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Objectives: The objective of this study was to explore a better adjuvant treatment for patients with high-grade (HG) neuroendocrine cervical carcinomas (NECC) who had undergone surgery as a primary treatment. Design: A retrospective cohort study, which involved women diagnosed as HG-NECC, was conducted in the Obstetrics and Gynecology Hospital of Fudan University. All patients had undergone radical surgery and pelvic lymphadenectomy with a laparotomy or a minimally invasive surgery. An analysis was made of the prognosis of HG-NECC. Methods: Overall survival (OS) and progression-free survival (PFS) curves were drawn using the Kaplan-Meier method to be compared via log-rank tests. A Cox proportional hazards model was used to estimate the independent prognostic factors. Results: A number of 110 patients diagnosed as HG-NECC at the pathological stage IA2 to IIIC2 according to the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging system were initially treated with a primary surgery between 2008 and 2020. The eligible patients had the median age of 42.5 years (range: 22–76), with the median follow-up period of 39.6 months (range: 1.0–156.6). The 5-year OS of the patients at pathological stage I, II, and III accounted for 84.9%, 85.7%, and 60.9%, respectively. The Kaplan-Meier survival curves revealed no significant differences in OS and PFS between postoperative chemoradiotherapy and chemotherapy alone (OS: p = 0.77; PFS: p = 0.41). Etoposide plus platinum therapy did not improve OS when compared with platinum plus paclitaxel therapy after surgery (p = 0.71). The univariable analysis showed that chemotherapy with cycles ≥4 presented a better prognosis than with cycles <4 (OS: p = 0.01; HR = 6.71; PFS: p = 0.02; HR = 5.18). The multivariate analysis indicated that the cycles of chemotherapy (p = 0.02; HR 0.29) were a prognostic factor for PFS. Limitations: A retrospective design and the absence of partial follow-up data are limitations of the study. Conclusions: In initially surgically treated HG-NECC, postoperative chemotherapy alone showed no inferiority when compared with chemoradiotherapy for HG-NECC, and 4+ cycles of chemotherapy tended to produce a better prognosis than 4-ones. [ABSTRACT FROM AUTHOR]

Synopsis: Postoperative non‐invasive mucosal implantation of cervical adenocarcinoma on the clitoris is rare. Surgical resection is appropriate for local recurrence in the vulva. [ABSTRACT FROM AUTHOR]

Objectives: Interleukin 33 (IL-33) is a crucial inflammatory factor that functions as an alarm signal in endometriosis (EMs). Epithelial-mesenchymal transition (EMT), a process related to inflammatory signals, intracellular reactive oxygen species (ROS) production, and lipid peroxidation, have been proposed as potential mechanisms that contribute to the development and progression of EMs. IL-33 is highly upregulated in the ectopic milieu. Moreover, ectopic endometrial cells constitutively express interleukin-33 receptor ST2 (IL-33R). However, the role of IL-33/ST2 in the EMT of EMs remains largely unknown. In this study, we aimed to mechanistically determine the role of IL-33/ST2 in EMs-associated fibrosis. Materials and methods: We established a non-lethal oxidative stress model to explore the conditions that trigger IL-33 induction. We performed α-smooth muscle actin (α-SMA) protein detection, cell counting kit-8 (CCK-8) assays, and scratch assays to analyze the impact of IL-33 on primary endometrial stromal cells (ESCs) proliferation and invasion. Clinical samples from patients with or without EMs were subjected to immunohistochemical (IHC) and and immunofluorescence(IF) staining to assess the clinical relevance of IL-33 receptor ST2 and EMT-related proteins. Furthermore, we used the ectopic human endometrial epithelial cell line 12Z and normal human epithelial cell line EEC to evaluate the effects of IL-33 on Wnt/β-catenin signaling. The effect of IL-33 on EMT-associated fibrosis was validated in vivo by intraperitoneal injections of IL-33 and antiST2. Results: We observed that ectopic milieu, characterized by ROS, TGF-β1, and high level of estrogen, triggers the secretion of IL-33 from ectopic ESCs. Ectopic endometrial lesions exhibited higher level of fibrotic characteristics and ST2 expression than that in the normal endometrium. Exogenous recombinant human (rhIL-33) enhanced ESC migration and survival. Similarly, 12Z cells displayed a higher degree of EMT characteristics with elevated expression of CCN4 and Fra-1, downstream target genes of the WNT/β-catenin pathway, than that observed in EECs. Conversely, blocking IL-33 with neutralizing antibodies, knocking down ST2 or β-catenin with siRNA, and β-catenin dephosphorylation abolished its effects on EMT promotion. In vivo validation demonstrated that IL-33 significantly promotes EMs-related fibrosis through the activation of Wnt/β-catenin signaling. Conclusion: Our data strongly support the vital role of the IL-33/ST2 pathway in EMs-associated fibrosis and emphasize the importance of the EMT in the pathophysiology of fibrosis. Targeting the IL-33/ST2/Wnt/β-catenin axis may hold promise as a feasible therapeutic approach for controlling fibrosis in EMs. [ABSTRACT FROM AUTHOR]

Background: As a dual-function metabolite, succinate has emerged in cell function and plays a key signaling role in linking mitochondrial function to other cellular functions. Succinate accumulation in the cytoplasm is commonly associated with hypoxia in the microenvironment and immune cell activation. Extracellular succinate released into the microenvironment is considered an inflammatory alarm that can be sensed by its membrane receptor SUCNR1, which boosts proinflammatory responses and acts akin to classical hormones and cytokines. Succinate plays an important role in the development of inflammatory diseases. Whether succinate facilitates the progression of endometriosis (EMs), characterized by chronic inflammation and peritoneal adhesion, is worth exploring. Objective: We mimicked the ectopic milieu in vitro and in vivo to evaluate the main source and potential role of succinate in endometriosis. We assessed the molecular and functional effects of succinate on macrophages and peritoneal mesothelial cells in peritoneal cavity. The effect of succinate/SUCNR1 signaling on ectopic endometrial stromal cells (ESCs) was further explored in this study. Methods: In this study, we used targeted organic acid metabolomics analysis and in vitro assays to assess the potential accumulation of succinate in the peritoneal fluid of EMs patients. We examined its correlation with disease severity, Visual Analogue Scale, and the Endometriosis Fertility Index. Flow cytometry, enzyme linked immunosorbent assay, western blot assay, quantitative real-time PCR, and other molecular biology techniques were used to explore the potential mechanisms. Results: By mimicking the ectopic milieu, we constructed an in vitro co-culture system and found that M1 polarized macrophages and that the peritoneal mesothelial cell line (HMrSV5) mainly released succinate into their microenvironment and activated the succinate receptor (SUCNR1) signal, which further polarized the macrophages and significantly enhanced the invasive survival of ESCs, and the adhesion to the peritoneum. We further investigated the pathological effects of extracellular succinate in vivo using a xenograft mouse models of endometriosis. Conclusions: Succinate-SUCNR1 signaling facilitates the creation of inflammatory cells and plays a vital role in EMs progression and peritoneal adhesion. Our work on the molecular mechanisms underlying succinate accumulation and function will help elucidate the phenotypic mysteries of pain and infertility in EMs. BkiB34NQBDvkGHWZYD1GB2 Video Abstract [ABSTRACT FROM AUTHOR]