Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia.

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial.

BACKGROUND: Cervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial. METHODS AND FINDINGS: In 2007-2010, the 1992-1995 birth cohorts of 33 Finnish communities were randomized to receive gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or no HPV vaccination (Arm C) (11 communities per trial arm). HPV16/18/31/33/35/45 seroprevalence differences between the pre-vaccination era (2005-2010) and post-vaccination era (2011-2016) were compared between all 8,022 unvaccinated women <23 years old and resident in the 33 communities during 2005-2016 (2,657, 2,691, and 2,674 in Arms A, B, and C, respectively). Post- versus pre-vaccination-era HPV seroprevalence ratios (PRs) were compared by arm. Possible outcome misclassification was quantified via probabilistic bias analysis. An HPV16 and HPV18 seroprevalence reduction was observed post-vaccination in the gender-neutral vaccination arm in the entire study population (PR16 = 0.64, 95% CI 0.10-0.85; PR18 = 0.72, 95% CI 0.22-0.96) and for HPV16 also in the herpes simplex virus type 2 seropositive core group (PR16 = 0.64, 95% CI 0.50-0.81). Observed reductions in HPV31/33/35/45 seroprevalence (PR31/33/35/45 = 0.88, 95% CI 0.81-0.97) were replicated in Arm C (PR31/33/35/45 = 0.79, 95% CI 0.69-0.90). CONCLUSIONS: In this study we only observed herd effect against HPV16/18 after gender-neutral vaccination with moderate vaccination coverage. With only moderate vaccination coverage, a gender-neutral vaccination strategy can facilitate the control of even HPV16. Our findings may have limited transportability to other vaccination coverage levels. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00534638, https://clinicaltrials.gov/ct2/show/NCT00534638.

Differing Age-Specific Cervical Cancer Incidence Between Different Types of Human Papillomavirus: Implications for Predicting the Impact of Elimination Programs.

The elimination of cervical cancer rests on high efficacy of human papillomavirus (HPV) vaccines. The HPV type distribution among cases of invasive cervical cancer (ICC) is used to make predictions about the impact of eliminating different types of HPV, but accumulating evidence of differences in age-specific cancer incidence by HPV type exists. We used one of the largest population-based series of HPV genotyping of ICCs (n = 2,850; Sweden, 2002-2011) to estimate age-specific ICC incidence by HPV type and obtain estimates of the cancer-protective impact of the removal of different HPV types. In the base case, the age-specific ICC incidence had 2 peaks, and the standardized lifetime risk (SLTR, the lifetime number of cases per birth cohort of 100,000 females) for HPV-positive ICC was 651 per 100,000 female births. In the absence of vaccine types HPV 16 and HPV 18, the SLTR for ICC was reduced to 157 per 100,000 female births (24% of HPV-positive SLTR). Elimination of all 9 types that can currently be vaccinated against reduced the remaining SLTR to 47 per 100,000 female births (7%), the remaining ICC incidence only slowly increasing with age. In conclusion, after elimination of vaccine-protected HPV types, very few cases of ICC will be left, especially among fertile, reproductive-age women.

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

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.

Disparities in glioblastoma survival by case volume: a nationwide observational study.

INTRODUCTION: High hospital case volumes are associated with improved treatment outcomes for numerous diseases. We assessed the association between academic non-profit hospital case volume and survival of adult glioblastoma patients. METHODS: From the nationwide Finnish Cancer Registry, we identified all adult (≥ 18 years) patients with histopathological diagnoses of glioblastoma from 2000 to 2013. Five university hospitals (treating all glioblastoma patients in Finland) were classified as high-volume (one hospital), middle-volume (one hospital), and low-volume (three hospitals) based on their annual numbers of cases. We estimated one-year survival rates, estimated median overall survival times, and compared relative excess risk (RER) of death between high, middle, and low-volume hospitals. RESULTS: A total of 2,045 patients were included. The mean numbers of annually treated patients were 54, 40, and 17 in the high, middle, and low-volume hospitals, respectively. One-year survival rates and median survival times were higher and longer in the high-volume (39%, 9.3 months) and medium-volume (38%, 8.9 months) hospitals than in the low-volume (32%, 7.8 months) hospitals. RER of death was higher in the low-volume hospitals than in the high-volume hospital (RER = 1.19, 95% CI 1.07-1.32, p = 0.002). There was no difference in RER of death between the high-volume and medium-volume hospitals (p = 0.690). CONCLUSION: Higher glioblastoma case volumes were associated with improved survival. Future studies should assess whether this association is due to differences in patient-specific factors or treatment quality.

