bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endocrine biomarkers in low-grade serous ovarian cancers (LGSC) and serous ovarian tumors of low malignant potential (LMP).
Authors: Taylor Sarah E. , Wield Alyssa , Fang Yusi , Bhargava Rohit , Lang Susan , Tseng George , Coffman Lan Gardner , Oesterreich Steffi 
Published: May 2020

e18045 Background: LGSC and serous ovarian LMP tumors are rare entities along a disease continuum. Because they are relatively chemotherapy resistant, there is interest in targeted treatment, including endocrine therapy. In studies of endocrine agents for treatment of recurrent ovarian cancer, tumor estrogen receptor (ER) status alone does not effectively predict outcomes. The objective of this study is to utilize protein and gene expression from ER and downstream targets to identify signaling components that will act as prognostic and predictive biomarkers. Methods: A single institution tumor registry was queried for patients with LGSC or serous LMP tumors between 1993-2016. Formalin-fixed, paraffin embedded (FFPE) tissue was obtained. Clinicopathologic data was collected. Immunohistochemistry (IHC) was performed and scored as dichotomous (+/-) and continuous (H-score). NanoString nCounter platform was used for gene expression of a predesigned endocrine biomarker panel. Wilcoxon Rank Sum was used to compare mRNA and protein expression. Survival analyses were performed using Cox proportional hazard (PH) method with elastic net to fit the prediction model for the gene panel. Results: Tissue was analyzed from 23 LGSC, 71 serous LMP tumors, and 2 recurrences. At diagnosis, 86% of patients with LMP tumors had stage I disease vs 78% of patients with LGSC had stage III/IV disease. There were 7 (10%) LMP and 13 (56.5%) LGSC recurrences. Median initial PFS was 76 and 37 months and median OS was 88 and 82 months for LMP and LGSC, respectively. Fourteen received endocrine therapy; nine for treatment of recurrent LGSC. Median therapy was 21 months, with 3 complete responses, 2 partial responses and 1 stable disease. All tumors were ER+ (median H-score 210) and 89% were PR+ (median H-score 130). ER H-scores and ESR1 expression levels were not significantly different between LGSC and LMP tumors (p = 0.1942, p = 0.0893). PR H-scores were higher in LMP tumors (p < 0.00001) but PGR expression was not significantly different (p = 0.6581). In the Cox PH analysis, ER H-score was a significant predictor of both PFS and OS (p < 0.001, p = 0.004). The Cox model identified independent sets of gene expression associated with PFS and OS in both the LGSC and LMP cohorts (c-indices 0.679, 0.570, 0.626, 0.689). Conclusions: Endocrine therapy is an active area of interest in the treatment of ovarian neoplasms. ER H-score and gene expression of downstream ER targets could improve upon the use of hormone receptors to determine risk of recurrence and guide use of adjuvant endocrine therapy.
Characterization of mutations in HRR genes, TMB, and PD-L1 expression in Chinese patients with ovarian cancer.
Authors: Zheng Hong , Gao Min , Gao Weijiao , Zhang Nan , Wang Hongguo , Song Nan , Zhang Naiyi , Wang Wei , Li Qian , Yuan Mingming , Chen Rongrong , Gao Yunong 
Published: May 2020

