bluuebunny/crossref_metadata_2025 huggingface dataset:
BIOM-10. EXAMINATION OF GROWTH DIFFERENTIATION FACTOR 15 (GDF15) EXPRESSION AS A POTENTIAL PROGNOSTIC BIOMARKER IN PEDIATRIC BRAIN TUMORS
Authors: Marlowe Elizabeth , Ferguson Michael J , Marshall Mark S , Runco Daniel V
Published: June 2024

BACKGROUND

Childhood brain tumors remain a leading cause of death with significant treatment-related morbidity and mortality, including disproportionate rates of altered metabolism, neuropathy, and poor quality-of-life. Growth Differentiation Factor 15 (GDF15), a circulating cytokine released by tissue injury, mediates nausea, vomiting, and anorexia, and promotes tumor growth, angiogenesis, and metastasis in adult cancers, predicting worse progression-free survival in adults with low-grade gliomas. Despite adult cancer data, GDF15 remains unexplored in children. Published pilot data demonstrate higher circulating GDF15 in children with cancer compared to healthy controls, but GDF15 expression has not been studied in pediatric brain tumors. We present GDF15 tumor tissue expression with tumor type, grade, metastasis, and progression to inform future study of GDF15’s role in pediatric brain tumors.

METHODS

Single-center retrospective review of 64 pediatric brain tumor specimens collected through our Precision Genomics Program. GDF15 RNA expression (normalized to ß-actin tissue expression) was log-transformed. Mean GDF15 expression based on diagnosis was compared (using ANOVA) and two-sample t-tests were used to compare metastatic, progressive, and high-grade disease.

RESULTS

Highest mean GDF15 expression was seen in medulloblastoma (1.96+0.66, N=3) and lowest in low-grade glioma (0.79+0.26, N=27), but groups were not statistically different (p=0.29). GDF15 expression was higher in progressive (1.46+0.22) versus non-progressive disease (0.76+0.24, p=0.04). Although not statistically different, GDF15 expression was higher in high-grade (1.43+0.27) compared to low-grade (1.03+0.21, p=0.24) and metastatic (1.80+0.44) versus non-metastatic disease (1.06+0.17, p=0.08).

CONCLUSIONS

This ongoing work suggests variable GDF15 expression in different pediatric brain tumors and may suggest GDF15 mediates disease progression. GDF15 may play a role in metastatic or high-grade disease, but further study is needed with larger disease-specific cohorts. We demonstrate feasibility of utilizing existing genomic data and are pursuing further characterizing these potential differences through international public databases (i.e., Children’s Brain Tumor Network).
CNSC-04. EXPLORATION OF INTERCELLULAR NETWORKS IN EPENDYMOMA REVEALS POTENTIAL THERAPEUTIC VULNERABILITIES
Authors: Sundheimer Julia K , Rettenmeier Johanna , Volz Stefanie , Bamberg Leonhard V , Federico Aniello , Azorín Daniel D , Ertel Paula , Heuer Sophie , Scheuermann Sophia , Seitz Christian , Winkler Frank , Kool Marcel , Pfister Stefan M , Maaß Kendra K , Pajtler Kristian W
Published: June 2024

BACKGROUND

Aggressive ependymoma (EPN) exhibit primary and secondary radio- and chemotherapy resistance with the poorest prognosis in the pediatric groups PF-EPN-A and ST-EPN-ZFTA. Recently, tumor cell networks formed by membrane protrusions, such as tunneling nanotubes (TNT) or tumor microtubes (TM), have been identified in other glial brain tumors. These structures facilitate intercellular hierarchical Ca2+-communication and contribute to therapy resistance. Previous data from our group suggested enhancer-regulated Ca2+-communication to be essential in EPN. This study aims to further characterize intratumoral interactions and to understand potential correlations between tumor cell connections and treatment resistance in EPN.

METHODS

Intercellular connections in EPN patients and model systems were characterized by scanning electron microscopy, immunofluorescence and ultra-high content imaging. Transcriptomic and proteomic data were analyzed to identify potential targetable vulnerabilities within network dynamics. Candidates were functionally validated in cell culture models applying Ca2+ live cell imaging.

RESULTS

Connectivity-related terms such as microtube-based movement or microtube bundle formation showed increased expression in EPN transcriptome data compared to healthy controls. EPN networks were found to be build of TM- and TNT-like structures with a higher abundance of TNT-like structures in PF-EPN-A compared to ST-EPN-ZFTA. All networks showed strong Nestin-positivity in cells, mouse models and human tumor tissue of ST-EPN-ZFTA and PF-EPN-A. Thrombospondin-1, a matricellular protein enhancing TMs in glioma cells, was strongly enriched in ST-EPN-ZFTA patients. The gap junction channel connexin 43, connecting glioma cells, was highly upregulated in PF-EPN-A. Active electrochemical communication was observed between ST-EPN-ZFTA cells performing Ca2+ imaging. Moreover, inhibition of T-type Ca2+ channels impaired intercellular signaling, leading to network perturbation in vitro.

CONCLUSIONS

Our study revealed the importance of gap junction-coupled networks for communication of aggressive EPN cells. Targeted disconnection of the EPN-specific network as demonstrated for Ca2+ channel inhibition suggests a new avenue for therapeutic strategies in EPN to overcome resistance.
CP-08. THE CLINICAL CHARACTERISTICS OF CHILDREN WITH CRANIOPHARYNGIOMA AND THEIR MANAGEMENT IN UGANDA: A RETROSPECTIVE REVIEW
Authors: Katasi Victoria Mwebe , Munube Deogratius , Chintagumpala Murali , Naitala Ronald , Kasirye Phillip , Muwonge Peter Wasswa , Lubega Joseph , Zungu Jennifer , Nabbagala Cathy , Akullo Anne , Nakirulu Annet , Namazzi Ruth , Ssekabunga Julie , Ssenyonga Peter , Onen Justin , Wegoye Emmanuel
Published: June 2024

BACKGROUND

Craniopharyngiomas are benign brain tumors that mostly arise in the sellar/suprasellar region. Histologically though benign, these tumors can locally infiltrate with involvement of surrounding structures. They have a 5-year survival rate of above 80% in High Income Countries (HIC). Craniopharyngioma management includes surgery, radiotherapy and intracystic treatments and requires a multi-disciplinary team. The morbidity associated with treatment must be weighed against tumor recurrence and quality of life after treatment. Endocrine deficiencies, especially growth hormone deficiency and visual deficits are common presenting features.

