bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing sentinel lymphadenectomy and complete lymphadenectomy among obese patients (BMI >30) undergoing minimally invasive hysterectomy for early-stage endometrial cancer: An ACS-NSQIP database study.
Authors: Hollingsworth Jessie , Beier Matthew , Adkoli Anusha , Stephenson Ruth 
Published: June 2023

e17618 Background: In patients with endometrial cancer, lymph node assessment is used for staging and adjuvant treatment planning. Sentinel lymphadenectomy (SLN) is an acceptable alternative to complete lymphadenectomy due to decreased risk of major complications. As obesity increases in the United States, so does the rate of endometrial cancer. Complete staging may be more challenging in obese patients. Our goal was to evaluate the relative use and complication rates of sentinel versus complete lymphadenectomy among obese patients undergoing minimally invasive hysterectomy (MIH) for early-stage endometrial cancer. Methods: The National Surgical Quality Improvement Program (NSQIP) database was queried for patients diagnosed with stage I to III endometrial carcinoma between 2015 and 2020 who underwent MIH, identified by Current Procedural Terminology (CPT) code. Extent of lymphadenectomy was also identified using CPT codes. Relative utilization of sentinel versus complete lymphadenectomy was evaluated over the study period. Propensity scores were used to control for potential confounders, and complication rates were compared between propensity matched cohorts of sentinel versus complete lymphadenectomy. Major and minor complications were defined by the Clavien-Dindo scale. Results: From 2015 to 2020 a total of 11,844 obese (BMI > 30) patients underwent MIH for stage I to III endometrial cancer. Of these 7,067 (59%) had a lymph node assessment. Sentinel lymphadenectomy was completed in 3,845 patients, and complete lymphadenectomy was completed in 3,222 patients. Over the five-year period, the utilization of SLN increased for obese and non-obese patients. Prior to 2018, complete lymphadenectomy was performed more often. After 2018, SNL was more common. After propensity matching, there was no increased risk of death (OR 0.67, 95% CI 0.06-5.8, p = 1.0), infection (OR 0.86, 95% CI 0.69-1.1, p = 0.20), thrombo-embolic events (OR 0.77, 95% CI 0.51-1.1, p = 0.21), major complications (OR 0.84, 95% CI 0.66-1.1, p 0.15), or minor complications (OR 0.87, 95% CI 0.69-1.1, P = 0.22) in obese patients who underwent SLN compared to complete lymphadenectomy. Conclusions: The average BMI of patients who underwent MIH over the study period was 35. After controlling for comorbidities and other baseline characteristics, there were no significant differences in complication rates between sentinel and complete lymphadenectomy in obese patients. With the adoption of SLN, more patients may be adequately staged, providing more prognostic information and targeted therapies. These results suggest that sentinel lymphadenectomy is a technically feasible and safe staging procedure in obese patients.
Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for human uterine sarcoma cells.
Authors: Omran Mervat Mostafa , Vafaei Somayeh , Al-Hendy Ayman , Yang Qiwei 
Published: June 2023

e17620 Background: Uterine sarcoma is strongly associated with poor prognosis, high rates of recurrence, and metastasis. However, the molecular mechanisms underlying the origin and development of uterine sarcoma and treatment options are limited. Enhancer of zeste homolog 2 (EZH2) and histone deacetylase (HDACs) play an important role in cancer progression. This study aimed to assess the effect of targeting both EZH2 and HDACs on the phenotype of uterine sarcoma (US) cells. Methods: Tazemetostat (EPZ-6438, E7438), a potent, and selective EZH2 inhibitor, was first approved by the US Food and Drug Administration (FDA) in 2020. Entinostat (MS-275, SNDX-275) is one of the strong inhibitors for HDAC1 and HDAC3, Vorinostat is used to treat cutaneous T-cell lymphoma, Tucidinostat (Chidamide, HBI-8000, CS-055) is a low nanomolar inhibitor of HDAC1, 2, 3, and 10. Uterine sarcoma cell line (MES-SA) was treated with different concentrations (1.56-200 mM) of Tazemetostat and/or Entinostat, Vorinostat, Tucidinostat (Chidamide). for 24, 48, 72 h, respectively. Further mechanistic confirmation was carried out on best combination in both 2D and 3D culturing using IHC and real time PCR. Results: Our data showed that Entinostat synergistically (with a combination index 0.539) augments the cytotoxic activity of Tazemetostat in both 2D and spheroids in vitro model systems. The IC50 values for Tazemetostat were significantly reduced to 4.5 mM after combination treatment with 6.25 mM Entinostat for 48 h. Entinostat enhanced the antiproliferative effect of Tazemetostat with a decrease in the expression of proliferative markers Ki67(P < 0.0001) and PCNA (P < 0.01). Furthermore, combination treatment significantly increased US cell apoptosis, concomitantly with increased both BAX and Caspase-3 levels and decreased Bcl-2 (P < 0.0001) using 2D and spheroid in vitro model (P < 0.001). The finding was confirmed by IHC analysis in the US cell-derived spheroids. Conclusions: Our studies demonstrate that Entinostat, in combination with Tazemetostat proves significantly superior to either single treatment. Dual targeting EZH2 and HDACs may provide a promising treatment option for this aggressive cancer disease.
Study of endometrial carcinoma on correlation between molecular typing and lymph node metastasis and construction of prediction model.
Authors: Jiang Quanhong , Han Qiuyue , Song Kun , Chu Ran , Zhao Yong , Zhang Zhaoyang , Li Zhuang 
Published: June 2023

