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Background: Poly adenosine-diphosphate-ribose polymerase (PARP) inhibitors (PARPi) have been approved to act as first-line maintenance (FL-M) therapy and as platinum-sensitive recurrent maintenance (PSR-M) therapy for ovarian cancer in China for >5 years. Herein, we have analyzed the clinical-application characteristics of olaparib and niraparib in ovarian cancer-maintenance therapy in a real-world setting to strengthen our understanding and promote their rational usage., Methods: A retrospective chart review identified patients with newly diagnosed or platinum-sensitive recurrent ovarian cancer, who received olaparib or niraparib as maintenance therapy at Sichuan Cancer Hospital between August 1, 2018, and December 31, 2021. Patient medical records were reviewed. We grouped and analyzed patients based on the type of PARPi they used (the olaparib group and the niraparib group) and the line of PARPi maintenance therapy (the FL-M setting and the PSR-M setting). The primary endpoint was the 24-month progression-free survival (PFS) rate., Results: In total, 131 patients (olaparib: n = 67, 51.1%; niraparib: n = 64, 48.9%) were enrolled. Breast cancer susceptibility genes (BRCA) mutations (BRCAm) were significantly less common in the niraparib group than in the olaparib group [9.4% (6/64) vs. 62.7% (42/67), P <0.001], especially in the FL-M setting [10.4% (5/48) vs. 91.4% (32/35), P <0.001]. The 24-month PFS rates in the FL-M and PSR-M settings were 60.4% and 45.7%, respectively. In patients with BRCAm, the 24-month PFS rates in the FL-M and PSR-M settings were 62.2% and 72.7%, respectively., Conclusions: Olaparib and niraparib were effective in patients with ovarian cancer without any new safety signals except for skin pigmentation. In patients with BRCAm, the 24-month PFS of the PARPi used in the PSR-M setting was even higher than that used in the FL-M setting., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Objective: The primary objective of this study is to explore the preoperative risk factors of pelvic lymph node metastasis (PLNM) in endometrial cancer patients, and construct a nomogram prediction model., Materials and Methods: We retrospectively collected various preoperative clinical characteristics of patients and analyzed their relationship with PLNM. Logistic regression analysis was used to screen for independent risk factors for PLNM of endometrial cancer. A nomogram prediction model was constructed, the receiver operating characteristic (ROC), calibration curve and decision curve analysis (DCA) were constructed and used to assess discrimination, calibration, and net benefit., Results: Out of the 276 patients, 74 (26.81%) with postoperative pathological confirmation of PLNM. Multivariate logistic regressive analysis demonstrated that preoperative depth of myometrial invasion (DIM) ≥50% determined by Magnetic Resonance Imaging (MRI) (p = 0.003), carbohydrate antigen 125 (CA125) (p = 0.030), carbohydrate antigen 19-9 (CA 19-9) (p = 0.044), and platelet/lymphocyte ratio (PLR) (p = 0.025) could serve as independent risk factors for PLNM. A risk factors-based nomogram prediction model was constructed, which showed good discrimination (AUC = 0.841, p < 0.001) and good efficacy (C-index = 0.842) and good calibration (mean absolute error = 0.046). DCA showed that the model can provide clinical benefits., Conclusions: Preoperative DIM ≥50% determined by MRI, serum CA 19-9, CA125 and PLR could be utilized to predict PLNM in endometrial cancer patients. This nomogram prediction model can provide preoperative help for evaluation and identification of patients with endometrial cancer, and provide a theoretical basis for clinical intervention., Competing Interests: Declaration of competing interest There are no conflicts of interest to report., (© 2024 Published by Elsevier Ltd.)

Objective: The purpose of this study was to assess the diagnostic efficacy of the vascular index (VI) on superb microvascular imaging (SMI) in distinguishing normal uterine cervical epithelium, high-grade cervical intraepithelial neoplasia (CIN), and cervical cancer., Methods: The retrospective study included women with pathology-confirmed CIN or cervical cancer, who underwent transvaginal ultrasound and SMI between April 2021 and October 2022. The SIM manifestations of normal cervix and cervical lesions were reviewed. SIM were measured and converted into vascular index (VI) which compared between cervical lesions and control groups. We have retrospectively compared ultrasound features of cervical lesions and characteristics of patients. Measurement reliability was evaluated by intra class correlation coefficient (ICC)., Results: A total of 235 consecutive females were enrolled, comprising 38 with high-grade CIN, 96 with cervical cancer, and 101 with a normal uterine cervix. The microvascular architecture exhibited significant variations between premalignant and malignant cervical lesions. Branch-like patterns were predominantly observed in high-grade CIN, while crab claw-like and fireball-like patterns were more commonly associated with cervical cancer. The median VI of cervical cancer (34.7 ± 10.3) was significantly higher than that of high-grade CIN (17.6 ± 4.2) (P < 0.001). Moreover, the VI values of cervical cancer differed significantly among different FIGO stages and pathological types (P < 0.001 and P = 0.003, respectively). The VI demonstrated superior diagnostic performance for cervical lesions compared to vascular patterns (AUC = 0.974 and 0.969, respectively). Using a cut-off value of 25.5, the VI yielded a sensitivity of 82.3% and a specificity of 99.3% for cervical lesion detection., Conclusions: The SMI parameter (VI) exhibited a significantly higher value in cervical cancer compared to high-grade CIN, with a high level of agreement among observers. These findings suggest that quantitative SMI holds promise as an imaging technique for the detection and characterization of cervical lesions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhu, Tang, Jiang, Zhang, Jia, Li, Luo, Kato and Zhang.)

