tbuckley/cabot-search huggingface dataset:
MBRS-73. AN EXPLORATORY ANALYSIS LOOKING AT THE ASSOCIATION OF GERMLINE CODING MUTATIONS WITH IMPAIRED DEVELOPMENT AND ADAPTIVE BEHAVIOR FUNCTION IN PEDIATRIC MEDULLOBLASTOMA PATIENTS TREATED ON HEAD START 4
Authors: Jessica L Fleming, Blake E Sells, Erica H Bell, Joseph P McElroy, Amy Webb, Yue Zhao, Richard T Graham, Yingshi Guo, Tom Liu, Cynthia Timmers, Girish Dhall, Stephen Sands, Jonathan Finlay, Arnab Chakravarti
Journal: Neuro-Oncology (2020)

Abstract Children with brain tumors often carry germline mutations known to contribute to tumorigenesis and treatment response; however, little is known about how these mutations impact developmental and behavioral outcomes. As the molecular mechanisms governing cancerous and normal tissues expand, we hypothesize that specific germline variants may impact baseline neurocognitive function and/or treatment-induced toxicities. In this pilot study, ten children on the Head Start 4 (HS4) clinical trial diagnosed with medulloblastoma were assessed for baseline adaptive functioning using the Adaptive Behavior Assessment System Third Edition (ABAS-III) and germline whole-exome sequencing was performed. After filtering for high impact variants, Welch’s T-tests were used to identify mutations associated with lower ABAS-III General Adaptive Composite (GAC) scores, reflecting developmental and adaptive behavior delays compared with peers their age. We found twenty genes with alterations associated with lower scores with p-values less than 0.05. Genes found to be significant included LAMC1 (p=0.04) and KRTAP1-1 (p=0.045), which encode members of the laminin and keratin family respectively and are involved in extracellular matrix adhesion. Mutations in PITX1, a known suppressor of RAS, were also associated with lower ABAS-III GAC scores (p=0.007). We hypothesize that additional analyses of HS4 patients will reveal alterations in cell-to-cell communication and signal transduction pathways, common molecular perturbations in tumors that would likely impact central nervous system function. Validation studies are essential to improve our understanding of the functional impact of germline variants on both tumor and regular tissue biology, allowing for novel strategies to circumvent these delays.
QOL-40. THE IMPACT OF TASK COMPLEXITY ON INFORMATION PROCESSING SPEED AND NEURAL COMMUNICATION IN PAEDIATRIC BRAIN TUMOUR SURVIVORS
Authors: Elizabeth Cox, Juanita Atton, Julie Tseng, Sonya Bells, Cynthia de Medeiros, Suzanne Laughlin, Eric Bouffet, Donald J Mabbott
Journal: Neuro-Oncology (2020)

Abstract Paediatric brain tumour survivors (PBTS) experience slower information processing speed (IPS) that contributes to difficulty performing tasks of minimal (MC) and greater complexity (GC), and is related to aberrant neural communication. It is still unknown whether deficient IPS exists during increasing complexity. We aim to determine if PBTS experience deficient IPS and neural communication relative to typically developing children (TDC) during an increasingly complex visual-motor reaction time (RT) task. During magnetoencephalography recording, participants (n=58, 12.69 ±3.24 years) pressed a button with their left or right thumb after an arrow pointing in the corresponding direction appeared on a screen. During two MC conditions, the arrow pointed in a single direction. During a GC condition, the arrow alternated direction randomly. Mean RT &amp;gt;3SD and signal artifacts were removed prior to analyses. The phase lag index (PLI) estimated neural communication between 90 cortical sources. Linear regression and Network Based Statistics assessed group differences in mean RT and the PLI. PBTS demonstrated increased RT relative to TDC during the GC condition (p=0.04, MPBTS=354.00s, MTDC=326.00s). Group differences in mean RT during MC conditions and the PLI during all conditions were not detected (p&amp;gt;0.05). These results suggest PBTS experience slower IPS during GC. Reduced IPS is thought to contribute to difficulty recruiting cognitive resources needed to perform more complex tasks. Subtle deficits in neural communication may underlie slower IPS. The weighted PLI is superior to the PLI when estimating small differences in neural communication. We will now use the weighted PLI to assess task-related neural communication.
