PErsonalized TReatment for Endometrial Carcinoma (PETREC): study design and methods of a prospective Finnish multicenter trial.

BACKGROUND: Endometrial carcinomas can be classified into four molecular subgroups - mismatch repair deficient (MMRd), p53 abnormal (p53abn), polymerase-ϵ (POLE) ultramutated, and 'no specific molecular profile' (NSMP). Retrospective data imply that the response to adjuvant therapies may depend on the molecular subgroup. These findings emphasize the need for adjuvant therapy trials where patients are randomized to treatment arms separately within each molecular subgroup. PRIMARY OBJECTIVE: The PErsonalized TReatment for Endometrial Carcinoma (PETREC) trial clarifies the value of molecular classification in the determination of adjuvant therapies of high-intermediate risk and early-stage high-risk endometrial carcinoma. STUDY HYPOTHESIS: Compared with vaginal brachytherapy, the utilization of whole pelvic radiotherapy may result in improved outcomes for either MMRd or NSMP high-intermediate risk carcinomas. Early-stage high-risk p53abn and nonendometrioid carcinomas are postulated to gain benefits from chemoradiotherapy, as opposed to chemotherapy alone. POLE ultramutated carcinomas harboring high-intermediate or high-risk clinicopathologic features are speculated to have favorable prognosis without any adjuvant therapy. TRIAL DESIGN: This prospective, multicenter, phase 3 trial compares the efficacy of vaginal brachytherapy vs whole pelvic radiotherapy in high-intermediate risk MMRd and NSMP molecular subgroups, and chemotherapy vs chemoradiotherapy in early-stage high-risk p53abn subtype and nonendometrioid carcinomas. Eligible women who consent to participation in the trial are randomly allocated (1:1) to treatment arms. MAJOR INCLUSION/EXCLUSION CRITERIA: Women with stages I-II molecular integrated high-intermediate risk or high-risk endometrial carcinoma will be included. PRIMARY ENDPOINT: The primary endpoint is the 5 year cumulative incidence of disease recurrence. SAMPLE SIZE: A total sample size of 294 patients (49 subjects in each treatment arm of the three subgroups intended for randomization) was estimated to be sufficient. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed in 2025, and follow-up will be completed in 2030. TRIAL REGISTRATION: NCT05655260.

Mode of delivery of Finnish dichorionic and monochorionic-diamniotic twins: A retrospective observational study including a risk score for intrapartum cesarean birth.

Background and Aims: Trial of labor is considered safe also among twins, yet nearly 50% are born via cesarean section in Finland. While planned cesarean births have declined among twins, intrapartum cesarean deliveries have risen, postulating evaluation of criteria for trial of labor. The objective of this study was to create an outline of the mode of delivery of dichorionic and monochorionic-diamniotic Finnish twins. By evaluating risk factors for intrapartum cesarean delivery (CD), we aimed at creating a risk score for intrapartum cesarean birth for twins. Methods: A retrospective observational study based on a cohort of dichorionic and monochorionic-diamniotic twin pregnancies considered as candidates for trial of labor in 2006, 2010, 2014, and 2018 (n = 720) was performed. Differences between parturients with vaginal delivery and intrapartum CD to identify potential risk factors for intrapartum CD were assessed. Logistic regression analysis (n = 707) was used to further define risk score points for recognized risk factors. Results: A total of 23.8% (171/720, 95% confidence interval [CI] = 20.7-26.9) of parturients experienced intrapartum CD. Induction of labor, primiparity, fear of childbirth, artificial reproductive technology, higher maternal age, and other than cephalic/cephalic presentation independently associated with intrapartum CD. The achieved total risk score ranged from 0 to 13 points with significantly higher points among the CD group (6.61 vs. 4.42, p < 0.001). Using ≥8 points as a cut-off, 51.4% (56/109) were delivered by intrapartum CD (sensitivity = 33.73%, specificity = 90.20%, positive predictive value = 51.38%, negative predictive value = 81.61%). The total risk score had a fair predictive capability for intrapartum CD (area under the curve = 0.729, 95% CI = 0.685-0.773). Conclusion: Fair-level risk stratification could be achieved with higher maternal age, primiparity, induction of labor, artificial reproductive technology, fear of childbirth, and other than cephalic/cephalic presentation increasing the risk. Parturients with low-risk score (0-7 points) appear to be the best candidates for trial of labor with acceptable CD rates in this group (18.4%).

Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma.

Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.

