tbuckley/cabot-search huggingface dataset:
Antenatal corticosteroid administration and early school age child development: A regression discontinuity study in British Columbia, Canada
Authors: Jennifer A. Hutcheon, Sam Harper, Jessica Liauw, M. Amanda Skoll, Myriam Srour, Erin C. Strumpf
Journal: PLoS Medicine (2020)

Background There are growing concerns that antenatal corticosteroid administration may harm children’s neurodevelopment. We investigated the safety of antenatal corticosteroid administration practices for children’s overall developmental health (skills and behaviors) at early school age. Methods and findings We linked population health and education databases from British Columbia (BC), Canada to identify a cohort of births admitted to hospital between 31 weeks, 0 days gestation (31+0 weeks), and 36+6 weeks, 2000 to 2013, with routine early school age child development testing. We used a regression discontinuity design to compare outcomes of infants admitted just before and just after the clinical threshold for corticosteroid administration of 34+0 weeks. We estimated the median difference in the overall Early Development Instrument (EDI) score and EDI subdomain scores, as well as risk differences (RDs) for special needs designation and developmental vulnerability (&lt;10th percentile on 2 or more subdomains). The cohort included 5,562 births admitted between 31+0 and 36+6 weeks, with a median EDI score of 40/50. We found no evidence that antenatal corticosteroid administration practices were linked with altered child development at early school age: median EDI score difference of −0.5 [95% CI: −2.2 to 1.7] ( p = 0.65), RD per 100 births for special needs designation −0.5 [−4.2 to 3.1] ( p = 0.96) and for developmental vulnerability of 3.9 [95% CI:−2.2 to 10.0] ( p = 0.24). A limitation of our study is that the regression discontinuity design estimates the effect of antenatal corticosteroid administration at the gestational age of the discontinuity, 34 + 0 weeks, so our results may become less generalisable as gestational age moves further away from this point. Conclusions Our study did not find that that antenatal corticosteroid administration practices were associated with child development at early school age. Our findings may be useful for supporting clinical counseling about antenatal corticosteroids administration at late preterm gestation, when the balance of harms and benefits is less clear.
SURG-29. CLINICAL FACTORS ASSOCIATED WITH RECURRENCE IN ATYPICAL MENINGIOMA: RETROSPECTIVE ANALYSIS OF 99 PATIENTS IN TWO INSTITUTES
Authors: Kyung Soo Sung, Young Jin Song, Young Zoon Kim
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE The objectives of this study were to examine the local control (LC) rate of atypical meningioma after surgical resection with or without adjuvant treatment, to identify risk factors for the recurrence of atypical meningioma, and to compare our results to known factors from the literature. METHODS Clinical and radiological records of patients with atypical meningiomas diagnosed at two institutes from January 2000 to December 2018 were reviewed retrospectively. Histopathological features were also reviewed using formalin-fixed paraffin embedded samples from pathological archives. RESULTS Of the 99 atypical meningiomas eligible for analysis, 36 (36.4%) recurred during the follow-up period (mean 83.3 months, range 12–232 months). The rate of 3-year LC and 5-year LC was 80.8% and 74.7% respectively. The mean time-to-recurrence was 49.4 months (range 12–150 months). Multivariate analysis using Cox proportional-hazard regression model showed that the extent of resection (Hazard ratio [HR] 4.761, p=0.013), Ki67 index (HR 8.541, p=0.004), mitotic index (HR 3.275, p=0.044), tumor size (HR 3.228, p=0.041), and radiotherapy (HR 3.816, p=0.029) were independently associated with 3-year LC. These factors was also statistically associated with recurrence-free survival. In terms of radiotherapy after surgical resection, the recurrence was not prevented by immediate radiotherapy because of the strong effect of proliferative index on recurrence. Three cases of malignant transformation to WHO grade III meningioma were histopathologically confirmed after repeated surgery. Two out of these three patients succumbed to malignant transformation. The mean Ki67 proliferative index increased for recurrent cases in 18 patients (58.1%) from 7.55% (range 4-16) to 11.81% (range 5-24). CONCLUSION The present study suggests that the extent of resection, proliferative index (according to Ki67 expression) and mitotic index, tumor size, and radiotherapy are associated with recurrence of atypical meningiomas. However, our results should be further validated through prospective and randomized clinical trials.
