Triage of high-risk HPV-positive women in population-based screening by miRNA expression analysis in cervical scrapes; a feasibility study.
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ABSTRACT:
SUBMITTER: Babion I
PROVIDER: S-EPMC5992707 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Triage of high-risk HPV-positive women in population-based screening by miRNA expression analysis in cervical scrapes; a feasibility study.
Babion Iris I Snoek Barbara C BC Novianti Putri W PW Jaspers Annelieke A van Trommel Nienke N Heideman Daniëlle A M DAM Meijer Chris J L M CJLM Snijders Peter J F PJF Steenbergen Renske D M RDM Wilting Saskia M SM
Clinical epigenetics 20180607
<h4>Background</h4>Primary testing for high-risk HPV (hrHPV) is increasingly implemented in cervical cancer screening programs. Many hrHPV-positive women, however, harbor clinically irrelevant infections, demanding additional disease markers to prevent over-referral and over-treatment. Most promising biomarkers reflect molecular events relevant to the disease process that can be measured objectively in small amounts of clinical material, such as miRNAs. We previously identified eight miRNAs with ...[more]
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Project description:ObjectiveTo assess triage compliance and the effect of the time from screening to triage on follow-up among HPV-positive women.MethodsWe recruited 1232 women in a screening campaign in Madagascar from February to October 2015. In the first period (February-May), HPV tests were performed remotely using the cobas test. In the second period (May-October), testing was performed on-site using the Xpert HPV assay. HPV-positive women were invited for triage with visual inspection with acetic acid (VIA) and Lugol's iodine (VILI). Systematic biopsy and endocervical brushing were performed on all HPV-positive women for quality control. Three groups were defined according to time from HPV testing to triage invitation for HPV-positive women-Group I: delayed (> 3 months), Group II: prompt (24-48 hours), and Group III: immediate (< 24 hours).ResultsA total 1232 self-sampled HPV tests were performed in the study period (496 in Group I, 512 in Group II, and 224 in Group III). Participants' mean age was 43.2 ± 9.3 years. Mean time from screening to VIA/VILI testing was 103.5 ± 43.6 days. Overall HPV prevalence was 28.0%. HPV prevalence was 27.2% in Group I (cobas test), 29.2% in Group 2 (Xpert test), and 26,7% in Group III (Xpert test). The VIA/VILI compliance rate was 77.8% for Group I, 82.7% for Group II, and 95.0% for Group III. Of women undergoing VIA/VILI, 56.3% in Group I and 43.5% in Groups II/III had positive results. Prevalence of cervical intraepithelial neoplasia grade 2 or worse among HPV-positive women was 9.8% for Group I and 6.8% for Groups II/III. Non-adherence was higher among rural women, uneducated women, and women in Group I.ConclusionHPV-positive women with immediate VIA/VILI triage invitation had the best triage compliance. A single-day test and triage strategy is preferred for low-resource settings.
| S-EPMC6692065 | biostudies-literature
Project description:Human papillomavirus (HPV)-based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case-control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25-65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50 <CIN2); Group 2: 103 HPV+, normal cytology with HPV persistence at 12 mo. (53 CIN2/3; 50 <CIN2); Group 3: 50 HPV+, normal cytology with HPV clearance at 12 mo. (assumed <CIN2), total n=257. For the combined groups, S5 risk score CIN2/3 relative sensitivity, specificity and positive predictive value (PPV) were compared with other triage approaches. Methylation showed a highly significant increasing trend with disease severity. For CIN3, S5 relative sensitivity and specificity were: 93.2% (95%CI: 81.4-98.0) and 41.8% (35.2-48.8), compared to 86.4% (75.0-95.7) and 49.8% (43.1-56.6) respectively for combined abnormal cytology/HPV16/18 positivity (differences not statistically significant at 5% level); adjusted PPVs were 18.2% (16.2-20.4) and 19.3% (16.6-22.2) respectively. S5 was also positive in baseline specimens from eight cancers detected during or after trial participation. The S5 methylation score had high sensitivity and PPV for CIN3, compatible with US and European thresholds for colposcopy referral. Methylation signatures can identify most HPV positive women at increased risk of cervical cancer from their baseline screening specimens.
