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Policy analysis of cervical cancer screening strategies in low-resource settings: clinical benefits and cost-effectiveness.
Goldie SJ, Kuhn L, Denny L, Pollack A, Wright TC.
Center for Risk Analysis, Department of Health Policy and Management, Harvard School of Public Health, 718 Huntington Ave, Suite 2, Boston, MA 02115-5924, USA. [email protected]
CONTEXT: Cervical cancer is a leading cause of cancer-related death among women in developing countries. In such low-resource settings, cytology-based screening is difficult to implement, and less complex strategies may offer additional options. OBJECTIVE: To assess the cost-effectiveness of several cervical cancer screening strategies using population-specific data. DESIGN AND SETTING: Cost-effectiveness analysis using a mathematical model and a hypothetical cohort of previously unscreened 30-year-old black South African women. Screening tests included direct visual inspection (DVI) of the cervix, cytologic methods, and testing for high-risk types of human papillomavirus (HPV) DNA. Strategies differed by number of clinical visits, screening frequency, and response to a positive test result. Data sources included a South African screening study, national surveys and fee schedules, and published literature. MAIN OUTCOME MEASURES: Years of life saved (YLS), lifetime costs in US dollars, and incremental cost-effectiveness ratios (cost per YLS). RESULTS: When analyzing all strategies performed as a single lifetime screen at age 35 years compared with no screening, HPV testing followed by treatment of screen-positive women at a second visit, cost $39/YLS (27% cancer incidence reduction); DVI, coupled with immediate treatment of screen-positive women at the first visit was next most effective (26% cancer incidence reduction) and was cost saving; cytology, followed by treatment of screen-positive women at a second visit was least effective (19% cancer incidence reduction) at a cost of $81/YLS. For any given screening frequency, when strategies were compared incrementally, HPV DNA testing generally was more effective but also more costly than DVI, and always was more effective and less costly than cytology. When comparing all strategies simultaneously across screening frequencies, DVI was the nondominated strategy up to a frequency of every 3 years (incremental cost-effectiveness ratio, $460/YLS), and HPV testing every 3 years (incremental cost-effectiveness ratio, $11 500/YLS) was the most effective strategy. CONCLUSION: Cervical cancer screening strategies that incorporate DVI or HPV DNA testing and eliminate colposcopy may offer attractive alternatives to cytology-based screening programs in low-resource settings.
PMID: 11427139 [PubMed - in process]
Negative predictive value of human papillomavirus test following conization of the cervix uteri.
Jain S, Tseng CJ, Horng SG, Soong YK, Pao CC.
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
Objective. The goal of this study was to determine/evaluate the negative predictive value of human papillomavirus (HPV) testing following conization of cervix uteri. Methods. A prospective analysis was undertaken on 79 cone biopsies of women with high-grade lesions (cervical intraepithelial neoplasia (CIN) III). HPV testing was performed on cervical smears before and after conization. We correlated the margin status (defined as positive cone margin or endocervical curettage status) and positive conization HPV status with the residual disease in a hysterectomy specimen. A Digene II kit was used to perform HPV testing. HPV detection was done by Hybrid Capture assay. Results. Of the 79 patients, 47(59.5%) had positive margins after conization. HPV testing was positive in 37 cases (78.7%) and negative in 10 cases (21.3%). Residual disease was found in 31 of 47 (66%) postconization hysterectomy specimens. No residual lesions were found in HPV-negative cases. Of the 32 cases with negative margins following conization, HPV testing was negative in 25 cases (78%) and was positive in 7 cases (22%). Among these 25 cases with negative HPV tests, no residual lesion was detected, and in 7 HPV-positive cases, only one residual lesion was found. Conclusion. HPV testing is potentially an effective tool in predicting residual dysplasia after conization and could potentially assist in the decision between hysterectomy and conservative follow-up in women with CIN III. Copyright 2001 Academic Press.
PMID: 11426982 [PubMed - in process]
High prevalence of oncogenic human papillomavirus in the genital tract of women with human immunodeficiency virus.
Volkow P, Rubi S, Lizano M, Carrillo A, Vilar-Compte D, Garcia-Carranca A, Sotelo R, Garcia B, Sierra-Madero J, Mohar A.
Division of Research, UNAM, Mexico City, Mexico
Objective. The goal of this study was to determine the prevalence of human papillomavirus (HPV) and squamous intraepithelial lesions (SILs) in women infected with human immunodeficiency virus (HIV) in Mexico. Methods. Cases included women who were positive for human immunodeficiency virus (HIV) and accepted to participate. There were two control groups in this study: group A, heterosexual partners of HIV+ men; group B, commercial sex workers. Gynecologic examination was performed in all participants. Also, a cervical smear with colposcopy and a sample for detection of HPV DNA by polymerase chain reaction (PCR) were obtained in all subjects, as were CD4+ counts. Relative risks (RR) and 95% confidence interval were calculated. Results. Eighty-five HIV+ women agreed to participate in this study; the route of HIV infection was heterosexual in 78.8%; transfusion in 8.2%; paid donors in 3.5%; and 9.4% unknown. A total of 9 controls were included: 4 from group A and 5 from group B. HPV DNA was detected by PCR in 57 (69%) cases and in 26 (29%) controls from both groups (P < 0.0001). The RR of HPV infection was 5.5 (2.7-11.5). Also, a significant difference in the prevalence of high-risk HPV types was observed between cases and controls, RR = 12.8 (4.07-42.9). These associations were independent of CD4+ counts and antiretroviral therapy. No association was observed between HIV infection and the risk for high-grade SIL. Conclusions. We observed a high prevalence of oncogenic HPV types in HIV-positive women. These women should be screened regularly for early diagnosis of premalignant lesions and prevention of cervical cancer. Copyright 2001 Academic Press.
PMID: 11426958 [PubMed - in process]
Human papillomavirus infection, risk for subsequent development of cervical neoplasia and associated population attributable fraction.
Lehtinen M, Luukkaala T, Wallin K, Paavonen J, Thoresen S, Dillner J, Hakama M.
National Public Health, Institute, FIN 00300, Helsinki, Finland
Background: Human papillomavirus (HPV) is the major cause of cervical neoplasia but estimates of the population attributable fraction (PAR%), of HPV vary. PAR% has not been derived from longitudinal studies although assessment of HPV exposure prior to the neoplasia diagnosis should increase validity of such estimates. Aims: Systematic review and meta-analysis of longitudinal studies on HPV associated relative risk (RR) for and PAR% of HPV16 in cervical neoplasia. Methods: Pertinent data from longitudinal studies was made available through Medline and substituted by various hand searches. HPV associated weighted mean RR, with 95% confidence interval (CI) of cervical neoplasia, and the PAR% of HPV16 in cervical carcinoma were estimated both for unselected and low HPV prevalence populations. Results: HPV associated RR of cervical carcinoma in PCR-based studies was 17 (95% CI 8.2-33). HPV16 associated RRs in seroepidemiological studies were 3.3 (95% CI 2.2-4.9) for the unselected population, HPV16 seroprevalence 11.0%, and 12.5 (95% CI 5.5-29) for a population with low HPV16 seroprevalence of 5.3%. Corresponding PAR% estimates of HPV16 were 27 and 44%, respectively. Conclusion: Protective vaccination against HPV16 infection would prevent up to 44% of cervical carcinoma.
PMID: 11418359 [PubMed - in process]
Biological evidence that human papillomaviruses are etiologically involved in a subgroup of head and neck squamous cell carcinomas.
van Houten VM, Snijders PJ, van den Brekel MW, Kummer JA, Meijer CJ, van Leeuwen B, Denkers F, Smeele LE, Snow GB, Brakenhoff RH.
Department of Otolaryngology/Head and Neck Surgery, Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands.
High-risk human papillomaviruses (HPVs) have been proposed to be associated with a subset of head and neck cancers (HNSCCs). However, clear biological evidence linking HPV-mediated oncogenesis to the development of HNSCC is hardly available. An important biological mechanism underlying HPV-mediated carcinogenesis is the inactivation of p53 by the HPV E6 oncoprotein. In the present study we investigated this biological relationship between HPV and HNSCC. In total 84 HNSCC tumors were analyzed for the presence of high-risk HPV nucleic acids by DNA polymerase chain reaction-enzyme immunoassay (PCR-EIA) and E6 reverse transcriptase (RT)-PCR as well as for the presence of mutations in the p53 gene. We found 20/84 HPV16 DNA-positive cases with one or more DNA assays, 10 of which were consistently positive with all assays. Only 9/20 cases showed E6 mRNA expression, indicative for viral activity. Only these nine E6 mRNA-positive cases all lacked a p53 mutation, whereas both the other HPV DNA-positive and HPV-DNA negative tumors showed p53 mutations in 36% and 63% of the cases, respectively. Moreover, only in lymph node metastases of HPV E6 mRNA-positive tumors both viral DNA and E6 mRNA were present. Our study provides strong biological evidence for a plausible etiological role of high-risk HPV in a subgroup of HNSCC. Analysis of E6 mRNA expression by RT-PCR or alternatively, semiquantitative analyses of the viral load, seem more reliable assays to assess HPV involvement in HNSCC than the very sensitive DNA PCR analyses used routinely. Copyright 2001 Wiley-Liss, Inc.
