tbuckley/cabot-search huggingface dataset:
Abstract 17368: The Novel P2X7 Receptor Antagonist SMW139 Inhibits Inflammasome Activation in STEMI Monocytes
Authors: Thomas Hansen, Kristen Bubb, Michael Kassiou, Gemma Figtree
Journal: Circulation (2018)

Introduction: The inflammasome and the downstream pro-inflammatory cytokine interleukin-1ß (IL-1ß) have emerged as critical modulators of atherosclerosis and acute coronary syndromes (ACS). It therefore represents an important therapeutic target to treat coronary artery disease. This study investigates the activation of the inflammasome in circulating monocytes of ACS patients, and the effectiveness of SMW139- a compound selected from a panel of over 70 novel P2X7 antagonists based upon its excellent pharmacokinetic properties- on modulating the downstream inflammatory signalling pathway. Hypothesis: The P2X7 antagonist SMW139 reduces inflammasome activation. Methods: In vitro: THP-1 monocytic cells were treated with interferon- γ and lipopolysaccharide for 3 hours, then pre-incubated with SMW139 (1-1000nM), prior to ATP stimulation to activate the inflammasome, and collection of supernatant for IL-1ß measurement. Ex vivo: Peripheral blood mononuclear cells (PBMCs) were collected from 19 STEMI patients at time of infarct, and 3 healthy controls. Monocytes were pre-incubated with SMW139 or DMSO control prior to ATP stimulation. IL-1ß and caspase-1 activity were measured by ELISA and fluorometric assay. Results: In vitro: Sigmoidal dose-response curve demonstrated a LogEC50 of -8.069±0.16. Ex vivo: High levels of detectable P2X7 expression in PBMCs was confirmed by flow cytometry. Baseline levels of secreted IL-1ß were significantly elevated in PBMCs from STEMI patients compared with healthy controls (STEMI: 8.2±0.6, Control: 4.2±0.1;p=0.02). There was a significant increase in IL-1ß secretion post ATP-induced inflammasome activation in STEMI PBMCs (53.8±9.4;p&lt;0.0001) but not control (9.8±0.9). P2X7 inhibition significantly attenuated this ATP-induced IL-1ß secretion in STEMI cells (13.9±2.4;p&lt;0.0001) but had no effect in controls (7.5±2.8). Similarly, P2X7 inhibition resulted in approximately 60% reduction of ATP-induced caspase-1 activity in STEMI cells (p=0.01). Conclusions: The P2X7 antagonist compound SMW139 effectively inhibits the inflammasome, causing a significant reduction in caspase-1 activity and IL-1ß cytokine levels, and holds promise as a novel therapy for patients with atherosclerosis and ACS.
Treating Residual Cardiovascular Risk: Will Lipoprotein-Associated Phospholipase A2 Inhibition Live Up to Its Promise?⁎⁎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: Wolfgang Koenig
Journal: Journal of the American College of Cardiology (2008)
TMOD-05. EXTRACRANIAL TUMORS INFLUENCE INTRACRANIAL RESPONSE TO IMMUNE CHECKPOINT INHIBITORS IN PRE-CLINICAL MODELS OF MELANOMA BRAIN METASTASIS
Authors: Naema Nayyar, Mohini Singh, Jackson Stocking, Michael Brehm, Priscilla Brastianos
Journal: Neuro-Oncology (2020)

Abstract Melanomas frequently spread to the brain, with up to 75% of patients developing brain metastases. Treatment of metastatic melanoma has been revolutionized by the advent of immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4. However, responses to ICI within the immune-specialized brain environment are not well understood owing to the lack of immunocompetent animal models for the investigation of intracranial responses to checkpoint blockade. We studied the effect of ICI in a syngeneic mouse model of melanoma brain metastasis with concurrent intracranial and subcutaneous tumors. Either D3UV3 cells, derived from a UVB irradiated clone of D4M.3A melanoma cell line, or vehicle were subcutaneously injected into the flank of C57BL/6 mice. 3 days later, D3UV3 cells tagged with firefly luciferase were implanted into the striatum using stereotactic injection. Mice were then treated with anti-PD-1 antibody, anti-CTLA-4 antibody, a combination of anti-PD-1 and anti-CTLA-4 antibodies, or isotype controls. We observed striking differences in survival between mice with concurrent intracranial and subcutaneous tumors compared to intracranial tumors alone. Mice with intracranial tumors alone experienced no benefit in survival following monotherapy with anti-PD-1 (p=1) or anti-CTLA-4 (p=0.1) compared to isotype-treated mice, and only a slight benefit with combination treatment (p=0.049). In contrast, mice with concurrent tumors experienced a significant increase in overall survival with anti-CTLA-4 monotherapy (p=0.01) and combination anti-CTLA-4 and anti-PD-1 treatment (p=0.01) compared to isotype-treated mice, although treatment with anti-PD-1 alone did not increase survival (p=0.28). These results indicate that the presence of extracranial disease can modulate intracranial immune responses following checkpoint blockade. We have therefore established a pre-clinical model with concurrent intracranial and extracranial tumors to better recapitulate the clinically observed context of brain metastases. We hope this model will lead to a better understanding of the setting in which ICI is effective for patients with melanoma brain metastases.
