bluuebunny/crossref_metadata_2025_split huggingface dataset:
MBCL-05. TREATMENT OF CHILDREN WITH MEDULLOBLASTOMA WITHOUT METASTATIC INVOLVEMENT IN THE AGE GROUP OLDER THAN 3 YEARS: RESULTS OF INTERCENTER TRIAL
Authors: Levashov Andrey , Stroganova Anna , Khochenkov Dmitry , Zagidullina Svetlana , Babelyan Stepan , Ryzhova Marina , Gorelyshev Sergey , Kadirov Shavkat , Subbotina Natalya , Daylidite Vidmante , Sidelnikov Dmitry , Mentkevich Georgy , Grigorenko Vasily 
Published: December 2020

Abstract
The aim of this study was to identify a group of patients aged 3 to 7 years for whom there is the possibility for reducing of craniospinal radiation dose (CSI). From 2008 to 2018 fifty one pediatric patients with primary diagnosed medulloblastoma in the age group 3 - 18 years were included in trial, 38 in standard risk group, 13 in high risk group. Treatment program consisted of surgical removal of the primary tumor site with subsequent radiation therapy (with CSI of 23,4 Gy or 36 Gy, depending on the risk group) and high-dose chemotherapy (with high-dose cyclophosphamide or thiophosphamide). As a result of this study, sufficiently high rates of overall survival and progression/relapse - free survival (PFS) were achieved in standard and high-risk groups patients, which amounted to 76,0 ± 8,8% and 83,3 ± 10,8% with median follow-up 62,9 ± 6,2 months and 52,2 ± 7,8 months, respectively. There was revealed patients group in the age 3 - 7 years with 100% PFS and median follow-up 66,9 ± 8,9 months. Morphological and molecular biological factors of an unfavorable outcome of the disease (large cell - anaplastic histology, MYC/MYC-N gene amplification, Iso17q and TP53 gene mutation) were absent in this tumor samples. We have also achieved 100% PFS in patients with desmoplastic tumor histology and in patients, who were treated with thiphosphamide - based chemotherapy regimen. Molecular - biological characteristics analysis of tumor cells showed a negative effect on PFS of DNMT - positive status (Score 4 and&gt;, by 3 markers) and presence of MYC-N gene amplification (SHH molecular subgroup).
MBCL-06. RISK STRATIFICATION IMPROVEMENT OF THE HIT2000 AND I-HIT-MED COHORTS USING MOLECULAR SUBTYPES I-VIII OF GROUP 3/4 MEDULLOBLASTOMAS
Authors: Mynarek Martin , Obrecht Denise , Sill Martin , Selt Florian , von Hoff Katja , Jones David , Sturm Dominic , Juhnke B - Ole , Ecker Jonas , Pietsch Torsten , von Deimling Andreas , Sahm Felix , Pfister Stefan M , Witt Olaf , Bockmayr Michael Ludwig , Schüller Ulrich , Rutkowski Stefan , Milde Till 
Published: December 2020

Abstract

OBJECTIVE
Molecular subtypes of Group 3/4 medulloblastoma have been identified by unsupervised clustering methods in different studies. We hypothesized that risk stratification using these subtypes I-VIII improves outcome prediction.

PATIENTS AND METHODS
n=340 patients with Group 3 or Group 4 medulloblastoma defined by DNA methylation array profiling enrolled into the HIT2000 study and HIT-MED registries were subtyped by the Heidelberg Medulloblastoma Classifier. The discovery cohort consisted of n=162 previously published samples, the validation cohort of n=178 newly analyzed samples. RESULTS AND DISCUSSION: n=300/340 (88%) MBs could be assigned to one of the subtypes with confidence (score &gt;0.8; Heidelberg Medulloblastoma classifier). Subtype II,III and V showed a poor PFS and OS and were classified as HR (discovery:5y-PFS 45%[95%-CI:33–62], 5y-OS 50%[37–67]; validation:5y-PFS 32%[20–50], 5y-OS 40%[27–61]). Subtypes I, IV, VI-VIII fared better (discovery:5y-PFS 67%[58–77], 5y_OS 84%[77–91]; Validation:5y-PFS 70%[58–83], 5y-OS 89%[81–99]). Survival prediction by subtype-based risk assessment was improved compared to Group 3 versus 4 differentiation in both cohorts in univariate and multivariable Cox regression models (PFS:Hazard ratio HR versus LR 2.474, p&lt;0.001; Group 3 versus Group 4 1.842, p=0.003; adjustment for anaplasia, age and metastatic disease). Patients older than 4 with subtype IV tumors (mainly Group 3) treated with radiotherapy achieved a 100% PFS, while subtype V patients (mainly Group 4) had poor survival.

