tbuckley/cabot-search huggingface dataset:
Abstract 13043: Pregnancy After Spontaneous Coronary Artery Dissection: A Case Series of 22 Women and 31 Pregnancies
Authors: Marysia S Tweet, Kathleen A Young, Carl H Rose, Patricia J Best, Rajiv Gulati, Sharonne N Hayes
Journal: Circulation (2019)

Introduction: Spontaneous coronary artery dissection (SCAD) presents as an acute coronary syndrome, often in women of childbearing age. The characteristics and outcomes of pregnancies in women with...
NCOG-63. PEDIATRIC NEURO-ONCOLOGY SURVIVOR IDENTITY: A PROJECT REACH STUDY
Authors: Chantel Cacciotti, Cheryl Medeiros-Nancarrow, Nicole Ullrich, Christopher Recklitis, Tabitha Cooney
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The degree to which adults treated for pediatric CNS tumors identify with cancer and survivorship, and factors influencing their identification, have been understudied. METHODS Self-reported data was collected from Project REACH, a locally-treated childhood cancer survivor cohort. Data included demographic (age, gender, race/ethnicity, marriage, education, employment, living situation, insurance), clinical (diagnosis, treatment), neurocognitive (CCSS NCQ), quality-of-life (QOL; SF-12, FACT-G) and survivorship identity variables. Participants were ≥ 18 years old, ≥ 2 years from diagnosis, and ≥ 1 year from therapy completion. RESULTS 132 participants; 59 males, and 118 non-Hispanic whites were included. Mean age at diagnosis and survey was 9.6 (range 0-22) and 26.7 (range 18-46) years, respectively. Treatment was diverse; 34% of participants received surgery only, 34% received surgery, chemotherapy, and radiation, and 32% received other treatment combinations. Most participants (67%) reported their cancer had “moderate,” “great,” or “total” effect on their current identity, and most (66%) thought of their diagnosis ≥ 1-2 times per month. A large proportion of survivors (83%) reported identifying as a “survivor.” Demographic and clinical variables were largely unelated to perceived effects of cancer, except for current age and QOL; 87% of survivors older than 30 reported moderate to great/total effect of cancer on their identity vs 51% of survivors age 18-21 (p=0.031). Participants reporting great/total effect on their identity had lower mental and physical health scores (SF-12) than those who reported no impact (48.5 vs 52.8, p=0.04; 42.6 vs 47.2, p =0.02 respectively). CONCLUSION The majority of participants report a significant impact from their childhood tumor diagnosis on their adult identity, and frequent diagnosis-related thoughts. Older survivors and those with poor QOL report greater effects on their identity. Interventions are needed to promote opportunities to make meaning of the pediatric CNS tumor experience as a way of achieving better quality of life.
Proton pump inhibitors and the risk of severe COVID-19: a post-hoc analysis from the Korean nationwide cohort
Authors: Seung Won Lee, Jee Myung Yang, In Kyung Yoo, Sung Yong Moon, Eun Kyo Ha, Abdullah Özgür Yeniova, Joo Young Cho, Min Seo Kim, Jae Il Shin, Dong Keon Yon
Journal: Gut (2020)

We appreciate the comment and discussion from Dr Roulet1 on our original article.2 The author criticised that (1) our study did not consider the dose-dependent exposure to proton pump inhibitors (PPIs); (2) our study did not investigate the relationship of PPI use in hospitalised patients with COVID-19 during treatment for COVID-19 and (3) although our study accounted for protopathic bias by excluding new non-steroidal anti-inflammatory drug users, protopathic bias occurred in patients who responded to the early digestive symptoms of COVID-19. We acknowledge that plausible academic concerns have been raised, which might improve the original discussion and extend the insight into the association between PPI usage and COVID-19.1 We have performed a post-hoc analysis from the Korean nationwide cohort, addressing these concern.

