Cervical Intraepithelial Neoplasia Grade Research Articles

Effectiveness of self-sampling human papillomavirus test on precancer detection and screening uptake in Japan: The ACCESS randomized controlled trial.

Japan is lagging in cervical cancer prevention. The effectiveness of a self-sampling human papillomavirus (HPV) test, a possible measure to overcome this situation, has not yet been evaluated. A randomized controlled trial was performed to evaluate the effectiveness of a self-sampling HPV test on detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and screening uptake. Women between 30 and 58 years old who did not participate in the cervical cancer screening program for ≥3 years were eligible and assigned to the intervention group (cytology or self-sampling HPV test) or control group (cytology). Participants assigned to the intervention group were sent a self-sampling kit according to their ordering (opt-in strategy). A total of 7337 and 7772 women were assigned to the intervention and control groups, respectively. Screening uptake in the intervention group was significantly higher than that in the control group (20.0% vs. 6.4%; risk ratio: 3.10; 95% confidence interval [CI]: 2.82, 3.42). The compliance rate with cytology triage for HPV-positive women was 46.8% (95% CI: 35.5%, 58.4%). CIN2+ was detected in five and four participants in the intervention and control groups, respectively; there was no difference for intention-to-screen analysis (risk ratio: 1.32; 95% CI: 0.36, 4.93). Self-sampling of HPV test increased screening uptake; however, no difference was observed in the detection of CIN2+, probably due to the low compliance rate for cytology triage in HPV-positive women. Efforts to increase cytology triage are essential to maximize precancer detections.

Impact of HPV Vaccination on the Incidence of High-Grade Cervical Intraepithelial Neoplasia (CIN2+) in Women Aged 20-25 in the Northern Part of Norway: A 15-Year Study.

Human papillomavirus (HPV), the most prevalent sexually transmitted infection globally, is a key risk factor for high-grade cervical lesions and cervical cancer. Since 2009, HPV vaccination has been part of the national immunization program for girls in 7th grade in Norway (women born 1997 and later). This study aimed to assess the impact of HPV vaccination on the incidence of high-grade cervical precursors (CIN2+) among women aged 20-25 in Troms and Finnmark over a 15-year period. In this time series study, we analyzed cervical screening data from 15,328 women aged 20-25 in Troms and Finnmark, collected between 2008 and 2022. Statistical methods, including linear and logistic regression, were employed to evaluate changes in cervical intraepithelial neoplasia grade 2 and worse (CIN2+) incidence and compare risks between vaccine-offered cohorts and pre-vaccine cohorts. The incidence of CIN2+ initially increased from 31 cases per year in 2008 to 110 cases in 2018, then significantly decreased to 44 cases per year by 2022 (p < 0.01). Women in pre-vaccine cohorts had a substantially higher risk of CIN2+ (OR 9.02, 95% CI 5.9-13.8) and CIN3+ (OR 19.6, 95% CI 7.3-52.6). Notably, no vaccinated women with CIN2+ tested positive for HPV types 16 or 18. Furthermore, none of the 13 cervical cancer cases recorded during the study were from the vaccinated cohorts. The findings suggest a significant reduction in the incidence of high-grade cervical precursors following the introduction of the HPV vaccine in Norway's national immunization program, highlighting its effectiveness in cervical cancer prevention among young women in Northern Norway.

FAM19A4 and hsa-miR124-2 Double Methylation as Screening for ASC-H- and CIN1 HPV-Positive Women.

The DNA methylation levels of host cell genes increase with the severity of the cervical intraepithelial neoplasia (CIN) grade and are very high in cervical cancer. Our study aims to evaluate FAM19A4 and hsa-miR124-2 methylation in Atypical Squamous cells with high-grade squamous intraepithelial lesions (ASC-H) and in CIN1, defined as low-grade squamous intraepithelial lesions (LSILs) by the Bethesda classification, as possible early warning biomarkers for managing women with high-risk HPV infections (hrHPV). FAM19A4 and hsa-miR124-2 methylation tests were conducted on fifty-six cervical screening samples from a subset of women aged 30-64 years old. Specimens were collected into ThinPrep PreservCyt Solution. Their HrHPV genotype and cytology diagnosis were known. A Qiasure (Qiagen) was used for FAM19A4 and hsa-miR124-2 methylation testing on bisulfite-converted DNA, according to the manufacturer's specifications. The reported results were hypermethylation-positive or -negative. We found that FAM194A4 and hsa-miR124-2 methylation was detected in 75% of ASC-H cases with a persistent infection of hrHPV. A total of 60% of CIN1 lesions were found to be positive for methylation, and 83.3% were when the cytology was CIN2/3. In addition, as a novelty of this pilot study, we found that combined FAM19A4 and hsa-miR124-2 methylation positivity rates (both methylated) were associated with the HPV genotypes 16, 18, and 59 and covered 22 and 25% of ASC-H and CIN1 cases, respectively. The methylation of these two genes, in combination with HPV genotyping, can be used as an early warning biomarker in the management and follow-up of women with ASC-H and CIN1 to avoid their progression to cervical cancer.