Occurrence of human papillomavirus (HPV) type replacement by sexual risk-taking behaviour group: Post-hoc analysis of a community randomized clinical trial up to 9 years after vaccination (IV).

Oncogenic non-vaccine human papillomavirus (HPV) types may conceivably fill the vacated ecological niche of the vaccine types. The likelihood of this may differ by the risk of acquiring HPV infections. We examined occurrence of HPV types among vaccinated and unvaccinated subgroups of 1992-1994 birth cohorts with differing acquisition risks up to 9 years post-implementation of HPV vaccination in 33 Finnish communities randomized to: Arm A (gender-neutral HPV16/18 vaccination), Arm B (girls-only HPV16/18 vaccination and hepatitis B-virus (HBV) vaccination of boys), and Arm C (gender-neutral HBV vaccination). Out of 1992-1994 born resident boys (31,117) and girls (30,139), 8,618 boys and 15,615 girls were vaccinated, respectively, with 20-30% and 50% coverage in 2007-2009. In 2010-2013, 8,868 HPV16/18 and non-HPV vaccinated females, and in 2014-2016, 5,574 originally or later (2010-2013) HPV16/18 vaccinated females attended two cervical sampling visits, aged 18.5 and 22-years. The samples were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68 using PCR followed by MALDI-TOF MS. HPV prevalence ratios (PR) between Arms A/B vs. C were calculated for Chlamydia trachomatis positives (core-group), and negatives (general population minus core group). At both visits the vaccine-protected HPV type PRs did not significantly differ between the core-group and non-core group. Among the vaccinated 18-year-olds, HPV51 occurrence was overall somewhat increased (PRcore = 1.4, PRnon-core. = 1.4) whereas the HPV52 occurrence was increased in the core-group only (PRcore = 2.5, PRnon-core = 0.8). Among the non-HPV vaccinated 18-year-olds, the HPV51/52 PRs were higher in the core-group (PRcore = 3.8/1.8, PRnon-core = 1.2/1.1). The 22-year-olds yielded no corresponding observations. Monitoring of the sexual risk-taking core-group may detect early tendencies for HPV type replacement.

Evaluation of HPV type-replacement in unvaccinated and vaccinated adolescent females-Post-hoc analysis of a community-randomized clinical trial (II).

Efficacy of human papillomavirus (HPV) vaccines promises to control HPV infections. However, HPV vaccination programs may lay bare an ecological niche for non-vaccine HPV types. We evaluated type-replacement by HPV type and vaccination strategy in a community-randomized trial executed in HPV vaccination naïve population. Thirty-three communities were randomized to gender-neutral vaccination with AS04-adjuvanted HPV16/18 vaccine (Arm A), HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (Arm B) and gender-neutral HBV vaccination (Arm C). Resident 1992-95 born boys (40,852) and girls (39,420) were invited. 11,662 boys and 20,513 girls were vaccinated with 20-30% and 45-48% coverage, respectively. HPV typing of 11,396 cervicovaginal samples was performed by high throughput PCR. Prevalence ratios (PR) between arms and ranked order of HPV types and odds ratio (OR) for having multiple HPV types in HPV16 or 18/45 positive individuals were calculated. The ranked order of HPV types did not significantly differ between arms or birth cohorts. For the non-HPV vaccinated 1992-1993 birth cohorts increased PR, between the gender-neutral intervention versus control arms for HPV39 (PRA 1.84, 95% CI 1.12-3.02) and HPV51 (PRA 1.56, 95% CI 1.11-2.19) were observed. In the gender-neutral arm, increased clustering between HPV39 and the vaccine-covered HPV types 16 or 18/45 (ORA16 = 5.1, ORA18/45 = 11.4) was observed in the non-HPV vaccinated 1994-1995 birth cohorts. Comparable clustering was seen between HPV51 and HPV16 or HPV18/45 (ORB16 = 4.7, ORB18/45 = 4.3), in the girls-only arm. In conclusion, definitively consistent postvaccination patterns of HPV type-replacement were not observed. Future occurrence of HPV39 and HPV51 warrant investigation.

