Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial.
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SUBMITTER: Koeneman MM
PROVIDER: S-EPMC5297094 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
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Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial.
Koeneman M M MM Kruse A J AJ Kooreman L F S LF Zur Hausen A A Hopman A H N AH Sep S J S SJ Van Gorp T T Slangen B F M BF van Beekhuizen H J HJ van de Sande A J M AJ Gerestein C G CG Nijman H W HW Kruitwagen R F P M RF
BMC cancer 20170207 1
The "TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia" (TOPIC) trial was stopped preliminary, due to lagging inclusions. This study aimed to evaluate the treatment efficacy and clinical applicability of imiquimod 5% cream in high-grade cervical intraepithelial neoplasia (CIN). The lagging inclusions were mainly due to a strong patient preference for either of the two treatment modalities. This prompted us to initiate a new study on the same subject, with a non-randomi ...[more]
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Project description:Cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer. Whereas not all high grade CIN lesions progress to cervical cancer, the natural history and risk of progression of individual lesions remain unpredictable. Therefore, high-grade CIN is currently treated by surgical excision: large loop excision of the transformation zone (LLETZ). This procedure has potential complications, such as acute haemorrhage, prolonged bleeding, infection and preterm birth in subsequent pregnancies. These complications could be prevented by development of a non-invasive treatment modality, such as topical imiquimod treatment. The primary study objective is to investigate the efficacy of topical imiquimod 5% cream for the treatment of high-grade CIN and to develop a biomarker profile to predict clinical response to imiquimod treatment. Secondary study objectives are to assess treatment side-effects, disease recurrence and quality of life during and after different treatment modalities.The study design is a randomized controlled trial. One hundred forty women with a histological diagnosis of high-grade CIN (CIN 2-3) will be randomized into two arms: imiquimod treatment during 16 weeks (experimental arm) or immediate LLETZ (standard care arm). Treatment efficacy will be evaluated by colposcopy with diagnostic biopsies at 20 weeks for the experimental arm. Successful imiquimod treatment is defined as regression to CIN 1 or less, successful LLETZ treatment is defined as PAP 1 after 6 months. Disease recurrence will be evaluated by cytology at 6, 12 and 24 months after treatment. Side-effects will be evaluated using a standardized report form. Quality of life will be evaluated using validated questionnaires at baseline, 20 weeks and 1 year after treatment. Biomarkers, reflecting both host and viral factors in the pathophysiology of CIN, will be tested at baseline with the aim of developing a predictive biomarker profile for the clinical response to imiquimod treatment.Treatment of high-grade CIN lesions with imiquimod in a selected patient population may diminish complications as a result of surgical intervention. More knowledge on treatment efficacy, side effects and long-term recurrence rates after treatment is necessary.EU Clinical Trials Register EU-CTR2013-001260-34 . Registered 18 March 2013. Medical Ethical Committee approval number: NL44336.068.13 (Medical Ethical Committee Maastricht University Hospital, University of Maastricht). Affiliation: Maastricht University Hospital. Registration number ClinicalTrials.gov: NCT02329171.
| S-EPMC4761416 | biostudies-literature
Project description:Topical imiquimod could be an alternative, noninvasive, treatment modality for high-grade cervical intraepithelial neoplasia (CIN). However, evidence is limited, and there are no studies that compared treatment effectiveness and side effects of topical imiquimod cream to standard large loop excision of the transformation zone (LLETZ) treatment. A multi-center, nonrandomized controlled trial was performed among women with a histologic diagnosis of CIN 2/3. Women were treated with either vaginal imiquimod (6.25 mg 3 times weekly for 8 to 16 wk) or LLETZ according to their own preference. Successful treatment was defined as the absence of high-grade dysplasia at the first follow-up interval after treatment (at 20 wk for the imiquimod group and at 26 wk for the LLETZ group). Secondary outcome measures were high-risk human papillomavirus (hrHPV) clearance, side effects, and predictive factors for successful imiquimod treatment. Imiquimod treatment was successful in 60% of women who completed imiquimod treatment and 95% of women treated with LLETZ. hrHPV clearance occurred in 69% and 67% in the imiquimod group and LLETZ group, respectively. This study provides further evidence on topical imiquimod cream as a feasible and safe treatment modality for high-grade CIN. Although the effectiveness is considerably lower than LLETZ treatment, imiquimod treatment could prevent initial surgical treatment in over 40% of women and should be offered to a selected population of women who wish to avoid (repeated) surgical treatment of high-grade CIN.