TAMI-24. BEHAVIOR OF GLIOBLASTOMA STEM-LIKE CELLS WITH KNOWN IDH1 STATUS IN CEREBRAL ORGANOIDS
Authors: Sanjay Singh, Maxime Munyeshyaka, Joy Gumin, Jing Yang, Daniel Ledbetter, Anwar Hossain, Brittany Parker Kerrigan, Frederick Lang
Journal: Neuro-Oncology (2020)

Abstract Glioblastomas (GBM) exhibit high proliferative index, areas of necrosis, high vascularization, and are highly invasive to normal brain tissues. The most common and lethal form of GBMs are primary GBMs, with no prior clinical history. Whereas, secondary GBMs arise from low-grade gliomas and are associated with IDH1 mutation. Pre-clinical studies of GBM largely depend on patient-derived GBM stem-like cells (GSCs) in vitro and in vivo as orthotopic xenografts. Cerebral organoids (COs) derived from induced pluripotent stem cells can serve as allogenic in vitro model systems to study interactions between normal brain and GSCs. COs have been shown to harbor neural stem cells and their differentiated progenies as well as microglia within distinct niches. Here, we co-cultured 45 day-old COs and MDA-GSCs lines representing mesenchymal sub-group (M-MDA-GSC), classical sub-group (C-MDA-GSC), and IDH1 mutant (IDH1R132H-MDA-GSC). MDA-GSCs stably express fluorescent proteins and is used to track GSCs within COs. These GSC bearing COs were fixed, embedded, sectioned, immuno-stained, and imaged by confocal microscope. There was a positive correlation between GSC numbers in allografted niche and invasion into COs as measured from the edge of organoid, M-MDA-GSC (R2=0.99; 0.89μm/cell), C-MDA-GSC (R2=0.92; 0.66μm/cell), and IDH1R132H-MDA-GSC (R2=0.89; 0.5μm/cell). Additionally, M-MDA-GSCs had significantly high percentage of Ki67+ve invasive cells (24%) in comparison to C-MDA-GSCs (5.1%; p=0.0057). As a measure of interaction of MDA-GSC with normal cells, we assessed proximity of IBA1+ve microglia in GSC niche within organoids and show that M-MDA-GSC and IDH1R132H-MDA-GSC highly co-localized with IBA1+ve microglia on day12 of co-culture. In conclusion, our cerebral organoid-based allograft study shows that mesenchymal GSCs (M-MDA-GSC) are most invasive whereas IDH1 mutant GSCs (IDH1R132H-MDA-GSC) are least invasive. C-MDA-GSCs are least proliferative while invading into normal COs. Uniqueness of CO based allograft system is highlighted by observed similarity between M-MDA-GSC and IDH1R132H-MDA-GSC for their potential to attract IBA1+ve microglia.
