Explore the anti-inflammation mechanism of safflower total flavonoids in the treatment of endometritis based on celluar transcriptomics.

OBJECTIVES: Safflower is a traditional Chinese medicine for the treatment of gynecological diseases and its flavonoids have potential anti-inflammatory effects. The purpose is to explore the possible effects of safflower total flavonoids (STF) on lipopolysaccharide (LPS)-induced inflammatory damage of Ishikawa cells. METHOD: In this study, LPS-induced endometrial carcinoma Ishikawa cells were used to establish an inflammatory injury model. The effective concentration of STF was screened by CCK-8 and enzyme-linked immunosorbent assay. The apoptosis of damaged Ishikawa cells was detected by flow cytometry. The contents of caspase11 and caspase 3 in Ishikawa cells were observed by fluorescence imaging. Western blot and RT-qPCR were used to detect the expression of related proteins and mRNA in damaged Ishikawa cells, and the possible mechanism of safflower flavonoids against LPS-induced endometrial carcinoma Ishikawa cells was analyzed by cell transcriptomics. KEY FINDINGS: The STF-reduced tumor necrosis factor α, interleukin-1ß, and interleukin-6 expression level; the expression level of the proteins ASK1, Caspase3, and Caspase11 was also significantly decreased, and the proteins ERα, p-PI3K, and p-AKT were significantly increased. The transcriptome results showed that the PI3K-Akt signal pathway may be the main signal pathway for the STF. CONCLUSION: The STF could regulate the PI3K/AKT signal pathway to treat the inflammatory injury of Ishikawa cells.

The Role of Hyperthermic Intraperitoneal Chemotherapy in Uterine Cancer Therapy.

Endometrial cancer and uterine sarcoma represent the two major types of uterine cancer. In advanced stages, both cancer entities are challenging to treat and correlate with a meagre survival and prognosis. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is a form of localized chemotherapy that is heated to improve the chemotherapeutic effect on peritoneal metastases. The aim of the current review is to study the role of HIPEC in the treatment of uterine cancer. A literature review was conducted using the MEDLINE and LIVIVO databases with a view to identifying relevant studies. By employing the search terms "hyperthermic intraperitoneal chemotherapy", "uterine cancer", "endometrial cancer", and/or "uterine sarcoma", we managed to identify 26 studies published between 2004 and 2023. The present work embodies the most up-to-date, comprehensive review of the literature centering on the particular role of HIPEC as treatment modality for peritoneally metastasized uterine cancer. Patients treated with cytoreductive surgery, alongside HIPEC, seem to profit from not only higher survival but also lower recurrence rates. Factors such as the completeness of cytoreductive surgery, the peritoneal cancer index, the histologic subtype, or the applied chemotherapeutic agent, all influence HIPEC therapy effectiveness. In summary, HIPEC seems to represent a promising treatment alternative for aggressive uterine cancer.

CTNNB1 p.D32A (c.95A > C) somatic mutation in stage I grade 1 endometrioid endometrial carcinoma with lung metastasis: a case report.

BACKGROUND: Most endometrial cancers are of low histological grade and uterine-confined, with a high 5-year survival rate. However, a small subset of women with low-grade and early-stage endometrioid endometrial cancer experience recurrence and death; thus, a more precise risk-stratification is needed. CASE PRESENTATION: A 29-year-old woman presented with abnormal vaginal bleeding and was diagnosed with FIGO grade 1 endometrioid endometrial carcinoma by curettage. Comprehensive cancer staging including pelvic and para-aortic lymphadenectomy was then performed. Postoperative pathological findings suggested an FIGO grade 1 endometrioid endometrial carcinoma infiltrating the superficial muscle layer. The patient did not receive adjuvant therapy. After 4 years of follow-up, the patient returned to our institution with lung metastasis. She underwent thoracoscopic resection of the affected lobes, followed by six cycles of combined chemotherapy of paclitaxel and carboplatin. Next-generation sequencing showed that the primary and lung metastatic tumors shared 4 mutations: PTEN (p.P248Lfs*8), CTNNB1 (p.D32A), BCOR (p.N1425S) and CBL (p.S439N). Immunohistochemistry revealed nuclear location of ß-catenin in the primary and lung metastatic tumor samples, indicating abnormal activation of ß-catenin. CONCLUSION: CTNNB1p.D32A (c.95A > C) mutation may be related to lung metastasis in this patient with low-grade early-stage endometrioid endometrial carcinoma.

