Yudong Wang

Gambogic Acid Based Coordination Polymer Reinforces High‐Intensity Focused Ultrasound Treatment of Gynecologic Malignancies

AbstractHigh‐intensity focused ultrasound (HIFU) is emerging as a promising non‐invasive treatment for solid tumors. Nevertheless, HIFU may also induce the upregulation of Heat Shock Protein 90 (HSP‐90), potentially resulting in resistance to HIFU. Besides, although it is effective against in situ tumors, challenges remain with tumor metastasis and recurrence. Herein, the innovative design of gambogic acid (GA) based coordination polymer—GAZn‐PEG nanoparticles (GAZn‐PEG NPs) are synthesized through the coordination of GA with zinc ions (Zn2+), and subsequently functionalized with lipid bilayer incorporating polyethylene glycol (PEG), sensitizing HIFU for the treatment of cervical and ovarian cancers. Briefly, under HIFU exposure, GA markedly suppresses the expression of HSP‐90, thereby increasing the tumor's sensitivity to HIFU therapy. Furthermore, Zn2+ not only overcome the issue of GA's poor water solubility but also synergistically stimulate immune responses in conjunction with GA. More intriguingly, it has been discovered that GAZn‐PEG can effectively activate the cyclic GMP‐AMP synthase‐stimulator of the interferon genes (cGAS‐STING) pathway, thereby enhancing the immune responses provoked by HIFU. Specifically, GAZn‐PEG NPs show a remarkable increase in dendritic cell activation and the effective stimulation of the cGAS‐STING pathway, crucial for long‐term protection against tumor recurrence and metastasis.

Targeting GRP75 with a Chlorpromazine Derivative Inhibits Endometrial Cancer Progression Through GRP75–IP3R‐Ca 2+ ‐AMPK Axis

Abstract Tumors often overexpress glucose‐regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose‐regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity‐based protein profiling and loss‐of‐function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75‐deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria‐associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum–mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP‐activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer.

Impact of peritoneal vaginoplasty combined with radical hysterectomy on the quality of sexual life for patients with early-stage cervical cancer: trial protocol for a multi-center superiority randomized controlled trial

Radical hysterectomy (RH) is commonly used to treat early-stage cervical cancer in women of childbearing age and sexual dysfunction due to postoperative vaginal shortening is a major concern. The impact of intraoperative vaginoplasty on prognosis and quality of sexual life in patients with early-stage cervical cancer remains controversial and lacks high-level evidence. However, there are few reports on vaginoplasty after RH to lengthen vagina in patients. This prospective, multi-center, randomized controlled trial aims to explore the impact of peritoneal vaginoplasty with or without ovarian transposition after laparoscopic RH on sexual dysfunction in patients with early-stage cervical cancer. Eligible patients will be randomly assigned (1:1) to receive peritoneal vaginoplasty or not. The primary evaluation indicators are female sexual function index (FSFI) and male sexual satisfaction scale. The secondary evaluation indicators include EORTC QLQ-CX24, 2-year overall survival (OS), 5-year OS, 2-year progression-free survival (PFS), 5-year PFS and surgery-related complications. The trial will enroll 368 patients from 6 hospitals in China over a 3-year period and follow up for 5 years. Chinese Clinical Trial Registry Identifier: ChiCTR2000040610.

Long-term Efficacy of Fibroid Devascularization with Ultrasound-Guided High-Intensity Focused Ultrasound

High-intensity focused ultrasound (HIFU) has been increasingly used for treatment of uterine leiomyoma. The superiority of HIFU therapy targeting uterine leiomyoma blood vessels, however, still needs to be further explored. This study aims to evaluate the long-term efficacy of fibroid devascularization with ultrasound-guided HIFU (USgHIFU) and the effects of treatment on the ovarian reserve and endometrial injury. Fibroid devascularization was assessed with the Adler grade obtained by color Doppler flow imaging and power Doppler imaging (PDI). The targeted vessels were covered and then sonicated by HIFU focal spots. The patients were followed up at 1 month, 3 months, 6 months, 1 year, 2 years and 3 years after treatment. Adverse effects and complications were recorded. The non-perfusion volume rate (NPVR), fibroid volume shrinkage rate (FVSR), Adler Grade, symptom severity score (SSS) and uterine fibroid symptom and quality of life (UFS-QOL) were evaluated. Adverse events (AEs) were recorded. In Center 1, the enrolled patients completed the anti-Müllerian hormone (AMH) test before and at 6 months after treatment. A total of 117 eligible patients were consecutively enrolled to receive interventions and follow-up evaluations of the three centers from January 2019 to May 2023. The 1-month and 6-month NPVRs were 66.60% ± 33.14% and 51.12% ± 39.84%, respectively. The mean FVSRs at 1 month and 6 months after treatment were 38.20% and 43.89%, respectively. No significant difference was observed in AMH levels before and after treatment (p > 0.05). No irreversible endometrial injury was observed in MR images after HIFU treatment. No significant difference was observed in both 1-month and 6-month FVSRs among Center 1, 2 and 3 (p > 0.05). No severe AEs occurred. For long-term outcomes, significant differences were observed in Adler grade, FV, FVSR, SSS, reduction in SSS and UFS-QOL before and after treatment (p  0.05). The SSSs were reduced by 33.42% at 1 year, 42.32% at 2 years and 52.46% at 3 years after treatment. For patients with uterine fibroids, USgHIFU-induced devascularization is a safe and effective treatment option. It has little effect on ovarian function and the endometrial injury is reversible, which could be attractive for patients who plan to become pregnant.

