Accuracy of different triage strategies for human papillomavirus positivity in an Italian screening population.

How to manage human papillomavirus (HPV)-positive women in cervical cancer screening remains debated. Our study compared different strategies to triage HPV positivity in a large cohort of women participating in a population HPV-based screening program. Women were tested for HPV (Cobas 4800; Roche), and those positive were triaged with cytology; cytology-positives were referred to colposcopy, while negatives were referred to 1-year HPV retesting. All HPV-positive women were also evaluated with p16/ki67 dual staining (Roche). All lesions found within 24 months of follow-up were included in the analyses. Of the 70 146 women tested, 4757 (6.8%) were HPV-positive. Of these, 1090 were cytology-positive and were referred to colposcopy. Of the 2958 HPV-positive/cytology-negative women who presented at 1-year retesting, 1752 (59.9%) still tested positive. Cumulatively, 532 CIN2+ (including 294 CIN3+) were found. The sensitivity of cytology, HPV16/18 and p16/ki67 as triage test for CIN3+ was 67.9%, 56.0% and 85.0%, respectively. The positive predictive value (PPV) for immediate colposcopy referral was 21.0%, 15.8% and 22.9%, respectively. Combining cytology with typing increased sensitivity to 83.9% and lowered PPV to 14.8%, while combining p16/ki67 and typing increased sensitivity to 91.1%, lowering the PPV to 15.9%. Women negative to p16/ki67 triage presented a cumulative 1-year CIN3+ risk of about 1%. In conclusion, when triaging HPV positivity, p16/ki67 performed better than cytology with or without HPV16/18 genotyping. The strategies that included dual staining achieved sensitivity and low 1-year risk for CIN3+ sufficiently high enough to permit considering extending the surveillance interval to 2 to 3 years for HPV-positive/triage-negative women.

Geospatial analysis of the influence of family doctor on colorectal cancer screening adherence.

BACKGROUND: Despite the well-recognised relevance of screening in colorectal cancer (CRC) control, adherence to screening is often suboptimal. Improving adherence represents an important public health strategy. We investigated the influence of family doctors (FDs) as determinant of CRC screening adherence by comparing each FDs practice participation probability to that of the residents in the same geographic areas using the whole population geocoded. METHODS: We used multilevel logistic regression model to investigate factors associated with CRC screening adherence, among 333,843 people at their first screening invitation. Standardized Adherence Rates (SAR) by age, gender, and socioeconomic status were calculated comparing FDs practices to the residents in the same geographic areas using geocoded target population. RESULTS: Screening adherence increased from 41.0% (95% CI, 40.8-41.2) in 2006-2008 to 44.7% (95% CI, 44.5-44.9) in 2011-2012. Males, the most deprived and foreign-born people showed low adherence. FD practices and the percentage of foreign-born people in a practice were significant clustering factors. SAR for 145 (21.4%) FDs practices differed significantly from people living in the same areas. Predicted probabilities of adherence were 31.7% and 49.0% for FDs with low and high adherence, respectively. DISCUSSION: FDs showed a direct and independent effect to the CRC screening adherence of the people living in their practice. FDs with significantly high adherence level could be the key to adherence improvement. IMPACT: Most deprived individuals and foreigners represent relevant targets for interventions in public health aimed to improve CRC screening adherence.

A comparative effectiveness trial of two faecal immunochemical tests for haemoglobin (FIT). Assessment of test performance and adherence in a single round of a population-based screening programme for colorectal cancer.

