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Endometrial (Uterus) Cancer

Endometrial cancer is a malignancy of the endometrium (the inner lining of the uterus, or womb) and is the most common gynaecological cancer, and accounts for 13% of all cancers in women. It is most frequently in women over age 50. A know risk factor is prior oestrogen-replacement therapy (however, oestrogen replacement also lowers risk of heart disease). Symptoms can include pelvic pain, and blood-soaked discharge - though these are also common symptoms related to menopausal changes.

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Information for Health Professionals / Researchers (10 links)

  • PubMed search for publications about Endometrial Cancer - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Endometrial Cancer
    MeSH term: Endometrial Neoplasms
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Haines K, Huang GS
Precision Therapy for Aggressive Endometrial Cancer by Reactivation of Protein Phosphatase 2A.
Cancer Res. 2019; 79(16):4009-4010 [PubMed] Related Publications
Critically important to reducing uterine cancer mortality is the development of more effective therapy for aggressive endometrial cancers, including uterine serous cancer and uterine carcinosarcoma, which together account for over half of deaths due to endometrial cancer. About one-third of these aggressive endometrial cancers harbor mutations in the protein phosphatase 2A (PP2A) Aα scaffold subunit encoded by

Husby A, Wohlfahrt J, Melbye M
Pregnancy duration and endometrial cancer risk: nationwide cohort study.
BMJ. 2019; 366:l4693 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To explore the association between pregnancy duration and risk of endometrial cancer.
DESIGN: Nationwide register based cohort study.
SETTING: Denmark.
PARTICIPANTS: All Danish women born from 1935 to 2002.
MAIN OUTCOME MEASURES: Relative risk (incidence rate ratio) of endometrial cancer by pregnancy number, type, and duration, estimated using log-linear Poisson regression.
RESULTS: Among 2 311 332 Danish women with 3 947 650 pregnancies, 6743 women developed endometrial cancer during 57 347 622 person years of follow-up. After adjustment for age, period, and socioeconomic factors, a first pregnancy was associated with a noticeably reduced risk of endometrial cancer, whether it ended in induced abortion (adjusted relative risk 0.53 (95% confidence interval 0.45 to 0.64) or childbirth (0.66, 0.61 to 0.72). Each subsequent pregnancy was associated with an additional reduction in risk, whether it ended in induced abortion (0.81, 0.77 to 0.86) or childbirth (0.86, 0.84 to 0.89). Duration of pregnancy, age at pregnancy, spontaneous abortions, obesity, maternal birth cohort, fecundity, and socioeconomic factors did not modify the results.
CONCLUSIONS: The risk of endometrial cancer is reduced regardless of whether a pregnancy ends shortly after conception or at 40 weeks of gestation. This reduction in risk could be explained by a biological process occurring within the first weeks of pregnancy, as pregnancies ending in induced abortions were associated with similar reductions in risk as pregnancies ending in childbirth.

Miyahara D, Yotsumoto F, Hirakawa T, et al.
Clinical Features of Recurrence in Patients Without Residual Tumour in Endometrial Cancer.
Anticancer Res. 2019; 39(8):4581-4588 [PubMed] Related Publications
BACKGROUND/AIM: Initial treatment of endometrial cancer with surgery and platinum and taxane-based chemotherapy is often successful, but it remains unclear as to whether certain types of the disease relapse. The aim of this study was to identify the clinical features of recurrence in patients without residual tumour in endometrial cancer.
PATIENTS AND METHODS: Clinical features, histological type, and time to recurrence were analyzed in 640 endometrial cancer patients without residual tumours.
RESULTS: Of 640 patients, 517 were type I and 123 were type II. For type I, early recurrent (ER) disease and late recurrent (LR) disease were noted in 80 and 8 patients, respectively, and 97.5% of ER occurred within 2 years. After recurrence, 76.2% of ER and 50% of LR patients died. In type II, ER and LR were noted in 41 and 1 patients, respectively, and 97.6% of ER occurred within 2 years, of which 75.6% died after recurrence. One LR case died of disease.
CONCLUSION: Most patients recurred within 2 years irrespective of clinical stage or type.

An HJ, Song DH
Displacement of Vitamin D Receptor Is Related to Lower Histological Grade of Endometrioid Carcinoma.
Anticancer Res. 2019; 39(8):4143-4147 [PubMed] Related Publications
BACKGROUND/AIM: Vitamin D analogs have a protective effect on carcinogenesis in humans. Since vitamin D receptor (VDR) is detected in many histotypes of cancer, this study evaluated the role of VDR expression in endometrioid carcinoma.
MATERIALS AND METHODS: Tumor samples were collected from 60 patients who had undergone surgery, and the pattern of VDR expression assessed in tissue microarray (TMA) blocks of tumor samples. When VDR expression in the cytoplasm was higher than that in the nucleus, this was noted as 'displacement'. Using statistical analysis, the relationship between VDR expression and clinicopathological factors was evaluated.
RESULTS: Immunohistochemical staining of nuclear VDR was as follows: Negative: 32 (53.3%); mild: 13 (21.7%); moderate: 14 (23.3%); strong: 1 (1.7%). For cytoplasmic VDR expression: Negative: 2 (3.3%); mild: 19 (31.7%); moderate: 31 (51.7%); strong: 7 (11.7%). VDR displacement was found in 42 (70%) cores. VDR displacement was significantly positively correlated with endometrioid carcinoma having lower histological grade (1, p=0.03).
CONCLUSION: Displacement of VDR was significantly correlated with lower histological grade. Clinicians might be able to predict prognosis and decide therapies related to vitamin D analogs using this remarkable biomarker for endometrial carcinoma.

