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A blood test based on the E6 and E7 proteins from human papillomavirus types 16 and 18 is not very accurate in identifying women infected with the virus who may develop cervical cancer, according to a study of 550,000 women. Only 7% of the women who eventually developed cervical cancer had antibodies to these viral proteins in blood samples taken up to 20 years earlier. Some types of human papillomavirus have been linked to cervical cancer, especially types 16 and 18.

Background: Seropositivity for several sexually transmitted infections (STIs) is often used as a surrogate measure of sexual behavior. The authors assessed the concomitant seropositivity for STIs in women. Goal: To estimate the excess of concomitant seropositivity for four STIs among fertile-aged women assuming no coinfections above what would be expected at random. Study Design: Antibodies to herpes simplex virus type 2, human papillomavirus type 16, HIV, Chlamydia trachomatis, and Treponema pallidum were determined from a random sample of 1110 pregnant women in Tallinn, Estonia. Results: A total of 310 combinations of the concomitant seropositivity were observed, whereas only 193 were expected by chance. Among persons seropositive for two STIs, 78 extra combinations were observed, whereas for three STIs, 35 extra combinations were observed. For four STIs, 3.8 extra combinations were found. Conclusions: Seropositivity to multiple STIs is not common. This fits the concept of different transmission probabilities and the spread of the STIs, and suggests that seropositivity alone should be used with caution as a surrogate to sexual behavior in women.

Introduction Experimental and epidemiological data have implicated human papillomavirus as a cause of cervical cancer.[1 2] Human papillomavirus DNA has been detected in more than 90% of invasive cancers.[3] Human [...]

Background: Major risk factors for invasive cervical cancer include infection with human papillomavirus (HPV), infection with other sexually transmitted pathogens (e.g., Chlamydia trachomatis), and smoking. Since exposures to these risk factors can be related, the contribution of any single factor to cervical carcinogenesis has been difficult to assess. We conducted a prospective study to define the role of HPV infection in cervical carcinogenesis, with invasive cancer as an end point. Methods: A nested case-control study within a joint cohort of 700 000 Nordic subjects was performed. The 182 women who developed invasive cervical cancer during a mean follow-up of 5 years were matched with 538 control women on the basis of age and time of enrollment. Serum samples taken at enrollment were analyzed for evidence of tobacco use (i.e., cotinine levels); for antibodies against HPV types 16, 18, and 33; and for antibodies against C trachomatis. Relative risks (RRs) were estimated by use of conditional logistic regression. Results: Presence of antibodies against HPV in serum (seropositivity) was associated with an increased risk of cervical cancer, and adjustment for smoking and for C trachomatis seropositivity did not affect this finding (RR = 2.4; 95% confidence interval [CI] = 1.6-3.7). HPV16 seropositivity was associated primarily with an increased risk of squamous cell carcinoma (RR = 3.2; 95 % CI = 1.7-6.2). In contrast, risk associated with HPV18 seropositivity tended to be higher for cervical adenocarcinoma (RR = 3.4; 95% CI = 0.8-14.9). In populations with a low prevalence of antibodies against C. trachomatis, the HPV16-associated risk of cervical cancer was very high (RR = 11.8; 95% CI = 3.7-37.0); in contrast, in populations with a high prevalence of antibodies against C. trachomatis, no excess risk was found. Conclusion: Past infection with HPV16 increases the risk of invasive cervical squamous cell carcinoma, most clearly seen in populations with a low prevalence of sexually transmitted diseases. [J Natl Cancer Inst 1997; 89:1293-9]

