Guonan Zhang

All- trans Retinoic Acid Sensitizes Epithelial Ovarian Cancer to PARP Inhibition after Exposure to Cisplatin

Abstract Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin (CDDP). Notably, platinum-based chemotherapy induces resistance of EOC to PARP inhibition. However, therapeutic approaches targeting PARP inhibitor (PARPi) resistance remain to be explored. In this study, we show that all-trans retinoic acid (ATRA) reduces PARPi resistance–associated EOC cells induced by CDDP treatment. Clinically applicable ATRA suppressed the outgrowth of CDDP-treated EOC cells both in vitro and in vivo. Moreover, a CDDP treatment followed by niraparib maintenance therapy in combination with ATRA improved the survival of EOC-bearing mice. These phenotypes correlated with the PARPi-resistant EOC signature, which consists of elevated expression of aldehyde dehydrogenase 1 family member A1, nicotinamide phosphoribosyltransferase, PARP1, and checkpoint kinase 1, as well as elevated NAD+ level–mediated high activity of aldehyde dehydrogenase 1 family member A1 and PARP1. Mechanistically, ATRA downregulates the expression of these genes and level of intracellular NAD+. Our results suggest that ATRA in conjunction with PARPi represents a promising maintenance therapeutic strategy for EOC.

Preoperative evaluation and a nomogram prediction model for pelvic lymph node metastasis in endometrial cancer

The primary objective of this study is to explore the preoperative risk factors of pelvic lymph node metastasis (PLNM) in endometrial cancer patients, and construct a nomogram prediction model. We retrospectively collected various preoperative clinical characteristics of patients and analyzed their relationship with PLNM. Logistic regression analysis was used to screen for independent risk factors for PLNM of endometrial cancer. A nomogram prediction model was constructed, the receiver operating characteristic (ROC), calibration curve and decision curve analysis (DCA) were constructed and used to assess discrimination, calibration, and net benefit. Out of the 276 patients, 74 (26.81%) with postoperative pathological confirmation of PLNM. Multivariate logistic regressive analysis demonstrated that preoperative depth of myometrial invasion (DIM) ≥50% determined by Magnetic Resonance Imaging (MRI) (p = 0.003), carbohydrate antigen 125 (CA125) (p = 0.030), carbohydrate antigen 19-9 (CA 19-9) (p = 0.044), and platelet/lymphocyte ratio (PLR) (p = 0.025) could serve as independent risk factors for PLNM. A risk factors-based nomogram prediction model was constructed, which showed good discrimination (AUC = 0.841, p < 0.001) and good efficacy (C-index = 0.842) and good calibration (mean absolute error = 0.046). DCA showed that the model can provide clinical benefits. Preoperative DIM ≥50% determined by MRI, serum CA 19-9, CA125 and PLR could be utilized to predict PLNM in endometrial cancer patients. This nomogram prediction model can provide preoperative help for evaluation and identification of patients with endometrial cancer, and provide a theoretical basis for clinical intervention.

Whole-cell tumor vaccines desialylated to uncover tumor antigenic Gal/GalNAc epitopes elicit anti-tumor immunity

Abstract Background Aberrant sialoglycans on the surface of tumor cells shield potential tumor antigen epitopes, escape recognition, and suppress activation of immunocytes. α2,3/α2,6Gal- and α2,6GalNAc (Gal/GalNAc)-linked sialic acid residues of sialoglycans could affect macrophage galactose-type lectins (MGL) mediated-antigen uptake and presentation and promote sialic acid-binding immunoglobulin-like lectins (Siglecs) mediated-immunosuppression. Desialylating sialoglycans on tumor cells could present tumor antigens with Gal/GalNAc residues and overcome glyco-immune checkpoints. Thus, we explored whether vaccination with desialylated whole-cell tumor vaccines (DWCTVs) triggers anti-tumor immunity in ovarian cancer (OC). Methods Sialic acid (Sia) and Gal/GalNAc residues on OC A2780, OVCAR3, and ID8 cells treated with α2-3 neuraminidase (α2-3NA) and α2-6NA, and Sigec-9 or Siglec-E and MGL on DCs pulsed with desialylated OC cells were identified using flow cytometry (FCM); RT-qPCR determined IFNG expression of T cells, TRBV was sequenced using Sanger sequencing and cytotoxicity of αβ T cells was measured with LDH assay; Anti-tumor immunity in vivo was validated via vaccination with desialylated whole-cell ID8 vaccine (ID8 DWCTVs). Results Gal/GalNAc but not Sia residues were significantly increased in the desialylated OC cells. α2-3NA-modified DWCTV increased MGL but decreased Siglec-9 or Siglec E expression on DCs. MGLbright/Siglec-9dim DCs significantly up-regulated IFNG expression and CD4/CD8 ratio of T cells and diversified the TCR repertoire of αβ T-cells that showed enhanced cytotoxic activity. Vaccination with α2-3NA-modified ID8 DWCTVs increased MGLbright/Siglec-Edim DCs in draining lymph nodes, limited tumor growth, and extended survival in tumor-challenged mice. Conclusion Desialylated tumor cell vaccine could promote anti-tumor immunity and provide a strategy for OC immunotherapy in a clinical setting.

