Role of immune checkpoint inhibitors combined with chemotherapy in recurrent drug-resistant gestational trophoblastic neoplasia: Four case reports and literature review.

BACKGROUND: Multiple studies have confirmed that programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) is widely expressed in gestational trophoblastic neoplasia (GTN) tissues. Therefore, immune checkpoint inhibitors may be an option for the treatment of recurrent and drug-resistant GTN. CASE: Four patients with recurrent or drug-resistant GTN who were treated with PD-1/PD-L1 checkpoint inhibitor agents combined with chemotherapy were reported. The mean age of recurrence was 45.8 years (35-56 years), including three cases of choriocarcinoma (CC) and one case of invasive mole (IM). International Federation of Gynecology and Obstetrics (FIGO) prognosis score: ≤6 (low risk) in one case, 7-12 (high risk) in one case, ≥13 (very high risk) in two cases. There were two cases of lung metastasis and one case of vulvar and inguinal lymph node metastasis. One of the four patients underwent total hysterectomy and one patient underwent resection of lung metastases. All the four patients received comprehensive treatment of immunotherapy combined with chemotherapy after relapse, among which one patient achieved complete response (CR), two patients achieved partial response (PR), and one patient developed progressive disease (PD). Three patients who achieved PR or CR were maintained by single agent immunotherapy after combination therapy, and there was no disease recurrence during follow-up. One patient with PD also achieved CR after using salvage chemotherapy after recurrence, and there was no disease recurrence during follow-up. During the treatment, four patients had different degrees of immune-related adverse reactions, all of which were grade I-II, and no severe adverse reactions were found. CONCLUSION: Immune checkpoint inhibitors combined with chemotherapy has an impressive therapeutic effect on recurrent or drug-resistant GTN with mild adverse reactions, which can be used as a treatment option for such patients. However, due to the lack of large sample data support, the specific time and treatment course of its use, long-term use of adverse reactions and whether it affects fertility function remain to be solved.

Drug resistance in ovarian cancer: from mechanism to clinical trial.

Ovarian cancer is the leading cause of gynecological cancer-related death. Drug resistance is the bottleneck in ovarian cancer treatment. The increasing use of novel drugs in clinical practice poses challenges for the treatment of drug-resistant ovarian cancer. Continuing to classify drug resistance according to drug type without understanding the underlying mechanisms is unsuitable for current clinical practice. We reviewed the literature regarding various drug resistance mechanisms in ovarian cancer and found that the main resistance mechanisms are as follows: abnormalities in transmembrane transport, alterations in DNA damage repair, dysregulation of cancer-associated signaling pathways, and epigenetic modifications. DNA methylation, histone modifications and noncoding RNA activity, three key classes of epigenetic modifications, constitute pivotal mechanisms of drug resistance. One drug can have multiple resistance mechanisms. Moreover, common chemotherapies and targeted drugs may have cross (overlapping) resistance mechanisms. MicroRNAs (miRNAs) can interfere with and thus regulate the abovementioned pathways. A subclass of miRNAs, "epi-miRNAs", can modulate epigenetic regulators to impact therapeutic responses. Thus, we also reviewed the regulatory influence of miRNAs on resistance mechanisms. Moreover, we summarized recent phase I/II clinical trials of novel drugs for ovarian cancer based on the abovementioned resistance mechanisms. A multitude of new therapies are under evaluation, and the preliminary results are encouraging. This review provides new insight into the classification of drug resistance mechanisms in ovarian cancer and may facilitate in the successful treatment of resistant ovarian cancer.

Integrated genomic and transcriptomic analysis reveals the activation of PI3K signaling pathway in HPV-independent cervical cancers.

