[show abstract][hide abstract] ABSTRACT: Colposcopy, the key step in the management of women with abnormal Pap smear results, is a visual technique prone to observer variation, which implies the need for prolonged apprenticeship, continuous training, and quality assurance (QA) measures. Colposcopy QA programmes vary in level of responsibility of organizing subjects, geographic coverage, scope, model, and type of actions. The programmes addressing the clinical standards of colposcopy (quality of examination and appropriateness of clinical decisions) are more limited in space and less sustainable over time than those focused on the provision of the service (resources, accessibility, etc.). This article reports on the protocol of a QA programme targeting the clinical quality of colposcopy in a population-based cervical screening service in an administrative region of northern Italy.Methods/design: After a situation analysis of local colposcopy audit practices and previous QA initiatives, a permanent web-based QA programme was developed. The design places more emphasis on providing education and feedback to participants than on testing them. The technical core is a log-in web application accessible on the website of the regional Administration. The primary objectives are to provide (1) a practical opportunity for retraining of screening colposcopists, and (2) a platform for them to interact with colposcopists from other settings and regions through exchange and discussion of digital colposcopic images. The retraining function is based on repeated QA sessions in which the registered colposcopists log-in, classify a posted set of colpophotographs, and receive on line a set of personal feedback data. Each session ends with a plenary seminar featuring the presentation of overall results and an interactive review of the test set of colpophotographs. This is meant to be a forum for an open exchange of views that may lead to more knowledge and more diagnostic homogeneity. The protocol includes the criteria for selection of colpophotographs and the rationale for colposcopic gold standards.
This programme is an ongoing initiative open to further developments, in particular in the area of basic training. It uses the infrastructure of the internet to give a novel solution to technical problems affecting colposcopy QA in population-based screening services.
BMC Health Services Research 06/2013; 13(1):237. · 1.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Although among women a decreasing prevalence of human papillomavirus (HPV) infection with increasing age has been consistently observed in high-resource countries, different age profiles have been reported elsewhere. METHODS: We compared the age profile of high-risk (HR)-HPV prevalence in nine different areas of Northern and Central Italy by studying the women recruited in the intervention arm of the New Technologies in Cervical Cancer study and tested by Hybrid Capture 2. Differences in the age-distribution of HPV infection were investigated in each centre by the joinpoint approach in a logistic model. 46,900 women aged 25 to 60 years were included in the analysis. RESULTS: The HR-HPV age-standardised (on Italian population) prevalence ranged from 5.7% (Trento) to 10.3% (Ravenna). HR-HPV prevalence decreased as a logistic function of increasing age in 6 of 9 centres (Trento, Verona, Florence, Bologna, Imola, and Viterbo). The effect of age on HR-HPV prevalence slopes did not differ significantly among these 6 centres, whereas significant heterogeneity in intercepts (p < 0.001) was found, reflecting different overall HR-HPV prevalence between centres. One significant joinpoint was observed in 2 centres (Padua and Ravenna), indicating that the decrease in HR-HPV prevalence by age was better described using a function composed with two logistic segments. In Padua HR-HPV prevalence decreased only slightly up to 39 years but showed a steep downturn thereafter. In Ravenna HR-HPV prevalence decreased steeply down to 45 years of age and then showed a plateau. Finally, in Turin two significant joinpoints were observed: prevalence decreased only after age 29 and showed a plateau after age 39. CONCLUSIONS: Our results showed substantial differences in overall and age-specific HR-HPV prevalence across Italian areas. These findings may be related to different timing of changes in sexual behaviours across regions. Age-specific HR-HPV prevalence in Italy does not support an influence of age per se.
