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Background: To investigate the mechanism by which apolipoprotein A1 (APOA1) enhances the resistance of cervical squamous carcinoma to platinum-based chemotherapy., Methods: Two cervical squamous carcinoma cell lines (SiHa and Caski) overexpressing APOA1 were constructed, treated with carboplatin, and compared to normal control cells., Results: In both SiHa and Caski cell lines, the clone-forming ability of CBP-treated cells was lower than that of untreated cells, and the change in the number of clones of overexpressing cells was lower than that of normal control cells (p < 0.05), indicating that APOA1 overexpression enhanced chemoresistance. A screen for APOA1 downstream proteins affecting platinum-based chemoresistance using Tandem Mass Tag revealed 64 differentially expressed proteins in SiHa cells, which were subjected to Gene Ontology (annotation, Kyoto Encyclopedia of Genes and Genomes enrichment, subcellular localization, structural domain annotation and enrichment, clustering, and interaction network analyses. Sixty-four differentially expressed proteins matching cancer-relavent association terms were screened and parallel response monitoring identified 29 proteins as possibly involved in the mechanism of platinum-based chemoresistance., Conclusions: Our analysis suggested that the mechanism may involve numerous regulatory pathways, including promoting tumor growth via the p38 MAPK signaling pathway through STAT1, promoting tumor progression via the PI3K signaling pathway through CD81 and C3, and promoting resistance to platinum-based chemotherapy resistance through TOP2A. The present study aimed to preliminarily explore the function and mechanism of APOA1 in platinum-based chemoresistance in cervical cancer, and the detailed mechanism needs to be further studied., (© 2022. The Author(s).)

Background: Human papillomavirus screen in female cervical cells has demonstrated values in clinical diagnosis of precancerous lesions and cervical cancers. Human papillomavirus tests of cervical cells by utilizing Polymerase Chain Reaction (PCR) method provides human papillomavirus infection status however no further virus in situ information. Although it is well known that the tests of human papillomavirus E6/E7 RNA location in infected cervical cells and cell internal malignancy molecular will provide clues for gynecologists to evaluate disease progression, there are technique difficulties to preserve RNAs in cervical scraped cells for in situ hybridization., Methods: In current study, after developing a cervical cell collection and preparation method for RNA in situ hybridization, we captured the chance to screen 98 patient cervical cell samples and detected human papillomavirus E6/E7 mRNAs of high-risk subtypes, low-risk subtypes and long non-coding RNA (lncRNA) TERC in the cells., Results: There were 69 samples exhibited consistence between human papillomavirus PCR and human papillomavirus RNA in situ hybridization results in cervical collected cells. Among them, 23 were both positive and 46 were both negative. In the rest 29 samples, 8 were HPV RNAscope positive, either high risk or low risk subtypes, however HPV PCR negative. Another 9 samples were HPV PCR results positive whereas RNAscope negative. The last 12 samples were HPV positive detected by both RNAscope and PCR methods, however inconsistent between high-risk and low-risk subtypes. In RNAscope positive samples, viral E6/E7 mRNAs were observed to distribute in cervical scraped cell nucleus and cytoplasm. Moreover, HPV viral RNA gathered clusters were observed outside of cells through human papillomavirus RNA in situ hybridization detection. Varied numbers of human papillomavirus infective cells were detected by RNAscope assay in different patients even though they were all human papillomavirus high-risk subtype positive discovered by human papillomavirus PCR results. A cell malignancy related long non-coding RNA, TERC, has been detected in seven patient samples. The patient follow-up information was further analyzed with RNAscope results which indicated a combination of RNAscope positive signals of TERC and human papillomavirus high risk signals in more than 10 cells (cytoplasm or nucleus) may connect with cervical lesion fast progression which deserves further studies in the future., C Conclusions: Taken together, current study has provided an observable clue for gynecologists to evaluate human papillomavirus infection stage and cell malignancy status which may contribute for assessment of cervical disease progression., (© 2022. The Author(s).)

Objective: In this meta-analysis, we aimed to evaluate the oncological outcomes of preoperative neoadjuvant chemotherapy followed by radical surgery compared with radical surgery alone for treatment of International Federation of Gynecology and Obstetrics (FIGO) stage I-II cervical cancer., Method: We searched for studies comparing the safety and efficacy of neoadjuvant chemotherapy plus surgery versus surgery alone in treatment outcomes of locally advanced cervical cancer. Meta-analysis was used to calculate the pooled odds ratios with corresponding 95% confidence intervals (CI)., Results: Sixteen studies were included in our analysis. Pooled analysis of overall survival rate [odds ratio (OR) = 1.09, 95% CI: 0.83-1.43] and progression-free survival rate (OR = 1.10, 95% CI: 0.77-1.57) showed that preoperative neoadjuvant chemotherapy did not have a benefit compared with surgery alone in terms of survival rates. The pooled results for postoperative parameters indicated that preoperative neoadjuvant chemotherapy followed by radical surgery was associated with a high rate of vascular space involvement (OR = 0.25, 95% CI: 0.17-0.35) and parametrial infiltration (OR = 0.60, 95% CI: 0.45-0.79)., Conclusions: This meta-analysis indicated that surgery following neoadjuvant chemotherapy for FIGO stage I-II cervical cancer and surgery alone had similar oncological outcomes.

