bluuebunny/crossref_metadata_2025 huggingface dataset:
LINC-32. REPORT OF AN INITIAL SITE VISIT TO DETERMINE FEASIBILITY AND IMPLEMENTATION OF A COMPREHENSIVE NEURO-ONCOLOGY PROGRAM IN KENYA
Authors: Armstrong Beth , Mbiro Mark , Magoha Michael , Okemwa Minda , Mwang’ombe Nimrod , Coven Scott
Published: December 2020

BACKGROUND

Pediatric central nervous system (CNS) tumors are the leading solid tumors in the United States, but vastly under-reported in the African population. There’s limited data on childhood brain tumors as well as the histopathological distribution in Kenya. This report surveys as an initial site visit to determine the feasibility of a comprehensive neuro-oncology program at Kenyatta National Hospital (KNH) in Nairobi, Kenya. DESIGN: This collaboration began with a visit from the director of neuropathology at KNH to our neuro-Oncology program at Riley Hospital for Children at Indiana University Health in May 2019. This report includes recommendations from the May 2019 trip, as well as a reciprocal site visit to Kenya in January 2020.

RESULTS

Building off the May 2019 trip, a brain tumor registry has been initiated and maintained. Additionally, the KNH program has many necessary components to forming a comprehensive neuro-oncology program, including capable neurosurgeons with a neurosurgical training program, radiology, intensive care unit, oncology ward, rehab, skilled nursing, and radiation oncology services. Currently, neurosurgery, radiology, and pathology meet weekly to review challenging cases.

CONCLUSION

Kenyatta National Hospital has the expertise to build a comprehensive neuro-oncology program. The program currently lacks a dedicated nurse coordinator and “specialist” in neuro-oncology. Ongoing discussions with local stakeholders are aimed to galvanize national support to improve awareness for children with brain tumors and to plan a multidisciplinary neuro-oncology symposium in 2021. In the meantime, telemedicine efforts can support nursing education and reiterate the multidisciplinary needs for children with brain tumors.
LINC-35. THE ST. JUDE GLOBAL ACADEMY NEURO-ONCOLOGY TRAINING SEMINAR: A MULTIDISCIPLINARY, INTERNATIONAL EDUCATION PROGRAM
Authors: Moreira Daniel , Patay Zoltan , Boop Frederick , Chiang Jason , Merchant Thomas , Santiago Teresa , Gajjar Amar , Rodriguez-Galindo Carlos , Qaddoumi Ibrahim
Published: December 2020

The success of the treatment of children with central nervous system (CNS) tumors relies on an effective multidisciplinary team, with up-to-date and broad knowledge and skills. The St. Jude Global Academy Neuro-Oncology Training Seminar was launched as course in globally applicable content in pediatric neuro-oncology with a focus on multidisciplinary teams in low- and middle-income countries (LMICs). To identify the content that is most relevant for the learners, a needs assessment survey that included evaluation of team dynamics, treatment capacity, existing knowledge, and educational goals was designed. Survey questions in 11 domains were answered by 24 sites in LMICs across the world. This information was used to create the course that consists of two components: a 9-week online course and a 10-day workshop at the St. Jude campus. 72 participants from 11 institutions enrolled in the online portion and 20 participants were selected based on grades to attend the workshop. A retrospective post-test evaluation established that learners improved their understanding of the barriers to care, possible solutions to improve care, understanding of diagnosis and treatment, and methodology to implement projects (p<0.01). All participating teams developed projects that are locally implemented. Those present at the workshop formed a multidisciplinary, international collaborative group (Global Alliance in Pediatric Neuro-Oncology). This experience establishes that educational programs with systematically created curricula can not only improved knowledge but be a mechanism to share experiences and create collaborative networks. Ultimately, patient outcomes will be tracked to monitor the true impact of the course.
LINC-39. PERFORMANCE STATUS OF PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS TREATED IN MEXICO, A SINGLE-CENTER EXPERIENCE
Authors: Madrigal-Avila Claudia , Perez-Bañuelos Alfonso , Ruvalcaba-Sanchez Rafael , Vega-Vega Lourdes , Escamilla-Asiain Gabriela
Published: December 2020

BACKGROUND

Central nervous system (CNS) tumors are the most common solid neoplasms in the pediatric age, they comprise about a quarter of all cancers at this age. Little is known about the specific epidemiology of this group in Mexico and there are no reports of results focused on the Performance Status of patients who are treated in a multidisciplinary setting.