e17621 Background: TCGA molecular typing was proposed by The Cancer Genome Atlas (TCGA) in 2013 and recommended by the fifth edition of WHO, which has a strong prognositic value and is included in the risk stratification system, clinical diagnosis and treatment decision-making system of endometrial cancer (EC) patients. Meanwhile, Lymph node management in patients with EC is still controversial. Lymph node dissection (LND) and sentinel lymph node biopsy (SLNB) have their own advantages and limitations. This study attempts to establish a predictive model for lymph node metastasis (LNM) in patients with EC based on molecular typing and other clinical features and establish risk stratification, in order to provide a feasible method for predicting LNM in EC. Methods: In this study, SPSS19, R 4.2.1 and python 3.6 were used to establish a nomogram and evaluate it through a number of indicators, and the model was repeatedly verified by machine learning algorithms. With LNM as the outcome, risk stratification was set through the cut-off value of nomogram score to guide clinical treatment. Finally, an online LNM prediction website was designed to help patients. Results: A total of 325 EC patients were included, 35 (10.8%) with LNM and 290 (89.2%) without LNM. CA125 and cervical involvement were significantly correlated with LNM (p < 0.001), molecular typing, neutrophil to lymphocyte ratio (NLR), menstrual status were associated with LNM (p < 0.05). Lasso analysis screened out four independent factors: molecular typing, CA125, cervical involvement and menstrual status. The nomogram model was established by logistics regression (LR), with the prediction accuracy of the training set and validation set of 0.890 and 0.886, respectively. Machine learning algorithms in the training set also validates the model. Meanwhile, a risk stratification is established by the cut-off value of nomogram. We define high-risk group of LNM with more than the cut-off value and LND is recommended, while below the value is low-risk group and SLNB is recommended. Conclusions: We have established a nomogram clinical prediction model incorporating four factors, practicing stratified medical treatment about LND and SLNB, and formed a website for LNM prediction, genuinely providing patients recommendations.
A novel prognostic model for high-grade endometrial cancer using combined neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR).
Authors: Zhang Zhaoyang , Chu Ran , Kong Beihua , Chen Gang , Li Yang , Song Kun 
Published: June 2023

e17622 Background: Endometrial carcinoma (EC) as a common malignant tumor of the female reproductive system, posing a serious threat to the health of women. Compared to low-grade EC, high-grade EC has more rapid progression and a worse prognosis. Among the high-grade EC, grade3 endometrioid carcinoma, serous carcinoma, and clear cell carcinoma were the most common. Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are potential biomarkers of the systemic inflammatory response, and the correlation with prognosis of high-grade EC remains unclear. We want to evaluate the predictive significance of NLR and PLR in the prognosis of high-grade endometrial carcinoma and to establish a predictive model combining clinical factors. Methods: This multicenter retrospective cohort study included 910 high-grade epithelial endometrial carcinoma patients from the Chinese Endometrial Carcinoma Consortium database who underwent initial surgical treatment between January 1, 2005, and December 31, 2019. Univariable Cox survival analysis(the 2-sided Log-rank test) was used to assess each factor. Then the least absolute shrinkage and selection operator (LASSO) method was used to select the independent risk factors for DFS (disease-free survival) and OS (overall survival) from the outcomes of the univariate analysis to proceed with model fitting. Cox proportional hazard regression models were developed to predict the risk of recurrence and death at 3, 5, and 10 years, and the models were validated and calibrated. The area under the curve was used to measure the predictive performance of the model. The decision curve analysis was used to explore the clinical net benefit of the nomograms. Results: NLR and PLR were risk factors for recurrence, and NLR was a risk factor for death. We established models for predicting death and recurrence. In the training cohort, the AUC of recurrence model at 3, 5 and 10-year was 0.85, 0.85 and 0.86. And for the death model, the AUC at 3, 5 and 10-year was 0.83, 0.84 and 0.86. In the validation cohort, the AUC of recurrence model at 3,5 and 10-year was 0.72, 0.77 and 0.77. And for death model was 0.72, 0.81 and 0.84. Kaplan–Meier survival analysis showed a significant difference between low-risk and high-risk groups. The calibration curve also revealed excellent predictive accuracy both in the training and validation cohort. Conclusions: NLR and PLR are risk factors affecting the prognosis of high-grade endometrial carcinoma patients. Combining NLR/PLR and clinicopathological factors, we established a novel and more comprehensive prognostic model for patients to achieve risk stratification. This prognosis predictive model has the potential to offer risk scores and precise risk stratification for patients with high-grade endometrial cancer.
Real world evidence on long-term survival of patients with endometrial cancer in Germany: Analysis of population-based cancer registry data on 49808 women.
Authors: Chinczewski Lukas , Zocholl Dario , Wagner Alexandra , Chekerov Radoslav , Braicu Elena Ioana , Sehouli Jalid 
Published: June 2023