Xi Z, Jing L, Le-Ni K, et al.
Evaluation of PTEN and CD4+FOXP3+ T cell expressions as diagnostic and predictive factors in endometrial cancer: A case control study.
Medicine (Baltimore). 2019; 98(30):e16345 [PubMed] Related Publications
To evaluate the potential role of Pten and CD4FOXP3 T cells in prognosis from endometrial cancer.Tissue samples and clinical data were collected from 200 patients with endometrial cancer and 100 control patients with benign uterine diseases. The expressions of Pten and CD4FOXP3 T cells were quantified by immunohistochemistry and immunofluorescence. After surgery, all patients were followed up for an average of 56.3 months. Surgical effects were evaluated based on the patients' symptoms and signs. A two-sided P value < .05 was considered significant.Pten diminished and CD4FOXP3 T cells significantly accumulated with the progression of endometial cancer, in comparison to the controls. Moreover, Pten expression was negatively correlated with the count of CD4FOXP3 T cells. Pten and CD4FOXP3 T cells were correlated with clinical characteristics, including tumor stage, differentiation and associated with patients' disease-free survival.Limited data were available between the expressions of Pten and CD4FOXP3 T cells in patients with endometrial cancer. Our study findings suggested that the expressions of Pten and CD4FOXP3 T cells might become possible biomarkers for the diagnosis and prediction in endometrial cancer.

Hu R, Jiang J, Song G, et al.
Mixed large and small cell neuroendocrine carcinoma of the endometrium with serous carcinoma: A case report and literature review.
Medicine (Baltimore). 2019; 98(29):e16433 [PubMed] Related Publications
RATIONALE: Endometrial neuroendocrine carcinoma is a rare histological subtype of endometrial cancer, divided into low-grade neuroendocrine carcinoma (carcinoid) and high-grade neuroendocrine carcinoma (small cell and large cell neuroendocrine carcinoma). It is characterized by high invasiveness and poor prognosis. L/SCNEC is an extremely rare pathological type of endometrial carcinoma, and the number of reports on this condition is few globally.
PATIENT CONCERNS: A 54-year-old Chinese female presented with vaginal bleeding.
DIAGNOSES: Outpatient hysteroscopy and endometrial biopsy were performed, and the pathological examination revealed that cervix was invaded by endometrial malignancy. The patient underwent a laparoscopic radical hysterectomy was diagnosed with the mixed large and small cell neuroendocrine carcinoma (L/SCNEC) of the endometrium combined with serous carcinoma III C2 (FIGO2009).
INTERVENTIONS: Chemotherapy-radiotherapy-chemotherapy "sandwich" treatment was performed as postoperative therapy.
OUTCOMES: After three chemotherapy circles, the patient showed no evidence of further disease progression.
LESSONS: L/SCNEC is a rare and invasive disease. Once diagnosed, comprehensive treatments including surgery, radiotherapy, and chemotherapy can prolong the survival of patients and improve the prognosis.

Namazov A, Volchok V, Liboff A, et al.
Sentinel Nodes Detection with Near-infrared Imaging in Gynecological Cancer Patients: Ushering in an Era of Precision Medicine.
Isr Med Assoc J. 2019; 21(6):390-393 [PubMed] Related Publications
BACKGROUND: The sentinel lymph node (SLN) biopsy procedure is a well-known method for identifying solid tumors such as breast cancer, vulvar cancer, and melanoma. In endometrial and cervical cancer, SLN has recently gained acceptance.
OBJECTIVES: To evaluate the detection rate of SLN with an indocyanine green and near-infrared fluorescent imaging (ICG/NIR) integrated laparoscopic system in clinically uterine-confined endometrial or cervical cancer.
METHODS: Patients with clinically early-stage endometrial or cervical cancer were included in this retrospective study. ICG was injected into the uterine cervix and an ICG/NIR integrated laparoscopic system was used during the surgeries. The National Comprehensive Cancer Network (NCCN) protocol was followed. SLN and/or suspicious lymph nodes were resected. Side-specific lymphadenectomy was performed when mapping was unsuccessful. Systematic lymphadenectomy was completed in patients with high-grade histology or deep myometrial invasion. Enhanced pathology using ultra-staging and immunohistochemistry were performed in all cases.
RESULTS: We analyzed 46 eligible patients: 39 endometrial and 7 cervical cancers. Of these, 44 had at least one SLN (93.6%). In 41 patients (89%) we detected bilateral SLN, in 3 (7%) only unilateral, and in 2 (4%) none were detected. Seven patients presented with lymph node metastasis. All were detected by NCCN/SLN protocol. Of these cases, two were detected with only pathological ultra-staging.
CONCLUSIONS: SLN mapping in endometrial and cervical cancer can easily be performed with a high detection rate by integrating ICG/NIR into a conventional laparoscopic system. Precision medicine in patients evaluated by SLN biopsy changes the way patients with endometrial or cervical cancer are managed.