[show abstract][hide abstract] ABSTRACT: Background: In some Italian areas, colonoscopic surveillance of first-degree relatives (FDRs) of colorectal cancer (CRC) patients is provided as a part of local population-based faecal occult blood test (FOBT) screening programmes. The objective of the present study was to assess the feasibility and early results of this surveillance model. Methods: Data from district screening centres were used to evaluate the process of identification and selection of eligible FDRs (residence in the Emilia-Romagna Region, age 40-75 years, no recent colonoscopy) of screen-detected CRC patients and the detected prevalence of disease. The probability for an FDR to undergo colonoscopy and to be diagnosed with CRC and advanced adenoma was estimated using the Kaplan-Meier method. The sex- and age-standardised ratio of detected prevalence to that expected based on results from a colonoscopy screening study of the Italian general population was estimated. Results: Between 2005 and 2011, 9319 FDRs of 2437 screen-detected CRC patients (3.8 per patient) were identified and contacted. Their likelihood of being eligible for, and accepting, colonoscopy was 0.11 (95% confidence interval: 0.11-0.12). Among the 926 subjects undergoing colonoscopy, the prevalence of previous negative screening FOBT was 63%. Eleven CRCs (1.2%) and 100 advanced adenomas (10.8%) were detected. The standardised ratio of detected prevalence to that expected was 0.91 (95% confidence interval: 0.19-2.66) for CRC and 1.48 (1.04-2.05) for advanced adenoma. Conclusions: The procedure of selection of FDRs was extremely ineffective. Due to previous negative screening tests, the prevalence of disease was less than expected. A population-based FOBT screening programme is a highly unsuitable setting for the provision of surveillance to FDRs of CRC patients.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Immunostaining for p16-INK4A (henceforth p16) is a sensitive and specific method for detection of high-grade cervical intraepithelial neoplasia (CIN) in women infected with human papillomavirus (HPV), but longitudinal data have not been obtained. We investigated the relation between p16 status and risk of CIN during 3 years of follow-up. METHODS: Women aged 25-60 years were enrolled between June 10, 2003, and Dec 31, 2004, in a multicentre randomised trial comparing HPV testing with cytology. HPV-positive women were referred for colposcopy and, in seven of nine centres, were tested for p16 overexpression by immunostaining. If no CIN was detected, these women were followed up at yearly intervals until clearance of HPV infection. The primary endpoint was histologically confirmed CIN of grade 2 or worse (CIN of grade 2 [CIN2], CIN of grade 3 [CIN3], or invasive cervical cancer) at recruitment or during follow-up. We calculated the absolute and relative risks by p16 status at recruitment. We also calculated the longitudinal sensitivity of p16 testing. Additionally, we assessed the relative sensitivity of an alternative strategy (referral to colposcopy and follow-up of only HPV-positive, p16-positive women) versus conventional cytology in two age groups. Percentages were weighted by the inverse of the tested fraction. The trial in which this study is nested is registered, number ISRCTN81678807. FINDINGS: Of 1042 HPV-positive women who were tested for p16 with no CIN detected during the first round of screening, 944 (91%) had further HPV tests. 793 (84%) of these 944 were followed up until detection of CIN2 or worse, HPV infection clearance, or for at least 3 years. CIN2 or worse was detected during follow-up in more p16-positive women (31 of 365, 8·8% [95% CI 5·8-11·8]) than in p16-negative women (17 of 579, 3·7% [1·9-5·4]; relative risk [RR] 2·61 [95% CI 1·49-4·59]). RR was higher in women aged 35-60 years at recruitment (3·37 [1·39-8·15]) than in those aged 25-34 years (2·15 [1·00-4·61]), but age was not a significant modifier. CIN3 or worse was detected during follow-up in more p16-positive women (16 of 365, 4·4% [2·3-6·6]) than in p16-negative women (six of 579, 1·3% [0·2-2·3]; RR 3·90 [95% CI 1·57-9·68]). Longitudinal sensitivity of p16 testing for detection of CIN3 or worse during follow-up at all ages was 77·8% (95% CI 63·9-91·6). The relative sensitivity of the alternative strategy compared with conventional cytology was 2·08 (1·13-3·56) in women aged 35-60 years and 2·86 (1·28-5·36) in those aged 25-34 years. HPV-positive, p16-negative women aged 35-60 years had a higher cumulative risk of CIN3 or worse during recruitment or follow-up (2·0%, 95% CI 0·3-3·7) than did HPV-negative women (0·01%, 0-0·04) or those who were cytologically normal (0·04%, 0·02-0·09) at recruitment. INTERPRETATION: p16 overexpression is a marker for CIN2 or worse or for development of CIN2 or worse within 3 years in HPV-positive women, especially those aged 35-60 years. HPV-positive, p16-positive women need immediate colposcopy and, if the assessment is negative, annual follow-up. Immediate colposcopy can be avoided in HPV-positive, p16-negative women, who can be safely managed with repeat screening after 2-3 year intervals. FUNDING: European Union; Italian Ministry of Health; Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia Romagna; and Public Health Agency of Lazio Region.
