Changing trends in the disease burden of uterine cancer globally from 1990 to 2019 and its predicted level in 25 years.

Background: We aim to evaluate the global, regional, and national burden of Uterine Cancer (UC) from 1990 to 2019. Methods: We gathered UC data across 204 countries and regions for the period 1990-2019, utilizing the Global Burden of Disease Database (GBD) 2019 public dataset. Joinpoint regression analysis was employed to pinpoint the year of the most significant changes in global trends. To project the UC trajectory from 2020 to 2044, we applied the Nordpred analysis, extrapolating based on the average trend observed in the data. Furthermore, the Bayesian Age-Period-Cohort (BAPC) model with integrated nested Laplace approximations was implemented to confirm the stability of the Nordpred analysis predictions. Results: Globally, the age-standardized rate (ASR) of incidence for UC has increased from 1990 to 2019 with an Average Annual Percentage Change (AAPC) of 0.50%. The ASR for death has declined within the same period (AAPC: -0.8%). An increase in the ASR of incidence was observed across all Socio-demographic Index (SDI) regions, particularly in High SDI regions (AAPC: 1.12%), while the ASR for death decreased in all but the Low SDI regions. Over the past 30 years, the highest incidence rate was observed in individuals aged 55-59 (AAPC: 0.76%). Among 204 countries and regions, there was an increase in the ASR of incidence in 165 countries and an increase in the ASR of deaths in 77 countries. Our projections suggest that both the incidence and death rates for UC are likely to continue their decline from 2020 to 2044. Conclusions: UC has significantly impacted global health negatively, with its influence stemming from a range of factors including geographical location, age-related and racial disparities, and SDI.

The efficacy of pre-operative conization in patients undergoing surgical treatment for early-stage cervical cancer: A meta-analysis.

BACKGROUND: Minimal invasive surgery (MIS) has been reported to increase the risk of cancer relapse and death compared with traditional open surgery in patients with early-stage cervical cancer (CC). Pre-operative conization is a protective procedure that as developed to reduce the risk caused by MIS. METHODS: Relevant publications were identified by searching medical databases prior to the December 31, 2022. The primary aim of this meta-analysis was to evaluate the efficacy of pre-operative conization on disease-free survival (DFS) in early-stage CC. The secondary objective was to assess the efficacy of pre-operative conization on overall survival (OS) in early-stage CC. RESULTS: Twelve studies were eligible for analysis. The pooled result of pre-operative conization showed a significantly improved DFS when compared with non-conization patients (HR, 0.28; 95% CI, 0.19-0.41), furthermore, pre-operative conization improved DFS by 75% (HR, 0.25; 95% CI, 0.13-0.46) in stage IB1 patients. In patients who underwent MIS, pre-operative conization also led to a significant improvement in DFS when compared with non-conization patients (HR, 0.21; 95% CI, 0.09-0.54). However, in patients who underwent pre-operative conization, MIS increased the risk of recurrence by 34% when compared with open abdominal radical hysterectomy (HR, 1.34; 95% CI, 0.41-4.38), although this difference was not statistically significant. Finally, the OS of early-stage CC was not significantly affected by surgical approach or conization. CONCLUSION: Pre-operation conization represents a protective effect and can improve DFS when compared with non-conization in early-stage CC, especially in stage IB CC. There was no statistical evidence to indicate that pre-operation conization could improve OS. High-quality randomized controlled trials are required to verify these results.

Effectiveness and safety of novel motorized spiral enteroscopy: a systematic review and meta-analysis.

