Publications by authors named "Kari Juhani Syrjanen"

19 Publications

  • Page 1 of 1

Human papillomavirus is not associated to non-small cell lung cancer: data from a prospective cross-sectional study.

Infect Agent Cancer 2019 2;14:18. Epub 2019 Aug 2.

1Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Barretos, Brazil.

Background: The pathogenesis of lung cancer is triggered by a combination of genetic and environmental factors, being the tobacco smoke the most important risk factor. Nevertheless, the incidence of lung cancer in non-smokers is gradually increasing, which demands the search for different other etiological factors such as occupational exposure, previous lung disease, diet among others. In the early 80's a theory linked specific types of human papillomavirus (HPV) to lung cancer due to morphological similarities of a subset of bronchial squamous cell carcinomas with other HPV-induced cancers. Since then, several studies revealed variable rates of HPV DNA detection. The current study aimed to provide accurate information on the prevalence of HPV DNA in lung cancer.

Methods: Biopsies were collected from 77 newly diagnosed non-small cell lung cancer (NSCLC) patients treated at the Thoracic Oncology Department at Barretos Cancer Hospital. The samples were formalin fixed and paraffin embedded (FFPE), histologic analysis was performed by an experienced pathologist. DNA was extracted from FFPE material using a commercial extraction kit and HPV DNA detection was evaluated by multiplex PCR and HPV16 specific real-time PCR.

Results: HPV was not identified in any of the samples analysed (69).

Conclusions: Our data demonstrated a lack of HPV DNA in a series of NSCL cancers.
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August 2019

HPV infection and p53 and p16 expression in esophageal cancer: are they prognostic factors?

Infect Agent Cancer 2017 13;12:54. Epub 2017 Oct 13.

Teaching and Research Institute, Barretos Cancer Hospital - Pius XII Foundation, Rua Antenor Duarte Vilela, 1331, Dr. Paulo Prata, Barretos, São Paulo 14784-400 Brazil.

Background: Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignant tumor. Currently, Human papillomavirus (HPV) is suggested as a potential risk factor for esophageal cancer (EC) in addition to the classic risk factors, alcohol and tobacco, but this hypothesis still remains contradictory. We sought to investigate wether HPV and well-known biomarkers (p16 and p53) and patient-related factors that may have impact on survival of ESCC.

Methods: We conducted a prospective cohort study. By using multiplex PCR, we determined the prevalence of high risk HPV in ESCC, and evaluated the immunohistochemical expression of p16 and p53, molecular markers related to esophageal carcinogenesis in order to verify the potential influence of these variables in patients's survival. Survival rates were estimated using Kaplan-Meier methods. A multivariate confirmatory model was performed using Cox proportional hazards regression.

Results: Twelve (13.8%) of 87 patients were HPV-DNA positive. Positive reactions of p16 and p53 were 10.7% and 68.6%, respectively. Kaplan-Meier analysis indicated that men ( = 0.025) had poor specific-cancer survival and a shorter progression-free survival ( = 0.050) as compared to women; III or IV clinical stage ( < 0.019) had poor specific-cancer survival and a shorter progression-free survival ( < 0.001) compared to I and II clinical stage; not submitted to surgery (<0.001) and not submitted to chemoradiotherapy ( = 0.039) had a poor specific-cancer survival, as well. The multivariate analysis showed that HPV, p16 and p53 status are not predictive parameters of progression-free and specific-cancer survival.

Conclusion: HPV infection and p53 and p16 expression are not prognostic factors in ESCC.
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October 2017

Prevalence of high risk HPV DNA in esophagus is high in Brazil but not related to esophageal squamous cell carcinoma.

Histol Histopathol 2018 Apr 6;33(4):357-363. Epub 2017 Sep 6.

Teaching and Research Institute, Barretos Cancer Hospital - Pius XII Foundation, Brazil.

Backgrounds: The first publication that associated Human Papillomavirus (HPV) infection and esophageal cancer was published in 1982. However, data are still contradictory and require further investigation. The aim of this study was to identify high risk HPV DNA in esophageal tissue of patients with and without esophageal squamous cell carcinoma (ESCC) and correlate HPV presence with classical risk factors.

