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Objective: The aim of the study was to evaluate the relationship between bacterial vaginosis (BV) and relapse of cervical intraepithelial neoplasia grade 2 or more (CIN2+) after Loop electrosurgical excision procedure (LEEP)., Patients and Methods: One hundred four patients who underwent LEEP for CIN2+ were followed up every six months for three years. Fifty-three were negative for BV and fifty-one were positive. Each clinical control included Pap test, colposcopy, Amsel criteria test, HPV-DNA, and HPV-mRNA test., Results: Patients' age, presence of BV, positivity to HPV-DNA and HPV-mRNA tests were analyzed. The average age of patients was 42.5 ± 8.92 years (median: 42.5; range from 27 to 58 years). The minimum follow-up was 6 months and maximum 36 months (average: 22.8 ± 4.53; median: 24). The 10% of the patients with HPV-mRNA test negative had relapsed, compared to 45% of patients with HPV-mRNA test positive. Among the 53 patients without BV the 20% had relapsed compared with 23% of 51 patients with diagnosis of BV., Conclusions: There is no evidence for higher percentage of relapse in patients with BV, submitted to excisional procedure for CIN2+ associated to HPV-m-RNA test positivity. There is only a correlation among BV and relapse of CIN2+ lesions after LEEP.

Objective: The increased use of the intrauterine contraception (IUC) in female population and its probable relationship with cervical squamous intraepithelial lesions and cervical cancer make necessary clarify the possible interaction between the device and the pre-neoplastic lesions., Patients and Methods: Seven hundred and eighty-nine patients users of IUC and 1491 patients ever users of IUC were followed every 6 months for 3 years. Each clinical control included Papanicolau test, colposcopy, HPV-DNA test and HPV-mRNA test. Also, in patients IUC users we analyzed the type of device, years of use and average age., Results: Cytological sampling, histological examination, HPV-DNA test and HPV-mRNA test showed that there are not significantly differences between patients with or without IUC., Conclusions: None difference arose regarding persistence and progression between patients IUC users and IUC no users, for this reason, intrauterine contraception does not seem to be a co-causal factor in the possible development of cervical cancer.

Background: The use of HPV-mRNA test in the follow-up after LEEP is still matter of debate, with regard to its capacity of prediction relapse., Objective: The aim of the present study is to evaluate the reliability of HPV-mRNA test to predict the residual and recurrent disease, and its accuracy in the follow-up of patients treated for CIN 2/3., Study Design: Multicenter prospective cohort study. Patients who underwent LEEP after a biopsy diagnosing CIN 2/3 were followed at 3, 6, 12, 24 and 36 months. Each check up included cytology, colposcopy, HPV-DNA test (LiPA) and HPV-mRNA test (PreTect HPV Proofer Kit NorChip). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), of HPV-DNA test and HPV-mRNA test to predict relapse, recurrent and residual disease. Using multiple logistic regression, the statistical significant variables as assessed in univariate analysis were entered and investigated as predictors of relapse disease., Results: The mRNA-test in predicting a residual disease had a sensitivity of 52% and a NPV of 91%, whereas DNA-test had 100% and 100%, respectively. On the contrary in the prediction of recurrent disease mRNA-test had a sensitivity and a NPV of 73.5% and 97%, whereas DNA-test had 44% and 93%. On the multivariate analysis, age, cytology, HPV DNA and mRNA test achieved the role of independent predictors of relapse., Conclusion: HPV-mRNA test has a higher sensitivity and a higher NPV in predicting recurrent disease, for this reason it should be used in the follow-up of patients treated with LEEP for CIN 2/3 in order to individualize the timing of check up., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Pap test, and especially HPV DNA test, identify a large group of women who do not have any clinically relevant lesions, i.e., CIN2+ (Cervical Intraepithelial Neoplasia grade 2 or worse), but who are at greater risk of getting lesions in the future. The follow up of these women needs new biomarkers with prognostic value. The objective of this study is to evaluate the prognostic value of E6/E7 mRNA over-expression assay (PreTect HPV-Proofer, Norchip) for 5 HR-HPV types (16, 18, 31, 33, and 45) for progression to CIN2+ after a negative colposcopy. This prospective study, conducted at four Italian centres, enrolled 673 women with either a negative colposcopy or a negative or CIN1 histology. The clinical end-point was histological confirmation of CIN2+. Women were classified at baseline according to mRNA results and managed according to local colposcopy protocols. At least one conclusive follow-up test was obtained for 347 women (25 months average lapse since recruitment, range 5-74). Only seven CIN2+ were detected during follow up, three among the 82 women positive for mRNA at baseline, two among the 250 negative (Fisher exact test, p = 0.02), and two among the 12 with an invalid test. Absolute CIN2+ risk was 6.7/1,000 person/years in the whole cohort. The absolute CIN2+ risk was 18.4/1,000 person/years and 3.6/1,000 person/years in mRNA-positive and mRNA-negative women, respectively. In conclusion, E6/E7 mRNA over-expression appears to be a good candidate as a prognostic biomarker to manage HR-HPV DNA-positive women with negative colposcopy or histology, particularly in order to decrease follow-up intensity in those who are negative.

