bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-64. A Phase II Study of Pegylated Interferon in Children with Recurrent or Refractory and Radiographically or Clinically Progressive Juvenile Pilocytic Astrocytomas and Optic Pathway Gliomas (NCT02343224)
Authors: Aguilera Dolly , Mazewski Claire , Janss Anna , MacDonald Tobey , Goldman Adam , Leong Tracy , Castellino Robert Craig 
Published: June 2022

Abstract
Unresectable Juvenile Pilocytic Astrocytomas (JPA) and Optic Pathway gliomas (OPG) are chronic diseases that can have solid +/- cystic components. We wanted to evaluate the objective response to pegylated interferon Alpha2B in this group of patients in a prospective single arm Phase II clinical trial. Eligibility criteria: age 3 -25 years, patients with neurofibromatosis (NF) were eligible, evidence of measurable disease in MRI, no limitation in the number of prior therapies including chemotherapy and radiation. Exclusion criteria: prior pegylated interferon exposure, less than 2 years from radiation, active autoimmune disease. Subjects enrolled received pegylated interferon 1 mcg/kg/dose SQ weekly, to a max dose of 150mcg/dose in 28 day cycles for up to 2 years. The study design is a Simon two stage design. If no complete or partial responses among the first 9 patients, the study will terminate. Nine subjects enrolled: 4 females, 5 males, median age of 11years, 6 Caucasians, 3 African Americans. Two subjects with NF. Molecular findings KIAA-BRAF fusion (6), V600E mutation (1), CDK2A loss (1). Location: brain (7), brain and spine (2). We enrolled a heavily pre-treated population, patients with prior radiation ( 1), nine with prior chemotherapy, the average number of regimens 4 (range 2-6). No complete responses or partial responses were seen. Two patients with prolonged stable disease 75+months and 66+ months. At 12 and 24 month EFS 76.2% (95%CI52.1-100%). Median EFS has not been reached. The 12 and 24 months survival estimate 75% (95% CI 50.3-100%), median survival has not been reached. Side effects as expected mostly grade 1-2. No grade 4 event related to pegylated interferon were seen. This is the first report of pegylated interferon in OPG and JPA, two patients with prolonged stable disease suggesting that pegylated interferon can offer potential benefit in this population and additional studies are important.
MEDB-63. Deciphering the role of LIN28B in Group 3 medulloblastoma
Authors: Shahab Shubin , Sun Jessica , Schnepp Robert , MacDonald Tobey , Kenney Anna 
Published: June 2022

Abstract
BACKGROUND: Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and many do not survive beyond 5 years. Several drivers for Group 3 MB have been identified but none have resulted in targeted therapy to date. LIN28B is a stem cell factor that is upregulated in Group 3 medulloblastoma and is associated with worse survival. Here we investigate the role of the LIN28B pathway in Group 3 MB development. Pharmacologic inhibition of the LIN28B pathway is feasible and may provide a unique opportunity to target this tumor. METHODS: Using LIN28B knockdown and overexpression in G3 MB cells we test LIN28B’s effect on proliferation, self-renewal and metastasis. Similarly, we used shRNAs targeting PBK and demonstrate a similar effect on G3 MB growth. We also investigate the role of let-7 as a target of LIN28B by introducing let-7 mimetics and overexpression vectors into MB cells. Finally, we use a LIN28 inhibitor 1632 and a PBK inhibitor HITOPK032 to treat G3 MB cell lines and then assess their impact on proliferation and apoptosis. RESULTS: We find that down-regulation of LIN28B or PBK using shRNA results in significant reduction in cell proliferation. In contrast overexpression of LIN28B increases Group 3 cell proliferation and tumor sphere formation. LIN28B knockdown also significantly (p&lt; 0.01) increases survival in mice with orthotopic Group 3 tumors. The LIN28 inhibitor 1632 also leads to significant reduction in G3 MB growth through decreased cell cycle entry and increased apoptosis. In addition, HITOPK032 also demonstrates significant reduction in Group 3 MB cell proliferation at low (nanomolar to low micromolar) concentration. CONCLUSIONS: Our study establishes a critical role for the LIN28B-let-7-PBK pathway in Group3 MB and provides encouraging preliminary preclinical results for drugs that target this pathway.
