Yu Kang

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.

Do survivors of borderline ovarian tumors have susceptibility to secondary primary malignancies? A SEER population‐based study

AbstractObjectiveTo describe the risk of women who have survived borderline ovarian tumors (BOT) developing second primary malignancies (SPM).MethodsThis work employed the Surveillance, Epidemiology, and End Results (SEER) Program to conduct a retrospective study of patients diagnosed with BOT. The SEER stat software was used to calculate the standardized incidence ratio (SIR). Cases with pathologic diagnosis and for which information on prognostic factors were available were obtained and analyzed using the Fine and Gray model, with non‐SPM death as a competing event.ResultsThe risk of developing SPM among BOT survivors was not elevated compared with that expected in the general population (SIR 0.88, 95% confidence interval [CI] 0.80–0.96) between 1975 and 2017. Of 3661 patients with BOT diagnosed between 1977 and 2000, 477 patients (13.03%) experienced the development of SPM during the median follow up of 19.43 years and the cumulative incidence of SPM over a span of 25 years was 15.52%. Patients with mucinous BOT (P = 0.028), age older than 50 years (P < 0.001), or no lymph node dissection (P = 0.042), had a higher cumulative incidence of SPM in univariate analysis. In the multivariable competing risk analysis, performing lymphadenectomy (subdistribution hazard ratios [sdHR] 0.79, 95% CI 0.64–0.98), age (sdHR 1.03, 95% CI 1.02–1.03) could strongly predict the risk of SPM.ConclusionIn contrast to ovarian cancer, women with BOT were not more prone to develop SPM.

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.

Identification of WTAP-related genes by weighted gene co-expression network analysis in ovarian cancer

Abstract Background Wilms tumor 1 associated protein (WTAP) modulates other genes via transcriptional and post-transcriptional regulation, in particular, by acting as a N6-methyladenosine writer or binding to the 3’UTR of mRNA, and promotes a variety of tumuors. However, the roles and mechanisms of WTAP in ovarian cancer are unknown. Results In this study, using univariate Cox analysis and online CPTA analysis, we found that WTAP was a poor prognostic factor for ovarian cancer, and its protein expression level was higher in ovarian cancer than in normal tissue. Functionally, WTAP promoted the proliferation, invasion, and migration capability of ovarian cancer, according to the results of real time cellular analysis (RTCA), EdU cell proliferation assay, transwell assay. Subsequently, we identified a module containing 133 genes that were carefully related to WTAP expression through weighted gene co-expression network analysis (WGCNA). By calculating the hazard ratios of these genes and comparing their differences in the WTAP high-expression group and the low-expression group, we observed that there was a significant positive correlation between WTAP and two poor survival-related genes, family with sequence similarity 76 member A (FAM76A) and HBS1 like translational GTPase (HBS1L), which was also verified by quantitative real-time PCR in SKOV3 and A2780 cells. Conclusion WTAP functions as an oncogenic factor that promotes the progression of ovarian cancer in which WTAP-HBS1L/FAM76A axis may be involved. Our study indicates the potential role of WTAP in prognostic biomarker and therapeutic target for ovarian cancer.

Dominant-negative transforming growth factor-β receptor-armoured mesothelin-targeted chimeric antigen receptor T cells slow tumour growth in a mouse model of ovarian cancer

AbstractOvarian cancer is a major cause of death among all gynaecological cancers. Although surgery, chemotherapy and targeted therapy have yielded successful outcomes, the 5-year survival rate remains < 30%. Adoptive immunotherapy, particularly chimeric antigen receptor (CAR) T-cell therapy, has demonstrated improved survival in acute lymphoblastic leukaemia with manageable toxicity. We explored CAR T-cell therapy in a preclinical mouse model of ovarian cancer. Second-generation CAR T cells were developed targeting mesothelin (MSLN), which is abundantly expressed in ovarian cancer. Cytotoxicity experiments were performed to verify the lethality of CAR T cells on target cells via flow cytometry. The in vivo antitumour activity of MSLN CAR T cells was also verified using a patient-derived xenograft (PDX) mouse model with human tumour-derived cells. We also evaluated the potency of CAR T cells directed to MSLN following co-expression of a dominant-negative transforming growth factor-β receptor type II (dnTGFβRII). Our data demonstrate that anti-MSLN CAR T cells specifically eliminate MSLN-expressing target cells in an MSLN density-dependent manner. This preclinical research promises an effective treatment strategy to improve outcomes for ovarian cancer, with the potential for prolonging survival while minimizing risk of on-target off-tumour toxicity.

An effective AKT inhibitor-PARP inhibitor combination therapy for recurrent ovarian cancer

Abstract Background Although the use of PARP inhibitor has received considerable amount of attention in ovarian cancer, PARP inhibitor resistance still emerges with disease progression. PI3K/AKT pathway inhibitors have been proposed to synergize with PARP inhibition to slow tumor growth, but the exact molecular mechanisms are still elusive. Methods Utilizing tumor samples from recurrent EOC patients with platinum resistance and prior PARP inhibitor use, Mini PDX and PDX models were established to study the anti-tumor effect of AKT inhibitor (LAE003) and LAE003/PARP inhibitor (Olaparib) in combination. Five ovarian cancer cell lines were treated with Olaparib or LAE003 or in combination in vitro. Cell viability and apoptosis rate were measured after the treatments. Combination index by the Chou–Talalay was used to evaluate in vitro combination effect of Olaparib and LAE003. The protein expression level of PARP1 and PAR was measured by Western blot in cell lines and by immunohistochemistry in PDX tumor tissues. Results Tumor cells from two out of five platinum-resistant ovarian cancer patients previously treated with PARP inhibitor were sensitive to AKT inhibition in Mini-PDX study. Inhibition of AKT further increased the response of tumor cells to Olaparib in a PDX model derived from a recurrent platinum-resistant ovarian cancer patient. Additive anti-proliferation effect of LAE003 and Olaparib was also observed in three ovarian cancer cell lines with high PARP1 protein level. Interestingly, mechanism study revealed that AKT inhibition decreased PARP enzyme activity as measured by PAR level and/or reduced PARP1 protein level in the tumor cell lines and PDX tumor tissues, which may explain the observed combined anti-tumor effect of LAE003 and Olaparib. Conclusion Collectively, our results suggest that the combination of AKT inhibitor and PARP inhibitor could be a viable approach for clinical testing in recurrent ovarian cancer patients.