Publications by authors named "Pekka Nieminen"

106 Publications

Distribution of HPV Genotypes Differs Depending on Behavioural Factors among Young Women.

Microorganisms 2021 Apr 2;9(4). Epub 2021 Apr 2.

Department of Obstetrics and Gynecology, Tampere University Hospital and Tampere University, 33100 Tampere, Finland.

Risk factors for the different human papillomavirus (HPV) genotypes are not well understood, although the risk of cancer is known to vary among them. Our aim was to evaluate the association of diverse behavioral and reproductive factors with genotype-specific HPV prevalence among 879 unvaccinated women aged 18-75 years referred to the colposcopy clinic at Helsinki University Hospital in Finland. Cervical swabs for HPV genotyping were collected in the first visit and assessed for 34 high-risk (hr) and low-risk (lr) HPV genotypes. Participants completed a questionnaire on behavioral, reproductive, and lifestyle factors. Differences in genotype-specific HPV prevalence were analyzed overall and in age groups using binary logistic regression. Smoking was associated with higher prevalence in HPV16 compared with other hrHPV genotypes together with decreasing age, being highest among younger women <30 years old, odds ratio (OR) 3.74 (95% CI 1.42-9.88). The later the sexual debut, the more it seemed to protect from HPV16 infection. The best protection was achieved when the sexual debut took place at >20 years of age, with an OR of 0.43 (95% CI 0.23-0.83). This association was not seen with other hrHPV genotypes. Methods of contraception seemed not to have an effect on hrHPV positivity, regardless of the HPV genotype. The genotype specific hrHPV prevalence differs, depending on behavioral factors, especially among younger women referred to colposcopy.
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http://dx.doi.org/10.3390/microorganisms9040750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066411PMC
April 2021

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27-45 years of age compared to women 16-26 years of age: An open-label phase 3 study.

Vaccine 2021 05 3;39(20):2800-2809. Epub 2021 Mar 3.

Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address:

Background: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16-26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27-45 versus 16-26 years of age.

Methods: This international, open-label study (NCT03158220) was conducted in women 16-45 years of age. Participants (16-26 years, n = 570 and 27-45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study.

Results: At month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27-45 years were compared to those in women 16-26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27-45 years to 16-26 years) was 0.60-0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27-45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16-26 years, and 85.2% and 24.1% of women 27-45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study.

Conclusions: The 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27-45 years compared with women 16-26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16-26 years to women 27-45 years of age. Clinical trial registration NCT03158220.
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http://dx.doi.org/10.1016/j.vaccine.2021.01.074DOI Listing
May 2021

Preterm birth rate after bivalent HPV vaccination: Registry-based follow-up of a randomized clinical trial.

Prev Med 2021 May 24;146:106473. Epub 2021 Feb 24.

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 2, 00290 Helsinki, Finland. Electronic address:

A registry-based follow-up of pregnancy data until the end of 2014 was conducted based on a community-randomized trial to assess human papillomavirus (HPV) vaccination strategies and a reference cohort from the same community with no intervention. Our objective was to determine whether prophylactic HPV vaccination (three doses of Cervarix® (AS04-HPV-16/18)-vaccine) affects preterm birth (PTB) rates. All identified 80,272 residents in 1992-95 birth cohorts in Finland were eligible for the trial and 20,513 of 39,420 (51.9%) females consented to participate. The final study population consisted of age-aligned 6226 HPV16/18 vaccinated females and 1770 HBV vaccinated (Engerix® B, hepatitis B-virus vaccine) females that did not receive HPV vaccine at the age of 18 from the 1992-93 birth cohorts, and 19,849 females from the 1990-91 non-vaccinated reference birth cohorts. We compared the rates of preterm (22 + 0-36 + 6 pregnancy weeks) and early preterm (22 + 0-31 + 6) per term (at least 37 + 0) singleton births among the HPV- and non-HPV-vaccinated women, using nationwide Medical Birth Registry data. We observed 409 singleton first pregnancies lasting at least 22 + 0 weeks among 6226 HPV-vaccinated and 1923 among 21,619 non-HPV-vaccinated women. In the first pregnancy the PTB rate was 13/409 (3.2%) among the HPV-vaccinated and 98/1923 (5.1%) among the non-HPV-vaccinated (OR 0.61, 95% CI 0.34-1.09). Early preterm birth rate was 0/409 (0%) in the HPV-vaccinated women and 20/1923 (1.0%) in the non-HPV-vaccinated women (p = 0.04). PTB rate, especially early PTB rate, was lower among the HPV-vaccinated women. Reduction of PTB incidence after prophylactic HPV vaccination would lead to public health benefits globally. Trial Registration:NCT00534638.
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http://dx.doi.org/10.1016/j.ypmed.2021.106473DOI Listing
May 2021

Options for triage and implications for colposcopists within European HPV-based cervical screening programmes.

Eur J Obstet Gynecol Reprod Biol 2021 Mar 16;258:332-342. Epub 2021 Jan 16.

Département Anatomocytopathologie, 95066, Paris, France.

The development of human papillomavirus (HPV)-based screening should detect more pre-cancerous changes and so reduce the incidence and mortality from cervical squamous carcinoma and cervical adenocarcinoma. However, many more women are high risk HPV (hrHPV) screen positive compared to cytology-based screening, especially in younger age-women. A variety of tests have become available which may triage into those hrHPV test-positive women who need immediate referral to colposcopy from those who need early repeat HPV tests or recall on the basis of their disease status. We performed a literature review of publications and a manual search from 2010, reporting cytology, HPV partial genotyping, dual-staining and DNA methylation for triage of hrHPV positive tests, including their comparative performance between these methods as well as the effectiveness of some triage combinations with reference to HPV-based screening services in Europe. Cost effectiveness and the structure of triage algorithms for colposcopists also have been considered. From one report evaluating four options for triage as single options or as combined algorithms, partial genotyping for HPV 16 and 18 with dual-staining yielded the highest risk of cervical intraepithelial neoplasia grade three or worse within an HPV positive population and with an acceptable colposcopy rate. From a separate paper, this option appeared cost effective. However, publications were difficult to compare objectively. All options have their merits but a combination triage involving any two of cytology, HPV partial genotyping or dual-staining seems most efficient at present. HPV vaccination may impact upon the performance of future partial genotyping. DNA Methylation may become an acceptable future option.
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http://dx.doi.org/10.1016/j.ejogrb.2020.12.061DOI Listing
March 2021

Activation of the Complement System in the Lower Genital Tract During Pregnancy and Delivery.

