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Ikenberg H.,Cytomol | Bergeron C.,Laboratoire Cerba | Schmidt D.,Institute for Pathology | Griesser H.,Cytodiagnostics | And 13 more authors.
Journal of the National Cancer Institute | Year: 2013

Background: Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2+ in screening while maintaining high specificity. Results were compared with Pap cytology and HPV testing. Methods: A total of 27349 women 18 years or older attending routine cervical cancer screening were prospectively enrolled in five European countries. Pap cytology, p16/Ki-67 immunostaining, and HPV testing were performed on all women. Positive test results triggered colposcopy referral, except for women younger than 30 years with only positive HPV test results. Presence of CIN2+ on adjudicated histology was used as the reference standard. Two-sided bias-corrected McNemar P values were determined. Results: The p16/Ki-67 dual-stained cytology positivity rates were comparable with the prevalence of abnormal Pap cytology results and less than 50% of the positivity rates observed for HPV testing. In women of all ages, dual-stained cytology was more sensitive than Pap cytology (86.7% vs 68.5%; P <. 001) for detecting CIN2+, with comparable specificity (95.2% vs 95.4%; P =. 15). The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older. HPV testing in women 30 years or older was more sensitive than dual-stained cytology (93.3% vs 84.7%; P =. 03) but less specific (93.0% vs 96.2%; P <. 001). Conclusions: The p16/Ki-67 dual-stained cytology combines superior sensitivity and noninferior specificity over Pap cytology for detecting CIN2+. It suggests a potential role of dual-stained cytology in screening, especially in younger women where HPV testing has its limitations. © The Author 2013. Published by Oxford University Press.


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.


Denton K.J.,North Bristol NHS Trust | Bergeron C.,Laboratoire Cerba | Klement P.,MTM Laboratories | Trunk M.J.,MTM Laboratories | And 3 more authors.
American Journal of Clinical Pathology | Year: 2010

We analyzed the performance of p16INK4a immunocytochemistry on a series of 810 retrospectively collected atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cases with available biopsy follow-up data, including 94 cases of cervical intraepithelial neoplasia (CIN) 2 and 128 cases of CIN 3. Human papillomavirus (HPV) testing was performed from the same residual liquid-based cytologic specimen, and results for both tests were correlated with histologic follow-up data. Sensitivity values for high-grade CIN (HGCIN) confirmed on biopsy within 6 months were 92.6% (ASC-US) and 92.2% (LSIL) for cytotechnologists' reviews of p16 cytology and 90.1% (ASC-US) and 95.7% (LSIL) for HPV testing. Sensitivity rates of initial pathologists' reviews were slightly lower, 76.4% to 80.1%, with levels comparable to cytotechnologists' results after adjudication. The specificity of p16 cytology for HGCIN detection was significantly higher than for HPV testing for cytotechnologists and pathologists: 63.2% to 71.1% (p16 cytology) vs 37.8% for HPV in ASC-US (P < .001) and 37.3% to 53.3% (p16 cytology) vs 18.5% for HPV in LSIL (P < .001). This evaluation of the diagnostic performance of p16 cytology confirms the potential of this stain for the efficient triage of ASC-US and LSIL cytologic results. © American Society for Clinical Pathology.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.2.4.1-3 | Award Amount: 4.19M | Year: 2011

Human papillomavirus (HPV) is responsible for approximately 25% of head and neck cancer (HNC) worldwide and appears to be associated with a better response to treatment and improved prognosis. Evidence suggests that HPV-induced HNC has steadily increased in the USA and some European countries in the last decades. However, whether this is a worldwide phenomenon and specific risk factors are associated with it remains to be proven. In addition, little is known on the natural history and risk factors of oral HPV infection. HPV-AHEAD network aims to address these and other unanswered questions on HNC etiology and epidemiology with a focus on the role of HPV. We will assemble and analyze a large collection of plasma/sera and HNC tissues from 42 centres in 16 European countries as well as HNC tissues from 7 Indian centres together with epidemiological and clinical data. HPV status in human specimens will be evaluated by different assays in central laboratories. Epidemiological studies will be conducted to establish the overall proportion and type distribution of HPV-positive HNC at different anatomical sites in European and Indian regions as well as the time trend of the proportion of HPV-positive HNC in recent decades. Using the follow-up information on HNC patients, we will further investigate whether HPV positivity confers a better prognosis and survival. We will also conduct a study in HPV-vaccinated and non-vaccinated women in order to determine risk factors and natural history of oral HPV infections. In addition, we will search for new surrogate markers for oral HPV infection to facilitate novel screening strategies. Finally, the HPV-AHEAD consortium aims to transfer technology to Indian centres as well as to develop several strategies for the training of European and Indian researchers in infections and cancers. This study will provide important insights for the screening, diagnosis, treatment and prophylaxis of HPV-associated HNC in Europe, India and elsewhere.


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.


The present invention relates to a method for discrimination of p16^(INK4a )overexpressing metaplasias from neoplastic or preneoplastic p16^(INK4a )overexpressing lesions by determination of the level of high risk HPV encoded gene-products such as e.g. HPV E2 and/or HPV E7 molecules in biological samples in the course of cytological testing procedures. The method thus enables for reduction of false positive results in the p16^(INK4a )based detection of anogenital lesions in cytological testing procedures.


Patent
MTM Laboratories | Date: 2013-03-13

The present invention relates to a method for improved diagnosis of dysplasias based on simultaneous detection of INK4a gene products and at least one marker for cell proliferation. Particularly the present invention provides a method for discriminating dysplastic cells over-expressing INK4a gene products from cells over-expressing INK4a gene products without being dysplastic by detection of a marker suitable for characterising the proliferation properties of the respective cell. The characterisation of the proliferation properties may comprise the detection of a marker or a set of markers characteristic for active cell proliferation and/or a marker or a set of markers characteristic for retarded or ceased cell proliferation. The method presented herein thus enables for a specific diagnosis of dysplasias in histological and cytological specimens.


Patent
MTM Laboratories | Date: 2013-03-13

The present invention relates to a method for improved diagnosis of dysplasias based on simultaneous detection of INK4a gene products and at least one marker for cell proliferation. Particularly the present invention provides a method for discriminating dysplastic cells over-expressing INK4a gene products from cells over-expressing INK4a gene products without being dysplastic by detection of a marker suitable for characterising the proliferation properties of the respective cell. The characterisation of the proliferation properties may comprise the detection of a marker or a set of markers characteristic for active cell proliferation and/or a marker or a set of markers characteristic for retarded or ceased cell proliferation. The method presented herein thus enables for a specific diagnosis of dysplasias in histological and cytological specimens.


Patent
MTM Laboratories | Date: 2014-07-24

The present invention relates to compounds and methods useful for the detection and treatment of disorders associated with frameshift mutations in coding microsatellite regions. The compounds and methods are applicable in cancers, especially of DNA mismatch repair deficient (MMR) sporadic tumors and HNPCC associated tumors. The compounds are useful for detection of disorders and in therapy such as immuno-therapy. The diagnostic methods relate to diagnosis and prognostic assessment of disorders associated with frameshift polypeptides originating from frameshift mutations in coding microsatellite regions of genes based on the detection of immunological entities directed against said frameshift polypeptides in body fluids. With respect to the treatment of cancer, the invention pertains to methods which use immuno therapy with combinatorial mixtures of tumor specific frameshift peptides to elicit a cytotoxic T-cell response specifically directed against tumor cells for prevention and curative treatment of cancers and pre-cancers.


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