Development and validation of a circulating tumor DNA-based optimization-prediction model for short-term postoperative recurrence of endometrial cancer

BACKGROUND Endometrial cancer(EC)is a common gynecological malignancy that typically requires prompt surgical intervention;however,the advantage of surgical management is limited by the high postoperative recurrence rates and adverse outcomes.Previous studies have highlighted the prognostic potential of circulating tumor DNA(ctDNA)monitoring for minimal residual disease in patients with EC.AIM To develop and validate an optimized ctDNA-based model for predicting shortterm postoperative EC recurrence.METHODS We retrospectively analyzed 294 EC patients treated surgically from 2015-2019 to devise a short-term recurrence prediction model,which was validated on 143 EC patients operated between 2020 and 2021.Prognostic factors were identified using univariate Cox,Lasso,and multivariate Cox regressions.A nomogram was created to predict the 1,1.5,and 2-year recurrence-free survival(RFS).Model performance was assessed via receiver operating characteristic(ROC),calibration,and decision curve analyses(DCA),leading to a recurrence risk stratification system.RESULTS Based on the regression analysis and the nomogram created,patients with postoperative ctDNA-negativity,postoperative carcinoembryonic antigen 125(CA125)levels of<19 U/mL,and grade G1 tumors had improved RFS after surgery.The nomogram’s efficacy for recurrence prediction was confirmed through ROC analysis,calibration curves,and DCA methods,highlighting its high accuracy and clinical utility.Furthermore,using the nomogram,the patients were successfully classified into three risk subgroups.CONCLUSION The nomogram accurately predicted RFS after EC surgery at 1,1.5,and 2 years.This model will help clinicians personalize treatments,stratify risks,and enhance clinical outcomes for patients with EC.

Expression and function of long non-coding RNA DLX6-AS1 in endometrial cancer

Background:LncRNA DLX6-AS1 has been uncovered to exert effects on various cancers.Nevertheless,the impacts of DLX6-AS1 on endometrial cancer(EC)development remained obscure.The study explored the influence of DLX6-AS1 on EC progression via the microRNA(miR)-374a-3p/zinc-finger protein(ZFX)axis.Methods:EC cell lines were collected and DLX6-AS1,miR-374a-3p,and ZFX levels in EC cell lines were detected.The EC cells were transfected with DLX6-AS1,miR-374a-3p,and ZFX constructs to examine the biological functions of EC cells.The xenograft model was established for detecting tumor growth.Rescue experiments were conducted to verify the interaction of DLX6-AS1,miR-374a-3p,and ZFX in EC cells.Results:DLX6-AS1 and ZFX levels were elevated,while miR-374a-3p exhibited a reduced level in EC cells.Silencing DLX6-AS1 and elevated miR-374a-3p expressions repressed the biological activities of EC cells.Reduced DLX6-AS1 repressed tumor development.MiR-374a-3p silencing reversed the impacts of DLX6-AS1 silencing,while ZFX overexpression abrogated the impacts of miR-374a-3p elevation on EC cell growth.Mechanically,DLX6-AS1 was found to bind to miR-374a-3p,and miR-374a-3p targeted ZFX.Conclusion:DLX6-AS1 depletion restricts the malignant phenotype of EC cells.The study might provide novel therapeutic biomarkers for EC treatment.

Superiority of indocyanine green-enhanced near-infrared fluorescence-guided imaging for laparoscopic lymph node dissection in patients with early-stage endometrial cancer: A retrospective cohort study