The aim is to investigate the in vivo and in vitro killing effect of mesothelin chimeric antigen receptor T cells (MESO-CAR-T) in cervical squamous cell carcinoma. MESO-CAR-T cells were successfully constructed. In vitro verification of the killing effect of MESO-CAR-T cells was evaluated in the presence of SiHa cells by the lactate dehydrogenase release assay and cytokine release assay. The in vivo experiments were performed in immunodeficient NCG mice. After successful tumor formation with the subcutaneous implantation of SiHa cervical cancer cells, the injections of MESO-CAR-T cells into the tumors at different doses and frequencies were performed. Subsequently, the growth rate and size of the tumors in NCG mice were observed. A 17-fold increase in the number of MESO-CAR-T cells and a 16-fold increase in the number of Con-CAR-T cells were observed. The result of marker detection in the prepared MESO-CAR-T cells showed that CD3 + T lymphocytes accounted for 97.0 % of all cells, indicating successful preparation of MESO-CAR-T cells. Expression of the membrane protein MESO was detected in 12.8 % of SiHa cells. When the ratio of MESO-CAR-T cells to SiHa cells was 20:1, the lysis of target cells was most significant and was observed in 22 % of the cells. In the presence of SiHa cells, the secretion of IL-4、IL-2、IL-5、TNF-α and IFN-γ in MESO-CAR-T cells was higher than that in the control group. The effect of two consecutive intratumoral injections of MESO-CAR-T cells was more obvious than that of one injection. The pharmacological effect of the injection was observed within 1 week. Our finding identified the certain in vivo and in vitro killing activity of MESO-CAR-T cells., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Radiosensitivity is limited in cervical cancer (CC) patients due to acquired radiation resistance. In our previous studies, we found that immediate-early response 5 (IER5) is upregulated in CC cells upon radiation exposure and decreases cell survival by promoting apoptosis. The details on the transcriptional regulation of radiation-induced IER5 expression are unknown. Studies in recent years have suggested that Pol II-associated factor 1 (PAF1) is a pivotal transcription factor for certain genes "induced" during tumor progression. In this study, we investigated the role of PAF1 in regulating IER5 expression during CC radiotherapy., Methods: PAF1 expression in CC cells was measured by western blotting, immunohistochemistry, and qRT-PCR, and the localization of PAF1 and IER5 was determined by immunofluorescence. The effect of PAF1 and IER5 knockdown by siRNA in Siha and Hela cells was studied by western blotting, qRT-PCR, CCK-8 assay, and flow cytometry. The physical interaction of PAF1 with the IER5 promoter and enhancers was confirmed using chromatin immunoprecipitation and qPCR with or without enhancers knockout by CRISPR/Cas9., Results: We confirmed that PAF1 was highly expressed in CC cells and that relatively low expression of IER5 was observed in cells with highly expressed PAF1 in the nucleus. PAF1 knockdown in Siha and Hela cells was associated with increased expression of IER5, reduced cell viability and higher apoptosis rate in response to radiation exposure, while simultaneous PAF1 and IER5 knockdown had little effect on the proportion of apoptotic cells. We also found that PAF1 hindered the transcription of IER5 by promoting Pol II pausing at the promoter-proximal region, which was primarily due to the binding of PAF1 at the enhancers., Conclusions: PAF1 reduces CC radiosensitivity by inhibiting IER5 transcription, at least in part by regulating its enhancers. PAF1 might be a potential therapeutic target for overcoming radiation resistance in CC patients.

Objective: This study aimed to identify proteins related to paclitaxel and carboplatin chemoresistance in cervical cancer., Methods: Quantitative proteomic analysis was performed on normal SiHa cells and those treated with paclitaxel and carboplatin for 14 days, with isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to identify related processes and differentially expressed proteins., Results: A total of 67 and 96 differentially expressed proteins were identified in the paclitaxel- and carboplatin- treated groups, respectively. GO and KEGG enrichment analyses identified 53 (43 upregulated and 10 downregulated) and 85 differentially expressed proteins (70 upregulated and 15 downregulated) in the paclitaxel- and carboplatin-treated groups, respectively. The cell counting kit-8 results revealed that APOA1 was overexpressed in both the paclitaxel- and carboplatin- resistant SiHa cells compared with the control cells. Immunohistochemistry showed that APOA1 was highly expressed in the paclitaxel- and carboplatin- resistant squamous cell carcinoma of the cervix., Conclusion: This study is the first to use iTRAQ to identify paclitaxel- and carboplatin- resistance proteins in cervical cells. We identified several proteins previously unassociated with paclitaxel and carboplatin resistance in cervical cancer, thereby expanding our understanding of paclitaxel and carboplatin resistance mechanisms. Moreover, these findings indicate that the APOA1 protein could serve as a potential marker for monitoring and predicting paclitaxel and carboplatin resistance levels., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

This study compared the efficacy of neoadjuvant chemotherapy (NACT) followed by radical surgery (RS) vs primary surgical treatment (PST) in patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IB2/IIA2 cervical cancer.Data of 303 cervical cancer patients who received primary therapy for stage IB2/IIA2 cervical cancer at 7 medical centers in Beijing, China between January 1, 2009 and December 31, 2016 and followed through December 31, 2017 were collected retrospectively. The response rates, surgical characteristics, and overall survival (OS) durations of patients who received NACT followed by RS were compared to those of patients who received PST.An improved short-term complete response rate was observed among patients who received intra-arterial chemotherapy compared with patients who had intravenous chemotherapy (18.3% vs 4.1%, Pdifference = .020). Patients who received NACT were more likely to undergo laparoscopic surgery and to have a lower blood loss volume (555.4 ± 520.2 ml vs PST, 682.5 ± 509.8 ml; P = .036) and increased estimated operative time (249.9 ± 101.9 vs PST, 225.1 ± 76.5 min; P = .022). No differences in high-risk factors (HRFs), the effects of supplemental treatment, or 5-year OS were observed between patients who received NACT and PST.Our findings indicate that patients who received NACT for FIGO stage IB2/IIA2 cervical cancer were more likely to undergo laparoscopic surgery. These findings have important implications regarding treatment with curative intent for stage IB2/IIA2 cervical cancer and warrant a further analysis of treatment strategies to ensure adequate treatment and patient-centered care.

