Cost-Effectiveness Analysis of Universal Human Papillomavirus Vaccination Using a Dynamic Bayesian Methodology: The BEST II Study.

BACKGROUND: Human papillomavirus (HPV) plays a role in the development of benign and malign neoplasms in both sexes. The Italian recommendations for HPV vaccines consider only females. The BEST II study (Bayesian modelling to assess the Effectiveness of a vaccination Strategy to prevent HPV-related diseases) evaluates 1) the cost-effectiveness of immunization strategies targeting universal vaccination compared with cervical cancer screening and female-only vaccination and 2) the economic impact of immunization on various HPV-induced diseases. OBJECTIVE: The objective of this study was to evaluate whether female-only vaccination or universal vaccination is the most cost-effective intervention against HPV. METHODS: We present a dynamic Bayesian Markov model to investigate transmission dynamics in cohorts of females and males in a follow-up period of 55 years. We assumed that quadrivalent vaccination (against HPV 16, 18, 6, and 11) is available for 12-year-old individuals. The model accounts for the progression of subjects across HPV-induced health states (cervical, vaginal, vulvar, anal, penile, and head/neck cancer as well as anogenital warts). The sexual mixing is modeled on the basis of age-, sex-, and sexual behavioral-specific matrices to obtain the dynamic force of infection. RESULTS: In comparison to cervical cancer screening, universal vaccination results in an incremental cost-effectiveness ratio of €1,500. When universal immunization is compared with female-only vaccination, it is cost-effective with an incremental cost-effectiveness ratio of €11,600. Probabilistic sensitivity analysis shows a relatively large amount of parameter uncertainty, which interestingly has, however, no substantial impact on the decision-making process. The intervention being assessed seems to be associated with an attractive cost-effectiveness profile. CONCLUSIONS: Universal HPV vaccination is found to be a cost-effective choice when compared with either cervical cancer screening or female-only vaccination within the Italian context.

An online quality assurance program for colposcopy in a population-based cervical screening setting in Italy: results on colposcopic impression.

OBJECTIVE: To report the results of an Internet-based colposcopy quality assurance program from a population-based cervical screening service in a large region of northern Italy. METHODS: In 2010 to 2011, a Web application was made accessible on the Web site of the regional administration. Fifty-nine colposcopists of the registered 65 participated. They logged-in, viewed a posted set of 50 high-quality digital colpophotographs selected by an expert committee, and rated them for colposcopic impression using a 4-tier classification (Negative; abnormal, grade 1 [G1]; abnormal, grade 2 [G2]; suspected invasive cancer [Cancer]) derived from the International Federation for Cervical Pathology and Colposcopy 2002 classification. kappa (κ) coefficients for intercolposcopist agreement and colposcopist-committee agreement were calculated. RESULTS: Colposcopist-committee agreement was greater than intercolposcopist agreement (overall κ 0.69 vs 0.60, p<.001). The κ values for colposcopist-committee agreement were 0.83 on Negative, 0.53 on G1, 0.66 on G2, and 0.80 on Cancer (all p values for pairwise comparisons<.001, except for Negative vs Cancer [p=.078]). There was no systematic tendency for colposcopists to underestimate or overestimate the colposcopic findings (2-tailed sign test, p=.13). Overall colposcopist-committee agreement was greater among patients 35 years or older (p<.001) and for colposcopists with previous quality assurance experiences (p<.01). Only 0.2% of Negative impressions were formulated for a cervical intraepithelial neoplasia grade 2 or worse. As a parallel finding, the impression of Cancer predicted cervical intraepithelial neoplasia grade 2 or less in 0.5% of cases. The histologic substrates of G1 were dispersed over a large spectrum. CONCLUSIONS: The reproducibility of colposcopic impression, when classified by trained colposcopists examining high-quality images, is higher than is generally thought.

Induction of ankylosis in the incisor for orthodontic tooth movement in rats.

