tbuckley/cabot-search huggingface dataset:
MBRS-20. CSF-DERIVED CIRCULATING TUMOR DNA AS A BIOMARKER FOR DISEASE PROGRESSION AND TUMOR EVOLUTION IN MEDULLOBLASTOMA
Authors: Anthony Pak-Yin Liu, Rahul Kumar, Smith Kyle, Leena Paul, Murali Chintagumpala, Eric Bouffet, Michael J Fisher, Tim Hassall, Sri Gururangan, Jordan Hansford, Richard Cohn, David W Ellison, Richard J Gilbertson, Amar Gajjar, Giles W Robinson, Paul A Northcott
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Cell-free DNA (cfDNA) profiling has been shown to carry utility as a clinically relevant biomarker in a variety of cancers, but studies in pediatric brain tumors, including medulloblastoma, are scarce. We hereby evaluated the actionability of profiling cfDNA from cerebrospinal fluid (CSF) based on a multi-institutional cohort of children with medulloblastoma. METHODS 103 children aged ≥ 3 years with medulloblastoma harboring chromosomal aneuploidy enrolled on two prospective therapeutic trials were included. cfDNA was extracted from CSF obtained longitudinally, and profiled by low-coverage whole-genome sequencing (lcWGS) for annotating copy-number variants (CNVs). cfDNA-derived CNVs were compared against patient-matched primary tumor-derived CNVs and correlated with outcome. cfDNA profiles at diagnosis and relapse were compared to evaluate tumor evolution. RESULTS Tumor-derived somatic CNVs were detected in 72% of baseline cfDNA samples, with higher detection rate in samples from patients with metastatic disease than those without (90% versus 50%, chi-square p=0.001). Longitudinal profiling of cfDNA revealed correlation between CNV detectability and clinical course, with detection of tumor-derived CNVs in cfDNA samples predating radiographic progression for ≥ 3 months in 62% of relapsing patients. Presence of cfDNA-derived CNVs in CSF collected during chemotherapy and at the end of therapy was significantly associated with inferior PFS (log-rank p&amp;lt;0.0001 for both time-points). Comparison of CNV profiles from cfDNA at baseline and relapse revealed molecular divergence in a subset of patients. CONCLUSION These results carry major implications and supports the incorporation of cfDNA profiling in upcoming medulloblastoma protocols for more sensitive and accurate disease monitoring and personalization of treatment.
STEM-18. DEVELOPMENT OF A NOVEL GENE THERAPY APPROACH TARGETING GLIOBLASTOMA FOLLOWING AI-DIRECTED IDENTIFICATION OF A MASTER REGULATORY GENE NETWORK
Authors: Son Le, Bo Ma, Sergei Zolotukhin, Darin Falk, David Tran
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Profound heterogeneity has severely hampered therapeutic advancements in glioblastoma (GBM). Remarkably, GBM exhibits broad clinical and histopathologic overlaps suggesting the presence of a common regulatory state. The GBM state embodies restructuring of the master regulatory gene network (MRGN) forced by founding mutations and perpetuated in subclones of GBM stem-like cells (GSC). Successful targeting and altering of the MRGN promise to circumvent the heterogeneity. METHODS To decipher the common MRGN in GSC, we applied a robust AI suite, NETZEN, that integrates deep neural networks with gene network-based ranking to the reference GBM network generated using TCGA’s entire GBM RNAseq dataset and a dataset containing &amp;gt; 30 diverse GSC and paired GBM differentiated cell lines, 6 normal astrocyte and 3 normal neuronal precursor cell lines. To develop a gene therapy against the MRGN, we performed a screen of a rAAV capsid library using GBM patient-derived orthotopic xenografts (PDX) to identify capsid variants with specific tropism for GBM cells to deliver shRNA-based cassettes. RESULTS We discovered a putative MRGN in GSC, anchored by developmentally restricted master regulators (MR). To confirm its critical role, we deconstructed it using shRNA in a panel of PDX and uniformly observed attenuated tumor growth and mortality compared to controls (p &amp;lt; 0.05 in all lines). More notably, when normal astrocytes were forced to reconstruct the MRGN, transformation into GSC-like cells occurred, as measured by single-cell analysis, sphere formation in vitro, and most importantly, development of lethal infiltrating brain tumors in 15/15 mice. Finally, selected novel AAV capsids with 10-40-fold higher specificity for GBM cells were utilized in a shRNA-based AAV platform to target key MR in the validated MRGN. CONCLUSIONS The GBM state is established by a developmental subnetwork permitting a first-of-its-kind, heterogeneity-agnostic AAV-based treatment approach. This AI-directed R&amp;D program can be expanded to target other cancers.