| S-EPMC6492122 | biostudies-literature
Project description:OBJECTIVE:To explore the relationship between the viral load reflected by the Ct value of Cobas 4800 HPV test and cervical lesions, and the effectiveness of the viral load for secondary triage of HPV-positive women. METHODS:The Chinese Multi-Center Screening Trial (CHIMUST) evaluated both self-collected samples and physician-collected samples from women, aged 30 to 59, who were screened for cervical cancer in 6 regions across China. Using physician collected samples, the relationship between the HPV-Ct values of different subtypes and the cervical lesions was analyzed. Then the combined use of the HPV-Ct values with the HPV subtypes was evaluated as a secondary screening algorithm for the women who were HPV positive. RESULTS:The Ct values of HPV16 and 12 other HPV subtypes(12-type pool), tested with Cobas decreased with the progression of cervical lesion (HPV16: r = -0.429, P<0.001; 12 other HR-HPV subtypes: r = -0.099, P<0.01). The HPV18-Ct value was not correlated with cervical lesion(P>0.05). Compared with HPV16/18 and cytology (HPV16/18 positive and 12-type pool plus cytology ? ASC-US), the sequential secondary screening using HPV16/18 and the viral load of 12-type pool (cut-point HPV-Ct?31) had equal sensitivities for CIN2+ and CIN3+ (83.1%vs.80.3%,100%vs.92.6%,P>0.05), with slightly lower specificities (96.2%vs.94.4%,96.5%vs.93.9%,P<0.001) and higher colposcopy referral rate (4.90%vs.6.59%, P<0.05), but required no cytology. CONCLUSION:Type-specific HPV viral load is closely related to cervical lesions severity. It is feasible and efficient to use HPV16/18 and the viral load of 12 other HPV subtypes (with cut-point HPV-Ct?31) as the secondary screening for HPV positive women. This algorithm may be useful in low resource regions.
| S-EPMC7205204 | biostudies-literature
Project description:ImportanceAs cervical cancer screening transitions to primary human papillomavirus (HPV) testing, effective triage and management of HPV-positive women is critical to avoid unnecessary colposcopy referral and associated harms while maintaining high sensitivity for cervical precancer. Triage with p16/Ki-67 dual-stain (DS) testing has shown high sensitivity and specificity for detection of cervical precancers; however, longitudinal studies are needed to determine the long-term risk of precancer following a negative DS result.ObjectiveTo evaluate the longitudinal performance of p16/Ki-67 DS triage for detection of cervical precancer in HPV-positive women over 5 years of follow-up in the context of clinical management thresholds.Design, setting, and participantsProspective cohort study of HPV-positive women 30 years or older undergoing routine cervical cancer screening in 2012 with HPV and Papanicolaou (hereinafter "cytology") co-testing within the Kaiser Permanente Northern California health care system. Follow-up of medical records was conducted through 2017.ExposuresAll p16/Ki-67 DS testing was performed on residual SurePath material, and slides were evaluated for p16/Ki-67 positivity.Main outcomes and measuresHistological end points were ascertained from the clinical database through 2017. We estimated 5-year cumulative risks of cervical intraepithelial neoplasia grades of 2 or worse (≥CIN2) or grades 3 or worse (≥CIN3) by baseline DS and cytology at yearly intervals using Logistic Weibull models. Risks were compared with clinical management thresholds for colposcopy referral and a 1-year return interval.ResultsAmong the 1549 HPV-positive women in this study, the mean age at enrollment was 42.2 years, and the median follow-up time was 3.7 years (range, 0.2-5.4 years). Positive DS results were associated with significantly higher cumulative 5-year risks of ≥CIN2 compared with abnormal cytology (31.0%; 95% CI, 27.2%-35.3% vs 25.0%; 95% CI, 21.7%-28.7%; P = .03). Women with DS-negative findings had significantly lower 5-year risks of ≥CIN2 compared with women with normal cytology (8.5%; 95% CI, 6.5%-11.1% vs 12.3%; 95% CI, 9.8%-15.4%; P = .04). In DS-negative women, the risks of both ≥CIN2 and ≥CIN3 remained below the colposcopy referral threshold for all 5 years, crossing the 1-year return threshold at 3 years.Conclusions and relevanceTriage with p16/Ki-67 DS provides better long-term risk stratification than cytology over 5 years. The low risk of cervical precancer in p16/Ki-67 DS-negative women permits safe extension of follow-up intervals for 3 years.