Objective: To investigate the effect of primary debulking surgery (PDS), NACT followed by interval debulking surgery (NACT-IDS), and chemotherapy alone on the prognosis of FIGO stage IV epithelial ovarian cancer (EOC) with different metastatic patterns., Methods: We retrospectively analyzed 133 cases of FIGO stage IV EOC with pleural effusion (stage IVA), parenchymal metastases (stage IVB), or extra-abdominal lymph node metastases (stage IVB) at our Hospital between January 2014 and July 2021., Results: Among 133 cases with stage IV disease, 16.5% (n=22) presented with pleural effusion, 46.6% (n=62) with parenchymal metastases, and 36.9% (n=49) with extra-abdominal lymph node metastases. Regardless of the metastatic patterns, the 90.2% (n=120) of cases who underwent PDS/NACT-IDS exhibited a significantly superior overall survival (OS) compared to the 9.8% cases (n=13) who received chemotherapy alone (32 vs 17 months, p =0.000). The cohort was further stratified into 58 cases (48.3%) with R0, 41 cases (34.2%) with R1, and 21 cases (17.5%) with R2. The median OS of cases with R0 was significantly better than that of cases with R1/R2 (74 vs 27 months, p =0.000). There was no significant difference in median OS between PDS and NACT-IDS (43 vs 31 months, p =0.676), as well as between FIGO IVA and IVB (35 vs 31 months, p =0.582). Additionally, the metastatic patterns and the number of neoadjuvant chemotherapy cycles (≤4 or >4) did not demonstrate any prognostic significance for median OS ( p =0.820 and 33 vs 26 months, p =0.280, respectively)., Conclusion: Regardless of FIGO IVA and IVB stages or metastatic patterns, patients diagnosed with stage IV EOC may benefit from cytoreductive surgery with abdominal R0, compared with chemotherapy alone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Luo, Peng, Huang, Wang, Huang and Zhang.)

Background: The impact of para-aortic lymphadenectomy (PALD) on prognosis and quality of life (QoL) for IB2-IIA2 cervical cancer patients remain controversial. And whether intraoperative frozen pathology exam on common iliac lymph nodes could help predict para-aortic lymph node (PALN) metastasis was unanswered with high-level evidence., Methods: A multi-center, randomized controlled study is intended to investigate the effect of PALD on the prognosis and QoL in cervical cancer patients and to assess the value of intraoperative frozen pathological evaluation of common iliac nodes metastasis for the prediction of PALN metastasis. After choosing whether to receive intraoperative frozen pathological examination of bilateral common iliac lymph nodes, eligible patients will be randomly assigned (1:1) to receive PALD or not. The primary end point is 2-year progression-free survival (PFS). The secondary end points include 5-year PFS, 2-year overall survival (OS), 5-year OS, adverse events (AEs) caused by PALD, AEs caused by radiotherapy and QoL. A total of 728 patients will be enrolled from 8 hospitals in China within 3-year period and followed up for 5 years., Trial Registration: Chinese Clinical Trial Register Identifier: ChiCTR2000035668., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objectives: As an ultrasound (US) image processing method, superb microvascular imaging (SMI) extracts and visualizes flow signals from vessels through advanced clutter suppression technology. We investigated the feasibility of SMI in monitoring treatment response in patients with locally advanced cervical cancer (LACC) undergoing chemoradiotherapy (CRT)., Methods: Forty-nine patients underwent CRT and received SMI examination at 3 time points: before therapy (baseline), 3 weeks during, and 1 month after CRT. The maximum tumor diameter (Dmax), vascularity index (VI), and their percentage changes (ΔDmax and ΔVI) were calculated. ΔDmax was compared with MRI results as the reference standard., Results: Based on the MRI findings, 44 were classified as complete response (CR) group and 5 as partial response (PR) group. The Dmax and ΔDmax showed decrease in CR and PR groups at 3 weeks during CRT (P< 0.05), but no significant difference between the two groups (P > 0.05). Compared to the baseline, significant decrease in VI and ΔVI were observed at during and after treatment in the two groups (P< 0.05). Moreover, there were significant differences in VI and ΔVI at 3 weeks during CRT between the CR and PR groups (P< 0.05). ΔVI at 3 weeks during CRT showed a better predictive performance for responder prognosis than VI (AUC = 0.964, AUC = 0.950, respectively, P = 0.001), with a cut-off value of 41.6% yielding 100% sensitivity and 86.4% specificity., Conclusions: The SMI parameters (VI and ΔVI) have potential for monitoring treatment response in LACC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhu, Tang, Zhang, Zhang, Li and Jiang.)

Sialylation is an enzymatic process that covalently attaches sialic acids to glycoproteins and glycolipids and terminates them by creating sialic acid-containing glycans (sialoglycans). Sialoglycans, usually located in the outmost layers of cells, play crucial biological roles, notably in tumor transformation, growth, metastasis, and immune evasion. Thus, a deeper comprehension of sialylation in cancer will help to facilitate the development of innovative cancer therapies. Cancer sialylation-related articles have consistently increased over the last four years. The primary subjects of these studies are sialylation, cancer, immunotherapy, and metastasis. Tumor cells activate endothelial cells and metastasize to distant organs in part by the interactions of abnormally sialylated integrins with selectins. Furthermore, cancer sialylation masks tumor antigenic epitopes and induces an immunosuppressive environment, allowing cancer cells to escape immune monitoring. Cytotoxic T lymphocytes develop different recognition epitopes for glycosylated and nonglycosylated peptides. Therefore, targeting tumor-derived sialoglycans is a promising approach to cancer treatments for limiting the dissemination of tumor cells, revealing immunogenic tumor antigens, and boosting anti-cancer immunity. Exploring the exact tumor sialoglycans may facilitate the identification of new glycan targets, paving the way for the development of customized cancer treatments.

