tbuckley/cabot-search huggingface dataset:
GCT-20. PRESENTATION AND OUTCOME OF BIFOCAL GERMINOMA TREATED ACCORDING TO SIOP CNS GCT II
Authors: Gabriele Calaminus, Claire Alapetite, Rolf Dieter Kortmann, Brigitte Bison, Cecile Faure Conter, Thankamma Ajithkumar, Nicolas Gerber, Andreas Peryl, Giovanni Morana, Matthew Murray, Stefan Schönberger, Herve Brisse, Martin Zimmermann, Didier Frappaz, James Nicholson
Journal: Neuro-Oncology (2024)

Abstract 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
MDB-39. HOW DO TUMOUR DERIVED EXTRACELLULAR VESICLES INTERACT WITH THE DEVELOPING NERVOUS SYSTEM AND LEAD TO ALTERED PAIN PROCESSING IN CANCER SURVIVORS?
Authors: Hannah K Jackson, Anna Grabowska, Victoria James, Federico Dajas-Bailador, Beth Coyle, Gareth Hathway
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Childhood cancer-related pain and its treatment lack sufficient clinical attention due to limited understanding of the underlying mechanisms. While chemotherapy-induced peripheral neuropathic pain (CIPN) mechanisms in adults have been extensively studied, those in early life remain unexplored. In the CIPN literature there is a growing body of evidence for tumour derived factors altering pain processing. Our study aims to understand how tumour derived extracellular vesicles (EVs) interact with the developing nervous system and impact pain processing in childhood brain tumour survivors. METHODS We determined dose-response curves and IC50 values for several medulloblastoma (MB) cell lines using standard-of-care chemotherapy drugs: vincristine, etoposide, cisplatin, and lomustine. EVs were isolated via size exclusion chromatography and characterised through western blotting, flow cytometry and electron microscopy. We quantified the effects of chemotherapy on EV release using ZetaView analysis. We then tested whether EVs from relevant MB cell lines could influence axon development in primary mouse embryonic day 16.5 dorsal root ganglion (DRG) neurons in vitro after pre-treatment with chemotherapy-treated EVs. RESULTS EVs from chemotherapy-treated and untreated cells exhibited similar size and shape. However, a combination of vincristine, etoposide, and cisplatin at low concentrations significantly increased EV secretion by MB cell lines. Moreover, 24-hours following treatment with chemotherapeutic exposed EVs there was complete cell death of embryonic DRG neurons compared to the PBS or control EV treated neurons. CONCLUSION Standard chemotherapy drugs substantially enhanced EV release from MB cells, and co-culture of embryonic DRG neurons with chemotherapy exposed EVs resulted in neuronal death. Our next step is to investigate whether administering these selected EVs in healthy animals alters pain responses and pain maturation. We also aim to study the biodistribution of these EVs within the nervous system and body, after infusion into the cerebrospinal fluid as well as how EV cargo is altered by chemotherapeutics.