Methods: Invited patients signed the informed consent form, and interviews were conducted in order to obtain information about sociodemographic and lifestyle behavior. During endoscopy, esophageal biopsies were collected from case and controls. Multiplex polymerase chain reaction genotyping was conducted on endoscopic biopsies to identify HPV types and HPV-16 was further evaluated by specific PCR real time.

Results: Among 87 cases, 12 (13.8%) had tumors harboring high risk HPV DNA and among 87 controls, 12 (13.8%) had high risk HPV DNA (OR:1.025 [CI:0.405:2.592]). Variables regarding consumption of alcohol and use of tobacco continued to characterize risk factors even after adjustments by presence or absence of high risk HPV.

Conclusion: HPV was demonstrated to be frequently and similarly associated to normal and malignant esophageal tissues, but not as an independent risk factor to esophageal cancer.

Impact: To contribute to the Brazilian population data on this subject, which is still contradictory.
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April 2018

High systemic IL-6 is associated with worse prognosis in patients with non-small cell lung cancer.

PLoS One 2017 17;12(7):e0181125. Epub 2017 Jul 17.

Teaching and Research Institute, Barretos Cancer Hospital-Pio XII Foundation, Barretos, Sao Paulo, Brazil.

Characteristic cytokine patterns have been described in different cancer patients and they are related to their diagnosis, prognosis, prediction of treatment responses and survival. A panel of cytokines was evaluated in the plasma of non-small cell lung cancer (NSCLC) patients and healthy controls to investigate their profile and relationship with clinical characteristics and overall survival. The case-controlled cross-sectional study design recruited 77 patients with confirmed diagnosis of NSCLC (cases) and 91 healthy subjects (controls) aimed to examine peripheral pro-inflammatory and anti-inflammatory cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, TNF and IFN-γ) by Cytometry Beads Arrays (CBA Flex) in. The cytokine IL-6 showed a statistically significant difference among groups with increased expression in the case group (p < 0.001). The correlation between the cytokines expression with patient's clinical characteristics variables revealed the cytokine IL-6 was found to be associated with gender, showing higher levels in male (p = 0.036), whereas IL-17A levels were associated with TNM stage, being higher in III-IV stages (p = 0.044). We observed worse overall survival for individuals with high levels of IL-6 when compared to those with low levels of this cytokine in 6, 12 and 24 months. Further studies of IL-6 levels in independent cohort could clarify the real role of IL-6 as an independent marker of prognostic of NSCLC.
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September 2017

The Relation of HPV Infection and Expression of p53 and p16 Proteins in Esophageal Squamous Cells Carcinoma.

J Cancer 2017 9;8(6):1062-1070. Epub 2017 Apr 9.

Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil.

To investigate the HPV prevalence and characterize the expression of potential molecular surrogate markers of HPV infection in esophageal squamous cell carcinoma. The prevalence of HPV in individuals with and without esophageal cancer (EC) was determined by using multiplex PCR; p16 and p53 protein levels were assessed by immunohistochemistry (IHC). High-risk HPV (hr-HPV) was found in the same frequency (13.8%) in esophageal squamous cell carcinoma (ESCC) and in healthy individuals. The p53 expression was positive in 67.5% of tumor tissue, 20.0% of adjacent non-tumoral tissue and 1.8% of normal esophageal tissue. p16 was positive in 11.6% of esophageal cancer cases and 4.7% of adjacent non-tumoral tissue. p16 was undetectable among control group samples. p53 and p16 levels were not significantly associated with the HPV status. These results suggest that hr-HPV types are not associated with the development of ESCC and that p53 and p16 protein expression have no relationship with HPV infection in normal or cancerous esophagus.
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April 2017

Retrospective analysis of breast cancer prognosis among young and older women in a Brazilian cohort of 738 patients, 1985-2002.