MEDB-69. Clinical and molecular meta-analysis of three major medulloblastoma clinical trials (ACNS0331, SJMB03, ACNS0332) uncovers novel strategies to improve risk-stratified therapy
Authors: Smith Kyle S , Billups Catherine A , Dhanda Sandeep K , Bihannic Laure , Vasilyeva Aksana , Li Yimei , Michalski Jeff M , Olsen James M , Leary Sarah , Fouladi Maryam , Gajjar Amar , Onar Arzu , Northcott Paul A , Robinson Giles W 
Published: June 2022

Abstract
BACKGROUND: Given the vast molecular heterogeneity present within medulloblastoma (MB) and considerable differences in therapy, we performed a meta-analysis of three large, recently published, prospective clinical trials (ACNS0331, SJMB03, ACNS0332) comprising 898 children with newly-diagnosed MB to shape future therapy.
METHODS: Molecular subgroups, subtypes, and copy number variations were uniformly procured from DNA methylation profiles and mutations from next-generation sequencing. Patients were stratified into six clinically homogeneous groups for cross-trial comparisons: (1) ACNS0331_LDCSI - patients with non-metastatic (M0), non-residual (R0), non-anaplastic MB treated with low-dose (LD) craniospinal irradiation(CSI); (2) ACNS0331_SDCSI - patients with M0R0 non-anaplastic MB treated with standard-dose(SD) CSI; (3) SJMB03_SDCSI - patients with M0R0 non-anaplastic MB treated with SDCSI; (4) SJMB03_HDCSI - patients with metastatic (M+) MB treated with high-dose (HD) CSI; (5) ACNS0332_HDCSI - patients with M+ MB treated with HDCSI; (6) ACNS0332_HDCSI_Carbo - patients with M+ MB treated with HDCSI and carboplatin.
RESULTS: 803 (WNT=125, SHH=122, G3=189, G4=367) of 898 patients formed the cohort. No significant difference was observed between the event-free survival (EFS) from ACNS0331_SDCSI and SJMB03_SDCSI or from SJMB03_HDCSI and ACNS0332_HDCSI when analyzed as a whole or by subgroup. ACNS0331_LDCSI outcome was inferior to the combined ACNS0331_SDCSI + SJMB03_SDCSI cohorts (p&lt;0.001) and in G3 (p=0.030). ACNS0332_HDCSI_Carbo EFS was superior to ACNS0332_HDCSI + SJMB03_HDCSI only in G3/G4_subtype III (p=0.045). Additional molecular risk factor analysis identified M0R0 G3/G4_subtype VII and SHH without high-risk features as very low risk (&gt;90% EFS) and M0R0 G3/G4_subtype III as high risk (&lt;40% EFS).
CONCLUSION: The comparable results observed across trials presents a welcome opportunity to reduce toxicity by eliminating excessive doses of chemotherapy (i.e. vincristine, cisplatin, and cyclophosphamide) from therapy. Furthermore, these results support molecularly driven risk classification as the means for a better, more-refined, treatment stratification.
