Comparative evaluation of two clinical sampling techniques for HPV detection in male genital sites: a randomized controlled study.

AIMS: The optimal sampling methods for detecting human papillomavirus (HPV) in male genital sites remain unclear. This study aimed to assess the performance, acceptability, and comfort of two sampling techniques for male genital HPV detection. METHODS AND RESULTS: A total of 490 men aged 18-45 were randomly assigned in a 1:1 ratio to undergo either the rub-brush (nail file followed by swab) or brush-only method (swab only) for sampling at external genitalia sites (PGS) and perineum/perianal (PA) sites. HPV distribution, specimen validity (ß-globin as a quality reference), and participant acceptability and comfort were evaluated between the two sampling methods. The brush-only method demonstrated non-inferiority in detecting 14 high-risk HPV types (16/18/31/33/35/39/45/51/52/56/58/59/66/68) compared to the rub-brush method in both PGS (18.9% vs. 16.9%) and PA (10.5% vs. 11.9%). Although no significant differences were observed in positive rates for other HPV types, the brush-only method had a significantly higher invalid rate in PA (8.5% vs. 1.5%). Approximately 85.0% of participants reported good acceptability and comfort with both sampling methods, regardless of anatomical sites. CONCLUSIONS: This study suggests comparable performance, acceptability and comfort between the two sampling techniques for HPV detection. However, the rub-brush method may offer an advantage in higher sample validity.

Association Between Common Vaginal Infections and Cervical Non-Human Papillomavirus (HPV) 16/18 Infection in HPV-Vaccinated Women.

BACKGROUND: How vaginal infections such as bacterial vaginosis, Candida spp, and Trichomonas vaginalis affect persistence of human papillomavirus (HPV) infection is not well established. Our study aimed to evaluate the association between common vaginal infections and cervical non-HPV16/18 infection, as risk factors associated with persistence of nonvaccine HPV types will become increasingly relevant in the setting of HPV vaccination. METHODS: We performed an analysis in 2039 AS04-HPV16/18-vaccinated women enrolled in a phase II/III trial in China, who were HPV DNA negative at month 0 and 6 and had at least 1 subsequent follow-up visit. Vaginal infections were detected in liquid-based cytology according to the diagnostic criteria of the Bethesda System. Associations between vaginal infections and incident and 6-month persistent non-HPV16/18 infections in the cervix were evaluated using generalized estimating equations, adjusting for the age at initial vaccination, as well as HPV types in the persistence analysis. RESULTS: Study visits with any vaginal infection had a statistically significant increased risk of incident non-HPV16/18 infection compared to those without vaginal infections (odds ratio [OR], 1.44 [95% confidence interval {CI}, 1.09-1.92]). However, vaginal infections were not associated with 6-month persistent non-HPV16/18 infection (OR, 1.02 [95% CI, .62-1.69]). CONCLUSIONS: Our study suggests that common vaginal infections are not associated with persistence of non-HPV16/18 infection among HPV16/18-vaccinated women.

Efficacy of point-of-care thermal ablation among high-risk human papillomavirus positive women in China.

Thermal ablation is a point-of-care ablative treatment technique for cervical intraepithelial neoplasia (CIN). However, limited information is available about its efficacy in low- and middle-income countries. We evaluated the efficacy of thermal ablation in treatment of CIN detected through high-risk human papillomavirus (HPV) screening in China. Women positive on high-risk HPV and having colposcopically suspected lesions eligible for ablation underwent colposcopy, biopsy and thermal ablation in one visit. Women ineligible were recalled for large loop excision of transformation zone (LLETZ) when histopathology results were high-grade CIN. Posttreatment follow-up at 6 months or more was with HPV test and cytology followed by colposcopy and biopsy for HPV and/or cytology-positive women. Cure was defined as either negative cytology and HPV test or absence of histopathology proved CIN in any positive women. Of total 218 HPV-positive women treated with thermal ablation (n = 170) or LLETZ (n = 48), 196 reported for follow-up evaluation. For women with histologically confirmed CIN at baseline (thermal ablation-104; LLETZ-38), cure rates were 84.6% for thermal ablation and 86.8% for LLETZ. Cure rates after thermal ablation were 90.3% for CIN grade one (CIN1) and 76.2% for CIN grade two or worse (CIN2+). HPV clearance rate was 80.4% in women undergoing thermal ablation, which was lower for HPV16/18 compared to other oncogenic types (67.6% vs 85.7%). HPV test had a negative predictive value (NPV) of 98.7% to detect CIN2+ at follow-up and the positive predictive value (PPV) was 40.4%. Thermal ablation is effective to treat CIN as well as to clear the high-risk HPV infection. HPV test has high PPV and NPV in following up patients posttreatment.