PMID: 11410871 [PubMed - indexed for MEDLINE]
Comment in:
- Lancet. 2001 Jun 9;357(9271):1816
Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study.
Woodman CB, Collins S, Winter H, Bailey A, Ellis J, Prior P, Yates M, Rollason TP, Young LS.
Centre for Cancer Epidemiology, University of Manchester, Withington, M20 4QL, Manchester, UK. [email protected]
BACKGROUND: Laboratory and epidemiological research suggests an association between human papillomavirus (HPV) and cervical intraepithelial neoplasia (CIN). We studied the natural history of incident cervical HPV infection and its relation to the development of CIN. METHODS: We recruited 2011 women aged 15-19 years who had recently become sexually active. We took a cervical smear every 6 months and stored samples for virological analysis. We immediately referred all women with any cytological abnormality for colposcopic assessment, but postponed treatment until there was histological evidence of progression to high-grade CIN. FINDINGS: In 1075 women who were cytologically normal and HPV negative at recruitment, the cumulative risk at 3 years of any HPV infection was 44% (95% CI 40-48): HPV 16 was the most common type. The cumulative risk at 3 years of detecting an HPV type not present in the first positive sample was 26% (20-32). 246 women had an abnormal smear during follow-up, of whom 28 progressed to high-grade CIN. The risk of high-grade CIN was greatest in women who tested positive for HPV 16 (risk ratio 8.5 [3.7-19.2]); this risk was maximum 6-12 months after first detection of HPV 16. All HPV types under consideration were associated with cytologically abnormal smears. Although abnormality was significantly less likely to be associated with low-viral-load samples, the cumulative risk at 3 years of a high-viral-load sample after a low-viral-load sample was 45% (95% CI 35-56). Five women who progressed to high-grade CIN consistently tested negative for HPV. INTERPRETATION: Our findings suggest that attempts to exploit the association between cervical neoplasia and HPV infection to improve effectiveness of cervical screening programmes might be undermined by the limited inferences that can be drawn from the characterisation of a woman's HPV status at a single point in time, and the short lead time gained by its detection.
PMID: 11410191 [PubMed - indexed for MEDLINE]
Comment on:
- Lancet. 2001 Jun 9;357(9271):1831-6
Natural history of cervical human papillomavirus infections.
Miller AB.
Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, D-69120, Heidelberg, Germany. [email protected]
Publication Types:
PMID: 11410184 [PubMed - indexed for MEDLINE]
Tetrasomy is induced by human papillomavirus type 18 e7 gene expression in keratinocyte raft cultures.
Southern SA, Noya F, Meyers C, Broker TR, Chow LT, Herrington CS.
Department of Pathology, University of Liverpool, Royal Liverpool University Hospital, Liverpool L69 3GA, United Kingdom [S. A. S., C. S. H.].
We have demonstrated previously that oncogenic human papillomaviruses (HPVs) induce basal cell tetrasomy in low-grade squamous intraepithelial lesions of the cervix. To identify HPV genes and growth conditions involved in this process, we analyzed: (a) organotypic raft cultures of primary human keratinocytes transfected with whole HPV-18 genomes; and (b) organotypic raft cultures acutely infected with recombinant retroviruses expressing the HPV-18 E6, E7, or E6/E7 genes from the differentiation-dependent HPV-18 enhancer-promoter. Cultures were examined for HPV DNA by in situ hybridization and for karyotype by interphase cytogenetics. Tetrasomy occurred in the suprabasal strata of raft cultures expressing E7 and E6/E7 but not in those expressing E6 alone or in a control culture. These data indicate that suprabasal tetrasomy occurs in association with expression of the E7 gene alone. Basal cell tetrasomy was additionally observed in the raft culture transfected with whole HPV-18 genomes, consistent with observations in low-grade squamous intraepithelial lesions. The distribution of tetrasomic cells in these raft cultures may reflect the involvement of additional viral genes or possibly differences in the pattern of viral oncogene and host gene expression.
PMID: 11406563 [PubMed - in process]
Immortalization of human esophageal keratinocytes by E6 and E7 of human papillomavirus type 16.
Sashiyama H, Shino Y, Kawamata Y, Tomita Y, Ogawa N, Shimada H, Kobayashi S, Asano T, Ochiai T, Shirasawa H.
Department of Molecular Virology, 1-8-1 Chiba University, Inohana, Chuo-ku, Chiba 260-8670, Japan.
Transduction of human papillomavirus type 16 (HPV16) E6/E7 into primary culture of human esophageal keratinocytes using a recombinant adenovirus prolonged the life-span, while untreated cells senesced within 14-16 population doublings (PDLs). Up-regulation of telomerase activity and acquisition of serum-resistant growth were observed in the esophageal keratinocytes with extended life-span between 50 and 100 PDLs, and drastically increased after 100 PDLs. A keratinocyte sample with a polymorphism of Pro/Pro at codon 72 of p53 showed resistance to HPV16 E6/E7-induced life-span-extension and immortalization, in contrast to others with p53 polymorphisms of Arg/Arg or Arg/Pro, which did not. The high efficiency of E6/E7-induction by adenovirus vector also revealed the M1 and M2 stages of keratinocyte immortalization first described in this report.
PMID: 11408928 [PubMed - in process]
Detection of Aberrations of Chromosome 17 and p53 Gene Expression and Their Correlation to Histologic Grading and Prognosis in Primary Invasive Squamous Cell Carcinoma of the Cervix.
Boabang P, Kurbacher CM, Waida A, Amo-Takyi BK.
Department of Obstetrics and Gynecology, University of Cologne, Cologne, Germany.
We analyzed tumor tissues from 14 patients with invasive squamous cell carcinoma of the cervix for aberrations of chromosome 17 and p53 expression. All but 3 patients were negative for p53 protein expression, the protein being detected in 2 International Federation of Obstetrics and Gynecology stage IIa cancers and 1 stage Ib G3 carcinoma. Significant cytogenetic aberrations in the form of losses and gains of chromosome 17 were diagnosed in 9 and 7 patients, respectively. There was no correlation with tumor prognosis, clinical stage or histologic grade. According to most reports, almost all cervical carcinomas contain integrated human papilloma virus (HPV) and express E6 oncoproteins. Increasing evidence suggests that E6 protein interaction leads to p53 mutation in HPV-infected cervical epithelium. Since most cervical tumors are infected with HPV, and the tumors originate through p53 gene mutation caused by the said interaction, which leads subsequently to the overexpression of p53 oncoprotein, lack of the latter in the remaining 11 cervical tumors may either be the result of technical shortcomings, or the tumor may arise in such circumstances through a p53-independent pathway. On the other hand, 2 of 3 stage IIa cancers and 1 Ib G3 carcinoma were found to be p53 positive, thus supporting the notion that p53 inactivation is a relatively late event in the progression of cervical cancer. Copyright 2001 S. Karger AG, Basel
PMID: 11408733 [PubMed - in process]
Quercetin, E7 and p53 in papillomavirus oncogenic cell transformation.
Beniston RG, Morgan IM, O'Brien V, Campo MS.
Department of Veterinary Pathology, Glasgow University, Garscube Estate, Glasgow G61 1QH, UK.
Bovine papillomavirus type 4 (BPV-4) infects the upper alimentary canal of cattle causing benign papillomas which can progress to squamous carcinomas in cattle grazing on bracken fern (BF). We have previously shown that quercetin, a well characterized and potent mutagen found in BF, causes cell cycle arrest of primary bovine cells (PalF), but that a single exposure to quercetin can cause full oncogenic transformation of PalF cells partially transformed by BPV-4. Here we show that cell cycle arrest correlates with an increase in p53 protein levels and transcriptional activity. However, in cells transformed but non-tumorigenic, p53 protein is elevated and transcriptionally activated in response to quercetin or other DNA damaging stimuli, but the cells bypass quercetin-induced G(1) arrest likely due to E7 expression. In transformed tumorigenic cells, p53 is elevated in response to quercetin but its transcriptional activity is inhibited due to mutation, and the cells fail to stop in G(1) in the presence of quercetin.
