bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-42. Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy
Authors: Chan Priya , Sabus Ashley , Hemenway Molly , Chatfield Kathryn , Foreman Nicholas , Dahl Nathan 
Published: June 2022

Abstract
INTRODUCTION: Event-free survival of pediatric low-grade glioma (pLGG) is poor, and patients often require multiple treatment strategies. The hallmark of pLGGs are genetic aberrations of the mitogen-activated protein kinase pathway, which lead to constitutive pathway activation. MEK and RAF inhibitors target this pathway and are efficacious in early phase trials in recurrent pLGGs. However, not all patients respond to monotherapy, and many experience progression after completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. Lenalidomide is an immunomodulatory agent with an anti-tumor effect demonstrated in phase 1 trials in recurrent pediatric central nervous system (CNS) tumors. OBJECTIVE: To describe our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system (PNS) tumors. METHODS: Retrospective review of patients’ medical records. RESULTS: Four patients with locally recurrent primary CNS or PNS tumors, three with WHO grade II pilomyxoid astrocytomas and one with a plexiform neurofibroma, were treated with trametinib and lenalidomide concurrently. Two patients developed severe thromboembolic events. One patient was treated with combination therapy for seven months until trametinib and lenalidomide were held after urgent ventriculoperitoneal shunt revision. Shortly following shunt revision, he experienced near-complete vision loss. MRI of the brain demonstrated a left posterior watershed territory hypoxic-ischemic injury. In a second patient, after four months of combination therapy, surveillance echocardiogram showed an incidental finding of severe biventricular dysfunction with a left ventricular ejection fraction (LVEF) of 17.7% and two mural thrombi in the left ventricular apex. She started losartan and enoxaparin and discontinued trametinib and lenalidomide. Her LVEF normalized four months later, and the mural thrombi resolved. CONCLUSIONS: Given the severe thromboembolic events experienced by these patients treated with concomitant trametinib and lenalidomide, this combination requires further investigation, and we urge caution if used concurrently.
LGG-51. Resection extent and BRAF V600E mutation status determine postoperative growth velocity in pediatric Low-grade glioma: Results from a single-center cohort analysis
Authors: Gorodezki David , Sosa Jordana , Holzer Ursula , Queudeville Manon , Zipfel Julian , Bevot Andrea , Schittenhelm Jens , Nägele Thomas , Ebinger Martin , Schuhmann Martin 
Published: June 2022

Abstract
Despite the favourable outcome and excellent long-term overall survival rates, pediatric LGG show vast variety of clinical behavior and limited predictability regarding progress or senescence. We comparatively analyzed the tumor growth velocity (TGV) of PLGG post subtotal resection (STR) to investigate the impact of surgery, histological subtype, tumor location and the most frequent BRAF aberrations (BRAF V600E mutation vs KIAA1549-BRAF fusion) on tumor growth rates, aiming to identify potential variables to prognosticate further progress or senescence. A total of 53 patients vs 94 patients in the pre- and postoperative cohort, respectively, could be observed over a mean follow-up time of 40.2 vs 60.1 months. Distribution of histopathological diagnosis and tumor sites showed similarity to previously published cohort studies. Comparative analysis of pre- and postoperative TGV showed a significant difference as mean preoperative TGV accounted for 0.264 cm³/mo, while postoperative TGV after 1st, 2nd and 3rd STR showed reduction to 0.085 cm³/mo, 0.024 cm³/mo and -0.016 cm³/mo, respectively (p &lt; 0.001). Results remained significant after excluding patients who had obtained (neo)adjuvant treatment. Resection extent showed remarkable correlation with postoperative reduction of TGV (R = 0.97, P &lt; 0.001). Comparison of postoperative TGV of BRAF V600E mutant LGG and BRAF wild-type LGG showed significant difference of means (0.123 cm³/mo and 0.016 cm³/mo, p = 0.47), consistent to previous analyses, suggesting BRAF V600E positive LGG as a high-risk subgroup. Histological type, tumor location and BRAF-KIAA1549 fusion showed no significant impact on postoperative TGV. The results suggest that surgery, beyond cytoreductive purpose, impacts PLGG kinetics post STR by inducing a significant deceleration of tumor growth. As postoperative growth velocity showed clear correlation to resection extent and residual tumor burden, surgery, as radical as possible while preserving neurological function, appears to remain the mainstay of therapy besides advancing therapeutic approaches.
LGG-53. Evaluation of KIAA-BRAF1549 fusions in pilocytic astrocytoma with clinicopathological correlation
Authors: Dandapath Iman , Mahajan Dr Swati , Sahu Dr Saumya , Sharma Dr Mehar Chand , Suri Dr Ashish , Suri Dr Vaishali 
Published: June 2022

Abstract

Background
Pilocytic astrocytomas (PAs) are the primary tumors most frequently found in children and adolescents, accounting for 5.4% of all gliomas. The overall prognosis of PAs is good, yet a substantial no of cases have a poor outcome, with recurrence, and ultimately death. The KIAA1549-BRAF fusion is a useful putative diagnostic marker for PAs and BRAF also is an important therapeutic marker.