MET Inhibits the Proliferation of EC Cells by Increasing MPA Sensitivity.

Context: The high resistance rate and high recurrence rate of progesterone only as a treatment for endometrial cancer (EC) limit its clinical application. Metformin (MET) may have antitumor ability. Combining MET and medroxyprogesterone acetate (MPA) may strengthen their inhibitory effects on proliferation of EC cells, but MET's mechanisms remain unclear. Objective: The study intended to identify the specific molecular mechanism that MET combined with MPA uses against EC progression. Design: The research team performed a controlled animal study. Setting: The study took place at Xuzhou Medical University in Xuzhou, China. Animals: The animals were16 female non-obese diabetic-severe combined immunodeficient (NOD-SCID) nude mice, about 12 to 16 g in weight. Interventions: The research team divided randomly, the mice into four groups and induced EC in all groups, four in each group: (1) The control group which received received normal saline, (2) the MPA group, which received 100 mg/kg of MPA; (3) the MET group, which received metformin at the rate of 200 mg/kg, each gavage volume was 0.1ml; (4) the MET+MPA group, which received 100 mg/kg of MPA and 200 mg/kg of MET. Outcome measures: The research team: (1) used a CCK-8 kit, an EdU assay, and a flow-cytometry assay to measure cancer-cell proliferation, count, and viability; determine the cell cycle; and measure apoptosis; (2) performed a Western blot analysis to determine the expression of the PR, CD133, pAkt, totalAkt, p-mTOR, and totalTOR antibodies; and (3) determined the size and volume of tumors in vivo and used immunohistochemical staining to determine expression of the Ki67 protein. Results: The MET+MPA group had a significantly lower number of cancer cells than the MET or MDA groups (both P < .001). That group also had significantly more stagnated cancer cells in the G0/G1 phase and significantly fewer cancer cells in the S phase or G2/M phase control, MET, or MPA groups (all P < .01). The MET+MPA group's PCNA and Ki-67 protein expression was significantly lower than that of the MET and MPA group. The EDU assay yielded similar results. Additionally, the MET+MPA group had significantly higher PR expression than that of to MET or MPA group (both P < .001). The MET and MPA groups' expression of CD133, p-Akt, and p-mTOR were significantly lower than those of the control group, while the MET+MPA group's levels were significantly lower than those of the MET and MPA groups. In-vivo experiments revealed that the MET and MPA groups did show decreased tumor size and volume. The MET+MPA group had tumor weights that were significantly lower and tumor volumes were significantly smaller than those of the MET and MPA groups (all P < .001). Immunohistochemical analysis revealed that the MET+MPA group's levels of the Ki-67 antigen were significantly lower than those of the MET and MPA groups. Conclusions: MET inhibited the proliferation of EC cells by increasing MPA-sensitivity, which was dependent on the inhibition of the CD133 expression and the Akt/mTOR pathway. In addition, if MET acts as an effective progestin sensitizer, it certainly offers promising therapeutic prospects for patients with early-stage EC or overgrown endometrium who have fertility requirements.

Long non­coding RNA BLACAT2/miR­378a­3p/YY1 feedback loop promotes the proliferation, migration and invasion of uterine corpus endometrial carcinoma.