Development of models for cervical cancer screening: construction in a cross-sectional population and validation in two screening cohorts in China.

BACKGROUND: Current methods for cervical cancer screening result in an increased number of referrals and unnecessary diagnostic procedures. This study aimed to develop and evaluate a more accurate model for cervical cancer screening. METHODS: Multiple predictors including age, cytology, high-risk human papillomavirus (hrHPV) DNA/mRNA, E6 oncoprotein, HPV genotyping, and p16/Ki-67 were used for model construction in a cross-sectional population including women with normal cervix (N = 1085), cervical intraepithelial neoplasia (CIN, N = 279), and cervical cancer (N = 551) to predict CIN2+ or CIN3+. A base model using age, cytology, and hrHPV was calculated, and extended versions with additional biomarkers were considered. External validations in two screening cohorts with 3-year follow-up were further conducted (NCohort-I = 3179, NCohort-II = 3082). RESULTS: The base model increased the area under the curve (AUC, 0.91, 95% confidence interval [CI] = 0.88-0.93) and reduced colposcopy referral rates (42.76%, 95% CI = 38.67-46.92) compared to hrHPV and cytology co-testing in the cross-sectional population (AUC 0.80, 95% CI = 0.79-0.82, referrals rates 61.62, 95% CI = 59.4-63.8) to predict CIN2+. The AUC further improved when HPV genotyping and/or E6 oncoprotein were included in the base model. External validation in two screening cohorts further demonstrated that our models had better clinical performances than routine screening methods, yielded AUCs of 0.92 (95% CI = 0.91-0.93) and 0.94 (95% CI = 0.91-0.97) to predict CIN2+ and referrals rates of 17.55% (95% CI = 16.24-18.92) and 7.40% (95% CI = 6.50-8.38) in screening cohort I and II, respectively. Similar results were observed for CIN3+ prediction. CONCLUSIONS: Compared to routine screening methods, our model using current cervical screening indicators can improve the clinical performance and reduce referral rates.

Comparison of the performance of paired urine and cervical samples for cervical cancer screening in screening population.

The main objective of this work is to determine the performance of urine for human papillomavirus (HPV) detection in cervical cancer screening in screening population. Paired urine and cervical samples were collected from 2038 women (careHPV group: 1002, cobas4800 group: 1036) in 2015. Urine was tested by a new urine-based HPV test and cervical samples by careHPV or cobas4800 HPV test. Women were triaged based on cervical results and then referred to colposcopy with biopsy as clinically indicated. In 2017, women were followed up and screened with cotesting strategy, women with any positive would be referred and biopsied if necessary. In careHPV group, the HPV prevalence of urine was 14.1%, and 16.4% for cervical samples. In cobas4800 group, it was 19.1% and 20.4%, correspondingly. The concordance of urine samples compared with cervical samples was moderate (careHPV group: 86.6%; κ = 0.48; cobas4800 group: 83%; κ = 0.46). The baseline sensitivity and specificity for urine against CIN2+ detection were 85.7%, 86.8% in careHPV group, and 69.2%, 82.3% in cobas4800 group, respectively. Cervical samples were 100% sensitive for both tests (careHPV and cobas4800) and 85.2% specific in careHPV group and 81.9% specific in cobas4800 group, respectively. The corresponding cumulative sensitivity and specificity were 68.8% and 87.1%, 58.8% and 81.9%, 87.5% and 85.5%, and 94.1% and 81.4%. Urine demonstrated certain potential in cervical cancer screening and could be an alternative if no better screening strategies available.

Outcomes in women with biopsy-confirmed cervical intraepithelial neoplasia grade 1 or normal cervix and related cofactors: A 15-year population-based cohort study from China.