Oncol Lett 2016 Dec 7;12(6):4911-4924. Epub 2016 Nov 7.

Department of Prevention, Barretos Cancer Hospital, Pio XII Foundation, Barretos, São Paulo 14784-400, Brazil; Department of Clinical Research, Biohit HealthCare Ltd., 00880 Helsinki, Finland.

Invasive breast cancer (BC) is infrequent among women aged ≤40 years, however, the disease outlook in these younger patients is generally worse than among older women. The present study aimed to compare socio-demographic, clinical and pathological characteristics, and their association with long-term survival, between two random cohorts of young (≤40 years) and older (50-69 years) Brazilian patients with BC. The cohort comprised of 738 randomly selected women who were diagnosed with BC at Barretos Cancer Hospital, Pio XII Foundation (Barretos, Brazil) between January 1985 and December 2002; the patients included young women (n=376) and older women (n=362). The current analysis suggested that BC in young women is associated with numerous pathological features of aggressiveness. Second cancer and bilateral BC were independent predictors of a poor outcome in the younger group. Furthermore, C-erB-2 was positively correlated with poor outcome in the older group, whereas estrogen receptor status and TNM stage were associated with disease prognosis in both groups. The overall survival rates of the two age groups were similar except when analyzed according the treatment period (1997-2002). Although patients aged ≤40 years harbored tumors with more aggressive clinicopathological characteristics, these characteristics were not independent predictors of overall survival. The present study indicates that medical advances associated with prevention of breast cancer may improve screening programs, which may therefore increase early diagnosis and subsequently lower mortality rates.
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December 2016

Associations of Body Mass Index and Physical Activity With Sexual Dysfunction in Breast Cancer Survivors.

Arch Sex Behav 2016 11 3;45(8):2057-2068. Epub 2016 Jun 3.

Department of Behavioral Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Sexual dysfunction is a common and distressing consequence of breast cancer (BC) treatment. In the present study, we investigated the sexual functioning of BC patients and its association with women's personal characteristics and cancer treatments. In this cross-sectional study, sexual function was assessed using the Female Sexual Function Index (FSFI). The health-related quality of life (HRQOL) was measured using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and its breast module BR-23. Of the 235 participants approached, 216 participants were included in the study. Of these, 63 patients reported no sexual activity in the last month and thus were analyzed only in relation to the sexual desire domain of FSFI. A total of 154 (71.3 %) patients were classified with hypoactive sexual desire disorder (HSDD). From those patients reporting sexual activity in the last month, 63.3 % (97 out of 153) were classified with sexual dysfunction. Using hierarchical logistic regression, the variance explained (change in R ) by the addition of body mass index (BMI) and mild to moderate physical activity in the prediction models of sexual dysfunction and HSDD were 6.8 and 7.2 %, respectively. Age, BMI, and physical activity were independently associated with sexual dysfunction and HSDD. Additionally, BC patients with sexual dysfunction reported lower scores on global HRQOL, role functioning, and fatigue. Based on our findings, BC survivors should be encouraged to practice regular physical activity and to lose weight in order to avoid sexual dysfunction. However, future clinical trials are needed to confirm these findings.
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November 2016

Lack of CD44 variant 6 expression in rectal cancer invasive front associates with early recurrence.

World J Gastroenterol 2012 Sep;18(33):4549-56

Department of Oncology and Radiotherapy, University of Turku and Turku University Hospital, FIN-20521 Turku, Finland.

Aim: To investigate the prognostic value of CD44 variant 6 (CD44v6), a membranous adhesion molecule, in rectal cancer.

Methods: Altogether, 210 rectal cancer samples from 214 patients treated with short-course radiotherapy (RT, n = 90), long-course (chemo) RT (n = 53) or surgery alone (n = 71) were studied with immunohistochemistry for CD44v6. The extent and intensity of membranous and cytoplasmic CD44v6 staining, and the intratumoral membranous staining pattern, were analyzed.

