bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-04. Intramedullary spinal high grade glioma with ALK fusion and excellent response to targeted treatment with alectinib: case report
Authors: Dvir Rina , Ringel Amit , Elhasid Ronit , Constantini Shlomi , Roth Jonathan 
Published: June 2022

Abstract
INTRODUCTION: Intramedullary spinal cord high grade gliomas are rare pediatric tumors , with a grim prognosis. Current therapeutical strategies include a surgical resection if feasible, and radiotherapy. Additional treatments with various chemotherapy agents have had a minor effect and did not change the course of the disease. New molecular targets are a source of hope. Recent molecular evidence regarding high grade infantile hemispheric gliomas describe specific tyrosine kinase receptor fusions or mutations in ALK, ROS, NTRK and MET domains which may lead to therapeutical targets. There is no data regarding these molecular changes in infantile intramedullary high grade gliomas. We present a two year old girl with a cervical high grade glioma with an ALK mutation which received targeted therapy. CASE REPORT: A two year old girl presented with progressive torticollis and hemiparesis. An intramedullary cervical tumor with ill -defined borders was diagnosed. A limited partial excision was performed and the pathological diagnosis was high grade glioma. Within weeks she developed progressive clinical and radiological deterioration. Molecular studies (Oncomine) revealed an ALK fusion (KIF5B) which was confirmed by immunohistochemistry. Treatment with ALK inhibitor alectinib at 150mg daily was initiated. Torticollis resolved within a week, and MRI after 3 months showed outstanding tumor shrinkage with a small residual mass. There were no adverse events to treatment. DISCUSSION: ALK fusion positive high grade glioma has recently been recognized in infants with hemispheric tumors, and a preliminary recent case report demonstrated excellent response to ALK inhibitors. Intramedullary spinal cord high grade gliomas are rare and harbor poor prognosis. This is the first case of ALK fusion glioma of the spine with excellent preliminary response to alectinib. The duration of treatment and long term prognosis is unknown. Molecular investigations can change the approach to pediatric rare CNS tumors.
HGG-08. Lorlatinib for the treatment of ALK fusion positive infant high grade glioma
Authors: Greenwell Alyssa , Altinok Deniz , Marupudi Neena , Kupsky William , Gorsi Hamza 
Published: June 2022

Abstract
BACKGROUND: High grade gliomas (HGG) are very rare in the infant age group with approximately 800 cases diagnosed in the USA and Europe each year. Histologically, HGG in infants resemble HGG in older children and adults but have distinct molecular features like ALK, NTRK, MET and ROS1 fusions. HGG in infants have superior outcomes compared to older age groups (5-year overall survival &gt;50%) when treated with a radiation sparing regimen. Here we present the unique treatment course for an infant with ALK fusion positive HGG, including molecularly targeted therapy. CASE DESCRIPTION: A 3-month-old African-American female presented with acute onset vomiting, right facial droop and focal seizures. MRI of the brain revealed a right frontal intraparenchymal mass. Upfront gross total resection (GTR) was performed and histologic diagnosis of epithelioid glioblastoma was made. The molecular analysis of the tumor showed ZNF397-ALK fusion. The patient was treated with a radiation sparing regimen consisting of Carboplatin 8 mg/kg x 2 days and Etoposide 3 mg/kg x 3 days for 6 cycles. The patient tolerated the chemotherapy and had no evidence of disease recurrence at the completion of chemotherapy. However, 8 months after completion of therapy, she had a localized relapse and underwent a second GTR. Repeat molecular analysis confirmed the presence of ZNF 397-ALK fusion. She was started on Lorlatinib at 95 mg/m2/day once a day. She continued on the medication for 15 months and had no evidence of disease at the end of 15 months. During the course of her treatment, she had excessive weight gain (CTCAE grade-3) despite dose reduction. CONCLUSION: Infant high grade gliomas have a high prevalence of gene fusions including ALK fusions. This case shows that these fusions may be amenable to molecularly targeted treatments and should be studied in prospective clinical trials.
