Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.

Evaluation of the Accuracy of a Polymerase Chain Reaction-Based Assay for Polymerase Epsilon Mutation Detection in Endometrial Carcinoma.

CONTEXT.­: Molecular stratification of endometrial carcinoma provides more accurate prognostic information than traditional clinicopathologic features. However, because next-generation sequencing is typically recommended for polymerase epsilon (POLE) mutation detection, the practical application of a test based on molecular stratification is limited in the clinical setting. OBJECTIVE.­: To evaluate a polymerase chain reaction (PCR)-based assay for POLE mutation detection in endometrial carcinoma. DESIGN.­: We developed a PCR-based technology called Dalton Mutation Identifier Technology (Dalton-MIT) that targets 9 mutation sites within POLE exons. Endometrial carcinoma specimens from 613 patients were tested for POLE mutations. Correlations between POLE mutations with patient clinicopathologic characteristics and prognosis were analyzed. RESULTS.­: PCR detection data showed that the incidence rate of POLE mutation was 11.4% (70 of 613). Patients with POLE mutations presented better clinicopathologic characteristics and prognosis than those with non-POLE mutations. Comparison between Dalton-MIT and next-generation sequencing in 59.5% (365 of 613) of specimens showed that the sensitivity of Dalton-MIT for detecting POLE pathogenic mutations was 100%, the specificity was 99.3%, the Youden index was .993, and the κ value was .981 (P < .001). CONCLUSIONS.­: Our data demonstrate that POLE mutation detection by Dalton-MIT correlates with next-generation sequencing. This suggests that Dalton-MIT represents a promising alternative assay for detecting POLE mutations and will facilitate the wider application of molecular stratification tools for endometrial carcinoma in the clinic.

Interactions between vaginal local cytokine IL-2 and high-risk human papillomavirus infection with cervical intraepithelial neoplasia in a Chinese population-based study.

Background: Although interleukin-2 (IL-2) has long been associated with cancer development, its roles in the development of cervical cancer remains unclear. Few studies examined the associations between IL-2 and high-risk human papillomavirus (HPV) with risk of cervical intraepithelial neoplasia (CIN). Objective: We aimed to assess the association of IL-2 and high-risk HPV infection with risk of CIN as well as their interactions on the risk of CIN. Design: We performed a cross-sectional analysis of screening data in 2285 women aged 19-65 years who participated in an ongoing community-based cohort of 40,000 women in Shanxi, China in 2014-2015. Both categorical and spline analyses were used to evaluation the association between IL-2 in the local vaginal fluids and prevalence of CIN. In addition, 1503 controls were followed up until January 31, 2019), the nested case-control study design was adopted to evaluate the association of vaginal lavage IL-2 levels and the risk of CIN progression. Results: After adjusting for potential confounders, IL-2 levels were statistically inversely associated with prevalence of CIN (the 1st versus 4th quartile IL-2 levels: the respective odds ratio [OR] and 95% confidence intervals [CI] was: = 1.75 [1.37, 2.23] for CIN, 1.32 [1.01, 1.73] for CIN I, and 3.53 [2.26, 5.52] for CIN II/III). Increased IL-2 levels were inversely associated with prevalence of CIN (P-overall<0.01, P-nonlinearity<0.01 for CIN; P-overall<0.01, P-nonlinearity = 0.01 for CIN I; P-overall <0.01, P-nonlinearity = 0.62 for CIN II/III). The highest prevalence of CIN was observed in women with high-risk HPV, who also had the lowest IL-2 levels (P-interaction < 0.01). Nested case-control study observed an inverse association between IL-2 levels and risk of CIN progression (OR=3.43, [1.17, 10.03]). Conclusions: IL-2 levels in the local vaginal fluids were inversely associated with the risk of CIN in Chinese women either with or without high-risk HPV infection.

Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.

Molecular profile-based recommendations for postoperative adjuvant therapy in early endometrial cancer with high-intermediate or intermediate risk: a Chinese randomized phase III trial (PROBEAT).

