bluuebunny/crossref_metadata_2025 huggingface dataset:
METB-10. GENOME-WIDE DNA METHYLATION PROFILING OF PRIMARY CELLS FROM PEDIATRIC BRAIN TUMORS IS AN INFORMATIVE TOOL TO ASSESS CELL CULTURE RELIABILITY AND IN VITRO SELECTION
Authors: Pedace Lucia , Abballe Luana , Pizzi Simone , Vinci Maria , Antonacci Celeste , Nardini Claudia , Patrizi Sara , Bufalo Francesca Del , Rossi Sabrina , Pericoli Giulia , Gianno Francesca , Besharat Zein Mersini , Tiberi Luca , Mastronuzzi Angela , Ferretti Elisabetta , Tartaglia Marco , Locatelli Franco , Ciolfi Andrea , Miele Evelina
Published: June 2024

BACKGROUND

Recent genomic and epigenomic profiling analyses have provided remarkable insights into biology of pediatric brain tumors (pBTs). Nonetheless, pBTs represent the deadliest childhood cancer worldwide and are associated with high morbidity. In vitro models of pBT are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor.

METHODS

We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples from medulloblastomas, high-grade gliomas, low-grade gliomas, ependymoma, and meningiomas. The cohort included 155 tumors and 86 pBT-derived cell cultures. For the analysis of pBT-derived cell cultures, we have considered the most significant variables: i) cultured medium (serum vs serum-free), ii) passages (late vs early), and iii) dimensionality (2D vs 3D cultures). As a complementary approach, the global relationships between the 241 samples based on the DNAm information were visualized using fast interpolation-based t-distributed stochastic neighbour embedding (t-SNE) and differentially methylated regions in tumors compared to cell models were identified.

RESULTS

Our findings showed that cell cultures cultured under stem-like cells enriching conditions (serum-free, 3D) and maintained in culture early passages are characterized by a higher degree of faithfulness to the parental tumors, in terms of methylation class and CNV profile, than the counterparts maintained in 2D cultures, in presence of serum, and maintained for extended passages. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration.

CONCLUSIONS

DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors.
GCT-03. MONOGERM, A NOVEL PROOF-OF-PRINCIPLE BAYESIAN PHASE II TRIAL DESIGN OF CARBOPLATIN OR VINBLASTINE MONOTHERAPY INDUCTION PRIOR TO RADIOTHERAPY FOR INTRACRANIAL GERMINOMA
Authors: Kirton Laura , Apps John R , Lawson Anna , Arvanitis Theodoros , Mitra Dipayan , Gagen Richard , Patel Hiten , Peet Andrew , Fern Lorna , Williams Emma , Coleman Nicholas , Ajithkumar Thankamma , Bison Brigitte , Veal Gareth , Stark Daniel P , Morana Giovanni , Nicholson James C , Billingham Lucinda , Murray Matthew J
Published: June 2024

BACKGROUND

Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely.

METHODS

Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440).

RESULTS

MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (<30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design.

CONCLUSION

MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial.
GCT-19. SIOP CNS GCT II: PRESENTATION AND OUTCOME OF BIFOCAL NON-GERMINOMATOUS GERM CELL TUMOURS (NGGCTS)
Authors: Calaminus Gabriele , Kortmann Rolf Dieter , Alapetite Claire , Bison Brigitte , Frappaz Didier , Ajithkumar Thankamma , Gerber Nicolas , Peyrl Andreas , Morana Giovanni , Murray Matthew , Schoenberger Stefan , Brisse Herve , Zimmermann Martin , Nicholson James , Conter Cecile Faure
Published: June 2024

BACKGROUND

Between 2/2012 and 7/2018, 112 patients with non-germinoma were registered as intend-to-treat patients within the SIOP CNS GCT II trial: 88 patients were male and 24 female. Median age was 13 years (range: 0,1-25,1 years). 95 patients had localised and 17 metastastic disease. 21 patients with bifocal tumors were reported, defined as a synchronous suprasellar and pineal tumour at diagnosis. 6/21 had metastases.

PATIENTS/METHODS

All Patients presented with several main clinical symptoms: diabetes insipidus (DI) (18), vision impairment (16), raised intracranial pressure (10), headache (10), cognitive impairments (7), somnolence (5). Diagnosis was confirmed by tumor markers in all, two with additional resection and 4 with biopsy. All patients received upfront PEI (cisplatin/etoposide/ifosfamide) chemotherapy, with dose-intensification (HD-PEI) for those with diagnostic serum or CSF AFP >1000 ng/ml (high-risk), before RT. Patients without dissemination received local radiotherapy (RT) of 54 Gy to both sites. Patients with dissemination received CSI 30 Gy plus boost to primary sites of 24 Gy and RT to visible metastases.

