bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEDB-30. Subclassification of Group 3/4 medulloblastoma as a potential prognostic biomarker to reduce the dose of craniospinal irradiation in patients with metastatic tumors: A Japanese Pediatric Molecular Neuro-Oncology Group study
Authors: Fukuoka Kohei , Kurihara Jun , Mori Makiko , Arakawa Yuki , Yoshioka Ema , Shofuda Tomoko , Matsushita Yuko , Hibiya Yuko , Honda Satoko , Nakazawa Atsuko , Kiyotani Chikako , Kagawa Naoki , Yamasaki Kai , Ando Ryo , Keino Dai , Miyairi Yosuke , Akai Takuya , Kanamori Masayuki , Ishida Joji , Park Young-Soo , Kawamura Atsufumi , Sasaki Atsushi , Nishikawa Ryo , Date Isao , Nagane Motoo , Koh Katsuyoshi , Ichimura Koichi , Kanemura Yonehiro 
Published: June 2022

Abstract
BACKGROUND: In patients with medulloblastoma, one of the most significant challenges is to reduce the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients treated using lower-dose CSI rather than standard therapy is important for further reducing the treatment burden. METHODS: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and were treated using lower-dose CSI rather than standard-dose radiation therapy. RESULTS: Among the patients, 23 were classified as having a “standard-risk” and 15 as having a “high-risk” according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months. The median CSI dose was 18 Gy in both groups, and 10 patients in the “high-risk” group received a CSI dose of 23.4 Gy or 24 Gy. Molecular subgrouping revealed the “standard-risk” cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the “high-risk” cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 13 of the 16 “standard-risk” patients were subclassified as subtypes I, IV, VI, and VII, which were associated with a good prognosis according to the novel sub-subclassification among Group 3/4 medulloblastomas. However, only 6 of the 15 “high-risk” patients were included in the subtypes. The good prognostic subtype cases among “high-risk” cohort were all survived without recurrence, in contrast to a worse prognosis (5-year progression free survival=33.3%; p=0.01) of the other cases. CONCLUSION: Although these findings require validation in a larger cohort, the present findings suggest that the novel sub-subclassification of Group 3/4 medulloblastoma may be a promising prognostic biomarker for reducing the dose of CSI in patients with metastatic medulloblastoma.
MEDB-31. THE CLINICAL SIGNIFICANCE OF EXTENT OF RESECTION IN MEDULLOBLASTOMA
Authors: Keeling Claire , Davies Simon , Hicks Debbie , Clifford Steven 
Published: June 2022

Abstract
Medulloblastoma (MB) patients determined to have a sub-total resection (STR), defined by &gt;1.5cm2 post-surgical tumour residuum, receive intensified treatment regimes, but recently the designation of STR as a high risk feature is being questioned. We aimed to assess the clinical correlates of extent of resection (EOR) and its impact on survival, with particular consideration of EOR in relation to the four MB consensus molecular subgroups (WNT, SHH, Group 3, Group 4). We collected data from 1113 patients (n=419, UK CCLG institutions; n=694, published data) representing the largest ever combined cohort constructed to assess the impact of EOR in medulloblastoma. We performed association analyses and univariate/multivariate survival analysis using Kaplan-Meier, log-rank and Cox proportional hazard modelling, analysing overall survival (OS) cohort-wide and with reference to molecular subgroups and clinical features. Association analysis of the combined cohort evidenced that infant patients were more likely to have STR (p=0.02). In this whole-cohort analysis, EOR was significantly associated with survival in univariate analysis (HR 1.64, 95% CI 1.30-2.07, p=&lt;0.001) but not in multivariate analysis. STR was variably prognostic in sub-cohort analyses of specific demographics and molecular subgroup; worse outcomes were observed in patients &lt;5 years in SHH (p=0.044) and Group 4 (p=0.044). This was true for WNT patients &gt;5 years old at diagnosis (p=0.034) although numbers were small and require validation in even larger cohorts. In this cohort of &gt;1100 MBs, STR was significantly associated with a lower OS in univariate analysis, but this was driven by specific disease contexts (SHH and Group 4 patients &lt;5 years old). STR was not independently prognostic overall or in any setting. We recommended that surgeons should continue to pursue maximal safe resection for all MB patients but suggest that consideration of STR as a high-risk feature should be disease context specific.