BACKGROUND: The use of molecular categorisation is shifting paradigm towards the use of molecular information to refine risk stratification in endometrial cancer (EC). To date, evidence to support molecular-guided therapies is limited to retrospective studies and secondary molecular analyses of patients receiving standard treatment. The PROBEAT study is the first randomized phase III trial to evaluate tailored adjuvant treatment based on WHO-endorsed molecular classification in Chinese EC patients. It is expected to provide a clinical decision-making tool for adjuvant treatment of patients with high-intermediate risk (HIR) or intermediate risk (IR) EC to better optimise and personalise patient care and increase relapse-free survival. METHODS: The PROBEAT trial is a prospective, multicentre study led by Women's Hospital of Zhejiang University Gynaecologic Oncology Group. Recruitment started on January 24, 2022, and 590 patients with HIR or IR endometrioid EC are expected to be recruited from 13 clinical centres in China. All tumor tissues will be classified into four molecular subtypes (POLEmut, MMRd, p53abn, or NSMP) based on WHO-endorsed molecular classification. Patients will be randomly assigned at a 2:1 ratio to either experimental arm and will receive molecular profile-based adjuvant treatment (observation in the POLEmut subgroup, vaginal brachytherapy in the MMRd or NSMP subgroup, or chemoradiotherapy in the p53abn subgroup) or to standard arm and will receive preferred adjuvant radiotherapy as recommended by the recent National Comprehensive Cancer Network guidelines version 1 (2022). The primary outcome is 3-year rates of recurrence. Secondary outcomes are relapse-free survival, overall survival, adverse events and health-related cancer-specific quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05179447.

Comparison of the safety between cervical conization and hysterectomy for patients with cervical adenocarcinoma in situ.

OBJECTIVE: To compare the safety between cervical conization (CC) alone and hysterectomy for patients with adenocarcinoma in situ (AIS) of the cervix. METHODS: Patients diagnosed with AIS after CC during 2007-2021 were identified by computerized databases at Women's Hospital of Zhejiang University School of Medicine. A total of 453 AIS patients were divided into 2 groups according to uterus preservation: hysterectomy group (n=300) and CC(s) alone group (n=153). The prevalence of residual disease and disease recurrence was compared between patients treated by CC(s) alone and hysterectomy. The prevalence of residual disease in specimens from women who had a hysterectomy and repeat CC were compared between positive and negative margins of CC. The factors influencing residual disease and disease recurrence were assessed. RESULTS: Among 310 specimens from women who had a hysterectomy or repeat CC, the prevalence of residual disease was 50.6% (45/89) for a positive margin and 2.3% (5/221) for a negative margin (p=0.000). Four patients had recurrence of vaginal intraepithelial neoplasia in those treated by hysterectomy and one had recurrence of cervical squamous intraepithelial neoplasia in those treated by CC(s) alone. The prevalence of recurrence was 0.7% (1/153) for CC(s) alone and 1.3% (4/300) for hysterectomy (p=0.431). Hysterectomy did not influence residual disease or disease recurrence. CONCLUSION: CC is an efficacious and safe option for patients with AIS of the cervix provided the margin is negative.

Neoadjuvant chemotherapy for patients with international federation of gynecology and obstetrics stages IB3 and IIA2 cervical cancer: a multicenter prospective trial.