Interpretable prognostic modeling of endometrial cancer.

Endometrial carcinoma (EC) is one of the most common gynecological cancers in the world. In this work we apply Cox proportional hazards (CPH) and optimal survival tree (OST) algorithms to the retrospective prognostic modeling of disease-specific survival in 842 EC patients. We demonstrate that linear CPH models are preferred for the EC risk assessment based on clinical features alone, while interpretable, non-linear OST models are favored when patient profiles can be supplemented with additional biomarker data. We show how visually interpretable tree models can help generate and explore novel research hypotheses by studying the OST decision path structure, in which L1 cell adhesion molecule expression and estrogen receptor status are correctly indicated as important risk factors in the p53 abnormal EC subgroup. To aid further clinical adoption of advanced machine learning techniques, we stress the importance of quantifying model discrimination and calibration performance in the development of explainable clinical prediction models.

Stillbirth aftercare in a tertiary obstetric center - parents' experiences.

OBJECTIVES: This study aimed to assess parents' satisfaction with received care and support when experiencing stillbirth. METHODS: This was a questionnaire survey conducted at Helsinki University Hospital, Helsinki, Finland during 2016-2020. Separate questionnaires were sent to mothers and partners who had experienced an antepartum singleton stillbirth at or after 22 gestational weeks during 2016-2019. The questionnaire covered five major topics: stillbirth diagnosis, delivery, information on postmortem examinations, aftercare at the ward, and follow-up appointment. RESULTS: One hundred nineteen letters were sent and 57 (47.9%) of the mothers and 46 (38.7%) of their partners responded. Both mothers and their partners felt well supported during delivery. They were also satisfied with the time holding their newborn. Partners reported even higher satisfaction in this aspect with a significant within-dyad difference (p=0.049). Parents were generally pleased with the support at the ward. However, both groups were less satisfied with social worker counseling (mothers 53.7%, partners 61.0%). The majority felt that the follow-up visit was helpful. Nonetheless, a remarkable proportion felt that the follow-up visit increased their anxiousness (25.9%, 14.0%, p=0.018). Partners rated their mood higher than mothers (p=0.001). Open feedback revealed that the support received after discharge from hospital was often insufficient. CONCLUSIONS: Our study showed that the parents who experience stillbirth in our institution receive mostly adequate care and support during their hospital stay. However, there is room for further training of healthcare professionals and other professionals contributing in stillbirth aftercare.

Molecular classification of endometrial carcinoma: a clinically oriented review.

The Cancer Genome Atlas research network performed a genome-wide analysis of endometrial carcinomas in 2013 and classified tumours into four distinct subgroups: polymerase-ϵ ultramutated, microsatellite unstable hypermutated, copy-number low and copy-number high. These molecular alterations are mostly mutually exclusive as only about 3% of tumours exhibit more than one molecular signature. Apart from the polymerase-ϵ ultramutated subgroup, molecular classification can be reproduced by using surrogate markers. This has facilitated the implementation of molecular diagnostics into routine patient care. Molecular subgroups are associated with different prognoses; thus, improved risk assessment is their most obvious clinical application. However, based on their unique molecular architectures, molecular subgroups should not be regarded simply as risk groups but rather as distinct diseases. This has prompted us and others to examine the role of molecular subgroups in modifying the prognostic effect of traditional risk factors, including clinical factors, uterine factors and tissue biomarkers, and in predicting the response to adjuvant therapies. In the following review, we summarise the current knowledge of molecularly classified endometrial carcinoma and present, based on our own experience, a proposal for implementing molecular classification into daily practice in pathology laboratories.

Testing for Lynch Syndrome in Endometrial Carcinoma: From Universal to Age-Selective MLH1 Methylation Analysis.

International guidelines recommend universal screening of endometrial carcinoma (EC) patients for Lynch syndrome (LS). This screening is generally based on mismatch repair (MMR) protein immunohistochemistry followed by MLH1 methylation analysis of MLH1-negative cases to exclude the likely sporadic cases from germline testing. As LS-associated EC is uncommon in the elderly, age-selective methylation testing could improve cost-efficiency. We performed MMR immunohistochemistry on 821 unselected ECs (clinic-based cohort) followed by a MLH1 promoter methylation test of all MLH1/PMS2-negative tumors. Non-methylated MLH1-deficient cases underwent NGS and MLPA-based germline analyses to identify MLH1 mutation carriers. A reduction in the test burden and corresponding false negative rates for LS screening were investigated for various age cut-offs. In addition, the age distribution of 132 MLH1 mutation carriers diagnosed with EC (registry-based cohort) was examined. A germline MLH1 mutation was found in 2/14 patients with non-methylated MLH1-deficient EC. When compared to a universal methylation analysis, selective testing with a cut-off age of 65 years, would have reduced the testing effort by 70.7% with a false negative rate for LS detection of 0% and 3% in the clinic and registry-based cohorts, respectively. The use of age-selective methylation analysis is a feasible way of reducing the costs and laboratory burden in LS screening for EC patients.

