bluuebunny/crossref_metadata_2025 huggingface dataset:
MBCL-23. PRELIMINARY ANALYSIS OF TREATMENT-RELATED TOXICITIES DURING INDUCTION CHEMOTHERAPY FOR PATIENTS ON THE HEAD START 4 TRIAL
Authors: Agarwal Vibhuti , Stanek Joseph , Jaeger Megan , Dhall Girish , Finlay Jonathan
Published: December 2020

The currently active, prospective multi-center Head Start 4 (HS4) trial for CNS embryonal tumors differs from prior HS I-III trials by utilizing absolute phagocyte count (APC) as a measure of myeloid recovery instead of absolute neutrophil count. The aim of this study was to determine if utilization of APC resulted in unanticipated treatment-related toxicities during induction chemotherapy for patients enrolled on HS4. Review of the RedCap database was conducted for treatment-related CTCAE grade 3 and 4 toxicities. Data were summarized descriptively. Nonparametric statistical methods were used for comparisons. At the time of this most recent analysis, a total of 180 induction cycles were completed for the 57 patients enrolled. Of the 57 patients, nine voluntarily discontinued therapy after completing a median of three cycles each. These patients had a higher number of documented infections (59% versus 24%, p=0.0004). Veno-occlusive disease (VOD) occurred in five patients, three of whom voluntarily discontinued therapy. Since the protocol amendment utilizing milligram per kilogram dosing for patients less than six years of age, there have been no documented episodes of VOD. The overall toxicities for this cohort were comparable to those reported for induction chemotherapy in HS I-II trials. The toxic death rate is lower for HS4 compared to HS I-II (0.018% versus 4.7–6%) (Chi et al 2004). Other than the high rate of infection, possibly associated with shorter duration of the immediately prior cycles, the use of APC as part of a dose-compression strategy in HS4 does not appear associated with more significant toxicities.
MBCL-25. PILOT STUDY OF A SURGERY AND CHEMOTHERAPY-ONLY APPROACH IN THE UPFRONT THERAPY OF CHILDREN WITH WNT-POSITIVE STANDARD RISK MEDULLOBLASTOMA: UPDATED OUTCOMES
Authors: Cohen Kenneth , Chi Susan , Hawkins Cynthia , Rodriguez Fausto , London Wendy , Castellino Robert Craig , Aguilera Dolly , Stapleton Stacie , Ashley David , Landi Daniel , Bandopadhayay Pratiti
Published: December 2020

BACKGROUND

Wnt+ medulloblastoma (WPM) is a favorable subtype with EFS > 90% when treating postoperatively with craniospinal irradiation and posterior fossa boost (CSI/XRT) followed by adjuvant chemotherapy. This pilot study explored the safety of omitting radiation in standard-risk WPM.

METHODS

Subjects had to meet standard-risk criteria (< 1.5 cm2 residual tumor, no metastatic spread, no anaplasia) and have a WPM. Subjects received chemotherapy following the COGACNS0331 AAB-AAB-AAB (A=cisplatin/CCNU/VCR; B=cyclophosphamide/vincristine) backbone.

RESULTS

Six children were enrolled on study treatment prior to early study closure. Subject #1 completed planned protocol therapy but relapsed 3 months following the completion of therapy. Subject #2 completed planned protocol therapy but relapsed 6 months following the completion of therapy. In both cases, relapse was local and disseminated. Further accrual was halted. Both subjects were salvaged with CSI/XRT followed by adjuvant chemotherapy. Of the remaining 4 subjects, two had recently completed planned protocol therapy at the time of study closure and received CSI/XRT while in remission and remain in remission approximately one year from the completion of treatment. One subject aborted protocol therapy and transitioned to a Head Start regimen and remains in remission 10 months from completion of therapy. The final subject had just completed protocol therapy and had new areas of restricted diffusion concerning for early relapse. Went on to receive CSI/XRT but subsequently relapsed and is now receiving salvage chemotherapy.

CONCLUSIONS

Chemotherapy following ACNS0331, omitting CSI/XRT, appears to be insufficient for the treatment of non-metastatic WPM.
MBCL-29. PHASE I/II STUDY OF SEQUENTIAL HIGH-DOSE CHEMOTHERAPY WITH STEM CELL SUPPORT IN CHILDREN YOUNGER THAN 5 YEARS OF AGE WITH HIGH-RISK MEDULLOBLASTOMA
Authors: Dufour Christelle , Masliah-Planchon Julien , Delisle Marie-Bernadette , Geoffray Anne , Abbas Rachid , Bourdeaut Franck , Bertozzi Anne-Isabelle , Faure-Conter Cecile , Chappe Celine , De Carli Emilie , Entz-Werle Natacha , Fouyssac Fanny , Andre Nicolas , Soler Christine , Pluchart Claire , Palenzuela Gilles , Leblond Pierre , Grill Jacques
Published: December 2020

PURPOSE

To assess the 3-year EFS rate of children younger than 5 years of age with high-risk medulloblastoma (MB) treated according to the prospective multicenter trial HR MB-5.

PATIENTS AND METHODS

After surgery, all children received 2 cycles of Etoposide- Carboplatine. If partial (PR) or complete response (CR) was achieved after induction chemotherapy, children received 2 courses of thiotepa (600mg/m²) with stem cell rescue. For patients in CR after high-dose chemotherapy, they received one course of Cyclophosphamide – Busilvex with stem cell rescue (Phase I part). The others patients (not in PR after induction or in CR after thiotepa) were treated with 2 cycles of Temozolomide-Irinotecan followed by age-adapted craniospinal irradiation and maintenance treatment.