BACKGROUND: Preoperative neoadjuvant chemotherapy (NACT) has been widely used in developing countries for the treatment of patients with International Federation of Gynecology and Obstetrics (FIGO) stages IB3 and IIA2 cervical cancer. However, the effectiveness of NACT and treatment options for NACT-insensitive patients have been concerning. This study will assess prognostic differences between NACT and primary surgery treatment (PST), determine factors associated with prognosis, and explore better adjuvant treatment modalities for NACT-insensitive patients. METHODS: This study analyzed clinical characteristics, pathological characteristics, treatment options, and follow-up information of 774 patients with FIGO stages IB3 and IIA2 cervical cancer from 28 centers from January 2016 to October 2019 who participated in a multicenter, prospective, randomized controlled trial. RESULTS: For patients undergoing NACT, the 5-year OS and PFS rate was 85.8 and 80.5% respectively. They were similar in the PST group. There was no significant difference in OS and PFS between clinical response (CR)/partial response (PR) groups and stable disease (SD)/progressive disease (PD) groups. Apart from deep cervical invasion (p = 0.046) affecting OS for patients undergoing NACT, no other clinical and pathological factors were associated with OS. 97.8% of NACT-insensitive patients opted for surgery. If these patients did not have intermediate- or high-risk factors, whether they had undergone postoperative adjuvant therapy was irrelevant to their prognosis, whereas for patients with intermediate- or high-risk factors, adjuvant chemotherapy resulted in better PFS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.019) and OS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.002). CONCLUSIONS: NACT could be a choice for patients with FIGO stages IB3 and IIA2 cervical cancer. The main risk factor influencing prognosis in the NACT group is deep cervical invasion. After systematic treatment, insensitivity to NACT does not indicate a poorer prognosis. For NACT-insensitive patients, Chinese prefer surgery. Postoperative adjuvant therapy in patients with no intermediate- or high-risk factors does not improve prognosis, and chemotherapy in patients with intermediate- and high-risk factors is more effective than radiation therapy and other treatments. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03308591); date of registration: 12/10/2017.

HPV16 E6-Activated OCT4 Promotes Cervical Cancer Progression by Suppressing p53 Expression via Co-Repressor NCOR1.

Human papillomaviruses (HPV), mainly HPV16 and HPV18, of high-risk classification are involved in cervical cancer carcinogenesis and progression. Octamer-binding transcription factor 4 (OCT4) is a key transcription factor that is increased in various cancer types. Cervical cancer patients with higher levels of OCT4 had worse survival rates. However, the definite mechanisms underlying its function in the development of cervical cancer still remain to be explicated. Here, our study demonstrated that OCT4 expression was slightly increased in cervical cancer tissues than in precancerous ones. However, OCT4 was significantly upregulated in HPV16-positive tissues, in contrast to the expression profiling for p53. Moreover, knockdown of HPV16 E6 in SiHa cells suppressed the expression of OCT4 with impaired activities of cell proliferation, migration, and invasion, while it recovered the expression of p53. Overexpression of OCT4 and p53 exerted opposite roles on cell proliferation, migration, invasion, and colony formation of cervical cancer cells. More importantly, the enforced expression of OCT4 augmented p53-inhibited cell migration, invasion, and colony formation in human cervical cancer by promoting EMT. Finally, we identified that OCT4 could bind to the p53 promoter region to repress p53 expression by recruiting co-repressor NCOR1 using luciferase, ChIP, and co-IP experiments. We further illustrated that OCT4 not only increased the lung metastasis of cervical cancer but also effectively reversed p53-inhibited lung metastasis. In conclusion, our results suggested that HPV16 E6 activated the expression of OCT4 and subsequently crippled the transcription of p53 via co-repressor NCOR1, which contributed to cervical cancer progression.

Associations of RBC and Serum Folate Concentrations with Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus Genotypes in Female Chinese Adults.

BACKGROUND: Although folate status is associated with cervical carcinogenesis, it is not clear whether folate deficiency is associated with risk of cervical intraepithelial neoplasia (CIN) progression and infection with high-risk human-papillomavirus (hrHPV). OBJECTIVES: To evaluate the associations of RBC and serum folate concentrations with prevalence of CIN grades and hrHPV infection, their interactions with prevalence of CIN grades, and RBC folate with the risk of CIN1 progressing to CIN2. METHODS: Using data from the Shanxi CIN cohort of 2304 female Chinese adults, we used logistic-regression model to estimate ORs and prevalence ratios (PRs) of RBC and serum folate concentrations with prevalence of CIN grades and hrHPV infection. Categoric and spline analyses were used to evaluate the dose-response relations. We estimated the association of RBC folate with risk of CIN1 progressing to CIN2 in the nested case-control cohort. RESULTS: An inverse association was observed between increased RBC folate concentration and the odds of all CIN grades [quartile 1 (Q1) compared with Q4: OR: 2.28; 95% CI: 1.77, 2.93; Ptrend < 0.001]. Significant interaction of RBC folate and hrHPV infection was observed for prevalence of CIN2 or above (Pinteraction < 0.01). No associations were found between RBC and serum folate with PRs of hrHPV in each CIN grade. Over a median follow-up of 21.0 mo, RBC folate was associated with increased risk of CIN1 progressing to CIN2 (Q1 compared with Q4: OR: 3.86; 95% CI: 1.01, 14.76). CONCLUSIONS: Our study indicates that RBC folate concentration is associated with prevalence of CIN grades and CIN1 progression in female Chinese adults. Maintenance of normal folate status is important for reducing the risk of CIN and its progression in women with or without hrHPV infection.