CONCLUSION
We showed that molecular subtypes I-VIII improved risk stratification of Group 3/4 medulloblastomas. Group 3 subtype IV MB treated with RT had very high cure rates.
MBCL-09. ISOLATED M1 METASTASES IN PEDIATRIC MEDULLOBLASTOMA: IS POSTOPERATIVE RADIOTHERAPY FOLLOWED BY MAINTENANCE CHEMOTHERAPY SUPERIOR TO POSTOPERATIVE SANDWICH-CHEMOTHERAPY AND RADIOTHERAPY?
Authors: Obrecht Denise , Mynarek Martin , Hagel Christian , Kwiecien Robert , Spohn Michael , Bockmayr Michael L , Bison Brigitte , Warmuth-Metz Monika , Pfister Stefan M , Jones David T W , Sturm Dominik , von Deimling Andreas , Sahm Felix , von Hoff Katja , Juhnke B - Ole , Benesch Martin , Gerber Nicolas U , von Bueren André O , Friedrich Carsten , Kortmann Rolf-Dieter , Schwarz Rudolf , Pietsch Torsten , Rutkowski Stefan 
Published: December 2020

Abstract

BACKGROUND
Impact of isolated spread into the cerebrospinal fluid (CSF) is still not investigated comprehensively for childhood medulloblastoma and the best therapeutic strategy is currently unclear. MATERIAL AND

METHODS
Sixty-six patients with isolated M1-MB registered to the HIT-MED-database from 2000–2018 were identified. CSF and MRI were centrally reviewed for all patients. Patients were stratified by age and either treated with upfront craniospinal irradiation (CSI) followed by maintenance chemotherapy (CT) or with postoperative CT and delayed CSI.

RESULTS
Forty-nine patients were non-infants ≥4 years and seventeen were infants &lt;4 years. Median age was 7.3y (1.1–18.0). 83.3% were histologically classified as CMB, 12.1% as LCA-MB and 4.6% as DMB. Molecular subgroup was Gr.3 in 25.8%, Gr.4 in 28.8%, SHH in 4.5%, WNT in 1.5% and not evaluated for 39.4%. Lumbar puncture was performed on median postoperative day 19 (range: 14–77). Median follow-up for survivors was 7.6y (range: 1.2–15.9). The whole cohort showed a 3y- and 5y-PFS of 68.0(±6.0) and 60.0(±6.5)%, while OS was 79.1(±5.2) and 72.9(± 5.9)%. 10y-OS was 54.4(±7.5). Patients with upfront CSI had more favourable outcomes (5y-PFS 66.1 vs. 55.8% [p=0.119]; 5y-OS 90.6 vs. 64.5% [p=0.035]). The trend towards improved survival in patients with postoperative CSI was retained when only non-infants were considered (pPFS=0.176, pOS=0.055). M1-persistence occurred exclusively in patients with postoperative CT.

CONCLUSION
Isolated M1-MB is rare. Patients without contraindication for CSI appear to benefit from treatment by upfront CSI followed by maintenance CT, while cumulative CT-doses would be reduced compared to sandwich strategies.
MBCL-10. LOCAL RECURRENCE AND SURVIVAL OUTCOMES OF MEDULLOBLASTOMA (MB) IN ADOLESCENT AND YOUNG ADULT PATIENTS (AYA)
Authors: Rongthong Warissara , Treechairusame Teeradon , Suntornpong Nan , Thephamongkhol Kullathorn 
Published: December 2020

Abstract

OBJECTIVE
The aim of this study is to evaluate the local recurrence-free survival (LRFS) and overall survival (OS) of MB in AYA patients at our institute.

METHOD
Patients 15–39 years old with MB who was sent for post-operative radiation therapy (RT) in 2007 - 2017 at our institute were included. Kaplan-Meier statistics were used to estimate the LRFS and OS.

RESULTS
Seven patients were included. The median age at RT was 18.3 years (16.7–28.6 years). Male was more common than female, 5 males vs. 2 females. NTR or GTR was achieved in 71.4% (5 in 7 patients). Only one patient had metastatic disease (M1) and received combined chemotherapy-RT. The rest 6 patients were received RT alone, all were M0. The median craniospinal irradiation (CSI) dose and total RT dose were 36Gy (23.4-46Gy) and 54Gy (54-56Gy), respectively. Five patients had available follow-up MRI brain. Local recurrence (LR) was found in one patient at 4.3 years after finished RT. Her initial treatment was subtotal resection (STR) followed by RT alone; CSI 36 Gy and posterior fossa boost to 55.8Gy. The 2-years and 5-years LRFS were 100% and 66.7%, respectively. Both 2-years and 5-years OS were 100%. The median follow-up time was 7.6 years (0.4–11.5 years).