BACKGROUND: Motorized spiral enteroscopy (MSE) is a novel advance in small bowel examination that is characterized as fast with a deep insertion. The aim of this study was to elucidate the effectiveness and safety of MSE. METHODS: Relevant articles that were published before November 1, 2022 were identified by searching PubMed, EMBASE, Cochrane, and the Web of Science. The technical success rate (TSR), total (pan)-enteroscopy rate (TER), depth of maximum insertion (DMI), diagnostic yield, and adverse events were extracted and analyzed. Forest plots were graphed based on random effects models. RESULTS: A total of 876 patients from 8 studies were eligible for analysis. The pooled results of the TSR were 95.0% [95% confidence interval (CI) 91.0-98.0%, I2 = 78%, p < 0.01] and the pooled outcome of the TER was 43.1% (95% CI 24.7-62.5%, I2 = 95%, p < 0.01). The pooled results of the diagnostic and therapeutic yields were 77.2% (95% CI 69.0-84.5%, I2 = 84%, p < 0.01) and 49.0% (95% CI 38.0-60.1%, I2 = 89%, p < 0.01), respectively. The pooled estimates of adverse and severe adverse events were 17.2% (95% CI 11.9-23.2%, I2 = 75%, p < 0.01) and 0.7% (95% CI 0.0-2.1%, I2 = 37%, p = 0.13), respectively. CONCLUSION: MSE is a novel alternative approach for small bowel examination that can achieve high TER and diagnostic and therapeutic yields, and relatively low rates of severe adverse events. Head-to-head studies comparing MSE and other device-assisted enteroscopies are warranted.

Age at menarche and polycystic ovary syndrome: A Mendelian randomization study.

OBJECTIVE: The authors aimed to use a large two-sample Mendelian randomization (MR) study to reveal the causality between age at menarche (AAM) and polycystic ovary syndrome (PCOS) incidence. METHODS: The authors collected summary statistics from the hitherto largest genome-wide association studies conducted in AAM and PCOS in the same ancestry. MR with inverse variance weighting was conducted as the main analysis method, while weighted median and MR-Egger regression were used for comprehensive analysis. As for pleiotropy detection, inverse variance weighting, MR-Egger regression, Mendelian Randomization Pleiotropy Residual Sum and Outlier, as well as leave-one-out analysis were used to detect pleiotropy. Risk factor analysis was conducted to investigate the underlying mechanisms linking AAM to PCOS. RESULTS: Each standard deviation increment in AAM was associated with a significantly lower incidence of PCOS (odds ratio, 0.86 [95% confidence interval, 0.75-0.98]). After adjustment in horizontal pleiotropy by eliminating four outliers, this pathogenic association was still statistically detected. All pleiotropy indexes were without statistical differences, which suggested the conclusions were robust. It showed the causal association between later AAM and lower body mass index, lower fasting insulin level and insulin resistance. CONCLUSION: Our MR analysis verified that a slightly later onset age (15 to 18 years) at menarche could reduce the risk of PCOS. A more comprehensive investigation in a prospective setting is strongly advised.

Effectiveness and safety of PD-1/PD-L1 inhibitors in advanced or recurrent endometrial cancer: a systematic review and meta-analysis.

Background: Studies in recent years have shown that PD-1/PD-L1 inhibitors may have better effectiveness in patients with advanced or recurrent endometrial cancer. The effectiveness of PD-1/PD-L1 inhibitors is thought to be related to mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) classification in advanced or recurrent endometrial cancer. This study aims to evaluate the effectiveness of PD-1/PD-L1 inhibitors in patients classified as dMMR and pMMR. Methods: Medical databases were searched to identify relevant publications up to 30 November 2022. The primary outcome was comparison of objective response rate (ORR) in patients with dMMR and pMMR following treatment with PD-1/PD-L1 inhibitors; secondary outcomes were single-group ORR in patients with dMMR and in patients with pMMR, respectively. Results: Eleven studies were eligible for analysis and patients with advanced or recurrent endometrial cancer with molecular classification of dMMR had a higher total ORR than those with pMMR [odds ratio (OR), 7.70; 95% confidence interval (CI), 3.22-18.38; p < 0.01], with low evidence of between-study heterogeneity (I2 = 0%). The total ORR of patients with advanced or recurrent endometrial cancer with molecular type dMMR was 51.9% (95% CI, 33.6%-69.9%). The overall ORR of patients with advanced or recurrent endometrial cancer with molecular type pMMR was 16.1% (95% CI, 5.5%-30.3%). Conclusion: In our including studies, the patients with advanced or recurrent endometrial cancer with molecular types of dMMR and pMMR, following treatment with PD-1/PD-L1 inhibitors, the total ORR of patients with dMMR was higher than that of patients with pMMR. Since the current number of studies is not very large, it is possible that more studies will be published in the future and more precise results will be discussed further.

Efficacy and Safety of Triple Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Patients With Cystic Fibrosis: A Meta-Analysis of Randomized Controlled Trials.

