tbuckley/cabot-search huggingface dataset:
NCOG-38. CLINICAL CHARACTERISTICS OF LOW GRADE GLIOMA PATIENTS WITH NON-CANONICAL IDH1 AND IDH2 MUTATIONS
Authors: Katherine Peters, Eric Lipp, Gloria Broadwater, James Herndon, Margaret Johnson, Dina Randazzo, Annick Desjardins, Henry Friedman, David Ashley, Mary Affronti
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Low grade gliomas (LGGs) develop in young adults and represent 10-15% of all glial tumors. While LGG patients can have longer survival than higher grade tumors, progression, transformation, and ultimately mortality occurs. Mutations in Isocitrate dehydrogenase 1/2 (IDH1/IDH2) are prevalent in LGG and are responsible for gliomagenesis. The classic IDH1 mutation is located at 132 codon and represented as p.Arg132His, but there are non-canonical IDH1 and IDH2 mutations. We sought to compare clinical characteristics of LGG patients with classic IDH1 p.Arg132His mutation to LGG patients with non-canonical IDH1 and IDH2 mutations. METHODS We queried an IRB-approved registry retrospectively from 12/2004- 9/2019. We included IDH1/IDH2 mutant LGG (WHO grade II) and known IDH1 and IDH2 targeted mutation analysis using standard PCR followed by DNA sequencing to detect point mutations in IDH1/IDH2 genes. We obtained available clinical and histopathological data. We estimated progression-free survival (PFS), time to transformation (TT), and overall survival (OS) using Kaplan-Meier methods. RESULTS We identified 267 LGG patients with median follow-up of 9.1 yrs (95%CI 8.4-9.9 yrs). Classic IDH1 p.Arg132His mutation occurred in 223 (83.9%) patients. IDH2 mutations occurred in 14 (5.2%) patients. Non-canonical IDH1 mutations were in 30 (11.2%) patients and included the following mutations: p.Arg132Cys (13), p.Arg132Gly (10), p.Arg132Ser (4), p.Arg132Leu (1), p.Arg119Gln (1), and p.Arg172Met (1). Initial presentation, OS, and TT did not differ between IDH1/IDH2 groups. PFS differed significantly between groups with improved median PFS in IDH2 mutant LGG (5.4 yrs; 95%CI 3.5-25.2) versus classic IDH1 mutant LGG (4.1 yrs; 95%CI 3.7-4.9 yrs) and non-canonical IDH1 mutant LGG (2.6 yrs; 95%CI 2.1-4.8) (log-rank p=0.019). Notably, non-canonical mutations were more common in astrocytoma (22/30; 73.3%) than other LGG histologies (p=0.018). CONCLUSIONS In this cohort, LGG patients with non-canonical mutations have a shorter time to progression than patients with classic p.Arg132His mutation and IDH2 mutations.
CTIM-31. USE OF A SINGLE PEPTIDE CHECKPOINT INHIBITOR FOR TREATMENT OF CENTRAL NERVOUS SYSTEM TUMORS
Authors: Christopher Moertel, Zhengming Xiong, David Zellmer, Elizabeth Pluhar, Elizabeth Neil, Emely Greengard, Michael Olin
Journal: Neuro-Oncology (2020)

Abstract Cancer immunotherapy has revolutionized clinical management of malignancies by generating long-term, durable control of tumors. Unfortunately, these therapies often cause serious immune-related adverse events. In addition, only a small percentage of solid tumors respond to these therapies and there is little efficacy in CNS tumors. Our research is focused on the CD200 immune checkpoint, which modulates the immune system through the inhibitory receptor (CD200R1) and activation receptors (CD200AR). We demonstrated that targeting the CD200AR with a checkpoint peptide ligand (CD200AR-L) activates the immune system and renders it impervious to the inhibitory effects of CD200. In a pre-clinical canine spontaneous high-grade glioma trial, CD200AR-L, with autologous tumor lysate vaccination, resulted in a 20% two-year progression-free survival; no toxicities or adverse effects were observed. We suggest this result was due to the ability of the CD200AR-L to modulate multiple immune checkpoints. During the characterization of the CD200AR-L, we discovered signaling molecules are shared by the CD200 and PD-1/PD-L1 checkpoint pathways, suggesting these immune checkpoints are connected. Our preliminary studies demonstrated that the inhibitory CD200R1 and PD-1 mediate immune checkpoint signaling activities through the SHIP1/2. Moreover, CD200AR-L overpowers the suppressive effects of CD200 and PD-L1, which are both shed by tumors, by downregulating the inhibitory CD200R1 and PD-1 on both antigen-presenting cells (APC) and T-cells. In addition, CD200AR-L downregulates PD-1 on APCs and inhibits the upregulation of PD-L1 and CTLA4. These studies led to the discovery that the novel peptide modulates the CD200, PD-1/PD-L1 and CTLA-4 pathways, providing the basis for the translatable development of a CD200-directed peptide for clinical use against multiple tumors including gliomas. These studies led to FDA approval of this peptide for the first in human phase I single center, open-label, dose-escalation clinical trial in adult and pediatric trial for children with recurrent malignant brain tumors.
