bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-18. BEVACIZUMAB: GOOD FOR EYES AND MRI’S! A NATIONAL UK ASSESSMENT OF VISUAL AND RADIOLOGICAL OUTCOMES OF BEVACIZUMAB THERAPY IN PAEDIATRIC LOW-GRADE GLIOMA (PLGG)
Authors: Green Katie L , Panagopoulou Paraskevi , D’Arco Felice , O’Hare Patricia , Bowman Richard , Walters Bronwen , Jorgensen Mette , Slater Olga , Ahmed Rehana , Bailey Simon , Carceller Fernando , Corley Elizabeth , English Martin , Hayden James , Kamal Ahmed , Kilday J P , Lowis Stephen , Lumb Blanche , Pace Erika , Picton Susan , Pizer Barry , Shafiq Ayad , Uzunova Lena , Wilson Shaun , Wayman Harriet , Hargrave Darren , Opocher Enrico 
Published: June 2024

Abstract

INTRODUCTION
Bevacizumab (BEV) is increasingly used for PLGGs in varying manners despite limited evidence. The potential for BEV to preserve or rescue vision in OPGs has not yet been explored. We performed a nationwide UK evaluation of BEV use for PLGG to provide large cohort safety & efficacy (radiological & visual) data.

METHODS
A retrospective UK multi-centre analysis of patients treated with BEV for PLGG 2009-2020. Clinical patient, tumour, treatment and toxicity data were analysed from medical records. Age-adjusted LOGMAR visual acuity and radiological MRI assessments (RANO) were reviewed from initiation of BEV until latest follow-up. Standardized radiological & visual criteria assessed efficacy and clinical–radiological correlation.

RESULTS
88 PLGG patients from 11 PTCs received BEV either 3rd-line with irinotecan (85%) or alongside 1st/2nd line chemotherapy (15%) at median age 6 years (0.65-17). Median duration from diagnosis to BEV was 38 months. PLGGs included:15% Non-OPGs, 85% OPGs. Cohort OS 92% at median follow-up 34 months(3-106). Toxicity was limited and minimal. 8% stopped BEV for CTCAE grade 2+ toxicities, & 3 patients had SAEs (2 intracranial haemorrhages, 1 thrombosis) after stopping BEV without obvious alternative cause. Overall radiological response (SD/PR/CR) was 88%; median duration to best response 3 months. Overall visual response (stable/improved) was 72%; median duration to best response 3-6 months. Superior visual outcomes were seen in NF1-OPGs (p=0.02). Concordance between visual and radiological responses was 36%; 48% using best eye only visual responses. 65% patients with treatment response had tumour progression (all-cause) within 8 months of BEV cessation. Visual responses endured significantly longer than radiological responses (p0.03).

CONCLUSIONS
BEV is a generally safe and effective treatment for PLGG. Most patients demonstrated on-treatment radiological and visual response. Preservation of response after BEV was limited, though visual responses endured better than radiological responses. BEV may have a unique role as a sight-saving strategy in OPG.
LGG-23. INHIBITORS IN THE TREATMENT OF LOW GRADE GLIOMAS- A SINGLE CENTER EXPERIENCE, BRATISLAVA, SLOVAKIA
Authors: Hederova Stanislava , Mocna Andrea , Slezakova Denisa , Bublakova Estera , Rychly Boris , Svajdler Marian , Kolenova Alexandra 
Published: June 2024

Abstract

BACKGROUND
Pediatric LGGs are the most common CNS tumors in children. They are a very heterogeneous group of tumors of different histological types, according to the WHO classification of grade 1- 2. The major molecular pathway affected in these tumors is the mitogen-activated protein kinase (MAPK) signaling cascade. The frequency of MAPK pathway activation makes this pathway an attractive candidate for targeted therapy, and direct inhibition via BRAF and/or MEK inhibitors is emerging as a clinically relevant strategy.

METHODS
We performed a retrospective analysis of patients treated with inhibitors at the Department of Pediatric Hematology and Oncology in Bratislava since 03/2020. Currently 9 patients, 5 boys and 4 girls, are treated with inhibitors. They are pLGG patients, two of them with concomitant genetically confirmed neurofibromatosis type 1. Six patients are treated with the MEK inhibitor trametinib in monotherapy and three patients with BRAF V600-mutated LGG with a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. In our cohort with a small number of patients, with a median follow-up of 13 months, we did not observe disease progression in even one patient on inhibitor therapy. Tolerance to treatment is reasonable.