RESULTS

Among 12 standard-risk patients with localised disease 3/12 achieved CR, 1/12 PR and 8/12 relapsed. Of the 8 relapses, 3 achieved a 2nd CR. Three patients with localised disease were high risk. Among them only one patient achieved CR after treatment, but all 3 -pts relapsed and 2 died. Among 6 patients with dissemination and standard risk 5/6 achieved CR, 1/6 PR, no relapses occurred. Bifocal localised non-Germinoma are not sufficiently controlled by chemotherapy and focal tumor boost. Other treatment concepts including upfront chemo-intensification in standard risk patients and whole-ventricular RT need to be explored. For the SIOP CNS GCT group, supported in part by German Childhood Cancer Aid
GCT-20. PRESENTATION AND OUTCOME OF BIFOCAL GERMINOMA TREATED ACCORDING TO SIOP CNS GCT II
Authors: Calaminus Gabriele , Alapetite Claire , Kortmann Rolf Dieter , Bison Brigitte , Conter Cecile Faure , Ajithkumar Thankamma , Gerber Nicolas , Peryl Andreas , Morana Giovanni , Murray Matthew , Schönberger Stefan , Brisse Herve , Zimmermann Martin , Frappaz Didier , Nicholson James
Published: June 2024

BACKGROUND

Between 2/2012 and 7/2018, 261 patients with germinoma were registered as intent-to-treat patients within the SIOP CNS GCT II trial. 209 patients were male/ 52 female. The median age was 14.1 years (range 5,0-41,0 years). 194 patients had localised and 67 had metastatic disease. 64 patients had bifocal germinoma, defined as synchronous suprasellar and pineal tumours at diagnosis.

PATIENTS/METHODS

The main symptoms were diabetes insipidus (DI) (n=47), visual impairment (33), raised intracranial pressure (21), headache (20), neurological symptoms (14), non-DI endocrine disturbances (14), and somnolence (12). Diagnosis was confirmed by biopsy in 38/64 patients and by resection in 4/64. 22/64 were diagnosed by imaging only. Patients with localised disease received 24 Gy whole-ventricular irradiation (WVI) alone if they achieved complete response (CR) after induction chemotherapy, or WVI with boost to both tumour sites (16 Gy) if partial response (PR) or stable disease (SD) was documented. Patients with metastases (dissemination on MRI or positive CSF cytology) received cranio-spinal irradiation (CSI) 24 Gy with boost to primary sites/ to visible metastases (16 Gy).

RESULTS

After induction chemotherapy, 17/40 with localised disease achieved CR, 21/40 PR, and 2/40 SD. After completion of treatment, 16/17 patients who achieved CR after chemotherapy remained in CR and one patient died after a relapse. 13/21 patients with PR post-chemotherapy achieved CR post-treatment, 3/21 remained in PR and 5/21 relapsed, one of which achieved a second CR. Both patients with SD remained in CR after radiotherapy and additional surgical intervention. Among patients with dissemination 21/24 achieved CR and 3/24 PR after completion of treatment (CSI). No relapses occurred.

CONCLUSION

Localised bifocal germinoma can be treated with WVI ± tumour boost depending on the response to chemotherapy. Bifocal germinoma with or without dissemination have an excellent prognosis. For the SIOP CNS GCT group, supported in part by German Childhood Cancer Aid
GCT-25. THE IMPACT OF RESIDUAL DISEASE ON THE OUTCOMES OF CENTRAL NERVOUS SYSTEM GERMINOMAS – A MULTICENTER INSTITUTION EXPERIENCE
Authors: Shin Jimin , Cochrane Anne , Ogle Andrea , Meyer Ashley , Brossier Nicole M , Shatara Margaret , Cluster Andrew , Knowles Truman , Mueller Sabine , Czogała Małgorzata , Cantor Evan , Abdelbaki Mohamed S
Published: June 2024

BACKGROUND

Germinomas make up about two-thirds of central nervous system (CNS) germ cell tumors and are highly radio-sensitive with excellent survival rate of more than 90%. Current standard of care involves the combination of chemotherapy with reduced-dose radiotherapy. Typically, patients with residual disease receive a higher dose of radiotherapy. However, recent clinical trials showed that there were no differences in the outcomes between those who had complete response (CR) versus partial response (PR) to initial chemotherapy. Hence, we aimed to assess the outcomes of germinoma patients based on the responses to both chemotherapy and radiotherapy.

METHODS

A multicenter retrospective chart review of patients with germinoma from four large academic institutions was conducted.

RESULTS

Data from 41 germinoma patients treated between 2011 and 2022 were analyzed. Thirty-two patients had stable disease (SD)(2), PR(28), or CR(2) to chemotherapy. At the end of radiotherapy, 12 had CR, 5 had PR, and 13 had SD. All patients were alive at the time of review, with a median duration of survival from diagnosis of 78.85 months (range 3.90-278.67). One patient experienced radiographic progression following chemotherapy with SD noted following radiotherapy.

CONCLUSION

Relapses are extremely rare in patients who have residual disease at the end of therapy for germinoma. Future prospective clinical trials are needed to test the possibility of treating germinoma patients who have residual disease with a dose of radiotherapy comparable to that used in patients who achieve complete response.
HGG-02. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TRK FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN UPDATED ANALYSIS
Authors: Perreault Sébastien , Doz François , Deyell Rebecca J , Kebudi Rejin , Nilsson Anna , Nysom Karsten , Geoerger Birgit , Zhang Yi-Zhuo , Bernard-Gauthier Vadim , Neu Natascha , De La Cuesta Esther , Laetsch Theodore W , van Tilburg Cornelis M
Published: June 2024

BACKGROUND

Larotrectinib is the first-in-class, highly selective TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer. We report data on larotrectinib-treated pediatric patients with TRK fusion primary CNS tumors.

METHODS

Patients aged <18 years with TRK fusion primary CNS tumors enrolled in two clinical trials (NCT02637687, NCT02576431) were included. Responses were independent review committee (IRC)-assessed per RANO. Patients were permitted to stop larotrectinib in the absence of on-treatment progression (wait-and-see) and remain on trial.