SARS-CoV-2 antibody responses in patients with acute leukaemia
Authors: J. O’Nions, L. Muir, J. Zheng, C. Rees-Spear, A. Rosa, C. Roustan, C. Earl, P. Cherepanov, R. Gupta, A. Khwaja, C. Jolly, L. E. McCoy
Journal: Leukemia (2020)
EPID-14. RACIAL DIFFERENCES AND DISPARITIES IN PATIENTS WITH GLIOMAS: A SINGLE COMPREHENSIVE CANCER CENTER EXPERIENCE FROM 2008–2020
Authors: Elizabeth Coffee, Zachary Tucker, Mina Lobbous, Monica Baskin, James Markert, John Fiveash, C Ryan Miller, Louis Nabors
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Disparities in healthcare delivery in the United States based on race and socioeconomic status are well-documented. Our study examined these disparities along with demographic differences in patients with gliomas. METHODS Data was collected retrospectively from an NCI Comprehensive Cancer Center between 2008–2020; 163 African-American patients and 1207 non-Hispanic white patients were included. Demographic variables were entered as predictors of tumor grade and type in an ANOVA model and multinomial logistic regression, respectively. A MANOVA model was used to assess differences in treatments received. Predictors of outcome were determined using cox regression. RESULTS Significant differences (p&amp;lt; 0.05) were found between African-American and non-Hispanic white patient groups in; age at diagnosis (48.68 vs 56.12 years, respectively), male/female gender ratio (0.75 vs 1.22), annual household income ($29,442 vs $40,028), insurance type (53.1% private and 42% public vs 63.4% private and 33.6% public) and marital status (43% married vs 74.1%). When controlling for these, there were no significant differences in tumor grade, type, MGMT methylation or IDH1 alteration statuses. Race alone did not predict treatment received, however, two-way interactions between race and other variables did. While gender differences in resection were small for non-Hispanic white controls, resection took place more often in African-American females than males (F = 4.779, p = 0.029). The deleterious effect of increased age on overall survival was diminished in African-Americans (B = -0.033, p &amp;lt; 0.001), while the effect of tumor grade was more pronounced (B = 0.595, p &amp;lt; 0.001). DISCUSSION This study suggests that disparities in outcomes are identified when race is considered within the context of other demographic, socioeconomic, and clinical factors. Moreover, these observations demonstrate the need for further studies into intersectional effects on treatment access and clinical outcomes, along with aggressive countermeasures to ensure equity of care.