Impact of high-performance human papillomavirus testing to improve cervical cancer screening in China: a prospective population-based multicentre cohort study

ObjectivesThe aim of the study was to evaluate the clinical performance of HBRT-H14, a real-time PCR-based assay that separates human papillomavirus (HPV) 16 and HPV18 from 12 other high-risk (HR) HPV types, in population according to Chinese guideline. MethodsA total of 9829 eligible women aged 21–64 years from Henan, Shanxi, and Guangdong provinces were performed by HBRT-H14 testing and liquid-based cytology (LBC) screening at baseline and followed up for 3-year. The sensitivity, specificity, positive predictive value (absolute risk), and negative predictive value of LBC diagnosis and HPV testing were calculated for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) Lesions. ResultsAt baseline, 80 (0.81%) participants were diagnosed with CIN2+. HR-HPV with reflex LBC had a significantly higher sensitivity (78/80, 97.50% [95% CI, 91.34–99.31%] vs. 62/80, 77.50% [67.21–85.27%], McNemar's test p < 0.001), and a slightly lower specificity (8528/9749, 87.48% [86.80–88.12%] vs. 8900/9749, 91.29% [90.72–91.83%], McNemar's test p < 0.001) than LBC with reflex HR-HPV for CIN2+. 7832 (79.6%) participants completed 3-year follow-up and 172 (2.20%) participants were cumulatively diagnosed with CIN2+. Compared with LBC with reflex HR-HPV, HR-HPV with reflex LBC significantly increased the sensitivity (161/172, 93.60% [88.91–96.39%] vs. 87/172, 50.58% [43.18–57.96%], McNemar's test p < 0.001), but marginally decreased the specificity (6776/7660, 88.46% [87.72–89.16%] vs. 6933/7660, 90.51% [89.83–91.15], McNemar's test p < 0.001). In addition, the absolute 3-year risk of CIN2+ in HPV16/18-positive individuals was as high as 33% (80/238), whereas the risk in the HPV-negative population was only 0.16% (11/6787), much lower than those in the negative for intraepithelial lesion or malignancy population (1.21%, 85/7018). Moreover, similar results were found in women ≥30 years old. DiscussionThe study has indicated that HBRT-14 has a reliable clinical performance for use in cervical screening. The validated HPV test would improve the quality of population screening.

YAP/TAZ-TEAD activity promotes the malignant transformation of cervical intraepithelial neoplasia through enhancing the characteristics and Warburg effect of cancer stem cells

A number of studies have confirmed that Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ)-transcriptional enhanced associate domain (TEAD) activity is the driver of cancer development. However, the role and mechanism of the YAP/TAZ-TEAD pathway in cervical intraepithelial neoplasia (CIN) remain to be clarified. Therefore, this study was designed to observe the effect of YAP/TAZ-TEAD activity on the development of CIN and provide new ideas for the diagnosis and treatment of CIN. Firstly, cervical tissues were collected from CIN patients in different stages [CIN grade 1 (CIN1) tissue, CIN grade 2/3 (CIN 2/3) and squamous cell carcinoma (SCC)] and healthy volunteers. Next, the expression levels of YAP, TAZ and TEAD in cervical tissues and cells were observed by immunohistochemistry, qRT-PCR and western blot. Besides, Z172 and Z183 cells were transfected with siRNA-YAP/TAZ (si-YAP/TAZ) and YAP/TAZ overexpression vector (YAP-5SA). Also, Z172 cells were co-transfected with YAP-5SA and si-TEAD2/4. Subsequently, the stemness characteristics, glycolysis level and malignant transformation of cells in each group were observed by sphere-formation assay, commercial kit, MTT, Transwell, scratch experiment, xenotransplantation and western blot.The expression of YAP, TAZ and TEAD increased significantly in cervical cancer tissue and cell line at the stage of CIN2/3 and SCC. When YAP/TAZ was knocked down, the stemness characteristics, glycolysis level and malignant transformation of cancer cells were notably inhibited; while activating YAP/TAZ exhibited a completely opposite result. In addition, activating YAP/TAZ and knocking down the TEAD expression at the same time significant weakened the effect of activated YAP/TAZ signal on precancerous cells and reduced inhibitory effect of knocking down TEAD alone. YAP/TAZ-TEAD signal activates the characteristics and Warburg effect of cancer stem cells, thereby promoting the malignant transformation of CIN.

