bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-34. THE LANDSCAPE OF GLIOMAS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS REVEALS INSIGHTS ON GLIOMAGENESIS: A CANADIAN ADOLESCENTS AND YOUNG ADULTS NEURO-ONCOLOGY NETWORK (CANON) STUDY
Authors: Bennett Julie , Levine Adrian , Nobre Liana , Negm Logine , Chung Jiil , Fang Karen , Johnson Monique , Komosa Martin , Krumholtz Stacey , Nunes Nuno Miguel , Rana Mansuba , Ryall Scott , Sheth Javal , Siddaway Robert , Bale Tejus A , Bouffet Eric , Cusimano Michael , Das Sunit , Detsky Jay , Dirks Peter , Karajannis Matthias , Kongkham Paul , Giantini-Larsen Alexandra , Li Bryan Kincheon , Lim-Fat Mary Jane , Lin Andrew , Mason Warren , Miller Alexandra , Perry James , Sahgal Arjun , Sait Sameer Farouk , Tsang Derek S , Zadeh Gelareh , Laperriere Normand , Nguyen Lananh , Gao Andrew , Keith Julia , Munoz David G , Tabori Uri , Hawkins Cynthia 
Published: June 2024

Abstract

BACKGROUND
Gliomas are a heterogenous and common cancer in children, adolescents and young adults (CAYA, ages 0-39 years). Little is known about the biologic and clinical implications of gliomas in AYA limiting our ability to appropriately manage these patients.

METHODS
We compiled a population-based cohort of patients with glioma aged 0-39 years diagnosed between 2000-2020, performed molecular characterization of the tumors and collected clinical data including therapy and long-term outcome.

RESULTS
A total of 1456 patients, including 873 AYA patients were included. A pathogenic molecular alteration was found in 98% of AYA samples available. Strikingly, pediatric-type mutations were found in 31% of AYA glioma of which 37% were BRAF V600E and 23% FGFR alterations. Important differences were observed between gliomas in children versus AYAs. First, hemispheric tumors were enriched in AYAs compared to midline tumors in children, especially for RAS/MAPK alterations. Second, increased incidence of high grade tumors in AYA compared to children were observed for BRAF V600E and FGFR mutations (p&lt;0.0001). In contrast, if these alterations were identified in AYA and the tumor was low grade, outcome was improved for BRAF V600E and FGFR mutant tumors in AYAs compared to pediatrics (for BRAF V600E 5 year PFS 55.6% &lt;10 years, 78.1% for 10-20 years and 87.1% for 10-20 years of age, p=0.0002). Third, a specific time window for transformation was observed for each alteration (BRAF, FGFR, IDH). This correlated with different methylation profiles and transcriptional patterns between early midline and late hemispheric tumors. Increased senescence signatures were observed in older patients with low grade RAS/MAPK driven tumors with superior outcome.

CONCLUSIONS
Different cell of origin and secondary mutations shape tumor behavior and lead to either transformation or senescence during gliomagenesis in CAYA. These can affect early interventions and tailored approaches for gliomas by age and molecular alteration.
LGG-37. A PHASE III STUDY COMPARING TWO CARBOPLATIN CONTAINING REGIMENS FOR CHILDREN AND YOUNG ADULTS WITH PREVIOUSLY UNTREATED LOW-GRADE GLIOMA
Authors: Lenen Alicia , Waanders Angela J , Bazzi Latifa , Zhang Hui , Lai Jin-Shei , Plant-Fox Ashley S , Cluster Andrew , Crawford John , Cohen Ken , Dickens David , Dole Mukund , Goodman Jessica , Hoffman Lindsey , Koschmann Carl , Lazow Margot , Marks Asher , Puccetti Diane , Skrypek Mary M , Tanaka Ryuma , Weintraub Lauren , Wright Karen , Rush Sarah Zieber , Fangusaro Jason , Lulla Rishi , Goldman Stewart , Pillay-Smiley Natasha 
Published: June 2024

Abstract

BACKGROUND
Low-grade glioma (LGG) is the most common childhood central nervous system tumor. Carboplatin/vincristine (CV) is a standard of care regimen used for incompletely resected tumors. Monthly carboplatin is an alternative regimen that has not been prospectively compared to CV previously in untreated patients.

METHODS
Patients ≤ 21 years with LGG and no treatment besides surgery were eligible. Patients were stratified according to NF1 status and randomized to Arm A (carboplatin/vincristine) or Arm B (carboplatin monthly). The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoint analysis is underway and includes quality of life, tumor response rates, toxicity and association of molecular alterations on outcomes. Analyses included log-rank test and descriptive statistics.