MEDB-70. Metabolism mediated radiation resistance in MYC-driven Medulloblastoma
Authors: Veo Bethany , Goodspeed Andrew , Prince Eric , Venkataraman Sujatha , Vibhakar Rajeev 
Published: June 2022

Abstract
Medulloblastoma (MB) is the most prevalent malignant brain tumor in children and demonstrates a high level of heterogeneity. Treatment for MB includes chemotherapy and radiation often resulting in long-term morbidity. MYC-driven MB, are high-risk tumors with poor long-term survival and increased susceptibility to develop recurrent tumors. Recurrent MB is far more aggressive with limited treatment options leading to a 5-year survival rate of 12%. To understand what drives MYC-amplified MB relapse we performed single-cell RNA sequencing of irradiated MB xenograft tumors. We identified an overall enhancement of metabolic activity in radiation-resistant cells. We further observe enhanced wild-type IDH1 and IDH2 expression in two clusters, which coincide with hypoxia and Nestin expression, marking a stem-cell like niche. Stem-like cancer cells are notoriously resilient against radiation therapy. Furthermore, wtIDH1 and IDH2 represent a unique target in radiation-resistant MB which has not previously been identified. Wild type IDH1/IDH2 are more recently shown to promote tumor proliferation and mediate metabolic reprogramming through the production of oncometabolites and substrates that functionally alter chromatin structure and gene transcription. We hypothesized that MYC modulation of wtIDH1/IDH2 facilitates metabolic reprogramming and promotes radiation-resistant cell populations. We show the change in the structural integrity of chromatin altered in radiation-resistant MB by metabolic adaptation and the effect of disrupting IDH1/IDH2 activity. We further compare these results to the chromatin profile of patient primary and matched relapsed MB samples at the single-cell level. We demonstrate that targeting IDH1/2 with chemical inhibitors suppresses MB cell growth. Our results disclose insights into the development of radiation resistance and provide a potential therapeutic target for the treatment of relapsed MYC-MB.
MEDB-84. The French experience of ELP1-related medulloblastomas
Authors: Tauziède-Espariat Arnault , Guerrini-Rousseau Léa , Perrier Alexandre , Torrejon Jacob , Bernardi Flavia , Filser Mathilde , Varlet Pascale , De Carli Emilie , Pagnier Anne , Leblond Pierre , Faure-Conter Cécile , Doz Francois , Bertozzi Anne-Isabelle , Mansuy Ludovic , Willems Marjolaine , Palenzuela Gilles , Entz-Werle Natacha , Bourneix Christine , Hasty Lauren , Delattre Olivier , Blauwblomme Thomas , Beccaria Kevin , Metais Alice , Ayrault Olivier , Chrétien Fabrice , Bourdeaut Franck , Dufour Christelle , Masliah-Planchon Julien 
Published: June 2022

Abstract
Medulloblastoma (MB), the most frequent embryonic tumor of the cerebellum is classified into four molecular subgroups (WNT group, SHH group, group 3 and group 4). Although the vast majority of MB are sporadic, predisposing genetic diseases have been described in rare WNT MB and more frequently in the SHH group. In a recent pediatric series of SHH-MB, germline alterations of the ELP1 gene have been described in 14% of cases, making this gene the most frequent genetic predisposition in MB. We have investigated the potential interest of ELP1 immunostaining on a large cohort of 132 MB. A complete loss of ELP1 staining was observed in 12 SHH MB (among 57 total SHH MB: 21%). The loss of ELP1 immunostaining was well correlated with the presence of a bi-allelic alteration of the gene except for one case for which the MB had a loss of ELP1 protein expression demonstrated by immunohistochemistry (IHC) and confirmed by whole proteome analysis, although no obvious genetic alteration in the coding sequence of ELP1 could be found. Molecular analysis of a large “molecular” cohort of 266 MB from French centers for which somatic ELP1 was sequenced allows to identify 12 additional MB with bi-allelic ELP1 genetic alterations. Our results demonstrate the benefit of the ELP1 IHC as an accurate and reliable tool to screen ELP1-deficient MB. This new immunohistochemical tool will now be advantageously used to screen SHH MB upfront for genetic alteration in ELP1, and will subsequently help orientating these patients towards genetic counseling.