Background: Aberrant sialoglycans on the surface of tumor cells shield potential tumor antigen epitopes, escape recognition, and suppress activation of immunocytes. α2,3/α2,6Gal- and α2,6GalNAc (Gal/GalNAc)-linked sialic acid residues of sialoglycans could affect macrophage galactose-type lectins (MGL) mediated-antigen uptake and presentation and promote sialic acid-binding immunoglobulin-like lectins (Siglecs) mediated-immunosuppression. Desialylating sialoglycans on tumor cells could present tumor antigens with Gal/GalNAc residues and overcome glyco-immune checkpoints. Thus, we explored whether vaccination with desialylated whole-cell tumor vaccines (DWCTVs) triggers anti-tumor immunity in ovarian cancer (OC)., Methods: Sialic acid (Sia) and Gal/GalNAc residues on OC A2780, OVCAR3, and ID8 cells treated with α2-3 neuraminidase (α2-3NA) and α2-6NA, and Sigec-9 or Siglec-E and MGL on DCs pulsed with desialylated OC cells were identified using flow cytometry (FCM); RT-qPCR determined IFNG expression of T cells, TRBV was sequenced using Sanger sequencing and cytotoxicity of αβ T cells was measured with LDH assay; Anti-tumor immunity in vivo was validated via vaccination with desialylated whole-cell ID8 vaccine (ID8 DWCTVs)., Results: Gal/GalNAc but not Sia residues were significantly increased in the desialylated OC cells. α2-3NA-modified DWCTV increased MGL but decreased Siglec-9 or Siglec E expression on DCs. MGL bright /Siglec-9 dim DCs significantly up-regulated IFNG expression and CD4/CD8 ratio of T cells and diversified the TCR repertoire of αβ T-cells that showed enhanced cytotoxic activity. Vaccination with α2-3NA-modified ID8 DWCTVs increased MGL bright /Siglec-E dim DCs in draining lymph nodes, limited tumor growth, and extended survival in tumor-challenged mice., Conclusion: Desialylated tumor cell vaccine could promote anti-tumor immunity and provide a strategy for OC immunotherapy in a clinical setting., (© 2022. The Author(s).)

Objective: We aimed to evaluate the effectiveness of different triage strategies for high-risk human papillomavirus (hrHPV)-positive women in primary healthcare settings in China., Methods: This study was undertaken in 11 rural and 9 urban sites. Women aged 35-64 years old were enrolled. HrHPV-positive women were randomly allocated to liquid-based cytology (LBC), visual inspection with acetic acid and Lugol's iodine (VIA/VILI) (rural only) triage, or directly referred to colposcopy (direct COLP). At 24 months, hrHPV testing, LBC and VIA/VILI were conducted for combined screening., Results: In rural sites, 1,949 hrHPV-positive women were analyzed. A total of 852, 218 and 480 women were randomly assigned to direct COLP, LBC and VIA/VILI. At baseline, colposcopy referral rates of LBC or VIA/VILI triage could be reduced by 70%-80%. LBC (n=3 and n=7) or VIA/VILI (n=8 and n=26) could significantly decrease the number of colposcopies needed to detect one cervical intraepithelial neoplasia (CIN) 2 or worse and CIN3+ compared with direct COLP (n=14 and n=23). For the 24-month cumulative detection rate of CIN2+, VIA/VILI triage was 0.50-fold compared with LBC triage and 0.46-fold with the direct COLP. When stratified by age, baseline LBC triage+ performed best (P<0.001), peaking among women aged 35-44 years (P trend =0.002). In urban sites, 1,728 women were hrHPV genotyping test positive. A total of 408, 571 and 568 women were randomly assigned to direct COLP for HPV16/18+, direct COLP for other hrHPV subtypes+, and LBC triage for other hrHPV subtypes+. LBC (n=12 and n=31) significantly decreased the number of colposcopies needed to detect one CIN2+ and CIN3+ compared with direct COLP (n=14 and n=44). HPV16/18+ increased the 24-month cumulative detection rate of CIN2+ (17.89%, P<0.001)., Conclusions: LBC triage for hrHPV-positive women in rural settings and direct COLP for HPV16/18+ women and LBC triage for other hrHPV subtype+ women in urban settings might be feasible strategies., (Copyright ©2022 Chinese Journal of Cancer Research. All rights reserved.)