RESULTS

As of July 2023, 38 patients were eligible for efficacy analyses by IRC, including 11 patients with only non-measurable disease at baseline. Median age at enrollment was 7 years (range 0–17). Tumor histologic groups included: high-grade glioma (HGG; n=18), low-grade glioma (LGG; n=12), and other (n=8). Eleven (29%) patients had received ≥2 prior systemic therapies. Overall response rate was 37% (95% CI 22–54): three complete response, 11 partial response, 17 stable disease, five progressive disease, and two not evaluable. The 24-week disease control rate was 74% (95% CI 57–87). Medians for duration of response, progression-free survival, and overall survival (OS) were 17.2 months (95% CI 5.7–not estimable [NE]), 19.8 months (95% CI 11.1–50.8), and not reached (95% CI 32.7–NE), respectively. The 48-month OS rate was 60%. At data cutoff, one patient with HGG and four with LGG entered wait-and-see; median duration of the first wait-and-see period was 20.2 months (range 4–29). One patient with LGG resumed treatment following wait-and-see. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. No patients discontinued treatment due to TRAEs.

CONCLUSION

Larotrectinib demonstrated rapid, durable responses and a manageable safety profile in pediatric patients with TRK fusion primary CNS tumors. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing pediatric patients with CNS tumors.
HGG-12. A PHASE IB/II STUDY ON ASIDNA™ IN ASSOCIATION WITH RE-IRRADIATION IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS WITH RELAPSING HIGH-GRADE GLIOMA
Authors: DOZ François , LEBLOND Pierre , CARDOEN Liesbeth , GRILL Jacques , JDEY Wael , DUTREIX Marie , AZZOUZ Fouzia , DIALLO Mamadou , CLAUDE Line , VARLET Pascale , ALAPETITE Claire
Published: June 2024

BACKGROUND

AsiDNA is a synthetic cholesterol-oligodeoxyribonucleotide conjugate, inducing false DNA damage signaling, which prevents DNA repair in tumor cells. AsiDNA therefore increases the vulnerability of tumor cells to irradiation without increasing toxicity in healthy tissues. Preclinical data showed encouraging results of AsiDNA combined to irradiation in glioma and medulloblastoma models. We aimed to determine the safety and efficacy of AsiDNA, a DNA-repair inhibitor, in children, adolescents and young adults with recurrent High-grade Glioma (HGG) eligible for re-irradiation.

METHODS

AsiDNA was administered intravenously using a 3 consecutive days loading dose, followed by a weekly dose (350 mg/m2/dose or 600 mg for patients ≥ 50kg) for 11 weeks. Focal radiotherapy, using 1.8 Gy daily fraction, 5 days a week, was administered in combination during the first weeks: 18 Gy for brainstem diffuse midline glioma (DMG) and 36 Gy for supra-tentorial HGG (DMG or non-DMG). The first part of the study aimed to assess the safety and to confirm the recommended phase-II dose based on dose limiting toxicities (DLT) during the first 8 weeks. A second part was planned to assess activity/efficacy of the combination based on the progression-free survival (PFS) rate at 3 months. AsiDNA pharmacodynamics (PD) was studied in peripheral blood mononuclear cells (PMBC).

RESULTS

Eight (8) patients were enrolled: median age 14 y (6.2-24.5), 5 DMG. No DLT was observed. Median FU was 9.1 months, disease progression was observed in 8 patients; 6 died because of disease progression. Median PFS was 3.9 months. The PD results showed no significant target engagement in PBMCs.

CONCLUSIONS

Considering the low PFS as well as lack of efficacy on PD markers, the DSMB recommended stopping the study.
HGG-13. INFANT-TYPE HEMISPHERIC GLIOMA (IHG): AN INDIVIDUAL PATIENT DATA META-ANALYSIS
Authors: Chavaz Lara , Bagchi Aditi , Toutain Fabienne , Pfister Stefan M , Sturm Dominik , Pietsch Torsten , Gielen Gerrit H , Waha Andreas , Clarke Matthew , Karremann Michael , Benesch Martin , Perwein Thomas , Nussbaumer Gunther , Kramm Christof , Massimino Maura , Biassoni Veronica , Vinci Maria , Mastronuzzi Angela , van Vuurden Dannis , van Zanten Sophie E M Veldhuijzen , Mackay Alan , Jones Chris , Jones David T W , Stucklin Ana S Guerreiro , Tabori Uri , Hawkins Cynthia , Ryall Scott , La Madrid Andrés Morales , Lassaletta Alvaro , Bailey Simon , Hargrave Darren , Chiang Jason , El-Ayadi Moatasem , Mançano Bruna Minniti , Reis Rui Manuel , Hagel Christian , Robinson Giles W , Gajjar Amar , Gorsi Hamza , Silvestrini Nicolas , von Bueren Andre O
Published: June 2024

BACKGROUND

Infant-type hemispheric gliomas (IHG) are epigenetically distinct pediatric high-grade gliomas characterized by fusions in receptor tyrosine kinase (RTK) genes.

METHODS

We performed a methodical literature search, including 30 publications (22 case reports), to identify patients who met the diagnostic criteria of IHG based on the 2021 WHO Classification of CNS Tumors. Individual patient data were obtained from published literature and/or via the authors of the publications. Survival analysis was conducted using the Kaplan-Meier method, and multivariate analysis was performed to investigate the effect of clinical and molecular variables on outcomes.