OBJECTIVE

To describe the Performance Status of CNS pediatric patients after being treated with a multidisciplinary approach in a tertiary center.

METHODS

We report a retrospective chart review of all pediatric patients who presented to the Neuro-Oncology Clinic at Teleton Pediatric Oncology Hospital in Queretaro, Mexico, from December 2014 to January 2020. We analyzed age, gender, the extent of surgical resection and histopathology. Performance Status was assessed using ECOG and Karnofsky/Lansky scores during every patient’s last follow-up visit.

RESULTS

A total of 56 patients were treated, epidemiology and histopathology variants are similar to those described in the international literature. With a median follow-up of 33 months, 35 patients are alive (62.5%), 28 of them (74.2%) have an excellent Performance Status (ECOG score 0 or Lansky/Karnofsky ≥ 90), 5 (14.2%) scored ECOG 1–2 and only 4 (11.4%) scored ECOG 3–4.

CONCLUSIONS

A multidisciplinary approach with a focus on Performance Status and the potential for neurological recovery is essential in the management of pediatric patients with CNS tumors. Efforts should be aimed at reducing post-surgical morbidity and early rehabilitation to reintegrate patients into society in the long term.
LINC-41. TREATMENT OF RECURRENT MEDULLOBLASTOMA IN CHILDREN IN LOW INCOME SETTINGS
Authors: Kizyma Roman , Zapotochna Khrystyna , Romanyshyn Bogdan , Kizyma Zoryana , Sobko Roman
Published: December 2020

INTRODUCTION

Children with recurrent medulloblastoma after initial therapy have very poor prognosis due to limited second line treatment options and significant treatment-related morbidity.

METHODS

A retrospective chart review of 18 children with recurrent or progressive medulloblastoma, treated initially with risk-adapted therapy in Western Ukrainian Specialized Pediatric Medical Centre from 2012 to 2019, was performed.

RESULTS

All patients received first line multimodal treatment: surgery, distant beam radiotherapy and chemotherapy. Recurrent disease in 11 patients presented with metastatic dissemination and in 7 patients as local relapse. The median time to recurrence was 10 months. The median follow-up after diagnosis of recurrent disease diagnosed was 2 years and 2 months. Second line therapy included re-surgery (5 cases), radiation therapy (10 cases) and various cytostatic agents as monotherapy or combination - carboplatin, cisplatin, cyclophosphamide, etoposide, methotrexate, temozolomide, lomustine. Patients treated with radiotherapy for salvage had prolonged local control compared to those that received chemotherapy only. On follow-up 8 children are currently alive.

CONCLUSION

Recurrent and progressive medulloblastoma had a poor prognosis with a 2-year overall survival (OS) of 28% on different salvage therapy. The variety in the treatment of all patients experiencing recurrence was observed due to low income country settings. The factors that influenced higher survival after recurrence of medulloblastoma were longer time to relapse, and local pattern of relapse/progression.
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

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>, 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

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 >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<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

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 <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

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

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

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 <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

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 > 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

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 < 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

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

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

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<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.
MBRS-21. CLINICAL AGGRESSIVENESS OF TP53-WILD TYPE SONIC HEDGEHOG MEDULLOBLASTOMA WITH MYCN AMPLIFICATION
Authors: Mitani Yuichi , Fukuoka Kohei , Matsushita Yuko , Hibiya Yuko , Honda Satoko , Mori Makiko , Arakawa Yuki , Ichimura Koichi , Kobayashi Masao , Tanami Yutaka , Nakazawa Atsuko , Kurihara Jun , Koh Katsuyoshi
Published: December 2020

