RESUMO
Using human papillomavirus (HPV) testing for cervical cancer screening in lower-resource settings (LRS) will result in a significant number of screen-positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV-positive women in LRS. This was a population-based study of women aged 25-65 years living in China (n = 7,541). Each woman provided a self-collected and two clinician-collected specimens. The self-collected and one clinician-collected specimen were tested by two HPV DNA tests-careHPV™ and Hybrid Capture 2; the other clinician-collected specimen was tested for HPV16/18/45 E6 protein. CareHPV™-positive specimens were tested for HPV16/18/45 DNA. HPV DNA-positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA-positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8-17.4% for VIA, 17.8-20.9% for an abnormal colposcopic impression; 7.9-10.5% for HPV16/18/45 E6; 23.4-28.4% for HPV16/18/45 DNA; and 48.0-62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA-positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.
Assuntos
Infecções por Papillomavirus/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , Triagem/economia , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , China , Colposcopia , DNA Viral/análise , Proteínas de Ligação a DNA/análise , Detecção Precoce de Câncer/economia , Feminino , Testes de DNA para Papilomavírus Humano/economia , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Programas de Rastreamento/economia , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/análise , Infecções por Papillomavirus/virologia , Lesões Pré-Cancerosas/virologia , Proteínas Repressoras/análise , Sensibilidade e Especificidade , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia , Esfregaço Vaginal , Displasia do Colo do Útero/virologiaRESUMO
OBJECTIVE: To determine the expression of human papillomavirus (HPV) type 16 E6 oncoprotein in cervical specimens of women with and without cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: Cervical specimens from 2,530 unscreened women aged 30 to 54 years from Shanxi, China, were obtained. All women were assessed by liquid-based cytology, high-risk HPV DNA tests, and colposcopy with directed biopsy and endocervical curettage as necessary. Women with abnormal cytologic results or positive HPV DNA results were recalled for colposcopy, 4-quadrant cervical biopsies, and endocervical curettage. Women with biopsy-proven CIN and cancer and a convenience sample of HC2-positive, disease-negative women were tested for the presence of HPV-16 infection via HPV-16 E6 DNA-specific polymerase chain reaction. A PDZ interaction-mediated E6 oncoprotein precipitation method followed by E6-specific Western blot was performed on specimens from women with HPV-16 infections. Associations between elevated expression of E6 oncoprotein and CIN 2 and 3 were determined using logistic regression and a reference category of CIN 1 and disease-negative. RESULTS: A significant trend for the detection of HPV-16 E6 oncoprotein in specimen of women with proven HPV-16 infection was determined: 0% (0/12), 12.5% (1/8), 36.4% (4/11), and 42.9% (3/7) of those with negative findings, CIN 1, 2, and 3, respectively (p = .01). Compared with the category combining negative findings and CIN 1, detection of E6 oncoprotein was associated with CIN 2 (odds ratio = 10.9, p = .05) and CIN 3 (odds ratio = 14.3, p = .04). CONCLUSIONS: There is a significant association between elevated expression of E6 oncoprotein and grade of CIN. This finding seems consistent with the role played by E6 oncoprotein in carcinogenesis.
Assuntos
Proteínas Oncogênicas Virais/metabolismo , Proteínas Repressoras/metabolismo , Regulação para Cima , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Adulto , Western Blotting/métodos , Colo do Útero/patologia , China , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Imunoprecipitação , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Neoplasias do Colo do Útero/metabolismo , Displasia do Colo do Útero/metabolismoRESUMO
In a feasibility study using a prototype, lateral-flow test for human papillomavirus type 16, 18, and/or 45 (HPV16/18/45) E6 oncoproteins, 51 of 75 (68%; 95% confidence interval [95% CI] of 56 to 78%) of HPV16/18/45 DNA-positive specimens from women with a diagnosis of CIN3+ (cervical intraepithelial neoplasia grade 3+ or cervical cancer) tested positive for HPV16/18/45 E6 oncoprotein. None of 16 (95% CI of 0 to 37%) HPV16/18/45 DNA-positive cervical specimens from women with a negative or CIN1 diagnosis tested positive for HPV16/18/45 E6 oncoprotein.