| S-EPMC6439556 | biostudies-literature
Project description:BackgroundAccelerated global control of cervical cancer would require primary prevention with human papillomavirus (HPV) vaccination in addition to novel screening program strategies that are simple, inexpensive, and effective. We present the feasibility and outcome of a community-based HPV self-sampled screening program.MethodsIn Ile Ife, Nigeria, 9406 women aged 30-49 years collected vaginal self-samples, which were tested for HPV in the local study laboratory using Hybrid Capture-2 (HC2) (Qiagen). HPV-positive women were referred to the colposcopy clinic. Gynecologist colposcopic impression dictated immediate management; biopsies were taken when definite acetowhitening was present to produce a histopathologic reference standard of precancer (and to determine final clinical management). Retrospective linkage to the medical records identified 442 of 9406 women living with HIV (WLWH).ResultsWith self-sampling, it was possible to screen more than 100 women per day per clinic. Following an audio-visual presentation and in-person instructions, overall acceptability of self-sampling was very high (81.2% women preferring self-sampling over clinician collection). HPV positivity was found in 17.3% of women. Intensive follow-up contributed to 85.9% attendance at the colposcopy clinic. Of those referred, 8.2% were initially treated with thermal ablation and 5.6% with large loop excision of transformation zone (LLETZ). Full visibility of the squamocolumnar junction, necessary for optimal visual triage and ablation, declined from 68.5% at age 30 to 35.4% at age 49. CIN2+ and CIN3+ (CIN- Cervical intraepithelial neoplasia), including five cancers, were identified by histology in 5.9 and 3.2% of the HPV-positive women, respectively (0.9 and 0.5% of the total screening population), leading to additional treatment as indicated. The prevalences of HPV infection and CIN2+ were substantially higher (40.5 and 2.5%, respectively) among WLWH. Colposcopic impression led to over- and under-treatment compared to the histopathology reference standard.ConclusionA cervical cancer screening program using self-sampled HPV testing, with colposcopic immediate management of women positive for HPV, proved feasible in Nigeria. Based on the collected specimens and images, we are now evaluating the use of a combination of partial HPV typing and automated visual evaluation (AVE) of cervical images to improve the accuracy of the screening program.