HGG-16. Final analysis of the HIT-HGG-2007 trial (ISRCTN19852453): Significant survival benefit for pontine and non-pontine pediatric high-grade gliomas in comparison to previous HIT-GBM-C/-D trials.
Authors: von Bueren Andrè O , Kwiecien Robert , Gielen Gerrit H , Benesch Martin , Perwein Thomas , Nussbaumer Gunther , Sturm Dominik , Jones David T W , Pfister Stefan M , Eyrich Matthias , Rutkowski Stefan , Fleischhack Gudrun , von Buiren Miriam , Karremann Michael , Kortmann Rolf-Dieter , Hagel Christian , Calaminus Gabriele , Faldum Andreas , Bison Brigitte , Pietsch Torsten , Hoffmann Marion , Kramm Christof M 
Published: June 2022

Abstract
The aim of the HIT-HGG-2007 trial (ISRCTN19852453) was to demonstrate therapeutic non-inferiority of temozolomide radiochemotherapy for pediatric patients (3-18 years) with high-grade gliomas (pedHGG) in comparison to the cisplatinum-based radiochemotherapy of the two previous clinical trials HIT-GBM-C/-D. Between 06/2009 and 12/2016, 456 patients were enrolled at 79 centers in Germany, Austria, and Switzerland (n=18 dropouts, remaining patients for confirmatory analysis: n=438). 438 patients from HIT-GBM-C/-D served as historical control. All pedHGG diagnoses had been confirmed by central neuroradiological and neuropathological review. Primary objective was achieved since non-inferiority of HIT-HGG-2007 in comparison to HIT-GBM-C/-D as indicated by 6 months event-free survival (EFS) was statistically confirmed (p=0.0125). Statistical survival analyses even revealed a better overall survival (OS) and EFS for HIT-HGG-2007 patients in comparison to their HIT-GBM-C/-D counterparts (EFS: p&lt;0.0001; OS: p=0.0328). While EFS subgroup analyses for pontine and non-pontine pedHGG also showed a better survival of HIT-HGG-2007 patients (median EFS pontine pedHGG: 8.2 (n=152; confidence interval (CI): 7.6-9.4) versus 6.2 (n=170; CI: 5.5-6.9) months, p=0.0079; median EFS non-pontine pedHGG: 10.7 (n=276; CI: 9.6-12.4) versus 7.4 (n=267; CI: 6.4-9.2) months, p&lt;0.0001), OS was only improved in HIT-HGG-2007 patients with non-pontine pedHGG (median OS non-pontine pedHGG: 19.3 (CI: 16.8-23.3) versus 16.2 (CI: 14.2-19.1) months; p=0.0181) but not with pontine pedHGG (median OS pontine pedHGG: 11.4 months versus 11.3 months, p=0.4021) Toxicity profile of HIT-HGG-2007 seemed very favorable with most CTCAE (common toxicity criteria adverse event) ≥ grade 3 as hematological toxicity, hepatotoxicity, and neurotoxicity. Less toxicity was observed during concomitant radiochemotherapy in comparison to HIT-GBM-C/-D. Further subgroup survival analyses as well as the assessment of the impact of MGMT promoter methylation are ongoing. In conclusion, our data show non-inferiority of the HIT-HGG-2007 trial with increased survival and less toxicity when compared with previous trials HIT-GBM-C/-D.
