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On February 6th, 2024, Gynecologic Oncology Reports and the Society of Gynecologic Oncology Education Committee co-hosted a webinar about ways to use social media for career enhancement and for dissemination of research. During the discussion, we reviewed:i.how to identify one's goals, target audience, and select a social media platform.ii.how to navigate the negatives of social media.iii.how to develop one's online academic brand.iv.how to use social media for academic promotion and career advancement.v.how to use social media as a research tool.vi.how to use visual tools to bring attention to one's research.The objective of this report is to review the literature on social media in oncology and review the webinar presentation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Teplinsky receives compensation from Meta. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

With the advancement of diagnostic molecular technology and the molecular classification of endometrial endometrioid carcinoma (EEC), it remains to be seen whether conventional International Federation of Gynecology and Obstetrics (FIGO) grading retains clinical significance in certain molecular subtypes of EECs. In this study, we explored the clinical significance of FIGO grading in microsatellite instability-high (MSI-H) and POLE-mutant EECs. A total of 162 cases of MSI-H EECs and 50 cases of POLE-mutant EECs were included in the analysis. Significant differences in tumor mutation burden (TMB), progression-free survival, and disease-specific survival were seen between the MSI-H and POLE-mutant cohorts. Within the MSI-H cohort, there were statistically significant differences in TMB and stage at presentation across FIGO grades, but not survival. Within the POLE-mutant cohort, there was significantly greater TMB with increasing FIGO grade, but there were no significant differences in stage or survival. In both the MSI-H and POLE-mutant cohorts, log-rank survival analysis showed no statistically significant difference in progression-free and disease-specific survival across FIGO grades. Similar findings were also seen when a binary grading system was utilized. Since FIGO grade was not associated with survival, we conclude that the intrinsic biology of these tumors, characterized by their molecular profile, may override the significance of FIGO grading., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features., Methods: Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests., Results: Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P < .001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47 of 75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination related genes, including BRCA1,BRCA2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)-high subtypes (3 of 12 [25%] POLE, 30 of 77 [39%] MSI-H, 27 of 60 [45%] CN-high, 9 of 57 [16%] CN-low; P < .001)., Conclusions: Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression., Competing Interests: Declaration of interests S.C. receives consulting fees from Novartis, Lilly, and Sanofi and research funding from Daiichi-Sankyo and Paige.ai. J.J.H. receives consulting fees from Bristol Myers Squibb, Merck, Exelexis, Eisai, QED, Cytomx, Zymeworks, Adaptiimmune, and ImVax and research funding from Bristol Myers Squibb. C.A.I.-D. receives research funding from Bristol Myers Squibb. P. Razavi received consultation/Ad board/Honoraria from Novartis, Foundation Medicine, AstraZeneca, Epic Sciences, Inivata, Natera, and Tempus and institutional grant/funding from Grail, Illumina, Novartis, Epic Sciences, and ArcherDx. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Astra Zeneca, Epizyme, Genentech/Roche, Ipsen, Jazz, Lilly, and Syros and serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. D.Z. receives research funding from Astra Zeneca, Plexxikon, and Genentech and consulting fees from Merck, Synlogic Therapeutics, GSK, Bristol Myers Squibb, Genentech, Xencor, Memgen, Immunos, Agenus, Hookipa, Calidi, and Synthekine. B.W. has an ad hoc membership advisory board Repare Therapeutics. W.A. receives speaking honoraria from Roche, Medscape, Aptitude Health, and Clinical Education Alliance; consulting fees from Clovis Oncology, Janssen, ORIC pharmaceuticals, Daiichi Sankyo; and research funding from AstraZeneca, Zenith Epigenetics, Clovis Oncology, ORIC pharmaceuticals, and Epizyme. G.K.A.-A. receives research funding from Arcus, Agios, Astra Zeneca, Bayer, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Sillajen, and Yiviva and consulting fees from Adicet, Agios, Astra Zeneca, Alnylam, Autem, Bayer, Beigene, Berry Genomics, Cend, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Loxo, Merck, MINA, Nerviano, QED, Redhill, Rafael, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, Twoxar, Vector, and Yiviva. E.M.O. receives research funding from Genentech/Roche, Celgene/BMS, BioNTech, BioAtla, AstraZeneca, Arcus, Elicio, Parker Institute, and AstraZeneca and consulting fees from Cytomx Therapeutics (DSMB), Rafael Therapeutics (DSMB), Sobi, Silenseed, Tyme, Seagen, Molecular Templates, Boehringer Ingelheim, BioNTech, Ipsen, Polaris, Merck, IDEAYA, Cend, AstraZeneca, Noxxon, BioSapien, Bayer (spouse), Genentech-Roche (spouse), Celgene-BMS (spouse), and Eisai (spouse). M.A.P. receive consulting fees from BMS, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Aduro, Eisai, and Pfizer; honoraria from BMS and Merck; research support from RGenix, Infinity, BMS, Merck, Array BioPharma, Novartis, and AstraZeneca. G.J.R. has institutional research funding from Mirait, Takeda, Merck, Roche, Novartis, and Pfizer. S.F.B. holds a patent related to some of the work described targeting CIN in advanced cancer. He owns equity in, receives compensation from, and serves as a consultant and the scientific advisory board and board of directors of Volastra Therapeutics Inc. A.N.S. has advisory board/personal fees from Bristol-Myers Squibb, Immunocore, and Castle Biosciences; research support from Bristol-Myers Squibb, Immunocore, Xcovery, Polaris, Novartis, Pfizer, and Checkmate Pharmaceuticals; and research funding from OBI-Pharma, GSK, Silenseed, BMS, and Lilly. R.Y. receives consulting fees from Array BioPharma/Pfizer, Mirati Therapeutics, and Natera and research funding from Pfizer and Boehringer Ingelheim. D.R.J. is member of the advisory council for Astra Zeneca and member of the Clinical Trial Steering Committee for Merck. D.M. reports disclosures from AstraZeneca, Johnson & Johnson, Boston Scientific, Bristol-Myers Squibb, and Merck. S.P.S. is shareholder and consultant for Canexia Health Inc. M.F.B receives consulting fees from Roche, Eli Lilly, and PetDx and research funding from Grail. D.B.S. has received consulted for and received honoraria from Pfizer, Lilly/Loxo Oncology, Vividion Therapeutics, Scorpion Therapetuics, and BridgeBio. B.N. is an employee of Loxo Oncology at Lilly., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Single-cell RNA sequencing (scRNA-seq) technology has emerged as a powerful tool for dissecting cellular heterogeneity and understanding the intricate biology of diseases, including cancer. Endometrial cancer (EC) stands out as the most prevalent gynecological malignancy in Europe and the second most diagnosed worldwide, yet its cellular complexity remains poorly understood. In this review, we explore the contributions of scRNA-seq studies to shed light on the tumor cells and cellular landscape of EC. We discuss the diverse tumoral and microenvironmental populations identified through scRNA-seq, highlighting the implications for understanding disease progression. Furthermore, we address potential limitations inherent in scRNA-seq studies, such as technical biases and sample size constraints, emphasizing the need for larger-scale research encompassing a broader spectrum of EC histological subtypes. Notably, a significant proportion of scRNA-seq analyses have focused on primary endometrioid carcinoma tumors, underscoring the need to incorporate additional histological and aggressive types to comprehensively capture the heterogeneity of EC. By critically evaluating the current state of scRNA-seq research in EC, this review underscores the importance of advancing towards more comprehensive studies to accelerate our understanding of this complex disease. [ABSTRACT FROM AUTHOR]

