Detection Of CIN2 Research Articles

Evaluation of p16/Ki-67 Dual-Stained Cytology in Triaging HPV-Positive Women during Cervical Cancer Screening.

We aimed to evaluate the utility of p16/Ki-67 dual-stained cytology for triaging human papillomavirus (HPV)-positive women. HPV-positive women ages ≥ 21 years were recruited in a multicenter prospective observational study between May 2016 and May 2017. The clinical performance of dual-stained cytology, with or without HPV16/18 genotyping, was evaluated for all HPV-positive women to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+). 846 HPV-positive women ages ≥ 21 years with valid cervical biopsies were enrolled for this study. For CIN2+ detection, dual-stained cytology showed statistically higher specificity (85.28%) than Pap cytology (80.00%, P < 0.001) and HPV16/18 genotyping (72.36%, P < 0.001), while the sensitivity of dual-stained cytology (63.49%) remained comparable with that of Pap cytology (61.90%, P = 0.832) and HPV16/18 genotyping (61.90%, P = 0.897). HPV16/18 genotyping in combination with dual-stained cytology was more specific (62.50% vs. 58.06%, P < 0.001), while it showed similar sensitivity (86.51% vs. 85.71%, P = 1.000), as compared with HPV16/18 genotyping in combination with Pap cytology. Similar patterns were also observed for CIN3+. p16/Ki-67 dual-stained cytology, either alone or in combination with HPV16/18 genotyping, showed a good stratification with high specificity and comparable sensitivity for HPV-positive women. This is one of the few studies that has evaluated the performance of dual-stained cytology for triaging HPV-positive women in China. The higher specificity and comparable sensitivity of dual-stained cytology in comparison with Pap cytology in the detection of CIN2+ or CIN3+ is of vital importance to developing countries, where Pap cytology faces many challenges.

SO015URINE NMR-BASED METABOLOMICS FOR EARLY DETECTION OF POST-PROCEDURAL CONTRAST NEPHROPATHY

Abstract Background and Aims Contrast induced nephropathy (CIN) has been reported to be the third foremost cause of acute renal failure. Metabolomics is a robust technique that has been used to identify potential biomarkers for early detection of renal damage after procedures with using contrast media. We aim to analyze the serum and urine metabolites changes, after using contrast for coronary angiography, to determine if metabolomics can use as a tool for early detection of CIN. Method Sixty-six patients with positive primary non-invasive diagnostic tests for coronary artery disease (CAD) who were candidate of elective coronary angiography recruited. Spot urine samples collected in the morning before angiography and 4 hours after angiography. Patients with &amp;gt; 0.5 mg/dL creatinine rise compared to baseline were considered as case (CIN group). Urine samples were centrifuged at 3000 rcf for 20 minutes at 4°C to remove the cell debris and after addition of sodium azide to prevent bacterial growth, were stored at -80 degree Celsius in aliquots until required. The mixtures were then transferred to a standard 5 mm NMR tube for analysis. 1H-NMR spectra were acquired at 300 K on a Bruker DRX 500 MHz spectrometer by using Carr–Pucell–Meiboom–Gill (CPMG) technique. For each spectrum, 154 scans were collected into 32K data points using a spectral width of 8389.26 Hz during the relaxation time of 2.5 s. Results Structure and outliers of the dataset composed of patient with CIN (n = 10) before angiography and after angiography were evaluated by PCA. A model with two principal components (PC1 and PC2) with R2X = 0.775 and Q2(cum) = 0.487 was obtained .A supervised OPLS-DA model was built to identify discriminative variables between metabolite profiles before and after angiography in patients with CIN. The high level of AUC 0.95 that was obtained from 10-fold cross validation besides decreased R2 (0.0, 0.415) and Q2 (0.0, -0.454) intercepts of 999 random permutations reflects the good validity of this diagnostic model. According to this valid OPLS-DA model, 15 chemical shifts were significant based on VIP &amp;gt; 1 and FC &amp;gt; 1.2. To check these suggested chemical shifts if their changes are due to kidney injury and not caused by contrast agent, a decoy OPLS-DA model was built for non-CIN patients before and after angiography .Two common significant chemical shifts (2.42 and 2.78 ppm) were found in comparison of these two models (i.e. before vs. after angiography in CIN group in compared with before vs. after angiography in non-CIN group) and were excluded from the results. Metabolites corresponding with the remaining list of 12 significant chemical shifts were identified and suggested as early detection biomarker candidates for CIN (Fig 1). The AUC value of a panel of four biomarker candidates were higher than single biomarkers that reflects the value of simultaneous measurement of these four metabolite candidates than single candidates. Figure 2 shows the list of diagnostic metabolite candidates with p &amp;lt; 0.05 . Pathway characterization was used to better understanding of pathophysiology of CIN. As the input data was small list of metabolites, only “Histidine_ lysine_ phenylalanine, tyrosine, proline and tryptophan catabolism” pathway (p &amp;lt; 0.05) was significant and suggested as the most important disturbed pathway in CIN. Conclusion Early detection of CIN as early as only 4 hours after using contrast can help better management of these patients. In this study, only after 4 hours passed from using contrast a panel of metabolites could be found in urine of patients who develop CIN, which facilitates early detection of CIN. This is the first study to investigate urine metabolic profile using NMR-based metabolomics for early detection of CIN after coronary angiography. The use of this suggested panel might significantly improve clinical consequences of this harmful complication.

