tbuckley/cabot-search huggingface dataset:
MDB-33. SIOPE-MB6 – THE RATIONALE FOR THE NEXT EUROPEAN STANDARD RISK MEDULLOBLASTOMA PHASE II/III TRIAL
Authors: Martin Mynarek, Francois Doz, Steve C Clifford, Simon Bailey, Stefan Rutkowski, Laeticia Padovani, Yassine Bouchoucha, Marita Partanen, Sarah Verity, Astrid Sehested, Anita Puhr, Anne Rossius, Mathilde Chevignard, Christian Dorfer, Ahmed El Damaty, Kevin Beccaria, Kristian Aquilina, Eelco W Hoving, Martin U Schuhmann, Ulrich W Thomale, Till Milde
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurocognitive impairment is one of the key late effects of childhood medulloblastoma and is potentially influenced by surgical resection, chemotherapy and/or radiotherapy. Still, reduction of therapy to reduce neurotoxicity may be associated with a higher risk of relapses. METHODS SIOP-MB6 is a European, prospective, randomized phase II/III trial, aiming to reduce late effects of neurosurgery, radiotherapy and chemotherapy using an improved clinico-molecular risk stratification. Four different interventional questions will be assessed. RESULTS Patients with clinically and biologically standard risk medulloblastoma (non-metastatic, no large cell/anaplastic histology, no MYC/MYCN amplification, SHH-medulloblastoma only if TP53 wildtype) are eligible for this trial. Surgical arm: The aim of surgery is randomized to be maximal safe resection (standard) or safe subtotal/near total resection, i.e. sparing critical structures, intending to leave small residual tumor behind (experimental), with systematic treatment of hydrocephalus. The primary endpoint is neurocognitive functioning. Risk-stratified adjuvant therapy: All patients receive one or two blocks of carboplatin/etoposide chemotherapy depending on degree of resection, risk stratification and randomization, followed by re-resection in case of residual tumor. Very favorable risk: Single arm Phase II trial for WNT-activated medulloblastoma. Intervention: reduction of radiotherapy and chemotherapy. Favorable risk: Single arm phase II trial for SHH medulloblastoma (TP53 wildtype) or non-WNT/non-SHH medulloblastoma (subtype VII or favourable whole chromosomal abberations phenotype). Intervention: reduction of radiotherapy and chemotherapy. Standard risk: Randomized phase III trial for non-WNT/non-SHH medulloblastoma not eligible for the favourable risk arm. Randomization in standard therapy (23.4Gy CSI, 4 cycles of cyclophosphamide/cisplatin based chemotherapy) or experimental tandem high-dose thiotepa with stem cell support, radiotherapy (23.4Gy CSI) and temozolomid maintenance. The primary endpoint of all three arms will be progression-free survival, with neurocognitive functioning among secondary endpoints. DISCUSSION Detailed rationales for this design will be presented during the presentation.
