Matti Lehtinen

Publications (112)487.37 Total impact

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

  Tapio Luostarinen, Proscovia B Namujju, Marko Merikukka, Joakim Dillner, Timo Hakulinen, Pentti Koskela, Jorma Paavonen, Heljä-Marja Surcel, Matti Lehtinen
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  ABSTRACT: Interactions of carcinogenic human papillomaviruses (most notably HPV types 16/18/31/33/45), and HPV6 or Chlamydia trachomatis are not well understood. We have used seroconversions to study effects the order of these infections has on the risk of high-grade cervical precancer. In a cohort of 94,349 Finnish women with paired sera from consecutive pregnancies within an average of 2.4 years, 490 were diagnosed with cervical CIN3/AIS. Serum antibodies to HPV6/16/18/31/33/45 and C.trachomatis were also measured in paired sera of a subcohort of 2,796 women with a minimum of two pregnancies. HPV16-adjusted rate ratios (RR) and confidence intervals were estimated by stratified Cox model. Compared to dual seropositivity already at the first serum sampling, RRs related to HPV6 seropositivity before and after HPV31 seroconversion were 0.4 (95% CI 0.0,4.4) and 10 (95% CI 1.8,57). Furthermore, RR related to seroconversions of both HPV18/45 and C.trachomatis between the consecutive pregnancies was 28 (95% CI 4.3,190). Virtually concomitant HPV18/45 and C.trachomatis infections are associated with very high CIN3 risk. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 03/2013; · 5.44 Impact Factor
• Source

  Available from: Elmar A Joura

  Dataset: joura vaccine 2008

  Elmar A Joura, Susanne K Kjaer, Cosette M Wheeler, Kristján Sigurdsson, Ole-Erik Iversen, Mauricio Hernandez-Avila, Gonzalo Perez, Darron R Brown, Laura A Koutsky, Eng Hseon Tay, [......], Christine Roberts, Amha Tadesse, Janine Bryan, Lisa C Lupinacci, Katherine E D Giacoletti, Shuang Lu, Scott Vuocolo, Teresa M Hesley, Richard M Haupt, Eliav Barr
• Article: An Increasing Proportion of Reported Chlamydia trachomatis Infections Are Repeated Diagnoses.

  Erika Wikström, Aini Bloigu, Hanna Ohman, Eija Hiltunen-Back, Mikko J Virtanen, Kaisa Tasanen, Jorma Paavonen, Matti Lehtinen, Heljä-Marja Surcel
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  ABSTRACT: In recent decades, increasing rates of Chlamydia cases have contrasted with decreasing Chlamydia trachomatis seroprevalence rates and decreasing Chlamydia-associated complication rates. We elucidated the conflicting trends by studying incidence of repeated Chlamydia infections over time. Chlamydia cases reported during 1995 to 2009 were identified in the Finnish National Infectious Diseases Registry. Trends of single and repeated diagnoses of Chlamydia infection were analyzed. Our study population comprised 147,148 individuals with a total of 177,138 genital chlamydial infections. The proportion of annual repeated diagnoses of genital infections increased among female and males from 4.9% to 7.3% and from 3.8% to 5.3%, respectively. In 2009, 24.8% of the females and 20.3% of the males had had an earlier Chlamydia infection ever during the follow-up time. Of all the repeated diagnoses, 34.1% occurred within 12 months. The highest rates of repeated infection diagnoses occurred in 25-year-old women (37.0%) and in 29-year-old men (30.9%) in a cohort of individuals born in 1979. A gradual increase of repeated Chlamydia infections resulted in 43% increase in annual infections between 1996 and 2009. The result is supportive of the existing seroprevalence data suggesting that Chlamydia infection burden is not increasing in the whole population. The increasing infection rates in males, in particular, justify development of effective strategy in preventing reinfections and onward transmission.
  Sexually transmitted diseases 12/2012; 39(12):968-72. · 2.58 Impact Factor
• Article: Understanding long-term protection of human papillomavirus vaccination against cervical carcinoma: Cancer registry-based follow-up.

