TMED3 stabilizes SMAD2 by counteracting NEDD4-mediated ubiquitination to promote ovarian cancer.

Ovarian cancer is a major cause of death among cancer patients. Recent research has shown that the transmembrane emp24 domain (TMED) protein family plays a role in the progression of various types of cancer. In this study, we investigated the expression of TMED3 in ovarian cancer tumors compared to nontumor tissues using immunohistochemical staining. We found that TMED3 was overexpressed in ovarian cancer tumors, and its high expression was associated with poor disease-free and overall survival. To understand the functional implications of TMED3 overexpression in ovarian cancer, we conducted experiments to knockdown TMED3 using short hairpin RNA (shRNA). We observed that TMED3 knockdown resulted in reduced cell viability and migration, as well as increased cell apoptosis. Additionally, in subcutaneous xenograft models in BALB-c nude mice, TMED3 knockdown inhibited tumor growth. Further investigation revealed that SMAD family member 2 (SMAD2) was a downstream target of TMED3, driving ovarian cancer progression. TMED3 stabilized SMAD2 by inhibiting the E3 ligase NEDD4-mediated ubiquitination of SMAD2. To confirm the importance of SMAD2 in TMED3-mediated ovarian cancer, we performed functional rescue experiments and found that SMAD2 played a critical role in this process. Moreover, we discovered that the PI3K-AKT pathway was involved in the promoting effects of TMED3 overexpression on ovarian cancer cells. Overall, our study identifies TMED3 as a prognostic indicator and tumor promoter in ovarian cancer. Its function is likely mediated through the regulation of the SMAD2 and PI3K-AKT signaling pathway. These findings contribute to our understanding of the molecular mechanisms underlying ovarian cancer progression and provide potential targets for therapeutic intervention.

Efficacy and safety of zimberelimab (GLS-010) monotherapy in patients with recurrent or metastatic cervical cancer: a multicenter, single-arm, phase II study.

OBJECTIVE: There is an unmet need to improve clinical outcomes for patients with recurrent/metastatic cervical cancer. Checkpoint inhibitors represent a promising treatment strategy. We evaluated the safety and anti-tumor activity of zimberelimab, an anti-programmed cell death protein-1 antibody, in patients with previously treated, recurrent, metastatic cervical cancer. METHODS: This phase II, single-arm, open-label study used a Simon two-stage minimax design. Eligible patients were women aged 18-75 years with programmed death ligand-1-positive recurrent or metastatic cervical cancer that had progressed after first- or subsequent-line chemotherapy (Eastern Cooperative Oncology Group (ECOG) performance status 0-1). Patients received intravenous zimberelimab (240 mg every 2 weeks) for 2 years until disease progression, intolerable adverse effects, or withdrawal from the study. The primary endpoint was objective response rate assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, by an independent review committee. RESULTS: A total of 105 patients were enrolled. Median age was 51 (range, 31-75) years; 63.8% had an ECOG performance status of 1. The median number of previous treatment lines was 1 (range, 1-4). Median follow-up was 16.9 (range, 16.3-18.4) months. The objective response rate was 27.6%, and the disease control rate was 55.2%. Median duration of response was not reached. Median overall survival was 16.8 months, and median progression-free survival was 3.7 months. The incidence of treatment-related adverse events of any grade was 78.1%, of which the most common were hypothyroidism (26.7%) and anemia (19.0%). CONCLUSION: Zimberelimab monotherapy demonstrated durable anti-tumor activity and an acceptable safety profile in patients with cervical cancer. CLINICAL TRIAL REGISTRATION: NCT03972722.

Intraoperative use of tranexamic acid to reduce blood loss during cytoreductive surgery for advanced ovarian cancer: A randomized controlled clinical trial.