Results: Membranous CD44v6 expression was seen in 84% and cytoplasmic expression in 81% of the cases. In 59% of the tumors with membranous CD44v6 expression, the staining pattern in the invasive front was determined as "front-positive" and in 41% as "front-negative". The latter pattern was associated with narrower circumferential margin (P = 0.01), infiltrative growth pattern (P < 0.001), and shorter disease-free survival in univariate survival analysis (P = 0.022) when compared to the "front-positive" tumors.

Conclusion: The lack of membranous CD44v6 in the rectal cancer invasive front could be used as a method to identify patients at increased risk for recurrent disease.
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September 2012

Short-term outcome of cervical intraepithelial neoplasia grade 2: considerations for management strategies and reproducibility of diagnosis.

Anticancer Res 2010 Jun;30(6):2319-23

Medical School, City São Paulo University (UNICID) Brazil, São Paulo, Brazil.

Aim: To compare two management strategies for cervical intraepithelial neoplasia (CIN) 2, and evaluate reproducibility of the diagnosis.

Patients And Methods: Ninety (90) women with biopsy-proven CIN2 diagnosed through the Brazilian public health service were randomly allocated into two groups: 45 in prospective follow-up without treatment, and 45 for radical loop electrosurgical excision procedure (LLETZ). As in the real-life situation, pathology-reviewed diagnoses and HPV genotypes were not available.

Results: Excision of the lesion proved to be more effective than prospective follow-up in reaching clearance of CIN2 (hazard ratio=3.66; 95% confidence interval 2.02-6.64). However, 44.1% of the lesions regressed without treatment during the 12-month follow-up.

Conclusion: CIN2 lesions regress without treatment in one year, although an ablative procedure is more effective. However, excision of CIN2 may lead to additional morbidity and costs, and tailoring the management on an individual basis may result in better outcome. Misclassification of CIN2 is not a negligible problem.
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June 2010

Genotype-specific persistence of genital human papillomavirus (HPV) infections in women followed for 6 years in the Finnish Family HPV Study.

J Infect Dis 2010 Aug;202(3):436-44

Medicity Research Laboratory and Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland.

Background: Persistent human papillomavirus (HPV) infection is the most important risk factor for cervical cancer, and understanding genotype-specific HPV persistence is essential for elucidating the natural history of HPV infections.

Methods: In the Finnish Family HPV Study, 329 pregnant women (mean age, 25.5 years) were recruited during the third trimester of pregnancy and were followed up for 6 years. Multiplex HPV genotyping for 27 low- and high-risk HPV types was used to define genotype-specific prevalence at each visit. Generalized estimating equation models were constructed to estimate predictors of type-specific persistence (positive results at 2 consecutive visits) of species 7 and 9 HPV genotypes.

Results: HPV16 was the most common type, followed by HPV types 18, 31, 35, 45, 58, 70, and 6. Prevalence of multiple infections ranged from 21% to 45%. Persistence was most prolonged for HPV types 35, 58, and 52, with durations of 38.7, 32.1, and 24.2 months, respectively, and was equal for multiple-type infections and HPV16, with durations of 21 and 24 months, respectively. Independent predictors of type-specific persistence of species 7 and 9 HPV genotypes were age (odds ratio, 1.13 [95% confidence interval, 1.02-1.25]; P=.017), oral sex (odds ratio, 0.37 [95% confidence interval, 0.17-0.81]; P=.013), and young age (<13 years) at initiation of smoking (odds ratio, 0.51 [95% confidence interval, 0.27-0.98]; P=.046).

Conclusion: HPV16 was the most frequent persisting HPV genotype followed by multiple infections. Early initiation of smoking, practicing oral sex and older age increase the risk for persistence of species 7 and 9 HPV genotypes.
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August 2010

Prevalence of human papillomavirus (HPV) DNA in oral mucosa of men with anogenital HPV infection.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009 Nov 17;108(5):732-7. Epub 2009 Sep 17.

Otolaryngology Department, Santa Casa São Paulo, Hospital, São Paulo, Brazil.

Objective: The aim of the present study was to determine the prevalence of concurrent oral and anogenital human papillomavirus (HPV) infection in male patients using polymerase chain reaction and reverse hybridization.