BACKGROUND: HPV-independent cervical cancers (HPV-ind CCs) are uncommon with worse prognosis and poorly understood. This study investigated the molecular characteristics of HPV-ind CCs, aiming to explore new strategies for HPV-ind CCs. METHODS: HPV status of 1010 cervical cancer patients were detected by RT-PCR, PCR and RNA-sequencing (RNA-seq). Whole exome sequencing (WES) and RNA-seq were performed in identified HPV-ind CCs. The efficacy of PI3Kα inhibitor BYL719 in HPV-ind CCs was evaluated in cell lines, patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). RESULTS: Twenty-five CCs were identified as HPV-ind, which were more common seen in older, adenocarcinoma patients and exhibited poorer prognosis as well as higher tumor mutation burden compared to HPV-associated CCs. HPV-ind CCs were featured with highly activated PI3K/AKT signaling pathway, particularly, PIK3CA being the most predominant genomic alteration (36%). BYL719 demonstrated superior tumor suppression in vitro and in vivo. Furthermore, HPV-ind CCs were classified into two subtypes according to distinct prognosis by gene expression profiles, the metabolism subtype and immune subtype. CONCLUSIONS: This study reveals the prevalence, clinicopathology, and molecular features of HPV-ind CCs and emphasizes the importance of PIK3CA mutations and PI3K pathway activation in tumorigenesis, which suggests the potential significance of PI3Kα inhibitors in HPV-ind CC patients.

Alveolar Soft Part Sarcoma in the Female Genital Tract: Case Series with Literature Review and SEER Database Analysis.

Introduction: Alveolar soft part sarcoma (ASPS) is a rare and distinct subtype of soft tissue sarcoma. This study aims to describe the unique presentation of ASPS in the female genital tract. Methods: Prognostic factors for cancer-specific overall survival (CSS) were evaluated using multivariate analyses. Results: In our case series, we identified a novel TFE3-PRCC gene fusion in a 24-year-old unmarried patient with cervical ASPS who underwent fertility-sparing surgery and remained recurrence-free for 41 months. The other two patients underwent radical hysterectomy and bilateral salpingo-oophorectomy. At the time of writing, the two patients had been disease-free for 49 and 71 months, fluorescence in situ hybridization showed break-apart signals for the ASPL-TFE3 gene. Among the 55 cases with available information from the PubMed/Medline database, most presented with localized disease, and at the last follow-up, all patients were alive and 45 patients showed no evidence of disease. The 5-year CSS rate in the female genital tract cohort from SEER database was 86.2%. Multivariate analysis revealed that older age was associated with a 1.042-fold increased risk of cancer-specific mortality (HR=1.042, 95% CI 1.022-1.063, P < 0.001), involvement of soft tissue including the heart was associated with a 4.786-fold higher risk (HR=4.7868, 95% CI 1.681-13.623, P= 0.003), and regional infiltration and distant metastasis were associated with approximately 8.6-fold and 18-fold higher risk of cancer-specific mortality compared to local disease, respectively (HR=8.652, 95% CI 2.529-29.63, P = 0.001; HR=18.366, 95% CI 6.153-54.817, P< 0.001). Patients who underwent radical excision did not show reduced cancer-specific mortality compared to those who underwent local excision (HR=0.492, 95% CI 0.224-1.081, P = 0.078). Discussion: Previously unrecognized genetic diversity exists in ASPS. Patients with ASPS in the female genital tract have the lowest likelihood of presenting with a distant disease and are associated with a more favorable survival outcome.

Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced cervical cancer constitutes around 37% of cervical cancer cases globally and has a poor prognosis due to limited therapeutic options. Immune checkpoint inhibitors in the neoadjuvant setting could address these challenges. We aimed to investigate the efficacy and safety of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer. METHODS: In this single-arm, phase 2 trial, which was done across eight tertiary hospitals in China, we enrolled patients aged 18-70 years with untreated cervical cancer (IB3, IIA2, or IIB/IIIC1r with a tumour diameter ≥4 cm [International Federation of Gynecology and Obstetrics, 2018]) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients underwent one cycle of priming doublet chemotherapy (75-80 mg/m2 cisplatin, intravenously, plus 260 mg/m2 nab-paclitaxel, intravenously), followed by two cycles of a combination of chemotherapy (cisplatin plus nab-paclitaxel) on day 1 with camrelizumab (200 mg, intravenously) on day 2, with a 3-week interval between treatment cycles. Patients with stable disease or progressive disease received concurrent chemoradiotherapy, and patients with a complete response or partial response proceeded to radical surgery. The primary endpoint was the objective response rate, by independent central reviewer according to Response Evaluation Criteria in Solid Tumours, version 1.1. Activity and safety were analysed in patients who received at least one dose of camrelizumab. This study is registered with ClinicalTrials.gov, NCT04516616, and is ongoing. FINDINGS: Between Dec 1, 2020, and Feb 10, 2023, 85 patients were enrolled and all received at least one dose of camrelizumab. Median age was 51 years (IQR 46-57) and no data on race or ethnicity were collected. At data cutoff (April 30, 2023), median follow-up was 11·0 months (IQR 6·0-14·5). An objective response was noted in 83 (98% [95% CI 92-100]) patients, including 16 (19%) patients who had a complete response and 67 (79%) who had a partial response. The most common grade 3-4 treatment-related adverse events during neoadjuvant chemo-immunotherapy were lymphopenia (21 [25%] of 85), neutropenia (ten [12%]), and leukopenia (seven [8%]). No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Neoadjuvant chemo-immunotherapy showed promising antitumour activity and a manageable adverse event profile in patients with locally advanced cervical cancer. The combination of neoadjuvant chemo-immunotherapy with radical surgery holds potential as a novel therapeutic approach for locally advanced cervical cancer. FUNDING: National Key Technology Research and Development Program of China and the National Clinical Research Center of Obstetrics and Gynecology.

Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease. Objective: To evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted). Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months. Interventions: Patients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of <77 kg and/or platelet count of <150 ×103/µL [to convert to ×109/µL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy. Main Outcomes and Measurements: The primary end point was blinded, independent central review-assessed PFS in the intention-to-treat population. Results: A total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P < .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events. Conclusion and Relevance: This randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting. Trial Registration: ClinicalTrials.gov Identifier: NCT03709316.

The prognosis of patients with small cell carcinoma of the cervix: a retrospective study of the SEER database and a Chinese multicentre registry.

BACKGROUND: Small cell carcinoma of the cervix is a rare but poor prognosis pathological type of cervical cancer, for which advice in clinical guidelines is unspecific. We therefore aimed to investigate the factors and treatment methods that affect the prognosis of patients with small cell carcinoma of the cervix. METHODS: In this retrospective study, we collected data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries cohort and a Chinese multi-institutional registry. The SEER cohort included females diagnosed with small cell carcinoma of the cervix between Jan 1, 2000, and Dec 31, 2018, whereas the Chinese cohort included women diagnosed between Jun 1, 2006, and April 30, 2022. In both cohorts, eligibility was limited to female patients older than 20 years with a confirmed diagnosis of small cell carcinoma of the cervix. Participants who were lost to follow-up or those for whom small cell carcinoma of the cervix was not the primary malignant tumour were excluded from the multi-institutional registry, and those with an unknown surgery status (in addition to those for whom small cell carcinoma of the cervix was not the primary malignant tumour) were excluded from the SEER data. The primary outcome of this study was overall survival (length of time from the date of first diagnosis until the date of death from any cause, or the last follow-up). Kaplan-Meier analysis, propensity score matching, and Cox-regression analyses were used to assess treatment outcomes and risk factors. FINDINGS: 1288 participants were included in the study; 610 in the SEER cohort and 678 in the Chinese cohort. Both univariable and multivariable Cox regression analysis (SEER hazard ratio [HR] 0·65 [95% CI 0·48-0·88], p=0·0058; China HR 0·53 [0·37-0·76], p=0·0005) showed that surgery was associated with a better prognosis. In subgroup analyses, surgery remained a protective factor for patients with locally advanced disease in both cohorts (SEER HR 0·61 [95% CI 0·39-0·94], p=0·024; China HR 0·59 [0·37-0·95]; p=0·029). Furthermore, the protective effect of surgery was observed among patients with locally advanced disease after propensity score matching in the SEER cohort (HR 0·52 [95% CI 0·32-0·84]; p=0·0077). In the China registry, surgery was associated with better outcomes in patients with stage IB3-IIA2 cancer (HR 0·17 [95% CI 0·05-0·50]; p=0·0015). INTERPRETATION: This study provides evidence that surgery improves outcomes of patients with small cell carcinoma of the cervix. Although guidelines recommend non-surgical methods as first-line treatment, patients with locally advanced disease or stage IB3-IIA2 cancer might benefit from surgery. FUNDING: The National Key R&D Program of China and the National Natural Science Foundation of China.

