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To make feasible future clinical trials with new-generation human papillomavirus (HPV) vaccines, novel virological surrogate endpoints of progressive disease have been proposed, including high-risk HPV (HR-HPV) persistence for six months (6M+) or 12 months (12M+). The risk estimates (relative risks [RRs]) of these 'virological endpoints' are influenced by several variables, not yet validated adequately. We compared the impact of three referent groups: (i) HPV-negative, (ii) HPV-transient, (iii) HPV-mixed outcome on the risk estimates for 6M+ or 12M+ HR-HPV persistence as predictors of progressive disease. Generalized estimating equation models were used to estimate the strength of 6M+ and 12M+ HR-HPV persistence with disease progression to squamous intraepithelial lesions (SILs), cervical intraepithelial neoplasia (CIN) grade 1+, CIN2+, CIN/SIL endpoints, comparing three optional reference categories (i)-(iii) in a prospective sub-cohort of 1865 women from the combined New Independent States of the Former Soviet Union (NIS) and Latin American Screening (LAMS) studies cohort (n = 15,301). The RRs of these viral endpoints as predictors of progressive disease are affected by the length of viral persistence (6M+ or 12M+) and the surrogate endpoint (SIL, CIN1, CIN2, CIN/SIL). Most dramatic is the effect of the referent group used in risk estimates, with the HPV-negative referent group giving the highest and most consistent RRs for both 6M+ and 12M+ viral persistence, irrespective of which surrogate is used. In addition to deciding on whether to use 6M+ or 12M+ persistence criteria, and cytological, histological or combined surrogate endpoints, one should adopt the HPV-negative referent group as the gold standard in all future studies using viral persistence as the surrogate endpoint of progressive disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the colposcopic accuracy according to the International Federation for Cervical Pathology and Colposcopy (IFCPC) 2002 terminology. MATERIALS AND METHODS: A series of 3,040 women derived from a general population were screened by means of Pap smear, unaided visual inspection, and high-risk human papillomavirus testing. All colposcopic examination results with abnormal findings and with biopsy confirmation (n = 468) were recorded, reviewed by 2 blinded colposcopists according to the IFCPC nomenclature, and included in this analysis. RESULTS: The IFCPC terminology was easily reproduced by the 2 observers with excellent interobserver agreement (kappa =.843). Colposcopy had a sensitivity of 86% and a specificity of 30.3% in distinguishing healthy cervix from that with cervical intraepithelial neoplasia (CIN)/carcinoma. In distinguishing healthy cervix/low-grade lesions (CIN 1) from that with high-grade lesions (CIN 2/3)/carcinoma, colposcopy had a sensitivity of 61.1% and a specificity of 94.4%. Colposcopic findings graded as major changes had the highest positive predictive value for detecting high-grade lesion/carcinoma. The colposcopic abnormalities within the transformation zone and large lesions were more closely related to high-grade lesion/carcinoma, whereas a sharp outer border, multiple colposcopic abnormalities, and iodine negativity were not statistically related to severe lesions. CONCLUSIONS: Colposcopy using the new IFCPC classification is a potentially effective screening method; when used for diagnosis, a histological sampling is necessary. The categorization of major changes and minor changes is appropriate. It is important to describe the lesion localization in relation to the transformation zone and the lesion size because these characteristics are related to high-grade lesions. [ABSTRACT FROM AUTHOR]

Importance: The effectiveness of goal-directed care to reduce loss of brain-dead potential donors to cardiac arrest is unclear., Objective: To evaluate the effectiveness of an evidence-based, goal-directed checklist in the clinical management of brain-dead potential donors in the intensive care unit (ICU)., Design, Setting, and Participants: The Donation Network to Optimize Organ Recovery Study (DONORS) was an open-label, parallel-group cluster randomized clinical trial in Brazil. Enrollment and follow-up were conducted from June 20, 2017, to November 30, 2019. Hospital ICUs that reported 10 or more brain deaths in the previous 2 years were included. Consecutive brain-dead potential donors in the ICU aged 14 to 90 years with a condition consistent with brain death after the first clinical examination were enrolled. Participants were randomized to either the intervention group or the control group. The intention-to-treat data analysis was conducted from June 15 to August 30, 2020., Interventions: Hospital staff in the intervention group were instructed to administer to brain-dead potential donors in the intervention group an evidence-based checklist with 13 clinical goals and 14 corresponding actions to guide care, every 6 hours, from study enrollment to organ retrieval. The control group provided or received usual care., Main Outcomes and Measures: The primary outcome was loss of brain-dead potential donors to cardiac arrest at the individual level. A prespecified sensitivity analysis assessed the effect of adherence to the checklist in the intervention group., Results: Among the 1771 brain-dead potential donors screened in 63 hospitals, 1535 were included. These patients included 673 males (59.2%) and had a median (IQR) age of 51 (36.3-62.0) years. The main cause of brain injury was stroke (877 [57.1%]), followed by trauma (485 [31.6%]). Of the 63 hospitals, 31 (49.2%) were assigned to the intervention group (743 [48.4%] brain-dead potential donors) and 32 (50.8%) to the control group (792 [51.6%] brain-dead potential donors). Seventy potential donors (9.4%) at intervention hospitals and 117 (14.8%) at control hospitals met the primary outcome (risk ratio [RR], 0.70; 95% CI, 0.46-1.08; P = .11). The primary outcome rate was lower in those with adherence higher than 79.0% than in the control group (5.3% vs 14.8%; RR, 0.41; 95% CI, 0.22-0.78; P = .006)., Conclusions and Relevance: This cluster randomized clinical trial was inconclusive in determining whether the overall use of an evidence-based, goal-directed checklist reduced brain-dead potential donor loss to cardiac arrest. The findings suggest that use of such a checklist has limited effectiveness without adherence to the actions recommended in this checklist., Trial Registration: ClinicalTrials.gov Identifier: NCT03179020.