e18048 Background: A great number of clinical studies have confirmed the promising efficacy of ICIs and PARPi in multiple solid tumors. Here we aim to investigate the biomarkers related to these emerging therapies, including mutations in DNA homologous recombination repair (HRR) genes, tumor mutation burden (TMB) and PD-L1 expression in Chinese patients (pts) with ovarian cancer. Methods: A total of 209 pts with ovarian cancer were enrolled. Matched tumor-normal NGS of 1021 cancer-related genes was performed in 98 pts (T: 71 pts, T+B: 25 pts, B: 2 pts). Germline variants in ovarian cancer susceptibility genes were analyzed in 209 pts. PD-L1 expression was assessed by immunohistochemistry (Dako 22C3). Pts with TPS≥50 were considered as high expression and pts with 1≤TPS<50 was considered as expression. Tissue TMB was calculated as the number of somatic non-synonymous SNVs and Indels per Mb in the coding region (with VAF ≥0.03). The threshold of TMB-high was 5.76 muts/MB. Results: Germline pathogenetic or likely pathogenetic variants were identified in 28.7% of pts ( BRCA1 15.3%, BRCA2 7.7%, RAD51D 2.0%, PALB2 1.0%, and 0.7% for CHEK2, MSH2, RAD51C and MSH6). Germline variants in HRR genes was identified in 27.3% of pts. The mutation detection rates in 96 tissue samples from surgery or biopsy and 25 ctDNA samples collected at disease recurrence were 100% and 96%, respectively. An average of 34.6% of tissue-derived mutations can be identified in ctDNA, and 55.2% of tissue-derived actionable mutations were observed in ctDNA. Besides, there were 83 private mutations, including PPMID (5), ARID2 (3), CHEK2 (3), PIK3CA (3) and ARID1B (2). Mutations in HRR genes were found in 36.5% (35/96) of tissue samples, and 12 pts harbored more than one HRR mutations. The detection rate of HRR mutations in ctDNA was 40% (10/25), and cases harbored more than one HRR mutations. The status of TMB and PD-L1 was analyzed in 30 pts. Two pts were evaluated as PD-L1 highly expressed and 9 pts were considered as expressed. Eight pts were assessed as TMB-high. Five pts with PD-L1 negative expression were TMB-high, and 8 pts with TMB-low were PD-L1 positive expression. TMB and PD-L1 expression are independent indicators with the spearman r of 0.01 (p = 0.96). Conclusions: The detection rate of germline and somatic mutations in HRR genes were 27.3% and 36.5-40%, respectively, which defined a large number of ovarian cancer pts who can benefit from PARPi. PD-L1 expression and TMB are independent biomarkers, which may be combined to predict the efficacy of immunotherapy in future exploratory trials.
Identification of new lesion with disease progression in Ovarian cancer per RECIST 1.1.
Authors: Sharma Manish , Bohnsack Oliver , Jarecha Rudresh , Narang Jayant , Singareddy Anitha , Bajpai Surabhi 
Published: May 2020

e18058 Background: Metastasis is the leading cause of ovarian cancer (OC) related death with more than 70% of OC patients diagnosed with metastasis with five-year survival rates below 45%. OC cells mainly metastasize within the peritoneal cavity at presentation and throughout the course of the disease in 85% of the patients which involves exfoliation from the primary tumor, followed by survival and transport in the peritoneal fluid and finally metastatic colonization of the organs within the peritoneal cavity. There is a tendency of conventional imaging to underestimate the frequency of peritoneal spread. The purpose of the study was to obtain the frequency of organ involvement in OC metastasis and identify the most common route of OC metastasis. Methods: Retrospective study and analysis of two randomized double-blind trials was performed in patients with OC. Data was analyzed from these studies using blinded independent central review using RECIST 1.1 involving a total of 895 subjects, 528 and 367 respectively. A double read with adjudication by independent radiologists was performed for each scan based on the RECIST 1.1 criteria. Baseline tumor burden was assessed for all subjects using RECIST 1.1 criteria. At follow-up visits, data was specifically analyzed for New lesions. The readers had to select New lesion location from a pre-defined location list from a drop-down menu. Data was tabulated with frequency of subjects with New lesion per each location. Results: With both studies combined involving 895 subjects, total subjects with new metastasis observed in decreasing order for various organs were peritoneum/omentum (406), lymph nodes (315), ascites (207), liver (94), pleural effusion (65), pelvis (52) & lung (56). Other less common locations for new metastasis was abdominal wall, pleural deposits, spleen, brain, retroperitoneum and adrenal. We also looked at the possibility of disagreement between 2 readers in identifying such lesions leading to progression as below. Conclusions: It can be concluded that subjects with ovarian cancer tend to develop metastasis leading to progression per RECIST 1.1 in peritoneum / omentum, lymph nodes, liver and lung. Due to significant variability in identification of such discrete, ill-defined and/or small nature of lesions, targeted awareness and training should be incorporated to improve clinical outcome. [Table: see text]
Capturing the pathway logic of cell signaling for epithelial-mesenchymal transition in ovarian cancer cell lines.
Authors: Morris Matthew , Clark Jeselle , Lyman Cole , Brown Broderick Jennifer , Kramer Zachary B. , Skuse Gary , Broderick Gordon 
Published: May 2020