Timing of interval debulking surgery and postoperative chemotherapy after neoadjuvant chemotherapy in advanced epithelial ovarian cancer: a multicenter real-world study.

BACKGROUND: To investigate the prognostic relevance of the time to interval debulking surgery (TTS) and the time to postoperative adjuvant chemotherapy (TTC) after the completion of neoadjuvant chemotherapy (NACT). METHODS: A retrospective real-word study included 658 patients with histologically confirmed advanced epithelial ovarian cancer who received NACT at seven tertiary hospitals in China from June 2008 to June 2020. TTS was defined as the time interval from the completion of NACT to the time of interval debulking surgery (IDS). TTC was defined as the time interval from the completion of NACT to the initiation of postoperative adjuvant chemotherapy (PACT). RESULTS: The median TTS and TTC were 25 (IQR, 20-29) and 40 (IQR, 33-49) days, respectively. Patients with TTS > 25 days were older (55 vs. 53 years, P = 0.012) and received more NACT cycles (median, 3 vs. 2, P = 0.002). Similar results were observed in patients with TTC > 40 days. In the multivariate analyses, TTS and TTC were not associated with PFS when stratified by median, quartile, or integrated as continuous variables (all P > 0.05). However, TTS and TTC were significantly associated with worse OS when stratified by median (P = 0.018 and 0.018, respectively), quartile (P = 0.169, 0.014, 0.027 and 0.012, 0.001, 0.033, respectively), or integrated as continuous variables (P = 0.018 and 0.011, respectively). Similarly, increasing TTS and TTC intervals were associated with a higher risk of death (Ptrend = 0.016 and 0.031, respectively) but not with recurrence (Ptrend = 0.103 and 0.381, respectively). CONCLUSION: The delays of IDS and PACT after the completion of NACT have adverse impacts on OS but no impacts on PFS, which indicates that reducing delays of IDS and PACT might ameliorate the outcomes of ovarian cancer patients treated with NACT.

A prospective randomized multicenter trial for lymphadenectomy in early-stage ovarian cancer: LOVE study.

BACKGROUND: The Lymphadenectomy in Ovarian Neoplasms (LION) study revealed that systemic lymphadenectomy did not bring survival benefit for advanced ovarian cancer patients with clinically normal lymph nodes and was associated with a higher incidence of operative complications. However, there is no consensus on whether lymphadenectomy has survival benefit or not in early epithelial ovarian cancer (EOC). METHODS: We designed the LOVE study, a multicenter, randomized controlled, phase III trial to compare the efficacy and safety of comprehensive staging surgery with or without lymphadenectomy in stages IA-IIB EOC and fallopian tube carcinomas (FTC). The hypothesis is that the oncological outcomes provided by comprehensive staging surgery without lymphadenectomy are non-inferior to those of conventional completion staging surgery in early-stage EOC and FTC patients who have indications for post-operative adjuvant chemotherapy. Patients assigned to experimental group will undergo comprehensive staging surgery, but lymphadenectomy. Patients assigned to comparative group will undergo completion staging surgery including systematic pelvic and para-aortic lymphadenectomy. All subjects will receive 3-6 cycles of standard adjuvant chemotherapy. Major inclusion criteria are pathologic confirmed stage IA-IIB EOC or FTC, and patients have indications for adjuvant chemotherapy either confirmed by intraoperative fast frozen section or previous pathology after an incomplete staging surgery. Major exclusion criteria are non-epithelial tumors and low-grade serous carcinoma. Patients with severe rectum involvement which lead to partial rectum resection will be excluded. The sample size is 656 subjects. Primary endpoint is disease-free survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04710797.