Raffone A, Travaglino A, Saccone G, et al.
Diagnostic and prognostic value of ARID1A in endometrial hyperplasia: a novel marker of occult cancer.
APMIS. 2019; 127(9):597-606 [PubMed] Related Publications
AT-rich interaction domain 1A (ARID1A) is a tumor suppressor protein involved in endometrioid carcinogenesis. The expression of ARID1A may be lost in the premalignant phase. Our aim was to assess ARID1A as: (i) diagnostic marker to differentiate premalignant endometrial hyperplasia (EH) form benign EH; (ii) prognostic marker for the risk of occult cancer in premalignant EH. A systematic review and meta-analysis were performed by searching electronic databases from their inception to October 2018 for all studies assessing ARID1A in EH by immunohistochemistry. Sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), and diagnostic odds ratio (DOR) were calculated for both diagnostic and prognostic accuracy. LR+ > 5, LR- < 0.2, DOR > 25 defined good accuracy; LR+ > 10, LR- < 0.1, DOR > 100 defined excellent accuracy. Seven studies with 467 EH were included. As diagnostic marker, ARID1A showed sensitivity = 0.12, specificity = 0.99, LR+ = 4.34, LR- = 0.85, DOR = 5.12. As prognostic marker for occult cancer, ARID1A showed sensitivity = 0.33, specificity = 0.99, LR+ = 20.70, LR- = 0.49, DOR = 49.59. In conclusion, ARID1A loss is highly specific, but little accurate as diagnostic marker of premalignant EH. Instead, ARID1A loss in premalignant EH is an accurate and almost perfectly specific prognostic marker for coexistent cancer.

Backes FJ, Cohen D, Salani R, et al.
Prospective clinical trial of robotic sentinel lymph node assessment with isosulfane blue (ISB) and indocyanine green (ICG) in endometrial cancer and the impact of ultrastaging (NCT01818739).
Gynecol Oncol. 2019; 153(3):496-499 [PubMed] Related Publications
OBJECTIVES: To assess the performance sentinel lymph node (SLN) biopsy and effect of ultrastaging in clinically early stage endometrial cancer.
METHODS: Patients with endometrial cancer prospectively enrolled after informed consent was obtained. The cervix was injected superficially with 1 mL of ISB and 1 mL of ICG (diluted 1:25) at 3 and 9 o'clock each. SLN biopsy was followed by complete pelvic lymphadenectomy (aortic lymphadenectomy at the discretion of the surgeon). Lymph nodes (LNs) were analyzed by standard sectioning with H&E; ultrastaging of SLN was done retrospectively and blinded to treating physicians.
RESULTS: 204 patients received dye injections. In 184 (90.2%) patients at least one SLN was identified. Of all patients, 138 (68%) had bilateral mapping. In the patients with successful mapping of a hemipelvis, ICG detected SLNs in 83% and ISB in 64% of cases (p < 0.0001). Median BMI (kg/m
CONCLUSIONS: SLN assessment in endometrial cancer is feasible and safe with high NPV (99%). ICG was more effective in detecting SLN compared to ISB. Although ultrastaging detected additional positive LNs, treatment based on standard sectioning appears reasonable but further research is needed.

Cebecioglu R, Yildirim M, Akagunduz D, et al.
Synergistic effects of quercetin and selenium on oxidative stress in endometrial adenocarcinoma cells.
Bratisl Lek Listy. 2019; 120(6):449-455 [PubMed] Related Publications
OBJECTIVE: The effects of quercetin and selenium on oxidative stress in endometrial adenocarcinoma cells are unclear. In this study, the effects of quercetin and selenium on oxidative stress caused by both hydrogen peroxide and UV radiation in endometrial adenocarcinoma cells were examined.
METHODS: The viability of endometrial adenocarcinoma cells cultured in vitro and treated with different concentrations of quercetin and sodium selenite was measured using the MTT assay. Malondialdehyde (MDA) levels were investigated, and expression levels of BAD and p53 genes were analysed using real‑time quantitative polymerase chain reaction. Acridine orange/ethidium bromide staining technique was applied to detect apoptosis. Mass attenuation coefficient of each quercetin and sodium selenite combinations was evaluated using Monte Carlo simulation.
RESULTS: The combination of quercetin and sodium selenite enhanced cell viability, and reduced MDA levels. The expression levels of BAD and p53 genes decreased by combined treatment with quercetin and selenium while showing synergistic effects in terms of gene expression. Fluorescent microscopic examination showed a decrease in apoptotic cells in endometrial adenocarcinoma cells treated with the combination of quercetin and selenium.
CONCLUSIONS: For the first time, selenium and quercetin have synergistic cytoprotective and radioprotective effects on oxidative stress caused by hydrogen peroxide in endometrial adenocarcinoma cells for the first time (Tab. 1, Fig. 7, Ref. 39).

Penolazzi L, Bonaccorsi G, Gafà R, et al.
SLUG/HIF1-α/miR-221 regulatory circuit in endometrial cancer.
Gene. 2019; 711:143938 [PubMed] Related Publications
BACKGROUND AND PURPOSE: The pathogenesis of endometrial cancer (EC) involves many regulatory pathways including transcriptional regulatory networks supported by transcription factors and microRNAs only in part known. The aim of this retrospective study was to explore the possible correlation in the EC microenvironment between master regulators of complex phenomena such as steroid responsiveness through estrogen receptor alpha (ERα) and progesterone receptor (PR), epithelial-to-mesenchymal transition (supported by SLUG transcription factor), hypoxia (with hypoxia inducible factor-1 alpha, HIF-1α), and obesity that has been recognized as a EC risk factor.
METHODS: Formalin-Fixed Paraffin-Embedded (FFPE) blocks from University of Ferrara Pathology Archive were used and allocated into 2 groups according to their immunohistochemical positivity to ERα and PR, distinguishing the samples with a more benign prognosis (ERα
RESULTS: We showed a comparable percentage of HIF1-α and SLUG positive samples in the ERα
CONCLUSIONS: A molecular circuit of mutual regulation between ERα, PR, HIF1-α, SLUG and miR-221 is feasible in the EC and was firstly suggested by our research. In this interplay miR-221 seems to be in a nodal point of the regulatory system that is particularly strengthened by the metabolic changes in obesity.

