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Objective: To determine whether treatment of cervical precancerous lesions in the follicular phase or luteal phase of the menstrual cycle affects perioperative and postoperative blood loss during the LEEP., Methods: In this randomized trial, 73 patients were assigned to either the follicular phase group (n = 37) or the luteal phase group (n = 36). Ultimately, the conditions of 36 patients in the follicular phase group and 34 patients in the luteal phase group were analyzed. The primary outcome measure was median early postoperative blood loss. Secondary outcomes were median intraoperative bleeding, the rate of late postoperative bleeding, and persistent vaginal bleeding., Results: Baseline demographic data were similar in the two groups. Median intraoperative blood loss was significantly lower in the follicular phase group than in the luteal phase group (32.7 [20.1-78.3] vs. 44.6 [30.4-104.2] mL, respectively; P < 0.001). Median early postoperative blood loss was also lower in the follicular phase group than in the luteal phase group (209.2 [67.7-468.6] vs. 289.0 [120.3-552.8] mL, respectively; P = 0.01). Moreover, the rate of late postoperative bleeding was higher in the luteal phase group than in the follicular phase group (20.6% vs. 2.8%, respectively; P = 0.02)., Conclusion: Performing LEEP during the follicular phase of the menstrual cycle significantly reduces median intraoperative blood loss, early postoperative blood loss, and the rate of late postoperative blood loss., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

COVID pandemic consists one of the most challenging medical realities. Apart from affecting respiratory system, current evidence has demonstrated multiorgan manifestations that SARS-Cov-2 infection may actually have. However, one of the medical hypotheses not yet thoroughly tested is the impact on female reproductive system and more specifically cervix. No large observational studies have been performed to test presence of SARS-Cov-2 in cervical samples, while potential correlation and impact on HPV infection has not yet been examined. In this context, our research team has already planned to begin a prospective observational study regarding detection rates of SARS-CoV-2 genetic material in cervical cytology. The collected specimen will be analyzed for the presence of COVID-19 genetic material and in case of positive results, HPV typing will be performed as well in order to detect potential correlations between SARS-CoV-2 infection and HPV-infection. We would therefore like to launch our idea to control for SARS-CoV-2 infection in cervical specimen as well as examine potential correlation with HPV infection. Potential scientific proof of such hypothesis would change much regarding follow-up of HPV-positive patients while also triggering further research regarding aitiopathogenetic pathways of COVID. Communication of such a medical hypothesis could potentially motivate colleagues worldwide to expand their interest also on the research of SARS-CoV-2 cervical infection, in an effort to optimize our level of knowledge towards this new threatening and unknown reality of SARS-CoV-2., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Cervical cancer is the second-most common gynecological cancer, early screening plays a key role in the diagnosis and treatment of cervical intraepithelial neoplasia (CIN). Sustained E7 protein expression is the pathological basis for CIN and cervical cancer., Methods: We collected the cervical cell samples of women who visited the gynecological clinic of Peking Union Medical College Hospital between September 2018 and September 2019 and submitted them to the high-risk human papillomavirus (Hr-HPV) test. We performed a magnetic particle-based chemiluminescence enzyme immunoassay to analyze the HPV16/18 E7 protein level in CIN of different severities and compared the results with those of cervical pathology (gold standard) and the HPV test., Results: The positive rate of HPV16/18 E7 protein increased with the severity of CIN: 26.6% in normal tissue, 58.3% in CIN1, and 70.6% in CIN2 or higher (CIN2+). For CIN2+, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the E7 protein were 70.6, 67.9, 52.2, and 82.3%, respectively. These values of the HPV test were 86.8, 44.5, 43.7, and 87.1%, respectively. With the combination of the E7 protein assay and HPV test, the specificity for diagnosing CIN2+ was 78.1%, which was significantly higher than that of the HPV test alone., Conclusions: HPV16/18 E7 protein level is correlated with the severity of CIN and has a high concordance rate with the pathological result. For cervical cancer screening, the combination of HPV16/18 E7 protein assay and HPV test improves the CIN diagnostic specificity, detection rate, and detection accuracy.

Introduction: Cervical cancer can be successfully prevented by timely detection of changes that precede it such as atypical (ASC-H) and high grade squamous lesions (HSIL)., Aim: To investigate the correlation between Pap smear and colposcopy in the detection of premalignant and malignant cervical lesions based on a pathohistological finding., Methods: In a retrospective study 118 patients with HSIL and ASC-H findings were examined. A Pap smear, colposcopic examination and cervical canal biopsy were performed. The study was conducted at the Gynecological Center "Dr Mahira Jahic" Tuzla and the Clinical Center Tuzla, Department of Gynecology and Obstetrics., Results: 1049 abnormal Pap tests were analyzed, ASCUS in 51,8% (N-544), LSIL 32,1% (N-337), HSIL 7,7% (N-81) and ASC-H 3,5% (N-37), AGC 4,8% (N-51). The mean age of the subjects with the abnormal Pap test was 46.33 ± 3.2. The age of patients with ASCUS lesion was 38,6 , LSIL 41,0, ASC-H was 47,3 , HSIL (CIN II and CIN III) 45,8 , while patients with CIS were 51,2 years. Pathological histology HSIL confirmed a high grade lesion in 67,7% (CIN II, CIN III and CIS) (N-55), in 32% (N-26) a lower grade CIN I in 18,5% and chronic cervicitis in 13,5% (N-11). In ASC-H lesion pathohistological HSIL was found in 13,5% (N-5), CIN I 13,5% (N-5) and chronic cervicitis 48,6 % (N-18). Abnormal colposcopic imaging with HSIL lesion was found in 72,9% (N-69), in 8,6% (N-7) was unsatisfactory and in 18,5% (N-15) the colposcopic finding was normal. In ASC-H lesions, abnormal colposcopic imaging was found in 40,5% (N-15), unsatisfactory findings in 10,8% (N-4), and normal findings in 48,6% (N-18)., Conclusion: Colposcopy has proven to be better method than cytology with an accuracy of 72,9% in high-grade lesion such as HSIL and ASC-H., Competing Interests: None declared., (© 2020 Mahira Jahic, Azra Hadzimehmedovic.)

Background: Treatments for cervical intraepithelial neoplasia remove precancerous cells from the cervix by excising or ablating the transformation zone. Most studies show no association between cervical intraepithelial neoplasia treatments and fertility outcomes. However, only 2 studies have examined time to pregnancy, both using retrospective study designs, with 1 study showing no association and the other showing a 2-fold increased risk of infertility (time to pregnancy >12 months) following excisional or ablative treatment., Objective: We examined the association between cervical intraepithelial neoplasia treatments and fecundability., Materials and Methods: We analyzed data from Pregnancy Study Online (PRESTO), a prospective cohort study of North American pregnancy planners enrolled during 2013-2019. At baseline, women reported whether they ever had an abnormal Papanicolaou test result, the number of abnormal Papanicolaou test results, and their age at first abnormal Papanicolaou test result. They also reported whether they underwent diagnostic (colposcopy) or treatment (excisional or ablative) procedures, and their age at each procedure. We restricted analyses to 8017 women with 6 or fewer cycles of attempt time at enrollment who reported receiving a Papanicolaou test in the previous 3 years. We estimated fecundability ratios and 95% confidence intervals using proportional probabilities models adjusted for sociodemographics, healthcare use, smoking, number of sexual partners, history of sexually transmitted infections, and human papillomavirus vaccination., Results: A history of abnormal Papanicolaou test results showed little association with fecundability (fecundability ratio, 1.00; 95% confidence interval, 0.95-1.06). Likewise, receipt of colposcopy or treatment procedures, and time since treatment were not materially associated with fecundability. Results were similar when stratified by age and smoking status., Conclusion: We observed no appreciable association of self-reported history of abnormal Papanicolaou test results, colposcopy, treatments for cervical intraepithelial neoplasia, or recency of treatment with fecundability. These results agree with the majority of previous studies in indicating little effect of cervical intraepithelial neoplasia treatments on future fertility., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Evaluate the effects of carboxy-methyl-beta-glucan on cervical epithelialization and on the vaginal microbiota in patients with HPV infection or low-grade cervical preneoplastic lesion (CIN 1)., Materials and Methods: Seven-hundred eighty-four women with positive HPV tests or diagnosed with CIN 1 were enrolled in a retrospective case-control study. All the recruited women performed, at baseline and after 6 months, Pap test, HPV test, evaluation of vaginal health according to the Amsel criteria, colposcopy, and punch biopsy. The study population was then divided into 2 groups in relation to the therapy performed during the follow-up period. Group A performed treatment with vaginal gel based on carboxy-methyl-beta-glucan (1 application/day for 20 days per month for 3 months). Group B was the control group., Results: The patients of group A had a significant improvement in the ectopia pattern and a greater number of cases with metaplasia in the maturation phase with a significant increase in Lugol uptake. In the experimental group, a significant improvement in the pH indices, a negative Swift test and a resolution of the leucorrhoea were observed. A negative result of the 37.1% Pap test and the 39.9% HPV test (vs. 15.2% and 16.5%, respectively) were demonstrated in the treatment group with respect to the control group. A negativization of the colposcopic pictures was observed with a reduction in the amount of CIN 1 found higher in the treatment group., Conclusions: Vaginal therapy based on carboxy-methyl-beta-glucan has been able to improve overall vaginal health; this effect seemed to positively impact the risk of persistence and progression of CIN., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2020 Giada Lavitola et al.)