MEDB-86. A re-induction regimen for children with recurrent medulloblastoma
Authors: O'Halloran Katrina , Phadnis Sheetal , Metrock Laura , Friedman Gregory , Davidson Tom , Robison Nathan , Dhall Girish , Margol Ashley 
Published: June 2022

Abstract
Medulloblastoma is the most common malignant brain tumor of childhood. Despite multi-modal therapies, ~30% of patients experience disease recurrence, which portends a poor prognosis. At initial recurrence, intensive chemotherapy may be effective prior to various consolidation therapies including high dose chemotherapy with autologous stem cell rescue or irradiation. We report outcomes for nine children treated at two institutions with the following regimen: cyclophosphamide 1500mg/m2/dose days 1,2; irinotecan 125mg/m2/dose days 1,8; temozolomide 150mg/m2/dose days 1-5, and oral etoposide 50mg/m2/dose days 1-7. Patients received 2-4 cycles based upon disease response and physician preference. The mean time from initial diagnosis to first recurrence was 19 months. After receiving two cycles of therapy, two patients had complete response (CR) and proceeded to consolidation. Of the remaining seven patients, five had partial response (PR) and two had stable disease (SD). Overall response rate was 78% after 2 cycles. Two patients with PR proceeded directly to consolidation with irradiation. Five patients (3 PR, 2 SD) received 2 additional cycles. After four cycles there was one CR, two with minimal residual disease, one SD and one progressive disease (PD). Four patients (44%) are alive with no evidence of disease (NED). One patient died of consolidation-related toxicity but had NED at time of death 28 months from initial recurrence. Five patients developed PD. Two patients died of disease, two are alive with disease, and one is alive with NED after PD and additional therapy. There were no treatment-related deaths. Infection was the most common complication. Five patients had febrile neutropenia and two developed sepsis. One patient required dose reduction for prolonged thrombocytopenia. Peripheral blood stem cell collection was achieved in all patients for whom it was attempted. This re-induction regimen is generally well-tolerated and effective in inducing responses for children with recurrent medulloblastoma.
NFB-09. Treatment of cardiac fibroma in aPTCH1-mutated Gorlin syndrome with medulloblastoma
Authors: Piccolo Gianluca , Verrico Antonio , Trocchio Gianluca , Derchi Maria , Siboldi Alessandra , Stagnaro Nicola , Crocco Marco , Giannatale Angela Di , Ghiorzo Paola , Milanaccio Claudia , Garrè Maria Luisa 
Published: June 2022

Abstract
A 2,5-year-old girl presented vomiting episodes associated with severe motor delay, macrocephaly, and distal hypotonia. Brain MRI showed hydrocephalus and a non-metastatic lesion in the posterior fossa. A pre-operative ECG showed isodifasic T waves in leads V4R and V1, follow-up was recommended. Histology after gross total resection was consistent with Desmoplastic/Nodular Medulloblastoma. At chest X-rays a bifid rib was noted, leading to the diagnosis of Gorlin syndrome (GS; c.3306 + 1G&gt;T in PTCH1). During chemotherapy, ventricular tachycardia (VT) occurred, requiring synchronized electrical cardioversion. An echocardiogram revealed an echogenic mass of the left ventricle free wall, but normal coronaries and ventricular function. Cardiac MRI (CMR) confirmed a 21x40x38mm mass, with eccentric development and intense homogeneous enhancement, indicative of cardiac fibroma (CF). A computed tomography excluded local calcifications. Therapy with amiodarone and beta-blocker was initiated. TREATMENT STRATEGY: priority to chemotherapy vs cardiac surgery; full-dose chemotherapy, preferring drugs with minor cardiotoxicity; administration in ICU under continuous vital parameters and ECG-monitoring. Other three VTs occurred during treatment or anesthesia, resolved after electrical cardioversion (unsuccessful attempts with i.v. adenosine and amiodarone). Lacking specific guidelines concerning CF in GS, a wait-and-see approach was preferred with close tumor follow-up and regular cardiological assessment (ECG, stress-test, Holter monitoring, CMR). No further arrhythmias were recorded in a 10-year-long follow-up and CMR confirmed CF stability. Medulloblastoma has never recurred. PTCH1 variants are rarely associated with medulloblastoma (&lt;2%). Only 3–5% of GS present CF, responsible for arrhythmias in 32%. Being non-regressing, total surgical resection is usually performed (without recurrence), with a 27-year-long median survival. When surgery risk/benefit ratio is not favorable or the patient is paucisymptomatic, the treatment plan remains unclear; probably, a conservative approach under a strict cardiological follow-up can be reasonable. In young children with syndromic medulloblastoma, a routine echocardiogram should be performed to rule out CF.