The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.

To establish the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women referred to colposcopy with persistent high-risk human papillomavirus (hrHPV) cytology-negative screening sample according to hrHPV genotype, age at referral and colposcopic performance. Prospective cohort study. Single colposcopy clinic linked to a population-based screening programme. Women referred with persistent hrHPV cytology-negative routine screening samples. Prospective study with descriptive statistics from a single colposcopy unit between June 2014 and July 2019. Prevalence of hrHPV genotypes and CIN2+, positive predictive value for colposcopic impression, and inadequate colposcopic examinations. A total of 3107 women were referred. Prevalence of CIN2+ was highest for persistent HPV16 infections (10.7%) compared with HPV18 (3.6%) or HPVO (4.7%). Prevalence of CIN2+ declined with age (25-34years 14.2% to 55-64years 1.1%) whereas the percentage of women with an inadequate colposcopic examination increased (25-34years 0.9% to 55-64years 29.5%). High-grade colposcopic impression fell over time during the study from 16.1 to 5.1%. The positive predictive value for colposcopic impression of CIN2+ was affected by hrHPV genotype (57.3% for HPV16 versus 32.1% for nonHPV16). The adjunctive use of electrical impedance spectroscopy detected an extra 42 cases of CIN2+, which was irrespective of hrHPV genotype. Primary hrHPV cervical screening increases detection of CIN2+; however, low specificity results in more women being referred to colposcopy with a low prevalence of CIN2+. Colposcopy performs poorly in some groups, particularly with HPVO infections and women over 50years of age. An appropriate threshold for referral to colposcopy in primary hrHPV screening has not been established. Low prevalence of CIN2+ in HPV-positive negative cytology samples. HPV genotype, age and prevalence of CIN2+ affect colposcopic performance.

Good performance of p16/Ki-67 dual-stain cytology for detection and post-treatment surveillance of high-grade CIN/VAIN in a prospective, cross-sectional study.

The limited sensitivity of Papanicolaou (Pap) cytology and the low specificity of HPV testing in detecting cervical or vaginal lesions means that either precancers are missed or women without lesions are overtreated. To improve performance outcomes, p16/Ki-67 dual-stain cytology has been introduced as a useful biomarker. A prospective, cross-sectional study was performed and included 599 patients. Clinical performance estimates of Pap cytology, HPV DNA assay, and p16/Ki-67 dual-stain cytology for the detection of CIN2+/VAIN2+ were determined and compared. The sensitivity and specificity of p16/Ki-67 dual-stain cytology in detecting histology proven CIN2+/VAIN2+ was 91.6% and 95.0%, respectively, while that of Pap cytology was 42.1% and 95.2%, respectively, and that of HPV DNA testing was 100% and 41.6%, respectively. Among the three tests, the AUC of p16/Ki-67 immunocytochemistry was the largest, both for detecting cervical lesions and vaginal lesions, at 0.932 and 0.966, respectively. Among women who were HPV 16/18 positive or 12-other hrHPV positive and Pap positive (≥ASCUS), dual staining reduced the number of unnecessary colposcopy referrals from 274 to 181. Among the women who were 12-other hrHPV positive and Pap negative, dual staining could prevent underdiagnosis in six patients with CIN2+/VAIN2+ when used as a triage marker. Dual staining also identified four women with high-grade lesions detected by diagnostic conization but with negative colposcopy-guided biopsy results. p16/Ki-67 dual staining may be a promising tool for predicting high-grade cervical and vaginal lesions.