RESULTS

Hundred-fifty-five previously reported and one unpublished IHG were identified: 131 (84%) had fusions in RTK genes, of which ALK was most prevalent (62/131), followed by NTRK1/2/3 (30/131), ROS1 (30/131), and MET (9/131). Twenty-five patients, with either no identified RTK fusion (6/156) or not assessable fusion (19/156), had methylation scores ≥ 0.9 for IHG (using the Molecular Neuropathology brain tumor classifier versions ≥ 11b4). Surgery followed by adjuvant chemotherapy in 69% (67/97) was the most common primary treatment used in our cohort. The 3-year EFS and OS were 55% (95%CI: 45-67) and 81 % (95%CI: 73-89). 41 patients with relapsed or progressive tumors received various second-line treatments including surgery, chemotherapy, radiotherapy, and targeted therapy. Based on multivariate analysis, complete resection resulted in better EFS (p = 0.05) and OS (p = 0.009), and the presence and type of RTK gene fusion were not associated with clinical outcomes.

CONCLUSION

Our results show that despite favorable OS, patients with IHG often show early progression, indicating that the primary optimal treatment for IHG is yet to be established. Our analysis further indicates that achieving a safe, complete resection may play an important role in treating these patients. A comprehensive analysis of the salvage regimen is required to understand their role in OS.
HGG-14. COMPARING THE RADIOSENSITIZATION POTENTIAL OF VARIOUS COMPOUND CLASSES IN PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA
Authors: Cais Alessia , Lipiec Szymon , Chan Kenneth Chun-Ho , Hofmann Nina , Gade Clara , von Soosten Laura , Imle Roland , Roscher Mareike , Euler-Lange Rosemarie , Zheng Tuyu , Manz Frederik , Kutscher Lena M , Pajtler Kristian W , Peterziel Heike , Oehme Ina , Witt Olaf , Kurth Ina , Jones David T W , Pfister Stefan M , Zuckermann Marc
Published: June 2024

BACKGROUND

The 5-year survival rate of patients suffering from pediatric-type diffuse high-grade glioma (pHGG) remains at only ~20%. Often resection and/or X-ray radiation therapy (RT) are the only treatment options for these patients, though only providing palliative benefits. To date, the concomitant combination of RT and targeted agents is largely unexplored, especially as first line treatment.

METHODS AND RESULTS

To identify drugs and compound classes that radiosensitize pHGGs, we performed a series of high-throughput drug screens in combination with RT. Using a custom library of ~90 FDA-approved compounds, we analyzed combinatorial efficacies in 10 pHGG cell cultures. We identified a variety of drugs demonstrating increased efficacy with RT that have not been described as radiosensitizers yet. Of these, we prioritized compounds that presumably cross the blood-brain-barrier (BBB) and are clinically relevant, yielding a selection of 6 drugs comprising HDAC-, Proteasome-, MEK- and BCL-inhibitors. Next, we analyzed whether these compounds act tumor-specifically by screening two non-cancer cell cultures: Neural stem cells and HEK293T cells. While 3 of those compounds also demonstrated efficacy in one of the control cell lines, the 3 remaining drugs potentiated RT specifically in pHGG. We then successfully validated the radiosensitization of selected compounds using cell viability and apoptosis assays, and are currently performing clonogenic assays to prioritize the most effective drug-RT combinations for in vivo trials.

OUTLOOK AND CONCLUSION

We will evaluate the most promising treatment combinations preclinically using established PDX-mouse models. We are also planning to perform pharmacokinetic analyses of selected compounds to validate BBB permeability. Ultimately, mechanisms of radiosensitization will be functionally investigated. Our comparative results will generate a comprehensive overview of the radiosensitization potential of different compound classes in a variety of pHGG models, allow mechanistic insights into the interplay of both modalities, and provide a basis for future clinical trials.
HGG-15. SYNERGISTIC EFFECTS OF COMBINED MEK/CDK4/6 INHIBITOR TREATMENT ON BRAFV600E POSITIVE HIGH-GRADE GLIOMA
Authors: Mayr Lisa , Mager Leah , Gabler Lisa , Madlener Sibylle , Kirchhofer Dominik , Lämmerer Anna , Bruckner Katharina , Lang Alexandra , Walter Romina , Schueler Julia , Peyrl Andreas , Azizi Amedeo A , Dorfer Christian , Haberler Christine , Müllauer Leonhard , Berger Walter , Lötsch-Gojo Daniela , Gojo Johannes
Published: June 2024

BACKGROUND

Pediatric high-grade glioma (pHGG) is associated with poor overall survival and standard care has remained unchanged for the past decade. BRAFV600E mutations occur in 5-10% and dabrafenib in combination with mekinist is approved in this subtype. Nevertheless, acquired resistance to targeted therapeutics is a common setback in highly aggressive tumors. Homozygous CDKN2A/B loss co-occurs in approximately 60% of this pHGG subtype. Taking advantage of those combined molecular alterations and exploiting acquired resistance mechanisms is of utmost importance to increase overall survival in these patients.

METHODS

Four HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss were tested for the effects of CDK4/6 inhibitor monotherapy (palbociclib, ribociclib, abemaciclib) and/or combination treatment with trametinib on cell survival, cell cycle, apoptosis and senescence.

RESULTS

Abemaciclib showed the highest efficacy of CDK4/6 inhibitors comparable to trametinib monotherapy in our cell models. Abemaciclib led to a cell cycle arrest and combined treatment with trametinib induced distinctly increased levels of apoptosis in our tumor models when compared to monotherapy and a great proportion of surviving cells were senescent. One cell model was orthotopically implanted in mice and abemaciclib and combined treatment with trametinib showed a slightly increased response when compared to trametinib alone.

