Human papillomavirus infection (HPV) and pregnancy.

Human papillomavirus (HPV) is the most common sexually transmitted viral infection worldwide, which may result in the development in benign lesions or malignant tumors. The prevalence of HPV infection is twice as high in pregnancy as in non-pregnant women. Additionally, there is a risk of vertical transmission of HPV from mother to fetus during pregnancy or childbirth. Various studies have reported an increased risk of adverse pregnancy outcomes in HPV-positive women, including miscarriage, preterm birth, premature rupture of membranes, preeclampsia, fetal growth restriction, and fetal death. HPV vaccination is not currently recommended during pregnancy. On the other hand, there is no evidence linking HPV vaccination during pregnancy with adverse pregnancy outcomes and termination of pregnancy is not justified in this case.

Prevalence of sexually transmitted infections in women of the Czech Republic Armed Forces: a cross-sectional pilot study.

INTRODUCTION: Sexually transmitted infections (STIs) are an everlasting health issue globally. The military environment is recognised as a high-risk setting. Human papillomavirus (HPV), Chlamydia trachomatis and Neisseria gonorrhoeae are the most frequent STIs worldwide. This prospective cross-sectional pilot study focuses on the prevalence of selected STIs in the female population of the Czech Republic's Armed Forces. METHODS: C. trachomatis, N. gonorrhoeae and HPV detection and genotyping were performed between August 2020 and December 2022 in 141 women. Participants were divided into three groups according to their military status-recruits (n=72), active soldiers (n=25) and control civilian group (n=44). Cervical smear tests were performed, and data on STI risk factors were obtained through a questionnaire. RESULTS: A significant difference in the HPV prevalence between recruits (64.5 %) and both active soldiers (46.4 %) and civilians (47.3 %) was found when adjusted for age (p=0.007 and p=0.01, respectively). Lower age of coitarche (median 16; p=0.005) and smaller agglomeration origin (p=0.013) were reported for military recruits. No difference was proven in other researched risk factors. Associations between HPV detection and the higher number of sexual partners (p=0.013), early coitarche (p=0.016) and single marital status (p=0.002) across the groups were observed. Not a single case of N. gonorrhoeae was detected in any of the 141 participants. The prevalence of C. trachomatis did not differ significantly between the three evaluated groups-recruits, control civilian group, and active soldiers (5.6%, 2.3%, 0%, respectively; p=0.567). CONCLUSIONS: This pilot study showed a significantly higher HPV prevalence in female military recruits compared with both active military and civilian women. Recruits reported earlier coitarche which is a strong STI risk factor. Further study is needed to expand on the findings of this pilot study and generate data to support adjustment of STI preventive measures within the Czech Republic Armed Forces.

The significance of p16 protein expression in oral squamous cell carcinoma.

INTRODUCTION: Human papillomavirus (HPV) infection plays an important role in the etiopathogenesis of oropharyngeal squamous cell carcinomas. HPV detection in these tumours is a positive prognostic marker. The p16 protein expression, which is detected immunohistochemically, is an indirect marker of active HPV infection. Unlike in oropharyngeal carcinoma, in oral carcinoma, the prognostic significance of HPV/p16 positivity is unclear. Some studies even show a worse prognosis in patients with HPV/p16 positive oral carcinoma. The aim of our study is to consider the significance of p16 protein expression in relation to clinicopathological parameters and prognosis in patients with oral squamous cell carcinomas.  Methods: One hundred and twenty patients treated surgically for oral carcinoma were enrolled in the study. The most common anatomical sites of oral carcinoma were the tongue body (54; 45% of cases) and floor of mouth (35; 29.2% of cases). All tumours were analysed immunohistochemically for p16 protein expression. The results were correlated with the clinicopathological parameters and analysed statistically. RESULTS: Ten patients (8.3%) tested positive for p16 expression. In the study cohort, p16 expression was identified as the most significant factor with a negative effect on survival (p=0.019). Based on the Cox proportional hazard model, the p16-positive patients had four times worse survival than the p16-negative ones. Other factors with a statistically significant effect on survival were T status, N status, and recurrence. CONCLUSION: The significance of p16 expression differs between oral and oropharyngeal carcinomas. The p16 positivity seems to be a negative prognostic factor in oral carcinomas. Nevertheless, the significance of HPV presence in tumours outside the oropharyngeal area remains unclear.

