Outcomes of cervical human papillomavirus (HPV) infections among mothers in the Finnish Family HPV Study

To understand the natural history of cervical human papillomavirus (HPV)-infections, more information is needed on their genotype-specific prevalence, acquisition, clearance, persistence and progression. This thesis is part of the prospective Finnish Family HPV study. 329 pregnant women (mean age 25.5 years) were recruited during the third trimester of pregnancy and were followed up for 6 years. The outcomes of cervical HPV infections were evaluated among all the mothers participating in the study. Generalized estimating equation (GEE)-models and Poisson regression were used to estimate the risk factors of type-specific acquisition, clearance, persistence and progression of Species 7 and 9 HPV-genotypes. Independent protective factors against incident infections were higher number of life-time sexual partners, initiation of oral contraceptive use after age 20 years and becoming pregnant during FU. Older age and negative oral HR-HPV DNA status at baseline were associated with increased clearance, whereas higher number of current sexual partners decreased the probability of clearance. Early onset of smoking, practicing oral sex and older age increased the risk of type-specific persistence, while key predictors of CIN/SIL were persistent HR-HPV, abnormal Pap smear and new sexual partners. HPV16, together with multiple-type infections were the most frequent incident genotypes, most likely to remain persistent and least likely to clear. Collectively, LR-HPV types showed shorter incidence and clearance times than HR-HPV types. In multivariate models, different predictors were associated with these main viral outcomes, and there is some tentative evidence to suggest that oral mucosa might play a role in controlling some of these outcomes.Siirretty Doriast

Human polyomavirus BKPyV and JCPyV serostatus has no impact on women´s human papillomavirus infection outcome

IntroductionPolyomaviruses have both structural and functional similarities with papillomaviruses. Accordingly, their role in human papillomavirus (HPV) associated malignancies has been studied with conflicting results. Our goal was to disclose any association between BK (BKPyV) and/or JC (JCPyV) polyomavirus serology and HPV data derived from Finnish women (327) in a 6-year prospective follow-up.MethodsGlutathione S-transferase fusion-protein-capture (ELISA) in combination with fluorescent bead technology was used to analyze antibodies to BKPyV and JCPyV. In the longitudinal setting, BKPyV or JCPyV serostatus was related to i) oral- and ii) genital low (LR)- and high risk (HR) HPV DNA detection, iii) HPV16 persistence at both these sites, iv) results of the Pap (Papanicolaou) smear taken at baseline, and v) development of incident CIN (cervical intraepithelial neoplasia) during the follow-up.ResultsBeing BKPyV or JCPyV seropositive was not significantly associated with HPV seropositivity to either LR- or HR-genotypes, genital- or oral HPV DNA positivity, persistence of genital- or oral HPV16 infection, grade of Pap smear, or development of incident CIN.DiscussionThus, the present study could not provide any confirmation to the concept that co-infections by HPyV and HPV have interactions that impact on the clinical manifestations or outcomes of HPV infections either in the genital tract or in the oral mucosa

Hinokitiol Dysregulates Metabolism of Carcinoma Cell Lines and Induces Downregulation of HPV16E6 and E7 Oncogenes and p21 Upregulation in HPV Positive Cell Lines

Background: Hinokitiol (beta-thujaplicin), isolated from the wood of Chamaecyparis taiwanensis, has a wide variety of biological properties including anti-inflammatory, anti-microbial, and anti-tumor effects. Therefore, hinokitiol has become a frequent additive in oral and other healthcare products. Objectives: Our goal was to determine the anti-tumor activity of hinokitiol on human papillomavirus (HPV) positive (n = 3) and negative (n = 2) cell lines derived from cervical or head and neck squamous cell carcinoma (HNSCC) and keratinocyte cell lines (n = 3) transformed spontaneously or with HPV16E6 and E7 oncogenes. Methods: The cell-lines were exposed to hinokitiol at different concentrations (0-200 mu M) for 24 h. Cell metabolism, proliferation, and the cell cycle distribution were assessed by MTT- and H-3-thymidine incorporation and flow cytometry. Expressions of p21 and on HPV16E6 and E7 oncogenes were assessed by qPCR. Results: In all carcinoma cell lines, hinokitiol treatment declined the metabolic activity irrespective of the HPV status. This decline was statistically significant, however, only in HPV-positive cell lines CaSki and UD-SCC-2 when exposed to hinokitiol concentrations at 100 and 200 mu M, respectively (p Conclusions: Our results indicate that hinokitiol might have potential in preventing the progress of immortalized cells toward malignancy and the growth of malignant lesions. Hinokitiol can also influence on the progression of HPV-associated lesions by downregulating the E6 and E7 expression.</p