Clinical implication of MYCN amplification in sonic hedgehog (SHH) medulloblastoma may still be controversial due to the frequent co-occurrence with TP53 mutation, which is one of the poorest prognostic factors among the subgroup. We described two cases of TP53-wild type SHH medulloblastoma with MYCN amplification, showing dismal clinical course with rapid disseminated relapse just after the end of treatment. CASE 1: A 7-year-old boy developed a non-metastatic cerebellar tumor. Pathology of the tumor was consistent with classic medulloblastoma. The patient received treatment that involved reduced-dose (18 Gy) craniospinal irradiation (CSI), local irradiation, and chemotherapy. However, sudden respiratory arrest developed due to massive intracranial disseminated relapse 9 months after the initial surgery. CASE 2: A 6-year-old boy presented a large mass in his 4th ventricle without dissemination. He diagnosed with large cell/anaplastic medulloblastoma and underwent radiation therapy (24 Gy of CSI and local irradiation) and chemotherapy, followed by high-dose chemotherapy. However, dissemination through neuroaxis occurred 9 months after the diagnosis. Methylation data of the cases was entered into a recently published classifier and both tumors were classified as “medulloblastoma, subclass SHH A (children and adult)”. Copy number analysis demonstrated MYCN amplification in both cases. TP53 mutation analysis from exon 2 to 10 indicated wild type in one case. Additionally, p53 immunochemistry in both cases also indicated wild type. The cases remind us of the clinical aggressiveness of SHH medulloblastoma with MYCN amplification, even if there is no TP53 mutation. The tumor should still be treated with the most intensified treatment.
MBRS-26. CDK7 MEDIATED TRANSCRIPTIONAL PROCESSIVITY OF DNA REPAIR NETWORKS REGULATES SENSITIVITY TO RADIATION IN MYC DRIVEN MEDULLOBLASTOMA
Authors: Veo Bethany , Danis Etienne , Fosmire Susan , Wang Dong , Pierce Angela , Dahl Nathan , Karam Sana , Serkova Natalie , Venkataraman Sujatha , Vibhakar Rajeev
Published: December 2020

Myc-driven Medulloblastoma remains a major therapeutic challenge due to frequent metastasis and a poor 5-year survival rate. Myc overexpression results in transcriptional dysregulation, proliferation, and survival of malignant cells. To identify therapeutic targets in Myc-amplified medulloblastoma we performed a CRISPR-Cas9 essentiality screen targeting 1140 genes annotated as the druggable genome. The cyclin-dependent kinase, CDK7, was identified as a top candidate. CDK7 phosphorylates the c-terminal domain of RNA Pol II facilitating transcriptional initiation and elongation. We subjected Myc-amplified cells treated with CDK7 inhibitors to whole transcriptomic analysis. The resultant data revealed gene networks mediating DNA repair were functionally repressed. Consistent with this data, ChIP-sequencing showed the most significant reduction in RNA Pol II and Myc promoter occupancy within a subset of DNA repair genes including BRCA2 and RAD51 but not across the whole genome. These data suggest that inhibition of CDK7 mechanistically limits Myc driven transcriptional processivity of DNA repair networks. Further, evaluation of genes mediating DNA repair show a muted response to DNA damage and increased cell death with CDK7 inhibition. We next evaluated Myc-amplified MB cell response to ionizing radiation in vitro and in vivo with CDK7 inhibition. Inhibition of CDK7 enhanced radiation sensitivity of Myc MB cells by potentiating DNA damage. Further, cotreatment produced decreased MRI T2 tumor volumes and enhanced survival benefit in orthotopic PDX xenografted mice compared to radiation alone. Our studies establish a mechanism for selective inhibition of Myc-driven MB by CDK7 inhibition combined with radiation as a viable therapeutic strategy for Myc-amplified medulloblastoma.
MBRS-29. PROSPECTIVE MOLECULAR PROFILING IN PEDIATRIC MEDULLOBLASTOMA PATIENTS ENROLLED ON THE “HEAD START 4” PROTOCOL
Authors: Fleming Jessica , Bell Erica , Graham Richard , Webb Amy , McElroy Joseph , Timmers Cynthia , Becker Aline , Guo Yingshi , Dhall Girish , Finlay Jonathan , Chakravarti Arnab
Published: December 2020

