tbuckley/cabot-search huggingface dataset:
EPID-08. PRE-SURGERY IMMUNE PROFILES OF ADULT GLIOMA PATIENTS
Authors: Paige Bracci, Terri Rice, Helen Hansen, Stephen Francis, Sean Lee, Lucie McCoy, Pavan Shrestha, Gayathri Warrier, Jennifer Clarke, Annette Molinaro, Jennie Taylor, John Wiencke, Margaret Wrensch
Journal: Neuro-Oncology (2020)

Abstract Changes in glioma patients’ immune profiles over the course of disease may predict outcomes. DNA based immunomethylomics quantifies blood immune cells based on cell specific DNA methylation signatures. To assess changes in immune profiles, we are longitudinally collecting blood samples from glioma patients pre-surgery and at other clinically relevant time points. Here we report patients’ pre-surgery immune profiles. All patients underwent biopsy or resection of a presumed new glioma or recurrent lower grade glioma. Blood DNA methylation was assessed with Illumina EPIC methylation arrays. Relative cell fractions of CD4, CD8, B-cells, natural killer cells, monocytes, and neutrophils, were estimated via our validated deconvolution algorithm. Total nucleated cell counts from Nexcelom cytometry were used to compute absolute cell counts. Other measures include total lymphocytes, CD4/CD8 ratio, neutrophil to lymphocyte ratio (NLR), and lymphocyte to monocyte ratio (LMR)). The first 125 participants includes 56 newly diagnosed glioblastomas (GBM), 28 newly diagnosed grade II-III gliomas, and 41 recurrent grade II-III gliomas. Median patient age is 49 years. 53 (43%) had recent dexamethasone exposure. In overall non-parametric analyses, most cell subsets, especially CD4, differed across grade, diagnosis group, WHO classification and dexamethasone exposure. In post-hoc pairwise analyses, immune profiles of IDH wildtype GBM patients who had taken dexamethasone differed from patients with GBM or grade II-III glioma who had not taken dexamethasone; they had clinically relevant and statistically significantly lower absolute CD4 counts, total white cell counts, and percent of total lymphocytes, and higher absolute neutrophil counts, NLR and LMR. However, some dexamethasone naïve GBM patients also had altered immune profiles. Comparisons of relative immune cell fractions with those from 454 non-glioma controls from the UCSF Adult Glioma Study showed that across grade and WHO classification, for the most part, immune profiles of glioma patients not exposed to dexamethasone did not differ from controls.
Tumor cell network integration in glioma represents a stemness feature
Authors: Ruifan Xie, Tobias Kessler, Julia Grosch, Ling Hai, Varun Venkataramani, Lulu Huang, Dirk C Hoffmann, Gergely Solecki, Miriam Ratliff, Matthias Schlesner, Wolfgang Wick, Frank Winkler
Journal: Neuro-Oncology (2020)

Malignant gliomas including glioblastomas are characterized by a striking cellular heterogeneity, which includes a subpopulation of glioma cells that becomes highly resistant by integration into tumor microtube (TM)-connected multicellular networks. A novel functional approach to detect, isolate, and characterize glioma cell subpopulations with respect to in vivo network integration is established, combining a dye staining method with intravital two-photon microscopy, Fluorescence-Activated Cell Sorting (FACS), molecular profiling, and gene reporter studies. Glioblastoma cells that are part of the TM-connected tumor network show activated neurodevelopmental and glioma progression gene expression pathways. Importantly, many of them revealed profiles indicative of increased cellular stemness, including high expression of nestin. TM-connected glioblastoma cells also had a higher potential for reinitiation of brain tumor growth. Long-term tracking of tumor cell nestin expression in vivo revealed a stronger TM network integration and higher radioresistance of the nestin-high subpopulation. Glioblastoma cells that were both nestin-high and network-integrated were particularly able to adapt to radiotherapy with increased TM formation. Multiple stem-like features are strongly enriched in a fraction of network-integrated glioma cells, explaining their particular resilience.