Purpose: This phase III trial aimed to explore the efficacy and safety of fuzuloparib (formerly fluzoparib) versus placebo as a maintenance treatment after response to second- or later-line platinum-based chemotherapy in patients with high-grade, platinum-sensitive, recurrent ovarian cancer., Patients and Methods: Patients with platinum-sensitive, recurrent ovarian cancer previously treated with at least two platinum-based regimens were assigned (2:1) to receive fuzuloparib (150 mg, twice daily) or matching placebo for 28-day cycles. The primary end points were progression-free survival (PFS) assessed by blinded independent review committee (BIRC) in the overall population and PFS by BIRC in the subpopulation with germline BRCA 1/2 mutation., Results: Between April 30, 2019, and January 10, 2020, 252 patients were randomly assigned to the fuzuloparib (n = 167) or placebo (n = 85). As of July 1, 2020, the median PFS per BIRC assessment in the overall population was significantly improved with fuzuloparib treatment (hazard ratio [HR], 0.25; 95% CI, 0.17 to 0.36; one-sided P < .0001) compared with that with placebo. The HR derived from a prespecified subgroup analysis showed a consistent trend of benefit in patients with germline BRCA 1/2 mutations (HR, 0.14; 95% CI, 0.07 to 0.28) or in those without mutations (HR, 0.46; 95% CI, 0.29 to 0.74). The most common grade ≥ 3 treatment-emergent adverse events reported in the fuzuloparib group were anemia (25.1%), decreased platelet count (16.8%), and decreased neutrophil count (12.6%). Only one patient (0.6%) discontinued fuzuloparib because of treatment-related toxicity (concurrent decreased white blood cell count and neutrophil count)., Conclusion: Fuzuloparib as maintenance therapy achieved a statistically significant and clinically meaningful improvement in PFS for patients with platinum-sensitive, recurrent ovarian cancer versus placebo, regardless of germline BRCA 1/2 mutation, and showed a manageable safety profile.

Background: Persistent HPV16 infection is the leading risk factor for developing cervical cancer. Anti-L1 antibodies against HPV16 produced in HPV16 infections play diverse roles in the clearance of virus infection and prevention of persistence. It has been implicated that the cervicovaginal squamous epithelial cells actually express TRIM21 and that some HPV16 particles could escape leaky endosomal compartment into the cytosol and that Fc receptor TRIM21 directly neutralize infection by targeting antibody-opsonized viruses for proteasomal degradation. We explored whether anti-L1 antibody opsonized HPV16 pseudovirus (PsV) entered into the cytosol could be neutralized by TRIM21-mediated activation of a proteasomal pathway to reduce the chance of persistent HPV16 infection., Methods: HPV16 PsV were generated and extracted in HEK 293FT cells co-transfected with pcDNA3.1-eGFP and p16sheLL plasmids according to the standard protocol. The HPV16 PsV with capsid protein L1 was characterized by fluorescence microscopy and western blot, and the HPV16 PsV titer and anti-L1-bound PsV entry efficiency were detected by flow cytometry. The expressions of transcription factors (TF) and cytokines elicited by the TRIM21-activated proteasomal pathway were confirmed by dual-luciferase reporter assay and RT-qPCR. The changes in HPV16 PsV load with or without inhibitors in the infected HEK 293FT cells were determinated by qPCR., Results: Simultaneous transfection with pcDNA3.1-eGFP and p16sheLL plasmids into the HEK 293FT cells resulted in the self-assembly of HPV16 PsV with capsid protein L1. Both HPV16 PsV and anti-L1-bound HPV16 PsV could infect HEK 293FT cells. Anti-L1-bound PsV up-regulated TRIM21 mediated-activation of proteasome and increased expressions of TF and cytokines in the infected cells where HPV16 PsV load reduced by ~ 1000-fold in the presence of anti-L1 antibody, but inhibition of proteasomal activity increased HPV16 PsV load., Conclusion: Our preliminary results indicate that anti-L1 antibody entered with HPV16 PsV into the cells could mediate degradation of HPV16 PsV by TRIM21-activated proteasomal pathway intracellularly, giving anti-capsid protein L1 antibody a role in host defense of persistent HPV16 infection., (© 2022. The Author(s).)

Epithelial ovarian cancer (EOC) is classified into five major histotypes: high-grade serous (HGSOC), low-grade serous (LGSOC), clear cell (CCOC), endometrioid (ENOC), and mucinous (MOC). However, the landscape of molecular and immunological alterations in these histotypes, especially LGSOC, CCOC, ENOC, and MOC, is largely uncharacterized. We collected 101 treatment-naive EOC patients. The resected tumor tissues and paired preoperative peripheral blood samples were collected and subjected to target sequencing of 1021 cancer-associated genes and T cell repertoire sequencing. Distinct characteristics of mutations were identified among the five histotypes. Furthermore, tumor mutation burden (TMB) was found to be higher in CCOC and ENOC, but lower in LGSOC and HGSOC. Alterations associated with DNA damage repair (DDR) pathways and homologous recombination deficiencies (HRD) were prevalent in five histotypes. CCOC demonstrated increased level of T cell clonality compared with HSGOC. Interestingly, the proportion of the 100 most common T cell clones was associated with TMB and tumor neoantigen burden in CCOC, highlighting more sensitive anti-tumor responses in this histotype, which was also evidenced by the enhanced convergent recombination of T cell clones. These findings shed light on the molecular traits of genomic alteration and T cell repertoire in the five major EOC histotypes and may help optimize clinical management of EOC with different histotypes., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Mutations at sites crucial for the interaction between RAD51 and BRC domains impair the ability of BRCA2 homologous recombination. We aimed to clarify whether BRCA2 BRC domain-associated mutation correlates with sensibility of platinum-based chemotherapy and survival in high-grade serous ovarian cancer (HGSOC)., Methods: We identified BRCA2 BRC domain mutations by sequencing PCR-amplified amplicons of genomic DNA isolated from tumor tissues and peripheral blood leukocytes (PBL)in 113 patients with advanced EOC, and assessed platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS)., Results: 21.23% (24 of 113) cases with somatic missense mutation but not germline mutation were identified. Among 24 cases with mutation, 33.3% (8 of 24) cases with nonsense mutation (C-terminal truncation) significantly prolonged median PFI (37 vs 8 months,P = 0.000), PFS (43 vs 14 months, p = 0.000) and OS (56 vs 31 months, P = 0.002); 66.7% (16 of 24) cases with missense mutation also prolonged median PFI (15 vs 8 months, P = 0.044), PFS (21 vs 14 months, P = 0.049) and OS (38 vs 31 months, P = 0.037), compared to those without any mutation., Conclusions: Somatic mutations in BRCA2 BRC domain confer a higher sensitivity to platinum-based therapy and are associated with a favourable survival in HGSOC., (Copyright © 2021. Published by Elsevier Inc.)