Aim and Objectives
To study the frequency of KIAA1549-BRAF fusion (16-9, 15-9 and 16-11) in different locations of PAs using qRT-PCR technique in FFPE samples.

Methodology
Three different exon rearrangements of KIAA1549-BRAF (16-9, 15-9 and 16-11) fusions were assessed in 50 cases of PAs by using qRT-PCR (gold standard). FISH assay was also performed in all the cases.

Results
Out of 50 PAs, 32 were localised in midline structures such as the cerebellum, optic pathway, hypothalamus, and brain stem while 18 in non-midline regions like the cerebral hemispheres. Majority of the cases (35/50); 70% were positive for KIAA1549-BRAF fusion by RT-PCR. Of these, (16/35); 45.7% harboured 15-9 fusion, (15/35); 42.8% harboured 16-9 fusion, and only (4/35); 11.4% had 16-11 fusion. Only (24/30); 48% KIAA1549-BRAF showed fusion by FISH assay. There was 54.2% concordance between FISH and RT-PCR results. KIAA1549-BRAF fusion was observed in 78% of midline and 55.5% of non-midline cases. The frequency of KIAA1549-BRAF fusion decreased with increasing age, 77% in the age group &lt;20, 54% in the age group 20-40 and 30% in the age group &gt;40.

Conclusion
15-9 and 16-9 KIAA1549-BRAF were the most frequently occurring fusions dominantly seen in the midline. The presence of fusion is inversely proportional to the age of patients. qRT-PCR is the gold standard technique and FISH assay has moderate concordance with qRT-PCR platform.
LGG-54. Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia
Authors: Chatterjee Jit , Sanapala Shilpa , Cobb Olivia , Bewley Alice , Cordell Elizabeth , Garbow Joel , Holtzman Michael , Gutmann David 
Published: June 2022

Abstract
To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage optic pathway glioma (Nf1-OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4-6 weeks of age (WOA), Nf1-OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFkB inhibitor treatment of Nf1-OPG mice at 4-6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma.
LGG-63 MEK inhibitor-associated retinopathy (MEKAR) in a pediatric patient with an optic pathway glioma
Authors: Bendel Anne , Skrypek Mary , Johnson Heather , Pribila Jonathan 
Published: June 2022

Abstract
Pediatric low-grade glioma (LGG) and plexiform neurofibroma (PN) universally have up-regulation of the RAS-mitogen-activated protein kinase (MAPK) pathway. Recent phase I and II clinical trials evaluating MEK inhibitors for the treatment pediatric LGG and PN report efficacy and tolerable side effects, including no reported ophthalmologic toxicity. Contrary to the pediatric experience, adult trials using MEK inhibitors describe several ophthalmologic side effects, including MEK inhibitor-associated retinopathy (MEKAR), also termed central serous-like retinopathy. MEKAR is defined as accumulation of subretinal fluid. It occurs in up to 90% of adults on MEK inhibitors, usually causing minimal to no symptoms, and typically resolving without MEK inhibitor dose adjustment. We report a case of MEKAR in a 15 year old boy with an optic pathway pilocytic astrocytoma with duplication of BRAF (7q34). Baseline ophthalmic exam showed 20/20 vision in his right eye with loss of the temporal hemifield and no light perception vision in the left eye. Nine months into treatment with Selumetinib his ophthalmologic exam and optical coherence tomography (OCT) showed asymptomatic bilateral subretinal fluid. Selumetinib was held for 2 weeks resulting in resolution of the subretinal fluid. Selumetib was resumed at the prior dose and MEKAR recurred 2 weeks later but then permanently resolved 4 weeks later despite remaining on Selumetib. Review of the literature discovered a single publication of 2 pediatric patients with optic pathway glioma who developed MEKAR around 6-7 months after initiating Selumetinib, which resolved after stopping Selumetinib. One patient was symptomatic and despite resolution of symptoms, Selumetinib was not resumed. The other patient was asymptomatic and resumed Selumetib, but redeveloped MEKAR 8 months after restarting Selumetinib. Based on adult experience and the limited pediatric experience outlined above, we recommend pediatric patients with asymptomatic and mild-moderate symptomatic MEKAR undergo close monitoring without Selumetinib dose interruption or modification unless symptoms progress.
MEDB-01. Management of the risk of medulloblastoma associated to familial adenomatous polyposis and dysregulated Wnt signalosome
Authors: Abdelmoula Balkiss , Abid Fatma , Karra Amir , Kammoun Sonda , Aloulou Samir , Abdelmoula Nouha Bouayed 
Published: June 2022