Public health insurance and the risk of cancer-specific mortality in patients with cervical cancer: A Chinese prospective cohort study.

Objective: Cervical cancer has one of the highest incidence and mortality rates of any malignant tumor of the female reproductive tract, and its longer treatment period will place significant financial strain on patients and their families. Little is known about how health insurance policies influence cervical cancer prognosis, particularly in developing countries. The relationship between cervical cancer specific death and cervical cancer all-cause mortality with public health insurance, self-payment rate, and the combined effect of public health insurance and self-payment rate was investigated in this study. Materials and methods: From 2015 to 2019, a prospective longitudinal cohort study on cervical cancer was carried out in Chongqing, China. We chose 4,465 Chongqing University Cancer Hospital patients who had been diagnosed with cervical cancer between 2015 and 2019. The self-payment rate and public health insurance are taken into account in our subgroup analysis. After applying the inclusion and exclusion criteria, we describe the demographic and clinical traits of patients with various insurance plans and self-payment rates using the chi-square test model. The relationship between cervical cancer patients with various types of insurance, the self-payment rate, and treatment modalities is examined using the multivariate logistic regression model. After applying the inclusion and exclusion criteria, we summarize the demographic and clinical traits of patients with various insurance plans and self-payment rates using the chi-square test model. The association between cervical cancer patients with various types of insurance, the self-payment rate, and treatment modalities is examined using the multivariate logistic regression model. The cumulative hazard ratio of all-cause death and cervical cancer-specific mortality for various insurance types and self-payment rates was then calculated using the Cox proportional hazard model and the competitive risk model. Results: This study included a total of 3,982 cervical cancer patients. During the follow-up period (median 37.3 months, 95% CI: 36.40-38.20), 774 deaths were recorded, with cervical cancer accounting for 327 of them. Patients who obtained urban employee-based basic medical insurance (UEBMI) had a 37.1% lower risk of all-cause death compared to patients who received urban resident-based basic medical insurance (URBMI) (HRs = 0.629, 95% CI: 0.508-0.779, p = 0.001). Patients with a self-payment rate of more than 60% had a 26.9% lower risk of cervical cancer-specific mortality (HRs = 0.731, 95% CI: 0.561-0.952, p <0.02). Conclusions: The National Medical Security Administration should attempt to include the more effective self-paid anti-tumor medications into national medical insurance coverage within the restrictions of restricted medical insurance budget. This has the potential to reduce not only the mortality rate of cervical cancer patients, but also their financial burden. High-risk groups, on the other hand, should promote cervical cancer screening awareness, participate actively in the state-led national cancer screening project and enhance public awareness of HPV vaccine. This has the potential to reduce both cervical cancer patient mortality and the financial burden and impact.

Efficacy of lymph node dissection on stage IIICr of cervical cancer before CCRT: study protocol for a phase III, randomized controlled clinical trial (CQGOG0103).

BACKGROUND: Cervical cancer is still present a major public health problem, especially in developing countries. In International Federation of Gynaecology and Obstetrics 2018, allowing assessment of retroperitoneal lymph nodes by imaging and/or pathological findings and, if deemed metastatic, the case is designated as stage IIIC (with r and p notations). Patients with lymph node metastases have lower overall survival (OS), progression free survival (PFS), and survival after recurrence, especially those who have unresectable macroscopical positive lymph nodes. Retrospective analysis suggests that there may be a benefit to debulking macroscopic nodes that would be otherwise difficult to sterilize with standard doses of radiation therapy. However, there are no prospective study reporting that resecting macroscopic nodes before concurrent chemoradiation therapy (CCRT) would improve PFS or OS of cervical cancer and no guidelines for surgical resection of bulky lymph nodes. The CQGOG0103 study is a prospective, multicenter and randomized controlled trial (RCT) evaluating lymph node dissection on stage IIICr of cervical cancer. METHODS: Eligible patients are histologically confirmed cervical squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma. Stage IIICr (confirmed by computed tomography [CT]/magnetic resonance imaging/positron emission tomography/CT) and the short diameter of image-positive lymph node ≥15 mm. 452 patients will be equally randomized to receive either CCRT (pelvic external-beam radiotherapy [EBRT]/extended-field EBRT + cisplatin [40 mg/m²] or carboplatin [the area under curve=2] every week for 5 cycles + brachytherapy) or open/minimally invasive pelvic and para-aortic lymph node dissection followed by CCRT. Randomization is stratified by status of para-aortic lymph node. The primary endpoint is PFS. Secondary endpoints are OS and surgical complications. A total of 452 patients will be enrolled from multiple hospitals in China within 4 years and followed up for 5 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04555226.