BACKGROUND/AIM: The present research evaluated the induction of ankylosis and the eruption rate in rat incisors, with the aim of achieving stable anchorage for orthodontic tooth movement (OTM) of the molars. MATERIAL AND METHODS: Fifteen male Wistar rats were used. In the Experimental group, the right superior incisor of each animal was extracted, denuded of the PDL and the dental papilla, and reimplanted. The Control group was the left superior incisors. The eruption rate was measured at 7, 10, 12, 14, and 16 days after replantation. NiTi closed springs with a 50cN release force were installed for additional 9 days, and the eruption rate was determined. Then, the rats were sacrificed, and ankylosis was examined by microscopic analysis. Differences with P < 0.01 were defined as statistically significant. RESULTS: The eruption rates were 0 and 0.39 mm day(-1) in the Experimental group and Control group, respectively. All incisors of the Experimental group showed ankylosis according to histological analysis. CONCLUSIONS: The methodology used to induce ankylosis in this study was effective for anchoring the incisors during the OTM of rat molars, eliminating the undesirable effects consequent to continuous eruption.

Competing-risks regression models in analysis of biomarkers as predictors of high-risk human papillomavirus (HPV) infection outcomes and incident CIN in the LAMS cohort.

To assess the prediction potential of a 5-biomarker panel for detecting high-risk human papillomavirus (HR-HPV) infections and/or cervical intraepithelial neoplasia (CIN) progression. Five biomarkers, lipocalin, plasminogen activator inhibitor-2, p300, interleukin-10, and stratifin, were assessed in cervical biopsies from 225 women of the Latin American Screening Study. Competing-risks regression models were constructed to assess their predictive power for (i) HR-HPV outcomes (negative, transient, or persistent infection) and (ii) CIN outcomes (no progression, incident CIN1, CIN2, or CIN3). p300, LCN2, stratifin were significantly associated with prevalent HR-HPV but lost their significance in multivariate analysis. In the multivariate model, only p300 was an independent predictor of CIN3 (odds ratio=2.63; 95% confidence interval, 1.05-6.61; P=0.039). In univariate competing-risks regression, lipocalin predicted permanent HR-HPV-negative status, but in the multivariate model, IL-10 emerged as a independent predictor of HPV-negative status (subhazard ratio=4.04; 95% confidence interval, 1.81-9.01; P=0.001). The clinical value of the panel in predicting longitudinal outcomes of HR-HPV infection and/or incident CIN is limited.

Follow-up study of patients with cervical intraepithelial neoplasia grade 1 overexpressing p16Ink4a.

OBJECTIVE: The p16 (p16(Ink4a)) tumor-suppressor protein is a biomarker for activated expression of human papillomavirus oncogenes. However, data are insufficient to determine whether p16 overexpression predicts the risk for progression of low-grade cervical intraepithelial neoplasia (CIN). This study was aimed at evaluating the risk for progression to CIN2 or worse during a 3-year follow-up of an unselected series of 739 patients with CIN1 biopsy specimens tested for p16 expression. METHODS: Positivity of p16 was defined as a diffuse overexpression in the basal/parabasal cell layers. Selection biases were ruled out using a control group of 523 patients with CIN1 biopsies not tested for p16 expression. Analysis was based on the ratio of progression rates. RESULTS: In the first year of follow-up, the 216 patients (29%) with p16-positive CIN1 had a higher progression rate (12.3%) than did the 523 patients with p16-negative CIN1 (2.2%) (rate ratio, 5.5; 95% confidence interval [CI], 2.59-11.71). In the second and third years, differences were smaller (rate ratio, 1.32 and 1.14, respectively) and not significant. The patients with p16-positive CIN1 also had a lower risk for regression to normal in the first year of follow-up (rate ratio, 0.55; 95% confidence interval, 0.42-0.71) and nonsignificant changes in the second and third years (rate ratio, 0.81 and 0.84, respectively). CONCLUSIONS: The patients with p16-positive CIN1 had an increased risk for progression that was concentrated in the first year of follow-up. Immunostaining of p16 could have a role in short-term surveillance of patients with CIN1. Further research should focus on midterm/long-term outcomes of p16-positive CIN1.