TMOD-19. INDIVIDUAL SPECIFIC HUMAN GUT MICROBE COMMUNITIES INFLUENCE RESPONSE TO IMMUNOTHERAPY IN A HUMANIZED MICROBIOME MOUSE MODEL OF GLIOMA
Authors: Kory Dees, Hyunmin Koo, J Fraser Humphreys, Joseph Hakim, David Crossman, Michael Crowley, Louis Nabors, Etty Benveniste, Casey Morrow, Braden McFarland
Journal: Neuro-Oncology (2020)

Abstract Although immunotherapy works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has not demonstrated efficacy in GBM patients. Since recent studies have linked the gut microbial composition to the success with immunotherapy for other cancers, we utilized a novel humanized microbiome (HuM) model in order to study the response to immunotherapy in a pre-clinical mouse model of GBM. We used five healthy human donors for fecal transplantation of gnotobiotic mice since it is now recognized that microbe strain level differences render individual humans with a unique microbial community composition. After the transplanted microbiomes stabilized, the mice were bred to generate 5 independent humanized mouse lines (humanized microbiome HuM1-HuM5). Analysis of shotgun metagenomic sequencing data from fecal samples revealed a unique microbiome composition with significant differences in diversity and microbial composition among HuM1-HuM5 lines. We next analyzed the growth of intracranial glioma cells in the HuM lines. All HuM mouse lines were susceptible to GBM transplantation, and exhibited similar median survival ranging from 19-26 days. Interestingly, we found that HuM lines responded differently to the immune checkpoint inhibitor anti-PD-1. Specifically, we demonstrate that HuM1, HuM4, and HuM5 mice are non-responders to anti-PD-1 resulting in the death of the mice from the intracranial tumors, while HuM2 and HuM3 mice are responsive to anti-PD-1 and displayed significantly increased survival compared to isotype controls. Bray-Curtis cluster analysis of the 5 HuM gut microbial communities revealed that HuM2 and HuM3 were closely related. Detailed taxonomic comparison analysis at the top 5 across all HuM mouse lines revealed that Bacteroides cellulosilyticus was commonly found between HuM2 and HuM3 with high abundances. The results of our study establish the utility of humanized microbiome mice as avatars to delineate features of the host interaction with gut microbe communities needed for effective immunotherapy against GBM.