Study Design: Thirty consecutive men were recruited among those attending the Clinic for Sexually Transmitted Diseases of the Outpatient Department of Dermatology and Sexually Transmitted Diseases, Santa Casa Hospital, São Paulo. The criteria for enrollment in the study were: age between 15 and 60 years, negative human immunodeficiency virus (HIV) status, and the presence of HPV anogenital lesion(s) confirmed by polymerase chain reaction and reverse hybridization. As a part of their management, all patients were subjected to punch biopsy of the anogenital lesions to confirm HPV and an HIV blood test to ensure that they were HIV negative. All patients had their oral mucosa examined with an artificial light. All oral lesions were sampled by biopsy, and subjects with no detectable lesions were sampled by oral mucosal scraping for HPV testing by polymerase chain reaction and reverse hybridization. All patients also completed a questionnaire that recorded their sexual preferences (heterosexual or homosexual, monogamous or polygamous), frequency of sexual activity, practice of oral and/or anal sex, and the use of condoms.

Results: Only 3 patients presented with a clinically detectable oral lesion. Among them, just 1 was HPV positive by the molecular assay. In all of the other patients (27 out of 30), oral clinical lesions were not detected and scrapings were all negative for HPV infection.

Conclusion: The prevalence of concurrent oral and anogenital HPV infection was very low in this study (1 out of 30).
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November 2009

Bayesian estimation of performance measures of cervical cancer screening tests in the presence of covariates and absence of a gold standard.

Cancer Inform 2008 14;6:33-46. Epub 2008 Feb 14.

Departamento de Medicina Social, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.

In this paper we develop a Bayesian analysis to estimate the disease prevalence, the sensitivity and specificity of three cervical cancer screening tests (cervical cytology, visual inspection with acetic acid and Hybrid Capture II) in the presence of a covariate and in the absence of a gold standard. We use Metropolis-Hastings algorithm to obtain the posterior summaries of interest. The estimated prevalence of cervical lesions was 6.4% (a 95% credible interval [95% CI] was 3.9, 9.3). The sensitivity of cervical cytology (with a result of >or= ASC-US) was 53.6% (95% CI: 42.1, 65.0) compared with 52.9% (95% CI: 43.5, 62.5) for visual inspection with acetic acid and 90.3% (95% CI: 76.2, 98.7) for Hybrid Capture II (with result of >1 relative light units). The specificity of cervical cytology was 97.0% (95% CI: 95.5, 98.4) and the specificities for visual inspection with acetic acid and Hybrid Capture II were 93.0% (95% CI: 91.0, 94.7) and 88.7% (95% CI: 85.9, 91.4), respectively. The Bayesian model with covariates suggests that the sensitivity and the specificity of the visual inspection with acetic acid tend to increase as the age of the women increases. The Bayesian method proposed here is an useful alternative to estimate measures of performance of diagnostic tests in the presence of covariates and when a gold standard is not available. An advantage of the method is the fact that the number of parameters to be estimated is not limited by the number of observations, as it happens with several frequentist approaches. However, it is important to point out that the Bayesian analysis requires informative priors in order for the parameters to be identifiable. The method can be easily extended for the analysis of other medical data sets.
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May 2010

Identification of males at increased risk for genital human papillomavirus (HPV) infection among patients referred for urological consultation.

Scand J Infect Dis 2007 ;39(11-12):1029-37

Instituto Garnet, Sao Paulo, Brazil.