Impact of gender-neutral or girls-only vaccination against human papillomavirus-Results of a community-randomized clinical trial (I).

Human papillomavirus (HPV) vaccine is efficacious but the real-life effectiveness of gender-neutral and girls-only vaccination strategies is unknown. We report a community-randomized trial on the protective effectiveness [(PE) = vaccine efficacy (VE) + herd effect (HE)] of the two strategies among females in virtually HPV vaccination naïve population. We randomized 33 Finnish communities into Arm A) gender-neutral vaccination with AS04-adjuvanted HPV16/18 vaccine (11 communities), Arm B) HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (11 communities) or Arm C) gender-neutral HBV vaccination (11 communities). All resident 39,420 females and 40,852 males born 1992-95 were invited in 2007-09. Virtually all (99%) 12- to 15-year-old participating males (11,662) and females (20,513) received three doses resulting in uniform 20-30% male and 50% female vaccination coverage by birth cohort. Four years later (2010-14) 11,396 cervicovaginal samples obtained from 18.5 year-old women were tested for HPV DNA, and prevalence of cervical HPV infections by trial arm and birth cohort was the main outcome measure. VEs against HPV16/18 varied between 89.2% and 95.2% across birth cohorts in arms A and B. The VEs against non-vaccine types consistent with cross-protection were highest in those born 1994-95 for HPV45 (VEA 82.8%; VEB 86.1%) and for HPV31 (VEA 77.6%, VEB 84.6%). The HEs in the non HPV-vaccinated were statistically significant in those born 1994-95 for HPV18 (HEA 51.0%; 95% CI 8.3-73.8, HEB 47.2%; 6.5-70.2) and for HPV31/33 in arm A (HEA 53.7%; 22.1-72.5). For HPV16 and 45 no significant herd effects were detected. PE estimates against HPV16/18 were similar by both strategies (PEA 58.1%; 45.1-69.4; PEB 55.7%; 42.9-66.6). PE estimates against HPV31/33 were higher by the gender-neutral vaccination (PEA 60.5%; 43.6-73.4; PEB 44.5%; 24.9-60.6). In conclusion, while gender-neutral strategy enhanced the effectiveness of HPV vaccination for cross-protected HPV types with low to moderate coverage, high coverage in males appears to be key to providing a substantial public health benefit also to unvaccinated females. Trial registration www.clinicaltrials.gov.com NCT000534638.

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

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.

The risk of cervical atypia in oral contraceptive users.

BACKGROUND: The interactions of oral contraceptive (OC) use, risk of human papillomavirus (HPV) infection and associated cellular atypia are complex. We investigated the association between history of OC-use, and cytological or histopathological abnormalities in a cohort of non-HPV vaccinated originally 16-17-year-old women participating the PATRICIA trial for 4 years. METHODS: The total number of hepatitis A-virus (control) vaccine recipients participating in the clinical PATRICIA trial in Finland was 2399. Nine-hundred and ninety-nine women returned questionnaires on living conditions-life habits and sexual health after completing the study. Mean age at answering the questionnaire at the end of the clinical trial was 22 years. Age at sexual debut varied between 12 and 16 years for majority of the women. Cervical cytological samples were obtained every 6 months throughout the PATRICIA trial. The relative risk of cervical atypia associated with time since start of oral contraceptives use was calculated as odds ratio (OR) with 95% confidence interval (CI) using logistic regression. RESULTS: Compared to never-users, the smoking and age-at-sexual-debut adjusted relative risk of cervical intraepithelial neoplasia grade 1 (CIN1) in women who had started the use of oral contraceptives for more than 1 year was low (OR 0.2, 95% CI: 0.1-0.7). Risk of cytological atypia was also reduced (OR 0.6) albeit not significantly (95% CI: 0.3-1.3). CONCLUSIONS: Use of oral contraceptives does not increase the risk of cervical atypia but when established might instead be protective.

