bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B52: Inhibition of ovarian cancer spheroid adhesion using graphene oxide nanomaterials
Authors: Lee Hak Rae , Geller Melissa A. , Azarin Samira M. 
Published: September 2020

Abstract
There is an urgent need for development of alternative treatment strategies for advanced-stage ovarian cancer. During metastatic spread, single cells or spheroids detach from the primary tumor and are carried by the peritoneal fluid until attaching to the mesothelial cells lining the abdominal cavity. While attachment of ovarian tumor cells and spheroids to the mesothelial layer is known to be mediated by β-integrins and CD44, efforts to block these receptors with antibodies have been insufficient to inhibit disease progression. As graphene oxide nanosheets have previously been shown bind to β-integrins on the surface of mesenchymal stem cells, we hypothesized that they would be able to attach to ovarian cancer spheroids, forming a physical barrier around the spheroids and thus inhibiting their adhesion to the mesothelium. SKOV-3 human ovarian cancer cells were used in this study, as this cell line was derived from ascites fluid. SKOV-3 cells were placed in poly(hydroxyethyl methacrylate) (polyHEMA)-coated plates for 24 hours to form spheroids, followed by 48-hour treatment with the nanosheets. The graphene oxide nanosheets were functionalized with 4-arm polyethylene glycol (PEG) to enhance biocompatibility and provide additional steric hindrance to prevent spheroid adhesion. Scanning electron microscopy confirmed that the nanosheets were able to bind to the tumor spheroids. Association of the nanosheets with the SKOV-3 spheroids reduced their adhesion to extracellular matrix proteins collagen and fibronectin as well as LP-9 human mesothelial cells over a 7-day time period, with the PEG-functionalized nanosheets showing the greatest reduction in adhesion. The nanomaterials did not exhibit cytotoxicity to LP-9 cells at the range of concentrations used to prevent adhesion. Receptor blocking studies confirmed that the nanosheets were predominantly engaging with the tumor spheroids via β-integrins. Finally, for tumor spheroids that did bind to the mesothelial cells, the presence of nanosheets on the surface of the spheroids decreased the rate of mesothelial layer clearance by the tumor cells. Taken together, these results demonstrate that graphene oxide nanomaterials can bind to ovarian tumor spheroids and inhibit their attachment to matrix proteins and mesothelial cells, while also reducing their ability to clear mesothelial cells once bound. Future efforts are focused on testing these materials with human ascites fluid and further modifying the nanosheets to enable ablation of tumor cells bound to the nanosheets to enhance their therapeutic potential.
Citation Format: Hak Rae Lee, Melissa A. Geller, Samira M. Azarin. Inhibition of ovarian cancer spheroid adhesion using graphene oxide nanomaterials [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B52.
Abstract B54: Adipogenic chemokines, body mass index, and ovarian cancer survival
Authors: Duque Sara , Anyanwu Nneka , Bukenya George , Karam Shriya , Son Deok-Soo , Wilson Andrew J. , Crispens Marta A. , Beeghly-Fadiel Alicia 
Published: September 2020

