Types Of Endometrial Cancer Research Articles

Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such as Tp53 and Pten However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressor Fbxw7 in endometrial cancer through defined genetic model systems. Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial-mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.

Development and Validation of an Algorithm to Identify Endometrial Adenocarcinoma in US Administrative Claims Data.

Background Endometrial adenocarcinoma is the most prevalent type of endometrial cancer. Diagnostic codes to identify endometrial adenocarcinoma in administrative databases, however, have not been validated. Objective To develop and validate an algorithm for identifying the occurrence of endometrial adenocarcinoma in a health insurance claims database. Methods To identify potential cases among women in the HealthCore Integrated Research Database (HIRD), published literature and medical consultation were used to develop an algorithm. The algorithm criteria were at least one inpatient diagnosis or at least two outpatient diagnoses of uterine cancer (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) 182.xx) between 1 January 2010 and 31 August 2014. Among women fulfilling these criteria, we obtained medical records and two clinical experts reviewed and adjudicated case status to determine a diagnosis. We then estimated the positive predictive value (PPV) of the algorithm. Results The PPV estimate was 90.8% (95% CI 86.9–93.6), based on 330 potential cases of endometrial adenocarcinoma. Women who fulfilled the algorithm but who, after review of medical records, were found not to have endometrial adenocarcinoma, had diagnoses such as uterine sarcoma, rhabdomyosarcoma of the uterus, endometrial stromal sarcoma, ovarian cancer, fallopian tube cancer, endometrial hyperplasia, leiomyosarcoma, or colon cancer. Conclusions An algorithm comprising one inpatient or two outpatient ICD-9-CM diagnosis codes for endometrial adenocarcinoma had a high PPV. The results indicate that claims databases can be used to reliably identify cases of endometrial adenocarcinoma in studies seeking a high PPV.

The role of nesfatin and selected molecular factors in various types of endometrial cancer.

Endometrial cancers (ECs) are the most common gynaecological cancers in well developed countries. Diabetes and metabolic syndrome are among the biggest risk factors. Nesfatin-1, the adipokine derivative of NUCB2 (nucleobindin derivative 2) is linked to the clinical course of EC. Molecular factors, including mutations in MLH1 and MHS2 genes, c-MET and ARID1A are also related to prognosis in endometrial cancer. Using sections of paraffin-embedded preparations and immunohistochemistry, the expression of NESF1, MLH1, MSH2,c-MET and ARID1A were examined. In this study on protein expression, EC tissues manifested (although insignificantly) an elevated expression of NESF-1 in type II EC. In type I EC, NESF-1 expression was significantly higher in G1 in comparison to G2 and G3 together. A significantly lower expression of MLH1 was demonstrated in type I EC. The most pronounced expression involved c-MET in all EC I and EC II tissues (in over 80% of cases). A tendency was detected for a high expression of NESF-1 in patients with type II EC, who also exhibited a high expression of MSH2.

Novel dihydroartemisinin dimer containing nitrogen atoms inhibits growth of endometrial cancer cells and may correlate with increasing intracellular peroxynitrite

In the present study, a novel dimer, SM1044, selected from a series of dihydroartemisinin (DHA) derivatives containing nitrogen atoms comprising simple aliphatic amine linkers, showed strong growth inhibition in six types of human endometrial cancer (EC) cells, with half maximal inhibitory concentration (IC50) and 95% confidence interval (CI) < 3.6 (1.16~11.23) μM. SM1044 evoked apoptosis and activated caspase-3, −8 and −9 in a concentration- and time-dependent manner, and these effects were manifested early in RL95-2 compared to KLE cells, possibly correlated with the induction of intracellular ONOO−. Catalase and uric acid attenuated the growth inhibitory effects of SM1044 on EC cells, but sodium pyruvate did not. In vivo, the average xenograft tumour growth inhibition rates ranged from 35.8% to 49.9%, respectively, after 2.5 and 5.0 mg/kg SM1044 intraperitoneal treatment, and no obvious behavioural and histopathological abnormalities were observed in SM1044-treated mice in this context. SM1044 predominantly accumulated in the uteri of mice after a single injection. SM1044 displayed efficacy as a tumour suppressor with distinct mechanism of action and unique tissue distribution, properties that distinguish it from other artemisinin analogues. Our findings provide a new clue for artemisinin analogue against cancer.

