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Fangbin Song,1,2 Hui Du,1,2 Aimin Xiao,1,2 Chun Wang,1,2 Xia Huang,1,2 Peisha Yan,1,2 Zhihong Liu,1,2 Xinfeng Qu,3 Jerome L Belinson,4,5 Ruifang Wu1,2 1Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China; 2Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecological Diseases, Shenzhen, People’s Republic of China; 3Sanming Project of Medicine in Shenzhen, Peking University Shenzhen Hospital, Shenzen, People’s Republic of China; 4Preventive Oncology International, Inc., Cleveland Heights, OH, USA; 5Gynecologic Oncology Division, Women’s Health Institute, Cleveland Clinic, Cleveland, OH,USACorrespondence: Ruifang Wu; Hui DuDepartment of Obstetrics and Gynecology, Peking University Shenzhen Hospital, No. 1120 Lianhua Road, Shenzhen, Guangdong 518036, People’s Republic of ChinaEmail wurfpush@126.com; duhui_107108@163.comPurpose: When used for cervical cancer primary screening, liquid-based cytology (LBC) has a high specificity but a low sensitivity. For histological diagnosis of high-grade lesions, p16INK4a immunostaining has proven to be useful. Therefore, our objective was to evaluate the use of p16INK4a immuno-cytology as a primary screen and a secondary screen after primary high-risk human papillomavirus (hrHPV) screening or LBC screening.Methods: A total of 1197 cytology slides were immuno-stained using automatic p16INK4a staining system (PathCIN®p16INK4a) in two studies from cervical screening programs. In the primary screening study, 875 slides were randomly selected and analyzed for p16INK4a. In the secondary screening study, 322 of the remaining slides were chosen by virtue of being HPV 16/18+, other hrHPV+/LBC≥ASC-US, or HPV-negative/LBC ≥LSIL. The sensitivity and specificity for detection of cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+) were compared based on p16INK4a, LBC and HPV test results.Results: In combining two studies, there were 431 cases with biopsy pathology. They included 83 cases with CIN2+ and 41 cases with CIN3+. The p16 positivity rate increased with pathologic and cytologic severity (P< 0.0001). For primary screening: p16 immuno-cytology was more specific than HPV testing and was similar in sensitivity. Also, p16 immuno-cytology compared favorably with routine LBC (≥ASC-US or ≥LSIL) in sensitivity and specificity. For secondary screening: after LBC screening, “Triaging ASC-US with p16” gave a higher specificity and a similar sensitivity as compared to the “Triaging ASC-US with hrHPV” algorithm. After HPV primary screening, p16 immuno-cytology was more specific than LBC (≥ASC-US); the calculated colposcopy referral rate was also decreased by using p16 immuno-cytology as triage. Triage of “HPV16/18 and p16” had higher specificity and similar sensitivity as compared to triage of “HPV16/18 and LBC ≥ASC-US”.Conclusion: For primary screening, p16INK4a immuno-cytology compares favorably to routine LBC and HPV testing. p16INK4a immunostaining could be an efficient triage to reduce the colposcopy referral rate after primary hrHPV screening or LBC screening. Therefore, p16INK4a immuno-cytology may be applicable as a favorable technology for cervical cancer screening.Keywords: cervical intraepithelial neoplasia, human papillomavirus, p16, immunochemical staining, cervical cancer screening

Objective: To determine the distribution of cervical intraepithelial neoplasia 2 or 3 on the uterine cervix.Materials and Methods: During two screening studies, 5,060 women underwent colposcopy with biopsy. If a cervical quadrant had no lesion, a random biopsy at the squamocolumnar junction was obtained.Results: Cervical intraepithelial neoplasia 2 or worse was more common on the posterior (426/806; 52.9%) than on the anterior (380/806; 47.2%) cervix (p < .05) and was equally likely on the right (411/806; 51.0%) and left (395/806; 49.0%) sides of the cervix. More quadrants with colposcopically detected lesions of human papillomavirus or worse came from the anterior (1,338; 57.5%) than posterior (991; 42.6%) cervix (p < .05), whereas similar numbers of these lesions were found on the left (1,163) and right (1,166) sides of the cervix.Conclusions: Cervical intraepithelial neoplasia 2 or worse is slightly more common on the posterior cervix. Using colposcopically detected lesions as a surrogate for cervical intraepithelial neoplasia 2 or worse inflates the prevalence of cervical intraepithelial neoplasia on the anterior cervix. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the sensitivity of screening tests that miss small cervical intraepithelial neoplasia (CIN) 2 or worse (e.g., acetic acid-aided visual inspection) is inflated when the criterion standard (colposcopic-directed biopsy) misses the same small CIN 2 or worse.Materials and Methods: One thousand nine hundred twenty-eight women were screened using acetic acid-aided visual inspection, self-tests, and direct tests for high-risk human papillomavirus, and using liquid-based cytologic screening. All women underwent colposcopy with biopsy. If a cervical quadrant had no lesion, a random biopsy at the squamocolumnar junction within that quadrant was obtained. All patients underwent endocervical curettage (ECC). Differences in sensitivity for CIN 2 or worse of screening tests were compared with criterion standards of colposcopically directed biopsy and colposcopically directed biopsy, random biopsy, plus ECC.Results: Sixty-two of 83 women with CIN 2 or worse were diagnosed by colposcopically directed biopsy, 19 by random biopsy, and 2 solely by ECC. Fifty-six of the 83 women had CIN 2 or worse involving 0 to 2 quadrants (2 with 0 quadrants were diagnosed solely by positive ECC) and 27 of 83 had CIN 2 or worse results involving 3 to 4 quadrants. Colposcopically directed biopsy detected 35 of 56 women (62.5%) with CIN 2 or worse involving 0 to 2 cervical quadrants and 27 of 27 women (100%) with CIN 2 or worse involving 3 to 4 quadrants (p < .005). Acetic acid-aided visual inspection and cytologic analysis of high-grade squamous intraepithelial lesion or cancer detected 35 of 56 (62.5%) and 36 of 56 (64.3%) lesions involving 0 to 2 quadrants and 27 of 27 (100%) (p < .005) and 24 of 27 (88.9%; p < .05) lesions involving 3 to 4 quadrants. The sensitivity of direct human papillomavirus tests (97.6%) and cytologic analysis of atypical squamous cells of undetermined significance or worse (94.0%) for CIN 2 or worse were high and unaffected by lesion size. When the criterion standard was changed from colposcopically directed biopsy, random biopsy, plus ECC to colposcopically directed biopsy, the sensitivity of acetic acid-aided visual inspection and cytologic analysis of high-grade squamous intraepithelial lesion or worse for CIN 2 or worse increased from 75.9% to 85.5% (p > .1) and from 71.1% to 79.0% (p > .25). Sensitivities of other screening tests were unaffected by changing the criterion standard.Conclusions: Criterion standards that miss the same CIN 2 or worse as the screening tests likely cause inflation of the sensitivity of those tests. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective of the study was to assess the effectiveness of primary chemoradiation for stage IB(2) cervical carcinoma. STUDY DESIGN: A retrospective study of patients treated with primary chemoradiation at selected hospitals in Cleveland, OH, from 1992 to 2006 was performed. Patients with regional or distant metastasis on pretreatment imaging were excluded. Patients received pelvic teletherapy with weekly concurrent cisplatin and high- or low-dose-rate brachytherapy. RESULTS: Forty-nine patients with a median age of 51 years were identified. The majority of patients were white (81.6%) and had squamous cell carcinomas (81.6%) and a median tumor diameter of 5 cm (range, 4.1-10 cm). The median duration of follow-up was 41 months. Progression of disease was observed in 10 (20.4%) patients. The local control rate was 86%. At 36 months, the progression-free survival (PFS) was 79% and the overall survival (OS) was 86%. CONCLUSION: Primary chemoradiation has a high clinical response rate, PFS, and OS for women with stage IB(2) cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Despite the promise of mail-based human papillomavirus (HPV) self-collection programs for increasing cervical cancer screening, few have been evaluated in the United States. We report the results of a mail-based HPV self-collection program for underscreened women living in Appalachia., Methods: We conducted a group randomized trial during 2021-2022 in the Appalachian regions of Kentucky, Ohio, Virginia, and West Virgnia. Participants were women ages 30-64 who were underscreened for cervical cancer and from a participating health system. Participants in the intervention group (n=464) were mailed an HPV self-collection kit followed by telephone-based patient navigation (if needed), and participants in the usual care group (n=338) were mailed a reminder letter to get a clinic-based cervical cancer screening test. Generalized linear mixed models compared cervical cancer screening between study groups., Results: Overall, 14.9% of participants in the intervention group and 5.0% of participants in the usual care group were screened for cervical cancer. The mail-based HPV self-collection intervention increased cervical cancer screening compared to the usual care group (OR=3.30, 95% CI: 1.90-5.72, p=0.005). One or more high-risk HPV types were detected in 10.5% of the returned HPV self-collection kits. Among participants in the intervention group who patient navigators attempted to contact, 44.2% were successfully reached., Conclusions: HPV self-collection increased cervical cancer screening, and future efforts are needed to determine how to optimize such programs, including the delivery of patient navigation services., Impact: Mail-based HPV self-collection programs are a viable strategy for increasing cervical cancer screening among underscreened women living in Appalachia.