OBJECTIVE

To describe the clinical characteristics and management of children with craniopharyngioma managed at Mulago National Referral Hospital from March 2019 to December 2023.

METHODOLOGY

A retrospective descriptive study was conducted among patients< 18 years of age, admitted to the Mulago National Referral Hospital (MNRH) from March 2019 to December 2023 with a radiological diagnosis of a craniopharyngioma.

RESULTS

A total of 151 children with a diagnosis of a brain tumor during this period were identified and of these 40 (26%) were diagnosed with craniopharyngioma. The median age was 8.4 years and 22 (55%) were males. Only 2 children had maximal safe resection (sub-total resection), one of whom later received adjuvant external beam radiotherapy. Thirty-eight patients had insertion of ommaya reservoirs as their tumors were predominantly cystic. Two patients received intracystic bleomycin and 11 received radical external beam radiotherapy. Twenty-seven patients had no additional therapy after ommaya reservoir placement. Fifteen (39%) of the patients had endocrine deficits with hypothyroidism, hypocortisolism and growth hormone deficiency being the most common. The median follow-up time was 1.45 years. The overall survival was 67.5%, 95%CI(42.5-83.5).

CONCLUSION

Management of patients with craniopharyngioma in Uganda is mostly conservative with the aim of intervention to preserve quality of life. Limited access to radiation therapy contributed to the poorer survival compared to HIC.
DIPG-08. PROBING THE BLOOD-BRAIN-TUMOR-BARRIER WITH A MICROVASCULAR MODEL OF DIFFUSE MIDLINE GLIOMA
Authors: Bennett Kimberly R , Teboh Tessy , Hajal Cynthia , Kamm Roger D , Hammond Paula T , Straehla Joelle P
Published: June 2024

BACKGROUND

Pediatric diffuse midline glioma (DMG) is a uniformly fatal brain tumor in children, with most patients surviving less than 12 months. Current treatment for DMG is limited, and outcomes for this tumor have not improved. The blood-brain-barrier (BBB) remains a key challenge for DMG therapeutics, preventing most drugs from entering brain tissue. Functional characterization of the blood-brain-tumor-barrier (BBTB) – the interaction between tumors and BBB vasculature – remains largely unexplored for DMG. There is a need for a preclinical model of DMG that can probe the functional, physiological, and biological properties of the BBTB in vitro as a platform to evaluate therapeutic efficacy that is representative of human physiology.

METHODS

To generate an in vitro model of DMG with human microvasculature (DMG-BBTB model), we co-cultured DMG neurospheres, human brain microvascular endothelial cells, human brain vascular pericytes, and human astrocytes. Cells are simultaneously seeded into microfluidic devices at varied concentrations within a fibrin matrix. Self-assembled microvascular networks are formed within 7-8 days and used for downstream functional and phenotypic assays.

RESULTS

Vascular morphology and solute permeability in microvascular networks are influenced by cell identity, growth pattern, and relative concentration. We show that DMG neurospheres exhibit different patterns of growth when co-cultured as uniform spheroids versus single cells in suspension. Devices representing each growth pattern are further characterized for paracellular diffusion and permeability compared to devices without DMG cells through perfusion of high molecular weight dextran. Permeability values are correlated to biologic features such as the abundance and localization of junctional proteins and transporters.

CONCLUSIONS

We developed a platform to evaluate the microvasculature of the DMG BBTB as a tool to develop new therapies informed by vascular biology. We probed the functional, physiological, and biological properties of the human DMG BBTB in vitro, and in ongoing work are assessing approved and experimental therapeutics.
DIPG-23. SAFETY AND TECHNICAL YIELD OF BRAINSTEM BIOPSIES IN CHILDREN – AN UPDATED META-ANALYSIS OF 1000 CASES
Authors: Sheikh Shehryar R , Patel Neha J , Recinos Violette
Published: June 2024

BACKGROUND

Brainstem tumors represent ~10% of pediatric brain tumors, ~80% of these are diffuse intrapontine gliomas (DIPG, primarily WHO Grade 4 midline glioma, H3 K27M-mutant). Given invariably poor prognosis in these cases, there continues to be immense variation (across the US and internationally) in performing biopsy of these lesions as opposed to making a presumptive diagnosis based on MRI. Several multi-center studies in recent years have aimed to show the safety profile of biopsy but an updated meta-analysis is lacking.

METHODS

We found 29 studies of pediatric brainstem biopsy in the last 20 years (2003-2023), representing data from 1002 children. We applied meta-analysis of proportions using a random-effects model to generate point estimates, confidence intervals, and measures of heterogeneity.

RESULTS

87% of procedures were stereotactic needle biopsies (of these, 62% with a frame, 14% without frame, and 24% robotic.) Biopsy yield (i.e. the rate at which biopsy resulted in a tissue diagnosis) was 94% (95% CI 92-97). Temporary complications were seen in 6% (95 CI 4-8), most commonly including 1) radiographic evidence of bleeding or air without an associated fixed neurological deficit, 2) cranial nerve dysfunction, and 3) delayed awakening. Permanent complications (excluding death) were seen in 1% (95% CI 0.5-2), most commonly including cranial nerve dysfunction and limb weakness. 5 deaths were reported in the entire pooled cohort of 1002 children (0.5%). Gliomas represented 92% of tumors (95% CI 89-95). Of the gliomas for which WHO grading was provided, 68% were high grade (III/IV).