2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors.

2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors.

Methylation analysis in urine fractions for optimal CIN3 and cervical cancer detection

IntroductionUrine sampling is an interesting solution for CIN3 and cervical cancer detection. Urine can be separated in different fractions: full void urine, urine sediment and urine supernatant. We aimed to determine which urine fraction is most competent for CIN3 and cervical cancer detection by methylation analysis. MethodsUrine samples (27 controls, 30 CIN3 and 17 cervical cancer) were processed into 3 fractions and tested for 5 methylation markers (ASCL1, GHSR, LHX8, SST, ZIC1). We determined Spearman correlation coefficients between fractions, compared methylation levels and calculated AUCs for CIN3 and cancer detection. ResultsIn general strong correlations (r > 0.60) were found between urine fractions. Methylation levels increased significantly with severity of underlying disease in all urine fractions. CIN3 and controls differed significantly for 2 markers in full void urine, 4 markers in urine sediment and 1 marker in urine supernatant, with AUCs of 0.55–0.79. Comparison of cancer to controls was highly significant for all markers in all fractions, yielding AUCs of 0.87–0.99. ConclusionMethylation analysis performs excellent in all urine fractions for cervical cancer detection. Our results indicate the potential of CIN3 detection by urinary methylation analysis, and demonstrate that urine sediment performs best to detect CIN3.

Test Accuracy of Human Papillomavirus in Urine for Detection of Cervical Intraepithelial Neoplasia.

The objective was to assess the diagnostic test accuracy of high-risk human papillomavirus (hrHPV) testing of self-collected urine and cervicovaginal samples for the detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+). We recruited a convenience sample of women 25 to 65 years of age who were undergoing clinically indicated colposcopy at two medical centers in North Carolina between November 2016 and January 2019. Women with normal cytology results and positive hrHPV results were also recruited. Urine samples, self-collected cervicovaginal samples, provider-collected cervical samples, and cervical biopsy samples were obtained from all enrolled women. Samples were tested for hrHPV DNA using the Onclarity assay (Becton Dickinson, Sparks, MD). Biopsy samples were histologically graded as CIN2+ or <CIN2. We calculated the sensitivity and specificity for detection of CIN2+ and assessed agreement between sample collection methods. We included 307 women (median age, 36 years) with valid histology results and triple-matched urine, self-collected cervicovaginal, and provider-collected cervical hrHPV results; 83 women (27%) had CIN2+. Urine-based hrHPV testing correctly identified 80% of CIN2+ cases (95% confidence interval [CI], 71 to 88%) using the PCR cycle threshold (CT ) established for provider-collected cervical samples, but sensitivity remained below the estimates for self-collected cervicovaginal and provider-collected cervical samples (both 94% [95% CI, 89 to 99%]). Using a higher CT cutoff value of ≤40, 90% sensitivity was achieved for urine-based hrHPV testing. Agreement between results for urine samples and self-collected cervicovaginal samples (kappa = 0.58) or provider-collected cervical samples (kappa = 0.54) was moderate. Urine-based hrHPV testing may be a promising approach to improve cervical cancer screening coverage, especially among women with limited access to health care.

Value of CCNA1 promoter methylation in triaging ASC-US cytology.