Clinical Validation of the Vitro HPV Screening Assay for Its Use in Primary Cervical Cancer Screening.

Many scientific societies have issued guidelines to introduce population-based cervical cancer screening with HPV testing. The Vitro HPV Screening assay is a fully automatic multiplex real-time PCR test targeting the L1 GP5+/GP6+ region of HPV genome. The assay detects 14 high risk (HR) HPV genotypes, identifying individual HPV16 and HPV18 genotypes, and the HPV-positive samples for the other 12 HR HPV types are subsequently genotyped with the HPV Direct Flow Chip test. Following international guidelines, the aim of this study was to validate the clinical accuracy of the Vitro HPV Screening test on ThinPrep-collected samples for its use as primary cervical cancer screening, using as comparator the validated cobas® 4800 HPV test. The non-inferiority analysis showed that the clinical sensitivity and specificity of the Vitro HPV Screening assay for a diagnosis of cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) were not inferior to those of cobas® 4800 HPV (p = 0.0049 and p < 0.001 respectively). The assay has demonstrated a high intra- and inter-laboratory reproducibility, also among the individual genotypes. The Vitro HPV Screening assay is valid for cervical cancer screening and it provides genotyping information on HPV-positive samples without further sample processing in a fully automated workflow.

Diagnostic value of HPV E6/E7 mRNA in screening for cervical intraepithelial neoplasia grade 2 or worse: A systematic review and meta‑analysis.

Histology is considered the gold standard for diagnosing the pathological progress of cervical cancer development, while cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) is the cutoff for intervention in clinical practice. The diagnostic value of human papillomavirus (HPV) E6/E7 mRNA in screening for CIN2+ has not been systematically summarized. A meta-analysis was conducted as part of the present study conducted to explore the diagnostic value of HPV E6/E7 mRNA in screening for CIN2+, aiming to provide a new marker for earlier clinical diagnosis of cervical cancer. The PubMed, Embase and Cochrane Library databases were searched from inception to May 2023. Studies reporting the true positive, false positive, true negative and false negative values in differentiating between CIN2+ and CIN2- were included, while duplicate publications, studies without full text, incomplete information or inability to conduct data extraction, animal experiments, reviews and systematic reviews were excluded. STATA software was used to analyze the data. A total of 2,224 patients were included of whom there were 1,274 patients with CIN2+ and 950 patients with CIN2-. The pooled sensitivity and specificity of the studies overall were 0.89 (95% CI, 0.84-0.92) and 0.59 (95% CI, 0.46-0.71), respectively; the positive likelihood ratio (LR) and the negative LR of the studies overall were 2.31 (95% CI, 1.61-3.32) and 0.21 (95% CI, 0.14-0.30), respectively. The pooled diagnostic odds ratio of the studies overall was 11.53 (95% CI, 6.85-19.36). Additionally, the area under the curve was 0.88. The analysis indicated that HPV E6/E7 mRNA has high diagnostic efficacy for CIN2+. HPV E6/E7 mRNA is highly sensitive in the diagnosis of CIN2+, which helps to reduce the rate of missed diagnoses. However, lower specificity may lead to a higher number of misdiagnoses in healthy patients.

Evaluation of the diagnostic performance of colposcopy in the detection of cervical high-grade squamous intraepithelial lesions among women with transformation zone type 3