Objective:Laparoscopic pelvic lymph node dissection(LPND),which is an effective therapy for endometrial cancer,is challenging because of the complexity of the procedure and the occurrence of postoperative complications.This study aimed to explore whether indocyanine green(ICG)-enhanced nearinfrared(NIR)fluorescence-guided LPND is superior to LPND in the context of early-stage endometrial carcinoma.Methods:In this retrospective study,we included the medical records of 190 patients with early-stage endometrioid adenocarcinoma who underwent LPND at the Department of Obstetrics and Gynecology,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine between January 2019 and January 2021.Depending on whether ICG-enhanced NIR fluorescence guidance was used,the patients were assigned to the ICG group or non-ICG group.Patients were followed-up for one year after surgery.Data on demographic characteristics,pathological results,operative outcomes,and complications were collected and analyzed.Results:The baseline characteristics were comparable between the ICG group and non-ICG group,including age,BMI,pregnancy history,and preoperative hemoglobin.For surgical outcomes,the patients in ICG group had significantly lower intraoperative blood loss(50 mL vs.120 mL,p<0.001),less postoperative pelvic drainage time(4.14±1.44 d vs.5.70±1.89 d,p¼0.001),shorter duration of hospital stay(5.26±1.41 d vs.7.37±1.85 d,p¼0.003),higher number of positive pelvic lymph nodes(PLNs)(1 vs.0,p¼0.003),and more PLN-positive cases(16.0%vs.3.6%,p¼0.003)than the patients in non-ICG group.However,no significant differences were noted in blood transfusion requirement,operative time,hemoglobin level decreases,number of PLNs harvested,or the presence of lymphocysts between the two groups.Conclusion:Our study showed that ICG-enhanced NIR fluorescence-guided operation may improve the accuracy and safety of LPND.

Efficacy and prognosis of adjuvant treatment of endometrial cancer with medroxyprogesterone acetate COX regression analysis

BACKGROUND Endometrial cancer is one of the most commonly diagnosed gynecological cancers worldwide,and early-stage high-risk endometrial cancer has a poor prognosis.Adjuvant treatments after surgery,such as chemotherapy and radiotherapy,have been widely used in clinical practice to improve patient survival.Medroxyprogesterone acetate is a synthetic progestogen that has been reported to have potential anticancer effects in endometrial cancer.However,its efficacy,safety,and longterm prognostic benefits as an adjuvant treatment for endometrial cancer remain controversial.Therefore,this study aimed to observe the efficacy and prognostic impact of adjuvant medroxyprogesterone acetate treatment in patients with earlystage high-risk endometrial cancer and evaluate its safety.AIM To observe the efficacy and prognosis of adjuvant treatment of endometrial cancer with medroxyprogesterone acetate and to evaluate its safety.METHODS We collected the clinical data of 200 patients with early-stage high-risk endometrial cancer who were admitted to the Department of Obstetrics and Gynecology of our hospital from January 2018 to December 2022.The control group(100 patients)underwent conventional surgical treatment,and the study group(100 patients)was administered adjuvant medroxyprogesterone acetate tablets on top of the control group.The Kaplan-Meier curve analysis and log-rank test were performed to determine the possible factors influencing the 5-year cumulative survival rate in the patients.The Cox regression analysis was performed to identify the factors influencing the survival prognosis of endometrial cancer.RESULTS According to the Cox regression analysis,age[hazard ratio(HR)=4.636,95%confidence interval(95%CI):1.411-15.237],pathological type(HR=6.943,95%CI:2.299-20.977),molecular typing(HR=5.789,95%CI:3.305-10.141),and myometrial infiltration(HR=5.768,95%CI:1.898-17.520)were factors influencing the prognosis of patients with early-stage high-risk endometrial cancer.CONCLUSION Age,pathological type,molecular typing,and myometrial infiltration were all relevant factors affecting the prognosis of early-stage high-risk endometrial cancer.The potential long-term prognostic benefit of adjuvant postoperative radiotherapy in patients with early-stage high-risk endometrial cancer is worthy of clinical consideration.

MiR-200a and miR-200b target PTEN to regulate the endometrial cancer cell growth in vitro

Objective:To study whether miR-200a and miR-200b target PTEN gene expression to regulate the endometrial cancer cell growth in vitro. Methods:Endometrial cancer cells ECC-1 were cultured and transfected with the miR-200a and miR-200b mimics and inhibitors as well as the negative control mimics and inhibitors,and then the cell proliferation activity as well as the expression of PTEN and downstream genes in cells was determined; after transfection of miR-200a and miR-200b mimics as well as PTEN-3'UTR luciferase report gene plasmids,the fluorescence activity of luciferase reporter gene was determined. Results:12 h,24 h and 48 h after transfection,the cell proliferation activity of miR-200a mimics group and miR-200b mimics group were significantly higher than those of NC mimics group while the cell proliferation activity of mi R-200 a inhibitor group and miR-200b inhibitor group were significantly lower than those of NC inhibitor group; 48 h after transfection,PTEN expression in cells and PTEN-3'UTR luciferase reporter gene fluorescence activity of miR-200 a mimics group and miR-200b mimics group were significantly lower than those of NC mimics group while p-PI3K and p-Akt expression were significantly higher than those of NC mimics group; PTEN expression in cells and PTEN-3'UTR luciferase reporter gene fluorescence activity of miR-200 inhibitor group and miR-200b inhibitor group were significantly higher than those of NC inhibitor group while p-PI3K and p-Akt expression were significantly lower than those of NC inhibitor group. Conclusion:miR-200 a and miR-200b can promote the endometrial cancer cell growth in vitro by targeted inhibition of PTEN gene expression.

