tbuckley/cabot-search huggingface dataset:
NCMP-01. THE ROLE OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR INHIBITORS IN PREVENTING CEREBRAL RADIATION NECROSIS: A RETROSPECTIVE COHORT STUDY
Authors: Iyad Alnahhas, Appaji Rayi, Joshua Palmer, Raju Raval, Edmund Folefac, Shirley Ong, Pierre Giglio, Vinay Puduvalli
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Radiation necrosis (RN) is a potential complication after radiation therapy to primary brain tumors and brain metastases. The pathophysiology of RN is not well understood but it is hypothesized that vascular endothelial growth factor (VEGF) plays an important role. Bevacizumab, a monoclonal antibody against VEGF-A, is often successful in the management of RN. The objective of this study is to assess whether VEGF receptor (VEGFR) inhibitors, a group of oral tyrosine kinase inhibitors (TKIs), can prevent or reverse cerebral radiation necrosis METHODS We retrospectively studied a cohort of 102 patients with renal cell carcinoma (RCC) and brain metastases seen at The Ohio State University James Cancer Center between 01/01/2011 and 04/30/2019. We identified those who developed RN and analyzed the temporal relationship between the use of VEGFR TKIs and the development of RN. RESULTS The cumulative incidence of RN in our cohort is 13.7% after radiation treatments that included LINAC-based stereotactic radiosurgery, fractionated stereotactic radiotherapy, or Gamma Knife radiosurgery. There was no statistically significant difference in the cumulative incidence of RN between patients taking TKIs and patients who were off TKIs (9.9% and 11.5% respectively, p= 0.741). The median time to development of RN was only numerically shorter in patients taking TKIs (151 versus 315 days, p=0.315). One patient developed RN after stopping cabozantinib. Three other patients developed RN while on cabozantinib. Two patients developed RN while on pazopanib, and 3 patients developed RN while on sunitinib. One patient was started on axitinib during active RN without significant improvement subsequently. CONCLUSIONS VEGFR TKIs do not consistently prevent or reverse cerebral radiation necrosis and do not seem to have the efficacy that bevacizumab has against RN.
GCT-33. A PHASE 2 TRIAL OF RESPONSE-BASED RADIATION THERAPY FOR PATIENTS WITH LOCALIZED CENTRAL NERVOUS SYSTEM GERM CELL TUMORS: A CHILDREN’S ONCOLOGY GROUP (COG) STUDY. IMPACT OF RAPID CENTRAL RADIOTHERAPY REVIEW ON RADIOTHERAPY QUALITY AND PATTERN OF FAILURE FOR NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Erin S Murphy, Girish Dhall, Jason Fangusaro, Ute Bartels, Maryam Fouladi, Dennis Shaw, Soumen Khatua, Ashok Panigraphy, Mark Souweidane, Amar Gajjar, Chris Williams-Hughes, Arzu Onar, Shengjie Wu, Daphne Haas-Kogan, Shannon MacDonald
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND COG ACNS 1123 tested reduced radiotherapy (RT) for non-metastatic, non-germinomatous germ cell tumor (NGGCT) patients. The impact of central review on quality of RT and pattern of failure for NGGCT patients is evaluated. METHODS Patients who achieved a complete response (CR) or partial response (PR) to induction chemotherapy were eligible for reduced dose and field RT of 30.6 Gy whole ventricular field (WVI) and 54 Gy tumor-bed total dose. An online contouring atlas was available. Within three days of RT start, WVI plans were submitted for rapid central review. Within one week of RT completion, the complete RT record was submitted. Brain and spine MRIs of relapsed patients were centrally reviewed. RESULTS Between 5/2012–9/2016, 107 eligible patients were accrued and 70 met reduced RT criteria. Rapid RT review was performed for 49 (70%) of 70 patients. Forty-four (89.8%) required no modification. All modifications were completed and plans became compliant. Final central review was performed for 66 evaluable patients: 62 (94%) were per protocol; there were 2 major (1 dose and 1 target) and 2 minor deviations. Eight patients progressed; none had deviations. Median time to progression was 3.54 months (range: 1.7–19.1) from RT start. All failures had a spine component; two also had cranial component: one local progression (within the RT boost volume) and one leptomeningeal disease. CONCLUSION Providing an online contouring atlas and performing a rapid central review lead to high quality radiotherapy on this prospective trial. The deviations did not contribute to the pattern of failure.