HGG-30. H3.3 G34R/V mutations disrupt H3.3 mitotic phosphorylation leading to high-grade glioma formation through the induction of chromosomal instability
Authors: Day Charles , Grigore Florina , Hakkim Faruck , Langfald Alyssa , Hinchcliffe Edward , Robinson James 
Published: June 2022

Abstract
Pediatric high-grade gliomas (pHGG) are among the most lethal of all human cancers. Histone H3.3 G34R/V mutations are an early event in these tumors and show reduced H3.3 K36 trimethylation; implicating epigenetic dysregulation in tumorigenesis. Here we present evidence that H3.3 G34R/V mutations promote tumor formation via the induction of chromosomal instability (CIN). Pericentromeric H3.3 is phosphorylated at S31 by Chk1 during mitosis. We observed that the H3.3 G34R mutation reduced Chk1 phosphorylation of H3.3 S31 by &gt;90% in vitro. Furthermore, H3.3 G34 mutant cells have reduced pericentromeric H3.3 S31 phosphorylation in mitosis compared to WT H3.3 cell lines. H3.3 G34 mutant pHGG cells also have significantly elevated rates of CIN as compared to H3.3 WT cells. Overexpression of H3.3 G34R, G34V or non-phosphorylatable S31A in H3.3 WT, diploid cells caused a significant increase in CIN, but H3.3 K36M overexpression had no effect on chromosome segregation. These studies demonstrate that H3.3 G34R/V mutations are sufficient to induce CIN in normal, diploid cells. To determine if this process contributes to tumorigenesis, we used RCAS Nestin-TVA mice to overexpress H3.3 WT, G34R, or S31A – P2A-linked to PDGFB in glial precursor cells of newborn mice. Over 100 days, S31A and G34R mice had drastically reduced survival (averaging 77, 81, and 100 days for S31A, G34R, and WT). Furthermore, most G34R and S31A mice developed HGG, while H3.3 WT mice remained tumor-free. Our work implicates CIN as a driver of H3.3 G34 mutant pHGG formation.
HGG-33. Prognostic factors of H3K27M histone-mutant diffuse midline gliomas in patients ≤18yrs
Authors: Hu Qingjun , Lai Mingyao , Li Juan , Cai Linbo 
Published: June 2022

Abstract
OBJECTIVE：Diffuse midline gliomas associated with high malignancy and poor prognosis. The primary treatment modalities include surgery, radiotherapy and chemotherapy. The purpose of this study was to investigate the prognostic factors of diffuse intracranial midline glioma. METHODS: A retrospective analysis was performed on 44 cases younger than 18 yrs of H3K27M histone-mutant diffuse midline gliomas diagnosed in Guangdong Sanjiu Brain Hospital from November 2017 to November 2021. The median age was 9 years (range:3-18), including 24 males and 20 females, lesions located in thalamus were 9, while in brain stem were 35. Treatment methods: 35 cases received radiotherapy, 9 cases did not. Among the patients who received RT, 26 cases with concurrent chemoradiotherapy + adjuvant chemotherapy, 8 cases with concurrent chemoradiotherapy only, and 1 case only with radiotherapy. Kaplan-meier method was used to calculate overall survival (OS), and log-rank test was used to test. P &lt; 0.05 was considered statistically significant. RESULTS: By January 27, 2022, 13 cases survived, 25 cases died, and 6 cases were lost to follow-up. The median survival time of 44 patients was 6.95 months (range：1-23.5 months). The median survival was 8.4 months in the radiotherapy group vs 3.7 months in the non-radiotherapy group (P＜0.001); The median survival time of radiotherapy without adjuvant chemotherapy vs radiotherapy with adjuvant chemotherapy was 6.2 months vs 9.35 months (P=0.479). CONCLUSION: Radiotherapy can prolong the survival time of diffuse midline glioma in children with H3K27M histone mutant but no survival benefit was observed in patients with concurrent chemotherapy.