MEDB-35. Relationship between genetic profile, histology, clinical features and long-term outcome in young children medulloblastoma (YCMB) treated with upfront high dose chemotherapy (HDCT) in Italy
Authors: Garrè Maria Luisa , Massimino Maura , Buttarelli Francesca Romana , Gandola Lorenza , Barra Salvina , Giangaspero Felice , Goschzik Tobias , Biassoni Veronica , Pastorino Lorenza , Pistorio Angela , Pietsch Torsten 
Published: June 2022

Abstract
AIMS: We report a cohort of YCMB cases homogeneously treated with HDCT in two Italian institutions, and the prognostic impact of histology and genetics retrospectively evaluated. METHODS: All YCMB (aged≤3 years) treated with upfront HDCT in the period 1998-2019 were included, reclassified according to the WHO2021 classification of CNS tumours. Mutational status ofPTCH1, SUFU, and TP53 was analysed in selected cases. Histology and genetics were correlated with survival, secondary tumours(STs), and cancer predisposition syndromes(CPSs). RESULTS: Fifty-three patients were enrolled (62.3% male), median age 2.2 years. 21 had classic(CMB), 15 desmoplastic/nodular(DMB), 11 MBEN and 6 large-cell/anaplastic(AMB/LCMB) medulloblastoma. Metastases were present in 18. Genomic pattern showed SHH-TP53wt in 29 cases, non-WNT/non-SHH in 22; 2 were SHH-TP53mut. Induction chemotherapy (VCR/HDMTX, HDVP16, VCR/HDCTX and HDCARBO) was followed by 2-3 HDCT courses; irradiation reserved to cases with metastatic disease and/or residual tumours. 22 patients never received irradiation. SHH-TP53wt cases had significantly less metastasis (p=0.002), while non-WNT/non-SHH received more often irradiation (p&lt;0.0001). OS at 5, 10, and 20 yrs was 0.73, 0.70 and 0.57 respectively in the entire cohort; stable at 0.85 (at 5, 10, and 20 yrs) in SHH-TP53wt patients while 0.58, 0.51 and 0.17 in the non-WNT/non-SHH. PFS at 5, 10, 20 yrs was stable at 0.89 in SHH-TP53wt and remained 0.35 in non-WNT/non-SHH. 13/53 patients presented Gorlin Syndrome; 1 had familial MB. 16 STs were reported in 14 cases; life-threatening, irradiation-related STs mainly in non-WNT/non-SHH cases. In SHH-TP53wt benign tumours or related to CPS were reported. CONCLUSIONS: This is one of the first series of YCMB treated with HDCT without stratification for stage and histology. The long follow-up highlights the frequency/types of associated CPS and STs; the latter, in non-WNT/non-SHH, were treatment-related and life-threatening.