e17623 Background: Endometrial cancer (EC) is the most common gynecological cancer worldwide. The understanding of clinicopathological characteristics has changed within the last years. Limited data are available regarding the long-term survival of EC patients. Methods: Clinical data and survival data for patients with EC diagnosed in Germany between 2010 and 2020 were gathered from the German national center for population-based cancer registry. Differentiated by histological subtype, 5- and 7-year survival rates were calculated. Results: 49,808 patients with newly diagnosed EC between 2010 and 2020 were included in the analysis. Median age at diagnosis was 68.1 years (IQR 59.0;76.4). 5-year and 7-year overall survival was 67.5% and 56.7%, respectively, and decreased with increasing FIGO-stage: 83.7% and 72.6% for FIGO IA, 71.0% and 56.3% for FIGO IB, 59.8% and 47.3% for FIGO II, 48.2% and 38.7% for FIGO IIIA , 32.5% and 20.7% for FIGO IIIB, 40.0% and 30.6% for FIGO IIIC, 13.3% and 8.2% for FIGO IVA, 16.4% and 13.9% for FIGO IVB, respectively. Regarding histological subtype, endometrioid carcinoma showed the best 5-year and 7-year overall survival rates with 72.5% and 61.3%, respectively, followed by clear cell carcinoma with 41.2% and 34.0%, serous carcinoma with 35.5% and 24.8%, and lastly carcinosarcoma with 28.5% and 23.0%. Of 3,765 patients with known cause of death, 53.8% were due to endometrial cancer. 19.0% died of cardiovascular disease and 18.8% of other malignancies. Conclusions: Our data represents deeper insight in the characterization of long-term survival patients of this tumor entity.
3D genomics identify alternate mechanisms of homologous recombination deficiency in uterine sarcoma.
Authors: Chiang Sarah , Hensley Martee Leigh , Vasudevaraja Varshini , Tran Ivy , Yang Yiying , Stewart Colin JR , Park Kay J , Ellenson Lora H , Sikkink Kristin , Schmitt Anthony , Snuderl Matija 
Published: June 2023