HGG-35. Radiation Induced High Grade Gliomas: A Single Center Experience
Authors: Joshirao Mrinal , Sait Sameer Farouk , Bouvier Nancy , Hill Katherine , Khakoo Yasmin , Kramer Kim , Gilheeney Stephen , Wolden Suzanne , Nolan Craig , Schaff Lauren , Rosenblum Marc , Bale Tejus A , Yang Jonathan T , Lin Andrew , Dunkel Ira J , Karajannis Matthias 
Published: June 2022

Abstract
INTRODUCTION: Patients receiving cranial radiotherapy (RT) are at risk for a subsequent radiation-induced glioma (RIG). RIGs are rare, generally develop with a latency of 2 years to several decades, display high-grade histology and an aggressive clinical course with poor prognosis. METHODS: We retrospectively analyzed patients with a diagnosis of RIG seen at our institution from 2001-2021, analyzing clinical, histological, molecular, and genetic characteristics. RESULTS: Twenty-one patients (n=15 male) with a history of ALL (n=6), medulloblastoma (n=5), germ cell tumors (n=4), or other (n=6) diagnosed at a median age of 8.3 years (range 1.6 to 36.4) were identified. Median age at RIG diagnosis was 18 years (range 7.8 to 66.9). Prior RT was focal+craniospinal (n=7), whole brain (n=5), total body (n=3), focal (n=1), or unknown (n=5). Median radiation dose received was 2,340 cGy (range 1,200 to 5,400). The median time from RT to RIG diagnosis was 7.7 years (range 1.6 to 23.8). All RIGs were histologically high grade (WHO Grade III or IV). Immunohistochemistry did not reveal IDH(R132H) (n=9) or H3K27M (n=8) in any tumor. Some tumors demonstrated loss of expression of ATRX (1/9) and/or H3K27me3 (3/6), and/or strong diffuse expression of p53 (0/3). Targeted panel sequencing (n=10) revealed recurrent somatic alterations including CDKN2A/B, PDGFRa/KIT/KDR, TEK, MTAP, ATM and NF1. Germline alterations were detected in 4/12 patients (pathogenetic variants in ATM, CHEK2, HOXB13 and NF1). With median follow-up of 4.5 years, two-year PFS and OS for the cohort (n=20) were 10% and 44% respectively. Two patients (with anaplastic oligodendroglioma and anaplastic astrocytoma) are alive without progression 5.4 and 13.6 years after diagnosis following surgery, RT and chemotherapy. CONCLUSION: Although RIGs are associated with a poor prognosis, they are not always fatal. Our findings suggest aggressive therapy should be considered for these patients.
IMMU-03. Synergy between TMZ and individualized multimodal immunotherapy to improve Overall Survival of IDH1 wild-type MGMT promoter-unmethylated GBM patients
Authors: Van Gool Stefaan , Makalowski Jennifer , Bitar Michael , Van de Vliet Peter , Schirrmacher Volker , Stuecker Wilfried 
Published: June 2022

Abstract
The prognosis of IDH1 wild-type MGMT promoter-unmethylated GBM patients remains poor. Addition of Temozolomide (TMZ) to first-line local treatment shifted the median overall survival (OS) from 11.8 to 12.6 months. We retrospectively analysed the value of individualized multimodal immunotherapy (IMI) to improve OS in these patients. All adults meeting the criteria and treated 06/2015-06/2021 were selected. Thirty-two patients (12f, 20m) had a median age of 47y (range 18-69) and a KPI of 70 (50-100). Extent of resection was complete (11), &lt;complete (12) or not documented (9). Seven patients were treated with surgery/radio(chemo)therapy and subsequent IMI (Group-1); 25 patients were treated with radiochemotherapy followed by maintenance TMZ plus IMI during and after TMZ (Group-2). Age, KPI and extent of resection were not different amongst both groups. The median OS of group-1 patients was 11m (2y OS: 0%). Surprisingly the median OS of group-2 patients was 22m with 2y OS of 36% (CI95%: 16-57), which was significantly (Log-rank: p = 0.0001) different from group-1. The data suggest that addition of IMI after local therapy on its own has no relevant effect on OS in these GBM patients, similar to maintenance TMZ. However, the combination of both TMZ + IMI significantly improved OS. This finding might also have implications in the search for novel combined treatment approaches for children with malignant glioma.