BackgroundInaccurate colposcopy diagnosis may lead to inappropriate management and increase the incidence of cervical cancer. This study aimed to evaluate the diagnostic accuracy of colposcopy in the detection of histologic cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women with transformation zone type 3 (TZ3).MethodsRecords from 764 patients with TZ3 who underwent colposcopy-directed biopsy and/or endocervical curettage in Putuo Hospital China between February 2020 and March 2023 were retrospectively collected. Colposcopy was carried out based on 2011 International Federation of Cervical Pathology and Colposcopy (IFCPC) and Colposcopy nomenclature. The diagnostic performance of colposcopy for identifying CIN2 + was evaluated compared with biopsies. The Kappa and McNemar tests were used to perform statistical analyses.ResultsAmong the study population, 11.0% had pathologic CIN2+. The relative sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of colposcopy for histologic CIN2 + were 51.2%, 96.5%, 64.2% and 94.1%, respectively. The senior colposcopists (80.6%) had a higher colposcopic accuracy to diagnose histologic CIN2 + than junior colposcopists (68.6%). In subgroup analyses, age group ≥ 60 years (70.3%) showed lowest diagnostic accuracy when compared with age groups of < 45 years (84.4%) and 45–59 years (74.9%).ConclusionOur findings suggest an increased risk of diagnostic inaccuracy of colposcopy in identifying CIN2 + in those ≥ 60 years of age with TZ3, and the accuracy of colposcopy is required to be further improved.

Knowledge of cytology results affects the performance of colposcopy: a crossover study

ObjectiveTo determine whether knowledge of cytology affects the colposcopist’s diagnostic accuracy in the identification of cervical intraepithelial neoplasia grade 2 and worse (≥ CIN2).MethodIn this cross-over study, healthcare professionals interpreted colposcopy images from 80 patient cases with known histological diagnoses. For each case, 2 images taken with a colposcope were provided (native and after acetic acid application). Inclusion criteria consisted of women with a transformation zone type 1 or 2, who had both a cytological and histological diagnosis. Cases were distributed across two online surveys, one including and one omitting the cytology. A wash-out period of six weeks between surveys was implemented. Colposcopists were asked to give their diagnosis for each case as < CIN2 or ≥ CIN2 on both assessments. Statistical analysis was conducted to compare the two interpretations.ResultsKnowledge of cytology significantly improved the sensitivity when interpreting colposcopic images, from 51.1% [95%CI: 39.3 to 62.8] to 63.7% [95%CI: 52.1 to 73.9] and improved the specificity from 63.5% [95%CI: 52.3 to 73.5] to 76.6% [95%CI: 67.2 to 84.0]. Sensitivity was higher by 38.6% when a high-grade cytology (ASC-H, HSIL, AGC) was communicated compared to a low-grade cytology (inflammation, ASC-US, LSIL). Specificity was higher by 31% when a low-grade cytology was communicated compared to a high-grade.ConclusionsOur data suggests that knowledge of cytology increases sensitivity and specificity for diagnosis of ≥ CIN2 lesions at colposcopy. Association between cytology and histology may have contributed to the findings.

Preterm Birth Following Active Surveillance vs Loop Excision for Cervical Intraepithelial Neoplasia Grade 2

Active surveillance for cervical intraepithelial neoplasia grade 2 (CIN2) is being implemented in many high-income countries due to the association of excisional treatment with preterm birth. However, it is unknown whether active surveillance results in lower risk of preterm birth given that cervical dysplasia itself is associated with higher risk of preterm birth. To compare the preterm birth risk between women with CIN2 undergoing active surveillance or immediate loop electrosurgical excision procedure (LEEP). This historical population-based cohort study included women with a first-time diagnosis of CIN2 and a subsequent singleton birth from 1998 to 2018 in Denmark. Women with prior CIN grade 3 or greater or LEEP were excluded. Data were collected from 4 Danish health care registries. Analyses were conducted from October 2022 to June 2023. Women were categorized into active surveillance (cervical biopsy and/or cytology) or immediate LEEP based on their first cervical sample after CIN2 diagnosis. The active surveillance group was further subdivided based on whether a delayed LEEP was performed within 28 months from CIN2 diagnosis. Risk of preterm birth (<37 + 0 weeks) was assessed and relative risks (RRs) were calculated using modified Poisson regression. Analyses used inverse probability treatment weighting of the propensity scores to adjust for age, parity, calendar year, index cytology, and smoking. A total of 10 537 women with CIN2 and a singleton birth were identified; 4430 (42%) underwent active surveillance and 6107 (58%) were treated with immediate LEEP. For both groups, most were aged 23 to 29 years at CIN2 diagnosis (3125 [70%] and 3907 [64%], respectively). Overall, 869 births (8.2%) were preterm. The risk of preterm birth was comparable between active surveillance and immediate LEEP (RR, 1.03; 95% CI, 0.90-1.18). However, for women undergoing delayed LEEP after active surveillance (1539 of the active surveillance group [35%]), the risk of preterm birth was higher than for women treated with immediate LEEP (RR, 1.29; 95% CI, 1.08-1.55). In this cohort study of women with CIN2, the risk of preterm birth was comparable between active surveillance and immediate LEEP. However, delayed LEEP was associated with 30% higher risk of preterm birth than immediate LEEP. Thus, risk stratification at CIN2 diagnosis is important to identify women with increased risk of delayed LEEP.