AIM: To compare acceptability and diagnostic accuracy of a recently available faecal immunochemical test (FIT) system (HM-JACKarc) with the FIT routinely used in an established screening programme (OC-Sensor). DESIGN: Randomised controlled trial (ISRCTN20086618) within a population-based colorectal cancer (CRC) screening programme. Subjects eligible for invitation in the Umbria Region (Italy) programme were randomised (ratio 1:1) to be screened using one of the FIT systems. RESULTS: Screening uptake among the 48 888 invitees was the same for both systems among subjects invited in the first round and higher with OC-Sensor than with HM-JACKarc (relative risk (RR): 1.03; 95% CI 1.02 to 1.04) among those invited in subsequent rounds. Positivity rate (PR) was similar with OC-Sensor (6.5%) as with HM-JACKarc (6.2%) among subjects performing their first FIT screening and higher with OC-Sensor (5.6%, RR: 1.25, 95% CI 1.12 to 1.40) than with HM-JACKarc (4.4%) among those screened in previous rounds. Positive predictive value (PPV) (OC-Sensor: 25.9%, HM-JACKarc: 25.6%) and detection rate (DR) (OC-Sensor: 1.40%; HM-JACKarc: 1.42%) for advanced neoplasia (AN: CRC + advanced adenoma) were similar among subjects performing their first FIT screening. The differences in the AN PPV (OC-Sensor: 20.3%, HM-JACKarc: 22.6%) and DR (OC-Sensor: 0.96%, HM-JACKarc: 0.83%) among those screened in previous rounds were not statistically significant. The number needed to scope to detect one AN was 3.9 (95% CI 5.8 to 2.9) and 3.9 (95% CI 5.5 to 2.9) at first and 4.9 (95% CI 5.8 to 4.2) and 4.4 (95% CI 5.3 to 3.7) at subsequent screening, with OC-Sensor and HM-JACKarc, respectively. CONCLUSIONS: Our results suggest that acceptability and diagnostic performance of HM-JACKarc and of OC-Sensor systems are similar in a screening setting. TRIAL REGISTRATION NUMBER: ISRCTN20086618; Results.

Guidance for faecal occult blood testing: quantitative immunochemical method (FIT-HB) in colorectal cancer screening programmes. / Guida per la determinazione del sangue occulto fecale: metodo immunochimico quantitativo (FIT-HB) nei programmi di screening per il carcinoma colorettale

BACKGROUND: in Italy, colorectal cancer screening is included as part of the Italian National Health Service - SSN (Servizio Sanitario Nazionale) Essential Levels of Care - LEA (Livelli Essenziali Assistenziali) and the European Guidelines, which specify quantitative FIT-Hb testing as the best strategy for organised screening programmes. To ensure consistent operating standards in Member States, European regulations require the implementation of certification and accreditation requirements for diagnostic and care-related processes. The requirement, based on ISO 17021 accreditation standards, includes ISO 9001 certification for systems and ISO 15189:2012 accreditation for laboratories. METHODOLOGY: various phases of the analytical process (pre-test, test, post-test) were evaluated in detail and provided operational guidelines for adjusting analytical and managerial procedures using: (a) feedback from members of GISCoR screening labs; (b) performance data obtained via a systematic review of the literature and the Osservatorio Nazionale Screening (ONS) Survey; (c) recommendations for laboratory practice issued by the World Endoscopy Organization "FIT for Screening" Working Group; (d) selected guidelines from the National Guidelines Clearinghouse database; and (e) Canadian, Australian and European screening programme websites. With respect to ISO 15189:2012 standards for accreditation of medical laboratories, GISCoR's guidance has been re-evaluated and revised by auditors from the Italian certification body (ACCREDIA) to assess its compliance and completeness with the aim of finalising operating procedures. CONCLUSIONS: the implementation and maintenance of operational standards required by complex systems (e.g. screening programmes) involving constant interaction between facilities and the supporting organisational structure are not easy to achieve. The guide aims to provide laboratories with the necessary guidance for proper process management.

Cervical human papilloma virus (HPV) DNA primary screening test: Results of a population-based screening programme in central Italy.

Objective To present the results of the first and second round human papilloma virus (HPV)-based screening programme in the Umbria region after three years. Methods From August 2010 to November 2011, the entire female population aged 35-64 in a local health district was invited for HPV testing (HPV-DNA cobas4800 on a liquid-based cytology sample). HPV-negative women were re-invited after three years. For HPV-positive women, a slide was prepared and interpreted. Positive cytologies were referred to colposcopy; negatives were referred to repeat HPV after one year. If HPV was persistently positive, women were referred to colposcopy; if negative, to normal screening. Indicators of the first and second round are compared with those of cytology screening in the same area in the preceding three years. Results Participation was 56.5%, the same as cytology (56.6%). HPV-positivity was 6.4% (396/6272), cytology triage positivity was 35.6%; 251 cytology negative women were referred to one-year HPV retesting, 84.1% complied, and 55.5% were positive. Total colposcopy referral was 4.1%, and for cytology 1%. The detection rate for cervical intraepithelial neoplasia grade 2 or more severe was 10‰, compared with 3.7‰ using cytology. After three years, HPV-positivity was 3.4% (129/3831), overall colposcopy referral was 2.3% (most at one-year follow-up), and detection rate was 0.5/1000. Conclusions The first round detection rate was more than twice that of cytology screening, while colposcopy referral increased fourfold. At the second round, the detection rate decreased dramatically, showing that longer interval and more conservative protocols are needed.

