Atypical glandular cells and development of cervical cancer: Population-based cohort study.

The effect of cervical screening on cervical adenocarcinoma has been variable, possibly because the risk associated with the precursor atypical glandular cells (AGC) is not well known. A cohort of all 885 women in the capital region of Sweden with AGC, a concomitant human papillomavirus (HPV) analysis, and a histopathology was followed until 2019. Cumulative incidence proportions of cervical intraepithelial lesion grade 3 or worse (CIN3+) by HPV type was determined by 1-Kaplan-Meier estimates. Hazard ratios (HR) for CIN3+ or for invasive cancer were estimated with Cox regression. After 2 years of follow-up, the cumulative incidence proportions of CIN3+ were 80% (95% confidence interval [CI]: 74-86%), 58% (95% CI: 50-60%) and 10% (95% CI: 5-18%) among HPV16/18 positive, "other HPV" positive and HPV-negative women, respectively. Among the 300 women with HPV16/18 positive AGC, 217 developed CIN3+ of which 35 were invasive cervical cancer. The 2-year cumulative invasive cancer risk for HPV16/18 positive AGC was 17% (95% CI: 12-24%). Primary HPV-screening had a similar yield of CIN3+ as cytology screening, albeit HPV-negative AGC is by design not detected by HPV screening. Among 241 women with HPV-negative AGC, 11 developed CIN3+ mostly after clinically indicated samples. We found no significant risk differences depending on age or sampling indication. The low CIN3+ risk after HPV-negative AGC implies safety of primary HPV screening. The high risk of invasive cervical cancer after HPV16/18 positive AGC implies that management of this finding is a priority in cervical screening.

Shared environment and colorectal cancer: A Nordic pedigree registry-based cohort study.

Risk of colorectal cancer (CRC) increases in relatives of patients with CRC. The extent to which this is attributable to genetic predisposition or shared environment is unclear. We explored this question using nationwide cohorts from Denmark, Finland and Sweden. From 1977 to 2013, we identified 359 879 individuals with a CRC diagnosis and 2 258 870 of their relatives who we followed for CRC incidence. We calculated standardized incidence ratios (SIR) and 95% confidence intervals (CI) for CRC in individuals with an affected relative. We used nationwide household and pedigree data along with national SIR estimates to calculate risk ratios (RR) for the contribution of shared household environment, childhood environment and genetic relationship to CRC risk in those with an affected relative. SIR of CRC was increased for individuals with an affected relative, across all countries and ages. For those with an affected parent, the SIR was 1.65 (95% CI: 1.61-1.69), 1.98 (95% CI: 1.87-2.09), for those with an affected sibling and 2.14 (95% CI: 1.84-2.49) for those with an affected halfsibling. In those <65 years old, shared childhood (RR: 1.41, 95% CI: 1.26-1.57) and household (RR: 2.08, 95% CI: 1.25-3.46) environments were significantly greater contributors to familial risk of CRC than genetics (RR: 0.88, 95% CI: 0.53-1.46). This large-scale Nordic population-based study of excess risk of CRC among relatives of those with CRC addresses the difficult disentangling of shared environment from genetic predisposition in the heritability of CRC. We found shared environment to be the most important contributor to CRC risk.

Audit of laboratory sensitivity of human papillomavirus and cytology testing in a cervical screening program.

The globally recommended public health policy for cervical screening is primary human papillomavirus (HPV) screening with cytology triaging of positives. To ensure optimal quality of laboratory services we have conducted regular audits of cervical smears taken before cervical cancer or cancer in situ (CIN3+) within an HPV-based screening program. The central cervical screening laboratory of Stockholm, Sweden, identified cases of CIN3+ who had had a previous cervical screening test up to 3 years before and randomly selected 300 cervical liquid-based cytology (LBC) samples for auditing. HPV testing with Roche Cobas was performed either at screening or with biobanked samples. HPV negative samples and subsequent biopsies were retrieved and tested with modified general primer HPV PCR and, if still HPV-negative, the LBCs and biopsies were whole genome sequenced. The Cobas 4800 detected HPV in 1020/1052 (97.0%) LBC samples taken before CIN3+. Further analyses found HPV in 28 samples, with nine of those containing HPV types not targeted by the Cobas 4800 test. There were 4 specimens (4/1052, 0.4%) where no HPV was detected. By comparison, the proportion of CIN3+ cases that were positive in a previous cytology were 91.6%. We find that the routine HPV screening test had a sensitivity in the real-life screening program of 97.0%. Regular laboratory audits of cervical samples taken before CIN3+ can be readily performed within a real-life screening program and provide assurance that the laboratory of the real-life program has the expected performance.