OBJECTIVE: To estimate long-term outcomes of biopsy-confirmed cervical intraepithelial neoplasia grade 1 (CIN1) or normal cervix and identify the cofactors during disease progression. METHODS: In 1999, a cervical cancer screening cohort in Shanxi, China, enrolled 1997 women aged 35-45. They were followed up at year 6, 11, and 15 after enrollment with high-risk human papillomavirus (hrHPV) DNA testing, liquid-based cytology, and visual inspection with acetic acid. Progression, persistence, and regression rates were calculated, stratified by baseline hrHPV and cytological status. Risk factors associated with hrHPV acquisition, persistence, and progression were examined. RESULTS: The cumulative rates of progression to CIN2+ among CIN1 over 6, 11, and 15 years were 7.5%, 21.4%, and 24.0%, respectively; the regression rates to normal cervix were 85.0%, 76.7%, and 72.9%, respectively. Over 6, 11, and 15 years, 0.7%, 2.9%, and 5.2% of normal cervix developed CIN2+, respectively, but over 90% remained normal after 15 years. CIN1 or normal cervix positive for hrHPV had significantly higher progression rates to CIN2+ than those without hrHPV. Similarly, the severity of cytological status was found to be associated with an increased risk of developing CIN2+. Women who had an earlier sexual debut were at a higher risk of acquiring new HPV infection and repeated HPV infections. CONCLUSIONS: Clinical follow-up strategies for women with CIN1 or normal cervix could be adjusted accordingly based on hrHPV/cytology status.

Clinical performance of Onclarity HPV assay and Cobas HPV test in detection of cervical precancer and cancer in Chinese women.

OBJECTIVE: The Roche Cobas (Cobas) and BD Onclarity (Onclarity) human papillomavirus (HPV) assays are convenient, PCR-based, HPV DNA tests; currently, data on performance of Onclarity in Chinese women is limited. We aimed to evaluate the clinical performance of Onclarity for detecting cervical lesions in Chinese women. METHODS: In total, 1122 women were enrolled into this study. Exfoliated cervical cells were collected in PreservCyt medium and were tested using Cobas and Onclarity. Cytology and histology were interpreted by senior cytologists and a panel of pathologists, respectively, at Cancer Hospital, Chinese Academy of Medical Sciences. RESULTS: The assays showed excellent concordance for HPV16 (kappa = 0.91, 95% CI: 0.85-0.97) and for 12 other high-risk types (HPV31/33/35/39/45/51/52/56/58/59/66/68, kappa = 0.84, 95% CI: 0.78-0.90), and very good concordance for HPV18 (kappa = 0.75, 95% CI: 0.69-0.81). No difference for ≥CIN2 sensitivity was observed between Onclarity and Cobas (both 90.5%); and the

Impact of HPV-16/18 AS04-adjuvanted vaccine on preventing subsequent infection and disease after excision treatment: post-hoc analysis from a randomized controlled trial.

BACKGROUND: It is widely acknowledged that HPV prophylactic vaccine could prevent new infections and their associated lesions among women who are predominantly HPV-naive at vaccination. Yet there still remains uncertainty about whether HPV vaccination could benefit to individuals who have undergone surgery for cervical disease. METHODS: This post-hoc analysis intends to focus on intent-to-treat participants who underwent excision treatment at baseline and the follow-up period in a phase II/III, double-blind, randomized trial ( ClinicalTrials.gov , number NCT00779766 ) conducted in Jiangsu province, China. We evaluate the impact of HPV vaccination on preventing women from subsequent infection and cervical lesions (LSIL+ and CIN2+) after excision treatment. RESULTS: One hundred sixty-eight (vaccine, n = 87; placebo, n = 81) performed excisional treatment in this clinical trial. We observed a significant effect of vaccination on acquiring 14 high-risk HPV (HR-HPV) infection after treatment (vaccine efficacy: 27.0%; 95% CI 4.9, 44.0%). The vaccine efficacy against new infections after treatment for 14 HR-HPV infection was estimated as 32.0% (95%CI 1.8, 52.8%), and was 41.2% (95%CI -162.7, 86.8%) for HPV16/18 infection. The accumulative clearance rates of the vaccine group and placebo group were 88.9 and 81.6% for HPV16/18 infection (P = 0.345), 63.4, 48.7% for 14 HR-HPV infection (P = 0.062), respectively. No significant difference was observed on the persistent rate of HPV16/18, 14 HR-HPV infection and occurrence rate of LSIL+ between the two groups. CONCLUSIONS: No significant evidence from this study showed that HPV-16/18 AS04-adjuvanted vaccine could lead to viral faster clearance or have any effect on the rates of persistent infection among women who had excision treatment. However, the vaccine may still benefit post-treatment women with "primary prophylactic" effect. Further research is required in clarifying the effect of using the prophylactic HPV vaccine as therapeutic agents. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00779766 . Date and status of trial registration: October 24, 2008. Completed; Has Results.

Role of Human Papillomavirus DNA Load in Predicting the Long-term Risk of Cervical Cancer: A 15-Year Prospective Cohort Study in China.