INTRODUCTION: Tranexamic acid reduces blood loss and allogeneic transfusion requirements in various surgical procedures. The role of tranexamic acid during cytoreductive procedures in advanced ovarian cancer is not clear. MATERIAL AND METHODS: This was a single center randomized, controlled, three-armed clinical trial. A total of 150 ovarian cancer patients undergoing cytoreductive surgery were recruited and assigned to three groups (n = 50/group): the control group (normal saline), low-dose group (10 mg/kg bolus + 1 mg/kg continuous infusion of tranexamic acid), and high-dose group (20 mg/kg bolus + 5 mg/kg continuous infusion of tranexamic acid). The primary endpoint was intraoperative blood loss volume and total blood loss volume, and secondary endpoints included intraoperative blood transfusion volumes, vasoactive agent consumption, admission into the intensive care unit, and incidence of postoperative complications within postoperative 30 days. The study was registered at ClinicalTrials.gov ID: NCT04360629. RESULTS: The patients in the high-dose group had less intraoperative (median [IQR]: 625.3 mL [343.5-1210.5]) and total blood loss volume (748.9 mL [292.2-1650.2]) than those in the control group (1015.5 mL [679.4-1015.5], p = 0.012; and 1700.7 mL [458.7-2419.8], p = 0.004, respectively). In contrast, the intraoperative (992.5 mL [539.0-1404.0], p = 0.874) and total blood loss volume (1025.0 mL [381.8-1819.9], p = 0.113) was not significantly reduced in the low-dose group when compared with the control group. Correspondingly, the relative risk of blood transfusion (RR [95% CI], 0.405 [0.180-0.909], p = 0.028) was reduced in the high-dose group and required less intraoperative noradrenaline (881.0 ± 438.3 mg) to maintain stable hemodynamics than the control group (1548.0 ± 349.8 mg, p = 0.001). Furthermore, compared with the control group, the two tranexamic acid groups had decreased intensive care unit admission rates (p = 0.016) without increasing the incidence of postoperative seizure, acute kidney injury, and thromboembolism. CONCLUSIONS: High-dose tranexamic acid is more effective in reducing blood loss and blood transfusion without increasing the risk of postoperative complications. The high-dose regime tended to have a better risk-benefit profile.

Extraperitoneal laparoscopy for para-aortic lymphadenectomy in endometrial carcinoma staging: an approach with higher efficiency.

BACKGROUND: Removing more inframesenteric nodes is not only significantly increases the likelihood of finding metastasis for endometrial cancer, but also can add survival advantage. As most patients diagnosed with endometrial cancer are overweight or obesity, a high efficiency approach is important. Aim of this study was to compare the surgical outcomes of extraperitoneal laparoscopic, transperitoneal laparoscopic, and laparotomic para-aortic lymphadenectomy in endometrial carcinoma staging. METHODS: We retrospectively reviewed data of all patients diagnosed with primary endometrial carcinoma who were treated at the Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center from 1 January 2017 to 31 December 2019. The numbers of para-aortic lymph nodes, surgical time, complications, blood loss and hospital stay were compared. The patients' medical records and pathological reports were carefully reviewed. Statistical significance was defined as p < 0.05. RESULTS: We retrospectively compared patients who underwent extraperitoneal laparoscopy (Group E, n = 20), transperitoneal laparoscopy (group T, n = 21), and laparotomy (group L, n = 135). The median number of para-aortic lymph nodes was significantly higher in group E than in groups T and L (9.5, 5, and 6, respectively; p = 0.004 and 0.0004, respectively). All patients in group E underwent successfully dissection to the renal vessel level. The median operation time was significantly shorter in group L than in groups T and E (94, 174, and 233 min, respectively; p < 0.0001). The median estimated blood loss volume was higher in group L than in groups T and E (200, 100, and 142.5 ml, respectively; all comparisons p < 0.001), and the length of hospital stay was significantly longer in group L than in Groups T and E (6, 5, and 6 days, respectively; all comparisons p < 0.001). CONCLUSION: The extraperitoneal laparoscopic approach for staging endometrial carcinoma harvested higher numbers of para-aortic lymph nodes which could be considered for endometrial carcinoma staging, especially for para-aortic lymph node harvest.

Simple conization and pelvic lymphadenectomy in early-stage cervical cancer: A retrospective analysis and review of the literature.