Factors Related to Type of Endometrial Cancer in RSUP Dr. M. Djamil Padang

Objective: This study aims to determine the relationship of risk factors with type of endometrial cancer.Method: This study used a cross sectional design in patients with endometrial cancer. Sampling uses total sampling technique, with a total sample of fifty six people. Data were obtained from the anatomical pathology section and medical records of Dr. RSUP M. Djamil Padang from 2016 until 2018. Analysis of data using Chi-Square test and logistic regressionResult: In this study, type I endometrial cancer is 75% cases while type II is 25% cases. Age, parity, diabetes mellitus, hypertension, genetics history and exclusive breastfeeding have no association with the type of endometrial cancer. The age of menarche and BMI have a relationship with the type of endometrial cancer. The dominant factor associated with the type of endometrial cancer is BMI (p = 0.042; OR = 6.547; 95% CI = 1.067-40.169), age (p = 0.037; OR = 4.854; 95% CI = 1.096-21.493), and age of menarche (p = 0.054; OR = 4.590; 95% CI = 0.974-21.635).Conclusion: On this research, BMI, age and age of menarche are the most dominant factor associated with the type of endometrial cancer. Faktor yang Berhubungan dengan Tipe Kanker Endometrium di RSUP Dr. M. Djamil PadangAbstrakTujuan: Penelitian ini bertujuan untuk mengetahui hubungan faktor risiko dengan tipe kanker endometrium.Metode: Penelitian ini menggunakan desain cross sectional pada penderita kanker endometrium. Pengambilan sampel menggunakan teknik total sampling, dengan jumlah sampel sebanyak 56 orang. Data diperoleh dari bagian patologi anatomi dan rekam medik RSUP Dr. M. Djamil Padang periode 2016 – 2018. Analisis data menggunakan uji Chi-Square dan regresi logistic.Hasil: Pada penelitian ini ditemukan 75% kasus merupakan kanker endometrium tipe 1 dan 25% kanker endometrium tipe II. Usia, paritas, diabetes mellitus, hipertensi, riwayat genetik dan pemberian asi eksklusif tidak memiliki hubungan dengan tipe kanker endometrium. Usia menarche dan IMT memiliki hubungan dengan tipe kanker endometrium. Faktor yang dominan berhubungan dengan tipe kanker endometrium adalah IMT (p = 0,042; OR = 6,547; 95% CI = 1,067-40,169), usia (p = 0,037; OR = 4,854; 95% CI = 1,096-21,493), dan usia menarche (p = 0,054; OR = 4,590; 95% CI = 0,974-21,635).Kesimpulan: Pada penelitian ini, IMT, usia dan usia menarche merupakan faktor yang paling dominan mempengaruhi tipe kanker endometriumKata kunci: Kanker Endometrium, Faktor Risiko.

The role of myeloid-derived suppressor cells in endometrial cancer displaying systemic inflammatory response: clinical and preclinical investigations

