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1.  Targeting Human Papillomavirus to Reduce the Burden of Cervical, Vulvar and Vaginal Cancer and Pre-Invasive Neoplasia: Establishing the Baseline for Surveillance 
PLoS ONE  2014;9(2):e88323.
Background
Infection with high-risk human papillomavirus (HPV) is causally related to cervical, vulvar and vaginal pre-invasive neoplasias and cancers. Highly effective vaccines against HPV types 16/18 have been available since 2006, and are currently used in many countries in combination with cervical cancer screening to control the burden of cervical cancer. We estimated the overall and age-specific incidence rate (IR) of cervical, vulvar and vaginal cancer and pre-invasive neoplasia in Denmark, Iceland, Norway and Sweden in 2004–2006, prior to the availability of HPV vaccines, in order to establish a baseline for surveillance. We also estimated the population attributable fraction to determine roughly the expected effect of HPV16/18 vaccination on the incidence of these diseases.
Methods
Information on incident cervical, vulvar and vaginal cancers and high-grade pre-invasive neoplasias was obtained from high-quality national population-based registries. A literature review was conducted to define the fraction of these lesions attributable to HPV16/18, i.e., those that could be prevented by HPV vaccination.
Results
Among the four countries, the age-standardised IR/105 of cervical, vaginal and vulvar cancer ranged from 8.4–13.8, 1.3–3.1 and 0.2–0.6, respectively. The risk for cervical cancer was highest in women aged 30–39, while vulvar and vaginal cancers were most common in women aged 70+. Age-standardised IR/105 of cervical, vulvar and vaginal pre-invasive neoplasia ranged between 138.8−183.2, 2.5−8.8 and 0.5−1.3, respectively. Women aged 20−29 had the highest risk for cervical pre-invasive neoplasia, while vulvar and vaginal pre-invasive neoplasia peaked in women aged 40−49 and 60−69, respectively. Over 50% of the observed 47,820 incident invasive and pre-invasive cancer cases in 2004−2006 can be attributed to HPV16/18.
Conclusion
In the four countries, vaccination against HPV 16/18 could prevent approximately 8500 cases of gynecological cancer and pre-cancer annually. Population-based cancer and vaccination registries are essential to assess the predicted public health effects of HPV vaccination.
doi:10.1371/journal.pone.0088323
PMCID: PMC3914976  PMID: 24505474
2.  Upscaling human papillomavirus vaccination in high-income countries: impact assessment based on transmission model 
Background
The decrease in human papillomavirus (HPV) vaccine prices may allow upscale already started vaccination programmes but the advantages of different options are unclear.
Methods
Using a mathematical model of HPV16 and 18 transmission and data on vaccination coverage from Italy, we compared 3 options to upscale an already started programme targeting 11-year old girls (coverage 65%): a) coverage improvement (from 65% to 90%); b) addition of 11-year-old boys (coverage 65%); or c) 1-year catch-up of older girls (coverage 50%).
Results
The reduction of cervical HPV16/18 infection as compared to no vaccination (i.e. effectiveness against HPV16/18) increased from 76% to 98% with coverage improvement in girls and to 90% with the addition of boys. With higher coverage in girls, HPV16/18 infection cumulative probability by age 35 decreased from 25% to 8% with a 38% increase in vaccine number. The addition of boys decreased the cumulative probability to 18% with a 100% increase in the number of vaccinees. For any coverage in girls, the number of vaccinees to prevent 1 woman from being infected by HPV16/18 by age 35 was 1.5, whereas it was 2.7 for the addition of boys. Catch-up of older girls only moved forward the vaccination effectiveness by 2–5 years.
Conclusions
Increasing vaccination coverage among girls is the most effective option for decreasing HPV16/18. If not achievable, vaccinating boys is justifiable if vaccine cost has at least halved, because this option would almost double the number of vaccinees.
doi:10.1186/1750-9378-9-4
PMCID: PMC3901332  PMID: 24438317
Human papillomavirus; Vaccination; High-income; Mathematical model
3.  Comparative effectiveness study on human papillomavirus detection methods used in the cervical cancer screening programme 
BMJ Open  2014;4(1):e003460.
Objectives
To compare the short-term and long-term effectiveness of human papillomavirus (HPV) tests in Norwegian Cervical Cancer Screening Programme (NCCSP).
Design
Nationwide register-based prospective follow-up study.
Setting
In 2005, the NCCSP implemented HPV testing in follow-up of unsatisfactory, atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cytology.
Participants
19 065 women with repeat cytology and HPV test after unsatisfactory ASC-US or LSIL screening result in 2005–2009.
Interventions
Through individual registry linkages we observed how women were treated in the regular medical care.
Main outcome measures
We estimated cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in 6 months and 3 years after repeat cytology and HPV test. Patients diagnosed with CIN2+ in 6 months and 3 years were assessed for initial HPV positivity.