OBJECTIVES: To evaluate the feasibility of cervical conization and laparoscopic pelvic lymphadenectomy as a fertility-sparing surgery to treat early-stage cervical cancer. METHODS: We conducted a retrospective analysis from a prospectively maintained database of patients with stage IA1-IB1 grossly invisible cervical cancers undergoing conization plus laparoscopic lymphadenectomy between January 2014 and July 2019. RESULTS: Forty patients were identified. Five patients (12.5%) had stage IA1 with lymphovascular space invasion, 21 (52.5%) had stage IA2, and 14 (35.0%) had stage IB1. All of the patients had tumors <2 cm. Histology included 35 (87.5%) squamous-cell carcinomas, three (7.5%) adenocarcinomas, and two (5.0%) adenosquamous carcinomas. Median duration of the procedure was 105 min (range, 31-219), and the median estimated blood loss was 50 ml (range, 30-200). One patient received abdominal radical trachelectomy due to the presence of positive margin after conization. Three patients developed postoperative cervical stenosis. After a median follow-up of 35 months (range, 8-74), only one patient (2.5%) developed a recurrence in the remaining cervix, and no patients died. Four of 17 patients attempting to conceive had a spontaneous pregnancy: three delivered at term and one was currently pregnant. CONCLUSION: Cervical conization and pelvic lymphadenectomy seems to be an acceptable treatment for well-selected patients with low-risk, early-stage cervical cancer who wish to preserve fertility. It offers excellent oncologic outcomes, low perioperative morbidities, and good reproductive results. Further large prospective studies are warranted to prove the effectiveness of this surgery.

Reproductive and obstetric outcomes after abdominal radical trachelectomy (ART) for patients with early-stage cervical cancers in Fudan, China.

OBJECTIVE: To report the reproductive and obstetric outcomes of patients undergoing abdominal radical trachelectomy (ART) for the treatment of early-stage cervical cancers in Fudan, China. METHODS: We retrospectively reviewed a prospectively collected database of 360 patients with stage IA1-IB1 cervical cancers who underwent ART between 2004 and 2018. RESULTS: Overall, 211 women (58.6%) did not plan to get pregnant immediately after ART, and 89.6% of them were due to childbearing before surgery or unmarried. Among 149 women who attempted to conceive, 26 (17.4%) of them achieved 30 pregnancies. Eighty-six patients (57.7%) had infertility problems, 44 attempted to conceive with assisted reproductive technologies, and 12 (27.3%) succeeded. Post-operative cervical stenosis (26, 27.4%) and fallopian tube obstruction (22, 23.2%) were the most common reasons for infertility after surgery. Among the patients who conceived, there were 3 first-trimester miscarriages, 6 second-trimester miscarriages, and 2 elective terminations. A total of 19 pregnancies reached the third trimester, and 84.2% of them ended after 36 weeks. Twelve of 20 cases in patients with cerclage placed had full-term birth, while 3 of 5 patients without cerclage placed suffered from second-trimester miscarriage or preterm birth. CONCLUSIONS: Immediately after ART, many patients were reluctant to conceive, while others suffered from cervical stenosis or fallopian tube obstruction, which had led to low pregnancy rate. Pregnant patients might experience miscarriage or preterm labor which could be prevented by cervical cerclage. Assisted reproductive technology should be encouraged to improve obstetric outcomes.

The Survival Rate and Surgical Morbidity of Abdominal Radical Trachelectomy Versus Abdominal Radical Hysterectomy for Stage IB1 Cervical Cancer.

PURPOSE: To compare the survival rates and morbidities of abdominal radical trachelectomy (ART) to abdominal radical hysterectomy (ARH) for stage IB1 cervical cancer and to evaluate the safety of ART for tumors measuring 2-4 cm. METHODS: We performed a retrospective study to compare the outcomes of patients with stage IB1 cervical cancer who underwent ART to patients treated with ARH who met the inclusion criteria of a fertility-sparing surgery. All of the patients were treated by the same surgeon at our institution in the same period. RESULTS: Of the 107 and 141 patients who underwent ART and ARH, respectively, 61 and 82 patients had a tumor ≥2 cm (P = NS). With a median follow-up of 30 and 49 months, 2 patients treated with ART and 3 patients treated with ARH recurred: the 5-year RFS rate was 96.5 and 94.8%, respectively, for tumors ≥2 cm (P = NS). Only 3 patients died in the ARH group: the 5-year OS rate was 100% for the ART and 94.8% for the ARH group for tumors ≥2 cm (P = NS). Incidence rates of intraoperative complications were similar in the two groups (1.9% for ART and 0.7% for ARH, P = NS). However, incidence rates of postoperative complications were higher in the ART group (36.4% for ART and 19.1% for ARH, P < 0.05). CONCLUSIONS: ART appears to have equal survival rates to ARH and can be performed safely in stage IB1 cervical cancers ≥2 cm. However, ART is associated with more postoperative morbidities compared with ARH.

Primary malignant melanoma of the vagina: a retrospective clinicopathologic study of 44 cases.