Recommendations for Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus.

The Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee developed recommendations for dual stain (DS) testing with CINtec PLUS Cytology for use of DS to triage high-risk human papillomavirus (HPV)-positive results. Risks of cervical intraepithelial neoplasia grade 3 or worse were calculated according to DS results among individuals testing HPV-positive using data from the Kaiser Permanente Northern California cohort and the STudying Risk to Improve DisparitiES study in Mississippi. Management recommendations were based on clinical action thresholds developed for the 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines. Resource usage metrics were calculated to support decision-making. Risk estimates in relation to clinical action thresholds were reviewed and used as the basis for draft recommendations. After an open comment period, recommendations were finalized and ratified through a vote by the Consensus Stakeholder Group. For triage of positive HPV results from screening with primary HPV testing (with or without genotyping) or with cytology cotesting, colposcopy is recommended for individuals testing DS-positive. One-year follow-up with HPV-based testing is recommended for individuals testing DS-negative, except for HPV16- and HPV18-positive results, or high-grade cytology in cotesting, where immediate colposcopy referral is recommended. Risk estimates were similar between the Kaiser Permanente Northern California and STudying Risk to Improve DisparitiES populations. In general, resource usage metrics suggest that compared with cytology, DS requires fewer colposcopies and detects cervical intraepithelial neoplasia grade 3 or worse earlier. Dual stain testing with CINtec PLUS Cytology is acceptable for triage of HPV-positive test results. Risk estimates are portable across different populations.

Conservative Management Outcome of Cervical Intraepithelial Neoplasia Grade 2: A Three-Year Follow-Up Study

Conservative Management Outcome of Cervical Intraepithelial Neoplasia Grade 2: A Three-Year Follow-Up Study

Value of high‑risk human papillomavirus detection combined with colposcopy in the diagnosis of cervical cancer and precancerous lesions.

In the present study, the diagnostic value of high risk-human papillomavirus (HR-HPV) combined with colposcopy for the detection of cervical cancer and precancerous lesions was evaluated. A total of 397 patients with confirmed cervical disease were enrolled between August 2020 and December 2021. According to the pathological diagnosis, the patients were divided into cervical intraepithelial neoplasia grade I (CIN I; n=153 cases), CIN II (n=101 cases), CIN III (n=86 cases) and cervical cancer (n=57 cases) groups. The HR-HPV-positive rate of the patients with different lesion types was compared, and the consistency of colposcopy and pathological examination results were assessed. For cervical cancer and precancerous lesions, the diagnostic value and efficacy of HR-HPV testing, colposcopy and combined HR-HPV testing and colposcopy examination were compared using pathological examination results as the gold standard. The results of the present study demonstrated that in patients with cervical cancer, the positive rate of HR-HPV (100.00%; n=57/57) was higher than that in patients with precancerous lesions, and the positive rate of HR-HPV in patients with CIN I type (36.60%, n=56/153) was lower than that in patients with CIN II (83.17%, n=84/101) and CIN III (82.56%, n=71/86) types (P<0.05). There was no significant difference in the HR-HPV-positive rate between patients with CIN II and CIN III (P>0.05). Cohen's κ coefficient for colposcopy examination and pathological examination of patients with cervical cancer and precancerous lesions was 0.622, the diagnostic accuracy was 90.43% (n=359/397), the positive predictive value was 65.57% (n=40/61), and the negative predictive value was 94.94% (n=319/336). Receiver operating characteristic curve analysis demonstrated that the area under the curve of the combined examination in the diagnosis of cervical cancer and precancerous lesions was 0.904, which was higher than that of colposcopy (0.820) or HR-HPV testing (0.802) alone (P<0.05). The results of the present study indicated that HR-HPV detection combined with colposcopy has diagnostic value for cervical cancer and precancerous lesions.

Consistency in human papillomavirus type detection between self-collected vaginal specimens and physician-sampled cervical specimens.