Background: Cystic fibrosis is a rare, recessive, progressive genetic disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Small molecules have recently been developed to treat the molecular consequences of CFTR mutations and restore CFTR protein function. However, the data on triple combination therapy (mainly from Vertex Pharmaceuticals, which is most tested in clinical trials) are limited. This meta-analysis was aimed to assess the efficacy and safety of this therapy according to different mutation genotypes and comparators. Methods: Relevant publications were identified through searching several medical databases before 31 December 2021. The primary outcomes of ppFEV1, sweat chloride concentration and Cystic Fibrosis Questionnaire-Revised (CFQ-R) score were pooled and analyzed. The secondary outcomes were adverse events in triple combination therapy. Results: Six randomized controlled trials were eligible for analysis. The total outcome of the ppFEV1 change was higher with triple combination therapy than triple placebo or active control (mean difference, MD, 13.6% and 8.74%, respectively). The pooled result of sweat chloride concentrations with triple combination therapy was lower than that of triple placebo or active control (MD, -44.13 and -39.26, respectively). The pooled estimate of the CFQ-R score was higher with triple combination therapy than triple placebo or active control (MD, 19.8% and 14.63%, respectively). No clear differences in adverse events were found between triple combination therapy and the control (placebo or active control). Conclusion: CFTR modulators in triple combination achieve better clinical results than placebo and active control, and result in comparable adverse events. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021293402, identifier PROSPERO 2021 CRD42021293402.

Efficacy and Safety of Radiofrequency Ablation vs. Endoscopic Surveillance for Barrett's Esophagus With Low-Grade Dysplasia: Meta-Analysis of Randomized Controlled Trials.

Background and Aims: Barrett's esophagus with low-grade dysplasia (BE-LGD) carries a risk of progression to Barrett's esophagus with high-grade dysplasia (BE-HGD) and esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) appears to be a safe and efficacious method to eradicate Barrett's esophagus. However, a confirmed consensus regarding treatment of BE-LGD with RFA vs. endoscopic surveillance is lacking. Therefore, this study aimed to elucidate the efficacy and safety for RFA vs. endoscopic surveillance in decreasing the risk of BE-LGD progression to BE-HGD or EAC. Methods: Relevant studies published before May 1, 2021 were identified by searching relevant medical databases. The primary outcome was the rate of progression BE-LGD to HGD and/or EAC after treatment with RFA and endoscopic surveillance. The secondary outcome was the rate of complete eradication of dysplasia (CE-D) and complete eradication of intestinal metaplasia (CE-IM) after treatment with RFA and endoscopic surveillance. Adverse events were also extracted and evaluated. Results: Three randomized controlled trials were eligible for analysis. The pooled estimate of rate of neoplastic progression of BE-LGD to HGD or EAC was much lower in the RFA group than the endoscopic surveillance group (RR, 0.25; 95% CI, 0.07-0.93; P = 0.04), with moderate heterogeneity (I2 = 55%). Subgroup analysis based on progression grade was performed. The pooled rate of progression of BE-LGD to HGD was much lower in the RFA group than the endoscopic surveillance group (RR, 0.25; 95% CI, 0.07-0.71; P = 0.01), with low heterogeneity (I2 = 15%). Although the pooled risk of progression of BE-LGD to EAC was slightly lower in the RFA group than the endoscopic surveillance group (RR, 0.56; 95% CI, 0.05-6.76), the result was not statistically significant (P = 0.65). RFA also was associated a higher rate of CE-D and CE-IM both at the end of endoscopic treatment and during follow-up. However, the rate of adverse events was slightly higher after RFA treatment. Conclusion: RFA decreases the risk of BE-LGD progression to BE-HGD. However, given the uncertain course of LGD and the potential for esophageal stricture after RFA, treatment options should be fully considered and weighed. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021266128, identifier PROSPERO (CRD42021266128).

Nomograms to predict the prognosis in malignant ovarian germ cell tumors: a large cohort study.