RESULTS
There were 95 evaluable patients with a median age of 5 (range 0-18) years; 67 non-NF1 subjects (32 Arm A, 35 Arm B) and 28 NF1 subjects (14 Arm A, 14 Arm B). Three-year PFS was superior for patients without NF1 treated on Arm A (58%; 95% CI: 38%, 74%) versus Arm B (33%; 95% CI: 18%, 49%) (p=0.04). In patients with NF1, there was no statistical difference in PFS between those treated on Arm A (71%; 95% CI: 41%, 88%) and Arm B (93%; 95% CI: 59%, 99%) (p=0.08). Grade 3/4 toxicity neutropenia was more commonly seen in Arm A patients compared to Arm B for both NF and non-NF1 patients. Peripheral neuropathy was also more commonly seen in non-NF1 patients (Grade 1-4; 32%) compared to NF1 patients (7%) for patients treated on Arm A. There were 15 carboplatin reactions (Grade 1-4); 7 non-NF1 on Arm A, 3 non-NF1 on Arm B, and 5 NF1 on Arm A.

CONCLUSIONS
Non-NF1 patients treated with carboplatin and vincristine show statistically significant improved PFS compared to monthly carboplatin. Patients with NF1 are statistically underpowered due to low accrual.
LGG-42. TWENTY YEARS OF PROGRESS IN MANAGING LOW GRADE GLIOMA: THE EXPERIENCE OF THE UNIVERSITY OF CAPE TOWN’S COMBINED PAEDIATRIC NEURO-ONCOLOGY SERVICE FROM 2001 TO 2022
Authors: Davidson Alan , Figaji Anthony , Pillay Komala , Hendricks Marc , Naiker Thuran , Parkes Jeannette 
Published: June 2024

Abstract

BACKGROUND
This study aimed to review the management of childhood low grade gliomas (WHO I and II) by the University of Cape Town’s combined neuro-oncology service at Red Cross War Memorial Children’s and Groote Schuur Hospitals.

METHODS
All patients diagnosed with low grade glioma between 2001 and 2022 were included in this retrospective study. Real time decision-making during the study period was achieved via a weekly neuroimaging meeting, and surveillance by a combined monthly clinic attended by paediatric endocrinology and educational psychology. Despite state of the art surgical and radiotherapy facilities, molecular diagnostics, monoclonal antibodies and small molecules were only available to selected patients.

RESULTS
Among 129 children, aged 0.38 to 14.58 years [median 5.36], six had Tuberous Sclerosis and 11 had Neurofibromatosis-1. The commonest sites were cerebellum (26%), hypothalamus (17%) and optic pathway (16%), and 12 patients (9%) had metastatic disease, mostly grade I supratentorial tumours. Twenty-three patients were diagnosed on imaging without histology, six of whom were biopsied subsequently, yielding a total of 96 grade I and 16 grade II tumours. Initial management was expectant in 16% (including 8 of the 11 Nf-1 tumours), surgery in the form of debulking or total resection in 53%, chemotherapy in 24% and radiotherapy in 8%. Ultimately 36% received chemotherapy and 29% radiotherapy (almost all of them focal RT), and only 16% of those treated with radiotherapy progressed. Estimated 5-year Overall Survival (OS) and Progression Free Survival (PFS) was 90.5% and 52.6% for the whole group. Patients treated with chemotherapy had an OS of 87.2% and a PFS of 39.2%. PFS and OS were inferior for metastatic disease but not for grade II tumours.

CONCLUSIONS
Low grade glioma can be managed effectively in a middle-income country setting. Multidisciplinary team management is crucial to achieving positive outcomes regardless of context.
LGG-43. LASER-ASSISTED ENDOSCOPIC RESECTION OF TECTAL GLIOMA IN A 3-YEAR-OLD CHILD
Authors: Tuniz Francesco , Fabbro Sara , Piccolo Daniele , Vindigni Marco , Liguoro Ilaria , Pilotto Chiara , Toniutti Maristella , D’Agostini Serena , De Colle Maria Cristina , Pegolo Enrico , Cogo Paola , Skrap Miran 
Published: June 2024

Abstract

BACKGROUND
Pediatric tectal gliomas generally have a benign clinical course. However, some patients may present with non-communicating hydrocephalus needing endoscopic procedures. Historically, lasers have been used in neurosurgical procedures including neuroendoscopy, but their adoption was limited by a significant rate of complication due to their inappropriate wavelength and uncontrollable tissue interaction. Recently, a 2-micron near-infrared laser with adequate wavelength and minimal tissue penetration became available.