Uterine corpus endometrial carcinoma (UCEC) is a common gynecological malignancy with high rates of mortality and morbidity. The expression of long non­coding RNA bladder cancer­associated transcript 2 (BLACAT2) has been previously found to be aberrantly upregulated in UCEC. However, the regulatory consequences of this in UCEC progression remain poorly understood. In the present study, human UCEC cell lines AN3CA and HEC­1­A were infected with lentiviruses to overexpress BLACAT2 (Lv­BLACAT2) or knock down BLACAT2 using short hairpin RNA (Lv­shBLACAT2). BLACAT2 overexpression was found to promote the G1/S transition of cell cycle progression and UCEC cell proliferation. In addition, BLACAT2 overexpression was observed to facilitate UCEC cell migration and invasion. By contrast, BLACAT2 knockdown resulted in inhibitory effects in UCEC cell physiology. BLACAT2 overexpression also contributed to the activation of the MEK/ERK pathway. Subsequently, BLACAT2 was demonstrated to bind to microRNA (miR)­378a­3p according to dual­luciferase assays, where it appeared to function as a sponge of miR­378a­3p in 293T cells. miR­378a­3p overexpression was found to suppress UCEC cell proliferation, invasion, and ERK activation. Lentivirus­mediated knockdown of its target, the transcription factor Yin Yang­1 (YY1), was observed to reverse the oncogenic effects of BLACAT2 overexpression. Furthermore, YY1 was found to bind to the promoter of BLACAT2, suggesting that YY1 can regulate BLACAT2 expression. To conclude, results from the present study suggest that BLACAT2, miR­378a­3p and YY1 can form a feedback loop instead of an unidirectional axis, which can in turn regulate UCEC tumorigenesis through the MEK/ERK pathway. The present study furthered the understanding of UCEC tumorigenesis and may provide novel therapeutic targets for UCEC treatment.

Molecular profile-based recommendations for postoperative adjuvant therapy in early endometrial cancer with high-intermediate or intermediate risk: a Chinese randomized phase III trial (PROBEAT).

BACKGROUND: The use of molecular categorisation is shifting paradigm towards the use of molecular information to refine risk stratification in endometrial cancer (EC). To date, evidence to support molecular-guided therapies is limited to retrospective studies and secondary molecular analyses of patients receiving standard treatment. The PROBEAT study is the first randomized phase III trial to evaluate tailored adjuvant treatment based on WHO-endorsed molecular classification in Chinese EC patients. It is expected to provide a clinical decision-making tool for adjuvant treatment of patients with high-intermediate risk (HIR) or intermediate risk (IR) EC to better optimise and personalise patient care and increase relapse-free survival. METHODS: The PROBEAT trial is a prospective, multicentre study led by Women's Hospital of Zhejiang University Gynaecologic Oncology Group. Recruitment started on January 24, 2022, and 590 patients with HIR or IR endometrioid EC are expected to be recruited from 13 clinical centres in China. All tumor tissues will be classified into four molecular subtypes (POLEmut, MMRd, p53abn, or NSMP) based on WHO-endorsed molecular classification. Patients will be randomly assigned at a 2:1 ratio to either experimental arm and will receive molecular profile-based adjuvant treatment (observation in the POLEmut subgroup, vaginal brachytherapy in the MMRd or NSMP subgroup, or chemoradiotherapy in the p53abn subgroup) or to standard arm and will receive preferred adjuvant radiotherapy as recommended by the recent National Comprehensive Cancer Network guidelines version 1 (2022). The primary outcome is 3-year rates of recurrence. Secondary outcomes are relapse-free survival, overall survival, adverse events and health-related cancer-specific quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05179447.

Sentinel lymph node mapping in endometrial cancer: A comparison of main national and international guidelines.

OBJECTIVES: To compare national and international guidelines regarding sentinel lymph node (SLN) mapping in endometrial cancer. METHODS: A descriptive comparative study of the National Comprehensive Cancer Network (NCCN), the Society of Gynecologic Oncology (SGO), the European Society of Gynecological Oncology (ESGO), the British Gynecological Cancer Society (BGCS), and the Japan Society of Gynecologic Oncology (JSGO) guidelines. RESULTS: There is a broad consensus that SLN mapping is an appropriate alternative to pelvic lymphadenectomy for uterine-confined endometrioid endometrial cancer (five of five guidelines). It is broadly accepted that a full lymphadenectomy should be performed in case of failed SLN mapping (four of five guidelines), and that mapping with the fluorescent dye indocyanine green is superior to other methods (four of five guidelines). It is agreed that the cervix is the preferable site for dye injection (four of five guidelines), and pathology ultrastaging is advocated by most guidelines (three of five guidelines). Regarding high-risk patients (i.e., high-grade histology and non-endometroid carcinomas), some guidelines accept (three of five), but others currently do not advocate (one of five guidelines), SLN mapping as a sole method for lymph node evaluation. There is no consensus regarding para-aortic lymph node evaluation in pelvic SLN-positive patients. CONCLUSION: Guidelines for SLN mapping are comparable with regards to surgical technique, ultrastaging, and management in case of failed mapping. Nevertheless, some variations exist regarding the management of high-grade histology and positive pelvic lymph nodes.