Correlation between integration of high-risk HPV genome into human DNA detected by molecular combing and the severity of cervical lesions: first results of the EXPL-HPV-002 study.

OBJECTIVES: The aim of the EXPL-HPV-002 study is to evaluate the integration of 14 high-risk HPV as a biomarker of the severity and the progression of cervical lesions. Such a „triage biomarker“ would help to reduce the number of unnecessary colposcopies, to avoid over-treatment of lesions that spontaneously regress and to better target the lesions requiring treatment. DESIGN: EXPL-HPV-002 is a prospective, open-label, single arm, GCP study conducted at 2 clinical sites in the Czech Republic. SETTINGS: Investigations centers: Private Gynecology Center, Brno; Gynecological and Obstetrical Clinic, Brno; Genotyping central lab: NRL for Papillomaviruses and polyomaviruses, IHBT, Prague; Histology Central reading: Aeskulab Pathology, Prague; Molecular combing HPV test: Genomic Vision, Bagneux. METHODS: From June 2016 to May 2018, 688 patients aged 25-65, referred to colposcopy after an abnormal Pap-smear, were enrolled in the study. Among them 60% were found HPV high-risk. The study is divided in two phases: 1. a cross-sectional phase using data collected at first visit (colposcopy images ± histology, pap-smear for HPV genotyping and molecular combing) to study the association between HPV integration status versus colposcopy and histology grades; 2. a longitudinal phase using data collected in follow-up visits: cytology at 6, 18 and 30 months and colposcopy ± histology at 12, 24 and 36 months. A pap-smear collected at 12, 24 and 36 months allows to perform genotyping and molecular combing. HPV integration status is analyzed in comparison with the evolution of lesions, viral clearance and HPV genotype. HPV genotyping and molecular combing were performed on pap-smear samples in central laboratories. Histology data were reviewed by central reading. RESULTS: The transversal phase of the study is achieved and shows that the HPV integration into the human DNA, monitored by molecular combing, can significantly differentiate normal subjects from women with cervical lesions or cancer. CONCLUSION: HPV integration into the host genome, monitored by Genomic Visions technology, is a reliable diagnostic biomarker that will greatly help clinicians to improve their medical decision tree.

Mucosal and skin HPV types in tumour-free tonsils and tonsillar tumours.

Human papillomavirus (HPV) infection is associated with tonsillar cancer (TC) whose incidence in humans is increasing. Tonsillar tumours are not ordinarily preceded by clinically apparent precancerous lesions, and no markers of the early stage disease are available. Therefore, we evaluated the presence of an active HPV infection also in tumour-free tonsillar tissue. Formalin-fixed paraffin-embedded (FFPE) tonsillar specimens from 114 patients with TC and 114 age and gender matched controls were screened for the presence of HPV DNA, expression of HR-HPV E6 mRNA, and p16 overexpression. HPV DNA was identified in 3.5% of tumour-free tissues, HR-HPV16 and 58 and LR-HPV111 and 17 were each detected in a single sample. No HR HPV E6 mRNA and p16 overexpression was found. The prevalence of HPV DNA in TC was 69.3%, with HPV16 being the most common (94.9%). Eighty-four percent of HPV16-positive tumours expressed HR HPV E6 mRNA, while no E6 mRNA was present in samples positive for HPV52 and 58. The overexpression of p16 correlated well with HPV DNA in TC, but in tumour-free tonsils no overexpression of p16 was detected.Our data provide further evidence of the etiological role of HPV16 in TC. In tumour-free tissue, the presence of HR-HPVs was rare and silent, as shown by direct and indirect markers.

The prevalence of oral HPV infection in healthy populations: A systematic review with a focus on European populations.