The lancet oncology 12/2012; · 14.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: The national meeting of the National Centre for Screening Monitoring (ONS) was given the title "The screening during the crisis" as we realize that the severe economical crises of our Country influences all the health policies and, as a consequence, screening programmes. Within this global scenarios, the results of 2010 concerning screening programmes can be considered as still positive even if the gap between the North and the Centre as compared to the South remains. In short, in 2010 almost 9.5 millions people were invited to undergo a screening examination (3,450,000; 2,496,000 and 3,464,000 for cervical, mammographic and colorectal cancer respectively). As compared to the previous year, a large increase was observed for colorectal screening.Whereas a slight decrease was observed both for cervical and for mammographic screening. The latter trend was partially due to the overload consequent to the extension of the programme to women younger than fifty in a couple of regions (Emilia-Romagna and Piemonte). More than 4.3 millions of subjects actually complied to the invitation (1,375,000; 1,382,000 and 1,582,000 for cervical, mammographic and colorectal cancer, respectively). As a consequence of these activities were identified 6,015 breast cancers (31% of annual occurring breast cancers in Italy in the age group 50-69 years according to the most update estimates of breast cancer occurrence), 4,597 CIN2 or more severe cervical lesions, 2,916 colorectal cancers (15% of annual occurring CRC cancer in Italy in the age group 50-69 years) and 15,049 advanced adenomas.
[show abstract][hide abstract] ABSTRACT: This survey, conducted by the Italian breast screening network (GISMa), collects yearly individual data on diagnosis and treatment on about 50% of all screen-detected, operated lesions in Italy. The 2010 results show good overall quality and an improving trend over time. Critical issues were identified, including waiting times and compliance with the recommendations on not performing frozen section examination on small lesions. Preoperative diagnosis improved constantly over the years, but there is still a large variation between regions and programmes. For almost 90% of screen-detected invasive cancers the sentinel lymph node technique (SLN) was performed on the axilla, avoiding a large number of potentially harmful dissections. On the other hand, potential overuse of SLN for ductal carcinoma in situ deserves further investigation. The detailed results have been distributed, also by means of a web data warehouse, to regional and local screening programmes in order to allow multidisciplinary discussion and identification of the appropriate solutions to any issues documented by the data. It should be assigned priority to the problem of waiting times. Specialist Breast Units with adequate case volume and enough resources would provide the best setting for making monitoring effective in producing quality improvements with shorter waiting times.
[show abstract][hide abstract] ABSTRACT: Italian national guidelines recommend to regions the implementation of organised screening programmes for cervical cancer. As in previous years since 1998 we collected aggregated tables of data from Italian organised cervical screening programmes in order to centrally compute process indicators. Data on women invited during 2010 and screened up to April 2011 were considered. In 2010, the target population of Italian organised screening programmes included 13,538,080 women, corresponding to 80.1% of Italian women aged 25-64 years. Compliance to invitation was 39.8%, with a strong North-South decreasing trend. However, it should be considered that many women are screened outside organised programmes. Among screened women, 4.7% were referred for repeat cytology and 62.7% of them complied; 2.5% of screened women were referred to colposcopy. Compliance with coldeposcopy referral was 85.9% among women referred because of ASC-US or more severe cytology and 88.7% among those referred because of HSIL or more severe cytology. The positive predictive value (PPV) of referral because of ASC-US or more severe cytology for CIN2 or more severe histology was 16.0%. The unadjusted detection rate of CIN2 or more severe histology was 3.2 per 1,000 screened women (3.5 standardised on the Italian population, truncated 25-64).