| S-EPMC7556552 | biostudies-literature
Project description:Background:State-of-the-art cervical cancer prevention includes human papillomavirus (HPV) vaccination among adolescents and screening/treatment of cervical precancer (CIN3/AIS and, less strictly, CIN2) among adults. HPV testing provides sensitive detection of precancer but, to reduce overtreatment, secondary "triage" is needed to predict women at highest risk. Those with the highest-risk HPV types or abnormal cytology are commonly referred to colposcopy; however, expert cytology services are critically lacking in many regions. Methods:To permit completely automatable cervical screening/triage, we designed and validated a novel triage method, a cytologic risk score algorithm based on computer-scanned liquid-based slide features (FocalPoint, BD, Burlington, NC). We compared it with abnormal cytology in predicting precancer among 1839 women testing HPV positive (HC2, Qiagen, Germantown, MD) in 2010 at Kaiser Permanente Northern California (KPNC). Precancer outcomes were ascertained by record linkage. As additional validation, we compared the algorithm prospectively with cytology results among 243 807 women screened at KPNC (2016-2017). All statistical tests were two-sided. Results:Among HPV-positive women, the algorithm matched the triage performance of abnormal cytology. Combined with HPV16/18/45 typing (Onclarity, BD, Sparks, MD), the automatable strategy referred 91.7% of HPV-positive CIN3/AIS cases to immediate colposcopy while deferring 38.4% of all HPV-positive women to one-year retesting (compared with 89.1% and 37.4%, respectively, for typing and cytology triage). In the 2016-2017 validation, the predicted risk scores strongly correlated with cytology (P < .001). Conclusions:High-quality cervical screening and triage performance is achievable using this completely automated approach. Automated technology could permit extension of high-quality cervical screening/triage coverage to currently underserved regions.
| S-EPMC6454428 | biostudies-other
Project description:BackgroundQuantitative methylation-specific PCR (qMSP) analysis for determining the methylation status of (candidate) tumor suppressor genes has potential as objective and valuable test to triage high-risk human papillomavirus (hrHPV) positive women in cervical screening. Particularly combined methylation analysis of a panel of genes shows most promising clinical performance, with sensitivity levels that equal or exceed that of cytology. However, the wide application of such methylation marker panels is hampered by the lack of effective multiplex assays allowing simultaneous methylation detection of various targets in a single reaction. Here, we designed and analyzed a multiplex qMSP assay for three genes whose methylation was previously found to be informative for cervical (pre)cancer (i.e. CADM1, MAL and hsa-miR-124-2) as well as a reference gene ?-actin. Based on our experience, we discuss the optimization of the parameters that provide a practical approach towards multiplex qMSP design.MethodsPrimers and PCR reagents were optimized for multiplex qMSP purposes and the resulting assay was analytically validated on serial dilutions of methylated DNA in unmethylated DNA, and compared with singleplex counterparts on hrHPV-positive cervical scrapings.ResultsUpon optimization, including primer redesign and primer limiting assays, the multiplex qMSP showed the same analytical performance as the singleplex qMSPs. A strong correlation between the obtained normalized ratios of the singleplex and multiplex qMSPs on cervical scrapes was found for all three markers: CADM1 (R(2) = 0.985), MAL (R(2) = 0.986) and hsa-miR-124-2 (R(2) = 0.944).ConclusionMultiplex qMSP offers a promising approach for high-throughput diagnostic analysis of the methylation status of multiple genes, which after proper design and validation can be equally specific, sensitive and reproducible as its singleplex versions.
| S-EPMC3517769 | biostudies-literature
Project description:In Norway, repeat cytology and HPV testing comprise delayed triage of women with minor cytological lesions. The objective of this study was to evaluate HPV DNA and HPV mRNA testing in triage of women with an ASC-US/LSIL diagnosis.We used repeat cytology, HPV DNA testing (Cobas 4800) and HPV mRNA testing (PreTect HPV-Proofer) to follow up 311 women aged 25-69 years with ASC-US/LSIL index cytology.Of 311 women scheduled for secondary screening, 30 women (9.6%) had ASC-H/HSIL cytology at triage and 281 women (90.4%) had ASC-US/LSIL or normal cytology. The HPV DNA test was positive in 92 (32.7%) of 281 instances, and 37 (13.2%) were mRNA positive. Of the 132 women with repeated ASC-US/LSIL, we received biopsies from 97.0% (65/67) of the DNA-positive and 92.9% (26/28) of the mRNA-positive cases. The positive predictive values for CIN2+ were 21.5% (14/65) for DNA positive and 34.6% (9/26) for mRNA positive (ns). The odds ratio for being referred to colposcopy in DNA-positive cases were 2.8 times (95% CI: 1.8-4.6) higher that of mRNA-positive cases. Compared to the mRNA test, the DNA test detected four more cases of CIN2 and one case of CIN3.The higher positivity rate of the DNA test in triage leads to higher referral rate for colposcopy and biopsy, and subsequent additional follow-up of negative biopsies. By following mRNA-negative women who had ASC-US/LSIL at triage with cytology, the additional cases of CIN2+ gained in DNA screening can be discovered. Our study indicates that in triage of repeated ASC-US/LSIL, HPV mRNA testing is more specific and is more relevant in clinical use than an HPV DNA test.