With the rising need for accessible cervical cancer screening, self-sampling methods offer a promising alternative to traditional physician-led sampling. This study aims to evaluate the efficacy of the HygeiaTouch Self Sampling Kit for Women in detecting human papillomavirus (HPV) types and predicting cervical lesions. We studied the concordance in identifying high-risk HPV (hrHPV) types between samples collected by physicians and those self-collected by women using a self-sampling kit for validation. Women aged 21-65, fitting into specific categories based on their cervical health history were eligible. Cohen's kappa coefficient to gauge concordance between the two specimen types and relative accuracy metrics in identifying cervical intraepithelial neoplasia (CIN) were also calculated, with physician-sampled specimens serving as a reference. A total of 1210 participants from three institutes were involved. The self-sampling kit closely matched the physician-led method in terms of collecting valid specimens (100% vs. 100%), identifying hrHPV types (kappa: 0.75, 95% confidence interval [95% CI]: 0.72-0.79; agreement: 87.7%, 95% CI: 85.8-89.6) and predicting CIN grade 2 or worse (CIN2+) (relative sensitivity: 0.949, relative accuracy: 0.959). Kappa values varied between 0.71 and 0.83 for different hrHPV types and combinations, with an overall value 0.75 (95% CI: 0.72-0.79) signifying robust compatibility between the two methods. Our study underscores the potential of the HygeiaTouch Self Sampling Kit as a reliable, efficient, and user-friendly alternative to traditional sampling methods. This suggests that self-sampling could be pivotal in expanding cervical cancer screening accessibility and enhancing detection rates.

The Role of β1 Integrin/CD29 as a Potential Prognostic Factor for the Risk of Progression to Cervical Carcinoma in HPV-Associated Lesions.

Background and Objectives: Available evidence reports the overexpression of β1 integrin in dysplastic rather than normal cervical tissue. We aimed to evaluate the involvement of β1 (CD29) integrin in the progressive pathogenesis of cervical intraepithelial neoplasia (CIN). Materials and Methods: From January 2019 to December 2021, we prospectively enrolled women undergoing a colposcopy with a cervical biopsy for abnormal cervical cytology and/or undefined cytology with a positive HPV DNA test and women with relapsing cervical inflammatory disorders. Based on the histopathological results, women were divided into four groups: group A (CIN1), group B (CIN2), group C (CIN3), and group D (no CIN diagnosis) as a control group. Subsequently, cytofluorimetry and immunohistochemical analysis (based on the identified positive cell ratios as follows: ≤10%, negative; 10-25%, 1+ (weak); 25-50%, 2+ (medium); ≥50%, and 3+ (high)) for β1 integrin were carried out. Results: In total, 154 women were included. The average fluorescence intensity in the four groups was 2.35 ± 1.37, 2.73 ± 1.56, 3.09 ± 1.56, and 2.13 ± 1.25 UA from groups A to D, respectively; this figure was significantly different for CIN3 (group C) women relative to the other groups (p = 0.0132). Higher β1 integrin/CD29 concentrations in the CIN groups with HR-HPV 16 and 18 were also detected (p = 0.0292, 0.0367, and 0.0357 respectively for CIN3, CIN2, and CIN1). Immunohistochemistry analysis showed higher results for the CIN3 group compared to controls and all the other groups (p < 0.001). Conclusions: β1/CD29 integrin expression increased with CIN grade, and it was significantly higher in CIN3 lesions. This could be used as a promising screening tool to identify women prone to developing high-grade cervical lesions. However, additional evidence is needed to strengthen these findings.

Escherichia coli and HPV16 coinfection may contribute to the development of cervical cancer

ABSTRACT Persistent human papillomavirus HPV infection is a necessary but insufficient condition for cervical cancer. Microorganisms are crucial environmental factors in cancers susceptibility and progression, recently attracting considerable attention. This study aimed to determine the infection status and relationship between high-risk HPV (HR-HPV) and lower genital tract infectious pathogens in cervical cancer and its precursors. From a retrospective and a prospective cohort analysis, Escherichia coli (E. coli) dominated the pathogens isolated from cervical discharges, and an isolation rate uptrend has been shown recently. HPV16 and E. coli’s coinfection rate gradually increased with the severity of cervical intraepithelial neoplasia. The adhesion and invasion abilities of the isolated E. coli to HPV16-positive SiHa cells were evaluated in vitro. The TCGA database and cervical tissues samples analysis showed that IL-10 was upregulated in cervical cancer. IL-10 expression levels increased in tissue samples with the severity of cervical cancer and its precursors with HPV16 and E. coli coinfection. Although no significant changes in IL-10 production were observed in the co-culture supernatant, we hypothesized that Treg immune cells in the tumour microenvironment might be responsible for the local IL-10 upregulation, according to our data showing Foxp3 upregulation and an upward trend with the cervical intraepithelial neoplasia grading to cancer and tumours with E. coli and HPV16 coinfection. Our data provide insights into the possible role of E. coli in cervical cancer progression and suggest that the application of HPV and E. coli screening programs may be an effective strategy to relieve the burden of cervical cancer and its precursor lesions.