Abstract P388: Childhood Obstructive Sleep Apnea May Track Into Adolescence and Role of Weight Dynamics
Authors: Fan He, Julio Fernandez-mendoza, Edward O Bixler, Duanping Liao
Journal: Circulation (2020)

Introduction: Childhood and adolescent OSA share certain pathophysiological mechanisms. Thus, adolescent OSA may be in a continuum of childhood OSA. However, this hypothesis remains controversial. Hypotheses: Childhood OSA is associated with higher odds of adolescent OSA. Weight changes in this transitional period are associated with the development of OSA. Methods: We, firstly, conducted a meta-analyses to associate childhood and adolescent OSA based on literatures in which apnea hypopnea index (AHI) and/or OSA during both childhood and adolescence were reported. Major search engines were used to identify relevant reports. An AHI ≥ 1 was used as homologized definition of OSA at childhood and adolescence periods across all studies. From eligible studies, numbers of participants with none, remitted, incident, and persistent OSA from childhood to adolescence were abstracted. Crude relative risks (RRs) between childhood and adolescence OSA were computed by using Cochran-Mantel-Haenszel tests. A random-effects model, based on the DerSimonian and Laird method, was used to summarize the findings across studies. We, then, used data from the Penn State Child Cohort (PSCC) to analyze the association between weight changes from childhood to adolescent and incident/persistent OSA. Based on the changes of participants’ weight status (normal: BMI percentile &lt; 85 vs. overweight/obese: BMI percentile ≥ 85) during childhood and adolescence, 4 mutually exclusive groups were formed and compared. Logistic regressions were used to associate weight gain (normal to overweight/obese) and weight loss (overweight/obese to normal) during this development stage and incident/persistent OSA. Sensitivity analyses were performed by using an AHI ≥ 5 to define OSA. Results: Four cohort studies, which included a total of 1473 participants, were included in the meta-analyses. The mean age during childhood and adolescence examinations were 8.5-9.8 years and 13.7-20.2 years. The pooled remission rate of childhood OSA was 52.8% (31.6%, 74.1%), while the incidence of adolescent OSA was 31.6% (15.8%, 47.4%). After weighing and summarizing RRs from individual studies, the overall RR was 1.54 (1.14, 2.08). The association was stronger [RR: 2.51 (1.65, 3.82)] in the sensitivity analysis. Based on PSCC data, we found a significant association between weight gain from childhood to adolescence and higher odds of incident OSA [OR: 2.61 (1.01, 6.81)] and a non-significant trend between weight loss and lower odds of incident OSA [OR: 0.23 (0.05, 1.06)]. Conclusion: While a substantial proportion of childhood OSA remits in the transition to adolescence, children with OSA are more likely to have adolescent OSA than those without OSA in childhood. Weight gain and loss may contribute to the natural course of OSA during transition from childhood to adolescent, especially the onset of incident OSA.
RTID-03. A PHASE I CLINICAL TRIAL TO EVALUATE MTD OF PERAMPANEL AND MEMANTINE IN COMBINATION WITH STANDARD CHEMORADIOTHERAPY FOR THE TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED GBM –A STUDY DESIGN
Authors: Xiao-Tang Kong, Bruce Albala, Senxi Du, Maya Hrachova, Daniela Bota
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults with poor prognosis. Effective treatment is urgently needed. Recent studies demonstrated cross-talk between neuron and glioma through neuro-transmitter glutamate receptors (AMPA and NMDA receptors) promotes glioma invasion and progression in vitro and in vivo. Therefore, dual blocking AMPA and NMDA receptor therapy is a potential strategy to prevent and treat GBM progression, particularly given the fact that the two blockers act through different anti-glioma mechanism. OBJECTIVE/ HYPOTHESIS We hypothesize that adding Perampanel (an AMPA receptor blocker) and Memantine (a NMDA receptor antagonist) to standard temozolomide plus radiation therapy for the treatment of newly diagnosed GBM patients may be well tolerated and have a safe profile to prevent tumor progression, seizure recurrence or cognition impairment from radiation. STUDY DESIGN 3 + 3 DESIGN: Maximum Tolerated Dose (MTD) is dose level at which 0/3 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. MTD will not be more than FDA approved maximized doses for Perampanel (12 mg daily) and Memantine (20 mg bid) for the treatment of neurological diseases. Once the MTD is found, the patient will continue at MTD for the completion of concurrent chemoradiation therapy plus completion of 6 cycles of adjuvant temozolomide therapy. SUMMARY A Phase I trial to study the safety and toxicity of combined Perampanel and Memantine with standard chemo-radiation therapy to treat patients with newly diagnosed glioblastoma (GBM). To find Maximum Tolerated Dose (MTD) Levels of Perampanel and Memantine at concurrent chemoradiation therapy phase and adjuvant chemotherapy phase to prepare for future phase II or III trial.