CASE-REPORT
We describe the case of a 3-year-old child who presented with gait ataxia, papilloedema and headache. Magnetic Resonance (MR) was performed and he was diagnosed with obstructive hydrocephalus due to tectal glioma. Endoscopic third ventriculostomy (ETV) and simultaneous endoscopic biopsy were performed during the same surgery using a single burr hole with a rigid endoscope, a 2-micron continuous-wave thulium laser and the aid of neuronavigation. After tumoral sample removal, the laser was used for hemostasis and to evaporate tissue near the tumour without mechanical stress to the brain tissue. The final histological analysis identified a non-otherwise specified (NOS) low-grade glioma. The hospitalization was uneventful and the boy was discharged home after 4 days. No new cognitive impairment was reported secondary to this procedure and the symptoms present in the preoperative period completely improved. At 1-year follow-up, neurological examination findings were unremarkable, and there was no radiographic evidence of tumour progression.

CONCLUSIONS
The use of the neuroendoscopic laser permits cutting and coagulating simultaneously, avoiding multiple instruments’ use (forceps and coagulation). It therefore makes neuroendoscopic procedures more straightforward with a minimum need to change tools, and particularly suitable also in a pediatric setting.
LGG-48. CLINICAL CHARACTERIZATION OF FGFR-ALTERED, PEDIATRIC LOW-GRADE GLIOMAS
Authors: Posorske Benjamin , Tiwari Nishant , Keller Lisa , Dorris Kathleen , Goldman Stewart , Hoffman Lindsey M , Mangum Ross 
Published: June 2024

Abstract

BACKGROUND
Pediatric low-grade glioma (pLGG) is the most common central nervous system tumor of childhood. Most pLGGs are driven by BRAF alterations, but a subset harbor activating mutations or fusions of FGFR1/2/3. Significantly less is known about the biologic activity, clinical course, and response to targeted inhibition of these FGFR-altered gliomas (FGFR pLGG). We sought to define the epidemiologic characteristics, molecular signature, prognostic markers, and clinical course of patients with FGFR pLGG.

METHODS
We performed a multi-institution, retrospective chart review of pediatric neuro-oncology patients treated at two large, academic cancer centers from 2012 – 2023 with tumor molecular profiling demonstrating any FGFR alteration.

RESULTS
Sixteen eligible patients were identified; 9 (56%) were female and median age was 12 years of age (range 6 - 18 years). Reported histologies included pilocytic astrocytoma (4), rosette-forming glioneuronal tumor (3), low grade glial/glioneuronal tumor (3), low grade glioma NOS (2), intermediate grade astrocytoma (1), dysembryoblastic neuroepithelial tumor (2), and pilomyxoid astrocytoma (1). FGFR point mutations were seen in 10/16 (62.5%) patients followed by FGFR-TACC1 fusions in 4/16 (25%) patients and two patients with FGFR1 tandem duplication. Metastatic disease was noted at diagnosis in two patients and upfront gross total resection was achieved in four patients. The most common systemic therapy for the remaining patients was Vincristine and/or Carboplatin. All sixteen patients are alive at median follow up of 52 months (range 6 - 198 months).

CONCLUSIONS
FGFR pLGG represent a distinct subset of tumors with unique biologic properties and clinical activity. Additional studies are needed to investigate this unique patient population to appropriately adapt our therapeutic approach and improve patient outcomes.
LGG-50. POOR RESPONSE TO MEKI RE-INITIATION IN PEDIATRIC LOW-GRADE GLIOMA AFTER TREATMENT DISCONTINUATION. A PLGG TASKFORCE STUDY
Authors: Bajin Inci Yaman , Siddaway Robert , Levine Adrian , McKeown Tara , Nobre Liana , Das Anirban , Bennett Julie , Ramaswamy Vijay , Huang Annie , Bouffet Eric , Lafay-Cousin Lucie , Quang Dong Anh Khuong , Hansford Jordan , Rajagopal Revathi , Gottardo Nicholas G , Rowe Rachel , Dutton Jordann , Li Amanda , McThenia Sheila , Fangusaro Jason , Perreault Sébastien , Hawkins Cynthia , Tabori Uri 
Published: June 2024

Abstract

BACKGROUND
Pediatric low-grade gliomas (pLGG) exhibit dramatic objective response to treatment with MEKi (Mitogen-Activated Protein Kinase inhibitors). Although the initial response to MEKi is promising, it is unknown whether it is safe to stop MEKi therapy and if the response to re-initiating MEKi would have the same impact. The study objective was to compare the first and second response to MEKi in patients with pLGG who stopped therapy and had further tumor progression.