Objective: The aim of the study is to validate the applicability and performance of the 2019 US risk-based guideline for Chinese women., Materials and Methods: We analyzed 10,055 cases with data on human papillomavirus testing, cytology, and pathologically confirmed diagnosis (analysis-set). According to the 2019 US risk-based guideline, we recorded the risk value and triage recommendations for each case. Then, we assessed the concordance of the guideline triage recommendations with pathology diagnosis for the relevant case from the real-world projects., Results: Among the analysis-set, 9,495 cases with an estimated risk value were identified as analysis cohort while the remaining 560 cases were cataloged as "special cases." Among the analysis cohort, 960 and 526 cases were pathologically confirmed as cervical intraepithelial neoplasia (CIN) 2+ and CIN3+, respectively. The US risk-based guideline recommended colposcopy or more aggressive interventions (Colp+) for 86.8% (833/960) of the CIN2+ and 95.8% (504/526) of the CIN3+ cases, with 87.1% sensitivity and 82.5% specificity for CIN3+ cases (AUC = 0.926, p < .0001). The US risk-based recommended no-Colp for 98.0% (6,142/6,269) of the pathologically confirmed CIN1 or benign cases. In addition, 97.3% (545/560) of the "special cases" cases were recommended as Colp+., Conclusions: The 2019 US risk-based guideline works well with satisfied clinical sensitivity for CIN2+ and CIN3+ and seems applicable for cervical cancer screening in China., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.)

Objectives: 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., Methods: 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., Results: 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., Conclusions: 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To evaluate the feasibility of an internet-facilitated community model for cervical cancer screening using self-collected HPV testing as primary screening., Method: A population-based cervical cancer screening program was conducted in the suburb of Shenzhen, China, from September 2014 to July 2017. Women with 25-60 years of age and no pregnancy were eligible for participation. Participants could register for screening by logging in a website by themselves or with the aids of local community workers. A unique barcode was issued to each applicant upon successful registration. After registration, women could get sampling kits from community screening site/study clinic, collect vaginal samples privately or in group, and provide their sample for Hr-HPV tests on Cobas4800 and SeqHPV assays. Testing reports were checkable through personal account for all participant and phone calls were given to all women positive of Hr-HPV. Participants positive of both or either the 2 assays were identified as the positives. The positives could return the study clinic for triage or search medical care in other clinics. Colposcopy directed or ramdom biopsies were performed on all positives who returned to the study clinics., Results: A total of 10,792 community women registered for screening, among whom, 10,010 provided their vaginal samples for tests. 99.5% of the participants were confirmed to have correct personal identifiable information and samples, and 98.9% of them got HPV testing results from both or either assays. No adverse event was reported., Conclusion: When self-collected HPV testing is used as the primary testing, the internet-based data platform facilitates the screening in registration, data collection, and data tracking, and increases the screening coverage. Internet-facilitated community model is promising to cervical cancer control and applicable in regions with variety of resources., (© 2023. The Author(s).)

Objective: To evaluate the safety, tolerability, and efficacy of topical artesunate ointment for treatment of biopsy-confirmed Human papillomavirus (HPV)-associated Vulvar intraepithelial neoplasia (VIN) 2/3., Methods: Participants were enrolled on a prospective, IRB-approved, dose-escalation phase I trial testing either 1, 2 or 3 treatment cycles (5 days), every other week, as applicable. Clinical assessments were completed prior to each dose cycle and included exam and review of adverse event (AE) diary cards. HPV testing and colposcopy was completed at 15 and 28 weeks. AEs were assessed according to CTCAE 4.0 criteria. Complete responders (CR) underwent biopsy of the treated site at the 28-weeks while partial (PR) and non (NR)-responders underwent surgical resection or biopsy and ablation., Results: Fifteen patients consented to and began treatment. Per-protocol assessments were completed in 100% at 15- and 80% at 28-weeks. All patients completed prescribed cycles with no grade 3 or 4 AEs. Vulvovaginal burning/ was the most common AE occurring in 93.3%. AEs were grade 2 in 23.7% and included vulvovaginal pruritus (n = 3), swelling (n = 3) and candidiasis (n = 2). The highest ORR was in the 3-cycle group (88.9% with 55.6% CR). HPV-16 was detected either alone (46.7%) or with other subtypes (33.3%) in 80% of lesions and 5 of 8 (62.5%) with CR had complete viral clearance., Conclusions: Topical artesunate for treatment of high-grade VIN shows high tolerability, low toxicity and evidence for clinical response in this initial small series. The safety and observed responses support further study in a Phase II trial., Competing Interests: Declaration of Competing Interest MP is employed by Frantz Medical Group, JLB has advised and run investigator-initiated clinical trials for multiple biotech companies including many that are involved in HPV related science. Specifically in regards to this study Dr. Belinson serves as a medical advisor to Frantz Viral Therapeutics. Outside of the presented work, CMM has recent/ current stock options/ ownership of MedaSync. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To validate the HPV viral loads that are reflected by the cycle threshold values of Cobas4800 as the viral load indicators by verifying the consistency of the viral loads per unit (10,000 cells) from the BMRT assay., Methods: The analysis is based on data from the Chinese Multi-Center Screening Trial (CHIMUST). The cases included in the analysis are all positive for physician-collected hrHPV on SeqHPV and/or Cobas4800 or negative for hrHPV but abnormal in cytology (≥LSIL), and some cases selected by nested case-control randomization from those negative for physician-collected hrHPV and cytology. With HPV testing results and relevant Ct values from Cobas4800 available, we tested the entire sample set with the BMRT HPV testing assay and analyzed their agreement with Cobas4800, followed by a comparison of the CtV from Cobas4800 and viral loads (lg) from BMRT by lesion grade., Results: We included 4,485 women (mean age: 45.4 years) in the study, and 4,290 had complete data. The consistency of genotypes from Cobas4800 and BMRT for hrHPV, HPV-16, HPV-18, and 12-HPV pools was 94.9% (4070/4290, Kappa = 0.827), 99.1% (4251/4290, Kappa = 0.842), 99.6% (4,273/4,290, Kappa = 0.777), and 95.3% (4,089/4,290, Kappa = 0.821), respectively. Further analysis shows that any inconsistency between the two assays is likely among samples with comparatively lower viral loads. When analyzing per lesions of CIN2+ and CIN3+, the CtV from Cobas4800 and VL (lg) from BMRT are highly correlated inversely and follow the linear regression for HPV16 and 12-HPV pool (Pearson's or Spearman's correlation coefficient (r): In CIN3+, r HPV16 = -0.641, P < 0.001; r 12-HPVpool = -0.343, P = 0.109; In CIN2+, r HPV16 = -0.754, P < 0.001; r 12-HPVpool = -0.429, P < 0.001)., Conclusion: The CtV from Cobas4800 and the viral loads (lg) of per unit cells from the BMRT are well correlated for lesion grading when tested on physician-collected samples. Cobas-CtV is worthy of further study for clinical application., Competing Interests: Author JB was employed by Preventive Oncology International, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Du, Qu, Dai, Gui, Li, Wang, Guo, Zhang, Wei, Belinson and Wu.)