Endometrial cancer in Lynch syndrome is characterized by a higher incidence, younger age at onset, and increased recurrence rates compared to sporadic cases, while the safety and efficacy of fertility-sparing treatments remain uncertain. This case report presents the oncology outcome of fertilitypreserving treatment in a 39-year-old woman diagnosed with Lynch syndrome and atypical endometrial hyperplasia. Initially, she responded favorably to fertility-preserving treatment but subsequently experienced disease relapse and rapid progression during retreatment. Final pathology revealed endometrial cancer with metastasis to the right ovary, categorized as FIGO 2023 stage IIIA1. This population's unique molecular mechanisms and genetic mutations warrant special consideration when opting for fertility-sparing treatment. We have reviewed and summarized the oncology and pregnancy outcomes among Lynch syndrome and MMR-deficient patients through previous literature. However, no studies have investigated retreatment after recurrence in Lynch syndrome. Our case highlights the potential risks associated with retreatment following relapse. Vigilant monitoring and prompt consideration of surgical intervention are recommended upon disease relapse. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is a heterogeneous disease with a rising incidence worldwide. The understanding of its molecular pathways has evolved substantially since The Cancer Genome Atlas (TCGA) stratified endometrial cancer into four subgroups regarding molecular features: POLE ultra-mutated, microsatellite instability (MSI) hypermutated, copy-number high with TP53 mutations, and copy-number low with microsatellite stability, also known as nonspecific molecular subtype (NSMP). More recently, the International Federation of Gynecology and Obstetrics (FIGO) updated their staging classification to include information about POLE mutation and p53 status, as the prognosis differs according to these characteristics. Other biomarkers are being identified and their prognostic and predictive role in response to therapies are being evaluated. However, the incorporation of molecular aspects into treatment decision-making is challenging. This review explores the available data and future directions on tailoring treatment based on molecular subtypes, alongside the challenges associated with their testing. [ABSTRACT FROM AUTHOR]