CONCLUSIONS

Summarizing, treatment with abemaciclib showed promising therapeutic effects in HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss comparable to trametinib alone. Levels of apoptosis were distinctly higher with combinatorial abemaciclib and trametinib treatment when compared to monotherapy alone and senescence was induced in a great number of surviving cells. In vivo abemaciclib was more efficient when compared to trametinib alone. Currently we are working on in vivo experiments and the effect on sustained induction of senescence and mechanisms of tumor cell growth after discontinuation of therapy and in a combinatorial metronomic approach and in combination with radiotherapy.
HGG-20. CANCER PREDISPOSITION SYNDROMES IN PEDIATRIC PATIENTS WITH HIGH-GRADE GLIOMAS
Authors: Baldo Giada Del , Cipri Selene , Boccuto Luigi , Agolini Emanuele , Novelli Antonio , Cacchione Antonella , Lodi Mariachiara , De Ioris Maria Antonietta , Barresi Sabina , Rossi Sabrina , Miele Evelina , Vinci Maria , Carai Andrea , Locatelli Franco , Mastronuzzi Angela
Published: June 2024

The association between pediatric high-grade gliomas (HGG) and cancer predisposition syndromes (CPS) remains inadequately elucidated in the existing literature, while next-generation sequencing (NGS) is increasingly utilized for diagnostic support. In this retrospective analysis, we evaluated a cohort of 95 consecutive pediatric patients with HGG reclassified according to the latest 2021 WHO classification, diagnosed and treated at the Bambino Gesù Children’s Hospital between 2011 and 2023. All patients underwent genetic germline testing with NGS technology to detect the presence of germline variants predisposing to cancer and were included in this study. Diagnosis of pHGG H3-IDH wild-type was performed in 23 patients (24.2%), diffuse midline glioma in 46 patients (48.4%), astrocytoma IDH-mutant in 7 patients (7.4%), anaplastic pleomorphic xanthoastrocytoma in 4 patients (4.2%), adult type HGG in 4 patients (4.2%), neuroepithelial tumor PATZ1 fusion-positive in 3 patients (3.2%), diffuse hemispheric glioma H3 G34-mutant in 2 patients (2.1%), infant-type hemisheric glioma in 2 patients (2.1%), other rare histologies in 4 patients (4.2%). Oncological family history was investigated up to the third generation for all patients and was positive in 43/95 (45.3%) cases. We identified a total of 65 variants in 95 patients, distributed as follows: 48 variants of uncertain significance (73.8%), 10 likely pathogenic (15.4%), and 7 pathogenic variants (10.8%). Notably, our findings reveal that pathogenic/likely pathogenic variants were detected in about 17% of the entire study population, higher than the 10% incidence reported in the existing literature. The high rate of mutations in CPS associated genes described in our work, leads to consider performing NGS even in the absence of clinical or anamnestic criteria suggestive of it. However, ethical and social issues are to be considered when we propose and investigate patients for CPS. Moreover, further research are needed to determine the role of variants of uncertain significance.
HGG-24. DIFFERENTIAL CELL SURFACE PROTEOMICS OF FLOTILLIN-1, HMGB1 AND AMINOPEPTIDASE N IN H3 MUTATED PAEDIATRIC HIGH-GRADE GLIOMAS
Authors: Fairley Hannah , Walugembe Chloe , Layfield Rob , Haque Farhana
Published: June 2024

High-grade gliomas (HGG) are the deadliest central nervous system tumour in children. Despite this, treatment options remain elusive, leaving children with a dismal prognosis. Histone H3.3 mutations, K27M and G34V/R have been identified as the two most common recurrent somatic mutations in paediatric HGG (pHGG). These mutations are present in 50% of pHGG compared to only 1% in adult gliomas. Our previous proteomic research on cell membrane protein through protein MS data analyses have identified different signatures of differentially expressed cell membrane proteins in H3-G34R/V mutated pHGG cells, in comparison to H3 wild type tumour cells in culture. Among these proteins we have identified flotillin-1, HMGB1 (High mobility group box 1) and aminopeptidase N. Flotillin-1 is associated with numerous malignancies and HMGB1 also functions as an oncogene and aminopeptidase N is a cell surface metalloprotease involved in tumour progression. We have now verified the expression and localisation of these cell surface proteins in H3 mutated and wild type tumour cells, in order to validate as targets for developing novel therapeutics. Expression and localisation of flotillin-1, HMGB1 and aminopeptidase N in H3.3 mutated pHGG cell lines in comparison to H3 wildtype glioma and control cells was analysed, using different protein expression assays including immunofluorescence microscopy and western blotting. Experimental analyses showed statistically significant differential protein expression and localisation of these proteins. Flotillin-1 had increased cell membrane localization in H3 mutated cells.HMGB1 expression was increased, while aminopeptidase N expression was decreased in the H3 mutated cells in comparison to wildtype pHGG. This new knowledge of the cell membrane proteomics of H3 mutated pHGG may help us utilise Flotillin-1, HMGB1 and aminopeptidase N, as potential therapeutic targets for these unique H3 mutated children’s brain tumours.
HGG-30. TARGETED THERAPY OF PEDIATRIC HIGH GRADE GLIOMAS
Authors: Papusha Ludmila , Druy Alexander , Salnikova Ekaterina , Zaytseva Margarita , Panferova Agnesa , Vilesova Irina , Flegontov Andrey , Kasich Igor , Merishavyan Artur , Sysoev Andrey , Degtyarev Vitaly , Koldasheva Marina , Sanakoeva Agunda , Artemov Anton , Procvetkina Anastasia , Karachunskiy Alexander , Hwang Eugene , Packer Roger , Novichkova Galina
Published: June 2024

BACKGROUND

The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Recent advances in understanding tumor biology facilitate utilization of targeted therapies (TT) in pediatric neuro-oncology.

