Massimo Confortini

Bio: Massimo Confortini is an academic researcher from University of Florence. The author has contributed to research in topics: Colposcopy & Cervical intraepithelial neoplasia. The author has an hindex of 28, co-authored 82 publications receiving 3920 citations.

Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial

Abstract: Summary Background 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. Methods 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. Findings 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. Interpretation 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. Funding European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.

Human Papillomavirus Testing and Liquid-Based Cytology: Results at Recruitment From the New Technologies for Cervical Cancer Randomized Controlled Trial

Abstract: Background: Although testing for human papillomavirus (HPV) has higher sensitivity and lower specifi city than cytology alone for detecting cervical intraepithelial neoplasia (CIN), studies comparing conventional and liquid-based cytology have had confl icting results. Methods: In the fi rst phase of a two-phase multicenter randomized controlled trial, women aged 35 – 60 years in the conventional arm ( n = 16 658) were screened using conventional cytology, and women in the experimental arm ( n = 16 706) had liquidbased cytology and were tested for high-risk HPV types using the Hybrid Capture 2 assay. Women in the conventional arm were referred to colposcopy with atypical cells of undetermined signifi cance (ASCUS) or higher and those in the experimental arm were referred with ASCUS or higher cytology or with a positive ( ≥ 1 pg/mL) HPV test. Sensitivity and positive predictive value (PPV) for detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) were calculated. Results: The screening methods and referral criterion applied in the experimental arm had higher sensitivity than that in the conventional arm (relative sensitivity = 1.47; 95% confi dence interval [CI] = 1.03 to 2.09) but a lower PPV (relative PPV = 0.40; 95% CI = 0.23 to 0.66). With HPV testing alone at ≥1 pg/mL and at ≥2 pg/mL, the gain in sensitivity compared with the conventional arm remained similar (relative sensitivity = 1.43, 95% CI = 1.00 to 2.04 and relative sensitivity = 1.41, 95% CI = 0.98 to 2.01, respectively) but PPV progressively improved (relative PPV = 0.58, 95% CI = 0.33 to 0.98 and relative PPV = 0.75, 95% CI = 0.45 and 1.27, respectively). Referral based on liquid-based cytology alone did not increase sensitivity compared with conventional cytology (relative sensitivity = 1.06; 95% CI = 0.72 to 1.55) but reduced PPV (relative PPV = 0.57; 95% CI = 0.39 to 0.82). Conclusions: HPV testing alone was more sensitive than conventional cytology among women 35 – 60 years old. Adding liquid-based cytology improved sensitivity only marginally but increased false-positives. HPV testing using Hybrid Capture 2 with a 2 pg/mL cutoff may be more appropriate than a 1 pg/mL cutoff for primary cervical cancer screening. [J Natl Cancer Inst 2006;98:765 – 74]

Results at Recruitment From a Randomized Controlled Trial Comparing Human Papillomavirus Testing Alone With Conventional Cytology as the Primary Cervical Cancer Screening Test

Abstract: Background 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. Methods 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. Results 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). Conclusions 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. J Natl Cancer Inst 2008;100: 492 – 501

Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial

Abstract: Objective To compare the accuracy of conventional cytology with liquid based cytology for primary screening of cervical cancer. Design Randomised controlled trial. Setting Nine screening programmes in Italy. Participants Women aged 25-60 attending for a new screening round: 22 466 were assigned to the conventional arm and 22 708 were assigned to the experimental arm. Interventions Conventional cytology compared with liquid based cytology and testing for human papillomavirus. Main outcome measure Relative sensitivity for cervical intraepithelial neoplasia of grade 2 or more at blindly reviewed histology, with atypical cells of undetermined significance or more severe cytology considered a positive result. Results In an intention to screen analysis liquid based cytology showed no significant increase in sensitivity for cervical intraepithelial neoplasia of grade 2 or more (relative sensitivity 1.17, 95% confidence interval 0.87 to 1.56) whereas the positive predictive value was reduced (relative positive predictive value v conventional cytology 0.58, 0.44 to 0.77). Liquid based cytology detected more lesions of grade 1 or more (relative sensitivity 1.68, 1.40 to 2.02), with a larger increase among women aged 25-34 (P for heterogeneity 0.0006), but did not detect more lesions of grade 3 or more (relative sensitivity 0.84, 0.56 to 1.25). Results were similar when only low grade intraepithelial lesions or more severe cytology were considered a positive result. No evidence was found of heterogeneity between centres or of improvement with increasing time from start of the study. The relative frequency of women with at least one unsatisfactory result was lower with liquid based cytology (0.62, 0.56 to 0.69). Conclusion Liquid based cytology showed no statistically significant difference in sensitivity to conventional cytology for detection of cervical intraepithelial neoplasia of grade 2 or more. More positive results were found, however, leading to a lower positive predictive value. A large reduction in unsatisfactory smears was evident. Trial registration Current Controlled Trials ISRCTN81678807.

Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: results at recruitment for a randomised controlled trial.

Abstract: Summary Background Testing for human papillomavirus (HPV) DNA is more sensitive but less specific than cytological analysis. Loss in specificity is most relevant in women younger than 35 years because of increased HPV prevalence. We aimed to compare conventional screening with an experimental strategy in women aged 25–34 years, and investigate the effect of different criteria of referral to define the best methods of HPV screening. Methods Women were randomly assigned to the conventional procedure (standard cytology, with referral to colposcopy if cytology showed atypical squamous cells of undetermined significance or more [ASCUS+]) or an experimental procedure (liquid-based cytology and testing for high-risk HPV types, with referral to colposcopy with ASCUS+ cytology). Women positive for HPV (cutoff ≥1 pg/mL) but with normal cytology were retested after 1 year. The main endpoint was the presence of cervical intraepithelial neoplasia at grade 2 or more (CIN2+) in reviewed histology. The main analysis was by intention to screen. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN81678807. Findings We randomly assigned 5808 women aged 25–34 years to the conventional group and 6002 to the experimental group. The experimental procedure was significantly more sensitive than the conventional procedure (55 vs 33 CIN2+ lesions detected; relative sensitivity 1·61 [95% CI 1·05–2·48]), but had a lower positive predictive value (PPV; relative PPV 0·55 [0·37–0·82]). HPV testing (≥1 pg/mL) with cytology triage was also more sensitive than conventional cytology (relative sensitivity 1·58 [1·03–2·44], relative PPV 0·78 [0·52–1·16]). Relative PPV could be improved, with minimum loss in sensitivity, by use of a 2 pg/mL cutoff for HPV testing. Compared with conventional cytology, liquid-based cytology had a relative sensitivity of 1·32 (0·84–2·06), relative PPV 0·58 [0·38–0·89]). Interpretation HPV testing alone with cytology triage could be a feasible alternative to conventional cytology for screening women younger than 35 years. Follow-up will provide data on possible overdiagnosis and on the feasibility of extended intervals.

Sexually transmitted diseases treatment guidelines, 2010.

Abstract: These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 18-30, 2009. The information in this report updates the 2006 Guidelines for Treatment of Sexually Transmitted Diseases (MMWR 2006;55[No. RR-11]). Included in these updated guidelines is new information regarding 1) the expanded diagnostic evaluation for cervicitis and trichomoniasis; 2) new treatment recommendations for bacterial vaginosis and genital warts; 3) the clinical efficacy of azithromycin for chlamydial infections in pregnancy; 4) the role of Mycoplasma genitalium and trichomoniasis in urethritis/cervicitis and treatment-related implications; 5) lymphogranuloma venereum proctocolitis among men who have sex with men; 6) the criteria for spinal fluid examination to evaluate for neurosyphilis; 7) the emergence of azithromycin-resistant Treponema pallidum; 8) the increasing prevalence of antimicrobial-resistant Neisseria gonorrhoeae; 9) the sexual transmission of hepatitis C; 10) diagnostic evaluation after sexual assault; and 11) STD prevention approaches.

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer

Abstract: An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections.

The history and future of targeting cyclin-dependent kinases in cancer therapy

Abstract: Cancer represents a pathological manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clinical development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clinical trials. Here, we review the biology of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clinical results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity.