Fertility-sparing re-treatment for endometrial cancer and atypical endometrial hyperplasia patients with progestin-resistance: a retrospective analysis of 61 cases.

OBJECTIVE: This study aimed to evaluate the oncological and reproductive outcomes of fertility-preserving re-treatment in progestin-resistant endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) women who desire to maintain their fertility. METHODS: Our study included 61 progestin-resistant EC/AEH patients. These patients underwent treatment with gonadotropin-releasing hormone agonist (GnRHa) solely or a combination of GnRHa with levonorgestrel-releasing intrauterine system (LNG-IUD) or aromatase inhibitor (AI). Histological evaluations were performed every 3-4 months. Upon achieving complete remission (CR), we recommended maintenance treatments including LNG-IUD, cyclical oral contraceptives, or low-dose cyclic progestin until they began attempting conception. Regular follow-up was conducted for all patients. The chi-square method was utilized to compare oncological and fertility outcomes, while the Cox proportional hazards regression analysis helped identify risk factors for CR, recurrence, and pregnancy. RESULTS: Overall, 55 (90.2%) patients achieved CR, including 90.9% of AEH patients and 89.7% of EC patients. The median re-treatment time was 6 months (ranging from 3 to 12 months). The CR rate for GnRHa alone, GnRHa + LNG-IUD and GnRHa + AI were 80.0%, 91.7% and 93.3%, respectively. After a median follow-up period of 36 months (ranging from 3 to 96 months), 19 women (34.5%) experienced recurrence, 40.0% in AEH and 31.4% in EC patients, with the median recurrence time of 23 months (ranging from 6 to 77 months). Among the patients who achieved CR, 39 expressed a desire to conceive, 20 (51.3%) became pregnant, 11 (28.2%) had successfully deliveries, 1 (5.1%) was still pregnant, while 8 (20.5%) suffered miscarriages. CONCLUSION: GnRHa-based fertility-sparing treatment exhibited promising oncological and reproductive outcomes for progestin-resistant patients. Future larger multi-institutional studies are necessary to confirm these findings.

Current research of Assisted Reproductive Technology for women with early endometrial cancer and atypical endometrial hyperplasia after conservative treatment.

As the incidence of endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) has been increasing, and has shown young trend. It is crucial to study the fertility-preserving treatment of endometrial lesions and fertility-promoting protocols. Age, obesity, and irregular ovulation are not only high-risk factors for endometrial lesions but also key factors affecting female fertility. Assisted reproductive technology (ART) can significantly improve pregnancy outcomes in patients with AEH and EC after conservative treatment. Based on the existing studies, this article reviews the progress of research on pregnancy outcomes of ART and its influencing factors in such patients. It helps physicians in providing optimal fertility guidance.

Effects of melatonin on disease improvement and serum levels of pro-inflammatory cytokines in patients with non-atypical endometrial hyperplasia.

BACKGROUND: Endometrial hyperplasia (EH), an abnormal proliferation of the endometrial cells, is considered as one of the most common causes of abnormal uterine bleeding. Previous studies have reported that melatonin plays a fundamental role in disease treatment. This study aimed the comparison of the effects of progesterone, as the most common therapeutic approach, and melatonin with progesterone alone in improvement of non-atypical endometrial hyperplasia (NEH) and changes in pro-inflammatory cytokine levels. METHODS: Study population consisted of 40 patients with NEH. Patients were divided into two groups, including 20 subjects treated with melatonin and progesterone and 20 individuals treated with progesterone alone. The blood and endometrial sampling was performed from participants before and after a three-month treatment. The histological examination was microscopically done. The serum levels of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were measured using ELISA. RESULTS: There was no significant difference in the diabetes status and mean age between patients treated with progesterone and melatonin and those treated with progesterone alone. The improvement rate in the EH was significantly higher in individuals treated with progesterone and melatonin than those treated with progesterone alone (p < 0.05). Additionally, the patients treated with progesterone and melatonin showed significant increases inIFN-γ and TNF-αlevels compared to the control group (p < 0.001-P < 0.05). CONCLUSION: Melatonin supplementation has a beneficial effect in the treatment of EH due perhaps to enhance the level of IFN-γ and TNF-α.

Plasma-based proteomic profiling identifies the distinct regulation of proteins in hyperplasia and endometrial cancer.

BACKGROUND: Among gynaecological malignancies, endometrial cancer (EC) is the most prevalent type of uterine cancer affecting women. This study explored the proteomic profiles of plasma samples obtained from EC patients, those with hyperplasia (Hy), and a control group (CO). A combination of techniques, such as 2D-DIGE, mass spectrometry, and bioinformatics, including pathway analysis, was used to identify proteins with modified expression levels, biomarkers and their associated metabolic pathways in these groups. METHODS: Thirty-four patients, categorized into three groups-10 with EC, 12 with Hy, and 12 CO-between the ages of 46 and 75 years old were included in the study. Untargeted proteomic analysis was carried out using two-dimensional difference in gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). RESULTS: In all three groups, 114 proteins that were significantly (p ≤ 0.05 and fold change ≥ 1.5) altered were successfully identified using peptide mass fingerprints (PMFs). Compared with those in the control group (CO), the EC samples had 85 differentially expressed proteins (39 upregulated and 46 downregulated), and in the Hy group, 81 proteins were dysregulated (40 upregulated and 41 downregulated) compared to those in the CO group, while 33 proteins exhibited differential regulation (12 upregulated and 21 downregulated) in the EC plasma samples compared to those in the Hy group. Vitamin D binding protein and complement C3 distinguished Hy and EC from CO with the greatest changes in expression. Among the differentially expressed proteins identified, enzymes with catalytic activity represented the largest group (42.9%). In terms of biological processes, most of the proteins were involved in cellular processes (28.8%), followed by metabolic processes (16.7%). STRING analysis for protein interactions revealed that the significantly differentially abundant proteins in the three groups are involved in three main biological processes: signalling of complement and coagulation cascades, regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor binding proteins (IGFBPs), and plasma lipoprotein assembly, remodelling, and clearance. CONCLUSION: The identified plasma protein markers have the potential to serve as biomarkers for differentiating between EC and Hy, as well as for early diagnosis and monitoring of cancer progression.

Levels of anxiety and depression in patients with endometrial hyperplastic processes and extragenital pathology in the perimenopausal period.

OBJECTIVE: Aim: The aim of the study was to determine the level of anxiety and depression in patients with endometrial hyperplastic processes and somatic pathology in the perimenopausal period. PATIENTS AND METHODS: Materials and Methods: Overall, 150 women who were split into 2 groups, participated in this study and answered on questionnaires that were conducted according to the Hospital Anxiety and Depression Scale (HADS) to assess the degree of anxiety and depressive symptoms in patients. PHQ-2 and PHQ-9 questionnaires were used to study the level of anxiety and depression. RESULTS: Results: Analysis of the results obtained using the HADS scale revealed that both anxiety and depressive symptoms in patients of the main group were more pronounced than in women of the control group. Identification of psycho-emotional disorders is the result of adverse effects of somatic diseases and gynecological pathology. CONCLUSION: Conclusions: The results of the study indicate the need to correct psycho-emotional disorders and take them into account when choosing a method of treatment in such patients.

Mismatch repair deficiency and abnormal p53 expression has significant predictive value for progesterone resistance and endometrial tumorigenesis in patients with endometrial atypical hyperplasia receiving fertility-preserving treatment.

OBJECTIVE: This study aimed to evaluate the prognostic ability of mismatch repair deficiency (MMR-d) and abnormal p53 expression (p53abn) in patients with endometrial atypical hyperplasia (EAH) who underwent fertility-preserving treatment. METHODS: This retrospective study evaluated 51 patients with EAH who underwent fertility-sparing treatment. Endometrial biopsy specimens obtained before hormone therapy were collected and used for immunohistochemical staining for MMR and p53 proteins. Response, relapse, and progression rates were assessed based on age, body mass index, diabetes, polycystic ovary syndrome, reproductive history, MMR status, and p53 status. RESULTS: Overall, 11/51 (21.6%) patients had loss of MMR proteins and 6/51 (11.8%) had p53abn. Patients with MMR-d had lower complete response (CR) rates than those with normal staining patients at 12 months after initial treatment (p = 0.049). Patients with MMR-d had significantly higher relapse rates than those with MMR-p at the 1-year follow-ups after achieving CR (p = 0.035). Moreover, patients with MMR-d had a higher incidence of disease progression at 2, 3, and 4 years after fertility-sparing treatment (p = 0.001, p = 0.01 and p = 0.035, respectively). Patients with p53abn had higher relapse rates than those with p53wt at the 1- and 2-year follow-ups after achieving CR (p = 0.047 and p = 0.036, respectively). Moreover, patients with p53abn had a higher incidence of disease progression at 3 and 4 years after fertility-sparing treatment (p = 0.02 and p = 0.049, respectively). CONCLUSIONS: EAH patients with MMR-d and p53abn have a significantly higher risk of disease relapse and progression. Thus, MMR-d and p53abn may be used as predictive biomarkers of progestin resistance and endometrial tumorigenesis in EAH.

Chinese guidelines on the management of endometrial hyperplasia.

• Endometrial hyperplasia can be classified as either hyperplasia without atypia or atypical hyperplasia. • Abnormal uterine bleeding is the most common symptom of endometrial hyperplasia. Transvaginal ultrasound is recommended for initial imaging to evaluate endometrial hyperplasia (evidence level 2+), while transrectal ultrasound is recommended for virgo patients (evidence level 3). • Endometrial biopsy should be used to confirm diagnosis in patients where endometrial lesions are suspected. Effective histological approaches to make definite diagnoses include diagnostic curettage (evidence level 2++), hysteroscopic-guided biopsy (evidence level 2+) and endometrial aspiration biopsy (evidence level 2-). • Progesterone is the preferred medication for the treatment of endometrial hyperplasia without atypia. Compared to oral progestins, placement of a levonorgestrel-releasing intrauterine system (LNG-IUS) has been associated with higher regression rates, lower recurrence rates and fewer adverse events which can be the initial treatment method. (Meta evidence level 1-, RCT evidence level 2+). Ultrasound and endometrial biopsies should be performed every 6 months during treatment to evaluate its effect and treatment should continue until no pathological changes are observed in two consecutive endometrial biopsies. Hysterectomy is not the preferred choice of treatment for patients with endometrial hyperplasia without atypia. • Minimally invasive hysterectomy is indicated for patients with endometrial atypical hyperplasia (evidence level 1+), bilateral fallopian tubes should also be removed (evidence level 2+). In cases where surgery cannot be tolerated, fertility is desired or the patient is younger than 45 years old, medical therapy is recommended (evidence level 3). LNG-IUS is the preferred medical therapy method (evidence level 2+). Endometrial pathologic evaluation should be performed every 3 months during conservative treatments, with adjustments made to dosages or approaches based on observed response to medication. Treatment should continue until no pathological changes are detected in two consecutive endometrial biopsies (evidence level 2++). There is no indication of sentinel lymph nodes biopsy and/or lymphadenectomy for hyperplasia with or without atypia. • Total hysterectomy is recommended to treat patients with recurrent endometrial atypical hyperplasia (evidence level 3); however, medical conservative therapy may be considered for patients hoping to become pregnant in the future. • Patients with fully regressed disease who would like to become pregnant should be advised to seek assistance through assisted reproductive technologies (evidence level 3). • Long-term follow-up is suggested for patients after endometrial hyperplasia treatment (evidence level 2+). Patient education is imperative for improving medication adherence, increasing regression rates and lowering recurrence rates (evidence level 3).

Genetic and epigenetic alterations in precursor lesions of endometrial endometrioid carcinoma.

The hyperplasia-carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH-AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the PTEN mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Factors associated with interobserver variation amongst pathologists in the diagnosis of endometrial hyperplasia: A systematic review.

OBJECTIVE: Reproducible diagnoses of endometrial hyperplasia (EH) remains challenging and has potential implications for patient management. This systematic review aimed to identify pathologist-specific factors associated with interobserver variation in the diagnosis and reporting of EH. METHODS: Three electronic databases, namely MEDLINE, Embase and Web of Science, were searched from 1st January 2000 to 25th March 2023, using relevant key words and subject headings. Eligible studies reported on pathologist-specific factors or working practices influencing interobserver variation in the diagnosis of EH, using either the World Health Organisation (WHO) 2014 or 2020 classification or the endometrioid intraepithelial neoplasia (EIN) classification system. Quality assessment was undertaken using the QUADAS-2 tool, and findings were narratively synthesised. RESULTS: Eight studies were identified. Interobserver variation was shown to be significant even amongst specialist gynaecological pathologists in most studies. Few studies investigated pathologist-specific characteristics, but pathologists were shown to have different diagnostic styles, with some more likely to under-diagnose and others likely to over-diagnose EH. Some novel working practices were identified, such as grading the "degree" of nuclear atypia and the incorporation of objective methods of diagnosis such as semi-automated quantitative image analysis/deep learning models. CONCLUSIONS: This review highlighted the impact of pathologist-specific factors and working practices in the accurate diagnosis of EH, although few studies have been conducted. Further research is warranted in the development of more objective criteria that could improve reproducibility in EH diagnostic reporting, as well as determining the applicability of novel methods such as grading the degree of nuclear atypia in clinical settings.

Glyphosate-based herbicide worsens alterations induced by cafeteria diet on rat uterus.

Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of GBH added to the CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: control, CAF, GBH, and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. With respect to the control group, no changes in the serum levels of 17ß-estradiol and progesterone were found. However, progesterone levels were higher in the CAF+GBH group than in the CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with the CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, with respect to control rats. These results indicate that the addition of GBH exacerbates the CAF effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.

Treatment outcomes according to various progestin treatment strategies in patients with atypical hyperplasia/endometrial intraepithelial neoplasia - Multicenter retrospective study (KGOG2033).

OBJECTIVE: To investigate pathologic complete response (pCR) and recurrence outcomes using various progestin treatment strategies in patients with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN). METHODS: Medical records of patients diagnosed with AH/EIN and undergoing follow-up endometrial biopsy after progestin treatment between 2011 and 2020 were retrospectively reviewed. Clinical factors and treatment outcomes were analyzed according to initial progestin treatment (oral progestin [OP], levonorgestrel-releasing intrauterine device [LNG-IUD], and combination), OP dose, and maintenance treatment using Pearson's χ2, Fisher's exact test, and Kaplan-Meier analysis. RESULTS: Of 124 patients included, 74, 37, and 13 were in the OP, LNG-IUD, and combination groups, respectively. The pCR rate was 79.8% and recurrence rate was 21.2%. The pCR rates within 3 and 6 months were significantly higher in the OP group than in the LNG-IUD group, but were not significantly different within 12 and 24 months. Recurrence rate was significantly higher in the OP group than in the LNG-IUD group. The pCR rate and recurrence rate had no significant differences between the combination group and the other groups. Excluding the LNG-IUD group, 53 and 34 patients received low- and high-dose OP, respectively. The pCR and recurrence rates were comparable between the low- and high-dose OP groups. Maintenance therapy was significantly associated with lower recurrence rate. CONCLUSIONS: Although OP alone achieved more short-term pCR than the other groups, more recurrences occurred after pCR than LNG-IUD alone. High-dose OP as well as combination of OP and LNG-IUD did not increase pCR or reduce recurrence. Maintenance therapy may reduce the recurrence rate after pCR.

Concurrent endometrial cancer in atypical endometrial hyperplasia and the role of sentinel lymph nodes: clinical insights from a multicenter experience.

OBJECTIVE: This study aimed to evaluate the prevalence of concurrent endometrial cancer in patients pre-operatively diagnosed with atypical endometrial hyperplasia undergoing hysterectomy. Additionally, we assessed the occurrence of high to intermediate-risk and high-risk tumors according to the ESGO-ESTRO-ESP classification. The study also compared surgical outcomes and complications between patients undergoing simple hysterectomy and those undergoing hysterectomy with sentinel lymph node biopsy. METHODS: In this multicenter retrospective study, patients with a pre-operative diagnosis of atypical endometrial hyperplasia were identified and divided into two groups: Group 1, which included patients treated with total hysterectomy with or without bilateral salpingo-oophorectomy, and Group 2, where sentinel lymph node biopsy was incorporated into the standard surgical treatment. RESULTS: Among 460 patients with atypical endometrial hyperplasia, 192 received standard surgical management (Group 1) and 268 underwent sentinel lymph node biopsy (Group 2). A total of 47.2% (95% CI 42.6% to 51.7%) of patients were upgraded to endometrial cancer on final histopathological examination. High to intermediate-risk and high-risk tumors constituted 12.3% and 9.2% in Group 2 and 7.4% and 3.7% in Group 1. Lymph node metastases were identified in 7.6% of patients with concurrent endometrial cancer who underwent nodal assessment with at least unilateral mapping. Of the 12 sentinel lymph node metastases, 75.0% were micrometastases, 16.7% macrometastases, and 8.3% isolated tumor cells. No significant differences were found in estimated blood loss, operative time, and intra-operative and post-operative complications between the two groups. The rate of patients undergoing sentinel lymph node biopsy doubled every 2 years (OR 2.010, p<0.001), reaching 79.1% in the last 2 years. CONCLUSION: This study found a prevalence of concurrent endometrial cancer of 47.2%, and sentinel lymph node biopsy provided prognostic and therapeutic information in 60.8% of cases. It also allowed for the adjustment of adjuvant therapy in 12.3% of high to intermediate-risk patients without increasing operative time or complication rates.

Evaluation of uterine antioxidants in bitches suffering from cystic endometrial hyperplasia-pyometra complex.

Cystic endometrial hyperplasia-pyometra complex (CEH-P) is a common disease in sexually mature bitches. Disease progression leads to oxidative stress, resulting in the depletion of uterine antioxidants and lipid peroxidation of associated cells, which further aggravates the condition. The concentration of antioxidant enzymes, the level of lipid peroxidation within the uterine tissue, and its reflection in the serum and urine need to be elucidated. The aim of this study was to analyze the concentration of antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and the lipid peroxidation marker malonaldehyde (MDA) in three types of samples, i.e., serum, urine, and uterine tissue. For this purpose, 58 pyometra-affected and 44 healthy bitches were included in the present study. All animals underwent ovariohysterectomy (OVH). Our data indicated highly significant difference (p<0.01) in the antioxidant concentrations of uterine, serum and urine samples. Furthermore, there was a highly significant (p<0.01) difference in the serum levels of ferric reducing antioxidant power (FRAP) and free radical scavenging activity (FRSA) indicated poor capacity to overcome oxidative stress in the CEH-Pyometra condition. We showed that CEH-P induces oxidative stress, which further depletes the antioxidant enzyme reserves in the uterus. Thus, the weak antioxidant defence predisposes to uterine damage and disease progression. The simultaneous depletion of antioxidants and an increase in lipid peroxidation in the serum and urine may also act as early indicators of uterine pathology.

Reproductive and Oncologic Outcomes in Young Women with Stage IA and Grade 2 Endometrial Carcinoma Undergoing Fertility-Sparing Treatment: A Systematic Review.

BACKGROUND: Endometrial cancer (EC) is the most common gynecological malignancy in both Europe and the USA. Approximately 3-5% of cases occur in women of reproductive age. Fertility-sparing treatment (FST) options are available, but very limited evidence regarding grade 2 (G2) ECs exists in the current literature. This systematic review aimed to comprehensively evaluate reproductive and oncologic outcomes among young women diagnosed with stage IA or G2EC disease who underwent FST. METHODS: A comprehensive search of the literature was carried out on the following databases: MEDLINE, EMBASE, Global Health, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), the Health Technology Assessment Database, and Web of Science. Only original studies that reported the oncologic and reproductive outcomes of patients with stage IA and G2EC tumors who underwent FST were considered eligible for inclusion in this systematic review (CRD42023484892). Studies describing only the FST for endometrial hyperplasia or G1 EC were excluded. RESULTS: Twenty-two papers that met the abovementioned inclusion criteria were included in the present systematic review. Preliminary analysis suggested encouraging oncologic and reproductive outcomes after FST. CONCLUSIONS: The FST approach may represent a feasible and safe option for women of childbearing age diagnosed with G2EC. Despite these promising findings, cautious interpretation is warranted due to inherent limitations, including heterogeneity in study designs and potential biases. Further research with standardized methodologies and larger sample sizes is imperative for obtaining more robust conclusions.

[The long-term efficacy of metformin in megestrol acetate-based fertility-sparing treatment for patients with endometrial atypical hyperplasia and endometrioid endometrial cancer].