High-risk endometrial cancer may be benefit from adjuvant radiotherapy plus chemotherapy

Objective： To present patterns of practice and outcomes in the adjuvant treatment of intermediate- and high-risk endometrial cancer. Methods： Retrospective data on 224 women with intermediate-risk and high-risk endometrial cancer from 1999 to 2006 were reviewed. All patients underwent surgical staging. Patterns of adjuvant treatment, consisting of pelvic radiotherapy, chemotherapy, and radiotherapy plus chemotherapy, were assessed. The 3- and 5-year disease-specific survival （DSS） rates were calculated using the Kaplan-Meier method. Results： The difference in 5-year DSS rate was statistically significant between adjuvant group and non-adjuvant group （80.65% vs. 63.80%, P=0.040）. In 110 high-risk patients who underwent adjuvant treatment, both 5-year DSS rate and recurrent rate were significantly different in combined radiotherapy and chemotherapy group compared with radiotherapy alone and chemotherapy alone groups （DSS rate, P=0.049; recurrent rate, P=0.047）. In 83 intermediate-risk women who underwent adjuvant treatment, there was no significant difference in 5-year DSS rate and recurrence rate among the combined radiotherapy and chemotherapy, radiotherapy alone and chemotherapy alone groups （DSS rate, P=0.776; recurrent rate, P=0.937）.

Leptin Activates STAT3 and ERK1/2 Pathways and Induces Endometrial Cancer Cell Proliferation

Obesity is an established risk factor for endometrial cancer.Leptin,a secreted protein of the ob gene by white adipose tissue,plays an important role in the regulation of food intake and energy consumption in the brain and acts as a potential growth stimulator in normal and neoplastic cancer cells.However,a direct role for leptin in endometrial cancer has not been demonstrated.In the present study,the effect of leptin on the proliferation of Ishikawa endometrial cancer cells was investigated as well as the possible mechanism（s） underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors.The expression of leptin receptor（ObRb） in Ishikawa cells was detected by RT-PCR and Western blotting.The cells after serum starvation,were treated by leptin with various concentrations（0,10,50,100,150 ng/mL） for different durations（6,12,24 h）.The effect of leptin treatment on cell proliferation was examined by MTT assay.Meanwhile,inhibitory effect of Janus tyrosine kinase 2（JAK2）/signal transducer and activator of transcription 3（STAT3） inhibitor AG490 or extracellular signal-regulated kinase 1/2（ERK1/2） inhibitor PD98059 on the proliferation of Ishikawa cells induced by leptin was also studied.Ishikawa cells were treated with 100 ng/mL leptin for various periods（0,20,40,60 min）,and the levels of STAT3 phosphorylation and ERK1/2 phosphorylation were examined by Western blotting.The results showed that leptin induced the phosphorylation of STAT3 and the activation of ERK1/2 in a time-and dose-dependent manner in the Ishikawa endometrial cancer cells.Blocking STAT3 phosphorylation with the inhibitor AG490,or blocking ERK1/2 activation by the specific ERK1/2 kinase inhibitor,PD98059,abolished leptin-induced proliferation of Ishikawa cells.In addition,leptin was found to potently induce the invasion of endometrial cancer cells in a Matrigel invasion assay.Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of STAT3（AG490） and ERK1/2 kinase（PD98059）.These results suggested that leptin promotes endometrial cancer growth and invasiveness by activating STAT3 and ERK1/2 signaling pathways and therefore blocking its action at the receptor level can be a rational therapeutic strategy.