Background and Objectives: Treatment of genital warts is problematic. Numerous treatment modalities are available, but response to any therapy often is unsatisfactory. Recently, studies have suggested that interferons would be effective in the treatment of some genital warts. Goal of this Study: To compare carbon dioxide laser with or without adjuvant subcutaneously administered interferon alpha-2b in the treatment of genital human papillomavirus infection. Study Design: One hundred randomized women with genital HPV infection were treated with carbon dioxide laser and adjuvant systemic interferon alpha-2b or carbon dioxide laser and placebo. Patients were followed colposcopically, cytologically, and by HPV DNA testing for 6 months. Results: Complete response was seen in 62% patients who received adjuvant interferon, and in 68% patients who received placebo. However, recurrence was less common in patients treated with interferon who were infected with HPV 16/18. Conclusion: Only a subgroup of patients, women infected with HPV DNA 16/18, benefited from adjuvant systemic interferon treatment., The addition of interferon alpha-2b to carbon dioxide laser treatment for genital warts appears to have little effect for most women. Ninety-four women diagnosed with genital warts caused by human papillomavirus (HPV) were treated with carbon dioxide laser vaporization and either systemic interferon alpha-2b or placebo. Carbon dioxide laser vaporization destroys the lesions. Injections of 1.5 million units of interferon alpha-2b were given three times a week in the three weeks after the laser treatments. About two-thirds of each group showed complete response after six months. Eighteen women who had received interferon and 15 of those who had received the placebo had a recurrence of the genital warts. The only significant difference between the interferon and placebo groups was among a small subgroup who were infected with HPV type 16/18. This group was slightly less likely to have a recurrence.

ABSTRACTThis manuscript discloses end-of-study safety data of a community-randomized controlled trial in Finland (NCT00534638), assessing the effectiveness of two vaccination strategies (gender-neutral versus females only) using the AS04-adjuvanted human papillomavirus (HPV)-16/18 (AS04-HPV-16/18) vaccine. The total vaccination cohort included 32,175 adolescents aged 12–15 y at vaccination of whom 14,837 received the AS04-HPV-16/18 vaccine and 17,338 received the hepatitis-B virus vaccine (control). Spontaneous reporting of serious adverse events (SAEs) combined with surveillance using nation-wide health registries showed an acceptable safety profile of the AS04-HPV-16/18 vaccine. During the study period (up to 6.5 y), the incidences (per 100,000 person-years) of reported SAEs considered as possibly related to vaccination were 39.1 (95% confidence interval [CI]: 25.3–57.7) and 39.8 (95%CI: 26.8–56.8) in the HPV and control groups, respectively. The most frequently reported new-onset autoimmune diseases (NOADs) were ulcerative colitis (incidence rates of 28.2 and 33.1 per 100,000 person-years in the HPV and control groups, respectively), insulin-dependent diabetes mellitus (21.9 and 37.1), Crohn’s disease (15.6 and 22.5), celiac disease (15.6 and 21.2), and juvenile idiopathic arthritis (14.1 and 15.9). Of 1,344 pregnancies reported (777 and 567 in the HPV and control groups, respectively), most resulted in elective termination (58.4% and 58.6%), birth of a live infant (32.7% and 32.3%), or in spontaneous abortion (8.0% and 7.9%). No major, registered congenital anomalies were identified. The incidence rates of NOADs and pregnancy outcomes were generally balanced between groups. No specific safety signals were identified in the population-based health registry surveillance.

Abstract Objective--To study human papillomavirus type 16 in the aetiology of cervical carcinoma. Design--Within a cohort of 18 814 Finnish women followed for up to 23 years a nested case-control [...]

ABSTRACTThis community-randomized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus (HPV) immunization strategies in over 80,000 girls and boys aged 12–15 y in 33 communities in Finland (ClinicalTrials.gov NCT00534638). Overall, 14,838 adolescents received HPV-16/18 vaccine (2,440 boys and 12,398 girls) and 17,338 received hepatitis-B virus (HBV) vaccine (9,221 boys and 8,117 girls). In an interim analysis, vaccine safety was assessed by active monitoring and surveillance via health registry linkage. Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys. In all study participants, the observed incidences (per 100,000 person-years) of serious adverse events (SAEs) possibly related to vaccination were 54.3 (95% Confidence Interval [CI]: 34.0–82.1) in the HPV-16/18 group and 64.0 (95% CI: 43.2–91.3) in the HBV group. During the follow-up period for this interim analysis, the most common new-onset autoimmune diseases (NOADs; with incidence rate ≥15 per 100,000) in any group based on hospital discharge registry (HILMO) download were ulcerative colitis, juvenile arthritis, celiac disease, insulin-dependent diabetes mellitus (IDDM) and Crohn's disease. No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients. In both the SAE possibly related- and HILMO-analyses, a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees (relative risks, 0.26 [95% CI: 0.03–1.24] and 0.16 [95% CI: 0.03–0.55], respectively).