Specific foods and nutrients help prevent the progression of persistent high-risk human papillomavirus (hrHPV) infection to cervical cancer (CC). The aim of this study was to investigate dietary patterns which may be associated with hrHPV status and the risk of high-grade cervical intraepithelial neoplasia (CIN2+). Overall, 539 eligible women, including 127 with CIN2+, were enrolled in a cross-sectional study, and tested for hrHPV infection. Food intake was estimated using a food frequency questionnaire. Logistic regression models were applied. Using the Mediterranean Diet Score, we demonstrated that, among 252 women with a normal cervical epithelium, medium adherence to the Mediterranean diet decreased the odds of hrHPV infection when compared to low adherence (adjOR = 0.40, 95%CI = 0.22-0.73). Using the principal component analysis, we also identified two dietary patterns which explained 14.31% of the variance in food groups intake. Women in the third and fourth quartiles of the "Western pattern" had higher odds of hrHPV infection when compared with first quartile (adjOR = 1.77, 95% CI = 1.04-3.54 and adjOR = 1.97, 95%CI = 1.14-4.18, respectively). Adjusting for hrHPV status and age, women in the third quartile of the "prudent pattern" had lower odds of CIN2+ when compared with those in the first quartile (OR = 0.50, 95%CI = 0.26-0.98). Our study is the first to demonstrate the association of dietary patterns with hrHPV infection and CC and discourages unhealthy habits in favour of a Mediterranean-like diet., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate the expression of microRNA (miRNA, miR) let-7e-3p in different cervical lesions and its clinical significance. Methods: The expression of miR-let-7e-3p in the tissues of normal cervix ( n =26), high-grade squamous intraepithelial lesion (HSIL) ( n =37), and cervix carcinoma ( n =101) were detected by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). The correlation of miR-let-7e-3p expression with the clinicopathological parameters of patients with cervical cancer was analyzed. miR-let-7e-3p mimic was transfected into cervical carcinoma Siha cells. The cell cycle and apoptosis were determined by flow cytometry; cell proliferation was determined by CCK-8 kit; and the migration and invasion of cells were determined by Transwell assay. Results: The relative expression levels of miR-let-7e-3p in normal cervix, HSIL, and cervical carcinoma were 1.45±0.24, 0.79±0.05 and 0.46±0.04, respectively (all P <0.05). After transfection with miR-let-7e-3p mimic, the S-phase fraction and apoptosis rate of Siha cells were increased significantly compared with control group[(29.76±6.6)% vs (13.38±1.3)%, P <0.05; (5.98±1.38)% vs (3.53±0.79)%, P <0.05, respectively]. OD of transfected Siha cells at 48, 72 and 96 h were 0.57±0.11,0.65±0.04 and 0.84±0.14, which were significantly lower than those of untransfected Siha cells (0.74±0.05, 0.93±0.10 and 1.47±0.14, all P <0.05). The migration and invasion abilities of transfected Siha cells were not significantly changed (all P >0.05). Conclusion: The expression of miR-let-7e-3p is down-regulated in cervical neoplasms, which is associated with cell cycle arrest and proliferation inhibition of cervical cancer cells.

Background: The burden of cervical cancer remains huge globally, more so in sub-Saharan Africa. Effectiveness of screening, rates of recurrence following treatment and factors driving these in Africans have not been sufficiently studied. The purpose of this study therefore was to investigate factors associated with recurrence of cervical intraepithelial lesions following thermo-coagulation in HIV-positive and HIV-negative Nigerian women using Visual Inspection with Acetic Acid (VIA) or Lugol's Iodine (VILI) for diagnosis., Methods: A retrospective cohort study was conducted, recruiting participants from the cervical cancer "see and treat" program of IHVN. Data from 6 sites collected over a 4-year period was used. Inclusion criteria were: age ≥18 years, baseline HIV status known, VIA or VILI positive and thermo-coagulation done. Logistic regression was performed to examine the proportion of women with recurrence and to examine factors associated with recurrence., Results: Out of 177 women included in study, 67.8 % (120/177) were HIV-positive and 32.2 % (57/177) were HIV-negative. Recurrence occurred in 16.4 % (29/177) of participants; this was 18.3 % (22/120) in HIV-positive women compared to 12.3 % (7/57) in HIV-negative women but this difference was not statistically significant (p-value 0.31). Women aged ≥30 years were much less likely to develop recurrence, adjusted OR = 0.34 (95 % CI = 0.13, 0.92). Among HIV-positive women, CD4 count <200cells/mm(3) was associated with recurrence, adjusted OR = 5.47 (95 % CI = 1.24, 24.18)., Conclusion: Recurrence of VIA or VILI positive lesions after thermo-coagulation occurs in a significant proportion of women. HIV-positive women with low CD4 counts are at increased risk of recurrent lesions and may be related to immunosuppression.

Introduction: Genital human papillomavirus (HPV) infections are very common in women 18 to 30 years old and substantially affect women's sexual health., Aim: To examine sexual activity, psychosexual distress, and fear of progression in women diagnosed with HPV-related precancerous genital lesions., Methods: In this observational study, women diagnosed with premalignant lesions of the cervix, vagina, or vulva were recruited from a university hospital-based colposcopy clinic., Main Outcome Measures: Quantitative data from three validated patient-administered questionnaires (Sexual Activity Questionnaire, German version of the Cervical Dysplasia Distress Questionnaire, and Fear of Progression Questionnaire) were compared within the study population, according to the location of the genital lesion, and with relevant reference populations. Qualitative data from two written open-ended questions about women's thoughts regarding diagnosis and information were analyzed., Results: Two-hundred nine women completed the questionnaires. Seventy-eight percent of women (n = 162) were referred for evaluation of suspect lesions of the cervix, 8% (n = 17) of the vagina, and 14% (n = 30) of the vulva. There were no significant differences in questionnaire results among the three patient groups, except for sexual consequences (Cervical Dysplasia Distress Questionnaire) and recent sexual activity (Sexual Activity Questionnaire). Women with vulvar lesions were most likely to worry about sexual consequences (ie, being unable to have children, being sexually less attractive, or infecting a sexual partner; P = .04). The Sexual Activity Questionnaire subscales sexual pleasure (P = .15) and sexual habits (P = 1.00) were similar to those in a healthy control population, whereas sexual discomfort (P = .51) was comparable to that in a reference population of women who survived cervical cancer. The subscale partner-specific concerns (Fear of Progression Questionnaire) was similar to that in a reference population of patients with cancer (P = .28)., Conclusion: HPV-related precancerous genital lesions, especially of the vulva, are likely to cause concerns about sexual health. Effective information and communication are important to lessen negative sexual consequences and anxiety., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC)., Methods and Findings: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7)., Conclusions: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