BACKGROUND: Biomarkers highly predictive of cervical cancer are urgently needed for triaging human papillomavirus (HPV)-positive women. METHODS: A total of 1997 women aged 35-45 years in Shanxi, China, were recruited in 1999, and follow-up visits were conducted in 2005, 2010, and 2014. HPV load was measured by the Hybrid Capture 2 assay. Findings were determined by relative light units/cutoff (RLU/CO) and categorized into 4 groups: negative ( <1.0), low (range, 1.0 to <10.0), moderate (range, 10.0 to <100.0), and high (range, 100.0-∞). Cumulative incidence rates (CIRs) and adjusted hazard ratios (aHRs) for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) were calculated for viral load subgroups, using survival analysis. RESULTS: Among 1739 women with normal or CIN1 pathological findings at baseline, 15-year CIRs for CIN2+ for those who were HPV negative and those with low, moderate, and high HPV loads groups were 3.1%, 8.4%, 19.9%, and 22.0%, respectively (Ptrend <.001). Compared with women who were negative for HPV from baseline through follow-up, those who had decreasing, increasing, or stable moderate/high loads had aHRs of 9.1, 38.7, or 379.7, respectively, for CIN2+. There was no significant difference between triage based on cytologic findings (for those with atypical squamous cells of undetermined significance or more-severe findings) and that based on a moderate/high HPV load for HPV primary screening (P = .343). CONCLUSION: A moderate/high HPV load may accelerate the progression of cervical precancers and potentially could be used as a triage indicator for HPV-positive women.

Value of multi-quadrants biopsy: Pooled analysis of 11 population-based cervical cancer screening studies.

OBJECTIVE: The accuracy of colposcopy-guided biopsy is key to the success of colposcopic triage in cervical cancer screening programs. However, there is no widely adopted biopsy guideline up to date. Our study aimed to determine whether multi-quadrants biopsy improves the yield of cervical lesions. METHODS: Eleven population-based cervical cancer screening studies were conducted in China. Cytology, high-risk human papillomavirus (hrHPV) testing and visual inspection were performed for primary screening. Females positive on one or more tests were referred for colposcopy and biopsy. The proportion of detected cervical intraepithelial neoplasia (CIN)2+ and yields by quadrant lesion-targeted biopsy or 4-quadrant random biopsy were compared. RESULTS: Among 4,923 females included, 1,606 had quadrant lesion-targeted biopsy, and 3,317 had 4-quadrant random biopsy. The cumulative CIN2+ yield increased from 0.10 for only one quadrant-targeted biopsy to 0.21, 0.34, and 0.58 for at most two, three and four quadrants targeted biopsies. Among hrHPV positive females with high-grade squamous intraepithelial lesion (HSIL)+ cytology, the cumulative CIN2+ yield of a second targeted biopsy in another quadrant was significantly increased (P<0.05). Among hrHPV-negative females, the yield of 4-quadrant random biopsies was 0.005, and the yield by lesion-targeted biopsies was 0.017. For hrHPV positive females who had 4-quadrant random biopsy, the additional CIN2+ yield for HSIL+, low-grade squamous intraepithelial lesion (LSIL) cytology, or abnormal visual inspection via acetic acid and Lugol's iodine (VIA/VILI) were 0.46, 0.11, 0.14. CONCLUSIONS: A 4-quadrant random biopsy is recommended only for hrHPV positive females with HSIL cytology, and is acceptable if hrHPV positive with LSIL cytology or with abnormal VIA/VILI. Our findings add evidences for an objective and practical biopsy standard to guide colposcopy in cervical cancer screening programs in low- and middle-income countries.

Eight-type human papillomavirus E6/E7 oncoprotein detection as a novel and promising triage strategy for managing HPV-positive women.

