Hui Wang

Sister Mary Joseph’s nodule as the first presenting sign of advanced fallopian tube carcinoma: A case report

Fallopian tube carcinoma has a rare incidence and dismal prognosis. Sister Mary Joseph’s nodule is an intra-abdominal tumor that metastasizes to the umbilicus. To date, fewer than 10 cases of fallopian tube carcinoma with Sister Mary Joseph’s nodule have been reported, with most of them exhibiting a very poor prognosis. Herein, we described a case of fallopian tube carcinoma with Sister Mary Joseph’s nodule. A 57-year-old woman was referred to the Affiliated Hospital of Shandong Second Medical University in May 2020 owing to a mass in the middle of her umbilicus. She was first diagnosed with an umbilical mass and underwent a resection of the umbilical mass, which revealed adenocarcinoma, most likely of reproductive origin. One month after the first surgery, she underwent laparoscopic cytoreductive surgery, and pathological examination revealed fallopian tube adenocarcinoma with pelvic lymph node metastasis. She was diagnosed with fallopian tube carcinoma (stage IIIC) and then underwent 10 cycles of chemotherapy. She achieved a complete response, and no recurrence or progression has been reported until now. The overall survival time exceeded 50 months. Thus, for patients with umbilical masses, physicians should consider the possibility of Sister Mary Joseph’s nodule. When a malignancy is suspected in the abdominal or pelvic cavity but the physical examination and imaging studies reveal no abnormality, laparoscopic surgery should be used for determining the primary tumor. For patients with fallopian tube carcinoma and Sister Mary Joseph’s nodule, surgery and adjuvant chemotherapy can achieve good results.

An immunosuppressive tertiary lymphoid structure is associated with adverse prognosis in gastric-type endocervical adenocarcinoma

Abstract Background Gastric-type adenocarcinoma (GAC) is the predominant subtype of HPV-independent endocervical adenocarcinoma, characterized by aggressive clinical behavior and poor prognosis. However, its tumor immune microenvironment (TIME) remains largely unexplored. Methods We systematically profiled the immune landscape using bulk RNA sequencing and multiplex immunofluorescence staining and comprehensively analyzed the associations between immune features, clinicopathological parameters, and patient outcomes in a multi-institutional cohort of 153 GAC cases. Results GAC tumors exhibited sparse T cell but abundant macrophage infiltration, predominantly with M2-polarized macrophages in advanced stage. Tumors with tertiary lymphoid structure (TLS) demonstrated an immunosuppressive milieu characterized by enrichment of B cells, PD1-CD8+ T cells, and regulatory T cells. While TLS-positive patients were associated with poorer prognosis, 2 patients showed improved survival with chemoradiotherapy. Moreover, the TLS and FIGO stage-based prognostic model was robust in the risk stratification for tumor recurrence. Conclusions We reveal a distinct immunosuppressive TIME and TLS in GAC. TLS might confer an adverse prognosis. Our findings provide valuable clues for individualized therapy for this aggressive cancer in future.

Targeting HK3 in tumor-associated macrophages enhances antitumor immunity through augmenting antigen cross-presentation in cervical cancer

Background Tumor-associated macrophages (TAMs) are among the most prevalent cells within the tumor microenvironment (TME) of cervical cancer (CC). Although TAMs frequently exhibit an immunosuppressive phenotype, their plasticity enables them as an intriguing reprogrammable target for immunotherapy of CC. Methods Consensus clustering was employed to delineate immune infiltration patterns in a cohort of 119 patients with CC. Single-cell RNA sequencing, complemented by flow cytometry analysis, was used to characterize hexokinase 3 (HK3)-expressing cell populations. In vivo tumor models were established to assess the functional impact of HK3-expressing cells on the TME, with interventions including Hk3 knockout and CD8+ T-cell depletion. A comprehensive approach involving bulk RNA sequencing, immunoprecipitation assays, confocal microscopy imaging, and in vitro co-culture systems was implemented to elucidate the mechanisms underlying HK3 inhibition-mediated enhancement of antitumor immunity. Furthermore, the therapeutic efficacy of HK3 inhibition, both as a monotherapy and in combination with immunotherapeutic strategies, was systematically evaluated in preclinical tumor models. Results We elucidated a cross-regulation between TAMs and CD8+ T cells, with HK3 serving as a central regulatory node. Upon HK3 expression was upregulated by CD8+ T cells through the IFN-γ-STAT1 signaling axis, TAMs exhibited impaired cross-presentation capacity, which in turn attenuated CD8+ T cell-mediated antitumor immunity. Mechanistically, HK3 physically interacted with mechanistic target of rapamycin (mTOR), promoting nuclear translocation of transcription factor EB (TFEB) and resulting in excessive lysosomal activation and antigen degradation. Moreover, targeting HK3 in combination with immune checkpoint blockade yielded a synergistic effect in enhancing antitumor immunity. Conclusions Targeting HK3 in TAMs represents a promising therapeutic strategy capable of enhancing antitumor immunity and synergizing with immune checkpoint blockade by restoring efficient antigen cross-presentation.