Uterus didelphys complicated with endometrial carcinoma: A case report of uterus didelphys with endometrial carcinoma.

RATIONALE: The incidence of uterine malformations is low (4%-7%). Currently, the National Comprehensive Cancer Network clinical practice guidelines in oncology recommend minimally invasive surgery for early endometrial cancer. Minimally invasive surgery for the treatment of uterine didelphys with endometrial cancer is rare due to the large size of the uterus. To date, only 2 such patients have been reported to have undergone laparoscopy. Whether such patients can be treated with minimally invasive surgery needs to be further explored. PATIENT CONCERNS: A 40-year-old woman with uterine didelphys was hospitalized for menorrhagia in the past 2 months. DIAGNOSIS: Endometrial adenocarcinoma was found in both the uterus and cervix using fractional dilation and curettage. INTERVENTIONS: The patient underwent laparoscopic surgery. Postoperative adjuvant radiotherapy and chemotherapy were administered. OUTCOMES: There was no sign of recurrence during routine follow-up. LESSONS: The use of a uterine manipulator to lift either side of the uterus could help to expose the narrow ipsilateral para-uterine field. It is difficult to remove the uterus entirely through the vagina, making it necessary to select appropriate cases wherein screening is performed to check if the vagina is loose, and the uterus is of appropriate size. Minimally invasive surgery may be feasible for suitable patients.

The role of TNFTNFα/p53 pathway in endometrial cancer mouse model administered with apple seed extract.

Recent studies regarding the ability to relieve and reconstitute the endometrium in the treatment of endometrial cancer are limited. In this study, to analyze endometrial cancer, early endometrial cancer was induced by injecting a colon cancer cell line into the lower abdominal cavity of mice. Subsequently, the apple seed extract was administered orally to determine if the extract could affect the endometrial cancer. Administration of apple seed extract to the endometrial cancer model confirmed that the apoptosis suppressing mechanism was downregulated concurrently with the reduced expression of NF-κB. In contrast, the TNFα/p53 pathway upregulated the apoptosis. A number of clinical inferences could be derived from the results of this study; moreover, the administration of apple seed extract in a cancer metastasis model has not been reported in earlier toxicity induction studies. The results of this study indicated that the apple seed extract partially enhances apoptosis and the immune function related factors in endometrial cells. By improving tissue remodeling, the extract may help to restore the endometrium.

Histone Deacetylase Inhibitors: A Promising Therapeutic Alternative for Endometrial Carcinoma.

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Epigenetic alterations are implicated in endometrial cancer development and progression. Histone deacetylase inhibitors are a novel class of anticancer drugs that increase the level of histone acetylation in many cell types, thereby inducing cell cycle arrest, differentiation, and apoptotic cell death. This review is aimed at determining the role of histone acetylation and examining the therapeutic potential of histone deacetylase inhibitors in endometrial cancer. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms histone deacetylase, histone deacetylase inhibitor, and endometrial cancer were employed, and we were able to identify fifty-two studies focused on endometrial carcinoma and published between 2001 and 2021. Deregulation of histone acetylation is involved in the tumorigenesis of both endometrial carcinoma histological types and accounts for high-grade, aggressive carcinomas with worse prognosis and decreased overall survival. Histone deacetylase inhibitors inhibit tumor growth, enhance the transcription of silenced physiologic genes, and induce cell cycle arrest and apoptosis in endometrial carcinoma cells both in vitro and in vivo. The combination of histone deacetylase inhibitors with traditional chemotherapeutic agents shows synergistic cytotoxic effects in endometrial carcinoma cells. Histone acetylation plays an important role in endometrial carcinoma development and progression. Histone deacetylase inhibitors show potent antitumor effects in various endometrial cancer cell lines as well as tumor xenograft models. Additional clinical trials are however needed to verify the clinical utility and safety of these promising therapeutic agents in the treatment of patients with endometrial cancer.