The management of HPV-positive women becomes particularly crucial in cervical cancer screening. Here we assessed whether detection of E6 or E7 oncoproteins targeting eight most prevalent HPV types could serve as a promising triage option. Women (N = 1,416) aged 50-60 from Shanxi, China underwent screening with HPV testing and liquid-based cytology (LBC), with any positive results referring to colposcopy and biopsy if necessary. Women with HPV-positive results received further tests using DNA-based genotyping, E6 or E7 oncoprotein detection targeting HPV16/18 (for short: E6 (16/18) Test) or HPV16/18/31/33/35/45/52/58 (for short: E6/E7 (8 types) Test), respectively. Among HPV-positive women, E6/E7 (8 types) oncoproteins had lower positivity (17.37%) compared to DNA-based genotyping for same eight types (58.30%) and LBC with ASC-US threshold (50.97%); HPV16 was the genotype showing the highest frequency (8.49%) for oncoprotein detection followed by HPV52 (3.47%), 58 (2.32%), 33 (1.54%), 18 (1.16%), 45 (0.77%), 35 (0.39%) and 31 (0%). For detection of cervical intraepithelial neoplasia Grade 3 or higher (CIN3+), E6/E7 (8 types) Test had similar sensitivity (100.00%) and superior specificity (85.94%) as well as positive predictive value (PPV, 22.22%) compared to both LBC and DNA-based genotyping (8 types); For detection of CIN2+, E6/E7 (8 types) Test was less sensitive (67.74%) but still more specific (89.47%) and risk predictive with PPV of 46.67%. Notably, E6/E7 (8 types) Test remarkably decreased the number of colposcopies needed to detect one CIN2+ and CIN3+ (2.14 and 4.50). E6/E7 oncoprotein detection showed a good "trade-off" between sensitivity and specificity with more efficient colposcopy referrals, which is of great importance to maximize the benefits of HPV-based screening program, especially applicable for the areas with high HPV prevalence and low-resources.

Durability of clinical performance afforded by self-collected HPV testing: A 15-year cohort study in China.

OBJECTIVE: Self-collected HPV testing could substantially reduce disparities in cervical cancer screening, with slightly lower sensitivity compared to physician-collected specimens cross-sectionally. We aimed to evaluate the comprehensive long-term performance of self-collected HPV testing prospectively. METHODS: In 1999, 1997 women were screened by HPV testing on self-collected and physician-collected samples, cytology and visual inspection with acetic acid (VIA) and followed up in 2005, 2010 and 2014, respectively. HPV testing was performed with Hybrid Capture II. Prospective performance, baseline clinical efficiency, and 15-year cumulative risk of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) were analyzed. RESULTS: Self-collected HPV testing prospectively detected 83.3% (95% CI:74.9%,89.3%), 70.3% (95% CI:62.5%,77.2%) and 63.3% (95% CI:55.7%, 70.2%) of cumulative CIN2+ at 6-year, 11-year and 15-year follow-up, respectively. Relative cumulative sensitivity of physician-collected HPV testing versus self-collected HPV testing was stable over 15 years at about 1.16. Cumulative sensitivity of self-collected HPV testing was comparable to cytology and significantly higher than VIA. Among women positive by self-collected HPV testing at baseline, 26.2% (95% CI:21.5%, 30.9%) developed CIN2+ during 6-year follow-up and no difference was observed with physician-collected HPV testing even 15 years after baseline. Negative self-collected HPV results provided greater protection against CIN2+ than VIA and ascertained CIN2+ cumulative incident rates as low as 1.1% at the 6-year follow-up. CONCLUSIONS: Self-collected HPV testing demonstrates lower sensitivity than physician-collected HPV testing but performs comparably to cytology prospectively and provides satisfactory assurance against CIN2+, indicating an alternative role in cervical cancer primary screening with five-year interval as an option especially in low-resource settings.

Evaluation of multiple primary and combination screening strategies in postmenopausal women for detection of cervical cancer in China.

As China's population ages, the importance of determining prevalence of cervical disease and accurate cervical cancer screening strategies for postmenopausal women is increasing. Seventeen population-based studies were analyzed to determine prevalence of cervical neoplasia in postmenopausal women. All women underwent HPV DNA testing, visual inspection with acetic acid (VIA) and cytology testing. Diagnostic values for primary and combinations screening methods included sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), referral rate and area under curve (AUC) were calculated using directed biopsy or four quadrants biopsy as reference standard. Premenopausal and postmenopausal women had equal HPV infection and cervical neoplasia rates (p > 0.05). HPV DNA testing CIN3+ sensitivity, specificity, PPV, NPV, referral rate and AUC were 97.9% (95% CI: 90.2-99.9%), 84.2% (95% CI: 82.8-85.5%), 9.9% (95% CI: 7.4-12.8%), 100% (95% CI: 99.8-100%), 17.2% (95% CI: 15.9-18.7%), 0.911, respectively. VIA values were 41.7% (95% CI: 28.4-55.9%), 94.5% (95% CI: 93.6-95.3%), 11.8% (95% CI: 7.5-17.3%), 98.9% (95% CI: 98.5-99.3%), 6.2% (95% CI: 5.3-7.1%) and 0.681, respectively. Values for VIA with HPV triage were 39.6% (95% CI: 26.6-53.8%), 99.2% (95% CI: 98.8-99.5%), 45.2% (95% CI: 30.8-60.4%), 98.9% (95% CI: 98.5-99.3%), 1.5% (95% CI: 1.1-2.0%) and 0.694, respectively. VIA and HPV DNA co-test values were 100% (95% CI: 94.0-100%), 79.5% (95% CI: 78.0-81.0%), 8.0% (95% CI: 6.0-10.3%), 100% (95% CI: 99.9-100%), 21.9% (95% CI: 20.4-23.4%) and 0.898, respectively. VIA sensitivity decreases significantly in postmenopausal women compared to premenopausal performance. HPV DNA testing maintains performance between pre- and postmenopausal women and is the most accurate primary modality for screening postmenopausal populations in low resource areas of China.