Background: The current management strategy for women with low-grade squamous intraepithelial lesions (LSILs) is inefficient and expensive because of the inability to identify patients at high risk for disease progression. The current study was designed to determine the genotypic patterns of human papillomavirus (HPV) associated with the persistence and progression of cervical lesions in women with an initial interpretation of LSIL., Methods: One hundred sixty-seven women with LSIL on Papanicolaou tests collected between December 1, 2009 and March 30, 2011 were studied. HPV DNA was extracted from residual SurePath specimens, genotypes were determined with a DNA microarray containing 40 HPV genotype probes, and microarray data were confirmed by sequencing. Follow-up Papanicolaou tests and/or biopsies were performed within a 20- to 46-month period after the initial diagnosis., Results: Ninety-seven of the 167 cases with follow-up results were included in the study. Compared with the women with a regressed cervical lesion, those with a persistent cervical lesion (PCL) were significantly more commonly infected with high-risk human papillomavirus (HR-HPV) genotypes (P < .01) and particularly with non-16/18 HR-HPV genotypes (P < .05). The PCL group also had a significantly higher average number of HR-HPV genotypes and non-16/18 HPV genotypes per specimen (P < .01). Infection with HPV-16/18 genotypes was not significantly associated with the persistence or progression of cervical lesions., Conclusions: Infection with non-16/18 HR-HPV genotypes but not with HPV-16/18 genotypes was a strong predictor of the persistence and progression of cervical disease upon follow-up. Genotyping solely for HPV-16/18 would miss the majority of patients with LSIL who progress to high-grade squamous intraepithelial lesions. Pooled HR-HPV tests provide a better predictive value than HPV-16/18 genotyping alone in guiding the clinical management of patients with LSIL., (© 2015 American Cancer Society.)

Prolactin receptor (PRLR) overexpression could play a role in tumorigenesis. The aim of this study was to determine prolactin (PRL) and PRLR expression in biopsies from patients with precursor lesions and uterine cervical cancer. PRLR expression was analyzed in 63 paraffin-embedded biopsies of uterine cervical tissue. In total, eleven low-grade squamous intraepithelial lesions (LSIL), 23 high-grade squamous intraepithelial lesions (HSIL), 21 uterine cervical cancers (UCC) and 8 normal epithelium (NE) were examined using immunoperoxidase staining and Western blot analysis. Additionally, PRL expression was identified in human cervical cancer serum and tissues. The PRLR expression was found to be significantly increased in cervical cancer in comparison with normal tissue and precursor lesions (P < 0.0003). The presence of the long isoform of the PRLR was observed only in cervical cancer tissues. Serum PRL levels were normal in all samples and local prolactin expression was similar in precursor lesions and cervical cancer by Western blot analysis. Our data suggest a possible role for PRLR in the progression of cervical cancer.

Little is known about the time span of progression from high-grade cervical intraepithelial neoplasia (CIN2/3) to invasive cervical cancer. Estimation of this duration from longitudinal studies is not permitted, as CIN2/3 should be treated when detected. Cross-sectional data on the age-specific incidence of detected CIN2/3 and cervical cancer cases are readily available in national registries, but these data are difficult to interpret because neither the moment of lesion development nor the onset of invasive cancer is observed. We developed a statistical model for estimating the duration of time between CIN2/3 and preclinical cancer using Dutch national registries for the years 2000-2005. Human papillomavirus (HPV) genotype data were used to separate CIN2/3 and cancer incidences to obtain estimates for HPV-16-positive and HPV-16-negative lesions. The median time from CIN2/3 to cancer was estimated to be 23.5 years (95% confidence interval: 20.8, 26.6), and 1.6% of the lesions progressed to cancer within 10 years. The median duration for HPV-16-positive lesions was similar, but 2.4% of the HPV-16-positive lesions progressed to cancer within 10 years, as compared with 0.6% for HPV-16-negative lesions. Estimated durations of time to cancer are essential for reassessment of the optimal screening interval in light of vaccination and novel screening tests.

Aim: The aim of this study was to evaluate the clinical performance of the Amplicor HPV test, which detects 13 high-risk human papillomaviruses (HR-HPV), and to determine the association between consistent HR-HPV infection and progression of cervical intraepithelial neoplasia (CIN) 2 to CIN3., Material and Methods: This multi-institutional prospective study enrolled 122 women diagnosed with CIN2 by central pathological review. Subjects were tested at study entry and every 6 months over a 24-month period by cytology, Amplicor HPV test and colposcopy. Central pathological review was performed at the end of the study or if CIN progression was suspected., Results: Ninety-three of the 122 participants completed all tests in the study and were included in the analysis. HR-HPV was detected in 87/93 (93.5%) participants at study entry. Twenty-four of the 87 HR-HPV-positive participants progressed to ≥CIN3, compared with none of the six participants who were HR-HPV-negative at study entry. The positive predictive value, negative predictive value, sensitivity and specificity of the Amplicor HPV test at study entry for predicting ≥CIN3 progression were 27.6%, 100%, 100% and 8.7%, respectively. Sixty-two participants were HR-HPV-positive from study entry through to study completion, 24 of whom progressed to ≥CIN3. None of 31 participants without continuous HR-HPV detection progressed to ≥CIN3. For continuous HR-HPV detection, the positive predictive value, negative predictive value, sensitivity and specificity of the Amplicor HPV test were 38.7%, 100%, 100% and 44.9%, respectively., Conclusions: All participants who progressed to ≥CIN3 were continuously HR-HPV-positive. The Amplicor HPV test thus demonstrated a good performance for predicting CIN3 progression., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Background: Human papillomavirus (HPV) infection is mostly associated with cervical cancer (CC). However, it can cause other illnesses as well, all of which impact on people's wellbeing and consume healthcare resources. Measures for prevention or early detection of these conditions differ in their effectiveness and cost. An informative evaluation of the projected benefit of these measures depends on understanding the current unmet need, not only limited to CC., Objective: To evaluate the burden of HPV-related conditions in Israel, including CC, cervical precancerous lesions and genital warts., Methods: A retrospective database analysis was conducted for the second largest health management organization (HMO) in Israel, covering approximately 1.8 million people. Records were drawn following a search for key words indicative of related diagnoses, lab results, medications, or procedures for the time period of 2006-2008. Prevalence, incidence and resource utilization were analysed. Findings were extrapolated to the whole Israeli population using age and gender incidence rates., Results: Incidence of CC was found to be 5 per 100,000 females. Incidences of cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3 were 74, 27 and 36 per 100,000 females, respectively. Incidence of genital warts was 239 and 185 per 100,000 for men and women, respectively. The overall annual economic burden was calculated to be $US48,838,058 (year 2010 values)., Conclusions: HPV poses a significant burden in terms of health (clinical and quality of life) and in monetary terms, even for conditions that are sometimes regarded as benign, such as CIN1 or genital warts. Current findings should be used for proper evaluation of measures to reduce HPV-related morbidity and mortality, such as regular screening and vaccination.

The inflammatory response is an active process in cervical cancer and may act in the progression and/or regression of the lesion. At the site of inflammation, macrophages and neutrophils are present as well as cytokines such as TNF-α and IFN-γ. This study aims to evaluate the inflammatory response levels in women with cervical intraepithelial lesions (CIN) and with squamous cell carcinoma (SCC) of the cervix. Serum samples obtained from women without evidence of disease (n=30), with CIN (n=30) and with SCC of the cervix (n=30) were analyzed for the activities of N-acetylglucosaminidase (NAG) and myeloperoxidase (MPO) by enzymatic assay and the serum levels of TNF-α and IFN-γ by ELISA assay. The activities of NAG and MPO and the level of TNF-α were higher in women with CIN compared to the women with SCC. The levels of IFN-γ were lower in the group of women with CIN compared to the group with SCC. There was not a significant association between the degree of the CIN and the staging of the SCC of the cervix and the degree of inflammation as assessed by the levels of inflammatory markers. The inflammatory response was inversely correlated with the progression of the carcinogenic process. In the three groups, the control group, women with CIN and women with invasive SCC, there was no association between the degree of preinvasive lesions and staging of the SCC of the cervix., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objective: To determine health related quality of life (QoL) of patients diagnosed with cervical intraepithelial neoplasia (CIN) and cervical cancer compared QoL among stages of cancer and to study the association between QoL and patients' characteristics., Material and Method: The questionnaire elicited information and QoL using Functional Assessment of Cancer Therapy General (FACT-G) questionnaire. The study population was patients with a diagnosis of one of the four FIGO stages of cervical cancer, Results: One hundred seventy two patients completed the present study. The adjusted mean scores QoL was 78.76. There were no significant differences between FIGO stages on the global QoL and subscale. The authors found negative association between age and physical wellbeing scores (p = 0.049) and a positive association between age and emotional wellbeing scores (p = 0.004). Lower educational attainment was associated with higher emotional wellbeing scores (p = 0.004)., Conclusion: For many patients, family, religion, or psycho-social support may be considered a necessity. The younger and better-educated groups may require more information and psycho-emotional support.