PMID: 11408351 [PubMed - in process]
DNA image cytometry and human papillomavirus (HPV) detection help to select smears at high risk of high-grade cervical lesions.
Lorenzato M, Clavel C, Masure M, Nou JM, Bouttens D, Evrard G, Bory JP, Maugard B, Quereux C, Birembaut P.
Laboratoire Pol Bouin, CHU Reims, France. [email protected]
Three samples were submitted from women undergoing routine screening (n=910): two smears (one for routine cytology and one for DNA image cytometry) and a scrape for human papillomavirus (HPV) testing. DNA histograms were classified as suspect in cases of aneuploidy, polyploidy, and/or diploidy with a high proliferation rate. Follow-up was available in 239 cases. The primary end-point was the presence of a high-grade squamous intraepithelial lesion (HGSIL) at biopsy. Seventy women (7.7%) had a high-risk (HR) HPV infection and a suspect DNA profile. In 77 women with cytological abnormalities, 28 HGSILs were detected: four with a prior diagnosis of ASCUS (all HR-HPV infected including three with a suspect DNA profile), three with smears evocative of LGSIL (all with HR-HPV infection and a suspect DNA profile), and 21 with smears evocative of HGSIL (all with HR-HPV infection and 20 with a suspect DNA profile). During the follow-up period, out of 239 women with a cytologically normal smear at first entry, five developed a HGSIL; all were HR-HPV-positive and four had a suspect DNA profile at the first smear. HR-HPV detection alone gives a sensitivity of 100% for the detection of HGSIL, with a specificity of 84.3%, whereas DNA measurement associated with HPV testing significantly enhances the specificity to 95.4%. Thus, the combination of HPV testing and DNA measurement provides a highly sensitive and specific evaluation of the risk of HGSIL on cervical smears. Copyright 2001 John Wiley & Sons, Ltd.
PMID: 11400145 [PubMed - indexed for MEDLINE]
Role of TP53 P72R polymorphism in human papillomavirus associated premalignant laryngeal neoplasm.
Aaltonen LM, Chen RW, Roth S, Makitie AA, Rihkanen H, Vaheri A, Aaltonen LA.
Publication Types:
PMID: 11403041 [PubMed - in process]
Human papillomavirus as a risk factor for oral squamous cell carcinoma: A meta-analysis, 1982-1997.
Miller CS, Johnstone BM.
UNIVERSITY OF KENTUCKY COLLEGE OF DENTISTRY AND COLLEGE OF MEDICINE AND ELI LILLY AND COMPANY.
Objective. Human papillomavirus (HPV) infection is a significant risk factor for uterine cervical carcinoma. However, the role of HPV infection in oral squamous cell carcinoma (OSCC) is less well defined. To determine the significance of the relationship of this virus in the progressive development of oral cancer, we estimated the risk of HPV detection in normal oral mucosa, precancerous oral tissue, and oral carcinoma using meta-analysis.Study design. Case reports and clinical series published in English-language journals were retrieved by searching MEDLINE (January 1980-August 1998). Review articles were also examined to identify additional studies. Studies that used biochemical, immunologic, microscopic, or molecular analyses to detect HPV in tissue or cells derived from normal oral mucosa (n = 25), benign leukoplakia (n = 21), intraepithelial neoplasia (ie, dysplasia and carcinoma in situ; n = 27), and oral cancer (n = 94) were included in the meta-analysis. Information on sample size, age, sex, method of tissue preservation (ie, fresh, frozen, paraffin-embedded), assay, primer amplification region (early, late), high-risk versus low-risk genotype, and use of tobacco or alcohol was abstracted by one author (C.S.M.).Results. Data from 94 reports that analyzed 4680 samples were included in the meta-analysis. Analyses made by means of a random-effects model with and without adjustments for assay sensitivity showed increased probability of HPV detection in tissue with precancerous and cancerous features compared with normal mucosa. The likelihood of detecting HPV in normal oral mucosa (10.0%; 95% confidence interval [CI], 6.1%-14.6%) was significantly less than of detecting benign leukoplakia (22.2%; 95% CI, 15.7%-29.9%), intraepithelial neoplasia (26.2%; 95% CI, 19.6%-33.6%), verrucous carcinoma (29.5%; 95% CI, 23%-36.8%), and OSCC (46.5%; 95% CI, 37.6%-55.5%). Adjustment of findings for differences in assay sensitivity indicated that these estimates may be conservative. Overall, HPV was between 2 and 3 times more likely to be detected in precancerous oral mucosa and 4.7 times more likely to be detected in oral carcinoma than in normal mucosa. The pooled odds ratio for the subset of studies directly comparing the prevalence of HPV in normal mucosa and OSCC was 5.37, confirming the trend observed in the overall sample. The probability of detecting high-risk HPVs in OSCCs was 2.8 times greater than that of low-risk HPVs.Conclusion. This meta-analysis indicates that HPV is detected with increased frequency in oral dysplastic and carcinomatous epithelium in comparison with normal oral mucosa. The findings provide further quantitative evidence that oral infection with HPV, particularly with high-risk genotypes, is a significant independent risk factor for OSCC.
PMID: 11402272 [PubMed - in process]
Human papillomavirus testing in primary screening for the detection of high-grade cervical lesions: a study of 7932 women.
Clavel C, Masure M, Bory JP, Putaud I, Mangeonjean C, Lorenzato M, Nazeyrollas P, Gabriel R, Quereux C, Birembaut P.
Laboratoire Pol Bouin, C.H.U. de Reims 45, rue Cognacq-Jay, Reims, 51100, France
High-risk human papillomaviruses (HR-HPV) are the necessary cause of cervical carcinomas. To determine whether HPR-HPV DNA detection in primary routine screening could represent a sensitive and reliable technique for the detection of high-grade squamous intraepithelial lesions (HGSIL), laboratory analysis using 2 cytologic techniques (conventional and liquid-based), HPV testing with Hybrid Capture II assay (HC-II), followed by colposcopic examination of women with abnormal cervical finding and/or persistent HR-HPV infection, was conducted in 7932 women who had routine cervical examination. The sensitivity of HPV testing for detecting a histologically proven HGSIL was 100%, higher than that of conventional (68.1%) and liquid-based (87.8%) cytology. The low specificities of 85.6% and 87.3% of HPV testing slightly increased to 88.4% and 90.1% if HPV testing was reserved for woman >30 years old. The quantitative approach provided by the HC-II assay for the assessment of the viral load was not reliable for predicting HGSIL in normal smears. HR-HPV testing could be proposed in primary screening in association with cytology. With conventional cytology it significantly improves the detection of HGSIL. With the use of the same cervical scrape for HPV testing and liquid-based cytology, HR-HPV testing would allow to select positive samples treated in a second time for cytology which gives a good specificity. Copyright 2001 Cancer Research Campaign http://www.bjcancer.com Copyright 2001 Cancer Research Campaign.
PMID: 11401314 [PubMed - in process]
Papanicolaou test screening and prevalence of genital human papillomavirus among women who have sex with women.
Marrazzo JM, Koutsky LA, Kiviat NB, Kuypers JM, Stine K.
Department of Medicine, University of Washington, Seattle, USA. [email protected]
OBJECTIVES: The purpose of this study was to examine frequency of and attitudes toward Papanicolaou (Pap) test screening in women who have sex with women (WSW) and to determine prevalence of genital human papillomavirus (HPV). METHODS: Women were eligible if they reported having engaged in sex with another woman in the preceding year Medical and sexual histories were obtained. Cervical specimens for Pap tests and cervical and vaginal specimens for HPV DNA testing were collected. RESULTS: HPV DNA was detected in 31 of 248 WSW (13%). Women who had never had sex with men were less likely to have undergone pelvic examinations and had fewer recent Pap tests. Reasons for not undergoing Pap tests included lack of insurance, previous adverse experiences, and belief that Pap tests were unnecessary. CONCLUSIONS: Despite the occurrence of genital HPV, WSW do not receive adequate Pap test screening. Pap test screening recommendations should not differ for WSW, regardless of sexual history with men.
PMID: 11392939 [PubMed - indexed for MEDLINE]
Cost-effectiveness of monolayers and human papillomavirus testing compared to that of conventional Papanicolaou smears for cervical cancer screening: protocol of the study of the French Society of Clinical Cytology.
