tbuckley/cabot-search huggingface dataset:
TAMI-54. THE PRESENCE OF IMMUNE CELL INFILTRATES IN THE TISSUE MICROENVIRONMENT OF HIGH-GRADE GLIOMAS AND THEIR ASSOCIATION WITH OVERALL SURVIVAL
Authors: Anupam Rishi, Homan Mohammadi, Daniela Martir, Eric Welsh, Timothy Robinson, Daniel Oliver, Steven Eschrich, Javier Torres-Roca, Hsiang-Hsuan Yu, George Grass, Kamran Ahmed
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Tumor-associated microglia and macrophages (TAMs) influence brain tumor biology and promote tumor-proliferating phenotype. Studies have shown these cell types predict outcomes in various tumor sites with limited evidence in high-grade gliomas (HGG). In this study, we assessed the presence of immune cell infiltrate (ICI) and overall survival (OS) in HGGs. METHODS A total of 97 consecutively treated patients with primary HGG with complete gene expression profiling were identified from our IRB-approved institutional tissue biorepository. Patients underwent primary surgical resection between 02/2004 and 03/2011. Gene expression levels were assessed by Affymetrix Hu-RSTA assays (Affymetrix; Santa Clara, CA). CIBERSORT estimated the presence of ICI via gene expression deconvolution. Tumor characteristics and the presence of 22 individual ICI subtypes were assessed with respect to OS. Time-to-event analyses were performed with Kaplan-Meier estimates and compared via log-rank test. Associations between the ICI and outcomes were explored using Cox-regression. P&amp;lt; 0.05 (two-tailed) was considered statistically significant. RESULTS Median follow-up from primary surgical resection was 12.8 months (range: 0.1-162.8), and median age was 58 years (20-85). Most patients were male (n=63; 65%) and had grade 4 tumors (n=71; 73%). OS differed by grade with 24-month actuarial OS rates of 81% and 34% (P&amp;lt; 0.0001) for grade 3 and 4 gliomas, respectively. The presence of M0 (HR 2.2; 95% CI 1.4-3.6; P=0.001), M1 (HR 1.8; 95%CI 1.1-2.9; P=0.01), and M2 macrophages (HR 1.9; 95%CI 1.2-3.2; P=0.007) predicted OS. No other ICI subtypes were predictive of OS. The presence of M0- and M2-polarized macrophages were more common in grade 4 compared to grade 3 gliomas 46% vs. 11% (P=0.002) and 69% vs. 31% (P=0.0007), respectively. CONCLUSION The increased presence of non-polarized or M2 TAMs within the glioma microenvironment was significantly associated with OS in HGG. Their presence may serve as unique stratification and a potential therapeutic target.
Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease
Authors: Zhanguo Gao, Alexes C. Daquinag, Cale Fussell, Zhongming Zhao, Yulin Dai, Angielyn Rivera, Brad E. Snyder, Kristin L. Eckel-Mahan, Mikhail G. Kolonin
Journal: Nature Metabolism (2020)
Dyspnoea, lung function and CT findings 3 months after hospital admission for COVID-19
Authors: Tøri Vigeland Lerum, Trond Mogens Aaløkken, Eivind Brønstad, Bernt Aarli, Eirik Ikdahl, Kristine Marie Aarberg Lund, Michael T. Durheim, Jezabel Rivero Rodriguez, Carin Meltzer, Kristian Tonby, Knut Stavem, Ole Henning Skjønsberg, Haseem Ashraf, Gunnar Einvik
Journal: European Respiratory Journal (2020)

The long-term pulmonary outcomes of coronavirus disease 2019 (COVID-19) are unknown. We aimed to describe self-reported dyspnoea, quality of life, pulmonary function and chest computed tomography (CT) findings 3 months following hospital admission for COVID-19. We hypothesised outcomes to be inferior for patients admitted to intensive care units (ICUs), compared with non-ICU patients. Discharged COVID-19 patients from six Norwegian hospitals were enrolled consecutively in a prospective cohort study. The current report describes the first 103 participants, including 15 ICU patients. The modified Medical Research Council (mMRC) dyspnoea scale, the EuroQol Group's questionnaire, spirometry, diffusing capacity of the lung for carbon monoxide ( D LCO ), 6-min walk test, pulse oximetry and low-dose CT scan were performed 3 months after discharge. mMRC score was &gt;0 in 54% and &gt;1 in 19% of the participants. The median (25th–75th percentile) forced vital capacity and forced expiratory volume in 1 s were 94% (76–121%) and 92% (84–106%) of predicted, respectively. D LCO was below the lower limit of normal in 24% of participants. Ground-glass opacities (GGO) with &gt;10% distribution in at least one of four pulmonary zones were present in 25% of participants, while 19% had parenchymal bands on chest CT. ICU survivors had similar dyspnoea scores and pulmonary function as non-ICU patients, but higher prevalence of GGO (adjusted OR 4.2, 95% CI 1.1–15.6) and lower performance in usual activities. 3 months after admission for COVID-19, one-fourth of the participants had chest CT opacities and reduced diffusing capacity. Admission to ICU was associated with pathological CT findings. This was not reflected in increased dyspnoea or impaired lung function.