IMMU-09. Interim analysis from BrainChild-03: Seattle Children’s Locoregional B7-H3 CAR T Cell Trial for Children with Recurrent Central Nervous System Tumors and DIPG
Authors: Vitanza Nicholas , Gust Juliane , Wilson Ashley , Huang Wenjun , Chen Dickson , Meechan Michael , Biery Matt , Myers Carrie , Tahiri Sophie , Crotty Erin , Leary Sarah , Cole Bonnie , Browd Samuel , Hauptman Jason , Lee Amy , Albert Catherine , Pinto Navin , Orentas Rimas , Gardner Rebecca , Jensen Michael , Park Julie 
Published: June 2022

Abstract
BrainChild-03 is a phase 1 clinical trial delivering repeated locoregional 2nd generation B7-H3 CAR T cells with 4-1BB co-stimulation to children with central nervous system (CNS) tumors without lymphodepleting chemotherapy. The primary endpoints are feasibility and safety, with secondary endpoints of disease response and correlatives of CAR T cell activity. There are 3 arms: (A) – weekly delivery into the tumor cavity, (B) – weekly delivery into the lateral ventricle for metastatic disease, (C) – biweekly delivery into the lateral ventricle for diffuse intrinsic pontine glioma (DIPG). In total, 23/24 (96%) enrolled patients have had successful CAR T manufacturing. 16/24 patients are evaluable and have received a total of 141 intracranial CAR T cell doses. Unevaluable patients include 5 never treated and 3 who progressed prior to receiving the minimum doses to become evaluable. The most common adverse events have been headache (16/16, 100%), nausea/vomiting (12/16, 75%), and fever (10/16, 63%). There has been 1 DLT for an intratumoral hemorrhage and no cytokine release syndrome (CRS). 7 evaluable patients with DIPG (Arm C) have received a cumulative 50 infusions. 5/7 DIPG patients enrolled after progression and have a median survival of 246.5 days post-initial CAR T cell infusion, with 4/5 still alive. The 2 DIPG patients enrolled prior to progression had radiographic improvement, including 1 with improvement of a cranial nerve 6 palsy who self-withdrew from protocol therapy after 18 infusions over 12 months and 1 still on protocol therapy after 11 infusions over 6 months. DIPG patients have had increased CSF levels of proinflammatory mediators (e.g. CXCL10, CCL2, IFNg, GM-CSF, IL-12) without systemic cytokine changes. 5/7 DIPG patients had detectable CAR T cells in their CSF post-infusion. Ultimately, the preliminary experience suggests locoregional delivery of B7-H3 CAR T cells may be feasible and tolerable in children with CNS tumors, including DIPG.
LGG-14. LOGGIC (Low Grade Glioma in Children) Core BioClinical Data Bank: Establishment and added clinical value of an international molecular diagnostic registry for pediatric low-grade glioma patients
Authors: Hardin Emily C , Schmid Simone , Sommerkamp Alexander , le Simon Michè , Caspar Claudia , Bodden Carina , Heipertz Anna-Elisa , Sievers Philipp , Wittmann Andrea , Perera Ashwyn A , Milde Till , Pfister Stefan M , von Deimling Andreas , Driever Pablo Hernáiz , Koch Arend , Hargrave Darren , Witt Olaf , Capper David , Sahm Felix , Jones David T W , van Tilburg Cornelis M 
Published: June 2022

Abstract
BACKGROUND: The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data. In addition to routine histopathological and molecular analyses, LOGGIC Core determines the driver alteration as precisely as possible to support treatment decisions and participation in interventional trials. Hence, the question arises whether comprehensive implementation of RNA sequencing using Fresh Frozen (FF) tumor tissue to identify underlying gene fusions improves diagnostic accuracy and provides a clinical benefit.
METHODS: Establishment of an international molecular and clinical registry including the logistical and analytical pipeline. First analysis of all patients age 0 to 18, which were included in Germany as part of the German HIT-LOGGIC-program between April 2019 and February 2021, and for whom FF tissue was available. This included histopathological evaluation, immunohistochemistry, 850k methylation analysis, gene panel sequencing, RNA sequencing using FF tissue.