In order to identify the probable risk groups, this study analysed the reasons for referral to a urological clinic and the indications for peniscopy among males with suspected genital HPV infection. The patients were derived from a series of 2370 consecutive males attending our urological clinic in Sao Paulo, of whom 652 males (27.5%) aroused a clinical suspicion of genital HPV infection. Patients were categorized into 7 groups, according to their indications for referral. Altogether, 459 (70.4%) were examined by peniscopy, and 403 (87.8%) were biopsied and tested for HPV by Hybrid Capture 2 (HCII) for both oncogenic and non-oncogenic HPV types. The most frequent indication for referral in HPV-positive males (both in peniscopy and by HCII) was other diseases (group 6), followed by those who had partners HPV positive (group 1). The highest HPV prevalence (42%) was found among those with visible lesions, followed by those (38%) with previous condyloma. Of the other STDs, urethritis was significantly associated with HPV detection. Importantly, HPV was detected in 27% of the males referred due to other conditions non-related to HPV. We conclude that the risk groups for genital HPV infections include males with visible lesions, previous history of condyloma, those with HPV-positive partners, recurrent balanitis, as well as those with other STDs. Urethritis is significantly associated with HPV. The most frequent indications for referral to urological clinic among HPV-positive males were other, non-HPV-related conditions. The HPV prevalence rate of 27% among these patients warrants them to be considered as another risk group for genital HPV infections.
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March 2008

Performance of Pap smear and human papilloma virus testing in the follow-up of women with cervical intraepithelial neoplasia grade 1 managed conservatively.

Acta Obstet Gynecol Scand 2006 ;85(4):444-50

Department of Obstetrics and Gynecology, Universidade Estadual de Campinas (UNICAMP), Rome, Italy.

Background: Conservative management (follow-up) of cervical intraepithelial neoplasia grade 1 (CIN1) is acceptable, but evidence on performance of follow-up tools, such as Pap smear and human papilloma virus (HPV) test, is still needed.

Methods: A cohort of 78 women with histologically confirmed CIN1, referred because of atypical squamous cell or low-grade squamous intraepithelial lesion in their Pap smear, was enrolled between August 2000 and September 2002 and was prospectively followed-up at 6 and 12 months, until September 2003. Follow-up examinations included Pap test and Hybrid Capture II (HCII) with high-risk HPV, colposcopy, and cervical biopsies in patients with persistent abnormalities. Odds ratios and performance indicators (with 95% confidence interval) were calculated for HPV and Pap test results in detecting biopsy-confirmed CIN during the follow-up.

Results: Thirty-seven (47%) of the women were HPV-positive at baseline. At first follow-up visit, 30 women had persistent CIN1 and one woman progressed to CIN2; 15 patients had CIN1 and one patient CIN2 at the second follow-up visit. Women with persistent CIN1 (or progression) during follow-up had a significantly higher HPV detection rate and abnormal Pap tests, compared to women with regressive disease. Cytology had a far better sensitivity in detecting CIN than HCII at the first follow-up visit (81 versus 52%, respectively), whereas both examinations had equivalent sensitivities at the second follow-up visit (69 and 56%, respectively). Cytology had a superior negative predictive value at the first follow-up visit and better positive predictive value, in addition, at the second visit.

Conclusions: Because cytological abnormalities correlated generally better with the persistence of biopsy-confirmed CIN1 in this follow-up protocol, HCII test is the second-hand option to Pap test, but the use of both Pap and HCII together seems an unnecessary waste of resources.
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May 2006

DNA recovery from Hybrid Capture II samples stored in specimen transport medium with denaturing reagent, for the detection of human papillomavirus by PCR.

J Virol Methods 2005 Jun;126(1-2):197-201

Department of Obstetrics and Gynecology, Universidade Estadual de Campinas (UNICAMP), Caminas, SP, Brazil.

The purpose of this study was to examine the quality of DNA recovered for human papillomavirus (HPV) detection using polymerase chain reaction (PCR) in samples that had been collected for Hybrid Capture II (HCII), testing and stored in specimen transport medium (STM) with denaturing reagent at -20 degrees C for 18 months. Endocervical tissue was collected from 92 women for HCII assay using the Digene STM, and a Papanicolaou smear was carried out in all cases. Seven women had normal colposcopy results. The remaining 85 patients underwent colposcopy-directed biopsy or cervical conization for histological investigation. Of the 92 samples tested, 84 were HCII-positive and 8 were negative. Quality control for amplification was carried out with beta-globin primers G73 and G74, and HPV was tested using PGMY09 and PGMY11. DNA was recovered from 83 of the 92 samples (90%). Among the 84 samples HCII-positive initially, HPV was detected by PCR in 56 (67%). PCR did not detect HPV DNA in the eight samples that were HCII-negative, although five of them were positive for beta-globin. This paper describes a novel DNA extraction technique that may permit exact HPV typing in stored samples collected originally for HCII testing, making it possible to carry out retrospective investigations to retrieve information on specific HPV types in large HCII series.
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June 2005