How selective are clinical CDK4/6 inhibitors?
Authors: Denisa Hendrychová, Radek Jorda, Vladimír Kryštof
Journal: Medicinal Research Reviews (2020)

Abstract Pharmacological inhibition of cyclin‐dependent kinase 4/6 (CDK4/6) has emerged as an efficient approach for treating breast cancer, and its clinical potential is expanding to other cancers. CDK4/6 inhibitors were originally believed to act by arresting proliferation in the G1 phase, but it is gradually becoming clear that the cellular response to these compounds is far more complex than this. Multiple context‐dependent mechanisms of action are emerging, involving modulation of quiescence, senescence, autophagy, cellular metabolism, and enhanced tumor cell immunogenicity. These mechanisms may be driven by interactions with unexpected targets. We review cellular responses to the Food and Drug Administration‐approved CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib, and summarize available knowledge of other drugs undergoing clinical trials, including data on their off‐target landscapes. We emphasize the importance of comprehensively characterizing drugs' selectivity profiles to maximize their clinical efficacy and safety and to facilitate their repurposing to treat additional diseases based on their target spectrum.
ATRT-15. LY6D – A CANDIDATE FOR NANOPARTICLE-BASED TARGETED THERAPIES OF ATRT
Authors: Lea Hagemeier, Marthe Sönksen, Natalia Moreno, Romy Ettlinger, Hana Bunzen, Kornelius Kerl
Journal: Neuro-Oncology (2020)

Abstract Atypical Teratoid Rhabdoid Tumors (ATRT) are aggressive brain malignancies of the infant. Despite intensive multimodal therapy, the overall prognosis remains poor, making investigations on targeted therapies crucial. Arsenic trioxide (ATO) is known to inhibit cell growth of ATRT in vitro and in vivo but its efficacy in solid tumors is limited by its adverse effects. We aimed to characterize whether a nanoparticle-based drug delivery could overcome these limitations. Therefore metal-organic frameworks containing ATO (MOF-ATO) were constructed. To improve drug specificity further, we searched for unique proteins on the surface of ATRT, in order to create antibody-drug-conjugates out of MOF-ATO and an ATRT-specific ligand. ATRT are marked by a biallelic loss of SMARCB1, which results in an activation of the repressive histone methyltransferase EZH2. After chemical inhibition of EZH2 with GSK126, a mass spectrometric based screening for differentially expressed surface proteins was performed. Treatment with ATO, as well as MOF-ATO and GSK126 each reduces the cell viability of ATRT cell lines. It results in a cell cycle arrest and an induction in apoptosis, being analysed via MTT test and flow cytometry. GSK126 treatment causes a significant upregulation of several cell surface proteins, upon them the Lymphocyte antigen 6 family member D (LY6D). Being rarely expressed on other human cells, this protein is an interesting candidate. An antibody-drug-conjugate consisting of MOF-ATO and LY6D-ligands could be a promising approach for future targeted therapies of ATRT.
Tissue Hypoxia and Alterations in Microvascular Architecture Predict Glioblastoma Recurrence in Humans
Authors: Andreas Stadlbauer, Thomas M. Kinfe, Ilker Eyüpoglu, Max Zimmermann, Melitta Kitzwögerer, Klaus Podar, Michael Buchfelder, Gertraud Heinz, Stefan Oberndorfer, Franz Marhold
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Insufficient control of infiltrative glioblastoma (GBM) cells is a major cause of treatment failure and tumor recurrence. Hence, detailed insights into pathophysiologic changes that precede GBM recurrence are needed to develop more precise neuroimaging modalities for tailored diagnostic monitoring and therapeutic approaches. Experimental Design: Overall, 168 physiologic MRI follow-up examinations of 56 patients with GBM who developed recurrence after standard therapy were retrospectively evaluated, that is, two post–standard-therapeutic follow-ups before and one at radiological recurrence. MRI biomarkers for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia were determined for brain areas that developed in the further course into recurrence and for the recurrent GBM itself. The temporal pattern of biomarker changes was fitted with locally estimated scatterplot smoothing functions and analyzed for pathophysiologic changes preceding radiological GBM recurrence. Results: Our MRI approach demonstrated early pathophysiologic changes prior to radiological GBM recurrence in all patients. Analysis of the time courses revealed a model for the pathophysiology of GBM recurrence: 190 days prior to radiological recurrence, vascular cooption by GBM cells induced vessel regression, detected as decreasing vessel density/perfusion and increasing hypoxia. Seventy days later, neovascularization activity was upregulated, which reincreased vessel density and perfusion. Hypoxia, however, continued to intensify for 30 days and peaked 90 days before radiological recurrence. Conclusions: Hypoxia may represent an early sign for GBM recurrence. This might become useful in the development of new combined diagnostic–therapeutic approaches for tailored clinical management of recurrent GBM. Further preclinical and in-human studies are required for validation and evaluation.