Since the introduction of the cytological screening programs, a significant reduction in the incidence of cervical cancer has been achieved. Almost all of these cancers are related to high-risk (HR) Human Papillomavirus (HPV) cervical infections. However, the natural history of HPV infection seems to be different in younger patients, resulting in a higher rate of regression. There is, therefore, the need to identify HPV-related biomarkers in order to enhance the effectiveness of screening of high-risk cytological lesions, in particular in women over 35 years of age. This study aims to evaluate the prognostic value of the HR HPV E6 and E7 mRNA expression in women with intraepithelial lesions of the cervix, older or younger than 35 years of age. One hundred and eighty-four HR HPV DNA positive patients with a low squamous intraepithelial lesion (LSIL) were tested for mRNA expressions, included in an observational study, and evaluated at follow-up with standard cytology up to 24 months from the mRNA test. The frequency of HSIL/LSIL cytology in the older cohort of mRNA positive patients was significantly higher compared to mRNA-negative patients, both at 1 and 2 years of follow-up (Chi-square: p 0.007 and p 0.009), but this difference was not found in the younger cohort. According to our results, the E6/E7 mRNA test could be a biomarker for viral activity, useful in identifying patients at higher risk of abnormal cytology, and in implementing the management of HR HPV DNA-positive women over 35 years of age.

Background: Human immunodeficiency virus (HIV)-positive women are at high risk of co-infection from human papillomavirus (HPV) and of developing squamous intraepithelial lesions of the cervix., Materials and Methods: From April 1997 to March 1999, 86 women, affected by high-grade squamous intra-epithelial lesions (H-SILs), were enrolled: 41 were HIV+ (CD4+ count >500/ml) and 45 were HIV-. The diagnosis of high-grade squamous intra-epithelial lesion (H-SIL) was established for each patient by Pap test, colposcopy and guided biopsy. For all samples, the HPV/DNA test was also performed by PCR. The patients' lesions and recurrence were treated by cone biopsy or large loop excision (LEEP). Annual controls were performed for 5 years., Results: A high rate of alcohol and drug use (60.7% vs. 31.4%; p=0.004; 80% vs. 27.5%; p<0.001, respectively) and number of male partners (4.5 vs. 3.0; p<0.001) were found in the HIV+ patients, compared to the HIV- patients. Both groups were HPV+ for high-risk types. No difference was found in the percentage of patients who had received a second LEEP., Conclusion: Our findings suggest the treatment of H-SIL in HIV-positive women, for a longer disease-free survival, or a lower risk of developing cervical cancer.

Background: Estimates for the prevalence of cervical HPV infection vary and are only available for a few populations with regard to male partners. Attention has been drawn to the male role in cancer progression from cervical intra-epithelial neoplasia, but most of the male lesions are subclinical and only visible after acetowhite staining. The prognostic significance of acetowhite areas, of male partners of women affected by HPV and preneoplastic lesions, was evaluated., Materials and Methods: A cohort of 3210 male partners of women affected by HPV infection and/or preneoplastic lesion of the lower genital tract was observed from 1987 to 2001. Acetowhite changes were assessed 5 min after the application of 5% solution of acetic acid and biopsies were tested for HPV-DNA by PCR. Patients with HPV lesions underwent CO2 laser surgery and follow-up., Results: Of the 3210 male partners, 39.12% exhibited clinical HPV lesions and 3.64% subclinical lesions identified as acetowhite areas. In the group of 117 male partners with acetowhite areas, the HPV-DNA test was positive (HPV 6-11) in 36.75% and negative in 63.24% (p<0.001). No statistical differences were observed between HPV+/- groups regarding their sexual habits. The HPV-positive infection group compared to the HPV-negative group showed a statistically significant difference for CO2 laser surgery (p<0.001)., Conclusion: The acetic acid test can give false-positives and is not a specific indicator of HPV infection, and thus the limited efficacy of tests for acetowhite areas was confirmed. The treatment of clinical lesions is necessary. Follow-up represents the major route to the diagnosis of preneoplastic lesions in men and for the prevention of cervical carcinoma in their female partners.

