tbuckley/cabot-search huggingface dataset:
BIOM-61. FUNCTIONAL DIAGNOSTIC TESTING OF LIVE-CELL DRUG RESPONSE USING 3D PATIENT DERIVED GLIOBLASTOMA SPHEROIDS ON THE INCUCYTE PLATFORM
Authors: Seth Malinowski, Mehdi Touat, Max Stockslager, Ross Giglio, Jack Geduldig, Claire Sinai, Kristine Pelton, David Reardon, Patrick Wen, Kin Hoe Chow, Scott Manalis, Keith Ligon
Journal: Neuro-Oncology (2020)

Abstract Three-dimensional patient derived cultures hold great potential for use as personalized functional diagnostics, enabling more accurate preclinical evaluations of drug treatments compared to conventional cell lines. Optical imaging of live cells allows for continuous, time lapsed measurements, and can provide drug response data based on rich phenotypic changes of cell cultures. However, current imaging techniques based on 2D microscopy evaluation aren’t readily adaptable to evaluate the drug response of intact spheroids, which may better represent the in vivo environment and retain critical cellular interactions within the tumor microenvironment. Using the IncuCyte live cell imaging platform, we successfully imaged a large cohort (n = 77) of patient derived glioblastoma spheroid cultures and evaluated whether changes in sphere volume could be used as a direct measure of treatment response. Improving on the default Incucyte analysis software, we developed an R data processing pipeline better suited for spheroid measurements, which quantified the heterogeneity in GBM baseline spheroid growth, and calculated a drug response score based on spheroid changes in response to DNA damaging agents (TMZ as an example). Compared to conventional viability measurements, this novel 3D drug response score was found to accurately identify both drug sensitive and resistant spheroids and showed robust concordance with genomic biomarkers of response (NGS and MGMT promoter methylation) and patient outcomes. Additionally, we coupled the 3D drug score with known genetic data to explore other key pathways and genes involved in TMZ response. We provide here novel analysis methods and public code (Github) to advance the use of IncuCyte spheroid measurements, and deconvolute 3D spheroid drug response into a quantifiable statistic. These methods are adaptable to freshly isolated patient cells for rapid evaluation of treatment response in GBM patients while remaining widely applicable to other cancers such as pancreatic, colon, and non-cancer organoids/spheroids with 3D growth.
TMOD-35. DEVELOPING RECURRENT GBM PDX, IN VIVO, FROM TREATMENT NAÏVE SOURCES
Authors: Charles James, Shi-Yuan Cheng, Craig Horbinski, Jann Sarkaria, Roger Stupp, Atique Ahmed
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Post-therapy recurrent glioblastoma (GBM) patient-derived xenografts (PDX), developed from corresponding treatment-naïve PDX, could serve as useful resources for identifying therapeutics with activity against recurrent GBM. The goal of this study was to determine whether treatment-naïve intracranial GBM PDX, in mice receiving radiotherapy (RT) and/or temozolomide (TMZ), acquire the same mutations that occur in post-RT+TMZ GBMs from patients. METHODS Luciferase-modified, treatment-naïve GBM PDX were engrafted in the brains of athymic nude mice, followed by treatment with RT only (2 Gy/day x 5), TMZ only (10 mg/kg/day x 5), or RT+TMZ. Bioluminescence imaging was used to monitor intracranial tumor growth, response to treatment, and recurrence from treatment. Some mice with recurrent tumors received additional TMZ treatment. When mice became symptomatic, intracranial tumors were resected and engrafted subcutaneously in a new mouse host, then sequentially propagated subcutaneously into additional host mice. After the third passage, whole-exome sequencing (WES) was done, comparing post-therapy with treatment-naïve PDX sequence variants. RESULTS Analysis of PDX WES showed the following: 1) TMZ consistently caused more genes to incur coding sequence mutations than RT, as much as 13x more; 2) TMZ-treated tumor mutations were mostly G-C to A-T transitions (71-92%), consistent with the known mutagenic effect of TMZ; and 3) post-therapy PDX acquire similar mutations as do recurrent GBMs in patients, for example involving DNA mismatch repair gene MSH6. One of the derivative PDX with MSH6 mutation has been retested for response to RT and TMZ, with results showing its having become TMZ, but not RT resistant. CONCLUSIONS The mutation profiles of RT+TMZ-treated PDX are similar to those reported for GBMs that recur after RT+TMZ in patients. The new PDX resources described here may prove useful for identifying effective treatments against recurrent GBM.