  Muhammad Mohsin Rana, Heini Huhtala, Dan Apter, Tiina Eriksson, Tapio Luostarinen, Kari Natunen, Jorma Paavonen, Eero Pukkala, Matti Lehtinen
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  ABSTRACT: Phase III clinical trials of human papilloma virus (HPV) vaccination have shown ≥95% efficacy against HPV16/18 associated cervical intraepithelial neoplasia (CIN) grade 2/3. Long-term surveillance is, however, needed to determine the overall vaccine efficacy (VE) against CIN3 and invasive cervical carcinoma (ICC). During population-based recruitment between September 2002 and March 2003, 1 749 16-17 year old Finns participated in a multi-national randomized phase III HPV6/11/16/18 vaccine (FUTURE II) trial for the determination of VE against HPV16/18 positive CIN2/3. The passive follow-up started at the country-wide, population-based Finnish Cancer Registry (FCR) six months after the active follow-up and voluntary cross-vaccination in April 2007. A cluster randomized, population-based reference cohort of 15 744 unvaccinated, originally 18-19 year old Finns was established in two phases in 2003 and 2005 after the FUTURE II recruitment. We linked these cohorts with the FCR in 2007-2011 (HPV vaccine and placebo cohorts) and 2006-2010 and 2008-2012 (unvaccinated reference cohorts 1 and 2) to compare their incidences of CIN3 and ICC. The 4 years passive follow-up resulted in 3 464, 3 444 and 62 876 person years for the HPV6/11/16/18, original placebo and reference cohorts, after excluding cases discovered during the clinical follow-up and individuals not at risk. The numbers of CIN3 and ICC cases identified were 0 and 0, 3 and 0, 59 and 3 for the HPV6/11/16/18, placebo and the unvaccinated reference cohorts. The corresponding CIN3 incidence rates were 0/100 000 (95% confidence interval 0.0-106.5), 87.1/100 000 (95% CI 17.9- 254.5) and 93.8/100 000 (95% CI 71.4-121), respectively. Long-term surveillance up to 8 years (and longer) post vaccination of the HPV6/11/16/18 vaccine and placebo cohorts, and the unvaccinated reference cohort (not exposed to interventions) for the most stringent efficacy end-points by passive cancer registry-based follow-up is feasible . © 2012 Wiley Periodicals, Inc.
  International Journal of Cancer 11/2012; · 5.44 Impact Factor
• Article: Proximity of First Intercourse to Menarche and Risk of High-Grade Cervical Disease.

  Angela María Ruiz, Jaime Enrique Ruiz, Andrés Velásquez Gavilanes, Tiina Eriksson, Matti Lehtinen, Gonzalo Pérez, Heather L Sings, Margaret K James, Richard M Haupt
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  ABSTRACT: Background. We assessed if risk of developing cervical intraepithelial neoplasia grade 2/3 (CIN2-3) or adenocarcinoma in situ (AIS) is associated with a short interval between menarche and first sexual intercourse (FSI).Methods. 1009 Colombian and 1012 Finnish non-virgins aged 16-23 enrolled in the phase 3 trials of a quadrivalent HPV-6/11/16/18 vaccine had non-missing data for age of menarche and first sexual intercourse. The impact of menarche interval on the odds of developing CIN2-3/AIS was evaluated in placebo recipients who were DNA-negative to HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59 and seronegative to HPV 6/11/16/18 at Day 1, and had a normal Pap result at Day 1 and Month 7, thus approximating sexually-naïve adolescents (n=504).Results. The mean age of menarche and FSI was 12.4 and 16.0 years, respectively. Among the women approximating sexually-naïve adolescents, 18 developed CIN2-3/AIS. Compared with women who postponed first intercourse beyond 3 years, those with first intercourse within 3 years of menarche had a greater risk of cytologic abnormalities (OR=1.65, 95%CI: 1.02─2.68; p=0.04) and CIN2-3/AIS (OR=3.56, 95%CI: 1.02─12.47; p=0.05).Conclusions. A short interval between menarche and FSI was a risk factor for cytologic abnormalities and high-grade cervical disease. These data emphasize the importance of primary prevention through education and vaccination.
  The Journal of Infectious Diseases 10/2012; · 6.41 Impact Factor
• Article: Sound efficacy of prophylactic HPV vaccination: Basics and implications.

  Matti Lehtinen, Jorma Paavonen
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  ABSTRACT: Prophylactic human papillomavirus vaccine efficacy is almost too good to be true. The benefits of herd immunity will, however, not be gained without high vaccine coverage. Here the authors of two recent papers on HPV16/18 vaccine efficacy elaborate on the basics and implications of this approach for infection and cancer prevention.
  Oncoimmunology. 09/2012; 1(6):995-996.
• Article: Prevalence and risk factors for cervical HPV infection and abnormalities in young adult women at enrolment in the multinational PATRICIA trial.