Background and Objectives: The 9-valent human papillomavirus (9vHPV) vaccine Phase III immunogenicity study in 9- to 15-year-old boys and girls was extended to assess immunogenicity and effectiveness through 10 years after the last vaccine dose (NCT00943722)., Methods: Boys (n = 301) and girls (n = 971) who received three 9vHPV vaccine doses in the base study (day 1, months 2 and 6) enrolled in the extension. Serum was collected through month 126 for antibody assessments by competitive Luminex immunoassay and immunoglobulin G-Luminex immunoassay. For effectiveness analysis starting at age 16 years, genital swabs were collected (to assess HPV DNA by polymerase chain reaction) and external genital examinations conducted every 6 months. Primary analyses were conducted in per-protocol populations., Results: Geometric mean antibody titers peaked around month 7, decreased sharply between months 7 and 12, then gradually through month 126. Seropositivity rates remained ≥81% by competitive Luminex immunoassay and ≥95% by immunoglobin G-Luminex immunoassay at month 126 for each 9vHPV vaccine type. After up to 11.0 (median 10.0) years of follow-up postdose 3, there were no cases of HPV6/11/16/18/31/33/45/52/58-related high-grade intraepithelial neoplasia or condyloma in males or females. Incidence rates of HPV6/11/16/18/31/33/45/52/58-related 6-month persistent infection in males and females were low (54.6 and 52.4 per 10000 person-years, respectively) and within ranges expected in vaccinated cohorts, based on previous human papillomavirus vaccine efficacy trials., Conclusions: The 9vHPV vaccine demonstrated sustained immunogenicity and effectiveness through ∼10 years post 3 doses of 9vHPV vaccination of boys and girls aged 9 to 15 years.

We conducted a cross-sectional study to assess how the top 3 highest circulation newspapers from 25 countries are comparing and presenting COVID-19 epidemiological data to their readers. Of 75 newspapers evaluated, 51(68%) presented at their websites at least one comparison of cases and/or deaths between regions of their country and/or between countries. Quality assessment of the comparisons showed that only a minority of newspapers adjusted the data for population size in case comparisons between regions (37.2%) and between countries (25.6%), and the same was true for death comparisons between regions (27.3%) and between countries (27%). Of those making comparisons, only 13.7% explained the difference in the interpretation of cases and deaths. Of 17 that presented a logarithmic curve, only 29.4% explained its meaning. Although the press plays a key role in conveying correct medical information to the general public, we identified inconsistencies in the reporting of COVID-19 epidemiological data., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: The long-term effects caused by COVID-19 are unknown. The present study aims to assess factors associated with health-related quality of life and long-term outcomes among survivors of hospitalization for COVID-19 in Brazil., Methods: This is a multicenter prospective cohort study nested in five randomized clinical trials designed to assess the effects of specific COVID-19 treatments in over 50 centers in Brazil. Adult survivors of hospitalization due to proven or suspected SARS-CoV-2 infection will be followed-up for a period of 1 year by means of structured telephone interviews. The primary outcome is the 1-year utility score of health-related quality of life assessed by the EuroQol-5D3L. Secondary outcomes include all-cause mortality, major cardiovascular events, rehospitalizations, return to work or study, physical functional status assessed by the Lawton-Brody Instrumental Activities of Daily Living, dyspnea assessed by the modified Medical Research Council dyspnea scale, need for long-term ventilatory support, symptoms of anxiety and depression assessed by the Hospital Anxiety and Depression Scale, symptoms of posttraumatic stress disorder assessed by the Impact of Event Scale-Revised, and self-rated health assessed by the EuroQol-5D3L Visual Analog Scale. Generalized estimated equations will be performed to test the association between five sets of variables (1- demographic characteristics, 2- premorbid state of health, 3- characteristics of acute illness, 4- specific COVID-19 treatments received, and 5- time-updated postdischarge variables) and outcomes., Ethics and Dissemination: The study protocol was approved by the Research Ethics Committee of all participant institutions. The results will be disseminated through conferences and peer-reviewed journals.

Background: The quality of clinical care of brain-dead potential organ donors may help reduce donor losses caused by irreversible or unreversed cardiac arrest and increase the number of organs donated. We sought to determine whether an evidence-based, goal-directed checklist for donor management in intensive care units (ICUs) can reduce donor losses to cardiac arrest., Methods/design: The DONORS study is a multicentre, cluster-randomised controlled trial with a 1:1 allocation ratio designed to compare an intervention group (goal-directed checklist for brain-dead potential organ donor management) with a control group (standard ICU care). The primary outcome is loss of potential donors due to cardiac arrest. Secondary outcomes are the number of actual organ donors and the number of solid organs recovered per actual donor. Exploratory outcomes include the achievement of relevant clinical goals during the management of brain-dead potential organ donors. The present statistical analysis plan (SAP) describes all primary statistical procedures that will be used to evaluate the results and perform exploratory and sensitivity analyses of the trial., Discussion: The SAP of the DONORS study aims to describe its analytic procedures, enhancing the transparency of the study. At the moment of SAP subsmission, 63 institutions have been randomised and were enrolling study participants. Thus, the analyses reported herein have been defined before the end of the study recruitment and database locking., Trial Registration: ClinicalTrials.gov, NCT03179020. Registered on 7 June 2017.

Importance: The effects of intensive care unit (ICU) visiting hours remain uncertain., Objective: To determine whether a flexible family visitation policy in the ICU reduces the incidence of delirium., Design, Setting and Participants: Cluster-crossover randomized clinical trial involving patients, family members, and clinicians from 36 adult ICUs with restricted visiting hours (<4.5 hours per day) in Brazil. Participants were recruited from April 2017 to June 2018, with follow-up until July 2018., Interventions: Flexible visitation (up to 12 hours per day) supported by family education (n = 837 patients, 652 family members, and 435 clinicians) or usual restricted visitation (median, 1.5 hours per day; n = 848 patients, 643 family members, and 391 clinicians). Nineteen ICUs started with flexible visitation, and 17 started with restricted visitation., Main Outcomes and Measures: Primary outcome was incidence of delirium during ICU stay, assessed using the CAM-ICU. Secondary outcomes included ICU-acquired infections for patients; symptoms of anxiety and depression assessed using the HADS (range, 0 [best] to 21 [worst]) for family members; and burnout for ICU staff (Maslach Burnout Inventory)., Results: Among 1685 patients, 1295 family members, and 826 clinicians enrolled, 1685 patients (100%) (mean age, 58.5 years; 47.2% women), 1060 family members (81.8%) (mean age, 45.2 years; 70.3% women), and 737 clinicians (89.2%) (mean age, 35.5 years; 72.9% women) completed the trial. The mean daily duration of visits was significantly higher with flexible visitation (4.8 vs 1.4 hours; adjusted difference, 3.4 hours [95% CI, 2.8 to 3.9]; P < .001). The incidence of delirium during ICU stay was not significantly different between flexible and restricted visitation (18.9% vs 20.1%; adjusted difference, -1.7% [95% CI, -6.1% to 2.7%]; P = .44). Among 9 prespecified secondary outcomes, 6 did not differ significantly between flexible and restricted visitation, including ICU-acquired infections (3.7% vs 4.5%; adjusted difference, -0.8% [95% CI, -2.1% to 1.0%]; P = .38) and staff burnout (22.0% vs 24.8%; adjusted difference, -3.8% [95% CI, -4.8% to 12.5%]; P = .36). For family members, median anxiety (6.0 vs 7.0; adjusted difference, -1.6 [95% CI, -2.3 to -0.9]; P < .001) and depression scores (4.0 vs 5.0; adjusted difference, -1.2 [95% CI, -2.0 to -0.4]; P = .003) were significantly better with flexible visitation., Conclusions and Relevance: Among patients in the ICU, a flexible family visitation policy, vs standard restricted visiting hours, did not significantly reduce the incidence of delirium., Trial Registration: ClinicalTrials.gov Identifier: NCT02932358.