NIMG-45. DEEP LEARNING-BASED PERITUMORAL MICROSTRUCTURE MAPPING IN GLIOBLASTOMAS USING FREE WATER VOLUME FRACTION
Authors: Zahra Riahi Samani, Drew Parker, Jacob Antony Alappatt, Steven Brem, Ragini Verma
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Characterization of the peritumoral microenvironment is a widely researched, but as yet unsolved problem. Determining the tissue microstructure differences between tumor types, arising from differences in infiltration, edema, and disease driven changes in cellularity is important to be able to guide treatment options. Diffusion tensor imaging with characterization of extracellular free water provides unique information of the tissue microstructure. The goal of this work is to leverage this information by applying deep learning on free water maps and create a microstructure map of the peritumoral area, to aid in targeted resection, radiotherapy and treatment management in the form of a crucial supplemental radiomic feature, replacing all other diffusion derived measures. METHOD We leveraged the widely different peritumoral microenvironments of GBMs and Metastatic tumors to create the microstructure maps. Tumor and peritumoral regions were automatically delineated in 143 patients with brain tumors (89 glioblastomas and 54 metastasis, ages 19-87 years, 77 females), and free water maps were computed in the peritumoral regions using their DTI data. We trained a Convolutional Neural Network (CNN) on 32x32 mm patches in the peritumoral area from GBMs and Mets, labeled as non-enhancing tumor (low free-water) and edema (high free-water), respectively. An independent test set was used and the CNN associated a voxel-wise probability to their peritumoral region to produce microstructure maps of GBMs and Mets which were then statistically compared. RESULT For comparison, a t-test was used showing significant group difference in the microstructure map between Mets and GBMs (p&amp;lt; 0.05). CONCLUSION The voxel-wise microstructure map is able to capture the cellularity differences in the peritumoral region, based on DTI-based characterization of the tissue microstructure. CLINICAL IMPORTANCE The microstructure map provides a novel insight into the peritumoral microenvironment using a measure that can be derived from clinically feasible DTI data, replacing pre-existing DTI measures.
Convalescent plasma-mediated resolution of COVID-19 in a patient with humoral immunodeficiency
Authors: Kazuhito Honjo, Ronnie M. Russell, Ran Li, Weimin Liu, Regina Stoltz, Edlue M. Tabengwa, Yutao Hua, Lynn Prichard, Ashton N. Kornbrust, Sarah Sterrett, Marisa B. Marques, Jose L. Lima, Chris M. Lough, Todd P. McCarty, Thomas J. Ketas, Theodora Hatziioannou, Paul D. Bieniasz, David T. Redden, John P. Moore, Paul A. Goepfert, Sonya L. Heath, Beatrice H. Hahn, Randall S. Davis
Journal: Cell Reports Medicine (2020)

Convalescent plasma (CP) is widely used to treat COVID-19, but without formal evidence of efficacy. Here, we report the beneficial effects of CP in a severely ill COVID-19 patient with prolonged pneumonia and advanced chronic lymphocytic leukemia (CLL), who was unable to generate an antiviral antibody response of her own. On day 33 after becoming symptomatic, the patient received CP containing high-titer (ID50 > 5,000) neutralizing antibodies (NAbs), defervesced, and improved clinically within 48 h and was discharged on day 37. Hence, when present in sufficient quantities, NAbs to SARS-CoV-2 have clinical benefit even if administered relatively late in the disease course. However, analysis of additional CP units revealed widely varying NAb titers, with many recipients exhibiting endogenous NAb responses far exceeding those of the administered units. To obtain the full therapeutic benefits of CP immunotherapy, it will thus be important to determine the neutralizing activity in both CP units and transfusion candidates.