Objective: To investigate the diagnostic performance of combining the visual inspection with Lugol's iodine (VILI) and cytology screening to detect high-grade cervical intraepithelial neoplasia (CIN-2 or CIN-3) in symptomatic women, using histological examination as the standard reference test., Study Design: Cross-sectional referral study utilizing secondary data from 538 medical records from a clinic specialized in cervical pathology in Brazil., Results: Although the sensitivity reached 96.8%, the specificity was only 8.1%, with positive predictive value of 18.3% and negative predictive value of 92.3%., Conclusion: The combination of both tests proved to be highly sensitive, leading to a large decrease in the false negative results. This was achieved, however, at the cost of an excess in the rate of false positive results, thus making the combination unviable for screening in symptomatic women., (Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the outcome of CIN 2 diagnosed by colposcopy-directed biopsy in women followed without treatment for 12 months and to verify whether the regression and progression of this lesion are associated with the woman's age at diagnosis and age at first sexual intercourse., Study Design: Women diagnosed with CIN 2 by biopsy and with previous cervical smear showing LSIL were included in this cohort study and followed up for one year with cervical smear and colposcopy every three months. The rates of progression, persistence and regression of the CIN 2 were evaluated. The Kruskal-Wallis test was used to analyze the woman's age at diagnosis, age at first sexual intercourse and interval since the first sexual intercourse according to the CIN 2 outcome, assuming a significance level of 5%., Results: At the end of 12 months of follow-up the CIN 2 regression rate was 74% (31/42), progression rate to CIN 3 was 24% (10/42) and in one case CIN 2 persisted (2%). Among women who had regression, this event was detected in the first six months of follow-up in 26 of the 31 cases. There was no statistically significant association between the evolution of CIN 2 and the woman's age at diagnosis, age at first sexual intercourse and interval since first sexual intercourse. Women whose lesions were restricted to one quadrant were more likely to have CIN 2 regression at three-month follow-up compared with women with a lesion extending to one or more quadrants (OR: 6.50; 95% CI: 1.20-35.23)., Conclusions: The results of this study indicate that the majority of CIN 2 diagnosed by biopsy in women with previous Pap smear showing LSIL will regress in 12 months and therefore an expectant approach could be considered in these cases, not only for young women. Nevertheless these findings are not conclusive, and larger studies are required in order to certify when it is safe to adopt expectant management for CIN 2., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Colposcopic evaluation and guided biopsy is an important diagnostic step and standard of management for abnormal cytology smears in developed countries., Aim: The present study evaluates the performance of colposcopy vs conventional cytology in estimating the presence and grade of cervical disease against the reference standard of histopathology as a secondary test modality to triage women found positive on primary screening by visual inspection with 5% acetic acid (VIA)., Settings and Design: Colposcopy and directed biopsy were performed after primary screening for cervical cancer in an urban hospital cancer screening clinic between January 2000 and June 2005, in Mumbai, India., Materials and Methods: Healthy women (8863) in the age group of 35-65 years participated in the cervical cancer early detection program in the hospital and community cancer screening clinics in Mumbai. Women found positive on the primary screening test by VIA underwent diagnostic evaluation by Pap smear cytology and colposcopy evaluation with directed biopsies., Statistical Analysis: Accuracy parameters and their 95% confidence intervals were calculated using 2 X 2 tables and standard formulae., Results: The test range of sensitivity of colposcopy for the detection of histologically confirmed cervical intraepithelial neoplasia grade 1+ (CIN1+) or CIN2+ was 58.0-74.7% and that of specificity was 57.5-92.9%. The sensitivity and specificity of cytology to detect CIN2+ was 57.4% and 99.4%, respectively., Conclusion: Colposcopy is a good sensitive test for the detection of CIN and can be considered as a secondary testing tool to triage women found positive on VIA.

BD ProExC (ProExC) and Ki-67, both used as biomarkers for high-grade cervical intraepithelial neoplasia (HG CIN), yield discordant staining in some cervical biopsies. This study compared ProExC and Ki-67 expression in 197 cervical biopsies with consensus diagnoses (55 negative, 21 atypical squamous metaplasia, 61 low-grade CIN, and 60 HG CIN). Percentages of immunostained nuclei were evaluated by 2 pathologists yielding 68 (35%) cases with discordant ProExC/Ki-67 immunostaining for analysis. In 78% of cases the difference in staining involved <25% of lesional cells. This was noted across all morphologic diagnoses, being most frequent in HG CIN. Discordant staining involving >50% of lesional cells occurred in 22% of discrepant cases, being most frequent in atypical squamous metaplasia. Using staining in >50% of lesional nuclei as a positive result, positive/negative discordance occurred in 25 cases (13% of all cases) including 18% of HG CIN cases. Fourteen cases were ProExC+ (7 of which were strongly p16+) and 11 were Ki-67+ (6 of which were strongly p16+).

We demonstrate that changes in the degree of polarization (DOP) depend on changes in the scattering coefficient, and they can be quantified by using a polarization-sensitive optical coherence tomography (PS-OCT) system. We test our hypothesis using liquid and solid phantoms made from Intralipid suspensions and gelatin, respectively. We also quantify the DOP changes with depth caused by changes in the concentration of scatterers in the liquid and solid phantoms. It is clearly shown that the DOP change has a linear relationship with the scattering change. In our previous study, we showed that the axial slope of the DOP is different between normal and pathologic cervical tissues. Our results demonstrate that the quantification of the axial DOP slope can be used for the systematic diagnosis of certain tissue pathology.

Background: Currently, there is clear evidence that apoptosis plays an important role in the development and progression of tumors. One of the best characterized apoptosis triggering systems is the CD95/Fas/APO-1 pathway; previous reports have demonstrated high levels of soluble CD95 (sCD95) in serum of patients with some types of cancer. Cervical cancer is the second most common cancer among women worldwide. As a first step in an attempt to design a minimally invasive test to predict the risk of developing cervical cancer in patients with precancerous lesions, we used a simple assay based on the capacity of human serum to induce apoptosis in Jurkat cells. We evaluated the relationship between sCD95 levels and the ability to induce apoptosis in Jurkat cells in cervical cancer patients and controls., Methods: Jurkat cells were exposed to serum from 63 women (20 healthy volunteers, 21 with cervical intraepithelial neoplasia grade I [CIN 1] and 22 with cervical-uterine carcinoma). The apoptotic rate was measured by flow cytometry using Annexin-V-Fluos and Propidium Iodide as markers. Serum levels of sCD95 and soluble CD95 ligand (sCD95L) were measured by ELISA kits., Results: We found that serum from almost all healthy women induced apoptosis in Jurkat cells, while only fifty percent of the sera from women with CIN 1 induced cell death in Jurkat cells. Interestingly, only one serum sample from a patient with cervical-uterine cancer was able to induce apoptosis, the rest of the sera protected Jurkat cells from this killing. We were able to demonstrate that elimination of Jurkat cells was mediated by the CD95/Fas/Apo-1 apoptotic pathway. Furthermore, the serum levels of sCD95 measured by ELISA were significantly higher in women with cervical cancer., Conclusion: Our results demonstrate that there is a strong correlation between low levels of sCD95 in serum of normal women and higher apoptosis induction in Jurkat cells. We suggest that an analysis of the apoptotic rate induced by serum in Jurkat cells and the levels of sCD95 in serum could be helpful during the prognosis and treatment of women detected with precancerous lesions or cervical cancer.