ABSTRACTSystemic inflammatory responses including thrombocytosis, leukocytosis, or neutrophilia have gained attention as prognostic indicators in patients with various solid malignancies.current study, we aimed to investigate the clinical implications and underlying biological mechanism of the systemic inflammatory response in endometrial cancer. Clinical data from 900 patients with endometrial cancer were analyzed to investigate the association between pretreatment leukocytosis, thrombocytosis, and treatment outcome. Clinical samples, endometrial cancer cell lines, and a mouse model of endometrial cancer were used to examine the mechanisms responsible for systemic inflammatory response in endometrial cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and MDSCs. Then, we showed that pretreatment concurrent leukocytosis and thrombocytosis is associated with significantly shorter survival and decreased chemosensitivity among patients with endometrial cancer. In vitro and in vivo experiments revealed that tumor-derived G-CSF and G-CSF-mediated IL-6 production from the tumor microenvironment are involved in the development of leukocytosis and thrombocytosis in patients with endometrial cancer. Moreover, increased tumor-infiltrating MDSCs induced by tumor-derived G-CSF, MDSC-mediated T cell suppression, and MDSC-mediated cancer stem cell induction are responsible for progression and chemoresistance in this type of endometrial cancer. MDSC depletion using an anti-Gr-1 neutralizing antibody or inhibition of MDSC activity by celecoxib inhibited tumor growth and enhanced chemosensitivity in endometrial cancer displaying concurrent leukocytosis and thrombocytosis. In conclusion, Pretreatment concurrent leukocytosis and thrombocytosis are associated with significantly shorter survival and decreased chemosensitivity among patients with endometrial cancer. Combining MDSC-targeting treatments with current standard chemotherapies might have therapeutic efficacy for these patients.

Association of Abnormal Pap Smear with Occult Cervical Stromal Invasion in Patients with Endometrial Cancer.

Objective:The purpose of this study was to determine the association between abnormal preoperative Pap smear results and occult cervical stromal invasion in endometrial cancer patients. Methods:Medical records were reviewed of patients with endometrial cancer who had undergone surgical staging at Srinagarind Hospital. Patients with gross cervical involvement, with an unsatisfactory Pap smear, without available Pap smear results, with no cervical intraepithelial lesion/invasive cervical cancer, or who had previously undergone pelvic radiation therapy were excluded. The patients were assigned to one of two groups according their Pap smear results (negative and epithelial cell abnormalities). Logistic regression was used to determine the independent association between an abnormal Pap smear and the risk of cervical stromal invasion. Results:All cervical smears in this study were performed as conventional Pap smears. Smears were abnormal in 50 (21.0%) of the 238 patients enrolled and normal in the remaining 188 (79.0%). The types of Pap smear abnormalities included adenocarcinoma (n=22); atypical endometrial cells (n=2); atypical glandular cells (n=17); high-grade squamous intraepithelial lesions (n=4); atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions (n=2); and atypical squamous cells of undetermined significance (n=3). After controlling for type of endometrial cancer, abnormal Pap smear results were found to be a significant independent factor that indicated cervical stromal invasion (adjusted OR 2.65; 95% CI 1.35 to 5.21). Conclusion:Endometrial cancer patients with abnormal Pap smears were strongly and independently associated with histopathologically diagnosed cervical stromal invasion.

Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies).

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.

Management of high-risk endometrial cancer: are we there yet?

Management of high-risk endometrial cancer: are we there yet?

Usefulness of immunohistochemistry for mismatch repair protein and microsatellite instability examination in adenocarcinoma and background endometrium of sporadic endometrial cancer cases.

Microsatellite instability (MSI), which reflects loss of DNA mismatch repair (MMR) activity, and immunohistochemistry (IHC) for MMR proteins are employed as screening examinations for Lynch syndrome (LS). Recent studies revealed that there is a population of MSI-high tumors in sporadic endometrial cancer (EC). However, MSI data for Japanese EC patients are scarce. Furthermore, sporadic estrogen-dependent EC (type I) is generally considered to arise from hyperplasia. Because LS is usually associated with type I EC, we hypothesized that MSI might be involved in the oncogenic process in some sporadic EC. We conducted MSI testing to reveal MSI status in sporadic Japanese EC. IHC for MMR proteins was also performed. Ninety-eight tissue samples of sporadic ECs from Japanese patients were used for IHC and MSI examinations. We also evaluated MMR protein expressions in the background normal endometrium. Microsatellite instability-high was observed in 10.2% of 98 cases with sporadic EC, a lower percentage than that in Western studies. Loss of some MMR proteins was observed in 23 cases (23.5%) and there was a significant correlation with MSI-high status (P < 0.001). Concerning the background endometrium, two cases showed partial loss of MLH1 and PMS2, corresponding to adjacent EC lesions, suggesting that MMR deficiency may already be present in the background endometrium. The MSI-high rate was low in our Japanese cohort. Our data confirmed the usefulness of MMR protein assessment for MSI screening in Japanese EC patients. Furthermore, IHC of the background endometrium might reveal the mechanism of MSI-high tumorigenesis.