Rationale and development of an on-line quality assurance programme for colposcopy in a population-based cervical screening setting in Italy.

BACKGROUND: 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. DISCUSSION: 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.

Novel health economic evaluation of a vaccination strategy to prevent HPV-related diseases: the BEST study.

BACKGROUND: The development of human papillomavirus (HPV)-related diseases is not understood perfectly and uncertainties associated with commonly utilized probabilistic models must be considered. The study assessed the cost-effectiveness of a quadrivalent-based multicohort HPV vaccination strategy within a Bayesian framework. METHODS: A full Bayesian multicohort Markov model was used, in which all unknown quantities were associated with suitable probability distributions reflecting the state of currently available knowledge. These distributions were informed by observed data or expert opinion. The model cycle lasted 1 year, whereas the follow-up time horizon was 90 years. Precancerous cervical lesions, cervical cancers, and anogenital warts were considered as outcomes. RESULTS: The base case scenario (2 cohorts of girls aged 12 and 15 y) and other multicohort vaccination strategies (additional cohorts aged 18 and 25 y) were cost-effective, with a discounted cost per quality-adjusted life-year gained that corresponded to €12,013, €13,232, and €15,890 for vaccination programs based on 2, 3, and 4 cohorts, respectively. With multicohort vaccination strategies, the reduction in the number of HPV-related events occurred earlier (range, 3.8-6.4 y) when compared with a single cohort. The analysis of the expected value of information showed that the results of the model were subject to limited uncertainty (cost per patient = €12.6). CONCLUSIONS: This methodological approach is designed to incorporate the uncertainty associated with HPV vaccination. Modeling the cost-effectiveness of a multicohort vaccination program with Bayesian statistics confirmed the value for money of quadrivalent-based HPV vaccination. The expected value of information gave the most appropriate and feasible representation of the true value of this program.

Factors predicting the outcome of conservatively treated adenocarcinoma in situ of the uterine cervix: an analysis of 166 cases.

OBJECTIVE: The present study assessed the clinical outcome of patients conservatively treated for cervical adenocarcinoma in situ (AIS) and their predictive factors using univariate and multivariate population averaged (PA) generalized estimating equation (GEE) model in a longitudinal setting. METHODS: A series of 166 consecutive women (mean age 39.8 yrs; range 23-63 yrs) underwent conservative treatment of AIS as the primary treatment and were followed-up (mean 40.9 mo) using colposcopy, PAP-smear, biopsy and HPV-testing with Hybrid Capture 2. RESULTS: Hysterectomy was performed as part of the primary management in 47 patients, who were excluded from the follow-up (FU) analysis. Out of 119 women closely followed-up, additional therapeutic procedures were performed in 69. At study conclusion, 7 patients (5.9%) showed persistent disease, while 8 (6.7%) had progressed to invasive adenocarcinoma (AC). Positive HR-HPV test was the only independent predictor of disease recurrence (adjusted OR=2.72; 95%CI 1.08-6.87), and together with free cone margins (OR=0.20; 95%CI 0.04-0.92), HR-HPV positivity was also the single most powerful predictor of disease progression to AC, with OR=3.74; 95%CI 1.84-7.61 (p=0.0001) in multivariate PA-GEE. CONCLUSIONS: These results suggest that testing HR-HPV positive at any time point during FU is the most significant independent predictor of progressive disease, while showing free margins in cone has a significant protective effect against progression to AC. Furthermore, because 4.3% women with persistent, recurrent or progressive disease experienced a late (5th and 6th FU) diagnosis of HG-CGIN or microinvasive AC, a close surveillance should be scheduled for at least three years in conservatively treated AIS patients.

Clinical Epidemiology of Microinvasive Cervical Carcinoma in an Italian Population Targeted by a Screening Programme.