Data were obtained from the Korean nationwide cohort study, which includes patients (≥18 years) who underwent SARS-CoV-2 testing between 1 January and 15 May 2020.2–4 We performed propensity score matching between current PPI users (prehospitalisation PPI usage) and non-users among patients with laboratory-confirmed COVID-19 (n=4785), as previously described.2 Posthospitalisation PPI usage was defined as in-hospital PPI use in general wards, not intensive care units. The outcomes were a composite endpoint 1 (requirement of oxygen therapy, intensive care unit admission, administration of invasive ventilation or death) and a composite endpoint 2 …
<i>The BMJ</i> appeal 2020-21: “Without good nutrition, children’s health outcomes worsen, as do their life chances”
Authors: Jane Feinmann
Journal: BMJ (2020)

<i>The BMJ</i>’s appeal this year supports the Independent Food Aid Network, a charity that has helped independent food banks and other community meal providers throughout the covid-19 pandemic, writes <b>Jane Feinmann</b>
MBRS-47. RAPID MOLECULAR SUBGROUPING OF MEDULLOBLASTOMA BASED ON DNA METHYLATION BY NANOPORE SEQUENCING
Authors: Julien Masliah-Planchon, Elodie Girard, Philipp Euskirchen, Christine Bourneix, Delphine Lequin, Maud Blanluet, Jean-Baptiste Aillaud, Francois Doz, Franck Bourdeaut, Olivier Delattre
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) can be classified into four molecular subgroups (WNT group, SHH group, group 3, and group 4). The gold standard of assignment of molecular subgroup through DNA methylation profiling uses Illumina EPIC array. However, this tool has some limitation in terms of cost and timing, in order to get the results soon enough for clinical use. We present an alternative DNA methylation assay based on nanopore sequencing efficient for rapid, cheaper, and reliable subgrouping of clinical MB samples. Low-depth whole genome with long-read single-molecule nanopore sequencing was used to simultaneously assess copy number profile and MB subgrouping based on DNA methylation. The DNA methylation data generated by Nanopore sequencing were compared to a publicly available reference cohort comprising over 2,800 brain tumors including the four subgroups of MB (Capper et al. Nature; 2018) to generate a score that estimates a confidence with a tumor group assignment. Among the 24 MB analyzed with nanopore sequencing (six WNT, nine SHH, five group 3, and four group 4), all of them were classified in the appropriate subgroup established by expression-based Nanostring subgrouping. In addition to the subgrouping, we also examine the genomic profile. Furthermore, all previously identified clinically relevant genomic rearrangements (mostly MYC and MYCN amplifications) were also detected with our assay. In conclusion, we are confirming the full reliability of nanopore sequencing as a novel rapid and cheap assay for methylation-based MB subgrouping. We now plan to implement this technology to other embryonal tumors of the central nervous system.
BIOM-10. PREVALENCE OF NF1 MISSENSE MUTATIONS AND CANDIDATE MODIFIER GENES IN SPINAL NEUROFIBROMATOSIS PATIENTS
Authors: Paola Riva, Donata Bianchessi, Eleonora Mangano, Claudia Cesaretti, Paola Bettinaglio, Roberta Bordoni, Viviana Tritto, Cristina Battaglia, Giulia Cagnoli, Veronica Saletti, Marina Melone, Carla Schettino, Federica Natacci, Gaetano Finocchiaro, Marica Eoli
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Spinal Neurofibromatosis (SNF), a distinct clinical entity of NF1, characterized by bilateral neurofibromas involving all spinal roots and a few, if any, cutaneous manifestations, entails greater morbidity than the classical form of disease. Nevertheless, there are no reliable patterns to sort out patients at risk for developing SNF. MATERIALS AND METHODS We investigated 19 NF1 families with at least one SNF member, 37 sporadic SNF patient and 100 NF1 patients with classical form of disease. We applied Targeted NGS using a panel consisting of 139 genes encoding RAS pathway effectors, neurofibromin interactors and genes mapping at 17q11.2 region. RESULTS In SNF patients we found a higher percentage of missense (21% versus 8%, p=0 0.016, OR 3.13 (95% CI 01.1 -8.2) and a lower percentage of nonsense NF1 mutations (12.5% versus 28%,, p= 0.026, OR 0.36 (95% CI 0.14–0.9) than in classical NF1 cases. Furthermore, we evaluated rare variants with damaging potential predictors in genes of the RAS pathway and in neurofibromin interactors. In more than one sporadic case possible pathogenic variants were found in LIMK2 (neurofibromin interactor), RASAL1, RASAL3, SOS1, A2ML1, MAP3K1 (RAS pathway effectors), while in more than one SNF family were detected RASAL1, RASAL3, MAP3K1 genes variations. CONCLUSIONS Our results confirm the correlation between NF1 genotype and SNF phenotype as previously reported (Ruggieri, 2015), suggesting that neurofibromin gain-of-functions mutations are associated to SNF. In some patients, the co-occurrence of potential pathogenic variants in NF1 related genes with severe phenotypes was detected supporting their role as modifier genes and promising therapeutic targets.
