Regression Of Cervical Intraepithelial Neoplasia Research Articles

Cervicovaginal microbiota long-term dynamics and prediction of different outcomes in persistent human papillomavirus infection.

Persistent human papillomavirus (HPV) infection can lead to cervical intraepithelial neoplasia (CIN) and cervical cancer, posing serious threats to the health of women. Although the cervicovaginal microbiota is strongly associated with CIN, the dynamics of the microbiota during CIN development are unknown. In this retrospective cohort study, we analyzed 3-year longitudinal data from 72 patients diagnosed with a persistent HPV infection almost all caused by high-risk HPV types. Patients were categorized into groups with HPV persistent infection (n = 37), progression to CIN (n = 16), and CIN regression (n = 19) based on infection outcome during the follow-up period. Furthermore, 16S rRNA gene sequencing was performed on consecutively collected cervical samples to explore the composition and dynamics of the cervicovaginal microbiota during the development and regression of CIN. Our results showed that the composition of the cervicovaginal microbiota varied among women with different HPV infection outcomes and remained relatively stable during the follow-up period. Notably, the serial follow-up data showed that these microbial alterations were present for at least 1-2 years and occurred before pathologic changes. In addition, microbial markers that were highly discriminatory for CIN progression or regression were identified. This study provides evidence for a temporal relationship between changes in the cervicovaginal microbiota and the development of CIN, and our findings provide support for future microbial intervention strategies for CIN.

Spontaneous regression of cervical intraepithelial neoplasia 3 in women with a biopsy—cone interval of greater than 11 weeks

BackgroundAlthough there is broad consensus that only a subset of CIN3 will progress to cancer, there is currently no surefire way to predict which CIN3 will regress. Understanding the natural history of CIN3 is important, and finding markers for progression or regression could improve treatment strategies. According to the guidelines of the American Society for Colposcopy and Cervical Pathology of 2006, positive CIN3 p16 in women should be managed with excisional treatment (LEEP). For ethical reasons we cannot fail to treat women with CIN3 in order to study their regression capacity so we conducted a retrospective study to evaluate the regression rate of CIN3 diagnosed with a biopsy by studying the histological result of the cone removed by LEEP. We also investigated age, HPV genotypes and biopsy-cone interval distance as possible regression factors.MethodsWe selected 171 women with a histological diagnosis of positive CIN3 p16 as an entry criterion. All patients underwent LEEP / biopsy. A histological diagnosis of the cone of CIN3 or higher was considered as persistence or progression, the diagnosis of CIN1 or lower was considered as regression of the lesion.We used out a logistic model to study the probability of spontaneous regression of CIN3 as a function of the patient’s age, the time elapsed between the biopsy and the cone (in weeks) and the HPV genotype.ResultsWe found that the spontaneous regression rate of CIN3 was 15,8%, which was strongly associated with the biopsy-cone interval > 11 weeks. Genotype 16, the most represented, was present both in cases of regression (77.8%) and in persistence (83.3%). Regarding age, the estimated odds ratio of the probability of observing a regression in women over 25 years of age was 0.0045 times that of women under 25 years of age (CI: 0.00020, 0.036). Neither age nor viral genotype are significant as predictors of regression.ConclusionTo wait at least 11 weeks from the biopsy before subjecting the woman to LEEP could prevent unnecessary LEEP procedures, considering also that from CIN3 to carcinoma it takes years before the neoplastic transformation takes place.

Photodynamic therapy of cervical intraepithelial neoplasia and cervical cancer

Purpose: to study the effectiveness of photodynamic therapy in combination with diathermoelectroconization in the treatment of cervical intraepithelial neoplasia and cervical cancer.Materials and methods. The study included 108 patients aged 33.13 ± 1.18 years. Human papillomavirus was detected in all patients. The study group consisted of 62 patients with cervical diseases. The fi rst subgroup included 28 patients with moderate to severe cervical intraepithelial neoplasia and pT1AN0M0 cervical cancer who underwent diathermoelectroconization and photodynamic therapy. The second subgroup included 34 patients with severe cervical intraepithelial neoplasia who underwent only cervical diathermoelectroconization. The control group included 46 patients with unchanged cervix. To carry out fl uorescent diagnostics and photodynamic therapy, the patients of the fi rst subgroup were intravenously injected with a solution of photosensitizer “Fotoditazin” (“Vetagrand”, Russia) at a dose of 0.8–1.2 mg/kg. Three hours later, using the AFS device (“Polironik”, Russia), fl uorescent diagnostics was performed followed by photodynamic therapy with an ALHT-ELOMED laser (“Elomed”, Russia) in continuous mode. The wavelength was 662 nm, the output power – 3 W, the radiation dose – 200–300 J/cm2 for the cervix and 100–125 J/cm2 – for the cervical canal. All patients underwent complex antiviral therapy.Results. All patients after photodynamic therapy showed complete eradication of human papillomavirus and regression of cervical intraepithelial neoplasia. Morphological studies have shown that the effectiveness of combined treatment of moderate and severe cervical intraepithelial neoplasia, reaching 100 %, was higher than with the use of diathermoelectroconization alone (95 %). There were no recurrences of cervical intraepithelial neoplasia and cervical cancer after combined treatment.Conclusion. Photodynamic therapy of cervical intraepithelial neoplasia and cervical cancer is a highly effective method.