Objectives: Progression and regression of premalignant cervical lesions cannot be predicted using conventional cytomorphological or histomorphological parameters. However, markers such as human papillomavirus (HPV) or makers indicating proliferation, genetic instability and chromosomal aberration may be of predictive value assessing short-term biological behavior of cervical intraepithelial neoplasia. In this paper, we have studied the usage of logistic regression models with Ki-67 labeling index (LI), chromosome index for chromosome 1 (CI#1) and aneusomy for chromosome 1 in cervical smears to predict progressive and regressive behavior of premalignant cervical lesions., Methods: Retrospectively, the intake smears of 42 women showing regression in follow-up and of 31 women showing progression in follow-up were assessed., Results: A multiparameter logistic regression model containing the parameters Ki-67 LI, CI#1 and the fraction of cells with four copies of chromosome 1 per nucleus appeared to be the best predicting model, overall correct classification of 93.2% (area under the receiver operating characteristic curve 0.96 +/- 0.02). After cross-validation, the model correctly classified 66 of 73 samples (90.4%). Moreover, the model predicted biological behavior perfectly assessing the smear taken subsequently to the intake smear of 46 women., Conclusion: Although measuring parameters indicating proliferation and chromosome 1 aberration is laborious, this study demonstrates that short-term progressive and regressive behavior is highly predictable using a model combing these parameters. We also showed that in the triage management of high-risk human papillomavirus-positive women with minimally abnormal smears applying a model as such can be useful.

Very little is known about cervical intra-epithelial neoplasia (CIN) and associated symptomatology. It is often quoted that that CIN is asymptomatic. We wanted to look at whether women with CIN were symptomatic or not. We are not aware of a similar study. We performed a case control study. Our cases were 22 women with abnormal cytology and histology results and our controls were 56 women who had been treated in the recent past and whose smears had returned to normal and those women whose smears had returned to normal spontaneously. Our study shows that there is no evidence that CIN is associated with post-coital bleeding, intermenstrual bleeding or discharge. Women with post-coital bleeding (PCB) are often fast tracked to the colposcopy clinic and women awaiting colposcopy suffer high levels of anxiety. There is no evidence for such practice.

Unlabelled: Two new viral vaccines have recently been approved by the Food and Drug Administration. Human papillomavirus (HPV) vaccine is intended to reduce infection with the most common HPV types that cause anogenital disease, including cervical cancer and genital warts. Herpes zoster (HZ) vaccine is intended to prevent shingles and its complications. The use of these two vaccines will immediately begin to impact dermatologic practice throughout the world and will reduce the healthcare burden associated with the diseases caused by the two viruses. The following review summarizes the relevant pathophysiology and epidemiology of genital warts, cervical neoplasia, and herpes zoster and describes the recent trials that have demonstrated efficacy and safety of the HPV and HZ vaccines., Learning Objectives: Following the completion of this learning activity, the participant will be able to describe the mechanisms of HPV and varicella zoster virus infection as well as pathogenesis, identify key aspects of the immune system involved in clearing the infection, and prescribe HPV and HZ vaccines for prevention of disease.

Objective: It is uncertain whether pregnancy influences the natural history of cervical intraepithelial neoplasia (CIN). Our aim was to evaluate the evolution of CIN in pregnant women., Design: Prospective study., Setting: Department of Obstetrics and Gynaecology, University of Insubria, Italy., Population: Women with histological CIN during pregnancy., Methods and Main Outcome Measures: Between 2003 and 2007, women with an abnormal Pap-smear during pregnancy underwent colposcopy. Patients with histological CIN were followed during pregnancy with colposcopy every 8 weeks and post-partum evaluation was scheduled 3-6 months after delivery. Women with post-partum histological diagnosis of CIN 2-3 underwent conization. To understand the impact of pregnancy on the evolution of CIN, women with CIN 1 discovered during pregnancy were compared to a group of non-pregnant fertile patients with first diagnosis of CIN 1., Results: A total of 78 women were included: 36 (46.2%) with CIN 2-3 and 42 (53.8%) with CIN 1. In women with CIN 2-3, no invasion was suspected during pregnancy and at post-partum evaluation, no invasive or microinvasive cancer, and 19 (52.7%) persistent CIN 2-3, and 17 (47.3%) regressions were diagnosed. In the group of CIN 1, we recorded six (14.3%) progressions to CIN 2-3, seven (16.6%) persistent CIN 1 and 29 (69%) regressions. The control group of non-pregnant women had a lower regression rate (37/76: 48.7%) in comparison to pregnant women (p=0.03)., Conclusions: Expectant management for CIN 2-3 diagnosed during gestation is safe. When discovered during pregnancy, CIN 1 has a significantly higher tendency to spontaneous regression in comparison to non-pregnant condition.

Cervical cancer is one of the most common cancers in women. The development of this disease involves reversible changes in the cervical tissue leading to various cellular abnormalities and ultimately to cervical cancer. Several well-defined stages of cervical neoplasia are described, namely, precancer lesions and cancer. Squamous cell carcinomas and adenocarcinomas are most frequent among them, the former being much more common. Each stage is characterized by specific morphological changes. These changes were analyzed in the context of recent molecular biology data. Cervical carcinogenesis associated with infection with high-risk human papillomaviruses (HPVs) contains several early genes that are necessary for viral replication and among them two genes (E6 and E7) play a key role in the induction of cervical carcinogenesis. The main targets of their products are tumor-suppressor genes p53 and retinoblastoma, and their function is inhibited by E6 and E7 proteins. Both E6 and E7 are multifunctional and participate in many cellular functions associated with cell proliferation. The viral genome persists in transformed cells in episomal or integrated form (or both), and possible role of such type of persistence in tumor progression is discussed. Progression of the disease also involves many epigenetic changes. These include methylation of the genes relevant to cell proliferation and differentiation, activation of telomerase, and global changes in cellular gene expression. The cervical cancer is the first cancer that can be effectively prevented by vaccination.

Cervical intraepithelial neoplasia is a premalignant (dysplastic) lesion that is characterized by abnormal cellular proliferation, maturation and nuclear atypia. The intraepithelial distribution, density, and nature (typical or atypical) of mitotic figures are routinely utilized diagnostic criteria to grade dysplasia and to distinguish high-grade dysplasia from potential histologic mimics such as transitional metaplasia, atrophy or immature squamous metaplasia. In this study, we evaluated the total mitotic indices of the cervical epithelia in hysterectomy specimens from patients with and without dysplastic lesions and investigated a possible relationship between mitotic index and hormonal status, using the endometrial maturation phase as a surrogate indicator of the latter. Two hundred seventy-four cervices from hysterectomy specimens (135 cases without dysplasia, 33, 35 and 71 cases with grades 1, 2 and 3 cervical intraepithelial neoplasia, respectively) were analyzed. A cervical mitotic index (total mitotic figures/10 high-power fields in the most proliferative area) was determined for each case. The endometrium in each case was classified into atrophic, early proliferative, late proliferative and secretory. For all three dysplasia grades, cases in the proliferative endometrium group always had a higher average mitotic index than those in the secretory and atrophic endometrium groups; this observation also held true for the benign cases. Furthermore, in all three dysplasia grades, the average mitotic index was always lowest in the atrophic endometrium group. Although the mitotic index showed expected patterns of increases with increasing dysplasia grades for most of the endometrial phases, this was not a universal finding. Notably, the average mitotic index for our cervical intraepithelial neoplasia 1 cases with late proliferative endometrium was higher than our cervical intraepithelial neoplasia 2 cases with secretory and atrophic endometrium. It is concluded that hormonal status, as reflected in endometrial maturation, can significantly affect the mitotic index of dysplastic squamous epithelium of the uterine cervix. Our findings confirm that the pathologic grading of dysplasia, especially in equivocal cases such as in metaplastic squamous epithelium, should not be solely dependent on the finding mitoses in the cervical squamous epithelium. The full composite of histopathologic features should form the basis for this determination.