Introduction: There is an increasing demand for multi-organ donors for organ transplantation programmes. This study protocol describes the Donation Network to Optimise Organ Recovery Study, a planned cluster randomised controlled trial that aims to evaluate the effectiveness of the implementation of an evidence-based, goal-directed checklist for brain-dead potential organ donor management in intensive care units (ICUs) in reducing the loss of potential donors due to cardiac arrest., Methods and Analysis: The study will include ICUs of at least 60 Brazilian sites with an average of ≥10 annual notifications of valid potential organ donors. Hospitals will be randomly assigned (with a 1:1 allocation ratio) to the intervention group, which will involve the implementation of an evidence-based, goal-directed checklist for potential organ donor maintenance, or the control group, which will maintain the usual care practices of the ICU. Team members from all participating ICUs will receive training on how to conduct family interviews for organ donation. The primary outcome will be loss of potential donors due to cardiac arrest. Secondary outcomes will include the number of actual organ donors and the number of organs recovered per actual donor., Ethics and Dissemination: The institutional review board (IRB) of the coordinating centre and of each participating site individually approved the study. We requested a waiver of informed consent for the IRB of each site. Study results will be disseminated to the general medical community through publications in peer-reviewed medical journals., Trial Registration Number: NCT03179020; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The purpose of this paper is to identify and describe hospital quality indicators, classifying them according to Donabedian's structure, process and outcome model and in specific domains (quality, safety, infection and mortality) in two care divisions: inpatient and emergency services., Design/methodology/approach: A systematic review identified hospital clinical indicators. Two independent investigators evaluated 70 articles/documents located in electronic databases and nine documents from the grey literature, 35 were included in the systematic review., Findings: In total, 248 hospital-based indicators were classified as infection, safety, quality and mortality domains. Only 10.2 percent were identified in more than one article/document and 47 percent showed how they were calculated/obtained. Although there are scientific papers on developing, validating and hospital indicator assessment, most indicators were obtained from technical reports, government publications or health professional associations., Research Limitations/implications: This review identified several hospital structure, process and outcome quality indicators, which are used by different national and international groups in both research and clinical practice. Comparing performance between healthcare organizations was difficult. Common clinical care standard indicators used by different networks, programs and institutions are essential to hospital quality benchmarking., Originality/value: To the authors' knowledge, this is the first systematic review to identify and describe hospital quality indicators after a comprehensive search in MEDLINE/PubMed, etc., and the grey literature, aiming to identify as many indicators as possible. Few studies evaluate the indicators, and most are found only in the grey literature, and have been published mostly by government agencies. Documents published in scientific journals usually refer to a specific indicator or to constructing an indicator. However, indicators most commonly found are not supported by reliability or validity studies.

Objective: To establish the prevalence of physical, cognitive and psychiatric disabilities, associated factors and their relationship with the qualities of life of intensive care survivors in Brazil., Methods: A prospective multicenter cohort study is currently being conducted at 10 adult medical-surgical intensive care units representative of the 5 Brazilian geopolitical regions. Patients aged ≥ 18 years who are discharged from the participating intensive care units and stay 72 hours or more in the intensive care unit for medical or emergency surgery admissions or 120 hours or more for elective surgery admissions are consecutively included. Patients are followed up for a period of one year by means of structured telephone interviews conducted at 3, 6 and 12 months after discharge from the intensive care unit. The outcomes are functional dependence, cognitive dysfunction, anxiety and depression symptoms, posttraumatic stress symptoms, health-related quality of life, rehospitalization and long-term mortality., Discussion: The present study has the potential to contribute to current knowledge of the prevalence and factors associated with postintensive care syndrome among adult intensive care survivors in Brazil. In addition, an association might be established between postintensive care syndrome and health-related quality of life.

Introduction: Human papillomavirus (HPV) is associated with the development of genital warts and different types of cancer, including virtually all cervical cancers and a considerable number of penile, anal and oropharyngeal cancers. Data regarding the prevalence of HPV infection in Brazil are limited and fragmented. We aim to determine HPV prevalence in sexually active women and men aged 16-25 years and to investigate regional differences in virus prevalence and types., Methods and Analysis: This is a nationwide, multicentric, cross-sectional, prospective study that will include participants aged 16-25 years from all Brazilian capital cities. Recruitment will occur in primary health units by trained health professionals who will be responsible for collecting biological samples and interviewing the volunteers. After signing informed consent, all participants will answer a questionnaire that will collect sociodemographic and behavioural data. All samples will be processed in a certified central laboratory, and strict quality control will be performed by many different procedures, including double data entry, training and certification of primary care health professionals responsible for data collection, simulation of interviews, and auditing and monitoring of visits. The sample size will be standardised based on the population distribution of each capital using SAS and R statistical software., Ethics and Dissemination: The project was approved by the research ethics committee of the main institution and the corresponding ethics committees of the recruitment sites. This will be the first Brazilian nationwide study to determine overall HPV prevalence and to examine regional differences and social, demographic and behavioural factors related to HPV infection. Critical analysis of the study results will contribute to epidemiological knowledge and will set a baseline for future evaluation of the impact of the National HPV Vaccination Program., Competing Interests: Competing interests: ASB, FMAdS, CD and AGKM work for the Ministry of Health of Brazil. LLV is a consultant for Merck for the HPV quadrivalent vaccine and for Qiagen, BD and Roche for HPV DNA tests., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: The aim of this study is to assess potential risk factors for breast cancer in a population in Southern Brazil and build a multivariate logistic model using these factors for breast cancer risk prediction., Methods: A total of 4242 women between 40 and 69 years of age without a history of breast cancer were selected at primary healthcare facilities in Porto Alegre and submitted to mammographic screening. They were evaluated for potential risk factors., Results: In all, 73 participants among the 4242 women had a breast cancer diagnosis during the follow-up of the project (10 years). The multivariate analysis considering all the patients aged 40-69 years showed that older age (OR 1.08, 95% CI 1.04-1.12), higher height (OR 1.04, 95% CI 1.01-1.09), and history of previous breast biopsy (OR 2.66, 95% CI 1.38-5.13) were associated with the development of breast cancer. Conversely, the number of pregnancies (OR 0.87, 95% CI 0.78-0.98) and use of hormone replacement therapy (OR 0.39, 95% CI 0.20-0.75) were considered a protective factor. Additionally, we performed an analysis separating the participants into groups of 40-49 and 50-69 years old, since a risk factor could have a specific behavior in these age groups. No additional risk factors were identified within these age brackets, and some factors lost statistical significance., Conclusion: The risk prediction model indicates that the following variables should be assessed in this specific population: age, height, having had previous breast biopsies, number of pregnancies, and use of hormone replacement therapy. These findings may help to better understand the causal model of breast cancer in Southern Brazil.