Validation of the 2018 FIGO Staging System for Predicting the Prognosis of Patients With Stage IIIC Cervical Cancer.

Background: Risk stratification of patients with cervical cancer accompanied by positive lymph nodes (stage IIIC) (the 2018 International Federation of Gynecology and Obstetrics [FIGO] new staging system) yields a clinically heterogeneous group. In this study, we investigated the prognostic performance of the 2018 FIGO staging system for stage IIIC cervical cancer. Methods: The study included patients with stage III cervical cancer based on the 2018 FIGO staging system, who visited Chongqing University Cancer Hospital between January 2011 and December 2014. Kaplan-Meier curves were generated to evaluate overall survival (OS), which was compared using the log-rank test. The Cox proportional hazard regression model was used for multivariable analysis. Results: A total of 418 patients were eligible for analysis. The 5-year OS was 54.1% for stage IIIC1, 43.3% for stage IIIA, 40.6% for stage IIIB, and 23.1% for stage IIIC2 (P < .001). Multivariable analysis revealed that compared with stages IIIA (hazard ratio [HR] 1.432, 95% confidence interval [CI] 0.867-2.366, P = .161) and IIIB (HR 1.261, 95% CI 0.871-1.827, P = .219), stage IIIC1 cancer was not significantly associated with an increased mortality risk. Stage IIIC2 was independently associated with an increased mortality risk compared with stages IIIA (HR 2.958, 95% CI 1.757-4.983, P < .001) and IIIB (HR 2.606, 95% CI 1.752-3.877, P < .001). We stratified patients with stage IIIC1 based on the T stage. The 5-year OS was significantly longer in patients with stage IIIC1 (T1) than in those with stage IIIA (P = .004) or IIIB (P < .001). Analysis of multiple factors revealed that the mortality risk was 2.75-fold higher in patients with stage IIIC1pN>2 than in patients with stage IIIC1pN1-2 (HR 2.753, 95% CI 1.527-4.965, P = .001). Conclusions: Patients with stage IIIC1 cervical cancer showed heterogeneous clinical characteristics that reflected variable prognoses, depending on the T stage and the extent of pelvic lymph node metastases.

Luteolin directly binds to KDM4C and attenuates ovarian cancer stemness via epigenetic suppression of PPP2CA/YAP axis.

Long-term use of low-toxic natural products holds the promise for eradicating cancer stem cells. In this study, we report that luteolin, a natural flavonoid, attenuates the stemness of ovarian cancer stem cells (OCSCs) by directly binding to KDM4C and epigenetic suppression of PPP2CA/YAP axis. Ovarian cancer stem like cells (OCSLCs) isolated by suspension culture and CD133 + ALDH+ cell sorting was employed as OCSCs model. The maximal non-toxic dose of luteolin suppressed stemness properties, including sphere-forming capacity, the expression of OCSCs markers, sphere-initiating and tumor-initiating capacities, as well as the percentage of CD133 + ALDH+ cells of OCSLCs. Mechanistic study showed that luteolin directly binds to KDM4C, blocks KDM4C-induced histone demethylation of PPP2CA promoter, inhibits PPP2CA transcription and PPP2CA-mediated YAP dephosphorylation, thereby attenuating YAP activity and the stemness of OCSLCs. Furthermore, luteolin sensitized OCSLCs to traditional chemotherapeutic drugs in vitro and in vivo. In summary, our work revealed the direct target of luteolin and the underlying mechanism of the inhibitory effect of luteolin on the stemness of OCSCs. This finding thus suggests a novel therapeutic strategy for eradicating human OCSCs driven by KDM4C.

