bluuebunny/crossref_metadata_2025 huggingface dataset:
HGG-36. ONC201 TARGETING IN DIPG
Authors: Abuarqoub Alqassem , McAnulty Tatiana , Amiel Eyal , Stafford James
Published: June 2021

Diffuse intrinsic pontine glioma (DIPG) is a group of predominantly pediatric brain tumors with an average age of diagnosis of 6–7 years old, and a poor prognosis (median survival of ~1 year). Given the location of DIPG in the brainstem, surgical approaches are limited. Furthermore, the tumors have limited responsivity to traditional chemotherapy or radiotherapy, ergo new therapeutic options are needed. Recently, the drug ONC201 has emerged as a potential therapeutic option with outcomes sometimes surpassing progression-free and expected survival outcomes. However, the selectivity of its effect and mechanism in DIPG is still unclear. Here, we pursue a better understanding of ONC201 and its mechanism of action directly in DIPG patient-derived cell lines. First, we demonstrate that a range of DIPG cell lines are highly sensitive to ONC201 and compare this sensitivity to other patient-derived brain tumor and normal controls. Next, we directly show that the mitochondrial protease, ClpP is the primary target of ONC201 in DIPG. Given recent literature implicating the activation of ClpP by ONC201 and dysregulation of the metabolome in other tumors, we are currently examining these downstream effects in DIPG. Ultimately we hope to elucidate whether ClpP targeting can be used to better diagnose and improve therapeutic options in DIPG
HGG-43. INTERROGATING THE ROLE OF PEA3 ONCOGENIC TRANSCRIPTION FACTORS IN PEDIATRIC HIGH-GRADE K27M GLIOMAS
Authors: Park Hannah , Kobritz Naomi , Mehdikhani Shaunt , Breunig; Joshua
Published: June 2021

Pediatric high-grade gliomas (HGGs) are an aggressive form of pediatric brain tumors which pose a grim five-year survival with little advancement in therapeutic efficacy, often requiring a multimodal therapeutic combination of chemotherapy, resection, and radiation. We have previously shown that proper function of ETS transcription factors is necessary for gliomagenesis in Ras/MAPK-driven pediatric gliomas. It is our hypothesis that ETS transcription factors are necessary for tumor initiation in HGGs by promoting the necessary glial cell fates in glioma. Further, we hypothesize that functional inhibition of ETS proteins following tumor formation will improve survival and outcome in HGG. Functional inhibition of ETS proteins using a competitive dominant-negative mutant was shown to completely rescue neural stem cell depletion, tumor formation and tumor-free survival in two rodent models of HGGs. Mechanistically, we show evidence that Pea3 factors may induce glial-cell fate by promoting Olig2 expression and activation of glial transcriptional programs. Indeed, transcriptomic analysis of ETS-perturbed HGG tumors revealed that Sox9 and Olig2 transcription factor networks were dependent on proper ETS function. Further, we show evidence that Etv5 can directly interact with promoter regions of glial fate master regulators in human primary glioma cell lines. To empirically determine the effect of Pea3 proteins on tumorigenesis, we have created a novel methodology for inducible gain- and loss-of-function genetic interrogation of these factors in vivo. Our survival results and combined single-cell RNA-sequencing of individual groups show that inhibition of the Pea3 family leads to a marked increase in survival in K27M glioma by regulating key features of glioblasts. All in all, our group provides evidence that the ETS family of transcription factors is necessary for glial specification of tumor cells and induce pro-glial transcriptional programs by activating OPC- and astrocyte-specific genes in K27M-driven tumors.
HGG-44. REVEALING VULNERABILITIES IN DIPG THROUGH ONC201
Authors: Stafford James , Abuarqoub Alqassem , Mcanulty Tatiana , Possemato Richard , Amiel Eyal , Snuderl Matija
Published: June 2021

Emerging evidence from clinical and preclinical studies suggests that the imipridone ONC201 is well tolerated and may have some clinical impact in discrete diffuse intrinsic pontine glioma patients (DIPG). A primary goal of our work is to determine if DIPG are uniquely sensitive to ONC201 and if so, whether ONC201 itself can be used as a tool to illuminate novel vulnerabilities in DIPG. To accomplish this, we are utilizing a combination of patient-derived cell lines as well as mouse xenografts that dovetail with a variety of molecular, epigenetic and metabolomic tools. A central finding from our work is that ONC201 primarily activates the mitochondrial protease, ClpP in DIPG patient-derived cell lines, an effect consistent with recently described ONC201 mechanism of action in other tumors. We further demonstrate that activation of ClpP by ONC201 leads to a host of downstream effects in DIPG model systems including distinctive effects on the metabolome leading to direct alterations in the unique epigenetic signature of DIPG. By directly manipulating these metabolic and epigenetic factors we provide prospective mechanistic insight into how ONC201 as well as ClpP activity impacts DIPG growth and tumorigenicity. These preclinical research findings shed light on potential therapeutic vulnerabilities in DIPG as well as ways that these strategies may be combined to enhance their potential.
IMMU-02. CH14.18 IN THE TREATMENT OF HIGH-RISK NEUROBLASTOMA: A META-ANALYSIS
Authors: Abdel-Khaleq Sameerah , Alim Lina , Johnston Atholl , Adam Khloud
Published: June 2021