Inhibition of Translation Initiation and Heat Shock Factor 1 (HSF1): A Novel Strategy Targeting FLT3 Double Mutant and Non-FLT3 Mutant AML Progenitor/Stem Cells
Authors: Jo Ishizawa, Ran Zhao, Lauren Heese, Alex Jaeger, Yuki Nishida, Rodrigo Jacamo, Kensuke Kojima, Man Chun John Ma, Vivian Ruvolo, Dhruv Chachad, R. Eric Davis, William Devine, John A Porco, Luke Whitesell, Michael Andreeff
Journal: Blood (2017)
Direct comparison of biopsy techniques for hepatic malignancies
Authors: Shang-Chin Huang, Ja-Der Liang, Shih-Jer Hsu, Tzu-Chan Hong, Hung-Chih Yang, Jia-Horng Kao
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: The core needle biopsy (CNB), fine needle aspiration cytology (FNAC) and touch imprint cytology (TIC) are commonly used tools for the diagnosis of hepatic malignancies. However, little is known about the benefits and criteria for selecting appropriate technique among them in clinical practice. We aimed to compare the sensitivity of ultrasound-guided CNB, FNAC, TIC as well as combinations for the diagnosis of hepatic malignancies, and to determine the factors associated with better sensitivity in each technique.Methods: From January 2018 to December 2019, a total of 634 consecutive patients who received ultrasound-guided liver biopsies at the National Taiwan University Hospital was collected, of whom 235 with confirmed malignant hepatic lesions receiving CNB, FNAC and TIC simultaneously were enrolled for analysis. The clinical and procedural data were compared.Results: The sensitivity of CNB, FNAC and TIC for the diagnosis of malignant hepatic lesions were 93.6%, 71.9%, and 85.1%, respectively. Add-on use of FNAC or TIC to CNB provided additional sensitivity of 2.1% and 0.4%, respectively. FNAC exhibited a significantly higher diagnostic rate in the metastatic cancers (P=0.011), hyperechoic lesions on ultrasound (P=0.028), and those with depth less than 4.5 cm from the site of needle insertion (P=0.036).Conclusions: The sensitivity of CNB is superior to that of FNAC and TIC for the diagnosis of hepatic malignancies. Nevertheless, for shallow (depth &lt;4.5 cm) and hyperechoic lesions not typical for primary liver cancers, FNAC alone provides excellent sensitivity.
QRS Width and Mechanical Dyssynchrony for Selection of Patients for Cardiac Resynchronization Therapy: One Can't Do Without the Other⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Theodore P. Abraham, Niels Thue Olsen
Journal: JACC. Cardiovascular imaging (2010)
INNV-14. UTILIZATION OF A PATIENT FAMILY ADVISORY COUNCIL TO ADVANCE PATIENT-CENTERED CARE OF BRAIN TUMOR PATIENTS
Authors: Jacob Pawloski, Lisa Scarpace, Nestelynn Gay, Hassan Fadel, Rachel Hunt, Sameah Haider, Adam Robin, James Snyder, Tobias Walbert, Steven Kalkanis, Ian Lee
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Developing and advancing patient-centered care within neuro-oncology is an essential element of any tertiary brain tumor center. Patient-centered care of neuro-oncology patients requires a holistic approach that integrates oncologic treatment with social and psychological support. OBJECTIVE The aim of this study is to evaluate how a Patient Family Advisory Council can be created within an existing brain tumor center and utilized to improve patient-centered care. METHODS Current patients and caregivers were recruited by brain tumor staff to participate in monthly meetings. All participants underwent screening and training by our Patient Education Research Center team. Discussions focused on current and future brain tumor center initiatives, and participants were encouraged to give feedback from the patient perspective. New ideas to improve the patient experience were solicited. RESULTS A total of 15 participants (female = 57%) were recruited, including 10 with grade 3 or higher brain tumors. Monthly meetings, in-person or virtual, were held for two years. Utilizing participant feedback, the group updated our 80-page patient handbook that contained a variety of patient-caregiver focused resources. Participants also provided feedback on other brain tumor center initiatives such as development of a magnet featuring key phone numbers, an easily accessible website URL for emergencies, and numerous updates to the external website. Additional discussions involved development of neuro-oncology care pathways as we move to a stand-alone cancer center facility and initiation of OncoSTAT and palliative services in this population. CONCLUSION Brain tumor patients require a comprehensive oncologic treatment team as well as a wide variety of support services. A Patient Family Advisory Council is an effective method of advancing patient-centered care and a step toward improving the neuro-oncology patient experience.