Multi-omics characterization of silent and productive HPV integration in cervical cancer.

Cervical cancer (CC) that is caused by high-risk human papillomavirus (HPV) remains a significant public health problem worldwide. HPV integration sites can be silent or actively transcribed, leading to the production of viral-host fusion transcripts. Herein, we demonstrate that only productive HPV integration sites were nonrandomly distributed across both viral and host genomes, suggesting that productive integration sites are under selection and likely to contribute to CC pathophysiology. Furthermore, using large-scale, multi-omics (clinical, genomic, transcriptional, proteomic, phosphoproteomic, and single-cell) data, we demonstrate that tumors with productive HPV integration are associated with higher E6/E7 proteins and enhanced tumor aggressiveness and immunoevasion. Importantly, productive HPV integration increases from carcinoma in situ to advanced disease. This study improves our understanding of the functional consequences of HPV fusion transcripts on the biology and pathophysiology of HPV-driven CCs, suggesting that productive HPV integration should be evaluated as an indicator of high risk for progression to aggressive cancers.

Does the primary treatment sequence affect post-relapse survival in recurrent epithelial ovarian cancer? A real-world multicentre retrospective study.

OBJECTIVE: To explore the impact of the primary treatment sequence (primary debulking surgery, PDS, versus neoadjuvant chemotherapy and interval debulking surgery, NACT-IDS) on post-relapse survival (PRS) and recurrence characteristics of recurrent epithelial ovarian cancer (REOC). DESIGN: Real-world retrospective study. SETTING: Tertiary hospitals in China. POPULATION: A total of 853 patients with REOC at International Federation of Gynaecology and Obstetrics stages IIIC-IV from September 2007 to June 2020. Overall, 377 and 476 patients received NACT-IDS and PDS, respectively. METHODS: Propensity score-based inverse probability of treatment weighting (IPTW) was performed to balance the between-group differences. MAIN OUTCOME MEASURES: Clinicopathological factors related to PRS. RESULTS: The overall median PRS was 29.3 months (95% CI 27.0-31.5 months). Multivariate analysis before and after IPTW adjustment showed that NACT-IDS and residual R1/R2 disease were independent risk factors for PRS (p < 0.05). Patients with diffuse carcinomatosis and platinum-free interval (PFI) ≤ 12 months had a significantly worse PRS (p < 0.001). Logistic regression analysis revealed that NACT-IDS was an independent risk factor for diffuse carcinomatosis (OR 1.36, 95% CI 1.01-1.82, p = 0.040) and PFI ≤ 12 months (OR 1.59, 95% CI 1.08-2.35, p = 0.019). In IPTW analysis, NACT-IDS was still significantly associated with diffuse carcinomatosis (OR 1.29, 95% CI 1.05-1.58, p = 0.015) and PFI ≤ 12 months (OR 1.90, 95% CI 1.52-2.38, p < 0.001). CONCLUSIONS: The primary treatment sequence may affect the PRS of patients with REOC by altering the recurrence pattern and PFI duration.

The first Chinese National Union of Real-world Gynaecological Oncology Research and Patient Management Platform: A retrospective study.

OBJECTIVE: To produce high-quality, real-world evidence for oncologists by collating scattered gynaecologic oncology (GO) medical records in China. DESIGN: Retrospective study. SETTING: The National Union of Real-world Gynaecological Oncology Research and Patient Management Platform (NUWA platform). SAMPLE: Patient-centred data pool. METHODS: The NUWA platform integrated inpatient/outpatient clinical, gene and follow-up data. Data of 11 456 patients with ovarian cancer (OC) were collected and processed using 91 345 electronic medical records. Structured and unstructured data were de-identified and re-collated into a patient-centred data pool using a predefined GO data model by technology-aided abstraction. MAIN OUTCOME MEASURES: Recent treatment pattern shifts towards precision medicine for OC in China. RESULTS: Thirteen first-tier hospitals across China participated in the NUWA platform up to 7 December 2021. In total, 3504 (30.59%) patients were followed up by a stand-alone patient management centre. The percentage of patients undergoing breast cancer gene (BRCA) mutation tests increased by approximately six-fold between 2017 and 2018. A similar trend was observed in the administration rate of poly(ADP-ribose) polymerase inhibitors as first-line treatment and second-line treatment after September 2018, when olaparib was approved for clinical use in China. CONCLUSION: The NUWA platform has great potential to facilitate clinical studies and support drug development, regulatory reviews and healthcare decision-making.