Background: Primary debulking surgery (PDS) is the main treatment for patients with advanced ovarian cancer, and neoadjuvant chemotherapy (NACT) is for bulky stage III-IV patients who are poor surgical candidates and/or for whom there is a low likelihood of optimal cytoreduction. NACT can increase the rate of complete cytoreduction, but this advantage has not translated to an improvement in survival. Therefore, we aimed to identify factors associated with the survival of patients who received NACT followed by interval debulking surgery (IDS)., Methods: A retrospective study was conducted in FIGO stage IIIC-IV epithelial ovarian cancer patients who underwent PDS or IDS in our center between January 1st, 2013, and December 31st, 2018., Results: A total of 273 cases were included, of whom 20 were lost to follow-up. Progression-free survival (PFS) and overall survival (OS) of the IDS and PDS groups were found to be similar, although the proportion of patients in stage IV and serum carbohydrate antigen 125 (CA125) levels before treatment in the IDS group were significantly higher than that in the PDS group. Body mass index (BMI), CA125 level before IDS, residual disease after surgery, and the interval between preoperative and postoperative chemotherapy were all found to be independent prognostic factors for PFS; FIGO stage, residual disease after surgery, and CA125 level before IDS were independent prognostic factors for OS. We found that PFS and OS were both significantly longer in patients with normal CA125 levels before IDS and when the interval between preoperative and postoperative chemotherapy was < 35.5 days (IDS-3 group) than for patients in the PDS group., Conclusions: The results suggested the importance of timely IDS and postoperative chemotherapy and potentially allowed the identification of patients who would benefit the most from NACT. Normal CA125 levels before IDS and an interval between preoperative and postoperative chemotherapy no longer than 5 weeks were associated with improved prognosis in advanced ovarian cancer patients.

Importance: Evidence is needed regarding the introduction of high-risk human papillomavirus (hrHPV) testing into China's national cervical cancer screening program., Objective: To evaluate hrHPV testing as a new screening modality for the national program., Design, Setting, and Participants: This population-based, multicenter, open-label, randomized clinical trial took place across 20 primary health care centers in urban and rural areas across China. At least 3000 women aged 35 to 64 years per site were invited to participate, for a total of 60 732 women evaluated., Interventions: At baseline, women were randomly assigned to cytology, hrHPV testing, or visual inspection with acetic acid and Lugol iodine (VIA/VILI) (rural only). Women who tested positive for hrHPV were randomized into cytology-triage, VIA/VILI-triage (rural only), or direct colposcopy arms. Regarding primary or triaging tests, women with cytological abnormalities or who tested positive with VIA/VILI were referred to colposcopy. After 24 months, combined screening of cytology, hrHPV testing, and VIA/VILI was performed, and all women with positive results were referred to colposcopy., Main Outcomes and Measures: The primary outcomes were cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3+ yields. The secondary outcome was colposcopy referral rate., Results: A total of 60 732 women were included in this study, with median (interquartile range) age of 47 (41-52) years. Among urban women, 8955 were randomized to cytology and 18 176 to hrHPV genotyping; among rural women, 11 136 were randomized to VIA/VILI, 7080 to cytology, and 15 385 to hrHPV testing. Participants who tested positive for hrHPV with direct colposcopy had higher risk ratios for disease yields at baseline (urban hrHPV vs cytology, CIN2+ 2.2 [95% CI, 1.6-3.2] and CIN3+ 2.0 [95% CI, 1.2-3.3]; rural hrHPV vs cytology, 2.6 [95% CI, 1.9-4.0] and 2.7 [95% CI, 2.0-3.6]; rural hrHPV vs VIA/VILI, 2.0 [95% CI, 1.6-2.3] and 2.3 [95% CI, 1.8-3.1]). At 24 months, baseline-negative women in the hrHPV arm had significantly lower risk ratios than those with cytology, or VIA/VILI for CIN2+ (0.3 [95% CI, 0.2-0.5], 0.3 [95% CI, 0.2-0.6]) and CIN3+ (0.3 [95% CI, 0.1-0.6], 0.4 [95% CI, 0.2-0.8]) in rural sites. The colposcopy referral rate for hrHPV-positive rural women was reduced to 2.8% by cytology triage, with significantly higher CIN2+ yields than cytology (2.1 [95% CI, 1.3-2.6]) or VIA/VILI arm (1.6 [95% CI, 1.03-2.1]). Genotyping for hrHPV with cytology triage significantly reduced the colposcopy referral rate compared with cytology (0.8 [95% CI, 0.7-0.9]) for urban women., Conclusions and Relevance: In this randomized clinical trial, testing for hrHPV was an effective primary screening method in primary health care centers. Incorporating hrHPV testing (polymerase chain reaction-based for urban areas, hybrid capture-based for rural areas) into China's national screening program is reasonable., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1900022530.