MDB-43. SHARED DECISION-MAKING (SDM) REGARDING RADIATION-AVOIDING (RA) THERAPY IN YOUNG CHILDREN WITH MEDULLOBLASTOMA (MB)
Authors: Andrew R Kugelmann, Naina L Gross, Anand Srinivasan, Rene Y McNall-Knapp
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Standard treatment for MB in patients age ≥ 3 years includes craniospinal radiation with tumor bed boost and chemotherapy. Radiation carries substantial risk of long-term issues, particularly in the youngest patients: second malignancy, neurocognitive issues, vasculopathy and endocrinopathies. Numerous trials have attempted to decrease or avoid the use of radiation by intensifying chemotherapy, some using high dose chemotherapy with autologous hematopoietic stem cell rescue (HDC). One of the most successful RA protocols, Children’s Oncology Group ACNS0334 enrolled children age &amp;lt; 36 months and treated with 3 cycles of induction (+/- high dose methotrexate) and 3 cycles HDC without planned radiation. Since 2012, we offer SDM with caregivers regarding treatment of their children ages 3-7 years with MB. Caregivers may choose standard radiation and chemotherapy (SRC) or the RA treatment above. OBJECTIVE Describe patient and disease characteristics and outcomes in patients aged 3-7 years treated for MB with SDM regarding the use of radiation. METHODS Retrospective analysis of diagnosis, treatment and clinical outcomes in all children &amp;lt;8 y.o. who completed treatment for MB between 2012 and 2023. RESULTS There were 16 patients offered SDM (all gross total resection without metastases) 7 chose RA and 9 SRC. The SRC group was enriched with molecularly high-risk patients (4 MYC or MYCN amplification, 1 SHH with P53 mutation). In the RA group, relapse occurred in 14% (n=1 of 7). In the SRC group, 44% relapsed (n=4 of 9). One patient developed high-grade glioma in the radiation boost field 10 years later. There was 1 death in the RA group due to disease progression and 5 deaths in the SRC group, 1 due to second malignancy. CONCLUSIONS We report excellent survival with RA therapy for appropriately selected young children (age 3-7 years) when SDM is used with families to determine the best treatment for their child.
GCT-08. THE PURSUIT OF OPTIMUM TREATMENT FOR NONGERMINOMATOUS GERM CELL TUMOURS (NGGCT) OF THE CNS – A PROGRESS REPORT FROM THE EUROPEAN GROUP (SIOP CNS GCT II)
Authors: James C Nicholson, Claire Alapetite, Beate Timmerman, Cecile Faure Conter, Stefan Schönberger, Matthew J Murray, Nicolas Gerber, Andreas Peyrl, Martin Zimmermann, Yasmin Lassen-Ramshad, Didier Frappaz, Rolf-Dieter Kortmann, Thankamma Ajithkumar, Gabriele Calaminus
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Controversy surrounds the optimum treatment for localised nongerminomatous germ-cell-tumours (NGGCT). The European group has employed more dose-intense chemotherapy followed by 54 Gy focal radiotherapy (fRT), whilst others additionally apply whole-ventricular or craniospinal radiotherapy (CSI). Historically, these approaches have led to comparable outcomes. PATIENTS/METHODS SIOP-CNS-GCT-II aimed to improve event free survival (EFS) for NGGCT by standardising the surgical approach for residual disease and by chemotherapy dose escalation in patients identified as high-risk (age &amp;lt;6 years and/or serum/CSF AFP &amp;gt;1000 ng/ml). Standard treatment with four courses of cisplatin, etoposide and ifosfamide (PEI) followed by 54 Gy fRT with 30 Gy CSI for metastatic disease, was retained from the SIOP-CNS-GCT-96 trial for patients not defined as high-risk. Radiotherapy technique (protons or photons) was not dictated in the trial, but the number of cases receiving proton beam therapy has increased over time. Between 02/2012 and 07/2018, 112 patients with NGGCT from eight European countries were treated according to the SIOP-CNS-GCT-II protocol; 89 were standard-risk, and 14 of these were metastatic. This compared with 149 NGGCT patients treated overall in SIOP-CNS-GCT-96, of which 33 were metastatic. RESULTS In SIOP-CNS-GCT-96, 3-year EFS for localised NGGCT receiving PEI chemotherapy and 54 Gy fRT was 0.72, and for metastatic cases, receiving PEI and 30 Gy CSI with boost, 0.68. In SIOP-CNS-GCT-II, 3-year EFS for metastatic cases receiving similar treatment was excellent at 0.94 (p=0.087 compared with SIOP-CNS-GCT-96) but for localised cases, only 0.63 (p=0.032). CONCLUSION To understand the impact of radiotherapy volumes on EFS and guide future trials, a detailed dosimetric study on the patterns of relapses is in progress. In the meantime, based on our current understanding, most participating countries are recommending addition of whole ventricular radiotherapy to fRT for localised NGGCT.