RESULTS

28 children (2 to 4 years; median: 3.0 years) were enrolled. Group 3 MB were most common (57%). The response rate to Etoposide-Carboplatine was 60.7%. Among 20 patients treated with Thiotepa, 13 children were in CR and received Cyclophosphamide – Busilvex without radiotherapy. Out of them, 9 patients (45%) are alive in CR without craniospinal irradiation (median follow-up 5 years). Among 15 patients treated with radiotherapy, 8 patients are alive (median follow-up 3.8 years). The study was prematurely stopped for an excess of events. The median follow-up was 4 years (range 1.5 - 6.1). The 3-year EFS and OS were 42.3% [25.9 - 60.6] and 71.3% [52.7 - 84.7], respectively.

CONCLUSIONS

This risk-adapted strategy did not improve EFS in young children with high-risk MB. However, the study shows that good responders to chemotherapy can be cured without recourse to irradiation.
MBCL-31. TREATMENT RESULTS AMONG 106 PATIENTS WITH MEDULLOBLASTOMA OF MOLECULAR SUBGROUP 3
Authors: Zheludkova Olga , Olkhova Lyudmila , Kushel’ Yuri , Melikyan Armen , Ryzhova Marina , Shishkina Lyudmila , Golanov Andrey , Kislyakov Alexey , Shultz Evgeny , Borodina Irina , Gorbatykh Svetlana , Popov Vladimir , Mushinskaya Marina , Polushkina Olga , Inyushkina Еugenia , Yudina Natalia , Privalova Lyudmila , Minkina Lyudmila , Zaichikov Artem , Matsekha Evgeny , Fisyun Ivan , Sakun Daniil , Dunaeva Nadezhda , Avanesyan Svetlana , Mitrofanov Vladislav , Kovalenko Sergey , Grishina Ekaterina , Chulkov Oleg , Pishchaeva Nadezhda , Vorob’ev Nikolay , Nechesnyuk Alexey , Popova Natalia , Pogorelov Dmitriy , Matitsyn Alexander , Shapochnik Alexander , Timofeeva Valentina , Korchunov Andrey , Slobina Elena
Published: December 2020

OBJECTIVE

To evaluate the treatment results among 106 patients of molecular subgroup 3 and to determine the factors affecting the prognosis.

PATIENTS AND METHODS

In all the patients, initial removal of the tumor was performed. All the patients got chemoradiotherapy according to the HIT protocol. There were 34girls and 72boys. Most patients were over 3 years:74 compared to 32 younger than 3. The majority of the patients had stage M+: 65; in 38 stage M0 was determined; in 3patients, stage was not specified, Mx.MYC amplification was found in 20 patients; MYCN amplification, in 4 patients. Classic medulloblastoma was predominant: 65, and 41 patients had anaplastic/large cell medulloblastoma.

RESULTS

The five-year progression-free survival was 0.51±0.05, the five-year overall survival was 0.52±0.04.The median survival was 82months,and the median progression-free survival was 37 months. There were no significant variations of PFS depending on the sex and age. The treatment results depended on the histological subtype: for classic medulloblastoma, the five-year PFS was 0.57; for the anaplastic/largecell,0.38(р = 0.02030). The presence of metastases significantly affected the survival: PFS for stage M0 was 0.77; for stage М+,0.35(р = 0.00062). Patients with MYC amplification had a significantly worse survival compared to MYCN patients and those without MYC amplification: 0.1, 0.75, and 0.58, respectively (р = 0.00002). Three patients with MYC amplification are alive: two patients had MGMT methylation detected.

CONCLUSIONS

The results of treatment among the patients with molecular subgroup 3 depended on the tumor subtype, presence of metastases, MYC amplification and MGMT methylation. In the absence of unfavorable factors, the survival was the same as in molecular subgroup 4.
MBCL-33. RARE PULMONARY TOXICITY IN THREE MEDULLOBLASTOMA PATIENTS UNDERGOING ANTIANGIOGENIC METRONOMIC COMBINATION THERAPY
Authors: Lenzen Alicia , Gryzlo Daniel , McKenzie Irene , Goldman Stewart , Pillay-Smiley Natasha
Published: December 2020

BACKGROUND

Metronomic and targeted anti-angiogenesis therapy (MEMMAT) has emerged as a promising treatment for recurrent/progressive medulloblastoma. This treatment includes bevacizumab, oral agents (thalidomide, celecoxib, fenofibrate, etoposide & cyclophosphamide) and intrathecal chemotherapy (etoposide & cytarabine). Common toxicities include myelosuppression, nausea, and infection. Mild respiratory toxicities can occur. We report three cases with significant respiratory toxicity.

METHODS

An IRB approved chart review was performed of three children with recurrent medulloblastoma on MEMMAT treatment and meaningful pulmonary toxicity. Literature review found no reports of similar findings.

RESULTS

Patient ages ranged from 3 to 11 years old. Patients completed a mean of 6.33 months on treatment. There was no history of chronic respiratory disease prior to starting MEMMAT. Patient #1 developed chronic cough requiring multiple respiratory and anti-infective treatments; CT scan demonstrated airspace opacities concerning for chronic inflammatory change. Each new viral infection led to significant respiratory distress. He eventually died from respiratory failure with large cystic lesions noted on CT. Patient #2 developed a chronic cough not responsive to antibiotics or respiratory treatments. Images reported airspace disease, bronchiectasis, and chronic inflammatory state. Patient #3 developed chronic cough without improvement despite antibiotics and inhaled respiratory treatments; images were suggestive of small airway disease. All three patients required numerous hospitalizations and additional treatment.