Front Immunol 2020 11;11:563073. Epub 2021 Jan 11.

Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.

Background: Human pregnancy alters profoundly the immune system. The local involvement and mechanisms of activation of the complement system in the cervicovaginal milieu during pregnancy and delivery remain unexplored.

Objectives: To determine whether normal pregnancy and delivery are associated with local activation of complement or changes in the immunoglobulin profile in the cervix.

Study Design: This study was designed to assess IgA, IgG, and complement activation in the cervicovaginal area in three groups of patients: i) 49 pregnant women (week 41+3-42+0) not in active labor, ii) 24 women in active labor (38+4-42+2), and iii) a control group of nonpregnant women (n=23) at child-bearing age. We collected mucosal samples from the lateral fornix of the vagina and external cervix during routine visits and delivery. The Western blot technique was used to detect complement C3 and its activation products. For semiquantitative analysis, the bands of the electrophoresed proteins in gels were digitized on a flatbed photo scanner and analyzed. IgA and IgG were analyzed by Western blotting and quantified by ELISA. One-way ANOVA and Tukey's Multiple Comparison tests were used for statistical comparisons.

Results: A higher abundance but lower activation level of C3 in both the external cervix (P<0.001) and lateral fornix of the vagina (P<0.001) was observed during delivery (58 ± 22, n= 24) in comparison to the groups of nonpregnant (72 ± 13%; mean ± SD, n=23) and pregnant women (78 ± 22%, n=49). Complement activating IgG was detected in higher abundance than IgA in the cervicovaginal secretions of pregnant women. In a small proportion samples also C3-IgG complexes were detected.

Conclusions: Our results reveal an unexpectedly strong activation of the complement system and the presence IgG immunoglobulins in the cervicovaginal area during pregnancy, active labor, and among nonpregnant women. In contrast to the higher amounts of C3 in the cervicovaginal secretions during labor, its activation level was lower. Complement activating IgG was detected in higher concentrations than IgA in the mucosal secretions during pregnancy and labor. Taken together our results imply the presence a locally operating humoral immune system in the cervicovaginal mucosa.
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http://dx.doi.org/10.3389/fimmu.2020.563073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829332PMC
May 2021

National guidelines for management of cervical squamous intraepithelial lesion: A survey of European Federation for colposcopy members.

Eur J Obstet Gynecol Reprod Biol 2021 Jan 28;256:46-50. Epub 2020 Oct 28.

Past-President European Federation of Colposcopy and University Hospitals of North Midlands, Stoke-on-Trent, UK.

Objectives: The management of women with cervical squamous intraepithelial lesions (SIL) is fundamental to prevention of cervical cancer in an organized cervical screening programme. Clinical guidance should improve quality of care and clinical effectiveness if developed and implemented appropriately. This survey provides an update on the current situation of national guidelines for management of cervical SIL amongst member countries of European Federation for Colposcopy (EFC).

Study Design: A questionnaire was sent to representatives of each member country of EFC. The questionnaire contained questions on: guidelines for management of cervical SIL of the National Societies/Associations of Colposcopy or others national societies/associations including the development and the consultation processes, guidelines for management of lower genital tract diseases and the regulations in each country for colposcopy practice.

Results: We received responses from all 34 member countries. Thirty countries reported a national guideline for management of cervical SIL that were developed by, or in conjunction with, their national societies or associations of colposcopy. In most cases there was adherence to the recommended steps for guideline development: they were developed by a multi-disciplinary group of specialists (29 countries) and society members were consulted before publication (21 countries). A small number of countries (8) reported to have guidelines for the management of lower genital tract dysplasia (e.g. vulval disease) developed by other national societies. In most countries (26) the colposcopists are obliged to follow the guidelines but this is regulated in only 6 and in 12 countries the colposcopists need to be certified by the national society of colposcopy in order to practice.

Conclusion: There are advances in the development and provision of country specific guidance on the management of cervical SIL. Most EFC member countries have appropriate national guidelines that were developed using a clear methodology, are updated according to progresses in the field and are accessible online to current practitioners. These guidelines support colposcopists to follow evidence-based practice and provides understanding of best practice in guideline development and access.
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http://dx.doi.org/10.1016/j.ejogrb.2020.10.028DOI Listing
January 2021

Fostering Prevention of Cervical Cancer by a Correct Diagnosis of Precursors: A Structured Case-Based Colposcopy Course in Finland, Norway and UK.

Cancers (Basel) 2020 Oct 30;12(11). Epub 2020 Oct 30.

Department of Obstetrics and Gynaecology, Helsinki University Hospital and Helsinki University, 00290 Helsinki, Finland.

High-quality colposcopy is essential in cervical cancer prevention. We performed a multicentre prospective interventional pilot-study, evaluating the effect of a six-hour case-based colposcopy course on short- and long-term learning of colposcopy-related knowledge, diagnostic accuracy levels and confidence. We recruited 213 colposcopists participating in three European Federation of Colposcopy (EFC) basic colposcopy courses (Finland, Norway, UK). The study consisted of three tests with identical content performed before, after and 2 months after the course, including ten colposcopic images, ten patient cases and scales for marking confidence in the answers. Outcome measures where mean scores in correct case-management, diagnosis (including high-grade lesion recognition), transformation-zone recognition and confidence in answers. Results were compared between the three tests and stratified according to experience. Mean test scores improved after the course for all participants. The increase was highest for beginners. Confidence in answers improved and the number of colposcopists showing high confidence with low scores decreased. A structured case-based course improves skills and confidence especially for inexperienced colposcopists; however, trainers should be aware of the risk of overconfidence. To complement theoretical training, further hands-on training including high-quality feedback is recommended. Conclusions drawn from long-term learning are limited due to the low participation in the follow-up test.
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http://dx.doi.org/10.3390/cancers12113201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692698PMC
October 2020

The European response to the WHO call to eliminate cervical cancer as a public health problem.