MEDB-37. Chemotherapy response prediction by molecular risk factors in metastatic childhood medulloblastoma
Authors: Obrecht Denise , Bockmayr Michael Ludwig , Bison Brigitte , Pfister Stefan M , Sturm Dominik , Sahm Felix , Jones David T W , Sill Martin , von Hoff Katja , Benesch Martin , Gerber Nicolas U , von Bueren André , Friedrich Carsten , Pietsch Torsten , Schüller Ulrich , Mynarek Martin , Rutkowski Stefan 
Published: June 2022

Abstract
BACKGROUND: Childhood metastatic medulloblastoma (MB) frequently receive postoperative chemotherapy (CT) before craniospinal irradiation. Some MB show stable (SD) or progressive disease (PD) upon CT. Identification of biomarkers for non-response might allow therapy-modifications. METHODS: Patients registered to the German HIT-MED database (2001–2019) were eligible if they were 4-21 years old at diagnosis of a M2/M3-metastasized MB, received therapy in analogy to the MET-HIT2000-AB4 protocol, had centrally reviewed response assessment after 2 cycles HIT-SKK-CT and DNA-methylation analysis was available. DNA-methylation-based tumor classification and whole chromosomal (WC) losses/gains were derived from DNA-methylation arrays. RESULTS: 51/163 (31.3%) patients (median age: 9.8±4.4 years, median follow-up: 6.2±4.0 years) presented SD/PD during/after HIT-SKK-CT and were classified as non-responder. Response to CT had high predictive value for PFS/OS (5-year PFS responder: 67.9±4.8 %, non-responder: 26.1±6.6%, p&lt;0.01 / 5-year OS responder: 80.0±4.2%, non-responder: 45.9±8.0%, p&lt;0.01). Patients with nonWNT/nonSHH-MB subtype II (response: 7/13), subtype III (response: 6/19) and/or MYC-amplification (n=27, overlap subtype II/III: n=11/8, response: 14/27) were less likely to respond, while all 6 of WNT, 8/9 SHH-TP53-wildtype and 1/1 SHH-TP53-mutant responded (Mann-Whitney-U-test p=0.04). Further, ≥2 WC losses/gains of chromosome 7/8/11 was associated with superior response (n=29/32, others: n=83/131, Mann-Whitney-U-test p&lt;0.01). We identified a very-high-risk-cohort (any two criteria of: &lt;2 WC losses/gains of chromosome 7/8/11, MYC-amplification, MB subtype II, III, V, or VIII, n=94), and a standard-risk-cohort (WNT or any ≥2 WC losses/gains of chromosome 7/8/11, n=37) with 40 vs. 8 % non-response and 44±5/60±5 vs. 79±7/87±6% 5-year PFS/OS (p&lt;0.01/p&lt;0.01), respectively. Non-response in n=32 non-VHR/non-SR-patients was 32% with a 5-years PFS/OS of 60±10/77±8%. CONCLUSION: Molecular information can be helpful to predict response to chemotherapy. Upon validation, this may contribute to improve treatment stratification in metastatic MB.
MEDB-38. Significance of CSF cytology and neurologic deterioration in relapsed medulloblastomas in the German HIT-REZ-97/-2005 Studies and the HIT-REZ-Register
Authors: Tschirner Sebastian , Adolph Jonas E , Gaab Christine , Tippelt Stephan , Mikasch Ruth , Mynarek Martin , Rutkowski Stefan , Pietsch Thorsten , Bison Brigitte , Warmuth-Metz Monika , Pfister Stefan M , Milde Till , Pajtler Kristian W , Witt Olaf , Frühwald Michael , Kramm Christof , Schlegel Paul-Gerhardt , Kortmann Rolf-Dieter , Dietzsch Stefan , Timmermann Beate , Fleischhack Gudrun 
Published: June 2022

Abstract
BACKGROUND: Follow-up examinations are an essential part of the aftercare of patients with brain tumours. We investigated survival in relation to neurological impairment and positive CSF findings at first relapse/progression of medulloblastomas. METHODS: We collected data from patients with relapsed medulloblastoma from the German HIT-REZ studies (HIT-REZ-1997, HIT-REZ-2005, HIT-REZ-Register, n=342). Survival differences dependent on tumour cell-positive and -negative CSF cytology as well as on new onset or worsening of neurological impairment (i.e. headache, nausea/vomiting, ataxia, seizures and others) were analysed. RESULTS: 247 patients with a recurrent medulloblastoma were evaluable for CSF cytology at first relapse/progression (positive n=97, negative n=150). Patients with tumour cell-positive CSF results showed a significantly shorter median PFS and OS time compared to patients with negative CSF cytology [PFS: 9.1 (CI: 5.3-12.9) vs. 16.8 (CI: 13.8-19.8) months, plog rank test=0.001; OS: 14.4 (CI: 12.3-16.4) vs. 41.8 (CI: 33.3–50.4) months, plog rank test&lt;0.001]. The shortest PFS and OS were observed in SHH-activated (n=18) and group 3 medulloblastomas (n=23) independently of CSF cytology result [median PFSSHH: 4.3 (CI:1.1-12.2), OSSHH: 6.3 (CI:1.1-18.7); PFSgroup3: 4.2 (CI:2.3-13.1), OSgroup3: 13.2 (CI:7.1-18.5) months]. For analysis of the impact of neurological deterioration on survival at first relapse, 249 Patients were evaluable. 105 patients with new or severely worsened neurological impairment at first relapse/progression displayed a significantly poorer PFS and OS time in comparison to 144 patients with unchanged or improved neurological symptoms [PFS: 8.2 (CI: 6.0-10.3) vs. 14.9 (CI: 12.0-17.9) months, plog rank test=0.001; OS: 15.1 (CI: 9.5-20.6) vs. 32.6 (CI: 26.2-38.4) months, plog rank test&lt;0.001]. CONCLUSIONS: Patients with relapsed medulloblastoma show significantly worse survival (PFS and OS) in presence of positive CSF cytology or neurologic deterioration at relapse. These findings could be relevant for patient/parents counselling and treatment recommendations at relapse. Funded by the German Children Cancer Foundation
MEDB-42. GermlineElp1 deficiency promotes genomic instability and survival of granule neuron progenitors primed for SHH medulloblastoma pathogenesis
Authors: Garcia-Lopez * Jesus , Ahmad * Shiekh Tanveer , Li * Yiran , Gudenas Brian , Kojic Marija , Manz Friedrik , Jonchere Barbara , Mayasundari Anand , Pitre Aaron , Hadley Jennifer , Paul Leena , Batts Melissa , Bianski Brandon , Tinkle Christopher , Orr Brent , Rankovic Zoran , Robinson Giles , Roussel Martine , Wainwright Brandon , Kutscher Lena , Lin # Hong , Northcott # Paul 
Published: June 2022

Abstract
Germline loss-of-function (LOF) mutations in Elongator complex protein 1 (ELP1) are found in 15-20% of childhood SHH medulloblastoma (MB) and are exceedingly rare in non-SHH-MB or other cancers. ELP1 germline carriers that develop SHH-MB harbor frequent somatic PTCH1 mutations and universally sustain loss-of-heterozygosity of the remaining ELP1 allele through chromosome 9q deletion. ELP1 functions as a scaffolding subunit of the Elongator complex that is required for posttranscriptional modification of tRNAs and maintenance of efficient translational elongation and protein homeostasis. However, the molecular, biochemical, and cellular mechanisms by which ELP1/Elongator LOF contribute to SHH-MB tumorigenesis remain largely unknown. Herein, we report that mice harboring germline Elp1 monoallelic loss (i.e., Elp1+/-) exhibit hallmark features of malignant predisposition in developing cerebellar granule neuron progenitors (GNPs), the lineage-of-origin for SHH-MB. Elp1+/- GNPs are characterized by increased replication stress-induced DNA damage, upregulation of the homologous recombination repair pathway, aberrant cell cycle, and attenuation of p53-dependent apoptosis. CRISPR/Cas9-mediated Elp1 and Ptch1 gene targeting in mouse GNPs reproduces highly penetrant SHH-MB tumors recapitulating the molecular and phenotypic features of patient tumors. Reactivation of the p53 pathway through MDM2 and PAK4 inhibitors promotes selective cell death in patient-derived xenograft tumors (PDX) harboring deleterious ELP1 mutations. Together, our findings reveal that germline Elp1 deficiency heightens genomic instability and survival in GNPs, providing a mechanistic model for the subgroup-restricted pattern of predisposition and malignancy associated with pathogenic ELP1 germline carriers. These results provide rationale for further preclinical studies evaluating drugs that overcome p53 pathway inhibition in ELP1-associated SHH-MB and a renewed outlook for improving treatment options for affected children and their families.*, # Contributed equally