High-risk neuroblastoma (HRNB) is a rare malignancy that mainly affects young children. Long-term survival remains low despite aggressive, multimodal treatment regimens. The aim is to assess the effect of Ch14.18, a novel anti-GD2 antibody, on survival in HRNB. In this meta-analysis, Pubmed/MEDLINE, EMBASE, Cochrane CENTRAL and Clinicaltrials.gov bibliographic databases were searched from inception to 1st July 2018. Prospective or retrospective interventional clinical trials with at least two arms or observational cohort or case-control studies were eligible. Participants had to have HRNB. Ch14.18 was the intervention of choice. Any control, comparator treatments were accepted. Studies were appraised for inclusion by two independent reviewers. Data was extracted from published reports. Primary outcomes assessed were Event-Free Survival (EFS) and Overall Survival (OS) and presented as Weighted Mean EFS (%) ± Standard Error (SE) and Weighted Mean OS (%) ± Standard Error (SE), respectively. Combined effect size was elicited for EFS±SE and OS±SE. The search yielded 367 results of which 7 studies conducted on 1727 patients were eligible for inclusion. The weighted mean EFS±SE for Ch14.18 regimens (n=779) and control regimens (n=787) were 55.6±2.0% and 41.2±1.7%, respectively. The weighted mean OS±SE for Ch14.18 regimens (n=430) and control regimens (n=348) were 63.4±2.3% and 53.6±2.7%, respectively. Results of the meta analysis yielded statistical power >94%. The combined effect size of Ch14.18 regimens for EFS±SE was 0.2907±0.05 [95% CI: 0.19–0.39, p<0.001] and the combined effect size for OS±SE was 0.26±0.07 [95% CI: 0.11- 0.4, p<0.001]. Significant superior survival outcomes were achieved with the use of Ch14.18 in the treatment of HRNB. These findings support using Ch14.18 as an adjunct in maintenance therapy in high-risk neuroblastoma. This meta analysis is the first of its kind. Survival outcomes are to be interpreted with caution due to confounding bias.
IMMU-04. FIRST-IN-CHILDREN PHASE 1B STUDY USING THE IDO PATHWAY INHIBITOR INDOXIMOD IN COMBINATION WITH RADIATION AND CHEMOTHERAPY FOR CHILDREN WITH NEWLY DIAGNOSED DIPG (NCT02502708, NLG2105)
Authors: S. Johnson Theodore , Pacholczyk Rafal , Aguilera Dolly , Al-Basheer Ahmad , Bajaj Manish , Berrong Zuzana , Castellino Robert C , Eaton Bree R , Esiashvili Natia , Foreman Nicholas , Heger Ian M , Kennedy Eugene P , Martin William , Ring Eric , Sadek Ramses F , Smith Amy , Smith Chris , Vaizer Rachel , MacDonald Tobey J , Munn David H
Published: June 2021

Background

Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal brain tumor with no available cure. Indoximod blocks the IDO (indoleamine 2,3-dioxygenase) pathway, thereby reversing IDO-mediated immune suppression in the tumor microenvironment.

Methods

Patients aged 3 to 21 years with treatment-naive DIPG were eligible for this phase 1b dose-confirmation study of indoximod. The treatment regimen comprised continuous oral indoximod (38.4 mg/kg/day divided twice daily) with conformal photon radiation (54 Gy in 30 fractions), followed by cycles of indoximod with temozolomide (200 mg/m2/day, days 1–5 in 28-day cycles).

Results

Thirteen patients (median age 9 years, range 5 to 20 years) with DIPG were treated. Median OS was 14.5 months (follow-up ranged 4.8 to 29.3 months), 12-month OS was 61.5% (8/13), and 18-month OS was 30.8% (4/13), with 1 patient remaining in follow-up at the data cutoff. This compared favorably to expected median OS of approximately 10.8 months, 12-month OS of 45.3%, and 18-month OS of 16.2% taken from published historical data from the Pediatric Brain Tumor Consortium. Two patients showed near-complete responses lasting until relapsing after 7.6 months and 13.3 months of study therapy, respectively. Many patients had increased circulating non-classical monocytes (nc-Monos, CD16+, CD14neg, CD33+, HLA-DR+) within the first 3 treatment cycles, and elevation of this early pharmacodynamic marker was predictive of subsequent OS. Patients with nc-Monos >10% (n=7) had median OS of 19 months, whereas patients with nc-Monos below 10% (n=5) had median OS of 7 months (p=0.0047). No patients stopped therapy for toxicity. The most common indoximod-attributed adverse events were thrombocytopenia, neutropenia, nausea, vomiting, dizziness, and fatigue.

Conclusions

Adding indoximod immunotherapy to conventional radiation and chemotherapy for front-line treatment of pediatric patients with DIPG was well-tolerated. Improved outcomes were observed in patients having evidence of pharmacodynamic response. A follow-on phase 2 study is in progress (NCT04049669).
IMMU-08. MICROENVIRONMENT MODULATION BY TIM-3 BLOCKADE IMPROVES THE OUTCOME OF PRECLINICAL DIPG MODELS
Authors: Ausejo-Mauleon Iker , Labiano Sara , Laspidea Virginia , Garcia-Moure Marc , de la Nava Daniel , Puigdelloses Montserrat , Becher Oren J , Jiang Li , Filbin Mariella G , Pastor Fernando , Alonso Marta M
Published: June 2021