Uterine cervical carcinogenesis is probably dependent on cellular genetic damage in addition to the integration of high-risk HPV DNA in the epithelial cell genome. Gain of chromosome 3q24-29 is commonly observed in cervical neoplasia. The putative oncogene PIK3CA located in this region encodes a phosphatidylinositol 3-kinase (PI3K). In a process reversed by PTEN, PI3K generates inositol phospholipids that trigger AKT phosphorylation, which in turn effects tumor driving signals. We studied 46 specimens of formalin-fixed, paraffin-embedded cervical neoplastic tissue. The activation state of the PI3K-AKT pathway was assessed immunohistochemically using an antibody with specificity towards serine 473-phosphorylated AKT. AKT phosphorylation was found in 39 out of 46 examined specimens. To examine the possible molecular basis for this activation, we searched for PIK3CA amplification using quantitative real-time polymerase chain reaction. PIK3CA gene copy number was estimated to be 3 or more in 28 out of 40 successfully examined cases. Further, a PTEN mutation analysis of all 9 PTEN exons was carried out, but except for 1 metastasis with an exon 9 V369I heterozygosity, all cases showed normal PTEN sequence. Immunohistochemical staining for PTEN was strong in all lesions. In conclusion, an increased activation state of AKT kinase appears to be present in cervical carcinogenesis, and may be accounted for by PIK3CA amplification, whereas PTEN mutation seems to be of little importance., (Copyright (c) 2005 Wiley-Liss, Inc.)

Background: To date, several mechanisms have been described by which malignant cells escape from the immune system. One of these is through the expression of FasL. The authors hypothesized that the Fas/FasL interaction enables cervical carcinoma cells to induce apoptosis of the cells of the immune system and thereby escape from them., Methods: The authors tested the expression of FASL on the surface of cervical carcinoma tissues. Next, they stained the same cervical tissues with anti-human leukocyte common antigen and TUNEL to identify apoptotic cells. An in vitro functional assay was then done to test if the FASL expressed on the surface of cervical carcinoma cell lines was or was not responsible for inducing apoptosis in T-cells. Finally, they compared the expression of FASL on normal and dysplastic cervical tissues., Results: Ninety-four percent of the cervical carcinoma tissues the authors tested expressed FasL and the majority of the apoptotic cells in the specimens were leukocytes with very few tumor cells. In the in vitro functional assay, only the Fasl expressing cell line and not the Fasl negative cell line was able to induce apoptosis of the Fas-expressing Jurkat cells. On examining the normal cervical tissues, the authors found that the expression of Fasl was confined to the basal cell layer with loss of expression observed in the suprabasal layers, which made it an immune privileged site. Conversely, there was persistent expression of FasL in the dysplastic layers in cervical dysplasia and squamous cell carcinoma specimens., Conclusions: The findings of the current study support the authors' hypothesis that persistent expression of FasL plays a role in the ability of cervical carcinoma cells to escape from the immune system.

Human papillomavirus (HPV) is a significant health care burden in the United States. The majority of sexually active men and women will be infected with HPV at some point in their lives and are subject to developing human papillomavirus-associated disease. Current estimates suggest that 20 million Americans are currently infected, and more than 5 million new infections occur each year. The prevalence of human papillomavirus is highest in populations in their late teens and early twenties, with nearly half of all new human papillomavirus infections occurring within 3 years of first intercourse. HPV is the necessary cause of genital warts, cervical intraepithelial neoplasia, and invasive cervical cancer. As such, human papillomavirus is responsible for significant medical morbidity and health care costs. Screening with cervical cytology has significantly reduced mortality rates; however, approximately 3900 women will die in 2005 from cervical cancer in the United States. Human papillomavirus DNA testing has shown promise in identifying high-grade abnormalities as an adjunct to traditional cytology, and should be used according to guidelines established by the American Cancer Society and the American College of Obstetricians and Gynecologists. The epidemiology of HPV infection and a brief introduction to the natural history of HPV infection will be presented here.

Retinoids are natural and synthetic derivatives of vitamin A, which can be obtained from animal products (milk, liver, beef, fish oils, and eggs) and vegetables (carrots, mangos, sweet potatoes, and spinach). Retinoids regulate various important cellular functions in the body through specific nuclear retinoic-acid receptors and retinoid-X receptors, which are encoded by separate genes. Retinoic-acid receptors specifically bind tretinoin and alitretinoin, whereas retinoid-X receptors bind only alitretinoin. Retinoids have long been established as crucial for several essential life processes-healthy growth, vision, maintenance of tissues, reproduction, metabolism, tissue differentiation (normal, premalignant cells, and malignant cells), haemopoiesis, bone development, spermatogenesis, embryogenesis, and overall survival. Therefore, deficiency of vitamin A can lead to various unwanted biological effects. Several experimental and epidemiological studies have shown the antiproliferative activity of retinoids and their potential use in cancer treatment and chemoprevention. Emerging clinical trials have shown the chemotherapeutic and chemopreventive potential of retinoids in cancerous and precancerous conditions of the uterine cervix. In this review, we explore the potential chemopreventive and therapeutic roles of retinoids in preinvasive and invasive cervical neoplasia.

Objective: Our study investigated the rate of recurrence of cervical intraepithelial neoplasia (CIN) in HIV-positive women after surgery in the era of highly active antiretroviral therapy (HAART)., Methods: One hundred twenty-one HIV-positive women were followed-up with cytology, colposcopy, and histology after surgery for CIN. We conducted univariate and multivariate analyses to determine the relation between recurrence of CIN and risk factors using Cox proportional hazard models with left truncation., Results: The rate of recurrence of any CIN was 22.3 per 100 patient-years and the rate of high-grade CIN was 8.6 per 100 patient-years during 166 and 279 patient-years of follow-up, respectively. In multivariate analysis, a positive margin was associated with a risk of recurrence of any CIN (relative risk [RR] = 3.5, 95% confidence interval [CI]: 1.2-9.8) and a risk of recurrence of high-grade CIN (RR = 9.0, 95% CI: 2.2-36.5). CD4 counts <200 cells/mm were associated with a risk of recurrence of any CIN (RR = 9.4, 95% CI: 2.7-32.7) but not with a risk of recurrence of high-grade CIN. HAART exhibited a protective effect on the recurrence of any CIN (RR = 0.3, 95% CI: 0.1-0.7) and of high-grade CIN (RR = 0.2, 95% CI: 0.1-0.7)., Conclusion: CD4 cell counts <200/mm(3) and a positive margin were predictors of recurrence, whereas HAART had a strong protective effect. Although surgery is highly effective in immunocompetent patients, it seems to be effective only in preventing progression to cancer in HIV-infected women.

We have analyzed the induction and role of phosphatidylinositol 3-kinase (PI3K) by Notch signaling in human papillomavirus (HPV)-derived cancers. Jagged1, in contrast to Delta1, is preferentially upregulated in human cervical tumors. Jagged1 and not Delta1 expression sustained in vivo tumors by HPV16 oncogenes in HaCaT cells. Further, Jagged1 expression correlates with the rapid induction of PI3K-mediated epithelial-mesenchymal transition in both HaCaT cells and a human cervical tumor-derived cell line, suggestive of Delta1;Serrate/Jagged;Lag2 ligand-specific roles. Microarray analysis and dominant-negatives reveal that Notch-PI3K oncogenic functions can be independent of CBF1;Su(H);Lag-1 activation and instead relies on Deltex1, an alternative Notch effector.

Most models of light propagation through tissue assume that the scattering properties of various tissue layers are the same. We present evidence that the scattering coefficient of cervical epithelium varies by a factor of 3 within the epithelium owing to variations in nuclear density and to the presence of keratin. We estimated the scattering coefficient from regions of normal and precancerous cervical epithelium by fitting reflectance measurements from confocal images to an exponential function of depth based on Beer's law of attenuation. The results suggest that the normal cervix is characterized by highly variable scattering in the superficial epithelium, low scattering in the intermediate epithelium, and high scattering in the basal and stromal regions. In high-grade dysplasia, high scattering from high-density nuclei is observed throughout the entire epithelium.