CONCLUSION
Our study shows high 2-years LRFS and OS of post-operative RT alone in AYA MB. Combined chemotherapy-RT should be considered in STR or M1. More number of patients and molecular histopathology subtype reports are still needed to confirm this report.
MBCL-18. ANALYSIS OF DNA METHYLATION PROFILES OF PEDIATRIC MEDULLOBLASTOMAS: EXPERIENCE AT THE BAMBINO GESÙ CHILDREN’S HOSPITAL
Authors: Miele Evelina , Petruzzellis Giuseppe , Pedace Lucia , Cacchione Antonella , Carai Andrea , Colafati Giovanna Stefania , Camassei Francesca Diomedi , Rossi Sabrina , Locatelli Franco , Mastronuzzi Angela 
Published: December 2020

Abstract

BACKGROUND
Medulloblastoma is the most frequent malignant brain tumor in children, still resulting fatal in about one third of affected patients. An accurate diagnosis is essential for correct therapeutic stratification. The DNA methylation profile (DMP) is a combination of changes in DNA methylation and genetic features that reflect the cell of tumor origin. DMP contributed to classify Medulloblastoma into four subgroups: WNT, SHH, Group 3/4 (the latter recently further subdivided into 8 subclasses). Each Methylation is associated with different genetic, demographic and clinical characteristics. We report our experience on Medulloblastoma molecular classification based on DMP.

MATERIALS AND METHODS
54 Medulloblastoma patients (28 males, 26 females) were selected. The DMP analysis was carried out via IlluminaEPICarrays. The results were obtained using the brain tumor classifier (Capper, 2018).

RESULTS
In all cases the DMP allowed to classify the neoplasm, with an optimal score, in a defined methylation class. 10 WNTs, 15 SHHs, 10 Group 3, 19 Group 4 were found. Groups 3/4 were further refined based on the new consensus (Sharma 2019) in group I (n = 1); group II (n = 5); group III (n = 2); group IV (n = 4); group V (n = 3); group VI (n = 2); group VII (n = 6); group VIII (n = 7).

CONCLUSIONS
This study carried out the first classification of Medulloblastomas diagnosed in Italy through DMP, demonstrating its high reproducibility, precision and accuracy. The molecular classification improves diagnostic accuracy and provides further information that can guide personalized treatment.
MBCL-19. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH DESMOPLASTIC/EXTENSIVE NODULAR MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS OF PROSPECTIVE MULTI-CENTER EUROPEAN AND NORTH AMERICAN TRIALS
Authors: Finlay Jonathan L , Mynarek Martin , Dhall Girish , Lafay-Cousin Lucie , Mazewski Claire , Ashley David , Leary Sarah , Cohen Bruce H , Robinson Giles , Geyer J Russell , Tait Diana , Stanek Joseph , Gajjar Amar , Rutkowski Stefan 
Published: December 2020

Abstract

BACKGROUND/OBJECTIVE
Survival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens incorporating both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens utilizing marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these strategies for young children with desmoplastic/extensive nodular medulloblastoma (D/ENMB).

DESIGN/METHODS
Data from 12 trials reported between 2005 and 2019 for children &lt;six-years-old with D/ENMB were reviewed; event-free (EFS) with standard errors were compared.

RESULTS
The German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported 49+/-10% EFS. Three trials (Head Start I/II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by 1/3 HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by 1/3 HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5-year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9%.

CONCLUSIONS
A trend towards better EFS for young children with D/ENMB is observed in trials including either HD-MTX as well as IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.
MBCL-28. LONG-TERM FOLLOW-UP RESULTS OF REDUCED DOSE CRANIOSPINAL RADIOTHERAPY AND TANDEM HIGH-DOSE CHEMOTHERAPY IN PATIENTS WITH HIGH-RISK MEDULLOBLASTOMA
Authors: Lee Ji Won , Lim Do Hoon , Son Meong Hi , Sung Ki Woong , Cho Hee Won , Ju Hee Young , Hyun Ju Kyung , Yoo Keon Hee , Jung Hye Lim , Koo Hong Hoe , Suh Yeon-Lim , Joung Yoo Sook , Shin Hyung Jin 
Published: December 2020

Abstract

BACKGROUND
In this study, we report the follow-up results of reduced-dose of craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) in patients with high-risk medulloblastoma (MB).