CONCLUSION

With MEMMAT, many side effects are expected though respiratory symptoms have rarely been reported. Our cases highlight the possible important correlation of pulmonary toxicity while being treated on MEMMAT, and its impact on patients’ overall health and quality of life.
MBCL-37. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH CLASSIC (CLMB) OR ANAPLASTIC/LARGE CELL (A/LCMB) MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS
Authors: Finlay Jonathan , Mynarek Martin , Dhall Girish , Mazewski Claire , Grundy Richard , Cohen Bruce H , Robinson Giles , Ashley David , Stanek Joseph R , Gajjar Amar , Rutkowski Stefan
Published: December 2020

BACKGROUND/OBJECTIVE

The introduction of German regimens, supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), report encouraging outcomes for young children with medulloblastoma. We performed a comparative outcomes analysis of treatment strategies for young children with ClMB or A/LCMB. DESIGN/

METHODS

Data from 12 prospective multi-center trials published between 2005 and 2019 for children <six-years-old with ClMB or A/LCMB were reviewed; survivals were compared.

RESULTS

COG-9921, UKCCSG-CNS9204, COG-P9934 and SJYCO7 employing standard chemotherapy with either no or risk-based irradiation, reported 3-5-year event-free survival (EFS) of 17+/-5%, 33+/-28% (ClMB), 14+/-7% and 13.8+/-9% (ClMB) respectively, with reported EFS of 0% for A/LCMB in UKCCSG-CNS9204 and SJYCO7. HIT-SKK’87, HIT-SKK’92 and HIT-SKK’00 incorporating HD-MTX and IVENT-MTX reported 2-10-year EFS of 30–34+/-10–11% for ClMB and 33+/-27% (HIT-SSK’00) for A/LCMB. Head Start HS-I-II combined, CCG-99703 and HS-III employing induction chemotherapy, with or without HD-MTX, followed by single or tandem HDCx+AuHCR reported 3-5-year EFS of 42+/-14%, 50+/-11% and 27+/-6% for ClMB, with EFS for A/LCMB of 38+/-13% (HS-III). Finally, 5-year overall survivals for ACNS0334, without or with induction HD-MTX, are 39% and 69% respectively for ClMB and A/LCMB combined.

CONCLUSIONS

A trend towards better outcomes for young children with ClMB and A/LCMB is observed in trials including either HD-MTX and 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-41. LYMPHOHEMATOPOIETIC TOXICITY IDENTIFIED IN PATIENTS WITH MEDULLOBLASTOMA RECEIVING CRANIOSPINAL IRRADIATION
Authors: Watanabe Atsuko , Shimizu Yuuki , Ohta Atsuhiko , Fukushima Takashi , Suzuki Tomonari , Nishikawa Ryo , Tanaka Ryuhei
Published: December 2020

BACKGROUND

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. MB easily disseminates through the spinal fluid. Surgery followed by radiotherapy, applied to the entire craniospinal axis (CSI), and adjuvant chemotherapy, represent the treatment of choice for patients aged ≥3 years. Since the bone marrow of the skull and vertebral column are the major hematopoietic organs, we investigated the myelosuppressive effect of irradiation treatment in patients with MB retrospectively.

METHODS

Medical records of newly diagnosed MB patients treated at our hospital from 2007–2019 were analyzed. Children <3 years old were excluded because they did not receive CSI to avoid potential neurotoxicity.

RESULTS

Medical records of 18 patients (11 males and 7 females, aged 6–26, median 11 years) were reviewed. Eight patients were stratified as high-risk disease and 10 patients with standard risk. All patients received CSI (dosage range 23.4–39.6 Gy based on disease risk) and posterior fossa boost. All patients developed lymphocytopenia (<0.5×109/L) during irradiation, and for 11 of 18 patients, lymphocytopenia (<0.2×109/L) was severe. Although 13 patients recovered from the lymphocytopenia before the initiation of chemotherapy, five patients underwent chemotherapy without recovery. Conversely, only six patients developed neutropenia (<1.0×109/L), and five of the six patients were <10 years old.

CONCLUSION

Although infectious episode associated with lymphocytopenia was not observed in this study, CSI treatment in children and adolescents may induce immunodeficient condition particularly in the lymphocytic system. Pediatric oncologists should pay attention to the impaired immunity of patients with MB who receive CSI.
MBCL-50. DISMAL OUTCOME OF HIGH RISK MEDULLOBLASTOMA TREATED WITH CHEMOTHERAPY FIRST APPROACH IN MALAYSIA
Authors: Quah Shiao Wei , Rahman E J Abdul , Ibrahim H Mohd , Muda Z , Othman I S , Unni M N Mohamed , Gunasagaran K , Ang M P , Goh C B , Teh K H
Published: December 2020

INTRODUCTION

Patients with high risk medulloblastoma are treated either with high dose chemotherapy or hyperfractionated radiotherapy. Both approaches are not feasible in resource-limited countries. POG9031 trial has reported favourable outcome for high risk medulloblastoma using standard chemotherapy and radiotherapy only. Hence, we have adopted the protocol using chemotherapy first approach due to logistical reasons.

OBJECTIVE

To review the outcome of children diagnosed with high risk medulloblastoma in Hospital Kuala Lumpur.

METHODS

Patients diagnosed with high risk medulloblastoma between January 2015 and June 2018 treated using the chemotherapy first approach as per POG9031 protocol were identified. Data was then extracted and analysed.

RESULTS

Nine patients were identified, 3 boys and 9 girls. Median age was 9.3 years (range 2.6 – 15.9 years). Median follow up for survivors are 3.6 years. Five patients (55.6%) had macroscopic metastatic disease at diagnosis. All patients had significant residual disease post-op. Only 3 patients are disease free till last follow up, giving a 3 years event free survival of 16%. Of the 6 patients who had relapsed, 4 have died, giving a 3 years overall survival of 46%. Patients with no metastasis at diagnosis (M0) fared better with 3 years event free survival of 38%, but 3 years event free survival for patients with macroscopic metastatic disease (M+) was 0%.