Human papillomavirus (HPV)-screening technologies and HPV vaccination are revolutionizing the management of cancers related to this virus, in particular, cervical neoplasms. At present, however, the effectiveness of these modalities is not optimal, owing to the limited scope of HPV-vaccination and cervical screening programmes. In this Perspectives, an international panel of experts describes for the first time a new campaign, termed 'HPV-FASTER', which aims to broaden the use of HPV vaccination coupled with HPV testing to women aged up to 30 years, and in some settings up to 50 years, with the aim of accelerating the reduction in the incidence of HPV infections and cervical cancer. The authors describe the evidence supporting this approach and details on how it might be implemented, discuss the opportunities—particularly in low-resource settings—and challenges associated with the strategy, and highlight key research gaps that need to be addressed in future studies.

ABSTRACTWe report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n= 9,319; control, n= 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n= 5,822; control, n= 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (-1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.govunder registration no. NCT001226810.)

ABSTRACTThe efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10PCR-DEIA/LiPA25plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hocanalysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.)

Highly efficacious vaccines are available to protect against persistent human papillomavirus (HPV) infection and, therefore, the associated neoplasias (most notably cervical cancer). This Review article discusses the two approved vaccines in terms of their structure, mode of action, efficacy, cross-reactivity with non-vaccine HPV types, safety and use in vaccination programmes.

Objectives:the study aims to estimate the clinical-impact and cost-effectiveness value of adding human papillomavirus 16/18 vaccination against cervical cancer among women currently undergoing organised screening in Finland.Methods:A Markov cohort model evaluating high-risk HPV infections and cervical cancer (CC) cases combined with screening has been customised to the Finnish setting. The model outcome for a cohort of 30,000 girls aged 10 years was calibrated to age-specific annual number of Pap smears, CC incidence and mortality.Results:The observed age-specific incidence and mortality rates of CC closely match the data replicated by the model. The model predicts that with a 90 vaccine coverage rate, CC cases and mortality would be reduced by 70. In the base-case analysis with a discount rate of 3 the incremental cost per quality-adjusted life-years (QALY) gained, from a healthcare perspective, was €17,294. Without discounting this value is €2,591/QALY gained.Conclusions:The analysis suggests that implementing prophylactic CC vaccination within the current screening system would substantially reduce CC cases and deaths, as well as the overall disease burden expressed in pre-cancer lesions averted. Vaccination could be a cost-effective intervention in Finland despite the fact that the number of CC cases and deaths are currently relatively low. Conservative estimates of the cost effectiveness of the vaccination were provided since it was not possible to assess herd protection induced by vaccination using this Markov model.

Vaccines were first developed in England over 200 years ago and have made a significant positive impact on human society since. Not often realised is the intimate relationship shared between vaccines and women. Women were key to the initial development of vaccines; some were even advocating the concept of protection against infectious disease through prior asymptomatic infection (by variolation) before the publication of the report of the first successful smallpox vaccination in 1798.Since that milestone, women have been important partners in the development of vaccines and advocates for their widespread introduction. Modern vaccine development would not be possible without the altruistic informed consent granted by many women for the participation of themselves or their children in vaccine clinical trials all over the world.Vaccines have rewarded women handsomely in return. Individual women benefit in many ways ranging from safer pregnancies to preventing cancers to attractive, unblemished skin. Some vaccines are even specifically designed to prevent diseases primarily affecting women such as cervical cancer.Vaccines also have offered societal benefits to women. These include better maternal health and fostering an environment more amenable to effective family planning. With these advances, women become more empowered and have access to better economic opportunities.The challenge of meeting the millennium development goals specifically targeted for women will be facilitated by vaccines. A better realisation by women of the benefits of this partnership secured over the past 200 years will enable them to reap fully the rewards of the future.

The aim of this interim analysis of a large, international phase III study was to assess the efficacy of an AS04 adjuvanted L1 virus-like-particle prophylactic candidate vaccine against infection with human papillomavirus (HPV) types 16 and 18 in young women.