CONCLUSIONS
In recent years, our understanding of the molecular biology of pediatric brain tumors has improved significantly. Alterations in the mitogen-activated protein kinase (MAPK) pathway are generally the most common molecular alterations in cancer, and dysregulation of this pathway also dominates the development of pediatric LGGs. The introduction of targeted drugs not only allows to improve the disease prognosis and survival of children with CNS tumors, to improve their quality of life on treatment, but also to reduce toxicity caused by e.g. radiotherapy, and at the same time to reduce the incidence of late sequelae of treatment.
LGG-35. ROBUST TUMOR RESPONSE TO CHEMOTHERAPY IN THALAMIC PILOCYTIC ASTROCYTOMA WITH LARGE CYSTIC COMPONENT: A CASE REPORT
Authors: Rocco Abbey , Beck Mary , McHugh Michele , Lampe Ashley , Meyer Ashley , Ogle Andrea , Brossier Nicole M , Shatara Margaret , Abdelbaki Mohamed S , Cluster Andrew 
Published: June 2024

Abstract

BACKGROUND
Pilocytic astrocytoma (PA) is the most common glioma in children. Prognosis is excellent when complete resection is achievable. However, in central locations, such as optic pathway, thalamus, and brainstem, resection may lead to extensive morbidity, necessitating alternative treatment strategies. Chemo- and targeted therapy options have demonstrated efficacy in controlling tumor growth and providing clinical benefit; however, cystic portions are not typically responsive to either option.

METHODS
Case report, Retrospective chart review

RESULTS
A 4-year-old male presented with left sided weakness and ventriculomegaly. MRI of the brain revealed a 3.5 x 3.3 x 4.4 cm mixed solid and cystic enhancing mass extending from the right thalamus down to the right middle cerebellar peduncle. An endoscopic third ventriculostomy and tumor biopsy was performed. Histology confirmed PA, WHO Grade 1. Sequencing confirmed BRAF-KIAA1549 fusion. Chemotherapy was initiated with Carboplatin and Vincristine. Each subsequent MRI of the brain obtained during therapy and at the end of therapy demonstrated significant decrease in both solid and cystic portion of the tumor with complete resolution of symptoms and neurologic deficits. End of therapy MRI demonstrated 1.2 x 1.4 x 1.2 cm mixed solid and cystic mass.

CONCLUSIONS
The unique aspect of this case is the exceptional and robust response achieved in both solid and cystic components, challenging the historical notion of cystic lesions being less sensitive to chemotherapy. This observation can contribute valuable insights to the evolving understanding of treatment responses in these tumors.
LGG-38. UNRESECTABLE PEDIATRIC LOW-GRADE GLIOMAS OF THE BRAIN: TARGETED THERAPY COMPARED WITH STANDARD CHEMOTHERAPY AS FIRST-LINE TREATMENT
Authors: Molteni Marta , Verrico Antonio , Ramaglia Antonia , Rossi Andrea , Bagnasco Francesca , Fragola Martina , Piccolo Gianluca , Mercuri Claudia , Piatelli Gianluca , Gaggero Gabriele , De Marco Patrizia , Garrè Maria Luisa , Milanaccio Claudia 
Published: June 2024

Abstract

BACKGROUND
Pediatric low-grade gliomas (pLGG) frequently harbor MAPK-pathway mutations that determine poor response to standard chemotherapy (sCt). Targeted agents against BRAF-V600E mutation (MAPK-i) are emerging as molecularly driven treatments. Few studies have compared sCt with MAPK-i. We aimed to compare response and progression-free survival (PFS) of unresectable brain pLGG treated with sCt or MAPK-i. MAPK-i were used in first line or at relapse.

METHODS
We conducted a single-center observational retrospective study of all brain pLGG consecutively diagnosed and treated at Gaslini Children’s Hospital between January 2008 and December 2021. Treatment was assessed using RAPNO criteria at 6, 12-18 months, and at last follow-up. MRI studies were reviewed by two experienced neuroradiologists.

RESULTS
Seventy-one patients were enrolled: 66 received sCt and 10 MAPK-i (5 in first line, 5 after sCt failure). All patients who received MAPK-i were BRAF-V600E mutated. Groups were homogeneous for tumor location and dissemination. sCt group was enriched for pilocytic astrocytoma, MAPK-I group for ganglioglioma. sCt patients were younger. SCt lasted 12-18 months, MAPK-i were continuously given. Tumor size reduction was 19.5% at 6 months and 40.5% at 12-18 months for sCt group; 48% at 6 months and 43.5% at 12-18 months for MAPK-i group. SCt determined at least stable disease in 74.2% of patients; 60% of responders reached the best response at 6 months, 40% at 12-18 months. 5y-PFS was 40.3% (median time for progression: 2.5 years). MAPK-i determined at least stable disease in all patients at first evaluation with long-lasting response (median time of follow-up: 5.1 years).