HGG-41. STRUCTURAL VARIANT DRIVERS IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Frank Dubois, Ofer Shapira, Noah Greenwald, Travis Zack, Jessica W Tsai, Ashot S Harutyunyan, Kiran Kumar, Claire Sinai, Hayley Malkin, Robert Jones, Patricia Ho, Ryan O’Rourke, Kyung S Kang, Nada Jabado, Mark W Kieran, Keith Ligon, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Driver single nucleotide variants (SNV) and somatic copy number aberrations (SCNA) of pediatric high-grade glioma (pHGGs), including Diffuse Midline Gliomas (DMGs) are characterized. However, structural variants (SVs) in pHGGs and the mechanisms through which they contribute to glioma formation have not been systematically analyzed genome-wide. METHODS Using SvABA for SVs as well as the latest pipelines for SCNAs and SNVs we analyzed whole-genome sequencing from 174 patients. This includes 60 previously unpublished samples, 43 of which are DMGs. Signature analysis allowed us to define pHGG groups with shared SV characteristics. Significantly recurring SV breakpoints and juxtapositions were identified with algorithms we recently developed and the findings were correlated with RNAseq and H3K27ac ChIPseq. RESULTS The SV characteristics in pHGG showed three groups defined by either complex, intermediate or simple signature activities. These associated with distinct combinations of known driver oncogenes. Our statistical analysis revealed recurring SVs in the topologically associating domains of MYCN, MYC, EGFR, PDGFRA &amp; MET. These correlated with increased mRNA expression and amplification of H3K27ac peaks. Complex recurring amplifications showed characteristics of extrachromosomal amplicons and were enriched in coding SVs splitting protein regulatory from effector domains. Integrative analysis of all SCNAs, SNVs &amp; SVs revealed patterns of characteristic combinations between potential drivers and signatures. This included two distinct groups of H3K27M DMGs with either complex or simple signatures and different combinations of associated variants. CONCLUSION Recurrent SVs associate with signatures shaped by an underlying process, which can lead to distinct mechanisms to activate the same oncogene.
TMOD-11. APPLICATION OF A NOVEL TRANSGENIC AND SYNGENEIC MOUSE MODELS OF HUMAN CLASSICAL GLIOBLASTOMA FOR DRUG SCREENING AND PRE-CLINICAL TRIALS
Authors: Olivia Singh, Mathew Voisin, Mira Li, Shirin Karimi, Kanwalpreet Walia, Hafsah Ali, Farshad Nassiri, Suganth Suppiah, Kenneth Aldape, Qingxia Wei, Gelareh Zadeh
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with 1 year median survival. The classical subtype of GBM occurs in about 10% of GBM cases and has the worst clinical outcome. The most frequent genetic alteration associated with classical GBM is amplification in the epidermal growth factor receptor (EGFR) and homozygous deletion in CDKN2A (Cyclin Dependent Kinase Inhibitor 2A). We generated a transgenic mouse harboring EGFRvIII, a constitutively active mutant of EGFR, knock in and homozygous deletion in p19 ARF, an alternative spliced form of the CDKN2a gene, restricted to glial cells. Transgenic mice develop tumors as early as 1 month and 73% of mice die by 6 months of age. MRIs reveal that mice develop infiltrative tumor cells throughout the brain and craniospinal junction with some infiltration within the leptomeninges that can result in hydrocephalus. Histology shows that 72% of tumors are high grade gliomas and some tumors demonstrate classical histological features of human GBM such as pseudopallisading necrosis, hyper vascularity and cellular atypia. We generated primary cell lines from transgenic mice that retained EGFRVIII expression and P19 ARF deletion and formed allografts in syngeneic mouse brains. Epigenetic modifications are considered a key mechanism in GBM development. We have therefore evaluated the efficacy of a panel of 42 compounds that target various epigenetic proteins including the readers, writers, and editors of several histone marks available from the Structural Genomics Consortium in primary cell lines derived from our mouse model. The primary cell lines were exposed to epigenetic drugs showing different responses to the same epigenetic modifiers. Key candidate drugs will further be tested pre-clinically in our syngeneic mouse model. In summary, we developed a novel transgenic and syngeneic mouse model for human classical GBM that can be used for drug screening and pre-clinical trials.