METHODS

We analyzed the efficacy of targeted therapy in patients with progressive pHGG treated with TT according to molecularly-identified actionable events. Molecular characterization of the tumor included DNA panel and transcriptomic RNA sequencing.

RESULTS

Eighteen patients were included (median age 3.7 years, range 0.1-17.7) with anaplastic pleomorphic xanthoastrocytoma (n=10), infant-type hemispheric glioma (n=4), and diffuse high-grade glioma (n=4). Metastatic disease was present in 3/18 patients. Molecular genetic alterations included BRAF V600E mutations (n=8), NTRK1/2/3 fusions (n=4), ROS1 fusions (n=4), MET fusion (n=1), KIT P627L mutation (n=1). Eight patients received an NTRK/ALK/ROS1 inhibitor (entrectinib), seven patients received combination therapy with BRAF and MEK inhibitors (dabrafenib and trametinib), and one patient anti-BRAF monotherapy (dabrafenib). Two patients were treated with a multi-tyrosine kinase inhibitor (cabozantinib). The median duration of targeted therapy was 10.6 months (1-42). Most patients tolerated treatment well with no grade 4-5 toxicities. The overall response rate was 66% (12/18), including 4 complete (22%) and 8 partial responses (44%). At 12 months, PFS was 86% with dabrafenib/trametinib and 42% with entrectinib; at 18 months PFS was 44 % with dabrafenib plus trametinib and 42% with entrectinib. Three out of four patients with ROS1 rearranged glioma experienced disease progression on entrectinib after an initial good response in all cases; two of them subsequently received lorlatinib with clinical benefit. All four patients with NTRK1/2/3 rearranged gliomas remain on entrectinib therapy without signs of progression. Cabozantinib therapy resulted in prolonged complete and partial responses in both cases.

CONCLUSIONS

TT for patients with progressive pHGG is feasible and provides unexpectedly good clinical efficacy.
HGG-31. GENOMIC CORRELATIONS WITH HEMORRHAGE RISK IN PEDIATRIC PATIENTS WITH DIFFUSE HEMISPHERIC GLIOMA
Authors: Joshi Nikhil , Bagheri Sina , Beaubien Ezra , Harvey Kyra , McManus Olivia , Wilson Cullen , Hajeebu Sreehita , Mishra Deepak , Nabavizadeh Ali , Madsen Peter , Foster Jessica
Published: June 2024

BACKGROUND

Pediatric diffuse hemispheric glioma (DHG) is a histone-mutated (H3.3G34R/V) high-grade glioma with poor prognosis. Clinical observation and previous reports have identified that a subset of patients present with tumor-associated hemorrhage. Here, we present our findings from radiological review of these patients and determine genomic risk factors predictive for hemorrhage risk in this cohort.

METHODS

Data was abstracted through the Children’s Brain Tumor Network (CBTN) and EGAS00001004301. Transcriptomic and genomic analyses were completed in R 4.3.1 using edgeR, msigdbr, and xCell. Presence of blood products was determined on preoperative MRI by a board certified pediatric neuroradiologist.

RESULTS

48 samples were available across cohorts with transcriptomic or genomic data. 10 samples (21%) had pre-operative imaging and transcriptomic data available. Initial analysis determined that 6 samples (60%) had acute/chronic hemorrhage based on radiological review. Samples with hemorrhage had increased levels of VEGFA (LFC: 3.45, p=2E-07) and CA9 (LFC: 5.97, p=8E-05) expression on the transcriptomic level suggesting that patients with high expression of these markers (AngioHi) had increased risk of hemorrhage compared to patients with low expression of these markers (AngioLo). AngioHi patients had notably higher levels of IL8 (LFC: 3.56, p=0.01) and increased macrophage populations. Genomic information was available for 15 samples (31%, 7 AngioHi, 8 AngioLo). PTEN alterations (n=4, 57%), FBXW7 alterations (n= 2, 29%), or PDGFRa driver alterations (n= 3, 43%) were found in the AngioHi cohort while none of these alterations were identified in the AngioLo cohort. Notably, at least one of these mutations was seen in all cases in the AngioHi cohort.

CONCLUSIONS

These findings identify potential mutational alterations predictive for tumor-associated hemorrhage in pediatric DHG. Current work is being completed to further characterize how these mutations impact vascular remodeling for patients with DHG and may offer targeted therapeutic opportunities.
HGG-44. BRAINSTEM HIGH-GRADE ASTROCYTOMA WITH PILOID FEATURES (HGAP) WITH AN NTRK FUSION: A HISTOLOGICAL MIMICKER AND RARE PEDIATRIC BRAIN TUMOR
Authors: Balikani Lame , Yilmaz Yasin , Mattera Emily , Leonard Jeffrey R , Leung Marco , Tsuchiya Karen , Schieffer Kathleen M , Akkari Yassmine , McEnroe Allison , McAllister Aaron , Cottrell Catherine , Mardis Elaine , Fouladi Maryam , Khan Sara , Boue Daniel R
Published: June 2024

BACKGROUND

HGAP is a recently defined rare glial neoplasm, whose classification requires pathognomonic epigenetic signatures. HGAP can arise anywhere within the central nervous system but most have been reported in the cerebellum (74%). Rarely seen in children, the diagnosis of HGAP can be challenging due to morphologic overlap with other glial neoplasms, especially pilocytic astrocytoma (PA).