BACKGROUND: Malignant ovarian germ cell tumors (MOGCTs) are rare gynecologic neoplasms. The use of nomograms that are based on various clinical indicators to predict the prognosis of MOGCTs are currently lacking. METHODS: Clinical and demographic information of patients with MOGCT recorded between 2004 and 2015 were obtained from the Surveillance, Epidemiology, and End Results database, and Cox regression analysis was performed to screen for important independent prognostic factors. Prognostic factors were used to construct predictive calculational charts for 1-year, 3-year, and 5-year overall survival (OS). The externally validated case cohort included a total of 121 MOGCT patients whose data were recorded from 2008 to 2019 from the database of the Shengjing Hospital of China Medical University. RESULTS: A total of 1401 patients with MOGCT were recruited for the study. A nomogram was used to forecast the 1-year, 3-year, and 5-year OS using data pertaining to age, International Federation of Gynecology and Obstetrics (FIGO) staging, histological subtype and grade, and surgical type. Nomograms have a more accurate predictive ability and clinical utility than FIGO staging alone. Internal and external validation also demonstrated satisfactory consistency between projected and actual OS. CONCLUSIONS: A nomogram constructed using multiple clinical indicators provided a more accurate prognosis than FIGO staging alone. This nomogram may assist clinicians in identifying patients who are at increased risk, thus implementing individualized treatment regimens.

Risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 or BRCA2 mutation carriers: A systematic review and meta-analysis.

AIM: BRCA mutation carriers have a high lifetime risk of developing breast cancer (BC) and ovarian cancer (OC). Risk-reducing salpingo-oophorectomy (RRSO) has been shown to reduce OC risk. This meta-analysis was aim to analyze the effect of RRSO on the BC risk among BRCA1/2 mutation carriers. METHODS: Embase, PubMed, Web of Science, and Cochrane databases were searched for all studies investigating the effect of RRSO on BC risk. The pooled results were used to evaluate the association between RRSO and BC risk. RESULTS: This meta-analysis included 13,965 BRCA1 and 7,057 BRCA2 mutation carriers from 14 observational studies. The pooled results showed that RRSO lowered BC risk among BRCA1 mutation carriers [hazard ratio (HR) = 0.63, 95% confidence interval (CI): 0.49-0.81, P < 0.01] and BRCA2 mutation carriers (HR = 0.51, 95% CI: 0.34-0.75, P < 0.01). RRSO reduced BC risk in younger women with BRCA1 mutation (HR = 0.48, 95% CI: 0.30-0.77, P < 0.01) and BRCA2 mutation (HR = 0.22, 95% CI: 0.08-0.65, P < 0.01). Analysis of the efficacy of RRSO at different time intervals after surgery showed a reduction of BC risk at <5 years after surgery in BRCA1 mutation carriers (HR = 0.60, 95% CI: 0.40-0.89, P = 0.01) and BRCA2 mutation carriers (HR = 0.42, 95% CI: 0.20-0.86, P = 0.02). CONCLUSIONS: RRSO is an effective way to reduce BC risk among women with BRCA1/2 mutation, especially in younger women. BRCA1/2 mutation carriers could benefit from RRSO in the immediate 5 years after surgery.

Feasibility and clinical effectiveness of transjugular intrahepatic portosystemic shunt creation in pediatric and adolescent patients: a meta-analysis.

OBJECTIVE: Transjugular intrahepatic portosystemic shunt (TIPS) is a useful approach in managing complications caused by severe portal hypertension (PH) in adults. In children, TIPS is technically challenging, and previous studies of TIPS in children have yielded inconsistent results. This study aimed to elucidate the feasibility and clinical effectiveness of TIPS in pediatric and adolescent patients. METHODS: This meta-analysis study identified relevant publications through medical databases. The primary outcomes included technical success, hemodynamic success, and clinical success. The secondary outcomes were primary patency rate, shunt revision rate, and secondary patency rate. RESULTS: A total of 286 patients representing 13 studies were eligible for analysis. The pooled rates of technical success, hemodynamic success, and clinical success were 95% (95% CI 88-99), 89% (95% CI 81-95), and 93% (95% CI 86-98), respectively. The portosystemic gradient decreased from 21.5 mmHg before TIPS to 8.3 mmHg after TIPS. The pooled estimates of primary patency rate, shunt revision rate, and secondary patency rate were 84% (95% CI 72-94), 35% (95% CI 21-51), and 100% (95% CI 92-100), respectively. CONCLUSION: Study results suggest that TIPS may be feasible and effective in children with PH of various etiologies as for long-term management.