Self-sampling in cervical cancer screening: comparison of a brush-based and a lavage-based cervicovaginal self-sampling device.

BACKGROUND: High coverage and attendance is essential for cervical cancer screening success. We investigated whether the previous positive experiences on increasing screening attendance by self-sampling in Finland are sampler device dependent. METHODS: All women identified to cervical cancer screening in 2013 in 28 Finnish municipalities were randomised to receive a lavage- (n = 6030) or a brush type of self-sampling device (n = 6045) in case of non-attendance after two invitation letters. Seven hundred seventy non-attending women in the lavage device group and 734 in the brush group received the self-sampling offer. Women's experiences were enquired with an enclosed questionnaire. RESULTS: Total attendance in the lavage group increased from 71.0 to 77.7% by reminder letters and further to 80.5% by self-sampling. Respective increase in the brush group was from 72.2 to 78.6% and then to 81.5%. The participation by self-sampling was 21.7% (95% CI 18.8-24.6) in the lavage group and 23.8% (95% CI 20.8-26.9) in the brush group. Women's self-sampling experiences were mainly positive and the sampler devices were equally well accepted by the women. CONCLUSION: Our study shows that the lavage device and brush device perform similarly in terms of uptake by non-attending women and user comfort. If self-sampling is integrated to the routine screening program in Finland, either of the devices can be chosen without the fear of losing participants due to a less acceptable device.

Longitudinal biobanks-based study on the joint effects of infections, nutrition and hormones on risk of prostate cancer.

Background To evaluate the individual and combined effects of enterolactone, vitamin D, free testosterone, Chlamydia trachomatis and HPV-18 on the risk of prostate cancer in a large population-based biochemical material that combined three Nordic serum sample banks. Material and methods A joint cohort of 209 000 healthy men was followed using cancer registry linkages. From this cohort altogether 699 incident cases of prostate cancer were identified. Four controls were selected by incidence density sampling and matching for country, age and date of the blood sampling. Complete data for all investigated exposures was available for 483 eligible cases and 1055 eligible controls. Multivariate regression analyses were performed to investigate the solitary and combined effects. Results The solitary effects were small. Significantly increased risk [rate ratio 1.6 (95% CI 1.0-2.5)] was found in those seronegative for C. trachomatis infection. The joint effect in risk levels of enterolactone and vitamin D was antagonistic [observed rate ratio (RR) 1.4 (1.0-2.1), expected RR 2.0 (1.0-4.1)] as well as that of HPV-18 and C. trachomatis [observed RR 1.9 (0.8-4.5), expected RR 9.9 (1.1-87.0)]. Conclusion A large follow-up study combining data from several previously investigated exposures to investigate joint effects found no evidence that exposure to two risk factors would increase the risk of prostate cancer from that expected on basis of exposure to one risk factor. If anything, the results were consistent with antagonistic interactions.

Improving cervical cancer screening attendance in Finland.

High attendance is essential to cervical cancer screening results. Attendance in the Finnish program is currently at 70%, but extensive opportunistic screening occurs beside the organized. A shift from opportunistic to organized screening is imperative to optimize the costs and impact of screening and minimize potential harms. We evaluated the effect of reminder letters (1st reminder) and self-sampling test (2nd reminder) on program attendance. The study population consisted of 31,053 screening invitees in 31 Finnish municipalities. 8,284 non-attendees after one invitation received a reminder letter and 4,536 further non-attendees were offered a self-sampling option. Socioeconomic factors related to participation were clarified by combining screening data to data from Statistics Finland. Reminder letters increased participation from 72.6% (95% CI 72.1, 73.1) to 79.2% (95% CI 78.8, 79.7) and self-sampling further to 82.2% (95% CI 81.8, 82.7). Reminder letters with scheduled appointments resulted in higher increase than open invitations (10 vs. 6%). Screening of original non-attendees increased the yield of CIN3+ lesions by 24%. Non-attendance was associated with young age, immigrant background, lower education level and having never been married. We showed that a total attendance of well over 80% can be achieved within an organized program when the invitational protocol is carefully arranged.

