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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. [ABSTRACT FROM AUTHOR]

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.)

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.)

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.

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.