NFB-13. Rhabdoid Tumor Predisposition Syndrome (RTPS) – Finding Evidence by systematic Analyses
Authors: Nemes Karolina , Bens Susanne , Johann Pascal D , Steinbügl Mona , Gruhle Miriam , Kachanov Denis , Teleshova Margarita , Hauser Peter , Simon Thorsten , Tippelt Stephan , Eberl Wolfgang , Woessmann Wilhelm , Kratz Christian , Abbink Floor , Hernáiz-Driever Pablo , Eyrich Matthias , Sumerauer David , Milde Till , Reinhard Harald , Leipold Alfred , de Wetering Marianne v , Gil-da-Costa Maria João , Ebetsberger-Dachs Georg , Marques Carmen Hernandez , Bauer Nina , Biassoni Veronica , Meneses Clarice Franco , Knirsch Stephanie , Lauten Melchior , Gerber Nicolas U , Chada Martin , Kerl Kornelius , Lemmer Andreas , Heidrun Boztug , Kuhlen Michaela , Furtwängler Rhoikos , Kordes Uwe , Schneppenheim Reiner , Vokuhl Christian , Hasselblatt Martin , Kröncke Thomas , Bison Brigitte , Melchior Patrick , Timmermann Beate , Gerss Joachim , Siebert Reiner , Frühwald Michael C 
Published: June 2022

Abstract
BACKGROUND: Individuals with rhabdoid tumor predisposition syndrome (RTPS1 – SMARCB1, RTPS2 – SMARCA4) have a propensity to develop malignant rhabdoid tumors (MRT). Affected patients typically present &lt; age 12 months with synchronous tumors (SYN) exhibiting an unusually aggressive clinical behavior. Due to the rarity of RTPS, standards for management are evolving. METHODS: Clinical, genetic, and treatment data of 90 patients with RTPS from 16 countries were analyzed (2004 – 2020). Therapy followed the EU-RHAB recommendations. Tumors and matching blood samples were investigated for SMARCB1 and/or SMARCA4 mutations using FISH, MLPA and sequencing. DNA-methylation subgroups were determined using DNA methylation arrays. RESULTS: The median age at diagnosis of 52 girls and 38 boys was 5.5 months (0 – 203). 55.5% (50/90) of patients presented with an atypical teratoid/rhabdoid tumor (ATRT), 23.5% (21/90) demonstrated SYN, and 21% (19/90) extracranial MRT. RTPS1 was present in 84-, RTPS2 in six patients. In 77% (65/84) complete data on SMARCB1 mutational status were generated. Methylation subgroup status was available in 59% (40/68) of ATRT or SYN. The 5-year overall- (OS) and event free survival rates of patients with RTPS1 were 19.8 ± 4.8% and 15 ± 4.2%, respectively. Age &lt; 1 year at diagnosis (10.1±4.3% vs. 46.7±11.1%), presence of SYN (5.3±5.1% vs. 24.8±6%), histological diagnosis (ATRT vs. eMRT/RTK/SYN) (26.8±7.1% vs. 11.9±5.6%), localized disease (34.5±8 vs. 8.3±4.6%), and presence of PGV at C-terminal (33±8.6% vs. 9.4±5.3%) were significant prognostic factors for 5-year OS in univariate analysis. INTERPRETATION: In the largest cohort of patients with RTPS, predictors significant for positive outcome could be detected: age &gt; 1 year, absence of SYN, histological diagnosis ATRT, localized disease and PGV located at C-terminal. In our research project, we aim to characterize the complete pheno- and genotype of patients with RTPS to develop a risk score including surveillance recommendation.