e17624 Background: Uterine sarcomas are rare tumors with diverse morphologic appearances, genetic underpinnings, and clinical behavior. Molecular characterization of these tumors by next generation sequencing (NGS) has improved disease classification and prognostication, but its impact on therapeutic selection remains limited. Analysis of 3D genomics datasets has recently been shown to detect large complex structural variants (SV) and chromatin architecture in normal and diseased human tissues. We applied genome-wide chromosome conformation capture (Hi-C) techniques in a variety of uterine sarcomas to identify novel therapeutic targets. Methods: Formalin-fixed paraffin-embedded tissue from 48 primary or recurrent uterine sarcomas were subjected to Hi-C to identify chromosomal rearrangements. The cohort included leiomyosarcoma (LMS, n = 7), adenosarcoma (AS, n = 7), endometrial stromal sarcoma (n = 7; high grade (HGESS), n = 4; low grade (LGESS), n = 3), sarcoma not otherwise specified (n = 17; high grade (HGNOS), n = 10, low grade (LGNOS), n = 7), undifferentiated uterine sarcoma (UUS, n = 6) and heterologous sarcoma (n = 2). Tumors were previously subjected to targeted DNA (n = 10) and/or RNA (n = 26) NGS with no therapeutic targets identified and only BCOR internal tandem duplication detected in a HGESS. Results: Hi-C detected SV in 73% of uterine sarcomas (n = 35/48), including those previously negative by targeted RNA NGS (n = 25/26). Homologous recombination repair (HRR) gene alterations were detected by Hi-C in 42% of tumors (n = 20/48), including AS (n = 5/7), HGESS (n = 2/4), LGESS (n = 1/3), LMS (n = 2/7), UUS (n = 2/6), heterologous sarcoma (n = 1/2), HGNOS (n = 3/10) and LGNOS (n = 1/7). SV included gene (gene to gene, n = 3; gene to non-coding DNA, n = 8) and proximity (n = 13) fusions disrupting HRR genes ( ATM, BRIP1, CDK12, CHEK1, CHEK2, NBN, PARP3, RAD51B, RAD51C, RAD51D) with enrichment for RAD51B fusions (50%, n = 10/20). Among all tumors with HRR gene alterations detected by Hi-C, only one uterine sarcoma harbored a missense ATM mutation by targeted DNA NGS (n = 1/5). Conclusions: Molecular characterization of uterine sarcomas by Hi-C may uncover HRR gene alterations not currently detectable by targeted DNA and RNA NGS. Homologous recombination deficiency (HRD) is not limited to LMS and may frequently result from SV, particularly between HRR gene to non-coding DNA in a variety of uterine sarcomas. These alternate mechanisms for HRD may serve as a potential therapeutic biomarker for HRD-targeted therapy in uterine sarcoma.
Risk reclassification of endometrial cancer according to molecular profiling: UK single centre experience.
Authors: Kebaier Ep Chaabouni Narda , Vroobel Katherine , Attygalle Ayoma , Proszek Paula , Lalondrelle Susan , Taylor Alexandra , George Angela Joy 
Published: June 2023

e17628 Background: Endometrial cancer (EC) ranks second among gynaecological malignancies worldwide. Traditionally, adjuvant treatment recommendation was based on risk stratification based on clinicopathological data. The Cancer Genome Atlas (TCGA) defined four distinct and prognostically significant molecular subgroups. Recent international guidelines recommend integrating molecular classification into risk stratification. The aim of our study was to evaluate the distribution of molecular groups in our population and its impact on treatment decision. Methods: Retrospective cohort study including all newly diagnosed endometrial cancer cases treated at the Royal Marsden Hospital between July 2020 and May 2022. Tumour specimens underwent next generation sequencing (NGS) of a two hundred gene panel including POLD1, POLE; MMR proteins and TP53; concordance for the latter two assessed also by immunohistochemistry (IHC). Risk stratification according to ESMO guidelines and following molecular classification was reviewed for each case and its potential impact on treatment decision. Results: 121 patients were included. POLE mutated tumours comprised 14 cases (11.6%), MSI hypermutated 24 cases (19.8 %), copy number high 36 cases (29.8%), copy number low 45 cases (37.2%) and 2 cases (1.6%) where classified as NOS (not otherwise specified). According to clinicopathological data, 39 tumours were categorised as low risk, 14 tumours as intermediate risk, 15 tumours as high-intermediate risk, 39 tumours as high risk and 14 were advanced/metastatic. According to final prognostic group when molecular profile was integrated 8.3 % (n = 10) of cases were reclassified: 8 cases were down staged (2 high, 3 high-intermediate, 3 intermediate) to low-risk category due to POLE mutations. 2 cases were upstaged from high-intermediate to high-risk category (copy number high tumours). There were no shifts noted in the low risk (based on clinicopathological data) prognostic group. One further case in the high-risk category (stage III, gr3 endometrioid tumour with substantial LVSI) was found to be POLE mutated and may be reclassified as low risk. For the 10 cases that were reclassified, adjuvant treatment recommendations may have been adjusted according to the most recent ESMO guidelines. Conclusions: Molecular classification refines traditional risk classification of EC and may change treatment recommendation in a non-negligible proportion of patients. Efforts should be made to implement molecular analysis in routine clinical practice to guide appropriate treatment.
Preclinical testing of farletuzumab ecteribulin (FZEC [MORAb-202]) and MORAb-109, folate receptor α and mesothelin targeting antibody-drug conjugates (ADCs), in rare gynecologic cancers.
Authors: Vandenberg Cassandra J. , Rybinski Katherine , Nesic Ksenija , Lim Ratana , Neagle Chloe , Ho Gwo-Yaw , Ratnayake Gayanie , Papenfuss Anthony T. , Furuuchi Keiji , Barker Holly E. , Scott Clare L. 
Published: June 2023