Results
5392 had ASC-US/LSIL and 13 673 had normal/unsatisfactory repeat cytology; for HPV detection 4715 used AMPLICOR HPV Test (Roche Diagnostics, Basel, Switzerland), 9162 Hybrid Capture 2 (HC2) High-Risk HPV DNA Test (QIAGEN, Gaithersburg, Maryland, USA) and 5188 PreTect HPV-Proofer (NorChip, Klokkarstua, Norway). Among those with ASC-US/LSIL repeat cytology, 3-year risk of CIN2+ was 15-fold in Amplicor/HC2-positives compared with Amplicor/HC2-negatives and sevenfold in Proofer-positives compared with Proofer-negatives; a 3-year risk of CIN2+ was 2.1% (95% CI 0.7% to 3.4%) in Amplicor-negatives and 7.2% (95% CI 5.4% to 8.9%) in Proofer-negatives. Close to 100% of patients with CIN2+ diagnosed within 6 months tested positive to HPV (all methods). Considering all patients diagnosed with CIN2+ in 3-year follow-up, 97% were initially positive in the Amplicor group and more than 94% in the HC2 group, compared with less than 80% in the Proofer group.
Conclusions
While the long-term evaluation of new screening routines showed a good overall performance of triage-HPV DNA testing, the management of HPV-negative women with persistent ASC-US/LSIL was suboptimal.
doi:10.1136/bmjopen-2013-003460
PMCID: PMC3902315  PMID: 24401720
4.  PROSPECTIVE STUDY OF HPV16 VIRAL LOAD AND RISK OF IN SITU AND INVASIVE SQUAMOUS CERVICAL CANCER 
Background
A strong association has been shown between high viral DNA load (VL) of human papillomavirus (HPV) type 16 and risk for cervical cancer in situ (CIS). However, little data is available for the significance of VL in invasive squamous cell carcinoma (SCC).
Methods
In two nested case-control studies among women participating in cervical screening, with a cytologically normal first smear, we collected 5665 smears from 621 women with CIS, 457 with SCC, and individually matched controls. All smears were tested for HPV, and VLs of HPV16 positive smears were quantified using realtime-PCR. The median follow-up until diagnosis of CIS or SCC was 6.1-7.7 years.
Results
Low VL’s were common among both CIS and SCC case women, until 1-2 years before diagnosis when a surge in VL occurred. The relative risk (RR) associated with low viral load of HPV16 was around 10 for CIS, and 10-20 for SCC throughout 10 years before diagnosis, compared to HPV16-negative women. For women with medium to high VL, the risk for CIS was greatly increased from five years before diagnosis (RR=19, 95% confidence interval 7-48). In SCC, a high VL conferred an increased risk, but only from 3 years before diagnosis (RR=60, 95% CI 6-580).
Conclusions
We demonstrate differing risk functions associated with HPV16 viral load in CIS and SCC, respectively. We further show that viral loads were unexpectedly low early in the SCC disease process.
Impact
HPV16 viral load appears highly complex which may limit its use in cervical screening.
doi:10.1158/1055-9965.EPI-12-0953-T
PMCID: PMC3538961  PMID: 23155137
Cervical cancer; HPV; HPV16; viral load; sensitivity
5.  Efficacy of RG1-VLP Vaccination against Infections with Genital and Cutaneous Human Papillomaviruses 
The Journal of investigative dermatology  2013;133(12):10.1038/jid.2013.253.
Licensed human papillomavirus (HPV) vaccines, based on virus-like particles (VLPs) self-assembled from major capsid protein L1, afford type-restricted protection against HPV types 16/18/6/11 (or 16/18 for the bivalent vaccine), which cause 70% of cervical cancers (CxCas) and 90% of genital warts. However, they do not protect against less prevalent high-risk (HR) types causing 30% of CxCa, or cutaneous HPV. In contrast, vaccination with the minor capsid protein L2 induces low-level immunity to type-common epitopes. Chimeric RG1-VLP presenting HPV16 L2 amino acids 17–36 (RG1 epitope) within the DE-surface loop of HPV16 L1 induced cross-neutralizing antisera. We hypothesized that RG1-VLP vaccination protects against a large spectrum of mucosal and cutaneous HPV infections in vivo. Immunization with RG1-VLP adjuvanted with human-applicable alum-MPL (aluminum hydroxide plus 3-O-desacyl-4′-monophosphoryl lipid A) induced robust L2 antibodies (ELISA titers 2,500–12,500), which (cross-)neutralized mucosal HR HPV16/18/45/37/33/52/58/35/39/51/59/68/73/26/69/34/70, low-risk HPV6/11/32/40, and cutaneous HPV2/27/3/76 (titers 25–1,000) using native virion- or pseudovirion (PsV)-based assays, and a vigorous cytotoxic T lymphocyte response by enzyme-linked immunospot. In vivo, mice were efficiently protected against experimental vaginal challenge with mucosal HR PsV types HPV16/18/45/31/33/52/58/35/39/51/59/68/56/73/26/53/66/34 and low-risk HPV6/43/44. Enduring protection was demonstrated 1 year after vaccination. RG1-VLP is a promising next-generation vaccine with broad efficacy against all relevant mucosal and also cutaneous HPV types.
doi:10.1038/jid.2013.253
PMCID: PMC3826974  PMID: 23752042
6.  Type-Specific Human Papillomavirus Biological Features: Validated Model-Based Estimates 
PLoS ONE  2013;8(11):e81171.