Use of Cytology, E6/E7 mRNA, and p16INK4a-Ki-67 to Define the Management of Human Papillomavirus (HPV)-Positive Women in Cervical Cancer Screening.

OBJECTIVES: 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.

Role of p16(INK4a) cytology testing as an adjunct to enhance the diagnostic specificity and accuracy in human papillomavirus-positive women within an organized cervical cancer screening program.

OBJECTIVE: We evaluated the performance of cytologic p16(INK4a) (p16) immunostaining within a cervical cancer screening program for the categories of atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LS after triage with high-risk human papillomavirus (HR-HPV) testing and atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesion (ASC-H) and high-grade squamous intraepithelial lesion (HSIL). We also verified whether the routine introduction of p16 staining might enhance the specificity and positive predictive value (PPV) for cervical intraepithelial neoplasia grade 2 or higher (CIN2+) lesions predicted by a cytological screening test. STUDY DESIGN: Performance of the p16 cytology test was estimated in 578 cytological samples, of which 213 were HR-HPV+ ASC-US, 186 were HR-HPV+ LSIL, 74 were ASC-H, 56 were HSIL-CIN2 and 49 were HSIL-CIN3. All samples had histological follow-up. RESULTS: In the ASC-US category, p16 sensitivity was 91% for CIN2+ and 100% for CIN3, while specificity was 64 and 58%, respectively, negative predictive value (NPV) was 96 and 100%, respectively, and PPV was 39%. In the LSIL category, sensitivity was 77 and 75%, respectively, for CIN2+ and CIN3, while specificity was 64 and 57%, NPV was 93 and 98% and PPV was 30%. Sensitivity for ASC-H and HSIL-CIN3 was 100% for CIN2+ and CIN3, while for HSIL-CIN2 it was 91 and 95%, respectively; NPV for ASC-H was 100%, and for HSIL-CIN2 it was 43 and 86%, respectively. Follow-up examinations of 8 cases diagnosed as p16+ ASC-H and HSIL-CIN3, but histologically negative or CIN1 on the first biopsy, showed 4 CIN2 and 4 CIN3 lesions. CONCLUSIONS: Sensitivity, specificity, PPV and NPV confirm the importance of the utilization of p16 in the categories ASC-US and LSIL after triage with an HR-HPV test. In the ASC-H and HSIL-CIN3 lesions, p16 was shown to be an excellent marker for picking up CIN2+ lesions, especially in cases with cytohistological discordance.

Evaluation of the FocalPoint GS system performance in an Italian population-based screening of cervical abnormalities.

OBJECTIVE: To evaluate the FocalPoint Location-Guided Screening (FPGS) performance in computer-assisted primary screening of Papanicolaou-stained cervicovaginal smears. STUDY DESIGN: A total of 37,306 routine consecutive conventional Pap slides were prospectively processed on the FPGS. Each slid designated by the instrument as Review was reported according to results obtained using a GS Review Station. Subsequently, all slides under went conventional manual rapid screening and reported results were compared. RESULTS: Of the slides initially submitted to the FPGS, 34,004 (91.15%) were qualified for scanning. Within these slides, the system classified 7,399 (21.8%) as needing No Further Review and ranked to Review the remaining 26,605 (78.2%). Of the 418 cellular abnormalities found, 409 were classified for Review by FPGS and 9 minor grade lesions were classified in the "No Further Review" population. Overall, 352 (86%) of atypical squamous cell (ASC)+ were ranked in high-score quintiles, including 96 (94%) of the 102 high-grade squamous intraepithelial lesion (HSIL) or worse. Location-guided software identified cellular abnormalities, in the automatically selected fields of view, in 378 (92%) of the ranked abnormal slides, showing a sensitivity > 95% on SILs. CONCLUSION: Slide ranking and location-guided screening features are of value in detecting and triaging abnormal smears.