CONCLUSIONS
In our study sCt was effective in inducing response but prolonged disease control is not always achieved. BRAF-V600E mutated patients upon MAPK-i start gained a rapid disease control with long-lasting response, also if they have been pretreated. Acknowledgement: this study was supported by ARTUCEBA ONLUS.
LGG-46. MEKI WITH MIRDAMETINIB: EXPLORING ADAPTIVE SIGNALING PATHWAY DYNAMICS AND IMMUNE MODULATION IN PEDIATRIC GLIOMAS
Authors: Pensabene Juliana M , Perez Natalia Muñoz , Yazejian Rita M , Moziak Kirsten , Martin Allison M 
Published: June 2024

Abstract

INTRODUCTION
Glial neoplasms are among the most common types of solid tumors in children. The mitogen-activated protein kinase (MAPK) pathway is implicated in glioma tumorigenesis. Drugs targeting this pathway hold promise as novel therapy for this disease. Vertical inhibition of the MAPK pathway has been linked to increased inflammation in several other cancers but similar exploration in pediatric brain tumors is limited. Within the MAPK pathway, MEK plays a significant role as a modulator of ERK phosphorylation. This study investigates the therapeutic potential of the MEK inhibitor, Mirdametinib, and evaluates the drugs’ capacity to induce tumor-intrinsic inflammation by characterizing changes in PD-L1 expression and proliferation in a panel of pediatric glial neoplasms.

METHODS
Three cell lines were included in the panel (Res186, Res259, SF188) and were treated with Mirdametinib for 3, 5, or 7 days. P-ERK expression, analyzed by western blot, verified successful inhibition of MEK by Mirdametinib. The CCK8 cytotoxic assay was utilized to determine the drug’s 50% inhibitory concentration as well as its direct effects on cell viability. Changes in Ki67 expression assessed by flow cytometry further characterized Mirdametinib’s effects on cell proliferation. Flow cytometry was also utilized to measure changes in PD-L1 expression following treatment.

RESULTS
Despite minimal effects on proliferation as measured by Ki67 and CCK8, expression of P-ERK verifies successful inhibition of MEK. Western blot data also reveals increased Pi3K/AKT pathway activity in SF188 groups treated with Mirdametinib. FACS data for SF188 also demonstrates increased PD-L1 expression in response to treatment.

CONCLUSIONS
Data suggests that, in response to MEKi, gliomas utilize compensatory growth mechanisms through Pi3K/AKT signaling. Findings also point to immune-modulatory effects of MEKi. Supporting results in ongoing experiments are expected to further our understanding of these mechanisms and may help inform effective combination treatment strategies for pediatric gliomas.
MDB-05. PERSONALIZED, RISK ADAPTED THERAPY FOR PEDIATRIC PATIENTS WITH MEDULLOBLASTOMA – A SINGLE CENTER 8-YEAR RETROSPECTIVE REVIEW
Authors: Martinez Devin Antonio , Fragoso Ruben , Zwienenberg Marike , Sharma Julia , Sadegh Cameron , Lee Han Sung , Patel Vihar , Beckham Melinda , Johnson Anita Rochelle , Antony Reuben 
Published: June 2024

Abstract

BACKGROUND
Clinically relevant risk stratification and optimal therapies for pediatric medulloblastoma molecular subgroups are still being investigated.

METHODS
We reviewed host/disease characteristics, patient/tumor specific risk adapted therapy and outcomes of patients treated for medulloblastoma at UC Davis since 2016.

