tbuckley/cabot-search huggingface dataset:
CTIM-11. PHASE I/II STUDY TO EVALUATE THE SAFETY AND CLINICAL EFFICACY OF ATEZOLIZUMAB (ATEZO) IN COMBINATION WITH TEMOZOLOMIDE (TMZ) AND RADIATION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Shiao-Pei Weathers, Carlos Kamiya-Matsuoka, Rebecca Harrison, Diane Liu, Edmund Sanqui, Shannon Dervin, Cindy Yun, Monica Loghin, Marta Penas-Prado, Nazanin Majd, W K Alfred Yung, Barbara O’Brien, John de Groot
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Immunotherapy strategies such as PD-1/PD-L1 inhibition may work synergistically with radiation, which is known to increase antigen presentation and promote a pro-inflammatory tumor microenvironment. This trial evaluated the safety and clinical efficacy of concurrent atezo (anti-PD-L1) with radiation therapy and TMZ followed by adjuvant atezo and TMZ in patients with newly diagnosed GBM, unselected for MGMT status. METHODS Eligibility criteria included patients age &amp;gt; 18 yrs who had undergone only surgery. The primary endpoint was safety in Phase I (n = 10) and OS in Phase II (n = 50). Secondary endpoints included progression free survival (PFS), overall response rate (ORR), and duration of response. All 60 patients were evaluated for efficacy. Correlative endpoints include profiling tumor immune cell populations, peripheral blood for circulating chemokines/cytokines, and stool for gut microbiome. RESULTS 60 patients were enrolled. With a median follow-up time of 17.1 months (data cutoff = 15 April 2020), 37 patients have progressed, of which 30 patients have died. Median OS was 19 months (95% CI: 14.9, not reached). Median PFS was 10.6 months (95% CI: 8.2–16.7). Median OS in MGMT methylated patients (n = 18) was 29.9 months (95% CI: 11.4, not reached) and 16.3 months (95% CI: 13.9, not reached) in MGMT unmethylated patients (n = 33). Treatment-related adverse events with maximum CTCAE grade &amp;gt; 3 occurred in 33 patients; the most common were LFT elevation (n = 5) and lymphopenia (n = 23). To date, 20 of the enrolled 60 patients underwent re-resection post atezo treatment. The matched paired tumor analysis of pre and post treatment tissue will provide valuable insights into mechanisms of anti-PD-L1 therapy resistance. Tumor immunocorrelative studies are pending. CONCLUSIONS Concurrent use of atezo with radiation and TMZ was tolerable and demonstrated efficacy in line with published trials for newly diagnosed GBM.
Implementing Mitigation Strategies in Early Care and Education Settings for Prevention of SARS-CoV-2 Transmission — Eight States, September–October 2020
Authors: Fátima Coronado, Sara Blough, Deborah Bergeron, Krista Proia, Erin Sauber-Schatz, Marco Beltran, Katherine Troy Rau, Andria McMichael, Tracye Fortin, Mark Lackey, Jovanna Rohs, Tracey Sparrow, Grant Baldwin
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

The Head Start program, including Head Start for children aged 3-5 years and Early Head Start for infants, toddlers, and pregnant women, promotes early learning and healthy development among children aged 0-5 years whose families meet the annually adjusted Federal Poverty Guidelines
CBIO-17. IDENTIFYING A NETWORK OF ESSENTIAL &amp; TUMORIGENIC GENES IN GLIOBLASTOMA USING WHOLE-GENOME CRISPR Cas9 SCREENING
Authors: Shivani Baisiwala, Miranda Saathoff, Crismita Dmello, Jack Shireman, Li Chen, Cheol Park, Chidibere Awah, Chirag Goel, Shreya Budhiraja, Clare Hardiman, Adam Sonabend, Atique Ahmed
Journal: Neuro-Oncology (2020)

Abstract GBM is the most common primary malignant brain tumor in adults, with a 100% recurrence rate and a median survival of 21 months. As such, advances in therapy are desperately needed. Genomic approaches have shown that GBM has high intra-tumoral heterogeneity. However, a comprehensive understanding of determinants of growth is required to identify new therapeutic targets. CRISPR-Cas9 screening technology has enabled whole-genome screens that allow objective identification of genes governing specific phenotypes. Here, we performed a genome-wide CRISPR knockout screen in H4 human glioma cells to identify genes that drive proliferation. Our screen identified ~150 novel essential growth genes. From this list, we identified 5 genes that were previously unstudied, show significant elevations in expression at the RNA and protein levels (p&amp;lt; 0.05), and show significant survival benefit in patient datasets (p&amp;lt; 0.05) – PSMB3, CHCHD4, THOC1, SPDYE5, HSPA1. Our validation experiments showed that knocking out these genes resulted in cell death in multiple GBM patient-derived xenograft (PDX) lines. In addition, animals with knockout cells implanted demonstrated extended survival (p&amp;lt; 0.01). Furthermore, overexpression of these genes in a normal neural stem cell line resulted in transformation to a cancer phenotype, as evidenced by sphere formation in a soft agar assay (p&amp;lt; 0.01). Further investigation of one of these genes, PSMB3, which is a subunit of the proteasome, showed that ubiquitinated proteins were significantly increased after PSMB3 knockdown, suggesting that disruption of the proteasome system was the likely cause of cell death. We performed a ubiquitin immunoprecipitation (IP) to identify which genes were being uniquely ubiquitinated in GBM. Results showed pathways involving retinoblastoma genes, DNA repair genes, and DNA replication. Together, this data suggests that both our CRISPR screens and our ubiquitin IP have yielded promising and novel therapeutic targets for GBM, a disease desperately in need of new strategies.