e18063 Background: Epithelial-to- mesenchymal transition (EMT) plays a key role not only in cancer invasiveness and progression but also in treatment resistance. Experimental models suggest that epithelial and mesenchymal phenotypes may represent steady states supported by the regulatory logic of intracellular signaling networks. Using known regulatory interactions between intracellular signaling molecules as a framework, we explored EMT in silico with the aim of identifying potentially novel means of inhibiting metastasis in ovarian cancer. Methods: A mathematical model connecting 27 genes involved in EMT through 153 regulatory interactions was assembled from the Mogrify, Reactome, String and Pathway Studio (PS) databases, the last of which used the MedScan natural language processing (NLP) engine to process over 8,000 full-text publications. Logic model parameters dictating the regulatory response dynamics of the EMT circuit were constrained to values that accurately predicted the proteomic profiles characterized as either epithelial or mesenchymal in 30 cell lines in the publicly available MaxQB database. Results: A total of 94,672 candidate models predicted the protein expression in stable epithelial and mesenchymal cells equally well, clustering into 24 classes of slightly different EMT transition kinetics. Discrete event simulations based on these models identified 7 unique combinations, involving the concurrent modulation of at least 3 gene products capable of effecting this transition successfully even in the presence of noise. Every combination required inactivation of ZEB2, along with 2 other manipulations. Inactivation of TP53, HOXA5, or IRF7 was required in 3 combinations, while inactivation of ICAM1 was required in 2 cases. Only BCL2 was required to be activated in any of these scenarios. Interestingly, BCL2 inhibition is now applied clinically in some hematologic cancers and proving effective in patient-derived cell lines for high-grade serous ovarian cancer when combined with MEK inhibition. Conclusions: This work suggests that EMT might at least in part be driven by normal regulatory interactions between specific proteins in a network of pathways, without the requirement for additional mutations or alterations in the underlying circuitry. Maintenance of ZEB2 or TP53 activation as well as BCL2 inhibition may thus represent promising avenues for future research in arresting EMT and associated chemo-resistance.
Effect of MUC5B mutation on prognosis by enhancing the infiltration and antitumor immunity of cytotoxic T lymphocytes in the endometrial cancer.
Authors: Zheng Hong , Duan Wei , Zhao Qun , Li Chengcheng , Wang Guoqiang , Zhang Yuzi , Bai Yuezong , Zhou Yingchun 
Published: May 2020

e18105 Background: Endometrial cancers have been categorized into four genomic classes by The Cancer Genome Atlas Research Network (TCGA) with comprehensive genomic analysis. However, TCGA molecular subtypes are hard to utilize in clinic as the expensive cost and a simply version of POLE, TP53 genes cannot fully differentiate the four subtypes. Therefore, more convenient and reliable biomarkers need to be identified for clinical practice. Methods: Whole-exome sequencing and RNA sequencing data for 515 patients with endometrial carcinomas were downloaded from TCGA. Associations between MUC5B mutation and survival and RNA expression were analyzed. Results: MUC5B mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.47; 95% CI, 0.28-0.79; P < 0.05), progression-free survival (PFS) (HR, 0.31; 95% CI, 0.17-0.56; P < 0.001) and overall survival (OS) (HR, 0.29; 95% CI, 0.14-0.60; P = 0.001) in endometrial cancers. MUC5B mutation was significantly associated with patients' age at diagnosis (P = 0.027) and histological type (P < 0.001) and grade (P < 0.001). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade, tp53, pole and TCGA molecular subtypes, the association between MUC5B mutation and PFS was still significant (HR, 0.40; 95% CI, 0.20-0.81; P = 0.011), indicating the MUC5B mutation is an independent prognostic factor for PFS. Moreover, MUC5B mutation have a tendency for a favorable OS (HR, 0.52; 95% CI, 0.23-1.22; P = 0.13). Patients harboring MUC5B have a higher tumor mutation burden (TMB). An analysis of immune signature revealed that MUC5B mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release. These results have further been confirmed by GSEA. Moreover, an increased level of cytotoxic T lymphocytes infiltration was observed in the patients with MUC5B mutations. Conclusions: MUC5B mutation was related with a favorable prognosis through increasing T cells signature. Identification of MUC5B mutation by genomic profiling provides a potentially novel and convenient approach for endometrial cancer patients to predict the prognosis.
Effect of inducing HR deficiency using AVB500, a receptor tyrosine kinase AXL inhibitor, on response to olaparib in uterine serous cancer.
Authors: Toboni Michael Driscoll , Blachut Barbara , Mullen Mary M , Tankou Jo'an , Noia Hollie M , Oplt Alyssa , Wilke Danny , Kuroki Lindsay M , Hagemann Andrea R. , McCourt Carolyn K , Thaker Premal H. , Mutch David Gardner , Powell Matthew A. , Fuh Katherine Cynthia 
Published: May 2020