CASE

We present an 11-year male with history of poor weight gain and bilateral sensorineural hearing loss detected on routine screening. Examination showed ataxia, with nystagmus on lateral gaze. MRI brain showed a solid/cystic, dorsally exophytic, cervicomedullary tumor with extension into the 4th ventricle, and hydrocephalus. The tumor showed heterogeneous enhancement with no restricted diffusion, nor intracranial or spinal metastases. Histologic sections from the biopsy suggested classic biphasic PA, with abundant Rosenthal fibers, vascular sclerosis, and no obvious mitoses. Ki67 index was low (<5%; hotspots up to 5-10%+). ATRX mostly retained, even within the most atypical nuclei. The histological impression was classic PA. Comprehensive molecular analysis with DNA methylation showed a high confidence match (0.9883) for HGAP. Paired exome sequencing revealed CDKN2A/2B biallelic loss, missense variant and copy number loss involving NF1, loss of function splice variant in ATRX with no germline alterations detected. Interestingly, fusion panel revealed a BCR::NTRK2 fusion. He received focal photon radiation (54Gy) and adjuvant therapy with Larotrectinib. He remains well with stable disease (EFS 7months).

CONCLUSION

A comprehensive 2023 review of literature revealed only 14 pediatric cases (range 4-18yo) out of 144 reported cases. Including our patient, 9 were male; 8 posterior fossa, 4 supratentorial, 1 spinal cord, and 2 of unknown location. Molecular analysis of the previously reported 14 pediatric cases showed only one case with a different NTRK fusion. We herein present a unique pediatric HGAP, with entirely classic biphasic and benign PA-like features, brainstem location, and targetable NTRK2 fusion.
HGG-50. LOW GRADE GLIOMA CAUGHT IN TRANSFORMATION: UTILITY OF COMPREHENSIVE GENOMIC PROFILING IN PEDIATRIC LI FRAUMENI SYNDROME ASSOCIATED HIGH-GRADE GLIOMA
Authors: Nagabushan Sumanth , Fuentes-Bolanos Noemi , Lau Loretta M S , Rumford Megan , Warby Meera , Courtney Eliza , Grant Andrew , Rodriguez Michael , Solinas Annalisa , Ziegler David S , Kellie Stewart J , Heath John , Ballinger Mandy , Tucker Katherine
Published: June 2024

BACKGROUND

Diffuse paediatric-type high-grade glioma (HGG), H3-wildtype (WT) and IDH-WT have been recognised as a distinct subgroup in the 5th edition of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) (2021).

METHODS

We describe two patients with LFS with conflict between histological and molecular findings. They underwent integrated multi-omics to guide personalised therapy.

RESULTS

The first patient is a 10-year-old female with a left thalamic diffuse astrocytoma, histologically at least CNS WHO grade 2, with H3K27M, BRAFV600E and IDH1R132H negativity by immunohistochemistry (IHC) and retained H3K27me3, prompting initial management as a low-grade glioma. ZERO2 multi-omics profiling demonstrated no DNA methylation match, (v11b4 and 12.5), but loss of TP53 function (heterozygous germline mutation with tumour whole copy chromosome 17 loss); single copy chromosome X loss with BCOR mutation, and NF1 and FGFR1 mutations. However, tumor aneuploidy, IDH-WT status, co-segregated NF1 alteration and LFS suggested malignant transformation, leading to HGG treatment. The second patient is a 6-year-old boy with LFS, detected on cascade testing, after his brother’s diagnosis of bithalamic diffuse paediatric-type HGG MYCN, following cancer surveillance through Surveillance Study in Multi-organ Cancer Prone Syndrome (SMOC-Junior). Baseline whole-body MRI identified an asymptomatic bithalamic glioma, histopathologically compatible with low-grade astrocytoma except for mosaic loss of H3K27me3. DNA methylation matched (0.99) to diffuse pediatric-type HGG MYCN-subtype, with multiple copy number aberrations, EGFR amplification/overexpression, NF1 mutations and TP53 loss of heterozygosity, without MYCN-alteration or increased expression. He received HGG-specific radiation therapy and is on an NF1-targeted maintenance therapy with trametinib, a MEK inhibitor. In both cases, molecular features suggested early transformation.

CONCLUSIONS

These patients highlight that integrated multi-omic diagnostic approaches can identify transformation in TP53-altered low grade gliomas and inform development of personalised management guidelines for patients and families with Li Fraumeni syndrome.
IMG-08. SYNTHESIZING MISSING MRI SEQUENCES IN PEDIATRIC BRAIN TUMORS USING GENERATIVE ADVERSARIAL NETWORKS; TOWARDS IMPROVED VOLUMETRIC TUMOR ASSESSMENT
Authors: Chrysochoou Dimosthenis , Familiar Ariana , Gandhi Deep , Storm Phillip B , Vossough Arastoo , Resnick Adam C , Davatzikos Christos , Nabavizadeh Ali , Kazerooni Anahita Fathi
Published: June 2024

BACKGROUND

Standard MRI sequences, such as pre- and post-contrast T1w, T2w, and FLAIR images, are essential for optimizing segmentation of tumor subregions and evaluating treatment responses in pediatric brain tumors (PBTs). However, MRI sets are often incomplete due to imaging artifacts or inconsistent acquisition protocols across various centers. Generative Adversarial Networks (GANs) have been effectively utilized to generate missing MRI sequences for adult brain tumors. This study applies image-to-image translation models using GANs to synthesize missing FLAIR images from T2w images in PBTs.