BIOM-21. CORRELATION BETWEEN EPHRIN-A2 EXPRESSION AND PROGNOSIS IN PATIENTS WITH GLIOBLASTOMA
Authors: Nozomi Hirai, Toshiya Ichinose, Sho Tamai, Riho Nakajima, Hemragul Sabit, Mitsutoshi Nakada
Journal: Neuro-Oncology (2020)

Abstract The Eph receptor/ephrin ligand system is the largest family of tyrosine kinase with signaling modality through cell to cell adhesion. Eph/ephrin is involved in malignant phenotype such as cell proliferation, migration, and invasion in cancer cells. Although the functions of the Eph receptors in glioblastoma have been elucidated, little is known on ephrin ligands, especially ephrin-A2. Here, we analyze the expression of ephrin-A2 in gliomas using surgical specimens. The expression level of ephrin-A2 mRNA in 14 normal brains and glioma (WHO grade II 13, III 10, and IV 40) was measured by quantitative real-time PCR. Ephrin-A2 expression level was significantly lower in glioblastoma than in normal brain (p= 0.0127). When we divided the glioblastoma cases into high and low ephrin-A2 expression groups based on the median value, the overall survival (OS) was significantly longer in the high expression group compared with the low expression group (p= 0.034, median 24.0 and 14.0 months, respectively). Furthermore, multivariate analysis of factors related to OS with ephrin-A2 expression level and general prognostic factors (age, sex, preoperative KPS, surgical resection rate, radiochemotherapy, IDH1 mutation, MGMT promotor methylation) was performed. Ephrin-A2 expression level (p= 0.039), MGMT promotor methylation (p= 0.0001), and surgical resection rate (p= 0.017) were identified as independent prognostic factors. Taken together, ephrin-A2 is an independent favorable prognostic factor in glioblastoma.
MBRS-68. SINGLE NUCLEUS RNA-SEQUENCING DECIPHERS INTRATUMORAL HETEROGENEITY IN MEDULLOBLASTOMA WITH EXTENSIVE NODULARITY (MBEN)
Authors: David N Ghasemi, Konstantin Okonechnikov, Jan-Philipp Malm, Kati Lappalainen, Katharina Bauer, Michelle S Liberio, Laura Giese, Kendra K Maass, Marcel Kool, David T W Jones, Andreas von Deimling, Stefan M Pfister, Andrey Korshunov, Kristian W Pajtler
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) with extensive nodularity (MBEN) represent a rare subtype of cerebellar tumors of infancy which comprise two histologically distinct components, nodular reticulin-free zones and inter-nodular reticulin-rich regions. We applied single nucleus RNA-sequencing (snRNA-seq) using the 10X Genomics and the SMARTseq V2 protocols, bulk RNA-sequencing, DNA-methylation profiling and DNA-panel sequencing to ten histologically confirmed MBEN specimens. All tumors were classified as sonic hedgehog (SHH) MB based on DNA methylation. Somatic mutations within the SHH-pathway were detected in seven samples (3x SUFU, 2x PTCH1, 2x SMO) by DNA panel sequencing. The combined snRNAseq approach resulted in data on ~30.000 single cells. Several non-malignant cell types were identified, e.g. endothelial cells, astrocytes, and microglia. Amongst malignant cell populations SHH-pathway activation and mitotic activity differed revealing actively cycling embryonic stem (ES) cell-like and more differentiated neuronal-like cell types. In addition, distinct histological components of these tumours were subjected to bulk RNA sequencing following microdissection. This approach was repeated for DNA methylation profiling in an independent paraffin embedded MBEN cohort. However, these analyses did not reveal significant transcriptomic differences or differential methylation patterns between the two histological components. In summary, snRNA-seq identified a strongly proliferating, ES-like subset of cells in MBEN, which might represent the driving cell population in these malignancies, while direct analyses of nodular and inter-nodular regions did not reveal any significant differences. These findings suggest that both components originate from the same cell of origin but represent different cellular developmental stages.
