Evaluation of secondary cytoreduction surgery in platinum-resistant ovarian cancer patients within three-line recurrent: a multicenter, randomized controlled study.

BACKGROUND: Epithelial ovarian cancer is the leading cause of death among gynecological malignancies. Platinum resistance remains a dilemma and bottleneck in treatment, and salvage chemotherapy has limited effectiveness. Recently, the role of secondary cytoreductive surgery (SCS) in patients with platinum-resistant recurrent ovarian cancer (ROC) has caused attention especially in patients with oligometastases. However, there is neither high-quality evidence-based evidence nor standardized criteria for selecting SCS for patients with platinum-resistant ROC until now. METHODS: This multicenter, randomized, controlled clinical trial is to evaluate the value of SCS and to clarify reliable criteria of utilizing SCS in women with ROC, which is led by Gynecologic Oncology Group, Women's Hospital, Zhejiang University School of Medicine. Recruitment has started on January 1st, 2023, and is scheduled to end in December 2026. One hundred and forty participants with platinum-resistant ROC who meet the "RSCS criteria" will be randomized assigned at a ratio of 1:1 to either the experimental arm or the standard arm. Patients in the experimental arm will receive SCS followed by non-platinum single agent chemotherapy (paclitaxel, gemcitabine or liposomal adriamycin) for at least 4 cycles while patients in the standard arm will be provided with only non-platinum single agent chemotherapy. The primary outcome is progression-free survival. The secondary outcomes are overall survival, adverse events and health-related cancer-specific quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05633199.

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.

Secondary cytoreduction surgery for recurrent epithelial ovarian cancer patients after PARPi maintenance: A multicenter, randomized, controlled clinical trial.

BACKGROUND: Poly ADP-ribose polymerase inhibitors (PARPi) treatment has radically changed the treatment strategy for epithelial ovarian cancer. Cancer progression with PARPi maintenance is a new problem that has arisen in clinical practice, and the value of secondary cytoreduction surgery remains unknown. PRIMARY OBJECTIVE: To evaluate the benefits of secondary cytoreductive surgery and to clarify the sensitivity to platinum in patients with firstline or secondline recurrent epithelial ovarian cancer who have completed ≥6 months of PARPi maintenance. STUDY HYPOTHESIS: Carefully selected patients who progress on PARPi maintenance will benefit from secondary cytoreductive surgery. TRIAL DESIGN: This is a multicenter phase III trial. Eligible patients will be randomly assigned at a ratio of 1:1 to either the experimental or standard arm. Patients in the experimental arm will receive secondary cytoreductive surgery followed by platinum based chemotherapy, while patients in the standard arm will be provided with chemotherapy alone. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients diagnosed with firstline or secondline recurrent epithelial ovarian cancer who had previously received ≥4 cycles of platinum based chemotherapy in initial treatment followed by PARPi maintenance therapy for ≥6 months prior to recurrence. PRIMARY ENDPOINT: Progression free survival. SAMPLE SIZE: 400 patients. ESTIMATED DATES FOR COMPETING ACCRUAL AND PRESENTING RESULTS: Accrual completion is expected in December 2024 with results mature after 2 years of follow-up in 2026. TRIAL REGISTRATION: ClinicalTrials.gov NCT05607329.

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.

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.

Preoperative and intraoperative assessment of myometrial invasion in patients with FIGO stage I non-endometrioid endometrial carcinoma-a large-scale, multi-center, and retrospective study.