NCOG-43. NEUROCOGNITIVE IMPAIRMENT AND FRAILTY IN GERIATRIC PATIENTS WITH HIGH GRADE GLIOMA AND THORACIC MALIGNANCY
Authors: Daniel Haggstrom, Armida Parala-Metz, Raghava Induru, Tiffany Kneuss, Markecia Cooper, Anthony Caprio, Ashley Sumrall
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The median age at diagnosis for high grade glioma is 64 years. With peak incidence 75-84, malignant glial tumors are frequently a disease of the elderly. Common assessment measures fail to accurately gauge geriatric cancer patient fitness. Comprehensive Geriatric Assessment (CGA) is recommended in patients older than 65 to gauge risk of toxicity and tolerance of therapeutic intervention. We reviewed data for older patients with high grade glioma (HGG) and thoracic malignancy (TM) who underwent CGA via Senior Oncology Clinic (SOC) at Levine Cancer Institute. METHODS From 2015 to 2019 104 thoracic malignancy patients and 19 high grade glioma patients completed CGA via SOC before treatment or a required change in therapy. Data was incorporated into the LCI Senior Oncology Database by the REDCap secure web application, allowing for both quantitative and qualitative data analysis. RESULTS The median age was 77 in the HGG cohort compared to 80 years with TM. The physician rated Karnofsky Performance Status (KPS) for HGG and TM were similar (76% v 79%) as were the percentages of patients that were frail or prefrail (90% v 87%). Montreal Cognitive Assessment scores were lower in HGG (20 v 23). Considerably more HGG had falls in the 6 months before their assessment (58% v 30%) and gait speed was slower (0.76 m/s v 0.85 m/s). CONCLUSIONS Older patients with high grade gliomas compared to similar thoracic malignancies had more neurocognitive impairment, falls in the preceding 6 months, and slower gait speed. Physician rated KPS and frailty were similar in both groups. The results illustrate the limitations of physician-rated performance measures and highlight the importance of CGA in older brain tumor patients.
QOL-48. INTERDISCIPLINARY SPIRITUAL CARE TRAINING IN PEDIATRIC NEURO-ONCOLOGY
Authors: Alex Lion, Saneta Maiko, Csaba Szilagyi, James Slaven, Christina Puchalski
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Pediatric neuro-oncology requires attention to not only cancer biology and therapeutics, but also to the suffering of the patient. In addressing patient suffering, consensus guidelines direct attention to the spiritual distress and resources of patients and families. A lack of training has been a key barrier to integrating this aspect of health into patient care. METHODS A neuro-oncologist and a chaplain participated in a train the trainer for the Interprofessional Spiritual Care Education Curriculum (ISPEC) through the George Washington University’s Institute for Spirituality and Health. After the train the trainer, the online curriculum was offered to interdepartmental team members, combined with in-person discussion groups, which met weekly for six sessions. A survey was given before and after the training, and Likert scores were analyzed using the Wilcoxon rank-sum non-parametric test. OUTCOMES: 17 interdisciplinary members participated in the training. These members included neuro-oncologists, neuro-surgeons, rehabilitation physicians, nurse practitioners, nurses, physical therapists, music therapists, a child life specialist, a school liaison, and a patient experience specialist. The training resulted in multiple improvements, including increased ability to identify spiritual issues (p=.0278) and increased ability to respond to these issues (p=.0056). CONCLUSION ISPEC addressed a key barrier to providing generalist spiritual care to patients with pediatric brain tumors. Diverse disciplines were represented during the training. With implementation of interdisciplinary spiritual care, outcomes that may be measured in the future include improved quality of life, patient satisfaction, and the resilience of both patients and team members.