Risk stratification and long-term risk prediction of E6 oncoprotein in a prospective screening cohort in China.

E6 oncoprotein is a necessary agent of HPV driven oncogenic transformation. This study is aimed at evaluating the risk stratification potency of HPV 16/18 E6 oncoprotein (E6) as a triage method for HPV positivity. Moreover, it also acts as a predictor of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The screening cohort of 1,997 women was followed for a 15 year period in approximate five-year intervals. Participants were concurrently screened by HPV DNA testing (HC2), liquid based cytology (LBC), visual inspection with acetic acid (VIA) and were referred to colposcopy and biopsy if any tests reflected positive. E6 was performed on cervical samples collected from this cohort in 2005 and 2014. The ability of E6 to predict CIN3+ risk after the five- and ten-year interval was evaluated. Among HPV positive women in 2005, E6 indicated the lowest positive rate (9.9%) compared to LBC (48.4%) and VIA (28.0%), however, a higher prevalence rate (10.3%) and 10-year cumulative incidence rate (53.0%) of CIN3+ were detected among women who were E6 positive. Meanwhile, only 4.2% and 2.9% of women with abnormal LBC and positive VIA were diagnosed as prevalent CIN3+ in 2005, 23.0% and 16.5% developed to CIN3+ after year 10, respectively. Strong associations were found between precedent and subsequent HPV persistence and E6 oncoprotein expression (ORadjusted = 40.0 and 21.2, respectively). E6 oncoprotein could serve as a low-cost, highly specific, strongly indicative point-of-care method in the triage and treatment of HPV positive women.

Accuracy of triage strategies for human papillomavirus DNA-positive women in low-resource settings: A cross-sectional study in China.

OBJECTIVE: CareHPV is a human papillomavirus (HPV) DNA test for low-resource settings (LRS). This study assesses optimum triage strategies for careHPV-positive women in LRS. METHODS: A total of 2,530 Chinese women were concurrently screened for cervical cancer with visual inspection with acetic acid (VIA), liquid-based cytology and HPV testing by physician- and self-collected careHPV, and physician-collected Hybrid Capture 2 (HC2). Screen-positive women were referred to colposcopy with biopsy and endocervical curettage as necessary. HPV-positivity was defined as ≥1.0 relative light units/cutoff (RLU/CO) for both careHPV and HC2. Primary physician-HC2, physician-careHPV and self-careHPV and in sequential screening with cytology, VIA, or increased HPV test-positivity performance, stratified by age, were assessed for cervical intraepithelial neoplasia (CIN) grade 2/3 or worse (CIN2/3+) detection. RESULTS: The sensitivities and specificities of primary HPV testing for CIN2+ were: 83.8%, 88.1% for physician-careHPV; 72.1%, 88.2% for self-careHPV; and 97.1%, 86.0% for HC2. Physician-careHPV test-positive women with VIA triage had a sensitivity of 30.9% for CIN2+ versus 80.9% with cytology triage. Self-careHPV test-positive women with VIA triage was 26.5% versus 66.2% with cytology triage. The sensitivity of HC2 test-positive women with VIA triage was 38.2% versus 92.6% with cytology triage. The sensitivity of physician-careHPV testing for CIN2+ decreased from 83.8% at ≥1.0 RLU/CO to 72.1% at ≥10.00 RLU/CO, while the sensitivity of self-careHPV testing decreased from 72.1% at ≥1.0 RLU/CO to 32.4% at ≥10.00 RLU/CO; similar trends were seen with age-stratification. CONCLUSIONS: VIA and cytology triage improved specificity for CIN2/3 than no triage. Sensitivity with VIA triage was unsuitable for a mass-screening program. VIA provider training might improve this strategy. Cytology triage could be feasible where a high-quality cytology program exists. Triage of HPV test-positive women by increased test positivity cutoff adds another LRS triage option.

Risk assessment to guide cervical screening strategies in a large Chinese population.