Medulloblastoma is the most common malignant embryonal brain tumor in children with only modest improvements in outcomes achieved over the last 20 years. The implementation of irradiation-avoiding strategies, including trials by the “Head Start” consortium, have demonstrated improved cure rates along with enhanced quality of life. Simultaneously, the classification of medulloblastomas has undergone a dramatic shift as molecular testing has made it possible to divide these tumors into distinctive subtypes. Currently, the WHO recognizes four medulloblastoma molecular subgroups; however it remains unclear how patients within these subgroups respond to modern irradiation-avoiding therapies. This study aims to demonstrate the feasibility of prospective molecular profiling in medulloblastoma patients enrolled on the “Head Start 4” trial. Whole-exome sequencing (SureSelect Human All Exon V6+COSMIC) and DNA methylation (Illumina EPIC Array) profiling were performed on 10 paired tumor/blood samples and 4 tumor samples, respectively. High-quality mutational and copy number data were produced for each of the 10 subjects demonstrating well-described gene mutations (SUFU) and chromosomal losses (9q and 10q). Four subjects had methylation profiling which successfully separated them into the WHO subgroups (two SHH and two Group 3). These data showed the feasibility of prospective high-dimensional mutational and DNA methylation analysis using “Head Start 4” patients. Future work will focus on finalizing these profiling efforts, enabling the development of models that predict response to irradiation-avoiding treatment and, in general, a better understanding of the molecular mechanisms underlying treatment resistance and tumor progression, leading to more personalized approaches to treating children with medulloblastoma.
MBRS-31. COMBINING IRRADIATION AND ANTI-CD47 TO ENHANCE THE TREATMENT OF GROUP 3 MEDULLOBLASTOMA
Authors: Youssef Osama , Turner Jeff , He Gongping , Yang Jingye , Cheshier Samuel
Published: December 2020

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. The Group 3 molecular subgroup of Medulloblastoma (Group 3 MB) is the deadliest with only 30% long term survival. Irradiation for Group 3 Medulloblastoma is required for long term survival of children. Methods to enhance the effect of irradiation against Group 3 MB are an active area of investigation. Immunotherapy using the anti-CD47 treatment has shown promise in treating Group 3 MB. We recently demonstrated that irradiation significantly enhanced anti-CD47-mediated phagocytosis of high-grade glioma cells in vitro. Furthermore, mice engrafted with human high-grade glioma that received anti-CD47 combined with irradiation showed a significant increase in the survival rate and a significant decrease in tumor growth than those that received a single treatment. We have now extended these studies to demonstrate the enhancement of anti-CD47-dependent phagocytosis of human Group 3 MB with irradiation. We also analyzed normal human neural stem cells exposed to the same treatments to assess for the potential toxicity that uniquely exists with this treatment combination.
MBRS-33. TEMPORARY RESTORATION OF p53 ACTIVITY DURING FRACTIONATED RADIOTHERAPY IN A GROUP3 MEDULLOBLASTOMA GEMM REPRESENTS A POWERFUL TOOL FOR RADIOBIOLOGY STUDIES
Authors: Morcavallo Alaide , Mandeville Henry , Barker Karen , Richardson Stacey , Lindsey Janet , Lockett Nikita , Boult Jessica K R , Robinson Simon P , Oelfke Uwe , Williamson Daniel , Clifford Steven C , Chesler Louis
Published: December 2020

TP53 pathway alterations are well-described events in medulloblastoma (MB) and are predictive of poor clinical outcome. Alterations are rare at diagnosis in Group3 (Gr3) and Group4, but enriched in Sonic Hedgehog and WNT subgroups. However, TP53 mutations are observed in all subgroups at relapse. Radiation therapy, along with surgery and chemotherapy, represents the standard of care treatment for MB. Loss of p53 function correlates with increased resistance to radiation in several cancers conferring poor survival for patients. In this study, we exposed the MYCN-driven/Trp53kiki (with tamoxifen-inducible p53 activation) Gr3 MB GEMM to a clinically relevant fractionated radiation therapy (RT) regime, to assess the role of p53 in Gr3 radio-resistance and relapse. Mice exhibiting tumour progression (bioluminescence (BLI) signal >109 photons/second) were randomized to treatment groups. A small animal radiation research platform was used to deliver CT-guided cranio-spinal irradiation (CSI) and a cranial boost (CB). Mice were followed for survival and tumour burden tracked using BLI. Bodyweight was monitored to evaluate treatment tolerability. Full dose radiation therapy (54Gy CB, 36Gy CSI, α/β=10) or dose modulation (12Gy CB, 8Gy CSI) was performed. The results showed comparable primary tumour regression in response to RT in p53 inactive and active backgrounds, followed by imminent relapse or prolonged remission respectively. No significant acute toxicity was observed. Temporary activation of p53 during RT improved tumour-free survival and decreased the incidence of relapse. In conclusion, we developed a new model which will help improve understanding of the radiobiology of high-risk MB and future preclinical trials.
MBRS-42. YB-1 - A NOVEL THERAPEUTIC TARGET IN HIGH-RISK MEDULLOBLASTOMA?
Authors: Taylor Louisa , Kerr Ian , Coyle Beth
Published: December 2020