Marek R, Dzvinčuk P, Hambálek J, et al.
Robotic paraaortic lymphadenectomy in oncogynecology. Double side docking of daVinci S system increases the success rates of high paraaortic lymph node dissection in endometrial cancer.
Ceska Gynekol. 2019; 84(1):4-17 [PubMed] Related Publications
OBJECTIVE: To present an overview of minimally invasive approaches to suprapelvic lymphadenectomy and compare two different methods of staging robotic transperitoneal paraaortic lymphadenectomies in patients with early stages of endometrial cancer.
DESIGN: Retrospective study and literature review.
SETTING: Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, Palacky University Olomouc, University Hospital Olomouc.
METHODS: In this retrospective study we enrolled 70 patients with early stages of endometrial cancer undergoing staging robotic surgery at the Department of Obstetrics and Gynecology, University Hospital Olomouc from January 2016 to March 2018. Primary systematic pelvic and paraaortic lymphadenectomy was suggested in all patients. In 39 out of 70 patients single docking was used for robotic staging surgery, whereas in 28 patients the procedure was done using double side docking approach. Number of patients with total and infra-renal suprapelvic lymphadenectomy, number of para-aortic lymphonodes retrieved and the rate of lymphadenectomy complications were compared.
RESULTS: Robotic surgery was performed in 67 (96%) out of 70 patients. In three cases (0,4%) laparoscopy was converted to laparotomy. Single side docking was used in 39 cases (58%), whereas in 28 patients (42%) double side docking was used. Paraaortic lymhadenectomy was performed in 45 cases (67%). In 16 patients (24%) the upper limit of the left renal wein was reached. Upper limit of paraaortic lymphadenectomy was above inferior mesenteric artery but did not reach left renal vein in 19 cases (28%). Inferior mesenteric represented upper limit of paraaortic lymphadenectomy in 10 patients (15%). Number of paraaortic lymphonodes retrived (4,9 ± 3,3 vs 3,7 ± 4,9, p = 0,028) as well as number of paraaortic lymphadenectomies with upper limit at the left renal vein (p < 0,0001) was higher in double side docking cases. Complication rates were low in both groups and the differences were not significant.
CONCLUSION: Number of lymphonodes retrieved as well as the number of paraaortic lymphadenectomy cases with upper limit at the left renal vein was higher in double side docking group. Operating time, complication and conversion rates were low without differences between both groups.

Wasniewski T, Kiezun J, Krazinski BE, et al.
WNT5A gene and protein expression in endometrial cancer.
Folia Histochem Cytobiol. 2019; 57(2):84-93 [PubMed] Related Publications
INTRODUCTION: WNT5A (Wnt family member 5A) belongs to the WNT family of secreted signaling glycoproteins that play essential role in developmental, physiological and pathological processes. WNT5A was shown to take part in carcinogenesis process playing both oncogenic and suppressor functions in various types of human malignancies. This study aimed to assess the expression of the WNT5A gene at the mRNA and protein levels in the specimens derived from endometrial cancer (EC) or unchanged control endometrium. The associations between the WNT5A expression levels and clinicopathological characteristics and survival of EC patients were evaluated.
MATERIALS AND METHODS: Total RNA was isolated in order to assess the relative amounts of WNT5A mRNA by quantitative polymerase chain reaction (QPCR) in samples of unchanged endometrial control (n = 8) and tumor samples of EC patients (n = 28). Immunohistochemistry (IHC) was used to determine the presence of WNT5A protein in the sections of formalin-fixed, paraffin-embedded tissue specimens derived from unchanged endome-trial controls (n = 6) and EC tumors (n = 19). Significance of differences in WNT5A expression levels between the studied groups of EC patients and correlations between the WNT5A and demographic data, pathological features, hematological parameters and overall survival of the patients were evaluated by statistical analysis.
RESULTS: The level of WNT5A mRNA was decreased in EC in comparison to unchanged endometrium. WNT5A expression was associated with primary tumor invasion status exhibiting reduced level of transcripts in EC that involved organs beyond the uterus when compared to the uterus-confined cancers. WNT5A immunoreactivity was visualized in the cytoplasm and nuclei of EC cells as well as in the luminal and glandular epithelial cells of unchanged endometrium. WNT5A mRNA expression levels correlated negatively with cytoplasmic, and positively with nuclear immunoreactivity of the WNT5A protein in the EC cells. In addition, the relationships between blood leucocyte count (in particular granulocytes and lymphocytes) of patients with EC and their WNT5A mRNA and protein expression levels were established. A positive correlation between the nuclear immunoexpression of WNT5A protein in the cancer cells in cell nuclei and mean platelet volume in blood was also found.
CONCLUSIONS: The results of the first study of WNT5A expression at the transcript and protein levels indicate that it could be considered as a potential marker of molecular changes that take place during EC development.

Matei D, Filiaci V, Randall ME, et al.
Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer.
N Engl J Med. 2019; 380(24):2317-2326 [PubMed] Related Publications
BACKGROUND: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence.
METHODS: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life.
RESULTS: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.
CONCLUSIONS: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).