Three different cervical screening methods [cytology, human papillomavirus(HPV) testing and visual inspection with acetic acid(VIA)] are being considered in China for the national cervical screening program. Comparing risks of CIN3 and cervical cancer (CIN3+) for different results can inform test choice and management guidelines. We evaluated the immediate risk of CIN3+ for different screening results generated from individual and combined tests. We compared tests using a novel statistic designed for this purpose called Mean Risk Stratification (MRS), in a pooled analysis of 17 cross sectional population-based studies of 30,371 Chinese women screened with all 3 methods and diagnosed by colposcopically-directed biopsies. The 3 tests combined powerfully distinguished CIN3+ risk; triple-negative screening conferred a risk of 0.01%, while HPV-positive HSIL+ that was VIA-positive yielded a risk of 57.8%. Among the three screening tests, HPV status most strongly stratified CIN3+ risk. Among HPV-positive women, cytology was the more useful second test. In HPV-negative women, the immediate risks of CIN3+ ranged from 0.01% (negative cytology), 0.00% (ASC-US), 1.1% (LSIL), to 6.6 (HSIL+). In HPV-positive women, the CIN3+ risks were 0.9% (negative cytology), 3.6% (ASC-US), 6.3% (LSIL) and 38.5% (HSIL+). VIA results did not meaningful stratify CIN3+ risk among HPV-negative women with negative or ASC-US cytology; however, positive VIA substantially elevated CIN3+ risk for all other, more positive combinations of HPV and cytology compared with a negative VIA. Because all 3 screening tests had independent value in defining risk of CIN3+, different combinations can be optimized as pragmatic strategies in different resource settings.

Factors Influencing the Reliability of Thyroid Fine-Needle Aspiration: Analysis of Thyroid Nodule Size, Guidance Mode for Aspiration and Preparation Method.

OBJECTIVE: We aimed to clarify the influence of ThinPrep preparation, nodule size and guidance mode on the accuracy of thyroid fine-needle aspiration (FNA). METHODS: A total of 1,240 thyroid FNAs were reviewed and 489 cases with histological correlations were enrolled in this study. RESULTS: Of the 489 total cases examined, 101 were processed with both ThinPrep and conventional preparation and 388 entirely with ThinPrep. The overall nondiagnostic rate, sensitivity and accuracy of FNA were 2.0, 91.0 and 89.4%, respectively. The cases with a preoperative ultrasound (n = 469) were grouped according to nodule size. The nondiagnostic rate, sensitivity and accuracy of FNA did not differ significantly with nodule size (p1 = 0.339, p2 = 0.179, p3 = 0.119). A total of 101 resections were performed with palpation-guided FNA and 388 were performed with ultrasound-guided FNA. The nondiagnostic rates, sensitivity and accuracy of FNA were similar in these two groups. CONCLUSIONS: The ThinPrep technique is a valid method for thyroid FNA and is effective for thyroid nodules ≥ 0.5 cm. The reliability of FNA results is not reduced with larger nodules. The use of palpation-guided FNA for palpable solid nodules is also effective.

[Value of liquid-based cytology of brushing specimens obtained via fiberoptic bronchoscopy for the diagnosis of lung cancer].

OBJECTIVE: To investigate the value of the liquid-based cytology (LBC) of brushing specimens obtained via fiberoptic bronchoscopy for clinical diagnosis of lung cancer. METHODS: We retrospectively analyzed the LBC cases in our hospital from January 2011 to May 2012, and evaluate its role in the diagnosis of lung cancer. RESULTS: The clinical data of a total of 4 380 cases were reviewed and 3 763 of them had histopathological or clinical follow-up results (including 3 306 lung cancer cases and 457 benign lesion cases). The sensitivity, specificity, and accuracy of LBC diagnosis for lung cancer were 72.4% (2 392/3 306), 99.3% (454/457) and 75.6% (2 846/3 763), respectively. Of the 1 992 lung cancer cases diagnosed by brushing LBC, 528 cases (26.5%) were failed to take forceps biopsy and 113 cases (5.7%) showed negative forceps biopsy results. The accurate rate of subtyping of LBC for non-small cell carcinoma and small cell carcinoma was 99.0% (1 487/1 502) (P < 0.001). Take the resection histopathology as gold standard, the accurate rates of subtyping squamous cell carcinoma, adenocarcinoma and small cell carcinoma by LBC were 95.6% (351/367), 95.6% (351/367) and 100% (367/367), respectively, (P < 0.001). The accurate rates of subtyping of squamous cell carcinoma, adenocarcinoma and small cell carcinoma by forceps biopsy were 97.0% (293/302), 97.4% (294/302) and 99.7% (301/302), respectively, (Kappa = 0.895, P < 0.001). There was no significant difference in subtyping respectively between forceps biopsy and brushing LBC (P > 0.05). CONCLUSIONS: Fiberoptic bronchoscopic brushing liquid-based cytology can significantly improve the detection rate of lung cancer, and have a high specificity and accurate rate of subtyping. It is an effective tool for the diagnosis and subtyping of lung cancer.