HGG-27. ANTI-CANCER POTENTIAL OF ARGINASE FOR HIGH-GRADE GLIOMA <i>IN VITRO</i> &amp; <i>IN-VIVO</i>
Authors: M K L Fung, S Chan, S Sun, P D Zhang, G K K Leung, G C F Chan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND High-grade glioma is currently incurable. It was reported that glioma may be auxotrophic to arginine due to the lack of urea cycle genes expressions, suggesting arginase may be a potential agent for high grade glioma. AIM: We investigated the efficacy of pegylated arginase I (pegArg-I) or in combination with other anti-cancer drugs for high-grade glioma in vitro and in vivo. METHODS 4 high-grade glioma cell lines (U87, U373, U138, D54) were treated with pegArg-I in vitro. The molecular mechanism of pegArg-I-induced cytotoxicity was tested in U87. The ultra-morphological changes of pegArg-I-treated U87 was investigated by both scanning and transmission electron microscopy. Orthotopic glioma xenograft model with luciferase-transfected U87 cell line was tested for anti-cancer efficacy of peg-Arg I in vivo. RESULTS We showed that pegArg-I induced significant cell death in all 4 cell lines in vitro. Temozolomide, difluoromethyornithine and chloroquine (CQ) were then tested together with pegArg-I in U87 in vitro. We found that only CQ showed additive effect with pegArg-I against glioma in vitro. Such additive cytotoxic effect may be associated with enhanced autophagy and necrosis as shown in transmission electron microscopy and autophagy markers’ expression by Western blotting. PegArg-I prolonged the survival of glioma mice, suggesting its possible anti-glioma efficacy. However, CQ+pegArg-I didn’t show further significant anti-cancer efficacy in vivo. CONCLUSION PegArg-I may be useful in slowing the progression of glioma, but additional drug candidate which works synergistically with pegArg-I remains to be explored.
Notice of Retraction. Hodkinson et al. Accelerometer- and Pedometer-Based Physical Activity Interventions Among Adults With Cardiometabolic Conditions: A Systematic Review and Meta-analysis. <i>JAMA Netw Open</i>. 2019;2(10):e1912895.
Authors: Alexander Hodkinson, Evangelos Kontopantelis, Charles Adeniji, Harm van Marwijk, Brian McMillan, Peter Bower, Maria Panagioti
Journal: JAMA Network Open (2020)
EXTH-25. THE CSF PENETRATION OF THE PROCASPASE-ACTIVATING COMPOUND (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE (TMZ) IN A NONHUMAN PRIMATE CSF ACCESS MODEL
Authors: Cynthia Lester McCully, Priya Shankarappa, Rafael Cruz Garcia, Cody Peer, Alexander Zakharov, James Fischer, Alexander Lyubimov, Paul Hergenrother, Marvin Thomas, William Figg, Katherine Warren
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The synergistic activity of temozolomide (TMZ) administered in combination with procaspase-activating compound (PAC-1) has been reported in pre-clinical mouse models and canine patients, leading to clinical trials in adults with glioblastoma. To optimize pediatric clinical trial design, a translational pharmacokinetic CSF penetration study was conducted using a pre-clinical nonhuman primate non-tumor bearing CSF access model with TMZ and PAC-1 administered alone and in combination. METHODS Four male rhesus macaques with CSF lateral ventricular reservoirs received PAC-1, 15 mg/kg orally [Human Equivalent Dose (HED) 558 mg/m2/day] or TMZ, 1-hr IV infusion, 7.5 mg/kg (HED 150 mg/m2) as single and combination agent administration. Paired plasma and CSF samples were collected for 0–96 hours. PAC-1 and TMZ were quantified by LC-MS/MS. Pharmacokinetic parameters were calculated using noncompartmental methods. Statistics were determined via Mann-Whitney test. RESULTS (Mean ± Standard Deviation): For TMZ: Plasma AUC0-24 (hr*ng/ml) single agent (n=4): 28590 ± 4888 and in combination (n=4): 32736 ± 10147. CSF AUC0-24 (hr*ng/ml) single agent (n=4):14406 ± 1279 and in combination (n=4):15614 ± 1767. CSF penetration (% AUCCSF: AUCPLASMA) single agent: 50.9% ± 2.2 and in combination:49.6% ± 8.4. For PAC-1: Plasma PAC-1 AUC0-24 (hr*ng/ml) single agent (n=4): 2556 ± 2157 and in combination (n=4): 1947 ± 1311. CSF PAC-1 AUC0-24 (hr*ng/ml) single agent (n=2): 8.7 ± 1.1 and in combination (n=3):12.9 ± 10.2. CSF penetration single agent: 0.2% ± 0.03 and in combination: 0.4% ± 0.38. CSF PAC-1 tlag and Tmax pharmacokinetic parameters decreased with concurrent TMZ administration. CONCLUSIONS In this non-tumor bearing pre-clinical nonhuman primate model the CSF penetration of PAC-1 was low and not notably affected by the concurrent administration of TMZ. TMZ CSF penetration for single administration was within previously reported ranges and also appeared unaffected when administered in combination with PAC-1.
MBRS-28. EXOSOMES DRIVE MEDULLOBLASTOMA METASTASIS IN A MMP2 AND EMMPRIN DEPENDENT MANNER
Authors: Hannah K Jackson, Franziska Linke, Ian Kerr, Beth Coyle
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Recurrent/metastatic medulloblastoma (MB) is a devastating disease with an abysmal prognosis of less than 10% 5-year survival. The secretion of extracellular vesicles (EVs) has emerged as a pivotal mediator for communication in the tumour microenvironment during metastasis. The most investigated EV’s are exosomes, nanovesicles secreted by all cell types and able to cross the blood-brain-barrier. Matrix metalloproteinases (MMPs) are enzymes secreted by tumour cells that can potentiate their dissemination by modification of the extracellular matrix. We hypothesise that exosomal MMP2 and its inducer EMMPRIN could enhance metastasis of MB. METHODS Proliferation, invasion and migration assays were used to evaluate the phenotypic behaviour of primary cell lines pre-treated with metastatic tumour cell-derived exosomes. Gelatin zymography and western blotting were performed to confirm MMP2 functional activity in cell lines and exosomes. Nanoscale flow cytometry was used to measure surface exosomal EMMPRIN levels. Exosomal MMP2 and EMMPRIN were modulated at the RNA level. RESULTS Number of exosomes is directly related to the migratory behaviour of parental MB cell lines (p&amp;lt;0.01). Notably, functional exosomal MMP2 and EMMPRIN levels also correlate with this. Furthermore, exosomes from metastatic cell lines conferred enhanced migration and invasion on their matched isogenic primary (non-metastatic) cell line pair by ~3.8-fold (p&amp;lt;0.01). Exosomes from metastatic cell lines also conferred increased migration on poorly migratory foetal neuronal stem cells. CONCLUSION Together this data suggests that exosomal MMP2 and EMMPRIN may promote medulloblastoma metastasis and supports analysis of exosomal MMP2 and EMMPRIN levels in patient cerebral spinal fluid samples.
An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation
Authors: Mirja Harms, Monica M.W. Habib, Simona Nemska, Antonella Nicolò, Andrea Gilg, Nico Preising, Pandian Sokkar, Sara Carmignani, Martina Raasholm, Gilbert Weidinger, Gönül Kizilsavas, Manfred Wagner, Ludger Ständker, Ashraf H. Abadi, Hassan Jumaa, Frank Kirchhoff, Nelly Frossard, Elsa Sanchez-Garcia, Jan Münch
Journal: Acta Pharmaceutica Sinica B (2020)

Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases. A natural fragment of serum albumin, named EPI-X4, has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases. To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4. Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4. The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100. EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model. Moreover, topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis. Thus, rationally designed EPI-X4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis. Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis, asthma and other CXCR4-associated diseases is highly warranted.