BACKGROUND: Human papillomaviruses (HPV), a group of small, tumorigenic DNA viruses, are causally linked to cervical cancer and various other anogenital, oral, and oropharyngeal malignancies in both males and females. The purpose of this systematic review is to summarize the most recent data on the prevalence of oral HPV in healthy populations in Europe. METHODS: A systematic review of the European studies on the prevalence of oral HPV infections published from January 2011 to September 2017. RESULTS: The overall prevalence rates of oral HPV in healthy populations vary between 1.2% and 11.6%, with high-risk types of HPV (HR HPV) detected in 2.2% to 7.2% of individuals and HPV16 in 0.2% to 2.9% of individuals. The overall prevalence rate of oral HPV infections was considerably higher in men having sex with men as compared to heterosexual men and women. CONCLUSION: The prevalence rates of oral HPV infection in European populations are comparable to the results of the studies conducted in the USA and Asia. However, the European studies did not focus on the risk factors for oral HPV infection in healthy populations. A statistically significant relationship between oral sex, smoking, and HPV infection as observed in extensive studies from the USA was confirmed by a single European study.

High level of Tregs is a positive prognostic marker in patients with HPV-positive oral and oropharyngeal squamous cell carcinomas.

BACKGROUND: Human papillomaviruses (HPVs) have been proved as one of the etiological factors of oropharyngeal squamous cell carcinoma (OPSCC). Patients with tumors of viral etiology have a lower recurrence rate and better prognosis. OPSCC is linked to an alteration in the immune system. Only a limited number of studies have correlated both the immunological parameters and HPV status with patient prognosis. The aim of this study was to determine whether HPV infection and the immunological status influence patient prognosis individually or in concurrence. MATERIAL AND METHODS: Sixty patients with oral and oropharyngeal carcinomas were enrolled. They were divided into HPV-positive and HPV-negative groups based on the expression of HPV 16 E6 mRNA. Basic lymphocyte subpopulations were determined in the peripheral blood by means of flow cytometry. RESULTS: Significantly better disease-specific survival (DSS) was observed in patients with HPV-positive tumors. Nodal status, tumor grade, recurrence, and CD8+/Tregs ratio were identified as factors influencing DSS. A higher level of Tregs and a lower ratio of CD8/Tregs influenced overall survival (OS) independently of HPV status and age. Patients with HPV-positive tumors and high levels of Tregs survived significantly better than patients from the other groups. CONCLUSION: Better survival is associated with HPV positivity and elevated Tregs levels. Our data suggest that HPV infection and Tregs do not influence patient prognosis in concurrence.

Human papillomavirus infection and tumours of the anal canal: correlation of histology, PCR detection in paraffin sections and serology.

Human papillomavirus infection is an important etiological factor in squamous cell carcinoma of the anus (SCCA). Different histological variants of anal carcinomas displaying squamous differentiation, previously classified as separate tumours, were recently reclassified as SCCA by the WHO. In our recent study the presence of HPV was detected by PCR in biopsy specimens of 42 different anal tumours, including SCCA and its histological variants (n=22), adenocarcinomas (n=5), tubulovillous adenomas (n=5) and anal condylomas (n=10). HR HPV16 (high risk - HR) was detected in 18 of SCCA specimens (81.8%). All histological variants, i.e. tumours with basaloid, squamous and mixed histological patterns, were represented among the HPV-positive cancers. Four tumours (18.2%) were HPV negative. Low-risk (LR) HPV types were not detected within the SCCA group. HPV16 was identified in one adenocarcinoma, while four cases were HPV negative. Two adenomas showed presence of HPV16; one showed simultaneous positivity for HPV33. The remaining three tumours were HPV negative. Seven anal condylomas (70%) were LR HPV 6 and/or 11 positive, while three were HPV negative. The presence of HR HPV types was not observed in anal condylomas. Our results provide further evidence in support of the etiological role of HR HPV infection in the development of SCCA regardless of its histological appearance.

[Progression and regression low grade intraepitelial squamous lesions in context of positivity of high risk human papillomavirus]. / Progrese a regrese low grade intraepiteliálních skvamózních neoplazií v závislosti na prítomnosti HPV HR viru.