EPID-04. THE SINGLE CENTER STUDY FOR BRAIN METASTASES OF UNDIAGNOSED PRIMARY TUMOR AND THE ROLE OF SURGICAL REMOVAL
Authors: Yuzaburo Shimizu, Mario Suzuki, Osamu Akiyama, Akihide Kondo
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The diagnosis of a brain metastases is generally made during the follow up examinations of patients with primary known cancer. However, there are some patients presenting brain metastases as the first manifestation of a previously undiagnosed primary tumor (UDP) pathological confirmation of the diagnosis. The timing of a subsequent neurosurgical intervention is influenced by the distribution of primary tumors in UDP patients. The purpose of this study was to investigate the optimal diagnostic approach and the role of surgery for UDP patients. METHODS In a retrospective study, 35 patients admitted to our institution and underwent brain tumor removal from 2017 to 2019 with the diagnosis of cerebral metastases and diagnosed lung cancer as primary tumor subsequently, or previously diagnosed lung cancer. RESULTS UDP patients represented 46% of the whole group. Primary tumor subtype was the adenocarcinoma (n=13, 81%), small cell carcinoma (n=2, 13%), and neuroendocrine carcinoma (n=1, 6%). They did not have bronchoscopy nor excision of lung cancer. On the other hand, the patients previously diagnosed lung cancer represented 54% and subtype was adenocarcinoma (n=14, 74%) and small cell carcinoma (n=5, 26%). EGFR mutation was detected from 7 patients (44%) in UDP group and treated by EGFR tyrosine kinase inhibitor. CONCLUSION The significance of surgical intervention in metastatic brain tumors has been limited. However, active surgical intervention in UDP patients could identify not only histological diagnosis but also molecular biological characteristics. Our study suggests the possibility to avoid whole brain radiation in UDP patient by the active surgery.
慢性期間中のアディポネクチン血しょう中濃度は,経皮的冠状動脈介入術(PCI)における再狭窄の予測因子である
Authors: Kunishima T, Sakakibara M, Mikami T, Aoyagi H, Kongoji K, Tsuchiya K, So T, Musha H, Miyake F
Journal: Circulation (2003)
Abstract 16935: Cardiovascular Disease in Head Neck Squamous Cell Carcinoma Patients - A Case-Control Study Using Electronic Medical Records Data
Authors: Amrita Mukherjee, Howard Wiener, Russell Griffin, Lisle M Nabell, Carrie G Lenneman, Cora E Lewis, Sadeep Shrestha
Journal: Circulation (2020)

Introduction: Cancer survivors have higher rates of cardiovascular disease (CVD) compared to age-adjusted general population. However, traditional CVD risk factors alone do not fully explain increased CVD risk in cancer patients. Cancer-related factors like cancer site, stage and chemotherapy may also contribute to CVD. Despite increase in head neck squamous cell carcinoma (HNSCC) cases in recent years, little is known about CVD risk in HNSCC patients. We aim to assess association of traditional risk factors and cancer-related factors with CVD in HNSCC patients. Methods: Electronic medical records data of 2391 HNSCC patients diagnosed between 2012-2018 at the UAB O’Neal Comprehensive Cancer Center, were included. ICD-9/10 codes were used to identify HNSCC patients, CVD cases and traditional risk factors. CVD cases were defined as those with composite events of ischemic heart disease and/ or heart failure; controls were without any CVD diagnosis. Cancer site, stage and treatment were included. Logistic regression [OR(95%CI)] was used to assess association of risk factors with CVD, adjusting for age, race, and gender. Results: HNSCC patients were mostly white (82.7%), male (74.7%) and had Stage III/IV cancer (46.6%). Oral cavity was the most common cancer site (32.9%), followed by oropharynx (31.7%); 55.4% patients had hypertension, 23.0% had dyslipidemia, and 16.1% had diabetes. CVD was diagnosed in 16.1% patients, who were more likely to be older [median age 67.0 vs 60.0 years, p&lt;0.0001]. In the multivariable model, hypertension [2.08(1.54-2.80)], diabetes [2.03(1.52-2.70)] and dyslipidemia [2.36(1.82-3.07)] were associated with CVD. Smoking status was not associated. Association of cancer stage with CVD varied by cancer site. Stage III/IV oropharynx cancer patients had lower odds of CVD than stage I/II oropharynx patients [0.38(0.30-0.92)]. No association with cancer stage was observed in oral cavity patients. Compared to chemotherapy, surgery [0.85(0.63-1.14)] and other treatments {0.61(0.41-0.89)] had lower odds of CVD. Conclusions: Traditional CVD risk factors remain associated with CVD in HNSCC patients. In addition, cancer-related factors (oropharynx cancer, advanced cancer stage and chemotherapy) are also associated with CVD.