[show abstract][hide abstract] ABSTRACT: We present the main results of the 2010 survey of the Italian screening programmes for colorectal cancer carried out by the National centre for screening monitoring (Osservatorio nazionale screening, ONS) on behalf of the Ministry of health. By the end of 2010, 105 programmes were active, 9 of which had been activated during the year, and 65% of Italians aged 50-69 years were residing in areas covered by organised screening programmes (theoretical extension). Twelve regions had their whole population covered. In the South of Italy and Islands, 5 new programmes were activated in 2010, with a theoretical extension of 29%. The majority of programmes employed the faecal occult blood test (FIT), while some adopted flexible sigmoidoscopy (FS) once in a lifetime and FIT for non-responders to FS. Overall, about 3,404,000 subjects were invited to undergo FIT, 47.2% of those to be invited within the year. The adjusted attendance rate was 48% and approximately 1,568,796 subjects were screened. Large differences in the attendance rate were observed among regions: 10% of programmes reported values lower than 24%. Positivity rate of FIT programmes was 5.5% at first screening (range: 1.6-11.3%) and 4.3% at repeat screening (range: 3.2-6.7%). The average attendance rate to total colonoscopy (TC) was 81.4% and in one region it was lower than 70%. Completion rate for total colonoscopy (TC) was 88.7%. Among the 740,281 subjects attending screening for the first time, the detection rate (DR) per 1,000 screened subjects was 2.4 for invasive cancer and 10.3 for advanced adenomas (AA - adenomas with a diameter ≥1 cm, with villous/tubulo-villous type or with high-grade dysplasia). As expected, the corresponding figures in the 843,204 subjects at repeat screening were lower (1.2‰ and 7.6‰ for invasive cancer and AA, respectively). The DR of cancer and adenomas increased with age and was higher among males. Many programmes reported some difficulties in guaranteeing TC in the appropriate time frame to FIT+ subjects: in 16% of cases the waiting time was longer than two months. Nine programmes employed FS as the screening test: 98% of the target population (about 60,000 subjects) were invited, and 13,629 subjects were screened, with an attendance rate of 24%. Overall, 87% of FS were classified as complete. TC referral rate was 9.5% and the DR per 1,000 screened subjects was 2.8 and 40.6 for invasive cancer and AA, respectively.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE OF THE PROJECT: The introduction of the HPV test as a primary screening test will cause important changes in the screening system based on cytology. The purposes of this report are: to define the best screening policies with HPV-based screening on the basis of the resulting efficacy and of undesired effects; comparing them to cytology-based screening; to identify their best conditions of application; to evaluate economic cost, feasibility and impact on the organisation of services of such policy in the Italian situation.
This report contains a section on efficacy and undesired effects based on a systematic review of literature conducted in strict coordination with the preparation of a supplement to the European Guidelines for quality assurance in cervical cancer screening. This chapter corresponds to a preliminary version of the chapter of the European Guidelines on primary screening with HPV. The sections on costs, impact on organisation, and social, ethical and legal impact reflect the Italian situation; they are based on a review of the available Italian data (including unpublished data, mainly from on-going pilot projects) and on a structured analysis of what will result if the proposed protocol is applied to the Italian situation.