Abstract
Objectives: Obesity affects more than one-third of US adults and promotes the development and progression of many cancers. One mechanism by which obesity may influence ovarian cancer is via adipocyte-tumor cell communication, including the production of chemotactic cytokines, or chemokines, in the tumor microenvironment. Our goal was to measure adipogenic chemokine expression and examine associations with body mass index (BMI) and ovarian cancer survival.
Methods: We selected 25 chemokines from laboratory experiments that modeled adipogenesis, of which 22 had expression data available for 302 high-grade serous ovarian cancer cases from The Cancer Genome Atlas (TCGA). We measured mRNA expression using Taqman quantitative real-time polymerase chain reaction (QPCR) in 50 high-grade serous tumor samples and ascertained BMI from electronic medical records (EMR) from the Vanderbilt University Medical Center (VUMC). We also evaluated peri-diagnosis BMI (± 4 weeks) from EMR for 298 tumor registry-confirmed (165 serous and 133 nonserous) cases. Expression data were log transformed and dichotomized at median values; associations with disease-free survival (DFS) and overall survival (OS) were quantified using proportional hazards regression.
Results: In TCGA analyses, two ligands and one receptor had significant associations with better (CCL8 and CXCL13) and worse (CX3CR1) OS, respectively. Higher CXCL13 expression was also associated with better DFS in VUMC tumors, but significance was attenuated after adjustment for clinical covariates. CX3CR1 was not expressed in all tumors but was positively associated with BMI (Pearson’s r=0.69, P=0.019). Finally, among all 298 tumor registry-confirmed VUMC cases, BMI was not associated with OS, although higher BMI was associated with a 4% significantly increased risk of death among 133 nonserous cases.
Conclusions: Our findings suggest that obesity impacts chemokine expression in the tumor microenvironment and ovarian cancer survival. Further, differences between serous and nonserous subtypes may influence the relationship between obesity and ovarian cancer prognosis.
Citation Format: Sara Duque, Nneka Anyanwu, George Bukenya, Shriya Karam, Deok-Soo Son, Andrew J. Wilson, Marta A. Crispens, Alicia Beeghly-Fadiel. Adipogenic chemokines, body mass index, and ovarian cancer survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B54.
Abstract B70: Rac1 as a therapeutic target in ovarian cancer
Authors: Rivera Melanie , Grimes Martha M. , Dominguez Dayna , Kenney S. Ray , Guo Yuna , Romero Elsa , Brayer Kathryn J. , Guo Yan , Ness Scott A. , Adams Sarah F. , Muller Carolyn , Hudson Laurie G. , Wandinger-Ness Angela 
Published: September 2020

Abstract
Rac1 is a high-value therapeutic target for cancer based on its tumor-promoting activities, yet clinical applications targeting Rac1 are in their infancy. High expression and hyperactivation of Rac1 in ovarian cancer, along with our identification of R-ketorolac as a novel Rac1 and Cdc42 selective inhibitor with translational potential, prompt us to test the hypothesis that targeting Rac1 has therapeutic utility for ovarian cancer. Ascites tumor cell samples from ovarian cancer patients in a prospective study receiving racemic ketorolac for clinically indicated use in pain relief were previously reported to show time-dependent reduction of Rac1 and Cdc42 activities post-treatment. New RNA seq data of these patient samples reveals significant downregulation of genes involved in endocytosis, regulation of actin cytoskeleton, ER protein processing, TNF and NOD signaling. Conversely, the identified downregulated genes were overexpressed and associated with worse survival in ovarian cancer patients analyzed through The Cancer Genome Atlas (TCGA). Among the downregulated genes in the NOD pathway are chemokines and proinflammatory cytokines. Follow-up cytokine panels from patients confirm that racemic ketorolac treatment reduces the levels of immunosuppressive cytokines IL-6, IL-10, and RANTES in ascites fluids. Together, these data indicate there may be a benefit to the anti-inflammatory activity of the S- enantiomer, as well as the GTPase inhibitory activity of the R-enantiomer of ketorolac for ovarian cancer treatment.
Citation Format: Melanie Rivera, Martha M. Grimes, Dayna Dominguez, S. Ray Kenney, Yuna Guo, Elsa Romero, Kathryn J. Brayer, Yan Guo, Scott A. Ness, Sarah F. Adams, Carolyn Muller, Laurie G. Hudson, Angela Wandinger-Ness. Rac1 as a therapeutic target in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B70.
Abstract IA11: Women at high risk for ovarian cancer: Novel strategies for identification and prevention
Authors: Lu Karen H. 
Published: September 2020