Self-sampling experiences among non-attendees to cervical screening.

OBJECTIVE: High coverage and attendance is essential to positive cervical cancer screening results. Offering self-sampling for HPV-testing to the non-attendees of the program may improve attendance rates. Information on women's perceptions and experiences with self-sampling (acceptability) is needed to further optimize attendance by this method. METHODS: A questionnaire study focusing on women's experiences on the screening method was embedded in a trial investigating the effects and feasibility of self-sampling among non-attendees of cervical screening in 31 Finnish municipalities in 2011-2012 (n=4688). Reasons for non-attendance in routine screening were also surveyed. RESULTS: Response rate to the questionnaire was 98.8% (909/920) among women who performed self-sampling. Self-sampling participants reported mainly good experiences. Negative experiences (difficulties in sample taking, pain, fear, anxiety, insecurity) were reported rarely, but more commonly among women with a mother tongue other than Finnish or Swedish (immigrants). Most common reason for non-attendance in routine screening was a recent Pap-smear elsewhere (opportunistic screening). Practical reasons (pregnancy, scheduling difficulties) were reported by 42%, emotional or attitudinal reasons by 17%, and 16% forgot to take part. Response yield to questionnaire was unsatisfactory among those women who declined the self-sampling option. CONCLUSIONS: Optimizing the practical aspects of screening and offering a self-sampling option to non-attendees can help to overcome a large variety of both practical and emotional barriers to traditional screening. More research is needed among the non-attendees to routine screening who decline also the self-sampling option.

Mortality audit of the Finnish cervical cancer screening program.

Incidence-based evaluations of cervical cancer screening programs have suggested age-specific impacts and there is uncertainty regarding the effectiveness of screening outside the ages of 30-60 years. We audited the screening histories of cervical cancer deaths and conducted a case-control evaluation of the effectiveness of organized screening in different ages with mortality as outcome. We included all 506 cervical cancer deaths in Finland in 2000-2009 due to cancers diagnosed in 1990 or later, and 3,036 controls matched by age at diagnosis to the cases. Squamous cell carcinoma constituted 59% of the cases, adenocarcinomas 29%, and the remaining 12% were other specified and unspecified cervical malignancies. Most deaths (54%) were due to cancers diagnosed more than 5 years after last screening invitation, 24% were diagnosed among nonattenders and only 14% of deaths occurred among women who had attended invitational screening. The risk reduction associated with attending a single program screen at an age below 40 was nonsignificant (OR 0.70; 95% CI 0.33-1.48), while clear risk reductions were observed after screening at the age of 40-54 (OR 0.33; CI 0.20-0.56) and 55-69 (OR 0.29; CI 0.16-0.54). This study also provides some indication of a long-lasting additional effect of screening at the age of 65. Possible avenues for improving the effectiveness of the Finnish screening program include efforts to increase attendance and an extension of the target ages to include 65-to 69-year-old women. The potential benefit of increasing the sensitivity of the screening test or shortening the screening interval is smaller.

Understanding long-term protection of human papillomavirus vaccination against cervical carcinoma: Cancer registry-based follow-up.