Zhang YY, Zhang F, Zhang YS, et al.
Mechanism of Juglone-Induced Cell Cycle Arrest and Apoptosis in Ishikawa Human Endometrial Cancer Cells.
J Agric Food Chem. 2019; 67(26):7378-7389 [PubMed] Related Publications
The molecular mechanism of Juglone-induced cell cycle arrest and apoptosis in human endometrial cancer cells was investigated. Juglone was purified from the green husk of Carya cathayensis Sarg and identified by HPLC, LC-MS/MS, and NMR. At an IC

Liu T, Sumida D, Wada T, et al.
A diagnostic challenge of seromucinous borderline tumor: A case report.
Medicine (Baltimore). 2019; 98(22):e15707 [PubMed] Related Publications
INTRODUCTION: Magnetic resonance (MR) relaxometry provides a noninvasive predictive tool to discriminate between benign ovarian endometrioma (OE) and endometriosis-associated ovarian cancer (EAOC). Transverse relaxation rate R2 value was determined using a single-voxel, multi-echo MR sequence (HISTO) by a 3T-MR system. R2 with cutoff value of 12.1 s was established to discriminate between benign and malignant tumors.
PATIENT CONCERNS: We present a case of a 39-year-old woman who was initially thought to be malignant transformation of endometriosis by diagnostic MR imaging of the vascularized solid components.
DIAGNOSIS: A R2 value of 42.62 s on MR relaxometry demonstrated that this case is non-malignant.
INTERVENTIONS: To confirm the diagnose, left salpingo-oophorectomy by laparoscopic surgery was performed.
OUTCOMES: Histopathological results revealed seromucinous borderline tumor (SMBT). Our experience suggests that preoperative MR relaxometry may be useful for discriminating "borderline (SMBT)" from "malignancy (EAOC)." Furthermore, immunohistochemical studies of this case demonstrated ovarian SMBT cells were positive for estrogen receptor, progesterone receptor, and hepatocyte nuclear factor-1beta. A similar expression pattern was also observed in patients with benign OE.
LESSONS: In many respects, SMBT characteristics differ from those of EAOC but resemble those of benign OE. MR relaxometry unveils a new clinical approach as an adjunctive modality for discriminating SMBT from EAOC.

Taylor SE, O'Connor CM, Wang Z, et al.
The Highly Recurrent PP2A Aα-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis.
Cancer Res. 2019; 79(16):4242-4257 [PubMed] Related Publications
Somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene

Robertson MC, Lyons EJ, Song J, et al.
Change in physical activity and quality of life in endometrial cancer survivors receiving a physical activity intervention.
Health Qual Life Outcomes. 2019; 17(1):91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Endometrial cancer survivors are at an increased risk of poor quality of life outcomes. Physical activity is positively associated with general quality of life in this population, however, little is known about how changes in physical activity may be associated with changes in specific aspects of quality of life. The aim of this secondary data analysis was to explore the relationships between change in physical activity and change in physical, mental, social, and other aspects of quality of life in endometrial cancer survivors receiving a physical activity intervention.
METHODS: Endometrial cancer survivors (N = 100) participated in a telephone-based physical activity intervention for six months. At baseline and post-intervention we measured physical activity via accelerometry and ecological momentary assessment, and quality of life via the Short Form Health Survey (SF-36), the Quality of Life of Adult Cancer Survivors instrument, the Brief Symptom Inventory, the Pittsburgh Sleep Quality Index, and the Perceived Stress Scale. We conducted structural equation modeling path analyses to investigate how physical activity post-intervention was associated with the quality of life measures' subscales post-intervention, adjusting for baseline levels and potentially confounding covariates.
RESULTS: Increasing physical activity was positively associated with improvements in general health (p = .044), role limitation due to physical health (p = .005), pain (p = .041), and somatic distress (p = .023). There was no evidence to indicate that change in physical activity was associated with change in other aspects of quality of life.
CONCLUSIONS: Endometrial cancer survivors are at higher risk for suffering from challenges to physical quality of life, and findings from this study suggest that increasing physical activity may alleviate some of these problems. Further research is needed to determine whether other aspects of quality of life are linked to change in physical activity.
TRIAL REGISTRATION: Trial registration number: NCT00501761 Name of registry: clinicaltrials.gov Date of registration: July 16, 2007. Date of enrollment: June 16, 2005.

Mileshkin L, Edmondson R, O'Connell RL, et al.
Phase 2 study of anastrozole in recurrent estrogen (ER)/progesterone (PR) positive endometrial cancer: The PARAGON trial - ANZGOG 0903.
Gynecol Oncol. 2019; 154(1):29-37 [PubMed] Related Publications
BACKGROUND: The clinical benefit rate with aromatase inhibitors and the impact of treatment on quality of life (QOL) in endometrial cancer is unclear. We report the results of a phase 2 trial of anastrozole in endometrial cancer.
METHODS: Investigator initiated single-arm, open label trial of anastrozole, 1 mg/d in patients with ER and/or PR positive hormonal therapy naive metastatic endometrial cancer. Patients were treated until progressive disease (PD) or unacceptable toxicity. The primary end-point was clinical benefit (response + stable disease) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life (QOL) and toxicity.
RESULTS: Clinical benefit rate in 82 evaluable patients at 3 months was 44% (95% CI: 34-55%) with a best response by RECIST of partial response in 6 pts. (7%; 95% CI: 3-15%). The median PFS was 3.2 months (95% CI: 2.8-5.4). Median duration of clinical benefit was 5.6 months (95% CI: 3.0-13.7). Treatment was well tolerated. Patients who had clinical benefit at 3 months reported clinically significant improvements in several QOL domains compared to those with PD; this was evident by 2 months including improvements in: emotional functioning (39 vs 6%: p = 0.002), cognitive functioning (45 vs 19%: p = 0.021), fatigue (47 vs 19%: p = 0.015) and global health status (42 vs 9%: p = 0.003).
CONCLUSION: Although the objective response rate to anastrozole was relatively low, clinical benefit was observed in 44% of patients with ER/PR positive metastatic endometrial cancer and associated with an improvement in QOL.