Preoperative markers for the prediction of high-risk features in endometrial cancer

BACKGROUND Preoperative evaluations aiming to assess high-risk features in clinical stage 1 endometrial cancer patients are crucial to refer these patients to gynecologic oncologists.Cancer antigen 125(CA125)and human epididymis protein 4(HE4)have been reported in endometrial cancer patients with poor prognostic factors.AIM To evaluate the association between preoperative levels of CA125 and HE4 and high-risk features and establish optimal cut-off values in clinical stage 1 endometrial cancer.METHODS A retrospective study was conducted in clinical stage 1 endometrial cancer patients who underwent primary surgery between January 2013 and December 2018.A total of 128 patients had preoperative serum CA125 and HE4 measurements.High-risk features included grade 3 tumors,large tumor sizes(more than 2 cm),deep myometrial invasion(more than 50%),lymphovascular space invasion(LVSI),cervical involvement,extrauterine involvement and node metastasis.Receiver operating characteristic(ROC)curves were generated to analyze the optimal cut-off values.RESULTS The mean age of the patients was 57.4 years,and 69.5%of them were postmenopausal.Most patients presented with stage I disease(67.2%)and had the endometrioid subtype(97.7%).The median CA125 and HE4 levels in all patients were 22.1 U/mL and 104.7 pmol/L,respectively.CA125 and HE4 levels were significantly elevated in those with large tumor sizes,deep myometrial invasion,LVSI,extrauterine metastasis,and advanced stage,but node metastasis was associated with elevated CA125 only.According to the ROC curve,both serum markers had statistical significance for the prediction of high-risk features only in postmenopausal patients,with an optimal cut-off value of 20 U/mL for CA125[area under the concentration-time curve(AUC)=0.72,P=0.002]and 113 pmol/L for HE4(AUC=0.70,P=0.006).The combination of both serum markers had 80%sensitivity and 64.4%positive predictive value.Significantly worse 5-year disease-free survival was observed in patients with high levels of CA125 and HE4(78.4%and 100%,respectively;P=0.01).CONCLUSION Preoperative CA125 levels greater than 20 U/mL or HE4 levels greater than 113 pmol/L are associated with an increased risk of having high-risk features and present as prognostic factors in clinical stage 1 postmenopausal endometrial cancer patients.This information is helpful for general gynecologists to refer high-risk patients to gynecologic oncologists to perform complete surgical staging.

Red meat intake and the risk of endometrial cancer:Metaanalysis of observational studies

AIM:To evaluate whether red meat intake is related to the risk of endometrial cancer(EC) using meta-analysis.METHODS:We searched Pub Med,EMBASE,and the Cochrane Library up to June 2013,using common keywords related to red meat and EC.Case-control studies and cohort studies comparing the risk of endometrial cancer among categories by the amount of intake were included.Eleven case-control studies and five cohort studies met our criteria.We performed a conventional and a dose-response meta-analysis of case-control studies using the Der Simonian-Laird method for random-effects.For cohort studies we performed a conventional meta-analysis.Publication bias was evaluated using Egger's test.RESULTS:In the meta-analysis of 11 case-control studies including 5419 cases and 12654 controls,higher red meat consumption was associated with an increased risk of EC [summary relative risk(SRR) = 1.43,95%CI:1.15-1.79;I2 = 73.3% comparing extreme intake categories).In a dose-response analysis,for red meat intake of 100 g/d,SRR was 1.84(95%CI:1.64-2.05).In contrast,in the meta-analysis of five prospective studies including a total of 2549 cases among 247746 participants,no significant association between red meat intake and EC risk(SRR = 0.97,95%CI:0.85-1.11;I2 = 4.9% comparing extreme intake categories) was observed.CONCLUSION:Our meta-analysis found a significantlinear association between red meat intake and EC risk based on case-control studies but this was not confirmed in prospective studies.

Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer:Clinical and pathological perspectives

Endometrial cancer is the most common gynecological cancer in developed countries,and its incidence has increased.The majority of patients with endometrial cancer have an early disease and favorable prognosis;however,a significant proportion of endometrial cancer,which mainly comprises high-grade or type II endometrial cancer such as serous,clear cell,and carcinosarcoma,shows advanced/recurrent disease and dismal prognosis.Novel therapeutic development is required for patients with aggressive endometrial cancers.Recent genomic and immunohistochemical analyses revealed human epidermal growth factor receptor 2(HER2)overexpression/gene amplification in 20%-40%of patients with type II endometrial cancer.Historically,HER2 targeted therapy has been developed for various major cancers,including breast and gastric cancer.Notably,recent advances in HER2 targeted therapy for patients with type II endometrial cancer are also expected to change.Simultaneously,an optimized HER2 test for endometrial cancer as companion diagnostics should be established.In this review,we summarize the recent findings on endometrial cancer,current treatment,optimized HER2 testing,key clinical trials on HER2 targeted therapy,and future directions in aggressive endometrial cancer,including serous carcinoma and carcinosarcoma.

Programmed cell death-1 inhibitor combination treatment for recurrent proficient mismatch repair/miscrosatellite-stable type endometrial cancer:A case report

BACKGROUND Endometrial cancer(EC)is one of the most common cancers of the female reproductive tract,and the incidence is increasing rapidly.Immunotherapy using programmed cell death-1(PD-1)inhibitors is an emerging research topic and treatment strategy for refractory gynecological malignancies.However,clinical management of EC with checkpoint inhibitors requires improvement.Herein,we discuss a case of refractory proficient mismatch repair(pMMR)/miscrosatellitestable(MSS)EC treated with a combination of PD-1 and angiogenesis inhibitors and offer a review of the pathophysiology and clinical outcomes based on previous studies.CASE SUMMARY A 62-year-old woman diagnosed with invasive or metastatic EC in 2015 was treated with six courses of chemotherapy and refused further radiotherapy.Four years later,she developed chest pain,and lung biopsy indicated thyroid transcription factor-1(-),Napsin A(-),estrogen receptor(+),progesterone receptor(+),anaplastic lymphoma kinase(D5F3)(-),and receptor tyrosine kinase(D4D6)(-)metastatic EC.Genetic testing results showed low tumor mutation burden,pMMR,PD ligand 1(-),MSS,and HLA-class 1 heterogeneous disease.The patient was started on toripalimab combined with nab-paclitaxel for seven cycles(every 3 wk),but this regimen was terminated because of an intolerable chemotherapy adverse event.The disease progressed in 2020,and the patient’s treatment was switched from nab-paclitaxel to anlotinib,while immunotherapy using toripalimab was continued.The patient achieved a major partial response with well-tolerated toxicities,and treatment is ongoing.CONCLUSION Molecular testing is advised for clinical classifications of EC owing to its high heterogeneity.In this case,the patient had pMMR/MSS EC and achieved a positive outcome with combination PD-1 inhibitor treatment.These results warrant further clinical exploration.

Real-time co-registered photoacoustic and ultrasonic imaging for early endometrial cancer detection driven by cylindrical diffuser

In illuminating tissues,a cylindrical diffuser(CD)has an advantage over regular laser sources due to its ability to illuminate a larger volume of the target tissue.This paper presents a co-registered large volume photoacoustic(PA)and ultrasonic(US)imaging for early endometrial cancer(EEC)detection using CD.It has the advantage that the US imaging system is outside the body and only the PA excitation device is inside the body,which makes the system more efficient and less invasive for EEC detection.The paper reports on two sets of experiments.Thefirst set produced real-time PA images of blood vessel phantom.The second set demonstrated the imaging of pig uterus ex vivo.The results show that the system has the potential for imaging and characterizing of EEC.

Could Surgery Improve Survival in Patients with Advanced Endometrial Cancer?

Background: Patients with endometrial cancer are mostly diagnosed at an early stage. But unfortunately 10% to 15% of endometrial cancer patients will present with advanced-stage disease, and hence poorer prognosis. When disease is primarily intraperitoneal, cytoreduction to <2 cm has also been correlated with better survival, with the maximum benefit in patients who can be reduced to no visible disease remaining. Aim: Of the work is to detect the survival rate benefits of primary surgery in patients with advanced endometrial cancer at gynecologic oncology unit in El Shatby Maternity University Hospital. Methods and Materials: Retrospective study was conducted on 102 patients diagnosed to have advanced endometrial cancer FIGO (stage III/IV) in a duration of 4 years between 2016 and 2020 and had undergone cytoreductive surgery. The patients were further subdivided into two groups: group 1 who underwent optimal cytoreduction with residual disease less than or equal 1 cm visible lesion, and group 2 who had residual disease more than 1 cm visible lesion and they were followed to check the survival benefits. Results: The mean of disease free survival in group: 1) patients was 2 years which was significantly longer than those in group;2) those who had residual disease > 1 cm, p < 0.001. Also cases with type I endometrial cancer had significantly longer (DFS) than those diagnosed to have type II endometrial cancer, p = 0.046. Conclusion: Primary complete cytoreductive (upfront) surgery when possible has a favorable impact on overall survival in patients with advanced endometrial cancer.