Mechanism of Tetrandrine Against Endometrial Cancer Based on Network Pharmacology.

BACKGROUND: Endometrial cancer (EC) is one of the most common gynaecological malignancies, and its incidence has been rising over the past decade. Tetrandrine, a bisbenzylisoquinoline alkaloid, has been isolated from a vine used in traditional Chinese medicine, Stephania tetrandra. However, the key mechanism of tetrandrine in EC is still unclear. PURPOSE: This research was designed to predict the molecular mechanisms of tetrandrine against EC based on network pharmacology and to further verify these predictions by in vitro experiments. METHODS: The potential therapeutic targets of tetrandrine against EC were predicted by using public databases. Afterwards, the protein-protein interaction (PPI) network of the common targets was constructed, and the key gene targets were obtained. Biological function and pathway enrichment analyses were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Furthermore, molecular docking and in vitro experiments were carried out to verify the predictions. The cell counting kit­8 (CCK­8) assay, Hoechst 33258 staining, flow cytometry analysis, qRT-PCR, Western blot analysis and an immunofluorescence assay were performed. RESULTS: Our findings identified 111 potential therapeutic targets of tetrandrine against EC. We obtained 7 key gene targets from the PPI network analysis. Furthermore, GO enrichment analysis indicated that these targets were mainly associated with metabolic processes, responses to stimulus, and biological regulation. The KEGG pathway analysis showed that the common targets were mainly distributed in the PI3K/Akt signalling pathway. A potential interaction of tetrandrine with Akt1 was revealed by molecular docking. In addition, in vitro experiments showed that tetrandrine significantly inhibited cell proliferation and induced apoptosis in Ishikawa and HEC-1-B cells in dose- and time-dependent manners. The results also revealed that tetrandrine can downregulate the expression of Bcl-2 and upregulate the expression of Bax at the mRNA level. The mRNA levels of Akt were not significantly different in the various tetrandrine (0, 10 and 20µM) groups. However, Western blot analysis demonstrated that the protein expression ratios of p-Akt/Akt decreased at the protein level. The results were further confirmed by immunofluorescence assays. CONCLUSION: Based on bioinformatic analysis and experimental verification, our findings demonstrated that tetrandrine exerted tumour-suppressive effects on EC by regulating the PI3K/Akt signalling pathway.

The Promotional Effect of Hollow MnO2 with Brucea Javanica Oil Emulsion (BJOE) on Endometrial Cancer Apoptosis.

Endometrial cancer (EC) is a common gynecological malignancy worldwide whose therapy mainly depends on chemotherapy. In past years, an increasing number of studies indicate that hollow MnO2 could serve as a nanoplatform in the drug delivery system. The Brucea javanica oil emulsion (BJOE) has been illustrated to play a vital role in cancers. However, knowledge about the combined effect of H-MnO2-PEG/BJOE in endometrial cancer remains ambiguous up to now. In the present work, we prepared a drug-delivery vector H-MnO2-PEG by chemical synthesis and found that H-MnO2-PEG significantly inhibited cell proliferation in endometrial cancer cells. Moreover, the combination of H-MnO2-PEG/BJOE could repress cell proliferation more efficiently and promote cell apoptosis. Mechanistically, we found that BJOE exerted its role as a promoter of endometrial apoptosis by regulating relative protein expressions. In general, the present study demonstrates that H-MnO2-PEG functions as a critical vector in the tumor microenvironment of endometrial cancer and the significant effect of H-MnO2-PEG/BJOE on cancer cells, suggesting a new paradigm for the treatment of endometrial cancer.

Trends in peritoneal cytology evaluation at hysterectomy for endometrial cancer in the United States.