LGG-33. ISOMORPHIC DIFFUSE GLIOMA HAS RECURRENT GENE FUSIONS OF <i>MYBL1</i> OR <i>MYB</i> AND CAN BE DISTINGUISHED FROM OTHER <i>MYB/MYBL1</i> ALTERED GLIOMAS BASED ON A DISTINCT MORPHOLOGY AND DNA METHYLATION PROFILE
Authors: Annika K Wefers, Damian Stichel, Daniel Schrimpf, Felix Sahm, Andreas von Deimling, Ingmar Blumcke, David T W Jones, David Capper
Journal: Neuro-Oncology (2020)

Abstract Isomorphic diffuse glioma (IDG) was first described in 2004 as an epilepsy-associated supratentorial diffuse glioma with low cellularity, low proliferation and very monomorphic tumour cells. Most patients had seizures since childhood but were operated on as adults. To study the position of these lesions among brain tumours we histologically, molecularly and clinically analysed 26 histologically typical IDGs. Tumour cells were GFAP-positive, MAP2-, OLIG2- and CD34-negative and the nuclear ATRX-expression was retained. Proliferation was very low. Sequencing of 24 cases revealed an IDH-wildtype status. Cluster analyses of DNA methylation data showed that IDG has a DNA methylation profile distinct from those of different glial/glio-neuronal brain tumours and normal hemispheric tissue. About half of IDGs had copy number alterations of MYBL1 or MYB (13/25) and half of the cases analysed by RNA-sequencing had gene fusions of MYBL1 or MYB with various gene partners (11/22), often associated with an increased RNA-expression of the respective MYB-family gene. Integrating all data available, 77% of IDGs had either MYBL1 (54%) or MYB (23%) alterations. All patients had a good outcome and most were seizure-free after surgery. In summary, we show that isomorphic diffuse glioma is a distinct benign tumour in the family of MYB/MYBL1-altered gliomas. DNA methylation analysis is very helpful for their identification. More recent analyses of a large cohort of MYB/MYBL1-altered brain tumours suggest the presence of a third methylation group that primarily contains paediatric cases and seems to be distinct from IDG and angiocentric gliomas. Further histological, molecular and clinical analyses are ongoing.
IMMU-30. UPREGULATED T CELL AND INTERFERON-Γ-RELATED GENE EXPRESSION IS ASSOCIATED WITH INCREASED SURVIVAL IN RECURRENT PEDIATRIC HIGH-GRADE GLIOMA
Authors: Tom Davidson, Willy Hugo, Anthony Wang, Jiyoon Kim, Gang Li, Robert Prins
Journal: Neuro-Oncology (2020)

Abstract Recurrent pediatric high-grade glioma (pHGG) is the leading cause of cancer-related mortality in children. Immunotherapy is a successful treatment approach for a growing number of cancers and is being investigated as a treatment strategy for pHGG. Immunotherapy has shown the most benefit in tumors with increased infiltrating T cells at baseline. Our recently published results revealed that neoadjuvant checkpoint inhibition in recurrent adult glioblastoma was associated with upregulation of a T cell and interferon-γ-related gene expression signature (Tcell-IFNγGES) and was correlated with a significantly extended overall survival (OS). In this study, we examined the immune landscape in recurrent pHGG and the association of Tcell-IFNγGES in the tumor with survival. We analyzed tumor RNAseq data collected at time of recurrence from a historical cohort of 42 pHGG patients from the Children’s Brain Tumor Tissue Consortium. We found a significant transcriptional enrichment of Tcell-IFNγGES in 54% of the tumors. The survival of patients with high Tcell-IFNγGES was observed to be significantly higher than patients with low Tcell-IFNγGES, (log-rank p=0.05). The 3-year OS for patients with low versus high Tcell-IFNγGE was 28.5% (95%, CI:13.7%-59.5%) compared to 50.2% (95%, CI:33.1%-76.1%). When patients were stratified by age, gender and race, low Tcell-IFNγGES was found to be a poor OS prognostic factor (hazard ratio=2.4 (1.14–5.14), p=0.02). This indicates a strong relationship of decreased Tcell-IFNγGES and increased risk of death. Future investigations are necessary to validate these findings, and to explore the value of Tcell-IFNγGES as a predictive biomarker for response to immunotherapy in pHGG.