Background: The disparities of hr-HPV infection among races/ethnicities have not been fully discussed. This study aimed to investigate the difference of hr-HPV infection between Chinese Han and Mongols minority women in Inner Mongolia., Methods: Genotyping and histopathology data of Chinese Han and Mongols minority women in Inner Mongolia from Chinese Multi-Center Screening Trial were used to analyze the hr-HPV prevalence, and type-specific distribution in abnormal pathology results., Results: The hr-HPV infection rates of Han women was 15.9% while of Mongols was 21.6% ( P < 0.001). The most prevalent genotypes in Han women were ranked as HPV-16,-52,-18/-58,-31/-39, and-59 while in Mongols were-16,-31,-58,-18 and-52. When analyzing the age-specific of hr-HPV infection, two peaks were found at age of 40-44 (20.5%) and 55-59 (23.5%) years in Han women while three peaks were observed at age of 30-34 (22.1%), 45-49 (22.9%), and 55-59 (31.8%) years, respectively, in Mongols. HPV-16 accounting for 62.5 and 53.8% of the CINII+ in Han and Mongols, respectively., Conclusion: The prevalence of hr-HPV was significantly different between the Han and Mongols minority women in Inner Mongolia, races/ethnicities background should be taken into consideration for the refinement of cervical cancer screening strategies and vaccine implementation in China., Competing Interests: JB was employed by Preventive Oncology International, Inc., and the Cleveland Clinic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guo, Du, Qu, Duan, Li, Li, Jin, Wang, Zhao, Bao, Luo, Wei, Belinson and Wu.)

Background: Asian American women face disproportionate burden of cervical cancer (CC) than non-Hispanic white women in the U.S. The goal of this study was to assess the feasibility and impact of a culturally tailored intervention to promote Human papillomavirus (HPV) self-sampling test among hard-to-reach Asian American women., Methods: We adopted the community-based participatory research (CBPR) approach to conduct this efficacy study. A total of 156 female participants (56 Chinese, 50 Korean, and 50 Vietnamese) were recruited from community-based organizations (CBOs) in the greater Philadelphia metropolitan area. The intervention components included HPV-related education, HPV self-sampling test kit and instructions, group discussions, and patient navigations, all available in Asian languages. We examined several outcomes, including the completion of HPV self-sampling, HPV-related knowledge, perceived social support, self-efficacy, and comfort with the self-sampling test at post-intervention assessment., Results: The majority of Asian American women had low annual household income (62.3% earned less than $20,000) and low educational attainment (61.3% without a college degree). We found significant increase in participants' knowledge on HPV (baseline: 2.83, post: 4.89, P <.001), social support (baseline: 3.91, post: 4.09, P < .001), self-efficacy (baseline: 3.05, post: 3.59, P < .001), and comfortable with HPV self-sample test (baseline: 3.62, post: 4.06, P < .001)., Conclusion: To the best of our knowledge, this is the first intervention study that promoted HPV self-sampling test among Asian American women. Our findings showed that CBPR culturally tailored intervention of self-sampling was highly effective in empowering low-income Asian American women to conduct HPV self-sampling tests.

Objective To investigate the epidemiological characteristics of high-risk human papillomavirus(HR-HPV) infection based on vaginal self-collected samples. Study Design and Setting The pooled data of 3045 self-collected samples used for the analysis derived from four previous studies on cervical cancer screening(The Chinese Multi-Center Screening Trial, CHIMUST; The Shenzhen Cervical Cancer Screening Trial-2, SHENCCAST-2; The Chinese Cervical Cancer Prevention Study, CHIPCAPS; Pingshan trial, PINGSHAN)conducted across China by our team since 2011. These cases were evaluated for HR-HPV type prevalence relative to lesion grade and age. The occurrence of cervical intraepithelial neoplasia(CIN) with specific HPV types and the influence of co-infection is explored. Results The top three most common genotypes among the HR-HPV positives were HPV-52(23.4%), HPV-16(18.0%), and HPV-58(15.50%). For women with CIN2+, the most frequent genotypes were HPV-16, 58, 52, and 18 in sequence. HPV-16 accounted for the majority of CIN2/CIN3/Ca with attribution rate of 23.86%, 44.78% and 50.00% respectively. HPV-58 accounted for 19.48%, 16.79% and 13.46% respectively. CIN2+ was found in the following types most frequently: HPV-16(31.23%), HPV-33(24.03%), HPV-58(18.41%), HPV-31(11.76%), HPV-18(7.75%), and HPV-52(7.30%). HPV-16 showed preference for co-infection with HPV-52 and HPV-58. Conclusion The prevalence of HR-HPV infection based on self-sampling among women in China exhibited some unique epidemiologic features., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The performance of Cobas4800 cycle threshold value (Ct-value, reflecting viral load) combined with human papillomavirus (HPV) 16/18 genotyping was explored as a method of risk stratification to triage patients after primary HPV screening of self-collected samples., Methods: The Chinese Multi-site Screening Trial database was reviewed, with focus on self-collected samples, using the results of Cobas4800 HPV assay. Quartiles of Ct-values of each genotype were used for grouping and developing screening algorithms. Diagnostic accuracy for paired comparisons between algorithms was obtained using McNemar's test., Results: A total of 10,498 women were included. The Ct-values of HPV16 and other high-risk HPV were inversely correlated with the severity of cervical lesions ( p  < 0.001). Risks for cervical intraepithelial neoplasia (CIN2+/CIN3+) were significantly stratified by Ct-values from channels detecting HPV16 and other high-risk HPV types. "HPV with HPV16/18 and reflex Ct <33.7" (algorithm G) achieved a favorable sensitivity to "HPV with atypical squamous cells of undetermined significance or worse (≥ASCUS)" (81.9% vs. 70.1% for CIN2+, p  < 0.001), a comparable sensitivity to "HPV with HPV16/18 reflex cytology ≥ASCUS" (81.9% vs. 81.3% for CIN2+, p  > 0.05), and resulted in a slightly lower specificity than the latter two algorithms (92.6% vs. 97.4% and 95.4% respectively for CIN2+, p  < 0.05). However, algorithm G achieved a comparable sensitivity to HPV testing alone for CIN3+, and reduced the colposcopy referral rate from 13.7% for HPV testing alone to 8.4%., Conclusions: HPV viral loads reflected by Ct-values are associated with the severity of cervical lesions. Ct-values with an appropriate cut-off of 33.7, combined with HPV16/18 genotyping, represent a promising triage of HPV-positive women particularly for self-collected samples.