MDB-35. DEVELOPMENT OF DUAL LUCIFERASE ASSAY FOR 3D-COMPATIBLE HIGH THROUGHPUT SCREENING IN MEDULLOBLASTOMA
Authors: Aderonke O Ajongbolo, Karen Sperle, Haozhe Zheng, Darrin J Pochan, Sigrid A Langhans
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most common malignant pediatric brain tumor, originating from the cerebellum, a part of the brain that controls balance, coordinated movement and other non-motor behaviors. 2D cell cultures are commonly used for testing of new compounds in high throughput screening (HTS) targeting this cancer, largely because there are numerous highly optimized assays available for analyzing this cell culture model. However, they have significant limitation in mimicking in vivo conditions of the tumor microenvironment. 3D cell-culture methods have been embraced to enhance the modeling of in vivo tissue, replicating the multicellular architecture and the characteristics of the extracellular matrix. Presently, there are efforts to integrate 3D cell-culture with HTS to yield more clinically relevant results. However, one of the requirements for this is a 3D-compatible cell-based assay suitable for HTS. We developed such an assay which measures the activity of YAP/TAZ, a central molecule of Hippo-signaling pathway, and has been implicated in medulloblastoma. It plays a crucial role in maintaining tissue balance by coordinating proliferation, apoptosis, and differentiation. METHODS We cloned 8xGTIIC-NlucP, a brighter and more sensitive luciferase (Nanoluciferase) reporter plasmid that detects YAP/TAZ activity. Responsiveness to YAP/TAZ activity, and its inhibition were detected using a dual luciferase assay in the medulloblastoma cell lines after transfection. A normalization plasmid with a constitutive promoter for firefly luciferase was used in this assay to differentiate compounds that affect YAP/TAZ activity specifically as opposed to those that are toxic to the cells. RESULTS A robust signal for YAP/TAZ activity, and its reduction when cells were treated with inhibitor, was seen in the three medulloblastoma cell lines used, which further validates the result. CONCLUSION In conclusion, we were able to develop a 3D-compatible cell-based assay with Nanoluciferase which can be a foundation for HTS targeting medulloblastoma using 3D cultures.
MDB-41. TARGETING PBK IN GROUP 3 MEDULLOBLASTOMA
Authors: Shubin W Shahab, Anna M Kenney, Tobey J MacDonald
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Group 3 medulloblastoma (MB) remains a challenging diagnosis especially due to a tendency for higher prevalence in infants and to develop frequent relapse. Targeted therapy remains elusive for these patients due to a lack of targetable alterations as well as poor understanding of driver mutations. PBK/TOPK has previously been identified as a hub gene in medulloblastoma and we have recently demonstrated that the LIN28B-PBK axis may be playing a crucial role in Group 3 MB development. METHODS Here we utilize transcriptomic profiling to identify pathways regulated by PBK in Group 3 MB to help identify potential vulnerabilities, immunofluorescence and cell viability analysis to calculate drug synergy. RESULTS Our analysis demonstrates that PBK knockdown leads to significant down regulation of cell cycle pathway genes. We also demonstrate that combining PBK inhibitor HI-TOPK-032 with the CDK 4/6 inhibitor palbociclib is synergistic in Group 3 MB cells. CONCLUSION Our investigations suggest PBK inhibition alone or in combination with other targeted agents may be a useful addition to existing therapy for these hard to treat cancers.