Enhanced Chemodynamic Therapy Mediated by a Tumor‐Specific Catalyst in Synergy with Mitophagy Inhibition Improves the Efficacy for Endometrial Cancer

AbstractChemodynamic therapy (CDT) relies on the tumor microenvironment (e.g., high H2O2 level) responsive Fenton‐like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H2O2 is insufficient for effective chemodynamic responses. An NAD(P)H: quinone oxidoreductase 1 (NQO1)high catalase (CAT)low therapeutic window for the use of NQO1 bioactive drug β‐lapachone (β‐Lap) is first identified in endometrial cancer (EC). Accompanied by NADH depletion, NQO1 catalyzes β‐Lap to produce excess H2O2 and initiate oxidative stress, which selectively suppress NQO1high EC cell proliferation, induce DNA double‐strand breaks, and promote apoptosis. Moreover, shRNA‐mediated NQO1 knockdown or dicoumarol rescues NQO1high EC cells from β‐Lap‐induced cytotoxicity. Arginine‐glycine‐aspartic acid (RGD)‐functionalized iron‐based metal‐organic frameworks (MOF(Fe)) further promote the conversion of the accumulated H2O2 into highly oxidative ·OH, which in turn, exacerbates the oxidative damage to RGD‐positive target cells. Furthermore, mitophagy inhibition by Mdivi‐1 blocks a powerful antioxidant defense approach, ultimately ensuring the anti‐tumor efficacy of stepwise‐amplified reactive oxygen species signals. The tumor growth inhibition rate (TGI) is about 85.92%. However, the TGI of MOF(Fe)‐based synergistic antitumor therapy decreases to only 50.46% in NQO1‐deficient KLE tumors. Tumor‐specific chemotherapy and CDT‐triggered therapeutic modality present unprecedented therapeutic benefits in treating NQO1high EC.

Laparoscopic radical hysterectomy with Karez technique for stage IB3 and IIA2 cervical cancer: a multicenter retrospective cohort study

Background: Laparoscopic radical hysterectomy with Karez technique (LRH-Karez) is a practical method which is based on special space anatomy. This study investigates the efficacy and safety of LRH-Karez against traditional surgical methods including abdominal radical hysterectomy (ARH) and conventional minimally invasive surgery (MIS). Methods: A multicenter retrospective cohort study was conducted, involving 413 eligible patients diagnosed with 2018 FIGO stage IB3 and IIA2 cervical cancer treated from January 2012 to January 2022. Among these, 66 patients underwent LRH-Karez, 56 patients underwent conventional laparoscopic or robotic surgery (Conventional MIS) and 291 patients received ARH. Patient data were obtained from three tertiary hospitals in China. Surgical outcomes, pathological results, and follow-up data were analyzed using SPSS and R statistical software. Kaplan–Meier survival analysis was performed alongside univariate and multivariate Cox regression analyses. Results: LRH-Karez has less intraoperative blood loss but longer operative time. The five-year progression-free survival (PFS) rates were 85% for LRH-Karez, significantly higher than the 53.6% from conventional MIS (P = 0.002) and comparable to ARH (78.3%, P = 0.898). In terms of overall survival, the five-year overall survival (OS) rate for the LRH-Karez group was 92.2%, compared to 51.9% for the conventional MIS group and 78.3% for the ARH group. Patients who underwent conventional MIS had significantly lower OS compared to those in the LRH-Karez group (P < 0.001). The log-rank test indicated no significant difference in OS between the LRH-Karez group and the ARH group (P = 0.218). However, the Gehan-Breslow-Wilcoxon test revealed a significant difference between the two groups during the early follow-up period (P = 0.047). Conclusions: The LRH-Karez technique has demonstrated superior intraoperative safety and survival prognosis compared to conventional MIS in patients with locally advanced cervical cancer (FIGO stages IB3 and IIA2), with its long-term survival outcomes comparable to ARH. This practical technique, based on refined understanding of surgical space anatomy, may represent a valuable minimally invasive surgical option that warrants further exploration.