Objective: To assess the long-term efficacy of metformin in megestrol acetate (MA)-based fertility-sparing treatment for patients with endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC). Methods: The randomized controlled trail study was conducted from October 2013 to October 2017 in the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. Patients with EAH or EEC were firstly stratified according to pathology, and randomized to receive MA (160 mg orally, daily) plus metformin (500 mg orally, three times a day) or MA (160 mg orally, daily). Baseline data between two groups of patients were compared. Estimates of time to complete remission (CR) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method. Cox proportional-hazards regression model was used to estimate hazard ratios (HR) of related factors for recurrence-free survival. Quantitative data were represented by M (Q1, Q3). Results: A total of 150 patients were included, and 76 patients were allocated to receive MA plus metformin with the age of 32.5 (28.0, 36.0), while 74 patients received MA alone with the age of 32.0 (28.0, 36.0). By the end of follow-up period, 96.7% (n=145) of patients achieved complete remission, with a median follow-up time of 57.7 (26.7, 70.5) months. The median CR time for the MA plus metformin group and the MA alone group were 6.3 (3.5, 8.3) months and 6.8 (4.0, 9.3) months, respectively (P=0.193), with 2-year cumulative CR rate of 98.6% and 98.5%, respectively (P=0.879). The median time of RFS was 28.1 (12.5, 57.3) months for the MA plus metformin group and 33.3 (14.1, 62.5) months for the MA alone group (P=0.213), with a cumulative RFS rate of 61.9% and 65.8%, respectively (P=0.560). In the subgroup of non-obese (body mass index<28 kg/m2) patients with EAH, the median RFS times were 25.7 (7.6, 60.3) months and 47.3 (17.5, 64.8) months for the MA plus metformin group and the MA alone group, respectively (P=0.033), with a cumulative RFS rate of 57.5% and 80.6%, respectively (P=0.029). According to Cox proportional hazards regression analysis, undergoing assisted reproductive treatment (HR=2.358, 95%CI: 1.069-5.204, P=0.034) was identified as an independent risk factor for recurrence-free survival after complete remission of endometrial lesions. Conclusion: The long-term follow-up outcome indicates that there is no significant difference in CR time and RFS time between MA plus metformin therapy and MA alone therapy for patients with EAH or EEC.

ARG1 Is a Potential Prognostic Marker in Metastatic Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy. While the majority of patients present with early-stage and low-grade EC and have an excellent prognosis, a subset has metastatic disease at presentation or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EC is a critical barrier. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers. In the present study, ARG1 expression was evaluated as a potential prognostic marker for metastatic EC in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. While Pten mutation in the uterus is not sufficient for distant metastasis, mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Our immunostaining and RT-qPCR analysis revealed that the expression of ARG1 in early stage of EC as well as endometrial hyperplasia from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. The results suggest that a high level of ARG1 is associated with poor prognosis in association with EC of mouse.

Machine learning for prediction of concurrent endometrial carcinoma in patients diagnosed with endometrial intraepithelial neoplasia.

OBJECTIVE: To identify predictive clinico-pathologic factors for concurrent endometrial carcinoma (EC) among patients with endometrial intraepithelial neoplasia (EIN) using machine learning. METHODS: a retrospective analysis of 160 patients with a biopsy proven EIN. We analyzed the performance of multiple machine learning models (n = 48) with different parameters to predict the diagnosis of postoperative EC. The prediction variables included: parity, gestations, sampling method, endometrial thickness, age, body mass index, diabetes, hypertension, serum CA-125, preoperative histology and preoperative hormonal therapy. Python 'sklearn' library was used to train and test the models. The model performance was evaluated by sensitivity, specificity, PPV, NPV and AUC. Five iterations of internal cross-validation were performed, and the mean values were used to compare between the models. RESULTS: Of the 160 women with a preoperative diagnosis of EIN, 37.5% (60) had a post-op diagnosis of EC. In univariable analysis, there were no significant predictors of EIN. For the five best machine learning models, all the models had a high specificity (71%-88%) and a low sensitivity (23%-51%). Logistic regression model had the highest specificity 88%, XG Boost had the highest sensitivity 51%, and the highest positive predictive value 62% and negative predictive value 73%. The highest area under the curve was achieved by the random forest model 0.646. CONCLUSIONS: Even using the most elaborate AI algorithms, it is not possible currently to predict concurrent EC in women with a preoperative diagnosis of EIN. As women with EIN have a high risk of concurrent EC, there may be a value of surgical staging including sentinel lymph node evaluation, to more precisely direct adjuvant treatment in the event EC is identified on final pathology.