There has been considerable progress in the development of a prophylactic human papillomavirus vaccine in the past 10 years, since the discovery of human papillomavirus virus-like particles. Licensure of the human papillomavirus vaccine is probably not far away. This would make it the first licensed vaccine against a common sexually transmitted infection. Although hepatitis B is a sexually transmitted infection for which there is an effective prophylactic vaccine, it is often not perceived as such by individuals taking the vaccine. Preclinical studies have already produced attractive vaccine candidates and recent clinical trials have yielded strikingly promising results. The candidate vaccines are generally well tolerated, induce high titers of serum antibodies to the human papillomavirus types and effectively prevent acquisition of infection and early clinical disease caused by common human papillomavirus types.

Persistent human papillomavirus (HPV) infection is an established cause of cervical cancer, but the role of other sexually transmitted agents, most notably Chlamydia trachomatis, has not been well defined. The women participating in the population-based cervical cancer screening program in Västerbotten county of Northern Sweden were followed up for up to 26 years to identify 118 women who developed cervical cancer after having had a normal Pap smear (on average 5.6 years later; range 0.5 months–26 years). As controls, we selected another 118 women who were matched by birth cohort, time-point of sampling of the baseline normal smear and who had a normal smear at the time when the corresponding case was diagnosed with cancer. The Pap smears and cervical cancer biopsies were analyzed by PCR for C. trachomatis DNA and for HPV DNA. At baseline, C. trachomatis DNA was present in 8% of cases but not among any one of the controls. The relative risk for cervical cancer associated with past C. trachomatis infection, adjusted for concomitant HPV DNA positivity, was 17.1 (95% CI 2.6–∞).The presence of C. trachomatis and of HPV were not interrelated. Whereas C. trachomatis was primarily found in specimens taken many years before cancer diagnosis, HPV DNA was associated with a short lag time before cancer diagnosis. Whereas most women who were HPV DNA-positive in the prediagnostic smear were also positive for the same virus in the cervical cancer biopsy, none of the women were positive for C. trachomatis in both the prediagnostic smear and in the subsequent cervical cancer. In conclusion, a prior cervical C. trachomatis infection was associated with an increased risk for development of invasive cervical cancer. © 2002 Wiley-Liss, Inc.

Enterolactone, a phytoestrogen belonging to the class of lignans, is produced by the intestinal microflora from precursors in plant foods and has been implicated in protection against cancer. We study the effect of enterolactone on the risk of a subsequent diagnosis of prostate cancer. We conducted a longitudinal, nested case-control study by linkage of 3 biobanks to the cancer registries in Finland, Norway and Sweden, respectively. Enterolactone concentrations were measured by time-resolved fluoroimmunoassay in serum from 794 men who had a diagnosis of prostate cancer at a mean follow-up time of 14.2 years after blood collection and among 2,550 control men matched within each cohort for age (±2 years), date of blood collection (±2 months) and county. The median enterolactone concentrations did not differ between case and control subjects in the full study group (8.4 nmol/L [25th–75th percentile = 4.5–15.0] vs. 8.5 nmol/L [25th–75th percentile = 4.3–15.9]), nor in the national groups. Odds ratios of prostate cancer risk estimated by conditional logistic regression for increasing concentrations of enterolactone in quartiles in the full study group were 1.00 (referent), 1.21 (95% confidence interval [CI] = 0.96–1.52), 1.16 (95% CI = 0.91–1.47) and 1.08 (95% CI = 0.83–1.39). The OR estimate for the highest vs. the lowest quartile of enterolactone in separate analyses of the Norwegian, Finnish and Swedish cohort was 1.21 (95% CI = 0.91–1.60), 1.02 (95% CI = 0.59–1.76) and 0.87 (95% CI = 0.45–1.67), respectively. No support for the hypothesis that high circulating enterolactone is protective against prostate cancer was found. © 2002 Wiley-Liss, Inc.