Cochand-Priollet B, Le Gales C, de Cremoux P, Molinie V, Sastre-Garau X, Vacher-Lavenu MC, Vielh P, Coste J; 20 Monolayers French Society of Clinical Cytology Study Group.
Service d'Anatomie et Cytologie Pathologiques, Hopital Lariboisiere, Paris, France. [email protected]
The French Society of Clinical Cytology is conducting a study to compare the cost-effectiveness of monolayers and human papillomavirus (HPV) testing with that of conventional Papanicolaou (Pap) smears for cervical cancer screening. The protocol of this study is presented. It includes 3,000 women who will be evaluated by the three methods (conventional Pap smears, or monolayers with or without HPV testing) and by the reference method: colposcopy followed, in cases with abnormalities, by cervical biopsy. Efficacy or performance of the methods will be compared on the basis of sensitivity. Cost comparisons and cost-effectiveness modeling will be based on the costs associated with methods themselves and also the costs of "false positives." This will require specific collection of data concerning the costs of the three methods, as these costs have not previously been accurately documented. Patient recruiting and data collection started in September 1999 and will be complete in June 2000. The first results are expected to be available in spring 2001. Copyright 2001 Wiley-Liss, Inc.
PMID: 11391824 [PubMed - in process]
Identification of differentially expressed genes in human papillomavirus type-16 infected oral cancer cells.
Brown JJ, Qin M, William-Smith L, Coker JF, Zhou H, Nishitani J, Liu X.
Departments of Otolaryngology-Head and Neck Surgery and Oral and Maxillofacial Surgery, Charles R. Drew University of Medicine and Science.
OBJECTIVE: The goal of this study was to determine the genes required for head and neck cancer development. Study design and setting: Differential mRNA display analysis was performed using human papillomavirus Type-16 infected immortalized human oral keratinocytes (HOK-16B) and its benzo(a)pyrene-exposed tumorigenic derivative (HOK-16B-BaP-T). RESULTS: Twenty-one differentially expressed cDNA clones were identified between the 2 cell lines. Clone 4 with no known homology showed lower expression in tumorigenic cells compared with either normal or immortalized oral keratinocytes. Clone 6 expression was elevated in several head and neck cancer cells, in addition to Burkitt's lymphoma Raji harboring latent Epstein-Barr virus. CONCLUSION: These findings suggested that clone 6 may be involved in the oncogenic transformation whereas clone 4 may potentially function as a tumor suppressor gene. SIGNIFICANCE: Differential mRNA analysis using the in vitro oral carcinogenesis model may help to identify important genetic markers for the early detection and progression of head and neck cancer.
PMID: 11391258 [PubMed - in process]
p21cip1 Degradation in differentiated keratinocytes is abrogated by costabilization with cyclin E induced by human papillomavirus E7.
Noya F, Chien WM, Broker TR, Chow LT.
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
The human papillomavirus (HPV) E7 protein promotes S-phase reentry in a fraction of postmitotic, differentiated keratinocytes. Here we report that these cells contain an inherent mechanism that opposes E7-induced DNA replication. In organotypic raft cultures of primary human keratinocytes, neither cyclin E nor p21cip1 is detectable in situ. However, E7-transduced differentiated cells not in S phase accumulate abundant cyclin E and p21cip1. We show that normally p21cip1 protein is rapidly degraded by proteasomes. In the presence of E7 or E6/E7, p21cip1, cyclin E, and cyclin E2 proteins were all up-regulated. The accumulation of p21cip1 protein is a posttranscriptional event, and ectopic cyclin E expression was sufficient to trigger it. In constract, cdk2 and p27kip1 were abundant in normal differentiated cells and were not significantly affected by E7. Cyclin E, cdk2, and p21cip1 or p27kip1 formed complexes, and relatively little kinase activity was found associated with cyclin E or cdk2. In patient papillomas and E7 raft cultures, all p27kip1-positive cells were negative for bromodeoxyuridine (BrdU) incorporation, but only some also contained cyclin E and p21cip1. In contrast, all cyclin E-positive cells also contained p27kip1. When the expression of p21cip1 was reduced by rottlerin, a PKC delta inhibitor, p27kip1- and BrdU-positive cells remained unchanged. These observations show that high levels of endogenous p27kip1 can prevent E7-induced S-phase reentry. This inhibition then leads to the stabilization of cyclin E and p21cip1. Since efficient initiation of viral DNA replication requires cyclin E and cdk2, its inhibition accounts for heterogeneous viral activities in productively infected lesions.
PMID: 11390614 [PubMed - indexed for MEDLINE]
Telomerase suppression by chromosome 6 in a human papillomavirus type 16-immortalized keratinocyte cell line and in a cervical cancer cell line.
Steenbergen RD, Kramer D, Meijer CJ, Walboomers JM, Trott DA, Cuthbert AP, Newbold RF, Overkamp WJ, Zdzienicka MZ, Snijders PJ.
Department of Pathology, Unit of Molecular Pathology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
BACKGROUND: High-risk human papillomavirus (HPV) types play a major role in the development of cervical cancer in vivo and can induce immortalization of primary human keratinocytes in vitro. Activation of the telomere-lengthening enzyme telomerase constitutes a key event in both processes. Because losses of alleles from chromosome 6 and increased telomerase activity have been observed in high-grade premalignant cervical lesions, we analyzed whether human chromosome 6 harbors a putative telomerase repressor locus that may be involved in HPV-mediated immortalization. METHODS: Microcell-mediated chromosome transfer was used to introduce chromosomes 6 and 11 to the in vitro generated HPV type 16 (HPV16)-immortalized keratinocyte cell line FK16A and to the in vivo derived HPV16-containing cervical cancer cell line SIHA: Hybrid clones were analyzed for growth characteristics, telomerase activity, human telomerase reverse transcriptase (hTERT) and HPV16 E6 expression, and telomere length. FK16A hybrid clones were also transduced with an hTERT-containing retrovirus to examine the effect of ectopic hTERT expression on growth. Statistical tests were two-sided. RESULTS: Introduction of human chromosome 6 but not of chromosome 11 to both cell lines yielded hybrid cells that demonstrated crisis-like features (i.e., enlarged and flattened morphology, vacuolation, and multinucleation) and underwent growth arrest after a marked lag period. In the chromosome 6 hybrid clones analyzed, telomerase activity and hTERT messenger RNA (mRNA) expression were statistically significantly reduced compared with those in the chromosome 11 hybrid clones (for telomerase activity, P =.004 for the FK16A hybrids and P =.039 for the SiHa hybrids; for hTERT mRNA expression, P =.003 for the FK16A hybrids). The observed growth arrest was associated with telomeric shortening. Ectopic expression of hTERT in FK16A cells could prevent the telomeric shortening-based growth arrest induced by chromosome 6. CONCLUSIONS: Chromosome 6 may harbor a repressor of hTERT transcription, the loss of which may be involved in HPV-mediated immortalization.
PMID: 11390536 [PubMed - indexed for MEDLINE]
Much higher risk of premalignant and malignant cervical diseases in younger women positive for HPV16 than in older women positive for HPV16.
Tanaka H, Karube A, Tanaka T, Nakagomi O.
Department of Obstetrics and Gynecology, Akita University School of Medicine, Japan.
Human papillomavirus (HPV), particularly HPV16, is strongly associated with premalignant lesions of the uterine cervix and cervical cancer. However, HPV infection is a common sexually transmitted disease and only a few women develop cervical cancer. Although the presence of HPV and abnormal cytology are independent risk factors for cervical diseases, implementing both tests on every woman is argued not to be recommended mainly in terms of cost-effectiveness. During a 20-month period between October, 1994, and May, 1996, cervical swabs from 207 women who were referred for colposcopy because of cervical dyskaryosis (Papanicolaou class IIIa or higher) were examined by PCR for the presence of HPV16. When these women were divided into two groups; i.e., group A consisting of women who were 44 years old or younger (n = 111), and group B consisting of women who were 45 years old or older (n = 96), the risk of having premalignant and malignant cervical diseases upon infection with HPV16 was approximately 8 times higher in group A than in group B. Thus, we conclude that HPV-testing should be implemented on every young woman with an abnormal Papanicolaou smear test.
PMID: 11386424 [PubMed - in process]
Human immunodeficiency virus type 1-related nucleic acids and papillomavirus DNA in cervicovaginal secretions of immunodeficiency virus-infected women.
Spinillo A, Debiaggi M, Zara F, De Santolo A, Polatti F, Filice G.