BIOM-04. BRAIN METASTASIS AMONG FEMALE PATIENTS DIAGNOSED WITH STAGE IV BREAST CANCER
Authors: Santhi Konduri, Maharaj Singh, George Bobustuc, Richard Rovin
Journal: Neuro-Oncology (2020)

Abstract Among the patients diagnosed with advanced stage of breast cancer there is a possibility of developing distant metastases, brain is one of the predominant sites. The objective of this study is to identify patient characteristics and biomarkers for brain metastasis. From National Cancer Database, 2010 through 2015, we identified 52,753 female patients diagnosed with stage IV breast cancer. Patient demographics, tumor characteristics and biomarkers were analyzed using descriptive statistics. Odds ratios (OR) were computed using logistics regression. Kaplan-Meier estimate was used to compute survival. Of 52,753 female patients diagnosed with stage IV breast cancer, there were 73% non-Hispanic white (NHW), 17% non-Hispanic black (NHB), 6% Hispanic and 4% from ‘other’ race category. The median age of the patients at the time of diagnosis was 62 years. Of the total patients only 8.2% had brain metastatic spread. Brain metastasis was less likely among NHB vs NHW (OR=0.85, p =0.01), among others vs NHW (OR=0.69, p =0.01), with insurance status, government vs no insurance, (OR=0.71, p&amp;lt; 0.01), with private vs no insurance (OR=0.66, p&amp;lt; 0.01), with laterality (left vs bilateral, OR=0.61, p=0.01), (right vs bilateral OR=0.61, p=0.01), ER positive (OR=0.69, p &amp;lt; 0.01), PR positive (OR=0.75, p &amp;lt; 0.01), tumor grade moderately or well differentiated vs poorly or undifferentiated (OR=0.54, p =0.02; OR=0.45, p =0.01) and with 10-year increment in age at the time of diagnosis (OR=0.89, p &amp;lt; 0.001). In this study population five-year survival with and without brain metastasis was 11% and 25% respectively. The protective factors for brain metastatic spread includes NHB or other race category, government or private insurance, cancer either left or right side, moderately or well differentiated tumor, the patients with ER and PR expression. The chance of brain metastatic spread decreases with increasing age. These finding might provide insights for clinicians in treating these patients.
SURG-04. SALVAGE RESECTION OF RECURRENT PREVIOUSLY-IRRADIATED BRAIN METASTASES: CLINICAL AND RADIOGRAPHIC OUTCOMES
Authors: Jessica Wilcox, William Newman, Anne Reiner, Samantha Brown, Robert Young, Justin Chen, Kathryn Beal, Cameron Brennan, Katherine Panageas, Viviane Tabar, Nelson Moss
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The management of brain metastasis (BrM) recurrence after stereotactic body radiotherapy (SBRT) poses a clinical challenge. The efficacy of salvage resection is undefined, and the role of adjuvant resection cavity reirradiation is unclear given the compounded risk of radiation injury. METHODS Retrospective analysis of previously-irradiated BrM that underwent resection between March 2003 and February 2020 at Memorial Sloan Kettering Cancer Center was performed. Only cases with histopathologic evidence of viable malignancy were included, and specimens were classified by the gross proportion of viable tumor versus treatment effect. Clinical and radiographic parameters were collected. Post-operative recurrence and radiation necrosis were based on RANO-BM criteria and distinguished by histopathologic, radiographic and clinical characteristics. Equivocal cases were adjudicated by a blinded neuroradiologist. RESULTS One-hundred fifty-five resected recurrent BrM following SBRT in 135 patients were evaluated. Seventeen received additional prior whole-brain radiation. Metastases derived from non-small-cell lung (36.8%), melanoma (27.1%), breast (21.3%), renal (3.9%), colorectal (1.9%) and other (9.0%) primary malignancies. Forty-eight (31.0%) had only microscopic malignant disease with extensive necrosis, 44 (28.4%) had mixed or unspecified tumor with treatment effect, and 63 (40.6%) were reported as purely viable tumor by histopathologic report. Thirty-nine (25.2%) post-operative cavities underwent adjuvant reirradiation within 60 days. At 6 and 12 months, local tumor recurrence occurred in 31.6% (95% CI: 24.4%-39.1%) and 40.4% (95% CI: 32.5%-48.2%), respectively, with a proportion of these lesions displaying mixed tumor plus treatment effect. Median overall survival was 13.4 months (95% CI: 10.5-17.7) from salvage resection. CONCLUSIONS Salvage of previously-irradiated BrM remains challenging. This represents the largest known series correlating salvage resection and histopathologically-confirmed viable recurrent BrM with long-term outcomes. Tumor recurrence risk remains high at one year. Further exploration will stratify local progression and radiation necrosis rates by features including extent of resection, degree of viable tumor and adjuvant reirradiation use.
