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 (16À23 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¢7À100) 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.

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Ovarian serous borderline tumors (SBTs) have been the subject of considerable controversy, particularly with regard to terminology and behavior. It has been proposed that they constitute a heterogeneous group of tumors composed, for the most part, of typical SBTs that are benign and designated “atypical proliferative serous tumor (APST)” and a small subset of SBTs with micropapillary architecture that have a poor outcome and are designated “non-invasive low-grade serous carcinoma (niLGSC)”. It also has been argued that the difference in behavior between the two groups is not due to the subtype of the primary tumor but rather the presence of extra-ovarian disease, specifically invasive implants. According to the terminology of the 2014 WHO Classification, typical SBTs are equivalent to APSTs and SBTs displaying micropapillary architecture are synonymous with niLGSC. In addition, “invasive implants” were renamed “low-grade serous carcinoma” (LGSC). The argument as to whether it is the appearance of the primary tumor or the presence of extra-ovarian LGSC that determines outcome remains unsettled. The current study was initiated in 2004 and was designed to determine what factors were predictive of outcome, with special attention to the appearance of the primary tumor (APST vs. niLGSC) and that of the extra-ovarian disease (non-invasive vs. invasive implants). Our study is population-based, involving the entire female population of Denmark. None of the women in the study were lost to follow-up, which ranged up to 36 years (median, 15 years). All the microscopic slides from the contributing hospitals were re-reviewed by a panel of two pathologists (RV and RJK) who were blinded to the follow-up. After excluding those that were not SBTs by the pathology panel, as well as cases with a prior or concurrent cancer or undefined stage, 942 women remained, of which 867 were APSTs and 75 were niLGSCs. The median patient age was 50 years (range, 16–97). Eight hundred nine women (86%) presented with FIGO stage I disease while 133 (14%) had advanced stage disease. Compared to APSTs, niLGSC exhibited a significantly greater frequency of bilaterality, residual gross disease after surgery, microinvasion/microinvasive carcinoma, advanced stage disease, and invasive implants at presentation (p-values <0.003). Because the cause of death is difficult to accurately ascertain from death certificates, we used development of invasive serous carcinoma as the primary endpoint since following development of carcinoma, the mortality is very high. In the entire cohort, subsequent development of carcinoma occurred in 4%, of which 93% were low-grade and 7% high-grade (median time, 10 years; range, up to 25 years). After adjusting for age at and time since diagnosis of APST or niLGSC, occurrence of subsequent carcinoma was significantly higher with niLGSC than APST among all stages combined (hazard ratio [HR] = 3.8; 95% confidence interval [CI]: 1.7–8.2). This difference was still significant for stage I but not advanced stage cases. Moreover, all-c...