Departments of Obstetrics and Gynecology, Microbiology and Infectious and Tropical Diseases, Policlinico S. Matteo, University of Pavia, Pavia, Italy. [email protected]
OBJECTIVE: To evaluate simultaneous human immunodeficiency virus (HIV)-related nucleic acids and human papillomavirus (HPV)-DNA in cervicovaginal secretions of HIV-seropositive women. METHODS: We collected 47 paired blood and cervicovaginal lavage samples from 124 known HIV-1-seropositive women. Proviral HIV-1 DNA, cell-associated, and cell-free HIV-1 RNA in cervicovaginal secretions were quantitatively evaluated by competitive polymerase chain reaction (PCR) and reverse transcription PCR. Polymerase chain reaction and subsequent restriction fragment length polymorphism analysis of PCR products were used to detect HPV types 6, 11, 16, 18, 31, 33, 35, and 56. RESULTS: Proviral HIV-1 DNA, cell-associated, and cell-free HIV-1 RNA were detected in 52.4% (65 of 124), 38.7% (48 of 124), and 33.9% (42 of 124) of lavage samples, respectively. Human papillomavirus-DNA in cervicovaginal secretions was detected in 64% (79 of 124) of participants. The rate of detection of HPV types of intermediate to high oncogenic risk was higher in HIV-positive women who tested positive for cell-associated (odds ratio [OR] 3.57, 95% confidence interval [CI] 1.17, 11.12) or cell-free (OR 4.63, 95% CI 1.42, 15.51) HIV-1 RNA in cervicovaginal secretions than their counterparts who tested negative. Logistic regression analysis showed that the association between HPV infection and the detection of HIV-1 RNA in cervicovaginal secretions persisted after adjustment for potential confounders such as CD4+ cell counts, HIV-1 RNA in plasma, use of antiretroviral drugs, vaginal infection, and regular condom use. In univariable and multivariable analysis, HPV-DNA detection was associated with amounts of cell-free and cell-associated HIV-1 RNA in cervicovaginal secretions (chi(2) for trend 10.35, and 9.84, P =.001 and.002, respectively). CONCLUSIONS: The rate of HPV detection in the genital tract of HIV-1-seropositive women is associated with the amount of cell-associated and cell-free HIV-1 RNA present in cervicovaginal secretions. The association does not appear to be attributable entirely to the effect of HIV-related immunodepression.
PMID: 11384710 [PubMed - indexed for MEDLINE]
A method that allows easy characterization of tumor-infiltrating lymphocytes.
Kowalczyk DW, Wlazlo AP, Blaszczyk-Thurin M, Xiang ZQ, Giles-Davis W, Ertl HC.
The Wistar Institute, 3601 Spruce St., 19104, Philadelphia, PA, USA
A method was developed to compare the lymphocytic infiltrates in regressing vs. progressing experimental mouse tumors using a model for human papillomavirus-16 (HPV-16) oncoprotein-linked cancer. Tumor cells mixed with matrigel, composed of natural matrix substances that provide a basement membrane structure for adherent cells, were inoculated into mice vaccinated with an efficacious vaccine to the E7 oncoprotein or a vaccine to a control antigen. The tumor cells remained within the solidified gel and recruited a cellular infiltrate that could readily be analyzed upon removal of the gelatinous mass containing progressing or regressing tumors. The results show that tumors recruit activated CD8(+) T cells regardless of their antigen specificity. In regressing tumors expressing an appropriate target antigen for the vaccine-induced CD8(+) T cells, a strong increase of the tumor antigen-specific T cell population was observed over time. Progressing tumors that lacked the target antigen for the activated CD8(+) T cell population did not show this selective enrichment.
PMID: 11384678 [PubMed - in process]
Women's knowledge of Pap smears, risk factors for cervical cancer, and cervical cancer.
Reid J.
Indiana University Southeast, New Albany 47150, USA.
OBJECTIVE: To review the literature on women's knowledge of Pap smears, risk factors for cervical cancer, and cervical cancer. DATA SOURCES: The review was based on a search of the relevant literature over a 10-year period using MEDLINE and CINAHL. DATA EXTRACTION: Articles from relevant, indexed journals and textbooks published within the past decade were included. Seminal articles were included as appropriate. DATA SYNTHESIS: Risk factors for the development of cervical cancer have been reevaluated. The case for human papillomavirus as the cause of cervical neoplasms has been strengthened. CONCLUSIONS: Cervical cancer is associated with early sexual debut, number of lifetime sexual partners, nonuse of condoms, and infection with human papillomavirus. Cigarette smoking facilitates development of cervical cancer.
PMID: 11383953 [PubMed - in process]
Pathogenesis of esophageal squamous cell carcinoma with lymphoid stroma.
Kuwano H, Sumiyoshi K, Sonoda K, Kitamura K, Toh Y, Nakashima H, Sugimachi K.
Department of Surgery I, Faculty of Medicine, Gunma University, 3-39-22, Showa-machi, Maebashi 371-8511, Japan.
BACKGROUND/AIMS: Lymphocyte infiltration in esophageal cancer, especially when beneath intraepithelial carcinoma, is frequently seen. However, cases of esophageal cancer with a dense stromal infiltration of lymphocytes are rare and the pathogenesis of such cases has yet to be clearly demonstrated. The objective of this study is to clarify its pathogenesis. METHODOLOGY: Four cases of esophageal squamous cell carcinoma with lymphoid stroma were investigated by immunohistochemical staining for the detection of Epstein-Barr virus, human papillomavirus, human leukocyte antigen-DR, as well as T and B cells in cancer tissue. RESULTS: In these four cases, neither positive staining of Epstein-Barr virus nor human papillomavirus infection was detected. On the other hand, the expression of human leukocyte antigen-DR antigen was evident in all cases with dense T-cell infiltration in the tumor tissue and moderate B-cell infiltration around the tumor. CONCLUSIONS: The expression of human leukocyte antigen-DR antigen without Epstein-Barr virus or human papillomavirus infection could thus be one possible pathogenesis of patients demonstrating esophageal squamous cell carcinoma with a lymphoid stroma.
PMID: 11379332 [PubMed - in process]
Low frequency of p53 mutations in cervical carcinomas among Brazilian women.
Pinheiro NA, Villa LL.
Departamento de Bioquimica, Instituto de Quimica, Universidade de Sao Paulo, Sao Paulo, SP, Brasil.
Human papillomavirus (HPV) infections of the high-risk types are strongly linked to the development of cervical carcinoma. The HPV oncoproteins E6 and E7 are thought to play a crucial role in this process through their interactions with the p53 protein and the retinoblastoma susceptibility gene product pRb, respectively. E6 binds to p53 protein promoting its degradation. This is considered to contribute to the oncogenesis of HPV-associated anogenital cancer. On the other hand, in HPV-negative cervical carcinoma, p53 mutations are thought to have a role in the transformation process. A total of 122 HPV-positive cervical carcinoma tissue samples were evaluated for the presence of mutations in exons 5-8 of the p53 gene by single-stranded conformation polymorphism analysis and DNA sequencing. Only four missense point mutations were detected. These findings suggest that other mechanisms independent of p53 inactivation may play a role in the genesis of cervical carcinomas.
PMID: 11378660 [PubMed - in process]
Changing rates of adenocarcinoma and adenosquamous carcinoma of the cervix in England.
Sasieni P, Adams J.
Department of Mathematics, Statistics, and Epidemiology, Imperial Cancer Research Fund, 61 Lincoln's Inn Fields, WC2A 3PX, London, UK. [email protected]
BACKGROUND: A recent analysis showed little or no effect of screening on the incidence of adenocarcinoma of the cervix between 1971 and 1992. We have used additional data on cancers diagnosed in 1993-94 in England and up to 1997 in five English cancer registries to investigate more recent trends. METHODS: After inputing the number of adenocarcinomas in women with unknown histology, we fitted an age-cohort model to 8062 adenocarcinomas of the cervix diagnosed in England between 1971 and 1987. Predictions from this model were applied to the more recent data on 5854 cases. Residual effects were plotted against year of diagnosis in each of four age-groups. FINDINGS: We estimated the underlying risk of cervical adenocarcinoma to be 14 times (95% CI 11-19) greater in women born in the early 1960s than in cohorts born before 1935. An age-cohort model fitted the data for England well up to 1987, but substantially overestimated the numbers of adenocarcinomas in young women from 1990 onwards. In 1996-97 the incidence rate in women aged 25-54 years was less than 40% of that predicted from the age-cohort model. INTERPRETATION: The substantial increase in cervical adenocarcinoma in recent years is largely a birth-cohort effect presumably associated with greater exposure to human papillomavirus after the sexual revolution in the 1960s. The relative decline in younger women observed in more recent years suggests an effect of cervical screening.