Choosing the right timing for interval debulking surgery and perioperative chemotherapy may improve the prognosis of advanced epithelial ovarian cancer: a retrospective study

Abstract Background Primary debulking surgery (PDS) is the main treatment for patients with advanced ovarian cancer, and neoadjuvant chemotherapy (NACT) is for bulky stage III-IV patients who are poor surgical candidates and/or for whom there is a low likelihood of optimal cytoreduction. NACT can increase the rate of complete cytoreduction, but this advantage has not translated to an improvement in survival. Therefore, we aimed to identify factors associated with the survival of patients who received NACT followed by interval debulking surgery (IDS). Methods A retrospective study was conducted in FIGO stage IIIC-IV epithelial ovarian cancer patients who underwent PDS or IDS in our center between January 1st, 2013, and December 31st, 2018. Results A total of 273 cases were included, of whom 20 were lost to follow-up. Progression-free survival (PFS) and overall survival (OS) of the IDS and PDS groups were found to be similar, although the proportion of patients in stage IV and serum carbohydrate antigen 125 (CA125) levels before treatment in the IDS group were significantly higher than that in the PDS group. Body mass index (BMI), CA125 level before IDS, residual disease after surgery, and the interval between preoperative and postoperative chemotherapy were all found to be independent prognostic factors for PFS; FIGO stage, residual disease after surgery, and CA125 level before IDS were independent prognostic factors for OS. We found that PFS and OS were both significantly longer in patients with normal CA125 levels before IDS and when the interval between preoperative and postoperative chemotherapy was &lt; 35.5 days (IDS-3 group) than for patients in the PDS group. Conclusions The results suggested the importance of timely IDS and postoperative chemotherapy and potentially allowed the identification of patients who would benefit the most from NACT. Normal CA125 levels before IDS and an interval between preoperative and postoperative chemotherapy no longer than 5 weeks were associated with improved prognosis in advanced ovarian cancer patients.

The impact of Pegylated liposomal doxorubicin in recurrent ovarian cancer: an updated meta-analysis of randomized clinical trials

Abstract Background Previous meta-analysis studies suggested that pegylated liposomal doxorubicin (PLD) may improve the survival rate of patients with recurrent ovarian cancer. The aim of the present meta-analysis, then, was to further update the role of PLD in the treatment of recurrent ovarian cancer. Methods We performed a literature search using the electronic databases Medicine, EMBASE, Web of Science, and the Cochrane Library to 27 July 2020. We only restricted the randomized clinical trials. Study-specific hazard ratios and 95% confidence interval (HR/95% CI) and risk ratios and 95% confidence interval (RR/95% CI) were pooled using a random-effects model. Results Ten studies (12 trials) were included after screening 940 articles. We categorized the eligible studies into two groups: the doublet regimens (four trials, 1767 patients) showed that PLD plus carbo provided superior progression-free survival (PFS) (HR, 0.85; 95% CI, 0.74–0.97) and similar overall survival (OS) (HR, 1.00; 95% CI, 0.88–1.14) compared to paclitaxel (PAC) plus carboplatin (carbo). PLD plus carbo was associated with significantly more anemia and thrombocytopenia, and other side effects were well tolerated. The monotherapy regimens (eight trials, 1980 patients) showed that PLD possessed a similar PFS (HR, 1.02; 95% CI, 0.90–1.16) and OS (HR, 0.88; 95% CI, 0.77–1.01) relative to other monotherapies. PLD alone was also more associated with mucositis/stomatitis and hand-foot syndrome, while other side effects were well tolerated. Conclusions In platinum-sensitive recurrent ovarian cancer, PLD plus carbo was more effective than PAC plus carbo, while in platinum-resistant or -refractory recurrent ovarian cancer, PLD exhibited similar survival to other monotherapies. Regarding side effects, PLD plus carbo and mono chemotherapy were both well tolerated.

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.

Clinical efficacy analysis of chemotherapy of isolated neck lymphatic metastasis in advanced epithelial ovarian cancer

The aim of this study was to retrospectively investigate the efficacy of chemotherapy for neck lymph node metastasis (NLNM) by determining the characteristics and survival of patients with isolated NLNMs metastases from epithelial ovarian carcinoma (EOC) at stage IV of the Federation of Gynecology and Obstetrics (FIGO). The clinicopathological characteristics and survival outcome of 24 cases with stage IV FIGO EOC with isolated NLNM were retrospectively analyzed between December 1, 2014, and November 30, 2021. Among the 24 patients, 2 (8.3%) underwent primary debulking surgery (PDS), 21 (87.5%) received neoadjuvant chemotherapy(NACT) followed by interval debulking surgery (IDS), and 1 (4.2%) received chemotherapy alone. Additionally, 13 (54.2%) cases achieved abdominal R0 debulking, while 11(45.8%) cases achieved R1/R2 debulking. The chemotherapy response of NLNMs included complete response (8/24, 33.3%), partial response (15/24,62.5%), or stable disease (1/24,41.7%). None of the patients received resection or radiotherapy of NLNMs. Recurrence was observed in 15 (62.5%) patients, with only 2 experiencing recurrence of NLNMs. The median progression-free survival (PFS) and overall survival (OS) were 35 months and 48 months, respectively. R0 debulking led to a significantly longer PFS (not reached) and OS (57 months) compared to non-R0 debulking (PFS: 10 months, P = 0.001; OS: 22 months, P = 0.001). Interestingly, patients with EOC with lymphatic recurrence had better OS ( 57 months) than did those with abdominal or distant recurrence (OS: 29 months; P = 0.012). Chemotherapy is an effective treatment for neck lymph nodes metastasis, and a favorable response to chemotherapy could eliminate the necessity for NLNM resection or radiotherapy. Effective control of abdominal disease with surgery may be a critical factor in managing FIGO stage IV EOC patients with isolated NLMNs.