Multinu F, Casarin J, Cappuccio S, et al.
Ultrastaging of negative pelvic lymph nodes to decrease the true prevalence of isolated paraaortic dissemination in endometrial cancer.
Gynecol Oncol. 2019; 154(1):60-64 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: This study aimed to determine the prevalence of occult pelvic lymph node metastasis in patients with endometrial cancer (EC) with isolated paraaortic dissemination who underwent pelvic and paraaortic lymphadenectomy.
METHODS: From 2004 to 2008, patients undergoing surgery for EC at our institution were prospectively treated according to a validated surgical algorithm relying on intraoperative frozen section. For the current study, we re-reviewed pathologic slides obtained at the time of diagnosis and performed ultrastaging of all negative pelvic lymph nodes to assess the prevalence of occult pelvic lymph node metastasis.
RESULTS: Of 466 patients at risk for lymphatic dissemination, 394 (84.5%) underwent both pelvic and paraaortic lymphadenectomy. Of them, 10 (2.5%) had isolated paraaortic metastasis. Pathologic review of hematoxylin-eosin-stained slides identified 1 patient with micrometastasis in 1 of 18 pelvic lymph nodes removed. Ultrastaging of 296 pelvic lymph nodes removed from the 9 other patients (median [range], 32 [20-50] nodes per patient) identified 2 additional cases (1 with micrometastasis and 1 with isolated tumor cells), for a total of 3/10 patients (30%) having occult pelvic dissemination.
CONCLUSIONS: Ultrastaging and pathologic review of negative pelvic lymph nodes of patients with presumed isolated paraaortic metastasis can identify occult pelvic dissemination and reduce the prevalence of true isolated paraaortic disease. In the era of the sentinel lymph node (SLN) algorithm for EC staging, which incorporates ultrastaging of the SLNs removed, these findings demonstrate that use of the SLN algorithm can further mitigate the concern of missing cases of isolated paraaortic dissemination.

Gao Y, Qian H, Tang X, et al.
Superparamagnetic iron oxide nanoparticle-mediated expression of
Int J Nanomedicine. 2019; 14:2719-2731 [PubMed] Free Access to Full Article Related Publications

Chapman BV, Swanick CW, Ning MS, et al.
Adjuvant combined-modality therapy for stage IIIC endometrioid and non-endometrioid endometrial cancer.
Gynecol Oncol. 2019; 154(1):22-28 [PubMed] Related Publications
OBJECTIVE: To identify the optimal adjuvant treatment regimen for patients with endometrioid and non-endometrioid node-positive endometrial cancer.
METHODS: We retrospectively identified 249 women with FIGO 2009 stage IIIC endometrial cancer at our institution who underwent surgical staging from 1985 to 2015 followed by external beam radiotherapy (RT), chemotherapy (CT), or a combination of CT + RT. Survival rates were calculated using the Kaplan-Meier method.
RESULTS: The 5-year disease-specific survival (DSS) rate for all patients was 65%. Adjuvant CT + RT conferred higher rates of 5-year DSS as compared to CT alone in patients with grade 3 endometrioid and non-endometrioid tumors (61% vs. 27%, P = 0.04 and 67% vs. 38%, P = 0.02, respectively). Among patients with non-endometrioid tumors, treatment with concurrent chemoradiotherapy followed by additional sequential chemotherapy had higher 5-year DSS rates than with concurrent chemoradiotherapy alone (74% vs. 50%, P = 0.02). The 3-year pelvic recurrence rate was 5% with RT ± CT and 35% with CT alone (P < 0.001) for all patients. No paraaortic nodal failures were observed following extended-field RT, but 14% of patients who received pelvic-only RT or CT alone developed recurrences in the paraaortic nodes (P < 0.001).
CONCLUSIONS: Combined-modality therapy including adjuvant external beam pelvic radiotherapy yields excellent outcomes for patients with all subtypes of node-positive endometrial cancer. The most pronounced DSS advantage from adjuvant chemoradiotherapy was evident in women with non-endometrioid endometrial cancer.

Yamada S, Tsuyoshi H, Tsujikawa T, et al.
Predictive Value of 16α-[18F]-Fluoro-17β-Estradiol PET as a Biomarker of Progestin Therapy Resistance in Patients With Atypical Endometrial Hyperplasia and Low-Grade Endometrial Cancer.
Clin Nucl Med. 2019; 44(7):574-575 [PubMed] Related Publications
For early-stage endometrial cancer patients who wish to preserve fertility, progestin treatment is effective. However, repeated endometrial curettage to evaluate treatment response may cause infertility. The clinical courses of 3 patients who were treated with fertility-sparing progestin treatment and underwent serial F-FES PET before and after treatment are presented. The SUVmean decreased greatly in patients with pathologically complete response (44.2%, 46.2%), whereas there was only a small change (22.5%) in the patient with pathologically stable disease who finally underwent hysterectomy. F-FES PET can be a noninvasive method to evaluate response to fertility-sparing progestin treatment.