METHODS
Newly diagnosed high-risk MB patients (metastatic disease, postoperative residual tumor &gt; 1.5 cm2 or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre-RT chemotherapy, RT including reduced-dose CSRT (23.4 or 30.6 Gy), 4 cycles of post-RT chemotherapy and tandem HDCT were given. NanoString and DNA sequencing were done with archival tissues.

RESULTS
Forty patients were enrolled, and molecular subgrouping was possible in 21 patients (2 WNT, 3 SHH, 8 Group 3 and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (10-year cumulative incidence 10.4 ± 0.3%). However, six patients died from treatment-related mortality (TRM) (4 acute TRMs and 2 late TRMs) resulting in 18.5 ± 0.5% of 10-year cumulative incidence. Taken together, the 10-year event-free survival and overall survival were 71.1 ± 8.0% and 68.9 ± 8.5%, respectively. Late effects were evaluated in 25 patients and high-tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.

CONCLUSIONS
Strategy using tandem HDCT following reduced-dose CSRT showed promising results in terms of low relapse/progression rate, however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can have benefit from HDCT will be needed in the future study.
MBCL-35. SALVAGE RADIATION THERAPY FOR PROGRESSIVE AND/OR RELAPSED PEDIATRIC MEDULLOBLASTOMA
Authors: Baig Muhammad , McAleer Mary , Grosshans David , Paulino Arnold , Baxter Patricia , Chintagumpala Murali , Zaky Wafik , McGovern Susan 
Published: December 2020

Abstract
Medulloblastoma (MB) has a dismal prognosis after progression or relapse, and there is no standard of care for salvage therapy. Medical records of pediatric patients with progressive/relapsed MB were reviewed for clinical characteristics. We identified 23 patients with recurrent MB with median age at diagnosis of 3.8 years, 14 males (60%). At diagnosis, 16 patients had gross total resection, 1 near total, 5 subtotal, and 1 had biopsy alone. Fifteen patients (66%) had metastatic disease. Tumor histology was classic/nodular in 10, 4 desmoplastic, 8 anaplastic and 1 myogenic. Ten patients (43%) ages &lt; 3 years, were treated with induction chemotherapy followed by high dose chemo and stem cell rescue. Other 13 patients were treated with chemoradiation (11 craniospinal and 2 posterior fossa radiation). Progression free survival after initial treatment was 11 months (range, 3–58 months); 8 patients (34%) had local recurrence, 10 patients (43%) had distant metastasis, 4 patients (17%) had local and distant, and one patient had CSF only recurrence. Salvage therapy was surgery followed by radiation in 12 patients (52%), radiation alone in 3 patients (13%), chemoradiation in 7 patients (30%), and chemotherapy alone in 1 patient. Thirteen patients (56%) received CSI, 6 (26%) received focal and 2 received spinal radiation only. Five year progression free survival and overall survival from the time of relapse were 25% and 45%, respectively. Multidisciplinary care is essential for patients with relapsed MB. Salvage radiation that accounts for the patient’s initial treatment volumes should be considered for these patients.
MBRS-03. SINGLE NUCLEUS TRANSCRIPTOME PROFILES FROM HUMAN DEVELOPING CEREBELLUM REVEAL POTENTIAL CELLULAR ORIGINS OF MEDULLOBLASTOMA BRAIN TUMORS
Authors: Okonechnikov Konstantin , Sepp Mari , Leiss Kevin , Kutscher Lena , Ernst Kati , Jones David , Jäger Natalie , Pajtler Kristian W , Kaessmann Henrik , Pfister Stefan M 
Published: December 2020

Abstract
Medulloblastoma (MB) is a highly malignant pediatric brain tumor originating from the cerebellum and brainstem. Identification of molecular subgroups forming this heterogeneous tumor entity was initially achieved from transcriptome characterization and further strengthened using DNA methylation profiling. While subgroup classification improved clinical diagnosis and treatment options, the lack of knowledge of the cell-of-origin for some of the subgroups hinders further treatment improvements. In addition identification of the precise cells of origin for each subgroup could help to understand tumor cell biology. Single cell sequencing is the optimal way to solve this task; recently, there were attempts to uncover putative MB cell-of-origin by using such information obtained from mouse embryonic cerebellum. However, such a comparative strategy can miss important results due to the differences between mouse and human. To solve this issue, we performed global single nucleus sequencing on human cerebellum pre- and postnatal materials across several developmental time points and generated transcriptome profiles from ~200k single cells. We identified known cell types forming the human cerebellum and performed detailed comparison of normal cells to RNA-seq bulk data from MB brain tumors across all subgroups. By selecting an optimal analysis strategy, we verified granule neuron precursors as cells of origin for the SHH MB subgroup. Additionally, we also found other cell types in conjunction with the remaining MB subgroups, suggesting new potential targets for investigation. Notably, this strategy can be further applied to the examination of other brain tumors and has perspectives in medical application.
MBRS-12. A TRANSPOSON MUTAGENESIS SCREEN IDENTIFIES Rreb1 AS A DRIVER FOR GROUP 3 MEDULLOBLASTOMA
Authors: Masihi Meher Beigi , Lee Catherine , Furnari Grace A , Garancher Alexandra , Wechsler-Reya Robert J 
Published: December 2020