Objectives: The aim of the study was to assess the 2 pathways of vulvar carcinogenesis and correlate immunohistochemical expression of p53 with histopathological findings., Materials and Methods: This cross-sectional study included 76 cases. Patients were classified according to the 2004 International Society for the Study of Vulvovaginal Disease Terminology, followed by a review of clinical records and immunohistochemical staining for p53., Results: Fifteen cases were in the human papillomavirus (HPV)-associated pathway (12 cases of usual vulvar intraepithelial neoplasia [VIN] and 3 of warty squamous cell carcinoma [SCC]), and 13 cases were in the HPV-independent pathway (5 cases of differentiated VIN and 8 of keratinizing SCC). Significant differences in p53 expression were observed between the 2 pathways of carcinogenesis: in the lesions related to the HPV-independent pathway, the percentage of p53-positive cells was greater (>25%, p < .001), and the staining pattern was basal (extending into the middle layer) in differentiated VIN and diffuse or infiltrative in warty SCC (p < 0.001). In the lesions HPV-associated pathway, p53 staining was less extensive (≤10% of cells, p < 0.001) and followed basal pattern in usual VIN, whereas warty SCCs were negative for p53 (p < 0.001)., Conclusions: Unique patterns of histological appearance and p53 expression can separate vulvar lesions into 2 distinct pathways of carcinogenesis. We propose that p53 immunohistochemistry may be performed simultaneously with histopathological examination in all cases of VIN and vulvar SCC, because it would aid in definition of the pathway of carcinogenesis and thus enable better clinical follow-up of patients with these conditions.

Introduction: Human papillomavirus (HPV) infection is a cause of premalignant and malignant cancer in the lower genital and digestive tracts. In Brazil, there have been no prevalence studies that included a nationwide sample, and the prevalence of HPV has not been determined in many regions., Methods: We will search the EMBASE, LILACS, MEDLINE, Web of Science and SciELO databases and previously published review articles to identify original research articles assessing HPV prevalence of the perineal (cervical, penile and anal) and oral areas. No exclusion criteria related to language or publication date will apply. 2 reviewers will independently screen for eligibility and perform data extraction. Discrepancies will be resolved through consensus; the opinion of a third reviewer will be sought as necessary. Relevant measures and data about study and population characteristics will be extracted from the included studies. Where possible, study prevalence will be pooled using a random-effects meta-analysis. The methodological quality of the studies will be assessed using an adapted version of the NIH 'Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies'. The overall quality of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Ethics and Dissemination: We expect to estimate the prevalence of perineal and oral HPV infection in the general population as well as the prevalence of HPV infection in individuals with premalignant and malignant lesions in Brazil and its 5 geographic regions. This systematic review does not require ethical approval., Trial Registration Number: CRD42016032751., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Patient education on pharmacological therapy may increase medication adherence and decrease hospitalizations. Our aim is to evaluate the effectiveness of pharmaceutical care at emergency department discharge in patients with hypertension and/or diabetes., Methods/design: This is a randomized controlled trial. Participants will be recruited from a public emergency department at Restinga district in Porto Alegre, southern Brazil. A total of 380 patients will be randomly assigned into 2 groups at the moment of emergency department discharge after receiving medical orientations: an intervention group, consisting of a structured individual counseling session by a pharmacist in addition to written orientations, or a control group, consisting only of written information about the disease. Outcomes will be assessed in an ambulatory visit 2 months after the randomization. The primary outcome is the proportion of patients with high medication adherence assessed using the Morisky-Green Test and the Brief Medication Questionnaire. The secondary outcomes are reduction of blood pressure, glycated hemoglobin, fasting plasma glucose, quality of life and number of visits to the emergency department., Discussion: Pharmaceutical care interventions have shown to be feasible and effective in increasing medication adherence in both hospital outpatient and community pharmacy settings. However, there have been no previous assessments of the effectiveness of pharmacy care interventions initiated in patients discharged from emergency departments. Our hypothesis is that pharmaceutical counseling is also effective in this population., Trial Registration: ClinicalTrials.gov registration number: NCT01978925 (11 November 2013) and Brazilian Registry of Clinical Trials U1111-1149-8922 (5 November 2013).

Background: There is no consensus in the literature regarding the effectiveness of lifestyle modification interventions, including recommendations about specific diet or exercise program for patients with breast cancer. Diet interventions and regular physical activity may reduce the risk of breast cancer and its recurrence. The primary aim of our study is to evaluate the effects of different lifestyle modification interventions (diet and physical activity) in the survival of patients with stages I to III breast cancer after treatment., Methods/design: This review will be conducted according to the Cochrane Handbook for Systematic Reviews of Intervention and will be reported following the PRISMA statement recommendations. CENTRAL, MEDLINE and EMBASE databases will be searched for peer-reviewed literature. Randomized controlled trials of diet, exercise, or both, compared with usual care, after treatment of breast cancer stage I to III will be included in the systematic review. Two authors will independently screen titles and abstracts of studies for potential eligibility. Data will be combined using random-effect meta-analysis models with restricted maximum-likelihood as variance estimator, and will be presented as relative risk or standardized mean difference with 95% CI. The quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework and summary of findings tables will be presented for patient important outcomes., Discussion: Our study may improve the current understanding of the role that lifestyle-modifiable factors can play in saving or prolonging the lives of women who have been treated for breast cancer, and also on modifying their quality of life., Systematic Review Registration: The review has been registered with PROSPERO (registration number CRD42014008743).

Purpose: This study aims to evaluate and to compare the performance of cervical digital photography (CDP) to the visual inspection with acetic acid (VIA) and visual inspection with Lugol's iodine (VILI) methods for screening the uterine cervix cancer and its precursor lesions in developing countries., Methods: A cross-sectional study was performed in Brazil. 176 women were evaluated by VIA, VILI, CDP with acetic acid and CDP with Lugol's iodine. Kappa statistic was used to estimate the interobserver and intermethod agreement. Sensitivity, specificity and diagnostic accuracy of the four methods (VIA, VILI, CDP with acetic acid, CDP with Lugol's iodine) was calculated., Results: Interobserver agreement for CDP with acetic acid was K = 0.441 and for CDP with Lugol's iodine was K = 0.533; intermethod agreement of VIA and CDP with acetic acid, K = 0.559; and of VILI and CDP with Lugol's iodine, K = 0.507. Sensitivity and specificity of CDP with acetic acid were 84.00 and 95.83 %, and of CDP with Lugol's iodine were 88.00 and 97.26 %, respectively. The diagnostic accuracy of CDP with acetic acid and CDP with Lugol's iodine was 92.78 and 94.90 %, respectively., Conclusion: This was the first study to assess the CDP with Lugol's iodine performance, which had similar performance to the CDP with acetic acid. CDP is considered a promising method for screening the uterine cervix cancer and its precursor lesions in developing countries.