RESULTS: FF tissue was available in 178/379 included cases. RNA sequencing was performed on 125 samples. In this prospective, population based cohort, we confirmed KIAA1549:BRAF-fusion (57%), BRAFV600E-mutation (9%) and FGFR1-changes (10%) as most frequent alterations. 12% of cases presented rare gene fusions (e.g. TPM3:NTRK1, EWSR1:VGLL1, GOPC:ROS1, SH3PXD2A:HTRA1, PDGFB:LRP1). In 19% of cases, RNA sequencing detected an actionable target not identified by conventional methods.
CONCLUSION: The addition of RNA sequencing reveals clinically relevant alterations including rare gene fusions. By demonstrating improvement of diagnostic accuracy and making precision oncology studies (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible, the added value for pLGG patients becomes apparent. LOGGIC Core is currently being rolled out internationally and aims to define the new state of the art standard molecular diagnostics. We propose to include RNA sequencing as part of routine diagnostic procedures for all pLGG patients, especially in tumors where no common MAPK alteration was identified.
LGG-25. The first-in-class ERK inhibitor ulixertinib (BVD-523) shows activity in MAPK-driven pediatric low-grade glioma models as single agent and in combination with MEK inhibitors or senolytics
Authors: Sigaud Romain , Rösch Lisa , Gatzweiler Charlotte , Benzel Julia , von Soosten Laura , Peterziel Heike , Najafi Sara , Ayhan Simay , Gerloff Xena F , Hofmann Nina , Büdenbender Isabel , Foerster Kathrin I , Burhenne Jürgen , Longuespée Rémi , van Tilburg Cornelis M , Jones David T W , Pfister Stefan M , Knoerzer Deborah , Kreider Brent , Sauter Max , Pajtler Kristian W , Zuckermann Marc , Oehme Ina , Witt Olaf , Milde Till 
Published: June 2022

Abstract
Ulixertinib (BVD-523) is a catalytic ERK1/2 inhibitor that showed promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. Pediatric low-grade gliomas (pLGG) are the most common pediatric brain tumors, with the most frequent driving alterations in the MAPK pathway. The anti-tumor activity of ulixertinib in pLGG and its potential synergism in combination with MEK inhibitors, senolytics, and chemotherapy were investigated in vitro using metabolic activity, MAPK reporter assay and high-content microscopy in pLGG-derived cell lines (DKFZ-BT66 - KIAA:BRAF fusion; BT40 - BRAF V600E mutation and CDKN2A/B deletion). The most clinically relevant combinations were further validated in vivo: 1) in zebrafish embryo models (BT40 and DKFZ-BT66 yolk sac injection) and 2) in NSG mice (BT40 orthotopic PDX) including in vivo pharmacokinetic and -dynamic analyses. Ulixertinib inhibited MAPK pathway activity in all models and reduced cell viability in the BRAF V600E mutated cell line at concentrations in the nanomolar range. In vivo pharmacokinetic and -dynamic analyses showed penetrance of the drug into mouse brain tissue and on-target activity, with concentrations above the in vitro IC50 and reduction of MAPK activity. Ulixertinib treatment slowed tumor growth and significantly increased survival in NSG mice with BT40 xenografts. Ulixertinib showed indications for anti-proliferative synergy in vitro in combination with MEK inhibitors (trametinib, binimetinib) or BH3 mimetics (navitoclax, A-1331852). Combinations with chemotherapy (carboplatin, vinblastine) were at most additive. Indications for synergy with binimetinib and navitoclax were confirmed in the zebrafish embryo models. In the NSG mouse model, the combination of ulixertinib with senolytics induced effects on tumor growth and survival comparable to ulixertinib monotherapy. Ulixertinib shows promising potential as a clinically relevant therapeutic option for the treatment of pLGG to be further investigated in upcoming clinical trials. Potential synergism with MEK inhibitors and BH3 mimetics was noted and warrants further investigation.