Efficacy and undesired effects. There is clear scientific evidence that a screening based on validated tests for the DNA of oncogenic HPV as primary test and applying an appropriate protocol is more effective than screening based on cytology in preventing invasive cancers of the uterine cervix. In addition, it entails a limited--if any--increase of the undesired effects both in terms of unneeded referral to diagnostic work-up and in terms of over-diagnosis and consequent overtreatment of spontaneously regressive lesions. The crucial elements of such protocol are the followings: HPV-positive women are not to be directly referred to colposcopy, but the use of triage systems is essential. The currently recommendable method is based on performing cytology in HPV positive women. If the result of this test is abnormal, the woman is immediately referred to colposcopy; if cytology is normal, the woman is invited to repeat a new HPV test after one year. In case such a test is still positive, the woman is referred to colposcopy; in case of negative result, the woman will be re-invited for a new screening round at the regular interval. In organised population-based screening programmes the interval after a negative primary HPV test should be at least 5 years. There is evidence that the 5-year cumulative risk of high-grade CIN after a negative HPV test is lower than the 3-year risk after a normal cytology. On the other hand, the probability of unneeded colposcopies and treatments would plausibly be relevant with 3-year intervals after a negative HPV test. HPV-based screening should not start before 30-35 years. There is evidence that below 30 years HPV-based screening leads to an increased overdiagnosis of CIN2 that would regress spontaneously, with consequent overtreatment. Some increase in overdiagnosis is plausible also between 30 and 34 years. Below such ages, cytological screening is the recommended test. Only tests for the DNA of oncogenic HPV, validated according to the European guidelines as for sensitivity and specificity for high-grade lesions, should be applied. There is no evidence that double testing with cytology and HPV is more protective than stand-alone HPV as primary test, although it entails a small and not relevant increase in sensitivity vs stand-alone HPV. On the contrary, there is evidence that double testing causes a substantial increase in referral to colposcopy and a decrease in its PPV. For this reason, if HPV is used as primary screening test, it is recommended not to add cytology in parallel. Cost and economic evaluation. It is estimated that, if the protocol described is applied, in the current Italian situation the overall costs of HPV-based screening are lower than those of conventional cytological screening applied at the current 3-year intervals, although the cost of each screening round is higher. Impact on organization. For reasons of quality and cost, both the interpretation of cytology and HPV testing require a centralisation. This need is particularly strong, in terms of costs, for HPV test execution. It is therefore recommended to perform the HPV test in a limited number of reference laboratories of large size. This also makes monitoring and evaluating the spontaneous activity easier. HPV-based screening entails problems of organisation related to the need of triage, to complex protocols and to reconversion of the activities of cytological interpretation. Social, ethical and legal impact. The communication of the result of the HPV test to women, particularly if positive, is a further crucial aspect in order to reduce not only the emotional impact, but also the possible risks that women are inappropriately managed or lost to follow-up. Great efforts must be put in the education of healthcare professionals, both directly involved in organised programmes or not, particularly private gynaecologists and general practitioners.
In conclusion, the crucial requirement to introduce HPV-based screening programmes is the capacity to guarantee the application of appropriate screening protocols. If protocols do not respect the criteria described above they can cause relevant increase of undesired effects and costs compared to cytology-based screening. Therefore they should be avoided, except in studies able to provide clear evidence about human and economic costs. For this purpose, correct education and information both to healthcare professionals and to the population is needed. In the Italian situation, where organised screening and a relevant spontaneous activity coexist, their interaction is crucial. Actions directed to integrate them and to guarantee as more uniformity of interventions as possible are needed, in particular through the integration of registries and thorough monitoring and a progressive homogenization of protocols. In order to grant the safety of transition, it is needed that the HPV-based organised screening activities are strictly monitored and that the National Centre for Screening Monitoring (ONS) ensures coordination. Knowledge about HPV based screening is still rapidly evolving. It is possible that currently on-going researches suggest changes to the optimal protocols in the next few years, particularly as for the management of HPV positive women. In addition, studies on the validation of new assays were recently published and others are expected. It is suggested to exploit the organised screening activity to produce scientific evidence, in order to clarify the still uncertain aspects of optimal protocols. Different protocols in terms of screening intervals, age of application and management of HPV positive women should be studied in the frame of controlled implementation, through multicentre projects coordinated by ONS. Finally, it is suggested the creation of a National working group to promptly update the recommendations for screening and the list of assays to be considered as validated. On the bases of the results obtained in the first vaccinated cohorts reaching the screening age, for the future, it will be crucial to deliver specific recommendations to the population vaccinated against HPV during adolescence.
[show abstract][hide abstract] ABSTRACT: Computer-aided diagnosis (CAD) has been extensively reported to increase sensitivity by about 10% when added to a single reading while increasing recall rate by 12%, and its current use can be safely recommended in clinical practice. CAD has been suggested as a possible alternative to conventional double reading in screening. Uncontrolled comparison is consistent and suggests that CAD is comparable to double reading in incremental cancer detection rate (CAD +10.6%, double reading +9.1%) and possibly better in recall rate (CAD +12.5%, double reading +28.8%). However, controlled studies comparing single reading + CAD to conventional double reading are not consistent and on average suggest a lower cancer detection rate (-5.1%) and a lower recall rate (-9.8%) for CAD. Scientific evidence is not sufficient for a safe recommendation of single reading + CAD as a current alternative to conventional double reading.
