[Real-world research on cervical cancer screening program and effect evaluation for Chinese population].

Objective: To evaluate the actual efficacy of cervical cancer and precancerous lesions screening approaches in real-world regions with different economic levels in China. Methods: The demonstrative application and effect evaluation of cervical cancer screening program were conducted in 21 hospitals nationwide from 2015 to 2018. Multi-stage sampling method was adopted to divide the country into 7 large areas according to geographical location. Two to four screening sites of two types of cancer (cervical cancer and breast cancer) were selected in each area, and the grassroots screening sites were implemented under the guidance of superior hospitals. In rural areas, women were initially screened using cytology, human papillomavirus (HPV) testing and visual inspection. The women with positive cytology or visual inspection were referred for colposcopy, and the women with positive HPV infection were randomly referred for reflex cytology or visual inspection, or direct colposcopy examination. In urban areas, women were primarily randomized into cytology or HPV testing groups. The women with abnormal cytology or positive HPV 16/18 infection were directly referred for colposcopy examination, whereas the women with positive infection of the other 12 high-risk subtypes of HPV were referred for reflex cytology or colposcopy. All of recruited women would be follow-up and screened by the baseline screening techniques in the third year while the positive women underwent colposcopy examination. The positive rates, referral rates, the detection rates of grade 2 and above of cervical intraepithelial neoplasia (CIN 2+ ) were compared. Results: A total of 63 931 women were recruited at the baseline. Among them, 11 rural sites included 33 823 women: 15 577, 11 157 and 7 089 women were screened by HPV testing, visual inspection via acetic acid or Lugol's iodine (VIA/VILI) and cytology, respectively. Additionally, 30 108 women were from 10 urban sites: 9 907 and 20 201 women were screened by cytology and HPV subtyping, respectively. The HPV positive rate for urban women was 9.34%, whereas that for rural women was 12.53%. The abnormal rate of cytology for urban women was 5.63%, and that for rural women was 4.24%. The positive rate of VIA/VILI in the rural women was 12.25% Furthermore, the detection rate of CIN2+ at the baseline was 0.56%, and that was statistically higher in HPV-positive group than cytology-positive group (P<0.05). Conclusions: All of screening sites completed the baseline screening tasks as expected. The prevalence of HPV infection is higher in rural women than urban women. The performance of HPV testing is better than cytology for detecting CIN2+ cases. This real-world demonstration study provides evidences for cervical cancer prevention and control in different regions.

[Performance of combined liquid based cytology and HPV nucleic acid test for detecting cervical precancer among women attending screening].

Objective: To evaluate the clinical performance of HPV genotyping with cytology for detecting cervical precancer among women attending co-testing. Methods: A total of 2 883 females who participated in cervical cancer screening program were recruited from Erdos in 2016. All the participants were tested by cytology and HPV genotyping. In 2017, women with abnormal cytology results or HPV positive were followed up. Pathological cervical intraepithelial neoplasia (CIN) 2+ was the study end-point. Clinical performance indexes were calculated, including sensitivity, specificity, positive predictive value, negative predictive value, referral rate and missed cases. Results: INNO-LiPA resulted in a detection rate of 18.87%(544/2 883) for the 14-type high risk HPV. HPV16 was the most common infectious genotype (4.06%), followed by HPV52 (3.61%), HPV51 (2.50%), HPV58 (1.98%), and HPV18 (1.56%). With more HPV genotypes added into the group, sensitivity increased and the specificity decreased. Addition of HPV16, 58, 33, 39, 52, 18, 31 for detection lead to the maximun value of area under the curve (AUC)=0.913 (95%CI: 0.882-0.944). Compared with traditional screening method by cytology, cotesting decreased the number of missed diagnosis. Meanwhile, the fifth method (co-testing: triage of women with HPV16/18+ , cytological minor abnormalities and HPV58, 33, 39, 52, 31+ or cytological high grade abnormalities) did not increase referral rate (8.99% vs. 8.71%, P=0.525), with five cases of missed diagnosis (sensitivity of 92.1% and specificity of 93.2%). Conclusions: Co-testing with triage of women with HPV16/18+ , cytological minor abnormalities and HPV58, 33, 39, 52, 31+ or cytological high grade abnormalities would provide better clinical performance. In co-testing, triage of HPV16/18 was used in women with normal cytology; triage of HPV58, 33, 39, 52 and 31 was used in women with low-grade abnormal cytology; referral colposcopy was used in women with high-grade abnormal cytology, which would provide better clinical performance.