GCT-09. VENTRICULAR RELAPSES OF INTRACRANIAL GERM CELL TUMORS FOLLOWING FOCAL RADIOTHERAPY
Authors: Natália Dassi, Mohamed S Abdelbaki, Andrea M Cappellano
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Non-germinomatous germ cell tumors (NGGCTs) require treatment involving combinations of chemotherapy, surgery, and radiotherapy. The radiotherapy field is typically focal in Europe and craniospinal in North America. Unlike germinomas, there are conflicting results for the effectiveness of ventricular field irradiation, and there is not enough data documenting the histology and tumor markers for tumors that relapse along the ventricles in patients who receive focal irradiation. METHODS We performed a literature review for English-language literature from 1998 to 2024 to to analyze the incidence, histopathology and tumor marker levels for NGGCT patients who initially received chemotherapy followed by focal radiotherapy and ended up having of ventricular relapses. RESULTS We identified 47 cases with relapsed NGGCT. However, only 8 cases were along the ventricles. Six of these were ventricular only, including two presumed germinomas based on tumor markers, three biopsy-proven germinomas, and only one case with bHCG levels exceeding ≥1000 IU/l. Two had combined relapses involving both the ventricular and spinal regions; one had pathology-proven germinoma but with elevated alpha-fetoprotein, and the other exhibited bHCG levels between 50 and 200 IU/l. CONCLUSION Ventricular relapses in NGGCT patients who receive focal radiotherapy should be investigated further. Whole ventricular radiotherapy may be required to prevent the relapse of germinoma elements. However, further information is essential before making any changes in the radiotherapy doses and fields.
MDB-40. DEFORMATION-HETEROGENEITY RADIOMIC MEASURES TO RISK-STRATIFY PEDIATRIC MEDULLOBLASTOMA PATIENTS: A PRELIMINARY ANALYSIS
Authors: Marwa Ismail, Hyemin Um, Ralph Salloum, Peter de Blank, Pallavi Tiwari
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND A significant challenge in medulloblastoma (MB), the most frequent malignant brain tumor in children, is to accurately identify ‘average-risk’ patients who may benefit from therapy de-escalation without affecting treatment outcomes, from ‘high-risk’ patients. Unfortunately, the current clinical risk-assessment approaches (Chang/molecular stratification) are sub-optimal in reliable risk-stratification in MB. This work evaluates the hypothesis that infiltration in aggressive tumors manifests as deformations (shifts) with larger magnitudes and positive orientations (angles) in the surrounding healthy tissue, on MRI scans, compared to average-risk tumors (smaller shift magnitudes and negative orientations). The proposed imaging marker, complementary with current approaches, may allow for more reliable risk-stratification. METHODS T1-weighted MRI scans of MB patients (2–18 years) were collected from Cincinnati Children’s Hospital Medical Center (Site1-training) (n=42) and Children’s Hospital Los Angeles (Site2-testing) (n=45). Preprocessing and annotations for the edema sub-compartment were performed. Scans were mapped to age-specific atlases using diffeomorphic registration and inverse transformations were employed to obtain the deformations. Deformation magnitudes (DefMag) were extracted within equidistant bands outside the edema by calculating the Euclidean norm of deformations, generating a magnitude statistics vector (median, skewness, kurtosis, mean, standard-deviation). Angles/Orientations (Defθ) were computed between deformation vectors and vectors connecting each voxel to the tumor’s centroid, then quantized to 6 intervals, creating an orientation vector per band. Deformation magnitudes and angles (DefMag+θ) were employed with Chang and molecular stratification within regression models for risk-stratification. RESULTS Our analysis demonstrated that deformation features, complementing molecular and Chang’s stratification, yielded best results for risk-stratification. Employing DefMag+θ+Chang+molecular on training yielded Concordance-index (CI) of 0.56, p=0.0014 (CI=0.6,p=0.03 testing). DefMag+θ+Chang’s yielded CI=0.64, p&amp;lt;0.0001 on training (CI=0.54,p=0.04 testing). Results were not significant when employing Chang’s or molecular classification alone. CONCLUSIONS Our results suggest that radiomic deformation features, complementing clinical and molecular approaches, may enable reliable risk-stratification in pediatric MB.