OBJECTIVE: This study aimed to identify prognostic factors of survival and improve treatment strategies in women diagnosed with primary malignant melanoma of the vagina. METHODS: Between December 2002 and August 2011, 44 patients with lesions confined to the vagina and diagnosed with melanoma at Fudan University Shanghai Cancer Center were evaluated retrospectively. Prognostic factors were analyzed by Kaplan-Meier method. RESULTS: With a median follow-up time of 18.9 months (range, 6.0-94.3 months), 30 (68.2%) patients developed recurrences, whereas 21 (47.7%) died of disease. Median progression-free survival (PFS) was 14.4 months and median overall survival (OS) was 39.5 months. Depth of invasion (DOI) was significantly associated with OS (P = 0.023), and there was an obvious tendency toward improved OS with a negative lymph node status (P = 0.063). The DOI was significantly associated with lymph node status (P = 0.047). The extent of surgery (wide local excision vs radical excision) was not associated with differences in PFS or OS (P = 0.573 and P = 0.842, respectively). Longer PFS was observed in patients who received adjuvant chemotherapy and radiotherapy (P = 0.038). CONCLUSIONS: The prognosis of primary vaginal melanoma is dependent on the DOI and lymph node status in our study. Surgical resection of disease, especially wide local excision, should be considered as the optimal treatment when complete removal of tumor with a negative margin is possible. Adjuvant therapy may be associated with a longer PFS.

PARP1-stabilised FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/ß-catenin signalling pathway.

Metastasis is an important factor that causes ovarian cancer (OC) to become the most lethal malignancy of the female reproductive system, but its molecular mechanism is not fully understood. In this study, through bioinformatics analysis, as well as analysis of tissue samples and clinicopathological characteristics and prognosis of patients in our centre, it was found that Forkhead box Q1 (FOXQ1) was correlated with metastasis and prognosis of OC. Through cell function experiments and animal experiments, the results show that FOXQ1 can promote the progression of ovarian cancer in vivo and in vitro. Through RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), Western blotting (WB), quantitative real-time polymerase chain reaction (qRT‒PCR), immunohistochemistry (IHC), luciferase assay, and ChIP-PCR, it was demonstrated that FOXQ1 can mediate the WNT/ß-catenin pathway by targeting the LAMB promoter region. Through coimmunoprecipitation (Co-IP), mass spectrometry (MS), ubiquitination experiments, and immunofluorescence (IF), the results showed that PARP1 could stabilise FOXQ1 expression via the E3 ubiquitin ligase Hsc70-interacting protein (CHIP). Finally, the whole mechanism pathway was verified by animal drug combination experiments and clinical specimen prognosis analysis. In summary, our results suggest that PARP1 can promote ovarian cancer progression through the LAMB3/WNT/ß-catenin pathway by stabilising FOXQ1 expression.

The feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 drives lipophagy to induce cisplatin resistance in epithelial ovarian cancer.

Platinum-taxane chemotherapy is the first-line standard-of-care treatment administered to patients with epithelial ovarian cancer (EOC), and faces the major challenge of cisplatin resistance. Aurora Kinase A (AURKA) is a serine/threonine kinase, acting as an oncogene by participating in microtubule formation and stabilization. In this study, we demonstrate that AURKA binds with DDX5 directly to form a transcriptional coactivator complex to induce the transcription and upregulation of an oncogenic long non-coding RNA, TMEM147-AS1, which sponges hsa-let-7b/7c-5p leading to the increasing expression of AURKA as a feedback loop. The feedback loop maintains EOC cisplatin resistance via activation of lipophagy. These findings underscore the feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 provides mechanistic insights into the combined use of TMEM147-AS1 siRNA and VX-680, which can help improve EOC cisplatin treatment. Our mathematical model shows that the feedback loop has the potential to act as a biological switch to maintain on- (activated) or off- (deactivated) status, implying the possible resistance of single use of VX-680 or TMEM147-AS1 siRNA. The combined use reduces both the protein level of AURKA using TMEM147-AS1 siRNA and its kinase activity using VX-680, showing more significant effect than the use of TMEM147-AS1 siRNA or VX-680 alone, which provides a potential strategy for EOC treatment.

A multicenter phase 2 trial of camrelizumab plus famitinib for women with recurrent or metastatic cervical squamous cell carcinoma.