OBJECTIVE: The collection of a peritoneal cytologic sample at the time of surgery for endometrial cancer has traditionally been an important part of surgical staging. In 2009, the International Federation of Gynecology and Obstetrics revised the cancer staging schema for endometrial cancer and removed peritoneal cytology from the staging criteria. The current National Comprehensive Cancer Network guidelines and the International Federation of Gynecology and Obstetrics organization, however, recommend evaluation of peritoneal cytology at the time of hysterectomy. This study examined population-based trends, characteristics, and outcomes of peritoneal cytologic sampling for endometrial cancer surgery following the 2009 staging revision in the United States. METHODS: This is a retrospective observational study querying the Surveillance, Epidemiology, and End Results Program to examine women with stage I-III endometrial cancer who underwent hysterectomy from 2010 to 2017. Trends, characteristics, and survival associated with peritoneal cytologic evaluation at the time of hysterectomy were assessed in multivariable analysis and with propensity score weighting. RESULTS: Among 62,809 women who underwent hysterectomy, 43,873 (69.9%) had peritoneal cytologic evaluation at surgery and 18,936 (30.1%) did not. Utilization of peritoneal cytologic evaluation decreased from 75.5% to 64.9% during the study period (P < 0.001). In multivariable analysis, more recent year of surgery was independently associated with a decreased likelihood of performance of peritoneal cytology (adjusted-odds ratio of peritoneal cytology evaluation in 2017 versus 2010 0.56, 95% confidence interval [CI] 0.52-0.60). Peritoneal cytologic evaluation at the time of hysterectomy was associated with improved all-cause mortality (hazard ratio in the whole cohort 0.94, 95%CI 0.89-0.99; and hazard ratio in endometrioid histology 0.90, 95%CI 0.84-0.97). CONCLUSION: Performance of peritoneal cytologic sampling has gradually decreased following the 2009 staging revision in the United States. Our study suggests that peritoneal cytology evaluation at hysterectomy may be associated with improved survival in certain tumor groups.

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients.

OBJECTIVE: Lynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV. METHODS: 341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13-12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified. RESULTS: Twenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total). CONCLUSIONS: Since double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.

Methylsulfonylmethane sensitizes endometrial cancer cells to doxorubicin.

BACKGROUND: Methylsulfonylmethane (MSM) is a commonly used diet supplement believed to decrease the inflammation in joints and fastens recovery in osteoarthritis, gastric mucosal injury, or obesity-related disorders. It was also suggested that MSM might play a beneficial role in cancer treatment. PURPOSE: So far, the MSM might have a potentially beneficial effect in endometrial cancer (EC) treatment. STUDY DESIGN: This study evaluated the effect and usefulness of MSM in combinatory therapy with known drug doxorubicin (DOX). METHODS: The effect of combinational treatment of MSM and DOX on the induction of apoptosis was evaluated in EC cell lines (ISHIKAWA, MFE-296, MFE-280). RESULTS: We observed that MSM itself induces apoptosis in EC cell lines, and pre-treatment with MSM for 24 h increases the sensitivity of EC cells to DOX-induced apoptosis and DNA damage and that effect might be regulated by p42/44 (Erk1/2) MAPK and Akt (protein kinase B). CONCLUSION: These results for the first time show that MSM might act as a sensitizer of EC cells to known drugs, for which EC cells quickly acquire resistance. Graphical abstract.

Controversies in Sentinel Lymph Node Biopsy for Gynecologic Malignancies.

