- 作者列表："Zhou H","Zhang C","Li H","Chen L","Cheng X
Background:Endometrial cancer was the commonest gynecological malignancy in developed countries. Despite striking advances in multimodality management, however, for patients in advanced stage, targeted therapy still remained a challenge. Our study aimed to investigate new biomarkers for endometrial cancer and establish a novel risk score system of immune genes in endometrial cancer. Methods:The clinicopathological characteristics and gene expression data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) of immune genes between tumors and normal tissues were identified. Protein-protein interaction (PPI) network of immune genes and transcriptional factors was integrated and visualized in Cytoscape. Univariate and multivariate analysis were employed for key genes to establish a new risk score system. Receiver operating characteristic (ROC) curve and survival analysis were performed to investigate the prognostic value of the model. Association between clinical characteristics and the model was analyzed by logistic regression. For validation, we identified 34 patients with endometrial cancer from Fudan University Shanghai Cancer Center (FUSCC). We detected 14-genes mRNA expression and calculated the risk scores of each patients and we performed survival analysis between the high-risk group and the low-risk group. Results:23 normal tissues and 552 tumor tissues were obtained from TCGA database. 410 immune-related DEGs was identified by difference analysis and correlation analysis. KEGG and GO analysis revealed these DEGs were enriched in cell adhesion, chemotaxis, MAPK pathways and PI3K-Akt signaling pathway, which might regulate tumor progression and migration. All genes were screened for risk model construction and 14 hub immune-related genes (HTR3E, CBLC, TNF, PSMC4, TRAV30, PDIA3, FGF8, PDGFRA, ESRRA, SBDS, CRHR1, LTA, NR2F1, TNFRSF18) were prognostic in endometrial cancer. The area under the curve (AUC) was 0.787 and the high-risk group estimated by the model possessed worse outcome (P < 0.001). Multivariate analysis suggested that the model was indeed an independent prognostic factor (high-risk vs. low-risk, HR = 1.14, P < 0.001). Meanwhile, the high-risk group was prone to have higher grade (P = 0.002) and advanced clinical stage (P = 0.018). In FUSCC validation set, the high-risk group had worse survival than the low-risk group (P < 0.001). Conclusions:In conclusion, the novel risk model of immune genes had some merits in predicting the prognosis of endometrial cancer and had strong correlation with clinical outcomes. Furthermore, it might provide new biomarkers for targeted therapy in endometrial cancer.
背景: 在发达国家，子宫内膜癌是最常见的妇科恶性肿瘤。尽管多模态管理取得了显著进展，但对于晚期患者，靶向治疗仍然是一个挑战。我们的研究旨在研究子宫内膜癌的新生物标志物，并建立子宫内膜癌免疫基因的新风险评分系统。 方法: 从癌症基因组图谱 (TCGA) 数据库中下载临床病理特征和基因表达数据。确定了肿瘤和正常组织之间免疫基因的差异表达基因 (DEGs)。免疫基因和转录因子的蛋白质-蛋白质相互作用 (PPI) 网络在 Cytoscape 中被整合和可视化。对关键基因进行单变量和多变量分析，建立新的风险评分系统。通过受试者工作特征 (ROC) 曲线和生存分析探讨该模型的预后价值。通过 logistic 回归分析临床特征与模型的相关性。为了验证，我们从复旦大学上海癌症中心 (FUSCC) 确定了 34 例子宫内膜癌患者。我们检测了 14 个基因 mRNA 的表达，计算了每个患者的风险评分，并对高危组和低危组进行了生存分析。 结果: 从 TCGA 数据库中获得 23 例正常组织和 552 例肿瘤组织。通过差异分析和相关分析鉴定了 410 例免疫相关 DEGs。KEGG 和 GO 分析显示这些 DEGs 富含细胞粘附、趋化、 MAPK 通路和 PI3K-Akt 信号通路，可能调控肿瘤的进展和迁移。所有基因筛选进行风险模型构建和 14 个中心免疫相关基因 (HTR3E，CBLC，TNF，PSMC4，TRAV30，PDIA3，FGF8，PDGFRA，ESRRA，SBDS，CRHR1，LTA,nrff1 、 TNFRSF18) 是子宫内膜癌的预后因素。曲线下面积 (AUC) 为 0.787，模型估计的高危组预后较差 (p <0.001)。多因素分析表明，该模型确实是一个独立的预后因素 (高风险 vs.低风险，hr = 1.14，p <0.001)。同时，高危组易出现较高的分级 (p = 0.002) 和较高的临床分期 (p = 0.018)。在 FUSCC 验证集中，高风险组的生存率低于低风险组 (p <0.001)。 结论: 新的免疫基因风险模型在预测子宫内膜癌的预后方面有一定的优势，并与临床结局有很强的相关性。此外，它可能为子宫内膜癌的靶向治疗提供新的生物标志物。