[Pap smear, hybrid capture II, and visual inspection in screening for uterine cervical lesions].

Cad Saude Publica 2005 Jan-Feb;21(1):141-9. Epub 2005 Jan 28.

Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.

The objective of this study was to evaluate alterations in Pap smear, hybrid capture II (HCII), and visual inspection with acetic acid (VIA) in 684 women treated at a primary health care unit. The performance and agreement of the exams were evaluated. The study also described social, demographic, and reproductive factors and their association with uterine cervical lesions. Women had specimens taken for Pap smear, HCII, and VIA. When at least one of the tests was positive, colposcopy was performed and targeted biopsies were taken from any suspicious lesions. Performance of tests was evaluated. Women's distribution in relation to social, demographic, and reproductive factors and histological diagnosis was evaluated using the odds ratio. Among 198 women with at least one positive screening test, only 21 showed histological disease. Sensitivities of the tests were similar. VIA and Pap smear presented higher specificity than HCII. Only absence of a previous Pap smear was associated with the presence of histological disease. Pap smear performed better than VIA and HC II. Absence of previous cytology was associated with histological disease.
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November 2005

Human papillomavirus DNA detection and histological findings in women referred for atypical glandular cells or adenocarcinoma in situ in their Pap smears.

Gynecol Oncol 2004 Dec;95(3):618-23

Department of Obstetrics and Gynecology, Universidade Estadual de Campinas (UNICAMP), Rua Alexander Fleming 101, CEP:13083-970, Campinas, SP, Brazil.

Objective: To evaluate the association between high-risk human papillomavirus (HPV) DNA detection and histological diagnosis in women referred for atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) at Pap smear.

Methods: In this cross-sectional study, 146 women referred for AGC (124), AGC with high-grade squamous intraepithelial lesion (HSIL) (15), or AIS (7) were tested for HPV DNA using Hybrid Capture II (HC II). All women underwent colposcopic examination, and cervical biopsy was performed for 95 patients. Fifty-one women referred due to AGC with normal colposcopy and normal second Pap smear were scheduled for control visits every 4 months.

Results: The overall prevalence of HPV DNA was 38%. HPV DNA was detected in 93% of the women with HSIL associated with AGC and in 71% of women with AIS Pap smear, being significantly higher when compared with the prevalence (29%) in women with AGC alone. Forty-five women (30.8%) had clinically significant histological lesions (CIN 2 or worse). High-risk HPV DNA was detected in only 16% of the women without significant abnormalities in biopsy, in contrast to 96% of those who had CIN 2 or CIN 3 and 75% of women with AIS. Eighty-five percent of women with invasive cervical carcinoma (squamous or adenocarcinoma) tested positive for HPV DNA. HPV DNA detection was significantly associated with histological diagnosis of CIN 2 or worse, with an odds ratio (OR) = 51.8 (95% CI 14.3-199.9).

Conclusion: HPV DNA detection was strongly associated with the severity of cervical lesion (CIN 2 or worse) in women referred for AGC or AIS in their Pap smear. These data implicate the use of HPV testing in triage of women with AGC Pap smears.
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December 2004

Human papillomavirus viral load in predicting high-grade CIN in women with cervical smears showing only atypical squamous cells or low-grade squamous intraepithelial lesion.

Sao Paulo Med J 2003 Nov 28;121(6):238-43. Epub 2004 Jun 28.

Department of Obstetrics and Gynecology, Universidade Estadual de Campinas, Campinas, Brazil.