FTO Facilitates Cervical Cancer Malignancy Through Inducing m6A‐Demethylation of PIK3R3 mRNA

ABSTRACTBackgroundThe incidence rate and mortality of cervical cancer rank the fourth in the global female cancer. N6‐methyladenosine (m6A) always plays an important role in tumor progression, and fat mass and obesity‐associated gene (FTO) works as the m6A demethylase.AimsOur study aimed to narrate the biological function and potential mechanisms for FTO in cervical cancer malignancy.Materials & MethodsWe analyzed potential clinical value of FTO in cervical cancer patients. The relative protein levels of FTO in cervical cancerous tissue and paracancerous tissue were verified by IHC. After changing the FTO expression level by lentivirus transfection, the proliferation and metastasis ability of cervical cancer cells were detected both in vitro and in vivo. Further, Merip‐seq and Merip‐qPCR are used to profile m6A transcriptome‐wide. Finally, western blot were performed to identify the regulatory mechanism.ResultsBased on TCGA‐CESC cohort and GEO dataset, FTO expression levels in HPV‐positive cancer patients were significantly higher than those in HPV‐negative cancer patients and could predict advanced FIGO stage. The protein level of FTO in cervical cancerous tissue was higher than that in paracancerous tissue. Functional assays indicated that FTO promoted the proliferation, migration and invasion of cervical cancer cells both in vitro and in vivo. The Merip‐seq and Merip‐qPCR evoked that relative PIK3R3 m6A level was significantly increased after FTO knockdown, which effected the activation of FoxO pathway. After knocking down FTO, upregulation of PIK3R3 can restore the malignancy of cervical cancer.ConclusionAll in all, these data suggest a vital role for FTO in occurrence and development of cervical cancer.

Evaluation of secondary cytoreduction surgery in platinum-resistant ovarian cancer patients within three-line recurrent: a multicenter, randomized controlled study

Epithelial ovarian cancer is the leading cause of death among gynecological malignancies. Platinum resistance remains a dilemma and bottleneck in treatment, and salvage chemotherapy has limited effectiveness. Recently, the role of secondary cytoreductive surgery (SCS) in patients with platinum-resistant recurrent ovarian cancer (ROC) has caused attention especially in patients with oligometastases. However, there is neither high-quality evidence-based evidence nor standardized criteria for selecting SCS for patients with platinum-resistant ROC until now. This multicenter, randomized, controlled clinical trial is to evaluate the value of SCS and to clarify reliable criteria of utilizing SCS in women with ROC, which is led by Gynecologic Oncology Group, Women's Hospital, Zhejiang University School of Medicine. Recruitment has started on January 1st, 2023, and is scheduled to end in December 2026. One hundred and forty participants with platinum-resistant ROC who meet the "RSCS criteria" will be randomized assigned at a ratio of 1:1 to either the experimental arm or the standard arm. Patients in the experimental arm will receive SCS followed by non-platinum single agent chemotherapy (paclitaxel, gemcitabine or liposomal adriamycin) for at least 4 cycles while patients in the standard arm will be provided with only non-platinum single agent chemotherapy. The primary outcome is progression-free survival. The secondary outcomes are overall survival, adverse events and health-related cancer-specific quality of life. ClinicalTrials.gov Identifier: NCT05633199.