Anti-Angiogenesis Maintenance Therapy in Newly Diagnosed and Relapsed Ovarian Cancer: A Meta-analysis of Phase III Randomized Controlled Trials.

Aim: Anti-angiogenesis agents have been added as maintenance therapy in ovarian cancer over the past decade. The aim of this meta-analysis was to analyze the efficacy of anti-angiogenesis therapy in newly diagnosed and relapsed ovarian cancer. Methods: PubMed, Embase, and Cochrane databases were searched for all phase III randomized controlled trials (RCTs) that assessed the efficacy and toxicity of anti-angiogenesis agents in ovarian cancer. Overall survival (OS) and progression-free survival (PFS) were used to evaluate the effectiveness of anti-angiogenesis therapy in ovarian cancer. Results: A total of 6097 patients with newly diagnosed ovarian cancer from 5 phase III RCTs and 2943 patients with relapsed ovarian cancer from 6 phase III RCTs were included in this meta-analysis. The pooled results showed that anti-angiogenesis maintenance therapy significantly improved PFS (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.76-0.93; p = 0.001), but not OS (HR, 0.98; 95% CI, 0.91-1.05; p = 0.49) compared with placebo in patients with newly diagnosed ovarian cancer. In patients with relapsed ovarian cancer, the pooled results showed a significant improvement on OS (HR, 0.89; 95% CI, 0.82-0.98; p = 0.02) and PFS (HR, 0.61; 95% CI, 0.52-0.72; p < 0.001). The pooled results also showed that the anti-angiogenesis agents were associated with an increase in the occurrence of severe hypertension, neutropenia, diarrhea, thrombocytopenia, headache, and bleeding in ovarian cancer. However, infrequent fatal adverse events occurred in the anti-angiogenesis groups. Conclusions: Study results suggest that anti-angiogenesis agents were an effective therapy for newly diagnosed and relapsed ovarian cancer, especially for relapsed ovarian cancer. Anti-angiogenesis agents may be associated with some severe but not fatal adverse events. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021283647.

Does Endometriosis Disturb Mental Health and Quality of Life? A Systematic Review and Meta-Analysis.

INTRODUCTION: This study aimed to evaluate whether endometriosis could disturb the mental health and health-related quality of life (HRQoL) of patients and to provide a new prospective for further treatment of endometriosis. METHODS: A comprehensive literature review was conducted among 4 international databases (PubMed, Embase, Web of Science, and Cochrane Library) and 2 of the largest Chinese databases (the China National Knowledge Infrastructure and Wangfang). The Newcastle-Ottawa Scale was used to assess the quality of the included articles. Six effect sizes were synthesized through a meta-analysis, and a subgroup analysis was performed to identify potential moderating factors, including types of control groups, methods of assessment, number of study groups, and origin of the study. Potential publication bias was examined using a funnel plot. RESULTS: This meta-analysis pooled 44 articles from 4 continents and 13 countries and compared 6 types of main effect sizes (the odds ratio [OR] for depression, the OR for anxiety, the standardized mean difference [SMD] for depression, the SMD for anxiety, the SMD for the physical component summary [PCS] and the SMD for the mental component summary [MCS]) between endometriosis patients and controls. Except for the SMD for depression, all other effect sizes revealed statistically significant differences between the study group and the controls. The main effect size outcomes of the subgroup analysis were also similar. The type of control group (I2 = 35% in non-endometriosis control groups for the SMD of anxiety; I2 = 47% in non-endometriosis control groups for the MCS of the 36-Item Short Form Health Survey) and the continent of origin (I2 = 0% in studies from South America for the OR of depression; I2 = 47% in studies from Europe for the SMD of anxiety) may influence heterogeneity in this analysis. Additionally, depression and anxiety symptoms in patients seemed to be more apparent compared with healthy controls when the sample was smaller and when a questionnaire was used. The publication bias of the articles was acceptable. CONCLUSION: Endometriosis can disturb mental health (specifically depression and anxiety) and decrease both the mental and physical HRQoL of patients. There may be some moderating factors that we were unable to identify in the subgroup analysis, but more research is necessary to develop proper management and improve the prognosis of endometriosis patients.

Malignant transformation of abdominal wall endometriosis: A systematic review of the epidemiology, diagnosis, treatment, and outcomes.