Possible role of negative human papillomavirus E6/E7 mRNA as a predictor of regression of cervical intraepithelial neoplasia 2 lesions in hr-HPV positive women

BackgroundThe aim of this study was to evaluate the regression rate of CIN2 p16 positive lesions in women over 25 years of age and identify possible predictors of regression.MethodsA total of 128 CIN2 p16 positive patients over 25 years old were considered. The women met the following inclusion criteria: HPV genotype 16, 18, 31, 33, 45 positive, HPV E6 / E7 mRNA test positive, without immune system pathologies, not pregnant and had completed at least two years of follow-up. At each follow-up examination patients were examined by colposcopy, HPV test, E6/E7mRNA, targeted biopsy and p16 protein detection. The final state after the two years of follow-up was classified as progression if the histology showed a CIN3, persistence if the lesion was a CIN2, regression if negative or LSIL. The predicted regression factors evaluated were: HPV E6/E7mRNA, protein p16.ResultsOverall, we had 35.1% (45 cases) of progression to CIN3, 41.4% (53 cases) of persistence and 23.4% (30 cases) of regression. The regression rate was higher in women with negative mRNA 92.8% (26/28), OR 312 (34.12–1798.76) p = 0.0001, while women with p16 negative had a regression of 22.6% (7/31), OR 0.94 (95% CI 0.36–2.46), p was not significant. We found no significant difference in regression between p16 positive (23.7%) and p16 negative (22.6%) CIN2 p16 lesions. p16 had a VPN of 22.6 (CI 95% 0.159–0.310), indicating that a p16 negative lesion does not exclude a CIN2 + .ConclusionsWe had a regression rate of 23.4%, which was low if we consider that in the literature the regression rates vary from 55 to 63%. The discrepancy in the results may indeed be explained by the fact that all lesions in our study were hr-HPV positive and belonged to “older women” reflecting a more "high-risk" population. As regression factors we studied p16 and HPV E6/E7 mRNA. The results of our study show that HPV mRNA, if negative, appears to be able to identify CIN2 lesions with a higher probability of regression and underlines how a p16 negative is not an indicator of regression.

Echinacea angustifolia and Echinacea purpurea Supplementation Combined with Vaginal Hyaluronic Acid to Boost the Remission of Cervical Low-Grade Squamous Intraepithelial Lesions (L-SILs): A Randomized Controlled Trial.

Background and Objectives: Echinacea angustifolia and purpurea have known immunomodulatory effects which boost viral clearance, including HPV infection. However, evidence regarding the improvement due to Echinacea-based supplements of cervical HPV-related pathologies is still lacking. The aim of this study is to evaluate the efficacy of Echinacea supplementation on the remission of cervical low-grade squamous intraepithelial lesions (L-SIL). Materials and Methods: A single-blind 1:1:1 parallel randomized controlled trial was conducted at the Colposcopy Unit of a tertiary care referral center. Reproductive-aged women were allocated either to (a) an oral supplement based on Echinacea extracts plus vaginal hyaluronic acid-based soft gel capsules, (b) the Echinacea supplement alone, or (c) vaginal hyaluronic acid-based soft gel capsules alone for 3 months. The primary outcome was the regression of cervical intraepithelial neoplasia (CIN)-1 for each treatment arm at 3, 6 and 12 months after the diagnosis. Secondary outcomes included changes in the epithelialization, pap smear, colposcopic parameters, histological reports, and vaginal health indexes (VHI) in the study groups. Results: 153 women (52 for arm A, 50 for arm B and 51 for arm C) completed the follow-up and were included in the analysis. There were no significant differences in both primary and secondary outcomes for the three groups after 3 months. At the 6-month follow-up, the number of persistent CIN-1 diagnoses was significantly lower in arm A (15/51), rather than in arm B (23/48, p = 0.03) and C (27/49, p = 0.03). Similarly, the same effect was seen after 12 months for treatment A (5/51) relative to B (15/48, p = 0.03) and C (14/48, p = 0.03). Colposcopic, histological and vaginal parameters were all significantly improved at 6 and 12 months for arm A relative to B and C, while no beneficial effects were seen after 3 months. Conclusions: Echinacea extracts supplementation in women with L-SIL/CIN-1 significantly boosts HPV lesion clearance, reducing the overall amount of diagnosis, histological, colposcopic and vaginal parameters after 6 and 12 months. However, a limited sample size reduces the quality of evaluated evidence, emphasizing the need for additional studies to validate these findings.