GCT-05. UPDATED REPORT ON TREATMENT MODALITIES IN METASTATIC GERMINOMA IN CHILDREN: A MULTI-INSTITUTIONAL ANALYSIS
Authors: Margaret Shatara, Alexia Thia, Mohammad H Abu-Arja, Jack M Su, Shannon MacDonald, Stephanie Perkins, Hamza Gorsi, Dinisha Govender, Hetal Dholaria, Jonathan Schwartz, Jen Chun Foo, Revathi Rajagopal, Ute Bartels, Katrina O’Halloran, Richard Sleightholm, Lucie Lafay-Cousin, Rose Daynielle A Cansanay, Mary-Pat Schlosser, Andrea M Cappellano, Natália Dassi, Michael J Fisher, Nisreen Amayiri, Yasin Yilmaz, Malgorzata Czogala, Richard Graham, Sofia Jares Baglivo, Rebecca Ronsley, Angela Mastronuzzi, George Michaiel, Sara Khan, Ross Magnum, Lindsey M Hoffman, Truman Knowles, Sabine Mueller, Mohamed S Zaghloul, Nada A Abdelhaleem, Moatasem El-ayadi, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors; germinoma accounts for two-thirds of cases. While neoadjuvant chemotherapy followed by response-based reduced radiotherapy dose and field is the established approach for managing localized CNS germinomas, controversy persists regarding the treatment of primary metastatic disease. Additionally, limited research exists on the utilization of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS A retrospective multi-institutional analysis was conducted to assess overall survival (OS) and event-free survival (EFS) among patients diagnosed with metastatic germinoma who were treated with various modalities. RESULTS We identified 88 patients, including 63 males and 25 females. The median age at presentation was 13.5 years. All patients, who had undergone both brain and spine MRIs, had their diagnoses confirmed through a biopsy, positive CSF cytology, and/or positive CSF tumor markers at presentation. Primary Tumor location was pineal (n=37), suprasellar (n=27), bifocal (n=14) and others (n=9). Eight patients underwent subtotal resection. Craniospinal irradiation (CSI; 21-24 Gy) was administered to 71 patients (81%), while eight patients (9%) received whole ventricular irradiation (WVI; 23.4-30 Gy). Whole brain radiation was given to four patients (5%; 24 Gy), and two patients (2%) had unknown fields. Boosts to primary and/or metastatic sites were administered in all but seven patients. Notably, thirty patients (34%) received CSI without neoadjuvant chemotherapy. At the end of therapy, 69 patients had complete response, 10 partial response and the response was unknown in six. Three patients did not receive irradiation, all died of disease progression. The median follow-up was 64 months (range 6-159 months), yielding an OS of 96.6%. Ongoing multi-institutional data collection and analysis will be presented at the meeting. CONCLUSION Our study is one of the largest studies to date in metastatic germinoma and may provide insight into the role of neoadjuvant chemotherapy with lower CSI doses.
GCT-07. CONTRIBUTORS TO DELAYED TREATMENT OF NON-GERMINOMATOUS GERM CELL TUMORS IN CHINA: A TERTIARY-CENTER REVIEW
Authors: Anan Zhang, Anthony P Y Liu, Rong Zhang, Bo Yang, Yali Han, Haiyan Chen, Ibrahim Qaddoumi, Zeena Salman, Godfrey C F Chan, Yijin Gao
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Non-Germinomatous Germ Cell Tumors (NGGCT) are rare malignancies with potential for treatment delays. This study aims to identify risk factors and systemic challenges contributing to delayed management of NGGCT in China. METHODS We reviewed the clinical features and referral pattern of 56 consecutively diagnosed NGGCT patients at Shanghai Children’s Medical Center (SCMC) from 9/2018-2/2023. Patients were diagnosed by pathology (n=42), or by elevated markers alone (n=14, AFP&amp;gt;10ng/ml, and/or β-HCG&amp;gt;50mIU/ml). Patients were treated per COG ACNS0122. Delay of treatment was defined as chemotherapy initiated more than 6 months after symptom onset. RESULTS Forty-three males and 13 females were included. Median age at diagnosis was 9.17year (4month-16year). Primary tumor locations included the pineal region (n=31), sellar region (n=19), basal ganglia (n=5), and posterior fossa (n=1). Presenting symptoms included features of increased intracranial pressure (ICP, n=29), endocrine symptoms (n=21), blurred vision or squint (n=7), and hemiplegia (n=4). Delayed treatment occurred in 16 cases (29%), and was more likely in patients with non-pineal region primary (Chi-square p=0.003), and absence of symptoms pertaining to increased ICP (Chi-square p&amp;lt;0.001). Reasons for delay included lack of parental recognition on symptoms (n=7), misdiagnosis (n=3), and inappropriate/incomplete workup (n=6). As a national referral center, patients commuted a median of 483 km (range: 12-2943km) to SCMC (median 2 hospitals (1,5) before SCMC), including 10 patients with obvious hydrocephalus travelling before any CSF diversion procedure. Three-year Event-Free Survival (EFS) was 76.9% and Overall Survival was 86.0%. There was a trend to inferior outcome in patients with delay in treatment (3y EFS 69.6%) compared with those without (3year EFS 80.6%, p=0.112). CONCLUSIONS Delay in treatment is common for children with NGGCT managed at a tertiary referral center in China. Improving public awareness, training for primary-care clinicians, and establishing a national referral network are potential strategies to enhancing the outcome.