Clinicopathologic vs. Molecular Integrated Prognostication of Endometrial Carcinoma by European Guidelines.

This was a retrospective study of 604 patients with endometrial carcinoma, classified into ESGO-ESTRO-ESP 2021 clinicopathologic and molecular integrated risk groups. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) and Leiden classifier were employed for molecular classification. Median follow-up time was 81 months. Clinicopathologic and molecular integrated risk groups were similarly associated with distinct prognoses (p < 0.001). Disease-specific survival was similar for all molecular subgroups within clinicopathologic intermediate-risk, high-risk, and advanced/metastatic groups. In contrast, the p53 abnormal subgroup (hazard ratio 9.1, 95% confidence interval 2.0-41; p = 0.004) and mismatch repair deficient subgroup (hazard ratio 3.5, 95% confidence interval 1.2-10; p = 0.024) were associated with disease-related death within clinicopathologic low-risk and high-intermediate-risk carcinomas, respectively. A risk-group shift occurred in 6.0% (36/604) and 7.4% (38/515) of patients classified by ProMisE and Leiden, respectively (p = 0.341). Of the 36 patients shifted in the ProMisE cohort, 27 were upshifted and 9 downshifted. Based on the Leiden classifier, polymerase-ϵ sequencing could be omitted in 60% (311/515) of patients without affecting the risk-group assessment. ESGO-ESTRO-ESP 2021 guidelines provide a platform for risk classification in future trials on molecularly directed treatment of endometrial carcinoma.

Delivery characteristics in pregnancies with stillbirth: a retrospective case-control study from a tertiary teaching hospital.

OBJECTIVES: We compared delivery characteristics and outcome of women with stillbirth to those with live birth. METHODS: This was a retrospective case-control study from Helsinki University Hospital, Finland. The study population comprised 214 antepartum singleton stillbirths during 2003-2015. Two age-adjusted controls giving live birth in the same year at the same institution were chosen for each case from the Finnish Medical Birth Register. Delivery characteristics and adverse pregnancy outcomes were compared between the cases and controls, adjusted for gestational age. RESULTS: Labor induction was more common (86.0 vs. 22.0%, p<0.001, gestational age adjusted odds ratio [aOR] 35.25, 95% confidence interval [CI] 12.37-100.45) and cesarean sections less frequent (9.3 vs. 28.7%, p<0.001, aOR 0.21, 95% CI 0.10-0.47) among women with stillbirth. Duration of labor was significantly shorter among the cases (first stage 240.0 min [115.0-365.0 min] vs. 412.5 min [251.0-574.0 min], p<0.001; second stage 8.0 min [0.0-16.0 min] vs. 15.0 min [4.0-26.0 min], p<0.001). Placental abruption was more common in pregnancies with stillbirth (15.0 vs. 0.9%, p<0.001, aOR 8.52, 95% CI 2.51-28.94) and blood transfusion was needed more often (10.7 vs. 4.4%, p=0.002, aOR 6.5, 95% CI 2.10-20.13). The rates of serious maternal complications were low. CONCLUSIONS: Most women with stillbirth delivered vaginally without obstetric complications. The duration of labor was shorter in pregnancies with stillbirth but the risk for postpartum interventions and bleeding complications was higher compared to those with live birth.

Low Expression of Stanniocalcin 1 (STC-1) Protein Is Associated With Poor Clinicopathologic Features of Endometrial Cancer.

Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors (p = 0.030), deep myometrial invasion (p = 0.003), lymphovascular space invasion (p = 0.050), and large tumor size (p = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women (p = 0.014) and in women with diabetes mellitus type 2 (DMT2; p = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium (p = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment.

Differential impact of clinicopathological risk factors within the 2 largest ProMisE molecular subgroups of endometrial carcinoma.