Infection with high-risk (hr) human papillomavirus (HPV) is considered the necessary cause of cervical cancer. Vaccination against HPV16 and 18 types, which are responsible of about 75% of cervical cancer worldwide, is expected to have a major global impact on cervical cancer occurrence. Valid estimates of the parameters that regulate the natural history of hrHPV infections are crucial to draw reliable projections of the impact of vaccination. We devised a mathematical model to estimate the probability of infection transmission, the rate of clearance, and the patterns of immune response following the clearance of infection of 13 hrHPV types. To test the validity of our estimates, we fitted the same transmission model to two large independent datasets from Italy and Sweden and assessed finding consistency. The two populations, both unvaccinated, differed substantially by sexual behaviour, age distribution, and study setting (screening for cervical cancer or Chlamydia trachomatis infection). Estimated transmission probability of hrHPV types (80% for HPV16, 73%-82% for HPV18, and above 50% for most other types); clearance rates decreasing as a function of time since infection; and partial protection against re-infection with the same hrHPV type (approximately 20% for HPV16 and 50% for the other types) were similar in the two countries. The model could accurately predict the HPV16 prevalence observed in Italy among women who were not infected three years before. In conclusion, our models inform on biological parameters that cannot at the moment be measured directly from any empirical data but are essential to forecast the impact of HPV vaccination programmes.
doi:10.1371/journal.pone.0081171
PMCID: PMC3882251  PMID: 24400036
7.  High Prevalence of Cutaneous Human Papillomavirus DNA on the Top of Skin Tumors but not in “Stripped” Biopsies from the Same Tumors 
The Journal of investigative dermatology  2004;123(2):10.1111/j.0022-202X.2004.23205.x.
Genomes of human papillomaviruses (HPV) are common in biopsies from non-melanoma skin cancers but are also found on healthy skin and it is possible that HPV positivity in tumor biopsies by PCR may merely reflect contamination of the lesion surface. To investigate this issue, 229 immunocompetent patients were tested for HPV DNA in swab samples collected on top of skin tumors and in biopsies of the same tumors, obtained after stripping with tape to remove superficial layers. HPV DNA was detected on top of 69% (159 of 229) of the lesions, and in 12% (28 of 229) of the stripped biopsies (p<0.001). The difference was seen for all four types of tumors studied. Seborrheic keratosis had 79% (34 of 43) HPV positivity on top of lesions versus 19% (eight of 43) in biopsies; actinic keratosis had 83% (38 of 46) HPV positivity on top versus 11% (five of 46) in biopsies; basal cell carcinoma had 63% (69 of 109) on top versus 8% (nine of 109) in biopsies and squamous cell carcinoma had 58% (18 of 31) on top versus 19% (six of 31) in biopsies. HPV DNA is common in superficial layers of lesions, but is not necessarily present throughout tumors.
doi:10.1111/j.0022-202X.2004.23205.x
PMCID: PMC3822504  PMID: 15245440
HPV; PCR; superficial; tumors
8.  Cutaneous human papillomavirus 88: Remarkable differences in viral load 
A human papillomavirus (HPV) was cloned from a patient with multiple squamous cell carcinomas (SCCs) and identified as HPV88, recently categorized into a new species within the genus Gamma. The HPV88 viral load in an SCC of the index patient exceeded 1 million copies/cell. By contrast, a survey of 447 skin lesions (79 actinic keratoses, 73 seborrhoeic keratoses, 169 basal cell carcinomas and 126 SCCs) and 362 healthy skin biopsies found detectable HPV88 DNA in only 7 specimens. All these had very low viral loads (<1 copy/103 cells) implying extreme biological variability in viral load.
doi:10.1002/ijc.23115
PMCID: PMC3795386  PMID: 17935140
tumor virology; infection; diagnostics; real-time PCR
9.  Cutaneous Human Papillomaviruses Found in Sun-Exposed Skin: Beta-papillomavirus Species 2 Predominates in Squamous Cell Carcinoma 
The Journal of infectious diseases  2007;196(6):876-883.
Background
A spectrum of cutaneous human papillomaviruses (HPVs) is detectable in nonmelanoma skin cancers, as well as in healthy skin, but the significance that the presence of these types of HPV DNA has for the pathogenesis of skin cancer remains unclear.
Methods
We studied 349 nonimmunosuppressed patients with skin lesions (82 with squamous cell carcinomas, 126 with basal cell carcinomas, 49 with actinic keratoses, and 92 with benign lesions). After superficial skin had been removed by tape, paired biopsy samples—from the lesion and from healthy skin from the same patient—were tested for HPV DNA. Risk factors for HPV DNA were analyzed in multivariate models.
Results
Overall, 12% of healthy skin samples were positive for HPV DNA, compared with 26% of benign lesions, 22% of actinic keratoses, 18% of basal cell carcinomas, and 26% of squamous cell carcinomas. HPV DNA was associated with sites extensively exposed to the sun, both for the lesions (odds ratio [OR], 4.45 [95% confidence interval {CI}, 2.44–8.11]) and for the healthy skin samples (OR, 3.65 [95% CI 1.79–7.44]). HPV types of Beta-papillomavirus species 2 predominate in squamous cell carcinomas (OR, 4.40 [95% CI, 1.92–10.06]), whereas HPV types of Beta-papillomavirus species 1 are primarily found in benign lesions (OR, 3.47 [95% CI, 1.72–6.99]).