Objective: To evaluate the efficacy and safety of PLD in treating of in patients who experience epithelial ovarian, fallopian tubal, and peritoneal cancer progression within 12 months after the first-line platinum-based therapy., Methods: This was an open-label, single-arm and multicenter clinical trial. The ORR was the interim primary objective, and the DCR, AEs and QOL were the secondary objectives. The impact of factors on efficacy outcomes, the change trend of CA125 and the artificial platinum-free interval were exploratory endpoints., Results: Totally, 115 patients were enrolled in this study and included in the ITT population. Moreover, 101 patients were included in the safety population. The median follow-up time was 4 months (IQR 2-6). In the ITT population, the confirmed ORR was 37.4% (95% CI, 28.4-46.4%), and the DCR was 65.2% (95% CI, 56.4-74.1%). The previous response status to platinum-based chemotherapy and baseline CA125 levels were significantly correlated with the ORR. The ORR was significantly higher in patients with a CA125 decrease after the first cycle than in the patients with a CA125 increase. The most common grade 3 or higher AE was hand-foot syndrome (3 [3.0%] of 101 patients). No statistically significant differences existed between the baseline and the postbaseline questionnaires., Conclusions: For patients who experience platinum-resistant and platinum-refractory relapse, the use of PLD may be acceptable because of the associated satisfactory efficacy, low frequency of AEs and high patient QOL. Moreover, a low CA125 level at baseline and a reduction in CA125 after the first cycle are predictive factors for satisfactory efficacy.

Paclitaxel (PTX) resistance in most epithelial ovarian cancers (EOCs) with increasing membrane expression of mucin 16 (MUC16) is mediated by the Toll-like receptor-myeloid differentiation factor 2/myeloid differentiation factor 88 (TLR4-MD2/MyD88) signaling pathway. 6-Shogaol (6S), an α,β-unsaturated carbonyl compound with lipophilic property, can block PTX-induced formation of the TLR4-MD2 complex that activates the MyD88/NF-κB signaling pathway. Herein, to improve the effectiveness of 6S, augment the sensibility of PTX, and enhance the targeting ability of PTX-resistant cancer therapies, we report a class of 6S-loaded phase transition nanobubbles conjugated with the MUC16 antibody (6S@NBs-MUC16A), which can enhance the sensitivity of PTX to EOC cells through ultrasound-controlled targeted-delivery of 6S. The 6S@NB-MUC16A could enhance the targeting efficiency and organizational distribution of 6S in MyD88 + EOC area, and the 1 MHz ultrasound can be used as an initiator to trigger the "explosion" of nanobubbles and promote the 6S release. Furthermore, in vivo assessment results indicate that ultrasound-augmented 6S@NB-MUC16A can significantly improve the response of EOC to PTX and the inhibition ratio of tumor growth compared to the control-treated with PTX alone, and exhibit less toxicity to the critical organs. The ultrasound-augmented 6S@NB-MUC16A with less cytotoxicity could be a potentially useful nanosystem to surmount PTX resistance in EOC, which provides potential possibilities for the applications in the biological field.

Background: Cluster of differentiation 44 (CD44)/myeloid differentiation factor 88 (MyD88) is the molecular characterization of EOC stem cells. An important characteristic of CD44+/MyD88+ epithelial ovarian cancer (EOC) cells, which differentiate them from the CD44-/MyD88- EOC cells, is the presence of a functional TLR4-MyD88-NFkB pathway. The aim of our study is to investigate the clinical significance of CD44/MyD88 co-expression in EOC., Methods: A total of 138 specimens of ovarian tissues was detected CD44 and MyD88 expression by immunocytochemistry, including EOC (N=108), borderline tumors (N=10), benign cysts (N=10) and normal ovarian tissue (N=10). The association of CD44/MyD88 co-expression with clinicopathological factors and outcomes was analyzed., Results: The expression of CD44 was showed distinct difference in EOC (53 of 108, 49.1%), in borderline tumors (3 of 10, 30.0%), in benign cysts (2 of 10, 20.0%) and normal ovarian (2 of 10, 20.0%). A total of 41 (38.0%) cancers showed a combined expression of CD44/MyD88. The expression of CD44 and MyD88 had definitely correlativity (r=0.21, P=0.026). CD44/MyD88 co-expression was associated with tumor progression, metastasis, and recurrence in advanced EOC, and an independent prognostic factor for disease-free survival and overall survival., Conclusions: CD44/MyD88 co-expression has been shown to contribute to EOC progression and outcome directly and has a promising as a therapeutic target in EOC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Perineural invasion (PNI) is the neoplastic invasion of nerves by cancer cells, a process that has attracted attention as a novel prognostic factor for cancer. The present study aimed to investigate the prognostic value of PNI in patients with early-stage cervical cancer (International Federation of Gynecology and Obstetrics stage IA2-IIA). A total of 210 patients who underwent radical hysterectomy and pelvic lymphadenectomy between 2007 and 2012 were included in the current study, of whom 8.57% (18/210) exhibited PNI. Patients with PNI were more likely to exhibit adverse histopathological features, such as increased tumor size, depth of stromal invasion, parametrial invasion, lymphovascular space invasion and lymph nodes metastases (all P<0.05). Patients with PNI exhibited shorter disease-free and overall survival (P=0.002 and P=0.017, respectively). However, PNI was not identified as an independent risk factor for either recurrence or death by multivariate analysis. Furthermore, 88.9% (16/18) of patients with PNI received adjuvant therapy following surgery. PNI was significantly associated with well-established indicators for adjuvant therapy. In conclusion, PNI was associated with multiple high-risk factors and its presence was indicative of a poor outcome in patients with early-stage cervical cancer, which may influence management decisions regarding adjuvant therapy.