Int J Cancer 2021 01 4;148(2):277-284. Epub 2020 Aug 4.

International Agency for Research on Cancer, Lyon, France.

The age-standardised incidence of cervical cancer in Europe varies widely by country (between 3 and 25/100000 women-years) in 2018. Human papillomavirus (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 nonscreened or underscreened 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 rollout 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 postepidemic phase, health professionals should focus on high-risk women and adhere to cost-effective policies including self-sampling.
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http://dx.doi.org/10.1002/ijc.33189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754400PMC
January 2021

Role of Colposcopy after Treatment for Cervical Intraepithelial Neoplasia.

Cancers (Basel) 2020 Jun 24;12(6). Epub 2020 Jun 24.

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.

Colposcopy is often used in follow-up after treatment for cervical intraepithelial neoplasia (CIN) despite its marked inter-observer variability and low sensitivity. Our objective was to assess the role of colposcopy in post-treatment follow-up in comparison to hrHPV (high-risk human papillomavirus) testing, cytology, and cone margin status. Altogether, 419 women treated for histological high-grade lesion (HSIL) with large loop excision of the transformation zone (LLETZ) attended colposcopy with cytology and hrHPV test at six months. Follow-up for recurrence of HSIL continued for 24 months. Colposcopy was considered positive if colposcopic impression was recorded as high grade and cytology if HSIL, ASC-H (atypical squamous cells, cannot exclude HSIL), or AGC-FN (atypical glandular cells, favor neoplasia) were present. Overall, 10 (10/419, 2.4%) recurrent HSIL cases were detected, 5 at 6 months and 5 at 12 months. Colposcopic impression was recorded at 407/419 6-month visits and was positive for 11/407 (2.7%). None of them had recurrent lesions, resulting in 0% sensitivity and 97% specificity for colposcopy. Sensitivity for the hrHPV test at 6 months was 100% and specificity 85%, for cytology 40% and 99%, and for margin status at treatment 60% and 82%, respectively. While the hrHPV test is highly sensitive in predicting recurrence after local treatment for CIN, colposcopy in an unselected population is not useful in follow-up after treatment of CIN.
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http://dx.doi.org/10.3390/cancers12061683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352967PMC
June 2020

Cervical screening: ESGO-EFC position paper of the European Society of Gynaecologic Oncology (ESGO) and the European Federation of Colposcopy (EFC).

Br J Cancer 2020 08 8;123(4):510-517. Epub 2020 Jun 8.

Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

This paper summarises the position of ESGO and EFC on cervical screening based on existing guidelines and opinions of a team of lead experts. HPV test is replacing cytology as this offers greater protection against cervical cancer and allows longer screening intervals. Only a dozen of HPV tests are considered as clinically validated for screening. The lower specificity of HPV test dictates the use of triage tests that can select women for colposcopy. Reflex cytology is currently the only well validated triage test; HPV genotyping and p16 immunostaining may be used in the future, although methylation assays and viral load also look promising. A summary of quality assurance benchmarks is provided, and the importance to audit the screening histories of women who developed cancer is noted as a key objective. HPV-based screening is more cost-effective than cytology or cotesting. HPV-based screening should continue in the post-vaccination era. Only a fraction of the female population is vaccinated, and this varies across countries. A major challenge will be to personalise screening frequency according to vaccination status. Still the most important factor for successful prevention by screening is high population coverage and organised screening. Screening with self-sampling to reach under-screened women is promising.
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http://dx.doi.org/10.1038/s41416-020-0920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434873PMC
August 2020

Identification of European-wide clinical priorities for guideline development in the management of pre-invasive cervical disease.

Eur J Obstet Gynecol Reprod Biol 2020 Aug 19;251:36-41. Epub 2020 May 19.

Department of Gynaecological Oncology, University Hospitals of North Midlands, Newcastle Road, Stoke on Trent, ST4 6QG, UK. Electronic address:

Objective: Addressing management controversies in the treatment of pre-invasive cervical disease is a key priority for the European Federation for Colposcopy/European Society of Gynaecologic Oncology who aim to develop a practical handbook of European centred guidelines to address areas where there is a lack of high-quality evidence or identifiable practice variation. Clinical opinion across the EFC network was sought to identify topics likely to have the most impact on clinical practice for systematic review and development of practice recommendations.

Study Design: A scoping exercise comprising of a three-iteration modified Delphi with representation from each member society of the EFC was conducted in 2018. Round one identified 19 potential topics which were scored for importance using a five-point Likert scale by EFC members in round two and ranked. Results from round two were discussed at an open EFC satellite meeting resulting in exclusion of five topics. A third round of the 14 remaining topics was conducted to allow members to modify scores after viewing the second-round rankings. Responses were analysed and topics were allocated a weighted score.

Results: Strategies for management of persistent HPV infection in the context of normal colposcopy and negative cytology was the highest overall weighted topic (4.40) followed by identification of appropriate length of follow up for ASCUS or LSIL prior to excisional treatment (3.95) and the impact of length of excision on patient outcomes (3.95). Topics to identify best practice for management of challenging topics scored highly including optimising follow up strategies for cervical stenosis (3.91) and management of HSIL in the under 25 year olds (3.64) or pregnancy (3.64).

Conclusion: A European wide systematic modified-Delphi has prioritised six topics for systematic review and generation of clinical practice recommendations aiming to assist management in areas of controversy in pre-invasive cervical disease.
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http://dx.doi.org/10.1016/j.ejogrb.2020.05.017DOI Listing
August 2020

Vaccination With Moderate Coverage Eradicates Oncogenic Human Papillomaviruses If a Gender-Neutral Strategy Is Applied.

J Infect Dis 2020 08;222(6):948-956

Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.

Background: Human papillomavirus (HPV) vaccination of girls with very high (>90%) coverage has the potential to eradicate oncogenic HPVs, but such high coverage is hard to achieve. However, the herd effect (HE) depends both on the HPV type and the vaccination strategy.