Conclusions
Cutaneous HPV types are primarily detected at sites extensively exposed to the sun. HPV types of Beta-papillomavirus species 2, but not of species 1, are associated with squamous cell carcinoma.
doi:10.1086/521031
PMCID: PMC3795387  PMID: 17703418
10.  Patterns of Human Papillomavirus Types in Multiple Infections: An Analysis in Women and Men of the High Throughput Human Papillomavirus Monitoring Study 
PLoS ONE  2013;8(8):e71617.
Background
To evaluate the pattern of co-infection of human papillomavirus (HPV) types in both sexes in Sweden.
Methods
Cell samples from genital swabs, first-void urine, and genital swabs immersed in first-void urine were collected in the present cross-sectional High Throughput HPV Monitoring study. Overall, 31,717 samples from women and 9,949 from men (mean age 25) were tested for 16 HPV types using mass spectrometry. Multilevel logistic regression was used to estimate the expected number of multiple infections with specific HPV types, adjusted for age, type of sample, and accounting for correlations between HPV types due to unobserved risk factors using sample-level random effects. Bonferroni correction was used to allow for multiple comparisons (120).
Results
Observed-to-expected ratio for any multiple infections was slightly above unity in both sexes, but, for most 2-type combinations, there was no evidence of significant departure from expected numbers. HPV6/18 was found more often and HPV51/68 and 6/68 less often than expected. However, HPV68 tended to be generally underrepresented in co-infections, suggesting a sub-optimal performance of our testing method for this HPV type.
Conclusions
We found no evidence for positive or negative clustering between HPV types included in the current prophylactic vaccines and other untargeted oncogenic types, in either sex.
doi:10.1371/journal.pone.0071617
PMCID: PMC3747214  PMID: 23977090
11.  Unbiased Approach for Virus Detection in Skin Lesions 
PLoS ONE  2013;8(6):e65953.
To assess presence of virus DNA in skin lesions, swab samples from 82 squamous cell carcinomas of the skin (SCCs), 60 actinic keratoses (AKs), paraffin-embedded biopsies from 28 SCCs and 72 kerathoacanthomas (KAs) and fresh-frozen biopsies from 92 KAs, 85 SCCs and 92 AKs were analyzed by high throughput sequencing (HTS) using 454 or Ion Torrent technology. We found total of 4,284 viral reads, out of which 4,168 were Human Papillomavirus (HPV)-related, belonging to 15 known (HPV8, HPV12, HPV20, HPV36, HPV38, HPV45, HPV57, HPV59, HPV104, HPV105, HPV107, HPV109, HPV124, HPV138, HPV147), four previously described putative (HPV 915 F 06 007 FD1, FA73, FA101, SE42) and two putatively new HPV types (SE46, SE47). SE42 was cloned, sequenced, designated as HPV155 and found to have 76% similarity to the most closely related known HPV type. In conclusion, an unbiased approach for viral DNA detection in skin tumors has found that, although some new putative HPVs were found, known HPV types constituted most of the viral DNA.
doi:10.1371/journal.pone.0065953
PMCID: PMC3696016  PMID: 23840382
12.  Expressed Prostate Secretions in the Study of Human Papillomavirus Epidemiology in the Male 
PLoS ONE  2013;8(6):e66630.
Introduction
Exploring different sampling sites and methods is of interest for studies of the epidemiology of HPV infections in the male. Expressed prostate secretions (EPS) are obtained during digital rectal examination (DRE), a daily routine urological diagnostic procedure, following massage of the prostate.
Materials and Methods
Urethral swabs and EPS samples were obtained from a consecutive sample of 752 men (mean age 32.4 years; median life-time sex partners 34) visiting urology outpatient clinics in St. Petersburg, Russia and tested for HPV DNA by general primer PCR, followed by genotyping using Luminex.
Results
Overall, 47.9% (360/752) of men were HPV-positive, with 42.0% (316/752) being positive for high-risk (HR-) HPV and 12.6% (95/752) for multiple HPV types. HPV-positivity in the EPS samples was 32.6% (27.7% HR-HPV) and in the urethral samples 25.9% (24.5% HR-HPV). 10.6% were HPV positive in both EPS and urethral samples. 6.4% had the same HPV-type in both EPS and urethral samples. 10.6% were HPV positive in both EPS and urethral samples. 6.4% had the same HPV-type in both EPS and urethral samples. The concordance between the urethral samples and EPS was 62.5% (470/752), with 80 cases double positive and 390 cases double negative in both sites. The sensitivity of urethral samples for overall HPV detection was 54.2% (195/360). Compared to analysis of urethral samples only, the analysis of EPS increased the HPV prevalence in this population with 26.2%.