BIOM-39. ESTABLISHMENT OF A CONNECTIVITY SIGNATURE FOR GLIOMAS
Authors: Tobias Kessler, Ling Hai, Dirk Hoffmann, Ruifan Xie, Henriette Mandelbaum, Erik Jung, Matthias Schlesner, Frank Winkler, Wolfgang Wick
Journal: Neuro-Oncology (2020)

Abstract Recent studies have demonstrated extensive cell-to-cell connectivity between tumor cells of gliomas with considerable relevance for tumor progression and therapy resistance. Tumor microtubes (TMs) are neurite-like tumor cell extensions that build these tumor cell networks. Measuring the extent of connectivity in individual tumors has been challenging and depended on anatomical parameters that are difficult to evaluate in patient samples. We performed bulk and single-cell (sc)RNA sequencing of connected vs. unconnected tumor cells from patient-derived xenograft tumors using a newly developed technology that exploits SR101 dye transfer within tumor cell networks. scRNA sequencing was performed with 17 human glioblastoma tumor samples. Three diffuse glioma cohorts from The Cancer Genome Atlas (n = 648), the Chinese Glioma Genome Atlas (n = 668) and the NCT Neuro Master Match (n = 38, IDH-wildtype only) were used to assess clinical properties. A connectivity signature both from bulk and scRNA sequencing data of xenografted primary glioblastoma tumor cells was established. Comparative analysis showed better performance and higher biological relevance of the single-cell derived signature that involves 71 genes. Most of the genes are related to neurogenesis and neural tube development, including several previously recognized TM-relevant genes. Highest connectivity was observed in astrocytic-like and mesenchymal-like tumor cells. Induction of connectivity in vitro was accompanied with increase of the connectivity signature. The connectivity signature was higher in astrocytic as compared to oligodendrocytic gliomas, and highest in IDH-wildtype gliomas. In accordance, connectivity correlated strongly with dismal survival in all three glioma cohorts. The connectivity signature established here is biologically plausible and associates with prognostically relevant glioma subtypes. It provides the first proof-of-principle that tumor cell connectivity is relevant for the clinical course of patients with gliomas, and at the same time serves as a robust biomarker that can be used for future studies, including prospective clinical trials.
Nanoparticles in pregnancy: the next frontier in reproductive therapeutics
Authors: Natasha Pritchard, Tu’uhevaha Kaitu’u-Lino, Lynda Harris, Stephen Tong, Natalie Hannan
Journal: Human Reproduction Update (2020)

Nanotechnology involves the engineering of structures on a molecular level. Nanomedicine and nano-delivery systems have been designed to deliver therapeutic agents to a target site or organ in a controlled manner, maximizing efficacy while minimizing off-target effects of the therapeutic agent administered. In both reproductive medicine and obstetrics, developing innovative therapeutics is often tempered by fears of damage to the gamete, embryo or developing foetus or of negatively impacting a woman's reproductive potential. Thus, nanomedicine delivery systems may provide alternative targeted intervention strategies, treating the source of the disease and minimizing long-term consequences for the mother and/or her foetus.
Vascular Responses to Percutaneous Coronary Intervention With Bare-Metal Stents and Drug-Eluting Stents: A Perspective Based on Insights From Pathological and Clinical Studies⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: L. Maximilian Buja
Journal: Journal of the American College of Cardiology (2011)
A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma
Authors: Weinan Guo, Jinyuan Ma, Sen Guo, Huina Wang, Sijia Wang, Qiong Shi, Lin Liu, Tao Zhao, Fengfan Yang, Shuyang Chen, Jianru Chen, Jianhong Zhao, Chen Yu, Xiuli Yi, Yuqi Yang, Jingjing Ma, Qingrong Ni, Guannan Zhu, Tianwen Gao, Chunying Li
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive. Methods The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism. Results We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8 + T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8 + T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1 + CD8 + T cells to tumor burden. Conclusions Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.