Background:Using HPV testing to triage ASC-US still has some problems of unnecessary colposcopy in many cases. A previous study reported that methylation of CCNA1, a tumor suppressor gene, can differentiate between low and high grade lesions. This study was designed to evaluate the diagnostic values and application of CCNA1 methylation in the patients with ASC-US group. Materials and Methods:Cross sectional analytic study was conducted in the patients with ASC-US cytology. HPV DNA testing and CCNA1 promoter methylation testing were performed. The patients were sent for colposcopic examination and biopsy. Biopsy results were considered as gold standard. Diagnostic test of HPV test and CCNA1 methylation test were calculated for sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), likelihood ratio for test positive and negative and 95% confidence interval. Results:One hundred and seventy patients were enrolled. Mean age was 39.7 years old. HR-HPV was positive in 70% of the patients. HPV type 16, type 18 and non-16,18 were 12.4%, 4.7% and 42.4%, respectively. CIN2+ were found in 12.4% (21 cases). CCNA1 promoter methylation was positive in 5 cases. CCNA1 had high specificity 99.3%, NPV 89.2% and PPV 80% in detection of CIN2+ but sensitivity was 19%. Likelihood ratio for positive test was 28.4 and likelihood ratio for negative test was 0.8. HPV test had sensitivity of 90.5% and NPV of 95.9% but low specificity and PPV as 31.5% and 15.7%, respectively. Conclusion:CCNA1 promoter methylation testing had very high specificity, likelihood ratio for the positive test and PPV (99.3%, 28.4 and 80.0, respectively). Therefore, CCNA1 promoter methylation test may be used in the HPV DNA positive cases to classify the urgency of colposcopy and the colposcopist should pay more attention to CCNA1 positive patients because of their higher chance to identify the significant lesions.

Primary HPV testing with cytology versus cytology alone in cervical screening-A prospective randomized controlled trial with two rounds of screening in a Chinese population.

We conducted a prospective randomized controlled trial with two screening rounds to evaluate the effectiveness of combining HPV testing with liquid-based cytology (LBC) as a co-test, compared to LBC only in cervical cancer screening of a Chinese population. First, 15,955 women aged 30-60 were randomized at a 1:1 ratio into an intervention group (Digene Hybrid Capture 2 HPV test with LBC) and a control group (LBC alone). Women in the intervention group would be referred for colposcopy and biopsy immediately if they were found to have high-risk HPV regardless of cytology results. The detection of cervical intraepithelial neoplasia grade 2 or above (CIN2+) lesions was significantly higher in the intervention group compared to the control (0.95% vs. 0.38%, OR 2.50, 95% CI 1.65-3.88). At the subsequent round of screening approximately 36 months later, CIN2+ detection was significantly lower in the intervention group (0.08% vs. 0.35%, OR 0.23, 95% CI 0.08-0.57). Over the two rounds of screening, the total detection of CIN2+ was higher in the intervention group (1.01% vs. 0.66%, OR 1.53, 95% CI 1.09-2.19). There was a fourfold increase (10.6% vs. 2.4%, p < 0.001) in the number of colposcopies performed in the intervention arm. Adding a high-risk HPV test to cytology for primary cervical screening led to earlier detection of clinically significant preinvasive lesions, resulting in a reduced detection of CIN2+ lesions in subsequent rounds and an increased rate of colposcopy.

To Evaluate the Role of p16Ink4a Immunocytochemistry for Detection of CIN2+ in Women Detected Screen Positive by Visual Inspection Using Acetic Acid.

Objective:To evaluate the role of p16Ink4a immunostaining for the detection of cervical intraepithelial neoplasia (CIN2+) in women who had a positive screening test using visual inspection with acetic acid (VIA).Methods:Opportunistic screening of women (30–50 years) coming to the gynecology clinic by VIA was performed; the screen-positive women were included in the study which had the institutional review board (IRB) approval. A cytology slide for p16Ink4a immunostaining, colposcopy, and biopsy was then performed sequentially. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of p16Ink4a immunocytochemistry were evaluated with histopathology as the gold standard.Results:p16Ink4a positivity showed a linear correlation with the increasing grade of CIN. p16Ink4a positivity was seen in 6% of CIN 1, 80% of CIN 2, 100% of CIN 3, and squamous cell carcinoma. The sensitivity and specificity of p16Ink4a immunocytochemistry for detecting CIN 2 or more was 87.5% (95%CI 61.65–98.45) and 97.06% (95%CI 84.67–99.93). Colposcopy had an equal sensitivity of 87.5% (95% CI 61.65–98.45) and specificity of 50% (95% CI 32.43–67.57), respectively.Conclusion:With high sensitivity and specificity, p16Ink4a immunocytochemistry could be a viable option for triaging VIA-positive women.