[Interpretation of guidance for establishing the performance characteristics of in vitro diagnostic devices for the detection or detection and differentiation of high-risk human papillomaviruses issued by Food and Drug Administration of United States and China].

To establish the standardization of clinical verification designs for in vitro diagnostic devices(IVDs) of human papillomavirus, China Food and Drug Administration (CFDA) and United States Food and Drug Administration (FDA) issued guidelines of detailed study designs and effectiveness evaluation for accuracy validation and clinical performance of nucleic acid detection, respectively, including triage of a typical squamous cells of undetermined significance(ASC-US) patients and validation of combined screening and preliminary screening. The design, study population, sample size estimation and statistical analysis of guidelines were moderately different from America to China, however, the evaluation indication was similar. According to the guideline issued by CFDA, prospective design suggested by FDA could be replaced by cross sectional study design to validate the triage of ASC-US patients. Alternatively, prospective design could be used to conduct the HPV product declaration and cellular parallel detection for the same natural population, and the clinical effectiveness of declared products could be validated by at least 3 years follow-up of cytology.

[Analysis of the survival of 123 patients with intrahepatic cholangiocarcinoma after surgical resection].

OBJECTIVE: To investigate the prognostic factors for patients with intrahepatic cholangiocarcinoma after surgical resection. METHODS: The clinicopathological and follow-up data of 123 patients with intrahepatic cholangiocarcinoma who underwent surgical resection in Cancer Hospital, Chinese Academy of Medical Sciences between January 1999 and June 2015 were collected and reviewed, and their survival and prognosis were analyzed with the Kaplan-Meier method and Cox regression model. RESULTS: The median follow-up time was 22 months and median recurrence-free survival time was 8.97 months. The 1-, 2- and 3-year recurrence rates were 58.6%, 68.9% and 76.5%, respectively. Cox multivariate regression analysis showed that preoperative rise in CEA, lymph node metastasis, multiple lesions, extrahepatic invasion, and combination of tumor necrosis were significant adverse prognostic factors affecting the postoperative recurrence-free survival in patients with intrahepatic cholangiocarcinoma after surgical resection (P<0.05 for all). The median overall survival time was 21.17 months, and the 1-, 3- and 5-year overall survival rates were 76.6%, 33.2% and 26.1%, respectively. The Cox multivariate regression analysis showed that preoperative rise in CEA, lymph node metastasis, multiple lesions, and extrahepatic invasion were significant adverse prognostic factors affecting the postoperative overall survival in patients with intrahepatic cholangiocarcinoma after surgical resection(P<0.05 for all). CONCLUSION: Preoperative rise in CEA, lymph node metastasis, multiple lesions and extrahepatic invasion are significant adverse prognostic factors for patients with intrahepatic cholangiocarcinoma after surgical resection.

[Prevalence of human papillomavirus infection and risk of cervical cancer or precancerous lesions in 15 years follow up: a prospective cohort study].

Objective: To evaluate the 15 years changing trends of prevalence of high risk HPV (HR-HPV) infection and the risks of cervical cancer and precancerous lesions (CIN2+ ) among a Chinese rural population. Methods: The screening cohort with 1 997 women aged 35 to 45 years old was built in 1999 in Xiangyuan County, Shanxi province (SPOCCS-I) and followed up by cytology and HR-HPV testing in the years of 2005, 2010, and 2014. The changes of HR-HPV prevalence and the risks of cervical precancerous lesions with CIN2+ as the endpoints were analyzed during the past 15 years. Results: The detection rates of HPV infection and CIN2+ were 15.7%-22.3% and 1.1%-4.3% for the baseline visit and the other 3 follow-ups, respectively. The cumulative risk of CIN2+ in HR-HPV positive women at baseline was significantly higher than HR-HPV negative women (P<0.01) during the 15-year follow-up. The risk of CIN2+ in the four-times HPV positive group was 40.0%, while the group with four-times negative HPV results was 0.6% (Adjusted RR = 55.0, 95% CI: 11.3 to 268.4). Conclusions: The prevalence of HR-HPV infection and CIN2+ lesions were high in Xiangyuan county during the 15 years. HR-HPV positivity elevated the risk of CIN2+ compared to women whose HR-HPV test was negative. The risks of CIN2+ incidence in 6 years were low among women with negative HR-HPV test. The risk of CIN2+ increased with the numbers of HPV infection events. The screening interval could be extended to 5-6 years.