Role of FoxP3-positive regulatory T-cells in regressive and progressive cervical dysplasia.

Forkhead Box Protein 3 (FoxP3) is known as a key mediator in the immunosuppressive function of regulatory T-cells (Tregs). The aim of our study was to investigate whether FoxP3-positive Tregs have the potential to act as an independent predictor in progression as well as in regression of cervical intraepithelial neoplasia, especially in patients with intermediate cervical intraepithelial neoplasia (CIN II). Nuclear FoxP3 expression was immunohistochemically analysed in 169 patient samples (CIN I, CIN II with regressive course, CIN II with progressive course, CIN III). The median numbers were calculated for each slide and correlated with the histological CIN grade. Statistical analysis was performed by SPSS 26 (Mann-Whitney U test, Spearman's rank correlation). An increased FoxP3 expression in CIN II with progression could be detected in comparison to CIN II with regression (p = 0.003). Total FoxP3 expression (epithelium and dysplasia-connected stroma) was higher in more advanced CIN grades (p < 0.001 for CIN I vs. CIN II; p = 0.227 for CIN II vs. CIN III). A positive correlation could be detected between FoxP3-positive cells in epithelium and total FoxP3 expression (Spearman's Rho: 0,565; p < 0.01). Expression of FoxP3 could be a helpful predictive factor to assess the risks of CIN II progression. As a prognosticator for regression and progression in cervical intraepithelial lesions it might thereby help in the decision process regarding surgical treatment vs. watchful waiting strategy to prevent conisation-associated risks for patients in child-bearing age. In addition, the findings support the potential of Tregs as a target for immune therapy in cervical cancer patients.

Evaluation of the efficiency of treatment with the domestic drug “Promisan” of patients with cervical intraepithelial neoplasia grade I

BACKGROUND: At present cervical cancer (CC) is one of the most common malignancies in women. The prevention of cervical cancer is early diagnosis and timely treatment of precancerous processes, which include cervical intraepithelial neoplasia (CIN).&#x0D; &#x0D; AIM: To evaluate the clinical efficacy of treatment of patients with CIN I with the use of domestic drug Promisan.&#x0D; MATERIALS AND METHODS: A total of 58 patients with CIN I were studied. They were divided into 4 groups (group I and group II are the treatment groups, group III and group IV are control groups). Group I included 16 patients who received treatment with the drug Promisan in conservative treatment. Group II included 18 patients who received complex treatment consisting of radio-wave excision of the cervix followed by the administration of Promisan. Group III included 14 patients with expectant treatment (without Promisan) and Group IV included 10 patients who underwent radio-wave excision of the cervix with subsequent dynamic observation (without Promisan).&#x0D; RESULTS: Improvement in the CIN regression indices of the 1st degree, improvement in colposcopic data and regression / elimination of the human papillomavirus were revealed in a greater percentage in patients who received Promisan as monotherapy and as part of complex therapy compared to the control groups.&#x0D; CONCLUSIONS: The results of the study make it possible to recommend Promisan for the prevention of cervical cancer in patients with dysplastic processes.