La radiologia medica 06/2010; 115(4):563-70. · 1.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing.
Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807.
In total for both phases, 47,001 women were randomly assigned to the cytology group and 47,369 to HPV testing. 33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0.004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0.028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3 together. At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3, and 0.51 (0.28-0.93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two. At round two the relative detection was 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) at round two.
HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2.
European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.
The lancet oncology 03/2010; 11(3):249-57. · 14.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although poorly described in the literature, the practice of early (short-interval) rescreen after a negative screening mammogram is controversial due to its financial and psychological burden and because it is of no proven benefit.
The present study targeted an Italian 2-yearly screening programme (Emilia-Romagna Region, 1997-2002). An electronic dataset of 647,876 eligible negative mammography records from 376,257 women aged 50-69 years was record-linked with the regional breast cancer registry. The statistical analysis addressed the following research questions: (1) the prevalence of recommendation for early (<24 months) rescreen (RES) among negative mammography reports; (2) factors associated with the likelihood of a women receiving RES; and (3) whether women receiving RES and women receiving standard negative reports differed in terms of proportional incidence of interval breast cancer, recall rate at the next rescreen, detection rate of breast cancer at the next rescreen and the odds of having late-stage breast cancer during the interscreening interval and at the next rescreen.
RES was used in eight out of 13 screening centres, where it was found in 4171 out of 313,320 negative reports (average rate 1.33%; range 0.05%-4.33%). Reports with RES were more likely for women aged 50-59 years versus older women (odds ratio (OR) 1.33; 95% CI 1.25-1.42), for the first versus subsequent screening rounds (OR 1.91; 95% CI 1.79-2.04) and with a centre-specific recall rate below the average of 6.2% (OR 1.41; 95% CI 1.32-1.50). RES predicted a 3.51-fold (95% CI 0.94-9.29) greater proportional incidence of first-year interval cancers, a 1.90-fold (95% CI 1.62-2.22) greater recall rate at the next screen, a 1.72-fold (95% CI 1.01-2.74) greater detection rate of cancer at the next screen and a non-significantly decreased risk of late disease stage (OR 0.59; 95% CI 0.23-1.53).
The prevalence of RES was in line with the maximum standard level established by the Italian national guidelines. RES identified a subset of women with greater incidence of interval cancers and greater prevalence of cancers detected at the next screen.
[show abstract][hide abstract] ABSTRACT: The aim of this study was the evaluation of the impact of service screening programmes on breast cancer mortality in five regions of Italy. We conducted a matched case–control study with four controls for each case. Cases were defined as breast cancer deaths occurred not later than 31 December 2002. Controls were sampled from the local municipality list and matched by date of birth. Screening histories were assessed by the local, computerised, screening database and subjects were classified as either invited or not-yet-invited and as either screened or unscreened. There were a total of 1750 breast cancer deaths within the 50 to 74-year-old breast cancer cases and a total of 7000 controls. The logistic conditional estimate of the cumulative odds ratios comparing invited with not-yet-invited women was 0.75 (95% CI: 0.62–0.92). Restricting the analyses to invited women, the odds ratio of screened to never-respondent women corrected for self-selection bias was 0.55 (95% CI: 0.36–0.85). The introduction of breast cancer screening programmes in Italy is associated with a reduction in breast cancer mortality attributable to the additional impact of service screening over and above the background access to mammography.
British Journal of Cancer 12/2008; 99(10):1756. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the adequacy of a routine screening to identify cervical intraepithelial neoplasia 2 or worse (CIN2+) in women over 50 years of age, a retrospective cohort was set in six Italian organised population-based screening programmes. In all, 287 330 women (1 714 550 person-years of observation, 1110 cases) screened at age 25-64, with at least two cytological screening tests, the first negative, were followed from their first negative smear until a biopsy proven CIN2+ lesion or their last negative smear. For women aged 25-49 and 50-64 years, crude and age-standardised detection rate (DR), cumulative risk (CR), adjusted hazard risk for number of previous negative screens, probability of false-positive CIN2+ after two or more smear tests were calculated. Detection rate is significantly lower over 50 years of age. Multivariable analysis shows a significant protective effect from four screening episodes (DR=0.70, 95% CI: 0.51-0.97); the effect of age >or=50 is 0.29 (95% CI: 0.24-0.35). The CR of CIN2+ is at least eightfold higher in women <50 (CR=2.06, 95% CI: 1.88-2.23) after one previous negative test than in women >or=50 years with four screens (CR=0.23, 95% CI: 0.00-0.46). Over 50 years of age, after four tests at least three false-positive cases are diagnosed for every true positive. Benefits arising from cytological screening is uncertain in well-screened older women.