Diffuse Midline Gliomas (DMGs), encompassing Diffuse Intrinsic Pontine Gliomas (DIPGs), are the most aggressive pediatric brain tumors. Their meagre survival has not changed despite the combination of radiotherapy with targeted therapies emphasizing the urgent need for effective treatments. Recent research suggested that the DIPG tumor microenvironment is neither highly immunosuppressive nor inflammatory. These analyses showed the lack of infiltrating lymphocytes and the abundance of CD11b+ cells. TIM-3 (HAVCR2) is a member of the T-cell immunoglobulin and mucin domain protein family which is expressed on multiple immune cell types including T cells, Tregs, NK cells, monocytes, dendritic cells and microglia, where it potently regulates not only adaptive immunity but also innate immunity. Therefore, the central hypothesis of this study is that TIM-3 inhibitors could stimulate a cytotoxic immune effect and challenge several components in the tumor microenvironment including microglia, thereby providing a potential effective treatment for DMGs. In silico assessment of TIM-3 expression in a DIPG datasets showed a robust expression of this gene. Moreover, single-cell sequencing analyses of DIPG biopsies uncover its expression on tumor cells, especially in the OPCs compartment. In vivo efficacy studies showed that treatment with anti-TIM-3 antibody significantly increase the overall survival in two DIPG immunocompetent orthotopic animal models (doubling the median), lead to long-term survivors (50%) and showed immune memory. Analyses of CD45+ populations in the tumor microenvironment showed a significant increase in B, NK and CD8+ cells corresponding with a T-cell activate phenotype in treated-mice. The potential therapeutic involvement of NK cells was certified using nude mice and functional studies. Involvement of microglia in currently being analysed. In summary, these data underscore TIM-3 as a potential target DIPGs and uncover the potential involvement of NKs and other immune mechanisms in the efficacy of anti-TIM-3 therapy.
LGG-06. COMPREHENSIVE GENOMIC CHARACTERIZATION AND INTEGRATED CLINICAL ANALYSIS OF LOW-GRADE GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1
Authors: Fisher Michael , Jones David , Li Yimei , Guo Xiaofan , Sonawane Poonam , Waanders Angela , Phillips Joanna , Weiss William , Resnick Adam , Gosline Sara , Banerjee Jineta , Guinney Justin , Gnekow Astrid , Kandels Daniela , Foreman Nicholas , Korshunov Andrey , Ryzhova Marina , Massimi Luca , Gururangan Sri , Kieran Mark , Wang Zhihong , Fouladi Maryam , Sato Mariko , Øra Ingrid , Holm Stefan , Markham Stephen , Beck Pengbo , Jäger Natalie , Wittmann Andrea , Sommerkamp Alexander , Sahm Felix , Pfister Stefan , Gutmann David
Published: June 2021

Background

Low-grade gliomas (LGGs) arising in children with neurofibromatosis type 1 (NF1) are usually not biopsied. To identify secondary genetic alterations or molecular features that may contribute to pathogenesis and correlate with clinical behavior, we initiated a comprehensive molecular and clinical analysis of pediatric NF1-LGGs.

Methods

NF1-LGGs were analysed by whole-genome sequencing (31), targeted gene panel sequencing (9), RNAseq transcriptomal profiling (33) and genome-wide DNA methylation analysis (67). Clinical annotation was available for 48 subjects.

Results

Most LGGs harbored bi-allelic NF1 inactivation as the sole genetic abnormality, but 11% had additional alterations (FGFR1 mutation, n=3; PIK3CA mutation, n=2; homozygous 9p21 deletion, n=2; MYB:QKI fusion, n=1; SETD2 mutation, n=1; EGFR amplification, n=1). FGFR1 mutation conferred additional growth advantage in multiple complementary murine Nf1 models. 88% of NF1-LGGs resembled sporadic pilocytic astrocytoma (PA) by methylation, higher than that based on histology. Non-PA methylation patterns included low-grade glial/glioneuronal tumors, rosette-forming glioneuronal tumors, MYB/MYBL1-altered glioma, and high-grade astrocytoma with piloid features (2 tumors histologically diagnosed as LGG). In total, 18% of samples were classified as non-PA and/or harbored an additional non-NF1 mutation. Non-PA methylation class tumors were more likely to harbor an additional non-NF1 mutation (p=0.005). 7.7% of optic pathway hypothalamic gliomas (OPHGs) had other mutations or were not classified by methylation as PA, compared with 20.6% of NF1-LGGs arising elsewhere. There was no difference based on age for the presence of an additional non-NF1 mutation or non-PA methylation class.

Conclusions

Given the overall low occurrence of non-NF1 mutations or non-PA methylation class tumors in this series, routine clinical biopsy of typically-appearing NF1-LGG may not be indicated, particularly for children with OPHG. Biopsy should be considered for non-OPHG tumors refractory to conventional treatment. As additional agents are developed and treatment strategies evolve, the rationale for biopsy of NF1-LGG may become stronger.
LGG-11. BH3-MIMETICS TARGETING BCL-XL SELECTIVELY IMPACT THE SENESCENT COMPARTMENT OF PILOCYTIC ASTROCYTOMA
Authors: Selt Florian , Sigaud Romain , Sievers Philipp , Zaman Julia , Peterziel Heike , Tsai Jessica W , Guiho Romain , Martínez-Barbera Juan Pedro , Pusch Stefan , Schuhmann Martin U , El Damaty Ahmed , Bandopadhayay Pratiti , Pfister Stefan M , Oehme Ina , Sahm Felix , Jones David T W , Witt Olaf , Milde Till
Published: June 2021

Introduction

Pilocytic astrocytoma (PA) is the most common brain tumor in children. Activation of the mitogen-activated protein kinase (MAPK) pathway is a hallmark of PA. Complete remission in non-resectable tumors is infrequently observed with current therapeutic approaches. Most PA tumors cells are in oncogene-induced senescence (OIS), which may explain the benign growth behavior of PAs but also account for resistance to therapy. Therefore, treatment of PA with senolytic agents such as BH3-mimetics is a promising new approach.

Methods

Three patient-derived PA cell lines, DKFZ-BT66, DKFZ-BT308 (both KIAA1549:BRAF-fusion positive) and DKFZ-BT314 (BRAF V600E-mutation positive) were used. Depending on inducible expression or repression of SV40 large T antigen all models can reflect both states of PA, proliferation and OIS. Cells in both states were treated with different BH3-mimetics. Inhibition of metabolic activity was measured after 72 hours. Target expression was assessed by RT-qPCR and Western blot. On-target activity of BH3-mimetics was determined by immunoprecipitation (IP) of Bcl-xL/BAK.