Leptin-induced Notch and IL-1 signaling crosstalk in endometrial adenocarcinoma is associated with invasiveness and chemoresistance.

BACKGROUNDObesity is a recognized risk factor for endometrial cancer (EmCa) and other cancer types. Leptin levels are significantly increased in obese individuals. Leptin-induced signaling crosstalk [Notch, Interleukin-1 (IL-1) and leptin outcome, NILCO] has been associated with breast cancer progression. This complex signaling crosstalk affects cancer cell proliferation, migration, invasion, angiogenesis, apoptosis and chemoresistance. NILCO expression was previously detected in human EmCa. However, it is unknown whether leptin regulates NILCO and alters EmCa’s response to chemotherapeutics. It is hypothesized that leptin induces NILCO and increases aggressiveness and chemoresistance in EmCa cells.AIMTo determine whether leptin induces NILCO molecules in EmCa affecting cell proliferation, aggressiveness and chemoresistance.METHODSLeptin’s effects on the expression of NILCO molecules [mRNAs and proteins for Notch receptors (Notch1-4), ligands (JAG1 and DLL4) and downstream effectors (survivin, Hey2), and leptin (OB-R) and IL-1 (IL-1R tI) receptors] was examined in EmCa cells (type I: Ishikawa, and HEC-1A, and type II: An3Ca and KLE) using Real-time PCR and Western blot analysis, respectively. In addition, the effects of leptin on cell cycle, proliferation and cell invasion were determined using cytometric analysis (Cellometer Vision CBA system), MTT cell proliferation and Matrigel-based invasion assays, respectively. Inhibitors of leptin (nanoparticle-bound leptin peptide receptor antagonist-2, IONP-LPrA2), IL-1 (anti-IL-1R tI antibody) and Notch (siRNA interference RNA) were used to investigate NILCO’s effects on cell proliferation and invasion. Leptin’s effects on Paclitaxel cytotoxicity in EmCa cells was determined by the CCK8 and Cellometer-based Annexin V assays.RESULTSFor the first time it was shown that leptin is an inducer of Notch in EmCa. Experimental data suggest that leptin induced the expression of NILCO molecules, promoted proliferation and S- phase progression, and reduced Paclitaxel cytotoxicity on EmCa cells. Leptin’s effects were higher in type II EmCa cells. The progression of this more aggressive form of the disease is associated with obesity. Remarkably, the use of the leptin signaling antagonist, IONP-LPrA2, re-sensitized EmCa cells to Paclitaxel.CONCLUSIONPresent data suggest the notion that leptin-induced NILCO could be a link between obesity and EmCa progression and chemoresistance. Most aggressive type II EmCa cells were higher sensitive to leptin, which appears to increase proliferation, cell cycle progression, aggressiveness, and chemoresistance to Paclitaxel. Therefore, leptin and NILCO could be novel therapeutic targets for type II EmCa, which does not have targeted therapy. Overall, IONP-LPrA2 has a potential as a novel adjuvant drug to enhance the effectiveness of type II EmCa chemotherapy.

MiRNAs as Candidate Biomarker for the Accurate Detection of Atypical Endometrial Hyperplasia/Endometrial Intraepithelial Neoplasia.