Methods: We randomized 33 Finnish communities into gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and hepatitis B virus vaccination arms. In 2007-2010, 11 662 of 20 513 of 40 852 of 39 420 resident boys/girls from 1992 to 1995 birth cohorts consented. In 2010-2014, cervicovaginal samples from vaccinated and unvaccinated girls at age 18.5 years were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68. Vaccine efficacy for vaccinated girls, HE for unvaccinated girls, and the protective effectiveness (PE) for all girls were estimated. We extended the community-randomized trial results about vaccination strategy with mathematical modeling to assess HPV eradication.

Results: The HE and PE estimates in the 1995 birth cohort for HPV18/31/33 were significant in the gender-neutral arm and 150% and 40% stronger than in the girls-only arm. Concordantly, HPV18/31/33 eradication was already predicted in adolescents/young adults in 20 years with 75% coverage of gender-neutral vaccination. With the 75% coverage, eventual HPV16 eradication was also predicted, but only with the gender-neutral strategy.

Conclusions: Gender-neutral vaccination is superior for eradication of oncogenic HPVs.
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http://dx.doi.org/10.1093/infdis/jiaa099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430169PMC
August 2020

Baseline findings and safety of infrequent vs. frequent screening of human papillomavirus vaccinated women.

Int J Cancer 2020 07 16;147(2):440-447. Epub 2019 Dec 16.

Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.

Less frequent cervical cancer screening in human papillomavirus (HPV) vaccinated birth cohorts could produce considerable savings without increasing cervical cancer incidence and loss of life-years. We report here the baseline findings and interim results of safety and accuracy of infrequent screening among HPV16/18 vaccinated females. The entire 1992-1994 birth-cohorts (30,139 females) were invited to a community-randomized HPV16/18-vaccination trial. A total of 9,482 female trial participants received HPV16/18-vaccination in 2007-2009 at age of 13-15. At age 22, 4,273 (45%) of these females consented to attend a randomized trial on frequent (ages 22/25/28; Arm 1: 2,073 females) vs. infrequent screening (age 28; Arm 2: 2,200 females) in 2014-2017. Females (1,329), who had got HPV16/18 vaccination at age 18 comprised the safety Arm 3. Baseline prevalence and incidence of HPV16/18 and other high-risk HPV types were: 0.5% (53/1,000 follow-up years, 10 ) and 25% (2,530/10 ) in the frequently screened Arm 1; 0.2% (23/10 ) and 24% (2,413/10 ) in the infrequently screened Arm 2; and 3.1% (304/10 ) and 23% (2,284/10 ) in the safety Arm 3. Corresponding prevalence of HSIL/ASC-H and of any abnormal cytological findings were: 0.3 and 4.2% (Arm 1), 0.4 and 5.3% (Arm 2) and 0.3 and 4.7% (Arm 3). Equally rare HSIL/CIN3 findings in the infrequently screened safety Arm A3 (0.4%) and in the frequently screened Arm 1 (0.4%) indicate no safety concerns on infrequent screening despite the up to 10 times higher HPV16/18 baseline prevalence and incidence in the former.
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http://dx.doi.org/10.1002/ijc.32802DOI Listing
July 2020

Vaginal microbiota in pregnancy: Role in induction of labor and seeding the neonate''s microbiota?

J Biosci 2019 Oct;44(5)

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Compared to other human microbiota, vaginal microbiota is fairly simple with low bacterial diversity and high relative abundance of Lactobacillus species. Lactobacillus dominance is even more pronounced during pregnancy. Genetic factors, such as ethnicity, along with environmental, individual and lifestyle factors all have an impact on vaginal microbiota composition. The composition of the vaginal microbiota appears to play an important role in pregnancy as recent studies have linked it to adverse obstetric outcomes such as preterm birth, a leading cause of neonatal morbidity and mortality worldwide. However, the same vaginal microbiota does not seem to cause the same response in all women, calling for future research to fully understand the complex host-microbiota interplay in normal and complicated pregnancies.
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October 2019

Methylation in Predicting Progression of Untreated High-grade Cervical Intraepithelial Neoplasia.

Clin Infect Dis 2020 06;70(12):2582-2590

Center for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.

Background: There is no prognostic test to ascertain whether cervical intraepithelial neoplasias (CINs) regress or progress. The majority of CINs regress in young women, and treatments increase the risk of adverse pregnancy outcomes. We investigated the ability of a DNA methylation panel (the S5 classifier) to discriminate between outcomes among young women with untreated CIN grade 2 (CIN2).

Methods: Baseline pyrosequencing methylation and human papillomavirus (HPV) genotyping assays were performed on cervical cells from 149 women with CIN2 in a 2-year cohort study of active surveillance.

Results: Twenty-five lesions progressed to CIN grade 3 or worse, 88 regressed to less than CIN grade 1, and 36 persisted as CIN1/2. When cytology, HPV16/18 and HPV16/18/31/33 genotyping, and the S5 classifier were compared to outcomes, the S5 classifier was the strongest biomarker associated with regression vs progression. The S5 classifier alone or in combination with HPV16/18/31/33 genotyping also showed significantly increased sensitivity vs cytology when comparing regression vs persistence/progression. With both the S5 classifier and cytology set at a specificity of 38.6% (95% confidence interval [CI], 28.4-49.6), the sensitivity of the S5 classifier was significantly higher (83.6%; 95% CI, 71.9-91.8) than of cytology (62.3%; 95% CI, 49.0-74.4; P = 0.005). The highest area under the curve was 0.735 (95% CI, 0.621-0.849) in comparing regression vs progression with a combination of the S5 classifier and cytology, whereas HPV genotyping did not provide additional information.

Conclusions: The S5 classifier shows high potential as a prognostic biomarker to identify progressive CIN2.
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http://dx.doi.org/10.1093/cid/ciz677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286376PMC
June 2020

Age-specific HPV type distribution in high-grade cervical disease in screened and unvaccinated women.

Gynecol Oncol 2019 08 5;154(2):354-359. Epub 2019 Jun 5.