| S-EPMC8906243 | biostudies-literature
Project description:BACKGROUND:Cervical dysplasia (cervical intraepithelial neoplasia (CIN)) is caused by Human Papillomavirus (HPV) and is most common in women of reproductive age. Current treatment of moderate to severe CIN is surgical. This procedure has potential complications, such as haemorrhage, infection and preterm birth in subsequent pregnancies. Moreover, 15% of women treated for high grade CIN develop residual/recurrent CIN or cervical cancer after surgical excision. Finally, 75-100% of patients with a residual and recurrent CIN 2-3 lesion are still HPV positive. They could possibly benefit from an alternative medical treatment, which aims to eliminate HPV. The primary study objective is to evaluate the effectivity of imiquimod 5% cream compared to treatment with Large Loop Excision of the Transformation Zone (LLETZ) for recurrent/residual CIN. METHODS/DESIGN:This study is a multicentre, non-inferiority randomized single blinded study. The study population consists of female patients with histological proven residual/recurrent CIN after previous surgical treatment. Four hundred thirty-three patients will be included in the Netherlands. The first 35 patients will be included in a pilot study to prove non-futility. Included patients will be randomized to receive either 5% imiquimod cream or LLETZ treatment. Imiquimod will be inserted three times a week intravaginally for a period of 16 weeks using a vaginal applicator. Ten weeks after the end of imiquimod treatment a biopsy will be taken for treatment response. In case of progressive or stable disease a LLETZ will be performed. At 12 and 24 months after the start of treatment cytology will be taken for follow up. The LLETZ group will be treated according to the current guidelines. Throughout the study, HPV typing and quality of life will be tested. DISCUSSION:Repeated LLETZ in women with residual/recurrent CIN lesions has complications. We would like to possibly offer alternative treatment in a selected group to avoid these risks. Moreover, we monitor treatment efficacy, side effects and long-term recurrence rates. TRIAL REGISTRATION:Medical Ethical Committee approval number: NL 53792.078.15. Affiliation: Erasmus Medical Center. Registration number ClinicalTrials.gov : NCT02669459 , date of registration: 27th January 2016.
| S-EPMC6003116 | biostudies-literature
Project description:ObjectiveTo evaluate the histologic response rate of high-grade squamous intraepithelial lesions (HSIL) of the cervix after topical application of 5% imiquimod cream.MethodsIn this phase II trial, women with cervical HSIL (cervical intraepithelial neoplasia [CIN] 2-3) were randomly assigned to 250 mg of 5% imiquimod cream applied to the cervix weekly for 12 weeks, followed by loop electrosurgical excision procedure (LEEP) without preceding treatment. The sample size was calculated based on the HSIL regression rates previously reported by Grimm et al. The primary outcome was rate of histologic regression (to CIN 1 or less) in LEEP specimens. Prespecified secondary endpoints included surgical margin status and adverse events. Outcomes were stratified by human papillomavirus type and lesion grade (CIN 2 or CIN 3). Results were reported according to per protocol (PP) and intention-to-treat (ITT) analyses.ResultsNinety women were enrolled: 49 in the experimental group and 41 in the control group. In the PP population, histologic regression was observed in 23 of 38 participants (61%) in the experimental group compared with 9 of 40 (23%) in the control group (P=.001). Surgical margins were negative for HSIL in 36 of 38 participants (95%) in the experimental group and 28 of 40 (70%) in the control group (P=.004). In the ITT population, rates of histologic regression also were significantly higher in the experimental group. Rates of adverse events in the experimental group were 74% (28/38) in the PP population and 78% (35/45) in the ITT population. Adverse events were mild, with abdominal pain being the most common. Three patients in the experimental group had grade 2 adverse events, including vaginal ulcer, vaginal pruritus with local edema, and moderate pelvic pain.ConclusionWeekly topical treatment with imiquimod is effective in promoting regression of cervical HSIL.Clinical trial registrationClinicalTrials.gov, NCT03233412.