PATH-14. GENETIC SUSCEPTIBILITY AND OUTCOMES OF PEDIATRIC, ADOLESCENT AND YOUNG ADULT IDH-MUTANT ASTROCYTOMAS
Authors: Miriam Bornhorst, Liana Nobre, Michal Zapotocky, Hayk Barseghyan, Jeremy Goecks, Daniel Boue, Uri Tabori, Cynthia Hawkins, Eric Bouffet, Tobey MacDonald, Matthew Schniederjan, Alberto Bronischer, Brent Orr, David Solomon, Sabine Mueller, Enrico Opocher, Alexander Vortmeyer, Asher Marks, Carl Koschmann, Denise Leung Leung, Rajen Mody, Eugene Hwang, Surajit Bhattacharya, Eric Vilain, Joyce Turner, Lindsay Kilburn, Brian Rood, Roger Packer, Javad Nazarian, Cheng-Ying Ho
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Previously thought to be rare, recent case series have shown that IDH mutations in young patients are more common than previously described. In this study, we analyzed IDH-mutant tumors to determine clinical significance of these mutations in children, adolescents and young adults. METHODS Through this multi-institution study (10 institutions), we collected 64 IDH1/2-mutant infiltrating astrocytoma specimens from 58 patients aged 4–26 (M:F, 0.4:0.6). Specimens included 46 low-grade (LGG) and 18 high-grade (HGG) astrocytomas. Tumor sequencing data (n=45), germline sequencing data (n=37) and outcome data (n=40) was analyzed. RESULTS Similar to adults, most sequenced tumors had a co-mutation in the TP53 gene, while ATRX mutations were less common and primarily seen in HGGs. Approximately 60% (n=21) of patients with germline data available had a mutation in a cancer predisposition gene. Mismatch repair (MMR) mutations were most common (n=12; MSH6 n=9), followed by TP53mutations (n=7). All patients with MMR gene mutations had HGGs and poor progression free (PFS=10% at 2 years, mean TTP=9 months) and overall (OS &amp;lt;30% at 2 years) survival. Despite an OS of 90% at 5 years, many LGG patients had tumor progression/recurrence requiring additional treatment (PFS= 80% at 2 yrs, 40% at 5 yrs, mean TTP=3.5 years). Four LGG tumors (2 with TP53+ATRXloss, 2 with TP53 loss+1p19q co-deletion) underwent malignant transformation. CONCLUSION IDH-mutant tumors in pediatric patients are strongly associated with cancer predisposition and increased risk for progression/recurrence or malignant transformation. Routine screening for IDH1/2 mutations in children with grade 2–4 astrocytomas could greatly impact patient management.
QOL-31. USE OF PATIENT-REPORTED OUTCOMES TO IDENTIFY YOUTH AT RISK FOR IMPAIRED OVERALL HEALTH
Authors: Lisa Ingerski, Rebecca Williamson Lewis, Ann Mertens, Tobey MacDonald
Journal: Neuro-Oncology (2020)

Abstract Pediatric brain tumor survivors often experience persistent and clinically significant late-effects following treatment. Critical to understanding morbidity is utilization of patient-reported outcomes (PROs). The current study evaluated PROs of individuals previously diagnosed with a pediatric brain tumor and identified risk factors for less optimal overall health. Participants included 127 youth 10.59±4.81 (M±SD) years old at survey completion and 4.45±3.82 years from diagnosis of a brain tumor (34.6% Pilocytic Astrocytoma, 9.4% Medulloblastoma, 9.4% Ependymoma, 7.9% Craniopharyngioma, 38.6% Other). Outcomes were assessed via Patient-Reported Outcomes Measurement Information System (PROMIS) parent-proxy measures. Overall health was assessed via PROMIS Global Health (i.e., a measure of general, physical, mental, and social health). Univariate and logistic regression analyses examined potential demographic, medical, and psychosocial factors (e.g., age, race, diagnosis, treatment) related to poor global health. Initial descriptive analyses suggested that most youth experienced anxiety symptoms (T-score M±SD=50.71±11.54), depressive symptoms (47.96±10.34), cognitive functioning (46.52±9.10), and fatigue (55.14±10.62) similar to their peers. However, 31.0% of youth experienced impaired global health (T-score&amp;lt;40). After adjusting for other potential covariates, the final model suggested that youth with significant anxiety (OR=6.20, CI=1.56–24.65), youth with significant fatigue (OR=3.96, CI=1.26–12.41), and youth who did not undergo a gross total resection (OR=0.25, CI=0.07–0.96) were at risk for impaired global health. Identifying those at-risk for impaired health is essential to reducing survivor morbidity and optimizing overall quality of life following treatment. Current data suggest potentially modifiable factors that may improve long-term outcomes for survivors of pediatric brain tumors.