[Value of 4-quadrant biopsies under colposcopy for detecting precancerous lesions in cervical cancer screening].

OBJECTIVE: To evaluate the value of colposcopical 4-quadrant biopsies for detecting precancerous lesion in cervical cancer screening. METHODS: We used the data of a cross-sectional screening study in 1999, in which 1,997 women received cervical cancer screening in Xiang Yuan County, Shanxi province. The sensitivity, specificity and accuracy of both 4-quadrant biopsy and colposcopy directed biopsy to detect high-grade or more severe squamous intraepithelial lesions (HSIL+) were calculated. RESULTS: 1,784(89.3%) women who received 4-quadrant biopsies and endocervical curettage were negative. 127(6.4%) women were diagnosed as LSIL, 74(3.7%) women as HSIL and 12(0.6%) cases of squamous cell carcinoma. 1,478(74.0%) women who received biopsies in the sites of abnormal lesions were negative, 463(23.2%) cases of LSIL, 41(2.1%) cases of HSIL, 15(0.8%) cases of squamous cell carcinoma. The positive rate was 26.0%(519/1,997) for colposcopy, and the coincidence rate was 73.7% with pathological diagnosis. Sensitivity and specificity were 81.4% and 76.5% of colposcopy for HSIL+. In total of 519 women were found to be with any abnormal colposcopic appearance. The consistency rate between 4-quadrant biopsies and suspicious lesion-directed biopsies was 96.3%. By suspicious lesion-directed biopsy alone, 14.8% cervical lesions were miss-diagnosed, of which 8.6%(5/58) cases of total HSIL and 24.1%(14/58) cases of all LSIL. CONCLUSIONS: 4-quadrant biopsy can detect more HSIL+ lesions and is more accurate than suspicious lesion biopsy alone. As an important triage technique to detect cervical precancerous lesions, it can improve the detection rate of HSIL+ lesions in cervical cancer screening.

Baseline prevalence and type distribution of human papillomavirus in healthy Chinese women aged 18-25 years enrolled in a clinical trial.

Baseline human papillomavirus (HPV) prevalence and type distribution were evaluated in young Chinese women enrolled in a clinical trial of an HPV vaccine (ClinicalTrials.gov registration NCT00779766). Cervical specimens and blood samples were collected at baseline from women aged 18-25 years (n = 6,051) from four sites across Jiangsu province. Cervical specimens were tested for HPV DNA by SPF10 PCR-DEIA-LiPA25 version 1, and HPV-16/18 type-specific polymerase chain reaction. Anti-HPV-16 and anti-HPV-18 antibody titres were quantified by enzyme-linked immunosorbent assay. At baseline, 15.3% of women were DNA positive for any of 14 HPV high-risk (hr) types (HPV-16/18/31/33/35/39/45/51/52/56/58/59/66/68). The most commonly detected hrHPV types in cervical specimens were HPV-52 (4.0%) and HPV-16 (3.7%). High-risk HPV DNA-positivity increased with severity of cytological abnormalities: 39.3% in atypical squamous cells of undetermined significance, 85.0% in low-grade squamous intraepithelial lesions and 97.8% in high-grade squamous intraepithelial lesions (HSIL). The hrHPV types most frequently detected in HSIL were HPV-16 (63.0%), HPV-18 (17.4%), HPV-52 (17.4%), HPV-58 (15.2%) and HPV-33 (15.2%). The hrHPV types most frequently detected in cervical intraepithelial neoplasia 2+ were HPV-16 (66.1%), HPV-33 (16.1%), HPV-52 (16.1%), HPV-58 (14.5%) and HPV-51 (11.3%). Multiple hrHPV infections were reported for 24.4% of hrHPV DNA positive women. Regardless of baseline HPV DNA status, 30.5% and 16.0% of subjects were initially seropositive for anti-HPV-16 and anti-HPV-18, respectively. In conclusion, the high baseline seropositivity rate and intermediate prevalence of cervical hrHPV types in Chinese women aged 18-25 years underlines the importance of early HPV vaccination in this population.