CTNI-71. TTFIELDS IN ROUTINE CLINICAL CARE OF NEWLY DIAGNOSED GBM PATIENTS IN GERMANY – FIRST REPORT ON THE FULLY ENROLLED TIGER STUDY POPULATION
Authors: Oliver Bähr, Ghazaleh Tabatabai, Rainer Fietkau, Roland Goldbrunner, Martin Glas
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Glioblastoma (GBM) is widely treated with surgery, chemoradiation and TTFields in combination with chemotherapy. Since the introduction of TTFields to first-line GBM treatment, prescribing physicians in Germany are interested to gain additional knowledge on the use in clinical practice. The TIGER study was designed to assess the therapy decision making process, safety and efficacy of TTFields in clinical routine, as well as evaluating quality of life (QoL) within 4 months after start of therapy, treatment compliance and duration. METHODS This multi-center prospective non-interventional study in Germany (NCT03258021) included newly diagnosed GBM patients eligible for TTFields therapy. Within the study, after receiving introduction to TTFields therapy, patients could decide for or against receiving TTFields. The study was designed to recruit 500 patients for each group, with and without TTFields. Demographic data, QoL and reasons for therapy decision 2–4 months after treatment start are assessed using the EORTC-QLQ-C30/BN-20 and a TTFields questionnaire, respectively, with 18 months follow-up. RESULTS At the last data cut-off (31st March, 2020), the median follow-up was 11 months (range: 0–28 months) and 581 (82%) of the 710 recruited patients in the trial had decided for TTFields therapy. According to preliminary analysis, this patient population represents a typical GBM population regarding median age (59 years, range: 19.0–85.0), gender (37 % female), median KPS (90, range: 40–100) and MGMT promoter methylation status (44% methylated). In this population 49 % received complete resection, 33 % partial resection and 19 % biopsy. CONCLUSION The TIGER study allows prospective and systematic analysis of TTFields treatment decision making and use of typical GBM patient population in routine clinical care. In addition, the study allows the evaluation of compliance and treatment duration. Here, we will present an updated analysis of the TIGER study.
HGG-09. FIRST LINE THERAPY OF PEDIATRIC GLIOBLASTOMA WITH LAROTRECTINIB
Authors: Musa Alharbi, Nahla Ali Mobark, Ali Abdullah O Balbaid, Fatmah A Alanazi, Wael Abdel Rahman Aljabarat, Eman A K Bakhsh, Murad Turkistani, Malak Abedalthagafi
Journal: Neuro-Oncology (2020)

Abstract PURPOSE In this case report, we document new recommendations for the treatment of pediatric glioblastoma based on a genetic understanding of the disease. PATIENTS AND METHODS A Saudi girl aged 18 months presented with a history of right sided weakness and partial seizures. MRI revealed the presence of large complex left frontal tumor. Craniotomy and gross total resection were performed. post-operatively The patient showed excellent recovery with no neurological deficits. Pathology reports confirmed glioblastoma (GBM). Due to the expected poor survival, the patient’s family declined standard therapy, including chemotherapy and/or radiation therapy. RESULTS Molecular analysis showed positive fusion mutations for ETV6-NTRK3 making the patient an ideal candidate for larotrectinib, an oral tyrosine kinase (TRK) inhibitor. Unfortunately, follow-up MRI showed local tumor recurrence at 3-months post-surgery. The family agreed to the initiation of oral larotrectinib as a less invasive therapy. The patient tolerated Larotrectinib very well with no reported side effects. Follow up MRI was performed 8-weeks post-larotrectinib treatment and showed significant tumor regression, indicating an excellent treatment response. CONCLUSION This case highlights how TRK-inhibitors can be integrated as a first-line therapy for pediatric high grade GBMs harboring TRK-fusions. We also highlight the need for the integration of genomic profiling and molecular analysis into the routine histopathologic analyses of pediatric patients with malignant primary intracranial tumors, to detect any genetic mutations that can be targeted with available therapies to avoid the morbidity associated with non-precision conventional therapies.