NFB-18. IMMUNE FUNCTION IN CHILDREN TREATED WITH TRAMETINIB
Authors: Perla Moukhaiber, Anna Samolej, Palita Somsri, Geoffrey McCowage
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Trametinib (Tr) has been applied in the treatment of children with various tumor types, often for prolonged periods. Little is known regarding immune function (IF) following prolonged Tr in this age group. OBJECTIVE Describe laboratory measures of IF in children on Tr. METHOD Patients receiving Tr had low grade glioma with BRAF anomalies (6), or neurofibromatosis-1 (16) with glioma or plexiform neurofibroma. IF was evaluated using leukocyte/lymphocyte counts, immunoglobulin levels, and antibody titres. RESULTS 22 patients received Tr. 2 also received Dabrafenib. Median age at Tr initiation of Tr was 7.75 years. As of June 2020, 7 patients have had IFT; results are pending on 15. Median duration of Tr therapy at time of IF was 3.5 years (0.8 – 4). In these 7 patients, median white cell count was 6.9 x 10^9/L (4.1 – 12.6), neutrophils 4.2 x 10^9/L (1.8 – 6.8) and lymphocytes 3.2 x 10^9/L (1.4 – 7). IgG levels, B cells and CD8 cytotoxic T cells were normal across 7/7 patients:medians 9.47 g/L (8.62 – 17), 0.51 x 10^9/L (0.2 – 1.26) and 0.58 x 10^9/L (0.25 – 2.03) respectively. CD3 and CD4 T cells: median 2.08 x 10^9/L (0.67 – 4.62) and 1.34 x 10^9/L (0.35 – 2.31), borderline low in 1 heavily pre-treated patient. An adequate immune response was present in all 4 vaccine antigens tested in 5/5 patients. CONCLUSION IF appears relatively intact, relevant for immunisation and infection precautions in children on Tr. Data on the complete cohort will be presented.
COVD-06. BRAIN TUMOURS AND COVID-19: THE PATIENT AND CAREGIVER EXPERIENCE
Authors: Mathew Voisin, Kathy Oliver, Stu Farrimond, Tess Chee, Gelareh Zadeh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Since the COVID-19 pandemic, thousands of medical procedures and appointments have been cancelled or delayed. The long-term effects of these drastic measures directly on brain tumour patients and their caregivers are unknown. The purpose of this study is to better understand how COVID-19 has affected this vulnerable population on a global scale. METHODS An online 79-question survey was developed by the IBTA, in conjunction with the SNO COVID-19 Task Force. The survey was sent to over 120 brain tumour charities and not-for-profits worldwide and disseminated to brain tumour patients and caregivers. All responses were subdivided by patient vs caregiver and by geographical region. RESULTS In total, 1989 participants completed the survey from 33 countries, including 1459 patients and 530 caregivers. There were no significant differences in COVID-19 testing rates (p = 0.662) or the number of positive cases for brain tumour patients between regions (p = 0.1068). Caregivers were significantly more anxious than patients (p = &amp;lt; 0.0001). Patients from the Americas were most likely to have lost their jobs due to the pandemic, practiced self-isolation, and received telehealth services (p = &amp;lt; 0.0001). Patients from Europe experienced the most treatment delays (p = 0.0031). Healthcare providers were ranked as the most trusted source of information. CONCLUSIONS As a result of COVID-19, brain tumour patients and caregivers have experienced significant stress and anxiety. Healthcare professionals, brain tumour charities, and not-for-profits must ensure that they continue to provide accessible, high-quality care, information, and support in the age of COVID-19.