Abstract
Most women carry a lifetime risk of 1.4% of ovarian cancer. However, certain women with germline mutations in BRCA1, BRCA2, or other hereditary cancer genes have elevated lifetime risks, some as high as 50%. Identification of these unaffected, high-risk women, followed by patient-centered prevention strategies, is key to decreasing overall mortality from ovarian cancer. A number of barriers exist for identification—including cost, patient preference, and availability of genetics services. In an effort to decrease these barriers, novel delivery systems of genetic testing have been developed. We are currently testing an on-line genetic counseling and testing strategy in a study called Making Genetic Testing Accessible (MAGENTA). We hypothesize that online genetic education and testing with access to board-certified genetic counselors could improve access to genetic testing while maintaining test quality and clinical utility. In this prospective, randomized, national clinical trial, over 3,000 women with a family history of breast or ovarian cancer will undergo genetic testing. We will compare the effectiveness of online genetic education with optional telephone counseling with three other strategies: online genetic education with required pretest telephone genetic counseling, online genetic education with required post-test telephone genetic counseling, and online genetic education with required pre- and post-test telephone genetic counseling. The primary outcome is cancer risk distress at 3 months post disclosure of genetic test results. Additional endpoints include testing completion rate (defined as receiving results), genetics knowledge, cognitive outcomes (i.e., decisional satisfaction, decisional regret), and behavioral outcomes. We currently have women enrolled from all 50 states in the United States. Preliminary data from this study will be presented. In addition, we will discuss our prospective, multicenter surgical prevention study that has enrolled over 200 women nationwide who have undergone either a salpingectomy or risk-reducing salpingo-oophorectomy (RRSO). The concept of salpingectomy with delayed oophorectomy as a cancer-prevention strategy for high-risk women is based on multiple studies implicating the fallopian tube epithelia as the cell of origin for BRCA-associated high-grade serous ovarian cancer. This information, coupled with high-risk women’s desire to minimize side effects associated with surgical menopause from RRSO, forms the rationale for the study. Finally, we will discuss plans for a prospective, international trial of salpingectomy in high-risk women that will be powered for a cancer efficacy endpoint.
Citation Format: Karen H. Lu. Women at high risk for ovarian cancer: Novel strategies for identification and prevention [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA11.
Abstract IA16: ER stress responses shape the ovarian cancer immune-microenvironment
Authors: Cubillos-Ruiz Juan R. 
Published: September 2020

Abstract
Harnessing the intrinsic ability of our immune system to eliminate malignant cells represents the most promising new anticancer strategy since the development of chemotherapy. While cancer immunotherapy has been designated a scientific breakthrough, tumor-induced immunosuppression represents a major impediment to the success of this new approach in ovarian cancer. We uncovered that ovarian cancer inhibits the development of protective antitumor immunity by inducing a state of persistent “endoplasmic reticulum (ER) stress” in intratumoral dendritic cells (DCs) and T cells. First, we identified that sustained activation of the IRE1-XBP1 arm of the ER stress response in DCs was necessary for the aggressive and accelerated progression of primary and metastatic ovarian cancers in various preclinical models of disease. Mechanistically, intratumoral DCs exhibited constitutive IRE1-XBP1 activation, which was fueled by lipid peroxidation byproducts that caused ER stress by modifying ER-resident chaperones. Persistent XBP1 activation induced a comprehensive triglyceride biosynthetic program promoting accumulation of lipid droplets that subsequently impaired DC antigen presentation to T cells. Conditional deletion or therapeutic silencing of IRE1 or XBP1 in DCs restored their immunogenic function in the tumor and delayed ovarian cancer progression by eliciting protective antitumor T-cell responses. In addition, we recently demonstrated that ovarian cancer also triggers abnormal IRE1-XBP1 activation in T cells to control their mitochondrial function and antitumor activity. XBP1 upregulation in T cells isolated from human ovarian cancer specimens was associated with decreased intratumoral T-cell infiltration and reduced IFNG expression. Ascites fluid from ovarian cancer patients inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, leading to XBP1-driven mitochondrial dysfunction. Mechanistically, maladaptive XBP1 signaling limited the influx of glutamine necessary to sustain mitochondrial respiration under glucose-deprived conditions. Hence, ovarian cancer hosts lacking XBP1 selectively in T cells demonstrated superior antitumor immunity, delayed malignant progression, and increased overall survival. Taken together, our studies revealed that ovarian cancer provokes persistent IRE1-XBP1 signaling in immune cells to shape the tumor microenvironment and evade immune control. These findings provide a new mechanistic understanding of immunosuppression in ovarian cancer and offer novel avenues for immunotherapeutic intervention.
Citation Format: Juan R. Cubillos-Ruiz. ER stress responses shape the ovarian cancer immune-microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA16.
Abstract IA20: Personalized whole-tumor antigen vaccines in ovarian cancer: Using tumors for therapy
Authors: Kandalaft Lana E. 
Published: September 2020