Organized primary human papillomavirus-based cervical screening: A randomized healthcare policy trial.

BACKGROUND: Clinical trials in the research setting have demonstrated that primary human papillomavirus (HPV)-based screening results in greater protection against cervical cancer compared with cytology, but evidence from real-life implementation was missing. To evaluate the effectiveness of HPV-based cervical screening within a real-life screening program, the organized, population-based cervical screening program in the capital region of Sweden offered either HPV- or cytology-based screening in a randomized manner through a randomized healthcare policy (RHP). METHODS AND FINDINGS: A total of 395,725 women aged 30 to 64 years that were invited for their routine cervical screening visit were randomized without blinding to either cytology-based screening with HPV triage (n = 183,309) or HPV-based screening, with cytology triage (n = 212,416 women) between September 1, 2014 and September 30, 2016 and follow-up through June 30, 2017. The main outcome was non-inferior detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Secondary outcomes included superiority in CIN2+ detection, screening attendance, and referral to histology. In total, 120,240 had a cervical screening sample on record in the study period in the HPV arm and 99,340 in the cytology arm and were followed for the outcomes of interest. In per-protocol (PP) analyses, the detection rate of CIN2+ was 1.03% (95% confidence interval (CI) 0.98 to 1.10) in the HPV arm and 0.93% (0.87 to 0.99) in the cytology arm (p for non-inferiority <0.0001; odds ratio (OR) 1.11 (95% CI 1.02 to 1.22)). There were 46 cervical cancers detected in the HPV arm (0.04% (0.03 to 0.06)) and 48 cancers detected in the cytology arm (0.05% (0.04 to 0.07)) (p for non-inferiority <0.0001; OR 0.79 (0.53 to 1.18)). Intention-to-screen (ITS) analyses found few differences. In the HPV arm, there was a modestly increased attendance after new invitations (68.56% (68.31 to 68.80) vs. 67.71% (67.43 to 67.98); OR 1.02 (1.00 to 1.03)) and increased rate of referral with completed biopsy (3.89% (3.79 to 4.00) vs. 3.53% (3.42 to 3.65); OR 1.10 (1.05 to 1.15)). The main limitations of this analysis are that only the baseline results are presented, and there was an imbalance in invitations between the study arms. CONCLUSIONS: In this study, we observed that a real-life RHP of primary HPV-based screening was acceptable and effective when evaluated against cytology-based screening, as indicated by comparable participation, referral, and detection rates. TRIAL REGISTRATION: ClinicalTrials.gov NCT01511328.

Human papillomavirus load and genotype analysis improves the prediction of invasive cervical cancer.

Human papillomavirus (HPV)-based cervical screening is a globally recommended health policy. Different HPV types have different risk for cervical cancer. For optimal HPV screening, the sensitivity and specificity for each HPV type at different viral loads should be known in a screening setting. HPV test results in about 1 million cervical samples analyzed during 2006 to 2014 were compared for 319 women who had developed invasive cervical cancer up to 8.5 years later and for 1911 matched control women. Detection including low viral loads resulted in markedly increased sensitivity for cervical cancer only for HPV types 16 and 18. Testing for HPV types 31, 33, 45 and 52 also increased the sensitivity for prediction of cervical cancer, but for these viruses, detection of low viral load did not further increase sensitivity. HPV types 35, 39, 51, 56, 58, 59, 66 and 68 only predicted occasional additional cervical cancer cases. Testing for HPV16/18 at low viral load plus testing for HPV31, 33, 45 and 52 at >3000 copies/µL predicted 86.5% of cancers occurring within a year after testing, similar to the 89.4% that were predicted by testing for 14 HPV types. By contrast, the type and viral load-restricted testing greatly increased specificity: 6.3% of healthy women tested positive as compared to 11.7% of healthy women testing positive for the 14 HPV types commonly screened for today. Adequate HPV screening sensitivity, with considerable increase in specificity, can be obtained by testing only for HPV16/18/31/33/45/52, with detection of low viral load required only for HPV16/18.