This phase 2 study assesses the efficacy and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (anti-angiogenic agent) in women with pretreated recurrent or metastatic cervical cancer (ClinicalTrials.gov NCT03827837). Patients with histologically or cytologically confirmed cervical squamous cell carcinoma experiencing relapse or progression during or after 1-2 lines of systemic therapy for recurrent or metastatic disease are enrolled. Eligible patients receive camrelizumab 200 mg intravenously on day 1 of each 3-week cycle plus famitinib 20 mg orally once daily. The primary endpoint is the objective response rate. Secondary endpoints are duration of response, disease control rate, time to response, progression-free survival, overall survival, and safety. The trial has met pre-specified endpoint. Thirty-three patients are enrolled; median follow-up lasts for 13.6 months (interquartile range: 10.0-23.6). Objective responses are observed in 13 (39.4%, 95% confidence interval [CI]: 22.9-57.9) patients; the 12-month duration of response rate is 74.1% (95% CI: 39.1-90.9). Median progression-free survival is 10.3 months (95% CI: 3.5-not reached) and the 12-month overall survival rate is 77.7% (95% CI: 58.9-88.7). All patients experience treatment-related adverse events; grade ≥3 events occur in 26 (78.8%) patients. Treatment-related serious adverse events and deaths are observed in 9 (27.3%) and 2 (6.1%) patients, respectively. Camrelizumab plus famitinib shows promising antitumor activity with a manageable and tolerable safety profile in patients with pretreated recurrent or metastatic cervical squamous cell carcinoma. This combination may represent a treatment option for this population.

Antitumor activity and safety of camrelizumab plus famitinib in patients with platinum-resistant recurrent ovarian cancer: results from an open-label, multicenter phase 2 basket study.

BACKGROUND: Combination treatments with immune-checkpoint inhibitor and antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a notable therapeutic strategy in recurrent ovarian cancer (ROC). We report the results of camrelizumab (an anti-programmed cell death protein-1 antibody) in combination with famitinib (a receptor tyrosine kinase inhibitor) for the treatment of platinum-resistant ROC from an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients with platinum-resistant ROC were enrolled to receive camrelizumab (200 mg every 3 weeks by intravenous infusion) and oral famitinib (20 mg once daily). All patients had disease progression during or <6 months after their most recent platinum-based chemotherapy. Primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 based on investigator's assessment. Secondary endpoints included disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS), 12-month OS rate and safety profile. RESULTS: Of the 37 women enrolled, 11 (29.7%) patients had primary platinum resistant, 15 (40.5%) patients had secondary platinum resistant and 11 (29.7%) patients had primary platinum refractory disease. As the cut-off date of April 9, 2021, nine (24.3%) patients had achieved a confirmed objective response, the ORR was 24.3% (95% CI, 11.8 to 41.2) and the DCR was 54.1% (95% CI, 36.9 to 70.5). Patients with this combination regimen showed a median TTR of 2.1 months (range, 1.8-4.1) and a median DoR of 4.1 months (95% CI, 1.9 to 6.3). Median PFS was 4.1 months (95% CI, 2.1 to 5.7), and median OS was 18.9 months (95% CI, 10.8 to not reached), with the median follow-up duration of 22.0 months (range, 12.0-23.7). The estimated 12-month OS rate was 67.2% (95% CI, 49.4 to 79.9). The most common ≥grade 3 treatment-related adverse events were hypertension (32.4%), decreased neutrophil count (29.7%) and decreased platelet count (13.5%). One (2.7%) patient died of grade 5 hemorrhage that was judged possibly related to study treatment by investigator. CONCLUSION: The camrelizumab with famitinib combination appeared to show antitumor activity in heavily pretreated patients with platinum-resistant ROC with an acceptable safety profile. This combination might provide a novel alternative treatment strategy in platinum-resistant ROC setting and warranted further exploration. TRIAL REGISTRATION NUMBER: NCT03827837.

Anlotinib in Chinese Patients With Recurrent Advanced Cervical Cancer: A Prospective Single-Arm, Open-Label Phase II Trial.