| S-EPMC8132915 | biostudies-literature
Project description:PurposeOnly a fraction of low-grade cervical intraepithelial neoplasia (CIN) progresses to high-grade CIN; however, the biological processes that differentiate progressive CIN from CIN that resolves naturally are poorly understood. MicroRNAs (miRNAs) are important epigenetic regulators of gene expression and thus, miRNA expression profiling can reveal the dysregulated biology underlying disease processes. The purpose of this case-control study was to reveal miRNA expression patterns and predict the underlying biological pathways that are associated with clinical outcomes of low-grade CIN.MethodsWomen with low-grade CIN diagnosis and definitive clinical outcomes (n = 51) were identified retrospectively using electronic clinical records. Comprehensive miRNA expression profiling was performed on the low-grade CIN diagnostic cervical biopsies retrieved from pathology archives. Differential miRNA expression was analyzed by comparing women with CIN that progressed to women with CIN that resolved naturally.ResultsDifferential expression of 29 miRNAs was observed in low-grade CIN that progressed to high-grade compared to low-grade CIN that resolved. Of these, 24 were significantly downregulated in progressive CIN, including miR-638, miR-3196, miR-4488, and miR-4508, while 5 miRNAs, including miR-1206a, were significantly upregulated. Computational gene ontology analysis based on the discovered miRNAs and their putative mRNA targets revealed biological processes associated with oncogenic phenotypes.ConclusionDistinct miRNA expression profiles are associated with clinical outcomes of low-grade CIN. The functional effects of the differentially expressed miRNAs may be biological determinants of CIN progression or resolution.
| S-EPMC10465678 | biostudies-literature
Project description:Few studies have investigated the absence of high-grade cervical intraepithelial neoplasia (CIN) in excised specimens, and sample sizes of these studies were limited. This study retrospectively analyzed clinical characteristics of 1695 patients with CIN 2/3 to determine the incidence rate and relative factors of CIN 1 or less in conization specimens from patients with colposcopic biopsy-confirmed CIN 2/3. The study group comprised 430 cases of CIN 1 or less in conization specimens, and the control group comprised 1142 cases with high-grade CIN lesions in conization specimens. Univariate and multivariate logistic regression models were established to evaluate relative factors. The 1-9 years follow-up data were analyzed to determine the persistence/recurrence rate. Multivariate logistic regression showed that patients aged 18-24 years (OR (95% CI) = 2.224 (1.014, 4.877)); with a negative hrHPV test result (OR (95% CI) = 3.210 (1.627, 6.331)); a cytology test result of normal (OR (95% CI) = 5.184 (3.138, 8.563)), ASC-US (OR (95% CI) = 3.420 (2.102, 5.564)), LSIL (OR (95% CI) = 2.588 (1.475, 4.541)), or ASC-H (OR (95% CI) = 2.434 (1.306, 4.539)); an indication of CIN 2 on biopsy (OR (95% CI) = 2.290 (1.694, 3.096)), and no glandular involvement (OR (95% CI) = 1.616 (1.205, 2.169)) were more likely to have an absence of high-grade dysplasia in conization specimens. There was no difference in the persistence/recurrence rate between the two groups (x2 = 1.55, P = 0.46). An age of 18-24 years, a negative hrHPV test result, a non-HSIL cytology test result, an indication of CIN 2 on biopsy, and no glandular involvement were relative factors for an absence of high-grade dysplasia in conization specimens. For patients with relative factors, especially young women, informed follow-up should be considered.