Objectives:To estimate the joint effects of infections with human papillomavirus type 16 (HPV16) and Chlamydia trachomatisand smoking on the risk of cervical cancer. To study whether the joint effects can be accounted for by misclassification in the HPV serology. Methods:A nested case–control study with incidence density sampling was conducted in three cohorts of 530,000 women, who donated serum samples to three Nordic serum banks in 1973–1994. The main outcome measure is the odds ratio (OR) of incidence rates of invasive cervical squamous cell carcinoma (SCC) among those seropositive for HPV16 and/or C. trachomatisand/or with increased levels of cotinine in serum compared to those negative for all the three exposures. Results:Two hundred eight women with SCC and 624 matched controls were identified during a mean follow-up of 5 years through linkage to the national cancer registries. Exposure to past infections and smoking was defined by presence of specific IgG antibodies to HPV16 and C. trachomatisand increased levels of serum cotinine. Observed ORs were compared to OR = 20 for HPV16 and accounting the differences for by misclassification bias. OR = 20 was elected as a gold standard on the basis of other studies with PCR-based analyses and a follow-up design. Each of the three exposures was associated with an increased risk of SCC (OR = 5.4 for HPV16, 3.4 for C. trachomatisand 1.8 for cotinine). The interaction was antagonistic (observed OR = 2.5 among those positive for all three exposures as compared to OR = 33 expected on the basis of multiplicative single effects (p= 0.047)). The antagonism could not totally be accounted for by any credible combination of sensitivity and specificity of HPV16 serology. Conclusion:HPV16, C. trachomatis, and smoking are likely to be risk factors of SCC with strong antagonistic joint effect. Non-differential misclassification in serology for HPV16 could be ruled out (but only some types of differential) as an alternative explanation for the observed antagonism.

Cervical carcinoma is a sexually transmitted disease most strongly linked with human-papillomavirus (HPV) infection. We conducted a prospective sero-epidemiologic study to evaluate the role of Chlamydia trachomatis infection in the development of cervical carcinoma, with invasive cancer as an end point. A nested case-control study within a cohort of 530000 Nordic women was performed. Linking data files of 3 Nordic serum banks and the cancer registries of Finland, Norway and Sweden identified 182 women with invasive cervical carcinoma diagnosed during a mean follow-up of 5 years after serum sampling. The serum samples of the cases and matched cancer-free controls were analyzed for IgG antibodies to C. trachomatis, C. pneumoniae (a control microbe) and HPV types 16, 18 and 33, as well as for serum cotinine (an indicator of tobacco smoking). Serum antibodies to C. trachomatis were associated with an increased risk for cervical squamous-cell carcinoma (HPV- and smoking-adjusted OR, 2.2; 95% CI, 1.3–3.5). The association remained also after adjustment for smoking both in HPV16-seronegative and -seropositive cases (OR, 3.0; 95% CI, 1.8–5.1; OR, 2.3, 95% CI, 0.8–7.0 respectively). No such association was found for C. pneumoniae. Our prospective study provides sero-epidemiologic evidence that infection with C. trachomatis confers an increased risk for subsequent development of invasive squamous-cell carcinoma of the uterine cervix. Int. J. Cancer 85:35–39, 2000. © 2000 Wiley-Liss, Inc.

Human papillomavirus (HPV) types 16 and 18 are the major risk factors for cervical carcinoma, whereas HPV types 6 and 11 cause benign genital lesions. We wanted to study the joint effect of simultaneous infections with the oncogenic and non-oncogenic HPV types on risk of subsequent development of cervical carcinoma. A cohort of 530,000 women who had donated blood samples to Nordic serum banks between 1973 and 1994 was followed up by linkage to national cancer registries. We identified 182 prospective cases with invasive cervical carcinoma and selected 538 matched controls at random. HPV 6, 11, 16, 18 and 33 seropositivity was used as a marker for the different HPV infections, and seropositivity for Chlamydia trachomatis and cotinine were used as markers for risk-taking sexual behavior and smoking respectively. The adjusted odds ratio (OR) of cervical squamous-cell carcinoma (SCC) was 2.2 for HPV6/11 among HPV16 seronegatives and 5.5 for HPV16 among HPV6/11 seronegatives. Assuming multiplicative joint effect, the expected OR for seropositivity to both HPV6/11 and HPV16 would have been 12, but the observed OR was 1.0. The antagonistic interaction was statistically significant (p = 0.001) and present also under deterministic considerations of possible misclassification bias. Antagonistic interactions were also detected for combinations of HPV16 and HPV18 and of HPV16 and HPV33. The results are in line with the concept that HPV-specific immunity protects against SCC and support primary prevention of SCC by vaccination against the HPVs. Int. J. Cancer 80:818–822, 1999. © 1999 Wiley-Liss, Inc.