(1) Background: This population-based study aimed at identifying the factors associated with the likelihood of detection of stage IA cervical carcinoma-versus the detection of stage IB through IV cervical carcinoma-and the patterns of surgical treatment. (2) Methods: Between 1995-2016, 3750 patients living in the Emilia-Romagna Region (northern Italy) were registered with cervical carcinoma, including 2942 eligible patients (median age, 53). Multivariate analysis was performed using binary logistic regression models. (3) Results: The likelihood of stage IA cervical carcinoma (n = 876, 29.8%) did not change over time, decreased with increasing patient age, and was lower for patients with adenocarcinoma and grade 3-4 disease. Three hundred and fifty (40.0%) patients had a conservative treatment, 317 (36.2%) had hysterectomy, 197 (22.5%) had hysterectomy with lymph node dissection (LND), and 12 (1.4%) had a conservative treatment with LND. The proportion of hysterectomy decreased from 70.6% in 1995-1999 to 46.9% in 2011-2016. The likelihood of hysterectomy increased above the age of 40. Among screening-aged (25-64 years) patients, the likelihood of hysterectomy did not differ between screen-detected and non-screen-detected ones. Hysterectomy was increasingly combined with LND. High tumour grade was the strongest determinant of LND during hysterectomy. (4) Conclusions: This study provided a multifaceted overview of stage IA cervical carcinoma over the last decades.

Hormonal contraceptives and the length of their use are not independent risk factors for high-risk HPV infections or high-grade CIN.

AIMS: To evaluate the role of hormonal contraceptives as a risk factor of high-risk human papillomavirus (HR-HPV), cervical intraepithelial lesions (CIN) and cervical cancer in our multi-center population-based LAMS (Latin American Screening) study. METHODS: A cohort study with >12,000 women from Brazil and Argentina using logistic regression to analyze the covariates of hormonal contraception (HOC - oral, injections, patches, implants, vaginal ring and progesterone intrauterine system) use followed by multivariate modeling for predictors of HR-HPV and CIN2+. RESULTS: HR-HPV infection was a consistent risk factor of high-grade CIN in all three groups of women. The length of HOC use was not significantly related to high-grade squamous intraepithelial lesions (HSIL)+ Pap (p = 0.069), LSIL+ Pap (p = 0.781) or ASCUS+ (p = 0.231). The same was true with the length of HOC use and histology CIN3+ (p = 0.115) and CIN2+ (p = 0.515). Frequently, HOC users have previously shown more HPV-related lesions, as well as lower HPV prevalence if they were current smokers. But HOC use and time of usage were not independent risk factors of either HR-HPV infection or high-grade CIN using multiple logistic regressions. CONCLUSIONS: No evidence was found for an association between the use of HOC with an increased risk for HR-HPV infection or high-grade CIN in this cohort.

Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK(1) receptor antagonists.

A focused exploration targeting conformationally restricted analogues of Vestipitant, resulted in the discovery of novel, in vitro potent NK(1) antagonists. In particular, two of the compounds reported exhibited a good pharmacokinetic (PK) profile and produced anxiolytic-like effects in the gerbil foot tapping (GFT) in vivo model.

p300 expression is related to high-risk human papillomavirus infections and severity of cervical intraepithelial neoplasia but not to viral or disease outcomes in a longitudinal setting.

To evaluate the role of the expression of the transcription factor p300 as an independent predictor of high-risk human papillomavirus (HR-HPV) infections and outcome of the cervical disease.Cervical biopsy samples taken at enrolment from 225 women of the Latin American Screening study cohort were analyzed for p300 using immunohistochemistry to assess its value as predictor of (a) cervical intraepithelial neoplasia (CIN) grade, and (b) HR-HPV at baseline, as well as (c) outcomes of HR-HPV infections, and (d) development of incident CIN as surrogate endpoints of progressive disease.There was a significant linear trend in increasing upregulation (=pattern shift) of p300 (P=0.0001) in parallel with increasing grade of CIN. When dichotomized (normal/moderately increase vs. strong-intense), upregulated p300 expression predicted CIN3+ with odds ratio=4.16 (95% confidence interval: 1.95-8.86) (P=0.0001) and CIN2+ with odds ratio=3.48 (95% confidence interval: 1.86-6.48) (P=0.0001). p300 was upregulated more often in HR-HPV+ lesions than in those remaining negative. Semiquantitative viral loads were also directly related to upregulation of p300 (P=0.036), but p300 was not a significant predictor of disease progression to either CIN1+ or CIN2+.p300 expression was upregulated in CIN lesions and related to detection and viral load of HR-HPV but not to their outcome or to incident CIN.