Objective: Self-sampling for human papillomavirus (HPV) testing is an effective option to increase the cervical screening coverage. How to best triage HPV-positive self-samples remains controversial. Here, we evaluated the performance of a novel p16 INK4a immunocytology approach (p16) and HPV genotyping in triaging HPV-positive self-samples., Methods: A cohort of 73699 women were screened via SeqHPV assay on self-samples. HPV-positive women who met any sequential positive result of HPV16/18 or VIA or p16 were referred for colposcopy. A triage strategy was considered favorable if the NPV for CIN3+ was ≥98%, combined with an improvement of sensitivity and specificity in comparison to the comparator, being the 'ASC-US+' triage and the guideline strategy (HPV16/18+ or ASC-US+)., Results: A total of 3510 HPV-positive women were included, 422 (12.0%) CIN2+ and 247 (7.0%) CIN3+ were identified. The positivity of p16 and ASC-US+ were 36.3% and 22.2%, respectively. p16 was more sensitive and less specific than ASC-US+ (P < 0.0001). However, when combined p16 with cytology or genotypes, two triage strategies were superior to the 'ASC-US+' strategy: p16 scored 3+; HPV16/33/58/31+ &p16+. Moreover, four strategies were favorable to the guideline strategy: ASC-US+ or p16+; LSIL+ or p16+; HPV16+ or p16+; HSIL+ or p16+ or HPV16+. These strategies achieved better balance between diseases detection and colposcopy referral., Conclusions: Our findings indicate the promising utility of p16 immunocytology via adjusting the staining score or serving as an ancillary tool to liquid-based cytology or combining with genotyping for the triage of HPV-positive self-samples, which promotes the precise screening of cervical cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate the efficacy of high-risk HPV (HR-HPV) genotyping with vaginal self-sampling in primary screening and combining cytology or viral load for HR-HPV positive as secondary screening strategies. Methods: The data referring to HR-HPV genotyping of self-collected sample with mass array matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS), HR-HPV viral load of physician-collected sample with hybrid capture Ⅱ (HC-Ⅱ), liquid-based cytology and histology of 8 556 women were from Shenzhen cervical cancer screening trial Ⅱ (SHENCCAST-Ⅱ) conducted between April 2009 and April 2010. The data were reanalyzed to determine the sensitivity and specificity to cervical intraepithelial neoplasia (CIN) of grade 2 or worse (CIN Ⅱ + ), CIN of grade 3 or worse (CIN Ⅲ + ) when HR-HPV genotyping combining with colposcopy as primary screening strategy based on varied HR-HPV subtype (strategy 1, including 5 sub-strategies: 1a: HPV 16/18 positive; 1b: HPV 16/18/58 positive; 1c: HPV 16/18/58/31/33 positive; 1d: HPV 16/18/58/31/33/52 positive; 1e: any HR-HPV positive). The data were also compared to determine the efficacy of cytology (strategy 2, including 5 sub-strategies: 2a, 2b, 2c, 2d, 2e) or HR-HPV viral load (strategy 3, including 4 sub-strategies: 3a, 3b, 3c, 3d) of physician-collected sample as a triage with HR-HPV genotyping for self-sampling HR-HPV positives. Results: (1) The HR-HPV positive rate was 13.77% (1 178/8 556) in the self-collected samples of 8 556 pregnant women. Of them,the prevalences of HPV 16/18, HPV 16/18/58, HPV 16/18/58/31/33 and HPV 16/18/58/31/33/52 were 3.16% (270/8 556), 5.14% (440/8 556), 6.66% (570/8 556) and 9.81% (839/8 556), respectively. The HR-HPV viral load ≥10 relative light units/control (RLU/CO) was 8.87%(759/ 8 556), while cytological results ≥atypical squamous cell of undetermined signification (ASCUS) were 12.05% (1 031/8 556). (2) The strategy 1e had the highest sensitivities for CIN Ⅱ + , CIN Ⅲ + which were 92.70% and 94.33%,respectively,among 14 sub-strategies,while the lowest specificity and positive predictive value (PPV). Meanwhile,the required colposcopy referral rates were much higher than other 13 sub-strategies (13.77%). The other 4 sub-strategies of strategy 1 (1a, 1b, 1c, 1d), strategy 1a had the highest specificities for CIN Ⅱ + and CIN Ⅲ + (97.92%, 97.69%, respectively), while 1d had the highest sensitivities for CIN Ⅱ + and CIN Ⅲ + (88.41%, 92.20%, respectively). (3) Both strategies of referring self-sampling HPV 16/18 positives for immediate colposcopy followed by triage physician-collected sample cytology (≥ASCUS) or viral load (≥10 RLU/CO) for non-HPV 16/18 positives had significantly higher sensitivity and specificity for CIN Ⅱ, CIN Ⅲ + , as well as lower referral rates (strategy 2a and 3a). Additionally, based on these two secondary screening strategies, cumulatively using the other four HR-HPV (HPV 58, 31, 33 and 52) positives as triage for immediate colposcopy showed an enhanced sensitivity. Conclusions: Primary HR-HPV cervical cancer screening strategy based on self-sampling with triage of cytology (≥ASCUS) or viral load (≥10 RUL/CO) provides a good balance among sensitivity, specificity for CIN Ⅱ + and CIN Ⅲ + and the number of tests required, referral rates. The efficacy of HR-HPV genotyping combining cytology or viral load secondary screening strategies will have a spiral escalation when HPV 58, 31, 33, 52 are included.

Objective: To assess the prevalence and distribution of HPV genotypes among Chinese Han women, and to explore the risk of high-grade cervical lesions associated with individual hr-HPV genotypes., Methods: Genotyping and histopathology data from the Chinese Multi-Center Screening Trial (CHIMUST) and its pilot screening trial, from 6 regions across mainland China, were re-analyzed. The data from physician- and self-collected samples from 10,867 Chinese Han women (ages 30-69) were used to determine the prevalence and distribution of hr-HPV and to explore the risk association between hr-HPV genotypes and precancerous lesions., Results: 9.2% of the study population tested hr-HPV positive in physician-collected sample. The prevalence varied regionally from the lowest in Guangdong (6.3%) to the highest in Inner Mongolia (13.0%). The most prevalent genotypes found were HPV-52 (21.7%), HPV-16 (19.2%), HPV-58 (15.0%), HPV-39 (8.9%), and HPV-51 (8.2%). The overall odds ratios for CIN2+ and CIN3+ for the presence of HPV-16 was 58.6 (95% CI 39.2-87.5) and, 91.6 (95%CI 54.3-154.6), respectively and remained the highest odds ratio for CIN3+ in all 6 regions., Conclusion: Geographical variation exists in the prevalence and distribution of hr-HPV in mainland China. HPV-16/52/58 were the most prevalent genotypes, and HPV-16 had the highest risk for high-grade cervical lesions., Trial Registration: CHIMUST, Registration number: ChiCTR-EOC-16008456 . Registered 11 May 2016.

Aim: To compare thermocoagulation and cryotherapy for treatment of high-grade cervical intraepithelial neoplasia (CIN)., Methods: From May 2017 to May 2018, women with CIN2/3 were randomized to thermocoagulation or cryotherapy at Peking University Shenzhen Hospital. Follow-up at 4 and 8 months included cytology and human papillomavirus (HPV) testing. Women who were HPV-positive or had atypical squamous cells of undetermined significance or higher-grade disease underwent colposcopy/biopsy., Results: Among 149 women enrolled, 74 were randomized to thermocoagulation, and 75 to cryotherapy (excluded four were immediately referred for thermocoagulation due to large lesions). At follow-up, there was no difference between the thermocoagulation and cryotherapy groups in HPV-negative (4/8 months: 72.5%/86.2% vs 68.6%/80.6%) and pathology-negative (97.1%/98.5% vs 94.3%/92.3%) rates (all P > 0.05). The cytology-negative rate was similar for thermocoagulation and cryotherapy at 4 months (79.7% vs 78.9%, P > 0.05), but higher for thermocoagulation at 8 months (100% vs 88.7%, P < 0.05). No lesions were observed among the four referral women at follow-up. As compared with cryotherapy, thermocoagulation was associated with shorter duration of treatment and less vaginal discharge, but higher pain during application and longer bleeding after treatment., Conclusion: Thermocoagulation was as effective and safe as cryotherapy and might be easily applied to treat high-grade cervical lesions., (© 2020 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Objective: The aim of the study was to evaluate the Cobas 4800 Assay and the SeqHPV Assay with self (S) and direct (D) cervical samples in the Chinese Multicenter Screening Trial (CHIMUST)., Materials and Methods: The CHIMUST is a large population-based multicenter clinical trial, and 10,885 women aged 30-59 years from 15 sites in 7 provinces with no cervical cancer screening for 3 years were eligible. All participating women contributed one self-collected sample (S) and 1 physician-collected endocervical sample (DL). The self-collected sample was first applied to the solid media transport card (SS), and then, the brush placed in 6 mL of ThinPrepSolution (SL). All samples were tested with Cobas 4800 and SeqHPV high-risk HPV assays. Patients human papillomavirus positive (self or direct) were recalled for colposcopy and biopsies., Results: A total of 10,399 women had complete data. The mean age was 43.9 years. A total of 1.4% (142/10,399) had cervical intraepithelial neoplasia (CIN) 2+ and 0.5% (54/10,339) had CIN 3+. In the liquid specimens, the overall HPV infection rates were 10.8% for Cobas and 10.9% for SeqHPV in D sample, and 13.7% for Cobas and 11.6% for SeqHPV in SL sample, respectively. The sensitivity of Cobas-DL, Cobas-SL, SeqHPV-DL, and SeqHPV-SL for CIN 2+ was 95.07%, 95.07%, 94.33%, and 96.48%, respectively. The specificity of Cobas-DL, Cobas-SL, SeqHPV-DL, and SeqHPV-SL for CIN 2+ was 90.38%, 87.35%, 90.21%, and 89.53%, respectively. There were no differences in sensitivity when applying the 2 assays to both self- and directly collected samples in liquid transport media (p > .05)., Conclusions: Both Cobas and SeqHPV screening assays using both self-collected and directly endocervical collected specimens demonstrate similar sensitivity for the detection of CIN 2+ and CIN 3+., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2020, ASCCP.)