Comparative epidemiological studies have for a long time suggested a link (or links) between infectious agents and hematological malignancies in the young. Identification of Epstein‐Barr virus (EBV) as the major cause of specific subtypes of Burkitt's lymphoma and Hodgkin's disease 20 and 10 years ago, respectively, and the recent involvement of human T‐cell leukemia virus in non‐Hodgkin's lymphomas of the T‐cell lineage in young adults in Jamaica have given further credit to early presumptions that these diseases have an infectious etiology. The spectrum of possibly involved viruses: old, EBV, and new, herpesviruses 6, 7 and 8, and unknown retroviruses – as well as the list of partially or totally unresolved disease entities: Hodgkin's disease in adolescents, non‐Hodgkin's lymphomas in the immunocompromised, and acute lymphocytic leukemia – is rapidly expanding. Both direct and indirect transforming effects of the above‐mentioned viruses are being rapidly disclosed. However, the complex interaction between the different viruses and other causes of hematological malignancies in the young guarantees that many things remain to be discovered also in the future.

Some epidemiological studies of prostate cancer have suggested the existence of a sexually transmitted risk factor, and some studies have reported the presence of human papillomavirus (HPV) DNA in prostate-cancer tissue. To perform a sero-epidemiological evaluation of whether HPV infection is associated with increased risk for prostate cancer, we performed a nested case-control study within a serum bank containing samples from 20,243 healthy Finnish men. We identified 165 cases of prostate cancer that were diagnosed up to 24 years after donation of the serum sample. Two control subjects per case were selected, matched for gender, age and municipality of residence. Serum samples were analyzed for the presence of IgG antibodies against 4 HPV types and against Chlamydia. The presence of antibodies against HPV type 18 was associated with a 2.6-fold increased risk of developing prostate cancer during follow-up (p < 0.005). HPV type 16 tended to be associated with subsequent prostate-cancer occurrence (relative risk: 2.4, p = 0.06), whereas seropositivity for HPV type 11 or type 33 or for Chlamydia was not associated with risk. The results suggest that infection with oncogenic HPV might be involved in the etiology of a minority of prostate cancers. Int. J. Cancer 75:564–567, 1998. © 1998 Wiley-Liss, Inc.

ABSTRACTThe diagnostic performance of a PCR test (Roche Cobas Amplicor CT/NG Test) and that of a ligase chain reaction (LCR) test (Abbott LCxChlamydia trachomatisassay) were compared by using endocervical and urethral swab specimen culture as a reference test. First-void urine (FVU) and endocervical and urethral swab specimens were collected from 1,015 unselected patients attending a sexually transmitted disease clinic and a clinic for adolescents in Helsinki, Finland. Chlamydia trachomatiswas cultured from samples from the endocervix or urethra. PCR was performed with fresh and frozen urine and the culture transport medium. LCR was performed with fresh and frozen urine and LCx swab transport medium. Diagnostic consistency and diagnostic accuracy were statistically tested. The test results were identical for 984 patients (97%). Discrepant results were observed for 31 patients. Overall, LCR and PCR showed excellent kappa coefficients of consistency for both swab and FVU specimens (0.93 and 0.95, respectively). Sixty-one patients (6%) were culture positive. Testing of FVU by LCR or PCR increased the overall positivity rates to 7.0 and 7.7%, respectively. While PCR of FVU detected the greatest number of C. trachomatisinfections (sensitivity, 96.1%), for some PCR-positive FVU specimens the results could not be confirmed (specificity, 99.6%). PCR and LCR were more sensitive than culture (sensitivities, 92 and 93% versus 79% for culture) in the diagnosis of genital C. trachomatisinfection. In conclusion, both tests can be recommended for use in the clinical laboratory and for the screening of asymptomatic C. trachomatisinfections.