[Changes in genotype prevalence of human papillomavirus over 10-year follow-up of a cervical cancer screening cohort].

Objective: To evaluate the dynamic variation of genotypes distribution of human papillomavirus (HPV) over 10-year follow-up in a cervical cancer screening cohort. Methods: Based on the Shanxi Province Cervical Cancer Screening Study Ⅰ cohort, we detected HPV genotypes on the well-preserved exfoliated cervical cells from women who were tested HPV positive from year 2005 to year 2014 using reverse linear probe hybridization assay. The changes of prevalence of type-specific HPV over time among the overall population were estimated using linear mixed models. The association between the type-specific HPV and cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) was calculated by linear Chi-square test. Finally, the trends of multiple infections of HPV with the increase of the age were analyzed. Results: During the cervical cancer screening of the overall population from 2005 to 2014, the most common genotypes among the population were HPV16 and 52. The prevalence of HPV16 decreased over time from 4.6% in 2005 to 2.2% in 2010 and 2014 (F=8.125, P<0.001). The prevalence of HPV52 remained pretty stable and HPV33, 51 and 58 slightly decreased then apparently increased. Further stratification analysis by pathological lesions showed the same trend of the HPV prevalence for the histology normal women with the overall population. Of note, for those women with the cervical intraepithelial neoplasia (CIN2 +), the detection rate of HPV16 decreased from 65.22% in 2005 to 41.03% in 2010 and finally to 31.58% in 2014 (χ(2)=4.420, P=0.036) and that of HPV33 substantially increased. No significant variation was found for other types of HPV. Multiple infection rate varied with the growing age of the women. Conclusions: The genotypes prevalence of HPV tended to vary over time during cervical cancer screening in the context of regular screening combining with immediate treatment for those CIN2 + women. HPV16 prevalence significantly decreased over time, which indicated that the variation of type-specific HPV prevalence should be considered when regular cervical cancer screening was organized using HPV technique.

[Risk assessment on cervical cancer in women with cytology atypical squamous cells of undetermined significance but negative human papillomavirus].

OBJECTIVE: To assess the risk of cervical cancer and high grade cervical intraepithelial in women with negative human papillomavirus (HPV) and cytology atypical squamous cells of undetermined significance (ASC-US) and to provide evidence for clinical management. METHODS: We pooled 17 population-based cross-sectional studies which were conducted across China from 1999 to 2008. Totally, 30 371 women aged 17-59 were included in these studies. All women received liquid-based cytology test (LBC), HPV testing (hybrid capture 2 test, HC2) and visual inspection with acetic acid test (VIA). Women with any positive result from above tests were referred to colposcopic examination. Totally, 28 810 women with complete results from HPV, cytology and pathology were included in the final analysis. Women with negative HPV (LBC-/HPV-) or negative cytology (LBC-) results served as the control, respectively. Risk on high grade cervical intraepithelial neoplasia (CIN2+) was calculated for women with HPV negative and ASC-US results (ASC-US/HPV-). RESULTS: There were 22 003 women with LBC-/HPV-, 24 139 women with LBC-, and 1 834 with ASC-US/HPV- indentified in our study. CIN2+prevalence rates to the above women appeared as 0.05%, 0.36% and 0.16%, respectively. Compared with women with LBC-/HPV- and women with LBC-, the odds ratios (ORs) for CIN2+in women with ASC-US/HPV-were 3.00 (95%CI: 0.85-10.65) and 0.46 (95%CI:0.15-1.45), with adjusted ORs as 4.00 (95%CI: 1.08-14.87) and 0.47(95%CI: 0.15-1.49), respectively. CONCLUSIONS: The risk of CIN2+ in women with ASC-US/HPV- was in between the risks of women with LBC-/HPV- or with LBC-. Based on the "equal risk, equal management" principle, women with ASC-US/HPV- were suggested to be followed under the '3-year interval' program, which was the same as for those cytology negative women. However, in areas with limited health resources, the follow-up interval can be extended to 5 years, similar to the management on women with LBC-/HPV-.