How Structural Racism Works — Racist Policies as a Root Cause of U.S. Racial Health Inequities
Authors: Zinzi D. Bailey, Justin M. Feldman, Mary T. Bassett
Journal: New England Journal of Medicine (2020)

In the 5 years since one of us published "#Black LivesMatter -A Challenge to the Medical and Public Health Communities" in the Journal, 1 we have seen a sea change in the recognition of racism as a durable feature of U.S. society and of its high cost in Black lives.Elected officials, corporate leaders, and academics alike use the slogan "Black Lives Matter," which has also been widely adopted by members of the public, who by the millions protested the extrajudicial killing of George Floyd. 2 With this change comes growing recognition that racism has a structural basis and is embedded in long-standing social policy.This framing is captured by the term "structural racism."4][5][6][7] All definitions make clear that racism is not simply the result of private prejudices held by individuals, 8 but is also produced and reproduced by laws, rules, and practices, sanctioned and even implemented by various levels of government, and embedded in the economic system as well as in cultural and societal norms. 3,8Confronting racism, therefore, requires not only changing individual attitudes, but also transforming and dismantling the policies and institutions that undergird the U.S. racial hierarchy.As a legacy of African enslavement, structural racism affects both population and individual health in three interrelated domains: redlining and racialized residential segregation, mass incarceration and police violence, and unequal medical care.These examples, among others, share certain cardinal features: harms are historically grounded, involve multiple institutions, and rely on racist cultural tropes.
THER-01. AWAKING THE IMMUNE SYSTEM WITH AN IMMUNO-ONCOLYTIC VIRUS AS A THERAPEUTIC STRATEGY FOR DIPGs
Authors: Virginia Laspidea, Montse Puigdelloses, Iker Ausejo-Mauleon, Dolores Hambardzumyan, Zhihong Chen, Naiara Martinez-Velez, Marta Zalacain, Jaime Gallego Perez de Larraya, Oren Becher, Juan Fueyo, Candelaria Gomez-Manzano, Marta M Alonso
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour, being the leading cause of paediatric death caused by cancer. Despite all the advances made regarding effective therapies, the survival is dismal. Our lab has engineered the oncolytic virus Delta-24-ACT armed with the costimulatory ligand 41BBL in order to increase the antitumoral effect of the adenovirus. 41BB is a costimulatory receptor which promotes the expansion of activated T cells and the generation and maintenance of CD8 T memory cells. Therefore, we propose the use of Delta-24-ACT as a therapeutic approach for DIPG tumours. We observed that Delta-24-ACT is able to infect and replicate in NP53 and PDGFB-driven, two DIPG murine cell lines. Furthermore, 41BBL is expressed in the membranes of the infected cells and results with immunogenic cell death as shown by the different DAMPs. Injection of Delta-24-ACT in DIPG model was safe, showed no sign of toxicity and led to a significantly increase in the median overall survival, generating anti-glioma memory in long-term survivors. Mechanistic experiments, showed an increase of T cell infiltration (mainly CD8), decrease of proliferating cells and a reduction of the number of vessels in FFPE brain samples in the treated mice. We are currently performing nanostring analyses to assess the changes in the transcriptional immune phenotype of treated versus control mice. In summary, our data suggest that Delta-24-ACT is safe and induces a potent antitumor immune response in DIPG models mainly based in the activation of CD8 lymphocytes recruited by the viral activity.
SURG-27. TREATING HYDROCEPHALUS IN DIFFUSE MIDLINE GLIOMAS WITH AN H3 K27M MUTATION
Authors: L Coombs, R LaRocca, Jessica Hata, H Nickols, A Spalding, Ian Mutchnick, Thomas Moriarity, William Gump, D Sun
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diffuse midline gliomas (DMG) are a subset of malignant gliomas that share a characteristic Histone H3K27M mutation. These tumors are centrally located and may cause hydrocephalus on initial presentation. DMG lack characteristic imaging that distinguish from other primary brain tumors in the midline. We conducted this retrospective chart review of 43 consecutive patients presenting with midline tumors to determine: how many had a DMG; whether DMG patients with hydrocephalus were candidates for resection; and what the outcomes of endoscopic third ventriculostomy (ETV) versus ventriculoperitoneal shunt (VPS) placement were, as compared to wild type (WT) tumors. METHODS We conducted an IRB approved retrospective chart review of patients presenting with midline tumors from 9/2016-3/2020 to determine H3K27M mutation status, hydrocephalus, and neurosurgery intervention. RESULTS The median age of all midline tumor patients was 19.1 years (range 1.1-80.1). 26% (11/43) of midline tumors presented with H3K27M mutation, with a higher rate of hydrocephalus compared to patients without mutation [7/11 (65%) for DMG vs. 6/32 (19%) for WT, p&amp;lt; 0.05]. Of the seven H3K27M patients presenting with hydrocephalus, none were candidates for resection, 5 underwent ETV, and 2 underwent VPS placement as initial management. 4 out of these 5 ETVs failed within an average of 24 days (6-42 days). 2 patients then underwent VP shunt placement; the other 2 underwent secondary ETV but both failed and required VP shunting as well. All 6 WT tumor patients had one procedure (1 ETV, 5 resection) to relieve hydrocephalus, and no patients had recurrent hydrocephalus. CONCLUSIONS Both pediatric and adult patients may present with DMG associated with a higher rate of unresectable tumors and hydrocephalus on presentation. Furthermore, these data suggest that neuroendoscopic third ventriculostomy and septum pellucidum fenestration for the management of obstructive hydrocephalus in patients with DMG may be less robust than shunting.