Aim: To explore the feasibility of using mesothelin (MESO) as a tumor-associated antigen (TAA) in cervical squamous cell carcinoma and its function in the development of cervical cancer., Methods: We collected eight cervical tissue samples of squamous cell carcinoma as the test group and eight samples of cervicitis as the control group from patients who underwent a hysterectomy because of a diagnosis of myoma. Then we used western blotting to screen for a potential TAA in cervical squamous cell carcinoma samples. In addition, Lentivirus-mediated RNAi was used to downregulate the expression of the MESO gene (MSLN) in SiHa cells. Fluorescence-activated cell sorting (FACS), 3‑(4,5)-dimethylthiahiazo (-z‑y1)‑3,5‑di‑phenytetrazoliumromide (MTT), and wound healing were used to examine cell apoptosis, cell proliferation, and cell migration respectively., Results: Results of the western blotting showed that the MESO protein expressed highly in the cervical squamous cell carcinoma and paracancerous tissues in contrast to the cervicitis tissue (p = 0.242). We used quantitative PCR to verify that the expression of MSLN was 21.6% in the cells undergoing knockdown compared to that in the control cells, and thus, decided to continue with further experiments. We confirmed by FACS that the apoptosis rate in the SiHa cell group undergoing MSLN knockdown (KD group) was significantly higher than that in negative control (NC) group of SiHa cells (p = 0.014). The proliferation of cells was examined by MTT and the difference between the KD and NC groups was found to be statistically significant (p = 0.002). However, since the difference was <20% we did not consider it to be clinically significant. Cell migration ability was verified by wound healing test and found to be 43% in the KD group and 38% in the NC group after 48 h, but the difference was not statistically significant (p > 0.05)., Conclusions: MESO might be used as a TAA for diagnosing cervical squamous cell carcinoma. When MSLN was knocked down in SiHa cells, cell apoptosis increased, but no significant effects were observed on cell proliferation and migration. Thus, our study shows that MSLN plays a role in the apoptosis of cervical squamous cell carcinoma cells, and since this might affect tumor progression, further research is warranted to understand how MSLN plays this role., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The purpose of this study is to investigate short-term efficacy as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) and pathological response of neoadjuvant chemotherapy (NACT) comprised of paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced cervical cancer (LACC).This is a prospective study involving 61 women with histologically confirmed LACC referred for NACT following radical surgery at Beijing Obstetrics and Gynecology Hospital between April 2013 and January 2015.The efficacy of NACT was evaluated by the RECIST. The total short-term efficacy of NACT was 91.8% (complete remission and partial remission). The cervical invasion ≤1/2 was 82.4% in the complete remission (CR) group, 46.2% in the partial remission (PR) group, and 20% in the stable disease (SD) group. The difference between groups was statistically significant (P = .012). The slides of all surgical specimens were reviewed and classified according to the Tumor Regression Grade (TRG). The good response was defined by good short-term efficacy (RECIST) and the difference between groups was statistically significant (P = .042). The route of administration of NACT is a factor predicting response to NACT. A significant higher response rate (P = .011) and lower chemotherapy-related adverse events (P < .05) were observed in the artery intervention (AI) group compared to those received NACT via intravenous (IV) route. All patients were followed-up to the last day of 2015 with the median follow-up time of 21.5 months for NACT. For the 61 patients referred for NACT in LACC, 2 patients had relapsed and 1 patient died from the disease.The study showed that the NACT comprised TP for LACC treatment had a significant local effect. It could reduce tumor myometrial invasion and regress tumor. The route of administrating NACT is a predicting factor to the NACT response; 2 cycles of NACT of AI treatment to LACC patients would obtain a desired response with low chemotherapy adverse events.

The purpose of this prospective cohort study is to evaluate the importance of screening and its diagnostic accuracy compared with the pathological diagnosis of cervical intraepithelial neoplasia (CIN) with vaginal intraepithelial neoplasia (VAIN).The prospective study enrolled 419 patients (pts) and was conducted between February 1, 2015 and January 31, 2016 at Beijing Obstetrics and Gynecology Hospital, Capital Medical University.All enrolled pts underwent multipoint biopsy of cervix and vaginal wall directed by colposcopy. All samples of biopsy underwent pathological examination. Among them, 201 pts (48.0%) were diagnosed with CIN, 218 pts (52.0%) were diagnosed with cervicitis, and 51 pts (12.2%) were diagnosed with VAIN. It was found that the incidence of CIN in pts was 4 times higher than that of VAIN. In all 419 patients enrolled, 218 pts had cervicitis with 13 pts (6.0%) of VAIN. There were 201 pts of CIN with 38 pts (18.9%) of VAIN: including 53 pts of CIN3 with 12 pts (22.6%) of VAIN; 49 pts of CIN2 with 9 pts of VAIN (18.4%), and 99 pts of CIN1 with 17 pts of VAIN (17.2%). The incidence of CIN with VAIN (18.9%) was significantly higher than cervicitis with VAIN (6.0%) (χ = 16.39, P = .00). Our results showed that there was a significant consistency between cervical lesions and vaginal lesions (χ = 135.91, P = .00), which indicated that the increase of CIN grades may be related to an increase of the VAIN grades. Our results also showed the significant (p < .05) increase of CIN and VAIN with age (<40 years Kappa = 0.04; 40-50 years Kappa = 0.11; >50 years Kappa = 0.28).This study showed that cytological test can be used as a routine screening method for cervical lesions and vaginal diseases. If the cytology result shows abnormality, and pathological examination confirms that there is no obvious abnormal cervical disease, colposcopy directed vaginal multipoint biopsy should be conducted to exclude vaginal disease. All patients of CIN should routinely undergo vaginal multipoint biopsy (1/3 upper vagina), especially in patients with high-grade CIN and age older than 50 years.