OBJECTIVE: Evaluation of regression and progression of histologically confirmed low grade squamous intraepithelial lesions (LG SIL) in women under the age of 35 in context of positivity of high risk human papillomavirus (HPV HR). Evaluation of sensitivity of PAP smear and HPV HR test in women with LG SIL. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology, Charles University Prague, 2nd Medical Faculty, University Hospital Motol. PATIENTS AND METHODS: 166 women with SIL low or repeated ASC-US PAP smear were included to the study. 1 to 3 punch biopsy under the expert colposcopy and HPV HR test were performed in all women. Follow up were done every 6 month in all women with histologically confirmed LG SIL. RESULTS: LG SIL was detected in 120 women. Sensitivity of PAP smear was 72.3% and sensitivity of HPV HR test 60.2 % in women with LG SIL. 84 women (70 %) were HPV HR positive. Regression of LG SIL was detected in 20 (23 %) HPV HR positive women and in 18 (50%) HPV HR negative women. This difference is statistically significant (p = 0.0094). Progression of LG SIL was detected in 24 (29 %) HPV HR positive women and in 4 (11%) women HPV HR negative women. This difference is borderline statistically significant (p = 0.058). Progression of LG SIL to the carcinoma in situ or invasive cancer had not been detected during follow up period. CONCLUSION: PAP smear is a standard for LG SIL detection in women under the age of 35 and HPV HR test is not so important for LG SIL detection in this group of women. HPV HR test could be useful for prediction of the risk of progression, but positivity of HPV HR in LG SIL cannot indicate surgical treatment (conisation) in this cohort of women under the age of 35.

[Screening for prevention of cervical cancer in the Czech Republic]. / Skrínink pro prevenci karcinomu delozního hrdla v Ceské republice.

Cytological diagnosis of atypical cells of cervix uteri by the Papanicolaou method was introduced in the Czech Republic (CR) very early--in 1947. In 1966 the Czech National Health Law was passed that guaranteed women a yearly preventive examination by a gynaecologist which is covered by the compulsory health insurance. This preventive examination was and is considered as an equivalent of screening for cervical cancer. Notwithstanding high frequency of screening visits and the fact that all women are eligible, the incidence of CC has not changed in the last 34 years. The reasons for this include the coverage of Czech women, which is estimated to be low (35% at the most), and that none of the cytology laboratories are accredited for screening, there are no national registries for any aspect of screening and there are no mechanisms for evaluation of the screening process. As a result, it is obvious that the majority of opportunistic cervical screening activity that is undertaken is ineffective and the implementation of an organized and quality controlled screening programme, in compliance with the recommendations of many European Institutions, is urgently required to ensure that Czech women are properly protected against this disease and that scarce healthcare resources are used in the most cost-effective manner. In the process of preparation of new screening programmes it is important to take into account the new achievements of science and new technologies, which are being gradually introduced into the clinical practice. Namely, the methods used for selection of women at risk that are based on the detection of nucleic acids of human papillomaviruses and vaccination against some types of these viruses, which are the etiological agents of precancerous lesions and cancer of cervix uteri.

Longitudinal study of patients after surgical treatment for cervical lesions: detection of HPV DNA and prevalence of HPV-specific antibodies.

The principal aims of this study were to test whether persistence of human papillomavirus (HPV) DNA is predictive of recurrent disease in women after surgical treatment for cervical lesions, to distinguish between persistent and newly acquired HPV infection, and to observe the effect of surgical treatment on levels of HPV-specific antibodies. A group of 198 patients surgically treated for low-grade and high-grade squamous intraepithelial lesions and 35 age-matched controls were monitored for 18 months at 6-month intervals. The presence of HPV DNA in cervical smears was detected by means of consensus polymerase chain reaction, and serum levels of HPV-specific antibodies to HPV types 16, 18, 31, 33, and 45 were measured. In ten patients positive for HPV type 16 in consecutive samples, the HPV 16 variants were identified using a polymerase chain reaction specific for the long control region. Data regarding demographics, risk factors for cervical cancer, and risks related to HPV exposure were collected through a patient questionnaire. Subjects persistently positive for HPV DNA were more likely to present with cytological and/or colposcopical abnormalities. A higher reactivity to HPV-specific antibodies was observed in these women at the 18-month follow-up visit. All ten patients with HPV 16 infection detected in consecutive samples showed persistence of either the same prototype or the same variant during the follow-up period. Risky sexual behavior and smoking were more common in patients than in controls. Persistent HPV infection as demonstrated by both HPV DNA detection and antibody detection appears to be a risk factor for the recurrence of pathological findings in women after surgery. An individually based approach to surgical treatment is an important factor in the outcome of disease at follow-up.