Objective: Fluorescence spectroscopy is a promising technology for the detection of cervical squamous intraepithelial lesions (SILs). In this study we took repeated measures in the cervix to determine whether the order of measurement produces changes in fluorescence intensity and whether there are differences in variation due to pressure., Methods: A pressure sensitive fiber-optic probe to measure fluorescence spectra was calibrated at light, medium, and firm levels (0.2, 0.4, 0.6 N). Measurements were made 3 times at each of 2 sites in the patient's cervix. Spectroscopic data were preprocessed and analyzed to compare order of pressure and intensity variability as a function of pressure on measurements., Results: Four providers took 3 measurements from 2 sites each in 18 patients, yielding 108 measurements. After corrections for multiple comparisons, neither the order of probe pressure nor the variability of probe pressure significantly affected variations in fluorescence intensity., Conclusion: This study shows that the probe pressure variability is probably not an issue for these devices.

The purpose of this study was to compare the plasma levels of the anti-oxidant system and oxidative stress between a cervical neoplasia group and a normal control group and to investigate the relationship between the levels of micronutrients of antioxidant system and various clinicopathological parameters of cervical carcinoma. A cross-sectional sample of 180 women, including 90 normal controls, was recruited from November 2000 to January 2001. Plasma concentration of malondialdehyde (MDA) was spectrophotometrically measured as the parameter of lipid peroxidation. Plasma levels of antioxidant vitamins were analyzed with the help of reverse-phase, high-pressure liquid chromatography, whereas glutathione peroxidase activity was evaluated by using coupled enzyme procedure. While the activity of glutathione peroxidase and the plasma levels of antioxidant vitamins, such as lutein, beta-carotene, lycopene, and zeaxanthin, were all significantly lower, the concentration of MDA was significantly higher in women with cervical intraepithelial neoplasia (CIN) or invasive cervical cancer, compared to those of the normal control group. The status of the plasma antioxidant system showed no significant correlation with the prognostic factors of cervical cancer. These findings suggest a potential role of oxidative stress-induced lipid peroxidation and the impairment of the anti-oxidant system in the pathogenesis of CIN and carcinoma of the uterine cervix.

Infection by high-risk human papillomaviruses (HPV) and persistent expression of viral oncogenes E6 and E7 are causally linked to the development of cervical cancer. These oncogenes are necessary but insufficient for complete transformation of human epithelial cells in vivo. Intracellular Notch1 protein is detected in invasive cervical carcinomas (ICC), and truncated Notch1 alleles complement the function of E6/E7 in the transformation of human epithelial cells. Here we investigate potential mechanisms of Notch activation in a human cervical neoplasia. We have analyzed human cervical lesions and serial passages of an HPV type 16-positive human cervical low-grade lesion-derived cell line, W12, that shows abnormalities resembling those seen in cervical neoplastic progression in vivo. Late-passage, but not early-passage, W12 and progression of the majority of human high-grade cervical lesions to ICC showed upregulation of Notch ligand and Jagged1 and downregulation of Manic Fringe, a negative regulator of Jagged1-Notch1 signaling. Concomitantly, an increase in Notch/CSL (CBF1, Suppressor of Hairless, Lag1)-driven reporter activity and a decrease in Manic Fringe upstream regulatory region (MFng-URR)-driven reporter activity was observed in late-passage versus early passage W12. Analysis of the MFng-URR revealed that Notch signaling represses this gene through Hairy Enhancer of Split 1, a transcriptional target of the Notch pathway. Expression of Manic Fringe by a recombinant adenovirus, dominant-negative Jagged1, or small interfering RNA against Jagged1 inhibits the tumorigenicity of CaSki, an ICC-derived cell line that was previously shown to be susceptible to growth inhibition induced by antisense Notch1. We suggest that activation of Notch in cervical neoplasia is Jagged1 dependent and that its susceptibility to the influence of Manic Fringe is of therapeutic value.

The Fragile Histadine Triad (FHIT) is a putative tumor suppressor gene involved in different tumors. The objective of this study was to examine the effect of codon 98 of FHIT on cervical carcinogenesis. The study subjects were patients who were pathologically diagnosed with cervical neoplasia and who had a positive result for human papillomavirus (n = 567) compared to normal healthy women as normal controls (n = 506). The FHIT-specific sequences of DNA from peripheral blood samples from study subjects were determined by PCR using allele-specific primers and were compared with those of the controls. The genetic susceptibility of codon 98 of the FHIT gene (3p14.2) in cervical carcinogenesis was determined by examining the effect of the gene and environmental factors vs. the different stages of cervical intraepithelial lesions and the different histopathologic types of invasive cervical cancers. On assessing FHIT polymorphisms, the percentages of individuals homozygous for the T allele, homozygous for the C allele, and heterozygous for these two alleles were 42.1%, 11.3, and 46.6% in the control group. The corresponding figures were 39.5%, 14.8%, and 45.7% among in women with cervical cancer. Compared with FHIT T/ T, odds ratio (95% confidence interval) for FHIT C/C was 1.4 (0.8-2.5) for invasive cervical cancer and 1.7 (0.9-3.1) for cervical intraepithelial neoplasia (CIN) II or III. The risks for invasive cervical cancer were higher with early onset cervical carcinogenesis (2.3, 1.0-5.5, P = 0.0438), than with late onset (1.0, 0.5-2.1, P = 0.9306). The risks of FHIT C/C or C/ T also increased for ever smokers or women with two or more children compared with FHIT T/ T. Polymorphisms of FHIT are associated with a higher risk of developing cervical cancer, in particular early onset cervical carcinogenesis.

The aim of this paper was to evaluate the factors that predict regression of untreated CIN 2 and 3. A total of 93 patients with colposcopic persistent CIN 2 and 3 lesions after biopsy were followed for 6 months. Human papillomavirus (HPV) types were determined by polymerase chain reaction at enrolment. We analysed the biologic and demographic predictors of natural regression using univariate and multivariate methods. The overall regression rate was 52% (48 out of 93), including 58% (22 out of 38) of CIN 2 and 47% (26 out of 55) of CIN 3 lesions (P=0.31 for difference). Human papillomavirus was detected in 84% (78 out of 93) of patients. In univariate analysis, 80% (12 out of 15) of lesions without HPV regressed compared to 46% (36 out of 78) of lesions with HPV infection (P=0.016). Women without HPV and those who had a resolution of HPV had a four-fold higher chance of regression than those with persistent HPV (relative odds=3.5, 95% CI=1.4-8.6). Women with five or fewer lifetime sexual partners had higher rates of regression than women with more than five partners (P=0.003). In multivariate analysis, HPV status and number of sexual partners remained as significant independent predictors of regression. In conclusion, HPV status and number of lifetime sexual partners were strongly predictive of regression of untreated CIN 2 and 3.

Human papillomavirus type 16 (HPV-16) L1- and E7-specific T cell responses were measured in 58 women with abnormal cervical cytology in a prospective study. On recruitment, patients responded most frequently and with the highest numbers of responding cells to the L1 region aa 311-345 and this response was significantly associated with the presence of cervical disease (P=0.041). Responses to the L1 peptide aa 281-295 were significantly higher in patients with CIN III than in those with HPV/CIN I or CIN II lesions (P=0.027). The E7 region aa 70-98 was the most immunogenic in patients with squamous intraepithelial lesions of the cervix (SIL) but the responses detected were not significantly higher than in patients without SIL. Following treatment, the T cell response profiles of patient groups did not change significantly. However, on analysis of the responses of individual patients with and without recurrent disease on follow-up, significant differences were found. Recurrence of disease was associated with T cell responses to the E7 region aa 70-98 at the patient's first clinic visit (P=0.017). Recurrence of disease was also accompanied by an increase in the total number of L1-specific short-term T cell lines (STLs) at follow-up, whereas absence of disease was accompanied by a decrease in L1-specific STLs. The data also suggested a possible link between E7 70-98-specific responses and acquisition of disease by patients who were previously disease-free. Further studies are warranted to determine whether this response could be useful as a marker of recurrent disease in some patients.