Background: In recent years, the incidence of cervical cancer has been rising, particularly in young adults, as the second most common gynecological cancer in China. The aim of this study was to explore the incidence change and the epidemiological characteristics of cervical cancer in Beijing over the past 16 years., Methods: All the cases of the study were limited to Beijing residents diagnosed with cervical cancer and registered in Beijing from January 1, 1993, to December 31, 2008. A total of 4100 patients with cervical cancer were obtained from the Statistics Database of Beijing Cancer Registry (BJCaR). According to the registered data, we retrospectively reviewed all original cases which we can acquired in reported hospital. Cervical situ cancer, cervical metastatic cancer, non-Beijing residents and repeatedly registered cases were excluded. Totally, 3641 registered cases were verified correctly. Meanwhile, we also collected the following data: Age, occupation, detected methods, histological type, and staging. The trends of incidence and mortality were analyzed by Joinpoint Regression Program 4.1.1.1 produced by National Cancer Institute (NCI, USA). The annual percent change (APC) was calculated using the Joinpoint regression model., Results: The crude rates of incidence and mortality were 10.4 and 1.0 per 100,000 women, respectively during 1993 to 2008. The average WHO age-standardized incidence rates were 11.5 per 100,000 women. There was a decrease in incidence annually by 8.0% (P = 0.3) during 1993-1996 and a rapid increase annually by 18.9% after 1999 (P < 0.01). The median age was 67 years in 1993, but the median age decreased to 45 years in 2008. The peak of the age-specific incidence curve was at 40 years in the most recent period (2005-2008), which was 25-30 years earlier than that in previous periods (1993-1996). In the 2224 cases, the numbers of patients with stage I, II, III and IV were 910 (40.9%), 601 (27%), 542 (24.4%), 171 (7.7%), respectively. The percentage of patients with stage I was 7.6% (13/171) in 1993-1996, but the percentage increased to 51.6% (643/1247) in 2005-2008 (P < 0.01). Otherwise the percentage of advanced stage (stage III-IV) during the same period was dropped down significantly from 52.0% (89/171) to 22.5% (280/1247) (P < 0.01). Unemployed and housewife ranked first accounting for 27.3% of the total (607/2224). Urban low-income people such as worker ranked the second accounting for 17.0% (377/2224), the third place was farmer accounting for 14.0% (312/2224). Only 381 (17.1%, 381/2224) women in 2224 were first detected cervical cancer by routine screenings. Company staff (36.5%, 139/381), professional and technical personnel (22.6%, 86/381), national official (22.0%, 84/381) occupied the top three (total 81.1%) in the 381 patients detected cervical cancer by screening., Conclusions: The cervical cancer incidence has showed a continuous rise in Beijing since 1999. Government-led mass screening should target the low socioeconomic population primarily. Meanwhile the government should enhance public health education of cancer screening to increase the rate of screening.

Objective: The aim of the study is to evaluate the clinical value of cold knife conization (CKC) as a conservative management in patients with microinvasive cervical squamous cell cancer (SCC)., Methods: This retrospective study enrolled 108 women with diagnosis of microinvasive cervical SCC (stage IA1) by pathology between 2009 to 2012 at Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Eighty-three patients underwent further hysterectomy., Results: Of the 83 patients (76.9%) who underwent further hysterectomy, 48 patients (57.8%) underwent extrafascial hysterectomy, 30 patients (36.1%) underwent extensive hysterectomy, and 5 patients (6.1%) underwent radical hysterectomy. A total of 19 patients underwent pelvic lymph node dissection without any lymph node metastasis, and a total of 5 patients (4.6%) had lymph vascular space invasion without any positive pelvic lymph node dissection. Of the 83 patients who underwent further hysterectomy and were followed up for 1 year, 18 patients with positive resection margins indicating cervical residual lesions (CIN1-3) have greater likelihood than 65 patients with clear resection margins, but there were no significant differences (P = 0.917); of the 25 patients who underwent CKC as final therapy and were followed up for 1 year, 2 patients with positive resection margins had the second CKC surgery, 1 was diagnosed with CIN1, and the other was diagnosed with cervicitis by pathology; 23 patients had clear resection margins, 2 patients underwent the second CKC 3 months after the first CKC because of the abnormal Thinprep Cytologic Test (TCT) result, and they were both diagnosed with microinvasive cervical SCC (stage IA1) by pathology with clear resection margins. No one enrolled in this study presented metastasis and progression within 1 year of follow-up., Conclusions: These findings provide the clinical evidences for the possibility of fertility-sparing treatments, especially CKC as conservative treatment for microinvasive cervical SCC. Appropriate further treatments (the second CKC) and follow-up are recommended for patients who strongly desire fertility sparing.