Abstract
Disappointing results have been observed with the first-generation therapeutic cancer vaccines. However, the renaissance of immunotherapy with the checkpoint inhibitors and the demonstration, in preclinical models, that personalized vaccines can induce efficient antitumor T-cell responses have led to a renewed interest in cancer vaccination. Personalized whole-tumor lysate vaccines can encompass all putative antigens in a patient’s tumor and can potentially induce a broader, more efficient immune response. We report here a clinical study utilizing a personalized vaccine generated by autologous dendritic cells (DC) pulsed with autologous whole-tumor cell lysate (OCDC), in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients in combination with bevacizumab or bevacizumab plus low-dose intravenous cyclophosphamide until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccine was shown to induce T-cell responses to autologous tumor antigen, which were associated with significantly prolonged survival (PFS). Vaccine was also shown to amplify T-cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes as well as novel T-cell clones of markedly higher avidity against previously recognized neoepitopes. Importantly, we demonstrate that the median PFS was 11.1 months in the population receiving the combination of vaccine plus bevacizumab and low-dose cyclophosphamide as compared to only 4.1 months in a historic population of patients from the same institution who received standard bevacizumab and low-dose cyclophosphamide without vaccine. We also demonstrate that survival at 2 years was 100% in the vaccine plus bevacizumab/cyclophosphamide group while it was only 40% in control patients receiving bevacizumab and cyclophosphamide alone. This proof-of-concept clinical study gives us a new horizon for the application of whole-tumor lysate personalized vaccines.
Citation Format: Lana E. Kandalaft. Personalized whole-tumor antigen vaccines in ovarian cancer: Using tumors for therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA20.
The Aged Microenvironment of Melanoma Feeds Escape from Targeted Therapy
Authors: Montal Emily D. , White Richard M. 
Published: September 2020

Abstract

Summary:
Alicea and colleagues demonstrate that aged fibroblasts secrete lipids into the tumor microenvironment, allowing for nutrient exchange with melanoma cells. This supportive function of fibroblasts results in increased resistance to BRAF/MEKi therapy in the context of an aged microenvironment, providing crucial mechanistic insight into age-related drug resistance.
See related article by Alicea et al., p. 1282.
Comparison Between Ticagrelor and Clopidogrel in Elderly Patients With an Acute Coronary Syndrome
Authors: Szummer Karolina , Montez-Rath Maria E. , Alfredsson Joakim , Erlinge David , Lindahl Bertil , Hofmann Robin , Ravn-Fischer Annica , Svensson Per , Jernberg Tomas 
Published: September 2020

Background:
The comparative efficacy and safety of ticagrelor versus clopidogrel in older patients with myocardial infarction (MI) has received limited study.

Methods:
We performed an observational analysis of all patients ≥80 years (n=14 005) who were discharged alive with aspirin combined with either clopidogrel (60.2%) or ticagrelor (39.8%) after a MI between 2010 and 2017 registered in the national registry SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies). Inverse probability treatment weighting was used in Cox regression models to adjust for differences in demographics, in-hospital therapies, and medications. The primary ischemic outcome (death, MI, or stroke), and bleeding were obtained from national registries at 1 year. A sensitivity analysis in <80-year-old patients was performed.