NURS-11. MARIJUANA, HEMP, AND THE CHILD WITH CANCER: PATIENT, PARENT, AND CLINICIAN EDUCATION
Authors: Molly Hemenway
Journal: Neuro-Oncology (2020)

Abstract Many pediatric oncology patients report medical marijuana (MMJ) and hemp-based CBD use. Eleven states and Washington, DC have legalized marijuana for recreational use for adults greater than 21. Medical marijuana is legalized in 33 states. Additionally, due to the bipartisan Farm Bill passed in December of 2018, hemp is federally legal. Marijuana has medical legalization in 23 countries worldwide. Clinical trials in adults have examined MMJ for cancer-related symptoms. New research is emerging on MMJ in anticancer therapy, MMJ receptors on tumor cells, and the potential role for MMJ as an immunomodulator. Few pediatric oncology studies have evaluated MMJ. We describe the initial findings of a prospective observational study of MMJ on the quality of life (QOL) in pediatric brain tumor patients. Specific aims included (1) MMJ’s association with symptoms (nausea, anxiety, pain, fatigue, and cognitive problems) and (2) MMJ’s impact on family dynamics. The legality of hemp plus the increasing use of MMJ raises concerns with pharmacological interactions with CBD and the medications routinely administered to children with cancer. Nurses are the frontline for discussions with patients about MMJ and must be aware of the emerging field of MMJ in pediatric cancer. Additionally, nurses can influence patient care protocols and processes for alternative therapy administration enabling an open dialogue between providers, parents, and patients regarding treatments, symptoms, adverse effects, and drug interactions. Education about how to have conversations about important facets to cover and consider is crucial to patient safety and increased quality of life.
EPEN-28. NOVEL ONCOGENE AMPLIFICATION IN SPINAL EPENDYMOMA INVOLVING THE MYC LOCUS (8q24)
Authors: Margaret Shatara, Daniel R Boué, Christopher R Pierson, Diana L Thomas, Eric A Sribnick, Jeremy Jones, Diana P Rodriguez, Kathleen M Schieffer, Carol Deeg, Elizabeth Hamelberg, Stephanie LaHaye, Vincent Magrini, Richard K Wilson, Elaine R Mardis, Catherine E Cottrell, Elizabeth A Varga, Mohamed S AbdelBaki, Jonathan L Finlay, Diana S Osorio
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND We report a unique case of spinal ependymoma with classic histology and aggressive clinical behavior which harbored a focal MYC (8q24) amplification. CASE REPORT: A-12-year old male presented with a three months history of back pain and acute onset weakness with ataxia. A spine MRI revealed an avidly enhancing intradural, extramedullary mass occupying the dorsal spinal canal from C6 through T2. The tumor demonstrated mild diffusion restriction and was associated with severe cord compression and mild edema. He underwent gross total resection. Pathological diagnosis was classic grade II ependymoma. Eleven months later, he re-presented with acute onset lower extremity paresthesia and left-handed weakness. Spine MRI demonstrated tumor recurrence extending from C2 through T1-T2 with resultant severe cord compression, again demonstrating avid enhancement and restricted diffusion. He underwent subtotal resection of the mass and focal proton beam irradiation. MOLECULAR CHARACTERISTICS: The patient was enrolled on an institutional comprehensive genomic profiling protocol. The tumor’s copy number profile was complex, including homozygous loss of 17p and notably, amplification of the MYC oncogene. Using fluorescence in situ hybridization, we identified &amp;gt;20 copies of MYC in interphase cells, confirming the gene amplification, while two copies of MYCN (2p24) were seen. DNA methylation further classified this tumor as clustering near posterior fossa group A (score=0.6073) tumors. CONCLUSION We report a unique case of an adolescent male with aggressive spinal ependymoma harboring focal MYC amplification. Testing for MYC amplification may be reasonable in newly-diagnosed spinal ependymomas to aid in characterization.
PATH-12. TEMOZOLOMIDE-INDUCED HYPERMUTATION IS ASSOCIATED WITH HIGH-GRADE TRANSFORMATION, DISTANT RECURRENCE AND REDUCED SURVIVAL IN INITIALLY LOW GRADE IDH-MUTANT GLIOMAS
Authors: Yao Yu, Javier Villanueva-Meyer, Susan Chang, Matthew Grimmer, Stephanie Hilz, David Solomon, Serah Choi, Michael Wahl, Tali Mazor, Chibo Hong, Anny Shai, Joanna Phillips, Michael McDermott, Daphne Haas-Kogan, Jennie Taylor, Nicholas Butowski, Jennifer Clarke, Mitchel Berger, Joseph Costello, Nancy Ann Oberheim Bush
Journal: Neuro-Oncology (2020)

Abstract Temozolomide, a commonly used alkylating agent, can induce somatic hypermutation in gliomas. The prevalence and implications of this phenomenon are not well characterized. Using targeted and whole exome sequencing from a cohort of 82 patients with recurrent IDH-mut LGG, we evaluated the clinical implications of hypermutation. Hypermutation was identified at transformation in 57% of recurrent gliomas exposed to TMZ and occurred for both IDH-mutant astrocytomas (52%) and oligodendrogliomas (64%). Among astrocytomas, receipt of radiotherapy prior to transformation was associated with decreased risk of hypermutation (11% vs 70%, p=0.0052), but this trend was not observed for oligodendrogliomas (78% vs 54%, p=NS). Among hypermutated tumors, 94% were transformed to higher WHO grades. Hypermutation was associated with transformation to higher WHO grade (OR 12.0 95% CI 2.5-115.5, p=0.002) and shorter survival after transformation (HR 2.1, 95% CI 1.1-4.0, p=0.018) compared with non-hypermutated transformed tumors. It remained prognostic (controlling for grade, molecular subtype, age, and prior radiotherapy. Patients with transformation to glioblastoma had poor survival regardless of hypermutation (p=0.78). Multivariate models were validated using an external, independent dataset (Harrel’s C=0.72). Strikingly, hypermutated tumors were also associated with development of discontiguous disease after transformation (3-year CI 41% vs 8% p=0.005), including ependymal and leptomeningeal distributions and four cases of spinal dissemination that were not observed in non-hypermutated tumors. These data have significant implications for management of IDH-mut LGG at recurrence.
Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis
Authors: Xiang Wang, Yan Zou, Zhidan Chen, Yang Li, Le Pan, Ying Wang, Ming Liu, Chao Yin, Jian Wu, Chunjie Yang, Lei Zhang, Chenze Li, Zheyong Huang, Daowen Wang, Juying Qian, Junbo Ge, Yunzeng Zou, Hui Gong
Journal: Theranostics (2020)

Rationale: Maladaptive cardiac remodeling is a critical step in the progression of heart failure. Low-density lipoprotein receptor-related protein 6 (LRP6), a co-receptor of Wnt, has been implicated in cardiac protection. We aimed to study the role of cardiomyocyte-expressed LRP6 in cardiac remodeling under chronic pressure overload. Methods: Cardiac parameters were analyzed in inducible cardiac-specific LRP6 overexpressing and control mice subjected to transverse aortic constriction (TAC). Results: Cardiac LRP6 was increased at an early phase after TAC. Cardiomyocyte-specific LRP6 overexpression improved cardiac function and inhibited cardiac hypertrophy and fibrosis four weeks after TAC. The overexpression significantly inhibited β-catenin activation, likely contributing to the inhibitory effect on cardiac hypertrophy after TAC. LRP6 overexpression reduced the expression and secretion of Wnt5a and Wnt11 by cardiomyocytes, and knockdown of Wnt5a and Wnt11 greatly inhibited cardiac fibrosis and dysfunction under pressure overload in vitro and in vivo. Cardiomyocyte-expressed LRP6 interacted with cathepsin D (CTSD, a protease) and promoted the degradation of Wnt5a and Wnt11, inhibiting cardiac fibrosis and dysfunction induced by TAC. The protease inhibitor leupeptin attenuated the interaction between LRP6 and CTSD, enhanced the expression of Wnt5a and Wnt11, and deteriorated cardiac function and fibrosis in cardiomyocyte-specific LRP6-overexpressing mice under pressure overload. Mutants from human patients, P1427Q of LRP6 and G316R of CTSD significantly inhibited the interaction between LRP6 and CTSD and increased Wnt5a and Wnt11 expression. Conclusion: Cardiomyocyte-expressed LRP6 promoted the degradation of Wnt5a and Wnt11 by regulating CTSD and inhibited cardiac fibrosis under pressure overload. Our study demonstrated a novel role of LRP6 as an anti-fibrosis regulator.
GCT-35. SALVAGE CRANIOSPINAL IRRADIATION FOR RECURRENT GERMINOMAS
Authors: Masayuki Kanamori, Ryuta Saito, Yukihiko Sonoda, Toshihiro Kumabe, Teiji Tominaga
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The treatment strategies for recurrence has not been established. PURPOSE To clarify the tumor control and complications of salvage craniospinal irradiation (CSI) for recurrent germinoma. METHODS We retrospectively reviewed the medical record. Among 153 germinomas treated in Tohoku University Hospital since 1983, 22 had recurrence of germinoma. At first recurrence, 7 cases received CSI, whereas 15 cases did chemotherapy and/or radiation therapy other than craniospinal field (non- CSI). CSI was performed at 24 Gy/ 12 fractions or 30 Gy/ 25 fractions. RESULTS CSI had statistically significant better recurrence-free survival rate after recurrence than non-CSI (100% vs 33%, p&amp;lt;0.001: log-rank test). In addition, tumor control was obtained in all of four cases with the failure after non- CSI treatments for recurrence. The late complications of these 11 cases were examined. The local dose before CSI was 24- 50 Gy, and the median interval from last irradiation to CSI was 33 months. Median follow- up period after CSI was 126 months. Three patients developed newly developed visual or cognitive deficits. These patients received high-dose irradiation at initial treatment or multiple treatment before CSI. There were no late complications in the cases which had prior chemotherapy and 24 Gy of irradiation to whole ventricle only before CSI. CONCLUSION Low dose CSI for the first recurrence of germinoma is effective and safe in the cases treated by chemotherapy and low dose irradiation to whole ventricle only.