Malignant transformation of abdominal wall endometriosis (AWE) is rare. The clinical characteristics and treatment of malignant transformation of AWE are not well known. Therefore, in this review, we performed a thorough search for malignant transformation of AWE on MEDLINE and Web of Science from their inception to May 2021. In total, the data of 46 patients with malignant transformation of AWE were retrieved, and all the data on these patients were collected. After reviewing and analyzing the clinical parameters, we found that cesarean scar was the most common site of malignant transformation of AWE, and the most common pathological type of malignant transformation of AWE was clear cell cancer, followed by endometrioid adenocarcinoma. The main symptoms of malignant transformation of AWE included an abdominal nodule or mass, and ultrasonography was the first choice for diagnosis. The most widely accepted treatment was surgical resection of local lesions with adjunctive chemotherapy and/or radiotherapy, and the overall survival of patients with malignant transformation of AWE was poor. In conclusion, malignant transformation of AWE is rare, and the prognosis is poor. Thus, improving abdominal surgical technology and avoiding iatrogenic ectopia and implantation of the endometrium are necessary to prevent malignant transformation of AWE.

Downregulation of SPOCK2 promotes the proliferation, adhesion, and invasion of endometrial epithelial cells.

PURPOSE: A previous study found that a lack of SPOCK2 expression was an early event that occurs during the malignant transformation of endometriosis (EMS); however, the role played by SPOCK2 in the pathogenesis of endometriosis and its malignant transformation remains unclear. MATERIALS AND METHODS: In this study, SPOCK2 expression in human endometrial epithelial cells (hEECs) was downregulated by transfection with shRNA, and the biological behavior of the transfected cells was observed. RESULTS: We found that downregulation of SPOCK2 promoted cell proliferation, adhesion, and invasion. CONCLUSIONS: Our data suggest that downregulation of SPOCK2 might participate in the pathogenesis and progression of EMS, as well as its malignant transformation, by promoting the proliferation, adhesion, and invasion of endometrial epithelial cells.

A Novel Predictive Tool for Determining the Risk of Early Death From Stage IV Endometrial Carcinoma: A Large Cohort Study.

BACKGROUND: Endometrial carcinoma is a common gynecological malignancy. Stage IV endometrial carcinoma is associated with a high risk of early death; however, there is currently no effective prognostic tool to predict early death in stage IV endometrial cancer. METHODS: Surveillance, Epidemiology, and End Results (SEER) data from patients with stage IV endometrial cancer registered between 2004 and 2015 were used in this study. Important independent prognostic factors were identified by univariate and multivariate logistic regression analyses. A nomogram of all-cause and cancer-specific early deaths was constructed using relevant risk factors such as tumor size, histological grade, histological classification, and treatment (surgery, radiotherapy, chemotherapy). RESULTS: A total of 2,040 patients with stage IV endometrial carcinoma were included in this study. Of these, 299 patients experienced early death (≤3 months) and 282 died from cancer-specific causes. The nomogram of all-cause and cancer-specific early deaths showed good predictive power and clinical practicality with respect to the area under the receiver operating characteristic curve and decision curve analysis. The internal validation of the nomogram revealed a good agreement between predicted early death and actual early death. CONCLUSIONS: We developed a clinically useful nomogram to predict early mortality from stage IV endometrial carcinoma using data from a large cohort. This tool can help clinicians screen high-risk patients and implement individualized treatment regimens.

A Novel Tool to Predict Early Death in Uterine Sarcoma Patients: A Surveillance, Epidemiology, and End Results-Based Study.

BACKGROUND: Uterine sarcoma is a rare gynecologic tumor with a high degree of malignancy. There is a lack of effective prognostic tools to predict early death of uterine sarcoma. METHODS: Data on patients with uterine sarcoma registered between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) data. Important independent prognostic factors were identified by univariate and multivariate logistic regression analyses to construct a nomogram for total early deaths and cancer-specific early deaths. RESULTS: A total of 5,274 patients with uterine sarcoma were included in this study. Of which, 397 patients experienced early death (≤3 months), and 356 of whom died from cancer-specific causes. A nomogram for total early deaths and cancer-specific early deaths was created using data on age, race, tumor size, the International Federation of Gynecology and Obstetrics (FIGO) staging, histological classification, histological staging, treatment (surgery, radiotherapy, chemotherapy), and brain metastases. On comparing the C-index, area under the curve, and decision curve analysis, the created nomogram showed better predictive power and clinical practicality than one made exclusively with FIGO staging. Calibration of the nomogram by internal validation showed good consistency between the predicted and actual early death. CONCLUSIONS: Nomograms that include clinical characteristics can provide a better prediction of the risk of early death for uterine sarcoma patients than nomograms only comprising the FIGO stage system. In doing so, this tool can help in identifying patients at high risk for early death because of uterine sarcoma.