Abstract
Medulloblastoma (MB) is the most common malignant childhood brain tumor. MB can be divided into four major subgroups – WNT, Sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4) – that exhibit distinct genetic alterations, gene expression profiles, and clinical outcomes. Patients with G3-MB have the worst prognosis, and a deeper understanding of this disease is critical for development of new therapies. Most G3-MBs express high levels of the MYC oncogene, suggesting that MYC plays an important role in tumorigenesis. To identify genes that cooperate with MYC to promote formation of G3-MB, we performed an in vivo mutagenesis screen using mice expressing the Sleeping Beauty (SB) transposon. Cerebellar stem cells from transposon/transposase-expressing mice were infected with viruses encoding Myc, and transplanted into the cerebellum of adult hosts. The resulting tumors were sequenced to identify transposon-targeted genes, and these genes were functionally analyzed to determine whether they could cooperate with Myc to drive G3-MB. These studies identified the transcription factor Ras-responsive element binding protein 1 (Rreb1) as a potent Myc-cooperating gene. Tumors driven by Myc and Rreb1 resemble G3-MB at a histological and molecular level. Moreover, RREB1 is overexpressed in human G3-MB, and knockdown of RREB1 impairs growth of G3-MB cell lines and patient-derived xenografts. Ongoing studies are aimed at identifying the mechanisms by which Rreb1 contributes to tumor growth. Our studies demonstrate an important role for RREB1 in G3-MB, and provide a new model that can be used to identify therapeutic targets and develop more effective therapies for medulloblastoma.
MBRS-20. CSF-DERIVED CIRCULATING TUMOR DNA AS A BIOMARKER FOR DISEASE PROGRESSION AND TUMOR EVOLUTION IN MEDULLOBLASTOMA
Authors: Liu Anthony Pak-Yin , Kumar Rahul , Kyle Smith , Paul Leena , Chintagumpala Murali , Bouffet Eric , Fisher Michael J , Hassall Tim , Gururangan Sri , Hansford Jordan , Cohn Richard , Ellison David W , Gilbertson Richard J , Gajjar Amar , Robinson Giles W , Northcott Paul A 
Published: December 2020

Abstract

BACKGROUND
Cell-free DNA (cfDNA) profiling has been shown to carry utility as a clinically relevant biomarker in a variety of cancers, but studies in pediatric brain tumors, including medulloblastoma, are scarce. We hereby evaluated the actionability of profiling cfDNA from cerebrospinal fluid (CSF) based on a multi-institutional cohort of children with medulloblastoma.

METHODS
103 children aged ≥ 3 years with medulloblastoma harboring chromosomal aneuploidy enrolled on two prospective therapeutic trials were included. cfDNA was extracted from CSF obtained longitudinally, and profiled by low-coverage whole-genome sequencing (lcWGS) for annotating copy-number variants (CNVs). cfDNA-derived CNVs were compared against patient-matched primary tumor-derived CNVs and correlated with outcome. cfDNA profiles at diagnosis and relapse were compared to evaluate tumor evolution.

RESULTS
Tumor-derived somatic CNVs were detected in 72% of baseline cfDNA samples, with higher detection rate in samples from patients with metastatic disease than those without (90% versus 50%, chi-square p=0.001). Longitudinal profiling of cfDNA revealed correlation between CNV detectability and clinical course, with detection of tumor-derived CNVs in cfDNA samples predating radiographic progression for ≥ 3 months in 62% of relapsing patients. Presence of cfDNA-derived CNVs in CSF collected during chemotherapy and at the end of therapy was significantly associated with inferior PFS (log-rank p&lt;0.0001 for both time-points). Comparison of CNV profiles from cfDNA at baseline and relapse revealed molecular divergence in a subset of patients.

CONCLUSION
These results carry major implications and supports the incorporation of cfDNA profiling in upcoming medulloblastoma protocols for more sensitive and accurate disease monitoring and personalization of treatment.