Hinokitiol Dysregulates Metabolism of Carcinoma Cell Lines and Induces Downregulation of HPV16E6 and E7 Oncogenes and p21 Upregulation in HPV Positive Cell Lines

Background: Hinokitiol (β‐thujaplicin), isolated from the wood of Chamaecyparis taiwanensis, has a wide variety of biological properties including anti‐inflammatory, anti‐microbial, and anti‐tumor effects. Therefore, hinokitiol has become a frequent additive in oral and other healthcare products. Objectives: Our goal was to determine the anti‐tumor activity of hinokitiol on human papillomavirus (HPV) positive (n = 3) and negative (n = 2) cell lines derived from cervical or head and neck squamous cell carcinoma (HNSCC) and keratinocyte cell lines (n = 3) transformed spon-taneously or with HPV16E6 and E7 oncogenes. Methods: The cell‐lines were exposed to hinokitiol at different concentrations (0–200μM) for 24 h. Cell metabolism, proliferation, and the cell cycle distribution were assessed by MTT‐ and3H‐thymidine incorporation and flow cytometry. Expres-sions of p21 and on HPV16E6 and E7 oncogenes were assessed by qPCR. Results: In all carcinoma cell lines, hinokitiol treatment declined the metabolic activity irrespective of the HPV status. This decline was statistically significant, however, only in HPV‐positive cell lines CaSki and UD‐SCC‐2 when exposed to hinokitiol concentrations at 100 and 200 μM, respectively (p < 0.05). Immortalized cell lines, HMK and HPV‐positive IHGK, were more sensitive as a similar metabolic effect was achieved at lower hinokitiol concentrations of 3.1, 6.25, and 50 μM, respectively. Hinokitiol blocked DNA synthesis of all carcinoma cell lines without evident association with HPV status. G1 cell cycle arrest and p21 upregulation was found in all cell lines after hinokitiol treatment at higher concen-tration. However, when the p21 results of all HPV‐positive cells were pooled together, the increase in p21 expression was statistically significantly higher in HPV‐positive than in HPV‐negative cell lines (p = 0.03), but only at the highest hinokitiol concentration (200 μM). In HPV‐positive cell lines hinokitiol declined the expression of HPV16E7 and E6 along the increase of p21 expression. The dose‐dependent inverse correlation between p21 and E7 was statistically significant in SiHa cells (r = −0.975, p‐value = 0.03) and borderline in UD‐SCC‐2 cells (r = −0.944, p‐value = 0.06), in which p21 and E6 were also inversely correlated (r = −0.989). Conclusions: Our results indicate that hinokitiol might have potential in preventing the progress of immortalized cells toward malignancy and the growth of malignant lesions. Hinokitiol can also influence on the progression of HPV‐associated lesions by downregulating the E6 and E7 expression.publishedVersionPeer reviewe

Longitudinal Dynamics of HPV16 Antibodies in Saliva and Serum among Pregnant Women

publishedVersionPeer reviewe

A synthesis of evidence for cancer-specific screening interventions : A Preventive Medicine Golden Jubilee Review