MEDB-43. Development of a bioinformatics pipeline for identification of differential DNA methylation events associated with medulloblastoma relapse
Authors: Kui Christopher , Richardson Stacey , Schwalbe Edward C , Thompson Dean , Keeling Claire , Strathdee Gordon , Dufour Christelle , Bailey Simon , Ramaswamy Vijay , Clifford Steven C , Hill Rebecca M 
Published: June 2022

Abstract
Relapsed medulloblastoma (rMB) is treatment-resistant and fatal in ~95% of cases. The epigenetic features of rMB, and any role as drivers of disease relapse/treatment-resistance have yet to be investigated. We therefore developed a pipeline to identify differentially methylated CpGs (DM-CpGs) and regions (DMRs) in a paired-rMB cohort. Our paired-rMB cohort (n=61, relapsed tumours matched with diagnosis counterparts) with available Illumina Methylation 450K/850K microarray data was processed in R-Studio. The packages Limma and DMRcate were used to perform a paired differential methylation analysis on a filtered selection of array probes (n=335,767), identifying DM-CpGs and DMRs with a 5% FDR. DMRs were further retained if they had a maximum-Δβ of &gt;0.2 and correlated with locus-specific gene expression in a separate paired DNA-methylation array/RNA-seq cohort from medulloblastoma diagnosis samples (n=202). Finally, we created univariable Cox models to assess the prognostic potential of DM-CpGs/DMRs in an independent survival cohort of medulloblastoma diagnosis samples (n=498). Across the paired-rMB cohort, there were few significant differential methylation events initially identified at relapse (n=258 DM-CpGs, n=32 DMRs). Upon sub-analysis by molecular group, MBGroup4 (n=18 pairs) alone yielded significant findings (n=189 DM-CpGs, n=26 DMRs). Most changes involved hypermethylation events detected at relapse. Multiple DM-CpGs identified at relapse were prognostic for both overall and event-free survival when assessed in our independent cohort (n=22 whole cohort, n=13 Group 4, BH-adjusted p&lt;0.05). When applying the DMR filters, only the MBGroup4 DMRs passed the Δβ filter (n=18/26), with few correlating with gene expression (n=2, p&lt;0.001), and none demonstrating prognostic significance. This pipeline facilitates exploration of the clinical relevance of epigenome-wide changes in a paired-rMB cohort. We highlight the potential prognostic significance of DM-CpGs, and future work will explore the potential functional role of candidate-genes associated with our DMRs, as novel drivers of rMB.
MEDB-49. Relapsed SHH medulloblastomas in young children. Are there alternatives to full-dose craniospinal irradiation?
Authors: Erker Craig , Craig Brandon , Bailey Simon , Massimino Maura , Larouche Valerie , L Finlay Jonathan , Kline Cassie , Michaiel George , Margol Ashley , Cohen Kenneth , Cacciotti Chantel , Harrods Virginia , Doris Kathleen , AbdelBaki Mohammed , Amayiri Nisreen , Wang Zhihong , Hansford Jordan , Hukin Juliette , Salloum Ralph , Hoffman Lindsay , Muray Jeffrey , Ginn Kevin , Zapotocky Zapotocky , Baroni Lorena , Ramaswamy Vijay , Gilheens Stephen , Aguiera Dolli , Mazewski Claire , Shah Shafqat , Strother Douglas , Muller Sabine , Gajjar Amar , Northcott Paul , Clifford Steve , Robinson Giles , Bouffet Eric , Lafay-Cousin Lucie 
Published: June 2022

Abstract