INTRODUCTION: Myometrial invasion is a prognostic factor for lymph node metastases and decreased survival in non-endometrioid endometrial carcinoma patients. Herein, we explored the mode of myometrial invasion diagnosis in FIGO stage I non-endometrioid carcinoma and evaluated the differences in diagnostic efficiency among intraoperative frozen section (IFS), intraoperative gross examination (IGE), magnetic resonance imaging (MRI), and computed tomography (CT) in clinical practice. Finally, we suggested which test should be routinely performed. METHOD: This was a historical cohort study nationwide with 30 centers in China between January 2000 and December 2019. Clinical data, including age, histology, method of myometrial invasion evaluation (MRI, CT, IGE, and IFS), and final diagnosis of postoperative paraffin sections, were collected from 490 non-endometrioid endometrial carcinoma (serous, clear cell, undifferentiated, mixed carcinoma, and carcinosarcoma) women in FIGO stage I. RESULTS: Among the 490 patients, 89.59% presented myometrial invasion. The methods reported for myometrial invasion assessment were IFS in 23.47%, IGE in 69.59%, MRI in 37.96%, and CT in 10.20% of cases. The highest concordance was detected between IFS and postoperative paraffin sections (Kappa = 0.631, accuracy = 93.04%), followed by IGE (Kappa = 0.303, accuracy = 82.40%), MRI (Kappa = 0.131, accuracy = 69.35%), and CT (Kappa = 0.118, accuracy = 50.00%). A stable diagnostic agreement between IFS and the final results was also found through the years (2000-2012: Kappa = 0.776; 2013-2014: Kappa = 0.625; 2015-2016: Kappa = 0.545; 2017-2019: Kappa = 0.652). CONCLUSION: In China, the assessment of myometrial invasion in non-endometrioid endometrial carcinoma is often performed via IGE, but the reliability is relatively low in contrast to IFS. In clinical practice, IFS is a reliable method that can help accurately assess myometrial invasion and intraoperative decision-making (lymph node dissection or not). Hence, it should be routinely performed in non-endometrioid endometrial carcinoma patients.

It is not the time to abandon intraoperative frozen section in endometrioid adenocarcinoma: A large-scale, multi-center, and retrospective study.

INTRODUCTION: Stage IB (deep myometrial invasion) high-grade endometrioid adenocarcinoma (EA), regardless of LVSI status, is classified into high-intermediate risk groups, requiring surgical lymph node staging. Intraoperative frozen section (IFS) is commonly used, but its adequacy and reliability vary between reports. Hence, we determined the utility of IFS in identification of high-risk factors, including deep myometrial invasion and high-grade. METHOD: We retrospectively analyzed 9,985 cases operated with hysterectomy and diagnosed with FIGO stage I/II EA in postoperative paraffin section (PS) results at 30 Chinese hospitals from 2000 to 2019. We determined diagnostic performance of IFS and investigated whether the addition of IFS to preoperative biopsy and imaging could improve identification of high-risk factors. RESULTS: IFS and postoperative PS presented the highest concordance in assessing deep myometrial invasion (Kappa: 0.834), followed by intraoperative gross examination (IGE Kappa: 0.643), MRI (Kappa: 0.395), and CT (Kappa: 0.207). IFS and postoperative PS presented the highest concordance for high-grade EA (Kappa: 0.585) compared to diagnostic curettage (D&C 0.226) and hysteroscope (Hys 0.180). Sensitivity and specificity for detecting deep myometrial invasion were 86.21 and 97.20% for IFS versus 51.72 and 88.81% for MRI, 68.97 and 94.41% for IGE. These figures for detecting high-grade EA were 58.21 and 96.50% for IFS versus 16.42 and 98.83% for D&C, 13.43 and 98.64% for Hys. Parallel strategies, including MRI-IFS (Kappa: 0.626), D&C-IFS (Kappa: 0.595), and Hys-IFS (Kappa: 0.578) improved the diagnostic efficiencies of individual preoperative examinations. Based on the high sensitivity of IFS, parallel strategies improved the sensitivities of preoperative examinations to 89.66% (MRI), 64.18% (D&C), 62.69% (Hys), respectively, and these differences were statistically significant (p = 0.000). CONCLUSION: IFS presented reasonable agreement rates predicting postoperative PS results, including deep myometrial invasion and high-grade. IFS helps identify high-intermediate risk patients in preoperative biopsy and MRI and guides intraoperative lymphadenectomy decisions in EA.