Medulloblastoma relapse occurs in 30–40% of patients and is typically fatal. The emergence of therapy resistant sub-clones likely plays a major role in a large proportion of recurrent medulloblastoma. Y-box binding protein 1 (YB-1) is a multifunctional transcription/translation factor and known onco-protein. Overexpression has been described in numerous cancers, where elevated expression and nuclear accumulation correlates with disease progression, metastasis and drug resistance. Genomic analysis of a large medulloblastoma cohort revealed YB-1 up-regulation across all subgroups of medulloblastoma, where elevated expression correlated with poor survival. Immunohistochemical staining of patient tissue microarrays displayed significant YB-1 expression, with a high proportion (83%) of patients exhibiting nuclear accumulation. High YB-1 expression was also observed at both protein and RNA level across medulloblastoma cell lines, with expression highest in Group 3 and 4. Hence, we hypothesised that YB-1 plays a role in medulloblastoma chemoresistance and progression. Treatment of Group 3 (HDMB-03 and D283MED) and SHH (DAOY) cell lines with vincristine and cisplatin and analysis of cellular localisation by nuclear/cytoplasmic fractionation and immunofluorescence demonstrated that YB-1 undergoes nuclear translocation in response to these standard medulloblastoma chemotherapy agents. Chromatin immunoprecipitation (ChIP) analysis of untreated Group 3 cell lines (D283MED and HDMB-03) demonstrated considerable YB-1 interaction with an inverted CCAAT box in the ATP-binding cassette subfamily B member 1 (ABCB1) promoter. RT-PCR analysis of ABCB1 following vincristine and cisplatin treatment revealed differences in transcript expression, indicative of different YB-1 promoter interactions dependent on chemotherapeutic treatment. Our results highlight YB-1 as a novel candidate chemoresistance driver in medulloblastoma.
MBRS-45. TWIST1 AND ABCB1 ARE FUNCTIONAL DETERMINANTS OF METASTASIS IN MEDULLOBLASTOMA
Authors: Cardall Alice , Linke Franziska , Kerr Ian , Coyle Beth
Published: December 2020

Paediatric medulloblastomas (MB) are frequently metastatic, resulting in a poor prognosis for the patient. Of the four MB subgroups, group 3 patients present with the highest rates of metastasis and worst outcomes. The mechanisms behind the metastatic process are poorly understood, limiting our ability to develop novel therapeutic treatments. We hypothesised that the epithelial-mesenchymal transition (EMT) transcription factor TWIST1 and the multidrug efflux pump ABCB1 (ATP-binding cassette subfamily B member 1) synergistically drive MB metastasis. TWIST1 protein expression was analysed in patient tissue microarrays by immunohistochemistry. High TWIST1 expression was associated with metastatic patients (p=0.041). Physical and functional interactions between TWIST1 and ABCB1 were investigated using chromatin immunoprecipitation (ChIP) and a 3D migration and invasion model. ChIP analysis confirmed TWIST1 binding to the ABCB1 promoter in SHH (ONS-76) and group 3 (D283MED and HD-MB03) metastatic cell lines. TWIST1 and ABCB1 were inhibited in HDMB03 cells with harmine and vardenafil respectively, resulting in attenuated cell migration in the 3D model. Western blot and qRT-PCR analysis of harmine treated cells confirmed a reduction in ABCB1 protein and gene expression. Overall our data reveals TWIST1 and ABCB1 to be key targets for MB metastatic disease. Using bioinformatics analysis and ChIP sequencing, additional TWIST1 downstream targets are now being identified and compared across the metastatic cell lines (ONS-76, D283MED and HD-MB03). This data will provide a deeper insight into the pathways associated with MB metastases, enabling personalised treatment approaches for patients with metastatic disease.
MBRS-46. CHARTING NEOPLASTIC AND IMMUNE CELL HETEROGENEITY IN HUMAN AND GEM MODELS OF MEDULLOBLASTOMA USING scRNAseq
Authors: Donson Andrew , Riemondy Kent , Venkataraman Sujatha , Gilani Ahmed , Sanford Bridget , Griesinger Andrea , Amani Vladimir , Hankinson Todd , Handler Michael , Hesselberth Jay , Gershon Timothy , Wechsler-Reya Robert , Foreman Nicholas , Vibhakar Rajeev
Published: December 2020