Smoldering Multiple Myeloma: What Is the Threshold to Start Treatment?
Authors: Natalie S. Callander
Journal: Journal of the National Comprehensive Cancer Network (2020)

Smoldering multiple myeloma represents approximately 10% to 15% of all myeloma cases, but more thorough evaluation may decrease that number in the future. Risk stratification is important in this patient population to avoid overtreatment or undertreatment. Patients with low-risk disease can be observed without treatment, but those at higher-risk should be enrolled on clinical trials. If a clinical trial is not an option in these patients, a time-limited intervention with lenalidomide ± dexamethasone can be considered.
ATRT-17. TARGETING GLUTAMINE METABOLISM LOWERS METHYLATION POTENCIALS IN AT/RT AND SYNERGIZE WITH TAZEMETOSTAT
Authors: Satoshi Nakata, Sabrina Wang, Jesse Alt, Barbara Slusher, Charles Eberhart, Eric Raabe, Jeffrey Rubens
Journal: Neuro-Oncology (2020)

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) have a single recurring genetic mutation in SMARCB1. This deletion leads to an abnormal SWI/SNF chromatin remodeling complex and the constitutive activation of EZH2. S-adenosyl-L-methionine (SAM) donates a methyl group to EZH2 which then methylates DNA and histones leading to the abnormal gene expression responsible for AT/RT’s aggressive phenotype. We have previously shown that glutamine metabolic inhibition with 6-diazo-5-oxo-L-norleucine (DON) confers a survival advantage in AT/RT. In this study, we identified with ultra-high performance liquid chromatography mass spectrometry that DON treatment lowered the methylation potential in AT/RT (Decreased SAM:SAH ratio, t-test in 5 AT/RT human-derived cell models comparing DON treatment to DMSO control, p&amp;lt;0.05). AT/RT cell lines grown in glutamine deplete media compared to normal growth conditions also had a reduced methylation potential (decreased SAM:SAH, t-test, p&amp;lt;0.05). DON treatment over 5 days decreased histone methylation (as determined by western blot for H3K27me3). Tazemetostat is a small molecule inhibitor that blocks the SAM methyl donor site on EZH2. We find that DON combines synergistically with Tazemetostat to slow AT/RT cell growth (MTS assay, p&amp;lt;0.01 t-test; MUSE viability assay, p&amp;lt;0.01 ANOVA) and enhances cytotoxicity (MUSE Annexin-V, p&amp;lt;0.01 by ANOVA). Synergies were especially pronounced at low concentrations of Tazemetostat which is significant given that Tazemetostat’s efficacy in AT/RT has been limited by poor CNS penetration. These studies identify a novel treatment strategy that has potential to improve survival in AT/RT.
NCMP-24. PRE-INFUSION NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS PREDICT THE DEVELOPMENT OF IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME (ICANS)
Authors: Omar Butt, Alice Zhou, Suzanne Schindler, Anne Fagan, John Dipersio, Armin Ghobadi, Beau Ances
Journal: Neuro-Oncology (2020)

Abstract Neurological side effects after chimeric antigen receptor-modified (CAR) T cell therapy are common and potentially devastating. Termed immune effector cell-associated neurotoxicity syndrome (ICANS), symptoms range from mild encephalopathy to diffuse cerebral edema. No predictive biomarkers exist to identify individuals at risk for developing ICANS. Serum neurofilament light chain (NfL) is a well-established marker of neural injury known to dynamically change in neuro-inflammatory disorders (e.g. multiple sclerosis). We hypothesized individuals undergoing CAR T cell therapy who ultimately developed ICANS would have early and sustained elevations in serum NfL. We performed a retrospective analysis of serum samples from 11 individuals treated with tisagenlecleucel or axicabtagene ciloleucel (mean age 61.3, 18% female, 27% ICANS, all with peak severity score 3). Most individuals had a longitudinal sampling at baseline, pre-infusion, post-transfusion day (PTD) 1, PTD 3, PTD 7, PTD 14, and PTD 30. Serum NfL were assayed using a Simoa HD-1/HD-X kit (QuanterixTM). We found that individuals who developed ICANS had early and sustained elevations in serum NfL levels at baseline (p = 0.0075), pre-infusion (p = 0.0172), and PTD 3 (p = 0.0026) and PTD 30 (p = 0.0066). All group comparisons survived multiple comparison testing using false-discovery rate (FDR). Receiver operating characteristic (ROC) curve classification by logistic regression of serum NfL revealed an area under the curve (AUC) of 1.0 with a cut-off of 44 pg/mL. No correlation was observed between NfL levels and age, sex, or history of central nervous system involvement of the underlying malignancy. In summary, we found serum NfL levels are a robust, early marker for the development of ICANS. Our findings suggest the risk of developing ICANS reflects pre-transfusion host-factors, permitting the screening well in advance of drug administration.