Comparison of the safety between cervical conization and hysterectomy for patients with cervical adenocarcinoma in situ.

OBJECTIVE: To compare the safety between cervical conization (CC) alone and hysterectomy for patients with adenocarcinoma in situ (AIS) of the cervix. METHODS: Patients diagnosed with AIS after CC during 2007-2021 were identified by computerized databases at Women's Hospital of Zhejiang University School of Medicine. A total of 453 AIS patients were divided into 2 groups according to uterus preservation: hysterectomy group (n=300) and CC(s) alone group (n=153). The prevalence of residual disease and disease recurrence was compared between patients treated by CC(s) alone and hysterectomy. The prevalence of residual disease in specimens from women who had a hysterectomy and repeat CC were compared between positive and negative margins of CC. The factors influencing residual disease and disease recurrence were assessed. RESULTS: Among 310 specimens from women who had a hysterectomy or repeat CC, the prevalence of residual disease was 50.6% (45/89) for a positive margin and 2.3% (5/221) for a negative margin (p=0.000). Four patients had recurrence of vaginal intraepithelial neoplasia in those treated by hysterectomy and one had recurrence of cervical squamous intraepithelial neoplasia in those treated by CC(s) alone. The prevalence of recurrence was 0.7% (1/153) for CC(s) alone and 1.3% (4/300) for hysterectomy (p=0.431). Hysterectomy did not influence residual disease or disease recurrence. CONCLUSION: CC is an efficacious and safe option for patients with AIS of the cervix provided the margin is negative.

Neoadjuvant chemotherapy for patients with international federation of gynecology and obstetrics stages IB3 and IIA2 cervical cancer: a multicenter prospective trial.

BACKGROUND: Preoperative neoadjuvant chemotherapy (NACT) has been widely used in developing countries for the treatment of patients with International Federation of Gynecology and Obstetrics (FIGO) stages IB3 and IIA2 cervical cancer. However, the effectiveness of NACT and treatment options for NACT-insensitive patients have been concerning. This study will assess prognostic differences between NACT and primary surgery treatment (PST), determine factors associated with prognosis, and explore better adjuvant treatment modalities for NACT-insensitive patients. METHODS: This study analyzed clinical characteristics, pathological characteristics, treatment options, and follow-up information of 774 patients with FIGO stages IB3 and IIA2 cervical cancer from 28 centers from January 2016 to October 2019 who participated in a multicenter, prospective, randomized controlled trial. RESULTS: For patients undergoing NACT, the 5-year OS and PFS rate was 85.8 and 80.5% respectively. They were similar in the PST group. There was no significant difference in OS and PFS between clinical response (CR)/partial response (PR) groups and stable disease (SD)/progressive disease (PD) groups. Apart from deep cervical invasion (p = 0.046) affecting OS for patients undergoing NACT, no other clinical and pathological factors were associated with OS. 97.8% of NACT-insensitive patients opted for surgery. If these patients did not have intermediate- or high-risk factors, whether they had undergone postoperative adjuvant therapy was irrelevant to their prognosis, whereas for patients with intermediate- or high-risk factors, adjuvant chemotherapy resulted in better PFS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.019) and OS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.002). CONCLUSIONS: NACT could be a choice for patients with FIGO stages IB3 and IIA2 cervical cancer. The main risk factor influencing prognosis in the NACT group is deep cervical invasion. After systematic treatment, insensitivity to NACT does not indicate a poorer prognosis. For NACT-insensitive patients, Chinese prefer surgery. Postoperative adjuvant therapy in patients with no intermediate- or high-risk factors does not improve prognosis, and chemotherapy in patients with intermediate- and high-risk factors is more effective than radiation therapy and other treatments. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03308591); date of registration: 12/10/2017.

Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (PARPi) in platinum-resistant OC are required. The present study aimed to investigate the combined therapy of arsenic trioxide (ATO) with olaparib, a common PARPi, and determine how this synergistic cytotoxicity works in platinum-resistant OC cells. Functional assays demonstrated that the combined treatment of olaparib with ATO significantly suppressed cell proliferation and colony formation, and enhanced DNA damage as well as cell apoptosis in A2780-CIS and SKOV3-CIS cell lines. Results of the present study also demonstrated that a combination of olaparib with ATO increased lipid peroxidation and eventually triggered ferroptosis. Consistently, the combined treatment synergistically suppressed tumor growth in mice xenograft models. Mechanistically, ATO in combination with olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1 (SCD1). Collectively, results of the present study demonstrated that treatment with ATO enhanced the effects of olaparib in platinum-resistant OC.

Evaluation of the prognostic value of lymphadenectomy for low-grade serous ovarian cancer: A case-control multicenter retrospective study.

BACKGROUND: The prognostic value of lymphadenectomy in low-grade serous ovarian cancer (LGSOC) remains uncertain. MATERIALS AND METHODS: A retrospective analysis of 155 patients with LGSOC who underwent surgery over a ten-year period (2011-2020) was performed. The propensity score matching (PSM) algorithm was performed between the lymphadenectomy and no lymphadenectomy groups, and Kaplan-Meier analyses were conducted to evaluate clinical prognosis. Finally, univariate and multivariate Cox proportional hazards regression analyses were performed to analyze high-risk factors associated with clinical prognosis. RESULTS: In the pre-PSM cohort, 110 (71.0%) patients underwent lymphadenectomy. Of these, 54 (34.8%) experienced recurrence, and 27 (17.4%) died. There were statistical differences in disease-free survival (DFS) (P = 0.018) and overall survival (OS) (P = 0.016) in the post-PSM cohort. In the subgroup analysis, there were no statistically significant differences in DFS (P = 0.449) or OS (P = 0.167) in the FIGO I/II cohort. However, in the FIGO III/IV cohort, DFS (P = 0.011) and OS (P = 0.046) were statistically different between the two groups. Age > 50 years, FIGO stage III/IV, and suboptimal cytoreductive surgery were risk factors associated with prognosis. In the lymphadenectomy group, the histological status of pelvic lymph nodes had no significant effect on DFS (P = 0.205) or OS (P = 0.114). CONCLUSION: Lymphadenectomy was associated with DFS and OS, particularly in patients with advanced LGSOC patients. Age > 50 years, advanced FIGO stage III/IV, and suboptimal cytoreductive surgery were high-risk factors associated with clinical prognosis in patients with LGSOC.

The impact of neoadjuvant chemotherapy on the tumor microenvironment in advanced high-grade serous carcinoma.

High-grade serous ovarian, fallopian tube or peritoneal carcinoma is an aggressive subtype of ovarian cancer that frequently develops resistance to chemotherapy. It remains contested whether the resistance is caused by the acquisition of novel molecular aberrations or alternatively through the selection of rare pre-existing tumor clones. To address this question, we applied single-cell RNA sequencing to depict the tumor landscape of 6 samples from a single case of advanced high-grade serous fallopian tube carcinoma during neoadjuvant chemotherapy (NACT). We analyzed a total of 32,079 single cells, with 17,249 cells derived from the pre-NACT multisite tumor tissue samples and 14,830 cells derived from the post-NACT multisite tumor tissue samples. We identified the diverse properties of the tumor, immune and stromal cell types between the pre-NACT and post-NACT tumors. The malignant epithelial cells displayed a high degree of intratumor heterogeneity in response to NACT. We showed that the primary resistant clone (clone 63) epithelial genotype was already present in the pre-NACT tumors, and was adaptively enriched after NACT. This clone 63 was correlated with a poor clinical prognosis. Furthermore, single-cell analysis of CD4+ T cells demonstrated that IL2RAhi-CCL22+-Tregs were selectively enriched in post-NACT tumors. Interestingly, this Treg subtype could recruit and enrich themselves through secreting the CCL22-CCR1 combination in pre-NACT and post-NACT tumors, and further express CD274 to suppress other CD4 and CD8 T cells through a CD274-PDCD1 axis in the post-NACT tumors, and this predicted an immunosuppressive state after NACT. Overall, our results provide important evidence for the adaptive resistance theory of HGSC, and for the potential development of therapeutic strategies to treat HGSC and improve the survival of patients with HGSC.

Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer.

PURPOSE: The heterogeneity of high-grade serous ovarian cancer (HGSOC) is not well studied, which severely hinders clinical treatment of HGSOC. Thus, it is necessary to characterize the heterogeneity of HGSOC within its tumor microenvironment (TME). EXPERIMENTAL DESIGN: The tumors of 7 treatment-naïve patients with HGSOC at early or late stages and five age-matched nonmalignant ovarian samples were analyzed by deep single-cell RNA sequencing (scRNA-seq). RESULTS: A total of 59,324 single cells obtained from HGSOC and nonmalignant ovarian tissues were sequenced by scRNA-seq. Among those cells, tumor cells were characterized by a set of epithelial-to-mesenchymal transition (EMT)-associated gene signatures, in which a combination of NOTCH1, SNAI2, TGFBR1, and WNT11 was further selected as a genetic panel to predict the poor outcomes of patients with HGSOC. Matrix cancer-associated fibroblasts (mCAF) expressing α-SMA, vimentin, COL3A, COL10A, and MMP11 were the dominant CAFs in HGSOC tumors and could induce EMT properties of ovarian cancer cells in the coculture system. Specific immune cell subsets such as C7-APOBEC3A M1 macrophages, CD8+ TRM, and TEX cells were preferentially enriched in early-stage tumors. In addition, an immune coinhibitory receptor TIGIT was highly expressed on CD8+ TEX cells and TIGIT blockade could significantly reduce ovarian cancer tumor growth in mouse models. CONCLUSIONS: Our transcriptomic results analyzed by scRNA-seq delineate an ecosystemic landscape of HGSOC at early or late stages with a focus on its heterogeneity with TME. The major applications of our findings are a four-EMT gene model for prediction of HGSOC patient outcomes, mCAFs' capability of enhancing ovarian cancer cell invasion and potential therapeutic value of anti-TIGIT treatment.

Prognostic-Related Metabolic Score for Survival Prediction in Early-Stage Endometrioid Endometrial Cancer: A Multi-Center and Retrospective Study.

Objective: Patients with endometrial cancer (EC) combined with metabolic syndrome (MetS) have a worse prognosis than those without MetS. This study aimed to investigate whether partial metabolic disorder significantly influenced early-stage endometrioid EC (EEC) survival and searched for a more efficient method to evaluate metabolic status. Methods: This is a nationwide, multicenter cohort study that included 998 patients with primary early-stage EEC from 2001 to 2018. Patients were divided into different metabolic groups based on the diagnostic criteria of the Chinese Medical Association (CDC). The progression-free survival (PFS) time was compared between various metabolic status. Meanwhile, we established an EC Prognostic-Related Metabolic Score (ECPRM Score) to explore the association of the severity of metabolic status and early-stage EEC PFS. A nomogram was established for predicting PFS, which was externally validated in a testing set that includes 296 patients. Results: A partial metabolic disorder, as well as MetS, was an independent risk factor of poor survival of patients with early-stage EEC [hazard ratio (HR) = 7.6, 95% CI = 1.01-57.5, p < 0.05]. A high ECPRM Score was associated with lower PFS (HR = 2.1, 95% CI = 1.05-4.0, p < 0.001). The nomogram, in which the ECPRM Score contributed most to the prognosis, exhibited excellent discrimination of survival supported by the internal and external validations. In addition, the calibration curve supports its robust predicting ability. Conclusion: Even though they do not meet the criteria of MetS, partial metabolic disorders were also associated with adverse outcomes in early-stage EEC. The ECPRM Score is beneficial for clinicians to evaluate the severity of metabolic abnormalities and guide patients to ameliorate the poor prognosis of metabolic disorders.