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing. [ABSTRACT FROM AUTHOR]

Complex atypical endometrial hyperplasia (CAH) carries a high probability of cancer. The intraoperative evaluation of endometrial cancer in cases of CAH has not been reliable. The safety and sensitivity of sentinel lymph node (SLN) sampling has been validated. In our study, we aimed to evaluate the efficacy and safety of SLN sampling in CAH managed by the da Vinci robotic platform. A total of 113 patients with a preoperative diagnosis of CAH were included in this retrospective cohort study. All of them underwent a robot-assisted total laparoscopic hysterectomy and bilateral salpingo-oophorectomy, with 69 patients undergoing SLN sampling. A statistical analysis calculated the probability of cancer, the SLN map rate, and surgical complications. The predictors of cancer were evaluated. Descriptive statistics were used to summarize the results; comparative statistics were used to compare the cohorts; and logistical regression analysis was used to predict the risk. Forty-seven percent of the entire cohort was diagnosed with endometrial cancer. The median age was 63 years in the SLN cohort (N = 69) and 61 in the No-SLN cohort (N = 44) (p = 0.363). The median BMI was 34 Kg/m2 in the SLN cohort and 40 in the No-SLN cohort (p = 0.004). The bilateral SLN map was 92.8%, and the unilateral SLN map rate was 7.2%. There were no grade-3–4 complications in the SLN cohort, and four grade-3–4 complications in the No-SLN group (p = 0.021). A preoperative diagnosis of CAH bordering on or unable to rule out cancer was the only predictor of cancer. Sentinel lymph node sampling has a high map rate and low complications in CAH. We recommend a prospective study investigating the clinical benefit of the procedure. [ABSTRACT FROM AUTHOR]