| S-EPMC9515539 | biostudies-literature
Project description:BACKGROUND: The development of cervical cancer and its high-grade precursor lesions (Cervical Intraepithelial Neoplasia grade 2/3 [CIN2/3]) result from a persistent infection with high-risk human papillomavirus (hrHPV) types and the accumulation of (epi)genetic host cell aberrations. Epidemiological studies have demonstrated variable CIN2/3 and cancer risks between different hrHPV types. Recent genomic profiling studies revealed substantial heterogeneity in the chromosomal aberrations detected in morphologically indistinguishable CIN2/3 suggestive of varying cancer risk. The current study aimed to investigate whether CIN2/3 with different hrHPV types vary with respect to their chromosomal profiles, both in terms of the number of aberrations and chromosomal loci affected. METHODS: Chromosomal profiles were determined of 43 p16INK4a-immunopositive CIN2/3 of women with long-term hrHPV infection (? 5 years). Sixteen lesions harboured HPV16, 3 HPV18, 14 HPV31, 1 HPV33, 4 HPV45, 1 HPV51, 2 HPV52 and 2 HPV58. RESULTS: Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two major clusters, characterised by either few or multiple chromosomal aberrations, respectively. A majority of 87.5% of lesions with HPV16 were in the cluster with relatively few aberrations, whereas no such unbalanced distribution was seen for lesions harbouring other hrHPV types. Analysis of the two most prevalent types (HPV16 and HPV31) in this data set revealed a three-fold increase in the number of losses in lesions with HPV31 compared to HPV16-positive lesions. In particular, losses at chromosomes 2q, 4p, 4q, 6p, 6q, 8q & 17p and gain at 1p & 1q were significantly more frequent in HPV31-positive lesions (FDR < 0.2). CONCLUSIONS: Chromosomal aberrations in CIN2/3 are at least in part related to the hrHPV type present. The relatively low number of chromosomal aberrations observed in HPV16-positive CIN2/3 suggests that the development of these lesions is less dependent on genetic insult than those caused by other types like HPV31.
| S-EPMC3305644 | biostudies-literature
Project description:BackgroundEpigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited.MethodsWomen (n = 419) were enrolled at colposcopic evaluation at Duke Medical Center in Durham, North Carolina. Human papillomavirus (HPV) was genotyped by HPV linear array and CIN grade was ascertained by biopsy pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of the IGF2/H19, IGF2AS, MESTIT1/MEST, MEG3, PLAGL1/HYMAI, KvDMR and PEG10, PEG3 imprinted domains, using Sequenom-EpiTYPER assays. Logistic regression models were used to evaluate the associations between HPV infection, DMR methylation and CIN risk overall and by race.ResultsOf the 419 participants, 20 had CIN3+, 52 had CIN2, and 347 had ≤ CIN1 (CIN1 and negative histology). The median participant age was 28.6 (IQR:11.6) and 40% were African American. Overall, we found no statistically significant association between altered methylation in selected DMRs and CIN2+ compared to ≤CIN1. Similarly, there was no significant association between DMR methylation and CIN3+ compared to ≤CIN2. Restricting the outcome to CIN2+ cases that were HR-HPV positive and p16 staining positive, we found a significant association with PEG3 DMR methylation (OR: 1.56 95% CI: 1.03-2.36).ConclusionsWhile the small number of high-grade CIN cases limit inferences, our findings suggest an association between altered DNA methylation at regulatory regions of PEG3 and high grade CIN in high-risk HPV positive cases.