Results

BH3-mimetics with strong binding affinity for Bcl-xL (Navitoclax, A-1131852, A-1155463) showed selectivity for senescent cells in 2/3 models (DKFZ-BT66 and DKFZ-BT314) and acted in nanomolar ranges. IC50s for Navitoclax (Cmax 6600nM in patients) were 40nM (OIS) vs. 200nM (proliferation) and 170nM (OIS) vs. 3700nM (proliferation) in DKFZ-BT66 and DKFZ-BT314, respectively. Target engagement was evident in the Bcl-xL/BAK-IP, and target expression of Bcl-xL was similar in all models studied. The relative resistance of senescent DKFZ-BT308 despite on-target activity is currently being investigated.

Conclusion

Senolytic treatment of PA with BH3-mimetics targeting Bcl-xL is a promising new strategy directly targeting the major senescent part of the tumor in clinically archivable concentrations. However, our data suggests that not all PAs may respond to treatment. The analysis of comparative gene expression analysis and BH3-profiling is ongoing to define predictive biomarkers.
LGG-17. CLINICAL OUTCOME OF PEDIATRIC LOW GRADE GLIOMA WITH POSITIVE BRAF-FUSION TREATED WITH MEK INHIBITOR
Authors: Dennis T L Ku , Liu Anthony P Y , Fu Eric , Luk Chung-Wing , Yau Jeffrey P W , Ling Siu-Cheung , Shing Matthew M K , Chan Godfrey C F
Published: June 2021

Background

Low grade glioma (LGG) is the most common central nervous system (CNS) tumor in children. Some are treated with surgery alone, while chemotherapy is given for unresectable tumor with clinical symptoms or progression. Conventional chemotherapy is effective but 30–40% patients may have reactivation of disease requiring re-treatment throughout lifetime. MEK inhibitor for BRAF-fusion positive LGG is a new treatment option for refractory cases.

Methods

Retrospective search in territory-wide pediatric oncology registry for children diagnosed with LGG from 2010–2020 in Hong Kong. To identify patients with molecular confirmed BRAF-fusion positive LGG and any treatment with MEK inhibitor.

Results

Twelve patients (N=12) were identified with BRAF-fusion positive LGG, male:female was 1:2, age 0.3–15.1yr (median 5.0yr) at presentation. The median follow up duration was 1.8yr. Five patients (42%) had surgical resection only. Seven patients (58%) were given chemotherapy with Carboplatin / Vincristine. Five out of seven (n=7) treated patients (71%) have partial response at their initial treatment. Two patients (29%) had progressive disease during treatment and switched to second-line chemotherapy, vinblastine however without improvement. Three patients required re-treatment as disease reactivation. Total five patients had refractory diseases were treated with MEK inhibitor, Trametinib including one diagnosed NF-1. All of them have adverse skin reaction and raised transaminase with one required dose reduction. They have been taking the MEK inhibitor for 0.1–3.3 yr with sustainable partial response.

Conclusion

Pediatric LGG has overall favourable prognosis. Some of them treated with surgery alone while conventional chemotherapy could also achieve satisfactory disease control. For refractory disease with BRAF-fusion positive, MEK inhibitor is a well tolerated treatment option showing sustainable partial response. However, prolonged medication and disturbing skin reaction are still a major concern for this group of patients. On-going clinical trials to compare conventional chemotherapy versus MEK inhibitor could give us more insight about the clinical benefit, patient selection and treatment duration.
OMIC-03. TRANSLATIONAL CONTROL IN MYC AND MYCN MEDULLOBLASTOMA
Authors: Schmidt Christin , Navickas Albertas , Zindy Frederique , Farmer Dana , Ruggero Davide , Goodarzi Hani , Roussel Martine F , Schwer Bjoern , Weiss William
Published: June 2021

Medulloblastoma has been extensively characterized at the genomic and transcriptional levels, but little is known about how alterations in translational control underlie tumor development. Myc and Mycn are often deregulated in medulloblastoma and play important roles in tumor initiation, maintenance and progression. Although both proteins have similar structures and are functionally redundant in hindbrain development, their amplification in cerebellar granule neural precursor cells leads to different medulloblastoma subtypes. In this project we are employing ribosome profiling on mouse medulloblastoma tumors generated from granule neural precursor cells with enforced expression of Myc or Mycn. Ribosome-protected mRNA sequencing allows us to quantitatively assess the specific transcripts regulated at the level of translation, identify translation regulatory sequences within the mammalian transcriptome, and understand genotype-to-phenotype processes. We discovered that Myc- and Mycn-driven tumors exhibit many more changes at the translational rather than at the transcriptional level. In particular, we found that Mycn-driven medulloblastoma upregulates the translation of Myc target genes, while mRNA levels of those genes show no difference between Myc- and Mycn-driven tumors. Furthermore, we find that the most significant translationally upregulated Myc target genes in the Mycn tumors are transcripts that encode ribosome biogenesis factors. We will further study the role of Myc and Mycn on translational regulation of the medulloblastoma transcriptome using our xenograft model of human iPSC-derived neuroepithelial stem cells overexpressing Myc or Mycn. Our goal is to understand the regulatory function of the translational landscape in Myc- and Mycn-driven medulloblastoma and to decipher the oncogenic signaling cascades leading to different medulloblastoma subtypes.
RARE-04. IMPACT OF LIVE, VIRTUAL EDUCATIONAL SYMPOSIA ON PEDIATRIC NEURO-ONCOLOGIST, NEURO-ONCOLOGIST, AND NEUROSURGEON CONFIDENCE, KNOWLEDGE, AND INTENTION TO EMPLOY TARGETED MEDICAL THERAPIES FOR THEIR PATIENTS WITH NEUROFIBROMATOSIS TYPE 1
Authors: Taylor Bryan , Weaver Rebecca , Gross Andrea , Korf Bruce , Blakeley Jaishri
Published: June 2021