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.

We sought to evaluate the performance of diagnostic tools to establish an affordable setting for early detection of cervical cancer in developing countries. We compared the performance of different screening tests and their feasibility in a cohort of over 12,000 women: conventional Pap smear, liquid-based cytology, visual inspection with acetic acid (VIA), visual inspection with Iodine solution (VILI), cervicography, screening colposcopy, and high-risk human papillomavirus (HPV) testing (HR-HPV) collected by physician and by self-sampling. HR-HPV assay collected by the physician has the highest sensitivity (80 %), but high unnecessary referrals to colposcopy (15.1 %). HR-HPV test in self-sampling had a markedly lower (57.1 %) sensitivity. VIA, VILI, and cervicography had a poor sensitivity (47.4, 55, and 28.6 %, respectively). Colposcopy presented with sensitivity of 100 % in detecting CIN2+, but the lowest specificity (66.9 %). Co-testing with VIA and VILI Pap test increased the sensitivity of stand-alone Pap test from 71.6 to 87.1 % and 71.6 to 95 %, respectively, but with high number of unnecessary colposcopies. Co-testing with HR-HPV importantly increased the sensitivity of Pap test (to 86 %), but with high number of unnecessary colposcopies (17.5 %). Molecular tests adjunct to Pap test seems a realistic option to improve the detection of high-grade lesions in population-based screening programs.

Background: The complex natural history of human papillomavirus (HPV) infections following a single HPV test can be modeled as competing-risks events (i.e., no-, transient- or persistent infection) in a longitudinal setting. The covariates associated with these competing events have not been previously assessed using competing-risks regression models., Objectives: To gain further insights in the outcomes of cervical HPV infections, we used univariate- and multivariate competing-risks regression models to assess the covariates associated with these competing events., Study Design and Methods: Covariates associated with three competing outcomes (no-, transient- or persistent HR-HPV infection) were analysed in a sub-cohort of 1,865 women prospectively followed-up in the NIS (n = 3,187) and LAMS Study (n = 12,114)., Results: In multivariate competing-risks models (with two other outcomes as competing events), permanently HR-HPV negative outcome was significantly predicted only by the clearance ofASCUS+ Pap during FU, while three independent covariates predicted transient HR-HPV infections: i) number of recent (< 12 months) sexual partners (risk increased), ii) previous Pap screening history (protective), and history of previous CIN (increased risk). The two most powerful predictors of persistent HR-HPV infections were persistent ASCUS+ Pap (risk increased), and previous Pap screening history (protective). In pair-wise comparisons, number of recent sexual partners and previous CIN history increase the probability of transient HR-HPV infection against the HR-HPV negative competing event, while previous Pap screening history is protective. Persistent ASCUS+ Pap during FU and no previous Pap screening history are significantly associated with the persistent HR-HPV outcome (compared both with i) always negative, and ii) transient events), whereas multiparity is protective., Conclusions: Different covariates are associated with the three main outcomes of cervical HPV infections. The most significant covariates of each competing events are probably distinct enough to enable constructing of a risk-profile for each main outcome.

In addition to oncogenic 'high-risk' human papillomaviruses (HR-HPV), several co-factors are needed in cervical carcinogenesis, but it is poorly understood whether these HPV co-factors associated with incident cervical intraepithelial neoplasia (CIN) grade 1 are different from those required for progression to CIN2 and CIN3. To gain further insights into the true biological differences between CIN1, CIN2 and CIN3, we assessed HPV co-factors increasing the risk of incident CIN1, CIN2 and CIN3. Data from the New Independent States of the Former Soviet Union (NIS) Cohort (n = 3187) and the Latin American Screening (LAMS) Study (n = 12,114) were combined, and co-factors associated with progression to CIN1, CIN2 and CIN3 were analysed using multinomial logistic regression models with all covariates recorded at baseline. HR-HPV-positive women (n = 1105) represented a subcohort of all 1865 women prospectively followed up in both studies. Altogether, 90 (4.8%), 39 (2.1%) and 14 (1.4%) cases progressed to CIN1, CIN2 and CIN3, respectively. Baseline HR-HPV was the single most powerful predictor of incident CIN1, CIN2 and CIN3. When controlled for residual HPV confounding by analysing HR-HPV-positive women only, the risk profiles of incident CIN1, CIN2 and CIN3 were unique. Completely different HPV co-factors were associated with progression to CIN1, CIN2 and CIN3 in univariate and multivariate analyses, irrespective of whether non-progression, CIN1 or CIN2 was used as the reference outcome. HPV co-factors associated with progression to CIN1, CIN2 and CIN3 display unique profiles, implicating genuine biological differences between the three CIN grades, which prompts us to re-visit the concept of combining CIN2 with CIN3 or CIN1.

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., (Copyright © 2010 S. Karger AG, Basel.)

Our objective was to assess whether neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin 2 (LCN2) expression in cervical human papillomavirus (HPV) lesions has implications on the outcome of HPV infections or disease progression. Cervical biopsy specimens from 225 women in the Latin American Screening study were analyzed for NGAL/LCN2 expression using immunohistochemical analysis, to assess associations with cervical intraepithelial neoplasia (CIN) grade, high-risk HPV, and in predicting outcomes of high-risk (HR)-HPV infections. Expression of NGAL/LCN2 increased with lesion grade (odds ratio [OR], 3.86; 95% confidence interval [CI], 1.53-9.71; P = .001). Up-regulation was also related to HR-HPV detection (OR, 2.21; 95% CI, 1.15-4.24; P = .016) and showed a linear relationship to HR-HPV load (P = .002). NGAL/LCN2 expression was of no value in predicting the outcomes of HR-HPV infections or the surrogate end points (incident CIN 1+ and CIN 2+) of progressive disease. Because the SV40 large T antigen is a powerful up-regulator of this lipocalin, up-regulation of NGAL/LCN2 in CIN is probably induced by HR-HPV E6 oncoprotein, most likely by eliminating its normal transcription repression exerted by wild-type p53.