OBJECTIVE: To assess whether the prognostic impact of conventional risk factors and ancillary biomarkers differs across the 2 largest ProMisE molecular subgroups of endometrial carcinoma (EC). METHODS: Direct sequencing of POLE exonuclease domain hot spots and immunohistochemistry for MLH1, PMS2, MSH2, MSH6 and p53 were performed on 745 unselected endometrioid ECs to identify mismatch repair deficient (MMR-D, n = 264) and no specific molecular profile (NSMP, n = 206) ECs. Molecular group-specific survival analyses and interaction analyses were performed to determine the prognostic relevance of clinicopathological factors and various biomarkers (L1 cell adhesion molecule, estrogen and progesterone receptor, beta-catenin, p16, E-cadherin, KRAS) within the subgroups. RESULTS: Molecular subgroup did not have an independent effect on disease-specific survival after adjustment for conventional risk factors (P = 0.101). High grade (G3) and p16 hyperexpression remained significant predictors of survival in NSMP. Stage II-IV, ≥50% myometrial invasion, lymphovascular space invasion and loss of E-cadherin were independent predictors in the MMR-D group. In the interaction analysis, molecular subclass significantly modified the prognostic effect of high grade and p16 hyperexpression, which showed a stronger negative effect on survival in NSMP as compared to MMR-D (P for interaction = 0.016 for grade and 0.033 for p16). CONCLUSIONS: Grade of differentiation and p16 hyperexpression appear to have a stronger prognostic impact in NSMP as compared to MMR-D EC. While these results need to be confirmed in a larger study population, they indicate that differential impact of risk factors needs to be taken into account when developing new molecular class-integrated risk stratification algorithms for EC.

Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma.

The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based on The Cancer Genome Atlas (TCGA), tumors with abnormal p53 staining or polymerase-ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, termed as "no specific molecular profile" (NSMP). Compared with NSMP (n = 218), MMR deficiency (n = 191) was associated with poor disease-specific survival (p = 0.001). MMR deficiency was associated with an increased risk of cancer-related death when controlling for confounders (hazard ratio 2.0). In the absence of established clinicopathologic risk factors, MMR deficiency was invariably associated with an increased risk of cancer-related death in univariable analyses (hazard ratios ≥ 2.0). In contrast, outcomes for MMR deficient and NSMP subgroups did not differ when risk factors were present. Lymphatic dissemination was more common (p = 0.008) and the proportion of pelvic relapses was higher (p = 0.029) in the MMR deficient subgroup. Our findings emphasize the need for improved triage to adjuvant therapy and new therapeutic approaches in MMR deficient endometrial carcinomas.

Mismatch repair protein and MLH1 methylation status as predictors of response to adjuvant therapy in endometrial cancer.

BACKGROUND: Mismatch repair (MMR) system has been implicated in the response of mammalian cells to ionizing radiation and DNA damaging agents. We investigated the value of the MMR system in predicting response to adjuvant therapy in endometrial cancer. METHODS: This was a single institution retrospective study. MMR protein status of endometrial carcinomas was assessed by immunohistochemistry. MMR deficient (MMR-D) tumors were identified as MLH1 methylated or nonmethylated by methylation-specific multiplex ligation-dependent probe amplification. Tumors with abnormal p53 staining or polymerase ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, which was termed as "no specific molecular profile" (NSMP). Disease-specific survival analyses were adjusted for age, stage, histology and grade, depth of myometrial invasion, and lymphovascular space invasion. RESULTS: A total of 505 patients were included in the study. Median follow-up time was 81 months (range 1-136). Whole pelvic radiotherapy (adjusted hazard ratio [HR] 0.092 vs. no adjuvant therapy) and chemotherapy combined with radiotherapy (adjusted HR 0.18) were associated with improved disease-specific survival in the NSMP subgroup (n = 218). In contrast, adjuvant therapies showed no effect on disease-specific survival in the full MMR-D cohort (n = 287) or in MLH1 methylated tumors (n = 154). Whole pelvic radiotherapy (adjusted HR 25 vs. no adjuvant therapy/vaginal brachytherapy) and chemotherapy combined with whole pelvic radiotherapy (adjusted HR 32) were associated with poor disease-specific survival in MMR-D nonmethylated tumors (n = 70). CONCLUSION: MMR protein and MLH1 methylation status predict the response to adjuvant therapy in endometrial cancer. The MMR system could be utilized for selection of patients who most likely benefit from adjuvant therapy.

Is there an association between postpartum hemorrhage, interventional radiology procedures, and psychological sequelae?

