Congjian Xu

Clinical characteristics and status of treatment of small-cell carcinoma of the ovary, hypercalcemic type in the Chinese population: a meta-analysis

This study aimed to comprehensively analyze the clinical characteristics and treatment status of Chinese small cell carcinoma of the ovary hypercalcemic type (SCCOHT) patients, providing insights into this unique population and comparing findings with international literature. Through a meta-analysis, we collected data from published case reports and records from the Obstetrics & Gynecology Hospital of Fudan University. Demographic information, clinical presentations, tumor attributes, treatment modalities, and survival outcomes were extracted and examined alongside relevant global studies. The analysis encompassed 80 Chinese SCCOHT patients, of which 62 from 33 previously reported literatures, and the other 18 were from Obstetrics & Gynecology Hospital of Fudan University. In 62 cases with stage information, A total of 25 tumors were International Federation of Gynecology and Obstetrics stage I, 3 were stage II, 19 were stage III, and 15 were stage IV. Most patients received surgery and chemotherapy, but regimens were varied. Median follow-up was 10 months (range=4-120). Elevated carbohydrate antigen 125 and serum calcium levels were consistent findings. Recurrence rates were notable, especially among stage I patients. Platinum-based chemotherapy, paclitaxel and carboplatin (n=11, 13.4%), constituted common treatment regimens. This study observed demographic and clinical similarities with international datasets. And the findings emphasize the urgency for innovative therapeutic approaches to improve outcomes in SCCOHT patients. Continued research efforts are essential to enhance the knowledge surrounding this rare malignancy and to optimize its clinical management.

Mannose Enhances Immunotherapy Efficacy in Ovarian Cancer by Modulating Gut Microbial Metabolites

Abstract The gut microbiome significantly influences the effectiveness of immune checkpoint blockade therapy. However, its clinical application is hindered by the absence of cost-effective production methods. In this study, we demonstrated that oral mannose supplementation inhibits ovarian tumor growth in immunocompetent mice through the enrichment of Faecalibaculum rodentium (F. rodentium). Administration of F. rodentium not only suppressed tumor progression but also enhanced antitumor immune responses. Mannose supplementation fostered an immune stimulatory tumor microenvironment, characterized by the expansion and differentiation of progenitor-exhausted CD8+ T cells (Tpex). Metabolomics analysis identified propionate and butyrate as critical metabolites driving the mannose-mediated tumor-suppressive effects, which was validated in vivo. Mechanistically, propionate and butyrate enhanced histone acetylation to promote Tpex-cell expansion. Moreover, a mannose-related gene signature was associated with favorable response to immune checkpoint blockade therapy across multiple cancer types. Supplementation with mannose also improved the efficacy of anti–PD-1 therapy and PARP inhibitor treatment. These findings highlight the role of F. rodentium–derived metabolites propionate and butyrate as key stimulators of Tpex-cell expansion, thereby activating antitumor immune responses. This underscores the therapeutic potential of mannose supplementation in enhancing cancer immunotherapy outcomes in high-grade serous ovarian cancer. Significance: Alterations to the gut microbiome induced by mannose engender an immune stimulatory tumor microenvironment responsive to immunotherapy, suggesting that mannose may be an effective and safe adjuvant therapy for stimulating immunotherapy sensitivity.

Establishment and characterization of a novel cell line (SCCOHT-CH-1) and PDX models derived from Chinese patients of small cell ovarian carcinoma of the hypercalcemic type

AbstractSmall cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and aggressive malignancy that poses a significant clinical challenge due to its grim prognosis. Unfortunately, only three SCCOHT cell lines are currently available for scientific research. In this study, we have successfully established a novel SCCOHT cell line from a recurrent lesion of a SCCOHT patient, named SCCOHT-CH-1. We comprehensively characterized the novel cell line by employing techniques such as morphological observation, CCK-8 assay, Transwell assay, clone formation assay, short tandem repeat sequence (STR) analysis, karyotype analysis, immunohistochemical staining, western blot assay, and xenograft tumor formation assay. SCCOHT-CH-1 cells were small circular and had a unique STR profile. The population-doubling time of SCCOHT-CH-1 was 33.02 h. The cell line showed potential migratory and invasive ability. Compared with another SCCOHT cell line COV434, SCCOHT-CH-1 exhibited higher expression of AKT, VIM, and CCND1. At the same time, SCCOHT-CH-1 has the ability of tumorigenesis in vivo. We also successfully constructed three patient-derived xenograft (PDX) models of SCCOHT, which were pathologically diagnosed to be consistent with the primary tumor, accompanied by loss of SAMRCA4 protein expression. The establishment of SCCOHT-CH-1 cell line and PDX models from Chinese people represent a pivotal step toward unraveling the molecular mechanism of SCCOHT and fostering the development of targeted interventions to tackle this challenging malignancy.