Gestational trophoblastic neoplasia with extrauterine metastasis but lacked uterine primary lesions: a single center experience and literature review.

BACKGROUND: To investigate the clinicopathological characteristics, diagnoses, treatments, and outcomes of a special type of gestational trophoblastic neoplasia (GTN) which only has extrauterine metastases without uterine primary lesions. METHODS: The medical records and pathological sections of the patients who were pathologically diagnosed as GTN, only had extrauterine metastatic lesions but lacked uterine primary lesions, in Women's Hospital of Zhejiang University School of Medicine from February 2014 to March 2021 were collected and reviewed. RESULTS: Thirteen patients with pathologically confirmed GTN presenting with extrauterine metastases from a missing primary site were included in the past 7 years. The median age was 31.2 years old. 76.9% of patients had a non-hydatidiform pregnancy last time. The intervals between the antecedent pregnancy were > 12 months in 61.5% of patients. Pretreatment serum human chorionic gonadotropin(hCG) levels ranged from 118.7 to 807,270 IU/L. Six patients were misdiagnosed as ectopic pregnancy at initial diagnosis, and 4 as primary tumors at metastatic sites. All of them were diagnosed definitely by surgical pathology including 8 choriocarcinomas (CC), 4 epithelioid trophoblastic tumors (ETTs), and 1 mixed GTN (CC mixed with ETT). All patients achieved complete remission (CR) after treatments. Three patients relapsed; no patient died by the end of follow-up. CONCLUSION: GTN presenting with extrauterine metastases from a missing primary site is easily misdiagnosed. Detection of serum hCG in these patients can reduce misdiagnosis. Chemotherapy combined with individualized surgery should be considered for these special GTN patients. Immune checkpoint inhibitors might be potential remedial measures for refractory and recurrent patients.

Risk Factors and Prognosis of Early Recurrence in Stage I-II Endometrial Cancer: A Large-Scale, Multi-Center, and Retrospective Study.

Objective: The aim of the present study was to determine overall survival (OS) and risk factors associated with early recurrence in patients with FIGO I-II stage endometrial carcinoma (EC). Methods: Clinical features were retrospectively extracted from the database of China Endometrial Cancer Consortium from January 2000 to December 2019. A total of 2,974 patients with Federation International of Gynecology and Obstetrics (FIGO) I-II stage endometrial cancer were included. Kaplan-Meier survival analysis was used to assess OS and disease-specific survival. Cox proportional hazard model and Fine-Gray model were used to determine the factors related to OS. Binary logistic regression model was used to determine independent predictors of early relapse patients. Results: Of these 2,974 ECs, 189 patients were confirmed to have relapse. The 5-year OS was significantly different between the recurrence and non-recurrence patients (p < 0.001). Three quarters of the relapse patients were reported in 36 months. The 5-year OS for early recurrence patients was shorter than late recurrence [relapse beyond 36 months, p < 0.001]. The grade 3 [odds ratio (OR) = 1.55, 95%CI 1.17-2.05, p = 0.002], lymphatic vascular infiltration (LVSI; OR = 3.36; 95%CI 1.50-7.54, p = 0.003), and myometrial infiltration (OR = 2.07, 95%CI 1.17-3.65, p = 0.012) were independent risk factors of early relapse. The protective factor of that is progesterone receptor (PR)-positive (OR = 0.50, 95%CI 0.27-0.92, p = 0.02). Bilateral ovariectomy could reduce recurrence risk rate (OR = 0.26, 95%CI 0.14-0.51, p < 0.001). Conclusion: The OS of early relapse EC is worse. Grade 3, LVSI, and myometrial infiltration are independent risk factors for early relapse EC. In addition, the protective factor is PR-positive for those people and bilateral salpingo-oophorectomy could reduce the risk of recurrence.