Endometrial cancer is the most common gynecologic malignancy in developed countries. Estrogen-dependent tumors (type I, endometrioid) account for 80% of cases and non-estrogen-dependent (type II, non-endometrioid) account for the rest. Endometrial cancer type I is generally thought to develop via precursor lesions along with the increasing accumulation of molecular genetic alterations. Endometrial hyperplasia with atypia/Endometrial Intraepithelial Neoplasia is the least common type of hyperplasia but it is the type most likely to progress to type I cancer, whereas endometrial hyperplasia without atypia rarely progresses to carcinoma. MicroRNAs are a class of small, non-coding, single-stranded RNAs that negatively regulate gene expression mainly binding to 3′-untranslated region of target mRNAs. In the current study, we identified a microRNAs signature (miR-205, miR-146a, miR-1260b) able to discriminate between atypical and typical endometrial hyperplasia in two independent cohorts of patients. The identification of molecular markers that can distinguish between these two distinct pathological conditions is considered to be highly useful for the clinical management of patients because hyperplasia with an atypical change is associated with a higher risk of developing cancer. We show that the combination of miR-205, −146a, and −1260b has the best predictive power in discriminating these two conditions (>90%). With the aim to find a biological role for these three microRNAs, we focused our attention on a common putative target involved in endometrial carcinogenesis: the oncosuppressor gene SMAD4. We showed that miRs-146a,−205, and−1260b directly target SMAD4 and their enforced expression induced proliferation and migration of Endometrioid Cancer derived cell lines, Hec1a cells. These data suggest that microRNAs-mediated impairment of the TGF-β pathway, due to inhibition of its effector molecule SMAD4, is a relevant molecular alteration in endometrial carcinoma development. Our findings show a potential diagnostic role of this microRNAs signature for the accurate diagnosis of Endometrial hyperplasia with atypia/Endometrial Intraepithelial Neoplasia and improve the understanding of their pivotal role in SMAD4 regulation.

Comparing theory and non-theory based implementation approaches to improving referral practices in cancer genetics: a cluster randomised trial protocol

BackgroundLynch syndrome (LS) is an inherited, cancer predisposition syndrome associated with an increased risk of colorectal, endometrial and other cancer types. Identifying individuals with LS allows access to cancer risk management strategies proven to reduce cancer incidence and improve survival. However, LS is underdiagnosed and genetic referral rates are poor. Improving LS referral is complex, and requires multisystem behaviour change. Although barriers have been identified, evidence-based strategies to facilitate behaviour change are lacking. The aim of this study is to compare the effectiveness of a theory-based implementation approach against a non-theory based approach for improving detection of LS amongst Australian patients with colorectal cancer (CRC).MethodsA two-arm parallel cluster randomised trial design will be used to compare two identical, structured implementation approaches, distinguished only by the use of theory to identify barriers and design targeted intervention strategies, to improve LS referral practices in eight large Australian hospital networks. Each hospital network will be randomly allocated to a trial arm, with stratification by state. A trained healthcare professional will lead the following phases at each site: (1) undertake baseline clinical practice audits, (2) form multidisciplinary Implementation Teams, (3) identify target behaviours for practice change, (4) identify barriers to change, (5) generate intervention strategies, (6) support staff to implement interventions and (7) evaluate the effectiveness of the intervention using post-implementation clinical data. The theoretical and non-theoretical components of each trial arm will be distinguished in phases 4–5. Study outcomes include a LS referral process map for each hospital network, with evaluation of the proportion of patients with risk-appropriate completion of the LS referral pathway within 2 months of CRC resection pre and post implementation.DiscussionThis trial will determine the more effective approach for improving the detection of LS amongst patients with CRC, whilst also advancing understanding of the impact of theory-based implementation approaches in complex health systems and the feasibility of training healthcare professionals to use them. Insights gained will guide the development of future interventions to improve LS identification on a larger scale and across different contexts, as well as efforts to address the gap between evidence and practice in the rapidly evolving field of genomic research.Trial registrationANZCTR, ACTRN12618001072202. Registered on 27 June 2018.