Abstract
APC is the key gene of the familial adenomatous polyposis (FAP). This tumor suppressor gene functions by negatively regulating the β-catenin protein and the majority of APC mutations disrupt the β-catenin degradation complex signalosome leading to the activation of the canonical Wnt pathway. Pathogenic APC mutations were reported in association to medulloblastoma. In this study, we report rare mutations of the APC gene detected in Tunisian families from the governorate of Sfax presenting clinically with various digestive and extra-digestive manifestations. Our goal was to assess the oncogenic risks encountered by our pediatric carriers to offer an accurate genetic counselling, particularly at the neurologic level. Molecular investigation of all members of two families was conducted, using bidirectional sequencing of all 15 exons of the APC gene. A phenotype-genotype correlation was conducted to elucidate the mutational pathophysiological mechanism. Two rare mutations were revealed in our familial study. The first mutation was located at exon 13 and was a missense mutation at codon 1690. The second mutation was a deletion identified at codon 4652 in exon 15. The mutations resulted both in truncated gene products. Clinical manifestations closely depending on the position of the mutation were respectively colic polyposis for the first mutation and soft tissue fibromatous tumors for the second. The localization of the APC mutations allows better targeting of surveillance for clinical manifestations that may be included in FAP. Mutations that remove the Axin-binding sites, as is the case for the first mutation, lead to severe clinical pictures whereas mutations that retain one or two of the Axin binding sites are associated with other features such as desmoid tumors. The risk of the Wnt- medulloblastoma subtype, higher among patients with FAP should be considered with a more awareness of signs and symptoms related to CNS tumors in the FAP context.
MEDB-18. Elongation control of mRNA translation supports Group 3 medulloblastoma adaptation to nutrient deprivation
Authors: Delaidelli Alberto , Yao Betty , Wang Que Xi , Huang Yue Zhou , Negri Gian Luca , Hughes Christopher , Zhang Haifeng , Leprivier Gabriel , Sorensen Poul 
Published: June 2022

Abstract
Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We pefrormed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p&lt; 0.05).Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.
MEDB-34. A very rare case: medulloblastoma relapse with bone marrow infiltration in a toddler
Authors: Zinke Claudia , Fleischhack Gudrun , Hauer Julia , Lange Björn Sönke , Dörnemann Jenny , Hahn Gabriele , Schackert Gabriele , Gurtner Kristin , Meinhardt Matthias , Jöhrens Korinna , Knöfler Ralf 
Published: June 2022

Abstract
We report about a female toddler congenitally deaf and diagnosed with a non-metastatic desmoplastic medulloblastoma (SHH activated, TP53-wt, variant in LDB1 gene). No tumor predisposition syndrome was found. After complete tumor resection the patient was treated according to I-HIT-MED-Guidance protocol. Five months later an asymptomatic localised relapse (same histology, PTEN frameshift deletion, TERT mutation, LDB1 mutation) detected by routine MRI was treated by complete resection, craniospinal irradiation and an antiangiogenic regimen adapted from the MEMMAT scheme including fenofibrate, thalidomide, celecoxib, topotecan, temozolomide, bevacizumab and intraventricular cytarabine. Before start of systemic treatment blood cell counts were normal. In the second cycle we had to interrupt chemotherapy due to a leukopenia while continuing the antiangiogenic treatment. In order to avoid relevant bone marrow toxicity chemotherapy doses were reduced. Nevertheless we had to stop the fourth cycle because of a severe pancytopenia. Same time the girl presented with fever, neck and leg pain. A full blood count showed: hemoglobin 6.92 g/dl, leukocytes 640/µl, platelets 8,000/µl. Suspecting an infection supported by the presence of a high CrP value of 230 mg/l the patient was treated with i.v. antibiotics. MRI showed an unspecific retropharyngeal soft tissue augmentation, a pleural effusion and high T2 signals in multiple vertebral bodies but no central tumor relapse. The bone marrow diagnostics revealed a diffuse medulloblastoma cell infiltration with the known PTEN frameshift deletion and LDB1 mutation. The liquor was tumor-cell free. We report on an extremely rare case of an early local relapse of desmoplastic medulloblastoma progressing to a diffuse bone marrow infiltration in a toddler. The girl died due to therapy resistance 9 weeks after bone marrow relapse. It remains unclear whether the fatal course was related to the hereditary deafness syndrome and the molecular alterations of the tumor.
MEDB-45. Functional genomics identifies epigenetic regulators as novel therapeutic targets for sonic hedgehog medulloblastoma
Authors: Tsiami Foteini , Piccioni Federica , Root David , Bandopadhayay Pratiti , Segal Rosalind , Tabatabai Ghazaleh , Merk Daniel 
Published: June 2022