Core clock gene Bmal1 deprivation impairs steroidogenesis in mice luteinized follicle cells.

Luteinization is the event of corpus luteum formation, a way of follicle cells transformation and a process of steroidogenesis alteration. As the core clock gene, Bmal1 was involved in the regulation of ovulation process and luteal function afterwards. Till now, the underlying roles of luteinization played by Bmal1 remain unknown. To explore the unique role of Bmal1 in luteal steroidogenesis and its underlying pathway, we investigated the luteal hormone synthesis profile in Bmal1 knockout female mice. We found that luteal hormone synthesis was notably impaired, and phosphorylation of PI3K/NfκB pathway was significantly activated. Then, the results were verified in in vitro cultured cells, including isolated Bmal1 interference granulosa cells (GCs) and theca cells (TCs), respectively. Hormones levels of supernatant culture media and mRNA expressions of steroidogenesis-associated genes (star, Hsd3ß2, cyp19a1 in GCs, Lhcgr, star, Hsd3ß2, cyp17a1 in TCs) were mutually decreased, while the phosphorylation of PI3K/NfκB was promoted during in vitro luteinization. After PI3K specific-inhibitor LY294002 intervention, mRNA expressions of Lhcgr and Hsd3ß2 were partially rescued in Bmal1 interference TCs, together with significantly increased androstenedione and T synthesis. Further exploration in TCs demonstrated BMAL1 interacted directly but negatively with NfκB p65 (RelA), a subunit which was supposed as a mediator in Bmal1-governed PI3K signaling regulation. Taken together, we verified the novel role of Bmal1 in luteal steroidogenesis, achieving by negative interplay with RelA-mediated PI3K/NfκB pathway.

Multiomics profile and prognostic gene signature of m6A regulators in uterine corpus endometrial carcinoma.

Uterine corpus endometrial carcinoma (UCEC) is the most common type of gynecologic malignancy worldwide. Despite advances in the treatments of UCEC, its incidence and mortality rates are still increasing. N6-methyladenosine (m6A) is the most common form of RNA modification and has attracted increasing interest in cancer pathogenesis and progression. Thus, we aimed to identify the landscape of m6A regulators and build a prognostic gene signature in UCEC. In this study, we first analyzed copy number variations (CNVs), single nucleotide variations (SNVs) and gene expression profiles as well as matched clinical information of UCEC patients from The Cancer Genome Atlas (TCGA) database. Next, we determined that CNVs in m6A regulatory genes had a significant negative impact on patient survival. The mRNA expression levels of a total of 16 m6A regulators were significantly correlated with different CNV patterns. Using univariate Cox regression analysis, IGF2BP1, KIAA1429, IGF2BP3, YTHDF3, and IGF2BP2 were found to be closely associated with UCEC patient survival outcomes. Based on the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression models, we built a 3-gene (IGF2BP3, KIAA1429 and IGF2BP1) signature of m6A regulators with prognostic value in UCEC that could effectively predict patient prognosis (log-rank test p-value < 0.0001). In addition, risk scores were significantly different between patients stratified by tumor stage, SNV, and CNV. Multivariate Cox regression analysis suggested that risk score might be an independent prognostic indicator for the overall survival of patients with UCEC (p-value < 0.05). Gene enrichment analysis indicated that high IGF2BP1 gene expression is associated with cytoplasmic stress granules. KIAA1429 gene expression is associated with cellular nucleic acid metabolism. The expression of the IGF2BP3 gene is associated with RNA binding processes. In conclusion, we determined that genetic alterations in m6A regulatory genes could be effective and reliable biomarkers for UCEC prognosis prediction.