Echo-color-Doppler balance in dialysis patient.

Ultrasonography is a non-invasive,well-controlled, quickly and easily available diagnostic procedure for the patient, is repeatable and not using ionizing radiation. For all these features plays an important role in the clinical management of patients undergoing dialysis. A census of the National Renal Ultrasound Study Group from Italian Society of Nephrology revealed that the 73.04% of Italian Departments of Nephrology and Dialysis are equipped with the ultrasound scanning and this one is commonly used in normal working routine. The main fields of application of this methodology in dialysis patient are: vascular pathology (damages due to systemic atherosclerosis, study and monitoring of arteriovenous fistula), muscle-tendon pathology (caused by hyperparathyroidism and amyloidosis), hyperparathyroidism (parathyroid assessment) and neoplastic disease.

Molecular analysis of HPV 16 E6I/E6II spliced mRNAs and correlation with the viral physical state and the grade of the cervical lesion.

The presence of HPV 16 E6*I/E6*II spliced transcripts, in cervical lesions of different grade, was analyzed to characterize the transcription pattern. The presence and amount of spliced transcripts were correlated with DNA viral markers such as E2/E6 ratio and physical state. The detection of HPV 16 E6*I/E6*II mRNAs was set up by an SYBR Green real-time reverse transcriptase PCR assay with an optimal dynamic range and sensitivity. The assay was applied to the analysis of 71 specimens, positive to HPV 16 as a sole infection, from women with abnormal cervical smears, precisely 31 low-grade squamous intraepithelial lesions and 40 high-grade lesions. Samples negative to both transcripts were found only in low-grade cervical lesions. Three different transcription profiles were found in the low- and high-grade lesions analyzed: in low-grade lesions samples positive only to E6*II and in high-grade lesions samples positive only to E6*I were detected. In low- and high-grade lesions, samples positive to both E6*I and E6*II were found. In the samples positive for both transcripts, the E6*I/E6*II ratio was higher than that in the majority of high-grade lesions and lower than that in all the low-grade lesions. Analyzing the transcription pattern in relation to E2/E6 ratio and to the DNA physical state, the presence of high values of E6*I was associated mainly with low values of E2/E6 ratio and of mixed DNA forms. The detection of HPV 16 E6*I/E6*II mRNAs may serve to identify transcription patterns indicative of cervical disease progression and help physicians to decide clinical management.

Increased risk of oncogenic human papillomavirus infections and incident high-grade cervical intraepithelial neoplasia among smokers: experience from the Latin American screening study.

BACKGROUND: The purpose of this study was to assess the effect of smoking on the prevalence and incidence of high-risk human papillomavirus (hr-HPV) infection and cervical intraepithelial neoplasia (CIN) in a large sample of Latin American women. METHODS: The study examines baseline data on over 12,000 women included in the Latin American Screening Study (Brazil and Argentina), and over 1000 women followed-up for a period of 36 months. Three groups were formed: never smokers, current, and past smokers. The prevalence of hr-HPV infection and CIN were compared between the study groups. In the prospective analysis, women were controlled at 6-month intervals to assess the cumulative risk of incident hr-HPV infection, smear abnormalities, and CIN. RESULTS: A higher prevalence (21.7%) of hr-HPV infection was found among current smokers as compared to never smokers (16.5%) or past smokers (13.5%). Being current smoker was significantly (P <0.01) associated with hr-HPV detection (OR = 1.6; 95% CI = 1.2-2.1). Being a current smoker was a significant predictor of incident hr-HPV during the follow-up [Hazards ratio (HR) = 1.4; 95% CI 1.0-1.9]. For incident CIN2+, being a past smoker (HR = 3.6; 95% CI 1.6-9.8) or current smoker (HR = 3.6; 95% CI 1.5-8.6) were the significant independent predictors. Current and past smokers had a significantly increased risk of incident CIN2+ (P <0.01). CONCLUSIONS: Smoking increases the risk of contracting hr-HPV infection and modifies the effect of a persistent hr-HPV infection by further increasing the risk of developing CIN2+. It seems that this effect modification persists over several years after smoking cessation.

