Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68 þ CD163 þ macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERa), but not ERb. Mechanistic investigations revealed that CD68 þ CD163 þ macrophages secreted cytokines, such as IL17A, that upregulated ERa expression through TET1-mediated epigenetic modulation of the ERa gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERa expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting.

Mean treatment duration to achieve CR was 6.7 ± 0.3 months, using progestin therapy combined with hysteroscopic evaluation. • Endometrial lesion size ≤2 cm correlated with a shorter treatment period to achieve CR. • Comprehensive hysteroscopic evaluation seems to be effective for EAH and EEC patients who wish to preserve fertility.

We aimed to evaluate the value of immunohistochemical markers and serum CA125 in predicting the risk of lymph node metastasis (LNM) in women with endometrial cancer and to identify a low-risk group of LNM. The medical records of 370 patients with endometrial endometrioid adenocarcinoma who underwent surgical staging in the Obstetrics & Gynecology Hospital of Fudan University were collected and retrospectively reviewed. Immunohistochemical markers were screened. A model using serum cancer antigen 125 (CA125) level, the immunohistochemical markers progesterone receptor (PR) and Ki67 was created for prediction of LNM. A predicted probability of 4% among these patients was defined as low risk. The developed model was externally validated in 200 patients from Shanghai Cancer Center. The efficiency of the model was compared with three other reported prediction models. Patients with serum CA125 < 30.0 IU/mL, either or both of positive PR staining > 50% and Ki67 < 40% in cancer lesion were defined as low risk for LNM. The model showed good discrimination with an area under the receiver operating characteristic curve of 0.82. The model classified 61.9% (229/370) of patients as being at low risk for LNM. Among these 229 patients, 6 patients (2.6%) had LNM and the negative predictive value was 97.4% (223/229). The sensitivity and specificity of the model were 84.6% and 67.4% respectively. In the validation cohort, the model classified 59.5% (119/200) of patients as low-risk, 3 out of these 119 patients (2.5%) has LNM. Our model showed a predictive power similar to those of two previously reported prediction models. The prediction model using serum CA125 and the immunohistochemical markers PR and Ki67 is useful to predict patients with a low risk of LNM and has the potential to provide valuable guidance to clinicians in the treatment of patients with endometrioid endometrial cancer.

ObjectiveOur previous study showed that insulin resistance (IR) was related to endometrial hyperplasia as well as endometrial cancer. But the exact impact of IR on fertility-sparing treatment in endometrial hyperplasic disease is unclear. This study investigated how IR affects fertility-sparing treatment in endometrial atypical hyperplasia (EAH) patients.MethodsThe 151 EAH patients received fertility-sparing treatment were retrospectively investigated. All patients received high-dose progestin combined with hysteroscopy. Therapeutic effects were evaluated by hysteroscopy every 3 months during the treatment.ResultsThe median age was 33.0 years old (range, 21–54 years old). Sixty-one patients (40.4%) were insulin resistant. Three patients were excluded from the analysis because they chose hysterectomy within 3 months after initiation of progestin treatment. The 141 out of 148 (95.3%) patients achieved complete response (CR). No difference was found in cumulative CR rate between those with or without IR (90.2% vs. 95.6%, p=0.320). IR significantly affected therapeutic duration to achieve CR (8.1±0.5 months with IR vs. 6.1±0.4 months without IR, p=0.004). Overweight (body mass index [BMI]≥25 kg/m2) was associated with higher risk of treatment failure (odds ratio=5.61; 95% confidence interval=1.11–28.35; p=0.040) and longer therapeutic duration to achieve CR (7.6±0.5 months vs. 6.3±0.4 months, p=0.019). EAH patients with both IR and overweight (IR+BMI+) had the longest therapeutic time compared with other patients (8.8±0.6 months vs. 5.6±0.7, 6.3±0.4, and 6.4±0.8 months for IR−BMI+, IR−BMI−, and IR+BMI−, respectively, p=0.006).ConclusionIR and overweight were associated with longer therapeutic duration in EAH patients receiving progestin-based fertility-sparing treatment.

This study was aimed to investigate brain function connectivity in premature ejaculation (PE) patients using the functional connectivity density (FCD) and network property of resting-state functional magnetic resonance imaging. Twenty PE patients (mean age: 27.95 ± 4.52 years) and 15 normal controls (mean age: 27.87 ± 3.78 years) with no self-reported history of neurologic or psychiatric disease were enrolled in this study. International Index of Erectile Function-5 and Chinese Index of Sexual Function for Premature Ejaculation-5 questionnaires and self-reported intravaginal ejaculatory latency time (IELT) were obtained from each participant for symptom assessment. Two-sample t-tests (intergroup comparison) were applied in the short-range FCD (SFCD) analysis, long-range FCD (LFCD) analysis, region of interest–based analysis, and network topological organization analysis. Pearson correlation analysis was performed to correlate IELT with FCD or the network property. The patients with PE showed significantly decreased SFCD in the bilateral middle temporal gyrus, left orbitofrontal cortex, nucleus accumbens, fusiform, caudate, and thalamus (p < 0.05, AlphaSim-corrected). Notably, all these aforementioned brain areas are located in the dopamine pathway. In contrast, increased LFCD was observed in the left insula, Heschl's gyrus, putamen, bilateral precuneus, supplementary motor area, middle cingulate cortex, and anterior cingulate cortex in PE patients (p < 0.05, AlphaSim-corrected). In addition, the network topological analysis found reinforced network connectivity between several nodes. The degree of hub nodes increased in the patients with PE. IELT was positively correlated with SFCD and negatively correlated with LFCD or the degree of hub nodes (p < 0.05, Pearson correlation). In summary, our results are important for understanding the brain network in PE patients. The present findings indicate that PE patients have a significant synergism disorder across the region of dopamine pathway, which implied neuronal pathological changes might be related with the change of dopamine. The FCD and network property can serve as new disease severity biomarkers and therapeutic targets in PE.