CONCLUSION

Outcome of children with high risk medulloblastoma treated with chemotherapy first approach was dismal.
MBRS-10. QUIESCENT SOX9-POSITIVE CELLS BEHIND MYC DRIVEN MEDULLOBLASTOMA RECURRENCE
Authors: Bolin Sara , Savov Vasil , Borgenvik Anna , Rosén Gabriela , Olausson Karl Holmberg , Zhao Miao , Garancher Alexandra , Rahmanto Aldwin Suryo , Hutter Sonja , Mainwaring Oliver , Rusert Jessica , Sundstrom Anders , Richardson Stacey , Fotaki Grammatiki , Hill Rebecca M , Dubuc Adrian M , Kalushkova Antonia , Remke Marc , Čančer Matko , Jernberg-Wiklund Helena , Ramaswamy Vijay , Chen Xingqi , Taylor Michael D , Sangfelt Olle , Schüller Ulrich , Clifford Steve C , Wechsler-Reya Robert J , Weishaupt Holger , Swartling Fredrik J
Published: December 2020

Tumor recurrence is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. Recurrence occurs when subpopulations of cancer cells evade standard therapy by acquiring features of immune escape, metastatic spread, and treatment resistance. The transcription factor SOX9 correlated with treatment resistance and dissemination in aggressive Group 3 medulloblastoma. By studying paired primary-recurrent medulloblastoma samples and patient-derived xenograft models, we identified rare SOX9-positive slow-cycling, therapy-resistant tumor cells that accumulate in relapses and in metastases. In an inducible transgenic Group 3 tumor model, doxycycline treatment kills all tumor cells by turning MYC off. However, when MYC expression was redirected to the SOX9 promoter, recurrences from rare, dormant SOX9-positive cells developed with 100% penetrance. Expression profiling revealed that recurrences were more inflammatory, metastatic, and showed elevated MGMT methyltransferase levels which depleted recurrent cells when selectively inhibited. Our model explains how recurrences develop from SOX9-induced quiescence in MYC-driven brain cancer.
MBRS-39. MAP4K4 CONTROLS PRO-INVASIVE SIGNALING IN MEDULLOBLASTOMA CELLS
Authors: Migliavacca Jessica , Capdeville Charles , Grotzer Buket Seçkin, Michael , Baumgartner Martin
Published: December 2020

The molecular mechanisms contributing to distant dissemination and local recurrence of medulloblastoma, the most common malignant brain tumor in childhood, are poorly understood and no targeted anti-invasion therapies exist till date. We explored regulators and effectors of MAP4K4, a pro-invasive kinase overexpressed in MB and associated with metastatic progression in different solid malignancies. MAP4K4 is upregulated both at mRNA and protein levels in primary pediatric brain tumors compared to normal cerebellum. MAP4K4 is required for growth factor- and irradiation-induced migration and invasion of medulloblastoma cells. It furthermore promotes turnover and activation of the receptor tyrosine kinase c-Met and of the ß1 integrin adhesion receptor 1. To characterize these clinically relevant consequences and to identify druggable targets of MAP4K4 function, we profiled the interactome of MAP4K4 in starved and growth factor stimulated medulloblastoma cells. To systematically address MAP4K4 impact on receptor expression and turnover, we determined the MAP4K4-dependent surface proteome in medulloblastoma cells. We found that MAP4K4 is part of the striatin-interacting phosphatase and kinase (STRIPAK) complex and that STRIPAK component striatin 4 is controlling cell motility and invasiveness in medulloblastoma cells. Invasiveness of medulloblastoma cells is abrogated by a truncation mutant of MAP4K4 lacking the striatin 4 interaction domain. We furthermore found that MAP4K4 mediates growth factor-induced surface expression of solute carriers and immunomodulatory proteins involved in chemoresistance and immune evasion. Thus, our study identified MAP4K4 as a missing link between pro-tumorigenic growth factor signaling and tumor cell functions relevant for disease progression. It may help identifying druggable vulnerabilities in medulloblastoma cells to restrict tumor growth and dissemination. 1. Tripolitsioti, D. et al., Oncotarget9, 23220–23236 (2018).
MBRS-43. ELUCIDATING HOW NOVEL EXTRACELLULAR MATRIX SUBTYPES DIFFERENTIALLY IMPACT THE SURVIVAL OF MEDULLOBLASTOMA SUBGROUPS
Authors: Johnson James , Linke Franziska , Merry Catherine L R , Coyle Beth
Published: December 2020

Medulloblastoma (MB) is the most common malignant paediatric brain tumour and frequently exhibits metastasis and chemoresistance. MBs are categorised into four molecular subgroups (WNT, Sonic hedgehog, Group 3 and Group 4), each associated with different demographics and clinical features. We have shown that the expression of specific extracellular matrix proteins in the brain tumour microenvironment differ between subgroups. A prime example is laminin (an ECM glycoprotein) the expression of which correlates with good overall survival in the SHH subgroup and poor overall survival in Group 4. Our aim is to determine the cause of this difference in survival. Candidate laminin-responsive-genes (LRGs) were identified using the Cavalli data set and RNA-Seq analysis of MB cells grown on 3D hydrogels with and without laminin. The role of laminin in the regulation of MMPs and the other LRG candidates was investigated by qRT-PCR, western blotting and zymography in 2D and long-term 3D-hydrogel assays. Thus far we have shown that in CHLA-01-R (metastatic Group 4 cell line) three of our LRGs are upregulated in response to laminin in 2D, as well as in preliminary 3D studies. Additionally, we have observed a unique MMP9 secretion profile of SHH cells grown in 3D compared to 2D, suggesting that our 3D assay allows us to observe relevant phenotypes absent in 2D culture. We are now in the process of identifying which of these LRG candidates are involved in metastasis and chemoresistance. This will enable the elucidation of novel therapeutic targets and crucially increase our understanding of MB-microenvironment interactions.
MBRS-47. RAPID MOLECULAR SUBGROUPING OF MEDULLOBLASTOMA BASED ON DNA METHYLATION BY NANOPORE SEQUENCING
Authors: Masliah-Planchon Julien , Girard Elodie , Euskirchen Philipp , Bourneix Christine , Lequin Delphine , Blanluet Maud , Aillaud Jean-Baptiste , Doz Francois , Bourdeaut Franck , Delattre Olivier
Published: December 2020