Human papillomavirus genotype-specific risks for cervical intraepithelial lesions.

Prevalence of different HPV genotypes is changing after HPV vaccination. The associated risks are needed for optimizing cervical cancer screening.To estimate HPV type-specific prevalence, odds ratio (OR), and positive predictive value (PPV) for cervical cytological abnormalities, we determined 41 different HPV genotypes in cervical samples from a population-based sample of 8351 women aged 18-51 years before HPV vaccination era (V501-033; NCT01077856).Prevalence of HPV16 was 4.9% (95% CI: 4.4-5.5) with the PPV for high-grade cytology 11.2%, and OR 11.9 (95% CI: 8.5-16.5). Carcinogenic HPVs included in the nonavalent vaccine (HPV16,18,31,33,45,52,58) had a population prevalence of 14.4% (95% CI: 13.5-15.4), with PPV of 8.0% (95% CI: 6.8-9.3) and OR 23.7 (95% CI: 16.0-63.5) for high-grade cytology. HPV types currently included in most screening tests, but not vaccinated against (HPV35,39,51,56,59,66,68) had a joint prevalence of 8.5% (95% CI: 7.8-9.2) with PPV of 4.4% (95% CI: 3.3-5.7) and OR of 2.9 (95% CI: 2.0-4.0) for high-grade cytology. The other 27 non-carcinogenic genotypes had a prevalence of 11.8%, PPV of 2.9% (95% CI:2.1-3.9), and OR 1.5 (95% CI: 1.1-2.2.) for high-grade cytology.These results suggest that HPV screening tests in the post-vaccination era might perform better if restricted to the HPV types in the nonavalent vaccine and screening for all 14 HPV types might result in suboptimal balance of harms and benefits.

Determinants of Human Papillomavirus Vaccine Uptake by Adult Women Attending Cervical Cancer Screening in 9 European Countries.

INTRODUCTION: Human papillomavirus-vaccinated cohorts, irrespective of age, will likely reduce their subsequent screening requirements, thus opening opportunities for global cost reduction and program sustainability. The determinants of uptake and completion of a 3-dose human papillomavirus vaccination program by adult women in a European context were estimated. STUDY DESIGN: This was an intervention study. SETTING/PARTICIPANTS: Study participants were women aged 25-45 years, attending opportunistic or population-based cervical cancer screening in Belgium, Denmark, Finland, France, Germany, Slovenia, Spain, Sweden, and the United Kingdom between April 2016 and May 2018. INTERVENTION: Study participants completed a questionnaire on awareness and attitudes on adult female human papillomavirus vaccination and were invited to receive free human papillomavirus vaccination. MAIN OUTCOME MEASURES: Main outcome measures were acceptance, uptake, and completion of vaccination schedule. Determinants of vaccine uptake were explored using multilevel logistic models in 2019. RESULTS: Among 3,646 participants, 2,748 (range by country=50%-96%) accepted vaccination, and 2,151 (range=30%-93%) received the full vaccination course. The factors associated with higher vaccine acceptance were previous awareness of adult female (OR=1.22, 95% CI=1.00, 1.48) and male (OR=1.59, 95% CI=1.28, 1.97) vaccination. Women in stable relationships (OR=0.56, 95% CI=0.45, 0.69) or with higher educational level (OR=0.76, 95% CI=0.63, 0.93) were more likely to refuse vaccination. Recruitment by postal invitation versus personal invitation from a healthcare professional resulted in lower vaccine acceptance (OR=0.13, 95% CI=0.02, 0.76). Vaccination coverage of >70% of adolescent girls in national public programs was of borderline significance in predicting human papillomavirus vaccine uptake (OR=3.23, 95% CI=0.95, 10.97). The main reasons for vaccine refusal were vaccine safety concerns (range=30%-59%) and the need for more information on human papillomavirus vaccines (range=1%-72%). No safety issues were experienced by vaccinated women. CONCLUSIONS: Acceptance and schedule completion were largely dependent on recruitment method, achieved coverage of national vaccination programs, and personal relationship status. Knowledge of benefits and safety reassurance may be critical to expanding vaccination target ages. Study results suggest that there are no major opinion barriers in adult women to human papillomavirus vaccination, especially when vaccination is offered face to face in healthcare settings. TRIAL REGISTRATION: EudraCT Number 2014-003177-42.