Background: Over the past decades, the rising incidence rates of endometrial cancer have made it a significant public health concern for women worldwide. Treatment strategies for endometrial cancer vary based on several factors such as stage, histology, the patient's overall health, and preferences. However, limited amount of research on treatment patterns and potential correlations with sociodemographic characteristics among Hispanics is available. This study analyzes the treatment patterns for patients diagnosed with endometrial cancer in Puerto Rico. Methods: A secondary database analysis was performed on endometrial cancer cases reported to the Puerto Rico Central Cancer Registry-Health Insurance Linkage Database from 2009 to 2015 (n = 2,488). The study population's sociodemographic and clinical characteristics were described, along with an overview of the therapy options provided to patients receiving care on the island. Logistic regression models were used to evaluate the association of sociodemographic/clinical characteristics with treatment patterns stratified by risk of recurrence. Results: In our cohort, most patients were insured through Medicaid and had a median age of 60 years. Almost 90% of patients received surgery as the first course of treatment. Surgery alone was the most common treatment for low-risk patients (80.2%). High-risk patients were more likely to receive surgery with radiotherapy and chemotherapy (24.4%). Patients with Medicare insurance were five times (HR: 4.84; 95% CI: 2.45–9.58; p < 0.001) more likely to receive surgery when compared with patients insured with Medicaid. In contrast, those with private insurance were twice as likely to receive surgery (HR: 2.38; 95% CI: 1.40–4.04; p = 0.001) when compared to those with Medicaid. Conclusion: These findings provide insight into the treatment patterns for endometrial cancer in Puerto Rico and highlight the importance of considering factors such as disease risk when making treatment decisions. Addressing these gaps in treatment patterns can contribute to effective management of endometrial cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Managing atypical endometrial hyperplasia (AEH) places the gynecologist in a challenging clinical situation. Therapeutic options include conservative or definitive treatment. The main concern is the possibility of concurrent endometrial cancer (EC). This occurrence can lead to undertreatment, whether in the case of conservative or surgical therapy. Therefore, the current literature has worked to identify a better diagnostic therapeutic work-up by focusing on variables predictive of occult cancer, the best preoperative endometrial sampling method, and the possibility of lymph node status assessment for women undergoing surgery. The present review aims to provide a complete overview of all these aspects to summarize the most relevant studies on these topics and better define the clinical management of women with AEH. The present review regarding atypical endometrial hyperplasia (AEH) focused on the main debated factors regarding this challenging clinical condition: (i) predictive variables of occult endometrial cancer (EC); (ii) the rate of EC underestimation according to different endometrial sampling methods; and (iii) the appropriateness of lymph node status assessment. When cancer is detected, approximately 90% of cases include low-risk EC, although intermediate/high-risk cases have been found in 10–13% of women with cancer. Older age, diabetes, high BMI, and increased endometrial thickness are the most recurrent factors in women with EC. However, the predictive power of these independent variables measured on internal validation sets showed disappointing results. Relative to endometrial sampling methods, hysteroscopic endometrial resection (Hys-res) provided the lowest EC underestimation, ranging between 6 and 11%. Further studies, including larger sample sizes of women undergoing Hys-res, are needed to confirm these findings. These data are urgently needed, especially for female candidates for conservative treatment. Finally, the evaluation of lymph node status measured on 660 of over 20,000 women showed a lymph node positivity of 2.3%. Although there has been an increase in the use of this procedure in AEH in recent years, the present data cannot recommend this option in AEH based on a cost/risk/benefit ratio. [ABSTRACT FROM AUTHOR]

Simple Summary: Cervical cancer ranks as the fourth most common malignant neoplasm among women worldwide. In low-income countries, the diagnosis usually occurs at advanced stages, with the recommendation of chemoradiotherapy. When this initial approach fails, with persistent disease or even in the context of tumor recurrence, pelvic exenteration (PE) becomes a therapeutic option to be considered. The criteria for recommending PE have evolved over time, influenced by advancements in surgical techniques and perioperative care. These developments have enhanced the capacity for extended resections and expanded treatment possibilities for patients who were previously limited to palliative measures. Through this review, we aim to provide insights and tools to facilitate the identification of patients who may benefit from such a complex procedure. Pelvic exenteration represents a radical procedure aimed at achieving complete tumor resection with negative margins. Although it is the only therapeutic option for some cases of advanced tumors, it is associated with several perioperative complications. We believe that careful patient selection is related to better oncologic outcomes and lower complication rates. The objectives of this review are to identify the most current indications for this intervention, suggest criteria for case selection, evaluate recommendations for perioperative care, and review oncologic outcomes and potential associated complications. To this end, an analysis of English language articles in PubMed was performed, searching for topics such as the indication for pelvic exenteration for recurrent gynecologic neoplasms selection of oncologic cases, the impact of tumor size and extent on oncologic outcomes, preoperative and postoperative surgical management, surgical complications, and outcomes of overall survival and recurrence-free survival. [ABSTRACT FROM AUTHOR]

Black women are twice as likely to die from endometrial cancer (EC) compared with white women. This represents one of the worst racioethnic disparities amongst all cancers globally. Compared with white women, black women are more likely to be diagnosed with advanced EC, have more barriers to accessing care and experience increased delays in obtaining an EC diagnosis and commencing treatment. Histological and molecular differences place black women at higher risk of being diagnosed with more aggressive EC subtypes that carry less favourable outcomes. Furthermore, EC diagnostic pathways are less reliable in black women, and black women are less likely to receive evidence-based treatment for EC. This racioethnic disparity in EC outcomes exists both in the UK and US, despite differences in healthcare systems. This review methodically describes the key factors along the patient journey that contribute to the disparity in black women and proposes multifaceted approaches to lessen these gaps. [ABSTRACT FROM AUTHOR]