OBJECTIVE: This phase II, single-arm, prospective study aimed to evaluate the efficacy and safety of anlotinib in Chinese patients with recurrent or metastatic cervical cancer (CC). METHODS: Patients with histologically proven recurrent or metastatic advanced CC were enrolled at Fudan University Shanghai Cancer Center. Patients received 12 mg of oral anlotinib daily before breakfast for 2 weeks of each 3-week (21 days) cycle separated by a 1-week interval. Anlotinib was administered orally until disease progression, patient withdrawal, intolerant toxicity, or death. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Between September 2018 and November 2019, 41 patients were recruited. The median age was 53 years old. The histological results revealed that 82.9% of the recruited patients had squamous cell carcinoma, 14.6% had adenocarcinoma, and 2.4% had other types. At the data cutoff date, six patients were still being treated, and 35 patients had discontinued treatment. Forty (40/41, 97.5%) patients were evaluated for treatment response. The median PFS and OS was 3.2 and 9.9 months, respectively, in patients who received anlotinib treatment. The ORR was 24.4%. In addition, 34.2% (14/41) of patients were confirmed to have stable disease, and 39.0% (16/41) of patients were confirmed to have progressive disease. The DCR was 58.5%. Ten patients (10/41) had a confirmed response during the follow-up period. Most adverse events (AEs) were grade 1 or 2. High-grade AEs (grade 3) included urinary leukocyte positivity (9.8%), hematuria (4.9%), and hypertension (2.4%). CONCLUSION: This is the first study to evaluate the efficacy and safety of anlotinib in Chinese patients with recurrent or metastatic CC. Anlotinib produced durable clinical responses with manageable safety in these patients.

Overexpression of NPTX2 Promotes Malignant Phenotype of Epithelial Ovarian Carcinoma via IL6-JAK2/STAT3 Signaling Pathway Under Hypoxia.

BACKGROUND: Epithelial ovarian cancer (EOC) is the main subtype of ovarian cancer and shows an aggressive phenotype and poor prognosis. Neuronal pentraxin II (NPTX2) is a member of the neuronal pentraxin family and plays a contradictory role in different tumors. However, there has been no report about the possible role and effect of NPTX2 in EOC. METHODS: Bioinformatics analysis, qPCR, western blotting and immunohistochemistry were used to detect the expression of NPTX2 in EOC. Lentivirus-based transfection for NPTX2 overexpression or knockdown was performed on the EOC cell lines A2780, HEY, SKOV3 and OVCAR-3. The effect of NPTX2 on the malignant phenotype of EOC was examined through methods of MTS assay, Edu assay, transwell assay, western blotting analysis, qPCR analysis, luciferase reporter assay and xenograft experiment. RESULTS: EOC tissues showed higher NPTX2 expression than the normal tissues with poor prognosis. NPTX2 overexpression can promote the proliferation, invasion, migration and tumorigenesis of EOC via IL6-JAK2/STAT3 signaling pathway. Moreover, hypoxia-inducible factor-1(HIF-1) can promote the transcription and expression of NPTX2 under the hypoxic environment. NPTX2 knockdown abolished the hypoxia-induced malignant phenotypes in ECO. CONCLUSIONS: The above results suggest that NPTX2 may play a novel role in ovarian cancer's malignant phenotype and act as a promising treatment target for EOC molecular therapy.

Programmed death ligand-1 regulates angiogenesis and metastasis by participating in the c-JUN/VEGFR2 signaling axis in ovarian cancer.

BACKGROUND: Although programmed cell death-ligand 1 (PD-L1) plays a well-known function in immune checkpoint response by interacting with programmed cell death-1 (PD-1), the cell-intrinsic role of PD-L1 in tumors is still unclear. Here, we explored the molecular regulatory mechanism of PD-L1 in the progression and metastasis of ovarian cancer. METHODS: Immunohistochemistry of benign tissues and ovarian cancer samples was performed, followed by migration, invasion, and angiogenesis assays in PD-L1-knockdown ovarian cancer cells. Immunoprecipitation, mass spectrometry, and chromatin immunoprecipitation were conducted along with zebrafish and mouse experiments to explore the specific functions and mechanisms of PD-L1 in ovarian cancer. RESULTS: Our results showed that PD-L1 induced angiogenesis, which further promoted cell migration and invasion in vitro and in vivo of ovarian cancer. Mechanistically, PD-L1 was identified to directly interact with vascular endothelial growth factor receptor-2 (VEGFR2) and then activated the FAK/AKT pathway, which further induced angiogenesis and tumor progression, leading to poor prognosis of ovarian cancer patients. Meanwhile, PD-L1 was found to be regulated by the oncogenic transcription factor c-JUN at the transcriptional level, which enhanced the expression of PD-L1 in ovarian cancer. Furthermore, we demonstrated that PD-L1 inhibitor durvalumab, combined with the antiangiogenic drug, apatinib, could enhance the effect of anti-angiogenesis and the inhibition of cell migration and invasion. CONCLUSION: Our results demonstrated that PD-L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c-JUN/VEGFR2 signaling axis, suggesting that the combination of PD-L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients.