QOLP-11. QUALITY OF END-OF-LIFE CARE IN PATIENTS WITH HIGH GRADE GLIOMAS
Authors: Alexander Ou, Rebecca Harrison, Diane Liu, Mujtaba Naqvi, Syed Mussadiq Naqvi, Barbara O’Brien, Shiao-Pei Weathers, John de Groot, Eduardo Bruera
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients with high-grade gliomas (HGG) face unique challenges toward the end of life (EoL), given their aggressive disease trajectory and progressive neurologic deterioration. The discipline of supportive care (SC) has been beneficial in improving quality of EoL care in patients with non-CNS cancers, however data on its contribution to EoL care in patients with HGG is lacking. METHODS We retrospectively reviewed charts of MDA patients from 2010-2017 to compare the demographic factors and clinical and quantitative EoL outcomes between patients with HGG--who were either referred (n=54) or not referred (n=85) to SC--and patients with non-CNS cancers who were referred to SC (n=72). A composite score for poor EoL quality outcomes was used with the following variables: death in hospital, chemotherapy within 14d of death, ≥2 hospitalizations, ≥2 ER visits, ICU admission and &amp;gt;14 days hospitalization within the last 30 days of life. Patients were eligible for SC based on poor/declining performance status, &amp;lt; 6 month prognosis, or recurrent GBM. RESULTS Patients with HGG had similar EoL quality regardless of SC referral, and these patients in general had better EoL quality than patients with non-CNS cancers (p=0.005). EoL quality was significantly worse in HGG patients who received late versus early SC referrals (p=0.0066). Both weakness (OR=1.27, p=0.0289) and number of disease progressions (OR=2.618, p=0.001) at the time of eligibility for SC were predictive of poorer quality of EOL. The majority of HGG patients (61.2%) eligible for SC were not referred. CONCLUSIONS EoL outcomes in patients with malignant gliomas are overall better than those of patients with non-CNS cancer, however certain clinical features and later SC referral remain significantly associated with poorer EoL quality. Our data suggest that the role of SC in improving EoL outcomes in our patient population warrants further evaluation.
EPID-20. NOVEL GLIOBLASTOMA POPULATION-BASED HISTOLOGIC STAIN NORMALIZATION
Authors: Jose Agraz, Caleb Grenko, Angela Viaene, Nasrallah MacLean, Michael Feldman, Hamed Akbari, Spyridon Bakas
Journal: Neuro-Oncology (2020)

Abstract Histopathologic evaluation has been an integral part of clinical diagnosis for central nervous system tumors, providing information essential for classification, management, and treatment of the disease. Hematoxylin and eosin (H&amp;E) staining is routinely used in histology, providing detail of tissue morphology, structure, and cellular composition. MOTIVATION: Slide staining is rife with color intensity variations, mainly due to differences in materials and staining protocols among others. These variations introduce inaccuracies in downstream computational analysis and quantification of disease, disabling the generalization of computational models. To overcome these variations, current approaches arbitrarily select a slide within the cohort to normalize all slides of the cohort, leading to non-reproducible results in other cohorts. We develop a population-based whole slide image (WSI) normalization method based on overall region driven stain vectors and color histogram, weighted by corresponding percent contribution to overall slide (PCOS). METHODS: We identified a cohort of 509 H&amp;E stained WSIs with corresponding anatomical annotations from the Ivy Glioblastoma Atlas Project. These WSIs and annotations were reviewed by two neuropathologists for correctly annotated regions. Each region was weighted according to PCOS, WSIs with PCOS &amp;lt; 0.05% were discarded. Then, the optical densities and histograms calculated. Resulting color histogram and optical density was applied to the WSI cohort. Finally, stain intensity variability pre- and post- normalization was compared. RESULTS: Normalizing WSIs based on our approach, results in a significant (p &amp;lt; 0.01, Wilcoxon) improvement in color intensity variation for eight of nine regions tested, with the exception of “Pseudopalisading Cells with no visible Necrosis” (p = 0.8). DISCUSSION: This novel transformative technique is insensitive to artificially staining background density and straightforward to apply. Furthermore, the approach shows promise towards a viable and robust tool for stain normalization in large WSIs cohorts, with the potential towards a stain normalization standard generalizable to other diseases.