  Edith Roset Bahmanyar, Jorma Paavonen, Paulo Naud, Jorge Salmerón, Song-Nan Chow, Dan Apter, Henry Kitchener, Xavier Castellsagué, Julio C Teixeira, S Rachel Skinner, [......], Tino F Schwarz, Willy A J Poppe, Newton S De Carvalho, Diane M Harper, F Xavier Bosch, Alice Raillard, Dominique Descamps, Frank Struyf, Matti Lehtinen, Gary Dubin
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  ABSTRACT: OBJECTIVE: We evaluated baseline data from the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) on the association between behavioral risk factors and HPV infection and cervical abnormalities. METHODS: Women completed behavioral questionnaires at baseline. Prevalence of HPV infection and cervical abnormalities (detected by cytological or histological procedures) and association with behavioral risk factors were analyzed by univariate and stepwise multivariable logistic regressions. RESULTS: 16782 women completed questionnaires. Among 16748 women with data for HPV infection, 4059 (24.2%) were infected with any HPV type. Among 16757 women with data for cytological abnormalities, 1626 (9.7%) had a cytological abnormality, of whom 1170 (72.0%) were infected with at least one oncogenic HPV type including HPV-16 (22.7%) and HPV-18 (9.3%). Multivariable analysis (adjusted for age and region, N=14404) showed a significant association between infection with any HPV type and not living with a partner, smoking, age <15years at first sexual intercourse, higher number of sexual partners during the past 12months, longer duration of hormonal contraception and history of sexually transmitted infection (STI). For cervical abnormalities, only history of STI (excluding Chlamydia trachomatis) remained significant in the multivariable analysis after adjusting for HPV infection. CONCLUSIONS: Women reporting 3+ sexual partners in the past 12months had the highest risk of HPV infection at baseline. HPV infection was the main risk factor for cervical abnormalities, and history of STIs excluding Chlamydia trachomatis increased risk to a lesser extent. Although behavioral factors can influence risk, all sexually active women are susceptible to HPV infection.
  Gynecologic Oncology 08/2012; · 3.89 Impact Factor
• Article: Occurrence of vaccine and non-vaccine human papillomavirus types in adolescent Finnish females 4 years post-vaccination.

  Johanna Palmroth, Marko Merikukka, Jorma Paavonen, Dan Apter, Tiina Eriksson, Kari Natunen, Gary Dubin, Matti Lehtinen
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  ABSTRACT: Control of human papillomavirus (HPV)-related cancers by inclusion of HPV vaccination into national vaccination programmes is likely. One open question is replacement of the vaccine types with other high-risk (hr) HPV types in the vaccination era. We studied occurrence of HPV types in adolescent females participating in a population-based vaccination trial. A total of 4,808 16- to 17-year-old females from Finland were enrolled in the 1:1 randomized phase III (PATRICIA) trial of the efficacy of vaccination with the AS04-adjuvanted HPV-16/18 virus-like particle vaccine as compared to hepatitis A virus (HAV) vaccine. HPV infection was assessed from cervical samples taken every 6 months for 4 years post-vaccination by polymerase chain reaction (PCR) for genital oncogenic HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 58, 59, 66, 68, and 73 as well as low-risk types HPV-6 and HPV-11. The HPV-16/18 vaccine coverage ranged between 1 and 22% by age-cohort and study community. Odds ratios (ORs) for infections with different HPV types in baseline PCR negative HPV-16/18 vs. HAV vaccinated women, and Poisson regression derived HPV incidence rate ratios (IRRs) in baseline positive vs. negative women were calculated. The OR and IRR estimates for acquisition of any genital HPV types showed no excess risk neither in baseline HPV DNA-negative HPV-16/18-vaccinated women compared to baseline HPV DNA-negative HAV vaccinated women nor in HPV-16/18-vaccinated baseline HPV-16/18-positive women compared to baseline HPV-16/18-negative women. In the HAV-vaccinated, baseline HPV-18-positive women showed an increased risk of acquiring other clade A7 HPV types (39, 45, 59, 68) (IRR 1.8, 95% confidence interval = 1.01.-3.1). We found no increased occurrence of non-vaccine HPV types suggestive of type-replacement 1-4 years post-vaccination among HPV-16/18-vaccinated Finnish adolescents.
  International Journal of Cancer 04/2012; 131(12):2832-8. · 5.44 Impact Factor
• Article: Just implementation of human papillomavirus vaccination.