SURG-14. AWAKE CRANIOTOMY VS CRANIOTOMY UNDER GENERAL ANESTHESIA FOR GLIOBLASTOMAS: EVALUATING THE IMPACT ON OVERALL SURVIVAL AND RISK OF RECURRENCE
Authors: Mario Moro
Journal: Neuro-Oncology (2020)

Abstract Maximum safe resection for eloquent glioblastomas (GBMs) is the maximum tumor resection achievable without causing neurological deficits. Although challenging, it must be considered the therapeutic target for GBMs. Indeed, the extension of resection positively correlates with the overall survival and recurrences risk. Awake surgery (AS) has become paramount for achieving maximum safe resection for tumors in eloquent areas. However, there is not a unanimous consensus on the extent of resection of eloquent GBMs, especially for what concerns the so-called supratotal resection (i.e.: resection over the contrast-enhancing limits of the lesion). Recently, several studies focused their attention on the residual tumor volume as estimated from T1-contrast enhanced sequences, but few analyzed the outcomes of patients with a more extended resection. Some authors speculated that increased surgical aggressiveness, thus removing peritumoral edematous area, correlates with improved overall survival and tumor control, without increasing adverse events rates. This study aimed to assess, through quantitative volumetric analysis, the outcomes of a prospectively collected cohort of patients with primary GBM located in eloquent areas. We furtherly subdivided our population into two treatment groups: awake surgery (AS) and general anesthesia (GA) craniotomies. We analyzed the overall outcomes, especially for what concerns MRI T2-Flair signal extent of resection, related to patients’ survival and recurrences formation. Eventually, we stratified our analysis by type of treatment (awake surgery vs. general anesthesia) to rule out any significant differences in survival and postoperative GBMs behaviors. Our data confirmed extensive that T2-Flair resection (EOR≥30%) and AS could improve overall survival and reduce risk of recurrence without, at the same time, causing an increase of surgical and medical complications
NCOG-62. CNS SARCOMA IN A TODDLER WITH NOVEL BALANCED TRANSLOCATION OF t(8;11)(q13;q13)
Authors: Prabhumallikarjun Patil
Journal: Neuro-Oncology (2020)

Abstract A CASE REPORT A 23-month-old boy was noted to have a brain tumor after being evaluated for chronic global developmental delay. The initial neurological exam was concerning for left leg circumduction and drag. Further investigation with MRI demonstrated a 7 x 9.3 x 7.4 cm supratentorial cystic encapsulated mass identified in the right lateral ventricle with heterogeneously enhancing mural nodule measuring 0.9 x 2.7 x 3.3 cm in diameter. Capsular enhancement was also noted after contrast administration. No diffusion restriction was seen. Mass effect on septum pellucidum was seen along with an increase in size of the left lateral ventricle. Following which the patient underwent right posterior parietal craniotomy and gross total resection of the tumor. Pathology report based on the cellular appearance, cell density, presence of necrosis, and the proliferative activity classified the tumor as likely intermediate grade undifferentiated sarcoma, mostly mesenchymal in origin. Tumor cytogenetics showed balanced translocation (8;11) (q13; q13) in all metaphase cells. Cytogenetics performed on the blood sample showed normal karyotype, suggesting that the translocation seen in tumor cells was somatic in nature rather and not a germline mutation. As the radiological signs and the long clinical course of the disease (evidenced by global developmental delay noted more than a year prior to a presentation and no signs of disseminated disease) suggested it to be a low-grade tumor a decision was made not to treat aggressively with further chemo and radiotherapy. However, the pathology of the tumor was suggestive of a primary malignant undifferentiated sarcoma of the brain. The patient continued to do well with no signs of recurrence on MRI and/or clinical picture for 4 years after the initial surgery. DISCUSSION Primary CNS sarcoma is rare. Balanced translocation (8;11) (q13; q13) has not been described in the literature before.
Abstract 12631: PRN Use of Antihypertensive Medications is Associated With Increased Mortality and Adverse Outcomes
Authors: Rajesh Mohandas, Shahab Bozorgmehri, Gajapathiraju Chamarthi, Tezcan Ozrazgat-Baslanti, Rupam Ruchi, Ashutosh M Shukla, Amir Kazory, Azra Bihorac, Mark S Segal
Journal: Circulation (2019)

Introduction: Despite absence of data demonstrating a clear benefit, intravenous medications are often used to treat asymptomatic increases in blood pressures (BP) in hospitalized patients, on an a...