RADT-21. NATIONAL PRACTICE PATTERNS AND OUTCOMES OF STEREOTACTIC BODY RADIOTHERAPY VS. CONVENTIONAL EXTERNAL BEAM RADIOTHERAPY FOR SPINAL METASTASES
Authors: Asad Lak, Nayan Lamba, Timothy Smith, Bryan Iorgulescu
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Up to 10% of cancer patients experience spinal cord compression from metastatic disease. Palliation and local control were traditionally pursued with conventional external beam radiotherapy (cEBRT), but advancements in image-guidance and intensity-modulation for stereotactic body radiotherapy (SBRT) have dramatically changed the management of these lesions. Herein we evaluate the national practice patterns and outcomes associated with cEBRT vs. SBRT. METHODS U.S. patients newly diagnosed with metastatic cancer necessitating RT to the spine were identified from the National Cancer Database (2004-2016), stratified by RT modality and cancer type, and evaluated using multivariable logistic regression and Cox proportional hazards. RESULTS 34,759 U.S. patients required spinal RT within 3 months of initial stage 4 cancer presentation, primarily for lung adenocarcinoma (25%), lung small cell carcinoma (14%), and prostatic (12%) metastases. Patients overwhelming received cEBRT (30Gy/10; 50%), followed by hypo-fractionated SBRT (15-30Gy/2-6; 11%) and single-fraction SBRT (i.e. stereotactic radiosurgery, SRS; 15-24Gy/1; 0.9%); whereas 38% received another regimen (e.g. 30-37.5Gy/12-15 or 40Gy/20). From 2004→2016, the rates of single-fraction SRS (0.4→1.9%) and hypo-fractionated SBRT (13.1→23.6%) increased, whereas cEBRT (86.5→74.4%) decreased. SBRT was significantly more likely to be utilized at academic hospitals as compared to cEBRT (OR 0.57; 95% CI: 0.49-0.66; p&amp;lt; 0.01). SBRT was more likely utilized for elderly or high comorbidity patients and varied across cancer types. Survival analysis indicated that across all cancer types, single-fraction SRS, was independently associated with improved overall survival compared to cEBRT (HR 1.51; 95%CI: 1.31-1.74; p&amp;lt; 0.01) after adjusting for patient characteristics, care setting, tumor type and systemic treatment. CONCLUSIONS Through analysis of cancer registry data, we found that practice patterns of RT for spinal metastases have been evolving nationally, with an increase in the use of SBRT. Single-fraction SBRT was associated with improved adjusted OS. Notably, we found that utilization of SBRT lags in the community setting.
Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice
Authors: Michael John Zobel, Abigail K Zamora, Hong-wei Wu, Jianping Sun, Danny Lascano, Jemily Malvar, Larry Wang, Michael A Sheard, Robert C Seeger, Eugene S Kim
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated before primary tumor removal. Using a surgical mouse model of human NB, we examined if initiating dinutuximab plus ex vivo-activated natural killer (aNK) cells before resection of the primary tumor improves survival. Methods In vitro, human NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc) were treated with dinutuximab and/or aNK cells and cytotoxicity was measured. In vivo, NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc, or COG-N-415x PDX) were injected into the kidney of NOD-scid gamma mice. Mice received eight intravenous infusions of aNK cells plus dinutuximab beginning either 12 days before or 2 days after resection of primary tumors. Tumors in control mice were treated by resection alone or with immunotherapy alone. Disease was quantified by bioluminescent imaging and survival was monitored. aNK cell infiltration into primary tumors was quantified by flow cytometry and immunohistochemistry at varying timepoints. Results In vitro, aNK cells and dinutuximab were more cytotoxic than either treatment alone. In vivo, treatment with aNK cells plus dinutuximab prior to resection of the primary tumor was most effective in limiting metastatic disease and prolonging survival. aNK cell infiltration into xenograft tumors was observed after 1 day and peaked at 5 days following injection. Conclusion Dinutuximab plus aNK cell immunotherapy initiated before resection of primary tumors decreases disease burden and prolongs survival in an experimental mouse model of NB. These findings support the clinical investigation of this treatment strategy during induction therapy in patients with high-risk NB.