RESULTS
Fifteen patients (age 1-19 years, 12 male, 3 with Li Fraumeni Syndrome (LFS), 2 with spinal cord disease) were included in our review. Tumor histologies included: Classic (n=8), Desmoplastic-Nodular (n=6), Anaplastic (n=1). Tumor genomic profiles were SHHP53WT(n=5), SHHP53 mutated (n=4), Group4 (n=3), NWNSHH (n=2), WNT (n=1). Gross total resection was achieved in 9 patients. Patients with post resection residual tumor, high risk genomic features or disseminated disease were stratified as high risk. We treated all radiation eligible patients (n=13) per COG ACNS0332 maintenance chemotherapy regardless of risk group with 12/13 receiving radiosensitization (Vincristine/Carboplatin) and either 23.4 Gy/36 Gy CSI (two patients treated per Headstart3D2 and ACNS0334 respectively). 2 patients with spinal cord disease were treated with intrathecal topotecan and liposomal cytarabine respectively. During ACNS0332 maintenance bacteremia, weight loss and hypomagnesemia were frequent complications. 5 patients required chemotherapy dose reductions (4 Vincristine/1 Cisplatin). Two patients with LFS developed glioblastoma/undifferentiated pleomorphic sarcoma following ACNS0332 therapy. Two patients (with WNT and NWNSHH subgroup tumors) experienced medulloblastoma relapse. These patients were treated using LITT/Intrathecal chemotherapy and ACNS0821 chemotherapy. Both are alive and one patient is NED off therapy. All patients who have not developed secondary malignancies (n=13) are alive. (follow up 7-72 months). All attend school with support, 10 have hearing impairment and 5 receive endocrine supplements.

CONCLUSIONS
Utilizing patient specific risk adapted therapy we have achieved favorable clinical outcomes in our patient cohort. Therapy deintensification for patients with WNT medulloblastomas should be approached with caution. Patients with LFS might require radiation sparing therapeutic protocols for longer term benefit.
MDB-06. ALTERNATIVE SPLICING MEDIATED BY OTX2 DRIVES THE DEVELOPMENT OF GROUP 3 MEDULLOBLASTOMA
Authors: Saulnier Olivier , Zagozewski Jamie , Liang Lisa , Hendrikse Liam D , Layug Paul , Gordon Victor , Aldinger Kimberly A , Haldipur Parthiv , Borlase Stephanie , Coudière-Morrison Ludivine , Cai Ting , Martell Emma , Palidwor Gareth , Porter Christopher J , Richard Stephane , Sharif Tanveer , Doble Brad W , Millen Kathleen J , Taylor Michael D , Werbowetski-Ogilvie Tamra E 
Published: June 2024

Abstract

BACKGROUND
OTX2 is a transcription factor and known molecular hallmark of Group 3 medulloblastoma (MB). While previous studies have focused on its association with active enhancer elements to modulate the chromatin landscape, here, we demonstrate an unexpected role for OTX2 in regulating Group 3 MB alternative splicing (AS).

METHODS
We used TurboID to broadly interrogate the Group 3 MB OTX2 protein interactome and identify associations with splicing regulators. RNA-sequencing was performed to identify OTX2-driven AS events, a subset of which were validated in Group 3 and Group 4 MB patient tumors and the developing human cerebellar rhombic lip (RL). Splice blocking morpholinos were used to mimic OTX2-regulated splicing events and to determine their role in MB cell fate decisions both in vitro and in vivo.

RESULTS
OTX2 associates with the Large Assembly of Splicing Regulators (LASR) complex through protein-protein interactions and modulates the localization of a LASR protein to help stabilize the complex and sustain a Group 3 MB splicing program. Motif enrichment analysis demonstrates that members of the LASR complex are also significantly enriched near OTX2-regulated alternatively spliced exons. OTX2 is found on nascent mRNA, and its role in AS is independent of DNA-regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in the human cerebellar RL origins. Among the OTX2-regulated spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumor growth, while enhancing differentiation and survival in vivo.

CONCLUSIONS
While splicing defects are commonly observed in adult cancers, the functional role of AS in the most aggressive MBs has never been explored. These findings identify OTX2-mediated AS as a major determinant of cell fate decisions and highlight AS events as novel therapeutic targets to drive Group 3 MB differentiation.
MDB-11. DOES THE INTRAOPERATIVE ASSESSMENT OF SITE OF ORIGIN OF MEDULLOBLASTOMA ALLOW FOR A TAILORING OF THE NEUROSURGICAL STRATEGY? DATA FROM A RETROSPECTIVE SINGLE-CENTER ASSESSMENT AND PROPOSAL OF A PROSPECTIVE MULTICENTER STUDY
Authors: Ciobanu-Caraus Olga , Czech Thomas , Peyrl Andreas , Haberler Christine , Kasprian Gregor , Furtner Julia , Kool Marcel , Sill Martin , Frischer Josa , Cho Anna , Slavc Irene , Rössler Karl , Gojo Johannes , Dorfer Christian 
Published: June 2024

Abstract

BACKGROUND
Developmental gene expression data from medulloblastoma (MB) suggest that WNT-MB originate from the region of the embryonic lower rhombic lip (LRL), whereas SHH-MB and non-WNT/non-SHH MB arise from cerebellar precursor matrix regions. This study aims to analyze detailed intraoperative data with regard to the site of origin (STO) and compare these findings with the hypothesized regions of origin associated with the molecular group.