HPV and other risk factors of oral cavity/oropharyngeal cancer in the Czech Republic.

OBJECTIVE: An association between high-risk human papillomavirus (HR HPV) infection and a risk of development of a subgroup of head and neck cancers has been proposed recently. The main risk factors of oral and oropharyngal cancer observed in our population are smoking and alcohol consumption. The incidence of oral/oropharyngeal tumours in the Czech Republic is relatively high and there are no data available about the prevalence of HPV DNA presence in these tumours. MATERIALS AND METHODS: Eighty patients with a primary oropharyngeal cancer were enrolled. The presence of HPV DNA has been evaluated by polymerase chain reaction in 68 cases from which the tumour tissue and demographical and clinical data were available. The typing of HPV was performed by nucleotide DNA sequencing. RESULTS: The HPV DNA was detected in 51.5% of samples tested. Among the HPV DNA positive tumours, 80% contained HPV16. In the analysed group there were 54 men and 14 women. The prevalence of HPV DNA was lower in oral (25%) than in oropharyngeal (57%) tumours, and higher in never smokers (100%) and never drinkers (68.8%). HPV DNA presence was not related to gender, age, number of lifetime sexual partners or practice of oral-genital sex, size of tumour or presence of regional metastases. CONCLUSIONS: The difference in the prevalence of HPV DNA positive tumours between cases of oral cavity and oropharyngeal carcinoma exposed and not exposed to tobacco or alcohol support the theory that HPV DNA positive tumours form an aetiologically distinct subgroup of head and neck tumours.

Cutaneous papillomatosis in cattle.

Three of four heifers housed together developed multiple cutaneous tumours in the linea alba and on the teats 3 months after the application of plastic muzzle plates with sharp tips to prevent mutual sucking and licking. Fibropapilloma with many koilocytes but few intranuclear inclusions was diagnosed histologically. The dermis showed neoplastic fibroblasts and a structureless intercellular matrix, and nonpurulent vasculitis was also recorded. Immunohistochemical examination with an antibody against L1 papillomavirus antigen demonstrated intranuclear positivity in single cells of the granular and cornified layers and in many mesenchymal cells in the fibrous parts of the tumours. CD3-positive lymphocytes were present in the wall of some blood vessels, and in the dermis and epidermis. Proliferating cell nuclear antigen was detected predominantly in the basal layer of the epidermis and in the superficial dermis. Electron microscopy revealed small intranuclear aggregates of virus particles in an epidermocyte, damage to desmosomes and disorganization of cytokeratin filaments in many epidermocytes. Aggregates of virus particles were revealed also in a fibroblast in the dermis. In blood capillaries of the corium, acute swelling, inflammation and necrosis of the endothelium were observed. By means of the polymerase chain reaction (PCR) and nucleotide DNA sequencing of the PCR product, the virus was identified as bovine papilloma virus type 1 (BPV 1). The presence of this virus in the tissue was further confirmed by in-situ hybridization with a BPV 1 probe.

Prospective study on cervical neoplasia: presence of HPV DNA in cytological smears precedes the development of cervical neoplastic lesions.

OBJECTIVES: The principal aim of the study was to verify whether HPV infection in healthy women, as determined by HPV DNA detection, was associated with an increased risk of development of cervical lesions. METHODS: Cervical smears collected at enrolment into the prospective study conducted in Prague during 1975-83 were tested for the presence of HPV DNA by means of a polymerase chain reaction (PCR) using the general GP5/6 primers and a mixture of primers specific for the E6 gene. 120 smears from patients in whom cervical neoplasia had been detected in the course of the prospective study and 208 smears from control women who had remained healthy throughout the observation period were analysed. Patients and controls were matched by age, number of sexual partners, age at first intercourse, and smoking habit. Patients were divided into three groups, A, B, and C, according to their cytological, colposcopic, and histological findings at enrolment. Group A consisted of 67 women found ill at enrolment, group B of 26 women with slightly suspicious findings, while group C comprised 27 women with normal findings at enrolment. In addition, sera taken at enrolment from these patients and controls were tested for the presence of antibodies reactive with virus-like particles (VLPs) of HPV 16, 18, and 33. RESULTS: For the whole cohort, there was a statistically highly significant difference in the presence of HPV DNA between patients and controls. Furthermore, the difference in the presence of HPV DNA between patients and controls was highly significant not only in those who had been found ill at enrolment (group A) but, most importantly, also in women who had developed the disease in the course of the follow up (groups B and C). Women positive for HPV DNA possessed HPV antibodies to VLP16, 18 and 33 significantly more often than those who were free of HPV DNA. CONCLUSION: This indicated that healthy women who were positive for HPV DNA at enrolment were at an increased risk of developing cervical neoplasia (OR = 18.5; CI 5.9 to 57.6).

Human papillomavirus 16 E6 polymorphisms in cervical lesions from different European populations and their correlation with human leukocyte antigen class II haplotypes.

Infection with high-risk human papillomavirus (HPV) is necessary for the development of a cervical lesion, but only a fraction of precursor lesions progress to cancer. Additional factors, other than HPV type per se, are likely to increase the probability for progression. Intratype genome variations have been reported to be associated with viral persistence and the development of a major cervical disease. We have recently shown that the prevalence of specific HPV16-E6 variants in invasive cervical cancer (ICC) varies between Italian and Swedish women. To extend our initial study we have analyzed E6 variants in cervical lesions from Czech women, ranging from low-grade cervical intraepithelial neoplasia (LCIN) to ICC and scaled up the sample size of our initial study of Swedish and Italian women. In addition, we have correlated the cases of cancers with human leukocyte antigen (HLA) class II haplotypes. In line with our earlier observation, the distribution of specific HPV16-E6 genotypes in CIN and ICC varied in the 3 cohorts. For instance, the HPV16-E6 L83V variant, which has been found to be positively associated with ICC in Swedish women (p = 0.002), was more prevalent in LCIN than in ICC in Italian and Czech women (p = 0.01 and = 0.03, respectively). These data indicate that host genetic factors, such as HLA polymorphism, may determine the potential oncogenicity of the HPV16-E6 L83V variant. Indeed, the DR04-DQ03 haplotype, which is approximately 3-fold more abundant in the normal Swedish population than in those in Italy and the Czech Republic, was found to be positively associated with HPV16-E6 L83V in the 3 cohorts investigated (p = 0.01). This observation may explain why L83V is a risk factor more in Sweden than in the other 2 countries.

Longitudinal follow-up of antibody response to selected antigens of human papillomaviruses and herpesviruses in patients with invasive cervical carcinoma.

A group of 21 cervical-carcinoma patients was followed longitudinally. All patients had undergone intensive radiotherapy. In the course of a more than 5-year observation period, 2 patients died of cervical cancer, 1 from other causes, 3 were lost from follow-up, and 15 survived without any signs of the disease. Sera taken before, up to 17 months after and more than 5 years after the start of therapy, were tested by ELISA for IgG antibodies reactive with a broad spectrum of HPV-derived antigens, glycoprotein G of HSV 2, whole virion antigen of HCMV, and a synthetic peptide corresponding to the immuno-dominant region of EBNA 1. The therapy was associated with a marked decrease in E2 and E7 antibodies in nearly all patients possessing pre-existing antibodies; the changes in VLP antibody levels in the treated women were more rare and less pronounced. In the course of the observation period, seroconversion to gG HSV2 positivity was seen in 5 patients, while, a marked increase in pre-existing gG HSV2 antibodies was observed in 5 out of 7 originally seropositive patients. At enrollment, only 2 patients were free of HCMV antibody and only 1 was free of EBNA1 antibody; no seroconversion relative to either antigen was seen during the observation period.

Human papillomavirus genotype spectrum in Czech women: correlation of HPV DNA presence with antibodies against HPV-16, 18, and 33 virus-like particles.