  Erik Malmqvist, Kari Natunen, Matti Lehtinen, Gert Helgesson
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  ABSTRACT: Many countries are now implementing human papillomavirus vaccination. There is disagreement about who should receive the vaccine. Some propose vaccinating both boys and girls in order to achieve the largest possible public health impact. Others regard this approach as too costly and claim that only girls should be vaccinated. We question the assumption that decisions about human papillomavirus vaccination policy should rely solely on estimates of overall benefits and costs. There are important social justice aspects that also need to be considered. Policy makers should consider how to best protect individuals who will remain unvaccinated through no fault of their own. This is especially important if these individuals are already disadvantaged in other ways and if vaccinating other people increases their risk of infection.
  Journal of medical ethics 12/2011; 38(4):247-9. · 1.21 Impact Factor
• Article: Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer.

  Lisen Arnheim Dahlström, Kristin Andersson, Tapio Luostarinen, Steinar Thoresen, Helga Ögmundsdottír, Laufey Tryggvadottír, Fredrik Wiklund, Gry B Skare, Carina Eklund, Kia Sjölin, Egil Jellum, Pentti Koskela, Göran Wadell, Matti Lehtinen, Joakim Dillner
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  ABSTRACT: Several sexually transmitted infections (STI) have been reported to interact with human papillomavirus (HPV) in the etiology of cervical cancer. A large cohort study is required to obtain a both unbiased and stable estimate of their effects. Four major biobanks in the Nordic Countries containing samples from about 1,000,000 subjects were linked with nation-wide cancer registries. Serum samples from 604 women with invasive cervical cancer (ICC) diagnosed on average 10 years after sampling and 2,980 matched control women were retrieved and analyzed with serology for key STI. Exposure to HPV16 was the strongest risk factor for cervical cancer [OR = 2.4; 95% confidence interval (CI), 2.0-3.0], particularly for squamous cell carcinoma (OR = 2.9; 95% CI, 2.2-3.7). HPV18 was strongly associated with increased risk for adenocarcinoma (OR = 2.3; 95% CI, 1.3-4.1). Baseline seropositivity for HPV16 did not confer any increased risk for HPV18 DNA-positive cancer and conversely HPV18 seropositivity had no association with HPV16 DNA-positive cancers. HPV6 had no effect on its own (OR = 1.1; 95% CI, 0.9-1.3), but had an antagonistic effect on the risk conferred by HPV16 (P < 0.01). Herpes simplex virus 2 had little or no association (OR = 1.1; 95% CI, 0.8-1.4). Previous exposure to Chlamydia trachomatis, as indicated by serum antibodies, had a strongly increased risk for cervical cancer (OR = 1.9; 95% CI, 1.5-2.3). A large prospective study has assessed the role of different STIs in cervical cancer. Prospective evidence supports cofactor role of some STI in cervical cancer.
  Cancer Epidemiology Biomarkers &amp Prevention 12/2011; 20(12):2541-50. · 4.12 Impact Factor
• Article: Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.

  Matti Lehtinen, Jorma Paavonen, Cosette M Wheeler, Unnop Jaisamrarn, Suzanne M Garland, Xavier Castellsagué, S Rachel Skinner, Dan Apter, Paulo Naud, Jorge Salmerón, [......], Newton S De Carvalho, Maria Julieta V Germar, Klaus Peters, Adrian Mindel, Philippe De Sutter, F Xavier Bosch, Marie-Pierre David, Dominique Descamps, Frank Struyf, Gary Dubin
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  ABSTRACT: Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults). Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681. Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. GlaxoSmithKline Biologicals.
  The lancet oncology 11/2011; 13(1):89-99. · 14.47 Impact Factor
• Article: Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.

  Cosette M Wheeler, Xavier Castellsagué, Suzanne M Garland, Anne Szarewski, Jorma Paavonen, Paulo Naud, Jorge Salmerón, Song-Nan Chow, Dan Apter, Henry Kitchener, [......], Willy A J Poppe, F Xavier Bosch, Diane M Harper, Warner Huh, Karin Hardt, Toufik Zahaf, Dominique Descamps, Frank Struyf, Gary Dubin, Matti Lehtinen
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  ABSTRACT: We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681. Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8). Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women. GlaxoSmithKline Biologicals.
  The lancet oncology 11/2011; 13(1):100-10. · 14.47 Impact Factor
• Article: Determinants of maternal sex steroids during the first half of pregnancy.