METHODS
A review of the institutional database identified 58 out of 72 pediatric patients who were operated on a MB at our department between 1996 and 2020 that had a detailed operative report, surgical video as well as clinical and genetic classification data available for analysis. The STO was assessed based on intraoperative findings.

RESULTS
Using the intraoperatively defined STO, “correct” prediction of molecular groups was feasible in 20% of WNT-MB, 60% of SHH-MB and 71% of non-WNT/non-SHH MB. The positive predictive values of the neurosurgical inspection to detect the molecular group were 0.21 (95% CI 0.08–0.48) for WNT-MB, 0.86 (95% CI 0.49–0.97) for SHH-MB and 0.73 (95% CI 0.57–0.85) for non-WNT/non-SHH MB.

CONCLUSION
In our series of 58 well-documented cases, the intraoperative assessment of the STO could not reliably predict the molecular group. Thus, the current evidence does still not allow for intraoperative group-specific risk stratification that would enable tailoring the neurosurgical strategy to the prognostic and predictive profile of the patient. Prospective multicenter assessments are necessary to systematically evaluate the growth pattern and site of origin of medulloblastoma. Accordingly, a study protocol of an international cohort study will be presented.
MDB-13. GERMLINEELP1 DEFICIENCY SENSITIZES CEREBELLAR GRANULE NEURON PROGENITORS TO SHH MEDULLOBLASTOMA
Authors: Ahmad Shiekh Tanveer , Garcia-Lopez Jesus , Li Yiran , Gudenas Brian , Hadley Jennifer , Paul Leena , Batts Melissa , Soliman Taha , Kojic Marija , Pitre Aaron , Manz Frederik , Zindy Frederique , Jones Alun , Mayasundari Anand , Bianski Brandon , Tinkle Christopher , Shirinifard Abbas , Janke Laura , Lu Meifen , Pfister Stefan M , Gajjar Amar , Baker Suzanne J , Roussel Martine F , Rankovic Zoran , Waszak Sebastian M , Robinson Giles W , Orr Brent A , Wainwright Brandon , Kutscher Lena M , Lin Hong , Northcott Paul A 
Published: June 2024

Abstract

BACKGROUND
Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events observed in medulloblastoma (MB), accounting for 30% of the Sonic Hedgehog 3 subtype (SHH-3). Molecularly, ELP1-associated SHH-MBs acquire somatic PTCH1 mutations in &gt;80% of cases, and universal loss-of-heterozygosity of the wild-type ELP1 and PTCH1 alleles through loss of chromosome-arm 9q, resulting in their biallelic inactivation. Notably, germline ELP1 LOF occurs mutually exclusive with somatic/germline TP53 mutations in the SHH-3 subtype, suggesting that genetic perturbation of either ELP1 or TP53 may promote similar tumorigenic consequences in cerebellar granule neuron progenitors (GNPs), the accepted cellular origin of SHH-MB. Despite these findings, the molecular, biochemical, and cellular mechanism(s) by which ELP1-deficiency provokes malignant pathogenesis remain unknown. In this study, we sought to close this knowledge gap and functionally determine why children harboring pathogenic ELP1 germline variants are at an increased risk of developing SHH-MB.

METHODS
Mice were genetically engineered to mimic heterozygous Elp1 LOF (Elp1HET). We studied the effect of Elp1 LOF in GNPs using a combination of molecular profiling, immunophenotyping, and cellular assays.

RESULTS
GNPs from Elp1HET mice exhibited a spectrum of molecular and biochemical hallmarks of malignant transformation including increased DNA replication stress, DNA damage, accelerated cell cycle progression, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs engineered to harbor somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the specificity of ELP1-associated tumors in SHH-3, and their exclusivity with TP53-mutant tumors. Treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivated p53-dependent apoptosis and extended survival.

CONCLUSIONS
Collectively, our findings functionally substantiate the role of ELP1 deficiency in predisposition to SHH-3 MB and nominate therapeutic strategies to overcome p53 inhibition as a rational treatment option.