| S-EPMC4236101 | biostudies-literature
Project description:A challenge in implementation of sensitive HPV-based screening is limiting unnecessary referrals to colposcopic biopsy. We combined two commonly recommended triage methods: partial HPV typing and "reflex" cytology, evaluating the possibility of automated cytology. This investigation was based on 1,178 exfoliated cervical specimens collected during the enrollment phase of The Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED, Oklahoma City, OK). We chose a colposcopy clinic population to maximize number of outcomes, for this proof-of-principle cross-sectional study. Residual aliquots of PreservCyt were HPV-typed using Linear Array (LA, Roche Molecular Systems, Pleasanton, CA). High-risk HPV typing data and cytologic results (conventional and automated) were used jointly to predict risk of histologically defined ?CIN2. We developed a novel computer algorithm that uses the same optical scanning features that are generated by the FocalPoint Slide Profiler (BD, Burlington, NC). We used the Least Absolute Shrinkage and Selection Operator (LASSO) method to build the prediction model based on a training dataset (n?=?600). In the validation set (n?=?578), for triage of all HPV-positive women, a cytologic threshold of ?ASC-US had a sensitivity of 0.94, and specificity of 0.30, in this colposcopy clinic setting. When we chose a threshold for the severity score (generated by the computer algorithm) that had an equal specificity of 0.30, the sensitivity was 0.91. Automated cytology also matched ?ASC-US when partial HPV typing was added to the triage strategy, and when we re-defined cases as ?CIN3. If this strategy works in a prospective screening setting, a totally automated screening and triage technology might be possible.
| S-EPMC5159264 | biostudies-literature
Project description:OBJECTIVES:The aim of this study was to understand causes of attendance and non-attendance to a follow-up cervical cancer screening among human papillomavirus (HPV)-positive women. DESIGN:Semistructured, individual interviews with HPV-positive women and cervical cancer screening nurses. The interview guide and initial data analysis were guided by existing health behaviour theories. However, as the theories limited the potential of the data material, a grounded theory framework guided the final data analysis. SETTING:Interviews were conducted in Dar es Salaam, Tanzania, at Ocean Road Cancer Institute (ORCI) or in the homes of screening clients. PARTICIPANTS:15 interviews were conducted with women who had tested HPV-positive during a patient-initiated screening and been appointed for a follow-up screening 14 months later. Nine women had not attended the follow-up appointment, four had delayed attendance and two had attended on the scheduled date. Further, individual interviews were conducted with the two nurses working at ORCI's screening clinic. RESULTS:Perceived benefits for attending a patient-initiated screening include treatment of gynaecological symptoms and prevention of disease. The key perceived benefit of a health provider-initiated follow-up screening is prevention, which is challenged by the circumstance that it is seen by women as having merely potential benefit and therefore can be postponed when competing needs are present. Perceived challenges for screening attendance include emotional costs, in the form of fear of the disease, fear of the gynaecological examination as well as direct and indirect economic costs, such as transportation costs, lost income and waiting time. CONCLUSION:Cervical cancer screening is one among many tasks that women living in a low-income setting must attend to. Since health provider-initiated follow-up screening is seen as having only potential benefit, attendance can be postponed when competing needs exist. TRIAL REGISTRATION NUMBER:NCT02509702.
| S-EPMC6398757 | biostudies-literature