The Pretreatment Gut Microbiome Is Associated With Lack of Response to Methotrexate in New‐Onset Rheumatoid Arthritis
Authors: Alejandro Artacho, Sandrine Isaac, Renuka Nayak, Alejandra Flor‐Duro, Margaret Alexander, Imhoi Koo, Julia Manasson, Philip B. Smith, Pamela Rosenthal, Yamen Homsi, Percio Gulko, Javier Pons, Leonor Puchades‐Carrasco, Peter Izmirly, Andrew Patterson, Steven B. Abramson, Antonio Pineda‐Lucena, Peter J. Turnbaugh, Carles Ubeda, Jose U. Scher
Journal: Arthritis & Rheumatology (2020)

Although oral methotrexate (MTX) remains the anchor drug for rheumatoid arthritis (RA), up to 50% of patients do not achieve a clinically adequate outcome. In addition, there is a lack of prognostic tools for treatment response prior to drug initiation. This study was undertaken to investigate whether interindividual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new-onset RA.
EPCT-09. CLR 131 IN PATIENTS WITH RELAPSED OR REFRACTORY PEDIATRIC MALIGNANCIES
Authors: Diane Puccetti, Mario Otto, Daniel Morgenstern, Kenneth DeSantes, Steven Cho, Lance Hall, Kate Oliver, Jarrod Longcor
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND CLR 131 is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers by malignant cells. CLR 131 selectively delivers radiation to malignant tumor cells, thus minimizing radiation exposure to normal tissues. OBJECTIVE CLR 131 is being examined in a Phase 1 trial, CLOVER-2 (NCT03478462), to determine the safety, tolerability, and initial efficacy of CLR 131 in children and adolescents with relapsed/refractory malignancies. METHODS Eligibility criteria include children with relapsed or refractory solid tumors or malignant brain tumors for which there are no standard treatment options with curative potential. Subjects must be between ages 2 and 21 with no limit to the number of prior therapies. CLR 131 is administered as a single infusion in escalating doses beginning at 15 mCi/m2. Adverse events (AEs) are graded by NCI-CTCAE v5. RESULTS As of 10Jan2020, four subjects with brain tumors have received CLR 131; one at 15 mCi/m2 and three at 30 mCi/m2. Diagnoses included DIPG (2), glioblastoma (1), and medulloblastoma (1). Median age is 13 years (range 10–15) and patients received a median of two prior therapies (range 1 to 8). There were no treatment emergent AEs at the 15 mCi/m2 dose level attributed to CLR 131 by the investigator. Assessment of the 30 mCi/m2 dose level is ongoing. CONCLUSIONS CLR 131 is a unique, first in class targeted radiotherapeutic for pediatric malignancies. Preliminary data shows an acceptable and expected safety profile in this patient population. Dose escalation to determine the highest tolerated dose is ongoing.