METHODS

This retrospective study developed two GAN models, pix2pix in both 2D and 3D, trained and validated on T2w and FLAIR image pairs from 79 and 19 patients, respectively, with pediatric-type diffuse high-grade gliomas (diffuse midline glioma (DMG) including diffuse intrinsic pontine glioma (DIPG)), collected from the Children’s Brain Tumor Network (CBTN). The 2D pix2pix model processes each T2w MRI volume slice-by-slice, generating corresponding FLAIR slices to reconstruct the complete image volume. The 3D pix2pix model allows translation of 3D FLAIR volumes directly from T2w volumes without the need for individual slice processing and reconstruction. The quality of the generated FLAIR volumes was evaluated using Structural Similarity Index (SSI; best closer to 1) and Mean Squared Error (MSE; best near 0) on the validation set.

RESULTS

The 2D and 3D models achieved robust performance with median SSI, MSE of 0.88, 0.004, and 0.92, 0.002, respectively.

CONCLUSIONS

The GAN models developed in this study effectively generate missing FLAIR MRI volumes from corresponding T2w images in PBTs. The 3D model, outperforming 2D, speeds the overall processing pipeline by eliminating volume slicing and reconstruction. Future work includes assessing the impact of these synthesized images on the accuracy of our pretrained autosegmentation models in differentiating tumor subregions and measuring tumor volumes in longitudinal MRIs.
IMG-23. AN MRI-BASED RADIOMIC SIGNATURE TO PREDICT LONG-TERM SURVIVAL IN PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Frouin Frédérique , Khalid Fahad , Frouin Vincent , Dangouloff-Ros Volodia , Boddaert Nathalie , Grill Jacques
Published: June 2024

BACKGROUND

Diffuse intrinsic pontine gliomas are characterized by a short life expectancy after diagnosis, with a mean overall survival of less than 12 months. To stratify patients and possibly better adapt therapy, we are proposing a radiomic signature that predicts, at the time of diagnosis, which patients might survive beyond 2 years.

METHODS

A retrospective database comprising 80 patients who had undergone 3D multimodal MRI at the time of diagnosis was compiled. All images were acquired at a single center, and the protocol included T1-weighted images acquired before and after contrast injection, T2-weighted and FLAIR images. Depending on the patient, some modalities were missing (around 10% per modality). After manual tumor delineation, a dedicated radiomic pipeline extracted 79 features (first-order statistics and texture parameters) per imaging modality. In addition, gender, age and 14 tumor shape features were collected without missing data. After feature selection (maximum of 4 features per model), five logistic regression models were defined, one per modality and another for clinical and shape variables. Each patient was eligible for 2 to 5 models, with an average score calculated over these models.

RESULTS

Based on a leave-one-out approach, the multi-model was able to define patients who survive more than 2 years correctly, (sensitivity=100%, specificity =79%). A prediction could be made for each patient despite missing MR modalities. Defining a radiomic signature based on the multi-model score (cut-off=0.5), Kaplan-Meier analysis shows a good separation of the two groups (p-value<0.001). This result is superior to that obtained with the TP53 mutation (available for 61 patients, with p-value<0.01).

CONCLUSIONS

We have demonstrated the value of multimodal 3D MRI in predicting which DIPG patients might survive beyond 2 years. The robustness of this radiomic signature has yet to be tested using multicentric images.
IMG-32. USER EVALUATION OF AN AI-POWERED WEB APPLICATION TO SUPPORT RADIOGRAPHIC INTERPRETATION OF PATIENTS WITH ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Prince Eric W , Mirsky David M , Görg Carsten , Hankinson Todd C
Published: June 2024

BACKGROUND

In neuro-oncology, accurately interpreting radiographic images, especially for diagnosing central nervous system (CNS) tumors like Adamantinomatous Craniopharyngioma (ACP), presents formidable challenges. Even with advanced imaging technologies such as Magnetic Resonance Imaging (MRI) and Computed Tomography (CT), pinpointing features related to ACP invasiveness remains daunting.

METHODS

We introduced an interactive web application that utilizes a custom AI model to analyze preoperative MRI and CT images of 50 patients with ACP. This application can predict a 12-point radiographic feature profile and rank patients based on similarity, aiming to support clinicians in making more precise diagnoses. We deployed our application on a hospital-grade radiographic reading terminal. Our application’s utility and user-friendliness were evaluated through a user study involving four neurosurgeons and two neuroradiologists, who constructed 12-point radiographic feature profiles for ten patients within a 30-minute timeframe given patient MRI and CT images.

RESULTS

Our study subjects reported high self-assessed numeracy (SNS scores ranging from 4 to 5.25) despite varied preferences in engaging with numerical data. Subjects could efficiently learn to navigate our software interface, with an average task completion time of approximately 3 minutes and 25 seconds per patient. Introducing AI into the task workflow resulted in a slight, statistically non-significant increase in completion time, indicating that while AI modifies interaction dynamics, it does not significantly hinder efficiency in task performance. We observed distinct agreement patterns between clinicians and AI prediction, utilizing Fleiss’ Kappa for categorization. AI assistance subtly boosted clinicians’ confidence and slightly lessened the perceived difficulty of interpreting radiographic images. However, these benefits were not statistically significant.

CONCLUSIONS

Our study highlights the promise of AI in improving neuro-oncology diagnostics, showing that clinicians quickly adapted to an AI-enhanced application, which subtly influenced their radiographic interpretation. This finding underscores the potential for AI to enhance decision-making accuracy in challenging cases like ACP.