Historical treatment options and management strategies for neurofibromatosis type 1 (NF1) have been limited, with a relative paucity of clinical studies and the traditional paradigm focused on an ineffectual, and possibly even harmful, trimodal combination of radiation, surgery, and surveillance. Fortunately, an emerging preponderance of trial data supporting the use of targeted medical therapies, including MEK inhibitors and multi-kinase TKIs, is expanding the stale treatment paradigm and broadening horizons for patients. Given the profound novelty of this paradigmatic shift in NF1 management, it is imperative that timely, adaptive, and evidence-based educational initiatives be developed and delivered to the interdisciplinary neuro-oncology treatment team in an effort to bridge both learning and practice gaps. With an appreciation of the intrinsically multi-system nature of NF1, which necessitates a longitudinal treatment approach encompassing the totality of the multidisciplinary team, CEC Oncology designed and tailored targeted NF1 educational activities to improve confidence, advance knowledge, and promote enhanced utilization of targeted medical therapies among pediatric neuro-oncologists, neuro-oncologists, and neurosurgeons who manage patients with NF1. We conducted two independent satellite symposia, one at the 2020 Society for Neuro-Oncology (SNO) Annual Meeting and another at the 2020 AANS/CNS Section on Pediatric Neurological Surgery (PNSS), and achieved robust educational outcomes across Moore’s Levels 1–5. There were notable statistical advancements in clinician confidence, knowledge, and intention to employ targeted medical therapies for NF1-related symptomatic, inoperable plexiform neurofibromas from pre-activity to post-activity assessment, and many of these improvements were retained at 6-week follow-up analysis. In conclusion, our outcomes data evidence the critical need for responsive educational activities in the NF1 treatment space, especially as trial data continue to galvanize evolution of this novel pharmacologic armamentarium. Such activities possess the capacity to improve clinician confidence, advance knowledge, and promote utilization of targeted medical therapies in NF1, thereby optimizing patient outcomes.
RARE-07. EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Perreault Sébastien , Doz François , Geoerger Birgit , Nysom Karsten , Øra Ingrid , Boni Valentina , Chisholm Julia , DuBois Steven G , Gerber Nicolas U , Goto Hiroaki , Grilley-Olson Juneko E , Hansford Jordan R , Kang Hyoung Jin , Capra Michael , Schulte Johannes H , Stefanowicz Joanna , Tahara Makoto , Ziegler David S , Norenberg Ricarda , Dima Laura , De La Cuesta Esther , Laetsch Theodore W , van Tilburg Cornelis M
Published: June 2021

Background

NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a highly selective TRK inhibitor approved to treat patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). We report updated data on pediatric patients with TRK fusion-positive primary CNS tumors.

Methods

Patients aged <18 years with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed.

Results

By July 2020, 26 pediatric patients with TRK fusion-positive CNS tumors were treated. Tumor histologic subtypes included high-grade glioma (n=13), low-grade glioma (n=7), glioneuronal tumor (n=2), neuroepithelial tumor (n=2), CNS neuroblastoma (n=1), and small round blue cell tumor (n=1). Median age was 7.0 years (range 1.3–16.7). The ORR was 38% (95% CI 20–59%): 3 complete responses, 7 partial responses (including 2 pending confirmation), 14 stable disease, and 2 progressive disease. The ORR in patients with high-grade glioma was 38% (95% CI 14–68%). Nineteen of 21 patients (90%) with measurable disease had tumor shrinkage. The 24-week disease control rate was 77% (95% CI 56–91%). Median duration of response (DoR), PFS and overall survival (OS) were not reached. The 12-month rates for DoR, PFS and OS were 75%, 65%, and 86%, respectively. Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events were reported for 15 patients (58%) and were Grade 3–4 in 3 patients (12%), with no discontinuations related to larotrectinib.

Conclusions

In pediatric patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated durable responses, high disease control rate, and good tolerability. These results support testing for NTRK gene fusions in pediatric patients with CNS tumors.
RARE-25. DISSECTING THE CONTEMPORARY EPIDEMIOLOGY OF PRIMARY AND SECONDARY BRAIN TUMORS IN INFANCY THROUGH CHILDHOOD
Authors: Lamba Nayan , Iorgulescu Bryan
Published: June 2021

Introduction

Herein we utilize national registry data to evaluate the epidemiology of primary and secondary pediatric brain tumors according to the WHO2016 classification.

Methods

Pediatric patients (age≤14) presenting between 2004–2017 with a brain tumor were identified by ICD-O-3 and brain metastasis (2010–2017) coding from the National Cancer Database (comprising >70% of newly-diagnosed cancers in the U.S.), and categorized by NICHD age stages: infant (<1yr; n=1,686), toddler (1-2yrs; n=1,732), early- (2-5yrs; n=6,712), middle- (6-11yrs; n=9,175), and late- (12-14yrs; n=5,042) childhood. Patients’ age, sex, race/ethnicity, and overall survival, and tumor location and size were evaluated by WHO2016 tumor type.

Results

24,347 pediatric brain tumor patients were identified. Overall, other astrocytic tumors (24% of females, 20% of males), diffuse astrocytic/oligodendroglial gliomas (23% of females, 21% of males – 64% of which were midline), embryonal (13% of females, 19% of males), and sellar region tumors (12% of females, 8% of males) predominated. Embryonal tumors prevailed in infancy (24%) and toddlerhood (24%), declining to 9% in late childhood; only 40% were female. Ependymal tumors peaked at 15% in toddlerhood (6% overall), whereas choroid plexus tumors peaked at 11% in infancy (1.9% overall). A minority of brain tumors were of neuronal & mixed neuronal-glial (6.1%), germ cell (3.8%), cranial nerve (3.2%), mesenchymal non-meningothelial (2.4%), meningioma (1.6%), pineal (1.1%), hematological/histiocytic (0.5%), and other glioma (0.2%) types. Brain metastases were rare (1.5% overall; from 4.0% in infancy to 0.8% in late childhood; and only 41% were female) – 61% came from adrenal neuroblastoma, 16% from sarcomas, and 6% from malignant rhabdoid tumors/extracranial AT/RT.