British Journal of Cancer 08/2008; 99(2):239-44. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the first recruitment phase of a randomized trial of cervical cancer screening methods (New Technologies for Cervical Cancer Screening [NTCC] study), we compared screening with conventional cytology with screening by human papillomavirus (HPV) testing in combination with liquid-based cytology. HPV-positive women were directly referred to colposcopy if aged 35 or older; if younger, they were retested after 1 year.
In the second recruitment phase of NTCC, we randomly assigned women to conventional cytology (n = 24,661) with referral to colposcopy if cytology indicated atypical squamous cells of undetermined significance or more severe abnormality or to testing for high-risk HPV DNA alone by Hybrid Capture 2 (n = 24,535) with referral to colposcopy if the test was positive at a concentration of HPV DNA 1 pg/mL or greater. For the main endpoint of the study, histologic detection of cervical intraepithelial neoplasia of grade 2 or more (CIN2+), we calculated and compared sensitivity and positive predictive value (PPV) of the two screening methods using HPV DNA cutoffs of 1 pg/mL and 2 pg/mL. All statistical tests were two-sided.
For women aged 35-60 years, the relative sensitivity of HPV testing for detection of CIN2+ at a cutoff of 1 pg/mL vs conventional cytology was 1.92 (95% CI = 1.28 to 2.87) and the relative PPV was 0.80 (95% CI = 0.55 to 1.18). At a cutoff of 2 pg/mL HPV DNA, the relative sensitivity was 1.81 (95% CI = 1.20 to 2.72) and the relative PPV was 0.99 (95% CI = 0.67 to 1.46). In this age group, there was no evidence of heterogeneity between study phases. Among women aged 25-34 years, the relative sensitivity for detection of CIN2+ of HPV testing at a cutoff of 1 pg/mL vs cytology was 3.50 (95% CI = 2.11 to 5.82), statistically significantly larger (P = .019) than that observed in phase 1 at this age (1.58; 95% CI = 1.03 to 2.44).
For women aged 35-60 years, HPV testing with a cutoff of 2 pg/mL achieves a substantial gain in sensitivity over cytology with only a small reduction in PPV. Among women aged 25-34 years, the large relative sensitivity of HPV testing compared with conventional cytology and the difference between relative sensitivity during phases 1 and 2 suggests that there is frequent regression of CIN2+ that are detected by direct referral of younger HPV-positive women to colposcopy. Thus, triage test or repeat testing is needed if HPV is to be used for primary testing in this context.
[show abstract][hide abstract] ABSTRACT: A number of BRCA1 and BRCA2 polymorphisms have been extensively studied in order to test their association with breast cancer risk. Subsequently, discordant results were reported. In the present study, the genotypes of one BRCA1 (Q356R) and three BRCA2 (203G>A, N372H, IVS21-66T>C) common variants were evaluated in a series of 252 breast cancer patients, 155 age-matched controls and analysed in relation to family history (low- or high-risk) and BRCA1/2 mutation status. A complete analysis of the BRCA1/2 coding regions was performed on the 217 women from high-risk families and 44 BRCA1/2 mutation carriers were identifed. According to a dominant inheritance model, the BRCA2 IVS21-66T>C variant showed a 1.79-fold (95% CI, 1.16-2.78; P=0.009) increased breast cancer risk for the overall series. The BRCA2 N372H polymorphism was associated with a 2.29-fold (95% CI, 1.16-4.49; P=0.016) increased risk in the subgroup of high-risk families with no BRCA1/2 mutations. Conversely, the BRCA1 Q356R and BRCA2 203G>A polymorphisms did not show any significant associations with breast cancer risk. In conclusion, the analysis of some BRCA2 variants could help to identify women at a higher risk of developing breast cancer who could be candidates for chemoprevention protocols.