PATH-34. GENETIC PROFILING OF AGGRESSIVE MENINGIOMAS REVEAL DIVERSE SPECTRUM OF ACCOMPANYING ALTERATIONS BEYOND NF2 INACTIVATION
Authors: Jessica Schulte, Stephen Magill, Minh Nguyen, Nancy Ann Oberheim Bush, Javier Villanueva-Meyer, Philip Theodosopoulos, Michael McDermott, Nicholas Butowski, Andrew Bollen, Tarik Tihan, Julieann Lee, Melike Pekmezci, Arie Perry, David Raleigh, David Solomon
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Meningiomas are the most common primary central nervous system tumor in adults. The majority are clinically indolent and WHO grade I. However, 20-30% are WHO grade II and 1-3% are WHO grade III, which have shorter progression-free (PFS) and overall survival. A subset of grade I meningiomas also follow an aggressive course, requiring serial resection and/or radiotherapy, similar to high-grade meningiomas. The objective of this study was to characterize the genetic alterations in meningiomas with an aggressive clinical course. METHODS Targeted next-generation sequencing (NGS) of 40 aggressive meningiomas was performed using the UCSF500 cancer panel, which assesses ~500 cancer-related genes. Information on patient demographics, tumor histopathology, and treatment history was also collected. RESULTS Meningiomas analyzed included 15 (38%) WHO grade I, 11 (28%) WHO grade II, and 13 (33%) WHO grade III. At the time of genetic profiling, 71% of patients had received prior treatment (68% surgery, 48% fractionated radiotherapy, 23% radiosurgery). The most commonly altered gene was NF2, with 71% of tumors demonstrating biallelic inactivation. Other common alterations included biallelic CDKN2A/B deletion (15%) and TERT amplification or promoter mutation (13%). Other recurrent alterations involved SUFU (8%), and ARID1A, ATM, BAP1, DMD, KDM6A, and PTEN (each 5%). Genes which are commonly altered in indolent WHO grade I meningiomas, such as AKT1, KLF4, PIK3CA, SMO, and TRAF7, were intact in this cohort. CONCLUSIONS The additional genetic alterations beyond NF2 inactivation that drive aggressive meningiomas are diverse and include homozygous deletion of CDKN2A (negative regulator of cyclin-dependent kinases 4/6), inactivating mutations in SUFU (a negative regulator of Hedgehog signaling), homozygous deletion of PTEN (a negative regulator of mTOR signaling), and mutations/deletions in epigenetic regulatory factors (e.g. ARID1A, KDM6A). Clinical trials are needed to assess the efficacy of therapeutics targeting these specific pathways in patients with meningiomas refractory to conventional treatments.
MBCL-34. EFFICACY OF METHOTREXATE (MTX) ACCORDING TO MOLECULAR SUB-TYPE IN YOUNG CHILDREN WITH MEDULLOBLASTOMA (MB): A REPORT FROM CHILDREN’S ONCOLOGY GROUP PHASE III TRIAL ACNS0334
Authors: Claire Mazewski, Guolian Kang, Stewart Kellie, Jeffrey Gossett, Sarah Leary, Bryan Li, Paul Aridgides, Laura Hayes, Alyssa Reddy, Dennis Shaw, Peter Burger, Alexander Judkins, Jeffrey Russell Geyer, Maryam Fouladi, Annie Huang
Journal: Neuro-Oncology (2020)

Abstract ACNS0334, a Phase 3 trial, compared outcomes of children &amp;lt;36 months treated with intensive chemotherapy +/-high-dose methotrexate. Nodular-desmoplastic M0-stage MB were excluded. Treatment included 3 induction cycles (cyclophosphamide/etoposide/vincristine/cisplatin+/-mtx) and 3 consolidation cycles (carboplatin/thiotepa with stem cell rescue). Radiation (RT) was at physician discretion. Molecular sub-typing was by DNA-methylation. Log-rank testing was used to compare survival differences. Molecular sub-typing of 38 MB identified 11 Sonic Hedgehog (SHH), 25 Group 3 (GP3), 2 Group 4 (GP4). Five-year survival (OS) was 100% for 5 SHH with MTX and 4 SHH without MTX; 80% for 10 GP3 with MTX, 40% for 15 GP3 without MTX (p=0.025). Only 6/14 survivors received RT: 4 for residual following therapy (1 SHH and 3 GP3) and 2 GP3 salvaged after progression. Two GP3 deaths were associated with toxicity; all others were due to disease. Histology among SHH was nodular-desmoplastic (8) or classic (3); GP3 histology was classic (17) or anaplastic (7). Whole-exome sequencing identified 6 somatic PTCH1 and 1 germline SUFU alteration(s) among 9 SHH. Among GP3, no p53 mutations were found; copy-number analysis identified 5/25 with myc-amplification, 5/25 iso17q, 11/25 with 8 loss, 14/25 with loss of 11. Among GP3, 14/19 had no significant germline mutation. ACNS0334 achieved 100% survival for metastatic SHH. Benefit of methotrexate was observed in GP3 MB supporting incorporation of methotrexate into standard therapy for GP3. Upfront central pathology review and molecular sub-typing are critical for future clinical trial risk stratification of young children with embryonal tumors.