METHODS
PLGG identified at neurooncology centers in Canada, Australia, and US, which were treated twice with MEKi were included. Second therapy was defined as MEKi upon progression for tumors where treatment was stopped. Response to MEKi between 2 treatments (MEKi1, MEKi2) were analyzed by using RANO criteria.

RESULTS
Mature data on 19 patients reveals a median patient age of 13 years (range 7–24), and the most common tumor location is hypothalamic/chiasmatic (89%). PLGG alterations include KIAA1549:BRAF fusion in 69%, NF1 in 21%, and other alterations in 10%. The overall response (minor and partial) to MEKi1 was 63% compared to 26% in MEKi2 (p=0.04). Furthermore, upon restarting MEKi2, 11% had further growth on therapy in contrast to none at MEKi1. MEKi1 resulted in average of 37% size decrease (range, 3%-98%), including 6 PLGG with over 50% response. In contrast, the average decrease to MEKi2 was 10% (range, 6%-40%, p=0.005), and none had &gt;50% size reduction. Comparing each patient MEKi1 to MEKi2 revealed that initial response was superior to the second one in all PLGG.

CONCLUSION
These data suggest that the second response to MEKi is inferior when compared to initial therapy. Expansion of this cohort and biomarker correlates are ongoing. Biological insights are required for this observation, and careful consideration should be made for stopping MEKi, especially in strategic locations such as the optic pathway.
LGG-53. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA
Authors: Robinson Giles W , Vinitsky Anna , Bag Asim K , Chiang Jason , Li QIan , Lin Tong , Hoehn Mary Ellen , Edwards Angela , Storment Diana , Singh Anjali , Larkin Jennifer , Freeman Jana , Pranica Johanna , Bertrand Kelsey , Bagchi Aditi , Baughman Todd , Hoang Thuy , Shearer Todd , Moreira Daniel 
Published: June 2024

Abstract

BACKGROUND
Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy.

METHODS
Phase 1 required patients to be &gt;2 and &lt;25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort planned to evaluate the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy.

RESULTS
Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), MYB (n=1;4%). The median time of follow-up was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on therapy; 4 (17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D.

CONCLUSIONS
Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior exposure to MEKi.
LGG-57. BH3 MIMETICS IMPROVE RESPONSE TO AUTOPHAGY INHIBITION IN BRAFV600E GLIOMAS
Authors: Crespo Michele , Zahedi Shadi , Morin Andrew , Wodetzski Darya , Groat Madeline , Bratbak Emil , Jones Kendra , Griesinger Andrea , Caino Cecilia , Levy Jean Mulcahy 
Published: June 2024

Abstract

BACKGROUND
Autophagy inhibition improves the effectiveness of RAF pathway inhibition (RAFi) and overcomes resistance mechanisms. Mechanistic links between autophagy and apoptotic cell death may explain this ability. BH3 mimetics with autophagy and RAFi further improves this response.

METHODS
RAFi sensitive (MAF 794, AM38) and resistant (MAF 794R, MAF 905-3, AM38R, B76) BRAFV600E tumor cell lines were analyzed at baseline, following RAFi (vemurafenib), autophagy inhibition (chloroquine or shRNAs), BH3 protein inhibition (navitoclax or shRNAs), and combination therapy. Growth assays and caspase activation were monitored by Incucyte Zoom. qRT-PCR evaluated key pro-apoptotic BH3-only members of the BCL-2 family. BH3 profiling was completed using the Letai JC-1 plate-based protocol. Western blot analysis assessed protein levels. Cell Titer Glo determined cell viability.

RESULTS
Combination therapy increased key pro-apoptotic BH3-only proteins including PUMA. shRNAs targeting ATG5 and ATG7 (proteins required for autophagosome formation) also increased PUMA protein and mRNA levels following RAFi. This suggests autophagy-mediated regulation of BH3 proteins helps determine cellular apoptotic thresholds. Combined autophagy and RAFi increased caspase activation and cell death compared to single drug treatment. BH3 profiling demonstrated BCL-2 dependence to inhibit apoptosis. Inhibition of pro-survival BCL-2 family members BCL-2 and BCL-XL (pharmacologically and genetically) with RAFi, MEKi, and autophagy inhibition further increased caspase activation and reduced cell viability.