Objective: To evaluate regeneration in cervical craters following large loop excision of the transformation zone (LLETZ) and to investigate possible differential healing patterns depending on the cone's size., Study Design: A prospective study of 100 nulliparous women who underwent LLETZ. They underwent transvaginal scanning estimation of the cervical craters (diameter, depth) immediately post-operatively and at 3, 6 and 12 months. The crater dimensions of the women with the 25 largest cones were compared to those of the women with the 25 smallest cones in each of the above points of time., Results: The mean crater size of all women at 12 months was significantly smaller from the crater size immediately post-operatively. Although, there was a statistically significant difference in mean crater dimensions between the two quartile groups immediately post-operatively, no difference was found at 6 and 12 months., Conclusion: There is a healing process of the cervical crater, which is almost completed by the sixth post-treatment month. The defect remaining in the cervix is similar whether a large or small excision was performed.

To evaluate the significance of mitotic activity and apoptosis in the differential diagnosis of endocervical glandular lesions, we examined the frequency of mitoses and apoptosis in 89 endocervical glandular lesions from 78 patients, which consisted of benign reactive changes (7 cases), lobular or diffuse laminar endocervical glandular hyperplasia (4), microglandular hyperplasia (3), tunnel clusters (7), nabothian cysts (2), mesonephric remnants (3), tubal metaplasia (3), endocervical glandular dysplasias (including atypical tubal metaplasia) (EGD) (7), adenocarcinoma in situ (AIS) (31), microinvasive adenocarcinoma (7), frankly invasive adenocarcinoma (12), and minimal deviation adenocarcinoma (3). Mitotic index (MI; mitotic figures per 1000 cells) was significantly higher in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma than any other lesions examined. Microinvasive adenocarcinoma showed the highest MI. Apoptosis was detected consistently and frequently in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma. AIS showed the highest apoptotic index (AI; apoptoses per 1000 cells). Frequent apoptotic bodies and mitotic figures are a common feature of endocervical glandular malignancies (except for minimal deviation adenocarcinoma) and are an important feature that can facilitate their differentiation from benign and borderline lesions. High MI in microinvasive adenocarcinoma might aid the distinction of microinvasive adenocarcinoma from AIS. Although both MI and AI of EGD were between those of benign reactive changes and of AIS, MI and AI alone are not sufficient to differentiate EGD from benign reactive changes. MI and AI are not helpful in the differential diagnosis between minimal deviation adenocarcinoma and its benign mimics.

Objectives: This case-control study was conducted to investigate the role of viral load of high-risk human papillomaviruses (HPVs) in the development of cervical squamous intraepithelial lesions (SILs) and invasive cancers., Methods: A total of 30 female cases who had histological evidence of low-grade SIL (n=10) or high-grade SIL and above (n=20) were identified as the case group at the Tri-Service General Hospital, Taipei between September 1998 and March 1999. In addition, 80 female controls who had normal cervical cytology were enrolled and individually matched on age (+/-5 years) and date of recruitment to each case. Cervical swabs collected from study subjects were tested for the positivity and viral load of high-risk HPVs by Hybrid Capture II assay. Additionally, subjects completed a risk factor questionnaire., Results: Among sex behavioral factors studied, younger age at first intercourse was associated with a significantly elevated risk of cervical SIL and invasive cancers. With respect to HPV infection, high-risk HPV DNA was present in 70% (21/30) of case and 21% (17/80) of control subjects, resulting in an odds ratio (OR) of 6.6 [95% confidence interval (C.I.)=2.6-17.0]. Moreover, women who had a high viral load were at significantly greater risk for cervical SIL and invasive cancers than those who were infected with a low viral load (OR=18.0, 95% C.I.=3.0-108.5)., Conclusions: Among the variables tested, infection with a high viral load of high-risk HPVs is the strongest determinant for cervical SIL and cervical cancers in Taiwan.

Background: Several epidemiological investigations have shown that cigarette smoking leads to increased serum IL-6 levels and is a risk factor for cervical cancer., Methods: We examined the levels of interleukin 6 (IL-6) and the amount of cotinine in the cervical fluid of 78 women and compared the presence of human papillomavirus (HPV) in smokers and nonsmokers., Results: The results of our study showed that IL-6 levels were higher in the cervical mucus of smokers than in nonsmokers. Fourteen percent of smokers were in the category with highest IL-6 levels compared to 6% of nonsmokers. However, our IL-6 results were not significant as they were probably influenced by the higher rates of HPV infection in smokers (17 cases) than in nonsmokers (4 cases). Significant findings showed that smokers had a higher prevalence of squamous intraepithelial lesions (SILs) than nonsmokers. Smokers' cotinine levels also exceeded those of nonsmokers: 13.95 ng/ml compared with 5.00 ng/ml. However, less IL-6 activity was evident in smokers with high-grade SILs and HPV infection of high-risk types., Conclusion: Our results suggest that smoking has a stimulatory effect on the production of IL-6 in the cervix. Furthermore, smokers show a higher genital HPV infection rate and a higher prevalence of SILs.

The degree of DNA-instability as revealed by the immunohistochemical staining with anti-single-stranded DNA antibody after acid hydrolysis (DNA-instability test) was used as a marker of malignancy. This was applied to mild dysplasia (42 cases), moderate dysplasia (43 cases), severe dysplasia (27 cases), squamous cell carcinoma in situ (CIS) (21 cases), invasive squamous cell carcinoma (SCC) (31 cases) and normal (7 cases) human uterine cervix. The expression of tumour suppressor gene p53 and oncogene bcl-2 was detected immunohistochemically. Proliferative activity was evaluated by PCNA immumohistochemistry and the quantitative analysis of the number, mean area, the largest area and maximum shape irregularities of AgNOR in a nucleus were performed for all these cases. The distribution of numeric chromosomal aberrations of chromosome 17 was also investigated in some of these cases. The results showed that 31 SCC (100%), 21 CIS (100%), 21 severe dysplasia (77.77%), 28 moderate dysplasia (65.11%), and 14 mild dysplasia (33.33%) were positively stained by the DNA-instability test diffusely or sporadically, indicating their malignancy. Reflecting the malignant character, these cases showed a remarkable increase in the PCNA-index with the loss of polarity of PCNA positive cell distribution and also an increase in number, mean and largest sizes and maximum shape irregularity of AgNOR dots. The mean chromosome index for chromosome 17, p53 and bcl-2 immunostaining positivity were also found to be significantly increased in moderate and severe dysplasia and in cancerous cases in comparison to normal and mild dysplasia cases. Moreover, the DNA-instability-test positive dysplasia cases showed statistically significant increased values of PCNA-index, AgNOR parameters, mean chromosome index, p53 and bcl-2 expression in comparison to those of DNA-instability-test negative dysplasia cases. In conclusion, some mild dysplasia (33.33%) and most of the moderate (65.11%) and severe dysplasia (77.77%) were regarded as malignant in nature, existing at an early stage of progression of malignancy.

A prospective study in gynaecology clinics was conducted in Abidjan, Côte d'Ivoire, to assess the short-term evolution of squamous intraepithelial lesions (SILs). Of 94 women with a cytological diagnosis of SIL, 38 were infected with HIV. The average follow-up period after the initial smear was 5 months. Detection of human papillomavirus (HPV) by polymerase chain reaction (PCR) was performed at both the time of enrolment and final follow-up smear. There were 39 cases of persistent SILs. HIV-positive women had a higher percentage of persistent SIL (76%) than HIV-negative women (18%, relative risk (RR)=4.3, 95% confidence interval (CI) = 2.4, 7.7). SILs were more frequent among women infected with HPV at the time of enrolment or with persistent HPV infection, but these associations disappeared after adjusting for HIV serostatus. Spontaneous regression of SILs commonly occurs in HIV-negative African women. HIV-infected women with cervical dyskaryosis require gynaecology follow-up.