Patterns of Recurrence in Low-Risk Endometrial Cancer

Objective: Endometrial cancer is the most common gynaecological cancer in high-income countries and has a good prognosis, particularly when diagnosed early. Early stage, low-grade endometrial cancer has a low risk of recurrence, and is detectable on routine follow up. This study aims to identify rates and patterns of recurrence in low-risk endometrial cancer patients and provide evidence for transitioning to community-based follow-up care. Methods: Retrospective study of patients with early-stage, low-grade endometrioid endometrial adenocarcinoma treated with surgery from January 1981 to December 2018. The rate and patterns of recurrence were identified and analysed. Results: Of 1215 eligible patients, 24 developed recurrent disease (1.98%). The majority of recurrences were pelvic (70%), and confined to the vaginal vault (41.7%). The median duration of follow up was 44.4 months, and time from primary surgery to diagnosis of recurrent disease was 30.5 months. No significant differences were found between the group of patients who recurred and the group of patients who did not. Twelve (50%) patients with recurrences were asymptomatic, but of these, 10 (83%) had obvious findings during routine surveillance physical examination. The remaining 12 patients (50%) presented with symptoms that prompted investigation that led to the recurrence diagnosis. 78% of recurrences were treated with combination therapy (surgical excision, chemotherapy, radiotherapy and hormonal). Ten patients (42%) had salvageable disease. For the non-salvageable cases, there was a mean of 2.1 years from recurrence diagnosis to death. Conclusions: The low recurrence rate of low-risk endometrial cancer following primary surgical management, and the feasibility of detection of recurrent disease, support transitioning surveillance to community-based settings.

Analysis of risk factors for lymphedema of the lower limbs after endometrial cancer surgery and suggestions for prevention and treatment

Objective:The objective of this study is to investigate the risk factors for the occurrence of lower limb lymphedema in patients with endometrial cancer after surgery and to make recommendations for prevention and treatment.Materials and Methods:We retrospectively reviewed the clinical data of 135 patients with endometrial cancer treated in the Department of Gynecology of the Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine from January 2013 to December 2019 and analyzed the risk factors of lower limb lymphedema in patients with endometrial cancer after surgery using single factor analysis and multi-factor logistic regression analysis.Results:The incidence of postoperative lower limb lymphedema in patients with endometrial cancer was 11.11%.The results of one-way Chi-square test analysis showed that body mass index(BMI),surgical method,number of lymph node dissection,and radiotherapy were related to the occurrence of lower limb lymphedema,and multi-factor logistic analysis showed that BMI(odds ratio[OR]=6.207),number of lymph node dissection(OR=4.223),and radiotherapy(OR=8.081)were the risk factors for lower limb lymphedema after endometrial cancer surgery.Conclusion:Patients with endometrial cancer with BMI≥≥25 kg/m^(2),high number of lymph node dissection,and postoperative radiotherapy are more likely to develop lower limb lymphedema,and they should be given priority attention and timely preventive and curative measures.