ATRT-14. MACROPHAGE-TUMOR CELL INTERACTION PROMOTES ATRT PROGRESSION AND CHEMORESISTANCE
Authors: Viktoria Melcher, Monika Graf, Marta Interlandi, Natalia Moreno, Flavia W de Faria, Su Na Kim, Dennis Kastrati, Sonja Korbanka, Amelie Alfert, Joachim Gerß, Gerd Meyer zu Hörste, Wolfgang Hartmann, Michael C Frühwald, Martin Dugas, Ulrich Schüller, Martin Hasselblatt, Thomas K Albert, Kornelius Kerl
Journal: Neuro-Oncology (2020)

Abstract Atypical teratoid/rhabdoid tumors (ATRT) are pediatric brain neoplasms that are known for their heterogeneity concerning pathophysiology and outcome. The three genetically rather uniform but epigenetically distinct molecular subgroups of ATRT alone do not sufficiently explain the clinical heterogeneity. Therefore, we examined the tumor microenvironment (TME) in the context of tumor diversity. By using multiplex-immunofluorescent staining and single-cell RNA sequencing (scRNA-seq) we unveiled the pan-macrophage marker CD68 as a subgroup-independent negative prognostic marker for survival of ATRT patients. ScRNA-seq analysis of murine ATRT-SHH, ATRT-MYC and extracranial RT (eRT) provide a delineation of the TME, which is predominantly infiltrated by myeloid cells: more specifically a microglia-enriched niche in ATRT-SHH and a bone marrow-derived macrophage infiltration in ATRT-MYC and eRT. Exploring the cell-cell communication of tumor cells with tumor-associated immune cells, we found that Cd68+ tumor-associated macrophages (TAMs) are central to intercellular communication with tumor cells. Moreover, we uncovered distinct tumor phenotypes in murine ATRT-MYC that share genetic traits with TAMs. These intermediary cells considerably increase the intratumoral heterogeneity of ATRT-MYC tumors. In vitro co-culture experiments recapitulated the capability of ATRT-MYC cells to interchange cell material with macrophages extensively, in contrast to ATRT-SHH cells. We found that microglia are less involved in the exchange of information with ATRT cells and that direct contact is a prerequisite for incorporation. A relapse xenograft model implied that intermediary cells are involved in the acquisition of chemotherapy resistance. We show evidence that TAM-tumor cell interaction is one mechanism of chemotherapy resistance and relapse in ATRT.