Gil KM, Pugh SL, Klopp AH, et al.
Expanded validation of the EPIC bowel and urinary domains for use in women with gynecologic cancer undergoing postoperative radiotherapy.
Gynecol Oncol. 2019; 154(1):183-188 [PubMed] Related Publications
OBJECTIVE: Women with endometrial or cervical cancer at risk for recurrence receive postoperative radiation therapy (RT). A patient reported outcomes (PRO) instrument to assess bowel and urinary toxicities is the Expanded Prostate Cancer Index Composite (EPIC), which has been validated in men with prostate cancer. As this instrument specifically measures bowel toxicity and the degree to which this is a problem, it was used in NRG Oncology/RTOG 1203 to compare intensity modulated RT (IMRT) to standard RT. This paper reports on the expanded validation of EPIC for use in women receiving pelvic RT.
METHODS: In addition to the EPIC bowel domain, urinary toxicity (EPIC urinary domain), patient reported bowel toxicities (PRO-CTCAE) and quality of life (Functional Assessment of Cancer Therapy (FACT)) were completed before, during and after treatment. Sensitivity, reliability and concurrent validity were assessed.
RESULTS: Mean bowel and urinary scores among 278 women enrolled were significantly worse during treatment and differed between groups. Acceptable to good reliability for bowel and urinary domain scores were obtained at all time points with the exception of one at baseline. Correlations between function and bother scores within the bowel and urinary domains were consistently stronger than those across domains. Correlations between bowel domain scores and PRO-CTCAE during treatment were stronger than those with the FACT.
CONCLUSION: Correlations within and among the instruments indicate EPIC bowel and urinary domains are measuring conceptually discrete components of health. These EPIC domains are valid, reliable and sensitive instruments to measure PRO among women undergoing pelvic radiation.

Grandi G, Perrone AM, Chiossi G, et al.
Increasing BMI is associated with both endometrioid and serous histotypes among endometrial rather than ovarian cancers: a case-to-case study.
Gynecol Oncol. 2019; 154(1):163-168 [PubMed] Related Publications
AIM: Although obesity has been associated with endometrioid (type I) and, to a lesser extent, with serous (type II) endometrial cancer (EC), the association with the same histotypes of ovarian cancer (OC) remains unclear. Therefore, we intended to compare the role of BMI in carcinogenesis of endometrioid and the serous malignancies, at both ovarian and endometrial level.
METHODS: A retrospective case-to-case study was performed in the University Hospital of Bologna (Italy), through the review of primary EC matched with the corresponding OC cases in the same period (1988-2017).
RESULTS: We included 1052 women diagnosed with EC (n = 897 endometrioid, n = 52 serous) and 955 women affected by OC (n = 132 endometrioid, n = 627 serous). EC patients had higher median BMI than women diagnosed with OC (27.3 [23.4-31.9] vs 24.9 [21.7-27.5], p < 0.01). After controlling for confounding, 1 unit increase in BMI was associated with a 5% higher odds of endometrial as opposed to ovarian cancer (OR for ovarian as opposed to endometrial cancer 0.95; 95% CI 0.91-0.98, p = 0.004).
CONCLUSIONS: Increasing BMI is associated with endometrial rather than ovarian cancer, among both serous and endometrioid histotypes.

Reijnen C, Küsters-Vandevelde HVN, Prinsen CF, et al.
Mismatch repair deficiency as a predictive marker for response to adjuvant radiotherapy in endometrial cancer.
Gynecol Oncol. 2019; 154(1):124-130 [PubMed] Related Publications
BACKGROUND: Mismatch repair (MMR) deficiency is found in 20 to 40% of endometrial cancers (ECs) and was recently identified as a discerning feature of one of the four prognostic subgroups identified by The Cancer Genome Atlas. There is accumulating evidence that MMR proteins are involved in the DNA repair processes following radiotherapy. We investigated the predictive value of MMR status for response to adjuvant radiotherapy in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC).
METHODS: A retrospective multicenter cohort study was performed to compare patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant radiotherapy. Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt. Multivariable Cox regression analysis explored associations between adjuvant treatment and outcome.
RESULTS: A total of 128 patients were analyzed, including 57 patients (43.0%) with MMR-deficient EECs. Baseline characteristics were comparable, except a higher proportion of MMR-deficient EECs were stage II (36.8% vs. 15.5%, p = 0.006). Eighty-two patients (64.1%) received adjuvant radiotherapy (external beam [n = 55], vaginal brachytherapy [n = 27]). In multivariable analysis, adjuvant radiotherapy was associated with improved disease-specific survival in patients with MMR-deficient EECs (hazard ratio 0.19, 95%-CI 0.05-0.77), but not in patients with MMR-proficient EECs (hazard ratio 0.92, 95%-CI 0.37-2.31).
CONCLUSION: Adjuvant radiotherapy improved survival in patients with MMR-deficient EECs. MMR status could be used as a predictive biomarker to select patients that benefit most from adjuvant radiotherapy.