CONCLUSION

When counseling families on the merits of brainstem biopsy in children, it is reasonable to state that permanent morbidity is rare (< 2%). If biopsy is performed specifically to facilitate enrollment in clinical trials requiring a molecular diagnosis, the risks of biopsy outlined here should be weighed against potential benefits of trial enrollment.
DIPG-31. IS RE-IRRADIATION A POTENTIAL SURVIVAL BENEFIT FOR PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA?
Authors: Dassi Natália , Torquato Ana C S , Chen Michael , Figueiredo Maria L , Rodrigues Jessica B , Cavalheiro Sergio , Dastoli Patricia A , Alves Maria T S , Silva Frederico A , Moraes Carlota V B , Silva Nasjla S , Cappellano Andrea M
Published: June 2024

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) is an aggressive infiltrative glioma with dismal prognosis. Radiation therapy (RT) offers a transient benefit and re-irradiation (reRT) may be an option at disease progression.

OBJECTIVE

To evaluate the outcome of patients with DIPG at progression in a single institution.

METHODS

Between 2010-2023, 55 patients were evaluated, retrospectively, in respect of their treatment-one RT course versus re-RT) and concomitant medications. Overall survival (OS) was measured from diagnosis to date of death and from reRT to death using Kaplan–Meier and log-rank test.

RESULTS

Median age was 7.1 years (range 2.9-16.2y). Twenty-two patients underwent biopsy with 11 performing immunohistochemistry for H3K27M (9 mutated). In nine cases molecular analyses was evaluated: 6 H3.3K27M-mutant (2 simultaneously TP53 + 1PTPRZ1-MET fusion), 1 H3.1K27M-mutant, 1 H3C2-mutant + ACVR1 mutation and 1 PDGFRA + KIT amplifications. Thirty-five patients completed the initial course of RT (54Gy- 13-33 daily fraction), 30/35 also received valproic acid (VA), 5/35 bevacizumab, 3/35 nimotuzumab and 1/35 nivolumab+ipilimumab. Twenty patients underwent re-RT at first progression, four with 54 Gy (30x 180Gy), nine with 50Gy (25x 200Gy) and seven with median dose of 30Gy (26-39Gy), depending on their clinical status. These group also received valproic acid(8/20), bevacizumab(8/20), nivolumab(1/20) and ONC 201(1/20). Patients who received reRT showed prolonged OS compared to no reRT (median 524 vs 351 days; p=0.013). ReRT was well tolerated with 15(75%) patients experiencing stable to improved neurologic function. Patients with better clinical status and 50-54Gy reRT doses, showed prolonged OS (median 238 vs 135 days; p=0.1). Median OS from re-RT to death was 174 days (range, 14-218 days) with eight patients alive to date.

CONCLUSIONS

Re-irradiation with 50-54Gy seems safe and feasible for DIPG patients after disease progression from the first treatment, with mostly patients experiencing neurological improvement and prolonged life period.
DIPG-40. LONG TERM SURVIVAL OF A 14 YEAR OLD GIRL WITH H3K27M MUTATED DIFFUSE MIDLINE GLIOMA FOLLOWING RADIOTHERAPY AND PROLONGED TUMOR TREATING FIELDS (TTFIELDS) -CASE REPORT
Authors: Dvir Rina
Published: June 2024

INTRODUCTION

Pediatric diffuse midline H3K27M mutated glioma has a dismal prognosis. Most cases are treated by radiotherapy and oral chemotherapy, with surgical resection having a debatable role in some. Tumor-treating fields (TTFields) is a noninvasive modality in which alternating electrical fields exert biophysical force on charged and polarizable molecules known as dipoles. TTFields has been shown to extend survival for adult patients with newly diagnosed and recurrent GBM, and is FDA approved for these indications. There is sparse data about pediatric patients.

CASE REPORT

A 14-year-old girl presented with headache and vomiting. A large left thalamic tumor was diagnosed and underwent subtotal resection. Diagnosis was diffuse midline glioma, H3K27M positive, IDH negative. Molecular Panel: Tumor mutation burden low, microsatellite stable. Genomic findings: FGFR1, NF1, H3F3A -K28M, ATRX R666, MAP3K1 She was re-operated due to a fast tumor relapse within a few weeks, prior to radiotherapy, followed with radiotherapy with local field 59Gy. She then received temozolamide (12 months) concomitant with TTfields (Optune, Novocure). TTfields therapy was administered for 5 years without adverse effects and excellent compliance (above 85%). After 5 years, therapy was withheld, and she is now off therapy NED for another 15 months.

DISCUSSION

Diffuse midline H3K27M glioma harbors a poor prognosis in children. Children refrain from this treatment both for lack of evidence and because of the difficulty in adhering to a regimen that demands carrying a battery of 1.5-2kg all day and shaving all hair every 3 days. Our patient had a high compliance and as she wore a head scarf for religious customs, the device was not visible. To our knowledge this is the first pediatric reported case of long-term survival of H3K27mutatted midline glioma using TTFields. Further pediatric studies are warranted.
DIPG-42. PHASE 1/2 CLINICAL TRIAL OF OMBIPEPIMUT-S IN JAPANESE PEDIATRIC PATIENTS WITH RECURRENT/REFRACTORY DIFFUSE INTRINSIC PONTINE GLIOMA, GLIOBLASTOMA, OR HIGH-GRADE GLIOMA
Authors: Hashii Yoshiko , Fujisaki Hiroyuki , Terashima Keita , Goto Hiroaki , Horibe Keizo , Sugiyama Kazuhiko , Yanagisawa Takaaki , Kikuta Atsushi , Kawamoto Hiroshi , Hashimoto Naoya , Hara Junichi , Sugiyama Haruo
Published: June 2024

BACKGROUND

Pediatric patients with recurred/relapsed diffuse intrinsic pontine glioma (DIPG), glioblastoma, or high-grade gliomas (HGGs) have a dismal prognosis. The present study investigated the impacts of 1) the absolute count of Wilms tumor 1 (WT1)-specific cytotoxic T cells (CTLs) at the initiation of WT-1 specific peptide vaccine (Ombipepimut-S) consisting of a killer peptide—adegramotide, a helper peptide—nelatimotide, and adjuvant MontanideTM ISA 51 VG and of 2) cumulative steroid dose on patients’ survival. We aimed to explore the optimal timing for initiating this cancer immunotherapy for them.