Final analysis of a 14-year long-term follow-up study of the effectiveness and immunogenicity of the quadrivalent human papillomavirus vaccine in women from four nordic countries.

BACKGROUND: The quadrivalent human papillomavirus (qHPV) vaccine prevented vaccine HPV type-related infection and disease in young women in the 4-year FUTURE II efficacy study (NCT00092534). We report long-term effectiveness and immunogenicity at the end of 14 years of follow-up after enrollment in FUTURE II. METHODS: Young women (16-23 years of age) from Denmark, Iceland, Norway, and Sweden who received three qHPV vaccine doses during the randomized, double-blind, placebo-controlled FUTURE II base study were followed for effectiveness for an additional ≥10 years through national registries. Tissue samples including but not limited to those collected during organized cervical cancer screening programs were obtained from regional biobanks to be adjudicated for histopathology diagnosis and tested for HPV DNA. The observed incidence of HPV16/18-related high-grade cervical dysplasia (primary outcome) was compared with recent historical background incidence rates in an unvaccinated population. Serum was collected at years 9 and 14 to assess antibody responses. FINDINGS: No cases of HPV16/18-related high-grade cervical dysplasia were observed in the per-protocol effectiveness population (N = 2121; 24,099·0 person-years of follow-up) during the entire study. Vaccine effectiveness of 100% (95% CI 94·7-100) was demonstrated for ≥12 years, with a trend toward continued protection through 14 years post-vaccination. Seropositivity rates at study conclusion were >90% (HPV6/11/16) and 52% (HPV18) using competitive Luminex immunoassay, and >90% (all four HPV types) using the more sensitive IgG Luminex immunoassay. INTERPRETATION: Vaccination of young women with qHPV vaccine offers durable protection against HPV16/18-related high-grade cervical dysplasia for ≥12 years, with a trend toward continued protection through 14 years post-vaccination, and induces sustained HPV6/11/16/18 antibody responses for up to 14 years post-vaccination. There was no evidence of waning immunity, suggesting no need for a booster dose during that period. FUNDING: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Use of real-world data for HPV vaccine trial follow-up in the Nordic region.

Post-marketing studies are commonly performed to follow-up on the safety and effectiveness of a drug or vaccine after approval has been obtained. These post-marketing studies may involve the collection of real-world data from registries and clinical biobanks in order to obtain real-world evidence. As this approach can monitor the effects of pharmaceutical products over decades, it is particularly necessary for the development of safe and effective vaccines. A long-term follow-up (LTFU) study was initiated as an extension of a phase 3 clinical study (V501-015; NCT00092534) to assess the effectiveness, immunogenicity and safety of the quadrivalent human papillomavirus (qHPV) vaccine for up to 14 years after the start of vaccination. The LTFU study included participants from Denmark, Iceland, Norway, and Sweden, and assessed qHPV vaccine effectiveness against cervical pre-cancers and cancers caused by the oncogenic HPV types 16 and 18. In particular, our study utilized Nordic national health registries, in which individual patient records were linked by a unique Personal Identity Number. Here, we describe the overall implementation and methodology of the qHPV vaccine LTFU study conducted in the Nordic region. The LTFU study format we describe here supported a comprehensive follow-up process, with near-complete retrieval of registry data and specimens from local laboratories achieved in a timely manner; therefore, we have demonstrated that such a collection is feasible and can be used to address stringent post-marketing requirements.

Human papillomavirus types in cervical dysplasia among young HPV-vaccinated women: Population-based nested case-control study.