Performance of urine samples compared to cervical samples for detection of precancer lesions among HPV-positive women attending colposcopy clinic in Mexico City.

High-risk human papillomavirus (hrHPV) detection in self-collected urine samples (SeCUS) may be a promising alternative for cervical cancer screening because of its greater acceptability, as long as it can offer comparable sensitivity to clinician-collected cervical samples (CCoS) for detecting precancer lesions. To evaluate the performance of the SeCUS compared to that of the CCoS for cervical intraepithelial neoplasia grade 3 (CIN3) detection among hrHPV-positive women receiving colposcopy in Mexico City using different specific extended HPV typing procedures: HPV16/18, HPV16/18/35/39/68 or HPV16/18/35/39/68/31. From March 2017 to August 2018, 4,158 female users of the cervical cancer screening program at Tlalpan Sanitary Jurisdiction in Mexico City were invited to participate in the FRIDA-Tlalpan study. All participants provided ≥ 30mL of SeCUS, and then a CCoS was obtained with Cervex-Brush®, which was used for hrHPV typing. Participants who tested positive for hrHPV in CCoS were referred for colposcopy for diagnostic confirmation, and all SeCUS of these women were also tested for hrHPV typing. In total, 561 hrHPV-positive women were identified by CCoS via colposcopy, and 82.2% of the SeCUS of these women were also hrHPV positive. From both CCoS and SeCUS, 7 cases of CIN3 were detected. Considering HPV16/18 typing, CCoS and SeCUS detected 4 cases of CIN3, but after HPV16/18/35/39/68/31 extension typing, both CCoS and SeCUS detected all 7 of the CIN3 cases among the hrHPV-positive women. Using extended hrHPV typing based on HPV16/18/35/39/68/31, our results suggest that the performance of SeCUS may be equivalent to that of CCoS for detecting CIN3 lesions. Although our results are inconclusive, they support the hypothesis that SeCUS may be an attractive alternative worthy of further research.

AmpFire HPV and ScreenFire RS HPV validation trial.

The human papillomavirus (HPV) screening assays from Atila Biosystems, including the new AmpFire (14 type) and ScreenFire RS (13 type), were subjected to a series of validation tests. We used a set of samples from the Chinese Multi-Site Screening Trial (previously tested with cobas 4800 and the next-generation SeqHPV) to satisfy Meijer's criteria for clinical end-point validation. We selected 556 self-collected specimens composed of 273 high-risk HPV (hrHPV) positives and 283 hrHPV negatives on the cobas 4800 and SeqHPV. Of the 273 hrHPV-positive cases, 108 had a disease end point of cervical intraepithelial neoplasia grade 2 (CIN2) or higher, including 47 with cervical intraepithelial neoplasia grade 3 (CIN3+) or higher. We simulated the VALGENT framework for inter- and intralaboratory validation and evaluated the new 4-channel risk-stratified ScreenFire assay in a hierarchal fashion. Both AmpFire and ScreenFire detected 106 (98.1%) of 108 cases with CIN2 or higher, with specificities of 56.7% and 58.1%, respectively. Intralaboratory concordance for 2 runs of AmpFire and ScreenFire was 95.13% and 96.03%, respectively, for overall hrHPV types and 99.10% and 99.46%, respectively, for HPV 16. The interlaboratory concordance of AmpFire and ScreenFire was 93.68% and 94.04% for overall hrHPV and 98.92% and 99.28%, respectively, for HPV 16. Other genotype correlation percentages were similarly high, with κs ranging from 0.86 to 0.94. The ScreenFire RS assay demonstrated excellent "genotype-specific concordance" when evaluated for "clinical guidance" in a hierarchal fashion (noting only the highest risk channel) with both the cobas 4800 and SeqHPV for less than CIN2, CIN2, and CIN3 or higher. The excellent intra- and interlaboratory reproducibility and the established clinical performance, together with the platforms' simplicity, make these assays particularly applicable to low-resource settings.