Background: TLR4/MD-2 complex-mediated MyD88-dependent activation of NF-κB and Akt promotes tumor-associated immunosuppression in epithelial ovarian cancer (EOC) via induction of immunesuppressive cytokines and indoleamine 2,3-dioxygenase (IDO). Atractylenolide I (AO-1) is a naturally occurring sesquiterpene lactone known to change the conformational ensemble of human MD-2 on EOC cells. This study examined the modulation by AO-1 of TLR4/MD-2 complex-mediated MyD88/NF-κB signaling., Methods: The expression and activation of NF-κB, Akt and IDO1 by MyD88(+) EOC SKOV3 cells was determined using western blot; the TLR4/MD-2 complex on SKOV3 cells and the phenotype of T lymphocytes were determined using flow cytometry; IDO activity was evaluated by measuring L-kynurenine; Immunesuppressive cytokines were detected using ELISA; T-cell proliferation to mitogen stimulation was assessed by MTT assay; the cytotoxicity of lymphocytes and NK cells was measured using LDH-cytotoxicity assay., Results: AO-1 could down-regulate expression of TLR4/MD-2 complex, resulting in downregulation of MyD88/NF-κB signaling and activation of NF-κB, Akt and IDO1 and secretion of IL-6, TGF-β1, VEGF and IL-17A by EOC SKOV3 cells, and further reduce increased levels of regulatory T cells (Treg cells) and improve decreased proliferative response and antitumor cytotoxicity of T lymphocytes exposed to EOC SKOV3 cell supernatant., Conclusion: AO-1 may reverse EOC cell-mediated immunosuppression through blocking TLR4/MD-2 complex-mediated MyD88/NF-κB signaling.

To explore the nucleotide sequence variability of the E2 gene in high-risk HPV types in cervical cancer patients from Sichuan province, China, the E2 genes of eight high-risk HPV types were amplified and sequenced. Several novel nucleotide substitutions and deletions were observed. The lineages to which the isolates belonged were determined by phylogenetic analysis, employing the sequence of the representative lineages/sublineages in the coherent classification and nomenclature system as references. This study updates the lineage distribution data on high-risk HPV types in Southwest China and helps broaden understanding of the polymorphism of the E2 gene.

The aim of this review was to provide an updated summary estimation of the accuracy of visual inspection with acetic acid (VIA) and with Lugol's iodine (VILI) in detecting cervical cancer and precancer. Studies on VIA/VILI accuracy were eligible in which VIA/VILI was performed on asymptomatic women who all underwent confirmatory testing of histology, combination of colposcopy and histology, or combination of multiple screening tests, colposcopy and histology, to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+ or CIN3+). A bivariate model was fitted to estimate the accuracy of VIA/VILI and provide estimates of heterogeneity. Subgroup analysis was used to investigate the source of heterogeneity. A total of 29 studies on VIA and 19 studies on VILI were included finally in the meta-analysis. The summary sensitivity and specificity of VIA for CIN2+ were 73.2% (95%CI: 66.5-80.0%) and 86.7% (95%CI: 82.9-90.4%), respectively, and those for VILI were 88.1% (95%CI: 81.5-94.7%) and 85.9% (95%CI: 81.7-90.0%), respectively. VIA and VILI were both more sensitive in detecting more severe outcome, although there was a slight loss in specificity. Apparent heterogeneity existed in sensitivity and specificity for both VIA and VILI. High sensitivity of both VIA and VILI for CIN2+ was found when a combination of colposcopy and histology was used as disease confirmation. VIA, VILI, even a combination of them in parallel, could be good options for cervical screening in low-resource settings. Significant differences in sensitivity between different gold standards might provide a proxy for optimization of ongoing cervical cancer screening programs., (© 2015 Japan Society of Obstetrics and Gynecology.)

Objective: To evaluate the incidence and significance of perineural invasion (PNI) in cervical cancer., Methods: Retrospective chart review of patients with cervical cancer (stages Ia2-IIb) who underwent radical hysterectomy and pelvic lymphadenectomy from 2007 to 2012. To evaluate the incidence and significance of PNI in cervical and uterine tissues by microscopic examination., Results: A total of 238 patients were included, 9.2% (22/238) patients with PNI in the cervical stroma. Patients with PNI were more likely to have adverse histopathologic features, including lymphoma vascular space invasion, parametrical invasion, depth of invasion, tomor size and lymph nodes metastases (all P < 0.05). PNI were independent of age, international federation of gynecology and obstetrics (FIGO) stage, histopathology type and grade, and positive vaginal margin (all P > 0.05). Patients with PNI had shorter disease-free and overall survival (P = 0.002 and P = 0.008, respectively). On multivariate analysis, risk factors for recurrence and death included parametrical invasion and depth of invasion (P < 0.05). Similarly, risk factors for recurrence included lymph nodes metastases (P = 0.024). However, PNI was not identified as an independent risk factor for either recurrence or death (P > 0.05)., Conclusions: PNI exists in early cervical cancer. PNI is associated with tumor size, depth of invasion, parametrical invasion, lymphoma vascular space invasion and lymph nodes metastases. PNI represente a decreasing disease-free and overall survival in patients with early-stage cervical cancer, and is independently associated with multiple high-risk factors, which be informed management decisions regarding adjuvant therapy.