METHODS

The absolute counts of WT1-specific CTLs and lymphocytes were examined at the initiation of vaccination. This first-in-child phase 1/2 study investigated survival (overall survival [OS] and progression-free survival [PFS]), as well as cumulative steroid dose until day 28 after vaccination initiation and immune responses according to the Kaplan-Meier method and receiver-operating curve (ROC) analysis, respectively.

RESULTS

18 patients (median age: 8.9 years [range: 2.8–18.7]), 11 (61.1%), 5 (27.8%), and 2 (11.1%) had DIPG, glioblastoma, and HGG, respectively) were intradermally injected with ombipepimut-S. WT1-specific immune responders accounted for 70.6% of patients. Median OS was significantly longer (P = 0.024) in WT1-specific immune responders (9.9 months [6.0−33.4]) than in nonresponders (4.9 months [2.2−16.5]). Under a low cumulative steroid dose (< 0.66 mg/kg body weight), ombipepimut-S significantly extended both OS (P=0.0015) and PFS (P=0.007). Immune responders tended to show the higher absolute counts of WT1-specific CTLs (P=0.091) and lymphocytes (P=0.087) at the initiation of vaccination.

CONCLUSIONS

Ombipepimut-S exhibited antitumor activity, and this cancer immunotherapy appeared to be preferably initiated when the patient’s immunity is relatively preserved immediately after the completion of standard therapy for primary disease or before the tumor recurs or relapses.
DIPG-58. TARGETING DISORDERED DNA METHYLATION IN DIPG TO CONSTRAIN VARIABILITY AND INDUCE IMMUNE SIGNALING
Authors: Tetens Ashley R , Martin Allison M , Arnold Antje , Novak Orlandi V , Idrizi Adrian , Tryggvadottir Rakel , Craig-Schwartz Jordyn , Liapodimitri Athanasia , Lunsford Kayleigh , Barbato Michael I , Eberhart Charles G , Resnick Adam C , Raabe Eric H , Koldobskiy Michael A
Published: June 2024

BACKGROUND

Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal pediatric brain cancer characterized by the histone H3 K27M mutation. The known downstream consequences of this mutation include loss of repressive chromatin marks, global DNA hypomethylation, and altered gene expression.

METHODS

We sought to investigate the role of epigenetic variability as a basis of DIPG cellular heterogeneity and plasticity by using Whole Genome Bisulfite Sequencing (WGBS). Existing methods of analysis of WGBS are limited in that they average/smooth methylation data and fail to capture intrinsic variability. We performed (WGBS) on 23 primary patient samples of DIPG and applied an analysis that captures the variability of DNA methylation reads to characterize methylation stochasticity. We then sought to modulate the epigenome pharmacologically using a DNA methyltransferase inhibitor and assessed changes through RNA-Seq and immunopeptidomics.

RESULTS

We find that DIPG has a marked increase in methylation stochasticity (quantified as methylation entropy). Additionally, while DIPG is globally hypomethylated, it retains DNA methylation at specific regulatory regions, such as bivalent promoters, and key genes, such as FOXG1, CXCR4, and KLF4. We sought to reverse these changes using the DNA methyltransferase inhibitor, decitabine, in 4 DIPG neurosphere cell lines. Treatment with decitabine reversed the entropy seen in DIPG and induced innate immune signaling and interferon signaling in DIPG cells. Using RNA-seq, we found that decitabine treatment dramatically alters gene expression, including activation of endogenous retroviral elements, activation of interferon signaling, de-repression of hypermethylated targets, and expression of putative neoantigens, such as PRAME and DAZL. Immunopeptidomics profiling of MHC Class I bound canonical and non-canonical peptides of DIPG cell lines after decitabine treatment also revealed decitabine-induced differences.

CONCLUSIONS

Taken together, our study finds that the methylome of DIPG is highly disordered but is also highly responsive to pharmacologic modulation by hypomethylating agents. Furthermore, hypomethylating drugs can increase the immunogenicity of DIPG, thus offering the potential for future combination with immunotherapy.
DIPG-76. PEDIATRIC PATIENTS WITH DIFFUSE MIDLINE GLIOMA DEMONSTRATE AN UNEXPECTED PREVALENCE OF GERMLINE VARIANTS IN HOMOLOGOUS RECOMBINATION GENES
Authors: Mateos Marion K , Ajuyah Pamela , Fuentes-Bolanos Noemi , Kamand Sam El , Barahona Paulette , Altekoester Ann , Mayoh Chelsea , Holiday Holly , Liu Jie , Cui Louise , Pfaff Elke , Mackay Alan , Resnick Adam , Pinese Mark , Lau Loretta M S , Khuong-Quang Dong-Anh , Dias Kimberly , Goudie Catherine , Salkeld Alison , Rokita Jo Lynne , Jones David T W , Juretic Nikoleta , Hayden Elisha , Pfister Stefan M , Kramm Christof M , Blattner-Johnson Mirjam , Jabado Nada , Tsoli Maria , Vittorio Orazio , Mueller Sabine , Guo Yiran , Tucker Katherine , Waszak Sebastian M , Perreault Sebastien , Jones Chris , Wong-Erasmus Marie , Cowley Mark J , Ziegler David S
Published: June 2024

BACKGROUND

Pediatric patients with Diffuse Midline Gliomas (DMG), H3K27M altered have a dismal prognosis and novel therapeutic approaches are urgently needed. Factors that drive development of pediatric DMG are unknown.

METHODS

To determine the prevalence of germline pathogenic/likely pathogenic variants (P/LPV) in DMG, we assembled an international cohort of 252 patients with germline whole genome or whole exome sequencing data, including diffuse intrinsic pontine glioma (DIPG; n=153), from Australian, European and North American centres.