Medulloblastoma (MB) can be classified into four molecular subgroups (WNT group, SHH group, group 3, and group 4). The gold standard of assignment of molecular subgroup through DNA methylation profiling uses Illumina EPIC array. However, this tool has some limitation in terms of cost and timing, in order to get the results soon enough for clinical use. We present an alternative DNA methylation assay based on nanopore sequencing efficient for rapid, cheaper, and reliable subgrouping of clinical MB samples. Low-depth whole genome with long-read single-molecule nanopore sequencing was used to simultaneously assess copy number profile and MB subgrouping based on DNA methylation. The DNA methylation data generated by Nanopore sequencing were compared to a publicly available reference cohort comprising over 2,800 brain tumors including the four subgroups of MB (Capper et al. Nature; 2018) to generate a score that estimates a confidence with a tumor group assignment. Among the 24 MB analyzed with nanopore sequencing (six WNT, nine SHH, five group 3, and four group 4), all of them were classified in the appropriate subgroup established by expression-based Nanostring subgrouping. In addition to the subgrouping, we also examine the genomic profile. Furthermore, all previously identified clinically relevant genomic rearrangements (mostly MYC and MYCN amplifications) were also detected with our assay. In conclusion, we are confirming the full reliability of nanopore sequencing as a novel rapid and cheap assay for methylation-based MB subgrouping. We now plan to implement this technology to other embryonal tumors of the central nervous system.
MBRS-60. THE ACTIONABLE GENOMIC LANDSCAPE OF RELAPSED MEDULLOBLASTOMA IS DEFINED BY MAINTENANCE AND ACQUISITION OF DRIVER EVENTS
Authors: Richardson Stacey , Hill Rebecca M , Kui Christopher , Lindsey Janet C , Grabovska Yura , Schwalbe Edward C , Hicks Debbie , Williamson Daniel , Crosier Stephen , Joshi Abjhit , Wharton Stephen B , Hansford Jordan , Pizer Barry , Vinci Maria , Mastronuzzi Angela , Carai Andrea , Michalski Anthony , Jacques Thomas S , Bailey Simon , Clifford Steven C
Published: December 2020

Medulloblastoma relapse (rMB) occurs in 30–40% of patients and is almost universally fatal. Understanding the genomic landscape of rMB, and its relationship to disease characteristics at diagnosis, will be essential to underpin the development of improved therapeutic strategies, delivered at both diagnosis and relapse. Utilising NGS and Illumina DNA methylation arrays, we interrogated the molecular landscape of >100 rMBs, alongside matched diagnostic samples (n>80), encompassing molecular subgroup, novel subtypes, copy number (CNV) and mutational variants. Molecular subgroup and novel subtypes were stable over disease-course. The majority of genomic aberrations were also maintained (total arm-level CNVs at relapse, 60% maintained/40% acquired; deleterious/driver mutations, 75% maintained/25% acquired). Importantly, however, the landscape of alterations differed markedly at relapse, through both selective maintenance and acquisition of specific gene and pathway aberrations. For instance, we observed significant enrichment of subgroup-specific events at relapse, including focal CDK6/CDK14 amplifications (4/26 (15%) of MBGroup4) and CDKN2A/CDKN2B deletions (3/48 (6%) of MBSHH). In contrast, mutations in DNA damage response pathways were commonly enriched across all molecular subgroups, most significantly in MBSHH (~40% of rMBSHH; TP53, 9/36 (25%); ATM, 5/36 (14%)). Driver events in rMB are characterised by both selective maintenance and acquisition across disease-course, and together combine to define its actionable genetic landscape. Evaluation of their clinical and biological significance will be essential to establish their potential (i) as biomarkers to direct disease management and (ii) as a basis for therapeutic strategies targeted against medulloblastoma relapse.
MBRS-62. CURAXIN CBL0137 INHIBITS THE VIABILITY OF CANCEROUS CELLS IN PRE-CLINIC MODELS OF MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Wang Jiajia , Wang Baocheng , Zhao Yang , Ma Jie
Published: December 2020

Medulloblastoma is a malignant brain tumour that mostly occurs in children, and MYC-amplified medulloblastoma is characterized by pronounced invasiveness and dismal prognosis. There is no effective treatment for Medulloblastoma and its precise pathological mechanism remains obscure. Previous studies indicated that the altered epigenetic machinery manifested in the neoplastic transformation of MYC-amplified MB has become increasingly evident. It is hypothesized that epigenetic genes dependencies associated with small molecule inhibitors that have been approved or are in advanced development may help identify the potential therapeutic targets. By integrating mRNA expression profiles and the corresponding clinic-pathologic information of patients suffering from medulloblastoma, and analysing prior CRISPR screening results, we demonstrated that SSRP1 is a negative prognostic factor that functions to stimulate the viability of MB cells. SSRP1 is a subunit of the FACT complex, an important histone chaperone required for transcriptional regulation, DNA replication and damage repair. Its biological effect on tumour proliferation was assessed by using RNA interference and administering CBL0137, a small molecular inhibitor of FACT. Gene expression analysis also demonstrated that CBL0137 selectively downregulated the expression of MYC and NEUROD1. Furthermore, the administration of CBL0137 suppressed tumour growth in mouse xenograft models. This pharmacological method to selectively target MYC transcription was demonstrated in our study, and therefore can be applied as a promising treatment strategy for MYC-amplified medulloblastoma. In Conclusion, we identified an attractive strategy of selectively downregulating MYC transcription by applying inhibitor CBL0137, thereby revealing the potential clinical utility of CBL0137 to improve the prognosis of MYC-amplified medulloblastoma patients.
MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA
Authors: Maegawa Shinji , Dobson Tara , Lu Yue , Estecio Marcos , Harmanci Arif , Gopalakrishnan Vidya
Published: December 2020