The effect of chemotherapy in patients with stage I mucinous ovarian cancer undergoing fertility-sparing surgery.

Objective: To determine the effect of adjuvant chemotherapy in patients with stage I mucinous ovarian cancer (MOC) undergoing fertility-preserving surgery. Patients and methods: The clinicopathological characteristics and survival information of young women with stage I MOC from SEER databases between 2004 and 2019 were collected. The relationship between chemotherapy and the characteristics was examined by univariate and multivariate logistic regression analyses. Univariable and multivariate Cox proportional hazards survival analysis were employed for cancer-specific survival. Cox analysis was performed to build a nomogram model. Results: All 901 eligible patients with stage I MOC were screened from the SEER database. There were 321(35.6%) patients aged 9-30 years, 580(64.4%) aged 31-45 years, 645 (71.6%) patients with stage IA/IB, 256 (28.4%) with stage IC disease, 411(45.6%) who underwent fertility-sparing surgery, and276(30.6%) who received postoperative adjuvant chemotherapy. Multivariate logistic regression analyses showed that postoperative chemotherapy was often used in patients aged 31-45 relative to aged 9-30 (HR: 2.215, 95%CI 1.443-3.401, P < 0.001) or with grade 3 compared to grade 1 tumors (HR: 7.382, 95%CI 4.054-13.443, P < 0.001) or with stage IC compared to stage IA/IB (HR: 6.436, 95%CI 4.515-9.175, P < 0.001) or with non-fertility sparing surgery relative to fertility-sparing (HR:2.226, 95%CI 1.490-3.327, P < 0.001). Multivariate analysis for the special population with fertility preservation indicated that patients with chemotherapy (HR: 2.905, 95% CI: 0.938-6.030, P=0.068) or with grade 3 (HR: 4.750, 95% CI: 1.419-15.896, P=0.011) had a greater risk of mortality. Significant CSS differences were observed between the non-chemotherapy and chemotherapy groups in MOC when patients were stage IA/IB-grade 2 (P=0.004) (10-year CSS rates of chemotherapy=84%, non-chemotherapy = 100%), but not when they were stage IA/IB-grade 1, stage IA/IB-grade 3 or stage IC (both P>0.05). A prognostic prediction nomogram model was built for stage I MOC patient who underwent fertility-sparing and the C-index was 0.709. Discussion: The patients aged 31-45 years, with grade 3, stage IC, and non-fertility-sparing surgery were more likely to receive adjuvant chemotherapy in the real world. For stage I MOC patient who underwent fertility-sparing surgery, the choice of chemotherapy may increase the risk of death, and it should be carefully selected in clinical practice.

METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis.

METTL3 encodes the predominant catalytic enzyme to promote m6A methylation in nucleus. Recently, accumulating evidence has shown the expression of METTL3 in cytoplasm, but its function is not fully understood. Here we demonstrated an m6A-independent mechanism for METTL3 to promote tumour progression. In gastric cancer, METTL3 could not only facilitate cancer progression via m6A modification, but also bind to numerous non-m6A-modified mRNAs, suggesting an unexpected role of METTL3. Mechanistically, cytoplasm-anchored METTL3 interacted with PABPC1 to stabilize its association with cap-binding complex eIF4F, which preferentially promoted the translation of epigenetic factors without m6A modification. Clinical investigation showed that cytoplasmic distributed METTL3 was highly correlated with gastric cancer progression, and this finding could be expanded to prostate cancer. Therefore, the cytoplasmic METTL3 enhances the translation of epigenetic mRNAs, thus serving as an oncogenic driver in cancer progression, and METTL3 subcellular distribution can assist diagnosis and predict prognosis for patients with cancer.