Condom use to enhance regression of cervical intraepithelial neoplasia: study protocol for a randomized controlled trial

BackgroundCondom use can reduce the risk of infection by human papillomavirus (HPV). Furthermore, it has been suggested that condom use can increase the regression rate of cervical lesions. In Denmark, women with cervical intraepithelial neoplasia grade 2 (CIN2) and a future wish to conceive are not treated immediately but are followed up by a gynecologist about 6 months later. The aim of this project was to determine if advising women to have their male partners to use a condom during sexual intercourse in the follow-up period can increase the regression rate of CIN2.Methods/designThis is a randomized clinical trial of women with CIN2. The intervention group was advised to use condoms between the date of diagnosis and the date of their follow-up visit. The control group received standard care. Cervical samples were tested for HPV. The primary endpoint will be the intention-to-treat analysis with the relative rate of CIN2 regression between the intervention group and the control group. Regression is defined as <CIN2 at the follow-up visit. In addition, a per-protocol analysis of the regression rate in women adhering to condom use compared with the control group will be performed. The secondary endpoint will be the HPV-clearance rate in the condom group.DiscussionIf condom use for 6 months can enhance the regression of cervical lesions, then more women can be spared conization. This is an efficient treatment of cervical lesions but is associated with an increased risk of preterm delivery.Trial registrationClinicalTrials.gov, NCT02907333. Registered on 14 September 2016.

Spontaneous Regression of Cervical Intraepithelial Neoplasia 2: A Meta-analysis

Background: Cervical intraepithelial neoplasia (CIN) is a precancerous condition that, if progresses, can cause cervical cancer. Less severe forms such as CIN1 regress spontaneously for most of the cases, but for high-grade CIN (CIN2 or CIN3), have higher potentials for progression. Objective: Aim of the present study was to obtain reliable estimates of spontaneous regression and progression rates of CIN2. Methods: Data were extracted from eligible studies identified after literature search in electronic databases, and meta-analyses were performed by pooling the regression and progression rates reported by these studies. Meta-regression analyses were performed for the identification of factors affecting regression rate. Results: Sixteen studies (1,481 patients; 14.86 months [95% CI 9.25–20.48] follow-up; 28.23 years [95% CI 25.07–31.39] age) were included in the meta-analysis. Overall regression rate in these conservatively observed patients was 42.66% (95% CI 35.41–49.91), but regression rate was higher in studies that recruited patients with CIN2 (50.85% [95% CI 36.11–65.60]) in comparison with those that recruited patients without discrimination of CIN2 with CIN3 (36.31% [95% CI 27.67–44.95]. Progression rate in CIN2 patients was 10.28% [95% CI 3.72–16.84]). Age was significantly negatively associated with regression rate (coefficient –1.72 [–3.53 to 0.10]; p = 0.061). Conclusion: Spontaneous regression rate of CIN2 is considerably high, especially in younger years.

Rates of regression of cervical dysplasia between initial biopsy and excisional procedure in routine clinical practice.

To determine rates and factors associated with regression of cervical intraepithelial neoplasia (CIN) 2 + between colposcopic biopsy and therapeutic excisional procedure in standard practice. A retrospective chart review was performed for women undergoing a cervical excisional procedure for CIN 2 + at clinics at three academic institutions over a 3-year period. Cytology, histology, patient age and time-to-excision were analyzed to determine factors influencing rates of regression. Of 356 women undergoing excision for CIN 2 + on colposcopic biopsy, 91 (25.3%) of final pathology diagnoses displayed clinically significant regression. Age and time-to-excision were not associated with regression, but referral cytology and severity of initial biopsy histology were, with ASC-H (aOR 0.1, CI 0.03, 0.8) and CIN 3/AIS (aOR 0.4, CI 0.2, 0.7) being less likely to regress than less severe lesions. Disease severity by referral cytology or diagnostic biopsy, as opposed to age or length of time-to-excision, is likely the most relevant factor in determination of regression for cervical intraepithelial neoplasia in women undergoing excisional treatment for biopsy-confirmed CIN2 +.

Mesenchymal Stem Cells from Cervix and Age: New Insights into CIN Regression Rate.

Cervical intraepithelial neoplasia (CIN) is a precancerous lesion of the uterine cervix that can regress or progress to cervical cancer; interestingly, it has been noted that young women generally seem to have higher rates of spontaneous regression and remission, suggesting a correlation between the patient's age and regression/progression rates of CIN. Even if the underlying mechanisms are still unclear, inflammation seems to play a pivotal role in CIN fate and inflammatory processes are often driven by mesenchymal stem cells (MSCs). This study was aimed at evaluating if age affects the behavior of MSCs from the cervix (C-MSCs) that in turn may modulate inflammation and, finally, regression rate. Fourteen samples of the human cervix were recovered from two groups of patients, “young” (mean age 28 ± 2) and “old” (mean age 45 ± 3), during treatment using the loop electrosurgical excision procedure (LEEP) technique. Progenitor cells were isolated, deeply characterized, and divided into young (yC-MSCs) and old cervixes (oC-MSCs); the senescence, expression/secretion of selected cytokines related to inflammation, and the effects of indirect cocultures with HeLa cells were analyzed. Our results show that isolated cells satisfy the fixed criteria for stemness and display age-related properties; yC-MSCs express a higher level of cytokines related to acute inflammation than oC-MSCs. Finally, in the crosstalk with HeLa cells, MSCs derived from the cervixes of young patients play a stronger antitumoral role than oC-MSCs. In conclusion, the immunobiology of MSCs derived from the cervix is affected by the age of donors and this can correlate with the regression rate of CIN by influencing their paracrine effect. In addition, MSCs from a young cervix drives an antitumoral effect by sustaining an acute inflammatory environment.