Background: The solid transport media is a small size card that allows fast, easy DNA extraction from a variety of biological samples. In 2016 we developed a solid media transport card; for that pilot study to control the self-collection we used a pseudo-self-collection technique. The current study expands this prior work using true self-collections and only the POI card, and aims to evaluate the solid media transport card to detect HR-HPV in self-samples compared to liquid transport media., Methods: Ten thousand eight hundred eighty-five women between the ages of 30-59 with no screening for 3 years were enrolled. The self-collected sample was first applied to a new solid media transport card (Labeled as SC) then the brush placed in 6 ml ThinPrep liquid (Labeled as SL). Then a physician collected a direct endocervical specimen into ThinPrep liquid (Labeled as DL). Samples were tested with Cobas 4800 and the SeqHPV NGS assay for HR-HPV. Patients positive on any test were recalled for colposcopy and biopsy., Results: Ten thousand three hundred thirty-nine participants had complete data. The mean age was 43.9 years. CIN 2+ rates were 1.4% (142/10339). The agreement in HPV detection between the two different self-sample collection media was also good (Cobas HPV kappa = 0.86; SeqHPV kappa = 0.98). Tested with Cobas, the sensitivity of Cobas-SL and Cobas-SC for CIN 2+ was95.07 and 94.37%; and for CIN3+ was 96.30, 96.30% respectively. The specificity of Cobas-SC, and Cobas-SL for CIN2+ was 88.74 and 87.35%; for CIN3 was 88.04and 86.65% respectively. Tested with SeqHPV, the sensitivity for CIN2+ of Seq-SC and Seq-SL was 95.77 and 96.48%; for CIN3+, both the SC and SL specimens had a sensitivity of 100%. The specificity for CIN2+ of Seq-SC and Seq-SL was 89.54 and 89.53%; for CIN3+ was 88.84,88.82% respectively. For both HR-HPV assays, the sensitivities were similar for the two self-sample media (SC vs SL, p = 1.00)., Conclusions: The solid transport card for collecting vaginal self-samples as accurate as liquid transport media assayed by two different PCR based HR-HPV tests. The solid transport media is a suitable medium for collecting and storing vaginal self-samples.

Objective: The aim of this research was to evaluate independently the performance of a new isothermal amplification assay for cervical cancer screening compared to two previously validated PCR-based assays and histologic endpoints., Methods: This is a sub-study from the Chinese multi-center screening trial (CHIMUST). The self-collected and clinician-collected specimens stored in PreservCyt at - 4 °C from 6042 women with complete data were tested with the AmpFire assay. These specimens had been previously tested with Cobas and SeqHPV assays. In the primary study all patients with an abnormal test were referred to colposcopy where all had directed and/or random biopsies plus ECC. No additional patients were called back based on the AmpFire results., Results: 6042/6619 women had complete data (mean age 44.1). There were 57 cases of CIN 2, 35 cases of CIN 3 and 2 cancers. The sensitivity for CIN2+ and CIN3+ were similar among the three assays (both direct and self-collected). For the specificities in all categories (CIN2+/CIN3+ and self and direct collection), isothermal amplification assay was either equal to or more specific than Cobas but consistently less specific than SeqHPV., Conclusion: The AmpFire HPV assay showed similar sensitivity to Cobas and SeqHPV for CIN2+ and CIN3+ on both self and clinician-collections ( P >0.05), with good specificity. The speed, low cost, and simplicity of this assay will make it particularly suited for low and middle resource settings. Its accuracy with self-collection makes it applicable for mass screening programs., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2020.)

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ ( P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test-negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities., (©2020 American Association for Cancer Research.)

Purpose: When used for cervical cancer primary screening, liquid-based cytology (LBC) has a high specificity but a low sensitivity. For histological diagnosis of high-grade lesions, p16 INK4a immunostaining has proven to be useful. Therefore, our objective was to evaluate the use of p16 INK4a immuno-cytology as a primary screen and a secondary screen after primary high-risk human papillomavirus (hrHPV) screening or LBC screening., Methods: A total of 1197 cytology slides were immuno-stained using automatic p16 INK4a staining system (PathCIN ® p16 INK4a ) in two studies from cervical screening programs. In the primary screening study, 875 slides were randomly selected and analyzed for p16 INK4a . In the secondary screening study, 322 of the remaining slides were chosen by virtue of being HPV 16/18+, other hrHPV+/LBC≥ASC-US, or HPV-negative/LBC ≥LSIL. The sensitivity and specificity for detection of cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+) were compared based on p16 INK4a , LBC and HPV test results., Results: In combining two studies, there were 431 cases with biopsy pathology. They included 83 cases with CIN2+ and 41 cases with CIN3+. The p16 positivity rate increased with pathologic and cytologic severity (P<0.0001). For primary screening: p16 immuno-cytology was more specific than HPV testing and was similar in sensitivity. Also, p16 immuno-cytology compared favorably with routine LBC (≥ASC-US or ≥LSIL) in sensitivity and specificity. For secondary screening: after LBC screening, "Triaging ASC-US with p16" gave a higher specificity and a similar sensitivity as compared to the "Triaging ASC-US with hrHPV" algorithm. After HPV primary screening, p16 immuno-cytology was more specific than LBC (≥ASC-US); the calculated colposcopy referral rate was also decreased by using p16 immuno-cytology as triage. Triage of "HPV16/18 and p16" had higher specificity and similar sensitivity as compared to triage of "HPV16/18 and LBC ≥ASC-US"., Conclusion: For primary screening, p16 INK4a immuno-cytology compares favorably to routine LBC and HPV testing. p16 INK4a immunostaining could be an efficient triage to reduce the colposcopy referral rate after primary hrHPV screening or LBC screening. Therefore, p16 INK4a immuno-cytology may be applicable as a favorable technology for cervical cancer screening., Competing Interests: The authors declare that they have no competing interests for this work., (© 2020 Song et al.)

Objective: To explore the relationship between the viral load reflected by the Ct value of Cobas 4800 HPV test and cervical lesions, and the effectiveness of the viral load for secondary triage of HPV-positive women., Methods: The Chinese Multi-Center Screening Trial (CHIMUST) evaluated both self-collected samples and physician-collected samples from women, aged 30 to 59, who were screened for cervical cancer in 6 regions across China. Using physician collected samples, the relationship between the HPV-Ct values of different subtypes and the cervical lesions was analyzed. Then the combined use of the HPV-Ct values with the HPV subtypes was evaluated as a secondary screening algorithm for the women who were HPV positive., Results: The Ct values of HPV16 and 12 other HPV subtypes(12-type pool), tested with Cobas decreased with the progression of cervical lesion (HPV16: r = -0.429, P<0.001; 12 other HR-HPV subtypes: r = -0.099, P<0.01). The HPV18-Ct value was not correlated with cervical lesion(P>0.05). Compared with HPV16/18 and cytology (HPV16/18 positive and 12-type pool plus cytology ≥ ASC-US), the sequential secondary screening using HPV16/18 and the viral load of 12-type pool (cut-point HPV-Ct≤31) had equal sensitivities for CIN2+ and CIN3+ (83.1%vs.80.3%,100%vs.92.6%,P>0.05), with slightly lower specificities (96.2%vs.94.4%,96.5%vs.93.9%,P<0.001) and higher colposcopy referral rate (4.90%vs.6.59%, P<0.05), but required no cytology., Conclusion: Type-specific HPV viral load is closely related to cervical lesions severity. It is feasible and efficient to use HPV16/18 and the viral load of 12 other HPV subtypes (with cut-point HPV-Ct≤31) as the secondary screening for HPV positive women. This algorithm may be useful in low resource regions., Competing Interests: Jerome L. Belinson is an expert in the research, and the entire research has no commercial interest relationship with his POI. POI did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: Evaluate the significance of BMRT HPV assay viral load and its performance for secondary screening., Methods: BMRT-HPV reports type-specific viral loads/10,000 cells. We tested 1,495 physician collected, stored specimens from Chinese Multiple-center Screening Trial (CHIMUST), that were positive by Cobas, SeqHPV, and/or Cytology (≥LSIL); and 2,990 age matched, negatives in a nested case control study. We explored the relationship between BMRT HR-HPV viral load and cervical lesions, determined alternative CIN2+ cut-points by ROC curve, and evaluated BMRT HR-HPV for primary / secondary cervical cancer screening., Results: The viral loads of HPV16/18, 12 other subtypes HR-HPV and 14 HR-HPV were statistically different in all grades of cervical lesions (P<0.05, among which HPV16, 33 and 58 showed the strongest relationship (P<0.01). The viral load of HR-HPV also increased with the grade of cervical lesions (P<0.05). The sensitivity for CIN2+ and CIN3+ of BMRT was comparable to Cobas (92.6% vs 94.3%, 100% vs 100%, P>0.05), specificity was higher than Cobas (84.8% vs 83.3%, 83.5% vs 82.0%, P<0.001). When using HPV16/18 viral load(log cut-point ≥3.2929), plus the viral-load of 12 other subtypes (log cut-point ≥3.9625) as secondary triage, compared with Cobas HPV16/18+ plus cytology ≥ASC-US as triage, the sensitivities for CIN2+ and CIN3+ were similar (P>0.05). However, the BMRT HR-HPV viral load combined with subtypes did not require cytology., Conclusion: BMRT is as sensitive as Cobas4800 for primary cervical cancer screening. BMRT HR-HPV viral load combined with subtypes can be used as a secondary strategy for cervical cancer screening, especially for areas with insufficient cytological resources., Competing Interests: JLB is affiliated with Preventive Oncology International, Inc, OH. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have declared that no other competing interests exist