Therapeutic inhibition of miR-802 protects against obesity through AMPK-mediated regulation of hepatic lipid metabolism
Authors: Yangyue Ni, Zhipeng Xu, Chen Li, Yuxiao Zhu, Ran Liu, Fan Zhang, Hao Chang, Maining Li, Liang Sheng, Zhong Li, Min Hou, Lin Chen, Hong You, Donald P. McManus, Wei Hu, Yinong Duan, Yu Liu, Minjun Ji
Journal: Theranostics (2020)

Background: The host-parasite relationship is based on subtle interplay between parasite survival strategies and host defense mechanisms. It is well known that helminth infection, which afflicts more than one billion people globally, correlates with a decreased prevalence of obesity. Dissecting the underlying mechanisms can provide new targets for treating obesity from the host-parasite interaction perspective. Methods: C57BL/6 mice received a normal or high-fat diet (HFD) with or without Sjp40 (one main component of schistosome-derived soluble egg antigens) treatment. Both the loss and gain-of-function experiments by the inhibitor suppression and lentivirus treatment of miR-802 were utilized to elucidate the role of miR-802/AMPK axis in host lipid metabolism. Hepatocyte lipogenesis assay and metabolic parameters were assessed both in vivo and in vitro. The potential interactions among Sjp40, CD36, miR-802, Prkab1, and AMPK were clarified by pull-down, miRNA expression microarray, quantitative RT-PCR, dual-luciferase reporter assay, and western blotting analysis. Results: We showed a link between decreased miR-802 and impaired lipid metabolism in Schistosoma japonicum infected mice. The decreased miR-802 promotes murine Prkab1 or human Prkaa1 expression, respectively, which increases levels of phosphorylated AMPK, resulting in a decrease in hepatic lipogenesis. Also, injection with schistosome-derived soluble egg antigens (SEA) attenuated metabolism. We demonstrated that Sjp40 as a main component of SEA interacted with CD36 on hepatocytes to inhibit miR-802, resulting in the activation of AMPK pathway and subsequent attenuation of lipogenesis. Collectively: Our study reveals the significant role of miR-802/AMPK axis in hepatic lipid metabolism and identifies the therapeutic potential of Sjp40 in treating obesity-related fatty liver.
CTIM-08. COMBINATION OF THE IMA950/POLY-ICLC MULTIPEPTIDE VACCINE WITH PEMBROLIZUMAB IN RELAPSING GLIOBLASTOMA PATIENTS
Authors: Valérie Dutoit, Eliana Marinari, Pierre-Yves Dietrich, Denis Migliorini
Journal: Neuro-Oncology (2020)

Abstract The IMA950 peptide vaccine is composed of 9 HLA-A2-restricted peptides eluted from the surface of GBM samples and of two HLA class II-binding peptides1. It was tested in combination with poly-ICLC in patients with newly diagnosed GBM, demonstrating safety. The vaccine was able to elicit CD4 and CD8 T cell responses in the peripheral blood in the majority of patients, with however an overall low magnitude of T cell responses and suboptimal migration of elicited T cells to the brain, probably limiting clinical efficacy2,3. With the aim to improve homing of vaccine-specific T cell to the tumor, we are conducting a phase II clinical trial in patients with recurrent GBM testing the IMA950/poly-ICLC multipeptide vaccine with or without the anti-PD1 antibody pembrolizumab (NCT03665545). 24 patients will be included (12 patients in each arm) and pre- and post-vaccination tumor sample will be available, allowing assessing effect of the vaccine at the tumor site. The primary objective of this trial is safety of IMA950/poly-ICLC given together with pembrolizumab. Secondary objectives include (i) estimation of 6, 9 and 12-month progression-free survival (PFS), (ii) overall survival, (iii) analysis of patient quality of life and (iv) of the synergy/immunogenicity of IMA950/poly-ICLC and pembrolizumab. Immunomonitoring will include measure of vaccine-induced immune responses, IHC for immune cell markers, RNA/TCR sequencing and methylome analysis, to assess vaccine-induced T cell responses, immune modulation and potential signatures predictive of response. Thus far, 6 patients have been included (3 in each arm). Preliminary results show CD4 and CD8 T cell responses to the vaccine are detected in both groups in the peripheral blood. Analysis at the tumor site and comparison between arms will be performed once all patients have been included. 1. Dutoit, V. et al. Brain (2012); 2. Migliorini, D. et al. Neuro Oncol (2019); 3. Rampling, R. et al. Clin Cancer Res(2016)
