title: Use of Cytology, E6/E7 mRNA, and p16INK4a-Ki-67 to Define the Management of Human Papillomavirus (HPV)-Positive Women in Cervical Cancer Screening.
abstract: OBJECTIVE
  We measured the accuracy of p16(INK4a)-Ki67 (CINtec PLUS, Roche, Mannheim, Germany), and E6/E7mRNA (types 16/18/31/33/45 NucliSENS easyQ, bioMérieux, Boxtel, The Netherlands) as triage test, alone and combined with cytology.
  
  
  METHODS
  Six thousand two hundred and seventy two women were recruited in a population-based screening using HPV DNA as primary test; 396 were positive and were tested for cytology and biomarkers. All tests were performed on the same sample. Cytology-positive women were referred to colposcopy; cytology-negative women were referred to one-year HPV re-testing. The endpoint was CIN2+ at baseline or follow up.
  
  
  RESULTS
  Sensitivity was 77.6% (95% confidence interval (CI) 65.3-86.7) and 53.2% (95%CI: 40.3-65.4) for cytology at atypical squamous cells of undetermined significance (ASC-US) and high-grade threshold, and 87.6% (95%CI:75.7-93.6), and 80.8% (95%CI: 67.6-89.8) for p16INK4a-Ki67, and E6/E7mRNA, respectively. Colposcopy referral was 36% (95%CI: 31.2-40.9) and 11.2% (95%CI: 7.8-14.1) for cytology at ASC-US and high-grade threshold, respectively, and 36.0% (95%CI: 29.9-29.6), and 47.5% (95%CI: 32.5-42.4) for p16(INK4a)-Ki67, and E6/E7mRNA, respectively. Strategies referring high-grade cytology or biomarker positive women to colposcopy reached sensitivity close to 100%, with modest increase in colposcopy referral.
  
  
  CONCLUSIONS
  The high sensitivity of combined strategies probably allows longer intervals in HPV-positive, triage-negative women.
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gustinucci
authors.affiliation: Servizio Interaziendale Di Epidemiologia, AUSL Reggio Emilia, Italy, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy, paolo.giorgirossi@ausl.re.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giorgi Rossi
authors.affiliation: Beneficiaria Di Un Aiuto Individuale per La Realizzazione Di Progetti Di Ricerca Co-Finanziato Dal Fondo Sociale Europeo (FSE) Nell'ambito Del Programma Operativo Regionale (POR) Umbria, FSE "Obiettivo Competitività Regionale E Occupazione" 2007-2013.
authors.forename: Elena
authors.initials: E
authors.lastname: Cesarini
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Broccolini
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bulletti
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Carlani
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: D'angelo
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'amico
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Di Dato
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Galeazzi
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Morena
authors.initials: M
authors.lastname: Malaspina
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Martinelli
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Spita
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Tintori
authors.affiliation: Sanità Veterinaria E Sicurezza Alimentare Regione Umbria, Servizio Prevenzione, Perugia, Italy.
authors.forename: Maria Donata
authors.initials: MD
authors.lastname: Giaimo
authors.affiliation: From Azienda USL Umbria 1 Perugia, Laboratorio Unico Di Screening, Perugia, Italy.
authors.forename: Basilio
authors.initials: B
authors.lastname: Passamonti
mesh_terms: D000328:Adult; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D003581:Cytodiagnosis; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D008875:Middle Aged; D027383:Papillomaviridae / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000175:diagnosis*; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen
keywords: Accuracy; Biomarkers; Cervical cancer; E6/E7 mRNA; HPV; Screening; p16INK4a