Results:
In patients ≥80 years, the incidence of the primary ischemic outcome (hazard ratio [HR], 0.97 [95% CI, 0.88–1.06]) was similar for ticagrelor- and clopidogrel-treated patients. Ticagrelor was associated with a 17% and 48% higher risk of death (HR, 1.17 [95% CI, 1.03–1.32]) and bleeding (HR, 1.48 [95% CI, 1.25–1.76]), but a lower risk of MI (HR, 0.80 [95% CI, 0.70–0.92]) and stroke (HR, 0.72 [95% CI, 0.56–0.93]). In <80-year-old patients, the incidence of the primary ischemic outcome was 17% (HR, 0.83 [95% CI, 0.77–0.89]) lower with ticagrelor. Ticagrelor was associated with 15% (HR, 0.85 [95% CI, 0.76–0.96]) lower risk of death, 32% higher risk of bleeding (HR, 1.32 [95% CI, 1.18–1.47]), but lower risk of MI (HR, 0.82 [95% CI, 0.75–0.91]) and stroke (HR, 0.82 [95% CI, 0.69–0.98]).

Conclusions:
Ticagrelor use among elderly patients with MI was associated with higher risk of bleeding and death compared with clopidogrel. A randomized study of ticagrelor versus clopidogrel in the elderly is needed.
Front Desk Duty Multitasking Test After Mild Stroke: Preliminary Reliability and Validity
Authors: Carroll Ginger L. , Radomski Mary , Halsten Jerry , Meyers Amy , Rabusch Stacey , Takimoto Romina , Kreiger Robert 
Published: September 2020

Background. Performance-based multitasking assessments may be more sensitive than cognitive screens to detect executive dysfunction after a mild stroke. Purpose. This cross-sectional study examined inter-rater reliability and preliminary convergent and discriminant validity of the Front Desk Duty Test (FDDT). Method. Adults with mild stroke ( n = 35) and community controls ( n = 33) were administered the FDDT and other measures of executive functions. Findings. Inter-rater reliability of the FDDT subscores were high (ICC 0.971–0.999). There were weak but statistically significant correlations between participants’ scores on some of the executive function tests and some FDDT subscores. Participants with mild stroke and community controls had statistically significant different FDDT scores (performance accuracy p = .006; performance time, p = .033), with rank order FDDT score patterns across community controls, participants with mild stroke who passed the executive function screen, and participants with mild stroke who failed the executive function screen. Implications. Preliminary validation results suggest that the FDDT warrants further study.
Tracheotomy in a High‐Volume Center During the COVID‐19 Pandemic: Evaluating the Surgeon’s Risk
Authors: Thal Arielle G , Schiff Bradley A. , Ahmed Yasmina , Cao Angela , Mo Allen , Mehta Vikas , Smith Richard V. , Cohen Hillel W. , Ow Thomas J. 
Published: September 2020

ObjectivePerforming tracheotomy in patients with COVID‐19 carries a risk of transmission to the surgical team due to potential viral particle aerosolization. Few studies have reported transmission rates to tracheotomy surgeons. We describe our safety practices and the transmission rate to our surgical team after performing tracheotomy on patients with COVID‐19 during the peak of the pandemic at a US epicenter.Study DesignRetrospective cohort study.SettingTertiary academic hospital.MethodsTracheotomy procedures for patients with COVID‐19 that were performed April 15 to May 28, 2020, were reviewed, with a focus on the surgical providers involved. Methods of provider protection were recorded. Provider health status was the main outcome measure.ResultsThirty‐six open tracheotomies were performed, amounting to 65 surgical provider exposures, and 30 (83.3%) procedures were performed at bedside. The mean time to tracheotomy from hospital admission for SARS‐CoV‐2 symptoms was 31 days, and the mean time to intubation was 24 days. Standard personal protective equipment, according to Centers for Disease Control and Prevention, was worn for each case. Powered air‐purifying respirators were not used. None of the surgical providers involved in tracheotomy for patients with COVID‐19 demonstrated positive antibody seroconversion or developed SARS‐CoV‐2–related symptoms to date.ConclusionTracheotomy for patients with COVID‐19 can be done with minimal risk to the surgical providers when standard personal protective equipment is used (surgical gown, gloves, eye protection, hair cap, and N95 mask). Whether timing of tracheotomy following onset of symptoms affects the risk of transmission needs further study.