Conclusion
EPS represent informative sampling material for the study of HPV epidemiology in the male.
doi:10.1371/journal.pone.0066630
PMCID: PMC3682962  PMID: 23799125
13.  Quadrivalent Human Papillomavirus Vaccine Effectiveness: A Swedish National Cohort Study 
Background
Incidence of condyloma, or genital warts (GW), is the earliest possible disease outcome to measure when assessing the effectiveness of human papillomavirus (HPV) vaccination strategies. Efficacy trials that follow prespecified inclusion and exclusion criteria may not be fully generalizable to real-life HPV vaccination programs, which target a broader segment of the population. We assessed GW incidence after on-demand vaccination with quadrivalent HPV vaccine using individual-level data from the entire Swedish population.
Methods
An open cohort of girls and women aged 10 to 44 years living in Sweden between 2006 and 2010 (N > 2.2 million) was linked to multiple population registers to identify incident GW in relation to HPV vaccination. For vaccine effectiveness, incidence rate ratios of GW were estimated using time-to-event analyses with adjustment for attained age and parental education level, stratifying on age at first vaccination.
Results
A total of 124 000 girls and women were vaccinated between 2006 and 2010. Girls and women with at least one university-educated parent were 15 times more likely to be vaccinated before age 20 years than girls and women whose parents did not complete high school (relative risk ratio = 15.45, 95% confidence interval [CI] = 14.65 to 16.30). Among those aged older than 20 years, GW rates declined among the unvaccinated, suggesting that HPV vaccines were preferentially used by women at high risk of GW. Vaccination effectiveness was 76% (95% CI = 73% to 79%) among those who received three doses of the vaccine with their first dose before age 20 years. Vaccine effectiveness was highest in girls vaccinated before age 14 years (effectiveness = 93%, 95% CI = 73% to 98%).
Conclusions
Young age at first vaccination is imperative for maximizing quadrivalent HPV vaccine effectiveness.
doi:10.1093/jnci/djt032
PMCID: PMC3614506  PMID: 23486550
14.  The 2010 Global Proficiency Study of Human Papillomavirus Genotyping in Vaccinology 
Journal of Clinical Microbiology  2012;50(7):2289-2298.
Accurate and internationally comparable human papillomavirus (HPV) DNA genotyping is essential both for evaluation of HPV vaccines and for effective monitoring and implementation of vaccination programs. The World Health Organization (WHO) HPV Laboratory Network (LabNet) regularly issues international proficiency studies. The 2010 HPV genotyping proficiency panel for HPV vaccinology contained 43 coded samples composed of purified plasmids of 16 HPV types (HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68a and 68b) and 3 coded extraction controls. Proficient typing was defined as detection in both single and multiple infections of 50 international units (IU) of HPV type 16 (HPV-16) and HPV-18 DNA and 500 genome equivalents (GE) for the other 14 HPV types. Ninety-eight laboratories worldwide submitted a total of 132 data sets. Twenty-four different HPV genotyping assay methods were used, with Linear Array being the most commonly used. Other major assays used were a line blot assay (Inno-LiPa), CLART, type-specific real-time PCR, PCR Luminex, and different microarray assays. Altogether, 72 data sets were proficient for detection of more than 1 type, and only 26 data sets proficiently detected all 16 HPV types. The major oncogenic HPV types, 16 and 18, were proficiently detected in 95.0% (114/120) and 87.0% (94/108) of data sets, respectively. Forty-six data sets reported multiple false-positive results and were considered nonproficient. A trend toward increased sensitivity of assays was seen for the 41 laboratories that participated in both 2008 and 2010. In conclusion, continued global proficiency studies will be required for establishing comparable and reliable HPV genotyping services for vaccinology worldwide.
doi:10.1128/JCM.00840-12
PMCID: PMC3405610  PMID: 22535980
15.  Performance of Commercial Reverse Line Blot Assays for Human Papillomavirus Genotyping 
Journal of Clinical Microbiology  2012;50(5):1539-1544.
The performance of three line blot assays (LBAs), the Linear Array HPV genotyping assay (LA) (Roche Diagnostics), INNO-LiPA HPV Genotyping Extra (LiPA) (Innogenetics), and the reverse hybridization assay (RH) (Qiagen), was evaluated using quantitated whole genomic human papillomavirus (HPV) plasmids (types 6, 11, 16, 18, 31, 33, 35, 39, 51, 52, 56, 58, 59, and 68b) as well as epidemiologic samples. In a plasmid titration series, LiPA and RH did not detect 50 international units (IU) of HPV type 18 (HPV18) in the presence of 5 × 104 IU or more of HPV16. HPV DNA (1 to 6 types) in the plasmid challenges at 50 IU or genome equivalents (GE) were identified with an accuracy of 99.9% by LA, 97.3% by LiPA, and 95.4% by RH, with positive reproducibility of 99.8% (kappa = 0.992), 88.2% (kappa = 0.928), and 88.1% (kappa = 0.926), respectively. Two instances of mistyping occurred with LiPA. Of the 120 epidemiologic samples, 76 were positive for high-risk types by LA, 90 by LiPA, and 69 by RH, with a positive reproducibility of 87.3% (kappa = 0.925), 83.9% (kappa = 0.899), and 90.2% (kappa = 0.942), respectively. Although the assays had good concordance in the clinical samples, the greater accuracy and specificity in the plasmid panel suggest that LA has an advantage for internationally comparable genotyping studies.
doi:10.1128/JCM.06576-11
PMCID: PMC3347105  PMID: 22357500
16.  A Nested Case-Control Study of Intrauterine Exposure to Persistent Organochlorine Pollutants and the Risk of Hypospadias 
PLoS ONE  2012;7(9):e44767.