Uterine carcinosarcoma is a rare high-grade endometrial cancer. Controversy has surrounded a number of aspects in the diagnosis and management of this unique clinicopathological entity, including the efficacy of adjuvant therapy, which has been questioned. An unusual surgico-pathological parameter with prognostic significance in a number of tumour sites is the lymph node ratio (LNR). The availability of data in this respect has been scarce in the literature. The primary aim of this collaborative study was to evaluate the prognostic value of LNR in patients with uterine carcinosarcoma. LNR is a recognized lymph node metric used to stratify prognosis in a variety of malignancies. In this European multinational retrospective study, 93 women with uterine carcinosarcoma were included in the final analysis. We used t-tests and ANOVA for comparison between quantitative variables between the groups, and chi-square tests for qualitative variables. A multivariate analysis using Cox regression analysis was performed to determine potential prognostic factors, including the LNR. Patients were grouped with respect to LNR in terms of 0%, 20% > 0% and >20%. The analysis revealed LNR to be a significant predictor of progression-free survival (HR 1.69, CI (1.12–2.55), p = 0.012) and overall survival (HR 1.71, CI (1.07–2.7), p = 0.024). However, LNR did not remain a significant prognostic factor on multivariate analysis. Due to limitations of the retrospective study, a prospective large multinational study, which takes into effect the most recent changes to clinical practice, is warranted to elucidate the value of the pathophysiological metrics of the lymphatic system associated with prognosis. [ABSTRACT FROM AUTHOR]

Nodal status is one of the most important prognostic factors for patients with apparent early stage endometrial cancer. The role of retroperitoneal staging in endometrial cancer is controversial. Nodal status provides useful prognostic data, and allows to tailor the need of postoperative treatments. However, two independent randomized trials showed that the execution of (pelvic) lymphadenectomy increases the risk of having surgery-related complication without improving patients' outcomes. Sentinel node mapping aims to achieve data regarding nodal status without increasing morbidity. Sentinel node mapping is the removal of first (clinically negative) lymph nodes draining the uterus. Several studies suggested that sentinel node mapping is not inferior to lymphadenectomy in identifying patients with nodal disease. More importantly, thorough ultrastaging sentinel node mapping allows the detection of low volume disease (micrometastases and isolated tumor cells), that are not always detectable via conventional pathological examination. Therefore, the adoption of sentinel node mapping guarantees a higher identification of patients with nodal disease than lymphadenectomy. Further evidence is needed to assess the value of various adjuvant strategies in patients with low volume disease and to tailor those treatments also on the basis of the molecular and genomic characterization of endometrial tumors. [ABSTRACT FROM AUTHOR]

CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti‐PD‐1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid‐derived suppressor cells (MDSCs) by tumor‐derived CXCL5 in an AMP‐dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD‐1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD‐1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer (EMC) is the most common female genital tract malignancy with an increasing prevalence in many countries including Japan, a fact that renders early detection and treatment necessary to protect health and fertility. Although early detection and treatment are necessary to further improve the prognosis of women with endometrial cancer, biomarkers that accurately reflect the pathophysiology of EMC patients are still unclear. Therefore, it is clinically critical to identify biomarkers to assess diagnosis and treatment efficacy to facilitate appropriate treatment and development of new therapies for EMC. Methods: In this study, wide-targeted plasma metabolome analysis was performed to identify biomarkers for EMC diagnosis and the prediction of treatment responses. The absolute quantification of 628 metabolites in plasma samples from 142 patients with EMC was performed using ultra-high-performance liquid chromatography with tandem mass spectrometry. Results: The concentrations of 111 metabolites increased significantly, while the concentrations of 148 metabolites decreased significantly in patients with EMC compared to healthy controls. Specifically, LysoPC and TGs, including unsaturated fatty acids, were reduced in patients with stage IA EMC compared to healthy controls, indicating that these metabolic profiles could be used as early diagnostic markers of EMC. In contrast, blood levels of amino acids such as histidine and tryptophan decreased as the risk of recurrence increased and the stages of EMC advanced. Furthermore, a marked increase in total TG and a decrease in specific TGs and free fatty acids including polyunsaturated fatty acids levels were observed in patients with EMC. These results suggest that the polyunsaturated fatty acids in patients with EMC are crucial for disease progression. Conclusions: Our data identified specific metabolite profiles that reflect the pathogenesis of EMC and showed that these metabolites correlate with the risk of recurrence and disease stage. Analysis of changes in plasma metabolite profiles could be applied for the early diagnosis and monitoring of the course of treatment of EMC patients. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) stands as the most prevalent gynecologic malignancy. In the past, it was classified based on its hormone sensitivity. However, The Cancer Genome Atlas has categorized EC into four groups, which offers a more objective and reproducible classification and has been shown to have prognostic and therapeutic implications. Hormonally driven EC arises from a precursor lesion known as endometrial hyperplasia, resulting from unopposed estrogen. EC is usually diagnosed through biopsy, followed by surgical staging unless advanced disease is expected. The typical staging consists of a hysterectomy with bilateral salpingo-oophorectomy and sentinel lymph node biopsies, with a preference placed on a minimally invasive approach. The stage of the disease is the most significant prognostic marker. However, factors such as age, histology, grade, myometrial invasion, lymphovascular space invasion, tumor size, peritoneal cytology, hormone receptor status, ploidy and markers, body mass index, and the therapy received all contribute to the prognosis. Treatment is tailored based on the stage and the risk of recurrence. Radiotherapy is primarily used in the early stages, and chemotherapy can be added if high-grade histology or advanced-stage disease is present. The risk of EC recurrence increases with advances in stage. Among the recurrences, vaginal cases exhibit the most favorable response to treatment, typically for radiotherapy. Conversely, the treatment of widespread recurrence is currently palliative and is best managed with chemotherapy or hormonal agents. Most recently, immunotherapy has emerged as a promising treatment for advanced and recurrent EC. [ABSTRACT FROM AUTHOR]

The dependence of cancer cells on the DNA damage response (DDR) pathway for the repair of endogenous- or exogenous-factor-induced DNA damage has been extensively studied in various cancer types, including endometrial cancer (EC). Targeting one or more DNA damage repair protein with small molecules has shown encouraging treatment efficacy in preclinical and clinical models. However, the genes coding for DDR factors are rarely mutated in EC, limiting the utility of DDR inhibitors in this disease. In the current review, we recapitulate the functional role of the DNA repair system in the development and progression of cancer. Importantly, we discuss strategies that target DDR proteins, including PARP, CHK1 and WEE1, as monotherapies or in combination with cytotoxic agents in the treatment of EC and highlight the compounds currently being evaluated for their efficacy in EC in clinic. Recent studies indicate that the application of DNA damage agents in cancer cells leads to the activation of innate and adaptive immune responses; targeting immune checkpoint proteins could overcome the immune suppressive environment in tumors. We further summarize recently revolutionized immunotherapies that have been completed or are now being evaluated for their efficacy in advanced EC and propose future directions for the development of DDR-based cancer therapeutics in the treatment of EC. [ABSTRACT FROM AUTHOR]

Simple Summary: Mounting evidence show that dedifferentiated and undifferentiated endometrial and ovarian carcinomas (DDC/UDC) are clinically distinct entities with rapid progression, poor response to adjuvant therapy, and grim outcome, even when compared to other high-grade gynecologic malignancies. Unfortunately, they are very challenging to diagnose and often receive a non-specific or ambiguous diagnosis. Immunohistochemical tests for core SWI/SNF proteins (i.e. ARID1B, SMARCA4, and SMARCB1) offer high specificity for DDC/UDC, low cost, and fast turnaround time, unlike DNA sequencing-based assays which currently have very limited use in predicting inactivation core SWI/SNF subunits. Recent reports show that among the known core SWI/SNF proteins, ARID1B inactivation are most common in these tumors, yet this test is rarely available even in tertiary centers. In this opinion I stress the importance of including ARID1B along with other core SWI/SNF proteins in the diagnostic workup of DDC/UDC. Dedifferentiated and undifferentiated endometrial and ovarian carcinomas (DDC/UDC) are aggressive malignancies defined by morphologic and molecular undifferentiation, and associated with core SWI/SNF deficiency. Their main differential diagnoses include high-grade endometrial and ovarian carcinomas that often show overlapping morphologic and molecular profiles. Loss of cell lineage markers expression by immunohistochemistry (IHC) is commonly used to assist diagnosis, but it has poor specificity, while core SWI/SNF deficiency is much more specific. Approximately half of SWI/SNF-deficient DDC/UDC are associated with loss of ARID1B expression, yet, unlike the other core SWI/SNF proteins (SMARCA4 and SMARCB1), this test is rarely available, even in tertiary centers. Mutational testing for ARID1B is increasingly common among targeted DNA sequencing panels, but it is difficult to interpret in the absence of IHC results. Overall, the importance of including ARID1B IHC as part of the routine panel for undifferentiated gynecologic malignancies should be emphasized, especially as SWI/SNF inactivation is becoming a necessary biomarker for diagnostics, clinical management, and clinical trial enrollment. [ABSTRACT FROM AUTHOR]