Inhibitory effect of pirfenidone on pulmonary fibrosis in patients with acute paraquat poisoning.

OBJECTIVE: To study the efficacy of pirfenidone (PFD) on patients with pulmonary fibrosis caused by acute paraquat (PQ) poisoning. METHODS: A total of 86 patients with pulmonary fibrosis caused by acute PQ poisoning admitted to our hospital were analyzed retrospectively. All of them successfully received the standard 21-day treatment based on "Taishan Consensus", and they were assigned to the PFD group or the NO-PFD group according to whether they received PFD treatment (at 200 mg/time, 3 times/day) for 6 months after discharge. The two groups were compared in effective treatment rate, mortality and incidence of adverse reactions such as liver and kidney function damage, pulmonary fibrosis-associated indexes, pulmonary function-associated indexes, and arterial blood gas indexes before and after therapy. RESULTS: The PFD group showed a notably higher effective treatment rate than the NO-PFD group (P<0.05). Additionally, the PFD group showed notably lower levels of serum hyaluronic acid (HA), laminin (LN), type IV collagen (CIV), and type III procollagen (PCIII), and notably higher levels of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC than the NO-PFD group (all P<0.001), and the PFD group also showed significantly higher levels of arterial blood gas indexes including arterial partial pressure of oxygen (PaO2) and PaO2/inspired oxygen (FIO2) than the NO-PFD group (both P<0.001). Moreover, the Kaplan-Meier survival curves showed that the survival rate of the patients in PFD group was significantly higher than that in the NO-PFD group (P<0.05). CONCLUSION: With a high safety, PFD can effectively improve the treatment efficacy in patients with pulmonary fibrosis caused by acute PQ poisoning. PFD can improve the pulmonary function and arterial blood gas status of patients, without causing obvious liver and kidney damage.

Potential of peptide-engineered exosomes with overexpressed miR-92b-3p in anti-angiogenic therapy of ovarian cancer.

INTRODUCTION: Exosomal microRNA (miRNA) as a mediator of intercellular communication plays an essential part in tumor-relevant angiogenesis. Therapy against angiogenesis has been demonstrated to have a remarkable antitumor efficacy in various malignancies, but not as expected in ovarian cancer. METHODS: Exosomes were isolated by ultracentrifugation. Exosomal miRNA sequencing and gene function experiments were used to identify the differential expressed miRNAs in exosomes and their mRNA targets. SKOV3 cell line that stably overexpressed miR-92b-3p was constructed by lentivirus. In vitro, angiogenesis was analyzed by tube formation assay and migration assay. The angiogenic and antitumor effects in vivo were assessed in zebrafish and nude mouse models. Combination index was calculated to assess the synergetic inhibition of angiogenesis between miR-92b-3p and Apatinib. Peptides were conjugated with exosomal membranes to obtain engineered exosomes. RESULTS: Ovarian cancer cell-derived exosomes facilitated the angiogenesis and migration capability of vascular endothelial cells in vitro and in vivo. The expression of miR-92b-3p was much lower in ovarian cancer cell-derived exosomes than that in immortalized ovarian epithelial cell-derived exosomes. The exosomal miR-92b-3p modulated tumor-associated angiogenesis via targeting SOX4. Besides, Peptide-engineered exosomes with overexpressed miR-92b-3p showed the stronger abilities of anti-angiogenesis and antitumor than parental exosomes, whether alone or combined with Apatinib. CONCLUSIONS: Our findings demonstrate the effect and mechanism of exosomal miR-92b-3p from ovarian cancer cells on tumor-associated angiogenesis and the potential of artificially generated exosomes with overexpressed miR-92b-3p to be used as anti-angiogenic agent, which may provide a new approach for anti-angiogenic therapy of ovarian cancer.