We estimated Epstein-Barr virus (EBV) antibody-associated relative risks (RR) of malignant lymphoma/leukemia within a cohort of 39,000 healthy Finnish adults followed up for 12 years. Antibody analyses to EBV capsid antigen (VCA), early antigen (EA), and nuclear antigens (EBNA, EBNA1, and EBNA2) were based on concomitantly evaluated ELISA techniques. No increased risk was associated with mere EBV seropositivity. However, elevated EBV EA and EBNA antibody levels were associated with a statistically significant excess risk of malignant lymphoma/leukemia (RREA=3.4, 95 percent confidence interval [CI]=1.0–11.0; RREBNA=4.5, CI=1.2–16.9). These elevated antibody responses may be due either to destruction of neoplastic EBV positive B-cells and/or to activation of latent EBV infection early in the lymphomagenesis.

This study was initiated to investigate the role of past herpes simplex virus type 2 (HSV-2) infection, as determined by serum antibody analysis, in the etiology of cervical neoplasia. Two Finnish registers, the registry of the Social Insurance Institution's Mobile Clinic Survey and the Finnish Cancer Registry, were linked. About 40,000 blood samples were drawn in 1968–72 and stored by the Social Insurance Institution. According to the Cancer Registry, 32 cases of cervical carcinoma or carcinoma in situ for which serum samples were available were diagnosed in this cohort during a follow-up of 12 years (1968–81). The serum samples of these individuals and age matched controls (2:1) from the cohort were analyzed for HSV-2 antibodies. HSV-2 infection as determined by the best available HSV-2 type-specific antibody assay, glycoprotein gG2-ELISA, was not related to cervical neoplasia, i.e., the risk of cervical neoplasia among the HSV-2 positive women was not higher than that among the negative ones (smoking-adjusted relative risk = 0.5, 95 percent confidence interval = 0.2–1.6). The results do not support the hypothesis that HSV-2 is an etiologic agent for cervical neoplasia.

To investigate the prevalence of human papillomavirus (HPV) DNA in squamous cell carcinoma of the vulva by polymerase chain reaction (PCR).

The DNA incorporation of a thymidine analogue bromodeoxyuridine (BrdUrd) in herpes simplex virus type 2 (HSV-2) infected cervical cancer cell lines (CaSki and C-33 A) was studied by dual parameter flow cytometry. HSV-2 infection resulted in an exponential increase in DNA synthesis in the CaSki cells. In the less permissive C-33 A cells the proportion of DNA-synthesizing cells cycled during HSV-2 infection. The inhibition of viral DNA synthesis by phosphonoformate (PFA) was able to inhibit the virus induced changes in the CaSki but not in the C-33 A cells. In the C-33 A cells a part of the virus induced cellular DNA synthesis represents repair replication of cellular DNA.

We analysed diagnostic phase plasma levels of thymidine kinase (TK) and mutated p53 in 81 patients with malignant lymphoma. Forty-three (53%) patients had increased (> 10 U/1) TK activity whereas 30 (37%) were positive for the mutated p53 gene product. In general, patients with p53 mutation positive tumors tended to have higher TK activity than those without. Furthermore, patients with high-grade non-Hodgkin's lymphoma (NHL) showed almost a linear correlation (rs = 0.79) between plasma levels of mutated p53 and TK. We conclude that the monoclonal antibody assisted detection of mutated p53 gene product may prove a useful adjunct to the diagnostic procedures of malignant lymphomas.

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.

Nat. Rev. Clin. Oncol. 10, 400–410 (2013); published online 4 June 2013; 10.1038/nrclinonc.2013.84 In the version of this Review article originally published online and in print in the July 2013 issue there were errors in the clinical data presented in Tables 2, 3 and 5. In addition, reference 68 should have been cited to support data in Table 2, and the efficacy of the bivalent vaccine in adenocarcinoma in situ was 76.