STEM-25. DIFFERENTIAL REGULATION OF GLIOMA STEM-CELL MARKER NESTIN AND CD24 IN IDH-MUTANT GLIOMA
Authors: Patricia Tiburcio, Mary Locke, Srivydia Bhaskara, Mahesh Chandrasekharan, Eric Huang
Journal: Neuro-Oncology (2020)

Abstract Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, resulting in predominantly arginine to histidine substitution at codon 132. Because IDH1R132H requires a wild-type allele to produce (D)-2-hydroxyglutarate for epigenetic reprogramming, glioma cells with loss of the remaining wild-type allele (hence IDH1R132H-hemizygous) exhibit an IDH1-wild-type-like glioma phenotype and aggressive tumor growth. Although previous studies reported that transgenic IDH1R132H induced the expression of nestin—a glioma stem-cell marker, the underlying mechanism remains unclear. Furthermore, this finding seems at odds with the better outcome of IDH-mutant glioma owing to a negative association of nestin with overall survival. To gain a comprehensive understanding of glioma stem-cell marker gene regulation in IDH-mutant glioma, we compared gene expression between IDH1R132H-heterozygous and IDH1R132H-hemizygous glioma cells under adherent and spheroid growth conditions and found that glioma stem-cell marker genes, including CD44, NES, and PROM1, are generally downregulated in the spheroid growth of IDH1R132H-heterozygous cells. This result was validated in patient samples of IDH-mutant glioma compared with those of IDH-wildtype glioma, even though modest NES upregulation was observed in the adherent growth of IDH1R132H-hemizygous glioma cells. In contrast, CD24 is specifically upregulated in the spheroid growth of IDH1R132H-heterozygous cells and patient samples of IDH-mutant glioma and is apparently associated with better survival. Mechanistically, CD24 and NES expression responds differentially to alteration of (D)-2-hydroxyglutarate levels. CD24 upregulation is associated with histone and DNA demethylation as opposed to hypermethylation in those downregulated glioma stem-cell marker genes. Therefore, the better outcome of IDH-mutant glioma is orchestrated exquisitely through epigenetic reprogramming that directs bidirectional expression of glioma stem-cell marker genes.
Perspectives of lived experience across continents: our reality and call for universal health coverage
Authors: Hannah L N Stewart, Matthew Jackman, Sanjay Agarwal, Marie A Abanga, Claire Kyalo, Angelica Mkorongo, Raluca Mirela Hagianu, Karen Athié, Swetha Bindu Jammalamadugu, Eleni Misganaw, Paida Mudzamba, Katrina McIntosh
Journal: The Lancet Psychiatry (2020)
Reply to Romero-Castro et al.
Authors: Carlos Robles-Medranda, Roberto Oleas, Manuel Valero, Miguel Puga-Tejada, Jorge Baquerizo-Burgos, Jesenia Ospina, Hannah Pitanga-Lukashok
Journal: Endoscopy (2020)

See also:Endoscopic ultrasound-guided therapy of gastric varices with coils plus cyanoacrylate injection versus coiling alone: getting evidence-based data but are they comparable?Endoscopy 2021; 53(01): 101-101DOI: 10.1055/a-1214-6213
Cluster analysis of 505 real‐life food‐induced anaphylaxis in children reveals two stable clinical phenotypes
Authors: Lukasz Blazowski, Joanna Jerzynska, Ryszard Kurzawa, Piotr Kuna, Pawel Majak
Journal: Allergy (2020)

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NIMG-66. AI-BASED PROGNOSTIC IMAGING BIOMARKERS FOR PRECISION NEUROONCOLOGY AND THE RESPOND CONSORTIUM
Authors: Christos Davatzikos, Chaitra Badve, Anahita Fathi Kazerooni, Vishnu Bashyam, Spyridon Bakas, Rivka Colen, Abhishek Mahajan, Carmen Balaña, Jaume Capellades, Josep Puig, Rajan Jain, Andrew E Sloan, Daniel S Marcus, Yoon Seong Choi, Seung-Koo Lee, Jong Hee Chang, Laila M Poisson, Brent Griffith, Adam P Dicker, Adam E Flanders, Thomas C Booth, Saima Rathore, Hamed Akbari, Chiharu Sako, Michel Bilello, Gaurav Shukla, Steven Brem, Robert Lustig, Suyash Mohan, MacLean Nasrallah, Donald M O’Rourke, Stephen Bagley, Jill S Barnholtz-Sloan
Journal: Neuro-Oncology (2020)

Abstract AI-based methods have shown great promise in a variety of biomedical research fields, including neurooncologic imaging. For example, machine learning methods have offered informative predictions of overall survival (OS) and progression-free survival (PFS), differentiation between pseudoprogression (PsP) and progressive disease (PD), and estimation of mutational status from imaging data. Despite their promise, AI, and especially the emerging deep learning (DL) methods, are challenged by several factors, including imaging heterogeneity across scanners and lack of sufficiently large and diverse training datasets, which limits their reproducibility and general acceptance. These challenges prompted the development of the ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium on glioblastoma, a growing effort to bring together a community of researchers sharing imaging, demographic, clinical and (currently) limited molecular data in order to address the following aims: 1) pool and harmonize data across diverse hospitals and patient populations worldwide; 2) derive robust and generalizable AI models for prediction of (initially) OS, PFS, PsP vs. PD, and recurrence; 3) test these predictive models across multiple sites. In its first phase, ReSPOND aims to pool together approximately 3,000MRI scans (from 10institutions plus TCIA), along with demographics, KPS, and (for a subset) MGMT/IDH1 status. We present initial results testing the generalization of a previously trained model of OS on 505Penn datasets to 2independent cohorts from Case Western Reserve University and University Hospitals (N=44), and Penn (N=67). The results indicate good generalization, with correlation coefficients between OS/predicted-OS between 0.25 to 0.5, depending on variable availability, which is comparable to cross-validated accuracy previously obtained from the training set itself (N=505). Additional preliminary studies evaluating prediction of future recurrence from baseline pre-operative scans in de novo patients (Penn model applied to CWR) indicated potential for guiding targeted dose escalation and supra-total resection (excellent predictions in 6/12 patients, modest in 1/12, and poor in 5/12).