Recently Storey et al. showed that p53 polymorphism at codon 72 was related to cervical cancer. This polymorphism encodes either arginine (p53Arg) or proline (p53Pro). p53Arg was found to be more susceptible than p53Pro to E6-mediated degradation. Many studies were performed but conclusions are controversial. In this paper, we report our results from 80 women of central Italy, 30 patients showing High-grade Cervical Intraepithelial Neoplasia or squamous cell carcinoma (SCC) and 50 healthy women of the same age. The polymorphism was examined using the Storey's procedure, a molecular method, from formalin-fixed, paraffin-embedded biopsies (patients) and from cytological oral-samples (controls). The distribution of the genotypes among the cases was 27% heterozygous, 27% p53Pro-homozygous and 46% p53Arg-homozygous, while among the controls it was 52%, 2% and 46%, respectively. There was not an increased risk of SCC associated with p53Arg-homozygous; indeed there is a tendency for the contrary (odds ratio, 0.06; 99.4% confidence interval, 0.006-0.63; p = 0.019). Considering: 1) the biological characteristics of p53Pro in vitro; 2) the DNA quality, from formalin-fixed tissue, of our patients; and 3) the small number of samples performed in our study, we can only confirm that p53Pro is not a risk factor in vivo for cervical carcinogenesis in central Italy.

Purpose: The tumor suppressor gene, FHIT, has been cloned and mapped at chromosome region 3p14.2, one of the regions most frequently deleted in cervical carcinoma. In this report, we show that the expression of the Fhit protein in relation to human papillomavirus (HPV) subtype, the type of the intraepithelial lesion, HIV-induced immunodeficiency, and the DNA content (ploidy) correlates with the biological behavior of the lesions., Experimental Design: To investigate involvement of the FHIT gene in squamous intraepithelial lesions of low and high grade (LGSILs and HGSILs, respectively) of the uterine cervix, we examined the Fhit protein expression by immunocytochemistry in 131 cervical smears of 96 HIV-seropositive patients (42 with LGSILs and 10 with HGSILs) and 35 HIV-seronegative (5 with LGSILs) persons., Results: Fhit protein was detected in normal cells, whereas dysplastic cells (independently of HPV infection and HPV subtypes) showed reduced expression of Fhit (P = 0.00001). Lesions from 52 HIV-seropositive patients, 42 LGSILs and 10 HGSILs, showed diploid DNA content in 63.5%, aneuploid in 32.7%, and polyploid in 3.8%, but 90% of the HGSILs showed an aneuploid DNA content, and all were infected by HPV 16/18 subtypes. 23.8% of LGSIL cases were associated with HPV 16., Conclusions: These data clearly suggest that loss of Fhit expression occurs in the early stages of cervical carcinogenesis. Pap test represents one of the most convenient and rapid procedures available in identification of cellular changes; hence, Fhit staining might be used as an useful tool in larger population screening to detect early alteration in cellular behaviors.

The role of human papillomavirus (HPV) in the development of squamous lesions of the uterine cervix has been clearly established but other factors could be involved in cervical tumorigenesis, such as microsatellite instability (MI). The aim of the present study was to analyze the relationship between HPV infection and MI. Thirty-two cervical samples were analyzed: 11 low-grade CIN (LCIN), 18 high-grade CIN (HCIN) and 3 carcinomas. DNA was extracted from formalin-fixed, paraffin embedded tissue for PCR study with HPV 6/11, 16, 18 and 7 microsatellite primers: D2S123 (cr2), MFD39 (cr8), 635-636 (cr15q), MFD67 (cr1), D11S905 (cr11), SCZD1 (cr5q) and DM (cr19). HPV was detected in 82% of LCIN (16 and 18 types in 64% of cases) and in 33% of HCIN (16 type in 22% of cases). The difference between LCIN and HCIN was statistically significant (p = 0.014), in particular for 16 and 18 HPV types (p = 0.033). Forty-seven per cent of total cases showed MI with no more than 3 different loci per case: 27% of LSIL, 61% of HCIN and 33% of carcinomas (not statistically significant). In 45% of HCIN cases there were both MI and HPV. In conclusion, cervical carcinoma is linked to HPV infection but MI could also be involved in cervical tumorigenesis.

Infections with high-risk strains of human papillomaviruses (HPVs) and with herpes simplex virus type 2 (HSV 2), as well as inactivation of the p53 tumor suppressor gene, are important cofactors in cervical carcinogenesis. We analyzed 41 paraffin-embedded cervical intraepithelial lesions, including 25 cases of low-grade cervical intraepithelia neoplasia (CIN), and 16 cases of high-grade CIN for the presence of HPV 16/18 and HSV 2 genomic sequences and for the nuclear accumulation of the p53 protein. HPV 16 DNA was detected in 24.% of low-grade CINs and in 43.7% of high-grade CINs. HPV 18 was found only in 8.% of low-grade CINs. None of the cases tested scored positive for HSV 2 DNA. Nuclear accumulation of p53 was found in 4% of low-grade CINs, and in 31.2% of high-grade CINs, including 57.1% of the lesions that were positive for HPV 16. These results indicate that HPV 16 infection was over sixfold more common than HPV 18 infection and that p53 overexpression was significantly associated with high-grade lesions.