To assess whether the potentially high-risk (HR) human papillomavirus (HPV)-related up-regulation of 14-3-3sigma (stratifin) has implications in the outcome of HPV infections or cervical intraepithelial neoplasia (CIN) lesions, cervical biopsy specimens from 225 women in the Latin American Screening Study were analyzed for 14-3-3sigma expression using immunohistochemical analysis. We assessed its associations with CIN grade and HR HPV at baseline and value in predicting outcomes of HR-HPV infections and the development of incident CIN 1+ and CIN 2+. Expression of 14-3-3sigma increased in parallel with the lesion grade. Up-regulation was also significantly related to HR-HPV detection (P = .004; odds ratio, 2.71; 95% confidence interval, 1.37-5.35) and showed a linear relationship to HR-HPV loads (P = .003). 14-3-3sigma expression was of no value in predicting the outcomes (incident, persistent, clearance) of HR-HPV infections or incident CIN 1+ and CIN 2+. 14-3-3sigma is not inactivated in cervical carcinoma and CIN but is up-regulated on transition from CIN 2 to CIN 3. Its normal functions in controlling G(1)/S and G(2)/M checkpoints are being bypassed by HR HPV.

Protease inhibitor serpin-B2 (plasminogen activator inhibitor-2 [PAI-2]) protects pRb from degradation in human papillomavirus (HPV)-18+ HeLa cells. Our objective was to assess whether the pRb-mediated HPV-suppressive effect of PAI-2 in cancer cell lines has implications in the outcome of HPV infections. Cervical biopsy specimens from 225 women were analyzed for PAI-2 expression to assess its value as a predictor of cervical intraepithelial neoplasia (CIN) grade, high-risk (HR) HPV at baseline, outcomes of HR-HPV infections, and the development of incident CIN. PAI-2 expression increased in parallel with lesion grade. Nuclear PAI-2 expression was significantly related to HR-HPV detection and had a linear relationship with HR-HPV load. PAI-2 expression was of no value in predicting the outcomes of HR-HPV infections. The same was true for PAI-2 as a predictor of surrogate end points (incident CIN 1+, CIN 2+) of progressive disease. PAI-2 expression is up-regulated on transition from CIN 2 to CIN 3. The HR-HPV suppressive effects of PAI-2 were not related to more favorable outcomes of HR-HPV infections or lower risk of disease progression to CIN.

Bypassing the local immunological defense reactions in the cervix is one of the prerequisites for human papillomaviruses (HPV) infections to progress to intraepithelial neoplasia (CIN). The role of potent immunosuppressive cytokines, e.g., interleukin-10 (IL-10), depressing these local virus-specific immunological responses is incompletely studied. To assess, whether IL-10 expression in cervical HPV lesions has any implications in the outcome of HPV infections or disease progression to CIN. Baseline cervical biopsies from 225 women of the LAMS study sub-cohort were analyzed for IL-10 expression using immunohistochemistry, to assess its associations with CIN grade, and high-risk HPV (HR-HPV) at baseline, as well as in predicting outcomes of HR-HPV infections, and development of incident CIN1+ and CIN2+ in this longitudinal setting. Expression of IL-10 in cervical lesions was up-regulated most often in high-grade CIN, and IL-10 over-expression retained its value as independent predictor of CIN2+ (odds ratio (OR) = 4.92) and CIN3+ (OR = 7.51) also in multivariate model, including HR-HPV and several known covariates of IL-10 expression. Up-regulation was not related to HR-HPV detection, and showed no relationship to HR-HPV viral loads. Using longitudinal predictive indicators (SE, SP, PPV, NPV), IL-10 expression was of no value in predicting (1) the outcomes of HR-HPV infections, or (2) the surrogate endpoints (incident CIN1+, CIN2+) of progressive disease. IL-10 over-expression (along with HR-HPV) was one of the independent covariates of CIN2/3. This immunosuppressive cytokine might play an important role in creating a microenvironment that favors progressive cervical disease and immune evasion by HR-HPV.

Objectives: We have previously demonstrated that aromatase mRNA is induced in cervical carcinomas compared to normal tissue, suggesting that in situ aromatase expression leading to elevated local estrogen production may contribute to cervical carcinogensis. Our objectives are to examine 1) whether aromatase protein and activity are induced in cervical carcinomas, 2) aromatase expression correlates with disease stage, and 3) inflammatory cytokines (e.g., IL-6 and TNFalpha) may correlate with aromatase expression., Methods: RNA and protein were isolated from human cervical carcinomas and normal cervical biopsies to examine aromatase expression, using real-time RT-PCR, Western blot analysis, and immunohistochemistry. Aromatase activity in tissue was measured using the tritiated water release method. IL-6 and TNFalpha expression was also examined., Results: Aromatase protein and activity levels were increased in cervical carcinomas compared to normal tissue. RNA levels correlated significantly with disease progression, with highest aromatase expression detected in stage IV tumors (p<0.001, R(2)=0.77). Aromatase promoters 1.3 and 1.4 were elevated in cervical carcinomas and in cervical cancer cells. The expression of inflammatory cytokines IL-6 and TNFalpha, known to induce aromatase, significantly correlated with aromatase expression (R(2)>0.9). TNFalpha treatment induced aromatase expression in cervical cancer cells., Conclusion: Increased aromatase protein and activity in cervical carcinomas and the correlation of its expression with disease stage implicates it in cervical carcinogenesis. The correlation of IL-6 and TNFalpha expression with aromatase suggests that these inflammatory cytokines may induce aromatase expression, which is confirmed by induction of aromatase expression due to TNFalpha treatment of cervical cancer cells.

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.

The use of loop electrosurgical conization (LEC) for the treatment of large high-grade cervical intraepithelial neoplasias (CINs) is often associated with a difficult procedure that results in accidental sample fragmentation, thermal damage and sometimes the presence of positive margins. This study aims to compare LEC that removes the cervical cone in two blocks (anterior and posterior cervical lips - LEC2) with LEC performed with one pass of the loop (LEC1). In a randomized, controlled trial, patients that needed conization due to high-grade CIN were assigned to one of the techniques. There were no differences in terms of age, cone histopathological diagnosis, blood loss, vaginal injuries, stenosis of the cervical os and specimen artifacts. LEC2 required less hemostatic sutures. LEC2 showed no specimen fragmentation, while LEC1 did (0 vs. 5.9%; p = 0.10). As expected, LEC2 samples were heavier (p = 0.01), included a larger ectocervical area (p = 0.001) and, therefore, had a greater volume (p < 0.001) compared to LEC1 samples. The height of the LEC2 specimens was smaller than that of LEC1 specimens (p < 0.001). LEC2 yielded fewer cases of positive margins (12.7%) than LEC1 (33.3%; p = 0.021). We conclude that the LEC2 technique is an effective treatment choice: it is safe for the patient, with better outcomes regarding sample quality than LEC1. Further studies are encouraged regarding this procedure., (Copyright (c) 2009 S. Karger AG, Basel.)