Two pairs of novel enantiomerically chiral clusters R/S-[NaMn(II)Mn(III)3L3(μ3-O)] (R/S-1) and R/S-[Na2Mn(II)2Mn(III)6L6(μ3-O)2] (R/S-2) have been obtained via the self-assembly of R/S-H2L Schiff base ligands and different auxiliary ligands (N3(-), dca(-)) with divalent manganese salt in an air-exposed methanol-ethanol solution. The structures of R/S-1 and R/S-2 were characterized by single-crystal X-ray diffraction analysis and powder X-ray diffraction. When the dicyanamide anion serves as an auxiliary ligand in the assembling reaction system, a pair of enantiomeric clusters R/S-[NaMn(II)Mn(III)3L3(μ3-O)] (R-1 and S-1) with a trigonal bipyramid configuration were obtained, while another pair of enantiomeric clusters R/S-[Na2Mn(II)2Mn(III)6L6(μ3-O)2] (R-2 and S-2) were formed in the case of the azide. Interestingly, the skeleton configuration of R/S-2 can be described as a 3-fold EO-azide bridging double trigonal bipyramid of [NaMn(II)Mn(III)3L3(μ3-O)]2via Mn(II) vertices. Circular dichroism (CD) spectra demonstrated the enantiomeric nature of the two pairs of clusters. Detailed direct current (DC) magnetic susceptibility studies in the temperature range 2-300 K suggested that R-1 and R-2 showed predominantly antiferromagnetic interactions between the manganese centers.

Objective: To evaluate the clinical significance of changes in peripheral lymphocyte count after surgery in early cervical cancer., Methods: The 123 patients with stage Ib1 and IIa1 treated by abdominal type III radical hysterectomy from May 2008 to December 2012 were reviewed. The median age of patients was 43 years old (range: 30 to 66 years). The median follow-up was 25 months with a range of 5-61 months. Peripheral blood samples were obtained on pre-operative, post-operation day 3 and 7. The log-rank test was used to compare the homogeneity of progression-free survival functions across strata defined by categories of prognostic variables. The Cox proportional hazard model was used to assess the significance of potential prognostic factors for progression-free survival., Results: Univariate analyses preoperative lymphocyte count (P = 0.012) and lymph nodes metastases status (P = 0.001) and parametrial invasion (P = 0.013) were significant risk factors for progression-free survival rate. On multivariate analyses, preoperative lymphocyte count [hazard ratio (HR) = 6.087, 95%CI: 1.743-21.251, P = 0.005] and lymph nodes metastases status (HR = 5.984, 95%CI: 1.803-19.802, P = 0.003) were independent risk factor of progression-free survival rate., Conclusion: Peripheral lymphocyte counts after cervical cancer surgery may be a important prognostic factor.

Objective: To evaluate the clinical significance of fertility-preserving comprehensive staging surgery (CSS) in the treatment of malignant ovarian germ cell tumors (MOGCTs)., Methods: A total of 92 cases of MOGCTs were retrospectively reviewed., Results: Forty-six patients (50%) received CSS, which includes ipsilateral adnexectomy+omentectomy+retroperitoneal lymphadenectomy (appendectomy and multiple biopsies as required). Forty-six patients (50%) received USO, which includes ipsilateral adnexectomy+clinical intraoperative evaluation (including retroperitoneal lymph nodes, great omentum, peritoneal, and contralateral ovary), biopsy of suspicious sites, and excision of all visible lesions. The mean operation time (177.0 vs. 114.8 min; p<0.0001) and the mean intraoperative blood loss (499.1 ml vs. 112.9 ml; p=0.04) were significantly higher in the CSS group compared to those in the USO group. The complication rate (17.4% vs 0%, p=0.003), the relapse rate (10.9% vs 2.2%, p=0.102) and the mortality rate (4.3% vs 2.2%, p=0.500) were higher in the CSS group compared to those in the USO group. The difference in complication rate was statistically significant. The overall 5 year survival rates were 92% and 97% in the CSS and USO groups, respectively (p=0.575). Tumor-free survival rates at 5 years were 87% and 97% in the CSS and USO groups, respectively (p=0.115)., Conclusions: The benefit of fertility-preserving CSS to MOGCT patients was not greater than that of USO. It is safer and more effective to perform ipsilateral adnexectomy+clinical intraoperative exploration surgery (including retroperitoneal lymph nodes, great omentum, peritoneal, and contralateral ovary), biopsy of suspicious sites, excision of all visible lesions, and adjuvant chemotherapy., (© 2013.)

Estrogen plays several important physiological and pathological functions in not only reproductive system but many other systems as well. Its transcriptional activation has been traditionally described as being mediated by classic nuclear estrogen receptors (ERs). It is however established recently that a novel functional estrogen transmembrane receptor, G protein-coupled receptor 30 (GPR30), modulates both rapid non-genomic events and genomic transcriptional events of estrogen. It has been demonstrated that GPR30 promotes the progress of estrogen-related tumors through mitogen-activated protein kinase (MAPK) signaling pathways. Effects mediated by GPR30 are maintained when classic ERs are absent or blocked. In addition, GPR30 is involved in drug resistance, which is often occurring during cancer treatments. All these new findings strongly imply that GPR30 may be an important therapeutic target for estrogen-related tumors. Simultaneously blocking both GPR30 and classic ERs may be a better strategy for the treatment of estrogen-related tumors.