HGG-54. HISTOLOGICAL AND MOLECULAR CHARACTERIZATION OF HIGH-GRADE BRAIN TUMORS SECONDARY TO TOTAL BODY IRRADIATION FOR HEMATOLOGICAL MALIGNANCIES
Authors: Evelina Miele, Daria Pagliara, Lucia Pedace, Francesca Diomedi Camassei, Antonella Cacchione, Giovanna Stefania Colafati, Andrea Carai, Franco Locatelli, Angela Mastronuzzi
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Hematopoietic stem cell transplantation (HSCT) is increasingly used in the treatment of acute leukemias (AL), non-Hodgkin lymphomas and other primary malignancies. However, a growing number of neoplasms secondary to HSCT are reported. The combination of total body irradiation (TBI) and high dose chemotherapy (HD-CT) as conditioning regimen is considered a risk factor. We present four children who survived AL, treated with HSCT and conditioning regimens including TBI/HD-CT. These patients developed a high-grade-brain tumor. We analyzed histological and molecular characteristics of neoplasms. METHODS Histologically, tumors were assessed for: presence of mitosis, necrosis and vascular proliferation; expression of ki67; expression of neuronal and glial markers, p53 and therapeutic targets. We analyzed the DNA methylation profile (DMP) of all tumors using IlluminaEPICarrays and compared it to the brain tumor classifier which allowed to generate the CNVs. RESULTS Morphologically two cases were defined as anaplastic astrocytoma, two cases as glioblastoma. Based on the DMP, all cases were found to belong to the methylation class “glioblastoma, IDH wildtype, subclass midline”, hypermutants, with gain of chromosome 1q and loss of 1p. Two cases showed PDGFRA amplification. All patients were treated with Temozolomide combination therapy +/- Bevacizumab and radiation therapy. At progression three patients were treated with checkpoint inhibitors. CONCLUSIONS The improvement of the precision medicine is fundamental in the therapeutic decision of brain tumors and even more in neoplasms secondary to antiblastic treatments. DMP and CNV have proven to be useful tools to complement the histological characterization of the reported cases.
LINC-03. MOLECULAR CLASSIFICATION OF PAEDIATRIC MEDULLOBLASTOMA FROM FOUR TERTIARY CENTRES IN MALAYSIA: DIAGNOSTIC DILEMMA WITH CONVENTIONAL METHODS
Authors: Revathi Rajagopal, Vida Jawin, Ay Jiuan Teng, Oy Leng Wong, Kein Seong Mun, Hakimah Mahsin, Nor Haizura Abd Rani, Kogilavani Gunasagaran, Seoh Leng Yeoh, Gek Bee Ong, Hany Ariffin, David Jones, Nicholas G Gottardo
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To determine the prognostic significance of the four molecular subgroups of medulloblastoma (MB) among children in Malaysia. METHODS We assembled MB samples of children &amp;lt; 18 years between January 1999 and July 2017 in University Malaya Medical Centre, Penang General Hospital, Sarawak General Hospital and Sabah Woman and Children’s Hospital. MB was sub-grouped using 850k DNA methylation profiling. RESULTS Fifty-one tumour samples were retrieved. Histopathological subtypes were classic (n=12), MB extensive nodularity/desmoplastic (n=9) and 30 MB results without subtypes. Thirteen patients were M1-M4. Fourteen patients were stratified as standard-risk (SR,27.4%), 22 as high-risk (HR,43.2%) and 15 as high-risk children ≤ 3 years old (iHR,29.4%). Molecular subgrouping revealed 16 Group4, 11 SHH, 10 Group3 and 4 Wnt. In 8 patients, DNA methylation profiling identified a diagnosis other than MB and in 2 samples the DNA was inadequate. For patients &amp;gt;3 years old, the 5-year event-free survival (EFS) was 35.7%±13% in HR and 39.7%±20% in SR. The 5-year overall survival (OS) in these two groups was 43.4%±14% and 41.7±30% respectively. iHR had 5-year EFS and OS of 48.0%±16% and 60.0%±16% respectively. WNT tumours had the best 5y-OS of 66.7±22% of the cohort, albeit significantly lower than other reports, followed by SHH (56.8±17%), Group4 (44.3±17.6%) and Group3 (41.7±18%). Treatment abandonment rate was 20%. CONCLUSION The discrepancy in the histological diagnoses highlights the importance of DNA methylation profiling technique for accurate diagnosis. We observed poor OS across all the subgroups, in part due to treatment abandonment.