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 2, 00290 Helsinki, Finland. Electronic address:

Background And Aim: Age-specific type-distribution of high-risk human papillomavirus (hrHPV) in cervical precancerous lesions is subject to change in the HPV vaccination era. Knowing the pre-vaccination type-distribution helps to anticipate changes induced by mass vaccination and optimize screening.

Methods: We recruited 1279 women referred to colposcopy for abnormal cytology into a population-based study on HPV type distribution in diagnostic cervical samples (ISRCTN10933736). The HPV genotyping findings were grouped as: HPV16/18+, other hrHPV+ (HPV31/33/35/39/45/51/52/56/58/59/66/68), non-vaccine targeted hrHPV+ (HPV35/39/51/56/59/66/68), low-risk HPV, and HPV negative. We estimated the HPV group-specific prevalence rates according to diagnostic histopathological findings in the age groups of <30 (n = 339), 30-44.9 (n = 614), and ≥45 (n = 326).

Results: Altogether 503 cases with high grade squamous intraepithelial lesion or worse (HSIL+) were diagnosed. More than half, 285 (56.7%) of HSIL+ cases were associated with HPV16/18: 64.3% (101/157) in women <30 years (reference group), 58.4% (157/269) in women 30-44.9 years (risk ratio (RR) 0.91, 95% confidence interval (95% CI) 0.78-1.06), and 35.1% (27/77) in women ≥45 years of age (RR 0.55, 95% CI 0.39-0.75). Conversely, other hrHPV's were associated with 191 (38.0%) of HSIL+: 31.9% (50/157) in women <30, 36.8% (99/269) in women 30-44.9 years, 54.6% (42/77) and in women ≥45 (RR 1.71, 95% CI 1.26-2.33). The proportion of non-vaccine targeted hrHPV and HPV negative HSIL+ increased with advancing age.

Conclusions: Pre-vaccination HPV type distribution in HSIL+ was distinctly polarised by age with HPV16/18 attributed disease being markedly more prevalent in women aged <30. In the older women the other hrHPV types, however, dominated suggesting a need for more age-dependent screening strategies.
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http://dx.doi.org/10.1016/j.ygyno.2019.05.024DOI Listing
August 2019

Vaginal Microbiota Composition Correlates Between Pap Smear Microscopy and Next Generation Sequencing and Associates to Socioeconomic Status.

Sci Rep 2019 05 23;9(1):7750. Epub 2019 May 23.

Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Recent research on vaginal microbiota relies on high throughput sequencing while microscopic methods have a long history in clinical use. We investigated the correspondence between microscopic findings of Pap smears and the vaginal microbiota composition determined by next generation sequencing among 50 asymptomatic women. Both methods produced coherent results regarding the distinction between Lactobacillus-dominant versus mixed microbiota, reassuring gynaecologists for the use of Pap smear or wet mount microscopy for rapid evaluation of vaginal bacteria as part of diagnosis. Cytologic findings identified women with bacterial vaginosis and revealed that cytolysis of vaginal epithelial cells is associated to Lactobacillus crispatus-dominated microbiota. Education and socio-economic status were associated to the vaginal microbiota variation. Our results highlight the importance of including socio-economic status as a co-factor in future vaginal microbiota studies.
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http://dx.doi.org/10.1038/s41598-019-44157-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533281PMC
May 2019

The efficacy and safety of Tipapkinogen Sovacivec therapeutic HPV vaccine in cervical intraepithelial neoplasia grades 2 and 3: Randomized controlled phase II trial with 2.5 years of follow-up.

Gynecol Oncol 2019 06 4;153(3):521-529. Epub 2019 Apr 4.

Roche Pharmaceutical Research & Early Development, Roche Innovation Center New York, 430 E. 29th Street New York City, New York 10016, USA. Electronic address:

Background: While prophylactic human papillomavirus (HPV) vaccination exists, women are still developing cervical intraepithelial neoplasia (CIN) grade 2 or 3 for which an immunotherapeutic, non-surgical, approach may be effective. The primary aim was to assess the efficacy of tipapkinogen sovacivec (TS) vaccine in achieving histologic resolution of CIN2/3 associated with high risk (HR) HPV types.

Methods: Women 18 years and older who had confirmed CIN2/3 were enrolled in a randomized, double blind, placebo-controlled phase II trial and assigned to drug in a 2:1 ratio (vaccine:placebo). The primary endpoint occurred at month 6 when the excisional therapy was performed; cytology and HR HPV typing were performed at months 3, 6 and every six months through month 30. The safety population included all patients who received at least one dose of study drug.

Results: Of the 129 women randomized to vaccine and 63 to placebo, complete resolution was significantly higher in the vaccine group than placebo for CIN 2/3 regardless of the 13 HR HPV types assayed (24% vs. 10%, p < 0.05); as well as for only CIN 3 also regardless of HR HPV type (21% vs. 0%, p < 0.01). Irrespective of baseline HPV infection, viral DNA clearance was higher in the vaccine group compared to placebo (p < 0.01). The vaccine was well tolerated with the most common adverse events being injection site reactions.

Conclusions: The TS vaccine provides histologic clearance of CIN 2/3 irrespective of HR HPV type in one third of subjects and is generally safe through 30 months.
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http://dx.doi.org/10.1016/j.ygyno.2019.03.250DOI Listing
June 2019

Canine models of human amelogenesis imperfecta: identification of novel recessive ENAM and ACP4 variants.

Hum Genet 2019 May 15;138(5):525-533. Epub 2019 Mar 15.

Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.