BACKGROUND: Postpartum hemorrhage (PPH) may cause post-traumatic psychological sequelae. Interventional radiology procedures (IRP) have been established in the management of PPH when conventional management fails. IRP is also used prophylactically in women who are at high risk for PPH in pregnancies with abnormally invasive placentation. We sought to determine if there is an association between PPH, IRP, and psychological sequelae. OBJECTIVES: Seventy-three women who underwent IRP due to PPH or were at high risk for PPH. METHOD: A structured questionnaire was sent to all women. RESULTS: Overall 49 women returned the questionnaire. Two-thirds of the women developed psychological sequelae and one-third reported a lack of professional support. Nine women had symptoms of post-traumatic stress disorder. Psychological sequelae were not associated with a volume of bleeding, whether or not hysterectomy was performed, or whether the IRP was performed as an emergency procedure or prophylactically. However, women who had elective IRP and no hysterectomy performed had significantly less fear of death compared to the rest of the study population. CONCLUSIONS: We observed a high rate of psychological sequelae associated with IRP. Lack of proper professional support may have contributed to the development of post-traumatic psychological sequelae suggesting a need for debriefing in such women.

Molecular characterization in the prediction of disease extent in endometrial carcinoma.

OBJECTIVE: Patients with endometrial carcinoma are usually triaged to staging lymphadenectomy selectively based on estimated risk of lymphatic spread. The risk is generally assessed by the presence of uterine risk factors, but their preoperative and intraoperative identification remain a challenge. The objective of this study was to assess the capability of molecular classification, described by The Cancer Genome Atlas (TCGA), to predict the stage of endometrial carcinoma. STUDY DESIGN: Sequencing of polymerase-ε (POLE) and immunohistochemistry of mismatch repair (MMR) proteins and p53 were performed to stratify endometrial carcinomas into subgroups of POLE exonuclease domain mutation (EDM), MMR deficiency, abnormal p53 (p53 abn) and 'no specific molecular profile' (NSMP). NSMP was the reference subgroup for comparisons. Associations of molecular subgroups and uterine risk factors with stage were examined in univariable and multivariable analyses. RESULTS: Six hundred and four patients were included in the study. None of the POLE EDM tumours extended beyond the uterine cervix. In an unadjusted analysis, p53 abn was associated with increased risk for stage IIIC-IV disease [odds ratio (OR) 4.6, 95% confidence interval (CI) 2.3-9.2; p < 0.0005]. When controlling for uterine risk factors (histotype and grade, depth of myometrial invasion, tumour size, lymphovascular space invasion), p53 was not an independent predictor of advanced disease. In contrast, POLE EDM independently predicted local disease (OR 0.12, 95% CI 0.015-0.99; p = 0.049 for stage II-IV cancer). Of the molecular subgroups, p53 abn was most strongly associated with the presence of high-risk uterine factors (ORs between 2.2 and 19; p ≤ 0.010). CONCLUSION: Of the TCGA-based molecular subgroups, POLE EDM independently predicted early-stage endometrial carcinoma. Although p53 abn was not an independent predictor of advanced disease, its association with uterine risk factors could allow utilization of molecular data in deciding the type of staging surgery if knowledge of uterine factors is deficient.

Clinical factors as prognostic variables among molecular subgroups of endometrial cancer.

BACKGROUND: Clinical factors may influence endometrial cancer survival outcomes. We examined the prognostic significance of age, body mass index (BMI), and type 2 diabetes among molecular subgroups of endometrial cancer. METHODS: This was a single institution retrospective study of patients who underwent surgery for endometrial carcinoma between January 2007 and December 2012. Tumors were classified into four molecular subgroups by immunohistochemistry of mismatch repair (MMR) proteins and p53, and sequencing of polymerase-ϵ (POLE). Overall, cancer-related, and non-cancer-related mortality were estimated using univariable and multivariable survival analyses. RESULTS: Age >65 years was associated with increased mortality rates in the whole cohort (n = 515) and in the "no specific molecular profile" (NSMP) (n = 218) and MMR deficient (MMR-D) (n = 191) subgroups during a median follow-up time of 81 months (range 1‒136). However, hazard ratios for cancer-related mortality were non-significant for NSMP and MMR-D. Diabetes was associated with increased overall and non-cancer-related mortality in the whole cohort and MMR-D subgroup. Overweight/obesity had no effect on outcomes in the whole cohort, but was associated with decreased overall and cancer-related mortality in the NSMP subgroup, and increased overall and non-cancer-related mortality in the MMR-D subgroup. Overweight/obesity effect on cancer-related mortality in the NSMP subgroup remained unchanged after controlling for confounders. High-risk uterine factors were more common, and estrogen and progesterone receptor expression less common in NSMP subtype cancers of normal-weight patients compared with overweight/obese patients. No clinical factors were associated with outcomes in p53 aberrant (n = 69) and POLE mutant (n = 37) subgroups. No cancer-related deaths occurred in the POLE mutant subgroup. CONCLUSIONS: The prognostic effects of age, BMI, and type 2 diabetes do not appear to be uniform for the molecular subgroups of endometrial cancer. Our data support further evaluation of BMI combined with genomics-based risk-assessment.

Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness.

Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.

Altered glycosylation of glycodelin in endometrial carcinoma.

Glycodelin is a major glycoprotein expressed in reproductive tissues, like secretory and decidualized endometrium. It has several reproduction related functions that are dependent on specific glycosylation, but it has also been found to drive differentiation of endometrial carcinoma cells toward a less malignant phenotype. Here we aimed to elucidate whether the glycosylation and function of glycodelin is altered in endometrial carcinoma as compared with a normal endometrium. We carried out glycan structure analysis of glycodelin expressed in HEC-1B human endometrial carcinoma cells (HEC-1B Gd) by mass spectrometry glycomics strategies. Glycans of HEC-1B Gd were found to comprise a typical mixture of high-mannose, hybrid, and complex-type N-glycans, often containing undecorated LacNAc (Galß1-4GlcNAc) antennae. However, several differences, as compared with previously reported glycan structures of normal human decidualized endometrium-derived glycodelin isoform, glycodelin-A (GdA), were also found. These included a lower level of sialylation and more abundant poly-LacNAc antennae, some of which are fucosylated. This allowed us to select lectins that showed different binding to these classes of glycodelin. Despite the differences in glycosylation between HEC-1B Gd and GdA, both showed similar inhibitory activity on trophoblast cell invasion and peripheral blood mononuclear cell proliferation. For the detection of cancer associated glycodelin, we established a novel in situ proximity-ligation based histochemical staining method using a specific glycodelin antibody and UEAI lectin. We found that the UEAI reactive glycodelin was abundant in endometrial carcinoma, but virtually absent in normal endometrial tissue even when glycodelin was strongly expressed. In conclusion, we established a histochemical staining method for the detection of endometrial carcinoma-associated glycodelin and showed that this specific glycodelin is exclusively expressed in cancer, not in normal endometrium. Similar methods can be used for studies of other glycoproteins.

Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in endometrioid endometrial carcinoma.

The pathogenesis of DNA mismatch repair (MMR)-deficient endometrial carcinoma (EC) is driven by inactivating methylation or less frequently mutation of an MMR gene (MLH1, PMS2, MSH2, or MSH6). This study evaluated the prognostic and clinicopathologic differences between methylation-linked and nonmethylated MMR-deficient endometrioid ECs. We performed MMR immunohistochemistry and methylation-specific multiplex ligation-dependent probe amplification, and classified 682 unselected endometrioid ECs as MMR proficient (MMRp, n = 438) and MMR deficient (MMRd, n = 244), with the latter subcategorized as methylated (MMRd Met) and nonmethylated tumors. Loss of MMR protein expression was detected in 35.8% of the tumors as follows: MLH1 + PMS2 in 29.8%, PMS2 in 0.9%, MSH2 + MSH6 in 1.3%, MSH6 in 2.8%, and multiple abnormalities in 0.9%. Of the 244 MMRd cases, 76% were methylation-linked. MMR deficiency was associated with older age, high grade of differentiation (G3), advanced stage (II-IV), larger tumor size, abundant tumor-infiltrating lymphocytes, PD-L1 positivity in immune cells and combined positive score, wild-type p53, negative L1CAM, ARID1A loss, and type of adjuvant therapy. MMRd-Met phenotype correlated with older age and larger tumor size, and predicted diminished disease-specific survival in the whole cohort. In the MMRd subgroup, univariate analysis demonstrated an association between disease-specific survival and disease stage II-IV, high grade (G3), deep myometrial invasion, lymphovascular invasion, ER negativity, and L1CAM positivity. In conclusion, MMR methylation profile correlates with clinicopathologic characteristics of endometrioid EC, and MMRd-Met phenotype predicts lower disease-specific survival. MMR deficiency, but not MLH1 methylation status, correlates with T-cell inflammation and PD-L1 expression.