Assuntos
Proteínas Oncogênicas Virais/análise , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/virologia , Virologia/métodos , Estudos de Viabilidade , Feminino , Humanos , Imunoensaio/métodosRESUMO
New, lower-cost tests that target high-risk human papillomavirus (HR-HPV) have been developed for cervical cancer screening in lower-resource settings but large, population-based screening studies are lacking. Women ages 25 to 65 years and living in rural China (n = 7,543) self-collected a cervicovaginal specimen, had 2 cervical specimens collected by a clinician, and underwent visual inspection after acetic acid (VIA). The self- and one clinician-collected specimens underwent HR-HPV DNA testing by careHPV (QIAGEN) and Hybrid Capture 2 (HC2; QIAGEN) and the other clinician-collected specimen was tested for HPV16, 18, and 45 E6 using OncoE6 (Arbor Vita Corporation). Women who screened positive for any test and a random sample of those negative on all tests underwent colposcopic evaluation. The percent test positive was 1.8% for HPV E6 oncoprotein, between 14% and 18% for HR-HPV DNA testing, and 7.3% for VIA. The sensitivity for cervical intraepithelial neoplasia grade 3 or more severe (CIN3(+); n = 99) was 53.5% for OncoE6, 97.0% for both careHPV and HC2 testing of the clinician-collected specimen, 83.8% for careHPV testing and 90.9% for HC2 testing of the self-collected specimen, and 50.5% for VIA. OncoE6 had the greatest positive predictive value (PPV), at 40.8% for CIN3(+), compared with the other tests, which had a PPV of less than 10%. OncoE6 tested 70.3% positive for HPV16, 18, or 45-positive CIN3(+) and tested negative for all HPV16-, 18-, or 45-negative CIN3(+) (P < 0.0001). HPV E6 oncoprotein detection is useful for identifying women who have cervical precancer and cancer.
Assuntos
Detecção Precoce de Câncer/economia , Infecções por Papillomavirus/economia , Displasia do Colo do Útero/economia , Neoplasias do Colo do Útero/economia , Adulto , Idoso , China , DNA Viral/genética , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Prognóstico , Curva ROC , Estudos Retrospectivos , População Rural , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/virologia , Esfregaço Vaginal , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/virologiaRESUMO
Human anal cancers are associated with high-risk human papillomaviruses (HPV) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including, but not limited to, their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors, whereas none of the like-treated nontransgenic mice showed tumors. Histopathologic analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer.
Assuntos
Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica , Modelos Animais de Doenças , Proteínas Oncogênicas Virais/fisiologia , Proteínas E7 de Papillomavirus/fisiologia , Proteínas Repressoras/fisiologia , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Neoplasias do Ânus/induzido quimicamente , Neoplasias do Ânus/virologia , Western Blotting , Carcinógenos/toxicidade , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Masculino , Camundongos , Camundongos Transgênicos , Papillomaviridae/genética , FenótipoRESUMO
PURPOSE: The implementation of vendor-based integrated clinical information technology was studied, and its effect on medication errors throughout the medication-use process in a health care system was evaluated. METHODS: The integrated systems selected for implementation included computerized physician order entry, pharmacy and laboratory information systems, clinical decision-support systems (CDSSs), electronic drug dispensing systems (EDDSs), and a bar-code point-of-care medication administration system. The primary endpoint was the reduction in related medication errors. Secondary endpoints included the reductions in medication order turnaround time and EDDS override transactions. RESULTS: Integrated clinical information system technology was implemented in a multihospital health care system with a phased-in approach. A positive effect of this integration on medication errors throughout the medication-use process was demonstrated. Most prescribing errors decreased significantly in the selected categories monitored, specifically drug allergy detection, excessive dosing, and incomplete or unclear orders. Pharmacists were also twice as likely to identify dosages requiring adjustment for renal insufficiency when the integrated technology was in place and more than six times as likely for drug levels outside of the therapeutic range. A positive effect on medication administration safety was also demonstrated: 73 administration-related errors were intercepted through electronic bar-code scanning for every 100,000 doses charted. CONCLUSION: Integration of clinical information system technology decreased selected types of medication errors throughout the medication-use process in a health care system and improved therapeutic drug monitoring in patients with renal insufficiency and in patients receiving drugs with narrow therapeutic ranges through the use of CDSS alerts.