HNRNPH1-stabilized LINC00662 promotes ovarian cancer progression by activating the GRP78/p38 pathway.

Numerous studies suggest an important role for copy number alterations (CNAs) in cancer progression. However, CNAs of long intergenic noncoding RNAs (lincRNAs) in ovarian cancer (OC) and their potential functions have not been fully investigated. Here, based on analysis of The Cancer Genome Atlas (TCGA) database, we identified in this study an oncogenic lincRNA termed LINC00662 that exhibited a significant correlation between its CNA and its increased expression. LINC00662 overexpression is highly associated with malignant features in OC patients and is a prognostic indicator. LINC00662 significantly promotes OC cell proliferation and metastasis in vitro and in vivo. Mechanistically, LINC00662 is stabilized by heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1). Moreover, LINC00662 exerts oncogenic effects by interacting with glucose-regulated protein 78 (GRP78) and preventing its ubiquitination in OC cells, leading to activation of the oncogenic p38 MAPK signaling pathway. Taken together, our results define an oncogenic role for LINC00662 in OC progression mediated via GRP78/p38 signaling, with potential implications regarding therapeutic targets for OC.

Preoperative PET/CT score can predict complete resection in advanced epithelial ovarian cancer: a prospective study.

BACKGROUND: To assess the ability of preoperative positron emission tomography/computed tomography (PET/CT) scans to predict postoperative residual disease in advanced epithelial ovarian cancer (AEOC). METHODS: Thirty-one women with suspected AEOC were enrolled in our prospective study before surgery from July 2016 to December 2017. Complete resection was determined as no residual disease (R0) after surgery. A PET/CT scan was obtained within 2 weeks before surgery in our hospital. The PET score was the sum of each score of the radiological criteria from Suidan's model. The correlations between the PET score and tumor burden and surgical complexity were evaluated by Pearson correlation analysis. T-test or Fisher's exact test was used to compare differences in the variables between the complete and incomplete resection groups. Receiver operating characteristic (ROC) curve analysis was performed to assess the accuracy of the PET score for predicting complete postoperative resection. RESULTS: The median [range] of PET score was 2 [0-8], and the PET score in 20 (65%) patients was less than 3. Complete resection was achieved in 11 (35.5%) patients after surgery, including 10 (90.91%) with low PET scores and only 1 (9.09%) with a high score. The PET score had a significant positive correlation with tumor burden [Eisenkop: r=0.603, P<0.001; peritoneal cancer index (PCI): r=0.522, P=0.003] but not with surgery complexity (Aletti: r=0.291, P=0.113). Patients with lower PET scores (P=0.046) and tumor burdens (Eisenkop: P=0.013; PCI: P=0.012) had higher rates of complete resection. The PET score and tumor burden were effective for predicting complete resection. The AUCPET, AUCEisenkop, and AUCPCI were 0.797 (95% CI: 0.633-0.961, P=0.01), 0.847 (95% CI: 0.707-0.988, P=0.003), and 0.811 (95% CI: 0.653-0.969, P=0.007), respectively. However, surgery complexity was not useful for assessing complete resection. CONCLUSIONS: The preoperative PET score can noninvasively reflect tumor burden and helps predict complete resection after surgery in AEOC patients.

Predictive value of preoperative serum squamous cell carcinoma antigen (SCC-Ag) level on tumor recurrence in cervical squamous cell carcinoma patients treated with radical surgery: A single-institution study.

OBJECTIVE: We seek to explore the clinical significance of serum squamous cell carcinoma antigen (SCC-Ag) and the optimal cut-off value for predicting tumor recurrence and survival in operable cervical squamous cell carcinoma patients. METHODS: A total of 3471 patients with cervical squamous cell carcinoma who underwent radical surgery were enrolled in this study. The cut-off value of serum SCC-Ag for tumor recurrence was calculated using the receiver operating characteristic (ROC) curve. The progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method and multivariate analysis was further performed. RESULTS: The optimal cut-off value of serum SCC-Ag level for predicting tumor recurrence was calculated and set at 2.75 ng/mL. Compared to the value of 1.5 ng/mL used in clinical practice, our results showed that serum SCC-Ag level >2.75 ng/mL was closely related to extrapelvic metastases in relapsed patients (P = 0.035). Multivariate analysis showed that neither serum SCC-Ag level >1.5 ng/mL nor serum SCC-Ag level >2.75 ng/mL was independent risk factors for PFS and OS in all patients. However, among 964 patients with at least one high-risk factor (parametrial invasion, vaginal margin invasion and lymph node metastasis), serum SCC-Ag level > 2.75 ng/mL, instead of serum SCC-Ag level > 1.5 ng/mL, could be used as an independent factor affecting PFS (P = 0.018). CONCLUSION: Preoperative serum SCC-Ag level > 2.75 ng/mL is closely related to extrapelvic recurrence, and is an independent factor for tumor recurrence and survival in cervical squamous cell carcinoma patients with high-risk factors.