Glycan-specific IgG anti-IgE autoantibodies are protective against allergic anaphylaxis in a murine model
Authors: Paul Engeroff, Kevin Plattner, Federico Storni, Franziska Thoms, Kayluz Frias Boligan, Lukas Muerner, Alexander Eggel, Stephan von Gunten, Martin F. Bachmann, Monique Vogel
Journal: Journal of Allergy and Clinical Immunology (2020)
Abstract P154: Disparities in Geographic and Temporal Trends of Myocardial Infarction Hospitalizations in Florida, 2005-2014
Authors: Evah W Odoi, Nicholas Nagle, Melissa Jordan, Chris DuClos, Kristina Kintziger
Journal: Circulation (2020)

Background: Knowledge of the extent of geographic disparities in the burden of myocardial infarction (MI) is useful for allocation of scarce public health resources to reduce health disparities and improve population health, regardless of whether MI is the primary or secondary cause for hospitalization. The objectives of this study were to identify: (a) geographic disparities in hospitalization risks for MI in Florida; and (b) the temporal changes in these disparities from 2005 to 2014. Methodology: We aggregated county-level data for principal and secondary inpatient MI-related hospital discharges in Florida between 2005 and 2014 by 2-year intervals and calculated age- and sex- adjusted MI hospitalization risks for each time interval. We identified spatial clusters of low- and high-risk MI hospitalization risks using circular spatial scan statistics and tracked MI risks in clusters that persisted throughout the 10-year study period. We also assessed health disparities between persistent high- and low-risk clusters at the end of the study (2013-2014) compared to the beginning of the study (2005-2006) periods. Results: MI hospitalization risks decreased by 15% in Florida overall during the 10-year study period. However, we found persistent disparities in MI risks by geographic location, with high-risk clusters occurring in north-, west-, south-central and southeast Florida, and low-risk clusters occurring in southeast and southwest Florida. A low-risk cluster that transitioned to high-risk status in the last four years of study was identified in northwest Florida. We also found substantial differences in the magnitude of decline in MI risks amongst clusters, with risks decreasing by 5%, 16% and 31% in high-risk clusters in west central, south central and north central Florida, respectively, and by 6.5% and 26% in low-risk clusters in southwest and southeast Florida, respectively. Furthermore, the risks only decreased during the first 6-8 years of study, after which they leveled off or ticked upwards. Consequently, health disparities between high- and low-risk clusters at the end of the study compared to the beginning of the study period decreased by 57% and 31.5% in north- and south-central Florida, respectively, but they remained relatively unchanged in west central Florida. Moreover, MI hospitalization risks in high-risk clusters lag behind those in low-risk clusters by at least a decade. Conclusion: Myocardial infarction hospitalization risks declined modestly during 10-year study period. However, persistent disparities continue to exist across space and time. Addressing these disparities will require targeting intervention efforts to counties with persistently high risks.
NCMP-16. THE ROLE OF p38 AND JNK MAPK PATHWAYS IN CISPLATIN CHEMOTHERAPY-RELATED COGNITIVE IMPAIRMENT
Authors: Naomi Lomeli, Kaijun Di, Daniela Bota
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES Chemotherapy-related cognitive impairment (CRCI) is an adverse sequela of cancer treatment commonly reported in cancer survivors. Cisplatin is used for the treatment of various malignancies including ovarian, testicular, head and neck cancers, and pediatric brain tumors. More than 30% of advanced ovarian cancer patients develop CRCI during and after platinum-based chemotherapy. We examined the role of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in cisplatin-induced CRCI, and whether the small molecule p38 MAPK inhibitor Neflamapimod and JNK inhibitor SP600125, can prevent cisplatin-induced neuronal damage. The p38 and JNK MAPK signaling pathways are involved in various stress response pathways in the CNS including oxidative stress. METHODS The effect of cisplatin on cognition in an ovarian cancer female rat model was assessed by novel object recognition (NOR). Hippocampal glutathione levels were measured post-behavioral testing. P38 and JNK MAPK signaling activation were assessed in the neural cell lines PC12 and SH-SY5Y by Western blot. Cultured hippocampal neurons were pretreated with Neflamapimod or SP600125 followed by cisplatin for 24 hours, and dendritic spine density and branch length were quantified. RESULTS Cisplatin increased phospho-p38 and phospho-JNK MAPK protein levels in PC12 and SH-SY5Y cells. Cisplatin reduced dendritic branching and spine density, which was prevented by Neflamapimod and SP600125 pre-treatment in hippocampal neurons, in vitro. Chronic cisplatin treatment decreased hippocampal glutathione levels and impaired cognitive function in the ovarian cancer rat model. DISCUSSION The cognitive deficits caused by cisplatin results in part from dendritic damage and neural apoptosis, which is mediated by oxidative stress and the p38 and JNK MAPK pathways. P38 and JNK MAPK inhibition mitigated cisplatin-induced dendritic spine loss and branching in vitro. Next, we will examine whether Neflamapimod and SP600125 administration in an ovarian cancer rat model is safe and if they can prevent cognitive impairment.