Human papillomavirus (HPV) vaccines protect against infections with the most oncogenic HPV types, cervical intraepithelial neoplasia (CIN) and cervical cancer. We investigated whether development of cervical intraepithelial neoplasia (CIN) lesions in HPV-vaccinated women is associated with vaccine-targeted HPV types or not. Linkage of the Swedish vaccination and cervical screening registries identified all females born 1980-2000 who had been HPV vaccinated before December 31, 2014 (n = 305,320) and had attended cervical screening in 2006-2018 (n = 79,491). We further selected women HPV vaccinated below 17 years of age and screened in the capital region (n = 5,874). Among those, 125 developed CIN and had a cervical cryopreserved sample available (42.5% of all eligible CIN cases). After 1:2 matching to disease-free HPV vaccinated controls (n = 242), samples were analyzed for HPV DNA and associations between HPV type and CIN diagnosis were estimated with conditional logistic regression. Vaccine-targeted HPV types were rare among both CIN cases (2.4% HPV16, 0.8% HPV18) and their matched controls (0.4% HPV16 and 18). No woman had HPV6 or 11. The CIN lesions were associated with the nonvaccine HPV types 31, 33, 42, 45, 51, 52, 56, 59 and 66. CIN lesions among young HPV vaccinated women are mostly attributable to infection with nonvaccine HPV types. The phenomenon may be important for surveillance and design of cervical cancer control strategies.

Human papillomavirus types in cervical high-grade lesions or cancer among Nordic women-Potential for prevention.

It is valuable to establish a population-based prevaccination baseline distribution of human papillomavirus (HPV) types among women with high-grade cervical intraepithelial neoplasia (CIN) grade 2 or 3 and cervical cancer in order to assess the potential impact of HPV vaccination. In four countries (Denmark, Norway, Sweden, and Iceland), we collected consecutive series of cervical cancers (n = 639) and high-grade precancerous cervical lesions (n = 1240) during 2004-2006 before implementation of HPV vaccination and subjected the specimens to standardized HPV genotyping. The HPV prevalence was 82.7% (95% confidence interval [CI] 79.0-86.4) in CIN2, 91.6% (95% CI 89.7-93.5) in CIN3, and 86.4% (95% CI 83.7-89.1) in cervical cancer. The most common HPV types in CIN2/3 were HPV16 (CIN2: 35.9%, 95% CI 31.2-40.6; CIN3: 50.2%, 95% CI 46.8-53.6) and HPV31 (CIN2: 10.9%, 95% CI 7.8-13.9; CIN3: 12.1%, 95% CI 9.9-14.3), while HPV16 and HPV18 were the most frequent types in cervical cancer (48.8%, 95% CI 44.9-52.7 and 15.3%, 95% CI 12.5-18.1, respectively). The prevalence of HPV16/18 decreased with increasing age at diagnosis in both CIN2/3 and cervical cancer (P < 0.0001). Elimination of HPV16/18 by vaccination is predicted to prevent 42% (95% CI 37.0-46.7) of CIN2, 57% (95% CI 53.8-60.5) of CIN3 and 64% (95% CI 60.3-67.7) of cervical cancer. Prevention of the five additional HPV types HPV31/33/45/52/58 would increase the protection to 68% (95% CI 63.0-72.2) in CIN2, 85% (95% CI 82.4-87.2) in CIN3 and 80% (95% CI 77.0-83.2) in cervical cancer. This study provides large-scale and representative baselines for assessing and evaluating the population-based preventive impact of HPV vaccination.

Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis.

Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8,742 persons with MS and 7,215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9 × 10-22), and increased risk of future MS (OR = 2.22, p = 2 × 10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

Cervical cancer screening in Sweden 2014-2016.

BACKGROUND: To enable incremental optimization of screening, regular reporting of quality indicators is required. AIM: To report key quality indicators and basic statistics about cervical screening in Sweden. METHODS: We collected individual level data on all cervical cytologies, histopathologies, human papillomavirus tests and all invitations for cervical screening in Sweden during 2013-2016. RESULTS: There were over 2,278,000 cervical samples collected in Sweden in 2014-2016. Organized samples (resulting from an invitation) constituted 69% of samples. The screening test coverage of all resident women aged 23-60 was 82%. The coverage has slowly increased for >10 years. There is large variability between counties (from 71% to 92%) over time. There were 25,725 women with high-grade lesions in cytology during 2013-2015. Only 96% of these women had a follow-up histopathology within a year. Cervical cancer incidence showed an increasing trend. CONCLUSION: Key quality indicators such as population coverage and follow-up rates were stable or improving, but there was nevertheless an unexplained cervical cancer increase.

Viremia preceding multiple sclerosis: Two nested case-control studies.