Efficient combination of Human Papillomavirus Genotyping for the triage of women with Atypical Squamous Cells of Undetermined Significance in Chinese rural population: A population-based study.

Objective: In this prospective, population-based study, we evaluated the utility of high-risk human papillomavirus (HR-HPV) genotyping for triaging women with atypical squamous cells of undetermined significance (ASC-US) in the Chinese rural area. Methods: A total of 40,000 women were recruited from rural areas of Shanxi Province, China, between June 2014 and December 2014. Women with Pap results of ASC-US underwent HPV genotyping, colposcopy and histopathological examination. For those with normal cervixes or cervical intraepithelial neoplasia (CIN) 1 on the initial evaluation, a 2-year follow-up study was performed. Results: The reporting rate of ASC-US was 5.76% (2,304/40,000) in the study population. The detection rates of CIN 2 or above (CIN2+) and CIN 3 or above (CIN3+) in women with ASC-US were 7.28% and 1.75%, respectively. HPV 16 (39.53%), HPV 58 (17.83%), and HPV 52 (15.50%) were the three most prevalent HR-HPV genotypes among all women with ASC-US cytology. The five most common HR-HPV genotypes in CIN3+ lesions were HPV16, HPV58, HPV33, HPV31 and HPV18. Compared with the 15 HR-HPV testing, genotyping for a combination of HPV16/18/31/33/58 increased specificity significantly with virtually no loss of sensitivity for detecting CIN2+ and CIN3+ lesions, as well as significantly reduced colposcopy referral rate (23.15% vs 33.70%, p<0.01). In addition, in the 2-year follow-up period, women with infection of HPV16, 18, 31, 33 or 58 genotypes were the most likely population (92%, 23/25) to develop CIN2 lesion. Conclusion: Our results demonstrate that genotyping for a combination of HPV16/18/31/33/58 provides a more efficient and cost-effective model to risk-stratify women with ASC-US in the Chinese rural population.

Lower dietary mineral intake is significantly associated with cervical cancer risk in a population-based cross-sectional study.

Population-based studies investigating the association between dietary mineral intake and risk of cervical intraepithelial neoplasia (CIN) or cervical cancer in Chinese women are few. We performed a cross-sectional analysis of screening data obtained from 2,304 women in 2014 within an ongoing cohort study comprising 40,000 women in China. Dietary intake was assessed using a semiquantitative food frequency questionnaire. Nutrition intake was calculated using a 26-item list of food sources drawn from a validated, comprehensive database. All participants were surveyed through in-person interviews, physical examinations, and laboratory tests. The Pearson chi-square test was used for categorical variables. Multivariable logistic regression models were used to evaluate the relationship between dietary mineral intake and CIN+ risk. The food frequency questionnaire exhibited acceptable reproducibility and reasonable validity in assessing nutrient intakes among these women. After adjusting for multiple potential confounders, low dietary calcium intake was associated with CIN2+ risk (first versus fourth quartile: odds ratio [OR]=1.52, 95% confidence interval [CI]: 1.01-2.32). Similar for magnesium (OR=1.80, 95% CI: 1.20-2.68), phosphorus (OR=1.69, 95% CI: 1.12-2.55), zinc (OR=1.55, 95% CI: 1.03-2.34), and potassium (OR=1.92, 95% CI: 1.28-2.88). Low dietary intakes of calcium and potassium were significantly associated with CIN1 risk. Increased CIN2+ risk correlated with rates of no oral contraceptives and lower levels of dietary Potassium. These results thus proposed that low dietary mineral intake was an independent risk factor, potential synergy may exist between low dietary mineral levels and oral contraceptives contribute to the development of higher-grade CIN and cervical cancer.

Preoperative predictive factor analysis of ovarian malignant involvement in premenopausal patients with clinical stage I endometrioid endometrial carcinoma.