We explored cellular heterogeneity in medulloblastoma using single-cell RNA sequencing (scRNAseq), immunohistochemistry and deconvolution of bulk transcriptomic data. Over 45,000 cells from 31 patients from all main subgroups of medulloblastoma (2 WNT, 10 SHH, 9 GP3, 11 GP4 and 1 GP3/4) were clustered using Harmony alignment to identify conserved subpopulations. Each subgroup contained subpopulations exhibiting mitotic, undifferentiated and neuronal differentiated transcript profiles, corroborating other recent medulloblastoma scRNAseq studies. The magnitude of our present study builds on the findings of existing studies, providing further characterization of conserved neoplastic subpopulations, including identification of a photoreceptor-differentiated subpopulation that was predominantly, but not exclusively, found in GP3 medulloblastoma. Deconvolution of MAGIC transcriptomic cohort data showed that neoplastic subpopulations are associated with major and minor subgroup subdivisions, for example, photoreceptor subpopulation cells are more abundant in GP3-alpha. In both GP3 and GP4, higher proportions of undifferentiated subpopulations is associated with shorter survival and conversely, differentiated subpopulation is associated with longer survival. This scRNAseq dataset also afforded unique insights into the immune landscape of medulloblastoma, and revealed an M2-polarized myeloid subpopulation that was restricted to SHH medulloblastoma. Additionally, we performed scRNAseq on 16,000 cells from genetically engineered mouse (GEM) models of GP3 and SHH medulloblastoma. These models showed a level of fidelity with corresponding human subgroup-specific neoplastic and immune subpopulations. Collectively, our findings advance our understanding of the neoplastic and immune landscape of the main medulloblastoma subgroups in both humans and GEM models.
MBRS-63. THE ROLE OF THE SWI/SNF COMPLEX SUBUNIT SMARCD3 IN MEDULLOBLASTOMA
Authors: Poore Brad , Zou Han , Sharma Vaibhav , Pollack Ian , Hu Baoli
Published: December 2020

Medulloblastoma is the most common malignant brain tumor in children, with the Group 3 (G3) having the worst prognosis of the subgroups (WNT, SHH, and Group 4). We aimed to determine the underlying differences between G3 and the other subgroups, with an emphasis on genes that control the epigenome for developing effective treatments for patients with this disease. To this end, we found that G3 has elevated expression of the SWI/SNF subcomponent, SMARCD3 (P<0.001), which serves to guide the SWI/SNF complex to different genomic regions through interactions with various transcription factors. However, little is known about function of SMARCD3 in cancer, particularly in medulloblastoma. Clinically, elevated SMARCD3 mRNA resulted in a poorer prognosis in medulloblastoma patients (P<0.0001), which was further validated in 63 patient tumors by immunohistochemical staining for SMARCD3. Interestingly, tumors that had metastasized often had elevated expression of SMARCD3, in all subgroups of medulloblastomas (P<0.0001) and G3 only (P<0.01) based on analyzing multiple published databases. An orthotopic mouse model further supported that SMARCD3 is highly expressed in metastatic tumors compared to primary tumors. Importantly, CRISPR-CAS9-mediated SMARCD3 deletion decreased cell migration in medulloblastoma cell lines. Mechanistically, SMARCD3 deletion led to decreased H3K27me3, suggesting that SMARCD3 may cooperate with PRC2 in regulation of gene expression. Together, our results indicate that SMARCD3 plays a significant role in the development of metastatic dissemination in medulloblastoma, especially in the G3 subgroup. Thus, targeting the SMARCD3-containing SWI/SNF Complex may effectively prevent tumor dissemination and improve clinical outcomes in children with medulloblastoma.