Chemotherapy resistance remains a major challenge in the treatment of gynecologic malignancies. Increasing evidence suggests that circular RNAs (circRNAs) play a significant role in conferring chemoresistance in these cancers. In this review, we summarize the current understanding of the mechanisms by which circRNAs regulate chemotherapy sensitivity and resistance in gynecologic malignancies. We also discuss the potential clinical implications of these findings and highlight areas for future research. CircRNAs are a novel class of RNA molecules that are characterized by their unique circular structure, which confers increased stability and resistance to degradation by exonucleases. Recent studies have shown that circRNAs can act as miRNA sponges, sequestering miRNAs and preventing them from binding to their target mRNAs. This can lead to upregulation of genes involved in drug resistance pathways, ultimately resulting in decreased sensitivity to chemotherapy. We discuss several specific examples of circRNAs that have been implicated in chemoresistance in gynecologic cancers, including cervical cancer, ovarian cancer, and endometrial cancer. We also highlight the potential clinical applications of circRNA-based biomarkers for predicting chemotherapy response and guiding treatment decisions. Overall, this review provides a comprehensive overview of the current state of knowledge regarding the role of circRNAs in chemotherapy resistance in gynecologic malignancies. By elucidating the underlying mechanisms by which circRNAs regulate drug sensitivity, this work has important implications for improving patient outcomes and developing more effective therapeutic strategies for these challenging cancers. [ABSTRACT FROM AUTHOR]

Background We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. Methods Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. Results Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P  = .002), more often White (P  = .009), and less obese (P  = .025) and had differences in distribution of tumor histology (P  = .017) and molecular subtype (P  < .001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47 of 75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination related genes, including BRCA1, BRCA2 , RAD51D , and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)–high subtypes (3 of 12 [25%] POLE, 30 of 77 [39%] MSI-H, 27 of 60 [45%] CN-high, 9 of 57 [16%] CN-low; P  < .001). Conclusions Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is termed as an obstetric issue that is characterized by hypertension (≧140/90 mm Hg), together with proteinuria following 20 weeks of pregnancy. Until today, PE still constitutes a severe threat to the lives of both the mothers and fetuses. In the past, long noncoding RNAs (lncRNAs) were considered as the transcriptional noise. However, some investigations have indicated that lncRNAs could be used as innovative indicators in PE. The current review aims to discuss the relationship between lncRNAs and PE in recent years. According to the retrieved data, we concluded that lncRNAs can exert an impact on both the occurrence and development of PE through the changes in the biological functions of trophoblasts, immune regulation, epigenetic regulation, decidualization, and energy metabolism. The mechanisms of lncRNAs in PE will help us to better understand the pathogenesis of PE and help us to find targets for predicting and diagnosing PE in the future. [ABSTRACT FROM AUTHOR]

Introduction Endometrial cancer (EC) constitutes the leading cause of gynecologic cancer-related death in the United States and one of the few cancer types with increasing incidence and disease-associated mortality (1). [...], BACKGROUND. Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association among BMI, body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. METHODS. We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat-mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAEs) after ICI was also assessed based on BMI status. RESULTS. 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared with normal BMI patients after treatment with ICI. Multivariable Cox&apos;s regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared with normal BMI individuals. CONCLUSION. Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. FUNDING. NIH/NCI Cancer Center; MSK Gerstner Physician Scholars Program; National Center for Advancing Translational Sciences (NCATS); Cycle for Survival; Breast Cancer Research Foundation.