Visualization of Motor Cortex Involvement by 18F-THK5351 PET Potentially Strengthens Diagnosis of Amyotrophic Lateral Sclerosis
Authors: Yuji Saitoh, Etsuko Imabayashi, Taiji Mukai, Hiroshi Matsuda, Yuji Takahashi
Journal: Clinical Nuclear Medicine (2020)

Amyotrophic lateral sclerosis (ALS) involves both upper motor neurons (UMNs) and lower motor neurons. The detection of UMN involvement, a core component of ALS criteria, is primarily dependent on neurological examination because of a lack of definitive biomarkers. We present the 18F-THK5351 PET images of a 76-year-old man diagnosed with ALS comorbid with Alzheimer disease, demonstrating marked accumulation of 18F-THK5351 in the bilateral precentral gyri. Because 18F-THK5351 binds to monoamine oxidase B highly expressed in astrocytes, where the neurodegenerative process is ongoing, our case highlights that 18F-THK5351 tracer should be a useful marker for detecting UMN neurodegeneration in ALS.
NCOG-08. A COMPARISON OF RESPONSE-ASSESSMENT AND DATA VISUALIZATION METHODS FOR CHARACTERIZATION OF TIME-DEPENDENT OUTCOMES FOLLOWING RADIOSURGERY (SRS) FOR BRAIN METASTASES
Authors: Tatiana Kashtanova, Andrew Keller, Naren Ramakrishna
Journal: Neuro-Oncology (2020)

Abstract PURPOSE We compared multiple response assessment and visualization techniques for characterization of post-SRS treatment outcomes in a cohort of breast cancer patients with long median follow-up. METHODS A retrospective IRB-approved review was completed of 75 breast cancer patients treated with SRS for 271 brain metastases with median follow up of 40 months. Tumor dimensions, brain failure events, corticosteroid use, and clinical status were analyzed utilizing RANO-BM, bidimensional product (BDP), and bidimensional sum (BDS) techniques. 46/75 patients were eligible for RANO-BM assessment. Response at each post-treatment assessment were scored as PD, SD, PR, or CR, and the concordance between techniques was determined. A scoring system-based outcome metric labelled ‘average state’ was derived to estimate fractional time/response state by each assessment method. Interactive timeline displays of outcome states were generated. RESULTS The concordance of patient response states was determined using either RANO-BM, BDP or BDS among the 46 eligible patients. The overall mean and median concordance between techniques were 0.82 and 0.83, (range 0.52 – 1). The average state for the patient population post-treatment was 1.98 by RANO-BM, 2.29 by BDP, and 2.19 by BDS. For patients excluded from RANO-BM secondary to lack of measurable disease, the average state was determined to be 2.44 by BDP and 2.35 by BDS. The average state for HER2+ vs. HER2- patients was 2.21 vs. 1.75 by RANO-BM, 2.58 vs. 2 by BDP, and 2.39 vs. 1.99 by BDS. An interactive timeline view was generated to display outcome states utilizing the 3 response assessment techniques, and the impact of inclusion of non-target lesions and variable response parameters was assessed graphically. CONCLUSIONS These results characterize the concordance and the limitations of multiple outcome assessment methodologies in a post-SRS cohort with long median follow-up. The utility of a novel ‘average state’ outcome metric is demonstrated in this cohort.
PATH-06. ASSESSMENT OF CIRCULATING TUMOR DNA IN CEREBROSPINAL FLUID BY WHOLE EXOME SEQUENCING TO DETECT GENOMIC ALTERATIONS OF GLIOBLASTOMA
Authors: Hao Duan, Zhenqiang He, Zhenghe Chen, Yonggao Mou
Journal: Neuro-Oncology (2020)

Abstract Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF comparing with the corresponding tumor tissue samples (3.56±0.75 vs. 2.22±0.32, P=0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.12% ± 6.03% vs. 73.83% ± 5.95%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3F3A which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.