Amelogenesis imperfecta (AI) refers to a genetically and clinically heterogeneous group of inherited disorders affecting the structure, composition, and quantity of tooth enamel. Both non-syndromic and syndromic forms of AI have been described and several genes affecting various aspects of the enamel physiology have been reported. Genetically modified murine models of various genes have provided insights into the complex regulation of proper amelogenesis. Non-syndromic AI occurs spontaneously also in dogs with known recessive variants in ENAM and SLC24A4 genes. Unlike rodents with a reduced dentition and continuously erupting incisors, canine models are valuable for human AI due to similarity in the dental anatomy including deciduous and permanent teeth. We have performed a series of clinical and genetic analyses to investigate AI in several breeds of dogs and describe here two novel recessive variants in the ENAM and ACP4 genes. A fully segregating missense variant (c.716C>T) in exon 8 of ENAM substitutes a well-conserved proline to leucine, p.(Pro239Leu), resulting in a clinical hypomineralization of teeth. A 1-bp insertion in ACP4 (c.1189dupG) is predicted to lead to a frameshift, p.(Ala397Glyfs), resulting in an abnormal C-terminal part of the protein, and hypoplastic AI. The ENAM variant was specific for Parson Russell Terriers with a carrier frequency of 9%. The ACP4 variant was found in two breeds, Akita and American Akita with a carrier frequency of 22%. These genetic findings establish novel canine models of human AI with a particular interest in the case of the ACP4-deficient model, since ACP4 physiology is poorly characterized in human AI. The affected dogs could also serve as preclinical models for novel treatments while the breeds would benefit from genetic tests devised here for veterinary diagnostics and breeding programs.
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http://dx.doi.org/10.1007/s00439-019-01997-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536466PMC
May 2019

Familial oligodontia and regional odontodysplasia associated with a PAX9 initiation codon mutation.

Clin Oral Investig 2019 Nov 26;23(11):4107-4111. Epub 2019 Feb 26.

Institute of Dentistry, Department of Cariology, Endodontology and Pedodontics, University of Oulu, POB 5281, 90014, Oulu, Finland.

Objective: Tooth agenesis is one of the most common craniofacial developmental anomalies. In hypodontia, one to five teeth are missing, whereas oligodontia refers to the absence of at least six teeth, excluding the third molars. Mutations in several genes including MSX1, PAX9, AXIN2, and WNT10A have been shown to cause non-syndromic tooth agenesis. Regional odontodysplasia (RO), also known as "ghost teeth," is a rare developmental anomaly of tooth formation affecting both dentitions. Some possible causes of RO have been suggested, yet the etiology remains unknown. Because the phenotypes of both oligodontia and RO co-occur in one Finnish family, the aim here was to investigate the genetic etiology of the two conditions.

Materials And Methods: A mutation screening of the genes MSX1, PAX9, AXIN2, and WNT10A was performed for the family members of a RO patient and family history of oligodontia.

Results: An initiation codon mutation of the PAX9 gene was found in the proband and segregating with oligodontia in the family.

Conclusions: The etiology of regional odontodysplasia (RO) may be genetic and the same genes can be involved both in RO and tooth agenesis.

Clinical Relevance: Our results give new insights into the etiology of regional odontodysplasia, yet further results are needed.
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http://dx.doi.org/10.1007/s00784-019-02849-5DOI Listing
November 2019

Gender-neutral vaccination provides improved control of human papillomavirus types 18/31/33/35 through herd immunity: Results of a community randomized trial (III).

Int J Cancer 2018 11 10;143(9):2299-2310. Epub 2018 Aug 10.

Gates Foundation, Seattle, Washington.

With optimal strategy, human papillomavirus (HPV) vaccines have the potential to control HPV. We have assessed vaccine efficacy (VE), herd effect (HE) of HPV vaccination and overall protective effectiveness (PE) against high-risk HPV infections by HPV type and vaccination strategy in a community-randomized trial using the bivalent HPV16/18 vaccine. We randomized 33 communities to gender-neutral HPV vaccination (Arm A), HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (Arm B) and gender-neutral HBV vaccination (Arm C). Entire 1992-1995 male (40,852) and female (39,420) birth cohorts were invited, and 11,662 males and 20,513 females vaccinated with 20-30% and 45% coverage in 2007-2010. During 2010-2014, 11,396 cervicovaginal samples were collected from 13,545 18.5-year-old attendees. HPV typing was performed by a high-throughput PCR. VE was calculated for HPV vaccinated women and HE for non-HPV-vaccinated women, using the HBV vaccinated, for HE all non-HPV vaccinated, Arm C women as controls. PE was calculated as coverage rate-weighted mean of VE + HE. HPV16/18/45 and 31/33/35 VEs varied between 86-94% and 30-66%, respectively. Only the gender-neutral vaccination provided significant HEs against HPV18 (61%) and HPV31 (72%) in the 1995 birth cohort-increased HEs against HPV33 (39%) and HPV35 (42%) were also observed. Due to the increased HEs, PEs for HPV16/18/45 and HPV31/33/35 were comparable in the gender-neutral arm 1995 birth cohort. High vaccine efficacy against HPV16/18/45 and, gender-neutral vaccination-enforced, herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provides comparable overall protective effectiveness against six oncogenic HPV types: 16/18/31/33/35/45.
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http://dx.doi.org/10.1002/ijc.31618DOI Listing
November 2018

2017 update of the European Federation for Colposcopy (EFC) performance standards for the practice of colposcopy.

Eur J Obstet Gynecol Reprod Biol 2018 May 16;224:137-141. Epub 2018 Mar 16.

Consultant Gynaecologist, Department of Obstetrics and Gynaecology, University Hospital of North Staffordshire, Stoke-on-Trent ST4 6QG, UK.

A refinement of quality indicators (QIs) is described whereby the quality of care can be measured across colposcopy services in different countries and healthcare settings. A five-round Delphi process was conducted at successive satellite meetings from 2011 to 2015 of leading European colposcopists to refine the most high-scoring QIs relevant to colposcopic practice. A review and refinement of the wording of the standards and their criteria was undertaken by national society representatives. Six quality indicators were identified and refined. "Documentation of whether the squamocolumnar junction (SCJ) has been visible or not" was changed into "for cervical colposcopy transformation zone (TZ) type (1, 2 or 3) should be documented". The standard "percentage of cases having a colposcopic examination prior to treatment for abnormal cytology" was changed to "percentage of cases having a colposcopic examination prior to treatment for abnormal cervical screening test". The standard "percentage of all excisional treatments/conizations containing CIN2+ (cervical intra-epithelial neoplasia grade two or worse)" was changed into "percentage of excisional treatments/conizations having a definitive histology of CIN2+. Definitive histology is highest grade from any diagnostic or therapeutic biopsies". The standard "percentage of excised lesions/conizations with clear margins" was unchanged. The remaining two QIs define the minimum caseloads required for colposcopists. However, "cytology" was replaced by "screening results" to acknowledge the introduction of human papillomavirus testing to European screening programmes. Six QIs were identified to define good practice in colposcopy.
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http://dx.doi.org/10.1016/j.ejogrb.2018.03.024DOI Listing
May 2018

Dentinogenesis imperfecta type II- genotype and phenotype analyses in three Danish families.