HGG-39. CLINICAL CHARACTERISTICS AND SURVIVAL OUTCOMES OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT: INTERIM RESULTS OF A MULTICENTRE INTERNATIONAL STUDY
Authors: Cameron Crowell, Julie Bennett, Pratiti Bandopadhayay, Dominik Sturm, Adam L Green, Mary MacNeil, Magimairajan Issai Vanan, Valérie Larouche, Samuele Renzi, Brandon Imber, Jacquelyn Jones, Sébastien Perreault, Daddy Mata-Mbemba, Charlotte Feddersen, Olivia Vizzini, Michal Zápotocký, Sylvia Cheng, Rebecca Harrison, Aimee Popovacki, Darren Klawinski, Jordan R Hansford, Sarah Lapointe, Romain Cayrol, Nikhil Mankuzhy, Christina Coleman, Mariah Wright-Nadkarni, Ralph Salloum, Matthias Karajannis, Cynthia Hawkins, David T W Jones, Keith L Ligon, Nada Jabado, Craig Erker
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse hemispheric glioma, H3 G34-mutant (G34-DHG) is generally associated with very poor outcome. Little is known, however, regarding long-term survivors and associated prognostic factors. METHODS This retrospective, multicentre study was designed to investigate clinical, molecular, and imaging variables that may impact the survival of patients with G34-DHG. Patients of any age diagnosed with G34-DHG after January 1, 1995, with at least one measure of survival or progression were eligible. RESULTS 69 patients with G34-DHG (62 G34R, 5 G34V, 2 diagnosed by methylation profiling only) have been included to date. Median age at diagnosis was 16.0 years (range: 2–38). 75% of patients were under the age of 18. 52% of patients were male. 8% of patients had multifocal/disseminated disease at diagnosis. Upfront therapy included gross/near total resection in 47% of patients, radiation therapy in 88% (89% focal, 6% CSI), and maintenance chemotherapy in 85% (62% TMZ-based, 33% TMZ/CCNU, 5% non-TMZ). Median follow-up time was 20.0 months (IQR=12.0–30.0). 86% of patients had progressive disease with a median time-to-progression of 14.0 months (IQR=6.6-22.5). At last follow-up, 70% of patients had died from disease, 23% were alive with disease, and 7% were alive without disease. Median overall survival was 24.7 months (IQR=18.8–30.6). Median time from progression to death was 6.0 months (IQR=2.0–10.8). Six patients were found to be long-term survivors &amp;gt; 5 years (four dead of disease, one alive with disease, one alive without disease). Log-rank assessment revealed improved survival to be associated with upfront gross/near-total resection (p=0.002) and age at diagnosis ≥ 18 years (p=0.012). CONCLUSIONS Surprisingly, we found that nearly 10% of G34-DHG patients survive 5 years or longer. Radical surgical resection and older age at diagnosis appear to be associated with longer survival. Imaging and molecular prognostic factors are being further investigated.
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: Laura Kirton, John R Apps, Anna Lawson, Theodoros Arvanitis, Dipayan Mitra, Richard Gagen, Hiten Patel, Andrew Peet, Lorna Fern, Emma Williams, Nicholas Coleman, Thankamma Ajithkumar, Brigitte Bison, Gareth Veal, Daniel P Stark, Giovanni Morana, James C Nicholson, Lucinda Billingham, Matthew J Murray
Journal: Neuro-Oncology (2024)

Abstract 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 (&amp;lt;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.