Medulloblastomas exhibit poor neuronal lineage specification. Expression of RE1 Silencing Transcription Factor (REST), a repressor of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Constitutive REST expression in mice (RESTTG) drives medulloblastoma genesis and promotes tumor progression in the context of Ptch1 haploinsufficiency (Ptch+/−), implicating it as a driver of tumorigenesis. Tumor formation in Ptch+/−/RESTTG mice showed significantly decreased latency and increased penetrance compared to that in Ptch+/− mice. Since REST silences gene expression by chromatin remodeling, we sought to identify cooperating epigenetic events that contributed to its oncogenic activity. To this end, we performed a loss of function screen employing a bar-coded library of short hairpin RNAs against epigenes, to identify candidates whose loss could create a proliferative vulnerability in the context of REST-elevation. This screen identified DNA methyltransferase 1 (DNMT1) as a high-priority epigenetic modifier. DNMT1 and the Ubiquitin like with PHD and Ring finger domain 1 (UHRF1) proteins are essential for methylation of hemi-methylated DNA at the replication fork during S-phase. Their expression is downregulated during neuronal differentiation. In human SHH-medulloblastoma tumors, REST and UHRF1 expression are positively correlated with higher levels of both genes noted specifically in the SHH-beta subtype, and is associated with poor prognosis. The requirement for DNMT1/UHRF1 in the context of REST elevation, was established by RNA-Seq and Reduced Representation Bisulfite Sequencing (RRBS), which revealed hypermethylation and downregulated expression of REST-target genes needed for neurogenesis. Thus, DNMT1/UHRF1 is a functional and potential therapeutic vulnerability in REST-elevated SHH medulloblastomas.
MODL-01. SAFETY IN CONCOMITANT USE OF MEK AND BRAF INHIBITORS WITH BEVACIZUMAB
Authors: Winzent Shelby , Sabus Ashley , Hemenway Molly , Nellan Anandani , Mulcahy-Levy Jean
Published: December 2020

BACKGROUND

MEK and BRAF inhibitors are increasingly common treatments for pediatric nervous system tumors. While effective in blocking Ras/Raf/MEK/ERK pathway activation driving tumor progression, the side effect profile differs from traditional cytotoxic chemotherapies. Little data exists on overlapping toxicities with other targeted agents like bevacizumab despite their potential combined therapeutic benefit.

METHODS

A retrospective review of patients treated with MEK +/- BRAF inhibitors and bevacizumab from 2015–2019 was conducted. Data collected included demographics, tumor type, neurofibromatosis status, treatment duration, reason for concurrent treatment, and toxicities.

RESULTS

Fifteen patients aged 3–24 years old (median age 14 years) were identified. Diagnoses included five high-grade gliomas, four low-grade gliomas, four benign nerve sheath tumors, and one ependymoma. Nearly half (46.7%) were positive for neurofibromatosis type 1. Three patients were treated with a BRAF + MEK inhibitor and twelve were treated with a MEK inhibitor combined with bevacizumab. Duration of treatment ranged from 16–420 days (median 119 days). Reasons for concomitant therapy included progressive disease with neurologic decline (46.7%), painful benign nerve sheath tumors (26.7%), and visual loss with optic pathway gliomas (26.7%). Toxicities while on concurrent therapy included one episode of grade 1 left ventricular dysfunction, one grade 1 bleeding episode, and one grade 2 wound complication. There were no episodes of hypertension, thrombosis, GI perforations, or cytopenias.

CONCLUSIONS

Our preliminary experience suggests bevacizumab in combination with MEK and BRAF inhibitors can be used safely across a variety of pediatric nervous tumors. Larger studies are needed to confirm these findings.
MODL-16. ABEMACICLIB, A SELECTIVE CDK4/6 INHIBITOR, RESTRICTS GROWTH OF PEDIATRIC GLIAL-LINEAGE TUMORS IN VITRO AND IN VIVO
Authors: Liang Muh-Lii , Hsieh Tsung-Han , Wong Tai-Tong
Published: December 2020

BACKGROUND

Glial-lineage tumors constitute a heterogeneous group of neoplasms, comprising gliomas, oligodendrogliomas, and ependymomas, which account for 40%–50% of all pediatric central nervous system tumors. Advances in modern neuro-oncological therapeutics are aimed at improving neoadjuvant chemotherapy and deferring radiotherapy because radiation exposure may cause long-term side effects on the developing brain in young children. Despite aggressive treatment, more than half the high-grade gliomas (pHGGs) and one-third of ependymomas exhibit recurrence within 2 years of initial treatment.

METHODS

By using integrated bioinformatics and through experimental validation, we found that at least one gene among CCND1, CDK4, and CDK6 was overexpressed in pHGGs and ependymomas.

RESULTS

The use of abemaciclib, a highly selective CDK4/6 inhibitor, effectively inhibited cell proliferation and reduced the expression of cell cycle–related and DNA repair–related gene expression, which was determined through RNA-seq analysis. The efficiency of abemaciclib was validated in vitro in pHGGs and ependymoma cells and in vivo by using subcutaneously implanted ependymoma cells from patient-derived xenograft (PDX) in mouse models. Abemaciclib demonstrated the suppression of RB phosphorylation, downstream target genes of E2F, G2M checkpoint, and DNA repair, resulting in tumor suppression.