Mol Genet Genomic Med 2018 05 6;6(3):339-349. Epub 2018 Mar 6.

Department of Odontology, Pediatric Dentistry and Clinical Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

Background: Dentinogenesis imperfecta (DI) is a rare debilitating hereditary disorder affecting dentin formation and causing loss of the overlying enamel. Clinically, DI sufferers have a discolored and weakened dentition with an increased risk of fracture. The aims of this study were to assess genotype-phenotype findings in three families with DI-II with special reference to mutations in the DSPP gene and clinical, histological, and imaging manifestations.

Methods: Nine patients participated in the study (two from family A, four from family B, and three from family C). Buccal swab samples were collected from all participants and extracted for genomic DNA. Clinical and radiographic examinations had been performed longitudinally, and the dental status was documented using photographic images. Four extracted and decalcified tooth samples were prepared for histological analysis to assess dysplastic manifestations in the dentin. Optical coherence tomography (OCT) was applied to study the health of enamel tissue from in vivo images and the effect of the mutation on the function and structure of the DSPP gene was analyzed using bioinformatics software programs.

Results: The direct DNA sequence analysis revealed three distinct mutations, one of which was a novel finding. The mutations caused dominant phenotypes presumably by interference with signal peptide processing and protein secretion. The clinical and radiographic disturbances in the permanent dentition indicated interfamilial variability in DI-II manifestations, however, no significant intrafamilial variability was observed.

Conclusion: The different mutations in the DSPP gene were accompanied by distinct phenotypes. Enamel defects suggested deficit in preameloblast function during the early stages of amelogenesis.
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http://dx.doi.org/10.1002/mgg3.375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014476PMC
May 2018

Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis.

BMJ 2018 02 27;360:k499. Epub 2018 Feb 27.

Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objective: To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols.

Design: Systematic review and meta-analysis.

Data Sources: Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016.

Eligibility Criteria: Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months.

Data Synthesis: Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I statistics.

Main Outcome Measures: Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months).

Results: 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I=77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I=82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I=90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I=0%), 23% (two studies, 226/938 women, 20% to 26%; I=97%), and 11% (three studies, 163/1033 women, 5% to 19%; I=67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%.

Conclusions: Most CIN2 lesions, particularly in young women (<30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring.

Systematic Review Registration: PROSPERO 2014: CRD42014014406.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826010PMC
http://dx.doi.org/10.1136/bmj.k499DOI Listing
February 2018

Incomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis.

Lancet Oncol 2017 12 7;18(12):1665-1679. Epub 2017 Nov 7.

Department of Cancer Studies, University of Leicester, Leicester, UK.

Background: Incomplete excision of cervical precancer is associated with therapeutic failure and is therefore considered as a quality indicator of clinical practice. Conversely, the risk of preterm birth is reported to correlate with size of cervical excision and therefore balancing the risk of adequate treatment with iatrogenic harm is challenging. We reviewed the literature with an aim to reveal whether incomplete excision, reflected by presence of precancerous tissue at the section margins, or post-treatment HPV testing are accurate predictors of treatment failure.

Methods: We did a systematic review and meta-analysis to assess the risk of therapeutic failure associated with the histological status of the margins of the tissue excised to treat cervical precancer. We estimated the accuracy of the margin status to predict occurrence of residual or recurrent high-grade cervical intraepithelial neoplasia of grade two or worse (CIN2+) and compared it with post-treatment high-risk human papillomavirus (HPV) testing. We searched for published systematic reviews and new references from PubMed-MEDLINE, Embase, and CENTRAL and did also a new search spanning the period Jan 1, 1975, until Feb 1, 2016. Studies were eligible if women underwent treatment by excision of a histologically confirmed CIN2+ lesion, with verification of presence or absence of CIN at the resection margins; were tested by cytology or HPV assay between 3 months and 9 months after treatment; and had subsequent follow-up of at least 18 months post-treatment including histological confirmation of the occurrence of CIN2+. Primary endpoints were the proportion of positive section margins and the occurrence of treatment failure associated with the marginal status, in which treatment failure was defined as occurrence of residual or recurrent CIN2+. Information about positive resection margins and subsequent treatment failure was pooled using procedures for meta-analysis of binomial data and analysed using random-effects models.

Findings: 97 studies were eligible for inclusion in the meta-analysis and included 44 446 women treated for cervical precancer. The proportion of positive margins was 23·1% (95% CI 20·4-25·9) overall and varied by treatment procedure (ranging from 17·8% [12·9-23·2] for laser conisation to 25·9% [22·3-29·6] for large loop excision of the transformation zone) and increased by the severity of the treated lesion. The overall risk of residual or recurrent CIN2+ was 6·6% (95% CI 4·9-8·4) and was increased with positive compared with negative resection margins (relative risk 4·8, 95% CI 3·2-7·2). The pooled sensitivity and specificity to predict residual or recurrent CIN2+ was 55·8% (95% CI 45·8-65·5) and 84·4% (79·5-88·4), respectively, for the margin status, and 91·0% (82·3-95·5) and 83·8% (77·7-88·7), respectively, for high-risk HPV testing. A negative high-risk HPV test post treatment was associated with a risk of CIN2+ of 0·8%, whereas this risk was 3·7% when margins were free.

Interpretation: The risk of residual or recurrent CIN2+ is significantly greater with involved margins on excisional treatment; however, high-risk HPV post-treatment predicts treatment failure more accurately than margin status.