Outcome of conservatively treated microinvasive squamous cell carcinoma of the uterine cervix during a 10-year follow-up.

UNLABELLED: To assess the rate, the cumulative proportion, and the predictors of cervical intraepithelial neoplasia grades 2-3 (CIN 2-3) and invasive disease during the follow-up of patients conservatively treated for microinvasive (stage Ia1-2) squamous cell carcinoma (MIC) of the uterine cervix. METHODS: Two hundred thirty women (median age, 37 years; range, 20-69 years) conservatively treated for MIC were followed up for 10 years and analyzed for cumulative proportion of CIN 2-3/invasive disease. The multivariate survival analysis was used to assess the clinicopathological features predicting the development of CIN 2-3/SCC. RESULTS: Of the 230 patients primarily treated by cone, 76 (33%) underwent hysterectomy as the immediate retreatment, and 13 had a residual disease. The remaining 154 women were subjected to posttreatment follow-up. The depth of stromal invasion was strongly associated with the prevalence of positive lymph nodes and lymphovascular space invasion (LVSI). The detection rate of CIN 2-3/SCC was stable at the first 2 visits (6.5% and 6.9%) and dropped thereafter. The cumulative proportion of patients whose conditions were diagnosed as CIN 2-3/carcinoma was 0.07, 0.09, 0.15, and 0.19 at 6, 12, 36, and 120 months, respectively. In multivariate survival analysis, involvement of 4 quadrants (odds ratio [OR], 5.8), LVSI (OR, 4.5), and cone margin involvement (OR, 5.6) were significant independent predictors of CIN 2-3/SCC after treatment. The upper age tertile (42-69 years) was an independent protective factor (OR, 0.3; 95% confidence interval, 0.1-0.9). CONCLUSIONS: A close, long-term surveillance should be scheduled for the MIC patients conservatively treated. Cone margin involvement, LVSI, and the number of quadrants involved on colposcopy are independent risk factors for disease persistence and/or progression to SCC.

Persistent high-risk human papillomavirus infections and other end-point markers of progressive cervical disease among women prospectively followed up in the New Independent States of the Former Soviet Union and the Latin American Screening study cohorts.

BACKGROUND: New end points are needed in future human papillomavirus (HPV) vaccine efficacy studies that accurately predict disease progression. OBJECTIVES: Potential intermediate end points were analyzed in the combined New Independent States of the Former Soviet Union (NIS) and the Latin American Screening (LAMS) study cohorts. STUDY DESIGN AND METHODS: Data files of 2 international screening trials, the NIS (n = 3187) and the LAMS (n = 12,114) study cohorts, were combined, and a subcohort of 1865 (n = 854 and n = 1011 for the NIS and the LAMS, respectively) women prospectively followed up for 19.7 (median, 22.2) months was analyzed for different intermediate end-point markers of disease progression to squamous intraepithelial lesion (SIL), cervical intraepithelial neoplasia grade 1 and higher (CIN1+), and CIN grade 2 and higher (CIN2+) as terminal events. RESULTS: : Altogether, 131 (7.0%), 90 (4.8%), and 39 (2.1%) cases progressed to SIL, CIN1+, and CIN2+, respectively, progression times being equal in the NIS (11.9, 16.8, and 19.6 months) and LAMS (13.6, 14.1, and 15.4 months) cohorts (P = 0.931, P = 0.335, and P = 0.535). The 2 most powerful end-point markers of disease progression to CIN2+ were high-grade squamous intraepithelial lesions based on Papanicolaou test results at 6-month (odds ratio [OR] = 47.1; 95% confidence interval [CI], 17.3-128.7) and 12-month (OR = 21.5; 95% CI, 5.1-90.8) follow-up visits, with longitudinal positive and negative predictive values of 42.1% and 98.0% (6 months) and 33.3% and 97.7% (12 months). Of the virological end points, more than 6 months of persistent high-risk HPV (HR-HPV) was the most powerful predictor of progression to CIN1+ (OR = 18.6; 95% CI, 2.5-136.5), with longitudinal positive and negative predictive values of 10.3% and 99.4%, respectively. No additional benefit was obtained using more than 12 months of persistent HR-HPV end point. CONCLUSIONS: High-grade squamous intraepithelial lesion based on a Papanicolaou test results at 6- or 12-month follow-up visits was the most powerful end point, either considering cytological end points alone or in comparison to any of the virological end points. Of the virological end points, more than 6-month HR-HPV persistence criteria give the most powerful estimate of a progressive disease.