Because the biological spectrum of human papillomavirus (HPV) genotypes present in cervical cancer lesions varies according to the geographical region studied, and because little genotype information is available for Central and Eastern European countries, we studied the endemic HPV-genotype spectrum in cervical samples collected from women visiting gynaecological departments of selected hospitals in the Czech Republic. In a series of 389 samples, 171 (44.0%) were positive for HPV DNA using a consensus-primer polymerase chain reaction (PCR). Genotyping of the HPV PCR products was done using dot-blot hybridisation with type-specific oligonucleotide probes and thermocycle DNA sequencing. Twenty-two different HPV types were detected, HPV-16 being the most prevalent type irrespective of severity of the lesions (55.0%). Multiple HPV types were found in 16.4% of our HPV-DNA-positive samples. The prevalence of HPV infection was 23.0% in women with normal findings and 59.4% in patients with cervical neoplasia, and increased significantly with the severity of the disease: 52.9% in low-grade lesions, 58.0% in high-grade lesions, and 73.5% in cervical carcinomas (P for trend < .00001). In the sera of 191 subjects, 89 with normal findings and 102 with different forms of cervical neoplasia, the prevalence of HPV-specific IgG antibodies was tested by an enzyme-linked immunosorbent assay (ELISA) using virus-like particles (VLPs) of HPV-16, -18, and -33. Antibodies were significantly more prevalent in HPV-DNA-positive than in HPV-DNA-negative women and there was no association with age. In agreement with the results of HPV genotyping, antibodies reactive with HPV-16 VLPs were the most frequent and, moreover, their prevalence increased with the cervical lesion severity. About half of the subjects with smears in which either HPV-16 or HPV-33 DNA had been detected possessed antibodies reactive with homotypic VLPs. With HPV-18-DNA-positive subjects, however, fewer than 25% displayed homotypic antibodies. In general, subjects older than 30 years of age had antibodies reactive to HPV-specific VLPs more often than subjects younger than 30 years of age. In women with benign findings, the seropositivity to HPV-16, -18, and -33 VLPs increased with age, whereas in women with cervical neoplasia the seropositivity decreased with age.

Correlation between human papillomavirus-associated cervical cancer and p53 codon 72 arginine/proline polymorphism.

High-risk mucosal human papillomaviruses encode an E6 oncoprotein, which binds the cellular p53 tumor suppressor protein, thereby marking it for degradation through the ubiquitin-mediated pathway. A common p53 polymorphism at codon-72 of exon 4 results in translation to either arginine or proline. Recently reported data suggested an increased susceptibility to E6/ubiquitin-mediated degradation of the Arg72-p53 isoform and an over-representation of the homozygous Arg72-p53 genotype in cervical cancer patients. We have analyzed this polymorphism in a larger series of patients with cervical cancer and in controls in the Czech Republic. We found no statistically significant differences between the codon-72 p53 genotypes of cervical cancer patients and the control women. Based on these results, it is unlikely that Arg72-p53 is associated with an increased risk for human papillomavirus-associated cervical tumor development in Czech women.

Lack of efficacy of interferon-alpha therapy in recurrent, advanced cervical cancer.

Human papillomavirus (HPV) is associated with 65-95% of in situ or early invasive squamous cell carcinomas of the cervix. A multiinstitutional, prospective phase II clinical trial was initiated by the Eastern Cooperative Oncology Group (ECOG) to study the activity of IFN-alpha 2b in women with metastatic or locally recurrent cervix cancer. The activity of IFN-alpha 2b was correlated with the presence of HPV as measured by Southern blot hybridization or polymerase chain reaction techniques in 17 patients. All patients had failed prior definitive therapy with surgery, radiation, and chemotherapy. IFN-alpha 2b was administered at 10 MU/m2 subcutaneously three times per week. Among 31 patients enrolled, 3 achieved a clinical response to treatment. Tumor was accessible for biopsy in 17 patients. The presence of HPV was assayed by Southern blot hybridization (2 of 17) and/or polymerase chain reaction (PCR) technology (15 of 17). Of the 17 assays, 16 were informative. HPV was detected in 5 of 16 patients. Of 5 HPV-positive women, 2 responded to treatment, versus 1 of 11 HPV-negative women, thus not permitting reliable statistical analysis. It is concluded that IFN-alpha 2b has only minimal activity against advanced, recurrent cervical cancer.