Earlier literature suggests that ovarian preservation in young premenopausal clinical stage I endometrioid endometrial carcinoma patients does not negatively impact prognosis. The main purpose of this study was to clarify the incidence of ovarian malignant involvement in this group and further identify potential preoperative predictive factors of ovarian malignant involvement. A total of 511 premenopausal (age ≤ 50 years) patients were enrolled for the study at Women's Hospital, Zhejiang University School of Medicine, between January 2002 and December 2016. Ovarian malignant involvements were detected in 23 of the patients (4.5%). Univariate and multivariate logistic analysis validated preoperative imaging of myometrial invasion depth and preoperative serum carbohydrate antigen 125 (CA125) level as independent risk predictors of postoperative ovarian malignant involvement. Receiver operating characteristic (ROC) curves was generated for a combination of the two factors. The area under curve (AUC) was 0.772 (95% confidence interval [CI] 0.661-0.884) for the combined two factors. The incidence of postoperative ovarian malignant involvement was relatively minimal. Preoperative imaging of myometrial invasion depth and serum CA125 level were independent risk predictors of ovarian malignant involvement. These findings may facilitate preoperative counseling of patients and informed clinical decision-making on ovarian preservation in these patients.

Dietary nutrient intake related to higher grade cervical intraepithelial neoplasia risk: a Chinese population-based study.

BACKGROUND: Dietary nutrient intake plays a significant role in carcinogenesis. Few studies have investigated the association between dietary nutrient intake and cervical intraepithelial neoplasia (CIN) risk in China. METHODS: Data on 2304 women from an ongoing cohort comprising 40,000 women from China in 2014 were included. Study randomly selected 218 out of 2304 people as subjects during 2019. All participants were surveyed through in-person interviews, physical examinations, and laboratory tests. Clinical data were obtained from physical examinations and laboratory tests. Dietary intakes were assessed using a semiquantitative food frequency questionnaire. Nutrition intakes from 26 food sources were calculated using a comprehensive validated database. Descriptive statistics were used to describe the frequency and proportion, and mean and standard deviation of the demographic characteristics. Characteristics were examined for significant differences, and Pearson chi-square tests were used for categoric variables. Logistic regression was used to obtain odds ratios (ORs) and confidence intervals (CIs) for CIN risk in each nutrient intake quartile relative to that in the highest quartile. RESULTS: The food frequency questionnaire exhibited acceptable reproducibility and reasonable validity in assessing nutrient intakes among these women. After adjusting for multiple confounders, several dietary nutrients showed significant associations with CIN2+ risk. Low dietary folate intake was associated with the risk of CIN2+ (first versus fourth quartile: OR = 1.55, 95% CI 1.03-2.33). Similar results were also observed for vitamin B6 (OR = 1.63, 95% CI 1.08-2.46), vitamin C (OR = 1.59, 95% CI 1.05-2.42), niacin (OR = 1.65, 95% CI 1.08-2.51), and vitamin K (second versus fourth quartile: OR = 1.60, 95% CI 1.05-2.44). CONCLUSIONS: Low folate; vitamin B6, C, and K; and niacin intakes were associated with CIN2+ risk. Nutrients may influence the development of higher grade CIN and cervical cancer. Trial registration The study was registered in the Chinese Clinical Trial Register (ChiCTR-ROC-15006479) ( https://www.chictr.org.cn ).

Combined Evaluation of Preoperative Serum CEA and CA125 as an Independent Prognostic Biomarker in Patients with Early-Stage Cervical Adenocarcinoma.