OBJECTIVE: Sentinel lymph node (SLN) biopsy represents an evolution in the advancement of minimally invasive surgical techniques for gynecologic cancers. Prospective and retrospective studies have consistently shown its accuracy in the detection of lymph node metastases for endometrial and cervical cancers. However, consistent with any emerging surgical technique in the early phases of adoption, new questions have arisen regarding its application and impact. This paper served as a scoping review to identify the key controversies that have arisen in the field of SLN biopsy for endometrial and cervical cancers. DATA SOURCES: Several key controversies were identified, and PubMed, the Cochrane Library (cochranelibrary.com) advanced search function, and the National Comprehensive Cancer Network guidelines were searched for supporting evidence. These included search terms such as "the accuracy of SLN biopsy for high grade endometrial cancer or cervical cancers >2-cm," "cost effectiveness of SLN biopsy for gynecologic cancers," "clinical significance of low volume metastases in endometrial cancer," "morbidity of SLN biopsy for endometrial and cervical cancer," and "impact on cancer survival of SLN biopsy for endometrial and cervical cancer." METHODS OF STUDY SELECTION: Studies were selected for review if they included significant numbers of patients, were level I evidence, or were prospective trials. Where this level of evidence failed to exist, seminal observational series that were published in high-quality journals were included. TABULATION, INTEGRATION, AND RESULTS: Similar studies were listed and subcategorized and cross-compared, excluding those that included repeated analyses of the same patient populations. The relevant clinical trials or observational studies were clustered and reviewed for each chosen controversy. Adequate evidence supports the accuracy of SLN biopsy in the staging of high-grade endometrial cancer and cervical cancer, and it seems to be a cost-effective strategy for invasive endometrial cancer. Conclusive evidence was lacking with respect to the oncologic outcomes related to SLN biopsy, the impact on patient morbidity, and whether clinicians should treat isolated tumor cells in SLNs with adjuvant therapy. CONCLUSION: SLN biopsy is an accepted staging strategy for cervical and endometrial cancer surgery; however, controversies remain in how it can be applied with the most safety and efficacy. These ultimately need to be resolved with further clinical trials and observations of larger series of patients.

Role of SMARCA4 (BRG1) and SMARCB1 (INI1) in Dedifferentiated Endometrial Carcinoma With Paradoxical Aberrant Expression of MMR in the Well-Differentiated Component: A Case Report and Review of the Literature.

INTRODUCTION: Dedifferentiated endometrial carcinoma is an uncommon highly aggressive uterine tumor. It comprises 2 components: a well-differentiated, low-grade epithelial carcinoma and an undifferentiated carcinoma. The undifferentiated carcinoma frequently exhibits rhabdoid cytologic features. Many of these tumors are characterized by an aberrant switch/sucrose non-fermenting (SWI/SNF) complex. They may also exhibit aberrant expression of mismatch repair (MMR) proteins. Together, these play an important role in the pathogenesis and aggressive nature of the tumor. MATERIAL AND METHODS: We present a case of dedifferentiated endometrial carcinoma in a 63-year-old female showing loss of expression of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4/BRG1), and aberrant expression of MMR proteins. We also review the literature starting from the earliest recognition of this entity and the various studies done to explain its molecular pathogenesis and prognostic importance. RESULTS AND CONCLUSIONS: Recognition of SWI/SNF complex-deficient dedifferentiated endometrial carcinoma is important as these tumors do not respond to platinum-based chemotherapy, and consideration of alternative therapies is often necessary. We also want to emphasize that though most of the studies have found MMR deficiency in the undifferentiated carcinoma component, it may be seen only in the low-grade, well-differentiated component, as observed in this case.

Methoxyeugenol regulates the p53/p21 pathway and suppresses human endometrial cancer cell proliferation.

ETHNOPHARMACOLOGICAL RELEVANCE: Plant-derived compounds are a reservoir of natural chemicals and can act as drug precursors or prototypes and pharmacological probes. Methoxyeugenol is a natural compound found in plant extracts, such as nutmeg (Myristica fragrans), and it presents anthelmintic, antimicrobial, anti-inflammatory activities. Recently, interest in the anticancer activity of plant extracts is increasing and the therapeutic activity of methoxyeugenol against cancer has not yet been explored. AIM OF THE STUDY: The present study aimed to evaluate the cancer-suppressive role and the molecular signaling pathways of methoxyeugenol in human endometrial cancer (Ishikawa) cell line. MATERIALS AND METHODS: Proliferation, viability, and cell toxicity were assessed by direct counting, MTT assay, and LDH enzyme release assay, respectively. Antiproliferative effect were evaluated by nuclear morphological changes along with the cellular mechanisms of apoptosis and senescence by flow cytometry. The underlying molecular and cellular mechanisms were investigated by RT-qPCR, reactive oxygen species (ROS) levels, mitochondrial dysfunction, and proliferative capacity. RESULTS AND CONCLUSIONS: Methoxyeugenol treatment significantly inhibited the proliferation and viability of Ishikawa cells. Probably triggered by the higher ROS levels and mitochondrial dysfunction, the gene expression of p53 and p21 increased and the gene expression of CDK4/6 decreased in response to the methoxyeugenol treatment. The rise in nuclear size and acidic vesicular organelles corroborate with the initial senescence-inducing signals in Ishikawa cells treated with methoxyeugenol. The antiproliferative effect was not related to cytotoxicity and proved to effectively reduce the proliferative capacity of endometrial cancer cells even after treatment withdrawal. These results demonstrated that methoxyeugenol has a promising anticancer effect against endometrial cancer by rising ROS levels, triggering mitochondrial instability, and modulating cell signaling pathways leading to an inhibition of cell proliferation.