Correlation between Depth of Myometrial Invasion and Degree of Lymph Node Affection in Cases of Endometrial Cancer

Introduction: Endometrial cancer is the fourth most frequent cancer in females. Many factors can affect prognosis of this type of cancer, these mainly are the degree of myometrial invasion by the tumour, pelvic and paraaortic lymph node spread as well as the tumour histological type (endometrioid vs non-endometrioid type). transvaginal ultrasound (TVS) is a highly accurate and easy method for preoperative evaluation of myometrial invasion. Aim of the Work: The aim of this work is to assess if there is relation between the depth of myometrial invasion by the tumor and the rate of lymph node involvement in cases of endometrial cancer. Results: It was found that there was a significant relation between lymph node affection and the depth of myometrial invasion, all the positive lymph node affections cases had myomterial invasion > 50.0%. Conclusion: The incidence of pelvic lymph node affection is very high in cases where the myometrium is deeply infiltrated with the tumor. Assessment of myometrial invasion preoperatively by TVU and microscopically by pathological examination of the myometrium after hysterectomy provides an accurate estimation of the rate of pelvic lymph node affection and hence necessitates lymphadenectomy procedures in cases where myometrium is deeply infiltrated by the tumor and omitted in cases where it is tumor free.

Association of 2-methoxyestradiol levels with the occurrence and development of endometrial cancer in humans

Objective The aim of the study was to determine the association of urinary levels of estradiol(E_(2))and 2-methoxyestradiol(2-MeOE_(2))with the occurrence and development of endometrial cancer.Methods In this case-control study,24-h urine specimens were collected from 28 postmenopausal patients with endometrial cancer and 28 postmenopausal healthy female controls.The concentration of 2-MeOE_(2) was determined using liquid chromatography-mass spectrometry with hollow fiber liquid-phase microextraction.The concentration of E_(2) was determined using an enzyme-linked immunosorbent assay.Results Estrogen levels were different between the patients with endometrial cancer and controls.The relative quantity of E_(2) in the case group was higher than that in the control group(P<0.05),whereas that of 2-MeOE_(2) was lower in the case group than that in the control group(P<0.05).The ratio of E_(2)-to-2-MeOE_(2) in the case group was significantly higher than that in the control group(P<0.05).Conclusion The results of this study indicate an imbalance of estrogen metabolites in endometrial carcinogenesis.Reduced 2-MeOE_(2) levels and elevated E_(2)-to-2-MeOE_(2) ratio may be used as potential biomarkers for the risk assessment of estrogen-induced endometrial cancer.

Long-Term Metformin Effect on Endometrial Cancer Development Depending on Glucose Environment <i>In Vitro</i>

Objectives: Hyperinsulinemia as well as prolonged and elevated estrogen exposure are considered as risk factors for endometrial cancer (EC) development. Metformin, an anti-hyperglycemic and insulin-sensitizing biguanide, displayed anti-proliferative effects in recent studies. In the present study, the effects of long-term exposure of endometrial cancer cells to low and moderate concentrations of metformin on cell viability, proliferation, clonogenicity and migration were investigated under different metabolic conditions. Study Design: EC cell lines HEC-1A and Ishikawa were cultured under normo- (NG, 5.5 mM) or hyperglycemic (HG, 17.0 mM) conditions and treated with metformin (0.01 - 5.0 mM) in the presence of β-estradiol (E2) for 7 d. Results: A concentration-dependent decrease of cellular viability was observed in the MTT and ATP assays after metformin treatment. IC50 values were between 0.7 - 3.7 mM (NG) and 3.0 - 18.3 mM (HG), respectively. A protective effect of glucose on cellular viability was detected only in the ATP assay. Furthermore, metformin (0.5 - 5.0 mM) led to a significant decrease in proliferation by 12% - 55% (NG). However, a decreased proliferation rate was only induced at 5.0 mM metformin (40%) in the presence of high glucose levels in HEC-1A cells, indicating a glucose-related resistance to anti-proliferative metformin effects, which—to a lesser extent—was also observed in Ishikawa cells. Metformin treatment also caused concentration-dependent effects on clonogenicity and decreased the number and size of colonies. In HEC-1A cells, metformin (0.5 - 5.0 mM) reduced the colony formation by 44% - 80% (NG) and 29% - 81% (HG), respectively. Slightly higher metformin concentrations (1.0 - 5.0 mM) were necessary in Ishikawa cells to reduce clonogenicity by 36% - 86% independent of glucose levels. An investigation of migration in the wound healing assay revealed that the % wound closure decreased with increasing metformin concentrations, but independent of glucose levels. After treatment with 5.0 mM metformin, migration was significantly reduced in both cell lines. Conclusion: Our in vitro findings support the hypothesis that metformin has a direct effect on endometrial cancer cell lines and reflects the importance of the local glucose environment, suggesting that metformin may be considered as a potential adjuvant agent in endometrial cancer therapy due to its direct and indirect effects on endometrial development. However, further studies are necessary that confirm the relevance of our data for clinical applications.