Smoking worsens the prognosis of mild abnormalities in cervical cytology.

OBJECTIVE: To examine the effect of smoking on the incidence of low- and high-grade cervical intraepithelial neoplasia (CIN) in women with a baseline Pap smear of atypical squamous cells (ASC) or a low-grade squamous intraepithelial lesion (LSIL). DESIGN: Prospective study in which a cohort of women with normal colposcopy and ASC/LSIL at baseline were followed at 6-month intervals of up to 36 months. Women were grouped in post-hoc analysis according to their smoking behavior: never (or past) smokers and current smokers. SETTING: This report was based on data from the Latin American Screening Study, conducted in Sao Paulo, Campinas, Porto Alegre (Brazil) and Buenos Aires (Argentina). POPULATION: A subset of 150 women derived from a cohort of 1,011 women. METHODS: Multivariate Cox analysis and Kaplan-Meier curves were used. MAIN OUTCOME MEASURES: Low- and high-grade CIN during follow-up. RESULTS: The only factor related to an increased risk of developing CIN was the positive high-risk (hr) HPV status (hazard ratio (HR) = 3.42; 95% CI: 1.11-9.43). A total of 21 cases of incident CIN were detected during follow-up. Of these, 11 appeared in the group of 67 smokers and 10 among the 83 non-smoker women (log-rank, p=0.33). Smoking status was not associated with the risk of developing CIN (HR = 0.73; 95% CI: 0.40-1.33). However, when restricting the analysis to high-grade CIN only (11 cases), the probability of developing the disease was significantly higher among smokers (p=0.04). CONCLUSIONS: Smoking contributes additional risk for developing high-grade CIN in women with ASC or LSIL cytology but normal colposcopy.

[HPV vaccination: not only female adolescents and not only prophylactic. Review and position paper of the Italian HPV Study Group (IHSG)].

HPV vaccination has been introduced in clinical practice in recent years and represents the most effective strategy of primary prevention of cervical carcinoma and of female genital preneoplastic conditions. One of the major issues of the subject is represented by vaccination coverage of the target population. Since its introduction, HPV vaccine efficacy has been progressively demonstrated also towards extragenital HPV-correlated conditions and in males too. Moreover, even subjects of older age groups or subjects who already had HPV infections have been demonstrated to received benefits from vaccination, due to improvements of their immunological response. Recently, vaccine efficacy has also been investigated in terms of adjuvant administration after treatments of preneoplastic or benign conditions of the female lower genital tract caused by HPVs; preliminary results indicate an interesting and promising field of application. On this basis, in this article an analysis of the state of the art has been performed, with specific regard to the Italian scenario and with the focus of future perspectives of implementation of the HPV vaccination policy. From the available evidences, the Italian HPV Study Group recommends the extension of systematic HPV vaccination to males too, to adult subjects and also after conservative treatment of genital HPV correlated conditions.