Clinicopathologic characteristics of recurrent endometrioid endometrial cancer patients and analysis of methods used durıing surveillance

ObjectiveTo determine cilinicopathologic characteristics of recurrent endometrioid type endometrial cancer patients and analyze the methods applied in detection of recurrent disease during follow-up period. MethodsWe have retrospectively reviewed the file records of the 226 patients who had endometrioid type carcinoma. Bimanual pelvic examination, speculum examination, carcinogenic antigen-125 (CA125) testing, vaginal cuff cytologic screening, transabdominal ultrasound (TAUS) and transvaginal ultrasound(TVUS) imagings were performed within the context of routine follow-up control examinations in the post-treatment period in every 3 months within the first 2 years and in every 6 months in the following 2 years and with annual control in the consecutive years. ResultsMean follow-up durations was 25.7±18.9 months while recurrence rate was 3.1%. The study patient group underwent totally 1116 times TVUS and 1084 times whole TA-US evaluations, 973 times vaginal cuff cytological screening, 1125 times pelvic and general physical examinations beside 1060 times CA-125 testings were performed in accordance with our routinely performed follow-up protocol. The asymptomatic recurrent cases ; one of those was dignosed with pelvic examination while diagnosis was established using TA-USG evaluation in the other asymptomatic patient. The other 5 cases were symptomatic. Pelvic examination, Computed Tomograhy and Magnetic Resonance Imaging were utilized in diagnosing 1, 3 and 1 of those patients, respectively. ConclusionThe presence of symptoms and pelvic examination seem to be the most effective modalities in detecting recurrence in follow-up of endometrial cancer. It would be reasonable to optimize intervals between follow-up visits and to determine the appropriate evaluations by considering risk levels of the patients.

Sex hormone, insulin, and insulin-like growth factor signaling in recurrence of high stage endometrial cancer: Results from the NRG Oncology/Gynecologic Oncology Group 210 trial.

5509 Background: Sex hormone and insulin/insulin-like growth factor (IGF) axis signaling pathways play an important role in endometrial cancer development but their role in endometrial cancer recurrence is unknown. In this study GOG-8015 we evaluated these pathways in a prospective cohort of patients diagnosed with the most common type of endometrial cancer, endometrioid adenocarcinoma. Methods: Stage II-IV endometrioid endometrial adenocarcinoma patients (N = 816) enrolled in the GOG-210 study with pre-treatment specimens were tested for tumor mRNA and protein expression levels of IGF1, IGF2, IGF binding proteins ( IGFBP) -1and -3, the insulin (IR) and IGF-I receptors (IGF1R), and phosphorylated (activated) IR/IGF1R as well as estrogen (ER) and progesterone receptors (PR) using quantitative PCR and immunohistochemistry (IHC). Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone and sex hormone binding globulin were measured using ELISAs. Hazard ratios (HR) and 95% confidence intervals (CI) for risk of recurrence were obtained from multivariable Cox proportional hazard’s models with adjustment for age, stage and grade. Results: Recurrence occurred in 280 (34%) cases during a mean of 5.4 years of follow-up. ER-positivity (HR 0.67, 95% CI 0.47-0.95), IR-positivity (HR 0.53, 95% CI 0.29-0.98) and serum IGF-I levels (highest versus lowest quartile, HR 0.66, 95% CI 0.47-0.92) were inversely associated with recurrence risk. Conversely, circulating estradiol (highest versus lowest tertile, HR 1.55, 95% CI 1.02-2.36) and insulin (per 10 uU/ml, HR 1.52, 95% CI 1.12-2.06) and phosphorylated IGF1R/pIR expression (HR 1.40, 95% CI 1.02-1.92) were associated with increased risk of recurrence. Conclusions: We identified novel sex hormone and insulin/IGF axis tissue and circulating biomarkers of recurrence in a prospective study of high stage endometrioid endometrial cancer. Circulating insulin and estradiol, and tissue phosphorylated (activated) IGR1R/IR were independently associated with recurrence. These findings support prioritizing studies to establish their clinical utility as prognostic biomarkers and to investigate new strategies that target these pathways for prevention and treatment of endometrial cancer recurrence.