RESULTS

We identified germline P/LPV in cancer predisposition genes in 7.5% (19/252) of patients, mainly homologous recombination (n=9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n=4). Germline P/LPV in mismatch repair genes (MSH2, PMS2) were found in two patients. Two patients each had two separate germline P/LPV. The prevalence of germline P/LPV was not significantly different according to age, location of DMG nor H3K27M mutational status. Furthermore, tumor profiles differed, with absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LPV compared to those without (P = 0.023). Knockdown of BRCA1 in DMG cell cultures sensitized tumor cells to PARP inhibition. Reflecting the potential therapeutic relevance of these findings, we describe one H3.3 K27M-mutant DMG patient with a pathogenic germline BRCA2 and FANCE variant and multiple recurrences, who was treated with a PARP inhibitor (olaparib) and immune checkpoint inhibitor, leading to a near complete radiological response after 4 months.

CONCLUSION

Our study is the largest series to date investigating germline P/LPV in cancer predisposition genes in DMG and provides new therapeutic insights. It is expected that these germline findings will also guide cascade testing for a proband’s relatives. Our data highlight the importance of germline testing in H3K27-altered DMG patients at diagnosis.
DIPG-81. PHASE IB CLINICAL TRIAL ASSESSING SAFETY, TOLERABILITY, AND PRELIMINARY EFFICACY OF ALOCELYVIR (ALLOGENEIC MESENCHYMAL CELLS + ONCOLYTIC ADENOVIRUS) COMBINED WITH RADIOTHERAPY IN PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Lassaletta Alvaro , Vazquez-Gomez Felisa , Rubio Alba , Moreno-Carrasco Jose Luis , Sansegundo Carmen Gonzalez , Gonzalez-Murillo Africa , Horcajo-Morera Beatriz , Bautista Francisco , Garcia-Aguilera Gonzalo , Castillo Ana , Solís Ines , Borrego Pedro , Llort Anna , Castellano Serafin , Perez-Somarriba Marta , Garcia-Ariza Miguel , Galera Ana , Melwani Kishore , Ippolito Hyaissa , Rivero Belen , Melen Gustavo , Garcia-Castro Javier , Ramirez Manuel
Published: June 2024

BACKGROUND

Despite recent advances in our understanding of biology, pediatric patients diagnosed with diffuse intrinsic pontine glioma (DIPG) still face a bleak prognosis. In recent years, oncolytic adenovirus therapy has emerged as a promising approach in cancer treatment.

METHODS

We conducted a phase Ib clinical trial in patients newly diagnosed with DIPG, utilizing ALOCELYVIR, an advanced therapy medicine that combines allogeneic mesenchymal stem cells carrying an oncolytic adenovirus. ALOCELYVIR was administered as weekly intravenously infusions from the first week of radiation for 8 doses, at a dose of 0.5x106 cells/kg/dose. The primary objective was to assess the safety of combining ALOCELYVIR with radiotherapy in patients with newly diagnosed DIPG. PCR analysis of adenovirus in plasma, anti-adenovirus type 5 antibodies, and immune reconstitution were analyzed.

RESULTS

A total of 6 patients, aged 5 to 15 years, were recruited. Four patients underwent biopsy, confirming an H3K27-mutated DIPG. All patients except one completed the trial; this patient progressed during radiotherapy, and after the fifth dose of ALOCELYVIR. Adenovirus replication in plasma was observed in four patients. Median OS was 11.5 months (range, 3-25), and median PFS was 7.5 months (range, 2-13). One patient is still alive 25 months after diagnosis. Adverse events among patients were all mild, including fever, asthenia, vomiting, headache, and myalgias, all grade I. Clinical and radiological pseudoprogression were documented in four patients, necessitating the addition of steroids +/- bevacizumab as anti-inflammatory treatment.

CONCLUSIONS

Our phase Ib clinical trial demonstrates the feasibility and safety of combining ALOCELYVIR with radiotherapy in pediatric patients newly diagnosed with DIPG. Furthermore, the manageable adverse event profile observed underscores the potential of ALOCELYVIR as a therapeutic option for DIPG. These findings warrant further investigation through larger clinical trials to elucidate the full therapeutic potential of ALOCELYVIR in improving outcomes for pediatric patients with DIPG.
DIPG-85. MALT1 IN H3K27-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Butterfield Hannah E , Azambuja Juliana Hofstatter , Maurer Lisa , Hu Dong , Cruz Andrea F , Halbert Matthew E , Gatesman Taylor A , IV John Little , Agnihotri Sameer , Lucas Peter C , McAllister-Lucas Linda M
Published: June 2024

BACKGROUND

H3K27-altered diffuse midline glioma (DMG) is a devastating pediatric brainstem tumor that affects 200-300 individuals in the US per year. Median survival is 9-11 months, and there are virtually no long-term survivors. Despite decades of clinical trials, radiation therapy remains standard of care, extending survival by 2-3 months. Elucidating the mechanisms that drive H3K27-altered DMG pathogenesis in order to uncover therapeutic vulnerabilities is of critical importance. Recent studies implicate MALT1 as a potential therapeutic target in gliomas. MALT1 is the effector molecule of the CARMA-BCL10-MALT1 (CBM) signalosome, a cytoplasmic protein complex that drives downstream pro-survival transcriptional activity. MALT1, which possesses scaffolding and protease functions, promotes cell viability, proliferation, and migration/invasion in multiple cancer types. We aim to evaluate the hypotheses that MALT1 promotes DMG cancer cell proliferation and migration and that MALT1 inhibition will abrogate tumor progression.

METHODS/RESULTS

We screened a panel of cells including astrocytes, neural stem cells, and DMG cell lines by Western blot and found that CBM complex members BCL10 and MALT1 are present in all cells tested. We next demonstrated that MALT1 is proteolytically active in DMG cell lines SF8628 and HSJD-DIPG-007. Specifically, we showed cleavage of the MALT1 protease substrate HOIL, which was abrogated by treatment with the MALT1 protease inhibitor MLT-748. We next generated multiple dox-inducible MALT1 shRNA DMG cell lines to assess the impact of MALT1 deficiency on DMG biology. Thus far, we find that shRNA knockdown of MALT1 does not impact SF8628 cell proliferation.