MDB-34. LITHIUM AND RADIATION REDUCE TUMOUR GROWTH IN GROUP 3 MEDULLOBLASTOMA
Authors: Yana Ruchiy, Daniela Nunes, Casandra Salinas, Shigeaki Kanatani, Gabriela Rosen, Miao Zhao, Fredrik J Swartling, Carlos F D Rodrigues, Klas Blomgren, Lena-Maria Carlson
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) is the most common high-grade paediatric brain tumour, accounting for ~20 % of all childhood CNS tumours. It is comprised of 4 distinct molecular subtypes, with Group 3 MB having the worst prognosis with an overall survival of around 50 %. Additionally, current treatments, especially radiotherapy (RT), come at a very high cost for the developing brain and result in permanent complications, including lower IQ, slower processing speed, as well as social problems and lifelong dependency. Lithium has been shown to protect neurogenesis and cognitive functions from the negative effects of RT on the juvenile brain in vivo and can therefore be hypothesised as a preventive treatment strategy to ameliorate these side effects. However, the effects and mechanisms of action of lithium on MB tumours remain largely unknown. In this study, we used GMYC GFP Group 3 MB cells (Mainwaring et al., 2023) to study the effects of lithium and RT in vitro, as well as creating a syngeneic model of Group 3 MB to study those effects in vivo. By using a whole brain immunostaining technique (iDISCO+) and light sheet microscopy, we created a 3D model of every tumour and quantified the tumour volume under different treatment conditions. Our results show that lithium – alone and in combination with radiation – significantly decreases Group 3 MB tumour growth both in vitro and in vivo. Additionally, we studied the transcriptomic changes induced by lithium, validating them through protein analysis that identified Klf4 as a potential effector of its underlying mechanism of action.
GCT-10. OUTCOME OF CHILDREN AND ADOLESCENTS DIAGNOSED WITH GERMINOMA WITH HCGΒ VALUES BETWEEN 100-200 MUI/ML TREATED ACCORDING TO THE BRAZILIAN CNS GCT PROTOCOL
Authors: Carol S Aguiar, Natália Dassi, Bruna Mançano, Sidnei Epelman, Simone S Aguiar, Nasjla S Silva, Jonathan L Finlay, Andrea M Cappellano
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Primary central nervous system (CNS) germ cell tumors (GCT) are rare tumors, classified according to histological components and tumor markers (TM) as Germinomas and Non-Germinomatous Germ Cell Tumors (NGGCT). The aim of this study is to assess the outcome of patients with Germinoma and HCGβ levels between 100-200mIU/ml treated according to the Brazilian CNS GCT Consortium Protocol. METHODS From 2013 to 2021, forty-three patients presented with histological and/or TM (serum and CSF) consistent with the diagnosis of germinoma, five of them with HCGβ levels between 100-200mIU/ml. The treatment plan performed was four cycles of carboplatin/etoposide followed by whole ventricular field irradiation (WVFI) of 18Gy with a boost to primary site(s) up to 30Gy and 24Gy craniospinal irradiation (CSI) for disseminated disease. RESULTS Average age 13.7 years (6.3-20.3 years), four males and one female. Diagnosis was made by TM (n=2), and biopsy +TM (n=3). The primary tumor location was pineal (n=2), suprasellar (n=1), and bifocal (n=2) with 1 case presenting ventricular spread at diagnosis. Three patients achieved complete response (CR) after two cycles of chemotherapy and one after four cycles. One patient showed partial radiological response (PR) with negative TM after four cycles and was submitted to a second-look surgery, with pathological report of residual scar tissue. Radiotherapy was performed as described in all patients with four patients receiving WVFI (18Gy+30Gy) and one CSI (24Gy+30Gy). In a mean follow-up of 64 months, overall and event-free survival was 100%. CONCLUSION Despite the small sample, the present study shows effectivity with excellent results and a possibility of increasing the cutoff and therefore reducing treatment for patients with HCGβ at levels up to 200mlU/ml currently treated in some protocols as NGGCT cases.