  Adetunji T Toriola, Marja Vääräsmäki, Matti Lehtinen, Anne Zeleniuch-Jacquotte, Eva Lundin, Kenneth-Gary Rodgers, Hans-Ake Lakso, Tianhui Chen, Helena Schock, Goran Hallmans, Eero Pukkala, Paolo Toniolo, Kjell Grankvist, Helja-Marja Surcel, Annekatrin Lukanova
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  ABSTRACT: To examine the associations of maternal and child characteristics with early pregnancy maternal concentrations of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, and estradiol (E2). We analyzed these hormones among 1,343 women with singleton pregnancies who donated serum samples to the Finnish Maternity Cohort from 1986 to 2006 during the first half of pregnancy (median 11 weeks). The associations of maternal and child characteristics with hormone concentrations were investigated by correlation and multivariable regression. Women older than age 30 years had lower androgen and E2 but higher progesterone concentrations than women younger than that age. Multiparous women had 14% lower testosterone, 11% lower androstenedione and 17-hydroxyprogesterone, 9% lower progesterone, and 16% lower E2 concentrations compared with nulliparous women (all P<.05). Smoking mothers had 11%, 18%, and 8% higher testosterone, androstenedione, and 17-hydroxyprogesterone levels, respectively, but 10% lower progesterone compared with nonsmoking women (all P<.05). E2 concentrations were 9% higher (P<.05) among women with a female fetus compared with those with a male fetus. Parity, smoking, and, to a lesser extent, maternal age and child sex are associated with sex steroid levels during the first half of a singleton pregnancy. The effects of smoking on the maternal hormonal environment and the possible long-term deleterious consequences on the fetus deserve further evaluation.
  Obstetrics and Gynecology 11/2011; 118(5):1029-36. · 4.73 Impact Factor
• Article: Long‐term persistence of systemic and mucosal immune response to HPV‐16/18 AS04‐adjuvanted vaccine in preteen/adolescent girls and young women

  Tiina Petäjä, Court Pedersen, Airi Poder, Gitte Strauss, Gregory Catteau, Florence Thomas, Matti Lehtinen, Dominique Descamps
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  ABSTRACT: Vaccination against oncogenic human papillomavirus (HPV) types is one key intervention for cervical cancer prevention. This follow-up study assessed the persistence of the systemic and mucosal immune responses together with the safety profile of the HPV-16/18 AS04-adjuvanted vaccine administered to young women aged 10–25 years. Serum and cervicovaginal secretion (CVS) samples were collected at prespecified time-points during the 48-month follow-up period. Anti-HPV-16/18 antibody levels in serum and CVS were measured by enzyme-linked immunosorbent assay (ELISA). At Month 48, all subjects remained seropositive for serum anti-HPV-16 and -18 antibodies. As previously observed, anti-HPV-16 and -18 antibodies levels (ELISA Units/mL) were higher in subjects vaccinated at the age of 10–14 years (2862.2 and 940.8) compared to subjects vaccinated at the age of 15–25 years (1186.2 and 469.8). Moreover, anti-HPV-16 and -18 antibodies in CVS were still detectable for subjects aged 15–25 years (84.1% and 69.7%, respectively). There was a strong correlation between serum and CVS anti-HPV-16 and -18 antibodies levels (correlation coefficients = 0.84 and 0.90 at Month 48, respectively) supporting the hypothesis of transudation or exudation of serum immunoglobulin G antibodies through the cervical epithelium. The HPV-16/18 AS04-adjuvanted vaccine had a clinically acceptable safety profile. In conclusion, this follow-up study shows that the HPV-16/18 AS04-adjuvanted vaccine administered to preteen/adolescents girls and young women induces long-term systemic and mucosal immune response and has a clinically acceptable safety profile up to 4 years after the first vaccine dose.
  International Journal of Cancer 10/2011; 129(9):2147 - 2157. · 5.44 Impact Factor
• Article: Insulin-like growth factor-I and C-reactive protein during pregnancy and maternal risk of non-epithelial ovarian cancer: a nested case-control study.