Le frottis cervical utérin

Cervical screening recommendation to perform a Pap smear every three years for women 25 to 65 exists since 1990. The liquid based cytology (LBC) has replaced the conventional smear because the quality of the sample was proven better. LBC used manually make reading under the microscope easier by reading selected fields with cameras connected to computer software. With advanced image analysis, the digitalisation of LBC is now feasible and allows remote review. The simultaneous detection of p16 and Ki-67 expression within the same cervical epithelial cell called p16/ki67 dual stained cytology corresponds to a morphology-independent marker of an HPV transformation infection. The clinical performance of this approach in cases categorized as ASC-US or LSIL indicate that p16/Ki67 dual-stained cytology provides a high sensitivity and a high specificity for detecting underlying CIN2+, especially in young women. The Haute Autorité de santé has recommended in July 2019 the HPV primary screening alone after 30 years because it is more sensitive for the detection of CIN 2+ compared to cytology and is more effective in preventing invasive cervical cancer. The triaging of the positive HPV test will be performed with cytology in the residual material. National organized screening program with the introduction of the HPV primary test after 30 years combined with vaccination of the teenagers should improve the incidence and the mortality of the invasive cancer of the cervix in the near future in France.

Risk of CIN2 or more severe lesions after negative HPV-mRNA E6/E7 overexpression assay and after negative HPV-DNA test: Concurrent cohorts with a 5-year follow-up.

Aim of this study was to compare the 5-year risk of cervical intraepithelial neoplasia grade 2+ (CIN2+)/CIN3+ and the performance parameters at 3-year rescreening of a negative E6/E7 mRNA-human papillomavirus (HPV) test with those of a HPV-DNA-negative test. We studied a cohort of HPV-negative women tested with the Aptima HPV-mRNA Assay ("HPV-mRNA cohort") versus a cohort of HPV negatives tested with the Hybrid Capture 2 (HC2) DNA test living in neighboring areas. Both cohorts were rescreened after 3 years by a HPV-DNA test (HC2 or Cobas 4800 HPV test). HPV test positivity, referral to colposcopy and detection of CIN2+ at 3-year rescreening were computed. The Veneto Cancer Registry was checked to search for invasive cancers and CIN3 diagnosed up to 5 years from the negative baseline test. Some 22,338 HPV-mRNA and 68,695 HPV-DNA-negative women were invited to 3-year rescreening, and, respectively, 16,641 (74.5%) and 54,630 (79.6%) complied with the invitation. The proportion of HPV-positive tests, referral to colposcopy and detection of CIN2+ in the HPV-mRNA and HPV-DNA cohorts were, respectively. 4.0 and 3.9% (ratio 1.08; 95% confidence interval [CI] 0.99-1.17), 2.6 and 2.5% (ratio 1.06, 95% CI 0.95-1.18) and 1.4 and 1.7‰ (ratio 0.85, 95% CI 0.54-1.33). The relative 5-year cumulative risk of cancer and of CIN2+ in the HPV-mRNA and HPV-DNA cohorts were 4.5 and 8.7/100,000 (ratio 0.51; 95%CI 0.01-4.22) and 1.1 and 1.5/1,000 (ratio 0.74; 95%CI 0.45-1.16), respectively. A negative HPV-mRNA test confers a risk of invasive cervical carcinoma and of CIN2+ at 5 years comparable to that of a negative HPV-DNA test.