Modified Intraperitoneal Chemotherapy Without Bevacizumab as a First-Line Therapy for Newly Diagnosed Advanced Epithelial Ovarian Cancer-Two Centers Experiences.

Objectives: To evaluate whether the modified intraperitoneal plus intravenous chemotherapy regimen as a first-line therapy for advanced epithelial ovarian cancer (EOC) in China can be well-tolerated or confer any potential benefit on survival. Methods: We evaluated the outcomes of women with newly diagnosed advanced-stage III-IV EOC treated with optimal cytoreductive surgery (<1 cm) and subsequent intraperitoneal plus intravenous chemotherapy or intravenous chemotherapy from January 2005 to December 2017 at two Gynecologic Oncology Centers in China. Kaplan-Meier survival analysis and Cox regression multivariate analysis models were performed to determine the toxicities and survival outcomes. Results: A total of 463 patients with stage III-IV EOC were enrolled. According to the propensity scores (1:2), 85 patients who received intraperitoneal plus intravenous chemotherapy (group A) were matched to 170 patients who received intravenous chemotherapy (group B). The median follow-up time was 41 months (range 6-155 months). However, there was no statistically significant difference in the median progression-free survival (PFS) (20 vs. 22 months, P = 0.351) or 3-year overall survival (OS) rate (80 vs. 78%, P = 0.749) between the two groups. R0 primary cytoreductive surgery was the only factor related to PFS (P = 0.028) and OS (P = 0.005) by Cox regression analysis. The incidence of grade 3/4 adverse events did not significantly differ between the two groups. Conclusion: The efficacy of intraperitoneal chemotherapy mainly comes from the intraperitoneal drug dose intensity and cumulative dose. High-efficiency and low-toxicity intraperitoneal chemotherapy regimens still need to be found and validated.

Implications of Isolated Para-Aortic Lymph Node Metastasis in Endometrial Cancer: A Large-Scale, Multicenter, and Retrospective Study.

Objective: To systematically evaluate lymph node metastasis (LNM) patterns in patients with endometrial cancer (EC) who underwent complete surgical staging, which included systematic pelvic and para-aortic lymphadenectomy. Methods: Four thousand and one patients who underwent complete surgical staging including systematic pelvic and para-aortic lymphadenectomy for EC were enrolled from 30 centers in China from 2001 to 2019. We systematically displayed the clinical and prognostic characteristics of patients with various LNM patterns, especially the PLN-PAN+ [para-aortic lymph node (PAN) metastasis without pelvic lymph node (PLN) metastasis]. The efficacy of PAN+ (para-aortic lymph node metastasis) prediction with clinical and pathological features was evaluated. Results: Overall, 431 of the 4,001 patients (10.8%) showed definite LNM according to pathological diagnosis. The PAN+ showed the highest frequency (6.6%) among all metastatic sites. One hundred fourteen cases (26.5%) were PLN-PAN+ (PAN metastasis without PLN metastasis), 167 cases (38.7%) showed PLN+PAN-(PLN metastasis without PAN metastasis), and 150 cases (34.8%) showed metastasis to both regions (PLN+PAN+). There was also 1.9% (51/2,660) of low-risk patients who had PLN-PAN+. There are no statistical differences in relapse-free survival (RFS) and disease-specific survival (DSS) among PLN+PAN-, PLN-PAN+, and PLN+PAN+. The sensitivity of gross PLNs, gross PANs, and lymphovascular space involvement (LVSI) to predict PAN+ was 53.8 [95% confidence interval (CI): 47.6-59.9], 74.2 95% CI: 65.6-81.4), and 45.8% (95% CI: 38.7-53.2), respectively. Conclusion: Over one-fourth of EC patients with LMN metastases were PLN-PAN+. PLN-PAN+ shares approximate survival outcomes (RFS and DSS) with other LNM patterns. No effective clinical methods were achieved for predicting PAN+. Thus, PLN-PAN+ is a non-negligible LNM pattern that cannot be underestimated in EC, even in low-risk patients.