Objective: To evaluate the clinical management of cervical intraepithelial neoplasia (CIN) and cervical microinvasive squamous cell carcinoma in pregnant and postpartum women., Methods: This prospective study enrolled 27,230 pregnant women undergoing routine gestational examinations between August 1, 2007 and July 31, 2010 in the Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Colposcopy and cervical biopsy were performed for patients with abnormal Thin Prep® Papanicolaou test (TCT) results. Periodic colposcopy was performed every 8-12 weeks and cervical biopsy was performed if progression was suspected. Cervical cold knife conization was recommended to patients diagnosed with CINIII or microinvasive cervical carcinoma 6-12 weeks after delivery., Results: A total of 2,260 patients had abnormal TCT results (8.12 %). Colposcopy and cervical biopsy were performed for 369 patients. Fifteen patients had microinvasive squamous cell carcinoma, 116 patients had cervicitis, and the number of CIN patients with histological grades I, II, and III were 124, 49, and 65, respectively. Tumor progression during pregnancy was found in 253 patients (CINI or above). Prognosis varied depending on the highest grade of pathological diagnosis results during pregnancy or initial pathological diagnosis results performed 6-12 weeks after delivery by cervical biopsy under colposcopy. Treatment and follow-up were carried out according to diagnoses, state of progression, and reversion (if any)., Conclusion: These findings underline a need for cervical lesion screening for all women during pregnancy, and colposcopy should be performed for pregnant women who have abnormal TCT results. Appropriate treatment and follow-up were recommended according to different diagnosis of CIN.

Aim: To investigate the relationship between cervical intraepithelial neoplasia (CIN) and high-risk human papilloma virus (HR-HPV) during pregnancy and postpartum in China., Methods: In this prospective case-control study, 168 pregnant women with CIN and cervicitis were diagnosed by colposcopic cervical biopsy. All the cases underwent hybrid capture assay version II (HCII) to detect HR-HPV DNA load amounts and the tests were completed in 3-6 months after childbirth., Results: During pregnancy: as the CIN grade increased, the HR-HPV infection rates increased (P = 0.002), but HR-HPV DNA load amounts (in logarithms) did not change obviously (P = 0.719). 3-6 months postpartum: as the CIN grade increased, the natural negative rate of HR-HPV decreased (P = 0.000), while the amount of HR-HPV DNA (in logarithms) increased (P = 0.036); especially the amount of HR-HPV DNA in pregnant women with CINIII was significantly higher than that of other grades. During pregnancy and 3-6 months postpartum : the amount of HR-HPV DNA (in logarithms) during pregnancy was higher than that of 3-6 months postpartum with the same grade of CIN., Conclusion: The findings emphasize the importance of undergoing the HCII test 3-6 months postpartum. It should be noted that HR-HPV may turn negative in pregnancy with CINIII 3-6 months after childbirth. Further treatments of pregnancy with CIN should be considered according to the CIN grade diagnosed by cervical biopsy via colposcopy 3-6 months after birth, but not according to the persistence of HR-HPV during pregnancy., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Objective: To investigate the perinatal outcomes of pregnant women with cervical intraepithelial neoplasia (CIN)., Method: The women in this retrospective case-control study were recruited from Beijing Obstetrics and Gynecology Hospital from August 1, 2007 to February 28, 2010. All the cases were 13-32 gestational weeks, who were diagnosed by colposcopy conducted cervical biopsy. A total of 108 cases were followed-up to the day of delivery., Results: (1) Complications of colposcopy conducted cervical biopsy: there were two cases of pregnant women, who suffered cervical local compression after undergoing colposcopy conducted cervical biopsy, as the bleeding could not be stopped, the wound was treated by local suture. The incidence of such event was 1.8% (2/108), without any colposcopy and biopsy-related adverse event. (2) Cesarean section rate was 63.6% (56/88) in CIN, which was higher than 30.0% (6/20) in cervicitis, and the cesarean section rate increased as CIN grades elevated, and gestational weeks of delivery advanced.(P < 0.05). (3) We did not detect significant difference for the incidence of polyhydramnios, premature rupture of fetal membranes, placental abruption, cervical laceration and postpartum hemorrhage, low birth weight infants, amniotic fluid II-III degree, neonatal deformity and neonatal asphyxia between pregnant women with CIN and cervicitis (P > 0.05); however, the incidence of oligohydramnios and premature infants in pregnant women with CIN group were higher than that in cervicitis group (P = 0.007; P = 0.020). (4) Vaginal delivery and HR-HPV infection did not increase the incidence of perinatal complication; the volume of postpartum hemorrhage within 2 h after birth in vaginal delivery was less than in cesearean section for pregnancies with CIN (P = 0.000)., Conclusion: Pregnant women with CIN can be diagnosed by colposcopy conducted cervical biopsy, and they should be carefully monitored oligohydramnios and preterm during pregnancy. Pregnant women with CIN during pregnancy, excluding other obstetric operation indications may choose vaginal delivery first.