Protective Effects of Epigallocatechin Gallate (EGCG) on Endometrial, Breast, and Ovarian Cancers.

Green tea and its major bioactive component, (-)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly antiproliferation, antimetastasis, and apoptosis induction. Many studies have widely investigated the anticancer and synergistic effects of EGCG due to the side effects of conventional cytotoxic agents. This review summarizes recent knowledge of underlying mechanisms of EGCG on protective roles for endometrial, breast, and ovarian cancers based on both in vitro and in vivo animal studies. EGCG has the ability to regulate many pathways, including the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), inhibition of nuclear factor-κB (NF-κB), and protection against epithelial-mesenchymal transition (EMT). EGCG has also been found to interact with DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which affect epigenetic modifications. Finally, the action of EGCG may exert a suppressive effect on gynecological cancers and have beneficial effects on auxiliary therapies for known drugs. Thus, future clinical intervention studies with EGCG will be necessary to more and clear evidence for the benefit to these cancers.

Combination of sentinel lymph node mapping and uterine frozen section examination to reduce side-specific lymphadenectomy rate in endometrial cancer: a Turkish Gynecologic Oncology Group study (TRSGO-SLN-002).

OBJECTIVE: This study aimed to find out whether side-specific pelvic lymphadenectomy can be omitted without compromising diagnostic efficacy according to "reflex frozen section" analysis of the uterus in case of sentinel lymph node (SLN) mapping failure. METHODS: Patients who underwent surgery for endometrial cancer with an SLN algorithm were stratified as low-risk or high-risk according to the uterine features on the final pathology reports. Two models for low-risk patients were defined to omit side-specific pelvic lymphadenectomy: strategy A included patients with endometrioid histology, grade 1-2, and <50% myometrial invasion irrespective of the tumor diameter; strategy B included all factors of strategy A with the addition of tumor diameter ≤2 cm. Theoretical side-specific pelvic lymphadenectomy rates were calculated for the two strategies, assuming side-specific pelvic lymphadenectomy was omitted if low-risk features were present on reflex uterine frozen examination, and compared with the standard National Comprehensive Cancer Network (NCCN) SLN algorithm. RESULTS: 372 endometrial cancer patients were analyzed. 230 patients (61.8%) had endometrioid grade 1 or 2 tumors with <50% myometrial invasion (strategy A), and in 123 (53.4%) of these patients the tumor diameter was ≤2 cm (strategy B); 8 (3.5%) of the 230 cases had lymphatic metastasis. None of them were detected by side-specific pelvic lymphadenectomy and metastases were limited to SLNs in 7 patients. At least one pelvic side was not mapped in 107 (28.8%) cases in the entire cohort, and all of these cases would require a side-specific pelvic lymphadenectomy based on the NCCN SLN algorithm. This rate could have been significantly decreased to 11.8% and 19.4% by applying reflex frozen section examination of the uterus using strategy A and strategy B, respectively. CONCLUSION: Reflex frozen section examination of the uterus can be a feasible option to decide whether side-specific pelvic lymphadenectomy is necessary for all the patients who failed to map with an SLN algorithm. If low-risk factors are found on frozen section examination, side-specific pelvic lymphadenectomy can be omitted without compromising diagnostic efficacy for lymphatic spread.