Objective: The aim of the study was to determine which women require loop electrosurgical excision procedure (LEEP) or cervical conization (cone) to exclude cervical cancer after colposcopy for evaluation of abnormal cervical cancer screening tests yet before simple hysterectomy., Materials and Methods: Review of electronic medical records from colposcopy clinics followed by chart review of women with cervical cancer was conducted., Results: Of 18,537 cervical colposcopies for evaluation of abnormal cervical cancer screening tests, 0.6% (103/18,537) had cervical cancer; of 103 women with cervical cancer, 57 had neither cervical biopsy nor endocervical curettage (ECC) showing cancer or rule-out cancer (occult cancers) and were diagnosed by subsequent LEEP (n = 22), cone (n = 31), failed cone (n = 1), or hysterectomy (n = 3). The relative risk of occult cervical cancer at colposcopy for ECC of cervical intraepithelial neoplasia (CIN) 2 or CIN 3 versus ECC not CIN 2 or CIN 3 was 51.5 (5.0% vs 0.1%), for cervical biopsy of CIN 3 versus not CIN 3, was 34.5 (3.9% vs 0.1%), and for colposcopic impression of CIN 2, CIN 3, or cancer (CIN 2+) versus impression not CIN 2+, was 8.5 (1.9% vs 0.2%). If the 10.9% (2,018/18,537) of colposcopies with ECC of CIN 2 or CIN 3, cervical biopsy of CIN 3, or colposcopic impression of CIN 2+ had subsequent LEEP or cone, 96.5% (55/57) of occult cervical cancers would be detected before hysterectomy., Conclusions: After colposcopy, women with ECC of CIN 2 or CIN 3, cervical biopsy of CIN 3, or colposcopic impression of CIN 2+ require LEEP or cone before simple hysterectomy.

Objective: The aim of the study was to assess whether lower proportions of cervical intraepithelial neoplasia 2+ diagnosed by random biopsy are from lower cut points defining an abnormal colposcopic impression or obtaining only one random biopsy when colposcopic impression is normal., Methods: We compared colposcopy experiences within Shanxi Province Cervical Cancer Screening Study (SPOCCS) (n = 1,383) and Shenzhen Cervical Cancer Screening Trial (SHENCCAST) (n = 631), which had instructive differences in the cut point defining an abnormal colposcopic impression., Results: The proportion of CIN 2+ diagnosed by random biopsy in SPOCCS (35.0%, 141/403) was higher than SHENCCAST (18.4%, 35/190, p < .001). Quadrant-specific receiver operating characteristic curves for diagnosis of CIN 2+ by colposcopic impression in SPOCCS and SHENCCAST were similar; a lower cut point for an abnormal colposcopic impression in SHENCCAST resulted in lower proportion of CIN 2+ diagnosed by random biopsy. Normal colposcopic impression was found in 85.1% (120/141) of cases of CIN 2+ diagnosed by random biopsy in SPOCCS and in 57.1% (20/35) of such cases in SHENCCAST. Of CIN 2+ diagnosed by random cervical biopsy with normal colposcopic impression, one cervical quadrant was involved with CIN 2+ in 66.7% (80/120) of colposcopies in SPOCCS and 80% (16/20) of colposcopies in SHENCCAST., Conclusions: Colposcopy series with higher proportions of CIN 2+ diagnosed by random biopsy likely have more stringent cut points defining an abnormal colposcopic impression and have more random biopsies when the colposcopic impression is normal. At colposcopy, we advise multiple biopsies of all acetowhite epithelium or multiple random biopsies to increase the sensitivity of colposcopy.

Background: Correlation with HPV viral load and worsening cervical lesions had been reported, but its potential for triage after primary HPV screening has not been adequately explored, especially when combined with HPV-16/18 genotyping., Objective: To evaluate combinations of human papillomavirus (HPV) viral load and genotyping for HPV-16/18 as secondary screening strategies., Methods: The Shenzhen Cervical Cancer Screening Trial Ⅱ (SHENCCAST Ⅱ) database was re-analyzed to explore new screening algorithms using the results of Hybrid Capture 2 (HC2), Mass Array Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass spectrometry System (MALDI-TOF-MS) and the ThinPrep cytologic test (TCT) obtained by endocervical sampling., Results: Compared with the recommended screening strategy of genotyping HPV-16/18 plus reflex to cytology, using viral load (10 RLU/CO as threshold) plus reflex to cytology resulted in less cytology but had a significantly higher sensitivity for cervical intraepithelial neoplasia 2+ (CIN2+)/CIN3+ without considerable changes in specificity and referral rates. Both of the strategy of using viral load ≥10 RLU/CO as cut-point for immediate colposcopy followed by triage genotyping HPV-16/18 for the other positive (≥1<10 RLU/CO) and the strategy of referring HPV-16/18 positives for immediate colposcopy followed by triage viral load (10 RLU/CO as threshold) for non-HPV-16/18 positives had comparable screening efficacy with algorithims that contain cytology., Conclusions: Primary HPV screening with triage of HPV-positive women by a combination of viral load and genotyping for HPV-16/18 provides good balance between sensitivity and specificity, the number of tests required, and referral rates., Competing Interests: The authors have declared that no competing interests exist.

The goal of this study was to use the biomarkers human papillomavirus (HPV) L1 and p16 to develop an algorithm that could triage the individual patient with CIN1 at risk for progression. A total of 82 patients initially diagnosed with CIN1 at Peking University Shenzhen Hospital in China had their initial and follow-up paraffin-embedded tissue blocks immune-stained for HPV L1 capsid protein and p16. For CIN1, any staining of abnormal epithelium was considered positive. All patients were followed until they developed CIN2+ or for ≥3 years. About 38 patients regressed (HPV-, Cytology-), 17 persisted (CIN1), and 27 progressed (≥CIN2+). At initial diagnosis, HPV L1 capsid protein was expressed in 42.7% of the CIN1 cases. There was no difference in L1 expression among the 3 groups. However, p16-positive staining in the progression group was significantly higher than in the regression group (P<0.05). In the regression group, the proportion of HPV L1-/p16- category was significantly higher than that in the progression group. In the progression group, when CIN1 lesions progressed to CIN2+, the L1-positive rate was significantly decreased from 51.9% to 18.5%, the p16+/HPV L1+ rate decreased from the initial (44.4%) to the final diagnosis (14.8%), and the p16+/HPV L1- rate increased from the initial (25.9%) to the final diagnosis (66.7%). P16 expression is a clear risk factor for the progression of CIN1. The p16-/HPV L1- pattern was significantly associated with the regression of CIN1. Moving from CIN1 to CIN2+ over time, p16+/HPV L1+ decreased, and p16+/HPV L1- increased. Unfortunately, our objective of finding a sensitive and specific triage algorithm for the individual patient with CIN1 was not achieved.

Background: High-risk human papillomavirus (hrHPV) testing to triage women with minor cervical lesions generates many referrals., Purpose: To evaluate the accuracy of genotyping for HPV types 16 and 18 and its utility as a second triage step after hrHPV testing in women with minor cervical lesions., Data Sources: Searches of 4 bibliographic databases, without language restrictions, from 1 January 1999 to 1 February 2016., Study Selection: Studies involving women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) who were triaged with tests for hrHPV and HPV 16/18 to find cervical intraepithelial neoplasia (grade ≥2 [CIN2+] or grade ≥3 [CIN3+])., Data Extraction: Independent study selection, extraction of data, and quality assessment by 2 reviewers., Data Synthesis: Twenty-four moderate- to good-quality studies involving 8587 women with ASC-US and 5284 with LSIL were found. The pooled sensitivity of HPV 16/18 genotyping for CIN3+ was about 70% for women with either ASC-US or LSIL. The pooled specificity (with a threshold of grade <2 CIN) was 83% (95% CI, 80% to 86%) for women with ASC-US and 76% (CI, 74% to 79%) for those with LSIL. The average risk for CIN3+ was 17% and 19% in HPV 16/18-positive women with ASC-US and LSIL, respectively, and was 5% in hrHPV-positive but HPV 16/18-negative women with either ASC-US or LSIL., Limitation: Methodological and technical heterogeneity among studies; insufficient data to assess accuracy of separate assays., Conclusion: Testing for HPV 16/18 to triage women with minor abnormal cytology is poorly sensitive but may be useful as a second triage test after hrHPV testing, with direct referral if the woman is positive for HPV 16/18. Whether colposcopy or repeated testing is recommended for hrHPV-positive but HPV 16/18-negative women depends on local decision thresholds that can be derived from pretest-posttest probability plots., Primary Funding Source: 7th Framework Programme of the European Commission.