Integrated Bioinformatics And Experimental Validation Reveal The Role Of Jarid2 In Ovarian Cancer

The application of CRISPR/Cas9 system in cervical carcinogenesis

AbstractIntegration of high-risk HPV genomes into cellular chromatin has been confirmed to promote cervical carcinogenesis, with HPV16 being the most prevalent high-risk type. Herein, we evaluated the therapeutic effect of the CRISPR/Cas9 system in cervical carcinogenesis, especially for cervical precancerous lesions. In cervical cancer/pre-cancer cell lines, we transfected the HPV16 E7 targeted CRISPR/Cas9, TALEN, ZFN plasmids, respectively. Compared to previous established ZFN and TALEN systems, CRISPR/Cas9 has shown comparable efficiency and specificity in inhibiting cell growth and colony formation and inducing apoptosis in cervical cancer/pre-cancer cell lines, which seemed to be more pronounced in the S12 cell line derived from the low-grade cervical lesion. Furthermore, in xenograft formation assays, CRISPR/Cas9 inhibited tumor formation of the S12 cell line in vivo and affected the corresponding protein expression. In the K14-HPV16 transgenic mice model of HPV-driven spontaneous cervical carcinogenesis, cervical application of CRISPR/Cas9 treatment caused mutations of the E7 gene and restored the expression of RB, E2F1, and CDK2, thereby reversing the cervical carcinogenesis phenotype. In this study, we have demonstrated that CRISPR/Cas9 targeting HPV16 E7 could effectively revert the HPV-related cervical carcinogenesis in vitro, as well as in K14-HPV16 transgenic mice, which has shown great potential in clinical treatment for cervical precancerous lesions.

miR-4454 up-regulated by HPV16 E6/E7 promotes invasion and migration by targeting ABHD2/NUDT21 in cervical cancer

Abstract The abnormal expression of HPV16 E6/E7 activates oncogenes and/or inactivates tumor suppressor genes, resulting in the selective growth and malignant transformation of cancer cells. miR-4454 was selected by sequencing due to its abnormal high expression in HPV16 E6/E7 positive CaSki cell compared with HPV16 E6/E7 negative C33A cell. Overexpression of miR-4454 enhances cervical cancer cell invasion and migration. ABHD2 and NUDT21 are identified as a target gene of miR-4454.The effects of ABHD2 and NUDT21 on migration and invasion of CaSki and C33A cells were determined. The dual luciferase and RT-qPCR assays confirmed that miR-4454 might regulate its targets ABHD2 and NUDT21 to promote the proliferation, invasion and migration, whereas, inhibit the apoptosis in CaSki and C33A cells.

The Antitumor Efficiency of Zinc Finger Nuclease Combined with Cisplatin and Trichostatin A in Cervical Cancer Cells

Background: Persistent infection with the high-risk of human papillomavirus (HR-HPVs) is the primary etiological factor of cervical cancer; HR-HPVs express oncoproteins E6 and E7, both of which play key roles in the progression of cervical carcinogenesis. Zinc Finger Nucleases (ZFNs) targeting HPV E7 induce specific shear of the E7 gene, weakening the malignant biological effects, hence showing great potential for clinical transformation. Objective: Our aim was to develop a new comprehensive therapy for better clinical application of ZFNs. We here explored the anti-cancer efficiency of HPV targeted ZFNs combined with a platinum-based antineoplastic drug Cisplatin (DDP) and an HDAC inhibitor Trichostatin A (TSA). Methods: SiHa and HeLa cells were exposed to different concentrations of DDP and TSA; the appropriate concentrations for the following experiments were screened according to cell apoptosis. Then cells were grouped for combined or separate treatments; apoptosis, cell viability and proliferation ability were measured by flow cytometry detection, CCK-8 assays and colony formation assays. The xenograft experiments were also performed to determine the anti-cancer effects of the combined therapy. In addition, the HPV E7 and RB1 expressions were measured by western blot analysis. Results: Results showed that the combined therapy induced about two times more apoptosis than that of ZFNs alone in SiHa and HeLa cells, and much more inhibition of cell viability than either of the separate treatment. The colony formation ability was inhibited more than 80% by the co-treatment, the protein expression of HPV16/18E7 was down regulated and that of RB1 was elevated. In addition, the xenografts experiment showed a synergistic effect between DDP and TSA together with ZFNs. Conclusion: Our results demonstrated that ZFNs combined with DDP or TSA functioned effectively in cervical cancer cells, and it provided novel ideas for the prevention and treatment of HPV-related cervical malignancies.