e18108 Background: Evidence suggests DNA repair is a therapeutic target in endometrial cancer (EC). Given this, we determined whether combination therapy with AVB500, an AXL inhibitor, could improve response in a uterine serous cancer (USC) model. Methods: Two USC cell lines (ARK1 & ARK4) were treated with AVB500 (Aravive Biologics, Houston, TX) in combination with the poly ADP ribose polymerase (PARP) inhibitor, olaparib. Colony forming assays were assessed after 4 days of treatment with either AVB500 alone, olaparib alone or combination treatment (olaparib + AVB500); colonies were stained and absorbance was obtained to calculate relative cell viability using Graph Pad Prism. Baseline homologous recombination (HR) status was determined after radiating cells with 10Gy and identifying RAD51 foci by immunofluorescence (IF). Cell lines were considered to be HR proficient if over 30% of the cells expressed RAD51 ( > 5 foci per cell). IF was conducted using a Leica confocal microscope and foci were quantified using FociCounter. In vivo studies were performed using NOD-SCID mice injected with 1 x 107 ARK1 cells intraperitoneally followed by treatment q3 days for a 14 and 21 day treatment period. Treatment groups were vehicle control, AVB500 alone, olaparib alone and olaparib with AVB500. Results: The absorbance for olaparib + AVB500 was significantly less than the olaparib only group in two assays involving ARK1s (0.417nm vs 0.756nm, p = 0.001; 0.320nm vs 0.620nm, p = 0.008) as well as in ARK4s (0.186nm vs 0.641nm, p = 0.003). The HR assay indicated both cell lines were HR proficient. After baseline HR proficiency was established, the cell lines were pretreated with AVB500 prior to radiation. When compared to cells without treatment with AVB500, IF showed a decrease in RAD51 foci per cell in ARK1 (2.7 vs 7.3, p = 0.0003) and ARK4 (6.3 vs 13.0, p = 0.0054). The proportion of ARK1 cells expressing RAD51 decreased to 21%, indicating HR deficiency. Lastly, NOD-SCID mice receiving olaparib + AVB500 had less tumor weight than those treated with olaparib alone (0.008g vs 0.138g, p = 0.002) and AVB500 alone (0.008g vs 0.145g, p = 0.0006) in a 14 day and a 21 day treatment period (0.212g vs 0.586g, p = 0.027 and 0.212 vs 0.494g, p = 0.005, respectively). Conclusions: HR proficient USC cell lines treated in vitro and in vivo with the combination of AVB500 and olaparib demonstrate an improved response to olaparib or AVB500 alone with a greater decrease in tumor burden. AVB500 appears to induce HR deficiency. Additional therapeutic and mechanistic experiments are ongoing.
Impact of inpatient hospitalization on opiate usage for minimally invasive hysterectomy amongst gynecologic oncology patients.
Authors: Gee Amy Dawn , Grabosch Shannon Michelle , Gavard Jeffrey 
Published: May 2020

e18109 Background: The overdose death rate related to opiates has quadrupled in the last two decades. Up to 27% of chronic opiate users report initiation in the post-op period. Among cancer patients, 10% of opioid-naive patients continue chronic use one year after surgery. Restrictive opiate prescribing has demonstrated promise in other studies. However, lacking from current literature is an analysis of the effect that same day discharge (SDD) has on post-op opiate usage at home. The objective of this study is to evaluate the impact of SDD versus physician-elected observation for 1 to 2 days on acute post-op opiate usage and safety following minimally-invasive hysterectomy (MIH). Methods: This is a prospective observational study of women undergoing MIH. Sixty patients were assigned to either the SDD or hospitalization group at provider discretion based on practice pattern, distance from hospital, or comorbidities. One patient was lost to follow up. Patients were followed through 30 days after surgery. Total opiate usage included the inpatient usage (if hospitalized) and home usage assessed at the post-op visit. Anonymous surveys were used to collect home opiate usage practices, satisfaction, and self-reported risk factors for continued use. Continuous variables were analyzed by independent Student’s t-test and the Mann-Whitney U test. Categorical variables were analyzed using Chi-square test and Fisher's Exact test. Results: 29 SDD and 30 hospitalized patients were available for review. Demographics including age, BMI, tobacco use, and procedure indication were well matched. SDD patients used a median 5.0 (1.5-13.5) versus 8.5 (2.25-14.25) 5mg oxycodone tabs (p 0.33). SDD patients used opiates less for non-pain indications including to sleep (4 vs 9, p 0.24) or relax (3 vs 5, p 0.71). One SDD patient had a complication of a cuff hematoma, which spontaneously drained. There were no readmissions. Only one SDD patient felt she would have benefited from longer stay due to nausea. All hospitalized patients took their own opiates at home while 7 SDD had a family member dispense. Psychiatric disorders were the highest comorbidities in both groups (depression n = 12 and 10, anxiety n = 10 and 12). Conclusions: SDD demonstrated a trend towards less opiate usage, although not statistically significant. Patients did not feel that they needed to stay longer in the hospital. The safety of SDD is supported by lack of readmissions and one minor post-op complication. The high rates of psychiatric disease are a concerning risk factor for chronic use.
Survey of the experience of head and neck cancer patients with a percutaneous endoscopic gastrostomy tube.
Authors: Sahu Kamal Kant , Gibbs Lisa , Siddiqui Ahmad Daniyal 
Published: May 2020