Steroid Sulfatase Inhibitor Reduces Proliferation of Ishikawa Endometrial Cancer Cells in Co-Culture Systems

Objectives: Estrogens significantly contribute toward the growth and development of endometrial cancers. Two principal pathways have been implicated in the final steps of estrogen synthesis: the steroid sulfatase (STS) and aromatase pathways. In this study, we aimed to evaluate the possible effects of tumor-stromal interactions on local estrogen biosynthesis in endometrial cancer. We also assessed the biological effects of inhibitors of steroid sulfatase and aromatase in the co-culture system compared with usual monocultures. Methods/Materials: We isolated stromal cells from endometrial cancer patients to examine local biosynthesis of estrogens and tumor-stromal interactions. Next we examined the effects of steroid sulfatase inhibitor and aromatase inhibitor in monoculture of endometrial cancer cell line (Ishikawa) and in a co-culture system involving an Ishikawa cells and stromal cells. Results: Estrogen receptor and steroid sulfatase mRNA levels in cancer cells were significantly higher in the co-cultures compared with the monocultures of endometrial cancer cells. Estradiol and androstenediol concentrations were also significantly higher in the co-cultured cells. Proliferation of the cancer cells was significantly increased through the steroid sulfatase pathway, which metabolizes androgens, estrone sulfate, and estradiol sulfate as its substrates. However, its proliferation was significantly decreased by the treatment of steroid sulfatase or aromatase inhibitors. The significant growth inhibition by the steroid sulfatase and aromatase inhibitors were also observed in the co-culture system. Conclusions: We evaluated the effects of STS inhibitor and aromatase inhibitors on the proliferation of estrogen-dependent endometrial cancer cells. Considering that intratumoral estrogen metabolism plays an important role, our co-culture systems provide an environment similar to that of the tumor in living patients in terms of metabolism and synthesis of intratumoral estrogens. The results of this study may aid in achieving improved clinical responses from patients treated with STS inhibitors.

Retrospective Analysis of Adjuvant Therapy in Intermediate and High Risk Endometrial Cancer Patients

Introduction: Endometrial cancer is the most common gynecologic malignancy in developed countries. The most significant prognostic factors are tumor stage, histological grade and type, depth of myometrial invasion, lympho-vascular space or nodal involvement. The optimal adjuvant therapy in high and intermediate risk endometrial cancer is still controversial. Aim of the work: Evaluating the impact of adjuvant chemotherapy in addition to radiotherapy on prognosis of high and intermediate risk endometrial cancer. Patients and methods: Forty six patients with high and intermediate risk endometrial cancer presenting to Kuwait Cancer Control Center (KCCC) underwent total abdominal hysterectomy, bilateral salpingo-ophorectomy, and 18 patients underwent lymphadenectomy (39.1%). All patients received adjuvant chemotherapy followed by adjuvant radiotherapy. According to GOG risk stratification, 28 patients (60.9%) were high risk, 6 (13%) high intermediate and 12 (26.1%) low intermediate. At the end of follow up period, 34.71% of patients relapsed, 21.71% locally and 13% systemic. Median PFS was 38.06 months(ms) (95% CI 36.94 - 39.18 ms). There was a statistically significant effect of lympho-vascular space invasion (LVSI), grade and near statistically significant effect of patients age on PFS (p = 0.01, 0.05, 0.06 respectively). Median OS for all patients was not reached;estimated survival at 3 years was 87.5%. There was no statistically significant effect of age, pathological subtype, grade, LVSI on survival (p = 0.35, 0.95, 0.53 and 0.09 respectively). On stratifying patients into high and intermediate risk based on GOG risk stratification, there was a statistically significant difference on PFS and near statistically significant difference on OS between those groups (p = 0.02 and 0.09 respectively). Conclusion: The most effective adjuvant treatment regimen for patients with intermediate and high risk endometrial cancer is still an area of controversy. Sequential chemotherapy and radiotherapy is both efficacious and well tolerated. Large-scale randomized controlled trials are necessary in the future.