Clinical performance of the HPV-Risk assay on cervical samples in SurePath medium using the VALGENT-4 panel

BackgroundThe VALidation of HPV GENoyping Tests (VALGENT) framework is designed for comparison and clinical validation of HPV assays. ObjectivesTo evaluate the accuracy of the HPV-Risk assay within VALGENT-4, relative to clinically validated comparator HPV tests. Study designThe VALGENT-4 panel comprises consecutive SurePath cervical samples from routine screening (n=998), of which 51 had abnormal cytology and 13 women had cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+), enriched with SurePath cervical samples from 297 women with abnormal cytology and 109 CIN2+. HPV-Risk assay was performed on DNA extracted panel samples (n=1,295), blinded to clinical data, cytology results, and results from other HPV assays evaluated in VALGENT-4. All assay results were reported to the central VALGENT coordination institute for data and statistical analysis. HPV prevalence was analysed and accuracy for detection of CIN grade 3 or worse (CIN3+) and CIN2+ were assessed relative to GP5+/6+-PCR-EIA and GP5+/6+-PCR-EIA-LMNX. ResultsThe sensitivity of the HPV-Risk assay for detection of CIN3+ and CIN2+ was similar to that of GP5+/6+-PCR-EIA (relative sensitivity for CIN3+1.01; 95%CI: 0.97-1.06; pMcN=1.000, and for CIN2+1.01; 95%CI: 0.96-1.06; pMcN=1.000) at significantly higher specificity (relative specificity 1.04; 95%CI: 1.02-1.06; pMcN<0.001). The accuracy of the HPV-Risk assay for CIN3+ and CIN2+ was non-inferior compared to GP5+/6+-PCR- EIA and GP5+/6+-PCR-EIA-LMNX, with all p-values ≤0.002. HPV16/18 genotype agreement between HPV-Risk assay and GP5+/6+-PCR-LMNX was high. ConclusionsThe HPV-Risk assay demonstrated non-inferiority to clinically validated comparator assays on cervical samples in SurePath medium using the VALGENT-4 panel, and is therefore suitable for cervical cancer screening.

Human Papillomavirus (HPV) 16 and 18/45 Genotyping-Directed Follow-up of Women With Messenger RNA HPV-Positive, Cytology-Negative Cervical Screening Test Results.

In this study, we sought to correlate genotype test results for human papillomavirus (HPV) types 16, 18, and 45 with histopathologic follow-up diagnoses in patients with messenger RNA (mRNA) high-risk HPV-positive, cytology-negative results. We identified 1,157 patients with mRNA HPV-positive, cytology-negative cervical screening test results between June 2015 and June 2018. Reflex HPV 16/18/45 genotype results were documented in 1,018 women aged 30 years or older, 318 of whom had follow-up within 18 months. Histopathologic findings of cervical intraepithelial neoplasia 2 or worse (CIN2+) were diagnosed in 14 of 122 (11.5%) patients positive for HPV 16/18/45 vs in seven of 196 (3.6%) HPV 16/18/45-negative patients. Three patients with high-risk HPV-positive, cytology-negative cervical screening test results were diagnosed with stage I cervical adenocarcinomas following early colposcopic referral and biopsy after HPV 16/18/45-positive genotype results. Immediate reflex HPV 16/18/45 genotyping of mRNA HPV-positive, cytology-negative patients led to early colposcopic referral and histopathologic diagnoses of three difficult-to-detect, low-stage, cervical adenocarcinomas and significantly increased overall early detection of CIN2+ lesions.

Using the VALGENT-3 framework to assess the clinical and analytical performance of the RIATOL qPCR HPV genotyping assay

Background and objectiveThe VALGENT framework is developed to assess the clinical performance of HPV tests that offer genotyping capability. Samples from the VALGENT-3 panel are used to identify an optimal viral concentration threshold for the RIATOL qPCR HPV genotyping assay (RIATOL qPCR) to assure non-inferior accuracy to detect high-grade cervical intraepithelial neoplasia (CIN), compared to Qiagen Hybrid Capture 2 (HC2), a standard comparator test validated for cervical cancer screening. Study designThe VALGENT-3 panel comprised 1300 samples from women participating in the Slovenian cervical cancer screening programme, enriched with 300 samples from women with abnormal cytology. In follow- up, 126 women were diagnosed with CIN2+ (defined as diseased) and 1167 women had two consecutive negative Pap smears (defined as non-diseased). All 1600 samples were analyzed with the RIATOL qPCR. Viral concentration was expressed as viral log10 of the number of copies/ml. A zone of viral concentration cut-offs was defined by relative ROC analysis where the sensitivity and specificity were not inferior to HC2. ResultsThe RIATOL qPCR had a sensitivity and specificity for CIN2+ of 97.6% (CI: 93.2–99.5%) and 85.1% (CI: 82.9–87.1%), respectively, when the analytical cut off was used. At a cut off of 6.5, RIATOL qPCR had a sensitivity of 96.0% (CI: 91.0–98.7%) and a specificity of 89.5% (87.6–91.2%). At optimized cut off, accuracy of the qPCR was non-inferior to the HC2 with a relative sensitivity of 1.00 [CI: 0.95–1.05 (p = 0.006)] and relative specificity of 1.00 [CI: 0.98–1.01 (p = 0.0069)]. ConclusionsThe RIATOL qPCR has a high sensitivity and specificity for the detection of CIN2 + . By using a fixed cut-off based on viral concentration, the test is non-inferior to HC2. HPV tests that provide viral concentration measurements or other quantifiable signals allow flexibility to optimize accuracy required for cervical cancer screening.