PURPOSE: There is currently a lack of research on preoperative prognostic analysis of early-stage cervical adenocarcinoma (ADC). The purpose of our study was to clarify whether preoperative serum tumor-marker levels were of prognostic value in early-stage ADC. PATIENTS AND METHODS: We performed a retrospective study of patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA1-IIA1 and pathology-proven invasive ADC. We evaluated the relationship between preoperative serum tumor-marker levels and clinicopathological characteristics, and identified the relative preoperative risk factors affecting disease-free survival (DFS) and overall survival (OS). The optimal cut-off point of meaningful tumor markers was determined by the analysis of receiver operating characteristics (ROC), and the accuracy of the results was evaluated by the area under the curve (AUC). RESULTS: Elevated carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), squamous cell carcinoma antigen (SCC-Ag), alpha-fetoprotein (AFP), carbohydrate antigen 153 (CA153) and carbohydrate antigen 199 (CA199) were associated with certain clinicopathologic features of early-stage ADC. The combination of elevated serum CEA and CA125 was significantly associated with FIGO stage, body mass index (BMI) and LNM. Kaplan-Meier survival curve and Cox regression analyses revealed that CEA and CA125 might have significant prognostic implications in early-stage ADC patients, and the combination of elevated serum CEA and CA125 served as an independent predictor of early-stage ADC. The optimal cut-off point of serum CA125 for prediction DFS and OS was 32.60 U/mL and of serum CEA were 2.85 ng/mL and 2.05 ng/mL, respectively. The AUC showed that serum CEA was a moderate predictor of OS. CONCLUSION: The preoperative serum levels of CEA and CA125 might have significant prognostic implications in early-stage ADC patients. Combined preoperative serum CEA and CA125 levels independently predicted the prognosis of early-stage ADC.

Diagnostic Yield and Performance of a Large Population-Based Cervical Cancer Screening Program in High-Risk Rural China.

Primary cervical cancer screening by liquid-based cytology alone or with adjunctive HPV testing are available worldwide. However, little if any information is available about cervical cancer diagnostic yield of population-based cervical cancer screening in China. In response to it, we conducted a large prospective study on 40,000 women cervical cancer screening within six-month period in rural Shanxi Province, where has been reported as the highest cervical cancer rates in China. A standard cross-sectional survey by self-completed questionnaire was collected and followed by the liquid-based cytology screening. Follow-up biopsy with the diagnosis of cervical intraepithelial neoplasia 2 or higher lesion (CIN2+) were analyzed. Of initial 40,000 women participating in this study, 6.76% (2702/40,000) women had ASC-US or higher cytology screening results with ASC/SIL ratio at 6.14 (2381:388). Among them, 1.96% (782/40,000) women were found CIN lesions (95% CI, 1.68-2.23%) on confirmatory biopsies, including 0.55% (218/40,000) CIN2+ and 19 SCCa (47.5/100,000, 95% CI, 29-74/100,000). Women in Yangqu County had lower ASC/SIL ratio, but higher CIN2+ detection rate in comparison with that of Jiexiu County (6.69 vs. 8.84 and 56.7% vs. 43.9%), which reflects the cervical cancer distribution in different populations and regions. Analysis in age-stratified cytology results indicated women aged 60-65 years had the highest incidence of cytologic abnormality among all the age group; likewise, women aged >50 years were at higher risk in developing cervical high grade dysplasia or cancer than women aged <50 years (0.82% vs. 0.49%). This large-scale cervical cancer screening study provided important references as the instructive for establishing the nation-wide cervical cancer screening strategy.

Transverse parallel compression suture: a new suturing method for successful treating pernicious placenta previa during cesarean section.

PURPOSE: To report a novel method to achieve hemostasis and to evaluate efficacy and safety of controlling hemorrhage from the lower uterine segment (LUS) during cesarean section for placenta previa and accrete compared with conventional surgery. METHODS: From January 2017 to June 2019, there were 65 cases of pernicious placenta previa admitted in our obstetric department. They all had performed selective cesarean sections. Transverse parallel compression suture was applied in 32 cases during cesarean sections. The bladder was reflected downward till the lowest point of placenta implanted. Two plastic drains were inserted into internal and through the external os, as a support for compressing and draining the uterine cavity. First, at one side of LUS, a Vicryl number one stitch was inserted borderline of myometrium from the anterior to the posterior. The stitch was then inserted borderline of myometrium from the posterior to anterior at the other side in horizontal direction and tightened on the anterior wall of uterine surface. Another suture was inserted superiorly or inferiorly to the first one, at 1 cm interval. Then, such sutures were stitched until the bleeding and dilated LUS became all compressed. The uterine incision was then stitched [group 1 (Gr1)]. Other 33 cases were managed with conventional surgery [group 2 (Gr2)]. The efficiency of this novel technique, in term of blood loss, operation time, the intensive-care unit (ICU) admission rate and hospitalization time after surgery, complications, and postoperative recovery, was compared over the same period. RESULTS: With our transverse parallel compression suture, we were able to preserve the uterus in all cases, while two patients underwent hysterectomy in Gr2. Our success rate in hemostasis was 93.8% (30/32). The operation time, the length of ICU stay, and the rate of ICU admission of Gr1 were lower than Gr2. All patients resumed a normal menstrual flow, and no long-term complications were observed during follow-up. CONCLUSION: Transverse parallel compression suture is an easy, effective, and safe method to stop bleeding from the lower uterine segment in women with placenta previa and accrete.