CTIM-22. PHASE 1 TRIAL OF OSIMERTINIB WITH STEREOTACTIC RADIOSURGERY (SRS) IN PATIENTS WITH BRAIN METASTASES FROM EGFR POSITIVE NON-SMALL-CELL LUNG CANCER (NSCLC)
Authors: Yasmeen Rauf, Rupesh Kotecha, Camilo Fadul, Wendi Evanoff, John Suh, Samuel Chao, Erin Murphy, Jennifer Yu, Lilyana Angelov, Gene Barnett, Alireza Mohammadi, Manmeet Ahluwalia
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Osimertinib is an oral, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor activating mutation (EGFRm) and the resistance mutation (T790M) that is FDA approved for patients with EGFR mutant lung cancer. The synergism between Osimertinib and radiation likely enhances DNA damage, leading to increased cell apoptosis. For patients with EGFR positive NSCLC with brain metastases, we hypothesize that the combination of Osimertinib and SRS will lead to better long term control of brain metastases as well as the systemic disease. METHODS This is an open label, single arm, phase I multi-institution study. It will employ a 3 + 3 design. After enrollment onto the study, patients will be started on Osimertinib at the predetermined level daily for 0–7 days, after which all patients will undergo radiosurgery and then receive Osimertinib daily concurrently until disease progression, withdrawal or until unacceptable toxicity. SRS will be given in single fraction as determined by the treating radiation oncologist and neurosurgeon. RESULTS Primary endpoint include Safety, tolerability and maximum tolerated dose (MTD) of Osimertinib, when administered in combination with SRS in patients with EGFR positive NSCLC with brain metastases. Secondary endpoints include Six-month intra-cranial and extra-cranial progression-free survival (PFS-6), overall survival, overall response rate, both intracranial and extra cranial in patients with EGFR positive NSCLC brain metastases. CONCLUSION This is an ongoing clinical trial.
Eradication of solid tumors by chemodynamic theranostics with H<sub>2</sub>O<sub>2</sub>-catalyzed hydroxyl radical burst
Authors: Nana Wang, Qin Zeng, Ruijing Zhang, Da Xing, Tao Zhang
Journal: Theranostics (2020)

Activatable theranostics, integrating high diagnostic accuracy and significant therapeutic effect, holds great potential for personalized cancer treatments; however, their chemodynamic modality is rarely exploited. Herein, we report a new in situ activatable chemodynamic theranostics PAsc/Fe@Cy7QB to specifically recognize and eradicate cancer cells with H2O2-catalyzed hydroxyl radical (•OH) burst cascade. Methods: The nanomicelles PAsc/Fe@Cy7QB were constructed by self-assembly of acid-responsive copolymers incorporating ascorbates and acid-sensitive Schiff base-Fe2+ complexes as well as H2O2-responsive adjuvant Cy7QB. Results: Upon systematic delivery of PAsc/Fe@Cy7QB into cancer cells, the acidic microenvironment triggered disassembly of the nanomicelles. The released Fe2+ catalyzed the oxidation of ascorbate monoanion (AscH-) to efficiently produce H2O2. The released H2O2, together with the endogenous H2O2, could be converted into highly active •OH via the Fenton reaction, resulting in enhanced Fe-mediated T1 magnetic resonance imaging (MRI). The synchronously released Cy7QB was activated by H2O2 to produce a glutathione (GSH)-scavenger quinone methide to boost the •OH yield and recover the Cy7 dye for fluorescence and photoacoustic imaging. Conclusion: The biodegradable PAsc/Fe@Cy7QB designed for tumor-selective multimodal imaging and high therapeutic effect provides an exemplary paradigm for precise chemodynamic theranostic.