Conclusions

Pediatric brain metastases overwhelmingly originate from adrenal neuroblastoma. Although, overall, diffuse astrocytic/oligodendroglial, other astrocytic, embryonal, and sellar region tumors predominate among pediatric brain tumors, together they only comprise 70% of cases and their distribution varies substantially by patients’ age and sex.
EPCT-09. CNS LEVELS OF PANOBINOSTAT IN A NON-HUMAN PRIMATE MODEL: COMPARISON OF BLOOD AND CEREBROSPINAL FLUID PHARMACOKINETIC METHODS AND MALDI MSI
Authors: Warren Katherine , McCully Cynthia Lester , Garcia Rafael Cruz , Stopka Sylwia , Regan Michael , Aye Thet , Zimmerman Sara , Peer Cody , Kramer Josh , Breed Matthew , Figg W Douglas , Agar Nathalie
Published: June 2021

Adequate exposure (effective concentration over time) of a therapeutic agent at its site of action is essential for antitumor efficacy. Given constraints of repeat tissue sampling, non-human primate models predictive of pharmacokinetics in pediatric patients have been utilized to assess central nervous system (CNS) exposure. Assessment of cerebrospinal fluid (CSF) drug levels have been used to extrapolate CNS penetration but the relationship of CSF drug levels with tissue distribution is unclear. Utilizing microdialysis, we previously demonstrated geographic variability of drug permeability across the blood:brain barrier (BBB), but this technique is complex and has a high standard deviation. We, therefore, explored a novel technique, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI), to compare plasma, CSF, and tissue drug levels in a terminal non-human primate model. Panobinostat, an HDAC inhibitor in clinical trials for DIPG/DMG, was selected for study as it has previously demonstrated poor CNS tissue penetration but suggested modest clinical activity.

Methods

Panobinostat (p.o., dose 1.6 mg/kg) was administered to non-tumor bearing primates (n=2). One hour following administration (Tmax), blood and CSF were collected, the animal euthanized, brain and spinal cord extracted, and immediately frozen at -80. Panobinostat distribution was mapped on ex vivo sagittal tissue sections using MALDI MSI. To provide specificity and degree of permeability, anatomical structures were segmented for analysis to determine drug concentrations. Blood, CSF and tissue levels of panobinostat were measured via LC-MS/MS.

Results

Segmentation analysis revealed quantifiable panobinostat, particularly in the lateral ventricles and choroid plexus, and also in the subventricular zone and brainstem, although the overall panobinostat concentration was below the limit of quantitation in these areas.

Conclusions

Although not reflected in CSF PK, panobinostat is widely distributed in brain tissue. MALDI MSI allows regional assessment of panobinostat penetration and complements CSF pharmacokinetics.
EPCT-12. NATIONAL MULTICENTERED RETROSPECTIVE REVIEW OF DEMOGRAPHIC, TUMOUR AND INTRAOPERATIVE FEATURES ASSOCIATED WITH THE DEVELOPMENT OF CEREBELLAR MUTISM AFTER PEDIATRIC POSTERIOR FOSSA TUMOUR RESECTION
Authors: Kameda-Smith Michelle , Elliott Cameron , Moore Hannna , Sader Nicholas , Tso Michael , Alsuwaihel Mosaab , Dakson Ayoub , Ajani Olufemi , Yarascavitch Blake , Fleming Adam , Mehta Vivek , Farrokhyar Forough , Yikilmaz Ali , Stein Nina , Singh Sheila
Published: June 2021

Background

Cerebellar mutism (CM) is a condition characterized by a significant lack or loss of speech in children following posterior fossa (PF) surgery. The biological origin of CM remains largely unclear and remains the subject of ongoing debate. Despite multidisciplinary rehabilitative interventions, the outcome is less favorable than initially described. Given the treatment refractory nature of CM, central to its management is prevention.

Methods

A national multi-centered retrospective review of all the children undergoing posterior fossa resection at 4 Canadian academic pediatric institutions was undertaken. Patient, tumour, surgical features suggested to be associated with the post-operative development of CM were reviewed to identify pre-operative and intra-operative factors that may predict post-operative CM occurrence.

Results

258 pediatric patients were identified after posterior fossa lesion resection. Mean age at surgery was 6.74 years (SD 4.60) and 42.2% were female. Frozen section was available in 90.3% of cases. The majority of final tumour histology was medulloblastoma (35.7%), pilocytic astrocytoma (32.6%), ependymoma (17.1%) and exophytic glioma (1.2%). Intra-operative impression of adherence to the floor of the 4th ventricle was negative in 47.7%, positive in 36.8% of cases. The extent of resection assessed intraoperatively as gross total resection was 69.8% of cases. Intra-operative abrupt changes in blood pressure and/or heart rate was identified in 19.4% and 17.8% of cases. CM was experienced in 19.5% of patients (N=50), with the majority of cases identified by post-operative day 7. The clinical resolution of CM as mainly assessed by a neurosurgeon (86%) and was complete, significantly resolved, slight improvement, no improvement or deterioration in 56.0%, 8.0%, 20.0%, 14.0%, 2.0% respectively.