Background
Environmental exposures to endocrine disrupting chemicals have been suggested as a risk factor for male genital abnormalities such as hypospadias. The aim of this case-control study was to investigate the association between fetal exposure to persistent organochlorine pollutants (POP) and the risk for hypospadias.
Methodology/Principal Findings
The Southern Sweden Maternity Cohort (SSMC) contains serum samples collected in early pregnancy among women in Southern Sweden. Linkages with the Medical Birth Register, the Malformation Register and the In-patient Register resulted in 390 SSMC mothers who had given birth to a boy with hypospadias in year 1986–2002 (mean 1995). For 237 of these (cases) sufficient amounts of serum for the chemical analyses were available. For each case, a control boy from the SSMC was randomly selected, matched for maternal age, birth year, parity and maternal smoking. PCB-153, p,p’-DDE and hexachlorbenzene (HCB) were used as biomarkers for POP exposure. The exposures were categorized into quartiles based on the distributions among the controls. There were no statistically significant trends between the a priori categorisation of the exposure variables and the risk for hypospadias. However, when the upper HCB quartile (>26 ng/ml) was compared to the other quartiles an odds ratio of 1.65 (95% CI 1.02 to 2.69) was obtained. p,p′-DDE levels above median (>1.0 ng/ml) compared to levels below 0.1 ng/ml gave an OR of 1.69 (95% CI 0.97 to 2.93).
Conclusions
The present study suggests that fetal exposure to HCB and p,p’-DDE may be a risk factor for hypospadias.
doi:10.1371/journal.pone.0044767
PMCID: PMC3459969  PMID: 23028613
17.  Human Papillomavirus Antibody Reference Reagents for Use in Postvaccination Surveillance Serology 
Suitably controlled serosurveillance surveys are essential for evaluating human papillomavirus (HPV) immunization programs. A panel of plasma samples from 18-year-old females was assembled, the majority of the samples being from recipients of the bivalent HPV vaccine. Antibody specificities were evaluated by three independent laboratories, and 3 pools that displayed no antibodies to any HPV type tested or intermediate or high levels of antibody to HPV16, HPV18, HPV31, and HPV45 were created. These pools will be useful as control reagents for HPV serology.
doi:10.1128/CVI.05641-11
PMCID: PMC3294620  PMID: 22278326
18.  Genetic predisposition, parity, age at first childbirth and risk for breast cancer 
BMC Research Notes  2012;5:414.
Background
Recent studies have identified several single-nucleotide polymorphisms (SNPs) associated with the risk of breast cancer and parity and age at first childbirth are well established and important risk factors for breast cancer. The aim of the present study was to examine the interaction between these environmental factors and genetic variants on breast cancer risk.
Methods
The Malmö Diet and Cancer Study (MDCS) included 17 035 female participants, from which 728 incident breast cancer cases were matched to 1448 controls. The associations between 14 SNPs and breast cancer risk were investigated in different strata of parity and age at first childbirth. A logistic regression analysis for the per allele risk, adjusted for potential confounders yielded odds ratios (OR) with 95% confidence intervals (CI).
Results
Six of the previously identified SNPs showed a statistically significant association with breast cancer risk: rs2981582 (FGFR2), rs3803662 (TNRC9), rs12443621 (TNRC9), rs889312 (MAP3K1), rs3817198 (LSP1) and rs2107425 (H19). We could not find any statistically significant interaction between the effects of tested SNPs and parity/age at first childbirth on breast cancer risk after adjusting for multiple comparisons.
Conclusions
The results of this study are in agreement with previous studies of null interactions between tested SNPs and parity/age at first childbirth with regard to breast cancer risk.
doi:10.1186/1756-0500-5-414
PMCID: PMC3439270  PMID: 22867275
19.  Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer 
BMC Women's Health  2012;12:17.
Background
Breast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT).
Methods
We analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case–control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model.
Results
One SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction = 0.03). There were no significant interactions after correction for multiple testing.
Conclusions
We conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials.
doi:10.1186/1472-6874-12-17
PMCID: PMC3460750  PMID: 22726230
20.  Prospective study of HPV types, HPV persistence and risk of squamous cell carcinoma of the cervix 
Background
The link between squamous cell cervical carcinoma and HPV 16/18 is well-established but the magnitude of the risk association is uncertain and the importance of other high-risk HPV types unclear.
Methods
In two prospective nested case-control series among women participating in cytological screening in Sweden, we collected 2772 cervical smears from 515 women with cancer in situ (CIS), 315 with invasive squamous cell carcinoma (SCC), and individually matched controls. All smears were tested for HPV with PCR assays and the median follow-up until diagnosis was 5-7 years. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI).