Four women are described with acute salpingitis confirmed by laparoscopy who had herpes simplex virus(HSY) isolated from the cervix or the upper genital tract (endometrium, fallopian tube, or cul-de-sac) or both. None of the patients had overt genital herpes, but one had typical HSV cervitis on a cervicovaginal smear stained with Papanicolaou's stain, one had a significant change in level of antibodies to HSV, and one had an endometrial biopsy specimen positive for HSV antigen. There are at least three potential explanations for these findings: chronic viral shedding, viral reactivation caused by acute pelvic inflammatory disease(PID), or that the PID was actually caused by HSV. Further prospective studies are needed to document the role of HSY in causing PID.

The association of seropositivity to human papillomavirus (HPV) capsids of types 11, 16, 18, or 33 with sexual behavior was investigated. Among 1002 women visiting family planning or youth clinics in Sweden, an age-matched subsample of 274 women stratified according to lifetime number of sex partners was analyzed. The proportion of HPV-16-seropositive subjects increased linearly at ∼4% per partner (P < .001), from 4% among those with 1 lifetime partner to 35% among those with >5 lifetime partners. Also, HPV-33 and HPV-18 seroprevalences were linearly dependent on the number of partners (P < .001, increase with 4% per partner, and P = .008, increase with ∼3% per partner, respectively), providing serologic confirmation that the important mode of transmission of HPV-16, -18, or -33 infection in women is sexual. HPV serology appears to be suitable as a marker of sexual behavior in populations.

To study antibody response to the hypersensitivity protein B of Chlamydia trachomatis, also known as the 60-kDa heat-shock protein (hsp60), epitope scanning was done over the entire protein. Human sera with antibodies to C. trachoma tis identified 5 major antigenic regions (peptides 2, 5, 9, 17, and 21) and several minor regions (peptides 34-37, 39, 50, and 59-62). Clear-cut IgG antibody responses to chlamydial peptide 2 (YNEEARKKIQKGVKT) and a corresponding mycobacterial peptide (YDEEARRGLERGLNA) were found in 8 of 16 infants with chlamydial pneumonitis and in 1 of 18 controls. Peptide 50 (RLAKLSGGVAVIRVG) showed an 80% identity with its human counterpart (RLAKLSDGVAVLKVG), which was derived from human mitochondrial protein P1, but specific antipeptide antibody responses were found in 3 of 16 cases only. In summary, both IgG antibody response to C. trachomatis hsp60 and occasional autoantibody formation in infants with chlamydial pneumonitis were found.

The stability over time of serum IgG antibody levels to human papillomavirus type 16 (HPV-16) was determined by comparing the HPV-16 capsid antibody levels in serial serum samples of an age-stratified random subsample of 1656 primiparous mothers resident in Helsinki who were followed until their second pregnancy, on average 29.5 months later. The correlation between the first and second pregnancy HPV-16 serum antibody levels of the same woman was high, even when > 4 years had elapsed between pregnancies (r = .822). Between negativity, indeterminate results, or quartiles of positivity, the predictive values for being classified in the same category on both occasions ranged between 42% and 91%. Correlation coefficients, predictive values, and κ coefficients between serial samples all were comparable with those of repeat analyses of the same sample, indicating that HPV capsid antibody levels are generally stable during several years of follow-up.

Highlights • Models for cervical cancer screening are complex due to the multiplicity of HPV types • Microsimulation is typically used for model-based evaluation of screening strategies • We developed a deterministic model of screening outcomes, using compressed mixture representations • Our method was accurate and reduced dramatically the required computation times Abstract Cervical cancer arises differentially from infections with up to 14 high-risk human papillomavirus (HPV) types, making model-based evaluations of cervical cancer screening strategies computationally heavy and structurally complex. Thus, with the high number of HPV types, microsimulation is typically used to investigate cervical cancer screening strategies. We developed a feasible deterministic model that integrates varying natural history of cervical cancer by the different high-risk HPV types with compressed mixture representations of the screened population, allowing for fast computation of screening interventions. To evaluate the method, we built a corresponding microsimulation model. The outcomes of the deterministic model were stable over different levels of compression and agreed with the microsimulation model for all disease states, screening outcomes, and levels of cancer incidence. The compression reduced the computation time more than 1000 fold when compared to microsimulation in a cohort of 1 million women. The compressed mixture representations enable the assessment of uncertainties surrounding the natural history of cervical cancer and screening decisions in a computationally undemanding way. [ABSTRACT FROM AUTHOR]