PCDHGB7 hypermethylation-based Cervical cancer Methylation (CerMe) detection for the triage of high-risk human papillomavirus-positive women: a prospective cohort study

Abstract Background Implementation of high-risk human papillomavirus (hrHPV) screening has greatly reduced the incidence and mortality of cervical cancer. However, a triage strategy that is effective, noninvasive, and independent from the subjective interpretation of pathologists is urgently required to decrease unnecessary colposcopy referrals in hrHPV-positive women. Methods A total of 3251 hrHPV-positive women aged 30–82 years (median = 41 years) from International Peace Maternity and Child Health Hospital were included in the training set (n = 2116) and the validation set (n = 1135) to establish Cervical cancer Methylation (CerMe) detection. The performance of CerMe as a triage for hrHPV-positive women was evaluated. Results CerMe detection efficiently distinguished cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) from cervical intraepithelial neoplasia grade 1 or normal (CIN1 −) women with excellent sensitivity of 82.4% (95% CI = 72.6 ~ 89.8%) and specificity of 91.1% (95% CI = 89.2 ~ 92.7%). Importantly, CerMe showed improved specificity (92.1% vs. 74.9%) in other 12 hrHPV type-positive women as well as superior sensitivity (80.8% vs. 61.5%) and specificity (88.9% vs. 75.3%) in HPV16/18 type-positive women compared with cytology testing. CerMe performed well in the triage of hrHPV-positive women with ASC-US (sensitivity = 74.4%, specificity = 87.5%) or LSIL cytology (sensitivity = 84.4%, specificity = 83.9%). Conclusions PCDHGB7 hypermethylation-based CerMe detection can be used as a triage strategy for hrHPV-positive women to reduce unnecessary over-referrals. Trial registration ChiCTR2100048972. Registered on 19 July 2021.

Ovarian Sertoli-Leydig cell tumors: an analysis of 13 cases

To report the clinical, ultrasound and histopathological characteristics, clinical management, and prognosis of 13 patients with Sertoli-Leydig cell tumors (SLCTs) of ovary. 13 patients with pathologically confirmed ovarian SLCTs at International Peace Maternity and Child Health Hospital from 2010 and 2019 were included in this study. The clinical, ultrasound and histopathological characteristics, clinical management, and prognosis of 13 patients were retrospectively analyzed. The age ranged 25-68 years. Of the 8 (62%) patients presenting endocrine symptoms, 4 had post-menopausal hemorrhage, 4 had menstrual irregularity, 2 had androgenic manifestations, 1 had hirsutism, and 1 showed acne with thyroid nodules. 1 patient had elevated cancer antigen 125 (CA125), and 2 had elevated testosterone (T). The other 5 patients showed no symptoms of whom masses were detected incidentally by physical examination. All tumors were at stage I and confined to unilateral ovary. 11 tumors were solid or mixed solid-cystic masses with clear boundaries on ultrasound, and 1 tumor was a cystic mass. 7 tumors were intermediately differentiated and 6 were poorly differentiated, among which 1 case had heterologous elements (poorly differentiated) and 8 had a retiform pattern. Grade 2 endometrial cancer occurred in 2 cases (1 intermediately differentiated and 1 poorly differentiated). One case had multinodular goiter (intermediately differentiated). The patients were classified into endocrine function group (8/13) and no endocrine function (5/13). The proportion of retiform pattern of the group with endocrine function was significantly higher than that of no endocrine function group (p < 0.05). However, the mean age, diameter of tumors, and the proportions of poor differentiation and rupture showed no significant difference. All patients were treated with surgical excision. Three cases underwent surgery twice after the pathological results came out. For the final surgery, 1 patient underwent cystectomy, 3 underwent unilateral salpingo-oophorectomy, and 9 underwent total hysterectomy and bilateral salpingo-oophorectomy. 7 had received postoperative chemotherapy. All of 13 patients exhibited disease-free survival (DFS) with the longest follow-up time being 9 years. The clinical characteristics and imaging findings may provide information for the diagnosis of SLCTs. Higher percentage of retiform pattern was found in endocrine function group. Concurrence of Grade 2 endometrial carcinoma with SCLTs was reported. The prognosis of SLCTs is good. Conservative surgery is acceptable for young patients wishing to preserve fertility.