BACKGROUND/RATIONAL: Following initial irradiation sparing therapy, many young children with relapsed medulloblastoma can be salvaged with craniospinal irradiation (CSI). However, the interval to relapse is short and neurocognitive sequelae remain a major concern. The contribution of molecular subgrouping may help refine indications and modalities of salvage strategies in this population. METHOD: From a cohort of 151 young children with molecularly characterized relapsed medulloblastoma, subset analysis of the SHH medulloblastoma was conducted to describe the practice of salvage radiotherapy and associated post-relapse survival (PRS). RESULTS: Sixty-seven SHH medulloblastoma patients (46 M0; 54 GTR; 11 non-ND/MBEN) received salvage therapy with curative intent. Before relapse, 54 (80.6%) received conventional chemotherapy (CC), 13 (19.4%) high-dose chemotherapy (HDC), while seven had additional focal radiotherapy (fRT). Median time to relapse was 11.1 months (range 3.8-41.0) and 43.3% were localized. Thirty patients (16 localized relapse) underwent surgery. Forty-seven (71.2%) received salvage radiotherapy (20 with CC; 10 with HDC; 15 alone, two unknown). CSI and fRT accounted for 82% and 18% respectively. CSI median dose was 36Gy (range 18-39Gy). Ten patients (eight with localized relapse) received CSI doses ≤23.4Gy. Nineteen patients (28.8%) did not receive any radiotherapy (nine HDC; 10 CC only). Radiotherapy was associated with better 3-year PRS (73.0% versus 36.1%; p=0.001). All patients treated with CSI ≤ 23.4Gy were alive at median follow-up of 69 months(24-142). Six of nine patients treated with HDC without irradiation were alive at last follow-up. Sixty-three percent of patients received reduced dose CSI(≤23.4Gy), fRT, or no radiotherapy, and their PRS did not significantly differ from those who received CSI ≥ 30.6Gy (p = 0.54). CONCLUSION: While salvage CSI provided PRS benefit in this SHH medulloblastoma cohort, we report the use of reduced salvage radiotherapy and irradiation avoidance in 63% of the patients, with 60% alive at last follow-up.
MEDB-54. Standard Risk Medulloblastoma treated solely with surgery and chemo-radiation
Authors: Cantor Evan , Meyer Ashley , Ogle Andrea , McHugh Michele , Beck Mary , Green Tammy , Ramachandran Lakshmi , Dahiya Sonika , Cluster Andrew , Brossier Nicole M , Abdelbaki Mohamed S , Limbrick David , Perkins Stephanie , Shatara Margaret 
Published: June 2022

Abstract
INTRODUCTION: Medulloblastoma is the most common malignant brain tumor in children, with 5-year overall survival (OS) ranging from 60%-95% depending on subgroup and risk status. The POG 8631/CCG 923 trial (accrual 1986-1990) found a 63% 5 year OS for patients with local disease after gross total resection treated with radiation at a dose of 23.4 Gy craniospinal radiation and posterior fossa boost to 54 Gy, vs. 80.5% 5-year OS for patients treated as per full ACNS0331 therapy including maintenance chemotherapy. Herein, we describe a long-term survival with standard-risk medulloblastoma who only received surgical resection and radiation therapy. CASE: A 17-year-old male presented with acute onset of hypertension, bradycardia, headache, and blurry vision and was found to have a heterogeneously enhancing posterior fossa mass with mass effect on the fourth ventricle and hydrocephalus on brain MRI. He underwent gross total resection of the tumor and histopathology revealed medulloblastoma with classic and large cell features. Fluorescence in situ hybridization (FISH) was negative for MYC, MYCN amplification, or HER2 gain. Cerebrospinal fluid cytology was negative for neoplastic cells, and spinal MRI did not reveal any drop metastases. The patient initiated therapy per ACNS0331 with craniospinal irradiation posterior fossa boost. He also received weekly vincristine. After completion of radiation therapy, the family declined further chemotherapy despite medical advice. He had no evidence of relapse most recently at 51 months from completion of therapy. Next generation sequencing and methylation testing are currently pending. CONCLUSION: Current efforts aim at optimizing therapy based on molecular subgrouping, to minimize long-term adverse events associated with current therapies. We report a unique case of an adolescent male with an standard-risk medulloblastoma, who achieved remission with only radiotherapy. Further molecular tumor analysis may elucidate the response of the tumor.