METHODS:STUDY OBJECTIVE:To evaluate the differences in perioperative outcomes and immediate complication rates between laparoscopic myomectomy for submucous myomas and laparoscopic myomectomy for myomas in other locations. DESIGN:Retrospective cohort study. SETTING:University-affiliated hospital in London. PATIENTS:A total of 350 patients with symptomatic uterine myomas underwent laparoscopic myomectomy. Thirty-three of these were performed for submucous myomas (group 1), and 317 were for myomas in other uterine locations (group 2). INTERVENTIONS:Analysis of prospectively collected data on patient demographics, myoma characteristics, perioperative outcomes, and immediate complications. MEASUREMENTS AND MAIN RESULTS:Patient demographics, including age, body mass index, and parity, were similar in the 2 groups. No significant differences in myoma characteristics were seen between groups 1 and 2, including the mean dimension of largest myoma (7.1 vs 7.8 cm, respectively; p = .35), mean number of myomas removed (3.8 vs 4.1; p = .665), and mean mass of myomas removed (142.0 g vs 227.3 g; p = .186). There were also no significant between-group differences in any perioperative outcomes, including mean blood loss (226.8 mL vs 266.4 mL; p = .373), duration of surgery (103 minutes vs 113 minutes; p = .264), and duration of hospital stay (1.4 days vs 1.7 days; p = .057). No complications arose from laparoscopic resection of submucous myomas. CONCLUSION:Laparoscopic myomectomy for submucous myomas has similar perioperative outcomes and immediate complications as laparoscopic myomectomy for other myomas and can be considered for large or type 2 submucous myomas.
METHODS:INTRODUCTION:Laparoscopic myomectomy can be difficult when fibroids are large and numerous. This may result in extensive intraoperative bleeding and the need for a conversion to a laparotomy. Medical pretreatment prior to surgery might reduce these risks by decreasing fibroid size and vascularization of the fibroid. We compared pretreatment with ulipristal acetate (UPA) vs gonadotropin-releasing hormone agonists (GnRHa) prior to laparoscopic myomectomy on several intra- and postoperative outcomes. MATERIAL AND METHODS:We performed a non-inferiority double-blind randomized controlled trial in nine hospitals in the Netherlands. Women were randomized between daily oral UPA for 12 weeks and single placebo injection or single intramuscular injection with leuprolide acetate and daily placebo tablets for 12 weeks. The primary outcome was intraoperative blood loss. Secondary outcomes were reduction of fibroid volume, suturing time, total surgery time and surgical ease. RESULTS:Thirty women received UPA and 25 women leuprolide acetate. Non-inferiority of UPA regarding intraoperative blood loss was not demonstrated. When pretreated with UPA, median intraoperative blood loss was statistically significantly higher (525 mL [348-1025] vs 280 mL[100-500]; P = 0.011) and suturing time of the first fibroid was statistically significantly longer (40 minutes [28-48] vs 22 minutes [14-33]; P = 0.003) compared with GnRHa. Pretreatment with UPA showed smaller reduction in fibroid volume preoperatively compared with GnRHa (-7.2% [-35.5 to 54.1] vs -38.4% [-71.5 to -19.3]; P = 0.001). Laparoscopic myomectomies in women pretreated with UPA were subjectively judged more difficult than in women pretreated with GnRHa. CONCLUSIONS:Non-inferiority of UPA in terms of intraoperative blood loss could not be established, possibly due to the preliminary termination of the study. Pretreatment with GnRHa was more favorable than UPA in terms of fibroid volume reduction, intraoperative blood loss, hemoglobin drop directly postoperatively, suturing time of the first fibroid and several subjective surgical ease parameters.
METHODS:AIMS:Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance. METHODS AND RESULTS:We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil-like cytoplasm. We found that six (86%) of seven FH-negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours. CONCLUSION:Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.