Maru Y, Tanaka N, Itami M, Hippo Y
Efficient use of patient-derived organoids as a preclinical model for gynecologic tumors.
Gynecol Oncol. 2019; 154(1):189-198 [PubMed] Related Publications
OBJECTIVE: The relevance of patient-derived cancer cells has been recently increasing, particularly in terms of drug discovery and precision medicine. Whereas Matrigel-based organoid culture is a promising technique that enables infinite proliferation of cells from many types of organs in a physiological condition, its validity in gynecologic tumors remains to be established. To address this issue, we aimed at developing an efficient method for organoid culture of both ovarian and endometrial tumors.
METHODS: We conducted 3D culture of 21 gynecologic tumors following our original and modified protocol for Matrigel bilayer organoid culture. We investigated whether propagated organoids retained various features of the original tumors by histopathological examination and targeted genome sequencing.
RESULTS: We customized the protocol we previously optimized for murine normal and cancer tissues, so as to circumvent the digestion-resistant nature inherent to gynecologic tumors. Indeed, this modified protocol improved the success rate from 45 to 90%, for robust propagation of organoids from tumors with various stages and subtypes. Finally, 14 patient-derived organoids were established. The recovered organoids were enriched for cancer cells that retained many aspects of the original tumors, including histological features, mutation profiles, and intra-tumoral heterogeneity. A subset of the expanded organoids could develop xenografts in immunodeficient mice, potentially paving the way to drug screening in vivo. Drug response assay in vitro for paclitaxel and cisplatin was feasible using organoid-derived spheroids.
CONCLUSIONS: We showed that patient-derived organoids closely resembled the original gynecologic tumors, and thereby would serve as a promising resource for preclinical studies.

Zhang L, Wan Y, Jiang Y, et al.
Overexpression of BP1, an isoform of Homeobox Gene DLX4, promotes cell proliferation, migration and predicts poor prognosis in endometrial cancer.
Gene. 2019; 707:216-223 [PubMed] Related Publications
The expression of homeobox gene DLX4 has been verified in some tumors, but not in endometrial cancer. We found that expression of DLX7, a splicing isoform of DLX4, did not show any significant difference in expression between endometrial cancer and endometrium. However, BP1, another splicing isoform of DLX4, was highly expressed in endometrial cancer, and its expression was positively correlated with patient prognosis, cancer pathological grade, tumor invasion and metastasis. Lentiviral-mediated expression of BP1 in HEC-1-B cells accelerated the cell cycle progression from G0/G1 into S phase, and promoted cell proliferation and migration both in vitro and in vivo. Real-time PCR and western blotting showed that the expression levels of p15, p21 and E-cadherin significantly decreased, and levels of cyclinD1 and MMP-2 increased in endometrial cancer cells. In conclusion, our results demonstrate that high expression of BP1 is associated with poor prognosis in patients with endometrial cancer and promotes cell proliferation and migration.

Giannone G, Tuninetti V, Ghisoni E, et al.
Role of Cyclin-Dependent Kinase Inhibitors in Endometrial Cancer.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine positivity of most endometrioid ECs, Endocrine Therapy (ET) is a reasonable and widely accepted option. Better knowledge of molecular mechanisms involved in cancer highlighted the deregulated activity of Cyclin-Dependent Kinases (CDKs) in the cell cycle as a hallmark of carcinogenesis supporting the development of a new class of drugs: CDK inhibitors (CDKis). The aim of this review is to give an overview on CDKis preclinical, early clinical activity and future development in EC. Use of CDKis has a strong preclinical rationale but we have poor clinical data. Similar to breast cancer, most ongoing trials are investigating synergistic associations between CDKis and ET. These trials will probably help in defining the best clinical setting of CDKis in ECs, which are the best partner drugs, and how to manage CDKis toxicities with a focus on potential biomarkers of response.

Liu Q, Wu Q, Yu M, et al.
Emerging relationships between papillary proliferation of the endometrium and endometrial carcinoma: evidence from an immunohistochemical and molecular analysis.
Virchows Arch. 2019; 475(2):201-209 [PubMed] Related Publications
Papillary proliferation of the endometrium (PPE) is an uncommon lesion that frequently shows mucinous metaplasia. PPE occasionally has concurrent or preceding endometrial hyperplasia and carcinomas, but there is little molecular evidence to support the relationships between PPEs and endometrial neoplasia. In this study, we analyzed the clinicopathological and immunohistochemical features in 30 PPEs (22 simple PPEs and 8 complex papillary hyperplasia (CPH)). Hotspot mutations of KRAS, PI3KCA, AKT1, PTEN (exons 3, 5, and 7), and ARID1A (exons 1 and 14) were detected by pyrosequencing or bidirectional Sanger sequencing. We found that endometrial hyperplasia and carcinoma were more common in CPHs (4/6, 66.7%) than in simple PPEs (4/21, 19.0%) (p < 0.05). Compared with the adjacent normal endometrium, PPEs frequently showed loss of PAX2 (56.7%) and PTEN (10%) expression, diffuse p16 expression (36.7%), decreased PR expression (84.3%), and lower Ki67 labeling index (median 1%, range 1-15%). Simple PPEs and CPHs had similar immunohistochemical features (p > 0.05). KRAS mutations were identified in 14 PPEs and 1 concurrent endometrial carcinoma. The prevalence of KRAS mutations was not statistically different between simple PPEs (10/21, 45.5%) and CPHs (4/8, 50%) (p > 0.05), but was higher in PPEs displaying mucinous metaplasia (12/24, 50%) than in those without (2/6, 33.3%) (p < 0.05). One simple PPE with a KRAS mutation had an AKT1 mutation. No PPEs demonstrated mutations in PI3KCA, PTEN, and ARID1A. In conclusion, both simple PPE and CPH share some common molecular alterations with endometrial neoplasia, in which, KRAS mutations might be a driver.

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