NCMP-20. A RETROSPECTIVE SINGLE-CENTER EXPERIENCE WITH NONBACTERIAL THROMBOTIC ENDOCARDITIS AND STROKE - OUTCOMES, ANTICOAGULATION STRATEGIES, AND INCORPORATION OF NEXT-GENERATION SEQUENCING DAT
Authors: Ashley Aaroe, Kristin Alfaro-Munoz, Charles Bornstein, Trey Kell, Samuel Camp, Merry Chen, Karin Woodman, Sudhakar Tummala, Anne Kleiman, John de Groot, Monica Loghin
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Acute ischemic stroke is a common neurologic complication of cancer and contributes to worse prognosis. Hypercoagulable state is an important stroke mechanism in cancer. Nonbacterial thrombotic endocarditis (NBTE) represents an extreme manifestation of such hypercoagulability. Evidence comparing LMHW to unfractionated heparin or direct oral anticoagulants (DOACs) for secondary stroke prevention is lacking in cancer patients. It is also unknown whether certain tumor mutations are associated with increased risk of NBTE. METHODS We reviewed clinical documents at MD Anderson Cancer Center using a RichSearch Natural Language Processing application to search for terms related to marantic endocarditis. Each patient was assessed for documentation of both valvular thickening or vegetations on echocardiogram, and negative blood cultures. Targeted next generation sequencing (NGS) information was interrogated using the PROACTIVE database. RESULTS 100 patient records were reviewed and of these 41 patients were determined to have likely NBTE based on the above criteria. 12 patients had recurrent strokes despite anticoagulation, two of whom had two recurrent strokes despite different anticoagulation strategies (4 strokes through therapeutic dose LMWH, 4 through rivaroxaban, 3 through apixaban, 1 through fondaparinux). The most common primary malignancies were non-small cell lung cancer (n=14) and pancreatic cancer (n=11). NGS data was available for 13 patients, and the most common mutations were KRAS (n=8), TP53 (n=7), EGFR (n=4), and BRAF (n=2) CONCLUSIONS NBTE is an important stroke mechanism in cancer, and the optimal secondary prevention strategy is unknown. These results confirm that NBTE is common in NSCLC and pancreatic cancer. These cancer types commonly harbor mutations such as KRAS, TP53 and EGFR, and work is ongoing to clarify how such mutations might contribute to hypercoagulability. Recurrent stroke is possible with all anticoagulation strategies. Further analysis of outcomes, serum biomarkers (ex. D-dimer), and comorbid medical diagnoses known to confer increased cardiovascular risk is underway.
Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia
Authors: Carlos Salama, Jian Han, Linda Yau, William G Reiss, Benjamin Kramer, Jeffrey D Neidhart, Gerard J Criner, Emma Kaplan-Lewis, Rachel Baden, Lavannya Pandit, Miriam L Cameron, Julia Garcia-Diaz, Victoria Chávez, Martha Mekebeb-Reuter, Ferdinando Lima de Menezes, Reena Shah, Maria F González-Lara, Beverly Assman, Jamie Freedman, Shalini V Mohan
Journal: New England Journal of Medicine (2020)

Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear.We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28.A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -﻿5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group.In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).
Stillbirths During the COVID-19 Pandemic in England, April-June 2020
Authors: Julia Stowe, Helen Smith, Kate Thurland, Mary E. Ramsay, Nick Andrews, Shamez N. Ladhani
Journal: JAMA (2020)

Asma Khalil, MD; Peter von Dadelszen, PhD; Tim Draycott, MD; Austin Ugwumadu, PhD; Pat O'Brien, MBBCh, MRCOG, MFFP; Laura Magee, PhD