ETMR-18. TARGETING Lin28 IN ETMR WITH ODC1 INHIBITOR DFMO
Authors: Austin Goodyke, Shannon Kelly, Joseph Zagorski, Elizabeth VanSickle, Tyler Maser, Caryl Sortwell, Christopher Kemp, Abhinav Nagulapally, Karl Dykema, Giselle Saulnier-Sholler
Journal: Neuro-Oncology (2020)

Abstract Embryonal tumor with multilayered rosettes (ETMR), is an aggressive brain tumor primarily occurring in young patients (&amp;lt;4 years of age) and characterized by C19MC amplification and Lin28 overexpression. These genetic hallmarks have been shown to participate in driving ETMR in a C19MC-Lin28-MYCN circuit. Reducing Lin28 disrupts this circuit and reduces cell viability in ETMR models. Investigation of therapeutic agents targeting this pathway is required to provide new treatment options for this deadly disease. We present data showing the effect of DFMO (α-difluoromethylornithine) in ETMR, an ODC1 inhibitor known to reduce Lin28 in neuroblastoma. DFMO treatment of the ETMR cell line BT-183 resulted in a significant reduction of intracellular Lin28 protein levels (P&amp;lt;0.05) as indicated by flow cytometry. In concert with this reduction in Lin28, there was a as significant reduction in viable cells (P&amp;lt;0.05), and the number of CD133+ cells were reduced 2-fold (P&amp;lt;0.05). High throughput drug testing of BT-183 identified a number of additional therapeutic agents with potential therapeutic efficacy for ETMR and combining these with cytostatic agent DFMO demonstrated the potential use of these drugs in combination. These in vitro data were complemented by testing of DFMO in an in vivo stereotaxic xenograft ETMR model, with inhibition of tumor burden monitored by bioluminescent imaging of the tumors. Together this work shows that Lin28 targeting agents such as DFMO merit further examination and integrating these types of agents into treatment strategies for ETMR may lead to better outcomes.
TBIO-13. USE OF NEXT GENERATION SEQUENCING TO IDENTIFY MOVE DRIVERS OF CRYPTIC, CLINICALLY AGGRESSIVE BRAIN TUMORS
Authors: Subhi Talal Younes, Amanda Boudreaux, Kristin Weaver, Cynthia Karlson, Betty Herrington
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Next generation sequencing (NGS) is an emerging technology which allows for in-depth analysis of pediatric brain tumors. NGS has particular use in the context of ambiguous or aggressive neoplasms, where it can be leveraged to discover novel drivers, inform pathologic classification, and direct targeted therapies. OBJECTIVE The objective of this case series was to utilize NGS technology to illuminate the biology of aggressive brain tumors with ambiguous pathologic features and clinically aggressive behavior. METHODS FFPE tumor tissue and matched germline DNA were subjected to whole exome sequencing (WES). Data were analyzed according to the GATK pipeline. RESULTS The first case is a 6-year-old male who presented with innumerable foci of leptomeningeal nodules throughout the neuroaxis. Original pathology was CNS embryonal tumor. WES identified loss of chromosome 1p and 16q with gain of 1q and amplification of MYC and OTX2 loci (cytogenetic aberrations characteristic of group 3 medulloblastoma) and a deleterious mutation in BCL7B, a known tumor suppressor gene. The second case is a 2-year-old female who presented with a parietal lobe mass diagnosed as high grade neuroepithelial tumor with C11orf95 translocation, but no RELA fusion. WES revealed loss of small region of chromosome 2p and mutations in IDH3G, TRAF2, and JMJD1C, suggesting novel targets for further study. CONCLUSIONS In both cases, NGS studies were able to shed light on the underlying tumor biology and/or refine the pathologic diagnosis. These data underscore the utility of applying NGS technology to study the biology of pediatric brain tumors.