CTNI-78. A PEDIATRIC AND YOUNG ADULT PHASE I DOSE ESCALATION SAFETY STUDY OF BXQ-350 FOR REFRACTORY SOLID AND CENTRAL NERVOUS SYSTEM TUMORS
Authors: Bhuvana Setty, Mohamed AbdelBaki, Mariko DeWire, Timothy Cripe, Rich Curry
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS) and has demonstrated antitumor effects in both in vitro and in vivo preclinical models. Many tumors, including high-grade glioma and diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly-exposed phosphatidylserine (PS)-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation. METHODS Nine refractory solid (2) and central nervous system (7) tumor patients (5F:4M, age 4–23 years of age) were enrolled in a 2-site dose escalation Phase I first-in-pediatric trial (NCT03967093) which completed in 2019. All patients received at least one dose of BXQ-350 which was administered as an intravenous infusion. Dosing began at 1.8 mg/kg and escalated to the highest planned dose level of 3.2mg/kg. RESULTS There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals. The highest planned dose of 3.2 mg/kg was achieved safely but a maximum tolerated dose was not established. One osteosarcoma patient had progressive disease prior to completing cycle one of treatment and was removed from trial. Eight patients (DIPG-3, HGG-1, GBM-1, Pineoblasotoma-1, Ependymoma-1, Osteosarcoma-1) completed at least one cycle, with one DIPG patient completing cycle five. CONCLUSION BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. A pediatric Phase I trial in newly diagnosed patients is planned for 3rd quarter 2020.
MBCL-10. LOCAL RECURRENCE AND SURVIVAL OUTCOMES OF MEDULLOBLASTOMA (MB) IN ADOLESCENT AND YOUNG ADULT PATIENTS (AYA)
Authors: Warissara Rongthong, Teeradon Treechairusame, Nan Suntornpong, Kullathorn Thephamongkhol
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE The aim of this study is to evaluate the local recurrence-free survival (LRFS) and overall survival (OS) of MB in AYA patients at our institute. METHOD Patients 15–39 years old with MB who was sent for post-operative radiation therapy (RT) in 2007 - 2017 at our institute were included. Kaplan-Meier statistics were used to estimate the LRFS and OS. RESULTS Seven patients were included. The median age at RT was 18.3 years (16.7–28.6 years). Male was more common than female, 5 males vs. 2 females. NTR or GTR was achieved in 71.4% (5 in 7 patients). Only one patient had metastatic disease (M1) and received combined chemotherapy-RT. The rest 6 patients were received RT alone, all were M0. The median craniospinal irradiation (CSI) dose and total RT dose were 36Gy (23.4-46Gy) and 54Gy (54-56Gy), respectively. Five patients had available follow-up MRI brain. Local recurrence (LR) was found in one patient at 4.3 years after finished RT. Her initial treatment was subtotal resection (STR) followed by RT alone; CSI 36 Gy and posterior fossa boost to 55.8Gy. The 2-years and 5-years LRFS were 100% and 66.7%, respectively. Both 2-years and 5-years OS were 100%. The median follow-up time was 7.6 years (0.4–11.5 years). CONCLUSION Our study shows high 2-years LRFS and OS of post-operative RT alone in AYA MB. Combined chemotherapy-RT should be considered in STR or M1. More number of patients and molecular histopathology subtype reports are still needed to confirm this report.
Atrial Fibrillation and C-Reactive Protein: Searching for Local Inflammation⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Antonio Hernández Madrid, Concepción Moro
Journal: Journal of the American College of Cardiology (2007)
Highlights 2020: framing health stories
Authors: Joanna Palmer, Grace Mwashigadi, Ramya Sampath, Ana S Ferrigno, Alejandra Platas, Beatriz Acevedo-Gattas, Cynthia Villarreal-Garza, Calyn Tan Jen Ai, Chanaki Amaratunga, Mehul Dhorda, Rupam Tripura, Rob W van der Pluijm, Thomas J Peto, Alexander Kumar, Arjen M Dondorp, Nicholas J White, Danilo Buonsenso, Aron D Rose, Prajjwal Pyakurel, Himmatrao Saluba Bawaskar, Michael John Baser, Pearl Gan, Mohib Raza, Greg G C Hugenholtz, Rachel Burns, Parth Patel, Robert W Aldridge, Ana Peixoto, Rui Silvestre Ferreira
Journal: The Lancet (2020)