Arsenic compound sensitizes homologous recombination proficient ovarian cancer to PARP inhibitors.

The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors show survival benefits in ovarian cancer patients with BRCA1/2 mutation or homologous recombination (HR) deficiency, but only limited efficacy in HR-proficient ones. Another drug, arsenic trioxide (ATO) or arsenic drug (RIF), exerts antitumor effects via inducing DNA damage. Here, we investigated the combined therapeutic effects of the PARP inhibitors and the arsenic compound in HR-proficient ovarian cancer. The combined treatment of niraparib, olaparib, or fluazolepali with ATO showed a significant suppression in tumor cell viability and colony formation. The drug treatment also induced synergistic inhibition of cell proliferation and DNA damage, and acceleration of cell apoptosis in two HR-proficient ovarian cancer cell lines SKOV3 and CAOV3, either by simultaneous or sequential administration. The mechanism underlying these synergistic effects were reflected by the significantly increased ratio of cleaved-PARP/total PARP and decreased ratio of p-AKT/total AKT. Consistently, the combination of olaparib with RIF synergistically reduced the tumor growth in mouse xenograft models. In conclusion, the arsenic compound greatly sensitizes HR-proficient ovarian cancer cells to the PARP inhibitors, and our findings provide an evidence for the clinical treatment development of this combination in HR-proficient ovarian cancer patients.

Neoadjuvant chemotherapy followed by radical surgery versus concurrent chemoradiotherapy in patients with FIGO stage IIB cervical cancer: the CSEM 006 study.

BACKGROUND: Concurrent chemoradiotherapy is the first-line treatment for FIGO stage IIB cervical cancer. Neoadjuvant chemotherapy followed by radical surgery may provide another treatment option. PRIMARY OBJECTIVE: To compare the therapeutic outcomes of neoadjuvant chemotherapy followed by surgery with cisplatin-based concurrent chemoradiotherapy for stage IIB cervical cancer. STUDY HYPOTHESIS: We hypothesize that the therapeutic effect of neoadjuvant chemotherapy combined with surgery and risk-adapted adjuvant treatment will be superior to that of concurrent chemoradiotherapy in stage IIB cervical cancer. TRIAL DESIGN: Patients with stage IIB cervical cancer will be randomized 1:1 to neoadjuvant chemotherapy followed by surgery (Arm A) or concurrent chemoradiotherapy (Arm B). In arm A, patients will receive three cycles of paclitaxel and cisplatin followed by a type C radical hysterectomy and pelvic ±paraaortic lymphadenectomy. Patients showing progression after neoadjuvant chemotherapy will be referred to concurrent chemoradiotherapy. Adjuvant therapy will be recommended according to the presence of pathological risks. In Arm B, all patients will receive definitive concurrent chemoradiotherapy, including external beam pelvic radiotherapy combined with concurrent weekly cisplatin followed by brachytherapy. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients between 18 and 60 years with histologically confirmed, untreated stage IIB cervical squamous carcinoma, adenocarcinoma, or adeno-squamous carcinoma. PRIMARY ENDPOINT: The primary endpoint is 2-year disease-free survival. SAMPLE SIZE: An estimated sample size of 240 is required to fulfill the study objectives. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: As of February 2020, 115 eligible patients from four institutions have been enrolled. Enrollment is expected to be completed by December 2022. TRIAL REGISTRATION NUMBER: ClinicalTrials. gov identifier: NCT02595554.