[show abstract][hide abstract] ABSTRACT: To estimate the total proportional incidence of interval breast cancers in a two-yearly mammography screening programme, and to perform subgroup analyses by woman's age, screening centre-specific recall rate and screening round.
Using unconverted electronic data-sets from the 13 screening centres in the Emilia-Romagna Region of northern Italy (540,450 women aged 50-69 years), a database of 919,538 mammography records was created. Of these, 655,175 eligible single-mammography records (1997-2002) from 379,318 women were record-linked with the regional Breast Cancer Registry. In the two-year inter-screening interval, a total of 1,022,694.3 woman-years at risk were accumulated, with 695 interval cancers observed and 2428.3 expected. The observed number of interval cancers was divided by the expected number to obtain the proportional incidence.
The total proportional incidence of first- and second-year interval cancers was 0.18 (95% CI 0.15-0.20) and 0.43 (0.39-0.47), respectively. Woman's age was inversely associated with proportional incidence in both interval years, with a cut-off point at age 60. A screening centre-specific recall rate greater than the regional average of 5% was associated with a proportional incidence of 0.14 (0.11-0.17) versus 0.20 (0.17-0.24) in the first interval year, and of 0.36 (0.31-0.41) versus 0.50 (0.44-0.56) in the second. The proportional incidence remained unchanged between the first and subsequent screening rounds.
The results were in line with the previous Italian data and with the recommended European standards. The inverse effect of woman's age and of recall rate was expected.
Journal of Medical Screening 02/2008; 15(1):30-5. · 2.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: The decision to introduce liquid-based cytology (LBC) and HPV as screening tests involves criteria based on resource consumption. We used cross-sectional data at recruitment from the NTCC trial [ISRCTN81678807] on 28,000 women aged 35-60, randomised to receive a conventional Pap test or LBC plus HPV. We computed the resources employed to detect a CIN2+ with different screening strategies. In order to result in the same overall cost per CIN2+ detected as screening by conventional cytology, the unit cost of LBC used alone should be less than that of a conventional Pap while its unit cost may be up to 20% higher if HPV-triage for Atypical Squamous Cells of Undetermined Significance is applied together. With the same criterion the unit cost of HPV used alone may be about 20% higher than that of a Pap-test using a 1 pg/ml cut-off and over 40% higher using a 10 pg/ml cut-off. If HPV testing is applied with cytology-triage, a single HPV test may cost 20-30% more than a conventional Pap to result in the same overall cost per CIN2+ detected.
International Journal of Cancer 01/2008; 121(12):2729-34. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: BRCA1/2 mutation status is of paramount importance to identify families at risk of Hereditary Breast and Ovarian Cancer (HBOC). Most HBOC and BRCA1/2 mutation studies have focused on highly selected sub-populations, and few data are available for large population cohorts. For this reason, as part of a regional cancer prevention strategy in North-Central Italy, we set up a population-based screening programme to identify all resident HBOC families, and to determine their BRCA1/2 mutation status. To date, 44 different BRCA1/2 variants have been identified in 55 HBOC families. Of the seven newly reported mutations, only BRCA1 Q284X is clearly deleterious. The analysis of clinical disease characteristics in relation to age of disease onset and family history showed a difference between BRCA1/2 wild type and mutation carrier families. Interestingly, BRCA1/2 mutations were significantly more common in women who developed breast cancer <or=40 years of age than in BRCA1/2 wild type women (50% vs. 29%, respectively, P = 0.005). The family history selection criteria most likely to indicate the presence of deleterious BRCA1/2 mutations are breast cancer <or=35 years (P = 0.012), two first-degree relatives with breast cancer <or=50 years (P = 0.022), and male breast cancer (P = 0.047). The penetrance of BRCA1/2 alterations in our cohort seems to be aligned with other published results. However, new data interpretations have emerged in relation to the clinical criteria and the presence of deleterious mutations. This information shows that a correct and accurate clinical selection could avoid unnecessary molecular tests and could better address genetic analysis and clinical management.
Breast Cancer Research and Treatment 12/2007; 112(2):343-9. · 4.47 Impact Factor