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Cergy-Pontoise, France

Von Knebel Doeberitz M.,University of Heidelberg | Reuschenbach M.,University of Heidelberg | Schmidt D.,Institute of Pathology Mannheim | Bergeron C.,Laboratoire Cerba
Expert Review of Proteomics | Year: 2012

Biomarkers indicating the initiation of neoplastic transformation processes in human papillomavirus (HPV)-infected epithelial cells are moving into the focus of cancer prevention research, particularly for anogenital cancer, including cancer of the uterine cervix. Based on the in-depth understanding of the molecular events leading to neoplastic transformation of HPV-infected human cells, the cyclin-dependent kinase inhibitor p16 INK4a turned out to be substantially overexpressed in virtually all HPV-transformed cells. This finding opened novel avenues in diagnostic histopathology to substantially improve the diagnostic accuracy of cervical cancer and its precursor lesions. Furthermore, it provides a novel technical platform to substantially improve the accuracy of cytology-based cancer early-detection programs. Here, we review the molecular background and the current evidence for the clinical utility of the p16 INK4a biomarker for HPV-related cancers, and cervical cancer prevention in particular. © 2012 Expert Reviews Ltd.

Roelens J.,Scientific Institute of Public Health | Reuschenbach M.,University of Heidelberg | Reuschenbach M.,German Cancer Research Center | Von Knebel Doeberitz M.,University of Heidelberg | And 4 more authors.
Cancer Cytopathology | Year: 2012

The best method for identifying women who have minor cervical lesions that require diagnostic workup remains unclear. The authors of this report performed a meta-analysis to assess the accuracy of cyclin-dependent kinase inhibitor 2A (p16INK4a) immunocytochemistry compared with high-risk human papillomavirus DNA testing with Hybrid Capture 2 (HC2) to detect grade 2 or greater cervical intraepithelial neoplasia (CIN2+) and CIN3+ among women who had cervical cytology indicating atypical squamous cells of undetermined significance (ASC-US) or low-grade cervical lesions (LSIL). A literature search was performed in 3 electronic databases to identify studies that were eligible for this meta-analysis. Seventeen studies were included in the meta-analysis. The pooled sensitivity of p16INK4a to detect CIN2+ was 83.2% (95% confidence interval [CI], 76.8%-88.2%) and 83.8% (95% CI, 73.5%-90.6%) in ASC-US and LSIL cervical cytology, respectively, and the pooled specificities were 71% (95% CI, 65%-76.4%) and 65.7% (95% CI, 54.2%-75.6%), respectively. Eight studies provided both HC2 and p16INK4a triage data. p16 INK4a and HC2 had similar sensitivity, and p16INK4a has significantly higher specificity in the triage of women with ASC-US (relative sensitivity, 0.95 [95% CI, 0.89-1.01]; relative specificity, 1.82 [95% CI, 1.57-2.12]). In the triage of LSIL, p16INK4a had significantly lower sensitivity but higher specificity compared with HC2 (relative sensitivity, 0.87 [95% CI, 0.81-0.94]; relative specificity, 2.74 [95% CI, 1.99-3.76]). The published literature indicated the improved accuracy of p16INK4a compared with HC2 testing in the triage of women with ASC-US. In LSIL triage, p16INK4a was more specific but less sensitive. (See related Commentary on pages OO-OO, this issue.). © 2012 American Cancer Society.

Costa J.-M.,Laboratoire Of Parasitologie Mycologie | Costa J.-M.,Laboratoire Cerba | Bretagne S.,Laboratoire Of Parasitologie Mycologie | Bretagne S.,University Paris Est Creteil
Journal of Clinical Microbiology | Year: 2012

Using the multicopy B1 gene and AF146527 element for the amplification of Toxoplasma gondii DNA raises the issue of reliable quantification for clinical diagnosis. We applied relative quantification to reference strains using the single-copy P30 gene as a reference. According to the parasite type, the copy numbers for the B1 gene and AF146527 element were found to be 5 to 12 and 4 to 8 times lower than the previous estimations of 35 and 230 copies, respectively. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Bergeron C.,Laboratoire Cerba | Ordi J.,Clinic Hospital Universitari | Schmidt D.,Institute of Pathology | Trunk M.J.,MTM Laboratories | And 3 more authors.
American Journal of Clinical Pathology | Year: 2010

The histopathologic interpretation of cervical intraepithelial neoplasia (CIN) is subject to a high level of interobserver variability and a substantial number of false-positive and false-negative results. We assessed the impact of the conjunctive interpretation of p16INK4a-immunostained slides on the accuracy of community-based pathologists in diagnosing high-grade cervical intraepithelial neoplasia (CIN; CIN 2 and CIN 3) in biopsy specimens. Twelve pathologists rendered independent diagnoses on a set of 500 H&E-stained cervical punch and conization specimens. Results were compared with a dichotomized "gold standard" established by consensus of 3 gynecopathology experts. When p16INK4a-immunostained slides were added and conjunctively interpreted with the H&E-stained slides, a significant increase in diagnostic accuracy for the detection of high-grade CIN was observed (P = .0004). Sensitivity for high-grade CIN was increased by 13%, cutting the rate of false-negative results in half. Agreement of community-based pathologists in diagnosing high-grade CIN was significantly improved (mean κ values advanced from 0.566 to 0.749; P < .0001). Reproducibility of p16INK4a stain interpretation was excellent ( κ = 0.899). Our results show that conjunctive interpretation of p16INK4a-stained slides could significantly improve the routine interpretation of cervical histopathology. © American Society for Clinical Pathology.

Schmidt D.,Institute of Pathology | Bergeron C.,Laboratoire Cerba | Denton K.J.,North Bristol NHS Trust | Ridder R.,MTM Laboratories
Cancer Cytopathology | Year: 2011

BACKGROUND: The objective of this study was to analyze the diagnostic performance of a newly established immunocytochemical dual-stain protocol, which simultaneously detects p16INK4a and Ki-67 expression in cervical cytology samples, for identifying high-grade cervical intraepithelial neoplasia (CIN2+) in women with Papanicolaou (Pap) cytology results categorized as atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesions (LSIL). METHODS: Residual liquidbased cytology material from 776 retrospectively collected ASCUS/LSIL cases that were available from a recent study evaluating p16 cytology and HPV testing were subjected to p16/Ki-67 dual staining. The presence of 1 or more double-immunoreactive cell(s) was regarded as a positive test outcome, irrespective of morphology. Test results were correlated to histology follow-up. RESULTS: Sensitivity of p16/Ki-67 dualstain cytology for biopsy-confirmed CIN2+ was 92.2% (ASCUS) and 94.2% (LSIL), while specificity rates were 80.6% (ASCUS) and 68.0% (LSIL), respectively. Similar sensitivity/specificity profiles were found for both age groups of women aged <30 years versus women aged ≥30 years. Dual-stain cytology showed comparable sensitivity, but significantly higher specificity, when compared with human papillomavirus (HPV) testing. CONCLUSIONS: The results of this study show that p16/Ki-67 dual-stain cytology provided a high sensitivity for the detection of underlying CIN2+ in women with ASCUS or LSIL Pap cytology results, comparable to the rates previously reported for HPV testing and p16 single-stain cytology. However, the specificity of this morphology-independent interpretation of p16/Ki-67 dual-stain cytology testing was further improved compared with the earlier p16 single-stain cytology approach, which required morphology interpretation, and it is significantly higher when compared with HPV testing. Cancer (Cancer Cytopathol) 2011;119:158-66. © 2011 American Cancer Society.

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