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Castle P.E.,American Society for Clinical Pathology Institute | Schiffman M.,U.S. National Cancer Institute
Journal of Clinical Microbiology | Year: 2012

High-risk human papillomavirus (HR-HPV) testing is increasingly important. We therefore examined the impact on accuracy of repeated versus one-time testing, type-specific versus pooled detection, and assay analytic sensitivity. By using a nested casecontrol design from the ASCUS-LSIL Triage Study, we selected women with incident cervical intraepithelial neoplasia grade 2 or grade 3 (CIN2/3; n = 325) and a random sample of women with Source

Castle P.E.,American Society for Clinical Pathology Institute | Stoler M.H.,University of Virginia | Wright T.C.,Columbia University | Sharma A.,Roche Molecular Systems | And 2 more authors.
The Lancet Oncology | Year: 2011

Background: The ATHENA study was designed to assess the performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping compared with liquid-based cytology for cervical cancer screening in a large US population aged 21 years and older. We did a subanalysis of this population to compare the screening performance of the cobas HPV test versus liquid-based cytology in women aged 25 years and older, and assess management strategies for HPV-positive women. Methods: Women aged 25 years or older who were attending routine cervical screening were enrolled from 61 clinical centres in 23 US states. Cervical specimens were obtained for liquid-based cytology and HPV DNA testing with two first-generation assays (Amplicor HPV test and Linear Array HPV genotyping test) and the second-generation cobas HPV test (with individual HPV16 and HPV18 detection). Colposcopy and diagnostic biopsies were done on women with atypical squamous cells of undetermined significance (ASC-US) or worse cytology, those who tested positive with either first-generation HPV test, and a random sample of women who tested negative for HPV and cytology. All women not selected for colposcopy received their results and exited the study. Participants and colposcopists were masked to cytology and HPV test results until the colposcopy visit was completed. The primary endpoint for this substudy was histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3) or worse. This study is registered with ClinicalTrials.gov, number NCT00709891; the study is in the follow-up phase, which is due to be completed in December, 2012. Findings: From May 27, 2008, to Aug 27, 2009, 47 208 women were enrolled, of whom 41 955 met our eligibility criteria. Valid cobas HPV and liquid-based cytology test results were available for 40 901 women (97%), who were included in this analysis. Of these, 4275 women (10%) tested cobas HPV positive and 2617 (6%) had abnormal cytology. 431 women were diagnosed with CIN2 or worse and 274 with CIN3 or worse. In women who had colposcopy, the cobas HPV test was more sensitive than liquid-based cytology for detection of CIN3 or worse (252/274 [92·0%, 95% CI 88·1-94·6] vs 146/274 [53·3%, 95% CI 47·4-59·1]; difference 38·7%, 95% CI 31·9-45·5; p<0·0001). Addition of liquid-based cytology to HPV testing increased sensitivity for CIN3 or worse to 96·7% (265/274, 95% CI 93·9-98·3), but increased the number of screen positives by 35·2% (5783/40 901 vs 4275/40 901) compared with HPV testing alone. As a triage test to identify CIN3 or worse in HPV-positive women, detection of HPV16, HPV18, or both alone was equivalent to detection of ASC-US or worse alone in terms of sensitivity (150/252 [59·5%] vs 133/252 [52·8%]; p=0·11) and positive predictive value (PPV) (150/966 [15·5%] vs 133/940 [14·1%]; p=0·20). Among HPV-positive women, detection of HPV16, HPV18, or both or low-grade squamous intraepithelial lesion or worse cytology had better sensitivity (182/252 [72·2%]; p<0·0001) and similar PPV (182/1314 [13·9%]; p=0·70) for detection of CIN3 or worse than ASC-US or worse cytology alone. Furthermore, detection of HPV16, HPV18, or both or high-grade squamous intraepithelial lesion or worse cytology had higher sensitivity (165/252 [65·5%]; p=0·0011) and PPV (165/1013 [16·3%]; p=0·031) for detection of CIN3 or worse than ASC-US or worse cytology alone. Interpretation: HPV testing with separate HPV16 and HPV18 detection could provide an alternative, more sensitive, and efficient strategy for cervical cancer screening than do methods based solely on cytology. Funding: Roche Molecular Systems. © 2011 Elsevier Ltd. Source

Castle P.E.,American Society for Clinical Pathology Institute | Gravitt P.E.,Johns Hopkins University | Wentzensen N.,U.S. National Institutes of Health | Schiffman M.,U.S. National Institutes of Health
American Journal of Clinical Pathology | Year: 2012