CONCLUSIONS

MALT1 is expressed and proteolytically active in DMG cells. Initial studies show that MALT1 knockdown does not affect proliferation of SF8628 cells. We will next evaluate the effect of MALT1 knockdown on proliferation of additional DMG cell lines, as well as the impact on other malignant features of DMG cells including migration/invasion.
TRLS-07. PNOC016: INTRATUMORAL PHARMACOKINETICS AND PHARMACODYNAMIC (PK/PD) RESULTS FROM A TARGET VALIDATION STUDY OF A NOVEL PAN-HDAC AND PI3K INHIBITOR, FIMEPINOSTAT, IN CHILDREN AND YOUNG ADULTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG), RECURRENT MEDULLOBLASTOMA (MB), AND RECURRENT HIGH-GRADE GLIOMA (HGG)
Authors: Kline Cassie , Crawford John R , Reddy Alyssa T , Gerber Nicolas , Stucklin Ana Guerreiro , Kilburn Lindsay , Packer Roger , Margol Ashley , Crotty Erin , Sayour Elias , Franson Andrea , Phillips Joanna , Singh Shefali , Hamanishi Erin , Lee Christopher , Bhatia Aashim , George Elizabeth , Rauschecker Andreas , Molinaro Annette , Prados Michael , Nazarian Javad , Venneti Sriram , Wechsler-Reya Robert , Mueller Sabine
Published: June 2024

BACKGROUND

An intact blood-brain barrier is a limitation to effective therapies for pediatric brain tumors. PNOC016 investigated the tumor penetration of an orally available, promising pan-HDAC and PI3K-inhibitor, fimepinostat, in high-risk pediatric brain tumors, including DIPG, MB, and HGG. Fimepinostat is active as a primary drug and via its metabolite, M2, which exhibits PI3K inhibition.

METHODS

Patients between 3 and 39 years old with newly diagnosed DIPG (stratum A), recurrent MB (stratum B), or recurrent HGG (stratum C) were eligible. Disease-based strata enrolled independently up to 10. Patients received 3 neoadjuvant doses before standard-of-care resection/biopsy and underwent tissue collection for PK/PD analysis. Patients continued single-agent maintenance therapy for up to 12 months with ongoing collection of circulating tumor DNA (ctDNA) from blood, quality of life (QOL) measures, survival, and response outcomes.

RESULTS

Thirty-one patients enrolled between August 2019 and August 2022 (n=1 replaced due to disease progression before treatment started). All patients with completed PK analysis had detectable fimepinostat (n=18), metabolite M1 (n=23), or metabolite M2 (n=24) in tumor. Median intratumoral levels of fimepinostat, M1, and M2 (nM) by stratum were as follows: stratum A-2.6, 4.9, 28.3; stratum B-9.5, 6.5, 32.4; stratum C-9.9, 10.7, 15.9. The lowest intratumoral levels were seen in stratum A. Pre-surgical blood PK positively trended with intratumoral PK. Phosphorylation and acetylation PD analyses are underway. The most common grade 3 or above related adverse events were hematologic, with platelet decrease being the most frequent (n=9). Median OS from the diagnosis for stratum A was 13 months. PFS from surgery for stratum B and C was 3 and 3 months.

CONCLUSION

Fimepinostat crossed the blood-brain barrier in newly diagnosed DIPG and recurrent MB and HGG. PD assessment is underway to correlate PK with biological effects. PD correlation, survival analyses, ctDNA, and QOL will be presented.
TRLS-09. CONNECT1903: A PILOT AND SURGICAL STUDY OF LAROTRECTINIB FOR TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED HGG WITH NTRK FUSION (NCT04655404)
Authors: Chi Susan N , Lazow Margot , Salloum Ralph , Lane Adam , Hargrave Darren , Witt Olaf , de Blank Peter , Leary Sarah E S , Gorsi Hamza , Pierson Christopher , Breneman John , Jones Jeremy , Yang Edward , Mikael Leonie , Jones David T W , Fouladi Maryam
Published: June 2024

BACKGROUND

Recurrent fusions in neurotrophic tropomyosin-receptor kinase genes NTRK 1-3 are found in variety of cancers, including pediatric HGG: DIPG (~4%) and non-brainstem HGG (~10%). For non-brainstem HGG seen in children <3 years of age, approximately 40% harbor NTRK alterations. NTRK fusions provide a promising target for gliomas and to that end, Larotrectinib, a globally approved, highly potent, small molecule inhibitor of TRKA/B/C, has previously been investigated and has shown tolerability and efficacy in children with recurrent solid tumors. Compassionate use in a case of infantile GBM showed proof-of-concept with blood-brain penetrance and efficacy. Further evidence of efficacy in two earlier clinical trials has also been previously demonstrated in children with recurrent TRK-fusion primary intracranial tumors (NCT02637687, NCT02576431).

METHODS

This international trial conducted through the CONNECT consortium, supported in part by Bayer, investigates larotrectinib monotherapy; its feasibility and tolerability in combination with standard systemic chemotherapy (Baby POG or HIT-SKK) or radiation therapy whereby treatment plan determination is response-based. Objectives include: to assess disease control rate (CR, CCR, PR and SD) after two cycles of larotrectinib monotherapy (28-day cycles); to assess feasibility and to describe toxicities of larotrectinib in combination with standard chemotherapy; to assess objective response rate (CR and PR); to assess OS and PFS as compared to historical data from Baby POG, HIT-SKK and radiotherapy. A phase 0 surgical cohort will be explored whereby patients who are planned to undergo a definitive resection will receive pre-surgery larotrectinib, and target inhibition, intratumoral and plasma pharmacokinetics will be investigated. Radiographic responses will also be quantitated. This trial is currently open to accrual at ten CONNECT sites across North America and Australia and has enrolled five patients to date. Sites in UK, Germany and Netherlands are pending activation. A total of 15 patients are anticipated to be enrolled and evaluable.
TRLS-12. EFFICACY AND SAFETY OF ENTRECTINIB IN CHILDREN WITHNTRK ORROS1 FUSION-POSITIVE (FP) PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Bagchi Aditi , Robinson Giles W , Desai Ami V , Wu Yeming , Wang Huanmin , Basu Ellen M , Casanova Michela , van Tilburg Cornelis M , Campbell-Hewson Quentin , Armstrong Amy E , André Nicolas , Devlin Clare , Wulff Jade , Cardenas Alison , Hutchinson Katherine E , Lian Qinshu , Ryklansky Carolina , Harmach Vesna Sneller , Fox Elizabeth , Gajjar Amar
Published: June 2024

BACKGROUND

Entrectinib (CNS-penetrant, TRK/ROS1 inhibitor) has shown efficacy and safety in children with NTRK/ROS1-fp CNS tumors. We present updated data from an integrated analysis of children with NTRK/ROS1-fp CNS tumors enrolled in three early-phase trials: STARTRK-NG (NCT02650401), TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267).