The goal of cancer screening guidelines is to inform health practitioners to practice evidence-based cancer prevention. Cancer screening aims to detect treatable precancerous lesions or early-stage disease to enable actions aimed at decreasing morbidity and mortality. Continuous assessment of the available evidence for or against screening interventions by various organizations often results in conflicting recommendations and create challenges for providers and policymakers. Here we have summarized the current cancer screening recommendations by five leading organizations in North America and Europe: the National Cancer Institute's Physician Data Query (PDQ), the U.S. Preventive Services Task Force (USPSTF), the Canadian Task Force on Preventive Health Care (CTFPHC), the Cochrane Database of Systematic Reviews (CDSR), and the UK National Screening Committee for the National Health Service (UK NSC). All organizations assess evidence based on strength, quality, and quantity, and recommendations are similar although with differences with respect to screening start and stop ages. Recommendations are consistent for colorectal cancer screening with fecal occult blood test or fecal immunochemical test, cervical cancer screening with Pap-test, HPV-test, or co-testing, and breast cancer screening with mammography. However, guidelines vary with respect to age to start and end screening and testing frequency. Tests that have proven to be inefficient or whose use is capable of causing harm are routinely recommended against. Continuous review of screening guidelines is necessary to evaluate the many promising screening tests currently under investigation.publishedVersionPeer reviewe

Methylation in predicting progression of untreated high-grade cervical intraepithelial neoplasia

BACKGROUND: There is no baseline prognostic test to ascertain whether cervical intraepithelial neoplasia (CIN) will regress or progress. The majority of CIN regress in young women and since local treatments are known to increase the risk of adverse pregnancy outcomes interventions need to be sparing. We investigated the ability of a DNA methylation panel (the S5-classifier) to discriminate between progression and regression among women of childbearing age with untreated CIN grade 2 (CIN2). METHODS: Pyrosequencing methylation and HPV genotyping assays were performed on exfoliated cervical cells from 149 young 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 lesions persisted as CIN1/2. When cytology, HPV16/18- and HPV16/18/31/33-genotyping, and S5 at baseline were compared to outcomes, S5 was the strongest biomarker associated with regression versus progression. S5 alone or in combination with HPV16/18/31/33-genotyping also showed significantly increased sensitivity versus cytology, comparing regression vs. persistence/progression. With both S5 and cytology tests set at a specificity of 38.6% (95% CI 28.4-49.6) the sensitivity of S5 was significantly higher (83.6%, 95% CI 71.9-91.8) than for cytology (62.3%, 95% CI 49.0-74.4) (p=0.005). The highest area under the curve (AUC) was 0.735 (95% CI 0.621-0.849) in the regression vs. progression outcome with a combination of S5 and cytology, whereas HPV16/18 or HPV16/18/31/33-genotyping did not provide additional prognostic information. CONCLUSIONS: The S5-classifier shows high potential as a prognostic biomarker to identify women with progressive CIN2.Peer reviewe

Outcomes of HPV type-specific serostatus do not associate with oral or genital HPV-carriage in non-vaccinated women followed for three years

BackgroundThe role of human papillomavirus (HPV) antibodies acquired through natural infection and their role in protection for subsequent cervical or oral HPV-carriage remains unclear.MethodsA total of 267 women, with a 36-months follow-up, from the Finnish Family HPV (FFHPV) study were evaluated to shed more light on persistent HPV-specific antibodies to genital or oral HPV-carriage, clearance or persistence during the three years follow-up. The type-specific seroprevalence for HPV genotypes 6, 11, 16, 18 and 45 in these women was assessed in relation to the detection of the same genotype or any HPV in their oral and genital samples. The following HPV serological outcomes where detected: being always seronegative, seroconversion or persistent seropositivity.ResultsGenital HPV16 infections were most prevalent at the end of the follow-up (24- and 36-month visit) among women who tested always seronegative for HPV16. No such associations between serology and HPV detection were established for the other HPV genotypes in the genital or oral samples. The development of long-term type-specific HPV 6,11,16,18 and 45 persistence (>= 24 months) or clearance of the genital or oral infections was not different among the women with high HPV genotype specific antibody levels and those testing always HPV-seronegative.ConclusionNo significant role was disclosed for the acquired natural high-level- or persistent HPV antibodies as determinants of the genital or oral HPV infection outcomes in these young, non-vaccinated women.</p

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

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 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

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

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 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