Clinical Application of Ultrasound Guidance for Parametrial Treatment of Advanced Cervical Cancer

ObjectivesTo evaluate the accuracy of ultrasound (US) in determining the positions of parametrial implants by comparing US with magnetic resonance imaging (MRI) for advanced cervical cancer.MethodsPatients undergoing brachytherapy with parametrial implantation for cervical cancer from February 2017 to February 2019 were involved in the study. The transverse section of the cervix (surface S1) and the transverse section 1 cm above the external cervix (surface S2) were selected from MRI and US images as the observation planes. In the MRI observation plane, the distances between the uterine titanium needles and the uterine tube/implanter were set as M1 to M4; in the US observation plane, the distances between the uterine titanium needles and the uterine tube/implanter were set as D1 to D4. The differences and consistency in M and D of each group were then compared.ResultsThere were no significant differences between M and D in each group (P = .058; P = .821; P = .870; and P = .936, respectively). The intraclass correlation coefficients of M and D in each group were 0.970, 0.968, 0.952, and 0.956. A regression analysis showed that the relationships between M and D in each group were as follows: M1 = 0.9449D1 + 0.1812; M2 = 0.9463D2 + 0.0965; M3 = 0.9176D3 + 0.1233; and M4 = 0.9253D4 + 0.1224.ConclusionsIn parametrial brachytherapy for cervical cancer, US can accurately determine the positions of parametrial implantation needles, which is already applicable on MRI, and can provide assistance in parametrial brachytherapy for advanced cervical cancer.

Testing for viral DNA integration among HPV‐positive women to detect cervical precancer: An observational cohort study

AbstractObjectiveHuman papillomavirus (HPV) integration is a crucial genetic step in cervical carcinogenesis. This study aimed to evaluate the performance of an HPV integration test for the triage of HPV‐positive women.DesignAn observational cohort study.SettingA cervical cancer screening programme in China.Population1393 HPV‐positive women aged 25–65 years undergoing routine cervical cancer screening and HPV integration testing with 1‐year follow‐up.MethodsThe sensitivity, specificity, positive predictive value and negative predictive value between HPV integration and cytology were compared.Main outcome measuresCervical intraepithelial neoplasia grade 3 or more severe (CIN3+).ResultsAmong 1393 HPV‐positive patients, 138 (9.9% [8.3–11.5%]) were HPV integration test positive compared with 537 who had abnormal cervical cytology (38.5% [36.0–41.1%]). Compared with cytology, HPV integration exhibited higher specificity (94.5% [93.3–95.8%] versus 63.8% [61.2–66.4%]) and equivalent sensitivity (70.5% [61.4–79.7%] versus 70.5% [61.4–79.7%]) for detection of CIN3+. HPV integration‐negative women accounted for 90.1% (1255/1393) of the total population and had a low immediate CIN3+ risk (2.2%). At 1‐year follow‐up, the progression rate in the HPV integration‐positive women was higher than in the HPV integration‐negative women (12.0% versus 2.1%, odds ratio 5.6, 95% CI, 2.6–11.9). In 10 conservatively managed integration‐negative CIN2 patients, all showed spontaneous regression and seven showed HPV clearance after 1‐year follow‐up.ConclusionThe HPV integration test may be a precise risk stratification tool for HPV‐positive women and could avoid excessive use of invasive biopsies.

The prognostic significance of primary tumor site in vulvar cancer: a population-based cohort study

To investigate the association of primary tumor site with prognosis in vulvar cancer, stratified by vulvar squamous cell carcinoma (SCC) and non-SCC histological types. This population-based retrospective study enrolled patients with vulvar cancer from the Surveillance, Epidemiology, and End Results database between January 2000 and December 2018. The primary outcome was cancer-specific survival (CSS). The prognostic difference between labium majus, labium minus and clitoris groups was investigated using Kaplan-Meier analyses and Cox proportional hazards regression analyses. A total of 3,465 eligible patients with vulvar cancer were included with a mean age of 54.5 years. Among the 1,076 (31.1%) patients with non-SCC, the multivariate Cox regression analyses showed that labium minus-sited disease (hazard ratio [HR]=1.85; 95% confidence interval [CI]=1.27-2.71; p=0.001) and clitoris-sited disease (HR=2.37; 95% CI=1.47-3.85; p0.05). Kaplan-Meier analyses also showed that the primary tumor site had a significant prognostic effect in vulvar non-SCC (p<0.001) but not in vulvar SCC (p=0.330). Among vulvar non-SCC, patients with labium minus-sited disease had a significantly worse prognosis than those with labium majus-sited disease, and a significantly better prognosis than those with clitoris-sited disease. Gynecologic oncologists should consider the prognostic effect of primary tumor site in vulvar non-SCC, and make optimal, personalized treatment and surveillance strategies based on different primary tumor sites.

Cytoreductive Surgery in Platinum-resistant Recurrent Ovarian Cancer

This novel study was specifically designed for platinum-resistant recurrent ovarian cancers with PFI\<6 months and aimed to compare prognosis of patients who received cytoreductive surgery followed by chemotherapy versus chemotherapy alone.