METHODS

TRK/ROS1 inhibitor-naïve patients <18 years old (YO) with NTRK/ROS1-fp CNS tumors with measurable/evaluable-only disease, who received ≥1 entrectinib dose before disease progression, unacceptable toxicity, or consent withdrawal, and with ≥6 months’ follow-up were efficacy evaluable. Any <18 YO on study who received ≥1 entrectinib dose, regardless of genetic alteration and follow-up duration, was evaluable for safety. Primary endpoint: blinded independent central review (BICR)-assessed confirmed objective response rate (ORR). Key secondary endpoints: BICR-assessed confirmed ORR in patients with measurable disease; duration of confirmed response (DoR); time to confirmed response (TtR); progression-free survival (PFS); safety.

RESULTS

On 16 July 2023 (cut-off for analysis), 27 patients were efficacy evaluable (NTRK-fp: n=20; ROS1-fp: n=7). Median age at enrolment: 4.0 Y (NTRK-fp) and 6.0 Y (ROS1-fp); 45.0% (NTRK-fp) and 42.9% (ROS1-fp) of patients received ≥2 prior therapy lines. Median survival follow-up: 26.2 months (NTRK-fp); 36.1 months (ROS1-fp). ORR: 50.0% (NTRK-fp) and 71.4% (ROS1-fp) in efficacy-evaluable patients, and 58.8% (n=10/17; NTRK-fp) and 83.3% (n=5/6; ROS1-fp) in patients with measurable disease. Median DoR: 25.4 months, TtR: 1.9 months, PFS: 23.1 months in NTRK-fp patients. DoR and PFS were not evaluable in ROS1-fp patients; median TtR was 1.9 months. In the safety-evaluable population (N=34), the most common adverse events were weight increase (50.0%), blood creatinine increase and anemia (each 41.2%). Bone fractures were reported in 26.5% of patients. Most fractures occurred in children 2–12 YO (n=7/9).

CONCLUSIONS

Our analysis confirms the rapid and durable activity of entrectinib in children with NTRK/ROS1-fp primary CNS tumors. The safety profile described was in line with previous reports.
ETMR-03. REPORT OF 9 CASES OF EMBRYONAL TUMORS OF THE CENTRAL NERVOUS SYSTEM WITH MULTILAYERED ROSETTES (ETMR)
Authors: Ai Ruyu , Li Juan , Lai Mingyao , Cai Linbo
Published: June 2024

OBJECTIVE

Embryonal Tumors of the Central Nervous System with Multilayered Rosettes (ETMR) are rare, and there’s no standard treatment protocol. This article reports on the current treatment status and prognosis of ETMR in our hospital.

METHODS

We retrospectively collected patients with ETMR who received treatment in the Oncology Department of Guangdong sanjiu Brain Hospital from January 2017 to January 2021, analyzed their clinical data.

RESULTS

Among 31 cases of central nervous system embryonic tumors (excluding medulloblastoma and ATRT), 9 (29.03%) were ETMR. The median age at diagnosis was 3 years old (1-15), and the male to female ratio was 4:5. Among them, 5 cases were accompanied by C19MC gene variation. Tumor location:6 was in supratentorial, 1 in the pineal region, 1 in the pons, 1 in the cerebellopontine. Eight patients underwent surgical resection at the first diagnosis, with 6 cases of total resection, 1 case of partial resection, and 1 case of biopsy. One case was misdiagnosed as a germinoma in the pineal region at the initial. After recurrence, surgical resection was performed to confirm the pathology as ETMR. One case was misdiagnosed as glioblastoma during the first surgery. The initial treatment for 4 patients after surgery was radiotherapy combined with concurrent chemotherapy. Recurrence patterns: 2 cases were intracranial dissemination, 2 cases were local recurrence, 1 was spinal cord dissemination. One patient did not receive treatment after surgery and tumor recurrence 3 months later. Survival analysis: The median survival time was 20 months. The 1-year progression-free survival rate (PFS) and overall survival rate (OS) were 22% and 61%, and the 2-year overall survival rate (OS) was 31%.

CONCLUSION

ETMR has a low incidence and poor prognosis. It is easy to misdiagnose and NGS is necessary to assist diagnosis when needed. More effective treatment methods need to be explored.
ETMR-05. DEVELOPMENT OF NOVEL PRECLINICAL MODELS AND THERAPEUTIC STRATEGIES FOR ETMR
Authors: Cocito Carolina , Arias-Stella Esteban Uceda , Padilla Christopher C , Zhang Xiaohu , McKnight Crystal , Itkin Zina , Klumpp-Thomas Carleen , Holland David , Beck Erin , Cruzeiro Gustavo Alencastro Veiga , Chi Susan N , Pisapia David J , Filbin Mariella G , Souweidane Mark M , Dahmane Nadia , Thomas Craig J , Greenfield Jeffrey P
Published: June 2024

BACKGROUND

Embryonal Tumor with Multilayered Rosettes (ETMR) is a very rare, aggressive pediatric brain tumor with a dismal 5-year overall survival rate. Few genetic aberrations in miRNA clusters and processing machinery have been detected in ETMRs with 90% of ETMR patients having the C19MC amplification. ETMRs show unique histopathological features which, together with the detection of C19MC or DICER alterations, are necessary for diagnosis. The cellular and molecular mechanisms underlying ETMR development are poorly understood, and targeted therapeutics have not been developed due to scarcity of preclinical models. To expand knowledge of ETMR biology and accelerate the design of novel and therapies, it is thus essential to develop preclinical models.