PMID: 11377601 [PubMed - indexed for MEDLINE]
Loss of sequences on the short arm of chromosome 17 is a late event in squamous carcinoma of the cervix.
Herrington CS, Worsham M, Southern SA, Mackowiak P, Wolman SR.
Department of Pathology, University of Liverpool, Royal Liverpool University Hospital, Liverpool L69 3GA, UK. [email protected]
AIMS: To determine by fluorescence in situ hybridisation (FISH) whether deletion of D17S34, a subtelomeric probe for 17p, occurs in invasive squamous carcinoma of the cervix, and to determine the extent of such loss by analysis of the p53 and HER2/NEU genes. METHODS: Fourteen invasive squamous cell carcinomas of the cervix were investigated by FISH for D17S34, p53, and HER2/NEU. Dual hybridisation of each probe with the chromosome 17 alpha satellite (D17Z1) probe was performed on paraffin wax embedded sections, and the fluorescence ratios of the paired signals were determined. Broad spectrum human papillomavirus (HPV) typing by ISH and GP5+/6+ polymerase chain reaction was also performed. RESULTS: Twelve tumours were HPV positive, nine with HPV-16, and one each with types 18, 31, and 39. Loss of D17S34 was identified in four tumours, one of which was HPV negative. In one tumour, D17S34 loss was accompanied by loss of p53 only, suggesting that deletion was limited to the p arm. A second tumour showed simultaneous losses of all probes, indicative of whole chromosome 17 loss during tumour growth. The two remaining specimens showed loss of D17S34 only, diffuse in one, and localised within the tumour in the other. Aberrations of p53 or HER2/NEU were not seen independently of D17S34 loss, and loss did not correlate with HPV presence or type. CONCLUSIONS: These data show that D17S34 loss is prevalent, marking 28% of the invasive squamous carcinomas in this study. The observed intratumoral heterogeneity indicates that, at least in some cases, this loss occurs after invasion and is therefore a late event in the path of cervical carcinogenesis.
PMID: 11376128 [PubMed - in process]
Human papillomavirus type 16 is an important infectious factor in the high incidence of esophageal cancer in Anyang area of China.
Li T, Lu ZM, Chen KN, Guo M, Xing HP, Mei Q, Yang HH, Lechner JF, Ke Y.
Laboratory of Genetics, Beijing Institute for Cancer Research, School of Oncology, Peking University, No. 1 Da Hong Luo Chang St, Beijing 100034, China.
To investigate the potential role of human papillomavirus (HPV) infection in the pathogenesis of esophageal carcinomas in the Anyang area of China, we have evaluated specimens collected by balloon cytology examination from volunteers in two regions with significantly different incidences of esophageal carcinoma. 138 donors were from a village in a county with an esophageal carcinoma (EC) age-adjusted mortality rate of 132x10(5), the remaining 68 were resident in a second village from another county with an EC mortality rate of 52x10(5). Specimens were evaluated using both polymerase chain reaction (PCR) amplification and in situ hybridization (ISH) protocols. PCR results showed that the prevalence of the human papillomavirus type 16 (HPV-16) E6 gene in the high incidence area was 1.9-fold higher than that of the low incidence area (72 and 37%, respectively, P < 0.01). Moreover, the positive rate corresponded with pathology grade. Similar results were obtained with the HPV-16 E7 gene. As the cells undergoing cytopathological progress, the HPV-16 E6 positive rate was increased, in both villages. In contrast to HPV-16 E6 and E7, detection of the HPV L1 gene was consistently lower, and its prevalence decreased with increasing dysplasia grades (P < 0.05). By ISH analyses, the expression rate of HPV-16 E6 in the specimens collected from the high incidence area was 2.2-fold higher than those from the low incidence area (49 versus 22%, respectively; P < 0.05), and transcription of the E6 gene paralleled cytopathology. HPV-18 was also detected in 17 and 15% of the specimens from the high and low incidence areas, respectively, but most of these samples were also simultaneously HVP-16 positive. These results suggest that HVP-16 plays a causative role in the high incidence of esophageal cancer in the Anyang region of CHINA:
PMID: 11375901 [PubMed - indexed for MEDLINE]
Human papillomavirus antigens and T-cell recognition.
Luxton J, Shepherd P.
Department of Immunobiology, Guy's, King's and St Thomas' School of Medicine, London, UK.
This review will summarize what is known about natural T-cell responses to human papillomavirus infections, including potential mechanisms for their dysregulation which may lead to the development of disease. We will also describe new strategies to enhance human papillomavirus specific T-cell responses following vaccination that are currently in development and recent reports on human vaccine trials with particular regard to the generation of appropriate T-cell responses.
PMID: 11375548 [PubMed - as supplied by publisher]
Detection of human papillomavirus in non-small cell lung carcinoma by polymerase chain reaction.
Miasko A, Niklinska W, Niklinski J, Chyczewska E, Naumnik W, Chyczewski L.
Department of Histology and Embryology, Medical Academy, Bialystok, Poland.
Human papillomavirus (HPV) infection is one of the risk factors contributing to the pathogenesis of lung cancer. The aim of the study was to determine the presence of HPV in non-small cell carcinomas of the lung. The study included 40 tumors: 22 squamous cell carcinomas, 13 adenocarcinomas and 5 large cell carcinomas. HPV was found in 4 cases (10%). High risk HPV was present in 3 tumors: in one squamous cell carcinoma, one large cell carcinoma and one adenocarcinoma, while low risk HPV was detected in one adenocarcinoma.
PMID: 11374789 [PubMed - in process]
Colposcopically directed biopsy findings in the young female.
Hassan EA, Creatsas GK, Diakomanolis ES, Sakellaropoulos GG, Rodolakis AJ, Konidaris SD, Michalas SP.
Colposcopy Units, 1st and 2nd Departments of Obstetrics and Gynecology, University of Athens, Athens, Greece
Study Objective: To evaluate the colposcopic findings of cervical alterations in the young sexually active female.Design, Setting, Participants: Colposcopic examination and follow-up of 51 young sexually active females aged 15-20 yr was conducted due to abnormal cytology or a suspicious abnormality of the cervix. The study was conducted at the Colposcopy Units of the 1(st) and 2(nd) Departments of Obstetrics and Gynecology, University of Athens, Greece.Interventions: Colposcopic examination, LEEP, conization.Mean Outcome Measures: Biopsy, human papillomavirus (HPV) typing.Results: Colposcopic examinations were within normal limits in 8 of 51 (15.7%) cases. Cervical alterations were related to HPV infection in 14 cases (27.4%), to cervical intraepithelial neoplasia (CIN) I in 15 (29.4%) cases, to CIN II in 13 (25.5%) cases, and to CIN III in 1 (2.0%) case. Of all CIN I cases, 8 of 15 (53.3%) were HPV positive, and HPV type 11, 16, 18, 31, 33, and 11& 16 were found. In CIN II cases, 5 of 13 (38.4%) were HPV positive, and HPV type 11, 16, 18, and 11 & 31 were found. In the CIN III case, only HPV type 16 was found.Conclusions: Our findings strongly confirm the necessity of obtaining cervicovaginal smears on all sexually active gynecologic and obstetric teenage patients. Colposcopy plays a major role in the evaluation of the cervix and in the treatment that should be given for any individual CIN lesion.
PMID: 11358705 [PubMed - in process]
Incidence and evaluation of an AGUS Papanicolaou smear in primary care.
Valdini A, Vaccaro C, Pechinsky G, Abernathy V.
Department of Family Medicine and Community Health, Tufts University School of Medicine, Boston, Mass, USA.