Human papillomavirus genotypes and risk of persistence and progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2

BackgroundIn recent years, active surveillance has been introduced as an alternative to excisional treatment in younger women with cervical intraepithelial neoplasia grade 2 (CIN2) since regression rates are high and because excisional treatment is associated with increased risk of preterm birth. However, early identification of women at increased risk of persistence/progression is important to ensure timely treatment. Evidence is limited on biomarkers that may be used to identify women at increased risk of persistence/progression. ObjectiveHere, we aimed to describe HPV type-specific persistence/progression in women undergoing active surveillance for CIN2. Study DesignWe conducted a historical cohort study on women aged 23-40 years diagnosed with CIN2 at Aarhus University Hospital, 2000-2010. Women were identified through the Danish Pathology Data Bank (DPDB) and were considered as undergoing active surveillance if they had a first record of a cervical biopsy within two years after index diagnosis and no LEEP prior to this. Archived tissue samples underwent HPV genotyping using the HPV SPF10-DEIA-LiPA25 system (DNA ELISA kit HPV SPF10 and RHA Kit HPV SPF10-LiPA25). Persistence/progression were defined as having a record of ≥CIN2 in the DPDB determined on the last and worst diagnosis on a biopsy or Loop Electrosurgical Excision Procedure (LEEP) specimen during follow-up. We estimated the relative risk (RR (95% CI)) of persistence/progression using a modified Poisson model. ResultsA total of 455 women were included. Two-thirds were ≤30 years (73.8%) at index diagnosis, and nearly half had a high-grade index cytology (48.8%). Overall, 52.2% of all women had ≥CIN2 during follow-up; 70.5% in HPV16 positive and 29.5% in those positive for other HPV types. HPV16 was associated with a significantly higher risk of persistence/progression (RR 1.64 (95% CI (1.37-1.95)) compared to non-HPV16. The risk persistence or progression was highest in HPV16-positive women with a high-grade index cytology compared to HPV16-positive women with a low-grade cytology (RR 1.29 (95% CI (1.03-1.61-)), whereas no differences were observed across age groups. ConclusionHighest risk of persistence/progression was observed among HPV16-positive women, particularly in those with an associated high-grade cytology. These findings suggest that early excisional treatment should be considered in this group of women.

Mueller matrix-based characterization of cervical tissue sections: a quantitative comparison of polar and differential decomposition methods.

Quantitative optical polarimetry has received considerable recent attention owing to its potential for being an efficient diagnosis and characterizing tool with potential applications in biomedical research and various other disciplines. In this regard, it is crucial to validate various Mueller matrix (MM) decomposition methods, which are utilized to extract and quantify the intrinsic individual polarization anisotropy properties of various complex optical media. To quantitatively compare the performance of both polar and differential MM decomposition methods for probing the structural and morphological changes in complex optical media through analyzing their intrinsic individual polarization parameters, which are extracted using the respective decomposition algorithms. We also intend to utilize the decomposition-derived anisotropy parameters to distinguish among the cervical tissues with different grades of cervical intraepithelial neoplasia (CIN) and to characterize the healing efficiency of an organic crystal. Polarization MM of the cervical tissues with different grades of CIN and the different stages of the self-healing crystal are recorded with a home-built MM imaging setup in the transmission detection geometry with a spatial resolution of . The measured MMs are then processed with both the polar and differential MM decomposition methods to extract the individual polarization parameters of the respective samples. The derived polarization parameters are further analyzed to validate and compare the performance of both the MM decomposition methods for probing and characterizing the structural changes in the respective investigated optical media through their decomposition-derived intrinsic individual polarization properties. Pronounced differences in the decomposed-derived polarization anisotropy parameters are observed for cervical tissue sections with different grades of CIN. While a significant increase in the depolarization parameter is obtained with the increment of CIN stages for both the polar [ for CIN grade one (CIN-I) and for CIN grade two (CIN-II))] and differential ( for CIN-I and for CIN-II) decomposition methods, a trend reversal is seen for the linear diattenuation parameter , indicating the structural distortion in the cervical morphology due to the CIN disease. More importantly, with the differential decomposition algorithm, the magnitude of the derived parameter decreases from 0.26 to 0.19 with the progression of CIN, which was not being probed by the polar decomposition method. Our results demonstrate that the differential decomposition of MM holds certain advantages over the polar decomposition method to characterize and probe the structural changes in the cervical tissues with different grades of CIN. Although the quantified individual polarization parameters obtained through both the MM decomposition methods can be used as useful metrics to characterize various optical media, in case of complex turbid media such as biological tissues, incorporation of the differential decomposition technique may yield more efficient information. Also, the study highlights the utilization of MM polarimetry with an appropriate decomposition technique as an efficient diagnostic and characterizing tool in the realm of biomedical clinical research, and various other disciplines.