Toll-like receptors: Important immune checkpoints in the regression of cervical intra-epithelial neoplasia 2.

Toll-like receptors (TLRs) are innate immune defenders thought to be critical for the clearance of human papillomavirus (HPV) infections hence preventing the development of HPV-associated high-grade cervical intra-epithelial neoplasia (CIN2 or 3), a potential cervical cancer precursor. However, the role of TLRs in the regression of established cervical lesions, such as CIN2, is hindered by a lack of prospective design studies. Using SYBR green real-time PCR assays, we have examined the gene expression of TLR2, TLR3, TLR7, TLR8 and TLR9, in cytobrush collected endocervical cells of 63 women diagnosed with CIN2 at study entry (baseline) and followed over a 3-year period. Wilcoxon rank-sum test was used to examine the association between TLR expression levels, measured at baseline, and CIN2 outcome (regression vs. persistence/progression) over time. HPV genotyping was performed using Roche Linear Array Assay detecting 37 HPV types. Women with CIN2 regression showed significantly higher baseline levels of TLR2 (p = 0.006) and TLR7 (p = 0.007), as well as a non-significant trend for a higher TLR8 expression (p = 0.053) compared to women with CIN2 persistence/progression. Six women with CIN2 regression, who presented with an HR-HPV DNA-negative CIN2 lesion at study entry, had significantly higher baseline levels of TLR2 (p = 0.005), TLR7 (p = 0.013) and TLR8 (p = 0.012), compared to women with CIN2 persistence/progression, suggesting their role in clearance of HPV prior to clearance of the lesion. Our results confirm a key role of TLRs in regression of CIN2 and support the potential use of TLR-agonists for treatment of these lesions.

Epithelial oestrogen receptor α is dispensable for the development of oestrogen-induced cervical neoplastic diseases.

Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa) development. Oestradiol (E2 ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin (K14) promoter. E2 mainly functions through oestrogen receptor α (ERα). However, the role of ERα in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERα-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not in the stroma. We found that E2 induced cervical epithelial cell proliferation in epithelial ERα-deficient mice. We also found that E2 promoted the development of CIN and CxCa in epithelial ERα-deficient K14E7 mice and that all neoplastic epithelial cells were negative for ERα. In addition, proliferation indices were similar between ERα- and ERα+ CxCa. These results indicate that epithelial ERα is not necessary for E2 -induced CIN and CxCa. Taking these findings together, we conclude that stromal ERα rather than epithelial ERα mediates oncogenic E2 signalling in CxCa. Our results support stromal ERα signalling as a therapeutic target for the disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Non-steroidal anti-inflammatory agents to induce regression and prevent the progression of cervical intraepithelial neoplasia.