DIPG-46. NON-DIPG PATIENTS ENROLLED IN THE INTERNATIONAL DIPG REGISTRY: HISTOPATHOLOGIC EVALUATION OF CENTRAL NEURO-IMAGING REVIEW
Authors: Margot A Lazow, Christine Fuller, Adam Lane, Mariko D DeWire-Schottmiller, Pratiti Bandopadhayay, Ute Bartels, Eric Bouffet, Sylvia Cheng, Kenneth J Cohen, Tabitha M Cooney, Scott L Coven, Hetal Dholaria, Blanca Diez, Kathleen Dorris, Motasem El-Ayadi, Ayman El-Sheikh, Paul G Fisher, Mercedes Garcia Lombardi, Robert J Greiner, Stewart Goldman, Nicholas Gottardo, Sridharan Gururangan, Jordan R Hansford, Tim Hassall, Cynthia Hawkins, Lindsay Kilburn, Carl J Koschmann, Sarah E Leary, Jie Ma, Jane E Minturn, Michelle Monje-Deisseroth, Roger J Packer, Yvan Samson, Eric S Sandler, Gustavo Sevlever, Christopher Tinkle, Karen Tsui, Lars M Wagner, Mohamed Zaghloul, David S Ziegler, Brooklyn Chaney, Katie Black, Anthony Asher, Rachid Drissi, Maryam Fouladi, Blaise V Jones, James L Leach
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION The role of diagnostic biopsy in diffuse intrinsic pontine glioma (DIPG) remains in question. Distinguishing radiographically between DIPG and other pontine tumors with more favorable prognosis and different therapy is critically important. METHODS Cases submitted to the International DIPG registry with histopathologic data were analyzed. Central imaging review was performed by two neuro-radiologists; all cases with imaging features or histopathology suggestive of alternative diagnoses were re-reviewed. Imaging features suggestive of alternative diagnoses included non-pontine origin, &amp;lt;50% pontine involvement (without typical DIPG pattern on follow-up), focally exophytic morphology, sharply-defined margins, or marked diffusion restriction throughout. RESULTS Among 297 patients with pathology from biopsy and/or autopsy available, 27 (9%) had histologic diagnoses not consistent with DIPG, commonly embryonal tumors (n=9) and pilocytic astrocytomas (n=11). 163 patients had diagnostic MRI available for central neuroimaging review. Among 81 patients classified as characteristic of DIPG, 80 (99%) had histopathology consistent with DIPG (diffuse midline glioma, H3K27M-mutant, glioblastoma, anaplastic astrocytoma, diffuse astrocytoma). Among 63 patients classified as likely DIPG, but with unusual imaging features, 59 (94%) had histopathology consistent with DIPG. 19 patients had imaging features suggestive of another diagnosis, including 13 with non-pontine tumor origin; the remaining 6 all had histopathology not consistent with DIPG. Association between central imaging review and histopathology was significant (p&amp;lt;0.001). CONCLUSIONS The important role and accuracy of central neuroimaging review in diagnosing or excluding DIPG is demonstrated. In patients with pontine tumors for which DIPG is felt unlikely radiographically, biopsy may be considered to guide diagnosis and treatment.