Conclusion

As a devastating surgical complication, identifying and understanding the biological origin of CM is the first step to complication avoidance. Maximal safe resection irrespective of intra-operative pathology remains the goal to avoid the devastating complication of CM.
EPCT-22 SAFETY AND EFFICACY OF INTRAVENTRICULAR IMMUNOVIROTHERAPY WITH ONCOLYTIC HSV-1 G207 FOR TREATMENT OF LEPTOMENINGEAL DISEASE
Authors: Kang Kyung-Don , Bernstock Joshua , Mott Bryan , Nan Li , Li Rong , Totsch Stacie , Gary Sam , Ghajar-Rahimi Gelare , Etminan Tina , Eisemann Tanja , Wechsler-Reya Robert , Beierle Elizabeth , Gillespie George , Markert James , Friedman Gregory
Published: June 2021

Leptomeningeal metastatic disease (LMD) occurs in 30–50% of newly diagnosed and recurrent pediatric malignant cerebellar tumors and 20–45% of malignant supratentorial tumors. Radiation and chemotherapy often cause substantial long-term neurotoxicity and outcomes remain poor for patients with LMD. At recurrence, LMD is generally minimally responsive to conventional therapies. Immunovirotherapy with engineered oncolytic HSV-1 G207 has emerged as a promising treatment for children with high-grade brain tumors. G207 infects and kills tumor cells while sparing normal cells and stimulates a robust anti-tumor immune response. Intratumoral G207 inoculation demonstrated safety and preliminary efficacy in a pediatric Phase 1 trial in recurrent/progressive high-grade glioma (NCT02457845), and a Phase 2 trial (NCT04482933) is forthcoming. Additionally, a Phase 1 trial of intratumoral G207 in recurrent/progressive malignant pediatric cerebellar tumors is ongoing (NCT03911388). While intratumoral inoculation delivers G207 directly to a primary tumor, it requires neurosurgical procedures thereby limiting repeat doses. Thus, we sought to establish the safety and efficacy of intraventricular G207. Utilizing an immunocompetent, HSV-sensitive murine strain, we determined that a standard 1x107 plaque-forming units (PFU) dose of G207 resulted in damage to the ependymal lining. However, interferon induction with an intraventricular low-dose (1x104 PFU) of G207 or polyinosinic-polycytidylic acid (poly I:C), a toll-like receptor 3 agonist, three days prior to standard treatment dose protected the ependymal lining. This approach enabled safe delivery of multiple subsequent doses. Importantly, with these protective measures, G207 significantly prolonged survival in pediatric patient-derived xenograft models and an immunocompetent murine LMD model of group 3 medulloblastoma, the most aggressive and fatal subtype. Collectively, these data indicate that toxicity from intraventricular G207 can be safely mitigated prior to a therapeutic dose, and that intraventricular G207 effectively targets group 3 medulloblastoma including LMD. These findings provide support for clinical translation of intraventricular G207.
Cotton Textiles and the Industrial Revolution in a Global Context
Authors: Riello Giorgio
Published: June 2021

In recent decades, economic historians have revisited the Industrial Revolution in a global context. Their interpretations rely mostly on comparative methods. This article shows instead that there is a profound and significant relationship between industrialization and global exchange, and that consumption of cotton textiles was central to such a relationship. Yet, historians should not consider global trade in the context of separate world regions. The history of cotton textiles reveals the extent to which the worldwide integration of different spaces of commerce and consumption, most especially those of the Atlantic and the Indian oceans, brought advantages to European traders and manufacturers. Taking this view, the article argues that the demand and consumption of textiles were important in determining the scale as well as the shape and specialisms of European textile production. This was not only the demand generated by European consumers — as supported by much of the European ‘consumer revolution’ literature — but also the demand of a wider group of users in the Atlantic region. The reshaping of trade and consumption in turn had important consequences for the production of cotton textiles both in India and in Europe.
Quantitative Proteome and PTMome Analysis of Arabidopsis thaliana Root Responses to Persistent Osmotic and Salinity Stress
Authors: Rodriguez Maria C , Mehta Devang , Tan Maryalle , Uhrig Richard G
Published: June 2021

Abiotic stresses such as drought result in large annual economic losses around the world. As sessile organisms, plants cannot escape the environmental stresses they encounter but instead must adapt to survive. Studies investigating plant responses to osmotic and/or salt stress have largely focused on short-term systemic responses, leaving our understanding of intermediate to longer-term adaptation (24 h to d) lacking. In addition to protein abundance and phosphorylation changes, evidence suggests reversible lysine acetylation may also be important for abiotic stress responses. Therefore, to characterize the protein-level effects of osmotic and salt stress, we undertook a label-free proteomic analysis of Arabidopsis thaliana roots exposed to 300 mM mannitol and 150 mM NaCl for 24 h. We assessed protein phosphorylation, lysine acetylation and changes in protein abundance, detecting significant changes in 245, 35 and 107 total proteins, respectively. Comparison with available transcriptome data indicates that transcriptome- and proteome-level changes occur in parallel, while post-translational modifications (PTMs) do not. Further, we find significant changes in PTMs, and protein abundance involve different proteins from the same networks, indicating a multifaceted regulatory approach to prolonged osmotic and salt stress. In particular, we find extensive protein-level changes involving sulfur metabolism under both osmotic and salt conditions as well as changes in protein kinases and transcription factors that may represent new targets for drought stress signaling. Collectively, we find that protein-level changes continue to occur in plant roots 24 h from the onset of osmotic and salt stress and that these changes differ across multiple proteome levels.
Pectin Modification in Seed Coat Mucilage by In Vivo Expression of Rhamnogalacturonan-I- and Homogalacturonan-Degrading Enzymes
Authors: McGee Robert , Dean Gillian H , Wu Di , Zhang Yuelin , Mansfield Shawn D , Haughn George W
Published: June 2021