CONCLUSION

Abemaciclib showed encouraging results in preclinical pediatric glial-lineage tumors models and represented a potential therapeutic strategy for treating challenging tumors in children.
NFB-05. AN UNUSUAL PRESENTATION OF RECURRENT LANGERHANS CELL HISTIOCYTOSIS OF THE CRANIOFACIAL BONES IN A PATIENT WITH NEUROFIBROMATOSIS TYPE I
Authors: Chaffee Blake , Judd Alexis , Rush Sarah , Wright Erin
Published: December 2020

Neurofibromatosis type 1 (NF1), predisposes patients to benign and malignant tumors due to lack of suppression of the mitogen activated protein kinase (MAPK) signaling pathway. Langerhans cell histiocytosis (LCH) manifests in numerous ways, from localized lesions to multisystem organ involvement secondary to a constitutively active MAPK signaling cascade often driven by BRAF mutations. While both LCH and NF1 are characterized by overactive MAPK signaling, there are few reports of the two diseases occurring simultaneously. We report a novel case of a patient with underlying NF1 and recurrent LCH without a BRAFV600E mutation. She initially presented at 2 years of age with an aggressive appearing mass of the left temporal bone found on surveillance imaging. Pathology was consistent with Langerhans histiocytosis and she was treated with the LCH-III protocol for patients with high-risk LCH due to the location of her lesion. Five years after completion of therapy, MRI demonstrated development of a calvarial mass consistent with relapsed LCH in a new risk site. Lesional curettage was performed and pathology confirmed recurrence of LCH with juvenile xanthogranulomatous features. BRAF testing of blood and the lesion were negative for any BRAF alterations. Further genomic evaluation of the tumor is in progress at this time to evaluate for other known mutations associated with LCH. The patient is currently receiving monthly cytarabine treatment which she has tolerated to date. Our patient represents a unique presentation of recurrent LCH in a patient with NF1 and further molecular evaluation may help identify other drivers of LCH activation.
NFB-13. TRAMETINIB FOR PLEXIFORM NEUROFIBROMA AND RECURRENT LOW-GRADE GLIOMA
Authors: Sato Aimee , Millard Nathan , Perez Francisco , Vitanza Nicholas , Leary Sarah
Published: December 2020

BACKGROUND

Based on early clinical efficacy data, Seattle Children’s established a standard clinical practice for MEK inhibitor therapy for children with plexiform neurofibroma (PN) or recurrent low-grade glioma (LGG).

METHODS

Data were collected under an IRB-approved retrospective chart review. Trametinib was prescribed off-label at 0.025 mg/kg daily for up to two years. Physical exam and laboratory monitoring were monthly for 3 months, then every 3 months. Retinal examination, ECHO/ECG were every 3 months. Tumor response was evaluated by MRI every 3 months for LGG; imaging for PN was dependent on tumor location.

RESULTS

30 patients received trametinib; 17 LGG, 16 PN (3 both); 22 with Neurofibromatosis, Type-1 (NF1); 16 female/15 male; median age 11 (range 4.1–22.6). Most common tumor location was optic pathway (n=11) and face/neck (n=10). Most common adverse events (AE) were dermatologic and gastrointestinal. Ten had dose interruption/reduction, only one discontinued therapy for AE. Six received dermatology specialty care for AE. With median follow-up of 12 months, only 3 patients had progression, one with NF1. One-year EFS was 100% for PN and 88%+7 for LGG. Driver mutations were identified in 9 of 10 tumors tested (5 BRAF fusion, 1 BRAFV600E, 1 FGFR1+NF1, 1 FGFR1+PTPN11, 1 NF1). Radiology review of response will be presented.

CONCLUSIONS

This real-world pediatric cohort supports efficacy and tolerability of MEK inhibitor therapy for short-term control of plexiform neurofibroma and low-grade glioma with and without NF1. Further studies are warranted to evaluate comparative efficacy, combination therapy and duration of therapy.
NURS-02. CLINICAL MANAGEMENT OF PATIENTS RECEIVING CAR T CELL THERAPY FOR CNS TUMORS
Authors: Holtzclaw Susan , Hoeppner Corrine
Published: December 2020

Chimeric antigen receptor (CAR) T cells are an innovative new therapy with proven efficacy in some pediatric cancers such as leukemia and lymphoma, but much less experience in solid tumors, especially tumors of the central nervous system (CNS). Seattle Children’s has three open Phase 1 CAR T cell studies (BrainChild-01, -02, and -03 targeting HER2, EGFR, and B7-H3, respectively) for recurrent/refractory CNS tumors and DIPG (BrainChild-03 only). As of December 2019, four patients have been treated at Seattle Children’s Hospital with CAR T cells infused on a weekly schedule through indwelling catheters into the tumor resection cavity or ventricular system. Given the scrutiny of clinical care needed for Phase 1 studies, we are now able to report detailed clinical information that we have learned during the treatment of these patients. Clinical care includes the judicious use of steroids, the clinical support of patient’s symptoms pre- and post-infusion, and the management of peritumoral edema. We will also discuss the psychosocial support needed for families who travel long distances to receive this therapy compounded by the many emotional components of being enrolled on any Phase 1 trial. Case studies and experience from a Nurse Practitioner role will be provided and discussed.
OTHR-09. CENTRAL DIABETES INSIPIDUS: A RARE UNREPORTED SIDE EFFECT OF TEMOZOLOMIDE IN PEDIATRICS
Authors: Kuo Christopher , Waters Kaaren , Cheung Clement , Margol Ashley
Published: December 2020