Objective: To explore the differentially expressed proteins in normal cervix, cervical intraepithelial neoplasia (CIN) and squamous cervical carcinoma (SCC) tissues by differential proteomics, and to provide a basis for studies on CIN molecular pathogenesis, clinical diagnosis and treatment., Methods: Uterine cervical tissue specimens from the patients treated between August 2008 and September 2009 in the Department of Oncology of Beijing Obstetrics and Gynecology Hospital were collected. There were samples of normal cervix (n = 9), CIN (n = 23, CIN I = 7, CIN II = 8, CIN III = 8) and SCC (n = 7). 2-D DIGE and DeCyder software were used to detect the differentially expressed protein-spots. Then MALDI-TOF/TOF MS was used to analyze the differentially expressed proteins. Collect normal cervix(n = 20), CIN (n = 60) and SCC (n = 20), immunohistochemistry (IHC) and Western blot were used to verify the differentially expressed proteins of S100A9 (S100 calcium-binding protein A9) , eEF1A1 (eukaryotic elongation factor 1-alpha-1) and PKM2 (pyruvate kinase isozymes M2) among the normal cervix, CIN and SCC tissues. Immunohistochemistry was used to detect the differentially expressed S100A9, eEF1A1 and PKM2 in the cervical tissues., Results: 2D gel electrophoresis images with high resolution and good repeatability were obtained. Forty-six differentially expressed proteins (27 were up-regulated and 19 were down-regulated) were selected among the normal, CIN, and SCC, and 26 proteins were successfully identified. Immunohistochemistry showed that protein S100A9 was mainly expressed in the cytoplasm, and its positive expression rate was 20.0% in normal cervical mucosa, 70.0% in CIN, and 100.0% in squamous cell carcinoma, with a significant difference between them (P = 0.006). eEF1A1 was mainly expressed in the cell plasma. Its positive expression rate was 70.0% in normal cervix, 73.3%in CIN and 60.0% in SCC tissues, with a non-significant difference between them (P = 0.758). The protein PKM2 was mainly expressed in the cell nuclei. Its positive expression rate was 100.0% in normal cervix, 93.3% in CIN and 75.0% in SCC tissues, showing a difference close to statistical significance (P = 0.059) between them. The results of Western blot were similar with that of immunohistochemical examination., Conclusions: There are differentially expressed proteins among normal cervix, CIN and SCC. S100A9, eEF1A1 and PKM2 may become candidate markers for early diagnosis of cervical cancer and new targets for therapy. It also provides a further basis for studies of the pathogenetic mechanism of CIN developing to cervical cancer.

Objective: To investigate diagnostic approaches of cervical glandular intraepithelial neoplasia (CGIN) for improving the diagnostic levels of CGIN., Methods: Clinical data of 106 cases with CGIN admitted in hospital from Jan.2008 to Dec. 2010 were analyzed retrospectively.All data from preoperative thin-prep cytologic test (TCT), cervical biopsies and postoperative pathological examination of the excised cervical tissues were reviewed., Results: Among 106 patients, 62 cases (58.5%, 62/106) were low grade CGIN (L-CGIN), 44 cases (41.5%, 44/106) were high grade CGIN (H-CGIN); 25 cases (23.6%, 25/106) were pure CGIN and 81 cases (76.4%, 81/106) were CGIN mixed with cervical intraepithelial neoplasia (CIN). Fifteen cases (14.2%, 15/106) were found atypical glandular cell (AGC) by TCT. In the 15 cases, there were 4 cases (6.5%, 4/62) L-CGIN, and 11 cases (25.0%, 11/44) H-CGIN, there was significant difference between the two groups (P < 0.05); among 15 cases with AGC, 11 cases of them (44.0%, 11/25) were pure CGIN, 4 cases (4.9%, 4/81) mixed with CIN, in which there were significant difference (P < 0.01).Seven cases (25.0%, 7/28) were detected glandular lesions in 28 cases by endocervical curettage (ECC). Totally 23 cases (22.8%, 23/101) were detected CGIN by colposcopy-directed biopsy, 11 cases (19.0%, 11/58) were with L-CGIN, 12 cases (27.9%, 12/43) H-CGIN, there was no significant difference between them (P > 0.05).Among the 23 cases, 13 cases (52.0%, 13/25) were pure CGIN, 10 cases (12.3%, 10/81) CGIN mixed with CIN, which showed significant difference (P < 0.01). All 106 patients were treated, 101 cases treated with cervical conization and 5 cases performed hysterectomy; 23 cases were diagnosed CGIN preoperation, the ratio of preoperative diagnosis was 21.7% (23/106), 83 cases (80.3%, 83/106) diagnosed postoperatively., Conclusions: Routine diagnostic methods of CGIN were not satisfaction, most CGIN were diagnosed after cervical resection.Cervical conization may play a very important role in diagnosis of CGIN.The positivity of TCT in H-CGIN was higher than L-CGIN. There was no different in diagnosing different CGIN grades by colposcopy-directed biopsy. The ratio of preoperative diagnosis of pure CGIN was higher than those with CGIN mixed with CIN.

The aim of the present study was to identify novel methylation markers for cervical cancer screening and to test the clinical application of the most promising biomarker in cervical scrapings. Methylated-CpG island recovery assay-based microarray analysis was carried out on a discovery set consisting of cervical cancer tissue and normal cervical tissue to identify significantly hypermethylated genes. Five hundred and four CpG islands, corresponding to 378 genes, were differentially methylated between cervical cancer tissue and normal cervical tissue. Among them, 30 genes were significantly hypermethylated. Of the 30 genes, SOX9, PKLR and DLX4 were selected for further validation by direct bisulfite sequencing. The SOX9 gene revealed complete methylation in the cervical cancer tissue and complete non-methylation in the normal control tissue. A TaqMan-based real-time PCR assay was performed to detect the methylation levels of the SOX9 gene in 156 cervical scrapings, including 48 normal cervical scrapings, 30 scrapings with cervical intraepithelial neoplasia 1 (CIN1), 30 scrapings with CIN2-3 and 48 scrapings with squamous cell carcinoma (SCC). The methylation levels (methylation score) of the SOX9 gene increased significantly with the severity of cervical squamous lesions. The area under the receiver operating characteristic (ROC) curve (AUC) revealed that the methylation score of the SOX9 gene could be used to segregate SCC/CIN2-3 from CIN1/normal (AUC, 0.961; p=0.000). At the optimal cut-off value, a sensitivity of 92.3% and a specificity of 89.7% were obtained. In conclusion, SOX9 methylation is frequently involved in cervical carcinogenesis, and may provide a valuable molecular biomarker for early detection of cervical cancer.