A practical method of using the anatomical space of the vesicouterine ligament for laparoscopic radical hysterectomy: a retrospective cohort study

Objective To investigate the practicality of a new method using anatomical spaces for performing standard laparoscopic radical hysterectomy (LRH) without ureteral injury in patients with cervical cancer. Methods Clinicopathological characteristics and perioperative complications were retrospectively analysed in 440 patients with stages IB1 to IIB cervical cancer. The patients were assigned to two of the following groups: LRH by our method of using anatomical landmarks (anatomical space group, n = 217) and the traditional method (traditional group, n = 223). Results The mean operative duration and time of vesicouterine ligament (VUL) dissection were significantly shorter (173.87 ± 30.39 vs. 210.83 ± 44.55 minutes; 32.75 ± 7.23 vs. 43.48 ± 11.22 minutes), and blood loss was less in the anatomical space group compared with the traditional group. The rate of the intraoperative complication of ureteral injury was also significantly lower in the anatomical space group compared with the traditional group (0 vs. 5). Conclusions LRH by the anatomical method, using the axillary space and other potential spaces as anatomical landmarks, results in less blood loss and reduced ureteral injury compared with the traditional method. This method is safe and practical for separating the ureter from the VUL in patients with cervical cancer.

HPV‐16/18 E6‐induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1

AbstractOncogenic high‐risk human papillomavirus (HR‐HPV) infection causes a majority of cases of cervical cancer and pre‐cancerous cervical lesions. However, the mechanisms underlying the direct evolution from HPV‐16/18‐infected epithelium to cervical intraepithelial neoplasia (CIN) III, which can progress to cervical cancer, remain poorly identified. Here, we performed RNA‐seq after laser capture microdissection, and found that APOBEC3B was highly expressed in cervical cancer specimens compared with CIN III with HPV‐16/18 infection. Furthermore, immunohistochemical analysis confirmed that high levels of APOBEC3B were correlated with lymph node metastasis in cervical cancer. Subsequent experiments revealed that HPV‐16 E6 could upregulate APOBEC3B through direct binding to the promoter of APOBEC3B in cervical cancer cells. Silencing of APOBEC3B by stable short hairpin RNA‐mediated knockdown reduced the proliferative capacity of Caski and HeLa cells in vitro and in vivo, but had only a small effect on the migration and invasion of two cervical cancer cell lines. Finally, we identified the changes in gene expression following APOBEC3B silencing in Caski cells by microarray, demonstrating a biological link between APOBEC3B and CCND1 in cervical cancer cells. Importantly, through methyl‐capture sequencing and pyrosequencing, APOBEC3B was found to affect the levels of the downstream protein Cyclin D1 (which is encoded by the CCND1 gene) through hypomethylation of the CCND1 promoter. In conclusion, our study supports HPV‐16 E6‐induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1. Thus, APOBEC3B may be a potential therapeutic target in human cervical cancer.

Intraoperative frozen pathology exam of Common iliac lymph nodes and Para-Aortic lymphadenectomy on the prognosis and quality of life for patients with IB2-IIA2 Cervical Cancer: trial protocol for a randomized controlled trial (C-PACC trial)

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. 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. Chinese Clinical Trial Register Identifier: ChiCTR2000035668.

Cervical cancer-produced neuromedin-B reprograms Schwann cells to initiate perineural invasion

AbstractPerineural invasion (PNI) is a new approach of cervical cancer invasion and metastasis, involving the cross-talk between tumor and nerve. However, the initiating signals and cellular interaction mechanisms of PNI remain largely elusive. The nerve-sparing radical hysterectomy (NSRH) proposed to improve postoperative quality of life is only applicable to cervical cancer patients without PNI. Therefore, it is important to elucidate the underlying mechanisms initiating PNI, and suggest the effective biomarkers to predict PNI before NSRH surgery. Here, we found that PNI is the characteristic of advanced cervical cancer, and Schwann cells were the antecedent cells that initiating PNI. Further, neuropeptide neuromedin B (NMB) produced by cervical cancer cells was determined to induce PNI by reprogramming Schwann cells, including driving their morphological and transcriptional changes, promoting their proliferation and migration, and initiating PNI by secreting CCL2 and directing axon regeneration. Mechanistically, cervical cancer cells-produced NMB activated its receptor NMBR in Schwann cells, and opened the T-type calcium channels to stimulate Ca2+ influx through PKA signaling, which could be blocked by the inhibitor. Clinically, combined examination of serum NMB and CCL2 levels was suggested to effectively predict PNI in cervical cancer patients. Our data demonstrate that cervical cancer-produced NMB initiates the reprograming of Schwann cells, which then direct axon regeneration, thus causing PNI onset. The elevated serum NMB and CCL2 levels may be useful for the decision-making to nerve sparing during hysterectomy surgery of cervical cancer patients.