e18501 Background: Many patients with advanced head and neck cancer become unable to obtain enough nutrition and hydration orally, leading to considerable weight loss and compromised clinical outcomes. PEG tube is ideal for this population who require longer term nutrition support because of cancer treatment. The study objective was to learn about the experience of patients with a PEG tube. Methods: A questionnaire was developed, tested, and used to collect data. This survey consisted of 20 questions pertinent to various domains of quality of life and aiming at various aspects of patient life: physical, emotional and social sectors and noting their experiences in the form of multiple-choice options using Likert scale and free text option for suggestions. Results: A total of 22 participants were involved in this study, 64 years,7 males and 5 females. Cancer site: Tongue (10), tonsils (5), pharynx (5) and larynx (2). All patients belonged to stage III or more. Majority were treated with chemoradiotherapy (17 ). Out of 22 patients, 18 had PEG tube placement before starting treatment and the other 4 agreed during the cancer treatment. Most patients had the PEG tube for 3-6 months (8/22 cases). 21 patients strongly agree that PEG tube insertion was useful to them for their treatment and nutrition. 21 patients agreed relying on PEG tube FOR > 75% of their daily nutrition. While 4 patients agreed that PEG hampered their ADLs, 13 patients suggested that only rarely (7 cases) or sometimes (6 cases) they encountered difficulty in managing their ADLs. Only 2 patients had often trouble with sleep.15 cases did not feel any social embarrassment with PEG and did not miss any social events.19 patients answered that they followed oncologists to have PEG tube placement. Majority (15) managed the tube feed on their own. 16 cases never had any clinic/ER visit solely due to PET tube issues. 20 patients considered dietician as the first person to connect for concerns. 8 patients experienced issues like tube site infection (5), leakage (5), bleeding from site (4), tube blockade (5) or tube replacement (2). All patients except one agreed to have PEG placement again in future if required for any medical reason and would recommend others as well. Similarly, all patients except one thought that they would not have completed the cancer treatment without PEG tube support. Conclusions: Results indicate that the patient experience with the PEG tube is generally positive. This study will help improve understanding regarding the experience of living with a PEG tube from the patient perspective.
Effectiveness of PD-L1 inhibitors in metastatic or recurrent squamous cell carcinoma of head and neck: An observational, indirect comparison.
Authors: Bila Michel , Clement Paul M. , Van Dessel Jeroen 
Published: May 2020

e18503 Background: The prognosis for recurrent or metastatic Squamous Cell Carcinoma of Head and Neck (HNSCC) remains dismal and its treatment poses a challenge for oncologists. Agents against programmed cell death ligand 1 (PD-L1) have shown beneficial effects on overall survival (OS) for HNSCC. The aim of the present study was to compare differential effects of PD-L1 inhibitors on recurrent and metastatic HNSCC. Methods: In an indirect comparison of patients with recurrent HNSCC were matched to patients with metastatic HNSCC. All patients were treated with PD-L1 inhibitors at the general medical oncology department of UZ Leuven. Kaplan-Meier methods and Cox regression models were used to calculate the overall survival. Results: From December 2013 to July 2019, 68 patients with metastatic and 59 with recurrent HNSCC were enrolled and evaluable. A significant difference in OS was found between recurrent and metastatic groups (p < 0.02). The mean OS was 7.6 months (95% CI: 2.4-11.3 months) for the recurrent group, while in the metastatic group the mean OS was 13.7 months (95% CI: 5.7-16 months). Conclusions: As a second-line therapy, PD-L1 inhibitors were associated with longer overall survival in metastatic compared to recurrent HNSCC.