Second primary uterine malignancies after radiation therapy for cervical cancer.

Radiation exposure has long been established as a risk factor for cancer development. The purpose of this study is to assess the risk of uterine malignancy in patients previously treated for cervical cancer with radiation therapy. A population-based cohort of 9092 patients diagnosed with cervical cancer who did not undergo surgery and received radiation therapy between 1973 and 2008 was identified from the Surveillance, Epidemiology and End Results Program database (SEER 9). Patients in this cohort who developed endometrial cancer after treatment of cervical cancer were identified. 55,140 patients with endometrial cancer were also identified. The distribution of the different histologic types of endometrial cancer was determined for each of these cohorts. 54 patients (0.6%) were diagnosed with an endometrial cancer more than 12months after diagnosis of cervical cancer. The average latency to endometrial cancer diagnosis was 160months, with a range of 14-374months. The average age of cervical cancer diagnosis was 52years and the average age at subsequent endometrial cancer diagnosis was 66years. Only 40% of the endometrial cancers diagnosed following treatment of cervical cancer were endometrioid. The majority were clear-cell adenocarcinomas (42%), 9% were carcinosarcomas and 5.5% were leiomyosarcomas. Of the 55,140 endometrial cancer patients in the database, a vast majority were endometrioid adenocarcinomas (91%), and only 2.3% clear-cell adenocarcinoma, 2.3% carcinosarcoma and 0.5% leiomyosarcoma. The difference in histologic type distribution between these two cohorts is highly significant (p < 0.01). A small proportion of women who receive radiation for cervical cancer go on to develop endometrial cancer. These are predominantly of the more aggressive histologic types when compared to primary endometrial cancers. The latency from cervical cancer diagnosis to endometrial cancer diagnosis is over a decade. In a patient who still has a uterus after receiving pelvic radiation, vaginal bleeding should be investigated.

Oncological outcome of surgical management in patients with recurrent uterine cancer-a multicenter retrospective cohort study-CEEGOG EX01 Trial.

To assess the survival of patients who have received an operation for recurrent cervical and endometrial cancer and to determine prognostic variables for improved oncologic outcome. A retrospective multicenter analysis of the medical records of 518 patients with cervical (N = 288) or endometrial cancer (N = 230) who underwent surgery for disease recurrence and who had completed at least 1 year of follow-up. The median survival reached 57 months for patients with cervical cancer and 113 months for patients with endometrial cancer after surgical treatment of recurrence (p = 0.036). Histological sub-type had a significant impact on overall survival, with the best outcome in endometrial endometrioid cancer (121 months), followed by cervical squamous cell carcinoma, cervical adenocarcinoma, or other types of endometrial cancer (81 vs 35 vs 35 months; p <0.001). The site of recurrence did not significantly influence survival in cervical or in endometrial cancer. Cancer stage at first diagnosis, tumor grade, lymph node status at recurrence, progression-free interval after first diagnosis, and free resection margins were associated with improved overall survival on univariate analysis. On multivariate analysis, the stage at first diagnosis and resection margins were significant independent predictive parameters of an improved oncologic outcome. Long-term survival can be achieved via secondary cytoreductive surgery in selected patients with recurrent cervical and endometrial cancer. An excellent outcome is possible even if the recurrence site is located in the lymph nodes. The possibility of achieving complete resection should be the main criterion for patient selection.