Results
Presence of HPV16/18 in the first smear was associated with 8.5-fold (95% CI 5.3-13.7), and 18.6-fold (95% CI 9.0-38.9) increased risks of CIS and SCC, respectively, compared to women negative for HPV. Infection with other high-risk HPV types in the first smear was also associated with significantly increased risks for both CIS and SCC. Persistence of HPV16 infection conferred a RR of 18.5 (95% CI, 6.5-52.9) for CIS and 19.5 (95% CI 4.7-81.7) for SCC. The HPV16/18 attributable risk proportion was estimated to 30-50% of CIS, and 41-47% of SCC. Other high-risk HPV types also conferred significant proportions.
Conclusions
Our large population-based study provides quantification of risks for different HPV types and prospective evidence that non-16/18 high-risk HPV types increase the risk for future cervical cancer.
Impact
This study gives further insights into cervical cancer risk stratification with implications for HPV-based prevention strategies.
doi:10.1158/1055-9965.EPI-10-0424
PMCID: PMC2952359  PMID: 20671136
Cervical cancer; HPV; risk; prevalence; persistence
21.  Global Proficiency Study of Human Papillomavirus Genotyping ▿  
Journal of Clinical Microbiology  2010;48(11):4147-4155.
Internationally comparable quality assurance of Human Papillomavirus (HPV) DNA detection and typing methods is essential for evaluation of HPV vaccines and effective monitoring and implementation of HPV vaccination programs. Therefore, the World Health Organization (WHO) HPV Laboratory Network (LabNet) designed an international proficiency study. Following announcement at the WHO website, the responding laboratories performed HPV typing using one or more of their usual assays on 43 coded samples composed of titration series of purified plasmids of 16 HPV types (HPV6, -11, -16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, and -68). Detection of at least 50 IU of HPV16 or HPV18 DNA and of 500 genome equivalents (GE) of the other 14 HPV types (in samples with single and multiple HPV types) was considered proficient. Fifty-four laboratories worldwide submitted a total of 84 data sets. More than 21 HPV-genotyping assays were used. Commonly used methods were Linear Array, Lineblot, InnoLiPa, Clinical Array, type-specific real-time PCR, PCR-Luminex and microarray assays. The major oncogenic HPV types (HPV16 and -18) were detected in 89.7% (70/78) and 92.2% (71/77) of the data sets, respectively. HPV types 56, 59, and 68 were the least commonly detected types (in less than 80% of the data sets). Twenty-eight data sets reported multiple false-positive results and were considered nonproficient. In conclusion, we found that international proficiency studies, traceable to international standards, allow standardized quality assurance for different HPV-typing assays and enable the comparison of data generated from different laboratories worldwide.
doi:10.1128/JCM.00918-10
PMCID: PMC3020877  PMID: 20844222
22.  Chlamydia trachomatis infection and risk of cervical intraepithelial neoplasia 
Sexually Transmitted Infections  2011;87(5):372-376.
Objectives
High-risk human papillomavirus (hrHPV) is the primary cause of cervical cancer. As Chlamydia trachomatis is also linked to cervical cancer, its role as a potential co-factor in the development of cervical intraepithelial neoplasia (CIN) grade 2 or higher was examined.
Methods
The placebo arms of two large, multinational, clinical trials of an HPV6/11/16/18 vaccine were combined. A total of 8441 healthy women aged 15–26 years underwent cervicovaginal cytology (Papanicolaou (Pap) testing) sampling and C trachomatis testing at day 1 and every 12 months thereafter for up to 4 years. Protocol-specified guidelines were used to triage participants with Pap abnormalities to colposcopy and definitive therapy. The main outcome measured was CIN.
Results
At baseline, 2629 (31.1%) tested positive for hrHPV DNA and 354 (4.2%) tested positive for C trachomatis. Among those with HPV16/18 infection (n=965; 11.4%) or without HPV16/18 infection (n=7382, 87.5%), the hazard ratios (HRs) associated with development of any CIN grade 2 according to baseline C trachomatis status were 1.82 (95% CI: 1.06 to 3.14) and 1.74 (95% CI 1.05 to 2.90), respectively. The results were comparable when only the 12 most common hrHPV infections were considered, but the excess risk disappeared when the outcome was expanded to include CIN grade 3 or worse.
Conclusion
Further studies based on larger cohorts with longitudinal follow-up in relation to the C trachomatis acquisition and a thorough evaluation of temporal relationships of infections with hrHPV types, C trachomatis and cervical neoplasia are needed to demonstrate whether and how in some situations C trachomatis sets the stage for cervical carcinogenesis.
Trial registration
NCT00092521 and NCT00092534.
doi:10.1136/sti.2010.044354
PMCID: PMC3252607  PMID: 21471141
Chlamydia trachomatis
23.  H. pylori Seropositivity before Age 40 and Subsequent Risk of Stomach Cancer: A Glimpse of the True Relationship? 
PLoS ONE  2011;6(3):e17404.