MDB-38. AN INTEGRATED MODEL FOR RESISTANCE TO BROMODOMAIN INHIBITORS IN CHILDHOOD MEDULLOBLASTOMA
Authors: Seung H Choi, Leslie Lupien, Adam N Boynton, Pratiti Bandopadhayay, John R Prensner
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Bromodomain inhibitors (BETi) have emerged as a potential treatment option for children with medulloblastoma, where hyperactivation of gene transcription by the MYC and MYCN transcription factors may lead to a transcriptional dependency. Yet, drug resistance limits the utility of these agents when employed as a monotherapy. We therefore sought to identify mechanisms of BETi resistance that inform rational development of multimodal therapy options. METHODS We used CRISPR screening of D458 medulloblastoma cells that have acquired resistance to the JQ1 inhibitor. We subsequently used small molecule inhibition and knockdown experiments to validate Menin as a target. Finally, we used RNAseq, ribosome profiling, and mass spectrometry to characterize transcriptional and post-transcriptional changes in D458 cells compared to D458 with JQ1 resistance. RESULTS In the setting of BETi resistance, we observed dependency on key transcriptional actors, such as MLL (KMT2A) and the Mediator complex, which we are now validating in mini-pool experiments. We further characterized aberrant MLL complex function through knockdown, small molecule inhibition, and RNA-sequencing of Menin, a critical MLL cofactor. Next, we were surprised to observe ribosome and proteosome genes as CRISPR dependencies in our initial screening of BETi-resistant cells, suggesting post-transcriptional regulation. Indeed, MYC, whose transcription is potently blocked by BETi, remained robust at the protein level in BETi resistance. We therefore performed integrated transcriptional, translational, and proteomic profiling to characterize gene regulation in BETi-resistance. We found that the BETi-resistant state leads to an “uncoupling” of transcriptional and post-transcriptional regulation for a subset of genes, leading us to test small molecule inhibitors of post-transcriptional processes in BETi-resistant medulloblastoma. CONCLUSIONS Taken together, our data inform an integrated model of BETi resistance based on both transcriptional and post-transcriptional mechanisms, suggesting new therapeutic angles that may be effective in combination with BETi therapies.
MDB-36. 22-HDOHE, A PREDICTIVE MARKER IN CSF OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA TREATED WITH MEMMAT
Authors: Andreas Peyrl, Gerhard Hagn, Natalia Stepien, Daniel Senfter, Sibylle Madlener, Jaroslav Sterba, Alvaro Lassaletta, Pierre Leblond, Karsten Nysom, Christine Haberler, Andrea Bileck, Amedeo A Azizi, Lisa Mayr, Johannes Gojo, Irene Slavc, Christopher Gerner
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND With the antiangiogenic metronomic MEMMAT combinatorial regimen, we could achieve sustained responses in a quarter of the patients with previously irradiated recurrent medulloblastoma. There are currently no molecular biomarkers predicting response to MEMMAT treatment for recurrent medulloblastoma. Lipid mediators, including classical arachidonic acid-derived eicosanoids and docosanoids, are locally acting bioactive signaling lipids that regulate a diverse set of homeostatic and inflammatory processes. Before initiation of MEMMAT treatment for relapsed medulloblastoma, we examined the bioactive lipid mediator profile in the cerebrospinal fluid (CSF) of patients and compared it with samples from patients with different neurological disorders, but without cancer. METHODS We analyzed CSF samples from 23 patients with relapsed MBL before initiation of MEMMAT treatment and from 12 controls. Lipid mediators were enriched via solid phase extraction and analyzed using liquid chromatography coupled to a high resolution orbitrap Exploris 480 mass spectrometer. RESULTS Mass spectrometry-based untargeted oxylipin analysis led to the identification of 98 lipid mediators. Several molecules were downregulated in medulloblastoma samples versus control, such as lipoxin A4 and 14(15)-DiHETE. Non-responders had lower levels of these molecules than responders. Glycodeoxycholic acid and deoxycholic acid were up-regulated in medulloblastoma patients, again with higher levels in non-responders. Remarkably, the docosahexaenoic acid (DHA)-derived 22-HDoHE was specifically identified in the CSF samples of medulloblastoma patients but not in control samples. CONCLUSION An oxylipin pattern in CSF might serve as a predictive biomarker signature for response in patients with recurrent medulloblastoma treated with the antiangiogenic metronomic MEMMAT regimen. Our findings advocate for the prospective assessment of CSF-derived lipid markers in future trials for recurrent medulloblastoma.