  Adetunji T Toriola, Helja-Marja Surcel, Eva Lundin, Helena Schock, Kjell Grankvist, Eero Pukkala, Tianhui Chen, Paolo Toniolo, Matti Lehtinen, Anne Zeleniuch-Jacquotte, Annekatrin Lukanova
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  ABSTRACT: Insulin-like growth factor-I (IGF-I) and C-reactive protein (CRP) may be positively associated with the risk of epithelial ovarian cancer (EOC) but no previous studies have investigated their associations with non-epithelial ovarian cancers (NEOC). A case-control study was nested within the Finnish Maternity Cohort. Case subjects were 58 women diagnosed with sex cord-stromal tumors (SCST) and 30 with germ cell tumors (GCT) after recruitment. Control subjects (144 for SCST and 74 for GCT) were matched for age, parity, and date of blood donation of the index case. Doubling of IGF-I concentration was not related to maternal risk of either SCST (OR 0.97, 95% CI 0.58-1.62) or GCT (OR 1.13, 95% CI 0.51-2.51). Similarly, doubling of CRP concentrations was not related to maternal risk of either SCST (OR 1.10, 95% CI 0.85-1.43) or GCT (OR 0.93, 95% CI 0.68-1.28). Pre-diagnostic IGF-I and CRP concentrations during the first trimester of pregnancy were not associated with increased risk of NEOC in the mother. Risk factors for NEOC may differ from those of EOC.
  Cancer Causes and Control 08/2011; 22(11):1607-11. · 2.88 Impact Factor
• Article: Risk of seropositivity to multiple oncogenic human papillomavirus types among human immunodeficiency virus-positive and -negative Ugandan women.

  P B Namujju, T Waterboer, C Banura, R Muwonge, E K Mbidde, R Byaruhanga, M Muwanga, H-M Surcel, M Pawlita, M Lehtinen
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  ABSTRACT: To understand the prospects for human papillomavirus (HPV) mass vaccination in the setting of a developing country, we studied the co-occurrence of seropositivity to multiple high-risk (hr) HPV types among HIV-positive and HIV-negative Ugandan women. Our seroepidemiological study was conducted among 2053 women attending antenatal clinics. Sera were analysed for antibodies to eight hrHPV types of the α-7 (18/45) and α-9 (16/31/33/35/52/58) species of HPV by using a multiplex serology assay. Our results show that seropositivity for greater than one hrHPV type was as common (18 %) as for a single type (18 %). HIV-positive women had higher HPV16, HPV18 and HPV45 seroprevalences than HIV-negative women. In multivariate logistic regression analysis, age (>30 years) and level of education (secondary school and above) reduced the risk, whereas parity (>5) and HIV-positivity increased the risk for multiple hrHPV seropositivity. However, in stepwise logistic regression analyses, HIV-status remained the only independent, stand-alone risk factor [odds ratio (OR) 1.7, 95 % confidence interval (CI) 1.0-2.8). On the other hand, the risk of HPV16 or HPV18 seropositive women, as compared to HPV16 or HPV18 seronegative women, for being seropositive to other hrHPV types was not significantly different when they were grouped by HIV-status (ORHPV16/HIV+ 12, 95 % CI 4.5-32 versus ORHPV16/HIV- 22, 95 % CI 15-31 and ORHPV18/HIV+ 58, 95 % CI 14-242 versus ORHPV18/HIV- 45, 95 % CI 31-65). In conclusion, seropositivity to HPV16, HPV18 and to non-vaccine hrHPV types is common in Ugandan women, suggesting that there is little natural cross-protective immunity between the types. HIV-positivity was an independent, stand-alone, albeit moderate risk factor for multiple hrHPV seropositivity. HPV mass vaccination may be the most appropriate method in the fight against cervical cancer in the Ugandan population.
  Journal of General Virology 08/2011; 92(Pt 12):2776-83. · 3.36 Impact Factor
• Article: Circulating insulin-like growth factor-I in pregnancy and maternal risk of breast cancer.