Infections have been suggested to be involved in Multiple Sclerosis (MS). We used metagenomic sequencing to detect both known and yet unknown microorganisms in 2 nested case control studies of MS. Two different cohorts were followed for MS using registry linkages. Serum samples taken before diagnosis as well as samples from matched control subjects were selected. In cohort1 with 75 cases and 75 controls, most viral reads were Anelloviridae-related and >95% detected among the cases. Among samples taken up to 2 years before MS diagnosis, Anellovirus species TTMV1, TTMV6 and TTV27 were significantly more common among cases. In cohort2, 93 cases and 93 controls were tested under the pre-specified hypothesis that the same association would be found. Although most viral reads were again related to Anelloviridae, no significant case-control differences were seen. We conclude that the Anelloviridae-MS association may be due to multiple hypothesis testing, but other explanations are possible.

Decline of HPV infections in Scandinavian cervical screening populations after introduction of HPV vaccination programs.

OBJECTIVE: To monitor the changes in prevalence of human papillomavirus (HPV) infections in women <50 years of age, participating in cervical screening programs of Denmark, Norway, and Sweden, before and after introduction of quadrivalent HPV (qHPV) vaccination. METHODS: Liquid-based cytology samples were collected from 6538 women who attended cervical screening in Denmark, Norway, and Sweden in 2006-2008 and from 6332 similarly enrolled women in 2012-2013. Denmark started organized qHPV vaccination in 2008, Norway in 2009, and Sweden in 2012. All HPV testing and genotyping was performed using identical enrollment and analysis methods, by accredited general primer polymerase chain reaction methods with typing using the Luminex system. RESULTS: Overall HPV positivity declined slightly from 36.5% in 2006-2008 to 34.5% in 2012-2013. The decline was most pronounced among women 18-26 years of age: from 54.4% to 48.1% (P < 0.001). The decline was substantial for vaccine HPV types (HPV6/11/16/18: decline from 22.3% to 16.6%; P < 0.001) and was seen for both low-risk vaccine types (HPV6/11 declined from 5.0% to 2.5%) and high-risk vaccine types (HPV16/18 declined from 18.9% to 14.9%). Among women 27-50 years of age, there was no change between the time periods (22.5% and 21.6%, respectively). The significant decline in the younger age group was different in the 3 countries. CONCLUSION: This population-based study enrolling >12,000 women participating in cervical screening in the 3 Nordic countries before and after introduction of organized qHPV vaccination demonstrated a marked decline in HPV infection in the younger population in the 2 countries where qHPV vaccination programs started in 2008-2009, suggesting that organized HPV vaccination programs resulted in a decrease of HPV types circulating in the general population.

A 12-Year Follow-up on the Long-Term Effectiveness of the Quadrivalent Human Papillomavirus Vaccine in 4 Nordic Countries.

Background: The long-term effectiveness of the quadrivalent human papillomavirus (qHPV) vaccine was assessed by monitoring the combined incidence of cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ (AIS), and cervical cancer related to HPV16 or HPV18. Methods: Women from Nordic countries of Denmark, Iceland, Norway, and Sweden who received a 3-dose regimen of the qHPV vaccine in the beginning of FUTURE II (Females United to Unilaterally Reduce Endo/Ectocervical Disease; V501-015, base study NCT00092534) are followed through different national registries. Effectiveness analyses were conducted approximately 2 years following completion of the base study and occur approximately every 2 years thereafter for 10 years (ie, 14 years from day 1 of the base study). Vaccine effectiveness against HPV16/18-related CIN2 or worse (CIN2+) was estimated by comparing the observed incidence with the expected incidence of CIN2+ in an unvaccinated cohort using historical registry data. Results: In the per-protocol population (2084 women) analysis of effectiveness after the first 12 years, there were no breakthrough cases of HPV16/18 CIN2+ after 9437 person- years of follow-up. Statistical power was sufficient to conclude that qHPV vaccine effectiveness remains above 90% for at least 10 years. The number of person-years during the follow-up interval of 10-12 years is continuing to accrue and shows a trend toward continuing effectiveness of the vaccine during that period. Conclusion: The qHPV vaccine shows continued protection in women through at least 10 years, with a trend for continued protection through 12 years of follow-up. Clinical Trials Registration: NCT00092534. Study Identification: V501-015.