Reconsidering reviews: the role of scoping reviews in digital medicine and pediatrics
Authors: Katherine E. Lewinter, Sharon M. Hudson, Lynn Kysh, Marielena Lara, Cecily L. Betz, Juan Espinoza
Journal: npj Digital Medicine (2020)

Digital health is a rapidly developing field which is positioned to transform the manner in which healthcare is delivered, especially amongst adolescents and young adults. In order to assess the efficacy of novel medical devices, clinicians and researchers often turn to the literature for guidance. Randomized control trials and the systematic reviews and meta-analyses that they inform are considered to be at the top of the evidence hierarchy. While they are excellent tools to identify and to summarize the best available evidence to answer a specific research question, they are poorly equipped to provide a more expansive understanding of the body of relevant literature in a timely manner. In this letter we discuss the utility of the scoping review, an underutilized style of academic writing designed to map key concepts in a body of literature. This method is ideal when reporting on the fast-paced field of digital medicine, as it allows for rapid synthesis of the available literature.
Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study
Authors: Camilla Ditlev Lindhardt Johannesen, Anne Langsted, Martin Bødtker Mortensen, Børge Grønne Nordestgaard
Journal: BMJ (2020)

Abstract Objective To determine the association between levels of low density lipoprotein cholesterol (LDL-C) and all cause mortality, and the concentration of LDL-C associated with the lowest risk of all cause mortality in the general population. Design Prospective cohort study. Setting Denmark; the Copenhagen General Population Study recruited in 2003-15 with a median follow-up of 9.4 years. Participants Individuals randomly selected from the national Danish Civil Registration System. Main outcome measures Baseline levels of LDL-C associated with risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by a priori defined centile categories with Cox proportional hazards regression models. Main outcome was all cause mortality. Secondary outcomes were cause specific mortality (cardiovascular, cancer, and other mortality). Results Among 108 243 individuals aged 20-100, 11 376 (10.5%) died during the study, at a median age of 81. The association between levels of LDL-C and the risk of all cause mortality was U shaped, with low and high levels associated with an increased risk of all cause mortality. Compared with individuals with concentrations of LDL-C of 3.4-3.9 mmol/L (132-154 mg/dL; 61st-80th centiles), the multivariable adjusted hazard ratio for all cause mortality was 1.25 (95% confidence interval 1.15 to 1.36) for individuals with LDL-C concentrations of less than 1.8 mmol/L (&lt;70 mg/dL; 1st-5th centiles) and 1.15 (1.05 to 1.27) for LDL-C concentrations of more than 4.8 mmol/L (&gt;189 mg/dL; 96th-100th centiles). The concentration of LDL-C associated with the lowest risk of all cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid lowering treatment, compared with 2.3 mmol/L (89 mg/dL) in individuals receiving lipid lowering treatment. Similar results were seen in men and women, across age groups, and for cancer and other mortality, but not for cardiovascular mortality. Any increase in LDL-C levels was associated with an increased risk of myocardial infarction. Conclusions In the general population, low and high levels of LDL-C were associated with an increased risk of all cause mortality, and the lowest risk of all cause mortality was found at an LDL-C concentration of 3.6 mmol/L (140 mg/dL).
Platelet Reactivity and Percutaneous Coronary Intervention: Another Clue in the Quest for the Holy Grail of Tailored Antithrombotic Therapy?⁎⁎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: Germano Di Sciascio, Fabio Mangiacapra
Journal: Journal of the American College of Cardiology (2012)