This is an updated version of the original Cochrane review published in 2014, Issue 4. Cervical intraepithelial neoplasia (CIN) precedes the development of invasive carcinoma of the cervix. Current treatment of CIN is quite effective, but there is morbidity for the patient related to pain, bleeding, infection, cervical stenosis and premature birth in a subsequent pregnancy. Effective treatment with medications, rather than surgery, would be beneficial. To evaluate the effectiveness and safety of non-steroidal anti-inflammatory agents (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, to induce regression and prevent the progression of CIN. Previously, we searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 11), MEDLINE (November, 2013) and Embase (November week 48, 2013). An updated search was performed in August 2017 for CENTRAL (2017, Issue 8), MEDLINE (July, week 3, 2017) and Embase (July week 31, 2017). Trial registries and journals were also searched as part of the update. Randomised controlled trials (RCTs) or controlled trials of NSAIDs in the treatment of CIN. Three review authors independently abstracted data and assessed risks of bias in accordance with Cochrane methodology. Outcome data were pooled using fixed-effect meta-analyses. In three RCTs, 171 women over the age of 18 years were randomised to receive celecoxib 400 mg daily for 14 to 18 weeks versus placebo (one study, 130 participants), celecoxib 200 mg twice daily by mouth for six months versus placebo (one study, 25 participants), or rofecoxib 25 mg once daily by mouth for three months versus placebo (one study, 16 participants). The study with rofecoxib was discontinued when the medicine was withdrawn from the market in 2004. The trials ran from June 2005 to April 2012, June 2002 to October 2003, and May to October 2004, respectively. We have chosen to include the data from the rofecoxib study as outcomes may be similar when other such NSAIDs are utilised.Partial or complete regression of CIN 2 or CIN 3 occurred in 31 out of 70 (44%) in the treatment arms and 19 of 62 (31%) in the placebo arms (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.93 to 2.27; P value 0.10), three studies, 132 participants; moderate-certainty evidence). Complete regression of CIN 2 or CIN 3 occurred in 15 of 62 (24%) of those receiving celecoxib versus 10 of 54 (19%) of those receiving placebo (RR 1.31, 95% CI 0.65 to 2.67; P value 0.45, two studies, 116 participants; moderate-certainty evidence). Partial regression of CIN 2 or CIN 3 occurred in 14 of 62 (23%) of those receiving celecoxib versus 8 of 54 (15%) of those receiving placebo (RR 1.56, 95% CI 0.72 to 3.4; P value 0.26), two studies, 116 participants; moderate-certainty evidence).Progression to a higher grade of CIN, but not to invasive cancer, occurred in one of 12 (8%) of those receiving celecoxib and two of 13 (15%) receiving placebo (RR 0.54, 95% CI 0.05 to 5.24; P value 0.60, one study, 25 participants; very low-certainty evidence). Two studies reported no cases of progression to invasive cancer within the timeframe of the study. No toxicity was reported in the two original articles. The trial added in this update had one Grade 3 gastrointestinal adverse effect in the treatment arm, but otherwise had similar Grade 1 to 2 side effects between treatment and placebo groups. Although the studies were well-conducted and randomised, some risk of bias was detected in all studies. Furthermore, the duration of the studies was short, which may mask identifying progression to cancer.The addition of the trial in this update quadrupled the number of patients in the original review and was a well-designed multicentre trial thus, increasing the overall certainty of evidence from very low to moderate for this review. There are currently no convincing data to support a benefit for NSAIDs in the treatment of CIN. With the addition of this new, larger randomised trial we would rate this as overall moderate-certainty evidence by the GRADE criteria.

Пути снижения диагностической и лечебной агрессии у пациенток с ВПЧ-инфекцией в репродуктивном возрасте

The problem of early diagnostics and prevention of cervical cancer is actual in Ukraine.The leading etiologic factor in the genesis of cervical neoplasia and a number of other organs is Human papillomavirus (HPV). The human papillomavirus is sexually transmitted and has high contagiosity. Cancer prevention consists in effective screening, early detection and treatment of pathological changes in the cervix. The aggressive treatment of diseases caused by (HPV) has been replaced by a tactic of a differentiated approach, taking into account to the age of the woman and her reproductive plans. The objective: was to study the efficacy and tolerability of the combined use of Proteflazid® systemically in drops form and locally in the form of suppositories for 3 months in patients with cervical intraepithelial neoplasia (CIN) of lung and moderate severity (CIN 1 and CIN 2) associated with the human papillomavirus (HPV); determination on the basis of the results of the need for further destructive treatment. Materials and methods. For the period from July 2016 to September 2017, we examined and treated 86 women with morphologically confirmed intraepithelial neoplasia of the cervix associated with HPV infection. Results. Based on the performed studies, it was found that 6 months after treatment with Proteplasid® systemically and locally for 3 months, regression of CIN was noted in 93% of patients. In all cases, a reduction in viral load of more than 2 Lg of HPV/105, which is a marker of the effectiveness of antiviral therapy, has been recorded. Six months after treatment in 84% of patients and 9 months in 88%, there was complete elimination of HPV or reduced viral load to clinically insignificant values – less than 3 Lg. Conclusion. The drug Proteflazid® suppositories and drops contributes to the elimination of human papillomavirus (HPV) and other viral-bacterial infections and reduces the risk of cervical neoplasia. Key words: cervical cancer, screening, cervical neoplasia, Human papillomavirus, viral-bacterial infections, Proteflazid®.