DIPG-05. HISTONE H3.3 K27M IMPAIRS SER31 PHOSPHORYLATION, RESULTING IN CHROMOSOMAL INSTABILITY, LOSS OF CELL CYCLE CHECKPOINT CONTROL, AND TUMOR FORMATION
Authors: Charles Day, Alyssa Langfald, Florina Grigore, Sela Fadness, Leslie Sepaniac, Jason Stumpff, Kevin Vaughan, James Robinson, Edward Hinchcliffe
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline gliomas with the H3.3 K27M mutation are lethal brain tumors in children. H3 K27M causes global loss of Lys27 triple methylation (Lys27me3), inducing epigenetic reprograming. Here we show that H3.3 K27M also causes decreased H3.3 Ser31 phosphorylation on mitotic chromosomes. We show that H3.3 K27M DIPG cells have reduced pericentromeric phospho-Ser31 and increased rates of chromosome missegregation compared to normal, diploid human cells. CRISPR-editing K27M to M27K restored phospho-Ser31 to WT levels and dramatically decreased the rate of chromosome missegregation. We confirm that Chk1 is the H3.3 Ser31 kinase: K27M mutant H3.3 protein exhibits ~60% reduced Chk1 phosphorylation of Ser31 in vitro. Chk1 knockdown completely abolishes phospho-Ser31 in cells and these have increased rates of chromosome missegregation. In normal, diploid cells, expression of K27M or an S31A non-phosphorylatable mutant increased chromosome missegregation; this is suppressed by expressing a phosphomimetic double mutant (K27M/S31E) that restores phospho-Ser31. WT cells arrest following chromosome missegregation. However, cells expressing H3.3 K27M or S31A fail to arrest - despite having WT p53. Finally, we expressed H3F3AS31A and PDGFb in an RCAS/TVA mouse model of DIPG and ~80% developed diffuse high-grade brain tumors and show significantly decreased survival. Our results suggest that loss of phospho-Ser31 alone is oncogenic because H3.3 S31A-expressing cells are WT for K27me3. Our results demonstrate that H3.3 K27M inhibits Ser31 phosphorylation both in vitro and in vivo, leading to both chromosome missegregation and loss of subsequent G1 arrest – thus creating diffuse midline gliomas with both dynamic, complex karyotypes and epigenetic reprogramming.
Determinants of Staphylococcus aureus carriage in the developing infant nasal microbiome
Authors: Emma K. Accorsi, Eric A. Franzosa, Tiffany Hsu, Regina Joice Cordy, Ayala Maayan-Metzger, Hanaa Jaber, Aylana Reiss-Mandel, Madeleine Kline, Casey DuLong, Marc Lipsitch, Gili Regev-Yochay, Curtis Huttenhower
Journal: Genome biology (2020)

Abstract Background Staphylococcus aureus is a leading cause of healthcare- and community-associated infections and can be difficult to treat due to antimicrobial resistance. About 30% of individuals carry S. aureus asymptomatically in their nares, a risk factor for later infection, and interactions with other species in the nasal microbiome likely modulate its carriage. It is thus important to identify ecological or functional genetic elements within the maternal or infant nasal microbiomes that influence S. aureus acquisition and retention in early life. Results We recruited 36 mother-infant pairs and profiled a subset of monthly longitudinal nasal samples from the first year after birth using shotgun metagenomic sequencing. The infant nasal microbiome is highly variable, particularly within the first 2 months. It is weakly influenced by maternal nasal microbiome composition, but primarily shaped by developmental and external factors, such as daycare. Infants display distinctive patterns of S. aureus carriage, positively associated with Acinetobacter species, Streptococcus parasanguinis , Streptococcus salivarius , and Veillonella species and inversely associated with maternal Dolosigranulum pigrum . Furthermore, we identify a gene family, likely acting as a taxonomic marker for an unclassified species, that is significantly anti-correlated with S. aureus in infants and mothers. In gene content-based strain profiling, infant S. aureus strains are more similar to maternal strains. Conclusions This improved understanding of S. aureus colonization is an important first step toward the development of novel, ecological therapies for controlling S. aureus carriage.
Immunological changes in peripheral blood following nasal allergen challenge in subjects with allergic rhinitis pre‐ and post‐peptide immunotherapy: An open‐label clinical study
Authors: Young Woong Kim, Elena Tonti, Pascal Hickey, Anne K. Ellis, Helen Neighbour, Mark Larché, Scott J. Tebbutt
Journal: Allergy (2020)

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