MON-309 Intratumoral Proliferation and Proinflammatory Macrophages in Obese and Non-Obese Patients with Different Molecular-Biological Types of Endometrial Cancer

Background and aims: Endometrial cancer (EC) is characterized in times of modern obesity epidemic by the rapid incidence increase and the recent update of the molecular-biological classification, which now distinguishes not two, as before, but four types of this tumor (Kandoth et al., 2013; Talhouk et al., 2017; Berstein et al., 2017) that need to be comprehensively studied. The objective of this work was to compare the proliferative potential of a tumor tissue (Ki67 index) and compare it with the expression of proinflammatory CD68-macrophages in obese and non-obese patients with different types of EC according to the PROMISE classification. Materials and methods: In all predominantly postmenopausal 216 treatment naive EC patients included in the study, the body mass index (BMI) was estimated due to which the females were divided into subgroups with BMI ≥30.0 and <30.0. According to genetic (high-resolution melting and sequencing) and immunohistochemical (DACO antibodies) analysis, endometrial carcinomas were classified in accordance with recommendations (Talhouk et al, 2017) into types with POLE gene mutations, defect of mismatch repair proteins (MMR-D), expression (positive or diffuse) of p53 oncoprotein and variant without characteristic molecular profile, WCMP. Immunohistochemistry was also used to evaluate the expression of Ki67 (DBS antibodies, clone SP6) and CD68 (DAKO antibodies, clone CD8/144B). Results: Obesity was more common in patients with a WCMP tumor type and, especially, in MMR-D group (BMI ratio ≥30.0/<30.0, respectively, 1.62 and 2.32). The highest Ki67 index values were detected with positive (59.3 ± 3.8%) and a combination of positive and diffuse (50.5 ± 3.7%) p53 expression, and the lowest (27.6 ± 1.7%) in the WCMP group. In all EC types (except for cases with p53+), Ki67 expression was lower at BMI ≥30.0, which was confirmed within this subgroup by negative Spearman correlation of Ki67 level with BMI value. CD68 expression showed a downward trend in the MMR-D and WCMP types (124.4 ± 7.8 and 115.0 ± 5.9 cond.un.) and a tendency to positive correlation with Ki67 in obese women belonging to the POLE and p53 groups. Conclusions: The findings suggest that the level of such important prognostic tumor markers as Ki67 and CD68 (Soeda et al., 2008) is characterized by a relationship with the presence/absence of obesity as well as with EC molecular-biological type, that expands target range for preventive and therapeutic interventions. Acknowledgement to grant 18-015-00026

Evolution of characteristics of women with endometrial cancer during a 40 years study period

ObjectivesThe aim of our work was to investigate changes in presentation and endometrial cancer (EC) types frequencies thorough a 40 years study period. Patients and methodsThe patient group consisted of consecutive women undergoing surgery for endometrial cancer in our institution between 1975, and 2014. Clinical data included age, BMI (Kg/m2), histological data from surgical staging and survival data. Results842 patients with the final diagnosis of endometrial cancer were enrolled. BMI was overweight rising through study decades. Age of diagnosis was also in constant augmentation since 1975. Type II EC proportion was 9.2% in the seventies and 27.9% after 2000. Overall survival was stable over time. Women with BMI < 18 kg/m2 had lower overall survival when compared to women with other BMI categories (p < 0.0001). Discussion and conclusionAn analysis on a larger population of underweight women with EC is needed to identify specific factors. A trend to develop more type II EC can partly explain these results. We identified a clear trend of augmentation of type II EC, known to have a poor prognosis while necessitating specific surgical management. Histologic analysis standardisation, surgical strategy and amelioration of adjuvant treatments permitted to maintain a stable overall survival for the whole population despite this augmentation.

The Results of Surgico-Pathologic Factors in Patients with Non-Endometrioid Type Endometrial Cancer: Is Tumor Type Important for Lymph Node Metastasis?

The Results of Surgico-Pathologic Factors in Patients with Non-Endometrioid Type Endometrial Cancer: Is Tumor Type Important for Lymph Node Metastasis?