Association of antiretroviral therapy with high-risk human papillomavirus, cervical intraepithelial neoplasia, and invasive cervical cancer in women living with HIV: a systematic review and meta-analysis

SummaryBackgroundThe interactions between antiretroviral therapy (ART) and high-risk human papillomavirus (HPV) and cervical lesions in women living with HIV are poorly understood. We reviewed the association of ART with these outcomes.MethodsWe did a systematic review and meta-analysis by searching MEDLINE and Embase databases for cross-sectional or cohort studies published in English between Jan 1, 1996, and May 6, 2017, which reported the association of ART with prevalence of high-risk HPV or prevalence, incidence, progression, or regression of histological or cytological cervical abnormalities, or incidence of invasive cervcal cancer. Studies were eligible if they reported the association of combination ART or highly active ART use with the following outcomes: high-risk HPV prevalence; squamous intraepithelial lesion (SIL) or cervical intraepithelial neoplasia (CIN) prevalence, incidence, progression, or regression; and invasive cervical cancer incidence among women living with HIV. We did random-effects meta-analyses to estimate summary statistics. We examined heterogeneity with the I2 statistic. This review is registered on the PROSPERO database at the Centre of Reviews and Dissemination, University of York, York, UK (registration number CRD42016039546).FindingsWe identified 31 studies of the association of ART with prevalence of high-risk HPV (6537 women living with HIV) and high grade cervical lesions (HSIL-CIN2+; 9288 women living with HIV). Women living with HIV on ART had lower prevalence of high-risk HPV than did those not on ART (adjusted odds ratio [aOR] 0·83, 95% CI 0·70–0·99; I2=51%, adjusted for CD4 cell count and ART duration), and there was some evidence of association with HSIL-CIN2+ (0·65, 0·40–1·06; I2=30%). 17 studies reported the association of ART with longitudinal cervical lesion outcomes. ART was associated with a decreased risk of HSIL-CIN2+ incidence among 1830 women living with HIV (0·59, 0·40–0·87; I2=0%), SIL progression among 6212 women living with HIV (adjusted hazard ratio [aHR] 0·64, 95% CI 0·54–0·75; I2=18%), and increased likelihood of SIL or CIN regression among 5261 women living with HIV (1·54, 1·30–1·82; I2=0%). In three studies among 15 846 women living with HIV, ART was associated with a reduction in invasive cervical cancer incidence (crude HR 0·40, 95% CI 0·18–0·87, I2=33%).InterpretationEarly ART initiation and sustained adherence is likely to reduce incidence and progression of SIL and CIN and ultimately incidence of invasive cervical cancer. Future cohort studies should aim to confirm this possible effect.FundingUK Medical Research Council.

Natural history of cervical intraepithelial neoplasia in pregnancy: postpartum histo-pathologic outcome and review of the literature.

BackgroundTo study the natural history of cervical intraepithelial neoplasia (CIN) during pregnancy and to compare the rates of persistence, progression and regression of CIN by colposcopically guided biopsy (CGB) during pregnancy with outcome in non-pregnant-women.MethodsA retrospective analysis of all pregnant women diagnosed with CIN at our outpatient clinic between 2005 and 2010 was performed. A CGB for histo-pathological analysis was obtained in all participants and observational management was performed. The histo-pathologic findings of initial and postpartum visits were collected. Rates of persistence, progression and regression of CIN were assessed. Results were compared to a matched control group of non-pregnant women where observational management was performed for at least three months. In addition a review of the literature and pooled analysis of published data was performed.ResultsA total of 51 pregnant women with CIN were included into analysis. CIN 1, 2, and 3 was diagnosed by CGB in 33.3, 13.7 and 52.9 % of all pregnant women, respectively. The postpartum histo-pathologic evaluation of the pregnant cohort revealed a significantly higher tendency to spontaneous regression (56.9 versus 31.4 %, p = 0.010) and a considerably, but not significantly higher complete remission rate (41.2 versus 27.5 %, p = 0.144) when compared to the non-pregnant cohort. In addition, we observed a significantly lower CIN persistence rate than in the non-pregnant cohort (39.2 versus 58.8 %, p = 0.048). The progression rate was notably low in the pregnant cohort (3.9 %) and no progression to invasive cancer was observed.ConclusionsCIN lesions show considerably high spontaneous regression rates postpartum. Once presence of invasive cancer is ruled out definitive treatment can be deferred to the postpartum period.