Stomach carcinogenesis involves mucosal and luminal changes that favor spontaneous disappearance of Helicobacter pylori. Therefore, the association between the infection and cancer risk might typically be underestimated. As acquisition of the infection almost invariably occurs before adulthood, the serostatus at age 16–40 should best reflect the lifetime occurrence of the infection. We therefore conducted a case-control study nested within a historic cohort of about 400,000 individuals who donated sera before age 40 to either of two large Swedish Biobanks between 1968 and 2006, and whose records were linked to complete nationwide registers. For each stomach adenocarcinoma case occurring at least 5 years after serum donation 2 controls were selected matched on age, sex and year of donation and biobank. Serum immunoglobulin G antibodies against H. pylori cell-surface antigens (Hp-CSAs) were measured with an enzyme–linked immunosorbent assay and antibodies against CagA with an immunoblot assay. Conditional logistic regression models were used to estimate odds ratios (ORs) for stomach adenocarcinoma among H. pylori infected relative to uninfected. We confirmed 59 incident cases of stomach adenocarcinoma (41 non-cardia tumors) during follow-up. ORs for non-cardia stomach adenocarcinoma among subjects with Hp-CSA antibodies (regardless of CagA serostatus), antibodies against CagA (regardless of Hp-CSA serostatus), and antibodies to both, relative to those who were seronegative to both, were 17.1 (95% confidence interval [CI] 4.0–72.9), 10.9 (95% CI 3.2–36.9), and 48.5 (95% CI 5.8–407.4), respectively. H. pylori infection is a much stronger risk factor for non-cardia stomach adenocarcinoma than initially realized. However, further studies are needed to answer whether it is a necessary cause, as the possibility of misclassification of H. pylori status could not be ruled out in our study.
doi:10.1371/journal.pone.0017404
PMCID: PMC3047545  PMID: 21399687
24.  Prospective study of Human Papillomavirus and Risk of Cervical Adenocarcinoma 
Human papillomaviruses (HPV) are established as a major cause of cervical carcinoma. However, causality inference is dependent on prospective evidence showing that exposure predicts risk for future disease. Such evidence is available for squamous cell carcinoma, but not for cervical adenocarcinoma. We followed a population-based cohort of 994 120 women who participated in cytological screening in Sweden for a median of 6.7 years. Baseline smears from women who developed adenocarcinoma during follow-up (118 women with in situ disease and 164 with invasive disease) and their individually matched controls (1434 smears) were analyzed for HPV using PCR. Conditional logistic regression was used to estimate odds ratios (OR) of future adenocarcinoma with 95% confidence intervals (CI). Being positive for HPV 16 in the first cytologically normal smear was associated with increased risks for both future adenocarcinoma in situ (OR 11.0, 95 % CI 2.6–46.8) and invasive adenocarcinoma (OR 16.0, 95 % CI 3.8–66.7), compared to being negative for HPV 16. Similarly, an HPV 18 positive smear was associated with increased risks for adenocarcinoma in situ (OR 26.0, 95 % CI 3.5–192) and invasive adenocarcinoma (OR 28.0, 95 % CI 3.8–206), compared to an HPV 18 negative smear. Being positive for HPV 16/18 in two subsequent smears was associated with an infinite risk of both in situ and invasive adenocarcinoma. In conclusion, infections with HPV 16 and 18 are detectable up to at least 14 years before diagnosis of cervical adenocarcinoma. Our data provide prospective evidence that the association of HPV16/18 with cervical adenocarcinoma is strong and causal.
doi:10.1002/ijc.25408
PMCID: PMC2930102  PMID: 20473898
Adenocarcinoma; adenocarcinoma in situ; HPV; cervical cancer; prospective
25.  Modified General Primer PCR System for Sensitive Detection of Multiple Types of Oncogenic Human Papillomavirus▿  
Journal of Clinical Microbiology  2009;47(3):541-546.
Human papillomavirus (HPV) infection is a necessary cause of cervical cancer and cervical dysplasia. Accurate and sensitive genotyping of multiple oncogenic HPVs is essential for a multitude of both clinical and research uses. We developed a modified general primer (MGP) PCR system with five forward and five reverse consensus primers. The MGP system was compared to the classical HPV general primer system GP5+/6+ using a proficiency panel with HPV plasmid dilutions as well as cervical samples from 592 women with low-grade cytological abnormalities. The reference method (GP5+/6+) had the desirable high sensitivity (five copies/PCR) for five oncogenic HPV types (HPV type 16 [HPV-16], HPV-18, HPV-56, HPV-59, and HPV-66). The MGP system was able to detect all 14 oncogenic HPV types at five copies/PCR. In the clinical samples, the MGP system detected a significantly higher proportion of women with more than two concomitant HPV infections than did the GP5+/6+ system (102/592 women compared to 42/592 women). MGP detected a significantly greater number of infections with HPV-16, -18, -31, -33, -35, -39, -42, -43, -45, -51, -52, -56, -58, and -70 than did GP5+/6+. In summary, the MGP system primers allow a more sensitive amplification of most of the HPV types that are established as oncogenic and had an improved ability to detect multiple concomitant HPV infections.
doi:10.1128/JCM.02007-08
PMCID: PMC2650955  PMID: 19144817

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