Cervical intraepithelial neoplasia grade 3 (CIN 3) is the best proxy in research and screening for invasive cancer risk. Yet the timing of CIN 3 development is uncertain because of measurement errors integral to its diagnosis. We were interested in estimating the proportions of prevalent vs incident CIN 3 within 2 years of finding a minor cytologic abnormality. We estimate that only 17 (2.8%) of 613 CIN 3 cases diagnosed during the 2-year duration of the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) triage study (ALTS) were incident CIN 3 following an incident human papillomavirus (HPV) infection that persisted until the CIN 3 diagnosis was made. Using prevalent high-grade cytology as a marker of prevalent CIN 3, we estimated that another approximately 23% of CIN 3 cases were incident CIN 3 following a prevalently detected HPV infection that persisted until the CIN 3 diagnosis was made. We concluded that most CIN 3 cases diagnosed within the 2-year time frame were prevalent cases, and most incident CIN 3 cases followed a prevalently detected HPV infection. Copyright© by the American Society for Clinical Pathology. Source

Guan Y.,Johns Hopkins University | Castle P.E.,American Society for Clinical Pathology Institute | Wang S.,Peking Union Medical College | Li B.,Peking Union Medical College | And 5 more authors.
Sexually Transmitted Infections | Year: 2012

Objective: To assess the acceptability of using self-collection as a method of sampling for human papilloma virus testing in rural China. Methods: 174 women from the national cervical cancer screening programme in Xiangyuan County, China, were enrolled in our study and underwent self-collection, clinician collection, colposcopy examination and were administered questionnaire. The questionnaire assessed the patients' preference and acceptability of collection method. Results: The mean overall acceptability score for self-collection, although significantly less than the overall score for clinician collection (p<0.01), still is well above 4 (4.33 of 5), indicating high acceptability. The acceptability scores for self-collection and clinician collection were not significantly different on scales measuring comfort and convenience (p>0.05). The scores were significantly lower for self-collection on scales measuring trust, ability to collect specimen and perceived effects of testing compared with clinician collection (p<0.01). 74% of participants preferred clinician collection, and of these participants, 86% preferred it because they thought the results were more accurate. Conclusions: The study shows that self-collection was highly acceptable and that self-collection and clinician collection were equally comfortable and convenient; however, the participants still preferred clinician collection because of lack of trust in the results of self-collection. This indicates that self-collection is an acceptable potential method for screening but education programmes about the validity of self-collection that target general population may be needed prior to implementation. Source

Darragh T.M.,University of California at San Francisco | Tokugawa D.,Kaiser Permanente | Castle P.E.,American Society for Clinical Pathology Institute | Follansbee S.,Kaiser Permanente | And 7 more authors.
Cancer Cytopathology | Year: 2013

BACKGROUND: The majority of anal cancers are caused by persistent infections with carcinogenic human papillomaviruses (HPV). Similar to cervical carcinogenesis, the progression from HPV infection to anal cancer occurs through precancerous lesions that can be treated to prevent invasion. In analogy to cervical cytology, anal cytology has been proposed as a screening tool for anal cancer precursors in high-risk populations. METHODS: The authors analyzed the interobserver reproducibility of anal cytology in a population of 363 human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Liquid-based cytology (LBC) specimens were collected in the anal dysplasia clinic before the performance of high-resolution anoscopy on all patients. Papanicolaou-stained LBC slides were evaluated by 2 cytopathologists, each of whom was blinded to the clinical outcome and the other pathologist's results, using the revised Bethesda terminology. RESULTS: Overall agreement between the 2 observers was 66% (kappa, 0.54; linear-weighted kappa, 0.69). Using dichotomizing cytology results (atypical squamous cells of undetermined significance [ASC-US] or worse vs less than ASC-US), the agreement increased to 86% (kappa, 0.69). An increasing likelihood of testing positive for markers associated with HPV-related transformation, p16/Ki-67, and HPV oncogene messenger RNA was observed, with increasing severity of cytology results noted both for individual cytologists and for consensus cytology interpretation (P value for trend [ptrend] < .0001 for all). CONCLUSIONS: Moderate to good agreement was observed between 2 cytopathologists evaluating anal cytology samples collected from HIV-positive MSM. A higher severity of anal cytology was associated with biomarkers of anal precancerous lesions. Anal cytology may be used for anal cancer screening in high-risk populations, and biomarkers of HPV-related transformation can serve as quality control for anal cytology. Source

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