Placental Delta-Like 1 Gene DNA Methylation Levels Are Related to Mothers' Blood Glucose Concentration.

PURPOSE: We aim to identify the methylation status of delta-like 1 (DLK1) in the placenta and the correlation between DLK1 methylation and maternal serum glucose level and fetal birth weight. METHODS: We analyzed the gene expression of DLK1 gene in both maternal and fetal sides of the placenta in a GDM group (n = 15) and a control group (n = 15) using real-time polymerase chain reaction. With MethylTargetTM technique, we detected the methylation status of DLK1 promotor in the placenta. Furthermore, Pearson's correlation was used to confirm the association of methylation alteration of DLK1 promoter and maternal 2 h OGTT glucose level and fetal birth weight. RESULTS: In our study, we found that DLK1 expression in both maternal and fetal sides of the placenta decreased significantly in GDM group compared with control group, and it was caused by hypermethylation of DLK1 promoter region. Additionally, the methylation status of DLK1 gene in the maternal side of the placenta highly correlated with maternal 2 h OGTT glucose level (coefficient = 0.7968, P < 0.0001), while the methylation status in the fetal side of the placenta was closely related to fetal birth weight (coefficient = 0.6233, P < 0.0001). CONCLUSIONS: Our results demonstrated that altered expression of DLK1 was caused by the hypermethylation of DLK1 promoter region in the placenta, and intrauterine exposure to GDM has long-lasting effects on the epigenome of the offspring.

The value of hysteroscopy and transvaginal ultrasonography in the diagnosis of endometrial hyperplasia: a systematic review and meta-analysis.

BACKGROUND: The systematic evaluation of the diagnostic value of hysteroscopy and transvaginal ultrasonography for endometrial hyperplasia. METHODS: A systematic search was performed using China Knowledge Network Database, Wanfang Chinese Database, China Biomedical Literature Database, China Science and Technology Journal Database, PubMed, Medline, The Cochrane Library, and web of science from their dates of inception to December 31, 2017, hysteroscopy and transvaginal ultrasonography were used for the diagnosis of endometrial lesions in those studies. Two researchers screened the literature, extracted data, and evaluated the methodological quality of the included studies independently based on the inclusion criteria. RESULTS: A total of 1,354 cases were incorporate into analysis from 9 diagnostic studies meta-analysis showed that the diagnostic accuracy of hysteroscopy for endometrial hyperplasia lesions were: combined sensitivity =0.73 (95% CI: 0.68-0.77), combined specificity =0.92 (95% CI: 0.90-0.93), combined positive likelihood ratio =9.87 (95% CI: 4.08-23.84), combined negative likelihood ratio =0.34 (95% CI: 0.22-0.52), combined diagnostic odds ratio =31.64 (95% CI: 10.34-96.78), area under the summary receiver operating characteristic curve =0.8830. The combined sensitivity of transvaginal ultrasonography for those lesions were 0.69 (95% CI: 0.64-0.74), combined specificity was 0.78 (95% CI: 0.76-0.81), combined negative likelihood ratio was 3.40 (95% CI: 2.46-4.70), combined negative likelihood ratio was 0.41 (95% CI: 0.34-0.50), combined diagnostic odds ratio was 8.94 (95% CI: 5.80-13.79), and area under the summary receiver operating characteristic curve was 0.8180. CONCLUSIONS: Compared with transvaginal ultrasonography, hysteroscopy have higher sensitivity, specificity, and area under the summary receiver operating characteristic curve for the diagnose of endometrial hyperplasia, hysteroscopy should be selected priority as the auxiliary diagnosis.