Funding: European Federation for Colposcopy and Institut national du Cancer (INCA).
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http://dx.doi.org/10.1016/S1470-2045(17)30700-3DOI Listing
December 2017

Ten-year follow-up of human papillomavirus vaccine efficacy against the most stringent cervical neoplasia end-point-registry-based follow-up of .

BMJ Open 2017 Aug 18;7(8):e015867. Epub 2017 Aug 18.

Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.

Objective: Due to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+).

Methods: We report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials' end.

Results: During the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88).

Conclusions: Ten years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects.

Trial Registration Number: NCT01393470.
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http://dx.doi.org/10.1136/bmjopen-2017-015867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629648PMC
August 2017

Testing for high-risk HPV in cervical and tonsillar paraffin-embedded tissue using a cartridge-based assay.

APMIS 2017 Oct 24;125(10):910-915. Epub 2017 Jul 24.

Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

This study evaluates the suitability of Xpert HPV (Cepheid, Sunnyvale, CA, USA) test for cervical and tonsillar formalin-fixed paraffin-embedded (FFPE) tissue samples as compared to the tests currently used in diagnostics. Cervical biopsies and liquid cytology (LC) samples were collected from 48 women attending colposcopy. Biopsies were processed for histology and tested for hrHPV using Xpert HPV. LC samples were tested using Xpert and Hybrid Capture 2 (HC2; Qiagen, Hilden, Germany) tests. Also 29 archived tonsillar carcinoma samples were tested using Xpert, and the results were compared with histology and immunohistochemical p16INK4a (p16) staining. Among valid cervical LC samples 46.8% were hrHPV positive using Xpert test and 55.3% with HC2. The sensitivity of Xpert was 84.6% as compared to HC2, and overall test concordance was 91.5%. Test concordance between valid Xpert results from biopsies and LC samples was 84.6%. Among valid tonsillar samples 70.4% were hrHPV positive, and concordance of 96.3% was found between Xpert and p16 staining. To conclude, Xpert HPV test cartridge provides a convenient platform to test individual samples, including FFPE samples. Further studies are needed to establish whether test sensitivity is sufficient to reliably differentiate between hrHPV positive and hrHPV negative head and neck carcinomas.
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http://dx.doi.org/10.1111/apm.12727DOI Listing
October 2017

Comparative analysis of vaginal microbiota sampling using 16S rRNA gene analysis.

PLoS One 2017 19;12(7):e0181477. Epub 2017 Jul 19.

Immunobiology Research Programme, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.

Background: Molecular methods such as next-generation sequencing are actively being employed to characterize the vaginal microbiota in health and disease. Previous studies have focused on characterizing the biological variation in the microbiota, and less is known about how factors related to sampling contribute to the results. Our aim was to investigate the impact of a sampling device and anatomical sampling site on the quantitative and qualitative outcomes relevant for vaginal microbiota research. We sampled 10 Finnish women representing diverse clinical characteristics with flocked swabs, the Evalyn® self-sampling device, sterile plastic spatulas and a cervical brush that were used to collect samples from fornix, vaginal wall and cervix. Samples were compared on DNA and protein yield, bacterial load, and microbiota diversity and species composition based on Illumina MiSeq sequencing of the 16S rRNA gene. We quantified the relative contributions of sampling variables versus intrinsic variables in the overall microbiota variation, and evaluated the microbiota profiles using several commonly employed metrics such as alpha and beta diversity as well as abundance of major bacterial genera and species.

Results: The total DNA yield was strongly dependent on the sampling device and to a lesser extent on the anatomical site of sampling. The sampling strategy did not affect the protein yield or the bacterial load. All tested sampling methods produced highly comparable microbiota profiles based on MiSeq sequencing. The sampling method explained only 2% (p-value = 0.89) of the overall microbiota variation, markedly surpassed by intrinsic factors such as clinical status (microscopy for bacterial vaginosis 53%, p = 0.0001), bleeding (19%, p = 0.0001), and the variation between subjects (11%, p-value 0.0001).

Conclusions: The results indicate that different sampling strategies yield comparable vaginal microbiota composition and diversity. Hence, past and future vaginal microbiota studies employing different sampling strategies should be comparable in the absence of other technical confounders. The Evalyn® self-sampling device performed equally well compared to samples taken by a clinician, and hence offers a good-quality microbiota sample without the need for a gynecological examination. The amount of collected sample as well as the DNA and protein yield varied across the sampling techniques, which may have practical implications for study design.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517051PMC
September 2017

Blepharocheilodontic (BCD) syndrome: New insights on craniofacial and dental features.

Am J Med Genet A 2017 Apr 9;173(4):905-913. Epub 2017 Feb 9.

Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Blepharocheilodontic (BCD) syndrome is a rare condition characterized by bilateral cleft lip and palate (BCLP), eyelid abnormalities, and oligodontia. Despite orofacial clefting and oligodontia being central features of the condition, detailed reports of dental and craniofacial characteristics are scarce. The aim of this study was to analyze the dental and craniofacial features in a group of patients with BCD syndrome (three of which were related). Cephalometric radiographic analyses were performed on BCD syndrome patients (all radiographs taken at age 8 years) and compared to 40 randomly selected age-matched controls (20 non-syndromic BCLP, 20 non-cleft). Also, we assessed clinical records, photographs, dental study casts, and dental radiographs to determine the extent and pattern of tooth agenesis, dental morphology and malocclusion. BCD syndrome patients showed a very severe skeletal III malocclusion (maxillary-mandibular sagittal discrepancy) and reduced anterior lower face measurement compared to non-syndromic BCLP and non-cleft controls (P = 0.001, P = 0.027). All patients exhibited oligodontia (mean number of missing permanent teeth 13.7, range 7-17). All patients exhibited missing upper central and lateral incisor, upper canine and premolar teeth. Variations in dental morphology included taurodontism, conical-shaped teeth, and notching of the incisal edges. All patients had a short and narrow maxilla which translated into anterior and posterior cross bites. We conclude that, in our BCD syndrome group, the craniofacial skeletal defects are more severe than patients with BCLP. The pattern of tooth agenesis is unusual as it included teeth that are normally highly resistant to agenesis, namely upper central incisor and canine teeth. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38088DOI Listing
April 2017