Five-year risk of CIN3 after short-term HPV-DNA negativity in cytology-negative women: a population-based cohort study.

To assess the 5-year risk of high-grade lesions in women with a transient high-risk HPV infection. Population-based cohort study. HPV primary testing within population-based organised cervical cancer screening programmes. Italian women enrolled in seven pilot projects and attending the second round. On the basis of the cytology triage performed on HPV-positive women, immediate colposcopy or HPV repeat at 12months was recommended. Data were collected at the subsequent round 3-4years after HPV infection clearance. Rates of HPV infection, CIN2+ and CIN3+ detection at subsequent round after HPV clearance, and relative risks (RR) in comparison with HPV-negative women (with 95% confidence interval). Data on 1230 women (1027 aged 25-64years and 203 aged 35-64years) have been analysed. Overall compliance with repeat HPV testing was 84%. In comparison with HPV-negative women, those with a transient HPV infection had higher proportions of HPV positivity (15% versus 3.7%) and of CIN2+ lesions (0.87% versus 0.23%) in round two; most of these (7/10) were CIN2; no cancers were detected, and CIN3 occurred in 3/1230 (0.24%). HPV-based protocols for cervical cancer screening allow long intervals for HPV-negative women; it is important to monitor the clinical outcome in the women with transient high-risk HPV infection. CIN3 detection is similar to that observed in routine European cytology-based screening programmes (CIN3+: 2.7‰); 5-year intervals may provide reasonable protection but longer intervals are not recommended. A screening interval of 5years (but no longer) appears safe in women with transient HPV detection.

The use of molecular markers for cervical screening of women living with HIV in South Africa.

To determine the performance of molecular screening strategies for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in comparison with cytology screening in women living with HIV. Post-hoc analysis using data from a South African study cohort. Cytology and human papillomavirus (HPV)-based strategies were evaluated, including single test and FAM19A4/miR124-2 methylation triage strategies. Participants underwent cytology screening and a colposcopy-directed biopsy. Valid results on cytology, HPV status, 16/18 genotyping and histology were available for 318 women. Detection of HPV and FAM19A4/miR124-2 hypermethylation was performed on DNA from cervical scrapes. Histological diagnosis of CIN3+ was used as outcome. Cytology provided highest specificity (91.6%), but lowest sensitivity (59.3%), whereas a single HPV test provided highest sensitivity (83.1%), but lowest specificity (66.4%). Combining cytology with methylation did not improve the performance compared with cytology alone: a slight increase in sensitivity was seen, at the cost of a decrease in specificity. Triage of high-risk HPV positive women with methylation increased specificity (76.1%) compared with a single HPV or cytology test, while maintaining acceptable sensitivity (72.9%). Similar performance was observed for HPV16/18 with methylation triage (sensitivity 79.7%, specificity 74.8%). The number of women needed to refer to detect one CIN3+ ranged from 1.5 (cytology) to 2.6 (single HPV test). Molecular screening strategies using HPV, with or without HPV16/18 genotyping, and FAM19A4/miR124-2 methylation have higher sensitivity with an acceptable loss in specificity compared with current cytology screening and are efficient for the detection of CIN3+ in South African women living with HIV.