  Adetunji T Toriola, Eva Lundin, Helena Schock, Kjell Grankvist, Eero Pukkala, Tianhui Chen, Anne Zeleniuch-Jacquotte, Paolo Toniolo, Matti Lehtinen, Helja-Marja Surcel, Annekatrin Lukanova
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  ABSTRACT: Elevated serum concentrations of insulin-like growth factor (IGF)-I have been associated with increased risk of developing breast cancer. Previously, we reported a similar association in samples obtained during pregnancy. This study was conducted to further characterize the association of IGF-I during pregnancy with maternal breast cancer risk. A case-control study was nested within the Finnish Maternity Cohort. The study was limited to primiparous women younger than 40 years, who donated blood samples during early (median, 12 weeks) pregnancy and delivered a single child at term. Seven hundred nineteen women with invasive breast cancer were eligible. Two controls (n = 1,434) were matched with each case on age and date at blood donation. Serum IGF-I concentration was measured using an Immulite 2000 analyzer. Conditional logistic regression was used to estimate ORs and 95% CIs. No significant associations were observed between serum IGF-I concentrations and breast cancer risk in both the overall analysis (OR, 1.08; 95% CI, 0.80-1.47) and in analyses stratified by histologic subtype, lag time to cancer diagnosis, age at pregnancy, or age at diagnosis. There was no association between IGF-I and maternal breast cancer risk during early pregnancy in this large nested case-control study. Serum IGF-I concentrations during early pregnancy may not be related to maternal risk of developing breast cancer.
  Cancer Epidemiology Biomarkers &amp Prevention 06/2011; 20(8):1798-801. · 4.12 Impact Factor
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  Available from: Kevin A Ault

  Article: Chlamydia trachomatis infection and risk of cervical intraepithelial neoplasia.

  Matti Lehtinen, Kevin A Ault, Erika Lyytikainen, Joakim Dillner, Suzanne M Garland, Daron G Ferris, Laura A Koutsky, Heather L Sings, Shuang Lu, Richard M Haupt, Jorma Paavonen
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  ABSTRACT: 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. 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. 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. 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.
  Sexually transmitted infections 04/2011; 87(5):372-6. · 2.18 Impact Factor
• Article: Circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer.

  Tianhui Chen, Helja-Marja Surcel, Eva Lundin, Marjo Kaasila, Hans-Ake Lakso, Helena Schock, Rudolf Kaaks, Pentti Koskela, Kjell Grankvist, Goran Hallmans, Eero Pukkala, Anne Zeleniuch-Jacquotte, Paolo Toniolo, Matti Lehtinen, Annekatrin Lukanova
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  ABSTRACT: Sex steroid hormones have been proposed to play a role in the development of non-epithelial ovarian cancers (NEOC) but so far no direct epidemiologic data are available. A case-control study was nested within the Finnish Maternity Cohort, the world's largest biorepository of serum specimens from pregnant women. Study subjects were selected among women who donated a blood sample during a singleton pregnancy that led to the birth of their last child preceding diagnosis of NEOC. Case subjects were 41 women with sex cord stromal tumors (SCST) and 21 with germ cell tumors (GCT). Three controls, matching the index case for age, parity at the index pregnancy, and date at blood donation were selected (n = 171). OR and 95% CI associated with concentrations of testosterone, androstenedione, 17-OH-progesterone, progesterone, estradiol, and sex hormone-binding globulin (SHBG) were estimated through conditional logistic regression. For SCST, doubling of testosterone, androstenedione, and 17-OH-progesterone concentrations were associated with about 2-fold higher risk of SCST [ORs and 95% CI of 2.16 (1.25-3.74), 2.16 (1.20-3.87), and 2.62 (1.27-5.38), respectively]. These associations remained largely unchanged after excluding women within 2-, 4-, or 6-year lag time between blood donation and cancer diagnosis. Sex steroid hormones concentrations were not related to maternal risk of GCT. This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST. Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC.
  Cancer Epidemiology Biomarkers &amp Prevention 03/2011; 20(2):324-36. · 4.12 Impact Factor
• Article: Circulating estrogens and progesterone during primiparous pregnancies and risk of maternal breast cancer.

  Annekatrin Lukanova, Helja-Marja Surcel, Eva Lundin, Marjo Kaasila, Hans-Ake Lakso, Helena Schock, Anika Husing, Rudolf Kaaks, Pentti Koskela, Kjell Grankvist, Eero Pukkala, Anne Zeleniuch-Jacquotte, Matti Lehtinen, Paolo Toniolo
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  ABSTRACT: Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (± 6 months) and date of sampling (± 3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥ age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40.
  International Journal of Cancer 03/2011; 130(4):910-20. · 5.44 Impact Factor