| S-EPMC8201933 | biostudies-literature
Project description:New prevention strategies are needed to detect cervical intraepithelial neoplasia (CIN). The microRNA expression analysis has already been reported as molecular biomarkers in the early detection of cervical cancer (CC) through minimally invasive samples, such as liquid biopsy, obtained through collection using liquid-based cytology (LBC). In this study, we aimed to identify molecular signatures of microRNAs in cervical precursor lesions from LBC cervical and the molecular pathways potentially associated with the CC progression. We analyzed 31 LBC cervical samples from women who underwent colposcopy. These samples were divided into two groups: the first group was composed of samples without precursor lesions of CC, considering the control group, referred to as healthy female subjects (HFS; n = 11). The second group corresponded to women diagnosed with cervical interepithelial neoplasia grade 3 (CIN 3; n = 20). We performed microRNA and gene expression profiling using the nCounter® miRNA Expression Assays (NanoString Technology) and PanCancer Pathways (NanoString Technology), respectively. A microRNA target prediction was performed by mirDIP, and molecular pathway interaction was constructed using Cytoscape. Bidirectional in silico analyses and Pearson's correlation were performed for associated the relation between genes, and miRNAs differentially expressed related cervical cancer progression were performed. We found that the expression of nine microRNAs was significantly higher, two were downregulated (miR-381-3p and miR-4531), and seven miRNAs were upregulated (miR-205-5p, miR-130a-3p, miR-3136-3p, miR-128-2-5p, let-7f-5p, miR-202-3p, and miR-323a-5p) in CIN 3 (fold change ≥ 2 and p ≤ 0.05). The miRNA expression patterns were independent of hr-HPV infection. We identified four miRNAs (miR-205-5p, miR-130a-3p, miR-4531, and miR-381-3p) that could be used as biomarkers for CIN 3 in LBC samples through multiple logistic regression analyses. We found 16 genes differentially expressed between CIN 3 and HSF samples (fold change ≥ 2 and p ≤ 0.05). We found the correlation between miR-130a-3p and CCND1(R = -0.52; p = 0.0029), miR-205-5p and EGFR (R = 0.53; p = 0.0021), and miR-4531 and SMAD2 (R = -0.54; p = 0.0016). In addition, we demonstrated the most significant pathways of the targets associated with cervical cancer progression (FDR-corrected p < 0.001). This study demonstrated that miRNA biomarkers may distinguish healthy cervix and CIN 3 and regulate important molecular pathways of carcinogenesis.
| S-EPMC8060087 | biostudies-literature
Project description:BackgroundThere is no prognostic test to ascertain whether cervical intraepithelial neoplasias (CINs) regress or progress. The majority of CINs regress in young women, and treatments increase the risk of adverse pregnancy outcomes. We investigated the ability of a DNA methylation panel (the S5 classifier) to discriminate between outcomes among young women with untreated CIN grade 2 (CIN2).MethodsBaseline pyrosequencing methylation and human papillomavirus (HPV) genotyping assays were performed on cervical cells from 149 women with CIN2 in a 2-year cohort study of active surveillance.ResultsTwenty-five lesions progressed to CIN grade 3 or worse, 88 regressed to less than CIN grade 1, and 36 persisted as CIN1/2. When cytology, HPV16/18 and HPV16/18/31/33 genotyping, and the S5 classifier were compared to outcomes, the S5 classifier was the strongest biomarker associated with regression vs progression. The S5 classifier alone or in combination with HPV16/18/31/33 genotyping also showed significantly increased sensitivity vs cytology when comparing regression vs persistence/progression. With both the S5 classifier and cytology set at a specificity of 38.6% (95% confidence interval [CI], 28.4-49.6), the sensitivity of the S5 classifier was significantly higher (83.6%; 95% CI, 71.9-91.8) than of cytology (62.3%; 95% CI, 49.0-74.4; P = 0.005). The highest area under the curve was 0.735 (95% CI, 0.621-0.849) in comparing regression vs progression with a combination of the S5 classifier and cytology, whereas HPV genotyping did not provide additional information.ConclusionsThe S5 classifier shows high potential as a prognostic biomarker to identify progressive CIN2.
| S-EPMC7286376 | biostudies-literature