NIR-II Fluorescence Imaging for the Detection and Resection of Cancerous Foci and Lymph Nodes in Early-Stage Orthotopic and Advanced-Stage Metastatic Ovarian Cancer Models

The high mortality rate of ovarian cancer can be primarily attributed to late diagnosis and early lymph node (LN) metastasis. The anatomically deep-located ovaries own intricate anatomical structures and lymphatic drainages that compromise the resolution and sensitivity of near-infrared first-window (NIR-I) fluorescence imaging. Reported NIR-II imaging studies of ovarian cancer focused on late-stage metastasis detection via the intraperitoneal xenograft model. However, given the significant improvement in patient survival associated with early-stage cancer detection, locating tumors that are restricted within the ovary is equally crucial. We obtained the polymer nanoparticles with bright near-infrared-II fluorescence (NIR-II NPs) by nanoprecipitation of DSPE-PEG, one of the ingredients of FDA-approved nanoparticle products, and benzobisthiadiazole, an organic NIR-II dye. The one-step synthesis and safe component lay the groundwork for its clinical translation. Benefiting from the NIR-II emission (∼1060 nm), NIR-II NPs enabled a high signal-to-noise (S/N) ratio (13.4) visualization of early-stage orthotopic ovarian tumors with NIR-II fluorescence imaging for the first time. Imaging with orthotopic xenograft allows a more accurate mimic of human ovarian cancer origin, thereby addressing the dilemma of translating existing nanoprobe preclinical research by providing the nano-bio interactions with early local tumor environments. After PEGylation, the desirable-sized probe (∼80 nm) exhibited high lymphophilicity and relatively extended circulation. NIR-II NPs maintained their accurate detection of orthotopic tumors, tumor-regional LNs, and minuscule (<1 mm) disseminated peritoneal metastases simultaneously (with S/N ratios all above 5) in mice with advanced-stage cancer in real time ∼36 h after systematic delivery. With NIR-II fluorescence guidance, we achieved accurate surgical staging in tumor-bearing mice and complete tumor removal comparable to clinical practice, which provides preclinical data for translating NIR-II fluorescence image-guided surgery.

Tumour-associated neutrophils orchestrate intratumoural IL-8-driven immune evasion through Jagged2 activation in ovarian cancer

Abstract Background Tumour associated neutrophils (TANs) play a controversial role in regulating immune surveillance and immune evasion in various malignancies. Here, we investigated the relevance of TANs with the prognosis and immune microenvironment of epithelial ovarian cancer (EOC). Methods We characterised TANs using flow cytometric analysis and immunofluorescence analysis. The prognostic merit of TANs in EOC was evaluated using cox regression analysis. Furthermore, we explored the therapeutic merit of targeting Notch signalling in EOC and determined its involvement in the immune microenvironment. Results High level of TANs is associated with a dismal prognosis and immune tolerance in EOC. TANs impaired cytotoxic effects of CD8+ T cells partly through Jagged2 (JAG2). Notch pathway blocked using γ-secretase inhibitor LY3039478 and anti-JAG2 antibody led to retarded tumour growth and augmented cytotoxic effects of CD8+ T cells. IL-8 contributes to the recruitment of TANs and the induction of JAG2 expression in TANs. Blockade of CXCR2 signalling reduces tumour growth rate, accompanied by a decreasing amount of TANs and increasing activity of CD8+ T cells. JAG2+TANs is an independent predictor of clinical outcomes. Conclusion JAG2+TANs are closely linked to IL-8-driven immune evasion microenvironment and may serve as a promising therapeutic target for the reinvigoration of anti-tumour immunity.

Rosiglitazone ameliorates senescence and promotes apoptosis in ovarian cancer induced by olaparib

Senescence mechanisms are vital to resistance to long-term olaparib maintenance treatment. Recently, peroxisome proliferator-activated receptor-γ agonists (e.g., rosiglitazone) have been reported to ameliorate the senescence-like phenotype by modulating inflammatory mediator production. This study examined synergistic effects on the anti-tumor activity of rosiglitazone combined with olaparib in ovarian cancer treatment. A2780 and SKOV3 mouse subcutaneous xenograft models were established for observing anti-tumor effects in living organisms and were randomly split into combination (both olaparib and rosiglitazone), rosiglitazone (10 mg/kg), olaparib (10 mg/kg), control (solvent) groups that received treatment once every 2 or 3 days (n = 6 per group). Cell counting kit-8 (CCK-8) assays were used to test the influences of rosiglitazone and olaparib on cell proliferation. PI and Annexin-V-FITC staining was used with flow cytometry to assess the cell cycle distribution and cell apoptosis. Senescence-associated β-galactosidase (SA-β-Gal) staining was used to observe cellular senescence. We performed quantitative real-time polymerase chain reaction assays to study the senescence-related secretory phenotype (SASP). Olaparib and rosiglitazone were observed to synergistically retard subcutaneous ovarian cancer growth in vivo, and synergistically suppress ovarian cancer cell proliferation in vitro. Compared with olaparib alone, the percentage of positive cells expressed SA-β-gal and SASP were significantly decreased in the treatment of combination of olaparib and rosiglitazone. Furthermore, olaparib plus rosiglitazone increased the percentage of apoptosis in ovarian cancer cell compared with olaparib alone. In A2780 cells, it showed lower expression of P53, phospho-p53 (Ser15), P21, and P18 protein in combination treatment compared with olaparib alone. While, in SKOV3 cells, it showed lower expression of phosphor-retinoblastoma protein (Rb) (Ser807/811), and higher expression of cyclin D1, P21, and P16 protein in combination treatment compared with olaparib alone. Rosiglitazone combined with olaparib can help manage ovarian cancer by ameliorating olaparib-induced senescence and improving anti-tumor effects.