Objective: The aim of the study was to evaluate the human papillomavirus (HPV) viral load combined with cytology as a secondary screening strategy after primary HPV screening., Materials and Methods: The data referring to direct Hybrid Capture 2 (HC2), cytology, and histology from Shenzhen Cervical Cancer Screening Trial II were re-analyzed to determine the correlation between viral load and cervical lesions. In addition, algorithms using different viral loads as cut points for immediate colposcopy plus cytology triage were compared with several recommended or controversial primary screening methods., Results: A total of 8,556 women with a mean age of 38.9 years were included in the analysis, of which 13.67% tested high-risk HPV positive with a prevalence of 2.72% for cervical intraepithelial neoplasia 2+ (CIN 2+) and 1.65% for CIN 3+. A significant correlation was observed between increasing relative light units/control (RLU/CO) values and worsening cervical lesions. The mean RLU/CO values for negative, CIN 1, CIN 2, CIN 3, and cancer were 6.86, 119.43, 410.90, 449.39, and 853.26, respectively. A larger proportion of HPV infections with relative high viral load (≥10 RLU/CO) were found in higher-grade lesions. The algorithm using 10 or greater RLU/CO as cut point for immediate colposcopy followed by triage cytology for the other positive (≥1 < 10 RLU/CO) had sensitivity of 93.13%/96.45% and specificity of 92.32%/91.44% for CIN 2+/3+, and the colposcopy referral rate was 10.00%., Conclusions: Human papillomavirus viral load level is positively associated with cervical lesion grade. Ten relative light units/control or greater is a viable threshold for immediate colposcopy whereas 1 or greater or less than 10 RLU/CO is advised to reflex cytology for optimizing sensitivity and specificity, as well as referral rates.

Objective: The aim of the study was to determine whether p16 positive/cervical intraepithelial neoplasia (CIN) 2, 3, and cancer (p16 + CIN 2/3+) detected by colposcopy-directed or random biopsy differ by age, referral cytology, human papillomavirus (HPV) 16, and lesion size., Materials and Methods: Data from the Shenzhen Cervical Cancer Screening Trial II where, at colposcopy, women who had directed and random cervical biopsies were reviewed to find women with CIN 2, 3, or cancer; 227 such women identified had their paraffin-embedded tissue blocks recut, reviewed, and then immune stained for p16. Data were analyzed by χ, Fisher exact test, and linear regression., Results: After histopathologic review and p16 staining of CIN 2, 175 women were diagnosed with p16 + CIN 2/3+. When compared with those diagnosed by colposcopy-directed biopsy (n = 138), those diagnosed by random biopsy (n = 37) were more likely to have Cytology-Lo (cytology of negative, atypical squamous cells of undetermined significance, or low-grade squamous intraepithelial lesion; p = .07), less likely to have HPV 16 (p = .041), more likely to be 51 years or older (p = .022), and more likely to have 1 quadrant lesions (p < .001). Logistic regression analysis showed p16 + CIN 2/3+ diagnosed by random biopsy was predicted by 1 quadrant lesions (p < .0001) and age of 51 years or older (p = .03) but not by Cytology-Lo (p = .71) nor HPV 16 (p = .26)., Conclusions: Women with p16 + CIN 2/3+ diagnosed by random biopsy are older and less likely to have HPV 16; hence, CIN diagnosed by random biopsy may not be as virulent as CIN diagnosed by colposcopy-directed biopsy. Regardless, we advise that CIN diagnosed by random biopsy be viewed like CIN diagnosed by colposcopy-directed biopsy.

Objective: The aim of this study was to determine if there is a different p16 expression pattern between colposcope-directed and random (colposcope-undetectable) biopsies of cervical intraepithelial neoplasia (CIN2) and CIN3., Methods: Cervical biopsies that were positive for CIN2 or CIN3 were selected from a database of samples acquired during a large population-based clinical trial in Guangdong Province in China (Shenzhen Cervical Cancer Screening Study II). Blocks were recut, reread, and then immunostained for p16. Biopsies were categorized as either colposcope-directed or random biopsies. Diffuse staining was considered p16 positive, whereas focal or no staining was considered p16 negative. Differences were determined by the Fisher exact test., Results: Among the patients with CIN3, there were 232 individual biopsies of CIN3. Sixty were randomly collected, and 172 were colposcopy directed. p16 positivity for the colposcope-directed and random biopsies was 97.7% and 91.7%, respectively (p = 0.052). Like the CIN3 biopsies, colposcope-directed and random CIN2 samples expressed p16 similarly (86.8% [46/53] and 82.6% [19/23], p = .73, respectively)., Conclusions: Based on our data, even small colposcope-undetectable biopsies of CIN3 are significant. Random biopsies of CIN2 or CIN3 demonstrate similar p16 positivity as visible lesions and therefore might be expected to have a similar natural history.

Objective: To exploit the prevalence of HPV genotypes 52/58 in a Chinese population, we evaluated algorithms that the use the Cervista Assay A9 group for primary cervical cancer screening., Methods: The SHENCCAST II trial database was re-analyzed, focussing on the A9 pool of the Cervista HR-HPV Assay. Results for the detection CIN2+ and CIN3+ were correlated with a genotyping assay (MALDI-TOF) and cervical cytology to explore various screening algorithms., Results: This analysis included 8,556 women with a mean age of 38.9. CIN 2+ rates were 2.7% (233/8556); CIN 3+ rates were 1.7% (141/8556). Overall HPV infection rates were 11.1% (950/8556) for Cervista, in which A5/A6, A7 and A9 groups were 26.5% (227/950), 22.9% (218/950) and 67.8% (644/950), respectively. The HPV A9 group is highly predictive of high-grade cervical lesions (CIN2+ OR = 103.61, CIN3+ OR = 128.059). Sensitivity and specificity for Cervista A9 group for CIN 2+ was 85.4% and 94.7%, and for CIN 3+ 89.4% and 93.8% respectively. Cervista A9 Assay followed by triage cytology for non-A9 positives has sensitivity and specificity for CIN2+ of 91.5% of 93.5%, and for CIN 3+ 94.3% and 92.6%., Conclusion: Using the Cervista A9 as the primary screen instead of the full Cervista assay, the percentage referred to colposcopy would decrease from 11.1% to 8.8% and percentage requiring cytology would decrease from 11.1% to 3.6%. Sensitivity of detecting CIN 2+(91.5%), CIN3+(94.3%) would remain similar to the complete Cervista HR-HPV assay for CIN 2+(93.1%), CIN3+(95.0%)., (© The Author(s) 2015.)

Objectives: Determine the ability of the Cobas 4800 assay to detect high-risk human papillomavirus (HrHPV) and high-grade cervical lesions when using cervico-vaginal samples applied to liquid medium and solid media cards compared to a direct cervical sample., Methods: Two cervico-vaginal specimens (pseudo self-collected) were obtained from 319 women. One was applied to an iFTA Card (FTA) then the brush placed in liquid-based medium (LSELF); the other was applied to a new solid media: POI card (POI). The clinical performance of Cobas4800 assay using the three aforementioned specimens was compared to direct collected endocervical specimens in liquid media (LDOC)., Results: The overall agreements of HrHPV detection were 84.2% (LSELF vs. LDOC), 81.0% (FTA vs. LDOC), and 82.3% (POI vs. LDOC). LSELF, FTA and POI identified 98.0%, 79.6%, and 97.5% positive cases of LDOC. Sensitivity to identify CIN2+ were 98.4% (LSELF), 73.8% (FTA), 95.1% (POI), and 93.4% (LDOC) respectively. FTA had 78.1% and 90.4% agreement with the LSELF samples for all HrHPV and HPV16/18 detection respectively, while POI had 91.6% for both., Conclusions: Cobas4800 HPV test combined with cervico-vaginal specimens applied to both liquid media and POI solid card are accurate to detect HrHPV infection and high-grade cervical lesions as compared with direct endocervical samples in liquid media.