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.

Objective: To compare performance of conventional Pap test, liquid based cytology (LBC) and visual inspection with acetic acid (VIA), as well as human papillomavirus (HPV) testing in 2 subcohorts of women, <35 and > or =35 years of age., Study Design: Performance indicators were calculated using colposcopic biopsies as the gold standard; all results were corrected for verification bias using maximum likelihood., Result: Both conventional Pap test n d Hybrid Capture 2 (HC2) assay performed significantly better among older women than younger; no difference was observed in performance of LBC and VIA, both inferior to Pap and HC2. The Pap test was more specific than HC2 in both subcohorts; HC2 had the highest sensitivity. For individual tests, the best balance between sensitivity and specificity was obtained for HC2 assay corrected for verification bias in the older women's subcohort; this was further improved by the combined use of the Pap test and HC2., Conclusion: Age of the target population is an important determinant of the performance of different screening tests. The choice of optimal test for women <35 and > or =35 years of age depends on whether the highest positive predictive value (Pap test).

Objectives: To describe the expression of vascular endothelial growth factor (VEGF), proto-oncogene macrophage colony-stimulating factor receptor (c-fms) and cyclooxygenase-2 (COX-2) in cervical carcinogenesis and to analyze the correlation of VEGF with c-fms and COX-2 expression., Methods: In this study, 26 cases of benign cervix, 28 low-grade cervical intraepithelial neoplasia (CIN; CIN 1), 30 high-grade CIN (CIN 2/3) and 28 squamous cervical carcinomas (SCC) were examined by immunohistochemistry (IHC) and analysis was performed separately for epithelium and stroma., Results: Positive epithelial expressions in normal cervix, low-grade CIN, high-grade CIN and SCC were, respectively: VEGF - 11.5%, 39.3%, 53.3% and 75% (P<0.001); c-fms - 0%, 10.7%, 40% and 67.9% (P<0.001); COX-2 - 7.7%, 39.3%, 80% and 100% (P<0.001). Stromal VEGF expression was higher than epithelial expression in all CIN grades and was also associated with the lesion grade, while c-fms and COX-2 stromal expression was weak. VEGF expression was statistically correlated to c-fms and COX-2 expression in high-grade CIN (P=0.020 and P=0.027, respectively) and SCC (P=0.015 and P=0.005, respectively)., Conclusions: On the basis of our findings, these factors may participate in the development and progression of CIN lesions, with possible interaction of c-fms and COX-2 on VEGF expression, and may be potential molecular targets for studies of cervical cancer prevention and treatment.

The aim of this study was to investigate whether activin A has an effect on the attachment and/or invasion of endometrial cells in a modeled peritoneum in vitro. Cultured endometrial stromal cells (ESCs) and endometrial epithelial cells (EECs) were treated with activin A (6.25-50 ng/ml) and with activin A (25 ng/ml) with and without inhibin A or follistatin. Fluorescent labeled cells were added to confluent peritoneal mesothelial cells (PMCs) and to a monolayer of confluent PMCs grown in a Matrigel invasion assay. The rate of endometrial cell attachment and invasion through PMCs was assessed. The expression of cell adhesion proteins N- and E-cadherin was evaluated with real-time RT-PCR. Activin A (25 ng/ml) promoted invasion of the endometrial cells through the modeled peritoneum (>2-fold versus control) and this effect was partially reversed by inhibin A and follistatin. Activin A had no effect on the rate of attachment of the endometrial cells to the PMCs or in the rate of proliferation. In addition, activin A induced a decreased mRNA expression of E-cadherin in cultured EECs. In conclusion, activin A increases invasion of EECs and ESCs into modeled peritoneum. In EECs, this effect may be related to down-regulation of E-cadherin expression. Further studies are warranted to evaluate the role of activin-A in the genesis of the endometriotic lesion.

Drug abuse (addiction) has been listed among the risk factors for human papillomavirus (HPV) infections, but no case-control studies exist to rule out sexual behaviour and other potential confounders. The aim of this study is to evaluate the role of drug addiction as an independent predictor of HR-HPV infections and (cervical intraepithelial neoplasia) CIN2+ in an age-matched case-control (1:4) study nested within the prospective Latin American Screening (LAMS) study cohort. All 109 women in the LAMS cohort (n=12,114) reporting drug abuse/addiction were matched with four controls (n = 436) of non-abusers strictly by age. Conditional logistic regression analysis was used to estimate the co-variates of drug abuse, and the whole series (n=545) was analysed for predictors of HR-HPV and CIN2+ using univariate and multivariate regression models. Oncogenic HPV infections were significantly (P=0.019) more prevalent among abusers (37.7%) than in controls (21.9%), but there was no difference in high-grade squamous intraepithelial lesions (P=0.180) or CIN2+ lesions (P=0.201). In multivariate conditional logistic regression, number of lifetime sexual partners (P=0.0001), ever smokers (P=0.0001), non-use of OCs (P=0.013), ever having sexually transmitted diseases (STD) (P=0.041) and no previous Pap smear (P=0.027) were independent co-variates of drug addiction. Drug abuse was not an independent risk factor of high-risk (HR)-HPV infection, which was significantly predicted by (1) age below 30 years (P=0.045), (2) more than five lifetime sexual partners (P=0.046) and (3) being current smoker (P=0.0001). In multivariate model, only HR-HPV infection was an independent risk factor of CIN2+ (P=0.031), with adjusted OR=11.33 (95% CI 1.25-102.50). These data indicate that drug addiction is not an independent risk factor of either HR-HPV infections or CIN2+, but the increased prevalence of HR-HPV infections is explained by the high-risk sexual behaviour and smoking habits of these women.

The study of biomarkers by immunohistochemistry (IHC) for cervical cancer and intraepithelial lesions is a promising field. However, manual interpretation of IHC and reproducibility of the scoring systems can be highly subjective. In this article, we present a novel and simple computer-assisted IHC interpretation method based on cyan-magenta-yellow-black (CMYK) color format, for tissues with diaminobenzidine cytoplasmatic staining counterstained with methyl green. This novel method is more easily interpreted than previous computer-assisted methods based on red-green-blue (RGB) color format and presents a strong correlation with the manual H-score. It is simple, objective, and requires only low-cost software and minimal computer skills. Briefly, a total of 67 microscopic images of cervical carcinoma, normal cervix, and negative controls were analyzed in Corel Photo Paint X3 software in CMYK and RGB color format, and compared with manual H-score IHC assessments. The clearest and best positive correlation with the H-score was obtained using the image in CMYK color format and crude values of magenta color (Spearman correlation coefficient=0.84; agreement of 93.33%, P<0.001). To obtain this value, only 3 steps were necessary: convert the image to CMYK format, select the area of interest for analysis, and open the color histogram tool to visualize the magenta value.

