies dealing with the detection of false negative Pap smears by RR were included in a metaanalysis.

RESULTS: The overall additional yield of positive slides, expressed as the percentage of all reviewed slides, is: 0.18% (95% confidence interval [CI]: .14-.21) for all cytologic abnormalities; 0.07% (CI: .05-.09) for squamous intraepithelial lesions (SIL) and 0.02% (CI: .01-.03) for high grade SIL. The false negative rate of primary screening, evaluated by RR, was 2.0% (CI: 1.5-2.6) for all cytologic abnormalities and 1.4% (CI: .8-2.1) for high grade SIL. The specificity of rapid rescreening was estimated as 97.2% (CI: 96.4-98.1). The positive predictive value of suspicion at RR is about 8.8%. Seven references contained historical data on full rescreening of a random sample of slides reported originally as negative. The results were also pooled and compared with RR. Complete rescreening is more sensitive, but if applied on only 10% of the negative workload, it would yield, on average, 4.7 times fewer extra positives, 5.6 times fewer SIL and 7.9 times fewer high grade SIL in comparison with RR of all sides.

CONCLUSION: RR of all smears initially reported as nonpositive is a more effective and a fortiori a more cost effective quality control method in comparison with full rescreening of a 10% random sample.

%B Acta Cytol %V 44 %P 949-57 %8 2000 Nov-Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/11127751?dopt=Abstract %0 Report %D 1999 %T Secundaire preventie van cervixkanker in Vlaanderen. Feiten en voorstellen voor een structurele aanpak. %A M. Arbyn %A Herman Van Oyen %K cancer %K cervix %K kanker %K preventie %K prevention %I WIV-ISP %C Brussel %P 106 %8 0/0/1999 %@ D/1999/2505/17 %G eng %1 33876 %2 Epi-serie 20 %0 Journal Article %J Eur J Cancer Prev %D 1997 %T Cervical cancer screening in the Flemish region (Belgium): measurement of the attendance rate by telephone interview. %A M. Arbyn %A Quataert, P %A Van Hal, G %A Herman Van Oyen %K ADOLESCENT %K Adult %K Age Distribution %K Aged %K Attitude to Health %K Belgium %K Confidence Intervals %K cross-sectional studies %K Female %K health surveys %K Humans %K incidence %K Interviews as Topic %K Mass Screening %K middle aged %K Multivariate Analysis %K ODDS RATIO %K Patient Compliance %K Risk Factors %K Rural Population %K Uterine Cervical Neoplasms %X

In November and December 1995 a computer assisted telephone interview (CATI) was organized in order to measure the rate of participation in cervical cancer screening among a sample of 1,477 women between 18 and 69 years old, residing in the Flemish Region and selected by random digit dialling. Associations between screening status and a set of explanatory variables (demographic, socioeconomic determinants and exposition to primary risk factors for cervical cancer) were studied by logistic regression modelling. The screening coverage meaning the percentage of women screened less than 3 years ago, increases sharply up to 25 years and remains higher than 85% up to 40 years; from then it decreases progressively. Socioeconomically deprived groups and single women are less likely to have a smear taken. Notable regional differences exist. Over-screening (interval between Papanicolaou smears less than 3 years) is an important phenomenon among screened women especially within the younger age groups. The prevalence of risk factors (sexual intercourse at young age, multiple sex partners, contraceptive pill use, smoking) has increased over time but women at higher risk are generally better screened. This survey provides useful baseline information necessary to monitor the achievement of some main objectives, formulated by the Europe Against Cancer programme and also included in Flemish public health policy.

%B Eur J Cancer Prev %V 6 %P 389-98 %8 1997 Aug %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/9370103?dopt=Abstract