e17634 Background: Rare gynecologic cancers, such as ovarian carcinosarcoma (OCS), uterine serous carcinoma (USC) and ovarian clear cell adenocarcinoma (OCCA), have limited treatment options and molecular alterations that drive cell proliferation and drug resistance, resulting in poor overall survival. The anti-microtubule agent (AMA) paclitaxel is used in first-line treatment of most gynecologic cancers; however, the AMA eribulin is known to have additional anticancer properties (Goto et al. Anticancer Res 38:2929, 2018; Ho et al. Cancer Res 82:4457, 2022). Eribulin ADCs have been developed for targeted delivery to limit toxicity and maximize response. FZEC is an anti-folate receptor α (FRA)-eribulin ADC (Shimizu et al. Clin Cancer Res 27:3905, 2021) and MORAb-109 targets eribulin to mesothelin (MSLN; Albone et al. Annals Oncol 31:S491, 2020). Here we provide preclinical data to support clinical trials of FZEC and MORAb-109 in rare gynecologic cancers. Methods: Fresh tumor tissue from patients consented to the WEHI Stafford Fox Rare Cancer Program was used to establish a cohort of patient-derived xenograft (PDX) models of high-grade serous ovarian carcinoma (HGSOC), OCS, USC and OCCA. PDX models were screened for FRA and MSLN expression by IHC and quantified by HALO software, and 15 models were selected for in vivo testing. Tumor-bearing mice were treated with eribulin (1 mg/kg TIW 3 wks), FZEC (12.5 mg/kg Q14Dx3) or MORAb-109 (25 mg/kg Q14Dx3) and compared to standard of care treatments. Results: About 80% of HGSOC PDX models were FRA positive with no difference between models from chemonaïve samples vs multiple lines of prior treatment. FRA expression was frequent in USC and OCCA models, with MSLN seen in a smaller subset. Despite most (80%) models being cisplatin refractory, 11/15 responded to eribulin with the 4 non-responders having high MDR1 expression and being from previously treated patients. Overall, responses to FZEC and MORAb-109 appeared to correlate with FRA and MSLN expression; importantly, some models with moderate to high target antigen expression showed deeper and more durable responses to FZEC and MORAb-109 compared to eribulin. Conclusions: Responses to FZEC and MORAb-109 correlated with FRA and MSLN expression, with equivalent or better activity compared to eribulin in target-positive PDX models of HGSOC, USC and OCCA. [Table: see text]
Nominating molecular/immunologic drivers of central nervous system (CNS) metastases in squamous cell carcinoma of the head/neck (SCCHN).
Authors: Kacew Alec , Wotman Michael , Quinn Charles T , MacConaill Laura E , Egloff Ann Marie , Jones Stephanie M , Pfaff Kathleen L. , Rodig Scott J. , Sehgal Kartik , Haddad Robert I. , Posner Marshall R. , Hanna Glenn J. 
Published: June 2023

e18002 Background: In the ~1% of patients with SCCHN who experience CNS metastases, median overall survival (mOS) is <1 year. We investigated whether molecular/immunologic features distinguish SCCHN cases that metastasize to the CNS. Methods: We performed a case-control study on a convenience sample of individuals with SCCHN treated at two academic institutions. Next generation targeted sequencing and/or immunoprofiling of primary and metastatic tumor sites were performed. Results: We identified 39 patients with SCCHN (21 with CNS metastases (cases), 18 without (controls)). Median age at diagnosis 60, 79% male, 46% current/former smokers, 51% oropharyngeal primary, 51% HPV+/31% HPV-/18% not tested (NT) across all cases, and 69% stage III or IV disease at diagnosis. HPV+ frequency trended higher among cases (52%+, 14%-, 33% NT) vs. controls (50%+, 50%-, 0% NT) (p=0.08). mOS from diagnosis was 34.4 months (95% CI 14.5-41.0) in cases and 44.4 months (95% CI 19.0-82.3) in controls. Genomic data was available for 18 (86%) cases and 12 (67%) controls. Most common mutations in cases were KMT2D (39%) and NOTCH1 (39%). There were no genes for which alteration frequency differed significantly between groups. Tumors of 18 (86%) cases and 18 (100%) controls underwent immunoprofiling. Mean PD-1 density at the tumor-stroma interface (TSI), CPS, and TPS were higher in controls (Table). In cases, TSI PD-1 density tended to be higher at primary sites than at sites of CNS metastases. No significant difference was seen in CD8 or FOXP3 staining. Conclusions: SCCHN with CNS metastases shows markers of lower immunogenicity at both the primary site and site of CNS metastasis vs. other SCCHN tumors, regardless of HPV status. This suggests that localized tumors with low immune infiltration and poor responsiveness to immunotherapy may be at higher risk of CNS metastasis and could imply reduced benefit from immunotherapy for patients with CNS metastases. [Table: see text]