Viruses in cancers among the immunosuppressed.

Most cancer forms known to be caused by viruses are increased among the immunosuppressed, but several cancer forms without established viral etiology are also increased, notably nonmelanoma skin carcinoma (NMSC). We followed all 13,429 solid organ transplantation patients in Sweden for cancer occurrence after transplantation. We requested these tumor specimens and sequenced the first 89 specimens received (62 NMSCs, 27 other cancers). The sequences were analyzed for viruses based on two bioinformatics algorithms (paracel-blast (sensitive for detection of known viruses) and hidden Markov model (HMM; sensitive for distantly related viruses)). Among the 62 NMSCs, the virus family detected in the largest proportion of specimens was Mimiviridae (9/62 NMSCs). The majority of the virus-related reads belonged to Papillomaviridae. The HMM analysis identified 86 additional previously not described viral contigs related to 11 virus families, with reads related to Mimiviridae being the most common (detected in 28/62 NMSCs) with the most prevalent contig (Mimivirus SE906, 1937 bp) detected in 17/62 NMSCs. Among the 27 other cancers, viral sequences were detected in only 5 specimens by blast analysis, compared to in all 27 specimens by HMM (Mimiviridae, Poxviridae, Phycodnaviridae and virus-related sequences yet unclassified to any family). 99% of the virus reads belonged to a single previously not described sequence (Mimivirus SE996, 911 bp). A multitude of viruses is readily detectable in specimens with cancers occurring among the immunosuppressed, with sequences related to Mimiviridae being the most prevalent. Further research would be needed to elucidate the biological significance of the viruses.

Randomised healthcare policy evaluation of organised primary human papillomavirus screening of women aged 56-60.

OBJECTIVE: The aim of this research is to implement and reliably evaluate primary human papillomavirus (HPV) screening in an established and routinely running organised, large-scale population-based screening programme. PARTICIPANTS: Resident women in the Stockholm/Gotland region of Sweden, aged 56-60 years were randomised to either (1) screening with cervical cytology, with HPV test in triage of low-grade cytological abnormalities (old policy) or (2) screening with HPV testing, with cytology in triage of HPV positives (new policy). OUTCOME: The primary evaluation was the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). RESULTS: During January 2012-May 2014, the organised screening programme sent 42 752 blinded invitations with a prebooked appointment time to the women in the target age group. 7325 women attended in the HPV policy arm and 7438 women attended in the cytology arm. In the new policy, the population HPV prevalence was 5.5%, using an accredited HPV test (Cobas 4800). HPV16 prevalence was 1.0% (73/7325) and HPV18 prevalence was 0.3% (22/7325). In the HPV policy arm, 78/405 (19%) HPV-positive women were also cytology positive. There were 19 cases of CIN2+ in histopathology, all among women who were both HPV positive and cytology positive. The positive predictive value for CIN2+ in this group was 33.3% (19/57). In the cytology policy, 153 women were cytology positive and there were 18 cases of CIN2+ in histopathology. Both the total number of cervical biopsies and the number of cervical biopsies with benign histopathology were much lower in thepositive predictive value policy (49 benign, 87 total vs 105 benign, 132 total). CONCLUSION: Primary HPV screening had a similar detection rate for CIN2+ as cytology-based screening, already before follow-up of HPV-positive, cytology-negative women with new HPV test and referral of women with persistence. TRIAL REGISTRATION NUMBER: NCT01511328.

Viruses in case series of tumors: Consistent presence in different cancers in the same subject.

Studies investigating presence of viruses in cancer often analyze case series of cancers, resulting in detection of many viruses that are not etiologically linked to the tumors where they are found. The incidence of virus-associated cancers is greatly increased in immunocompromised individuals. Non-melanoma skin cancer (NMSC) is also greatly increased and a variety of viruses have been detected in NMSC. As immunosuppressed patients often develop multiple independent NMSCs, we reasoned that viruses consistently present in independent tumors might be more likely to be involved in tumorigenesis. We sequenced 8 different NMSCs from 1 patient in comparison to 8 different NMSCs from 8 different patients. Among the latter, 12 different virus sequences were detected, but none in more than 1 tumor each. In contrast, the patient with multiple NMSCs had human papillomavirus type 15 and type 38 present in 6 out of 8 NMSCs.