CTIM-26. PATIENT-SPECIFIC DENDRITIC CELL VACCINE (DC-ATA) PULSED WITH ANTIGENS FROM SELF-RENEWING AUTOLOGOUS TUMOR CELLS IN THE TREATMENT OF NEWLY-DIAGNOSED GLIOBLASTOMA: A PHASE II TRIAL
Authors: Daniela Bota, David Piccioni, R LaRocca, Christopher Duma, Santosh Kesari, Jose Carrillo, Robert T O’Donnell, Robert Aiken, Frank Hsu, Xiao-Tang Kong, Candace Hsieh, Chris Langford, Krystal Carta, Adrienne Wang, James Langford, Thomas Taylor, Gabriel Nistor, Robert Dillman
Journal: Neuro-Oncology (2020)

Abstract GBM standard treatment is associated with poor survival. Adjunctive therapy with patient-specific vaccines may improve outcomes by enhancing anti-GBM immune responses. A multi-institutional phase II clinical trial was designed with a primary objective of 75% survival 15 months after intent-to-treat enrollment. IL-4 and GM-CSF were used to generate dendritic cells (DC) from monocytes. DC were incubated with autologous tumor antigens (ATA) from the lysate of cultured GBM cells to produce each patient-specific DC-ATA vaccine. Each dose was admixed with 500 mcg GM-CSF at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Enrollment has been completed in April 2020 (n=60). Three patients withdrew from the study prior to starting treatment leaving 57 patients for whom data is available. So far 57 patients have received 344 doses; 27 have completed all 8 doses, 11 received fewer than 8 doses at the time they discontinued treatment, 19 are currently in treatment. No patient has discontinued treatment because of toxicity. 9 pt had died and the preliminary 12 months overall survival is 74%. In a preliminary serologic analysis 12 of 16 patients (75%) had an increase in markers associated with Th1/NK, Th2/immunoglobulins, and Th2 hypersensitivity (eotaxins, IgE and IL17F) by week-3; 9 of 15 (60%) had a decrease in angiogenesis factors, growth factors, and tumor markers by week-8. Immunologic data for all 55 patients who received at least two injections will be available November 2020. This patient-specific DC-ATA immunotherapy approach is feasible, is associated with changes in serologic markers, and may be increasing intratumor inflammation that may be associated with on-target toxicity and efficacy. A interim survival analysis will be conducted in mid-October 2020, 15 months after the 28th patient was enrolled; results will be available November 2020 [Clinicaltrials.gov NCT03400917].
SURG-17. CLINICAL CHARACTERISTICS AND OUTCOMES OF EPILEPSY-RELATED BRAIN TUMOR IN CHILDREN
Authors: Kenichi Usami, Keita Terashima, Yuichi Abe, Chikako Kiyotani, Hideki Ogiwara
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Epilepsy is one of the earliest symptoms in pediatric brain tumor. Gross total resection (GTR) of the tumor does not necessarily achieve seizure free, therefore it is controversial whether surrounding epileptic foci should be resected at the initial surgery. The aims of this study are to report clinical characteristics and outcome of pediatric epilepsy-related brain tumor (ERBT) and to discuss treatment strategy. METHODS Subjects were children less than 18 years old who underwent surgery for ERBT. Patients in whom epilepsy had been controlled before surgery were excluded. Data were collected from medical record and retrospectively reviewed. RESULTS Twenty-one children (8 boys and 13 girls) were analyzed in this study. The mean age at surgery was 6.8 years. Tumor was astrocytic tumor in 10, gangliogioma in 4 and dysembryoplastic neuroepithelial tumor in 3. Intracranial subdural electrodes were placed prior to tumor resection in 5 cases. GTR was achieved in 14 (67%). Seizure free was achieved in 15 (71.4%). GTR was significantly associated with seizure free (p=0.002). CONCLUSION In most of ERBT, seizure free can be achieved by lesionectomy alone. However, the resection of surrounding epileptic foci is required in some cases. Detailed examinations to detect the epileptic foci should be performed in ERBT, particularly in case of drug-resistant intractable epilepsy.