The cell wall is essential for plant survival. Determining the relationship between cell wall structure and function using mutant analysis or overexpressing cell wall–modifying enzymes has been challenging due to the complexity of the cell wall and the appearance of secondary, compensatory effects when individual polymers are modified. In addition, viability of the plants can be severely impacted by wall modification. A useful model system for studying structure–function relationships among extracellular matrix components is the seed coat epidermal cells of Arabidopsis thaliana. These cells synthesize relatively simple, easily accessible, pectin-rich mucilage that is not essential for plant viability. In this study, we expressed enzymes predicted to modify polysaccharide components of mucilage in the apoplast of seed coat epidermal cells and explored their impacts on mucilage. The seed coat epidermal-specific promoter TESTA ABUNDANT2 (TBA2) was used to drive expression of these enzymes to avoid adverse effects in other parts of the plant. Mature transgenic seeds expressing Rhamnogalacturonate lyase A (RglA) or Rhamnogalacturonate lyase B (RglB) that degrade the pectin rhamnogalacturonan-I (RG-I), a major component of mucilage, had greatly reduced mucilage capsules surrounding the seeds and concomitant decreases in the monosaccharides that comprise the RG-I backbone. Degradation of the minor mucilage component homogalacturonan (HG) using the HG-degrading enzymes Pectin lyase A (PLA) or ARABIDOPSIS DEHISCENCE ZONE POLYGALACTURONASE2 (ADPG2) resulted in developing seed coat epidermal cells with disrupted cell–cell adhesion and signs of early cell death. These results demonstrate the feasibility of manipulating the seed coat epidermal cell extracellular matrix using a targeted genetic engineering approach.
Effects of ad libitum food intake, insufficient sleep and weekend recovery sleep on energy balance
Authors: Depner Christopher M , Melanson Edward L , Eckel Robert H , Higgins Janine A , Bergman Bryan C , Perreault Leigh , Knauer Oliver A , Birks Brian R , Wright Kenneth P
Published: June 2021

Study Objectives

Insufficient sleep is believed to promote positive energy balance (EB) and weight gain. Increasing weekend sleep duration to “recover” from weekday sleep loss is common, yet little is known regarding how weekend recovery sleep influences EB. We conducted a randomized controlled trial to assess how: (1) 2 days and 8 days of insufficient sleep and (2) ad libitum weekend recovery sleep impact EB (energy intake [EI] – energy expenditure [EE]).

Methods

Following ten baseline days with 9 h per night sleep opportunities, participants completed one of three 10-day experimental protocols with ad libitum EI: control (9 h sleep opportunities; n = 8; 23 ± 5 years [mean ± SD]); sleep restriction (SR; 5 h sleep opportunities; n = 14; 25 ± 5 years); sleep restriction with weekend recovery sleep (SR + WR; 5 days insufficient sleep, 2 days ad libitum weekend recovery sleep, 3 days recurrent insufficient sleep; n = 14; 27 ± 4 years).

Results

Twenty-four hour EB increased (p < 0.001; main effect) by an average of 797.7 ± 96.7 (±SEM) kcal during the 10-day experimental protocol versus baseline with no significant differences between groups. Percent change from baseline in 24 h-EE was higher (p < 0.05) on day 2 of insufficient sleep (SR and SR + WR groups; 10 ± 1%) versus adequate sleep (control group; 4 ± 3%).

Conclusions

In this between-group study, the effects of adequate sleep and insufficient sleep, with or without or weekend recovery sleep, on 24 h-EB were similar. Examining EB and body weight changes using within-subject cross-over designs and “free-living” conditions outside the laboratory (e.g. sleep extension) are needed to advance our understanding of the links between insufficient sleep, weekend recovery sleep and weight-gain.
A Model Template Approach for Rapid Evaluation and Application of Physiologically Based Pharmacokinetic Models for Use in Human Health Risk Assessments: A Case Study on Per- and Polyfluoroalkyl Substances
Authors: Bernstein Amanda S , Kapraun Dustin F , Schlosser Paul M
Published: June 2021

Physiologically based pharmacokinetic (PBPK) models are commonly used in risk assessments to perform inter- and intraspecies extrapolations as well as to extrapolate between different dosing scenarios; however, they must first undergo quality assurance review, which can be a time-consuming process, especially when model code is not readily available. We developed and implemented (using R and MCSim) a PBPK model template capable of replicating published model results for several chemical-specific PBPK models. This model template allows for faster quality assurance review because the general model equations only need to be reviewed once, and application to a specific chemical then only requires reviewing input parameters. The model template can implement PBPK models with oral and intravenous exposure routes, varying numbers of tissue compartments, renal reabsorption, and multiple elimination pathways, including fecal, urinary, and biliary. Using the model template, we reproduced published model simulation results for perfluorohexanesulfonic acid, perfluorononanoic acid, perfluorodecanoic acid, perfluorooctanoate, and perflouorooctane sulfonate. We also show that the template can be a useful tool for identifying potential model errors. Thus, the model template allows for faster evaluation and review of published PBPK models and provides a proof of concept for using this approach with broader classes of chemical-specific PBPK models.
Update on cardiovascular risk in nonalcoholic fatty liver disease
Authors: Johnston Michael P. , Patel Janisha , Byrne Christopher D.
Published: June 2021

Purpose of review

To summarize recent evidence demonstrating increased cardiovascular disease (CVD) risk, and how CVD risk may be reduced, in patients with nonalcoholic fatty liver disease (NAFLD).

Recent findings

NAFLD is a multisystem disease, defined by a spectrum of liver fat-associated conditions extending from simple steatosis, to inflammation, fibrosis and cirrhosis. NAFLD not only increases the risk of liver morbidity and mortality but also increases the risk of CVD morbidity and mortality and is associated with recognized CVD risk factors such as hypertension, atherogenic dyslipidaemia, type 2 diabetes mellitus and chronic kidney disease. Evidence suggests that the liver fibrosis stage may be a strong CVD risk factor. Lifestyle measures (e.g. weight loss and increased physical activity) are effective in improving CVD risk factors. Hypoglycaemic agents, such as the peroxisome proliferator-activated receptor gamma agonist pioglitazone and the glucagon-like peptide-1 receptor agonist liraglutide, reduce cardiovascular risk and may improve liver histology. Statin and antihypertensive treatments are well tolerated and currently it is unclear whether novel antifibrotic drugs will reduce CVD risk.

Assessment and treatment of increased cardiovascular risk is important in patients with NAFLD. If not contra-indicated, pioglitazone or a glucagon-like peptide 1 agonist should be considered and may benefit both CVD risk and early liver disease.