BACKGROUND: The category atypical glandular cells of undetermined significance (AGUS) occurs in about 0.5% of Papanicolaou smears. Although recent case series report a great many dysplastic, cancerous, and precancerous lesions of the cervix and endometrium associated with AGUS, little attention has been focused on this issue in primary care literature. METHODS: We report a case series of 52 women with AGUS Papanicolaou smears in a family health center during 2 years (1997 to 1998), along with colposcopy and biopsy results and 18 months of follow-up findings. These results were compared with findings of recent reports. RESULTS: The incidence of AGUS was 0.5%, 52 of 10,564 Papanicolaou smears. Colposcopy was performed in 45. Biopsy (n = 46) showed 2 adenocarcinomas of the endometrium, and 6 high-grade dysplastic lesions, including 1 squamous cell carcinoma in situ. Nineteen women had cervical intraepithelial neoplasia stage I-changes of human papillomavirus effect, and 4 had endocervical polyps. Three women were lost to follow-up. The frequency of dysplastic and cancerous lesions in our population (17.4%) is consistent with series findings from cytology and obstetrics and gynecology literature, reporting that 19.5% of women with AGUS have either cancer--adenocarcinoma of the endometrium, squamous cell carcinoma, or extrauterine (8%)--or high-grade lesions--cervical intraepithelial neoplasia II-III, carcinoma in situ, or cervical adenocarcinoma in situ, (11.5%). CONCLUSIONS: A relatively large percentage of women with AGUS on Papanicolaou smears have cancerous and dysplastic squamous and glandular lesions of the exocervix, endocervix, and endometrium. Clinical practice guidelines recommend patients with AGUS should be evaluated with colposcopy and endocervical curettage. Consensus supports endometrial sampling in women 35 years and older and in those with a laboratory report of AGUS, favors neoplasia or suggests an endometrial source.
PMID: 11355048 [PubMed - in process]
High prevalence of human papillomavirus infection in Mexican males: comparative study of penile-urethral swabs and urine samples.
Lazcano-Ponce E, Herrero R, Munoz N, Hernandez-Avila M, Salmeron J, Leyva A, Meijer CJ, Walboomers JM.
Center for Population Health Research-National Institute of Public Health of Cuernavaca Morelos, Mexico. [email protected]
BACKGROUND: Although extensive information has been gathered about the prevalence and determinants of human papillomavirus infection among women, little is known about the prevalence and natural history of this infection among males. GOAL: To investigate the potential usefulness of urine specimens to assess the presence of genital human papillomavirus DNA infection. STUDY DESIGN: The authors conducted a study of 120 healthy men from Cuernavaca, Mexico. A urine specimen and urethral and coronal sulcus swab samples were collected and tested for human papillomavirus using the GP5+/6+ polymerase chain reaction enzyme immunoassay method. RESULTS: In 95% of the urethral-coronal sulcus samples, the beta-globin gene was detectable, indicating adequacy of the specimen for DNA amplification; however, only 14% of the urine specimens had detectable beta-globin. Removal of inhibitors by DNA purification in a sample of subjects produced beta-globin amplification, but no increase in human papillomavirus DNA positivity was detected. Human papillomavirus DNA was not detectable in penile-urethral swab samples in any of the subjects who reported not having engaged in sexual activity but was present in 43% of men who reported sexual activity, a strong indication of the sexual transmission of human papillomavirus. CONCLUSIONS: Human papillomavirus is a common sexually transmitted infection among Mexican males, and urine sample specimens cannot adequately detect the presence of this infection in males.
PMID: 11354266 [PubMed - in process]
Detection of viral DNA and E4 protein in basal keratinocytes of experimental canine oral papillomavirus lesions.
Nicholls PK, Doorbar J, Moore RA, Peh W, Anderson DM, Stanley MA.
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom. [email protected]
We studied experimental canine oral papillomavirus (COPV) infection by in situ hybridization and immunohistochemistry of weekly biopsies. After 4 weeks, viral DNA in rete ridges suggested a keratinocyte stem cell target. Abundant viral DNA was seen in E4-positive cells only. E4 was predominantly cytoplasmic but also nuclear, being concentrated in the nucleoli during wart formation. Infected cells spread laterally along the basal layer and into the parabasal layers, accompanied by E7 transcription and increased mitoses. Most of the lower epithelium was positive for viral DNA, but, in mature warts, higher levels of E4 expression and genome amplification occurred in only sporadic superficial cells. L1 expression was late and in only a subset of E4-positive cells. During regression, viral DNA was less abundant in deep epithelial layers, suggesting downregulation of replication prior to replacement of infected cells from beneath. Detection of viral DNA in post-regression tissue indicated latent infection. Copyright 2001 Academic Press.
PMID: 11352670 [PubMed - indexed for MEDLINE]
Cervical dysplasia, ploidy, and human papillomavirus status correlate with loss of fhit expression.
Vecchione A, Zanesi N, Trombetta G, French D, Visca P, Pisani T, Botti C, Vecchione A, Croce CM, Mancini R.
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [A. V., N. Z., C. M. C., R. M.].
PURPOSE: The tumor suppressor gene, FHIT, has been cloned and mapped at chromosome region 3p14.2, one of the regions most frequently deleted in cervical carcinoma. In this report, we show that the expression of the Fhit protein in relation to human papillomavirus (HPV) subtype, the type of the intraepithelial lesion, HIV-induced immunodeficiency, and the DNA content (ploidy) correlates with the biological behavior of the lesions. Experimental DESIGN: To investigate involvement of the FHIT gene in squamous intraepithelial lesions of low and high grade (LGSILs and HGSILs, respectively) of the uterine cervix, we examined the Fhit protein expression by immunocytochemistry in 131 cervical smears of 96 HIV-seropositive patients (42 with LGSILs and 10 with HGSILs) and 35 HIV-seronegative (5 with LGSILs) persons. RESULTS: Fhit protein was detected in normal cells, whereas dysplastic cells (independently of HPV infection and HPV subtypes) showed reduced expression of Fhit (P = 0.00001). Lesions from 52 HIV-seropositive patients, 42 LGSILs and 10 HGSILs, showed diploid DNA content in 63.5%, aneuploid in 32.7%, and polyploid in 3.8%, but 90% of the HGSILs showed an aneuploid DNA content, and all were infected by HPV 16/18 subtypes. 23.8% of LGSIL cases were associated with HPV 16. CONCLUSIONS: These data clearly suggest that loss of Fhit expression occurs in the early stages of cervical carcinogenesis. Pap test represents one of the most convenient and rapid procedures available in identification of cellular changes; hence, Fhit staining might be used as an useful tool in larger population screening to detect early alteration in cellular behaviors.
PMID: 11350899 [PubMed - in process]
Conversion of normal to malignant phenotype: telomere shortening, telomerase activation, and genomic instability during immortalization of human oral keratinocytes.
Kang MK, Park NH.
School of Dentistry and Dental Research Institute, University of California, Los Angeles 90095, USA.
Normal somatic cells terminate their replicative life span through a pathway leading to cellular senescence, which is triggered by activation of p53 and/or pRb in response to critically shortened telomere DNA. Potentially neoplastic cells must first overcome the senescence checkpoint mechanisms and subsequently activate telomerase to propagate indefinitely. Although telomerase activation is closely associated with cellular immortality, telomerase alone is not sufficient to warrant tumorigenicity. Environmental factors, including chemical carcinogens and viral infection, often contribute to aberrant changes leading to tumorigenic conversion of normal cells. Of particular importance in oral cancer development are tobacco-related chemical carcinogens and human papillomavirus (HPV) infection. To describe the molecular mechanisms by which these environmental factors facilitate the genesis of oral cancer, we first established an in vitro multistep oral carcinogenesis model by sequential exposure of normal human oral keratinocytes (NHOK) to "high risk" HPV and chemical carcinogens. Upon introduction of the HPV genome, the cells bypassed the senescence checkpoint and entered into an extended, but not immortal, life span during which telomere DNA continued to shorten. In a few immortal clones surviving beyond the crisis, we found a marked elevation of telomerase activity and stabilization of telomere length. Furthermore, the E6 and E7 oncoproteins of "high risk" HPV disrupted the cell cycle control and DNA repair in immortalized HOK, and enhanced mutation frequency resulting from genomic instability. However, HPV infection alone failed to give rise to a tumorigenic cell population, which required further exposure to chemical carcinogens in addition to HPV infection. Analysis of the data presented suggests that oral carcinogenesis is a series of discrete genetic alterations that result from a continued genotoxic challenge by environmental risk factors. Our in vitro model may be useful for investigators with interest in furthering our understanding of oral carcinogenesis.
PMID: 11349961 [PubMed - in process]
Determinants of genital human papillomavirus detection in a US population.
Peyton CL, Gravitt PE, Hunt WC, Hundley RS, Zhao M, Apple RJ, Wheeler CM.
University of New Mexico, Department of Molecular Genetics and Microbiology, Albuquerque, New Mexico 87131-5276, USA.