Objective: To evaluate the population of macrophages during the cervical malignant transformation and its influence in CIN outcome., Methods: Biopsies from 26 normal cervix, 28 low-grade (LSIL), 30 high grade squamous intraepithelial lesions (HSIL) and 28 squamous cell carcinomas (SCC) were stained by H&E to assess inflammation and by immunohistochemistry with anti-CD68 to detect macrophages. The macrophage count was corrected for the epithelial and stromal compartments using appropriate software. Clinical and prospective follow-up data were also available., Results: We identified that macrophage count increased linearly with disease progression (median count per case at x200 magnification: normal, 5.1; LSIL, 5.5; HSIL, 9.9; SCC, 14.5; P<0.001), that inflammation also increased (moderate-intense inflammation present in 25%, 46.1%, 58.4% and 89.3% of normal, LSIL, HSIL and SCC, respectively; P<0.001) and that macrophage count was independently associated with the lesion grade (P<0.001). Moreover, macrophages showed an increasing migration into the epithelium along with the progression of CIN to invasive cancer. Of the 24 LSIL cases with information available, followed-up for 805+/-140 days, 16 regressed, 6 persisted and 2 progressed. Age, high-risk HPV or inflammation were not risk factors for persistent/progressed LSIL in our cohort. However, LSIL that persisted or progressed showed a higher macrophage count (median of 10.8) than lesions that regressed (7; P=0.031)., Conclusions: The study on macrophages offers a potential approach for cervical cancer treatment, since macrophages are closely related to progression of CIN, and can be used as an applicable marker of such a risk.

Cervical cancer is the third most common gynecologic cancer in the United States. The presence and possible involvement of several cytokines have been studied in cervical cancer; however, very little data, if any, are available on whether cervical tumors are responsive to stimulation by the macrophage colony-stimulating factor-1 (CSF-1). Given the involvement of c-fms and its ligand CSF-1 in gynecologic cancers, such as that of the uterus and the ovaries, we have examined the expression of c-fms and CSF-1 in cervical tumor (n = 17) and normal cervix (n = 8) samples. The data show that c-fms and its ligand are significantly higher in cervical carcinomas compared with normal samples. Immunohistochemistry not only showed that tumor cells expressed significantly higher levels of c-fms but also c-fms levels were markedly higher in tumor cells than tumor-associated stromal cells. Blocking c-fms activity in cervical cancer cells, which express CSF-1 and c-fms, resulted in increased apoptosis and decreased motility compared with control, suggesting that CSF-1/c-fms signaling may be involved in enhanced survival and possibly invasion by cervical cancer cells via an autocrine mechanism. Combined, the data show for the first time the induction of CSF-1 and c-fms in cervical carcinomas and suggest that c-fms activation may play a role in cervical carcinogenesis. Additionally, our data suggest that transforming growth factor-beta1 may be a factor in inducing the expression of c-fms in cervical cancer cells. The data suggest that c-fms may be a valuable therapeutic target in cervical cancer.

Objective: To compare the expulsion rates of intrauterine devices (IUDs) inserted in the immediate postpartum after vaginal birth and cesarean section., Methods: Nineteen patients who had a vaginal birth and 19 patients who had a cesarean section at Hospital de Clínicas de Porto Alegre, Brazil, were selected for copper T 380A IUD insertion. With the aim of detecting clinically unnoticed dislodged devices, ultrasound examinations were performed at 1 month and between 3 and 12 months after delivery. The IUDs were considered completely expelled when found outside the endometrial cavity (e.g., in the cervical canal) or outside the uterus (in the vagina)., Results: Expulsion rates were statistically different between the two groups: after a vaginal birth, 50% (ultrasound only) + 27.8% (clinical examination); and post-cesarean section, 0% (p < .001; OR 5.75, 95% CI 2.36-14.01)., Conclusion: Considering that the contraceptive efficacy of IUDs is associated with their intrauterine location, the high expulsion rates seen when they are inserted immediately after vaginal delivery contraindicate their use in this setting. The use of IUDs immediately after a cesarean section is still a reasonable alternative because its expulsion rate was zero. Ultrasound assessment of IUD positioning performed better than clinical examination, which failed to detect expulsion after postpartum insertion in 75% of the cases (9 from 12 cases).

Objectives: This is a European Commission (EC)-funded ongoing study known as the LAMS (Latin American Screening) study, where PAP smear/liquid-based cytology and screening colposcopy were compared with i) three optional screening tools [visual inspection with acetic acid (VIA), or Lugol's iodine (VILI), cervicography] and with ii) Hybrid Capture II from a) conventional samples and from b) self-samples, in women at different risk for cervical cancer in Brazil and Argentina., Study Design: During 2002-2003, a cohort of 12,107 women attending four clinics: Campinas (CA), Sao Paulo (SP), Porto Alegre (PA) and Buenos Aires (BA), were interviewed for risk factors, and examined using the 8 diagnostic arms. Colposcopy was performed for women positive in any test and for 5% of women with baseline PAP-negative and 20% of HCII-negatives. All high-grade lesions (CIN2/3) were treated, and low-grade CIN are prospectively followed-up., Results: Of the 12,107 women, the following baseline data are available: epidemiological data (n=11,996), conventional PAP smears (n=10,363), LBC, SurePATH (n=320), LBC, DNA-Citoliq (n=1,346), VIA (n=12.067), VILI (n=3,061), cervicography (n=279), screening colposcopy (n=3,437), HCII conventional (n=4,710), HCII self-sampling (n=246) and cervical biopsies (n=1,524). The four sub-cohorts differ significantly in all their baseline data on the implicated risk factors of cervical cancer, consonant with their origin from regions with different cancer incidence. Around 95% of all PAP smears were negative, with slight variations in the prevalence of LSIL and HSIL between the four centers. Significant differences were found in the detection rates of abnormal findings in VIA, VILI and colposcopy between the four centers (p=0.0001). The prevalence of HPV was practically identical (16.5-18.8%) in all four cohorts (p=0.486), with no differences in the relative viral loads. Biopsy results were different depending on whether the women underwent screening colposcopy (BA) or elective colposcopy (others)., Conclusion: Four cohorts with significantly different baseline data are available, and prospective follow-up of these women permits analysis of whether variations in cervical cancer incidence in these regions is due to i) different natural history of the precursor lesions, or ii) due to different levels of exposure to the known risk factors.