HGG-38. COMBINING TARGETED THERAPY AND RADIATION OUTPERFORMS SINGLE TREATMENTS IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Kenneth Chun-Ho Chan, Nina Hofmann, Mareike Roscher, Rosemarie Euler-Lange, Kevin Steimel, Mathea Fransisca, Alessia Cais, Ivana Dokic, David T W Jones, Jürgen Burhenne, Ina Kurth, Stefan M Pfister, Marc Zuckermann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric-type diffuse high-grade gliomas (pHGGs) are a diverse group of central nervous system tumors in children and adolescents with typically fatal outcomes. Addressing this disease requires new treatment approaches to enhance both survival and quality of life for affected patients. Recently, targeting oncogenic receptor tyrosine kinases (RTKs) has provided promising initial responses in different pHGG subtypes. However, even in these cases, the disease invariably relapses. METHODS We utilized murine tumor cell cultures carrying oncogenic alterations in different RTKs, such as an NTRK fusion, an ALK fusion and activating FGFR1 mutations to evaluate the synergy of radiotherapy and a variety of specific small molecule inhibitors using viability and apoptosis assays. By conducting pharmacokinetic analyses in murine models, we quantified the availability of selected compounds in the mouse brain in vivo, informing downstream preclinical experiments. RESULTS We found that concomitant radiation potentiated the antitumor effect of all tested targeted compounds, mostly outperforming calculated additivity of single treatments. Of note, the level of potentiation was comparable between different inhibitors targeting the same RTK, but was highly dependent on the underlying tumor genotype. Using erdafitinib or futibatinib and a dose of 2 Gy in a FGFR1-driven pHGG model, the combined treatment resulted in a remarkably high late apoptosis rate of 90%, warranting ongoing in vivo studies. Through pharmacokinetic analyses, we identified that among all tested small-molecule-inhibitors, only lorlatinib and futibatinib reach clinically relevant concentrations in the murine brain. CONCLUSIONS Our preliminary data showed that the combination of targeted therapy and radiation elicits encouraging anti-tumor effects in different pHGG cultures. We are currently performing preclinical in vivo studies using immunocompetent orthotopic mouse models to evaluate benefits of combined treatment. Our data will inform future clinical trials and hopefully improve the prognosis and quality of life for a fraction of pediatric patients diagnosed with pHGG.
NFS-16. NOVEL AUSTRIAN CARE AND PREVENTION GUIDE FOR CHILDREN AND ADOLESCENTS WITH NF1
Authors: Amedeo A Azizi, Alicia-Christina Baumgartner, Cora Hedrich, Markus Seidl, Joachim Zobel, Georg Ebetsberger-Dachs, Herta Zellner, Christian Rauscher, Robert Birnbacher, Ursula Pichler, Edda Haberlandt, Anna Sophie Bergmeister-Berghoff, Robert Gruber, Tobias Welponer, Markus Hutterer, Thomas Pletschko, Kerstin Krottendorfer, Claas Röhl
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Unified strategies for the care of children and adolescents affected by Neurofibromatosis type 1 (NF1) are lacking in Europe. While ERN GENTURIS developed guidelines for the tumour surveillance and management in NF1, these recommendations do not cover all other aspects of the disease. This holds not only true on an international level, but also on the national level in Austria. Despite being a small country with a uniform health and social security system, approaches to patient care may be comparable but not identical. AIM In order to standardise and improve patient care for children with NF1 in Austria, a care and prevention sheet was developed. METHODS In close cooperation with the Austrian patient organisation NF Kinder the Austrian NF network was established. This network is composed of dedicated health-care providers (medical as well as psychosocial) involved in the care of patients with NF1 in ten Austrian centres as well as patient representatives, some of whom were also involved in drafting the novel ERN GENTURIS recommendations. This network undertook the task of reviewing existing guidelines and incorporate the national healthcare structure and best practice guidelines into a consensus document. RESULTS The recommendations were condensed into a single sheet that is divided in four sections: clinical examination, lab investigations, imaging, additional consultations. For each parameter, the document advises on the age specific intervals for screening. Furthermore, it indicates the appropriate time points during follow-up (e.g. at initial presentation, at transition, if clinically indicated, …). The recommendations thereby focus not only on the inherent tumour risk but address the broad spectrum of possible symptoms (such as orthopaedic or surgical), specifically emphasising also psychosocial and neurocognitive issues. CONCLUSION The novel Austrian care and prevention guide for children and adolescents with NF1 will facilitate uniform best practice care for affected kids on a national level