Identification of Chemoresistance-Associated Key Genes and Pathways in High-Grade Serous Ovarian Cancer by Bioinformatics Analyses.

PURPOSE: High-grade serous ovarian cancer (HGSOC) is the leading cause of death among gynecological malignancies. This is mainly attributed to its high rates of chemoresistance. To date, few studies have investigated the molecular mechanisms underlying this resistance to treatment in ovarian cancer patients. In this study, we aimed to explore these molecular mechanisms using bioinformatics analysis. METHODS: We analyzed microarray data set GSE51373, which included 16 platinum-sensitive HGSOC samples and 12 platinum-resistant control samples. Differentially expressed genes (DEGs) were identified using RStudio. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using DAVID, and a DEG-associated protein-protein interaction (PPI) network was constructed using STRING. Hub genes in the PPI network were identified, and the prognostic value of the top ten hub genes was evaluated. MGP, one of the hub genes, was verified by immunohistochemistry. RESULTS: All samples were confirmed to be of high quality. A total of 109 DEGs were identified, and the top ten enriched GO terms and four KEGG pathways were obtained. Specifically, the PI3K-AKT signaling pathway and the Rap1 signaling pathway were identified as having significant roles in chemoresistance in HGSOC. Furthermore, based on the PPI network, KIT, FOXM1, FGF2, HIST1H4D, ZFPM2, IFIT2, CCNO, MGP, RHOBTB3, and CDC7 were identified as hub genes. Five of these hub genes could predict the prognosis of HGSOC patients. Positive immunostaining signals for MGP were observed in the chemoresistant samples. CONCLUSION: Taken together, the findings of this study may provide novel insights into HGSOC chemoresistance and identify important therapeutic targets.

Comparison of different lymph node staging systems in patients with node-positive cervical squamous cell carcinoma following radical surgery.

Objective: We compared the prognostic accuracy of four lymph node (LN) staging systems - the 2018 International Federation of Gynecology and Obstetrics (FIGO) stage, number of positive lymph node (PLN), metastatic lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) systems - in patients with node-positive cervical squamous cell carcinoma (CSCC) following radical surgery and explored the optimal choice for clinical applications. Materials and methods: Data were retrospectively collected from 928 node-positive CSCC patients who underwent radical surgery between 2006 and 2014 in our center. Tree-based recursive partitioning was applied to split variables (PLN, LNR, and LODDS) into low-risk and high-risk groups. The log-rank test was used to compare survival curves, and Cox regression analysis was performed to identify prognostic factors. The relative discriminative abilities of the different staging systems were assessed using Harrell's concordance index (C index) and the Akaike information criterion (AIC). Results: The mean number of PLNs was 3.8 (range: 1-44 nodes). According to the 2018 FIGO staging system, 831 patients had stage IIIC1, and 97 had stage IIIC2. For the PLN system, 761 patients were included in the low-risk group, and 167 were included in the high-risk group. For the LNR system, 658 patients were included in the low-risk group, and 270 were included in the high-risk group. The low-risk LODDS group included 694 patients, while the high-risk LODDS group included 234 patients. All four staging systems had a significant influence on patients' progression-free survival (PFS, P < 0.001) and overall survival (OS, P < 0.001). Univariate analysis and multivariate Cox analysis adjusted for significant factors indicated that the four staging systems were significant prognostic factors for PFS and OS. Among them, the PLN system was noted to have the best prognostic performance for both PFS (C index: 0.582; AIC: 8213.33) and OS (C index: 0.624; AIC: 8433.80). Conclusion: The PLN system seemed to be the most accurate LN staging method for predicting node-positive CSCC following radical surgery.