Objective: To evaluate the maternal and fetal outcomes of planned delay in treatment for cervical microinvasive squamous cancer during pregnancy., Methods: A prospective study of pregnant women was done from August 1, 2007 to May 31, 2010. Pregnant women who had not been carried out cervical cytological screening within one year were got thin-prep cytology test (TCT) screening at their initial prenatal visit. Patients with abnormal cytological results were performed colposcopic examination and directed biopsy. Women with cervical microinvasive cancer were followed up every 8 to 12 weeks. If lesion progression were suspected, compared with previous image, repeated biopsy directed by colposcopy should be performed. Once worsening invasive cancer was confirmed, the pregnancy should be terminated timely. All patients should be reevaluated 6 to 12 weeks postpartum with repeated colposcopic examination and biopsy. All mothers were performed cold knife conization (CKC) at 6 to 12 weeks postpartum., Results: We totally diagnosed 17 cases cervical microinvasive squamous carcinoma during pregnancy. The positive rate is 6.2/10 000 (17/27 230). After informed consent, 15 pregnant women decided to delay treatment until fetal maturation. The mean gestational age of initial diagnosis was (19.3 ± 5.9) weeks. The women were followed up 2 to 4 times during pregnancy. Only 1 patient was verified lesion progression by directed biopsy at 34 weeks and delivered by cesarean section. The progression rate during pregnancy was 1/15. The mean delivered time was (37.1 ± 1.8) weeks (ranged from 34 to 40 weeks). The mean diagnosis-to-delivery interval was (18.4 ± 5.2) weeks. All patients were delivered by cesarean section and all newborns had good outcomes. Finally we confirmed 1 case with cervical cancer stage Ia2, 11 cases with stage Ia1, 3 cases with cervical intraepithelial neoplasia (CIN) III by pathological diagnosis after CKC during 6 to 12 weeks postpartum. All cases were disease free after follow-up ranged from 22 to 48 months., Conclusions: It is necessary to perform TCT screening for pregnant women who have not been carried out cervical cytology screening within 1 year. If cervical microinvasive squamous cancer were suspected during pregnancy, in order to achieve fetal maturity it is acceptable for the women who desired pregnancy to delay treatment under closely monitoring until postpartum.

Objective: To investigate the relationship between cervical intraepithelial neoplasia (CIN) and high-risk (HR) HPV infection among late pregnant women., Methods: From Aug. 2007 to Feb. 2010, 168 women at 13 to 32 gestational weeks undergoing prenatal examination in Beijing Obstetrics and Gynecology Hospital went through three stage cervical disease screening, including 21 women with cervicitis and 147 women with CIN (42 women with CIN III, 37 women with CIN II and 68 women with CIN I). Hybrid capture assay version II (HC-II) test was used to measure HR-HPV DNA load, and the logarithmic transtormation (log(10)) was performed. All 168 women were followed up to postpartum 3 - 6 months. HR-HPV infections rates of cervicitis and different CIN, the rate of HR-HPV infection turned naturally negative at postpartum of 3 to 6 months, and HR-HPV load at pregnancy and 3 - 6 months postpartum were observed., Results: (1) HR-HPV infection rate: CIN III, II, I and cervicitis pregnant women's HR-HPV positive infection rates were 98% (41/42), 86% (32/37), 76% (52/68) and 62% (13/21) respectively, which reached statistical difference (P = 0.002). (2) HR-HPV naturally negative: the rate of pregnant women with different levels of CIN who turned HR-HPV naturally negative within 3 - 6 months of postpartum were CIN III 5% (2/41), CINII 47% (15/32), CINI52% (27/52) and cervicitis 10/13, which also reached statistical difference among those four groups (P = 0.000). (3) HR-HPV load: pregnant women with different grade of CIN and cervicitis HR-HPV DNA load were CIN III 2.02 ng/L(1.53, 2.67 ng/L), CINII 1.94 ng/L (0.75, 2.75 ng/L), CINI2.04 ng/L (0.08, 2.95 ng/L) and cervicitis 1.98 ng/L (-0.07, 2.47 ng/L). There was no significantly different HPV load in women with cervicitis and different CIN (P = 0.719). At 3 - 6 months postpartum, HR-HPV load was CIN III 1.55 ng/L (0.90, 2.10 ng/L), which was significantly higher than the amount of CINII 0.09 ng/L (-0.69, 1.74 ng/L), CINI0.48 ng/L (-0.56, 2.2 ng/L) and cervicitis -0.46 ng/L (-0.78, 1.40 ng/L, P = 0.036)., Conclusions: With the increasing of CIN grade, the rate of HR-HPV infection in pregnant women was increased, however, the rate of HR-HPV turning negative naturally at 3 - 6 months postpartum decreased. With different CIN grade during pregnancy, HR-HPV DNA load did not change significantly, but HR-HPV DNA load increased at 3 - 6 months of postpartum. HR-HPV DNA loads with the same grade of CIN and cervicitis during pregnancy higher than that of postpartum among pregnant women.