QOL-01. Inflammatory biomarkers and psychological sequela in pediatric brain tumor survivors
Authors: Turner Emily , Johal Sonal , Marshall Gailen , Herrington Betty , Criddle Jannie , Reddy Alyssa , Sukumaran Anju , Hmada Youssef Al , Shiflett James M , Karlson Cynthia 
Published: June 2022

Abstract
BACKGROUND AND AIMS: Pediatric brain tumors are the second most common type of pediatric cancer, and these patients face the worst health related quality of life (HRQOL) outcomes. Adult studies show increased inflammation association with lower HRQOL in adult brain tumor survivors. This relationship has not been explored in pediatric brain tumor survivors (PBTS). We conducted a case-control study to explore the relationship between inflammatory biomarkers and psychological sequela (i.e., sleep disturbance, fatigue, pain, negative affect) in PBTS. METHODS: Survivors aged 7-14 years with a primary brain tumor diagnosis were recruited from UMMC (N=29) and UAB (N=4) between 2016-2019. A control group (N=12) was recruited from UMMC well-child appointments. Parents and children completed self-reported surveys of pain, sleep, fatigue, and mood. The primary aims were to: (1) examine levels of C-reactive protein (CRP) inflammation in PBTS compared to controls (2) examine if higher CRP and SOX2 (from tumor tissue) were associated with psychological sequela. Independent samples T-Tests and spearman correlations evaluated aims. RESULTS: The final sample included 33 PBTS: median age=12.42 years; sex=51.5% female; race=63.6% Caucasian, 33.3% African American; pathologic diagnoses=67% astrocytoma/glioma, 11% medulloblastoma, 6% ependymoma, 12% other. Twelve controls had a median age=11.98 years; sex=41.7% female; race=16.7% Caucasian, 83.8% African American. There were marginal elevations in CRP for PBTS (44%, n=13) compared to controls (13%, n=1) (p=0.06). In PBTS, higher CRP levels were associated with greater parent-reported fatigue (p=0.035), sleep-wake disorders (p=0.017), excessive somnolence (p=0.042) and longer pain duration (p=0.037). From 13 tumor samples, positive SOX2 (69% of samples) was associated with increased parent-reported sleep-wake disorders (p=0.016), excessive somnolence (p=0.036), and both child and parent-reported sleep disturbance (child: p=0.014; parent: p=0.034). CONCLUSIONS: Elevated inflammation in PBTS, up to 9 years post-treatment, is consistently associated with increased sleep disturbance and fatigue. These relationships warrant further investigation in PBTS.
OTHR-03. Oxaliplatin as a hearing-sparing alternative to carboplatin in tandem autologous stem cell transplants in pediatric CNS malignancy
Authors: Cho Soohee , Miller Kristen , Rowley Jacqueline , Sabus Ashley , Winzent-Oonk Shelby , Bray Stacy , Koo Jane , Levy Jean Mulcahy 
Published: June 2022

Abstract
BACKGROUND: Intensive chemotherapy with tandem autologous stem cell transplants (autoSCT) is shown to improve survival for children with CNS malignancy. Platinum-based chemotherapeutic agents in these regimens, mainly cisplatin and carboplatin, have resulted in significant sensorineural hearing loss. Oxaliplatin, a newer platinum-based agent, is considered less ototoxic. Empiric substitution of oxaliplatin for carboplatin in preparative regimens for autoSCT have been tried. However, the survival and ototoxicity outcomes have not been studied. OBJECTIVE: To compare the overall survival and ototoxicity of oxaliplatin versus carboplatin preparatory chemotherapy regimens in children who received tandem autoSCT for treatment of CNS malignancy. METHODS: We performed a retrospective chart review of all pediatric patients with primary CNS tumors who received tandem autoSCT from 2011 to 2018 at Children’s Hospital Colorado. Demographics, clinical outcomes, and medication administration records were extracted from electronic medical records. Hearing evaluations, performed at pre-transplant, after each transplant episode, and at follow-up visits, were reviewed and graded by an audiologist. Comparisons were performed using Fisher’s exact tests and log rank test statistics. RESULTS: 32 pediatric patients with CNS tumors met inclusion criteria. Seven patients received oxaliplatin in place of carboplatin in one or more preparatory regimens. There was no statistically significant difference in overall survival between the two groups (p=0.99). A total of 85 follow-up audiograms were available for assessment, including long-term follow up. Of the 13 audiograms that showed hearing loss, one (8%) had prior oxaliplatin exposure, compared to 18/72 (25%) audiograms without hearing loss had prior oxaliplatin exposure (p=0.28). CONCLUSIONS: Oxaliplatin is effective and well-tolerated when used in lieu of carboplatin in preparatory regimen for autoSCT for pediatric CNS malignancy. This study is limited by its small size. A larger, multi-center study is warranted to confirm oxaliplatin’s safety and effect on survival and ototoxicity in pediatric autoHSCT.