CONCLUSIONS
BH3 mimetics competitively bind pro-survival BCL-2 family members, increasing apoptosis. Autophagy inhibition improves treatment response by overcoming the apoptotic threshold in RAFi resistant cells and magnifying the apoptotic response in sensitive cells. BH3 profiling reveals CNS BRAFV600E are BCL-2 and BCL-XL dependent, making them good candidates for additional treatment with BH3 mimetics. The addition of navitoclax increased caspase activation and reduced cell viability. Autophagy inhibition can magnify this response even more. This presents an attractive treatment for MAPK activated CNS tumors by enhancing apoptotic cell death by targeting the MAPK pathway, autophagy and BH3.
MDB-04. LONG-TERM OUTCOME OF THE MILANO STRATEGY FOR HIGH-RISK MEDULLOBLASTOMA, INCLUDING THE IMPACT OF MOLECULAR SUBTYPE
Authors: Massimino Maura , Dossena Chiara , Minasi Francesco , Barretta Francesco , Buttarelli Francesca Romana , Biassoni Veronica , Oriani Matilde , Schiavello Elisabetta , Ficorilli Marica , Nigro Olga , Pollo Bianca , Antonelli Manila , Donofrio Vittoria , Maggioni Marco , Kool Marcel , Pecori Emilia , Vennarini Sabina , Gianno Francesca , nigro olga , Erbetta Alessandra , Chiapparini Luisa , Luksch Roberto , Barzanò Elena , Meazza Cristina , Podda Marta , Spreafico Filippo , Terenziani Monica , Bergamaschi Luca , Ferrari Andrea , Casanova Michela , Chiaravalli Stefano , Gattuso Giovanna , Bailey Simon , Modena Piergiorgio , De Cecco Loris 
Published: June 2024

Abstract

BACKGROUND
Since 2008 we have been using the same strategy as for M+ medulloblastoma for all other high-risk subgroups(LC/A histology,TP53 mutations,and/or MYC/MYCN amplification).

METHODS
After surgery,patients &gt;3-year-old received staging/histo-biological revision and sequential HD-methotrexate,HD-VP16,HD-Cyclo,HD-Carbo.HART-CSI,in two daily 1.3 Gy-fractions/5-days-a-week, reached doses tailored to age and pre-radiation response to chemotherapy:31.2 Gy under 10 years-old if CR+PR or no metastases,39 Gy in other/older patients.Boosts to posterior fossa/residual M+ deposits were given reaching total doses of 59.7–60 Gy and 9 Gy,respectively and avoided if metastatic nodules very big or patients very young.Two courses of high-dose thiotepa were delivered in case of not-optimal response after pre-RT phase and in all M0 patients either in pre/post-RT phase.Subgrouping was obtained through IHC and methylation EPICv2.0 in rescued samples.

RESULTS
Patients were 89,median age 8.8 years,64 males,median fup 136 months. OS/PFS/EFS at 5/15-years were 75.9/66.5%,71.1/69.8%,68.2/65.3%,respectively; 6/28 fatal events were not correlated to medulloblastoma relapse(four 2nd tumors).Sex,age below 10/over 15 years, post-sugical residues,histological subtype(#24 LC/A,#57 classic,#7 nodular-desmoplastic),MYC amplification(#17),CSI dose reduction(#31),absence of boosts(#16),use of myeloablative courses(#45),presence/absence of metastases(#77 M+) did not impact prognosis.Patients progressing after pre-HART chemotherapy(#14) and SD+PD after HART(# 10) did significantly worse(P&lt;0.001)with 1/0 survivors, respectively.Subgrouping done in 44/89 patients so far,showed significant worse PFS/EFS for patients with SHH-tumors(#11, 2 with constitutional Tp53-mutations) vs. groups3 and 4(11 and 22 patients, respectively).Patients younger than 10 had worse response to CT and less boosts (P=0.03 in both) but could receive lower CSI-doses if stratified according to CT-response.

CONCLUSIONS
This strategy, partly adopted in the ongoing SIOPE protocol, confirmed satisfying results in all high-risk categories; SHH tumors appeared the most aggressive in this context.