This study investigated the association of selected demographic and behavioral characteristics with the detection of low-risk, high-risk, and uncharacterized genital human papillomavirus (HPV) in women attending clinic for routine nonreferral gynecologic health care. Cervical specimens obtained from 3863 women 18-40 years old (mean, 28 years) with no history of high-grade cervical disease were analyzed for 38 HPV types. Overall, HPV prevalence was 39.2%. The prevalence of high-risk, low-risk, and uncharacterized HPV types was 26.7%, 14.7%, and 13.0%, respectively. As expected, the characteristics most strongly associated with overall HPV detection were age and numbers of lifetime and recent sex partners. Low-risk, high-risk, and uncharacterized HPV detection increased with increasing numbers of sex partners. There was a decline in high-risk and low-risk HPV detection with increasing age but little change in uncharacterized HPV detection. These results suggest that the uncharacterized HPV types have a different natural history than either low-risk or high-risk HPV types.
PMID: 11343204 [PubMed - indexed for MEDLINE]
Centrosome abnormalities, genomic instability and carcinogenic progression.
Duensing S, Munger K.
Department of Pathology and Center for Cancer Biology, Harvard Medical School, Armenise Research Building, D2 544A, 200 Longwood Avenue, Boston, MA 02115-5701, USA.
Centrosome abnormalities are a frequent finding in various malignant tumors. Since centrosomes form the poles of the mitotic spindle, these abnormalities have been implicated in chromosome missegregation and the generation of aneuploid cells which is commonly found in many human neoplasms. It is a matter of debate, however, whether centrosome alterations can drive cells into aneuploidy or simply reflect loss of genomic integrity by other mechanisms. Since these two models have fundamentally different implications for the diagnostic and prognostic value of centrosome abnormalities, we will discuss the relevance of abnormal centrosomes in the context of different oncogenic events as exemplified by high-risk human papillomavirus-associated carcinogenesis.
Publication Types:
PMID: 11342187 [PubMed - indexed for MEDLINE]
alpha(6) Integrin is the main receptor of human papillomavirus type 16 VLP.
Yoon CS, Kim KD, Park SN, Cheong SW.
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Taejeon, 305-600, Korea.
The present study was performed to determine the specific receptor of type HPV-16 using recombinant human papillomavirus-like particle (HPV-16 L1-VLP). The expression levels of alpha(6), beta(1), and beta(4) integrins were determined and compared with the amount of HPV-VLP binding in ten cell lines by flow cytometry. Our results show that the amount of VLP binding and the expression level of alpha(6) integrin are correlated, which was confirmed by an inhibition experiment using antibodies and by immunocytochemistry. Both the expression level of alpha(6) integrin and the amount of HPV-VLP binding were high in cervical cancer cell lines, as the type HPV-16 is the main cause of cervical cancer. The degree of binding of HPV-VLP matched the alpha(6) integrin expression level in cell lines but was not correlated with beta(1) and beta(4) levels, which suggests that alpha(6) integrin is the main receptor of HPV type 16. Copyright 2001 Academic Press.
PMID: 11341777 [PubMed - indexed for MEDLINE]
Poor antibody response against human papillomavirus in adult-onset laryngeal papillomatosis.
Aaltonen LM, Auvinen E, Dillner J, Lehtinen M, Paavonen J, Rihkanen H, Vaheri A.
Department of Virology, Haartman Institute, University of Helsinki, Helsinki University Central Hospital, Finland. [email protected]
To investigate whether adult-onset laryngeal papillomatosis induces serum antibodies to the human papillomavirus (HPV), 60 patients underwent a clinical examination, and HPV DNA from their laryngeal biopsy was assayed by PCR and HPV serology with virus-like particles as the antigen. Patients and controls (n = 53) showed no differences in their HPV 6 and 16 antibodies. Patients more often had HPV 11 antibodies, female patients more often than female controls or male patients. Of the female patients, 5 of 15 had a history of genital condylomas and, at the follow-up visit, 5 of 9 had cervical cytology consistent with genital HPV infection. The fact that HPV antibodies did not correlate with clinical features of the laryngeal disease or with HPV DNA detected in the larynx, suggests that HPV antibodies in female patients were induced by genital rather than laryngeal HPV infection. The high prevalence of abnormal Pap smears indicates that gynaecological examination of female adult-onset laryngeal papilloma patients is warranted.
PMID: 11339256 [PubMed - indexed for MEDLINE]
Papillomata masquerading as vocal fold nodules.
Dean CM, Hawkshaw M, Sataloff RT.
American Institute for Voice and Ear Research, Philadelphia, USA.
PMID: 11338640 [PubMed - indexed for MEDLINE]
HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica.
Hildesheim A, Herrero R, Castle PE, Wacholder S, Bratti MC, Sherman ME, Lorincz AT, Burk RD, Morales J, Rodriguez AC, Helgesen K, Alfaro M, Hutchinson M, Balmaceda I, Greenberg M, Schiffman M.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
We examined factors associated with high-grade squamous intraepithelial lesions (HSIL) and cervical cancer among human papillomavirus (HPV)-infected women in a prevalent case-control study conducted within a population-based cohort of 10 077 women in Costa Rica. We compared 146 women with HPV-positive HSIL or cancer (HSIL/CA) against 843 HPV-positive women without evidence of HSIL/CA. Subjects completed a risk factor questionnaire. We evaluated the associations between exposures and HSIL/CA among women positive for any HPV and restricted to those positive for high-risk HPV types. Risk of HSIL/CA increased with increasing number of live births (P(trend)= 0.04). Women who smoked 6+ cigarettes/day had a RR for HSIL/CA of 2.7 (95% CI = 1.1-6.7) compared to non-smokers. Current use of barrier contraceptives was associated with a reduction in risk of HSIL/CA (RR = 0.39; 95% CI = 0.16-0.96). Sexual behaviour and a self-reported history of sexually transmitted diseases (STDs) other than HPV were not associated with HSIL/CA. Oral contraceptive use was associated with HSIL/CA among women with <3 pregnancies. Effects were similar in analysis restricted to women positive for high-risk HPV types. Among women positive for high-risk HPV types, 44% of HSIL/CA could be attributed to multiparity (>/=3 pregnancies) and/or smoking. Among HPV-positive women, multiparity and smoking are risk factors for HSIL/CA. Oral contraceptive use may be associated with HSIL/CA in subgroups of women. Copyright 2001 Cancer Research Campaign http://www.bjcancer.com.
PMID: 11336474 [PubMed - indexed for MEDLINE]
Cervical cancer: epidemiology, prevention and the role of human papillomavirus infection.
Franco EL, Duarte-Franco E, Ferenczy A.
Department of Oncology, McGill University, Montreal, Que.
Organized screening has contributed to a decline in cervical cancer incidence and mortality over the past 50 years. However, women in developing countries are yet to profit extensively from the benefits of screening programs, and recent trends show a resurgence of the disease in developed countries. The past 2 decades have witnessed substantial progress in our understanding of the natural history of cervical cancer and in major treatment advances. Human papillomavirus (HPV) infection is now recognized as the main cause of cervical cancer, the role of coexisting factors is better understood, a new cytology reporting terminology has improved diagnosis and management of precursor lesions, and specific treatment protocols have increased survival among patients with early or advanced disease. Current research has focused on the determinants of infection with oncogenic HPV types, the assessment of prophylactic and therapeutic vaccines and the development of screening strategies incorporating HPV testing and other methods as adjunct to cytology. These are fundamental stepping stones for the implementation of effective public health programs aimed at the control of cervical cancer.
PMID: 11314432 [PubMed - indexed for MEDLINE]
Relationships between 80 human papillomavirus genotypes and different grades of cervical intraepithelial neoplasia: association and causality.
Matsukura T, Sugase M.
Laboratory of Tumor Viruses, Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan. [email protected]
To clarify the causal relationship between human papillomavirus (HPV) and cervical intraepithelial neoplasia (CIN), we analyzed 386 unfixed biopsy specimens by blot hybridization at Tm -40 degrees C, targeting 38 skin and 42 genital HPVs. By the recognition of PstI, BanI, and MspI cleavage patterns, single genital, but no skin's HPVs were identified with more than 10 copies per cell in 354 CIN (88 CIN I, 94 CIN II, and 172 CIN III). HPVs 40, 42, 43, 54, 62, or 71 was found in 10 CIN I, while HPVs 18, 30, 39, 51, 56, 59, 66, 68, 69, or 82 was found in 35 CIN I, 20 CIN II, or 8 CIN III. On the other hand, HPVs 16, 31, 33, 35, 52, 58, or 67 was identified in 43 CIN I, 74 CIN II, or 164 CIN III. The results are strongly indicative that most genital HPVs have potency to induce CIN I; however, HPV 16 and its closely related types are able to efficiently induce CIN III. We discuss the definition of causal HPV for CIN with regard to viral prevalence and viral load. Copyright 2001 Academic Press.
PMID: 11312670 [PubMed - indexed for MEDLINE]
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