Abstract
Medulloblastoma (MB) is among the most common malignant childhood brain tumors that comprises a group of four molecularly distinct diseases. A significant proportion of these tumors is characterized by aberrant activation of the canonical sonic hedgehog (SHH) signaling pathway. Although small-molecule inhibitors targeting Smoothened (SMO) have proven a promising treatment approach for SHH-MB subgroup, primary or acquired resistance impedes its clinical efficacy. Therefore, novel targeted approaches are urgently needed to improve therapeutic strategies for this tumor entity. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in a murine and a human SHH-MB cell line, SMB21 and DAOY, respectively, in order to decipher tumor-specific genetic dependencies. Our data demonstrate that SMB21 cells highly depend on positive regulators of the SHH pathway, such as Smo and Gli1 for their survival, as opposed to DAOY cells, suggesting that the latter does not represent a faithful model of SHH-MB. Members of the epigenetic machinery such as Dnmt1 and Smarca5 scored strongly as SMB21-context specific essentialities. Pharmacologically, we show that DNMT1 inhibition is efficacious at clinically relevant concentrations against SMO inhibitor- sensitive, as well as resistant SHH-MB cell lines, indicating novel therapeutic avenues for SHH-MB. By performing RNA sequencing of SMB21 cells, we identified early and late changes in global gene expression induced by DNMT1 inhibition, including decreased expression of mediators of SHH signaling, such as Gli1 and Gli2. Of note, gene set enrichment analysis revealed that DNMT1 inhibition downregulates top gene sets associated with cell cycle progression, corroborating the screening results that Dnmt1 is essential for SMB21 proliferation. Further global DNA methylation profiling in SMB cells will help to define the molecular basis of sensitivity to DNMT1 inhibitors in SHH-MB. Summarizing, our data highlight the potential of inhibitors targeting epigenetic regulators in SMO inhibitor- sensitive and resistant MB for more efficacious treatment options.
MEDB-48. Infant medulloblastoma - SHH subtype – with residual disease. To treat or not to treat
Authors: Dahl Christine , Depani Sarita , Hedges Kriti , Aguirregomezcorta Fernando , Aquilina Kristian , Jeelani Owase , Carney Olivia , Sudhakar Sniya , Loebel Ulrike , d′Árco Felice , Mankad Kshitij , Hargrave Darren , Jorgensen Mette 
Published: June 2022

Abstract
Management of infant medulloblastoma remains a challenge. Front-line chemotherapy can successfully avoid radiation in low-risk infant medulloblastoma. Patients that do relapse can be salvaged long-term with radiotherapy. We report 4 cases of infants with medulloblastoma treated with chemotherapy (HIT2000 protocol) with residual or progressive disease. RESULTS: Four cases of infant medulloblastoma, all MBEN/nodular desmoplastic SHH type B, p53 WT, no MYC / MYCN amplification. CASE 1: 16 month old girl, metastatic lesions in the cerebellum and meningeal enhancement. Germline SUFU mutation. After 3 cycles of chemotherapy MRI showed more enhancement of the residual disease. To inform management, second look surgery was performed. Pathology showed fibrous tissue only, no malignant cells. The child continues to be treated as per HIT2000. CASE 2: 5 month old girl, metastatic lesions in the cerebellum. Germline SUFU mutation. 2 months after end of treatment, MRI demonstrated progression of cerebellar lesion. Surgical resection was performed, pathology showed differentiated mature neuronal tissue. No further treatment; remains in remission 1 year after suspected progression. CASE 3: 27 month old boy, metastatic lesions in cerebellum. Germline SUFU mutation. 1 month post-completion of treatment progressive prominent nodules along the cerebellum and cerebellar leptomeningeal enhancement. Biopsy not feasible so close MRI surveillance was initiated. MRI remains stable 1 year after suspected progression. CASE 4: 30 months old boy, non-metastatic disease. Complete resection. No germline mutation. End-of-treatment MRI showed subtle new intraspinal leptomeningeal deposits and a suspicious left optic tract nodule, subsequent MRI 8 weeks later showed clear progressive disease. Unfortunately, the child died before radiotherapy could be delivered. CONCLUSION: Salvage radiotherapy for infants with medulloblastoma who progress following chemotherapy treatment can be life-saving but risk significant cognitive impairment. Differentiation of medulloblastoma following radio/chemotherapy has been reported. We recommend considering tissue confirmation prior to embarking on further treatment for suspected relapse.