Temozolomide is a chemotherapeutic agent commonly used in the treatment of central nervous system tumors. While there are case reports of temozolomide associated central diabetes insipidus (CDI) in adults, this has not been reported in children. We describe the first case of temozolomide associated CDI in a pediatric patient. The patient was a previously healthy 12yr old male diagnosed with anaplastic astroblastoma. He underwent gross total resection of the lesion and was subsequently treated with focal radiation therapy and concurrent temozolomide. On day 21 of therapy he developed thrombocytopenia, severe polyuria and polydipsia. Temozolomide was held and he underwent a preliminary evaluation for CDI. Initial laboratory findings were concerning for CDI, and he was admitted for further work-up and to assess the need for desmopressin. Additional laboratory tests demonstrated normal anterior pituitary function and his serum sodium normalized when allowed to drink to thirst, mitigating the need for desmopressin. Temozolomide was not restarted and the symptoms of polyuria and polydipsia resolved and did not recur. Upon review, the tumor did not involve the pituitary or hypothalamus. Additionally, these areas were not involved in the irradiation field. CDI is a rare but clinically significant side effect of temozolomide, reported in adults. Given this is the first report of CDI secondary to temozolomide in a pediatric patient, we speculate that this is likely under-recognized in children. Prompt recognition and treatment is necessary to prevent severe sequelae of hypernatremia.
PATH-17. INTRAGENIC COPY NUMBER BREAKPOINT ANALYSIS OF METHYLATION DATA FROM CNS TUMOURS IDENTIFIES NOVEL SUBGROUP-SPECIFIC CANDIDATE FUSION GENE ENRICHMENTS
Authors: Mackay Alan , Grabovska Yura , Clarke Matthew , Carvalho Diana , Temelso Sara , Jones Chris
Published: December 2020

Methylation array-based molecular profiling has redefined the classification of brain tumours and now forms an important part of their integrated diagnosis, providing both subgroup assignment and genome wide DNA copy number profiles. These latter data can be used to identify intragenic breakpoints which are frequently associated with structural variations resulting in therapeutically targetable oncogenic fusion genes. To systematically assess the landscape of these alterations, we combined publicly available methylation datasets resulting in a total of 5660 CNS tumours, around half paediatric, and including >1000 high grade glioma and DIPG. These were analysed by standard methodology (MNP, conumee), and intragenic breakpoint enrichment was compared within methylation subgroups, superfamilies, and tumours with no high-scoring classification. Benchmarking included sequence-verified cases such as infant hemispheric gliomas (IHG) with ALK(15%) and ROS1(7%) fusions, and pathognomic alterations associated with specific entities such as RELA-EPN, MYB-LGG and HGNET-MN1. We identified previously unreported enrichments of well-recognised fusion targets such as NTRK2in GBM_MID and NTRK3in DMG_K27 (both 5%), METin A_IDH / A_IDH_HG (3–5%), and FGFR1/3in GBM_G34 (8–9%). Novel recurrent kinase gene candidates to be verified and explored further include IGF1Rin 2–12% cases spanning glioma subgroups, and TIE1in poorly classified tumours. This latter ‘NOS’ group were also enriched in various transcription factor targets of breakpoints, including TCF4and PLAGL2. Despite limitations due to sample quality, resolution or balanced translocations, breakpoint analysis of methylation copy number profiles provides simple screening for structural rearrangements which may directly influence targeted therapy in paediatric CNS tumours.
PATH-18. HIGH-GRADE NEUROEPITHELIAL TUMOR (HGNET) IN A PEDIATRIC CASE-SERIES
Authors: Sanders Felipe Hada , Azambuja Alessandra , Frasseto Fernando , Rosemberg Sergio , Matushita Hamilton
Published: December 2020

The central nervous system (CNS) high-grade neuroepithelial tumor is a recently described molecular entity. We report 2 new CNS HGNET cases sharing common clinical presentation and pathologic features. In summary, CNS HGNET represents a rare tumor occurring in young patients with dismal prognosis. We think it is important to report these cases to spread the experience and raise the knowledge of the medical community.
PATH-19. MOLECULAR CLASSIFICATION BASED ON THE DNA METHYLATION PROFILE OF CENTRAL NERVOUS SYSTEM (CNS) TUMORS IN CHILDREN: TWO-YEARS EXPERIENCE AT THE BAMBINO GESÙ HOSPITAL
Authors: Miele Evelina , Rossi Sabrina , Pedace Lucia , Camassei Francesca Diomedi , Antonelli Manila , Cacchione Antonella , Colafati Giovanna Stefania , Carai Andrea , Gianno Francesca , Alzoubi Hiba , Gessi Marco , Tartaglia Marco , Giangaspero Felice , Locatelli Franco , Mastronuzzi Angela
Published: December 2020

INTRODUCTION

Pediatric brain tumors (PBT) represent the second most common pediatric cancer, with the highest mortality rate among childhood malignancies. Improvement of PBT diagnostic accuracy is fundamental to optimize treatment strategy. OBJECTIVES: We aimed to explore the impact of DNA methylation arrays implementation in PBT clinical practice.

METHODS

214 PBT were analyzed by Illumina 850KEPICmethylation array. Low score and discordant cases were collegially reviewed.

RESULTS

Calibrated score was 0.8 or higher in 159 cases (74.3%), with pathological diagnosis confirmation in 132 cases and molecular subgroup definition in 47 of them, including cases of medulloblastoma, CNS neuroblastoma FOXR2, HGNET MN1; methylation profiling amended diagnosis in 10 cases, e.g. HGNET BCOR and anaplastic PXA, was non-contributory in 4 and misleading in 12 cases, including glioneural tumors and tumors arising in syndromic contexts. Calibrated score ranged between 0.8 and 0.3 in 37 cases (17.3%) and was below 0,3 (no match) in 18 cases (8.4%). Calibrated score below 0,8 was more frequently assigned to low grade gliomas and low grade glioneural tumors (p <0.0006). Challenging/very rare cases, e.g. intracranial AFH with EWSR1:CREM fusion and nonRELA supratentorial ependymomas, were assigned to “no match subgroup”; in syndromic patients the score tended to be lower (p=0.07); no correlation between score and age < 3-years was found (p=0.1).

CONCLUSION

Methylation profiling refine on diagnostic accuracy in PBT classification. Improvements are needed in classifying low grade glioma/glioneuronal tumors and challenging/very rare PBT. In syndromic cases, there is a high rate of misleading profiles and/or low scores.