Objectives: The aims of the study were to examine barriers to cervical cancer screening among women who have experienced intimate partner violence (IPV) and accessed domestic violence shelters, to compare barriers among those up-to-date (UTD) and not UTD on screening, and to evaluate acceptability of human papillomavirus self-sampling., Materials and Methods: This is a cross-sectional survey in which domestic violence shelters in Ohio were identified and women completed an anonymous survey assessing UTD screening status, barriers related to screening, history of IPV, intention to follow up on abnormal screening, and acceptability of self-sampling. Characteristics of UTD and not UTD women were compared using Mann-Whitney U tests., Results: A total of 142 women from 11 shelters completed the survey. Twenty-three percent of women were not UTD. Women who were not UTD reported more access-related barriers (mean = 2.2 vs 1.8; p = .006). There was no difference in reported IPV-related barriers between women who were not UTD and those who are UTD (mean = 2.51 in not UTD vs 2.24 in UTD; p = .13). Regarding future screening, of the women who expressed a preference, more women not UTD preferred self-sampling than UTD women (32% vs 14%; p = .05)., Conclusions: In this study, access-related barriers were more commonly reported among women not UTD with screening. Addressing these barriers at domestic violence shelters may improve screening among not UTD women. Self-sampling may also be one feasible approach to support screening in this population.

Objectives: The objective of this work was to determine the risk of invasive cervical cancer at colposcopy based on the woman's age, associated cervical cytology, and colposcopic impression., Methods: Review of electronic medical records from colposcopy clinics followed by chart review of women with cervical cancer., Results: Between March 1, 1996, and April 23, 2013, 27,381 cervical colposcopies for evaluation of abnormal cervical cytology and/or positive high-risk human papillomavirus tests were performed. Median age at colposcopy was 32 years (range, 11-91 years). Biopsy at colposcopy or at subsequent loop electrocautery excision procedure, cervical conization, or hysterectomy diagnosed cervical cancer in 0.5% (132/27,381) of women. At colposcopy, the risk of cervical cancer for women younger than 30 years was 0.07% (8/12,131), for women with Cytology-Lo (low-grade squamous intraepithelial lesion, atypical squamous cells of uncertain significance, benign endometrial cells, or negative), it was 0.17% (43/25,779); and for women with normal colposcopic impressions, it was 0.17% (18/11,389). The risk of cervical cancer for women younger than 30 years with Cytology-Lo was 0.01% (1/11,663)., Conclusions: At colposcopy, cervical cancer is not excluded by a normal colposcopic examination result, Cytology-Lo, or age younger than 30 years, but is virtually excluded by the combination of age younger than 30 years and Cytology-Lo.

Objectives: Although endocervical curettage (ECC) is often performed at colposcopy, it remains unclear whether it should be done in all women, only women over a certain age, only women with unsatisfactory colposcopy, or only in women with normal colposcopic impressions. To clarify the indications for ECC, we determined the proportion of colposcopies with CIN 3, or cancer (CIN 3+) detected only by ECC showing CIN 2, CIN 3, or cancer (CIN 2+)., Methods: Review of electronic medical records from colposcopy clinics., Results: Between March 1, 1996, and April 23, 2013, approximately 18,537 cervical colposcopies with no missing results evaluated women with abnormal cervical cytology and/or positive high-risk human papillomavirus tests. In 7.5% (1,398/18,537) of colposcopies, the final diagnosis, based on the worst biopsy from cervix; ECC; or subsequent loop electrocautery excision procedure, cervical conization, or hysterectomy, was CIN 3+. The proportion of colposcopies with CIN 3+ detected only by ECC showing CIN 2+ was 0.5% (101/18,537). Limiting the ECC to women with unsatisfactory colposcopy, colposcopic impressions suggestive of CIN 2+, or impressions of normal resulted in fewer ECC performed but also greatly decreased the proportion of CIN 3+ that could have been detected only by ECC showing CIN 2+. Limiting the ECC to colposcopies in women age 25 years and older resulted in 29.3% (5,433/18,537) fewer ECCs while detecting 96.0% (97/101) of the CIN 3+ that could have been detected only by ECC showing CIN 2 + ., Conclusions: Endocervical curettage should be performed at colposcopy in women age 25 and older.

Cancers of the breast, uterine cervix, and lip or oral cavity are three of the most common malignancies in India. Together, they account for about 34% of more than 1 million individuals diagnosed with cancer in India each year. At each of these cancer sites, tumours are detectable at early stages when they are most likely to be cured with standard treatment protocols. Recognising the key role that effective early detection and screening programmes could have in reducing the cancer burden, the Indian Institute for Cytology and Preventive Oncology, in collaboration with the US National Cancer Institute Center for Global Health, held a workshop to summarise feasible options and relevant evidence for screening and early detection of common cancers in India. The evidence-based recommendations provided in this Review are intended to act as a guide for policy makers, clinicians, and public health practitioners who are developing and implementing strategies in cancer control for the three most common cancers in India., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To investigate the value of multiply biopsies and endocervical curettage (ECC) on diagnosing cervical lesions., Methods: For the detection of cervical lesions, Shenzhen cervical cancer screening trial II (SHENCCAST II) program combined methods of HPV screening with liquid-based cytology (LBC), any positive indicators was then performed multiply biopsies and ECC under colopscopy. A total of 2,558 clear colposcopic images and pathological diagnoses were reviewed. To analyse the pathological results and primary screening results of the negative colopscopic images for discussing the value of multiply biopsies and ECC., Results: Overall 2,558 women's colposcopic images and sampling results were completed and validated. 69.98% (1,790/2,558) women had normal colposcopy appearances. Among them, 2.23% (40/1,790) were diagnosed as cervical intraepithelial neoplasia II or worse (CIN II+). The odds ratio of high-grade squamous intraepithelial lesion (HSIL) was 28.37 (P=0.000) and atypical squamous cell cannot exclude HSIL (ASC-H) was 15.07 (P=0.001). HPV types 16, 52, 58, 31, 33 and 18 were related to high-grade cervical lesion with the odds ratio of 3.11 (P=0.017). Hybrid capture II (HC-II) DNA test results shown that women with HPV positive were 3.58 times more risky than those of HPV negative, which was related to high-grade cervical lesion (P=0.025). Among the 2,558 women, CIN II+ detective rate from ECC were 40.7% (44/108) in older group (≥40 years) were higher than that of 19.2% (24/125) in younger group (<40 years; χ2=13.01, P=0.000). CIN II+ detective rate from multiply biopsies were 90.7% (98/108) in older group (≥40 years) were higher than that of 88.8% (111/125) in younger group (<40 years; χ2=0.24, P>0.05). The highest risky items of detecting CIN II+ were as follows: (1) HSIL or ASC-H; (2) HPV types 16, 18, 52 and 58 positive (either one); (3) HC-II HPV positive, at least 2 of the 3 items were included among 32 cases of the 40 CIN II+ with normal colposcopy appearances., Conclusions: The results shown that only performed multi-site biopsies with abnormal colposcopy appearances may be missed some highgrade cervical lesion. For the positive indicators during screening should be performed randomly multi-sites biopsies and ECC under colopscopy, which may be helpful to reduce miss diagnosis.

Oral, cervical and breast cancers, which are either preventable and/or amenable to early detection and treatment, are the leading causes of cancer-related morbidity and mortality in India. In this paper, we describe implementation science research priorities to catalyze the prevention and control of these cancers in India. Research priorities were organized using a framework based on the implementation science literature and the World Health Organization's definition of health systems. They addressed both community-level as well as health systems-level issues. Community-level or "pull" priorities included the need to identify effective strategies to raise public awareness and understanding of cancer prevention, monitor knowledge levels, and address fear and stigma. Health systems-level or "push" and "infrastructure" priorities included dissemination of evidence- based practices, testing of point-of-care technologies for screening and diagnosis, identification of appropriate service delivery and financing models, and assessment of strategies to enhance the health workforce. Given the extent of available evidence, it is critical that cancer prevention and treatment efforts in India are accelerated. Implementation science research can generate critical insights and evidence to inform this acceleration.