METHODS

We have generated two novel patient-derived ETMR cell lines from resected patient derived tumor samples (CTBP-03A and CBTP-139) and created three patient-derived xenograft (PDX) models (CTBP-03A, CBTP-139 and CBTP-38). We have used these unique patient-derived cell lines to identify mechanisms driving ETMR development and progression. To identify novel therapeutic targets, we conducted high-throughput drug screening (HTDS) utilizing 2480 approved and investigational drugs, against the CBTP-03A and CBTP-139 lines.

RESULTS

Among the candidate drugs showing an inhibitory effect on both lines, compounds were selected based on their activity, CNS penetration ability, mechanism of action, and bioavailability, if known. The top selected hits were screened in an all-versus-all format, totaling 1953 combinations. The rapidity of action and efficacy of the top choice compounds used as single agent or in double and triple combination was assessed by caspase glow and cell titer glow assays. This initial combination screen identified DNA replication stress, retinoid receptor agonist and FGF signaling as potential combinatorial targets. Data are currently being validated in vivo.

CONCLUSIONS

This is the first combinatorial HTDS on two novel patient-derived cell lines which highlighted potential drug combination strategies for the treatment of ETMR.
ETMR-09. HEALTH-RELATED QUALITY OF LIFE OF CHILDREN, ADOLESCENTS AND ADULTS AFTER DIAGNOSIS OF CHILDHOOD-ONSET MENINGIOMA
Authors: Wagener Katharina , Beckhaus Julia , Friedrich Carsten , Müller Hermann L
Published: June 2024

BACKGROUND

Meningiomas are rare intracranial tumors in childhood. Childhood-onset meningiomas differ from their adult counterparts in terms of frequency, molecular features and clinical presentation. There is limited data on health-related quality of life (HRQoL) of pediatric meningioma patients. The aim of this study was to analyze the HRQoL of pediatric or adult patients after completion of treatment for childhood-onset meningioma. Further, the influence of disease-specific characteristics on HRQoL, fatigue or functional capacity was analyzed.

METHODS

In this cross-sectional study, the HRQoL of 8 pediatric and 27 adult meningioma patients from the clinical trials HIT-ENDO, KRANIOPHARYNGEOM 2000/2007 and KRANIOPHARYNGEOM Registry 2019 was assessed. The validated questionnaires EQ-5D-Y, EQ-5D-3L, PedsQL Generic Core Scale, EORTC QLQ-C30 and QLQ-BN20 were used. Patients’ fatigue and functional capacity were scored using the EORTC QLQ-C30, the PedsQL Multidimensional Fatigue Scale and the FMH questionnaire. Exploratory data analysis was performed using univariate, bivariate and multivariate analyses (α=0.05).

RESULTS

The HRQoL was assessed in median 10 (IQR: 5-17) years after diagnosis. The mean HRQoL value was 86 (IQR: 79-92) for pediatric and 75 (IQR: 67-92) for adult patients using the PedsQL Generic Core Scale or EORTC QLQ-C30 questionnaire, respectively. Most limitations were reported in emotional function and fatigue. The median functional capacity of patients was at the 90th (IQR: 65-90) percentile. HRQoL was lower in adults with neurofibromatosis type 2 or at older age (p=0.009) and higher HRQoL after progressive disease. Age at diagnosis, WHO grade, residual tumor, use of radiotherapy, tumor location, tumor entity (meningioma vs. craniopharyngioma), degree of disability, or time since diagnosis did not affect HRQoL in adults.

CONCLUSION

The median HRQoL of childhood-onset meningioma patients indicates that it is comparable to the healthy normal population. Nevertheless, HRQoL is a construct that can be influenced in many ways. Further research on HRQoL is warranted.
ETMR-26. MIR-34/449 FAMILY PLAYS A CRUCIAL ROLE IN CHOROID PLEXUS MULTICILIATION AND TUMORIGENESIS
Authors: Guru Navjot , Zaman Ahnaf , Umer Maheen , Zahran Mariam , Siluveru Anjali , Faltings Lukas , Virga James , Attia Andrew , Cao Ping , Zhao Haotian
Published: June 2024

BACKGROUND

Choroid plexus (CP), an epithelial structure within the brain ventricles, produces cerebrospinal fluid and serves barrier functions in the brain. Primary CP neoplasms are rare intracranial tumors that predominantly occurs in childhood. Recent studies revealed multiciliated cells in the CP in humans and mice. In contrast, benign CP papilloma, and malignant CP carcinoma (CPC) in humans are characterized by solitary cilia, and disturbances to multiciliation program directed by transcription factor GMNC. Additionally, most CPC in humans carry mutations in TP53 tumor suppressor. Consistently, Trp53-deficient CPC in mice display singular cilia consequent to defects in GMNC multiciliation program. Thus, the impairment of multiciliation enables tumor cell proliferation. MicroRNAs (miRNAs) are non-coding small RNAs with gene regulatory functions. Specifically, the mir-34/449 family comprises of six miRNAs collaborate to influence multiciliation in diverse tissues but role of mir-34/449 family in the brain is poorly understood. Knowledge of multiciliation program regulation may provide crucial insights into tumor suppression mechanisms in CPC.

METHODS

To investigate the role of mir-34/449 family in the CP, human CP organoid and mir-34/449 mutant animals were used. RNAscope, In situ hybridization as well as immunofluorescence staining was utilized to identify gene expression in tissues.

RESULTS

Preliminary studies revealed GMNC program activity and multiciliated cells in CP organoid derived from human induced pluripotent stem cells. Disruption of the mir-34/449 family led to supernumerary cilia and ectopic multiciliation program activity in the CP. Importantly, Trp53-deficient CPC exhibited distinct expression of the mir-34/449 family. Further, sequencing studies revealed an overlap of differentially expressed miRNAs in CP tumors in humans and mice, with an enrichment of the mir-34/449 family.

CONCLUSIONS

Together, these findings indicate that the mir-34/449 family regulates multiciliation in the CP, whereas the study of its interactions with the multiciliation program holds the key to understanding multiciliation as a tumor suppression pathway in CPC.