Phase III clinical trials of human papilloma virus (HPV) vaccination have shown ≥95% efficacy against HPV16/18 associated cervical intraepithelial neoplasia (CIN) Grade 2/3. Long-term surveillance is, however, needed to determine the overall vaccine efficacy (VE) against CIN3 and invasive cervical carcinoma (ICC). During population-based recruitment between September 2002 and March 2003, 1,749 16- to 17-year old Finns participated in a multi-national randomized Phase III HPV6/11/16/18 vaccine (FUTURE II) trial for the determination of VE against HPV16/18 positive CIN2/3. The passive follow-up started at the country-wide, population-based Finnish Cancer Registry (FCR) six months after the active follow-up and voluntary cross-vaccination in April 2007. A cluster randomized, population-based reference cohort of 15,744 unvaccinated, originally 18-19 year old Finns was established in two phases in 2003 and 2005 after the FUTURE II recruitment. We linked these cohorts with the FCR in 2007-2011 (HPV vaccine and placebo cohorts) and 2006-2010 and 2008-2012 (unvaccinated reference cohorts 1 and 2) to compare their incidences of CIN3 and ICC. The four years passive follow-up resulted in 3,464, 3,444 and 62,876 person years for the HPV6/11/16/18, original placebo and reference cohorts, after excluding cases discovered during the clinical follow-up and individuals not at risk. The numbers of CIN3 and ICC cases identified were 0 and 0, 3 and 0, 59 and 3 for the HPV6/11/16/18, placebo and the unvaccinated reference cohorts. The corresponding CIN3 incidence rates were 0/100,000 (95% confidence interval 0.0-106.5), 87.1/100,000 (95% CI 17.9-254.5) and 93.8/100,000 (95% CI 71.4-121), respectively. Long-term surveillance up to 8 years (and longer) post vaccination of the HPV6/11/16/18 vaccine and placebo cohorts, and the unvaccinated reference cohort (not exposed to interventions) for the most stringent efficacy end-points by passive cancer registry-based follow-up is feasible.

Prospective study of genital human papillomaviruses and nonmelanoma skin cancer.

Genital high-risk human papillomaviruses (HPVs) cause cervical cancer and are also found in a small proportion of nonmelanoma skin cancers (NMSCs). We used cancer registry linkages to follow the 856,000 serum donors included in the Southern Sweden Microbiology Biobank or the Janus Biobank in Norway, for incident skin cancers occurring up to 30 years after serum donation. Serum samples taken before diagnosis of squamous cell carcinoma (SCC) (N = 633), basal cell carcinoma (BCC) (N = 1990) or other NMSC (N = 153) and matched samples from control donors were tested for antibodies to the genital HPV types 16 and 18. Both HPV 16 and 18 were associated with increased risk for SCC [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.6 and OR 1.7, 95% CI 1.1-2.5, respectively] and other NMSC (OR 2.3, 95% CI 1.0-5.2 and OR 3.5, 95% CI 1.4-8.7, respectively), but not for BCC. Tumor blocks from HPV16 or 18 seropositive cases were tested with real-time polymerase chain reaction for presence of HPV16 or 18 DNA. No HPV18 DNA was found and only four of 79 SCC cases (two of which were from the perineum/perianal area), one of 221 BCC cases and zero of five cases with other NMSC contained HPV16 DNA. In conclusion, we found prospective evidence that HPV16 and 18 antibodies associate with SCC and other NMSC risk, but not with BCC risk. As only a small proportion of seropositive subjects had evidence of the corresponding HPV DNA in the tumor, most of this excess risk is likely to be due to confounders associated with genital HPV infection.

Order of HPV/Chlamydia infections and cervical high-grade precancer risk: a case-cohort study.

Interactions of carcinogenic human papillomaviruses (most notably HPV types 16/18/31/33/45), and HPV6 or Chlamydia trachomatis are not well understood. We have used seroconversions to study effects the order of these infections has on the risk of high-grade cervical precancer. In a cohort of 94,349 Finnish women with paired sera from consecutive pregnancies within an average of 2.4 years, 490 were diagnosed with cervical CIN3/AIS. Serum antibodies to HPV6/16/18/31/33/45 and C. trachomatis were measured in paired sera of the cases and a subcohort of 2,796 women with a minimum of two pregnancies. HPV16-adjusted rate ratios (RR) and confidence intervals were estimated by stratified Cox model. Compared to dual seropositivity already at the first serum sampling, RRs related to HPV6 seropositivity before and after HPV31 seroconversion were 0.4 (95% CI 0.0, 4.4) and 10 (95% CI 1.8, 57). Furthermore, RR related to seroconversions of both HPV18/45 and C.trachomatis between the consecutive pregnancies was 28 (95% CI 4.3, 190). Virtually concomitant HPV18/45 and C.trachomatis infections are associated with very high CIN3 risk.