Context: Human papillomavirus (HPV) viral load may have an important role in predicting high-grade cervical intraepithelial neoplasia (CIN) in women with cervical smears showing atypical squamous cells or LSIL.

Objective: To determine whether the assessment of the viral load of high-risk HPV DNA is useful in predicting the detection of high-grade cervical intraepithelial neoplasia (CIN2 and 3) in women referred because of cervical smears showing only atypical squamous cells or LSIL.

Type Of Study: Cross-sectional.

Setting: Colposcopy Clinic in a University hospital.

Methods: A series of 119 women referred because of atypical squamous cells or LSIL between August 2000 and April 2001 were included. All women were subjected to a new cervical smear, HPV testing for the high-risk types using hybrid capture II (HCII), viral load measurement in relative light units (RLU) and colposcopy, with cervical biopsies (n = 97). Cervical lesions were graded using the CIN classification.

Results: Cervical biopsies revealed CIN2 or CIN3 in 11% of the cases, equally among women referred because of atypical squamous cells or LSIL. The HCII test was positive in 16% of women with atypical squamous cells and 52% of those with LSIL (OR = 5.8; 95% CI 1.4 to 26.7). There was strong correlation between CIN2 or CIN3 and positivity for HPV DNA when this group was compared with women with only CIN1 or normal cervix (OR = 7.8; 95% CI 1.5 to 53.4). In ROC analysis for HCII in diagnosing CIN2 and CIN3, the area under the ROC curve was 0.784, and the viral load cutoff point of 10.0 RLU/cutcuff presented 77% sensitivity and 73% specificity. Second cytology showing at least atypical squamous cells did not accurately detect CIN2 or CIN3 (OR = 6.4; 95% CI 1.0 to 50.9). The sensitivities of the second cervical smear and HCII were similar, although the specificity of HCII was significantly higher than the second cervical smear.

Conclusions: The viral load of high-risk HPV types was significantly associated with the diagnosis of CIN2 or CIN3 in women referred because of atypical squamous cells and LSIL abnormalities in their cervical smear.
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November 2003

Regulation of cell cycles is of key importance in human papillomavirus (HPV)-associated cervical carcinogenesis.

Sao Paulo Med J 2003 May 8;121(3):128-32. Epub 2003 Aug 8.

State Health Department, Maternity Hospital Leonor Mendes de Barros, São Paulo, Brazil.

The rapid progress in molecular biology has allowed the identification of the genes involved in different functions of normal cells and has also improved our understanding of the mechanisms of human carcinogenesis. The human papillomavirus (HPV) is a small double-stranded DNA tumor virus and its genes can manipulate cell cycle control to promote viral persistence and replication. The E6 and E7 proteins of high-risk HPV bind to cell cycle regulatory proteins and interfere with both G1/S and G2/M cell cycle checkpoints much more effectively than the low-risk HPV. The difference between the ability of low and high-risk HPV types to induce immortalization and transformation may well lie in their abilities to interact with the various cell cycle components, resulting in the loss of multiple cell cycle checkpoints, which are important in host genome fidelity, thus potentially resulting in accumulation of genetic abnormalities. Cervical cancer is one of the leading malignancies in women worldwide, with substantial morbidity and mortality. According to current concepts, HPV is recognized as the single most important causal agent in the pathogenesis of this cancer. HPV infection clearly precedes the development of malignancy, while being regularly associated with cervical cancer precursor lesions (all grades of squamous intraepithelial lesions). HPV-infected low-grade squamous intraepithelial lesion (SIL) has three possible outcomes: a) it may regress; b) it can persist; or c) it can make a clinical progression to in situ or invasive carcinoma. It has been well established by prospective cohort studies that the spontaneous regression rate increases in parallel with follow-up duration. In contrast, the clinical progression of lesions usually takes place quite rapidly, i.e. during the first two years from diagnosis. The mechanisms responsible for this divergent clinical behavior of HPV-associated squamous intraepithelial lesions are largely unknown, but currently under intense study in different laboratories worldwide.
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May 2003