Objective: MicroRNA (miRNA) plays an essential role in the progression of a variety of cancers, but its role in cervical cancer progression is not well defined. We aimed to test whether special miRNAs and their target mRNAs contribute to cervical cancer progression., Methods: The expression profiles of 1145 microRNAs in cervical squamous cell carcinomas (CSCC) and adjacent non-tumor tissues were investigated using an Illumina microRNA microarray platform. Differentially expressed miRNAs were validated by RT-PCR. Downstream target validation was performed for miR-886-5p., Results: We found that the expression levels of seven miRNAs differed significantly between CSCC tissues and adjacent non-tumor tissues. Forced expression of one miRNA, miR-886-5p, over-expressed in CSCC tissues lowered expression of the pro-apoptotic protein Bax, reduced apoptosis and promoted cell proliferation in H8, an HPV16-immortalized human cervical squamous epithelial cell line. Knockdown of miR-886-5p increased Bax protein and apoptotic cell death in cells of the cervical squamous carcinoma cell line, SiHa., Conclusion: MicroRNA miR-886-5p inhibits apoptosis of cervical cancer cells by down-regulating the production of Bax., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To investigate the risk factors associated with abnormal cervical cytology findings in pregnant women., Methods: From Sep. 2007 to Sep. 2008, 12,112 pregnant women who underwent their antenatal examinations at 12-36 gestational weeks in Beijing Obstetrics and Gynecology Hospital were enrolled in this study. They were all excluded from the following pathologic obstetrics factors including threatened abortion, premature rupture of membranes or placental previa. Thinprep cytology test (TCT) were given at their first examination, meanwhile, a personal clinic file was established to record her occupation, education, address, family income, nationality, age of first intercourse, number of sex partners, contraception, marriage and pregnancy, current gynecologic diseases, family history of gynecologic tumors, history of gynecologic diseases and smoking and result of pelvic examination. Those risk factors leading to abnormal cervical cytology were analyzed., Results: The complete clinical data were collected from 11 906 cases (98.30%, 11,906/12,112). It was found that 10,354 women were shown with normal TCT result, however, 1134 women (9.52%, 1134/11,906) with atypical squamous cells of undetermined significance (ASCUS), 112 women (0.94%, 112/11,906) with atypical glandular cells of undetermined significance (AGUS), 229 women (1.92%, 229/11,906) with low grade squamous intraepithelial (LSIL), 74 women (0.62%, 74/11,906) with high grade squamous intraepithelial (HSIL). Multiple factorial non-conditioned logistic regression analysis showed that age of first sexual intercourse (OR(ASCUS) = 2.90, OR(AGUS) = 7.32), number of sex partners (OR(ASCUS) = 1.49, OR(AGUS) = 2.02), number of abortion (OR(ASCUS) = 1.68, OR(AGUS) = 3.50) were correlated with ASCUS and AGUS. In LSIL group and HSIL group, age of first sexual intercourse (OR(LSIL) = 6.34, OR(HSIL) = 9.26), number of sex partners (OR(LSIL) = 1.69, OR(HSIL) = 1.65), number of abortion (OR(LSIL) = 1.53, OR(HSIL) = 5.33), smoking (OR(LSIL) = 1.84, OR(HSIL) = 1.77) were remarkable variables. The infection of human papilloma virus (HPV) and trichomonas vaginitis were correlated with abnormal cervical cytology (including ASCUS, AGUS, LSIL and HSIL) significantly (P < 0.01). Columnar epithelium dystopia were also significantly correlated with abnormal cervical cytology (chi(2) = 43.269, P = 0.000). However, abnormal cervical cytology was uncorrelated with degrees of Columnar epithelium dystopia., Conclusions: The risk factors associated with abnormal cervical cytology in pregnant women were the same with those of non-pregnant women.

Objective: To explore the situation of residual lesions in excision margin after loop electrosurgical excision procedure (LEEP) and cold knife conization (CKC) and the risk factors of recurrence in the cases featuring with positive margin., Methods: The medical records of 1213 women undergoing LEEP or CKC, aged (35 +/- 5) (22-40), were retrospectively reviewed. 148 of the 1213 patients (12.2%) who were identified as with positive margin were re-underwent pathological reexamination. 118 of the 148 patients were diagnosed as with cervical intraepithelial neoplasia III (CIN III) and 30 as with stage Ia invasive cervical carcinoma. These patients were followed up for 12-99 months. The pathologic diagnoses, position of positive margin, and residual lesion in subsequent specimens were analyzed., Results: Endocervical positive margins were identified in 30 of the 118 (25.4%) CIN III patients and 26 of the 30 (86.6%) stage Ia patients. Residual lesions were found in 15 of the 28 (53.6%) stage Ia cases and 4 pf the 19 (19%) CIN III cases. The rates of endocervical positive margin and residual lesion were higher in stage Ia patients. The risk of residual lesion was 53.1% (17/32) in the patients with endocervical positive margins, significantly higher than that of the patients with extracervical positive margin (16.7%). Recurrence was found in 90 patients during follow-up., Conclusion: Residual lesions often occur in some patients with positive margin. Choice between additional surgery and closely follow-up in the young patients with positive margins who want to preserve their fertility depends on the lesion seriousness and positive position. Residual lesions more frequently exist in the patients with microinvasion and endocervical positivity. Additional surgery should be considered in these cases.