Effects of long-term folate supplementation on metabolic status and regression of cervical intraepithelial neoplasia: A randomized, double-blind, placebo-controlled trial

ObjectiveThis study was conducted to determine the effects of long-term folate supplementation on regression and metabolic status of patients with cervical intraepithelial neoplasia grade 1 (CIN1). MethodsThis randomized, double-blind, placebo-controlled trial was performed among 58 women diagnosed with CIN1, ages 18 to 55 y old. Participants were randomly divided into two groups to receive 5 mg/d folate supplements (n = 29) or placebo (n = 29) for 6 mo. Fasting blood samples were taken at baseline and 6 mo after intervention to quantify related markers. ResultsA greater percentage of women in the folate group had regressed CIN1 (83.3 versus 52.0%, P = 0.019) than those in the placebo group. Long-term folate supplementation resulted in a significant decrease in serum insulin levels (−1.6 ± 6.2 versus +2.6 ± 6.9 μIU/mL, P = 0.018) and homeostatic model assessment-beta cell function (HOMA-B) (−13.0 ± 39.0 versus +11.2 ± 42.3, P = 0.028) compared with the placebo. Additionally, plasma glutathione (GSH) levels were significantly increased (+81.5 ± 264.1 versus −220.9 ± 342.5 μmol/L, P < 0.001) and malondialdehyde (MDA) levels were significantly reduced (−1.0 ± 1.1 versus +0.1 ± 1.6 μmol/L, P = 0.004) in the folate group compared to the placebo. ConclusionsTaken together, folate supplementation (5 mg/d) for 6 mo among women with CIN1 resulted in its regression as well as led to decreased serum insulin, HOMA-B, plasma MDA and increased plasma GSH levels; however, it did not affect other metabolic profiles.

Double-blind randomized placebo-controlled multicenter clinical trial (phase IIa) on diindolylmethane's efficacy and safety in the treatment of CIN: implications for cervical cancer prevention.

BackgroundThe article presents the results of a clinical trial on the efficacy and safety of a novel pharmaceutical composition in the form of vaginal suppositories containing diindolylmethane in the course of cervical intraepithelial neoplasia (CIN) I–II conservative treatment. It offers an attractive drug therapy for more personalized prevention of cervical cancer.MethodsA total of 78 women of reproductive age were included. This was a multicenter, randomized, placebo-controlled, double-blind, parallel-group trial with efficacy determined by histological evaluation of cervical biopsies. The efficacy of active drug treatment (100 and 200 mg/day) in both treatment groups was significantly higher in comparison with the placebo group, according to the primary efficacy end point (proportion of patients with complete CIN regression after 90–180 days of the study drug treatment).ResultsThe efficacies were 100.0 % (confidence interval (CI) 95 %: 82.35–100.00 %), 90.5 % (CI 95 %: 69.62–98.83 %), and 61.1 % (CI 95 %: 35.75–82.70 %), for the high dose, low does, and placebo, respectively. Adverse events in the placebo group were reported in 22 % of patients (CI 95 %: 7.5–43.7 %); in the first treatment group (100 mg/day), adverse events were reported in 40.0 % of patients (CI 95 %: 21.1–61.3 %); in the second treatment group (200 mg/day), adverse events were reported in 42.0 % of patients (CI 95 %: 22.1–63.4 %). The differences in side effects between treatment groups treated with the active drug and placebo were statistically significant. No serious adverse events were reported in any of the groups.ConclusionsThus, the use of diindolylmethane in the form of intravaginal suppositories can be effective in patients with CIN I–II and is not accompanied by clinically significant side effects. This approach could be a better option for young women with CIN I–II as it takes in attention their reproductive plans.Trial registrationID: ChiCTR-INR-15007497 (2 December 2015)

Towards therapeutic vaccination against cervical precancer?

In The Lancet, Cornelia Trimble and colleagues 1 Trimble CL Morrow MP Kraynyak KA et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet. 2015; (published online Sept 17.)http://dx.doi.org/10.1016/S0140-6736(15)00239-1 Summary Full Text Full Text PDF Scopus (398) Google Scholar report the results of a double-blind, randomised controlled trial of therapeutic human papillomavirus (HPV) vaccination. Three doses of an intramuscular HPV-16 and HPV-18 plasmid vaccine significantly increased histological regression of cervical precancers caused by HPV types 16 and 18. At 36 weeks after the first dose, regression of cervical intraepithelial neoplasia 2/3 was 48·2% compared with a spontaneous rate in the placebo group of 30·0% (difference 18·2%, 95% CI 1·3–34·4). In 40% of vaccine recipients, HPV DNA became undetectable, compared with about 10% in women who received placebo. The vaccine was well tolerated. Follow-up will assess the durability of the enhanced cell-mediated immune response, and whether it protects against recurrence. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trialVGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Full-Text PDF