Human papillomavirus (HPV) DNA and mRNA primary cervical cancer screening: Evaluation and triaging options for HPV-positive women.

Objective Cervical cancer is the second most common cancer in Thai women; human papillomavirus (HPV) is the main cause. This study aimed to determine the clinical performance of HPV mRNA compared with HPV DNA testing. Methods Cervical specimens were collected from women aged 35 to 60 who attended the routine organized screening programme. We compared accuracy parameters of standalone HPV mRNA and HPV DNA tests, and those of triaging with liquid-based cytology or HPV genotyping and liquid-based cytology for those positive only for the less oncogenic HPV types. Test accuracy parameters were estimated using latent class analysis using Bayesian models. Results Of the 5046 women enrolled, 174 (3.4%) were HPV DNA positive and 141 (2.8%) HPV mRNA positive. Colposcopy compliance was 95.4% ( n = 166) among HPV DNA-positive women and 94.3% ( n = 133) among those HPV mRNA positive. The estimated sensitivity, specificity, and positive predictive value for detection of CIN2 or worse were 67.4%, 97.1%, 12.1% for HPV DNA testing, and 73.1%, 97.8%, 16.3% for HPV mRNA testing. These estimates for triaging of HPV DNA-positive women with liquid-based cytology were 64.4%, 98.8%, and 19.0%, respectively, and slightly better for liquid-based cytology triage of HPV mRNA-positive women, at 71.8%, 98.9%, and 22.1%. Conclusion A triaging strategy based on HPV genotyping and liquid-based cytology for those positive only for the less oncogenic HPV types had test characteristics comparable with that of liquid-based cytology triage. The HPV mRNA detection-based strategies had non-significant advantages over the HPV DNA detection-based strategies.

Searching for an ideal cervical cancer screening model to reduce false-negative errors in a country with high prevalence of cervical cancer

The purpose of this study was to develop an ideal cervical cancer screening model to reduce false-negative errors in Korea where there is a high prevalence of cervical cancer. We conducted a cross-sectional study including 33,531 women who underwent routine cervical cancer screening in Korea. Colposcopic examinations were performed after abnormal results on their screening tests. Diagnostic capacities including sensitivity, specificity, and false-negative rate of each screening scenario were analysed at the CIN1 or worse (CIN1+) threshold with colposcopic biopsy results considered the gold standard. A total of 4117 women had valid results for Papanicolaou (Pap) cytology, human papilloma virus (HPV) tests, cervicography, and colposcopically directed biopsy were included in this study. The disease prevalence of CIN1+ was 38.1%. Pap-alone resulted in the highest false-negative rate of 46.9%, followed by HPV-alone at 25.1%, cervicography-alone at 18.7%, Pap/HPV-combined at 15.0%, Pap/cervicography-combined at 6.9% and Pap/HPV/cervicography-combined at 2.9% in a sample of 1570 women with CIN1+ lesions. Therefore, cervicography demonstrated excellent performance for the detection of CIN or cervical cancer and markedly reduced false-negative errors when used in combination with Pap cytology and HPV tests.IMPACT STATEMENTWhat is already known on this subject? False-negative rate of Pap smears is as high as approximately 40–50%. Limitations of the Papanicolaou (Pap) test have led to the development of new screening programmes for cervical cancer, such as combination screenings with human papillomavirus (HPV) tests or cervicography.What do the results of this study add? Pap-alone resulted in the highest false-negative rate of 46.9%, followed by HPV-alone at 25.1%, cervicography-alone at 18.7%, Pap/HPV-combined at 15.0%, Pap/cervicography-combined at 6.9% and Pap/HPV/cervicography-combined at 2.9% in a sample of 1570 women with CIN1+ lesions.What are the implications of these findings for clinical practice and/or further research? Cervicography demonstrated excellent performance for the detection of CIN or cervical cancer and markedly reduced false negative errors when used in combination with Pap cytology and HPV tests.

Self- and clinician-collected cervical samples for HPV screening did not differ for detection of CIN+ lesions.

Source Citation Polman NJ, Ebisch RMF, Heideman DAM, et al. Performance of human papillomavirus testing on self-collected versus clinician-collected samples for the detection of cervical intraepith...