SWK-09. SELF-CARE OUTCOMES AND INTERVENTIONS FOR CHILDREN WHO HAVE HAD A BRAIN TUMOUR: EVIDENCE AND HYPOTHESES. WHAT SHOULD SELF-CARE INTERVENTIONS FOR CHILDREN WITH PAST OR PRESENT BRAIN TUMOUR BE?
Authors: Elizabeth Rowen, Niina Kolehmainen, Simon Bailey
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To determine the evidence with regards to self-care outcomes and interventions for children who have been treated for a brain tumour and identify when best to intervene. METHODS A scoping review of the literature with regards to self-care interventions, outcomes and mechanisms was undertaken. The information from these themes were populated onto a logic model alongside the clinical expertise of the team. The logic model was used to develop hypotheses to inform subsequent research; and identified areas for further patient and public involvement. RESULTS Of 27 papers found, 13 were deemed relevant. The literature suggested the diagnosis of a brain tumour can have a long-term negative impact on self-care outcomes whilst evidence with regards to interventions to promote self-care is scarce. The child’s physical and cognitive functions were identified as hypothesised factors influencing self-care, while health related quality of life and participation in other life domains were secondary consequences of self-care. The team expertise was further used to hypothesise that parent factors (emotions, identity, actions), the child’s emotional functions and personal factors as well as peer relationships and norms may influence children’s self-care. These factors were not covered in the existing literature. CONCLUSIONS Subsequent research will investigate the hypotheses developed to further specify factors that self-care interventions for children and young people with a brain tumour should target. This will involve specifying when, how and to whom interventions should be targeted.
NIMG-42. HOROS SOFTWARE FOR POSTOPERATIVE ANALYSIS OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Yasmeen Elsawaf, Stephanie Anetsberger, Ana Aguilar-Bonilla, Amy Smith, Samer Elbabaa
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Horos (LGPL 3.0) is a free, open source medical image viewer that has gained attention in the neurosurgical community because of the familiar OsiriX-based interface and its useful three-dimensional (3D) volumetric rendering capabilities. We present the use of Horos software as a postoperative tool for residual tumor volume analysis in children with high-grade gliomas. METHODS A retrospective study of 11 pediatric patients with histologically confirmed HGG underwent tumor resection (n=8) or biopsy (n=3) as definitive treatment from 6/2011 to 6/2019. Volumetric data and extent of resection were obtained via region of interest-based 3D analysis using Horos image-processing software. Age, initial tumor volume, extent of resection, and postoperative residual volume were assessed as predictors of overall survival or event free survival. TECHNIQUE Region of interest (ROI) segmentation was performed utilizing the “Closed Polygon Tool” to outline the tumor and the “Generate Missing ROIs” function to capture the entirety of the tumor within the MRI series. The “Computer Volume” function was used to render the 3D tumor volumes. The preoperative and postoperative tumor volumes were compared per patient to yield the percent extent of resection and residual volume. RESULTS The Horos software is a highly effective means of volumetric analysis for high-grade gliomas depicted in T1 and T2 MRI series. In our series, eight (73%) patients underwent tumor resection and three (27%) underwent biopsy. Patients who underwent resection were older than biopsy patients [12 (8-18) vs. 9 (8-21) years old]. Age, initial tumor volume, extent of resection, and postoperative residual volume were not significant predictors of overall survival or event free survival. CONCLUSION Horos software provides increased accuracy and confidence in determining post-operative volume and is useful in assessing the impact of residual volume on outcome after maximal safe resection in pediatric patients with high-grade gliomas.
Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study
Authors: Shahab Abtahi, Johanna H M Driessen, Andrea M Burden, Patrick C Souverein, Joop P van den Bergh, Tjeerd P van Staa, Annelies Boonen, Frank de Vries
Journal: Annals of the Rheumatic Diseases (2020)

Patients with rheumatoid arthritis (RA) commonly use oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), both associated with osteoporotic fractures. We investigated the association between concomitant use of oral GCs and PPIs and the risk of osteoporotic fractures among patients with RA.This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997 and 2017. Exposure to oral GCs and PPIs was stratified by the most recent prescription as current use (<6 months), recent use (7-12 months) and past use (>1 year); average daily and cumulative dose; and duration of use. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, statistically adjusted for lifestyle parameters, comorbidities and comedications.Among 12 351 patients with RA (mean age of 68 years, 69% women), 1411 osteoporotic fractures occurred. Concomitant current use of oral GCs and PPIs was associated with a 1.6-fold increased risk of osteoporotic fractures compared with non-use (adjusted HR: 1.60, 95% CI: 1.35 to 1.89). This was statistically different from a 1.2-fold increased osteoporotic fracture risk associated with oral GC or PPI use alone. Most individual fracture sites were significantly associated with concomitant use of oral GCs and PPIs. Among concomitant users, fracture risk did not increase with higher daily dose or duration of PPI use.There was an interaction in the risk of osteoporotic fractures with concomitant use of oral GCs and PPIs. Fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs.
Desensitization of the pulmonary adenylyl cyclase system: A cause of airway hyperresponsiveness in congestive heart failure?11Part of this work was awarded the 1996 Rudolf Thauer Prize of the German Cardiac Society.
Authors: Mathias M Borst, Wilke Beuthien, Carsten Schwencke, Paul LaRosée, Rainer Marquetant, Markus Haass, Wolfgang Kübler, Ruth H Strasser
Journal: Journal of the American College of Cardiology (1999)
PATH-30. CLINICAL AND GENETIC CHARACTERISTICS OF HISTONE H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMAS IN ADULTS
Authors: Jessica Schulte, Robin Buerki, Sarah Lapointe, Annette Molinaro, Yalan Zhang, Javier Villanueva-Meyer, Arie Perry, Joanna Phillips, Tarik Tihan, Andrew Bollen, Melike Pekmezci, Nicholas Butowski, Nancy Ann Oberheim Bush, Jennie Taylor, Susan Chang, Philip Theodosopoulos, Manish Aghi, Shawn Hervey-Jumper, Mitchel Berger, David Solomon, Jennifer Clarke
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND “Diffuse midline glioma, H3 K27M-mutant” is a new tumor entity established in the 2016 WHO Classification of Tumors of the CNS that comprises a set of diffuse gliomas arising in midline structures that is molecularly defined by a recurrent K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited. Given the more frequent origin in the thalamus or spinal cord in adults versus the brainstem in children, gliomas with this mutation may encompass a heterogeneous population of tumor subtypes that vary based on patient age, anatomic site of origin, and concurrent genetic alterations. METHODS The 60 patients included were 18 years or older at initial diagnosis, during the period of 2014-2019 at UCSF. Cases were identified using immunohistochemistry with a H3 K27M-mutant specific antibody and/or next-generation sequencing of histone 3 genes H3F3A, HIST1H3B and HIST1H3C. Targeted NGS was performed on tumors from 21 patients, utilizing an UCSF institutional panel or a variety of commercial sources. RESULTS Patients presented primarily in the 3rd decade of life, and 57% of tumors were located in the thalamus. Genomic profiling revealed p.K27M mutations exclusively in H3F3A and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric diffuse midline gliomas. Additionally, these adult H3 K27M-mutant diffuse midline gliomas are universally IDH-wildtype, and have frequent mutations in TP53, PPM1D, FGFR1, NF1, and ATRX. The overall survival of this adult cohort is longer than historical averages for both H3 K27M-mutant diffuse midline glioma in children and IDH-wildtype glioblastomas in adults. CONCLUSIONS Together, these findings indicate that H3 K27M-mutant diffuse midline glioma represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in children versus adults.
Response to: ‘Correspondence on ‘Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study’’ by De Santis<i>et al</i>
Authors: Sofia Ramiro, Rémy L M Mostard, Robert B M Landewé
Journal: Annals of the Rheumatic Diseases (2021)

We read with interest the letter from De Santis et al 1 on our COVID-19 High-intensity Immunosuppression in Cytokine storm syndrome (CHIC) study.2 We thank De Santis et al for sharing their word of caution on the widespread use of glucocorticoids that is indeed very relevant. We totally agree that (at least so far) it has only been demonstrated that patients with severe COVID-19 who need to be hospitalised benefit from treatment with systemic glucocorticoids, either in the form of methylprednisolone or dexamethasone.2 3 As emphasised by De Santis et al , no evidence has been …