SURG-09. EXTRAOPERATIVE CORTICAL MAPPING VIA IMPLANTED SUBDURAL AND DEPTH ELECTRODES FOR MAXIMIZING ELOQUENT AREA GLIOMA RESECTION
Authors: Konstantinos Fountas, Thanasis Paschalis, Eftychia Kapsalaki
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Aggressive, even supramarginal, resection without compromising the neurological status of the patient remains a great challenge in the management of glioma cases. Accurate cortical and subcortical functional mapping allows more radical glioma resection. Numerous imaging, electrophysiological, and hybrid methodologies have been employed in the cortical mapping of patients with gliomas in eloquent areas. Despite the recent advances of these non-invasive modalities, direct electrical cortical and subcortical stimulation and mapping through an awake craniotomy remains the gold standard for maximal glioma resection and preservation of eloquent cortex functions. Extraoperative stimulation and mapping via implanted subdural and/or depth electrodes may be a valid alternative mapping method in these cases that an awake procedure is not feasible. The role of this mapping method is examined in our current study. MATERIAL &amp; METHODS In a retrospective study, 51 patients undergoing extraoperative stimulation and mapping for glioma resection were included. The demographic data, the clinical characteristics, the stimulation parameters and complications, the extent of resection, the perioperative complications, and the tumor histological grade were analyzed. Shapiro-Wilk test, as well as uni- and multi-variate regression analysis was used for our statistical analysis. RESULTS The mean age of our participants was 58 (SD: 9.4) years. The location of the glioma was on the left side in 80.4%, while the frontal lobe was affected in 51.0%. Extraoperative cortical and subcortical stimulation and mapping was successful in 94.1%. The median stimulation procedure was 2.0 hours, while the median implantation time was 72 hours. Stimulation-induced seizures occurred in 13.7%, while CSF leakage in 5.9% of our cases. The mean extent of resection was 91.6%, while transient dysphasia occurred in 21.6%, and transient hemiparesis in 5.9% of our cases. CONCLUSIONS Extraoperative stimulation and mapping constitutes a valid alternative mapping option in glioma patients, who cannot undergo an awake craniotomy.
Repurposing drugs to fight aging: The difficult path from bench to bedside
Authors: Alexander Vaiserman, Alexander Koliada, Oleh Lushchak, Manuel J. Castillo
Journal: Medicinal Research Reviews (2020)

Abstract The steady rise in life expectancy occurred across all developed countries during the last century. This demographic trend is, however, not accompanied by the same healthspan extension. This is since aging is the main risk factor for all age‐associated pathological conditions. Therefore, slowing the rate of aging is suggested to be more efficient in preventing or delaying age‐related diseases than treat them one by one, which is the common approach in a current pharmacological disease‐oriented paradigm. To date, a variety of medications designed to treat particular pathological conditions have been shown to exhibit pro‐longevity effects in different experimental models. Among them, there are many commonly used prescription and over‐the‐counter pharmaceuticals such as metformin, rapamycin, aspirin, statins, melatonin, vitamin antioxidants, etc. All of them are being increasingly investigated in preclinical and clinical trials with the aim of determine whether they have potential for extension of human healthspan. The results from these trials are frequently inconclusive and fall short of initial expectations, suggesting that innovative research ideas and additional translational steps are required to overcome obstacles for implementation of such approaches in clinical practice. In this review, recent advances and challenges in the field of repurposing widely used conventional pharmaceuticals to target the aging process are summarized and discussed.
MBRS-31. COMBINING IRRADIATION AND ANTI-CD47 TO ENHANCE THE TREATMENT OF GROUP 3 MEDULLOBLASTOMA
Authors: Osama Youssef, Jeff Turner, Gongping He, Jingye Yang, Samuel Cheshier
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. The Group 3 molecular subgroup of Medulloblastoma (Group 3 MB) is the deadliest with only 30% long term survival. Irradiation for Group 3 Medulloblastoma is required for long term survival of children. Methods to enhance the effect of irradiation against Group 3 MB are an active area of investigation. Immunotherapy using the anti-CD47 treatment has shown promise in treating Group 3 MB. We recently demonstrated that irradiation significantly enhanced anti-CD47-mediated phagocytosis of high-grade glioma cells in vitro. Furthermore, mice engrafted with human high-grade glioma that received anti-CD47 combined with irradiation showed a significant increase in the survival rate and a significant decrease in tumor growth than those that received a single treatment. We have now extended these studies to demonstrate the enhancement of anti-CD47-dependent phagocytosis of human Group 3 MB with irradiation. We also analyzed normal human neural stem cells exposed to the same treatments to assess for the potential toxicity that uniquely exists with this treatment combination.
Abstract 12266: Fuster-bewat Score versus Cardiovascular Health Score to Predict Subclinical Target Organ Damage: Insights From a Large-scale Asian Population
Authors: Haoyu Wang, Kefei Dou
Journal: Circulation (2019)

Background: We aimed to investigate the relationships of cardiovascular health score (CVHS) and Fuster-BEWAT Score (FBS) with several subclinical markers of target organ damage (TOD) representing m...