bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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 (&lt; 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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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 &lt;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

Abstract

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 &lt;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 &lt;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.